2

Albert: Albert & Jakobiec's Principles &

Practice of Ophthalmology

THIRD EDITION

Daniel M. Albert, MD MS
Chair Emeritus, F. A. Davis Professor and Lorenz F. Zimmerman Professor, Department of
Ophthalmology and Visual Sciences, Retina Research Foundation Emmett A. Humble Distinguished
Director, of the Alice R. McPherson, MD, Eye Research Institute, University of Wisconsin
Medical School, Madison, Wisconsin, USA
Joan W. Miller, MD
Henry Willard Williams Professor of Ophthalmology, Chief and Chair, Department of
Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston,
Massachusetts, USA
Associate Editors:
Dimitri T. Azar, MD
B.A. Field Chair of Ophthalmologic Research, Professor and Head, Department of Ophthalmology
and Visual Sciences, University of Illinois Eye and Ear Infirmary, Chicago, Illinois, USA
Barbara A. Blodi, MD
Associate Professor, Department of Ophthalmology and Visual Sciences, University of Wisconsin
Medical School, Madison, Wisconsin, USA
Managing Editors:
Janet E. Cohan
Administrative Manager, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary,
Harvard Medical School, Boston, Massachusetts, USA
Tracy Perkins, MPH
Administrative Director, Alice R. McPherson, MD Eye Research Institute, University of
Wisconsin Medical School, Madison, Wisconsin, US
DEDICATION

To CLAES H. DOHLMAN
Superb surgeon, mentor, teacher, innovator and friend.
D.M.A & J.W.M
SAUNDERS ELSEVIER
SAUNDERS is an imprint of Elsevier Inc.
? 2000, 1994 by W.B Saunders Company
? 2008, Elsevier Inc. All rights reserved.
First published 2008
First edition 1994
Second edition 2000
Third edition 2008
No part of this publication may be reproduced, stored in a
retrieval system, or transmitted in any form or by any means,
electronic, mechanical, photocopying, recording or otherwise,
without the prior permission of the Publishers. Permissions may
be sought directly from Elsevier's Health Sciences Rights
Department, 1600 John F. Kennedy Boulevard, Suite 1800,
Philadelphia, PA 19103-2899, USA: phone: (+1) 215 239 3804;
fax: (+1) 215 239 3805; or, e-mail:
healthpermissions@elsevier.com. You may also complete your
request on-line via the Elsevier homepage (http://
www.elsevier.com), by selecting ‘Support and contact’ and then
‘Copyright and Permission’.
ISBN: 978-1-4160-0016-7
Notice
Medical knowledge is constantly changing. Standard safety
precautions must be followed, but as new research and clinical
experience broaden our knowledge, changes in treatment and drug
therapy may become necessary or appropriate. Readers are
advised to check the most current product information provided
by the manufacturer of each drug to be administered to verify
the recommended dose, the method and duration of
administration, and contraindications. It is the responsibility
of the practitioner, relying on experience and knowledge of the
patient, to determine dosages and the best treatment for each
individual patient. Neither the Publisher nor the author assume
any liability for any injury and/or damage to persons or
property arising from this publication.
The Publisher
Preface to the 3rd Edition
Do clinicians and trainees really need textbooks anymore? In an
era of ever-expanding connectivity and immediate access to
published articles, why would anyone consult a textbook, which
by its very nature is incomplete before it is even published? No
doubt these are strange questions coming from the editors of
the third edition of the most popular multi-volume ophthalmic
textbook, but they must be asked and answered. Our answer
is an unequivocal “yes”! Books like this serve an extremely
important function – that of a repository for expert reviews of
our current understanding of ophthalmic health and disease.
The chapters and sections in Albert and Jakobiec are an
important resource for the clinician and student, providing a
comprehensive information base on an extensive list of topics.
Of course journal articles continue to be the most useful source
of information about new developments in the field but they do
not replace books. Constraints on the length of journal articles,
inattention to the provenance of the ideas they contain, and an
understandable tendency to self-promote the authors’ thesis,
limit the value of many “original contributions.” Readers
of journal articles forearmed with information found in an
encyclopedic text can place these articles into perspective.
Thus, the two sources are complimentary. In a very real sense
this textbook serves as a springboard to the constantly
expanding universe of published scientific literature.
What is new in the third edition? The second edition (2002)
was a reworking of the very successful first edition (1996) of
Albert and Jakobiec’s Principles and Practice of Ophthalmology.
For the third edition we undertook a critical evaluation of each
section and chapter to ensure that topics were well-covered with
minimal redundancy, that new areas of practice and research
were adequately described, and that topics that were over-
represented could be substantially shortened or deleted. This
evaluation involved all of the editors (Dan Albert, Joan Miller,
Barbara Blodi and Dimitri Azar) as well as new and returning
section editors. As an example, under the direction of Dimitri
Azar, we incorporated a new section on refractive surgery that
provides the principles of refractive surgery as well as useful
descriptions of evaluation techniques and procedures. The
Oncology section was substantially expanded and revised under
the section editorship of Evangelos Gragoudas and Joan
O’Brien. Pediatrics was also extensively revised by David
Hunter and Monte Mills, and the Pharmacology and Toxicology
sections were combined and revised under the direction of Mark
Abelson. Barbara Blodi and Joan Miller reworked the extensive
retina section, to include current techniques, new diagnostic
modalities (including OCT), and new drug therapies. The
human genome project and modern genetics are revolutionizing
medicine, and genetics information has been incorporated into
all sections. Finally, the last section of the textbook headed by
Kathy Colby and Nancy Holekamp is a section on Ethics and
Professionalism topics that are increasingly important to
practicing clinicians, and an ACGME requirement for resident
training. A concerted effort was made throughout the third
edition to complement the text with diagrams, line drawings
and color figures. In addition, each chapter contains a key
points section. Overall, the third edition has exceeded the
expectations of all of the editors. We were pleased by the
enthusiasm of new and returning authors, more than 600 in
total, as well as new and returning section editors, and were
excited by the teamwork and cooperation shown in upgrading
and improving this important project. The result is a definitive
textbook in ophthalmology, available in hardcover and by web
access.
The editorial team has been a wonderful collaboration and
the senior editors are very grateful for the prodigious efforts of
Drs. Dimitri Azar and Barbara Blodi. We were saddened that Dr.
Frederick Jakobiec, a co-founder of this project and co-editor on
editions 1 and 2, was unable to participate as an editor in the
third edition, although still contributing as a co-author. We look
forward to his return to the ophthalmology community, and we
can report that Dr. Jakobiec is pleased and supportive of the
upcoming 3rd edition of the textbook named for him and Dr.
Albert. All of the editorial team is most appreciative of the
unstinting and generous support of Elsevier Publishing; in
particular the leadership of the senior editor, Russell Gabbedy,
and the hard work and diligence of Zak Knowles, contributing
editor, whose efforts in collecting and coordinating chapters, as
well as initial editing of chapters were unsurpassed. The
managing editors, Tracy Perkins and Janet Cohan, provided
important coordination between the authors, section editors,
editors and publisher, and handled all of their responsibilities
with aplomb. Above all, the contributing authors who wrote the
chapters and the section editors who delineated the section
content and edited the component chapters deserve the greatest
credit for the superb quality of the textbook.
We sincerely hope that the third edition of Albert and
Jakobiec’s Principles and Practice in Ophthalmology provides
ophthalmologists and trainees with a gateway into the
wonderful science and art of ophthalmology in order to provide
the best care for our patients, and to continually advance
our field.
Daniel M. Albert and Joan W. Miller
xvii
Preface to the 1st Edition
“INCIPIT.” The medieval scribe would write this Latin word,
meaning so it begins, to signal the start of the book he was
transcribing. It was a dramatic word that conveyed promise of
instruction and delight. In more modern times INCIPIT has
been replaced by the PREFACE. It may be the first thing the
reader sees, but it is, in fact, the last thing the author writes
before the book goes to press. I appreciate the opportunity to
make some personal comments regarding Principles and
Practice of Ophthalmology.
One of the most exciting things about writing and editing a
book in a learned field is that it puts the authors and editors in
touch with those who have gone before. Each author shares
with those who have labored in past years and in past centuries
the tasks of assessing the knowledge that exists in his or her
field, of determining what is important, and of trying to convey
it to his or her peers. In the course of the work the author
experiences the same anticipation, angst, and ennui of those
who have gone before. He or she can well envision the various
moments of triumph and despair that all authors and editors
must feel as they organize, review, and revise the accumulating
manuscripts and reassure, cajole, and make demands of their
fellow editors, authors, and publisher.
This feeling of solidarity with early writers becomes even
more profound when one is a collector and reviewer of books,
and conversant with the history of one’s field. In Ecclesiastes
it is stated, “of the making of books, there is no end” (12:12).
Indeed, there are more books than any other human artifact on
earth. There is, however, a beginning to the “making of books”
in any given field. The first ophthalmology book to be published
was Benvenuto Grassi’s De Oculis in Florence in 1474. Firmin
Didot in his famous Bibliographical Encyclopedia wrote that
Grassus, an Italian physician of the School of Solerno, lived in
the 12th century and was the author of two books, the Ferrara
Quarto (1474) and the Venetian Folio (1497). Eye care in the
15th century was in the hands of itinerant barber surgeons and
quacks, and a treatise by a learned physician was a remarkable
occurrence. The next book on the eye to appear was an anony-
mous pamphlet written for the layperson in 1538 and entitled
Ein Newes Hochnutzliches Büchlin von Erkantnus der
Kranckheyten der Augen. Like Principles and Practice of
Ophthalmology, the Büchlin stated its intention to provide
highly useful knowledge of eye diseases, the anatomy of the eye,
and various remedies. It was illustrated with a fullpage woodcut
of the anatomy of the eye (Fig. 1). At the conclusion of the book,
the publisher, Vogtherr, promised to bring more and better
information to light shortly, and indeed, the next year he
published a small book by Leonhart Fuchs (1501–1566) entitled
Alle Kranckheyt der Augen.
Fuchs, a fervent Hippocratist, was Professor first of Philo-
sophy and then of Medicine at Ingolstadt, Physician of the
Margrave Georg of Brandenburg, and finally Professor at
Tübingen for 31 years. Like the earlier Büchlin, his work begins
with an anatomic woodcut (Fig. 2) and then lists in tabular
form various eye conditions, including strabismus, paralysis,
amblyopia, and nictalops. The work uses a distinctly Greco
Roman terminology, presenting information on the parts of the
eye and their affections, including conjunctivitis, ophthalmia,
carcinoma, and “glaucoma.” The book concludes with a remedy
collection similar to that found in the Büchlin. Most significant
in the association of Leonhart Fuchs with this book is the fact
that a properly trained and well recognized physican addressed
the subject of ophthalmology.
Julius Hirschberg, the ophthalmic historian, noted that
Fuch’s Alle Kranckheyt, along with the anonymous Büchlin,
apparently influenced Georg Bartisch in his writing of Das Ist
Augendienst. This latter work, published in 1583, marked the
founding of modern ophthalmology. Bartisch (1535–1606) was
an itinerant barber surgeon but nonetheless a thoughtful and
skillful surgeon, whose many innovations included the first
procedure for extirpation of the globe for ocular cancer. Bartisch
proposed standards for the individual who practices eye surgery,
noting that rigorous training and concentration of effort were
needed to practice this specialty successfully.
By the late 16th century, eye surgery and the treatment of eye
disease began to move into the realm of the more formally
trained and respected surgeon. This is evidenced by Jacques
Guillemeau’s Traité des Maladies de L’Oeil, published in 1585.
Guillemeau (1550–1612) was a pupil of the surgical giant
Ambroise Paré, and his book was an epitome of the existing
knowledge on the subject.
The transition from couching of cataracts to the modern
method of treating cataracts by extraction of the lens, as
introduced by Jacques Daviel in 1753, further defined the skill
and training necessary for the care of the eyes. The initiation
of ophthalmology as a separate specialty within the realm of
medicine and surgery was signaled by the publication of George
Joseph Beer’s two volume Lehre von den Augenkrankheiten in
1813–1817. Beer (1763–1821) founded the first eye hospital in
1786 in Vienna, and his students became famous ophthalmic
surgeons and professors throughout Europe.
In England, it was not only the demands of cataract surgery
but also the great pandemic of trachoma following the Napo-
leonic wars that led to the establishment of ophthalmology as a
recognized specialty. Benjamin Travers (1783–1858) published
the earliest treatise in English on diseases of the eye, A Synopsis
of the Diseases of the Eye, in 1820. In the United States,
acceptance of ophthalmology as a specialty had to await the
description of the ophthalmoscope by Helmholtz in 1851,
and the additional special skills that using the early primitive
“Augenspiegel” required.
As the complexity of ophthalmology increased and as sub-
specialization began to develop in the 19th century, multi-
authored books began to appear. This culminated in the
appearance in 1874 of the first volume of the GraefeSaemisch xix
 Preface to the 1st Edition
FIGURE 1.
Handbuch. The final volume of this great collective work, of
which Alfred Carl Graefe (1830–1899) and Edwin Theodor
Saemisch (1833–1909) were editors, appeared in 1880. The
definitive second edition, which for more than a quarter of a
century remained the most comprehensive and authoritative
work in the field, appeared in 15 volumes between 1899 and
1918. The great French counterpart to the Graefe Saemisch
Handbuch was the Encyclopédie Française d’Ophtalmologie,
which appeared in nine volumes (1903–1910), edited by Octave
Doin, and filled a similar role for the French speaking
ophthalmologist.
In 1896, the first of four volumes of Norris and Oliver’s
System of Diseases of the Eye was published in the United
States. The senior editor, Dr. William Fisher Norris
(1839–1901), was the first Clinical Professor of Diseases of
the Eye at the University of Pennsylvania. Charles A. Oliver
(1853–1911) was his student. Norris considered the System
to be his monumental work. For each section he chose an
outstanding authority in the field, having in the end more than
60 American, British, Dutch, French, and German ophthal-
mologists as contributors. Almost 6 years of combined labor on
the part of the editors was needed for completion of the work.
In 1913, Casey A. Wood (1856–1942) introduced the first of
his 18 volumes of the American Encyclopedia and Dictionary
of Ophthalmology. The final volume appeared in 1921. Drawn
largely from the Graef Saemisch Handbuch and the Encyclo-
pédie Française d’Ophtalmologie, Wood’s Encyclopedia
provided information on the whole of ophthalmology through a
strictly alphabetic sequence of subject headings.
The book from which the present work draws inspiration
is Duke Elder’s Textbook of Ophthalmology (7 volumes; 1932)
and particularly the second edition of this work entitled System
of Ophthalmology (15 volumes, published between 1958 and
1976). The System of Ophthalmology was written by Sir
Stewart Duke Elder (1898–1978) in conjunction with his
colleagues at the Institute of Ophthalmology in London. In
1976, when the last of his 15 volumes appeared, Duke Elder
xx wrote in the Preface:
FIGURE 2.
The writing of these two series, the Textbook and the System,
has occupied all my available time for half a century. I cannot
deny that its completion brings me relief on the recovery of my
freedom, but at the same time it has left some sadness for I have
enjoyed writing it. As Edward Gibbon said on having written
the last line of The Decline and Fall of the Roman Empire:
“A sober melancholy has spread over my mind by the idea
that I have taken everlasting leave of an old and agreeable
companion.”
Duke Elder adds a final line that I hope will be more àpropos
to the present editors and contributors. “At the same time
the prayer of Sir Francis Drake on the eve of the attack of the
Spanish Armada is apposite: ‘Give us to know that it is not the
beginning but the continuing of the same until it is entirely
finished which yieldeth the true glory.”’ The void that developed
as the Duke Elder series became outdated has been partially
filled by many fine books, notably Thomas Duane’s excellent 5
volume Clinical Ophthalmology.
Inspiration to undertake a major work such as this is derived
not only from the past books but also from teachers and role
models. For me, this includes Francis Heed Adler, Harold
G. Scheie, William C. Frayer, David G. Cogan, Ludwig von
Sallmann, Alan S. Rabson, Lorenz E. Zimmerman, Frederick C.
Blodi, Claes H. Dohlman, and Matthew D. Davis.
Whereas the inspiration for the present text was derived from
Duke Elder’s Textbook and System and from teachers and role
models, learning how to write and organize a book came for
me from Adler’s Textbook of Ophthalmology, published by
W.B. Saunders. This popular textbook for medical students and
general practitioners was first produced by Dr. Sanford Gifford
(1892–1945) in 1938. Francis Heed Adler (1895–1987), after
writing the 6th edition, published in 1962, invited Harold G.
Scheie (1909–1989), his successor as Chairman of Ophthal-
mology at the University of Pennsylvania, and myself to take
over authorship. We completely rewrote this book and noted
in the Preface to the 8th edition, published in 1969: “This
book aims to provide the medical student and the practicing
physician with a concise and profusely illustrated current text,

organized in a convenient and useable manner, on the eye and
its disorders. It is hoped that the beginning, or even practicing,
ophthalmologist may find it of value.”
In 1969 it was apparent that even for the intended audience,
contributions by individuals expert in the subspecialties of
ophthalmology were required. The book was published in
Spanish and Chinese editions and was popular enough to
warrant an updated 9th edition, which appeared in 1977. One
of the high points of this work was interacting with John
Dusseau, the Editor in Chief for the W.B. Saunders Company.
As a 10th edition was contemplated, I became increasingly
convinced that what was needed in current ophthalmology was
a new, comprehensive, well illustrated set of texts intended
for the practicing ophthalmologist and written by outstanding
authorities in the field. I envisioned a work that in one series of
volumes would provide all of the basic clinical and scientific
information required by practicing ophthalmologists in their
everyday work. For more detailed or specialized information,
this work should direct the practitioner to the pertinent journal
articles or more specialized publications. As time progressed, a
plan for this work took shape and received support from the
W.B. Saunders Company.
Memories of the formative stages of the Principles and
Practice of Ophthalmology remain vivid: Proposing the project
to Frederick Jakobiec in the cafeteria of the Massachusetts
Eye and Ear Infirmary in early 1989. Having dinner with Lewis
Reines, President and Chief Executive Officer, and Richard
Zorab, Senior Medical Editor, at the Four Seasons Hotel in
May 1989, where we agreed upon the scope of the work. My
excitement as I walked across the Public Garden and down
Charles Street back to the Infirmary, contemplating the work
we were to undertake. Finalizing the outline for the book in
Henry Allen’s well stocked “faculty lounge” in a dormitory at
Colby College during the Lancaster Course. Meeting with
members of the Harvard Faculty in the somber setting of the
rare book room to recruit the Section Editors. Persuading Nancy
Robinson, my able assistant since 1969, to take on the job of
Managing Editor. The receipt of our first manuscript from Dr.
David Cogan.
We considered making this work a departmental under-
taking, utilizing the faculty and alumni of various Harvard
programs. However, the broad scope of the series required
recruitment of outstanding authors from many institutions.
Once the Section Editors were in place, there was never any
doubt in my mind that this work would succeed. The Section
Editors proved a hardworking and dedicated group, and their
choice of authors reflects their good judgment and persuasive
abilities. I believe that you will appreciate the scope of
knowledge and the erudition.
The editorship of this book provided me not only with an
insight into the knowledge and thinking of some of the finest
minds in ophthalmology but also with an insight into their
lives. What an overwhelmingly busy group of people! Work was
completed not through intimidation with deadlines but by
virtue of their love of ophthalmology and their desire to share
their knowledge and experience. The talent, commitment,
persistence, and good humor of the authors are truly what made
this book a reality.
It was our intent to present a work that was at once scholarly
and pragmatic, that dealt effectively with the complexities
and subtleties of modern ophthalmology, but that did not
overwhelm the reader. We have worked toward a series of
volumes that contained the relevant basic science information
to sustain and complement the clinical facts. We wanted a
well illustrated set that went beyond the illustrations in any
Preface to the 1st Edition
textbook or system previously published, in terms of quantity
and quality and usefulnesss of the pictures.
In specific terms, in editing the book we tried to identify
and eliminate errors in accuracy. We worked to provide as
uniform a literary style as is possible in light of the numerous
contributors. We attempted to make as consistent as possible
the level of detail presented in the many sections and chapters.
Related to this, we sought to maintain the length according to
our agreed upon plan. We tried, as far as possible, to eliminate
repetition and at the same time to prevent gaps in information.
We worked to direct the location of information into a logical
and convenient arrangement. We attempted to separate the
basic science chapters to the major extent into the separate
Basic Sciences volume, but at the same time to integrate basic
science information with clinical detail in other sections as
needed. These tasks were made challenging by the size of the
work, the number of authors, and the limited options for
change as material was received close to publishing deadlines.
We believe that these efforts have succeeded in providing
ophthalmologists and visual scientists with a useful resource in
their practices. We shall know in succeeding years the level of
this success and hope to have the opportunity to improve all
these aspects as the book is updated and published in future
editions. Bacon wrote: “Reading maketh a full man, conference
a ready man, and writing an exact man.” He should have added:
Editing maketh a humble man.
I am personally grateful to a number of individuals for
making this book a reality. Nancy Robinson leads the list. Her
intelligent, gracious, and unceasing effort as Managing Editor
was essential to its successful completion. Mr. Lewis Reines,
President of the W.B. Saunders Company, has a profound
knowledge of publishing and books that makes him a worthy
successor to John Dusseau. Richard Zorab, Senior Medical
Editor, and Hazel N. Hacker, Developmental Editor, are
thoroughly professional and supportive individuals with whom
it was a pleasure to work. Many of the black and white
illustrations were drawn by Laurel Cook Lhowe and Marcia
Williams; Kit Johnson provided many of the anterior segment
photographs. Archival materials were retrieved with the aid
of Richard Wolfe, Curator of Rare Books at the Francis A.
Countway Library of Medicine, and Chris Nims and Kathleen
Kennedy of the Howe Library at the Massachusetts Eye and Ear
Infirmary.
The most exciting aspect of writing and editing a work of
this type is that it puts one in touch with the present day
ophthalmologists and visual scientists as well as physicians
training to be ophthalmologists in the future. We hope that this
book will establish its own tradition of excellence and useful-
ness and that it will win it a place in the lives of ophthal-
mologists today and in the future.
“EXPLICIT,” scribes wrote at the end of every book.
EXPLICIT means it has been unfolded. Olmert notes in The
Smithsonian Book of Books, “the unrolling or unfolding of
knowledge is a powerful act because it shifts responsibility from
writer to reader.... Great books endure because they help us
interpret our lives. It’s a personal quest, this grappling with the
world and ourselves, and we need all the help we can get.” We
hope that this work will provide such help to the professional
lives of ophthalmologists and visual scientists.
DANIEL M. ALBERT, M.D., M.S.
MADISON, WISCONSIN
xxi
List of Contributors

Juan-Carlos Abad MD Lloyd P Aiello MD PhD Ibrahim A Al Jadaan MD

Clinica Oftalmologica de Medellin Director of Beetham Eye Institute Chief
Medellin Section Head of Eye Research Glaucoma Division
Colombia Joslin Diabetes Center King Khaled Eye Specialist Hospital
Beetham Eye Institute Riyadh
Mark B Abelson MD CM FRCS Boston MA Kingdom of Saudi Arabia
Associate Clinical Professor of USA
Ophthalmology Sabah Al-Jastaneiah MD
Massachusetts Eye and Ear Infirmary Levent Akduman MD Consultant Ophthalmologist
Harvard Medical School Assistant Professor of Ophthalmology Anterior Segment and Refractive Surgery
Clinical Senior Scientist Department of Ophthalmology Division
Schepens Eye Research Institute St Louis University School of Medicine King Khaled Eye Specialist Hospital
Boston MA St Louis MO Riyadh
USA USA Kingdom of Saudi Arabia
David H Abramson MD Marissa L Albano MD Calliope E Allen MD
Chief c/o Robert P Murphy Fellow
Ophthalmic Oncology Service The Retina Group of Washington Eye Plastics, Orbital and Cosmetic Surgery
Department of Surgery Fairfax VA Massachusetts Eye & Ear Infirmary
Memorial Sloane Kettering Cancer Center USA Boston MA
New York NY USA
USA Daniel M. Albert MD MS
Chair Emeritus, F. A. Davis Professor and David Allen BSc FRCS FRCOphth
Martin A Acquadro MD Lorenz F. Zimmerman Professor Consultant Ophthamologist
Perioperative Medical Doctor Department of Ophthalmology and Visual Sunderland Eye Infirmary
Director Sciences Sunderland
Department of Anesthesiology and Pain Retina Research Foundation Emmett A. United Kingdom
Caritas Carney Hospital Humble Distinguished Director
Dorchester MA Alice R. McPherson, MD, Eye Research Robert C Allen MD (deceased)
USA Institute Formerly Professor of Ophthalmology and
University of Wisconsin Pharmacology
Anthony P Adamis MD Madison WI Formerly Chairman, Department of
Chief Scientific Officer USA Ophthalmology
Executive Vice President, Research & Virginia Commonwealth University
Development Terry J Alexandrou MD Richmond VA
(OSI) Eyetech Pharmaceuticals Chief Resident USA
New York NY Department of Ophthalmology and Visual
USA Science Albert Alm MD PhD
University of Chicago Professor
Wesley H Adams MD Chicago IL Department of Neuroscience, Ophthalmology
Ophthalmology Resident USA University Hospital
Department of Ophthalmology Uppsala
Wake Forest University Eye Center Eduardo C Alfonso MD Sweden
Winston-Salem NC Professor, Edward W D Norton Chair in
USA Ophthalmology Samar Al-Swailem MD
Medical Director Consultant Ophthalmologist
Natalie A Afshari MD Ocular Microbiology Laboratory Anterior Segment Division
Associate Professor of Ophthalmology Bascom Palmer Eye Institute King Khaled Eye Specialist Hospital
Department of Ophthalmology University of Miami Riyadh
Duke University Eye Center Miami FL Kingdom of Saudi Arabia
Durham NC USA
USA Abigail K Alt BA
Jorge L Alió MD PhD c/o Thaddeus P Dryja MD
Everett Ai MD Professor and Chairman of Ophthalmology, Massachusetts Eye and Ear Infirmary
Director Miguel Hernandez University Harvard Medical School
Retina Unit Medical Director, VISSUM Boston MA
California Pacific Medical Center Instituto Oftalmológico de Alicante USA
San Francisco CA Alicante
USA Michael M Altaweel MD FRCS(C)
Spain Assistant Professor & Co-Director, Fundus
Lloyd M Aiello MD Hassan Alizadeh PhD Photograph Reading Center
Clinical Professor of Medicine Assistant Professor of Ophthalmology Department of Ophthalmology and Visual
Joslin Diabetes Center – Beetham Eye Department of Ophthalmology Science
Institute University of Texas Southwestern Medical University of Wisconsin
Harvard Medical School Center Madison WI
Boston MA Dallas TX USA xxiii
USA USA
 List of Contributors

Russell Anderson BA Isabelle Audo MD PhD George B Bartley MD

Medical Writer Ophthalmologist Professor of Ophthalmology
Dry Eye Department Laboratory of Cellular Physiopathology and Mayo Medical School
Ophthalmic Research Associates Retinal Molecules Chief Executive Officer
North Andover MA Faculty of Medicine Mayo Clinic
USA INSERM Jacksonville FL
Université Pierre et Marie Curie USA
Christopher M Andreoli MD Hôpital St Antoine
Ophthalmologist Paris Jason J S Barton MD PhD FRCPC
Department of Ophthalmology France Director of Neuro-Ophthalmology
Massachusetts Eye and Ear Infirmary Professor and Canada Research Chair
Harvard Medical School Gerd U Auffarth Priv-Doz Dr med Neuro-Ophthalmology
Boston MA Research Group Leader VGH Eye Care Center
USA Heidelberg IOL & Refractive Surgery Vancouver BC
Research Group Canada
Sofia Androudi MD Department of Ophthalmology
First Department of Ophthalmology University of Heidelberg Irmgard Behlau MD
Aristotle University of Thessaloniki Heidelberg Department of Ophthalmology
Thessaloniki Germany Massachusetts Eye and Ear Infirmary
Greece Instructor In Medicine, Harvard Medical
Robin K Avery MD School
Leonard P K Ang MD MMed(Ophth) FRCS(Ed) Section Head, Transplant Infectious Disease Boston MA
MRCOphth Department of Infectious Diseases USA
Consultant Cleveland Clinic Foundation
Department of Cataract and Comprehensive Cleveland OH Jose I Belda MD PhD EBO
Ophthalmology USA Chairman
Singapore National Eye Centre Department of Ophthalmology
Singapore Dimitri T Azar MD Hospital de Torrevieja
B A Field Chair of Ophthalmologic Research Alicante
Fahd Anzaar MD Professor and Head, Department of Spain
Research Coordinator Ophthalmology and Visual Sciences
Massachusetts Eye Research and Surgery University of Illinois Eye and Ear Infirmary Jeffrey L Bennett MD PhD
Institute Chicago IL Associate Professor of Neurology &
Cambridge MA USA Ophthalmology
USA Department of Neurology
Ann S Baker MD (deceased) University of Colorado Health Sciences
David J Apple MD Formerly Director of the Infectious Disease Center
Professor of Ophthalmology and Pathology Service Denver CO
Director of Research Pawek-Vallotton Massachusetts Eye and Ear Infirmary USA
University of South Carolina Formerly Associate Professor of
Charleston SC Ophthalmology Timothy J Bennett CRA FOPS
USA Harvard Medical School Ophthalmic Photographer
Boston MA Department of Ophthalmology
Claudia A Arrigg MD MEd Penn State Milton S Hershey Medical Center
Senior Surgeon USA
Hershey PA
Lawrence General Hospital Mark Balles MD USA
Lawrence MA Retina Center of Maine
USA South Portland ME Gregg J Berdy MD FACS
USA Assistant Professor of Clinical Ophthalmology
Pablo Artal PhD & Visual Science
Professor of Optics Scott D Barnes MD Department of Ophthalmology and Visual
Centro de Investigacion en Optica y Fellow, Cornea Service, Massachusetts Eye Science
Nanofisica (CiOyN) and Ear Infirmary and Harvard Medical Washington University School of Medicine
Universidad de Murcia School St Louis MO
Murcia Chief, Ophthalmology and Refractive Surgery USA
Spain Department of Ophthalmology
Womack Army Medical Center Carlo Roberto Bernardino MD FACS
Penny Asbell MD Associate Professor of Ophthalmology
Professor of Ophthalmology Fort Bragg NC
USA Yale University School of Medicine
Department of Ophthalmology New Haven CT
Mount Sinai Medical Center Donald M Barnett MD USA
New York NY Assistant Clinical Professor of Medicine
USA Joslin Diabetes Center Vitaliano Bernardino MD
Beetham Eye Institute Ophthalmologist
George K Asdourian MD Private Practice
Chief, Division of Ophthalmology Harvard Medical School
Boston MA Langhorne PA
University of Massachusetts Memorial USA
Medical Center USA
Worcester MA Neal P Barney MD Eliot L Berson MD
USA Associate Professor of Ophthalmology Director, Electroretinography Service
Department of Ophthalmology and Visual Massachusetts Ear and Eye Infirmary
Neal Atebara MD William F Chatlos Professor of
Ophthalmologist Sciences
University of Wisconsin School of Medicine Ophthalmology
Retina Center of Hawaii Harvard Medical School
Honolulu HI Madison WI
USA Boston MA
USA USA
Pelin Atmaca-Sonmez Fina C Barouch MD
Research Fellow Assistant Professor of Ophthalmology
Department of Ophthalmology Eye Institute
University of Michigan Lahey Clinic Medical Center
Peabody MA
xxiv Ann Arbor MI
USA
USA
 List of Contributors

Amitabh Bharadwaj MD Luigi Borrillo MD Alfred Brini MD

Ophthalmologist Retina-Vitreous Associates Inc Emeritus Professor of Ophthalmology
Department of Ophthalmology El Camino Hospital Louis Pasteur University
Wills Eye Hospital Mountain View, CA Strasbourg
Philadelphia PA USA France
USA
Gary E Borodic MD Donald L Budenz MD MPH
Robert Bhisitkul MD PhD Ophthalmologist Associate Professor
Assistant Professor of Clinical Ophthalmology Department of Ophthalmology Epidemiology and Public Health
Department of Ophthalmology Massachusetts Eye and Ear Infirmary Bascom Palmer Eye Institute
UCSF Beckman Vision Center Harvard Medical School Miami FL
San Francisco CA Boston MA USA
USA USA
Angela N Buffenn MD MPH
Ravinder D Bhui BApSc in Elec Eng S Arthur Boruchoff MD Assistant Professor of Clinical Ophthalmology
Senior Medical Student Professor (Retired) Childrens Hospital Los Angeles
Schulich School of Medicine and Dentistry Department of Ophthalmology Department of Ophthalmology
The University of Western Ontario Boston University School of Medicine Los Angeles CA
London ON Boston MA USA
Canada USA
Scott E Burk MD PhD
Jurij Bilyk MD Swaraj Bose MD Ophthalmologist
Attending Surgeon Associate Professor Department of Ophthalmology
Oculoplastic and Orbital Surgery Service Department of Ophthalmology Cincinnati Eye Institute
Wills Eye Institute University of California, Irvine Cincinnati OH
Philadelphia PA Irvine CA USA
USA USA
Salim Butrus MD
Valérie Biousse MD Michael E Boulton PhD Associate Clinical Professor
Associate Professor of Ophthalmology and Director of AMD Center Department of Ophthalmology
Neurology Department of Ophthalmology and Visual George Washington University
Emory Eye Center Sciences Washington DC
Emory University School of Medicine University of Texas Medical Branch USA
Atlanta GA Galveston TX
USA USA David Callanan MD
Vitreoretinal Specialist
Alan C Bird MD FRCS FRCOphth R W Bowman MD Texas Retina Associates
Professor Professor Arlington TX
Department of Clinical Ophthalmology Department of Ophthalmology USA
Moorfields Eye Hospital University of Texas Southwestern Medical
London Center J Douglas Cameron MD
United Kingdom Dallas TX Professor of Ophthalmology
USA Clinical Ophthalmology
Norman Paul Blair MD Scheie Eye Institute
Professor of Ophthalmology, Director of Elizabeth A Bradley MD University of Pennsylvania
Vitreoretinal Service Assistant Professor of Ophthalmology Philadelphia PA
Department of Ophthalmology and Visual Department of Ophthalmology USA
Sciences Mayo Clinic
University of Illinois Rochester MN Louis B Cantor MD
Chicago IL USA Professor of Ophthalmology
USA Department of Ophthalmology
Periklis D Brazitikos MD Indiana University School of Medicine
Barbara A Blodi MD Associate Professor of Ophthalmology Indianapolis IN
Associate Professor, Specialist in Retinal Department of Ophthamology USA
Disease Aristotle University of Thessaloniki
Department of Ophthalmology & Visual Thessaloniki William A Cantore MD
Sciences Greece Associate Professor of Ophthalmology and
University of Wisconsin-Madison Neurology
Madison WI Robert Breeze MD Department of Ophthalmology
USA Professor and Vice Chair Penn State University College of Medicine
Deparment of Neurosurgery Hershey PA
Mark S Blumenkranz MD University of Colorado Health Sciences USA
Professor and Chairman Center
Department of Ophthalmology Aurora CO Jorge Cantu-Dibildox MD
Stanford University School of Medicine USA Centro de Oftalmologia San Jose, S C
Stanford CA Fundación de Ojos Vidaurri, A C
USA Neil M Bressler MD Monterrey NL
Professor of Ophthalmology Mexico
H Culver Boldt MD The Wilmer Eye Institute
Professor of Ophthalmology The Johns Hopkins University School of Victoria Casas MD
Department of Ophthalmology Medicine Research Fellow
University of Iowa Baltimore MD Ocular Surface Research & Education
Iowa City IA USA Foundation
USA Miami FL
Susan B Bressler MD USA
Mark S Borchert MD Professor of Ophthalmology
Associate Professor of Ophthalmology Department of Ophthalmology Miriam Casper MD
Department of Ophthalmology John Hopkins Hospital c/o David J Apple MD
Children’s Hospital Los Angeles Baltimore MD University of South Carolina
Los Angeles CA USA Charleston SC
USA USA
xxv
 List of Contributors

Robin J Casten PhD Joe Chen MD Antonio P Ciardella MD

Assistant Professor c/o Keith L Lane MD Chief, Department of Ophthalmology
Department of Psychiatry and Human ORA Clinical Research and Development Denver Health Medical Center
Behaviour North Andover MA Denver CO
Thomas Jefferson University USA USA
Philadelphia PA
USA Julie A Chen MD Mortimer Civan MD
c/o Joan M O’Brien MD Professor of Physiology
Yara P Catoira MD Division of Ophthalmology Department of Physiology
Assistant Professor of Clinical Ophthalmology University of California San Francisco University of Pennsylvania Health System
Department of Ophthalmology Medical Center Philadelphia PA
Indiana University School of Medicine San Francisco CA USA
Indianapolis IN USA
USA Liane Clamen MD
Teresa C Chen MD Harvard Medical School
Jerry Cavallerano OD PhD Assistant Professor of Medicine Boston MA
Assistant to the Director Glaucoma Service USA
Joslin Diabetes Center Massachusetts Eye and Ear Infirmary
Beetham Eye Institute Assistant Professor of Medicine, Harvard John I Clark PhD
Boston MA Medical School Professor, Biological Structure
USA Boston MA School of Medicine
USA University of Washington
Samantha J Chai MD Seattle WA
Medical Resident Zhou Chen PhD USA
Department of Ophthalmology Senior Pharmacologist and Toxicologist
Cullen Eye Institute Center for Drug Evaluation and Research Glenn Cockerham MD
Baylor College of Medicine Food & Drug Administration Clinical Associate Professor
Houston TX Silver Spring MD Department of Ophthalmology
USA USA Stanford University
Stanford CA
Maria R Chalita MD PhD Patricia Chévez-Barrios MD USA
Director of Cornea and Refractive Surgery Clinical Assistant Professor
Department of Ophthalmology Departments of Ophthalmology & Pathology Andre Cohen MD
Federal University of Brazil Baylor College of Medicine and the Texas Ophthalmologist
Sao Paulo Children’s Cancer Center Marietta Eye Consultants
Brazil Houston TX Marietta GA
USA USA
Sherman M Chamberlain MD FACP FACG
Assistant Professor of Medicine Emily Y Chew MD Elisabeth J Cohen MD
Gastroenterology and Hepatology Medical Officer, Division of Biometry and Director Cornea Service, Attending Surgeon,
Medical College of Georgia Epidemiology Wills Eye Hospital
Augusta GA National Eye Institute Professor, Department of Ophthalmology
USA National Institutes of Health Jefferson Medical College of Thomas
Bethseda MD Jefferson University
Audrey S Chan MD USA Philadelphia PA
Cornea and Refractive Surgery Fellow USA
Massachusetts Eye and Ear Infirmary Mark Chiang MBBS
Harvard Medical School Birmingham and Midland Eye Centre Kathryn A Colby MD PhD
Boston MA Birmingham Director, Joint Clinical Research Center
USA United Kingdom Attending Surgeon, Cornea Service
Massachusetts Eye and Ear Infirmary
Chi-Chao Chan MD James Chodosh MD Assistant Professor of Ophthalmology,
Head, Immunopathology Section Professor of Ophthalmology Harvard Medical School
National Eye Institute Department of Ophthalmology Boston MA
National Institutes of Health University of Oklahoma Health Sciences USA
Bethesda MD Center
USA Oklahoma City OK Anne L Coleman MD PhD
USA Professor of Ophthalmology and
Paul Chan MD Epidemiology
Assistant Professor of Ophthalmology Eva-Marie Chong MBBS Departments of Ophthalmology and
New York Presbyterian Physician Epidemiology
Wiell Medical College of Cornell University Department of Ophthalmology Jules Stein Eye Institute
New York NY Arizona Medical Center Los Angeles CA
USA Peoria AZ USA
USA
Matthew J Chapin MD Hanna R Coleman MD
Ophthalmic Research Associates, Inc Denise Chun BS Staff Clinician
North Andover MA Doctoral Candidate in Genetics, Harvard Department of Ophthalmology
USA Medical School New York Presbyterian Hospital
Department of Molecular Biology Columbia University Medical Center
Karen L Chapman MD Massachusetts General Hospital New York NY
University of South Florida Boston MA USA
Sarasota Memorial Hospital USA
Sarasota FL Joseph Colin MD
USA Leo T Chylack Jr MD Professor of Ophthalmology
Director of Research Department of Ophthalmology
Eric Chen MD Center for Ophthalmic Research C H U Morvan
Retina Research Center Brigham & Women’s Hospital Brest
Austin TX Boston MA France
USA USA

xxvi
 List of Contributors

J Michael Collier PhD Donald J D’Amico MD Adam G de la Garza MD

Instructor, Harvard Medical School Professor and Chairman Chief Resident, Wake Forest University Eye
Senior Medical Physicist Ophthalmologist-in-Chief Center
Department of Radiation Oncology Department of Ophthalmology Wake Forest University School of Medicine
Massachusetts General Hospital Weill Cornell Medical College Winston-Salem NC
Boston MA New York NY USA
USA USA
Margaret M DeAngelis PhD
Grant M Comer MD Reza Dana MD MSc MPH Instructor of Ophthalmology
Assistant Professor Director, Cornea and Refractive Surgery Massachusetts Eye & Ear Infirmary
Kellogg Eye Center Services Boston MA
University of Michigan Massachusetts Eye and Ear Infirmary USA
Ann Arbor MI Professor, Harvard Medical School
USA Senior Scientist & W Clement Stone Scholar Sheri L DeMartelaere MD
Schepens Eye Research Institute Director of Orbital and Ocular Trauma
M Ronan Conlon MD FRCSC Boston MA Ophthalmology Service
Eye Physician and Surgeon USA Brooke Army Medical Center
Midwest Eye Care Institute Fort Sam Houston TX
Saskatoon SK Aude Danan-Husson MD USA
Canada Service d’ophtalmologie
Centre Hospitalier National d’Ophtalmologie Joseph L Demer MD PhD
Kim E Cooper MD des Quinze-vingts Leonard Apt Professor of Ophthalmology
Associate Professor Paris Departments of Ophthalmology and
Southwest College of Naturopathic Medicine France Neurology
Tempe AR Jules Stein Eye Institute
USA Helen B Danesh-Meyer MBChB MD Los Angeles CA
FRANZCO USA
James J Corbett MD Associate Professor of Ophthalmology
McCarty Professor and Chairman for Department of Ophthalmology Avninder Dhaliwal MD
Neurology University of Auckland Medical School University of Minnesota Medical School
Department of Neurology Auckland Minneapolis MN
University of Mississippi Medical Center New Zealand USA
Jackson MS
USA Ronald P Danis MD J Paul Dieckert MD
Professor of Ophthalmology and Visual Center Director, Division of Ophthalmology
Miguel C Coma MD FEBOphth Science Scott and White Memorial Hospital
Massachusetts Eye Research and Surgery Director, Fundus Photograph Reading Center Temple TX
Institute Department of Ophthalmology and Visual USA
Cambridge MA USA Science
Department of Ophthalmology Diana V Do MD
University of Wisconsin Fellow in Advanced Speciality Training in
Hospital de León, León, Spain Madison WI Medical and Surgical Diseases of the Retina
Marshall N Cyrlin MD USA Assistant Professor of Ophthalmology
Clinical Professor of Biomedical Sciences Jason K Darlington MD The Johns Hopkins University School of
Eye Research Institute Department of Ophthalmology Medicine
Oakland University University of California at Davis The Wilmer Eye Institute
Rochester MN Sacramento CA Baltimore MD
USA USA USA
Linda R Dagi MD Stefanie L Davidson MD Marshall G Doane PhD
Director of Adult Strabismus, Instructor in Assistant Clinical Professor, University of Emeritus Senior Scientist
Ophthalmology Pennsylvania Department of Ophthalmology
Department of Ophthalmology Division of Ophthalmology Schepens Eye Research Institute
Childrens Hospital Childrens Hospital of Philadelphia Harvard Medical School
Boston MA Philadelphia PA Boston MA
USA USA USA
Matthew A Dahlgren MD Janet L Davis MD MA Christopher Dodds MBBS MRCGP FRCA
Fellow, Cornea and Anterior Segement, Associate Professor of Ophthalmology Professor of Anaesthesia
Department of Ophthalmology Division of Ophthalmology Academic Anaesthetic Department
University of Minnesota Medical School University of Miami James Cook University Hospital
Minneapolis MN Miami FL Middlesbrough
USA USA United Kingdom
Timothy J Daley BS Elizabeth A Davis MD FACS Claes H Dohlman MD PhD
University of Wisconsin Hospital and Clinics Adjunct Clinical Assistant Professor, Professor of Ophthalmology, Harvard Medical
Madison WI University of Minnesota School, Chief Emeritus
USA Director, Minnesota Eye, Laser and Surgery Cornea Service
Center Massachusetts Eye and Ear Infirmary
Andrea P Da Mata MD Harvard Medical School
Ocular Immunology and Uveitis Foundation Bloomington MN
USA Boston MA
Massachusetts Eye Research and Surgery USA
Institute Jose J de la Cruz MD
Cambridge MA Cornea Fellow, Department of Guy Donati MD
USA Ophthalmology and Visual Science Chare D’Ensign
University of Illinois at Chicago Department of Pathology
Bertil Damato MD PhD FRCOphth University of Geneva
Professor of Ophthalmology Chicago IL
USA Geneva
Ocular Oncology Service Switzerland
Royal Liverpool University Hospital
Liverpool
United Kingdom xxvii
 List of Contributors

Eric D Donnenfeld MD FACS Chiara M Eandi MD Frederick L Ferris III MD

Co-director, Cornea Division The LuEsther T Mertz Retinal Research Director, Division of Epidemiology and
Ophthalmic Consultants of Long Island Fellow Clinical Research
New York NY Manhattan Eye, Ear and Throat Hospital National Eye Institute
USA New York NY National Institutes of Health
USA Bethesda MD
Arlene Drack MD USA
Chief of Ophthalmology, Children’s Hospital Deepak P Edward MD
Associate Professor Professor and Chairman Howard F Fine MD MHSc
Department of Ophthalmology Department of Ophthalmology - Suma Health Vitreoretinal surgical fellow
University of Colorado Health Sciences Systems Vitreous Retina Macula New York
Center Northeastern Ohio University School of New York NY
Aurora CO Medicine USA
USA Akron OH
USA Donald C Fletcher MD
Thaddeus P Dryja MD Medical Director
Director, David C Cogan Eye Pathology Robert A Egan MD Frank Stein & Paul May Center for Low Vision
Laboratory Assistant Professor of Ophthalmology and Rehabilitation
Massachusetts Eye and Ear Infirmary Neurology California Pacific Medical Center
Harvard Medical School Departments of Ophthalmology and Scientist, Smith-Kettlewell Eye Research
Boston MA Neurology Institute
USA Casey Eye Institute San Francisco CA
Portland OR USA
David Dueker MD USA
Professor of Ophthalmology Paul Flikier MD
The Eye Institute David A Eichenbaum MD Farmacia Alvarez, Heredia
Medical College of Wisconsin Associate Director, Centro Medico de la Vision
Milwaukee WI Retina-Vitrous Associates of Florida San Jose
USA St Petersburg FL Costa Rica
USA
Jay S Duker MD Richard P Floyd MD
Director New England Eye Center Susan E Eklund BA Clinical Instructor
Chairman and Professor of Ophthalmology Assistant, Department of Ophthalmology Department of Ophthalmology
Tufts University School of Medicine Children’s Hospital Harvard Medical School
Tufts New England Medical Center Boston MA Boston MA
Boston MA USA USA
USA
Elizabeth C Engle MD Harry W Flynn Jr, MD
Jennifer A Dunbar MD Associate Professor of Neurology Professor, The J Donald M Gass
Director of Pediatric Ophthalmology Harvard Medical School Distinguished Chair of Ophthalmology
Department of Ophthalmology Department of Neurology, Program in Bascom Palmer Eye Institute
Loma Linda University Genomics, Children’s Hospital The University of Miami Miller School of
Loma Linda CA Boston MA Medicine
USA USA Miami FL
USA
James P Dunn MD Kristine Erickson OD PhD
Associate Professor of Ophthalmology Senior Director Clinical Affairs Donald S Fong MD MPH
The Wilmer Eye Institute Unigene Corporation Director, Cinical Trials Research
John Hopkins School of Medicine Boonton NJ Kaiser Permanente Southern California
Baltimore MD USA Pasadena CA
USA USA
Bita Esmaeli MD FACS
William J Dupps Jr, MD PhD Associate Professor of Ophthalmology; Ramon L Font MD
Associate Staff, Ophthalmology and Director of Ophthalmic Plastic and Professor of Pathology and Ophthalmology
Biomedical Engineering Reconstructive and Orbital Surgery The Sarah Campbell Blaffer Chair of
Cole Eye Institute Fellowship Ophthalmology
Cleveland Clinic and Lerner Research Department of Medicine The Neurosensory Center
Institute The University of Texas Houston TX
Cleveland OH Houston TX USA
USA USA
Brian J R Forbes MD PhD
Marlene L Durand MD Aaron Fay MD Assistant Professor of Ophthalmology
Director of Infectious Diseases, Interim Director, Ophthalmic Plastic Surgery Department of Ophthalmology
Massachusetts Eye and Ear Infirmary Massachusetts Eye and Ear Infirmary The Childrens Hospital of Philadelphia
Assistant Professor of Medicine, Harvard Assistant Clinical Professor of Wallingford PA
Medical School; Ophthalmology, Department of USA
Infectious Diseases Unit Ophthalmology, Harvard Medical School
Massachusetts General Hospital Boston MA Rod Foroozan MD
Boston MA USA Assistant Professor of Ophthalmology
USA Department of Ophthalmology
Leonard Feiner MD PhD Baylor College of Medicine
Jonathan J Dutton MD PhD Ophthalmology Department Houston TX
Professor and Vice Chair Montefiore Medical Center USA
Department of Ophthalmology Lawrence NY
University of North Carolina USA Bradley S Foster MD
Chapel Hill NC Assistant Clinical Professor of Ophthalmology
USA Sharon Fekrat MD New England Retina Consultants
Assistant Professor West Springfield MA
Department of Ophthalmology USA
Vitreoretinal Surgery
Duke Eye Center
xxviii Durham NC
USA
 List of Contributors

C Stephen Foster MD FACS David Friedman MD James A Garrity MD

Founder and President Assistant Professor Professor of Ophthalmology
The Massachusetts Eye Research Institute Ophthalmology Department Department of Ophthalmology
Clinical Professor of Ophthalmology Wilmer Eye Institute Mayo Clinic
Harvard Medical School John Hopkins University School of Medicine Rochester MN
Cambridge MA Baltimore MD USA
USA USA
Damien Gatinel MD
Jill A Foster MD Deborah I Friedman MD FAAN Assistant Professor
Assistant Clinical Professor Associate Professor of Ophthalmology and Ophthalmology Department
The William H Havener Eye Institute Neurology Fondation Ophtalmologique A de Rothschild
The Ohio State University Departments of Ophthalmology and Paris
Columbus OH Neurology France
USA University of Rochester School of Medicine
and Dentistry Steven J Gedde MD
Gary N Foulks MD FACS Rochester NY Professor of Ophthalmology and Residency
Arthur & Virginia Keeney Professor of USA Program Director
Ophthalmology Department of Ophthalmology
Department of Ophthalmology Ephraim Friedman MD Bascom Palmer Eye Institute
University of Louisville School of Medicine Former Chief, Department of Ophthalmology Miami FL
Louisville KY Massachusetts Eye and Ear Infirmary USA
USA Harvard Medical School Retina Service
Boston MA Craig E Geist MD FACS
Tamara R Fountain MD USA Chairman, Department of Ophthalmology
Associate Professor Associate Professor, Ophthalmology,
Department of Ophthalmology Arthur D Fu MD Neurology, Neurological Surgery
Rush University in Chicago Ophthalmologist Director, Oculoplastics, Orbit, Lacrimal
Northbrook IL Pacific Vision Foundation Director, Neuro-Ophthalmology
USA California Pacific Medical Center The George Washington University
San Francisco CA Washington DC
Gregory M Fox MD USA USA
Clinical Instructor of Ophthalmology
Department of Ophthalmology Anne B Fulton MD Steve Gerber MD
Allegheny University Associate Professor of Ophthalmology and Chairman
Wilmington DE Senior Associate in Ophthalmology Department of Ophthalmology
USA Department of Ophthalmology Memorial Hospital
Children’s Hospital South Bend IN
Thomas F Freddo OD PhD FAAO Boston MA USA
Professor and Director USA
School of Optometry Ramon C Ghanem MD
University of Waterloo Ahmed Galal MD PhD Sadalla Amin Ghanem
Waterloo ON Department of Refractive Surgery Hospital de Olhos
Canada Vissum/Instituto Oftalmologico de Alicante Batista
Alicante Joinville - SC
Sharon F Freedman MD Spain Brazil
Associate Professor of Ophthalmology
Associate Professor of Pediatrics Steven Galetta MD Jon P Gieser MD
Department of Pediatric Ophthalmology & Director, Neuro-Ophthalmology Services Wheaton Eye Clinic
Strabismus Hospital of the University of Pennsylvania Wheaton IL
Duke University Eye Center Philadelphia PA USA
Durham NC USA
USA Michael S Gilmore PhD
Mark Gallardo MD Charles L Schepens Professor of
K Bailey Freund MD Resident Physician Ophthalmology
Retina Specialist Office of Border Health President and Ankeny Director of Research
Vitreous-Retina-Macula Consultants of Texas Tech University Health Sciences Center The Schepens Eye Research Institute
New York El Paso TX Harvard Medical School
New York NY USA Boston MA
USA USA
Brenda Gallie MD FRCS(C)
Thomas R Friberg MD Professor of Ophthalmology Howard V Gimbel MD MPH FRCSC FACS
Professor of Ophthalmology, Professor of Departments of Medical Biophysics and Chair and Professor of The Department of
Bioengineering Molecular and Medical Genetics Ophthalmology
Director of the Retina Service University of Toronto Refractive Surgery, Department of
Departments of Ophthalmology and Head of Cancer Informatics Ophthalmology
Bioengineering University Health Network Loma Linda University
UPMC Eye Center Ontario Cancer Institute Loma Linda CA
Pittsburgh PA Princess Margaret Hospital USA
USA Toronto ON
Canada Ilene K Gipson PhD
Alan H Friedman MD Senior Scientist and Professor of
Department of Ophthalmology Alec Garner MD Ophthalmology
Mount Sinai School of Medicine Head of Department Department of Ophthalmology
New York NY Department of Pathology Schepens Eye Research Institute
USA Institute of Ophthalmology Boston MA
London USA
United Kingdom

xxix
 List of Contributors

Tyrone Glover MD David B Granet MD FACS FAAP FAAO Vamsi K Gullapalli MD PhD
Clinical Professor, Ophthalmology Anne F Ratner Professor of Ophthalmology & Resident
Oculoplastic Surgery Pediatrics Department of Ophthalmology and Visual
Kaiser Permanente Director, Pediatric Ophthalmology & Adult Science
Sacramento CA Re-Alignment Services Institute of Ophthalmology and Visual
USA Anne F & Abraham Ratner Children’s Eye Center Science
Shiley Eye Center University of Medicine and Dentistry of
Robert A Goldberg MD FACS University of California, San Diego New Jersey
Associate Professor of Ophthalmology La Jolla CA Newark NJ
Chief, Division of Orbital and Ophthalmic USA USA
Plastic Surgery
Jules Stein Eye Institute Michael J Greaney Padma Gulur MD
Los Angeles CA Senior Clinical Lecturer, Department of Instructor in Anaesthesia, Harvard Medical
USA Ophthalmology, University of Bristol School
Senior Consultant Pain Center Department of Anesthesia and
Mordechai Goldenfeld MD
Bristol Eye Hospital Critical Care
Senior Attending Ophthalmologist
Bristol Massachusetts General Hospital
The Sam Rothberg Glaucoma Centre
United Kingdom Boston MA
Goldschleger Eye Institute
USA
Sheba Medical Center Daniel G Green PhD
Tel-Hashomer Professor Emeritus, Ophthalmology and Jonathan Gunther MD
Israel Visual Sciences Department of Ophthalmology and Visual
Scott M Goldstein MD Professor, Biomedical Engineering Sciences
Clinical Associate The University of Michigan Kellogg Eye University of Wisconsin Medical School
Childrens Hospital of Philadelphia Center Madison WI
Tricounty Eye Physicians & Surgeons Ann Arbor MI USA
Southampton PA USA
Manish Gupta DNB FRCS(Glasg), MRCS(Ed)
USA Franz Grehn Dr h.c. NHS Greater Glasgow and Clyde
Cintia F Gomi MD Professor of Ophthalmology Stobhill and Gartnevel Hospital
Hamilton Glaucoma Center Chairman, Department of Ophthalmology Glasgow
University of California, San Diego, University of Würzburg United Kingdom
La Jolla CA Würzburg
Germany Mayank Gupta
USA
c/o Deepak P Edward MD
Haiyan Gong MD MS PhD Jack V Greiner DO PhD Northeastern Ohio University School of
Research Assistant Professor Instructor of Ophthalmology Medicine
Department of Ophthalmology Schepens Eye Research Institute Akron OH
Boston University School of Medicine Harvard Medical School USA
Boston MA Boston MA
USA USA David R Guyer MD
Clinical Professor
John A Gonzales MD Craig M Greven MD FACS Department of Ophthalmology
Physician Director, Professor and Chairman NYU Medical Center
Immunopathology Section Department of Ophthalmology New York NY
Laboratory of Immunology Wake Forest University Eye Center USA
National Eye Institute Wake Forest University School of Medicine
National Institutes of Health Winston-Salem NC Darin R Haivala MD
Besthesda MD USA Clinical Assistant Professor
USA Department of Ophthalmology
Gregory J Griepentrog MD University of Oklahoma
John Goosey MD Chief Resident Associate Dean A McGee Eye Institute
Director Mayo Clinic Oklahoma City OK
Houston Eye Associates Rochester MN USA
Houston TX USA
USA Julia A Haller MD
Carl Groenewald MD Robert Bond Welch Professor of
Justin L Gottlieb MD
Consultant Vitreoretinal Surgeon Ophthamology
Associate Professor
St Paul’s Eye Unit Wilmer Ophthalmological Institute
Department of Ophthalmology and Visual
Royal Liverpool University Hospital Johns Hopkins Medical Institutions
Sciences
Liverpool Baltimore MD
University of Wisconsin
United Kingdom USA
Madison WI
USA Cynthia L Grosskreutz MD PhD G M Halmagyi MD BSc FACS DCH
Joshua Gould DO Co-Director, Glaucoma Service Professor of Neurology
Physician Massachusetts Eye and Ear Infirmary Department of Neurology
Eye Care Center of New Jersey Associate Professor of Ophthalmology Royal Prince Albert Hospital
Bloomingfield NJ Harvard Medical School Sydney NSW
USA Boston MA Australia
USA
Evangelos S Gragoudas MD Lawrence S Halperin MD FACS
Director, Retina Service Lori Latowski Grover OD Physician
Massachusetts Eye and Ear Infirmary Assistant Professor of Ophthalmology Retina Vitreous Consultants of South Florida
Professor of Ophthalmology, Harvard Medical Department of Ophthalmology Fort Lauderdale FL
School Lions Vision Research and Rehabilitation USA
Boston MA Center
Baltimore MD Islam M Hamdi FRCS MD
USA Magrabi Center
USA
Jeddah
Kingdom of Saudi Arabia

xxx
 List of Contributors

Steven R Hamilton MD Yasutaka Hayashida MD PhD Ahmed A Hidayat MD

Clinical Associate Professor of Research Fellow Chief, Ophthalmic Pathology
Ophthalmology and Neurology Ocular Surface Research and Education Armed Forces Institute of Pathology
Department of Ophthalmology and Neurology Foundation Rockville MD
University of Washington Miami FL USA
Neuro-Ophthalmic Associates Northwest USA
Seattle WA Eva Juliet Higginbotham MD
John R Heckenlively MD FRCOpath Professor of Ophthalmology and Chair
USA
Paul R Lichter Professor of Ophthalmic Department of Ophthalmology
Kristin M Hammersmith MD Genetics University of Maryland Medicine
Assistant Surgeon, Cornea Service, Wills Eye Professor of Ophthalmology and Visual Baltimore MD
Hospital Science USA
Instructor, Thomas Jefferson Medical College Kellogg Eye Centre
Wills Eye Institute University of Michigan Tatsuo Hirose MD
Thomas Jefferson University Ann Arbor MI Clinical Professor of Ophthalmology
Philadelphia PA USA Schepens Retina Associates
USA Boston MA
Thomas R Hedges III, MD USA
Dennis P Han MD Director, Neuro-Ophthalmology Service
Jack A and Elaine D Klieger Professor of Co-Director, Electrophysiology Service Allen C Ho MD
Ophthalmology, Vitreoretinal Section Head Director, Neuro-Ophthalmology Fellowship Professor of Ophthalmology
Department of Ophthalmology Program Retina Service
Medical College of Wisconsin New England Eye Center Thomas Jefferson University
Milwaukee WI Boston MA Philadelphia PA
USA USA USA

Ronald M Hansen PhD Alfred D Heggie MD ThucAnh T Ho MD

Instructor Professor Emeritus of Pediatrics Vitreoretinal Fellow
Department of Ophthalmology Departments of Pediatrics, Preventive Illinois Retina Associates
Children’s Hospital and Harvard Medical Medicine, and Obstetrics and Gynecology Rush University Medical Center
School Case Western Reserve University School of Chicago IL
Boston MA Medicine USA
USA Cleveland OH R Nick Hogan MD PhD
J William Harbour MD USA Associate Professor of Ophthalmology
Distinguished Professor of Ophthalmology, Department of Ophthalmology
Katrinka L Heher MD
Cell Biology, and Medicine (Molecular University of Texas South Western Medical
Director, Aesthetic Eyelid & Facial Surgery
Oncology) Center
Director, Oculoplastic & Orbital Surgery
Director, Ocular Oncology Service Dallas TX
Service
Department of Ophthalmology USA
Director, Ophthalmic Plastics and
Washington University School of Medicine Reconstructive Surgery Fellowship Program David E Holck MD
St Louis MO New England Eye Center Director, Oculoplastic, Reconstructive, Orbit,
USA Tufts University School of Medicine and Ocular Oncology Service
Seenu M Hariprasad MD Boston MA Department of Ophthalmology
Assistant Professor and Director of Clinical USA Wilford Hall Medical Center
Research Assistant Professor of Surgery, USUHS
Jeffrey S Heier MD Assistant Professor of Ophthalmology
Chief, Vitreoretinal Service Vitreoretinal Specialist
Department of Ophthalmology and Visual University of Texas
Ophthalmic Consultants of Boston San Antonio TX
Science Boston MA
University of Chicago USA
USA
Chicago IL Nancy M Holekamp MD
USA J Fielding Hejtmancik MD PhD Associate Professor of Clinical
Medical Officer Ophthalmology
Mona Harissi-Dagher MD Ophthalmic Genetics and Visual Function
Assistant in Ophthalmology Department of Ophthalmology and Visual
Branch Science
Massachusetts Eye and Ear Infirmary National Eye Institute
Harvard Medical School Washington University School of Medicine
National Institutes of Health Barnes Retina Institute
Boston MA Bethesda MD
USA St Louis MO
USA USA
Shirin E. Hassan PhD
Bonnie A Henderson MD FACS Peter G Hovland MD PhD
c/o David Friedman
Assistant Clinical Professor Physician
Assistant Professor
Department of Ophthalmology Colorado Retina Associates
Wilmer Eye Institute
Harvard Medical School Denver CO
John Hopkins University School of Medicine
Boston MA USA
Baltimore MD
USA
USA Thomas C Hsu MD
Mark P Hatton MD Peter S Hersh MD FACS Tufts University School of Medicine
Clinical Instructor, Harvard Medical School Professor of Ophthalmology New England Eye Center
Adjunct Clinical Scientist Director, Cornea and Laser Eye Institute - Boston MA
Schepens Eye Research Institute Hersh Vision Group USA
Ophthalmic Consultants of Boston Clinical Professor of Ophthalmology
Chief, Cornea and Refractive Surgery William C Hsu MD
Boston MA Assistant Professor of Medicine
USA University of Medicine and Dentistry New
Jersey Joslin Diabetes Center
Pamela Hawley MS Teaneck NJ Beetham Eye Institute
Genetic Counseling Center USA Harvard Medical School
Children’s Hospital Boston MA
Harvard USA
Boston MA xxxi
USA
 List of Contributors

Andrew J W Huang MD MPH Fei Ji PhD Alon Kahana MD PhD

Director of Cornea and Refractive Surgery Research Associate Assistant Professor; Eye Plastics, Orbit and
Department of Ophthalmology Laboratory of Statistical Genetics Facial Cosmetic Surgery
University of Minnesota Rockefeller University Department of Ophthalmology and Visual
Minneapolis MN New York NY Sciences
USA USA Kellogg Eye Center
Ann Arbor MI
Mark S Hughes MD David L Johnson MD USA
Adjunct Assistant Clinical Scientist Clinical Instructor/Vitreoretinal Fellow
The Schepens Eye Research Institute Department of Ophthalmology and Visual Malik Y Kahook MD
Boston MA Sciences Assistant Professor and Director of Clinical
USA University Of Wisconsin Medical School Research
Jennifer Hui MD Madison WI Rocky Mountain Lions Eye Institute
Ophthalmology Resident USA University of Colorado at Denver Health
Department of Ophthalmology Sciences Center
Douglas H Johnson MD (deceased) Aurora CO
Bascom Palmer Eye Institute Formerly Professor of Ophthalmology
Miami FL USA
Department of Ophthalmology
USA Mayo Clinic Elliott Kanner MD PhD
David G Hunter MD PhD Rochester MN Assistant Professor of Ophthalmology
Associate Professor of Ophthalmology, USA Hamilton Eye Institute
Harvard Medical School University of Tennessee Health Science
Mark W Johnson MD Center
Ophthalmologist-in-Chief Professor
Richard Robb Chair in Ophthalmology Memphis TN
Kellogg Eye Center USA
Department of Ophthalmology University of Michigan
Children’s Hospital Boston Ann Arbor MI Kevin Kalwerisky MD
Boston MA USA Department of Otolaryngology, Head & Neck
USA Surgery
R Paul Johnson MD The New York Presbyterian Hospital
Laryssa A Huryn MD Associate Professor of Medicine
Bascom Palmer Eye Institute Weill Medical College of Cornell University
Infectious Diseases Unit New York NY
Miami FL Massachusetts General Hospital
USA USA
Charlestown MA
Deeba Husain MD USA Henry J Kaplan MD
Assistant Professor of Ophthalmology Professor and Chairman
Robert N Johnson MD Department of Ophthalmology and Visual
Retina Service - Dept of Ophthalmology Assistant Clinical Professor of Ophthalmology
Boston University School of Medicine Sciences
Department of Ophthalmology University of Louisville
Boston MA University of California
USA Louisville KY
West Coast Retina Medical Group USA
Robert A Hyndiuk MD San Francisco CA
The Eye Institute USA Ekaterini C Karatza MD
Medical College of Wisconsin Staff Ophthalmologist
Karen M Joos MD PhD Cincinnati Eye Institute
Milwaukee WI Associate Professor
USA Cincinnati OH
Department of Ophthalmology and Visual USA
Michael Ip MD Sciences
Associate Professor of Ophthalmology Vanderbilt University Randy Kardon MD PhD
Department of Ophthalmology and Visual Nashville TN Associate Professor of Ophthalmology
Sciences USA Director of Neuro-ophthalmology
Fundus Photograph Reading Center The University of Iowa Hospitals and Clinics
Nancy C Joyce PhD Iowa City IA
Madison WI Schepens Eye Research Institute
USA USA
Senior Scientist Associate Professor, Harvard
Brian J Jacobs MD Medical School James A Katowitz MD
Assistant Professor of Ophthalmology Boston MA Attending Surgeon
Rush University Medical Center USA Ophthalmology
Chicago IL Childrens Hospital of Philadelphia
J Michael Jumper MD Philadelphia PA
USA Assistant Clinical Professor of Ophthalmology USA
Frederick A Jakobiec MD DSc(Med) University of California
Former Henry Willard Williams Professor and Director, Retina Service William R Katowitz MD
Former Chief of Ophthalmology West Coast Retina Medical Group Department of Ophthalmology
Departments of Pathology and San Francisco CA University of Rochester School of Medicine
Ophthalmology USA and Dentistry
Harvard Medical School Rochester NY
Ula V. Jurkunas MD USA
Boston MA Instructor in Ophthalmology
USA Massachusetts Eye and Ear Infirmary Melanie Kazlas MD
Lee M Jampol MD Clinical Scientist Acting Director; Instructor
Louis Feinberg Professor and Chairman Schepens Eye Research Institute Pediatric Ophthalmology & Strabismus
Department of Ophthalmology Harvard Medical School Massachusetts Eye & Ear Infirmary
Northwestern University Medical School Boston MA Boston MA
Chicago IL USA USA
USA Kelly S Keefe CAPT MC USN
Harold G Jensen PhD Staff Ophthalmic Pathologist
Clinical Project Manager Comprehensive Ophthalmologist
Allergan, Inc Naval Medical Center
Irvine CA San Diego CA
xxxii USA USA
 List of Contributors

Lara Kelley MD Jonathan W Kim MD Thomas Kohnen MD

Assistant Professor, Dermatology Physician Professor of Ophthalmology
Harvard Medical School Memorial Sloan-Kettering Cancer Center Deputy Chairman
Beth Israel Deaconess Medical Center New York NY Klinik fur Augenheilkunde
Boston MA USA Johann Wolfgang Goethe University
USA Frankfurt
Rosa Y Kim MD Germany
Charles J Kent MD Physician
Fellowship Training in Ocuplastics and Ocular Vitreoretinal Consultants Takeshi Kojima MD PhD
Pathology Houston TX Research Group for Environmental
Everett & Hurite Ophthalmology Associates USA Conservation Processing
Pittsburgh PA Department of Material Development
USA Stella K Kim MD Takasaki Radiation Chemistry Research
Assistant Professor of Ophthalmology Establishment
Kenneth R Kenyon MD FACS Section of Ophthalmology Japan Atomic Energy Research Institute
Associate Clinical Professor MD Anderson Cancer Center Takasaki-shi
Harvard Medical School; Houston TX Japan
Eye Health Vision Centers USA
North Dartmouth MA Tobias Koller MD
USA Tae-Im Kim MD PhD Refractive Surgeon
Department of Ophthalmology Institute of Ophthalmic and Refractive
Bilal F Khan MD Yonsei University Health System Surgery
Assistant in Ophthalmology Seoul Zurich
Massachusetts Eye and Ear Infirmary South Korea Switzerland
Harvard Medical School
Boston MA Christina M Klais MD David A Kostick MD
USA Retina Fellow Assistant Professor of Ophthalmology
LuEsther T Mertz Retinal Research Center Department of Ophthalmology
Jemshed A Khan MD Manhattan Eye, Ear and Throat Hospital Mayo Clinic College of Medicine
Clinical Professor of Ophthalmology New York NY Jacksonville FL
Kansas University USA USA
Kansas City MO
USA Stephen R Klapper MD FACS Joel A Kraut MD
Ophthalmologist Medical Director
Naheed W Khan PhD Klapper Eyelid & Facial Plastic Surgery Vision Rehabilitation Service
Electrophysiologist Carmel IN Massachusetts Eye and Ear Infirmary
Department of Ophthalmology and Visual USA Harvard Medical School
Sciences Boston MA
W K Kellogg Eye Center Barbara E K Klein MD MPH
USA
University of Michigan Professor of Medicine
Ann Arbor MI Department of Ophthalmology and Visual Chandrasekharan Krishnan MD
USA Sciences Assistant Professor of Ophthalmology
University of Wisconsin Medical School Tufts University School of Medicine
Peng Tee Khaw PhD FRCP FRCS FRCOphth Madison WI Glaucoma and Cataract Service
FIBiol FRCPath FMedSci USA New England Eye Center
Professor of Glaucoma and Ocular Healing Boston MA
and Consultant Ophthalmic Surgeon Guy Kleinmann MD
USA
Biomedical Research Centre (Ophthalmology) Adjunct Assistant Professor of
UCL Institute of Ophthalmology and Ophthalmology Ronald R Krueger MD MSE
Moorfields Eye Hospital Department of Ophthalmology Director of Refractive Surgery, Cleveland
London Herman Eye Center Clinic Foundation, Cleveland, OH, USA
United Kingdom Houston TX Saint Louis University Eye Institute
USA Saint Louis University School of Medicine
Femida Kherani MD FRCSC St Louis MO
Ophthalmic Cosmetic Surgeon Thomas Klink DrMed USA
Heights Laser Centre Scientific Assistant
Burnaby BC Department of Ophthalmology Joseph H Krug Jr, MD
Canada University of Würzburg Assistant Director of Glaucoma Consultation
Würzburg Service
Eva C Kim MD Germany Massachusetts Eye and Ear Infirmary
Fellow in Ocular Inflammation/Uveitis Harvard Medical School
The Proctor Foundation Dino D Klisovic MD Boston MA
University of California San Francisco Department of Ophthalmology USA
San Francisco CA Nationwide Children’s Hospital
USA Midwest Retina Inc Sara Krupsky MD
Columbus OH Goldschleger Eye Institute
Hee Joon Kim MD USA Sheba Medical Center
Resident Tel Hashomer
Department of Ophthalmology and Visual Stephen D Klyce Israel
Science Executive Editor
Department of Ophthalmology Rachel W Kuchtey MD PhD
University of Texas Health Science Center at
Louisiana State University Eye Institute Clinical Ophthalmologist, Glaucoma
Houston
New Orleans LA Vanderbilt University of Ophthalmology &
Houston TX
USA Visual Sciences
USA
Nashville TN
Ivana K Kim MD Tolga Kocaturk MD USA
Instructor of Ophthalmology Department of Ophthalmology
Retina Service Adnan Menderes University Medical School
Massachusetts Eye and Ear Infirmary Aydin
Harvard Medical School Turkey
Boston MA
USA xxxiii
 List of Contributors

Ramsay S Kurban MD Jonathan H Lass MD Andrea Leonardi MD

Clinical Assistant Professor Charles I Thomas Professor and Chairman Assistant Professor in Ophthalmology
Department of Dermatology CWRU Department of Ophthalmology and Department of Neuroscience, Ophthalmology
Penn State University Visual Sciences Chairman Unit
Milton S Hershey Medical Center Department of Ophthalmology and Visual University of Padua
Hershey PA Sciences Padua
USA University Hospitals Case Medical Center Italy
Cleveland OH
Paul A Kurz MD USA Simmons Lessell MD
Instructor of Ophthalmology Director, Neuro-Ophthalmology Service
Casey Eye Institute Mary G Lawrence MD MPH Massachusetts Eye and Ear Infirmary
Oregon Health & Science University Associate Professor, Glaucoma, Cataract and Professor, Harvard Medical School
Portland OR Visual Rehabilitation Boston MA
USA Glaucoma Service USA
University of Minnesota Medical School
J R Kuszak PhD Minneapolis MN Leonard A Levin MD PhD
Departments of Ophthalmology and USA Professor of Ophthalmology and Visual
Pathology Sciences, Neurology, and Neurological
Rush University Medical Center Andrew G Lee MD Surgery
Chicago IL Professor of Ophthalmology, Neurology and University of Wisconsin School of Medicine
USA Neurosurgery and Public Health
Departments of Ophthalmology, Neurology Madison WI
Young H Kwon MD PhD and Neurosurgery USA
Associate Professor of Ophthalmology University of Iowa Hospitals Canada Research Chair of Ophthalmology
Department of Ophthalmology Iowa City IA and Visual Sciences
University of Iowa USA University of Montreal
Iowa City IA Montreal QC
USA Carol M Lee MD Canada
Clinical Professor, Department of
Thad A Labbe MD Ophthalmology Grace A Levy-Clarke MD
Glaucoma Specialist NYU Medical Center Fellowship Program Director
Ophthalmologist New York NY Uveitis and Ocular Immunology
Eye Associates of Central Texas USA Laboratory of Immunology
Austin TX National Eye Institute
USA Michael S Lee MD National Institutes of Health
Associate Professor Bethesda MD
Deborah L Lam MD Departments of Ophthalmology, Neurology,
Pacific Northwest Eye Associates USA
and Neurosurgery
Tacoma WA University of Minnesota Julie C Lew MD
USA Minneapolis MN Assistant Clinical Professor
Jeffrey C Lamkin MD USA Suny Downstate Medical Centre
Department of Ophthalmology Department of Ophthalmology
Paul P Lee MD JD Brooklyn NY
Akron City Hospital Professor of Ophthalmology
The Retina Group of NE Ohio Inc USA
Department of Ophthalmology
Akron OH Duke University Eye Center Craig Lewis MD
USA Durham NC Cole Eye Institute
Kathleen A Lamping MD USA Cleveland Clinic
Associate Clinical Professor Cleveland OH
William B Lee MD USA
Department of Ophthalmology Eye Consultant
Case Western Reserve University Eye Consultants of Atlanta Wei Li MD PhD
South Euclid OH Piedmont Hospital Research Fellow
USA Atlanta GA Ocular Surface Center
Anne Marie Lane MPH USA Miami FL
Clinical Research Manager, Retina Service USA
Igal Leibovitch MD
Massachusetts Eye and Ear Infirmary Oculoplastic and Orbital Division Laurence S Lim MBBS
Instructor in Ophthalmology, Harvard Medical Ophthalmology Department Principal Investigator
School Tel-Aviv Medical Center Singapore National Eye Centre
Boston MA Tel-Aviv Singapore
USA Israel
Lyndell L Lim MBBS FRANZCO
Katherine A Lane MD Bradley N Lemke MD FACS Mankiewicz-Zelkin Crock Fellow
Resident, Oculoplastic and Orbital Surgery Clinical Professor of Oculofacial Surgery Centre for Eye Research Australia
Service Department of Ophthalmology and Visual University of Melbourne
Wills Eye Hospital Sciences East Melbourne VIC
Philadelphia PA University of Wisconsin - Madison Australia
USA Madison WI
USA Wee-Kiak Lim FRCOphth FRCS(Ed) MMED
Keith J Lane MD Associate Consultant
Senior Manager, Research and Development Craig A Lemley MD Ocular Inflammation and Immunology
/Preclinical The Eye Institute Singapore National Eye Centre
ORA Clinical Research and Development Medical College of Wisconsin Singapore
North Andover MA Milwaukee WI
USA USA Grant T Liu MD
Neuro-ophthalmologist
Children’s Hospital of Philadelphia
Philadelphia PA
USA

xxxiv
 List of Contributors

John I Loewenstein MD Robert E Marc PhD Michael McCrakken

Associate Professor of Ophthalmology Director of Research Clinical Instructor
Retina Service John A Moran Eye Center Department of Ophthalmology
Massachusetts Eye and Ear Infirmary Salt Lake City UT University of Colorado Health Sciences
Harvard Medical School USA Center
Boston MA Denver CO
USA Mellone Marchong USA
Department of Applied Molecular Oncology
McGregor N Lott MD Ontario Cancer Institute - University Health James P McCulley MD
Department of Ophthalmology Network Professor & Chairman of Ophthalmology
Medical College of Georgia Princess Margaret Hospital Department of Ophthalmology
Augusta GA Toronto ON University of Texas Southwestern Medical
USA Canada Center
Dallas TX
Jonathan C Lowry MD Dennis M Marcus MD USA
Ophthalmologist Professor of Clinical Ophthalmology
Morganton Eye Physicians Department of Clinical Ophthalmology John A McDermott
Morganton NC Southeast Retina Center Assistant Clinical Professor of Ophthalmology
USA Augusta GA Department of Ophthalmology
USA New York Eye and Ear Infirmary
David B Lyon MD FACS New York NY
Associate Professor Julie A Mares PhD USA
Department of Ophthalmology Professor
University of Missouri-Kansas City School of Department of Ophthalmology & Visual H Richard McDonald MD
Medicine Sciences Director, San Francisco Retina Foundation
Prairie Village KS WARF Co-Director, Vitreoretinal Fellowship
USA Madison WI California Pacific Retina Center
USA West Coast Retina Medical Group
Robert E Lytle MD San Francisco CA
Ophthalmologist Brian P Marr MD USA
Massachusetts Eye and Ear Infirmary Oncology Service
Harvard Medical School Wills Eye Institute Marguerite B McDonald MD FACS
Boston MA Thomas Jefferson University Ophthalmic Consultants of Long Island
USA Philadelphia PA Lynbrook NY
USA USA
Mathew MacCumber MD PhD
Associate Professor Carlos E Martinez MS MD Peter J McDonnell MD
Associate Chairman of Research Eye Physicians of Long Beach William Holland Wilmer Professor of
Rush University Medical Center Long Beach CA Ophthalmology
Chicago IL USA Director, Wilmer Ophthalmological Institute
USA Johns Hopkins University School of Medicine
Robert W Massof PhD Baltimore MD
Bonnie T Mackool MD MSPH Professor of Ophthalmology, Professor of USA
Director of Dermatology Neuroscience
Consultation Service Director, Lions Vision Research and Robert McGillivray BSEE CLVT
Massachusetts General Hospital Rehabilitation Center Director
Boston MA Wilmer Ophthalmological Institute Low Vision Services
USA Johns Hopkins University School of Medicine The Carroll Center for the Blind
Baltimore MD Low Vision Engineering Consultant
Nalini A Madiwale MD USA Massachusetts Commission for the Blind
Physician Newton MA
Albany-Troy Cataract & Laser Associates Yukihiro Matsumoto USA
Troy NY Research Fellow
USA Ocular Surface Research and Education Craig A McKeown MD
Foundation Associate Professor of Clinical
Francis Mah MD Miami FL Ophthalmology
Assistant Professor of Ophthalmology USA Bascom Palmer Eye Institute
Department of Ophthalmology Miller School of Medicine
University of Pittsburgh Medical Center Cynthia Mattox MD University of Miami
Pittsburgh PA Assistant Professor of Ophthalmology Miami FL
USA Ophthalmology - New England Eye Center USA
Tufts-New England Medical Center
Martin A Mainster PhD MD FRCOphth Boston MA James McLaughlin MD
Fry Endowed Professor and Vice Chairman of USA Medical Writer
Ophthalmology Ophthalmic Research Associates, Inc
Department of Ophthalmology Marlon Maus MD North Andover MA
University of Kansas School of Medicine DrPH Candidate USA
Kansas City MO University of California at Berkeley
USA Berkeley CA W Wynn McMullen MD
USA Vitereoretinal Consultant
Michael H Manning Jr Coastal Eye Associates
c/o Sherman M Chamberlain MD FACP Cathleen M McCabe MD Houston TX
FACG Indiana LASIK Center USA
Medical College of Georgia Fort Wayne IN
Augusta GA USA Shlomo Melamed MD
USA The Sam Rothberg Glaucoma Centre
Steven A McCormick MD Goldschleger Eye Institute
Steven L Mansberger MD MPH Director of Pathology and Laboratory Sheba Medical Center
Associate Scientist Medicine Tel-Hashomer
Devers Eye Institute The New York Eye and Ear Infirmary Israel
Portland OR New York NY
USA USA xxxv
 List of Contributors

George Meligonis FRCPath Neil R Miller MD A Linn Murphree MD

Corneoplastic Unit Professor of Ophthalmology, Neurology and Director
Queen Victoria Hospital Neuro-Ophthalmology The Retinoblastoma Centre
East Grinstead Departments of Ophthalmology, Neurology Childrens Hospital of Los Angeles
East Sussex and Neuro-Ophthalmology Los Angeles CA
United Kingdom Wilmer Eye Institute USA
Johns Hopkins Hospital
Efstratios Mendrinos MD Baltimore MD Robert P Murphy MD
Ophthalmic Fellow USA The Retina Group of Washington
Ophthalmic Service Fairfax VA
Geneva University David M Mills MD USA
Geneva Oculofacial Plastic, Reconstructive, and
Switzerland Cosmetic Surgeon Timothy G Murray MD MBA FACS
Nicolitz Eye Consultants Professor of Ophthalmology
Dale R Meyer MD Jacksonville FL Department of Ophthalmology
Director, Ophthalmic Plastic Surgery USA Bascom Palmer Eye Institute
Professor of Ophthalmology Miami FL
Lions Eye Institute Monte D Mills MD USA
Albany Medical Center Chief, Division of Ophthalmology
Albany NY Children’s Hospital of Philadelphia Philip I Murray PhD FRCP FRCS FRCOphth
USA Philadelphia PA Professor of Ophthalmology
USA Academic Unit of Ophthalmology
Catherine B Meyerle MD Birmingham and Midland Eye Centre
Retinal Physician Tatyana Milman MD City Hospital NHS Trust
National Eye Institute Assistant Professor of Ophthalmology Birmingham
National Institutes of Health Co-director, Ophthalmic Pathology Division United Kingdom
Bethesda MD Institute of Ophthalmology and Visual
USA Science Karina Nagao MD
UMDNJ-New Jersey Medical School Harvard Medical School
William F Mieler MD Newark NJ Boston MA
Professor and Chairman USA USA
Department of Ophthalmology and Visual
Science Lylas Mogk MD Jay Neitz PhD
University of Chicago Director R D and Linda Peters Professor
Chicago IL Visual Rehabilitation and Research Center Department of Ophthalmology
USA Henry Ford Health System Medical College of Wisconsin
Livonia MI Milwaukee WI
Michael Migliori MD USA USA
Clinical Associate Professor
The Warren Alpert Medical School Marja Mogk PhD Maureen Neitz PhD
Brown University Assistant Professor of English Richard O Schultz-Ruth A
Providence RI California Lutheran University Works-Ophthalmology Research Professor
USA Los Angeles CA The Eye Institute
USA Medical College of Wisconsin
Martin C Mihm Jr, MD Milwaukee WI
Clinical Professor of Pathology Jordi Monés MD USA
Senior Dermatopathologist Associate Professor of Ophthalmology
The Pigmented Lesion Clinic Institut de la Macula i de la Retina Peter A Netland MD PhD
Massachusetts General Hospital Barcelona Siegal Professor of Ophthalmology, Director
Boston MA Spain of Glaucoma, Academic Vice-Chair
USA Department of Ophthalmology
Robert Montes-Micó OD MPhil Hamilton Eye Institute
Darlene Miller DHSc MPH SM CIC Optica University of Tennessee Health Science
Research Assistant Professor Facultat de Fisica Center
Scientific Director Universidad de Valencia Memphis TN
Abrams Ocular Microbiology Laboratory Valencia USA
Bascom Palmer Eye Institute Spain
Anne Bates Leach Eye Hospital Arthur H Neufeld PhD
Miller School of Medicine Christie L Morse MD Professor of Ophthalmology
University of Miami Concord Eye Care Forsythe Laboratory for the Investigation of
Miami FL Concord NH Aging Retina
USA USA Northwestern University Fienberg School of
Medicine
David Miller MD Asa D Morton MD Chicago IL
Associate Clinical Professor of Ophthamology Eye Care of San Diego/CA Laser Vision, Inc USA
Department of Ophthalmology Escondido CA
Harvard Medical School USA Nancy J Newman MD
Jamaica Plain MA Professor of Ophtalmology and Neurology
Anne Moskowitz OD PhD Neuro-Ophthalmology Unit
USA Research Associate in Ophthalmology Emory Eye Center
Joan W Miller MD Children’s Hospital, Boston Atlanta GA
Henry Willard Williams Professor of Instructor of Ophthalmology USA
Ophthalmology Harvard Medical School
Chief and Chair, Department of Boston MA Eugene W M Ng MD
Ophthalmology USA Eyetech Pharmaceuticals, Inc
Massachusetts Eye and Ear Infirmary New York NY
Shizuo Mukai MD USA
Harvard Medical School Assistant Professor of Ophthalmology
Boston MA Massachusetts Eye and Ear Infirmary
USA Harvard Medical School
Boston MA
xxxvi USA
 List of Contributors

Quan Dong Nguyen MD MSc Yen Hoong Ooi MD Louis R Pasquale MD

Assistant Professor of Ophthalmology c/o Douglas Rhee MD Co-Director, Glaucoma Service
Diseases of the Retina and Vitreous, and Massachusetts Eye and Ear Infirmary Assistant Professor of Ophthalmology
Uveitis Harvard Medical School Department of Ophthalmology
Wilmer Eye Institute Boston MA Massachusetts Eye and Ear Infirmary
Johns Hopkins Hospital USA Harvard Medical School
Baltimore MD Boston MA
USA E Mitchel Opremcak MD USA
Clinical Associate Professor
Jerry Y Niederkorn PhD Department of Ophthalmology Neha N Patel MD
Professor of Ophthalmology Ohio State University College of Medicine Resident
Department of Ophthalmology Columbus OH Department of Ophthalmic and Visual
University of Texas Southwestern Medical USA Science
Center University of Chicago
Dallas TX George Ousler BS Chicago IL
USA Director USA
Dry Eye Department
Robert J Noecker MD Ophthalmic Research Associates Sayjal J Patel MD
Vice Chair, Clinical Affairs North Andover MA Wilmer Eye Institute
Eye and Ear Institute USA Baltimore MD
Associate Professor USA
University of Pittsburgh School of Medicine Randall R Ozment MD
Pittsburgh PA Physician Thomas D Patrianakos DO
USA Dublin Eye Associates Attending Physician
Dublin GA Division of Ophthalmology
Robert B Nussenblatt MD MPH USA John H Stroger Hospital of Cook County
Scientific Director and Chief, Laboratory of Chicago IL
Immunology, Intramural Program Samuel Packer MD USA
Section Head, Clinical Immunology Section Professor of Clinical Ophthalmology,
National Eye Institute New York University School of Medicine James R Patrinely MD FACS
National Institutes of Health Chair, Department of Ophthalmology Plastic Eye Surgery Associates PLLC
Bethesda MD North Shore Long Island Jewish Health Houston TX
USA System USA
New York NY
Joan M O’Brien MD USA Deborah Pavan-Langston MD FACS
Professor of Ophthalmology and Pediatrics Associate Professor of Ophthalmology
Director of Ocular Oncology Millicent L Palmer MD Surgeon and Director of Clinical Virology
Division of Ophthalmology Associate Professor, Department of Surgery Massachusetts Eye and Ear Infirmary
University of California San Francisco Creighton University Medical School Harvard School of Medicine
Medical Center Division of Ophthalmology Boston MA
San Francisco CA Creighton University Medical Center USA
USA Omaha NE
USA Eli Peli MSc OD
Paul D O’Brien FRCSI MRCOphth MMedSci Professor of Ophthalmology
Specialist Registrar in Ophthalmology George N Papaliodis MD Harvard Medical School
Royal Victoria Eye and Ear Hospital Instructor in Ophthalmology and Internal Moakley Scholar in Aging Eye Research
Dublin Medicine Schepens Eye Research Institute
Ireland Massachusetts Eye and Ear Infirmary Boston MA
Harvard Medical School USA
Terrence P O’Brien MD Boston MA
Professor of Ophthalmology USA Susan M Pepin MD
Charlotte Breyer Rodgers Distinguished Chair Assistant Professor of Surgery
in Ophthalmology D J John Park MD Section of Ophthalmology
Director of the Refractive Surgery Service Resident Dartmouth Hitchcock Medical Center
Bascom Palmer Eye Institute Department of Plastics and Reconstructive Lebanon NH
Palm Beach FL Surgery USA
USA University of California
Victor L Perez MD
Irvine CA
Assistant Professor
Denis O’Day MD FACS USA
Bascom Palmer Eye Institute
Professor of Ophthalmology
David W Parke II MD University of Miami School of Medicine
Department of Ophthalmology
Edward L Gaylord Professor and Chairman Miami FL
Vanderbilt Eye Institute
Department of Ophthalmology USA
Nashville TN
USA President and CEO Juan J Pérez-Santonja MD PhD
The Dean A McGee Eye Institute Instituto Oftalmológico de Alicante
R Joseph Olk MD Oklahoma City OK Alicante
Bond Eye Associates USA Spain
Peoria IL
USA Cameron F Parsa MD John R Perfect MD
Assistant Professor of Ophthalmology Director, Duke University Mycology Research
Karl R Olsen MD Krieger Children’s Eye Center Unit (DUMRU)
Clinical Assistant Professor of Ophthalmology The Wilmer Eye Institute Division of Infectious Diseases
University of Pittsburgh School of Medicine Baltimore MD Department of Medicine
Retina Vitreous Consultants USA Duke University
Pittsbrugh PA Winston-Salem NC
USA M Andrew Parsons FRCPath
Honorary Consultant in Ophthalmic USA
Sumru Onal MD Pathology
Department of Ophthalmology Academic Unit of Pathology
Marmara University School of Medicine Royal Hallamshire Hospital
Istanbul Sheffield
Turkey United Kingdom xxxvii
 List of Contributors

Henry D Perry MD FACS Valerie Purvin MD Elias Reichel MD

Founding Partner Clinical Professor of Ophthalmology & Associate Professor of Ophthalmology
Director: Cornea Division Neurology Vitreoretinal Diseases
Ophthalmic Consultants of Long Island Departments of Ophthalmology and New England Eye Center
Rockville Center NY Neurology Tufts University School of Medicine
USA Indiana Medical Center Boston MA
Indianapolis IN USA
Joram Piatigorsky PhD USA
Chief Martin H Reinke MD
Laboratory of Molecular and Developmental David A Quillen MD Private Practice
Biology George and Barbara Blankenship Professor Southlake TX
National Eye Institute - National Institute of and Chair USA
Health Department of Ophthalmology
Bethesda MD Penn State College of Medicine Douglas Rhee MD
USA Hershey PA Assistant Professor of Ophthalmology
USA Department of Ophthalmology
Dante Pieramici MD Massachusetts Eye and Ear Infirmary
Co-Director Graham E Quinn MD Harvard Medical School
California Retina Consultants Attending Surgeon, Research Fellow Boston MA
Santa Barbara CA Department of Ophthalmology USA
USA The Childrens Hospital of Philadelphia
Philadelphia PA Claudia U Richter MD
Eric A Pierce MD PhD Ophthalmic Consultants of Boston
Assistant Professor of Ophthalmology USA
Boston MA
F.M. Kirby Center for Molecular Melvin D Rabena BSc USA
Ophthalmology Director of Research
Scheie Eye Institute California Retina Consultants Joseph F Rizzo lll MD
University of Pennsylvania School of Medicine Santa Barbara CA Associate Professor of Ophthalmology
Philadelphia PA USA Massachusetts Eye and Ear Infirmary
USA Harvard Medical School
James L Rae PhD Boston MA
Roberto Pineda II MD Professor of Ophthalmology and Physiology USA
Assistant Professor Physiology and Biomedical Engineering
Massachusetts Eye and Ear Infirmary Mayo Clinic Richard M Robb MD
Chief of Ophthalmology, Brigham & Women’s Rochester MN Associate Professor of Ophthalmology
Hospital, Boston USA Harvard Medical School
Assistant Professor, Department of Department of Ophthalmology
Ophthalmology, Harvard Medical School Michael B Raizman MD Children’s Hospital Boston
Boston MA Ophthalmic Consultant Boston MA
USA Ophthalmic Consultants Of Boston USA
Associate Professor of Ophthalmology
Misha L Pless MD Tafts University School of Medicine Anja C Roden MD
Director, Division of General Neurology Boston MA c/o Diva R Salomao MD
Massachusetts General Hospital USA Department of Pathology
Boston MA Mayo Clinic
USA Alessandro Randazzo MD Rochester MN
Department of Ophthalmology USA
Howard D Pomeranz MD PhD Istituto Clinico Humanitas Rozzano
Clinical Associate Professor Milano University I Rand Rodgers MD
Department of Ophthalmology Milan Assistant Clinical Professor, Mount Sinai
North Shore Long Island Jewish Health Italy Medical Center
System Director of Ophthalmic Facial and Plastic
Great Neck NY Narsing A Rao MD Surgery
USA Professor of Ophthalmology and Pathology North Shore University Hospital NYU
Doheny Eye Institute Private Practice
Constantin J Pournaras MD University of California New York NY
Department of Ophthalmology Los Angeles CA USA
Geneva University Hospitals USA
Geneva Merlyn M Rodrigues MD PhD
Switzerland Christopher J Rapuano MD c/o Kelly S Keefe MD
Co-Director Cornea Service Naval Medical Center
William Power MBBCH FRCS FRCOphth Co-Director Professor of Ophthalmology, San Diego CA
Consultant Ophthalmic Surgeon Jefferson Medical College USA
Blackrock Clinic Thomas Jefferson University
Blackrock Co-Director, Cornea Service Yonina Ron MD
Co Dublin Refractive Surgery Department Department of Ophthalmology
Ireland Wills Eye Hospital Rabin Medical Center
Philadelphia PA Beilinson Campus
Manvi Prakash MD Petah Tiqva
Postdoctoral Fellow USA
Israel
Joslin Diabetes Center Sherman W Reeves MD MPH
Beetham Eye Institute Cornea, External Disease and Retractive Geoffrey E Rose DSC MS MRCP FRCS
Harvard Medical School Surgery FRCOphth
Boston MA Minnesota Eye Consultants Consultant Ophthalmic Surgeon
USA Minneapolis MN Adnexal Department
USA Moorfields Eye Hospital
Anita G Prasad MD London
Department of Ophthalmology and Visual Carl D Regillo MD FACS United Kingdom
Sciences Professor of Ophthalmology
Washington University Medical School Wills Eye Hospital
St Louis MO Philadelphia PA
xxxviii USA USA
 List of Contributors

Emanuel S Rosen MD FRCS FRCOphth Mark S Ruttum MD Michael A Sandberg PhD

Consultant Ophthalmic Surgeon Professor of Ophthalmology Associate Professor of Ophthalmology
Manchester Central Health Care Authority Head, Pediatric Ophthalmology and Adult Berman-Gund Laboratory
Manchester Strabismus Section Massachusetts Eye and Ear Infirmary
United Kingdom Medical College of Wisconsin Harvard Medical School
Milwaukee WI Boston MA
James T Rosenbaum MD USA USA
Professor of Medicine, Ophthalmology and
Cell Biology Allan R Rutzen MD FACS Virender S Sangwan MD
Chief, Division of Arthritis and Rheumatic Associate Professor of Ophthalmology Head, Cornea and Anterior Segment Services
Diseases Department of Ophthalmology L V Prasad Eye Institute
Director, Uveitis Clinic Casey Eye Institute University of Maryland Hyderabad
Oregon Health and Science University Baltimore MD India
Portland OR USA
Maria A Saornil MD
USA
Edward T Ryan MD Ocular Pathology Unit
Perry Rosenthal MD Director, Tropical & Geographic Medicine Hospital Clinico Universitario
Assistant Clinical Professor of Ophthalmology Center Valladolid
Department of Ophthalmology Massachusetts General Hospital Spain
Boston Foundation for Sight Associate Professor of Medicine Joseph W Sassani MD
Boston MA Harvard Medical School Professor of Ophthalmology and Pathology
USA Assistant Professor Pennsylvania State University
Dept of Immunology and Infectious Diseases Hershey Medical Center
Strutha C Rouse II MD Harvard School of Public Health
Horizon Eye Care Hershey PA
Boston MA USA
Charlotte NC USA
USA Rony R Sayegh MD
Alfredo A Sadun MD PhD Research Fellow
Barry W Rovner MD Thornton Professor of Ophthalmology and
Professor & Medical Director Cornea and Refractive Surgery Service
Neurosurgery Massachusetts Eye and Ear Infirmary
Department of Psychiatry and Human Doheny Eye Institute
Behavior Department of Ophthalmology
Kech School of Medicine Boston MA
Thomas Jefferson University University of California
Philadelphia PA USA
Los Angeles CA
USA USA Andrew P Schachat MD
Malgorzata Rozanowska PhD Vice Chairman for Clinical Affairs
José-Alain Sahel MD Cole Eye Institute
Lecturer Professor of Ophthalmology
School of Optometry and Vision Sciences Cleveland Clinic Foundation
Head, Laboratory of Retinal Pathobiology Cleveland OH
Cardiff University University Louis Pasteur
Cardiff USA
Strasbourg
United Kingdom France Wiley A Schell MD
Michael P Rubin MD Director, Medical Mycology Research Center
Leorey Saligan MD Assistant Professor of Medicine Department
Fellow in Vitreoretinal Diseases and Surgery Nurse Practitioner
Massachusetts Eye and Ear Infirmary, of Medicine
National Eye Institute Division of Infectious Diseases and
Harvard Medical School National Institutes of Health
Boston MA International Health
Bethesda MD Duke University Medical Center
USA USA Durham NC
Peter A D Rubin MD FACS Sarwat Salim MD FACS USA
Eye Plastics Consultant Assistant Clinical Professor of Ophthalmology
Brookline MA Amy C Schefler MD
Yale Eye Center Resident in Ophthalmology
Associate Clinical Professor Yale University School of Medicine
Harvard Medical School Bascom Palmer Eye Institute
New Haven CT Miami FL
USA USA USA
Shimon Rumelt MD John F Salmon MD FRCS FRCOphth
Attending Physician Tina Scheufele MD
Consultant Ophthalmic Surgeon Vitreoretinal Surgeon
Ophthalmology Department The Radcliffe Infirmary
Western Galilee - Nahariya Medical Center Ophthalmic Consultants of Boston
Oxford Eye Hospital Boston MA
Nahariya Oxford
Israel USA
United Kingdom
Anil K Rustgi MD Vivian Schiedler MD
Diva R Salomão MD Oculoplastic and Orbital Surgeon,
Professor of Medicine and Genetics Associate Professor of Pathology
Chief of Gastroenterology Charlottesville, VA
Department of Pathology Ophthalmic Plastic & Reconstructive Surgery
University of Pennsylvania Medical Center Mayo Clinic
Philadelphia PA Fellow
Rochester MN Department of Ophthalmology
USA USA University of Washington
Tina Rutar MD David Sami MD Seattle WA
Resident Division Chief for PSF Ophthalmology USA
Department of Ophthalmology CHOC Children’s Hospital
University of California San Francisco Gretchen Schneider MD
Orange CA Adjunct Assistant Professor in the Genetic
San Francisco CA USA
USA Counseling program
Genetic Counseling Faculty
Brandeis University
Waltham MA
USA
xxxix
 List of Contributors

Alison Schroeder BA Irina Serbanescu BA Bradford J Shingleton MD

Laboratory Manager Research Assistant Clinical Professor of
Department of Ophthalmology Division of neurology Ophthalmology, Harvard Medical School
Boston University School of Medicine The Hospital for Sick Children Ophthalmic Consultants of Boston
Boston MA Toronto ON Boston MA
USA Canada USA
Ronald A Schuchard PhD Briar Sexton MD FRCSC John W Shore MD FACS
Director of Rehabilitation Research and Fellow in Neuro-Ophthalmology Texas Oculoplastics Consultants
Development Center VGH Eye Care Center Austin TX
Associate Professor Vancouver BC USA
Department of Neurology Canada
Emory University School of Medicine Lesya M Shuba MD PhD
Atlanta GA Tarek M Shaarawy MD Assistant Professor
USA Chef Department of Ophthalmology & Visual
Clinique d’ophtalmologie Sciences
Joel S Schuman MD Secteur du Glaucome Dalhousie University
Eye and Ear Foundation Professor and Hôpitaux Universitaires de Génève Halifax NS
Chairman Génève Canada
Department of Ophthalmology Switzerland
University of Pittsburgh School of Medicine Guy J Ben Simon MD
Pittsburgh PA Peter Shah BSc (Hons) MBChB FRCOphth Goldschleger Eye Institute
USA Consultant Sheba Medical Center
Birmingham and Midland Eye Centre Tel Hashomer
Ivan R Schwab MD FACS City Hospital Israel
Professor of Ophthalmology Birmingham
Department of Ophthalmology United Kingdom Richard J Simmons MD
University of California at Davis Emeritus Ophthalmic Surgeon
Sacramento CA Aron Shapiro BS Harvard Medical School
USA Director Boston MA
Anti-inflammatory/Anti-infectives Department USA
Adrienne Scott MD Ophthalmic Research Associates
Clinical Associate North Andover MA Michael Simpson
Vitreoretinal Surgery USA c/o David Miller MD
Duke University Eye Center Department of Ophthalmology
Durham NC Savitri Sharma MD MAMS Harvard Medical School
USA Associate Director, Laboratory Services Jamaica Plain MA
L V Prasad Eye Institute USA
Ingrid U Scott MD MPH Bhubaneswar, Orissa
Professor of Ophthalmology and Health India Arun D Singh MD
Evaluation Sciences Director
Department of Ophthalmology Jean Shein MD Department of Ophthalmic Oncology
Penn State College of Medicine Attending Physician Cole Eye Institute and Taussing Cancer Center
Hershey PA Crane Eye Care Hana Kukui Center Cleveland OH
USA Lihue HI USA
USA
Marvin L Sears MD Omah S Singh MD
Professor and Chairman Emeritus Debra J Shetlar MD Director
Department of Ophthalmology and Visual Associate Professor of Ophthalmology New England Eye Center
Science Baylor College of Medicine Beverley MA
Yale University School of Medicine Staff Physician USA
New Haven CT Michael E DeBakey V A Medical Center
Houston TX Karen Sisley BSc PhD
USA Non-Clinical Lecturer Ocular Oncology
USA
Johanna M Seddon MD ScD Academic Unit of Ophthalmology and
Professor of Ophthalmology M Bruce Shields MD Orthoptics
Tufts University School of Medicine Professor of Ophthalmology and Visual University of Sheffield
Director, Ophthalmic Epidemiology and Science Sheffield
Genetics Service Yale Eye Center United Kingdom
New England Eye Center New Haven CT
USA Arthur J Sit MD
Boston MA Assistant Professor of Ophthalmology
USA Carol L Shields MD Mayo Clinic
Theo Seiler MD PhD Professor of Ophthalmology, Thomas Rochester MN
Professor Jefferson Medical College USA
Institut für Refractive und Ophthalmochirurgie Attending Surgeon and Associate Director
David Smerdon FRCSEd FRCOphth
(IROC) Wills Eye Hospital
Consultant Ophthalmologist
Zürich Philadelphia PA
James Cook University Hospital
Switzerland USA
Middlesbrough
Jerry A Shields MD United Kingdom
Robert P Selkin MD
Private Practice Professor of Ophthalmology, Thomas William E Smiddy MD
Plano TX Jefferson University Professor of Ophthalmology
USA Director Department of Ophthalmology
Oncology Services Bascom Palmer Eye Institute
Richard D Semba MD MA MPH Wills Eye Hospital Miami FL
W Richard Green Professor of Philadelphia PA USA
Ophthalmology USA
Wilmer Eye Institute
Baltimore MD
USA
xl
 List of Contributors

Ronald E Smith MD Tomy Starck MD Timothy J Sullivan FRANZCO FRACS

Professor and Chair Director Eyelid, Lacrimal and Orbital Clinic
Department of Ophthalmology UltraVision Center Department of Ophthalmology
Keck School of Medicine of USC San Antonio TX Royal Brisbane Hospital
Los Angeles CA USA Herston QLD
USA Australia
Walter J Stark MD
Terry J Smith MD Professor of Ophthalmology Jennifer K Sun MD
Professor and Head Director of the Stark-Mosher Center Lecturer
Division of Molecular Medicine The John Hopkins Hospital, Wilmer Eye Joslin Diabetes Center
David Geffen School of Medicine Institute Beetham Eye Institute
Harbor-UCLA Medical Center Baltimore MD Harvard Medical School
Torrance CA USA Boston MA
USA USA
Joshua D Stein MD MS
Neal G Snebold MD Assistant Professor Janet S Sunness MD
Ophthalmologist Department of Ophthalmology and Visual Medical Director
Massachusetts Eye and Ear Infirmary Sciences Richard E Hoover Rehabilitation Services for
Harvard Medical School Kellogg Eye Center Low Vision and Blindness
Boston MA Ann Arbor MI Greater Baltimore Medical Center
USA USA Baltimore MD
Lucia Sobrin MD USA
Roger F Steinert MD
Instructor of Ophthalmology Professor of Ophthalmology and Biomedical Francis C Sutula MD
Retina and Uvetis Services Engineering Milford Eye Care
Massachusetts Eye and Ear Infirmary Director of Cornea, Refractive and Cataract Milford MA
Harvard Medical School Surgery USA
Boston MA Vice Chair of Clinical Ophthalmology
USA Department of Ophthalmology Nasreen A Syed MD
University of California Irvine Assistant Professor, Ophthalmology and
John A Sorenson MD Pathology
Attenting Surgeon Irvine CA
USA Department of Ophthalmology and Visual
Vitreoretinal Service Sciences
Manhattan Eye, Ear, and Throat Hospital Leon Strauss MD University of Iowa
New York NY Instructor Iowa City IA
USA Wilmer Eye Institute USA
Sarkis H Soukiasian MD John Hopkins University School of Medicine
Baltimore MD Christopher N Ta MD
Director: Cornea and External Disease
USA Associate Professor of Ophthalmology
Director: Ocular Inflammation and Uveitis
Department of Ophthalmology
Lahey Clinic
Barbara W Streeten MD Stanford University
Burlington MA
Professor of Ophthalmology and Pathology Palo Alto CA
USA
State University of New York USA
George L Spaeth MD FRCO FACS Upstate Medical University
Louis Esposito Research Professor of Syracuse NY Hidehiro Takei MD
Ophthalmology USA Staff Pathologist
Jefferson Medical College Department of Pathology
Director of the William & Anna Goldberg J Wayne Streilein MD (deceased) The Methodist Hospital
Glaucoma Service Formerly Senior Scientist, President, Charles Houston TX
Wills Eye Institute L Schepens Professor of Ophthalmology, USA
Philadelphia PA Professor of Dermatology
Formerly Vice Chair for Research, Jonathan H Talamo MD
USA Associate Clinical Professor of
Department of Ophthalmology
Richard F Spaide MD Harvard Medical School Ophthalmology
Associate Clinical Professor of Ophthalmology Boston MA Department of Ophthalmology
Manhattan Eye, Ear, and Throat Hospital USA Harvard Medical School
New York NY Waltham MA
USA James D Strong CRA USA
Senior Ophthalmic Imager
Monika Srivastava MD Department of Ophthalmology Richard R Tamesis MD
Clinical Assistant Professor Penn State Milton S Hershey Medical Center Department of Ophthalmology
Department of Dermatology Hershey PA Loma Linda University Medical Center
New York University USA Loma Linda CA
New York NY USA
USA Ilene K Sugino MS
Director, Ocular Cell Transplantation Madhura Tamhankar MD
Sunil K Srivastava MD Laboratory Associate Professor
Assistant Professor of Ophthalmology Institute of Ophthalmology and Visual Science Department of Ophthalmology
Section of Vitreoretinal Surgery & Disease New Jersey Medical School University of Pennsylvania Medical School
Emory Eye Center Newark NJ Philadelphia PA
Atlanta GA USA USA
USA Kristen J Tarbet MD SACS
Eric B Suhler MD MPH
Alexandros N Stangos MD Chief of Ophthalmology Private Practice
Division of Ophthalmology Portland VA Medical Center Bellevue WA
Department of Clinical Neurosciences Assistant Professor of Ophthalmology and USA
University Hospitals of Geneva Co-director
Geneva Department of Ophthalmology
Switzerland Casey Eye Institute
Portland OR
USA
xli
 List of Contributors

Michelle Tarver-Carr MD PhD Gail Torkildsen MD Russell N Van Gelder MD PhD

Assistant, Ocular Immunology Physician Associate Professor of Ophthalmology and
Wilmer Eye Institute Andover Eye Associates Visual Sciences
Departments of Medicine and Epidemiology Andover MA Department of Ophthalmology and Visual
Johns Hopkins University School of Medicine USA Sciences
Baltimore MD Washington University School of Medicine
USA Cynthia A Toth MD St Louis MO
Associate Professor of Ophthalmology and USA
Mark A Terry MD Biomedical Engineering
Director, Corneal Services Duke Eye Center Gregory P Van Stavern MD
Clinical Professor, Department of Durham NC Assitant Professor of Ophthalmology,
Ophthalmology USA Neurology and Nerosurgery
Devers Eye Institute Kresge Eye Institute
Oregon Health Sciences University Elias I Traboulsi MD Wayne State University
Portland OR Professor of Ophthalmology Detroit MI
USA The Cole Eye Institute USA
Cleveland OH
Joseph M Thomas MD USA Deborah K Vander Veen MD
Associate Clinical Professor Assistant Professor
Department of Neurology Michele Trucksis PhD MD Department of Ophthalmology
Case Western Reserve University School of Associate Clinical Professor Children’s Hospital and Harvard Medical
Medicine Harvard Medical School School
Cleveland OH Associate Director Clinical Pharmacology Boston MA
USA Merck & Co. Inc USA
Boston MA
Vance Thompson MD USA Demetrios Vavvas MD PhD
Assistant Professor of Medicine Instructor in Ophthalmology
University of South Dakota School of James C Tsai MD Retina Service Department of Ophthalmology
Medicine Robert R Young Professor and Chairman Massachusetts Eye and Ear Infirmary
Director of Refractive Surgery Department of Ophthalmology and Visual Harvard Medical School
Sioux Valley Clinic Science Boston MA
Vance Thompson Vision Yale University School of Medicine USA
Sioux Falls SD New Haven CT
USA USA David H Verity MA FRC Ophth
Consultant Ophthalmic Surgeon
Jennifer E Thorne MD PhD Julie H Tsai MD Adnexal Departments
Assistant Professor of Ophthalmology Assistant Professor Moorfields Eye Hospital
Division of Ocular Immunology Department of Ophthalmology London
Wilmer Eye Institute University of South Carolina School of United Kingdom
Baltimore MD Medicine
USA Columbia SC Paolo Vinciguerra MD
USA Medical Director
Matthew J Thurtell BSc(Med) MBBS MScMed Studio Oculistico Vincieye SRL
Neuro-Ophthalmology Fellow David T Tse MD FACS Milan
Department of Neurology Professor of Ophthalmology Italy
Royal Prince Albert Hospital Department of Ophthalmology
Sydney NSW Bascom Palmer Eye Institute Paul F Vinger MD
Australia Miami FL Clinical Professor
USA Ophthalmology
David P Tingey MD FRCSC Tufts University School of Medicine
Associate Professor Scheffer C G Tseng MD PhD New England Medical Center
Ivey Eye Institute Research Director Boston MA
London Health Sciences Center Ocular Surface Center USA
London ON Miami FL
Canada USA Nicholas J Volpe MD
Professor of Ophthalmology and Neurology
King W To MD Elmer Y Tu MD Vice Chair and Residency Program Director
Clinical Professor of Ophthalmology Associate Professor of Clinical Department of Ophthalmology
Brown University School of Medicine Ophthalmology PENN Eye Care
Barrington RI Director of the Cornea and External Disease Philadelphia PA
USA Service USA
Department of Ophthalmology
Faisal M Tobaigy MD University of Illinois at Chicago Werner Wackernagel MD
Department of Ophthalmology Chicago IL Physician
Massachusetts Eye and Ear Infirmary and the USA Department of Ophthalmology
Schepens Eye Research Institute Medical University Graz
Harvard Medical School Ira J Udell MD Graz
Boston MA Professor of Ophthalmology Austria
USA Albert Einstein College of Medicine
New York NY Sonal Desai Wadhwa MD
Michael J Tolentino MD USA Assistant Professor of Ophthalmology
Director of Research, Center for Retina and Division of Ophthalmology
Macular Disease Alejandra A Valenzuela MD University of Maryland
Center for Retina and Macular Disease Assistant Professor Baltimore MD
Winter Haven FL Department of Ophthalmology and Visual USA
USA Sciences
Dalhousie University
Melissa G Tong BSc Halifax NS
Department of Medicine Canada
Jefferson Medical College
Philadelphia PA
xlii USA
 List of Contributors

Michael D Wagoner MD Scott M Whitcup MD Jules Winokur MD

Professor of Ophthalmology Executive Vice President North Shore Long Island Jewish Health
Department of Ophthalmology and Visual Head of Research and Development System
Sciences Allegran Inc New York NY
University of Iowa Hospitals and Clinics Irvine CA USA
Iowa City IA USA
USA William J Wirostko MD
Valerie A White MD FRCPC Associate Professor of Ophthalmology
Nadia K Waheed MD Professor The Eye Institute
Fellow Department of Pathology & Laboratory Medical College of Milwaukee
Immunology and Uveitis Service Medicine, Milwaukee WI
Department of Ophthalmology University of British Columbia USA
Massachusetts Eye and Ear Infirmary Vancouver General Hospital
Harvard Medical School Vancouver BC Gadi Wollstein MD
Boston MA Canada Assistant Professor and Director
USA Ophthalmic Imaging Research Laboratories
William L White MD The Eye & Ear Institute
David S Walton MD Department of Ophthalmology Dept of Ophthalmology
Clinical Professor of Ophthalmology The Eye Foundation UPMC Eye Center
Harvard Medical School University of Missouri-Kansas City Pittsburgh PA
Boston MA Kansas City MO USA
USA USA
Albert Chak Ming Wong FCOph(HK)
Martin Wand MD Jason Wickens MD FHKAM(Ophth)
Clinical Professor of Ophthalmology Barnes Retina Institute Associate Consultant
University of Connecticut School of Medicine Department of Ophthalmology Caritas Medical Center
Farmington CT Washington University School of Medicine Shamshuipo, Kowloon
USA St Louis MO Hong King
USA China
Jie Jin Wang MMed PhD
Associate Professor of Epidemiology Janey L Wiggs MD PhD Tien Y Wong MBBS MMED (Ophth) FRCSE
Westmead Millennium Institute Associate Professor of Ophthalmology FRANZCO FAFPHM MPH PhD
University of Sydney Massachusetts Eye and Ear Infirmary Professor of Ophthalmology
Sydney NSW Harvard Medical School Department of Ophthalmology & Centre for
Australia Boston MA Eye Research Australia
USA University of Melbourne
Scott M Warden MD East Melbourne VIC
Retina Service Jacob T Wilensky MD Australia
Massachusetts Eye and Ear Infirmary Professor of Ophthalmology
Department of Ophthalmology Director, Glaucoma Service John J Woog MD FACS
Harvard Medical School University of Illinois College of Medicine Associate Professor of Ophthalmology,
Boston MA Chicago IL Ophthalmic Plastic and Reconstructive
USA USA Surgery
Department of Ophthalmology
Lennox Webb FRCOphth FRCS(Ed) Charles P Wilkinson MD Mayo Clinic
Consultant Ophthalmic Surgeon Chairman, Department of Ophthalmology Rochester MN
Royal Alexandra Hospital Greater Baltimore Medical Center USA
Paisley Professor, Department of Ophthalmology
United Kingdom John Hopkins University Michael Wride PhD
Baltimore MD Lecturer
David Weber MD USA School of Optemetry and Vision Sciences
Assistant Professor Cardiff University
Department of Physical Medicine & Patrick D Williams MD Cardiff
Rehabilitation Vitreo Retinal Specialist United Kingdom
Mayo Clinic College of Medicine Texas Retina Associates
Rochester MN Arlington TX Carolyn S Wu MD
USA USA Instructor of Ophthalmology
Harvard Medical School
Daniel Wee MD David J Wilson MD Boston MA
Department of Ophthalmology Associate Professor USA
The Palmetto Health/ University of South Department of Ophthalmology;
Carolina School of Medicine Director, Christensen Eye Pathology Darrell WuDunn MD PhD
Columbia SC Laboratory Associate Professor of Ophthalmology
USA Casey Eye Institute Indiana University School of Medicine
Oregon Health Sciences University Indianapolis IN
Corey B Westerfeld MD Portland OR USA
Research Fellow USA
Department of Ophthalmology Jean Yang MD
Massachusetts Eye and Ear Infirmary M Roy Wilson MD MS Department of Ophthalmology
Harvard Medical School Chancellor North Shore-Long Island Jewish Medical
Boston MA University of Colorado and Health Sciences Center
USA Center Great Neck NY
Denver CO USA
Christopher T Westfall MD USA
Professor of Ophthalmology Lawrence A Yannuzzi MD
Jones Eye Institute & Arkansas Children’s Steven E Wilson MD Vice-Chairman, Department of
Hospital Director of Corneal Research and Professor Ophthalmology
University of Arkansas for Medical Sciences of Ophthalmology Director of Retinal Services
Little Rock AR The Cleveland Clinic Foundation Manhattan Eye, Ear and Throat Hospital
USA Cole Eye Institute New York NY
Cleveland OH USA
USA xliii
 List of Contributors

Michael J Yaremchuk MD Jenny Y Yu MD Marco Zarbin MD PhD FACS

Clinical Professor of Surgery Consulting Physician Professor of Ophthalmology and
Harvard Medical School Department of Ophthalmology Neuroscience
Boston MA UPMC Children’s Hospital of Pittsburgh Department of Ophthalmology
USA Pittsburgh PA Institute of Ophthalmology and Visual
USA Science
R Patrick Yeatts MD FACS University of Medicine and Dentistry,
Professor and Vice Chairman Beatrice Y J T Yue PhD New Jersey
Department of Ophthalmology Thanis A Field Professor of Ophthamology Newark NJ
Wake Forest University Eye Center Department of Ophthalmology & Visual USA
Winston-Salem NC Sciences
USA University of Illinois at Chicago Leonidas Zografos MD
Chicago IL Professor and Chairman
Richard W Yee MD USA Jules Gonin Eye Hospital
Medical Director LADARVISION Center Lausanne
Hermann Eye Center Charles M Zacks MD Switzerland
Memorial Hermann Hospital Corneal Specialist
Houston TX Maine Eye Center Christopher I Zoumalan MD
USA Portland ME Resident in Ophthalmology
USA Department of Ophthalmology
Steven Yeh MD Stanford University Medical Center
Clinical Fellow Bruce M Zagelbaum MD FACS Stanford CA
Uveitis and Ocular Immunology Associate Clinical Professor of USA
Laboratory of Immunology Ophthalmology
National Eye Institute New York University School of Medicine
National Institute of Health New York NY
Bethesda MD USA
USA
Maryam Zamani MD
Lucy H Y Young MD PhD FACS Oculoplastic Fellow
Associate Professor London
Massachusetts Eye and Ear Infirmary United Kingdom
Harvard Medical School
Boston MA
USA

xliv
SECTION 10 RETINA AND VITREOUS
Edited by Barbara A. Blodi
CHAPTER
122 Functional Anatomy of the Neural Retina
Robert E. Marc
Overview
This chapter provides an outline of the organization of the
mammalian retina, with a strong focus on primate vision and in
the context of a nearly complete cellular catalog and extensive
new understanding of the molecular diversity of signaling
pathways. The mammalian neural retina, albeit simplified by
evolutionary losses in cone-driven pathways, is proving to be
more complex than anticipated, with over 60 classes of neurons,
yielding at least 15 and perhaps 20 different ganglion cell ‘filters’
for the visual world. Elucidating the wiring of these filters for any
retina remains a major challenge. Though several canonical
signaling pathways have been mapped (including a novel
scotopic path), we have not been able to reconstruct the likely
networks of most of the filters. New discoveries regarding the
molecular mechanisms of red and green cone visual pigment
expression have profound implications for the development of
color-selective circuits and color vision. A new ganglion cell class
has intrinsic phototransduction mediated by a novel
photopigment, melanopsin, and is selectively wired to at least
three different functional pathways. Finally, the wiring of the
retina is dynamic and manifests significant connectivity changes
both under postnatal visual drive and retinal degenerations.
INTRODUCTION
The retina evolved to report spatiotemporal and chromatic
patterns of photons imaged by the eye.1 The plan of the human
neurosensory retina is generically vertebrate in form and
development, with key specializations. Photoreceptors form a
discrete photon capture screen roughly similar in scale to a
high-end color imaging chip (Fig. 122.1, panels 1–3).2
Vertebrate retinas contain rods, cones, bipolar cells (BCs),
horizontal cells (HCs), amacrine cells (ACs), association cells
(AxCs), interplexiform cells (IPCs), and ganglion cells (GCs).
Cones, BCs, and HCs connect to each other in the outer
plexiform layer (OPL). BCs, ACs, AxCs, and GCs connect in the
inner plexiform layer (IPL).
The basic vertical channel is the cone ˜ BC ˜ GC chain.
Vertical channel signals are encoded by vesicular glutamate
release (Fig. 122.2) and decoded by ionotropic or metabotropic
glutamate receptors (iGluRs, mGluRs) expressed by target
neurons.3–5 Lateral channels mediate signal comparisons
over time, space, or color via feedback and feedforward
signaling. Lateral channels are numerous and include cone ˜
HC ˜ target cell transfers in the OPL and many BC ˜ AC ˜
target cell transfers in the IPL. AC signals are largely encoded
by vesicular g-aminobutyric acid (GABA) or glycine release
(Fig. 122.2) and decoded by cognate receptors expressed on
target cells.3,6 HC signaling mechanisms remain in debate.7
Signaling in the IPL is also mediated by specialized AxCs
(previously lumped with ACs) that signal over long distances
with intraretinal axons.8 The molecular determinants of signal
amplification, signaling speed, signal integration, and memory
systems associated with synaptic transfers will be reviewed in
the context of cell-specific associations and canonical (main)
pathways that encode and decode them.
Every species has a subtly different retina reflecting its dis-
tinctive evolutionary history. Features that are diagnostically
vertebrate, mammalian, or primate will be noted when they
highlight the special attributes of human vision. This chapter
reviews the functional anatomy of primate and mammalian
neural retinas in the context of discoveries that have revolu-
tionized our understanding of the retinal cells and their associa-
tions (Box 122.1). The details of most of these discoveries are
beyond the scope of this chapter but the era of purely descriptive
neuroanatomy is past and new molecular, physiological, and
connective contexts accompany descriptions of cell class. New
technologies have revolutionized cell visualization and analysis,
including cell specific reporter gene expression,9 ballistic
labeling,10 and more. This knowledge is more than academic, as
studies of animal models of human disease have revealed new
dynamics in retinal neuroanatomy.11,12 Neurodegenerative
brain disorders and some slow photoreceptor degenerations
similarly involve protein misfolding and proteasome stress.13 In
retina, as in brain, this stress induces anomalous neural rewiring.
Ultimately, devising interventions that ameliorate vision
impairment in macular degeneration, retinitis pigmentosa (RP),
glaucoma, or vasculopathies will require in-depth understand-
ing of the molecular nuances of contact specificity, signaling,
cell form, and cell patterning in the retina.
THE EVOLUTIONARY CONTEXT
INTRODUCTION
Molecular biology has added new rigor to comparative biology.
It is now clear that the mammalian retina reflects a major
evolutionary reduction in neuronal diversity and a simpler
structure than those of most other vertebrates. The genetics of
that reduction is linked to an array of inherited eye defects.
Every distinctive mammalian feature has been shaped by an
evolutionary bottleneck that occurred over 200 million years
(MY) ago in the late Triassic/early Jurassic as stem radiations of
therapsid reptiles gave rise to early mammals (Fig. 122.3). This
included the collapse of the ancestral mammalian axial
skeleton, cranium, and visual system.
This sequence from early amniotes to mammals is the most
fully documented of the major transitions in vertebrate
evolution. The entire skeleton was modified, as was the soft
anatomy, behavior, and physiology down to the level of cellular 1565
 RETINA AND VITREOUS
SECTION 3
FIGURE 122.1. Cellular elements of the parafoveal primate retina
(vertical plane, left panel; serial horizontal planes 1–7 at right).
Schematics of cells are layered onto a computationally enhanced
toluidine blue thin section of baboon retina (http://prometheus.med.
utah.edu/imagery.html) taken at ~10° eccentricity. The vascular supply
for the sensory retina distal to the ELM is formed by the choroid (CH)
and the choriocapillaris (CC), apposed to the basal surface of the RPE.
Black cells in the CH are resident melanocytes; RPE cells contain dark
melanosomes. The vascular supply for the neural retina proximal to the
ELM is formed by capillary nets in the horizontal cell layer (HCL),
amacrine cell layer (ACL) and distal GCL. Capillary lumens are marked
with asterisks. Rod and cone outer segments (ros, cos) form a discrete
layer (OSL) and abut the apical face of the RPE. Rod and cone inner
segments extend to the OPL where they form their synaptic terminals:
rod spherules and cone pedicles. Cones (tinted red, green, and blue)
contact sets of ON and OFF BCs and the somas of HCs (e.g., H1 HCs),
while rods (white) contact only rod BCs and the axon terminals of HCs
(H1ATs). Cones distal to the ELM are gently tilted in the periphery
proportional to their displacement from the visual axis. It is thought that
they ‘point’ toward the nodal point of the eye at all eccentricities. The
slight curvature is a defect of tissue processing. Cone BCs send their
axons into the IPL to contact specific classes of cone GCs, while rod
BCs contact rod-specific ACs. The INL in primate retina can be clearly
divided into discrete HC, BC, MC and AC layers (HCL, BCL, MCL,
ACL). The IPL is segmented into sublayers specific for the output
synapses of OFF cone BCs (sublayer a), ON cone BCs (sublayer b), and
rod BCs (sublayer c). The supporting glial MCs span the neural retina
from the ELM to the inner limiting membrane (ILM), sealing the optic
fiber layer (OFL) and GC layer (GCL) from the vitreous. Right: Seven
horizontal plane views of the primate retina viewed as 30 mm µ 30 mm
patches. Panel 1: cone myoids in the foveola at the level ELM. Panel 2:
cone and rod myoids at ~10° in the periphery with a Bayer-filter overlay
(see text). Panel 3: cone and rod myoids at ~10° in the periphery. Panel
4: Rod spherules (cyan) interspersed with cone axons (red–yellow).
Panel 5: Cone pedicles (red–yellow) surrounded by processes of rod BC
and HC axon processes. Panel 6: HCL. H1 HCs (yellow); H2 HCs (bright
green); rod BCs (blue, r); MCs (black, m). Panel 7: GCL. Midget GCs
(Blue, M), parasol GCs (Cyan, P), starburst ACs (s, yellow). All images
1566 are at the same scale and each square is 30 mm wide.
© REM 2006.
BOX 122.1 Advances in retinal anatomy in the past
decade
• The assembly of a nearly complete cellular catalog
• The assembly of a primitive catalog of transcriptional
regulators of cell phenotype
• New connectivity implications of primate VP gene evolution
• Neuronal phototransduction in melanopsin-expressing GCs
• Neural plasticity in the developing and mature retina
• Circuitry remodeling in retinal disease
• Extensive molecular understanding of the diversity, function
and cellular dispositions of
• glutamate-gated AMPA, KA, NMDA, and mGluR
receptors
• GABA-activated and glycine-activated receptors
• glutamate, GABA, glycine, and anion transporters
• calcium channels, CNG channels, other ion channels
• connexins
• Resources of particular value
• Oyster. The Human Eye. 1999 Raven Press. A wonderful,
readable and comprehensive book on functional anatomy
of the human eye
• The Visual Neurosciences Vols 1 and 2 (Chalupa and
Werner, eds), MIT Press. 2004 A detailed treatment of
visual system signaling structures and mechanisms
• Webvision: http://webvision.med.utah.edu. A
comprehensive and dynamic resource.
metabolism. Many of these changes are demonstrated, either
directly or indirectly, through the fossil record.14
The adoption of a nocturnal, fossorial, and insectivorous
niches by early mammals triggered the loss of over half the
retinal neuron phenotypes still manifested by extant non-
mammalians (Tables 122.1 and 122.2). The dominant visual
stream was switched from the color-rich nonmammalian
collothalamic stream (retina ˜ tectum ˜ N. rotundus ˜
ectostriatum) to the largely achromatic lemnothalamic stream
(retina ˜ lateral geniculate nucleus (LGN) ˜ striate cortex).
Further, the widespread epithalamic (pineal and parapineal
parietal) pathways disappeared in mammals as functional photo-
sensitive systems. The following sections summarize the major
evolutionary revisions of mammalian and primate retinas.
THE REEVOLVED MAMMALIAN ROD CIRCUIT
Mammalian rod circuits represent a complex revision of
ancestral scotopic vision. The primary mammalian rod path-
ways are now well understood as the following stream:4,15–18
rods ˜ rod BC ˜ rod (AII) AC ˜ cone BCs ˜ cone GCs
Remarkably, this pathway loops back into cone pathways after
traversing the entire retina. It has no known antecedent in
any other vertebrate group. In most nonmammalians, rods
and cones share BCs and scotopic paths to the brain are direct:
rods ˜ BCs ˜ GCs˜ CNS.19 The mammalian rod AC must
have developed from an extant but still unknown non-
mammalian sister cell. The molecular genetics of rod pathway
development,20–22 especially comparative patterns of transcrip-
tional regulation and growth factor signaling across vertebrates,
is likely the key to discovering how the rod circuit lost direct
access to GCs. That knowledge may be central in learning how
to repair wiring anomalies in retinal degenerations.
 Functional Anatomy of the Neural Retina

FIGURE 122.2. Visualization of GABA (red), glycine (green), and glutamate (blue) signals in the primate retina. Glutamate signals are enriched in
rods, cones, BCs, and GCs. Glycine signals are preferentially enriched in a subset of ACs with sparse terminals. GABA signals are expressed by
a large subset of ACs with widely distributed terminals. Mixed GABA–glutamate magenta signals are expressed by a subset of BCs in some
primates. MCs express little or no glutamate, GABA or glycine and appear black. Each of these signatures can be resolved in the IPL as synaptic
terminals or processes from each of these cell classes (inset). The image is 0.9 mm wide.
© REM 2005.

CHAPTER 122
Paleozoic Mesozoic Cenozoic
C O S D Cm Cp P Tr J K T
Group Hyperoartia
Lampreys

Group Chondrichthyes Sharks

Skates & Rays
Ratfishes
Sturgeons
Teleosts
Group Osteichthyes Lungfishes
Frogs & Toads
Caecelians
Group Amphibia Salamanders
Turtles
Lizards
Group Reptilia Order Serpentes Snakes
Crocodilians
Group Dinosaura
Class Aves
Avians
Order Primates
Group Mammalia
Mammals
590 505 438 408 360 320 286 248 144 65 0 MY BP

FIGURE 122.3. Spectral mixtures of rods and cones mapped on the evolution of the major vertebrate taxa. Solid lines indicate a continuous
fossil record; dashes indicate gaps. Cone LWS, cone SWS1 and rod RH1 VPs (see text) evolved early and were likely expressed by Cambrian
ancestors of the lampreys (Group Hyperoartia, yellow cone, blue cone, and green rod icons). These pigments were extensively diversified during
the evolution of the Osteichthyes to include LWS cones (red icons), RH2 cones (green icons), SWS1 cones (blue icons), and SWS2 UV cones
(violet icons), as well as rods. This diversity persists in modern descendent groups (Amphibia, Reptilia, Aves). With the evolution of mammals at
200–240 MY BP (million years before present, arrow), the RH2 and SWS2 systems were lost. Roughly 20 MY BP (arrow), trichromatic primates
evolved a new green pigment from the LWS system. C, Cambrian; O, Ordivician; S, Silurian; D, Devonian; Cm, Carboniferous Mississippian; Cp,
Carboniferous Pennsylvanian; P, Permian; Tr, Triassic; J, Jurassic; K, Cretaceous; T, Tertiary.
© REM 2004.

TABLE 122.1. Retinal Attributes of the 7 Vertebrate Classes and Primates

Cl Cl Cl Cl Cl Cl Cl Order
Hyperoartia Chondrichthyes Osteichthyes Amphibia Reptilia Aves Mammalia Primates

Divergence MY < 500 450 417 500 500 500 200 200
Cone classes 3 0–2 ? 3–7 4 3–7 3–7 0–2 2–3
Rod classes 1 1 1 1–2 1–2 1 1 1
Rod pathway Direct Direct Direct Direct Direct Direct Indirect Indirect
Neuronal classes ? ? >120 >100 >100 >100 50–60 50–60
Distinct ACs, or foveas 0 0 0–1 0–1 0–1 0–2 0–1 1
Intraretinal vessels — — — — — — + +
Pineal/parietal organs 1 1 1 2 2 1 0 0
Divergence is the time in millions of years (MY) before present that the taxon is clearly identified in the fossil record. Cone classes are defined by combined opsin
expression and structural phenotype. Neuronal classes are identified by morphology.
–, absent; +, present; ?, uncertain or unknown.
1567
 RETINA AND VITREOUS
TABLE 122.2. Neuronal Diversity in Selected Mammals Compared with a Teleost Fish
Goldfish Mouse
Cone classes 7 2
Cone chromatypes 7 2
Cone visual pigments 4 2
Horizontal cells 4 1
Bipolar cells ~20 ~10
Amacrine cells >70 ? ?
Ganglion cells >20 ? ~20
REDUCTION OF THE IMAGE-FORMING CONE
COHORT TO TWO TYPES: LWS AND SWS1
SECTION 3
Old-world primate retinas express three cone classes: red-
sensitive, green-sensitive, and blue-sensitive or R, G, B cones
(Box 122.2). The massive loss of cones and reduction in cone
diversity was the prelude to creating a predominantly nocturnal
retina. Some mechanisms must have repressed cone progenitor
proliferation and enhanced rod progenitor expansion. Again,
this history is not merely of academic interest, since defects in
these genes are associated with eye degenerations. In most
nonmammalians (>95% of all vertebrate species), color-coding
pathways are constructed from 3 to 6 structurally distinct
cone types predominantly expressing one of 3–4 cone visual
pigment (VP) genes,23 as well as many distinctive neurons that
selectively contact those classes. Each cone is a member of a
chromatype: a phenotype complex that includes genes for
cone shape, patterning, and connectivity in addition to VP
expression. It would not be surprising if red and green cone
phenotypes in nonmammalians differed in expressions of tens-
to-hundreds of genes. In contrast, primate red and green cone
phenotypes may differ in only one gene: the VP.
Mammals, including primates, express cone VPs derived
from two primordial gene groups (long-wave (LWS) and short-
wave (SWS1) systems) yielding retinas with two cone chroma-
types: green-yellow and violet-blue absorbing. SWS1 cones
differ from LWS cones in timing of developmental emergence,
BOX 122.2 Issues in naming cones
• Two schemes have been used: RGB (red, green, blue) and
LMS (long-, mid-, and short-wave)
• The LMS system denotes a cone’s relative spectral peak to
avoid confusion between perceptual names (red, green, blue)
and VP absorption peaks (yellow-green, green, violet)
• The LMS system is adequate for mammals, but is awkward
for nonmammalian species that express four cone VPs and
up to seven chromatypes
• A rich tradition of primate CNS physiology exploits the RGB
terminology
• The LMS system can be confused with VP gene groups:
primate L and M cones are group LWS cones; fish L and M
cones are group LWS and Rh2 cones, respectively
• Perceptual channels initiated by RGB cones do match color
names well
• Increment threshold spectral sensitivities of trichromatic
primates show three peaks: 610 nm (orange-red), 535 nm
(green), and 430 nm (blue), each primarily driven by R, G, or
B cones
1568
Cat Rabbit Macaque Human
2 2 3 3
2 2 2 2
2 2 3 3
2 2 3 3
~12 ~12 ~12 ~12
~30 ? ?
>15 ? ?
spatial patterning, subtleties of shape (in primates) and
connectivity.24–26 Within the past 30–40 MY, a gene duplication
event resulted in the formation of a tandem head-to-tail array
of red (lmax ~ 560 nm) and green (lmax ~530 nm) pigment
genes on the primate X chromosome.27 Historically, primate red
and green cones have been viewed as the initiators of separate
color channels, with separate connectivities leading to hard-
wired color-opponent neural assemblies at the GC level. This
deterministic model is now in doubt; a stochastic process likely
controls whether a cone stably expresses green or red pigment.28
Thus it is difficult to see how pathway-specific genes could be
specifically coupled to a green or red phenotype. All mammals
may express only two image-forming cone chromatypes and
this would reduce the required diversity of retinal neurons and
the number of neuron types.
The full set of cone chromatypes may not yet be in hand.
Recently, a sparse, orderly population of novel cones has been
described in mouse retina that exclusively expresses a vesicular
glutamate transporter type vGlut2.29 Further, a small set of
human cones has been shown to express melanopsin, a novel
photosensitive pigment.30
REDUCTION OF NEURONAL DIVERSITY
Over half of the retinal neuron classes expressed by non-
mammalians have been lost in the mammalian retina
(Table 122.1), including many cone-driven HC, BC, AC, and
GCs. In addition to expressing more than three cone chroma-
types, some nonmammalians possess as many as four HC,
>20 BC and >70 AC classes (Table 122.2). Further, there are
likely at least four classes of IPCs in teleost fishes31 and none
of their homologs have been identified in mammals. Most
teleost IPCs evolved fairly recently; i.e., they are apomorphic.
However, glycinergic IPCs are expressed by pre- and post-
osteichthyan vertebrates and are thus ancient.31 But they are
absent in mammals. While tools to precisely classify all
neuronal classes are still emerging, it is clear that the
mammalian retina represents a reduced set of antecedent
neuron classes that have persisted in other taxa.
APPARENT LOSS OF NEURAL RENEWAL
MECHANISMS
One of the more remarkable features of many nonmammalian
retinas is the persistence of neuronal progenitor cells in the eye
throughout life, near the retina and perhaps in the retina. In
fishes, rod progenitor cells are known to be able to migrate far
from the progenitor-rich ciliary marginal zone, a torus some
10–20 cells thick interposed between the termination of the
retina and the ciliary epithelium.32 The amphibian marginal
zone is similar and some urodele amphibians can regenerate

an entire retina at any point in life. There is also evidence
that new photoreceptors and retinal neurons can replace
damaged patches in mature fish retinas and that glial Müller
cells (MCs) can proliferate and may even become neuroprog-
enitor cells. The mammalian retina lacks these robust pro-
cesses, as far as is known though small clusters of potential
neuroprogenitor cells have been found at the mammalian
retinal margin.33
NEW RETINAL ENERGETICS AND
VASCULARIZATION
The success of the mammals was largely due to the emergence
of a lightweight vascularized skeleton, a more space-efficient
cortical expansion, endothermy, and improved respiratory and
vascular systems.14 The mammalian retina is the only truly
vascularized retina.1 However, this bias toward high mito-
chondrial energy supply engages several risks. The first is poor
tolerance of low oxygen tensions. Aquatic species, even those
that demand high oxygen levels (e.g., salmonids), are also
remarkably resistant to both hypoxia (a common event in fresh
water environments) and hyperoxia.34 The neural retinas of
turtles and tortoises are thick, contain perhaps triple the
number of neuronal classes as mammals, have complex
chromatic processing and high-acuity fovea-like specializations,
but are robust in hypoxic settings. Second, the mammalian
dependence on high-speed blood gas and metabolite transport
via fine capillary networks in the OPL and IPL entails
significant light scattering and demands that MCs play an
active role in retinal homeostasis by investing the endothelial
layer in the same manner as protoplasmic astrocytes in brain.1
Finally, the unique vascularization of the mammalian retina
also exposes it to the danger of renewed angiogenesis.
THE FUNDAMENTALS OF RETINAL
STRUCTURE
THE LAYOUT OF THE NEURAL RETINA
The retina is designed to do two things; sample the torrent of
photons in the retinal image plane and edit the neural signals
produced by photoreceptors into several sets of filtered neural
images.1 This requires a large number of sensory cells, neurons,
glia, and supporting epithelia and vasculature. Like most brain
nuclei, the retina is a lattice of neurons framed by glia and sealed
from its supporting vasculature (Fig. 122.1). At the outer (distal,
sclerad) retinal margin (Box 122.3), the retinal pigmented
epithelium (RPE) forms coupled, high-resistance basolateral
barrier between the endothelia of the choroicapillaris and the
outer segments of the photoreceptors next to the RPE apical
face. At the inner (proximal, vitread) retinal margin, the end feet
of MCs and sparse astrocytes in the optic fiber layer form an
intermediate junction seal between neural retina and vitreous.
Between these two seals, vascularized mammalian retinas
BOX 122.3 Glossary of orientations
Term Reference Object Use
Sclerad ˜ Vitread Layers of the eye, Global location in
outside ˜ inside the eye
Outer ˜ Inner Layers of the eye, Fine tissue layering
outside ˜ inside
Distal ˜ Proximal Distance from the Position along a
CNS, far˜ near neural chain
Vertical ˜ Image plane, normal Histologic plane of
Horizontal ˜ parallel view
Functional Anatomy of the Neural Retina
contain four dense capillary nets; two bordering the inner
nuclear layer (INL) and two bordering the ganglion cell layer
(GCL).1 The retina is functionally partitioned into outer sensory
and inner neural layers. The sensory layer is composed of rod
and cone photoreceptors, surrounded by distal MC processes.
Similar to other high-gain sensory systems, the sensory layer is
separated by the external limiting membrane (ELM) into
ionically distinct distal and proximal extracellular compartments.
The ELM is a precise border of macromolecule-impermeant
intermediate-junctions between MCs and photoreceptors (Fig.
122.1). The ELM and the basolateral tight junctions of the RPE
delimit the subretinal space; a dynamic regime transited by high
fluxes of water, oxygen, bicarbonate, protons, inorganic ions,
sugars, amino acids, osmolytes, and retinoids. The part of the
MC proximal to the ELM is responsible for regulating a similar
array of moieties in the neural retina, in addition to critical
recycling of carbon skeletons derived from synaptic overflow of
glutamate and GABA.3 MCs ensheath the entire neural retina,
CHAPTER 122
comprising ~30% of the INL in the primate central retina and
up to 50% in the far periphery.35 This vertical view masks the
elegant spatial tiling of the retina. At the level of the ELM in the
foveola, an array of ~160 000/mm2 cone myoids sample visual
space with apertures of <2 mm each (Fig. 122.1, panel 1). In the
near periphery, where cone density drops to ~9000/mm2
(Fig. 122.1, panels 1 and 3) large cone apertures are evenly
distributed in a matrix of rods that have nearly the same density
as foveolar cones, i.e., 150 000/mm2. The same field is also
shown with a scale overlay of a Bayer-style filter2 for color-
imaging chips, with a conventional 7.5 mm pixel size (Fig.
122.1, panel 2). This fine screen of rod and cone apertures is
remapped into separate arrays of rod and cone synaptic
terminals (Fig. 122.1, panels 4 and 5). Because rod spherules are
so large (>2 mm diameter), they cannot be packed into a single
plane and, at this eccentricity, are stacked four deep, just distal
to the layer. Some extracellular matrix mechanism may control
this precise lamination. Foveolar cones have long axons (fibers
of Henle) that spray out like an aster from the central foveola
and array their pedicles into a ring packed edge-to-edge in a
single tile layer. As the cone density drops, the tile spacing
increases and in the periphery the cone pedicle mosaic roughly
maps onto the myoid mosaic. Just beneath the pedicles, diverse
classes of HCs and BCs form rough patterns to cover image
space (Fig. 122.1, panel 6), ultimately converging on a complex
tiling of GCs (Fig. 122.1, panel 7).
BASIC NEURONAL PHENOTYPES
There are two major retinal neuron phenotypes; sensory neurons
and multipolar neurons. The sensory neuron phenotype
includes rods, cones, and BCs (Fig. 122.1), all of which display
essential attributes of a polarized epithelium.36 Cells of the
sensory phenotype possess the following distinctive features:
• Ciliary apical and secretory basal specializations
characteristic of polarized epithelium
• Apical poles specialized as photoreceptor outer
segments or BC dendrites
• G-protein coupled receptor-mediated transduction (e.g.,
photoreceptors and ON-center BCs)
• Basal poles specialized as a single axon terminating in a
secretory synaptic ending
• Synaptic release driven by high-capacity ribbon-assisted
vesicle fusion
• A glutamatergic phenotype
The multipolar neuron phenotype includes ACs, AxCs, and
GCs and these display classic projection or local circuit neuron
features: 1569
 RETINA AND VITREOUS
• Ovoid somas with weak apical–basal polarization
• One to many primary dendrites arising from one
hemisphere of the cell
• One or more classical axons in many cell types
• Both axons and dendrites can form many synaptic sites
• Synaptic release driven by low-capacity conventional
vesicle fusion
• ACs tend to be GABAergic or glycinergic
• GCs are predominantly glutamatergic
HCs have no clear homology to either bipolar or multipolar
cells and been provisionally designated their own phenotype.
Though HCs appear multipolar, express iGuRs, and respond
directly to photoreceptors, they have a number of anomalous
features:
• Few or no defined presynaptic sites
• Unresolved synaptic signaling mechanisms
SECTION 3
• Nonspiking axons that appear longer than their cable
space constant
• Direct contact with capillaries
• Unresolved neurotransmitter phenotypes
• Intermediate filament expression characteristic of glia.
SIGNALING MECHANISMS
Neurons encode their voltage signals as changing rates of
neurotransmitter release and decode incoming neurotrans-
mitter signals via transmembrane receptors. Neurotransmitter
systems of the vertebrate retina have been extensively
reviewed3,6,37 and will be summarized only briefly. Many types
of vertebrate sensory neurons use ribbon synapses37 for high
rates of tonic release, while multipolar neurons use conven-
tional synapses.37 Photoreceptors and BCs are glutamatergic
neurons and use ribbon synapses for release. Each photo-
receptor uses a single specialized presynaptic terminal
containing thousands of vesicles and ribbon-associated vesicle
fusion sites that mobilize a smaller releasable pool of vesicles.18
Rods contain one or two ribbon sites38 and large primate cones
contain ~20–50. BCs use branched axon terminals that contain
similarly large numbers of ribbon synapses. The ribbon is a
mechanism for collecting vesicles at high density near the
membrane fusion active zone and such synapses are capable of
sustained fusion at 500–2000 vesicles/s.39,40 In general, ACs are
either GABAergic or glycinergic neurons and use conventional
synapses for release. Each AC cell contains hundreds of small
presynaptic assemblies ranging in size from 10 to 1000 vesicles
and specialized for low release rates (20–100 vesicles/s).41 GCs
are generally glutamatergic, project to central targets and use
conventional synapses.1,3 The diversity of coding and signaling
mechanisms is summarized in Boxes 122.4 and 122.5. We are
still untangling the molecular mechanisms of these processes.
For example, four different glutamate subunit genes (GluR1–4)
produce many posttranslationally modified proteins that can
apparently associate in any stoichiometry, generating AMPA
receptors with different glutamate affinities, conductances,
kinetics, and co-protein associations.3 Box 122.5 summarizes
the ionic mechanisms mediated by the major signaling
pathways in the retina.
THE NEURON SET AND ITS CONNECTIVITY
Box 122.6 summarizes the neuronal classes in the mammalian
retina. Signals from rods and cones diverge to at least 10
distinct BC classes (4) and thence into ~15 GC42,43 and ~30
AC classes.44 Ultimately, photoreceptor signals drive at least
1570 15 distinct synaptic chains of neurons representing different
BOX 122.4 Encoding molecules and decoding
molecules
Many different small transmitter molecules are used to encode
retinal signals:
• Glutamate is used by photoreceptors and BCs for fast
vertical channel signaling
• GABA is used by AC subsets for fast lateral inhibition,
usually within IPL strata
• Glycine is used by AC subsets for fast lateral inhibition,
usually across IPL strata
• Acetylcholine (ACh) is used by starburst ACs for fast
lateral excitation within IPL strata
• Dopamine (DA) is used by large AxCs for slow
modulation events
• Nitric oxide is used by many cells and certain AxCs for
slow modulation events
• Peptides are produced by both ACs and AxCs for
modulatory signaling
• Melatonin is produced by photoreceptors in a diurnal
pattern
Different macromolecules are used to decode retinal signals and
most cells express more than one:
• All cells express ionotropic (iGluR) and/or metabotropic
(mGluR) glutamate receptors
• mGluR6 receptors are fast, high-gain, and sign-inverting
group C mGluRs (ON BCs)
• AMPA receptors are fast, medium-gain, and sign-
conserving iGluRs (OFF BCs, HCs, ACs, GCs)
• KA receptors fast, high-gain, and sign-conserving iGluRs
(OFF BCs)
• NMDA receptors are slow, low-gain, and sign-conserving
iGluRs (some ACs, most GCs)
• GABAA ionotropic receptors are fast, low-gain, and sign-
inverting (BCs, ACs, GCs)
• GABAB metabotropic receptors are slow, high-gain, and
sign-inverting (mostly BCs)
• GABAC ionotropic receptors are slow, high-gain, and
usually sign-inverting (mostly BCs)
• Gly ionotropic receptors are fast, low-gain, and sign-
inverting (BCs, ACs, GCs)
• nACh receptors are fast, high-gain, and sign-conserving
(GC subsets)
• mAch receptors are slow, high-gain, and usually sign-
inverting (AC subsets)
• DA1 receptors are very slow, low-gain, and usually
increase cAMP levels in many cells
• DA2 receptors are very slow, high-gain, and usually
decrease cAMP levels in many cells
• Nitric oxide activates soluble guanyl cyclase and raises
cGMP levels in many cells
filtered versions of the visual world. Each of these chains
represents a distinct class of sampling unit with biases toward
various stimulus qualities.
Each retinal neuron collects photoreceptor signals from
specific synaptic chains. GCs collect direct signals from cone
˜ BC ˜ GC vertical channels and indirect signals that pass
through lateral channels containing HC or AC elements
(Fig. 122.4). This collection of vertical and lateral signals is
combined by the target neuron to form its receptive field: a
response waveform Í stimulus map. In the simplest receptive
fields, a patch of light generates a single response polarity, such
as cone responses to small spots. Most BCs and GCs possess
concentric center–surround receptive fields,45 where vertical

BOX 122.5 Five major signaling mechanisms
• Metabotropic photoreceptor >i ON BC signaling
Glutamate released by photoreceptors binds to mGluR6 and
initiates a G protein signal cascade thought to lead to the
closure of nonselective cation channels permeant to Na+, K+,
Ca2+, and Mg2+. As photoreceptors hyperpolarize,
intrasynaptic glutamate levels drop and unbound mGluR6
becomes permissive of cation channel opening, increasing
Dg and depolarizing ON BCs through an inward cation
current.
• Ionotropic photoreceptor > HC and OFF BC signaling, BCs
> AC and GC signaling
Glutamate released by photoreceptors or BCs binds to
iGluRs and initiates the opening of nonselective cation
channels, increasing Dg and depolarizing target cells through
inward cation currents. As photoreceptors or BCs
hyperpolarize, intrasynaptic glutamate levels drop, unbound
iGluRs gate cation channel closure and hyperpolarize target
neurons.
• Ionotropic AC >i BC, AC, and GC signaling
GABA or glycine release from ACs binds to ionotropic GABA
or glycine receptors and initiates the opening of a
nonselective anion channel (Cl– is the prime permeant),
increasing Dg and hyperpolarizing target cells through inward
anion currents. When these currents are large, they constitute
hyperpolarizing inhibition. Unlike cation conductances, anion
conductances often operate near the chloride equilibrium
potential and polarization changes may be small. Even so, Dg
may be large, constituting shunting inhibition.
• Metabotropic AC > BC and GC signaling
GABA release from ACs binds to metabotropic GABA
receptors and initiates a G protein signal cascade thought to
lead to (1) a desensitization of the voltage sensitivity of BC
synaptic Ca2+ channels, depressing glutamate release or (2)
opening of voltage-gate K+ channels, increasing Dg and
hyperpolarizing target cells through outward K+ currents.
• Gap junction signaling
Gap junctions composed of connexin rafts permit direct sign-
conserving current flow between pairs of identical
(homocellular coupling) or different (heterocellular coupling)
neuron classes. Slow signals (dopamine, NO) can modulate
connexin conductance.
channels drive a center response and lateral channels generate
annular surrounds of opposite polarity (Fig. 122.5). More
complex fields encode time-dependent events.
PHOTORECEPTORS – STAGE 1 OF THE
VERTICAL CHANNEL
The primate retina possesses three image-forming photoreceptor
chromatypes.
• Rods express the RH1 opsin group VP 499, have a
unique rod structural phenotype, and selectively
contact rod BCs and HC axon terminals.
• Blue cones express the SWS1 opsin group VP 420, have a
subtle but unique blue cone morphology, contact cone
BCs and HCs, with a strong preference for a blue
ON BC.
• Red and green cones express VP 530 or VP 560 from
the LWS opsin group, are structurally indistinguishable
from each other, contact cone BCs and HCs, but avoid
the blue ON BC.
Functional Anatomy of the Neural Retina
BOX 122.6 Retinal neuron phenotypes
1. The Sensory Neuron Phenotype (bipolar shape, ribbon-
based vesicle fusion)
1.1. Photoreceptors (VP family = class)
1.1.1. Red/Green Cones (Stochastic LWS VP530 or
LWS VP560, 1 class)
1.1.2. Blue Cones (SWS1 VP 410, 1 class)
1.1.3. Rods (RH1 VP499, 1 class)
1.2. Bipolar Cells
1.2.1. ON Bipolar Cells (mGluR6 expression)
1.2.1.1. Rod ON Bipolar Cells (1 class)
1.2.1.2. Blue Cone ON Bipolar Cells (1 class)
1.2.1.3. RGB Cone ON Bipolar Cells
1.2.1.3.1. Midget ON Bipolar Cells
(1 class)
1.2.1.3.2. Diffuse ON Bipolar Cells
(~3 or more classes)
CHAPTER 122
1.2.2. OFF Bipolar Cells (iGluR expression)
1.2.2.1. RG or RGB Cone OFF Bipolar Cells
1.2.2.2. Midget OFF Bipolar Cells (1 class)
1.2.2.3. Diffuse OFF Bipolar Cells (~3 or
more classes)
2. The Multipolar Neuron Phenotype
2.1. Projection Cells (axon-bearing, spiking)
2.1.1. Ganglion Cells (>15 classes)
2.1.2. Association Cells (>6 classes)
2.2. Local Circuit Neurons
2.2.1. Lateral Amacrine Cells (mostly GABAergic,
20–25 classes)
2.2.2. Vertical Amacrine Cells (mostly Glycinergic,
5–10 classes)
3. The Horizontal Cell Phenotype (2–3 classes)
Rod and cone photoreceptors are complex, polarized sensory
neurons (Fig. 122.6) whose structures and biologies are detailed
in the following chapter. Peripheral primate rods and cones
are cylindrical cells ~70–80 mm long, each possessing a sensory
outer segment ~10–30 mm long (species-dependent) and a
larger, neuron-like inner segment. Rods and cones exhibit sig-
nificant functional similarity to fiber optics and ‘guide’ captured
photons. Primate rod outer segments and the optically active
inner segment portion have a diameter of ~1.5 mm. Large
diurnal or crepuscular mammals such as primates have large
cones with optically active inner segment diameters of
~5–7 mm, yielding a large photon-capture cross section. In con-
trast, both rods and cones of mouse are small and ~1–2 mm in
optical diameter. The outer segment is an expansion of the
membrane enclosing single nonmotile cilium to form hundreds
to thousands of rod disks or cone lamellae specialized for
photon capture and signal transduction. The cilium provides
microtubule-based bidirectional transport of cytosolic proteins.
The dominant membrane proteins, opsins, are delivered to
nascent discs and lamellae via a targeted vesicle fusion pathway
surrounding the cilium. Just proximal to the cilium is the
ellipsoid region of the photoreceptor; an array of longitudinally
oriented mitochondria providing high rates of ATP production
for visual transduction and Na+/K+ ATPase in the inner
segment. Primate cone ellipsoids are ~6–8 mm in diameter and
~12 mm long (a gross volume of ~340 fL), precisely positioned
in a single band centered ~8 mm distal to the ELM in peripheral
retina. Primate rod ellipsoids are 20-fold smaller in volume.
In contrast, both mouse rod and cone ellipsoids are small
and similar to primate rods.46 This is an important neuro-
anatomical distinction. First, the energetics of mouse cones are 1571
 SECTION 3 RETINA AND VITREOUS
FIGURE 122.4. The basic cone-driven elements of the retina. Vertical
channels are formed by cone ˜ BC ˜ GC chains. Cones (C) are
presynaptic (arrows) to ON BCs via sign-inverting (䊊) mGluR6
receptors, OFF BCs via sign-conserving (䊉) KA receptors, and HCs
via sign-conserving AMPA receptors. ON BCs and OFF BCs drive
matched ON ACs/GCs and OFF ACs/GCs via sign-conserving AMPA
and NMDA receptors. Surround channels are formed by HCs in the
OPL and ACs in the IPL. HCs are coupled into homocellular networks
by gap junctions (resistor symbol) and engage in feedback onto cones
and feedforward onto BCs. The mechanisms of these feedback
schemes are not well understood (see text), but it has been argued
that HC ˜ cone signaling could be ephaptic (ⵧ), rather than
transmitter-mediated. GABAergic ACs dominate feedback and
feedforward in the IPL via sign-inverting synapses, usually of complex
receptor composition. AC ˜ BC signaling is dominated by GABAC
receptors, while AC ˜ GC and AC ˜ AC signaling are dominated by
GABAA receptors.
© REM 2006.
likely specialized for use in crepuscular contexts, rather than
the high bleach rates of the noon-time savannah. Second, as the
mouse model has become a key tool for understanding human
retinal disease, these energetic differences associated with cone
size may be relevant to interpreting disease progression. Mouse
cones appear quite susceptible to indirect or bystander killing in
some retinal degenerations,11,47 while human cones seem much
more resistant.
The component of most relevance to this chapter is the
photoreceptor synaptic terminal (Fig. 122.7). Mammalian rod
synaptic terminals are termed spherules and are spheroids of
~2 mm in diameter. Each rod axon terminates in a single
spherule containing thousands of synaptic vesicles, one or two
synaptic ribbons that serve as vesicle tethering stations next to
the vesicle fusion sites of the spherule presynaptic membrane,40
many multivesicular bodies thought to represent synaptic
vesicle recycling pathways, and apparently one mitochondrion.
The glutamate signal from each rod spherule’s synaptic vesicle
release is ‘sampled’ by two to four fine rod BC dendritic
processes and one to four lobular HC axon terminal processes.40
Mammalian cone synaptic terminals are termed pedicles,
and they have the shape of an architectural pediment, with a
2 mm axon at the peak widening to a base width of >5 mm in
1572 primates. Each cone axon terminates in a single pedicle
FIGURE 122.5. GC center-surround receptive fields. GCs at the left
view a brief light pulse (white band, elevated profile) in their receptive
field centers. This elicits a hyperpolarizing voltage in illuminated cones
and connected OFF BCs and HCs via sign-conserving synapses (䊉);
mGluR6 receptors invert (䊊) the signal in ON BCs, producing a
depolarization. ON BCs synaptically depolarize ON GCs and elicit
spiking. Concurrently, OFF BCs synaptically hyperpolarize OFF GCs
and inhibit spiking. GCs at the right view a brief light pulse in their
receptive field surrounds. Responses from distant cones propagate
decrementally through the HC layer and reach nonilluminated center
cones and their connected BCs. Sign-inverting HC ˜ cone and
HC ˜ OFF BC signals lead to a small depolarization in OFF BCs;
sign-conserving HC ˜ OFF BC signals lead to a small hyperpolarization
in ON BCs. Thus HCs create opponent surrounds in BCs. These are
passed directly to GCs, so that surround light, with a small delay (arrows),
excites OFF GCs and inhibits ON GCs. Matched ACs mediate the same
pattern of surround signals in the IPL. In summary, bright centers and
dark surrounds excite ON center cells, while dark centers and bright
surrounds excite OFF center cells.
© REM 2006.
containing many thousands of synaptic vesicles, ~50 or more
synaptic ribbons,48 multivesicular bodies, and a larger mito-
chondrial volume than rods. The glutamate signal from each
ribbon site is sampled by several cone BC and HC dendrites,
and each cone pedicle is thus sampled by hundreds of dendrites
from 8 to 12 different cell classes.
There is weak electrical coupling mediated by small gap
junctions between the pedicles of neighboring cones, between
spherules of neighboring rods, and between cone pedicles and
rod spherules, mediated by connexin36.49–52 Rod–cone coupling
(Fig. 122.8) allows rod signals to enter the cone pathway at high
scotopic levels. Coupling also occurs between pairs of cones.
Evidence from the dichromatic ground squirrel show that LWS
green and SWS1 blue cones do not form G–B coupled pairs,
whereas G–G pairs are common.53 Similarly, red and green
cones are coupled extensively in macacque.54
BCS – STAGE 2 OF THE VERTICAL CHANNEL
Primates display at least 10 distinct BC classes (Figs 122.9 and
122.10).
 Functional Anatomy of the Neural Retina

FIGURE 122.6.
Generic
photoreceptors from
vertebrates with large
rod–cone dimorphisms
(e.g., primates). Broad
outer segments,
ellipsoids and myoids
both a larger entrance
pupil and higher
metabolic and protein
synthesis capacity in
cones compared to
rods. Large cone
nuclei are located in a
layer just proximal to
the ELM, while rod
nuclei are diversely
positioned throughout a b

CHAPTER 122
the ONL. Thick cone
and thin rod axons FIGURE 122.7. Electron micrographs of rod and cone synapses with
terminate in unique HC and BC processes. (a) The invaginating synapse of a rod
synaptic terminal spherule. The rod vesicle fusion apparatus is composed of a synaptic
shapes. Rod spherules ribbon that organizes vesicles for release at active zones located on
contain one or two either side of the dense protuberance known as the synaptic ridge.
synaptic ribbons and Opposite each face of the synaptic ridge are HC axon terminal
contact ~1–2 HCs and processes (H). (b) An invaginating synapse of a cone pedicle
4–5 BCs, while cone containing two lateral HC dendrites (H) and the dendrite of an
pedicles contain ~50 invaginating midget ON BC (IMB). The arrowheads show basal
ribbon and contact contacts between the cone pedicle and the dendrites of flat contact
50–100 BC and HC with OFF BCs. Each vesicle is ~25–30 nm in diameter.
processes. From Fawcett DW: Bloom and Fawcett: a textbook of histology. 11th edn.
© REM 2006. Philadelphia: WB Saunders; 1986.

• Blue cone BCs (ON) contact blue cones and express the
mGluR6 receptor
• Rod BCs (ON) contact only rods and express the
mGluR6 receptor

BC cells effectively copy photoreceptor signals, mix cone

• dB1 cone BCs (OFF) may contact all cones and express
KA/AMPA receptors
• dB2 cone BCs (OFF) may contact only red/green cones
and express KA receptors
• dB3 cone BCs (OFF) may contact all cone classes and
express AMPA receptors
• OFF midget BCs contact red, green, or blue cones and
express KA/AMPA receptors
• dB4 cone BCs (ON) seem to contact all cone classes
and express mGluR6 receptors
• dB5 cone BCs (ON) seem to contact all cone classes
and express mGluR6 receptors
• dB6 cone BCs (ON) seem to contact all cone classes
and express mGluR6 receptors
• ON midget BCs contact either red or green cones and
express mGluR6 receptors
channels, and produce the essential functional dichotomy of all
vertebrate retinas: ON and OFF channels.4 ON BCs respond to
light onset with sustained nonspiking depolarizations,45 display
long axons that extend deep into the proximal half of the IPL
(known as sublamina b) and slender invaginating dendrites that
preferentially terminate near the synaptic ribbons of rod and
cone photoreceptors.18,55–58 OFF BCs respond to light onset with
sustained nonspiking hyperpolarizations, display short axons
that extend into the distal half of the IPL (known as sublamina
a) and either short flat-contact or semi-invaginating dendrites
that preferentially terminate further from the synaptic ribbons
of cone photoreceptors (Figs 122.7 and 122.9).59 In general,
cone BCs are thought not to be part of the direct rod-driven path
but there is now evidence that nonprimate OFF cone BCs do
make sparse OFF-like contacts at rod spherules.18,60 This will be
reviewed in more detail later.
The final patterns and mechanisms of selectivity among BCs
have not been fully resolved, but we have broad models for most
classes (Fig. 122.11). For example, it appears that most OFF
BCs will contact any cone class and midget OFF BCs exist for
red, green and blue cones.61 The presence of a midget blue
pathway is puzzling, as chromatic aberration should blur blue
targets when optimally focused for long-wave targets. It has
been established that the ground squirrel homolog (squirrel type
b3 OFF BC) to the primate dB2 BC selectively avoids contact
with blue cones, making it an LWS cone-driven cell.62 This will
be presumed to be true for primates as well. As far as is known,
other diffuse cone BCs are not selective and contact all cone
classes. The exceptions are the blue cone ON BC that has 1573
 RETINA AND VITREOUS
SECTION 3
a b
c d
sparse dendrites and avoids all red and green cones26 and,
apparently, midget ON BCs that avoid blue cones.61 The
mechanisms that guide selective contacts are unknown and
could involve paired-cell adhesion and recognition mechanisms
or competition for synaptic targets, or both. On balance, it is
1574 clear that rods and blue cones are either targeted or avoided,
FIGURE 122.8. Gap junctions between
photoreceptor pairs in the primate retina. (a) A
cone pedicle and a rod spherule coupled by a
punctate junction (arrow). Inset, At higher
magnification with lanthanum tracer in the
intercellular space the junction is characterized
by a focal apposition of the adjoining
extracellular leaflets of the two plasma
membranes. C, cone; R, rod. (b) Freeze fracture
imaging shows that such focal appositions
represent the fortuitous cross section of a linear
array of connexons. (c and d), A pair of cone
pedicles connected by gap junctions (arrows)
that consist of a circular array of connexons.
Scaling for transmission images: each vesicle is
~25–30 nm in diameter. Scaling for freeze
fracture images: each connexon is ~6.5 nm in
diameter.
From Raviola E, Gilula NB: Gap junctions between
photoreceptor cells in the vertebrate retina. Proc Natl
Acad Sci USA 1973; 70:1677–1681.
FIGURE 122.9. Topologically simplified vesicle
fusion and glutamate diffusion patterns around
a single cone synaptic ribbon (thick black line in
the gray box). Vesicles loaded with high levels
of glutamate (dark gray) fuse with the cone
membrane (EX) at active zones on either side of
the synaptic ribbon and are recovered from
sites displaced from the ribbon (EN). HCs
expressing sign-conserving (+) AMPA receptors
are likely closest to sites of vesicle fusion. ON
BCs expressing sign-inverting (–) mGluR6
receptors are centered under the ribbon but are
slightly displaced from fusion sites. OFF BCs
expressing sign-conserving (+) KA receptors are
most distant from vesicle fusion sites.
Alternatively, HCs and OFF BCs are closest to
cone glutamate transporters that remove
glutamate from the cleft. The glutamate
released into the cleft is progressively cleared
as it diffuses from the ribbon. Thus OFF BC
receptors likely sense a much lower mean
glutamate level.
© REM 2006.
suggesting that their synaptic terminals represent distinct
chromatypes. There is no evidence that any postsynaptic cell
can discriminate red and green cones terminals.
The ultrastructural patterns of contacts are specialized by
class. Most ON BCs tend to generate slender invaginating
dendritic tips that form a narrow adhesion en passant contacts
 Functional Anatomy of the Neural Retina

FIGURE 122.10. Three diffuse BC classes from Rhesus monkey retina,

visualized by the Golgi technique. At left, one of the OFF cone BC
classes (diffuse flat cone bipolar or DFCB) makes flat contacts with
cones in the OPL and has a broadly stratified terminal in sublamina a of
the IPL. At center, an ON rod BC (RB) makes invaginating ribbon
contacts with cones in the OPL and has a varicose terminal in sublamina
c of the IPL. At right, one of the ON cone BC classes (diffuse
invaginating cone bipolar or DICB) generates invaginating ribbon
contacts with cones in the OPL and has a narrowly stratified terminal in
sublamina b of the IPL.
From Mariani AP: a diffuse, invaginating cone bipolar cell in primate retina.
J Comp Neurol 1981; 197:661.

FIGURE 122.11. A summary of ten BC classes

and their connections in the trichromatic primate

CHAPTER 122
retina. (Class 1) Three short OFF midget BCs
terminate in the OFF sublayer. (Class 2) Two
long ON midget BCs terminate in the ON
sublayer. (Classes 3–5) Three diffuse OFF cone
BCs with flat contacts terminate in different
levels of the OFF sublayer. Classes dB1 and
dB3 have narrow terminal stratifications and
may contact all cone classes. Class dB2 has a
broadly stratified terminal and may contact only
R and G cones. (Classes 6–8) Three diffuse ON
cone BCs with invaginating contacts terminate
in different levels of the ON sublayer. (Class 9)
Blue BCs contact B cones with invaginating
contacts and terminate deep in the ON
sublayer. (Class 10) Rod BCs contact rods with
invaginating contacts and have the deepest
terminals in the ON sublayer. The circles
indicate representative cone contact patterns
for dB1, dB2, and blue BCs.
© REM 2006.

with cone membrane and terminate in a so-called central
position (Fig. 122.7) in a triad of processes near the synaptic
ribbons of photoreceptors.48,56–58 This means that ON BC
mGluR6 receptors are positioned close to the source of vesicle
fusion and experience a relatively high mean glutamate level,
modulated by cone voltage-dependent increases and decreases
in release and clearance.18 This is consistent with the modest
glutamate sensitivity of the mGluR6 receptor.3 Conversely,
most OFF BCs tend to generate blunt ‘flat’ dendritic tips that
form wide adhesion contacts with the cone plasmalemma and
terminate in a position distant from the synaptic ribbons of
photoreceptors (Figs 122.7 and 122.9). This means that OFF
BC iGluR receptors are positioned farther from the source of
vesicle fusion, experience a lower mean glutamate level
modulated by cone voltage-dependent increases and decreases
in release and clearance.3 This is consistent with the relatively
high glutamate sensitivity of the KA receptor found on subsets
of OFF BCs.63–65 On an intermediate scale, some OFF BCs are
known to invaginate some dendrites much closer to the ribbon
than those that make flat contacts59 and these invaginating OFF
BCs express AMPA receptors.65 The fluctuations in glutamate
levels are also faster near the ribbon and smoothed at flat
contacts, suggesting that KA and AMPA receptors represent key
temporal filters for BCs.65 The complex topology of this
arrangement of processes is represented in a simplified two-
dimensional form (Fig. 122.9).
BC outputs, like those of photoreceptors, are restricted to
the axon terminal specialization of the basal pole of the cell
(Fig. 122.12). Again, like photoreceptors, BCs utilize synaptic
ribbons to facilitate high rates of vesicle release. The ribbons are
generally smaller than rod and cone ribbons and quite
numerous, with each BC having many small synaptic ridges,
each targeting a pair of postsynaptic AC dendrites or,
less frequently, a GC–AC pair. BC synaptic terminals tend to be
(1) lobular and branched in a local cluster of small telodendria
(midget, rod, and blue BCs) with a lateral spread similar to the
diameter of the soma or (2) filamentous and branched in a
pattern resembling the dendritic arbor in shape and extent.
Thus some BCs provide output to only a few target cells and
preserve a narrow receptive field structure, while others branch
to reach many targets, facilitating a divergence of signals.
The axon terminals of BCs are the vertical structuring
elements of the IPL. OFF BCs terminate in the distal half
(sublamina a) and ON BCs in the proximal half (sublamina b)
(classical refs). The late Brian Boycott pointed out that the deep
proximal IPL where rod BCs drive rod ACs is structurally
unique and he proposed it to be sublayer c.66 Each AC and GC
thus sends its dendrites to specific levels of the IPL where the
specific BCs are sampled. GCs targeting sublamina a or b are
respectively dominated by OFF or ON BCs, while those whose
dendrites span both sublayers typically show mixed ON–OFF
behavior.45 It has long been common to separate the IPL into
five sublayers, though there is no biological basis for the prac-
tice. Indeed, various immunochemical markers show that the
mammalian IPL can be segmented into no fewer than seven
sublayers and nonmammalian retinas easily possess up to 15
sublayers.3 The best practice is to specify the level of the IPL by
setting the ACL/IPL border at 0 and the GCL/IPL border at 100. 1575
 RETINA AND VITREOUS
SECTION 3
FIGURE 122.12. Cone BC synaptic terminals in the mammalian IPL.
BC ribbon synapses generally target two postsynaptic processes in
dyad synapse. In this instance, both postsynaptic processes are AC
dendrites, one of which (asterisk) makes a conventional reciprocal
feedback synapse (curved arrow) with the BC. Another AC synapses
on the BC the right margin of the terminal. Rb, synaptic ribbon;
primate retina. Inset upper left, A ribbon synapse at higher
magnification showing the pentalaminar ribbon structure, a halo of
synaptic vesicles, enlarged synaptic cleft, postsynaptic densities in
the target cells (arrowheads). Rabbit retina. Inset lower right, a BC ˜
AC ˜ GC feedforward chain. The curved arrows indicate the direction
of signaling. Primate retina. Scaling for transmission images: each
vesicle is ~25–30 nm in diameter.
From Raviola E, Raviola G: Structure of the synaptic membranes in the inner
plexiform layer of the retina: a freeze fracture study in monkeys and rabbits.
J Comp Neurol 1982; 209:233–248.
1576
GCS– STAGE 3 OF THE VERTICAL CHANNEL
Mammals display at least 15 distinct GC classes (Figs 122.13
and 122.14).
The diversity of mammalian retinal GCs has been assessed
by Golgi impregnation, dye labeling, transgene expression and
molecular phenotyping strategies.42,43,67–71 The exact numbers
are not known but clearly exceed 15 and may even exceed
20,68,70 even in primates. Exact homologies have not been estab-
lished across mammals, but there are some basic commonalties
of structure. Nearly all GCs have their somas in the GC layer
proper and exhibit a variety of dendritic patterns, ranging from
compact narrow-field to highly branched wide-field, with
laminar patterns ranging from narrowly stratified to bistratified
and ultimately to diffuse laminations. In the primate retina,
several GC classes have been studied described anatomically
and physiologically.
• Midget GCs (OFF) contact OFF midget BCs
• Midget GCs (ON) contact ON midget BCs
FIGURE 122.14. A horizontal plane view of medium-field class b ON
center (A, B, C) and OFF center (D, E, F) GCs of cat retina visualized
with the Golgi technique. Cells A and D are near the area centralis,
cells B and E from the near periphery, and cells C and F from the
periphery at 9 mm eccentricity (~40°). All are the same class of cell
with graded field diameters reflecting changes in cone density. Bar =
100 mm.
From Wässle H, Boycott BB, Illing RB: Morphology and mosaic of on and off
beta cells in the cat retina and some functional considerations. Proc R Soc Lond
[B] 1981; 212:177–195.
FIGURE 122.13. Primate narrow-field midget,
medium field parasol and wide-field garland
GCs visualized with the Golgi technique and
labeled according to Steven Polyak’s 1941
classification. Two different parasol GCs (P)
send their dendritic arbors to the distal OFF and
proximal ON sublayers of the IPL, as do several
midget GCs (unlabeled). A shrub GC (S)
appears to have a small diffusely bistratified
arbor. A garland GC (G) arborizes widely in the
OFF sublayer. The arrowheads denotes the IPL
borders.
Modified from Polyak SL: The retina. Chicago:
University of Chicago Press; 1941.
 Functional Anatomy of the Neural Retina

TABLE 122.3. Provisional Functional and Anatomical Assignments of Mammalian GCs

Physiology MacNeil/Marc/Famiglietti Structural Features, Level Primate Homologs

Class (Coupling), Percent

Concentric Brisk Linear

ON sustained X, b G4 / 3 / IIa, 12.2% Medium monostratified, 35–45 ON midget
OFF sustained X, b G4 / 6 / IIb1 (g), 15% Medium monostratified, 55–65 OFF midget
ON transient G? / 1b Medium monostratified, 35–45 ON parasol?
OFF transient G? / 5 (g) Medium monostratified, 35–45 OFF parasol?
Concentric Brisk Nonlinear
ON transient Y, a G11 / 1a / Ia2, 2.8% Wide monostratified, 60–80 ?
OFF transient Y, a G11 / 9 / Ib2 (g), 1.4% Wide monostratified, 30–40 ?
Concentric Sluggish Linear

CHAPTER 122
ON sluggish sustained G? / 2, 4.2% ?
OFF sluggish sustained G? / 8 (g) , 12.2% ?
Concentric Sluggish Nonlinear
ON + OFF sluggish transient G? / 12 (g), 5.2% ?
Complex
Local edge detector G1 / 7 (gG), 5.6% Narrow monostratified, 50 ?
Uniformity detector G6 / 5 (g) or 1b? Medium monostratified, 80 Melanopsin GC ?
Orientation selective G? / 11 (g), 6.6% ?
ON–OFF DS G7 / 1c & 10 (g) Wide bistratified, 25 and 75 ?
ON DS G10 / 4, 7.7% Medium monostratified, 70–80 ?
Blue ON Green OFF G3 ? / ? Medium bistratified, 20 and 80 Blue ON Yellow OFF

• Large bistratified blue ON GCs contact blue BCs and Narrow-field GCs, such as midget GCs (Fig. 122.13), are
OFF bB2-like BCs monostratified cells with medium-sized somas that selectively
• Small bistratified blue ON GCs contact blue BCs and contact the axon terminals of midget BCs, and are ON or OFF
OFF bB2-like BCs cells.45 Such cells typically generate relatively sustained spiking
• Parasol GCs (OFF) contact diffuse OFF BCs (likely dB3) patterns to a maintained light stimulus. In the foveola each
• Parasol GCs (ON) contact diffuse ON BCs (likely dB4) midget GC contacts a single midget BC but midget GCs may
• Inner giant melanopsin GCs contact diffuse ON BCs contact several midget BCs in peripheral retina.72,73 Midget
(likely dB6) GCs project to the dorsal parvocellular (small cell) P layers of
• Outer giant melanopsin GCs contact unknown cell the LGN that in turn project to layer 4Cb of striate visual cortex
classes area V1.74 Projection neurons along parvocellular retina ˜ LGN
˜ cortex stream appear to be key elements in high-acuity
GC populations in cat and rabbit retina have been analyzed vision, and tend to have sustained responses. Their roles in hue
more comprehensively and, based on several recent studies can discrimination have been debated, but it is likely that the
be parsed into at least a dozen clear structural, molecular, and essential information for hue discrimination is embedded in
physiological categories (Table 122.3 and Table 122.4). their signals.1 As they share some morphological features, func-
tions and projections, primate74 and ground squirrel midget
GCs,75 b cells of the cat retina76 and classes 3 (IIb2) and 6 (IIa)
TABLE 122.4. Optical Sampling Across Species GCs of rabbit42,67 are likely homologs. Species differences in GC
morphology are partly due to variations in cone density and
Species Visual Angle in (mm/deg) patterning. In trichromatic primates, midget cells are thought
Human 280–300 to generate the VP 560-driven and VP 530-driven ON and OFF
sustained GCs that may subserve red–green hue discrimi-
Macaque 246 nation. However, just as midget BCs likely do not discriminate
Cat 220 between red and green cones, parafoveal midget GCs that
collect signals from a few midget BCs do not appear to have any
Rabbit 160–180
color selectivity1,77 and lack color opponency.73
Rat 75 Medium to wide-field GCs (Fig. 122.13) are the most com-
Goldfish 60 mon types in most retinas but likely represent mixed functional
classes. One distinctive class in most species is a medium-
Mouse 31 density to sparse population of large somas with very large
Zebrafish 10 (estimated) dendritic arbors, such as parasol GCs in primates and a or
a-like cells in other mammals. These cells sharply stratify their 1577
 RETINA AND VITREOUS
dendrites at specific levels of the IPL, suggesting that they
preferentially sample from cells such as OFF dB2/3 BCs78 or ON
dB4/5 BCs. Parasol GCs preferentially project to the ventral
magnocellular (large cell) or M layers of the LGN, thence to
layer 4Ca of striate visual cortex area V179 and are achromatic
or luminance-driven neurons. In cat and rabbit, such cells show
transient responses; brief bursts of spikes to a step of light at
light onset (ON cells) or offset (OFF cells).45 However, the
presumed parasol GCs of primate retina and most LGN mag-
nocellular neurons are rather linear in their responses79 and
may not be true a homologs, or may be a re-derived variant
(e.g., progenitor duplication instead of gene duplication). Large
sparse GCs with even larger dendritic arbors are plausibly the
primate a OFF cell.69,70
Bistratified GCs arborize in both sublayers of the IPL, giving
them the opportunity to capture signals from BCs with opposite
polarities. There are several known examples, but the attributes
of none are known particularly well. In cat, ON–OFF transient
SECTION 3
cells resemble bistratified a cells. In rabbit, a set of GCs sample
from sublamina a and b near the midline of the IPL and
generate independent ON and OFF directionally selective (DS)
responses. ON–OFF DS cells are one of the most complex
neurons known and, though their receptive field mechanisms
have been studied intensively, the underlying biological basis of
its tuning remains controversial.80 DS cells have not been
studied thoroughly in primates, but the ACs most often
associated with them are present in primates81 and likely
candidates for both monostratified ON DS and bistratified
ON–OFF DS cells have recently been described in macaque.70
The most distinctive primate small-field bistratified cell is the
blue ON bistratified GC that collects inputs from a diffuse OFF
BC (likely dB2) and blue ON BCs. Thus the receptive field
center of this cell is spectrally biphasic, depolarizing and spiking
to blue light and hyperpolarizing to yellow light.82
Melanopsin GCs in primate are ‘giant’ GCs that narrowly
stratify at the proximal or distal margins of the primate retina.83
Some giant melanopsin GCs appear misplaced or displaced to
the ACL. Melanopsin GCs (also known as intrinsically photo-
sensitive or ipGCs) are present in other mammals,84–86 project
widely in the thalamus and pretectum, and partly drive the
pupillary response.87 In primates, these cells appear to be the
rare blue OFF/yellow ON (B–/Y+) GCs of the retina.87 In
addition to a full range of rod and cone responses, these cells
express melanopsin; a photosensitive G-protein coupled
receptor (GPCR) that uses 11-cis retinaldehyde as a chromo-
phore.88 At high photopic levels, melanopsin directly drives
highly sustained spiking activity, partially compensating for
the transient nature of cone-driven responses.83 Melanopsin
GCs in many species project to the suprachiasmatic nucleus
(SCN) as part of the circadian clock pathway and to the olivary
pretectal complex as part of the pupillary response pathway. In
primates they also project to the LGN.83 Evidence is building for
the existing of several subclasses of melanopsin GCs.86 Most
importantly, these cells likely underlie the persistence of photic
entrainment of circadian cycles, even after photoreceptor
degeneration.89,90
GCs are purely postsynaptic neurons from a neurochemical
perspective, and decode BC signals with a mixture of AMPA
and NMDA receptor subtypes.3,42,91,92 AC signals are decoded
with a variety of GABA and glycine receptors.6 GC dendrites
make no presynaptic contacts and are thought to be entirely
postsynaptic. However, some GC classes make heterocellular
gap junctions with ACs, forming specific GC::AC::GC
syncitia.8,42,93,94 Each retinal GC generates a single unmye-
linated axon that becomes myelinated in the optic nerve and
projects to one or more CNS targets: LGN, SCN, pretectum,
1578 and superior colliculus.
HCS – THE LATERAL CHANNEL FOR
PHOTORECEPTOR ˜ BC SIGNALING
Every GC is a logical device that compares vertical channel
signals with those from several lateral channels. There are at
least two formal lateral channel topologies in the OPL:
• cone1 ˜ HC ˜ cone1 reciprocal feedback (temporal)
• cone1 ˜ HC ˜ cone2 lateral feedback (spatial, spectral)
• cone ˜ HC ˜ BC lateral feedforward (temporal,
spatial, spectral)
These chains partly shape GC responses that encode contrast,
color, and spatial timing of natural stimuli. A general
engineering principle states that each step of high gain
(photoreceptor or BC ribbon synapses) requires a stabilizing
negative feedback element.95 The quantitative differences
between feedback and feedforward are beyond the scope of this
chapter. HCs are the lateral processing elements of the OPL
and enable BCs to compare direct light signals captured by
photoreceptors they contact and indirect light signals from
surrounding photoreceptors they do not. Neither the mech-
anisms of HC signaling or the relative strengths of the cone ˜
HC ˜ cone lateral feedback and the cone ˜ HC ˜ BC lateral
feedforward paths are known though several models exist.3
Topologically, HCs exhibit two forms in mammals; axon-
bearing and axonless.96–99 All HCs contact cones with their
dendritic arbors while axon-bearing HCs form large axon
terminal arbors that contact rods (Fig. 122.15).99 Many
mammalian species display both, while rodents apparently
develop only a single class of axon-bearing cells.100 No evidence
exists to support the idea that the axons of mammalian HCs are
electrically functional.101 HCs do not generate action potentials
and the somatic and axon terminal fields respectively generate
cone-selective and rod-selective light responses with no
evidence of signal mixing that can be attributed to the axon.
Indeed we might consider an axon-bearing HC to be two
separate cells that share a single nucleus. The primate retina is
more complex than any other mammal as it likely harbors three
HC classes.101–104
• H1 HC somatic dendrites contact all cones and lack
axons in the rod-free foveola
• H1 HC responses indicate dominance by R and G cone
inputs
• H1 HC axon terminals contact rods
• H2 HC somatic dendrites appear to contact all cone
classes, with a blue cone bias
• H2 HC axon terminals appear to contact all cones,
with a blue cone bias
• H3 HC somatic dendrites contact cones, apparently
avoiding blue cones
• H3 HC axon terminals contact rods
H1 and H2 cells are the main HC classes, and H1 cells are
four times as abundant as H2 cells.105 H3 HCs have been
described only in Golgi preparations and have been difficult
to document. But Golgi studies have rarely been incorrect and
so the search for the H3 cell by molecular means continues.
The somas of primate HCs and mammalian axon-bearing
HCs are ovoid and give rise to 8–12 dendrites that ultimately
contact ~12 cones in the foveola and 20 cones in the periphery.
The axons contact a few hundred rods in primates and many
more in cat. Though primate H1 somas appear to contact
all cones, they clearly have responses dominated by R and G
cones, with little B input.106–108 Conversely H2 HCs are
enriched in blue responses, reflecting their tendency to contact
a disproportionate number of blue cones.108 Axon terminals
have rod-driven responses.

FIGURE 122.15. A horizontal plane view of H1 (HI) and H2 (HII) HCs
from the macaque visualized with the Golgi technique. ax, axon. Bar =
15 mm.
Slightly modified from Kolb H, Mariani A, Gallego A: A second type of horizontal
cell in the monkey retina. J Comp Neurol 1980; 189:31–44. Copyright © 1994
John Wiley & Sons.
The processes of both HC somas and axon terminals are
dendritic in nature. The dendrites are lobular and flank the
synaptic ridges of photoreceptors as lateral elements of a
synaptic triad (Fig. 122.7).99 The dendrites are thus close to the
sites of photoreceptor vesicle fusion. HCs express AMPA
receptors.3,91,109,110 but the precise locations of the functional
receptor patches are not certain. Since geometric factors such
as the spatial coherence of vesicle release and the distribution
of glutamate transporters along the diffusion path, the precise
receptor position is a key datum.
While HCs are clearly postsynaptic to photoreceptors, it has
been extremely difficult to discover their outputs. This issue has
been treated extensively elsewhere,3,18 but classical presynaptic
specializations are missing in HCs. Presence of GABA in some
mammalian HCs has led to the view that they must be
GABAergic, though compelling demonstrations of that fact are
few. Wilson39 provides a comprehensive and insightful review of
these issues. However, there are many mammalian HCs that
completely lack any evidence of GABA content. Further, there is
no evidence for transporter-mediated export found in
Functional Anatomy of the Neural Retina
nonmammalians. Physiological studies in nonmammalians
imply that there is no feedback path from HCs to rods but there
is to cones. Paradoxically, vesicles similar to classical synaptic
vesicles are more common in HC dendrites contracting rod
spherules than those contacting cone pedicles,111 but there is no
obvious conventional presynaptic assembly and no evidence of
stimulated fast exocytosis or endocytosis in HC dendrites.
Indeed, similar dendritic accumulations of vesicles in brain
neurons appear to be involved in the regulated cytoskeletal
delivery and turnover of postsynaptic AMPA receptors to
dendrites as vesicular cargo.112 HC dendrites have also been
argued to serve as ephaptic feedback devices via patches of
hemijunctions (arrays of half-connexins) through which
currents leak constitutively.7 In fishes, connexin+ hemi-
junctions are very close to the voltage-sensitive Ca2+ channels
that regulate cone vesicle fusion.113 When the HC layer is
hyperpolarized by closure of AMPA receptor channels, the focal
inward current through hemijunctions makes the local
CHAPTER 122
intrasynaptic potential more negative than the adjacent
intracellular cone potential and this relative depolarization is
perhaps sensed by cone Ca2+ channels which begin to open,
increasing transmitter release briefly. This feedback effect
requires no transmitter-dependent or vesicle mechanism, which
nicely explains why many HCs contain no measurable
inhibitory transmitter, yet apparently function quite effectively.
Finally, HCs somas are strongly coupled to each other by
large dendritic gap junctions, so that synaptic currents gener-
ated by cones spread readily in the HC layer.101 In nonprimates
such as rabbits, axonless HCs are more strongly coupled than
the far more abundant axon-bearing HCs.114,115 This generates
two distinct spatial classes of HCs, though the functional
significance of this dichotomy remains unknown. Coupling
efficacy of axon-bearing primate H1 cells coupling resembles
the weak coupling of rabbit axon-bearing coupling.116 H1 and
H2 cells form separate coupled mosaics.105
ACS – LATERAL CHANNELS FOR BC ˜ GC
SIGNALING
• BC ˜ AC ˜ BC reciprocal lateral feedback
• BC1 ˜ AC ˜ BC2 lateral feedback
• BC ˜ AC ˜ GC lateral feedforward
• AC ˜ AC concatenated feedforward chains
ACs are the most diverse group of neurons in the retina,8 with
over 70 classes in teleost fishes117 and over 25 classes in
mammals.44 Most ACs, by definition, lack classical axons and
function as local circuit neurons via dendritic synapses, usually
as negative feedback and feedforward control elements. While a
precise tally is still uncertain, about two-third of AC classes
appear GABAergic, with the rest glycinergic. Other candidate
AC transmitters often co-localize with GABA.3 ACs exhibit
diverse morphologies with lateral spread of dendrites ranging
from narrow (<100 mm) through medium (100–200 mm) to
wide (>200 mm, with some cells > 1 mm) based on a com-
prehensive study of rabbit ACs.44 Narrow-field cells such as the
classic glycinergic rod (AII) AC (Fig. 122.16) typifies many
narrowly stratified, bistratified, and diffusely arborized
classes.15–17,118,119 Most medium-field cells have diffuse arbors
while most wide-field cells such as GABAergic starburst ACs
(Fig. 122.17) are narrowly stratified.120,121 Similarly, the wide-
field type S1 and S1 GABAergic rod ACs (also known as A17,
AI, and indoleamine-accumulating ACs), appear to have very
diffuse arbors but, in reality have most of their inputs and
outputs very narrowly stratified within sublayer c at ~90–100
level of the IPL.68,122–125 Thus there are two broad signaling
motifs of importance; narrowly stratified and usually 1579
 SECTION 3 RETINA AND VITREOUS
FIGURE 122.16 A narrow-field rod AC (AII) viewed in vertical (image
A) and horizontal planes in the OFF (image B) and ON (image C)
sublayers of the IPL in rabbit retina. In the OFF sublayer, tortuous fine
branches arise from the cell body and primary dendrite and terminate
as large lobular appendages (asterisks). In ON sublayer, the primary
dendrite gives rise to a conical tuft of arboreal branches that spread
tangentially at the IPL–GCL border and carry small swellings
(arrowheads). Image A was visualized with the Golgi technique, and
images B and C are optical sections visualized by single cell dye
injection. The IPL width is ~25 mm.
Slightly modified from Dacheux RF, Raviola E: The rod pathway in the rabbit
retina: a depolarizing bipolar and amacrine cell. J Neurosci 1986; 6:331–345.
GABAergic ACs provide lateral signals within a set of BCs and
their targets, while diffuse (often glycinergic) ACs provide lateral
signals across different sets of BCs and their targets. As there
are at least twice as many AC classes as BC and GC classes,
each BC should thus drive at least two different kinds of ACs.
But things are clearly more complex than this, as dendrites
from at least ten different ACs arborize at any level of the IPL
between 0 and 90. This emphasizes our nearly complete lack of
understanding of the various inputs and outputs for any AC
across levels except for one archetypal neuron; the glycinergic
rod (AII) AC. This AC is actually a tristratified cell that receives
rod BC input at level 90–100, makes gap junctions with cone
ON cone BCs at levels 55–80 and forms inhibitory glycinergic
1580 synapses on cone OFF BCs at levels 10–35.3,16–18 Many other
FIGURE 122.17 A horizontal plane view of a wide-field starburst AC
from the rabbit retina. Note the regular dichotomous branching of its
dendrites and the concentration of endings at the periphery. Visualized
by single-cell dye injection. The dendritic field is ~140 mm µ 200 mm.
From Tauchi M, Masland RH: The shape and arrangement of the cholinergic
neurons in the rabbit retina. Proc R Soc Lond [B] 1984; 223:101–119.
diffuse or bistratified ACs may have similarly diverse patterns
of inputs and outputs. There is an exception to this complex
lamination. The proximal band at level 90–100 contains the
axon terminals of rod BCs and only the arbors of only three
classes of rod ACs; the narrow-field glycinergic AC and two
wide-field GABAergic rod ACs.44,125 This further supports the
designation of this band of IPL as a unique sublayer.66 One
additional feature tends to correlate with signaling within
versus across levels and that is neurotransmitter class. Many
narrowly stratified cells tend to be GABAergic and AC ˜ BC
reciprocal synapses and the BC > AC >i BC chain are almost
exclusively GABAergic.3 Correspondingly, the density of GABA
synapses is extremely high and accounts for ~90% of the
synaptic innervation in the vertebrate IPL (Fig. 122.2). Several
diffuse or multistratified cells may mediate BC > gly AC >i GC
or BC signaling across strata. Cholinergic signaling is mediated
in mammals by the ON and OFF starburst ACs3,8,80,126 which
are also GABAergic neurons.3 These cells are narrowly stratified
and form two excitatory output systems at levels 20–25 and
65–75 of the IPL. Their presumed primary targets are DS GCs
in rabbits80 and DS candidate GCs have been described in
macaque.81 Expression patterns of AC neurotransmitters are
reviewed in detail by Marc3 and Brecha.37
LARGE-SCALE PATTERNING OF RETINAL
CELLS
Vertebrates with large eyes also show large-scale variations in
cell density and composition of the neural retina,1 likely reflec-
ting the power of niche selection to control global tissue
patterning signals (Fig. 122.18). Many species concentrate
cones in retinal regions where the optical quality is high (central
foveas in primates) or in horizontal streaks that reflect a strong
behavioral bias for horizon-related visual transitions (urodele
amphibians, chelonian reptiles, lagomorph mammalians). The
biophysics of foveal formation are poorly understood, though
Springer and Hendrickson127 have argued that increased
intraocular pressure and growth-induced retinal stretch induce
the primate foveal pit. While these ideas do not easily explain
other patterns, especially the deep convexiclivate foveas of

FIGURE 122.18. Large-scale spatial variations in cone density. (1) Most
rodents display weak central elevations in cone density. (2) Carnivores
have strong concentrations of cones and GCs in the central retina.
(3) Prey animals such as rabbits (Lagomorpha) express distinct linear
bands of high cone, BC, AC, and GC density. (4) Diurnal primates
express compact, high-density, pure-cone foveas centered in a large
low-density cone field. (5) Avians express the most complex density
variations, with a central pure cone region exceeding primate densities
and a second moderately high density region specialized for binocular
vision. (6) Many rodents, such as domestic mice, display pure blue
cone ventral fields. (7) Aquatic reptilians such as turtles (Chelonia)
possess very high-density linear streaks (approaching primate
densities) enriched in cones with red oil droplets. (8) Primates are
unique among all vertebrates (as far as is known) in having a tritanopic
fovea where the central 15’ arc contains few or no blue cones and a
peak of blue density at 0.3–1° eccentricity. (9) Finally, the bifoveate
avians possess differential enhancements of cones, with high red-oil
droplet cones dominating the temporal fovea and yellow oil cones
dominating the central fovea and most of the peripheral retina.
© REM 2005.
lizards or the dual and differently shaped foveas of avians that
may involve both local proliferation and cell migration, they
offer testable models. Developing genetic models for studying
tissue sculpting in large eyes will be challenging,128 although
Functional Anatomy of the Neural Retina
FIGURE 122.19. Sampling of image space by photoreceptors. Cone
density (red), rod density (cyan), and cone coverage (yellow) profiles in
the human retina as a function of retinal eccentricity in the equatorial
CHAPTER 122
plane. Temporal retina is left and nasal is right on the abscissa, with a
gap centered on ~14° eccentricity representing the optic nerve head.
The left ordinate is density data replotted from Curcio129 on a square
root scale. The right ordinate is linear fractional coverage: the fraction
of image space captured by cones. Cone density forms a wide
pedestal at ~5000 cones/mm2 with an extremely steep peak in the
central 2° reaching ~160 000 cones/mm2 in the foveola. Rod density
is a broad profile of 90 000–140 000 rods/mm2 that would also peak
at ~160 000 rods/mm2 were it not for a deep declivity formed by their
displacement in the central 2°. The foveola is rod free. Cone myoid
and ellipsoid diameters increase with eccentricity so that cones never
capture less than ~30% of the available image data.
development of transgenic and knockout avians and advanced
quantitative trait locus analyses may offer new ways to
understand the genes that control foveal formation and global
neuron patterning.
The description of human retinal neuron distributions and
patternings in Oyster1 is without peer and will only be sum-
marized briefly. The relative numbers of rods and cones change
radically across human retina (Fig. 122.19), ranging from
~160 000 cones/mm2 at the foveola to 5000 cones/mm2 at
~20° eccentricity.1,129 Rods show a broad profile ranging
from ~90 000 to 140 000 rods/mm2 with shoulders at
~15–20°. But it is clear from the trend that rods would also
peak in the central retina at ~160 000 rods/mm2 were it not for
the fact that cones displace them. This is about the maximum
density possible for any photoreceptor, corresponding to a
spacing of ~2.5 mm (including MC space at the ELM). As cones
develop early and capture the foveola, rods can encroach only
from the outer margins, leading to a deep declivity in the rod
profile and a rod-free foveola. In addition to changing density,
cone size also changes with eccentricity. While this negatively
affects acuity, it increases cone photon capture. In fact, the
coverage factor (CF) of the cone mosaic (the fraction of the
retinal image captured by cones) never drops much below 0.3
outside 15°, and smoothly rises to 100% over the foveola.
Remarkably, overall cone density in rodents130 can be much
higher than primate peripheral cone density, reaching ~12 000
cones/mm2. But as rodent cones and rods are similar in size and
cones comprise only 3% of the photoreceptors, their coverage is
only 0.03. The significance of this is more obvious when we
normalize sampling for the relative optical sizes of the eyes
(Table 122.4). An image in peripheral human retina that
subtends a circle 1° in diameter covers a patch of 425 cones,
whereas the same 1° image in mouse131 covers a patch of only
eight cones. The statistical danger of generalizing visual losses
or recoveries in mouse models of retinal degeneration should be
gauged carefully.11 1581
 RETINA AND VITREOUS
Relative acuity loss with eccentricity in the human eye is
partially a consequence of cone density decline and partly the
increased receptive field sizes of retinal GCs that drive
perception. Indeed, many neuron classes show large changes in
local density over the eye.1 The foveola itself (the central 20 s
arc of the retina) is composed solely of cones with all other
neurons and cone axons and pedicles displaced to a ring around
the foveola. However, the corresponding GC and BC density
profiles roughly track cone density. The cortical magnification
factor (the disproportionate area of cortex devoted to foveal
vision), reflects a relatively constant volume of cortex captured
per GC axon. Visual acuity does not simply follow either cone
density or the density of midget GCs. A mixture of GC
sampling units exists at any retinal position. GCs with small
receptive fields can resolve smaller targets, but are not as light
sensitive as those with larger receptive fields. Thus supra-
threshold acuity depends highly on image contrast and mean
luminance. Multiple classes of sampling units likely participate
SECTION 3
in setting visual performance.
Large-scale chromatic patterning also accompanies these
variations in cone density. Many species show variations in
the distributions of blue cones, with many mammals (some
rodents and lagomorphs), exhibiting ventral (inferior) fields
entirely composed of or enriched in blue cones.132–134 No
exploration has been made of connectivity in these regions, but
one might imagine that BCs or HCs that might avoid blue
cones elsewhere cannot do so in these regions; or they may
be excluded from them. Blue cones are not the only variable
types. The linear visual streak in turtles, where cone densities
approach primate foveal levels, is disproportionately enriched
in red cones expressing VP620 and red oil droplets. The tem-
poral foveas of some avians are positioned within a red-field
some 4–5 mm in diameter highly enriched in red cones
expressing VP580 and red oil droplets. Finally, but no less com-
pelling, the tritanopic or blue-blind fovea of the primate foveola
is a small zone of ~15 min of arc with few or no blue
cones.24,135,136 Roughly following rods, blue cones increase in
frequency until they represent 5–10% of the cones (depending
on species), peaking at ~0.3–1°, thereafter following the density
decline of the cones. The mechanisms controlling fine
variations are unknown but the molecular control of overall
cone differentiation may involve selective fibroblast growth
factor (FGF) receptor expression.137 The mechanism that
1582
prevents mature blue cone expression in the foveola also may
regulate patterning of the rods.
FINE-SCALE PATTERNING OF RETINAL CELLS
The retina is an assembly of sampling units that cover the image
plane.1 Over 60 classes of neural elements are patterned across
this plane and, if we treat them as tiles, we find them arranged
in different pattern types,1,138 partly quantified by their CFs.
• Packings have no overlaps: Photoreceptor arrays are
packings with CF < 1
• Coverings have no gaps: AC arrays are coverings with
CF > 1
• Tilings have no overlaps or gaps: BC and GC arrays
resemble tilings with CF ~1
• Mosaics are general patterns of any type, with tile
subtypes.
Cone arrays are mosaics of three tile subtypes (R, G, B) with
CFs < 1 (Fig. 122.20). CFs for complex, branched cells such
as HCs, ACs, or GCs can be more precisely defined as CF =
A µ D, where A is the dendritic or receptive field area (defined
as its convex hull or Voronoi domain) of a single cell in a given
class and D is the density of cells per unit retinal area. Thus, an
AC with a dendritic field 0.5 mm in diameter and a density of
200 cells/mm2 has a CF of 39; each point in the image is
sampled by the receptive fields of 39 ACs of that class. Each
kind of retinal neuron has a coverage that reflects the sampling
necessary to create a seamless set of signals. Patterns can be
very orderly (crystalline), statistically orderly, uniformly dis-
orderly (random) or statistically clumped. One measure of order
within a cell class is the conformity ratio: CR = NND/s, where
NND is the mean nearest-neighbor spacing between cells in
a class and s is the standard deviation of that spacing.139,140 For
large samples, CR ~3 when patterns are statistically orderly
and C > 10 when patterns become nearly crystalline, with clear
axes of object orientation. The primate peripheral blue cone
pattern can reach CR > 3–5, while patterning near the fovea
seems random. Human blue cone patterns seem less rigid than
those of other primates. Nonmammalians, especially teleost
fishes, can display stunning crystalline mosaics141 and blue
cones in those mosaics have CR values approaching 30
(Fig. 122.18), which is so precise that such images can be used
as optical diffraction masks. No mammalian neuron has
FIGURE 122.20. Fine-scale cone patterns.
(Left) Blue cones in the baboon retina visualized
with a redox probe (135). The nonblue cones
were randomly selected to represent VP560
(red) or VP530 (green) cones. The blue cone CR
is 5.5 in the larger data set (not shown). (Right)
Precise blue cone patterns from flatfish retina
(Pleuronectes sp) associated with a precise,
repeating cone mosaic, with CR = 26.7.
(Left) © REM 2003. (Right) Derived from Engstrom K,
Ahlbert IB: Cone types and cone arrangement in the
retina of some flatfishes. Acta Zool 1963; 44:1–11,
edge filtered and thresholded.

FIGURE 122.21. Three major rod pathways in the mammalian retina.
Pathway one is initiated by the high-gain rod >i rod BC > glycinergic
rod AC chain. Glycinergic rod ACs are fanout devices that pass rod
signals to ON cone BCs via gap junctions (resistor symbol) and to
OFF cone BCs via sign-inverting glycinergic synapses. Pathway 2 is
initiated at higher scotopic brightnesses by direct rod > OFF BC
signaling. Pathway 3 is initiated by small gap junctions (Fig. 122.8) at
mesopic ranges and mediate signaling directly though cone pedicles.
© REM 2005.
patterning this rigid. Conversely, widely spaced cells such as
dopamine neurons, other AxCs and IPCs142 in many species
have apparently random mosaics. This would be expected of
neurons with global signaling modes, mediated more by volume
diffusion (e.g., dopamine) than by specific cell contacts. Again,
CR is of more than academic interest. Though the genetic and
signaling mechanisms that control spatial patterning are still
largely unknown,143,144 defects in these pathways may cause
serious sensory impairment.
THE BASIC PATHWAYS OF RETINAL
SIGNALING
The Basic Rod Pathways
Five discrete variants of three major pathways inject rod signals
into the visual system (Fig. 122.21, Box 122.7).18 No known
GC population exclusively carries rod signals, although it
was reported that GC-like biplexiform cells made direct rod
contacts with their dendrites.145 This CG has not yet been vali-
dated to form a distinct population in the mammalian retina.
In pathway 1, the so-called ‘starlight’ circuit, narrow-field gly-
cinergic rod (AII) ACs collect signals from several rod BCs and
redistribute them via gap junctions to ON cone BCs and via
sign-inverting glycinergic synapses to OFF cone BCs. The same
brain pathways that carry cone signals process perception of
scotopic signals. At near-threshold levels, detection is mediated
Functional Anatomy of the Neural Retina
BOX 122.7 Multiple pathways for rod signals
• Canonical “Starlight’’ pathways
• Canonical Scotopic OFF pathway
rods >i rod BCs > rod ACs >i OFF cone BCs > OFF
cone GCs
• Canonical Scotopic ON pathway
rods >i rod BCs > rod ACs :: ON cone BCs > ON
cone GCs
• Noncanonical “Moonlight” pathway
• Noncanonical direct OFF pathway
rods > mixed OFF BC > OFF cone GCs
• Noncanonical “Twilight’’ pathways
• Noncanonical OFF coupling pathway
rods :: cones > OFF cone BCs > OFF cone GCs
CHAPTER 122
• Noncanonical ON coupling pathway
rods :: cones >i ON cone BCs > ON cone GCs
by these high-gain canonical scotopic ON and OFF pathways.
The integration of rod signals by rod BCs generates a response
far more sensitive than an individual rod.18 Rod BCs drive
glycinergic rod ACs with AMPA receptors, making the gly-
cinergic rod AC one of the most light-sensitive elements in the
retina.146 Glycinergic rod ACs, or perhaps the aggregate IPL rod
network, likely generate the scotopic threshold potential of
the electroretinogram (ERG).147 At slightly higher brightnesses,
it is thought that a small population of OFF cone BCs behave as
mixed rod–cone BCs (a cell type abundant in nonmam-
malians19) and collect a small number of rod inputs.18 These
cells may require higher brightnesses and larger rod responses
to generate perceptual responses. Why these are segregated to
OFF channels remains unclear, and these paths have only been
found in nonprimates so far. However, Li et al148 have shown
that all rabbit OFF BC classes show some minor rod input,
though not all individual cells do. Any cell in the equivalent of
class dB2 and dB3 BCs has ~80% chance of contacting a few
rods. Finally, in the mesopic range where both rods and cones
begin to operate, a ‘twilight’ system allows significant leakage of
numerous rod signals into a sparse array of cone pedicles directly.
The Achromatic Cone Pathways
As normal human vision seems richly colored, the concept of
abundant achromatic channels seems odd. But sampling units
in retina must measure the spectral dispersion of light reflected
from an object as the sum of R+G+B (or at least R+G) signals
so that the visual system can encode both object brightness
and the spectral purity or saturation of a patch of light. This is
one role of the diffuse cone BC system. Put simply, these cells
collect summed cone signals and pass them on to parasol GCs
and other wide-field GCs (Fig. 122.22, Box 122.8). However, the
pathways for brightness are clearly more complex, as color-
coded midget systems become noncolor-coded in parafovea and
beyond, as they randomly collect signals from midget BCs
contacting R and G cones.108 There are two likely pathways for
cone OFF BCs. Extending concepts gleaned from homologous
BCs in ground squirrel retinas, primate class dB1 and dB2 likely
use KA receptors,64–65 which are highly glutamate sensitive,
explaining the positioning of their dendrites as flat contacts far
from the ribbon active site. KA receptors are also slightly
slower and more sustained in current responses than AMPA
receptors likely used by dB3 cells. The idea that AMPA and KA
receptors parse the visual world into more and less transient
temporal events deserves careful analysis. Consistent with 1583
 RETINA AND VITREOUS
BOX 122.8 Pathways for diffuse cone BC signals
• Major Diffuse OFF pathways
cones > diffuse OFF KA BCs (dB1, dB3) > OFF cone
GCs
cones > diffuse OFF AMPA BCs (dB2) > OFF cone GCs
• Minor Diffuse OFF pathways
SECTION 3
rods > diffuse OFF BC (mostly dB2, dB3) > OFF cone
GCs
• Diffuse ON pathways
cones > diffuse ON BCs (dB4, 5, 6) > ON cone GC
this, it would appear that large transient GCs sample the
dB3 arbor.79
The Blue Cone Pathways
Blue ON / yellow OFF (B+/Y–) GCs are the only known mam-
malian retinal cells with spectrally biphasic receptive field
centers.82,108 Many nonmammalians have such color-opponent
GCs, BCs, and HCs.101 Both large and small classes of
bistratified GC sample from level 80 of the IPL to capture
signals from the unique blue cone BCs and levels 20–30 to
capture dB2 BC R+G signals (Fig. 122.23, Box 122.9).69 It is
presumed that both arbors of the B+/Y– GCs express the same
mixture of AMPA and NMDA receptors, but this is not known.
Recent evidence suggests the existence of a midget blue–OFF
pathway,61 although how this cell would function in vision is
less clear given the problem of chromatic aberration, where
optimal focus on R and G cones would blur images on the B
cone mosaic. Blurring is arguably one of the selection pressures
forcing sparse distributions of B cones in all species. Finally, the
newly described melanopsin GC is a large-field Y+/B– cell,83
though the path by which the B– signals are acquired is not
clear.
Red–Green Color-Opponent Pathways
Since the early 1970s it has been clear that the primate retina
passes an assortment of color opponent signals to the LGN and
that these tend to be grouped into four categories:
• R+ center / G– surround
• R– center / G+ surround
• G+ center / R– surround
• G– center / R+ surround.
One physiological view originally held that the surround paths
of midgets must also be spectrally pure, while other studies
support spectral mixing by random contacts.73,108,149–151 On
balance, the evidence suggests that cone-specific contacts are
not present in the R and G channels of the primate retina. For
example, though a midget BC ˜ midget GC transfer may report
the signals of a single R cone, the ACs that comprise the lateral
elements collect from nearly all adjacent midget BCs,152 so that
the composition of the surround might be spectrally mixed
1584 (Fig. 122.23, Box 122.10). And if HCs clearly collect from all
FIGURE 122.22. Wide-field achromatic signaling
via OFF (left) and ON (right) parasol GCs in
primate retina. Each GC collects signals directly
from a set of diffuse cone BCs in its central
dendritic field and captures sign-inverting signals
from distant BCs via BC > AC >i BC > GC lateral
feedback and BC > AC >i GC lateral feedforward
chains.
© REM 2005.
FIGURE 122.23. Narrow-field chromatic signaling in bistratified blue
ON/yellow OFF GCs (left) and monostratified ON and OFF foveal
midget (right) GCs in primate retina. Blue ON signals are captured via
blue cone >i blue BC > blue GC chains in the proximal arbor. Yellow
(R+G) OFF signals are captured via R + G cone > dB2 OFF BC > blue
GC chains. Midget GCs that contact single cones have pure R
(VP560) or pure G (VP530) centers and AC-mediated surrounds driven
by varied mixtures of R+G cones. There is also evidence for blue cone
> OFF midget BC signaling (not shown).
© REM 2005.
BOX 122.9 Pathways for blue cone signals
• B+ center/Y- center pathway:
B cones >i blue ON BCs > B+/Y- small and large bistratified
GCs
RG cones > diffuse OFF KA BCs (dB2) > B+/Y- small and
large bistratified GCs
• Blue OFF center/surround pathways
B cones > blue OFF midget BCs > blue OFF midget GC
• B-/Y+ large field pathways
Pathway for B cones not known for this cell
cones or at least R+G cones, that mixture might be present in
all midget BC surrounds.153 If R and G cones are not
chromatypes and downstream BCs, ACs, and GCs make
opportunistic contacts, how can nearly pure R or G surrounds
appear?149 The answer may partly come from two features of
cone patterning. First, the proportions of R and G cones can
vary across individuals (and perhaps species), with human R:G
values ranging from 16 to 1.154–156 Second, fine-scale patterning
of R and G cones is often statistically clustered rather than
randomly uniform.156 Thus a single G cone ˜ midget BC ˜
midget GC chain in an R cone-dominated retina may show
nearly pure R surround signaling. And similarly, that chain in a
retina with equal numbers of R and G cones can plausibly be
found centered in a patch of R cones, since the dendritic fields
of ACs associated with midget cells also tend to be small.157

BOX 122.10 Pathways for red and green cone signals
• Red or Green ON center pathway:
R or G cones >i midget ON BC > midget ON GC
• Red or Green ON center pathway:
R or G cones > midget OFF BC > midget OFF GC
• Generic surround pathways:
RG cones > H1 HC >i RG cones > …
RG cones > H1 HC > midget ON BC …
RG cones > H1 HC >i midget OFF BC …
R and G midget BCs > small-field ACs >i midget BCs >
midget GC
R and G midget BCs > small-field ACs >i midget GC
BOX 122.11 Increment spectral sensitivity functions in
trichromatic primates
• The absorption peaks of cones do not predict the daylight
increment threshold spectral sensitivities of primates
(Fig. 122.24).
• No sum of absorptions reproduces the spectral sensitivity
envelope.
• Cones express VP560 (yellow-green), VP530 (green), or
VP420 (violet-blue).
• Sensitivity peaks are 610 nm (orange-red), 520–530 nm
(green), and 430 nm (blue).
• A number of factors shape the sensitivity channels of the
eye, but the most important are opponent interactions.
• In the absence of opponent functions, the R sensitivity peak
moves to the VP peak:
If green cones are desensitized by adapting lights, the long-
wave sensitivity peak progressively moves from 610 to
560 nm.
Given the individual variability in the R/G cone ratio, it is
surprising that many aspects of color vision seem stable across
individuals, such as the photopic increment threshold spectral
sensitivity (see Box 122.11, Fig. 122.24) and the wavelength of
unique yellow.158 Other measures that probe the densities of
current generators in the eye (e.g., the ERG spectral sensitivity)
show that known variations in the R/G ratio roughly predict
spectral peaks.158 Perception does not vary much. This suggests
that there is a normalization mechanism in the visual system,
such as activity-dependent axon sorting; a major mechanism for
organizing sensory fields. Cortical area V2 in macaque shows
strong evidence of such spectral sorting.159 Furthermore, color
perception itself shows evidence of highly plastic properties that
tune vision, perhaps regardless of R/G cone ratio.160
Melanopsin Pathways
The melanopsin pathway is an exciting discovery, but not easy
to understand as these cells integrate signals from rods, cones
and their own intrinsic phototransduction. Dacey et al show
that primate melanopsin GCs are also rare Y+/B– cells but that
both inner and outer classes of melanopsin GCs show the same
polarity of response.83 The signaling channels for melanopsin
GCs (Box 122.12) include rods and cones via directly glutamate
gated AMPA and/or NMDA receptors. The intrinsic 11-cis
retinaldehyde isomerization coupled transduction88 accesses an
unknown conductance to initiate spiking. Melanopsin GCs
appear to be a diverse population morphologically and target the
LGN, SCN, and olivary pretectum. The fact that they project to
LGN and give extremely sustained light responses proportional
Functional Anatomy of the Neural Retina
FIGURE 122.24. The mismatch between primate photopic spectral
CHAPTER 122
sensitivity profiles and VP absorption functions plotted on a
normalized log10 sensitivity ordinate (log S) and a linear wavelength
abscissa (l). Dotted lines from left to right are normalized VP420,
VP499, VP530, and VP560 absorbance functions. The circles are the
4-day mean increment threshold spectral sensitivity for a rhesus
monkey in log S = log (1/Q) for a 2° foveally centered test flash on a
10° neutral white 10 000 K background Maxwellian view field. Data
recorded by REM in 1971.There are several mismatches with the
pigment curves: (1) The long-l peak is at 610 nm;(2) The mid-l
complex is broad; (3) There is a minimum at 580 nm; (4) There is a
minimum at 470 nm; (5) The short-l peak is at 450+ nm; (6) The short-
l band is narrow; (7) No sum of VPs matches the spectral sensitivity.
© REM 2005.
BOX 122.12 Speculative pathways for melanopsin GCs
• RG Cones >i ON diffuse BCs (dB6?) > inner melanopsin GCs
• RG cones > OFF diffuse KA BCs (dB1?) > GABA ACs
>i outer melanopsin GCs
• B cones >i blue ON BCs > GABA ACs >i inner melanopsin
GCs
• B cones > ? > outer melanopsin GCs
• Melanopsin GCs > LGN > Cx > brightness perception?
• Melanopsin GCs > SCN > photoentrainment
• Melanopsin GCs > pretectum > pupillary reflex
? denotes unknown or uncertain.
to flux over many decades83 argues that they may correspond to
intrinsic luminosity cells of the visual system.
FURTHER ELEMENTS OF RETINAL
STRUCTURE
INTRODUCTION
The retina is a complex, dynamic neural structure. Despite the
accumulation of apparently precise pathway models, they are
incomplete in many ways. The modes and weights of HC
signaling are still uncertain. The most common synapses in the
IPL, serial AC ˜ AC elements, have had no formal place in
any model until recently. Many modes of physiological sig-
naling involve widespread targets and multiple sources,
including retinal efferents, and their roles in vision is not
understood. MCs could clearly locally modulate neural efficacy
through ATP-gated channels and regulation of extracellular ion
and neurotransmitter levels, but it is not known if they do. 1585
 RETINA AND VITREOUS
Visual experience in development influences GC maturation
and loss of visual drive in retinal degenerations triggers neural
remodeling of the retina. Some GCs are intrinsically
photosensitive, as has been seen. This next section will briefly
review the imports of some of these topics.
SERIAL SYNAPSES AND NESTED FEEDBACK
Serial AC ˜ AC synapses comprise about two-third of the IPL
synapses in nonmammalians161 and a smaller fraction in
mammals,162 yet they had no established role in any pathway,
until recently. Indeed, AC ˜ AC ˜ AC triplets are far from
rare, which offers significant opportunities to shape circuits,
but why? And how? At the least, this argues that most network
models are incomplete. Some evidence indicates that such
synapses are part of nested feedback and feedforward paths
• Feedback: BC > AC >i BC
• Nested Feedback: BC > AC >i > AC >i BC
SECTION 3
• Feedforward: BC > AC >i GC
• Nested Feedforward: BC > AC >i > AC >i GC
Concatenating sign-inverting paths formally represent positive
feedback, which is potentially destabilizing: AC >i AC >i BC ß
AC > BC. Biological reality is more complex. First, the
abundance of serial chains means that positive feedback, if it
occurs, does not destabilize vision. Second, these signals are
progressively delayed in time, so their effects do not sum
statically. Finally, the gains of inhibitory synapses are typically
fractional (<1), so the net pathway gain becomes even
smaller.161 This suggests that serial synapses could effectively
shape many pathways in subtle ways and may be generic to
many feedback and feedforward networks.
More recently, Hennig et al163 implemented nested AC
elements in a comprehensive mathematical model of linear and
nonlinear retinal GC signaling, and found that the influence of
nesting was weak, consistent with subtle shaping rather than
destabilizing positive feedback. Results from the laboratory of
the late Ramon Dacheux strongly implicate serial synapses in
signaling asymmetries that may contribute to the directional
biases of DS GCs.80,164
EFFERENTS
Efferent pathways from CNS systems are well known in
nonmammalians but have been controversial in mammals,
though both Ramón y Cajal165 and Polyak166 described them.
Polyak clearly identified efferent fibers in the optic nerve that
arborized in the IPL of primate retina166 and separate serotonin-
and histamine-immunoreactive efferents targeted the IPL have
now been described.167–170 The roles of these efferents for vision
remains unknown, but the close association of both systems
with retinal vessels is provocative. Further, both rod and cone
ON BCs in baboon express HR3 histamine receptors on their
dendritic tips, but the relation between neuronal expression of
histamine receptors and IPL efferents is uncertain.171 However,
the discovery of serotonin-immunoreactive efferents gives the
first compelling physiological drive path for serotonin-receptor
systems in the retina, as there are no known intrinsic sero-
toninergic neurons in the mammalian retina, unlike nonmam-
malians3 which express elegant wide-field GABAergic/
serotoninergic ACs.
THE DOPAMINE PATHWAY
Dopamine neurons represent the quintessential AxC
pathway.3,18,171 The dominant TH1 (tyrosine hydroxylase
1586 type 1) AxCs, are narrowly stratified cells that arborize at level
0–10 of the IPL with medium-field dendritic arbors and fine,
complex axon terminal fields.172 It has long been suspected that
most retinas harbor more than one class of TH immunoreactive
cell173,174 and rodents clearly possess at least two; TH1 cells are
typical AxCs and are not GABA immunoreactive, while TH2
cells are more AC-like (lacking axons), often express epitope-
masked or phosphorylation-masked TH immunoreactivity and
are also GABA immunoreactive.175,176 TH1 AxCs appear to be
spontaneously spiking ‘clock-like’ cells that resemble spon-
taneously signaling dopamine neurons in brain.177,178 They
have some weak excitatory inputs but many inhibitory inputs
appear to be under strong GABAergic control.3 In any case, TH1
cells appear to be activated by photopic stimuli, making them
signalers of dawn. Dopamine released by vesicular means
probably diffuses through the retina to its various targets.171
Virtually every class of retinal cell, including photoreceptors and
MCs has been reported to express dopamine receptors.171
Basically, dopamine signals appear to light-adapt the retina by
diverse G-protein coupled mechanisms such as HC uncoupling179
and enhancement of GC response speed.180 The scale and scope
of these adaptive signals are under intense study, but it is of
great interest that retinal dopamine cells also display high levels
of circadian clock gene expression, potentially making them key
elements for intrinsic retinal photoperiod control.181 This
pathway appears separate from the melanopsin GC path, but it
is intriguing that the dendrites of outer melanopsin GCs co-
stratify with TH1 cells.
NONCANONICAL SIGNALING MODES
In many ways the retina is a complex neuroendocrine organ
whose operations we understand poorly. We can only offer a
brief survey of many intrinsic ‘parahormonal’ systems in retina
that depend on nonvesicular or diffusion-based signaling
(e.g., dopamine neurons). Photoreceptors are known to syn-
thesize and release melatonin at night, and this signaling is
thought to modulate both RPE-mediated photoreceptor outer
segment phagocytosis and the activity of dopaminergic
neurons.3,182 There is now evidence, in addition to cyclic cons-
titutive regulation, that excessive melatonin exposure enhances
the sensitivity of photoreceptors to light damage and specifically
regulates the expression of a restricted set of ocular genes.182
Neurons with the capacity to express high levels of nitric
oxide (NO) synthase and generate NO as a signaling molecule
have been termed nitrergic.3,8,183 Some of these cells are clearly
AxCs.8 By local diffusion across cell membranes, NO binds to
the heme core of soluble guanyl cyclase and activates high levels
of cGMP production which, in turn, has the capacity to
modulate gap junction permeability184 as well as open local
cyclic nucleotide gated cation channels. The regulation of these
systems and their light stimulus selectivities are not well
known and it is suspected that many cell classes can produce
NO beyond the identified nitrergic AxCs.183
GABA has intermittently been identified in BCs of the
mammalian retina, including cat and monkey, with no clear
mechanism of action.3 Recently it has been suggested that
a set of OFF cone BCs in cat retina similar to dB1 in monkey are
dual GABA/glutamate-releasing neurons.185 The co-stratification
of the terminals of these BCs with the dopaminergic TH1
plexus in the distal IPL suggests the possibility of OFF BC >i
dopamine AC signaling, which would be consistent with the
apparent depolarization of dopamine cells by light, yet
restriction of synaptic inputs to the OFF BC region of the IPL.
GABA-immunoreactive BCs appear more abundant in monkey
and it is not clear, however, that they can all be OFF BCs.
MCs and the optic fiber layer are key positions to modulate
the signaling of neurons in the retina. Indeed it appears that

excitation-induced calcium waves that propagate locally in the
GCL and OFL in the astrocyte and MC network can directly
modulate GC excitability.186 Moreover, MCs have now been
shown to release ATP, which may directly activate calcium entry
via purinergic receptors on vascular pericytes, in turn triggering
local vasoconstriction.187 Thus retinal activity has the potential
to locally regulate blood flow through MC signal integration.
The scope and strength of such MC signaling is yet unknown.
Peptide-releasing neurons in the mammalian retina include
different cohorts of wide-field GABAergic ACs that express
neuropeptide Y (NPY), substance P (SP) or vasoactive intestinal
peptide (VIP), AxC-like cells expressing somatostatin (SRIF)
and minor (but not necessarily unimportant) populations
expressing several other neuroactive peptides.37 The detailed
relationships between fast neurotransmitter versus slow peptide
secretion signaling from the same cell are simply unclear. But it
has long been suspected that peptide-containing vesicles are
released by an exocytosis mechanism that requires much more
calcium entry (and hence stronger depolarization) than fast
neurotransmitter vesicle fusion. Even when there is evidence of
a possible signaling mode, we have little insight as to the
purpose. For example, SRIF appears excitatory on a seconds-to-
minutes timescale in GCs188 and induces an increase in input
resistance in ON BCs.189 How these events are related remain
unclear. Though it is widely accepted that specific peptides
likely have circuit-specific modulatory functions, specific roles
in any of the canonical pathways are not known. It is also not
known how far peptides diffuse and how long they persist in the
extracellular space. Other peptide-like associations have even
less certain functions. The blue cone BCs of primates also
express cholecystokinin (CCK)-like immunoreactivity26,37 and
CCK does suppress GC activity, but no correspondence has
been established for this in the canonical blue cone ˜ blue cone
BC ˜ B+/Y– GC pathway. And it is not clear that blue cone
BCs actually release bona fide CCK.
ACTIVITY-DEPENDENT PLASTICITY, RETINAL
REMODELING, AND PHOTORECEPTOR
DEGENERATIONS
The elegant structure of the mammalian retina can no longer
be viewed as static and hard-wired. Indeed, the retina undergoes
postnatal refinement in synaptic connectivity,190,191 possible
revisions in gene expression in response to visual environments
at maturity, and reactive rewiring when challenged by
photoreceptor degenerations.11 We are only beginning to
understand the scope of these physical transformations, but it
is now clear that adult retinal neurons can revise their patterns
of synaptic contacts and generate new processes.11 During
postnatal life in rodents, the visual environment influences the
onset of bouts of spontaneous signaling thought to be required
for synaptic maturation144,190 and modulates the segregation of
the IPL into ON and OFF sublayers, apparently through a
dendritic pruning process.191 While previous research in the
1970s produced contentious views on activity-dependent retinal
maturation,11 many studies can now be revisited in light of
modern findings. The IPL is clearly the site of most of these
effects, but it would now be imprudent to exclude the OPL.
Recently, Fisher and colleagues have detailed a range of
cellular remodeling phenomena and mechanisms including
rapid neurite sprouting, neuronal migration and MC hyper-
trophy in response to chronic retinal detachment.192 These
plastic abilities of adult neuron cells presaged discoveries
perhaps even more surprising to retinal biologists (but not to
CNS biologists); the amazing propensity for retinal neurons to
rewire aggressively in response to retinal degenerations.11,193 So
far, all known photoreceptor degenerations trigger major
Functional Anatomy of the Neural Retina
revisions of retinal circuitry in three phases.11 In phase 1,
photoreceptor stress triggers the retraction of BC dendrites from
rod and/or cone synapses. Indeed, the first signs of visual
impairment in RP are likely to be a result of the phase 1 loss of
dendritic compartment in BCs before there is significant loss in
photoreceptor signaling. Indeed, given the ability of BCs to
report even small photoreceptor signals, early visual
impairment more readily implies defects in synaptic signaling
than phototransduction. The diverse genetic types of RP exhibit
different modes of photoreceptor loss. If the mode of degener-
ation is cone-sparing, rod BCs attempt to transient capture
inputs from surviving cones. If the degeneration is rod–cone
lethal, all BCs disassemble their dendritic modules, including
their signaling receptors. In phase 2, photoreceptor death leads
to loss of the ONL and the development of a MC seal between
the remnant RPE (if it survives) or the choroid and the remnant
neural retina. Finally, in phase 3, the retina undergoes a
prolonged epoch of revision that involves additional neuronal
CHAPTER 122
death, formation of new process fascicles and new ectopic
synaptic microneuromas, and even neuronal migration leading
to mixing of the INL and GCL through disrupted zones of the
IPL.11,193 Synaptogenesis leads to new networks in micro-
neuromas, and these networks appear to be random collections
of opportunistic connections. These generate networks that
seem optimized for self-excitation rather than visual sig-
naling.194 In general, these transformations challenge thera-
peutic intervention windows and repair strategies of all types,
from genetic to bionic, for all forms of retinal degeneration.
SUMMARY AND PERSISTENT QUESTIONS
Our understanding of the populations of neurons that make up
a retina has expanded. Clearly, at least 60 and maybe even
80 cell classes are involved, and our catalog is likely to become
even more detailed.195 Though most of the canonical pathway
neurons have likely been identified, every pathway is beset with
questions regarding signaling modes and strengths; almost
every pathway has undefined synaptic partners, especially
among the AC cohort; and every retina almost certainly harbors
small populations of poorly defined or even yet-unknown
neuron classes.195 Sparseness or difficulty in identification of a
cell class does not imply relative unimportance. TH1 dopamine
AxCs are among the rarest of neurons in the ACL and their
actions are global and powerful. Melanopsin GCs are among the
rarest of GCs and they are essential carriers of photoperiod and
pupillary control signals. We still do not have a proven role for
a clearly heterogeneous set of retinal efferent fibers originating
in hypothalamus and brainstem.
Even simple issues; such as how neurons choose partners to
contact, remains elusive. This is especially true of the R and G
cones of trichromatic primates, which seemed to have evolved
so recently via VP gene duplication that no other gene
expression differences have clearly emerged that would ‘label’
them as specific chromatypes for putative R–G opponent neu-
rons, as did occur in nonmammalians. Conversely, B cones and
rods each express many different genes (beyond VP expression),
some of which clearly drive formation of selective contacts. But
what are we to make of new patterns of cones that selectively
express vGlut2 but are still G cones in mouse,29 or sparse
human cones that express no opsin except melanopsin?30
HCs, the first cells in the outer retina from which
intracellular recordings were ever made, remain one of the most
enigmatic. Are they truly neurons? How do they signal their
targets? Why do they form nearly half of the capillary
endothelial ensheathment in the mature retina?196 What does
the rod-specific axon terminal actually do? Is signaling
transmitter-mediated by GABA or is it ephaptic, or both? 1587
 RETINA AND VITREOUS

Why do most HCs express no GABA? Where are the vesicles
and are the vesicles we can see presynaptic or cargo vesicles?
What are the selective roles of H1 and H2 HCs. And where is
the H3 HC array?
The BC population is clearly settling into 10 defined classes;
a single rod BC class, a single blue cone ON BC class, two
midget cone BC classes (ON and OFF), and at least three classes
each of diffuse ON cone BCs and diffuse OFF cone BCs. The
canonical rod ˜ rod BC ˜ rod AC ˜ cone BC ˜ cone GC
pathway has now been augmented with a minor rod ˜ diffuse
OFF cone BC ˜ OFF cone GC path, owing to very small
numbers of rod contacts made by some OFF cone BCs.148 The
stochastic nature of these contacts gives pause (not all OFF BCs
of a given class make them), but they clearly function. The
discovery of blue OFF midget BCs61 might partly explain the
sparse appearance of B–/Y+ neurons in the primate LGN197
except for the fact that the fields of these cells tend to large and
better match those of melanopsin GCs, whose dendrites likely
SECTION 3
essential functions, which are likely nonperceptual, likely
involve more types of GCs than the major perceptual
pathways,1 which in turn demand the bulk of retinal wiring.
Further classification and reconstructing the connectivity of
diverse GC classes remains a key target for the next decade.
In the end, why should such effort be applied to the details
and the nuances of neuronal form and retinal circuitry? First,
discoveries based on new molecular imaging tools continue to
challenge any simplistic model of retinal organization by
finding new cells, new contacts and new functions in the retina.
Second, a range of inherited disorders arise from genes associ-
ated with building the neural retina and those genes represent
both our evolutionary path and mechanisms we must under-
stand if we are ever to make retinal repair a reality. Third, the
details of wiring and global control, and the scope and speed of
disease-triggered rewiring reveal that the effects of many forms
of retinal degenerations once thought to be restricted to the
outer retina actually propagate aggressively into the neural

never go near the terminals of blue OFF midget BCs. An
exciting new concept in BC physiology is the idea that AMPA
receptors and KA receptors are differentially expressed on dB3
and dB1/2 OFF cone BCs respectively, perhaps setting up the
basis of fast (transient) and slow (sustained) BC channels64 and
matching GC contacts. If this is a basic format, then one might
expect mGluR6-mediated transduction to vary in kinetics across
classes of diffuse ON cone BCs. Specifically, might not dB4
resemble dB3 in being the ‘fast’ cone BC for the ON channel?
The ACs and the specialized, axon-bearing group we term
association or AxCs (which include polyaxonal cells), remain
our biggest challenge to understand. The diversity of AC
dendritic arbors clearly does not fit a simplistic world of ACs
monostratified for corresponding BCs44 but does argue for
highly circuit-selective functions.195 It is possible that glycine
AC systems are biased to signal across BC channels while
GABA AC systems mostly signal within BC channels. The
signaling of GABA receptors remains complex and likely finely
tuned. Each conventional inhibitory synapse access a mixture of
receptors or individually pure receptor patches. This fine-scale
analysis is just beginning.
The cohort of GCs has been better circumscribed over the
past decade, but has also become far more complex with the
advent of multimodal melanopsin GC signaling and more cell
classes than we have models for. We are closer than ever to
understanding how DS GCs work, though study of such cells in
primates is just beginning. Many classes of GCs clearly have
more to do with the optical ‘plant’ of the eye; guiding fast and
fine eye movements, driving foveation, discriminating self-
movement from world-movement, creating the optic flow field,
harmonizing visual drift and vestibular information, etc. These
retina and likely the brain. Learning the rules and molecular
mechanisms underlying postnatal plasticity is required to
realize retinal restoration in diseases and traumas we cannot yet
prevent. Finally, the neural retina remains unbowed. Though
we believe we have disclosed its essences, it is proving to be a
far richer organ than anticipated.
Retinal neuroanatomy is not a static field. The accelerating
pace of discoveries augurs major revelations in retinal circuitry
in the next decade, rather than mere refinements of current
views. Since the last revision of this chapter, over 1500 papers
have been published with reference to cones alone; over 1000
on retinal GCs alone; over 1000 on ACs and BCs combined.
Over half of the references cited herein have been published
since the year 2000. Many of the references are reviews and
space limitations prevent a traditional historical treatment of
the literature. It is no longer practical to cite the first instance
of an idea or discovery (e.g., Ramón y Cajal or Tartuferi), much
less its most lucid modern declamation or important related
papers. It is hoped that readers will use this chapter as a point
of departure in a greater scientific and medical adventure.
ACKNOWLEDGMENTS
These last lines are the most difficult. On 30 May 2006 Ramon F Dacheux
passed away: untimely, much beloved and admired. He and Elio Raviola
crafted the modern view of retinal neuroanatomy for Principles and
Practice of Ophthalmology a decade ago. It strongly guided my revisions.
Much new science has transpired and I have retained few references.
I believe that nothing would have pleased Ray more than the inclusion of
one of his most vivid recent accomplishments: Dacheux RF, Chimento MF,
Amthor FR. Synaptic input to the on-off directionally selective ganglion cell
in the rabbit retina. J Comp Neurol 2003; 456:267–278.

REFERENCES
1. Oyster C: The human eye. New York:
Sinauer; 1999.
2. Bayer BE: Color imaging array. US patent
no. 3971065; 1976.
3. Marc RE: Retinal neurotransmitters. In:
Chalupa LM, Werner J, eds. The visual
neurosciences. Cambridge: MIT Press;
2004:315–330.
4. Wässle H: Parallel processing in the
mammalian retina. Nat Rev Neurosci 2004;
5:747–757.
5. Copenhagen D: Excitation in the retina: the
flow, filtering and molecules of visual
signaling in the glutamatergic pathways
from photoreceptors to ganglion cells. In:
Chalupa LM, Werner J, eds. The visual
1588
neurosciences. Cambridge: MIT Press;
2004:320–333.
6. Slaughter M: Inhibition in the retina. In:
Chalupa LM, Werner J, eds. The visual
neurosciences. Cambridge: MIT Press;
2004:355–368.
7. Kamermans M, Fahrenfort I: Ephaptic
interactions within a chemical synapse:
hemichannel-mediated ephaptic inhibition
in the retina. Curr Opin Neurobiol 2004;
14:531–541.
8. Vaney D. Retinal Amacrine Cells. In:
Chalupa LM, Werner J, eds. The visual
neurosciences. Cambridge: MIT Press;
2004: 395–409.
9. Feng G, Mellor RH, Bernstein M, et al:
Imaging neuronal subsets in transgenic
mice expressing multiple spectral
variants of GFP. Neuron 2000;
28:41–51.
10. Morgan J, Huckfeldt R, Wong RO: Imaging
techniques in retinal research. Exp Eye Res
2005; 80:297–306.
11. Marc RE, BW Jones, CB Watt, Strettoi E:
Neural remodeling in retinal degeneration.
Prog Retin Eye Res 2003; 22:607–655.
12. Marc RE, BW Jones, Watt CB: Retinal
remodeling: circuitry revisions triggered by
photoreceptor degeneration. In: Pinaud R,
Tremere LA, De Weerd P, eds. Plasticity in
the visual system: from genes to circuits.
Springer; 2005: 33–54.

13. Illing ME, Rajan RS, Bence NF, Kopito RR:
A rhodopsin mutant linked to autosomal
dominant retinitis pigmentosa is prone to
aggregate and interacts with the ubiquitin
proteasome system. J Biol Chem 2002; 37,
34150–34160.
14. Carroll R: Vertebrate paleontology and
evolution. New York: W. H. Freeman and
company; 1988:698.
15. Famiglietti EV, Kolb H: A bistratified
amacrine cell and synaptic circuitry in the
inner plexiform layer of the retina. Brain
Res 1975; 84:293–300.
16. Strettoi E, Dacheux RF, Raviola E: Synaptic
connections of rod bipolar cells in the inner
plexiform layer of the rabbit retina. J Comp
Neurol 1990; 295:449–466.
17. Strettoi E, Raviola E, Dacheux RF: Synaptic
connections of the narrowfield, bistratified
rod amacrine cell (AII) in the rabbit retina.
J Comp Neurol 1992; 325:152–168.
18. Sterling P: How retinal circuits optimize the
transfer of visual information. In:
Chalupa LM, Werner J, eds. The visual
neurosciences. Cambridge: MIT Press;
2004:234–259.
19. Ishida A, Stell W, Lightfoot D: Rod and
cone inputs to bipolar cells in goldfish
retina. J Comp Neurol 1980;
191:315–335.
20. Graham DR, Overbeek PA, Ash JD: Leukemia
inhibitory factor blocks expression of Crx
and Nrl transcription factors to inhibit
photoreceptor differentiation. Invest
Ophthalmol Vis Sci 2005; 46:2601–2610.
21. Bumsted O’Brien KM, Cheng H, Jiang Y,
et al: Expression of photoreceptor-specific
nuclear receptor NR2E3 in rod
photoreceptors of fetal human retina. Invest
Ophthalmol Vis Sci 2004; 45:2807–2812.
22. Cheng H, Khanna H, Oh ECT, et al:
Photoreceptor-specific nuclear receptor
NR2E3 functions as a transcriptional
activator in rod photoreceptors. Hum Mol
Genet 2004; 13:1563–1575.
23. Register EA, Yokoyama R, Yokoyama S:.
Multiple origins of the green-sensitive opsin
genes in fish. J Mol Evol 1994; 39:268–273.
24. Bumsted K, Hendrickson A: Distribution
and development of short-wavelength
cones differ between Macaca monkey
and human fovea. J Comp Neurol 1999;
403:502–516.
25. Ahnelt PK, Kolb H, Pflug R: Identification of
a subtype of cone photoreceptor, likely to
be blue sensitive, in the human retina.
J Comp Neurol 1987; 255:18–34.
26. Kouyama N, Marshak DW: Bipolar cell
specific for blue cones in the macaque
retina. J Neurosci 1992; 12:1233–1252.
27. Nathans J: The evolution and physiology of
human color vision: insights from molecular
genetic studies of visual pigments. Neuron
1999; 24:299–312.
28. Wang Y, Smallwood PM, Cowan M, et al:
Mutually exclusive expression of human
red and green visual pigment-reporter
transgenes occurs at high frequency in
murine cone photoreceptors. Proc Natl
Acad Sci USA 1999; 96:5251–5256.
29. Wässle H, Regus-Leidig H, Haverkamp S:
Expression of the vesicular glutamate
transporter vGluT2 in a subset of cones of
the mouse retina. J Comp Neurol 2006;
496:544–555.
30. Dkhissi-Benyahya O, Rieux C, Hut RA,
Cooper HM: Immunohistochemical
evidence of a melanopsin cone in human
Functional Anatomy of the Neural Retina
retina. Invest Ophthalmol Vis Sci 2006;
47:1636–1641.
31. Marc RE: Interplexiform cell connectivity in
the outer retina. In: Archer S, Djamgoz MBA,
Vallerga S, eds. Neurobiology of the
vertebrate outer retina. London: Chapman
and Hall; 1995:369–393.
32. Wehman AM, Staub W, Meyers JR, et al:
Genetic dissection of the zebrafish retinal
stem-cell compartment. Dev Biol 2005;
281:53–65.
33. Perron M, Harris WA: Retinal stem cells in
vertebrates. Bioessays 2000; 22:685–688.
34. Hoffert JR, Baeyens DA, Fromm PO: The
resistance of teleost ocular tissues to
oxygen toxicity. Invest Ophthalmol 1973;
12:858–861.
35. Kalloniatis M, Marc RE, Murry R: Amino
acid signatures in the primate retina.
J Neurosci 1996; 16:6807–6829.
36. Morgan JL, Dhingra A, Vardi N, Wong RO:
Axons and dendrites originate from
neuroepithelial-like processes of retinal
bipolar cells. Nat Neurosci 2006;
9:85–92.
37. Brecha N: Peptide and peptide receptor
expression and function in the vertebrate
retina. In: Chalupa LM, Werner J, eds. The
visual neurosciences. Cambridge: MIT
Press; 2004:334–354.
38. Migdale K, Herr S, Klug K, et al: Two ribbon
synaptic units in rod photoreceptors of
macaque, human, and cat. J CompNeurol
2003; 455:100–112.
39. Sterling P, Matthews G: Structure and
function of ribbon synapses. Trends
Neurosci 2005; 28:20–29.
40. Matthews G: Synaptic mechanisms of
bipolar cell terminals. Vision Res 1999;
39:2469–2476.
41. Wilson M. Retinal Synapses. In: Chalupa LM,
Werner J, eds. The visual neurosciences.
Cambridge: MIT Press; 2004:279–303.
42. Marc RE, Jones BW: Molecular
phenotyping of retinal ganglion cells.
J Neurosci 2002; 22:413–427.
43. Rockhill RL, Daly FJ, MacNeil MA, et al:
The diversity of ganglion cells in a
mammalian retina. J Neurosci 2002;
22:3831–3843.
44. MacNeil MA, Heussy JK, Dacheux RF, et al:
The shapes and numbers of amacrine cells:
matching of photofilled with Golgi-stained
cells in the rabbit retina and comparison
with other mammalian species. J Comp
Neurol 1999; 413:305–326.
45. Nelson R., Kolb H: On and off pathways in
the vertebrate retina and visual system
(2004). In: Chalupa LM, Werner J, eds.
The visual neurosciences. Cambridge:
MIT Press; 2004:260–278.
46. Perkins GA, Ellisman MH, Fox DA:
Three-dimensional analysis of mouse rod
and cone mitochondrial cristae
architecture: bioenergetic and functional
implications. Mol Vis 2003; 9:60–73.
47. Ripps H: Cell death in retinitis pigmentosa:
gap junctions and the ‘bystander’ effect.
Exp Eye Res 2002; 74:327–336.
48. Chun MH, Grunert U, Martin PR, Wässle H:
The synaptic complex of cones in the fovea
and in the periphery of the macaque
monkey retina. Vision Res 1996;
36:3383–3395.
49. Raviola E, Gilula NB: Gap junctions
between photoreceptor cells in the
vertebrate retina. Proc Natl Acad Sci USA
1973; 70:1677–1681.
50. Raviola E, Gilula NB: Intramembrane
organization of specialized contacts in the
outer plexiform layer of the retina. A freeze
fracture study in monkeys and rabbits.
J Cell Biol 1975; 65:192-222.
51. Güldenagel M, Ammermüller J,
Feigenspan A, et al: Visual transmission
deficits in mice with targeted disruption
of the gap junction gene connexin36.
J Neurosci 2001; 21:6036–6044.
52. Deans MR, Volgyi B, Goodenough DA,
et al: Connexin36 is essential for
transmission of rod-mediated visual signals
in the mammalian retina. Neuron 2002;
36:703–712.
53. Li W, DeVries SH: Separate blue and green
cone networks in the mammalian retina.
Nat Neurosci 2004; 7:751–756.
54. Hornstein EP, Verweij J, Schnapf J:
Electrical coupling between red and green
CHAPTER 122
in primate retina. Nat Neuroscience 2004;
7:745–750.
55. Nelson R, Famiglietti EV, Kolb H:
Intracellular staining reveals different levels
of stratification for on and offcenter
ganglion cells in cat retina. J Neurophysiol
1978; 41:472–483.
56. Missotten L: The ultrastructure of the
human retina. Brussels: Editions Arscia
Uitgaven; 1965.
57. Kolb H: Organization of the outer plexiform
layer of the primate retina: electron
microscopy of Golgi impregnated cells.
Phil Trans R Soc Lond B 1970;
258:261–283.
58. Dowling JE, Boycott BB: Organization of
the primate retina: electron microscopy.
Proc R Soc Lond B 1966; 166:80–111.
59. Boycott BB, Hopkins M: Cone synapses of
a flat diffuse cone bipolar cell in the
primate retina. J Neurocytol 1993;
22:765–778.
60. Tsukamoto Y, Morigiwa K, Ueda M,
Sterling P: Microcircuits for night vision in
mouse retina. J Neurosci 2001;
21:8616–8623.
61. Klug K, Herr S, Tran Ngo I, et al: Macaque
retina contains an s-cone off midget
pathway. J Neurosci 2003; 23:9881–9887.
62. Li W, DeVries SH: Bipolar cell pathways for
color and luminance vision in a dichromatic
mammalian retina. Nat Neurosci 2006;
9:669–675.
63. Haverkamp S, Grunert U, Wässle H:
Localization of kainate receptors at the
cone pedicles of the primate retina.
J Comp Neurol 2001; 436:471–486.
64. DeVries SH: Bipolar cells use kainate and
AMPA receptors to filter visual information
into separate channels. Neuron 2000;
28:847–856.
65. Devries SH, Li W, Saszik S: Parallel
processing in two transmitter
microenvironments at the cone
photoreceptor synapse. Neuron 2006;
50:735–748.
66. Boycott B, Wässle H: Parallel processing in
the mammalian retina: the proctor lecture.
Invest Ophthalmol Vis Sci 1999;
40:1313–1327.
67. Famiglietti EV Jr: Class I and class II
ganglion cells of rabbit retina: a structural
basis for X and Y (brisk) cells. J Comp
Neurol 2004; 478:323–346.
68. Kolb H, Nelson R, Mariani A: Amacrine
cells, bipolar cells and ganglion cells of the
cat retina: a Golgi study. Vision Res 1981;
21:1081–1114. 1589
 RETINA AND VITREOUS
69. Dacey DM, Peterson BB, Robinson FR,
Gamlin PD: Fireworks in the primate retina:
in vitro photodynamics reveals diverse
LGN-projecting ganglion cell types. Neuron
2003; 37:15–27.
70. Yamada ES, Bordt AS, Marshak DW:
Wide-field ganglion cells in macaque
retinas. Vis Neurosci 2005; 22:383–393.
71. Coombs J, van der List D, Wang GY,
Chalupa LM: Morphological properties of
mouse retinal ganglion cells. Neuroscience
2006; 140:123–136.
72. Kolb H, Marshak DW: The midget pathways
of the primate retina. Doc Ophthalmol
2003; 106:67–81.
73. Diller L, Packer OS, Verweij J, et al: L and
M cone contributions to the midget and
parasol ganglion cell receptive fields of
macaque monkey retina. J Neurosci 2004;
24:1079–1088.
74. Dowling JE, Boycott BB: Organization of
SECTION 3
the primate retina: electron microscopy.
Proc R Soc Lond B 1966; 166:80–111.
75. West RW, Dowling JE: Synapses onto
different morphological types of retinal
ganglion cells. Science 1972; 178:510–512.
76. Wässle H, Boycott BB, Illing RB:
Morphology and mosaic of on and off beta
cells in the cat retina and some functional
considerations. Proc R Soc Lond [B] 1981;
212:177–195.
77. Jusuf PR, Martin PR, Grunert U: Random
wiring in the midget pathway of primate
retina. J Neurosci 2006; 26:3908–3917.
78. Jacoby RA, Marshak DW: Synaptic
connections of db3 diffuse bipolar cell
axons in macaque retina. J Comp Neurol
2000; 416:19–29.
79. Calloway EM: Cell types and local circuits
in primary visual cortex of the macaque
monkey. In Chalupa LM, Werner J, eds.
The visual neurosciences. Cambridge:
MIT Press; 2004:680–694.
80. Masland RH: Directional selectivity in
retinal ganglion cells. In Chalupa LM,
Werner J, eds. The visual neurosciences.
Cambridge: MIT Press; 2004:451–562.
81. Yamada ES, Dmitrieva N, Keyser KT, et al:
Synaptic connections of starburst amacrine
cells and localization of acetylcholine
receptors in primate retinas. J Comp
Neurol 2003; 461:76–90.
82. Dacey DM, Lee BB: The blue-ON opponent
pathway in primate retina originates from a
distinct bistratified ganglion cell type.
Nature 1994; 367:731–735.
83. Dacey DM, Liao HW, Peterson BB, et al:
Melanopsin-expressing ganglion cells in
primate retina signal colour and irradiance
and project to the LGN. Nature 2005;
433:749–754.
84. Berson DM, Dunn FA, Takao M:
Phototransduction by retinal ganglion cells
that set the circadian clock. Science 2002;
295:1070–1073.
85. Hattar S, Lucas RJ, Mrosovsky N, et al:
Melanopsin and rod–cone photoreceptive
systems account for all major accessory
visual functions in mice. Nature 2003;
424:76–81.
86. Tu DC, Zhang D, Demas J, et al:
Physiologic diversity and development of
intrinsically photosensitive retinal ganglion
cells. Neuron 2005; 48:987–999.
87. Lucas RJ, Hattar S, Takao M, et al:
Diminished pupillary light reflex at high
irradiances in melanopsin-knockout mice.
1590 Science 2003; 299:245–247.
88. Fu Y, Zhong H, Wang MH, et al: Intrinsically
photosensitive retinal ganglion cells detect
light with a vitamin A-based photopigment,
melanopsin. Proc Natl Acad Sci USA 2005;
102:10339–10344.
89. Freedman MS, Lucas RJ, Soni B, et al:
Regulation of mammalian circadian
behavior by non-rod, non-cone, ocular
photoreceptors. Science 1999;
284:502–504.
90. Silva MM, Albuquerque AM, Araujo JF:
Light-dark cycle synchronization of
circadian rhythm in blind primates.
J Circadian Rhythms 2005; 3:1–5.
91. Marc RE: 1999 Mapping glutamatergic
drive in the vertebrate retina with a channel
permeant organic cation. J Comp Neurol
1999; 407:47–64.
92. Marc RE: Kainate activation of horizontal,
bipolar, amacrine and ganglion cells in the
rabbit retina. J Comp Neurol 1999;
407:65–76.
93. Vaney DI, Weiler R: Gap junctions in the
eye: evidence for heteromeric, heterotypic
and mixed-homotypic interactions.
Brain Res Brain Res Rev 2000;
32:115–120.
94. Kenyon GT, Marshak DW: Gap junctions
with amacrine cells provide a feedback
pathway for ganglion cells within the retina.
Proc Biol Sci 1998; 265:919–925.
95. Marc RE: The structure of GABAergic
circuits in ectotherm retinas. In: Mize R,
Marc RE, Sillito A, eds. GABA in the retina
and central visual system. Elsevier:
Amsterdam; 1992:61–92.
96. Dacheux RF, Raviola E: Horizontal cells in
the retina of the rabbit. J Neurosci 1982;
2:1486–1493.
97. Raviola E, Dacheux RF: Variations in
structure and response properties of
horizontal cells in the retina of the rabbit.
Vision Res 1983; 23:1221–1227.
98. Nelson R: Cat cones have rod input: a
comparison of the response properties of
cones and horizontal cell bodies in the
retina of the cat. J Comp Neurol 1977;
172:109–136.
99. Fisher SK, Boycott BB: Synaptic connexions
made by horizontal cells within the outer
plexiform layer of the retina of the cat
and rabbit. Proc R Soc Lond B 1974;
186:317–331.
100. Peichl L, González-Soriano J:
Morphological types of horizontal cell in
rodent retinae: a comparison of rat, mouse,
gerbil, and guinea pig. Vis Neurosci 1994;
11:501–517.
101. Perlman I, Kolb H, Nelson R: Anatomy,
circuitry, and physiology of vertebrate
horizontal cells. In Chalupa LM, Werner J,
eds. The visual neurosciences. Cambridge:
MIT Press; 2004:369–394.
102. Boycott BB, Kolb H: The horizontal cells of
the rhesus monkey retina. J Comp Neurol
1973; 148:115–140.
103. Kolb H, Mariani A, Gallego A: A second
type of horizontal cell in the monkey retina.
J Comp Neurol 1980; 189:31–44.
104. Kolb H, Fernandez E, Schouten J, et al:
Are there three types of horizontal cell in
the human retina? J Comp Neurol 1994;
343:370–386.
105. Wässle H, Dacey DM, Haun T, et al: The
mosaic of horizontal cells in the macaque
monkey retina: with a comment on
biplexiform ganglion cells. Vis Neurosci
2000; 17:591–608.
106. Dacheux RF, Raviola E: Physiology of HI
horizontal cells in the primate retina. Proc R
Soc Lond B 1990; 239:213–230.
107. Dacey DM, Lee BB, Stafford DK, et al:
Horizontal cells of the primate retina: cone
specificity without spectral opponency.
Science 1996; 271:656–659.
108. Dacey DM: Parallel pathways for spectral
coding in primate retina. Annu Rev
Neurosci 2000; 23:743–775.
109. Blanco R, de la Villa P: Ionotropic
glutamate receptors in isolated horizontal
cells of the rabbit retina. Eur J Neurosci
1999; 11:867–873.
110. Haverkamp S, Grunert U, Wässle H: The
synaptic architecture of AMPA receptors at
the cone pedicle of the primate retina.
Neurosci 2001; 21:2488–2500.
111. Lindberg KA, Fisher SK: Ultrastructural
evidence that horizontal cell axon terminals
are presynaptic in the human retina.
J Comp Neurol 1988; 268:281–297.
112. Setou M, Seog D-H, Tanaka Y, et al:
Glutamate-receptor-interacting protein
GRIP1 directly steers kinesin to dendrites.
Nature 2002; 417:83–87.
113. Kamermans M, Fahrenfort I, Schultz K,
et al: Hemichannel-mediated inhibition in
the outer retina. Science 2001;
292:1178–1180.
114. Mills SL, Massey SC: Distribution and
coverage of A- and B-type horizontal cells
stained with Neurobiotin in the rabbit
retina. Vis Neurosci 1994; 11:549–560.
115. Mills SL, Massey SC: A series of
biotinylated tracers distinguishes three
types of gap junction in retina. J Neurosci
2000; 20:8629–8636.
116. Packer OS, Dacey DM: Synergistic
center-surround receptive field model of
monkey H1 horizontal cells. J Vision 2005;
5:1038–1054.
117. Wagner HJ, Wagner E: Amacrine cells in
the retina of a teleost fish, the road (Rutilus
rutilus): a Golgi stidy on differentiation
and layering. Phil Trans Roy Soc Lond B
1988; 321: 263–324.
118. Pourcho RG, Goebel DJ: A combined Golgi
and autoradiographic study of (3H) glycine
accumulating amacrine cells in the cat
retina. J Comp Neurol 1985; 233:473–480.
119. Vaney DI: The morphology and topographic
distribution of AII amacrine cells in the cat
retina. Proc Roy Soc (Lond) 1985;
224:475–488.
120. Tauchi M, Masland RH: The shape and
arrangement of the cholinergic neurons in
the rabbit retina. Proc R Soc Lond B 1984;
223:101–119.
121. Famiglietti EV Jr: Synaptic organization of
starburst amacrine cells in rabbit retina:
analysis of serial thin sections by electron
microscopy and graphic reconstruction.
J Comp Neurol 1991; 309:40–70.
122. Sandell JH, Masland RH: A system of
indoleamine-accumulating neurons in the
rabbit retina. J Neurosci 1986; 6:3331–3347.
123. Vaney DI: Morphological identification of
serotonin-accumulating neurons in the
living retina. Science 1986; 233:444–446.
124. Sandell JH, Masland RH, Raviola E,
Dacheux RF: Connections of indoleamine-
accumulating cells in the rabbit retina.
J Comp Neurol 1989; 283:303–313.
125. Li W, Zhang J, Massey SC: Coupling
pattern of S1 and S2 amacrine cells in
the rabbit retina. Vis Neurosci 2002;
19:119–131.

126. Rodieck RW, Marshak DW: Spatial density
and distribution of choline acetyltransferase
immunoreactive cells in human, macaque,
and baboon retinas. J Comp Neurol 1992;
321:46–64.
127. Springer AD, Hendrickson AE:
Development of the primate area of high
acuity, 3: temporal relationships between
pit formation, retinal elongation and cone
packing. Vis Neurosci 2005; 22:171–185.
128. Hendrickson A, Troilo D, Possin D,
Springer A: Development of the neural
retina and its vasculature in the marmoset
Callithrix jacchus. J Comp Neurol 2006;
497:270–286.
129. Curcio CA, Sloan KR, Kalina RE,
Hendrickson AE: Human photoreceptor
topography. J Comp Neurol 1990;
292:497–523.
130. Jeon CJ, Strettoi E, Masland RH: The
major cell populations of the mouse retina.
J Neurosci 1998; 18:8936–8946.
131. Remtulla S, Hallett PE: A schematic eye for
the mouse, and comparisons with the rat.
Vis Res 1985; 25:21–31.
132. Szel IA, Rohlich P, Caffe AR, et al: Unique
topographic separation of two spectral
classes of cones in the retina. J Comp
Neurol 1992; 325:327–342.
133. Juliusson B, Bergstrom A, Rohlich P, et al:
Complementary cone fields of the rabbit
retina. Invest Ophthalmol Vis Sci 1994;
35:811–818.
134. Lukats A, Szabo A, Rohlich P, et al:
Photopigment coexpression in mammals:
comparative and developmental aspects.
Histol Histopathol 2005; 20:551–574.
135. Marc RE, Sperling HG: The chromatic
organization of primate cones. Science
1977; 196:454–456.
136. Curcio CA, Allen KA, Sloan KR, et al:
Distribution and morphology of human
cone photoreceptors stained with
anti-blue opsin. J Comp Neurol 1991;
312:610–624.
137. Cornish EE, Madigan MC, Natoli R, et al:
Gradients of cone differentiation and FGF
expression during development of the
foveal depression in macaque retina. Vis
Neurosci 2005; 22:447–459.
138. Grünbaum B, Shephard GC: Tilings and
patterns. New York: WH Freeman;
1987:700.
139. Cook JE. Spatial regularity among retinal
neurons. In Chalupa LM, Werner J, eds.
The visual neurosciences. Cambridge: MIT
Press; 2004:463–478.
140. Cook JE: Spatial properties of retinal
mosaics: an empirical evauation of some
existing measures. Vis Neurosci 1996;
13:15–30.
141. Engstrom K, Ahlbert IB: Cone types and
cone arrangement in the retina of some
flatfishes. Acta Zool 1963; 44:1–11.
142. Kalloniatis M, RE Marc: Interplexiform cells
of the goldfish retina. J Comp Neurol 1990;
297:340–358.
143. Reese BE, Galli-Resta L: The role of
tangential dispersion in retinal mosaic
formation. Prog Ret Eye Res 2002;
21:153–168.
144. Wong ROL, Godhino L: Development of the
vertebrate retina. In Chalupa LM, Werner J,
eds. The visual neurosciences. Cambridge:
MIT Press; 2004:77–94.
145. Mariani AP: Biplexiform cells: ganglion cells
of the primate retina that contact photo-
receptors. Science 1982; 216:1134–1136.
Functional Anatomy of the Neural Retina
146. Trexler EB, Li W, Massey SC: Simultaneous
contribution of two rod pathways to AII
amacrine and cone bipolar cell light
responses. J Neurophysiol 2005;
93:1476–1485.
147. Saszik SM, Robson JG, Frishman LJ: The
scotopic threshold response of the
dark-adapted electroretinogram of the
mouse. J Physiol 2002; 543:899–916.
148. Li W, Keung JW, Massey SC: Direct
synaptic connections between rods and
OFF cone bipolar cells in the rabbit retina.
J Comp Neurol 2004; 474:1–12.
149. Reid RC, Shapley RM: Spatial structure of
cone inputs to receptive fields in primate
lateral geniculate nucleus. Nature 1992;
356:716–718.
150. Lee BB, Kremers J, Yeh T: Receptive fields
of primate retinal ganglion cells studied
with a novel technique. Vis Neurosci 1998;
15:161–175.
151. Sun H, Smithson HE, Zaidi Q, Lee BB:
Specificity of cone inputs to macaque
retinal ganglion cells. J Neurophys 2006;
95:837–849.
152. Calkins DJ, Sterling P: Absence of
spectrally specific lateral inputs to midget
ganglion cells in primate retina. Nature
1996; 381:613–615.
153. Dacey D, Packer OS, Diller L, et al: Center
surround receptive field structure of cone
bipolar cells in primate retina. Vision Res
2000; 40:1801–1811.
154. Williams DR, Hofer H. Formation and
Acquisition of the Retinal Image. In
Chalupa LM, Werner J, eds. The visual
neurosciences. Cambridge: MIT Press;
2004: 795–810.
155. Roorda A, Williams DR: The arrangement of
the three cone classes in the living human
eye. Nature 1999; 397:520–522.
156. Hofer H, Carroll J, Neitz J, et al:
Organization of the human trichromatic
cone mosaic. J Neurosci 2005;
25:9669–9679.
157. Kolb H, Dekorver L: Midget ganglion cells
of the parafovea of the human retina: a
study by electron microscopy and serial
section reconstructions. J Comp Neurol
1991; 303:617–636.
158. Brainard DH, Roorda A, Yamauchi Y, et al:
Functional consequences of the relative
numbers of L and M cones. J Opt Soc Am
A 2000; 17:607–614.
159. Xiao Y, Wang Y, Felleman DJ: A spatially
organized representation of colour in
macaque cortical area V2. Nature 2003;
421:535–539.
160. Neitz J, Carroll J, Yamauchi Y, et al: Color
perception is mediated by a plastic neural
mechanism that is adjustable in adults.
Neuron 2002; 35:783–792.
161. Marc RE, Liu WL: Fundamental GABAergic
amacrine cell circuitries in the retina:
nested feedback, concatenated inhibition,
and axosomatic synapses. J Comp Neurol
2000; 425:560–582.
162. Dubin MW: The inner plexiform layer of the
vertebrate retina: a quantitative and
comparative electron microscopic analysis.
J Comp Neurol 1970; 140:479–505.
163. Hennig MH, Funke K, Wörgötter F: The
influence of different retinal subcircuits
on the nonlinearity of ganglion cell
behavior. J Neurosci 2002;
22:8726–8738.
164. Dacheux RF, Chimento MF, Amthor FR:
Synaptic input to the on-off directionally
selective ganglion cell in the rabbit retina.
J Comp Neurol 2003; 456:267–278.
165. Cajal SR: La rétine des vertébrés. La
Cellule 1893; 9:119–257.
166. Polyak SL: The retina. Chicago: University
of Chicago Press; 1941.
167. Gastinger MJ, O’Brien JJ, Larsen NB,
Marshak DW: Histamine im-munoreactive
axons in the macaque retina. Invest
Ophthalmol Vis Sci 1999; 40:487–495.
168. Gastinger MJ, Barber AJ, Khin SA, et al:
Abnormal centrifugal axons in
streptozotocin-diabetic rat retinas. Invest
Ophthalmol Vis Sci 2001; 42:2679–2685.
169. Gastinger MJ, Bordt AS, Bernal MP,
Marshak DW: Serotonergic retinopetal
axons in the monkey retina. Curr Eye Res
2005; 30:1089–1095.
170. Gastinger MJ, Barber AJ, Vardi N, Marshak
DW: Histamine receptors in mammalian
CHAPTER 122
retinas. J Comp Neurol 2006; 495:658–667.
171. Witkovsky P: Dopamine and retinal
function. Doc Ophthalmol 2004; 108:17–39.
172. Dacey DM: The dopaminergic amacrine
cell. J Comp Neurol 1990; 301:461–489.
173. Nguyen-Legros J: Morphology and
distribution of catecholamine neurons in
mammalian retina. In: Osborne NN,
Chader G, eds. Progress in retinal research.
Oxford: Pergamon; 1988:113–147.
174. Mariani AP, Hokoc JN: Two types of
tyrosine hydroxylase-immunoreactive
amacrine cell in the rhesus monkey retina.
J Comp Neurol 1988; 276:81–91.
175. Oh SJ, Kim IB, Lee EJ, et al:
Immunocytological localization of
dopamine in the guinea pig retina. Cell
Tissue Res 1999; 298:561–565.
176. Zhang D-Q, Stone JF, Zhou T, et al:
Characterization of genetically labeled
catecholamine neurons in the mouse retina.
Neuroreport 2004; 15:1761-1765.
177. Feigenspan A, Gustincich S, Bean BP,
Raviola E: Spontaneous activity of solitary
dopaminergic cells of the retina. J Neurosci
1998; 18:6776–6789.
178. Xiao J, Cai Y, Yen J, et al: Voltage-clamp
analysis and computational model of
dopaminergic neurons from mouse retina.
Vis Neurosci 2004; 21:835–849.
179. Hampson EC, Vaney DI, Weiler R:
Dopaminergic modulation of gap junction
permeability between amacrine cells in
mammalian retina. J Neurosci 1992;
12:4911–4922.
180. Ishida AT: Retinal ganglion cell excitability.
In: Chalupa LM, Werner J, eds. The visual
neurosciences. Cambridge: MIT Press;
2004:422–450.
181. Ruan GX, Zhang DQ, Zhou T, et al:
Circadian organization of the mammalian
retina. Proc Natl Acad Sci USA. 2006;
103:9703–9708.
182. Wiechmann AF: Regulation of gene
expression by melatonin: a microarray
survey of the rat retina. J Pineal Res 2020;
33:178–185.
183. Eldred WD, Blute TA: Imaging of nitric
oxide in the retina. Vision Res 2005;
45:3469–3486.
184. Mills SL, Massey SC: Differential properties
of two gap junctional pathways made by
AII amacrine cells. Nature 1995;
377:734–737.
185. Kao YH, Lassova L, Bar-Yehuda T, et al:
Evidence that certain retinal bipolar cells
use both glutamate and GABA. J Comp
Neurol 2004; 478:207–218. 1591
 RETINA AND VITREOUS
186. Newman EA: Glial modulation of synaptic
transmission in the retina. Glia 2004;
47:268–274.
187. Kawamura H, Sugiyama T, Wu DM, et al:
ATP: a vasoactive signal in the
pericyte-containing microvasculature of
the rat retina. J Physiol 2005;
551:787–799.
188. Zalutsky RA, Miller RF: The physiology of
somatostatin in the rabbit retina. J Neurosci
1990; 10:383–393.
189. Johnson J, Caravelli ML, Brecha NC:
Somatostatin inhibits calcium influx into rat
rod bipolar cell axonal terminals. Vis
Neurosci 2001; 18:101–108.
SECTION 3
1592
190. Tian N, Copenhagen DR: Visual deprivation
alters development of synaptic function in
inner retina after eye opening. Neuron
2001; 32:439–449.
191. Tian N: Visual experience and maturation of
retinal synaptic pathways. Vision Res 2004;
44:3307–3316.
192. Fisher SK, Lewis GP, Linberg KA, Verardo
MR: Cellular remodeling in mammalian
retina: results from studies of experimental
retinal detachment. Prog Retin Eye Res
2005; 24:395–431.
193. Jones BW, Marc RE: Retinal remodeling
during retinal degeneration. Exp Eye Res
2005; 81:121–244.
194. Marc RE, Jones BW, Watt CB: Retinal
remodeling: circuitry revisions triggered by
photoreceptor degeneration. In: Pinaud, et
al, eds. Plasticity in the visual system: from
genes to circuits. Springer; 2005; 33–54.
195. Masland RH: The fundamental plan of the
retina. Nat Neurosci 2004; 4:877–886.
196. Ochs M, Mayhew TM, Knabe W: To what
extent are the retinal capillaries ensheathed
by muller cells? A stereological study in the
tree shrew Tupaia belangeri. J Anat 2000;
196:453–461.
197. Chatterjee S, Callaway EM: Parallel
colour-opponent pathways to primary
visual cortex. Nature 2003; 426:668–671.
 CHAPTER

123 Visual Acuity, Adaptation, and Color Vision

Maureen Neitz, Daniel G. Green, and Jay Neitz

We so readily use our eyes to organize and process information,

making it is easy to ignore the truly remarkable adjustments the
eye makes to enable us to see. When our interest focuses on an
object, such as a colorful bird, both eyes are directed so that an
image of the bird is focused on the foveas of both the retinas.
These two planar projections of the object are encoded and
transformed in the retina into elaborate patterns of neural
activity and relayed to various targets in the brain. As we orient
and move around, the retinal projection of an object, its
distance from us, its spectral content, and its intensity vary, and a
yet we continue to see the object as having the same shape, size,
color, and brightness.
The eye often is compared to a camera, and because each
shares common functions, this can be a useful starting point for
understanding visual processes. The eye and the camera both
have mechanisms for adjusting focus, setting exposure, and
storing an image. Yet the differences between vision and photo-
graphy are probably greater than the similarities. Photography is
a process that captures a permanent record of the variations in
intensity falling on a light-sensitive surface of the film. The
process has similarities only to events that occur in the earliest
stages of visual processing. The information we capture in a
photograph is equivalent to visualizing the pattern of activity
b
occurring at a particular instant in the mosaic of photoreceptors.
Thus, the photograph itself replicates only the simplest aspects
FIGURE 123.1. (a) Examples of visual acuity targets. The smallest
of vision. Without an eye to see it, a photograph is but a feeble detail is indicated by arrows. (b) Spatial relationships that define visual
shadow of the reality around us. When we look at a photograph, angle.
our eyes instantly see the color, form, and shape of objects from
the real world.
The biologic processes transforming the shower of photons 1.0 and 2.0 min–1. In conventional charts, with black patterns
falling on a mosaic of photoreceptors into the stable and invari- of various sizes on a white background, acuity is quantified in a
ant experience of sight have long been of immense scientific slightly different fashion. The letters on this chart have been
interest. This chapter touches on what we have discovered designed with the assumption that normal acuity corresponds
about those processes, the information our eyes make available to being able to resolve 1 min of arc (an acuity of 1.0 min–1).
to us, and the details of the psychophysics of acuity, adaptation, The size of each letter is such that its strokes will subtend
and color. 1 min of arc at a specified distance. The letter sizes can be
thought of as being designated by these distances (Fig. 123.1b).
VISUAL ACUITY This leads to the familiar fractional acuity notation, in which
the numerator of the fraction indicates the viewing distance and
Ordinarily, seeing refers to our ability to recognize forms and the denominator the size of the letter. An observer who from 20
patterns. An essential part of being able to see is the ability to ft away can just recognize the line with letters having strokes of
appreciate the fine detail in a scene. Visual acuity, the ability 1 min has a visual acuity of 20/20, an observer who requires
to resolve fine detail in a pattern, is usually determined by letters twice that size has a vision of 20/40, and so forth.
reducing the size of a test pattern until the smallest detail in the
pattern can just be resolved. Visual acuity can be expressed OPTICS
numerically in terms of the reciprocal of the size of the smallest
resolvable detail. The size is expressed as the angle that the The first stage of visual processing is the formation of an image
detail subtends at the eye of the observer. Figure 123.1a shows of the world on the mosaic of photoreceptors. Good vision
a Snellen letter and two other examples of acuity targets. Using depends on having a high-quality retinal image. Ideally, there is
such targets, visual acuity for normal observers ranges between only a single distance plane where a given object is brought to 1593
 RETINA AND VITREOUS
sharpest optical focus. However, because we are tolerant of
small amounts of optical blur, objects at a range of distances
appear to be in sharp focus1. To bring targets closer or farther
than this into focus, the lens of the eye must change its focal
length through the process of accommodation. When the target
is moved closer than the range of accommodation, the image
plane falls behind the retina, and fine detail begins to be blurred.
Even when an object is in best focus, there is loss of image detail
owing to both aberrations and diffraction. These degradations in
the sharpness of the retinal image are potentially more serious
than focus errors because they are not correctable with the
ordinary spherical and cylindrical lenses. The word aberration
refers to a failure of the rays originating from a point source to
be brought to a point focus. Inaccuracies and irregularities in
the shapes of the curved refracting surfaces of the cornea and
lens produce aberrations. Also, there is chromatic aberration
because the refractive properties of the eye’s dioptrics vary with
wavelength, and different wavelengths are brought to focus at
SECTION 10
different points. Chromatic difference of focus amounts to a
change of power of ~2 D over the 400–700 nm visible spectrum.
It has been suggested that for large pupils it is the dominant
aberration that limits retinal image quality.2 Diffraction that
occurs when light waves are abruptly truncated by an edge, such
as the edge of the iris, also degrades the retinal image. As the
result of interference between light waves and the edge of the
pupil, a point, for example, will be imaged onto the retina as a
fuzzy disk. The angular size of the disk varies inversely with
pupil diameter.
The exact magnitude of the loss in image quality, resulting
from focus errors and aberrations, also depends on the size of
the pupil. Small pupils make diffraction effects worse; however,
as the pupil becomes smaller, depth of focus increases and a
small pupil also tends to reduce the deleterious effects of
aberrations by limiting the area of the optically imperfect
cornea and lens that are involved in producing the image. Over
the physiologic range of pupil sizes (2 to about 7 mm), the
balance between the effects of diffraction and those of
aberrations occurs when the pupil is ~3 mm in diameter,
approximately the size that it tends to achieve under normal
bright light conditions.3,4 Under these conditions, the quality of
the retinal image is quite high and deviates only slightly from
an ideal system limited only by diffraction.
The density of packing in the mosaic of foveal cones is also
an important limiting factor. Each photoreceptor samples the
local intensity at a point in the retinal image. Consequently, the
size and the density of packing of the receptors must be
adequate if we are to appreciate the fine detail in the retinal
image. The foveal cones are very thin and tightly packed,
making them particularly well suited to encode the fine detail in
the image (Fig. 123.2a). The effect of the mosaic of foveal cones
on vision is illustrated in Figure 123.2b. Acuity test patterns
close to the limits of resolution have been drawn as a pattern of
stimulated and unstimulated foveal cones. Because the density
a b
1594
of receptors in the mosaic of foveal cones is just barely adequate
to reproduce the image of these targets, one can readily
appreciate that visual acuity is close to the limits set by the
retinal mosaic. Of the two factors, optics and retinal packing,
which is of primary importance? A direct experimental answer
to this question has been obtained by using laser-generated
interference fringes. Interference fringes, which are not images
of objects but patterns resulting from the intrinsic wave proper-
ties of light, are not degraded by the eye’s optics.5 Consequently,
it is possible to produce exceedingly fine high-contrast gratings
directly on the retina. Visual acuity is ~50% higher with
interference fringes (20/ to 20/10).4 Thus, the resolution limit
set by the packing density of the cones is similar to, but slightly
higher than, the limit set by the optics of the eye. As a result,
under ideal conditions, an observer with excellent vision can
just resolve fine detail whose angular subtense approaches that
of a single cone.6
To transmit to the brain the information about fine detail
that is available at the level of the photoreceptors, there must be
at least as one ganglion cell for each cone. For the fovea, where
acuity is highest, there are between two and three ganglion cells
transmitting information to the brain for every cone. A neural
network compares the number of photons absorbed by a cone to
the average number absorbed by its neighbors and projects the
result via two ‘private lines’ to the brain in the form of one
ON- and one OFF-center midget ganglion cell. These midget
ganglion cells are responsible for transmitting the information
about fine details in the image.
The response properties of the ganglion cells represent a first
level of processing of photoreceptor signals into visual percepts.
Each cone provides input to several types of ganglion cells each
specialized to carry specific information about the visual
stimulus. As shown in Figure 123.2, when part of the image of
a black horizontal stroke of the Snellen E falls on a cone, its
OFF-center ganglion cell fires, signaling the presence of a dark
area in the image. When the image of the white background
between two strokes of the E falls on a cone, the ON-center
ganglion cell fires, signaling the presence of a light area of the
image. The ratio of ganglion cells to cones is greater than 2:1 in
the fovea because foveal cones connect to other types of
ganglion cells that collect signals from larger numbers of cones
and carry other types of information. There are ganglion cells
that transmit the presence of a hue, for example, ‘blueness’, and
other ganglion cells transmit information responsible for the
percept of movement.
RETINAL POSITION
Visual acuity falls rapidly as the focal point moves away from
the fovea, as would be expected from the decrease both in
density of cone photoreceptors and in the relative number of
ganglion cells available to carry information from the retina.
The exact shape of the fall in acuity with eccentricity depends
FIGURE 123.2. (a) Section through cone inner
segments at the center of human fovea. The
bar indicates 2 min of arc (10 mm distance on
retina). The particular retina illustrated had the
lowest peak density of the four retinas studied.
(b) 20/20 Snellen letter drawn as a pattern of
stimulated and unstimulated cones.
(a) Reprinted from Curcio CA, Sloan KRJ, Packer O,
et al: Distribution of cones in human and monkey
retina: individual variability and radial asymmetry.
Science 1987; 236:579. Copyright 1987 American
Association for the Advancement of Science.
 Visual Acuity, Adaptation, and Color Vision

on the type of target used, but acuity falls roughly to half at 1°
and to one-fourth at 5°.7 To separate the optical factors from re-
tinal factors, one can use interference fringes formed directly on
the retina. With the stimulus near the fovea, the fall in acuity
for interference fringes parallels the fall in cone density.6 Beyond
~5° of eccentricity, the rate of decrease is too great for which the
peripheral cone spacing happens to be the limiting factor. At
these eccentricities, the fall-off in resolution and the estimated
decrease in spacing between ganglion cells seem to agree
reasonably well.8
CONTRAST
Although visual acuity is frequently used to characterize an
individual’s ability to see, there is considerably more to func-
tioning in everyday life than being able to resolve fine detail in
well-illuminated, high-contrast black-and-white patterns. In
the real world, one must detect and recognize a variety of targets
(1) any stimulus can be considered to be a sum of sinusoidal
components, and (2) purely sinusoidal patterns are imaged by
optical systems in a uniquely simple way. That is, the spatial
variations in the image of a sinewave target are also sinusoidal,
of the same spatial frequency but of reduced contrast. Thus, for
any grating, a contrast reduction factor (and sometimes a phase
shift factor) completely describes the object to image trans-
formation. This number as a function of frequency defines the
optical-transfer function.16 Because any pattern of luminances
can be described by a sum of sinewaves in two dimensions,
knowing how sinewaves are imaged (i.e., the transfer function),
it is possible to calculate the image that will be formed by any
arbitrary pattern. That is, the optical-transfer function com-
pletely describes the imaging properties of the eye, and using the
transfer function it is possible to quantify the quality of an image
and to give a detailed account of how one or another factor
influences the image quality. Figure 123.3a shows measure-
ments of the optical-transfer function for an observer in good

varying in contrast, size, and shape.
In recent years, we have increasingly come to appreciate the
importance of the effects of contrast on visual performance.4,9–15
To study the effects of contrast, an approach borrowed from
optical engineering has been quite useful. The optical-transfer
function is frequently used to characterize the imaging abilities
of cameras and television systems. The idea of using the optical-
transfer function stems from two key facts about linear systems:
CHAPTER 123
focus with a range of pupil sizes. Because at 30 cycles/degree the
bars of the grating are of the same width as the strokes in the
20/20 letter; the curves show that near the ‘normal’ limit of reso-
lution, the image of a grating is reduced in contrast by ~50%.
In an attempt to extend the idea of an optical transfer to the
processing occurring in the retina and brain, the contrast-
sensitivity function has been evolved. To characterize the eye’s
ability to process spatial information, the observer is presented

a b

FIGURE 123.3. (a) Optical-transfer functions for the in-focus eye of a normal observer at several pupil sizes (•, 2 mm; ▼, 2.8 mm; ■, 3.8 mm;
▲, 5.8 mm). (b) Contrast-sensitivity functions for 10 normal observers. Each point plots the contrast at which an observer could just detect the
sinewave grating.
(a) From Campbell FW, Green DG: Optical and retinal factors affecting visual resolution. J Physiol 1965; 181:576. (b) From Green DG: Visual acuity: The influence of
refraction and diffraction and the use of interference fringes. Int Ophthalmol Clin 1978; 18:21. 1595
 RETINA AND VITREOUS
with a periodic pattern, usually a sinewave, and adjusts the con-
trast of the target until it can be just detected. The reciprocal of
the threshold contrast defines the contrast sensitivity. Contrast
sensitivity is then plotted as a function of the grating fineness,
with the fineness of the grating expressed in terms of the
number of bars in 1° of visual angle (cycles/degree). The shape
of the contrast-sensitivity function reflects, both the optical-
transfer function of the eye’s dioptric apparatus and the neural
processing of spatial frequency information.
Typical contrast-sensitivity functions are shown in Figure
123.3b. The contrast sensitivity, the reciprocal of the just-
visible contrast, peaks at an intermediate spatial frequency.
Gratings that are coarser or finer than this optimal frequency
require more contrast to be seen. The point where the contrast-
sensitivity function intersects the horizontal axis establishes
the highest spatial frequency that an observer can detect.
Because one cycle of a grating contains a dark and a light bar, a
30 cycles/degree grating has bars that subtend 1 min of arc and
SECTION 10
corresponds in size to the strokes in the 20/20 letter.
Thus, in the same way that the optical-transfer function char-
acterizes the imaging properties of a lens, the contrast-sensitivity
function describes a patient’s ability to see. In general, by con-
sidering the spatial frequency content of targets and knowing an
observer’s ability to process sinewave information at a variety of
spatial frequencies, one obtains information relevant to asses-
sing an observer’s functional visual capabilities.
Contrast sensitivity provides information that supplements
what one can obtain from acuity measurements alone. For
example, two patients can have the same acuity and yet have
different middle- and low-frequency contrast sensitivities. The
differences in middle- and low-frequency sensitivity can have
dramatic effects on the patients’ visual performances. Moreover,
contrast-sensitivity loss not only can influence the detection of
larger low-contrast targets but also seems to affect tasks that
one might have thought would require only good acuity. It has
been reported that patients with only slight losses in acuity but
with losses in contrast sensitivity over a wide range of spatial
frequencies can experience difficulties in reading.17,18 The expla-
nation, in part, is provided by Rubin and Legge’s19 finding that
peak contrast sensitivity is an important determinant of how
rapidly low-vision observers can read letters. On the basis of
these and other studies, it seems likely that contrast-sensitivity
determinations will continue to be useful in assessing func-
tional visual capacities, and in predicting such things as the
benefit that might be derived from a particular low-vision aid.
INTENSITY
Our ability to see is strongly dependent on having adequate
light. At the lowest light levels, a few quanta absorbed in an area
containing 500 rods can produce a visual sensation. At these
levels, some semblance of form vision is possible, but acuity is
exceedingly low. Even at an intensity of ~10–5 cd/m2, which is
about a log unit above absolute threshold, visual acuity is only
~20/1000.20 As luminance of the target is increased, the ability
to resolve details continuously improves up to luminances of
~10 cd/m2, where it reaches a plateau (Fig. 123.4).21 A number
of factors contribute to the dependence on target luminance.
With the dimmest targets, vision is mediated by rods 4° or more
from the fovea.22 As stimulus intensity increases, there is move-
ment of fixation from the periphery toward the fovea. At lowest
levels of illumination, where the stimuli are so weak that not
every receptor will absorb a quantum, the quantal nature of the
stimulus can severely limit the eye’s ability to appreciate details
and contrast. Smaller pupil sizes that accompany higher lumi-
nances can also contribute improved vision because the quality
1596 of the retinal image with a fully dilated pupil is not optimal. As
FIGURE 123.4. Visual acuity intensity functions under free viewing
conditions.
From Pirenne MH, Denton EJ: Accuracy and sensitivity of the human eye. Nature
1952; 170:1039.
light intensity increases, there is a changeover from vision
mediated by rods with high sensitivity but poor resolution to
vision mediated by cones with intrinsically better resolution.
This switch from rods to cones frequently produces a sharp and
rather abrupt increase in the acuity-intensity relationship.
EYE MOVEMENT
The eyes are continuously executing small involuntary move-
ments. The pattern of involuntary eye movements is a mixture
of tremor, slow drifts, and rapid saccades. By analogy with a
camera, one might think that any movement would be detri-
mental. In fact, eye movements seem to be an essential prere-
quisite to normal vision. If the retinal image is stabilized,
within seconds the visual image fades.23,24 After a minute or so,
only a very blurred, cloudy version of the original scene persists.25
These subjective reports of the appearance of stabilized images
might suggest that high-frequency information disappears more
quickly than coarser detail, but systematic measurements with
gratings seem to suggest the reverse.26 The key point is that for
vision to be possible, there have to be eye movements. The eye
movements move the retinal image, and as a result, the photo-
receptors are subjected to continually changing spatial and
temporal transients.
LIGHT AND DARK ADAPTATION
We are largely unaware of the great variations in illumination
that occur in the real world because the eye light-adapts. By
increasing (or decreasing) sensitivity when the environmental
intensity increases (or decreases), our perception of the visual
world remains relatively constant. The term light adaptation is
used to describe the changes in visual sensitivity produced by
steady background lights. An everyday example of this change
is the disappearance of the stars with the coming of dawn. This,
of course, is not due to a change in the amount of light emitted
by the stars but rather is a result of the desensitization produced
by the veil of scattered light in the sky. Dark adaptation is the
recovery of sensitivity with time after exposure to a background
that reduces sensitivity. Light adaptation works well in the
natural world because we are attempting to sense objects around
us that are not self-luminous but rather are illuminated from a
distant source and seen by reflected light (Box 123.1).

Increment thresholds and dark adaptation are the two classic
adaptation paradigms that have been used to reveal the changes in
sensitivity occurring in the eye. In both, the dependent measure
is usually an observer’s ability to detect a small, briefly presented
test flash. To determine increment thresholds, the small incre-
mental test stimulus is usually presented on a spatially uniform
background field, which is systematically varied in intensity.
BOX 123.1 Adaptation and Weber’s law
If E is the intensity of the illumination locally, and r(x,y) is the
spatial variation in the reflectivity of the objects in a scene, the
equation L = r(x,y)E gives the point-by-point variations in the
luminance from particular region of the scene. The information
extracted by the visual system from the image on the retina is an
impression of r(x,y), which is relatively independent of E. The eye
does this by adjusting its sensitivity according to Weber’s law,
which states that sensitivity varies inversely with E, the intensity
of the illumination. When E increases by, say, a factor of 10, the
retinal gain decreases by this same factor, and consequently the
neural signal, which depends on the product of retinal
illumination by retinal gain, remains unchanged.
LIGHT ADAPTATION
In controlled laboratory conditions, one typically finds that
when a small test flash is added to steady background over a
considerable range of background intensities, the intensity of
the just-detectable increment is approximately proportional to
background intensity. This property, that the ratio of the test
flash intensity to the background intensity is roughly constant,
is Weber’s law relationship (Box 123.1). There are, however,
failures at both ends of the scale, when the background is either
very bright or very dim. At the low end, Weber’s law fails when
the background becomes so dim that it no longer affects sen-
sitivity. At the other extreme, a bright background can overload
the system. If the background is sufficiently intense, a new
phenomenon called saturation occurs. That is, in order to be
seen, the increment needs to be made considerably brighter than
one would predict from Weber’s law.27 In addition, increment
threshold curves frequently have a discontinuity. Rod signals
mediate low-intensity vision, and cones subserve the upper
range of intensities. As a result, plots of increment threshold as
a function of intensity yield curves that frequently are divisible
into two distinctly different portions, with a kink in the curve
marking the changeover from predominantly rod to predomi-
nantly cone control of sensitivity (Fig. 123.5).
The foregoing description of the behavior of the visual system
during adaptation says little about what is happening in the eye
during these changes. Because exposure to light bleaches visual
pigment, the simplest possible mechanism imaginable to account
for losses in sensitivity would be a decrease in the potency of the
test probe caused by the direct removal of visual pigment. This,
however, is not the case. Many years ago, Rushton28 showed
that a background can be so dim that only a few rods can absorb
photons and yet significantly elevate threshold. Only one rod in
50 needs to absorb a photon of light for the threshold of a
stimulus that falls on the receptors not directly affected by the
background to be elevated by a factor of four. Even at back-
ground levels where rods saturate, only small amounts of visual
pigment are bleached.
Cones may be a bit different in this regard. It is not com-
pletely clear to what extent backgrounds can desensitize the
photoreceptors themselves. In addition, with cones the adapting
backgrounds can bleach pigment, and so the depletion of visual
pigment may contribute to sensitivity loss in cones at high
light levels.
Visual Acuity, Adaptation, and Color Vision
CHAPTER 123
FIGURE 123.5. Increment threshold functions. The lower limb is for
rods, and the upper limb is for cones.
DARK ADAPTATION
It takes time for the threshold to reach a new equilibrium value
after a background abruptly changes from one intensity to
another. The recovery of sensitivity in the dark after prior expo-
sure to a bright stimulus is called dark adaptation. The speed
with which a new equilibrium is reached depends on the direc-
tion and magnitude of the change. In general, reduction in
sensitivity occurs quickly relative to restoration of sensitivity.
That is, it takes a matter of seconds to adapt to a brighter back-
ground, whereas adjustment to decreases in background inten-
sity is slower. In particular, the recovery to total darkness may
proceed very slowly. After exposure to a bright stimulus, the
exact time needed to adjust to a dimmer background depends
on whether rods or cones are being tested and on the intensity
of the prior exposure. In the extreme situation, in which one is
plunged from a very bright environment into complete
darkness, it can take up to an hour for rod sensitivity to recover
fully. Measuring the dark-adaptation curve is the standard
method for tracking this recovery process. One plots the thres-
hold as a function of time after the termination of the condi-
tioning light stimulus. The shape of the dark-adaptation curve
depends on the test stimulus parameters, such as size, color,
and retinal location, as well as conditioning stimulus para-
meters, such as its intensity, duration, and color. Fortunately, to
a great degree these multiple factors can be reduced to just two
principal determining variables. These are the extent to which
the test light stimulates rods and cones and the quantity of
visual pigment that has been bleached by the exposure to the
conditioning stimulus (see Box 123.2).
If the size, color, and retinal location are arranged so that the
test flash stimulates both rods and cones, and significant
amounts of rod and cone pigment are bleached by the condi-
tioning stimulus, then dark adaptation proceeds in two distinct
phases. In the first phase or branch, typically lasting ~5–10 min,
the threshold is determined by the cones as they recover their
sensitivity. The time course of the process parallels the regen-
eration of cone pigment. Later, the rods recover sufficiently for
their thresholds to be lower than those of the cones, and they
mediate threshold, giving rise to a rod branch in the curve.
Complete recovery of rod sensitivity takes as long as it takes for
rod pigment to regenerate. During this time, sensitivity can
increase by a factor of 10 000 (Fig. 123.6). 1597
 RETINA AND VITREOUS

COLOR VISION
Humans value color perception highly as a sensory capacity.
Few of us would accept a black and white television or
monochrome computer monitor in place of color ones even in
exchange for large savings in cost. One reason color is
important to us is that it has a powerful effect on our emotions.
This is presumably, in part, because some components of our
color vision system are evolutionarily ancient, predating other
sensory capacities. Color cues are associated with time of day,
the season, and an organism’s position and orientation in
space. Color can signal the presence of an injury or illness, the
presence and or quality of food, and the identity of a mate. In
our modern world color-coding is extremely important in
transmitting information visually. Objects identified by color
among a large number of distracters can be located nearly
instantly in visual search and color is invaluable in perceptual
grouping and segmenting objects.
SECTION 10

With regard to mechanism, color vision is based on three

FIGURE 123.6. A typical dark-adaptation curve. The first limb of the
curve reflects recovery of cones, and the second, slower limb reflects
rod recovery.
BOX 123.2 Adaptation and the Dowling–Rushton Law
The Dowling–Rushton Law is the empirical relationship between
bleached pigment and sensitivity. Rather than being linear it is, to
a good approximation, logarithmic, given by the equation
L It = a(1 – r) where It is threshold, r is the proportion of pigment,
and a is a constant.
types of cone photoreceptors which are the basis for all vision
with the exception of vision under very dim light conditions,
which is dependent on rods. Information about pattern, lumi-
nance, and color are all extracted from a mosaic of three types
of cone, one class most sensitive to short wavelength light (S),
a second class (M) most sensitive to middle wavelength light and
a third (L) most sensitive to long wavelength light (Fig. 123.7).
Perception of black, white, and gray, the hues of red, green, blue,
and yellow and their patterns in the retinal image are extracted
by different types of ganglion cells each specialized to carry
specific information about the visual stimulus from one mosaic
of cones.

a b

FIGURE 123.7. (a) Illustration of the arrangement of the three types of cones, L-, M-, or S-, which represent classes of photoreceptors that are
primarily sensitive to long wavelength light (L), middle wavelength light (M), and short wavelength light (S) within the visible spectrum. In this
diagram the cones are colored blue, green, or red in order to represent the different photoreceptor classes. S cones represent a minority, ~5% of
the total. The arrangement in a trichromat is very close to random for L and M cone classes. Midget ganglion cells have center surround-
receptive fields with the center derived from a single cone (for example, within the inner ring of the two black concentric circles). The six
adjacent cones are the most important contributors to the surround (for example, the cones within the outer ring of the two black concentric
circles). In a normal trichromat the surrounds of many L or M cones will have some cones of a different type than the center. Thus most midget
ganglion cells have spectrally opponent responses to diffuse red and green lights; they are either excited by red and inhibited by green or vice
versa. (b) Arrangement of cones in a deuteranope, a dichromat, with only two different cone classes L and S. In a dichromat, usually all the
cones in the surround are of the same class as the center input to a midget ganglion cell. Such ganglion cells do not respond to diffuse colored
1598 lights; they are specialized to signal patterns of light and dark on the retina.

A great deal is known about the neural types and their inter-
connections in the retina responsible for luminance, color, and
form, and there is a growing body of information about the
higher visual centers; yet, how these operate to give us vision
remains a fascinating puzzle. Clues toward solving the puzzle
come from information about the evolution and development of
visual system and about its anatomy and physiology. In contrast
to our persisting ignorance about color vision circuitry, the last
20 years has seen an explosion of information about the cone
photopigments. Many of the long standing questions about these
pigments and their role in normal vision and vision disorders
have now been answered. In humans there are three types of
cone photopigment, one for each class of cone (see Box 123.3).
The L and M cone opsins and the genes that encode them are
unusually variable, presumably due to the unstable tandem
arrangement of the genes and their unique evolutionary history.
Among the mammals, red-green color vision first evolved in a
primate ancestor. Strong selective pressure favoring trichromatic
color vision acted on primates in the wild, minimizing the
prevalence of mutant L and M opsin gene arrays despite the
extreme instability inherent in tandemly duplicated genes.
However, in humans, selection against mutant X-linked pig-
ment genes has been relaxed. The variability that has resulted
includes gene arrangements responsible for color blindness,
BOX 123.3 Normal color vision: terms and genetics
Normal human color vision is trichromatic, mediated by three
well-separated classes of cone photoreceptor commonly referred
to as the blue, green, and red cones. Calling them short-,
middle-, and long-wavelength sensitive, abbreviated S, M, and L
cones minimizes confusion that can arise from giving them color
names.
Photopigment molecules within each cone are responsible
for the spectral properties of the cones. Each photopigment
molecule is composed of two parts; a protein termed the opsin,
and an 11-cis-retinal chromophore.
The official names for the genes encoding the L, M, and S
cone opsins are OPN1LW, OPN1MW, and OPN1SW respectively.
Both OPN1LW and OPN1MW are on the X-chromosome at
position Xq28, OPN1SW is located on chromosome 7 at 7q32.1.
The location of OPN1LW and OPN1MW on the X-chromosome
accounts for the great gender difference in the prevalence of
color vision deficiencies.
BOX 123.4. Red-green color vision deficiency:
classification and terminology
Red-Green color vision defects fall into two categories
depending on which cone class does not contribute to color
vision. The noncontributing cone class is indicated by the
prefixes:
Protan- for absence of L cone contribution to vision.
Deutan- for absence of M cone contribution to vision.
Further categorization of color vision defects depends on
whether the remaining color vision is based on two (dichromacy)
versus three (anomalous trichromacy) spectrally distinct types of
cones. The suffix -opia denotes dichromacy. The suffix -anomaly
denotes anomalous trichromacy in which two of the cone classes
are more similar in spectral sensitivity than the corresponding
normal cones:
Deuteranopia. color vision mediated by L and S cones.
Protanopia. color vision mediated by M and S cones.
Protanomaly. color vision mediated by S and two spectrally
distinct classes of M cone.
Deuteranomaly. color vision mediated by S and two
spectrally distinct classes of L cones.
Visual Acuity, Adaptation, and Color Vision
which is the most common of all human single locus genetic
disorders. The increasing proportion of mutant cone pigment
genes is also presumably the root of a growing number of other
problems and complications of human vision.
INHERITED RED-GREEN COLOR VISION
DEFICIENCY
Inherited color vision deficiency occurs at an extraordinarily
high frequency in human populations although the prevalence
varies with ethnicity and race.29 Caucasians exhibit among the
highest rates with 7–8% of males affected, and native Fijians
have the lowest rate with 0.82% of males affected, while
Japanese and Africans have intermediate rates with 4.17% and
2.61% of males affected, respectively. Compared to many other
common inherited recessive disorders, such as cystic fibrosis
and sickle cell anemia, color vision deficiency is unusual in
occurring at an exceptionally high frequency with no compelling
CHAPTER 123
evidence of a strong heterozygote advantage to explain why. For
example, cystic fibrosis is the most-common life-limiting auto-
somal recessive disorder among humans, estimated to occur at
a rate of about one in 3200 live births.30 Heterozygotes for cystic
fibrosis are protected against heat- and disease-induced
dehydration, thereby providing them with a survival advantage
over the history of human existence. Another example is sickle
cell anemia in which heterozygotes are protected against the
severe pathogenesis of malaria.30 The answer to why color
vision deficiency is so prevalent in human populations lies in
the evolutionary origin and arrangement of the OPN1LW and
OPN1MW genes in the human genome, and on the strength of
natural selection on trichromatic color vision.
Genetic evidence indicates that all vertebrate opsin genes
evolved from a common ancestor through a process of gene
divergence and duplication.31 Most mammals have two types of
cone photoreceptor, one maximally sensitive to short-wave-
length (S) or in some cases ultraviolet (UV) light and another
maximally sensitive to light in the middle-to-long wavelengths
(M/L).32 The opsin components of the photopigment molecules
that determine the spectral properties of the cones are encoded
by an autosomal gene in the case of the S or UV opsin, and a
gene on the X-chromosome in the case of M/L opsin. Together,
the two cone types form the basis for dichromatic color vision.
In New World primates, trichromatic color vision was acquired
through evolution of allelic diversity in the X-chromosome
opsin gene, which produced variety in spectral sensitivity of the
encoded photopigments.33 Males have only one X-chromosome,
but females have two. In female New World monkeys who are
heterozygous at the X-chromosome opsin gene locus,
X-inactivation segregates expression of the alleles into separate
populations of cones, producing three cone types. The heterozy-
gous females have trichromatic color vision,34 indicating that
they have all of the components necessary to form fully func-
tional circuits for trichromatic color vision. In Old World
primates, trichromatic color vision arose via a gene duplication
that placed two opsin genes together in tandem on the
X-chromosome.31 X-inactivation cannot segregate expression of
tandem OPN1LW and OPN1MW genes into separate popula-
tions of cones; however, a critical enhancer known as the locus
control region (LCR) was not duplicated along with the opsin
gene, thereby limiting the photoreceptor to expressing one opsin
gene at a time. 35–38 Ultimately, in the adult cone photoreceptor,
only one opsin gene is expressed to the exclusion of all others.39
Tandemly duplicated genes are inherently unstable because
they are prone to unequal homologous recombination between
misaligned arrays during meiotic cell division in females, which
produces gene rearrangements that underlie inherited color
vision deficiency,31 as illustrated in Figure 123.8. Natural selection 1599
 RETINA AND VITREOUS

Parental arrays

Recombinant arrays

Normal Color Vision Proton-type color Deutan-type color

Deutan-type color Deuteranope
vision defect Protanope S L M vision defect vision defect
S M S L
S L L S M M S L L

photoreceptors

Trichromat Dichromat
Dichromat
Dichromat or Dichromat or
Dichromat or
anomalous trichromat anomalous trichromat
anomalous trichromat

a b c

FIGURE 123.8. The variety of normal and defective color vision phenotypes in humans is produced by unequal homologous recombination
during meiotic cell division in females. Red and green arrows represent the OPN1LW and OPN1MW genes, respectively; arrows that are half red
and half green represent chimeric genes produced by a crossover between an OPN1LW and an OPN1MW gene. The color of the arrowhead
indicates whether the gene encodes an L pigment (red) or M pigment (green). (a) A crossover between an OPN1LW and OPN1MW in the
parental arrays produces two recombinant arrays. Only the two 5„ genes (left-most) in the three gene array are expressed and both of these
SECTION 10

encode L-class pigments. The array produces dichromatic color vision if the encoded L-class pigments have identical spectral properties, or it
produces anomalous trichromacy if the pigments differ in spectral properties. (b) A crossover in the region between the genes in one array and
the region downstream of the last gene in another array produces a three gene array that encodes an L and an M pigment and thus will produce
normal color vision. The other recombinant array contains a single gene, which encodes an L opsin and thus produces dichromatic color vision.
(c) Recombination between an OPN1MW in a three gene array and OPN1LW in a two gene array gives rise to two recombinant arrays, both of
which give rise to color vision defects. One array will have two genes, an OPN1LW/OPN1MW hybrid followed by an OPN1MW gene, which if
both genes encode pigments identical in spectral properties will cause dichromacy, or if the encoded pigments differ in spectral poperties, the
array will cause anomalous trichromacy. Likewise the array with an OPN1LW gene followed by an L-pigment encoding chimeric gene will either
cause dichromacy or trichromacy if the encoded pigments are identical or different in spectral properties, respectively.

is expected to virtually eliminate visual pigment gene arrays
that confer color vision defects; however, if selection is relaxed,
then arrays causing color vision defects can accumulate in the
population giving rise to an increase in color vision deficient
males and in female carriers. In the US, about one in 12 males
is affected by red-green color vision deficiency and one in seven
females is a carrier.
When color defective arrays initially began to accumulate in
the population, female carriers would have had one normal
array with one OPN1LW and one OPN1MW gene and another
array that either had one or three opsin genes (Fig. 123.8a,b). In
either case, the unequal number of opsin genes on the two
X-chromosomes produces instability because there is no perfect
alignment of the two arrays during meiotic cell division. Recom-
bination between two arrays with different numbers of opsin
genes will give rise to variability in the number of opsin genes
per X-chromosome and an increase in the prevalence of chimeric
genes resulting from intermixing of OPN1LW and OPN1MW
genes (Fig. 123.8c). As will be discussed below, the diversity
introduced by intermixing L and M opsin gene sequences
underlies the variety of phenotypes associated with anomalous
trichromacies.
Only among humans is there widespread variability in the
number of visual pigment genes on the X-chromosome with
a high frequency of arrays containing more than two opsin
genes.31,40 Since normal trichromatic color vision requires expres-
sion of only one L and one M opsin gene, this raises the ques-
tion of whether the extra genes beyond the necessary two are
expressed. Experiments have shown both by inference41 and by
direct analysis of opsin gene expression in human retinas from
color deficient donors42 that usually only the two opsin genes at
the 5’ end of the X-chromosome opsin gene array are expressed,
although exceptions have been observed.43 Thus, the order of
the genes in the array on the X-chromosome and the spectral
sensitivity of the photopigments encoded by the expressed genes
play a central role in determining color vision phenotype.
1600
CAUSES OF COLOR VISION DEFICIENCY
A common misconception is that inherited red-green color
vision deficiency is a single entity; it is not. Instead it is a group
of disorders that can be dichotomized at the first level according
to what is missing to cause the perceptual loss, and at a second
level according to the degree of color vision that remains
(Box 123.4). The most common cause of color vision deficiency
is the deletion of all OPN1LW (protan defects) or all OPN1MW
(deutan defects) genes. The degree to which color vision is
impaired is determined by the spectral properties of the
pigments encoded by the genes that remain.
DICHROMACY
The most severe of the common inherited red-green color vision
defects are the dichromacies, protanopia and deuteranopia in
which color vision is mediated by just two pigments in two types
of cone. Protanopia and deuteranopia (Box 123.4) each occur at
a rate of ~1% in Caucasian males, and although dichromacy is
much rarer in females, about one in 4000 females is affected.
In most cases, the direct cause of dichromacy is the deletion
of the genes that encode one class of cone photopigment from
the X-chromosome through unequal homologous recom-
bination31,44–47 as illustrated in Figure 123.8a,b. For example, in
a recent study 53 of 55 protanopes lacked genes for L opsin, and
51 of 73 deuteranopes lacked genes for M opsin.47
PROTANOPIA
One common cause of protanopia is the deletion of all but one
opsin gene on the X-chromosome with the one remaining gene
encoding an M-class pigment (Fig. 123.8a).31,48–49 Another com-
mon gene arrangement among protanopic men is an array that
lacks all OPN1LW genes, and that has a chimeric OPN1LW/
OPN1MW gene in the first position and an OPN1MW gene in
the second position (Fig. 123.8c).46,47 For protanopes with this

arrangement, the chimeric gene and the OPN1MW gene do not
encode photopigments that differ in spectral properties,
accounting for the protanopic phenotype.47
Occasionally, protanopes who have an apparently intact
OPN1LW gene have been identified31,46,47 and presumably the
gene is either not expressed or does not encode a functional
photopigment. In cases where this hypothesis has been tested
experimentally, the OPN1LW gene has either been found to be
displaced to the 3’ end of the array where it is not expressed,46,47
or it has been found to carry a particular deleterious com-
bination of amino acids at polymorphic positions encoded by
exon 3. The same combination was observed in OPN1MW
genes in deuteranopes where its effect on the cone mosaic and
its contribution to dichromacy has been examined in more
detail, as will be described below under deuteranopia.
DEUTERANOPIA
The majority (about two-thirds in some studies) of deuteranopes
have undergone a deletion of all X-chromosome opsin genes
except for one remaining OPN1LW gene, accounting for the
phenotype.31,44,50,51 Nearly one-third of deuteranopes have an
OPN1MW gene; however quite often they have a chimeric
OPN1LW/OPN1MW gene inserted between the OPN1LW and
OPN1MW genes, displacing the OPN1MW gene to a non-
expressed position.31,52 Another relatively common cause of
deuteranopia is the presence of an inactivating mutation in the
OPN1MW.47,53 By far the most common inactivating mutation
found in OPN1MW genes is a nucleotide change that results in
the substitution of arginine for a highly conserved cysteine at
position 203 (C203R) of the cone opsin molecule, preventing the
opsin from folding properly.54,55 Other inactivating amino acid
substitutions have also been found but most are quite rare.47
Perhaps the most interesting inactivating mutation found in
OPN1MW, which as was alluded to above has also been found
in OPN1LW genes, is a combination of amino acids at normally
polymorphic positions. OPN1LW and OPN1MW have been
intermixed by recombination so that in the present day
population of humans with normal color vision, there are 11
dimorphic positions among L and M pigments. As a result,
there is tremendous variation in the amino acid sequences of
the L and M cone photopigments found in humans with normal
color vision.56–59 A specific combination of amino acids at the
dimorphic positions has been observed to always be associated
with a color vision deficiency in which there is a perfect
correlation between the opsin with the deleterious combination
and the absence of function of the corresponding cone. High
resolution adaptive optics imaging of the retina of a deuter-
anope, whose OPN1MW gene specified an M pigment with the
deleterious combination, was shown to have gaps in his cone
mosaic, presumably where M cones had once been.60 In addi-
tion, the deuteranope was shown to have a reduction in cone
density by about one-third. When the gaps in his mosaic were
modeled as M cones and cone density recalculated taking into
account the modeled cones, the density estimate was normal.
Taken together, these observations support the hypothesis that
in some forms of color vision deficiency, the cause is a loss of
photoreceptor cells that is due to a malfunction in the produc-
tion or function of the photopigment.
Males who have opsin gene arrays in which the first two
genes encode photopigments of the same functional class but
with a difference in peak sensitivity of less than 2.5 nm, occa-
sionally perform as dichromats on standard color vision tests,
including the anomaloscope color matching tests.47 Thus, their
performance is worse than would be predicted strictly by the
complement of opsin genes they have. When there is a very
Visual Acuity, Adaptation, and Color Vision
small spectral separation on which the person must rely to make
color discriminations, there appear to be a variety of other fac-
tors including physiological factors, personality factors, differ-
ences between naïve and experienced observers, and differences
in the relative ratios of the underlying cone photoreceptors to
name a few, that contribute to variability in phenotype.
In summary, the most severe red-green color vision defects,
the dichromacies, are commonly explained by the straight-
forward deletion of cone opsin genes. Another relatively com-
mon cause is a point mutation that disrupts the function of the
encoded opsin. Recent evidence indicates that there is a funda-
mental difference in the effects on the cone mosaic that results
from these two mechanisms for color vision deficiency, specifi-
cally with regard to what happens to the subpopulation of cones
that do not contribute to color vision. In the case of the single-
gene dichromat, it appears that all of the cones that would have
become L or M cones express the available X-chromosome
opsin gene and so no cone photoreceptors are lost. In contrast,
CHAPTER 123
evidence indicates that in dichromats with two or more opsin
genes in which the first or second gene encodes an opsin with
an inactivating amino acid substitution(s), a subpopulation of
photoreceptors express the mutant gene, which ultimately results
in the death of the photoreceptor, giving rise to a lower than
normal cone density and leaving gaps in the cone mosaic.60 What
occupies the gaps left by the absent cones remains unknown.
ANOMALOUS TRICHROMACIES
The milder forms of red-green color vision deficiencies are the
anomalous trichromacies. As the term for their condition
implies, affected individuals have trichromatic color vision, but
it is not based on L, M, and S pigments like normal color vision.
Classical descriptions of anomalous trichromacy postulated the
existence of ‘anomalous pigments’ such that in addition to S
cones, protanomalous individuals are said to have normal M
and anomalous L pigments while deuteranomalous individuals
are said to have normal L and anomalous M pigments. Results
of molecular genetic analyses have provided insight into what
the anomalous pigments are, and as a consequence it has become
clear that the classical concept of the ‘anomalous pigment’ is
unbefitting.52 For example, ‘anomalous L’ pigments are often
indistinguishable from normal M pigments in spectral sensi-
tivity and in amino acid sequence, and there is similar overlap
between ‘anomalous M’ pigments and normal L pigments.51,52
The ‘anomalous pigments’ have been generated by recombi-
nation between the ancestral OPN1LW and OPN1MW genes;
however, over evolutionary time, multiple rounds of recombina-
tion have intermixed the ancestral pigment genes so thoroughly
that among modern human males with normal color vision,
there is a family of photopigments specified by the OPN1LW
genes that differ in amino acid sequence and in the wavelength
of peak sensitivity (Fig. 123.9). Similarly, there is a family of
pigments encoded by the OPN1MW genes found in color
normal individuals (Fig. 123.9). The variant forms of the L and
M photopigments underlying normal color vision overlap with
the forms that correspond to what were classically termed the
‘anomalous pigment’. Referring to the photopigments underlying
anomalous trichromacy according to their spectral sensitivities
promotes a clearer understanding of the cause of the differences
between normal versus anomalous trichromacy.
The genes can be categorized as encoding an L-class or an M-
class pigment by the sequence of exon 5. Whether the encoded
pigment will have peak sensitivity near 560 nm or near 530 nm
is determined by the amino acids at two of the polymorphic
amino acid positions encoded by exon 5 (Fig. 123.10).61–63 Amino
acids encoded by five other polymorphic positions encoded by
1601
 RETINA AND VITREOUS
FIGURE 123.9. During human evolution, recombination has
intermixed the OPN1LW and OPN1MW genes so thoroughly that there
is not just one L- and one M-pigment encoded. Instead, the OPN1LW
and OPN1MW genes found in males with normal color vision encode
a family of L-cone photopigments (L-class) and a family of M-cone
photopigments (M-class). The OPN1SW gene has not been observed
SECTION 10
to vary, and hence among humans there is only one know functional
S-cone photopigment.
C-terminus
233
277
230
chromophore
65 180
285
attachment site
312
309
116
dimorphic sites:
spectral tuning sites:
Long (Y277, T285) vs middle
N-terminus
(F277, A285)-wave determining
sites
FIGURE 123.10. Spectral tuning of the L and M cone photopigments
is achieved through amino acid substitutions at a limited number of
positions. The balls represent the amino acids that comprise the L and
M opsins. The photopigments are seven transmembrane proteins. The
red balls indicate amino acids positions 277 and 285. Substitutions at
these positions distinguish the L-class from the M-class pigments.
The yellow balls indicate amino acid positions at which substitutions
produce spectral shifts, and that are responsible for variability in the
absorption spectrum among the L-class, among the M-class, and
between the L- and M-classes. Substitutions at the yellow positions
have a relatively small effect on the absorption spectrum in
comparison to the red positions. The blue balls indicate amino acid
positions that are variable among L- and M-class pigments but that
do not influence the absorption spectrum.
exon 2, 3, and 4 produce spectral variants of the L-class. Only
the polymorphic amino acid positions specified by exon 3 and 4
produce shifts in spectral peak of M pigments, and thus, there
are fewer variant forms of M- than of L-class pigments62
(Fig. 123.9). In addition, the spectral shifts produced by the
polymorphisms in the M-class pigments are relatively small
compared to shifts made by the same amino acid substitutions
at the corresponding positions of the L pigments. From the
deduced amino acid sequences of the pigments encoded by the
genes in the first two positions of the X-chromosome opsin gene
array, the spectral separation of the pigments underlying color
vision can be predicted.
It is the large difference in spectral absorption between L and
1602 M cones that underlies the excellent color discrimination in the
red-to-green region of the visible spectrum that is enjoyed by
people with normal color vision. Individuals with deuteranomaly
lack M cones but they have two distinct classes of L-cone that
are different enough in spectrum to provide the basis for limited
color vision in the red-green region of the spectrum.62–64 Like-
wise, individuals with protanomaly lack L cones but they have
two different classes of M-cone. An anomalous trichromat
with a large spectral difference between the L or M cone sub-
types has the basis for much better color vision than a person
with two cone subtypes that are nearly identical.44,51,64–65 Spectral
separations of 5 nm or larger give rise to only a very mild color
vision deficit,64 and affected individuals often perform as nearly
normal in standard color vision tests. When the underlying
pigments are separated in peak sensitivity by between 2.5 and
5 nm, color vision is more than mildly impaired, but is none-
theless quite excellent compared to smaller separations. When
color vision in the red-green region of the spectrum is mediated
by cones that differ in peak sensitivity by fewer than 2.5 nm,
color discrimination is quite impaired, and some affected indi-
viduals’ performance on standard color vision tests is indistin-
guishable from the performance of a dichromat.64
PROTANOMALY
Protanomalous individuals usually have a rearranged visual
pigment gene locus in which the first gene is an
OPN1LW/OPN1MW chimera with exon 5 derived from the
parental OPN1MW gene and thus it encodes a pigment of the
M class. The chimeric gene is followed by an OPN1MW gene
(Fig. 123.8c). Amino acid sequence differences between the
M-class pigments encoded by the two genes produce a spectral
difference between them, enough to support a small degree of
trichromatic color vision (Fig. 123.10).51,52,64
DEUTERANOMALY
Deuteranomalous individuals usually have a rearranged visual
pigment gene locus so that the first gene is a normal OPN1LW
gene, which is followed by a chimeric gene that is an
OPN1MW/OPN1LW gene that was produced by unequal homo-
logous recombination and that encodes an L-class photopig-
ment (Fig. 123.8a). It is not uncommon for the chimeric gene to
be followed by one or more additional chimeric genes or normal
OPN1MW genes (Fig. 123.8a), however, because genes down-
stream of the first two at the 5„ end of the array are usually not
expressed, the additional genes do not bear on the color vision
phenotype.
TRITAN COLOR VISION DEFICIENCY
Color vision defects caused by abnormalities of the S cones are
denoted with the prefix tritan, and exhibit autosomal dominant
inheritance. In addition, tritan defects show incomplete
penetrance, meaning that there is variability in the degree to
which color vision is impaired among individuals with the same
underlying gene defect, even within a family. That is, even
among members of the same family, some individuals might
exhibit a complete loss of S-cone function, whereas other mem-
bers may exhibit a milder, incomplete loss.66–69 Thus, tritan
defects do not parallel red-green color vision defects and cannot
be dichotomized into analogous dichromatic and anomalous
trichromatic forms.
Tritan deficiencies have been associated with mutations of
the S-opsin gene resulting in four different amino acid
substitutions.70–72 In one study,70 it was concluded that unlike
mutations in the rod pigment rhodopsin that cause autosomal
dominant retinitis pigmentosa (adRP), amino acid substitutions

in the S opsin do not cause retinal degeneration. Given that
only ~5% of the cone photoreceptors in humans are S
cones,73–74 this is not surprising. However, the absence of retinal
degeneration does not imply that the S cones do not degenerate.
An explanation for the low penetrance of tritan defects has yet
to be found, but one interesting possibility is that the S cones
degenerate over time, analogous to the degeneration of rods in
adRP. If so, the tritan phenotype would be a function of age,
reflecting a progressive loss of S cones over time. The low pene-
trance aspect of the disorder may simply reflect that younger
observers have not yet lost enough S cones to manifest symp-
toms. The prevalence of inherited tritan defects have been
reported to be quite low, but they may be grossly underestimated
for a variety of reasons including the fact that standard
color vision tests do not test for tritan defects, they are
extremely difficult to test for, and the phenotype may be age-
dependent. The true incidence of inherited tritan defects and
the ultimate fate of the S cones in affected individuals must
await further experimentation. A particularly exciting prospect
is the application of cutting edge imaging technologies using
adaptive optics to the study of the retinal architecture in tritan
subjects.
ACHROMATOPSIA
Also extremely rare are the monochromatic color vision defects
known as achromatopsias. These disorders are associated with
reduced or absent cone function, denoted as incomplete and
complete achromotopsia, respectively. Blue cone monochro-
macy is a form of incomplete achromatopsia in which affected
individuals base their vision on S cones and rods, and thus have
diminished capacity for all aspects of vision mediated by cones
including color vision and acuity. Rod monochromacy is a form
of complete achromatopsia in which vision is mediated only by
rods. Affected individuals are completely colorblind and have
very poor acuity. Achromatopsia has been reported to affect
fewer than one in 30 000 individuals.29
BLUE CONE MONOCHROMACY
Genetically, blue cone monochromacy is a heterogeneous dis-
order, but in all cases the underlying cause is loss of function of
both L and M cones. One major cause of blue cone mono-
chromacy is the deletion of a critical DNA element known as
an enhancer or LCR responsible for facilitating the expression
of the L and M opsin genes. In the absence of the LCR, none of
the X-chromosome opsin genes are expressed normally, and
thus functional L and M cones are not produced.35–37 The
second major cause of blue cone monochromacy is the deletion
of all except one of the X-chromosome opsin genes and the
presence of an inactivating mutation in the remaining gene.35,37
The most common mutation is the C203R mutation that has
been found in conjunction with red-green color vision defects.
Blue cone monochromats who in psychophysical tests appear to
have more than one class of functional cone have been
reported.75–76 A complete understanding of this disorder must
await further experimentation.
COMPLETE ACHROMATOPSIA AND FORMS
OF INCOMPLETE ACHROMATOPSIA OTHER
THAN BLUE CONE MONOCHROMACY
Although achromatopsias are extremely rare, specific human
populations have been identified that exhibit an extraordinarily
high incidence of the disorder. One example is autosomal reces-
sive incomplete achromatopsia which has a prevalence of 5%
among the Pingelapese islanders in Micronesia.77 The under-
Visual Acuity, Adaptation, and Color Vision
lying genetic cause of the disorder among the Pingelapses is an
amino acid substitution in the beta subunit of the cyclic-GMP
gated ion channel. Phototransduction in all three cone types
relies on the function of the same cyclic-GMP gated ion channel,
which has two subunits, the alpha subunit encoded by the
CNGA3 gene on chromosome 2, and the beta subunit encoded
by the CNGB3 gene on chromosome 8. Mutations in the gene
encoding the alpha subunit have also been found in families
with rod monochromacy, and in patients with incomplete achro-
matopsia.78 Patients with incomplete forms of achromatopsia
appear to have residual cone function whereas patients with the
complete forms do not, implying that not all of the mutations
identified completely abolish channel function.
COLOR APPEARANCE
The human eye is popularly described as being capable of dis-
criminating as many as 10 million ‘colors’. This is offered as a
CHAPTER 123
reason that computer displays are made to be capable of
displaying 256 intensities for each of the red, green, and blue
channels which makes the total number of possible ‘colors’ for
each pixel equal to 16 777 216 (often approximated as 16 million).
In this context, differences in ‘color’ include differences in
brightness, hue, and saturation. It has long been understood
that the ‘millions’ of colors humans can discriminate represent
subtle gradations of a much smaller set of basic sensations. For
example, most people agree that all color experience can be
described using eleven basic color terms which in English are
white, black, red, green, yellow, blue, brown, gray, orange,
purple, and pink. Among these ‘basic’ colors, theorists agree that
some are more fundamental than others. For example, pink
might be described as a very pale red, brown – a very dark
orange, and purple – a reddish-blue. Seven of the basic colors-
red, green, blue, yellow, black, white, and gray-seem to be truly
fundamental in that each of these sensations seem to be unique
and not describable as a combination of the others.
Thus, color experience can be reasonably explained as the
combination of six unique sensations. Accordingly, navy blue is
the simultaneous sensation of blue and black. Pale violet is the
combined sensation of white, red, and blue. The seventh ‘color’,
gray, in this scheme is the absence of all color sensation. Unique
hues were first described by Hering.79 He also noted that red
and green are opposite hues because they cannot be elicited
simultaneously by a single color stimulus. There is no reddish-
green color nor is there a bluish-yellow. Blue and yellow form a
second opponent pair. The same is true of black and white if
one accepts that gray is not the simultaneous sensation of black
and white but rather the absence of either. Hering’s concept of
opponency consequently organizes the six fundamental sensa-
tions into the activity of three pairs of opponent sensations,
black and white, red and green, and blue and yellow. In systems
designed to represent all the possible hues on a continuous
surface such as Figure 123.11, the four fundamental hues
standout as unique while all other colors are seen as blends of
the unique hues.
The facts of our vision are that three types of cone photo-
receptor are responsible for three pairs of sensations. The
question is: how are the signals from the three types of receptors
combined in the nervous system to yield the three opponent
pathways? A great deal is known about the anatomy and physi-
ology of the visual system that can be brought to bear on that
question, but many aspects of the neural circuits for coding
color remain puzzling. In the task of understanding the neural
operations responsible for transforming the cone signals into
perception, a simplification is that of considering reduced color
vision systems with fewer cone types and fewer fundamental
sensations. 1603
 SECTION 10 RETINA AND VITREOUS
FIGURE 123.11. Fan of colors in three-dimensional pigment space.
The fan represents the signal that various colored lights evoke in the
S, M, and L cones.
THE CIRCUITRY FOR CODING BLACK-
WHITE, RED-GREEN, AND BLUE-YELLOW
Information from the retina is carried to higher centers via
the axons of ganglion cells. At the ganglion cell stage, the
responses of receptors has already been combined by post-
receptoral circuitry to produce neurons with specialized response
properties. As introduced in Chapter 111, this processing
begins at the output terminal of the cone itself, the cone pedicle.
Every cone pedicle receives a lateral inhibitory input from sur-
rounding cones via horizontal cells (Fig. 123.12). Thus, for a
cone near the fovea, the response communicated to post-
synaptic bipolar cells is the result of a cone’s own electrical
response to light and the opposing responses of its neighboring
cones that arrive via horizontal cell input. Thus, at its synaptic
terminal (pedicle), every cone compares the number of quanta
it absorbs as opposed to the average number of quanta absorbed
by its neighbors. Assuming that the potential change at the
pedicle produced by a cone absorbing light is evenly balanced
with the opposing input from the average of its neighbors, then,
if the number of quanta absorbed by a cone is greater than the
average absorbed by its neighbors, it hyperpolarizes. If a cone
absorbs fewer quanta than its average neighbor it depolarizes.
Most importantly, when the number of quanta absorbed by a
cone is somewhere near equal to its average neighbor, no signal
is transmitted, i.e., the two opposing inputs null. Thus, a cone
does not signal information about its photon catch, rather it
signals information about the number of photons it has absorbed
relative to the average number it’s neighbors have absorbed. In
the central retina a cone’s neighbors would include an average
of six cones that immediately surround it and cones more
distant tiers away; however, the strength of the signal falls off
exponentially with distance making the nearest neighbors the
most important.
The central retina near the fovea, the region that serves
highest visual acuity, more than 90% of ganglion cells are of the
‘midget’ variety, so called because of their small dendritic arbor,
which in the central 7–10° connects to a single cone via a
‘midget’ bipolar cell. Each cone provides input to many ganglion
cells each presumably specialized to carry specific information
about the visual stimulus. These include one of each of two
midget ganglion cell subtypes for each cone (Fig. 123.12), one
1604 ON-center and one OFF-center which receive input through a
FIGURE 123.12. The wiring diagram of midget ganglion cells in the
human fovea. In the central retina, each midget bipolar cell receives
input from a single middle- (M) or long-wavelength sensitive (L) cone,
and contacts a single midget ganglion cell. This one-to-one
organization allows the signal from each M or L cone to be
transmitted to higher brain regions. However, at the cone terminal
prior to the transmission to the bipolar cell, a cone’s response is
compared in an opponent fashion to the responses of the neighboring
cones. This comparison is achieved via horizontal cells that provide
lateral reciprocally inhibitory interconnections between all cones.
Every cone is served by two midget ganglion cells, one ON-center
and one OFF-center. Neither will respond to stimuli, such as diffuse
uniform white light, that produce activity in a cone that is equal to the
average activity of its neighbors.
corresponding pair of ON- and OFF-midget bipolar cells that
have opposite responses to the neurotransmitter, glutamate
(Chapter 112), released by cones. While some types of ganglion
cells are specialized to carry information collected from many
cones, each midget ganglion cell of the central retina is special-
ized to transmit information from a single cone.
By virtue of its horizontal cell interconnections, a cone com-
pares the number of quanta it absorbs opposed to the average
number of quanta absorbed by its neighbors. The ON-center
midget ganglion cell is specialized to signal with an increased
rate of action potentials when its cone absorbs a greater number
of photons than the average absorbed by its neighbors as would
happen when a relatively lighter region of an image falls on a
cone while its neighboring cones ‘see’ adjacent darker parts of
the image. The OFF-center ganglion cell is specialized to signal
the reverse, i.e., when a cone absorbs fewer quanta than its
average neighbor as when a relatively darker region of the scene
falls on the cone. When the number of quanta absorbed by a cone
is equal to its average neighbor, no signal is transmitted, i.e., the
two opposing inputs null and both ON- and OFF-center
ganglion cells fire at their spontaneous rates.
The midget ON and OFF midget gangion cells have all the
qualities to serve as the biological substrate for the opponent
percepts of black and white as proposed by Hering. This is
particularly evident for individuals with a red-green color vision
defect who have a reduced number of cone types from three
to two and they have a reduced number of fundamental color
sensations. As explained above, individuals with only two

d that represent the simultaneous sensation of
a both blue and yellow. (c) Digitally resampling
b e
c f
spectrally different types of cones are refered to as dichromats.
The prefix ‘di-’ in dichromacy does not refer to two types of
cone. Dichromacy means, literally, two hues and derives from
the fact that dichromats can match any color using mixtures of
just two ‘primary’ hues. However, the term dichromat is also
appropriate because dichromats see only two hues. To them,
objects are black, white, shades of gray, or one of two hues. The
image in Figure 123.13 has been digitally altered to simulate the
appearance for a dichromat. For the dichromat there is only
black and white and blue and yellow. In contrast, people with
normal color vision see more than 100 different hues in
addition to black, white, and gray. Dichromats confuse red with
green, and they confuse, with red and green, all colors in the
spectrum that fall between them, including yellow, orange, and
brown. They see blue and violet as the same color, and blue-
green is indistinguishable from white or gray. Magenta and its
pastel counterpart pink also appear white or gray.
During evolution, the midget ganglion cell system is believed
to have arisen in an ancestor to modern primates prior to the
emergence of trichromatic color vision. Like most other mam-
mals, that ancestor presumably had two cone types, S cones and
a second type of cone sensitive in the middle-to-long wave-
lengths (Fig. 123.7b). The midget ganglion cells do not receive
direct center input from S cones. Thus, in a dichromatic ancestor
to humans, the midget ganglion cell system’s major function
was to compare absorptions of middle-to-long wavelength cones
with their neighbors. The neighbors of an L/M cone would have
been predominately of the identical spectral type because S
Visual Acuity, Adaptation, and Color Vision
FIGURE 123.13. (a) A digital image of fruit that
has been digitally processed in subsequent
panels to represent the activity of different
subsystems for coding color in the human
visual system. (b) The image processed to
appear as it would to a dichromat having color
vision based on just S and L cones. The
dichromat has only four color sensations, blue,
yellow, black, and white. Because blue and
yellow are processed in an opponent fashion,
for a dichromat, there are no intermediate hues
the image at a much lower spatial resolution
removes the fine details from the image and
significantly degrades its quality. (d) The black
and white components are separated from
(e) the hue components of the image. Here the
hue components have been resampled with the
CHAPTER 123
same reduced resolution as in panel (c). (f) The
image is reconstituted combining the high
resolution black and white components of (d)
with the low resolution hue components of (e).
The spatial resolution of the hue components
(b) and (f) are very different but on casual
inspection they appear nearly identical. If you
look closely you can see that the yellow color is
blurred outside the black lines. This is largely
ignored by the visual system that uses the
black and white edges to define detailed
boundaries in the image. The hue information is
used to define qualities of the objects other
than spatial detail.
cones are many times fewer in number (~5% of the total in
humans). Assuming a balanced center versus surrounds, this
system signals the presence of light/dark boundaries in a visual
scene. If a dark area in an image falls on a cone, but adjacent
lighter areas illuminate neighboring cones, the OFF-center
midget ganglion will signal with increased firing. Conversely, a
light area bounded by darker regions will be signaled by increased
firing of the ON-center ganglion cell. These are exactly the
stimulus conditions we associate with the percepts of black
and white.
In addition to serving the percepts of black and white, this
system presumably evolved to serve high acuity spatial vision,
signaling the presence of dark/light edges with great detail and
precision. Representing more than 90% of the ganglion cells that
serve the central retina, the midget ganglion cells are the only
output neurons that have sufficient numbers to transmit infor-
mation about fine detail in the image. Accordingly, the midget
ganglion cells appear to simultaneously serve two purposes in
vision for a dichromat. The ON- and OFF-center midget ganglion
cells form the basis for the percepts of black and white, respec-
tively. In turn, the percepts of black and white in the
dichromatic image are responsible for coding information about
fine detail in the image. This is evident when the black and
white of an image (Fig. 123.13c) is separated digitally from its
color, all the detail of the image is preserved.
We use information about hue to find out about the internal
qualities of objects. For example, a trichromat can tell that a
banana is ripe by its yellow color. However, to determine its 1605
 RETINA AND VITREOUS

ripeness we do not need information about the fine detail of the
spatial distribution of the yellow color. This is true of all the
information we extract from the hue of objects. We know that
it is evening because of the red of the sunset or that a colleague
is embarrassed because of the redness in his face. However, we
do not need to know details of the spatial distribution of the
colored areas. Even when we use hue to locate objects in visual
search, the color can ‘catch our eye’ in the absence of the spatial
details of the object. The S cones are used in color vision but
they do not participate in providing high acuity. They can parti-
cipate in providing hue information at a much lower sampling
density than the L and M cones that provide information about
spatial detail. The unimportance of extracting color vision with
high spatial resolution is illustrated in Fig. 123.13. In Fig 123.13e,
the hue components of the image were separated and resampled
at a much lower resolution. These low resolution hue compo-
nents provide almost no information that allows us to recognize
the objects in the scene. However, when the low quality hue
SECTION 10
vision and they could be important for providing the required
two opponent parts of the system.
The story would be relatively simple if humans were all
dichromats. If this were true, details of the specialized functions
of each of three major ganglion cell populations carrying infor-
mation to the brain would be easily understood. The midget
ganglion cells provide the biological substrate for percepts of
black and white and are responsible for carrying information
about high acuity spatial detail. The second major ganglion cell
population, the parasol cells, are responsible for the perception
of motion. These make up only ~5% of ganglion cells in the
fovea but are a much larger proportion of ganglion cells in the
peripheral retina where our motion perception is most acute.
Although details are left to be worked out, the third major
ganglion cell population, the small bistratified ganglion cells
must participate in blue-yellow color vision. However, the
introduction of red-green color vision complicates the story
because adding a randomly distributed third cone type makes

components are recombined with (d), the black and white
components of the image, (Fig. 123.13f) the result is almost
imperceptibly different than the original image (b).
It is not completely clear which ganglion cell subtypes are
specialized for carrying information corresponding to Herring’s
blue-yellow opponent channel. Small bistratified ganglion cells
make up less than 10% of the total output of the retina and they
have opponent blue-yellow responses. Thus, they are candidates
to have some role in blue-yellow color vision. However, they all
respond to blue and inhibit to yellow, leaving us without an
explanation of the physiological basis for the yellow half of the
blue-yellow opponent system. It is possible that a subpopulation
of midget ganglion cells is also involved in blue-yellow color
almost every midget ganglion cell respond to either diffuse red
or diffuse green light in addition to dark and light edges. A
guiding principle in our understanding the biological basis of
sensation for more than 150 years is Johannes Müller’s (1833)
‘Law of Specific Nerve Energies’ which states “Qualitatively
different sensations must derive from different organs.” Accord-
ingly, even though the midget ganglion cells in trichomats
respond to both diffuse red and green lights and black and white
edges, ultimately the two percepts must be separated from each
other at a higher level of visual processing, into two perceptually
opponent processes of black and white and red and green.
How this is accomplished is one of the fascinating remaining
mysteries of our visual system.

REFERENCES
1. Green DG, Powers MK, Banks MS: Depth
of focus, eye size and visual acuity. Vision
Res 1980; 20:827.
2. VanMeeteren A: Calculations on the optical
modulation transfer function of the human
eye for white light. Opt Acta 1974; 15:47.
3. Campbell FW, Gregory AH: Effect of size of
pupil on visual acuity. Nature 1960;
187:1121.
4. Campbell FW, Green DG: Optical and
retinal factors affecting visual resolution.
J Physiol 1965; 181:576.
5. Green DG: Visual acuity: The influence of
refraction and diffraction and the use of
interference fringes. Int Ophthalmol Clin
1978; 18:21.
6. Green DG: Regional variations in the visual
acuity for interference fringes on the retina.
J Physiol 1970; 207:351.
7. Le Grand Y: Form and space vision.
Bloomington: Indiana University Press;
1967.
8. Thibos LN, Cheney FE, Walsh DJ: Retinal
limits to the detection and resolution of
gratings. J Opt Soc Am A 1987; 4:1524.
9. Lovegrove WJ, Bowling A, Badcock D,
Blackwood M: Specific reading disability:
differences in contrast sensitivity as a
function of spatial frequency. Science 1980;
210:439.
10. Hyvarinen L, Rovamo J, Laurinen P,
Peltomaa A: Contrast sensitivity function in
evaluation of visual impairment due to
retinitis pigmentosa. Acta Ophthalmol
1981; 59:763.
11. Hyvarinen L: Contrast sensitivity in visually
impaired children. Acta Ophthalmol 1983;
157(Suppl):58.
1606
12. Hyvarinen L, Rovamo J, Laurinen P, et al:
Contrast sensitivity in monocular glaucoma.
Acta Ophthalmol 1983; 61:742.
13. Hyvarinen L, Laurinen P, Rovamo J:
Contrast sensitivity in evaluation of visual
impairment due to macular degeneration
and optic nerve lesions. Acta Ophthalmol
1983; 61:161.
14. Hyvarinen L, Laurinen P, Rovamo J:
Contrast sensitivity in evaluation of visual
impairment due to diabetes. Acta
Ophthalmol 1983; 61:94.
15. Koskela PU, Hyvarinen L: Contrast
sensitivity in amblyopia. IV. Assessment of
vision using vertical and horizontal gratings
and optotypes at different contrast levels.
Acta Ophthalmol 1986; 64:570.
16. Gaskill JD: Linear systems, Fourier
transforms, optics. New York: John Wiley;
1978.
17. Bodis-Wollner I: Visual acuity and contrast
sensitivity in patients with cerebral lesions.
Science 1972; 178:679.
18. Brown B: Reading performance in low
vision patients: relation to contrast and
contrast sensitivity. Am J Optom Physiol
Opt 1981; 58:218.
19. Rubin GS, Legge GE: Psychophysics of
reading. VI. The role of contrast in low
vision. Vision Res 1989; 29:79.
20. Pirenne MH, Denton EJ: Accuracy and
sensitivity of the human eye. Nature 1952;
170:1039.
21. Shlaer S, Smith E, Chase A: Visual acuity
and illumination in different spectral
regions. J Gen Physiol 1942; 25:553.
22. Mendelbaum J, Sloan LL: Peripheral visual
acuity. Am J Ophthalmol 1947; 30:581.
23. Yarbus AL: The perception of an image
fixed with respect to the retina. Biophysics
1957; 2:683.
24. Riggs LA, Tulunay SU: Visual effects of
varying the extent of compensation for
eye movements. J Opt Soc Am 1959;
49:741.
25. Barlow HB: Slippage of contact lenses and
other artefacts in relation to fading and
regeneration of supposedly stable retinal
images. Q J Exp Psychol 1963; 15:36.
26. Tulunay-Keesey U, Jones RM: The effect of
micromovements of the eye and exposure
duration on contrast sensitivity. Vision Res
1976; 16:481.
27. Aquilar M, Stiles WS: Saturation of the rod
mechanisms of the retina at high levels of
stimulation. Opt Acta 1954; 1:59.
28. Rushton WAH: The sensitivity of rods under
illumination. J Physiol 1965; 178:141.
29. Sharpe LT, Stockman A, Jägle H,
Nathans J: Opsin genes, cone
photopigments, color vision, and color
blindness. In: Gegenfurtner KR, Sharpe LT,
eds. Color vision: from genes to
perception. New York: Cambridge
University Press; 1999:3.
30. Dean M, Carrington M, O’Brien SJ:
Balanced polymorphism selected by
genetic versus infectious human disease.
Ann Rev Genom Human Genet 2002;
3:263.
31. Nathans J, Piantanida TP, Eddy RL, et al:
Molecular genetics of inherited variation in
human color vision. Science 1986; 232:203.
32. Jacobs GH: The distribution and nature of
colour vision among the mammals. Biol
Rev 1993; 68:413.

33. Jacobs GH: A perspective on color vision
in platyrrhine monkeys. Vision Res 1998;
38:3307.
34. Jacobs GH, Neitz J: Color vision in
monkeys: sex related differences suggest
the mode of inheritance. Vision Res 1985;
25:141.
35. Nathans J, Davenport CM, Maumenee IH,
et al: Molecular genetics of blue cone
monochromacy. Science 1989; 245:831.
36. Wang Y, Macke JP, Merbs SL, et al: A locus
control region adjacent to the human red
and green visual pigment genes. Neuron
1992; 9:429.
37. Nathans J, Maumenee IA, Zrenner E, et al:
Genetic heterogeneity among blue-cone
monochromats. Am J Hum Genet 1993;
53:987.
38. Smallwood PM, Wang Y, Nathans J: Role
of a locus control region in the mutually
exclusive expression of human red and
green cone pigment genes. PNAS 2002;
99:1008.
39. Hagstrom SA, Neitz M, Neitz J: Cone
pigment gene expression in individual
photoreceptors and the chromatic
topography of the retina. J Opt Soc Am A
Opt Image Sci Vis 2000; 17:527.
40. Onishi A, Koike S, Ida M, et al:
Dichromatism in macaque monkeys. Nature
1999; 402:139.
41. Hayashi T, Motulsky AG, Deeb SS: Position
of a ‘green-red’ hybrid gene in the visual
pigment array determines colour-vision
phenotype. Nat Genet 1999; 22:90.
42. Bollinger K, Sjoberg S, Neitz M, Neitz J:
Topographical cone photopigment gene
expression in deutan-type red-green color
vision defects. Vision Res 2004; 34:135.
43. Sjoberg SA, Neitz M, Balding SD, Neitz J:
L-cone pigment genes expressed in normal
colour vision. Vision Res 1998; 38:3213.
44. Shevell SK, He JC, Kainz PM, et al:
Relating color discrimination to
photopigment genes in deutan observers.
Vision Res 1998; 38:3371.
45. Neitz M, Neitz J: A new mass screening
test for color-vision deficiencies in children.
Color Res Appl 2001; 26:S239.
46. Jagla WM, Jägle H, Hayashi T, et al:
The molecular basis of dichromatic color
vision in males with multiple red and green
visual pigment genes. Hum Mol Genet
2002; 11:23.
47. Neitz M, Carroll J, Renner A, et al: Variety
of genotypes in males diagnosed as
dichromatic on a conventional clinical
anomaloscope. Vis Neurosci 2004; 21:205.
48. Kainz PM, Neitz M, Neitz J: Molecular
genetic detection of female carriers of
protan defects. Vision Res 1998; 38:3365.
Visual Acuity, Adaptation, and Color Vision
49. Neitz J, Neitz M, He JC, Shevell SK:
Trichromatic color vision with only two
spectrally distinct photopigments. Nat
Neurosci 1999; 2:884.
50. Deeb SS, Lindsey DT, Hibiya Y, et al:
Genotype-phenotype relationships in
human red/green color-vision defects:
molecular and psychophysical studies. Am
J Hum Genet 1992; 51:687.
51. Carroll J, Neitz M, Neitz J: Testing
hypotheses about visual pigments
underlying deutan color vision. Color Res
Appl 2001; 26:S106.
52. Neitz M, Neitz J: Molecular genetics of
color vision and color vision defects. Arch
Ophthalmol 2000; 118:691.
53. Winderickx J, Sanocki E, Lindsey DT, et al:
Defective colour vision associated with a
missense mutation in the human green
visual pigment gene. Nat Genet 1992; 1:251.
54. Karnik SS, Khorana HG: Assembly
functional rhodopsin requires a disulfide
bond between cysteine residues 110 and
187. J Biol Chem 1990; 265:17520.
55. Kazmi MA, Sakmar TP, Ostrer H: Mutation
of a conserved cysteine in the X-linked
cone opsins causes color vision
deficiencies by disrupting protein folding
and stablilty. Invest Ophthalmol Vis Sci
1997; 38:1074.
56. Nathans J, Thomas D, Hogness DS:
Molecular genetics of human color vision:
the genes encoding blue, green, and red
pigments. Science 1986; 232:193.
57. Winderickx J, Battisti L, Hibibya Y, et al:
Haplotype diversity in the human red and
green opsin genes: evidence for frequent
sequence exchange in exon 3. Hum Mol
Genet 1993; 2:1413.
58. Neitz M, Neitz J, Grishok A: Polymorphism
in the number of genes encoding long-
wavelength sensitive cone pigments among
males with normal color vision. Vision Res
1995; 35:2395.
59. Carroll J, McMahon C, Neitz M, Neitz J:
Flicker-photometric electroretinogram
estimates of L : M cone photoreceptor ratio
in men with photopigment spectra derived
from genetics. J Opt Soc Am A Opt Image
Sci Vis 2000; 17:499.
60. Carroll J, Neitz M, Hofer H, et al: Functional
photoreceptor loss revealed with adaptive
optics: an alternate cause of color
blindness. Proc Natl Acad Sci USA 2004;
101:8461.
61. Neitz M, Neitz J, Jacobs GH: Spectral
tuning of pigments underlying red-green
color vision. Science 1991; 252:971.
62. Asenjo AB, Rim J, Oprian DD: Molecular
determinants of human red/green color
discrimination. Neuron 1994; 12:1131.
63. Merbs SL, Nathans J: Absorption spectra
of the hybrid pigments responsible for
anomalous color vision. Science 1992;
258:464.
64. Neitz J, Neitz M, Kainz PM: Visual pigment
gene structure and the severity of human
color vision defects. Science 1996; 274:801.
65. Regan BC, Reffin JP, Mollon JD:
Luminance noise and the rapid
determination of discrimination ellipses in
colour deficiency. Vision Res 1994; 34:1279.
66. Wright WD: The characteristics of
tritanopia. J Opt Soc Am 1952; 42:509.
67. Kalmus H: The familial distribution of
congenital tritanopia. Ann Hum Genet
1955; 20:39.
68. Pokorny J, Smith VC, Went LN: Color
matching in autosomal dominant tritan
defect. J Opt Soc Am 1981; 71:1374.
69. Went LN, Pronk N: The genetics of tritan
CHAPTER 123
disturbances. Hum Genet 1985; 69:255.
70. Weitz CJ, Miyake Y, Shinzato K, et al:
Human tritanopia associated with two
amino acid substitutions in the blue
sensitive opsin. Am J Hum Genet 1992;
50:498.
71. Weitz CJ, Went LN, Nathans J: Human
tritanopia associated with a third amino
acid substitution in the blue sensitive visual
pigment. Am J Hum Genet 1992; 51:444.
72. Gunther KL, Neitz J, Neitz M: A novel
mutation in the short-wavelength sensitive
cone pigment gene associtated with a tritan
color vision defect. Vis Neurosci 2006;
23:403.
73. Curcio CA, Allen KA, Sloan KR, et al:
Distribution and morphology of human
cone photoreceptors stained with anti-blue
opsin. J Comp Neurol 1991; 312:610.
74. Hofer H, Carroll J, Neitz J, et al:
Organization of the human trichromatic
cone mosaic. J Neurosci 2006; 26:722.
75. Smith VC, Pokorny J, Delleman JW, et al:
X-linked incomplete achromatopsia with
more than one class of functional cones.
Invest Ophthalmol Vis Sci 1983; 24:451.
76. Crognale MA, Fry M, Highsmith J, et al:
Characterization of a novel form of X-linked
incomplete achromatopsia. Vis Neurosci
2004; 21:197.
77. Sundin OH, Yang JM, Li Y, et al: Genetic
basis of total colourblindness among the
Pingelapese islanders. Nat Genet 2000;
25:289.
78. Wissinger B, Gamer D, Jägle H, et al:
CNGA3 mutations in hereditary cone
photoreceptor disorders. Am J Hum Genet
2001; 69:722.
79. Hering E: Outlines of a theory of the light
sense. (Hurvich LM, Jameson D, transl)
Cambridge: Harvard University Press; 1964.
1607
 CHAPTER
124 Objective Assessment of Retinal Function
Michael A. Sandberg
INTRODUCTION
This chapter describes the methodology application, and
normal variation of some objective measures of retinal function
that are used to establish diagnoses in known or suspected
hereditary retinal diseases. Objective assessment of retinal
function is important for at least three reasons. First, it provides
evidence about the site of localization of visual loss (e.g.,
whether the site of visual loss is within the eye or visual
pathways or whether the abnormality is restricted to the macula
or involves the entire retina). Second, in most cases it permits
a quantitative assessment of the degree of malfunction that can
be followed up over time for the purpose of projecting long-term
prognosis or evaluating a prospective treatment. Third, outcomes
from these measures may be shown to the patient as variations
in fundus reflectance or as waveforms on photographs or paper
so that the patient can appreciate the type and magnitude of his
or her visual malfunction and thereby actively participate with
the ophthalmologist in the initial and follow-up examinations.
The techniques addressed include fundus reflectometry, fundus
autofluorescence, optical coherence tomography (OCT), early
receptor potential (ERP) recording, electrooculography, full-field
and focal flash electroretinography, pattern-reversal electroretino-
graphy, and pattern-reversal visual evoked response (VER) record-
ing. The first three methods, though not measures of function
per se, are always presented in the context of measures of function
in interpreting hereditary retinal disease. (OCT is considered in
greater detail elsewhere in this publication.) Although VER record-
ing does not reflect retinal function directly, it is a necessary test
when measures of retinal function fail to disclose the site of
abnormality. It is therefore discussed briefly at the end of the
chapter. Guidelines are presented for obtaining reliable and repro-
ducible results and, in some cases, for interpreting variations
within a single session and between visits in a given patient as
well as differences that may exist among normal subjects.
FUNDUS REFLECTOMETRY
Fundus reflectometry (also known as retinal densitometry) is a
method for estimating the mass optical density, absorption spectra,
and regeneration kinetics of the photolabile pigments within
photoreceptors. Although still primarily a research tool, it may
be used clinically to help identify stationary forms of nyctalopia
that have normal rhodopsin densities but a defect in transmission
between rod photoreceptors and more proximal retinal cells1;
diseases of dark adaptation involving slowed pigment regenera-
tion, such as fundus albipunctatus (Fig. 124.1)2; diseases of dark
adaptation with normal pigment regeneration, such as Oguchi’s
disease3; and photoreceptor mosaicism in carriers of X-linked
retinitis pigmentosa.4,5 It is also useful in subtyping patients
with dominant retinitis pigmentosa based on generalized rod
loss versus regionalized rod and cone loss6 and in monitoring
the course of diseases affecting the uvea and retinal pigment
epithelium (RPE).7
Two types of reflectometer are in use at present, normally in
a clinical research setting. The first, and original, type involves
collecting and comparing the amount of light reflected by 1–2°
of the fundus, initially from the dark-adapted eye and then again
after exposure to a light that bleaches most of the available visual
pigment.8–10 The light from a brief test flash, which in itself
bleaches little of the visual pigment, is reflected from the fundus
and focused on the head of a photomultiplier tube. The differ-
ence in the reflected light before and after the bleaching episode
provides a measure of the amount of visual pigment. The second,
and more recent, type of reflectometer involves imaging the fundus
over a visual angle of at least 10° and capturing the reflected
light either photographically or on videotape. Density differences
are then quantified by comparing unbleached with bleached
areas captured in a single image11,12 or between successive
images.13,14
Both systems may be properly used only in patients with clear
media and stable fixation. The pupil is maximally dilated and
the eye undergoes dark adaptation for at least 30 min, during
which time an impression of the patient’s bite is made with
dental wax. With the patient’s head stabilized by the wax impres-
sion and the fellow eye fixating on a red lamp or light-emitting
diode, the examiner aligns the eye to be tested in dim red or
infrared light that causes negligible bleaching. For assessing
rhodopsin density, the mid-peripheral fundus, in which cone
photoreceptors are scarce, is generally chosen. For assessing cone
pigment density, the fovea, in which rods are fewest, is chosen.
A test flash of narrow-band wavelength near the peak of the absorp-
tion spectrum (i.e., ~500 nm for rods and ~560 nm for cones)
is then presented to quantify reflectance of the dark-adapted eye.
After reaffirming alignment in red light, a bright white light is
usually presented for many seconds to bleach at least 95% of the
visual pigment. The test flash is presented again to quantify reflect-
ance without significant absorption by visual pigment. The
logarithmic difference between the two measurements repres-
ents the pigment density. This is a ‘double-density’ difference in
that the test beam has passed through the photoreceptor layer
twice, the second time by reflection from the pigment epithelium
and choroid. Additional test flashes may be presented either at
other wavelengths in rapid succession to both dark-adapted and
bleached eyes to determine the absorption spectrum of the visual
pigment or at known intervals after the bleaching episode to
assess the time course of pigment regeneration. Figure 124.2
illustrates results from an imaging densitometer. In this case, a
mid-peripheral region of retina was initially bleached for 10 s
over only the right half of the image, the left half remaining 1609
 RETINA AND VITREOUS

FIGURE 124.1. Visual pigment regeneration for two brothers (LD and
ED) with fundus albipunctatus. Recovery times to 50% of maximum
were ~1 h for rhodopsin in the peripheral retina and 20 min for cone
SECTION 10

pigments in the fovea, increases of approximately 20-fold and 16-fold,

respectively, compared with normal times with this test system.
Modified from Carr RE, Ripps H, Siegel IM: Visual pigment kinetics and
adaptation in fundus albipunctatus. Doc Ophthalmol Proc Ser 1974; 4:193.
Reprinted from Kluwer Academic Publishers.
adapted to the dark. The figure shows the image photographed
by a 500-nm test flash and captured on videotape. The bleached
half appears brighter than the unbleached half, indicating less
remaining visual pigment in the former.
Normal values for rhodopsin double density range from 0.08
to 0.15 log-unit in different peripheral regions for young adult
subjects15 and from 0.06 to 0.14 log-unit between regions of a
single subject.16 For cone pigment, the range between subjects is
0.14–0.30 log-unit within the central 2°, which falls to 0.05–0.11
log-unit at an average eccentricity of 2.5° degrees.14 Foveal cone
pigment density has been reported to decline linearly with age.17
FUNDUS AUTOFLUORESCENCE
Delori and associates in 1995 used noninvasive fundus spectro-
photometry to demonstrate that lipofuscin in the human RPE
exhibits a red fluorescence when stimulated by a shorter-wave-
length light.18 Emission peaked between 620 and 640 nm, and
excitation peaked at 510 nm. The shape of the emission spectrum
changed for excitation wavelengths ≤ 470 nm, indicating a second
fluorophore. The authors also showed that fluorescence was
minimal at the fovea, apparently due to excitation absorbance by
FIGURE 124.2. Midperipheral regions of a normal human fundus
photographed on videotape with 502-nm light immediately after a
greater than 95% rhodopsin bleach over the right half performed with
an imaging reflectometer. Squares at the bottom were copied from
areas designated with letters to facilitate comparison of double-
density gray values, which differ by ~0.2 log unit.
macular pigment and by the increased melanin in this region,
and increased markedly with increasing age for excitation
>470 nm (Fig. 124.3, left).
Later in the same year, Delori et al showed that patients with
autosomal recessive juvenile macular degeneration (Stargardt
disease/fundus flavimaculatus) and a dark choroid on fluorescein
angiography had increased autofluorescence of the RPE after
taking into account age (Fig. 124.3, right), indicating abnormally
high accumulation of lipofuscin in these patients.19 Since then,
the adaptation of a confocal scanning laser ophthalmoscope in
London has led to a series of papers describing the imaging of
fluorescence of the RPE in patients with different retinal diseases.
These authors reported increased autofluorescence in patients with
macular dystrophy in general (i.e., even in the absence of a dark
choroid on fluorescein angiography),20 although some patients
with Stargardt disease had reportedly normal or reduced auto-
fluorescence.21 Measurements with this instrument have also
been performed in retinitis pigmentosa, where rings of increased

FIGURE 124.3. (Left) Variation of RPE fluorescence with retinal location and age. Fluorescence at 620 nm was excited by a wavelength of
510 nm. Spatial resolution = 2°. (Right) Fluorescence of the RPE at 620 nm to an excitation of 510 nm for one or both eyes of patients with
Stargardt disease/fundus flavimaculatus (triangles) and for healthy controls (circles, n = 45). Error bars designate ±1 standard deviation. The solid
and dashed lines represent the best-fitting regression line and its 99.99% confidence limits.
(Left) From Delori FC, Dorey CK, Staurenghi G, et al: In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest
Ophthalmol Vis Sci 1995; 36:718. (Right) From Delori FC, Staurenghi G, Arend O, et al: In vivo measurement of lipofuscin in Stargardt’s disease – Fundus
1610 Flavimaculatus. Invest Ophthalmol Vis Sci Mar 1995; 36:2327.

OD OS
autofluorescence in the macula and areas of decreased fluores-
cence in the periphery have been observed.22,23 Conversely, some
patients with Leber congenital amaurosis, an early-onset severe
form of retinitis pigmentosa, have been found to have minimally,
if at all, disturbed autofluorescence, which the authors interpreted
as indicating morphologically preserved photoreceptors and
RPE in those regions.23 However, since the confocal scanning
laser ophthalmoscope excites autofluorescence with a lower wave-
length (488 nm) and measures autofluorescence over a broader
spectrum (with a 50% cut-on at 510 nm) than the results of Delori
and colleagues would recommend, it is possible that differences
in lenticular absorption, in macular pigment density, in uveal
pigment density, and in the relative concentrations of multiple
retinal and RPE fluorophores may, in part, confound interpre-
tation when this instrument is applied to different types and
stages of hereditary retinal degeneration.
OPTICAL COHERENCE TOMOGRAPHY
OCT is a new rapid noninvasive method for obtaining cross-
sectional images of the retina based on differential near-infrared
light reflection at optical interfaces. Although its most obvious
application has been to help monitor the surgical treatment of
macular holes, epiretinal membranes, and retinal tears, OCT can
also be used to help assess hereditary retinal disease. Figure 124.4
illustrates representative tomograms from a normal control sub-
ject and two patients with retinitis pigmentosa. The tomograms
were obtained with a commercial third-generation instrument
(OCT3). The upper tomograms from the normal control show
the low-reflectance outer nuclear layer peaking in thickness in
the center beneath the foveal depression and visible from edge
to edge. A third high-reflectance band can be distinguished just
above a thicker high-reflectance RPE/choriocapillaris complex;
the third high-reflectance band is slightly convex in the center,
possibly reflecting longer cone outer segments in this region.
The middle tomograms from a patient with retinitis pigmentosa
and normal visual acuities have a normal appearance in the
center (with an intact third high-reflectance band) but show loss
of the outer nuclear layer more peripherally. The lower tomo-
grams from a patient with retinitis pigmentosa and poor visual
acuities show widespread loss of the outer nuclear layer with
apparent thinning of the inner retina. By examining patients
with retinitis pigmentosa and no cystic changes in the macula,
Objective Assessment of Retinal Function
FIGURE 124.4. Tomograms recorded with a
Zeiss Stratus High-Resolution Optical
Normal Coherence Tomographer from a 39-year-old
female normal control with Snellen visual
ONL
acuities of 20/20 OD and 20/20 OS (upper
rd
3 HRB
RPE
images), a 34-year-old male with retinitis
pigmentosa (RP) and visual acuities of 20/20
OD and 20/20 OS (middle images), and a 33-
year-old male with RP and visual acuities of
20/200 OD and 20/80 OS (lower images). Each
RP tomogram subtended 6 mm centered on the
fovea. The horizontal arrows (upper right)
designate the low-reflective outer nuclear layer
(ONL), the third high-reflectance band possibly
designating the photoreceptor inner
segment/outer segment junction (third HRB),
and the high-reflective RPE/choriocapillaris
(RPE).
RP Sandberg MA, Brockhurst RJ, Gaudio AR, Berson EL:
CHAPTER 124
The association between visual acuity and central
retinal thickness in retinitis pigmentosa. Invest
Ophthalmol Vis Sci 2005; 46:3349.
these investigators showed that both retinal thinning (due to
cell loss) and retinal thickening (due to presumed edema) were
associated with lower visual acuity (Fig. 124.5).24 This study
also found that an increase or decrease in retinal thickness of
more than 17 mm at fixation at follow-up can be considered a sig-
nificant (p < 0.01) change in patients with retinitis pigmentosa.
OCT has also been used to detect cystoid macular edema
(CME) in patients with retinitis pigmentosa. One of these studies
found that the area of the cystoid spaces was positively correlated
with the grade of the fluorescein angiogram and the visual acuity,25
and two studies have reported that some eyes with cystoid lesions
showed no angiographic evidence of dye leakage or pooling.25,26
FIGURE 124.5. Regression of ETDRS visual acuity on OCT retinal
thickness at fixation based on data from 288 eyes of 162 patients with
retinitis pigmentosa without macular cysts. The straight line with large
dashes is the best-fitting linear function. The curve with small dashes
is the best-fitting log function. The solid curve is the best-fitting
second-order polynomial and best describes the data. The different
symbols designate the definition of the third high-reflectance band
(third HRB) which is thought to represent the inner segment/outer
segment junction.
From Sandberg MA, Brockhurst RJ, Gaudio AR, Berson EL: The association
between visual acuity and central retinal thickness in retinitis pigmentosa.
Invest Ophthalmol Vis Sci 2005; 46:3349. 1611
 RETINA AND VITREOUS

FIGURE 124.6. OCT images from the right eye

of a 44-year-old male with retinitis pigmentosa
before (a) and 3 weeks after (b) beginning
treatment with acetazolamide, at which time
the macular cysts had decreased in size.
From Apushkin MA, Fishman GA, Janowicz MJ:
Monitoring cystoid macular edema by optical
coherence tomography in patients with retinitis
pigmentosa. Ophthalmology 2004; 111:1899.
a b

Figure 124.6 illustrates tomograms from a patient with retinitis

pigmentosa, before and after treatment with acetazolamide for
CME; the patient showed no evidence of CME on fundus
examination or fluorescein angiography prior to treatment.26
Several studies have also used OCT to visualize cystic lesions in
patients with hereditary retinoschisis.27–30
SECTION 10

EARLY RECEPTOR POTENTIAL

RECORDING
The ERP is a very short latency, biphasic response from the eye
elicited by a very bright flash of light.31 It consists of a cornea-
FIGURE 124.7. Normal human ERP followed by an a-wave of ERG
positive component (R1) followed by a cornea-negative compo-
(left tracing) and normal ERP with high sweep speed and amplification
nent (R2), which is then followed by the cornea-negative a-wave (right tracing). Both cornea-positive peak (R1) and later cornea-
of the electroretinogram (ERG) (Fig. 124.7). It derives almost negative peak (R2) of ERP are designated. Stimulus onset is at the
entirely from photoreceptors32 – R1 reflects the conversion of beginning of each trace. Calibration symbol = 2 ms horizontally and
lumirhodopsin to metarhodopsin I,33 whereas R2 reflects the 100 µV vertically for the left tracing; 0.5 ms horizontally and 50 µV
conversion of metarhodopsin I to metarhodopsin II.34 As the ERP vertically for the right tracing.
amplitude is proportional to the amount of pigment bleached by From Berson EL, Goldstein EB: The early receptor potential in dominantly
the flash35 and depends on the orientation of visual pigment mole- inherited retinitis pigmentosa. Arch Ophthalmol 1970; 83:412. Copyright 1970,
cules within the outer segment,36 it may be used as a measure American Medical Association.
of mass outer segment optical density over most of the retina.
In humans, 60–70% of the R2 response is generated by cones
and the remainder by rods,37,38 so that it may not be possible to
specify whether one or both receptor systems are involved if the
amplitude reduction is less than 40%. The ERP has been used
to demonstrate photoreceptor impairment in a variety of retinal
diseases, including retinitis pigmentosa.31,39,40
The ERP must be elicited with a light flash ~10 million
times brighter than that required to elicit the b-wave of the ERG
(Fig. 124.8).41 This can be achieved, for example, with a flash-
gun focused in the plane of the pupil in Maxwellian view. Care
must be taken to avoid a photovoltaic artifact superimposed on
R1. Investigators have developed custom monopolar contact
lenses with either nonmetallic electrodes or metallic electrodes
shielded from incident light42–44 to record an ERP uncontami-
nated by a photovoltaic artifact. Since the light flash must bleach
a considerable amount of visual pigment to generate a detect-
able response, time for pigment regeneration must be allowed
before presenting successive flashes to illustrate reproducibility.
Intraindividual and interindividual variations in ERP amplitude
may be as much as 3:1.45
FIGURE 124.8. Amplitudes of the b-wave and a-wave of the ERG
ELECTROOCULOGRAPHY and the R2 component of the ERP for the dark-adapted albino rat as
a function of the log of the flash energy. Responses were obtained
The light-rise of the electrooculogram (EOG) is a measure of the with 0.7-ms full-field white flashes. Log flash energy of zero
integrity of the RPE and overlying photoreceptors. It arises from corresponds to one quantum absorbed/rod. Amplitudes were
a depolarization of the basal (i.e., choroidal side) membrane of measured from baseline.
the RPE.46 The EOG is a measure of the slowly changing voltage From Cone RA: The early receptor potential of the vertebrate eye. Cold Spring
Harbor Symp Quant Biol 1965; 30:483.
difference between the front (positive) and the rear (negative)
surfaces of the globe recorded over time under different condi-
tions of illumination (Fig. 124.9). The light-rise represents the the EOG light-rise is reduced or absent.48–51 Asymptomatic carriers
largest difference measured in illumination divided by the of Best’s disease may also have abnormal EOGs.50 The EOG
smallest difference measured in darkness.47 In clinical practice, also differentiates Best’s disease from pseudovitelliform macular
its important use is to help diagnose Best’s vitelliform macular degeneration, in which there is generally a normal ratio.51 In
1612 degeneration, a dominantly inherited condition. In this disease, other retinal diseases, EOG testing does not add to whatever
 Objective Assessment of Retinal Function

FIGURE 124.9. EOG recorded from a normal subject. Eye

movements were made twice each minute by alternately viewing
fixation points separated by 30° in a Ganzfeld dome, differentially
amplified at a gain of 200 (–3 dB at 0.1 and 100 Hz), digitized, and
peak-to-peak amplitudes for each saccade quantified by computer.
Vertical dotted lines are separated by 2.5-min intervals; horizontal

CHAPTER 124
dotted lines are separated by 200 µV. Arrow designates onset of
background illumination.

diagnosis may have been made with the ERG alone.52 Fast
oscillations of the EOG have also been recorded53 and have been
found to be dissociated from the light-rise of the EOG in some
maculopathies. For example, in one report the fast oscillations
were found to be normal or nearly normal, while the light-rise
was abnormal, in Best’s disease (Fig. 124.10).54
The EOG may be measured in cooperative patients with
stable fixation who have a visual-field diameter of at least 60°.
After exposure to ambient room illumination for 30 min or
longer, during which time the pupils are dilated, cup electrodes
filled with electrode cream are attached with tape just lateral to
the inner and outer canthus of each eye (i.e., two electrodes per
eye) and to the forehead as ground. On verbal instruction from
the examiner, the subject alternately fixates red light-emitting
diodes in a Ganzfeld dome placed at 0° and 30° with respect to
forward gaze, first in the dark for ~12 min and then in the
presence of a full-field 10 ftL white background for ~12 min to
monitor the light-rise. A Ganzfeld dome, rather than an X-ray
viewing box (or equivalent), should be used so that the entire
retina will be illuminated as evenly as possible. Otherwise the
EOG will reflect primarily only posterior pole function.55 Inter-
vals of ~12 min of darkness and 12 min of illumination are said
to reduce the normal variation.56 The maximal voltage in the
light is compared with the minimal voltage in the dark to derive
the light-rise to dark-trough ratio, which is normally greater than
1.8 in patients younger than 50 years. Care should be taken
that the onset of illumination is not too abrupt or else the tested
eye might begin to tear, which could alter electrode resistance. Fast
oscillations may be elicited with light-dark periods of 2.5 min
and can be immediately followed by monitoring the dark phase
of the conventional EOG.54 Responses from each eye should be
differentially amplified at a gain of ~200 (0.1-100 Hz) and
displayed on an x–y plotter or digitized and displayed by com-
puter. Repeat recordings on a given patient should be done at
approximately the same time of day because of the presence of
an underlying circadian rhythm (see further on).
Intraindividual variability in the light-rise to dark-trough ratio
of the EOG generally does not exceed 60%.57–59 The normal range
for the light-rise to dark-trough ratio has been placed at 1.9–2.8,60
although values of 1.5–3.4 have been reported.61 It should be
noted that the ratio increases with luminance.62 The ratio also
appears to decline with age, at least among women.60,61,63 Signifi-
cant differences in the ratio between sexes have been reported,
with larger values for females.59,61 Between 20% and 50% of the
variation in the EOG light-rise may be due to circadian rhyth-
micity.64 Recordings done at 2-h intervals for six normal subjects
FIGURE 124.10. EOG from a normal subject (A) and from three
patients with Best disease (B–D). Event marker line below indicates
‘on’ or ‘off’ of the 20 ftL background illumination. Fast oscillation
peaks, indicated on normal EOG by closed arrows, are normal for the
patients. Peaks of the light-rise are indicated by open arrows, and are
prolonged and/or subnormal for the patients.
From Weleber RG: Fast and slow oscillations of the electrooculogram in Best’s
macular dystrophy and retinitis pigmentosa. Arch Ophthalmol 1989; 107:530.
showed a sinusoidal temporal pattern in which the ratio was
highest in the early morning and late afternoon and lowest
around midday.
FULL-FIELD ELECTRORETINOGRAPHY
The normal human ERG elicited by a moderate-intensity white
flash from the dark-adapted eye consists of a cornea-negative
deflection, called the a-wave, followed by a cornea-positive
deflection, called the b-wave (Fig. 124.11). The a-wave is known
to reflect photoreceptor function,65,66 and the b-wave is
generated by Müller’s cells reflecting activity in the inner
nuclear layer of the retina.67,68 In actuality, the recorded b-wave
is a summation of photoreceptor and more proximal retinal
function, since the photoreceptor component continues beyond
the onset of the b-wave.66 Several wavelets, known as oscillatory
potentials (Fig. 124.11), may normally be seen superimposed on
the ascending portion of the b-wave. These wavelets reflect bipo-
lar cell responses generated by feedback from amacrine cells.69,70
It is also possible to record a positive response – the d-wave – to
light offset, most typically for square-wave light modulation
but, recently, also to sawtooth-modulated stimuli.71,72 If the
conventional brief strobe- or photo-flash is used to elicit the 1613
 SECTION 10 RETINA AND VITREOUS
FIGURE 124.11. Dark-adapted ERGs recorded from a normal subject
in response to full-field white flashes of varying integrated luminance.
Traces begin at flash onset. Cornea-negative a-wave and cornea-
positive b-wave are designated by letters; oscillatory potentials are
designated by asterisks. Arrow points to inflection in the a-wave,
representing a combination of cone and rod components.
From Sandberg MA, Lee H, Gaudio AR, et al: Relationship of oscillatory potential
amplitudes to a-wave slope over a range of flash luminances in normal subjects.
Invest Ophthalmol Vis Sci 32:1508, 1991. © Association for Research in Vision
and Ophthalmology.
ERG, it is thought that the response lacks the positive d-wave
that otherwise occurs at light-offset.73
Separation of the ERG into a-wave, b-wave, and oscillatory
potentials has important application for objectively diagnosing,
classifying, and staging retinal diseases. For example, in
response to a moderate-intensity white light presented to the
dark-adapted eye, loss of the a-wave with a slowing of the b-wave
in patients with clear media may signify a photoreceptor degen-
eration in which photoreceptors have lost optical density. This
follows from the fact that in normal eyes reducing stimulus
intensity affects a-wave amplitude before b-wave amplitude (see
Fig. 124.11). Conversely, loss of the b-wave with preservation of
the a-wave may signify retinoschisis74 or congenital nyctalopia
with myopia1 (Fig. 124.12). In both of these conditions, synaptic
transmission from photoreceptors to more proximal elements is
disturbed. When ‘on’ versus ‘off ’ responses to sawtooth stimuli
were compared in patients with retinoschisis, the investigators
found that the patients with retinoschisis had a normal a-wave
but a b-wave to light onset that was relatively reduced when
1614
FIGURE 124.12. Dark-adapted ERGs recorded from a normal
subject, a patient with juvenile X-linked retinoschisis, and a patient
with congenital nyctalopia with myopia in response to a full-field white
flash. Calibration – 100 mV vertically and 50 ms horizontally.
compared to their positive d-wave to light offset (Fig. 124.13).71
The authors concluded that the patients had a greater
impairment of their depolarizing bipolar system than their
hyperpolarizing bipolar system. Selective loss of oscillatory
potentials, in contrast, is usually interpreted as specifically reflect-
ing inner retinal ischemia, as occurs in diabetic retinopathy75
and central retinal vein occlusion (Fig. 124.14).76
Careful inspection of the a-wave reveals an inflection (see
Fig. 124.11, arrow) that reflects a summation of cone and rod
components of differing time course. Although not apparent, the
same is true of the b-wave. The fact that the normal dark-adapted
ERG is a summation of rod and cone components may be demon-
strated in two ways. First, placing in turn a blue filter or a red
filter scotopically matched to the blue filter (i.e., matched in
brightness for the rods) in front of the eye and then flashing a
white light results in different waveforms (Fig. 124.15). The
waveform with the blue filter in front of the eye consists of a
late-onset, bell-shaped b-wave, whereas that with the red filter
in front of the eye consists of an early-onset a-wave and b-wave
(with oscillations) followed by the same late-onset b-wave. The
early components observed for red, but not blue, light represent
cone activity, whereas the late b-wave represents rod activity. When
the cone and rod components are well separated in time, they
appear to summate linearly.77–79 However, when the two b-waves
occur at the same time with near-maximal amplitudes, as for
the conventional white flash, the summation appears to be non-
linear, as may be seen by using a method of digital subtraction.80
Linear subtraction of a cone-isolated response to red light from
a mixed cone and rod response to a bright blue light photo-
pically matched to the red light yields a rod-isolated waveform
in which the b-wave is ‘scalloped’ (Fig. 124.16). This implies
that the b-wave to the bright blue light represents a sublinear
summation of rod and cone components. Conversely, even for
these bright lights, the two a-waves appear to summate linearly.

FIGURE 124.14. Dark-adapted ERGs recorded from a normal
subject, a patient with central retinal vein occlusion (CRVO), and a
patient with diabetic retinopathy in response to a full-field bright white
flash.
The presence of a steady white background that desensitizes rods
and eliminates their contribution to the ERG reveals a ‘photopic’
a-wave and b-wave from the cone system (Fig. 124.17).81 In
addition to background illumination, a flash rate of 30 Hz may be
used to isolate cone function to white light (see Fig. 124.15).78
This is true because the rod system is normally incapable of
responding to these rates of flicker. Lights of different wave-
length and background adaptation have been used to demonstrate
both a rod and a cone contribution to oscillatory potentials.82
Objective Assessment of Retinal Function
FIGURE 124.13. ERG waveforms of patients
with X-linked retinoschisis (XLRS) (panels 1 and
3) and control subjects (panels 2 and 4) in
response to 8-Hz rapid-on (panels 1 and 2) and
rapid-off (panels 3 and 4) sawtooth flicker.
Dashed lines: time of stimulus onset; stimulus
waveform is illustrated on the x-axis. The
waveforms are arranged in order of increasing
b-wave amplitude. Numbers next to the
waveforms in the left panel refer to patient
designations.
From Alexander KR, Fishman GA, Barnes CS,
Grover S: ON-response deficit in the electroretinogram
of the cone system in X-linked retinoschisis. Invest
Ophthalmol Vis Sci 2001; 42:453.
CHAPTER 124
Isolation of rod and cone contributions to the ERG, like com-
parative analysis of the a-wave and b-wave components, is also
important for classifying retinal diseases. For example, selective
loss of cone function may signify congenital rod monochroma-
tism or advanced cone degeneration, whereas loss of a rod con-
tribution may signify an early stage of dominant retinitis
pigmentosa. In the cone-isolated response to flicker, the high
rate of presentation and sinusoidal nature of the waveform in
cases of advanced retinitis pigmentosa make it possible to
resolve amplitudes as small as 0.05 mV with signal averaging
and electronic filtering (see further on), which can be used to
follow up the course of this condition.83
The full-field ERG may also be used to quantify the amount
of remaining function for each of the three cone mechanisms.
The middle-wavelength or green-cone system and the long-
wavelength or red-cone system may be evaluated by comparing
cone ERGs elicited by a short-wavelength flash or a photopically
matched long-wavelength flash superimposed on a photopic
background (see Fig. 124.15)78 or flickering at 30 Hz.84 If the
responses are equivalent in amplitude, the patient is considered
to have comparable numbers of cones of each type, as has been
observed in carriers of blue-cone monochromatism.85 However,
if the two responses are unequal in amplitude or differ by a factor
of two or greater, then one of the two cone systems is considered
to be reduced in number relative to the other or absent,
respectively.84 Use of a short-wavelength flash superimposed on
a bright white background has been shown to isolate in time the
short-wavelength or blue-cone system from the other systems
(Fig. 124.18).86
Interest has developed in clinical recording of b-wave ampli-
tude versus flash intensity functions under conditions of dark
adaptation in patients with retinal disease. The intent of this
approach is to distinguish changes in maximal amplitude (Vmax),
which are thought to reflect cell number and response gain,
from changes in sensitivity (k), which are thought to reflect outer
segment optical density and media clarity. Some studies have
used white flashes to elicit these functions,87–89 which complicates
interpretation because of the variable summation of cone and
rod contributions in diseases that may affect these two systems
unequally. One study used digital subtraction to isolate rod func-
tion in patients with retinitis pigmentosa or cone–rod degen-
eration and showed that reductions in sensitivity, irrespective of
changes in maximal amplitude, may be used to infer losses of
rod photoreceptor optical density.90 Another study showed that
patients with an apparently rare form of retinal degeneration could
have increased maximal rod b-wave amplitude with reduced
1615
 RETINA AND VITREOUS

FIGURE 124.15. Full-field ERGs to scotopically matched red (column 1) and blue (column 2) flashes, to photopically matched orange (column 3)
and blue-green (column 4) flashes in the presence of 5-10 ftL of background light and to 30-Hz white flashes (column 5) are shown successively
from top to bottom for a patient with Nougaret-type night blindness, a normal subject, and a patient with advanced cone degeneration. Two or
three responses to the same stimulus are superimposed. Calibration – 60 ms horizontally and 50 µV vertically for columns 1 and 2; 30 ms
horizontally and 50 µV vertically for columns 3 and 4; 60 ms horizontally and 100 µV vertically for column 5. Corneal positivity is an upward
SECTION 10

deflection. Stimulus onset, vertical hatched line for columns 1–4; shock artifacts for column 5.
From Berson EL, Gouras P, Hoff M: Temporal aspects of the electroretinogram. Arch Ophthalmol 1969; 81:207-214. Copyright 1969, American Medical Association.

FIGURE 124.16. Computer-averaged dark-adapted full-field ERGs

from a normal subject to photopically matched blue (top) and red
(middle) flashes and the result of subtracting the second response
from the first to derive a rod ERG in isolation (bottom). The rod
component elicited by the red flash had already been eliminated by
subtracting the response to a scotopically matched blue flash. In the
bottom waveform, the lower solid line represents the result of
subtraction and the hatched area illustrates the suggested rod b-wave
correction for nonlinear summation of the cone and rod components
to blue light.
From Sandberg MA, Miller S, Berson EL: Rod electroretinograms in an elevated
cyclic guanosine monophosphate-type human retinal degeneration. Comparison
with retinitis pigmentosa. Invest Ophthalmol Vis Sci 1990; 31:2283.
© Association for Research in Vision and Ophthalmology.
FIGURE 124.17. Analysis of ERG in a dark-adapted human eye as
the resultant of photopic (dashed line) and scotopic (dotted line)
components. The a-wave is composed of photopic (ap) and scotopic
(as) components, and the b-wave is similarly composed of photopic
(bp) and scotopic (bs) components. The solid line shows the algebraic
sum of the lower waveforms.
From Armington JC, Johnson EP, Riggs LA: The scotopic a-wave in the
electrical response of the human retina. J Physiol (Lond) 1952; 118:289.

1616
 Objective Assessment of Retinal Function

FIGURE 124.18. Full-field ERGs elicited by red

and blue flashes at different levels of
background illumination indicated by the
photopic troland values on the left above each
trace. L, M, and S signify the responses of,
respectively, the long-wavelength-, the middle-
wavelength-, and the short-wavelength-
sensitive cone systems. Calibration – vertically
4 µV for the upper four and 40 µV for the lower
four traces and 9 ms horizontally.
From Gouras P, MacKay CJ: Electroretinographic
responses of the short-wavelength-sensitive cones.
Invest Ophthalmol Vis Sci 1990; 31:1203.
© Association for Research in Vision and
Ophthalmology.

CHAPTER 124
sensitivity, as well as implicit times that were more delayed for
dim flashes than for bright flashes (Fig. 124.19), a combination
that could better be explained by an elevation of retinal cyclic
guanosine monophosphate than in terms of cell and optical
density loss.80
A corresponding approach has been used by a few laboratories
to evaluate the a-wave and, by inference, the photoreceptor
response. a-Waves were elicited by a series of flash intensities
that included intensities far brighter than those needed to saturate
the b-wave. A computational model was then applied to the
leading edge of the a-wave to estimate parameters of the photo-
transduction cascade. Representative cone a-waves obtained in the
presence of a rod-saturating background and rod a-waves derived
from subtracting the cone a-waves from dark-adapted responses
of a normal observer and the fitted functions are illustrated in
Fig. 124.20.91 With such fitted functions it is possible to
estimate the maximal amplitude, sensitivity, and delay of the
respective photoresponse. Normative values are presented in
the afore-mentioned paper.91 When this methodology was applied
to patients with retinitis pigmentosa, the authors found that
cone and rod a-waves were quantifiable in 30–33% of cases and,
in those cases, the maximum amplitude and sensitivity parameters
were below normal in all subgroups.92 In this cross-sectional
study there was no evidence that phototransduction efficiency
decreased with increasing age.
Full-field ERGs, like EOGs, are conventionally elicited with a
Ganzfeld dome (Fig. 124.21) that provides a nearly homoge-
neous distribution of light over the central 120° of the retina.93 FIGURE 124.19. Rod b-wave amplitude and implicit time (i.e., time to
Although retinal illuminance falls as a consequence of decreas- peak) versus retinal illuminance functions for 17 normal subjects
ing apparent pupillary area for retinal eccentricities greater than (mean ± SD) and three patients with an elevated cyclic guanosine
60°, this is compensated in large part by the curvature of the monophosphate-type retinal degeneration. Rod ERGs were elicited
retina and by reduced light absorption in the ocular media with with full-field blue flashes at low retinal illuminances and by a method
eccentricity.94 With virtually uniform retinal illumination, the of digital subtraction involving photopically matched blue and red
faster cone and slower rod components of the ERG across the flashes at high retinal illuminances.
retina respond with a minimal variation in latency and there- From Sandberg MA, Miller S, Berson EL: Rod electroretinograms in an elevated
cyclic guanosine monophosphate-type human retinal degeneration. Comparison
fore may be separated in time and quantified. In addition, this
with retinitis pigmentosa. Invest Ophthalmol Vis Sci 1990; 31:2283.
retinal light distribution is altered little by small changes in eye
© Association for Research in Vision and Ophthalmology.
position, which fosters reproducibility between successive
responses.93,95
The eye(s) to be tested should be initially dilated and adapted
to the dark for at least 45 min. Dilatation maximizes amplitudes best done with a bipolar contact lens electrode, with the positive
and generally minimizes implicit times.96,97 Complete dark adap- electrode being a ring around the contact lens and the negative
tation, which may require 45 min or longer depending on the level or reference electrode a conductive coating on a lid speculum
of prior exposure, also maximizes amplitudes (Fig. 124.22)98 (Fig. 124.23). The bipolar configuration, in which the lid versus
while also tending to maximize implicit times. Recordings are ground response is subtracted from the cornea versus ground 1617
 RETINA AND VITREOUS
a b
c d
SECTION 10
FIGURE 124.21. Ganzfeld stimulator. Flashlamp enclosed in case and
attached to the top of the diffusing sphere illuminates the inner white
surface of this dome (40 cm in diameter), providing a full-field stimulus.
Lights are recessed in the top of the dome so that the patient can be
tested in the presence of steady full-field background light.
From Rabin AR, Berson EL: A full-field system for clinical electroretinography.
Arch Ophthalmol 1974; 92:59. Copyright 1974, American Medical Association.
response, localizes the response to the eye and provides the best
elimination of surrounding 60-Hz noise and any photovoltaic
artifact that may be generated by the flash lamp. The lid spe-
culum also prevents the upper and lower eyelids from partially
covering the cornea and thereby obstructing the passage of light
into the eye. A reduction in retinal illuminance could arti-
1618
FIGURE 124.20. Representative a-waves from
a 65-year-old control subject. (a) Responses in
dark to intensities ranging from 3.2 to 4.4 log
scotopic troland-seconds (log sc td-s).
(b) Same 4 intensities presented against a
3.2-log td background. (c) Rod-isolated
responses and fitted functions (dashed lines).
(d) Cone responses and model fits (dashed
lines.
From Birch DG, Hood DC, Locke KG, et al:
Quantitative measures of phototransduction in cone
and rod photoreceptors. Normal aging, progression
with disease, and test-retest variability. Arch
Ophthalmol 2002; 120:1045.
FIGURE 124.22. Computer-averaged full-field rod ERG percent
amplitudes to a 0.5-Hz 10-µs blue flash (max 440 nm) of 16 ftL
recorded over time in the dark from a normal observer after a 10-min
full-field white light bleach of 10 or 500 ftL presented to the dilated
pupil. Amplitudes for 60 min of dark adaptation were arbitrarily
designated 100%. All the data appear to reflect rod function, except
for the low-amplitude 5-min value after the stronger bleach, which
probably represents residual cone function. Each set of data
represents a single run.
From Sandberg MA: Technical issues in electroretinography. In: Heckenlively J,
Arden G, eds. Principles and practice of clinical electrophysiology of vision.
St Louis: Mosby-Year Book; 1991.
factually reduce ERG amplitudes and increase implicit times.
Some facilities use alternative electrodes for recording ERGs. In
this country, these include the disposable Jet electrode, the Arden
gold foil electrode, and the Dawson–Trick–Litzkow (DTL) fiber
electrode. All three are monopolar electrodes that will give
larger voltages than the bipolar Burian–Allen electrode,99 but
also be more subject to artifact contamination.
With the patient fixating on a red light-emitting diode, 0.5-Hz
dim, short-wavelength flashes may be given first to isolate the
rod ERG. Next, 0.5-Hz scotopically matched long-wavelength
flashes can be given to obtain a mixed response consisting of a
faster cone component and a slower rod component of amplitude
comparable with that elicited by the short-wavelength flash.
After that, 0.5-Hz dim white flashes may be given to elicit an
a-wave and maximal b-wave consisting of a summation of both
cone and rod components. Finally, 30-Hz dim white flashes or
0.5-Hz dim white flashes superimposed on a background to
 Objective Assessment of Retinal Function

single flashes because of reduced stimulus retinal illuminance.

An electronic photoflash, with ~1000 times the energy of the
conventional full-field flash when illuminating a Ganzfeld dome,
can be used to elicit larger responses from such eyes.103 In order
to separate the optical density effect of the media obstruction from
any change that may be due to a retinal abnormality, responses
to a series of stimulus intensities should be compared with
those obtained with conventional full-field flashes in normal
eyes (e.g., see Fig 124.11). If a-wave and b-wave amplitudes and
implicit times to the brighter flashes in eyes with opaque media
can be matched to those obtained to the dimmer flashes in normal
eyes with clear media, large areas of the retina can be considered
to be functioning normally.104 In eyes with large pupils and
relatively clear media, these bright flashes may be used to elicit
a maximal a-wave with oscillatory potentials superimposed on
the ascending limb of the b-wave.103 Bright flash stimulation
should be presented to the dark-adapted eye (i.e., before flicker
or background illumination), with each flash separated from the

FIGURE 124.23. Double-electrode (Burian–Allen) contact lenses used
to obtain ERG responses.
From Rabin AR, Berson EL: A full-field system for clinical electroretinography.
Arch Ophthalmol 1974; 92:59. Copyright 1974, American Medical Association.
isolate a cone response may be given.95 For cases of generalized
cone degeneration or when abnormal color vision is found, the
spectral lights described earlier may be presented to assess the
different cone systems across the retina. When isolating the cone
response with flicker or background illumination, the retina may
need to be illuminated for several minutes before a maximal
response is obtained.100–102
Patients with small dilated pupils or those whose pupils can-
not be dilated or, in some cases, those who have media opacities
that obscure visualization of the fundus may have ERGs that
are smaller in amplitude than expected or nondetectable with
CHAPTER 124
next by an interval of ~1 min to minimize light adaptation
from the preceding flash.
Full-field ERG responses may be photographed in real time
from an oscilloscope or digitized and stored for subsequent analy-
sis and hard copy. Digitization may be used to eliminate baseline
variation and to isolate oscillatory potentials, whose frequency
content (50–180 Hz) exceeds that of the a-wave (<50 Hz) and
b-wave (<25 Hz).103,105–107 Oscillatory potentials may then be
quantified either in conventional time domain or, by Fourier
analysis, in frequency domain (Fig. 124.24). Consecutive digi-
tized responses may also be summed and averaged and, for 30-Hz
flicker, smoothed with narrow band-pass filtering to resolve very
small amplitudes (Fig. 124.25).83,108 However, for this purpose,
recordings should be performed with a bipolar contact lens elec-
trode to minimize contamination of the waveform with electrical
or photovoltaic artifacts. Figure 124.26 shows responses to 30-Hz
xenon flashes recorded without and with narrow band-pass
filtering from different electrodes placed in saline solution. The
monopolar gold foil electrode generates a large artifact with con-
stant phase for both types of filtering. The monopolar Jet elec-
trode generates smaller responses reflecting an electrical artifact
alone. In contrast, the two bipolar electrodes (the Burian–Allen
and GoldLens) show minimal noise.109 With a well-conditioned
Burian–Allen contact lens electrode, test–retest reproducibility for

FIGURE 124.24. Quantification of mean oscillatory potential amplitude in the time domain between the a-wave and the b-wave peaks after
62-Hz high-pass filtering for a normal subject in response to a bright full-field flash white flash. Vertical lines represent some of the amplitudes
whose absolute values with respect to baseline were summed before calculation of the mean (left). Quantification of mid- and high-frequency
amplitudes for oscillatory potentials by the magnitude fast Fourier transform for a normal subject in response to the same flash (right).
From Sandberg MA, Lee H, Gaudio AR, et al: Relationship of oscillatory potential amplitudes to a-wave slope over a range of flash luminances in normal subjects.
Invest Ophthalmol Vis Sci 1991; 32:1508. © Association for Research in Vision and Ophthalmology.
1619
 RETINA AND VITREOUS
SECTION 10
FIGURE 124.25. ERGs elicited with full-field white 30-Hz flashes from
a normal subject and four patients with different genetic types of RP
at ages spanning intervals of 11–15 years. Responses were recorded
without (left column) or with (right column) computer averaging and
band-pass filtering. Stimulus onset, vertical markers. Calibration (left
column, lower right) – 100 µV vertically for the normal subject and the
top three patients; 40 µV vertically for the bottom patient; 50 ms
horizontally for all traces. Calibration (right column, lower right) – 2 µV
vertically for the dominant, X-linked, and isolate patients; 0.3 µV for
the recessive patient; 20 ms horizontally for all traces. The b-wave
implicit times are designated with arrows.
From Andreasson SOL, Sandberg MA, Berson EL: Narrow-band filtering for
monitoring low-amplitude cone electroretinograms in retinitis pigmentosa.
Am J Ophthalmol 1988; 105:500, copyright 1988, from Elsevier Science.
sub-mV full-field cone ERGs to 30-Hz flashes revealed highly
correlated implicit times and amplitudes.109 Signal averaging may
also be used to reduce large voltages due to eye movements, as,
for example, in cases of nystagmus.
The variation in full-field ERG amplitude for a given stimulus
condition across normal subjects is as much as 2.5:1.110,111 Age,
sex, refraction, ocular pigmentation, and time of day may all
contribute to this variation: with increasing age among adults,
a-wave amplitude declines,110 b-wave amplitude declines,110,112–114
oscillatory potential amplitude declines (Fig. 124.27), and
1620
b-wave implicit time increases.110,114 The same trends have
been observed in the b-wave component isolated from the short-
wavelength-sensitive cones in response to a blue flash on a bright
background.115 These decreases in ERG amplitudes and increases
in ERG implicit times with increasing age probably reflect
decreasing retinal illuminance with increasing age caused by
reduced light transmissivity by the lens116 and, possibly, to a
smaller dilated pupillary diameter with increasing age. Similarly,
increased uveal pigmentation lowers amplitude, and decreased
uveal pigmentation raises it.117,118 Increased uveal pigmentation
related to race appears to reduce the maximal amplitude by an
average of 17%, but does not affect the sensitivity or the implicit
time of the b-wave as measured in response to blue flashes of
varying retinal illuminance.119 The ERG b-wave is also larger in
hyperopic eyes than in myopic eyes (Fig. 124.28)112,120,121 and is
slightly larger in women than in men.110,112,120,122,123
Intrasubject variation in amplitude in normal subjects across
days can be as much as ±25% for large responses. Normal sub-
jects, unentrained to a cyclical pattern of illumination, have shown
no significant variations in rod ERG amplitude over daylight
hours.124 However, in normal subjects entrained to cyclical illu-
mination for at least 3 days, rod ERG amplitudes follow a regular
pattern, being on average 10–15% smaller 1.5 h after light onset
than at other times of day.124 The physiologic basis for this ERG
diurnal rhythm appears to be an alteration in photoreceptor
function associated with rod outer segment disk shedding, since
recordings in normal light-entrained rats have demonstrated an
ERG variation similar to that seen in humans and that is sig-
nificantly correlated with the number of phagosomes appearing
in the RPE.125
FOCAL CONE ELECTRORETINOGRAPHY
Since only some 7% of cone photoreceptors are in the central
macula, patients with macular degeneration typically retain nor-
mal full-field ERGs and must be assessed with a focal stimulus
in order to reveal and quantify malfunction.52 Foveal cone ERGs
have been used by various centers since the late 1960s to detect
macular malfunction.126–133 Abnormal foveal cone responses have
been found in patients with Stargardt’s disease,129,134 in which
amplitude varied directly with visual acuity, and in those with
age-related macular degeneration (Fig. 124.29).130,135 Patients
with age-related macular degeneration may also show delays in
foveal cone ERG implicit time that are associated with abnormal
choroidal perfusion.136 In patients with macular holes, foveal
amplitude varied inversely with hole diameter, and subnormal
responses appeared to predict impending holes in the fellow eye.137
Foveal ERGs may be abnormal in symptomatic patients even
when no diagnostic abnormalities can be seen by ophthalmoscopy
and fluorescein angiography,138,139 and thus they provide an aid
in early detection of macular malfunction (i.e., the so-called ‘occult
maculopathy’). Conversely, foveal cone ERGs are normal in
patients with strabismic amblyopia140 or optic neuropathy,140–142
indicating that the test provides a differential diagnosis for dis-
eases of the macula versus diseases of the optic nerve or visual
cortex (Fig. 124.30). Focal cone ERGs should, in general, be
used in conjunction with full-field recording in order to rule out
generalized cone degeneration, which may not have visible signs
of peripheral retinal disease.
Focal cone ERGs may be elicited with a commercially avail-
able hand-held stimulator ophthalmoscope, the Maculoscope.
With this instrument, the examiner can visualize the fundus
through a short-stalk Burian–Allen bipolar contact lens electrode
over the dilated pupil. A 42-Hz, white, 4° diameter stimulus is
placed on the fovea and centered within a steady white 12° sur-
round. This stimulus/surround configuration allows the

examiner to visually track an area to be tested even in patients
with eccentric or variable fixation. The high rate of flicker not
only isolates cone function but also renders the response sinu-
soidal so that amplitudes less than 1 mV, which occur normally,
can be resolved with the help of electronic filtering, computer
averaging, and Fourier analysis.129 White flashes, rather than red,
are used to avoid eliciting subnormal amplitudes from patients
with congenital protanopia. Focal cone ERGs may be performed
in an unshielded room in dim ambient room illumination. Since
foveal cone ERG amplitudes are very small and tend to increase
during continued light adaptation,143 consecutive response
averages should be recorded over a period of a few minutes to
prove reproducibility.
Foveal cone ERG amplitude has been reported to be inversely
correlated with age for 100 normal eyes of subjects between the
ages of 5 and 75 years.130 A fourfold range for normal foveal cone
ERG amplitude has been reported.134 Although the reason for
this large normal range is unclear, it can be effectively reduced
by 30% on average by adopting a foveal to parafoveal amplitude
ratio.144 This approach should be used with caution, as some
regional variation in the parafoveal cone ERG has been
reported.145 The foveal cone ERG is also smaller in amplitude
in eyes with brown irides than in eyes with lighter-pigmented
irides, presumably because of the corresponding differences in
uveal pigmentation.146 Normal intervisit variability in foveal
cone ERG amplitude has not been reported.
Another commercial instrument (the VERIS System) exists
for recording focal cone ERGs simultaneously over an interval of
Objective Assessment of Retinal Function
FIGURE 124.26. Responses to full-field 30-Hz
xenon flashes of 1.3 log td-s without (left) and
with (right) narrow-band filtering from four
different electrodes placed in saline solution.
From Birch DG, Sandberg MA: Sub-microvolt full-field
cone electroretinograms: artifacts and reproducibility.
Doc Ophthalmol 1997; 92:269. Reprinted from Kluwer
Academic Publishers, Spuiboulevard 50, P.O. Box 17,
3300 AA Dordrecht, The Netherlands.
CHAPTER 124
16 min from up to 241 locations within the central 50°, called
the ‘multifocal ERG’.147 Although this approach assumes phase
(implicit time) constancy between adjacent 5° locations and relies
on the voluntary fixation of the patient, the output is a detailed
three-dimensional plot of response amplitude by location.
These a-wave and b-wave responses appear to be the same as
those obtained by conventional recording and, thereby, appear
to be of value in identifying which cells are contributing to the
retinal malfunction.148 This approach ought to be most useful for
characterizing maculopathies149–151 by revealing a relative foveal
amplitude depression (e.g., Fig. 124.31),150 but the diagnosis of
maculopathy rests on the assumption that the patients
maintained stable central fixation throughout testing.
The multifocal ERG may be most appropriate for generating an
objective map of the central visual field of patients with gener-
alized retinal disease who retain central fixation. Several studies,
for example, have performed multifocal ERG testing on patients
with early stages of retinitis pigmentosa. Based on a sample of
111 patients with retinitis pigmentosa, 24% who were anti-
cipated to have sufficiently large signals for testing were found
to have a detectable multifocal ERG, consisting of a central peak
of variable diameter, with implicit times that tended to increase
towards the periphery.152 A study on a small group of patients
with retinitis pigmentosa tried to correlate multifocal cone ERGs
with multifocal rod ERGs and multifocal ERG values with visual
field sensitivities by location. The authors reported a significant
correlation between multifocal cone ERG amplitude and cone-
mediated visual field sensitivity, but there were many instances
1621
 RETINA AND VITREOUS
SECTION 10
FIGURE 124.27. A-wave, b-wave, and oscillatory potential amplitude
versus age in normal subjects. Responses were elicited from dark-
adapted eyes with full-field dim white flashes for the upper and middle
graphs or bright white flashes for the lower graph. Oscillatory potential
amplitudes are calculated as described for Figure 124.24.
of reduced amplitude with normal sensitivity. The correlations
between rod ERG amplitude and rod-mediated visual field sen-
sitivity and between cone ERG amplitude and rod ERG ampli-
tude were very low, perhaps due to methodological problems in
isolating multifocal rod ERGs.153
Although full-field ERG recording has been shown to detect
retinal malfunction in 90–96% of obligate carriers of X-linked
retinitis pigmentosa,154,155 complementary tests of localized
function could potentially enhance this sensitivity by revealing an
underlying mosaicism as predicted by random X-chromosome
inactivation. Multifocal ERG recording in five carriers from
three families revealed local amplitude losses and implicit time
delays in two patients, local amplitude losses alone in one patient,
local implicit time delays alone in one patient, and no abnor-
mality in one patient. In the two patients with both types of
defect there was poor correspondence between the locations show-
ing amplitude losses and the locations showing implicit time
delays.156 Although based on only a small number of patients,
1622
FIGURE 124.28. Linear regression of b-wave amplitude on refraction
based on average of regression equations for men and women from
measurements on 86 normal subjects. Maximal b-waves were elicited
from the semi-dark-adapted eye with white light flashes derived from
a lamp at different distances from the subject and presented through
the dilated pupil.
From Sandberg MA: Technical issues in electroretinography. In: Heckenlively J,
Arden G, eds. Principles and practice of clinical electrophysiology of vision.
St Louis: Mosby-Year Book; 1991. Data from Pallin E: The influence of the axial
size of the eye on the size of the recorded b-potential in the clinical single-flash
electroretinogram. Acta Ophthalmol 1969; 101(Suppl):1.
these results suggest that multifocal ERG recording may not be
a useful additional test to detect carriers of X-linked retinitis
pigmentosa.
Multifocal ERG recording has also been used to reveal the dis-
tribution of retinal malfunction in patients with X-linked juvenile
retinoschisis.157,158 These patients present with a foveal schisis
in all cases and a peripheral schisis in 50% of cases. Multifocal
ERG recording has demonstrated a greater amplitude loss cen-
trally than peripherally, and amplitudes have been found to be
normal even in areas with visible peripheral schisis. The multi-
focal ERG waveform also generally does not show the negativity
characteristic of the full-field ERG, perhaps because of constraints
in the software algorithm that derives the multifocal ERG wave-
form. Interestingly, multifocal ERG implicit times have been
found to be delayed at all, or nearly, all tested locations, indi-
cating involvement of areas without visible schisis and areas
with normal amplitudes.
FOCAL ROD ELECTRORETINOGRAPHY
Since rod photoreceptors are especially sensitive to reflected light,
it has been impossible, until recently, to record rod ERGs to bright
flashes of light from localized areas. In addition to allowing one
to characterize transduction among homogeneous populations
of rod photoreceptors,159 these techniques allow the assessment
of retinal function in areas outside of the macula that are not
easily assessed by focal cone ERGs because cone photoreceptors
are normally scarce. For example, Figure 124.32 shows dark-
adapted focal rod ERGs from a patient with the multiple
evanescent white dot syndrome and an enlarged blind spot in her
left eye.160 In comparison with the large, symmetric focal responses
recorded from the nasal and temporal retina of a normal subject,
the response from the nasal retina (within the scotoma) was non-
detectable whereas the response from the temporal retina was
normal in the patient. These recordings prove that her visual
loss was of retinal origin.

One approach involving three steps allows one to record the
focal rod a-wave.159 In step 1, ERGs are recorded from the dark-
adapted eye in response to a 40°-diameter stimulus. In step 2,
ERGs are recorded in response to the same stimulus 1 s after a
white conditioning flash of the same diameter. The conditioning
flash is used to desensitize rods directly illuminated by the flash
without significantly affecting the a-wave generated by rods and
cones illuminated by reflected light. Subtracting the a-wave
obtained in step 2 from that obtained in step 1 derives the a-wave
generated by rods directly illuminated by the flash. The validity of
this method rests on the assumption that the rods and cones out-
side the stimulus are not light-adapted by the conditioning flash.
A second technique allows recording both a-waves and b-waves
from the dark-adapted eye in response to stimuli as small as 10°.160
This technique is illustrated in Figure 124.33. The response to
a 30°-diameter focal blue flash (a) consists of a faster, smaller
‘focal’ component and a slower, larger ‘stray light’ component.
The response to some dimmer full-field blue flash (b) consists
of a negative deflection (a-wave) followed by a positive deflection
(b-wave) that closely matches the stray light b-wave of the first
response. Subtraction of the second from the first response (a–b)
results in isolation of a local response (c) with an a-wave and
b-wave that are smaller than, but otherwise similar to, those of
the full-field, rod-isolated response to a blue flash of the same
Objective Assessment of Retinal Function
FIGURE 124.29. Representative foveal cone
ERGs from a normal subject and four patients
with AMD. Responses were recorded with a
stimulator ophthalmoscope. Each 100-ms trace
contains 4 responses to the 42-Hz stimulus.
Two consecutive traces (each the average of
200 sweeps) are shown for each patient.
Arrows indicate b-wave implicit time (time
between light flash and response).
From Fish GE, Birch DG, Fuller DG, et al: A
comparison of visual function tests in eyes with
maculopathy. Ophthalmology 1986; 93:1177–1182.
CHAPTER 124
retinal illuminance (d). The focal response appeared to be gener-
ated entirely by rods because the ERG to a 30°-diameter red flash
that would elicit the same cone response as the blue flash was
nondetectable for these recording conditions (e). When using a
10°-diameter stimulus, the stray light component may not over-
lap the focal component that can then be quantified without
resorting to a subtractive technique.
PATTERN ELECTRORETINOGRAPHY
Pattern electroretinography uses a spatiotemporal exchange of
stripes or checks in which mean luminance is held fixed to elicit
a focal ERG.161 The theory is that local, time-varying changes in
luminance responses generated by photoreceptors cancel at the
cornea (or at least make a minimal contribution to the response),
whereas cells with center-surround receptive fields (i.e., retinal
ganglion cells) are strongly stimulated. One defense of this idea
is that the pattern electroretinogram (PERG) shows spatial
tuning under some situations. That is, amplitude is larger for
stimulus elements of medium size and smaller for stimulus
elements of smaller or larger sizes (Fig. 124.34).162–170 In other
instances, however, a low-pass relationship occurs in which
amplitude increases monotonically with the size of the
stimulus element.168 In these cases, primarily resulting from
1623
 RETINA AND VITREOUS
SECTION 10
high-luminance, high-contrast targets, a significant luminance
component is thought to contaminate the responses to large
stimulus elements.162,167 Luminance components presumably
arise from nonlinear summation of opposite sign responses to
on and off stimulation.169,170
Unlike the focal luminance-evoked ERG (usually referred to
as the focal ERG or FERG), the PERG has been found to be
predominantly abnormal in patients with glaucoma,171–174 optic
neuritis,175,176 or optic atrophy (Fig. 124.35),177,178 which further
1624
FIGURE 124.30. Foveal and parafoveal cone
ERGs recorded with a stimulator
ophthalmoscope from a normal subject and
four patients with visual acuity 6/60. Two or
more consecutive computer summations
(n = 128) are shown. Vertical lines denote
stimulus onset; arrows denote b-wave implicit
time to corresponding response peak.
Calibration symbol in lower right corner
denotes 20 ms horizontally and 0.25 µV
vertically.
From Jacobson SG, Sandberg MA, Effron MH, Berson
EL: Foveal cone electroretinograms in strabismic
amblyopia. Comparison with juvenile macular
degeneration, macular scars and optic atrophy. Trans
Ophthalmol Soc UK 1979; 99:353.
FIGURE 124.31. Multifocal ERGs and the
corresponding three-dimensional plot for a
normal control subject (left) and a patient with
occult macular degeneration (right).
From Piao CH, Kondo M, Tanikawa A, et al: Multifocal
electroretinogram in occult macular dystrophy. Invest
Ophthalmol Vis Sci 2000; 41:513.
supports the idea that it derives from ganglion-cell activity. It
has been reported to be both more sensitive179 and less
sensitive180 than full-field oscillatory potentials in detecting inner
retinal malfunction in patients with early stages of diabetic reti-
nopathy. It remains controversial whether the PERG tends to be
abnormal in ocular hypertension, as some studies have found
many abnormal responses,181,182 whereas others have found mostly
normal responses.183 It also remains controversial whether the
PERG is abnormal in amblyopia, as some studies have found
 Objective Assessment of Retinal Function

CHAPTER 124
b

FIGURE 124.32. (a) Kinetic visual field for the left eye (visual acuity =
20/25) of a patient with multiple evanescent white dot syndrome
(MEWDS) and an enlarged blind spot. The visual field was to a V4e
white test light presented with a Goldmann perimeter on a
background luminance of 31.5 asb. The blind spot normally subtends
~5° between 10° and 20° eccentricity in the temporal field. (b) Focal
rod ERGs to a 30°-diameter blue flash of 2.1 log scot. td.-s. along the
horizontal meridian at an eccentricity of 25° in the temporal or nasal
field of the eye of a normal volunteer and the affected eye of the
patient. Responses were computer averaged (n = 4). Focal rod ERGs
for another normal volunteer (not illustrated) had b-wave amplitudes
that were 44 µV temporally and 43 µV nasally.
(a and b) From Sandberg MA, Pawlyk BS, Berson EL: Isolation of focal rod
electroretinograms from the dark-adapted human eye. Invest Ophthalmol Vis Sci
1996; 37:930. Reprinted from Lippincott-Raven Publishers, 227 East Washington
Square, Philadelphia.

mainly abnormal responses,184–186 whereas others have found

normal responses.165,187
Based on the preceding normative and clinical studies, studies
in mammals involving section of the optic nerve,188,189 and cur-
rent source density analysis,190 it is now fairly certain that the
PERG derives, at least in part, from the ganglion cells. However, the
PERG should not be used alone to diagnose the site of retinal mal-
function, since it necessarily depends on photoreceptor function
and has been shown to be abnormal in macular disease involving
the photoreceptors.191 If the PERG is abnormal, it would also be
advisable to obtain a focal flash ERG to evaluate photoreceptor
function before assuming that the inner retina is abnormal.
PERGs are usually elicited by phase-reversing square-wave
stripes or checks presented on a television monitor or modulated
by a moving mirror within an optical system. The temporal modu-
lation may be at a low frequency (i.e., <8 Hz) to elicit transient
responses (see Fig. 124.35), or at a high frequency (i.e., ≥8 Hz) to
elicit a steady-state, sinusoidal response. The transient response
consists of a cornea-negative deflection followed by a cornea-
FIGURE 124.33. ERGs from a normal volunteer. (a) ERG to a 30°-
diameter blue flash of 2.1 log scot. td.-s. at a temporal retinal
eccentricity of 30°. (b) Full-field ERG to a blue flash of 0.4 log scot.
td.-s. (c) Subtraction of (b) from (a). (d) ERG to a full-field blue flash of
2.1 log scot. td.-s. after subtraction of the response to a photopically
matched full-field red flash. (e) ERG to a 30°-diameter red flash at a
temporal retinal eccentricity of 30°s and photopically matched to the
blue flash used to elicit (a). Responses were computer averaged
(n = 4). A second normal volunteer gave similar ERGs (not illustrated).
From Sandberg MA, Pawlyk BS, Berson EL: Isolation of focal rod
electroretinograms from the dark-adapted human eye. Invest Ophthalmol Vis Sci
1996; 37:930. Reprinted from Lippincott-Raven Publishers, 227 East Washington
Square, Philadelphia.
positive deflection (see Fig. 124.35), much like the luminance
ERG. The temporal modulation is usually square wave but may
be sinusoidal. Contrast (i.e., the luminance difference between
light and dark elements relative to the mean luminance) may be
100% or less. Field size is typically 20° or less, but the pattern
1625
 RETINA AND VITREOUS
SECTION 10
must contain an even number of spatial elements in order to
minimize any luminance component, particularly if low spatial
frequencies are used.
The patient’s pupil may or may not be dilated. In either case,
care must be taken that the patient is properly refracted and can
focus on the pattern, which is usually placed between 0.5 and 1 m
distant. A pattern that is not focused will have reduced retinal
contrast and result in a reduction in amplitude.162,165 Two diopters
of blur may reduce the amplitude by 50%.165 The probability that
patterns will be out of focus for patients with reduced acuity must
be considered when interpreting responses, an issue that has
been raised with respect to evaluating strabismic amblyopia.165
Signals may be monitored with a silver cup skin electrode on
the lower lid,192 a corneal gold foil or DTL electrode placed in
the lower conjunctival sac,192–194 or a Burian–Allen bipolar contact
lens electrode.195 With the gold foil electrode, but apparently not
with the DTL electrode,196 pattern stimulation of one eye can
by volume conduction lead to an artifactual response from the
fellow eye.197–199 With the DTL electrode, the ratio of signal to
noise was said to be best if the reference electrode was placed by
the outer canthus of the stimulated eye.196 If a contact lens is used,
the eye must be refracted with it in place. PERG signals are typi-
cally less than 5 mV in amplitude and must be averaged, prefer-
ably with an artifact reject buffer. The skin electrode is reported
to be little affected by blinking but yields smaller amplitudes
than does a corneal electrode.192 The contact lens electrode alone
prevents reduction of stimulus luminance resulting from lid
closure.
Although the stimulus fields for eliciting PERGs are usually
large relative to those used for eliciting FERGs, fixation near the
center of the pattern is still important because the major contri-
bution to the response for a mid-frequency check size comes
from the fovea. It has been shown that PERG amplitude can fall
by 50% for an eccentricity of 4°165 and by 63% for an eccentricity
of 12°.200 Eccentric fixation may also help to generate a lumi-
nance component, which may be conveniently checked by quan-
tifying the fundamental component of the response by Fourier
analysis.166
Interocular differences in PERG amplitude among normal sub-
jects have been estimated to be as much as 100%.165 Test–retest
correlations were 0.58 comparing two measurements made on the
same day but only 0.01 comparing measurements made 1 week
apart.201 The PERG does not appear to be significantly different
1626
FIGURE 124.34. Pattern ERG amplitude and
phase versus spatial frequency for a normal
subject. Responses were elicited with a
1.6 µ 1.7°, 100% contrast sinusoidal grating
reversing sinusoidally at 8 Hz. Responses were
recorded with a gold-foil electrode.
From Hess RF, Baker CL Jr: Human pattern-evoked
electroretinogram. J Neurophysiol 1984; 51:939.
between males and females,195 but a small decline in ampli-
tude195,202 and an increase in latency195 with increasing age have
been reported. In a comparison of responses for a group of normal
subjects of mean age 21 years with a group of normal subjects
of mean age 72 years, the latter had an average 40% reduction
in amplitude.203
VISUAL EVOKED RESPONSE TESTING
Pattern-reversal VERs are now preferred over flash VERs for the
evaluation of the visual pathways, owing in large part to their
smaller range of variation in normal subjects and, undoubtedly
related to this, their enhanced sensitivity in detecting axonal con-
duction defects. The pattern VER is a multiphasic response that,
when detectable, contains an inion-positive component with a
latency of ~100 ms, called P100 (see Fig. 124.35). The primary
use of the pattern-reversal VER is to identify visual loss second-
ary to diseases of the optic nerve and anterior visual pathways
versus those of psychogenic origin. For example, demyelination
and compressive lesions of the optic nerve produce reliable
slowing of the pattern response (Fig. 124.36), whereas flash
responses in these cases often have normal latencies.204 As many
as 96% of patients with multiple sclerosis might be expected to
have delayed pattern VERs.205 Although P100 remains delayed,
its amplitude varies monotonically with visual acuity during
recovery from optic neuritis.206 Determining contrast thresholds
for a range of spatial frequencies permits the objective assess-
ment of visual acuity (at 100% contrast),207 which can be used
to detect malingering.
The stimulus for the pattern VER may be essentially the same
as for the PERG, allowing for both measures to be recorded simul-
taneously, as is becoming increasingly the custom.163,184,195,200,202
It is essential that the checkerboard pattern be in proper focus,
since lack of focus leads to decreases in VER amplitude208,209
and increases in VER latency.210 Recordings are generally made
from the midline, using either a bipolar configuration with the
positive electrode above the inion and the negative electrode on
the vertex or monopolar configurations with positive electrodes
above the inion and over the parietal lobe. Earlobes may serve
as reference and ground. The electrodes may be conventional
electroencephalographic cup electrodes and should be filled with
electrode cream and applied to the scalp after reducing scalp
resistance with an abrasive. The intent is to obtain a resistance

FIGURE 124.35. Pattern-reversal ERGs (PERRs) (a) and VERs (b)
from the right and left eyes of a patient with a traumatic unilateral
(right) optic nerve section. Responses were elicited by a matrix of
40 min of arc dots, as illustrated at upper right. Arrows designate
major negative and positive components, respectively. The pattern
ERGs were recorded simultaneously from both eyes with DTL
electrodes. The pattern VERs were recorded sequentially with the
positive electrode 2 cm above the inion referenced to an earlobe.
(a and b) From Dawson WW, Maida TM, Rubin ML: Human pattern-evoked
retinal responses are altered by optic atrophy. Invest Ophthalmol Vis Sci 1982;
22:796. © Association for Research in Vision and Ophthalmology.
less than 5000 W. The electrodes may be held in place with
colloidin. Responses must be averaged by computer because
amplitudes are generally less than 10 mV.
The use of on–off modulated gratings (in which a grating alter-
nates with a blank screen of the same mean luminance) has
been recommended as superior to pattern-reversal stimulation
for eliciting the steady-state VER.211 The on–off grating stimu-
lus has been reported to evoke a bell-shaped spatial-frequency
tuned response more consistently across normal subjects than
the pattern-reversal stimulus. In addition, the spatial-tuning
characteristics obtained by psychophysical testing and by the
VER are more similar for the on–off grating stimulus than for
the pattern-reversal stimulus (Fig. 124.37).
Objective Assessment of Retinal Function
Unlike retinal responses, scalp responses to pattern reversal
show marked interindividual variation in waveform among nor-
mal subjects.212 Nevertheless, remarkable agreement exists for
the normal latency for the P100 component across studies. Upper
limits for latency differences between left and right eyes of normal
subjects have been estimated at 8–10 ms.213 Repeat testing of
the same subjects on separate days showed a substantial variation
in latency with values that still mostly fell within normal limits
obtained on the same patients at a single session.213 P100 latency
increases with age in normal subjects, at a rate of ~2 ms/decade
depending on spatial frequency (Fig. 124.38).214 In addition, a
50-year increase among adults was associated with a 50%
reduction in VER amplitude for temporal modulation below 6 Hz.
For faster modulation, age had no effect on amplitude.203 VER
acuity (derived by extrapolating VER amplitude as a function of
increasing spatial frequency to zero amplitude) increased 300%
in infants for increasing age up to the adult level reached at age
30 weeks.215 P100 latency is also greater for small pupils than
CHAPTER 124
for large pupils.216 Some (but not all) of the increase with age
may be due to age-related miosis.
CHOOSING A TEST
When a patient presents with reduced visual acuity, blur, or meta-
morphopsia or with difficulty seeing at night, increased sensi-
tivity to bright lights, or an impairment in discriminating colors
(or any combination of these symptoms), the ophthalmologist
must decide whether objective tests of visual function are required
in addition to a routine examination. It has been our preference
to first rule out distal retinal malfunction by performing full-field
and focal flash electroretinography. Tests based on differential
fundus reflectance – especially OCT – can be used to corroborate
this impression. If results from these tests are abnormal, no addi-
tional measurements of function are necessary, and the patient
can be advised that the problem is within the eye in the outer
retina. If results from flash electroretinography are normal, it
would be appropriate to consider the PERG to rule out ganglion
cell and optic nerve dysfunction, and then the pattern VER to
rule out visual pathway and cortical dysfunction.
Key Features
• Measures optical density and regeneration kinetics of
rhodopsin or cone visual pigment
• Measures lipofuscin concentration
• In vivo microscopy of the retina
• Noninvasive detection and quantification of cystoid macular
edema
• Amplitude proportional to amount of bleached visual pigment
• Requires very bright light flashes
• Measures RPE integrity
• Used to distinguish Best disease from pseudovitelliform
macular degeneration
• Measures mass retinal response from the entire retina to
flashes of light
• Components derive from different cell types
• Insensitive to maculopathies
• Allows detection of maculopathies
• Should employ visualization of the retina during testing to
insure appropriate placement and stabilization of stimulus
• Allows detection of regional losses of retinal function due to
rod system disease
• Can be used to detect specific ganglion cell dysfunction when
distal foveal retinal function is normal
• Can be used to detect specific cortical malfunction when
ocular function is normal
1627
 RETINA AND VITREOUS

FIGURE 124.36. (Left) Pattern-reversal VERs

recorded from a midline occipital electrode
from the left and right eyes of a normal subject
(a) and two patients who were recovering from
acute attacks of optic neuritis in the right eye
with onset 4 weeks (b) and 3 weeks
(c) previously. Pattern reversal is at 20 ms;
positivity downward. (Right) Distribution of the
peak latencies of the major positive component
of the pattern-reversal VER from the affected
eye of 18 patients with optic neuritis (upper
histogram), from the unaffected eye of 19
patients with optic neuritis (middle histogram),
and from the right eye of 17 normal subjects
(lower histogram).
From Halliday AM, McDonald WI, Mushin J: Delayed
visual evoked response in optic neuritis. Lancet 1972;
1:982.
SECTION 10

FIGURE 124.37. Contrast-sensitivity function

(CSF) as obtained through the visual-evoked
potential (VEP) regression technique (filled
symbols) and psychophysically (open symbols).
(Left) Pattern reversal (Rev.). (Right) On–off
modulation.
From Strasburger H, Remky A, Murray IJ, et al:
Objective measurement of contrast sensitivity and
visual acuity with the steady-state visual evoked
potential. Germ J Ophthalmol 1996; 5:42. Reprinted
from Springer-Verlag.

FIGURE 124.38. P100 (P1) latency for 48 min

(closed circles) and 12 min (open circles)
checks as a function of age. Each data point is
the mean latency of the right and left eyes of
each subject. For 48-min checks, y = 0.14x +
101.8; for 12-min checks, y = 0.26x + 105.6.
For ease of comparison, the regression line for
48-min checks has also been plotted as a
dashed line on the 12-min graph.
From Sokol S, Moskowitz A, Towle VL: Age-related
changes in the latency of the visual evoked potential:
influence of check size. Electroencephalogr Clin
Neurophysiol 1981; 51:559.

1628

REFERENCES
1. Carr RE, Ripps H, Siegel IM, et al:
Rhodopsin and the electrical activity of the
retina in congenital night blindness. Invest
Ophthalmol Vis Sci 1966; 5:497.
2. Carr RE, Ripps H, Siegel IM: Visual
pigment kinetics and adaptation in fundus
albipunctatus. Doc Ophthalmol Proc Ser
1974; 4:193.
3. Carr RE, Ripps H: Rhodopsin kinetics and
rod adaptation in Oguchi’s disease. Invest
Ophthalmol Vis Sci 1967; 6:426.
4. Bird AC, Hyman V: Detection of
heterozygotes in families with X-linked
pigmentary retinopathy by measurements
of retinal rhodopsin concentration. Trans
Ophthalmol Soc UK 1972; 93:221.
5. Bird AC: X-linked retinitis pigmentosa.
Br J Ophthalmol 1975; 59:175.
6. Kemp CM, Jacobson SG, Faulkner DJ:
Two types of visual dysfunction in
autosomal dominant retinitis pigmentosa.
Invest Ophthalmol Vis Sci 1988; 29:1235.
7. Alpern M, Krantz D: Visual pigment kinetics
in abnormalities of the uvea-retinal
epithelium in man. Invest Ophthalmol Vis
Sci 1981; 20:183.
8. Campbell FW, Rushton WAH: Measurement
of the scotopic pigment in the living human
eye. J Physiol 1955; 130:131.
9. Weale RA: Photo-sensitive reactions in
foveae of normal and cone monochromatic
observers. Optica Acta 1959; 6:158.
10. Alpern M: Rhodopsin kinetics in the human
eye. J Physiol 1971; 217:447.
11. Highman VN, Weale RA: Rhodopsin density
and visual threshold in retinitis pigmentosa.
Am J Ophthalmol 1973; 75:822.
12. Sheorey UB: Clinical assessment of
rhodopsin in the eye. Br J Ophthalmol
1976; 60:135.
13. Kemp CM, Faulkner DJ: Rhodopsin
measurement in human disease: fundus
reflectometry using television. Dev
Ophthalmol 1981; 2:130.
14. Kilbride PE, Fishman M, Fishman GA, et al:
Foveal cone pigment density difference and
reflectance in retinitis pigmentosa. Arch
Ophthalmol 1986; 104:220.
15. Ripps H, Brin KP, Weale RA: Rhodopsin
and visual threshold in retinitis pigmentosa.
Invest Ophthalmol Vis Sci 1978; 17:735.
16. Faulkner DJ, Kemp CM: Human rhodopsin
measurement using a T.V.-based imaging
fundus reflectometer. Vision Res 1984;
24:221.
17. Kilbride PE, Hutman LP, Fishman M, et al:
Foveal cone pigment density difference in
the aging human eye. Vision Res 1986;
26:321.
18. Delori FC, Dorey CK, Staurenghi G, et al:
In vivo fluorescence of the ocular fundus
exhibits retinal pigment epithelium
lipofuscin characteristics. Invest
Ophthalmol Vis Sci Mar 1995; 36:718.
19. Delori FC, Staurenghi G, Arend O, et al:
In vivo measurement of lipofuscin in
Stargardt’s disease – Fundus
Flavimaculatus. Invest Ophthalmol Vis Sci
Mar 36:2327.
20. Von Ruckmann A, Fitzke FW, Bird AC:
In vivo fundus autofluorescence in macular
dystrophies. Arch Ophthalmol 1997;
115:609.
21. Lois N, Halfyard AS, Bird AC, et al: Fundus
autofluorescence in Stargardt macular
Objective Assessment of Retinal Function
dystrophy-fundus flavimaculatus. Am J
Ophthalmol 2004; 138:55.
22. Robson AG, Egan CA, Luong VA, et al:
Comparison of fundus autofluorescence
with photopic and scotopic fine-matrix
mapping in patients with retinitis
pigmentosa and normal visual acuity. Invest
Ophthalmol Vis Sci 2004; 45:4119.
23. Sholl HPN, Chong NHV, Robson AG, et al:
Fundus autofluorescence in patients with
Leber congenital amaurosis. Invest
Ophthalmol Vis Sci 2004; 45:2747.
24. Sandberg MA, Brockhurst RJ, Gaudio AR,
Berson EL: The association between visual
acuity and central retinal thickness in
retinitis pigmentosa. Invest Ophthalmol Vis
Sci 2005; 46:3349.
25. Hirakawa H, Iijima H, Gohdo T, Tsukahara S:
Optical coherence tomography of cystoid
macular edema associated with retinitis
pigmentosa. Am J Ophthalmol 1999;
128:185.
26. Apushkin MA, Fishman GA, Janowicz MJ:
Monitoring cystoid macular edema by
optical coherence tomography in patients
with retinitis pigmentosa. Ophthalmology
2004; 111:1899.
27. Azzolini C, Pierro L, Codenotti M, Brancato
R: OCT images and surgery of juvenile
Macular retinoschisis. Eur J Ophthalmol
1997; 7:196.
28. Eriksson U, Larsson E, Holmstrom G:
Optical coherence tomography in the
diagnosis of juvenile X-linked retinoschisis.
Acta Ophthalmol Scand 2004; 82:218.
29. Apushkin MA, Fishman GA, Janowicz MJ:
Correlation of optical coherence
tomography findings with visual acuity and
macular lesions in patients with X-linked
retinoschisis. Ophthalmology 2005;
112:495.
30. Hayashi T, Kitahara K: Optical coherence
tomography in enhanced S-cone
syndrome: large macular retinoschisis
with disorganized retinal lamination. Eur J
Ophthalmol 2005; 15:643.
31. Berson EL, Goldstein EB: The early
receptor potential in dominantly inherited
retinitis pigmentosa. Arch Ophthalmol
1970; 83:412.
32. Brown KT, Crawford JM: Melanin and the
rapid light-evoked responses from pigment
epithelial cells of the frog eye. Vision Res
1967; 7:165.
33. Pak WL: Some properties of the early
electrical response in the vertebrate retina.
Cold Spring Harbor Symp Quant Biol 1965;
30:493.
34. Cone RA: Early receptor potential:
photoreversible charge displacement in
rhodopsin. Science 1967; 155:1128.
35. Cone RA: Early receptor potential of
the vertebrate retina. Nature 1964;
204:736.
36. Cone RA, Brown PK: Dependence of the
early receptor potential on the orientation
of rhodopsin. Science 1967; 156:536.
37. Goldstein EB, Berson EL: Cone dominance
of the human early receptor potential.
Nature 1969; 222:1272.
38. Carr RE, Siegel IM: Action spectrum of the
early receptor potential. Nature 1970;
225:88.
39. Galloway NR: Early receptor potential in the
human eye. Br J Ophthalmol 1967; 51:261.
40. Tamai A: Studies on the early receptor
potential in the human eye. III. ERP in
primary retinitis pigmentosa. Yonago Acta
Med 1974; 18:18.
41. Cone RA: The early receptor potential of
the vertebrate eye. Cold Spring Harbor
Symp Quant Biol 1965; 30:483.
42. Berson EL, Goldstein EB: The early
receptor potential in dominantly inherited
retinitis pigmentosa. Arch Ophthalmol
1970; 83:412.
43. Barber C, Cotterill DJ, Larke JR: A new
contact lens electrode. Doc Ophthalmol
Proc Ser 1977; 13:385.
44. Sieving PA, Fishman GA, Maggiano JM:
Corneal wick electrode for recording
bright flash electroretinograms and early
receptor potentials. Arch Ophthalmol 1978;
CHAPTER 124
96:899.
45. Muller W, Topke H: The early receptor
potential (ERP). Doc Ophthalmol 1987;
66:35.
46. Steinberg RH, Linsenmeier RA, Griff ER:
Three light-evoked responses of the retinal
pigment epithelium. Vision Res 1983;
23:1315.
47. Arden GB, Barrada A, Kelsey JH: New
clinical test of retinal function based upon
the standing potential of the eye. Br J
Ophthalmol 1962; 46:449.
48. Krill AE, Morse PA, Potts AM, et al:
Hereditary vitelliruptive macular
degeneration. Am J Ophthalmol 1966;
61:1405.
49. Francois J, De Rouck A, Fernandez-Sasso
D: Electro-oculography in vitelliform
degeneration of the macula. Arch
Ophthalmol 1967; 77:726.
50. Deutman AF: Electro-oculography in
families with vitelliform dystrophy of the
fovea. Detection of the carrier state. Arch
Ophthalmol 1969; 81:305.
51. Sabates R, Pruett RC, Hirose T:
The electrooculogram in ‘vitelliform’
macular lesions. Doc Ophthalmol Proc Ser
1983; 37:93.
52. Berson EL: Electrical phenomena in the
retina. In: Hart WM, ed. Adler’s physiology
of the eye. Clinical application. 9th edn.
St Louis: CV Mosby; 1992.
53. Kolder H, Brecher GA: Fast oscillations of
the corneoretinal potential in man. Arch
Ophthalmol 1966; 75:232.
54. Weleber RG: Fast and slow oscillations of
the electro-oculogram in Best’s macular
dystrophy and retinitis pigmentosa. Arch
Ophthalmol 1989; 107:530.
55. Fishman GA, Young RSL, Schall SP, et al:
Electro-oculogram testing in fundus
flavimaculatus. Arch Ophthalmol 1979;
97:1896.
56. Kolder HE, Hochgesand P: Empirical model
of electro-oculogram. Doc Ophthalmol
1973; 34:229.
57. Kelsey JH: Variations in the normal electro-
oculogram. Br J Ophthalmol 1967; 51:44.
58. Lith GHM, Balik J: Variability of the electro-
oculogram (EOG). Acta Ophthalmol 1970;
48:1091.
59. Jones RM, Stevens TS, Gould S: Normal
EOG values of young subjects. Doc
Ophthalmol Proc Ser 1977; 13:93.
60. Arden GB, Barrada A: Analysis of the
electro-oculogram of a series of normal
subjects. Br J Ophthalmol 1962; 46:468.
1629
 RETINA AND VITREOUS
61. Adams A: The normal electro-oculogram
(EOG). Acta Ophthalmol 1973; 51:551.
62. Jackson SA: The optimum illuminance level
for clinical electro-oculography. Acta
Ophthalmol 1979; 57:665.
63. Krogh E: Normal values in clinical
electrooculography. IV. Analysis of two
dimensionless EOG parameters and their
relation to other variables. Acta Ophthalmol
1977; 55:739.
64. Anderson ML, Purple RL: Circadian
rhythms and variability of the clinical
electro-oculogram. Invest Ophthalmol Vis
Sci 1980; 19:278.
65. Brown KT, Wiesel TN: Localization of
origins of electroretinogram components by
intraretinal recording in the intact cat eye.
J Physiol (Lond) 1961; 158:257.
66. Brown KT, Watanabe K: Isolation and
identification of a receptor potential from
the pure cone fovea of the monkey retina.
SECTION 10
Nature 1962; 193:958.
67. Miller RF, Dowling JE: Intracellular
responses of the Müller (glial) cells of
mudpuppy retina: their relation to b-wave
of the electroretinogram. J Neurophysiol
1970; 33:323.
68. Newman EA: Current source density
analysis of the b-wave of the frog retina.
Am J Neurophysiol 1980; 43:1335.
69. Ogden TE: The oscillatory waves of the
primate electroretinogram. Vision Res 1973;
13:1059.
70. Heynen H, Wachtmeister L, van Norren D:
Origin of the oscillatory potentials in the
primate retina. Vision Res 1985; 25:1365.
71. Alexander KR, Fishman GA, Barnes CS,
Grover S: ON-response deficit in the
electroretinogram of the cone system in
X-linked retinoschisis. Invest Ophthalmol
Vis Sci 2001; 42:453.
72. Dryja TP, McGee TL, Berson EL, et al:
Night blindness and abnormal cone
electroretinogram ON responses in patients
with mutations in the GRM6 gene encoding
mGluR6. PNAS 2005; 102:4884.
73. Seiple W, Holopigian K: The ‘off’ response
of the human electroretinogram does not
contribute to the brief flash ‘b-wave’. Visual
Neurosci 1994; 11:667.
74. Hirose T, Wolf E, Hara A:
Electrophysiological and psychophysical
studies in congenital retinoschisis of
X-linked recessive inheritance. Doc
Ophthalmol Proc Ser 1977; 13:173.
75. Yonemura D, Aoki T, Tsuzuki K:
Electroretinogram in diabetic retinopathy.
Arch Ophthalmol 1962; 68:19.
76. Gaudio AR, Lee H, Kini M, et al: Oscillatory
potentials in central retinal vein occlusion.
Invest Ophthalmol Vis Sci 1989;
30(Suppl):477.
77. Gouras P: Rod and cone independence in
the electroretinogram of the dark-adapted
monkey’s perifovea. J Physiol 1966;
187:455.
78. Berson EL, Gouras P, Hoff M: Temporal
aspects of the electroretinogram. Arch
Ophthalmol 1969; 81:207.
79. Chatrian GE, Nelson PL, Lettich E, et al:
Computer-assisted quantitative
electroretinography. II. Separation of rod
and cone components of the
electroretinogram in congenital
achromatopsia and congenital nyctalopia.
Am J EEG Technol 1980; 20:79.
80. Sandberg MA, Miller S, Berson EL: Rod
1630 electroretinograms in an elevated cyclic
guanosine monophosphate-type human
retinal degeneration. Comparison with
retinitis pigmentosa. Invest Ophthalmol Vis
Sci 1990; 31:2283.
81. Armington JC, Johnson EP, Riggs LA: The
scotopic a-wave in the electrical response
of the human retina. J Physiol (Lond) 1952;
118:289.
82. King-Smith PE, Loffing DA, Jones R: Rod
and cone ERGs and their oscillatory
potentials. Invest Ophthalmol Vis Sci 1986;
27:270.
83. Berson EL, Sandberg MA, Rosner B, et al:
Natural course of retinitis pigmentosa over
a three-year interval. Am J Ophthalmol
1985; 99:240.
84. Reichel E, Bruce AM, Sandberg MA, et al:
An electroretinographic and molecular
genetic study of X-linked cone degeneration.
Am J Ophthalmol 1989; 108:540.
85. Berson EL, Sandberg MA, Maguire A, et al:
Electroretinograms in carriers of blue cone
monochromatism. Am J Ophthalmol 1986;
102:254.
86. Gouras P, MacKay CJ: Electroretinographic
responses of the short-wavelength-
sensitive cones. Invest Ophthalmol Vis Sci
1990; 31:1203.
87. Arden GB, Carter RM, Hogg CR, et al:
A modified ERG technique and the results
obtained in X-linked retinitis pigmentosa.
Br J Ophthalmol 1982; 67:419.
88. Moloney JB, Mooney DJ, O’Connor MA:
Retinal function in Stargardt’s disease and
fundus flavimaculatus. Am J Ophthalmol
1983; 96:57.
89. Massof RW, Wu L, Finkelstein D, et al:
Properties of electroretinographic intensity
response functions in retinitis pigmentosa.
Doc Ophthalmol 1984; 57:279.
90. Birch DG, Fish GE: Rod ERGs in retinitis
pigmentosa and cone-rod degeneration.
Invest Ophthalmol Vis Sci 1987; 28:140.
91. Birch DG, Hood DC, Locke KG, et al:
Quantitative measures of
phototransduction in cone and rod
photoreceptors. Normal aging, progression
with disease, and test-retest variability.
Arch Ophthalmol 2002; 120:1045.
92. Tzekov RT, Locke KG, Hood DC, Birch DG:
Cone and rod ERG phototransduction
parameters in retinitis pigmentosa. Invest
Ophthalmol Vis Sci 2003; 44:3993.
93. Berson EL, Gouras PL, Gunkel R: Rod
responses in retinitis pigmentosa,
dominantly inherited. Arch Ophthalmol
1968; 80:58.
94. Le Grand Y: Form and Space Vision.
Bloomington: Indiana University Press; 1967.
95. Rabin AR, Berson EL: A full-field system for
clinical electroretinography. Arch
Ophthalmol 1974; 92:59.
96. Karpe G, Wulfing B: Importance of pupil
size in clinical ERG. Acta Ophthalmol 1961;
70(Suppl):53.
97. Brunette JR, Olivier P, Lafond G: Decreased
ocular light penetration and
electroretinographic response time. Can J
Ophthalmol 1980; 15:24.
98. Sandberg MA: Technical issues in
electroretinography. In: Heckenlively J,
Arden G, eds. Principles and practice of
clinical electrophysiology of vision.
St Louis: Mosby-Year Book; 1991.
99. Hennessy MP, Vaegan: Amplitude scaling
of Burian–Allen, gold foil and Dawson, Trick
and Litzkow electrodes. Doc Ophthalmol
1995; 89:235.
100. Miyake Y, Horiguchi M, Ota I, et al:
Characteristic ERG flicker anomaly in
incomplete congenital stationary night
blindness. Invest Ophthalmol Vis Sci 1987;
28:1816.
101. Gouras P, MacKay CJ: Growth in amplitude
of the human cone electroretinogram with
light adaptation. Invest Ophthalmol Vis Sci
1989; 30:625.
102. Miller S, Sandberg MA: Cone
electroretinographic change during light
adaptation in retinitis pigmentosa. Invest
Ophthalmol Vis Sci 1991; 25:2536.
103. Sandberg MA, Lee H, Gaudio AR, et al:
Relationship of oscillatory potential
amplitudes to a-wave slope over a
range of flash luminances in normal
subjects. Invest Ophthalmol Vis Sci 1991;
32:1508.
104. Fuller DG, Knighton RW, Machemer R:
Bright-flash electroretinography for the
evaluation of eyes with opaque vitreous.
Am J Ophthalmol 1975; 80:214.
105. Algvere P, Westbeck S: Human ERG in
response to double flashes of light during
the course of dark adaptation: a Fourier
analysis of the oscillatory potentials. Vision
Res 1972; 12:195.
106. Gur M, Zeevi Y: Frequency-domain analysis
of the human electroretinogram. J Opt Soc
Am 1980; 70:53.
107. Van der Torren K, Groenweg G, Van Lith G:
Measuring oscillatory potentials: Fourier
analysis. Doc Ophthalmol 1988; 69:153.
108. Andreasson SOL, Sandberg MA, Berson
EL: Narrow-band filtering for monitoring
low-amplitude cone electroretinograms in
retinitis pigmentosa. Am J Ophthalmol
1988; 105:500.
109. Birch DG, Sandberg MA: Sub-microvolt
full-field cone electroretinograms: artifacts
and reproducibility. Doc Ophthalmol 1997;
92:269.
110. Martin DA, Heckenlively JR: The normal
electroretinogram. Doc Ophthalmol Proc
Ser 1982; 31:135.
111. Berson EL: Electroretinographic findings in
retinitis pigmentosa. Jpn J Ophthalmol
1987; 31:327.
112. Peterson H: The normal b-potential in the
single-flash clinical electroretinogram:
a computer technique study of the
influence of sex and age. Acta Ophthalmol
1968; 99(Suppl):5.
113. Weleber RG: The effect of age on human
cone and rod Ganzfeld electroretinograms.
Invest Ophthalmol Vis Sci 1981; 20:392.
114. Wright CE, Williams DE, Drasdo N, et al:
The influence of age on the
electroretinogram and visual evoked
potential. Doc Ophthalmol 1985; 59:365.
115. Gouras P, MacKay CJ, Yamamoto S: The
human S-cone electroretinogram and its
variation among subjects with and without
L- and M-cone function. Invest Ophthalmol
Vis Sci 1993; 34:2437.
116. Said FS, Weale RA: The variation with age
of the spectral transmissivity of the living
human crystalline lens. Gerontologia 1959;
3:213.
117. Dodt E, Copenhaver RM, Gunkel RD:
Electroretinographic measurement of the
spectral sensitivity in albinos, caucasians,
and negroes. Arch Ophthalmol 1959;
62:795.
118. Krill AE, Lee GB: The electroretinogram in
albinos and carriers of the ocular albino
trait. Arch Ophthalmol 1963; 69:32.

119. Wali N, Leguire LE: Fundus pigmentation
and the dark-adapted electroretinogram.
Doc Ophthalmol 1992; 80:1.
120. Pallin E: The influence of the axial size of the
eye on the size of the recorded b-potential in
the clinical single-flash electroretinogram.
Acta Ophthalmol 1969; 101(Suppl):1.
121. Perlman I, Meyer E, Haim T, et al: Retinal
function in high refractive error assessed
electroretinographically. Br J Ophthalmol
1984; 68:79.
122. Karpe G, Rickenbach K, Thomasson S:
The clinical electroretinogram. I. The
normal electroretinogram above fifty years
of age. Acta Ophthalmol 1950; 28:301.
123. Zeidler I: The clinical electroretinogram. IX.
The normal electroretinogram. Value of the
b-potential in different age groups and its
difference in men and women. Acta
Ophthalmol 1959; 37:294.
124. Birch DG, Berson EL, Sandberg MA:
Diurnal rhythm in the human rod ERG.
Invest Ophthalmol Vis Sci 1984; 25:236.
125. Sandberg MA, Pawlyk BS, Berson EL:
Electroretinogram (ERG) sensitivity and
phagosome frequency in the normal
pigmented rat. Exp Eye Res 1986; 43:781.
126. Arden GB, Bankes JLK: Foveal
electroretinogram as a clinical test.
Br J Ophthalmol 1966; 50:740.
127. Biersdorf WR, Diller DA: Local
electroretinogram in macular degeneration.
Am J Ophthalmol 1969; 68:296.
128. Hirose T, Miyake Y, Hara A: Simultaneous
recording of electroretinogram and visually
evoked response: focal stimulation under
direct observation. Arch Ophthalmol 1977;
95:1205.
129. Sandberg MA, Jacobson SG, Berson EL:
Foveal cone electroretinograms in retinitis
pigmentosa and juvenile macular
degeneration. Am J Ophthalmol 1979;
88:702.
130. Fish GE, Birch DG, Fuller DG, et al:
A comparison of visual function tests in
eyes with maculopathy. Ophthalmology
1986; 93:1177.
131. Seiple WH, Siegel IM, Carr RE, et al:
Evaluating macular function using the focal
electroretinogram. Invest Ophthalmol Vis
Sci 1986; 27: 1123.
132. Miyake Y, Shiroyama N, Ota I, et al: Local
macular electroretinographic responses in
idiopathic central serous chorioretinopathy.
Am J Ophthalmol 1988; 106:546.
133. Brodie SE, Naidu EM: Combined amplitude
and phase criteria for evaluation of macular
electroretinograms. Invest Ophthalmol Vis
Sci 1990; 31(Suppl):425.
134. Sandberg MA, Hanson AH, Berson EL:
Foveal and parafoveal cone
electroretinograms in juvenile macular
degeneration. Ophthalmic Paediatr Genet
1983; 3:83.
135. Birch DG, Fish GE: Focal cone
electroretinograms: aging and macular
disease. Doc Ophthalmol 1988; 69:211.
136. Remulla JFC, Gaudio AR, Miller S,
Sandberg MA: Foveal electroretinograms
and choroidal perfusion characteristics in
fellow eyes of patients with unilateral
neovascular age-related macular
degeneration. Br J Ophthalmol 1993;
79:558.
137. Birch DG, Jost BF, Fish GE: The focal
electroretinogram in fellow eyes of patients
with idiopathic macular holes. Arch
Ophthalmol 1988; 106:1558.
Objective Assessment of Retinal Function
138. Miyake Y, Ichikawa K, Shiose Y, et al:
Hereditary macular dystrophy without
visible fundus abnormality. Am J
Ophthalmol 1989; 108:292.
139. Matthews GP, Sandberg MA, Berson EL:
Foveal cone electroretinograms in patients
with central visual loss of unexplained
etiology. Arch Ophthalmol 1992; 110:1568.
140. Jacobson SG, Sandberg MA, Effron MH,
et al: Foveal cone electroretinograms in
strabismic amblyopia. Comparison with
juvenile macular degeneration, macular
scars and optic atrophy. Trans Ophthalmol
Soc UK 1979; 99:353.
141. Biersdorf WR: The foveal electroretinogram
is normal in optic atrophy. Doc Ophthalmol
Proc Ser 1984; 40:127.
142. Sandberg MA, Baruzzi CM, Berson EL:
Foveal cone ERGs in optic neuropathy.
Invest Ophthalmol Vis Sci 1986;
27(Suppl):104.
143. Weiner A, Sandberg MA: Normal change in
the foveal cone ERG with increasing
duration of light exposure. Invest
Ophthalmol Vis Sci 1991; 32:2842.
144. Weiner A, Sandberg MA, Berson EL:
Abnormal foveal to parafoveal cone ERG
amplitude ratios in patients with reduced
visual acuity and suspected foveal disease.
Invest Ophthalmol Vis Sci 1990;
31(Suppl):426.
145. Miyake Y, Shiroyama N, Horiguchi M, et al:
Asymmetry of focal ERG in human macular
region. Invest Ophthalmol Vis Sci 1989;
30:1743.
146. Sandberg MA, Miller S, Gaudio AR: Foveal
cone ERGs in fellow eyes of patients with
unilateral neovascular age-related macular
degeneration. Invest Ophthalmol Vis Sci
1993; 34:3477.
147. Bearse MA, Sutter EE: Imaging localized
retinal dysfunction with the multifocal
electroretinogram. J Opt Soc Am 1996;
13:634.
148. Hood DC, Seiple W, Holopigian K,
Greenstein V: A comparison of the
components of the multifocal and full-field
ERGs. Vis Neurosci 1997; 14:1.
149. Kretschmann U, Seeliger MW, Ruether K,
et al: Multifocal electroretinography in
patients with Stargardt’s macular
dystrophy. Br J Ophthalmol 1998; 82:267.
150. Piao CH, Kondo M, Tanikawa A, et al:
Multifocal electroretinogram in occult
macular dystrophy. Invest Ophthalmol Vis
Sci 2000; 41:513.
151. Wildberger H, Niemeyer G, Junghardt A:
Multifocal electroretinogram (mfERG) in a
family with occult macular dystrophy
(OMD). Klin Monatsbl Augenheilkd 2003;
220:111.
152. Seeliger M, Kretschmann U, Apfelstedt-
Sylla E, et al: Multifocal electroretinography
in retinitis pigmentosa. Am J Ophthalmol
1998; 125:214.
153. Holopigian K, Seiple W, Greenstein VC, et
al: Local cone and rod system function in
patients with retinitis pigmentosa. Invest
Ophthalmol Vis Sci 2001; 42:779.
154. Berson EL, Rosen JB, Simonoff EA:
Electroretinographic testing as an aid in
detection of carriers of X-chromosome-
linked retinitis pigmentosa. Am J
Ophthalmol 1979; 87:460.
155. Fishman GA, Weinberg AB, McMahon TT:
X-linked recessive retinitis pigmentosa:
clinical characteristics of carriers. Arch
Ophthalmol 1986; 104:1329.
156. Vajaranant TS, Seiple W, Szlyk JP,
Fishman GA: Detection using the multifocal
electroretinogram of mosaic retinal
dysfunction in carriers of X-linked retinitis
pigmentosa. Ophthalmology 2002;
109:560.
157. Piao C-H, Kondo M, Nakamura M, et al:
Multifocal electroretinograms in X-linked
retinoschisis. Invest Ophthalmol Vis Sci
2003; 44:4920.
158. Huang S, Wu D, Jiang F, et al: The
multifocal electroretinogram in X-linked
juvenile retinoschisis. Doc Ophthalmol
2003; 106:251.
159. Nusinowitz S, Hood DC, Birch DG: Rod
transduction parameters from the a wave
of local receptor populations. J Opt Soc
Am 1995; 12:2259.
160. Sandberg MA, Pawlyk BS, Berson EL:
Isolation of focal rod electroretinograms
CHAPTER 124
from the dark-adapted human eye. Invest
Ophthalmol Vis Sci 1996; 37:930.
161. Riggs LA, Johnson EP, Schick AML:
Electrical responses of the human eye to
moving stimulus pattern. Science 1964;
144:567.
162. Odom JV, Maida TM, Dawson WW: Pattern
evoked retinal response (PERR) in human:
effects of spatial frequency, temporal
frequency, luminance and defocus. Curr
Eye Res 1982–83; 2:99.
163. Sokol S, Jones K, Nadler D: Comparison of
the spatial response properties of the
human retina and cortex as measured by
simultaneously recorded pattern ERGs and
VERs. Vision Res 1983; 23:723.
164. Hess RF, Baker CL Jr: Human pattern-
evoked electroretinogram. J Neurophysiol
1984; 51:939.
165. Hess RF, Baker CL Jr, Verhoeve JN, et al:
The pattern evoked electroretinogram:
its variability in normals and its relationship
to amblyopia. Invest Ophthalmol Vis Sci
1985; 26:1610.
166. Plant GT, Hess RF, Thomas SJ: The pattern
evoked electroretinogram in optic neuritis.
Brain 1986; 109:469.
167. Drasdo N, Thompson DA, Thompson CM,
et al: Complementary components and local
variations of the pattern electroretinogram.
Invest Ophthalmol Vis Sci 1987; 28:158.
168. Trick GL, Wintermeyer DH: Spatial and
temporal frequency tuning of pattern-
reversal retinal potentials. Invest
Ophthalmol Vis Sci 1982; 23:774.
169. Spekreijse H, Estevez O, Van der Tweel LH:
Luminance responses to pattern reversal.
Doc Ophthalmol Proc Ser 1973; 2:205.
170. Baker CL, Hess RF: Linear and nonlinear
components of human electroretinogram.
J Neurophysiol 1973; 51:9521984.
171. Arden GB, Vaegan, Hogg CR: Clinical and
experimental evidence that the pattern
electroretinogram (PERG) is generated in
more proximal retinal layers than the focal
electroretinogram (FERG). Ann N Y Acad
Sci 1982; 388:580.
172. May JG, Ralston JV, Reed JL, et al: Loss in
pattern-elicited electroretinograms in optic
nerve dysfunction. Am J Ophthalmol 1982;
93:418.
173. Wanger P, Persson HE: Pattern-reversal
electroretinograms in unilateral glaucoma.
Invest Ophthalmol Vis Sci 1983; 24:749.
174. Boback P, Bodis-Wollner I, Harnois C, et al:
Pattern electroretinograms and visual
evoked potentials in glaucoma and multiple
sclerosis. Am J Ophthalmol 1983; 96:72. 1631
 RETINA AND VITREOUS
175. Kirkham TH, Coupland SG: The pattern
electroretinogram in optic nerve
demyelination. Can J Neurol Sci 1983;
10:256.
176. Mashima Y, Oguchi Y: Clinical study of the
pattern electroretinogram in patients with
optic nerve damage. Doc Ophthalmol 1985;
61:91.
177. Fiorentini A, Maffei L, Pirchio M, et al: The
ERG in response to alternating gratings in
patients with diseases of the peripheral
visual pathway. Invest Ophthalmol Vis Sci
1981; 21:490.
178. Dawson WW, Maida TM, Rubin ML: Human
pattern-evoked retinal responses are
altered by optic atrophy. Invest Ophthalmol
Vis Sci 1982; 22:796.
179. Arden GB, Hamilton AMP, Wilson-Holt J,
et al: Pattern electroretinograms become
abnormal when background diabetic
retinopathy deteriorates to a preproliferative
SECTION 10
stage: possible use as a screening test.
Br J Ophthalmol 1986; 70:330.
180. Coupland SG: A comparison of oscillatory
potential and pattern electroretinogram
measures in diabetic retinopathy. Doc
Ophthalmol 1987; 66:207.
181. Weinstein GW, Arden GB, Hitchings RA,
et al: The pattern electroretinogram (PERG)
in ocular hypertension and glaucoma. Arch
Ophthalmol 1988; 106:923.
182. Trick GL, Bickler-Bluth M, Cooper DG,
et al: Pattern reversal electroretinogram
(PERG) abnormalities in ocular
hypertension: correlation with glaucoma
risk factors. Curr Eye Res 1988; 7:201.
183. Wanger P, Persson HE: Pattern-reversal
electroretinograms from normotensive,
hypertensive and glaucomatous eyes.
Ophthalmologica 1987; 195:205.
184. Sokol S, Nadler D: Simultaneous
electroretinograms and visual evoked
potentials from adult amblyopes in
response to pattern stimuli. Invest
Ophthalmol Vis Sci 1979; 18:848.
185. Arden GB, Vaegan, Hogg CG, et al: Pattern
ERGs are abnormal in many amblyopes.
Trans Ophthalmol Soc UK 1980;
100:435–460.
186. Arden GB, Wooding SL: Pattern ERGs in
amblyopia. Invest Ophthalmol Vis Sci 1985;
26:88.
187. Gottlob I, Welge-Lussen L: Normal pattern
electroretinograms in amblyopia. Invest
Ophthalmol Vis Sci 1987; 28:187.
188. Maffei L, Fiorentini A: Electroretinographic
responses to alternating gratings before
and after section of the optic nerve.
Science 1981; 211:953.
1632
189. Maffei L, Fiorentini A, Bisti S, et al: Pattern
ERG in the monkey after section of the
optic nerve. Exp Brain Res 1985; 59:423.
190. Sieving PA, Steinberg RH: Proximal retinal
contribution to the intraretinal 8-Hz pattern
ERG of cat. J Neurophysiol 1987; 57:104.
191. Vaegan, Billson FA: Macular
electroretinograms and contrast sensitivity
as sensitive detectors of early
maculopathy. Doc Ophthalmol 1986;
63:399.
192. Kakisu Y, Mizota A, Adachi E: Clinical
application of the pattern electroretinogram
with lid skin electrode. Doc Ophthalmol
1986; 63:187.
193. Arden GB, Carter RM, Hogg C, et al:
A gold foil electrode: extending the
horizons for clinical electroretinography.
Invest Ophthalmol Vis Sci 1979; 18:421.
194. Dawson WW, Trick GL, Litzkow CA:
Improved electrode for electroretinography.
Invest Ophthalmol Vis Sci 1979; 18:988.
195. Celesia GG, Kaufman D, Cone S: Effects of
age and sex on pattern electroretinograms
and visual evoked potentials.
Electroencephalogr Clin Neurophysiol
1987; 68:161.
196. Odom JV, Maida TM, Dawson WW, et al:
Pattern electroretinogram: effects of
reference electrode position. Doc
Ophthalmol 1987; 65:297.
197. Seiple WH, Siegel IM: Recording the
pattern electroretinogram: a cautionary
note. Invest Ophthalmol Vis Sci 1983;
24:796.
198. Peachey NS, Sokol S, Moskowitz A:
Recording the contralateral PERG: effect of
different electrodes. Invest Ophthalmol Vis
Sci 1983; 24:1514.
199. Arden GB, Carter RM, Hogg C: Uniocular
recording of pattern ERG. Vision Res 1986;
26:281.
200. Rover J, Bach M: Pattern electroretinogram
plus visual evoked potential: a decisive test
in patients suspected of malingering. Doc
Ophthalmol 1987; 66:245.
201. Jacobi PC, Walter P, Brunner R, Krieglstein
GK: Reproducibility and intraindividual
variability of the pattern electroretinogram.
Germ J Ophthalmol 1994; 3:216.
202. Trick GL, Trick LR, Haywood KM: Altered
pattern evoked retinal and cortical
potentials associated with human
senescence. Curr Eye Res 1986; 10:717.
203. Porciatti V, Burr DC, Morrone MC, Fiorentini
A: The effects of ageing on the pattern
electroretinogram and visual evoked
potential in humans. Vision Res 1992;
32:1199.
204. Halliday AM, McDonald WI, Mushin J:
Delayed visual evoked response in optic
neuritis. Lancet 1972; 1:982.
205. Halliday AM, McDonald WI, Mushin J:
Visual evoked responses in the diagnosis
of multiple sclerosis. BMJ 1973; 4:661.
206. Halliday AM, McDonald WI, Mushin J:
Delayed pattern evoked responses in optic
neuritis in relation to visual acuity. Trans
Ophthalmol Soc UK 1973; 93:315.
207. Howe JW, Mitchell KW, Robson C: Some
clinical experiences using contrast evoked
potential techniques in organic and non-
organic visual dysfunction. Doc Ophthalmol
Proc Ser 1982; 31:353.
208. Harter MR, White CT: Evoked cortical
responses to checkerboard patterns: effect
of check size as a function of visual acuity.
Electroencephalogr Clin Neurophysiol
1970; 28:48.
209. Millodot M, Riggs LA: Refraction
determined electrophysiologically:
responses to alternation of visual contours.
Arch Ophthalmol 1970; 84:272.
210. Sokol S, Moskowitz A: Effect of retinal blur
on the peak latency of the pattern evoked
potential. Vision Res 1981; 21:1279.
211. Strasburger H, Remky A, Murray IJ, et al:
Objective measurement of contrast
sensitivity and visual acuity with the
steady-state visual evoked potential. Germ
J Ophthalmol 1996; 5:42.
212. Airas KA: Interindividual variation and
additivity of the visual evoked potentials to
the local checkerboard stimulation of the
central and paracentral retina. Acta
Ophthalmol 1986; 64:557.
213. Meienberg O, Kutak L, Smolenski C, et al:
Pattern reversal evoked cortical responses
in normals. A study of different methods of
stimulation and potential reproducibility.
J Neurol 1979; 222:81.
214. Sokol S, Moskowitz A, Towle VL:
Age-related changes in the latency of the
visual evoked potential: influence of check
size. Electroencephalogr Clin Neurophysiol
1981; 51:559.
215. Allen D, Tyler CW, Norcia AM: Development
of grating acuity and contrast sensitivity in
the central and peripheral visual field of the
human infant. Vision Res 1996; 36:1945.
216. Hawkes CH, Stow B: Pupil size and the
pattern evoked visual response. J Neurol
Neurosurg Psychiatry 1981; 44:90.
 CHAPTER
125 Müller Cells and the Retinal Pigment Epithelium
Vamsi K. Gullapalli, Ilene K. Sugino, and Marco A. Zarbin
MÜLLER CELLS
INTRODUCTION
Müller cells, first described by Heinrich Müller in 1851,1 often
are thought of as providing a structural framework for the
retina. They are large cells spanning the entire width of the
retina, from the internal limiting membrane (ILM) to processes
extending into the subretinal space. Müller cells belong to the
class of glial cells called astrocytes, which are characterized by a
large nucleus, prominent cellular processes, and participation in
neural homeostasis. However, Müller cells also exhibit func-
tions of another type of glia, oligodendrocytes, which supply
energy to neurons. Müller cells are truly retinal cells, as they
originate in the retina, are found exclusively in the retina, and
are the major glial cells of the retina.
OVERVIEW OF THE MÜLLER CELL AND ITS
FUNCTIONS
Based on the intricate and extensive processes emanating from
a single cell body, it is easy to imagine the Müller cell having the
function of support, as Müller cells fill all extracellular spaces in
the retina. Besides providing support for retinal neurons, Müller
cells define outer and inner boundaries of the retina. Their
endfeet terminate at the ILM, and their junctional complexes
form the outer limiting membrane (OLM). The elaborate struc-
ture of the Müller cell involves contact with all parts of the
retina, which enables Müller cells to provide functions other
than support to the various cells they contact. During retinal
development, Müller cells show extreme plasticity; they localize
to areas of the retina undergoing development and differen-
tiation and show localized development of processes in parallel
with development of the adjacent neuroblast. In the mature
retina, Müller cells provide support for adjacent cells, main-
taining control of the extracellular environment and providing
nutrients to maintain the high metabolic rate of the retina.
Additionally, Müller cells are very important in the visual cycle
of cones, providing the substrate for regeneration of cone opsin.
Regional specializations to support these functions are present
within each Müller cell.
EMBRYOLOGY AND DEVELOPMENT OF
MÜLLER CELLS
The earliest morphologically distinct step in the development of
the eye is the bilateral evagination of the diencephalon region
of the neural tube on day-25 postconception.2 However, it is
likely that the cells in this region are already committed to
the eye long before this event. Continued evagination of the
diencephalon leads to the formation of the optic vesicle that
abuts against the surface ectoderm. The cornea and lens develop
from the surface ectoderm. The optic vesicle then invaginates
on day-27 to form a bilayered optic cup. The inner layer com-
prises progenitor cells that give rise to the cells of the neural
retina; the outer layer develops into retinal pigment epithelium
(RPE). As in other parts of nervous system, the neural retina
initially consists of a neural epithelium and inner marginal
zone. The neural epithelium develops into an inner and outer
neuroblastic layer and a transient layer of Chievitz. By the
fourth month, all the layers of retina are discernible.3
Cell division generating the cells of the neural retina occurs
in two phases. In phase one, ganglion, cone, and horizontal cells
develop. In phase two, rod, bipolar, and Müller cells develop.
Amacrine cells develop during both phases.4 Animal studies
suggest that a single progenitor cell gives rise to a column of
cells containing one Müller cell ensheathing a defined number
of rod, bipolar, and amacrine cells.5
Immunohistochemical studies of fetal human tissue show
that the progenitor cell itself may differentiate into a Müller
cell.6 Müller cells are thought to be a key component in this
columnar arrangement of cells, providing nutrients, guiding
associated neurons in migration to their final positions, and
acting as a substrate for neurite outgrowth.5,7 In cell culture
experiments utilizing stratospheroids of retinal cells of two dif-
ferent species (chick and quail), Willbold and coworkers demon-
strated that spheroids composed of species-specific radial
sectors or columns form, surrounded by a Müller cell forming a
barrier to cross species cell lateral migration.8 Selective damage
to Müller cells showed their continued presence was necessary
to maintain the columnar arrangement.8 Cell recognition markers
such as L1/NgCAM, 5A11, and F11 are present in Müller cells,
which supports their role in migration and formation of radial
columns. In addition to these migration cues, Müller cells also
express barrier proteins providing negative cues that may con-
stitute a repulsive barrier (e.g., EAP-300; embryonic avian poly-
peptide and clustrin).4,8 Of note, these experiments showed that
while cross species cell migration between radial columns is
inhibited, lateral processes from Müller cells and their associ-
ated neurons can cross the species-specific border, suggesting
their role in neurite outgrowth. Studies of neonatal rat retinal
cells show that Müller cells can support long neurite extensions
in rods while other retinal neurons are less supportive.7
Morphological studies of the human fetus have demonstrated
the anatomic distribution of Müller cells during develop-
ment.9,10 Müller cells are present at gestation week-7 (20 mm)
and are present in both neuroblastic layers although they are
more common in the inner half of the inner neuroblastic layer.
Dense processes extend from the Müller cells to the surface of
the nerve fiber layer (NFL), and radial processes are found 1633
 RETINA AND VITREOUS
between ganglion cell axons. At gestation week-9 (40–43 mm),
Müller cells are the major component of the inner neuroblastic
layer, forming columns and extending across the full thickness
of the retina. Dense inner processes are present near ganglion
cells and are thought to guide the ganglion cells into the inner
retina. At 66 mm, Müller cell nuclei and outer processes are
observed between differentiating cones. By gestation week-13
(96 mm), Müller cells are present in all layers of the retina. At
159–200 mm, when the rods and cones are present, Müller cell
nuclei are still present in the outer nuclear layer (ONL), are
numerous in the inner nuclear layer (INL), and are still present
in the ganglion cell layer and NFL. At week-20 (180 mm),
Müller cell processes extend microvilli into the subretinal space.
Observations from these studies show that Müller cell pro-
cesses differentiate sequentially from the inner (vitread) to the
outer (sclerad) retina, differentiating in synchrony with the cell
on which the process abuts. Different parts of the same cell can
differentiate at different times while other processes can differ-
SECTION 10
entiate at the same time but in morphologically different ways.
It is not clear whether the differentiation of different portions of
the Müller cell is in response to the demands of adjacent cells
or if Müller cell process differentiation leads to an induction of
neuronal differentiation.10 The apparent shifts in location of
Müller cell nuclei are believed to be due to migration of the
nucleus along the cell length, cell loss, and, possibly, cell
division.9
ANATOMY
Generally, Müller cells are recognized histologically and ultra-
structurally by their relatively dense cytoplasm, which contains
numerous glycogen particles, abundant filaments measuring
100Å in diameter, and well-developed smooth endoplasmic
reticulum consisting of vesicles of varying sizes and shapes.11 In
the adult eye, Müller cells span the entire width of the retina
with their cell bodies located in the INL and nuclei located in
the middle of this layer. Radial processes (Fig. 125.1a) extend
vitread to terminate near the ILM and sclerad to contribute to
the OLM, and lateral processes extend out at all levels of the
neural retina. In the nuclear layers, lamellae form a network
surrounding cell bodies (Fig. 125.1b, ‘honeycomb meshwork’).
In the plexiform layers, processes are interwoven between
synaptic processes of neurons, ensheath dendrites, and
surround axons in the NFL (Fig. 125.1c, ‘horizontal fibers’).
Müller cells cover most, but not all, of the neuronal surfaces.
Small branches extend out to contact and surround blood
vessels along with astrocytes, forming alternate layers of astro-
cyte and Müller cell processes, completely isolating vessels from
the rest of the neural retina.12 Radial trunk extensions thin in
the inner plexiform layer (IPL), pass through the ganglion cell
layer, and intertwine with astrocytes and microglia forming an
endfoot expansion terminating at the ILM. Viewed en face, the
endfeet form a mosaic pattern. Particle arrays, referred to as
intramembranous orthogonal arrays of particles (OAPs), are
prominent in the endfeet near the vitreous surface and in areas
where processes contact blood vessels. The function of OAPs is
not certain, although based on their location, they have been
proposed to function as sites of K+ conductance.13
At their outermost ends, Müller cells exhibit junctions (zonula
adherens) between other Müller cells and photoreceptors to
form the OLM, which is thought to have a supportive function
in maintaining the alignment and orientation of the photo-
receptors.14 Extending past the OLM into the subretinal space
are long, thin apical Müller cell processes filling the spaces
between photoreceptor inner segments (Figure 125.1d, ‘fiber
baskets’).11
1634
INTERNAL
LIMITING MEM.
c NERVE
FIBER L.
GANGLION
b CELL L.
a INTERNAL
c
PLEXIFORM L.
INTERNAL
b
NUCLEAR L.
c
EXTERNAL
PLEXIFORM L.
a
a – RADIAL PROCESSES
b – HONEYCOMB
MESHWORK
EXTERNAL
b c – HORIZONTAL FIBERS NUCLEAR L.
d – FIBER BASKETS
EXTERNAL
LIMITING MEM.
d
FIGURE 125.1. Schematic drawing illustrating the complex structure
of Müller cells. Müller cells (shown with dark cytoplasm and dark
nuclei) extend radial processes (a) from the cell body to form the
internal limiting membrane of the retina surface and the external
limiting membrane facing the retinal pigment epithelium (RPE). Lateral
processes (b, honey comb meshwork) extend from the radial
processes to ensheath cell bodies of the ganglion cells, cells of the
internal (inner) nuclear layer, and cell bodies of the photoreceptors in
the external (outer) nuclear layer. Horizontal fibers (c) are found in the
plexiform layers and the nerve fiber layer where they ensheath
neurons and their processes.
From Hogan MJ, Alvarado JA, Weddall JE: Histology of the human eye.
Philadelphia: W.B. Saunders; 1971, Figure 9–57.
In the fovea centralis, Müller cell processes occupy most of
the inner third of the retinal thickness. The processes form an
inverted cone-shaped zone whose apex faces the ONL (Fig. 125.2).
In the 50 mm diameter apex of the Müller cell cone, Müller cell
processes are present with atypical watery cytoplasm separating
the foveal cone cells.15 The Müller cell cone is hypothesized to
be a reservoir for retinal xanthophylls in addition to providing
structural support for the receptor cells of the fovea.16 The
Müller cell cone is thought to be involved in idiopathic age-
related macular holes.16 The role of Müller cells in creating
structural support in the retina is illustrated by the condition,

b
b
a Line P
a
a
FIGURE 125.2. Details of the fovea centralis. The nuclei of the
photoreceptors are displaced internally (a) and the curving internal
receptor fibers are seen at (b). The lighter cytoplasm of the Müller
cells (arrow) is seen in the center of the fovea.
Legend and figure from Hogan MJ, Alvarado JA, Weddell JE: Histology of the
human eye. Philadelphia: W.B. Saunders; 1971, Figure 9–80.
juvenile X-linked retinoschisis (JXRS). JXRS is caused by
mutations in RS1, which encodes the protein, retinoschisin.
Retinoschisin is secreted by photoreceptor and bipolar cells.17–19
JXRS is a congenital disease characterized by foveal schisis in
100% of patients and peripheral retinoschisis in ~50% of
patients. The electroretinogram demonstrates reduced b-wave
amplitude and relative a-wave preservation. Visual acuity usually
is in the range of 20/40–20/60. Three dimensional optical
coherence tomography demonstrates a large cystic space in the
fovea (probably in the outer plexiform layer (OPL)) as well as
cleavage planes in the NFL, GCL, and OPL (Fig. 125.3).20
Bridging columns spanning these cystic spaces probably
represent Müller cells and demonstrate the mechanical effect of
these cells on retinal architecture.
FUNCTIONS
The complex structure of Müller cells, spanning the width of
the retina with processes extending laterally, places them in a
position to perform many different functions in the retina.
Across the width of the retina, Müller cells are thought to
control and regulate molecules and ions. In localized areas,
Müller cells can control the extracellular microenvironment
of neuronal cell bodies and synapses. Müller cells play an
important role in retinal signaling processes by removing
neurotransmitters rapidly from the extracellular space. Also,
due to intimate association with the retinal vasculature, Müller
cells are implicated in movement of substances into and out of
the retinal vessels. Specialized regions of Müller cells, located
adjacent to the regulated region of the neuron or endothelial
cell, contain the specific molecules needed to carry out these
support functions. The following sections describe some of the
functions attributed to Müller cells in the adult eye.
Regulation of the Extracellular Space
Potassium
Light-evoked neuronal activity causes an increase in extra-
cellular K+ concentration ([K+]0) in the synaptic layers while
[K+]0 decreases adjacent to the photoreceptor nuclei. One very
important function of Müller cells is the regulation of [K+]0
since fluctuations alter neuronal excitability. In a process
termed ‘K+ siphoning’,21 movement of K+ from areas of high
Müller Cells and the Retinal Pigment Epithelium
Line M
Line N
FIGURE 125.3. B-scans of 3-D OCT from a patient with juvenile
X-linked retinoschisis. Two wide hyporeflective spaces split the retina.
Anteroposterior or oblique linear columns form a bridge across a
superficial wide hyporeflective space. In the same layer, there is a
large cystoid space in the fovea (line N). This layer is probably the
outer plexiform layer. Deeper cleavage is seen in the parafoveal area
but not in the fovea (line P). This layer is probably the outer nuclear
layer. Small cystoid spaces (arrowhead) are seen in the superficial
parafoveal retina that split the retina (line M). This layer is probably the
CHAPTER 125
nerve fiber layer or the ganglion cell layer.
Reproduced with permission from Minami Y, Ishiko S, Takai Y, et al: Retinal
changes in juvenile X linked retinoschisis using three dimensional optical
coherence tomography. Br J Ophthalmol 2005; 89:1663–1664 (BMJ Publishing
Group Ltd).
[K+]0 to low concentration is thought to be achieved by
nonuniform distribution of potassium channels.22 Several types
of potassium channels have been identified in Müller cells, and
it appears that the type of channel may vary considerably
among different species.14 An important K+ channel thought to
contribute significantly to the Müller cell K+ buffering system is
the Kir channel, found in the plasma membrane. Studies per-
formed in mice identified two Kir channels with very different
subcellular concentrations.23 Kir2.1, a strongly inward rectify-
ing channel, was identified in regions of high K+ flow into
Müller cells (i.e., membrane domains localized near retinal
neurons, including the synaptic layers). These channels are
such that K+ enters more readily than it can exit; thus, these
channels are described as inwardly rectifying potassium
channels. A weakly rectifying channel (i.e., movement of K+
inward or outward depends upon the K+ concentration), Kir4.1,
was detected in Müller cells throughout the retinal layers and
was highly concentrated in the membrane domains of the endfeet
facing the vitreous humor and in membranes of processes
ensheathing blood vessels. Thus, the vitreous humor and blood
vessels may act as potassium sinks. A third Kir channel, Kir5.1,
was found in rats to be present diffusely in Müller cell bodies
and appeared to form a heteromeric channel with Kir4.1 in the
distal processes (fiber baskets, Fig. 125.1) in the subretinal
space and in processes of Müller cells located in the IPL, INL,
OPL, and ONL but not in the endfeet and processes surround-
ing blood vessels where homomeric Kir4.1 channels are found.
The properties of the two channels are different (e.g., pH
sensitivity of the Kir4.1/Kir5.1 channel), and therefore, they are
thought to play different functional roles in K+ buffering.24
Studies in rodents have shown co-localization of Kir4.1 chan-
nels with the water channel, aquaporin-4, in membrane domains
facing the vitreous humor and blood vessels, indicating that
potassium and water movement are closely linked in Müller
cells. The localized distribution of aquaporin in Müller cell mem-
branes indicates that Müller cells mediate osmotic gradients
associated with K+ movement and function to direct water flux
to specific extracellular compartments. The tight co-localiza-
tion of the two channels may support the movement of K+
while preventing osmotic imbalances in the retina.25
Another type of potassium channel, the tandem pore chan-
nels TASK-1 and TASK-2, has been localized in the cell body
1635
 RETINA AND VITREOUS
and fiber baskets of mammalian Müller cells (e.g., rat, mouse,
and guinea pig). These channels, along with Kir 4.1 channels,
are thought to maintain the negative resting potential of Müller
cells in nonpathological conditions and could play a minor role
in K+ siphoning. Skatchkov et al. suggest these channels are
important in maintaining membrane hyperpolarization in areas
where Kir4.1 channels are sparse and strongly rectifying
channels, such as Kir2.1, are located (e.g., photoreceptor cell
bodies). TASK channels may become important in potassium
regulation when Kir4.1 channels are downregulated (see section
on Müller cell gliosis).26
CO2 and pH regulation
The high metabolic rate of the retina leads to the generation
of large amounts of CO2. Müller and RPE cells contain the
sodium–bicarbonate co-transporter, pNBC1,27 and large stores
of carbonic anhydrase, an enzyme that converts CO2 to bicar-
bonate in a reaction helping to maintain the extracellular pH.28
SECTION 10
One form of carbonic anhydrase, CAXIV, is located in the
membrane domains of Müller cells facing the photoreceptors
and is also enriched in the Müller cell endfeet. The presence of
CAXIV in the Müller cell endfeet has led to the notion that the
endfeet are a clearance route for CO2 to the vitreous cavity and
retinal blood vessels.28
Neurotransmitter uptake and conversion
Müller cells are important in regulating the extracellular levels
of glutamate, the major excitatory transmitter of neurons of the
retina, and g-aminobutyric acid (GABA), the major inhibitory
transmitter. Potent uptake systems and degradative pathways
exist for both transmitters in Müller cells. Glutamate is also
taken up by neurons where it is recycled, but in Müller cells it
is thought to be inactivated by conversion to glutamine in a
reversible reaction catalyzed by glutamine synthetase, which in
the retina is present only in Müller cells. The conversion of
glutamate to glutamine involves ammonia fixation, ammonia
production being associated with increased synaptic activity.
Thus, another important function of Müller cells may be extra-
cellular ammonia detoxification.29 Both glutamine synthetase
and the Müller cell-specific glutamine transporter, GLAST (L-
glutamate–L-aspartate transporter), are co-localized in the fine
horizontal processes of Müller cells that ensheath rod photo-
receptor synaptic terminals.30
Müller cells contain GABA transporters (GAT-1 and GAT-3)
and the GABA-degrading enzymes, GABA-transaminase
(GABA-t) and succinic semialdehyde dehydrogenase (SSADH),
located in mitochondria, indicating their role in the regulation
of GABA concentration in the extracellular space. In mam-
malian Müller cells, the predominant transporter is GAT-3,
which is found in the plasma membrane throughout the cell.31
Once transported into the cell, GABA and a-ketoglutarate are
catalyzed by GABA-t to glutamate and succinic semialdehyde.
Succinic semialdehyde is then degraded by SSADH to succinate,
which can then enter the tricarboxylic acid cycle.14
Glycogen Metabolism
Müller cells are thought to play a central role in maintaining the
nutritional needs of the retina (see Winkler et. al and references
therein32). Glucose is thought to be transported from the blood
by Müller cells via facilitated diffusion mediated by the glucose
transporter, GLUT 1, converted into glycogen, and stored.33
GLUT 1 has been demonstrated in the plasma membrane of
human Müller cells.33 (GLUT 2 has been localized to the apical
processes of rat Müller cells (fiber baskets of Fig. 125.1),
indicating one possible function for these structures.34) Müller
cells contain the metabolic pathways for glycogen deposition
1636 and are the sole site of glycogen storage in the retina. Glucose
Cone Müller cell
Light E
X 11-cis-retinal
T
R RGR
A all-trans-retinal
11-cis-retinal C
11-cis-retinol E
L RDH10
all-trans-retinal L
U
11-cis-retinol
L
all-trans-retinol A
(vitamin A) R all-trans-retinol
S isomerase
P
A
C
E
FIGURE 125.4. Cone opsin recycling pathway in Müller cells.
Generation of 11-cis-retinol from all-trans-retinol (released into the
extracellular space) (black text).35,36 Proposed generation of 11-cis-
retinal from all-trans-retinol involving the enzymes, retinal G protein-
coupled receptor (RGR) and all-trans retinol dehydrogenase (RDH10)
(blue text).37
uptake is thought to be stimulated by synaptically released
glutamate.29 Similarly, glycogen breakdown and release of
metabolic substrates is thought to be regulated by neuroactive
substances released by neurons.14
Visual Pigment Recycling
In studies of cone-dominant eyes of chicken and ground
squirrel, Müller cells were found to contain an alternate visual
cycle for cone opsin regeneration that is distinct from the visual
cycle in RPE cells (Fig. 125.4, cycle indicated with black text
and black arrows). All-trans-retinol, which is released into the
extracellular space by rods and cones following light activation
of an opsin pigment molecule, can be taken up by Müller cells,
directly converted to 11-cis-retinol by a unique all-trans-retinol
isomerase, and bound by cellular retinaldehyde binding protein
(CRALBP). The 11-cis-retinol is released into the extracellular
space where it can be taken up by cones for regeneration of
visual pigment utilizing the cone-specific 11-cis-dehydrogenase.
Both 11-cis-retinol and all-trans-retinol are bound to interpho-
toreceptor retinoid binding protein (IRBP) during translocation
between the cones and Müller cells.35 The energy source for this
isomerization may be a palmitoyl CoA-dependent esterification
of 11-cis-retinol and all-trans-retinol.35,36
In RPE cells, RDH10 (an all-trans-retinol dehydrogenase)
oxidizes all-trans-retinol to all-trans-retinal in the photic visual
cycle (see section on Role in Visual Cycle in The Retinal
Pigment Epithelium). When exposed to light, the RPE retinal G
protein-coupled receptor (RGR) isomerizes all-trans-retinal to
11-cis-retinal. Both RDH10 and RGR have been found in
Müller cells (although in lower levels than found in RPE),
indicating the possibility that Müller cells can generate 11-cis-
retinal from all-trans-retinol utilizing mechanisms similar to
those found in RPE cells (Fig. 125.4, proposed cycle indicated by
blue text and blue arrows).37
Neuronal Activation of Müller Cells
As noted above, Müller cells affect the function of retinal
neurons by regulating the extracellular environment. However,
neurons seem to be able to affect Müller cells directly by
neuronal signaling. Light stimulation of the retina, for example,
results in a transient increase in Ca2+ in the Müller cell

processes located in the IPL, which spreads to the cell endfeet at
the vitreal surface. The resultant release of ATP by Müller cells
is thought to enhance or depress neuronal activity in a neuronal
excitability feedback mechanism.38
Müller Cell Contribution to the ERG
Early studies by Witkovsky39 on isolated retina showed that
Müller cells contribute to the negative slow PIII of the c-wave of
the ERG. The Müller cell response was attributed to the photo-
receptor-dependent light-evoked decrease in subretinal extra-
cellular [K+]0.40 (RPE contributes to the positive component
of the c-wave; please see section, Ion Transport in The Retinal
Pigment Epithelium). Further evidence indicating that K+
movement by Müller cells contributes to the ERG is the loss of
the PIII wave in Kir4.1 knockout animals.41 Some studies
indicate that K+ buffering by Müller cells may also contribute to
the b-wave although conflicting studies attribute the b-wave to
depolarizing bipolar cells.14 The lack of change in the b-wave
response in the Kir4.1 knockout mice supports the neuronal
origin of the b-wave.41
Phagocytosis
Müller cells can phagocytose a variety of substances (e.g., latex
beads, carbon, copper particles, blood cells) and are thought to
assist the RPE cells in phagocytosis of outer segments.14 In devel-
opment and in retinal disease, Müller cells can phagocytose
debris from dying neurons.42 Also, the phagocytotic capacity of
Müller cells may aid in maintaining the clarity of the vitreous
humor.42
PATHOLOGY
Müller cells play a prominent role in injury and diseases of the
retina. They exhibit the ability to respond to subtle insults by
modulation of normal functions (e.g., moderating the rise in
extracellular K+ and glutamate following plasma leakage into
the retina43) as well as the ability to undergo marked functional
and morphological change in response to more severe insults.
Müller cells can undergo cell division and migration.44 Müller
cells can respond to a number of growth factors, cytokines, and
neurotransmitters derived from photoreceptors and other
neurons and RPE cells. In pathological conditions, inflam-
matory cells, platelets, and plasma can activate Müller cells.45
Some Müller cell responses are related to tissue repair (e.g.,
resurfacing of Bruch’s membrane following RPE and photo-
receptor loss to maintain the blood–retina barrier in atrophic
macular lesions14) and wound healing (e.g., Müller cell wound
closure of the OLM following macular hole repair by vitrectomy
with cortical vitreous and epicortical vitreous membrane
peeling46) while other responses are related to neuroprotection
(see section on Growth Factor, Cytokine, and Neurotrophic
Factor Secretion) and detoxification (e.g., Müller cell response to
elevated ammonia levels in hepatic retinopathy47,48).
Additionally, since Müller cells play a prominent role in
retinal homeostasis, any dysfunction involving Müller cells can
have a profound effect on retinal function. For example, long-
term replacement of the vitreous with a fluid, such as perfluoro-
carbon or silicon oil, incapable of acting as a K+ sink could
interfere with Kir function and might lead to outer retina
degeneration especially when little vitreous fluid remains.49
Similarly, damage to the Müller cell endfeet, such as occurs in
retinoschisis, would impair spatial K+ buffering capabilities of
damaged cells.42 In a study comparing healthy versus diseased
eyes, Müller cell ion channels appeared to be affected in the
diseased eye. For example, changes in Müller cell membrane
properties (e.g., down-regulation of Kir current density) have
been found in diseased retinae from human eyes with secondary
Müller Cells and the Retinal Pigment Epithelium
glaucoma, mechanical injury, choroidal melanoma, and retinal
tissue obtained from partial retinectomies to relieve traction.50,51
Loss or diminished activity of ion channels can lead to a change
in the Müller cell membrane potential and affect the ability of
Müller cells to take up glutamate. Since glutamate is highly toxic
to the photoreceptors, extracellular regulation of glutamate is
critical for vision preservation.50,52,53
Although there are no diseases of the retina in which Müller
cells are known to be the primary site affected, Müller cells
appear to be involved in many retinal disorders.14 The role of
Müller cells in specific diseases is addressed elsewhere
(Chapters 182 and 183). Müller cell responses in general are
discussed in the following sections.
Müller Cell Gliosis
Pathologies involving neuronal degeneration in the retina
appear to be associated with some level of Müller cell activation
(gliosis).44 Müller cell response or activation can be detrimental
CHAPTER 125
or beneficial, depending on the magnitude of the response. For
example, Müller cell activation can be beneficial if modest, as
activation could be helpful due to increased growth factor
secretion by the cells (see section on Neuroprotection). If gliosis
results in proliferation and/or is long-lasting, gliosis can lead to
neuronal degeneration (e.g., subretinal fibrosis following retinal
detachment and epiretinal membrane formation leading to
retinal detachment).54 Müller cell activation can be detected by
upregulation of the intermediate filaments, vimentin and glial
fibrillary acidic protein (GFAP). Since GFAP expression is not
detected in healthy retinas, GFAP detection can be used as an
early indicator of reactive Müller cells.14 Another early indicator
of Müller cell activation is activation of ERKs (extracellular
signal-regulated kinases) and release of neuroprotective growth
factors (see section on Growth Factor, Cytokine, and Neuro-
trophic Factor Secretion).55 Gliosis can lead to changes in cell
shape including changes to or loss of processes.56 In the
detached retina, gliotic responses also include downregulation
of glutamine synthetase, cellular retinaldehyde-binding protein,
K+ channel expression, and carbonic anhydrase.57 Studies per-
formed in rats (ischemia model), pigs, and rabbits (detachment
models) show that one of the consequences of Müller cell
activation can be the loss or relocation of Kir4.1 channels.
Impairment of potassium buffering capabilities through loss of
Kir channels could lead to the inability of the cells to maintain
their hyperpolarized state and thus lead to breakdown of normal
homeostasis (e.g., K+ buffering and water regulation) resulting
in edema and retinal degeneration.57–59 In the rabbit and pig
detachment models, and as sometimes occurs in patients
following retinal reattachment, loss of photoreceptors (or visual
function) can be seen in attached areas adjacent to the
reattached retina. This loss is attributed to activation of Müller
cells adjacent to the area of detachment.57,59
As previously mentioned, Müller cells can respond to a
number of stimuli, in particular mitogenic growth factors.45
Blood-derived factors (e.g., thrombin) released from the break-
down of the blood–brain barrier may trigger the proliferative
response through downregulation of Kir channels.45,60 In
addition to Kir channels, which mediate potassium levels
during light-activated K+ elevation in the extracellular space (K+
siphoning), Müller cells express other ion channels including
Ca2+-activated K+ channels.60 Studies comparing Müller cells
from diseased and healthy retinae show impaired K+
conductance due to loss of Kir channels in cells from diseased
retinae although Ca2+-dependent K+ channels are activated.50,52
The Ca2+-dependent K+ channels are activated when the mem-
brane potential of the cell is markedly reduced (as in patho-
logical conditions when the Kir channels are lost) and are not
thought to play an important role in potassium siphoning in the 1637
 RETINA AND VITREOUS
normal retina.61 Müller cell proliferation can be triggered by
mechanisms activating these Ca2+-dependent K+ channels.60
The mechanism of Ca2+-dependent K+ channels activation is
thought to be through activation of P2 receptors. The P2Y
receptor, minimally active in healthy retinae, is activated by
ATP. Following P2Y receptor activation, the cells become
unresponsive to ATP and cease to proliferate. The receptors can
be re-sensitized to ATP following exposure to growth factors
(e.g., platelet-derived growth factor (PDGF), epidermal growth
factor (EGF) and nerve growth factor (NGF).57,62
Müller cell proliferation also can be initiated by mitogenic
growth factors. Basic fibroblast growth factor (bFGF), which
has been shown to be released intraretinally following injury
(mechanical or light-induced) and retinal detachment, is a
potent growth factor in Müller cell activation and proliferation.
Other growth factors shown to evoke Müller cell proliferation
include PDGF, heparin-binding epidermal growth factor (HB-
EGF), and transforming growth factors (TGF).63
SECTION 10
Neuroprotection
Elevation of the extracellular glutamate concentration is highly
toxic to retinal neurons.56 Extracellular glutamate concentra-
tions are highly regulated through Müller cell uptake involving
the GLAST transporter. Excess glutamate can be generated in a
variety of retinal conditions including ischemia, hypoglycemia,
glaucoma, diabetes, and trauma.14,56 Accordingly, some studies
have correlated increases in GLAST activity with elevated
glutamate levels.56 However, in diabetic retinopathy, GLAST
levels appear to decrease (possibly due to oxidative damage since
the effects can be reversed by exposure to a disulfide-reducing
agent) leading to elevated glutamate levels and resultant glutamate
excitotoxicity.64,65
Studies in rodents have shown that intraocular injection of
neurotrophic factors can promote photoreceptor survival in
retinal degenerations caused by genetic or environmental
factors.66–68 Neuroprotection of photoreceptors following injec-
tion of growth factors (e.g., brain-derived neurotrophic factor
(BDNF), ciliary neurotrophic factor (CNTF), neurotrophin-3
(NT-3), or bFGF) is thought to be mediated by activation of
Müller cells, since photoreceptors are not activated by exposure
to these growth factors as indicated by lack of intracellular sig-
naling pathway activation.69,70 Sustained growth factor delivery
by viral vectors to activate Müller cells offers a possible treat-
ment to prevent retinal degeneration.71,72 The mechanism by
which activated Müller cells affect photoreceptor survival is not
known.
Nitric Oxide Synthetase
Nitric oxide synthetase (NOS) catalyzes the formation of highly
reactive nitric oxide (NO) from L-arginine. Nitric oxide has
been implicated in the regulation of retinal blood flow, in visual
transduction, and is toxic to microorganisms.73 As such, NO
may also contribute to retinal pathology and has been impli-
cated in reperfusion injury following ischemia, diabetic vascular
damage, HIV retinitis, and endotoxin-induced uveitis.73,74
Histochemical staining for NOS has shown its presence
throughout the retina;73 mRNA for inducible and constitutive
forms of nitric oxide synthetase (iNOS and cNOS, respectively)
have been found in human retinal tissue.75 cNOS is calcium-
dependent; iNOS is calcium-independent. iNOS is expressed in
Müller cells following stimulation by interferon (IFN)-g and
lipopolysaccharide76 and, following upregulation, can produce
sustained levels of NO. cNOS (found in mammalian Müller
cells of mice77 and the tree shrew,78) is relatively short-lived and
produces picomolar quantities of NO.73 (iNOS has also been
detected in human RPE following stimulation by interleukin-1
1638 and IFN.73) mRNA for iNOS found in Müller cells of mice is
similar in size to that of macrophage iNOS and thus may
be important as a reactive mediator in inflammation and
infection.79 However, the exact role of iNOS in pathology and
regulation of NO by Müller cells is not understood fully.
Müller Cell Immune Modulation
Experimental evidence from in vitro cell culture studies
indicates that Müller cells may provide an immune modulation
function in the retina. Müller cells, along with RPE and vascular
endothelial cells, have been shown to express MHC class II
(MHCII) antigens.14 Müller cells from rat retina can be induced
to proliferate following addition of conditioned media from
activated spleen cells or activated lymphocytes and can express
MHCII antigens.80 Müller cells in the human eye of a patient
with hypopigmented subretinal fibrosis and uveitis syndrome
were shown to express MHCII antigens by immunohisto-
chemical staining.81 However, when Müller cells expressing
MHCII antigens were cultured with activated T cells,
proliferation of the latter was inhibited. The prevention of T cell
proliferation required physical contact between Müller cells and
T cells, indicating that the inhibition was through a membrane
bound protein present in the cells.82 When this membrane
bound protein is inhibited (e.g., using glucocorticoids), Müller
cells can function as an antigen presenting cell.83 Thus, Müller
cells have the potential to inhibit or stimulate T cell prolifera-
tion. Since lymphocytes migrating out of retinal capillaries con-
tact Müller cells, the interaction between the two cells could
either suppress retinal inflammation or enhance it.14
Growth Factor, Cytokine, and Neurotrophic Factor
Secretion
Müller cells and RPE can up-regulate the expression of growth
factors, cytokines, and neurotrophic factors in response to
retinal injury or other stimuli (Table 125.1).84 In addition to
acting on photoreceptors, Müller cells also may be involved in
ganglion cell and bipolar cell neuroprotection.56 Secreted growth
factors such as bFGF, VEGF (vascular endothelial growth
factor), and PEDF (pigment epithelium-derived factor) appear
to provide constitutive trophic support to the photoreceptors
and vascular endothelia.85–87 Changes in the endogenous
concentration of these growth factors can affect surrounding
cells. For example, PEDF downregulation results in increased
Müller cell secretion of VEGF and TNF-a (tumor necrosis
factor), which may contribute to inflammation and vascular
changes associated with diabetic retinopathy.86,87 Müller cells
contribute to the endogenous levels of VEGF, PEDF, TGF-b2,
TSP-1 (thrombospondin), BDNF, and bFGF.88–90 Changes in
bFGF secretion by Müller cells can result in either protection
(increased bFGF secretion) or increased apoptosis (decreased
bFGF secretion) in adjacent photoreceptors.91 Microglia are
an endogenous source of growth factors leading to Müller cell
stimulation resulting in increased (e.g., NT-3) or decreased (e.g.,
NGF) bFGF secretion.92
Both in vivo and in vitro studies show that Müller cells respond
to many different stimuli and can secrete different growth factors,
depending on the stimulus or culturing conditions (Table 125.1).
In addition to providing neuroprotective growth factors and
factors capable of modulating blood flow and vascular
permeability, Müller cells can produce several pro-inflammatory
cytokines in response to viral infections.93,94
Two types of receptors, Trk (high-affinity neurotrophin
tyrosine kinase receptor) and p75 (low-affinity neurotrophin
receptor), have been identified in pro-survival (Trk) and anti-
survival (p75) signaling by neurotrophins.104 In a light damaged
mouse model, enhanced TrK and p75 labeling was localized to
different parts of Müller cells.92 These studies showed photo-
receptor survival following light damage with p75 blockade
 Müller Cells and the Retinal Pigment Epithelium

TABLE 125.1. Müller Cell Growth Factor, Cytokine, and Neurotrophin Secretion Following Stimulation

Growth Factor Secreted Stimulus Model Associated Retina Pathology or Function References
95
BDNF, NGF, NT-3, NT-4, Glutamate Cultured rat MC Neuroprotection during glutamate toxicity
GDNF
96
VEGF TGF-b, hypoxia Cultured rat MC Hypoxia-induced angiogenesis
97
TNF-a, NO IFN-g and LPS RCS cultured PR degeneration in retinal dystrophies
rat MC
93,94
TNF-a, IL-6, IFN-a, IFN-b HSV-1, IFN-g Mouse and Immune and inflammatory responses
cultured mouse MC
44
bFGF, CNTF, GDNF Light, mechanical Light damaged rat Neuroprotection
98,99
injury
88
VEGF, TSP-1 Hypoxia Cultured human TSP-1 angiogenesis inhibition; VEGF
MIO-M1 cells and angiogenesis induction
guinea-pig MC

CHAPTER 125
100
VEGF HB-EGF MIO-M1 PVR
87
VEGF, TNF-a Reduced PEDF level Cultured rat MC Diabetic retinopathy
101
VEGF Advanced glycation Cultured human Diabetic retinopathy
endproducts (AGE) MC
102
bFGF bFGF Cultured rat MC Injury response to secreted bFGF
(neuroprotection)
92
bFGF NT-3 Cultured rat MC Neuroprotection
103
CNTF Optic nerve damage rat Neuroprotection
BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; NT, neurotrophin; GDNF, glial cell line-derived neurotrophic factor; MC, Müller cells; VEGF, vascular
endothelial growth factor; TGF, transforming growth factor; TNF, tumor necrosis factor; NO, nitric oxide; IFN, interferon; LPS, lipopolysaccharide; RCS, Royal College of
Surgeons; PR, photoreceptor; IL, interleukin; HSV-1, herpes simplex virus type 1; bFGF, basic fibroblast growth factor; CNTF, ciliary neurotrophic factor; TSP,
thrombospondin; MIO-M1, spontaneously immortalized human Müller cell line; HB-EGF, heparin-binding epidermal growth factor-like growth factor; PVR, proliferative
vitreoretinopathy; PEDF, pigment epithelium-derived factor.

or p75 absence in p75 knockout mice p75 activation was
hypothesized to suppress growth factor release. Based on the
results of experimental studies in different model systems, it
may be that p75 signaling is not the main pathway mediating
cell death by Müller cells.105–107 Additional stress pathways or
impairment of survival signals such as those initiated by TrK
receptors may be required for p75 mediated activation of cell
death.104
of the vision-mediating visual pigments of the photoreceptors,
transport from the systemic circulation of molecules necessary
for the structure and function of photoreceptors and
maintenance of a dry, pH-balanced, and immune-privileged
subretinal space. Unlike Müller cells, RPE are easy to study,
isolate, and culture. This fact has resulted in a vast and rich
database of knowledge on RPE structure and function.108,109
This chapter provides a broad introduction to the RPE.

FUTURE DEVELOPMENTS EMBRYOLOGY AND DEVELOPMENT OF RPE

Müller cells have complex involvement in a variety of functions
in the developing, normal, and pathological retina. Much work
remains to be done to characterize and clarify the mechanisms
involved in retinal homeostasis, particularly in the human eye.
Additionally, the mechanisms underlying the morphological,
cellular, and molecular changes Müller cells undergo as part of
the retina’s pathophysiological responses are not understood
fully. Future studies will lead to insights to these unanswered
questions, which should foster the development of therapies
specifically targeting Müller cell reactivity or dysfunction in
retinal pathology.
THE RETINAL PIGMENT EPITHELIUM
OVERVIEW OF THE RETINAL PIGMENT
EPITHELIAL CELL AND ITS FUNCTIONS
Retinal pigment epithelium (RPE) is a simple monolayer of
postmitotic, melanin-laden cells lying between the photorecep-
tors and the choroid but serving functions that are critical to the
eye. These include the formation of a blood–retinal barrier,
phagocytosis of the photoreceptor outer segments (OS), recycling
RPE progenitors originate from the dorsal portion of the optic
vesicle (Fig. 125.5). Cells in the early stages of optic vesicle
development are similar morphologically and molecularly and
express numerous transcription factors (e.g., Otx2, Pax6, Rx1,
Six3)110 that initiate eye development (Fig. 125.5). At this stage,
all the cells of the optic vesicle can give rise to the neural retina,
optic stalk, or RPE.111–113 Signals from the surrounding tissues
determine the fate of different regions of the optic vesicle, e.g.,
whether the cells develop into RPE or neural retina. The surface
ectoderm generates signals that promote neural retinal develop-
ment and suppress RPE development.114 These signals are
molecules that belong to the FGF family. Thus, the outer rim
of optic vesicle adjacent to the surface ectoderm (that later
invaginates to form the inner layer of the optic cup) eventually
develops into the neural retina rather than into RPE.115,116
Conversely, the mesenchyme surrounding the posterior aspect
of the optic vesicle (the prospective RPE) generates signals that
activate the RPE development pathway and suppress neural
retinal pathway.117 Members of TGF-b superfamily have been
shown to play a role.117,118 These signals act on the target cells
and activate or suppress transcription factors like Mitf
(microphthalmia-associated transcription factor),119,120 Otx 1639
 RETINA AND VITREOUS

A 1 2 3
presumptive neural retina
extraocular RPE
RPE
mesenchyme
lens

lens placode
lens pit

presumptive
neural retina

optic stalk optic nerve

optic vesicle

B 1 2 3

extraocular
mesenchyme

Otx2
SECTION 10

TGF-b like Otx Wnt Pax6 Wnt

Otx1 Otx
Pax6 Mitf Hh
Mitf
Six3
Rx1
prospective RPE BMP
melanogenic
genes
Otx2 Pax6 Rx1
Otx1
Pax6 Six3 Chx10 differentiated RPE
Six3
Rx1 FGF
prospective neural retina

lens placode
naive optic vesicle patterned optic vesicle RPE of the optic cup

FIGURE 125.5. Diagrammatic representation of the development of the RPE. A. The optic vesicle develops as an outpouching of the diencephalon
(A-1). The vesicle invaginates to form an optic cup (A2, and A3). Signals from the surface ectoderm (e.g., FGF and others) (A-1) promote neural
retinal development (A3) from the ventral part of the optic vesicle while the dorsal part of the optic vesicle develops into the RPE following activation
by signals (e.g., TGF-b) from the adjacent mesenchyme. B. Until the activation of signals specifying the fate, the cells of the optic vesicle are
indistinguishable (multiple colors). TGF-b from extraocular mesenchyme favors development of RPE while FGF from the lens placode suppresses
RPE development and favors neural retinal development (B1). Different transcription factors activated by the extracellular signals become
confined to prospective RPE and prospective neural retina (B2). The interaction of the activated transcription factors with other regulatory
molecules consolidates the identity of the cells and promotes differentiation. Otx: orthodenticle-related transcription factor; Pax6: paired-box
transcription factor; Hh: hedgehog; BMP: bone morphogenetic protein; Wnt: wingless and integration site gene; Six: sine oculis homeobox;
Chx10: C.elegans ceh-10 homeo domain containing homolog; Mitf: microphthalmia-associated transcription factor; Rx: retina homeobox.
See text for details. Figure based on Martinez-Morales JR, Rodrigo I, Bovolenta P: Eye development: a view from the retina pigmented epithelium. Bioessays 2004;
26:766–777. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. copyright 2004.

(orthodenticle-related transcription factors),121,122 and Pax6
(paired-box transcription factors).123,124 Mitf, for example, binds
and transactivates the genes involved in terminal differentiation
of RPE, including tyrosinase.119 Further differentiation of
RPE may be influenced by a different set of signaling factors,
including bone morphogenetic protein (BMP)125 and hedgehog
(Hh)126,127 families and cell-cycle regulators. The factors men-
tioned above are not unique to RPE. How these factors promote
formation of RPE in the optic vesicle and different structures in
different parts of the forebrain is not clearly understood.
By day-30, the invagination is complete, and the two layers of
the optic vesicle are apposed. RPE initially is pseudostratified
but matures into a monolayer.3 On day-35, melanin granules
appear in RPE cells. This is the earliest site of pigmentation
in the body. By 6-weeks gestation, RPE basement membrane
becomes evident, and by 10-weeks, the apical processes develop.
Further differentiation results in apicobasal polarity and for-
mation of tight junctions to establish the outer blood–retinal
barrier. Development of tight junctions occurs in three stages.
In the first stage, specific proteins, g-tubulin in the apical
portions of the cells, and a1b3 integrin in basal portions are
expressed, but tight junctions are rudimentary. In the second
stage, Na+–K+–ATPase is apically polarized. In the final stage,
mature tight junctions composed of ZO-1, occludin, and
claudin are formed.128
In accordance with a general theme of development, inter-
action of the RPE with the surrounding structures is important
1640 for RPE development and maturation. Conversely, RPE is
important for development of the adjacent neural retina,
choroid, and sclera.129,130
The presence of RPE is necessary for the formation of photo-
receptor discs131 and photoreceptor differentiation.132 Loss of
RPE leads to improper retinal development.129,131 Neural retinal
development (generation of cells and differentiation) occurs along
a gradient starting in the center and extending to periphery.133,134
RPE maturation precedes neural retinal maturation135 but retinal
development does not depend solely on RPE (e.g., hedgehog
signaling from ganglion cells is important for the development
of laminar organization of neural retina127). Photoreceptors also
influence development of RPE. Neural cell adhesion molecule
(NCAM) localization to apical regions of RPE, for example,
requires the presence of photoreceptors; absence of photo-
receptors leads to basolateral redistribution.136 One possible
mechanism by which RPE may be influencing development of
neural retina is by release of a soluble factor.129,137 This factor is
believed to be ATP, and it increases cell proliferation in the
neural retina.138 Melanin-related agents in RPE appear to be
responsible for some aspects of retinal development. Human
albino eyes can exhibit foveal hypoplasia and have abnormal
chiasmal projections.139,140 Lack of pigment results in temporal
delay in neural retinal differentiation as well as abnormalities in
ganglion cell axon decussation (i.e., greater numbers of crossed
fibers compared to pigmented eyes). These retinae are under-
developed with abnormally thin INLs and ONLs. There is a rod
cell deficit (30%), but the cone cell numbers and cone mosaic
are unaffected.140

RPE cells also may play a role in melanocyte differentiation
and vascular development in the choroid.130 RPE secretes
growth factors that influence endothelial cell and photoreceptor
differentiation.141–144 Through its transport capabilities, RPE
may relay growth regulating signals from the neural retina that
influence choroidal and scleral growth, thereby potentially
modulating the development of the latter structures.145 RPE is
capable of secreting all the components of Bruch’s membrane.146
Bruch’s membrane layers develop sequentially from inside-out,
i.e., the RPE basement membrane forms first, followed by pro-
gressive development of the outer laminae. The choriocapillaris
basement membrane is the last layer to form.147,148
ANATOMY AND CELL BIOLOGY
RPE forms a monolayer of cells sclerad to the neural retina,
extending from the edge of the optic disc, posteriorly, to the ora
serrata, anteriorly. When viewed en face, the cells appear
hexagonal. In cross section, cells are cuboidal and contain a
basally located nucleus and apically located pigment granules.
The RPE size varies with the location in the eye; submacular
RPE cells have a diameter of 14 mm and are 10–14 mm tall. RPE
in the peripheral regions, especially near the ora serrata, are
flatter and can have a diameter of up to 60 mm.149,150 The RPE
apical surface is characterized by numerous microvilli, which
are of two different lengths; fine, filopodia-like microvilli of
5–7 mm in length interdigitate with the photoreceptor outer seg-
ments; shorter, broader, lamellopodia-like microvilli of ~3 mm
length enclose the tips of the OS (Fig. 125.6). The basal RPE
surface exhibits complex infoldings that may extend 1 mm or
more into the cytoplasm. The RPE rests on Bruch’s membrane,
which is a pentalaminar structure that includes the RPE base-
ment membrane (on which RPE rests directly), the inner
collagenous layer, the elastic layer, the outer collagenous layer,
and the choriocapillaris basement membrane.
There are ~4–6 million RPE cells in each human eye. The
cell density decreases from center (4000 cells/mm) to mid-
periphery (3000 cells/mm) to far periphery (1600 cells/mm).151
This distribution is likely due to the growth of the eye being
confined to the ora–equatorial region from infancy to adoles-
cence and the lack of RPE cell proliferation after development.
RPE cells increase in size in the peripheral region near the ora
serrata from infancy to adolescence. In the periphery, RPE cell
density is highest in the nasal quadrant; all other quadrants
have a lower packing density. Cell density decreases by ~0.3%
per year with increasing age, most marked under the fovea and
mid-peripheral retina.151 This rate of loss is more in blacks than
in whites.152 Cell number or cell density is not affected by
gender, but it correlates with rod cell density. The rod:RPE ratio
is 0 in the fovea and increases to ~19 rods for every RPE in the
periphery.151 In the periphery, ratio of RPE to rods is highest in
the nasal followed by the superior quadrant. The other two
quadrants have similar densities. The cone:RPE ratio is highest
under the fovea (~40 cones/RPE), declines toward mid-
periphery (~1), and increases toward the far periphery because
of high cone density in that region.151,153 The ratio of RPE cells
to photoreceptors does not change with age because the cone
and rod numbers also decline with age.152,154–158 Hexagonal
shape is lost under the foveal area with age.159
In addition to the topographic variation, there is cell-to-cell
heterogeneity in the RPE monolayer. This heterogeneity has
been termed cellular mosaicism-patches of cells of varying
phenotype forming the monolayer, cells within a patch being
identical but differing from cells in an adjacent patch.160
The RPE nucleus is 5–12 mm in diameter and is somewhat
oval with the long axis parallel to the basal surface. The nucleus
contains one or two nucleoli and diffusely distributed chro-
Müller Cells and the Retinal Pigment Epithelium
matin. Many RPE are bi- or multinucleated (one out of 30 RPE
have multiple nuclei), more commonly in peripheral RPE
cells.149,161 Mitosis has not been seen in adult RPE cells in situ.
If there is a defect resulting from cell loss due to any reason, the
neighboring cells spread to fill in the defect.162 However, RPE
are capable of proliferating if cells are isolated and grown in
culture.
RPE cell cytoplasm contains mitochondria (present mostly
between the nucleus and the basal surface) and extensive
smooth endoplasmic reticulum (characteristic of only one other
cell in the eye, the Müller cell). In the periphery, the amount of
smooth endoplasmic reticulum is lower, but cells have more
rough endoplasmic reticulum (present in the apical portion
of the cell). RPE cells contain lysosomal granules, melanin
granules, and lipofuscin. Pigment granules measure 2–3 mm in
length and 1 mm in diameter. They are present mostly in the apical
portion of the cell. The granules are either ovoid or needle
shaped, the former located in perinuclear cytoplasm and the
CHAPTER 125
latter near the apical region. Melanin granules may fuse with
lysosomal granules or lipofuscin to form complex melano-
lysosomal or melanolipofuscin granules. The content of ‘pure’
melanin declines with age, whereas the number of complex
melanin granules increases. Submacular RPE cells contain more
complex granules than RPE elsewhere, particularly in young
eyes. With age, lipofuscin granules increase in RPE cells, the
largest increase occurring between the first and second decade
of life. Due to the increase in granules, cytoplasmic volume not
occupied by pigments (‘free space’) decreases with age.163
The RPE is polarized with a distinct distribution of molecules
and ion channels on the apical and basal surfaces. For example,
the apical membrane contains avb5 integrin and Na+–K+–ATPase
while the basal membrane contains a6b1 integrin. The polarity
is achieved by a specific distribution of molecules to either
surface and is maintained by the presence of tight junctions
that prevents intra-membrane diffusion of molecules between
the apical and basal domains of the cell membrane.164 Organ-
ization of the cytoskeletal elements also helps to maintain the
polarity.165
Laterally, RPE connect with each other via tight junctions
(zonula occludens [ZO]), adherens junctions (zonula adherens),
and gap junctions.365 Tight junctions are responsible for the
barrier function of RPE monolayer. In freeze-fracture images,
tight junctions appear as ‘sealing strands’ encircling the cell
near the apex. By transmission electron microscopy, the tight
junctions appear as close apposition of the plasma membrane of
adjacent cells near their apices. These strands are extracellular
domains of tight junction proteins claudin and occludin.164 The
cytoplasmic side of the cell membrane contains ZO proteins,
ZO-1 and ZO-2, that connect to the actin filaments present
in the cytoplasm as well as activate signal transduction
pathways.164
The zonula adherens is formed by interaction of cadherin
molecules. These junctions appear as a 200Å separation between
the plasma membranes of adjacent cells. The cytoplasmic domain
of cadherins interacts with vinculin, catenins, a-actinins, and
actin filaments. Actin filaments are arranged circumferentially
and maintain the hexagonal shape of RPE cells. Gap junctions
are present toward the base of the cell and are formed by
connexins.166 These junctions allow intercellular communica-
tion and transport of ions and metabolites.
FUNCTIONS
Role in Retinal Adhesiveness
The development of the retina by invagination of the optic cup
results in a potential space between the neural retina and the
RPE. Yet in a fully developed eye the neural retina is attached 1641
 RETINA AND VITREOUS
to the RPE. A force of ~100 dynes is needed to detach one
centimeter of retina in live rabbits; ~180 dynes in cats, and
~140 dynes in monkeys.167 Numerous factors are responsible
for keeping the retina attached. The most important contribu-
tions to retinal adhesiveness come from interphotoreceptor
matrix (IPM), which passively glues the neural retina to RPE;
the metabolic activity of the RPE; and fluid transport across the
RPE.168,169
Induction of retinal detachment by experimentally induced
perturbations demonstrates the role of RPE metabolic activity
in retinal adhesiveness. Removal of Ca2+ and Mg2+, for
example, leads to reversible decrease in retinal adhesiveness;
reducing the pH also leads to a decrease in adhesiveness.170,171
A decrease in oxidative metabolism resulting from ischemia
leads to reduced retinal adhesiveness.168
Due to the resistance to free fluid movement across RPE
resulting from the tight junctions, there is a hydrostatic
pressure differential across the retina. This pressure differential
SECTION 10
forces fluid movement from the retina into the choroid. This
differential, which could be as little as 0.001 mmHg, may be
sufficient to keep the retina attached.172 If the direction of fluid
movement is reversed by injection of hyperosmolar solution
into the vitreous cavity, retinal detachment occurs.173 Similarly,
if choroidal osmolarity is increased, there is an increase in
retinal adhesiveness.174 Vitreous gel plays some role in retinal
attachment by physically keeping the retina apposed to RPE. Of
uncertain importance to retinal-RPE adhesion is the physical
ensheathment of OS by RPE microvilli as well as the frictional
and electrostatic resistance resulting from the ensheathment.
Recently, integrin avb5 has been shown to play a role in retinal-
RPE adhesion, and, interestingly, the strength of adhesion
mediated by avb5 was maximal at 3.5 hr after light onset when
the phagocytosis is complete.175
Phagocytosis
While RPE cells are capable of nonspecific phagocytosis, a
property shared with other phagocytic cells like macrophages,
RPE cells show a strong preference for photoreceptor OS.176
Nonspecific phagocytosis and phagocytosis in vitro is not
rhythmic while phagocytosis of OS is. By the time a human
RPE cell is 80 years old, it has phagocytosed ~108 OS.177
Dysfunctional phagocytosis can lead to accumulation of debris
in the subretinal space and cause loss of vision as is evident in
Royal College of Surgeons (RCS) rats. These rats have a genetic
mutation in the MerTK receptor (vide infra) that mediates
binding to OS (vide infra), and, therefore, RCS RPE cells have
defective OS phagocytosis. Rod OS are maintained at a fixed
length,178 and there is a need to create new discs/opsin in photo-
receptors to replace damaged OS due to light exposure.179,180
The constant length is achieved by RPE phagocytosis of OS.179
Phagocytosis also allows for recycling of retinoids and fatty
acids present in photoreceptor OS (discussed earlier).
The nature of structural interface between RPE and photo-
receptor OS is different in rods and cones. Rod OS (ROS) con-
tact the apical surface of RPE while cone OS (COS) do not reach
the surface. In the case of COS, RPE cells extend one or more
processes of 10–20 mm length to reach the tip. Each process
expands near the COS tip to ensheath it. These processes
surround the COS to form a supracone space. COS discs are
shed into this space and guided to RPE.181,182 Since the COS is
shorter than ROS and has a narrow tip, the resulting phago-
somes are smaller, and there are fewer phagosomes in the RPE
that contact cones vs. rods.
Phagocytosis can be divided into the following stages:
shedding of OS, binding of OS to RPE, internalization, migra-
tion to the basal cytoplasm, and digestion.183 Photoreceptors
1642 shed their OS cyclically, based on the circadian rhythm, in a
process mediated by dopamine (which provides the light signal)
and melatonin (which provides the dark signal). It is not clear
whether the initiation of disc shedding occurs in the photo-
receptors (e.g., shedding can sometimes occur in the absence of
RPE in vitro 184), whether RPE cells play a role (i.e., do RPE
processes ‘bite’ off the tips?), or whether both processes occur
during the initiation. Regardless, the interdigitation of OS with
RPE microvilli is important for phagocytosis to occur. When
there is no interdigitation, as occurs in retinal detachment 185 or
in mutant vitiligo mice that have RPE with short apical villi
that do not ensheath the OS,186 phagocytosis does not occur
even though the RPE is capable of phagocytosis. The trigger
may be the length of OS,184 or some other signal that has not
yet been identified. Light-induced oxidized tips of OS have been
proposed as a signal for phagocytosis by Sun and co-workers.187
Recognition and binding of OS to the RPE apical surface
occurs by receptor-ligand interactions. The receptors on RPE
that have been implicated include mannose receptor,188 CD36,
MerTK,189 integrin avb5,190,191 and a gp55 glycoprotein.
Blocking the mannose receptor inhibits RPE phagocytosis of
ROS.188,192 The identity of the natural ligand for this receptor is
not known. CD36 is a macrophage receptor that is involved in
phagocytosis and binds to Toll-like receptor, TLR4.193 CD36
may also bind to light-induced oxidative products of photo-
receptor lipids, and the latter may be a physiological signal to
initiate phagocytosis.187 CD36 binding is a necessary and
sufficient signal for activation of phagocytosis.190
MerTK is tyrosine kinase receptor, i.e., the cytoplasmic
domain of the receptor is a tyrosine kinase that becomes
activated when an appropriate ligand binds to the receptor on
the cell surface. Cells lacking MerTK are capable of binding to
OS but are not able to ingest them.194 The cognate receptor for
MerTK is believed to be a vitamin K-dependent growth arrest-
specific protein, Gas6.195,196 The role of Gas6 in phagocytosis
has been demonstrated in vitro,197 but its role in vivo is not
known. Integrin avb5 present on the apical membrane of RPE
binds to vitronectin. However, vitronectin may not be involved
in OS phagocytosis in situ, and there may be other proteins
involved;191 avb5 interacts with MerTK to mediate phago-
cytosis. It activates MerTK via focal adhesion kinase.198
OS binding to RPE surface receptors activates second
messenger systems that lead to reorganization of cytoskeletal
elements to cause ingestion. MerTK activation causes an
increase in inositol triphosphate (IP3) which, in turn, leads to an
increase in intracellular free calcium concentration.199 Together,
these two initiate phagocytosis by influencing the reorganiza-
tion of cytoskeletal filaments. Increased calcium also results in
activation of protein kinase C that shuts off phagocytosis.200
Cyclic AMP (cAMP) modulates the rate of phagocytosis:
increased cAMP results in decreased phagocytosis.201,202
Following phagocytosis, the phagosomes are guided to the
basal region by microtubules203 and fuse with lysosomes in the
basal region of the cell. Initially, small lysosomes fuse with
phagosomes. Subsequently, large lysosomes fuse with the
phagosomes via pore-like structures through which lysosomal
contents may enter the phagosome.204 Cathepsin D is the major
lysosomal enzyme involved in degradation of OS with possible
involvement of cathepsin S.205–207 The degraded products are
either reused or eliminated. The rapid and transient increase in
gene and protein expression that follows OS phagocytosis does
not occur following nonspecific phagocytosis of latex beads in
vitro. These genes include c-fos, zif-268, tis-1, and peroxisome
proliferator-activated receptor g that is a regulator of lipid
metabolism.208,209
Molecules that have been implicated in regulation of phago-
cytosis include b-adrenergic agonists, adenosine A2 receptors,210
serotonin, bFGF, acetylcholine, glutamate dopamine, and

melatonin.183 The latter two are responsible for the circadian
regulation of shedding and phagocytosis.211 Melatonin is a
hormone secreted rhythmically by the pineal gland and also by
photoreceptors at night. It activates light-induced OS shedding
in dark. During daytime, dopamine synthesis results in
inhibition of melatonin and inhibition of OS shedding. RPE
cells express receptors for both dopamine and melatonin so that
shedding and phagocytosis are synchronized. Recently, the
role of avb5 integrin in synchronized phagocytosis has been
demonstrated.212
Secretion
RPE cells secrete numerous growth factors.213 These include
PDGF, PEDF, FGF, TGF, CNTF, VEGF, insulin-like growth
factor (IGF), lens-epithelium derived growth factor, cytokines
(interleukins), and tissue inhibitor of metalloproteinases (TIMP).
Some of these are secreted by cultured RPE while others like
VEGF, TGF-b, IGF, and FGF are secreted in vivo as well.
PEDF is a 50 kD protein present in RPE and secreted into
the adjacent IPM.214 PEDF is neurotrophic, prevents cell
proliferation, and promotes differentiation in retina and other
tissues.215 PEDF has neuroprotective effects against ischemic
damage,216 glutamate excitotoxicity, oxidative stress, and retinal
degeneration. It has antiangiogenic effects, stabilizing the
choriocapillaris endothelium.217,218 VEGF219 is secreted in low
concentrations in healthy eyes and prevents apoptosis of
choriocapillaris endothelium. PEDF is secreted apically from
RPE cells and VEGF basally.220,221 PEDF also influences glial cell
maturation. RPE removal results in failure of Müller cells to
form adherens junctions with photoreceptors.222
TGF-b was initially demonstrated in eyes with proliferative
vitreoretinopathy (PVR). Vitreous samples from these eyes con-
tained three times more TGF-b than eyes with uncomplicated
retinal detachment. RPE cells can synthesize and secrete TGF-b
normally. RPE cells display increased production of predomi-
nantly TGF-b2 in response to photocoagulation,223 decreased
oxygen tension,224 PVR,225 age-related macular degeneration,226
myopia, and sickle cell retinopathy.227 In PVR, RPE cells are a
major component of the proliferating cells. In addition, the
TGF-b produced by RPE increases the fibrotic response.228
PDGF is chemotactic and mitogenic to RPE and glial cells.229
PDGF receptors are also expressed by RPE.230
Growth factors like FGF and CNTF play a neurotrophic role
in maintenance of photoreceptors.68
Lipofuscin Accumulation and other Aging
Changes
Lipofuscin (‘age pigment’) is an intralysosomal complex of
protein, lipid, carbohydrate, metals, and other compounds that
accumulates in postmitotic, metabolically active cells.231 The
amount accumulated in these cells has a linear correlation with
age, hence the label, age pigment, and has a negative correlation
with longevity. Accumulation in RPE seems to be inversely
related to melanin content.232 Lipofuscin content of RPE cells
depends on the location in the eye. Cells in the posterior pole
have a higher amount of lipofuscin with subfoveal RPE showing
a lower accumulation relative to cells in the subparafoveal
region.233 Lipofuscin is nondegradable and cannot be eliminated
from the cell via exocytosis.231 Formation and accumulation of
lipofuscin may occur by autophagy of cytoplasmic organelles
and contents and subsequent fusion with lysosomes or by
phagocytosis of material from a different cell (heterophagy).
Phagocytosed photoreceptor OS are a major source of
lipofuscin; if RPE that are unable to phagocytose photoreceptor
OS or have mutations in RPE 65 (and therefore lack 11-cis-
retinal and vitamin A aldehyde), they do not accumulate
lipofuscin as much as native RPE.234,235 If photoreceptors are
Müller Cells and the Retinal Pigment Epithelium
eliminated by light exposure, lipofuscin accumulation is not
significant.236 Thus, phagocytosed photoreceptors probably are
a major source of lipofuscin in RPE. RPE cells phagocytose
6000–8000 discs every day, and the digestion is not
complete.183 The residual structures are fluorescent and can be
seen as early as 16 months after birth.237 Autophagy also con-
tributes to the debris.238–240 Since many RPE cells persist through
the life span, this debris can occupy up to 70% of the cyto-
plasmic volume, which leads to decreased RPE phagocytic
activity.241 Lipofuscin deposition also depends on dietary
vitamin A.242
The natural autofluorescence of the fundus (between 500 and
750 nm with maximum emission at ~590–630 nm) is attri-
buted to RPE lipofuscin. The autofluorescence increases with
age and declines after age 70.243 The latter could be either due
to loss of RPE or due to decreased fluorescence of A2E as a
result of photo-oxidation.244
A prominent component of lipofuscin is A2E (C42H58NO,
CHAPTER 125
molecular weight 592): vitamin A aldehyde (generated upon
photoisomerization of 11-cis-retinal) + ethanolamine in 2:1 ratio.
A2E is often named as N-retinylidene-N-retinylethanolamine,
but the name does not reflect the pyridinium ring present in the
structure.245 Sparrow hypothesizes that since A2E structure is
unprecedented, it may not be recognized by RPE lysosomal
enzymes.245 A2E formation starts with condensation of
phosphatidylethanolamine (from the photoreceptor membrane)
and light-generated 11-cis-retinal to form N-retinylidene-
phosphatidylethanolamine (NRPE) (NRPE is the substrate for
ABCA4; vide infra), followed by a series of intermediate
products, including A2PE, the immediate precursor of
A2E.246,247 A2E is formed by cleavage of A2PE in RPE.247 The
cyclical phagocytosis of OS prevents accumulation of A2PE in
the photoreceptor OS. A2PE is the fluorescent pigment in
photoreceptor OS. Thus, accumulation of A2PE due to defects
in phagocytosis contributes to the fluorescence in photo-
receptors (e.g., RCS rats, Stargardt disease). A2E undergoes
further photoisomerization to generate iso-A2E and other cis-
isomers that are not as abundant as A2E.248
One hypothesis for age-related accumulation of lipofuscin
was age-related decline in activity of lysosomal enzymes like
cathepsins.249 However, lipofuscin accumulation itself appears
to alter lysosomal degradation.231 What makes lipofuscin
resistant to degradation? It is believed that oxidative damage to
cellular components results in cross-linking of proteins and
other biomolecules,250 rendering them indigestible. Thus, cells
exposed to oxidative stress tend to accumulate lipofuscin.
Accumulation of lipofuscin in the cell affects cell function and
health. Lipofuscin-containing cells are more susceptible to
oxidative damage.251 Lipofuscin is a photoinducible generator of
oxygen radicals, e.g., superoxide anion, singlet oxygen, and
hydrogen peroxide.252 These free radical species, in turn, react
with biomolecules to cause lipid peroxidation, protein
oxidation, loss of lysosomal integrity, and RPE cell death.253,254
A2E is one of the photosensitizers in lipofuscin, and there may
be other as yet unidentified molecules in lipofuscin that are also
photosensitizers. Even though lipofuscin is compartmentalized,
there is increased production of reactive oxygen species within
the lipofuscin-containing lysosomes due to the presence of iron
that reacts with H2O2.255 Lipofuscin accumulation results in
decreased phagocytosis by RPE, including that of photoreceptor
OS.241 Proteins in lipofuscin granules are modified by
peroxidation; the presence of mitochondrial proteins indicate
autophagy and a possible role in lipofuscin formation.256
Nonenzymatic oxidative modification of amino acids may
result in inhibition of proteolysis, and incomplete proteolysis of
proteins may promote lipofuscin formation.257 The presence
of A2E in RPE results in delayed degradation of phospholipids 1643
 RETINA AND VITREOUS
Retina
(apical)
2K 2Cl K Na nHCONa Na, K
1
Vac = -50mV
3Na
K 3Na
K
TEP
5mV
HCO2
K Cl HCO2
Cl
K
Vta = -45mV
SECTION 10
Cl, HCO2
Cl
Choroid
(basal)
FIGURE 125.6. Ion channels in RPE cells.
Redrawn from Marmor MF, Wolfensberger TJ: The retinal pigment epithelium.
New York: Oxford University Press; 1998.
as well.258 Melanosomes are photoprotective, but with age
melanosomes become photoreactive. (This change could be due
to association of A2E with melanosomes although contamina-
tion of the melanosome preparation with A2E in the experi-
ments cannot be ruled out.) Aggregates of A2E have a
detergent-like property of compromising membrane integrity
leading to membrane blebbing.259
Ion Transport
RPE cells express ion channels on their apical and basolateral
surfaces that mediate transport of Na+, K+, HCO3–, Cl–, etc.
One of the consequences of RPE cell fluid transport is
dehydration of the subretinal space and maintenance of neural
retina–RPE apposition (vide infra). Fluid movement is linked to
the ion movement. In RPE, H+/lactate, and Cl⫺ movement are
the main ions that are linked to fluid movement.260,261 The ion
differences between the cytoplasm and the surrounding tissues
result in a potential difference across the RPE cell monolayer.
This transepithelial potential (TEP) is ~5–15 mV.262
Ion channels present in RPE cells are summarized in Figure
125.6. Sodium is secreted actively into the subretinal space by
a Na+/K+ ATPase pump present in the apical surface.263,264 This
pump creates a sodium gradient from the subretinal space to
the RPE cytoplasm that facilitates as well as provides energy
for the transepithelial transport. HCO3–, K+, and Cl– are co-
transported with Na+ (vide infra). The mechanism of Na+ entry
from the basal plasma membrane is not known. Cl– is absorbed
actively by apical Na+K+–2Cl– co-transport present in the apical
membrane,265,266 Ca+-dependent Cl– channels,267,268 ClC-2
channels (a family of chloride conducting, voltage-gated
channels),269 and cystic fibrosis transmembrane conductance
regulator (CFTR)270 present in the basolateral membrane.
Na+/HCO3– enters the cell via an apical Na+/HCO3–
cotransporter271,272 and leaves the RPE through a basal
Cl–/HCO3– exchanger and possibly a Na+/HCO3– co-transporter.
The transport of HCO3– regulates the pH of subretinal space
and the intracellular pH of RPE cells. If the pH is high in the
subretinal space or in RPE, HCO3– is moved out of RPE into the
choroid via a NaHCO3 co-transporter in the apical membranes
1644 and Cl–/HCO3– exchanger in the basal membranes. When pH is
B-wave
600mV
ERG
A-wave
100 msec
C-wave
B-wave
1 mV
C-wave
10 seconds
Light peak
4 mV
Light C-wave
response “2nd C”
“Fast oscillation”
10 minutes
Light peak
5 mV
Slow C
Oscillations
oscillation
“Fast oscillation”
2 hours
FIGURE 125.7. Electrical changes recorded from a corneal electrode
in a dark-adapted eye after exposure to a bright light. The response
has been depicted in four different time scales from top to bottom;
a- and b-waves occur relatively rapidly and represent neural retinal
responses. The light-induced drop in subretinal K+ concentration
causes hyperpolarization of the RPE apical membrane and the distal
ends of Müller cells resulting in the c-wave. The hyperpolarization of
the RPE basal membrane is recorded as a fast oscillation. The
depolarization of the RPE basolateral membrane by increased
conductance of Cl– results in light peak generation.
Redrawn from Marmor MF, Wolfensberger TJ: The retinal pigment epithelium.
New York: Oxford University Press; 1998.
low, the direction is reversed so that HCO3– moves through RPE
from choroid into the subretinal space. There is a net secretion
(i.e., movement of ion across the RPE into the subretinal space)
of Ca+, with movement out of the apical membrane via a
Na+/Ca2+ exchanger and Ca2+–ATPase. K+ enters RPE on the
apical side via a Na+K+–ATPase and a Na+K+–2Cl co-
transporter and leaves via apical or basal K+ channels. There is
a net transepithelial transport of K+ from the subretinal space
to choroid. Movement of Cl– and K+ drives the movement
of water.
The ion channels maintain the ion homeostasis in the sub-
retinal space, especially the changes that occur in ion concen-
trations as a result of light stimulation of photoreceptors. In the
dark, the apical RPE membrane is more hyperpolarized than the
basal membrane. Voltage across the apical membrane in a
resting RPE cell is ~ –50mV and across the basal membrane is
–45mV. Thus, a transepithelial potential, TEP (Vba–Vap= 5mV),
exists across the RPE.262 Membrane potential across the apical
membrane is primarily due to K+ channels with additional
contributions from the Na+/K+ pump and a Na+/HCO3–
cotransporter (Fig. 125.6). K+ and Cl– channels in the basal
membrane contribute to the membrane potential. The
difference in membrane potential between the apical and basal
membrane is due to the large Cl– conductance. This difference
manifests as the standing potential in a dark-adapted eye when
an electrode is placed on the cornea and amplified, with the
cornea positive.
Exposure to light induces a series of changes that are recorded
in the electroretinogram (ERG) and electrooculogram (EOG).
The ERG response begins with a rapid dip in voltage (a-wave)
followed by a rapid upward deflection (b-wave) that does not
quite return to the baseline (Fig. 125.7); a- and b-waves reflect
electrical activity in the neural retina.273 These waves are

followed by a slow rising c-wave for which the RPE is
responsible.274 In the dark, Na+ flows into the photoreceptors
via the cGMP-gated Na+ channels in the OS and is pumped out
by the Na+/K+ pump in the inner segment. There is a passive
efflux of K+ out of the inner segment. In response to light,
cGMP-gated channels close, and the OS is hyperpolarized.
Additionally, the passive efflux of K+ is also shut down.
Decreased concentration of K+ in the subretinal space and the
large conductance of K+ at the RPE apical membrane results in
hyperpolarization of the latter.262 Additionally, the distal ends of
Müller cells hyperpolarize as well, resulting in a slow negative
transretinal potential termed slow PIII.275 Since the RPE
contribution is larger, a positive deflection is recorded on the
surface of the cornea. In summary, both RPE and Müller cells
contribute to c-wave. The former results in a positive deflection,
and the latter results in a negative deflection. Since RPE
contribution is greater than Müller cell’s, the net change is a
positive c-wave in the EOG. The c-wave is followed by fast
oscillation, which is a negative slow potential fall toward or
below the dark-adapted baseline. This change is produced by
the hyperpolarization of the RPE basal membrane as a
consequence of the above-mentioned fall in subretinal K+.276
The decrease in K+ slows the activity of Na+/K+/2Cl– activity
causing a decrease in Cl– influx across the apical membrane of
RPE. The resultant decrease in intracellular Cl– concentration
produces a change in Cl– equilibrium across the basolateral Cl–
channels leading to a hyperpolarization of basal membrane.
The latter is termed fast because it is fast relative to the next
response, the light peak. The light peak is the slowest and
largest component of the EOG and refers to the slow increase in
potential that follows the fast oscillation. It is generated by an
increased conductance of Cl– in the basolateral membrane,
depolarizing it, and increasing the transepithelial potential.262
Transport of other molecules
The RPE also eliminates waste produced by photoreceptors.
Lactic acid is an excellent example. Photoreceptor OS produce
lactic acid, which is removed by RPE via a lactate–H+ co-
transporter, MCT1, in the apical membrane, and MCT3, in the
basal membrane.277
Glucose is transported from blood to photoreceptors by GLUT
1 and GLUT3. The latter transports glucose routinely, and the
former functions when there is an increased metabolic
demand.278,279 Vitamin A is taken up on the basal surface by
receptor binding to vitamin A bound to retinol-binding protein/
transthyretin complex and enters the visual cycle.280,281 RPE
also transports docosahexaenoic acid synthesized in the liver
and circulating in the blood.282 Docosahexaenoic acid, which is
enriched in photoreceptor membranes, is not synthesized in
neuronal tissue.283
Mutations in the bestrophin molecule (product of VMD2
gene), which functions as Ca+-sensitive Cl– channel, are
associated with three diseases: Best vitelliform macular
dystrophy,284 adult-onset vitelliform dystrophy, and autosomal
dominant vitreoretinalchoroidopathy.285 In the former two con-
ditions, appearance of an egg yolk-like yellow lesion in the fun-
dus is characteristic and results from accumulation of deposits,
including lipofuscin, in the subretinal space and sub-RPE region
as well as RPE hypertrophy. Vitreoretinalchoroidopathy is cha-
racterized by a circumferential zone of hyperpigmentation
anterior to the equator along with punctate white pre-retinal
opacities, fibrillar condensation of vitreous, and breakdown of
the blood–retinal barrier.286
Patients with cystic fibrosis have defective Cl– channels in RPE
cells as well.270,287 However, retinal degeneration is not seen,
probably because of the presence of other channels that
compensate.
Müller Cells and the Retinal Pigment Epithelium
Fluid Transport
About 10–20% of aqueous fluid is absorbed posteriorly with the
rate limiting structure being the neural retina. The RPE also
limits passive fluid movement across Bruch’s membrane, but it
has an active pumping mechanism that has a large capacity and
helps to keep the subretinal space dehydrated. The fluid
permeability across dog retina is 0.03 m1 min–1 mmHg–1 sqcm–1
and across dog RPE is 0.01 ml min–1 mmHg–1 sqcm–1.
Permeability across monkey RPE is 0.005 m1min–1 mmHg–1
sqcm–1.288,289 The transretinal pressure of 0.5 µ 10–3 mmHg172
that exists across the retina is sufficient to keep retina attached
but has no effect on the fluid movement across it. In the
monkey eye, a pressure drop of ~4 mmHg exists between the
vitreous and choroid, which implies a possible fluid flow across
the RPE of 0.3 m1/min.290
The forces driving the fluid movement across the retina in
the eye include intraocular pressure, osmotic/oncotic pressure,
and the active solute-linked fluid transport by the RPE mono-
CHAPTER 125
layer. A change in intraocular pressure from 0 to 38 mmHg
leads to a 39% increase in rate of fluid absorption from sub-
retinal space in rabbits.291 Because of the higher protein content
in the choroid and because osmotic pressure in vitreous and
subretinal space is maintained at somewhat similar levels, there
is a net osmotic pressure that drives fluid outwards only.292,293
In a normal eye, active transport by RPE cells is the major force
eliminating water from the subretinal space; intraocular
pressure and osmotic pressure contribution to fluid transport is
minor but effective when RPE cells are damaged. Müller cells
may play a role in water transport in the inner retina.25 RPE is
estimated to transport fluid at a rate of 0.1 m1 h–1 sqmm–1.294
The ion channels responsible for solute-linked fluid movement
are the apical Na+,K+,2Cl– channel, basal Cl– channels, and the
H+/lactate co-transporter.260,261 Recently aquaporin that forms
“water channels” in secretory and absorptive epithelia,295 have
been shown to play a significant role in water transport across
RPE cells.296
Melanin
Melanin granules are ovoid in shape and measure ~2–3 mm in
length, 1 mm in diameter, and are distributed near the apical
region of the cell. Melanin granules contain polymerized
melanin in a protein matrix. The melanin can be pheomelanin
or eumelanin, imparting yellowish/reddish or brown/black color,
respectively. The human eye contains eumelanin.297 While
uveal melanin-containing cells are derived from melanoblasts
originating from neural crest, RPE, ciliary epithelium, and iris
pigment epithelium develop from the neurectoderm.297,298
Melanin is produced during development. However, it is
possible that melanin is synthesized in adult cells as well.299,300
Tyrosinase synthesis can be induced in adult cultured RPE by
feeding them photoreceptor OS.301
Melanin synthesis begins with the production of pre-
melanosomes and synthesis of tyrosinase, the two processes
being independent of one another (Fig. 125.8).302,303 Preme-
lanosomes are vesicular bodies that contain the structural
proteins of melanin but no tyrosinase enzyme. They are
assembled in smooth endoplasmic reticulum and released into
the cytoplasm. Tyrosinase is synthesized in rough endoplasmic
reticulum and transported through the Golgi apparatus during
which the enzyme undergoes posttranslational modification,
predominantly glycosylation. The enzyme is then assembled
into coated vesicles that bud off and fuse with the
premelanosomes to form melanosomes.
Tyrosinase catalyzes the first two steps of melanin
synthesis: hydroxylation of the amino acid, L-tyrosine, to
3,4–dihydroxyphenylalanine (DOPA) and oxidation of DOPA
to dopaquinone. Spontaneous endocyclic ring formation 1645
 RETINA AND VITREOUS
L-tyrosine
Tyrosinase
DOPA
Tyrosinase
Dopaquinone
Tyrosinase
Leucodopachrome
Dopachrome
SECTION 10
DHICA DHI
Melanin (polymers of DHICA and DHI)
FIGURE 125.8. Melanin synthesis begins with hydroxylation of
L-tyrosine to 3,4-dihydroxyphenylalanine (DOPA) followed by oxidation
of DOPA to dopaquinone. Both reactions are catalyzed by tyrosinase.
Spontaneous endocyclic ring formation results in formation of
leucodopachrome from dopaquinone. Leucodopachrome undergoes
oxidation to form dopachrome and DOPA. This oxidation is coupled
with re-oxidation of DOPA to dopaquinone by tyrosinase. Dopachrome
is converted to 5,6 dihydroxyindole-2-carboxylic acid (DHICA). A small
portion of dopachrome undergoes spontaneous conversion to 5,6
dihydroxyindole (DHI). Oxidative polymerization of DHICA and DHI
results in melanin formation.
Boulton M: Melanin and the RPE. In: Marmor MF, Wolfensberger TJ, eds. The
retinal pigment epithelium. New York: Oxford University Press; 1998:68–85.
results in formation of leucodopachrome from dopaquinone.
Leucodopachrome undergoes oxidation to form dopachrome
and DOPA; this oxidation is coupled with re-oxidation of DOPA
to dopaquinone by the tyrosinase enzyme. Dopachrome is
converted to 5,6 dihydroxyindole-2–carboxylic acid (DHICA). A
small portion of dopachrome undergoes spontaneous conver-
sion to 5,6 dihydroxyindole (DHI). Oxidative polymerization of
DHICA and DHI results in eumelanin polymer. Pheomelanin is
formed by addition of cysteine to dopaquinone.297
The different stages of melanin granule maturation can be
seen by electron microscopy.149 Premelanosomes are
membrane-bound, ovoid, nonpigmented organelles containing
a protein matrix. Stage I granules have protein filaments pole to
pole, in an ordered arrangement; melanin synthesis becomes
evident at this stage. Increasing melanin synthesis become
evident in stages II and III, and by stage IV, a fully melanized
melanosome, i.e., melanin granule, is formed.
RPE cells are the first to synthesize melanin in the eye.149 By
7-weeks gestation, immature melanosomes are visible, and in
the subsequent few weeks (~7 or more weeks), continued
melanin synthesis is evident by the appearance of melanosomes
of various stages. Production of new melanosomes then stops,
but the polymerization of melanin within the granules con-
1646 tinues for up to two years.
RPE cells exhibit regional variation in melanin content. Cells
in the periphery have higher melanin content, and the amount
decreases posteriorly.304,305 With age, melanin content decreases
in the periphery while there is no change under the macula.
There is no difference in RPE melanin content in whites and
blacks.305
Melanin absorbs light passing through the retina, preventing
reflection of light within the fundus that might affect the clarity
of the image formed by the photoreceptors and protecting the
photoreceptors from excess light.306 Absorption of excess light
raises the possibility of an RPE photoprotective effect. However,
there are conflicting data. In vitro studies show that intra-
cellular melanin clearly protects the cell from light-induced
DNA damage.307 Some in vivo studies show that RPE
pigmentation protects the overlying photoreceptors from light-
induced damage in rodents.308,309 In another study using
chimeric mice expressing pigmented and nonpigmented RPE
cells, light damage to photoreceptors was more severe in the
central retina than in the periphery, regardless of the pigmen-
tation of the underlying RPE.310
Even though synthetic melanin has been shown to have
strong free-radical scavenging properties, natural melanin is not
very effective.306,311 Thus, it is unlikely that it plays as signifi-
cant a role in RPE cells as other antioxidants, e.g., superoxide
dismutase.306 Melanin is also capable of generating free-radicals
and was thought to be responsible for damage caused by light of
shorter wavelength.312,313 However, this blue light damage is
now attributed to the presence of liposfuscin.314
Melanin traps radiation and dissipates energy, which can
result in tissue damage if there is acute exposure to high
intensity radiation as occurs in laser photocoagulation.315
Hansen and Fine have demonstrated in melanin models that a
temperature increase above 10°C will cause a zone of
denaturation in the vicinity of the granule that would spread
with the conduction of heat from the granule, or, if the energy
is great enough, generation of steam at the granule cytoplasm
interface. The heat and the steam lead to coagulative damage as
well as disruption of the structures.316
Melanin can bind to numerous chemicals, thus becoming an
effective sink or storage site responsible for toxicity.317,318
Chlorpromazine and chloroquine can bind irreversibly to melanin
and can lead to toxicity.319 Since melanins are polyanions, ionic
interaction is one mechanism by which they bind to chemicals.
The role of melanin in development is discussed in the
embryology section. With increasing age, complex melanin-
containing granules begin to appear. In addition to melanin,
these contain a cortex of lipofuscin (melanolipofuscin) or a
cortex of enzyme-reactive material (melanolysosomes).163 The
amount of complex granules increases with age while pure
melanin declines. The highest density of complex granules is in
the submacular region and declines toward periphery and fovea.
In human eyes over 90 years old, there are no pure melanin
granules.163 Pigment-free cytoplasm in the RPE also declines
with age.163 The fluorescence of the melanosomes shows a shift
toward red with increasing age.300
Role in Visual Cycle
Transduction of a light signal to vision begins with absorption
of light by rhodopsin (or cone opsin). Rhodopsin (or cone opsin)
is formed by binding opsin, a G-protein coupled protein that
is present within the membranes of the photoreceptor discs,
with the visual chromophore, 11-cis-retinal, in the intradiscal
space (Fig. 125.9). Absorption of light results in irreversible
isomerization of 11-cis-retinal to all-trans-retinal, which leads
to a conformational change in the rhodopsin molecule, thus
activating it.320,321 Activated rhodopsin initiates the photo-
transduction cascade. Rhodopsin is phosphorylated and

The Rod Visual Cycle
CRALBP CRALBP
11-Ral 11-Rol
11-RDH
11-Ral 11-Rol t-RE
IMH
Retinal Pigment Epithelium
11-Ral IRBP ? Subretinal Space
Rod Outer Segment
hv
Rho Rho*
11-Ral t-Ral
Opsin
inactivated by rhodopsin kinase and subsequent binding to
arrestin. Inactivated rhodopsin releases all-trans-retinal and
binds to 11-cis-retinal so that it can become activated again by
exposure to light. All-trans-retinal generated in the photo-
receptor disk space cannot be converted back to 11-cis-retinal in
the photoreceptor. This conversion occurs in RPE cells and
possibly in Müller cells. Transport of all-trans-retinal to RPE,
however, is not a matter of simple diffusion. All-trans-retinal in
the disk space is transported to the extra-discal space by an
ATP-binding cassette protein (ABCR), known as ABCA4.322,323
This is a flippase for NRPE, flipping the molecule across the
disk membrane. All-trans-retinal is converted to NRPE by
reacting with phosphatidylethanolamine. Once in the
photoreceptor extra-discal cytoplasm, all-trans-retinal is
released. It is then reduced to all-trans-retinol (vitamin A) by a
membrane-bound retinol dehdyrogenase (RDH) in the
photoreceptor extra-discal cytoplasm. All-trans-retinol is then
transported to RPE cells from the rods or to Müller cells from
cones by interphotoreceptor-binding protein (IRBP) present in
the interphotoreceptor space.324,325
All-trans-retinol transport within the RPE cell is not well
characterized. Water-insoluble all-trans-retinol in the RPE is
bound to cellular retinol-binding protein (CRBP), thus trapping
it within the RPE cell as well as protecting it from oxidation or
isomerization. CRBP-bound all-trans-retinol is carried to the
endoplasmic reticulum where it undergoes esterification to
long-chain fatty acids derived from membrane phospholipids.
This reaction, catalyzed by lecithin:retinol acyl transferase
(LRAT), leads to formation of all-trans-retinyl esters. Hydrolysis
of retinyl esters coupled with isomerization results in formation
of 11-cis-retinol.326 The coupling of hydrolysis is important
because isomerization requires energy and is provided by the
energy generated during hydrolysis. An additional protein
involved in the isomerization step is RPE-65, which acts as a
chaperone for all-trans retinyl esters.327 RPE-65 exists in two
forms: a membrane bound form that is triply palmitoylated and
a soluble form that is not. The former has high affinity to
all-trans retinyl esters and donates a palmitoyl group for the
reaction mediated by LRAT. This ensures 11-cis-retinal production
during light. The soluble form of RPE-65 reduces the
Müller Cells and the Retinal Pigment Epithelium
FIGURE 125.9. Schematic of the rod visual
cycle. See text for details. ABCR: ATP-binding
cassette, retina; CRBP: cellular retinol-binding
CRBP
protein; CRALBP: cellular retinaldehyde-binding
t-Rol
protein; IMH: isomerohydrolase; IRBP:
LRAT
interphotoreceptor retinoid-binding protein;
t-Rol LRAT: lecithin:retinol acyltransferase; RDH: all-
trans-retinol dehydrogenase; 11-RDH: 11-cis-
retinol dehydrogenase; Rho: rhodopsin; Rho*:
activated rhodopsin; 11-Ral: 11-cis-retinal;
11-Rol: 11-cis-retinol; at-Ral: all-trans-retinal;
? IRBP t-Rol at-Rol: all-trans-retinol; at-RE: all-trans-retinyl
ester. Reproduced with permission from Saari,
J C: Biochemistry of visual pigment
regeneration: the Friedenwald lecture. Invest
Ophthalmol Vis Sci, 2000; 41(2):337–48
t-Ral NADPH NADP (Association for Research in Vision and
t-Rol Ophthalmology).
ABCR RDH
CHAPTER 125
t-Ral
production of 11-cis-retinal in the dark. The switch between the
membrane and soluble forms of RPE-65 is controlled by LRAT
and by the concentration of 11-cis-retinol in RPE.328 11-cis-
retinol is either esterified by LRAT and stored in the cell or
oxidized to 11-cis-retinal, a reaction catalyzed by 11-cis-retinol
dehydrogenase or RDH5.329 Cellular retinaldehyde-binding
protein (CRALBP) accelerates the latter enzymatic reaction:330
11-cis-retinal is transported back to photoreceptors by
IRBP.324,325
An alternate pathway for regeneration of 11-cis-retinal has
been described.331 This pathway is the reverse of the light-
induced reaction occurring in the photoreceptors, i.e., all-trans-
retinal is converted to 11-cis-retinal by RPE retinal G protein
coupled receptor (RGR) using light energy. The source of all-
trans-retinal is the RPE pool of all-trans-retinol acquired from
the photoreceptors. The conversion is mediated by a RDH that
is presumed to be different from RDH5. This alternate pathway
maintains a constant level of 11-cis-retinal despite changes in
ambient light, i.e., maintains the levels of 11-cis-retinal after
onset of light. The main pathway is important for the acute
changes in levels that occur during the process of vision.
Therefore, loss of RDH5 results in delayed recovery from light
exposure.
Why does a two-cell system involving Müller and RPE cells
exist for 11-cis-retinal renewal? It is speculated that such a
system separates molecules in different compartments so that
thermodynamically unfavorable reactions can proceed by mass
action.332 An alternative explanation could be that there may be
no room for all the molecules required due to the high packing
density of visual pigments in the OS.332
Mutations in the molecules involved in visual cycle result
in retinal degenerations. Total loss of ABCA4 function causes
retinitis pigmentosa.333 Partial loss results in Stargardt disease
or fundus flavimaculatus.323 Loss of ABCA4 may also play a role
in age-related macular degeneration.334–336 Loss of CRALBP causes
retinitis punctata albescens and autosomal recessive retinitis
pigmentosa due to decreased efficiency of regeneration of visual
pigment.337,338 Loss of RDH5 causes fundus albipunctatus,339
and loss of RGR leads to retinitis pigmentosa.340,341 Mutations
in RPE-65 can cause Leber congenital amaurosis and autosomal 1647
 RETINA AND VITREOUS

recessive childhood-onset severe retinal dystrophy.342,343 Finally,
loss of function mutations in LRAT leads to early onset retinal
dystrophy.344
An opsin that is localized exclusively to RPE has been
identified. It is present in the microvilli of the RPE. The exact
role has not been elucidated.345
Immune Functions
The subretinal space is an immune-privileged site and can
accept allografts for prolonged periods compared to a
nonimmune-privileged site (e.g., the subconjunctival space).346
Immune-privileged tissue can survive for prolonged periods in
nonimmune-privileged sites compared to nonimmune-
privileged tissue. RPE is an immune-privileged tissue. Neonatal
RPE sheets, when placed in heterotopic sites (i.e., anatomic
locations in which the transplanted tissue is not found
normally) do not undergo rejection when compared to
nonprivileged tissue.347 Constitutive expression of Fas ligand on
SECTION 10
surface of fetal RPE cells.358,359 They do not seem to express
MHC class II antigens normally but do so if exposed to IFN-
g.360 Culturing RPE cells also can induce MHC antigen
expression.360 RPE cells can process antigen prior to antigen
presentation, thereby potentially acting as antigen-presenting
cells.361 Higher levels of IFN-g-induced MHC class II antigen
expression on RPE cells leads to increased activation of antigen-
specific T-cells as manifested by the production of pro-
inflammatory TNF-a.362 This activation does not include T-cell
proliferation or production of IL-2, however, as is the norm for
T-cell activation.
FUTURE DEVELOPMENTS
Due to the critical functions performed by RPE cells, perturba-
tions in cell function can have serious consequences that affect
vision. Their central role in visual physiology is demonstrated
by the numerous visually debilitating conditions that are caused

the RPE may contribute to its status as immune-privileged
tissue.347,348 RPE contributes to the immune-privilege of
subretinal space by maintaining a blood–retinal barrier; RPE
cells create a local immune suppressive microenvironment
through the production of immuno-modulatory factors such as
TGF-b,349–352 through suppression of T-cell activation,353,354 and
through the induction of activated-T cell apoptosis.355–357
RPE cells express transplantation antigens. Major and minor
histocompatibility (MHC) class I antigens are present on the
by mutations in RPE. RPE cells already are the target of thera-
peutic interventions for conditions such as Leber congenital
amaurosis.363 The ease of RPE isolation, the straightforward
surgical access to the subretinal space, and the facile inter-
digitation of transplanted RPE cells with host photoreceptors
renders the RPE a logical choice for initial attempts at cell-based
therapy in the retina.364 Newer experimental techniques like
gene chip array and protein chips will continue to add to our
knowledge of structure and function of RPE.

REFERENCES
1. Müller H: Zur histologie der netzhaut.
Z Wiss Zool 1851; 3:234–237.
2. Chow RL, Lang RA: Early eye development
in vertebrates. Annu Rev Cell Dev Biol
2001; 17:255–296.
3. Hollenberg MJ, Spira AW: Early
development of the human retina. Can J
Ophthalmol 1972; 7:472–491.
4. Sharma RK, Johnson DA: Molecular signals
for development of neuronal circuitry in the
retina. Neurochem Res 2000; 25:1257–1263.
5. Reichenbach A, Stolzenburg JU,
Eberhardt W, et al: What do retinal muller
(glial) cells do for their neuronal ‘small
siblings’? J Chem Neuroanat 1993;
6:201–213.
6. Walcott JC, Provis JM: Muller cells express
the neuronal progenitor cell marker nestin
in both differentiated and undifferentiated
human foetal retina. Clin Experiment
Ophthalmol 2003; 31:246–249.
7. Kljavin IJ, Reh TA: Muller cells are a
preferred substrate for in vitro neurite
extension by rod photoreceptor cells.
J Neurosci 1991; 11:2985–2994.
8. Willbold E, Layer PG: Muller glia cells and
their possible roles during retina
differentiation in vivo and in vitro. Histol
Histopathol 1998; 13:531–552.
9. Rhodes RH: A light microscopic study of
the developing human neural retina. Am J
Anat 1979; 154:195–209.
10. Rhodes RH: Ultrastructure of Muller cells in
the developing human retina. Graefes Arch
Clin Exp Ophthalmol 1984; 221:171–178.
11. Hogan MJ, Alvarado JA, Weddell JE:
Histology of the human eye. Philadelphia:
W.B. Saunders; 1971.
12. Ramirez JM, Trivino A, Ramirez AI, et al:
Structural specializations of human
retinal glial cells. Vision Res 1996;
1648 36:2029–2036.
13. Wolburg H, Berg K: Distribution of
orthogonal arrays of particles in the Muller
cell membrane of the mouse retina. Glia
1988; 1:246–252.
14. Sarthy V, Ripps H: The Retinal Müller cell.
New York: Plenum Publishers; 2001.
15. Yamada E: Some structural features of the
fovea centralis in the human retina. Arch
Ophthalmol 1969; 82:151–159.
16. Gass JD: Muller cell cone, an overlooked
part of the anatomy of the fovea centralis:
hypotheses concerning its role in the
pathogenesis of macular hole and
foveomacualr retinoschisis. Arch
Ophthalmol 1999; 117:821–823.
17. Grayson C, Reid SN, Ellis JA, et al:
Retinoschisin, the X-linked retinoschisis
protein, is a secreted photoreceptor protein,
and is expressed and released by Weri-Rb1
cells. Hum Mol Genet 2000; 9:1873–1879.
18. Molday LL, Hicks D, Sauer CG, et al:
Expression of X-linked retinoschisis protein
RS1 in photoreceptor and bipolar cells.
Invest Ophthalmol Vis Sci 2001;
42:816–825.
19. Sauer CG, Gehrig A, Warneke-Wittstock R,
et al: Positional cloning of the gene
associated with X-linked juvenile
retinoschisis. Nat Genet 1997;
17:164–170.
20. Minami Y, Ishiko S, Takai Y, et al: Retinal
changes in juvenile X linked retinoschisis
using three dimensional optical coherence
tomography. Br J Ophthalmol 2005;
89:1663–1664.
21. Newman EA, Frambach DA, Odette LL:
Control of extracellular potassium levels by
retinal glial cell K+ siphoning. Science
1984; 225:1174–1175.
22. Kofuji P, Connors NC: Molecular substrates
of potassium spatial buffering in glial cells.
Mol Neurobiol 2003; 28:195–208.
23. Kofuji P, Biedermann B, Siddharthan V,
et al: Kir potassium channel subunit
expression in retinal glial cells: implications
for spatial potassium buffering. Glia 2002;
39:292–303.
24. Ishii M, Fujita A, Iwai K, et al: Differential
expression and distribution of Kir5.1 and
Kir4.1 inwardly rectifying K+ channels in
retina. Am J Physiol Cell Physiol 2003;
285:C260–C267.
25. Nagelhus EA, Horio Y, Inanobe A, et al:
Immunogold evidence suggests that
coupling of K+ siphoning and water
transport in rat retinal Muller cells is
mediated by a coenrichment of Kir4.1 and
AQP4 in specific membrane domains. Glia
1999; 26:47–54.
26. Skatchkov SN, Eaton MJ, Shuba YM, et al:
Tandem-pore domain potassium channels
are functionally expressed in retinal (Muller)
glial cells. Glia 2006; 53:266–276.
27. Bok D, Schibler MJ, Pushkin A, et al:
Immunolocalization of electrogenic sodium-
bicarbonate cotransporters pNBC1 and
kNBC1 in the rat eye. Am J Physiol Renal
Physiol 2001; 281:F920–F935.
28. Nagelhus EA, Mathiisen TM, Bateman AC,
et al: Carbonic anhydrase XIV is enriched in
specific membrane domains of retinal
pigment epithelium, Muller cells, and
astrocytes. Proc Natl Acad Sci U S A 2005;
102:8030–8035.
29. Tsacopoulos M: Metabolic signaling
between neurons and glial cells: a short
review. J Physiol Paris 2002; 96:283–288.
30. Derouiche A: Possible role of the Muller cell
in uptake and metabolism of glutamate in
the mammalian outer retina. Vision Res
1996; 36:3875–3878.
31. Biedermann B, Bringmann A, Reichenbach
A: High-affinity GABA uptake in retinal
glial (Muller) cells of the guinea pig:

electrophysiological characterization,
immunohistochemical localization, and
modeling of efficiency. Glia 2002;
39:217–228.
32. Winkler BS, Starnes CA, Sauer MW, et al:
Cultured retinal neuronal cells and Muller
cells both show net production of lactate.
Neurochem Int 2004; 45:311–320.
33. Mantych GJ, Hageman GS, Devaskar SU:
Characterization of glucose transporter
isoforms in the adult and developing
human eye. Endocrinology 1993;
133:600–607.
34. Watanabe T, Mio Y, Hoshino FB, et al:
GLUT2 expression in the rat retina:
localization at the apical ends of Muller
cells. Brain Res 1994; 655:128–134.
35. Mata NL, Radu RA, Clemmons RC, Travis
GH: Isomerization and oxidation of vitamin
a in cone-dominant retinas: a novel
pathway for visual-pigment regeneration in
daylight. Neuron 2002; 36:69–80.
36. Mata NL, Ruiz A, Radu RA, et al: Chicken
retinas contain a retinoid isomerase activity
that catalyzes the direct conversion of all-
trans-retinol to 11-cis-retinol. Biochemistry
2005; 44:11715–11721.
37. Wu BX, Moiseyev G, Chen Y, et al:
Identification of RDH10, an All-trans Retinol
Dehydrogenase, in Retinal Muller Cells.
Invest Ophthalmol Vis Sci 2004;
45:3857–3862.
38. Newman EA: Glial modulation of synaptic
transmission in the retina. Glia 2004;
47:268–274.
39. Witkovsky P, Dudek FE, Ripps H: Slow PIII
component of the carp electroretinogram.
J Gen Physiol 1975; 65:119–134.
40. Frishman LJ, Steinberg RH: Light-evoked
increases in [K+]o in proximal portion of the
dark-adapted cat retina. J Neurophysiol
1989; 61:1233–1243.
41. Kofuji P, Ceelen P, Zahs KR, et al: Genetic
inactivation of an inwardly rectifying
potassium channel (Kir4.1 subunit) in mice:
phenotypic impact in retina. J Neurosci
2000; 20:5733–5740.
42. Reichenbach A, Robinson SR: The
involvement of Muller cells in the outer
retina. In: Djamgoz MBA, Archer SN,
Vallerga S, eds. Neurobiology and clinical
aspects of the outer retina. London, New
York: Chapman & Hall; 1995:395–416.
43. Kusaka S, Kapousta-Bruneau NV, Puro DG:
Plasma-induced changes in the physiology
of mammalian retinal glial cells: role of
glutamate. Glia 1999; 25:205–215.
44. Bringmann A, Reichenbach A: Role of
Muller cells in retinal degenerations. Front
Biosci 2001; 6:E72–E92.
45. Puro DG: Growth factors and Müller cells.
Prog Retin Eye Res 1995; 15:89–101.
46. Madreperla SA, Geiger GL, Funata M,
et al:Clinicopathologic correlation of a
macular hole treated by cortical vitreous
peeling and gas tamponade.
Ophthalmology 1994; 101:682–686.
47. Bringmann A, Kuhrt H, Germer A, et al:
Muller (glial) cell development in vivo and in
retinal explant cultures: morphology and
electrophysiology, and the effects of
elevated ammonia. J Hirnforsch 1998;
39:193–206.
48. Reichenbach A, Fuchs U, Kasper M, et al:
Hepatic retinopathy: morphological features
of retinal glial (Muller) cells accompanying
hepatic failure. Acta Neuropathol (Berl)
1995; 90:273–281.
Müller Cells and the Retinal Pigment Epithelium
49. Winter M, Eberhardt W, Scholz C,
Reichenbach A: Failure of potassium
siphoning by Muller cells: a new hypothesis
of perfluorocarbon liquid-induced
retinopathy. Invest Ophthalmol Vis Sci
2000; 41:256–261.
50. Reichenbach A, Faude F, Enzmann V, et al:
The Muller (glial) cell in normal and
diseased retina: a case for single-cell
electrophysiology. Ophthalmic Res 1997;
29:326–340.
51. Francke M, Pannicke T, Biedermann B,
et al: Loss of inwardly rectifying potassium
currents by human retinal glial cells in
diseases of the eye. Glia 1997; 20:210–218.
52. Reichelt W, Pannicke T, Biedermann B,
et al: Comparison between functional
characteristics of healthy and pathological
human retinal Muller glial cells. Surv
Ophthalmol 1997; 42 (Suppl 1):S105–S117.
53. Francke M, Pannicke T, Biedermann B,
et al: Sodium current amplitude increases
dramatically in human retinal glial cells
during diseases of the eye. Eur J Neurosci
1996; 8:2662–2670.
54. Fisher SK, Lewis GP, Linberg KA, Verardo
MR: Cellular remodeling in mammalian
retina: results from studies of experimental
retinal detachment. Prog Retin Eye Res
2005; 24:395–431.
55. Bringmann A, Pannicke T, Grosche J, et al:
Muller cells in the healthy and diseased
retina. Prog Retin Eye Res 2006;
25:397–424.
56. Garcia M, Vecino E: Role of Muller glia in
neuroprotection and regeneration in the
retina. Histol Histopathol 2003;
18:1205–1218.
57. Francke M, Faude F, Pannicke T, et al: Glial
cell-mediated spread of retinal
degeneration during detachment: a
hypothesis based upon studies in rabbits.
Vision Res 2005; 45:2256–2267.
58. Iandiev I, Tenckhoff S, Pannicke T, et al:
Differential regulation of Kir4.1 and Kir2.1
expression in the ischemic rat retina.
Neurosci Lett 2006; 396:97–101.
59. Iandiev I, Uckermann O, Pannicke T, et al:
Glial cell reactivity in a porcine model of
retinal detachment. Invest Ophthalmol Vis
Sci 2006; 47:2161–2171.
60. Bringmann A, Francke M, Pannicke T, et al:
Role of glial K(+) channels in ontogeny and
gliosis: a hypothesis based upon studies
on Muller cells. Glia 2000; 29:35–44.
61. Puro DG: Müller cells; dynamic
components of the retina. In: Toyoda J-I,
Murakami M, Kaneko A, Saito T, eds. The
retinal basis of vision. Amsterdam, New
York: Elsevier; 1999:233–248.
62. Weick M, Wiedemann P, Reichenbach A,
Bringmann A: Resensitization of P2Y
receptors by growth factor-mediated
activation of the phosphatidylinositol-3
kinase in retinal glial cells. Invest
Ophthalmol Vis Sci 2005; 46:1525–1532.
63. Hollborn M, Jahn K, Limb GA, et al:
Characterization of the basic fibroblast
growth factor-evoked proliferation of the
human Muller cell line, MIO-M1. Graefes
Arch Clin Exp Ophthalmol 2004;
242:414–422.
64. Lieth E, Barber AJ, Xu B, et al: Glial
reactivity and impaired glutamate
metabolism in short-term experimental
diabetic retinopathy. Penn State Retina
Research Group. Diabetes 1998;
47:815–820.
65. Puro DG: Diabetes-induced dysfunction of
retinal Muller cells. Trans Am Ophthalmol
Soc 2002; 100:339–352.
66. Faktorovich EG, Steinberg RH, Yasumura D,
et al: Basic fibroblast growth factor and
local injury protect photoreceptors from
light damage in the rat. J Neurosci 1992;
12:3554–3567.
67. LaVail MM, Unoki K, Yasumura D, et al:
Multiple growth factors, cytokines, and
neurotrophins rescue photoreceptors from
the damaging effects of constant light.
Proc Natl Acad Sci U S A 1992;
89:11249–11253.
68. LaVail MM, Yasumura D, Matthes MT, et al:
Protection of mouse photoreceptors by
survival factors in retinal degenerations.
Invest Ophthalmol Vis Sci 1998; 39:592–602.
69. Wahlin KJ, Campochiaro PA, Zack DJ,
Adler R: Neurotrophic factors cause
CHAPTER 125
activation of intracellular signaling
pathways in Muller cells and other cells of
the inner retina, but not photoreceptors.
Invest Ophthalmol Vis Sci 2000;
41:927–936.
70. Wahlin KJ, Adler R, Zack DJ, Campochiaro
PA: Neurotrophic signaling in normal and
degenerating rodent retinas. Exp Eye Res
2001; 73:693–701.
71. Di Polo A, Aigner LJ, Dunn RJ, et al:
Prolonged delivery of brain-derived
neurotrophic factor by adenovirus-infected
Muller cells temporarily rescues injured
retinal ganglion cells. Proc Natl Acad Sci
U S A 1998; 95:3978–3983.
72. Gauthier R, Joly S, Pernet V, et al: Brain-
derived neurotrophic factor gene delivery
to muller glia preserves structure and
function of light-damaged photoreceptors.
Invest Ophthalmol Vis Sci 2005;
46:3383–3392.
73. Goldstein IM, Ostwald P, Roth S: Nitric
oxide: a review of its role in retinal function
and disease. Vision Res 1996;
36:2979–2994.
74. Roth S: Role of nitric oxide in retinal cell
death. Clin Neurosci 1997; 4:216–223.
75. Park CS, Pardhasaradhi K, Gianotti C, et al:
Human retina expresses both constitutive
and inducible isoforms of nitric oxide
synthase mRNA. Biochem Biophys Res
Commun 1994; 205:85–91.
76. Goureau O, Regnier-Ricard F, Courtois Y:
Requirement for nitric oxide in retinal
neuronal cell death induced by activated
Muller glial cells. J Neurochem 1999;
72:2506–2515.
77. Darius S, Wolf G, Huang PL, Fishman MC:
Localization of NADPH-diaphorase/nitric
oxide synthase in the rat retina: an electron
microscopic study. Brain Res 1995;
690:231–235.
78. Cao QL, Murphy HA, Petry HM:
Localization of nitric oxide synthase in the
tree shrew retina. Vis Neurosci 1999;
16:399–409.
79. Goureau O, Hicks D, Courtois Y, De Kozak
Y: Induction and regulation of nitric oxide
synthase in retinal Muller glial cells.
J Neurochem 1994; 63:310–317.
80. Roberge FG, Caspi RR, Chan CC, et al:
Long-term culture of Muller cells from adult
rats in the presence of activated
lymphocytes/monocytes products. Curr
Eye Res 1985; 4:975–982.
81. Kim MK, Chan CC, Belfort R Jr, et al:
Histopathologic and immunohistopathologic
features of subretinal fibrosis and uveitis 1649
 RETINA AND VITREOUS
syndrome. Am J Ophthalmol 1987;
104:15–23.
82. Caspi RR, Roberge FG: Glial cells as
suppressor cells: characterization of the
inhibitory function. J Autoimmun 1989;
2:709–722.
83. Roberge FG, Caspi RR, Nussenblatt RB:
Glial retinal Muller cells produce IL-1
activity and have a dual effect on
autoimmune T helper lymphocytes. Antigen
presentation manifested after removal of
suppressive activity. J Immunol 1988;
140:2193–2196.
84. Chaum E: Retinal neuroprotection by
growth factors: a mechanistic perspective.
J Cell Biochem 2003; 88:57–75.
85. Stone J, Maslim J, Valter-Kocsi K, et al:
Mechanisms of photoreceptor death and
survival in mammalian retina. Prog Retin
Eye Res 1999; 18:689–735.
86. Boehm BO, Lang G, Volpert O, et al: Low
SECTION 10
content of the natural ocular anti-
angiogenic agent pigment epithelium-
derived factor (PEDF) in aqueous humor
predicts progression of diabetic
retinopathy. Diabetologia 2003;
46:394–400.
87. Zhang SX, Wang JJ, Gao G, et al: Pigment
epithelium-derived factor (PEDF) is an
endogenous antiinflammatory factor. Faseb
J 2006; 20:323–325.
88. Eichler W, Yafai Y, Keller T, et al: PEDF
derived from glial Muller cells: a possible
regulator of retinal angiogenesis. Exp Cell
Res 2004; 299:68–78.
89. Ohsato M, Hayashi H, Oshima K, et al: In
situ localization of basic fibroblast growth
factor protein and mRNA in the retina.
Ophthalmic Res 1997; 29:24–30.
90. Seki M, Nawa H, Fukuchi T, et al: BDNF is
upregulated by postnatal development and
visual experience: quantitative and
immunohistochemical analyses of BDNF in
the rat retina. Invest Ophthalmol Vis Sci
2003; 44:3211–3218.
91. Harada T, Harada C, Kohsaka S, et al:
Microglia-Muller glia cell interactions
control neurotrophic factor production
during light-induced retinal degeneration.
J Neurosci 2002; 22:9228–9236.
92. Harada T, Harada C, Nakayama N, et al:
Modification of glial-neuronal cell
interactions prevents photoreceptor
apoptosis during light-induced retinal
degeneration. Neuron 2000; 26:533–541.
93. Drescher KM, Whittum-Hudson JA:
Evidence for induction of interferon-alpha
and interferon-beta in retinal glial cells of
Muller. Virology 1997; 234:309–316.
94. Drescher KM, Whittum-Hudson JA: Herpes
simplex virus type 1 alters transcript levels
of tumor necrosis factor-alpha and
interleukin-6 in retinal glial cells. Invest
Ophthalmol Vis Sci 1996; 37:2302–2312.
95. Taylor S, Srinivasan B, Wordinger RJ,
Roque RS: Glutamate stimulates
neurotrophin expression in cultured Muller
cells. Brain Res Mol Brain Res 2003;
111:189–197.
96. Behzadian MA, Wang XL, Al-Shabrawey M,
Caldwell RB: Effects of hypoxia on glial cell
expression of angiogenesis-regulating
factors VEGF and TGF-beta. Glia 1998;
24:216–225.
97. de Kozak Y, Cotinet A, Goureau O, et al:
Tumor necrosis factor and nitric oxide
production by resident retinal glial cells
1650 from rats presenting hereditary retinal
degeneration. Ocul Immunol Inflamm 1997;
5:85–94.
98. Wen R, Song Y, Cheng T, et al: Injury-
induced upregulation of bFGF and CNTF
mRNAS in the rat retina. J Neurosci 1995;
15:7377–7385.
99. Harada C, Harada T, Quah HM, et al:
Potential role of glial cell line-derived
neurotrophic factor receptors in Muller glial
cells during light-induced retinal
degeneration. Neuroscience 2003;
122:229–235.
100. Hollborn M, Tenckhoff S, Jahn K, et al:
Changes in retinal gene expression in
proliferative vitreoretinopathy: glial cell
expression of HB-EGF. Mol Vis 2005;
11:397–413.
101. Hirata C, Nakano K, Nakamura N, et al:
Advanced glycation end products induce
expression of vascular endothelial growth
factor by retinal Muller cells. Biochem
Biophys Res Commun 1997;
236:712–715.
102. Cao W, Wen R, Li F, et al: Induction of basic
fibroblast growth factor mRNA by basic
fibroblast growth factor in Muller cells. Invest
Ophthalmol Vis Sci 1997; 38:1358–1366.
103. Chun MH, Ju WK, Kim KY, et al:
Upregulation of ciliary neurotrophic factor
in reactive Muller cells in the rat retina
following optic nerve transection. Brain Res
2000; 868:358–362.
104. Casaccia-Bonnefil P, Gu C, Chao MV:
Neurotrophins in cell survival/death
decisions. Adv Exp Med Biol 1999;
468:275–282.
105. Vecino E, Caminos E, Ugarte M, et al:
Immunohistochemical distribution of
neurotrophins and their receptors in the rat
retina and the effects of ischemia and
reperfusion. Gen Pharmacol 1998;
30:305–314.
106. Nakamura K, Harada C, Okumura A, et al:
Effect of p75NTR on the regulation of
photoreceptor apoptosis in the rd mouse.
Mol Vis 2005; 11:1229–1135.
107. Rohrer B, Matthes MT, LaVail MM,
Reichardt LF: Lack of p75 receptor does
not protect photoreceptors from light-
induced cell death. Exp Eye Res 2003;
76:125–129.
108. Marmor MF, Wolfensberger TJ: The retinal
pigment epithelium. New York: Oxford
University Press; 1998.
109. Strauss O: The retinal pigment epithelium
in visual function. Physiol Rev 2005;
85:845–881.
110. Martinez-Morales JR, Rodrigo I, Bovolenta
P: Eye development: a view from the retina
pigmented epithelium. Bioessays 2004;
26:766–777.
111. Zuber ME, Gestri G, Viczian AS, et al:
Specification of the vertebrate eye by a
network of eye field transcription factors.
Development 2003; 130:5155–5167.
112. Wetts R, Fraser SE: Microinjection of
fluorescent tracers to study neural cell
lineages. Development 1991;
(Suppl 2):1–8.
113. Turner DL, Snyder EY, Cepko CL: Lineage-
independent determination of cell type in
the embryonic mouse retina. Neuron 1990;
4:833–845.
114. Wetts R, Fraser SE: Multipotent precursors
can give rise to all major cell types of the
frog retina. Science 1988; 239:1142–1145.
115. Pittack C, Grunwald GB, Reh TA: Fibroblast
growth factors are necessary for neural
retina but not pigmented epithelium
differentiation in chick embryos.
Development 1997; 124:805–816.
116. Tcheng M, Fuhrmann G, Hartmann MP,
et al: Spatial and temporal expression
patterns of FGF receptor genes type 1 and
type 2 in the developing chick retina. Exp
Eye Res 1994; 58:351–358.
117. Fuhrmann S, Levine EM, Reh TA:
Extraocular mesenchyme patterns the optic
vesicle during early eye development in the
embryonic chick. Development 2000;
127:4599–4609.
118. Dohrmann CE, Hemmati-Brivanlou A,
Thomsen GH, et al: Expression of activin
mRNA during early development in
Xenopus laevis. Dev Biol 1993;
157:474–483.
119. Goding CR: Mitf from neural crest to
melanoma: signal transduction and
transcription in the melanocyte lineage.
Genes Dev 2000; 14:1712–1728.
120. Takeda K, Yasumoto K, Kawaguchi N, et al:
Mitf-D, a newly identified isoform,
expressed in the retinal pigment epithelium
and monocyte-lineage cells affected by
Mitf mutations. Biochim Biophys Acta
2002; 1574:15–23.
121. Bovolenta P, Mallamaci A, Briata P, et al:
Implication of OTX2 in pigment epithelium
determination and neural retina
differentiation. J Neurosci 1997;
17:4243–4252.
122. Martinez-Morales JR, Signore M,
Acampora D, et al: Otx genes are required
for tissue specification in the developing
eye. Development 2001; 128:2019–2030.
123. Grindley JC, Davidson DR, Hill RE: The role
of Pax-6 in eye and nasal development.
Development 1995; 121:1433–1442.
124. Baumer N, Marquardt T, Stoykova A, et al:
Retinal pigmented epithelium determination
requires the redundant activities of Pax2 and
Pax6. Development 2003; 130:2903–2915.
125. Belecky-Adams T, Adler R: Developmental
expression patterns of bone
morphogenetic proteins, receptors, and
binding proteins in the chick retina. J Comp
Neurol 2001; 430:562–572.
126. Marti E, Bovolenta P: Sonic hedgehog in
CNS development: one signal, multiple
outputs. Trends Neurosci 2002; 25:89–96.
127. Wang YP, Dakubo G, Howley P, et al:
Development of normal retinal organization
depends on Sonic hedgehog signaling from
ganglion cells. Nat Neurosci 2002;
5:831–832.
128. Rahner C, Fukuhara M, Peng S, et al: The
apical and basal environments of the retinal
pigment epithelium regulate the maturation
of tight junctions during development.
J Cell Sci 2004; 117:3307–3318.
129. Layer PG, Rothermel A, Willbold E:
Inductive effects of the retinal pigmented
epithelium (RPE) on histogenesis of the
avian retina as revealed by retinospheroid
technology. Semin Cell Dev Biol 1998;
9:257–262.
130. Zhao S, Overbeek PA: Regulation of
choroid development by the retinal pigment
epithelium. Mol Vis 2001; 7:277–282.
131. Hollyfield JG, Witkovsky P: Pigmented
retinal epithelium involvement in
photoreceptor development and function.
J Exp Zool 1974; 189:357–378.
132. Gaur VP, Liu Y, Turner JE: RPE conditioned
medium stimulates photoreceptor cell
survival, neurite outgrowth and

differentiation in vitro. Exp Eye Res 1992;
54:645–659.
133. Rapaport DH, Rakic P, LaVail MM:
Spatiotemporal gradients of cell genesis in
the primate retina. Perspect Dev Neurobiol
1996; 3:147–159.
134. Provis JM, van Driel D, Billson FA, Russell
P: Development of the human retina:
patterns of cell distribution and
redistribution in the ganglion cell layer.
J Comp Neurol 1985; 233:429–451.
135. Fleming PA, Braekevelt CR, Harman AM,
Beazley LD: Retinal pigment epithelium
and photoreceptor maturation in a wallaby,
the quokka. J Comp Neurol 1996;
370:47–60.
136. Gundersen D, Powell SK, Rodriguez-
Boulan E: Apical polarization of N-CAM in
retinal pigment epithelium is dependent on
contact with the neural retina. J Cell Biol
1993; 121:335–343.
137. Raymond SM, Jackson IJ: The retinal
pigmented epithelium is required for
development and maintenance of the
mouse neural retina. Curr Biol 1995;
5:1286–1295.
138. Pearson RA, Dale N, Llaudet E, Mobbs P:
ATP released via gap junction hemichannels
from the pigment epithelium regulates
neural retinal progenitor proliferation.
Neuron 2005; 46:731–744.
139. Land PW, Lund RD: Development of the
rat’s uncrossed retinotectal pathway and its
relation to plasticity studies. Science 1979;
205:698–700.
140. Jeffery G: The albino retina: an abnormality
that provides insight into normal retinal
development. Trends Neurosci 1997;
20:165–169.
141. Behling KC, Surace EM, Bennett J:
Pigment epithelium-derived factor
expression in the developing mouse eye.
Mol Vis 2002; 8:449–454.
142. Jablonski MM, Tombran-Tink J, Mrazek
DA, Iannaccone A: Pigment epithelium-
derived factor supports normal
development of photoreceptor neurons and
opsin expression after retinal pigment
epithelium removal. J Neurosci 2000;
20:7149–7157.
143. King GL, Suzuma K: Pigment-epithelium-
derived factor—a key coordinator of retinal
neuronal and vascular functions. N Engl J
Med 2000; 342:349–351.
144. Burns MS, Hartz MJ: The retinal pigment
epithelium induces fenestration of
endothelial cells in vivo. Curr Eye Res
1992; 11:863–873.
145. Rymer J, Wildsoet CF: The role of the
retinal pigment epithelium in eye growth
regulation and myopia: a review. Vis
Neurosci 2005; 22:251–261.
146. Campochiaro PA, Jerdon JA, Glaser BM:
The extracellular matrix of human retinal
pigment epithelial cells in vivo and its
synthesis in vitro. Invest Ophthalmol Vis Sci
1986; 27:1615–1621.
147. Takei Y, Ozanics V: Origin and development
of Bruch’s membrane in monkey fetuses:
an electron microscopic study. Invest
Ophthalmol 1975; 14:903–916.
148. Olson MD: Development of Bruch’s
membrane in the chick: an electron
microscopic study. Invest Ophthalmol Vis
Sci 1979; 18:329–338.
149. Hogan MJ, Alvarado JA, Weddell JE: Retina
Histology of the Human Eye. Philadelphia:
W B Saunders; 1971:393–522.
Müller Cells and the Retinal Pigment Epithelium
150. Ts’o MO, Friedman E: The retinal pigment
epithelium. I. Comparative histology. Arch
Ophthalmol 1967; 78:641–649.
151. Panda-Jonas S, Jonas JB, Jakobczyk-
Zmija M: Retinal pigment epithelial cell
count, distribution, and correlations in
normal human eyes. Am J Ophthalmol
1996; 121:181–189.
152. Dorey CK, Wu G, Ebenstein D, et al: Cell
loss in the aging retina. Relationship to
lipofuscin accumulation and macular
degeneration. Invest Ophthalmol Vis Sci
1989; 30:1691–1699.
153. Krebs W, Krebs IP: Quantitative
morphology of the central fovea in the
primate retina. Am J Anat 1989;
184:225–236.
154. Curcio CA, Millican CL, Allen KA, Kalina
RE: Aging of the human photoreceptor
mosaic: evidence for selective vulnerability
of rods in central retina. Invest Ophthalmol
Vis Sci 1993; 34:3278–3296.
155. Feeney-Burns L, Burns RP, Gao CL: Age-
related macular changes in humans over
90 years old. Am J Ophthalmol 1990;
109:265–278.
156. Gao H, Hollyfield JG: Aging of the human
retina. Differential loss of neurons and
retinal pigment epithelial cells. Invest
Ophthalmol Vis Sci 1992; 33:1–17.
157. Panda-Jonas S, Jonas JB, Jakobczyk-
Zmija M: Retinal photoreceptor density
decreases with age. Ophthalmology 1995;
102:1853–1859.
158. Panda-Jonas S, Jonas JB, Jakobczyk M,
Schneider U: Retinal photoreceptor count,
retinal surface area, and optic disc size in
normal human eyes. Ophthalmology 1994;
101:519–523.
159. Watzke RC, Soldevilla JD, Trune DR:
Morphometric analysis of human retinal
pigment epithelium: correlation with age and
location. Curr Eye Res 1993; 12:133–142.
160. Burke JM, Skumatz CM, Irving PE, McKay
BS: Phenotypic heterogeneity of retinal
pigment epithelial cells in vitro and in situ.
Exp Eye Res 1996; 62:63–73.
161. Ts’o MO, Friedman E: The retinal pigment
epithelium. III. Growth and development.
Arch Ophthalmol 1968; 80:214–216.
162. Nagai H, Kalnins VI: Normally occurring
loss of single cells and repair of resulting
defects in retinal pigment epithelium in situ.
Exp Eye Res 1996; 62:55–61.
163. Feeney-Burns L, Hilderbrand ES, Eldridge
S: Aging human RPE: morphometric
analysis of macular, equatorial, and
peripheral cells. Invest Ophthalmol Vis Sci
1984; 25:195–200.
164. Aijaz S, Balda MS, Matter K: Tight
junctions: molecular architecture and
function. Int Rev Cytol 2006; 248:261–298.
165. Zhao S, Rizzolo LJ, Barnstable CJ:
Differentiation and transdifferentiation of
the retinal pigment epithelium. Int Rev
Cytol 1997; 171:225–266.
166. Nicholson BJ: Gap junctions – from
cell to molecule. J Cell Sci 2003;
116:4479–4481.
167. Kita M, Marmor MF: Retinal adhesive force
in living rabbit, cat, and monkey eyes.
Normative data and enhancement by
mannitol and acetazolamide. Invest
Ophthalmol Vis Sci 1992; 33:1879–1882.
168. Marmor MF, Yao XY: The metabolic
dependency of retinal adhesion in rabbit
and primate. Arch Ophthalmol 1995;
113:232–238.
169. Yao XY, Hageman GS, Marmor MF: Retinal
adhesiveness is weakened by enzymatic
modification of the interphotoreceptor
matrix in vivo. Invest Ophthalmol Vis Sci
1990; 31:2051–2058.
170. Marmor MF, Yao XY, Hageman GS: Retinal
adhesiveness in surgically enucleated
human eyes. Retina 1994; 14:181–186.
171. Yao XY, Hageman GS, Marmor MF: Retinal
adhesiveness in the monkey. Invest
Ophthalmol Vis Sci 1994; 35:744–748.
172. Fatt I, Shantinath K: Flow conductivity of
retina and its role in retinal adhesion. Exp
Eye Res 1971; 12:218–226.
173. Marmor MF: Retinal detachment from
hyperosmotic intravitreal injection. Invest
Ophthalmol Vis Sci 1979; 18:1237–1244.
174. Kita M, Marmor MF: Systemic mannitol
increases the retinal adhesive force in vivo.
Arch Ophthalmol 1991; 109:1449–1450.
CHAPTER 125
175. Nandrot EF, Anand M, Sircar M, Finnemann
SC: Novel role for alphavbeta5–integrin in
retinal adhesion and its diurnal peak. Am J
Physiol Cell Physiol 2006;
290:C1256–C1262.
176. Mayerson PL, Hall MO: Rat retinal pigment
epithelial cells show specificity of
phagocytosis in vitro. J Cell Biol 1986;
103:299–308.
177. Young RW: The Bowman Lecture, 1982.
Biological renewal. Applications to the eye.
Trans Ophthalmol Soc U K 1982; 102
(Pt 1):42–75.
178. LaVail MM: Kinetics of rod outer segment
renewal in the developing mouse retina.
J Cell Biol 1973; 58:650–661.
179. Young RW, Bok D: Participation of the
retinal pigment epithelium in the rod outer
segment renewal process. J Cell Biol 1969;
42:392–403.
180. Bok D: The retinal pigment epithelium: a
versatile partner in vision. J Cell Sci Suppl
1993; 17:189–195.
181. Steinberg RH, Wood I: Pigment epithelial
cell ensheathment of cone outer segments
in the retina of the domestic cat. Proc R
Soc Lond B Biol Sci 1974; 187:461–478.
182. Steinberg RH, Wood I, Hogan MJ: Pigment
epithelial ensheathment and phagocytosis
of extrafoveal cones in human retina. Philos
Trans R Soc Lond B Biol Sci 1977;
277:459–474.
183. Nguyen-Legros J, Hicks D: Renewal of
photoreceptor outer segments and their
phagocytosis by the retinal pigment
epithelium. Int Rev Cytol 2000; 196:245–313.
184. Young RW: An hypothesis to account for a
basic distinction between rods and cones.
Vision Res 1971; 11:1–5.
185. Williams DS, Fisher SK: Prevention of rod
disk shedding by detachment from the
retinal pigment epithelium. Invest
Ophthalmol Vis Sci 1987; 28:184–187.
186. Sidman RL, Kosaras B, Tang M: Pigment
epithelial and retinal phenotypes in the
vitiligo mivit, mutant mouse. Invest
Ophthalmol Vis Sci 1996; 37:1097–1115.
187. Sun M, Finnemann SC, Febbraio M, et al:
Light-induced oxidation of photoreceptor
outer segment phospholipids generates
ligands for CD36–mediated phagocytosis
by retinal pigment epithelium: a potential
mechanism for modulating outer segment
phagocytosis under oxidant stress
conditions. J Biol Chem 2006;
281:4222–4230.
188. Boyle D, Tien LF, Cooper NG, et al: A
mannose receptor is involved in retinal 1651
 RETINA AND VITREOUS
phagocytosis. Invest Ophthalmol Vis Sci
1991; 32:1464–1470.
189. Feng W, Yasumura D, Matthes MT, et al:
Mertk triggers uptake of photoreceptor
outer segments during phagocytosis by
cultured retinal pigment epithelial cells.
J Biol Chem 2002; 277:17016–17022.
190. Finnemann SC, Silverstein RL: Differential
roles of CD36 and alphavbeta5 integrin in
photoreceptor phagocytosis by the retinal
pigment epithelium. J Exp Med 2001;
194:1289–1298.
191. Finnemann SC, Bonilha VL, Marmorstein
AD, Rodriguez-Boulan E: Phagocytosis of
rod outer segments by retinal pigment
epithelial cells requires alpha(v)beta5
integrin for binding but not for
internalization. Proc Natl Acad Sci U S A
1997; 94:12932–12937.
192. Gregory CY, Hall MO: The phagocytosis of
ROS by RPE cells is inhibited by an
SECTION 10
antiserum to rat RPE cell plasma
membranes. Exp Eye Res 1992;
54:843–851.
193. Kindzelskii AL, Elner VM, Elner SG, et al:
Toll-like receptor 4 (TLR4) of retinal pigment
epithelial cells participates in
transmembrane signaling in response to
photoreceptor outer segments. J Gen
Physiol 2004; 124:139–149.
194. Chaitin MH, Hall MO: Defective ingestion of
rod outer segments by cultured dystrophic
rat pigment epithelial cells. Invest
Ophthalmol Vis Sci 1983; 24:812–820.
195. Chen J, Carey K, Godowski PJ:
Identification of Gas6 as a ligand for Mer, a
neural cell adhesion molecule related
receptor tyrosine kinase implicated in
cellular transformation. Oncogene 1997;
14:2033–2039.
196. Hall MO, Prieto AL, Obin MS, et al: Outer
segment phagocytosis by cultured retinal
pigment epithelial cells requires Gas6. Exp
Eye Res 2001; 73:509–520.
197. Hall MO, Agnew BJ, Abrams TA, Burgess
BL: The phagocytosis of os is mediated by
the PI3-kinase linked tyrosine kinase
receptor, mer, and is stimulated by GAS6.
Adv Exp Med Biol 2003; 533:331–336.
198. Finnemann SC: Focal adhesion kinase
signaling promotes phagocytosis of
integrin-bound photoreceptors. Embo J
2003; 22:4143–4154.
199. Heth CA, Marescalchi PA: Inositol
triphosphate generation in cultured rat
retinal pigment epithelium. Invest
Ophthalmol Vis Sci 1994; 35:409–416.
200. Hall MO, Abrams TA, Mittag TW: ROS
ingestion by RPE cells is turned off by
increased protein kinase C activity and by
increased calcium. Exp Eye Res 1991;
52:591–598.
201. Hall MO, Abrams TA, Mittag TW: The
phagocytosis of rod outer segments is
inhibited by drugs linked to cyclic adenosine
monophosphate production. Invest
Ophthalmol Vis Sci 1993; 34:2392–2401.
202. Edwards RB, Flaherty PM: Association of
changes in intracellular cyclic AMP with
changes in phagocytosis in cultured rat
pigment epithelium. Curr Eye Res 1986;
5:19–26.
203. Burnside MB: Possible roles of microtubules
and actin filaments in retinal pigmented
epithelium. Exp Eye Res 1976; 23:257–275.
204. Bosch E, Horwitz J, Bok D: Phagocytosis
of outer segments by retinal pigment
1652 epithelium: phagosome-lysosome
interaction. J Histochem Cytochem 1993;
41:253–263.
205. Rakoczy PE, Lai CM, Baines M, et al:
Modulation of cathepsin D activity in retinal
pigment epithelial cells. Biochem J 1997;
324 (Pt 3):935–940.
206. Zimmerman WF, Godchaux W III, Belkin M:
The relative proportions of lysosomal
enzyme activities in bovine retinal pigment
epithelium. Exp Eye Res 1983; 36:151–158.
207. Rakoczy PE, Mann K, Cavaney DM, et al:
Detection and possible functions of a
cysteine protease involved in digestion of
rod outer segments by retinal pigment
epithelial cells. Invest Ophthalmol Vis Sci
1994; 35:4100–4108.
208. Ershov AV, Lukiw WJ, Bazan NG: Selective
transcription factor induction in retinal
pigment epithelial cells during
photoreceptor phagocytosis. J Biol Chem
1996; 271:28458–28462.
209. Ershov AV, Bazan NG: Photoreceptor
phagocytosis selectively activates
PPARgamma expression in retinal pigment
epithelial cells. J Neurosci Res 2000;
60:328–337.
210. Gregory CY, Abrams TA, Hall MO: Stimulation
of A2 adenosine receptors inhibits the
ingestion of photoreceptor outer segments
by retinal pigment epithelium. Invest
Ophthalmol Vis Sci 1994; 35:819–825.
211. Cahill GM, Besharse JC: Circadian
rhythmicity in vertebrate retinas: regulation
by a photoreceptor oscillator. Prog Retin
Eye Res 1995; 14:267–291.
212. Nandrot EF, Kim Y, Brodie SE, et al: Loss of
synchronized retinal phagocytosis and age-
related blindness in mice lacking
alphavbeta5 integrin. J Exp Med 2004;
200:1539–1545.
213. Tanihara H, Inatani M, Honda Y: Growth
factors and their receptors in the retina and
pigment epithelium. Prog Retin Eye Res
1997; 16:271–301.
214. Tombran-Tink J, Shivaram SM, Chader GJ,
et al: Expression, secretion, and age-
related downregulation of pigment
epithelium-derived factor, a serpin with
neurotrophic activity. J Neurosci 1995;
15:4992–5003.
215. Steele FR, Chader GJ, Johnson LV,
Tombran-Tink J: Pigment epithelium-
derived factor: neurotrophic activity and
identification as a member of the serine
protease inhibitor gene family. Proc Natl
Acad Sci U S A 1993; 90:1526–1530.
216. Ogata N, Wang L, Jo N, et al: Pigment
epithelium derived factor as a neuroprotective
agent against ischemic retinal injury. Curr Eye
Res 2001; 22:245–252.
217. Dawson DW, Volpert OV, Gillis P, et al:
Pigment epithelium-derived factor: a potent
inhibitor of angiogenesis. Science 1999;
285:245–248.
218. Barnstable CJ, Tombran-Tink J:
Neuroprotective and antiangiogenic actions
of PEDF in the eye: molecular targets and
therapeutic potential. Prog Retin Eye Res
2004; 23:561–577.
219. Adamis AP, Shima DT, Yeo KT, et al:
Synthesis and secretion of vascular
permeability factor/vascular endothelial
growth factor by human retinal pigment
epithelial cells. Biochem Biophys Res
Commun 1993; 193:631–638.
220. Becerra SP, Fariss RN, Wu YQ, et al:
Pigment epithelium-derived factor in the
monkey retinal pigment epithelium and
interphotoreceptor matrix: apical secretion
and distribution. Exp Eye Res 2004;
78:223–234.
221. Blaauwgeers HG, Holtkamp GM, Rutten H,
et al: Polarized vascular endothelial growth
factor secretion by human retinal pigment
epithelium and localization of vascular
endothelial growth factor receptors on the
inner choriocapillaris. Evidence for a
trophic paracrine relation. Am J Pathol
1999; 155:421–428.
222. Jablonski MM, Tombran-Tink J, Mrazek
DA, Iannaccone A: Pigment epithelium-
derived factor supports normal Muller cell
development and glutamine synthetase
expression after removal of the retinal
pigment epithelium. Glia 2001; 35:14–25.
223. Yoshimura N, Matsumoto M, Shimizu H,
et al: Photocoagulated human retinal
pigment epithelial cells produce an inhibitor
of vascular endothelial cell proliferation.
Invest Ophthalmol Vis Sci 1995;
36:1686–1691.
224. Khaliq A, Patel B, Jarvis-Evans J, et al:
Oxygen modulates production of bFGF and
TGF-beta by retinal cells in vitro. Exp Eye
Res 1995; 60:415–423.
225. Baudouin C, Fredj-Reygrobellet D, Brignole
F, et al: Growth factors in vitreous and
subretinal fluid cells from patients with
proliferative vitreoretinopathy. Ophthalmic
Res 1993; 25:52–59.
226. Amin R, Puklin JE, Frank RN: Growth factor
localization in choroidal neovascular
membranes of age-related macular
degeneration. Invest Ophthalmol Vis Sci
1994; 35:3178–3188.
227. Lutty GA, Merges C, Crone S, McLeod DS:
Immunohistochemical insights into sickle
cell retinopathy. Curr Eye Res 1994;
13:125–138.
228. Raymond MC, Thompson JT: RPE-mediated
collagen gel contraction. Inhibition by
colchicine and stimulation by TGF-beta.
Invest Ophthalmol Vis Sci 1990;
31:1079–1086.
229. Campochiaro PA, Glaser BM: Platelet-
derived growth factor is chemotactic for
human retinal pigment epithelial cells. Arch
Ophthalmol 1985; 103:576–579.
230. Nagineni CN, Kutty V, Detrick B, Hooks JJ:
Expression of PDGF and their receptors in
human retinal pigment epithelial cells and
fibroblasts: regulation by TGF-beta. J Cell
Physiol 2005; 203:35–43.
231. Brunk UT, Terman A: Lipofuscin:
mechanisms of age-related accumulation
and influence on cell function. Free Radic
Biol Med 2002; 33:611–619.
232. Sundelin SP, Nilsson SE, Brunk UT:
Lipofuscin-formation in cultured retinal
pigment epithelial cells is related to their
melanin content. Free Radic Biol Med
2001; 30:74–81.
233. Wing GL, Blanchard GC, Weiter JJ: The
topography and age relationship of
lipofuscin concentration in the retinal
pigment epithelium. Invest Ophthalmol Vis
Sci 1978; 17:601–607.
234. Katz ML, Drea CM, Eldred GE, et al: Influence
of early photoreceptor degeneration on
lipofuscin in the retinal pigment epithelium.
Exp Eye Res 1986; 43:561–573.
235. Lorenz B, Wabbels B, Wegscheider E,
et al: Lack of fundus autofluorescence to
488 nanometers from childhood on in
patients with early-onset severe retinal
dystrophy associated with mutations in

RPE65. Ophthalmology 2004;
111:1585–1594.
236. Katz ML, Eldred GE: Retinal light damage
reduces autofluorescent pigment
deposition in the retinal pigment epithelium.
Invest Ophthalmol Vis Sci 1989; 30:37–43.
237. Feeney L: Lipofuscin and melanin of human
retinal pigment epithelium. Fluorescence,
enzyme cytochemical, and ultrastructural
studies. Invest Ophthalmol Vis Sci 1978;
17:583–600.
238. Burke JM, Skumatz CM: Autofluorescent
inclusions in long-term postconfluent
cultures of retinal pigment epithelium. Invest
Ophthalmol Vis Sci 1998; 39:1478–1486.
239. Katz ML, Gao CL, Rice LM: Formation of
lipofuscin-like fluorophores by reaction of
retinal with photoreceptor outer segments
and liposomes. Mech Ageing Dev 1996;
92:159–174.
240. Wassell J, Ellis S, Burke J, Boulton M:
Fluorescence properties of autofluorescent
granules generated by cultured human RPE
cells. Invest Ophthalmol Vis Sci 1998;
39:1487–1492.
241. Sundelin S, Wihlmark U, Nilsson SE, Brunk
UT: Lipofuscin accumulation in cultured
retinal pigment epithelial cells reduces their
phagocytic capacity. Curr Eye Res 1998;
17:851–857.
242. Katz ML, Drea CM, Robison WG Jr:
Relationship between dietary retinol and
lipofuscin in the retinal pigment epithelium.
Mech Ageing Dev 1986; 35:291–305.
243. Delori FC, Goger DG, Dorey CK: Age-
related accumulation and spatial
distribution of lipofuscin in RPE of normal
subjects. Invest Ophthalmol Vis Sci 2001;
42:1855–1866.
244. Sparrow JR, Zhou J, Ben-Shabat S, et al:
Involvement of oxidative mechanisms in
blue-light-induced damage to A2E-laden
RPE. Invest Ophthalmol Vis Sci 2002;
43:1222–1227.
245. Sparrow JR, Boulton M: RPE lipofuscin and
its role in retinal pathobiology. Exp Eye Res
2005; 80:595–606.
246. Liu J, Itagaki Y, Ben-Shabat S, et al: The
biosynthesis of A2E, a fluorophore of aging
retina, involves the formation of the
precursor, A2–PE, in the photoreceptor
outer segment membrane. J Biol Chem
2000; 275:29354–29360.
247. Ben-Shabat S, Parish CA, Vollmer HR,
et al: Biosynthetic studies of A2E, a major
fluorophore of retinal pigment epithelial
lipofuscin. J Biol Chem 2002;
277:7183–7190.
248. Parish CA, Hashimoto M, Nakanishi K,
et al: Isolation and one-step preparation of
A2E and iso-A2E, fluorophores from human
retinal pigment epithelium. Proc Natl Acad
Sci U S A 1998; 95:14609–14613.
249. Ivy GO, Kanai S, Ohta M, et al: Lipofuscin-
like substances accumulate rapidly in brain,
retina and internal organs with cysteine
protease inhibition. Adv Exp Med Biol
1989; 266:31–45; discussion 45–47.
250. Kikugawa K, Kato T, Beppu M, Hayasaka
A: Fluorescent and cross-linked proteins
formed by free radical and aldehyde
species generated during lipid oxidation.
Adv Exp Med Biol 1989; 266:345–356;
discussion 357.
251. Terman A, Abrahamsson N, Brunk UT:
Ceroid/lipofuscin-loaded human fibroblasts
show increased susceptibility to oxidative
stress. Exp Gerontol 1999; 34:755–770.
Müller Cells and the Retinal Pigment Epithelium
252. Boulton M, Dontsov A, Jarvis-Evans J,
et al: Lipofuscin is a photoinducible free
radical generator. J Photochem Photobiol B
1993; 19:201–204.
253. Davies S, Elliott MH, Floor E, et al:
Photocytotoxicity of lipofuscin in human
retinal pigment epithelial cells. Free Radic
Biol Med 2001; 31:256–265.
254. Schutt F, Davies S, Kopitz J, et al:
Photodamage to human RPE cells by
A2–E, a retinoid component of lipofuscin.
Invest Ophthalmol Vis Sci 2000;
41:2303–2308.
255. Terman A, Brunk UT: Ceroid/lipofuscin
formation in cultured human fibroblasts: the
role of oxidative stress and lysosomal
proteolysis. Mech Ageing Dev 1998;
104:277–291.
256. Schutt F, Bergmann M, Holz FG, Kopitz J:
Proteins modified by malondialdehyde,
4–hydroxynonenal, or advanced glycation
end products in lipofuscin of human retinal
pigment epithelium. Invest Ophthalmol Vis
Sci 2003; 44:3663–3668.
257. Katz ML: Incomplete proteolysis may
contribute to lipofuscin accumulation in the
retinal pigment epithelium. Adv Exp Med Biol
1989; 266:109–116; discussion 116–118.
258. Finnemann SC, Leung LW, Rodriguez-
Boulan E: The lipofuscin component A2E
selectively inhibits phagolysosomal
degradation of photoreceptor phospholipid
by the retinal pigment epithelium. Proc Natl
Acad Sci U S A 2002; 99:3842–3847.
259. Sparrow JR, Fishkin N, Zhou J, et al: A2E,
a byproduct of the visual cycle. Vision Res
2003; 43:2983–2990.
260. Hamann S: Molecular mechanisms of water
transport in the eye. Int Rev Cytol 2002;
215:395–431.
261. Hughes BA, Gallemore RP, Miller SS:
Transport mechanisms in the retinal
pigment epithelium. In: Marmor MF,
Wolfensberger TJ, eds. The retinal pigment
epithelium. New York: Oxford University
Press; 1998.
262. Steinberg RH, Linsenmeier RA, Griff ER:
Retinal pigment epithelial cell contributions to
the electroretinogram and electrooculogram.
Prog Retin Eye Res 1985; 4:33–66.
263. Jaffe GJ, Burke JM, Geroski DH: Ouabain-
sensitive Na+-K+ ATPase pumps in
cultured human retinal pigment epithelium.
Exp Eye Res 1989; 48:61–68.
264. Miller SS, Steinberg RH, Oakley B II:The
electrogenic sodium pump of the frog
retinal pigment epithelium. J Membr Biol
1978; 44:259–279.
265. Hu JG, Gallemore RP, Bok D, Frambach
DA: Chloride transport in cultured fetal
human retinal pigment epithelium. Exp Eye
Res 1996; 62:443–448.
266. Kennedy BG: Na(+)-K(4)-Cl- cotransport in
cultured cells derived from human retinal
pigment epithelium. Am J Physiol 1990;
259:C29–C34.
267. Sun H, Tsunenari T, Yau KW, Nathans J: The
vitelliform macular dystrophy protein defines
a new family of chloride channels. Proc
Natl Acad Sci U S A 2002; 99:4008–4013.
268. Ueda Y, Steinberg RH: Chloride currents in
freshly isolated rat retinal pigment epithelial
cells. Exp Eye Res 1994; 58:331–342.
269. Weng TX, Godley BF, Jin GF, et al: Oxidant
and antioxidant modulation of chloride
channels expressed in human retinal
pigment epithelium. Am J Physiol Cell
Physiol 2002; 283:C839–C849.
270. Blaug S, Quinn R, Quong J, et al: Retinal
pigment epithelial function: a role for
CFTR? Doc Ophthalmol 2003; 106:43–50.
271. Hughes BA, Adorante JS, Miller SS, Lin H:
Apical electrogenic NaHCO3 cotransport.
A mechanism for HCO3 absorption across
the retinal pigment epithelium. J Gen
Physiol 1989; 94:125–150.
272. Lin H, Kenyon E, Miller SS: Na-dependent
pHi regulatory mechanisms in native
human retinal pigment epithelium. Invest
Ophthalmol Vis Sci 1992; 33:3528–3538.
273. Celesia GG: Anatomy and physiology of
visual evoked potentials and
electroretinograms. Neurol Clin 1988;
6:657–679.
274. Steinberg RH, Schmidt R, Brown KT:
Intracellular responses to light from cat
pigment epithelium: origin of the
electroretinogram c-wave. Nature 1970;
CHAPTER 125
227:728–730.
275. Karowski CJ, Proenza LM: Relationship
between Muller cell responses, a local
transretinal potential, and potassium flux.
J Neurophysiol 1977; 40:244–259.
276. Linsenmeier RA, Steinberg RH: Delayed
basal hyperpolarization of cat retinal
pigment epithelium and its relation to the
fast oscillation of the DC electroretinogram.
J Gen Physiol 1984; 83:213–232.
277. Philp NJ, Yoon H, Grollman EF:
Monocarboxylate transporter MCT1 is
located in the apical membrane and MCT3
in the basal membrane of rat RPE. Am J
Physiol 1998; 274:R1824–R1828.
278. Senanayake P, Calabro A, Hu JG, et al:
Glucose utilization by the retinal pigment
epithelium: evidence for rapid uptake and
storage in glycogen, followed by glycogen
utilization. Exp Eye Res 2006; 83:235–246.
279. Ban Y, Rizzolo LJ: Regulation of glucose
transporters during development of the
retinal pigment epithelium. Brain Res Dev
Brain Res 2000; 121:89–95.
280. Blomhoff R, Green MH, Berg T, Norum KR:
Transport and storage of vitamin A.
Science 1990; 250:399–404.
281. Bok D, Heller J: Transport of retinol from
the blood to the retina: an autoradiographic
study of the pigment epithelial cell surface
receptor for plasma retinol-binding protein.
Exp Eye Res 1976; 22:395–402.
282. Bazan NG, Gordon WC, Rodriguez de
Turco EB: Docosahexaenoic acid uptake
and metabolism in photoreceptors: retinal
conservation by an efficient retinal pigment
epithelial cell-mediated recycling process.
Adv Exp Med Biol 1992; 318:295–306.
283. Jeffrey BG, Weisinger HS, Neuringer M,
Mitchell DC: The role of docosahexaenoic
acid in retinal function. Lipids 2001;
36:859–871.
284. Petrukhin K, Koisti MJ, Bakall B, et al:
Identification of the gene responsible for
Best macular dystrophy. Nat Genet 1998;
19:241–247.
285. Yardley J, Leroy BP, Hart-Holden N, et al:
Mutations of VMD2 splicing regulators
cause nanophthalmos and autosomal
dominant vitreoretinochoroidopathy
(ADVIRC). Invest Ophthalmol Vis Sci 2004;
45:3683–3689.
286. Kaufman SJ, Goldberg MF, Orth DH,
et al: Autosomal dominant
vitreoretinochoroidopathy. Arch Ophthalmol
1982; 100:272–278.
287. Wu J, Marmorstein AD, Peachey NS:
Functional abnormalities in the retinal 1653
 RETINA AND VITREOUS
pigment epithelium of CFTR mutant mice.
Exp Eye Res 2006; 83:424–428.
288. Tsuboi S, Pederson JE: Volume flow across
the isolated retinal pigment epithelium of
cynomolgus monkey eyes. Invest
Ophthalmol Vis Sci 1988; 29:1652–1655.
289. Tsuboi S: Measurement of the volume flow
and hydraulic conductivity across the
isolated dog retinal pigment epithelium.
Invest Ophthalmol Vis Sci 1987;
28:1776–1782.
290. Emi K, Pederson JE, Toris CB: Hydrostatic
pressure of the suprachoroidal space. Invest
Ophthalmol Vis Sci 1989; 30:233–238.
291. Negi A, Kawano S, Marmor MF: Effects of
intraocular pressure and other factors on
subretinal fluid resorption. Invest
Ophthalmol Vis Sci 1987; 28:2099–2102.
292. Takeuchi A, Kricorian G, Yao XY, et al: The
rate and source of albumin entry into
saline-filled experimental retinal
SECTION 10
detachments. Invest Ophthalmol Vis Sci
1994; 35:3792–3798.
293. Takeuchi A, Kricorian G, Marmor MF:
Albumin movement out of the subretinal
space after experimental retinal
detachment. Invest Ophthalmol Vis Sci
1995; 36:1298–1305.
294. Chihara E, Nao-i N: Resorption of
subretinal fluid by transepithelial flow of the
retinal pigment epithelium. Graefes Arch
Clin Exp Ophthalmol 1985; 223:202–204.
295. Nielsen S, Smith BL, Christensen EI, Agre
P: Distribution of the aquaporin CHIP in
secretory and resorptive epithelia and
capillary endothelia. Proc Natl Acad Sci U
S A 1993; 90:7275–7279.
296. Stamer WD, Bok D, Hu J, et al: Aquaporin-
1 channels in human retinal pigment
epithelium: role in transepithelial water
movement. Invest Ophthalmol Vis Sci 2003;
44:2803–2808.
297. Boulton M: Melanin and the RPE. In:
Marmor MF, Wolfensberger TJ, eds. The
retinal pigment epithelium. New York:
Oxford University Press; 1998:68–85.
298. Boissy RE: The melanocyte. Its structure,
function, and subpopulations in skin, eyes,
and hair. Dermatol Clin 1988; 6:161–173.
299. Schraermeyer U: Does melanin turnover
occur in the eyes of adult vertebrates?
Pigment Cell Res 1993; 6:193–204.
300. Boulton M, Docchio F, Dayhaw-Barker P,
et al: Age-related changes in the
morphology, absorption and fluorescence
of melanosomes and lipofuscin granules of
the retinal pigment epithelium. Vision Res
1990; 30:1291–1303.
301. Schraermeyer U, Kopitz J, Peters S, et al:
Tyrosinase biosynthesis in adult
mammalian retinal pigment epithelial cells.
Exp Eye Res 2006; 83:315–321.
302. Seiji M, Fitzpatrick TB, Birbeck MS: The
melanosome: a distinctive subcellular
particle of mammalian melanocytes and the
site of melanogenesis. J Invest Dermatol
1961; 36:243–252.
303. Seiji M, Shimao K, Birbeck MS, Fitzpatrick
TB: Subcellular localization of melanin
biosynthesis. Ann N Y Acad Sci 1963;
100:497–533.
304. Schmidt SY, Peisch RD: Melanin
concentration in normal human retinal
pigment epithelium. Regional variation and
age-related reduction. Invest Ophthalmol
Vis Sci 1986; 27:1063–1067.
305. Weiter JJ, Delori FC, Wing GL, Fitch KA:
1654 Retinal pigment epithelial lipofuscin and
melanin and choroidal melanin in human
eyes. Invest Ophthalmol Vis Sci 1986;
27:145–152.
306. Sarna T: Properties and function of the
ocular melanin—a photobiophysical view.
J Photochem Photobiol B 1992; 12:215–258.
307. Kobayashi N, Muramatsu T, Yamashina Y,
et al: Melanin reduces ultraviolet-induced
DNA damage formation and killing rate in
cultured human melanoma cells. J Invest
Dermatol 1993; 101:685–689.
308. Rapp LM, Williams TP: The role of ocular
pigmentation in protecting against retinal
light damage. Vision Res 1980;
20:1127–1131.
309. Sanyal S, Zeilmaker GH: Retinal damage
by constant light in chimaeric mice:
implications for the protective role of
melanin. Exp Eye Res 1988; 46:731–743.
310. LaVail MM, Gorrin GM: Protection from
light damage by ocular pigmentation:
analysis using experimental chimeras and
translocation mice. Exp Eye Res 1987;
44:877–889.
311. Sarna T, Menon IA, Sealy RC:
Photosensitization of melanins: a
comparative study. Photochem Photobiol
1985; 42:529–532.
312. Felix CC, Hyde JS, Sarna T, Sealy RC:
Melanin photoreactions in aerated media:
electron spin resonance evidence for
production of superoxide and hydrogen
peroxide. Biochem Biophys Res Commun
1978; 84:335–341.
313. Ham WT Jr, Ruffolo JJ Jr, Mueller HA,
Guerry D III: The nature of retinal radiation
damage: dependence on wavelength,
power level and exposure time. Vision Res
1980; 20:1105–1111.
314. Rozanowska M, Jarvis-Evans J, Korytowski
W, et al: Blue light-induced reactivity of
retinal age pigment. In vitro generation of
oxygen-reactive species. J Biol Chem
1995; 270:18825–18830.
315. Marshall J: Lasers in ophthalmology: the
basic principles. Eye 1988; 2:S98–S112.
316. Hansen WP, Fine S: Melanin granule
models for pulsed laser induced retinal
injury. Appl Opt 1968; 7:155–158.
317. Koneru PB, Lien EJ, Koda RT: Oculotoxicities
of systemically administered drugs. J Ocul
Pharmacol 1986; 2:385–404.
318. Drager UC: Calcium binding in pigmented
and albino eyes. Proc Natl Acad Sci U S A
1985; 82:6716–6720.
319. Larsson BS: Interaction between chemicals
and melanin. Pigment Cell Res 1993;
6:127–133.
320. Arshavsky VY, Lamb TD, Pugh EN, Jr: G
proteins and phototransduction. Annu Rev
Physiol 2002; 64:153–187.
321. Burns ME, Baylor DA: Activation,
deactivation, and adaptation in vertebrate
photoreceptor cells. Annu Rev Neurosci
2001; 24:779–805.
322. Sun H, Nathans J: Stargardt’s ABCR is
localized to the disc membrane of retinal
rod outer segments. Nat Genet 1997;
17:15–16.
323. Molday LL, Rabin AR, Molday RS: ABCR
expression in foveal cone photoreceptors
and its role in Stargardt macular dystrophy.
Nat Genet 2000; 25:257–258.
324. Pepperberg DR, Okajima TL, Wiggert B,
et al: Interphotoreceptor retinoid-binding
protein (IRBP). Molecular biology and
physiological role in the visual cycle of
rhodopsin. Mol Neurobiol 1993; 7:61–85.
325. Gonzalez-Fernandez F: Interphotoreceptor
retinoid-binding protein—an old gene for
new eyes. Vision Res 2003; 43:3021–3036.
326. Arshavsky V: Like night and day: rods and
cones have different pigment regeneration
pathways. Neuron 2002; 36:1–3.
327. Mata NL, Moghrabi WN, Lee JS, et al:
Rpe65 is a retinyl ester binding protein that
presents insoluble substrate to the
isomerase in retinal pigment epithelial cells.
J Biol Chem 2004; 279:635–643.
328. Xue L, Gollapalli DR, Maiti P, et al: A
palmitoylation switch mechanism in the
regulation of the visual cycle. Cell 2004;
117:761–771.
329. Jang GF, Van Hooser JP, Kuksa V, et al:
Characterization of a dehydrogenase
activity responsible for oxidation of 11-cis-
retinol in the retinal pigment epithelium of
mice with a disrupted RDH5 gene. A model
for the human hereditary disease fundus
albipunctatus. J Biol Chem 2001;
276:32456–32465.
330. Saari JC, Nawrot M, Kennedy BN, et al:
Visual cycle impairment in cellular
retinaldehyde binding protein (CRALBP)
knockout mice results in delayed dark
adaptation. Neuron 2001; 29:739–748.
331. Chen P, Hao W, Rife L, et al: A photic visual
cycle of rhodopsin regeneration is dependent
on Rgr. Nat Genet 2001; 28:256–260.
332. McBee JK, Palczewski K, Baehr W,
Pepperberg DR: Confronting complexity:
the interlink of phototransduction and
retinoid metabolism in the vertebrate retina.
Prog Retin Eye Res 2001; 20:469–529.
333. Martinez-Mir A, Paloma E, Allikmets R,
et al: Retinitis pigmentosa caused by a
homozygous mutation in the Stargardt
disease gene ABCR. Nat Genet 1998;
18:11–12.
334. Allikmets R, Shroyer NF, Singh N, et al:
Mutation of the Stargardt disease gene
(ABCR) in age-related macular degeneration.
Science 1997; 277:1805–1807.
335. Stone EM, Webster AR, Vandenburgh K,
et al: Allelic variation in ABCR associated
with Stargardt disease but not age-related
macular degeneration. Nat Genet 1998;
20:328–329.
336. Kuroiwa S, Kojima H, Kikuchi T, Yoshimura
N: ATP binding cassette transporter retina
genotypes and age related macular
degeneration: an analysis on exudative
non-familial Japanese patients. Br J
Ophthalmol 1999; 83:613–615.
337. Maw MA, Kennedy B, Knight A, et al:
Mutation of the gene encoding cellular
retinaldehyde-binding protein in autosomal
recessive retinitis pigmentosa. Nat Genet
1997; 17:198–200.
338. Morimura H, Berson EL, Dryja TP:
Recessive mutations in the RLBP1 gene
encoding cellular retinaldehyde-binding
protein in a form of retinitis punctata
albescens. Invest Ophthalmol Vis Sci 1999;
40:1000–1004.
339. Cideciyan AV, Haeseleer F, Fariss RN, et al:
Rod and cone visual cycle consequences
of a null mutation in the 11-cis-retinol
dehydrogenase gene in man. Vis Neurosci
2000; 17:667–678.
340. Bernal S, Calaf M, Garcia-Hoyos M, et al:
Study of the involvement of the RGR,
CRPB1, and CRB1 genes in the
pathogenesis of autosomal recessive
retinitis pigmentosa. J Med Genet 2003;
40:e89.

341. Morimura H, Saindelle-Ribeaudeau F,
Berson EL, Dryja TP: Mutations in RGR,
encoding a light-sensitive opsin
homologue, in patients with retinitis
pigmentosa. Nat Genet 1999; 23:393–394.
342. Marlhens F, Bareil C, Griffoin JM, et al:
Mutations in RPE65 cause Leber’s
congenital amaurosis. Nat Genet 1997;
17:139–141.
343. Gu SM, Thompson DA, Srikumari CR, et al:
Mutations in RPE65 cause autosomal
recessive childhood-onset severe retinal
dystrophy. Nat Genet 1997; 17:194–197.
344. Thompson DA, Li Y, McHenry CL, et al:
Mutations in the gene encoding lecithin
retinol acyltransferase are associated with
early-onset severe retinal dystrophy. Nat
Genet 2001; 28:123–124.
345. Sun H, Gilbert DJ, Copeland NG, et al:
Peropsin, a novel visual pigment-like
protein located in the apical microvilli
of the retinal pigment epithelium.
Proc Natl Acad Sci U S A 1997;
94:9893–9898.
346. Streilein JW: Regional immunity and ocular
immune privilege. Chem Immunol 1999;
73:11–38.
347. Wenkel H, Streilein JW: Evidence that
retinal pigment epithelium functions as an
immune- privileged tissue. Invest
Ophthalmol Vis Sci 2000; 41:3467–3473.
348. Zamiri P, Zhang Q, Streilein JW:
Vulnerability of allogeneic retinal pigment
epithelium to immune T-cell-mediated
damage in vivo and in vitro. Invest
Ophthalmol Vis Sci 2004; 45:177–184.
349. Campochiaro PA: Cytokine production by
retinal pigmented epithelial cells. Int Rev
Cytol 1993; 146:75–82.
350. Liversidge J, McKay D, Mullen G, Forrester
JV: Retinal pigment epithelial cells
modulate lymphocyte function at the
Müller Cells and the Retinal Pigment Epithelium
blood-retina barrier by autocrine PGE2 and
membrane-bound mechanisms. Cell
Immunol 1993; 149:315–330.
351. Tanihara H, Yoshida M, Matsumoto M,
Yoshimura N: Identification of transforming
growth factor-beta expressed in cultured
human retinal pigment epithelial cells.
Invest Ophthalmol Vis Sci 1993;
34:413–419.
352. Holtkamp GM, de Vos AF, Kijlstra A, Peek
R: Expression of multiple forms of IL-1
receptor antagonist (IL-1ra) by human
retinal pigment epithelial cells: identification
of a new IL-1ra exon. Eur J Immunol 1999;
29:215–224.
353. Ishida K, Panjwani N, Cao Z, Streilein JW:
Participation of pigment epithelium in
ocular immune privilege. III. Epithelia
cultured from iris, ciliary body, and retina
suppress T-cell activation by partially non-
overlapping mechanisms. Ocul Immunol
Inflamm 2003; 11:91–105.
354. Kaestel CG, Jorgensen A, Nielsen M, et al:
Human retinal pigment epithelial cells
inhibit proliferation and IL2R expression of
activated T cells. Exp Eye Res 2002;
74:627–637.
355. Jorgensen A, Wiencke AK, la Cour M, et al:
Human retinal pigment epithelial cell-
induced apoptosis in activated T cells.
Invest Ophthalmol Vis Sci 1998;
39:1590–1599.
356. Farrokh-Siar L, Rezai KA, Patel SC, Ernest
JT: Cryoprecipitate: an autologous
substrate for human fetal retinal pigment
epithelium. Curr Eye Res 1999; 19:89–94.
357. Rezai KA SR, Farrokh-Siar L, Hamann KJ,
et al: Human fetal retinal pigment epithelial
cells induce apoptosis in allogenic T-cells in
a fas ligand and PGE2 independent
pathway. Current Eye Research 1999;
18:430–439.
358. Rezai KA, Semnani RT, Patel SC, et al: The
immunogenic potential of human fetal
retinal pigment epithelium and its relation
to transplantation. Invest Ophthalmol Vis
Sci 1997; 38:2662–2671.
359. Dutt K, Waldrep JC, Kaplan HJ, et al: In
vitro phenotypic and functional
characterization of human pigment
epithelial cell lines. Curr Eye Res 1989;
8:435–440.
360. Liversidge JM, Sewell HF, Forrester JV:
Human retinal pigment epithelial cells
differentially express MHC class II (HLA,
DP, DR and DQ) antigens in response to in
vitro stimulation with lymphokine or purified
IFN-gamma. Clin Exp Immunol 1988;
73:489–494.
361. Percopo CM, Hooks JJ, Shinohara T, et al:
Cytokine-mediated activation of a neuronal
retinal resident cell provokes antigen
CHAPTER 125
presentation. J Immunol 1990;
145:4101–4107.
362. Sun D, Enzmann V, Lei S, et al: Retinal
pigment epithelial cells activate uveitogenic
T cells when they express high levels of
MHC class II molecules, but inhibit T cell
activation when they express restricted
levels. J Neuroimmunol 2003; 144:1–8.
363. Acland GM, Aguirre GD, Bennett J, et al:
Long-term restoration of rod and cone
vision by single dose rAAV-mediated gene
transfer to the retina in a canine model of
childhood blindness. Mol Ther 2005;
12:1072–1082.
364. Gullapalli VK, Khodair MA, Wang H, et al:
Retinal pigment epithelium and
photoreceptor transplantation frontiers. In:
Ryan SJ, ed. Retina. Philadelphia: Elsevier-
Mosby; 2006:2597–2613.
365. Rizzolo LJ. Development and role of tight
junctions in the retinal pigment epithelium.
Int Rev Cytl 2007; 258:195–234.
1655
 CHAPTER
126 Retinal and Choroidal Circulations
Constantin J. Pournaras and Guy Donati
The knowledge of the mechanisms underlying the pathophy-
siology of the retinal microcirculation is of fundamental clinical
importance, since ischemic microangiopathies of the inner
retina1–3 are the most common cause of blindness in developed
countries.4 Impairment of the choroidal and retinal circulations
results in blood flow modifications, which in turn affects the
delivery of oxygen and metabolic substrates, necessary for the
maintenance of the energy generating processes to the retina
tissue. The neuronal cells reach certain energy state through the
formation of adenosine triphosphate (ATP), produced by means
of two fundamental metabolic pathways, namely glycolysis and
oxidative phosphorylation coupled to the citric acid cycle. In
order to maintain an adequate ATP level in the cells, both its
production and utilization rates have to be even. This requires
not only control of the activity of the glycolytic and citric acid
cycle enzymes, but also adequate oxygen and glucose delivery.
The mammalian retina possesses a high rate of glycolysis
and lactate production5–8 but also, like the brain an elevated rate
of oxygen consumption.9–12 The above are needed for the active
neuronal transport processes, which maintain the ionic
gradients necessary for electrical activity and visual trans-
duction.13 In addition to the impairment of the energy-
dependent transport processes, the release of excitatory amino
acids,14,15 the rise of intracellular calcium, the disruption of
calcium-modulated processes,16 the reperfusion-reoxygenation,
oxygen-derived free readicals release,17,18 nitric oxide (NO)
mediated neurotoxicity19 and contribution to delayed cell
death,20 have been demonstrated as interrelated pathophy-
siologic pathways involved in the ischemic neuronal damage.
Developements in fluorescein and indocyanine green
angiography, as techniques for non invasive measurements of
the retinal and choroidal blood flow, and new experimental
findings on the regulation of the retinal and choroidal vascular
tone, improved our understanding of retinal and choroidal
circulation in health as in diseased eyes.
ANATOMY OF THE RETINAL AND
CHOROIDAL CIRCULATIONS
Metabolic substrate and oxygen delivery of the retina in higher
mammals including humans and other primates is supported
by the two separate vascular systems, the retinal and choroidal
circulations. In some lower mammals, as rabbits and guinea
pigs, the retina is almost completely dependant upon the
choroid, since retinal vessels can be found only in a small area
of the retina or can be totally lacking.21 Both retinal and
choroidal vessels derived from the ophthalmic artery, branch of
the internal carotid, have distinctive morphological and
functional behavior.
VASCULAR SUPPLY OF THE RETINA
The retinal circulation is end-arterial without any anastomoses;
the central retinal artery appears at the optic disk where it
divides into two major branches. These in turn divides in
arterioles extending outward from the optic disk each supplying
one quadrant of the retina. Retinal arteries and veins divide by
dichotomous and site-arm branching, the terminal arterioles
come off at almost right angles from the main stream. In ~25%
of humans a cilioretinal artery hooks around the temporal
margin of the optic disk and provides a portion of the macula
with the arteriolar supply.22
The larger retinal vessels lie in the inner-most portion of the
retina close to the inner limiting membrane; retinal glial cells,
mainly astrocytes, extend over large areas in close spatial rela-
tionship with retinal vessels wall.23 Astrocytes constrains the
retinal vessels to the retina and maintains their integrity.24 At
the arteriovenous crossing sites, the deeper vessels may indent
the retina down to the outer plexiform or outer nuclear layer.21
The venous system has a certain similarity to the arteriolar
arrangement; the retinal venous blood is drained by the central
retinal vein that leaves the eye through the optic nerve and
drains into the cavernous sinus. Both the terminal vessels,
namely precapillary arterioles, and the postcapillary venules are
linked by the interposed capillary bed. Even though there are no
arteriovenous shunts in the normal retina, at the periphery of
the retina, the terminal arterioles and veins are linked by large
capillary communications. Similar anastomotic capillaries
connect the perifoveal terminal arterioles with the venules,
leaving a capillary free zone of 400–500 mm in diameter.
The retinal arterioles give rise to a plexus of capillaries each
measuring ~5 mm in diameter. These capillaries lie in an
interconnecting network, which is arranged in a basic two-
layered pattern. The first one resides in the nerve fiber and
ganglion cell layer, and the second deeper one, lies in the inner
nuclear layer. In the peripapillary area, an additional capillary
network, lies in the superficial portion of the nerve fiber layer,
which constitutes the radial peripapillary capillaries. It is
distributed around the optic disk and along the temporal
superior and inferior retinal vessels.25 Toward the periphery, the
deep net disappears leaving in this way a single layer of wide-
mesh capillaries. At the extreme retinal periphery an area of
~1.5 mm width is avascular. A capillary free zone also
surrounds the arterioles; it is probably due to local high oxygen
tension during vascular remodelling occuring during
maturation of the retinal vascular system.26 The outer retinal
layers, including the photoreceptors, are avascular and receive,
as the peripheral avascular retinal area does, metabolic energy
support from the choroid (Fig. 126.1).
1657
 RETINA AND VITREOUS
SECTION 3
FIGURE 126.1. Distribution of the retinal capillaries in a monkey
retina digest preparation. Note the broad capillary-free zone present
around the artery, and the absence of sphincters (insert).
FINE STRUCTURE OF THE RETINAL
VASCULATURE
All the branches of the main retinal arteries have the structure
of small arteries. According to electron microscopic studies,
these arteries are proved to have an arteriolar structure beyond
a b
1658
the equator. The retinal arteries differ from those of the same size
in other organs, in that of the unusually developed smooth muscle
layer and that they lack an internal elastic lamina. Near the optic
disk the arterial wall has five to seven layers of smooth muscle
cells, which diminish to two or three layers at the equator and one
to two at the periphery. The muscle cells are oriented both
circularly and longitudinally, each being surrounded by a
basement membrane that contains an increasing amount of
collagen toward the adventitia.27 Retinal arteriolar precapillary
annuli were observed in a number of animals at the side-arm
branches of retinal arteries, but not in humans (see Fig. 126.2).
There is no evidence that annuli contain muscular or elastic
tissue components, instead it is more likely that they are
composed of basement membrane or immature collagen.28
The capillary wall is composed of three distinct elements:
endothelial cells, intramural pericytes, and basement mem-
brane. The endothelial cells are oriented along the axis of the
capillaries; they present at their thickest areas a nucleus bulging
into the lumen, and express cytoplasmic extensions which
encircle the lumen. Tight junctional complexes with con-
tinuous fusion of the outer leaflets of the cell membranes are
found along the opposing surfaces of adjacent endothelial
cells.29 Frequently the endothelial cell processes overlap, and a
lip like protrusion often marks the junction of two cells. The
continuous layer of endothelial cells is surrounded by a thick
basement membrane within which there is a discontinuous
layer of intramural pericytes in almost a one to one ratio with
the endothelial cells. Clinical and experimental observations
suggests that pericytes contribute to the regulation of micro-
vascular growth and function.30
VASCULAR SUPPLY OF THE CHOROID
The choroid, a highly vascularized and pigmented layer, con-
stitutes the posterior portion of the uvea. It is ~0.2 mm thick
posteriorly, tapering to 0.1–0.15 mm thick in the periphery. The
FIGURE 126.2. (a) Schematic representation of
capillary distribution within the inner layers of
the retina. The photoreceptor layer is avascular,
receiving oxygen and metabolic substrate
support from choroidal capillaries. ILM, internal
limiting membrane; GL, ganglion cell layer;
IPL, inner plexiform layer; OPL, outer plexiform
layer; ONL, outer nuclear layer; RPE, retinal
pigmentary epithelium. (b) Semithin section of a
human retina.

FIGURE 126.3. After scleral penetration the short posterior ciliary
arteries expand toward the periphery with a chevron configuration.
Indocyanine green angiograms showing choroidal arterial filling with a
chevron pattern.
choroid is composed of the choriocapillaris layer, the medium
vessels layer (Sattler’s layer) and the outer layer of large vessels
(Haller’s layer). In primates, the medium layer contains large
arteries measuring 40–90 mm, large veins measuring
20–100 mm, nerves, and lymphatics.31,32
The choriocapillaris and the medium-sized choroidal vessels
are sandwiched between the apical retinal pigment epithelium
(RPE) of neuroepithelial origin and the outer choroidal pigment
of neural crest origin. Two collagenous structures, one on the
inside (Bruch’s membrane) and one on the outside (subcapillary
fibrous tissue), are connected by the intercapillary pillars.31
Most medium-sized vessels are external to the subcapillary
fibrous tissue.33 External to it, an anatomical cleavage plane
referred to as intervascular space, may be found between the
inner medium sized and outer large-vessel choroidal layers.31
Choroidal Arteries
The vascular supply to the choroid derives from the ophthalmic
artery via branches of the anterior and posterior ciliary arteries.
The ophtalmic artery gives off 2–3 main ciliary arteries that is
the nasal, the temporal, and occasionally the paraoptic one,
supplying the corresponding hemisphere of the choroid.34,35
These in turn, branch into 10–20 short posterior ciliary
arteries, that enters into the globe at the posterior pole and
assume a peripapillary and perimacular pattern, the papillo-
macular oval,36 before branching peripherally in a wheel-shaped
arrangement, and two long posterior ciliary arteries.32,33
Secondary and tertiary branches of the short posterior ciliary
arteries are subsequently divided into the major choroidal
arteries.34,35 The short posterior ciliary arteries also contribute
paraoptic branches to the Zinn–Haller circle as well as pial
branches. They provide segmental supply to the lamina
cribrosa, retro and prelaminar optic nerve head (ONH).35,37
Some branches of these short posterior ciliary arteries are
selectively directed to the macular region vessels, i.e., the very
short posterior ciliary arteries.38 Histological examination
showed that they have a spiral shaped configuration, consistent
Retinal and Choroidal Circulations
FIGURE 126.4.
Artwork of the
equatorial choroid of a
60-year-old man.
Scleral view showing
microarchitecture of
the equatorial
choroids, scleral view.
Lobules are marked by
broken lines. A, artery;
v, vein; CH,
choriocapillaris.
CHAPTER 126
with the vascular pattern of the arterial phase of ICG
angiography. This pattern differs from short posterior ciliary
arteries not directed to the macular area, in that it expands in a
typical chevron configuration (Fig. 126.3).39
The long posterior ciliary arteries follow long, oblique
intrascleral courses and travel in the virtual suprachoroidal
space, giving off recurrent branches to the macula and to the
anterior choroid at the ora serrata. Recurrent branches supply
choroidal areas at 3 and 9 o’clock meridians.40
The anterior ciliary arteries perforate the sclera at the
insertion of the tendons of the muscles and pass through the
suprachoroidal space to enter the ciliary body. These primarily
supply the ciliary body and iris. Before joining the major arterial
circle of the iris, anterior ciliary arteries are divided into 7–12
recurrent branches that supply the anterior choroid.40,41
Choriocapillaris
The functional unit of the choroidal circulation is the chorio-
capillary lobule. The lobules measure 0.6–1.0 mm and are
supplied by precapillary arterioles and drained by postcapillary
veinules.42,43 Lobules subdivide the choroid into several functional
islands. Each lobule consists of a capillary meshwork with radial
and circumferential arrangement, that contains an arteriole in
the middle and a venule at its periphery (Fig. 126.4).44,45 Lobules
in the equatorial part of the choriocapillaris are larger (200 mm)
than those located both at the posterior pole (100 mm), and in
the submacular area (30–50 mm).38 The structure of the
choriocapillary resembles mostly a dense network of freely con-
nected capillaries in the peripapillary and submacular area. This
pattern changes to a lobule-like arrangement in the posterior
pole and to a palm-like organization, more peripherically.44
Choroidal Veins
Blood discharges the lobules of the choriocapillaris by collecting
venules that join the afferent veins. At the posterior pole, the
venule is located at the periphery of the lobule, stays on the
same plane of the lobule, and possibly also drains adjacents
lobules.40 Small venular channels commonly connect the
posterior aspect of the choriocapillaris with collecting venules. 1659
 RETINA AND VITREOUS
SECTION 3
FIGURE 126.5. Intermediate-size veins. Indocyanine green angiogram
showing a superior vortex vein.
Intervenular channels between collecting venules and larger
veins, direct arteriovenous anastomosis, and interdigitation
between the choriocapillaris and venules were also reported in
histological studies.40,44 Postcapillary venules are closely
arranged in the macular region. The meshwork of the venous
plexus becomes less dense with increasing distance from the
macula, the vessels become straighter, losing the tortuous
aspect, which is characteristic of the macular region. Vessels of
larger lumen form the subcapillary plexus and eventually flow
into the vortex veins.40
Four to six vortex veins receive the blood collected in the
ampullae of the vortex veins by the afferent ones. The vortex
veins are located 2.5–3 mm posterior to the equator, closer to
the vertical meridian than to the horizontal one and drain
into the superior and inferior orbital veins (Fig. 126.5).46 Some
drainage also occurs through the anterior ciliary veins of the
ciliary body. Venous drainage sems to be segmentally organized
into quadrants, with watersheds oriented horizontally through
the disk and fovea and vertically through the papillomacular
area (Fig. 126.6).43,47
a b
1660
Fine Structure of the Choriocapillaris
The capillaries of the choriocapillaris usually have a diameter
of 18–50 mm. They are flat and often have a narrow segment.48
The endothelial cells of the choriocapillaris are connected by
a discontinuous row of ‘zonulae occludens’. The part of the
choriocapillaris that faces the RPE has large fenestrations
covered by a thin membrane with a central thickening.49,50
The fenestrations are larger and more numerous in the
submacular area.51 Experimental destruction of the RPE
causes focal atrophy of the choriocapillaris, suggesting that
the localization of the fenestrae toward the RPE could be
the result of a modulating action of the RPE on the
choriocapillaris.52 These fenestrations have high permeability,
and as the analysis of suprachoroidal fluids suggests, such
permeability of the choriocapillaris is similar to that of an
isoporous membrane with a pore diameter of 144 Å.53 These
high permeability probably accounts for the maintenance of
an adequate concentration of glucose and other nutrients at
the RPE level.49
Innervation of Retinal and Choroidal Vessels
Histologic studies and stimulation experiments have revealed a
rich supply of autonomic vasoactive nerves to the choroidal
vessels but not to the retina. Sympathetic nerves derived from
the superior cervical sympathetic ganglion, innervate the
choroidal vascular bed, as well as the central retinal artery up to
the lamina cribrosa.54,55 The choroidal vessels contain alpha-
adrenergic vasoconstrictor receptors but no beta-adrenergic
vasodilator receptors. Thus, alpha adrenergic agonists constrict
the long posterior ciliary arteries in vitro and reduce blood flow
through the choroid, while beta-adrenergic agonist isopro-
terenol has no effect.56
From this point on, although a- and b-adrenergic receptors57
and receptors for angiotensin58 are present, the retinal vessels
are devoid of sympathetic fibers.55 The parasympathetic system
provides vasodilating fibers to the choroid through the facial
nerve,59 the neurotransmitter may be the vasoactive intestinal
peptide (VIP).60–62 A neuronal NO release has been identified in
autonomic nerves in the choroid,63 confirming the role of
perivascular nerve fibers around choroidal vessels staining
for NOS.64
STRUCTURE OF THE BLOOD–OCULAR
BARRIERS
Inner Blood–Retinal Barrier
The retina is a part of the brain and, as a result, retinal
capillaries have a similar structure to cerebral ones. As in the
brain, adjacent endothelial cells are connected by a continuous
FIGURE 126.6. Indocyanine green angiogram
of early (a) and late (b) choroidal arteriovenous
phase. Note the subfoveal entry of short
posterior macular arteries, the vertical arterial
watershed area running through the papilla, and
the venous watersheds oriented horizontally
though the disk and fovea and vertically
through the papillomacular region.

TABLE 126.1. Comparison between Retinal and Choroidal
Circulation Blood Flow and Oxygen Extraction [82,88,95,98,99].
Retinal Low level of flow High O2 extraction
circulation (15 – 34 mg/min) (40%)
Choroidal High level of flow Low O2 extraction
circulation (677 – 735 mg/min) (4%)
network of membranous ridges (tight junctions).65 Junctions
between endothelial cells and pericytes also occur through
fenestrations in basement membranes.66 These types of capil-
laries, called nonfenestrated ones, only have two kinds of small
pores, with a diameter of 9–24 to 70 nm.65,67 The permeability
of such nonfenestrated capillaries has been estimated to be less
than 1% of those in skeletal muscle and less than 0.1% of those
in the mesentery.68 In the retinal vessels, endothelial cells and
astrocyte interactions,23,24 are of fundamental importance for
the efficient function of the inner blood–retinal barrier, as
contact with glial neighboring cells is a prerequisite for the
development of tight junctions.69
Thus, the permeability of the retinal capillaries is similar to
that of cerebral vessels with no or at the most minimal leakage
of fluorescein,70 or small ions like sodium.71 As in all vascular
beds, retinal capillaries are highly permeable to lipid-soluble
substances such as gases (O2, CO2). Water also diffuses rapidly
through the endothelial cells. However, the inner blood–retinal
barrier is largely impermeable not only to large molecules as
albumin and others proteins72 but also to small water-soluble
substances, like glucose and amino-acids. This means that
metabolic substrates have to be transported through the inner
blood–retinal barrier by means of carrier-mediated transports
systems.
Active transport takes place either through specific channels
constituted of trans membranous proteins, i.e., intracellular
and extracellular lactate to pyruvate ratios are in near equilib-
rium, which is established by monocarboxylate transporters,73,74
or by pinocytosis through the cytoplasm of the endothelial
cells.75 The above has been demonstrated for glucose,76 and
amino-acids,77 the main nutrients of neuronal cells.
Outer Blood Retinal Barrier
The retinal pigment epithelial (RPE) cells form the outer blood
retinal barrier. RPE cells measure 16 mm in height and
10–60 mm in diameter. The apical zonulae occludens
constitute the location of the blood–retinal barrier. The basal
lamina of the RPE form the most inner layer of the Bruch’s
membrane. Inner collagen, elastic fibers, outer collagen, and
basement membrane of the choriocapillaris constitute
the remaining layers.48 Active transport takes place also at the
outer blood–retinal barrier as it has been demonstrated for
glucose and amino-acids.78
Several ocular diseases and surgical trauma alter the permea-
bility of the blood–ocular barriers. Disruption of the blood–retinal
barrier has been demonstrated, using ocular fluorophotometry
in diabetes and in systemic hypertension.79,80 Proteins and
other substances of high molecular weight can enter the
interstitial space, due to the fenestrated nature of the choroidal
capillaries. Retinal binding protein, vitamin A, and many other
micronutrients and ions become available to the RPE for
transport to the outer layers of the retina. The movement of
metabolites takes place across both the RPE and Bruch’s
membrane. Both active and passive transport mechanisms
facilitate the movement of selected nutrients and of waste
Retinal and Choroidal Circulations
products across the blood–retinal barrier in and out of the
retina. Physiologically Bruch’s membrane doesn’t constitute a
barrier to the movement of these molecules except in aging.
Lipoprotein accumulation occurs in the Bruch’s membrane
from rod outer segment degradation in aging that may obstruct
the movement of water and perhaps of waste products, from the
RPE to the choroids.81
PHYSIOLOGY OF THE RETINAL AND
CHOROIDAL CIRCULATION
TECHNIQUES OF BLOOD FLOW
MEASUREMENTS (ANIMALS/HUMANS)
In the last decades, non invasive clinical methods as digital
fluorescein and ICG angiography Laser Doppler Velocimetry
(LDV) coupled to vessels diameter measurements,82 blue field
entoptic phenomenon83 gave much information on the retinal
CHAPTER 126
blood flow modifications and regulation in normal and diseased
eyes. In addition techniques has also been used in animal
models in order to obtain quantitative information on retinal
and choroidal blood flow including calorimetry84 direct
measurements from choroidal veins,85 radioactive krypton
desaturation,86 labeled microspheres,87,88 hydrogen clearance,89
laser doppler flowmetry (LDF).90–92 Among all these techniques,
injection of radioactive labeled microsphere has been widely
used to calculate tissue blood flow in animals.
As such techniques are not useful for humans, most of our
knowledge about physiology of the retinal and choroidal
circulations come from animal studies, confirmed by recent
findings mainly using LDV and flowmetry. Computer-assisted
analysis of fluorescein93 and ICG94 angiograms have been made
to provide qualitative information about choroidal blood flow,
but they do not measure flow rates.
RETINAL AND CHOROIDAL BLOOD FLOW
A 35–80 mL/min retinal blood flow has been calculated using the
LDV and monochromatic fundus photography in humans.82–95
Marked regional differences in blood flow through the
choroid was found, as choroidal blood flow near the fovea and
around the ONH is much higher than the blood flow in the
periphery of the eye.88 Choroidal blood flow is extremely high,
~10 times higher than the flow of the gray matter of the brain
and four times the flow of kidney (Table 126.1).96
Even though a corresponding difference in metabolic require-
ments does not exist, the large rate of blood flow in the capillary
bed of the choroid is probably owing to the large caliber of the
vascular lumen and the consequent low resistance to flow.
Eighty-five percent of the total blood supply to the eye is
distributed to the choroid and only 4% to the retina. From the
remaining 11%, 10% is distributed to the ciliary body and 1% to
the iris.87,88,96 Consequently, the oxygen extraction from the
uveal blood is very low, the arteriovenous difference for the
choroidal blood is ~3%.97 On the other hand, in humans98 and
pigs,99 the oxygen content of the retinal venous blood is ~38%
lower than the one in arterial blood. Despite the low oxygen
extraction from the choroidal blood, in pigs, ~60% of oxygen
and 75% of glucose are delivered by the choroidal circulation.99
The reason for the high volume of choroidal blood flow is not
completely understood. A thermoregulating action by removal
of heat generated during visual transduction has been advo-
cated,100 as exposition of the eye to a moderate-intensity light
source causes a reflexive increase in choroidal blood flow in
monkeys and humans.101 Fluid removal from the outer retina
by the high choroidal oncotic pressure, or subserving the
metabolic needs of the retina has also been suggested.11 1661
 RETINA AND VITREOUS

RETINAL AND CHOROIDAL OXYGEN

DISTRIBUTION
In the retina direct measurements of tissue oxygen partial
pressure (PO2) were performed in animals using oxygen
sensitive microelectrodes.102,103 The PO2 was found to be
heterogenously distributed close to the vitreoretinal interface.
Juxtaarteriolar preretinal or transretinal PO2 profiles indicates
that O2 diffusion from the retinal arterioles affects the juxtaar-
teriolar preretinal and inner retinal layers PO2. In contrast, the
preretinal and inner retinal (30% depth) PO2 far beyond the
retinal vessels remains constant in all retinal areas.104,105
Transretinal intervascular PO2 profiles, indicated that the
intraretinal PO2 gradually decreases from both the retinal
surface and the choroid toward the mid-retina with the
minimum value recorded at 50% of retinal depth.105 Close to
the pigment epithelium the PO2 is significantly higher than that
at the inner limiting membrane level. This is probably due to
SECTION 3

much higher O2 delivery by the choroidal circulation than by

the retinal one and the very low arteriovenous oxygen
a
difference.97 These PO2 profiles indicate that there is O2
diffusion from the inner retina and the choroid toward the
middle of the retina (Fig. 126.7). The above comes in
accordance with previous theoretical calculations,106 and
measurement obtained in other species.12,107,108

REGULATION OF THE RETINAL AND

CHOROIDAL BLOOD FLOW
The general concept of the regulation of blood flow in a vascular
bed is that systemic factors (circulating hormones and the
autonomic nervous system) regulate the distribution of the
cardiac output over the different vascular beds as a function of
the hemodynamic situation of the whole body and that local
factors (such as PO2, PCO2, pH, metabolic products) try to
adapt flow to local needs.
The blood flow through the eye is directly related to the mean
perfusion pressure (PPm), and inversely related to the vascular
resistance (Rm) within the ocular vascular bed.
Rm further depends on blood viscosity (n), the length (L)
and diameter (2r) of the blood vessels (cf. Law of Poiseuille:
R = 8 nL/r4). Thus, the blood flow F = DP pr4/8 nL, is related
to the PPm and the diameter of the resistance vessel, and inver-
sely related to the vascular blood viscocity and length of the
vascular bed.
The PPm
Is determined as the local arterial blood pressure minus the
venous pressure. As the venous pressure almost equals
intraocular pressure, PPm is defined as the difference between
the mean ophthalmic artery blood pressure (MOAP) minus the
intraocular pressure (IOP).The MOAP, was assumed to be 2/3 of
the mean arterial blood pressure (MABP), and was calculated as
MABP = 2/3 [BPdiast + 1/3 (BPsyst - BPdiast)]. BPdiast and BPsyst are
the brachial artery blood pressures during diastole and systole,
respectively.
The retinal blood flow is autoregulated (i.e., maintained à
constant values) to a mean systemic blood pressure to 41% up
to baseline values.109 Similarly, autoregulation occurs during an
increase of IOP up to 27–30 mmHg, which results in a mean
retinal perfusion pressure decrease of less than 50%.110 As a
result, the inner retinal-tissue partial pressure of O2 (PO2) is
maintained at constant values during moderate reductions of
the perfusion pressure.111,112 The Rm vascular resistance is
related to (1) the blood viscosity, (2) length, and (3) the diameter
of the blood vessel. Any change of each of those parameters
1662 influence retinal blood flow.
b
FIGURE 126.7. (a) Intervascular transretinal PO2 profiles recorded in
miniature pigs during normoxia (each point is the mean + SE, N = 13).
Minimal PO2 value is reached at 50% retinal depth. ILM, inner limiting
membrane; RPE, retinal pigment epithelium; (b) The drawing indicates
the pathway of the microelectrode through the retina.
Viscosity
Blood viscosity varies as a function of the shear rate, being high
at low shear rate. Blood viscosity diminishes and becomes
almost constant at a high shear rate.113 An increase in plasma
viscosity (e.g., hyperglobulinemias, high Ht, leukemia, sickle
cell anemia), substantially influences the flow through the
retinal circulation. Slowdown of the retinal perfusion may lead
to stasis in the retinal veins and ultimately to venous occlusion.
Retinal perfusion could be normalized by correction of the
hyperviscosity.114
Length of the Vascular Bed
Changes in the total length of the vascular bed can be modified
by precapillary sphincters lying at the bifurcations of the arte-
rioles, which causes the opening and closing of the capillary
bed. Although such a sphincter is seen in many tissues, it is not
found in choroidal or retinal arterioles28; in contrast to the
capillaries in the pulmonary circulation, all of which can be
mobilized or not, depending on the circulatory needs.
The Diameter of Vessels
Is determined by the contractile state of the arteriolar smooth
muscle and the capillaries pericytes. Numerous factors
influence the vascular resistance such as systemic factors
including autonomic nerves, circulating substances and
systemic PaO2 and PCO2, local metabolic factors including

substances released by the vascular endotheliun and/or the
neuroglial cells surrounding the vessels which get involved in
the moment to moment regulation of the distribution of the
cardiac output depending on the metabolic needs of the tissue.
Systemic factors
Innervation The eye has a rich autonomic innervation only to
the uvea and the extraocular parts of the retinal blood vessels.
Sympathetic nerves reach the eye from the sympathetic cervical
superior ganglion, while parasympathetic nerves reach the
eye through the oculomotor nerve, the facial nerve and through
the ophthalmic and maxillary division of the trigeminal nerve.
The choroidal vessels contain alpha-adrenergic vasocon
strictor receptors A considerable number of perivascular nerve
fibers around choroidal vessels stain for NOS forming a dense
network of choroidal ganglion cells; 64 such distibution is
found only in humans and higher monkeys which have a fovea
centralis. Thus the choroidal circulation appears to be under the
influence of basal release of NO released either by the vascular
endothelium or the nitrergic choroidal nerve terminals.
Arterial oxygen partial pressure (PaO2) Hyperoxia (100%
oxygen breathing) induces a marked vasoconstriction of the inner
retinal arterioles in both normal humans,115,116 and
anesthetized animals.104,117 By the autoregulatory vasocon-
striction in the inner retina, PO2 is maintained at constant
values during systemic hyperoxia.104,105 The responses of the
retinal circulation to changes in arterial O2 are similar to those
of the cerebral circulation,118 however, the retinal blood flow
decrease in response to hyperoxia is quantitatively more
important.104,116
In humans and anesthetized animals, hypoxia (decrease in
PO2 in the arterial blood) induces vasodilation of retinal
arterioles117,119 which can be clearly measured only under an
arterial PO2 (PaO2) of 65 mmHg. A similar observation was
observed in cerebral blood-flow studies.118,120
Transretinal PO2, profiles made during variations in PaO2, by
steps of 10 mmHg between 120 and 30 mmHg have shown that
the PO2 values measured in the inner-retina up to half of its
thickness remained rather stable during different steps of
hypoxia. In contrast, the PO2, measured near the choroid and in
the outer-retina decreased in a linear manner according to the
variations of systemic PaO2.121–123 A decrease in PO2 near the
photoreceptor–pigment epithelium complex during systemic
hypoxia is expected to lower the ATP supply to the rods and,
thus, inhibit the Na+/K+ pump, and inducing a rapid alteration
of light-induced response of the RPE.124 Photoreceptors are
apparently more vulnerable to steps of hypoxia, indicating that
high oxygen delivery by the choroidal circulation, is necessary
to maintain mitochondrial respiration in photoreceptors and,
as a result, their normal function. The choroidal circulation is
not influenced by hyperoxia possibly because of increased NO
synthesis.125
Arterial PaCO2 Changes in the partial pressure of arteriolar
CO2 (PaCO2) affect retinal blood flow. The sensitivity of the
retina to variations of PaCO2 is such that a PaCO2 rise of
1 mmHg induces a 3% rise in blood flow.126 There is a tight
parallelism between changes of PaO2 and changes of interstitial
pH in the inner retina; variations of systemic PaCO2 (DPaCO2
= 3 7.6 ± 6 mmHg) induce a decrease in pH in the retina of
0.158 + 0.025 units. Acidification of the blood by infusing HCl
or by injecting lactate127 affects neither interstitial pH nor
retinal blood flow, suggesting that interstitial acidosis and not
systemic acidosis might be a step in the induction of vasomotor
response in hypercapnia,128 a finding which confirms those
reported in the cerebral cortex.129
Retinal and Choroidal Circulations
Hypercapnia induces an increase in retinal blood flow through
a mechanism involving either neuronal NO synthase (NOS-I)130
or PGE2-mediated endothelial NO synthase (NOS-III) release.131
Metabolic acidosis induced by intravenous acetazolamide
injection produces an increase of preretinal and optic disk
PO2,132 suggesting that acetazolamide increases retinal blood
flow, as observed in the case of cerebral blood flow,133 probably
by increasing the PaCO2.134 This PaCO2 increase is due to
significant bicarbonate loss in the renal tubules, resulting in
hyperchloremic metabolic acidosis. The CO2 produced by the
cells cannot be eliminated by carbonic anhydrase and so
increases the PaCO2 by diffusing through the basement
membrane.135 The PaCO2 increase and pH decrease induced by
acetazolamide are not affected either by hyperventilation or by
bicarbonate intravenous infusion.128
Circulating substances The influence of circulating molecules
and hormones on the retinal and choroidal circulation is rather
CHAPTER 126
unclear.
High levels of angiotensin-converting enzyme136 and recep-
tors for angiotensin II58 are found in retinal and choroidal blood
vessels, suggesting that angiotensin II might play a role in the
regulation of ocular circulation. Studies of the effect of
angiotensin II on the ocular circulation, however, have yielded
controversial results. In contrast to previous studies, more
recent ones indicated no evidence that angiotensin II contract
retinal arteries,137 or choroidal and optic nerve blood flow.138,139
Similarly controversial results have been reported after
administration of adrenergic drugs, a decrease, an increase or no
effect on the retinal circulation has been described.139
Whatever the effects of these molecules on the ocular
circulation, none seems to have a direct contribution to the
adaptations of the choroidal and retinal circulation to the
varying metabolic needs of the retina.
Local factors
These factors may be either ionic or molecular or related to gas
modifications under physiological stimuli or pathological
conditions. Interactions between substances released either by
the vascular endothelial cells or by neuroglial or neuronal tissue
surrounding the retinal arterioles i.e., relaxing factors as NO,
prostacyclin (PGI2), lactate or contracting factors such as
endothelin-1 (ET-1), Angiotensin II, cyclooxygenase (COX)
products such as thromboxane-A2 (TXA2) and prostaglandin H2
(PGH2), should affect the arteriolar tone, thus regulating the
retinal vasomotor responses.140–142
The endothelium located between the circulating blood and
the vascular smooth muscle cells, regulates permeability, affect
coagulation, platelet function, and fibrinolysis but it also exerts
metabolic functions by activating and inactivating hormones.
In addition, vasoactive substances that either inhibit (i.e.,
endothelium-derived relaxing factors: EDRF) or activate (i.e.,
endothelium-derived contracting factors: EDCF) the underlying
smooth muscle cells can also be released by endothelial cells.
Role of NO Since the initial observation indicating that
acetylcholine-induced vasodilation is dependent on the
presence or absence of the vascular endothelium,143 from
numerous experiments it became obvious that the endothelium
produces a vasodilator, which was initially defined as EDRF. NO
released by endothelial cells accounts for the biological
properties of the EDRF.143–147
NO is a nonpolar gas soluble in tissues, freely diffusible
across membranes, synthetized by the enzyme nitric oxide
synthase (NOS) from the oxidation of L-arginine and formation
of L-citrulline.144,148–150 Previously the NO synthases were
classified as inducible and constitutive, but recent experiments 1663
 RETINA AND VITREOUS

FIGURE 126.8. Putative NO metabolic

pathway in the retina. NO is constitutively
released by both neuronal cells and
endothelium in the retina and acts on the
vascular smooth muscle.
SECTION 3

have demonstrated that all NOS isoforms are regulated

dynamically. Three isoforms of NOS are classified as neuronal
NOS (NOS1), endothelial NOS (NOS3), and NOS (NOS2).
The isoform NOS-I has been found in neurons of the central
and peripheral nervous system,151 and in the retina of
mammals, in ganglion, amacrine, horizontal, Müller glial cells,
and photoreceptors,147,150–154 and human retina.155 The NOS-III
is mainly expressed by the vascular endothelium cells including
the retinal,156,157 and choroidal157 vessels endothelial cells and
the endothelial cells and pericytes of the retinal capillaries (Fig.
126.8).158
NO is produced when NOS-I and NOS-III are activated via
the calcium/calmodulin complex. Preretinal NO gradient from
the vitreal surface of the retina toward the vitreous indicates a a
continuous release of NO by the retinal tissue (Fig. 126.9), and,
since the NO gradient is also recorded far from visible arterioles,
this confirms that cells in the retina, other than endothelial
cells, may release NO.159 Juxta-arteriolar vitreal microinjections
of nitro-L-arginine (L-NA), a non specific inhibitor of NOS,
inducing segmental vasoconstriction159 suggest that a
continuous production of NO is necessary in order to maintain
a dilating arteriolar tone in the inner retina.
Experimental evidence suggests that in the ocular circulation
NO also plays a role, since relaxation of isolated ophthalmic
and ciliary artery rings induced by acetylcholine is markedly
reduced by the NO synthase inhibitor NG monomethyl-L-
arginine (L-NMMA) nitro-L-arginine.160,161 NO also induces
ralaxation of the contracting tone of the retinal bovine pericytes
via a cGMP dependnt mechanism.162 In addition, endothelium-
derived NO release under basal conditions or stimulated by
bradykinin regulates the ophthalmic circulation of the perfused
porcine eye.163
Finally, red blood cells (RBCs) provide a novel NO mediated b
vasodilator activity in which hemoglobin acts as an O2 sensor
FIGURE 126.9. Intervascular preretinal (NO) profile: (a) Continuous
and O2-responsive NO signal transducer, thereby regulating
NO recording obtained as the NO microprobe was advanced toward
both peripheral and pulmonary vascular tone. In blood, NO the inner retinal surface (rising phase) and then retracted 200 µm into
binds to cysteine-b-93 forming S-nitrosohemoglobin. Deoxy- the vitreous (falling phase). Current was maximal at the retinal surface,
genation is accompanied by allosteric transition in S- that portion of recording between the inner retinal surface (0 µm) and
nitrosohemoglobin that releases the NO group. The NO 200 µm out in the vitreous. (b) Values are means + SEM of nine
1664 released from the Hb may be transferred directly to the vascular recordings of the type shown in (a).159

endothelium. In that way, S-nitrosohemoglobin contracts the
blood vessels and decreases perfusion in tissues with high O2
affinity and relaxes the vessels to improve blood flow in
structures with low O2 affinity.164,165
Role of prostaglandins In the cerebral circulation, the effects
of different subclasses of prostaglandins (PGs) have been largely
studied under physiological and pathological conditions.166–168
Studies on isolated cerebral vessels,169 isolated pericytes of
retinal capillaries170 and incubated rabbit retinas171 have shown
that some subclasses of PGs (PGE2, PGF2, PGI2) may be
synthesized from their precursor, the arachidonic acid. PGI2 was
shown to exert a vasodilating action on isolated bovine retinal
arterioles,172 and acts as a vasodilator in rabbit eyes.173
Microinjections of PGE2 induced a segmental vasodilation119 of
the retinal arterioles.
Perfusion of the eye either through the sublingual artery or
microinjections close to the retinal arterioles by inhibitors of
PG synthase (indomethacin) produced a transitory reversible
vasoconstricton of the retinal arterioles in normoxia/
normocapnia as well as inhibition of the retinal vasodilation
normally induced by hypercapnia,119 in contrast did not affect
the hypoxia nor lactate-induced vasodilation.127 Thus,
vasodilater PG release, as in the brain,174 should be a possible
mechanism maintaining either the arteriolar tone in normo-
capnia or of hypercapnia-induced arteriolar vasodilation, but
the hypoxia and lactate induce vasodilation through a PG
independent pathway. PGE2 and PGF2 are the predominant PGs
produced by the retina and choroid and potentially plays a role
during physiological adaptations, such as hypercapnia and
autoregulation.175,176
Endothelins Are a family of three 21-amino-acid peptides
secreted by a variety of cells in the eye.177 Three members of the
ET family have been identified so far: ET-1, ET-2, and ET-3,178
and two subtypes of receptors with different sensibilities to the
three isoforms.
ETA receptor, which is expressed on vascular smooth muscle
cells and pericytes,179 is characterized by a very high affinity to
ET-1. ET-1 is the most potent vasoconstricting substance
known and has been shown to induce vasoconstriction after
intravitreal injection in rabbit,180 cat,181 and rat retinal
arterioles.182 ET-1 affects smooth muscle cells and pericytes,141
and contributes to induced retinal vasoconstriction in human
retinal arterioles in normoxia and hyperoxia.183,184
Two types of ETB receptors have been identified. The ETB1
receptor, which is expressed in endothelial cells, has equal
affinity for each ET isoform and mediates vasorelaxation
through release of NO in the pulmonary circulation of lambs
under physiological conditions185 or under hypoxia.186 The
activation of ETB1 receptors elicits also the release of NO in the
rat187 and rabbit kidney.188
ETB receptors have been identified in cultured bovine retinal
pericytes179 and endothelial cells,186,189 suggesting a similar
vasodilating effect through NO release in the retina. ETB
blockage induces a sustained hypertension in conscious
nonhuman primates, which is mediated by ETA receptors.
These data suggest that ETB1 receptors might influence arterial
blood pressure homeostasis by reducing plasma ET-1 levels and
minimizing ETA activation.190 The ETB2 receptor has a high
affinity for ET-3 and mediates direct vasoconstriction.191
Role of lactate The mammalian retina has been found to
possess an unusually high rate of glycolysis: ~70% of the
total glucose utilized by the retina is converted to lactate.7
Lactate released by isolated Müller cells is metabolized by
photoreceptors.192 In addition, 70% of oxygen consumption in
Retinal and Choroidal Circulations
the retina is due to the oxidation of glucose to CO2.6 Systemic
hypoxia induces an increase in the retinal lactate release,7
which potentially affects the arteriolar tone as preretinal
microiniections (30–100 nL) of L-lactate (0.5 mol, pH 7.4) close
to the retinal arterioles locally dilate the arteriolar wall.127
Since retinal metabolism produces significant amounts of L-
lactic acid which crosses cell membranes, it is not yet clear
whether lactic acid microinjected into the preretinal vitreous
exerts its effect on the endothelial cells or on the smooth
muscle cells by interfering with the metabolism of cells
surrounding the arterioles. Indeed, lactate could be transported
from the vitreous side of the vascular wall by means of a specific
transporter,193 which affects endothelial cell metabolism, and
thus induces endothelial release of vasoactive substances.
Intravenous administration of sodium lactate increases
retinal bood flow.194 Since intracellular and extracellular lactate
to pyruvate ratios are in near equilibrium, which is established
by monocarboxylate transporters,73,74 intravenously injected
CHAPTER 126
lactate could be transported affecting the endothelial cell
metabolism, inducing endothelial release of vasoactive
substances (i.e., NO) or could exert its effect on the smooth
muscle cells by interfering with the metabolism of cells
surrounding the arterioles. Indeed, the increase of the lactate-
to-pyruvate ratio leads to reduction of the NADH-to-NAD+
ratio which in turn increases the intracellular NADH
concentration,195 inducing an increase of retinal blood flow in
stimulated retina.196,197
AUTOREGULATION OF THE RETINAL BLOOD
FLOW
The autoregulation of the blood flow in a tissue vascular bed is
defined as the ability of the tissue to maintain its blood flow
relatively constant despite moderate variations of perfusion
pressure.198,199 This can be achieved to the some extent, by
changing the vascular resistance. This occurs through changes
of the contractile state of the arterioles and possibly of the
capillary pericytes. Changes in vessel tone have been observed
both as a physiologic adaptation and in pathologic conditions.
As retinal vessels are not sympathetically innervated, the
mechanism which underlies the autoregulation of retinal blood
flow is the balanced result of a myogenic component and
metabolic component i.e., interactions between factors release
by the retinal metabolism and the vascular endothelium.
Myogenic Mechanism
By means of a myogenic mechanism, with the increase or
decrease of the PPm, the arterioles constrict or dilate respec-
tively, in order to regulate the blood flow to constant values (i.e.,
autoregulation). However, regulation becomes ineffective when
the perfusion pressure rises or falls beyond certain limits.
The variation in the vascular transmural pressure difference
serves as the stimulus for a myogenic mechanism. This
happens by changing the vascular resistance during moderate
modifications in perfusion pressure, a mechanism which
resembles that of kidney and brain. Pacemakers cells in the
arteriolar wall may modify the arteriolar tone and consequently,
adapt the vascular resistance.96
Endothelium dependent regulation of ophthalmic arteries
tone during quick strech200–202 and a contracting endothelium-
derived factor203 released during increase in transmural pressure
seems to be other components of the myogenic autoregulation.
Ion channels in endothelial cells may act as mechano-
transducers, accounting for the apparent capacity of the
endothelium to sense mechanical forces and respond to
them.204 Indeed, L-type voltage-gated calcium channels are
involved in transforming the stretch of the vascular smooth 1665
 RETINA AND VITREOUS
muscle cells induced by an increase of the intraluminal pressure
into a contraction.205 However, depolarization-independent
mechanisms on the vascular smooth muscle seem to be
involved, as after depolarization of the vascular smooth muscle
by K+ (120 mM) a pressure-induced contraction is still
observed.206
The Metabolic Control
The metabolic control of the retina is defined as the effect of
factors released by tissue metabolism, which strives to optimize
the blood flow according to the metabolic needs of the tissue.
The retinal circulation adapts very well to changes in retinal
metabolism. During flicker stimulation the increased
metabolism of retinal tissue207,208 is coupled to an increase in
retinal and ONH perfusion.209–211
In cerebral212 and ocular circulation, NO is in part
responsible for the functional vasodilation. A role for NO was
also established in neurovascular coupling in the eye as diffuse
SECTION 3
flicker light stimulation induces an increase of the retinal213 and
ONH blood flow, associated with a transient increase of NO.214
The retinal blood flow flicker response is blunted by NOS
inhibition.215 In healthy young subjects, the contribution of
basal NO release on retinal vascular tone, was investigated
using Zeiss retinal vessel analyzer. L-NMMA significantly
reduced arterial diameter (3 mg/kg: –2%) and venous diameter
(3 mg/kg: –5%). In addition, the flicker induced vasodilation of
the human retinal vasculature was significantly attenuated.216
In dogs, inhibition of NO release by intravenous perfusion of
L-NMMA induces a 40% decrease in the choroidal blood flow
without any significant modifications of the retinal blood
flow.217 Perfusion of the eye either through the sublingual artery
by inhibitors of PG synthase (indomethacin) produced a tran-
sient reversible vasoconstricton of the retinal arterioles in
normoxia/normocapnia127 suggesting that in the retina,
vasodilating substances release non affected by PGs inhibitors
i.e., NO release, adapt the vascular tone, leading to regulation
of retinal blood flow.
Interaction between the two mediators has been provided
previously in other preparations218–222 could be a possible
mechanism affecting either the arteriolar tone in normocapnia
or the hypercapnia-induced retinal arteriolar vasodilation.223 In
addition, endothelium-derived NO has been reported to be a
vasodilating mediator in response to hypoxia in retinal vessels
in cats.224
AUTOREGULATION OF THE CHOROIDAL
BLOOD FLOW
Autonomic Regulation of the Choroidal Blood
Flow
The choroidal vasculature is richly innervated by vasoactive
nerves. Stimulation of the cervical sympathetic chain in
monkeys had no effect on blood flow through either the retina
or ONH,225 in contrast to the marked reduction of the choroidal
blood flow in monkeys and cats.225,226 The choroidal vessels
contain alpha-adrenergic vasoconstrictor receptors but no beta-
adrenergic vasodilator receptors. Thus, alpha-adrenergic
agonists constrict the long posterior ciliary arteries in vitro and
reduce blood flow through the choroid, while beta-adrenergic
agonist iso-proterenol has no effect.56
Choroidal blood flow changes very little during sudden
increments in blood pressure, as an increased sympathetic
activity and consequent vasoconstriction of the choroidal
vessels maintain choroidal blood flow constant.92,227 The
choroidal blood flow seems to be regulated by the autonomic
nervous system by alpha adrenergic receptors located at the
1666 choroidal vessels. This control represents a protective
mechanism during the flight or fight response, as well as during
moderate hypertension.209,227 Loss of sympathetic innervation
may cause an almost linear choroidal perfusion pressure-flow
relationships227 leading to accumulation of fluid in the retina
and retinal edema. This is important in diseases such as
diabetes and hypertension, in which autonomic control is
altered.
Decreases in mean arterial pressure with the IOP are held
constant, even if inducing a decrease in the perfusion pressure,
do not affect choroidal blood flow, which is maintained by a
myogenic mechanism at constant values.228
However, a lack of choroidal autoregulation and linear
choroidal perfusion pressure–flow relationships have been
obtained in studies where the perfusion pressure gradient was
decreased by raising the venous pressure with ramp or step
increases in intraocular pressure.88,143,229 Due to lack of choroidal
autoregulation, during increments of intraocular pressure, the
PO2 in the choroid and the outer retina decreases.112
Electrical stimulation of the parasympathetic vasodilator
fibers, provided to the choroid through the facial nerve, results
in marked vasodilation in the uvea and increased blood
flow.230,231 In rabbits NO at low frequences61 and VIP released
at high frequences,62 may be the transmmitters for the effect of
the stimulation of the facial nerve. The physiological
importance of the parasympathetic system in the regulation of
the choroidal blood flow, though, is yet to be defined.
Role of NO
A neuronal NO release has been identified in autonomic nerves
in the choroid,63 confirming the role of perivascular nerve fibers
around choroidal vessels staining for NOS.64 Studies in
rabbits232 showed evidences for a continuous neuronal NO-
induced vasodilator tone in the choroid.
Several animal experiments indicate that NO plays an
important role in the maintenance of basal vascular tone in the
choroid. Deussen and co-workers first established NO as a
major determinant of uveal blood flow using intravenous
infusion L-NMMA in dogs and the radioactive microsphere
technique. Despite an increase in mean arterial pressure of
20mmHg the authors observed a significant decrease in
choroidal blood flow (–40%), ciliary body blood flow (–40%) and
iris blood flow (–48%) and a slight reduction in retinal blood
flow (–12%).217 These experiments were confirmed in cats by
using LDF, where L-NA reduced choroidal blood flow in a dose-
dependent fashion despite an increase in systemic blood
pressure.233 The observation that NO is a major determinant of
choroidal blood flow was confirmed in a variety of studies using
the radioactive microsphere technique and LDF in various
species.
In humans, L-NMMA induced a fundus pulsation amplitude
(FPA) reduction, indicating that the choroid is particularly
sensitive to changes in NO release. L-NMMA induced a slight
increase in systemic blood pressure and reduced NO content in
the exhaled air by ~50%234 indicating that L-NMMA is capable
of reducing endogenous NO production. Similar findings in
humans where the choroidal perfusion was assessed with LDF,
indicated a dose-dependent reduction of the choroidal blood
flow parameter after administration of L-NMMA.235 In
addition, endothelium-derived NO has been reported to be a
vasodilating mediator in response to marked hypoxia in the
forearm resistant vessels in healthy humans,236 in interaction
with vasodilating PGs.237,238 These results clearly indicate that
NO is physiologically released in human choroidal vessels.
However the reduction of endogenous NO production by the l-
NMMA does not mean that NO production from NOS-1 and/or
NOS-3 was inhibited by the same extent in the choroid. An
interaction between NO and ET1 in the choroid has been

speculated, as ET-1 causes vasoconstriction of choroidal blood
vessels when injected intravenously in cats only when the
release of NO was inhibited.239 In fact the effect of ET1 on a
vascular bed apart from causing vasoconstriction, it can also
release both the vasodilators PGI2 and NO.240
PHYSIOPATHOLOGY OF THE RETINAL AND
CHOROIDAL CIRCULATION
RETINAL CIRCULATION
Acute retinal ischemia following experimental occlusion of the
retinal arterioles, induces drop of the inner retinal PO2 leading
to anoxic damage of the inner retinal cells.123,241,242 Retinal
areas affected by acute branch vein occlusion (BRVO) reveal also
a inner retinal tissue hypoxia,132,243,244 as oxygen diffusing from
the choroid does not reach the inner retina. Accordingly, a
hypoxic damage of the neuronal cells of the inner retina. has
been confirmed by histological data.245,246 Tissue hypoxia is
probably secondary to a decrease of blood flow in the affected
retinal areas, secondary to myogenic vasoconstriction of the
retinal arterioles or a decrease of NO release.247
During systemic hyperoxia, O2 diffusing from the choroid
supplies also the inner ischemic retina affected by an acute
BRVO.123 A decrease of PO2 of the damaged inner retinal
neuronal layers, enables oxygen to diffuse from the choroid and
increases the inner retinal PO2. In contrast, 100% O2 breathing
fails to produce an increase in PO2 in the center of fresh anoxic
postarteriolar embolism foci.248 Thus hyperoxia could be a
useful way to prevent hypoxic inner retinal layers damage, in
eyes with vein occlusion.
Carbogen breathing significantly increased preretinal PO2 in
normal and in ischemic postexperimental BRVO areas of mini-
pigs. The concomitant use of acetazolamide injection and
carbogen breathing or hyperoxia could restore an appropriate
oxygenation of BRVO areas. Acetazolamide induced an increase
of the preretinal PO2 to a greater extent when it was associated
with carbogen breathing than when it was combined with
hyperoxia.132,249
However, this finding conflicts with previous data obtained in
humans.249,250 Indeed, the ischemic retina, even if adequately
supplied with oxygen, still requires a supply of other
metabolites, such as glucose, to maintain a normal function.
Ischemia-Induced Retinal Metabolic Changes
Glutamate uptake
Electrophysiological and pharmacological evidence support the
notion that glutamate is the main excitatory neurotransmitter
in various regions of the brain and the vertebrate retina.251–255
In the retina, it can be electrogenically taken up by neuroglial
Müller cells and astrocytes.256–258 In astrocytes, glutamate is
predominantly converted to glutamine through an ATP-
requiring reaction catalyzed by the astrocytes specific glutamine
synthase. Glutamine released by astrocytes is taken up by
neurons to replenish the neurotransmitter pool of glutamate.259
This uptake has physiological significance since there is no
extracellular enzyme to degrade glutamate. Therefore, some
cells have to take up glutamate in order to facilitate its clearance
by diffusion from the synaptic clefts and to maintain synaptic
function.
Glutamate transport into astrocytes triggers aerobic
glycolysis in the glial cells, utilization of glucose and lactate
production.258,259 Glutamate-stimulated increase in glucose
uptake and phosphorylation in the astrocytes is abolished in the
absence of sodium in the extracellular medium, which is
consistent with the necessity of an electrochemical gradient for
the ion to drive glutamate uptake. The intracellular increase of
Retinal and Choroidal Circulations
sodium leads to the activation of the Na+/K+-ATPase which
triggers aerobic glycolysis and lactate production. Once lactate
is released, it can be transformed by neurons into pyruvate and
enter the TCA cycle to serve as an energy fuel. One molecule of
lactate entering the TCA cycle can yield in normoxic conditions
17 ATPs.260
Since glutamate uptake is electrogenic and strongly
dependent on trans-membrane Na+ influx, ischemia, by
causing a decrease in ATP concentration in the cell and, in turn,
inhibition of the Na+ pump, or high extracellular K+ conditions,
impairs the uptake of glutamate in Müller cells or astrocytes.261
Intravitreal measurement demonstrates a significant glutamate
increase in the rabbit vitreous following ischemia–reperfusion
induced by large increases of the intraocular pressure.262,263
However, measurements done before and following
experimental BRVO failed to demonstrate a glutamate increase
following the occlusion (personal findings). We cannot exclude
that artifacts induced by various amino-acid modifications in
CHAPTER 126
the vitreous after the occlusion (like the observed preretinal
vitreous exudation from the occluded vein) were not responsible
for altered measurements. Yet, measurement of glutamate
release in the retina and the cerebral cortex by a microdialysis
electrode perfused with L-glutamate oxidase, as well as the
recording of the current evoked between two voltage-clamped
electrodes, indicated differences between retina and cerebral
cortex glutamate release following ischemia/reperfusion. More
specifically, ischemia was reported to induce in the retina a
decrease of preretinal glutamate release, in contrast to the
increase induced in the cerebral cortex. Glutamate release
changes were reversible following reperfusion.264
Thus, in vivo data are lacking with regard to the extracellular
glutamate concentration and glutamate-mediated neurotoxicity
in acute ischemia/hypoxia induced by BRVO. That knowledge
would be crucial for the application of neuroprotective
treatments.
Preretinal L-lactate measurements
Preretinal lactate release was measured, lactate-sensitive
microelectrodes, following experimental BRVO. Following a
steady state measurements, an experimental BRVO 30 min
after the occlusion induced a significant decrease in preretinal
lactate (83.4 ± 10.0%, n = 10, p <0.01) compared with the
values measured before BRVO. One hour after BRVO, a 76.4 ±
12.9% decrease in preretinal lactate (n = 10, p < 0.01) was
measured. Two hours later, this decrease was 58 ± 20.0% (n =
9, p <0.01). Four hours after BRVO, the preretinal lactate was
not further decreased (58 ± 11.3%, n = 5, p < 0.01).265 Those
results suggest that acute BRVO increases the venous blood
pressure upstream to the occlusion and strongly decreases the
capillary blood flow and thus the flux of glucose from the
plasma to Müller cells. Impaired glycolysis could lead to a
decrease in preretinal lactate as measured in our experiments.
Perturbation of glycolysis, worsened by hypoxia, could provoke
retinal metabolism modifications leading to cellular dys-
function and death.
The role of NO
The role of NO in the pathophysiology of focal ischemia in the
central nervous system is complex, since both modifications in
constitutive and induced NO release are implicated. Previous
studies showed that NO could protect brain tissue during focal
ischemia266 by acting on blood vessels and platelets,149 whereas
it could increase ischemic damage by mediating neurotoxicity19
and by contributing to delayed cell death.20
Neurotoxicity has been reported to be associated with NO by
excessive stimulation of the NMDA receptors.267 Postsynaptic
NMDA-receptor activation could lead to an intracellular 1667
 RETINA AND VITREOUS
b vessel lying intravitreally in experimental
SECTION 3
a c
increase in NO production, which in turn would cause
nitrosylation of thiols (inhibition of GAPDH), DNA nitration,
oxidation of intracellular protein sulfhydrils, and inhibition of
mitochondrial respiration by binding to iron-sulfur com-
plexes.19 NO can also act as a second messenger on neighboring
cells, leading to an excessive increase in cGMP, which is an
intracellular effector regulating many vital cell functions, such
as the transduction of light signals in retinal photoreceptor
cells.268
NO can also elicit an indirect neurotoxicity via formation of
peroxynitrite (ONOO–), which decomposes to another reactive
oxygen species related to the hydroxy free radical (OH-) and to
the radical nitrogen dioxide (NO2), which is a potent activator
of lipid peroxidation. This form of toxicity is mainly related to
late inflammatory reaction and/or reperfusion of an injured
area.19,269,270
Because of the complex role played by NO and its potential
implication in both neurotoxicity and free radicals toxicity,
experiments aiming at suppressing or increase NO release have
been conducted in the past years. It has been shown that
selective inhibition of inducible NO synthase by amino-
guanidine diminishes the cerebral ischemic damage in a rat
model,271 whereas supplementation of NO by the NO-donor
nitroprusside can improve blood flow and reduce brain damage
after focal ischemia.272 Constitutive NO release is probably
impaired in the first hours after the onset of ischemia in the
mammalian brain; increasing local NO availability during the
first hours following the onset of ischemia could improve blood
flow and be neuroprotective.273
In the aorta and cerebral vessels from hypercholesterolemic
rabbits with impaired endothelium-dependent relaxation, L-
arginine restores the vasodilator response to achety-
lcholine.274,275 In pulmonary arteries and cultured endothelial
cells, depletion of L-arginine causes a loss of endothelium-
dependent relaxation that is reversible with addition of
extracellular L-arginine.276 In humans, the effect of NOS
inhibition by bolus infusion of 3 mg/kg of L-NMMA over 5 min
on the renal vasculature can be reversed by simultaneous
infusion of L-arginine (17 mg kg–1 min–1 over 30 min).277
In the long term evolution of ischemic microangiopathies, as
retinal vein occlusion or diabetic microangiopathy, the
hemodynamic modifications on the retinal vascular bed leads to
the formation of ischemic areas, where the blood flow
1668 decreases, as it was measured by LDV in diabetic patients with
FIGURE 126.10. (a) Semithin section through
the vitreoretinal interface over an ischemic
retinal area (R) shows a new vessel lying on the
modified vitreoretinal interface. L, vessel lumen;
ILM, internal limiting membrane. (b) Electron
microscopy shows an interendothelial junction
of a new vessel with nonfenestrated
endothelium that had grown intravitreally.
E, endothelial cell. (c) Electon microscopy of a
fenestrated (arrow) endothelial cell of a new
vasoproliferative microangiopathy in miniature
pigs. V, vitreous.
PDR278 and animals following experimental branch vein
occlusion.279 Preretinal tissue hypoxia was measured at the
ischemic areas as probably the oxygen which diffuses from both
the large retinal vessels and the choroid, does not reach the
ischemic inner retinal territories.280–282 Eyes with ischemic
microangiopathy complicated by neovascularization have poor
clinical prognosis as a result of the abnormal structure and
function of the new vessels.283–285 The clinical appearance and
the fine structure of new vessels, in experimental ischemic
microangiopathy,281 are similar to those observed in human
eyes with vasoproliferative microangiopathy. The new vessels
are composed by continuous-type, endothelial cells, surrounded
by a basal lamina and pericytes. The intercellular junctions of
the endothelial cells were scarce, fusion plates are observed
occasionally and exceptionally the endothelial cell fenestrations
(Fig. 126.10).
Neovascularization, that occurs in ischemic/hypoxic retinal
areas support the hypothesis that it is tissue hypoxia that
triggers neovascularization. Tissue hypoxia indirectly affects the
new vessels growth by the release of growth modulators by the
endothelial cells and modyfing the response of the endothelial
cells to growth modulators (probably via receptor upregulation).
An increase in hypoxia-inducible factor-1 (HIF-1) expression
has been shown to be correlated with vascular endothelial
growth factor (VEGF) expression both during normal and
pathologic retinal vascularization in mouse which confirms the
essential role of hypoxia in the regulation of VEGF expression
in the retina.286
In addition, in retinal or nonocular microvascular endothelial
cells cultures, the release of factors as insulin growth factor-I
(IGF-I),287 platelet-derived growth factor (PDGF),288 VEGF,289
tissue plasminogen activator (t-PA) and its inhibitor PAI-I
(factors which modulate extracellular matrix turnover),290,291
increases under steps of hypoxia. Moreover basic fibroblast
growth factor (bFGF), acts as a potent stimulator of endothelial
cells in culture to form capillary-like tubules,292 and induces
cellular growth if added to hypoxic cultures of aortic capillary
endothelial cells.293
The production of the VEGF, known to induce angiogenesis
in ischemic regions of tumors,289,294 was detected in retinas
with ischemic microangiopathy295–297 and in the vitreous of
human eyes with proliferative diabetic retinopathy.298–300
Hypoxia is considered a functional stimulus for VGEF expres-
sion in the ischemic regions of tumors and retina.289,301,302
 Retinal and Choroidal Circulations

In ischemic retinas of adult primates, VEGF gene expression
was reduced by systemic hyperoxia which reverses the retinal
tissue hypoxia.282
CHOROIDAL CIRCULATION
Choroidal Pressure Gradients
Even though there is marked permeability of the chorio-
capillaris (as discussed earlier), very little fluid flows into or out
from the extravascular space. Colloid osmotic pressure gradient
across the choriocapillary is 8–9 mmHg toward the lumen of
the vessels resulting in a tendency to absorb fluid into the
choriocapillaris.303 The hydrostatic pressure in the chorio-
capillaris is 7–8 mmHg above the intraocular pressure.304 Thus
the hydrostatic pressure gradient across the walls of the chorio-
capillaris is about the same as the colloid osmotic pressure,
resulting in little or no net flow between the choroidal vascular
bed and the extravascular space. Any change in the hydrostatic
circumscribed pigmented lesions the so called Elschnig’s spots.
A number of systemic diseases as systemic hypertension,
toxemia of pregnancy, disseminated intravascular coagulopathy,
acute posterior multifocal placoid pigment epitheliopathy, giant
cell arteritis, Goodpasture’s syndrome, and sickle cell disease
induces this pattern of choroidal lesions.309
Occlusion of larger choroidal arteries, such as short posterior
ciliary ones, causes triangular areas of chorioretinal damages
much smaller than expected.307 Moreover, ischemic lesions of
the choroid tend to resolve rapidly over several days, much
faster than expected by recanalization of a single terminal
arteriole.310,311 Similar observations have been reported first by
Amalric after large sectorial choroidal ischemia caused by
temporal arteritis or carotid obstruction.312 Thus, it seems that
if the RPE and the outer retina can survive even under marked
reductions in choroidal blood flow.
The anatomically observed anastomotic channels which
connects the lobules together and do not seem to contribute to

or colloid-osmotic pressures of the choroid would disturb the
Starling equilibrium causing a net filtration or absorption of
choroidal extravascular fluid. A marked increase in the hydro-
static pressure causing spontaneous choroidal detachment has
been reported in patients with arteriovenous fistulas of the
cavernous sinus.305 A sudden reduction in IOP brings about the
same effect, as transient choroidal detachments are common
after intraocular surgery.306
Choroidal Blood Flow and Aging
It was proposed that reduced blood flow through sclerotic
choroidal arteries would reduce perfusion mainly in the peri-
phery (watershed area) of the area supplied by one short
posterior ciliary artery. The submacular area is a meeting place
for many such watershed zones, which could explain the
tendency of the macula to undergo degenerative changes. There
is evidence that when light is focused on the macula, it causes
a much higher rise in temperature, whenever choroidal blood
flow is reduced.101 Dilated choroidal arteries in the submacular
area were observed on choroidal angiography in about half the
patients suffering of age related macular degeneration.81
Although, degeneration of the RPE and Bruch’s membrane
alterations seems to be crucial alterations in age related macular
degeneration, they are unlike to be due to reduced choroidal
blood flow. Indeed, considering the enormous flow rate through
the choroid, the nutrition of these tissues should not be at risk.
Choroidal Vascular Occlusions
The existence of anatomic connections between the lobules in
the choriocapillaris (as discussed earlier) suggests that ischemic
lesions caused by vascular occlusions are rare in the choroid.
However, induced choroidal ischemia tends to have a segmental
geographic pattern not consistent with alternative flow through
rich anastomotic channels. Choroidal blood flow is functionally
segmented, and the precapillary arterioles act as end-
arterioles.35,307,308 The occlusion of a single end arteriole in the
choriocapillaries lobule leads to the development of small
CHAPTER 126
the pattern of blood flow in normal states, may play a role in the
regulation of flow, when the blood flow or perfusion pressure is
markedly reduced in adjacent lobules as this occurs during
ischemia.309,313 A partial late filling from episcleral and pial
arteries, as retrograde filling from the vortex veins have also
been advocated.314,315 Complete abolition of choroidal blood
supply would destroy both the RPE and the photo-
receptors.316,317 Occlusion of the vortex veins without arterial
occlusion causes venous stasis, with a generalized breakdown of
the blood aqueous barrier. Occlusion of two or more vortex
veins results in hyphema, forward movement of the iris-lens
diaphragm, and increased intraocular pressure.47
SUMMARY
The vascular tone of the resistant vessels (arterioles, capillaries)
in the eye is modulated by the interaction of multiple
mechanisms affecting the arteriolar smooth muscle and the
vascular pericytes. The retinal blood flow is autoregulated by
the interaction of myogenic and metabolic mechanisms
through the release of vasoactive substances by the retinal
tissue surrounding the arteriolar wall and/or the vascular
endothelium. Mechanical stretch and increases in arteriolar
transmural pressure evoke the release of contracting factors by
the endothelial cells; NO or lactate, released during neuronal
activity and energy-generating reactions of the retina, strive to
optimize blood flow according to the metabolic needs of retinal
tissue. A close interaction between PG and NO metabolic
pathways indicates that, when one system is inhibited, the
other could rapidly compensate for the deficient system, and
maintain constant blood flow. The interaction of those
metabolic pathways is probably implicated in the control of the
vasomotion and autoregulation in the inner retina. Therefore, it
appears that the impairment of structure and function of the
retinal neuronal tissue and endothelium is the mechanism of
retinal blood abnormal regulation observed during the evolution
of ischemic microangiopathies.

REFERENCES
1. Group DRSR: Preliminary report of effects
of photocoagulation therapy. Am J
Ophthalmol 1976; 81:383–396.
2. Group DRSR: Photocoagulation treatment
of proliferative diabetic retinopathy: clinical
application of diabetic retinopathy study
(DRS) findings. DRS report number 8.
Ophtalmology 1981; 88:583–600.
3. Group BVOS: Argon laser scatter
photocoagulation for prevention of
neovascularization and vitreous hemorrhage
in branch vein occlusion. Arch Ophthalmol
1986; 104:34–41.
4. Leibowitz HMK, Maunder DE, Milton LR,
et al: The Framingham Eye Study
monograph: an ophthalmological and
epidemiological study of cataract,
glaucoma, diabetic retinopathy, macular
degeneration, and visual acuity in a
general population of 2631 adults,
1973–1975. Surv Ophthalmol 1980;
24(Suppl):335–610.
5. Cohen LH, Noell WK: Glucose catabolism
of rabbit retina before and after
development of visual function.
J Neurochem 1960; 5:253–276.
6. Winkler BS: Glycolytic and oxidative
metabolism in relation to retinal function.
J Gen Physiol 1981; 77:667–692.
7. Winkler BS: The intermediary metabolism of
the retina: biochemical and functional
aspects. Am Acad Ophtalmol 1983; 77: 1669
227–242.
 RETINA AND VITREOUS
8. Graymore CN, ed: Biochemistry of the
retina. In: Biochemistry of the eye. London:
Academic Press; 1970:645–735.
9. Kimble EA, Svoboda RA, Ostroy SE:
Oxygen consumption and ATP changes of
the vertebrate photoreceptor. Exp Eye Res
1980; 31:271–288.
10. Weiter JJ, Zuckerman R: The influence of
the photoreceptor-RPE complex on the
inner retina. An explanation for the
beneficial effects of photocoagulation.
Ophthalmology 1980; 87:1133–1139.
11. Tsacopoulos M: Physiopathology of the
uveal circulation. J Fr Ophtalmol 1979;
2:134–142.
12. Linsenmeier RA: Effects of light and
darkness on oxygen distribution and
consumption in the cat retina. J Gen
Physiol 1986; 88:521–542.
13. Penn RD, Hagins WA: Kinetics of the
photocurrent of retinal rods. Biophys J
SECTION 3
1972; 12:1073–1094.
14. Rothman SM, Olney JW: Glutamate and
the pathophysiology of hypoxic–ischemic
brain damage. Ann Neurol 1986;
19:105–111.
15. Choi DW: Cerebral hypoxia: some new
approaches and unanswered questions.
J Neurosci 1990; 10:2493–2501.
16. Stys PKR, Waxman BR, Davis SG, et al: Role
of extracellular calcium in anoxic injury of
mammalian central white matter. Proc Natl
Acad Sci USA 1990; 87:4212–4216.
17. McCord JM: Oxygen-derived free radicals
in postischemic tissue injury. N Engl J Med
1985; 312:159–163.
18. Traystman RJ, Kirsch JR, Koehler RC:
Oxygen radical mechanisms of brain injury
following ischemia and reperfusion. J Appl
Physiol 1991; 71:1185–1195.
19. Dalkara TM: The complex role of nitric
oxide in the pathophysiology of focal
cerebral ischemia. Brain Pathol 1994;
4:49–57.
20. Dawson VL, DT, London ED, Bredt DS,
Snyder SH: Nitric oxide mediates
glutamate neurotoxicity in primary cortical
culture. Proc Natl Acad Sci USA 1991;
88:6368–6371.
21. Wise GN, Dollery CT, Henkind P: The retinal
circulation. New York: Harper and Row;
1975:20–82.
22. Hayreh SS: The cilio-retinal arteries. Br J
Ophthalmol 1963; 47:71–89.
23. Rungger-Brandle EM, Niemeyer JM,
Eppenberger G, HM: Confocal microscopy
and computer-assisted image
reconstruction of astrocytes in the
mammalian retina. Eur J Neurosci 1993;
5:1093–1106.
24. Zhang Y, Stone J: Role of astrocytes in the
control of developing retinal vessels. Invest
Ophthalmol Vis Sci 1997; 38:1653–1666.
25. Henkind P, De Oliveira LF: New
observations on the radial peripapillary
capillaries. Invest Ophthalmol Vis Sci 1967;
6:103–108.
26. Henkind P, De Oliveira LF: Development of
the retina vessels in the rat. Invest
Ophthalmol Vis Sci 1967; 6:520–523.
27. Hogan MJ, Feeney L: The ultrastructure of
the retinal blood vessels. I. The large
vessels. J Ultrastruct Res 1963; 39:10–28.
28. Henkind P, De Oliveira LF: Retinal arteriolar
annuli. Invest Ophthalmol 1968; 7:584–591.
29. Shakib M, Cunha-Vaz JG: Studies on the
permeability of the blood-retinal barrier. IV.
1670 Junctional complexes of the retinal vessels
and their role in the permeability of the
blood-retinal barrier. Exp Eye Res 1966;
5:229–234.
30. Hirschi KK, D’Amore PA: Pericytes in the
microvasculature. Cardiovasc Res 1996;
32:687–698.
31. Krebs W, Krebs IP: Quantitative
morphology of the central fovea in the
primate retina. Am J Anat 1989;
184:225–236.
32. Sattler H: Uber den feineren Bau der
choroidea des Mensche. Beitragen zur
pathologischen un vergleichenden
Anatomie des Aderhaut. Von Graefe’s Arch
1976; 428–440.
33. Nuel IP: De la vascularisation de la
choroide et de la nutrition de la rétine
principalement au niveau de la fovea
centralis. Arch Ophthalmol 1992; 70–87.
34. Weiter JJE, JT: Anatomy of the choroidal
vasculature. Am J Ophthalmol 1974;
78:583–590.
35. Hayreh SS: Segmental nature of the
choroidal vasculature. Br J Ophthalmol
1975; 59:631–648.
36. Shubert HD: Topographic anatomy of the
central retina and segmental choroidal
circulation. In: Yannuzzi LA, Slatker JS,
eds. Indocyanine green angiography. St
Louis: Mosby; 1997:18–23.
37. Hayreh SS: Physiological anatomy of the
choroidal vascular bed. Int Ophthalmol
1983; 6:85–93.
38. Carella E, Carella G: Microangioarchitecture
of the choroidal circulation using latex
casts. In: Yannuzzi LA, Slatker JS, eds.
Indocyanine green angiography. St Louis:
Mosby; 1997:24–28.
39. Hayreh SS: Submacular choroidal vascular
pattern. Experimental fluorescein fundus
angiographic studies. Albrecht Von Graefes
Arch Klin Exp Ophthalmol 1974;
192:181–196.
40. Hayreh SS: The long posterior ciliary
arteries. An experimental study. Albrecht
Von Graefes Arch Klin Exp Ophthalmol
1974; 192:197–213.
41. Heimann K: Development of blood vessels
in the macular–choroidal zone. Klin
Monatsbl Augenheilkd 1970; 157:636–642.
42. Torczynski E, Tso MO: The architecture of
the choriocapillaris at the posterior pole.
Am J Ophthalmol 1976; 81:428–440.
43. Fryczkowski AW, Sherman MD, Walker J:
Observations on the lobular organization of
the human choriocapillaris. Int Ophthalmol
1991; 15:109–120.
44. Hayreh SS: The choriocapillaris. Albrecht
Von Graefes Arch Klin Exp Ophthalmol
1974; 192:165–179.
45. Fryczkowski AW: Topographic anatomy of
the central retina and segmental choroidal
circulation. In: Yannuzzi LA, Slatker JS,
eds. Indocyanine green angiography.
St Louis: Mosby; 1997:29–34.
46. TorczynskiE: Choroid and suprachoroid.
Biomedical foundations of ophthalmology.
In: Duane TD, ed. Philadelphia: JB
Lippincott; 1987.
47. Hayreh SS, Baines JA: Occlusion of the
vortex veins. An experimental study. Br J
Ophthalmol 1973; 57:217–238.
48. Hogan MJ, Alvarado JA, Weddel JE:
Histology of the human eye. Philadelphia:
Saunders Publishers; 1971:369.
49. Bill A, Tornquist P, Alm A: Permeability of
the intraocular blood vessels. Trans
Ophthalmol Soc UK 1980; 100:332–336.
50. Spitznas M, Reale E: Fracture faces of
fenestrations and junctions of endothelial
cells in human choroidal vessels. Invest
Ophthalmol 1975; 14:98–107.
51. Sugita A, Hamasaki M, Higashi R: Regional
difference in fenestration of choroidal
capillaries in Japanese monkey eye. Jpn J
Ophthalmol 1982; 26:47–52.
52. Korte GE, Reppucci V, Henkind P: RPE
destruction causes choriocapillary atrophy.
Invest Ophthalmol Vis Sci 1984;
25:1135–1145.
53. Chylack LT Jr, Bellows AR: Molecular
sieving in suprachoroidal fluid formation in
man. Invest Ophthalmol Vis Sci 1978;
17:420–427.
54. Ehinger B: Adrenergic nerves to the eye
and to related structures in man and
cynomolgus monkey. Invest Ophthalmol Vis
Sci 1966; 5:42–52.
55. Laties AM: Central retinal artery
innervation. Absence of adrenergic
innervation to the intraocular branches.
Arch Ophthalmol 1967; 77:405–409.
56. Dalske HF: Pharmacological reactivity of
isolated ciliary arteries. Invest Ophthalmol
1974; 13:389–392.
57. Denis P. Elena PP: Retinal vascular beta-
adrenergic receptors in man.
Ophtalmologie 1989; 3:62–64.
58. Ferrari-Dileo GD, Anderson EB, DR:
Angiotensin binding sites in bovine and
human retinal blood vessels. Invest
Ophthalmol Vis Sci 1987; 28:1747–1751.
59. Ruskell GL: Facial parasympathetic
innervation of the choroidal blood vessels
in monkeys. Exp Eye Res 1971;
12:166–172.
60. Stone RAT, Tervo T, Tarkkanen K, A:
Vasoactive intestinal polypeptide-like
immunoreactive nerves to the human eye.
Acta Ophthalmol (Copenh) 1986;
64:12–18.
61. Nilsson: Nitric oxide as a mediator of
parasympathetic vasodilation in ocular and
extraocular tissues in the rabbit. Invest
Ophthalmol Vis Sci 1996; 37:2110–2119.
62. Nilsson: Vasoactive intestinal paptide (VIP):
effects on the eye and on the regional
blood flow. Acta Physiol Scand 1984;
121:385–392.
63. Bredt DS, Hwang PM, Snyder SH:
Localization of nitric oxide synthase
indicating a neural role for nitric oxide.
Nature 1990; 347:768–770.
64. Lötjen-Drecoll E: Funktionelle Morphologie
der Aderhaut mit šberraschungen. 1998.
65. Büngard M: The three-dimensional
organisation of tight jonctions in a capillary
endothelium revealed by serial-section
microscopy. J Ultrastruct Res 1984;
88:1–17.
66. Carlson EC: Fenestrated subendothelial
basement membranes in human retinal
capillaries. Invest Ophthalmol Vis Sci 1989;
30:1923–1932.
67. Grotte G: Passage of dextran molecules
across the blood-lymph barrier. Acta Chir
Scand 1956; 211:1–84.
68. Crone C: The Malpighi lecture. From
‘Porositates carnis’ to cellular
microcirculation. Int J Microcirc Clin Exp
1987; 6:101–122.
69. Neuhaus J, Risau W, Wolburg H: Induction
of blood-brain barrier characteristics in
bovine brain endothelial cells by rat
astroglial cells in transfilter coculture. Ann
N Y Acad Sci 1991; 633:578–580.

70. Grayson MCL, AM: Ocular localization of
sodium fluorescein. Effects of
administration in rabbit and monkey. Arch
Ophthalmol 1971; 85:600–603.
71. Tornquist P, Alm A, Bill A: Studies on ocular
blood flow and retinal capillary permeability
to sodium in pigs. Acta Physiol Scand
1979; 106:343–350.
72. Pappenheimer JR: Passage of molecules
through capillary walls. Physiol Rev 1953;
33:387–423.
73. Gerhart DZ, Leino RL: Distribution of
monocarboxylate transporters MCT1 and
MCT2 in rat retina. 1999; 92:367–375.
74. Poole RC: Transport of lactate and other
monocarboxylates across mammalian
plasma membranes. Am J Physiol 1993;
264:761–782.
75. Palade GE, Simionescu M, Simionescu N:
Structural aspects of the permeability of
the microvascular endothelium. Acta
Physiol Scand Suppl 1979; 463:11–32.
76. Alm A, Tornquist P: The uptake index
method applied to studies on the blood-
retinal barrier. I. A methodological study.
Acta Physiol Scand 1981; 113:73–79.
77. Tornquist P, Alm A: Carrier-mediated
transport of amino acids through the
blood-retinal and the blood-brain barriers.
Graefes Arch Clin Exp Ophthalmol 1986;
224:21–25.
78. Miller S, Steinberg RH: Transport of taurine,
L-methionine and 3-o-methyl-D-glucose
across frog retinal pigment epithelium. Exp
Eye Res 1976; 23:177–189.
79. Krogsaa BL-A, Mehlsen H, Sestoft JL:
Blood-retinal barrier permeability versus
diabetes duration and retinal morphology in
insulin dependent diabetic patients. Acta
Ophthalmol (Copenh) 1987; 65:686–692.
80. Krogsaa BL-A, Parving H, Bjaeldager HH,
P: The blood-retinal barrier permeability in
essential hypertension. Acta Ophthalmol
(Copenh) 1983; 61:541–544.
81. Foulds WS: The choroidal circulation and
retinal metabolism – an overview. Eye
1990; 4(Pt 2):243–248.
82. Riva CEG, Sinclair JE, Petrig SH, BL: Blood
velocity and volumetric flow rate in human
retinal vessels. Invest Ophthalmol Vis Sci
1985; 26:1124–1132.
83. Riva CE, Petrig B: Blue field entoptic
phenomenon and blood velocity in the
retinal capillaries. J Opt Soc Am 1980;
70:1234–1238.
84. Bill A: Calorimetric procedures for the study
of the blood flow through the ciliary region
and the choroid in rabbits. Acta
Ophthalmol (Copenh) 1962; 40:131–148.
85. Bill A: Intraocular pressure and blood flow
through the uvea. Arch Ophthalmol 1962;
67:336–348.
86. Friedman E, KH, Smith TR: Retinal and
choroidal blood flow determined with
krypton-85 in anesthetized animals. Invest
Ophtalmol Vis Sci 1964; 3:539.
87. Alm A, Bill A: The oxygen supply to the
retina. II. Effects of high intraocular
pressure and of increased arterial carbon
dioxide tension on uveal and retinal blood
flow in cats. A study with radioactively
labelled microspheres including flow
determinations in brain and some other
tissues. Acta Physiol Scand 1972;
84:306–319.
88. Alm A, Bill A: Ocular and optic nerve blood
flow at normal and increased intraocular
pressures in monkeys (Macaca irus): a
Retinal and Choroidal Circulations
study with radioactively labelled
microspheres including flow determinations
in brain and some other tissues. Exp Eye
Res 1973; 15:15–29.
89. Yu DYA, Cringle VA, Brown SJ, MJ:
Choroidal blood flow measured in the dog
eye in vivo and in vitro by local hydrogen
clearance polarography: validation of a
technique and response to raised
intraocular pressure. Exp Eye Res 1988;
46:289–303.
90. Gherezghiher T, Okubo H, Koss MC:
Choroidal and ciliary body blood flow
analysis: application of laser Doppler
flowmetry in experimental animals. Exp Eye
Res 1991; 53:151–156.
91. Riva CEC, Mann SD, Barnes RM, GE: Local
choroidal blood flow in the cat by laser
Doppler flowmetry. Invest Ophthalmol Vis
Sci 1994; 35:608–618.
92. Riva CET, Hero P, Movaffaghy M, et al:
Choroidal blood flow during isometric
exercises. Invest Ophthalmol Vis Sci 1997;
38:2338–2343.
93. Klein GJB, Flower RH, RW: An image
processing approach to characterizing
choroidal blood flow. Invest Ophthalmol Vis
Sci 1990; 31:629–637.
94. Flower RW: Extraction of choriocapillaris
hemodynamic data from ICG fluorescence
angiograms. Invest Ophthalmol Vis Sci
1993; 34:2720–2729.
95. Feke GTT, Deupree H, Goger DM, et al:
Blood flow in the normal human retina.
Invest Ophthalmol Vis Sci 1989;
30:58–65.
96. Alm A, Bill A: Ocular circulation. In: Moses
RA, ed. Adler’s physiology of the eye.
St Louis: Mosby; 1987.
97. Alm A, Bill A: Blood flow and oxygen
extraction in the cat uvea at normal and
high intraocular pressures. Acta Physiol
Scand 1970; 80:19–28.
98. Hickam JB, Frayser R, Ross JC: A study of
retinal venous blood oxygen saturation in
human subjects by photographic means.
Circulation 1963; 27:375–385.
99. Tornquist P, Alm A: Retinal and choroidal
contribution to retinal metabolism in vivo.
A study in pigs. Acta Physiol Scand 1979;
106:351–357.
100. Parver LM: Temperature modulating action
of choroidal blood flow. Eye 1991; 5(Pt
2):181–185.
101. Parver LM, Auker C, Carpenter DO:
Choroidal blood flow as a heat dissipating
mechanism in the macula. Am J
Ophthalmol 1980; 89:641–646.
102. Tsacopoulos M, Lehmenkuhler A: A
double-barrelled Pt-microelectrode for
simultaneous measurement of PO2 and
bioelectrical activity in excitable tissues.
Experientia 1977; 33:1337–1338.
103. Tsacopoulos M, Poitry S, Borsellino A:
Diffusion and consumption of oxygen in the
superfused retina of the drone (Apis
mellifera) in darkness. J Gen Physiol 1981;
77:601–628.
104. Riva CE, Pournaras CJ, Tsacopoulos M:
Regulation of local oxygen tension and
blood flow in the inner retina during
hyperoxia. J Appl Physiol 1986;
61:592–598.
105. Pournaras CJR, Tsacopoulos CE,
Strommer M, K: Diffusion of O2 in the retina
of anesthetized miniature pigs in normoxia
and hyperoxia. Exp Eye Res 1989;
49:347–360.
106. Dollery CT, Bulpitt CJ, Kohner EM: Oxygen
supply to the retina from the retinal and
choroidal circulations at normal and
increased arterial oxygen tensions. Invest
Ophthalmol 1969; 8:588–594.
107. Alder VAC, Constable SJ, IJ: The retinal
oxygen profile in cats. Invest Ophthalmol
Vis Sci 1983; 24:30–36.
108. Ahmed JB, Dunn RD, Linsenmeier R Jr, RA:
Oxygen distribution in the macaque retina.
Invest Ophthalmol Vis Sci 1993; 34:516–521.
109. Robinson FR, Grunwald CE, Petrig JE, et
al: Retinal blood flow autoregulation in
response to an acute increase in blood
pressure. Invest Ophthalmol Vis Sci 1986;
27:722–726.
110. Riva CE, Sinclair SH, Grunwald JE:
Autoregulation of retinal circulation in
response to decrease of perfusion
pressure. Invest Ophthalmol Vis Sci 1981;
CHAPTER 126
21(1 Pt 1):34–38.
111. Alm A, Bill A: The oxygen supply to the
retina. I. Effects of changes in intraocular
and arterial blood pressures, and arterial P
O2 and P CO2 on the oxygen tension in the
vitreous body of the cat. Acta Physiol
Scand 1972; 84:261–274.
112. Yancey CM, Linsenmeier RA: Oxygen
distribution and consumption in the cat
retina at increased intraocular pressure.
Invest Ophthalmol Vis Sci 1989;
30:600–611.
113. Stoltz JF, DM: New trends in clinical
hemorheology: an introduction to the
concept of the hemorheological profile.
Schweiz Med Wochenschr 1991;
43(Suppl):41–49.
114. Knabben H, WS, Remky A, et al: Retinal
hemodynamics in patients with
hyperviscosity syndrome Klin Monatsbl
Augenheilkd 1995; 206:152–156.
115. Hickam JB, Frayser R: Studies of the retinal
circulation in man: observation on vessel
diameter, arteriovenous oxygen difference
and mean circulation time. Circulation
1966; 33:302–316.
116. Riva CE, Grunwald JE, Sinclair SH: Laser
Doppler Velocimetry study of the effect of
pure oxygen breathing on retinal blood
flow. Invest Ophthalmol Vis Sci 1983;
24:47–51.
117. Eperon G, Johnson M, David NJ: The effect
of arterial PO2 on relative retinal blood flow
in monkeys. Invest Ophthalmol 1975;
14:342–352.
118. Kety SS, Schmidt CE: Effect of altered
arterial tension of carbon dioxide and
oxygen on cerebral blood flow on normal
young man. J Clin Invest 1948;
27:484–492.
119. Pournaras C, Tsacopoulos M, Chapuis P:
Studies on the role of prostaglandins in the
regulation of retinal blood flow. Exp Eye
Res 1978; 26:687–697.
120. Kogure KS, Reinmuth P, Fujishima OM,
et al: Mechanisms of cerebral
vasodilatation in hypoxia. J Appl Physiol
1970; 29:223–229.
121. Linsenmeier RA, Braun RD: Oxygen
distribution and consumption in the cat
retina during normoxia and hypoxemia.
J Gen Physiol 1992; 99:177–197.
122. Moret PP, Munoz CJ, Brazitikos JL, et al:
Profile of pO2. I. Profile of transretinal pO2
in hypoxia. Klin Monatsbl Augenheilkd
1992; 200:498–499.
123. Pournaras CJ, Ilic J, Gilodi N: The
physiopathology of retinal circulation: 1671
 RETINA AND VITREOUS
consequences of acute retinal vascular
occlusion. Klin Monatsbl Augenheilkd 1985;
186:471–476.
124. Linsenmeier RA, Steinberg RH: Effects of
hypoxia on potassium homeostasis and
pigment epithelial cells in the cat retina.
J Gen Physiol 1984; 84:945–970.
125. Hardy PP, Lahaie KG, Isabelle V, et al:
Increased nitric oxide synthesis and action
preclude choroidal vasoconstriction to
hyperoxia in newborn pigs. Circ Res 1996;
79:504–511.
126. Tsacopoulos M, David NJ: The effect of
arterial PCO2 on relative retinal blood flow
in monkeys. Invest Ophthalmol 1973;
12:335–347.
127. Brazitikos PDP, Munoz CJ, Tsacopoulos JL,
M: Microinjection of L-lactate in the
preretinal vitreous induces segmental
vasodilation in the inner retina of miniature
pigs. Invest Ophthalmol Vis Sci 1993;
SECTION 3
34:1744–1752.
128. Tsacopoulos M, Levy S: Intraretinal acid-
base studies using pH glass
microelectrodes: effect of respiratory and
metabolic acidosis and alkalosis on inner-
retinal pH. Exp Eye Res 1976; 23:495–504.
129. Harper AM: Physiology of cerebral blood
flow. Br J Anaesth 1965; 37:225–325.
130. Sato E, STNT, Mori F, et al: Role of nitric
oxide in regulation of retinal blood flow
during hypercapnia in cats. Invest
Ophthalmol Vis Sci 2003; 44:4947–4953.
131. Checchin D, HX, Hardy P, et al: PGE(2)-
mediated eNOS induction in prolonged
hypercapnia. Invest Ophthalmol Vis Sci
2002; 43:1558–1566.
132. Pournaras JAP, Munoz IK, Pournaras JL,
CJ: Experimental retinal vein occlusion:
effect of acetazolamide and carbogen
(95% O2/5% CO2) on preretinal PO2. Invest
Ophthalmol Vis Sci 2004; 45:3669–3677.
133. Vorstrup S, HI, Paulson OB: Effect of
acetazolamide on cerebral blood flow and
cerebral metabolic rate for oxygen. J Clin
Invest 1984; 74:1634–1639.
134. Taki K, KH, Endo S, et al: Cascade of
acetazolamide-induced vasodilatation. Res
Commun Mol Pathol Pharmacol 1999;
103:240–248.
135. Harlan JM: Diuretics agents. In: Katzung
BG, ed. Basic and clinical pharmacology.
7th edn. 1998:246–249.
136. Ferrari-Dileo G, RJ, Rockwood EJ, et al:
Angiotensin-converting enzyme in bovine,
feline, and human ocular tissues. Invest
Ophthalmol Vis Sci 1988; 29:876–881.
137. Nyborg NC, NP, Prieto D, Benedito S:
Angiotensin II does not contract bovine
retinal resistance arteries in vitro. Exp Eye
Res 1990; 50:469–474.
138. Krejcy K, WM, Kreuzer C, et al:
Characterization of angiotensin-II effects on
cerebral and ocular circulation by
noninvasive methods. Br J Clin Pharmacol
1997; 43:501–508.
139. Alm A: Effects of norepinephrine,
angiotensin, dihydroergotamine,
papaverine, isoproterenol, histamine,
nicotinic acid, and xanthinol nicotinate on
retinal oxygen tension in cats. Acta
Ophthalmol 1972; 50:707–719.
140. Haefliger IOB, Luscher JL, TF:
Endothelium-dependent vasoactive
modulation in the ophthalmic circulation.
Prog Retin Eye Res 2001; 20:209–225.
141. Haefliger IOM, Flammer P, Luscher J, TF:
1672 The vascular endothelium as a regulator of
the ocular circulation: a new concept in
ophthalmology? Surv Ophthalmol 1994;
39:123–132.
142. Brown SM, Jampol LM: New concepts of
regulation of retinal vessel tone. Arch
Ophthalmol 1996; 114:199–204.
143. Furchgott RF, Zawadzki JV: The obligatory
role of endothelial cells in the relaxation of
arterial smooth muscle by acetylcholine.
Nature 1980; 288:373–376.
144. Palmer RM, Ferrige AG, Moncada S: Nitric
oxide release accounts for the biological
activity of endothelium-derived relaxing
factor. Nature 1987; 327:524–526.
145. Ignarro LJB, Wood GM, Byrns KS, et al:
Endothelium-derived relaxing factor
produced and released from artery and
vein is nitric oxide. Proc Natl Acad Sci USA
1987; 84:9265–9269.
146. Feelisch MtP, Zamora M, Deussen R, et al:
Understanding the controversy over the
identity of EDRF. Nature 1994; 368:62–65.
147. Koch KWL, Haberecht HG, Redburn M,
et al: Functional coupling of a
Ca2+/calmodulin-dependent nitric oxide
synthase and a soluble guanylyl cyclase in
vertebrate photoreceptor cells. EMBO J
1994; 13:3312–3320.
148. Ignarro LJ: Biosynthesis and metabolism of
endothelium–derived nitric oxide. Ann Rev
Pharmacol Toxicol 1990; 30:535–560.
149. Moncada S, Palmer RM, Higgs EA: Nitric
oxide: physiology, pathophysiology, and
pharmacology. Pharmacol Rev 1991;
43:109–142.
150. Venturini CM, Knowles RG, Palmer RM,
Moncada S: Synthesis of nitric oxide in the
bovine retina. Biochem Biophys Res
Commun 1991; 180:920–925.
151. Dawson TMB, Fotuhi DS, Hwang M, et al:
Nitric oxide synthase and neuronal NADPH
diaphorase are identical in brain and
peripheral tissues. Proc Natl Acad Sci USA
1991; 88:7797–7801.
152. Goureau OH, Courtois D, De Kozak Y, Y:
Induction and regulation of nitric oxide
synthase in retinal Muller glial cells.
J Neurochem 1994; 63:310–317.
153. Yamamoto RB, Snyder DS, Stone SH, RA:
The localization of nitric oxide synthase in
the rat eye and related cranial ganglia.
Neuroscience 1993; 54:189–200.
154. Osborne NN, Barnett NL, Herrera AJ:
NADPH diaphorase localization and nitric
oxide synthetase activity in the retina and
anterior uvea of the rabbit eye. Brain Res
1993; 610:194–198.
155. Park CSP, Gianotti K, Villegas C, et al:
Human retina expresses both constitutive
and inducible isoforms of nitric oxide
synthase mRNA. Biochem Biophys Res
Commun 1994; 205:85–91.
156. Knowles RGM, S: Nitric oxide synthases
in mammals. Biochem J 1994;
298:249–258.
157. Meyer PC, Schlotzer-Schrehardt C,
Flammer U, et al: Localization of nitric
oxide synthase isoforms in porcine ocular
tissues. Curr Eye Res 1999; 18:375–380.
158. Chakravarthy US, McNally AW, Bailie J,
et al: Nitric oxide synthase activity and
expression in retinal capillary endothelial
cells and pericytes. Curr Eye Res 1995;
14:285–294.
159. Donati GP, Munoz CJ, Poitry JL, et al: Nitric
oxide controls arteriolar tone in the retina of
the miniature pig. Invest Ophthalmol Vis Sci
1995; 36:2228–2237.
160. Haefliger IOF, Luscher J, TF: Nitric oxide
and endothelin-1 are important regulators
of human ophthalmic artery. Invest
Ophthalmol Vis Sci 1992; 33:2340–2343.
161. Haefliger IOF, Luscher J: Heterogeneity of
endothelium-dependent regulation in
ophthalmic and ciliary arteries. Invest
Ophthalmol Vis Sci 1993; 34:1722–1730.
162. Haefliger IO, Zschauer A: Relaxation of
retinal pericyte contractile tone through the
nitric oxide-cyclic guanosine
monophosphate pathway 1994;
35:991–997.
163. Meyer PF, Luscher J: Endothelium–
dependent regulation of the ophthalmic
microcirculation in the perfused porcine
eye: role of nitric oxide and endothelins.
Invest Ophthalmol Vis Sci 1993;
34:3614–3621.
164. Stamler JS, JL, Eu JP, et al: Blood flow
regulation by S-Nitrosohemoglobin in the
Physiological Oxygen Gradient. Science
1997; 276:2034–2037.
165. Singel DJ, SJ: Chemical physiology of
blood flow regulation by red blood cells:
the role of nitric oxide and S-
nitrosohemoglobin. Annu Rev Physiol 2005;
67:99–145.
166. Pickard JDM, MacKenzie LA, Harper ET:
Response of the cerebral circulation in
baboons to changing perfusion pressure
after indomethacin. Circ Res 1977;
40:198–203.
167. Ellis EF, Wei EP, Kontos HA: Vasodilation of
cat cerebral arterioles by prostaglandins
D2, E2, G2, and I2. Am J Physiol 1979;
237:H381–H385.
168. Kontos HAW, Ellis EP, Dietrich EF, et al:
Prostaglandins in physiological and in
certain pathological responses of the
cerebral circulation. Fed Proc 1981;
40:2326–2330.
169. Hagen AA, White RP, Robertson JT:
Synthesis of prostaglandins and
thromboxane B2 by cerebral arteries.
Stroke 1979; 10:306–309.
170. Hudes GRL, Rockey WY, White JH:
Prostacyclin is the major prostaglandin
synthesized by bovine retinal capillary
pericytes in culture. Invest Ophthalmol Vis
Sci 1988; 29:1511–1516.
171. Preud’homme Y, Demolle D, Boeynaems
JM: Metabolism of arachidonic acid in
rabbit iris and retina. Invest Ophthalmol Vis
Sci 1985; 26:1336–1342.
172. Nielsen PJ, Nyborg NC: Contractile and
relaxing effects of arachidonic acid
derivatives on isolated bovine retinal
resistance arteries. Exp Eye Res 1990;
50:305–311.
173. Starr MS: Effects of prostaglandings on
blood flow in the rabbit eye. Exp Eye Res
1990; 50:305–311.
174. Hsu P, Albuquerque ML, Leffler CW:
Mechanisms of hypercapnia-stimulated PG
production in piglet cerebral microvascular
endothelial cells. Am J Physiol 1995; 268(2
Pt 2):H591–H603.
175. Chemtob SB, Rex K, Chatterjee J, et al:
Ibuprofen enhances retinal and choroidal
blood flow autoregulation in newborn
piglets. Invest Ophthalmol Vis Sci 1991;
32:1799–807.
176. Stiris TS, Hehre C, Goldberg D, et al: Effect
of cyclooxygenase inhibition on retinal and
choroidal blood flow during hypercarbia in
newborn piglets. Pediatr Res 1992;
31:127–130.

177. Levin ER: Endothelins. N Engl J Med 1995;
333:356–363.
178. Inoue AY, Kimura M, Kasuya S, et al: The
human endothelin family: three structurally
and pharmacologically distinct isopeptides
predicted by three separate genes. Proc
Natl Acad Sci USA 1989; 86:2863–2867.
179. McDonald DMB, Archer JR, Chakravarthy
DB: Characterization of endothelin A (ETA)
and endothelin B (ETB) receptors in
cultured bovine retinal pericytes. Invest
Ophthalmol Vis Sci 1995; 36:1088–1094.
180. Takei KS, Nonoyama T, Miyauchi T, et al:
A new model of transient complete
obstruction of retinal vessels induced by
endothelin-1 injection into the posterior
vitreous body in rabbits. Graefes Arch Clin
Exp Ophthalmol 1993; 231:476–481.
181. Granstam E, Wang, Bill A: Ocular effects of
endothelin-1 in the cat 1992; 11:325–332.
182. Bursell SEC, Oren AC, King B, GL: The in
vivo effect of endothelins on retinal
circulation in nondiabetic and diabetic rats.
Invest Ophthalmol Vis Sci 1995;
36:596–607.
183. Dallinger SD, Wenzel GT, Graselli R, et al:
Endothelin-1 contributes to hyperoxia-
induced vasoconstriction in the human
retina. Invest Ophthalmol Vis Sci 2000;
41:864–869.
184. Polak KL, Frank A, Jandrasits B, et al:
Regulation of human retinal blood flow by
endothelin-1. Exp Eye Res 2003;
76:633–640.
185. Wong J, VP, Fineman JR, et al:
Endothelin-1 produces pulmonary
vasodilation in the intact newborn lamb.
Am J Physiol 1993; 265:H1318–H1325.
186. Eddahibi S, Monirul M, et al: Dilator effect
of endothelins in pulmonary circulation:
damages associated with chronic hypoxia.
Am J Physiol 1993; 265:L571–L580.
187. Filep JG, Rousseau A, et al: Vascular
response to endothelin-1 following inhibiton
of nitric oxide synthesis in the conscious
rat 1993; 110:1213–1221.
188. D’Orleans-Juste P, Telemaque S, et al:
Block of endothelin-1-induced release of
thromboxane A2 from the guinea pig lung
and nitric oxide from the rabbit kidney by a
selective ETB receptor antagonist, BQ-788.
Br J Pharmacol 1994; 113:1257–1262.
189. Hirata Y, Eguchi S, et al: Endothelin
receptor subtype B mediates synthesis of
NO by cultured bovine endothelial cells.
J Clin Invest 1993; 91:1367–1373.
190. Reihart GA, Burke SE, et al: Hypertension
induced by blockade of ET(B) receptors in
conscious nonhuman primates: role of
ET(A) receptors. Am J Physiol Heart Circ
Physiol 2002; 283:H1555–H1561.
191. Sokolvsky M, Galron R: A novel subtype of
endothelin receptors. J Biol Chem 1992;
267:20551–20554.
192. Poitry-Yamate CL, Poitry S, Tsacopoulos
M: Lactate released by Muller glial cells is
metabolized by photoreceptors from
mammalian retina. J Neurosci 1995;
15(7 Pt 2):5179–5191.
193. Oldendorf WH: Carrier-mediated
blood–brain barrier transport of short-chain
monocarboxylic organic acids. Am J
Physiol 1973; 224:1450–1453.
194. Garhofer G, Resch H, et al: Effect of
intravenous administration of sodium-
lactate on retinal blood flow in healthy
subjects. Invest Ophthalmol Vis Sci 2003;
44:3972.
Retinal and Choroidal Circulations
195. Williamson DH, Krebs HA: The redox strate
of free nicotinamide-adenine dinucleotide
in the cytoplasm and mitochondria in the
rat liver. Biochem J 1967; 103:514–527.
196. Ido Y, Chong K, Williamson JR: NADH
augments blood flow in physiologically
activated retina and visual cortex. Proc Natl
Acad Sci USA 117:653–658.
197. Garhofer G, Huemer KH, et al: Flicker light-
induced vasodilatation in the human retina:
effect of lactate and changes in mean
arterial pressure. Invest Ophthalmol Vis Sci
2003; 44:5309–5314.
198. Granger HJ, Shepperd AP: Intrinsic
microvascular control of tissu oxygen
delivery. Microvasc Res 1973; 5:49.
199. Johnson PC: The myogenic response. In:
Bohr DF, Somlyo AP, Sparks HV, eds:
Handbook of physiology. The
cardiovascular system. Baltimore: Waverly
Press; 1980; 2:772–726.
200. Yao KT, Flammer M, Luscher J: Endothelium-
dependent regulation of vascular tone of the
porcine ophthalmic artery. Invest Ophthalmol
Vis Sci 1991; 32:1791–1798.
201. Harder DR: Pressure-induced myogenic
activation of cat cerebral arteries is
dependent on intact endothelium. Circ Res
1987; 60:102–107.
202. Harder DR: Pressure-dependent membrane
depolarization in cat middle cerebral artery.
Circ Res 1984; 55:197–202.
203. Harder DR, Kauser K, et al: Pressure
releases a transferable endothelial
contractile factor in cat cerebral arteries.
Circ Res 1989; 65:193–198.
204. Lansman JB, Hallam TJ, Rink TJ: Single
stretch-activated ion channels in vascular
endothelial cells as mechanotransducers?
Nature 1987; 325:811–813.
205. Jeppesen P, Aalkjoer C, Bek T: Bradykinin
relaxation in small porcine retinal arterioles.
Invest Ophthalmol Vis Sci 2002;
43:1891–1895.
206. Delaey C, Van de Voorde J: Pressure-
induced myogenic responses in isolated
bovine retinal arteries. Invest Ophthalmol
Vis Sci 2000; 41:1871–1875.
207. Bill A, Aspects of oxygen and glucose
consumption in the retina: effects of high
intraocular pressure and light. Graefes Arch
Clin Exp Ophthalmol 1990; 228:124–127.
208. Wang L, Bill A: Glucose metabolism in cat
outer retina. Effects of light and hyperoxia.
Invest Ophthalmol Vis Sci 1997; 38:48–55.
209. Bill A, Control of retinal and choroidal blood
flow. Eye 1990; 4:319–325.
210. Kondo M, Wang L, Bill A: The role of nitric
oxide in hyperaemic response to flicker in
the retina and optic nerve in cats. Acta
Ophthalmol Scand 1997; 75:232–235.
211. Riva CE, Shonat RD, Petrig BL: Flicker
evoked increase in optic nerve head blood
flow in anesthetized cats. Neurosci Lett
1991; 128:291–296.
212. Iadecola C: Regulation of the cerebral
microcirculation during neural activity: is
nitric oxide the missing link? 1993;
16:206–214.
213. Scheiner AJR, Kazahaya CE, Petrig K:
Effect of flicker on macular blood flow
assessed by the blue field simulation
technique. Invest Ophthalmol Vis Sci 1994;
35:3436–3441.
214. Buerk DG, Riva CE, Cranstoun SD: Nitric
oxide has a vasodilatory role in cat optic
nerve head during flicker stimuli. Microvasc
Res 1996; 52:13–26.
215. Kondo M, Wang L, Bill A: The role of nitric
oxide in hyperaemic response to flicker in
the retina and optic nerve in cats. Acta
Ophthalmologica Scandinavica 1997;
75:232–235.
216. Dorner GT, et al: Nitric oxide regulates
retinal vascular tone in man. Am J Physiol
Heart Circ Physiol 2003; 10(1152 L1 –
Available at:
\\Siro\public\Administration\Reference
Manager\PDF Files\3953.pdf).
217. Deussen A, Sonntag M, Vogel R:
L-arginine-derived nitric oxide: a major
determinant of uveal blood flow. Exp Eye
Res 1993; 57:129–134.
218. Moncada S: Pharmacology and
endogenous roles of prostaglandins
endoperoxides, thromboxane A2 and
Prostacyclin 1979; 30:293–331.
219. Radomski MW, Moncada S: The
CHAPTER 126
antiaggregation properties of vascular
endothelium: interactions between
prostacyclin and nitric oxide. Br J
Pharmacol 1987; 93:639–646.
220. de Nucci GG, Warner RJ, Vane TD:
Receptor-mediated release of endothelium-
derived relaxing factor and prostacyclin
from bovine aortic endothelial cells is
coupled. Proc Natl Acad Sci USA 1988;
85:2334–2338.
221. Doni MGW, Palmer BJ, Moncada RM:
Actions of nitric oxide on the release of
prostacyclin from bovine endothelial cells in
culture. Eur J Pharmacol 1988; 151:19–25.
222. Shimokawa HF, Lorenz NA, Vanhoutte RR:
Prostacyclin releases endothelium-derived
relaxing factor and potentiates its action in
coronary arteries of the pig. Br J
Pharmacol 1988; 95:1197–1203.
223. Petropoulos IK, Munoz JL, Pournaras CJ:
Effect of carbogen breathing and
acetazolamide on optic disc PO2. Invest
Ophthalmol Vis Sci 2005; 46:4139–4146.
224. Nagaoka T, Mori F, et al: The effect of nitric
oxide on retinal blood flow during hypoxia
in cats. Invest Ophthalmol Vis Sci 2002;
43:3037–3044.
225. Alm A: The effect of sympathetic
stimulation on blood flow through the uvea,
retina and optic nerve in monkeys (Macaca
irus). Exp Eye Res 1977; 25:19–24.
226. Alm A, Bill A: The effect of stimulation of
the cervical sympathetic chain on retinal
oxygen tension and on uveal, retinal and
cerebral blood flow in cats. Acta Physiol
Scand 1973; 88:84–94.
227. Bill A, Linder M, Linder J: The protective
role of ocular sympathetic vasomotor
nerves in acute arterial hypertension. Bibl
Anat 1977; 16(Pt 2):30–35.
228. Kiel JWS: Autoregulation of choroidal blood
flow in the rabbit. Invest Ophthalmol Vis Sci
1992; 33:2399–2410.
229. Riva CET, Hero P, Petrig M: Effect of acute
decreases of perfusion pressure on
choroidal blood flow in humans. Invest.
Ophthalmol Vis Sci 1997; 38:1752–1760.
230. Nilsson Bill A: Characteristicss of uvea
vasodilation produced by facial nerve
stimulation in monkeys, cats, and rabbits.
Exp Eye Res 1985; 40:841–852.
231. Nilsson SFE: Studies on ocular blood flow
and acqueous humour dynamics. Acta
Universitatis Upsaliensis 1986; 43:1–38.
232. Seligsohn EE, Bill A: Effects of NG-nitro-L-
arginine methyl ester on the cardiovascular
system of the anaesthetized rabbit and on
the cardiovascular response to thyrotropin- 1673
 RETINA AND VITREOUS
releasing hormone. Br J Pharmacol 1993;
109:1219–1225.
233. Mann RM, et al: Nitric oxide and choroidal
blood flow regulation. Invest Ophthalmol
Vis Sci 1995; 36:925–930.
234. Schmetterer L, et al: The effect of systemic
nitric oxide-synthase inhibition on ocular
fundus pulsations in man. Exp Eye Res
1997; 64:305–312.
235. Luksch A, et al: Effects of systemic NO
synthase inhibition on choroidal and optic
nerve head blood flow in healthy subjects.
Invest Ophthalmol Vis Sci 2000;
41:3080–3084.
236. Blitzer ML, LS, Creager MA: Endothelium-
derived nitric oxide mediates hypoxic
vasodilation of resistance vessels in
human. Am J Physiol 1996;
271:H1182–H1185.
237. Hardy PN, Abran AM, St-Louis D, et al:
Nitric oxide in retinal and choroidal blood
SECTION 3
flow autoregulation in newborn pigs:
interactions with prostaglandins. Pediatr
Res 1996; 39:487–493.
238. Van-Bel F, Roman C, Rudolph AM:
Perinatal regulation of the cerebral
circulation: role of nitric oxide and
prostaglandins. Pediatr Res 1997;
42:299–304.
239. Granstam E, Wang L, Bill A: Vascular
effects of endothelin-1 in the cat;
modification by indomethacin and L-NAME.
Acta Physiol Scand 1993; 148:165–176.
240. MacCumber MW, Jampel HD, Snyder SH:
Ocular effects of the endothelins. Abundant
peptides in the eye. Arch Ophthalmol 1991;
109:705–709.
241. Alder VAB-N, Cringle J, PO2 profiles and
oxygen consumption in cat retina with an
occluded retinal circulation. Invest
Ophthalmol Vis Sci 1990; 31:1029–1034.
242. Bardy M, Tsacopoulos M: Metabolic
changes in the retina after experimental
microembolism in the miniature pig
(author’s transl). Klin Monatsbl Augenheilkd
1978; 172:451–460.
243. Pournaras CJR, Munoz A, Abdesselem JL,
Experimental venous branch occlusion:
change in the preretinal oxygen pressure
pO2 by dexamethasone. Klin Monatsbl
Augenheilkd 1990; 196:475–480.
244. Pournaras CJT, Bovet M, Roth J: Diffusion
of O2 in the normal and the ischemic retina
of miniature pigs. Ophtalmologie 1990;
4:17–19.
245. Kohner EMD, Shakib CT, Henkind M, et al:
Experimental retinal branch vein occlusion.
Am J Ophthalmol 1970; 69:778–825.
246. Hockley DJ, Tripathi RC, Ashton N:
Experimental retinal branch vein occlusion
in rhesus monkeys. III. Histopathological
and electron microscopical studies. Br J
Ophthalmol 1979; 63:393–411.
247. Donati G, Pournaras, Pizzolato CJ, et al:
Decreased nitric oxide production accounts
for secondary arteriolar constriction after
retinal branch vein occlusion. Invest
Ophthalmol Vis Sci 1997; 38:1450–1457.
248. Tsacopoulos M: Role of metabolic factors
in the regulation of retinal blood minute
volume. Adv Ophthalmol 1979;
39:233–273.
249. Bietti G: Effects of experimentally
decreased or increased oxygen supply in
some ophthalmic diseases; practical value
for diagnosis, prognosis, and treatment.
AMA Arch Ophthalmol 1953; 49:
1674 491–513.
250. Anderson B Jr: Ocular effects of changes in
oxygen and carbon dioxide tension. Trans
Am Ophthalmol Soc 1968; 66:423–474.
251. Watkins JC, EH: Excitatory amino acid
transmitters. Annu Rev Pharmacol Toxicol
1981; 21:165–204.
252. Rothman SM: Glutamate and the patho-
physiology of hypoxic-ischemic brain
damage 1986; 19:105–111.
253. Rothman SM: Excitotoxicity and the NMDA
receptor. Trends Neurosci 1987;
10:299–302.
254. Rothman SM: Synaptic release of
excitatory amino acids neurotransmitter
mediates anoxic neuronal death.
J Neurosci 1984; 4:884–891.
255. Andine P, Ellren K et al: The excitatory
amino acid antagonist kynurenic acid
administered after hypoxic-ischemia in
neonatal rats offers neuroprotection.
Neurosci Lett 1988; 90:208–212.
256. Barbour B, Attwell D: Electrogenic uptake
of glutamate and aspartate into glial cells
isolated from the salamander (Ambystoma)
retina. J Physiol 1991; 436:169–193.
257. Brew H: Electrogenic glutamate uptake is a
major current carrier in the membrane of
axolotl retinal glial cells. Nature 1987;
327:707–709.
258. Tsacopoulos M: Metabolic coupling
between glia and neurons. J Neurosci
1996; 16:877–885.
259. Pellerin L: Glutamate uptake into astrocytes
stimulates aerobic glycolysis: a mechanism
coupling neuronal activity to glucose
utilization. Proc Natl Acad Sci USA 1994;
91:10625–10629.
260. Magistretti PJ: Astrocytes couple synaptic
activity to glucose utilization in the brain.
News Physiol Sci 1999; 14:177–182.
261. Napper GA, Kalloniatis M: Reduced
glutamate uptake by retinal glial cells under
ischemic/hypoxic conditions. Vis Neurosci
1999; 16:149–158.
262. Adachi K, Masai H, et al: Mechanism of the
pathogenesis of glutamate neurotoxicity in
retinal ischemia. Graefes Arch Clin Exp
Ophthalmol 1998; 236:766–774.
263. Kageyama T, Tamail M: Glutamate elevation
in rabbit vitreous during transient ischemia-
reperfusion. Jpn J Ophthalmol 2000;
44:110–114.
264. Iijima T, Iwao Y, Sankawa H: Differences in
glutamate release between retina and
cerebral cortex following ischemia.
Neurochem Int 2000; 36:221–224.
265. Pournaras CJ, Poitry S, Donati G: Preretinal
lactate measurements after experimental
branch retinal vein occlusion. Invest
Ophthalmol Vis Sci 2001; 42:239.
266. Morikawa E, Huang Z, Moskowitz MA:
L–arginine decreases infarct size caused by
middle cerebral arterial occlusion in SHR.
Am J Physiol 1992; 263(5 Pt
2):H1632–H1635.
267. Garthwaite J, Palmer RMJ, Moncada S:
NMDA receptor activation induces nitric
odixe synthesis from arginine in rat brain
slices. Eur J Pharmacol 1989;
172:413–416.
268. Garthwaite J: Nitric oxide and cell-cell
signaling in the nervous system 1991;
14:60–88.
269. Beckman JS, et al: Apparent hydroxyl
radical production by peroxynitrite:
implications for endothelial injury from nitric
oxide and superoxide. Proc Natl Acad Sci
USA 1990; 87:1620–1624.
270. Beckman JS: The double-edged role of
nitric oxide in brain function and
superoxide-mediated injury. J Dev Physiol
1991; 15:53–59.
271. Iadecola C, Zhang F, Xu X: Inhibition of
inducible nitric oxide synthase ameliorates
cerebral ischemic damage. Am J Physiol
1995; 268:R286–R292.
272. Zhang F, IC: Nitroprusside improves blood
flow and reduces brain damage after focal
ischemia. Neuroreport 1993; 4:559–562.
273. Carreau A, Duval D, Poignet H, et al:
Neuroprotective efficacy of N omega-nitro-
L-arginine after focal cerebral ischemia in
the mouse and inhibition of cortical nitric
oxide synthase. Eur J Pharmacol 1994;
256:241–249.
274. Cooke JP, Girerd XJ, et al: Arginine restores
cholinegic relaxation of
hypercholesterolemic rabbit thoracic aorta.
Circulation 1991; 83:1057–1062.
275. Rossitch E, Black McLP, Cooke JP: L-
arginine normalizes endothelial function in
cerebral vessels from hypecholesterolemic
rabbits. J Clin Invest 1991; 87:1295–1299.
276. Carville C, Eddahibi S, et al: Loss of
endothelium-dependent relaxation in
proximal pulmonary arteries from rats
exposed to chronic hypoxia: effects of in
vivo and in vitro supplementation with-
Arginine. J Cardiov Pharmac 1993;
22:889–896.
277. Wolzt M, Schmetter L, Ferver W, et al:
Effect of nitric oxide synthase inhibition on
renal hemodynamics in humans: reversal
by L-arginine. In: The American
Physiological Society 1997:F178–F182.
278. Grunwald JEB, Grunwald AJ, Riva SE:
Retinal hemodynamics in proliferative
diabetic retinopathy. a laser Doppler
velocimetry study. Invest Ophthalmol Vis
Sci 1993; 34:66–71.
279. Rosen DAM, Kohner J, Hamilton EM, et al:
Experimental retinal branch vein occlusion
in rhesus monkeys. II. Retinal blood flow
studies. Br J Ophthalmol 1979; 63:388–392.
280. Pournaras CJT, Strommer M, Gilodi K,
et al: Experimental retinal branch vein
occlusion in miniature pigs induces local
tissue hypoxia and vasoproliferative
microangiopathy. Ophthalmology 1990;
97:1321–1328.
281. Pournaras CJ: Retinal oxygen distribution.
Its role in the physiopathology of
vasoproliferative microangiopathies. Retina
1995; 15:332–347.
282. Pournaras CJM, Gragoudas JW, Husain
ES, et al: Systemic hyperoxia decreases
vascular endothelial growth factor gene
expression in ischemic primate retina. Arch
Ophthalmol 1997; 115:1553–1558.
283. Wallow IH, Geldner PS: Endothelial
fenestrae in proliferative diabetic
retinopathy. Invest Ophthalmol Vis Sci
1980; 19:1176–1183.
284. Hamilton CWC, Klintworth D, Machemer
GK: A transmission and scanning electron
microscopic study of surgically excised
preretinal membrane proliferations in
diabetes mellitus. Am J Ophthalmol 1982;
94:473–488.
285. Miller HM, Zonis B: Diabetic
neovascularization: permeability and
ultrastructure. Invest Ophthalmol Vis Sci
1984; 25:1338–1342.
286. Ozaki HY, Della AY, Ozaki N, et al: Hypoxia
inducible factor-1alpha is increased in
ischemic retina: temporal and spatial

correlation with VEGF expression. Invest
Ophthalmol Vis Sci 1999; 40:182–189.
287. Boulton MP, Khaliq B, Moriarty A, et al:
Modulators and milieu in preretinal
neovascularisation. Eye 1992; 6(Pt
6):560–565.
288. Bounelis PM, King W, et al: Hypoxia
stimulates platelet derived growth factor
gene expression by pulmonary artery
endothelial cells. Clin Res 1988; 36:503A.
289. Shweiki DI, Soffer A, Keshet D: Vascular
endothelial growth factor induced by
hypoxia may mediate hypoxia-initiated
angiogenesis. Nature 1992; 359:843–845.
290. Wojta JJ, Jones RL, Binder RL, Hoover BR:
Reduction in pO2 decreases the fibrinolytic
potential of cultured bovine endothelial
cells derived from pulmonary arteries and
lung microvasculature. Blood 1988;
71:1703–1706.
291. Shatos MAD, Stump JM, Thompson DC,
et al: Oxygen radicals generated during
anoxia followed by reoxygenation reduce
the synthesis of tissue-type plasminogen
activator and plasminogen activator
inhibitor-1 in human endothelial cell culture.
J Biol Chem 1990; 265:20443–20448.
292. Montesano RV, Baird JD, Guillemin A, et al:
Basic fibroblast growth factor induces
angiogenesis in vitro. Proc Natl Acad Sci
USA 1986; 83:7297–7301.
293. Shreeniwas RO, Cozzolino S, Torcia F, et al:
Macrovascular and microvascular
endothelium during long-term hypoxia:
alterations in cell growth, monolayer
permeability, and cell surface coagulant
properties. J Cell Physiol 1991; 146:8–17.
294. Plate KHB, Weich G, Risau HA: Vascular
endothelial growth factor is a potential
tumour angiogenesis factor in human
gliomas in vivo. Nature 1992; 359:845–848.
295. Miller JWA, Shima AP, D’Amore DT, et al:
Vascular endothelial growth factor/vascular
permeability factor is temporally and
spatially correlated with ocular
angiogenesis in a primate model. Am J
Pathol 1994; 145:574–584.
Retinal and Choroidal Circulations
296. Pierce EA, Avery RL, Smith LEH: Vascular
endothelial growth factor/vascular
permeability factor expression in a mouse
model of retinal neovascularisation. Proc
Natl Acad Sci 1995; 92:905–909.
297. Shima DTG, Miller A, Tolentino JW, et al:
Cloning and mRNA expression of vascular
endothelial growth factor in ischemic
retinas of Macaca fascicularis. Invest
Ophthalmol Vis Sci 1996; 37:1334–1340.
298. Adamis AP, Bernal M-T: Increased vascular
endothelial growth factor levels in the
vitreous of eyes with proliferative diabetic
retinopathy. Am J Ophthalmol 1994;
118:445–450.
299. Aiello LPA, Arrigg RL, Keyt PG, et al:
Vascular endothelial growth factor in ocular
fluid of patients with diabetic retinopathy
and other retinal disorders. N Engl J Med
1994; 331:1480–1487.
300. Malecaze FC, Simorre-Pinatel S, Mathis V,
et al: Detection of vascular endothelial
growth factor messenger RNA and vascular
endothelial growth factor-like activity in
proliferative diabetic retinopathy. Arch
Ophthalmol 1994; 112:1476–1482.
301. Pe’er j AD, Itin A, Hemo J, et al: Hypoxia-
induced expression of vascular endothelial
growth factor by retinal cells is a common
factor in neovascularizing ocular diseases.
Lab Invest 1995; 72:638–645.
302. Shima DTA, Ferrara AP, Yeo N, et al:
Hypoxic induction of endothelial cell
growth factors in retinal cells: identification
and characterization of vascular endothelial
growth factor (VEGF) as the mitogen. Mol
Med 1995; 1:182–193.
303. Bill A: Capillary permeability to and
extravascular dynamics of myoglobin,
albumin and gammaglobulin in the uvea.
Acta Physiol Scand 1968; 73:204–219.
304. Mäepa O: Pressure in the anterior ciliary
arteries, choroidal veins and
choriocapillaris. Exp Eye Res 1992;
54:731–735.
305. Klein RM, Smith SM, Myers JL, et al:
Abnormal chloroidal circulation: association
with arteriovenous fistula in the cavernous
sinus area. Arch Ophthalmol 1978;
96:1370–1373.
306. Brubaker RF, Pederson JE: Ciliochoroidal
detachment. Surv Ophthalmol 1983;
27:281–289.
307. Shimizu K: Segmental nature of the
angioarchitecture of the choroid.
Proceedings of the XXIII international
Congress in Ophthalmology. Kyoto; 1978.
308. Hayreh SS: In vivo choroidal circulation and
its watershed zones. Eye 1990; 4(Pt
2):273–289.
309. Gass JMD: Stereoscopic atlas of macular
disease. St Louis: Mosby; 1997:187–197.
310. Collier RH: Experimental embolic ischemia
of the choroid. Arch Ophthalmol 1967;
77:683–692.
311. Buettner HM, Charles R, Anderson S:
Experimental deprivation of choroidal blood
CHAPTER 126
flow. Retinal morphology, early receptor
potential, and electroretinography. Am J
Ophthalmol 1973; 75:943–952.
312. Almaric P: Circulation choroidienne. In:
Compte rendu du symposium international
d’angiographie fluorescéinique, Albi 1969.
Karger: Basel; 1971:193–203.
313. Bischoff PM, Flower RW: High blood
pressure in choroidal arteries as a possible
pathogenetic mechanism in senile macular
degeneration. Am J Ophthalmol 1983;
96:398–399.
314. Condon PI, Serjeant GR, Ikeda H: Unusual
chorioretinal degeneration in sickle cell
disease. Possible sequelae of posterior
ciliary vessel occlusion. Br J Ophthalmol
1973; 57:81–88.
315. Jampol LML, Albert M, Craft DM: Ocular
clinical findings and basement membrane
changes in Goodpasture’s syndrome. Am J
Ophthalmol 1975; 79:452–463.
316. Spolaore RG, Coscas A, de Margerie G:
Acute sectorial choroidal ischemia. Am J
Ophthalmol 1984; 98:707–716.
317. Gaudric A, Coscas G, Bird AC: Choroidal
ischemia. Am J Ophthalmol 1982;
94:489–498.
1675
 CHAPTER
Examination of the Retina: Ophthalmoscopy and
127 Fundus Biomicroscopy
Thomas R. Friberg
INTRODUCTION
The essentials of the clinical examination techniques used to
evaluate the ocular fundus have changed little over the past
decade. While additional ancillary testing and methods have been
developed, a thorough funduscopic examination remains a main-
stay of clinical practice. Excellent and efficient retinal examin-
ation skills are critical to virtually all ophthalmologists, and this
chapter explains the principles of this evaluation.
A thorough examination of the ocular fundus requires excel-
lent powers of observation and clinical experience with ophthal-
moscopy and biomicroscopy. Some individuals have almost a
natural ability to use these specialized instruments to discover
and document subtle retinal abnormalities. Most have consid-
erably more difficulty, however. For instance, a novice might
struggle and then finally see scattered retinal hemorrhages in the
fundus of a patient’s eye but then fail to note the location of the
hemorrhages with respect to retinal landmarks. With practice, pro-
per use of the instrumentation can be learned by almost anyone.
Unfortunately, some clinicians never become good observers and
remain unaware of the important distinction between seeing an
abnormality and observing it.1 Observation is a high-level activity,
requiring mental processing and categorization of what is seen.
One method of improving observational skills is to use an
examination routine whereby different regions of the fundus are
evaluated in a specific sequence. For instance, an ophthalmo-
logist might begin by examining the optic nerve; move on to the
temporal vascular arcades, macula, and nasal retina; and finish
by evaluating the equatorial and peripheral retina. By using an
organized system of fundus evaluation, diagnostic oversights
will be minimized.
PUPILLARY DILATATION
Examination of the fundus and especially the retinal periphery
is greatly facilitated by a well-dilated pupil. Suggested mydriatic
agents include 1% tropicamide (Mydriacyl) and 2.5% phenyl-
ephrine hydrochloride drops (Mydfrin), one drop of each in both
eyes. Instillation of a topical anesthetic, such as 0.5% proparacaine
hydrochloride, before instilling the dilating drops promotes
more rapid mydriasis, as the anesthetic prevents reflex tearing
and subsequent dilution of the mydriatic agent. Most patients’
pupils dilate adequately after 20–30 min using this regimen.
However, darkly pigmented irises dilate more slowly and remain
dilated longer than do lightly colored irises, probably because
the mydriatic agents are bound to the iris melanin and are
released gradually.2 After the examination, mydriasis can be
reversed more quickly by medications designed for this purpose
such as 0.5% dapiprazole hydrochloride (Rev-Eyes, Storz
Ophthalmics).
DIRECT OPHTHALMOSCOPE
To examine the ocular fundus, specialized instruments are neces-
sary. The simplest is the direct ophthalmoscope, which is in
essence a miniature flashlight held very close to the patient’s eye
and shined through the pupil (Fig. 127.1). The fundus is viewed
monocularly through a small peephole located just above the
illumination source of the instrument, producing an upright
virtual image that magnifies the area of interest ~15 times.3
This ophthalmoscope also has a dial containing neutralizing
lenses, which is rotated to achieve the clearest retinal image.
Although magnification and resolution are quite good with the
direct ophthalmoscope, difficulties inherent with its use include
lack of stereopsis, inadequate illumination in the presence of
media opacities, the necessity of placing the examiner’s face in
close proximity to the patient’s face, a retinal image covering only
~8° of the fundus,3 and severe degradation of the image when
significant lens opacities are present.4,5 It may be impossible to
adequately examine eyes with a high degree of astigmatism or
spherical ametropia using this instrument. Furthermore, the direct
ophthalmoscope does not allow an undistorted view of the periph-
eral retina, limiting its use to visualizing the posterior retina only.
Largely because of its portability and simplicity, the direct
ophthalmoscope is a useful screening device for the general
practitioner who may wish to rule out papilledema, macular
degeneration, or hypertensive or diabetic retinopathy. Many
ophthalmologists have become facile with binocular slit-lamp
biomicroscopes and specialized contact and noncontact fundus
examination lenses, however, and observation of the ocular
fundus with the direct ophthalmoscope is often redundant and
unnecessary in the office setting.
BINOCULAR INDIRECT OPHTHALMOSCOPE
The binocular indirect ophthalmoscope, in conjunction with a
high-quality aspherical hand-held lens, has become the indis-
pensable standard for the proper examination of the fundus,
especially when evaluating areas located outside the posterior
pole (Fig. 127.2). Introduced by Schepens,6 binocular indirect
ophthalmoscopy offers a typical field of view of 25º or more and
excellent resolution of fundus details.5 Stereopsis is enhanced,
allowing the examiner to detect nuances of elevation and exca-
vation of the retinal contour. The device is portable, permits
evaluation of the retina with the patient in either the sitting or
the supine position, and quickly gives a view of relatively large
retinal areas. Furthermore, binocular indirect ophthalmoscopy
has been incorporated into laser delivery systems, providing an
important alternative to slit-lamp photocoagulation systems.7
Although an examination of the posterior fundus using the
direct ophthalmoscope can be performed after a minimum of 1677
 SECTION 10 RETINA AND VITREOUS

FIGURE 127.1. The direct ophthalmoscope is used like a flashlight to

illuminate the patient’s eye while the examiner looks through a small a
peephole. The left eye of the examiner is used to study the fundus of
the patient’s left eye. Conversely, the right eye is used to examine the
patient’s right eye.

instruction, effective use of the indirect ophthalmoscope requires

several hours of practice. The image formed by the indirect
ophthalmoscope is physically located above the plane of the
lens and, as with all real images, is inverted (Fig. 127.3). This
inversion creates considerable problems for the novice, especially
when he or she tries to draw the observed abnormalities. In
addition, the alignment of the indirect ophthalmoscope’s illu-
mination beam, the hand-held lens, the patient’s pupil, and the
ophthalmoscope oculars is crucial to obtaining a sharp image.
Hence, before examining patients, it is beneficial to examine a
model eye (Mira, Waltham, MA) manufactured for the purpose
of practicing indirect ophthalmoscopy (Fig. 127.4). Another aid
to learning this important skill is a specially designed interac-
tive computer program contained on a compact disk (CD-ROM)
(‘Indirect Ophthalmoscopy and Fundus Drawing’, © 1996 by
The New York Eye and Ear Infirmary).

EXAMINATION TECHNIQUE WITH THE

INDIRECT OPHTHALMOSCOPE
To use the indirect ophthalmoscope, the examiner first adjusts
the headbands so that the scope fits comfortably. A lightweight
instrument is preferred. The illumination beam is turned on, and
the interpupillary distance of the eyepieces is adjusted so that
both eyes can see the examiner’s outstretched hand simulta-
neously. Next, the knob on the headset that controls the location
of the illumination beam is rotated until the ‘footprint’ of the b
light illuminates the superior portion of the outstretched hand.
The head and body of the examiner should be positioned so that FIGURE 127.2. (a) An example of a binocular indirect
her or his viewing axis is in a line with the center of the patient’s ophthalmoscope. The coronal and sagittal headbands and the
dilated pupil. When this is done, a bright red reflex should appear interpupillary distance are adjustable. A transformer provides power
through the oculars of the indirect ophthalmoscope. for illumination. (b) With the indirect ophthalmoscope adjusted and in
Once a red reflex is visualized, the indirect hand-held lens is place on the head, the examiner holds a lens over the patient’s eye to
interposed along the imaginary line drawn between the examiner’s form a retinal image.
pupil and the patient’s pupil. The indirect lens should be held
between the thumb and the forefinger of either hand and
1678
 Examination of the Retina: Ophthalmoscopy and Fundus Biomicroscopy
FIGURE 127.3. With indirect ophthalmoscopy, a real, inverted image
of the patient’s fundus is formed in a plane located just above the
hand-held lens.
positioned a few centimeters from the patient’s eye. The lens sur-
face is oriented almost perpendicular to the illumination beam.
To minimize problems with light reflections, the lens should be
tilted very slightly, with the most convex side of the indirect
lens facing the examiner (Fig. 127.5).
To steady the lens, the fourth and fifth digits of the hand hold-
ing the lens should rest on the patient’s face during the exam-
ination. The distance between the patient’s eye and the lens
should otherwise be as great as possible. To optimize the view,
the lens is slowly moved toward or away from the patient’s eye.
When the lens is properly positioned, the image of the patient’s
fundus fills the lens and is in sharp focus. To examine different
areas of the fundus, the viewing axis of the indirect ophthalmo-
scope, the center of the hand-held lens, and the patient’s pupil
CHAPTER 127
FIGURE 127.4. Pliable model eyes with realistic fundus details are
valuable when learning binocular indirect ophthalmoscopy. They can
also be indented to simulate scleral depression.
FIGURE 127.5. The most convex side of the hand-held lens is placed
so that it faces the examiner. By tilting the lens very slightly, the bright
light reflexes produced by the lens surfaces (left) do not enter the
examiner’s eye.
must remain in alignment. A useful aid is to envision a solid
rod representing the viewing axis of the indirect scope to which
the center of the hand-held lens is fixed. This imaginary rod
pivots at the center of the patient’s pupil when the entire extent
of the retina is examined (Fig. 127.6). Indirect ophthalmoscopy
is facilitated by having the patient in the supine position with
the examiner standing, as this allows easy access to all retinal
regions.
Key Feature
• Proper alignment of the ophthalmoscope and the hand-held
lens facilitates the examination. When the fundus image is
difficult to visualize, the novice should check this alignment as
an initial step.
1679
 SECTION 10 RETINA AND VITREOUS
FIGURE 127.6. To view different regions of the fundus, the examiner
moves his or her head and the hand-held lens as if there were an
imaginary rod connecting the center of the patient’s pupil, the center
of the lens, and a point midway between the eyepieces of the indirect
ophthalmoscope. The examiner then pivots around the central pupil to
view the complete fundus.
Many patients, especially those with light complexions, are
photophobic when examined with bright light. Hence, the
illumination level of the ophthalmoscope must be low enough
to allow examination of the fundus without causing patient dis-
comfort and resultant squeezing of the eyelids. Conversely, the
light must be sufficiently bright to allow observation of retinal
details. For patient comfort, it is best to start with a dimmer
light and increase its intensity as necessary.
The patient’s eyelids should be held open with the examiner’s
fingers or a lid speculum during indirect ophthalmoscopy. Either
the hand holding the lens or the free hand can be used for this
purpose, depending on whether scleral depression is being per-
formed. Although use of a lid speculum potentially frees up one
of the examiner’s hands, an irrigating balanced salt solution
(BSS) must be periodically instilled to prevent corneal drying
when a speculum is used.
CHOICE OF HAND-HELD LENS
Numerous lenses are available for binocular indirect ophthal-
moscopy. When selecting a lens, recall that angular magnifica-
tion of fundus details is inversely proportional to the power of
the hand-held lens. For example, a 20-D lens will magnify the
fundus details of an emmetropic eye ~2.3 times, whereas a 30-D
lens magnifies it ~1.5 times.8 A high-quality 20-D aspherical
lens is widely used because it offers a good compromise between
field of view and magnification. However, when viewing eyes
with small pupils or eyes with hazy media, a 30- or 28-D lens
is often a better choice for the beginner. The field of view of the
lens is generally directly proportional to the lens power, with a
20-D aspherical lens providing about a 35º field.3 Field of view
is also a function of the diameter of the lens, with a larger field
offered by a larger diameter lens. A comparison of field of view
obtained when using a direct ophthalmoscope versus an indirect
1680 ophthalmoscope is shown in Figure 127.7.
FIGURE 127.7. The field of view of the indirect ophthalmoscope
using a 20-D lens (outer circle) is much larger than that provided by
the direct ophthalmoscope (inner circle). However, the size of a given
retinal lesion obtained using the direct ophthalmoscope appears
commensurately bigger.
SMALL-PUPIL INDIRECT
OPHTHALMOSCOPES
Many indirect ophthalmoscopes incorporate a small pupil feature
which facilitates the examination of eyes when the pupils dilate
poorly or eyes that harbor focal media opacities. Typically, a
small lever located under the eye pieces is moved in position to
engage this feature. The lever physically places the illumination
and visualization pathways closer together by moving a
triangular prism. Such a feature is extremely useful and makes
the instrument more versatile.
SCLERAL DEPRESSION
To view the total extent of the peripheral fundus of the emmet-
ropic eye, the wall of the eye must be depressed inward toward
the visual axis. This examination technique, called scleral
depression, should not be attempted until one is first accom-
plished at obtaining a sharp image of the posterior pole. If one
cannot reliably image the posterior segment, attempting to view
the retinal periphery with scleral depression is usually futile as
well as uncomfortable for the patient.
Several types of scleral depressors have been designed, and
each has its advocates. The working end of most depressors con-
sists of a metal shaft with an enlargement or crosspiece at the
tip. Some depressors have a more elaborate construction with
moving parts. Alternatively, one can simply use a cotton-tipped
applicator pressed against the lids to accomplish the same goal,
although the tip is too bulky for many patients.
Pressure is exerted on the globe by pressing gently on the
patient’s partially opened eyelid until the peripheral retina is
brought into view (Fig. 127.8). If excessive pressure is used, the
patient will become uncomfortable, squeeze the eyelids shut,
and prevent the examination from proceeding. With practice,
patient discomfort should be minimal. Typically, scleral depres-
sion of the entire 360º of the retinal periphery is easier to
 Examination of the Retina: Ophthalmoscopy and Fundus Biomicroscopy
accomplish if the patient is in the supine position. The shaft of
the depressor, the area of interest in the retinal periphery, and
the central cornea should all be kept in the same plane during
scleral depression.9
Scleral depression is not a static process whereby the peri-
pheral retina is merely brought into view and observed. Gentle
FIGURE 127.8. To perform scleral depression, light pressure is
exerted on the globe through the patient’s eyelids with the tip of the
scleral depressor. The shaft of the depressor, the area of interest in
the fundus, and the central cornea should all be in the same plane.
FIGURE 127.9. The scleral depressor is carefully repositioned along
the upper and lower eyelids to completely examine all 360º of the
retinal periphery.
movement of the depressor in the vicinity of a suspicious area
during observation may open up a previously unseen tear or
demonstrate areas of vitreoretinal traction. Hence, to detect and
diagnose subtle retinal abnormalities, dynamic scleral depression
is required.
Topical anesthesia, such as a drop of 0.5% proparacaine hydro-
chloride, may facilitate the examination with scleral depression.
To limit patient discomfort, the complete examination should
be performed without placing the depressor directly onto the
conjunctival surface (Fig. 127.9). Occasionally, evaluation of
some peripheral areas, particularly those at the 3 and 9 o’clock
meridians, necessitates placement of the depressor directly on
the globe.
DOCUMENTING THE RETINAL FINDINGS
Detailed sketches of the fundus are made on durable drawing
paper to document the retinal pathologic condition (Fig. 127.10).
CHAPTER 127
The location of a given lesion is drawn in reference to the major
retinal veins, the meridional location of the lesion within the
eye, and its relative peripheral location. The arteries are not
typically drawn. By convention, the 12 o’clock meridian is placed
at the top of the retinal drawing because it represents the upper-
most part of the clock face. Keep in mind that mapping the
retinal surface, which is spherical, on a flat piece of paper neces-
sarily produces inaccuracies of scale in the finished drawing. For
instance, the peripheral retina is disproportionately represented,
just as the size of equatorial regions of the world is exaggerated
in flat, polar maps generated by gnomonic projection.10 Hence,
a lesion of a given area will appear larger on the retinal drawing
FIGURE 127.10. Drawing of a retinal detachment on conventional
retinal drawing paper. The center of the paper represents the fovea,
the inner circle (E) represents the equator, and the outer circle (O)
represents the ora serrata. The region defined by the two outermost
circles represents the pars plana. On this paper, labeled O.S. for the
left eye, the optic nerve is predrawn and located to the left of the
fovea. Drawing paper labeled O.D. has the optic nerve drawn to the
right of the fovea. Findings located on the drawing correspond to their
clock-hour location within the patient’s eye, with 12 o’clock
representing the superiormost portion of the globe. In this figure, a
retinal detachment has been drawn extending from the 9:30 to the
12:30 positions. The retinal tear is drawn at the 11:45 position. 1681
 RETINA AND VITREOUS

FIGURE 127.11. (Left) Some fundus details located along the meridian at the 1:30 position on the clock are outlined by three circular areas,
representing three areas to be viewed by indirect ophthalmoscopy. (Center) The individual image fields of the fundus, as seen through the
examiner’s lens. Each field has been inverted by the optical system. (Right) The salient details of each image field are drawn onto the fundus
drawing paper. The paper is oriented with the 12 o’clock meridian directed toward the patient’s feet. This allows the examiner to draw what she
or he sees within each field as if it were being ‘pasted’ directly onto the drawing paper. If the drawing paper were not inverted, the examiner
would have to mentally invert the images before drawing them.
SECTION 10

paper if it is located in the peripheral fundus than it would if it

were located in the macula.
Because the retinal image is inverted during indirect ophthal-
moscopy, beginners often make the mistake of assuming that
the pathologic condition seen at the 6 o’clock position in the
hand-held lens must be located at the 12 o’clock position in the
eye. In fact, since only part of the fundus is imaged at a time,
only the small fundus region that is being viewed is inverted
(Fig. 127.11).5 To avoid confusion, one can move the hand-held
lens out of the way occasionally to observe which quadrant of
the patient’s eye the indirect ophthalmoscope is being directed
toward.

Key Feature
• The retinal image is inverted using the indirect
ophthalmoscope examination technique. When learning
ophthalmoscopy, it is often helpful to look at the eye without
the lens in position to confirm what region of the fundus is
being viewed.

When drawing the fundus, it is helpful to place the drawing

paper on a clipboard and have the patient hold or support the
clipboard on his or her chest. By orienting the paper so that its
12 o’clock meridian is directed inferiorly toward the patient’s
feet, the image fields can be visually translated directly onto the
paper without having to mentally invert them. Holding a pencil
in one hand while holding the lens and the patient’s eyelids
open with the other hand greatly speeds up the process of
generating an accurate retinal drawing (Fig. 127.12). FIGURE 127.12. The patient’s fundus findings can be documented
As retinal features are color-coded by convention (Table 127.1), rapidly if the examiner holds the lens in one hand while drawing on
color pencils are characteristically used for the retinal drawing. the paper with a pencil held in the other hand. Again, the paper is
purposely inverted.

LIMITATIONS OF THE INDIRECT

OPHTHALMOSCOPE
TABLE 127.1 Color Coding for Retinal Drawing
Although the indirect ophthalmoscope is an invaluable instru-
ment, it has limitations. A major drawback is that its magnifi- Color Anatomic Feature
cation is insufficient to allow detection of very small retinal
Red Retinal arteries, retinal hemorrhage,
abnormalities, particularly subtle macular lesions. For example, attached retina, retinal neovascularization
retinal microaneurysms, tiny areas of subretinal neovasculari-
zation, foveal cysts, and small round retinal breaks may be Blue Retinal veins, detached retina, retinal
edema
difficult to resolve with this instrument. For this reason, other
ancillary devices are necessary to thoroughly evaluate the fundus. Green Media opacities, vitreous hemorrhage
Yellow Retinal and choroidal exudates
BIOMICROSCOPY OF THE RETINA Brown Pigmented lesions, choroidal detachments
The slit lamp is an essential instrument for fundus examination, Red lined with blue Retinal breaks
1682 particularly when a high degree of magnification is desired. It
 Examination of the Retina: Ophthalmoscopy and Fundus Biomicroscopy
consists of a movable binocular biomicroscope mounted on a
table and an intense illumination beam or slit beam of adjustable
width that can be rotated 360º in the vertical plane. Focusing is
accomplished by moving a joystick located on the microscope
platform. The slit lamp is used in conjunction with a diagnostic
contact lens or hand-held lens to provide a high-quality magni-
fied stereoscopic image of the fundus. Slit-lamp biomicroscopy
of the fundus is particularly useful in determining whether the
location of a hemorrhage is preretinal, intraretinal, or sub-
retinal; in detecting cystoid macular edema; and in diagnosing
clinically significant macular thickening.
The slit lamp also provides optical sections of the vitreous body
to allow detection of posterior vitreous detachments, abnormal
vitreous surfaces, and vitreous floaters. Furthermore, the surface
contours of a chorioretinal lesion are more apparent if a narrow
beam of light is projected onto the lesion’s surface. If an
elevation or depression of a chorioretinal lesion is present, the
slit beam on the retina will appear curved rather than straight
(Fig. 127.13a). In some cases, when there is very little
subretinal fluid, illumination of the retinal vessels with the slit
beam produces shadows of the vessels at the level of the retinal
pigment epithelium (Fig. 127.13b). Such shadows are further
proof of retinal elevation.
FIGURE 127.13. (a) A slit beam has been directed over a
questionably elevated choroidal lesion. Bending of the beam is
observed, indicating that the lesion is indeed elevated. (b) To detect a
subtle elevation of the sensory retina, the area of suspicion is
illuminated by the slit beam. Shadows of the retinal vessels are seen
at the pigment epithelial level, indicating the presence of subretinal
fluid and a shallow serous detachment of the sensory retina.
If the slit beam of the biomicroscope is placed across an ele-
vated retinal lesion, the behavior of the scattered light also pro-
vides important diagnostic clues. Often the borders of a small
serous retinal or pigment epithelial detachment can be made to
glow by positioning the slit beam across the elevation, making
the lesion easier to demarcate. This technique is very useful in
evaluating the posterior pole for the presence of a macular hole
or for detecting cystic spaces within the fovea.
Slit-lamp examination methods can be separated into two
major categories: (1) contact methods requiring the placement of
a specialized contact lens onto the corneal surface to neutralize
its power and (2) noncontact methods, which use the refractive
power of the cornea and a special lens to form a fundus image.
Noncontact fundus examinations are generally performed more
rapidly, particularly if only the posterior pole requires evaluation.
However, the patient may squeeze the eyelids shut during non-
contact fundus evaluations. With diagnostic contact lenses, the
eyelids cannot be closed, but corneal irritation may result if the
CHAPTER 127
examination is not performed gently. Furthermore, excessive
pressure exerted on the eye during a contact lens evaluation may
induce vasovagal reactions such as fainting and nausea. These
side effects rarely occur if the examiner is experienced.
NONCONTACT METHODS OF
BIOMICROSCOPIC RETINAL EXAMINATION
PLANOCONCAVE LENSES
A planoconcave lens of high negative optical power, such as a
Hruby lens, is incorporated into some slit-lamp biomicroscopes.
To use this lens, a broad vertical slit beam is first rotated to
illuminate the fundus from virtually a straight-on direction until
the red reflex is clearly seen through the oculars. The lens is
centered over the patient’s cornea, positioned a few centimeters
from the patient’s eye, and focused via a lever until the fundus
comes into view (Fig. 127.14). Some systems focus the lens
more or less automatically. The image formed is upright and
vertical, but the image quality is not uniformly good, especially
near the edges of the field of view. This lens is used almost
exclusively to view the posterior pole, as distortion seriously
degrades the image if the fundus is viewed along any axis other
than the approximate optical axis of the patient’s eye.11
ASPHERICAL LENSES (60 D, 78 D, 90 D) AND
SLIT-LAMP INDIRECT OPHTHALMOSCOPY
A real image of the fundus is formed at the slit lamp several
centimeters in front of the patient’s eye when a high-powered
plus lens is positioned in front of the cornea. This aerial image
of the fundus is magnified by the slit-lamp optics. The resultant
image is real, inverted, and of high quality if a superior high-
power aspherical lens made for this purpose is used. Typically,
indirect biomicroscopic lenses are positioned farther from the
patient’s eye than is the Hruby-type lens. With a lens of lower
power or longer focal length, the image is produced at a location
farther in front of the patient’s eye than with a higher-power
lens. Because some slit-lamp focusing tracks are limited in
travel away from the patient, it may be impossible to obtain a
clear fundus image with certain low-power indirect lenses.
Indirect ophthalmoscopy at the slit lamp is performed by
placing the lens between the thumb and the forefinger, with the
elbow supported by the slit-lamp table (Fig. 127.15). Because
these lenses are of relatively high power, any movement of the
examiner’s hand induces sizable prism shift movements of the
image. Some examiners prefer, therefore, to have the lens
mounted on a small jointed holder affixed to the slit lamp
(Volk Optical, Mentor, OH). As with indirect ophthalmoscopy, 1683
 RETINA AND VITREOUS
SECTION 10
FIGURE 127.14. A high-power minus lens placed in front of the
cornea forms a virtual image of the fundus. Moving a lever on the lens
holder focuses the image, which is observed through the slit-lamp
binoculars.
higher-power lenses provide wider fields of view at the expense
of magnification.
Although noncontact lenses are suitable for viewing the
posterior pole, they do not by themselves provide an adequate view
of the retinal periphery. Scleral depression can be attempted
while viewing the fundus through these lenses, but this tech-
nique requires considerable practice and is technically difficult.
CONTACT LENS METHODS OF
BIOMICROSCOPIC RETINAL EXAMINATION
Before placing the diagnostic contact lens on the patient’s cornea,
a drop of a mild anesthetic agent such as 0.5% proparacaine
hydrochloride is instilled. A viscous, clear liquid such as methyl-
cellulose or hydroxypropyl methylcellulose (Goniosol) is placed in
the concave portion of the lens to optically couple the lens to the
cornea. With the patient looking up, the lids are held open and
the lens is placed gently on the patient’s cornea (Fig. 127.16).
Small air bubbles are eliminated by exerting gentle pressure on
the lens. When fundus photography is scheduled directly after
removal of the diagnostic contact lens, any residual interface solu-
tions remaining on the cornea can degrade the retinal image.
Hence, many examiners prefer to use low-viscosity BSSs rather
than thicker, more tenacious interface liquids. Unfortunately,
BSSs are of such low viscosity that they spill out of the fundus
contact lens unless the lens is placed on the cornea in a smooth,
rapid motion while the patient gazes ahead.
GOLDMANN THREE-MIRROR LENS
The three-mirror lens has a clear central portion for viewing the
posterior pole, surrounded by three radially arranged mirrors
1684 (Fig. 127.17, left). Each mirror has a different inclination between
a
b
FIGURE 127.15. (a) Binocular indirect ophthalmoscopy at the slit
lamp is accomplished by holding a high-power plus lens in front of the
cornea and focusing the slit lamp on the aerial image that forms
anterior to the lens. (b) Lenses of various powers provide the
examiner with an array of magnification and field of view options.
its surface and the axis of the lens. Through the central posterior
pole portion, the field of view is ~30º for an emmetropic eye.
The smallest mirror is used to view the anterior chamber angle
and occasionally the far periphery of the fundus. The middle-sized
mirror is configured to allow viewing of the retinal periphery
anterior to the equator, and the largest mirror is chosen when
the area of interest is within the equatorial and posterior
equatorial regions of the fundus (Fig. 127.18).12
The beam of the slit lamp should be projected along the radial
axis of the mirror being used. This is achieved by rotating a
collar or knob on the slit lamp, which, in turn, rotates the slit
beam. With the patient gazing straight ahead, the best image is
obtained when the front surface of the lens is kept perpendicular
to the viewing axis of the slit lamp. By rotating the examination
mirror and readjusting the slit beam, all meridians of the retina
can be evaluated.
Redirection of the patient’s gaze facilitates viewing of more
anteriorly or posteriorly located retinal regions positioned
within a given mirror. If the patient moves her or his eye toward
the mirror, a more posteriorly located portion of the fundus
comes into view. If the eye is moved away from the mirror, more
peripheral areas of the fundus are seen (Fig. 127.19). This change
in image field with a change in the patient’s gaze is especially
 Examination of the Retina: Ophthalmoscopy and Fundus Biomicroscopy
a
b
FIGURE 127.16. (a) A diagnostic fundus contact lens containing an
optical coupling fluid is placed on the anesthetized cornea by holding
the lids open while the patient looks up. (b) The patient then gazes
straight ahead to center the lens, which is held in place with very light
pressure.
FIGURE 127.17. Specialized fundus contact examination lenses.
(Left) Goldmann three-mirror contact lens. (Center) Mainster
biomicroscopic lens. (Right) Rodenstock panfunduscopic lens. Each
lens has specific attributes and shortcomings.
FIGURE 127.18. (Left) The Goldmann three-mirror lens has a clear
central zone (D) for examination of the posterior pole. The adjacent
mirrors (A, B, C) are each inclined at different angles to the optical
axis of the lens, providing visual access to different regions of the
fundus, as depicted at right.
CHAPTER 127
FIGURE 127.19. The patient’s direction of gaze will influence the field
being observed through each mirror of the Goldmann lens. If the
patient looks toward the particular mirror being used for viewing, a
more posterior region of the fundus will be seen.
important to note when photocoagulating a patient’s eye
through a mirror. The fovea may inadvertently appear within the
treatment mirror of the lens on extreme gaze. Failure to recog-
nize the fovea in this situation can lead to its destruction by
photocoagulation.
THREE-MIRROR LENS EXAMINATION
COUPLED WITH SCLERAL DEPRESSION
A highly magnified view of the ora serrata and the most peri-
pheral retina can be achieved by performing scleral depression
during the three-mirror lens examination. This magnified exam-
ination of the retinal periphery is often easier to accomplish if
the Goldmann lens is placed in a specialized conical holder, which,
in turn, has a small depressor located along its circumference
(Fig. 127.20). The middle-sized or smallest mirror should be
inserted into the position opposite the depressor location. The
lens holder is then held gently but firmly against the patient’s
eye, producing the desired scleral indentation. One type of lens
holder incorporates an adjustable depressor that can be moved
more posteriorly along the sclera in any meridian.13 Unfortu-
nately, many patients find these scleral depression devices very
uncomfortable, especially in inexperienced hands. 1685
 RETINA AND VITREOUS

purposes. The image plane is located quite anterior to the lens

surface, however, making it difficult to view the fundi of patients
with hyperopia or exophthalmos when using slit lamps with
limited forward travel.

SPECIALIZED RETINAL EXAMINATION

FIGURE 127.20. Placement of the Goldmann lens into a conical
holder containing a scleral depressor at its periphery allows the
examiner to perform scleral depression while using the slit-lamp
biomicroscope. Two of these devices are illustrated.
SECTION 10
TECHNIQUES
If a fiber optic probe or other suitable light source is placed against
the sclera in a darkened room, the retina can be visualized using
indirect ophthalmoscopy with the illuminating scope light
turned off. This examination technique (transillumination
ophthalmoscopy) requires that light be transmitted through the
sclera and choroid. If an eye contains a solid pigmented mass,
transillumination is useful in that the tumor will appear dark,
whereas other choroidal lesions, such as a choroidal detachment,
will be much more brightly illuminated.
Alternately, a transillumination light can be placed on the

cornea so that it shines through the pupil. The examiner then

GOLDMANN POSTERIOR FUNDUS CONTACT
LENS
If the examiner is primarily interested in studying the posterior
retina, a small lightweight lens incorporating a peripheral flange
at the point at which it touches the eyelids is often preferred over
a larger, bulkier lens. The flange and smaller contact diameter
make this lens more difficult to dislodge if the patient squeezes
the eyelids.
observes the surface of the sclera, which should glow a uni-
formly orange color. A pigmented tumor or foreign body within
the choroid will prevent the transillumination light from illumi-
nating the sclera beneath it, and a dark shadow will be present
within the affected scleral quadrant. In eyes that are lightly
pigmented, a bright transilluminator may be applied directly to
the sclera to achieve a similar effect (Fig. 127.21).

PANFUNDUSCOPIC LENS
The panfunduscopic lens (Rodenstock, Munich, Germany) (see
Fig. 127.17, right) consists of a meniscus lens coupled with a
spherical lens located within the same lens holder housing.
When the meniscus lens is placed on the cornea, the resultant
image of the fundus is inverted, real, minified, and located well
forward of the anterior lens surface. Magnification provided by
the slit lamp counteracts the minification produced by the lens
configuration. A wide-angle view of the fundus in an emmetropic
eye, extending from the fovea to the equatorial region, is produced
by such a panfunduscopic lens.14 This device also facilitates the
examination of the fundus through a poorly dilated pupil. How-
ever, panfunduscopic lenses are used more often during laser
photocoagulation than for diagnostic purposes, primarily
because the image of the retina is small and the view through
the peripheral portions of this lens is not excellent.

MAINSTER LENS
The Mainster lens (Ocular Instruments, Bellevue, WA) (see
Fig. 127.17, center) provides a somewhat reduced field of view
(45º) compared with the panfunduscopic lens but also produces
less minification.15 Resolution with this lens is sufficient to detect
retinal thickening from macular edema. The image size is com-
parable with that provided by the Goldmann lens, making the
Mainster lens versatile for diagnostic as well as therapeutic
FIGURE 127.21. Transillumination. The globe is illuminated, through
the sclera in this illustration, via a fiberoptic light source placed on the
globe externally or on the cornea. In a darkened room, the sclera is
observed, glowing yellow-orange. A dark choroidal lesion will block
the transmission of light through the eye wall and will appear as a
dark shadow surrounded by the red glow of the remainder of the
sclera.

REFERENCES
1. Doyle AC: A scandal in Bohemia. In: The
complete works of sherlock holmes. Garden
City, NY: Doubleday; 1892–1927:162.
2. Thompson HS: The pupil. In: Moses RA,
Hart WM, eds. Adler’s physiology of the
eye, clinical application. St. Louis: CV
Mosby; 1987:321.
3. Rubin ML: Magnification; practical
instruments: the indirect ophthalmoscope.
In: Optics for clinicians. 2nd edn.
Gainesville, FL: Triad; 1974:235, 298.
4. Schepens CL: Methods of examination.
In: Retinal detachment and allied diseases.
Philadelphia: WB Saunders; 1983:99–133.
5. Rosenthal ML, Fradin S: The technique
of binocular indirect ophthalmoscopy.
Highlights Ophthalmol 1966;
9:179–257.
6. Schepens CL: Progress in detachment
surgery. Trans Am Acad Ophthalmol
Otolaryngol 1951; 55:607–615.

1686
 Examination of the Retina: Ophthalmoscopy and Fundus Biomicroscopy
7. Friberg TR: Clinical experience with a
binocular indirect ophthalmoscope laser
delivery system. Retina 1987; 7:28–31.
8. Rubin ML: The optics of indirect
ophthalmoscopy. Surv Ophthalmol 1964;
9:449–464.
9. Chignell AH: Techniques of examination.
In: Retinal detachment surgery. 2nd edn.
Berlin: Springer-Verlag; 1988:14–25.
10. Kemp P, ed: The oxford companion to
ships and the sea. London: Oxford
University Press; 1976:346.
11. Tolentino FI, Schepens CL, Freeman HM:
Instrumentation. In: Vitreoretinal
disorders. Diagnosis and management.
Philadelphia: WB Saunders;
1976:45–70.
12. Benson WE: Fundus examination and
pre-operative management. In: Retinal
detachment: diagnosis and management.
2nd edn. Philadelphia: JB Lippincott;
1988:85–111.
13. Eisner G: Attachment for Goldmann three-
mirror contact glass. For examination of the
ora serrata and pars plana. Am J
Ophthalmol 1967; 64:467–468.
14. Michels RG, Wilkinson CP, Rice TA: Pre-
operative evaluation. In: Michels RG, ed.
Retinal detachment. St. Louis: CV Mosby;
1990:325–378.
15. Mainster MA, Crossman JL, Erickson PJ,
Heacock GL: Retinal laser lenses:
magnification, spot size, and field of view.
Br J Ophthalmol 1990; 74:177–179.
CHAPTER 127
1687
 CHAPTER

128 Principles of Fluorescein Angiography

Timothy J. Bennett, David A. Quillen, and James D. Strong

Since its introduction in the early 1960s, fluorescein angiography
has become an essential tool in the understanding, diagnosis,
and treatment of retinal disorders. While direct examination of
the fundus with slit-lamp biomicroscopy and indirect ophthal-
moscopy is indispensable in the diagnosis of retinal disease,
fluorescein angiography provides additional information
concerning the anatomy, physiology, and pathology of the retina
and choroid. This diagnostic procedure utilizes a specialized
fundus camera or scanning laser ophthalmoscope (SLO) to
capture rapid-sequence photographs of the retina following an
intravenous injection of fluorescein sodium. Photographic or
video images taken as the dye courses through the eye can demon-
strate abnormalities within the neurosensory retina, pigment
epithelium, sclera, choroid, and optic nerve, providing clinically
useful information for nearly the entire spectrum of posterior
segment disorders.
CHARACTERISTICS OF FLUORESCEIN
Fluorescein sodium absorbs blue light, with peak excitation
occurring at wavelengths between 465 and 490 nm. The
resulting fluorescence occurs at the yellow–green wavelengths of
520–530 nm (Fig. 128.1). Dye concentration and pH can affect
the intensity of fluorescence. Maximum fluorescence occurs at
a pH of 7.4, but the pH of fluorescein sodium for angiographic
use is adjusted to a range of 8–9.8 for stability. In powdered
or concentrated solution form, fluorescein sodium appears
orange–red in color. Fluorescence is detectable in concentrations
between 0.1% and 0.0000001%. In broad-spectrum illumi-
nation, diluted fluorescein sodium appears bright yellow–green
in color. When illuminated with blue light, the yellow–green
color intensifies dramatically.
The fluorescent properties of this dye have made it useful
in a variety of industrial, scientific, military, and medical appli-
cations. Fluorescein sodium was the first fluorescent dye used
for water tracing purposes.4 It has been used as a visible marker
for search-and-rescue operations, to track and measure flow

FLUORESCENCE
Fluorescein angiography is an application of the physical phe-
nomenon of fluorescence.1 Fluorescence is a type of photolumi-
nescence that occurs when susceptible molecules known as
fluorophores absorb electromagnetic energy, temporarily
exciting them to a higher energy state. As the molecules return
to their original energy level, they emit light of a different,
usually longer wavelength. Unlike phosphorescence, which con-
tinues to occur after the excitation source is removed, fluores-
cence requires continuous excitation. Once the excitation
source is removed, emission of fluorescence stops almost
immediately (10–8 s).
Fluorescence occurs naturally in certain compounds and may
occasionally be observed in the human eye. Optic nerve drusen,
astrocytic hamartomas, lipofuscin pigments in the retina, and
the aging human lens are all believed to exhibit natural fluores-
cence that can be documented with various photographic
techniques.

FLUORESCEIN SODIUM
Although commonly referred to as fluorescein, the dye used
for fluorescein angiography is actually fluorescein sodium
(C20H10Na2O5).2 It is the water-soluble salt of fluorescein, also
known as resorcinolphthalein sodium, or uranine. A member of
the xanthene group of dyes, it is a highly fluorescent chemical
compound synthesized from the petroleum derivatives resor- FIGURE 128.1. Excitation and emission. Representative excitation
cinol and phthalic anhydride.3 The dye was first synthesized in and emission curves of fluorescein sodium. Peak excitation occurs at
1871 by Adolf von Baeyer, who later received the Nobel Prize in wavelengths between 465 and 490 nm (blue–green). Peak
Chemistry (1905) for his work in organic dyes. fluorescence occurs at wavelengths of 520–530 nm (green–yellow). 1689
 RETINA AND VITREOUS

dynamics of water sources, map subterranean water courses,
track hazardous spill dispersion patterns, identify point sources
of pollution, and to detect leaks or obstructions in plumbing
and sewage systems. In fact, its common use in industrial
plumbing led a plumbers union to start the tradition of using
fluorescein to stain the Chicago River green for the annual
St Patrick’s Day celebration.
Many of the medical and ophthalmic applications of
fluorescein are analogous to its uses in plumbing or industrial
flow dynamics. For example, it has been used for intraoperative
assessment of blood flow in surgical resections and grafts with
a Wood’s Light to excite fluorescence.5–9 It has also been employed
as an intraoperative predictor of intestinal viability,10,11 as an
indicator of local perfusion in gangrene or severe burns,12,13 and
to monitor perfusate leak in systemic tissues during isolated
limb perfusion with high dose chemotherapeutic agents.14 In
ophthalmology, topical application of fluorescein sodium is
routinely used for applanation tonometry, and as a vital stain in
SECTION 10
In 1959, two medical students, Harold Novotny and David
Alvis worked on a research project to develop a photographic
technique to estimate blood oxygen concentrations in the retinal
vascular bed as a visible segment of the cerebral circulation.
They mixed fluorescein with a blood sample and measured it
with a spectrofluorometer to determine the excitation and
emission wavelengths of fluorescein. They found the peak
excitation of fluorescein to be 490 nm and peak emission,
520 nm. Then they equipped a fundus camera with broadband
absorption filters, a Kodak Wratten 47B for excitation and a
Kodak Wratten 58 green for the barrier. They confirmed the
technique on rabbits and then flipped a coin to see who would
be the first human ‘patient’. Alvis lost, so he was the subject of
the first successful fluorescein angiogram in a human. After
their initial success, they refined the technique on numerous
patients with diabetes and hypertension. The landmark paper
describing their technique was published in the journal
Circulation in 1961, after being rejected by the ophthalmic

the documentation of ocular surface disorders such as corneal
ulcers, abrasions, or other epithelial defects.15 It is sometimes
used to determine tear film breakdown time, check the fit of
contact lenses, verify the patency of lacrimal passageways, and
to detect leakage of aqueous humor from corneal or con-
junctival wounds using the Seidel Test.
HISTORY
In 1881, just a decade after the discovery of fluorescein, Ehrlich
observed anterior chamber fluorescence following an injection
of fluorescein. In 1910, Burke described fluorescent staining of
retinal and choroidal lesions in white light, after ingestion of a
mixture of fluorescein in coffee.16 In the late 1950s, Flocks and
co-workers investigated methods to determine retinal circulation
times with various dyes, including trypan blue and fluorescein.17,18
Using a 16 mm movie camera attached to a fundus camera with
a carbon arc light, they succeeded in obtaining fluorescein angio-
grams in cats, but were unsuccessful in attempts on humans
due to insufficient light. MacLean and Maumenee performed
fluorescein angioscopy with a blue exciter light to diagnose a
choroidal hemangioma following intravenous injection in 1960.19
literature as unoriginal work.20 Following their report, several
investigators studied various clinical applications of angiography,
quickly establishing the intrinsic value of the technique.21
Further innovations were made gradually, including improved
filter combinations, fast recycling flash units, digital imaging
techniques, and SLOs, but the basic principles described by
Novotny and Alvis remain unchanged (Fig. 128.2).
INDICATIONS AND USES
The most common uses of fluorescein angiography are in retinal
or choroidal vascular diseases such as diabetic retinopathy, age-
related macular degeneration, hypertensive retinopathy, and
vascular occlusions (Table 128.1). For the most part, these are
clinical diagnoses. The angiogram is used to determine the
extent of damage, to develop a treatment plan or to monitor the
results of treatment. In diabetic retinopathy the angiogram is
useful in identifying the extent of ischemia, the location of
microaneurysms, the presence of neovascularization and the
extent of macular edema. In age-related macular degeneration,
angiography is useful in identifying the presence, location and
characteristic features of choroidal neovascularization for

a b

FIGURE 128.2. Fluorescein angiography, then and now. (a) Photographs from the first fluorescein angiogram by Novotny and Alvis demonstrate
significant crossover of their simple filter combination, resulting in incomplete blockage of the exciting wavelengths. Results were also limited by
the slow recycle time of the flash unit, more than 12 s between exposures. (b) Modern high-resolution digital fluorescein angiogram
demonstrates improvement in technical quality, but the basic technique developed by Novotny and Alvis is essentially the same.
1690 (a) Courtesy of Indiana University Medical Center.

TABLE 128.1. Common Diagnostic Uses and Indications for
Fluorescein Angiography
Diabetic retinopathy
Age related macular degeneration
Subretinal neovascular membrane from other causes (myopic
degeneration, histoplasmosis, etc.)
Central retinal vein occlusion
Branch retinal vein occlusion
Central serous chorioretinopathy
Cystoid macular edema
Hypertensive retinopathy
Central retinal artery occlusion
Branch retinal artery occlusion
Retinal arterial macroaneurysms
Pattern dystrophies of the retinal pigment epithelium
Choroidal tumors
Chorioretinal inflammatory conditions
Hereditary retinal dystrophies
possible treatment with laser photocoagulation, photodynamic
therapy, or antiangiogenic medications.
Fluorescein angiography can be very useful in certain degen-
erative and inflammatory conditions. Some of these conditions
exhibit characteristic fluorescence patterns, which support the
diagnosis. For example, Stargardts Disease exhibits a ‘silent
choroid’ and a central bulls-eye fluorescence pattern in the macula
while acute posterior multifocal placoid pigment epitheliopathy
(APMPPE) demonstrates a characteristic ‘block early, stain late’
pattern.
Angiography has long played a role in advancing the under-
standing of retinal vascular disorders and potential treatment
modalities. A number of multicenter clinical trials utilize
fluorescein angiography in investigating new treatment options
in diabetic retinopathy, age-related macular degeneration, and
retinal vein occlusions.22
DOSAGE AND ADMINISTRATION
Fluorescein angiography is performed by injecting fluorescein
sodium dye as a bolus into a peripheral vein. The normal adult
dosage is 500 mg, and is typically packaged in doses of 5 mL of
10% or 2 mL of 25%. For pediatric patients, the dose is adjusted
to 35 mg/10 pounds of body weight.23 Upon entering the
circulation, ~80% of the dye molecules bind to plasma proteins,
which significantly reduces fluorescence because the free electrons
that form this chemical bond are subsequently unavailable for
excitation.1 The remaining unbound or free fluorescein
molecules fluoresce when excited with light of the appropriate
wavelength. With a molecular weight of 376, fluorescein diffuses
freely out of all capillaries except those of the central nervous
system, including the retina.
The dye is metabolized by the kidneys and is eliminated
through the urine within 24–36 h of administration. During
this period of metabolism and elimination, fluorescein has the
potential to interfere with clinical laboratory tests that use fluo-
rescence as a diagnostic marker.24,25 To avoid any false readings,
it may be prudent to schedule clinical lab tests either before the
angiogram, or postpone testing for a day or two to allow
sufficient elimination of the dye. Side effects of intravenous
Principles of Fluorescein Angiography
fluorescein include discoloration of the urine for 24–36 h and a
slight yellow skin discoloration that fades within a few hours.
Nursing mothers should be cautioned that fluorescein is also
excreted in human milk.26
COMPLICATIONS AND ADVERSE REACTIONS
Key Features
Fluorescein angiography is well-tolerated by the vast majority of
individuals. The most common adverse reactions are transient
nausea and occasional vomiting.
Fluorescein sodium is well tolerated by most patients, but
angiography is an invasive procedure with an associated risk of
complication or adverse reaction (Table 128.2). Use of fluorescein
sodium may be contraindicated in patients with a history of
CHAPTER 128
allergic hypersensitivity to fluorescein. Although generally con-
sidered safe for patients receiving dialysis, one manufacturer
of fluorescein suggests using half the normal dose in dialyzed
patients.27 There are no known risks or adverse reactions asso-
ciated with pregnancy but most practitioners avoid performing
fluorescein angiography in pregnant women, especially in their
first trimester.28–30
Historically, adverse reactions occur in 5–10% of patients and
range from mild to severe.31–37 Anecdotal evidence suggests a
lower incidence of reaction in recent years and the first large
study conducted in over a decade seems to confirm that,
reporting a frequency of adverse reaction of just over 1%.38
Continued improvements in manufacturing processes and
implementation of tighter pharmacopeial standards are credited
with this reduction and may lead to lower rates of reaction in
the future.39
Transient nausea and occasional vomiting are the most com-
mon reactions and require no treatment. These mild reactions
typically occur 30–60 s after injection and last for ~1–2 min.
Fortunately, they seldom compromise the diagnostic quality of
the angiogram. The incidence of nausea and vomiting seems to
be related to the volume of dye and rate of injection. A relatively
slow rate of injection often reduces or eliminates this type of
reaction but can adversely affect image quality and alter arm-
to-retina circulation times. Premedication with promethazine
TABLE 128.2. Complications and Adverse Reactions
Extravasation of dye
Transient nausea
Vomiting
Pruritis
Urticaria
Bronchospasm
Laryngeal edema
Anaphylaxis
Hypotension
Syncope
Seizures
Myocardial infarction
Cardiac arrest
1691
 RETINA AND VITREOUS
hydrochloride or prochlorperazine may prevent or lessen the
severity of nausea and vomiting in patients with a history of
previous reactions to fluorescein, but is rarely needed and one
study noted a higher frequency of these reactions in patients
that had been premedicated.35 Some patients report a strong
taste sensation or hypersalivation following injection of fluorescein.
Moderate reactions occur less frequently, affecting less than
2% of patients that undergo angiography. Allergic reactions such
as pruritus or urticaria can be treated with antihistamines, but
any patient who experiences these symptoms should be observed
carefully for the possible development of anaphylaxis. The
advisability of performing angiograms in patients with a history
of allergic reaction to fluorescein should be considered carefully,
as allergic sensitization to the dye can increase with each
subsequent use. Patients with previous history of mild allergic
reaction to fluorescein can be pretreated with an antihistamine,
such as diphenhydramine, 30–40 min prior to any subsequent
angiograms to limit allergic response, although this may not
SECTION 10
prevent serious reactions.40 Vasovagal attacks happen in some
patients,41 most likely due to anxiety about the procedure or
their ocular condition. Usually the angiogram needs to be aborted
or postponed, but some patients are able to tolerate the angio-
gram during the initial stages of a syncopal episode. However,
the drop in blood pressure and heart rate can dramatically alter
the angiographic results.42
More severe reactions are rare, but include laryngeal edema,
bronchospasm, anaphylaxis, tonic–clonic seizure, myocardial
infarction and cardiac arrest.43–47 The overall risk of death from
fluorescein angiography has been reported as one in 222 000.35
Although life-threatening reactions during angiography are rare,
angiographic facilities and personnel should be properly equipped
and prepared to manage serious reactions to the procedure. A
resuscitative crash cart and appropriate agents to treat severe
reactions should be readily available including epinephrine
for intravenous or intramuscular use, soluble corticosteroids,
aminophylline for intravenous use, oxygen, and airway instru-
mentation. It is generally recommended that a physician be
present or available during angiographic procedures.
Extravasation of fluorescein dye during the injection can be
a serious complication of angiography. With a pH of 8–9.8,
fluorescein infiltration can be quite painful. If fluorescein dye
extravasates, cold compresses should be placed on the affected
area for 5–10 min, and the patient should be reassessed until
edema, pain, and redness resolve. Serious complications are
more likely to occur when large amounts of dye extravasate.
Sloughing of the skin, localized necrosis, subcutaneous granuloma,
and toxic neuritis have been reported following extravasation of
fluorescein.48–50 To avoid these problems, continual observation
of the injection site during the course of the injection and
monitoring the patient for pain is recommended. Accidental
arterial injections are rare, but can be quite painful. The dye
remains concentrated and stains the effected extremity with
little or no dye reaching the retinal vasculature (Fig. 128.3). With
proper technique, these complications of injection can usually
be avoided.
In cases when venous access is severely compromised or the
patient is known to be highly allergic to the dye, fluorescein can
be administered orally.51,52 Although oral fluorescein adminis-
tration is typically well tolerated, severe adverse reactions can
occur.53,54 Due to the slow absorption rate, an early transit
sequence is not possible. The resulting images are less than
ideal, but have traditionally provided limited diagnostic
information in conditions where late phase photographs are
helpful, such as cystoid macular edema. The use of optical
coherence tomography (OCT) to detect the presence of edema
or fluid within the retinal tissues has essentially eliminated this
1692 use of oral fluorescein.
FIGURE 128.3. Accidental arterial injection. Unusual fluorescein
staining pattern distal to the injection site in a patient with an AV
malformation in the forearm. Photograph was taken with a blue filter
over the light source to excite fluorescence to illustrate the distribution
of dye.
EQUIPMENT AND TECHNIQUE
The instrumentation used for fluorescein angiography must
be capable of delivering the proper excitation wavelengths and
capturing rapid sequence images of the retina as the dye courses
through the vasculature. The modern mydriatic fundus camera
is the tool most commonly used for this purpose, but SLOs and
some specialized wide-field fundus cameras can also be used.
Fluorescein angiography can be performed using 35 mm black-
and-white panchromatic films or with digital cameras. A
number of major ophthalmic instrument manufacturers produce
fluorescein-ready fundus cameras in both film and digital
configurations. Third-party vendors offer digital conversion
solutions for a variety of film-only cameras.
Although fluorescein angiography could be done in color,
black-and-white imaging offers increased light sensitivity and
ease of contrast enhancement to compensate for the low levels
of fluorescence in the bloodstream. Film-based angiography
requires either the use of a processing service, or access to a
darkroom for processing films on-site. Films with an ISO film
speed rating of 400 or higher are used and push processed in
high contrast developers to increase both light sensitivity and
contrast. Films developed in this way exhibit an increase in the
silver halide grain structure and a reduction in apparent
resolution. These films however are often more forgiving of
exposure inconsistencies than are digital cameras
FUNDUS CAMERA
Successful retinal imaging relies on the interaction between the
optics of the fundus camera with those of the eye itself. Fundus
cameras utilize an aspheric design, that when combined with
the optics of the subject eye, matches the plane of focus to the
curvature of the fundus. The focus control of the fundus camera
is used to compensate for refractive errors in the subject eye.
Conditions such as myopia or astigmatism are routinely
encountered and many fundus cameras have additional controls
to compensate for these optical irregularities in patients’ eyes.
The fundus-illuminating beam is delivered axially, through the
image forming optics and filters of the fundus camera. Pharma-
cologic dilation is necessary to obtain adequate illumination. A
xenon-filled flash tube delivers a brief burst of intense light to
expose the photographs.
Fundus cameras are often categorized by their optical angle of
view (Fig. 128.4). An angle of 30–40° is considered the normal
angle of view for documenting macular detail and creates a film
image ~2.5 times life size. Fixed-angle cameras usually offer the
sharpest optics, but variable-angle cameras provide wide-angle

a b
FIGURE 128.4. Fundus camera angle of view. Images of a patient with age-related macular degeneration taken with a variable angle fundus
camera at (a) 50°, (b) 35°, (c) 20° magnification settings.
capabilities between 45° and 60°. Wide-angle cameras need to
illuminate a large area of retina, requiring a more-widely dilated
pupil to accommodate a larger ring of light.
Fundus cameras equipped for fluorescein angiography have a
timer that records the angiographic sequencing on each frame of
the study, a matched pair of exciter and barrier filters and a fast
recycling electronic flash tube that allows a capture rate of up to
one frame per second. Narrow-band pass-interference filters are
utilized to allow maximum transmission of peak wavelengths,
while minimizing any crossover of transmission curves. The
exciter filter transmits blue–green light at 465–490 nm, the peak
excitation range of fluorescein. The barrier filter transmits a
narrow band of yellow at fluorescein’s peak emission range
of 520–530 nm. The barrier filter effectively blocks all visible
wavelengths but the specific color of fluorescein.
Images are captured either with high-speed black-and-white
35 mm panchromatic film or electronically, with a charge-
coupled device (CCD) and computerized system for digital
imaging. Increasingly, the use of digital imaging is replacing the
majority of film-based systems.
DIGITAL IMAGING
Key Features
Digital angiography has become the imaging modality of choice
based on the ability to capture, process, enhance, store, and
distribute images electronically.
The ophthalmic community was quick to adopt digital imaging
technology for fluorescein angiography. Commercial digital
systems designed specifically for fluorescein angiography and
retrofitted to existing film-capable fundus cameras began to
appear on the market as early as 1983.55 This configuration
continues to be the most common type of instrumentation used
for angiography, offering choice and flexibility between film and
digital camera backs. In recent years, new instruments have
been developed that rely entirely on digital capture technology
for angiography. Digital-only devices include SLOs and special-
ized wide-field retinal imaging devices that can be configured for
fluorescein angiography. Digital imaging hardware and software
continues to evolve and improve in quality, and we are likely to
see more digital-only devices for angiography in the future.
Spatial resolution in current retinal imaging systems varies
from 800 µ 600 to over 3000 µ 2000 pixels. Monochrome digital
backs are considered better for angiography than their color
counterparts since they are usually more light sensitive, and all
pixels are available for exposure to fluorescence. The narrow
Principles of Fluorescein Angiography
c
CHAPTER 128
band of wavelengths generated by fluorescein will expose only
the green channel pixels in RGB color sensors, reducing resolution
through interpolation. However, both monochrome and color
CCDs with pixel counts of three Megapixels or above surpass
the spatial resolution of the 400 speed films commonly employed
for film-based angiography. Resolution comes at a cost in terms
of light efficiency. High-resolution digital sensors require more
light for proper exposure and flash settings often need to be
increased. New high-transmission filter sets have been developed
to improve light efficiency and performance with high-resolution
digital sensors.
Digital imaging offers several distinct advantages over tradi-
tional film-based angiography. Computer technology offers a
variety of powerful tools that can be used to enhance diagnostic
information. Software tools provide adjustments for brightness,
contrast and sharpness. Digital analysis enables measurement
of pathologic structures, digital overlays can be used to identify
potential changes in lesion size in serial photographs, and
multiple fields can be linked together to form composite wide-
field images. Images can be stored on magnetic or optical media
like CD or DVD-ROMs and transmitted electronically across
computer networks for remote viewing or storage on servers.
Commercially available digital angiography systems typically
conform to the Digital Imaging and Communications in Medicine
(DICOM) Standards. This is a set of universal standards for
transferring diagnostic images and associated information
between devices manufactured by different vendors.56–59 Con-
formance to these standards facilitates connectivity to picture
archiving and communication systems (PACS) used in radio-
logy, and integration with electronic medical records and other
hospital information systems.
In addition to well-known advantages in capturing, processing,
enhancing, storing, and distributing images electronically, having
instant access to digital images can increase clinical efficiency
and enhance patient education opportunities through the ability
to review images on large screen computer monitors with the
patient. Another significant advantage to digital imaging is that
it can shorten the learning curve for novice angiographers trying
to master the complex techniques of angiography. Having instant
feedback allows the operator to adjust exposure settings and
camera alignment to correct any flaws in technique.
Despite these advantages, the high initial cost of digital
systems has prevented them from being employed universally,
although they are now more common than film-based systems.
A pair of surveys looking at tasks performed by retinal angio-
graphers indicated that over 70% of respondents (71% in 2002,
72% in 2004) are utilizing digital technology for some or all of
their fluorescein angiograms.60,61 1693
 RETINA AND VITREOUS
SCANNING LASER OPHTHALMOSCOPY
Fluorescein angiography can also be recorded using a confocal
SLO in place of the conventional fundus camera. This complex
instrument uses a laser beam of the appropriate excitation wave-
length to scan across the fundus in a raster pattern to illuminate
successive elements of the retina, point-by-point.62,63 The laser can
deliver a very narrow wavelength band for more efficient excitation
of fluorescence than the flash illumination generated by a fundus
camera flash tube. A confocal aperture is positioned in front of the
image detector at a focal plane conjugate to the retina, effectively
blocking non image-forming light. The confocal optical system and
laser illumination combine to produce high contrast, finely detailed
images. The laser scan rate is synchronized at a frame rate
compatible with digital video display, providing a continuous
high-speed representation of the flow dynamics of the retina
and choroid. This can be especially useful when documentation
of the very early filling stages is necessary, such as in identifi-
SECTION 10
cation of choroidal neovascular (CNV) feeder vessels.
The SLO lessens the need for pupillary dilation and patients
easily tolerate the low light level of the laser. SLO technology
can also be used for indocyanine green (ICG) angiography of the
choroidal vasculature, as well as simultaneous fluorescein and
ICG angiography, and fundus autofluorescence (FAF) of retinal
pigment abnormalities. The major drawback of scanning laser
technology is the high cost of the equipment.
STEREO IMAGING
Stereo imaging techniques can be used during angiography to
enhance diagnostic information. Stereo images provide a visual
sense of depth that is particularly useful in identifying the histo-
pathologic location of angiographic findings within the retina.
Use of this technique in retinal photography dates back as far as
1909, but it wasn’t until the 1960s that stereo photography
became widely employed after Lee Allen described a practical
technique for sequential stereo fundus photography.64 Stereo
imaging is a standard protocol for many clinical trials inves-
tigating treatment of retinal diseases.22
Stereo separation is achieved by laterally shifting the fundus
camera a few millimeters between sequential photographs. The
lateral shift causes the illuminating beam of the fundus camera
to fall on opposite slopes of the cornea. The resulting cornea-
induced parallax creates a hyperstereoscopic effect that is evident
when the sequential pair of photographs is viewed together.
There are a variety of optical stereo viewers available for viewing
side-by-side 35 mm film images on a light box, or digital images
on a computer monitor. All stereo viewing devices are designed
to deliver the separate stereo images simultaneously but inde-
pendently to each eye allowing the brain to fuse the pair.
The common use of digital projection has resulted in a resur-
gence in stereo projection using the color anaglyph technique.65
This technique works very well with grayscale angiographic
images. A stereo pair can be digitally color encoded as a single
image using image-editing software. Instead of employing optics
or polarization to display a stereo effect, the anaglyph method
uses complementary colors to encode and deliver stereo infor-
mation. Digital imaging software facilitates accurate and
effective registration of anaglyph stereo pairs. Anaglyph stereo
pairs can be viewed with inexpensive eyewear either on a
computer monitor or projected with an LCD projector and are
useful in educational settings.
SEQUENCING
Proper sequencing of the angiographic series is essential in
1694 obtaining maximum diagnostic information. Color fundus
photographs as well as black-and-white monochromatic green
filter images are routinely taken as baseline views before admin-
istering the dye. The early transit phase is the most critical part
of the angiogram and usually lasts less than a minute. Before
injecting the dye, the illuminating beam of the fundus camera
is centered within the dilated pupil. The angiographer then
prefocuses the camera on the appropriate area of interest. The
dye is administered as a bolus injection, typically through a
small gauge needle into an antecubital vein. The timer is started
and photography commences. The arm-to-retina circulation time
varies, but normally takes 10–12 s. Experienced angiographers
anticipate the initial appearance of the dye and begin the photo-
graphic sequence before the dye is visible. Images are routinely
captured at a rate of one frame per second until maximum
fluorescence occurs. During this dynamic early phase only one
eye can be captured. After completion of the early phase, photo-
graphs of the fellow eye or other areas of interest in the primary
retina can be taken.
Over the next few minutes, the appearance of the dye stabilizes
and begins to slowly fade. The angiographer can capture appro-
priate views as necessary without the urgency needed during the
early phase. Late phase photographs are taken as the dye dissipates,
anywhere from 7 to 15 min after injection.
Many facilities develop disease specific protocols for both
sequencing and field of view. For example, peripheral shots of
the retina are routinely taken after the early transit in diabetic
retinopathy, whereas the macula is the major area of interest in
age-related macular degeneration and peripheral views are not
usually necessary. The angiographer often adjusts the specific
protocol based on visible changes that may occur as the
angiogram progresses.
QUALITY ISSUES AND THE ROLE OF THE
ANGIOGRAPHER
Some ophthalmologists perform their own angiography, but this
is an exception rather than the rule. Most facilities employ a
photographer or technician dedicated to performing ophthalmic
photography procedures.
Quality angiographic results rely on a number of factors. The
skill of the angiographer and the optical and mechanical quality
of the instrumentation can have a direct effect on results, but
there are a number of common factors that can adversely affect
angiographic quality. Media opacities can cause illumination
artifacts and blurring of the images. Inadequate pupillary dilation
reduces light reaching the retina, causing uneven illumination.
Excess topical fluorescein staining of the cornea from the initial
patient workup can compete with and degrade retinal fluorescence.
Inadequate patient cooperation such as poor fixation or inability
to hold steady during the procedure often results in loss of
field definition during the important early transit phase.
Extravasation of the dye not only causes discomfort to the
patient, but the resulting incomplete dose reduces the amount
of dye in the retinal vessels. Some of these causes are beyond
the direct control of the angiographer, but every attempt should
be made to minimize their detrimental effects in order for each
angiogram to be of adequate and consistent diagnostic quality
(Table 128.3).
Since fluorescein angiography is a dynamic process, success-
ful results depend on complete preparation before the dye is
injected. Many angiographers follow a specific protocol or check-
list to ensure that everything is ready. Good communication
between the ophthalmologist and angiographer is essential to
ensure that maximum diagnostic information is obtained. The
photographic timing sequence and the angiographer’s ability to
adapt to changing conditions are also important elements in
producing quality angiographic results. Experience is invaluable,
 Principles of Fluorescein Angiography

TABLE 128.3. Factors Effecting Image Quality

The skill of the angiographer

Optical/mechanical quality of the instrumentation
Presence of media opacities
Absorption of blue excitation light by cataracts
Residual topical fluorescein staining of the cornea
Inadequate pupillary dilation
Poor fixation
Inadequate patient cooperation
Extravasation of the dye

especially in managing the patient if complications occur during

CHAPTER 128
the critical early phase of the study.
FIGURE 128.5. Blood–retinal barrier. The inner and outer
Unfortunately, there is very little education available in
blood–retinal barriers are demonstrated in this photomicrograph. The
fluorescein angiography. In the absence of formal education, fluorescein is retained within the retinal vessels by the endothelial cell
certification plays an important role in developing competent tight junctions and the choriocapillaris by the RPE.
practitioners in angiography. The Ophthalmic Photographers Reprinted from Eagle RC Jr: Mechanisms of maculopathy. Ophthalmology 1984;
Society offers a voluntary certification program in fluorescein 91:613-625.
angiography that has established standards of competence in
angiography. The Certified Retinal Angiographer (CRA)
program was established in 1978. The program is accredited by
the National Commission for Certifying Agencies and has
certified over 800 individuals to date. Although certification is
not mandatory, the CRA credential offers some assurance of
competence and safety to both patient and physician.
The responsibility for injecting the dye sometimes falls to the
angiographer or a technician. In some practice settings this
makes sense. There are however, some legal issues associated
with unlicensed personnel performing fluorescein injections.66
It is generally recommended that angiographic facilities check
their current state or local laws regarding the credentialing
requirements of personnel performing intravenous injections.67

INTERPRETATION
Fluorescein angiography records the dynamic interaction of
fluorescein with both normal and abnormal anatomic structures
of the ocular fundus. A thorough understanding of the circu-
lation phases and appearance of the dye in a normal eye is
essential for interpretation of abnormalities.
THE NORMAL ANGIOGRAM
In a normal eye, the retinal blood vessels and the retinal
pigment epithelium (RPE) both act as barriers to fluorescein
leakage within the retina (Fig. 128.5). The tight junctions of the
endothelial cells in normal retinal capillaries make them imper-
meable to fluorescein leakage. The tight cellular junctions of
the healthy RPE provide an outer blood–retinal barrier
preventing the normal choroidal leakage from penetrating the
retinal tissues.
Additional anatomical features contribute to the interpretation
of the fluorescein angiogram. The choriocapillaris is the capillary-
rich layer of the choroid characterized by fenestrated capillary
walls that leak fluorescein dye freely into the extravascular
space within the choroid. In the posterior fundus, the chorio-
capillaris is arranged in a mosaic of lobules that accounts for the
patchy choroidal fluorescence often seen in the early phases of
the angiogram (Fig. 128.6). The taller, more pigmented retinal
pigment epithelial cells along with the presence of xanthophyll
pigment and absence of retinal capillaries in the center of the
FIGURE 128.6. Patchy choroidal filling. In the posterior fundus, the
choriocapillaris is arranged in a mosaic of lobules that contributes to
the patchy choroidal fluorescence often seen in the early phases of
the angiogram.
fovea (foveal avascular zone) contribute to the relative hypo-
fluorescence of the center of the macula (Fig. 128.7).
Early Phase
The early phase of the angiogram can be divided into distinct
circulation phases that are useful for interpreting the results
(Fig. 128.8a–d).
Choroidal flush
In a normal patient, the dye appears first in the choroid ~10 s
following injection. The major choroidal vessels are imperme-
able to fluorescein, but the choriocapillaris leaks fluorescein dye
freely into the extravascular space. There is usually little detail
in the choroidal flush as the RPE acts as an irregular filter that
partially obscures the view of the choroid. If a cilioretinal artery 1695
 RETINA AND VITREOUS

is present, this fills along with the choroidal flush as both are
supplied by the short posterior ciliary arteries.

Arterial phase
The retinal arterioles typically fill one to 2 s after the choroid;
therefore, the normal ‘arm-to-retina’ circulation time is ~12 s.
A delay in the arm-to-retina time may reflect a problem with
the fluorescein dye injection or circulatory problems with the
patient including heart and peripheral vascular disease.

Arteriovenous phase
Complete filling of the retinal capillary bed follows the arterial
phase and the retinal veins begin to fill. In the early
arteriovenous phase, thin columns of fluorescein are visualized
along the walls of the larger veins (laminar flow). These
columns become wider as the entire lumen fills with dye.

Venous phase
SECTION 10

Complete filling of the veins occurs over the next 10 s with

FIGURE 128.7. Normal macular anatomy. The central 500 mm of the
fovea is devoid of blood vessels (foveal avascular zone or FAZ). This
maximum vessel fluorescence occurring ~30 s after injection.
finding, along with the presence of xanthophyll pigment and taller, The perifoveal capillary network is best visualized in the peak
more pigmented retinal pigment epithelial cells, contributes to the venous phase of the angiogram.
relative hypofluorescence of the macula.

a b c

d e f

FIGURE 128.8. Normal fluorescein angiogram. (a) Choroidal flush. Fluorescein dye appears first in the choroid, 1–2 s before the dye reaches the
retinal arterial circulation. When present, cilioretinal arteries fill along with the choroidal flush since both are supplied by the short posterior ciliary
arteries. (b) Arterial phase. The arterial phase occurs when the fluorescein dye enters the retinal arteries. The normal ‘arm-to-retina’ circulation
time is ~12 s. (c) Arteriovenous phase. The arteriovenous phase of the angiogram comprises the time when the retinal arteries, capillaries, and
veins contain fluorescein. In the early arteriovenous phase, thin columns of fluorescein are visualized along the walls of the larger veins (laminar
flow). (d) Venous phase. As the fluorescein dye begins to exit from the retinal arteries and capillaries, the concentration of fluorescein within the
veins increases, resulting in a decrease in fluorescence of the arteries and an increase of fluorescence of the veins. (e) Mid phase. The
recirculation phase occurs ~2–4 min after injection. The veins and arteries remain roughly equal in brightness. The intensity of fluorescence
diminishes slowly during this phase as fluorescein is removed from the bloodstream by the kidneys. (f) Late phase. The late phase of the
angiogram demonstrates the gradual elimination of dye from the retinal and choroidal vasculature. Staining of the optic disk is a normal finding.
1696 Any other areas of late hyperfluorescence suggest the presence of an abnormality, usually the result of fluorescein leakage.

Mid Phase
Also known as the recirculation phase, this occurs ~2–4 min
after injection. The veins and arteries remain roughly equal in
brightness. The intensity of fluorescence diminishes slowly
during this phase as much of the fluorescein is removed from
the bloodstream on the first pass through the kidneys (see Fig.
128.8e).
Late Phase
The late or elimination phase demonstrates the gradual
elimination of dye from the retinal and choroidal vasculature
(see Fig. 128.8f). Photographs are typically captured 7–15 min
after injection. Late staining of the optic disk is a normal
finding. Any other areas of late hyperfluorescence suggest the
presence of an abnormality.
THE ABNORMAL ANGIOGRAM
In evaluating diseases of the macula, fluorescein angiography is
helpful in detecting abnormalities in blood flow, vascular
permeability, the retinal and choroidal vascular patterns, the
RPE, and a variety of other changes.68 Interpretation of the
abnormal angiogram relies on the identification of areas that
exhibit hypofluorescence or hyperfluorescence. These are
descriptive terms that refer to the time specific, relative
brightness of fluorescence in comparison with a normal study
(Table 128.4).
Hypofluorescence
Key Features
Hypofluorescence is usually caused by the blockage of normal
fluorescence or abnormal vascular perfusion.
TABLE 128.4. Abnormal Angiographic Findings
Hypofluorescence
Filling defect
Blocking defect
Hyperfluoresence
Autofluorescence
Pseudofluorescence
Transmission or ‘window’ defect
Leakage
Pooling
Staining
a b
Principles of Fluorescein Angiography
Pseudofluorescence is the reduction or absence of normal
fluorescence. Hypofluorescence is caused by either blockage of
the normal fluorescence pattern or abnormalities in choroidal
or retinal vascular perfusion.
Blocked fluorescence
Blocked fluorescence is most commonly caused by blood but
can result from the deposition of abnormal materials such as
lipid exudate, lipofuscin, xanthophyll pigment, or melanin
pigment. Fluorescein angiography is very helpful in determining
the anatomic location of the blocking material, which in turn,
is important in identifying the etiology of the abnormality. For
example, preretinal hemorrhage from proliferative diabetic
retinopathy blocks visibility of both the retinal and choroidal
vasculature while subretinal blood from exudative age-related
macular degeneration obscures only the choroidal circulation
(Fig. 128.9).
CHAPTER 128
Abnormal vascular perfusion
Abnormal vascular perfusion results in hypofluorescence of the
retinal and/or choroidal circulation depending on the location of
the abnormality. Common causes of retinal hypoperfusion include
retinal arterial and venous occlusions and ischemic disease due
to diabetes and other causes. Choroidal hypoperfusion may be
produced by ophthalmic artery occlusion, giant cell arteritis,
and hypertensive choroidopathy. It is important to understand
the relationship between hypofluorescence due to filling defects
and the specific phase of the angiogram. For example, in many
vascular occlusions the hypofluorescence may be a temporary
finding until delayed filling of the affected vessel occurs in the
later phases of the study (Fig. 128.10).
Hyperfluorescence
Key Features
Hyperfluorescence usually results from atrophy of the pigment
epithelium (transmission or ‘window’ defect) or leakage of
fluorescein dye.
Hyperfluorescence is an increase in fluorescence resulting from
the increased transmission of normal fluorescence or an ab-
normal presence of fluorescein at a given time in the angiogram.
Autofluorescence and pseudofluorescence are terms to
describe the appearance of apparent hyperfluorescence in the
absence of fluorescein.
Autofluorescence
Autofluorescence refers to recordable hyperfluorescence that is
believed to occur naturally in certain pathologic entities such as
optic nerve drusen and astrocytic hamartomas. Some, but not
FIGURE 128.9. Hypofluorescence: blockage.
(a) This fluorescein angiogram of an eye with a
central retinal vein occlusion demonstrates
widespread hypofluorescence resulting from
intraretinal hemorrhages. The majority of
hemorrhages are located in the nerve fiber
layer, which accounts for the ‘flame-shaped’
pattern of hypofluorescence along the major
vascular arcades. (b) Hypofluorescence related
to subretinal hemorrhage is demonstrated in
this patient with a ruptured retinal arterial
macroaneurysm. The ability to visualize the
retinal circulation overlying the blocking defect
confirms the subretinal location of the
hemorrhage. 1697
 RETINA AND VITREOUS

FIGURE 128.10. Hypofluorescence:

nonperfusion. (a) In this patient with advanced
diabetic retinopathy, there is marked
hypofluorescence throughout the retina as a
result of widespread ischemia. Note that there
are scattered patches of more prominent
hypofluorescence from intraretinal hemorrhages.
(b) This patient with diabetic macular edema
has significant macular ischemia with capillary
dropout and enlargement and irregularity of the
foveal avascular zone. Contrast this with the
normal perifoveal capillary network shown in
Figure 128.7.
a b

FIGURE 128.11. Hyperfluorescence:

autofluorescence. (a) Red-free photograph of a
patient with disk drusen. (b) A photograph
SECTION 10

taken with fluorescein exciter and barrier filters

demonstrates autofluorescence of the disk
drusen in the absence of fluorescein.

a b

all disk drusen appear to fluoresce under blue light (Fig.

128.11). Some controversy exists over whether this is actual
fluorescence or reflectance.69 These structures are highly
reflective in the same spectral range of fluorescence and could
actually be exhibiting pseudofluorescence.

Pseudofluorescence
Pseudofluorescence occurs as a result of crossover in the
spectral transmission curves of the exciter and barrier filters. If
too much crossover is present, reflectance from bright fundus
structures will not be fully blocked by the barrier filter.
Crossover can be the result of mismatched or aging filters.
Modern interference filters rarely exhibit significant crossover
unless they have deteriorated. Control photographs are
routinely taken before injection of fluorescein to detect the
possible presence of pseudofluorescence.

Transmission defect
Depending on the density of retinal pigmentation, background
fluorescence from the choroid can be visible as hyper-
fluorescence in the angiogram. A ‘window defect’ is an area of
hyperfluorescence that occurs when there is an absence or
reduction of pigmentation due to damage of the RPE. The loss
of pigment allows visualization of the fluorescence created by
the underlying choriocapillaris (Fig. 128.12). Window defects
remain uniform in size throughout the angiogram. Their
brightness rises and falls with the choroidal fluorescence. It is
important to differentiate hyperfluorescence due to trans-
mission defects from leakage.
Leakage
Leakage refers to hyperfluorescence in the angiogram due to
extravasation of fluorescein dye. Leakage can result from
1698 disruption of the retinal vascular endothelial cell tight junctions
FIGURE 128.12. Hyperfluorescence: transmission defect. A
transmission or ‘window’ defect is seen in this patient with age-related
macular degeneration with geographic atrophy. Atrophy of the RPE
allows visualization of the underlying choroidal fluorescence. The
hyperfluorescence usually appears early in the angiogram and is not
associated with leakage in the late phase.
or the breakdown of the tight junctions between retinal pigment
epithelial cells (the inner and outer blood–retinal barriers,
respectively). Examples include macular edema from diabetic
retinopathy (Fig. 128.13), cystoid macular edema, and central
serous chorioretinopathy. In addition to abnormalities of the
retinal vascular system or pigment epithelium, leakage is
 Principles of Fluorescein Angiography

FIGURE 128.13. Hyperfluorescence: leakage.

The phenomenon of hyperfluorescence related
to fluorescein leakage is demonstrated in this
patient with diabetic retinopathy. (a) The
arteriovenous phase image reveals multiple
hyperfluorescent spots corresponding to
microaneurysms. (b) In the late phase
angiogram, there is diffuse hyperfluorescence
related to leakage from the microaneurysms
and irregular capillaries.

a b

FIGURE 128.14. Hyperfluorescence: leakage.

This pair of images demonstrates fluorescein

CHAPTER 128
leakage from exudative age-related macular
degeneration. (a) During the arteriovenous
phase, the abnormal choroidal blood vessels
become visible (they are surrounded by a zone
of hypofluorescence caused by the blocking
effect of hemorrhage). (b) In the late phase
angiogram, there is significant leakage of
fluorescein throughout the macula.

a b

observed in a variety of conditions associated with the

development of new blood vessels. For example, fluorescein
leakage is seen in eyes with choroidal neovascularization related
to age-related macular degeneration. In these patients,
fluorescein angiography is needed to identify the location and
features of the choroidal neovascular membrane which, in turn,
influences the course of treatment (Fig. 128.14). In eyes with
proliferative diabetic retinopathy, optic disk or retinal
neovascularization is characterized by intense fluorescein
leakage (Fig. 128.15). Leakage can lead to late staining or
pooling of dye.

Staining
Staining refers to late hyperfluorescence resulting from the
accumulation of fluorescein dye into certain tissues. Drusen and
chorioretinal scars commonly exhibit staining. Normal staining
can occur in the optic nerve and sclera as a result of normal
choroidal leakage. Scleral staining is usually only visible when
there is a reduction or absence of the pigment epithelium (window
defect) and the sclera can be seen clinically (Fig. 128.16).
FIGURE 128.15. Hyperfluorescence: leakage. Retinal
Pooling neovascularization is characterized by profuse leakage on fluorescein
Pooling is the accumulation of dye within a distinct anatomic angiography. The areas of retinal neovascularization usually are
space. Pooling can occur in serous detachments of the sensory located at the junction of the perfused and nonperfused retina.
retina or the RPE due to a breakdown of the blood–retinal
barrier. Central serous chorioretinopathy is a condition that
often demonstrates the pooling of fluorescein (Fig. 128.17). insights and value to the ‘Gold Standard’ of retinal imaging.
Color stereo fundus photography is a natural complement to
COMPLEMENTARY IMAGING TECHNIQUES fluorescein angiography and has traditionally been included in
standard angiography protocols along with monochromatic
Fluorescein angiography continues to be a vital tool in the detec- green light ‘red free’ photographs. Monochromatic fundus photo-
tion of retinal vascular disorders. A number of additional graphy with other colors of light has been used for decades, but
diagnostic imaging procedures serve as an adjunct to angiography. is probably underutilized given its inherent value. More
Some have a long history of complementary use with fluorescein recently, ICG angiography, OCT, and FAF have expanded the
angiography, while newer techniques can add new diagnostic available arsenal of diagnostic imaging procedures. 1699
 RETINA AND VITREOUS
ICG ANGIOGRAPHY
Digital technology facilitates the use of another fluorescent dye,
ICG, for retinal and choroidal angiography. With peak absorption
(805 nm) and emission (835 nm) in the near-infrared range,
ICG provides greater transmission through the RPE and
hemorrhage than the visible wavelengths used in fluorescein
angiography. ICG also binds more completely with blood
albumins, so it normally remains within the fenestrated walls
of the choriocapillaris, unlike fluorescein, which leaks freely
from these vessels.
ICG choroidal angiography was first performed in humans
in 1972, but results were limited by insufficient sensitivity of
available infrared films.70 In the early 1990s, two groups
reported improved results with commercially available digital
angiography systems.71,72 The infrared sensitivity of available
CCD cameras was combined with new lens coatings applied to
fundus camera optics to improve infrared transmission for ICG
SECTION 10
angiography. In the early to mid 1990s, enthusiasm for this
procedure exceeded its practical applications. Use of this
technique waned by the late 1990s as clinical research had
defined a vital, but limited role for ICG angiography as an
adjunct to fluorescein angiography.
Today, ICG angiography is used in combination with
fluorescein angiography in a limited number of diagnoses where
choroidal circulation is effected, particularly in patients with
FIGURE 128.16. Hyperfluorescence: staining. This late phase
angiogram demonstrates staining of drusen. Hyperfluorescence is
observed as fluorescein accumulates within the drusen material.
a b
1700
age-related macular degeneration.73 The goal in age-related
macular degeneration is to identify localized areas of choroidal
neovascularization or choroidal feeder vessels that can be
treated with a laser to prevent damage to the retina.74–76
MONOCHROMATIC FUNDUS PHOTOGRAPHY
Monochromatic fundus photography is the practice of imaging
the ocular fundus with the use of colored or monochromatic
illumination. In 1925, Vogt described the use of green light to
enhance the visual contrast of anatomical details of the fundus.77
The technique is still commonly used today in combination
with fundus photography. Monochromatic fundus photography
is based on increased scattering of light at shorter wavelengths
and the use of contrast filters to alter subject tones in black
and white photographs. By limiting the spectral range of the
illuminating source, the visibility of various fundus structures
can be enhanced (Fig. 128.18).78–81 This technique is most
effective when combined with high-resolution black-and-white
film or digital sensors.
Blue light increases visibility of the anterior retinal layers,
which normally are almost transparent in white light. Blue light
is absorbed by retinal pigmentation and blood vessels, providing
a dark background against which the specular reflections and
scattering in the anterior layers of the fundus is enhanced.
Scattering in the ocular media can limit the effectiveness of
these wavelengths. The retinal nerve fiber layer, the internal
limiting membrane, retinal folds, cysts and epiretinal membranes
are examples of semitransparent scattering structures that are
enhanced with short wavelength illumination. Because of excessive
scattering at very short wavelengths, fluorescein exciter filters at
blue–green wavelengths of 490 nm are often used.
Green light is also absorbed by blood, but is reflected more
than blue light by retinal pigmentation. There is less scatter
than with shorter wavelengths, so media opacities are not quite
as troublesome. Green light provides excellent contrast and the
best overall view of the fundus. It enhances the visibility of the
retinal vasculature, and common findings such as hemorrhages,
drusen and exudates. For this reason, green filter ‘red-free’
photos are routinely taken as baseline images before fluorescein
angiography.
Retinal pigmentation appears more transparent in red light,
revealing the choroidal pattern. Overall fundus contrast is
greatly reduced with red illumination. Retinal vessels appear
lighter and become less obvious at longer wavelengths. The
optic nerve appears lighter and almost featureless. Red light is
useful for imaging pigmentary disturbances, choroidal ruptures,
choroidal nevi, and choroidal melanomas.
Traditionally, monochromatic photography has required use
of high-resolution black-and-white films and customized film
processing techniques to maximize diagnostic information.
FIGURE 128.17. Hyperfluorescence: pooling.
This pair of angiographic images demonstrates
the phenomenon of pooling. (a) Central serous
chorioretinopathy is characterized by a
hyperfluorescent spot that increases in size and
intensity throughout the study. (b) Ten minutes
after injection, this patient has the characteristic
‘smokestack’ appearance as fluorescein
accumulates or ‘pools’ within the localized
neurosensory retinal detachment.

a b
a b
These film and developer combinations could be difficult to
control, which may explain why monochromatic photography
never gained universal acceptance. Digital imaging facilitates
immediate control of exposure settings and easy contrast
enhancement, making the monochromatic technique more
practical for widespread use.
OPTICAL COHERENCE TOMOGRAPHY
OCT is useful in the diagnosis of several retinal disorders that
have traditionally been imaged with fundus photography or
fluorescein angiography. OCT imaging provides direct cross-
sectional images of the macula, retinal nerve fiber layer and
optic nerve for objective measurement and clinical evaluation in
the detection of retinal diseases and glaucoma. It is particularly
useful in the detection of changes in normal retinal architecture
such as macular holes, epiretinal membranes, vitreomacular
traction, cystoid macular edema, subretinal fluid, and retinal
pigment epithelial detachments.82,83 Its greatest value however,
may lie in the ability to quantify and monitor change in retinal
thickness due to macular edema from diabetic retinopathy or
other causes.
Although the technology has been available since 1991, OCT
was mostly used in academic settings or for research appli-
cations until 2002, when the evolution of the instrumentation,
in the form of increased resolution and ease of operation,
matured to the point where OCT imaging became both practical
and affordable. Since its introduction, OCT has rapidly gained
widespread acceptance and for certain retinal conditions, is now
the diagnostic procedure of choice. Compared to angiography,
OCT is less expensive, noninvasive, faster, well tolerated and
easy to perform. The procedure can be conducted in ~10 min,
usually without dilation or discomfort to the patient. Enthusiasm
for OCT continues to grow as new instruments are being devel-
oped by a number of manufacturers. Advances in technology
that use spectral or Fourier domain OCT techniques, promise
improvement in resolution and acquisition speed, as well as
3-D viewing of retinal structures.
Principles of Fluorescein Angiography
FIGURE 128.18. Monochromatic Imaging.
(a) Fluorescein angiogram of a choroidal lesion.
(b) Mononchromatic red light (peak
transmission at 615 nm) imaging is particularly
useful for documenting lesions deep within the
retina and choroid. Longer wavelengths partially
penetrate the retina pigment epithelium and
make it appear more transparent, revealing the
borders of the nevus.
FIGURE 128.19. Optical coherence
tomography. OCT imaging can be used as an
CHAPTER 128
adjunct to, or a replacement for, fluorescein
angiography. OCT imaging has become the
diagnostic procedure of choice to detect
cystoid macular edema, a condition that was
traditionally confirmed with fluorescein
angiography.
Fluorescein angiography was originally developed to look
specifically at retinal blood flow. An unexpected benefit was the
ability to detect structural changes in certain retinal conditions
by observation of fluorescein staining patterns in abnormal
retinal tissues or anatomic spaces caused by structural change.
OCT has demonstrated great application in detecting many of
these structural abnormalities and fluorescein angiography is
no longer needed for some of these diagnoses (Fig. 128.19). The
true strength of angiography lies in its original purpose, to look
specifically at flow dynamics in the retinal and choroidal vascu-
lature. Used in tandem, OCT and fluorescein angiography provide
a wealth of diagnostic information to aid in the management of
retinal disease (Fig. 128.20).
FUNDUS AUTOFLUORESCENCE
FAF is a recently developed noninvasive imaging technique for
documenting the presence of lipofuscin in the RPE. Lipofuscin
is a fluorescent pigment that accumulates in the RPE as a result
of incomplete degradation of photoreceptor outer segments as
the eye ages. When excited with short wavelength illumination,
lipofuscin granules autofluoresce, exhibiting a broad emission
spectrum from 500 to 750 nm with peak emission at ~630 nm.84
The original technique used a confocal SLO with the excita-
tion wavelength set at 488 nm and a wide band-pass filter with
short wavelength cutoff at 521 nm.85 Several frames are captured
with the SLO, then aligned and averaged to reduce noise. Because
several frames are required, image quality may be affected by
eye movement during capture. More recently, digital fundus-
camera based systems have been developed which use high-
sensitivity monochrome sensors with an excitation filter at
580 nm and a barrier filter at 695 nm to avoid confounding
autofluorescence from the crystalline lens.86 Both systems
require significant amounts of light and increased gain settings
to achieve adequate exposure, and are subject to image noise.
Despite the disparity in excitation wavelength and barrier filters
between the SLO and fundus camera systems, these two tech-
niques obtain results that are quite similar in appearance. 1701
 RETINA AND VITREOUS

FIGURE 128.20. Optical coherence

tomography. The combination of fluorescein
angiography and OCT can provide the clinician
with greater diagnostic information as
demonstrated in this case of idiopathic central
serous chorioretinopathy. Angiography identifies
the area of active leakage, while OCT illustrates
a compartmentalized serous detachment.

a b

FIGURE 128.21. Fundus autofluorescence.

(a) Fluorescein angiography image of a patient
with geographic atrophy in age-related macular
degeneration. (b) Fundus autofluorescent
SECTION 10

imaging (excitation at 580 nm and barrier at

695 nm) noninvasively identifies RPE atrophy as
areas of hypofluorescence due to an absence
or reduction of lipofuscin accumulation.

a b

Autofluorescence imaging has the potential to provide useful
information in conditions where the health of the RPE plays a
key role. Hyperfluorescence is a sign of increased lipofuscin
accumulation, which may indicate degenerative changes or
oxidative injury. Areas of hypofluorescence indicate missing or
dead RPE cells. Geographic atrophy that appears as a window
defect in fluorescein angiography will appear dark in autofluo-
rescent imaging (Fig. 128.21). A number of investigators have
been exploring potential applications of this imaging technique
in a variety of retinal diseases including: retinitis pigmentosa,87
central serous chorioretinopathy,88 macular dystrophies,89 pseu-
doxanthoma elasticum,90 and age-related macular degeneration.86
The role of lipofuscin in the pathogenesis of macular degen-
eration is currently unknown, but increased autofluorescence
may precede development or progression of geographic atrophy
in AMD.91
SUMMARY
Fluorescein angiography has revolutionized the understanding,
diagnosis and treatment of retinal vascular disorders. For over
40 years, ophthalmologists have used fluorescein angiography
as a guide for laser treatment, benefiting many thousands of
patients. This important diagnostic tool continues to evolve
with new advances in digital imaging technique. As new treat-
ment modalities are developed, fluorescein angiography will
continue to play an important role in the management of
retinal conditions.

REFERENCES
1. Wolfe DR: Fluorescein angiography basic
science and engineering. Ophthalmology
1986; 93:1617–1620.
2. Morris PF: Fluorescein sodium and
indocyanine green: uses and side effects.
In: Saine PJ, Tyler ME, eds. Ophthalmic
photography: retinal photography,
angiography and electronic imaging. 2nd
edn. Boston: Butterworth-Heinemann;
2002:137–165.
3. Jacobs J: Fluorescein sodium – what is it?
J Ophthal Photography 1992; 14:62.
4. Dole RB: Use of fluorescein in the study of
underground waters. USGS Water Supply
Paper 1906; 160:73–85.
5. Myers B: Prediction of skin sloughs at the
time of operation with the use of
fluorescein dye. Surgery 1962;
51:158–162.
6. McCaw JB, Myers B, Shanklin KD: The
1702 value of fluorescein in predicting the
viability of arterialized flaps. Plast Reconstr
Surg 1977; 60:710–719.
7. Singer R, Lewis CM, Franklin JD, et al:
Fluorescein test for prediction of flap
viability during breast reconstructions. Plast
Reconstr Surg 1978; 61:371–375.
8. Smith JA Jr, Middleton RG: The use of
fluorescein in radical inguinal
lymphadenectomy. J Urol 1979;
122:754–756.
9. Sloan GM, Sasaki GH: Noninvasive
monitoring of tissue viability. Clin Plast
Surg 1985; 12:185–195.
10. Stolar CJ, Randolph JG: Evaluation of
ischemic bowel viability with a fluorescent
technique. J Pediatr Surg 1978; 13:221–225.
11. Marfuggi R, Greenspan M: Intraoperative
prediction of intestinal viability. Surg Gynae
Obstet 1981; 152:33–35.
12. Crimson J, Fuhrman F: Studies on
gangrene following cold injury. IV. The use
of fluorescein as an indicator of local blood
flow: fluorescein test in experimental
frostbite. J Clin Invest 1947; 26:259–268.
13. Gatti JE, LaRossa D, Silverman DG, et al:
Evaluation of the burn wound with
perfusion fluorometry. J Trauma 1983;
23:202–206.
14. Minor DR, Allen RE, Alberts D, et al: A
clinical and pharmacokinetic study of
isolated limb perfusion with heat and
melphalan for melanoma. Cancer 1985;
55:2638–2644.
15. Martonyi CL, Bahn CF, Meyer RF: Clinical
slit lamp biomicroscopy and photo slit lamp
biomicrography. Ann Arbor, MI: Time One
Ink; 1985:64–67.
16. Saine PJ: Landmarks in the development of
fluorescein angiography. J Ophthal
Photography 1993; 15:17–23.
17. Chao P, Flocks M: The retinal circulation
time. Am J Ophthalmol 1958; 46:8–10.

18. Flocks M, Miller J, Chao P: Retinal
circulation time with the aid of fundus
cinematography. Am J Ophthalmol 1959;
48:3–6.
19. MacLean AL, Maumenee AE: Hemangioma
of the choroid. Am J Ophthalmol 1960;
50:2–11.
20. Novotny HR, Alvis DL: A method of
photographing fluorescence in circulating
blood of the human retina. Circulation
1961; 24:82–86.
21. David NJ, Justice J: The early days of
fluorescein angiography. J Ophthal
Photography 1994; 16:83–86.
22. Quillen DA, Gardner TW, Blankenship GW:
The Diabetic Retinopathy Study. In: Kertes
PJ, Conway MD, eds. Clinical trials in
ophthalmology: a summary and practice
guide. Baltimore: Williams & Wilkins;
1998:1–13.
23. Physicians’ desk reference for ophthalmic
medicines. Montvale: Thompson PDR;
2006:207.
24. Palestine AG: Does intravenous fluorescein
interfere with clinical laboratory testing?
J Ophthal Photography 1991; 13:27–28.
25. Bloom JN, Herman DC, Elin RJ, et al:
Intravenous fluorescein interference with
clinical laboratory tests. Am J Ophthalmol
1989; 108:375–379.
26. Mattern J, Mayer PR: Excretion of
fluorescein into breast milk [letter]. Am J
Ophthalmol 1990; 109:598.
27. AK-FLUOR package insert, rev. 08/05.
Akorn, Inc Buffalo Grove, IL. Available:
http://www.akorn.com/documents/catalog/
package_inserts/17478–254–10.pdf.
28. Halperin LS, Olk RJ, Soubrane G, et al:
Safety of fluorescein angiography during
pregnancy. Am J Ophthalmol 1990;
109:563–566.
29. Greenberg F, Lewis RA: Safety of fluorescein
angiography during pregnancy [letter]. Am J
Ophthalmol 1991; 110:323–325.
30. Berkow JW, Flower RW, Orth DH, Kelley
JS: Fluorescein and indocyanine green
angiography. 2nd edn. San Francisco:
American Academy of Ophthalmology;
1997:7.
31. Chazan BI, Balodimos MC, Koncz L:
Untoward effects of fluorescein retinal
angiography in diabetic patients. Ann
Ophthalmol 1971; 3:42.
32. Pacirariu RI: Low incidence of side effects
following intravenous fluorescein
angiography. Ann Ophthalmol 1982;
14:32–36.
33. Butner RW, McPherson AR: Adverse
reactions in intravenous fluorescein
angiography. Ann Ophthalmol 1983;
15:1084–1086.
34. Marcus DF, Bovino JA, Williams D: Adverse
reactions during intravenous fluorescein
angiography. Arch Ophthalmol 1984;
102:825.
35. Yannuzzi LA, Rohrer KT, Tindel LJ, et al:
Fluorescein angiography complication
survey. Ophthalmology 1986; 93:611–617.
36. Karhunen U, Raitta C, Kala R: Adverse
reactions to fluorescein angiography. Acta
Ophthalmol 1986; 64:282–286.
37. Kwiterovitch KA, Maguire MG, Murphy RP,
et al: Frequency of adverse systemic
reactions occurring after fluorescein
angiography – results of a prospective
study. Ophthalmology 1991; 98:1139–1142.
38. Kwan AS, Barry CJ, McAllister IL, et al:
Fluorescein angiography and adverse drug
Principles of Fluorescein Angiography
reactions revisited: the Lions Eye experience.
Clin Exp Ophthalmol 2006; 34:33–38.
39. Eutick M: Sodium fluorescein – colourful
past, bright future. J Ophthal Photography
2006; 28:66–70.
40. Ellis PP, Schoenberger M, Rendi MA:
Antihistamines as prophylaxis against side
reactions to intravenous fluorescein. Trans
Am Ophthalmol Soc 1980; 78:190–205.
41. Buchanan RT, Levine NS: Blood pressure
drop as a result of fluorescein injection.
Plast Reconstr Surg 1982; 70:363–368.
42. Merin LM, Lam BL: Case report: fluorescein
angiogram during vasovagal syncope.
J Ophthal Photography 1994; 16:94–95.
43. Gombos GM, Lieberman RM: Seizures
associated with fluorescein angiography.
Ann Ophthalmol 1989; 21:89–90.
44. Kelly SP, Mcdermott NJ, Saunders DC,
et al: Convulsion following fluorescein
angiography. Br J Ophthalmol 1989;
73:655–656.
45. Hess JB, Pacirariu RI: Acute pulmonary
edema following intravenous fluorescein
angiography. Am J Ophthalmol 1976;
82:567–570.
46. Deglin SM, Deglin EA, Chung EK: Acute
myocardial infarction following fluorescein
angiography. Heart Lung 1977; 6:505–509.
47. Acasco FJ, Tiestos MT, Navales J, et al:
Fatal acute myocardial infarction after
intravenous fluorescein angiography. Retina
1993; 13:238–239.
48. Schatz H: Sloughing of skin following
fluorescein extravasation. Ann Ophthalmol
1978; 10:625.
49. Elman MJ, Fine SL, Sorenson J, et al: Skin
necrosis following fluorescein
extravasation. A survey of the Macula
Society. Retina 1987; 7:89–93.
50. Lipson BK, Yannuzzi LA: Complications of
fluorescein injections. Int Ophthalmol Clin
1989; 29:200–205.
51. Kelley JS, Kincaid M: Retinal fluorography
using oral fluorescein. Arch Ophthalmol
1979; 97:2331–2332.
52. Hara T, Inami M, Hara T: Efficacy and
safety of fluorescein angiography with
orally administered sodium fluorescein. Am
J Ophthalmol 1998; 126:560–564.
53. Kinsella FP, Mooney DJ: Anaphylaxis
following oral fluorescein angiography. Am
J Ophthalmol 1988; 106:745–746.
54. Gomez-Ulla F, Gutierrez C, Seonae I:
Severe anaphylactic reaction to orally
administered fluorescein. Am J Ophthalmol
1991; 112:94.
55. Saine PJ, Tyler ME, eds: Ophthalmic
photography: retinal photography,
angiography and electronic imaging. 2nd
edn. Boston: Butterworth-Heinemann;
2002:247–248.
56. Oosterwijk H: DICOM versus HL7 for
modality interfacing. J Digit Imaging 1998;
11(3 Suppl 1):39–41.
57. Kabachinski J: DICOM: key concepts-part
I. Biomed Instrumen Technol 2005;
39:214–216.
58. Kabachinski J: DICOM: key concepts-part
II. Biomed Instrumen Technol 2005;
39:292–294.
59. Bidgood WD Jr, Horii SC: Introduction to
the ACR-NEMA DICOM standard.
Radiographics 1992; 12:345–355.
60. Bennett TJ, MacGregor G, Scheuneman
JD: Digital Imaging and the certified retinal
Angiographer Program. J Ophthal
Photography 2004; 26:28–36.
61. Benetz BA, Bennett TJ, Tomer TL: What
does today’s ophthalmic photographer do?
J Ophthal Photography 2005; 27:85–87.
62. Woon WH, Fitzke FW, Chester GH, et al:
The scanning laser ophthalmoscope: basic
principles and applications. J Ophthal
Photography 1990; 12:17–23.
63. Clark TM: Scanning laser
ophthalmoscopes. In: Saine PJ, Tyler ME,
eds. Ophthalmic photography: retinal
photography, angiography and electronic
imaging. 2nd edn. Boston: Butterworth-
Heinemann; 2002:306–321.
64. Allen L: Ocular fundus photography:
suggestions for achieving consistently
good pictures and instructions for
stereoscopic photography. Am J
Ophthalmol 1964; 57:13–28.
65. Bennett TJ: Stereo anaglyph preparation
for PowerPoint. J Ophthal Photography
CHAPTER 128
2005; 27:38–45.
66. Ellis JH, Weber P: Legal issues arise when
unlicensed personnel administer IV
fluorescein. Argus 1995; Nov–Dec:28–31.
67. Ophthalmic photographers’ society
standards of practice. J Ophthal
Photography 1999; 21:26.
68. Gass JDM: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 4th edn.
St Louis: Mosby; 1997.
69. Barry C, Singh J, Constable IJ: Are optic
disc drusen exhibiting Autofluorescence,
pseudofluorescence or reflectance?
J Ophthal Photography 2000; 22:32–35.
70. Flower RW, Hochheimer BF: Clinical
infrared absorption angiography of the
choroids. Am J Ophthalmol 1972;
73:458–459.
71. Guyer DR, Puliafito CP, Mones JM, et al:
Digital indocyanine-green angiography in
chorioretinal disorders. Ophthalmology
1992; 99:287–290.
72. Yannuzzi LA, Slakter JS, Sorenson JA, et al:
Digital indocyanine green videoangiography
and choroidal neovascularization. Retina
1992; 12:191–223.
73. Stanga PE, Lim JI, Hamilton P: Indocyanine
green angiography in chorioretinal
diseases: indications and interpretation: an
evidence-based update. Ophthalmology
2003; 110:15–21.
74. Shiraga F, Ojima Y, Matsuo T, et al: Feeder
vessel photocoagulation of subfoveal
choroidal neovascularization secondary to
age-related macular degeneration.
Ophthalmology 1998; 105:662–691.
75. Flower RW: Experimental studies of
indocyanine green dye-enhanced
photocoagulation of choroidal
neovascularization feeder vessels. Am J
Ophthalmol 2000; 129:501–512.
76. Flower RW: Optimizing treatment of
choroidal neovascularization feeder vessels
associated with age-related macular
degeneration. Am J Ophthalmol 2002;
134:228–239.
77. Vogt A: Die Ophthalmoskopie im rotfreiem
licht. GraefSaemisch Handbuch der
gesamten Augenheilkunde. Berlin: Springer
Verlag; 1925.
78. Delori FC, Gragoudas ES: Examination of
the ocular fundus with monochromatic
light. Ann Ophthalmol 1976; 8:703–709.
79. Behrendt T, Slipakoff E: Spectral
reflectance photography. Int Ophthalmol
Clin 1976; 16:95–100.
80. Delori FC, Gragoudas ES, Francisco R,
et al: Monochromatic ophthalmoscopy and 1703
 RETINA AND VITREOUS
fundus photography. The normal fundus.
Arch Ophthalmol 1977; 95:861–868.
81. Ducrey NM, Delori FC, Gragoudas ES:
Monochromatic ophthalmoscopy and
fundus photography. II. The pathological
fundus. Arch Ophthalmol 1979;
97:288–293.
82. Puliafito CA, Hee MR, Lin CP, et al: Imaging
of macular diseases with optical coherence
tomography. Ophthalmology 1995;
102:217–229.
83. Costa RA, Skaf M, Melo LA Jr, et al: Retinal
assessment using optical coherence
tomography. Prog Retin Eye Res 2006;
25:325–353.
84. Delori FC, Dorey CK, Staurenghi G, et al:
In vivo fluorescence of the ocular fundus
SECTION 10
1704
exhibits retinal pigment epithelium
lipofuscin characteristics. Invest
Ophthalmol Vis Sci 1995; 36:718–729.
85. von Ruckman A, Fitzke FW, Bird AC:
Distribution of fundus autofluorescence
with a scanning laser ophthalmoscope.
Br J Ophthalmol 1995; 79:407–412.
86. Spaide RF: Fundus autofluorescence and
age-related macular degeneration.
Ophthalmology 2003; 110:392–399.
87. Robson AG, Egan C, Holder GE, et al:
Comparing rod and cone function with
fundus autofluorescence images in retinitis
pigmentosa. Adv Exp Med Biol 2003;
533:41–47.
88. Spaide RF, Klancnik JM Jr: Fundus
autofluorescence and central serous
chorioretinopathy. Ophthalmology 2005;
112:825–833.
89. Von Ruckmann A, Fitzke FW, Bird AC: In
vivo fundus autofluorescence in macular
dystrophies. Arch Ophthalmol 1997;
115:609–615.
90. Sawa M, Ober MD, Freund KB, et al:
Fundus autofluorescence in patients with
pseudoxanthoma elasticum.
Ophthalmology 2006; 113:814–820.
91. Hopkins J, Walsh A, Chakravarthy U:
Fundus autofluorescence in age-related
macular degeneration: an epiphenomenon?
Invest Ophthalmol Vis Sci 2006;
47:2269–2271.
 CHAPTER
129 Indocyanine Green Videoangiography
Jordi Monés, David R. Guyer, Sara Krupsky, Ephraim Friedman,
Evangelos S. Gragoudas, and Antonio P. Ciardella
Fluorescein angioscopy1 and angiography2 were important tech-
nological advances in the study of retinal disorders. Although
choroidal circulation patterns have been described with fluor-
escein angiography, the limitations of this technique for studying
the choroid are well known.3–6 The excitation and fluorescence
of blue-green wavelengths (peak absorption 465 nm peak fluor-
escence 525 nm) are absorbed and scattered by the pigment layers
of the fundus, including the macular xanthophyll. Thus, the
choroidal layers cannot be well visualized.7–10 In addition, sodium
fluorescein, which is 60–80% bound to plasma albumin,11 rapidly
leaks from the fenestrated choriocapillaris4 and produces a dif-
fuse background fluorescence, which further obscures the details
of the choroidal vessels.12 Finally, the intricate branching of the
choroidal vascular system13 is difficult to study with fluorescein
angiography.12
Because the choroid is the major blood supply of the eye14
and the outer retinal layers, a better method of studying this
important tissue was needed. Near-infrared absorption angio-
graphy, using indocyanine green (ICG) as an absorbing dye, was
first studied in the canine brain by Kogure and Choromokos in
1969.15 This study led to the development of ICG choroidal
angiography.
HISTORY OF ICG ANGIOGRAPHY
In 1969, a qualitative method of studying choroidal blood flow
using reflective densitometry with ICG was reported.16 After
using infrared absorption ICG angiography to study the circula-
tion of the dog cerebral surface,15 Kogure and associates first
demonstrated choroidal absorption angiography using intra-
arterial ICG injection and false-color infrared film in monkeys.17
These investigators demonstrated filling of the smaller choroidal
veins and occasional laminar filling of the larger choroidal veins.
A choroidal arterial phase was not noted. David was the first to
perform ICG absorption choroidal angiography in human patients
in 1969.18 These patients underwent intraarterial ICG injections
during carotid angiography. He described diffuse choriocapillaris
filling and choroidal veins draining toward the vortex veins. In
1971, Hochheimer performed choroidal absorption angiography
in cats using intravenous ICG injections and black-and-white
infrared film.19 This study solved two major problems. The first
was the use of intraarterial injections and the second was the
inconsistency of the false-color infrared film.
Intravenous ICG absorption angiography was first successfully
performed in humans by Flower and Hochheimer in 1972.20,21
With this method, the fundus is illuminated with infrared light
and the reflected light exposes the photographic film. If larger
vessels are filled with enough dye to absorb the incident light, the
film will not be exposed.21,22 In 1973, Flower and Hochheimer
described a method of ICG fluorescence angiography.23 With
this technique, direct fluorescence of the vessels occurred, the
resolution improved, and the arterial and capillary dye phases
were evident. In 1974, Flower developed a multispectral fundus
camera.12 Simultaneous ICG fluorescence and absorption angio-
graphy with fluorescein angiography was performed. This
combination allowed comparison of the various types of angio-
grams. Clinical reports of ICG angiographic imaging of choroidal
neovascularization (CNV), choroidal tumors, choroideremia,
choroidal hemangiomas, and the presumed ocular histoplas-
mosis syndrome were published.24–31 Further technological
improvements followed.32–34 Visualization of the choriocapillaris
filling pattern with ICG and study of the temporal differences
of ICG and fluorescein choroidal filling were performed in
monkeys.33 Hyvärinen and Flower presented a case of CNV in
which the feeding choroidal artery was identified and
photocoagulated.35
In 1985, Bischoff and Flower reported their 10 years of expe-
rience with ICG choroidal angiography.36 This series included
180 angiograms of normal volunteers and 500 angiograms of
patients with various fundus diseases. Hayashi and colleagues in
1986 performed ICG angiography in patients with central serous
chorioretinopathy using an infrared-sensitive video camera.37
Videoangiography has also been used by other investigators to
study CNV38–40 and choroidal blood flow.41,42 A digital computer
system has also been used to study choroidal blood flow.43,44
Preliminary results with ICG videoangiography with the scanning
laser ophthalmoscope were reported by Scheider and Schroedel
in 1989,45 and Scheider and co-workers described their first
experience with this technique and CNV.46
In 1992, Guyer and co-workers47 and Yannuzzi and asso-
ciates48 introduced the use of a 1024-line digital imaging system
to produce high-resolution enhanced ICG images. These
systems have improved the resolution of ICG videoangiography
such that this technique is now of practical clinical value.
DIGITAL IMAGING SYSTEMS
The coupling of a digital imaging system with an ICG camera
allows production of enhanced high-resolution (1024-line) images,
which are necessary for ICG angiography. These systems pro-
duce instantaneous images that decrease patient waiting time
and expedite possible laser photocoagulation treatment. Digital
imaging systems allow image archiving, hard-copy generation,
and direct qualitative comparison between fluorescein and ICG
angiography findings. In addition, these systems are useful for
planning preoperative laser treatment strategies and for moni-
toring the adequacy of treatment postoperatively.
Digital imaging systems contain film and video cameras with
special antireflective coatings and appropriate excitatory and bar-
rier filters. A video camera is mounted in the camera viewfinder 1705
 RETINA AND VITREOUS

and is connected to a video monitor. The photographer selects

the image and activates a trigger that sends the image to the video
adapter. The digitally charged coupling device camera (mega-
plus camera) then captures the images and transmits these
digitized (‘1024 line µ 1024 line’ resolution) images to a video
board within a computer processing unit. Flash synchronization
allows high-resolution image capture. These images are captured
at one frame per second, stored in buffer memory, and displayed
on a high-contrast, high-resolution video monitor. Optical discs
are used to store images after editing. Hard-copy photographs
can be obtained through a printer or slides can be produced
directly from a slide-making device. Finally, via telecommuni-
cations, satellite stations can be placed in laser treatment areas
and in other offices.

TECHNIQUES IN ICG ANGIOGRAPHY

SECTION 10

Advances in ICG angiography were real-time angiography,49

wide-angle angiography,49 and digital subtraction ICG
angiography.50
Real-time ICG angiography uses a modified fundus camera
with a diode laser illumination system that has an output at
805 nm that can produce images at 30 frames per second, and
allows continuous recording. The images can be acquired either
FIGURE 129.1. Wide-angle ICG angiography picture of a patient with
as a videotape or as a single image at a frequency of 30 images
a choroidal nevus. Note the typical butterfly distribution of the
per second. choroidal circulation.
Wide-angle image of the fundus can be obtained by perform- From Yannuzzi LA, Flower RW, Slakter JS: Indocyanine green angiography.
ing ICG angiography with the aid of wide-angle contact lenses. St. Louis: Mosby-Year Book; 1997.
The contact lenses used are the Volk SuperQuad 160, the Volk
Quadraspheric, or the Volk Transequator (Volk, Mentor, OH).
Because the image formed by these lenses lies ~1 cm in front of
the lens, the fundus camera is set on A or +, so that the camera
is focused on the image plane of the contact lens.
This technique allows instantaneous imaging of a large area of
the fundus. The combined use of the contact lens and of the laser
illumination system allows real-time imaging of a wide field of
the choroidal circulation up to 160º of field of view (Figs 129.1
and 129.2).
Digital subtraction ICG angiography uses digital subtraction
of sequentially acquired ICG angiographic frames to image the
progression of the dye front in the choroidal circulation. A
method of pseudocolor imaging of the choroid allows differen-
tiation and identification of choroidal arteries and veins. Digital
subtraction ICG angiography allows imaging of occult CNV
with greater detail and in a shorter period of time than with
conventional ICG angiography.

PHARMACOLOGY OF ICG
ICG was first used in 1957 to measure cardiac output.51 It is a
water-soluble tricarbocyanine dye, which is an anhydro-
3,3,3„,3„-tetramethyl-1,1„-di-(4-sulfobutyl)-4,5,4„,5„-
dibenzoindotricarbocyanine hydroxide sodium salt.
Its molecular weight is 775 Da, and its empirical formula is FIGURE 129.2. A wide-angle ICG angiography picture of a patient
C43H47N2O6S2Na.52 After intravenous injection, ICG is rapidly with a subretinal hemorrhage secondary to idiopathic polypoidal
and almost completely bound to plasma proteins. It has been choroidal vasculopathy. The image shows 160º of the fundus.
thought that ICG is bound to albumin in the blood.53 However, Courtesy of Richard F. Spaide, MD, New York.
80% of ICG in human serum is actually bound to globulins,
such as a-lipoproteins.54
The spectral absorption of ICG in aqueous solution with TOXICITY OF ICG
albumin is between 790 and 805 nm.54–56 ICG is eliminated
from the blood almost exclusively by the liver and is excreted ICG is not very toxic in animals.61–65 Only a few side effects
into the bile. Reabsorption of ICG from the intestine does not have been reported with clinical use.53,61,66,67 In 1978, 240 000
occur.55–58 ICG is not detected in the cerebrospinal fluid,58,59 nor cases of ICG use were reviewed.68 In the early years, when the
1706 does it cross the placental barrier.60 presence of 5% iodide in Cardio-Green was not appreciated,

there were some side effects in patients with iodide allergies. In
addition, one patient had urticaria and three patients had anaphy-
lactic reactions. One of these patients died. Among 43 patients
who underwent chronic hemodialysis, three patients with nausea
and one patient with a reversible anaphylactoid reaction to ICG
were reported.69
No side effects have been reported in the ophthalmic litera-
ture. There were no complications after intravenous doses of
150–200 mg of ICG in one study.70 During 700 procedures in
another study, no side effects were reported.36 Thus, ICG is
relatively nontoxic and appears to be safer than fluorescein dye.
Between 5% and 20% of patients receiving fluorescein dye suffer
from nausea, headache, or dizziness, and 5–10 in 1000 patients
have allergic reactions.11
In a study that reported on ICG angiography performed on
1226 consecutive patients, there were three (0.15%) mild adverse
reactions, four (0.2%) moderate reactions, and one (0.05%)
severe adverse reaction. There were no deaths.71
Nevertheless, ICG may cause a severe anaphylactic reaction.
ICG angiography should not be performed in patients who are
allergic to iodide, in those who have a history of severe allergies,
or in those who are uremic.36 In addition, we would not rec-
ommend its use in patients with liver disease, as the dye is
eliminated exclusively by this organ.
SPECIAL PROPERTIES OF ICG FOR
CHOROIDAL ANGIOGRAPHY
ICG absorbs light in the near-infrared region of the spectrum
(maximal absorption is approximately at 790 nm)17 and also
fluoresces in the near-infrared region (maximal emission is
approximately at 835 nm).72–75 Because of its activity at these
longer wavelengths, ICG fluoresces through pigment and hemor-
rhage when it is excited by near-infrared light.
Approximately 98% of ICG is bound to plasma proteins,53
and, therefore, the dye probably does not leak from the chorio-
capillaris.72 This property allows better visualization of the cho-
roidal vessels because ICG remains in the choroidal vasculature
longer than fluorescein does. However, some authors believe that
ICG can pass through the fenestrations of the choriocapillaris.37,40
Bill stated that the choroidal blood vessels are permeable to sub-
stances with molecular weights of 17–156 kDa, such as myo-
globin, albumin, and gamma globulin.76 Thus, protein-bound
ICG may pass through the fenestrations of the choriocapillaris to
some extent.36
The liver rapidly removes ICG from the blood after intra-
venous injection.53,57,77 Therefore, there is no significant ICG
staining of normal ocular tissues.17,78
Another advantage of ICG is that its peak absorption coincides
with the emission spectrum of the diode laser. This property
may allow selective ablation of chorioretinal lesions using ICG
dye-enhanced diode laser photocoagulation when a target tissue
containing ICG is exposed to the diode laser beam.49,50,75
TECHNIQUE OF ICG INJECTION
A dye concentration of 0.03 mg/mL is required for maximal
fluorescence of ICG in the choroidal vessels. The dye is diluted
600 times before it enters the choroidal circulation. Thus, ~20 mg
of ICG in 1 mL of aqueous solvent has to be rapidly injected
intracubitally. We currently inject ~50 mg of ICG for diagnostic
studies. Rapid injection is essential in order to delineate various
choroidal filling phases because the majority of the dye bolus
must be in the choroidal vessels before reaching the retinal
vasculature.79 This injection should be immediately followed by
a flush of 5 mL of normal saline solution. The timing of photo-
graphy should be determined by arm to retina time,36 since the
Indocyanine Green Videoangiography
fundus cannot be observed. This transit time is ~10 s in young
patients and ~12–18 s in older patients.11
CHARACTERISTICS OF INFRARED
WAVELENGTHS
Near-infrared light is used to perform choroidal angiography
because it can penetrate pigmented layers7–9 better than the shorter
wavelengths of visible light. The percentage of absorption in
human retinal pigment epithelium and choroid for equal inten-
sities is between 59% and 75% for 500 nm (blue-green visible
light) and between 21% and 38% for 800 nm (near-infrared light).10
Near-infrared light causes ICG to fluoresce. Patients note that
infrared light appears as barely visible red light. Therefore, photo-
phobic patients may tolerate this procedure better than
fluorescein angiography.20
Since longer wavelengths are less scattered than shorter wave-
lengths, near-infrared angiography may be performed in patients
CHAPTER 129
with diffuse opacities in the ocular media, such as cataract or
vitreous hemorrhage.24 Infrared light is less harmful than
shorter-wavelength light to the retina; thus, a continuous light
source may be used for high-speed angiography.36 Thermal retinal
damage, however, can be produced with the infrared light. With
energies greater than 1 W/cm2, the retinal temperature may rise by
10°C, and acute retinal damage can occur. The safe time expo-
sure must be calculated.80 The risk of near-infrared-induced
lens damage is minimal with choroidal angiography.36
MORPHOLOGIC FEATURES OF THE
CHOROIDAL VASCULATURE
NORMAL MORPHOLOGIC CHOROIDAL
PATTERNS
Most of the short posterior ciliary arteries enter the eye near the
macula. These choroidal arteries travel radially to the equator.
After they have perforated the sclera and have entered the choroid,
they divide into smaller branches. Interarterial anastomoses are
common in the choroid,81 but they cannot be distinguished with
ICG angiography. The choroidal arteries do not fill at the same
time. The earliest detectable filling of the arteries is usually nasal
to the fovea. This region is the area of highest blood perfusion
pressure in the eye.21 The individual vessels of the chorio-
capillaris cannot be distinguished. The choriocapillaris filling
pattern produces a faint and diffuse homogeneous fluorescence
that prevents a clear visualization of the deeper choroidal layers
(Fig. 129.3).79 Choroidal veins run parallel to the periphery and
eventually form the vortex veins (Fig. 129.4). Venous anastomoses
occur between large vessels.81 Veins are larger and more fluor-
escent than arteries, but these changes cannot be used to differ-
entiate them. A horizontal watershed area between the superior
and the inferior vessels is sometimes present (Fig. 129.5).36
Choroidal arteries fill between 0.5 and 1 s earlier than does the
central retinal artery. Different phases of the ICG angiogram
have been described.36,82 The mean time values reported follow:
Choroidal artery to choroidal vein 1.8 s
Central retinal artery to retinal vein (laminar) 2.0 s
Central retinal artery to retinal vein (full) 6.2 s
Choroidal artery to vortex vein (initial) 2.0 s
Choroidal artery to vortex vein (maximal) 5.0 s
ICG ANGIOGRAPHY OF CHORIORETINAL
DISORDERS
Age-Related Macular Degeneration
Macular disorders may occur secondary to specific choroidal
vascular properties of this specialized area.83 Only short arteries 1707
 RETINA AND VITREOUS
SECTION 10
FIGURE 129.3. The choroidal venous phase of ICG angiography of a
normal fundus. A diffuse homogeneous fluorescence is noted in the
macular area. Details of the deeper vessels in this area are not seen.
Around the macular area, the choroidal veins are homogeneous in
caliber and distributed uniformly to converge to form the vortex veins.
and arterioles are present between the ciliary arteries and the
choriocapillaris in the macula. This cluster of arterial branches
is greater in the macula than in any other region. These findings
may be responsible for the high pressure and rapid blood flow of the
macula.13,21,83 These pressure changes may cause choriocapil-
laris disease83 and CNV.84 The loss of contractility of the arterial
wall that occurs with age may cause dilatation of the vessel.85,86
Watershed areas of both arterial and venous circulations may
be present in the macular area.87,88,89 Hayashi and de Laey
described a relationship between these choroidal ‘watershed
zones’ and macular lesions and showed evidence of abnormal
a b
FIGURE 129.4. (a and b) The choroidal veins converge to form the vortex veins, with a large variability of patterns.
1708
choroidal vessels. They suggested that chronic choroidal
insufficiency may cause CNV.88
Bischoff and Flower36 reviewed 100 ICG angiograms of age-
related macular degeneration (AMD) and described four abnormal
findings:
1. Delayed or irregular choroidal filling, or both. In some
patients, the interval between choroidal arterial and
choroidal venous filling was 3–4 s. However, as these
authors suggest, the significance of this finding is
uncertain because the investigators did not study an age-
matched control group.
2. Generalized arterial changes. These authors describe
‘wandering arteries’ in some patients with AMD.
3. Localized arterial changes. Marked dilatation of macular
choroidal arteries was observed in some patients. These
arteries filled earlier than other vessels and often formed a
loop close to the entrance site. These loops were
anatomically related to overlying fundus lesions. The
authors felt that a higher blood pressure in the
choriocapillaris overlying vascular abnormalities may cause
dilatation of the choriocapillaris and subsequent macular
disease (Fig. 129.6).84
4. CNV. This finding was observed by ICG angiography in
only a small number of cases in Bischoff and Flower’s
series (Fig. 129.7).
Hayashi and co-workers reported that ICG angiography was par-
ticularly useful to detect occult CNV.38 The same investigators
showed that ICG leaks from CNV into the subretinal space.
However, the leakage is slower and of lesser magnitude than
fluorescein leakage of CNV. This slow ICG leakage is some-
times useful in defining the borders of CNV and has delineated
neovascularization not well identified with fluorescein angio-
graphy.40 Destro and Puliafito39 also found this technique very
useful to study occult CNV, particularly those with overlying
hemorrhage or those that had recurred on the edge of previously
treated areas. CNV adjacent to chorioretinal scars showed greater
contrast between the new vessels and the adjacent scar with
ICG than with fluorescein angiography. Chorioretinal scars
were hypofluorescent because of less ICG extravasation and the

FIGURE 129.5. A horizontal watershed area between the superior
and the inferior vessels found in a minority of patients.
FIGURE 129.6. The choroidal mid-transit phase of an ICG angiogram
in a patient with age-related macular degeneration. Dilated tortuous
arterial loops can be observed on the temporal side.
relative lack of choroidal vessels in those areas. ICG remained
selectively in and around the CNV.39 In addition, Scheider and
colleagues described enhanced imaging of CNV by using the
scanning laser ophthalmoscope with ICG angiography.46
High-resolution ICG images can now be produced by com-
bining digital imaging systems and an ICG camera.47,48 This
technological advance now allows the theoretical advantage of
ICG over fluorescein dye to finally be realized.
Yannuzzi and associates48 showed that occult CNV could be
converted into classic, well-defined CNV in 39% of the 129
Indocyanine Green Videoangiography
patients in their series because of information obtained through
digital ICG videoangiography. These authors found that digital
ICG videoangiography is especially useful for patients with
poorly defined CNV, pigment epithelial detachments (PEDs),
and recurrent CNV. In many cases, the late ICG images reveal
a hyperfluorescent area corresponding to an area of subretinal
neovascularization that cannot be detected by fluorescein angio-
graphy. The finding of a hyperfluorescent spot on the late ICG
angiogram can separate the neovascularized portion from the
serous portion of a PED.
Yannuzzi and co-workers used ICG angiography to study 235
consecutive AMD patients with occult CNV and associated vas-
cularized PED. These eyes were divided into two groups, depend-
ing on the size and delineation of the CNV. Of the 235 eyes, 89
(38%) had a solitary area of neovascularization that was well
delineated, no more than one disk diameter in size, and defined
as focal CNV. The other 146 eyes (62%) had a larger area of
neovascularization, with variable delineation defined as a
CHAPTER 129
plaque CNV.90
In a further report, 657 consecutive eyes with occult CNV by
fluorescein angiography were studied with ICG angiography. Of
413 eyes with occult CNV without PEDs, focal areas of neovas-
cularization were noted in 89 (22%). Overall, 142 eyes (34.3%)
had lesions that were potentially treatable by laser photoco-
agulation based on additional information provided by ICG
angiography. Of the 235 eyes with occult CNV and vascularized
PEDs, 98 (42%) were eligible for laser therapy based on ICG
angiography findings. The authors calculated that ICG angio-
graphy enhances the treatment eligibility by approximately
one-third.91
In an expanded series, the same authors reported their results
on ICG angiography study of 1000 consecutive eyes with occult
CNV by fluorescein angiography.92 They recognized three morpho-
logic types of CNV, which included focal spots (Figs 129.8 and
129.9), plaques (Fig. 129.10) (well-defined and poorly defined),
and combination lesions (Fig. 129.11) (in which both focal spots
and plaques are noted). Combination lesions were further sub-
divided into marginal spots (focal spots at the edge of a plaque of
neovascularization), overlying spots (hot spots overlying plaques
of neovascularization), or remote spots (a focal spot remote from
a plaque of neovascularization).
The relative frequency of these lesions was as follows: focal
spots 29%; plaques 61%, consisting 27% of well-defined plaques
and 34% of poorly defined plaques; and combination lesions
8%, consisting of 3% of marginal spots, 4% of overlying spots,
and 1% of remote spots (Table 129.1).92 A follow-up study from
the same authors of patients with newly diagnosed unilateral
occult CNV secondary to AMD showed that the patients tended
to develop the same morphologic type of CNV in the fellow eye.93
Finally, Chang and associates94 reported on the clinicopatho-
logic correlation of AMD with CNV detected by ICG angio-
graphy. Histopathologic examination of the lesion revealed a
thick subretinal pigment epithelium CNV corresponding to the
plaquelike lesion seen with ICG angiography.
The studies just discussed demonstrate that ICG videoangio-
graphy is an important adjunctive study to fluorescein angiography
in the detection of CNV. Fluorescein angiography appears to be
more sensitive than ICG videoangiography in imaging fine capil-
laries that connect larger vessels and capillaries at the prolifer-
ating edge of well-defined CNV. Although fluorescein angiography
may image well-defined CNV better than ICG videoangio-
graphy in some cases, ICG videoangiography can convert occult
CNV by fluorescein angiography into well-defined classic CNV
eligible for ICG-guided laser treatment in ~30% of cases.95,96
Thus, the best imaging strategy to detect CNV is to perform
fluorescein angiography and ICG videoangiography.
1709
 RETINA AND VITREOUS

FIGURE 129.7. (a and b) Red-free

photography and the late phase of the
fluorescein angiogram of a poorly defined
choroidal neovascular membrane. (c–e) In the
ICG angiograms, the limits of the neovascular
membrane can be better visualized.
(f) Increased magnification shows some FVs.
(g and h) With computer analysis, the
membrane observed in the ICG angiogram can
be traced and superimposed on the fluorescein
angiogram. In some instances, ICG
angiography improves the definition of a
choroidal neovascular membrane.

a b
SECTION 10

c d

e f

g h

1710
 Indocyanine Green Videoangiography

a b c

FIGURE 129.8. (a) Clinical photograph of a patient with exudative macular detachment. (b) Fluorescein angiography shows occult CNV and a
serous PED. (c) ICG angiography study reveals a focal area, ‘hot spot’, of neovascularization at the superonasal edge of the serous PED.
(a–c) From Yannuzzi LA, Flower RW, Slakter JS: Indocyanine green angiography. St. Louis: Mosby-Year Book; 1997.

CHAPTER 129
a b c

FIGURE 129.9. (a) Clinical photograph of a patient with exudative macular detachment and subretinal hemorrhage. Note the presence of a
blood level in the PED. (b) Fluorescein angiography shows blockage of fluorescence by the subretinal hemorrhage. By fluorescein angiography,
there is probably occult CNV in the temporal macula. (c) ICG angiography of the same patient reveals a hot spot superior to the optic disk
corresponding to a polypoidal choroidal vasculopathy. No active CNV is visible in the macular area.
(a–c) From Yannuzzi LA, Flower RW, Slakter JS: Indocyanine green angiography. St. Louis: Mosby-Year Book; 1997.

FIGURE 129.10. (a) Clinical photograph of a

patient who underwent multiple laser
treatments for recurrent CNV. (b) Fluorescein
angiography shows a large area of staining in
the macula that may be interpreted as occult
CNV. (c) Mid-phase ICG study reveals a plaque
of CNV corresponding in morphology to the
area of staining on fluorescein angiography.
(d) Late-phase ICG study better shows the
plaque lesion.
(a–d) From Yannuzzi LA, Flower RW, Slakter JS:
Indocyanine green angiography. St. Louis: Mosby-Year
a b Book; 1997.

c d
1711
 RETINA AND VITREOUS

a b c

FIGURE 129.11. (a) Clinical photograph of a large serous PED surrounded by an exudative detachment of the neurosensory retina. (b) Mid-
phase ICG study demonstrates a focal spot at the margin of the PED. (c) Late-phase ICG study reveals the presence of a plaque of inactive CNV
that is not evident in the earlier phase of the study. This is an example of combination lesion: a hot spot at the margin of a plaque. As in this
case, many hot spots evidenced by ICG angiography may correspond to the variant neovascularization secondary to polypoidal choroidal
vasculopathy.
SECTION 10

(a–c) From Yannuzzi LA, Flower RW, Slakter JS: Indocyanine green angiography. St. Louis: Mosby-Year Book; 1997.

(37.5%) of 16 eyes.99 Importantly, these studies set the founda-

TABLE 129.1 Relative Frequency of Various Lesions Using
Indocyanine Green Angiography in Eyes With Occult Choroidal
tion for future prospective studies of ICG-guided laser treat-
Neovascularization ment. In addition, they proved that the presence of a PED is a
poor prognostic factor in the treatment of exudative AMD.
Lesion No. of Eyes (%) A recent study prospectively evaluated 185 consecutive eyes
Focal spots 283 (29) with exudative AMD and a well-delineated area (hot spot or focal
area) of hyperfluorescence by ICG angiography. All the patients
Plaques 597 (61) were divided into two groups (with PED and without PED). Of
Well-defined plaques 265 (27) the 185 eyes, 99 eyes without PED achieved a 71% rate of oblitera-
tion at 6 months and a 48% rate of obliteration at 12 months.
Poorly defined plaques 332 (34)
Eyes with PED did significantly worse, with an obliteration rate
Combination lesions 84 (8) of the CNV of 23% at 12 months. The overall success rate was
Marginal spots 35 (3) 36% at 12 months.96
A possible explanation for the high recurrence rate of occult
Overlying spots 37 (4) CNV after laser photocoagulation, particularly when a vascu-
Remote spots 12 (1) larized PED is present, may be found in the peculiar anatomy of
the CNV in such cases. It has been observed that there is a
Other lesions 20 (2)
variant of CNV where the neovascularization is fed both by a
Multiple spots 7 (1) choroidal and by a retinal component to create a retinochoroidal
Null 13 (1) anastomosis (RCA) (Figs 129.12 and 129.13) (JS Slakter, LA
Yannuzzi, U Schneider, et al, personal communication, 1998).100
From Guyer DR, Yannuzzi LA, Slakter JS, et al: Classification of choroidal
neovascularization by indocyanine green angiography. Ophthalmology 1996;
In a report by Kuhn and colleagues, RCAs were identified as
103:2054, 1996. occurring in 93% of patients with CNV associated with a serous
PED. They reported a poor success rate from laser treatment
as well.100
Slakter and co-workers followed prospectively 150 patients
with newly diagnosed exudative AMD (JS Slakter, LA Yannuzzi,
ICG-Guided Laser Treatment of CNV in AMD U Schneider, et al, personal communication, 1998). All had
Slakter and associates performed ICG-guided laser photocoagu- clinical and fluorescein angiographic evidence of occult CNV,
lation in 79 eyes with occult CNV.97 The occult CNV was suc- and each demonstrated focal areas of hyperfluorescence on ICG
cessfully eliminated with stabilized or improved visual acuity in angiography, believed to be representative of CNV. Thirty-one
29 (66%) of 44 eyes with occult CNV associated with neurosen- (21%) of the 150 eyes were found to have an RCA. In 82 eyes,
sory retinal elevations, and in 15 (43%) of 35 eyes with occult the occult CNV was associated with a serous PED. Twenty-two
CNV associated with PED. This study demonstrated that in (27%) of these patients were noted to have RCA. In the remain-
some cases, ICG videoangiography imaging can successfully ing 68 cases (occult CNV without serous PED), nine eyes (13%)
guide laser photocoagulation of occult CNV. were found to have an RCA. Associated clinical features of
In another pilot study of ICG-guided laser treatment of occult RCAs were identified in preretinal or intraretinal hemorrhages
CNV, Regillo and colleagues had similar results.98 at the site of the lesion, dilated tortuous retinal vessels, sudden
Guyer and co-workers reported on a pilot study of ICG- termination of a retinal vessel, and cystoid macular edema.
guided laser photocoagulation of 23 eyes that had untreatable The same authors found that the success rate of laser photo-
occult CNV secondary to AMD with focal spots at the edge of a coagulation of RCAs without serous PED was 66%, whereas with
plaque of neovascularization on the ICG study.99 ICG-guided serous PED it dropped to 14% (JS Slakter, LA Yannuzzi, U
laser photocoagulation was applied solely to the focal spot at the Schneider, et al, personal communication, 1998). Thus, the pres-
edge of the plaque. At 24 months of follow-up, anatomic success ence of an RCA may well provide a key to understanding the
1712 with resolution of the exudative findings was obtained in six poor outcome for laser treatment in this subgroup of patients.

a b
a b
c d
Sorenson and associates reported on ICG-guided laser treat-
ment of recurrent occult CNV secondary to AMD.101 Of 66 eyes
that entered in the study, only 29 (44%) were eligible for laser
treatment, and of these 29 eyes, 18 (62%) had anatomic success
with an average follow-up of 6 months. Interestingly, 56% of the
patients remained untreatable by ICG angiography guidance,
and even with treatment, 11 of 29 patients had incomplete
resolution or worsening of the exudative manifestations.
The spectrum of neovascular AMD expanded over the past
decade, and entities such as retinal angiomatous proliferation
(RAP) and polypoidal choroidal vasculopathy (PCV) emerged.102–107
After retina specialists became aware of these variants of neo-
vascular AMD, many of the previously described ‘hot spots’
appeared to be RAP or polypoidal lesions. That might explain
the variability in the response of ICG guided treated CNV, espe-
cially regarding the ‘hot spots’. Fernandes et al described the
nature of focal areas of hyperfluorescence or hot spots imaged
with ICG from a total of 190 patients (220 eyes) with exudative
ARMD. Thirty patients and 34 eyes (16%) with hot spots
Indocyanine Green Videoangiography
FIGURE 129.12. (a) Clinical photograph of a
patient with a serous PED and subretinal
hemorrhage. (b) High-magnification early-phase
ICG study reveals retina arterial and venous
branches connecting to the intraretinal
neovascularization of a retinal angiomatous
proliferation.
(a and b) From Yannuzzi LA, Flower RW, Slakter JS:
Indocyanine green angiography. St. Louis: Mosby-Year
Book; 1997:166.
CHAPTER 129
FIGURE 129.13. (a) Clinical photograph
demonstrates a serous PED and two focal
subretinal hemorrhages at the site of two RAPs.
(b) High-magnification red-free photograph
better shows two small retinal vessels that
appear to extend into each of intraretinal new
vessels. (c) Mid-phase ICG study reveals two
focal hot spots corresponding to the RAPs.
(d) Clinical photograph after laser treatment.
Note the persistence of an anastomotic red
blood vessel at the center of the white laser
burn.
(a–d) From Yannuzzi LA, Flower RW, Slakter JS:
Indocyanine green angiography. St. Louis: Mosby-Year
Book; 1997:166.
were identified. Hot spots were noted to be of three distinct
patterns: polypoidal choroidal neovascularization (polypoidal
CNV) in 21 of 34 eyes, or 62%; retinal angiomatous
proliferation (RAP) in 11 of 34 eyes, or 30%; and focal occult
CNV in two of 34 eyes, or 8%. The authors concluded that focal
area of intense hyperfluorescence or so-called hot spot seen
on ICG angiography in exudative ARMD was due to one of
three possible forms of neovascularization: most frequently
polypoidal CNV, less commonly RAP, and infrequently
nonspecific, focal occult CNV. 108
Central Serous Chorioretinopathy
ICG angiography of patients with central serous chorioretino-
pathy may show, in the early phase of the study, diffuse or
multifocal areas of choroidal hyperpermeability not associated
with abnormalities detectable by fluorescein angiography or
clinical examination (Fig. 129.14); in the late phase of the ICG
study, there is dispersion of the fluorescence and a distinctive
silhouetting of the larger choroidal vessels.47,127–129 1713
 RETINA AND VITREOUS
a b
FIGURE 129.14. (a) Fluorescein angiography of a patient with central serous chorioretinopathy demonstrates multifocal pinpoint areas of
leakage at the posterior pole. (b) Wide-angle ICG study reveals diffuse choroid hyperpermeability and scattered areas of hyperfluorescence.
SECTION 10
(c) Late-phase ICG study shows multifocal areas of leakage throughout the fundus.
Diabetic Retinopathy
The choroidal angiography findings of 60 patients with diabetic
retinopathy were reported by Bischoff and Flower.36 Most of the
patients with proliferative diabetic retinopathy showed irregular
and delayed choroidal filling. Approximately 50% of patients
with background diabetic retinopathy showed such changes.
Choroidal Tumors
Choroidal ICG absorption angiography and ICG fluorescence
angiography have been used to study choroidal
tumors.24,25,27,29,36,70,112–115 This technique can visualize the vas-
cularization and filling patterns of nonpigmented and lightly
pigmented tumors. The near-infrared light is absorbed by mela-
nin of heavily pigmented tumors, such as choroidal melanomas,
and thus blocks ICG fluorescence (Fig. 129.15). Nevertheless,
FIGURE 129.15. Late-phase ICG angiogram of a patient with a
juxtapapillary choroidal melanoma. No intratumoral vessels can be
noted because the heavy pigmentation of the tumor absorbs the
1714 near-infrared wavelengths.
c
the borders of the pigmented tumors may be better delineated
by ICG angiography than by fluorescein angiography, and there-
fore ICG angiography may serve as a more accurate tool for
assessment of tumor growth.24,25,36 Bischoff and Flower reported
that in some lightly pigmented tumors, ICG angiography was
able to resolve some of the larger vessels of the tumor with
staining of their walls and leakage into the mass.34
In contrast to pigmented choroidal melanomas, choroidal
hemangiomas show progressive hyperfluorescence because they
are composed of vascular channels29,112–114; thus, ICG angio-
graphy may be useful in distinguishing choroidal hemangiomas
from some choroidal melanomas. Choroidal metastasis originat-
ing from different primary tumors will show different angiographic
characteristics, depending on the vascularity and pigmentation
of the mass: Metastasis of breast carcinoma blocks choroidal
fluorescence,115 whereas metastasis of thyroid carcinoma70 and
metastatic bronchial carcinoid tumors115 are hyperfluorescent on
ICG angiography. However, intense late hyperfluorescence may
be more characteristically observed with choroidal hemangio-
mas than with choroidal metastasis.
Choroiditis
In patients with birdshot choroiditis, ICG angiography was found
to be superior to fluorescein angiography in defining the typical
patches. Multiple hypofluorescent lesions radiating to the peri-
phery are observed between the choroidal veins.115 These lesions
are consistent with choriocapillary dropout and sometimes are
more evident on later stages of the angiogram (Fig. 129.16). In
patients with serpiginous choroiditis, actively inflamed areas
within the lesion block choroidal fluorescence (Fig. 129.17).114
With resolution, the fluorescence of choroidal vessels can be
seen in the previously hypofluorescent areas. Late hyperfluor-
escence can be seen at sites at which CNV has evolved. Overt
leakage from choroidal vessels was observed on ICG angiography
in a patient with acute choroiditis.115 Complete clinical angio-
graphic resolution was noted after treatment.
Slakter and associates reported on the ICG angiography find-
ings in a series of 14 patients with multifocal choroiditis. Fourteen
(50%) of the 28 eyes were found to have large hypofluorescent
spots in the posterior pole on ICG angiography, which, in most
cases, did not correspond to clinically or fluorescein angiograph-
ically detectable lesions. In seven eyes exhibiting enlarged blind
spots on visual-field testing, ICG angiography showed confluent
hypofluorescence surrounding the optic nerve (Fig. 129.18).
The ICG angiogram was found useful in evaluating the natural

FIGURE 129.16. Multiple hypofluorescent lesions straddle the
choroidal veins in birdshot choroiditis.
course in two patients with multifocal choroiditis as well as a
response to oral prednisone therapy in four others. The ICG angio-
graphy performed in these patients showed changes correlating
with the clinical course. After administration of the oral pred-
nisone, the patients were noted to have decreased symptoms
and less vitreitis on clinical examination. The ICG angiography
a b
c d
Indocyanine Green Videoangiography
showed a reduction in the size and number of the hypofluor-
escent spots in three patients, with complete resolution of these
angiographic lesions noted in the fourth patient.116
Acute multifocal posterior placoid pigment epitheliopathy
(AMPPPE) lesions are hypofluorescent by ICG angiography in
both the early and the late phases of the study (Fig. 129.19).
The ICG choroidal hypofluorescence in this condition may be
due to a partial choroidal vascular occlusion secondary to
occlusive vasculitis.117,118
Multiple evanescent white dot syndrome presents with a
characteristic ICG angiography picture in the acute phase of the
disease (Fig. 129.20).119 Unlike the subtle white dots seen
clinically or the indistinct punctate hyperfluorescence seen with
fluorescein angiography, ICG angiography shows a pattern of
hypofluorescent spots throughout the posterior pole and periph-
eral retina. These hypofluorescent spots appear ~10 min after
the dye injection in the mid-ICG phase and persist throughout
the remainder of the study. These spots appear larger than the
CHAPTER 129
white dots seen clinically, varying in diameter from less than 50
to ~500 mm. Many more lesions can easily be identified on ICG
angiography than on fundus examination or fluorescein
angiography.
In a few cases, there is also a ring of hypofluorescence sur-
rounding the optic nerve. In these patients, a blind spot enlarge-
ment on visual-field examination is always present. The
resolution of the hypofluorescent ring around the optic nerve is
accompanied by a normalization of the visual field.
During the convalescent phase, there is resolution of the hypo-
fluorescent spots seen on ICG angiography with return of visual
function and normalization of the clinical examination.
Digital ICG videoangiography is thus valuable in the diagnosis
and monitoring of patients with choroiditis. Further investigation
is warranted in this area.
FIGURE 129.17. (a and b) Late-phase
fluorescein angiograms of an eye with a
recurrence of serpiginous choroidopathy.
(c and d) Late-phase ICG angiograms show
marked hypofluorescence in the areas of active
inflammation.
1715
 RETINA AND VITREOUS
a b
FIGURE 129.18. (a) Fluorescein angiography of a patient with multifocal choroiditis. Note the presence of an atrophic ring around the optic disk.
(b) Late-phase ICG angiography reveals the presence of multifocal hyperfluorescent lesions that do not have a clinical or fluorescein angiography
correspondence. (c) Wide-angle ICG shows scattered hypofluorescent spots around the optic disk and around the superotemporal vortex vein.
SECTION 10
Polypoidal Choroidal Vasculopathy
ICG angiography has been used to detect and characterize the
abnormality of polypoidal choroidal vasculopathy with enhanced
sensitivity and specificity.120–122 In the initial phases of the ICG
study, a distinct network of vessels within the choroid becomes
visible.
Early in the course of the ICG study, the larger vessels of the
polypoidal choroidal vasculopathy network start to fill before the
retinal vessels, but the area within and surrounding the network
is relatively hypofluorescent compared with the uninvolved
choroid. Shortly after the network can be identified on the ICG
angiogram, small hyperfluorescent ‘polyps’ become visible
within the choroid.
a b
c d
1716
c
These polypoidal structures correspond to the reddish orange
choroidal excrescence seen on clinical examination. In the later
phase of the angiogram, there is a uniform disappearance of the
dye (‘washout’) from the bulging polypoidal lesions. The late
ICG staining characteristic of occult CNV is not seen in the
polypoidal choroidal vasculopathy vascular abnormality.
Retinal Angiomatous Proliferation
ICG angiography is useful in determining the characteristics of
the variant of exudative AMD, retinal angiomatous proliferation,
better than fluorescein angiography.102–107 At stage I, the neo-
vascularization appears as a focal area of usually very intense
hyperfluorescence (hot spot). There is also some late extension
FIGURE 129.19. (a) Clinical photograph of a
patient with acute multifocal posterior placoid
pigment epitheliopathy demonstrates the pale,
flat, and the placoid lesions involving the
pigment epithelium. (b) Late-phase fluorescein
angiography demonstrates the optic nerve
staining and mottled hyperfluorescence at the
periphery of the lesion. (c) Early-phase ICG
study shows uniform hypofluorescence of the
lesion. (d) Late-phase ICG study demonstrates
a well-demarcated hypofluorescent lesion.
(a–d) From Yannuzzi LA, Flower RW, Slakter JS:
Indocyanine green angiography. St. Louis: Mosby-Year
Book; 1997:242.
 Indocyanine Green Videoangiography

a b c

CHAPTER 129
d e f

g h i

FIGURE 129.20. (a) Color photograph of a patient with acute onset of multiple evanescent white
dot syndrome. Only a few yellowish spots are visible temporally. (b) The spots are better seen
with a red-free light. (c) Mid-phase fluorescein angiography demonstrates a few hyperfluorescent
spots and staining of the disk margin. (d) Late-phase fluorescein angiography shows marked
staining of the optic nerve. (e) Late-phase ICG study shows a hypofluorescent ring around the
optic nerve. (f and g) There is also evidence of multiple hypofluorescent spots at the posterior
pole and in the mid-periphery. (h) Goldmann visual field demonstrates an enlarged blind spot.
(i) Late-phase ICG study 4 months later demonstrates resolution of the hypofluorescent ring
around the optic nerve. (j) Goldmann visual field of the same day shows resolution of the
enlarged blind spot.
(a–j) From Yannuzzi LA, Slakter JS, Flower R: Indocyanine green angiography. St. Louis: Mosby-Year Book; 1997.

1717
 RETINA AND VITREOUS
of leakage within the retina from the intraretinal neovasculari-
zation (IRN) which is quite characteristic for RAP. In some
cases, a retinal–retinal anastomosis can be visualized. In stage II,
the ICG angiogram, besides the hot spot of the IRN, reveals a
serous PED that remains hypofluorescent. In stage III, ICG angio-
graphy differentiates the serous component of the PED that
remains dark, from the vascularized component which becomes
hyperfluorescent. At this stage, ICG angiography may sometimes
reveal RCA.
OTHER CONDITIONS
Choroidal involvement in the presumed ocular histoplasmosis
syndrome has been described with ICG angiography.31,36
Bischoff and Flower reported no significant abnormality in ICG
angiograms of patients with Best’s disease.36 In these eyes, it is
our experience that a hypofluorescent lesion in the macula can
be found, which most likely corresponds to a blocking effect of
SECTION 10
the abnormal material, although choroidal nonperfusion at that
area cannot be ruled out.
Reduced filling of the choriocapillaris in cases of myopia has
been noted with ICG angiography.36 ICG angiography is also
particularly useful in patients with mild vitreous hemorrhage,
which prevents evaluation by fluorescein angiography.36
CHOROIDAL BLOOD FLOW STUDIES
ICG angiography has also been used to investigate ocular hemo-
dynamics. This technique is enhanced by the low affinity of ICG
to ocular tissue structures as shown with 123I ICG measure-
ments.76 Flower, Bischoff, Prünte and their associates41–44 have
used choroidal filling times to assess the velocity of the choroidal
circulation with some success. These techniques have yet to
demonstrate clinical usefulness. In 1979, Ernest and Goldstick
estimated choroidal blood flow in monkeys by determining the
rate of clearance of ICG from the choroidal circulation.117 Several
authors have attempted to quantify morphologic and dynamic
parameters in the choroidal circulation. Quantification of effec-
tive nutrient choroidal blood flow is difficult, however. Fluor-
escence is a superficial phenomenon. It is not proportional to
the quantity of dye in the blood vessel,79,124 and it depends on
multiple variables such as vessel size, the cardiovascular system,
and the injection technique.125
FEEDER VESSEL TREATMENT OF
CHOROIDAL NEOVASCULARIZATION
Photocoagulation of the feeder vessels (FVs) has been investigated
for the treatment of the CNV, especially when the neovascular
membranes are under the fovea in which direct treatment with
laser would cause a large and irreversible scotoma. Before the
availability of antiangiogenic therapy, many cases of subfoveal
CNV had a poor visual prognosis, both with laser photocoa-
gulation and with photodynamic therapy, due to the size or
angiographic subtype of the lesion.
Feeder vessel treatment (FVT) is an attractive combination
since it is not drug-based and acts directly on the source of CNV
blood flow, rather than the membrane itself.126 The rationale of
treatment of the FVs of the choroidal neovascular membranes
arose from the initial concept of laser photocoagulation of the
FVs in diabetic retinopathy.109
Early attempts of FVT failed due to lack of optimal technology
in the imaging of the fundus as well as in delivery of laser with
precision.126 New equipment in the late 1990s demonstrated
the feasibility of FVT of subfoveal and juxtafoveal CNV with
efficacy.110,111,130
1718
Shiraga et al110 and Staurenghi et al111 reported improved or
stabilized visual acuity between 70% and 75% of the cases
following FV photocoagulation. In many cases, the resolution of
CNV and associated edema resolved dramatically and within
hours of the FVT.
FVT is a two-step process, including identification and location
of FVs with high-speed ICG angiography, and FV photocoagu-
lation delivery of laser energy through a slit-lamp delivery sys-
tem. It is necessary, therefore, to transfer information regarding
FV location from the ICG image of the angiograms to the slit-
lamp view of the fundus of the eye to be treated. Since the
landmarks between the angiograms and the fundus are different,
their reinterpretation is needed, with potential minor deviations
and thus lack of precision. This may result in a larger area being
treated than really necessary, which limits how close the treat-
ment can be applied to the fovea.
The main advantages of FVT are: (1) Even when the CNV is
large only a small fundus area is photocoagulated; (2) the photo-
coagulation is away from the CNV, thus sparing the fovea and
the presumably damaged RPE associated with the CNV; (3)
there are no adverse events due to the laser burn even after
multiple laser treatments; (4) there are no untoward side effects
to the treatment, even when administered multiple times; and
(5) the worst adverse event reported to date is failure of treat-
ment, in which case other treatments can be applied. FVT does
not cause irreversible damage or adverse events that might
impede other therapies.126 The main disadvantages are: (1) the
difficulty in precisely aiming the laser beam to the FV since the
location needs be transferred from the angiogram to the fundus
view; (2) reopening of the successfully treated FVs; (3) damage
to the overlying RPE producing a paracentral scotoma that can
be seen bt the patient; (4) changes in fundus pigmentation
may cause a large variability in the efficiency of the photocoa-
gulation; and (5) limitations in getting the treatment close to
the fovea.126
Characterizing and defining FVs is not an easy task; the same
can be stated about understanding the angiographic–anatomic
correlation, epecially when often the anatomic and functional
relationships are also difficult to interpret. To solve this problem
Flower proposed a theoretical anthropomorphic model of the CNV
and the FVs.130 The model implies that FVs are not the small
abnormal capillary-like vessels that arise from the choriocapil-
laris and feed directly the CNV, but vessels of the inner layer of
medium-sized choroidal arterioles and venules that supply the
region of the choriocapillaris that feeds the CNV. Thus, it is not
necessary that there is a direct anatomic connection between the
FVs identified in the ICG angiogram and the CNV. The close
proximity of these FVs in the inner layer of the medium-sized
choroidal arterioles and the associated CNV vessel penetrating
Bruch’s membrane may result in the FV and CNV appearing to
be contiguous in an ICG angiogram image. In the model system,
the choriocapillaris acts like a relief valve inserted in the afferent
vessel pathway, proximal to the CNV membrane.
In some classic lesions, the capillary-like segments connect-
ing the CNV to the choriocapillaris (i.e., the penetrating vessels)
actually can be long enough to be detectable as FVs in angiogram
images and, therefore, directly treatable by photocoagulation,
instead of photocoagulating the associated Sattler’s layer vessel
as in the case of occult CNV lesions (Fig. 129.21).
Since the submacular choriocapillaris is a true vascular plexus,
based on available histologic and hemodynamic data, a more
sophisticated model was developed to simulate changes in blood
flow through larger choriocapillaris areas after FV photocoagu-
lation.131 This model can explain why partial closure of the FV
is enough to reduce the blood flow through the CNV achieving
its functional closure. If reduced choriocapillaris blood flow is a
 Indocyanine Green Videoangiography

a b

CHAPTER 129
c d

FIGURE 129.21. Treatment of a ‘mixed’ CNV lesion. (a) Pretreatment angiogram. (b) The penetrating vessel (yellow arrow) leading to the
‘classic’ component was photocoagulated, resulting in closure of only the ‘classic’ component, as demonstrated on subsequent ICGA. (c) About
2 weeks later, the photocoagulated penetrating vessel reopened. Rather than re-treating the penetrating vessel, the FV (green arrow) that
supplied blood to both the ‘classic’ and ‘occult’ components was photocoagulated. (d) Subsequent ICGA showed that both lesion components
had been closed, demonstrating that closure of the Sattler’s layer FV supplying blood to the area of choriocapillaris (CC) from which the lesion’s
penetrating vessels originated resulted in stopping blood flow through both CNV components. The mixed lesion is shown schematically in the
cartoon to the left of the angiogram images showing the penetrating vessels in yellow and the FVs in green.
(a–d) From Flower RW, Staurenghi G: Trataminento de los vasos nutrícios de la neovascularización coroidea. In: Monés J, Gómez Ulla, eds. Degeneración Macular
Asociada a la Edad. Barcelona: Prous Science; 2005.

hemodynamic mechanism of successful CNV treatment, the end-
point of any modality of laser treatment is not total obliteration
of the CNV, which may result frequently in recurrence, but
reduction of the CNV blood flow.131,132
Dye-enhanced photocoagulation of FVs using ICG had been
demonstrated in animal studies,130 and in human eyes.133 In prev-
ious studies, dye-enhanced photocoagulation with ICG con-
sisted of intravenous injection of large amounts of ICG dye in
order to accumulate the dye in the CNV and thus theoretically
enhancing the uptake of laser energy during confluent
photocoagulation.134,135
Flower has described a technique by which FV can be identified
and treated at the same time with ICG dye-enhanced photo-
coagulation with an adapted fundus camera that can deliver a
diode laser beam.136,137 With this modality, the laser burns can
be more accurately placed and it is possible to get closer to the
fovea. On the other hand, the thermal energy is more selectively
confined in the vessel, making its closure more efficient and
thus avoiding unnecessary thermal energy absorption by the
surrounding tissues (Fig. 129.22). Immediately following FV
closure, the presence of incarcerated ICG dye in the vessel
adjacent to the burn proves that the blood flow has stooped in
the treated vessel. (Fig. 129.23)
Compared to some of the current treatments for CNV, FVT
has some advantages for the patient, if ICG is not contra-
indicated: it is minimally invasive, safe, inexpensive, has no
cumulative effect, and its failure does not preclude use of other
therapies since it does not leave an irreversible damage. These
attributes make FVT another attractive first-line option to treat
exudative AMD.126
1719
 RETINA AND VITREOUS

FIGURE 129.22. The effects of FVT by

conventional photocoagulation compared to
ICG-dye enhanced photocoagulation (ICG-
DEP). The cartoons suggest the differences in
location for the epicenter of light to heat
transduction and the volume of fundus tissue
involved in the two methods of
photocoagulation. With ICG-DEP the tissue
volume in which transduction takes place is
shifted away from the RPE to the target vessel,
and it becomes more focused, thereby
reducing the volume of surrounding tissue
damaged. The left-hand image is from a late
phase ICGA of an eye in which FVT was by
conventional photocoagulation; the thermal
damage was great enough that the nerve fiber
layers overlying the laser spot were sufficiently
damaged to produce a scotoma, and the
associated dark arcuate area presumably was
due to atrophic nerve fibers. The right-hand
SECTION 10

image is from a posttreatment ICGA that

demonstrates an additional advantage to ICG-
DEP, namely that immediately following
successful FV closure, incarcerated ICG dye
often can be detected at the laser burn site,
which provides immediate proof that blood flow
in the target vessel had stopped.
From Flower RW, Staurenghi G: Trataminento de los
vasos nutrícios de la neovascularización coroidea. In:
Monés J, Gómez Ulla, eds. Degeneración Macular
Asociada a la Edad. Barcelona: Prous Science; 2005.

FIGURE 129.23. Results of ICG-DEP FVT of a

classic CNV. The circles indicate the location of
the CNV area in each ICGA image, and the
arrow in the pretreatment image identifies the
FV. In this case, immediately posttreatment,
ICG-stained blood was incarcerated in the CNV
as well as in the short FV segment distal to the
photocoagulation site. Shortly thereafter, a
posttreatment angiogram demonstrated no
filling of the CNV’s FV, although fluorescence
from the dye-stained blood incarcerated in the
CNV persisted – less intensely, however, than in
the immediate posttreatment angiogram.
Subsequent angiograms demonstrated that
blood flow to the CNV had been successfully
stopped by the treatment.
From Flower RW, Staurenghi G: Trataminento de los
vasos nutrícios de la neovascularización coroidea. In:
Monés J, Gómez Ulla, eds. Degeneración Macular
Asociada a la Edad. Barcelona: Prous Science; 2005.

1720

REFERENCES
1. MacLean AL, Maumenee AE: Hemangioma
of the choroid. Trans Am Ophthalmol Soc
1959; 57:171.
2. Novotny HR, Alvis DL: A method of
photographing fluorescence in circulating
blood of the human eye. Am J Ophthalmol
1960; 50:176.
3. Maumenee AE: Fluorescein angiography in
the diagnosis and treatment of lesions of
the ocular fundus. (The 1968 Doyne
Lecture.) Trans Ophthalmol Soc UK 1968;
88:529.
4. Hyvärinen L, Maumenee AE, George T,
et al: Fluorescein angiography of the
choriocapillaris. Am J Ophthalmol 1969;
67:653.
5. Archer D, Krill AF, Newell FW: Fluorescein
studies of normal choroidal circulation. Am
J Ophthalmol 1970; 69:543.
6. Archer DB, Krill AE, Ernest JT: Choroidal
vascular aspects of degenerations of the
retinal pigment epithelium. Trans
Ophthalmol Soc UK 1972; 92:187.
7. Wald G: The photochemistry of vision. Doc
Ophthalmol 1949; 3:94.
8. Geeraets WJ, Williams RC, Chang G, et al:
The loss of light energy in retina and
choroid. Arch Ophthalmol 1960; 64:606.
9. Behrendt T, Wilson LA: Spectral reflectance
photography of the retina. Am J
Ophthalmol 1965; 59:1079.
10. Geeraets WJ, Berry ER: Ocular spectral
characteristics as related to hazards from
lasers and other light sources. Am J
Ophthalmol 1968; 66:15.
11. Bloome MA: Fluorescein angiography:
risks. Vision Res 1980; 20:1083.
12. Flower RW: Choroidal angiography using
indocyanine green: a review and progress
report. Opthalmol Dig 1974; 36:18.
13. Ring HG, Fujino T: Observations on the
anatomy and pathology of the choroidal
vasculature. Arch Ophthalmol 1967;
78:431.
14. Friedman E, Kopald HH, Smith TR, et al:
Retinal and choroidal blood flow
determined with krypton-85 anesthetized
animals. Invest Ophthalmol 1964; 3:539.
15. Kogure K, Choromokos E: Infrared
absorption angiography. J Appl Physiol
1969; 26:154.
16. Collela ME, Pilkerton AR: Determination of
choroidal blood flow in man. Invest
Ophthalmol 1969; 8:460.
17. Kogure K, David NJ, Yamanouchi U, et al:
Infrared absorption angiography of the
fundus circulation. Arch Ophthalmol 1970;
83:209.
18. David NJ: Infrared absorption fundus
angiography. In: Proceedings international
symposium fluorescein angiography, Albi
1969. Basel: Karger; 1971:189.
19. Hochheimer BF: Angiography of the retina
with indocyanine green. Arch Ophthalmol
1971; 86:564.
20. Flower RW, Hochheimer BF: Clinical
infrared absorption angiography of the
choroid. Am J Ophthalmol 1972; 73:458.
21. Flower RW: Infrared absorption
angiography of the choroid and some
observations on the effects of high
intraocular pressures. Am J Ophthalmol
1972; 74:600.
22. Brown N, Strong R: Infrared fundus
angiography. Br J Ophthalmol 1973; 57:797.
Indocyanine Green Videoangiography
23. Flower RW, Hochheimer BF: A clinical
technique and apparatus for simultaneous
angiography of the separate retinal and
choroidal circulations. Invest Ophthalmol
1973; 12:248.
24. Patz A, Flower RW, Klein ML, et al: Clinical
application of indocyanine green
angiography. Doc Ophthalmol Proc Ser
1976; 9:245.
25. Orth DH, Patz A, Flower RW: Potential
clinical applications of indocyanine green
choroidal angiography. Preliminary report.
Eye Ear Nose Throat Monthly 1976; 55:15.
26. Craandijk A, Van Beek CA: Indocyanine
green fluorescence angiography of the
choroid. Br J Ophthalmol 1976; 60:377.
27. Chopdar A, Turk AM, Hill DW: Fluorescent
infra-red angiography of the fundus oculi
using indocyanine green dye. Trans
Ophthalmol Soc UK 1978; 98:142.
28. Forsius H, Hyvärinen L, Nieminen H, et al:
Fluorescein and indocyanine green
fluorescence angiography in study of
affected males and in female carriers with
choroideremia. A preliminary report. Acta
Ophthalmol 1977; 55:459.
29. Bonnet M, Habozit F, Magnard G: Valeur de
l’angiographie en infra-rouge au vert
d’indocyanine dans le diagnostic clinique
des angiomes de la choroide. Bull Soc
Ophthalmol Fr 1976; 76:713.
30. Bacin F, Buffet JM: Un diagnostic
difficile: L’angiome choroidien isole.
J Fr Ophthalmol 1978; 1:197.
31. Saari M: Disciform detachment of the
macula. II. Fluorescein and indocyanine
green fluorescence angiographic findings in
juvenile haemorrhagic macular
choroidopathy. Acta Opthalmol 1977;
55:530.
32. Flower RW: Simple adaptors for fast
conversion of a fundus camera for rapid-
sequence ICG fluorescence choroidal
angiography. J Biol Photogr Assoc 1977;
45:43.
33. Flower RW: Choroidal fluorescent dye filling
patterns. A comparison of high-speed
indocyanine green and fluorescein
angiograms. Int Ophthalmol 1980; 2:143.
34. Hayashi K, Nakase Y, Nishiyama A, et al:
Indocyanine green fluorescence
angiography, report 2: studies of new
interference filters. Acta Soc Ophthalmol
Jpn 1982; 86:1532.
35. Hyvärinen L, Flower RW: Indocyanine green
fluorescence angiography. Acta Ophthalmol
1980; 58:528.
36. Bischoff PM, Flower RW: Ten years’
experience with choroidal angiography
using indocyanine green dye: a new routine
examination or an epilogue? Doc
Ophthalmol 1985; 60:235.
37. Hayashi K, Hasegawa Y, Tokoro T:
Indocyanine green angiography of central
serous chorioretinopathy. Int Ophthalmol
1986; 9:37.
38. Hayashi K, Hasegawa Y, Tokoro T, et al:
Value of indocyanine green angiography in
the diagnosis of occult choroidal
neovascular membrane. Jpn J Clin
Ophthalmol 1988; 42:827.
39. Destro M, Puliafito CA: Indocyanine green
videoangiography of choroidal
neovascularization. Ophthalmology 1989;
96:846.
40. Hayashi K, Hasegawa Y, Tazawa Y, et al:
Clinical application of indocyanine
angiography to choroidal
neovascularization. Jpn J Ophthalmol
1989; 33:57.
41. Prünte P, Niesel P: Quantification of
choroidal blood-flow parameters using
indocyanine green video-fluorescence
angiography and statistical picture analysis.
Ophthalmologica 1988; 226:55.
42. Bischoff P: Quantitative Untersuchung der
normalen Aderhautzirkulation. Fortschr
Ophthalmol 1989; 86:107.
43. Flower RW, Klein GJ: Pulsatile flow in the
choroidal circulation: a preliminary
investigation. Eye 1990; 4:310.
44. Klein GJ, Baumgartner R, Flower RW:
An image processing approach to
CHAPTER 129
characterizing choroidal blood flow.
Invest Ophthalmol Vis Sci 1990; 31:629.
45. Scheider A, Schroedel C: High resolution
indocyanine green angiography with
scanning laser ophthalmoscope.
Am J Ophthalmol 1989; 108:458.
46. Scheider A, Kaboth A, Neuhauser L:
Detection of subretinal neovascular
membranes with indocyanine green and
infrared scanning laser ophthalmoscope.
Am J Ophthalmol 1992; 113:45.
47. Guyer DR, Puliafito CA, Monés JM, et al:
Indocyanine-green digital angiography and
choroidal neovascularization.
Ophthalmology 1992; 92:287.
48. Yannuzzi LA, Slakter JS, Sorenson J, et al:
Digital indocyanine green videoangiography
and choroidal neovascularization. Retina
1992; 12:191.
49. Spaide RF, Orlock DA, Herrmann-
Delamazure B, et al: Wide-angle
indocyanine green angiography. Retina
1998; 18:44.
50. Spaide RF, Orlock DA, Yannuzzi LA, et al:
Digital subtraction indocyanine green
angiography of occult choroidal
neovascularization. Ophthalmology 1998;
105:680.
51. Fox IJ, Wodd EH: Applications of dilution
curves recorded from the right side of the
heart or venous circulation with the aid of a
new indicator dye. Proc Mayo Clin 1957;
32:541.
52. Paumgartner G: The handling of
indocyanine green by the liver. Schweiz
Med Wochenschr 1975; 105(17 Suppl):1.
53. Cherrick GR, Stein SW, Leevy CM, et al:
Indocyanine green: observations on its
physical properties, plasma decay, and
hepatic extraction. J Clin Invest 1960;
39:592.
54. Baker KJ: Binding of sulfobromophthalein
(BSP) sodium and indocyanine green (ICG)
by plasma a1-lipoproteins. Proc Soc Exp
Biol Med 1966; 122:957.
55. Leevy CM, Bender J, Silverberg M, et al:
Physiology of dye extraction by the liver:
comparative studies of
sulfobromophthalein and indocyanine
green. Ann N Y Acad Sci 1963; 111:161.
56. Goresky CA: Initial distribution and rate of
uptake of sulfobromophthalein in the liver.
Am J Physiol 1964; 207:13.
57. Wheeler HO, Cranston WI, Mettzer JI:
Hepatic uptake and biliary excretion of
indocyanine green in the dog. Proc Soc
Exp Biol Med 1958; 99:11.
1721
 RETINA AND VITREOUS
58. Ketterer SG, Wiegand BD: Hepatic
clearance of indocyanine green. Clin Res
1959; 7:289.
59. Ketterer SG, Wiegand BD: The excretion of
indocyanine green and its use in the
estimation of hepatic blood flow. Clin Res
1959; 7:71.
60. Probst P, Paumgartner G, Caucig H, et al:
Studies on clearance and placental transfer
of indocyanine green during labor. Clin
Chim Acta 1970; 29:157.
61. Fox IJ, Wodd EH: Indocyanine green:
physical and physiologic properties. Mayo
Clin Proc 1960; 35:732.
62. Warner GS: Laboratory animal toxicity
studies on cardiogreen. Documentation of
Hynson. Baltimore: Wescott & Dunning; 1971.
63. Tokoro T, Hayashi K, Muto M, et al: Studies
on choroidal circulation. Report I:
fundamental studies on the infrared
absorption angiography. Jpn J Ophthalmol
SECTION 10
1976; 30:173.
64. Lutty GA: The acute intravenous toxicity of
biological stains, dyes, and other
fluorescent substances. Toxicol Appl
Pharmacol 1978; 44:225.
65. Lutty GA: An intraperitoneal survey of
biological stains, dyes, and other
fluorescent substances. Bull Nippon
Kanhoh-Shihiso Kenkyusho 1979; 50:25.
66. Leevy CM, Smith F, Kierman T: Liver
function test. In: Bochus HL, ed.
Gastroenterology. 3rd edn. Philadelphia:
WB Saunders; 1976:68.
67. Shabetai R, Adolph RJ: Principles of
cardiac catheterization. In: Fowler NO, ed.
Cardiac diagnosis and treatment. 3rd edn.
Hagerstown, MD: Harper & Row; 1980:117.
68. Carski TR, Staller BJ, Hepner G: Adverse
reactions after administration of
indocyanine green. JAMA 1978; 240:635.
69. Iseki K, Onoyama K, Fujimi S: Shock
caused by indocyanine green dye in
chronic hemodialysis patients. [Letter] Clin
Nephrol 1980; 14:210.
70. Bacin F, Buffet JM, Mutel N: Angiographie
par absorption, en infrarouge, au vert
d’indocyanine. Aspects chez le sujet
normal et dans les tumeurs choroidiennes.
Bull Soc Ophthalmol Fr 1981; 81:315.
71. Hope-Ross M, Yannuzzi LA, Gragoudas
ES, et al: Adverse reactions due to
indocyanine green. Ophthalmology 1994;
101:529.
72. Flower RW: High-speed human choroidal
angiography using indocyanine green dye
and a continuous light source. Doc
Ophthalmol Proc Ser 1976; 9:59.
73. Flower RW, Hochheimer BF: Indocyanine
green dye fluorescence and infrared
absorption choroidal angiography
performed simultaneously with fluorescein
angiography. Johns Hopkins Med J 1976;
138:33.
74. Benson RC, Kues HA: Fluorescence
properties of indocyanine green as related
to angiography. Phys Med Biol 1978;
23:159.
75. Puliafito CA, Destro M, To K, et al: Dye
enhanced photocoagulation of choroidal
neovascularization. ARVO abstracts. Invest
Ophthalmol Vis Sci 1988; 29(Suppl):414.
76. Bill A: Capillary permeability to and
extravascular dynamics of myoglobin,
albumin and gammaglobulin in the uvea.
Acta Physiol Scand 1968; 73:204.
77. Ketterer SG, Wiegard BD, Rapaport E:
1722 Hepatic uptake and biliary excretion of
indocyanine green and its use in estimation
of hepatic blood flow in dogs. Am J Physiol
1960; 199:481.
78. Ansari A, Lambrecht RM, Packer S, et al:
Note on the distribution of iodine
123-labeled indocyanine green in the eye.
XVIII. Invest Ophthalmol 1975; 14:780.
79. Flower RW: Injection technique for
indocyanine green and sodium fluorescein
dye angiography of the eye. Invest
Ophthalmol 1973; 12:881.
80. American National Standards Institute
(ANSI): Safe use of lasers, Standard
Z-136.1. New York: ANSI; 1976.
81. Shimizu K, Ujiie K, eds: The structure of
the ocular vessels. Tokyo, New York:
Ikagu-Shoin; 1978:51.
82. Bischoff PM, Speiser P: Angiographic
study of the vortex vein circulation. Graefes
Arch Clin Exp Ophthalmol 1986; 224:122.
83. Potts AM: An hypothesis on macular
disease. Trans Am Acad Ophthalmol
Otolaryngol 1966; 70:1058.
84. Bischoff PM, Flower RW: High blood
pressure in choroidal arteries as a possible
pathogenetic mechanism in senile macular
degeneration. [Letter] Am J Ophthalmol
1983; 96:398.
85. Green WR, Key SN: Senile macular
degeneration. A histopathological study.
Trans Am Ophthalmol Soc 1977; 75:180.
86. Garner A: Vascular disorders. In: Garner A,
Klintworth GK, eds. Pathobiology of ocular
disease, part B. New York: Dekker;
1982:1479.
87. Hayreh SS: Recent advances in fluorescein
fundus angiography. Br J Ophthalmol 1974;
58:391.
88. Hayashi K, de Laey JJ: Indocyanine green
angiography of choroidal neovascular
membranes. Ophthalmologica 1985;
190:30.
89. François P, Turut P, Delannoy C:
L’angiofluorographie choroidienne a
l’indocyanine. Bull Soc Ophthalmol Fr
1977; 77:971.
90. Yannuzzi LA, Hope-Ross M, Slakter JS,
et al: Analysis of vascularized pigment
epithelium detachments using indocyanine
green videoangiography. Retina 1994;
14:99.
91. Guyer DR, Yannuzzi LA, Slakter JS, et al:
Digital indocyanine-green
videoangiography of occult choroidal
neovascularization. Ophthalmology 1994;
101:1727.
92. Guyer DR, Yannuzzi LA, Slakter JS, et al:
Classification of choroidal
neovascularization by digital indocyanine
green videoangiography. Ophthalmology
1996; 103:2054.
93. Chang B, Yannuzzi LA, Ladas ID, et al:
Choroidal neovascularization in second
eyes of patients with unilateral exudative
age-related macular degeneration.
Ophthalmology 1995; 102:1380.
94. Chang TS, Freund KB, de la Cruz Z, et al:
Clinicopathologic correlation of choroidal
neovascularization demonstrated by
indocyanine green angiography in a patient
with retention of good vision for almost four
years. Retina 1994; 14:114.
95. Guyer DR, Yannuzzi LA, Ladas ID, et al:
Indocyanine green guided laser
photocoagulation of focal spots at the
edge of plaques of choroidal
neovascularization: a pilot study. Arch
Ophthalmol 1996; 114:693.
96. Schwartz SG, Guyer DR, Yannuzzi LA, et al:
Indocyanine green videoangiography
guided laser photocoagulation of primary
occult choroidal neovascularization in
age-related macular degeneration. Invest
Ophthalmol Vis Sci 1995; 36:186.
97. Slakter JS, Yannuzzi LA, Sorenson JA,
et al: A pilot study of indocyanine green
videoangiography-guided laser
photocoagulation of occult choroidal
neovascularization in age-related macular
degeneration. Arch Ophthalmol 1994;
112:465.
98. Regillo SD, Benson WE, Maguire JI, et al:
Indocyanine green angiography and occult
choroidal neovascularization.
Ophthalmology 1994; 101:280.
99. Guyer DR, Yannuzzi LA, Ladas ID, et al:
Indocyanine green-guided laser
photocoagulation of focal spots at the
edge of plaques of choroidal
neovascularization. Arch Ophthalmol 1996;
114:693.
100. Kuhn D, Meunier I, Soubrane G, Coca G:
Imaging of chorioretinal anastomoses in
vascularized retinal pigment epithelium
detachments. Arch Ophthalmol 1995;
113:1392.
101. Sorenson JA, Yannuzzi LA, Slakter JS,
et al: A pilot study of digital indocyanine
green videoangiography for recurrent
occult choroidal neovascularization in
age-related macular degeneration. Arch
Ophthalmol 1994; 112:473.
102. Hartnett ME, Weiter JJ, Gardts A, Jalkh AE:
Classification of retinal pigment epithelial
detachments associated with drusen.
Graefes Arch Clin Exp Ophthalmol 1992;
230:11–19.
103. Yannuzzi LA, Negrao S, Iida T, et al: Retinal
angiomatous proliferation in age-related
macular degeneration. Retina 2001;
21:416–434.
104. Kuhn D, Meunier I, Soubrane G, Coscas G:
Imaging of chorioretinal anastomoses in
vascularized retinal pigment epithelium
detachments. Arch Ophthalmol 1995;
113:1392–1398.
105. Hartnett ME, Weiter JJ, Staurenghi G,
Elsner AE: Deep retinal vascular anomalous
complexes in advanced age-related
macular degeneration. Ophthalmology
1996; 103:2042–2053.
106. Slakter JS, Yannuzzi LA, Schneider U, et al:
Retinal choroidal anastomoses and occult
choroidal neovascularization in age-related
macular degeneration. Ophthalmology
2000; 107:742–754.
107. Lafaut BA, Aisenbrey S, Broecke CV,
Bartz-Schmidt KU: Clinicopathological
correlation of deep retinal vascular
anomalous complex in age-related macular
degeneration. Br J Ophthalmol 2000;
84:1269–1274.
108. Fernandes LH, Freund KB, Yannuzzi LA,
et al: The nature of focal areas of
hyperfluorescence or hot spots imaged
with indocyanine green angiography. Retina
2002; 22:557–568
109. Behrendt T: Therapeutic vascular
occlusions in diabetic retinopathy. Arch
Ophthal. 1972; 87:629–633.
110. Shariga F, Ojima Y, Matsuo T, et al:
Feeder vessel photocoagulation of
subfoveal choroidal neovascularization
secondary to age-related macular
degeneration. Ophthalmology 1998;
105:662–669.

111. Staurenghi G, Orzalesi N, La Capria A,
Aschero M: Laser treatment of feeder
vessels in subfoveal choroidal neovascular
membranes: a revisitation using dynamic
indocyanine green angiography.
Ophthalmology 1998; 105:2297–2305.
112. Bonnet M, Francoz-Taillanter N:
Hemangiomes caverneux de la choroide
(revue clinique de 10 cas). Bull Soc
Ophthalmol Fr 1981; 81:455.
113. Quentel G, Coscas G: Angiographie en
fluorescence infrarouge au vert
d’indocyanine. Bull Soc Ophthalmol Fr
1984; 84:559.
114. Bischoff P: Badeutung der
Infrarotangiographie fur die
Differentialdiagnostik der Aderhauttumoren.
Klin Monatsbl Augenheilkd 1985; 186:187.
115. Krupsky S, Friedman E, Foster CS, et al:
Indocyanine green angiography in choroidal
diseases. Invest Ophthalmol Vis Sci 1992;
33:723.
116. Slakter JS, Giovannini A, Yannuzzi LA, et al:
Indocyanine green angiography of
multifocal choroiditis. Ophthalmology 1997;
104:1813.
117. Howe LJ, Woon H, Graham EM, et al:
Choroidal hypoperfusion in acute multifocal
posterior placoid pigment epitheliopathy.
An indocyanine green angiography study.
Ophthalmology 1995; 102:790.
118. Park D, Schatz H, McDonald HR, et al:
Indocyanine green angiography of acute
multifocal posterior placoid pigment
epitheliopathy. Ophthalmology 1995;
102:1877.
119. Ie D, Glaser BM, Murphy RP, et al:
Indocyanine green angiography in multiple
evanescent white dot syndrome. Am J
Ophthalmol 1994; 117:7.
120. Yannuzzi LA, Sorenson JS, Spaide RF, et
al: Idiopathic polypoidal choroidal
vasculopathy. Retina 1990; 10:1.
Indocyanine Green Videoangiography
121. Spaide RF, Hall L, Haas A, et al:
Indocyanine green videoangiography of
older patients with central serous
chorioretinopathy. Retina 1996; 16:203.
122. Yannuzzi LA, Ciardella AP, Spaide RF, et al:
The expanding clinical spectrum of
idiopathic polypoidal choroidal
vasculopathy. Arch Ophthalmol 1997;
115:478.
123. Ernest JT, Goldstick TK: Choroidal blood
flow measurement in the monkey by
clearance of indocyanine green dye. Exp
Eye Res 1979; 29:7.
124. Miszalok V: Video-Angiographie: Methode
und Nomenklatur. Klin Monatsbl
Augenheilkd 1987; 190:217.
125. Flower RW, Hochheimer BF: Quantification
of indicator dye concentration in ocular
blood. Exp Eye Res 1977; 25:103.
126. Flower RW, Staurenghi G: Trataminento de
los vasos nutrícios de la neovascularización
coroidea. In: Monés J, Gómez Ulla, eds.
Degeneración Macular Asociada a la Edad.
Barcelona: Prous Science; 2005.
127. Guyer DR, Yannuzzi LA, Slakter JS, et al:
Digital indocyanine green videoangiography
of central serous chorioretinopathy. Arch
Ophthalmol 1994; 112:1057.
128. Spaide RF, Hall L, Haas A, et al:
Indocyanine green videoangiography of
older patients with central serous
chorioretinopathy. Retina 1996; 16:203.
129. Spaide RF, Campeas L, Hass A, et al:
Central serous chorioretinopathy in younger
and older adults. Ophthalmology 1996;
103:2070.
130. Flower RW: Experimental studies of
indocyanine green dye enhanced
photocoagulation of choroidal
neovascularization feeder vessels. Am J
Ophthalmol 2000; 129:501–512.
131. Flower RW, von Kerczek C, Zhu L, et al:
A theoretical investigation of the role of
choriocapillaris blood flow in treatment of
sub-foveal choroidal neovascularization
associated with age-related Macular
degeneration. Am J Ophthalmol 2001;
132:85–93.
132. Staugenghi G, Flower RW: Clinical
observations supporting a theoretical
model of choriocapillaris blood flow in
treatment of choroidal neovascularation
associated with age-related macular
degeneration. Am J Ophthalmol 2002;
133:801–808.
133. Flower RW: Optimizing treatment of
choroidal neovascularization feeder vessels
associated with age-related macular
degeneration. Am J Ophthalmol 2002;
134:228–239.
134. Reichel E, Puliafito CA, Duker JS, Guyer DR:
Indocyanine green dye-enhanced diode
laser photocoagulation of poorly defined
CHAPTER 129
subfoveal choroidal neovascularization.
Ophthalmic Surg 1994; 25:195–201.
135. Obana A, Gohto Y, Nishiguchi K, et al:
A retrospective pilot study of indocyanine
green enhanced diode laser
photocoagulation for subfoveal choroidal
neovascularization associated with
age-related macular degeneration.
Jpn J Ophthalmol 2000; 44:668–676.
136. Flower RW: Extraction of choriocapillaris
hemodynamic data from ICG fluorescence
angiograms. Invest Ophthalmol Vis Sci
1993; 34:2720–2729
137. Flower RW: Variability in choriocapillaris
blood flow distribution. Invest Ophthalmol
Vis Sci 1995; 36:1247–1258.
1723
 CHAPTER
130 Optical Coherence Tomography
Michael M. Altaweel and David L. Johnson
INTRODUCTION
Optical coherence tomography (OCT) allows noninvasive real-
time cross-sectional imaging of living tissues by measuring
their optical properties (see Fig. 130.1). The use of OCT in
posterior segment imaging was first reported by Huang et al in
1991.1 Since, it became readily available for clinical use in the
mid-1990s, OCT has revolutionized the way ophthalmologists
diagnose and manage certain eye conditions. This is in large
part due to its technical ease of use, noninvasive nature, and the
incredible amount of information it provides, particularly
regarding the condition of the retina and its relationship to
surrounding structures. It has also gained greater use as an
imaging modality for glaucoma and for anterior segment
evaluation and management.2
Low-Coherence
Light Source
Reference
Fiber-Optic Mirror
Interferometer
Detector Transverse
Scanning
Electronics Computer
Condensing
Lens
Beamsplitter
Slit-lamp
Viewing
Objective
FIGURE 130.1. OCT performs cross-sectional imaging of structures
within the eye, allowing a noninvasive ‘optical biopsy’ with resolutions
nearing that of histopathology. OCT is similar in principle to ultrasound
but uses light rather than sound to generate images. For posterior
segment imaging, light is generated from a superluminescent diode.
This light is split into a reference beam and a measurement beam by a
partially reflecting mirror. A portion of the measurement beam light is
backscattered or reflected back from different microstructural features
in the posterior segment. The reference beam is reflected back from
the mirror which is at a known distance. The two light waves can
combine and interfere, producing an output which is processed and
quantified by the photodetector within the machine.8–10 The technique
of low-coherence interferometry is utilized to allow measurement.8,9
The low-coherence light utilized by the OCT only causes interference
when the reference beam echo delay equals the echo delay in the
measurement beam. The interferometer therefore correlates the
measurement light with the reference light that has a known delay to
allow measurement of the echo delay and amplitude of the
backscattered or backreflected light.
OCT is also useful in other medical specialties, including
otolaryngology, cardiology, gastroenterology, and vascular
surgery.3-7 Conventional imaging modalities such as magnetic
resonance imaging (MRI), computerized tomography (CT), or
ultrasound have maximum resolutions that are 1/10th to
1/100th that of commercially available OCT systems. OCT
affords unprecedented in vivo resolution of biological tissues.
The purpose of this chapter is to introduce the technology of
OCT imaging, more specifically retinal imaging. It will also
provide a framework for interpretation of normal images and
those of certain pathologic conditions. The examples will
highlight how OCT has improved our diagnostic ability, added
to our understanding the pathogenesis of retinal disorders, and
influenced their management. The role of OCT in clinical trials
will be discussed. OCT imaging of multiple retinal disorders
will also be found in other clinical chapters. OCT imaging for
the anterior segment and glaucoma will be discussed in other
portions of this book.
TECHNOLOGY
The globe lends itself well to be studied using OCT because of
its optical accessibility with relatively transparent tissues.11
Posterior segment OCT utilizes light in the 800–820 nm
wavelength generated from a superluminescent diode. Anterior
segment OCT utilizes a longer wavelength of 1300 nm in order
to permit deeper penetration of denser biologic tissues such as
the sclera. OCT has limited clinical usefulness in tissue depths
greater than 2–3 mm. Because of the extremely high detection
sensitivity of the photodetector, <1 mW of power is required to
obtain adequate images. This is well within safe acceptable
limits.
‘Tomography’ refers to the fact that OCT forms a two-
dimensional cross-sectional image of the retina based on a
series of axial or longitudinal scans and measurements taken by
the machine. With each scan pass of the retina, anywhere from
128 to 512 axial range samples are captured. Each range sample
is analogous in many ways to conventional A-scans. Each of
these scans is composed of 1024 data points which are 1–2 mm
in depth. In order to construct a tomographic image, these data
points are integrated and transformed into an image displayed
in a meaningful way on the computer screen.12
Commercially available instrument such as the Stratus
OCT-3 (Carl Zeiss Meditec Inc, Dublin, CA) have axial reso-
lutions of 8 mm and transverse resolution of 20 mm. Machines
used in research settings are capable of axial resolutions of
2–3 mm13–15 These ultrahigh-resolution OCT machines provide
an unprecedented level of microstructural detail.16
The OCT unit consists of an acquisition module connected
to a computer. Test results are displayed on a computer screen. 1725
 RETINA AND VITREOUS

Currently available software packages have ~20 acquisition
modules or scanning modes. Modes vary according to scan
patterns, resolution of microstructure, acquisition times, and
target tissue of interest. Automated analysis protocols facilitate
interpretation of data. Quantitative data regarding retinal
thickness and qualitative information regarding morphology are
obtained from the evaluation of an OCT scan. Longitudinal
follow-up is possible as data from prior scans is stored on the
computer hard drive or an external storage device.
OBTAINING IMAGES
high-resolution cross-hair scan is often used to provide greater
detail for assessment of morphological changes in the retina
and adjacent structures.
Key Features of OCT
• Non-invasive
• Cross-sectional image of retinal architecture
• Retinal thickness can be assessed and followed longitudinally
• Provides new information on pathophysiology of retinal
disorders and response to therapy
• Excellent for patient education

One of the chief advantages of OCT versus other retinal

imaging modalities is the noninvasive nature of the test. The INTERPRETATION OF NORMAL RETINAL
patient is placed into the acquisition module, which is similar
in design to a slit lamp. Mydriasis is helpful but not always
ANATOMY
necessary. The operator views in real time an infrared video The ability to image normal morphology and structural abnor-
image of the fundus displayed on the computer monitor to malities with OCT is based upon the fact that biologic tissues
SECTION 10

ensure proper alignment. The patient views a fixation light. As
the scanning light used is near infrared, the patient rarely
perceives it during the scan and therefore experiences minimal
or no discomfort.
A sequence of axial measurements at various transverse
positions is obtained in order to form a tomographic or two-
dimensional representation of the retina. The faster the image
acquisition time, the lower the pixel density or transverse
resolution will be. Conversely, the opposite is true. Commer-
cially available OCT instruments obtain scans at ~400 axial
scans per second. In order to obtain higher-resolution scans
with 512 transverse pixels, 1.28 s are required (T = 512/400)
per scan line. Lower resolution scan lines with a transverse pixel
density of 128 require only 0.32 s to acquire. These faster scans
sacrifice transverse resolution while decreasing the amount of
motion artifact and required patient cooperation.12
Typical macular scans are 6 mm in length but can be adjusted
by the operator. Depending upon the acquisition protocol,
anywhere from 2 to 24 scan lines are performed. Scan patterns
can also be adjusted. The most commonly employed scanning
patterns for macular pathology are the ‘fast macular’ scan and
high-resolution radial scan. Fast macular scans obtain six cross-
sectional scans 30° apart, with each passing through the center
of the macula. The fast macular scan has a transverse reso-
lution of 128 pixels and is obtained in 2.5 s. The radial line scan
has a transverse resolution of 512 pixels, thus providing a much
higher level of detail, but requires much more time to obtain
and repeated efforts at fixation. Macular thickness and gross
abnormalities can be sufficiently interpreted using the fast
macular protocol12 and the results of testing are more reliable
in situations where fixation is difficult for the patient.17 The
of differing densities (i.e., normal retina, RPE, choroid, vitreous,
hemorrhage, edema, drusen, etc) have different backscattering
properties.12 The OCT scan of a normal retina demonstrates
characteristic features, including a distinct ability to distinguish
between the retina and the vitreous, the retina and the RPE, and
between the RPE and the choroid. The foveal depression is well
demonstrated. Details of retinal layers have been progressively
better visualized with more recent versions of the OCT.
Displayed in Figure 130.2a is a cross-sectional image of the
posterior pole in a normal eye obtained on the Stratus OCT-III
machine. By convention the vitreous cavity is superior and the
external layers of the retina and choroid are inferior. Figure
130.2b is an ultrahigh-resolution scan of a normal retina, which
demonstrates much more distinction between structural
elements within the retina.
As demonstrated above, the OCT image closely resembles
the histological anatomy of the retina. Delineation of cellular
details with commercially available OCT technology is not yet
possible. However, it is possible to distinguish between cellular
and noncellular elements of the retina.12 Ultrahigh-resolution
imaging technology delivers an even greater level of resolu-
tion.13,15 The interface between the posterior hyaloid and the
internal limiting membrane (ILM) can usually only be
visualized if the hyaloid is elevated off the surface of the retina
(Fig. 130.7).10 The fovea is displayed with its normal thinning,
which is due to the absence of the inner retinal layers and the
presence of only a thickened photoreceptor layer and the outer
nuclear layer.
A false color coding system ascribed by the image processing
algorithm is used to distinguish between the different micro-
structural layers of the retina. The reflectivity of different

Nerve Fiber Layer FIGURE 130.2. (a) Normal retinal anatomy.

Ganglion Cell Layer
Inner Plexiform Layer
Inner Nuclear Layer
Outer Plexicom Layer
Outer Nuclear Layer
Inner/Outer Photoreceptor Junction
Retinal Pigment
a Epithelium/Choriocapillaris complex
b
1726
Notice how the NFL increases in thickness
nasally toward the optic nerve (right side of
image). Cellular layers, such as the ganglion cell
layers and the inner and outer nuclear layers
have less intense backscattering due to the
density and orientation of their respective
elements. Layers with more intense reflectivity
include the RPE/Choriocapillaris, the junction
between the inner and outer segments of the
photoreceptor layer, the inner and outer
plexiform layers, as well as the NFL. Axial
resolution is 8 mm. (b) Ultrahigh-resolution OCT
of a normal retina. Axial resolution is 2 mm.
Notice the greater ability to identify retinal
structures/layers.
Photo courtesy of Dr JS Duker.

a b
FIGURE 130.3. (a) The retinal thickness map is derived from six radial scans oriented 30° apart, all passing through the center of the macula.
(b) Retinal thickness map: the thickness for each of the nine macular subfields is displayed in both numerical as well as color coded formats.
Central point thickness in this patient is 181 mm, and the standard deviation is 5 mm. The displayed scan is oriented from inferior to superior.
retinal layers is based upon the arrangement of their structures
as well as their biological densities and degree of pigmentation.
Those structures with high biological reflectivity are repre-
sented by red, medium reflectivity with yellow/green, and those
with low reflectivity are blue. Absence of a reflectivity signal is
represented by black. The nerve fiber layer (NFL) and plexiform
layers are highly reflective due to the horizontally oriented
axonal structures. The NFL increases in thickness and
reflectivity close to the optic nerve. The nuclear layers are less
reflective and appear blue to black on cross-sectional images.
The RPE and choriocapillaris form the outermost highly
reflective structure visible due to their high melanin and vas-
cular content respectively. These two layers cannot usually be
distinguished on conventional OCT imaging because of their
close proximity to one another. External to the choriocapillaris
are the larger sized choroidal vessels. These vessels, as well as
deeper structures, cannot usually be seen on OCT due to the
shadowing from the overlying RPE and choriocapillaris.10
Scanned images have a legend that indicates the direc-
tionality of the currently displayed scan, as demonstrated in
Figure 130.3b. The scan direction is proceeded from inferior to
superior in the scan displayed. By convention, the right side of
the image corresponds to the arrowhead. OCT quantitative
results are generally represented in a retinal map. The macula
is artificially divided into nine regions and the average retinal
thickness is calculated for each region. The inner circle of the
map has a diameter of 1.0 mm and correlates roughly with the
fovea. The middle circle has a diameter of 3.0 mm and the outer
circle a diameter of 6.0 mm, which is the length of the axial
scans. A color coded map along with a legend is displayed in
order to facilitate rapid interpretation of numerical values.
Greater retinal thickness is represented by the ‘hotter’ colors
such as red and white. Average retinal thickness is represented
by green, and thin or atrophic areas of retina are represented by
the ‘cooler’ colors such as blue or black. Central retinal or foveal
thickness and total volume of the macula are displayed in
numerical format. The standard deviation of the center point is
determined by comparing the six points which cross through
the center in the scanning protocol and is recorded with the
center point.
Image processing algorithms allow automated measurement
of retinal thickness. This is accomplished by first determining
the anterior and posterior surfaces of the retina. The anterior
surface of the retina is defined by the transition from the low
reflectivity of the vitreous cavity to the high reflectivity of the
Optical Coherence Tomography
CHAPTER 130
NFL. The posterior surface of the retina is typically defined by
the high reflectivity of the junction between retinal tissue and
the RPE/choriocapillaris complex.12 Normal retinal thickness is
182 mm for the OCT-III.18 Determinations of retinal thickness
are performed automatically and can be the source of erroneous
measurements.
DISTINGUISHING ARTIFACTS
In order to interpret OCT and determine whether the quanti-
tative information is accurate, one must assess the quality of an
OCT scan and recognize OCT artifacts. Fortunately, obtaining
adequate OCT images is a quick process. Most artifacts are
derived from difficulty with patient cooperation or abnor-
malities within the ocular media rather than operator error.19
Mydriasis is not always necessary to obtain OCT but may
provide a higher signal-to-noise ratio and consequently better
microstructural details. Dilation also decreases the amount of
‘vignetting’ which is described below. Obtaining quality OCT
images depends upon the light being able to reach the target
tissue. If there is significant media opacification such as corneal
opacification or severe cataract there will be less light reaching
the posterior segment and less light returning to the infero-
meter for detection. This ‘signal-to-noise ratio’ is displayed on
the screen and labeled as ‘signal strength’. A signal strength of
10 represents the highest quality imaging whereas a signal
strength of zero represents the lowest quality. If there is little
light reaching the tissue, the images appear dull or ‘washed out’
and it is difficult to detect subtle abnormalities and differences
in tissue reflectivity. Figure 130.4 shows an example of low
signal strength. Notice how the ordinarily highly reflective
structures appear blue or even black. Moderate media opacities
such as early cataract, asteroid hyalosis, and mild vitreous
hemorrhage do not preclude adequate imaging.20,21 OCT can be
performed through silicone oil, but not through intraocular gas.
Another artifact that must be recognized is that of ‘vignetting’.
Vignetting occurs as the light beam is obscured by part of the
iris, causing less light to reach the retina in that area.12 The find-
ings are quite characteristic and easily recognized (Fig. 130.5).
Poor patient cooperation can lead to abnormalities on the
OCT image. Image processing software corrects for a certain
amount of longitudinal movement by the patient but there is
little to no software correction for transverse movement or poor
patient fixation. This results in reduced image quality and
transverse resolution. This is particularly a problem in patients 1727
 RETINA AND VITREOUS
FIGURE 130.4. Example of low ‘signal-to-noise ratio’. Notice how the
SECTION 10
entire image appears ‘washed out’. It is difficult to discern details of
the retinal microstructure. The signal strength is relatively low at three.
FIGURE 130.5. OCT image of a normal macula. The right side of the
image displays a common artifact known as vignetting. This occurs
when the iris blocks a portion of the light. This may occur with poor
pupil dilation.
FIGURE 130.6. Misdrawn borders results in erroneous measurement
in a portion of the retinal thickness map.
with poor visual acuity. Retinal thickness data is often less
reliable in such situations. This is best demonstrated as a large
standard deviation in the center-point thickness measurement.
The problem is partially alleviated by utilizing the fast map
protocol rather than the high-resolution scanning protocol for
such patients.17
The automated algorithm, which determines and draws the
anterior and posterior borders of the retina to allow retinal
thickness measurements, can be erroneous. This is noted as
misdrawn borders on the retinal thickness map (Fig. 130.6). If
this occurs, the data generated by the OCT would not be
correct. For a prior version of the OCT (OCT II), a graphical
1728 user interface was developed which allowed correction of this
interface and subsequent measurement data.22 This tool is
being developed for future versions of the OCT.
ENSURING HIGH-QUALITY OCT DATA
1. All six underlying scans present for retinal thickness map
2. ILM and RPE borders drawn correctly
3. Standard deviation of the center point <10% (of center-
point value)
4. Adequate signal strength (5 or more)
5. Macula centered in the scan
CLINICAL CONDITIONS
OCT has improved our understanding of the pathophysiology
of retinal disorders, our ability to distinguish between differen-
tial diagnoses with a similar clinical appearance, our ability to
follow conditions in a noninvasive manner, our ability to make
treatment decisions, and our ability to educate our patients.
The following examples demonstrate the utility of OCT and
illustrate commonly identified abnormalities.
VITREORETINAL INTERFACE ABNORMALITIES
Posterior Vitreous Detachment
Posterior vitreous detachment (PVD) is a common pheno-
menon, observed in 63% of eyes over the age of 70. It results
from syneresis of the vitreous gel. When the liquefied vitreous
obtains access to the retro-hyaloid space through a defect in the
posterior hyaloid face, PVD can occur.23–25
PVD often shows up on OCT as a thin, faint hyper reflective
line lying above the surface of the retina. In order for the
posterior hyaloid to be visualized on OCT the hyaloid must be
within 100–200 mm of the surface of the retina.12,26 Figure
130.7, shows an example of a PVD.
Vitreomacular Traction Syndrome
Vitreomacular traction syndrome (VMT) results from an
abnormally firm adherence of the posterior hyaloid to the
macular region with anteroposterior and tangential traction
causing distortion of the macular architecture and retinal
thickening.27,28 Vision is frequently decreased secondary to the
retinal edema as well as the abnormal macular contour. The
condition may be difficult to appreciate on clinical exam, but is
clearly demonstrated by OCT imaging.29–36
Figure 130.8 demonstrates a case of VMT traction. This is a
series of OCT images taken from the same patient over the course
of 13 months. Notice the thin band representing the posterior
hyaloid which is inserting onto the surface of the retina. The
retina displays cystic changes and there can be subretinal and
FIGURE 130.7. PVD. Notice the thin hyperreflective band just above
the surface of the retina representing the posterior vitreous cortex, or
hyaloid.

a a
b b
FIGURE 130.8. (a–c) This series of figures demonstrates a case of
VMT that progressed over the course of 13 months. The patient
complained of increasingly distorted and decreased vision.
sub-RPE fluid as well. There is obvious distortion of normal
foveal anatomy in the later images.
OCT is very useful in understanding and planning the
management for VMT and provides an excellent tool for patient
education. These patients can clearly understand the rationale for
proceeding with a vitrectomy and release of adhesions as their
condition deteriorates. The OCT is equally useful in assessing
management outcomes.
Epiretinal Membrane
Epiretinal membranes are caused by glial proliferation and con-
tracture on the surface of the retina. This can lead to abnormal
macular and vascular architecture. Fluorescein angiography
frequently will demonstrate vascular leakage.27,37–41
On OCT, epiretinal membranes are manifested by an abnor-
mal highly reflective structure lying on the surface of the retina.
The membrane is more easily distinguished if there is some
separation between the membrane and the surface of the retina.
If there is no separation one may be able to use indirect clues to
appreciate the presence of the membrane such as surface con-
tracture and macular edema.
OCT is helpful in confirming the diagnosis as well as quanti-
fying the amount of macular distortion present. It is often quite
useful in following the patients in the pre- and postoperative
stages. Figure 130.9 demonstrates a case of epiretinal mem-
Optical Coherence Tomography
CHAPTER 130
FIGURE 130.9. (a) demonstrates an epiretinal membrane causing
distortion of macular anatomy with loss of the foveal depression and
thickening of the retina. The epiretinal membrane is easily identified
as the highly reflective structure lying on the surface of the retina.
(b) Four months after membrane peeling, the patient’s macular
anatomy has returned to near normal with return of a foveal
depression. One can appreciate the extent of the epiretinal membrane
peeling by noticing the residual membrane on the right side of the
image.
FIGURE 130.10. Macular pseudohole associated with an epiretinal
membrane. Notice the highly reflective membrane lying just above the
surface of the retina. One can appreciate that this membrane has
caused an irregular retinal surface as well as intraretinal edema. There
is a layer of photoreceptors at the base of the pseudohole.
brane causing decreased vision with images of the same patient
after epiretinal membrane peeling.
Epiretinal membranes can lead to the appearance of a
‘pseudohole’. OCT can be useful in distinguishing a ‘pseu-
dohole’ from a full thickness macular hole, which can be a
difficult clinical distinction. Figure 130.10 demonstrates a severe
ERM with pseudohole resulting in the appearance of a
steepened foveal contour, intraretinal edema, and separation of
the outer nuclear layer and the outer plexiform layer. In contrast
to a macular hole, the photoreceptor layer remains intact.42–45
In providing patient education regarding their ERM, the OCT
is invaluable, particularly since the abnormalities may be subtle
on fundus photographs. 1729
 RETINA AND VITREOUS
a
SECTION 10
FIGURE 130.11. (a) Demonstrates an impending macular hole with a
foveolar detachment. Notice the thin posterior hyaloid band above the
surface of the retina inserting onto the fovea. (b) Three months later
the posterior hyaloid completely detached and the stage I hole
spontaneously resolved. Notice once again the separated posterior
hyaloid lying above the surface of the retina.
Idiopathic Macular Holes
Macular holes are full thickness defects in the neurosensory
retina caused by abnormal tangential or oblique vitreous trac-
tion on the foveal region. OCT assists in the diagnosis of
macular hole by clearly demonstrating the retinal defect and has
enhanced our understanding of the pathophysiology of hole
formation.45–47 Such images are of great benefit in patient
education regarding their disorder and proposed surgical
correction. Demonstration of the pathophysiology of various
stages of macular holes also assists the surgeon in making
treatment decisions, including whether surgery is required or
not.48,49 Early stage holes may appear as a yellow dot or circle on
biomicroscopic examination, with a long differential diagnoses.
OCT can demonstrate the early stages of a hole and the
tractional elements responsible for hole formation. Figure
130.11 demonstrates a stage I impending macular hole. There
is mild loss of visual acuity and mild metamorphopsia. A
foveolar detachment is present. 50% of stage I holes will
spontaneously resolve.50,51 Therefore the OCT helped in
making the correct diagnosis and in making the decision to
observe the condition rather than operate.
Surgical developments in the repair of macular hole have
included the increasing addition of ILM peeling in an effort to
improve hole closure rates.52–56 Controversy exists concerning
whether final visual outcome is improved, and whether ILM
peeling is necessary.57–59 For stage II macular holes, OCT may
be instrumental in directing the choice of surgical procedure. As
illustrated in Figure 130.12, stage II holes (Gass biomicroscopic
staging) may be distinguished as stage IIA if the posterior
hyaloid is still attached and causing traction on the edge of the
macular hole or stage IIB if such traction has already been
released.60 It is postulated that a stage IIA hole may be less
likely to require an ILM peel to improve closure rates than a
stage IIB hole. This would avoid the additional risk imposed by
1730 performing a membrane peel during surgery.
b
FIGURE 130.12. (a and b) Stage IIA macular hole with a persistent
attachment of the posterior vitreous leading to traction. Stage IIB hole
with posterior vitreous separation may be more appropriate to treat
with additional intervention such as ILM peel.
OCT can also be useful in determining the prognosis for
patients with a macular hole. Figure 130.13a represents a full
thickness stage IV macular hole. The rounded edges of the hole,
cystic changes in the adjacent retina, and large width of the hole
indicates a severe macular hole and may suggest features of
chronicity. There is a higher percentage of nonclosure or lack of
visual improvement despite hole closure with stage IV holes
than with smaller macular holes.61–64 The OCT is an excellent
tool in providing patient education regarding macular hole and
in demonstrating the anatomical success of surgical repair
(Fig. 130.13b).
VASCULAR ABNORMALITIES
Diabetic Macular Edema
Macular edema is the leading cause of vision loss in diabetics.
It affects ~14–25% of patients who have had diabetes for 10
years or more.65–69 OCT can be used to help detect and quantify
the amount of diabetic macular edema present, the proximity
and involvement of the foveal region by the edema, as well as
the response to therapy.70,71 Subclinical macular edema may
only be appreciated with OCT imaging. A National Eye Institute
sponsored trial is assessing the utility of early intervention for
such patients (Subclinical Diabetic Macular Edema Study). A
number of clinical trials have recently incorporated retinal
 Optical Coherence Tomography

aii

CHAPTER 130
ai b

FIGURE 130.13. (a) Represents a stage IV full thickness macular hole with a PVD (not visible). Notice the signs of severity such as the rounded
contour at the edge of the hole as well as the cystic changes within the retina adjacent to the hole. (b) Successful closure of this macular hole
after pars plana vitrectomy with ILM peeling and intraocular gas tamponade. There is a return to a relatively normal foveal anatomy.

a b

FIGURE 130.14. OCT and corresponding color fundus image of a patient with clinically significant diabetic macular edema. The transverse scan
demonstrates intraretinal edema collecting on the temporal side of the fovea. The topographical image shows the location and extent of the
retinal edema. Notice on the cross-sectional image the hard exudate immediately temporal to the fovea causing a mild shadowing effect.

thickness as measured by OCT as a secondary endpoint. Com-
parisons with standardized visual acuity have found variable
correlation, however morphological responses to therapy are
well visualized with OCT.72–74 Retinal thickness parameters are
utilized in making re-treatment decisions. In clinical practice,
the use of OCT to follow patients with diabetic macular edema
has increased greatly, particularly for those managed with
intravitreal steroid or anti-VEGF injections.
Figure 130.14, shows the transverse image and macular
thickness assessment in a patient with clinically significant
diabetic macular edema.
Proliferative Diabetic Retinopathy
Diabetes can lead to the development of extraretinal fibro-
vascular proliferation extending beyond the ILM into the
vitreous. Partial PVD in these cases can lead to the development
of vitreous hemorrhage, macular heterotopia, and tractional
retinal detachment.
Figure 130.15 illustrates the utility of OCT in surgical
planning, with points of adhesion and traction evident.75 Pars-
plana vitrectomy with membrane peeling resulted in an
improved macular anatomy.
Cystoid Macular Edema
Visually significant cystoid macular edema (CME) is one of the
most common reasons for suboptimal visual recovery after
uncomplicated cataract extraction, occurring in ~1–2% of
patients. Occurrence rates may be higher in complicated cases,
aphakia, diabetics, and in patients receiving topical glaucoma
therapy with prostaglandin analogs.76,77 Onset is usually
6–8 weeks after surgery.
OCT is a noninvasive alternative to fluorescein angiography
in making the diagnosis and following CME. The amount of
intraretinal edema can be quantified. The edema is often con-
tained within cystoid spaces in the outer plexiform layer. OCT
also helps to determine if there is a component of vitreous 1731
 RETINA AND VITREOUS

aii

ai b
SECTION 10

FIGURE 130.15. (a) Diabetic tractional detachment of the macula. There is a thick fibrovascular membrane lying on the surface of the macula
causing a tractional detachment with accumulation of a large amount of intraretinal edema. (b) Following pars plana vitrectomy with membrane
peeling there is a return to a more normal macular architecture. There is still a large amount of cystic intraretinal edema present.

ai aii

aiii b

FIGURE 130.16. (a) Patient with CME after uncomplicated extracapsular cataract extraction. Cystoid spaces are evident. There is no VMT.
1732 (b) After 2 months of treatment with topical nonsteroidal antiinflammatory drops, much of the edema has resolved.

ai
aii
traction contributing to the macular edema. Figure 130.16
reveals a case of CME after uncomplicated cataract extraction.
OCT is particularly helpful in the diagnosis of CME associated
with the therapeutic use of Niacin, as the fluorescein angiogram
generally does not demonstrate leakage in these cases.78–80
Branch Retinal Vein Occlusion
Branch retinal vein occlusions (BRVO) occur most commonly at
arteriovenous crossings in the setting of systemic hypertension.
The retinal artery can compress the vein within their common
adventitial sheath, resulting in turbulent flow and thrombosis.
Systemic abnormalities such as vasculitis or coagulation
disorders may also lead to BRVO. The clinical picture is one of
sudden painless vision loss due to ischemia, hemorrhage, or
associated macular edema.
Optical Coherence Tomography
CHAPTER 130
b
FIGURE 130.17. Inferior branch vein occlusion. Notice the cystic
intraretinal edema on the cross-sectional image. The macular thickness
map confirms that most of the edema is inferior to the fovea.
OCT is useful for evaluating the severity of macular edema
associated with retinal vascular occlusion. It does not replace
fluorescein angiography in the initial diagnostic evaluation
but compliments it and quantifies the degree of edema (Fig.
130.17).81,82 It is very useful in following the natural history or
response to therapy in a noninvasive manner. It has been used
to assist in management decisions and is a secondary endpoint
in current therapeutic trials, including the standard care versus
intravitreal triamcinolone for retinal vein occlusion (SCORE)
study. The standard of care for BRVO with secondary center
involving macular edema has been observation for a period of 3
months, followed by a treatment with grid laser in the area of
ischemia and leakage if the visual acuity was less than or equal
to 20/40.83 OCT can be helpful in determining if the macular
edema is worsening before this point and whether intervention 1733
 RETINA AND VITREOUS
ai
SECTION 10
aii
may be required earlier. Conversely, it can also determine if the
macular edema has been improving over the 3 months and
further observation might be reasonable. Intravitreal steroids and
anti-VEGF intravitreal agents have been utilized as alternative
treatments with the response to therapy generally evaluated by
a combination of visual acuity and retinal thickness on OCT. As
these agents have a temporary effect, repeat OCTs assist the
clinician in determining the optimal timing for re-treatment.
Central Retinal Vein Occlusion
Central retinal vein occlusion (CRVO) is due to occlusion of the
central retinal vein at or posterior to the level of the lamina
cribrosa. An atherosclerotic central retinal artery may impinge
upon the vein, causing turbulence, endothelial damage, and
1734 thrombus formation.84 Clinical examination often reveals
FIGURE 130.18. (a) CRVO. Notice the large amount of intraretinal
edema manifest on the cross-sectional image and the macular thickness
map. The apparent concavity of the RPE/choriocapillaris band is an
artifact due to the automated image processing software. (b) Four weeks
after receiving 4 mg of intravitreal Triamcinolone, the patient’s macular
thickness decreased markedly.
dilated and tortuous veins, optic disk edema, intraretinal
hemorrhages, and retinal edema. Vision loss in CRVO may due
to ischemic insult or macular edema or both. OCT has been
useful in evaluating the degree of retinal thickening, which is
often very severe (center-point thickness greater than 500 mm is
common) (Fig. 130.18a). The Central Vein Occlusion Study
found that grid laser reduced macular edema but did not result
in improved visual acuity.85,86 Therefore the standard of care for
macular edema associated with this disorder has been under
observation. Among the many treatments more recently
attempted for CRVO, the most frequently utilized is the
injection of intravitreal steroid or anti-VEGF agents. OCT
demonstrates well the effect of such medications on the
macular edema (Fig. 130.20b) and can assist the clinician in
making treatment decisions.87,88 If the edema resolves but the
 Optical Coherence Tomography

FIGURE 130.19. CSCR with accumulation of subretinal fluid. The FIGURE 130.21. Geographic atrophy associated with ARMD. There is
shadow effects lateral to the neurosensory detachment are a result of increased reflectivity of deeper structures centrally due to RPE
larger caliber native intraretinal blood vessels. atrophy beneath the fovea. Irregularities of the RPE/choriocapillaris
complex on the right side of the scan are representative of drusen.

CHAPTER 130
a

FIGURE 130.20. CSCR with a pigment epithelial detachment. The

pigment epithelial detachment was much more clearly visualized with
OCT than with fluorescein angiography.

visual acuity remains poor then the degree of ischemia probably

limits the visual potential and makes further injections less
valuable. Conversely, if the edema resolves well and visual
acuity improves, then repeating injections for future
recurrences of edema makes sense. In ongoing clinical trials,
retinal thickness measured by OCT is a secondary endpoint.

Central Serous Chorioretinopathy

Central serous chorioretinopathy (CSCR) results from localized
dysfunction of the retinal pigment epithelial cells, resulting in
accumulation of fluid in the subretinal space (Fig. 130.19).89,90,27
OCT is helpful in diagnosing the condition as well as following
the patients longitudinally. OCT may also demonstrate asso-
ciated lesions which may be more difficult to discern on
examination or with fluorescein angiography, such as pigment
epithelial detachment (Fig. 130.20). The OCT is very useful in
educating the patient regarding their condition, and in
b
demonstrating their progress and/or resolution over time.
FIGURE 130.22. OCT and corresponding fluorescein angiography of
Age-Related Macular Degeneration an occult choroidal neovascular membrane with a large amount of
Age-related macular degeneration (ARMD) is the leading cause intraretinal fluid present. There is disruption and elevation of the RPE.
of irreversible vision loss in the Western world. It affects ~10
million people in the United States with 200 000 new cases of
advanced ARMD diagnosed annually. The disease is divided Exudative ARMD
into two basic categories: nonexudative and exudative. Exudative ARMD lesions are classified according to fluorescein
angiography findings as either predominantly classic,
Nonexudative ARMD minimally classic, or occult with no classic features. OCT
Nonexudative ARMD can lead to changes in the macula such findings do not necessarily correlate with the fluorescein
as RPE hyper- and hypopigmentation as well as basal laminar classification. OCT demonstrates abnormalities in the retinal
and basal linear deposits. RPE hyperpigmentation can cause architecture in most cases of exudative AMD, with common
increased reflectivity of the external band on OCT while RPE findings of subretinal fluid, retinal thickening, pigment
atrophy results in hyperreflectivity of structures deep to the epithelial detachment, (Fig. 130.24) and choroidal neovasculari-
RPE/choriocapillaris (Fig. 130.21).91 Drusen will often produce zation (CNV).92 Occult CNV generally causes thickening of the
a stippling effect of the external band consistent with deposits RPE layer. The typical appearance with inability to distinguish
along Bruch’s membrane.92 the CNV from the RPE layer is termed type I (Fig. 130.22). This 1735
 RETINA AND VITREOUS

FIGURE 130.23. OCT and corresponding fluorescein angiogram of a

classic CNV. Notice the discontinuity in the RPE/choriocapillaris band
with a thick hyperreflective neovascular membrane in the subretinal
space. There is accumulation of subretinal fluid as well as intraretinal
fluid.
SECTION 10

is by far more common. Classic CNV may have a similar

appearance, or in some cases may break through Bruch’s
membrane and grow more clearly in the subretinal space (Fig.
130.23). This is termed a type II CNV. From a therapeutic
perspective, this may influence the response to surgical therapy.
A type II CNV complex would be more likely to respond to
surgical removal without RPE damage, whereas removal of a
type I membrane would be much more likely to damage the
normal structure of the RPE and subsequently result in poor
visual acuity. This was demonstrated in the Submacular
Surgery Trial.93,94

OCT in the management of age related macular
degeneration
Traditional therapy for exudative macular degeneration has
consisted of either thermal laser photocoagulation or photo-
dynamic therapy (PDT). Intravitreal injections with anti-
vascular endothelial growth factor (anti-VEGF) compounds
have demonstrated higher rates of vision retention and
improvement and have increased greatly in use.95–98
OCT has been invaluable in helping retina specialists decide
when to re-treat their patients with exudative ARMD.
Fluorescein angiography is no longer needed at every follow up
visit to make a determination of whether to re-treat or not.
Typically fluorescein angiography is obtained along with OCT
at the initial visit in order to confirm the diagnosis and to
characterize the choroidal neovascular membrane. Once treat-
ment is initiated, particularly with an intravitreal injection of
an anti-VEGF agent, the patients can often be followed-up with
serial OCT imaging and re-treated if intraretinal or subretinal
fluid persists or recurs.
Key Features: Utility of OCT in Retinal Disorders
• Supplements other imaging modalities in making diagnosis
• Can discern and quantify more subtle changes in response to
therapy
• Non-invasive test-very helpful considering that some treatment
regimens require frequent intervention
• Can assist in decision making process regarding retreatment
1736
FIGURE 130.24. Serous Pigment Epithelial Detachment associated
with ARMD. Notice the excrescences on the surface of the RPE. There
is a small amount of subretinal fluid as well.
Data from a recent study using OCT to guide decisions
about re-treatment suggests that this is an efficient and effective
way to follow patients with exudative ARMD. In this study,
patients received on average five to six intravitreal injections of
an anti-VEGF compound over 1 year based on recurrence of
retinal thickening rather than the 12 consecutive monthly
injections required over a period of 1 year in the phase III
trials.99,100 The visual outcomes were similar with both dosing
regimens.
Despite the utility of this imaging method in guiding
management, retinal thickness measured on OCT does not
always correlate with visual acuity. Resolution of retinal
thickening may occur with the formation of a disciform scar or
with the development of atrophy resulting in poor visual acuity.
Resolution of retinal thickening could also occur with a
favorable response to treatment resulting in stable or improved
visual acuity. Therefore interpretation of the OCT data must be
correlated with the visual acuity and the findings on biomicros-
copic examination.
OCT in clinical trials
The use of OCT measurements as secondary endpoints in
clinical trials has increased greatly in the last few years. The
advantages of OCT include the noninvasive nature of the test,
 Optical Coherence Tomography

the ease of use for photographers and subjects, the objective
measurements of retinal thickness, and the additional infor-
mation regarding morphology of the retina and adjacent
structures. Quantitative results are usually reported by
comparing the mean change in retinal thickness or abnormal
retinal thickening (total retinal thickness minus normal retinal
thickness) between the treatment groups and sham group.
Results may also be reported as the percentage of a group which
reach a prespecified goal, such as reduction of retinal thickness
by 100 mm or reduction of abnormal thickening by 50%.
Eligibility determination OCT determined retinal thickness
criteria have been utilized in recent trials of ARMD, retinal vein
occlusion, and diabetic macular edema to ensure that subjects
who are enrolled have sufficient center involving retinal
thickening to evaluate if the therapy under investigation is
efficacious. A common requirement is the presence of a center-
point retinal thickness of at least 250 mm. In addition, OCT is
Grading morphology In addition to evaluating OCT quantita-
tive results, reading centers also assess morphological changes
such as vitreoretinal interface abnormalities, intraretinal cysts,
CNV, subretinal fluid, and PED. These features are graded for
presence or absence and may be quantified (extent of cysts,
thickness of subretinal fluid, thickness of CNV complex).
Correlations are performed to evaluate whether the presence of
such features at baseline are predictive of outcome, and whether
the features change over time, in response to therapy.
Longitudinal follow-up As a secondary endpoint OCT has
been very useful in assessing response to therapy for macular
disease. Retinal thickness measurements on OCT can be used
to make retreatment decisions. For example, in ongoing trials of
intravitreal triamcinolone for the management of macular
edema associated with retinal vein occlusion and diabetic
retinopathy, comparisons of baseline and current OCT findings
are used to help determine whether treatment has been

used to exclude patients who demonstrate vitreoretinal
abnormalities which would preclude resolution of retinal
thickening with medical therapy.101
OCT quality Several clinical trials have found that the
reliability and reproducibility of the measurements obtained by
OCT scanning are much higher if the OCT meets certain
quality criteria. All six underlying scans must be present for the
retinal thickness map, the ILM and RPE borders must be drawn
correctly, the standard deviation of the center point must be
<10% (of center-point value), signal strength should be five or
greater, and the macula must be centered in the scan. In a study
comparing OCT II and OCT III (current generation)
measurements for diabetic macular edema, OCT III
measurements were found to be reliable in 91.5% of cases
compared with only 59.6% for the OCT II measurements. The
advantage of the OCT III was the ability to obtain the
measurements over 2.5 s compared with the requirement to
obtain six separate scans for the OCT II.102 This finding was
corroborated by a comparison of fast macular scans versus six
high-resolution scans to obtain retinal thickness data for an
exudative macular degeneration study. With 383 visits, 93.7%
(359/383) of fast macular thickness maps had a center-point
standard deviation of less than or equal to 10% (good quality)
versus 59.0% (226/383) of high-resolution macular thickness
maps. Subjects with this disorder often have difficulty fixating
and were much more likely to have reliable data with the fast
macular scans.17 Scans of high quality are highly reproducible
with a correlation coefficient of 0.981 for repeated OCT III
scans. Ensuring OCT quality in a clinical trial setting is critical
to our ability to trust the data.
Correlation with visual acuity Hee et al demonstrated a
correlation of visual acuity with retinal thickness in patients
with diabetic macular edema (R2 = 0.79).73 Subsequent clinical
trials have found variable results and in some cases the
correlation is poor (R2 = 0.07).103 OCT measurements of retinal
thickness therefore continue to be a secondary rather than
primary endpoint in clinical trials. They can be useful as a
marker of the biological activity of a treatment.
CHAPTER 130
successful or not, and secondarily whether to continue
treatment or not.
FUTURE TRENDS
Several aspects of OCT are being improved upon at present.
Ultrahigh-resolution OCT improves resolution from 8 to 2 mm,
allowing greater visualization of structural detail which may
enhance further our understanding of the pathophysiology of
macular disorders.13–15
Spectral domain OCT also allows improved resolution,104
with decreased acquisition time. The combination of OCT with
simultaneous registration of retinal images with scanning laser
ophthalmoscopy will allow improved reproducibility of measure-
ments and ensure centration of measurements. 3 dimensional
representation of retinal morphology has become possible.105
Software developments including a graphical user interface to
allow correction of misdrawn borders will enhance our ability to
obtain accurate measurements.
SUMMARY
OCT is a noninvasive test that provides clinicians and
researchers objective information on the presence and severity
of retinal, RPE, and vitreoretinal interface abnormalities. Our
understanding of the pathophysiology of macular diseases has
been enhanced by OCT, leading to modifications in clinical
management based on OCT findings. OCT has improved our
diagnostic ability, especially for subtle macular disease. There
has ensued a great increase in the use of this imaging modality
for the baseline evaluation and follow-up of retinal disorders.
The assessment of retinal thickness and morphology has
become particularly useful in making re-treatment decisions,
and has led to a decreased necessity for invasive imaging tests
in follow-up. Therapeutic clinical trials have increasingly
incorporated OCT measurements as secondary endpoints. OCT
images are very useful in enhancing patient education regarding
their disorder and management. Further refinements in
technology will further improve our ability to incorporate OCT
into clinical and research applications.

REFERENCES
1. Huang D, Swanson EA, Lin CP, et al:
Optical coherence tomography. Science
1991; 254:1178–1181.
2. Schuman JS, PC, Fujimoto JG: Optical
coherence tomography of ocular diseases.
2nd edn. Thoroughfare, New Jersey: Slack;
2004.
3. Kwon RS, Brugge WR: New advances in
pancreatic imaging. Curr Opin
Gastroenterol 2005; 21:561–567.
4. Fujimoto JG, Pitris C, Boppart SA, et al:
Optical coherence tomography: an emerging
technology for biomedical imaging and
optical biopsy. Neoplasia 2000; 2:9–25.
5. Pitris C, Jesser C, Boppart SA, et al:
Feasibility of optical coherence tomography
for high-resolution imaging of human
gastrointestinal tract malignancies.
J Gastroenterol 2000; 35:87–92.
6. Boppart SA, Brezinski ME, Pitris C, et al:
Optical coherence tomography for 1737
 RETINA AND VITREOUS
neurosurgical imaging of human intracortical
melanoma. Neurosurgery 1998; 43:834–841.
7. Brezinski ME, Tearney GJ, Bouma BE, et al:
Imaging of coronary artery microstructure
(in vitro) with optical coherence
tomography. Am J Cardiol 1996; 77:92–93.
8. Born M, Wolf E, Bhatia AB: Principles of
optics: electromagnetic theory of
propagation, interference and diffraction of
light. 7th edn. Cambridge, England:
Cambridge University Press; 1999.
9. Youngquist R, Carr S, Davies D: Optical
coherence domain reflectometry: a new
optical evaluation technique. Opt Lett
1987; 12:158.
10. Hee MR, Izatt JA, Swanson EA, et al:
Optical coherence tomography of the
human retina. Arch Ophthalmol 1995;
113:325–332.
11. Swanson EA, Izatt JA, Hee MR, et al: In
vivo retinal imaging by optical coherence
SECTION 10
tomography. Opt Lett 1993; 18:1864–1866.
12. Schuman JS, Puliafito CA, Fujimoto JG:
Principles of optical coherence
tomography. In: Schuman JS, Fujimoto JG,
eds. Optical coherence tomography of
ocular diseases. 2nd edn. Thoroghfare,
New Jersey: Slack; 2004:3–20.
13. Drexler W, Morgner U, Ghanta RK, et al:
Ultrahigh-resolution ophthalmic optical
coherence tomography. Nat Med 2001;
7:502–507.
14. Drexler W, Sattmann H, Hermann B, et al:
Enhanced visualization of macular
pathology with the use of ultrahigh-
resolution optical coherence tomography.
Arch Ophthalmol 2003; 121:695–706.
15. Drexler W: Ultrahigh-resolution optical
coherence tomography. J Biomed Opt
2004; 9:47–74.
16. Gloesmann M, Hermann B, Schubert C,
et al: Histologic correlation of pig retina
radial stratification with ultrahigh-resolution
optical coherence tomography. Invest
Ophthalmol Vis Sci 2003; 44:1696–1703.
17. Altaweel M, Timm R, Webster M, et al:
Assessing AMD with optical coherence
tomgraphy (OCT): fast macular thickness
maps versus high resolution macular
thickness maps. IOVS 2006; 47:abstract
5716.
18. Chan A, Duker JS: A standardized method
for reporting changes in macular thickening
using optical coherence tomography. Arch
Ophthalmol 2005; 123:939–943.
19. Goulding A, Altaweel M: Reproducibility
and quality assessment of stratus optical
coherence tomography (OCT3): fast
macular thickness scans. IOVS 2006;
46:abstract 1545.
20. Hwang JC, Barile GR, Schiff WM, et al:
Optical coherence tomography in asteroid
hyalosis. Retina 2006; 26:661–665.
21. Browning DJ, Fraser CM: Optical
coherence tomography to detect macular
edema in the presence of asteroid hyalosis.
Am J Ophthalmol 2004; 137:959–961.
22. Koozekanani D, Boyer K, Roberts C:
Retinal thickness measurements from
optical coherence tomography using a
Markov boundary model. IEEE Trans Med
Imaging 2001; 20:900–916.
23. Hayreh SS, Jonas JB: Posterior vitreous
detachment: clinical correlations.
Ophthalmologica 2004; 218:333–343.
24. Foos RY: Vitreoretinal juncture;
topographical variations. Invest Ophthalmol
1738 1972; 11:801–808.
25. Foos RY, Kreiger AE, Forsythe AB, et al:
Posterior vitreous detachment in diabetic
subjects. Ophthalmology 1980;
87:122–128.
26. Witkin AJ, Ko TH, Fujimoto JG, et al:
Redefining lamellar holes and the
vitreomacular interface: an ultrahigh-
resolution optical coherence tomography
study. Ophthalmology 2006; 113:388–397.
27. Gass J: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 4th edn.
St Louis: Mosby; 1997.
28. Smiddy WE, Green WR, Michels RG, et al:
Ultrastructural studies of vitreomacular
traction syndrome. Am J Ophthalmol 1989;
107:177–185.
29. Smiddy WE, Michels RG, Glaser BM, et al:
Vitrectomy for macular traction caused by
incomplete vitreous separation. Arch
Ophthalmol 1988; 106:624–628.
30. Margherio RR, Trese MT, Margherio AR,
et al: Surgical management of
vitreomacular traction syndromes.
Ophthalmology 1989; 96:1437–1445.
31. McDonald HR, Johnson RN, Schatz H:
Surgical results in the vitreomacular
traction syndrome. Ophthalmology 1994;
101:1397–1402; discussion 1403.
32. Hikichi T, Yoshida A, Trempe CL: Course of
vitreomacular traction syndrome. Am J
Ophthalmol 1995; 119:55–61.
33. Carpineto P, Ciancaglini M, Aharrh-Gnama A,
et al: Optical coherence tomography
imaging of surgical resolution of bilateral
vitreomacular traction syndrome related to
incomplete posterior vitreoschisis: a case
report. Eur J Ophthalmol 2004;
14:438–441.
34. Carpineto P, Mastropasqua L: Incomplete
posterior vitreoschisis and vitreomacular
traction. Am J Ophthalmol 2005;
140:765–766; author reply 766.
35. Thomas D, Bunce C, Moorman C, et al:
Frequency and associations of a taut
thickened posterior hyaloid, partial
vitreomacular separation, and subretinal
fluid in patients with diabetic macular
edema. Retina 2005; 25:883–888.
36. Catier A, Tadayoni R, Paques M, et al:
Characterization of macular edema from
various etiologies by optical coherence
tomography. Am J Ophthalmol 2005;
140:200–206.
37. Smiddy WE, Maguire AM, Green WR, et al:
Idiopathic epiretinal membranes.
Ultrastructural characteristics and
clinicopathologic correlation. Ophthalmology
1989; 96:811–820; discussion 821.
38. Smiddy WE, Maguire AM, Green WR, et al:
Idiopathic epiretinal membranes:
ultrastructural characteristics and
clinicopathologic correlation. Retina 2005;
25(5 Suppl):811–820; discussion 821.
39. Appiah AP, Hirose T, Kado M: A review of
324 cases of idiopathic premacular gliosis.
Am J Ophthalmol 1988; 106:533–535.
40. Smiddy WE, Michels RG, Gilbert HD, et al:
Clinicopathologic study of idiopathic macular
pucker in children and young adults. Retina
1992; 12:232–236.
41. Smiddy WE, Michels RG, Green WR:
Morphology, pathology, and surgery of
idiopathic vitreoretinal macular disorders. A
review. Retina 1990; 10:288–296.
42. Wilkins JR, Puliafito CA, Hee MR, et al:
Characterization of epiretinal membranes
using optical coherence tomography.
Ophthalmology 1996; 103:2142–2151.
43. Mori K, Gehlbach PL, Sano A, et al:
Comparison of epiretinal membranes of
differing pathogenesis using optical
coherence tomography. Retina 2004;
24:57–62.
44. Suzuki T, Terasaki H, Niwa T, et al: Optical
coherence tomography and focal macular
electroretinogram in eyes with epiretinal
membrane and macular pseudohole. Am J
Ophthalmol 2003; 136:62–67.
45. Haouchine B, Massin P, Tadayoni R, et al:
Diagnosis of macular pseudoholes and
lamellar macular holes by optical
coherence tomography. Am J Ophthalmol
2004; 138:732–739.
46. Gaudric A, Haouchine B, Massin P, et al:
Macular hole formation: new data provided
by optical coherence tomography. Arch
Ophthalmol 1999; 117:744–751.
47. Hee MR, Puliafito CA, Wong C, et al:
Optical coherence tomography of macular
holes. Ophthalmology 1995; 102:748–756.
48. Tanner V, Chauhan DS, Jackson TL, et al:
Optical coherence tomography of the
vitreoretinal interface in macular hole
formation. Br J Ophthalmol 2001;
85:1092–1097.
49. Haouchine B, Massin P, Gaudric A: Foveal
pseudocyst as the first step in macular hole
formation: a prospective study by optical
coherence tomography. Ophthalmology
2001; 108:15–22.
50. Smiddy WE, Michels RG, de Bustros S,
et al: Histopathology of tissue removed
during vitrectomy for impending idiopathic
macular holes. Am J Ophthalmol 1989;
108:360–364.
51. Smiddy WE, Michels RG, Glaser BM, et al:
Vitrectomy for impending idiopathic
macular holes. Am J Ophthalmol 1988;
105:371–376.
52. Ang A, Snead DR, James S, et al: A rationale
for membrane peeling in the repair of stage
4 macular holes. Eye 2006; 20:208–214.
53. Posselt D, Rahman R, Smith M, et al:
Visual outcomes following ICG assisted
ILM peel for Macular Hole. Eye 2005;
19:279–283.
54. Smiddy WE, Feuer W, Cordahi G: Internal
limiting membrane peeling in macular hole
surgery. Ophthalmology 2001;
108:1471–1476; discussion 1477–1478.
55. Da Mata AP, Burk SE, Foster RE, et al:
Long-term follow-up of indocyanine green-
assisted peeling of the retinal internal
limiting membrane during vitrectomy
surgery for idiopathic macular hole repair.
Ophthalmology 2004; 111:2246–2253.
56. Da Mata AP, Burk SE, Riemann CD, et al:
Indocyanine green-assisted peeling of the
retinal internal limiting membrane during
vitrectomy surgery for macular hole repair.
Ophthalmology 2001; 108:1187–1192.
57. Haritoglou C, Reiniger IW, Schaumberger M,
et al: Five-year follow-up of macular hole
surgery with peeling of the internal limiting
membrane: update of a prospective study.
Retina 2006; 26:618–622.
58. Kumagai K, Furukawa M, Ogino N, et al:
Long-term outcomes of internal limiting
membrane peeling with and without
indocyanine green in macular hole surgery.
Retina 2006; 26:613–617.
59. Kimura T, Takahashi M, Takagi H, et al: Is
removal of internal limiting membrane
always necessary during stage 3 idiopathic
macular hole surgery? Retina 2005;
25:54–58.

60. Altaweel M, Ip M: Macular hole: improved
understanding of pathogenesis, staging,
and management based on optical
coherence tomography. Semin Ophthalmol
2003; 18:58–66.
61. Williams GA: Macular holes: the latest in
current management. Retina 2006; 26(6
Suppl):S9–S12.
62. Tadayoni R, Massin P, Haouchine B, et al:
Spontaneous resolution of small stage 3
and 4 full-thickness macular holes viewed
by optical coherence tomography. Retina
2001; 21:186–189.
63. Larsson J, Holm K, Lovestam M-Adrian:
The presence of an operculum verified by
optical coherence tomography and other
prognostic factors in macular hole surgery.
Acta Ophthalmol Scand 2006; 84:301–304.
64. Jaycock PD, Bunce C, Xing W, et al:
Outcomes of macular hole surgery:
implications for surgical management and
clinical governance. Eye 2005; 19:879–884.
65. Wong TY, Klein R, Islam FM, et al: Diabetic
retinopathy in a multi-ethnic cohort in the
United States. Am J Ophthalmol 2006;
141:446–455.
66. Knudtson MD, Klein BE, Klein R, et al: Age-
related eye disease, quality of life, and
functional activity. Arch Ophthalmol 2005;
123:807–814.
67. Kempen JH, O’Colmain BJ, Leske MC,
et al: The prevalence of diabetic
retinopathy among adults in the United
States. Arch Ophthalmol 2004;
122:552–563.
68. Klein R, Klein BE, Moss SE, et al: The
Wisconsin epidemiologic study of diabetic
retinopathy: XVII. The 14-year incidence
and progression of diabetic retinopathy and
associated risk factors in type 1 diabetes.
Ophthalmology 1998; 105:1801–1815.
69. Klein R, Klein BE, Moss SE, et al: The
Wisconsin epidemiologic study of diabetic
retinopathy. XV. The long-term incidence of
macular edema. Ophthalmology 1995;
102:7–16.
70. Kim BY, Smith SD, Kaiser PK: Optical
coherence tomographic patterns of
diabetic macular edema. Am J Ophthalmol
2006; 142:405–412.
71. Goebel W, Franke R: Retinal thickness in
diabetic retinopathy: comparison of optical
coherence tomography, the retinal
thickness analyzer, and fundus
photography. Retina 2006; 26:49–57.
72. Cunningham ET Jr, Adamis AP, Altaweel M,
et al: A phase II randomized double-
masked trial of pegaptanib, an anti-
vascular endothelial growth factor aptamer,
for diabetic macular edema.
Ophthalmology 2005; 112:1747–1757.
73. Hee MR, Puliafito CA, Duker JS, et al:
Topography of diabetic macular edema
with optical coherence tomography.
Ophthalmology 1998; 105:360–370.
74. Hee MR, Puliafito CA, Wong C, et al:
Quantitative assessment of macular edema
with optical coherence tomography. Arch
Ophthalmol 1995; 113:1019–1029.
75. Imai M, Iijima H, Hanada N: Optical
coherence tomography of tractional
macular elevations in eyes with proliferative
diabetic retinopathy. Am J Ophthalmol
2001; 132:458–461.
76. Jaffe GJ: Cystoid macular edema. focal
points: clinical modules for
ophthalmologists; 1994.
77. Kraff MC, Sanders DR, Jampol LM, et al:
Factors affecting pseudophakic cystoid
mascular edema: five randomized trials.
J Am Intraocul Implant Soc 1985;
11:380–385.
78. Dajani HM, Lauer AK: Optical coherence
tomography findings in niacin maculopathy.
Can J Ophthalmol 2006; 41:197–200.
79. Bressler NM: Cystoid macular edema from
niacin typically is not accompanied by
fluorescein leakage on angiography. Am J
Ophthalmol 2005; 139:951; author reply 951.
80. Callanan D, Blodi BA, Martin DF: Macular
edema associated with nicotinic acid
(niacin). JAMA 1998; 279:1702.
81. Spaide RF, Lee JK, Klancnik JK Jr, et al:
Optical coherence tomography of branch
retinal vein occlusion. Retina 2003;
23:343–347.
82. Lerche RC, Schaudig U, Scholz F, et al:
Structural changes of the retina in retinal
vein occlusion – imaging and quantification
with optical coherence tomography.
Ophthalmic Surg Lasers 2001; 32:272–280.
83. BVOS: Argon laser scatter
photocoagulation for prevention of
neovascularization and vitreous
hemorrhage in branch vein occlusion. A
randomized clinical trial. Branch Vein
Occlusion Study Group. Arch Ophthalmol
1986; 104:34–41.
84. Green WR, Chan CC, Hutchins GM, et al:
Central retinal vein occlusion: a prospective
histopathologic study of 29 eyes in 28
cases. Retina 1981; 1:27–55.
85. CVOS: Baseline and early natural history
report. The Central Vein Occlusion Study.
Arch Ophthalmol 1993; 111:1087–1095.
86. Hayreh SS: The CVOS Group M and N
reports. Ophthalmology 1996;
103:350–352; author reply 353–354.
87. Ip M, Kahana A, Altaweel M: Treatment of
central retinal vein occlusion with
triamcinolone acetonide: an optical
coherence tomography study. Semin
Ophthalmol 2003; 18:67–73.
88. Ip MS, Gottlieb JL, Kahana A, et al:
Intravitreal triamcinolone for the treatment
of macular edema associated with central
retinal vein occlusion. Arch Ophthalmol
2004; 122:1131–1136.
89. Hussain D, Gass JD: Idiopathic central
serous chorioretinopathy. Indian J
Ophthalmol 1998; 46:131–137.
90. Quillen DA, Gass DM, Brod RD, et al:
Central serous chorioretinopathy in women.
Ophthalmology 1996; 103:72–79.
91. Ahlers C, Michels S, Elsner H, et al:
Topographic angiography and optical
coherence tomography: a correlation of
imaging characteristics. Eur J Ophthalmol
2005; 15:774–781.
92. Hee MR, Baumal CR, Puliafito CA, et al:
Optical coherence tomography of age-
related macular degeneration and choroidal
neovascularization. Ophthalmology 1996;
103:1260–1270.
Optical Coherence Tomography
93. Stone TW, Sternberg P Jr: Submacular
surgery trials update. Ophthalmol Clin
North Am 2002; 15:479–488.
94. Bressler NM, Bressler SB, Hawkins BS,
et al: Submacular surgery trials randomized
pilot trial of laser photocoagulation versus
surgery for recurrent choroidal
neovascularization secondary to age-
related macular degeneration. I.
Ophthalmic outcomes submacular surgery
trials pilot study report number 1. Am J
Ophthalmol 2000; 130:387–407.
95. Rosenfeld PJ, Intravitreal avastin: the low
cost alternative to lucentis? Am J
Ophthalmol 2006; 142:141–143.
96. Gragoudas ES, Adamis AP, Cunningham ET,
et al: Pegaptanib for neovascular age-
related macular degeneration. N Engl J
Med 2004; 351:2805–2816.
97. Rosenfeld PJ, Brown DM, Heier JS, Boyer
CHAPTER 130
DS: MARINA Study Group. Ranibizumab
for neovascular age-related macular
degeneration. N Engl J Med 2006 Oct 5;
355(1):1419–1431.
98. Brown DM, Kaiser PK, Michels M,
Soubrane G, Heier JS: ANCHOR Study
Group. Ranibizumab versus verteporfin for
neovascular age-related macular
degeneration. N Eng J Med 2006 Oct 5;
355(14):1432–1444.
99. Rosenfield PJ, Moshfeghi AA, Puliafito CA:
Optical coherence tomography findings
after an intravitreal injection of bevacizumab
(avastin) for neovascular age related
macular degeneration. Ophthalmic Surg
Lasers Imaging 2005; 26:331–335.
100. Fung AE, Lalwani GA, Rosenfeld PJ,
Dubovy SR: An optical coherence
tomography-guided, variable dosing
regimen with intravitreal ranibizumab
(Lucentis) for neovascular age-related
macular degeneration. Am J Ophthalmol
2007 Apr; 143(4):566–583.
101. Altaweel M, Hubbard L, Gagnon R: The
utility of optical coherence tomography in
eligibility determination for clinical trials of
macular disease therapy. Invest Ophthalmol
Vis Sci 2005; 46:abstract 1577.
102. Salm D, Altaweel M, Chew E, et al:
Reproducibility of macular thickness
measurements within stratus OCT3 and
between OCT3 and OCT2. IOVS 2005;
46:abstract 1591.
103. Diabetic Retinopathy Clinical Research
Network, Browning DJ, Glassman AR,
Aiello LP, Beck RW. Relationship between
optical coherence tomography-measured
central retinal thickness and visual acuity in
diabetic macular edema. Ophthalmology
2007 Mar; 114(3):525–536.
104. Chen TC, Cense B, Pierce MC, et al:
Spectral domain optical coherence
tomography: ultra-high speed, ultra-high
resolution ophthalmic imaging. Arch
Ophthalmol 2005; 123:1715–1720.
105. Hangai M, Ojima Y, Gotoh N, Inoue R:
Three-dimensional imaging of macular
holes with high-speed optical coherence
tomography. Ophthalmology 2007 Apr;
114(4):763–773.
1739
 CHAPTER
131 Retinal Arterial Occlusions
Craig M. Greven and Wesley H. Adams
Overview
Retinal artery occlusion leads to profound functional deficits in
the distribution of the visual field supplied by the affected vessel.
These events, although relatively rare, not only have effects on
the visual system of the patient, but may be the initial indication
of a systemic life-threatening disease.
The average age at presentation of patients with central retinal
artery occlusion (CRAO) is the early to mid-60s. However, arterial
occlusive disease can occur at any age. Males are affected
slightly more commonly than females, and there is no racial
predilection.
Numerous mechanisms of retinal arterial occlusion have been
documented, but the most common are embolic, thrombotic,
vasculitic, and vasospastic. The most common sources of
embolic occlusion are atherosclerotic disease of the carotid
artery and cardiac disease. Thrombosis is also a major cause of
retinal arterial occlusions. Hereditary and acquired conditions, as
well as local factors, can promote thrombosis. The number of
hereditary conditions associated with retinal arterial occlusive
disease continues to grow as our understanding of the
coagulation system increases. Vasculitis is another mechanism
associated with arterial occlusive disease of the retina. Systemic
vasculitic conditions like giant cell arteritis, as well as local areas
of vasculitis of the retina, can promote obstruction.
Retinal arterial occlusive disease can be classified as
ophthalmic artery, central retinal artery, branch artery, and
cilioretinal artery. Ophthalmic and central have the worst visual
prognosis, whereas branch and cilioretinal artery occlusions
typically have better visual prognosis. The hallmark of arterial
occlusive disease of the retina on clinical examination is ischemic
retinal whitening, and on fluorescein angiography is delayed
perfusion of the affected vessel.
Management of retinal arterial occlusive disease includes
attempting to reestablish retinal arterial blood flow, determining
the associated systemic disease processes and reason for
occlusion, and management of long-term ocular complications.
The single most important factor in determining visual outcome
in patients with retinal arterial occlusive disease is duration of
retinal ischemia. Histopathologic studies have shown that total
occlusion of the central retinal artery leads to irreversible visual
loss in less than 2 h. Aggressive management is indicated in
patients who present within 24 h of symptoms and the individual
management of each patient must be determined on a case-by-
case basis.
Systemic workup should include carotid ultrasound to look for
atherosclerotic disease, echocardiography, and hematologic
workup to rule out a potential thrombotic or vasculitic condition.
In age-appropriate patients, a sedimentation (sed) rate and C-
reactive protein must be considered when the diagnosis of
temporal arteritis is entertained.
INTRODUCTION
Occlusion or obstruction of the ophthalmic, central retinal,
branch retinal, or a cilioretinal artery leads to acute loss of vision
in the distribution of the affected retina. von Graefe initially
described CRAO secondary to emboli related to bacterial endo-
carditis in the nineteenth century.1 Since then our understanding
of retinal arterial occlusion has increased dramatically. Although
relatively infrequent, these events can profoundly impact not
only the visual function of the individual, but also can be the
initial indication of life-threatening systemic disease. An under-
standing of the basic anatomy and pathologic mechanisms of
occlusion is essential in determining the appropriate manage-
ment and evaluation of patients presenting with acute retinal
arterial occlusions.
VASCULAR ANATOMY
The ophthalmic artery is the first intracranial branch of the
internal carotid artery. After entering the orbit, the ophthalmic
artery gives off the central retinal artery, which runs adjacent to
the inferior margin of the optic nerve. The central retinal artery
penetrates 13 mm posterior to the globe to course through the
substance of the nerve to supply the inner retina. Approximately
20 short posterior ciliary arteries arise from the ophthalmic artery
and penetrate the sclera in a ring around the optic nerve to supply
the choroid and outer retina. Cilioretinal arteries arise from
these short posterior ciliary arteries and are present in 30% of
eyes and 50% of individuals.2,3 In 15% of people a cilioretinal
artery supplies some portion of the macular circulation.3
The surface of the optic disk is supplied by branches of the
central and branch retinal arteries. The laminar and prelaminar
optic nerve is supplied by branches of the posterior ciliary
arteries. The deeper optic nerve in supplied by intraneuronal
branches from the central retinal artery and recurrent pial
branches of the central retinal and ophthalmic artery.
Within the retina, larger branches of the central artery course
through the nerve fiber and ganglion cell layers. As the arterial
circulation divides and lumen size narrows smaller arterioles
and capillaries extend through these layers into the inner
nuclear layer.4 Central retinal artery circulation does not extend
past the boundary of the inner nuclear and inner plexiform
layers. The choroidal circulation and choriocapillaris supply the
outer retina.
While retinal circulation is generally end arterial in nature,
two anastomoses exist in the region of the optic disk between
branches of the central retinal artery and short posterior ciliary
arteries.5 The first occurs in the capillary beds of the optic nerve
head. Here superficial capillaries derived from the central
1741
 RETINA AND VITREOUS
retinal artery lie adjacent to those capillaries that penetrate the
deeper regions of the prelaminar and lamina cribrosa, that
originate from posterior ciliary circulation. The second anasto-
mosis occurs within the dural sheath of the optic nerve. There
intraneuronal branches of the central retinal artery communi-
cate with recurrent pial branches.
HISTOPATHOLOGY OF ARTERIAL
OCCLUSIONS
The retina has a high oxidative capacity and a high level of
glycolytic activity. The decrease or absence of perfusion caused
by central retinal artery obstruction leads to decreased delivery
of glucose and more importantly oxygen6 to the tissues of the
retina. Ischemia leads to edema as neuron cellular membranes
burst4,7 producing the associated funduscopic whitening of the
retina caused by opacification of the ganglion cell layer. The
opacification is most prominent in the macular region where
SECTION 10
the multiple layers of ganglion cells reside. Retinal opacification
generally decreases toward the periphery as the ganglion cell
population diminishes, and is also absent from the avascular
zone of the foveola where ganglion cells are absent.8 The classic
‘cherry red spot’ is a result of the visible red reflex of the
perfused choroid at this location.
Optical coherence tomography (OCT) of acute CRAO corre-
lates with these histopathologic features and/or characteristics.
Findings on OCT demonstrate an increase in inner layer
reflectivity and muted outer layer reflectivity around the foveola
with normal reflectivity of the retinal pigment epithelium
beneath the foveola (Fig. 131.1).9 Eventually, cellular debris in
the ischemic inner layers of the retina undergoes phagocytosis
and gliosis leading to atrophy.
Animal studies have demonstrated swelling of the organelles
that precede axonal and dendritic rupture with decreased
neuronal cell count. Mitochondria, the first organelle affected in
the ganglion cells,6 began to swell as early as 15 min after
CRAO in squirrel monkeys.7 Microtubules and cisternae of the
endoplasmic reticulum are also acutely susceptible to ischemia.6
In Kroll’s experimental occlusion of the central retinal artery in
squirrel monkeys, swelling of the endoplasmic reticulum had
occurred by 3.5 h.7 Müller cells were relatively more resistant to
ischemia than the ganglion cells in both species, presumably
due to their proximity to retinal capillaries and the chorio-
capillaris, and a greater ability to metabolize under anaerobic
conditions. These changes are similar to those seen in
humans.7,10,11
Retinal cellular survival and thus final visual outcome in
humans is related to duration of ischemia and the presence of
residual circulation. However, no controlled data are available
in humans. In squirrel monkeys, Kroll observed axonal and
FIGURE 131.1. OCT of CRAO demonstrating increased thickness in
the inner retinal layers and muted outer layer/retinal pigment
epithelium reflectivity surrounding the foveola. Note that there is
1742 normal reflectivity of the retinal pigment epithelium at the foveola.
dendritic lysis by 3.5 h and extensive cellular loss by 16 h.7
Hayreh and associates found that rhesus monkey retinas could
tolerate 97–98 min of total occlusion, and that only half of eyes
occluded for 102 min recovered vision. However, all eyes
occluded 105 min or more suffered irrecoverable ischemia.6,12,13
DEMOGRAPHICS/INCIDENCE/
PREVALENCE
Retinal arterial occlusions may occur at any age, but the average
age of patients with CRAO in two large series is 62 and 67.8,14
Most series demonstrate a slight male predominance.8,14,15
There does not appear to be any racial predilection, however.
Additionally, the right and left eyes appear to be involved equally.
Common systemic risks factors for retinal arterial occlusive
disease include hypertension, diabetes, lipid disorders, and car-
diac and systemic atherosclerotic disease.
It is difficult to determine the precise incidence and preva-
lence of arterial occlusive events in the retina. However, Brown
and co-authors suggested that 1 in 10 000 patient visits to a
tertiary-care eye hospital was related to CRAO.16 Additionally,
he estimated that less than 1 in 50 000 outpatient visits to an
ophthalmologist will be a patient less than age 30 with retinal
arterial occlusive disease.16
MECHANISMS OF OCCLUSION
The principal mechanisms operative in occlusion of the retinal
arterial system are embolic, thrombotic, vaso spastic, extra-
vascular compression, and vasculitic. Other mechanisms such
as radiation and elevated intraocular pressure occur much less
commonly. It is important to note that more than one mechan-
ism may occur at the same time in a patient. An embolism to
the retinal arterial circulation can originate as a venous throm-
bosis reaching the arterial circulation via a right to left cardiac
shunt. CRAO secondary to giant cell arteritis is primarily a
vasculitic phenomenon, with thrombosis being the ultimate
occlusive event.
In general, age is an important factor in determining the mech-
anism of occlusion. Patients aged 50 and greater are likely to
have occlusions associated with embolic disease while younger
patients are more likely to have occlusions secondary to
thrombosis.
EMBOLISM/ENDOGENOUS
Since retinal arterial occlusive disease is primarily a disease of
the elderly, embolic occlusion represents the most common
mechanism. Atherosclerosis of the carotid system is the most
common source of retinal emboli with 80% being associated
with carotid artery disease.17,18 A common misconception
regarding carotid disease leading to emboli is that the degree of
obstruction of the carotid artery is of paramount importance.
Although degree of obstruction is important, the presence of an
ulcerative plaque, even with minimal stenosis, can be more
likely to lead to emboli than an extensively occluded carotid
artery. Carotid artery disease can be evaluated by carotid ultra-
sonography, arteriography, and CT angiography.
The heart and major vessels are another important source of
emboli that must be considered when confronted with a patient
with embolic retinal arterial occlusions. Valvular abnormal-
ities,19–21 tumors, like atrial myxomas,22,23 and thrombus forma-
tion in the left atrium secondary to conditions like atrial
fibrillation, can lead to emboli formation and vascular occlu-
sion. Additionally, right to left shunts, like patent foramen
ovale, can allow emboli from venous thrombotic disease to
reach the arterial circulation.24 Important in evaluating embolic
 Retinal Arterial Occlusions

disease originating from the heart is echocardiography. Trans-

thoracic echocardiography is the preferred initial screening
technique. In cases where there is a high suspicion of disease
that is not detected by transthoracic echocardiography, trans-
esophageal echocardiography can be helpful in identifying a
source of emboli.25,26 Other rare sources of endogenous emboli
include fat emboli from long bone fractures,27 amniotic fluid
emboli at the time of delivery,28,29 and leukoembolization
secondary to conditions like pancreatitis.

Emboli/Exogenous Source
Exogenous emboli can reach the retinal circulation leading to
arterial occlusive events. Examples include talc emboli associ-
ated with intravenous drug abuse30 and emboli from injections
of steroids in the nasal or periorbital area,31,32 or related to blood
products like platelet emboli during transfusion. Fragments of
catheter tips and artifical heart valves may also cause arterial
occlusion.

CHAPTER 131
FIGURE 131.3. CRAO with cilioretinal sparring. Note elongated
Retinal Emboli/Types platelet fibrin emboli in retinal arterial tree.
Although embolic obstruction is presumably the most common
cause of retinal arterial occlusions, visible emboli detected
ophthalmoscopically are only evident in 20–30% of patients
with retinal arterial occlusive disease.14 Clinically the most
common are cholesterol emboli, platelet fibrin emboli, and
calcific emboli (Figs 131.2–131.4).
Cholesterol emboli are small, glistening yellow in color, and
typically do not occlude the vessel distal to the emboli. These
most commonly arise from atherosclerotic plaques of the
carotid artery. Platelet fibrin emboli may appear gray-white, are
larger and longer than cholesterol emboli, and may be seen to
pass through the retinal vessels.
Calcific emboli are larger, gray-white in color, and associated
with more severe local obstructions. Arruga felt that calcific
emboli were more likely to arise from cardiac valvular disease.15
A comprehensive list of emboli types is provided in Table 131.1.

THROMBOSIS
Thrombosis is another mechanism causing arterial occlusive
disease of the retina. Virchow’s classic triad concerning the
pathogenesis of thrombosis includes vessel wall abnormalities,
stasis of blood flow, and changes in the blood components.
While any one of these factors alone may lead to thrombosis, FIGURE 131.4. Inferior hemiretinal artery occlusion in right eye. Note
calcific emboli at the inferior margin of the disk causing occlusion.
combinations of these factors significantly increase the likelihood

TABLE 131.1 Emboli

I. Endogenous
A. Carotid atheroma
B. Cardiac valvular disease
C. Cardiac tumor
D. Fat emboli
E. Leukoemboli
F. Amniotic fluid emboli
G. Septic emboli
II. Exogenous
A. Injected steroids
B. Catheter tips
C. Talc
FIGURE 131.2. Cholesterol emboli at bifurcation of the inferior nasal
retinal artery. Note glistening characteristics. No functional deficit was D. Artificial heart valves
present. 1743
 RETINA AND VITREOUS

of these episodes. While venous thrombosis occurs most com-

monly, arterial thrombotic disease of the retina also does occur.
Structural abnormalities in a vessel like prepapillary arterial
loop can contribute to retinal arterial occlusion by thrombosis.
This structural abnormality, which leads to turbulence and
stasis of flow, has been reported to cause CRAOs.33
Tremendous advances have occurred during the last two
decades in understanding abnormalities of blood components
and their relationship to intravascular thrombosis. Both here-
ditary and acquired abnormalities have been identified. Throm-
bophilia is the term used to describe conditions that are
genetically determined and increase the likelihood of vascular
thrombosis (Table 131.2). These abnormalities typically lead to
venous thrombosis, but when they interact with other local
or systemic hypercoagulable factors like trauma, malignancy,
pregnancy, oral contraceptive use, autoimmune disease, and
cigarette smoking, they may lead to arterial thrombosis. These
hereditary thrombophilic states should be considered in patients
SECTION 10

with retinal arterial occlusions, particularly with a positive family

FIGURE 131.5. Twenty-four-year-old with diabetes, pregnancy, and
history of thrombotic events occurring at a young age. While protein S deficiency. Note branch macular artery occlusion in left eye.
entire textbooks have been devoted to discussing these throm-
bophilic conditions, a brief explanation of some of the more
common of these conditions that have been associated with
retinal arterial occlusive events will be useful.

Antithrombin Deficiency
Human antithrombin (AT) is a plasma protein that is a protease
inhibitor and prevents the formation of thrombi.34 Previously
termed AT III deficiency, AT deficiency was the first hereditary
deficiency of an anticoagulant protein described. Inherited as an
autosomal dominant trait, AT deficiency is associated with a
thrombotic tendency typically manifested as venous thrombo-
embolism. However, retinal arterial occlusions secondary to
thrombosis have been reported.35

Protein C and S Deficiency

Protein C and protein S are vitamin K dependent plasma glyco-
proteins synthesized in the liver. Deficiency in these proteins
occurs primarily as a hereditary condition inherited as an auto-
somal dominant trait, but can be an acquired defect associated
with advanced severe liver disease. Both protein C and protein FIGURE 131.6. Fluorescein angiogram of BRAO secondary to protein
S serve as cofactors for the anticoagulant function of activated S deficiency in left eye.
protein C, a protein that inactivates factors 5A and 8A, and

TABLE 131.2 Thrombophilias Associated with Retinal Arterial downregulates thrombosis.34 Deficiencies of either protein C or
Occlusions protein S leads to a thrombotic tendency, and arterial occlusive
disease of the retina has been described with each (Figs 131.5
I. Factor V Leiden
and 131.6).36,37
II. Antithrombin deficiency
Activated Protein C Resistance and Factor V
III. Protein C deficiency
Leiden
IV. Protein S deficiency As mentioned previously, activated protein C inactivates factor
V. Hyperhomocystinemia V-A and factor VIII-A and downregulates thrombosis. Activated
protein C resistance refers to an abnormally reduced anti-
VI. Anti-phospholipid antibodies
coagulant response of a subject’s plasma to activated protein C
VII. Lupus anticoagulant in in vitro testing. Although any genetic abnormality of the
VIII. Anticardiolipin protein C pathway can cause activated protein C resistance, more
than 90% of hereditary activated protein C resistance subjects
IX. Homozygous C677T polymorphism in methylene have the same genetic abnormality termed factor V Leiden.
tetrahydrofolate reductase
Factor V Leiden is an abnormal factor V associated with a point
X. Prothrombin G20210A mutation and a single amino acid change. Factor V Leiden is
XI. Dysfibrogenemia resistant to the proteolytic action of activated protein C, leading
to increased thrombin formation.34 The subsequent hyper-
XII. Elevated factor VIII coagulable state is one of the most common hereditary causes
XIII. Elevated factor IX of thrombophilia and has been associated with arterial occlusive
1744 disease of the retina.38,39
 Retinal Arterial Occlusions

Hyperhomocystinemia
Homocysteine is an intermediate in the metabolism of the
amino acids methionine and cysteine. Hyperhomocystinemia
refers to elevated plasma levels of homocysteine and can be
caused by numerous factors. The most common genetic cause
of hyperhomocystinemia is a mutation in the enzyme methylene
tetrahydrofolate reductase (MTHFR) leading to elevated levels
of plasma homocysteine. Present in 10–20% of Caucasians,
10% of Asians, and rare in blacks, either alone or in combi-
nation with low folate, B6 or B12 levels or other conditions like
renal failure, hypothyroidism, smoking, excess caffeine con-
sumption, and inflammatory bowel disease, this defect can be
associated with increased levels of plasma homocysteine. The
exact mechanism of thrombosis associated with hyperhomo-
cystinemia is poorly understood40 but endothelial toxicity and
smooth muscle proliferation have been proposed. Arterial
thrombotic disease of the retina has been reported.41,42

CHAPTER 131
Antiphospholipid Syndrome
The antiphospholipid syndrome (previously known as anti-
phospholipid antibody syndrome, anticardiolipin antibodies FIGURE 131.7. BRAO associated with vasculitis secondary to retinitis
syndrome, and lupus anticoagulant) is an acquired disorder due to Bartonella henselae.
associated with thrombotic complications. The condition is
considered secondary if associated with other diseases like
systemic lupus erythematosus, other autoimmune disorders,
viral infections, malignancies, or those associated with medi-
VASOSPASM
cations. It is considered primary when it occurs in the absence Vasospasm as a primary cause of retinal arterial occlusive
of any of these conditions. The syndrome is characterized by disease57–62 is felt to be a rare occurrence. Gass has suggested
the presence of antibodies to phospholipid protein complexes that some degree of reflex spasm may play a role in retinal
(anticardiolipin, antiphosphatidyl serine or anti-b 2 glyco- arterial occlusions from many causes including migraine, collagen
protein) or by the detection of lupus anticoagulants.43 The vascular disease, and sickle cell hemoglobinopathies.63,64
precise mechanism by which these antiphospholipid antibodies
promote thrombosis is poorly understood, but may be related to
the inhibition of prostacyclin, a platelet inhibitory prosta- OTHER MECHANISMS
glandin. It has also been speculated that it might impair protein Local conditions in the eye and orbit may lead to situations pre-
C and AT III anticoagulant mechanisms. While venous occlusive disposing to retinal arterial occlusive events. Examples of con-
disease is most common, arterial occlusive disease of the ditions associated with retinal arterial occlusion from intrinsic
retina also has been associated with the antiphospholipid structural anomalies include peripapillary arterial33 loop, optic
syndrome.44–50 nerve head drusen,65 and intraocular foreign body (Figs 131.8
and 131.9).
Elevated intraocular pressure secondary to angle-closure
VASCULITIS AND GIANT CELL ARTERITIS glaucoma or compression of the globe can lead to CRAO.
The classic vasculitis-related CRAO occurs in giant cell arteritis. External compression of the ophthalmic artery or central retinal
As mentioned previously, giant cell arteritis is an example of an
arterial occlusion occurring from a combined mechanism, both
vasculitis and thrombosis.51 Often associated with ocular pain
because of the profound ischemia, patients of the appropriate
age (greater than 55 years) who present with CRAO should be
questioned for associated symptoms like headache, scalp tender-
ness, jaw claudication, malaise, anorexia, fever, and weight loss,
recognizing that 20% of patients with giant cell arteritis are with-
out systemic symptoms. Patients with acute CRAO secondary
to giant cell arteritis may have prodromal transient blurring of
vision for weeks to months prior to the occlusive event.
The suspected diagnosis is solidified by an elevated erythrocyte
sedimentation rate and C-reactive protein and confirmed by
temporal artery biopsy. Making an accurate diagnosis and
initiation of high-dose steroid therapy is imperative because
second eye involvement may occur soon following presentation.
Systemic vasculitis associated with collagen vascular diseases
can cause retinal arterial occlusions. Classic examples are rheu-
matoid vasculitis and systemic lupus erythematosus. Other
systemic vasculities like Behçet’s disease52 may lead to branch
retinal arterial occlusions. Localized vasculitis in the retina
can occur in other conditions like toxoplasmosis retinitis
and Bartonella henselae leading to retinal arterial occlusions FIGURE 131.8. BRAO in right eye secondary to prepapillary arterial
(Fig. 131.7).53–56 loop. 1745
 SECTION 10 RETINA AND VITREOUS

FIGURE 131.9. Inferior BRAO secondary to intraocular foreign body

imbedded in the retina with distal occlusion of the inferior temporal
artery. There is hemorrhage overlying the intraocular foreign body.
FIGURE 131.10. Ophthalmic artery occlusion in left eye secondary to
atrial myxoma emboli. Note pallid swelling of the optic nerve. No
evidence of cherry red spot. Note segmentation of the blood column
artery caused by orbital cellulitis, orbital hemorrhage abscess in the retinal vessels.
formation, cavernous sinus thrombosis, and neoplastic disease
may lead to CRAO.

CLINICAL FINDINGS

AMAUROSIS FUGAX
Amaurosis fugax refers to transient monocular loss of vision,
either total or altitudinal, that may serve as a prodromal
symptom for retinal arterial occlusion. Visual loss in amaurosis
fugax typically lasts 7–30 min with total resolution to normal.
Patients with classic symptoms of amaurosis fugax should
undergo complete ophthalmic examination, specifically looking
for the presence of retinal emboli. In these patients, a systemic
workup should be performed for the presence of embolic
disease. Specifically, an evaluation of the carotid artery system
as well as cardiac evaluation with echocardiography should be
performed. Consultation with the patient’s internist or
neurologist is indicated to determine whether anticoagulants
should be initiated.

OPHTHALMIC ARTERY OCCLUSIONS

Ophthalmic artery occlusion causes profound painless unilateral
loss of vision. Visual function in these cases is extremely poor
as both the retinal and choroidal circulation is interrupted.
Visual acuity ranges from counting fingers to no light per-
ception. An afferent pupillary defect is present. The classic
fundus picture is that of an acutely infarcted retina with
extensive retinal whitening (Fig. 131.10). Often there is pallid
swelling of the optic disk. Because the choroidal circulation is
compromised, a cherry red spot is not visualized. There is often
boxcarring or segmentation of the blood column of the retinal
vessels. Fluorescein angiography shows no or markedly delayed
background choroidal flush and minimal or delayed filling of
the retinal vasculature.
Visual recovery is rare in cases of ophthalmic artery occlusion.
Electroretinographic testing can help differentiate ophthalmic
artery occlusions from CRAO. In ophthalmic artery occlusions,
1746
FIGURE 131.11. Chronic ophthalmic artery occlusion in right eye.
Note pale disk and ischemic retinal arteries and veins.
both the B wave and A wave are absent, while in CRAO with
intact choroidal perfusion, the A wave is present.
The chronic picture of ophthalmic artery occlusion is a pale
disk with attenuation of the retinal arterials and venules
(Fig. 131.11). Often, retinal pigment epithelial abnormalities
will occur related to the profound ischemia of the retinal
pigment epithelium and choriocapillaris.
CENTRAL RETINAL ARTERY OCCLUSIONS
CRAOs also present with painless unilateral profound loss of
vision. Visual acuity of less than 20/400 occurs in more than
 Retinal Arterial Occlusions

CHAPTER 131
a

FIGURE 131.12. CRAO in left eye. Note cherry red spot with
edematous ischemic retina. Note segmentation of blood column.

90% of eyes at the time of presentation. An afferent pupillary

defect is present. Visual fields are depressed in the area of the
ischemic retina. The retina shows ischemic whitening, and
the retinal arterials and veins manifest boxcarring. A cherry
red spot is present due to the intact choroidal circulation
(Fig. 131.12). The diagnosis may not be obvious in patients
presenting within 1–2 h of occlusion, prior to the development
of an edematous retina. In these cases, fluorescein angiography
is useful and will show an intact choroidal flush with absent,
incomplete, or delayed filling and a leading edge of dye in the
retinal circulation (Fig. 131.13a,b).
The median final visual acuity following resolution of edema
in CRAOs is counting fingers. However, in select cases with
intact cilioretinal arteries supplying the fovea, Snellen visual
acuity may improve to 20/20 (Figs 131.14 and 131.15). Visual
field defects persist in the area of the infarcted retina. Chronic b
fundus changes in CRAO include optic atrophy, attenuated
retinal arterials and venules, and an atrophic-appearing retina. FIGURE 131.13. Fluorescein angiogram of CRAO left eye at (a) 33 s
and (b) 47 s showing a leading edge of dye in the arterial system.
BRANCH RETINAL ARTERY OCCLUSIONS
Branch retinal artery occlusion (BRAO) presents as an acute
painless loss of visual field in the distribution of the occluded
artery. Visual acuity may range from 20/20 to 20/400 depending
CILIORETINAL ARTERY OCCLUSIONS
on the degree of foveal involvement. An afferent pupillary defect Approximately 35% of eyes and 50% of people have cilioretinal
may be present, depending on the degree of retina involvement. arteries. As mentioned previously, cilioretinal arteries are derived
Retinal whitening, along the distribution of the artery is usually from the short ciliary arteries. Typical symptoms of patients
present, but may not occur in nasal branch artery occlusions with cilioretinal artery occlusions are pericentral scotomas,
due to the single layer of ganglion cells present there. Emboli are often subtle, in the distribution of the artery.67 As the area
identified in ~30% of cases. Fluorescein angiogram depicts supplied by the occlusion is usually small, afferent pupillary
delayed transit of the dye through the affected vessel, and often defects are often not present. Although any of the previously
retrograde filling of the vessel can be observed later in the described mechanisms of occlusion may be operational, cilio-
angiogram (Figs 131.16 and 131.17). Combined branch retinal retinal artery occlusions may occur in conjunction with central
artery and vein occlusions are relatively rare (Fig. 131.18). retinal venous occlusive disease and anterior ischemic optic
Patients with BRAOs typically retain excellent visual acuity neuropathy (Figs 131.19 and 131.20).68
following the acute event, as long as a portion of the foveal Cilioretinal artery occlusions occurring in isolation usually
vasculature maintains normal perfusion. Visual acuity improves have a prognosis as good as or better than BRAOs, with 90%
to 20/40 or better in 80% of these eyes, but visual field defects improving to 20/40 or better visual acuity. When cilioretinal
persist.66 The fundus appearance may return to near normal artery occlusions occur concomitant with CRVO, the prognosis
weeks to months following the event. varies depending on resolution of complications associated with
1747
 SECTION 10 RETINA AND VITREOUS
FIGURE 131.14. Fundus photograph of right eye with CRAO with
cilioretinal sparing. Visual acuity improved to 20/20.
FIGURE 131.15. Fluorescein angiogram of right eye showing
perfused cilioretinal artery, but CRAO and delayed filling of the retinal
arterials.
the central retinal vein occlusion like macular edema, ischemia,
and hemorrhage.69
MANAGEMENT
Management of patients with retinal arterial occlusions can be
considered in three aspects: (1) management of the acute occlusive
event in an attempt to restore visual function; (2) workup of the
patient looking for potential systemic conditions requiring
treatment; and (3) management of the remote complications
and sequelae of the arterial occlusive event. Although the first
two are the most important aspects, all are critical for optimal
1748
FIGURE 131.16. Inferior BRAO with calcific emboli at inferior margin
of the optic disk beneath overlying vein.
FIGURE 131.17. Fluorescein angiogram of inferior BRAO showing
delayed perfusion of inferior retina with retrograde filling of inferior
retinal veins.
patient management. With regards to visual function, attempts
to restore visual function are most critical in central and
ophthalmic artery occlusions and many of the methods we will
describe are often not utilized in branch or cilioretinal artery
occlusions. Patients with BRAO or cilioretinal artery occlusion
typically have an excellent prognosis for regaining visual acuity.
However, the management of each case much be individualized.
As previously mentioned, the duration of retinal ischemia is
the most important factor in determining prognosis. Since it is
often difficult to pinpoint the actual initial occlusive event,
aggressive management is appropriate, particularly in patients
with a duration of occlusion less than 24 h. While there are
many reports of successful outcomes with various treatments in
select cases, unfortunately, there is no proven beneficial
treatment for improving visual outcomes in patients with these
events.70 Therapeutic goals are to restore blood flow as quickly

FIGURE 131.18. Combined branch retinal artery and vein occlusion in
right eye.
FIGURE 131.19. Inferior cilioretinal artery occlusion with associated
central retinal vein occlusion.
as possible to limit the damage to the cellular constituents of
the retina.
Digital ocular massage is a simple, common, noninvasive
initial technique utilized to restore retinal circulation. In this
technique the fingers are used to compress the globe, raising the
intraocular pressure with subsequent release of the pressure
hoping that the arterial pulse will displace any occlusive emboli
into the distal retinal arterioles and restore flow. No statistical
benefit of ocular massage has been noted, but as it is a simple
treatment with low morbidity, it should be tried in all patients
with CRAO.
Reduction of intraocular pressure through ocular antihyper-
tensives and paracentesis which theoretically may also dislodge
Retinal Arterial Occlusions
CHAPTER 131
FIGURE 131.20. Cilioretinal artery occlusion in right eye, associated
with anterior ischemic optic neuropathy.
an embolus have been attempted to improve retinal arterial
circulation. Studies have shown no significant difference in final
versus initial visual outcomes in use of topical beta blockers,
oral acetazolamide, or paracentesis.71,72
Medical vasodilatation utilizing sublingual nitroglycerin,
calcium channel blockers and pentoxifylline have also been
used to improve the retinal arterial circulation. While results of
one study found that the pentoxifylline group had less neovas-
cularization compared to standard treatment, there was no defi-
nitive improvement in visual outcomes.73 To date there are only
anecdotes of effectively treating CRAO with nitroglycerin.74,75 It
has been hypothesized that nifedipine or other calcium channel
blockers may reduce the effects of calcium overload in ischemic
retina;76 however, to date no studies showing an improvement
in final visual outcome have been documented. Carbogen, 95%
oxygen and 5% carbon dioxide, is an inhalation treatment that
may cause dilation of retinal arterioles,77 and has been used to
treat CRAO. This modality of treatment has not shown benefit
to final visual outcome and is generally no longer used.72
There are case reports of thrombolytic therapy improving
visual recovery even when initiated more than 2 h after occlu-
sion. However, less than 16% of CRAO cases are due to platelet-
fibrin obstruction.15 Given the lack of clinical evidence of
improved visual outcome, potential for systemic complications,
and inherent difficulty establishing nonembolic etiology, the
decision to attempt fibrinolytic therapy using drugs like TPA
should be made carefully.8,78 More data may justify more
widespread future use of local or systemic modalities of
treatment.71,79–82
Surgical treatments have been tried with embolic arterial
occlusion with occasional/rare efficacy. Laser photo disruption
of an embolus has been reported in select patients to cause
passage of the embolus through the arterial tree with improve-
ment in outcomes.83 Vitrectomy with cannulation of the central
retinal artery has also been proposed for management of
embolic retinal arterial occlusive disease.84 No randomized trial
data have confirmed the efficacy of any of these treatments.
Although mentioned previously, in patients with CRAO, if
giant cell arteritis is suspected by clinical and laboratory para-
meters, high-dose steroid therapy should be initiated while
awaiting temporal artery biopsy.
The second aspect of management of retinal arterial occlusive
disease is systemic workup. This has been covered thoroughly
1749
 RETINA AND VITREOUS

is estimated at up to 40%.95 Visual prognosis in the ocular

TABLE 131.3 Initial Workup
ischemic syndrome is poor with the majority of cases pro-
I. Carotid ultrasound gressively losing vision. Panretinal laser photocoagulation may
be efficacious in preventing the development of neovascular
II. Echocardiography – transthoracic, transesophageal
glaucoma. Focal laser photocoagulation in ocular ischemic
III. ESR, C-reactive protein syndrome patients with macular edema is another treatment
IV. CBC, platelet count modality where efficacy has not been proven through random-
ized controlled clinical trials, but may be reasonable. Prompt
V. PT, PTT referral to an internist, neurologist, or vascular surgeon is
VI. Protein C, protein S, activated protein C, factor V Leiden, necessary to address modifiable risk factors and to consider
fasting plasma homocysteine level, anti-phospholipid carotid endarterectomy in the appropriate patient. The efficacy
antibodies of endarterectomy in stroke prevention in symptomatic patients
with 70–99% stenosis has been demonstrated in the North
American symptomatic carotid endarterectomy trial.96
within this chapter, but carotid artery studies including duplex
Doppler ultrasound, transthoracic or transesophageal echo-
cardiography,85 and hematologic testing to rule out various
vasculitic and thrombosis type syndromes must be performed
SECTION 10

(see Table 131.3).86 In general the workup should be tailored to

the patient’s age16,87,88 and co-morbidities. In up to 30% of
patients, no systemic associated condition leading to arterial
occlusion is documented.
The most devastating long-term ocular complication of retinal
arterial occlusive disease is neovascular glaucoma. Neovascular
glaucoma has been reported to occur in 2–16% of these eyes.89,90
The time from occlusion to development of neovascular
glaucoma ranges from one week to years with most events
occurring during the first 2 months. While the eye typically has
limited vision secondary to the initial occlusion, the preference
of a limited vision, comfortable, cosmetically acceptable eye
versus a blind painful eye is obvious. Treatment is as with any
other form of neovascular glaucoma with laser or cryotherapy
to the retina and ciliary body and topical antihypertensive
medications.

OCULAR ISCHEMIC SYNDROME

While the ocular ischemic syndrome is not a ‘retinal arterial
occlusion’ it does represent chronic arterial insufficiency to the FIGURE 131.21. Red free photograph of right eye showing fairly
retina, choroid, and entire globe. The ocular ischemic syndrome normal posterior pole. Neovascularization of the disk is present.
can be defined as a syndrome of hypoperfusion to the globe
secondary to carotid artery or more rarely ophthalmic artery
occlusive disease. Patients with the ocular ischemic syndrome
may be asymptomatic initially or may note gradual blurring,
often of a transient nature. Patients are typically 50 years old or
older and often have significant atherosclerotic disease with
other cardiovascular or cerebral vascular symptoms.91
Anterior segment findings include chronic flare with minimal
cellular response and neovascularization of the iris or angle
structures. Posterior segment findings include retinal hemor-
rhages in all four quadrants, typically present in the midzone.
Arterials are narrowed and veins are typically of normal caliber.
This is a differentiating feature from central retinal vein occlu-
sion where veins are dilated. Microaneurysms and macular
edema may be present and in advanced cases neovascular-
ization of the disk or retina may be present.
On fluorescein angiography there is often delayed asym-
metric filling of the choroid, delayed retinal arterial filling,92 and
prolonged venous transit time.93 Additionally, the retinal
vessels often stain late in the study indicating chronic retinal
ischemia.94 Electroretinography typically shows decreased
amplitude of the A and B wave secondary to global posterior
ischemia (Figs 131.21–131.24).
It is critical to make the diagnosis of ocular ischemic syn-
drome because these patients often develop cerebral vascular FIGURE 131.22. Fluorescein angiogram shows delayed filling of
accidents. The 5-year mortality in ocular ischemic syndrome retinal arterials with asymmetric filling of the choroid.
1750

FIGURE 131.23. Progressive arterial filling with delayed venous filling
and prolonged venous transit time and continued asymmetric filling of
the choroid.
REFERENCES
1. von Graefe A: Uber embolie der arteria
centralis retinae als ursache plötzlicher
erblingdung. Arch für Ophthalmology 1859;
5:136–157.
2. Awan KJ: Arterial vascular anomalies of the
retina. Arch Ophthalmol 1977; 95:1197–1202.
3. Brown GC, Shields JA: Cilioretinal arteries
and retinal arterial occlusion. Arch
Ophthalmol 1979; 97:84–92.
4. Wise GN, Dollery CT, Henkind P, et al: The
retinal circulation. New York, NY: Harper &
Row; 1971.
5. Singh SS, Dass R: The central artery of the
retina – II. Distribution and anastomoses.
Br J Ophthalmol 1960; 44:280–299.
6. Hayreh SS, Weingeist TA: Experimental
occlusion of the central retinal artery of the
retina. IV. Retinal tolerance time to acute
ischemia. Br J Ophthalmol 1980;
64:896–912.
7. Kroll AJ: Experimental central retinal artery
occlusions. Arch Ophthalmol 1968; 79.
8. Hayreh SS, Zimmerman B: Central retinal
artery occlusion: visual outcome. Am J
Ophthalmol 2005; 140:376–391.
9. Ozdemir H, Karacorlu S, Karacorlu M, et al:
Optical coherence tomography findings in
central retinal artery occlusion. Retina
2006; 26:110–112.
10. Dahrling BE: The histopathology of early
central retinal artery occlusion. Arch
Ophthalmol 1965; 73:506–510.
11. Ashton N, et al: Focal retinal ischemia,
ophthalmoscopic, circulatory and
ultrastructural changes. Br J Ophthalmol
1966; 50:285–384.
12. Hayreh SS, Jonas JB: Optic disc and
retinal nerve fiber layer damage after
transient central retinal artery occlusion: an
experimental study in rhesus monkeys. Am
J Ophthalmol 2000; 129:786–795.
13. Hayreh SS, Karacorlu S, Karacorlu M, et al:
Central retinal artery occlusion and retinal
tolerance time. Ophthalmology 1980;
87:75–78.
FIGURE 131.24. Leakage from neovascularization of the disk with
late staining of the retinal vessels.
14. Brown GC, Magargal LE: Central retinal
artery obstruction and visual acuity.
Ophthalmology 1982; 89:14–19.
15. Arruga J, Sanders MD: Ophthalmologic
findings in 70 patients with evidence of
retinal embolism. Ophthalmology 1982;
89:1336–1347.
16. Brown GC, Magargal LE, Shields JA, et al:
Retinal arterial obstruction in children and
young adults. Ophthalmology 1981;
88:18–25.
17. Kollarits CR, Lubow M, Hissong SL: Retinal
strokes. I. Incidence of carotid atheromata.
JAMA 1972; 222:1273–1275.
18. Shah HG, Brown GC, Goldberg RE: Digital
subtraction carotid angiography and retinal
arterial obstruction. Ophthalmology 1985;
92:68–72.
19. Penner R, Font RL: Retinal embolism from
calcified vegetations of aortic valve.
Spontaneous complication of rheumatic
heart disease. Arch Ophthalmol 1969;
81:565–568.
20. Rush JA, Kearns TP, Danielson GK: Cloth-
particle retinal emboli from artificial cardiac
valves. Am J Ophthalmol 1980;
89:845–850.
21. Jampol LM, Wong AS, Albert DM: Atrial
myxoma and central retinal artery
occlusion. Am J Ophthalmol 1973;
75:242–249.
22. Zamora RL, Adelberg DA, Berger AS, et al:
Branch retinal artery occlusion caused by a
mitral valve papillary fibroelastoma. Am J
Ophthalmol 1995; 119:325–329.
23. Zamora RL, Adelberg DA, Berger AS, et al:
Branch retinal artery occlusion caused by a
mitral valve papillary fibroelastoma –
correction. Am J Ophthalmol 1995; 120:126.
24. Clifford L, Sievers R, Salmon A, Newsom
RS: Central retinal artery occlusion:
association with patent foramen ovale.
Eye 2005.
25. Kramer M, Goldenberg-Cohen N, Shapira
Y, et al: Role of transesophageal
Retinal Arterial Occlusions
CHAPTER 131
echocardiography in the evaluation of
patients with retinal artery occlusion.
Ophthalmology 2001; 108:1461–1464.
26. Wisotsky BJ, Engel HM: Transesophageal
echocardiography in the diagnosis of
branch retinal artery obstruction. Am J
Ophthalmol 1993; 115:653–656.
27. Chuang EL, Miller FS 3rd, Kalina RE. Retinal
lesions following long bone fractures.
Ophthalmology 1985; 92:370–374.
28. Chang M, Herbert WN: Retinal arteriolar
occlusions following amniotic fluid
embolism. Ophthalmology 1984;
91:1634–1637.
29. Kim IT, Choi JB: Occlusions of branch
retinal arterioles following amniotic fluid
embolism. Ophthalmologica 2000;
214:305–308.
30. AtLee WE Jr: Talc and cornstarch emboli
in eyes of drug abusers. JAMA 1972;
219:49–51.
31. Whiteman DW, Rosen DA, Pinkerton RM:
Retinal and choroidal microvascular
embolism after intranasal corticosteroid
injection. Am J Ophthalmol 1980;
89:851–853.
32. Wilkinson WS, Morgan CM, Baruh E,
Gitter KA: Retinal and choroidal vascular
occlusion secondary to corticosteroid
embolisation. Br J Ophthalmol 1989;
73:32–34.
33. Brown GC, Magargal L, Augsburger JJ,
Shields JA: Preretinal arterial loops and
retinal arterial occlusion. Am J Ophthalmol
1979; 87:646–651.
34. Seligsohn U, Griffin JH: Hereditary
Thrombophilia.. In: Lichtman MA, et al, eds.
Williams Hematology. 7th edn. New York:
McGraw-Hill; 2005:1981–1996.
35. Bertram B, Remky A, Arend O, et al:
Protein C, protein S, and antithrombin III in
acute ocular occlusive diseases. Ger J
Ophthalmol 1995; 4:332–335.
36. Greven CM, Weaver RG, Owen J, Slusher
MM: Protein S deficiency and bilateral
1751
 RETINA AND VITREOUS
branch retinal artery occlusion.
Ophthalmology 1991; 98:33–34.
37. Greiner K, Hafner G, Dick B, et al: Retinal
vascular occlusion and deficiencies in the
protein C pathway. Am J Ophthalmol 1999;
128:69–74.
38. Tayyanipour R, Pulido JS, Postel EA, et al:
Arterial vascular occlusion associated with
factor V Leiden gene mutation. Retina
1998; 18:376–377.
39. Dhar-Munshi S, Ayliffe WH, Jayne D:
Branch retinal arteriolar occlusion
associated with familial factor V Leiden
polymorphism and positive rheumatoid
factor. Arch Ophthalmol 1999;
117:971–973.
40. Weger M, Stanger O, Deutschmann H,
et al: The role of hyperhomocysteinemia
and methylenetetrahydrofolate reductase
(MTHFR) C677T mutation in patients with
retinal artery occlusion. Am J Ophthalmol
SECTION 10
2002; 134:57–61.
41. Pianka P, Almog Y, Man O, et al:
Hyperhomocystinemia in patients with
nonarteritic anterior ischemic optic
neuropathy, central retinal artery occlusion,
and central retinal vein occlusion.
Ophthalmology 2000; 107:1588–1592.
42. Wilson RS, Ruiz RS: Bilateral central
retinal artery occlusion in homocystinuria.
A case report. Arch Ophthalmol 1969;
82:267–268.
43. Rand JH, Senzel L: The Antiphospholipid
Syndrome.. In: Lichtman MA, et al, eds.
Williams Hematology. 7th edn. New York:
McGraw-Hill; 2005:2009–2027.
44. Dori D, Beiran I, Gelfand Y, et al: Multiple
retinal arteriolar occlusions associated with
coexisting primary antiphospholipid
syndrome and factor V Leiden mutation.
Am J Ophthalmol 2000; 129:106–108.
45. Gold D, Feiner L, Henkind P: Retinal arterial
occlusive disease in systemic lupus
erythematosus. Arch Ophthalmol 1977;
95:1580–1585.
46. Levine SR, Deegan MJ, Futrell N, Welch
KM: Cerebrovascular and neurologic
disease associated with antiphospholipid
antibodies: 48 cases. Neurology 1990;
40:1181–1189.
47. Snyers B, Lambert M, Hardy JP: Retinal
and choroidal vaso-occlusive disease in
systemic lupus erythematosus associated
with antiphospholipid antibodies. Retina
1990; 10:255–260.
48. Singh R, Conway MD, Wilson WA:
Antiphospholipid syndrome in a patient
with sarcoidosis: a case report. Lupus
2002; 11:756–758.
49. Cobo-Soriano R, Sanchez-Ramon S,
Aparicio MJ, et al: Antiphospholipid
antibodies and retinal thrombosis in
patients without risk factors: a prospective
case-control study. Am J Ophthalmol 1999;
128:725–732.
50. Glacet-Bernard A, Bayani N, Chretien P,
et al: Antiphospholipid antibodies in retinal
vascular occlusions. A prospective study of
75 patients. Arch Ophthalmol 1994;
112:790–795.
51. Fineman MS, Savino PJ, Federman JL,
Eagle RC, Jr: Branch retinal artery
occlusion as the initial sign of giant cell
arteritis. Am J Ophthalmol 1996;
122:428–430.
52. Ozdal PC, Ortac S, Taskintuna I, et al:
Central retinal artery occlusion associated
1752
with ocular Behcet’s disease. Eur J
Ophthalmol 2002; 12:328–330.
53. Williamson TH, Meyer PA: Branch retinal
artery occlusion in toxoplasma
retinochoroiditis. Br J Ophthalmol 1991;
75:253.
54. Morgan CM, Gragoudas ES: Branch retinal
artery occlusion associated with recurrent
toxoplasmic retinochoroiditis. Arch
Ophthalmol 1987; 105:130–131.
55. Gray AV, Michels KS, Lauer AK, Samples
JR: Bartonella henselae infection
associated with neuroretinitis, central
retinal artery and vein occlusion,
neovascular glaucoma, and severe
vision loss. Am J Ophthalmol 2004;
137:187–189.
56. Ormerod LD, Skolnick KA, Menosky MM,
et al: Retinal and choroidal manifestations
of cat-scratch disease. Ophthalmology
1998; 105:1024–1031.
57. Katz B: Migrainous central retinal artery
occlusion. J Clin Neuroophthalmol 1986;
6:69–75.
58. Beversdorf D, Stommel E, Allen C, et al:
Recurrent branch retinal infarcts in
association with migraine. Headache 1997;
37:396–399.
59. Clarke WN, Vomiero G, Leonard BC:
Bilateral simultaneous retinal arteriolar
obstruction in a child with hemoglobin SS
sickle cell disease. J Aapos 2001;
5:126–128.
60. Al-Abdulla NA, Haddock TA, Kerrison JB,
Goldberg MF: Sickle cell disease
presenting with extensive peri-macular
arteriolar occlusions in a nine-year-old boy.
Am J Ophthalmol 2001; 131:275–276.
61. Fine LC, Petrovic VV, Irvine AR, Bhisitkul
RB: Correction-spontaneous central retinal
artery occlusion in hemoglobin SC disease.
Am J Ophthalmol 2000; 130:906–907.
62. Kachmaryk MM, Trimble SN, Gieser RG:
Cilioretinal artery occlusion in sickle cell
trait and rheumatoid arthritis. Retina 1995;
15:501–504.
63. Gass JD, Tiedeman J, Thomas MA:
Idiopathic recurrent branch retinal arterial
occlusion. Ophthalmology 1986;
93:1148–1157.
64. Johnson MW, Thomley ML, Huang SS,
Gass JD: Idiopathic recurrent branch retinal
arterial occlusion. Natural history and
laboratory evaluation. Ophthalmology 1994;
101:480–489.
65. Newman NJ, Lessell S, Brandt EM:
Bilateral central retinal artery occlusions,
disk drusen, and migraine. Am J
Ophthalmol 1989; 107:236–240.
66. Ros MA, Magargal LE, Uram M: Branch
retinal-artery obstruction: a review of 201
eyes. Ann Ophthalmol 1989; 21:103–107.
67. Leavitt JM: Occlusion of the cilioretinal
artery. Arch Ophthalmol 1948; 40:152–156.
68. Brown GC, Moffat K, Cruess A, et al:
Cilioretinal artery obstruction. Retina 1983;
3:182–187.
69. Keyser BJ, Duker JS, Brown GC, et al:
Combined central retinal vein occlusion
and cilioretinal artery occlusion associated
with prolonged retinal arterial filling. Am J
Ophthalmol 1994; 117:308–313.
70. Rumelt S, Brown GC: Update on treatment
of retinal arterial occlusions. Curr Opin
Ophthalmol 2003; 14:139–141.
71. Mueller AJ, Neubauer AS, Schaller U,
Kampik A: European Assessment Group for
Lysis in the Eye, et al: Evaluation of
minimally invasive therapies and rational for
a prospective randomized trial to
evaluateselective intra-arterial lysis for
clinically complete central retinal artery
occlusion. Arch Ophthalmol 2003;
121:1377–1381.
72. Atebara NH, Brown GC, Cater J, et al:
Efficacy of anterior chamber paracentesis
and carbogen in treating acute nonarteritic
central retinal artery occlusion.
Ophthalmology 1995; 102:2029–2035.
73. Iwafune Y, Yoshimoto H: Clinical use of
pentoxifylline in haemorrhagic disorders of
the retina. Pharmatherapeutica 1980;
2:429–438.
74. Kuritzky S: Nitroglycerin to treat acute loss
of vision. N Engl J Med 1990; 323:1428.
75. Charness ME, Liu GT: Central retinal artery
occlusion in giant cell arteritis: treatment
with nitroglycerin. Neurology 1991;
41:1698–1699.
76. Crosson CE, Willis JA, Potter D, et al:
Effect of the calcium antagonist, nifedipine,
on ischemic retinal dysfunction. J Ocul
Pharmacol 1990; 6:293–299.
77. Frayser R, Hickam JB, et al: Retinal
vascular response to breathing increased
carbon dioxide and oxygen concentrations.
Invest Ophthalmol 1964; 3:427–431.
78. Hayreh SS: Retinal artery occlusion with
LIF using rTPA. Ophthalmology 1999;
106:1236–1238.
79. Richard G, Lerche RC, Krospe V, et al:
Treatment of retinal arterial occlusion with
local fibrinolysis using recombinant tissue
plasminogen activator. Ophthalmology
1999; 106:768–773.
80. Richard G: Retinal artery occlusion with LIF
using rTPA. Ophthalmology 1999;
106:1238–1239.
81. Kattah JC, Wang DZ, Reddy C, et al:
Intravenous recombinant tissue-type
plasminogen activator thrombolysis in
treatment of central retinal artery occlusion.
Arch Ophthalmol 2002; 120:1234–1236.
82. Beatty S, AuEong AK: Local intra-arterial
fibrinolysis for acute occlusion of the
central retinal artery: a meta-analysis of
published data. Br J Ophthalmol 2000;
84:914–916.
83. Ciulla TA, D’Amico DJ, Miller JW:
Laser photodisruption of visible retinal
artery emboli. Br J Ophthalmol 1995;
79:964–965.
84. Peyman GA: Removal of emboli from the
branches of the central retinal artery. Arch
Ophthalmol 2001; 119:1224–1225.
85. Sharma S, Sharma SM, Cruess AF, Brown
GC: Transthoracic echocardiography in
young patients with acute retinal arterial
obstruction. RECO Study Group. Retinal
Emboli of Cardiac Origin Group. Can J
Ophthalmol 1997; 32:38–41.
86. Sharma S: The systemic evaluation of
acute retinal artery occlusion. Curr Opin
Ophthalmol 1998; 9:1–5.
87. Greven CM: Retinal arterial occlusions in the
young. Curr Opin Ophthalmol 1997; 8:3–7.
88. Greven CM, Slusher MM, Weaver RG:
Retinal arterial occlusions in young adults.
Am J Ophthalmol 1995; 120:776–783.
89. Duker JS, Sivalingam A, Brown GC, Reber R:
A prospective study of acute central retinal
artery obstruction. The incidence of
secondary ocular neovascularization. Arch
Ophthalmol 1991; 109:339–342.

90. Hayreh SS, Podhajsky P: Ocular
neovascularization with retinal vascular
occlusion. II. Occurrence in central and
branch retinal artery occlusion. Arch
Ophthalmol 1982; 100:1585–1596.
91. Mizener JB, Podhajsky P, Hayreh SS:
Ocular ischemic syndrome. Ophthalmology
1997; 104:859–864.
92. Wessing A: Fluorescein angiography of the
retina; textbook and atlas. St Louis, MO:
Mosby; 1969:xii, 222.
93. Brown GC: The ocular ischemic syndrome.
In: Ryan SJ. Retina. St Louis, MO: Mosby;
1989:547–559.
94. Brown GC, Magargal LE: The ocular
ischemic syndrome. Int Ophthalmol 1988;
11:239–251.
95. Sivalingam A, Brown GC, Magargal LE,
Menduke H: The ocular ischemic
syndrome. II. Mortality and systemic
morbidity. Int Ophthalmol 1989;
13:187–191.
Retinal Arterial Occlusions
96. Beneficial effect of carotid endarterectomy
in symptomatic patients with high-grade
carotid stenosis. North American
symptomatic carotid endarterectomy trial
collaborators. N Engl J Med 1991;
325:445–453.
CHAPTER 131
1753
 CHAPTER
132 Retinal Venous Occlusive Disease
Jonathan Gunther, Ingrid U. Scott, and Michael Ip
INTRODUCTION
Retinal vein occlusion (RVO) is the second most common
retinal vascular disease following diabetic retinopathy.1 There
are three distinct types of RVO: branch retinal vein occlusion
(BRVO), central retinal vein occlusion (CRVO), and an
anatomical variant of CRVO, namely, hemiretinal vein occlu-
sion (HRVO) (Table 132.1). Retinal venous occlusive disease
typically occurs at an arteriovenous crossing in BRVO or at the
lamina cribrosa in CRVO and HRVO. Retinal vein occlusions
have a characteristic, although somewhat variable, appearance
with intraretinal hemorrhage, cotton-wool spots, tortuous and
dilated retinal veins, retinal edema and, occasionally, optic disk
swelling. These findings are present segmentally in BRVO, in
either the superior or inferior two quadrants in HRVO, and in
all quadrants of the fundus in CRVO. Vision loss can vary from
minimal or no vision loss to complete blindness. Causes of
vision loss associated with RVO include macular edema,
macular nonperfusion, epiretinal membrane, dense intraretinal
hemorrhages, vitreous hemorrhage, neovascular glaucoma, or
tractional retinal detachment (TRD).2–6 Timely intervention
can reduce the incidence and severity of these complications.
Many systemic diseases are risk factors for RVO development.
Recognition and treatment of an underlying systemic disease
can benefit the patient visually and improve overall health.
The overall incidence of RVO in population-based studies
varies depending on age and the study. In a large population-
based study in Israel, the 4 year incidence of retinal vein occlu-
sion was 2.14/1000 among persons aged 40 years and older, and
5.36/1000 among individuals older than 64 years.7 In the Blue
Mountains Eye Study8 (BMES) in Australia, the prevalence of
retinal vein occlusion was 0.7% among persons aged 49–60
years, 1.2% for persons aged 60–69 years, 2.1% for those 70–79
years, and 4.6% for persons 80 years and older. The mean age
of onset of vein occlusion was 63 years. Hayreh9 reported that
after any RVO in one eye, the incidence of developing a second
vein occlusion in the next 4 years was 2.5% in the same eye and
TABLE 132.1. Key Characteristics of Vein Occlusions
RVO type Occlusion location Area involved Neovascular
location
BRVO Retinal A–V crossing Segmental Posterior pole
CRVO Lamina cribrosa 4-Quadrant Anterior
segment
HRVO Lamina cribrosa 2-Quadrant Post. Pole>ant.
(vertical) segment
11.9% in the fellow eye. Of all the RVO in the BMES, 69.5%
were BRVO, 25% CRVO, 5.1% HRVO, and 5.1% were bilateral.
BRANCH RETINAL VEIN OCCLUSION
Synonym
• Branch vein occlusion
Key Features
• Segmental retinal involvement in the distribution of the
involved occluded vein
• Dilated, tortuous veins
• Superficial and deep retinal hemorrhages
• Cotton-wool spots
• Optic nerve swelling/hemorrhages
• Macular/retinal edema
• Optociliary shunt vessels on disk
• Neovascularization of the retina (less common: disk, iris)
INTRODUCTION
The fundoscopic findings of BRVO are similar to those of
CRVO; however, the extent of retinal involvement is typically
much less. The involved vein takes on a dilated and tortuous
appearance, deep and superficial retinal hemorrhages form,
cotton-wool spots can be observed, and retinal edema may
develop. A BRVO typically occurs at the crossing of a retinal
artery and vein. The involved area is usually wedge-shaped with
the apex near the site of the occlusion, extending outward to the
periphery (Fig. 132.1). The area drained by the involved vein
defines the extent of retinal involvement. The greater the area
of retinal involvement, the greater the impact it is likely to have
on vision. The location of the occlusion is an important factor
in the visual prognosis. In general, the closer the occlusion
occurs to the optic nerve, the more extensive the retinal damage
and visual impact.10–12 The clinical course and visual outcome
of BRVO is highly variable.
EPIDEMIOLOGY
BRVO is more than twice as common as CRVO and more than
10 times as common as HRVO.7,8,13,14 Numerous studies have
assessed the incidence of venous occlusive diseases over the
years. The Beaver Dam Eye Study13 was a population-based
study of 4926 residents of Beaver Dam, WI aged 43–84 years.
Initial RVO evaluation was performed between 1988 and 1990
with follow-up examinations 5 years later (1993–1995). Diag- 1755
 RETINA AND VITREOUS
SECTION 10
FIGURE 132.1. Large superotemporal branch retinal vein occlusion
(BRVO) occurring at an arteriovenous intersection near the superior
margin of the disc.
nosis of RVO was made by grading 30° stereo fundus photo-
graphs. The prevalence and 5 year incidence of BRVO were each
0.6%. Prevalence increased with age and there was no gender
predilection.
The Blue Mountain Eye Study8 in Australia was a prospective
study including 3654 participants aged 49 years or older.
Follow-up consisted of detailed eye examinations including
stereoscopic fundus photography. Diagnosis of RVO was based
on clinical findings and fundus photographic grading. The
overall incidence of BRVO was 1.1% with a strong age-related
predilection and no gender predilection.
PATHOPHYSIOLOGY
BRVO is defined as a focal occlusion of a retinal vein.15–17 With
rare exceptions, such as in association with sarcoidosis and
other ocular inflammatory disorders, BRVO develops at arterio-
venous crossing sites where the artery passes anteriorly
(superficially) to the vein.16–19 In normal eyes, retinal arteries
cross over retinal veins in 70–75% of the intersections.15,17 The
most common location of a BRVO is the superotemporal
quadrant of the retina. This may be due to a higher risk of
occlusion in this area, or may be due to increased diagnosis due
to increased symptoms of a temporal versus a nasal occlusion.
Most BRVOs involve the area inside the temporal vascular
arcades (macular BRVO), whereas peripheral BRVOs are
observed less commonly, likely because they tend to be less
symptomatic. Of temporal BRVOs, ~62% occur in the
superotemporal quadrant and 38% in the inferotemporal
quadrant.10,11,15,17,20–23
The precise mechanism causing the venous occlusion is
poorly understood. Multiple theories, often contradictory, exist.
Histological examination has shown that BRVO is associated
with arteriosclerotic changes in the retinal arterioles.17 The
resultant thickening of the artery could cause compression of
the adjacent vein, a process that may be aggravated because, at
arteriovenous crossing sites, the two vessels are confined within
a common adventitial sheath.24 With increased compression,
venous blood flow velocity at the crossing site may gradually
increase until local shear stress causes endothelial cell loss,
thrombus formation, and vein occlusion.24–26 Theoretically,
shear stress is maximal when the velocity is high enough to
1756 induce transition to a turbulent flow pattern.27
Another theory is that venous compression is not the cause
of BRVO. Seitz demonstrated histologically that the retinal vein
is not compressed by the artery at intersections at which
nicking is observed.28 Jefferies found that the vein took a much
more pronounced deviation around an artery when the artery
overlies the vein, compared to when the vein overlies the artery.
He also found focal stratification of the venous endothelial base-
ment membrane opposite the point of contact with the artery.
Localized venous luminal narrowing was not typical. Jefferies
proposed that hemodynamic variations due to venous con-
touring are responsible for the much higher risk in artery over
vein intersections.29
It has been suggested that BRVO is the result of arterial
insufficiency.24,25 However, in a histopathologic study of nine
cases of BRVO, Franghieh demonstrated that all cases had fresh
or recanalized venous thrombus at the site of occlusion. He con-
cluded that branch vein thrombosis was likely the primary event
and that the other vascular findings occurred secondarily.30 Other
studies have demonstrated that the manifestations of arterial
insufficiency can be reproduced in animals by experimental
occlusion of the retinal veins.31–36
The average age of patients with BRVO is between 60 and
70 years.7,8,13,14 The incidence increases with age.8 Certain
systemic diseases have also been shown to be risk factors for
BRVO. The Eye Disease Case-Control Study Group reported
‘cardiovascular risk profile’ as a risk factor for BRVO.37,38 A
significantly increased risk was found for systemic hyperten-
sion, history of cardiovascular disease, smoking, increased body
mass index and higher serum levels of alpha2-globulin. One-
half to two-thirds of patients in large series of BRVO have been
reported to have systemic hypertension.10–12,20,39,40 A decreased
risk of BRVO was associated with alcohol consumption and
higher levels of high density lipoprotein (HDL) cholesterol.
Diabetes mellitus and open angle glaucoma occurred more
frequently among BRVO patients than among controls, but the
differences were not statistically significant.41
CLINICAL FEATURES
Patients with BRVO may complain of painless, decreased vision,
complete loss of vision, or a blind spot in their visual field.
Others may be asymptomatic. Vision loss in BRVO may be due
to macular edema, macular nonperfusion, dense intraretinal
hemorrhages, vitreous hemorrhage, neovascular glaucoma,
epiretinal membrane, or tractional retinal detachment.2,42
A complete ocular examination should be performed,
including evaluation for iris or angle neovascularization and a
dilated fundus examination to evaluate for macular edema,
neovascularization of disk and/or retina, presence of intraretinal
hemorrhages, cotton wool spots, vitreous hemorrhage,
narrowing and sheathing of the adjacent artery. Close attention
should be paid to the distribution of the involved area of the
fundus.
Visual acuity is generally less affected in BRVO when com-
pared to CRVO. However, there can be great variation in visual
outcome ranging from no visual impairment to severe vision
loss. Typically, patients presenting with visual complaints have
associated retinal hemorrhage, edema, and/or nonperfusion.
Symptoms may worsen or improve with time. At later stages,
visual complications may include macular edema, vitreous
hemorrhage from neovascularization, epiretinal membrane, or
retinal detachment. Generally, the visual prognosis of BRVO is
quite good. Approximately 50–60% of untreated patients will
have a final visual acuity of 20/40 or better. However, severe
vision loss is not uncommon, with 20–25% of patients having
a visual acuity of 20/200 or worse. A final visual acuity of hand
motion or worse is uncommon.2,10,11,20,42

The classic fundus findings of BRVO are similar to CRVO,
although the area of distribution is distinct. BRVO fundus find-
ings may include optic disk swelling, retinal swelling, including
the macula, markedly dilated and tortuous retinal veins, super-
ficial and deep retinal hemorrhages radiating outward from the
optic disk, and cotton-wool spots (Fig. 132.2). However, a small
or peripheral BRVO may produce findings that are much more
subtle and difficult to detect on examination. With time, the
fundus findings may become less distinct and appear similar to
what one would expect to see in diabetic retinopathy, hyper-
tensive retinopathy, or other systemic diseases causing retinal
microaneurysms and hemorrhages. Clues suggestive of an old
BRVO include segmental microvascular abnormalities and
intraretinal collateral vessels draining across the median raphe.
In nonperfused cases, sclerosis and sheathing of the retinal
veins and arteries in the distribution of the occlusion may be
observed.43,44
Intravenous FA can assist in evaluating BRVO. Angiographic
findings reflect changes in vessel permeability, caliber, and
patency and assist in identifying areas of macular edema,
neovascularization, and nonperfusion. Vitreous or retinal
hemorrhage may impair the utility of FA. Venous filling delay is
often noted in the area drained by the occluded vein. The
venous tributaries often appear narrowed. Occasionally, early
hyperfluorescence just proximal to the site of occlusion is
observed.10,45 Retinal edema often appears as diffuse hyper-
fluorescence on angiography. The edema is commonly found
within the area of distribution of the occluded vein. Macular
edema often takes on a petalloid pattern typical of cystoid
macular edema. When evaluating for macular edema, it is
important to note whether capillary perfusion is present. Retinal
nonperfusion appears on fluorescein angiography (FA), as areas
of capillary hypofluorescence. Neovascularization of the retina
or disk appear as early hyperfluorescent, thin, tortuous vessels
that leak in the later stages of testing.
COMPLICATIONS
Microvascular changes result in numerous findings. Leaking
vessels lead to retinal edema and deposition of hard exudates.
Retinal edema becomes much more visually significant when it
involves the fovea (Fig. 132.3). Macular edema is the most
common complication, and leading cause of vision loss,
FIGURE 132.2. BRVO with hemorrhage, cotton-wool spots, and
fibrous sheathing of the retinal veins.
Retinal Venous Occlusive Disease
associated with BRVO.10,46 In patients with perfused macular
edema, approximately one-third will regain some vision spon-
taneously. However, this becomes less likely the longer the
edema persists. Spontaneous visual improvement is less com-
mon in nonperfused macular edema. Interleukin-6 (IL-6) and
vascular endothelial growth factor (VEGF) have been implicated
in the development of macular edema following nonperfused
BRVO.47
Other microvascular changes result in dilated capillaries,
causing formation of microaneurysms and dot-blot hemor-
rhages.48,49 Retinal vessels may become fibrosed leading to
sheathing. Collateral vessels may develop between an area of
nonperfused and an area of perfused retina. Collateral vessels
appear as small, tortuous venous channels that cross the hori-
zontal raphe and drain into an uninvolved venous circulation
(Fig. 132.4). Collateral vessels are distinct from neovascular
vessels in that collaterals are flat while neovascular vessels are
elevated; the former do not leak on FA while the latter leak.
CHAPTER 132
Retinal hemorrhage is one of the most striking features of
BRVO. Intraretinal hemorrhages located within the macula can
FIGURE 132.3. A small inferotemporal BRVO. Although the area of
affected retina is small, the hemorrhage and edema extend into the
fovea and are associated with reduced vision.
FIGURE 132.4. Appearance of venous collaterals after a BRVO. The
channels cross the median raphe temporal to the fovea and drain
from the affected to the nonaffected quadrant. 1757
 SECTION 10 RETINA AND VITREOUS
FIGURE 132.5. Fluorescein angiogram of a nonperfused BRVO
demonstrates widespread capillary nonperfusion and staining of the
retinal veins. The two areas of intense hyperfluorescence (arrows) are
due to retinal neovascularization.
cause severe vision loss. Vision often will improve as the
hemorrhage resolves. Retinal hemorrhages typically resolve over
weeks to months, but can persist for years. Hemorrhage blocks
fluorescence on angiography and can impair the usefulness of
such evaluation. Vitreous hemorrhage, if it occurs, is typically
observed later in the course of BRVO. Vitreous hemorrhage may
develop after rupture of thin, friable neovascular vessels that
grow in response to retinal nonperfusion. The majority of eyes
with retinal or disk neovascularization will develop vitreous
hemorrhage if left untreated.10,11,39,42
Nonperfusion can lead to both early and late complications of
BRVO. Early in the course of BRVO, nonperfusion can result in
permanent vision loss. The closer the nonperfusion is to the
macula, the more significant the visual loss will be. Large areas
of persistent retinal nonperfusion can lead to neovasculariza-
tion of the retina or disk (Fig. 132.5). It is important to recog-
nize that perfused BRVO may progress to the nonperfused type
during the ensuing weeks, months and even years after the
initial insult.39,42,44,50
The most common site of neovascularization following
BRVO is the retina (Fig. 132.6). Optic disk neovascularization is
much less common and iris neovascularization is rare in BRVO.
When disk neovascularization does occur, retinal neovascu-
larization typically is present as well.39 Numerous studies have
reported a 20–30% incidence of retinal neovascularization
following BRVO.10,20,42,51 The Branch Vein Occlusion Study
(BVOS)42 was a multicentric, randomized, controlled clinical
trial designed to answer questions regarding the management
of complications of branch vein occlusion. These questions
included: ‘Can peripheral scatter argon laser photocoagulation
prevent the development of neovascularization?’, and ‘Can
peripheral scatter argon laser photocoagulation prevent vitreous
hemorrhage?’ In the BVOS, retinal neovascularization developed
in 22% of all eyes with BRVO. The incidence of retinal neo-
vascularization increased to 36% in eyes with five disk-
diameters or more of retinal nonperfusion. Shilling and Kohner
reported a 62% incidence of neovascularization among eyes
with greater than four disk-diameters of nonperfusion and 0%
among eyes with less nonperfusion.39 Retinal neovascu-
larization typically develops at the border between perfused and
nonperfused retina; it rarely develops outside the area of
1758 nonperfusion. Neovascular vessels are believed to form in
FIGURE 132.6. A tuft of retinal neovascularization (arrow) along the
vascular arcade in an eye with long-standing inferotemporal BRVO.
response to the release of angiogenic factors (such as VEGF and
IL-6) from nonperfused retina. Retinal neovascularization
typically forms in the first 6–12 months following a BRVO;
however, it may develop years later also.51
Tractional retinal detachment (TRD) can form following
BRVO if fibrovascular proliferation develops. Rhegmatogenous
retinal detachments are a rare complication of BRVO. They
typically form following posterior retinal breaks caused by
fibrovascular proliferation and traction.52–55 Nonperfused
retina can lead to degeneration and retinal hole formation
following BRVO.55–58 Exudative retinal detachments can occur
in the area of occlusion and are usually associated with
nonperfusion.54,59,60
Other visually significant complications of BRVO include
epiretinal membrane formation, retinal pigment epithelial
irregularity, and subretinal scarring.54,59,60
DIFFERENTIAL DIAGNOSIS
Diabetic retinopathy can present with findings similar to BRVO
with dot-blot hemorrhages, microaneurysms, and neovascu-
larization. In diabetic retinopathy, the retinal findings are
generally bilateral and involve all four quadrants. In BRVO, the
retinal hemorrhages are almost always unilateral, except in
the infrequent case of a bilateral BRVO. Also, the retinal
hemorrhages involve only the sector of retina that is drained by
the occluded vein.
Hypertensive retinopathy is another disease that must be
considered in the differential diagnosis of BRVO. Distinguishing
characteristics of hypertensive retinopathy include bilateral
narrowed retinal arterioles and hemorrhages that involve the
entire fundus.
Radiation retinopathy may be unilateral or bilateral. A
history of irradiation is essential for the diagnosis. Similar to
BRVO, disk swelling, disk hemorrhages, retinal neovascu-
larization, and cotton-wool spots may be present.
TREATMENT
The treatment of BRVO is continually evolving. Available data
concerning many of the reported treatment modalities are based
on case series without controls or randomization. As our

understanding of the disease improves, the standard of care is
likely to continue to evolve.
Medical Treatment
Evaluation should include a thorough medical history,
including past ocular history, review of current medications,
and a thorough review of systems. The most common reported
risk factors associated with BRVO are systemic hypertension,
diabetes, hyperlipidemia, glaucoma, smoking, and age-related
atherosclerosis.10–12,20,39–41 Identifying and treating individual
risk factors are important in the early treatment and prevention
of future RVO. Systemic evaluation of commonly associated risk
factors is an important part of the examination process.
Extensive work-up following BRVO is typically not necessary in
older individuals as the common risk factors are often elicited
on basic screening. However, in patients under age 50 years or
with bilateral vein occlusions, a more thorough work-up may be
warranted. The primary care physician should be notified when
a patient is diagnosed with a BRVO. Initial evaluation may
include testing for hypertension, diabetes, and a hyper-
coagulable state. Initial testing may include a fasting blood
glucose level, complete blood count with differential and plate-
lets, coagulation studies, and erythrocyte sedimentation rate.
Systemic anticoagulation has not been shown to be of ocular
benefit in patients with BRVO and may potentially worsen con-
current or future intraretinal hemorrhage.61 Further
cardiovascular disease evaluation may be needed; however, the
primary care physician often is helpful in coordinating this.
Follow-up generally consists of ophthalmologic evaluation every
1–3 months for the first year, followed by every 3–12 months
thereafter.
Grid Pattern Laser Photocoagulation
In 1984, the BVOS2 reported the results of a randomized trial of
no treatment versus grid laser photocoagulation for treatment
of macular edema associated with BRVO in patients with a
visual acuity of 20/40 to 20/200. Patients with distinct areas of
macular capillary nonperfusion were excluded. At 3 years, 65%
of treated eyes gained two or more lines of visual acuity
compared to 37% of untreated eyes. The mean visual acuity
improvement was 1.3 ETDRS lines in the treated group versus
0.2 lines in the untreated group. Overall, mean visual acuity in
the treatment group was 20/40 to 20/50, compared to 20/70
in the untreated group.
Although it is not understood how laser treatment to the
retinal pigment epithelium reduces retinal edema, experimental
studies in the normal primate have shown a decrease in
capillary diameter when this form of therapy is administered.62
Grid treatment may produce retinal thinning that permits the
choroidal vasculature to provide oxygen to the inner retina; this
may lead to autoregulatory constriction of the retinal vascu-
lature, which may result in decreased macular edema.
Grid pattern photocoagulation is typically delayed for at least
3 months after the development of a BRVO to allow for
spontaneous resolution of edema and intraretinal blood. Treat-
ment may be considered in patients with a visual acuity of
20/40 or worse in the absence of capillary nonperfusion. Grid
laser is applied to the area of macular edema. Suggested treat-
ment parameters include argon green laser with a spot size of
50–100 mm, 0.1 second duration and a power setting sufficient
to produce a light to medium white burn. The laser should be
focused on the edematous retina within the arcades and the
areas of perifoveal capillary leakage as identified by FA. Laser
photocoagulation should not be placed over substantial intra-
retinal hemorrhage, as the nerve fiber layer may be damaged,
producing preretinal fibrosis. The fovea should be avoided in
the treatment process. When significant intraretinal edema is
Retinal Venous Occlusive Disease
present, higher laser powers may be necessary for adequate
uptake.
Typical follow-up is approximately 8–12 weeks after treat-
ment. If macular edema persists and the acuity and other
clinical findings have not improved, repeat FA is suggested. If
residual fluorescein leakage is observed, another session of grid
laser photocoagulation may be indicated.63
Scatter Laser Photocoagulation
Retinal and disk neovascularization can lead to visually com-
promising vitreous hemorrhage. The BVOS showed that scatter
sectoral laser photocoagulation reduces the risk of developing
retinal neovascularization from 22% to 12%. However, the
study concluded that treatment should be reserved until after
the development of retinal neovascularization. In eyes with
retinal neovascularization, subsequent laser photocoagulation
reduces the risk of vitreous hemorrhage from 60% to 30%.2 If
vitreous hemorrhage is already present, staged sessions of
CHAPTER 132
scatter laser photocoagulation may be necessary, or peripheral
cryoablation may be performed. Scatter photocoagulation is not
without its own set of complications. Most notably, some
patients report peripheral scotoma following scatter photo-
coagulation,64 and this has been confirmed with visual field
testing showing peripheral visual field loss.65
Commonly, scatter laser photocoagulation is applied with the
argon green laser to achieve ‘medium’ white burns (200–500 mm
in diameter) spaced one burn width apart and covering the
entire area of capillary nonperfusion, as defined by fluorescein
angiogram. Treatment should extend no closer than two disk-
diameters from the center of the fovea.
Conventional Pars Plana Vitrectomy for
Complications of BRVO
Various studies have shown favorable surgical result in subjects
who undergo vitrectomy for complications of BRVO.57,59,60,66–70
Surgical indications include vitreous hemorrhage, TRD involv-
ing the macula, epiretinal membrane, removal of loculated
preretinal subhyaloid hemorrhage, removal of subfoveal laser-
induced choroidal neovascularization, and complications of
ghost cell glaucoma.
Several preoperative clinical features are associated with
better postoperative visual acuity outcome, including better pre-
operative visual acuity, absence of an afferent pupillary defect,
and absence of macular edema. The presence of disk neovascu-
larization, retinal tear, or retinal detachment are associated with
a less favorable outcome.67
Pars Plana Vitrectomy Alone for Macular Edema
Pars plana vitrectomy (PPV) with the creation of a posterior
vitreous detachment (PVD) has been reported to be effective in
reducing macular edema and improving visual acuity, although
the mechanisms that contribute to this have not been
elucidated.71,72 It may not be intuitive that vitrectomy with
posterior hyaloid removal alone would improve macular edema,
because macular traction is uncommon in eyes with BRVO.73
However, it has been suggested that removal of the posterior
hyaloid by vitrectomy may improve oxygenation of the retina
resulting in vasoconstriction and thus decreased vascular
leakage and macular edema.74 Another theory postulates that
vitrectomy may facilitate diffusion of harmful cytokines that
promote increased vascular permeability, such as VEGF, away
from the retina.
Arteriovenous Adventitial Sheathotomy
Most BRVOs are believed to occur at an arteriovenous crossing
site, where the arteriole and venule share a common adventitial
sheath. Arteriovenous adventitial sheathotomy (AAS) is an 1759
 RETINA AND VITREOUS
attempt to decompress the involved venule by separating the
overlying retinal artery from the underlying branch vein by
sectioning the shared adventitial sheath. Patients who have
macular edema recalcitrant to grid laser photocoagulation may
be candidates for AAS.75
Numerous nonrandomized studies have demonstrated
improved visual acuity, reduction in intraretinal hemorrhage,
return of retinal perfusion and reduction of macular edema after
AAS surgery.76–96 In one such series, Mason et al79 reported a
prospective, nonrandomized interventional trial of 40 eyes with
decreased visual acuity secondary to BRVO. Twenty of the eyes
underwent vitrectomy and surgical decompression by means of
arteriovenous sheathotomy with a microvitreoretinal blade and
were compared with 20 control eyes (10 observation and 10 grid
laser photocoagulation at a mean of 9 months after diagnosis).
The mean preoperative visual acuity was 20/250 in the surgical
group and 20/180 in the control group (statistically similar
in the observation group and laser-treated group). The mean
SECTION 10
14 month visual acuity was 20/63 in the surgical group and
20/125 in the control group (P = 0.02). Seventy-five percent
of the surgical group halved their visual angle compared with
40% of the control group (40% observation versus. 40% laser;
P = 0.025). Average lines of visual acuity gained were 4.55 in
the surgical group and 1.55 in the control group (P = 0.0226;
1.1 lines in observation group and laser-treated group). Reported
complications include retinal gliosis at the incision site, nerve
fiber layer defects, vitreous hemorrhage, retinal tears, retinal
detachment and acceleration of nuclear sclerosis.95 It is
important to recognize that AAS has not been investigated in a
large-scale, prospective, randomized controlled clinical trial.
Intraocular Corticosteroids
Corticosteroids have been proposed for the management of
macular edema due to various retinal vascular disorders. Intra-
vitreal triamcinolone acetonide has been investigated for per-
sistent macular edema in RVO, diabetic retinopathy, chronic
uveitis, proliferative vitreoretinopathy, and postsurgical cystoid
macular edema.97–100 The mechanism of action of corti-
costeroids in the treatment of macular edema in RVO is not
entirely clear. Experimental studies have shown that functional
and structural changes occur in the retinal capillaries induced
by the hypoxic environment after venous occlusion, leading to
increased capillary permeability and accompanying retinal
edema possibly mediated in part by VEGF, a 45kDa
glycoprotein.35 Triamcinolone has been shown experimentally
to reduce the breakdown of the blood–retinal barrier by inhibiting
such factors as prostaglandins, interleukins, VEGF and protein
kinase C.101,102
Small case studies have suggested that there may be a benefit
from intravitreal injection of steroids for macular edema and
vision loss associated with BRVO.103–109 Some patients with
BRVO may have a favorable anatomical response to this treat-
ment, as demonstrated by optical coherence tomographic (OCT)
images, measurements demonstrating reduction in macular
thickness, and resolution of the large cystic spaces in the outer
plexiform layer within several weeks of injection. However, a
favorable visual acuity response may be more likely in patients
with perfused rather than nonperfused macular edema. Re-
treatment may also be performed in some patients due to
recurrent macular edema. A human pharmacokinetics study of
nonvitrectomized eyes, found a single 4 mg intravitreal injec-
tion of triamcinolone to have a mean half-life of 18.6 days
with measurable concentrations expected to last approximately
3 months.110 Reported side effects include cataract, increased
intraocular pressure and injection-related complications
including noninfectious and infectious endophthalmitis, retinal
1760 detachment, vitreous hemorrhage, and lens injury.
The Standard Care versus COrticosteroid for REtinal Vein
Occlusion (SCORE) study is a multicenter, randomized, phase
III National Eye Institute-sponsored study that is investigating
the efficacy and safety of standard care versus intravitreal
injection(s) of triamcinolone for macular edema secondary to
BRVO and CRVO.111 Individuals with BRVO or CRVO with
associated macular edema of up to 24 months duration and
best-corrected visual acuity between 19 and 73 ETDRS letters
(corresponding to approximately 20/40 to 20/400 Snellen visual
acuity) are eligible for participation in the SCORE study.
Another prospective randomized study (Posurdex Trial) is
underway to evaluate treatment with extended delivery of a
bioerodable dexamethasone PLGA (polylactic acid polyglycolic
acid) copolymer complex in patients with RVO.
Isovolemic Hemodilution
BRVO has been reported to be associated with hyperviscosity,
due to higher hematocrit and plasma viscosity.112 Higher blood
viscosity is less important when blood flow is rapid but in
conditions of low flow, as is likely in a vein predisposed to
occlusion, the effect of viscosity becomes increasingly signi-
ficant as a result of increased red cell aggregation. Viscosity is
dependent primarily upon the hematocrit (the greater the
number of red cells, the larger the aggregates) and plasma
fibrinogen (required for aggregation to occur). Studies have demon-
strated that hypervolemic113 or isovolemic hemodilution,114 com-
menced within 3 months of the onset of symptoms of a BRVO,
accelerates the rate of visual recovery and also has a positive
effect on the final visual acuity at 1 year. However, reported
complications of hemodilution include deep-vein thrombosis
and hypotension.115
Antivascular Endothelial Growth Factor
(Anti-VEGF)
Experimental studies have shown that functional and structural
changes occur in the retinal capillaries induced by the hypoxic
environment after RVO. This can lead to increased capillary
permeability and accompanying retinal edema. This appears to
be mediated, at least in part, by VEGF, a 45 kDa glycoprotein.35
Intravitreal VEGF levels have shown to be increased in patients
with macular edema with BRVO and are correlated significantly
with the area of nonperfusion and the severity of macular
edema.116 The role of anti-VEGF agents in the treatment in
BRVO has yet to be determined.
CENTRAL RETINAL VEIN OCCLUSION
Synonym
• Central vein occlusion
Key Features
• 4 quadrant retinal involvement
• Dilated, tortuous veins
• Superficial and deep retinal hemorrhages
• Cotton-wool spots
• Optic nerve swelling/hemorrhages
• Macular/retinal swelling
• Optociliary shunt vessels on disc
• Neovascularization of the iris (less commonly of the optic disc
and retina)
INTRODUCTION
CRVO typically presents in a fairly acute and dramatic fashion,
often permitting early diagnosis. Classically, a CRVO presents

with marked dilation and tortuosity of the retinal veins, exten-
sive retinal edema, pronounced superficial and deep retinal hemor-
rhages radiating outward from the optic disk in all quadrants,
cotton-wool spots, and optic disk swelling (Fig. 132.7). In its
acute phase, the diagnosis is often made with little doubt. In
less severe instances or late in the course of the disease, the
diagnosis may be less obvious. With time, the dramatic retinal
findings may resolve and the diagnosis may become more
difficult.
In its mildest form, CRVO may consist of only vascular
dilatation and tortuosity, disk hyperemia, and a few retinal
hemorrhages (Fig. 132.8). In this form, the condition is likely to
resolve without sequelae. At the other extreme, there may be
nearly confluent retinal hemorrhages, cotton-wool spots,
massive retinal and macular edema, and extensive capillary
nonperfusion. In the latter cases, one expects to observe severe
visual impairment and a tendency for the development of
macular edema and anterior segment neovascularization,
including neovascular glaucoma.
While early diagnosis of a dramatic presentation of a CRVO
may not require much effort on the part of the clinician,
FIGURE 132.7. Typical appearance of a fresh central retinal vein
occlusion (CRVO), with disk edema, venous dilatation and tortuosity,
cotton-wool spots, and retinal hemorrhages in all quadrants.
FIGURE 132.8. CRVO demonstrates disk hyperemia and venous
dilatation and tortuosity, with mild retinal hemorrhages.
Retinal Venous Occlusive Disease
predicting the clinical course and choosing treatment options
can be much more difficult and challenging. The pathogenesis
and treatment of CRVO continues to be highly debated.
Research continues to direct the understanding and treatment
options of the disease.
EPIDEMIOLOGY
CRVO is a relatively common cause of severe vision loss. The
majority of patients who develop CRVO are over the age of 50
years and 50–70% have associated hypertension, cardiovascular
disease, or diabetes mellitus.117 Numerous studies have
assessed the incidence of CRVO with varying results. In the
Beaver Dam Eye Study,13 the incidence of CRVO was 0.2%
during the 5-year follow-up study of 4926 residents of Beaver
Dam, WI aged 43–84 years. There was no gender predilection.
In the BMES8 the overall incidence of CRVO was 0.4% with an
increasing incidence with age. The BMES also showed no
CHAPTER 132
gender predilection.
PATHOGENESIS
The pathogenesis of CRVO is not completely understood,
despite being first described by Leibreich in 1855.118 Numerous
theories have been presented over the years, without consensus
on the pathogenesis of the disease. Hayreh has suggested that
perfused CRVO occurs after occlusion of retinal venous flow,
while nonperfused CRVO develops after occlusion of venous
and arterial flow. His studies were based on animal models with
occlusion of the retinal vessels at their entry into the optic
nerve.83–85 However, Fujino’s pathologic studies found that
occlusion of the retinal vein alone could produce clinical
findings similar to nonperfused CRVO.86
Green et al reported a histopathologic study which supports
the theory of thrombus formation as the inciting event causing
CRVO.87 In this study, a fresh or a re-canalized thrombus was
observed in 29 eyes from 29 patients with CRVO. The study
considered the temporal aspects (6 h to 10 years from onset) of
the cases, and noted the different morphologic features of the
occlusion. These observations explain most of the variability of
the changes observed in previous reports and are likely to be
associated with the evolution of the thrombus. Endothelial cell
proliferation was a conspicuous feature in 14 (48.3%) of the
eyes, chronic inflammation in the area of the thrombus and/or
vein wall or perivenular area was observed in 14 (48.3%),
arterial occlusive disease in seven (24.6%), and cystoid macular
edema in 26 (89.7%) of the eyes. Most of the eyes included in
the study had chronic, nonperfused CRVO and had been
enucleated for neovascular glaucoma. The few recent-onset
occlusions occurred in patients in the terminal stages of severe
systemic disease. Eyes with recent-onset and perfused CRVOs
were underrepresented in this series.
The reason that thrombus formation tends to occur in the
region of the lamina cribrosa is unknown. The close anatomic
association of the central retinal artery and the central retinal
vein in this region, as well as the narrowing of the central
retinal vessels as they pass through the lamina cribrosa, may
contribute to turbulent flow and thrombus formation.119
Numerous risk factors for CRVO have been identified,
including systemic, ocular, and localized abnormalities. A con-
current systemic disease is present in at least half of the patients.
The Eye Disease Case-Control Study found an increased risk of
either type of CRVO in persons with systemic hypertension and
diabetes mellitus.120 Other studies have shown that approxi-
mately 60% of patients diagnosed with CRVO have a history of
hypertension. Vasculitis associated with diseases such as
sarcoid, syphilis, systemic lupus erythematosus is also a risk 1761
 RETINA AND VITREOUS
factor. Retrobulbar external compression from thyroid disease
or orbital tumor also increases the risk of CRVO.25,121–126
Systemic disease appears to play a significant role in CRVO
development. Atherosclerosis has been reported to be a major
risk factor for CRVO development. One theory is that athero-
sclerosis of the adjacent central retinal artery compresses the
central retinal vein in the region of the lamina cribrosa, second-
arily inducing thrombosis in the lumen of the vein. Younger
patients with CRVO have been reported to have an increased
risk of cardiovascular death and collagen vascular disease.121,127,128
However, much of these data have come from case series
without control groups. Elman compared the prevalence of
hypertension, diabetes, cardiovascular and cerebrovascular
disease, and mortality among CRVO patients and a control
group from the Wilmer Ophthalmological Institute and another
control group from a national survey.129 He found a higher
prevalence of hypertension in the CRVO patients when com-
pared to both control groups, but diabetes was more prevalent
SECTION 10
only when compared with the national survey control group.
Rates of cardiovascular disease, cerebrovascular disease, and
mortality did not differ significantly among the groups. When
comparing with a general ophthalmology patient population,
Rath found a higher association of CRVO with male gender,
systemic hypertension, and open-angle glaucoma.126 Elevated
serum lipid levels have also been reported to be associated with
increased risk.125,130 The Eye Disease Case-Control Study
Group compared patients with CRVO to age-matched controls.
There was a higher cardiovasacular risk profile, which included
hypertension or diabetes, less physical activity, and decreased
alcohol consumption, among patients with CRVO. The
association was more significant in patients with nonperfused
rather than perfused CRVO. In women, the risk increased with
higher erythrocyte sedimentation rates and decreased with use
of postmenopausal estrogen.120
Certain hematologic abnormalities are risk factors for CRVO,
especially in young adults. Thrombophilic factors have been
shown to be associated with an increased risk of RVO. Hyper-
homocysteinemia appears to be one of the most common and
significant thrombophilic risk factors for development of CRVO.
Less evidence exists for Factor V Leiden mutation, protein C
and S deficiency, antithrombin deficiency, antiphospholipid
antibodies, activated protein C resistance, prothrombin gene
mutation, anticardiolipin antibodies, abnormal fibrinogen
levels, and lupus anticoagulant.120,131–148
Homocysteine is a naturally occurring molecule in the body
and is required in several reactions that occur within the cells.
If the pathways to either cysteine or methionine are blocked,
then homocysteine levels may rise. A patient who is hetero-
zygous for this mutation has no evidence of hyperhomo-
cysteinemia or increased risk of thrombotic disorders. Patients
who are homozygous for the defect can develop hyperhomo-
cysteinemia. Additionally, deficiencies in vitamin B6 and folate
can lead to increased levels of homocysteine. Other causes
include certain medications and kidney disease. The prevalence
of hyperhomocysteinemia in the general population is not
known. Hyperhomocysteinemia can be treated with vitamin
supplementation; folate and vitamin B12 have shown to
decrease serum homocysteine levels. However, there is no con-
vincing data that decreasing homocysteine levels with vitamin
supplementation will reduce the risk of CRVO.143,144,148
Protein C is a naturally occurring anticoagulant. Protein C
deficiency is a rare cause of RVO; however, activated protein C
resistance is the most common identifiable cause of systemic
venous thrombosis.149,150 The inheritable condition is trans-
ferred in an autosomal dominant pattern. While systemic levels
of protein C are normal, the usual anticoagulation response is
1762 abnormal leading to increased thrombosis. One study of 31
patients younger than 50 years with a CRVO found that 26% of
the subjects had activated protein C resistance, compared with
2–7% in the general population.151 Some studies have suggested
that factor V Leiden is a risk factor for the development of
CRVO in patients younger than 60 years of age,152,146 however,
other studies have not supported this notion.140,145
Lupus anticoagulant factor is a circulating immunoglobulin
that may cause mild prolongation of coagulation studies,
especially partial thromboplastin time, but paradoxically is
associated with thrombosis. This factor can be seen in some
patients with systemic lupus, but can be present in the absence
of lupus. Patients with this factor frequently test positive for
antiphospholipid antibodies, including anticardiolipin, and may
test falsely positive on Venereal Disease Research Laboratory
(VDRL) testing. Systemic manifestations of the disease include
retinal vein, retinal artery, and choroidal occlusions as well as
spontaneous abortions and systemic occlusions.149,153–158
Hyperviscous states such as elevated hematocrit, increased
erythrocyte aggregation, decreased erythrocyte deformability,
elevated fibrinogen, dehydration, polycythemia, lymphoma,
leukemia, sickle cell disease, multiple myeloma, cryo-
globulinemia, and Waldenstrom macroglobulinemia have been
associated with CRVO.159–161 Common medications that can
contribute to hematologic abnormalities that may increase the
risk of CRVO include diuretics and oral contraceptives.
Abnormal platelet function can also contribute to CRVO
formation. Some have speculated that increased blood viscosity
may increase the risk of nonperfused CRVO.112,125,132,162–164
Certain ocular findings have been shown to be risk factors for
CRVO; however, the mechanism affecting the risk of CRVO is
poorly understood. An increased risk has been noted in eyes
with open-angle glaucoma. In uncontrolled studies, 40% of
patients with CRVO had preexisting open-angle glaucoma, or
developed glaucoma during follow-up.165,166 The Eye Disease
Case-Control Study found that patients with a CRVO were five
times more likely than age-matched controls to have either
glaucoma or an intraocular pressure greater than 20 mmHg.120
Other ocular findings associated with increased risk of CRVO
include increased cup-to-disk ratio (independent of glaucoma
and increased introcular pressure),167 ischemic optic neuropathy,
tilted optic nerve head, optic nerve head drusen, optic disk
traction syndrome, pseudotumor cerebri, external compression
of the optic nerve and globe from thyroid-related ophthalmo-
pathy, and mass lesions or head trauma with orbital fracture.117
Systemic workup is a vital part of the examination process if
no identifiable risk factor is known. Many of the risk factors
for CRVO are treatable systemic diseases that, if left untreated,
can result in high morbidity and mortality. Common diseases
associated with CRVO include hypertension, diabetes mellitus,
and atherosclerosis.25,120–126,129 However, other diseases should
be considered, especially in persons younger than 56 years of
age and in those with bilateral CRVO. In general, further work-
up is not indicated in persons older than 55 years of age with
known systemic vascular risk factors for CRVO.168,169
CLINICAL FEATURES
Historically, confusion has existed regarding the classification of
CRVO subtypes. In 1904, Coats was the first to describe two
types of CRVO. He recognized that one group of patients often
had marked vision loss and a poor prognosis, while another
group had much less visual disturbance and had a better
prognosis.170 With the advent of FA, these two types of CRVO
were then classified based on retinal capillary perfusion
characteristics. Multiple terms have been used in an attempt to
differentiate the two clinical pictures. Terms used to refer to the
more severe type include ‘hemorrhagic retinopathy’, ‘complete’,

‘nonperfused’, or ‘ischemic CRVO’. Conversely, the more
benign type has been referred to as ‘venous stasis retinopathy’,
‘partial’, ‘perfused’, or ‘nonischemic’.8 Our discussion will use
the terms perfused and nonperfused. It is important to under-
stand the distinguishing features of the two groups in order to
guide patient counseling, understand prognosis, and guide
treatment (Table 132.2).
A common presenting symptom in CRVO is abrupt decrease
in vision. However, some patients will describe transient vision
loss lasting a few seconds to minutes over the preceding days to
weeks. Some patients will report symptoms of photophobia and
red eye; however, these symptoms, if present, typically last for a
few days to weeks only. Rarely, presenting symptoms include
pain, blurry vision from corneal haze, and increased intraocular
pressure. These patients may have a subacute or chronic CRVO
that has not been detected and has resulted in the more severe
complication of neovascular glaucoma.
Initial evaluation should include distinguishing between
perfused and nonperfused CRVO. Typically, two-thirds of all
CRVOs are perfused, while the remaining one-third are
nonperfused.51,121,171 Clinical examination combined with FA
are most commonly used to differentiate between the two broad
categories. Electrophysiologic testing and visual field testing
may also be helpful in the evaluation process when FA cannot
demonstrate the extent of nonperfusion (e.g., in cases with
extensive intraretinal hemorrhage). Serial monitoring of the
CRVO subtype is important during follow-up examinations, as
up to one-third of perfused CRVOs progress to nonperfused over
the course of the disease.4,51,121,123,172 The Central Vein
Occlusion Study (CVOS)4–6 was a multicentric, international
clinical trial sponsored by the National Eye Institute evaluating
725 patients and 728 eyes with CRVO followed at least 3 years.
Eyes were entered into four predefined study groups: perfused,
nonperfused, indeterminate, and macular edema. The CVOS
reported that in the first 4 months of follow-up, 81 (15%) of the
547 eyes with perfusion converted to nonperfusion. During the
next 32 months of follow-up, an additional 19% of eyes were
found to have converted to nonperfusion for a total 34% after
3 years. Risk factors for progression include worse presenting
visual acuity, severe macular edema, and progressive intra-
retinal hemorrhage.172
Nonperfused CRVO is often more dramatic in its presen-
tation and is associated with a worse visual outcome than
perfused CRVO.119 The nonperfused type typically presents
with multiple cotton-wool spots, extensive retinal hemorrhage,
a relative afferent pupillary defect, visual acuity worse than
20/400, widespread capillary nonperfusion on FA, and
abnormal electroretinography (ERG) testing. One of the great
difficulties in evaluating CRVO is understanding the risks
associated with varying degrees of retinal nonperfusion. Retinal
nonperfusion rarely occurs throughout the entire fundus. Often,
TABLE 132.2. Common Clinical Findings in CRVO
Test Perfused Nonperfused
Fluorescein angiogram Uniform capillary Patchy capillary
fluorescence hypoflouresence
Afferent papillary defect Minimal/absent Present
Visual acuity >20/400 <20/400
Electroretinogram Normal/ Delayed
supernormal
Risk of Low risk High risk
neovascularization
Retinal Venous Occlusive Disease
only certain areas appear nonperfused on evaluation. Retinal
hemorrhage may prevent correct quantification of retinal
nonperfusion due to blockage of fluorescence in the area of
hemorrhages. Although no standard criteria have been
established, the CVOS defined ‘ischemia’ (synonymous with
nonperfusion in our discussion) as 10 or more disk areas of
nonperfusion on FA.
Perfused CRVO typically has mild fundus changes, no
afferent pupillary defect, visual acuity better than 20/400, less
extensive capillary nonperfusion on FA, and nearly normal
ERG testing. Ocular neovascularization rarely develops in
perfused CRVO eyes and visual prognosis is generally more
favorable.
A complete ocular examination, including intraocular
pressure measurement, slit-lamp biomicroscopy, gonioscopy to
rule out neovascularization of the iris or angle, and a dilated
fundus examination is recommended at the initial presenta-
tion and at monthly follow-up examinations during the first
CHAPTER 132
9 months. Neovascularization of the iris or angle is an ominous
sign of potential development of neovascular glaucoma.
Visual Acuity
There is wide variability in visual acuity following a CRVO;
however, the presenting visual acuity is highly predictive of final
visual outcome. Visual acuity can range from 20/20 to hand
motion, or even no light perception in those with end stage
neovascular glaucoma. The CVOS4–6 reported that in 65% of
patients with presenting visual acuity better than 20/40, the
vision remained stable. Patients with poor visual acuity at
presentation (<20/200) had an 80% chance of having a visual
acuity worse than 20/200 at the final visit.
Visual acuity can be helpful in distinguishing perfused versus
nonperfused CRVO. Patients with perfused CRVO tend to have
better visual acuity; however, vision may still be quite poor due
to macular edema or other complications.51,121,122 While poor
visual acuity can be seen in either perfused or nonperfused
CRVO, relatively good initial visual acuity is suggestive of
perfused CRVO. Hayreh reported a visual acuity better than
20/200 (6/60) in 58% of the eyes with perfused CRVO, as
compared to only 1.7% of eyes with nonperfused CRVO. A
visual acuity better than 20/400 (6/120) was measured in 81%
of eyes with perfused CRVO, compared to about 7% of the eyes
with nonperfused CRVO. A visual acuity of 20/400 or worse was
measured in only 19% of the eyes with perfused CRVO,
compared to 93% of the eyes with nonperfused CRVO.119
Afferent Pupillary Defect
Evaluation for a relative afferent pupillary defect can be helpful
in distinguishing perfused and nonperfused CRVO. Eyes with
nonperfused CRVO are much more likely to have a relative
afferent pupillary defect. Ninety percent of eyes with perfused
CRVO were found to have a relative afferent pupillary defect of
0.3 log units or less. However, 91% of eyes with nonperfused
CRVO had a relative afferent pupillary defect of 1.2 log units
or more.173
Intraocular Pressure
Relative intraocular pressure difference is less helpful in the
evaluation process. However, immediately after CRVO, the
intraocular pressure is typically slightly lower in the affected eye
as compared to the fellow eye. This relative difference in intra-
ocular pressure diminishes with time, and symmetry returns
over the ensuing weeks to months.174
Visual Field Testing
Visual field testing is widely variable in CRVO, but may be bene-
ficial for better understanding the patient’s visual perception. 1763
 RETINA AND VITREOUS
Abnormalities are more common and more severe in eyes with
nonperfused rather than perfused CRVO.175
Fluorescein Angiography (FA)
FA can be very helpful in evaluating the extent and mechanism
of retinal dysfunction based on perfusion characteristics. The
characteristic findings in CRVO are due to changes in vascular
caliber, vascular permeability, and capillary nonperfusion. Wide-
angle FA using a 60° fundus camera is helpful in evaluating
peripheral retinal perfusion. The overall arterial perfusion time
after injection is normal to slightly delayed in CRVO; however,
the delay in arteriovenous transit time is typically significantly
delayed (Fig. 132.9).43 A delay beyond 20 seconds is associated
with a greater risk of iris neovascularization.123 Nonperfused
areas may be visualized as patchy areas of hypofluorescence
with a ground-glass appearance (Fig. 132.10). Staining of the
SECTION 10
FIGURE 132.9. Delayed filling of the retinal venous system in a
CRVO. This frame, taken 14 s after the appearance of fluorescein in
the retinal arteries, shows minimal filling of the retinal venous system.
FIGURE 132.10. Fluorescein angiogram of a profoundly nonperfused
1764 CRVO. Note the nearly complete absence of retinal capillaries.
walls of the retinal veins has been demonstrated to be an
indicator of nonperfusion. Retinal capillary nonperfusion is an
important feature in identifying those eyes at greatest risk of
developing neovascularization.171,176,177 There are no definite
guidelines for assessing the risk of neovascularization; however,
the CVOS used 10 disk diameters of nonperfusion as its cut-off
for predicting risk.4 The location of the nonperfusion is also
important in terms of predicting long-term visual potential.
Nonperfusion near the fovea is associated with worse visual
prognosis. Overlying retinal hemorrhage may impede the ability
to evaluate the underlying capillary perfusion status.
FA is also helpful in evaluating causes of central vision loss.
Central vision loss is common following CRVO and can be the
result of macular edema, parafoveal capillary nonperfusion,
intraretinal hemorrhage, or retinal pigment epithelial damage
due to deep retinal or subretinal hemorrhage. In macular edema,
FA shows parafoveal and paramacular capillary leakage that
appears as hyperfluorescence that increases in size and intensity
with time, often in a petalloid type pattern. The hyper-
fluorescence persists longer than that of normal retinal tissue.
Hemorrhage causes persistent blocking of the fluorescence
throughout the angiographic evaluation.
Electrophysiologic Testing
Electrophysiologic testing with electroretinogram (ERG) may be
helpful in distinguishing between perfused and nonperfused
CRVO.178 Matsui et al reported that the ERG b/a-wave ampli-
tude ratios, photopic and scotopic b-wave amplitudes, and
flicker amplitudes were significantly smaller in eyes with exten-
sive capillary nonperfusion, than in eyes without. When the
photopic or scotopic b-wave amplitudes were normal or super-
normal, extensive capillary nonperfusion on FA was absent in
all eyes. When the b/a-wave ratios were greater than or equal
1.0, or when the b-wave amplitudes with white flash or flicker
amplitudes were normal or supernormal, extensive capillary
nonperfusion was present in less than 32% of eyes. When the
b/a ratio was less than one, there was a higher probability of
retinal nonperfusion and a higher risk of developing iris
neovascularization.179
Optical Coherence Tomography (OCT)
OCT is a helpful tool in evaluating the macula following CRVO.
The OCT can aid the clinician in evaluating macular edema,
epiretinal membrane formation, and subretinal fluid accumula-
tion following CRVO.180,181
COMPLICATIONS
The clinical course after a CRVO is highly variable. The retinal
hemorrhages and microaneurysms may resolve over weeks or
may persist for years. The Blue Mountains Eye Study reported
a 10% incidence of residual retinopathy lesions (microaneurysms,
hemorrhages, hard or soft exudates) at the 5 year follow-up in
nondiabetic patients.182 Macular edema may resolve quickly,
persist chronically, vary intermittently, or develop late in the
course of the disease. Neovascularization typically occurs on the
iris in CRVO; however, neovascularization may develop on
the disk and, or retina. Fundus neovascularization very rarely
develops in eyes with perfused CRVO.8,121,123,176,183,184 If neo-
vascularization develops, it usually is present within the first 7
months of the CRVO. The venous dilatation and tortuosity
typically resolve with time, and marked fibrous sheathing of the
retinal veins and arteries may develop. The disk swelling slowly
resolves and may develop disk pallor in nonperfused cases.
Collateral vessels at the optic disk may develop.
Macular dysfunction is common following CRVO. The visual
disturbances may be transient or chronic. A common cause of

macular dysfunction is retinal edema. Retinal edema may
develop from abnormal vascular permeability following CRVO
in any part of the retina. It often presents as a petalloid pattern
of cystoid macular edema.180 Severe macular edema is a risk
factor for progression of perfused CRVO to nonperfused.172 The
exact mechanism causing the leakage is unknown, but may
be due to vascular congestion, capillary damage, or localized
inflammatory reactions.
Serous retinal detachment has also been described following
CRVO. With the advent of better cross-sectional retinal imaging
using OCT, serous retinal detachments are reported to occur
more frequently than recognized previously.181
Microaneurysms are a common finding following CRVO (Fig.
132.11). Less commonly, macroaneurysms may develop.48 Hard
exudates are a less common finding following CRVO. Large
amounts of hard exudates are associated with nonperfusion,
poor visual acuity, and elevated serum triglyceride levels.185,186
The hard exudates typically resolve with time. Retinal hemor-
rhage can vary in its presentation; however, at least mild retinal
hemorrhage is virtually always present following CRVO. The
location of the hemorrhage is typically intraretinal and superficial.
Occasionally, vitreous hemorrhage may develop following an
acute CRVO; vitreous hemorrhage is usually a result of neovas-
cularization of the retina or disk at a later stage of the disease.
Iris and angle neovascularization are dreaded complications
of CRVO because of the risk of developing neovascular
glaucoma. Neovascular glaucoma often leads to intractable
elevated intraocular pressure, blindness, and extreme eye pain.
Evisceration or enucleation, is all too often the final treatment
option once neovascular glaucoma becomes medically uncon-
trollable. Of those that develop neovascular glaucoma, 66–71%
do so within the first 6 months of CRVO development. The
incidence of rubeosis among all CRVOs is approximately 20%.
Among non-perfused eyes, the incidence is 45–80%. In perfused
eyes, the rate of iris neovascularization is one to ten percent.
Of eyes that develop iris neovascularization, approximately
two-thirds will develop neovascular glaucoma without
treatment.51,121,123,176,183 Early treatment of neovascularization
of the iris with PRP results in resolution of the iris
neovascularization in approximately two-thirds of the cases.187
VEGF appears to play an important role in the development of
neovascularization and macular edema. Hypoxia-induced
upregulation of VEGF may be an important factor in retinal
FIGURE 132.11. Large capillary aneurysms that occurred after a
CRVO. Peripheral to the aneurysms is a large area of nonperfusion.
Retinal Venous Occlusive Disease
ischemia with iris and retinal neovascularization in CRVO.
Upregulation of VEGF production appears to occur most
consistently in the inner nuclear layer in hypoxic retina.188–190
The clinician must take care not to confuse disk neovascu-
larization with optociliary shunt vessels of the disc. Optociliary
shunt vessels develop commonly following CRVO (Fig. 132.12).
The vessels form as collateral channels between the retinal and
ciliary circulations. The shunt vessels are typically larger in
caliber and do not leak on FA as compared to typical disk
neovascularization. Opinions differ as to whether optociliary
vessel formation is associated with an improved visual
prognosis;121,127,191,192 there may be a decreased risk of
developing anterior segment neovascularization in eyes with
retinochoroidal collateral vein formation.167
DIFFERENTIAL DIAGNOSIS
Diabetic retinopathy can present with findings similar to CRVO
CHAPTER 132
with dot-blot hemorrhages and microaneurysms. However, in
diabetic retinopathy, the retinal findings are generally bilateral,
compared with CRVO, in which the insult is typically uni-
lateral. Bilateral CRVO is an uncommon presentation.
Ocular ischemic syndrome due to carotid occlusive disease
must also be distinguished from CRVO. In the ocular ischemic
syndrome the veins are similarly dilated and irregular, but are
not as tortuous as those seen in CRVO. Neovascularization of
the disk may be present in either disease without disk swelling
or hemorrhages. Retinal hemorrhages are typically seen in the
mid-periphery in ocular ischemic syndrome. Patients with
ocular ischemic syndrome may have a history of amaurosis
fugax, transient ischemic attacks, or orbital pain. Intraocular
pressure may be low.
Papilledema may present similarly to CRVO. Disk swelling is
generally bilateral due to increased intracranial pressure.
Similar disk hemorrhages may be observed; however, the
hemorrhages are generally localized to the optic disk with
papilledema and typically do not involve the peripheral retina.
Radiation retinopathy may be unilateral or bilateral. A his-
tory of irradiation is essential for the diagnosis. Similar to
CRVO, disk swelling, disk hemorrhages, retinal neovascu-
larization, and cotton-wool spots may be present.
Hypertensive retinopathy also may be considered in the
differential diagnosis of CRVO. Distinguishing characteristics of
FIGURE 132.12. Typical, tortuous appearance of disk collaterals after
a CRVO. 1765
 RETINA AND VITREOUS
hypertensive retinopathy include narrowed retinal arterioles
and bilateral involvement of the retinal hemorrhages.
TREATMENT
Medical Treatment
Identification and treatment of systemic vascular risk factors in
conjunction with the internist is important in individuals with
CRVO. In general, a systemic workup is not indicated in per-
sons older than 55 years of age with known systemic vascular
risk factors for CRVO.168,169 If no known systemic vascular risk
factor is present, initial investigation may include checking
blood pressure, intraocular pressure, complete blood count,
glucose levels, and a lipid panel on all patients with CRVO.
More extensive evaluation may be considered if the initial
screen does not reveal the presence of a systemic risk factor. The
role of systemic anticoagulation in CRVO is unclear, as there is
no evidence that agents such as aspirin, heparin or warfarin
SECTION 10
prevent or alter the natural history of CRVO. Patients taking
warfarin have been reported to develop CRVO despite main-
taining therapeutic levels of anticoagulation.193 Limited data
suggests that systemic hemodilution and/or pentoxifylline
(lowers blood viscosity) may be beneficial in improving visual
acuity and macular edema, and reducing the risk of progression
to ischemic CRVO.194,195
Laser Photocoagulation
One of the most feared complications of CRVO is neovascular
glaucoma. Early signs of developing neovascular glaucoma
include neovascularization of the iris and angle. The CVOS4–6
found that the most important predictive factor of iris neo-
vascularization in CRVO is poor visual acuity. Other risk factors
identified included increasing amounts of retinal capillary
nonperfusion and intraretinal blood. The study found that,
prophylactic PRP decreased the risk of iris neovascularization
compared to untreated eyes, but the difference was not statis-
tically significant. Laser treatment after the development of iris
or angle neovascularization was followed by prompt regression
(within 1 month) in 18 (56%) of 32 previously untreated eyes
and in four (22%) of 18 eyes that had undergone prophylactic
PRP. The authors recommended PRP be delivered promptly
after the development of iris or angle neovascularization in eyes
with nonperfused CRVO. Hayreh et al conducted a prospective,
study of argon laser PRP in nonperfused CRVO over a 10 year
period in 123 eyes. On comparing the laser-treated eyes versus
the eyes not treated by laser, there was no statistically sig-
nificant difference between the two groups in the incidence of
development of angle neovascularization (NV), neovascular
glaucoma (NVG), retinal and/or optic disk NV, or vitreous
hemorrhage, or in visual acuity. The study, however, did show a
statistically significant (P = 0.04) difference in the incidence of
iris NV between the two groups, with iris NV less prevalent in
the laser group than in the nonlaser group, but only when the
PRP was performed within 90 days after the onset of CRVO.196
The delivery of PRP before the development anterior segment
neovascularization may be considered in eyes with nonperfused
CRVO when monthly ophthalmologic examination is not possible.
However, 20% of these patients will develop iris-neovascular-
ization despite laser photocoagulation treatment. It should be
kept in mind that some patients who undergo PRP will have
permanent peripheral visual field defects following treatment.196
Patients with CRVO who present with neovascular glaucoma
should undergo PRP, or, if the media is hazy, cryoablation.
Topical intraocular pressure lowering drugs should be given and
a surgical glaucoma procedure may be indicated.
The CVOS also studied the effectiveness of grid pattern argon
1766 laser photocoagulation in improving visual acuity in eyes with
perfused macular edema and 20/50 acuity or worse. Laser treat-
ment involved a grid pattern in the area of leaking capillaries
within two disk diameters of the foveal center but not within
the foveal avascular zone. There was no significant difference in
mean visual acuity between treated (20/200) and untreated
(20/160) eyes at 36 months. There was angiographic resolution
of the macular edema by 1 year in 31% of treated eyes (com-
pared with 0% of untreated eyes), but there was a lack of visual
recovery likely secondary to widespread damage to the
perifoveal capillary network. Therefore, the CVOS did not
recommend grid laser photocoagulation for CRVO-associated
macular edema. However, in the younger patients there was a
trend toward improved visual acuity in the treatment group.
This possibly was not statistically significant given the small
sample size.
Chorioretinal Venous Anastomosis
Laser-induced chorioretinal venous anastomosis was initially
described by McAllister and Constable.197 The goal is to bypass
the occluded vein in perfused CRVO. Overall, the treatment
consists of producing an intense focal laser burn directed at or
near a tributary vein in an attempt to disrupt the wall of the
vein and rupture underlying Bruch’s membrane.198,199 Various
laser wavelengths have been employed, including argon green,
argon blue–green, dye yellow, and Nd-YAG. Successful anasto-
mosis formation is achieved in 33–100% of cases with variable
visual function recovery.197,198,200–202 However, the treatment is
associated with complications in up to 67% of cases; these
complications include posterior vitreous detachment, choroidal
or vitreous hemorrhages, preretinal fibrosis, choroidal neo-
vascularization, segmental retinal ischemia, choriovitreal
neovascularization, and retinal detachment.197,198,200–206
Some surgeons have attempted to create a successful chorio-
retinal venous anastomosis by means of surgery, especially in
nonperfused CRVO.207,208 This technique may offer improved
visual status in eyes with perfused CRVO and BRVO, but the
precise treatment variables and method to reliably create an
anastomosis while minimizing complications have yet to be
determined.
Conventional Pars Plana Vitrectomy for
Complications of CRVO
Pars plana vitrectomy techniques are often employed to address
complications of CRVO, especially nonclearing vitreous
hemorrhage.209 At the time of vitrectomy, evacuation of the
hemorrhage can be combined with removal of epiretinal
membranes and endolaser photocoagulation if warranted.
Pars Plana Vitrectomy for Macular Edema
Some authors believe that the absence of posterior vitreous
detachment can contribute to the occurrence or the persistence
of macular edema in CRVO and that relieving the vitreous
traction over the macula by means of vitrectomy-induced
posterior vitreous detachment may assist in improving the
macular edema.71,209,210 Sekiryu et al211 reported on five patients
with macular edema caused by CRVO that were examined
using OCT. The retinal thickness through fixation was reduced
in all five eyes. Preoperatively, the retina thickness at the
foveola was more than 500 mm in three eyes and more than
1000 mm in two eyes. The retina thickness was reduced to
311+/– 80 mm within 2 weeks on average. Visual acuity was
improved by two or more lines in three of five eyes.
Radial Optic Neurotomy
Opremcak et al212 hypothesized that the pathogenesis of CRVO
may be similar to ‘compartment syndromes’ elsewhere in the
body, where pressure within a confined space results in tissue

ischemia. According to this hypothesis, an anatomic ‘bottle-
neck’ exists at the lamina cribrosa where the central retinal
artery, central retinal vein and optic nerve lie within a 1.5 mm-
diameter area with dense connective tissue encircling these
structures, restricting the central retinal vein luminal
diameter.213 Optic nerve sheath decompression was initially
attempted using an external approach by Vasco–Posada214 and
Arcienigas.215 More recently, Opremcak proposed radial optic
neurotomy to achieve the decompression of the scleral outlet
via an internal, vitreoretinal approach.212 Such a surgical
approach was performed in 11 cases, achieving visual acuity
improvement in eight cases (73%). Seven of the 11 eyes (64%)
achieved a final visual acuity of 20/200 or better, and five (45%)
achieved a final acuity of 20/70 or better. No significant com-
plications were observed postoperatively. Other authors have
noted varying degrees of clinical improvement following surgical
radial optic neurotomy including a decline in macular edema
and decreased or resolved intraretinal hemorrhages.216–220
However, others have reported no statistically significant
improvement of vision following the procedure.221,222 Reported
complications associated with this procedure include optic
nerve damage, vitreous hemorrhage, subretinal hemorrhage,
peripapillary retinal detachment, choroidal neovascularization,
and temporal visual field defect.223–230
Tissue Plasminogen Activator
Thrombolytic agents have been proposed as a treatment
directed against a suspected thrombus in the central retinal
vein. Recombinant tissue plasminogen activator (r-tPA) is a
synthetic fibrinolytic agent that converts plasminogen to
plasmin and destabilizes intravascular thrombi. Reduction in
clot size may facilitate dislodging of the entire thrombus or re-
canalization of the occluded retinal vein. As therapy for CRVO,
r-tPA has been administered by several routes: systemic,
intravitreal, subretinal and via endovascular cannulation of
retinal vessels.
Systemic administration of low-dose (50 mg) front-loaded
r-tPA has been attempted in two pilot studies with visual acuity
improvement in 30–73% of patients.229,231 However, this treat-
ment has been associated with serious complications, including
patient mortality, which have curbed the use of systemic
administration of r-tPA for CRVO.
Intravitreal delivery of r-tPA has potential advantages includ-
ing directed delivery to the retinal vessels as well as decreased
risk of ocular and systemic complications. Of 47 persons in
three studies of intravitreal r-tPA for both ischemic and
nonischemic CRVO of less than 21 days duration, 28–44%
experienced three lines of visual acuity improvement with
6 months follow-up.232–234 However, the significance of the
visual outcome is severely limited, as none of the studies
included a control group. Administration of r-tPA did not sig-
nificantly alter final perfusion status. Ghazi et al reported
intravitreal r-tPA in 12 eyes with acute nonperfused CRVO of
less than 3 days duration.235 In all eyes, perfusion status
remained unchanged at last follow-up. Nine patients (75%) had
best-corrected visual acuity of 20/200 or worse at presentation
compared with four patients (33%) at the last follow-up after
treatment. Five (55%) of these nine patients had final visual
acuity that improved to 20/50 or better. The remaining four
patients did not have improvement or their vision continued to
worsen. Overall, eight (67%) of 12 patients had a final visual
acuity of 20/50 or better. No side effects related to tPA injection
were observed. This report suggests that prompt use of intra-
vitreal r-tPA, especially in perfused CRVO, may provide signi-
ficant visual improvement, although study limitations, such
as the lack of a control group, preclude definitive conclusions
to be drawn.
Retinal Venous Occlusive Disease
Lam et al236 reported subretinal peripapillary tPA injection
with vitreopapillary and epipapillary membrane dissection and
peripheral photocoagulation in a patient with unresolved CRVO
at 4 months with a modest improvement of visual acuity from
finger counting to 20/400. Endovascular delivery of r-tPA
involves cannulation of retinal vessels, either through a
neuroradiologic237 or a vitreoretinal approach238–240 and allows
for delivery of minute quantities of r-tPA directly to the
occluded vessels. Retinal endovascular surgery (REVS) involves
vitrectomy followed by insertion of a microcannula into
branches of the retinal vasculature with injection of pharma-
cologic agents such as tPA. Weiss and Bynoe have reported their
technique of pars plana vitrectomy followed by cannulation of a
branch retinal vein with injection r-tPA toward the optic nerve
head.239 Of 28 eyes with CRVO of greater than 1 month dura-
tion and worse than 20/400 preoperative acuity, 50% recovered
more than three lines of acuity with a mean follow-up of
12 months. There was a trend toward increased perfusion on
CHAPTER 132
FA attributed in part to the resolution of intraretinal
hemorrhages after the procedure. Complications included
vitreous hemorrhage in seven eyes and retinal detachment in
one eye.
Intraocular Corticosteroids
High-dose oral corticosteroids have been reported to be
associated with a transient reduction in macular edema with
improved vision over the short term in a small number of
patients with CRVO, but were associated with systemic side
effects and recurrence of macular edema.242 Small case studies
have suggested that there may be a transient benefit from
intravitreal injection of steroids for macular edema and vision
loss associated with CRVO.243–251 The outcome appears to be
dependent on whether the CRVO is perfused or nonperfused.
One such study by Ip et al248 reviewed the medical records of 13
consecutive patients (13 eyes) with macular edema associated
with CRVO who were treated with an injection of intravitreal
triamcinolone acetonide (4 mg) at the University of Wisconsin
and the Bascom Palmer Eye Institute. Each intravitreal injection
was delivered through the pars plana using a 27- or 30-gauge
needle. The median age of the 13 patients was 67 years
(interquartile range, 57–77 years), and the median duration of
symptoms before injection was 8 months (interquartile range,
4–9 months). Mean baseline visual acuity was 20/500 in the
affected eye. Mean visual acuity at the 6 month follow-up
examination was 20/180 in the affected eye. All 13 patients
completed the 6 month examination. Eyes with perfused CRVO
(n = 5) demonstrated a significant improvement in visual
acuity, whereas eyes with nonperfused CRVO (n = 8)
demonstrated a nonsignificant visual acuity improvement. No
patient had a decrease in visual acuity. Mean baseline foveal
thickness as measured by OCT was 590 mm (retinal thickening
= 416 mm). Mean foveal thickness as measured by OCT at the
1month follow-up examination in 12 patients was 212 mm
(retinal thickening = 38 mm). Between the 3- and 6-month
follow-up examinations, four patients developed a recurrence of
macular edema. Three of the four patients were retreated with
a second injection of triamcinolone. Two of these three patients
experienced an improvement in visual acuity following retreat-
ment. At the 6 month follow-up examination, mean foveal
thickness as measured by OCT for 13 patients was 281 mm
(retinal thickening = 107 mm).
The mechanism of action of corticosteroids for macular
edema in CRVO is not clear and has been discussed above with
BRVO. Most patients with CRVO, both nonperfused and
perfused, may have a favorable anatomical response to this
treatment as demonstrated by OCT images and measurements
demonstrating reduction in macular thickness and resolution of 1767
 RETINA AND VITREOUS
the large cystic spaces in the outer plexiform layer within
several weeks of injection. However, a favorable visual acuity
response appears more likely in patients with perfused CRVO.
Re-treatment may also be necessary in some patients due to the
recurrence of macular edema. There may be intravitreal steroid-
related adverse events (including cataract and increased intra-
ocular pressure) and injection-related adverse events (including
noninfectious and infectious endophthalmitis, retinal detach-
ment, vitreous hemorrhage, and lens injury) that could negate
the benefit of reduction in macular edema. The SCORE study
and the Posurdex trial will further clarify the role of cortico-
steroids in CRVO.
Anti-VEGF Agents
Experimental studies have shown that functional and structural
changes occur in the retinal capillaries induced by the hypoxic
environment after venous occlusion. This leads to increased
capillary permeability and accompanying retinal edema. VEGF,
SECTION 10
a 45kDa glycoprotein redundant,35 appears to play a role in this
process. Numerous anti-VEGF agents are available. Pegaptanib
(Macugen) and ranibizumab (Lucentis) have been approved by
the Food and Drug Administration (FDA) for the treatment
of neovascular age-related macular degeneration. The use of
pegaptanib in a small, randomized series of patients with CRVO
is currently in progress. Another anti-VEGF medication is
bevacizumab (Avastin), which is approved by the FDA for the
treatment of metastatic colon cancer, but has been used in off-
label settings for the treatment of numerous ocular conditions.
A single case report of intravitreal injection of bevacizumab in
CRVO reported resolution of macular edema and improvement
in visual acuity from 20/200 to 20/50 maintained at 4 weeks.252
A retrospective study of 16 eyes in 15 patients with macular
edema secondary to CRVO supported the previous case report.
The series included nine patients who had received previous
intravitreal triamcinolone injections but had either not im-
proved or developed intraocular pressure (IOP) elevation. The
patients received a mean of 2.8 injections of 1.25 mg in
0.05 mL of bevacizumab per eye. The mean baseline acuity was
20/600 that improved to a mean of 20/200 at 1 month, and
20/138 at 3 months. Halving of the visual angle was observed
in 14 of the 16 eyes.253 There is a published report of intra-
vitreal bevacizumab injection for treatment of neovascular
glaucoma after failed intraocular pressure control with
transscleral cyclophotocoagulation and PRP; the intraocular
pressure improved within 2 days and the patient experienced
marked improvement in comfort.254 The long term risks and
effects of intravitreal anti-VEGF therapy remain unclear.
Until the results of long-term, randomized studies are avail-
able, the optimal management of CRVO will remain unclear.
HEMIRETINAL VEIN OCCLUSION
Synonym
• Hemivein occlusion
Key Features
• Hemi-retinal involvement in the distribution of the involved
occluded vein
• Dilated, tortuous veins
• Superficial and deep retinal hemorrhages
• Cotton-wool spots
• Optic nerve swelling/hemorrhages
• Macular/retinal swelling
• Optociliary shunt vessels on disk
• Neovascularization of the optic disk, retina, or iris
1768
INTRODUCTION
Epidemiology
HRVO is the least common type of venous occlusive disease. As
discussed previously, HRVO makes up only a fraction of the
incidence of vein occlusions. In the BMES, the overall incidence
of RVO was 1.6% and only 5.1% of those were HRVO.8
Pathogenesis
In approximately 20.3% of humans, a two-trunked central retinal
vein persists proximal to the lamina cribosa.255 One of the two
trunks may become occluded near the lamina cribrosa, as in
CRVO, to produce a HRVO.256,257 The trunks typically drain the
superior and inferior halves of the retina, respectively. The risk
factors of HRVO appear to be similar to those for CRVO.258
Clinical Features
HRVO presents clinically with involvement of either the
superior or inferior retinal hemisphere, (Fig. 132.13) although it
may involve one-third to two-thirds of the retina.
Visual prognosis appears to be better in HRVO than in CRVO.
Macular edema is common. Prognosis appears to correlate with
the extent of retinal perfusion. The extent of nonperfusion has
been reported to correlate positively with a worse prognosis.259
In one study including 97 eyes, 32% of HRVO were nonper-
fused, while 68% were perfused. Like CRVO, neovascularization
is uncommon in perfused HRVO. The distribution of neovascu-
larization is distinct from CRVO. The study showed that 13%
of nonperfused HRVO developed iris neovascularization, 29%
developed disk neovascularization, and 42% developed retinal
neovascularization.51 Collateral vessels may form at the disk as
in CRVO as well as across the median raphe, as in BRVO.257
Differential Diagnosis
The differential diagnosis of HRVO is similar to that of CRVO
and BRVO, including diabetes mellitus, hypertensive retino-
pathy, ocular ischemic syndrome, and radiation retinopathy.
Treatment
Although the utility of photocoagulation for prevention and
treatment of complications in HRVO has not been established,
prophylactic application of scatter photocoagulation in the
affected retinal hemisphere has been suggested in view of the
relatively higher rate of neovascular complications after
FIGURE 132.13. Typical appearance of an inferior hemicentral retinal
vein occlusion. Findings are similar to those of CRVO but affect only
half of the retina.

nonperfused HRVO. Many of the treatment modalities for
BRVO and CRVO may be beneficial in HRVO; however, formal
studies have not been performed due to the low incidence of
REFERENCES
1. Orth DH, Patz A: Retinal branch vein
occlusion. Surv Ophthalmol 1978; 22:357.
2. Branch Vein Occlusion Study Group: Argon 19.
laser photocoagulation for macular edema
in branch vein occlusion. Am J Ophthalmol
1984; 98:271.
3. Central Vein Occlusion Study: Baseline and
early natural history report. Arch 20.
Ophthalmol 1993; 111:1087.
4. Central Vein Occlusion Study Group:
Natural history and clinical management of
central retinal vein occlusion. Arch 21.
Ophthalmol 1997; 115:486.
5. Central Vein Occlusion Study Group: 22.
Evaluation of grid pattern photocoagulation
for macular edema in central vein occlusion.
The central vein occlusion study group m
report. Ophthalmology 1995; 102:1425. 23.
6. Central Vein Occlusion Study Group: A
randomized clinical trial of early panretinal
photocoagulation for ischemic central vein
occlusion. The central vein occlusion study 24.
group n report. Ophthalmology 1995;
102:1434.
7. David R, Zangwill L, Badarna M, et al:
Epidemiology of retinal vein occlusion and 25.
its association with glaucoma and
increased intraocular pressure.
Ophthalmologica 1988; 197:69.
8. Mitchell P, Smith W, Chang A: Prevalence 26.
and associations of retinal vein occlusion in
australia. The blue mountains eye study.
Arch Ophthalmol 1996; 114:1243.
9. Hayreh S: Ocular neovascularization in 27.
central retinal vein occlusion. In:
Symposium on Central Vein Occlusion,
10th Annual Macula Society Meeting.
France: Cannes.
10. Gutman FA, Zegarra H: The natural course 28.
of temporal retinal branch vein occlusion.
Trans Am Acad Ophthalmol Otolaryngol
1974; 78:OP178. 29.
11. Blankenship GW, Okun E: Retinal tributary
vein occlusion. History and management
by photocoagulation. Arch Ophthalmol
1973; 89:363.
12. Joffe L, Goldberg RE, Magargal LE, et al: 30.
Macular branch vein occlusion.
Ophthalmology 1980; 87:91.
13. Klein RKB, Moss SE, Meuer SM: The
epidemiology of retinal vein occlusion: the 31.
beaver dam eye study. Trans Am
Ophthalmol Soc 2000; 98:133.
14. Hayreh SS, Zimmerman MB, Podhajsky P: 32.
Incidence of various types of retinal vein
occlusion and their recurrence and
demographic characteristics. Am J
Ophthalmol 1994; 117:429. 33.
15. Jensen V: Clinical studies of tributary
thrombosis in central retinal vein. Acta
Ophthalmol Supp 1936; 10:1.
16. Duker JS, Brown GC: Anterior location of 34.
the crossing artery in branch retinal vein
obstruction. Arch Ophthalmol 1989;
107:998.
17. Weinberg D, Dodwell DG, Fern SA:
Anatomy of arteriovenous crossings in 35.
branch retinal vein occlusion. Am J
Ophthalmol 1990; 109:298.
18. Feist RM, Ticho BH, Shapiro MJ, et al:
Branch retinal vein occlusion and quadratic
Retinal Venous Occlusive Disease
HRVO. Treatment decisions for HRVO will continue to be based
on the discretion of the clinician until more study results
become available.
variation in arteriovenous crossings. Am J
Ophthalmol 1992; 113:664.
Zhao J, Sastry SM, Sperduto RD, et al:
Arteriovenous crossing patterns in branch
retinal vein occlusion. The eye disease
case-control study group. Ophthalmology
1993; 100:423.
Michels RG, Gass JD: The natural course
of retinal branch vein obstruction. Trans Am
Acad Ophthalmol Otolaryngol 1974;
78:OP166.
Sedney SC: Photocoagulation in retinal
vein occlusion. Doc Ophthalmol 1976; 40:1.
Weinberg DV, Egan KM, Seddon JM:
Asymmetric distribution of arteriovenous
crossings in the normal retina.
Ophthalmology 1993; 100:31.
Christoffersen NL, Larsen M:
Pathophysiology and hemodynamics of
branch retinal vein occlusion.
Ophthalmology 1999; 106:2054.
Rabinowicz IM, Litman S, Michaelson IC:
Branch venous thrombosis—a pathological
report. Trans Ophthalmol Soc UK 1969;
88:191.
Paton A, Rubinstein K, Smith VH: Arterial
insufficiency in retinal venous occlusion
(a short symposium). Trans Ophthalmol Soc
UK 1964; 84:559.
Bowers DK, Finkelstein D, Wolff SM, et al:
Branch retinal vein occlusion. A
clinicopathologic case report. Retina 1987;
7:252.
Kumar B, Yu DY, Morgan WH, et al: The
distribution of angioarchitectural changes
within the vicinity of the arteriovenous
crossing in branch retinal vein occlusion.
Ophthalmology 1998; 105:424.
Seitz R: The retinal vessels. In: The
crossing phenomenon. St Louis: Mosby;
1964:20
Jefferies P, Clemett R, Day T: An
anatomical study of retinal arteriovenous
crossings and their role in the pathogenesis
of retinal branch vein occlusions. Aust N Z
J Ophthalmol 1993; 21:213.
Frangieh GT, Green WR, Barraquer-
Somers E, et al: Histopathologic study of
nine branch retinal vein occlusions. Arch
Ophthalmol 1982; 100:1132.
Kohner EM, Dollery CT, Shakib M, et al:
Experimental retinal branch vein occlusion.
Am J Ophthalmol 1970; 69:778.
Hamilton AM, Marshall J, Kohner EM, et al:
Retinal new vessel formation following
experimental vein occlusion. Exp Eye Res
1975; 20:493.
Hamilton AM, Kohner EM, Rosen D, et al:
Experimental retinal branch vein occlusion
in rhesus monkeys. I. Clinical appearances.
Br J Ophthalmol 1979; 63:377.
Hockley DJ, Tripathi RC, Ashton N:
Experimental retinal branch vein occlusion
in the monkey. Histopathological and
ultrastructural studies. Trans Ophthalmol
Soc UK 1976; 96:202.
Hockley DJ, Tripathi RC, Ashton N:
Experimental retinal branch vein occlusion
in rhesus monkeys. Iii. Histopathological
and electron microscopical studies.
Br J Ophthalmol 1979; 63:393.
36. Rosen DA, Marshall J, Kohner EM, et al:
Experimental retinal branch vein occlusion
in rhesus monkeys. Ii. Retinal blood flow
studies. Br J Ophthalmol 1979; 63:388.
37. The Eye Disease Case-control Study
Group: Risk factors for branch retinal vein
occlusion. Am J Ophthalmol 1993;
116:286.
38. Martin SC, Butcher A, Martin N, et al:
Cardiovascular risk assessment in patients
with retinal vein occlusion. Br J Ophthalmol
2002; 86:774.
39. Shilling JS, Kohner EM: New vessel
formation in retinal branch vein occlusion.
CHAPTER 132
Br J Ophthalmol 1976; 60:810.
40. Appiah AP, Trempe CL: Risk factors
associated with branch vs. Central retinal
vein occlusion. Ann Ophthalmol 1989;
21:153.
41. Johnston RL, Brucker AJ, Steinmann W,
et al: Risk factors of branch retinal vein
occlusion. Arch Ophthalmol 1985;
103:1831.
42. Branch Vein Occlusion Study Group: Argon
laser scatter photocoagulation for
prevention of neovascularization and
vitreous hemorrhage in branch vein
occlusion. A randomized clinical trial. Arch
Ophthalmol 1986; 104:34.
43. Gass JD: A fluorescein angiographic study
of macular dysfunction secondary to retinal
vascular disease. Ii. Retinal vein obstruction.
Arch Ophthalmol 1968; 80:550.
44. Shilling JS: Vascular changes after retinal
branch vein occlusion. Trans Ophthalmol
Soc UK 1976; 96:193.
45. Clemett RS: Retinal branch vein occlusion.
Changes at the site of obstruction. Br J
Ophthalmol 1974; 58:548.
46. Gutman FA: Macular edema in branch
retinal vein occlusion: prognosis and
management. Trans Sect Ophthalmol Am
Acad Ophthalmol Otolaryngol 1977;
83:488.
47. Noma H, Funatsu H, Yamasaki M, et al:
Pathogenesis of macular edema with
branch retinal vein occlusion and
intraocular levels of vascular endothelial
growth factor and interleukin-6. Am J
Ophthalmol 2005; 140:256.
48. Schulman J, Jampol LM, Goldberg MF:
Large capillary aneurysms secondary to
retinal venous obstruction. Br J Ophthalmol
1981; 65:36.
49. Sanborn GE, Magargal LE: Venous
macroaneurysm associated with branch
retinal vein obstruction. Ann Ophthalmol
1984; 16:464.
50. Brown GC, Kimmel AS, Magargal LE, et al:
Progressive capillary nonperfusion in
temporal branch retinal vein obstruction.
Ann Ophthalmol 1989; 21:290.
51. Hayreh SS, Rojas P, Podhajsky P, et al:
Ocular neovascularization with retinal
vascular occlusion-iii. Incidence of ocular
neovascularization with retinal vein
occlusion. Ophthalmology 1983; 90:488.
52. Joondeph HC, Joondeph BC: Posterior
tractional retinal breaks complicating
branch retinal vein occlusion. Retina
1988; 8:136. 1769
 RETINA AND VITREOUS
53. Joondeph HC, Goldberg MF:
Rhegmatogenous retinal detachment after
tributary retinal vein occlusion. Am J
Ophthalmol 1975; 80:253.
54. Gutman FA, Zegarra H: Retinal detachment
secondary to retinal branch vein occlusions.
Trans Sect Ophthalmol Am Acad
Ophthalmol Otolaryngol 1976; 81:491.
55. Regenbogen L, Godel V, Feiler-Ofry V, et al:
Retinal breaks secondary to vascular
accidents. Am J Ophthalmol 1977; 84:187.
56. Ramos-Umpierre A, Berrocal JA: Retinal
detachment following branch vein occlusion:
Case report. Ann Ophthalmol 1977; 9:339.
57. Chess J, Eichen AL: Rhegmatogenous
retinal detachment associated with branch
vein occlusion. Ann Ophthalmol 1989;
21:309.
58. Zauberman H: Retinopathy of retinal
detachment after major vascular
occlusions. Br J Ophthalmol 1968; 52:117.
SECTION 10
59. Schatz H, Yannuzzi L, Stransky TJ: Retinal
detachment secondary to branch vein
occlusion. Part I. Ann Ophthalmol 1976;
8:1437.
60. Schatz H, Yannuzzi L, Stransky TJ: Retinal
detachment secondary to branch vein
occlusion: Part ii. Ann Ophthalmol 1976;
8:1461.
61. Fekrat S, Finkelstein D: In: Regillo B,
Brown GC, Flynn HW, eds: Vitreoretinal
disease: the essentials. New York: Thieme
Medical Publishers; 1999:117.
62. Wilson DJ, Finkelstein D, Quigley HA, et al:
Macular grid photocoagulation. An
experimental study on the primate retina.
Arch Ophthalmol 1988; 106:100.
63. Esrick E, Subramanian ML, Heier JS, et al:
Multiple laser treatments for macular
edema attributable to branch retinal vein
occlusion. Am J Ophthalmol 2005; 139:653.
64. Early Treatment Diabetic Retinopathy Study
Research Group: Early photocoagulation
for diabetic retinopathy. Ophthalmology
1991; 98:766.
65. Hayreh SS, Rubenstein L, Podhajsky P:
Argon laser scatter photocoagulation in
treatment of branch retinal vein occlusion.
A prospective clinical trial. Ophthalmologica
1993; 206:1.
66. Amirikia A, Scott IU, Murray TG, et al:
Outcomes of vitreoretinal surgery for
complications of branch retinal vein
occlusion. Ophthalmology 2001; 108:372.
67. Ikuno Y, Tano Y, Lewis JM, et al: Retinal
detachment after branch retinal vein
occlusion: Influence of the type of break on
the outcome of vitreous surgery.
Ophthalmology 1997; 104:27.
68. Ikuno Y, Ikeda T, Sato Y, et al: Tractional
retinal detachment after branch retinal vein
occlusion. Influence of disc neovascu-
larization on the outcome of vitreous
surgery. Ophthalmology 1998; 105:417.
69. Murakami K, Ho PC, Trempe CL, et al:
Tractional detachment of the macula
following branch retinal vein occlusion.
Ann Ophthalmol 1983; 15:760.
70. Smiddy WE, Isernhagen RD, Michels RG,
et al: Vitrectomy for nondiabetic vitreous
hemorrhage. Retinal and choroidal vascular
disorders. Retina 1988; 8:88.
71. Tachi N, Hashimoto Y, Ogino N: Vitrectomy
for macular edema combined with retinal
vein occlusion. Doc Ophthalmol 1999;
97:465.
72. Saika S, Tanaka T, Miyamoto T, et al:
1770 Surgical posterior vitreous detachment
combined with gas/air tamponade for
treating macular edema associated with
branch retinal vein occlusion: Retinal
tomography and visual outcome. Graefes
Arch Clin Exp Ophthalmol 2001; 239:729.
73. Thompson JT: What is the role of
vitrectomy for macular edema from branch
retinal vein occlusion? Am J Ophthalmol
2004; 138:1037.
74. Stefansson E, Novack RL, Hatchell DL:
Vitrectomy prevents retinal hypoxia in
branch retinal vein occlusion. Invest
Ophthalmol Vis Sci 1990; 31:284.
75. Osterloh MD, Charles S: Surgical decom-
pression of branch retinal vein occlusions.
Arch Ophthalmol 1988; 106:1469.
76. Opremcak EM, Bruce RA: Surgical
decompression of branch retinal vein
occlusion via arteriovenous crossing
sheathotomy: a prospective review of 15
cases. Retina 1999; 19:1.
77. Shah GK, Sharma S, Fineman MS, et al:
Arteriovenous adventitial sheathotomy for
the treatment of macular edema associated
with branch retinal vein occlusion. Am J
Ophthalmol 2000; 129:104.
78. Mester U, Dillinger P: Vitrectomy with
arteriovenous decompression and internal
limiting membrane dissection in branch
retinal vein occlusion. Retina 2002; 22:740.
79. Mason J 3rd, Feist R, White M Jr, et al:
Sheathotomy to decompress branch retinal
vein occlusion: A matched control study.
Ophthalmology 2004; 111:540.
80. Horio N, Horiguchi M: Effect of
arteriovenous sheathotomy on retinal blood
flow and macular edema in patients with
branch retinal vein occlusion. Am J
Ophthalmol 2005; 139:739.
81. Yamaji H, Shiraga F, Tsuchida Y, et al:
Evaluation of arteriovenous crossing
sheathotomy for branch retinal vein
occlusion by fluorescein videoangiography
and image analysis. Am J Ophthalmol
2004; 137:834.
82. Charbonnel J, Glacet-Bernard A,
Korobelnik JF, et al: Management of branch
retinal vein occlusion with vitrectomy and
arteriovenous adventitial sheathotomy, the
possible role of surgical posterior vitreous
detachment. Graefes Arch Clin Exp
Ophthalmol 2004; 242:223.
83. Kube T, Feltgen N, Pache M, et al:
Angiographic findings in arteriovenous
dissection (sheathotomy) for
decompression of branch retinal vein
occlusion. Graefes Arch Clin Exp
Ophthalmol 2005; 243:334.
84. Lu L, Li Y, Yi C, et al: Preliminary clinical
observation of arteriovenous sheathotomy
for treatment of branch retinal vein
occlusion. Yan Ke Xue Bao 2003; 19:33.
85. Fujimoto R, Ogino N, Kumagai K, et al:
[the efficacy of arteriovenous adventitial
sheathotomy for macular edema in branch
retinal vein occlusion]. Nippon Ganka
Gakkai Zasshi 2004; 108:144.
86. Cahill MT, Kaiser PK, Sears JE, et al: The
effect of arteriovenous sheathotomy on
cystoid macular oedema secondary to
branch retinal vein occlusion. Br J
Ophthalmol 2003; 87:1329.
87. Chalam KV, Shah GY, Shah VA: Vitrectomy
with or without arteriovenous adventitial
sheathotomy for macular edema associated
with branch retinal vein occlusion. Am J
Ophthalmol 139:1146; author reply 1146,
2005.
88. Fujii GY, de Juan E Jr, Humayun MS:
Improvements after sheathotomy for
branch retinal vein occlusion documented
by optical coherence tomography and
scanning laser ophthalmoscope.
Ophthalmic Surg Lasers Imaging
2003; 34:49.
89. Cahill MT, Fekrat S: Arteriovenous
sheathotomy for branch retinal vein
occlusion. Ophthalmol Clin North Am 2002;
15:417.
90. Mandelcorn MS, Nrusimhadevara RK:
Internal limiting membrane peeling for
decompression of macular edema in retinal
vein occlusion: a report of 14 cases. Retina
2004; 24:348.
91. Han DP, Bennett SR, Williams DF, et al:
Arteriovenous crossing dissection without
separation of the retina vessels for
treatment of branch retinal vein occlusion.
Retina 2003; 23:145.
92. Liu DT, Lai WW, Chan WM, et al:
Sheathotomy for vein occlusion.
Ophthalmology 112:1321; author reply
1321, 2005.
93. Le Rouic JF, Bejjani RA, Rumen F, et al:
Adventitial sheathotomy for decompression
of recent onset branch retinal vein
occlusion. Graefes Arch Clin Exp
Ophthalmol 2001; 239:747.
94. Kroll P, Meyer CH, Mester U, et al:
Sheathotomy to decompress brvo.
Ophthalmology 2005; 112:528.
95. Shah GK: Adventitial sheathotomy for
treatment of macular edema associated
with branch retinal vein occlusion. Curr
Opin Ophthalmol 2000; 11:171.
96. Scott IU: Vitreoretinal surgery for
complications of branch retinal vein
occlusion. Curr Opin Ophthalmol 2002;
13:161.
97. Jonas JB, Kreissig I, Sofker A, et al:
Intravitreal injection of triamcinolone for
diffuse diabetic macular edema. Arch
Ophthalmol 2003; 121:57.
98. Martidis A, Duker JS, Greenberg PB, et al:
Intravitreal triamcinolone for refractory
diabetic macular edema. Ophthalmology
2002; 109:920.
99. Young S, Larkin G, Branley M, et al: Safety
and efficacy of intravitreal triamcinolone for
cystoid macular oedema in uveitis. Clin
Experiment Ophthalmol 2001; 29:2.
100. Benhamou N, Massin P, Haouchine B, et al:
Intravitreal triamcinolone for refractory
pseudophakic macular edema. Am J
Ophthalmol 2003; 135:246.
101. Wilson CA, Berkowitz BA, Sato Y, et al:
Treatment with intravitreal steroid reduces
blood-retinal barrier breakdown due to
retinal photocoagulation. Arch Ophthalmol
1992; 110:1155.
102. Fischer S, Renz D, Schaper W, et al: In
vitro effects of dexamethasone on hypoxia-
induced hyperpermeability and expression
of vascular endothelial growth factor. Eur J
Pharmacol 2001; 411:231.
103. Lee H, Shah GK: Intravitreal triamcinolone
as primary treatment of cystoid macular
edema secondary to branch retinal vein
occlusion. Retina 2005; 25:551.
104. Hayashi K, Hayashi H: Intravitreal versus
retrobulbar injections of triamcinolone for
macular edema associated with branch
retinal vein occlusion. Am J Ophthalmol
2005; 139:972.
105. Yepremyan M, Wertz FD, Tivnan T, et al:
Early treatment of cystoid macular edema

secondary to branch retinal vein occlusion
with intravitreal triamcinolone acetonide.
Ophthalmic Surg Lasers Imaging 2005;
36:30.
106. Ozkiris A, Evereklioglu C, Erkilic K, et al:
The efficacy of intravitreal triamcinolone
acetonide on macular edema in branch
retinal vein occlusion. Eur J Ophthalmol
2005; 15:96.
107. Jonas JB, Akkoyun I, Kamppeter B, et al:
Branch retinal vein occlusion treated by
intravitreal triamcinolone acetonide. Eye
2005; 19:65.
108. Tewari HK, Sony P, Chawla R, et al:
Prospective evaluation of intravitreal
triamcinolone acetonide injection in
macular edema associated with retinal
vascular disorders. Eur J Ophthalmol 2005;
15:619.
109. Chen SD, Sundaram V, Lochhead J, et al:
Intravitreal triamcinolone for the treatment
of ischemic macular edema associated
with branch retinal vein occlusion. Am J
Ophthalmol 2006; 141:876.
110. Beer PM, Bakri SJ, Singh RJ, et al:
Intraocular concentration and
pharmacokinetics of triamcinolone
acetonide after a single intravitreal
injection. Ophthalmology 2003; 110:681.
111. Scott IU IM: It’s time for a clinical trial to
investigate intravitreal triamcinolone for
macular edema due to retinal vein
occlusion: The score study. Arch
Ophthalmol 2005; 123:581.
112. Ring CP, Pearson TC, Sanders MD, et al:
Viscosity and retinal vein thrombosis.
Br J Ophthalmol 1976; 60:397.
113. Remky A, Wolf S, Hamid M, et al: [effect of
hemodilution on retinal hemodynamics in
retinal branch vein occlusion].
Ophthalmologe 1994; 91:288.
114. Chen HC, Wiek J, Gupta A, et al: Effect of
isovolaemic haemodilution on visual
outcome in branch retinal vein occlusion.
Br J Ophthalmol 1998; 82:162.
115. Janvrin SB, Davies G, Greenhalgh RM:
Postoperative deep vein thrombosis
caused by intravenous fluids during
surgery. Br J Surg 1980; 67:690.
116. Noma H, Minamoto A, Funatsu H, et al:
Intravitreal levels of vascular endothelial
growth factor and interleukin-6 are
correlated with macular edema in branch
retinal vein occlusion. Graefes Arch Clin
Exp Ophthalmol 2006; 244:309.
117. Gutman FA: Evaluation of a patient with
central retinal vein occlusion.
Ophthalmology 1983; 90:481.
118. Liebreich R: Apoplexia retinae. Albrecht
von Graefes Arch Ophthalmol 1855; 1:346.
119. Green WR: Retina. In: Spencer WH, ed:
Ophthalmic pathology, an atlas and
textbook. WB Saunders; 1985:589.
120. Eye Disease Case-Control Study Group:
Risk factors for central retinal vein
occlusion. Arch Ophthalmol 1996; 114:545.
121. Quinlan PM, Elman MJ, Bhatt AK, et al: The
natural course of central retinal vein
occlusion. Am J Ophthalmol 1990; 110:118.
122. Zegarra H, Gutman FA, Conforto J: The
natural course of central retinal vein
occlusion. Ophthalmology 1979; 86:1931.
123. Sinclair SH, Gragoudas ES: Prognosis for
rubeosis iridis following central retinal vein
occlusion. Br J Ophthalmol 1979; 63:735.
124. Zegarra H, Gutman FA, Zakov N, et al:
Partial occlusion of the central retinal vein.
Am J Ophthalmol 1983; 96:330.
125. McGrath MA, Wechsler F, Hunyor AB, et al:
Systemic factors contributory to retinal vein
occlusion. Arch Intern Med 1978; 138:216.
126. Rath EZ, Frank RN, Shin DH, et al: Risk
factors for retinal vein occlusions. A case-
control study. Ophthalmology 1992; 99:509.
127. Priluck IA, Robertson DM, Hollenhorst RW:
Long-term follow-up of occlusion of the
central retinal vein in young adults. Am J
Ophthalmol 1980; 90:190.
128. Tsaloumas MD, Kirwan J, Vinall H, et al:
Nine year follow-up study of morbidity and
mortality in retinal vein occlusion. Eye
2000; 14:821.
129. Elman MJ, Bhatt AK, Quinlan PM, et al: The
risk for systemic vascular diseases and
mortality in patients with central retinal vein
occlusion. Ophthalmology 1990; 97:1543.
130. Dodson PM, Galton DJ, Hamilton AM, et al:
Retinal vein occlusion and the prevalence
of lipoprotein abnormalities. Br J
Ophthalmol 1982; 66:161.
131. Green WR, Chan CC, Hutchins GM, et al:
Central retinal vein occlusion: a prospective
histopathologic study of 29 eyes in 28
cases. Trans Am Ophthalmol Soc 1981;
79:371.
132. Williamson TH, Rumley A, Lowe GD: Blood
viscosity, coagulation, and activated
protein c resistance in central retinal vein
occlusion: A population controlled study.
Br J Ophthalmol 1996; 80:203.
133. Hayreh SS: Pathogenesis of occlusion of
the central retinal vessels. Am J
Ophthalmol 1971; 72:998.
134. Hayreh SS: Prevalent misconceptions
about acute retinal vascular occlusive
disorders. Prog Retin Eye Res 2005;
24:493.
135. Gottlieb JL, Blice JP, Mestichelli B, et al:
Activated protein c resistance, factor v
leiden, and central retinal vein occlusion in
young adults. Arch Ophthalmol 1998;
116:577.
136. Cahill MT, Stinnett SS, Fekrat S: Meta-
analysis of plasma homocysteine, serum
folate, serum vitamin b(12), and
thermolabile mthfr genotype as risk factors
for retinal vascular occlusive disease. Am J
Ophthalmol 2003; 136:1136.
137. Janssen MC, den Heijer M, Cruysberg JR,
et al: Retinal vein occlusion: a form of
venous thrombosis or a complication of
atherosclerosis? A meta-analysis of
thrombophilic factors. Thromb Haemost
2005; 93:1021.
138. Chua B, Kifley A, Wong TY, et al:
Homocysteine and retinal vein occlusion: a
population-based study. Am J Ophthalmol
2005; 139:181.
139. Yildirim C, Yaylali V, Tatlipinar S, et al:
Hyperhomocysteinemia: a risk factor for
retinal vein occlusion. Ophthalmologica
2004; 218:102.
140. Cruciani F, Moramarco A, Curto T, et al:
Mthfr c677t mutation, factor ii g20210a
mutation and factor v leiden as risks factor
for youth retinal vein occlusion. Clin Ter
2003; 154:299.
141. Hvarfner C, Hillarp A, Larsson J: Influence
of factor v leiden on the development of
neovascularisation secondary to central
retinal vein occlusion. Br J Ophthalmol
2003; 87:305.
142. Abu El-Asrar AM, Abdel Gader AG,
Al-Amro SA, et al: Hyperhomocysteinemia
and retinal vascular occlusive disease. Eur
J Ophthalmol 2002; 12:495.
Retinal Venous Occlusive Disease
143. Weger M, Stanger O, Deutschmann H,
et al: Hyperhomocyst(e)inemia and mthfr
c677t genotypes in patients with central
retinal vein occlusion. Graefes Arch Clin
Exp Ophthalmol 2002; 240:286.
144. Brown BA, Marx JL, Ward TP, et al:
Homocysteine: A risk factor for retinal
venous occlusive disease. Ophthalmology
2002; 109:287.
145. Aras S, Yilmaz G, Alpas I, et al: Retinal vein
occlusion and factor v leiden and
prothrombin 20210 g:A mutations. Eur J
Ophthalmol 2001; 11:351.
146. Marcucci R, Bertini L, Giusti B, et al:
Thrombophilic risk factors in patients with
central retinal vein occlusion. Thromb
Haemost 2001; 86:772.
147. Johnson TM, El-Defrawy S, Hodge WG,
et al: Prevalence of factor v leiden and
activated protein c resistance in central
CHAPTER 132
retinal vein occlusion. Retina 2001; 21:161.
148. Weger M, Stanger O, Haas A:
Hyperhomocysteinemia: a risk factor for
central retinal vein occlusion. Am J
Ophthalmol 2001; 131:290.
149. Vine AK, Samama MM: The role of
abnormalities in the anticoagulant and
fibrinolytic systems in retinal vascular
occlusions. Surv Ophthalmol 1993; 37:283.
150. Svensson PJ, Dahlback B: Resistance to
activated protein c as a basis for venous
thrombosis. N Engl J Med 1994; 330:517.
151. Larsson J, Olafsdottir E, Bauer B: Activated
protein c resistance in young adults with
central retinal vein occlusion. Br J
Ophthalmol 1996; 80:200.
152. Arsene S, Delahousse B, Regina S, et al:
Increased prevalence of factor v leiden in
patients with retinal vein occlusion and
under 60 years of age. Thromb Haemost
2005; 94:101.
153. Levine SR, Crofts JW, Lesser GR, et al:
Visual symptoms associated with the
presence of a lupus anticoagulant.
Ophthalmology 1988; 95:686.
154. Pulido JS, Ward LM, Fishman GA, et al:
Antiphospholipid antibodies associated
with retinal vascular disease. Retina 1987;
7:215.
155. Kleiner RC, Najarian LV, Schatten S, et al:
Vaso-occlusive retinopathy associated with
antiphospholipid antibodies (lupus
anticoagulant retinopathy). Ophthalmology
1989; 96:896.
156. Asherson RA, Merry P, Acheson JF, et al:
Antiphospholipid antibodies: a risk factor
for occlusive ocular vascular disease in
systemic lupus erythematosus and the
‘primary’ antiphospholipid syndrome. Ann
Rheum Dis 1989; 48:358.
157. Snyers B, Lambert M, Hardy JP: Retinal
and choroidal vaso-occlusive disease in
systemic lupus erythematosus associated
with antiphospholipid antibodies. Retina
1990; 10:255.
158. Glacet-Bernard A, Bayani N, Chretien P,
et al: Antiphospholipid antibodies in retinal
vascular occlusions. A prospective study of
75 patients. Arch Ophthalmol 1994;
112:790.
159. Spalter HF: Abnormal serum proteins and
retinal vein thrombosis. Arch Ophthalmol
1959; 62:868.
160. Luxenberg MN, Mausolf FA: Retinal
circulation in the hyperviscosity syndrome.
Am J Ophthalmol 1970; 70:588.
161. Francis PJ, Stanford MR, Graham EM:
Dehydration is a risk factor for central 1771
 RETINA AND VITREOUS
retinal vein occlusion in young patients.
Acta Ophthalmol Scand 2003; 81:415.
162. Trope GE, Lowe GD, McArdle BM, et al:
Abnormal blood viscosity and haemostasis
in long-standing retinal vein occlusion.
Br J Ophthalmol 1983; 67:137.
163. Arend O, Remky A, Jung F, et al: Role of
rheologic factors in patients with acute
central retinal vein occlusion.
Ophthalmology 1996; 103:80.
164. Glacet-Bernard A, Chabanel A, Lelong F,
et al: Elevated erythrocyte aggregation in
patients with central retinal vein occlusion
and without conventional risk factors.
Ophthalmology 1994; 101:1483.
165. Dryden RM: Central retinal vein occlusions
and chronic simple glaucoma. Arch
Ophthalmol 1965; 73:659.
166. Bertelsen T: The relationship between
thrombosis in the retinal veins and primary
glaucoma. Acta Ophthalmol (Copenh)
SECTION 10
1961; 39:603.
167. Fuller JJ, Mason JO 3rd, White MF Jr, et al:
Retinochoroidal collateral veins protect
against anterior segment neovascularization
after central retinal vein occlusion. Arch
Ophthalmol 2003; 121:332.
168. Lahey JM, Kearney JJ, Tunc M:
Hypercoagulable states and central retinal
vein occlusion. Curr Opin Pulm Med 2003;
9:385.
169. Lahey JM, Tunc M, Kearney J, et al:
Laboratory evaluation of hypercoagulable
states in patients with central retinal vein
occlusion who are less than 56 years of
age. Ophthalmology 2002; 109:126.
170. Coats G: Thrombosis of the central vein of
the retina. R Long Ophthalmic Hosp Rep
1904; 16:62.
171. Laatikainen L, Kohner EM, Khoury D, et al:
Panretinal photocoagulation in central
retinal vein occlusion: a randomised
controlled clinical study. Br J Ophthalmol
1977; 61:741.
172. Minturn J, Brown GC: Progression of
nonischemic central retinal vein obstruction
to the ischemic variant. Ophthalmology
1986; 93:1158.
173. Servais GE, Thompson HS, Hayreh SS:
Relative afferent pupillary defect in central
retinal vein occlusion. Ophthalmology 1986;
93:301.
174. Hayreh SS, Zimmerman MB, Beri M, et al:
Intraocular pressure abnormalities associated
with central and hemicentral retinal vein
occlusion. Ophthalmology 2004; 111:133.
175. Hayreh SS: Classification of central retinal
vein occlusion. Ophthalmology 1983;
90:458.
176. Magargal LE, Brown GC, Augsburger JJ,
et al: Neovascular glaucoma following
central retinal vein obstruction.
Ophthalmology 1981; 88:1095.
177. May DR, Klein ML, Peyman GA, et al:
Xenon arc panretinal photocoagulation for
central retinal vein occlusion: A randomised
prospective study. Br J Ophthalmol 1979;
63:725.
178. Matsui Y, Katsumi O, Mehta MC, et al:
Correlation of electroretinographic and
fluorescein angiographic findings in
unilateral central retinal vein obstruction.
Graefes Arch Clin Exp Ophthalmol 1994;
232:449.
179. Morrell AJ, Thompson DA, Gibson JM,
et al: Electroretinography as a prognostic
indicator or neovascularisation in crvo. Eye
1772 1991; 5(Pt 3):362.
180. Lerche RC, Schaudig U, Scholz F, et al:
Structural changes of the retina in retinal
vein occlusion-imaging and quantification
with optical coherence tomography.
Ophthalmic Surg Lasers 2001; 32:272.
181. Ozdemir H, Karacorlu M, Karacorlu S:
Serous macular detachment in central
retinal vein occlusion. Retina 2005; 25:561.
182. Cugati S, Cikamatana L, Wang JJ, et al:
Five-year incidence and progression of
vascular retinopathy in persons without
diabetes: The blue mountains eye study.
Eye 2005.
183. Magargal LE, Donoso LA, Sanborn GE:
Retinal ischemia and risk of
neovascularization following central retinal
vein obstruction. Ophthalmology 1982;
89:1241.
184. Ferris FL 3rd SR: Standardized illumination
for visual acuity testing in clinical research.
Am J Ophthalmol 1982; 94:97.
185. Weinberg D, Jampol LM, Schatz H, et al:
Exudative retinal detachment following
central and hemicentral retinal vein
occlusions. Arch Ophthalmol 1990; 108:271.
186. Brown GC: Central retinal vein obstruction
with lipid exudate. Arch Ophthalmol 1989;
107:1001.
187. Duker JS, Brown GC: The efficacy of
panretinal photocoagulation for
neovascularization of the iris after central
retinal artery obstruction. Ophthalmology
1989; 96:92.
188. Boyd SR, Zachary I, Chakravarthy U, et al:
Correlation of increased vascular endothelial
growth factor with neovascularization and
permeability in ischemic central vein
occlusion. Arch Ophthalmol 2002;
120:1644.
189. Pe’er J, Folberg R, Itin A, et al: Vascular
endothelial growth factor upregulation in
human central retinal vein occlusion.
Ophthalmology 1998; 105:412.
190. Chen KH, Wu CC, Roy S, et al: Increased
interleukin-6 in aqueous humor of
neovascular glaucoma. Invest Ophthalmol
Vis Sci 1999; 40:2627.
191. Blinder KJ, Khan JA, Giangiacomo J, et al:
Optociliary veins and visual prognosis after
central retinal vein occlusion. Ann
Ophthalmol 1989; 21:192.
192. Im CY, Lee SY, Kwon OW: Collateral
vessels in branch retinal vein occlusion.
Korean J Ophthalmol 2002; 16:82.
193. Mruthyunjaya P, Wirostko WJ,
Chandrashekhar R, et al: Central retinal
vein occlusion in patients treated with long-
term warfarin sodium (coumadin) for
anticoagulation. Retina 2006; 26:285.
194. Hansen LL, Wiek J, Schade M, et al: Effect
and compatibility of isovolaemic
haemodilution in the treatment of
ischaemic and non-ischaemic central
retinal vein occlusion. Ophthalmologica
1989; 199:90.
195. Wolf S, Arend O, Bertram B, et al:
Hemodilution therapy in central retinal vein
occlusion. One-year results of a
prospective randomized study. Graefes
Arch Clin Exp Ophthalmol 1994; 232:33.
196. Hayreh SS, Klugman MR, Podhajsky P, et al:
Argon laser panretinal photocoagulation in
ischemic central retinal vein occlusion. A
10-year prospective study. Graefes Arch
Clin Exp Ophthalmol 1990; 228:281.
197. McAllister IL, Constable IJ: Laser-induced
chorioretinal venous anastomosis for
treatment of nonischemic central retinal
vein occlusion. Arch Ophthalmol 1995;
113:456.
198. Fekrat S, Goldberg MF, Finkelstein D:
Laser-induced chorioretinal venous
anastomosis for nonischemic central or
branch retinal vein occlusion. Arch
Ophthalmol 1998; 116:43.
199. Leonard BC, Coupland SG, Kertes PJ,
et al: Long-term follow-up of a modified
technique for laser-induced chorioretinal
venous anastomosis in nonischemic central
retinal vein occlusion. Ophthalmology 2003;
110:948.
200. Browning DJ: Fundus photographic,
fluorescein angiographic, and indocyanine
green angiographic signs in successful
laser chorioretinal venous anastomosis for
central retinal vein occlusion.
Ophthalmology 1999; 106:2261.
201. Browning DJ, Antoszyk AN: Laser
chorioretinal venous anastomosis for
nonischemic central retinal vein occlusion.
Ophthalmology 1998; 105:670.
202. McAllister IL, Douglas JP, Constable IJ,
et al: Laser-induced chorioretinal venous
anastomosis for nonischemic central retinal
vein occlusion: Evaluation of the
complications and their risk factors. Am J
Ophthalmol 1998; 126:219.
203. Luttrull JK: Epiretinal membrane and
traction retinal detachment complicating
laser-induced chorioretinal venous
anastomosis. Am J Ophthalmol 1997;
123:698.
204. Eccarius SG, Moran MJ, Slingsby JG:
Choroidal neovascular membrane after
laser-induced chorioretinal anastomosis.
Am J Ophthalmol 1996; 122:590.
205. Browning DJ, Rotberg MH: Vitreous
hemorrhage complicating laser-induced
chorioretinal anastomosis for central retinal
vein occlusion. Am J Ophthalmol 1996;
122:588.
206. Bavbek T, Yenice O, Toygar O: Problems
with attempted chorioretinal venous
anastomosis by laser for nonischemic crvo
and brvo. Ophthalmologica 2005; 219:267.
207. Fekrat S, de Juan E Jr: Chorioretinal
venous anastomosis for central retinal vein
occlusion: Transvitreal venipuncture.
Ophthalmic Surg Lasers 1999; 30:52.
208. Peyman GA, Kishore K, Conway MD:
Surgical chorioretinal venous anastomosis
for ischemic central retinal vein occlusion.
Ophthalmic Surg Lasers 1999; 30:605.
209. Kado M, Jalkh AE, Yoshida A, et al:
Vitreous changes and macular edema in
central retinal vein occlusion. Ophthalmic
Surg 1990; 21:544.
210. Hikichi T, Konno S, Trempe CL: Role of the
vitreous in central retinal vein occlusion.
Retina 1995; 15:29.
211. Sekiryu T, Yamauchi T, Enaida H, et al:
Retina tomography after vitrectomy for
macular edema of central retinal vein
occlusion. Ophthalmic Surg Lasers 2000;
31:198.
212. Opremcak EM, Rehmar AJ, Ridenour CD,
et al: Radial optic neurotomy for central
retinal vein occlusion: 117 consecutive
cases. Retina 2006; 26:297.
213. Lit ES, Tsilimbaris M, Gotzaridis E, et al:
Lamina puncture: Pars plana optic disc
surgery for central retinal vein occlusion.
Arch Ophthalmol 2002; 120:495.
214. Vasco-Posada J: Modification of the
circulation in the posterior pole of the eye.
Ann Ophthalmol 1972; 4:48.

215. Arciniegas A: Treatment of the occlusion of
the central retinal vein by section of the
posterior ring. Ann Ophthalmol 1984;
16:1081.
216. Nagpal M, Nagpal K, Bhatt C, et al: Role of
early radial optic neurotomy in central
retinal vein occlusion. Indian J Ophthalmol
2005; 53:115.
217. Martinez-Jardon CS, Meza-de Regil A,
Dalma-Weiszhausz J, et al: Radial optic
neurotomy for ischaemic central vein
occlusion. Br J Ophthalmol 2005; 89:558.
218. Garciia-Arumii J, Boixadera A, Martinez-
Castillo V, et al: Chorioretinal anastomosis
after radial optic neurotomy for central
retinal vein occlusion. Arch Ophthalmol
2003; 121:1385.
219. Weizer JS, Stinnett SS, Fekrat S: Radial
optic neurotomy as treatment for central
retinal vein occlusion. Am J Ophthalmol
2003; 136:814.
220. Patelli F, Radice P, Zumbo G, et al: Optical
coherence tomography evaluation of
macular edema after radial optic neurotomy
in patients affected by central retinal vein
occlusion. Semin Ophthalmol 2004; 19:21.
221. Kim TW, Lee SJ, Kim SD. Comparative
evaluation of radial optic neurotomy and
panretinal photocoagulation in the
management of central retinal vein
occlusion. Korean J Ophthalmol. 2005;
19:269.
222. Martinez-Jardon CS, Meza-de Regil A,
Dalma-Weiszhausz J, et al. Radial optic
neurotomy for ischaemic central vein
occlusion. Br J Ophthalmol. 2005; 89:558.
223. Hayreh SS: Radial optic neurotomy for
central retinal vein occlusion. Retina 2002;
22:374.
224. Williamson TH, Poon W, Whitefield L, et al:
A pilot study of pars plana vitrectomy,
intraocular gas, and radial neurotomy in
ischaemic central retinal vein occlusion.
Br J Ophthalmol 2003; 87:1126.
225. Schneider U, Inhoffen W, Grisanti S, et al:
Characteristics of visual field defects by
scanning laser ophthalmoscope
microperimetry after radial optic neurotomy
for central retinal vein occlusion. Retina
2005; 25:704.
226. Takaya K, Suzuki Y, Nakazawa M: Massive
hemorrhagic retinal detachment during
radial optic neurotomy. Graefes Arch Clin
Exp Ophthalmol 2006; 244:265.
227. Samuel MA, Desai UR, Gandolfo CB:
Peripapillary retinal detachment after radial
optic neurotomy for central retinal vein
occlusion. Retina 2003; 23:580.
228. Bakri SJ, Beer PM: Choroidal
neovascularization after radial optic
neurotomy for central retinal vein occlusion.
Retina 2004; 24:610.
229. Hattenbach LO, Steinkamp G, Scharrer I,
et al: Fibrinolytic therapy with low-dose
recombinant tissue plasminogen activator
in retinal vein occlusion. Ophthalmologica
1998; 212:394.
230. Tsujikawa A, Hangai M, Kikuchi M, et al:
Visual field defect after radial optic
neurotomy for central retinal vein occlusion.
Jpn J Ophthalmol 2006; 50:158.
231. Hattenbach LO, Wellermann G, Steinkamp
GW, et al: Visual outcome after treatment
with low-dose recombinant tissue
plasminogen activator or hemodilution in
ischemic central retinal vein occlusion.
Ophthalmologica 1999; 213:360.
232. Lahey JM, Fong DS, Kearney J: Intravitreal
tissue plasminogen activator for acute
central retinal vein occlusion. Ophthalmic
Surg Lasers 1999; 30:427.
233. Glacet-Bernard A, Kuhn D, Vine AK, et al:
Treatment of recent onset central retinal
vein occlusion with intravitreal tissue
plasminogen activator: A pilot study. Br J
Ophthalmol 2000; 84:609.
234. Elman MJ, Raden RZ, Carrigan A:
Intravitreal injection of tissue plasminogen
activator for central retinal vein occlusion.
Trans Am Ophthalmol Soc 2001; 99:219.
235. Ghazi NG, Noureddine B, Haddad RS, et
al: Intravitreal tissue plasminogen activator
in the management of central retinal vein
occlusion. Retina 2003; 23:780.
236. Lam HD, Blumenkranz MS: Treatment of
central retinal vein occlusion by vitrectomy
with lysis of vitreopapillary and epipapillary
adhesions, subretinal peripapillary tissue
plasminogen activator injection, and
photocoagulation. Am J Ophthalmol 2002;
134:609.
237. Paques M, Vallee JN, Herbreteau D, et al:
Superselective ophthalmic artery fibrinolytic
therapy for the treatment of central retinal
vein occlusion. Br J Ophthalmol 2000;
84:1387.
238. Weiss JN: Treatment of central retinal vein
occlusion by injection of tissue
plasminogen activator into a retinal vein.
Am J Ophthalmol 1998; 126:142.
239. Weiss JN, Bynoe LA: Injection of tissue
plasminogen activator into a branch retinal
vein in eyes with central retinal vein
occlusion. Ophthalmology 2001; 108:2249.
240. Bynoe LA, Weiss JN: Retinal endovascular
surgery and intravitreal triamcinolone
acetonide for central vein occlusion in
young adults. Am J Ophthalmol 2003;
135:382.
241. Bynoe LA, Hutchins RK, Lazarus HS, et al:
Retinal endovascular surgery for central
retinal vein occlusion: initial experience of
four surgeons. Retina 2005; 25:625.
242. Shaikh S, Blumenkranz MS: Transient
improvement in visual acuity and macular
edema in central retinal vein occlusion
accompanied by inflammatory features
after pulse steroid and anti-inflammatory
therapy. Retina 2001; 21:176.
243. Greenberg PB, Martidis A, Rogers AH, et al:
Intravitreal triamcinolone acetonide for
macular oedema due to central retinal vein
occlusion. Br J Ophthalmol 2002; 86:247.
244. Ip MS, Kumar KS: Intravitreous
triamcinolone acetonide as treatment for
macular edema from central retinal vein
occlusion. Arch Ophthalmol 2002;
120:1217.
Retinal Venous Occlusive Disease
245. Jonas JB, Kreissig I, Degenring RF:
Intravitreal triamcinolone acetonide as
treatment of macular edema in central
retinal vein occlusion. Graefes Arch Clin
Exp Ophthalmol 2002; 240:782.
246. Ip M, Kahana A, Altaweel M: Treatment of
central retinal vein occlusion with
triamcinolone acetonide: An optical
coherence tomography study. Semin
Ophthalmol 2003; 18:67.
247. Degenring RF, Kamppeter B, Kreissig I,
et al: Morphological and functional
changes after intravitreal triamcinolone
acetonide for retinal vein occlusion. Acta
Ophthalmol Scand 2003; 81:399.
248. Ip MS, Gottlieb JL, Kahana A, et al:
Intravitreal triamcinolone for the treatment
of macular edema associated with central
retinal vein occlusion. Arch Ophthalmol
2004; 122:1131.
CHAPTER 132
249. Bashshur ZF, Ma’luf RN, Allam S, et al:
Intravitreal triamcinolone for the
management of macular edema due to
nonischemic central retinal vein occlusion.
Arch Ophthalmol 2004; 122:1137.
250. Krepler K, Ergun E, Sacu S, et al:
Intravitreal triamcinolone acetonide in
patients with macular oedema due to
central retinal vein occlusion. Acta
Ophthalmol Scand 2005; 83:71.
251. Williamson TH ODA: Intravitreal triamcinolone
acetonide for cystoid macular edema in
nonischemic central retinal vein occlusion.
Am J Ophthalmol. 2005; 139:860.
252. Rosenfeld PJ, Fung AE, Puliafito CA:
Optical coherence tomography findings
after an intravitreal injection of bevacizumab
(avastin) for macular edema from central
retinal vein occlusion. Ophthalmic Surg
Lasers Imaging 2005; 36:336.
253. Iturralde D, Spaide RF, Meyerle CB, et al:
Intravitreal bevacizumab (avastin) treatment
of macular edema in central retinal vein
occlusion: A short-term study. Retina 2006;
26:279.
254. Kahook MY, Schuman JS, Noecker RJ:
Intravitreal bevacizumab in a patient with
neovascular glaucoma. Ophthalmic Surg
Lasers Imaging 2006; 37:144.
255. Chopdar A: Dual trunk central retinal vein
incidence in clinical practice. Arch
Ophthalmol 1984; 102:85.
256. Chopdar A: Hemi-central retinal vein
occlusion. Pathogenesis, clinical features,
natural history and incidence of dual trunk
central retinal vein. Trans Ophthalmol Soc
UK 1982; 102 (Pt 2):241.
257. Hayreh SS, Hayreh MS: Hemi-central
retinal vein occulsion. Pathogenesis,
clinical features, and natural history. Arch
Ophthalmol 1980; 98:1600.
258. Appiah AP, Trempe CL: Differences in
contributory factors among hemicentral,
central, and branch retinal vein occlusions.
Ophthalmology 1989; 96:364.
259. Zhang H, Xia Y: [analysis of visual
prognosis and correlative factors in retinal
vein occlusion]. Zhonghua Yan Ke Za Zhi
2002; 38:98.
1773
 CHAPTER
Diagnosis, Management, and Treatment of
133 Nonproliferative Diabetic Retinopathy
Lloyd P. Aiello, Jerry Cavallerano, Manvi Prakash, and Lloyd M. Aiello
SIGNIFICANCE OF APPROACHING
HIGH-RISK PROLIFERATIVE DIABETIC
RETINOPATHY AND CLINICALLY
SIGNIFICANT DIABETIC MACULAR EDEMA
Studies first demonstrated evidence of the benefit of scatter
(panretinal) laser photocoagulation (PRP) surgery to treat
diabetic retinopathy (DR) in 1967.1 (see Table 133.1 for a list of
common abbreviations used in this chapter). Since these
promising beginnings, dramatic strides in treating proliferative
diabetic retinopathy (PDR) and diabetic macular edema (DME)
have been made through the effective use of PRP and other
surgical techniques. These benefits have been strongly sup-
ported by the findings of three major nationwide randomized
controlled clinical trials: the Diabetic Retinopathy Study
(DRS),2–15 the Early Treatment Diabetic Retinopathy Study
(ETDRS),16–34 and the Diabetic Retinopathy Vitrectomy
Study (DRVS).35–39 With appropriate diagnosis, timely
intervention and careful follow-up, the risk of severe visual
loss from PDR can be virtually eliminated.
TABLE 133.1. Abbreviations and Definitions
PDR Proliferative diabetic retinopathy
NPDR Nonproliferative diabetic retinopathy
H/Ma Hemorrhages or microaneurysms, or both
HE Hard exudates
SE (CWS) Soft exudates (cotton-wool spots)
VB Venous beading
IRMA Intraretinal microvascular abnormality
NVD New vessels on or within 1 disk diameter of disc
margin
NVE New vessels elsewhere in the retina outside of disc
and 1 disc diameter from disk margin
FPD Fibrous proliferations on or within 1 disc diameter of
disc margin
FPE Fibrous proliferations elsewhere, not FPD
SVL Severe visual loss: Visual acuity ≤5/200 at two
consecutive completed 4-mo follow-up visits
MVL Moderate visual loss: A doubling of the visual angle
(e.g., 20/40 to 20/80 at two consecutive completed
4-mo follow-up visits)
CSME Clinically significant macular edema
Nevertheless, DR remains a leading cause of new-onset
blindness in the United States for citizens between the ages of
20 and 74 years. Today this blindness usually results from non-
resolving vitreous hemorrhage, traction retinal detachment, or
DME. However, the 5-year risk of severe visual loss (SVL –
visual acuity of 5/200 or worse on two consecutive visits 4
months apart) can be reduced to less than 5% if a person with
DR approaching or just reaching high-risk proliferative retino-
pathy (defined below) receives timely PRP. Furthermore, people
with clinically significant diabetic macular edema (CSME) can
have the risk of moderate visual loss (MVL - doubling of the
visual angle i.e., 20/20 to 20/40) reduced to ~12% or less if they
undergo appropriate focal laser surgery. Along with the
mainstays of current therapy which include laser surgery and
intensive glycemic, blood pressure and lipid control, newer and
evolving strategies for eye care include oral protein kinase C
inhibitors and intravitreal injections of corticosteroids, and
antiangiogenic agents. These novel therapies hold the promise
of providing additional efficacious treatment modalities, with
fewer side effects than present-day interventions.
Since diabetic retinopathy is often asymptomatic in its most
treatable stages, its early detection through regularly scheduled
evaluations of DR and DME severity is critical. This chapter
reviews the prognostic implications of the lesions of diabetic
retinopathy and the risks of progression, with particular
emphasis on identifying patients at risk of visual loss and in
need of laser surgery. The laser treatment techniques are only
generally described in this chapter but are discussed in the
chapter on Proliferative DR and are carefully detailed in ETDRS
Report no 3 & 4.18,19
EPIDEMIOLOGY OF DIABETIC
RETINOPATHY
The Center for Disease Control and Prevention estimates that
20.8 million people or 7.0% of the total U.S. population have
diabetes, of which 6.2 million people are undiagnosed.40,41 The
vast majority (>90%) of diabetic patients have type 2 diabetes,
which is usually diagnosed after 40 years of age, although the
prevalence of type 2 diabetes is increasing in children and
adolescent populations.42 People with type 1 diabetes have a
lack of insulin production, generally requiring insulin therapy,
while people with type 2 diabetes initially demonstrate insulin
resistance, although they may also eventually require insulin
treatment as the disease progresses or to maximize diabetes
control. Although, the likelihood of developing some level of
diabetic retinopathy during a lifetime is somewhat higher for
persons with type 1 diabetes, people with type 2 diabetes
account for the majority of clinical cases of diabetic eye disease
because of their overall larger numbers. 1775
 RETINA AND VITREOUS

TABLE 133.2. Medical Complications

Condition Comment

Risk Indicators of Diabetic Retinopathy

Joint contractures Association of retinopathy and contractures has been established. Eye examination is indicated.
Care of joint contractures is important.
Neuropathy Peripheral neuropathy may result in difficulty handling contact lenses. Neuropathy in lower extremities
may alter mobility in such a way that restoration and maintenance of as much vision as possible is
important. Cardiovascular autonomic neuropathy is an independent risk factor for proliferative
diabetic retinopathy.
Conditions That May Affect the Course of Diabetic Retinopathy
Hypertension Appropriate medical treatment is indicated for prevention of cardiovascular disease, stroke, and death.
Hypertension itself may result in hypertensive retinopathy superimposed on diabetic retinopathy.
Elevated triglycerides and lipids Appropriate management to normalize is important. Proper diet and reduced levels may result in less
retinal vessel leakage.
Proteinuria; elevated creatinine Aggressive management of renal disease is indicated to avoid renal retinopathy, which may increase
SECTION 10

risk of progression of diabetic retinopathy.

Cardiovascular disease
Clinical trials
Increased risk of cardiac disease, particularly coronary vascular disease, is often associated with an
increase in the attenuation and arteriosclerotic closure of the arterial system of the retina.
A decreased risk of hemorrhage into the vitreous may result, but there also may be a decrease in
retinal function with associated decrease in vision. Management of cardiovascular disease may help
relieve some of the ischemic process in the retina. Aggressive cardiovascular management is
important.
There are no clinical trials that have specifically shown that control of systemic conditions that may
affect the eyes (the four previous entries) prevents the progression of diabetic retinopathy. However,
clinical experience suggests an association with the systemic benefits of appropriate treatment of
these problems.

DR is a highly specific vascular complication common to
both type 1 and type 2 diabetes mellitus. Duration of diabetes
is a significant risk factor for the development of retinopathy.
After 20 years of diabetes, nearly all patients with type 1
diabetes, and more than 60% of patients with type 2 diabetes,
have some degree of retinopathy.43,44 A pooled data analysis
of eight population-based surveys estimates that among ~10.2
million US adults known to have diabetes who are age 40 years
or older, the prevalence rates for DR and sight-threatening
retinopathy are 40.3% and 8.2%, respectively.45 Overall, DR
affects ~4.1 million US adults age ≥ 40 years, and one out of
every 12 persons in this age group has advanced, vision-
threatening retinopathy.46
At the present time, there are no known cures for DR or
DME, and no known means to completely prevent these con-
ditions from occurring. Laser photocoagulation surgery reduces
the risk of moderate vision loss from DME and severe vision
loss from PDR, but in general does not restore vision once loss
has occurred. Laser treatment is generally most effective when
initiated at the time a person approaches or just reaches
‘high-risk PDR’ and before the visual acuity is lost from DME.24
The 5-year risk of SVL from untreated high-risk PDR may be as
high as 60%. DME will develop in up to 10% of all diabetic
patients. In 4% of cases, DME affects the central fovea, and, up
to 30% of patients with CSME will develop MVL.47 Since PDR
and CSME may cause no ocular or visual symptoms when the
retinal lesions are most amenable to treatment, the overriding
concern is to identify eyes at risk of visual loss and ensure that
patients receive timely evaluation and initiation of laser surgery
and other interventions when indicated. Even minor clinical
errors in diagnosing the severity of retinopathy (Table 133.9)
can result in delay in appropriate care plans and significantly
increase the person’s risk of visual loss.48
In addition, identification and optimum control of coexisting
health and medical problems are critically important as they
1776 present a significant risk for the development and progression
of DR. (Table 133.2). These factors include pregnancy49–51 and
the metabolic syndromes like chronic hyperglycemia,52–55
hypertension,56 renal disease,54 abdominal obesity, hypercholes-
terolemia, and dyslipidemia.34,57,58 Cardiovascular and
peripheral autonomic neuropathies are associated with the
presence of PDR.59 Patients with these conditions require
careful medical evaluation and treatment, diligent follow-up for
progression of diabetic retinopathy, and consideration of early
laser photocoagulation surgery.
Research studies are investigating how lifestyle changes can
delay or even prevent the onset of type 2 diabetes in individuals
at high-risk such as >20 million Americans with impaired
glucose tolerance. The Diabetes Prevention Program, a study
looking at preventing type 2 diabetes in people at high risk,
found that the development of diabetes was reduced 58% over
3 years by lifestyle interventions including diet and physical
activity.60 The study also found that in some populations the
drug metformin reduced the risk of developing diabetes by 31%
over 3 years. The group with greatest response consisted of
younger (20–40 years old) people 50–80 pounds overweight.
Another medication, acarbose, was found to reduce the risk of
developing diabetes by 25% over 3 years in the STOP-NIDDM
Trial.61
FUNDAMENTAL CLINICAL TRIALS
Large randomized clinical trials have largely determined the
strategies for appropriate clinical eye care and management of
patients with diabetic retinopathy.
The DRS (Table 133.3) conclusively demonstrated that PRP
significantly reduces the risk of SVL from PDR, particularly
when high-risk PDR is present.
The ETDRS provided valuable information concerning the
timing of PRP for advancing diabetic retinopathy and
conclusively demonstrated that focal photocoagulation for
CSME reduces the risk of MVL by 50% or more (Table 133.4).
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy
TABLE 133.3. Diabetic Retinopathy Study
Major Eligibility Criteria
1. Visual acuity: ≥20/100 in each eye.
2. PDR in at least one eye or severe NPDR in both.
3. Both eyes suitable for photocoagulation.
Major Design Features
1. One eye of each patient was assigned randomly to
photocoagulation (scatter [panretinal], local [direct confluent
treatment of surface new vessels], and focal [for macular edema]
as appropriate). The other eye was assigned to follow up without
photocoagulation.
2. The eye assigned to treatment was then randomly assigned to
argon laser or xenon arc photocoagulation.
Major Conclusions
1. Photocoagulation reduced risk of severe visual loss by 50% or
more. (SVL = VA* <5/200 at two consecutively completed
4-month follow-up visits.)
2. Modest risks of decrease in visual acuity (usually only 1 line) and
visual field (risks greater with xenon than argon
photocoagulation).
3. Treatment benefit outweighs risks for eyes with high-risk PDR
(50% 5-yr rate of SVL in such eyes without treatment was
reduced to 20% by treatment).
Prepared by M. Davis, M.D. and the ETDRS Research Group for the American
Academy of Ophthalmology Diabetes 2000 Program
*VA = visual activity
Furthermore, the ETDRS demonstrated that both early PRP
(before the onset of high-risk PDR) and deferral of treatment
‘until and as soon as high-risk PDR developed’ are effective in
reducing the risk of SVL. PRP, therefore, should be considered
as an eye approaches the high-risk PDR and “usually should
not be delayed if the eye has reached the high-risk proliferative
stage.”24
Subsequent analysis of the ETDRS data shows that early PRP
is particularly beneficial for patients with type 2 diabetes.62 In
type 2 diabetes patients, early PRP substantially reduced sub-
sequent visual loss and the need for vitrectomy. In contrast, in
type 1 diabetic patients there was no major benefit compared to
the waiting for development of high risk characteristics.
Consequently, PRP should be considered in patients with severe
or very severe nonproliferative diabetic retinopathy (NPDR)
levels, or with PDR less than high risk, especially if they have
type 2 diabetes.
The DRVS provided guidelines for the most opportune time
to consider vitrectomy surgery for patients with type 1 and
type 2 diabetes mellitus with vitreous hemorrhage35,36,39 or
severe PDR in eyes with useful vision.37,38 Early vitrectomy for
eyes with recent severe vitreous hemorrhage and visual acuity
less than 5/200 was beneficial, especially for patients with type
1 diabetes mellitus. Furthermore, the chances of achieving
visual acuity of 10/20 or better increased when early vitrectomy
was performed in eyes with severe new vessels, again, especially
for patients with type 1 diabetes mellitus. At the present time,
the findings of the DRVS should be viewed with the under-
standing that substantial subsequent developments in vitrectomy
instrumentation, techniques, and the application of endo-laser
have come into common use after the conclusion of this study.
The multicenter Sorbinil Retinopathy Trial tested whether a
daily dose of sorbinil, an aldose reductase inhibitor (ARI),
reduces the complications of DR. Over a 3 year period, the drug
had no clinically important effect on the course of DR in adults
TABLE 133.4. Early Treatment Diabetic Retinopathy Study
Major Eligibility Criteria
1. Visual acuity: ≥20/40 (≥20/400 if reduction caused by macular
edema).
2. Mild to very severe NPDR and/or non-high-risk PDR, with or
without macular edema.
3. Both eyes suitable for photocoagulation.
Major Design Features
1. One eye of each patient assigned randomly to early
photocoagulation and the other to deferral (careful follow-up and
photocoagulation if high-risk PDR develops).
2. Patients assigned randomly to aspirin or placebo.
3. Eyes with diabetic macular edema were assigned to immediate
or deferred focal photocoagulation.
CHAPTER 133
Major Conclusions
1. Focal photocoagulation (direct laser for focal leaks and grid laser
for diffuse leaks) reduced the risk of moderate visual loss
(doubling of the visual angle) by 50% or more and increased the
chance of a small improvement in visual acuity.
2. Both early scatter with or without focal photocoagulation and
deferral were followed by low rates of severe visual loss (5-yr
rates in deferral subgroups were 2–10%; in early
photocoagulation groups these rates were 2–6%).
3. Focal photocoagulation should be considered for eyes with CSME.
4. Scatter photocoagulation is not indicated for mild to moderate
NPDR but should be considered as retinopathy approaches the
high-risk stage and usually should not be delayed when the
high-risk stage is present.
Prepared by M. Davis, M.D. and the ETDRS Research Group for the American
Academy of Ophthalmology Diabetes 2000 Program.
with type 1 diabetes of moderate duration.63 The group taking
sorbinil, however, did show a slightly slower progression rate
in microaneurysm count. Findings also showed no beneficial
effect of sorbinil on DR.64 There were complications from the
use of this drug in the study population. Nearly 7% of the initial
202 participants had adverse reactions, including toxic
epidermal necrolysis, erythema multiforme, and the Stevens–
Johnson syndrome. It is unlikely that sorbinil will achieve
prophylactic usage because of the hypersensitivity reactions and
outcome similarities between the group treated with sorbinil
and the control group in the study.
The Diabetes Control and Complications Trial (DCCT)
(Table 133.5) was designed to test whether intensive insulin
therapy resulting in improved glycemic control could reduce
the risk of onset or progression of retinopathy for persons with
type 1 diabetes.(Table 133.6)65–68 The DCCT found that regard-
less of the baseline level of glycemic control, a 10% reduction
of glycosylated hemoglobin level significantly reduced the risk of
onset of DR, retarded the progression of DR, and reduced
the need for laser treatment. Intensive therapy reduced the risk
of onset of retinopathy by 76%, and resulted in a 63% reduction
in the risk of progression of retinopathy. In the intensive insulin
therapy group, the risk of developing severe NPDR or PDR was
reduced by 47%, the risk of developing CSME was reduced by
23%, and the risk of requiring laser surgery was reduced by 56%.
The Epidemiology of Diabetes Intervention and Compli-
cations (EDIC) Study followed the DCCT patient cohort after
all patients were converted to intensive insulin therapy. Of
major clinical importance was the finding that despite the fact
that glycemic control as measured by HbA1c became virtually
equivalent between groups, the benefits of early intensive 1777
 RETINA AND VITREOUS

TABLE 133.5. Diabetes Control and Complications Trial TABLE 133.6. PDR AT 1-YR Visit by Severity of Individual
Lesion
Major Eligibility Criteria
Lesion Grade PDR in 1 Year (%)
Type 1 Insulin Dependent Diabetes Mellitus Age 13–39 years
HMA Present in 2–5 fields 9
Absence of hypertension, hypercholesterolemia, and severe
diabetic or medical complications Very severe 57
Primary-Prevention Cohort IRMA None 9
IDDM for one to five years Moderate in 2–5 fields 57
No diabetic retinopathy of seven-field stereoscopic fundus VB Lacking 15
photography
Present in 2–5 fields 59
Urinary albumin secretion < 40 mg/24 hrs
Secondary-Intervention Cohort
IDDM for 1 to 15 years
Very-mild-to-moderate nonproliferative diabetic retinopathy
SECTION 10

Urinary albumin secretion < 200 mg/24 h

Major Design Features
Patients randomized to Conventional Treatment or Intensive
Treatment Group
Conventional Treatment Group
insulin injections once or twice a day
daily blood glucose tests
daily self-monitoring of urine or blood glucose
clinical visits every three months
education about diet and exercise
Intensive Treatment Group
insulin pump or three or more insulin injections a day
insulin dosage adjusted according to self-monitoring of blood
glucose, diet, and exercise FIGURE 133.1. Standard photograph No. 2A of the Modified Airlee
House Classification of Diabetic Retinopathy demonstrating a
blood sugar tests four or more times/day moderate degree of hemorrhage or microaneurysms, or both.
diet and exercise plan Courtesy of the Early Treatment Diabetic Retinopathy Study [ETDRS].

initial hospitalization to implement treatment

weekly to monthly clinical visits with frequent telephone
contact
Major Conclusions
Reduced clinically meaningful retinopathy by 27–76%
Reduced clinically meaningful nephropathy by 34–57%
therapy persisted with continuing benefit of reduced rates of
retinopathy progression observed in patients who formerly had
intensive insulin therapy. Similar risk reductions of other
microvascular complications such as renal disease and
neuropathy were also observed. Thus, early optimal control of
blood glucose is critically important for long-term ocular and
systemic outcome.69,70
The United Kingdom Prospective Diabetes Study
(UKPDS)71,72 and studies in Japan73 found similar results in
patients with type 2 diabetes and also identified elevated blood
pressure as an independent risk factor for the onset and pro-
gression of DR. The UKPDS enrolled 3867 patients with newly
diagnosed type 2 DM. Intensive blood glucose control with
either sulphonylureas or insulin resulted in a 17% risk reduc-
tion for progression of DR, a 29% risk reduction in the need for
laser photocoagulation surgery, a 23% risk reduction for the
development of vitreous hemorrhage, and a 16% risk reduction
1778 in legal blindness.
DIAGNOSIS, CLASSIFICATION, AND
MANAGEMENT OF DIABETIC
RETINOPATHY
RETINAL LESIONS
Various retinal lesions identify the risk of progression of
retinopathy and visual loss. (Table 133.6)
Subtle venous caliber changes and retinal ‘microaneurysms’
are generally the first clinically evident signs of DR.
Microaneurysms are saccular outpouchings of retinal capillaries
possibly due to endothelial cell proliferation.(Fig. 133.1)
Ruptured microaneurysms, decompensated capillaries, and
intraretinal microvascular abnormalities result in ‘intra-retinal
hemorrhages.’ The clinical appearance of these hemorrhages
reflects the retinal architecture at the level at which the
hemorrhage occurs. Hemorrhages in the nerve fiber layer
assume a more flame-shaped appearance, coinciding with the
structure of the nerve fiber layer that runs parallel to the retinal
surface. Hemorrhages deeper in the retina, at which point the
arrangement of nerve fibers is more or less perpendicular to the
surface of the retina, assume a dot or blot shape.
‘Intra-retinal microvascular abnormalities’ (IRMAs)
(Fig. 133.2) represent preexisting vessels with endothelial cell
proliferation that become ‘shunts’ through the areas of
nonperfusion. IRMAs may be seen adjacent to cotton-wool
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy
FIGURE 133.2. Standard photograph No. 8A of the Modified Airlie
House Classification of Diabetic Retinopathy demonstrating
intraretinal microvascular abnormalities (IRMAs) (arrows).
Courtesy of the ETDRS.
FIGURE 133.3. Standard photograph No. 6B of the Modified Airlie
House Classification of Diabetic Retinopathy demonstrating venous
beading.
Courtesy of the ETDRS.
spots. Multiple IRMAs mark a severe stage of nonproliferative
retinopathy with a high risk of development of frank neovas-
cularization. Retinal neovascularization commonly occurs in
areas of previously existing IRMA.
‘Venous caliber abnormalities’ (Fig. 133.3) are indicators of
retinal hypoxia. These abnormalities can be venous dilatation,
venous beading, or venous loop formation. There are often large
areas of nonperfusion adjacent to these veins. PRP may cause
these abnormal veins to become less dilated and more regular.
‘Proliferative retinopathy’ (Fig. 133.4) is marked by devel-
opment of retinal neovascularization. The rate of growth of
these new vessels is variable. They most commonly appear at or
near the optic disc (neovascularization of the disk NVD) or
elsewhere in the retina (neovascularization elsewhere NVE) and
proliferate on the posterior vitreous face. They may also arise in
the perifoveal area.
CHAPTER 133
FIGURE 133.4. Standard photograph No. 10A of the Modified Airlie
House Classification of Diabetic Retinopathy demonstrating
neovascularization of the optic disc (NVD) (arrow), covering
approximately one quarter to one third of the disc area.
Courtesy of the ETDRS.
FIGURE 133.5. Standard photograph No. 7 of the Modified Airlie
House Classification of Diabetic Retinopathy demonstrating
neovascularization elsewhere (NVE) in the retina greater than one half
disk diameter with a fresh hemorrhage present.
Courtesy of the ETDRS.
Patients with high-risk PDR require immediate PRP (see
Chapter 135). High-risk PDR is characterized by one or more of
the following lesions:
• NVD that is ~one-quarter to one-third disc area or more
in size (i.e., ≥ 1/4 – 1/3 disk area) (Fig. 133.4),
• NVD < one-quarter disc area in size if fresh vitreous or
preretinal hemorrhage is present, and
• NVE ≥ 1/2 disc area in size if fresh vitreous or preretinal
hemorrhage is present (Fig. 133.5).
Thus, the evaluation of the diabetic retina for PDR requires
attention to the presence, location and extent of new vessels
and the presence or absence of preretinal or vitreous
hemorrhages.4 1779
 RETINA AND VITREOUS
NONPROLIFERATIVE DIABETIC RETINOPATHY
(NPDR) AND EARLY PDR
As described earlier, it is critically important to consider PRP
as retinopathy approaches or reaches the high-risk stage of
PDR. An eye is considered to be approaching the high-risk stage
when there are retinal signs of severe or very severe NPDR or
the presence of PDR without high risk characteristics. The
baseline severity of retinopathy is closely correlated with the
risk of NPDR progression to early PDR and to high-risk PDR
(Tables 133.6 to 133.8), making accurate assessment of NPDR
severity not only important for identifying timing of laser
surgery, but also for determining future follow-up schedules to
minimize risk between ophthalmic examinations.
Nonproliferative Diabetic Retinopathy Severity
DR is broadly classified as NPDR and PDR. DME can occur
with either NPDR or PDR and is discussed separately. Accurate
SECTION 10
diagnosis of a patient’s ‘DR severity level’ is critical because
there is a varying risk of progression to PDR and high-risk PDR
depending on the specific NPDR severity level.(Fig. 133.6);
(Table 133.8)
‘Mild NPDR’ is marked by at least one retinal micro-
aneurysm, but hemorrhages and microaneurysms are less than
those in ETDRS standard photograph No. 2A (Fig. 133.1 and
Table 133.7). No other retinal lesion or abnormality associated
with diabetes is present. Those with mild NPDR have a 5% risk
of progression to PDR within 1 year and a 15% risk of
progression to high-risk PDR within 5 years (Table 133.8).
‘Moderate NPDR’ (Table 133.7) is characterized by
hemorrhages or microaneurysms, or both (H/Ma), greater than
or equal to those pictured in ETDRS standard photograph No.
2A. Soft exudates, venous beading, and IRMAs are definitely
present in a mild degree. The risk of progression to PDR within
1 year is 12–27%, and the risk of progression to high-risk PDR
within 5 years is 33 percent (Table 133.8).
Patients with mild or moderate NPDR generally are not
candidates for PRP and can be followed safely at 6–12 month
intervals as determined by the examiner. The presence of
macular edema, even with mild or moderate degrees of NPDR,
requires follow-up in a shorter period, and if CSME is present,
focal laser treatment should be considered (Table 133.8).
Coincident medical problems or pregnancy will generally
necessitate a more frequent period of reevaluation.
‘Severe NPDR’, based on the severity of H/Ma, IRMAs, and
venous beading, is characterized by any one of the following
lesions (see Table 133.7):
• H/Ma ≥ standard photograph No. 2A (Fig. 133.1) in four
quadrants, or
• Venous beading (Fig. 133.3) in two or more quadrants, or
• IRMAs ≥ standard photograph No. 8A (Fig. 133.2) in at
least one quadrant.
These criteria are often referred to as the ‘4–2–1- rule’ for
determination of severe NPDR. Any two or more of the above
findings reflects very severe NPDR. Eyes with severe NPDR
have a 52% risk of developing PDR within 1 year and a
60% risk of developing high-risk PDR within 5 years. These
patients require follow-up evaluation at 2–4 months intervals.
Treatment of CSME is strongly indicated because of the risk of
the development of PDR and high-risk PDR. In addition, some
eyes with macular edema, even if not clinically significant, may
require focal treatment in preparation for impending PRP
(Table 133.8).
Eyes with very severe NPDR (Table 133.7) have two or more
lesions of severe NPDR but no frank neovascularization. There
1780 is a 75% risk of developing PDR within 1 year. Patients with
TABLE 133.7. Levels of Retinopathy
Nonproliferative Diabetic Retinopathy (NPDR)
A. Mild NPDR
At least one microaneurysm
Definition not met for B, C, D, E, F
B. Moderate NPDR
H/Ma ≥ standard photograph No. 2A
Soft exudates, VB, and IRMA definitely present
Definition not met for C, D, E, F
C. Severe NPDR
H/Ma ≥ standard photograph No. 2A (Fig. 133.1) in all
4 quadrants
VB in 2 or more quadrants (Fig. 133.3)
IRMA > standard photograph No. 8A in at least 1 quadrant
(Fig. 133.2)
D. Very Severe NPDR
Any two or more of C.
Definition not met for E, F
Proliferative Diabetic Retinopathy (PDR)
(Composed of:(1) NVD or NVE, (2) preretinal or vitreous
hemorrhage, (3) fibrous tissue proliferation)
E. Early PDR
New vessels
Definition not met for F
F. High-risk PDR
NVD ( 1/3 – 1/2 disc area (Fig. 133.4) or
NVD and vitreous or preretinal or vitreous hemorrhage
(Fig. 133.5) or
NVE ≥ 1/2 disc area and vitreous or preretinal hemorrhage
Clinically Significant Macular Edema (CSME)
1. Thickening of the retina at or within 500 mm from the center of
the macula or
2. Hard exudates with thickening of the adjacent retina located at
or within 500 mm from the center of the macula or
3. A zone of retinal thickening, 1 disc area or larger in size located
at or within 1 disc diameter from the center of the macula.
very severe NPDR may be candidates for PRP, and, macular
edema if present, may require treatment. Very close follow-up
evaluation at 2–3 month intervals is important (Table 133.8).
For type 2 diabetes, early PRP should be considered for patients
with severe or very severe NPDR.62
Early Proliferative Diabetic Retinopathy
Diabetic retinopathy marked by NVD or NVE on the retina
or by fibrous tissue proliferation is designated PDR. Early PDR
does not meet the definition of high-risk PDR (Table 133.7).
Eyes with early PDR (< high-risk PDR) have a 75% risk of
developing high-risk PDR within a 5-year period. These eyes
may prompt PRP; and macular edema, sometimes even if not
clinically significant, may benefit from focal treatment before
scatter treatment is initiated (Table 133.8).
Patients with severe and very severe NPDR and early PDR
(<high-risk PDR) should be considered for early PRP. This is
particularly true if there are new vessels in the presence of
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy

TABLE 133.8. General Management Recommendations

Natural Course Evaluation Treatment Strategies

Rate of Progression to:
Level of Retinopathy PDR 1 Yr HRC* 5 Yr Color Fundus FA† PRP‡ Focal Follow-Up
Photograph (mos)

Mild NPDR 5% 15%

No macular edema No No No No 12
Macular edema Yes Occasionally No No 4–6
CSME Yes Yes No Yes 2–4
Moderate NPDR 12–27% 33%
No macular edema Yes No No No 6–8
Macular edema (not CSME) Yes Occasionally No No 4–6

CHAPTER 133
CSME Yes Yes No Yes 2–4
Severe NPDR 52% 60%
No macular edema Yes No Rarely No 3–4
Macular edema (not CSME) Yes Occasionally Occasionally Occasionally 2–3
after focal
CSME Yes Yes Occasionally Yes 2–3
after focal
Very severe NPDR 75% 75%
No macular edema Yes No Occasionally No 2–3
Macular edema (not CSME) Yes Occasionally Occasionally Occasionally 2–3
after focal
CSME Yes Yes Occasionally Yes 2–3
after focal
Nonhighrisk PDR 75%
No macular edema Yes No Occasionally No 2–3
Macular edema (not CSME) Yes Occasionally Occasionally Occasionally 2–3
after focal
CSME Yes Yes Occasionally Yes 2–3
after focal
Highrisk PDR
No macular edema Yes No Yes No 2–3
Macular edema Yes Yes Yes Usually 1–2
CSME Yes Yes Yes Yes 1–2
* HRC = highrisk characteristic proliferative retinopathy
† FA = fluorescein angiography.
‡ PRP = pan-retinal photocoagulation.

severe or very severe NPDR, elevated new vessels, or NVD. In
the presence of macular edema, patients with severe NPDR or
worse should be considered for prompt focal treatment of
macular edema, possibly whether the macular edema is
clinically significant or not, in preparation for the impending
need of PRP which can exacerbate any DME present at the time
of treatment (Table 133.8).
INTERNATIONAL CLASSIFICATION OF
DIABETIC RETINOPATHY
In an effort to simplify classification and standardize com-
munication, the American Academy of Ophthalmology
initiated a project to establish a consensus International
Classification of DR and DME.74,75 This International
Classification of DR and DME described five clinical levels of
diabetic retinopathy: no apparent retinopathy (no abnormalities),
mild NPDR (microaneurysms only), moderate NPDR (more
than microaneurysms only but less than severe NPDR), severe
NPDR (any of the following: >20 intraretinal hemorrhages in
each of four quadrants, definite VB in two or more quadrants,
prominent IRMA in one or more quadrant and no PDR), and
PDR (one or more of retinal neovascularization, vitreous
hemorrhage, or preretinal hemorrhage). Table 133.9 compares
levels of DR in the International Classification of DR to ETDRS
levels of DR.
The International Classification identified two broad levels of
DME: macular edema apparently absent (no apparent retinal
thickening or hard exudates (HE) in posterior pole) and macular
edema apparently present (some apparent retinal thickening
or HE in posterior pole); if present, macular edema was
subclassified as ‘mild DME’ (some retinal thickening or HE in 1781
 RETINA AND VITREOUS

ROLE OF FLUORESCEIN ANGIOGRAPHY IN

FIGURE 133.6. Life table cumulative event rates of high-risk
proliferative retinopathy by level of retinopathy severity scale at
SECTION 10
THE MANAGEMENT OF DIABETIC
RETINOPATHY
Fluorescein angiography of the macula in the presence of
CSME is fundamental for the detection of treatable lesions, as
described below. However, its use to identify lesions such as
NVE, NVD, or retinal thickening is generally not necessary as
these lesions are usually detectable by clinical exam.
Angiographic risk factors for progression of NPDR to PDR have
been identified.26,28 Analysis of data from the untreated
(deferred) eyes in the ETDRS indicates that the following
lesions are independently related to outcome: (1) fluorescein
leakage, (2) capillary loss on fluorescein angiography,
(3) capillary dilatation on fluorescein angiography, and (4) the
following color fundus photographic risk factors: IRMAs,
venous beading, and H/Ma. Hard and soft exudates have an
inverse relationship to progression. It is widely accepted that

baseline in eyes assigned to deferral of photocoagulation in the
ETDRS. Level < 35, mild nonproliferative diabetic retinopathy (NPDR);
level 43, moderate NPDR; level 47, moderate to severe NPDR; level
53A-D, severe NPDR; level 53E, very severe NPDR; level 61, early
proliferative diabetic retinopathy (PDR); level 65, PDR < high-risk
PDR.27
Courtesy of the ETDRS.
posterior pole but distant from center of the macula), ‘moderate
DME’ (retinal thickening or HE approaching the center of
the macula but not involving the center), or ‘severe DME’
(retinal thickening or HE involving the center of the macula).
Table 133.10 compares levels of DME in the International
Classification to ETDRS levels of DME.
This International Classification of DR and DME reduces
the number of levels of DR, simplifies descriptions of the
categories, and describes the levels without relying on reference
to the standard photographs of the Airlie House Classification
of DR. Thus, the International Classification simplifies the
clinical levels of diabetic retinopathy, easing the communication
between clinicians. However, since the International Classifica-
tion is less detailed than the ETDRS retinopathy severity scale,
the International Classification of DR and DME is not a
replacement for the ETDRS scale in large clinical trials or
studies where precise retinopathy classification is required.
capillary loss as documented on fluorescein angiography is a
risk factor for progression of NPDR to PDR.26,28,76–78 However,
capillary dilatation on fluorescein angiography, fluorescein leak-
age, and capillary loss on fluorescein angiography, and the
ETDRS color fundus photographic retinopathy severity levels
are all closely correlated. Although the fluorescein angiography
abnormalities provide additional prognostic information, the
color fundus photographic grading of retinopathy severity levels
give the same prognostic results.27,28 The increased power to
predict progression from NPDR to PDR by fluorescein
angiography is generally considered “not of significant clinical
importance to warrant routine fluorescein angiography.”28
Periodic follow-up retinal examinations, however, are
necessary. The appropriate interval can be determined by skillful
grading of seven standard field stereo color fundus photographs
or by retinal examination by an ophthalmologist experienced in
the management of diabetic eye disease. Since the severity of
diabetic retinopathy is predictive of progression and establishes
frequency of follow-up, and since initiation of PRP should be
considered as diabetic retinopathy approaches the high-risk
stage, routine life-long “periodic follow-up of all patients with
diabetic retinopathy continues to be of fundamental clinical
importance.”28
Other imaging modalities also add vital information to the
evaluation of DR. The introduction of optical coherence

TABLE 133.9. Comparison of the International Clinical DR Scale and the Early
Treatment Diabetic Retinopathy Study (ETDRS) Scale of Diabetic Retinopathy

International Classification Level of DR ETDRS Level of DR

No apparent retinopathy Level 10: DR absent

Mild NPDR Level 20; very mild NPDR
Moderate NPDR Levels 35, 43, 47; moderate NPDR
Severe NPDR Levels 53A-E; severe to very severe NPDR
PDR Levels 61,65,71,75,81,85; PDR, high-risk
PDR, very severe or advanced PDR
DR =diabetic retinopathy; NPDR = Nonproliferative diabetic retinopathy; PDR = Proliferative diabetic
retinopathy
Derived from: (Wilkinson CP, Ferris FL III, Klein RE, et al: Proposed international clinical diabetic retinopathy
and diabetic macular edema disease severity scales. Ophthalmology 2003; 110:1677–1682. Chew EY: A
simplified diabetic retinopathy scale. Ophthalmology 2003; 110:1675–1676. Fundus Photographic Risk
Factors for Progression of Diabetic Retinopathy. ETDRS Report Number 12. Early Treatment Diabetic
Retinopathy Study Research Group. Ophthalmology 1991; 98(5 Suppl):823–833. Grading Diabetic
Retinopathy From Stereoscopic Color Fundus Photographs—an Extension of the Modified Airlie House
Classification. ETDRS Report Number 10. Early Treatment Diabetic Retinopathy Study Research Group.
Ophthalmology 1991; 98(5 Suppl):786–806.)
1782
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy

TABLE 133.10. Comparison of International Clinical DME Scale and ETDRS Scale

Disease Severity Level Findings DME vs. ETDRS scale

DME apparently absent No apparent retinal thickening or hard No DME

exudates (HE) in posterior pole
DME apparently present Some apparent retinal thickening or HE Mild DME: some retinal thickening or HE in posterior pole but
in posterior pole distant from center of the macula (ETDRS: DME but not CSME)
Moderate DME: retinal thickening or HE approaching the center
but not involving the center (ETDRS: CSME)
Severe DME: retinal thickening or HE involving the center of the
macula (ETDRS: CSME, center involved)
DME=diabetic macular edema; HE=hard exudates; CSME=clinically significant macular edema.

tomography (OCT) has permitted evaluation of macular thick-

ening and vitreo-retinal interface abnormalities in a quan-

titative, highly sensitive and reproducible manner.79 OCT is
valuable in confirming or elucidating subtle macular pathology
such as persistent edema, preretinal fibrosis, and vitreo-macular
traction that might otherwise be difficult or impossible to
appreciate on clinical exam. However, OCT does not provide
substantive information on the extent or location of the retinal
lesions characterizing NPDR as does photography, nor does it
identify the source or activity of retinal leakage as can
angiography. Although visual acuity is generally correlated with
central macular thickness, the variability is large, making
current models of OCT inadequate for use as a surrogate for
visual acuity in clinical trials.80 New spectral domain models
of OCT have been approved by the FDA and promise entirely
new methods and sensitivity of evaluating retinal pathology
that will require study to fully elucidate their role in the
clinical management and research investigation of diabetic
retinopathy.
DIABETIC MACULAR EDEMA
Diabetes can affect the macula and macular function through a
variety of mechanisms including:
1. Macular edema; i.e., a collection of intra-retinal fluid in
the macula, with or without lipid exudates and with or
without cystoid changes;
2. Nonperfusion of perifoveal capillaries, with or without
intra-retinal fluid;
3. Traction in the macula by fibrous or glial tissue causing
dragging of the retinal tissue, surface wrinkling, or
detachment of the macula;
4. Intra-retinal or preretinal hemorrhage in the macula;
5. Lamellar or full-thickness retinal hole formation;
6. Any combination of the preceding and other
mechanisms.
Diabetic macular edema may be present at any level of
retinopathy (Table 133.8). For clinical purposes, ‘macular
edema’ is defined as retinal thickening within two disk diam-
eters of the center of the macula (not fluorescein leakage
without thickening). Retinal thickening or hard exudates with
adjacent retinal thickening that threatens or involves the center
of the macula is considered to be clinically significant.
CSME as defined by the ETDRS includes any one of these
lesions (see Table 133.7):
1. Retinal thickening at or within 500 mm of the center of the
macula (Fig. 133.7); or
2. Hard exudates at or within 500 mm s of the center of
the macula, if there is thickening of the adjacent retina
(Fig. 133.8); or
CHAPTER 133
FIGURE 133.7. Schematic representation of clinically significant
macular edema (CSME), with thickening of the macula less than
500 mm from the center of the macula.
Courtesy of Robert Murphy, M.D.
3. An area or areas of retinal thickening at least one disk area
in size, at least part of which is within 1 disk diameter of
the center of the macula (Figs 133.9 and 133.10).
There are particular retinal lesions identified on fluorescein
angiography that are amenable to treatment. The ‘treatable
lesions’ associated with macular edema include:
1. Focal leaks >500 mm from the center of the macula
thought to be causing retinal thickening or hard exudates
(Fig. 133.11),
2. Focal leaks 300 to 500 mm from the center of the macula
thought to be causing retinal thickening or hard exudates if
the treating ophthalmologist does not believe that
treatment is likely to destroy the remaining perifoveal
capillary network (Fig. 133.11),
3. Areas of diffuse leakage that have not been treated
previously (Fig. 133.12), or
4. Avascular zones, other than the normal foveal avascular
zone, not previously treated (Fig. 133.12b).
Focal laser surgery for CSME consists of either direct laser treat-
ment, grid laser treatment, or a combination of direct laser to
focal leaks and grid laser treatment to diffuse leakage or thick-
ened avascular macula. These treatment methods are described
in detail elsewhere.17,19 Table 133.8 summarizes the manage-
ment recommendations for CSME at the various retinopathy
levels. 1783
 RETINA AND VITREOUS

a b
SECTION 10

FIGURE 133.8. (a) Schematic representation of CSME with hard exudates at or within 500 mm of the center of the macula, with thickening of the
retina adjacent to the exudates. (b) Clinical appearance of hard exudates less than 500 mm from the center of the macula. There is thickening of
the adjacent retina, which is not appreciated without stereoscopic observation.
(a) Courtesy of Robert Murphy, M.D. (b) Courtesy of the ETDRS.

FIGURE 133.9. Schematic representation of area of thickening, 1 disk

diameter in size, part of which is within 1 disk diameter of the center FIGURE 133.10. Clinical photograph showing macular edema greater
of the macula. than 500 mm from the center of the macula (the edema is not
Courtesy of Robert Murphy, M.D. appreciated without stereoscopic evaluation).
Courtesy of the ETDRS.

LASER PHOTOCOAGULATION FOR DIABETIC

MACULAR EDEMA AND NONPROLIFERATIVE
DIABETIC RETINOPATHY
The 5-year risk of MVL from macular edema in the ETDRS
without focal laser treatment was 30%. Focal laser surgery for
CSME reduced this risk to 15%,16 amounting to a 50%
reduction in the risk of moderate visual loss. Focal treatment
also increased the chance of improvement in visual acuity of
one line or more, but in general, vision remains approximately
constant. Conversely, PRP was not effective in treating diabetic
macular edema and in some cases may have had a deleterious
effect on the progression of macular edema.
Eyes with CSME and retinopathy that is approaching high-
risk PDR are best treated first with focal photocoagulation for
the macular edema 6–8 weeks before initiating PRP. Eyes with
mild or moderate NPDR and CSME respond best to prompt
focal photocoagulation, with scatter treatment delayed unless
severe or very severe NPDR or high-risk PDR occurs. Delaying
1784 PRP while focal treatment is being completed in these patients
is unlikely to increase the risk of SVL provided that the
retinopathy is not progressing rapidly and careful follow-up can
be maintained. In contrast, in eyes with CSME and high-risk
PDR, delaying PRP while focal treatment is completed usually
is not advisable. In these cases, the DME treatment will
generally be completed and the PRP begun during the same
initial laser treatment session.
Focal treatment was not attended by adverse effects on
central visual field or color vision when compared with eyes
assigned to deferral of focal treatment.17Any harmful effects
of early photocoagulation reflected by constriction of the
peripheral visual fields were primarily attributable to PRP. Since
the principal benefit of laser for CSME is to prevent a further
decrease in visual acuity, laser surgery should be considered in
all eyes with CSME, especially if the center of the macula is
threatened or involved, even if normal visual acuity is present.
The DRS had demonstrated in 1976 that PRP was effective
in reducing the risk of severe visual loss from high-risk PDR.
Since, the DRS did not provide a clear choice between prompt
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy

a b c

CHAPTER 133
d e

FIGURE 133.11. (a) There is a small area of retinal thickening just above the center of the macula (poorly appreciated without stereopsis), which
is detectable monocularly because of blurring of the choroidal pattern. Several microaneurysms are visible within the thickened area. There are
hard exudates around the edges of the edematous patch, some of which extends almost to the center of the macula. Thickening extends to
within 500 mm of the center of the macula (clinically significant macular edema). Visual acuity is 20/15. (b) In the 17- to 18-sec phase of the
fluorescein angiogram, microaneurysms and slightly dilated capillaries are visible in the area of thickening. (c) The 7-min phase of the angiogram
shows leakage into the retina from the two groups of microaneurysms noted in (b). (d) Treatment has been applied to most of the
microaneurysms. (e) Four months later, the appearance of the retina is satisfactory: The center of the macula is flat and most of the thickening
noted before treatment has disappeared. Visual acuity remains at 20/15.
(a–e) Courtesy of the ETDRS.

treatment and deferral of treatment unless there was progres-
sion to high-risk PDR, one question of concern for the
subsequent ETDRS was whether earlier PRP, before the
development of high-risk PDR, justified the side effects and
attendant risks of laser surgery. (Table 133.11)
In the ETDRS, early treatment, compared with deferral of
photocoagulation until high-risk PDR developed,22 was
associated with a small reduction in the incidence of SVL, but
5 year rates of SVL were low for both the early treatment group
and the group assigned to deferral of treatment (2.6% and
3.7%, respectively). However, for patients with type 2 diabetes,
earlier laser photocoagulation, even for eyes with severe or very
severe NPDR, does reduce the risk of severe vision loss.62
Provided careful follow-up can be maintained, PRP is not
recommended for eyes with mild or moderate NPDR since the
benefits are small and the risks equivalent as compared with
treating more severe retinopathy.24 When retinopathy is more
severe (i.e., severe or very severe NPDR and early PDR), PRP
should be considered especially in patients with type 2 diabetes
24
as the benefits of early photocoagulation are greater. When
both eyes are approaching the high-risk stage, initiating PRP
early in at least one eye seems particularly appropriate as
optimal timing of photocoagulation may be difficult if both eyes
need photocoagulation simultaneously. Also, prompt PRP
should be considered for eyes with neovascularization in the
anterior chamber angle, whether or not high-risk proliferative
retinopathy is present.
Table 133.8 presents the treatment program for DR, and the
evaluation and treatment of PDR is discussed extensively in
the PDR chapter. Focal photocoagulation for macular edema
generally uses a 50 mm spot size (50–100 mm in the ETDRS) to
photocoagulate discrete lesions (such as microaneurysms that
fill or leak during fluorescein angiography) or to place a
grid over diffusely thickened areas and nonperfusion. Treatment
is placed from 500–3000 mm from the center of the macula
as discussed earlier. Response to treatment is generally asses-
sed after 3–4 months and retreatment or a new therapeutic
approach considered at that time for persistent or worsening
CSME. Complications and side effects of laser photocoa-
gulation are summarized in Table 133.11.
In summary, focal/grid laser photocoagulation reduces
moderate visual loss from CSME by 50%. PRP significantly
reduces the risk of SVL from PDR but can also exacerbate DME.
Thus, treatment of DME in patients approaching high risk
retinopathy should be considered before PRP is urgently
required (i.e., with the development of high risk PDR). Early
PRP reduces the risk of severe visual loss, but the rates of SVL
are low. Nevertheless, there is a clear benefit for early treatment
in patients with type 2 diabetes. Consequently, it is recom-
mended that PRP not be used for mild to moderate NPDR. For
severe NPDR and early PDR, PRP is most appropriate when
close follow-up is unlikely, the disease process is progressing
rapidly, or for patients with type 2 diabetes.
NOVEL AND EVOLVING THERAPIES FOR
DIABETIC RETINOPATHY AND DIABETIC
MACULAR EDEMA
The rapid advancement of scientific research over the past
decade has tremendously expanded our understanding of the 1785
 RETINA AND VITREOUS

a b c
SECTION 10

d e f

FIGURE 133.12. (a) Clinical photograph showing retinal thickening temporal to the center of the
macula extending just to the center. Visual acuity is 20/40+3. (b) Early phase of the angiogram
shows capillary loss adjacent to the foveal avascular zone, capillary dilatation, and scattered
microaneurysms. (c) The 7-min phase of the angiogram shows extensive small cystoid spaces
temporal to the center of the macula and above and below it. The center appears uninvolved.
(d) The microaneurysms have been treated focally. In addition, laser burns have been applied in
a grid pattern to the areas of diffuse leakage. (e) The temporal extent of the grid laser treatment.
(f) Four months later, hemorrhages and hard exudates have decreased, and the retinal thickening
can no longer be detected. Visual acuity is 20/25. (g) The 7-min phase of the angiogram showing
disappearance of most of the cystoid spaces visible in (c).
(a–g) Courtesy of the ETDRS.
g

molecular and cellular mechanisms underlying the develop-
ment of NPDR, PDR and DME. With this added knowledge
has come new insight into targets for therapeutic intervention.
Currently new agents that may reduce complications of diabetes
in the eye are in various stages of evaluation. Among those with
significant clinical trial and use are intra-vitreal steroids, intra-
vitreal antiangiogenic agents and oral PKC-b inhibitors as
agents of particular interest. These agents hold promise not
only for additional, possibly more efficacious therapies, but also
for fewer associated side effects since they do not share the
inherently retinal destructive nature of laser treatment.
The need to evaluate numerous new therapies in a
scientifically rigorous and timely manner has prompted
development of clinical trial networks. The National Eye
Institute funded Diabetic Retinopathy Clinical Research
Network (DRCR.net), initiated in 2002, is a collaborative effort
with the goal of facilitating multicentric clinical research to
study the effectiveness of new treatments of diabetic
retinopathy and diabetic macular edema. The DRCR.net
currently includes over 160 participating sites in more than 40
states, representing in excess of 500 physicians and 1000 other
personnel.
To date, two DRCR.net studies have been reported. The first
study was an observational study evaluating the relationship
between OCT measured retinal thickness and visual acuity.80
1786 Diurnal variation in retinal thickening as measured by OCT
was also assessed.81 The study showed occasional diurnal
variation in retinal thickening in patients with CSME but not
to an extent that would generally affect clinical trial research.
However, it was found that although retinal thickness and
visual acuity are modestly correlated, there is substantial
variability. Substantial proportions of patients may have
paradoxical responses (i.e., improved vision despite retinal
thickening, or declining vision with resolution of excess retinal
thickening).
The second study compared standard laser (modified ETDRS
protocol) with a mild macular grid (MMG) treatment for
treating CSME.82 MMG entailed light burns spread across the
macula in areas of both thickened and unthickened retina.
Although both MMG and modified ETDRS treatment were
found effective in reducing retinal thickening and improving
vision in patients with CSME, the magnitude of effect of MMF
was not as robust as modified ETDRS and side effects were
similar. Thus, the MMG approach is not being evaluated
further by large scale studies.
There are three DRCR.net studies currently in the follow-up
phase, all involving the treatment of CSME. The first study is
comparing peribulbar triamcinolone acetonide (Kenalog) with
focal laser (modified ETDRS) photocoagulation. Patients were
randomized to receive either laser, steroid (by anterior subtenon
or posterior subtenon injection), or both. Completion of the
initial primary endpoint follow-up phase presented at a national
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy

endophthalmitis. (see also PDR chapter for further details on

TABLE 133.11. Complications and Side Effects of Scatter
intra-vitreal steroid therapies).
(Panretinal) Laser Photocoagulation
Another set of DRCR.net studies is evaluating the anti-
Side Effects angiogenic agents Bevacizumab (Avastin, Genentech, Inc.)84,85
Field constriction and nyctalopia: Depends upon extent and
and Ranibizumab (Lucentis, Genentech, Inc.)86 for the treat-
intensity of scatter laser burns ments of CSME. These agents block the potent angiogenic and
permeability factor called vascular endothelial growth factor
Serous or choroidal detachment (VEGF). VEGF is known to be involved in mediating PDR
Pain and DME and is described in detail in the chapter on PDR.
Bevacizumab and Ranibizumab are humanized antibodies or
Peripheral retina-more painful
antibody fragments, respectively, that bind all isoforms of VEGF
Use retrobulbar anesthesia as needed with high affinity. Ranibizumab is FDA approved for the treat-
Reassurance ment of neovascular age-related macular degeneration (AMD)
while bevacizumab is FDA approved for the systemic treatment
Hypoglycemia of certain cancers.
Anxiety, pain, shock, seizure Pegaptanib (Macugen, Eyetech Pharmaceuticals) is an
Complications
aptamer with high affinity for only the VEGF120 isoform and is
FDA approved for the treatment of neovascular AMD. Recently,

CHAPTER 133
Foveal burn a pharmaceutically sponsored Phase II trial of pegaptanib intra-
Identify landmarks prior to treatment vitreally injected every 6 weeks was completed involving 172
patients. Median visual acuity, visual acuity improvement of
Macular edema 10 or more letters, median retinal thickness and need for
May result in permanent decrease in visual acuity photocoagulation were all better after 36 weeks of treatment
Foveal traction
with 0.3 mg pegaptanib as compared with sham injections.87
Phase III trials with pegaptanib for diabetic macular edema are
Do not treat over blood currently underway.
Avoid puncture of Bruch’s membrane The DRCR.net is currently recruiting or will soon initiate
several additional clinical trials. These trials include evaluating
Acute angle-closure glaucoma
if subgroups of DME will benefit from vitrectomy, determining
Possible but rare the incidence of macular edema (as measured by OCT) follow-
Anterior segment
ing various modalities of PRP, identifying risks of subsequent
DME in patients with subclinical DME, evaluating the effect of
Posterior synechiae adjunctive therapies (steroids or VEGF inhibitors) when used
Cornea and lens burns with PRP for the prevention and/or treatment of macular
edema, and the effect of adjunctive therapies at the time of cat-
Internal ophthalmoplegia
aract surgery to evaluate their ability to prevent and/or improve
Less frequent with multiple sessions and light to moderately diabetic macular edema.
intense burns At this time, the available clinical evidence suggests that
Retrobulbar hemorrhage following retrobulbar injection anti-VEGF and possibly other antiangiogenic agents will have
a substantial effect on ameliorating neovascular disease.
Continue with treatment Although it is likely that these will also have benefit for the
Watch central retinal artery treatment of CSME, initial data suggests that the effect may be
partial and require repetitive administration to maintain the
Retrobulbar anesthesia required infrequently
effects. Results of ongoing clinical trials will be necessary before
Loss of follow-up may result from enough is known about the efficacy and side effects of these new
Pain agents to assess their impact on the clinical care of diabetic eye
disease. The role of these agents for preventing progression of
Retrobulbar hemorrhage NPDR is theoretical at present and awaits trials specifically
Intercurrent illness designed to address this issue.
Lack of caring explanation
PKC-b activation is induced by hyperglycemia through
several mechanisms and in part mediates the development of
Lack of persistent rescheduling vascular dysfunction, vascular permeability, VEGF expression
and VEGF signal transduction. Thus, inhibition of PKC-b might
be expected to ameliorate diabetes-induced vascular compli-
scientific meeting demonstrated that the peribulbar application cations by several mechanisms. The synthesis of a PKC-b
of Kenalog did not show any additional benefit to laser isoform-selective inhibitor (ruboxistaurin, Eli Lilly) has pro-
treatment alone.83 vided diverse data to substantiate this hypothesis.88 Orally
Another study is comparing 1 or 4 mg intra-vitreal injection ingested ruboxistaurin ameliorates diabetes-induced abnor-
of a preservative free triamcinolone acetonide with laser for malities of retinal blood flow, glomerular filtration rate and
treatment of CSME. This study is currently ongoing. Early albumin excretion rate in animals.89 These data supported the
studies of intravitreal administration of corticosteroids have evaluation of orally administered ruboxistaurin in clinical trials
shown a transient reduction in excess retinal thickening in as a potential noninvasive and nondestructive inhibitor of the
patients with CSME. Vision can improve, although this progression of diabetic retinopathy and diabetic macular
improvement does not always occur, and the effect generally edema.90
wears off necessitating repetitive injections. Intra-vitreal Data from two 3-year Phase III trials of ruboxistaurin in
injection of steroid is associated with development of cataract patients with moderate to severe NPDR have been reported.91,92
and the potentially severe side effects of glaucoma and Results were very similar in both trials. In the larger PKC-DRS2 1787
 RETINA AND VITREOUS
TABLE 133.12. Eye Examination Schedule
Type of Diabetes Mellitus Recommendation Time of
First Examination
Type 1 Diabetes Mellitus 5 yr after onset or during puberty
Type 2 Diabetes Mellitus At time of diagnosis
During pregnancy Prior to pregnancy for counseling
Early in first trimester
Each trimester or more frequently
as indicated
*Abnormal findings dictate more frequent follow-up examinations.
study, 685 patients with moderate to severe NPDR and no PRP
SECTION 10
in at least one eye were evaluated after receiving orally
administered ruboxistaurin (32 mg/day) over a period of 36
months.92 Moderate visual loss sustained for at least 6 months
(SMVL) occurred in 5.5% of ruboxistaurin-treated patients and
9.1% of placebo-treated patients (40% risk reduction, p=0.03).
In individual eyes, ruboxistaurin reduced SMVL by 45%
(p=0.01). Mean visual acuity was better in the ruboxistaurin-
treated patients from 12 months onward. In ruboxistaurin-
treated patients, visual improvement of 15 or more letters was
twice as frequent (4.9% vs 2.4%). Ruboxistaurin treatment also
reduced progression of macular edema to within 100 mm from
the center of the macula and the need for initial laser treatment
for macular edema was 26% less frequent in eyes of ruboxis-
taurin-treated patients. Ruboxistaurin therapy was very well
tolerated and has had an excellent safety profile to date.93 No
effect was observed on progression of NPDR severity. The com-
pound has received an ‘Approvable’ rating by the FDA under the
trade name Arxxant (Eli Lilly). Requirements for additional
studies for full regulatory approval are currently under discussion.
PRECLINICAL STUDIES
A wide array of other interventions are in various stages of
preclinical evaluation. Such studies hold promise for eventually
even more effective, more specific and safer therapies than are
currently available. However, several years of further inves-
tigation will be required before any potential clinical impact is
known. Ongoing research is addressing mechanisms contri-
buting to altered retinal blood flow and retinal vascular
complications in diabetes.94,95 Retinal blood flow is decreased in
patients who have had diabetes less than 5 years and may be
important in the onset of clinical retinopthy.94 A direct relation-
ship between decreased retinal blood flow and the activation of
protein kinase C in the rat model has been shown.95 Oxidant
stress may also be involved in the early progression of DR
suggesting that antioxidants may have therapeutic usefulness.
Modulators of NPDR may also include vasoactive agents such
as angiotensin II, histamine, and oxygen. A wide array of other
targets are evolving from the studies of angiogenic agents and
their mechanism of action over the past decade based on work
initiated by Michelson nearly six decades ago.96–106
PATIENT CARE AND GUIDELINES
Although this is an exciting period with new and forthcoming
clinical trial data on a variety of novel therapeutic approaches,
until we have treatment modalities to prevent or cure diabetic
retinopathy, the emphasis for our patients with diabetes
1788 remains focused upon early identification, accurate determi-
Routine Minimal
Follow-up*
Yearly
Yearly
1–2 months post partum
nation of retinopathy severity, optimization of systemic factors,
routine careful follow-up and timely laser photocoagulation,
vitrectomy surgery and/or novel therapies. Proper care results
in substantial reduction of personal suffering and substantial
cost savings.107
For patients who do not have access to diabetes eye care,
novel methods of delivery of such care have been evolving.
Ocular telemedicine is one approach that has the potential to
extend high quality diabetes eye care to patients who face socio-
economic, geographic, or other challenges to care. While some
programs have demonstrated a high degree of reliability in
identifying level of diabetic retinopathy compared to clinical
examination and standard retinal photography, it is important
for both patients and health care providers to recognize
strengths and limitations of ocular telemedicine programs. To
assist in guiding expectations, the American Telemedicine
Association has prepared ‘Practice Recommendations for
Ocular Telemedicine for Diabetic Retinopathy’.
Strict guidelines have been established for the ocular care of
people with diabetes (Tables 133.8 and 133.12). All diabetic
patients should be informed of the possibility of the devel-
opment of retinopathy with or without symptoms and the
associated threat of visual loss. The natural course and treat-
ment of DR should be discussed and the importance of routine
examination stressed. The patient must understand that the
risks of diabetes complications in the eye and elsewhere in the
body may be reduced by diligent personalized health care and
routine follow-up examinations, and that early efforts despite
lack of symptoms can yield long term benefits that are lost if
care is initiated late. Thus, in many ways, the care of the
patient with no or early NPDR is of paramount importance.
Patients should be informed of the strong relationship between
diabetes control and the subsequent development of ocular and
other medical complications. The association of hypertension,
dyslipidemia, abdominal obesity, eating disorders, renal disease,
pregnancy, joint contractures, cardiovascular disease, and
peripheral neuropathy with onset and progression of DR should
be noted and care taken to assure that the patient has
appropriate medical follow-up for these conditions. Patients
with permanent visual impairment, including legal or total
blindness, should be informed of the availability of visual,
vocational, and psychosocial rehabilitation programs. Diabetic
women contemplating pregnancy should have a complete eye
examination prior to conception if possible. Since pregnancy
may dramatically exacerbate existing retinopathy and may be
associated with hypertension, diabetic women should have their
eyes examined early in the first trimester of pregnancy and
generally at least each trimester thereafter and again 1–2
months post partum. Severe retinopathy may impact optimal
delivery methods.
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy

CONCLUSIONS team share the responsibility of assuring such care is offered to

In its earliest stages, DR usually causes no symptoms. Visual
acuity may be excellent, and the patient may be completely
unaware of even advanced retinopathy. Preservation of vision can
be maximized by early initiation of a careful eye care program
which includes patient education, close follow-up, and efficient
communication between the entire team of health care providers.
Accurate assessment of DR severity is essential on an ongoing
basis to determine the likelihood of retinopathy progression,
risk of vision loss and timing of follow-up and therapy. Optimal
control of systemic factors such as blood glucose, blood
pressure, and lipids is also critical. All members of the health
the patient.
Faced with the current inability to prevent or cure diabetic
retinopathy, the eye care for patients with diabetes must pri-
marily focus on patient access, early detection, accurate
retinopathy assessment, careful medical and ophthalmic follow-
up, timely laser photocoagulation and appropriate use of novel
therapies. With this approach, and the continuum of connected
diabetes eye and medical care evolving from advances in
information technology and telemedicine, our twenty-first
century mission of preserving vision in patients with diabetes
will become increasingly successful.

REFERENCES
1. Aiello LM, Beetham WP, Balodimos MC, et 13. Diabetic Retinopathy Study Report Number Airlie House Classification. Ophthalmology

al: Ruby laser photocoagulation in
treatment of diabetic proliferating
retinopathy: Preliminary report. In: Goldberg
MF, Fine S, eds. Symposium on the
Treatment of Diabetic Retinopathy. Public
Health Service Publication No. 1890.
Washington, DC: US Government Printing
Office; 1969:437–463.
2. Diabetic Retinopathy Study Report Number
1: Preliminary report on effects of
photocoagulation therapy. Am J Ophthalmol
1976; 81:1–14.
3. Diabetic Retinopathy Study Report Number
2: Photocoagulation of proliferative diabetic
retinopathy. Ophthalmology 1978; 85:82.
4. Diabetic Retinopathy Study Report Number
3: Four risk factors for severe visual loss in
diabetic retinopathy. Arch Ophthalmol 1979;
97:658.
5. Diabetic Retinopathy Study Report Number
4: A short report of long-range results.
Proceedings of the 10th Congress of
International Diabetes Federation. New
York: Excerpta Medica; 1980.
6. Diabetic Retinopathy Study Report Number
5: Photocoagulation treatment of
proliferative diabetic retinopathy.
Relationship of adverse treatment effects to
retinopathy severity. Dev Ophthalmol 1981;
2:1–15.
7. Diabetic Retinopathy Study Report Number
6: Design, methods, and baseline results.
Invest Ophthalmol Vis Sci 1981;
21:149–209.
8. Diabetic Retinopathy Study Report Number
7: A modification of the Airlie House
Classification of Diabetic Retinopathy.
Invest Ophthalmol Vis Sci 1981;
21:210–226.
9. Diabetic Retinopathy Study Report Number
8: Photocoagulation treatment of
proliferative diabetic retinopathy. Clinical
application of Diabetic Retinopathy Study
(DRS) Findings. Ophthalmology 1981;
88:583–600.
10. Diabetic Retinopathy Study Report Number
9: Assessing possible late treatment effects
in stopping clinical trials early: a case study.
Controlled Clin Trials 1984; 5:373–381.
11. Diabetic Retinopathy Study Report Number
10: Factors influencing the development of
visual loss in advanced diabetic retinopathy.
Invest Ophthalmol Vis Sci 1985;
26:983–991.
12. Diabetic Retinopathy Study Report Number
11: Intraocular pressure following panretinal
photocoagulation for diabetic retinopathy.
Arch Ophthalmol 1987; 105:807–809.
12: Macular edema in Diabetic Retinopathy
Study patients. Ophthalmology 1987;
94:754–760.
14. Diabetic Retinopathy Study Report Number
13: Factors associated with visual outcome
after photocoagulation for diabetic
retinopathy. Invest Ophthalmol Vis Sci 1989;
30:23–28.
15. Diabetic Retinopathy Study Report Number
14: Indications for photocoagulation
treatment of diabetic retinopathy. Int
Ophthalmol Clin 1987; 27:239–253.
16. Early Treatment Diabetic Retinopathy Study
Report Number 1: Photocoagulation for
diabetic macular edema. Arch Ophthalmol
1985; 103:1796–1806.
17. Early Treatment Diabetic Retinopathy Study
Report Number 2: Treatment techniques
and clinical guidelines for photocoagulation
of diabetic macular edema. Ophthalmology
1987; 94:761–774.
18. Early Treatment Diabetic Retinopathy Study
Report Number 3: Techniques for scatter
and local photocoagulation treatment of
diabetic retinopathy. Int Ophthalmol Clin
1987; 27:254–264.
19. Early Treatment Diabetic Retinopathy Study
Report Number 4: Photocoagulation for
diabetic macular edema. Int Ophthalmol
Clin 1987; 27:265–272.
20. Early Treatment Diabetic Retinopathy Study
Case Reports Numbers 3 and 4: Case
reports to accompany Early Treatment
Diabetic Retinopathy Study Reports
Numbers 3 and 4. Int Ophthalmol Clin
1987; 27:273–333.
21. Early Treatment Diabetic Retinopathy Study
Report Number 5: Detection of diabetic
macular edema. Ophthalmoscopy versus
photography. Ophthalmology 1989;
96:746–751.
22. Early Treatment Diabetic Retinopathy Study
Report Number 7: Early Treatment Diabetic
Retinopathy Study design and baseline
patient characteristics. Ophthalmology
1991; 98:741–756.
23. Early Treatment Diabetic Retinopathy Study
Report Number 8: Effects of aspirin
treatment on diabetic retinopathy.
Ophthalmology 1991; 98:757–765.
24. Early Treatment Diabetic Retinopathy Study
Report Number 9: Early photocoagulation
for diabetic retinopathy. Ophthalmology
1991; 98:766–785.
25. Early Treatment Diabetic Retinopathy Study
Report Number 10: Grading diabetic
retinopathy from stereoscopic color fundus
photographs-An extension of the modified
CHAPTER 133
1991; 98:786–806.
26. Early Treatment Diabetic Retinopathy Study
Report Number 11: Classification of
diabetic retinopathy from fluorescein
angiograms. Ophthalmology 1991;
98:807–822.
27. Early Treatment Diabetic Retinopathy Study
Report Number 12: Fundus photographic
risk factors for progression of diabetic
retinopathy. Ophthalmology 1991; 98:823.
28. Early Treatment Diabetic Retinopathy Study
Report Number 13: Fluorescein
angiographic risk factors for progression of
diabetic retinopathy. Ophthalmology 1991;
98:834–840.
29. Early Treatment Diabetic Retinopathy Study
Report Number 14: Aspirin effects on
mortality and morbidity in patients with
diabetes mellitus. JAMA 1992;
268:1292–1300.
30. Chew EY, Williams GA, Burton TC, et al:
Early Treatment Diabetic Study Report 16.
Aspirin effects on the development of
cataracts in patients with diabetes mellitus.
Arch Ophthalmol 1992; 110:339–342.
31. Flynn HW, Chew EY, Simons BD, et al: Early
Treatment Diabetic Retinopathy Study
Report Number 17. Pars plana vitrectomy in
the Early Treatment Diabetic Retinopathy
Study. Ophthalmology 1992; 99:1351–1357.
32. Early Treatment Diabetic Retinopathy Study
Report Number 19: Focal photocoagulation
treatment of diabetic macular edema:
Relationship of treatment effect to
fluorescein angiographic and other retinal
characteristics at baseline. Arch Ophthalmol
1995; 113:1144–1155.
33. Chew EY, Klein ML, Murphy RP, et al: Early
Treatment Diabetic Retinopathy Study
Report Number 20. Effects of aspirin on
vitreous/preretinal hemorrhage in patients
with diabetes mellitus. Arch Ophthalmol
1995; 113:52–55.
34. Chew EY, Klein ML, Ferris FL III, et al: Early
Treatment Diabetic Retinopathy Study
Report Number 22. Association of elevated
serum lipid levels with retinal hard exudates
in diabetic retinopathy. Arch Ophthalmol
1996; 114:1079–1084.
35. Diabetic Retinopathy Vitrectomy Study
Report Number 1: Two-year course of visual
acuity in severe proliferative diabetic
retinopathy with conventional management.
Ophthalmology 1985; 92:492–502.
36. Diabetic Retinopathy Vitrectomy Study
Report Number 2: Early vitrectomy for
severe vitreous hemorrhage in diabetic
retinopathy. Two-year results of a 1789
 RETINA AND VITREOUS
randomized trial. Arch Ophthalmol 1985;
103:1644–1652.
37. Diabetic Retinopathy Vitrectomy Study
Report Number 3: Early vitrectomy for
severe proliferative diabetic retinopathy in
eyes with useful vision. Results of a
randomized trial. Ophthalmology 1988;
95:1307–1320.
38. Diabetic Retinopathy Vitrectomy Study
Report Number 4: Early vitrectomy for
severe proliferative diabetic retinopathy in
eyes with useful vision. Clinical application
of results of a randomized trial.
Ophthalmology 1988; 95:1331–1334.
39. Diabetic Retinopathy Vitrectomy Study
Report Number 5: Early vitrectomy for
severe vitreous hemorrhage in diabetic
retinopathy. Four-year results of a
randomized trial. Arch Ophthalmol 1990;
108:958–964.
40. Cowie CC, Rust KF, Byrd-Holt D, et al:
SECTION 10
Prevalence of diabetes and impaired
fasting glucose in adults – United States,
1999–2000. MMWR 2003; 52:833–837.
41. National Diabetes Surveillance System.
Centers for Disease Control and
Prevention. Available:
http://www.cdc.gov/diabetes/statistics/inde
x/htm. Accessed 12 April 2006.
42. National Diabetes Fact Sheet: CDC’s
Diabetes Program-Publications & Products;
2003.
43. Klein R, Klein BEK, Moss SE, et al: The
Wisconsin Epidemiologic Study of Diabetic
Retinopathy. II. Prevalence and risk of
diabetic retinopathy when age at diagnosis
is less than 30 years. Arch Ophthalmol
1984; 102:520–526.
44. Klein R, Klein BEK, Moss SE, et al: The
Wisconsin Epidemiologic Study of Diabetic
Retinopathy. III. Prevalence and risk of
diabetic retinopathy when age at diagnosis
is 30 or more years. Arch Ophthalmol 1984;
102:527–532.
45. Vision Problems in the US Prevent
Blindness America, National Eye Institute;
2002.
46. The Eye Diseases Prevalence Research
Group: The Prevalence of Diabetic
Retinopathy Among Adults in the United
States. Arch Ophthalmol 2004;
122:552–563.
47. Ali FA:. A Review of Diabetic Macular
Edema. DJO 2002.
48. Aiello LM: Perspective on diabetic
retinopathy. Am J Ophthalmol 2003;
136:122–135.
49. Moloney JBM, Drury MI: The effect of
pregnancy on the natural course of diabetic
retinopathy. Am J Ophthalmol 1982;
93:745–756.
50. Serup L: Influence of pregnancy on diabetic
retinopathy. Acta Endocrinol 1986;
277:122–124.
51. Phelps RL, Sakol P, Metzger BE, et al:
Changes in diabetic retinopathy during
pregnancy: Correlations with regulation of
hyperglycemia. Arch Ophthalmol 1986;
104:1806–1810.
52. The Kroc Collaborative Study Group: Blood
glucose control and the evolution of
diabetic retinopathy and albuminuria. N
Engl J Med 1984; 311:365–372.
53. Grunwald JE, Riva CE, Martin DB, et al:
Effect of insulin-induced decrease in blood
glucose on the human diabetic retinal
circulation. Ophthalmology 1987;
1790 94:1614–1620.
54. Chase HP, Jackson WE, Hoops SL, et al:
Glucose control in the renal and retinal
complications of insulin-dependent
diabetes. JAMA 1989; 261:1155–1160.
55. Brinchmann-Hansen O, Dahl-Jorgensen K,
Hanssen KF, et al: Effects of intensified
insulin treatment on various lesions of
diabetic retinopathy. Am J Ophthalmol
1985; 100:644–653.
56. Krolewski AS, Canessa M, Warram JH,
et al: Predisposition to hypertension and
susceptibility to renal disease in insulin-
dependent diabetes mellitus. N Engl J Med
1988; 318:140–145.
57. Aiello LP, Cahill MT, Wong JS: Perspective:
Systemic considerations in the
management of diabetic retinopathy. Am J
Ophthalmol 2001; 132:760–776.
58. Stern MP, Patterson JK, Haffner SM, et al:
Lack of awareness and treatment of
hyperlipidemia in type II diabetes in a
community survey. JAMA 1989;
262:360–364.
59. Fong DS, Warram JH, Aiello LM, et al:
Cardiovascular autonomic neuropathy and
proliferative diabetic retinopathy. Am J
Ophthalmol 1995; 120:317–321.
60. Diabetes Prevention Program Research
Group: Diet and exercise dramatically delay
type 2 diabetes. Reduction in the incidence
of type 2 diabetes with lifestyle intervention
or metformin. N Engl J Med 2002;
346:393–403.
61. Chiasson JL, Josse RG, Gomis R, et al:
Acarbose for prevention of type 2 diabetes
mellitus: the STOP-NIDDM randomised
trial. Lancet 2002; 359:2072–2077.
62. Ferris FL III: Early photocoagulation in
patients with either Type I or Type II diabetes.
Tr Am Ophth Soc 1996; 94:505–537.
63. The Sorbinil Retinopathy Trial Research
Group: A randomized trial of sorbinil, an
aldose reductase inhibitor in diabetic
retinopathy. Arch Ophthalmol 1990;
108:1234–1244.
64. The Sorbinil Retinopathy Trial Research
Group. The Sorbinil Retinopathy Trial:
Neurology results. Neurology 1993;
43:1141–1149.
65. The Diabetes Control and Complications
Trial Research Group: The effect of
intensive treatment of diabetes on the
development and progression of long term
complications in insulin-dependent
diabetes mellitus. N Engl J Med 1993;
329:977–986.
66. The Diabetes Control and Complications
Trial Research Group: The relationship of
glycemic exposure (HbA1c) to the risk of
development and progression of
retinopathy in the Diabetes Control and
Complications Trial. Diabetes 1995;
44:968–983.
67. The Diabetes Control and Complications
Trial Research Group: Progression of
retinopathy with intensive versus
conventional treatment in the Diabetes
Control and Complications Trial.
Ophthalmology 1995; 102:647–661.
68. The Diabetes Control and Complications
Trial Research Group: Hypoglycemia in the
Diabetes Control and Complications Trial.
Diabetes 1997; 46:271–286.
69. Diabetes Control and Complications
Trial/Epidemiology of Diabetes Intervention
and Complications Research Group:
Retinopathy and nephropathy in patients
with type 1 diabetes four years after a trial
of intensive therapy. N Engl J Med 2000;
342:381–389.
70. The Writing Team for the Diabetes Control
and Complications Trial/ Epidemiology of
Diabetes Interventions and Complications
Research Group: Effect of intensive therapy
on the microvascular complications of type
1 diabetes mellitus. JAMA 2002;
287:2563–2569.
71. Kohner EM, Aldington SJ, Stratton IM, et
al: Diabetic retinopathy at diagnosis of non-
insulin-dependent diabetes mellitus and
associated risk factors: United Kingdom
Prospective Diabetes Study, 30. Arch
Ophthalmol 1998; 116:297–303.
72. UK Prospective Diabetes Study Group:
Effect of intensive blood-glucose control
with sulphonylureas or insulin compared
with conventional treatment and risk of
complications in patients with type 2
diabetes: UKPDS 33. Lancet 1998;
352:837–853.
73. Ohkubo Y, Kishikawa H, Araki E, et al:
Intensive insulin therapy prevents the
progression of diabetic microvascular
complications in Japanese patients with
non-insulin-dependent diabetes mellitus: a
randomized prospective 6-year study.
Diabetes Res Clin Pract 1995; 28:103–117.
74. Wilkinson CP, Ferris FL III, Klein RE, et al:
Proposed international clinical diabetic
retinopathy and diabetic macular edema
disease severity scales. Ophthalmology
2003; 110:1677–1682.
75. Chew EY: A simplified diabetic retinopathy
scale. Ophthalmology 2003; 110:1675–1676.
76. Bresnick GH: Background diabetic
retinopathy. In: Ryan SJ, ed. Retina.
Medical Retina. St Louis: Mosby;
1989:327–366.
77. Shimizu K, Kobayashi Y, Muraoka K:
Midperipheral fundus involvement in
diabetic retinopathy. Ophthalmology 1981;
88:601–612.
78. Takashi N, Muroka K, Shimizu K:
Distribution of capillary nonperfusion in
early-stage diabetic retinopathy.
Ophthalmology 1984; 91:1431–1439.
79. Schuman JS, Puliafito CA, Fujimoto JG:
Optical coherence tomography of ocular
disease second edition. Slack Copyright;
2004.
80. The Diabetic Retinopathy Clinical Research
Network: The Relationship between OCT-
measured Central Retinal Thickness and
Visual Acuity in Diabetic Macular Edema.
Ophthalmology 2007; 114:525–536.
81. The Diabetic Retinopathy Clinical Research
Network: Diurnal Variation in Retinal
Thickening Measurement by OCT in
Center-involved Diabetic Macular Edema.
Arch Ophthalmol 2006; 124:1701–1707.
82. Diabetic Retinopathy Clinical Research
Network: Comparison of Modified-ETDRS
and Mild Macular Grid Laser
Photocoagulation Strategies for Diabetic
Macular Edema. Arch Ophthalmol 2007;
125:469–480.
83. Diabetic Retinopathy Clinical Research
Network: Retinal Subspecialty Day
Symposium, American Academy of
Ophthalmology Annual Meeting. Las Vegas;
2006.
84. Spaide RF, Fisher YL: Intravitreal
bevacizumab (Avastin) treatment of
proliferative diabetic retinopathy
complicated by vitreous hemorrhage.
Retina 2006; 26:275–278.
 Diagnosis, Management, and Treatment of Nonproliferative Diabetic Retinopathy
85. Avery RL, Joel Pearlman J, Pieramici DJ, et
al: Intravitreal bevacizumab (Avastin) in the
treatment of proliferative diabetic
retinopathy. Ophthalmology 2006;
113:1695–1715.
86. Chun DW, Heier JS, Topping TM, et al: A
pilot study of multiple intravitreal injections
of ranibizumab in patients with center-
involving clinically significant diabetic
macular edema. Ophthalmology 2006;
113:1706–1712.
87. Macugen Diabetic Retinopathy Study
Group: A phase II randomized double-
masked trial of pegaptanib, an anti-
vascular endothelial growth factor aptamer,
for diabetic macular edema.
Ophthalmology 2005; 112:1747–1757.
88. Jirousek MR, Gillig JR, Gonzalez CM, et al:
(S)-13-[(dimethylamino)methyl]-
10,11,14,15-tetrahydro-4,21; 9:16-
dimetheno-1H, 13H-
dibenzo[e,k]pyrrolo[3,4-
h][1,4,13]oxadiazacyclohexadecene-
1,3(2H)-d ione (LY333531) and related
analogues: isozyme selective inhibitors of
protein kinase C beta. J Med Chem 1996;
39:2664–2671.
89. Ishii H, Jirousek MR, Koya D, et al:
Amelioration of vascular dysfunctions in
diabetic rats by an oral PKC beta inhibitor
[see comments]. Science 1996;
272:728–731.
90. Aiello LP. The potential role of PKC beta in
diabetic retinopathy and macular edema.
Surv Ophthalmol 2002; 47:S263–S269.
91. The PKC-DRS Study Group: The effect of
ruboxistaurin on visual loss in patients with
moderately severe to very severe
nonproliferative diabetic retinopathy: initial
results of the Protein Kinase C beta
Inhibitor Diabetic Retinopathy Study (PKC-
DRS) multicenter randomized clinical trial.
Diabetes 2005; 54:2188–2197.
92. The PKC-DRS2 Research Group: Effect of
ruboxistaurin on visual loss in patients with
diabetic retinopathy. Ophthalmology 2006;
113:2221–2230.
93. McGill JB, King GL, Berg PH, et al: Clinical
safety of the selective PKC-beta inhibitor,
ruboxistaurin. Expert Opin Drug Saf 2006;
5:835–845.
94. de la Rubia Sanchez G, Oliver-Pozo J,
Shiba T, King GL: Modulation of
endothelin-1 (ET-1) receptor on retinal
pericytes by elevated glucose levels. Invest
Ophthalmol Vis Sci 1991; 32:3110.
95. Shiba T, Bursell S-E, Clermont A, et al:
Protein kinase C (PKC) activation is a
causal factor for the alteration of retinal
blood flow in diabetes of short duration.
Invest Ophthalmol Vis Sci 1991; 32:785.
96. Michaelson IC. The mode of development
of the vascular system of the retina, with
some observations on its significance for
certain retinal disease. Trans Ophthalmol
Soc UK 1948; 68:137–180.
97. Ashton N: Retinal vascularization in health
and disease. Am J Ophthalmol 1957;
44:7–24.
98. Aiello LP, Avery RL, Arrigg PG, et al:
Vascular endothelial growth factor in ocular
fluids of patients with diabetic retinopathy
and other ocular disorders. N Engl J Med
1994; 331:1480–1487.
99. Amin RH, Frank RN, Kennedy A, et al:
Vascular endothelial growth factor is
present in glial cells of the retina and optic
nerve of human subjects with
nonproliferative diabetic retinopathy. Invest
Ophthalmol Vis Sci 1997; 38:36–47.
100. Pierce EA, Avery R, Folet ED, et al:
Vascular endothelial growth factor/vascular
permeability factor expression a mouse
model of retinal neovascularization. Proc
Natl Aca Sci USA 1995; 92:905–909.
101. Adamis AP, Miller JW, Bernal MT: Increased
vascular endothelial growth factor levels in
the vitreous of eyes with proliferative
diabetic retinopathy. Am J Ophthalmol
1994; 118:445–450.
102. Tilton RG, Kawamura T, Chang KC, et al:
Vascular dysfunction induced by elevated
glucose levels in rats mediated by Vascular
endothelial growth factor. J Clin Invest
1997; 99:2192–2202.
103. Pu X, Aiello LP, Ishii H, et al:
Characterization of vascular endothelial
growth factor’s effect on the activation of
protein kinase C, its isoforms and
endothelial growth. J Clin Invest 1996;
98:2018–2026.
104. Aiello LP, Bursell SE, Clermont A, et al:
Vascular endothelial growth factor-induced
retinal permeability is mediated by protein
kinase C in vivo and suppressed by an
orally effective beta isoform-selective
inhibitor. Diabetes 1997; 46:1473–1480.
105. Robinson GS, Pierce EA, Rook SL, et al:
Oligodeoxynucleotides inhibit retinal
neovascularization in a murine model of
proliferative retinopathy. Proc Natl Acad Sci
1996; 93:4851–4856.
106. Ishii H, Jiroousek MR, Koya D, et al:
Amerlioration of vascular dysfunctions in
diabetic rats by an oral PKC beta inhibitor.
Science 1996; 279:728–731
107. Javitt JC, Aiello LP, Bassi LJ, et al:
Detecting and treating retinopathy in
patients with type I diabetes mellitus.
Savings associated with improved
implementation of current guidelines.
Ophthalmology 1991; 98:1565–1574.
108. Aiello LM, Cavallerano J, Cavallerano A,
Bursell S-E. The Joslin Vision Network
(JVN) Innovative Telemedicine Care for
Diabetes. Ophthalmol Clin North Am 2000;
13: 213–224.
109. Wilson C, Horton M, Cavallerano J, Aiello
LM. Addition of primary-care based retinal
imaging technology to an existing eye care
professional referral program increased the
rate of surveillance and treatment of
CHAPTER 133
diabetic retinopathy. Diabetes Care 2005;
28:318–322.
110. Bursell S-E, Cavallerano JD, Cavallerano
AA, et al: Stereo nonmydriatic digital-video
color retinal imaging compared with Early
Treatment Diabetic Retinopathy Study
seven standard field 35-mm stereo color
photos for determining level of diabetic
retinopathy. Ophthalmology 2001;
108:572–585.
111. Cavallerano AA, Cavallerano JD, Katalinic
P, et al: Use of Joslin Vision Network
digital-video nonmydriatic retinal imaging to
assess diabetic retinopathy in a clinical
program. Retina 2003; 23:215–223.
112. Cavallerano JD, Aiello LP, Cavallerano AA,
et al: Nonmydriatic digital retinal imaging
alternative for annual retinal examination in
persons with previously documented no or
mild diabetic retinopathy. Am J Ophthalmol
2005; 140:667–673.
113. Pey S-P, Aiello LM, Cavallerano JD, et al:
Comparison of nonmydriatic digital retinal
imaging vs. dilated ophthalmic examination
for nondiabetic eye disease in persons with
diabetes. Ophthalmology 2006;
113:833–840.
114. Cavallerano J, Lawrence MG, Zimmer-
Galler I, et al: Telehealth practice
recommendations for diabetic retinopathy.
Telemedicine J e-Health 2004; 10:469–482.
1791
 CHAPTER
134 Diabetic Macular Edema
Ronald P. Danis
Overview
Diabetic macular edema (DME) remains the most common cause
of vision loss among diabetic patients. New understanding of the
underlying pathophysiology has heightened interest in the
potential benefits of specific pharmacologic therapy, such as
treatment with intraocular steroids, anti-vascular endothelial
growth factor (VEGF), and protein kinase C-beta (PKCb)
inhibition. At this time, laser photocoagulation according to the
guidelines of the Early Treatment of Diabetic Retinopathy Study
(ETDRS) continues to be the primary standard of care treatment
in most communities, while the evidence base for alternative or
supplementary treatments accrues. Recent advances in imaging
technology, most notably the wide commercial availability and
acceptance of optical coherence tomography (OCT), have
yielded new tools for the clinician and researcher in monitoring
macular edema progression and response to treatment.
DEFINITION
Diabetic macular edema is manifested as retinal thickening
primarily due to exudation from incompetent macular retinal
capillaries. While retinal thickening may occur peripheral to the
macula, such edema is not vision threatening. In order to define
a threshold severity level of edema at which retreatment was
specified for the protocol, the ETDRS coined the term ‘clinically
significant macular edema’.1,2 This term has been incorporated
into most clinicians’ understanding as a level of disease at
which it is appropriate to initiate laser treatment. The phrase
clinically significant macular edema is often applied as a clinical
description of ocular status (e.g., the eye has ‘non-clinically
significant DME’). While a useful and time-honored term, a
number of other descriptors can be applied to the clinical
appearance of DME which may be more appropriate as new
treatments become available. For instance, an eye with
clinically significant macular edema by the ETDRS definition
could have center involvement with cystoid changes, or, it could
have focal edema with a normal foveal contour and thickness.
These very different presentations may merit different
treatments.
The standard of care for varying presentations of DME is in
evolution at this time. For several decades, the guidelines of the
ETDRS were generally applied in the medical community to
manage patients with a level of DME meeting threshold criteria
for clinically significant macular edema, particularly when the
center of the macula was involved or immanently threatened by
retinal thickening or hard exudates very close to it. However,
recent clinical trials have been investigating treatment of DME
Key Features: ETDRS Criteria for Clinically Significant
Macular Edema
• Retinal thickening at the center of the macula.
• Retinal thickening and/or adjacent hard exudates at or within
500 microns of the center of the macula.
• An area of retinal thickening greater than or equal to one disc
area, any part of which is within 1 disc diameter of the center
of the macula.
• A disk diameter is a standardized unit of measurement
derived from the measurement of the average optic nerve
head on slide film images and, in the ETDRS, presumed to
correspond to 1.5 mm on the retina.
• Most digital camera systems today use a revised
assumption that a disc diameter measures 1.8 mm for disc
diameter and a disk area 2.54 mm2.
• The disc diameter or disc area as a measurement on the
photographic image is the same, the underlying
presumptions regarding the image magnification scale
have changed.
at less severe stages.3 In recognition that eyes with severe
edema at the center of the macula may not respond well to laser
treatment, and with the availability of new pharmacologic
agents administered by intravitreal injection, many clinicians
are using drugs off-label to treat DME, without the evidence
from large randomized trials.
PREVALENCE AND INCIDENCE
In the first detailed population-based assessment of diabetic
retinopathy (DR), the Wisconsin Epidemiologic Study of
Diabetic Retinopathy (WESDR), documented a prevalence of
macular edema (defined as retinal thickening within one
disk-diameter of the macular center in stereoscopic retinal
photographs) of 11.1% overall among patients with diabetes in
Southern Wisconsin in the early 1980s.4 The prevalence was
slightly higher in early onset compared to older-onset diabetes
and was strongly associated with duration of diabetes and
glycemic control. Proteinuria and vascular hypertension were
additional factors associated with increased prevalence.
Subsequent population-based studies have yielded prevalence
rates between 2%,5 and over 10%6–9 and confirmed the afore-
mentioned associations. In some diabetic populations, the
prevalence of retinopathy, including DME, appears to be declining
due to improved glycemic control of diabetes in the community.6,10
However, the absolute prevalence of DME might be increasing
due to the overall increased prevalence of diabetes in
industrialized nations.11 The incidence of new cases of DME 1793
 RETINA AND VITREOUS
in a diabetic population has been characterized in a population-
based longitudinal assessment within the WESDR. The WESDR
determined a 10 year rate of developing DME of 20.1% in
younger onset diabetic patients, 25.4% in older-onset diabetic
patients taking insulin, and 13.9% in the older-onset group
not taking insulin.12 It is expected that the incidence of DME
will decrease as excellent metabolic control is increasingly
embraced as a therapeutic goal by patients and health care
workers.
CLINICAL ASSOCIATIONS AND RISK
FACTORS
Macular edema is strongly positively associated with diabetic
retinopathy severity.12 This is particularly problematic for the
clinician who must frequently manage coexistent DME and
proliferative diabetic retinopathy (PDR), as will be discussed.
Undoubtedly, the molecular processes leading to the loss of
SECTION 10
retinal capillary integrity and subsequent edema are closely
related to, but not identical to those causing capillary closure
and ultimate neovascularization. This is evident from the
observation that most patients with macular edema do not have
PDR, and many patients with proliferative retinopathy do not
have DME.13 This partial disconnect between related com-
plications in the same tissue led the ETDRS to exclude retinal
thickening from the overall diabetic retinopathy (DR) severity
scale.14,15 The severity scale is based on rate of progression to
high-risk PDR, and retinal thickening per se was not identified
as conferring additional risk beyond that represented by the
other abnormalities characteristic of diabetic retinopathy.
Glycemic control is a conclusively identified risk factor for
retinopathy progression as well as for DME. The Diabetes
Complications and Control Trial (DCCT) evaluated intensive
glycemic control versus good control in type 1 diabetic patients
with no or minimal DR over 4–6 years, and found a marked
reduction in the progression of retinopathy, nephropathy, and
neuropathy.16 In the follow-on study of this cohort, the
Epidemiology of Diabetes Interventions and Control (EDIC)
study demonstrated that subjects in the former intensive treat-
ment group had a lower rate of progression to DME requiring
laser treatment than those in the good control group.17,18
Similar results have been demonstrated in type 2 diabetic
patients in the United Kingdom Prospective Diabetes Study
(UKPDS).19 Clear relationships between serum glycohemo-
globin levels and DR complications have been established.20–22
Older-onset patients requiring insulin have a higher incidence
of macular edema (and other diabetic complications) than non-
insulin dependent diabetic patients.23 This is likely an effect
related to poorer glycemic control in patients ultimately
requiring insulin therapy.
Duration of diabetes is strongly correlated with prevalence
and incidence of macular edema, retinopathy progression, and
other diabetic complications.12,24 The diagnosis of diabetes in
type 2 subjects occasionally occurs some time after subclinical
diabetes has been manifest, which yields a small proportion of
patients who may present with macular edema at the time
of diagnosis, or even have decreased vision from macular edema
as the presenting sign.25–27 In contrast, persons with type 1
diabetes are very unlikely to experience advanced retinopathy
and macular edema before 5 years of duration. Age-corrected
prevalence rates suggest that there is no definite age interaction
with duration of disease8,11 but because of the increasing inci-
dence of diabetes with age, retinopathy rates are correspondingly
higher with advancing age. Consequently, early detection of
type 2 diabetes and institution of excellent glycemic control is
paramount in decreasing the risk of vision loss from macular
1794 edema in the older population.28–30
Hypertension significantly exacerbates vision loss from
macular edema.22,31 The UKPDS has demonstrated that strict
control of systemic hypertension has an ameliorative effect on
retinopathy progression and vision loss from macular edema in
type 2 diabetes.32,33 The WESDR study also documented an
adverse association of hypertension with vision loss from diabetic
retinopathy.31 It has been suggested that not only is hyper-
tension a risk factor for the development of macular edema, but
its treatment may have important benefits in patients with
uncontrolled hypertension.34
Proteinuria and retinopathy are strongly correlated because of
their common risk factors of glycemic control, duration of
diabetes, and hypertension.17,31,35–37 Less clear is the relationship
between renal failure and macular edema. There appear to be
patients who have increased macular edema as a collateral
adverse event due to fluid retention, and who improve after
institution of diuretics or hemodialysis,38 but this is difficult
to demonstrate among populations of patients undergoing
dialysis.34,39,40 Retinal HE and macular edema were significantly
and independently associated with proteinuria in a cohort of
African American patients.41 It is accepted that fluid retention
from cardiac failure, renal failure, or other causes can exacerbate
DME and may be important concerns in managing it.1
Dyslipidemia has been implicated as an independent risk
factor for vision loss and DME.42–44 This may be in part due to
increased quantities of HE in the eyes of hyperlipidemic diabetic
patients, which has been a consistent observation between
studies.41,45–48 However, such observations also suggest that
dyslipoproteinemia or excessive dietary exposure to fats may
contribute to macular edema, perhaps through lipid peroxidation
or other vasculopathic influences.49–51
Development or worsening of DME during pregnancy is
occasionally observed and is most often associated with poor
glycemic control,32,52 preexisting retinopathy, and pre-
eclampsia.53–55 The DME associated with pregnancy may at
least partially respond to laser treatment, but may also resolve
postpartum.56 Clinicians faced with a pregnant patient with
DME may, therefore, elect to observe the patient without treat-
ment for several months during her pregnancy, and following
her delivery before making the determination that laser
treatment is required. With excellent prenatal care and careful
metabolic control, those women who experience some retino-
pathy worsening during pregnancy generally have only transient
changes.32,53,57 Some of the worsening that may occur during
pregnancy may be due to rapid institution of strict glycemic
control, which can cause transient worsening as well.58–60
Cataract surgery, other types of intraocular surgery, and ocular
inflammatory disease may produce inflammatory and angio-
genic mediators which can produce macular edema in eyes with
or without diabetic retinopathy.61 However, eyes with pre-existing
DME are at high risk for exacerbation. Patients with cataract
and DME, who undergo surgery, will occasionally experience vision
worsening due to increased DME rather than the expected
visual improvement from cataract removal.62,63 Therefore,
DME should be treated prior to surgery to minimize this risk.64
Laser treatment for PDR, panretinal photocoagulation (PRP), or
scatter laser is documented to cause vision loss due to worsening
macular edema.65 Eyes with preexisting macular edema appear to
be more at risk. The ETDRS Research group suggested that in eyes
with both DME and PDR, the risk of vision loss from PRP was
minimized by first treating the DME with macular focal/grid
photocoagulation, and later treating the PDR (if such a delay is
acceptable).1 The underlying mechanism may be the production of
an inflammatory response to the laser treatment, which worsens
vascular leakage and exacerbates DME.66 This has led some
investigators to consider adjunctive steroid treatment with PRP to
minimize the risk of early vision loss.67,68
 Diabetic Macular Edema

Extracellular fluid in the retina may cause diffuse thickening

Key Features: Clinical Associations with Diabetic
of the tissue. In early stages, Mueller cell and other glial cell
Macular Edema Severity
edema can be observed, which appear to be compensatory.91,92
• Diabetic retinopathy severity level
Severe edema generally results in development of loculated
• Duration of Diabetes
fluid, called cystoid spaces, in the middle retinal layers (Fig.
• Glycemic control
134.1). Cystoid spaces initially develop in the outer plexiform
• Hypertension
layer of the retina, hypothesized to be the loosest and most
• Dyslipidemia
elastic cellular stratum of the retina and therefore the most
• Nephropathy
accommodating layer for this expansion.93 In very severe or
• Fluid retention
chronic edema, the cystoid spaces may occupy nearly the entire
• Pregnancy
retinal thickness with gross distortion of the retina. In very
• Intraocular surgery
chronic cases, there is eventual disorganization of the retinal
• Uveitis
tissue, which may be partly related to co-existent capillary
• Panretinal Photocoagulation
ischemia and reactive glial responses. At this point, the retina
may resume normal thickness, or even become abnormally
thin, as the macula assumes a more atrophic appearance.
PATHOLOGY AND PATHOPHYSIOLOGY Cystoid spaces may rapidly disappear with treatment, yielding a
normal-appearing retina in cases where chronic cellular changes

CHAPTER 134
OF DME
have not yet occurred.
Capillary damage is manifest in the earliest stages of DR by loss In the foveal region, the outer plexiform layer has a radial
of the retinal pericytes and capillary basement membrane orientation due to the centrifugal displacement of the bipolar
thickening.69 With increasing duration and severity of hyper- cell layer, the nerve-fiber layer of Henle. This layer may host
glycemia, eventual capillary closure and microaneurysm cystoid spaces of very large proportions. Most cases of clinically
formation occur.70 At what point, the blood–retinal permeability apparent cystoid change are in this region, due to the large size
barrier is permanently compromised in this cascade of events is of the cysts. The clinical cyst pattern often appears as one or
not clear, but hyperglycemia alone of relatively short duration more central large cysts surrounded by a region of somewhat
can cause retinal vascular leakage in the absence of detectable smaller cysts, and finally by a region of smaller cysts that may
retinopathy or structural damage by light microscopy in animal not be clinically visible (Fig. 134.2). Fluorescein angiography
models.71 The intimate ultrastructural connections between the has been historically helpful in defining cystoid edema, since
capillary cells and the neighboring neuronal and glial tissue the fluorescein dye from the leaking capillaries tends to pool in
suggest important functional relationships.72,73 This raises the the cystoid spaces in the late phases of the study, highlighting
question as to whether the observed vascular changes are primary these structures (Figs 134.2d and 134.3d).94 OCT has allowed
or secondary to neuroglial dysfunction. The ultrastructural visualization of high resolution cross sectional retinal morphology
basis for the blood–retinal barrier is the tight junctions between and demonstrated that cystoid spaces are more common than
the retinal capillary endothelial cells and the relative paucity of has been appreciated by clinical examination or fluorescein
transendothelial transport vesicles compared to endothelial cells angiography (Figs 134.2d and 134.3d).95 An additional feature
in other tissues.74 With hyperglycemia, there is a disorganiza- visible by OCT and not apparent clinically or on angiography is
tion of the interendothelial junctions and an increase in a common appearance of subretinal fluid in cases of severe
transcellular endocytosis, with resultant fluid flow through the DME (Fig. 134.2e).96 The source of the fluid has been presumed
capillary walls into the retinal tissue.74,75 Fluid homeostasis of to be due to excessive retinal capillary leakage, but there is some
the retina is poorly understood. However, increased permeability evidence that the retinal pigment epithelium may also have
of the retinal capillaries at some point overwhelms the fluid dysfunctional fluid homeostatic function in diabetes and
reuptake mechanisms and retinal edema occurs. The extent of contribute to this appearance.93,97
retinal vascular leakage into the vitreous cavity can also be
detected in vivo.76
The pathophysiologic mechanisms underlying the breakdown
of the blood–retinal barrier are multifactorial and are continuing
to be understood in the context of the myriad biochemical
pathways affected by hyperglycemia. One of the dominant
emerging themes surrounds the role of the soluble growth factor
VEGF in the diabetic retina. While better known as an
angiogenic stimulus upregulated by hypoxia,77,78 VEGF is a
potent permeability agent which is found in animal diabetic
models and in human diabetic retinas associated with increased
vasopermeability.79–81 Therefore, VEGF inhibition has emerged
as a target molecule for treatment of DME. Another target
molecule for pharmacotherapy is the intracellular signaling
molecule PKCb (protein kinase Cb). Selectively upregulated in
hyperglycemia, this protein appears to mediate in part a variety
of diabetes-induced pathophysiologic events,82 including VEGF
production,83 leukostasis and vascular permeability,83,84 abnormal
blood flow,82 and angiogenesis.85 The generation of reactive
lipoxidative products and glycation end products86 in diabetes
can cause direct cellular damage and also induce inflammation.87
Steroids can inhibit inflammatory responses, stabilize inter- FIGURE 134.1. Photomicrograph of cystoid spaces and subretinal
endothelial junctions, and inhibit VEGF, thereby accounting for fluid in the retina of a diabetic patient with severe DME. H&E, original
interest in this class of compounds for treating DME.88–90 magnification µ100. Image furnished by Daniel Albert MD. 1795
 RETINA AND VITREOUS

a b c
SECTION 10

d e

FIGURE 134.2. Right eye of a patient with untreated DME. Visual acuity measured 66 letters (~20/50). (a) Red-free (green channel) image from a
digital fluorescein angiogram of a patient with diffuse DME with cystoid changes. (b) Early phase of the fluorescein angiogram with numerous
microaneurysms and patchy loss of capillaries. (c) Mid-phase of the angiogram demonstrating early diffuse fluorescein dye leakage. (d) Late
phase of the angiogram with fluorescein dye pooling in cystoid spaces and diffuse retinal fluorescein staining. (e) OCT scan demonstrating retinal
thickening and a large central cyst and smaller cystoid spaces in the outer plexiform layer of the retina and retinal elevation from subretinal fluid.
Printed with permission of the Diabetic Retinopathy Clinical Research (DRCR) Network.

One of the most characteristic clinical appearances of DME
is the presence of hard exudates (HE), which are lipoproteinaceous
deposits from the transudation of fluid from retinal capillaries
(Fig. 134.4). Abnormal fluid homeostasis in the retina results
in a high rate of flux of plasma components in and out of the
retinal capillaries. Slower absorption of transudated larger
plasma molecules from the retinal tissues results in a net
accumulation, which may eventually form a macroscopically
visible accretion, the hard exudate. As with cystoid spaces, hard
exudates develop in the outer plexiform layer (Fig. 134.5).98 Not
unexpectedly, several reports correlate increased quantities of
hard exudates in patients with DME who also suffer from
dyslipidemia.48 Hard exudates may accumulate in the foveal
center, leading to loss of central visual function.99 A large
amount of hard exudates at the center may tend to cause fibrotic
organization which portends poor visual prognosis.
A paradoxical increase in the presence of HE may occur
temporarily in recently treated eyes with DME. This may be
due to increased fluid reuptake in the retinal capillaries, leaving
behind a greater proportion of lipoproteins that previously were
dispersed throughout the edema in the retinal tissue. This effect
has clinical relevance for those eyes that have hard exudates
close to, but not yet in, the macular center. Treating the macular
edema could, in such a case, cause increased hard exudate
accumulation into the center leading to loss of visual acuity.100
HE may gradually reabsorb over a period of months if macular
edema is reduced. Eyes with aggregation of hard exudates in the
center of the macula may have some visual recovery at that
1796 point.
Chronic severe DME, in addition to retinal atrophy, can lead
to subretinal fibrosis, particularly if chronic hard exudates and
subretinal fluid are present.101 In some cases, subretinal non-
vascular membranes appear to be stimulated by laser treatment
of macular edema. Often, such membranes are subclinical but
may be noted on histopathology in autopsy eyes or clinically by
OCT. If subretinal fibrosis occurs under the fovea, eventual
photoreceptor loss and poor vision result. Macular ischemia
may coexist with DME, which may also yield visual acuity
worse than expected based on the appearance of the macula.
Other confounding abnormalities, that can coexist and confuse
the relationship between DME and vision and treatment
include, epiretinal membranes and vitreous traction.95,102,103
CLINICAL PRESENTATION OF DIABETIC
MACULAR EDEMA
Patients with DME present with a range of visual symptoms
depending on the degree to which the fovea is involved and the
chronicity of the edema. If the macula center is not involved,
patients are rarely symptomatic; only a few very observant
individuals may notice relative paracentral scotomas corresponding
to focal edema and hard exudates. Some patients with central
macular involvement have excellent acuity and no visual
complaints, presumably because of only recent involvement of
the center. Over time, patients experience a gradual progressive
vision loss over weeks to months. Patients may complain of
loss of color vision,104 poor night vision, and washing-out of
vision in bright sunlight with poor dark–light adaptation.
 Diabetic Macular Edema

a b c

CHAPTER 134
d e

FIGURE 134.3. Same eye from the patient shown in Figure 134.2, one year later, after one modified ETDRS laser treatment was performed at
baseline. Visual acuity improved to 73 letters (20/40) at the 12 month visit. (a) Red-free image demonstrating no visible cystoid spaces.
(b) Early phase of the angiogram with early leakage from neovascularization from the optic nerve head and the inferior temporal arcade vessels.
(c) Mid-phase of the angiogram demonstrating persistent diffuse retinal capillary leakage and retinal staining. (d) Late phase of the angiogram,
showing diffuse leakage, but less than at baseline, with reduction in pooling of dye in cystoid spaces. (e) OCT scan showing resolution of
subretinal fluid, resolution of cystoid spaces, and marked reduction in retinal thickening after laser treatment.
Printed with permission of the DRCR Network.

FIGURE 134.5.
Photomicrograph of
hard exudates in the
outer plexiform layer of
the retina in the retina
of a diabetic patient.
H&E, original
magnification µ100.
Image furnished by
Daniel Albert, MD.
Printed with
permission of the
DRCR Network.

FIGURE 134.4. Color photograph of the left eye of a diabetic patient

with focal macular edema, center-involved, with circinate hard
exudates roughly circumscribing the area of retinal thickening.
Printed with permission of the DRCR Network.

1797
 RETINA AND VITREOUS

Metamorphopsia is not uncommon. Frequently, patients with
center-involved DME note fluctuation of vision from day-to-day
or even over the course of a day.34 In some cases, the patient
may relate such changes to fluid retention, hyper or hypoglycemia,
or ambient lighting. Some patients may experience a diurnal
variation in macular edema,105–109 though this appears to be of
low frequency and magnitude and of uncertain clinical relevance.
On fundus examination with slit lamp biomicroscopy or
contact lens, retinal thickening may present in some commonly
identified clinical patterns. Focal edema often occurs associated
with a cluster of microaneurysms, sometimes surrounded by an
incomplete ring of hard exudates (this pattern is termed
circinate hard exudates) (Fig. 134.4). Multiple foci of edema
may be present, varying in size, and sometimes merging
together over time. The macula center may or may not be
involved. Diffuse DME may be very difficult to identify
clinically if the retina is of uniform thickness, due to the lack of
reference landmarks. Clues include the height of the retinal
SECTION 10
progress. The standardized seven-fields photography protocol,
allow thorough documentation of mid-peripheral and posterior
retinal lesions and has been a mainstay in clinical trials where
both DR severity and macular edema are to be analyzed. As
many ophthalmology offices transition from, film imaging to
digital camera systems for a variety of reasons, issues with
color contrast, display, and stereo viewing in the digital
environment bring some challenges that can decrease the
utility of color imaging. However, with adequate quality and
display, high resolution color images are comparable to film.110
Standardized protocol color imaging (film and digital) is employed
extensively for clinical research and is comparable to biomicro-
scopic clinical examination for the detection and classification
of retinal thickening.111 However, many clinicians rely
increasingly on OCT to monitor the status of the macula,
particularly if the center is involved.
Fluorescein angiography yields useful information regarding
macular perfusion and the extent of capillary leakage. At this

blood vessels over the pigment epithelium, loss of the foveal
depression or even cystoid spaces. If the pupil is small or there
is lens opacity interfering with the examination, such features
are easily missed. Other features sometimes seen with macular
edema include variable loss of retinal transparency, a large burden
of microaneurysms and intraretinal hemorrhages, and dispersed
flecks of hard exudate.
Stereoscopic fundus photographs have been obtained historically
to document the extent of macular edema and monitor
time, angiography is the only common clinical method that can
document retinal capillary ischemia, although good photographic
quality is required. Areas of fluorescein leakage which may not
correlate with retinal thickening are sometimes noted (Fig. 134.6);
in contrast, sometimes areas of retinal thickening may not
demonstrate notable fluorescein leakage. Partly for this reason,
the ETDRS did not include fluorescein angiographic
characteristics in the definition of clinically significant macular
edema or criteria for retreatment,2 although angiography was

a b c

d e

FIGURE 134.6. Left eye of a diabetic patient prior to laser treatment. Baseline visual acuity measured 42 letters (20/160). (a) Color fundus
photograph with central edema, hard exudates, and scattered intraretinal hemorrhages and microaneurysms. (b) Early phase angiogram,
scanned from a negative film strip, with early leakage from microaneurysms. (c) Mid-phase of the angiogram showing patching fluorescein
leakage. (d) Late cystoid staining. (e) OCT scan demonstrates cystoid edema. The hyper-reflective dot at the center (arrow) represents hard
1798 exudate in the outer plexiform layer.

performed within the study.100,112 However, angiographic
features were used to guide treatment. The treatable lesions
associated with macular edema include: focal leaks greater than
500 mm from the center of the macula believed to be causing
retinal thickening or HE; focal leaks 300–500 mm from the
center of the macula believed to be causing retinal thickening
or HE if the treating ophthalmologist does not believe that
treatment is likely to destroy the remaining perifoveal capillary
network; areas of diffuse leakage that have not been treated
previously; areas of capillary nonperfusion not previously
treated. In many eyes with significant disease, the location of
the fovea is not distinct, and angiography assists with topographical
localization of the center and identification of microaneurysms
for laser treatment.
OCT technology was commercialized for retinal imaging in
1995 and quickly penetrated ophthalmology offices because of
the advantageous and unique display of retinal topography and
cross sectional anatomy.113 Third-generation OCT machines
display mean retinal thickness measurements in nine subfields
that approximate (but are slightly smaller than) the macular
grid used for measurement and grading in the ETDRS. The
center point thickness and total macular volume within the grid
are provided along with a false-color topographical map. The
reproducibility of good-quality scans is very high and allows
detection of moderate change in center retinal thickness over
time.114–116 However, quality issues in scan acquisition, media
opacity, unstable fixation, and indistinct tissue planes causing
measurement algorithm errors are relatively common and
require interpretation.117 Nevertheless, the ability to measure
retinal thickness has not been available with other modalities
and has been an important advance. Detection of subtle
thickening at the center is more sensitive by OCT scans than
clinical examination.118,119 Cystoid spaces, subretinal fluid, and
vitreoretinal abnormalities not visible on clinical examination
or photography are often imaged on OCT scans.96 Less clear
is how robust current OCT technology is for measurement
and tracking of noncenter involved macular edema. DME
features on OCT correlate well with classification by fundus
photographs114,120,121 and fluorescein angiography.122
RELATIONSHIP BETWEEN MACULAR EDEMA
AND VISUAL ACUITY AND OTHER MEASURES
OF VISUAL FUNCTION
Untreated patients with center-involved DME experience a
gradual loss of visual acuity. In the ETDRS, the 3-year risk of
moderate vision loss (defined as loss of three lines of acuity on
the standardized acuity chart) was ~33% at 3 years in the group
with CSME.2 However, the rate of moderate vision loss for eyes
with clinically significant edema without center involvement
was close to 20%, and untreated eyes with DME that was less
than clinically significant had a rate of ~15%.123 Unless
ischemia, traction, or other confounding macular pathology is
present, DME does not cause visual acuity loss until the center
of the macula is involved. Even then, vision loss tends to be
gradual, and it is not unusual to observe patients with obvious
involvement of the foveal region by DME, yet have excellent
acuity and no symptoms.123 Conversely, as noted previously,
patients with chronic edema may eventually undergo retinal
disorganization and atrophy; such maculae may have poor
acuity yet retinal thickness within the normal range. Therefore,
a cross sectional assessment of a population with DME may
display only a fair relationship between thickness and acuity,
because it includes patients with a range of disease duration.
OCT assessment of retinal thickness is therefore a limited
predictor of vision in a cross-sectional sample of persons with
DME.
Diabetic Macular Edema
Successful reduction of DME early in the course of the
disease is likely to stabilize or improve visual function. The
ETDRS demonstrated that laser-treated eyes not only had a
significant reduction in the rate of vision loss, but those eyes
were also twice as likely to experience visual acuity improvement.
Unfortunately, eyes with long-standing DME that have
reduction in retinal thickening, may not experience any visual
improvement with treatment.124
Persons with no or minimal diabetic retinopathy may have
subtle abnormalities of contrast sensitivity and color perception.
DME decreases contrast sensitivity roughly in proportion to
visual acuity. Threshold retinal sensitivity also decreases, and
color vision is progressively impaired.125,104 Light–dark adap-
tation is also prolonged.126 These measures confirm the
subjective complaints of many subjects with DME regarding
loss of night vision, dimness of vision, and impairment of color
perception. On multifocal electroretinogram testing, reduced
amplitudes and latencies can be found, again roughly parallel to
CHAPTER 134
the extent of acuity loss.127,128 The oscillatory potentials measured
from standard bright flash electroretinogram protocols may also
be more sensitive than visual acuity as a measure of early
impairment from diabetic retinal vasculopathy.126,34 Carefully
microperimetric analyses of diabetic maculae correlated with
fluorescein angiograms demonstrate relative scotomas and
other abnormalities.129,130
LASER PHOTOCOAGULATION FOR DIABETIC
MACULAR EDEMA
The ETDRS conclusively demonstrated that focal/grid laser
photocoagulation was safe and effective in reducing vision loss
due to DME (Figs 134.2, 134.3, 134.6, and 134.7). In eyes with
center-involved DME, the rate of moderate visual loss (loss of
15 or more letters on the ETDRS chart) was reduced from 33%
among eyes in the deferral of treatment arm to 13% among
those eyes in the immediate laser treatment group,123 a relative
reduction in the rate by ~60%. At 3 years, in eyes with center-
involved DME and acuity 20/40 or worse, improvement in
acuity by six or more letters was observed in ~40% of eyes
assigned to immediate treatment, versus ~20% in eyes assigned
to deferral.2 There was a similar two-fold increase in the rate
of gain of 15 or more letters, ~15% versus ~7% (ETDRS,
unpublished data). The 3 year results were sufficiently
compelling that the data safety and monitoring committee of
the ETDRS halted the study before the scheduled end of the
trial so that subjects in the deferred laser treatment group
could be offered treatment. While laser treatment increased the
probability that a patient might have visual improvement, the
number of patients actually manifesting substantial improve-
ment was disappointingly small. In addition, the mean acuity of
treated patients in the ETDRS had a progressive decline in
vision over time despite treatment. The advent of laser photo-
coagulation for DME was a great contribution for management
of an otherwise untreatable condition, and laser treatment has
saved useful vision in countless individuals. However, the
burden of vision loss among patients with DME remains high,
thus spurring the investigation of pharmacologic treatments
that might be adjunctive to laser treatment, salvage therapy for
those patients who continue to lose vision after laser, or
potential new primary therapies.
The technique of ETDRS focal/grid photocoagulation has
been used as standard therapy in the community since the
study results were disseminated, with little modification over
the years.123 The original study employed argon blue–green
laser with laser spot sizes up to 100 mm in diameter. Newer
lasers routinely allow spot sizes of 50 mm in diameter, which is
preferable to avoid complications from laser scar expansion. 1799
 RETINA AND VITREOUS

a b c
SECTION 10

d e

FIGURE 134.7. Same eye shown in Figure 134.6 at one year post baseline, after a total of 3 modified ETDRS focal/grid photocoagulation
treatments at baseline, 3.5 months and 8 months. Visual acuity improved to 65 letters (20/50) at 12 months. (a) Color photograph demonstrating
reduction in hard exudates and visible microaneurysms. (b) Early phase fluorescein angiogram showing hyperfluorescent pigment epithelial
defects from laser burns (arrow). (c) Mid-phase angiogram showing reduced leakage. (d) Late phase angiogram with only mild fluorescein
leakage and no cystoid edema. (e) OCT scan from the 12 month visit demonstrating no significant retinal thickening, and resolution of
cystoid spaces.
Printed with permission of the DRCR Network.

a b c

FIGURE 134.8. Same eye shown in Figure 134.6, immediately after the first laser application (a), and immediately following the second laser
application (b), at 3.5 months after the first. Pale gray laser spots can be observed in both photographs (arrows). (c) OCT scan of the same eye
at 8 months, demonstrating reduction in retinal edema, but persistent cystoid changes and hard exudate.
Printed with permission of the DRCR Network.

The blue argon wavelengths have been filtered out from modern
argon lasers, since, the luteal pigments in the inner retinal
layers absorb blue light and yield unnecessary thermal damage
to the retinal nerve fiber layer. In addition, solid state lasers are
available to provide treatment with green wavelengths. The
intensity of application tends to be slightly less among retinal
surgeons today, again out of concern for laser scar expansion
(Fig. 134.8). The ETDRS protocol recommends focal treatment
1800 to leaking microaneurysms that are at least 500 mm from the
fovea and grid laser treatment to areas of diffuse retinal thickening.
In addition, areas of ischemia identified on fluorescein angio-
graphy could be treated with grid laser. Repeat laser treatment
may be applied if clinically significant DME persists. In the
ETDRS, leaking microaneurysms up to 300 mm from the fovea
could be treated if additional treatment was needed at sub-
sequent visits. Laser burns this close to the fovea increase the
risk of scotomas, accidental fovea burns, and late damage to
the fovea from laser scar enlargement and are rarely used today.

Tips: Modified ETDRS Focal/Grid Laser
Photocoagulation of DME
• Do not treat lesions closer than 500 mm from the fovea on the
first treatment
• Avoid intense laser burns/scars – endpoint of light gray burns
• Avoid excessive density – space burns at least one burn width
apart
• Do not treat intraretinal hemorrhage or over preretinal
hemorrhage
• Consider treat large (>40 mm) microaneurysms that appear to
be principal causes of leakage focally to the ETDRS endpoint
of color change (either whitening or darkening)
• Apply grid treatment over areas of diffuse edema
• Optionally grid areas of nonperfusion seen on angiography
Adverse effects of macular laser treatment according to the
ETDRS protocol are remarkable few. The most feared
complication is accidental foveal photocoagulation, which may
occur from inopportune ocular movement or from surgeon
disorientation and error.131 This may produce immediate and
permanent visual acuity loss and a central scotoma. Closure of
microaneurysms in a very ischemic macula may contribute to
worsening of ischemia.123 Very severe laser burns, particularly if
they are small and well focused, may rupture Bruch’s membrane
and cause subretinal and vitreous bleeding. Late complications
from severe laser scars include choroidal neovascularization.
Subretinal fibrosis may occur associated with laser scars,
perhaps more commonly in patients with very severe DME.132
Very severe laser burns, particularly if applied over hemorrhage,
may also cause epiretinal proliferation with retinal traction.
Finally, a common observation is that laser scars tend to enlarge
over time due to a phenomenon termed ‘RPE creep’. The retinal
pigment epithelium (RPE) at the margins of macular laser scars
tends to atrophy over time, causing progressively enlarging
regions of RPE that may become confluent or may erode under
the fovea, causing photoreceptor dysfunction and vision loss.1,100
Because focal/grid macular laser treatment is not entirely
without risk, the ETDRS noted that for eyes with clinically
significant macular edema without center involvement,
observation for a period is acceptable management.100 In
particular, if a patient has fluid retention, management of the
systemic issues may occasionally benefit the patients DME and
forestall the need for laser treatment.34
Alternatives to ETDRS-style focal/grid macular photo-
coagulation have been evaluated in numerous studies. The
Diabetic Retinopathy Clinical Research Network (DRCR.net)
has evaluated a diffuse grid style of very mild burns compared
to standard of care focal/grid treatment, and found no advantage
to the former (DRCR Network Research Group, manuscript
submitted). Subthreshold burns with diode laser133 or green
laser134,135 have been employed to reduce the risk of perifoveal
scotoma and laser scarring.
Complicating any discussion of laser treatments alternative
to the ETDRS method is the fact that the underlying cause for
the treatment effect of laser is not well understood. Some
evidence for increased oxygen tension after laser suggests an
effect in downregulating VEGF production.136 Pigment epithelium
derived growth factor (PEDF) is a candidate inhibitor of vascular
permeability that has VEGF antagonist and antiinflammatory
properties,137 and is upregulated in RPE cells by laser treatment.138
OCT is more sensitive than clinical examination for
identifying subtle thickening of the foveal region.118,119 This
raises the question of what threshold of retinal thickening is
of sufficient risk to merit laser or any other treatment. The
findings of the ETDRS are based upon clinician-determined
identification of retinal thickening to guide treatment and
Diabetic Macular Edema
reading center interpretation of stereoscopic color photographs
for statistical analysis. Patients with edema detectable only on
OCT fall into a category that is unstudied in regard to risk of
vision loss and requirement for treatment. The DRCR.net is
currently enrolling subjects with subclinical DME, detected on
OCT but not on clinical examination, into a protocol for a
longitudinal cohort study (www.DRCRnet.org).
Complications: Potential Complications of Laser
Photocoagulation of DME
• Fovea burns
• Subretinal hemorrhage
• Vitreous hemorrhage
• Laser scar expansion over time
• Paracentral scotomas
• Subretinal fibrosis
• Choroidal neovascularization
CHAPTER 134
• Exacerbation of ischemia
• Migration of hard exudates into the fovea
VITRECTOMY SURGERY
A subset of patients with DME has coexistent epiretinal
membranes and/or partial posterior vitreous detachment with
retinal traction. These patients may benefit from pars plana
vitrectomy to address the mechanical issues contributing to
the retinal edema.139,102,140 Even without obvious retinal
traction, some clinicians believe that many cases of DME
respond to removal of the vitreous, with or without removal of
the internal limiting membrane.141 The rationale for this
approach is that there may be some subclinical traction from a
taut posterior vitreous face, or that the intact vitreous serves as
a reservoir for inflammatory macromolecules which promote
edema.81,142,143,144 No large randomized trials have evaluated
this treatment to date.
TRIAMCINOLONE ACETONIDE
The rationale for use of steroids to treat DME is compelling.88,145
As noted previously, the molecular biology of diabetic vascular
change includes leukostasis and other mechanisms of
inflammation, endothelial decompensation, and increased
levels of pro-inflammatory cytokines. Steroids may be useful to
treat DME because of antiinflammatory effects which include
decreased inflammatory cell activation and adhesion, and growth
factor signaling. Steroids also have a direct effect on the maturation
of interendothelial cell junctions and improved barrier properties.
Intravitreous injection of triamcinolone acetonide often has
a marked beneficial effect on retinal thickening in DME and
thus has sparked considerable interest and clinical use.
Numerous small studies have demonstrated robust anatomic
results, but often the visual results do not correlate well with
reduction in retinal thickening,124,146,147 probably because of the
aforementioned complicating factors for lack of vision recovery
with chronic DME. The duration of drug in the vitreous cavity
approximates the duration of clinical effect (2–3 months for a
4.0 mg injection of triamcinolone).147–151 Repeated injections
may be needed to maintain clinical benefit. The complications
of triamcinolone acetonide injection are well documented and
include endophthalmitis, elevated intraocular pressure
requiring topical therapy or even surgical intervention to
prevent vision loss,152–155 and cataract.156,157
A large randomized clinical trial of serial intravitreal
injections of triamcinolone has completed enrollment within
the DRCR.net, with results not yet available at this time. While
short-term effects of intravitreal triamcinolone are encouraging, 1801
 RETINA AND VITREOUS
a longer-term trial is essential to determining whether the
known risks of intravitreal injection of steroids are outweighed
by the ultimate clinical benefits.
Because the risks of intravitreal injection are relatively high,
there is high-clinical interest in evaluating the potential benefits
of peribulbar injection of high-dose triamcinolone acetonide.
The risks of cataract and intraocular pressure elevation are
somewhat less from peribulbar injection, but with repeated
injections there may be ptosis, orbital fat atrophy and
enophthalmos, and diplopia from extraocular muscle damage.
A 40 mg dose of triamcinolone in the orbit may produce
detectable serum levels and affect glycemic control in diabetic
patients. Small studies have suggested benefit in the treatment
of DME, although there is considerable variability in intraocular
penetration from peribulbar injection, and clearly intraocular
drug levels are lower than with direct intraocular admini-
stration.67,158 At this time, both peribulbar and intravitreous
triamcinolone steroids are widely employed clinically in the
SECTION 10
management of DME, but without a sufficient evidence base to
merit recommendation as standard therapy.
ANTI-VEGF THERAPY
Given the previous discussion of the importance of VEGF in
vascular permeability and its upregulation in diabetic retino-
pathy, the rationale for use of anti-VEGF drugs is clear. Current
specific anti-VEGF therapy is given intravitreal at frequent
intervals, which may temporarily blunt the effects of VEGF and
lessen macular edema. Unknown is whether treatment will
alter the underlying disease process (although it may cause at
least temporary regression of neovascularization).159,160 There-
fore, as the drug effect wears off, the underlying production of
VEGF appears to continue unabated and it is likely that long
term intravitreal therapy is required for management.161
Results from a phase II clinical trial of intravitreal injection
of pegaptanib (Macugen: Eyetech OSI) over 36 weeks
demonstrated beneficial effects,162 and a phase III trial is in
progress at this time. Median VA was better at week 36 with
0.3 mg/0.05 ml pegaptanib (20/50), as compared with sham
injection (20/63) (P = 0.04), and a larger proportion of patients
receiving pegaptanib had > or =15 letters of visual gain (18%
versus. 7%, P = 0.12). Mean central retinal thickness decreased
by 68 mm with 0.3 mg, versus an increase of 4 mm with sham
(P = 0.02). Pegaptanib is an engineered RNA fragment bearing
specific binding sites for the VEGF 165 isoform. It is currently
administered as an intravitreal injection at 6 week intervals.
Early phase clinical trials of ranabizumab (Lucentis: Genentech)
are in progress. Off label use of bevacizumab (Avastin: Genentech)
has been presented in small cohorts of patients with macular
edema from various causes,163,164 but no randomized trials of
DME have been reported. Ranabizumab and bevacizumab are
fusion proteins with a human antibody backbone and bind all
VEGF subtypes. Both of these drugs are given as intravitreal
injections, but the optimal delivery schedule and dosing level
have not been elucidated.
INHIBITION OF PROTEIN KINASE C
PKC is a family of intracellular signaling peptides that act as
intermediaries for growth factor and integrin signaling between
ligand binding and nuclear transcription. Broad inhibition of
PKC is highly toxic, however specific isoforms are upregulated
in response to particular stimuli. The PKCb isoform is specifically
upregulated in hyperglycemia in multiple tissues, including
vascular endothelial cells, and therefore is hypothesized to
mediate some of the myriad biochemical disturbances induced
1802 by chronic hyperglycemia.165 In animal models of diabetes, a
specific PKCb inhibitor, ruboxistaurin (Arxxant: Eli Lilly),
decreased abnormal vascular permeability and blood flow,82,83
and also inhibited angiogenesis in a nondiabetic retinal ischemia
model.85
Phase III clinical trials of oral administration of ruboxistaurin
have demonstrated efficacy in the prevention of sustained
moderate vision loss in diabetic patients with nonproliferative
DR.3 In a trial designed to test the effects of the study drug on
progression of diabetic retinopathy, it was found that
ruboxistaurin reduced the rate of sustained moderate vision loss
(loss of 15 or more letters for at least two consecutive study
visits) in eyes with definite diabetic macular edema at baseline
(10% 32 mg/day study drug versus 25% placebo, P = 0.017). A
separate study evaluated the ruboxistaurin specifically in regard
to the reduction of progression of retinal thickening from more
than 300 m to within 100 m of the center as measured in
stereoscopic fundus photographs. The 32 mg/day dose reduced
progression of DME compared to placebo (hazard ratio = 0.66
(95% CI 0.47–0.93P = 0.016) (PKC-DMES Study Group, manu-
script submitted). This product is currently under regulatory
review for the treatment of early diabetic macular edema.
Complications of local drug injection
• Intraocular steroids
• Endophthalmitis (rare) or sterile pseudoendophthalmitis
(rare)
• Intraocular pressure elevation (common, about 25%)
• Cataract (moderate frequency)
• Needle damage (retinal tears, lens damage, vitreous
hemorrhage)(rare)
• Injection site pain and bleeding (mild)
• Periocular Steroids
• Accidental globe penetration (rare)
• Orbital fat atrophy – enophthalmos (rare)
• Diplopia (rare)
• Ptosis (rare)
• Foreign body encapsulation (rare)
• Cataract (rare)
• Intraocular pressure elevation (common, not as common
as intraocular)
• Injection site pain and bleeding (mild)
• Anti-VEGF Product Intravitreal Injection
• Endophthalmitis (rare)
• Injection site pain and bleeding (mild)
• Needle damage to globe (tears, cataract, vitreous
hemorrhage) (rare)
SUMMARY AND FUTURE DIRECTIONS
The landscape of DME management is rapidly changing with
the advent of research advances leading to better understanding
of pathophysiologic mechanisms and discovery of potential
therapeutic compounds. There are several challenges that remain
in bringing forth new treatments with an adequate evidence
base to guide clinicians in timely patient care.
1. Diabetic retinopathy is a complicated disease. It is clear
that a number of altered cellular mechanisms work in
concert to bring about clinical complications. It is unclear
how impacting only one or a few of these pathways will
result in effective treatment, and it may be that a
combination approach will be necessary for management of
some cases.
2. Vascular leakage from hyperglycemia can be produced in
animal models, but there is no robust animal model of
DME, which limits the preclinical testing of potential new
treatments before clinical development.
 Diabetic Macular Edema

3. Diabetic retinopathy is a chronic disease: onset is gradual
over years, and treatment may be required indefinitely.
Consequently, clinical trials are large and lengthy, creating
huge financial burdens in bringing potential new
treatments to market, slowing their introduction and
adding to the costs, thereby creating barriers for patient care.
4. Visual acuity is an imprecise and subjective measure of visual
function, although it is highly relevant and clearly the best
test available. It correlates only modestly with advanced
DME, not at all with early (not center involved) DME.
5. The OCT has become the standard method for assessing
the status of the central macula in DME, but current
technology is of uncertain sensitivity for detection or
monitoring of edema that is not center-involved (for both
patient care and in clinical trials). Retinal thickness
measurement (on exam, in photos, or by OCT) correlates
only moderately with visual acuity, but remains the most
important variable for disease presence and progression.
Despite these caveats, research continues intensively
because the public health burden of DME and other
diabetic compli-cations is so great. This has led to the
current era of an array of treatments of uncertain benefit
and risk, and lack of clinician certainty as to how and
when to apply what treatments and in what combination,
if any. It will take years to sort out these issues, and in the
meantime, new treatments will be introduced which may
further complicate the decision making process for patient
and physician. Nevertheless, this is clearly a superior
situation over the converse, having no promising
treatments to offer. While clinical trials continue to work
toward testing new approaches, the results of the ETDRS
remains a solid foundation for clinicians to refer to when
faced with a difficult treatment decision.
The results of the DCCT/EDIC and UKPDS trials demonstrate
that DME and other complications can be prevented or delayed

There is, therefore, room for improvement in functional
and anatomic assessments of DME. Validation of other,
early functional assessments with disease outcome may
shorten the drug development timeline and result in
increased efficiency of clinical research.
CHAPTER 134
through excellent metabolic management, and this should
continue to be a major focus of conversation between physician
and patient at any phase of the disease. Early disease detection
and treatment are the next greatest priority, and all health care
providers need to work in concert to educate, screen and monitor
patients with diabetes and those at high risk for diabetes.

REFERENCES
1. Early Treatment Diabetic Retinopathy Study
Research Group: Treatment techniques and
clinical guidelines for photocoagulation of
diabetic macular edema. Early treatment
diabetic retinopathy study report number 2.
Ophthalmology 1987; 94:761–774.
2. Early Treatment Diabetic Retinopathy Study
Research Group. Photocoagulation for
diabetic macular edema. Early Treatment
Diabetic Retinopathy Study report number
1. Arch. Ophthalmol. 1985;
103:1796–1806.
3. PKC-DRS Study Group. The effect of
ruboxistaurin on visual loss in patients with
moderately severe to very severe
nonproliferative diabetic retinopathy: initial
results of the Protein Kinase C beta
Inhibitor Diabetic Retinopathy Study
(PKC-DRS) multicenter randomized clinical
trial. Diabetes. 2005; 54:2188–2197.
4. Klein R, Klein BE, Moss SE et al. The
Wisconsin epidemiologic study of diabetic
retinopathy. IV. Diabetic macular edema.
Ophthalmology. 1984;91:1464–1474
5. Klein R, Klein BE, Moss SE, Linton KL. The
Beaver Dam Eye Study. Retinopathy in
adults with newly discovered and
previously diagnosed diabetes mellitus.
Ophthalmology. 1992; 99:58–62.
6. Wong TY, Klein R, Islam FM et al. Diabetic
retinopathy in a multi-ethnic cohort in the
United States. Am. J. Ophthalmol. 2006;
141:446–455.
7. Roy MS, Klein R, O’Colmain BJ et al. The
prevalence of diabetic retinopathy among
adult type 1 diabetic persons in the United
States. Arch. Ophthalmol. 2004;
122:546–551.
8. Kempen JH, O’Colmain BJ, Leske MC et
al. The prevalence of diabetic retinopathy
among adults in the United States. Arch.
Ophthalmol. 2004; 122:552–563
9. Varma R, Torres M, Pena F et al.
Prevalence of diabetic retinopathy in adult
Latinos: the Los Angeles Latino eye study.
Ophthalmology. 2004; 111:1298–1306.
10. Lecaire T, Palta M, Zhang H et al. Lower-
than-Expected Prevalence and Severity of
Retinopathy in an Incident Cohort followed
during the First 4–14 Years of Type 1
Diabetes. Am. J. Epidemiol. 2006.
11. Cugati S, Kifley A, Mitchell P, Wang JJ.
Temporal trends in the age-specific
prevalence of diabetes and diabetic
retinopathy in older persons: Population-
based survey findings. Diabetes Res. Clin.
Pract. 2006.
12. Klein R, Klein BE, Moss SE, Cruickshanks
KJ. The Wisconsin Epidemiologic Study of
Diabetic Retinopathy. XV. The long-term
incidence of macular edema.
Ophthalmology. 1995; 102:7–16.
13. Early Treatment Diabetic Retinopathy Study
Research Group. Case reports to
accompany Early Treatment Diabetic
Retinopathy Study Reports 3 and 4. Int.
Ophthalmol. Clin. 1987; 27:273–333.
14. Early Treatment Diabetic Retinopathy Study
Research Group. Grading diabetic
retinopathy from stereoscopic color fundus
photographs—an extension of the modified
Airlie House classification. ETDRS report
number 10. Ophthalmology. 1991;
98:786–806.
15. Group. ETDRSR. Fundus photographic risk
factors for progression of diabetic
retinopathy. ETDRS report number 12.
Ophthalmology. 1991; 98:823–833.
16. The effect of intensive treatment of
diabetes on the development and
progression of long-term complications in
insulin-dependent diabetes mellitus. N.
Engl. J. Med. 1993; 329:977–986.
17. Retinopathy and nephropathy in patients
with type 1 diabetes four years after a trial
of intensive therapy. . N. Engl. J. Med.
2000; 342:381–389.
18. Writing Team for the Diabetes Control and
Complications Trial/Epidemiology of
Diabetes Interventions and Complications
Research Group. Effect of intensive therapy
on the microvascular complications of
type 1 diabetes mellitus. JAMA. 2002;
287:2563–2569.
19. UK Prospective Diabetes Study (UKPDS)
Group. Effect of intensive blood-glucose
control with metformin on complications in
overweight patients with type 2 diabetes
(UKPDS 34). Lancet. 1998; 352:854–865.
20. Klein R, Klein BE, Moss SE et al.
Glycosylated hemoglobin predicts the
incidence and progression of diabetic
retinopathy. JAMA. 1988; 260:2864–2871.
21. The absence of a glycemic threshold for
the development of long-term
complications: the perspective of the
Diabetes Control and Complications Trial.
Diabetes. 1996; 45:1289–1298.
22. Zander E, Herfurth S, Bohl B et al.
Maculopathy in patients with diabetes
mellitus type 1 and type 2: associations
with risk factors. Br. J. Ophthalmol. 2000;
84:871–876.
23. Klein R, Klein BE. Relation of glycemic
control to diabetic complications and
health outcomes. Diabetes Care. 1998;
21:C39–43.
24. Moss SE, Klein R, Klein BE. The 14–year
incidence of visual loss in a diabetic
population. Ophthalmology. 1998;
105:998–1003.
25. Balme M, McAllister I, Davis WA, Davis TM.
Retinopathy in latent autoimmune diabetes
of adults: the Fremantle Diabetes Study.
Diabet. Med. 2002; 19:602–605.
26. Wong TY, Mohamed Q, Klein R, Couper DJ.
Do retinopathy signs in non-diabetic
individuals predict the subsequent risk of
diabetes? Br. J. Ophthalmol. 2006;
90:301–303.
27. Kohner EM, Aldington SJ, Stratton IM et al.
United Kingdom Prospective Diabetes
Study, 30: diabetic retinopathy at diagnosis
of non-insulin-dependent diabetes mellitus
and associated risk factors. Arch.
Ophthalmol. 1998; 116:297–303.
28. Newcomb PA, Klein R, Massoth KM.
Education to increase ophthalmologic care 1803
 RETINA AND VITREOUS
in older onset diabetes patients: indications
from the Wisconsin Epidemiologic Study of
Diabetic Retinopathy. J. Diabetes
Complications. 1992; 6:211–217.
29. Klein R. Prevention of visual loss from
diabetic retinopathy. Surv. Ophthalmol.
2002; 47 Suppl 2:S246–252.
30. Harris MI, Klein R, Welborn TA, Knuiman
MW. Onset of NIDDM occurs at least 4–7
yr before clinical diagnosis. Diabetes Care.
1992; 15:815–819.
31. Klein R, Klein BE, Moss SE, Cruickshanks
KJ. The Wisconsin Epidemiologic Study of
Diabetic Retinopathy: XVII. The 14–year
incidence and progression of diabetic
retinopathy and associated risk factors in
type 1 diabetes. Ophthalmology. 1988;
105:1801–1815.
32. Effect of pregnancy on microvascular
complications in the diabetes control and
complications trial. The Diabetes Control
SECTION 10
and Complications Trial Research Group.
Diabetes Care. 2000; 23:1084–1091.
33. Matthews DR, Stratton IM, Aldington SJ et
al. Risks of progression of retinopathy and
vision loss related to tight blood pressure
control in type 2 diabetes mellitus: UKPDS
69. Arch. Ophthalmol. 2004; 122:1631–1640.
34. Bresnick GH. Diabetic macular edema. A
review. Ophthalmology. 1986; 93:989–997.
35. Sjolie AK, Porta M, Parving HH et al. The
DIabetic REtinopathy Candesartan Trials
(DIRECT) Programme: baseline
characteristics. J Renin Angiotensin
Aldosterone Syst. 2005; 6:25–32.
36. Klein R, Zinman B, Gardiner R et al. The
relationship of diabetic retinopathy to
preclinical diabetic glomerulopathy lesions
in type 1 diabetic patients: the
Renin-Angiotensin System Study. Diabetes.
2005; 54:527–533.
37. Agardh CD, Agardh E, Torffvit O. The
association between retinopathy,
nephropathy, cardiovascular disease and
long-term metabolic control in type 1
diabetes mellitus: a 5 year follow-up study
of 442 adult patients in routine care.
Diabetes Res. Clin. Pract. 1997;
35:113–121.
38. Bresnick GH. Diabetic maculopathy. A
critical review highlighting diffuse macular
edema. Ophthalmology. 1983;
90:1301–1317.
39. Tokuyama T, Ikeda T, Sato K. Effects of
haemodialysis on diabetic macular leakage.
Br. J. Ophthalmol. 2000; 84:1397–1400.
40. Watanabe Y, Yuzawa Y, Mizumoto D et al.
Long-term follow-up study of 268 diabetic
patients undergoing haemodialysis, with
special attention to visual acuity and
heterogeneity. Nephrol. Dial. Transplant.
1993; 8:725–734.
41. Roy MS, Klein R. Macular edema and
retinal hard exudates in African Americans
with type 1 diabetes: the New Jersey 725.
Arch. Ophthalmol. 2001; 119:251–259.
42. Miljanovic B, Glynn RJ, Nathan DM et al. A
prospective study of serum lipids and risk
of diabetic macular edema in type 1
diabetes. Diabetes. 2004; 53:2883–2892.
43. Effects of intensive diabetes therapy on
neuropsychological function in adults in the
Diabetes Control and Complications Trial.
The DCCT Research Group. Ann. Intern.
Med. 1996; 124:379–388.
44. Ferris FL, 3rd, Chew EY, Hoogwerf BJ,
Early Treatment Diabetic Retinopathy Study
1804 Research Group. Serum lipids and diabetic
retinopathy. Diabetes Care. 1996;
19:1291–1293.
45. Klein R, Klein BE, Moss SE, Surawicz TS.
The Wisconsin Epidemiologic Study of
Diabetic Retinopathy. XIII. Relationship of
serum cholesterol to retinopathy and hard
exudate. Ophthalmology. 1991;
98:1261–1265.
46. Klein R, Sharrett AR, Klein BE et al. The
association of atherosclerosis, vascular risk
factors, and retinopathy in adults with
diabetes : the atherosclerosis risk in
communities study. Ophthalmology. 2002;
109:1225–1234.
47. Davis MD, Fisher MR, Gangnon RE et al.
Risk factors for high-risk proliferative
diabetic retinopathy and severe visual loss:
Early Treatment Diabetic Retinopathy Study
Report #18. Invest. Ophthalmol. Vis. Sci.
1998; 39:233–252.
48. Chew EY, Klein ML, Ferris FLr et al.
Association of elevated serum lipid levels
with retinal hard exudate in diabetic
retinopathy. Early Treatment Diabetic
Retinopathy Study (ETDRS) Report 22.
Arch. Ophthalmol. 1996; 114:1079–1084.
49. Jenkins AJ, Lyons TJ, Zheng D et al.
Serum lipoproteins in the diabetes control
and complications trial/epidemiology of
diabetes intervention and complications
cohort: associations with gender and
glycemia. Diabetes Care. 2003;
26:810–818.
50. Klein RL, McHenry MB, Lok KH et al.
Apolipoprotein C-III protein concentrations
and gene polymorphisms in Type 1
diabetes: associations with microvascular
disease complications in the DCCT/EDIC
cohort. J. Diabetes Complications. 2005;
19:18–25.
51. Lyons TJ, Jenkins AJ, Zheng D et al.
Diabetic retinopathy and serum lipoprotein
subclasses in the DCCT/EDIC cohort.
Invest. Ophthalmol. Vis. Sci. 2004;
45:910–918.
52. Klein BE, Moss SE, Klein R. Effect of
pregnancy on progression of diabetic
retinopathy. Diabetes Care. 1990;
13:34–40.
53. Temple RC, Aldridge VA, Sampson MJ et
al. Impact of pregnancy on the progression
of diabetic retinopathy in Type 1 diabetes.
Diabet. Med. 2001; 18:573–577.
54. Lovestam-Adrian M, Agardh CD, Aberg A,
Agardh E. Pre-eclampsia is a potent risk
factor for deterioration of retinopathy
during pregnancy in Type 1 diabetic
patients. Diabet. Med. 1997;
14:1059–1065.
55. Axer-Siegel R, Hod M, Fink-Cohen S et al.
Diabetic retinopathy during pregnancy.
Ophthalmology. 1996; 103:1815–1819.
56. Sinclair SH, Nesler C, Foxman B et al.
Macular edema and pregnancy in
insulin-dependent diabetes. Am. J.
Ophthalmol. 1984; 97:154–167.
57. Chew EY, Mills JL, Metzger BE et al.
Metabolic control and progression of
retinopathy. The Diabetes in Early
Pregnancy Study. National Institute of Child
Health and Human Development Diabetes
in Early Pregnancy Study. Diabetes Care.
1995; 18:631–637.
58. Phelps RL, Sakol P, Metzger BE et al.
Changes in diabetic retinopathy during
pregnancy. Correlations with regulation of
hyperglycemia. Arch. Ophthalmol. 1986;
104:1806–1810.
59. Hellstedt T, Kaaja R, Teramo K, Immonen I.
The effect of pregnancy on mild diabetic
retinopathy. Graefes Arch. Clin. Exp.
Ophthalmol. 1997; 235:437–441.
60. Davis MD. Worsening of diabetic
retinopathy after improvement of glycemic
control. Arch. Ophthalmol. 1998;
116:931–932.
61. Patel JI, Hykin PG, Cree IA. Diabetic
cataract removal: postoperative
progression of maculopathy—growth factor
and clinical analysis. Br. J. Ophthalmol.
2006; 90:697–701.
62. Krepler K, Biowski R, Schrey S et al.
Cataract surgery in patients with diabetic
retinopathy: visual outcome, progression of
diabetic retinopathy, and incidence of
diabetic macular oedema. Graefes Arch.
Clin. Exp. Ophthalmol. 2002; 240:735–738.
63. Squirrell D, Bhola R, Bush J et al. A
prospective, case controlled study of the
natural history of diabetic retinopathy and
maculopathy after uncomplicated
phacoemulsification cataract surgery in
patients with type 2 diabetes.
Br. J. Ophthalmol. 2002; 86:565–571.
64. Menchini U, Cappelli S, Virgili G. Cataract
surgery and diabetic retinopathy. Semin.
Ophthalmol. 2003; 18:103–108.
65. Ferris FLr, Podgor MJ, Davis MD. Macular
edema in Diabetic Retinopathy Study
patients. Diabetic Retinopathy Study
Report Number 12. Ophthalmology. 1987;
94:754–760.
66. Shimura M, Yasuda K, Nakazawa T et al.
Quantifying alterations of macular thickness
before and after panretinal
photocoagulation in patients with severe
diabetic retinopathy and good vision.
Ophthalmology. 2003; 110:2386–2394.
67. Wilson CA, Berkowitz BA, Sato Y et al.
Treatment with intravitreal steroid reduces
blood-retinal barrier breakdown due to
retinal photocoagulation. Arch. Ophthalmol.
1992; 110:1155–1159.
68. Zein WM, Noureddin BN, Jurdi FA et al.
Panretinal photocoagulation and intravitreal
triamcinolone acetonide for the
management of proliferative diabetic
retinopathy with macular edema. Retina.
2006; 26:137–142.
69. Cogan DG, Kuwabara T. The mural cell in
perspective. Arch. Ophthalmol. 1967;
78:133–139.
70. Kuwabara T, Cogan DG. Retinal vascular
patterns. VII. Acellular change. Invest.
Ophthalmol. 1965; 4:1049–1064.
71. King GL, Shiba T, Oliver J et al. Cellular
and molecular abnormalities in the vascular
endothelium of diabetes mellitus. Annu.
Rev. Med. 1994; 45:179–188.
72. Gardner TW, Antonetti DA, Barber AJ et al.
Diabetic retinopathy: more than meets the
eye. Surv. Ophthalmol. 2002; 47 Suppl
2:S253–262.
73. Feit-Leichman RA, Kinouchi R, Takeda M et
al. Vascular damage in a mouse model of
diabetic retinopathy: relation to neuronal
and glial changes. Invest. Ophthalmol. Vis.
Sci. 2005; 46:4281–4287.
74. Harhaj NS, Antonetti DA. Regulation of
tight junctions and loss of barrier function
in pathophysiology. Int. J. Biochem. Cell
Biol. 2004; 36:1206–1237.
75. Vinores SA, Derevjanik NL, Ozaki H et al.
Cellular mechanisms of blood-retinal barrier
dysfunction in macular edema. Doc.
Ophthalmol. 1999; 97:217–228.

76. Bursell SE, Delori FC, Yoshida A et al.
Vitreous fluorophotometric evaluation of
diabetics. Invest. Ophthalmol. Vis. Sci.
1984; 25:703–710.
77. Ferrara N. Role of vascular endothelial
growth factor in regulation of physiological
angiogenesis. Am J Physiol Cell Physiol.
2001; 280:C1358–1366.
78. Adamis AP, Shima DT, Tolentino MJ et al.
Inhibition of vascular endothelial growth
factor prevents retinal ischemia-associated
iris neovascularization in a nonhuman
primate. Arch. Ophthalmol. 1996;
114:66–71.
79. Suarez S, Ballmer-Hofer K. VEGF
transiently disrupts gap junctional
communication in endothelial cells. J. Cell
Sci. 2001; 114:1229–1235.
80. Antonetti DA, Barber AJ, Hollinger LA et al.
Vascular endothelial growth factor induces
rapid phosphorylation of tight junction
proteins occludin and zonula occluden 1.
A potential mechanism for vascular
permeability in diabetic retinopathy and
tumors. J. Biol. Chem. 1999;
274:23463–23467.
81. Patel JI, Tombran-Tink J, Hykin PG et al.
Vitreous and aqueous concentrations of
proangiogenic, antiangiogenic factors and
other cytokines in diabetic retinopathy
patients with macular edema: Implications
for structural differences in macular
profiles. Exp. Eye Res. 2006; 82:798–806.
82. Ishii H, Jirousek MR, Koya D et al.
Amelioration of vascular dysfunctions in
diabetic rats by an oral PKC beta inhibitor.
Science. 1996; 272:728–731.
83. Aiello LP, Bursell SE, Clermont A et al.
Vascular endothelial growth factor-induced
retinal permeability is mediated by protein
kinase C in vivo and suppressed by an
orally effective beta-isoform-selective
inhibitor. Diabetes. 1997; 46:1473–1480.
84. Miyamoto K, Khosrof S, Bursell SE et al.
Prevention of leukostasis and vascular
leakage in streptozotocin-induced diabetic
retinopathy via intercellular adhesion
molecule-1 inhibition. Proc. Natl. Acad. Sci.
U. S. A. 1999; 96:10836–10841.
85. Danis RP, Bingaman DP, Jirousek M, Yang
Y. Inhibition of intraocular
neovascularization caused by retinal
ischemia in pigs by PKCbeta inhibition with
LY333531. Invest. Ophthalmol. Vis. Sci.
1998; 39:171–179.
86. Pachydaki SI, Tari SR, Lee SE et al.
Upregulation of RAGE and its ligands in
proliferative retinal disease. Exp. Eye Res.
2006; 82:807–815.
87. Joussen AM, Poulaki V, Le ML et al. A
central role for inflammation in the
pathogenesis of diabetic retinopathy.
FASEB J. 2004; 18:1450–1452.
88. Ip MS. Intravitreal injection of
triamcinolone: an emerging treatment for
diabetic macular edema. Diabetes Care.
2004; 27:1794–1797.
89. Martidis A, Duker JS, Greenberg PB et al.
Intravitreal triamcinolone for refractory
diabetic macular edema. Ophthalmology.
2002; 109:920–927.
90. Felinski EA, Antonetti DA. Glucocorticoid
regulation of endothelial cell tight junction
gene expression: novel treatments for
diabetic retinopathy. Curr. Eye Res. 2005;
30:949–957.
91. Yanoff M, Fine BS, Brucker AJ, Eagle RC,
Jr. Pathology of human cystoid macular
edema. Surv. Ophthalmol. 1984; 28
Suppl:505–511.
92. Kincaid MC, Green WR, Fine SL et al. An
ocular clinicopathologic correlative study of
six patients from the Diabetic Retinopathy
Study. Retina. 1983; 3:218–238.
93. Antcliff RJ, Marshall J. The pathogenesis of
edema in diabetic maculopathy. Semin.
Ophthalmol. 1999; 14:223–232.
94. Fluorescein angiographic risk factors for
progression of diabetic retinopathy. ETDRS
report number 13. Ophthalmology. 1991;
98:834–840.
95. Catier A, Tadayoni R, Paques M et al.
Characterization of macular edema from
various etiologies by optical coherence
tomography. Am. J. Ophthalmol. 2005;
140:200–206.
96. Panozzo G, Parolini B, Gusson E et al.
Diabetic macular edema: an OCT-based
classification. Semin. Ophthalmol. 2004;
19:13–20.
97. Ferris FL, 3rd, Patz A. Macular edema. A
complication of diabetic retinopathy. Surv.
Ophthalmol. 1984; 28 Suppl:452–461.
98. Yanko L, Ungar H, Michaelson IC. The
exudative lesions in diabetic retinopathy
with special regard to the hard exudate.
Acta Ophthalmol. (Copenh). 1974;
52:150–160.
99. Patz A, Fine SL. Diabetic macular edema.
Int. Ophthalmol. Clin. 1976; 16:105–113.
100. Early Treatment Diabetic Retinopathy Study
Research Group. Focal photocoagulation
treatment of diabetic macular edema.
Relationship of treatment effect to
fluorescein angiographic and other retinal
characteristics at baseline: ETDRS report
no. 19. Arch. Ophthalmol. 1995;
113:1144–1155.
101. Chester EM, Banker BQ. The role of lipid
thrombi in the pathogenesis of diabetic
retinopathy. Arch. Intern. Med. 1967;
120:397–407.
102. Johnson MW. Tractional cystoid macular
edema: a subtle variant of the
vitreomacular traction syndrome. Am.
J. Ophthalmol. 2005; 140:184–192.
103. Gaucher D, Tadayoni R, Erginay A et al.
Optical coherence tomography assessment
of the vitreoretinal relationship in diabetic
macular edema. Am. J. Ophthalmol. 2005;
139:807–813.
104. Fong DS, Barton FB, Bresnick GH.
Impaired color vision associated with
diabetic retinopathy: Early Treatment
Diabetic Retinopathy Study Report No. 15.
Am. J. Ophthalmol. 1999; 128:612–617.
105. Frank RN, Schulz L, Abe K, Iezzi R.
Temporal variation in diabetic macular
edema measured by optical coherence
tomography. Ophthalmology. 2004;
111:211–217.
106. Sternberg P, Jr., Fitzke F, Finkelstein D.
Cyclic macular edema. Am. J. Ophthalmol.
1982; 94:664–669.
107. Larsen M, Wang M, Sander B. Overnight
thickness variation in diabetic macular
edema. Invest. Ophthalmol. Vis. Sci. 2005;
46:2313–2316.
108. Polito A, Del Borrello M, Polini G et al.
Diurnal variation in clinically significant
diabetic macular edema measured by the
Stratus OCT. Retina. 2006; 26:14–20.
109. Danis RP, Glassman AR, Aiello LP et al.
Diurnal variation in retinal thickening
measurement by optical coherence
tomography in center-involved diabetic
Diabetic Macular Edema
macular edema. Arch. Ophthalmol. 2006;
124:1701–1707.
110. Fransen SR, Leonard-Martin TC, Feuer WJ,
Hildebrand PL. Clinical evaluation of
patients with diabetic retinopathy: accuracy
of the Inoveon diabetic retinopathy-3DT
system. Ophthalmology. 2002;
109:595–601.
111. Kinyoun J, Barton F, Fisher M et al.
Detection of diabetic macular edema.
Ophthalmoscopy versus photography—
Early Treatment Diabetic Retinopathy Study
Report Number 5. Ophthalmology. 1989;
96:746–750, discussion 750–741.
112. Classification of diabetic retinopathy from
fluorescein angiograms. ETDRS report
number 11. Ophthalmology. 1991;
98:807–822.
113. Hee MR, Puliafito CA, Duker JS et al.
Topography of diabetic macular edema
CHAPTER 134
with optical coherence tomography.
Ophthalmology. 1998; 105:360–370.
114. Diabetic Retinopathy Clinical Research
Network. Reproducibility of macular
thickness and volume using Zeiss optical
coherence tomography in patients with
diabetic macular edema. Submitted.
115. Browning DJ. Interobserver variability in
optical coherence tomography for macular
edema. Am. J. Ophthalmol. 2004;
137:1116–1117.
116. Polito A, Del Borrello M, Isola M et al.
Repeatability and reproducibility of fast
macular thickness mapping with stratus
optical coherence tomography. Arch.
Ophthalmol. 2005; 123:1330–1337.
117. Sadda SR, Wu Z, Walsh AC et al. Errors in
retinal thickness measurements obtained
by optical coherence tomography.
Ophthalmology. 2006; 113:285–293.
118. Brown JC, Solomon SD, Bressler SB et al.
Detection of diabetic foveal edema: contact
lens biomicroscopy compared with optical
coherence tomography. Arch. Ophthalmol.
2004; 122:330–335.
119. Browning DJ, McOwen MD, Bowen RM,
Jr., O’Marah TL. Comparison of the clinical
diagnosis of diabetic macular edema with
diagnosis by optical coherence
tomography. Ophthalmology. 2004;
111:712–715.
120. Strom C, Sander B, Larsen N et al. Diabetic
macular edema assessed with optical
coherence tomography and stereo fundus
photography. Invest. Ophthalmol. Vis. Sci.
2002; 43:241–245.
121. DRCR.net. Comparison of the modified
Early Treatment Diabetic Retinopathy and
mild macuilar grid laser strategies for
diabetic macular edema. Arch Ophthalmol.
2007; 114:525–536.
122. Kang SW, Park CY, Ham DI. The correlation
between fluorescein angiographic and
optical coherence tomographic features in
clinically significant diabetic macular
edema. Am. J. Ophthalmol. 2004;
137:313–322.
123. Diabetes Control and Complications Trial
(DCCT): results of feasibility study. The
DCCT Research Group. Diabetes Care.
1987; 10:1–19.
124. Massin P, Audren F, Haouchine B et al.
Intravitreal triamcinolone acetonide for
diabetic diffuse macular edema: preliminary
results of a prospective controlled trial.
Ophthalmology. 2004; 111:218–224.
125. Abraham FA, Haimovitz J, Berezin M. The
photopic and scotopic visual thresholds in 1805
 RETINA AND VITREOUS
diabetics without diabetic retinopathy.
Metab. Pediatr. Syst. Ophthalmol. 1988;
11:76–77.
126. Brinchmann-Hansen O, Dahl-Jorgensen K,
Hanssen KF, Sandvik L. Oscillatory
potentials, macular recovery time, and
diabetic retinopathy through 3 years of
intensified insulin treatment.
Ophthalmology. 1988; 95:1358–1366.
127. Han Y, Adams AJ, Bearse MA, Jr., Schneck
ME. Multifocal electroretinogram and short-
wavelength automated perimetry measures
in diabetic eyes with little or no retinopathy.
Arch. Ophthalmol. 2004; 122:1809–1815.
128. Bearse MA, Jr., Han Y, Schneck ME,
Adams AJ. Retinal function in normal and
diabetic eyes mapped with the slow flash
multifocal electroretinogram. Invest.
Ophthalmol. Vis. Sci. 2004; 45:296–304.
129. Bengtsson B, Heijl A, Agardh E. Visual
fields correlate better than visual acuity to
SECTION 10
severity of diabetic retinopathy.
Diabetologia. 2005; 48:2494–2500.
130. Agardh E, Stjernquist H, Heijl A, Bengtsson
B. Visual acuity and perimetry as measures
of visual function in diabetic macular
oedema. Diabetologia. 2006; 49:200–206.
131. Ishiko S, Ogasawara H, Yoshida A, Hanada
K. The use of scanning laser
ophthalmoscope microperimetry to detect
visual impairment caused by macular
photocoagulation. Ophthalmic Surg.
Lasers. 1998; 29:95–98.
132. Fong DS, Segal PP, Myers F et al.
Subretinal fibrosis in diabetic macular
edema. ETDRS report 23. Early Treatment
Diabetic Retinopathy Study Research
Group. Arch. Ophthalmol. 1997;
115:873–877.
133. Akduman L, Olk RJ. Subthreshold
(invisible) modified grid diode laser
photocoagulation in diffuse diabetic
macular edema (DDME). Ophthalmic Surg.
Lasers. 1999; 30:706–714.
134. Bandello F, Polito A, Del Borrello M et al.
“Light” versus “classic” laser treatment for
clinically significant diabetic macular
oedema. Br. J. Ophthalmol. 2005;
89:864–870.
135. Sinclair SH, Alaniz R, Presti P. Laser
treatment of diabetic macular edema:
comparison of ETDRS-level treatment with
threshold-level treatment by using high-
contrast discriminant central visual field
testing. Semin. Ophthalmol. 1999;
14:214–222.
136. Pournaras CJ. Retinal oxygen distribution.
Its role in the physiopathology of
vasoproliferative microangiopathies. Retina.
1995; 15:332–347.
137. Zhang SX, Wang JJ, Gao G et al. Pigment
epithelium-derived factor (PEDF) is an
endogenous antiinflammatory factor.
FASEB J. 2006; 20:323–325.
138. Ogata N, Tombran-Tink J, Jo N et al.
Upregulation of pigment epithelium-derived
factor after laser photocoagulation. Am. J.
Ophthalmol. 2001; 132:427–429.
1806
139. Lewis H, Abrams GW, Blumenkranz MS,
Campo RV. Vitrectomy for diabetic macular
traction and edema associated with
posterior hyaloidal traction. Ophthalmology.
1992; 99:753–759.
140. Yanyali A, Nohutcu AF, Horozoglu F, Celik
E. Modified grid laser photocoagulation
versus pars plana vitrectomy with internal
limiting membrane removal in diabetic
macular edema. Am. J. Ophthalmol. 2005;
139:795–801.
141. Stefansson E, Landers MB, 3rd. How does
vitrectomy affect diabetic macular edema?
Am. J. Ophthalmol. 2006; 141:984; author
reply 984–985.
142. La Heij EC, Hendrikse F, Kessels AG,
Derhaag PJ. Vitrectomy results in diabetic
macular oedema without evident
vitreomacular traction. Graefes Arch. Clin.
Exp. Ophthalmol. 2001; 239:264–270.
143. Stolba U, Binder S, Gruber D et al.
Vitrectomy for persistent diffuse diabetic
macular edema. Am. J. Ophthalmol. 2005;
140:295–301.
144. Ouchi M, West K, Crabb JW et al.
Proteomic analysis of vitreous from
diabetic macular edema. Exp. Eye Res.
2005; 81:176–182.
145. Flynn HWJ, Scott IU. Intravitreal
triamcinolone acetonide for macular edema
associated with diabetic retinopathy and
venous occlusive disease: it’s time for
clinical trials. Arch. Ophthalmol. 2005;
123:258–259.
146. Tewari HK, Sony P, Chawla R et al.
Prospective evaluation of intravitreal
triamcinolone acetonide injection in
macular edema associated with retinal
vascular disorders. Eur. J. Ophthalmol.
2005; 15:619–626.
147. Patelli F, Fasolino G, Radice P et al. Time
course of changes in retinal thickness and
visual acuity after intravitreal triamcinolone
acetonide for diffuse diabetic macular
edema with and without previous macular
laser treatment. Retina. 2005; 25:840–845.
148. Schindler RH, Chandler D, Thresher R,
Machemer R. The clearance of intravitreal
triamcinolone acetonide. Am.
J. Ophthalmol. 1982; 93:415–417.
149. Tano Y, Chandler D, Machemer R.
Treatment of intraocular proliferation with
intravitreal injection of triamcinolone
acetonide. Am. J. Ophthalmol. 1980;
90:810–816.
150. Scholes GN, O’Brien WJ, Abrams GW,
Kubicek MF. Clearance of triamcinolone
from vitreous. Arch. Ophthalmol. 1985;
103:1567–1569.
151. Bakri SJ, Beer PM. Intravitreal
triamcinolone injection for diabetic macular
edema: a clinical and fluorescein
angiographic case series. Can. J.
Ophthalmol. 2004; 39:755–760.
152. Smithen LM, Ober MD, Maranan L, Spaide
RF. Intravitreal triamcinolone acetonide and
intraocular pressure. Am. J. Ophthalmol.
2004; 138:740–743.
153. Jonas JB, Degenring RF, Kreissig I et al.
Intraocular pressure elevation after
intravitreal triamcinolone acetonide
injection. Ophthalmology. 2005;
112:593–598.
154. Bakri SJ, Beer PM. The effect of intravitreal
triamcinolone acetonide on intraocular
pressure. Ophthalmic Surg Lasers Imaging.
2003; 34:386–390.
155. Wingate RJ, Beaumont PE. Intravitreal
triamcinolone and elevated intraocular
pressure. Aust. N. Z. J. Ophthalmol. 1999;
27:431–432.
156. Challa JK, Gillies MC, Penfold PL et al.
Exudative macular degeneration and
intravitreal triamcinolone: 18 month follow
up. Aust. N. Z. J. Ophthalmol. 1998;
26:277–281.
157. Thompson JT. Cataract formation and
other complications of intravitreal
triamcinolone for macular edema. Am.
J. Ophthalmol. 2006; 141:629–637.
158. Cardillo JA, Melo LA, Jr., Costa RA et al.
Comparison of intravitreal versus posterior
sub-Tenon’s capsule injection of
triamcinolone acetonide for diffuse diabetic
macular edema. Ophthalmology. 2005;
112:1557–1563.
159. Avery RL. Regression of retinal and iris
neovascularization after intravitreal
bevacizumab (Avastin) treatment. Retina.
2006; 26:352–354.
160. Spaide RF, Fisher YL. Intravitreal
bevacizumab (Avastin) treatment of
proliferative diabetic retinopathy
complicated by vitreous hemorrhage.
Retina. 2006; 26:275–278.
161. Rosenfeld PJ, Fung AE, Puliafito CA.
Optical coherence tomography findings
after an intravitreal injection of
bevacizumab (avastin) for macular edema
from central retinal vein occlusion.
Ophthalmic Surg Lasers Imaging. 2005;
36:336–339.
162. Cunningham ET, Jr., Adamis AP, Altaweel M
et al. A phase II randomized
double-masked trial of pegaptanib, an
anti-vascular endothelial growth factor
aptamer, for diabetic macular edema.
Ophthalmology. 2005; 112:1747–1757.
163. Iturralde D, Spaide RF, Meyerle CB et al.
Intravitreal bevacizumab (Avastin) treatment
of macular edema in central retinal vein
occlusion: a short-term study. Retina. 2006;
26:279–284.
164. Mason JO, 3rd, Albert MA, Jr., Vail R.
Intravitreal bevacizumab (Avastin) for
refractory pseudophakic cystoid macular
edema. Retina. 2006; 26:356–357.
165. Aiello LP. The potential role of PKC beta in
diabetic retinopathy and macular edema.
Surv. Ophthalmol. 2002; 47 Suppl
2:S263–269.
 CHAPTER
135 Proliferative Diabetic Retinopathy
Jennifer K. Sun, Joan W. Miller, and Lloyd P. Aiello
INTRODUCTION AND DEFINITION
With the introduction of insulin in the 1930s, diabetes mellitus
rapidly ceased to be a fatal disease of young people, with coma
as a cause of death falling from 60–4%.1 The medical care
of diabetic patients instead shifted to the management of vas-
cular complications, including cardiac disease, renal failure, and
diabetic retinopathy. In the 1970s, it was well demonstrated
that laser photocoagulation could substantially reduce visual
loss and blindness from diabetic retinopathy.2,3 Advances in
vitreoretinal surgery have made a further impact on severe
proliferative diabetic retinopathy (PDR). Even so, diabetic eye
disease remains a severe medical and social problem afflicting
individuals during their productive years. The prevalence of
diabetes and its associated micro and macrovascular compli-
cations is steadily increasing. Currently, at least 177 million
people suffer from diabetes worldwide. It is estimated that
by the year 2030, this number will increase to approximately
370 million individuals.3a Diabetic retinopathy is responsible for
at least 12% of the new cases of blindness each year in the United
States.4 In the United States alone approximately 700 000 persons
have PDR. The health care costs of retinopathy-associated dis-
orders exceeds $620 million in the US each year.4a
PDR is characterized by new vessels arising from the surface
of the retina. New vessels may grow from the vessels on the
surface of the optic disk (neovascularization at the disk (NVD)).
They may also originate from the retinal vascular arcades else-
where (neovascularization elsewhere in the retina (NVE)) and
grow along the partially detached posterior hyaloid, also termed
the ‘posterior vitreous face’ (Fig. 135.1). Fibroblasts and glial
elements accompany the new vessels, and proliferation of this
fibroglial tissue can become the predominant feature of the
retinopathy. PDR also includes rubeosis iridis or new vessels on
the surface of the iris or in the anterior chamber angle.
a b
PATHOGENESIS
Early functional changes have been observed in diabetes,
including alterations in retinal blood flow4b and a breakdown in
the blood–retinal barrier, which is demonstrated by increased
leakage from retinal blood vessels measured by vitreous fluoro-
photometry.5–7 Recent evidence suggests that angiogenic factors
may play a role in these early changes as well.8,9 Morphologic
changes in nonproliferative diabetic eye disease include micro-
aneurysms, blot and dot hemorrhages, cotton-wool spots, venous
caliber abnormalities, intraretinal microvascular abnormalities
(IRMAs), hard exudates, and macular edema. Microaneurysms
appear in clusters and surround areas of capillary closure.
IRMAs are also found adjacent to areas of capillary closure.
Controversy has existed as to whether IRMAs represented
dilated and abnormal retinal capillaries or early intraretinal
neovascularization.6 However, recent evidence has demon-
strated the continuity of intraretinal microvascular changes and
preretinal neovascularization.10 In a retrospective study of serial
photographs of NVE, Chang and associates found that NVE
originated at the same location as an earlier IRMA in 40 of
57 locations (70.2%), and the average time span between the
appearance of IRMA and that of NVE was 3 years.11
As more advanced retinopathy develops, retinal neovascu-
larization occurs. NVE develops from retinal vessels and tends
to appear adjacent to regions of nonperfusion. NVD originates
from vessels on the disk and appears coincident with significant
areas of nonperfusion in the midperiphery. The exact patho-
genesis of retinal neovascularization remains to be elucidated.
Retinal neovascularization is not a response limited to diabetes
but is probably a programmed response to retinal ischemia. In
1948, Michaelson hypothesized that a diffusible factor was
released from ischemic retina that stimulated the development
of embryonic vasculature.12 Ashton proposed that oxygen
FIGURE 135.1. Proliferative diabetic
retinopathy (PDR). (a) Neovascularization at the
disk (NVD) a fan-shaped configuration of new
vessels branching out from the optic nerve
head. Additional findings include extensive
vascular caliber changes, intraretinal
hemorrhages and microaneurysms and cotton
wool spots. (b), Neovascularization elsewhere
in the retina (NVE) new vessels along the
superotemporal arcade with associated
preretinal hemorrhage.
1807
 RETINA AND VITREOUS
a b
SECTION 10
c d
deprivation stimulated the production of an angiogenic factor
in both development and retinopathy of prematurity.13 Wise
expanded the idea of an angiogenic factor to explain a number
of adult retinopathies, including diabetic retinopathy, and
the clinical correlation of retinal ischemia and retinal
neovascularization has been well established.2,14–16 These
angiogenic factors are released from ischemic retina and
stimulate new vessel growth from susceptible vessels both
locally and at distant locations in the eye (Fig. 135.2).
Angiogenic factors have been isolated from ocular and other
tissues and studied in clinical specimens and experimental
models of neovascularization. Whereas the number of known
angiogenic factors continues to increase, growth factors and
signaling molecules that appear to have particular relevance
to diabetic retinopathy include basic fibroblast growth factor
(bFGF), insulin-like growth factor (IGF), vascular endothelial
growth factor (VEGF), and the beta isoform of protein
kinase c (PKC).
bFGF is the best characterized of the fibroblast growth factors
(FGFs) and the one-most strongly implicated in the angiogenic
process. bFGF stimulates endothelial cell proliferation and
migration, induces protease production by endothelial cells, and
stimulates endothelial cells to migrate into 3-dimensional
collagen matrices to form capillary-like tubes.17–19 bFGF stimu-
lates angiogenesis in vivo in the chick chorioallantoic mem-
brane and corneal micropocket, in concentrations as low as
100 ng.20–22 bFGF has been isolated from corpus luteum, adrenal
gland, kidney, and retina, and it has been implicated in tumor-
mediated angiogenesis.17,23
When considering the FGFs as ocular angiogenic factors, one
perplexing attribute of both acidic fibroblast growth factor
(aFGF) and bFGF is their lack of a consensus signal peptide for
secretion.24 As a result, demonstration of aFGF25,26 and bFGF27
in the retina does not necessarily mean that the factors are
exerting any action at that moment. bFGF related messenger
RNA (mRNA) and protein levels have been reported to be
elevated in a number of experimental systems and clinical
settings, including the retinas of newborn mice exposed to
hyperoxia,28 the retinal pigment epithelium (RPE) after krypton
1808 laser injury,29 and ocular fluids from individuals with PDR.30
FIGURE 135.2. Severe retinal ischemia with
rubeosis. (a) The right eye of a 27-year old
diabetic man who presented with rubeosis and
neovascular glaucoma in each eye. There is
NVD, and visual acuity is 20/200. (b) View of
the inferotemporal arcade with numerous
intraretinal hemorrhages and subtle intraretinal
whitening. (c) Fluorescein angiogram
documents severe capillary nonperfusion of the
entire temporal macula and beyond. There is
also hyperfluorescence indicating NVD.
(d) Inferior view shows nearly complete
absence of capillary perfusion outside the
peripapillary area.
However, FGF has not been shown to have a causal role. The
FGFs have a high affinity for heparin and heparin sulfate, and a
significant proportion remains associated with the cell matrix.31
This has led to the concept of matrix-associated FGF as a stored
growth factor. Intracellular FGF may be secreted via alternate
pathways, possibly in response to sublethal injury.32
The IGFs (IGF-I and IGF-II) are growth-promoting peptides
with multiple biologic effects.33 IGF-I was initially identified as
a circulating factor that appeared to mediate the effects of
growth hormone.34 The role of this growth factor and its
associated factors in ocular neovascularization was first
suggested by the clinical observation of regression of PDR after
infarction of the pituitary during pregnancy.35 IGF-I stimulates
migration and proliferation of endothelial cells36 and has been
demonstrated to be angiogenic in vivo at high doses.37 Grant
and colleagues demonstrated increased levels of IGF-I in the
vitreous of patients with PDR compared with controls.38
VEGF was first identified in tumor and developmental sys-
tems as a vasopermeability factor and angiogenesis factor, which
was upregulated by hypoxia, a component of ischemia.39 VEGF
and mRNA and protein were shown to be elevated in several
experimental systems, including a model of retinal ischemia
and iris neovascularization in the monkey and retinopathy of
prematurity in the mouse and the rat.40–43 Various strategies to
inhibit VEGF either completely prevented or greatly reduced
neovascularization in these models.44,45 VEGF protein levels
were found to be increased in the ocular fluids of patients with
PDR or ischemic retinal vein occlusion and decreased after
successful laser retinal ablation.46,47 Surgical specimens from
eyes with PDR consistently demonstrated VEGF expression, in
contrast to other growth factors.48 Finally, VEGF has been
demonstrated to be sufficient to produce neovascularization, by
injecting VEGF into normal animal eyes49 or by means of a
transgenic mouse model.50
Recent work has further suggested that the serine/threonine
kinase PKC also appears to play a role in the development of
diabetes-associated neovascularization, primarily through its
influence on the activity of growth factors such as VEGF.50a In
human vascular smooth muscle cells, hyperglycemia-induced
expression of VEGF is prevented by administration of PKC

inhibitors.50b Inhibition of PKCb by the selective inhibitor
ruboxistaurin blocks VEGF’s proliferative, angiogenic, and pro-
permeability effects.50c,50d Using a model of ischemia-induced
proliferative retinopathy, there is a significant increase in
VEGF-mediated retinal neovascularization in transgenic mice,
overexpressing the PKCb2 isoform, and a corresponding
decrease in angiogenic activity in PKCb isoform null mice.50e
Besides acting as a reservoir for growth factors, the vitreous
may exert a mechanical effect in the development of pro-
liferative tissue. Retrospective studies have shown that, whereas
a complete posterior vitreous detachment (PVD) occurs in
diabetes as a function of aging, partial PVD is seen in diabetics
with PDR far more commonly than in individuals without
diabetes or in diabetics with background retinopathy.51 The
posterior vitreous face remains attached to the retinal vessels at
the sites of proliferation and provides a scaffold along which the
new vessels and fibrous tissue can grow. The resulting tractional
forces can lead to the development of traction retinal detach-
ment. Precocious PVD, before the development of proliferative
retinopathy, appears to protect patients from traction retinal
detachments.52
EPIDEMIOLOGY
Epidemiologic studies are important in elucidating the sys-
temic, ocular, and genetic factors associated with the develop-
ment and progression of diabetic retinopathy. Understanding
these factors gives insight into the pathophysiology of the disease,
as well as indicating where treatment should be directed, in
individual patients, and in the healthcare system as a whole.
The Wisconsin Epidemiologic Study of Diabetic Retinopathy
(WESDR) is a large population-based study of 2366 subjects
divided into two groups: the younger-onset group, or those
diagnosed with diabetes before age 30 years, and the older-onset
group, or those diagnosed with diabetes after age 30 years.53,54
The older-onset group was subdivided into those taking insulin
and those who did not. In the younger-onset group, the
prevalence of any retinopathy was closely related to duration of
diabetes, ranging from 2% in subjects with diabetes for less than
2 years to 98% in subjects with diabetes for 15 years or more.53
The severity of retinopathy in this group also increased with
duration of diabetes: the prevalence of PDR ranged from 0% in
subjects with diabetes for less than 5 years to 25% in subjects
with diabetes for 15 years and 56% in subjects with diabetes for
20 years or more. In the younger-onset group, macular edema is
rare before diabetes has been present for 10 years, but the
incidence reaches 21% after 20 or more years of disease. In a
population examined at the Joslin Clinic, macular edema was
more common in the older-onset group; and in patients under
the age of 50 years, it was associated with preproliferative or
proliferative retinopathy.55
In contrast to the younger-onset group, the older-onset group
was more likely to have retinopathy present at the time diabetes
was diagnosed. The prevalence of any retinopathy in this group
in the WESDR was 30% in insulin-taking subjects and 23%
in those not taking insulin who had diabetes for less than
2 years.54 This increased to 85% in the group taking insulin and
58% in the group not taking insulin after 15 years or more of
diabetes. After 15 years or more of diabetes, the prevalence
of PDR was 20% in those taking insulin and 4% in those not
taking insulin.
Incidence and progression of retinopathy were also studied in
the WESDR. The younger-onset group had the highest 4 year
incidence of any retinopathy (59%), as well as progression
(41%), and progression to PDR (10.5%).53 Older-onset patients
taking insulin had a 47% 4 year incidence of any retinopathy,
34% incidence of progression, and 7% incidence of progression
Proliferative Diabetic Retinopathy
to PDR.54 In those not using insulin, these numbers were all
lower, with only a 34% incidence of any retinopathy. The
incidence of legal blindness was 3% over 4 years in the older-
onset group on insulin versus 1.5% in the younger-onset group.
Various investigators have attempted to determine the
characteristics associated with the severity or progression of
retinopathy. As already evidenced, the duration of diabetes is
important in all patients. The WESDR also found that elevated
glycosylated hemoglobin levels were associated with more
severe retinopathy in all groups. Proteinuria was associated with
severe retinopathy in younger-onset subjects who had diabetes
for 10 years or more, as well as in the older-onset group.
Elevated diastolic blood pressure and male sex were associated
with more severe retinopathy in the younger-onset group and
with elevated systolic blood pressure in the older-onset
group.53,54
A prospective study was carried out at the Joslin Clinic in
153 patients with long-standing diabetes, 90% of whom were in
CHAPTER 135
the early-onset category.56 The risk of progression to preprolif-
erative or proliferative retinopathy increased in the presence of
background retinopathy, even if it was slight. The risk of pro-
gression increased exponentially with increasing hemoglobin
A1c. Diastolic blood pressure less than 70 mmHg, and increas-
ing age were protective factors. Since the study involved patients
with long-standing diabetes (duration 16–60 years), the results
may not apply to patients in the early course of the disease.
Genetic factors have been investigated, particularly the histo-
compatibility antigens (human leukocyte antigen (HLA)) with
varying findings.57 Baker and Rand and associates reported that
patients with HLA-DR phenotypes 4/0, 3/0, and X/X (neither
3 nor 4) had three to four times the risk of proliferative
retinopathy of that found in patients with the HLA-DR pheno-
types usually associated with diabetes (HLA-DR 3/4, 3/X, 4/X).
In patients with myopia (2 D or greater), this risk was not
evident.57,58
Several studies have reported significant mortality associated
with PDR. In a cohort study at the Joslin Clinic, Rand and col-
leagues demonstrated that the risk of death was not attributable
to PDR itself.59 The increased risk of death was found only in
PDR patients with diabetic nephropathy as evidenced by per-
sistent proteinuria.
OCULAR AND SYSTEMIC RISK FACTORS
FOR PROGRESSION TO PDR
GLUCOSE CONTROL
With the introduction of insulin arose the question, is there a
level of glycemic control that will prevent the secondary
complications of diabetes? If there is such a level, at what point
in the course of the disease must the intervention be made?
Most clinical studies have shown an association between
poor control of blood glucose and increased severity of
retinopathy.53,54,56,58,60 In the WESDR, an elevated glycosylated
hemoglobin was associated with more severe retinopathy in the
younger-onset and older-onset diabetics.53,54 In a series at the
Joslin Clinic, the risk of PDR in long-standing diabetes was
related to elevated glycosylated hemoglobin levels.56,58 Several
prospective studies have begun placing diabetic patients on
continuous subcutaneous insulin infusion (CSII) systems or
multidose (three to four doses per day) insulin treatment
regimens with home glucose monitoring.61–63
The Kroc Collaborative Study involved 70 patients with
diabetes and nonproliferative retinopathy who were randomized
to CSII or conventional injection treatment.61 Over 8 months,
glycosylated hemoglobin and blood glucose levels reached near-
normal levels in the treatment group. The level of retinopathy 1809
 RETINA AND VITREOUS
progressed in both groups but was worse in the treatment group,
with increased cotton-wool spots and IRMA. After 2 years of
follow-up, however, little difference was found in the rates of
progression between the two groups. The Oslo group, studying
45 patients randomized to CSII, multidose insulin, or con-
ventional insulin therapy, also reported an initial worsening of
retinopathy, with microaneurysms and IRMA.62 One patient
experienced severe preproliferative retinopathy in both eyes
after 3 months of CSII and was followed up without laser inter-
vention but continued on CSII with regression of the
retinopathy after several months.64 After 2 years of follow-up,
patients receiving CSII or multiple injections had a lower rate
of progression of retinopathy, as measured by number of
microaneurysms and hemorrhages, than did the conventionally
treated group. Both studies, as well as other case reports,65
suggest that rapid achievement of good glycemic control in
diabetics with previously poor metabolic control may be detri-
mental, particularly in patients with preproliferative or prolifer-
SECTION 10
ative retinopathy.
These trials are limited because of their small study popula-
tion, short duration, and patient makeup, with varying degrees
of retinopathy. The Diabetes Control and Complications Trial
(DCCT) was a large, randomized, controlled trial, involving
1441 insulin-dependent subjects, designed to study both primary
prevention and secondary intervention.63,66,67 Patients were ran-
domized to standard therapy or intensive therapy of multidose
insulin injections or CSII. The primary prevention study involved
726 subjects who had diabetes for 1–5 years and lacked retino-
pathy or evidence of renal disease. The secondary intervention
study involved 715 subjects who had diabetes for 1–15 years,
with minimal background retinopathy and minimal diabetic
nephropathy. Retinopathy was the principal outcome in the
DCCT. The primary prevention cohort was followed up to deter-
mine whether intensive therapy could prevent the development
of retinopathy, and the secondary intervention cohort was
followed up to determine whether intensive therapy could delay
the progression of retinopathy. Patients in the primary cohort
were followed up for an average of 6.0 years, and those in the
secondary intervention cohort were followed-up for 7.0 years. In
the primary prevention cohort, both treatment groups showed a
steady rise in the cumulative incidence of any retinopathy
(defined as ≥1 microaneurysm in two consecutive 6 month sets
of photographs), reaching 90% in the conventional group and
70% in the intensive treatment group. Intensive treatment
slowed the development of retinopathy over the 9 years of
follow-up, with an average risk reduction of 27%, but did not
prevent its onset.68 Using a more conservative outcome of at
least three microaneurysms at two consecutive visits, the size of
the risk reduction with intensive retreatment increased to 63%.
Intensive therapy was more effective when initiated early in the
course of insulin-dependent diabetes.
In the secondary intervention cohort, the 9 year cumulative
incidence of three or more steps of progression, was 56% in
patients who received intensive treatment versus 78% in patients
treated conventionally. The incidence of severe nonproliferative
retinopathy was 9.2% versus 26%, and the incidence of neo-
vascularization was 8% versus 24%. For macular edema, the
cumulative incidence was 27% versus 44%. Although all levels
of retinopathy included in the study benefited from intensive
therapy, the effects were less marked in eyes with more advanced
retinopathy. Since the DCCT did not include patients with
truly advanced retinopathy, it does not address the question of
whether these eyes would benefit from intensive therapy. All
of the observed risk reductions reflected an initial period of 2
years or more in which there was no benefit from intensive
treatment, averaged against a period beyond 3 years in which
1810 intensive therapy showed increasing reductions in risk.
OCULAR SURGERY
Cataracts occur commonly in diabetic patients and may require
surgical intervention for both visual rehabilitation and visual-
ization of the fundus. Cataract surgery in diabetics may be
more complicated than in the general population, however, with
poorer postoperative results, including an increased incidence
of cystoid macular edema, an increased risk of progression of
the retinopathy, and an increased risk of anterior segment
neovascularization. The outcome of cataract surgery in
individuals with diabetes has been studied by a number of
investigators.
Visual outcome in cataract surgery appears to be affected by
the presence or absence of retinopathy preoperatively. In a series
of 28 eyes of patients with diabetes, but without retinopathy
undergoing extracapsular surgery with lens implantation, the
corrected visual acuity achieved 12 months postoperatively was
20/40 or better in 88% of the patients.69 These results compare
favorably with those in nondiabetic individuals. Conversely,
patients with retinopathy preoperatively had a poorer visual
outcome, with one-third of the 18 eyes achieving a post-
operative visual acuity less than 20/200. Eight out of the 18 eyes
developed cystoid macular edema. Severe exudative maculopathy
has been described after cataract extraction in patients with
preoperative background diabetic retinopathy.70 Postoperative
visual acuity may be worse, despite medical treatment and
macular laser photocoagulation.
In another retrospective series, Benson and associates studied
the visual acuity results in diabetic patients undergoing
extracapsular cataract extraction with placement of a posterior
chamber lens.71 They found that in this referral population, the
final visual acuity was 20/40 or better in 48% of eyes, and that
28% had 20/200 or worse visual acuity. Sixty-five percent had
an improvement in visual acuity of two or more Snellen lines.
Interestingly, they found that age was a predictor of final visual
acuity, patients aged 63 years or younger were more likely to
achieve improved visual acuity. The poorer results in the older
patients were due to complications of macular edema.
Neovascularization of the iris developed in 6% of patients, and
the risk of iris neovascularization in their study population was
not increased by posterior capsulotomy.
Studies of the risk of progression of diabetic retinopathy,
apart from macular edema, have reached differing conclusions.
Sebestyen studied 74 patients with, either no background
diabetic retinopathy, or mild background diabetic retinopathy,
who were undergoing cataract extraction with lens implanta-
tion. He found a similar risk of progression between the operated
and the unoperated eyes.72 In another study comparing extra-
capsular and intracapsular techniques, Alpar found the lowest
incidence of progression of retinopathy in the group undergoing
extracapsular extraction.73 However, he did not differentiate on
the basis of preoperative retinopathy, which appears from other
studies to be an important factor.
Aiello and co-workers retrospectively studied 154 diabetic
patients, who had undergone routine intracapsular cataract
extraction in one eye only.74 The second eye served as a control,
and neither eye received laser photocoagulation before surgery
or during the first year after surgery. Although most of the eyes
had either no diabetic retinopathy or background retinopathy,
eyes were included with both quiescent PDR and active PDR. In
all patients, regardless of the degree of preoperative retinopathy,
there was a statistically significant increased risk of rubeosis
iridis and neovascular glaucoma (8% vs 0%). In patients with
active PDR, preoperatively the risk was even higher (40% vs
0%). There was also an increased risk of vitreous hemorrhage
after surgery, but this was significant only for the group with
no background retinopathy or mild background retinopathy

preoperatively, and not for those with proliferative retinopathy,
probably because of the small number of patients in this group.
Hykin and colleagues retrospectively compared visual acuity
results in 90 patients with PDR or background retinopathy under-
going extracapsular cataract extraction with lens implantation.75
They found that final visual acuity was better in eyes with
background retinopathy (67% ≥ 20/40) compared with eyes with
PDR (21% ≥ 20/40). Eyes with quiescent PDR and lacking
maculopathy did somewhat better, with 52% achieving 20/40 or
better. Deterioration of retinopathy occurred postoperatively, in
50% of eyes with active PDR preoperatively, and immediate
postoperative fibrinous anterior uveitis preventing early
panretinal photocoagulation occurred in over half the patients
with active proliferative retinopathy. Eyes with active prolifer-
ative retinopathy and cataract are better treated with combined
cataract removal and pars plana vitrectomy with intraoperative
endolaser.
Given the increased risks associated with cataract surgery in
patients with diabetic retinopathy, special consideration should
be made, both preoperatively and postoperatively. The preoper-
ative assessment of the visual impairment caused by cataract
may be more difficult in the diabetic patient, and use of blue-
field entoptoscope and potential acuity meter may be helpful.76
Even in cases where the retina appears unremarkable, patients
should be cautioned that there may be progression of diabetic
changes postoperatively, with resultant poorer visual acuity.
When a cataract is developing in a diabetic patient, effort should
be made to perform indicated laser photocoagulation, particu-
larly panretinal photocoagulation for active PDR, before the
density of the cataract precludes treatment.
Surgery should be directed toward maintaining an adequate
aperture for viewing (and possibly treating) the fundus; and
phacoemulsification or extracapsular technique with ‘in the bag’
placement of an intraocular lens is preferred. Because of the
increased rate of macular edema postoperatively in diabetic
patients, it may be worth considering topical or oral non-
steroidal antiinflammatory agents as well as topical or depot
steroids. Wounds should be sutured well to allow laser photo-
coagulation with a contact lens within 2–3 weeks of surgery
if this proves necessary. If yttrium–aluminum–garnet (YAG)
capsulotomy is indicated postoperatively, again the aperture
should allow visualization of the retina to the equator. Close
follow-up postoperatively is essential, with examination of the
iris for neovascularization, and a dilated examination of the
fundus for macular edema or progression of retinopathy, with
consideration of focal or scatter photocoagulation, as indicated.
PREGNANCY
The role of pregnancy in the progression of diabetic retinopathy
remains somewhat controversial. In his 1950 report, Beetham
found that disease in pregnant diabetic patients without retino-
pathy did not progress during the pregnancy.77 However,
patients with evidence of proliferative retinopathy at the onset
of pregnancy did so poorly, that he recommended them not to
undertake pregnancy. In a study by Rodman and associates in
1979, 8% of 201 pregnant diabetic women, with no background
retinopathy, or mild background retinopathy at the onset of
pregnancy, had progression of their retinopathy during
pregnancy.78 In 127 women with proliferative disease, 25% had
retinopathy progress during pregnancy. Laatikainen and col-
leagues prospectively studied 73 consecutive pregnant patients
and noted no significant progression of retinopathy in patients
who lacked or had minimal retinopathy at the beginning of
pregnancy.79 However, 13 of the 20 patients (65%) with frank
retinopathy in the first trimester were observed to progress
during pregnancy.
Proliferative Diabetic Retinopathy
Klein and co-workers reported on a prospective case-control
study comparing pregnant and nonpregnant insulin-taking
diabetic women.80 Risk factors that were evaluated for the
progression of retinopathy included glycosylated hemoglobin,
duration of diabetes, current age, diastolic blood pressure, num-
ber of past pregnancies, and current pregnancy. Women with
evidence of proliferative retinopathy or evidence of previous
panretinal photocoagulation were not considered to be at risk
for progression, and their data were not included in evaluating
risk factors for progression. After correcting for glycosylated
hemoglobin level, current pregnancy was found significantly
associated with progression, with an adjusted odds ratio of 2:3.
Diastolic blood pressure had a smaller effect on progression.
Pregnant women were significantly more likely to have a
decrease in visual acuity, although this was only a mean dif-
ference of less than 1 Snellen letter poorer. Klein and co-workers
noted that the metabolic control of the pregnant group was
markedly better than that of the nonpregnant group.80 This is
CHAPTER 135
probably because of the current obstetric practice of attempting
tighter metabolic control during pregnancy. It has been pos-
tulated that progression of retinopathy during pregnancy may
be at least partly related to the rapid tightening of metabolic
control. Laatikainen and associates studied 40 pregnant
patients randomized at the end of their first trimester to
conventional insulin therapy and CSII.81 They found that the
risk of progression of retinopathy was the same. However, two
of the patients in the CSII group progressed from background to
proliferative retinopathy. Both patients had a rapid decrease in
their glycosylated hemoglobin level as they entered CSII treat-
ment. None of the patients in the conventional therapy group
developed proliferative changes.
Diabetic retinopathy may also be a predictor of pregnancy
outcome. Diabetic patients taking insulin are known to be at
increased risk of an adverse pregnancy outcome, including abor-
tion, perinatal death, and severe congenital anomalies. Klein
and colleagues evaluated various risk factors as predictors for
adverse outcome and found that the severity of retinopathy was
the only variable to significantly predict an adverse outcome.82
Pregnancy in diabetic patients is a crucial time for coordi-
nated care by ophthalmologists, obstetricians, and internists.
Guidelines for patient care should be understood by all
members of the team. Pregnant diabetic patients should be seen
during the first month of the pregnancy. If no retinopathy is
found, follow-up in each trimester is sufficient unless the
patient becomes symptomatic. An exception is made if the
patient is being brought under tighter metabolic control, which
could increase the risk of progression of the retinopathy.
Improvement in metabolic control should be gradual. Patients
with preproliferative or proliferative disease should be followed
up every 1–2 months. Laser photocoagulation should be con-
sidered earlier in pregnant diabetics than in nonpregnant
diabetics, when there is evidence of early proliferative or active
preproliferative retinopathy. These findings will be revealed by
careful ophthalmoscopic and biomicroscopic examination, and
fluorescein angiography can usually be avoided in the assessment
of the pregnant diabetic patient. Although there are no firm data
on the risk of vitreous hemorrhage in patients with proliferative
retinopathy, PDR is not an indication for cesarean section.
HYPERTENSION
The relationship between hypertension and the development of
diabetic retinopathy is not clear. In the WESDR, the presence
and severity of retinopathy were associated, with elevated
diastolic blood pressure in younger-onset diabetics after 10 years
or more of diabetes, and with elevated systolic blood pressure
in the older-onset diabetics.53,54 In a case-control study at the 1811
 RETINA AND VITREOUS
Joslin Clinic, Rand and co-workers found that hypertension was
associated with proliferative retinopathy in patients who had
had diabetes for 15 years or more.58 This association remained
significant even if cases with renal disease were excluded. In a
prospective study at the Joslin Clinic, Janka and associates
found different rates of progression of severe retinopathy in
patients with diastolic blood pressures less than or greater than
70 mmHg.56,83 Chase and colleagues also found that elevated
diastolic blood pressure, even just to ‘high-normal’ values,
carried an increased risk of retinopathy in young diabetics.84
Since hypertension is a known risk factor for stroke and myo-
cardial infarction, it is important that elevated blood pressure
be treated in the diabetic patient, regardless of its effect on
retinopathy.
RENAL DISEASE
Approximately one-third of juvenile-onset insulin-dependent
SECTION 10
diabetics experience diabetic nephropathy, with the highest risk
in the second decade of diabetes.85 Several risk factors may be
involved in the development of diabetic nephropathy, including
genetic predisposition, hypertension, and poor glycemic control.
Severe retinopathy is more likely to be found in patients with
renal insufficiency. In the WESDR, proteinuria was strongly
associated with severe retinopathy in the younger-onset dia-
betics with 10 years or more of diabetes.53 Older-onset diabetics
with proteinuria were also more likely to have proliferative
retinopathy.54 Renal retinopathy will overlie diabetic retino-
pathy in uremic patients and consists of a hypertensive com-
ponent and a uremic component.12 The hypertensive changes
include nerve fiber layer hemorrhages, cotton-wool spots, and a
narrowing and irregular caliber of the retinal arterioles. The
uremic changes include disk edema and diffuse retinal edema,
which may lead to massive macular edema. Treatment of the
renal failure, with diuretics, dialysis, or renal transplantation,
may result in decreased retinal and macular edema. Laser
photocoagulation is not very effective in this group of patients;
it is important to consider laser photocoagulation treatment for
preproliferative retinopathy or early proliferative changes in the
diabetic patient experiencing renal failure.
The treatment of renal failure may result in a different set of
ocular problems. Patients on hemodialysis are at increased risk
of developing elevated intraocular pressure, particularly in eyes
that have undergone vitrectomy. Renal transplant patients are
at an increased risk of acquiring cataract from chronic cortico-
steroid treatment or cytomegalovirus retinitis from chronic
immunosuppression.86
PANCREAS TRANSPLANTATION
Pancreas transplantation, alone or in combination with renal
transplantation, is a relatively new and risky procedure per-
formed on diabetic patients with advanced diabetic nephropathy
in conjunction with renal transplantation. Several investigators
have begun to examine the effect of transplantation on diabetic
retinopathy, although all the studies to date have been limited
by low numbers and short follow-up. Petersen and Vine reported
on eight patients who underwent combined pancreas and renal
transplantation from cadaver donors.87 Four patients success-
fully retained functioning pancreas transplants for at least
12 months, whereas four patients with failed pancreas transplants
but functioning renal transplants served as the controls. Suc-
cessful pancreas transplantation led to a euglycemic state, with
normal fasting blood glucose, and glycosylated hemoglobin levels.
However, the progression of retinopathy appeared unaffected.
Three of the study group eyes had an increase in capillary
1812 closure versus no increase in the control eyes. Four of the study
group eyes versus two of the control eyes had an increase in
preretinal gliosis. One eye in each group had worsening of
proliferative retinopathy. Comparison of the variables of visual
acuity, macular edema, capillary closure, NVD, preretinal
neovascularization, preretinal gliosis, and severity of retino-
pathy showed no statistically significant difference between
the two groups.
Ramsay and co-workers reported on the ophthalmic out-
comes of pancreas transplant recipients, again comparing suc-
cessful and unsuccessful transplantations.88 Twenty-two
patients were in the successful transplantation group and 16
in the control group, with follow-up averaging 24 months.
Although the investigators noted no substantial difference
in the progression of retinopathy in the two groups after 2
years, they observed a trend toward less progression of
retinopathy in the treated group after 3 years. In order to
adequately study the ophthalmic outcomes of pancreas
transplant recipients, it will probably be necessary to pool the
patients in transplantation centers across the United States
under a common protocol.
Pancreas transplantation still carries significant morbidity
and mortality and requires chronic immunosuppression. As a
result, the procedure has been limited to patients with end-
stage nephropathy, which is a group with a high incidence of
advanced retinopathy, many of whom have already received
panretinal photocoagulation. It may be difficult to show an
effect of pancreas transplantation and normoglycemia on this
advanced and already treated eye disease.
OCULAR CONSEQUENCES OF
NEOVASCULAR PROLIFERATION
NVD AND NVE
Neovascularization occurs most frequently in the posterior pole
or within 45o of the optic disk.89 It is very commonly observed
on the disk itself. New vessels on the disk can be easily over-
looked in their early stages, beginning as fine loops or networks
of vessels. The vessels gradually increase in caliber from one-
eighth to one-quarter the diameter of a retinal vein at the optic
disk. The vessels often form a cartwheel configuration with vessels
radiating out from the center to a circumferential peripheral
vessel (Fig. 135.1a). Occasionally, new vessels will appear similar
to normal retinal vessels, with a large caliber and extending
across the retina without forming networks. However, these
vessels can be distinguished from normal retinal vasculature by
the fact that they cross both arterioles and venules. NVD is best
identified using a magnified stereoscopic view, either by contact
or precorneal lens or with stereoscopic photography.
NVE is best detected by a thorough fundus examination, with
binocular indirect ophthalmoscopy combined with biomicro-
scopy using a lens. Fundus photographs are also helpful in
detecting early NVE. Neovascularization typically occurs
adjacent to areas of capillary closure, marked by cotton-wool
spots and hemorrhagic microaneurysms (Fig. 135.1b). IRMA
may be difficult to differentiate from early NVE. IRMA is used
to describe irregular, segmental dilatation of intraretinal
capillaries, representing early neovascular changes or shunt
vessels. On fluorescein angiography, IRMA typically does not
leak as profusely as do new vessels (Fig. 135.3).
VITREOUS AND PRERETINAL HEMORRHAGE
While the posterior hyaloid remains attached, neovascular
proliferations appear to be on or slightly anterior to the retina,
and are usually asymptomatic. Small hemorrhages may occur
near the growing tips of the vessels, but these usually remain
 Proliferative Diabetic Retinopathy

a b c

FIGURE 135.3. Fluorescein angiography of neovascularization. (a) NVE along the vascular arcade. (b) Early fluorescein transit defines NVE.
(c) Late transit shows continued leakage from NVE.

CHAPTER 135
subhyaloid. As the posterior hyaloid detaches, hemorrhages
become less confined and visual acuity may diminish in propor-
tion to the extent and diffusion of the hemorrhage (Fig. 135.4).
Vitreous detachment usually begins in the posterior pole on
either side of the vascular arcades, over the fovea, or temporal
to the macula. Progression of detachment of the vitreous is
halted whenever a tuft of neovascularization or a particularly
strong attachment to a retinal vessel is encountered. The tuft
may be pulled forward as the vitreous contracts, with or without
detachment of the underlying retina. The vitreous detachment
will continue to the periphery, at which point the vitreous is
permanently attached to the vitreous base. The vitreous usually
remains attached at the disk if fibrovascular proliferations are
present.
This process leads to a variety of complex patterns of partial
vitreous detachment. In general, however, the pathophysiology
of partial vitreous detachment favors attachment of the vitreous
to neovascularization, major retinal vessels, the disk, and
obligatorily, the peripheral vitreous base. The outer contour of
the partially detached vitreous has been termed the ‘vitreous
cone’, with the widest aspect of the cone anteriorly and a
variable stem of the cone oriented at the posterior pole. The FIGURE 135.4. A complication of neovascularization. Vitreous
posterior vitreous face and its attachments in a given eye are hemorrhage from NVD.
critical to the understanding of the surgical approaches in PDR
(Fig. 135.5). The posterior vitreous face serves as a surface that seen adjacent to the vessels. This tissue increases as the vessels
may loculate hemorrhage. In addition, it may also have perfo- develop, and it may subsequently contract. Distortion and dis-
rations, which at times may cause it to be confused with an ruption of the normal retinal tissue may result in conjunction
epiretinal membrane or even a macular hole. with the process of vitreous detachment (Fig. 135.6).
Vitreous hemorrhage may occur as a result of vitreous trac- Contraction of the posterior vitreous face and fibrovascular
tion on new vessels. Contraction of the vitreous or fibrovascular proliferation may lead to tractional retinal detachment. Since
proliferation can lead to avulsion of a retinal vessel, usually fibrous proliferation usually progresses along the temporal
a vein, and vitreous hemorrhage. Hemorrhage may also be arcades, the retina along the temporal arcades is usually the
associated with Valsalva’s maneuvers related to coughing or first to detach. Progression of the detachment can then extend
vomiting or occasionally is associated with insulin reactions.90 centrally and peripherally. The rate of progression of an extra-
Most of the time, it occurs during sleep and is unrelated to macular tractional detachment to involve the macula may be as
any obvious factor. Results of the Early Treatment Diabetic low as 15% in a single year.92 In contrast to rhegmatogenous
Retinopathy Study (ETDRS) indicate that aspirin use does not retinal detachments, tractional detachments are typically con-
increase the risk of vitreous hemorrhage.91 cave, are localized, and do not extend to the ora serrata. Trac-
Blood in the fluid vitreous behind the detached posterior tional retinal detachments in PDR have many configurations,
vitreous face remains red until it is absorbed, which usually depending on the location, number, and severity of attachments
occurs over weeks to months. Hemorrhage into the formed of the posterior vitreous face to neovascularization and its
vitreous tends to turn white over time and may require months associated fibrovascular tissue. The activity of the neovascu-
to clear. larization also plays a role. Configurations of tractional detach-
ments may range from an isolated tractional detachment
outside the arcades associated with an area of NVE that has
FIBROUS PROLIFERATION AND RETINAL regressed, to a tractional detachment of the entire posterior
TRACTION retina with extensive contact of the retina, neovascular tissue,
Early in the course of neovascularization, the new vessels appear and the posterior vitreous face. The various configurations have
bare, but as they develop, delicate white fibrous tissue can be implications for the indications for surgical intervention and for 1813
 RETINA AND VITREOUS
a b
SECTION 10
c d
the prognosis for successful reattachment. Tractional retinal
detachments may also develop retinal breaks, either atrophic or
tractional. The resulting combined tractional–rhegmatogenous
detachment typically progresses, although in some cases the
detachment may remain stable despite the break, particularly in
an eye with extensive panretinal photocoagulation (Fig. 135.7).
Detachments involving the fovea have obvious impact on
vision. However, in other cases, the fibrovascular tissue may
overgrow and obscure the fovea, reducing vision without actual
foveal detachment. Contraction of fibrovascular tissue can also
lead to distortion or horizontal displacement of the macula
(tangential traction). Visual acuity may be reduced in this
condition owing to striae in the macula, and surgery may result
in visual improvement.93
RUBEOSIS
Iris neovascularization or rubeosis is a complication of pro-
liferative retinopathy. Rubeosis is characterized by the networks
of branching vessels over the surface of the iris, with vessels
crossing the scleral spur on gonioscopy. Usually, the new vessels
are apparent on clinical examination, but fluorescein angio-
graphy is occasionally helpful in demonstrating leakage from
the new vessels. Rubeosis is observed in the setting of
proliferative changes and retinal ischemia and also in long-
standing retinal detachment related to diabetic retinopathy. It is
most dramatically evident in eyes with retinal detachment after
unsuccessful vitrectomy. In this setting, rubeosis will develop in
almost all cases and will progress rapidly if the underlying
detachment is not repaired.
INVOLUTIONAL PROLIFERATIVE DIABETIC
RETINOPATHY
All diabetic retinopathy eventually reaches an involutional
stage. The visual outcome is variable and depends on the
1814 degree of structural alteration in the posterior pole. Vitreous
FIGURE 135.5. Posterior hyaloid (posterior
vitreous face) configurations in PDR. (a) The
posterior hyaloid is attached across the macula,
at the disc, and just beyond each arcade.
Outside of these areas, the vitreous is
detached. In this eye, the posterior hyaloid is
fibrotic and slightly separated from the surface
of the macula, rendering it visible. The
underlying retina is totally attached and the
visual acuity is 20/30. (b) Posterior hyaloid with
a large hole centrally, simulating an epiretinal
membrane with hole. The residual attachment
points of the posterior hyaloid at the disk in
superior, inferior, and inferotemporal locations
may be seen. The retina is attached, and visual
acuity is 20/30. (c) Ultrasound demonstrates
traction retinal detachment and vitreous
attachments (vitreous cone). (d) Intraoperative
view of vitreous surgery with creation of an
opening in the detached peripheral vitreous
with the vitrectomy instrument. The
membranous character of this tissue is shown.
FIGURE 135.6. Very severe neovascularization with vascular
overgrowth obscuring the retina and traction retinal detachment.
detachment is completed, except in the areas where fibro-
vascular proliferations prevent complete separation, and
fibrovascular proliferation ceases. In an untreated eye, there is
usually some element of tractional detachment by the time this
phase is reached, and it typically involves the macula. The optic
nerve develops some pallor, and the retinal arterioles become
attenuated. Retinal hemorrhages and microaneurysms are rare,
and pigmentary changes in the RPE may be seen. Fibrous tissue
may be thinner and translucent, with the appearance of vitreous
veils in contact with diaphanous retina. Visual loss at the
involutional phase may relate to macular detachment, macular
ischemia, long-standing macular edema, or optic nerve disease
(Fig. 135.8).
 Proliferative Diabetic Retinopathy

a b c

FIGURE 135.7. Posterior break in tractional retinal detachment. (a) Tractional detachment along the superior arcade with a retinal break just
inferior to the neovascular stalk. (b) Confluent laser applied to surround the detachment. (c) Four months later, the detachment is unchanged
and visual acuity remains 20/20. The detachment has remained stable over the subsequent 2.5 years of observation.

CHAPTER 135
a b c

d e f

g h

FIGURE 135.8. Macular ischemia in a 21-year-old man with PDR. (a) Intraretinal hemorrhages and cotton-wool spots. Visual acuity is 20/30.
(b) Fluorescein angiogram demonstrates macular capillary nonperfusion and early disk neovascularization. (c) Late phase of the angiogram
shows continued ischemia with diffuse leakage in the macula. (d) Six months later, the cotton-wool spots have increased and visual acuity is
20/50. (e) Fluorescein angiogram now displays extensive capillary nonperfusion, most prominent in the temporal macula. NVD has increased,
and visual acuity is 20/50. (f) Eight years later, after extensive panretinal photocoagulation and also a vitrectomy for vitreous hemorrhage,
regressed proliferative changes are noted. Sclerotic vessels are seen temporally, and visual acuity is 20/80. (g) Fluorescein angiogram shows
delayed filling of temporal vessels and a greatly increased foveal avascular zone. (h) Late phase of the angiogram shows continued ischemia,
vascular wall leakage in the temporal vessels, and macular edema due to intraretinal vascular abnormalities. 1815
 RETINA AND VITREOUS
TREATMENT OF PROLIFERATIVE DIABETIC
RETINOPATHY
PITUITARY ABLATION
Some of the earliest attempts at treating PDR involved pituitary
ablation. However, this treatment modality has subsequently
been supplanted by other procedures that are more effective and
that have fewer complications, including laser photocoagulation
and vitrectomy. Thus, the technique of pituitary ablation is of
primarily historical interest today.
Houssay first noted that hypophysectomy reduced the severity
of diabetes in pancreatectomized dogs in 1930.94 Interest was
further generated by a report by Poulsen in 1953 of remission of
diabetic retinopathy in a woman with Sheehan’s syndrome, or
postpartum anterior pituitary insufficiency.35 Luft and co-
workers introduced the technique in humans in the 1950s.95
Various techniques of pituitary ablation were tried, including
SECTION 10
surgical hypophysectomy, transsphenoidal hypophysectomy,
yttrium-90 implantation, x-irradiation, proton beam irradia-
tion, and stereotactic hypophysectomy using radiofrequency
coagulation.
Both short- and long-term follow-up of patients undergoing
pituitary ablation demonstrated a stabilization of visual acuity
in survivors, an improvement in both disk and peripheral neo-
vascularization, and a reduction in exudates, microaneurysms,
and hemorrhages.12,35,96 However, the complications of treat-
ment were frequent and significant. As reported by Sharp and
colleagues, they included debilitating postural hypotension and
asymptomatic hypoglycemia, with several related deaths.
Osteoporosis and avascular necrosis of the hip were reported
and were related to steroid replacement. Sterility led to episodes
of severe depression in several patients and suicide in at least one
case. In the group from London treated with yttrium-90, the
5 year mortality rate was 18% and the 10 year rate was 51%.96
BEETHAM’S OBSERVATIONS LEADING TO
RATIONALE FOR LASER THERAPY
Early investigators observed that certain ocular conditions seemed
to prevent severe diabetic retinopathy. Eyes with chorioretinal
scarring, optic atrophy, retinitis pigmentosa, and high myopia
were protected from severe proliferative retinopathy.97 Beetham,
studying patients at the Joslin Clinic, described spontaneous
resolution of PDR in approximately 10% of patients.98 The
fundus picture in these patients consisted of lacy, reticulated
proliferative tissue; attenuated arterioles, and obliterated vessels
appearing as white lines. The fundus picture resembled that of
the ocular conditions described earlier, as well as the fundus
picture that developed after successful hypophysectomy for PDR.
Over a period of time, it was recognized that this appearance
and the subsequent possibility of inducing regression of PDR
with preserved visual acuity could be achieved with laser
photocoagulation.
EARLY LASER TRIALS (DIRECT ABLATION)
Meyer-Schwickerath and Schott first used light photo-
coagulation to treat diabetic retinopathy in 1955.99 The xenon
arc they used produced white light emitting multiple wave-
lengths. Lesions of moderate therapeutic intensity were full-
thickness retinal burns histologically, with destruction of inner
retina, explaining the frequent occurrence of visual-field defects.
With the xenon arc, one could obliterate vessels directly, treat-
ing flat neovascular patches, dilated retinal capillaries, micro-
aneurysms, and edematous retina. Treating elevated vessels
1816 required increased power and resulted in extensive retinal des-
truction. The best results were obtained by Meyer-Schwickerath
and Schott in patients with nonproliferative and early PDR.99
Several months to years after treatment with the xenon arc, flat
neovascular patches remained scarred and atrophic, there was a
decrease in exudates, retinal edema, and venous dilatation. New
retinal vessels disappeared even if not treated directly. Atrophic
changes progressed over 4–8 years. Of 73 patients with non-
proliferative diabetic retinopathy treated with the xenon arc and
followed up for 1–9 years, only one patient developed PDR. How-
ever, diffuse treatments of the retina resulted in large visual-
field defects, hemorrhage, and fibrous proliferation and traction.
Aiello and co-workers, postulated that in order to reproduce
the involutional fundus picture, one needed to be able to
produce multiple small ‘harmless’ chorioretinal scars in the
posterior pole.100 Clearly, this was not possible with the xenon
arc. However, with the development of the ruby laser, this
treatment approach became possible. The ruby laser emits
monochromatic energy at 694.3 nm, a wavelength transmitted
through ocular media and absorbed well by the RPE and
choroid. It transmits fairly well through blood, permitting treat-
ment through mild vitreous hemorrhage but also making the
laser less effective in treating vessels directly. The laser emits
energy for less than 1 ms. In experimental studies by Campbell
and associates, the thermal changes were smaller and more
narrowly confined than those found with the xenon arc. In
1965, Campbell and associates reported the results of treating
220 patients for a variety of conditions, including retinal tears,
retinoschisis, retinal detachment, angiomas, and chorioretinitis.101
Beetham and colleagues began using the ruby laser to treat
patients with diabetic retinopathy in 1967. By 1969, they had
treated 329 patients with various degrees of proliferating retino-
pathy, treating one eye and using the second eye as a control, in
patients in whom the degree of retinopathy was approximately
the same.97 Most of the patients treated had flat neovascu-
larization of the retina, or early NVD plus or minus NVE.
Patients were medically evaluated and followed up by complete
ocular examinations, including refraction, field examination,
fundus photography, and fluorescein angiography. The ruby
laser was used at a 2.5o aperture to produce 750 individual
chorioretinal lesions of grade I or II intensity. Applications were
placed in all areas of the posterior pole, avoiding the disk,
macula, and papillomacular bundle.
With 1–2 years of follow-up, there was regression of neovas-
cularization in the treated eyes that was statistically significant.97
Eighty percent of the treated eyes showed some regression, and
54% had complete disappearance of neovascularization, with
the control eyes remaining unchanged or worsening. Aiello and
co-workers also noted a decrease in the diffuse angiopathy of the
posterior pole, even in the untreated area of the papillomacular
bundle.100 Results in patients with more severe proliferative
retinopathy were more disappointing, although with fewer
patients falling into these groups so that statistical comparisons
could not be made. Of seven patients with elevated disk neo-
vascularization who were treated with ruby laser, two patients
showed improvement, three patients suffered severe vitreous
hemorrhage with one developing severe fibrous proliferation
after the hemorrhage, and two patients remained stable. None
of the treated patients in any group developed sector visual-field
defects, and there was no related vitreous traction, iritis, cata-
racts, or elevated intraocular pressure.
Aiello and Beetham and their associates noted the following
results after treatment: neovascular nets disappeared or became
nonfilling, diffuse angiopathy improved, dot-blot hemorrhages
decreased, retinal edema decreased, the disk became paler, there
was no change in fibrous proliferation, and the retinal veins
were noted to be less ‘leaky’ by fluorescein.97,100 The patho-
physiologic mechanism by which the laser treatment worked

was unclear, possibly involving the reduction in metabolic
demand by destroying functioning retinal tissue, or altering the
hemodynamic statues of the retinal-choroid layer. Several
decades later, the issue is still not completely resolved, although
alterations in the levels of various modulators of angiogenesis,
such as VEGF, likely play a role.46,47 Aiello and Beetham and
their associates believed that a ‘green’ laser might be useful to
directly treat elevated vessels prone to hemorrhage because
there would be greater absorption by the blood column. They
also believed that their results warranted a large, long-term,
controlled study.
DIABETIC RETINOPATHY STUDY AND
MODERN PANRETINAL PHOTOCOAGULATION
(PRP)
Indications
The early studies of Beetham and Aiello and associates
suggested a beneficial effect of laser photocoagulation in con-
trolling PDR. DRS was a multicentric randomized prospective
study designed to determine whether laser treatment in
diabetics prevented severe visual loss. It proved very quickly
that severe visual loss (visual acuity < 5/200) occurred ~60% less
frequently in eyes treated with photocoagulation than in eyes
assigned to no treatment.2,3 The study was also able to identify
certain high-risk characteristics in subgroups of patients that
led to poor outcome without treatment and in which treatment
clearly was of benefit.102 After 4 years, the study was changed to
allow treatment of previously untreated eyes that developed
these high-risk characteristics.
The high risk characteristics demonstrated by the DRS are:
• moderate to severe NVD (greater than standard
photograph 10A),
• any NVD with vitreous or preretinal hemorrhage, and
moderate to severe NVE with vitreous or preretinal
hemorrhage.
Other indications, although not clearly demonstrated by the
study, are also widely employed, and these are summarized in
Table 135.1. These include widespread capillary dropout, moderate
to severe NVE alone, and rubeosis with or without neovascular
TABLE 135.1 Indications for Panretinal Photocoagulation for
Proliferative Diabetic Retinopathy
DRS High-Risk Characteristics
NVD of moderate to severe degree (greater than standard
photo 10A)
NVD of any degree if associated with preretinal or vitreous
hemorrhage
NVE of moderate to severe degree if associated with preretinal or
vitreous hemorrhage
Additional Indications Widely Employed
Rubeosis with or without neovascular glaucoma
Moderate to severe NVE alone, particularly in juvenile diabetic
patients
Widespread retinal ischemia and capillary drop-out on fluorescein
angiography
Special Situations for Consideration of Panretinal
Photocoagulation
PDR developing in pregnancy, particularly with the institution of
tight metabolic control
Preproliferative retinopathy in the second eye of a juvenile diabetic
patient with severe PDR in the other eye
Abbreviations: DRS, Diabetic Retinopathy Study; NVD, neovascularization at the
disc; NVE, neovascularization elsewhere in the retina; PDR, proliferative diabetic
retinopathy.
Proliferative Diabetic Retinopathy
glaucoma. Special consideration should also be given to the
history, compliance, medical complications precluding follow-
up, and other clinical aspects seen in the patient. For instance,
it may be argued that a juvenile diabetic with visual loss caused
by severe proliferative retinopathy in one eye should be treated
in the second eye when any degree of proliferative retinopathy,
preproliferative retinopathy, or increasing retinal ischemia is
documented. Similarly a pregnant woman with proliferative
changes may be treated sooner because of the possibility of
rapid progression of the retinopathy, particularly if tight
metabolic control is instituted.
Technique
Laser photocoagulation has effectively replaced the xenon arc
photocoagulator as the instrument of choice. Multiple wave-
lengths and instruments are available and effective. Argon green
(514 nm) is most commonly employed, and the energy is well
absorbed by blood-filled vessels and by pigment in the RPE.
CHAPTER 135
Argon blue-green (488 nm) is rarely used, although it was the
standard of therapy for the DRS. It is more widely scattered by
media and may lead to long-term retinal toxicity in the treating
physician. Dye yellow (577 nm) is well absorbed by blood and
may permit direct treatment of new vessels in certain instances,
such as NVE persisting after panretinal photocoagulation.
Krypton red (647 nm) offers better penetration through nuclear
sclerotic cataracts and, to a lesser extent, vitreous hemorrhage
than does the argon green wavelength. Improved penetration to
the choroid may make this wavelength more painful to the
patient. More recently, solid-state diode lasers emitting wave-
lengths between 780 and 850 nm have become available for
medical use. They offer the advantage of small size and porta-
bility, as well as low power requirements. The longer wave-
lengths can penetrate media opacity, but they do require more
power to produce equivalent retinal lesions, and they may be
associated with more patient discomfort.
Laser photocoagulation can be delivered through a slit-lamp
system, an indirect ophthalmoscope, or an endolaser probe.
Transpupillary slit-lamp delivery is the most common delivery
system for the treatment of adults. The indirect ophthalmo-
scope laser is available with argon, krypton, or diode lasers and
permits panretinal photocoagulation in patients under general
anesthesia or in a recumbent position. The endolaser, argon,
krypton, or diode is restricted to be used at vitrectomy.
Topical anesthesia is usually adequate, although retrobulbar
or peribulbar anesthesia may be needed for re-treatments, or for
treatment with longer wavelengths, or for indirect ophthalmo-
scope delivery. Oral diazepam supplementation can also be
useful in a patient who is very nervous. The lenses used for slit-
lamp delivery include the Rodenstock panfunduscopic lens, the
Volk quadraspheric lens, and the Goldmann three-mirror lens.
The Rodenstock and Volk lenses allow one to view a large area
of the fundus during treatment and are popular for the perfor-
mance of panretinal photocoagulation. With these lenses, the
image is inverted and far peripheral burns are more difficult to
place than with the Goldmann lens. The Rodenstock and Volk
lenses magnify the spot size, and relatively more power is
required for these lenses. The Goldmann lens allows placement
of far peripheral burns, but it provides a view of only a small
area of the retina.
Spot size depends on the lens selected, usually 500 mm for the
Goldmann lens and 200 mm for the Rodenstock lens, to achieve
~500 mm burn. Occasionally, larger lesions are employed for
heavy therapy (e.g., when treating rubeosis). The duration is
typically 0.1–0.2 s. Longer durations can be used in patients
with media opacity, as well as for treatment with longer wave-
lengths. The power should be titrated to produce a gray-white
burn. Treatment should begin at 100 mW with the Goldmann 1817
 RETINA AND VITREOUS
lens or 150 mW with the Rodenstock or Volk lens, although a
heavily pigmented fundus in an aphakic or pseudophakic eye
suggests an even lower initial setting. The number of spots is
less critical than the response to therapy and follow-up. The
DRS protocol specified 800–1600 spots 500 mm in size. The
burns should be placed 1–1.5 burn widths apart, with focal con-
fluent bombardment of the NVE. If possible, the treatment
inferiorly should be heavier than the treatment superiorly to
preserve downgaze field. In treating the temporal raphe, a
barrier line should be placed 2.5 disk diameters temporal to the
center of the macula, with treatment extending distal to the
barrier. Panretinal treatments are usually divided over two to
three sessions, but they may be given in a single session if
required. One study found no significant long-term differences
in single-session versus multiple-session treatment, but fewer
transient choroidal and exudative retinal detachments were
observed in the multiple-session group.103
SECTION 10
Results
The DRS clearly demonstrated that photocoagulation in
selected diabetics reduced the risk of severe visual loss. Eligible
patients for the DRS had proliferative retinopathy in at least
one eye or severe nonproliferative retinopathy in two eyes, and
visual acuity of 20/100 or better in each eye. One eye was ran-
domly assigned to treatment, and treatment was randomized
between argon laser and xenon arc photocoagulation. The rate
of severe visual loss (visual acuity < 5/200) was reduced by treat-
ment from 16% in nontreated eyes over 2 years to 6% in treated
eyes, a reduction of 57%.2,3,104 The DRS identified certain sub-
groups, based on severity of the retinopathy, for which the treat-
ment effect outweighed any harmful effect. Severe visual loss in
patients with these retinopathy gradings (called ‘high-risk cha-
racteristics’ and discussed earlier) fell from 26% in nontreated
eyes to 11% in treated eyes.3,102,104 Harmful effects of treatment
were also identified and were somewhat greater in the xenon-
treated group of the DRS. Estimates of persistent visual acuity
loss attributable to treatment in the xenon-treated eyes were
19% with loss of one line of visual acuity and 11% with loss of
two lines.104,105 In the argon-treated group, these numbers were
11% and 3%, respectively. Twenty-five percent of the xenon-
treated eyes demonstrated a modest loss of visual field, and an
additional 25% had more severe field loss. Five percent of the
argon group showed some constriction in visual field. It was felt
that some adverse treatment effects were related to focal treat-
ment of NVD and elevated NVE, and this aspect of treatment
was abandoned.104 Other studies comparing the use of xenon
arc and laser photocoagulation failed to demonstrate any signi-
ficant difference in the two modalities, either in effectiveness or
in the rate of visual loss related to treatment.106,107 However, they
did confirm the greater risk of field loss occurring after xenon
arc treatment, which probably correlates with the inner retinal
damage with a xenon arc burn evident on histopathology.108
Regression of neovascularization occurs in 30–55% of eyes
after laser photocoagulation using various treatment approaches
and may correlate with visual prognosis (Fig. 135.9). The DRS
found complete regression of NVD in 29.8% and partial regres-
sion in 24.5% of eyes 12 months after treatment.2 Blankenship
compared central and peripheral photocoagulation and found a
trend toward decreased visual loss (related to treatment) in the
peripheral distribution group and a slightly smaller loss of
visual field. Regression of NVD was similar in both groups, with
47% complete regression in the peripheral distribution group
versus 40% in the central distribution group. In both groups,
33% of patients had partial regression of NVD after photo-
coagulation.108 Regression of NVD should be assessed several
weeks after photocoagulation as a prognostic indicator and to
1818 determine whether additional treatment is necessary. Doft and
Blankenship have shown that regression of neovascularization
3 weeks after treatment is a good indicator of longer-term visual
results.109 Vine suggested that eyes be assessed 6–8 weeks
after laser treatment and that treatment be augmented if high-
risk characteristics persist.110 He described a group of
‘nonresponders’ who continued to have high-risk characteristics
despite augmented PRP averaging 3000 Goldman burns.
Approximately 50% of these ‘nonresponders’ did respond to
additional low-intensity, but extensive, photocoagulation,
reaching an average of 7550 Goldman burns, with preservation
of visual acuity.
Although the DRS used blue-green argon wavelengths or
xenon arc for photocoagulation, other wavelengths are
employed by treating ophthalmologists. Argon green has
replaced argon blue-green to avoid long-term retinal toxicity in
the treating physician. Dye yellow, krypton red, and diodes
emitting in the near-infrared have all been utilized for PRP.
Studies have compared the effectiveness of certain wavelengths
but not all. Krypton red photocoagulation was demonstrated to
be as effective as argon blue-green for the treatment of PDR,
comparing visual outcome, regression of vessels, and incidence
of complications.111
There is some controversy regarding photocoagulation in the
presence of tractional retinal detachment. If the tractional
retinal detachment involves the fovea, vitrectomy is indicated.
However, concerns are often expressed that photocoagulation in
patients with extrafoveal tractional detachments will lead to
worsening of the detachment and involvement of the fovea. The
DRS found that harmful treatment effects, including decreased
visual acuity, were associated with preexisting fibrous prolifera-
tions and localized retinal detachments, particularly in the
xenon-treated group.105 However, the report also confirmed that
those patients with severe proliferative retinopathy still bene-
fited from argon laser treatment. Some authors have suggested
‘prophylactic vitrectomy’ for traction retinal detachments
‘threatening’ the macula.112 This approach may unnecessarily
subject some patients to the risks of vitrectomy surgery. One
study investigating argon laser photocoagulation in patients
with severe proliferative retinopathy and posterior extrafoveal
traction detachments found that detachments rarely progress
after treatment to involve the fovea.113 In this study, the area of
detachment was avoided with otherwise standard photocoagu-
lation techniques and without any effort to wall off the
detachment.113 PRP with careful follow-up should be the first
line of therapy in patients with proliferative retinopathy and
traction retinal detachments not involving the fovea.
The DRS found that eyes with high-risk characteristics have
a 2 year risk of severe visual loss of 25%. Scatter photocoagula-
tion reduces the risk of severe visual loss by 50% or more. Eyes
with severe nonproliferative retinopathy or proliferative retino-
pathy without high-risk characteristics have a 2 year risk of
severe visual loss of 3–7%. Thus, the risk of visual-acuity loss
relating to treatment assumes greater relative importance.104
The DRS was unable to determine whether deferral of treat-
ment with observation in this group was better than early
treatment. The Early Treatment of Diabetic Retinopathy Study
was designed in part to determine the optimal timing of photo-
coagulation. Early treatment for nonproliferative retinopathy
was compared with deferral of photocoagulation until high-risk
characteristics developed. There was a small reduction in the
rate of severe visual loss with early treatment, but the rates of
severe visual loss were low in both groups (2.6% for the early
treatment group, and 3.7% for the deferral group).114 Therefore,
the study group initially recommended that as long as careful
follow-up can be provided for the patient, PRP is not recom-
mended for eyes with mild or moderate nonproliferative retino-
pathy. It is important to note that the data was subsequently
 Proliferative Diabetic Retinopathy

a b c

CHAPTER 135
d e f

g h i

j k

FIGURE 135.9. Progression of PDR despite panretinal photocoagulation. (a) A 29-year-old man with preproliferative changes in the right eye.
Vascular dilatation, cotton-wool spots, and intraretinal hemorrhages are seen. Visual acuity is 20/25. (b) Superior retina with similar
preproliferative changes. (c) Fluorescein angiogram shows numerous microaneurysms with leakage and an enlarged foveal avascular zone.
(d) Superior retina with capillary nonperfusion and leakage into the vascular walls. (e) Patient was lost to follow-up for 1.5 years and presented
with severe NVD. Visual acuity is 20/25. (f) Fluorescein angiogram shows marked progression of ischemic changes in association with prominent
leakage from NVD. (g) Angiogram of the superior retina shows greatly increased ischemia compared with the previous angiogram. (h) Angiogram
of the nasal retina documents almost total closure of the capillary bed in association with areas of neovascularization. (i) Six months later, NVD
progressed despite extensive and repeated panretinal photocoagulation. (j) After an additional 10 months, a traction retinal detachment involving
the fovea developed. The retina was obscured by neovascular tissue, and visual acuity is counting fingers at 1 ft. (k), One year after vitrectomy
and endolaser treatment, the retina is attached but displays vascular and optic atrophy, and visual acuity is 20/200.

1819
 RETINA AND VITREOUS

re-analyzed taking into account the type of diabetes, type 1 or
type 2. In this analysis, there was an advantage in treating
severe nonproliferative or early PDR with PRP in patients with
type 2 diabetes.115 The physician must also incorporate clinical
judgment, including assessment of the fellow eye, progression
of lens opacities, and other conditions.
Complications
Laser photocoagulation is clearly an effective treatment but can
result in complications (Table 135.2). These complications may
occur during treatment in the immediate postoperative period
or present as long-term problems (Fig. 135.10). Pain during
treatment is usually transient but may require retrobulbar
anesthesia for completion of the session. Increased intraocular
TABLE 135.2 Complications of Panretinal Photocoagulation
SECTION 10
pressure can occur, particularly after heavy treatment, because
of choroidal swelling and angle shallowing, but it usually
resolves after 48 h.116 It can usually be avoided with divided
sessions or lighter treatment. The cornea in diabetic patients is
very sensitive to contact lens trauma, and corneal abrasion
during treatment may result in a persistent epithelial defect.
The cornea should be inspected after treatment and any abrasions
treated appropriately. Mydriasis is the result of laser damage to
nerves in the uveal tract and is permanent. Paralysis of accom-
modation can occur but is usually transient.117
Macular edema and visual acuity loss of one to three lines can
occur and are more common in patients with perifoveal capillary
nonperfusion. Maximum macular edema after panretinal
photocoagulation can occur anywhere from 4 to 7 weeks after
the initial laser treatment. However, visual recovery is usually
good.117a Visual-field loss secondary to photocoagulation was
documented in the DRS and is related to the extent of
treatment;104 loss of dark adaptation can also occur after PRP.118

Foveal burn Choroidal detachment and exudative retinal detachment are

Optic disc damage usually the result of very heavy PRP and generally resolve
spontaneously.119 Choroidal hemorrhage can occur with a very
Macular edema
heavy burn, particularly with longer wavelengths, but is usually
Choroidal hemorrhage limited and resolves spontaneously. Subretinal neovasculariza-
Choroidal neovascularization
tion has been reported and should be treated if it is macular.120
Foveal burns are the result of the surgeon’s disorientation or
Choroidal detachment unfortunate ocular movement and result in permanent loss of
Exudative retinal detachment central acuity, but there may be some improvement after the
initial loss. Vision loss has also been reported in association
Vitreous hemorrhage
with peripapillary treatment.121 Vitreous hemorrhage can result
Pain during treatment from rupture of neovascular vessels during treatment (rarely) or
Increased intraocular pressure from shrinkage and regression of neovascular tissue after treat-
ment (commonly). Hemorrhage that occurs after panretinal
Corneal abrasion photocoagulation usually resolves with time but may occasion-
Mydriasis and paresis of accommodation ally require vitrectomy. Direct treatment of elevated neovascu-
larization with green (514 nm) or yellow (577 nm) wavelengths
Loss of visual field
has a limited role and is restricted to eyes with recurrent
Loss of dark adaptation vitreous hemorrhage and persistent neovascularization despite
Lens opacities complete PRP.
Lens opacities can occur with high energy and misfocusing,
Increase in traction detachments particularly with the panfundus-style lenses, and are usually
permanent but nonprogressive.122,123 Vascular occlusion can

FIGURE 135.10. Panretinal photocoagulation

and complications. (a) Wide-angle photograph
of a typical panretinal photocoagulation pattern.
(b) Choroidal and exudative retinal detachment
after extensive photocoagulation for rubeosis.
(c) Macular edema 2 weeks after panretinal
photocoagulation. Visual acuity is at the
counting fingers at 2 ft level, and was 20/30
before laser. (d) Fluorescein angiogram
documents cystoid edema. Edema resolved in
1 month with visual recovery.
a b

c d
1820

result from placement of burns over a vessel. Frequently, the
vessel will again become patent. Although heavy treatment with
the xenon arc photocoagulator in eyes with active vitreoretinal
traction can lead to progression of an extrafoveal tractional
retinal detachment into the fovea in certain cases, data indicate
that argon laser therapy may be safely performed in these
eyes.113 Care should be taken to avoid heavy treatment near
areas of vitreoretinal traction.
THE ROLE OF VITRECTOMY FOR
PROLIFERATIVE DIABETIC RETINOPATHY
Indications
Laser photocoagulation allows effective treatment of moderate
to severe PDR. However, although treatment substantially
reduces the risk of severe visual loss, PDR in a certain number
of eyes progresses to tractional retinal detachment and vision
loss. Standard laser cannot be performed in eyes with vitreous
hemorrhage precluding visualization of the retina. Vitrectomy
was first introduced by Machemer in the 1970s as a method
of removing nonclearing vitreous hemorrhage.124 As techniques
and instrumentation have improved, its indications have
broadened (Table 135.3).125,126
Removing dense, nonclearing vitreous hemorrhage remains
an important indication for vitrectomy in diabetics. The Diabetic
Vitrectomy Study Group studied the timing of vitrectomy and
its effect on visual outcome and complications.127,128 They
included patients with severe vitreous hemorrhage (visual
acuity < 5 /200) and compared early vitrectomy (after 1 month)
with deferred vitrectomy (after 1 year). In patients with type 1
diabetes, early vitrectomy offered a greater chance of visual
recovery. In type 2 diabetics and mixed type, the visual results
were essentially the same whether vitrectomy was performed
early or after 1 year. However, the study was performed without
TABLE 135.3 Indications for Vitrectomy in Proliferative Diabetic
Retinopathy
Vitreous hemorrhage
Nonclearing, based on duration and visual need
To permit photocoagulation of active retinopathy
Traction retinal detachment involving the fovea
Visual loss owing to macular striae or distortion (tangential traction)
Combined traction-rhegmatogenous retinal detachment
Rubeosis with media opacity precluding panretinal photocoagulation
Visual loss owing to epiretinal membrane or opacified posterior
vitreous face
Progressive neovascularization unresponsive to retinal ablation
a b
Proliferative Diabetic Retinopathy
standardized photocoagulation management in the deferred
vitrectomy group and without the use of endolaser photocoagu-
lation in diabetic vitrectomy in either group, and the validity
of its conclusions may be questioned. Nevertheless, early
vitrectomy offers the chance for prompt recovery of vision,
which is of greatest importance to patients who do not have
useful vision in the fellow eye.126
Progressive fibrovascular proliferation in diabetes can lead to
tractional retinal detachment. Posterior tractional detachments
not involving the fovea may remain stable and should be
observed.92,113,126 However, once the fovea is involved, vitrec-
tomy is indicated. Surgery should be performed promptly because
degenerative changes in the detached retina will prevent visual
recovery after reattachment (Fig. 135.11). The combination of
vitreous traction and membrane contraction can lead to retinal
holes and combined traction-rhegmatogenous retinal detach-
ments, which need to be approached via pars plana vitrectomy.
Some patients will present with cataract and proliferative
CHAPTER 135
disease. If adequate PRP cannot be performed because of media
opacity, there are several management options. Cataract surgery
can be performed using extracapsular or phacoemulsification
techniques, with PRP performed within a few days of surgery. It
should be kept in mind that proliferation may progress rapidly
after cataract extraction. Alternatively, pars plana vitrectomy and
the endolaser can be performed in conjunction with cataract
removal, either pars plana lensectomy or phacoemulsification
via a limbal approach, with intraocular lens placement.92,126,129,130
Lensectomy can be performed with preservation of the anterior
capsule and sulcus fixation of a posterior chamber intraocular
lens after completion of the vitrectomy. Alternatively,
phacoemulsification may be performed, with placement of the
intraocular lens in the capsular bag either preceding pars plana
vitrectomy or after its completion. The advantage to placement
of the intraocular lens after the vitrectomy is improved visual-
ization of the retina during vitrectomy. A combined surgical
approach may be most useful in cases when the cataract is
visually significant and would prevent visualization of the fun-
dus during vitrectomy and when the anticipated retinal surgery
is not unduly complicated.
Iris neovascularization, with or without angle involvement
and glaucoma, is conventionally treated with panretinal photo-
coagulation. In cases of rubeosis, vitrectomy with endolaser use,
with or without lensectomy, is indicated in patients with media
opacities such as cataract or vitreous hemorrhage or when
retinal reattachment is also necessary.126,131
Epiretinal membranes develop in diabetes after premacular
hemorrhages or after extensive photocoagulation. Vitrectomy is
indicated when the patient’s vision is compromised enough to
warrant surgery.
Technique
The goals of vitrectomy in diabetic retinopathy are simple in
concept. One major objective is to remove media opacities,
FIGURE 135.11. Tractional retinal detachment
involving the fovea. (a) Preoperative
photograph illustrates extensive
neovascularization emanating from the disk
with tractional detachment. Visual acuity is
20/400. (b) Postoperative photograph after
vitrectomy shows retinal reattachment and
removal of neovascular tissue. Visual acuity is
20/40.
1821
 RETINA AND VITREOUS
either vitreous hemorrhage or cataract. The second objective is
to relieve vitreous traction causing detachment, distortion, or
displacement of the fovea, either transvitreal traction from
anterior vitreous to posterior attachments or tangential traction
from proliferative tissue adherent to the retinal surface. As
dissection is performed, it is important to obtain hemostasis to
preserve visualization and allow for effective endophoto-
coagulation. The final goal is to perform retinal ablation, usually
by laser, to prevent subsequent neovascular proliferation.126
Two major differences in the technical approach to diabetic
vitrectomy are (1) the segmentation technique, and (2) the
delamination and en-bloc resection techniques. In all approaches,
the anterior vitreous is removed to permit visualization and to
create a fluid space posterior to the lens. In segmentation, an
opening is made in the mid-peripheral detached vitreous where
it is typically separated from the underlying retina.124,126 This
opening is extended 360o at the equator and eliminates antero-
posterior traction. This ‘truncation of the vitreous cone’ sepa-
SECTION 10
rates the posterior vitreous face with its attachments to the
retina from the vitreous base anteriorly. Segmentation then
proceeds with dissection of the posterior vitreous face with
vertical scissors cuts around each neovascular attachment of
the posterior vitreous face to the underlying retina.92,126 The
end result is the segmentation of the posterior vitreous face into
small islands of residual neovascular attachments, and this
segmentation relieves contraction between these points and
permits reattachment of the retina. These islands can then be
trimmed with the vitrectomy instrument.
In delamination and en-bloc resection techniques, the
anteroposterior traction is not relieved initially but is used to
facilitate dissection of the posterior vitreous face in a horizontal
fashion. In the delamination technique, an opening is created in
the posterior vitreous face over the macula, gaining access to
the surgical plane between the posterior vitreous face and the
retina. Horizontal scissors transection across the neovascular
attachments above the disk and major vascular arcades is
performed radiating outward from the posterior pole, ultimately
freeing the retina from the posterior vitreous face entirely.92 In
the conceptually similar en bloc technique, access to this same
surgical plane is accomplished by creating an opening in the
peripheral detached vitreous and then proceeding with hori-
zontal scissors transection across the posterior pole.132 In both
techniques, the dissection is concluded by using the vitrectomy
instrument to remove the now freed posterior vitreous face as it
hangs supported by the remaining attachments to the anterior
vitreous base.
It should be emphasized that each of the techniques men-
tioned previously has adherents and detractors. The segmenta-
tion technique is criticized for the incomplete removal of
proliferative tissue from the retina with possible recurrent
hemorrhage or membrane proliferation, and the horizontal dis-
section techniques are criticized because there is a greater
a b
1822
frequency of retinal breaks and a possibility of increased intra-
ocular hemorrhage from transection across the neovascular
stalks. In actual practice, a combination of surgical approaches
is frequently required in a given eye.
Diathermy is used as needed to obtain hemostasis, but most
hemorrhages can be controlled by elevation of the infusion fluid
height.126 Airfluid exchange with internal drainage of subretinal
fluid is used in cases of retinal detachment with a posterior
retinal break. Panretinal endophotocoagulation is performed
when there is active neovascularization or preoperative iris
neovascularization or if panretinal photocoagulation has not
been performed before surgery.92,131 Endophotocoagulation is
also used to treat iatrogenic retinal breaks. Trans-scleral
cryopexy remains a useful tool when extensive retinal ablation
is required or the fundus view is lost. Intraocular tamponade
with air, long-acting gas, or silicone oil is used in cases of retinal
detachment.
Results
The results of vitrectomy for PDR have improved steadily since
the mid-1970s owing to increasing vitreoretinal surgical sophis-
tication in general and the introduction of the endolaser and the
continuing development of intraocular tamponade in particular.
Surgical results in patients with vitreous hemorrhage alone
suggest that 71–78% of patients will have improved vision
6 months after vitrectomy133–135 and that 76% of patients will
have visual acuity of 5/200 or better. For patients with traction
retinal detachment involving the fovea, 57–75% of patients will
have improved visual acuity,136–141 with 20/200 or greater acuity
at 6 months in 40–54% of patients (Fig. 135.12).138,140,141
Anatomic reattachment of the macula can now be obtained
intraoperatively in the great majority of cases,137,138 but recur-
rent macular detachment (resulting from recurrent epiretinal
tissue or rhegmatogenous detachment) occurs in 5–23%
of cases.137,140,141 For patients with combined tractional–
rhegmatogenous retinal detachment who require vitrectomy for
management, long-term macular re-attachment is obtained in
64% of cases, and improved visual acuity is observed in 53% of
cases, with 55% of these patients having postoperative visual
acuity greater than 5/200.142 These results are an improvement
over earlier series in which scleral buckling alone was available
for repair, in which the retina was reattached in 46% of cases
and 43% had improved visual acuity.143 For patients with
distortion of the macula from contraction of proliferative tissue
(tangential traction syndrome), visual acuity was improved in
four of four of patients in one report (Fig. 135.13).93 In a large
series, preoperative factors associated with a negative prognostic
value for visual recovery include iris neovascularization, cata-
ract, visual acuity less than 5/200, and retinal detachment.144
Long-term studies indicate the stability of visual and anatomic
results of vitreoretinal surgery for PDR.145 However, postoper-
ative complications such as rubeosis (with or without neovascular
FIGURE 135.12. Tractional retinal detachment
involving the fovea. (a) Preoperative photograph
shows severe neovascularization with
detachment of the fovea. Visual acuity is
20/400. (b) Postoperative appearance after
vitrectomy shows retinal reattachment with
continued inferior distortion of the macula.
Visual acuity is 20/200.
 Proliferative Diabetic Retinopathy

a b c

FIGURE 135.13. Tangential traction on the fovea with decreased vision. (a) Preoperative appearance shows macular striae to regressed
neovascular tissue to the disc. Visual acuity is 20/80. (b) Fluorescein angiogram documents extensive cystoid edema, primarily affecting the area
of traction. (c) Postoperative photograph 2 months after vitrectomy and removal of posterior vitreous face. Traction is relieved and visual acuity
is 20/70.

CHAPTER 135
a b

FIGURE 135.14. Complications of vitrectomy. (a) Rubeosis, hyphema, neovascular glaucoma, and recurrent detachment after failed vitrectomy
for traction retinal detachment involving the fovea; visual acuity is at the no-light perception level. (b) Anterior hyaloid fibrovascular proliferation in
a 22-year-old man after phakic diabetic vitrectomy. Visual acuity is at the seeing-hand motions level, and the eye was lost despite repeat surgery.

glaucoma), retinal detachment, recurrent vitreous hemorrhage,
and anterior hyaloid fibrovascular proliferation are the chief
causes of irreparable visual loss in these patients.133–142,146,147
Complications
Postoperative complications after vitrectomy can be early
(within the first week) or late (weeks to months later). Early
complications are frequent but can usually be treated
successfully. The cornea of the diabetic individual is susceptible
to injury at surgery, and epithelial defects may be difficult to
heal, requiring pressure patching and, occasionally, bandage
contact lens for resolution.126 Cataract formation may occur
from direct lens trauma at the time of vitrectomy or from
exposure to intraocular gas postoperatively.92,126 Lens removal
should be performed, if visually significant, after the posterior
segment is stable, or sooner if significant complications arise
from lens-induced glaucoma or inflammation.
Postoperative hemorrhage usually resolves spontaneously
over several weeks. If the fundus is obscured, ultrasound should
be performed periodically to exclude retinal detachment.92,126 If
the blood does not clear within several weeks or if there is a
concurrent retinal detachment, reoperation is indicated. Ghost
cell glaucoma is an infrequent complication but usually requires
a washout procedure to control the intraocular pressure.92
Retinal detachment after vitrectomy may result from unrecog-
nized retinal holes or traction and requires reoperation.92,126
Endophthalmitis is rare and should be diagnosed and treated
emergently. Glial recurrence occurs rarely, the glial tissue
proliferates directly on the retinal surface and is managed
surgically with a segmentation–delamination approach.92
Iris and angle neovascularization may develop after vitrectomy;
it is usually related to rhegmatogenous retinal detachment or
extensive retinal ischemia (Fig. 135.14a).92,126 Surgery for the
retinal detachment with extensive panretinal photocoagulation
is indicated. Anterior hyaloidal fibrovascular proliferation is a
serious complication of diabetic vitrectomy and is most
commonly observed in juvenile diabetics with severe retinal
ischemia undergoing vitrectomy without lens removal.146,147 In
this situation, extensive neovascularization develops posterior
to the lens and along the anterior hyaloid (Fig. 135.14b). Unless
surgical intervention, including lensectomy and extensive
peripheral retinal ablation, is performed promptly, these eyes
are invariably lost.
INTRAVITREAL INJECTION OF
ANTIANGIOGENIC AGENTS
Much recent attention has focused on the role of intravitreal
injections of antiangiogenic agents in the treatment of a number
of retinal conditions, including age-related macular degenera- 1823
 RETINA AND VITREOUS

tion, diabetic macular edema, and diabetic PDR. There are a
number of potential complications of intraocular injections,
including endophthalmitis, retinal tears/detachments, vitreous
hemorrhage, cataract, hypotony, and glaucoma. In spite of these
risks, however, a review of the literature indicates that the risk
of a serious adverse event from an intravitreal injection is relatively
low. Jager et al analyzed data from 14 866 intravitreal injections
in 4382 eyes and found a prevalence of 0.2% per injection and
0.5% per eye of endophthalmitis after excluding cases reported
specifically as pseudoendophthalmitis.148 Guidelines for proper
technique in intravitreous injections are still evolving,149
although certain procedures, including the routine use of a wire
lid speculum, sterile preparation with povidone iodine, and the
avoidance of a paracentesis have gained widespread acceptance
as means toward reducing the risk of endophthalmitis.
Intravitreal steroids have.been used as adjuncts to both PRP
and vitrectomy for PDR. Although there are no large-scale,
randomized, placebo-controlled clinical trials in the literature to
SECTION 10
its effects are less well-established regarding proliferative
disease.151 Some surgeons have advocated the intraoperative use
of triamcinolone acetonide in order to improve staining and
visualization of the vitreous to facilitate the identification and
removal of the posterior hyaloid face.
Anti-VEGF agents that have been used in the treatment of
PDR include the nonselective VEGF inhibitors ranibizumab
and bevacizumab as well as pegaptanib sodium which is a
targeted aptamer against the VEGF isoform 165. Although there
is extensive data on these agents in the treatment of choroidal
neovascularization from age-related macular degeneration, the
literature on their use in treatment of PDR is limited to case
reports and series. Nonetheless, the anecdotal evidence that
exists suggests that anti-VEGF therapy is effective in at least
some patients in regressing iris and retinal neovascularization
and reducing vitreous hemorrhage.152,153 The Macugen Diabetic
Retinopathy Study Group reported that in patients with PDR
who were enrolled in a study of pegaptanib sodium for diabetic

address the efficacy of intravitreal steroids for retinal neovascu-
larization, the available case reports suggest that intraocular
steroids are well tolerated at least in the short term.150 Well-
documented complications of long-term steroid administration
include cataract and glaucoma. Although intraocular steroid
often has a beneficial, if temporary effect on macular edema,
macular edema, 62% (eight of 13) of patients treated with
pegaptanib demonstrated regression of neovascularization on
fundus photographs and/or decreased fluorescein leakage from
their neovascularization. None of the fellow, nonstudy eyes or
eyes randomized to sham injection showed a similar regression
of neovascularization.154

REFERENCES
1. Waite J, Beetham W: The visual mechanism
in diabetes mellitus: comparative study of
2002 diabetics and 457 non-diabetics for
control. N Engl J Med 1935; 212:367–429.
2. The Diabetic Retinopthay Study Research
Group: Photocoagulation treatment of
proliferative diabetic retinopathy: the
second report of Diabetic Retinopathy
Study findings. Ophthalmology 1978; 85:82.
3. The Diabetic Retinopathy Study Group:
Preliminary report on effects of
photocoagulation therapy. Am J Ophthalmol
1976; 81:383–396.
3a. World Health Organization. Diabetes fact
sheet. Available: http://www.who.int/
hpr/NPH/docs/gs_diabetes.pdf#search=%2
2370%20million%20diabetes%20world%2
0health%20organization%22 30 Sept
2006.
4. Klein R, Klein B: Vision disorders in
diabetes. In: Harris M, Hamman R, eds.
Diabetes Data Compiled 1984, p XIII.
Washington, DC: US Government Printing
Office; 1985.
4a. Aiello LP: Angiogenic pathways in diabetic
retinopathy. N Engl J Med 2005;
353:839–841.
4b. Bursell SE, Clermont AC, Kinsley BT, et al:
Retinal blood flow changes in patients with
insulin-dependent diabetes mellitus and no
diabetic retinopathy. Invest Ophthalmol Vis
Sci 1996; 37:886–897.
5. Michaelson IC: The mode of development
of the vascular system of the retina, with
some observations on its significance for
certain retinal disease. Trans Ophthalmol
Soc UK 1948; 68:137–180.
5. Plehwe W, Sleightholm M, Kohner E, et al:
Does vitreous fluorophotometry reflect
severity of early diabetic retinopathy? Br J
Ophthalmol 1989; 73:225–260.
6. Frank R: Diabetic retinopathy: current
concepts of evaluation and treatment. Clin
Endocrinol Metab 1986; 15:933–969.
7. Aiello L, Li R, Sebestyen J, et al: The eyes
1824 and diabetes. In: Marble A, ed. Joslin’s
Diabetes Mellitus. 12th edn. Philadelphia:
Lea & Febiger; 1985.
8. Tolentino MJ, Miller JW, Gragoudas ES,
et al: Intravitreous injections of vascular
endothelial growth factor produce retinal
ischemia and microangiopathy in an adult
primate. Ophthalmology 1996;
103:1820–1828.
9. Amin R, Frank R, Kennedy A, et al: Vascular
endothelial growth factor is present in glial
cells of the retina and optic nerve of human
subjects with nonproliferative diabetic
retinopathy. Invest Ophthalmol Vis Sci 1997;
38:36–47.
10. Pascal DI, Bindley CO, Wallow IHL:
Clinicopathologic correlation of intraretinal
microvascular abnormalities. Retina 1997;
17:321–329.
11. Chang S, Leonard-Martin T, Feman S:
Relationship between IRMA and diabetic
neovascularization. Invest Ophthalmol Vis
Sci 1995; 36:S483.
13. Ashton N: Retinal vascularization in health
and disease. Am J Ophthalmol 1957;
44:7–24.
14. Kohner E, Schilling J, Hamileton A: The role
of avascular retina in new vessel formation.
Metab Ophthalmol 1976; 1:15.
15. Wise G: Retinal neovascularization. Trans
Am Ophthalmol Soc 1956; 54:729–826.
16. Branch Vein Occlusion Study Group: Argon
laser scatter photocoagulation for prevention
of neovascularization and vitreous
hemorrhage in branch vein occlusion. Arch
Ophthalmol 1986; 104:34–41.
17. Baird A, Böhlen P: Fibroblast growth
factors. In: Roberts AB, Sporn MB, eds.
Handbook of Experimental Pharmacology:
Peptide Growth Factors and Their
Receptors. Berlin: Springer-Verlag;
1990:369–418.
18. Mignatti P, Tsuboi R, Robbins E, et al: In
vitro angiogenesis on the human amniotic
membrane: requirement for basic fibroblast
growth factor-induced proteinases. J Cell
Biol 1989; 108:671–682.
19. Montesano R, Vassali JD, Baird A, et al:
Basic fibroblast growth factor induces
angiogenesis in vitro. Proc Natl Acad Sci
USA 1986; 83:7297–7301.
20. Lobb RR, Alderman EM, Fett JW: Induction
of angiogenesis by bovine brain derived
class I heparin-binding growth factor.
Biochemistry 1985; 24:4969–4973.
21. Shing Y, Folkman J, Haudenschild C, et al:
Angiogenesis is stimulated by a tumor-
derived endothelial cell growth factor. J Cell
Biochem 1985; 29:275–287.
22. Esch F, Ueno N, Baird A, et al: Primary
structure of bovine brain acidic fibroblast
growth factor. Biochem Biophys Res
Commun 1986; 133:554–562.
23. Gospodarowicz D: Fibroblast growth
factors. In: Pimental E, Perucho M, eds.
Critical Reviews in Oncogenesis. Boca
Raton, FL: CRC; 1989:1–26.
24. Abraham JA, Mergia A, Whang JL, et al:
Nucleotide sequence of a bovine clone
encoding the angiogenic protein, basic
fibroblast growth factor. Science 1986;
233:545–548.
25. D’Amore PA, Klagsbrun M: Endothelial
mitogens derived from retina and
hypothalamus: Biological and biochemical
similarities. J Cell Biol 1984; 99:1545–1549.
26. Caruelle D, Groux MB, Gaudric A, et al:
Immunological study of acidic fibroblast
growth factor (aFGF) distribution in the eye.
J Cell Biochem 1989; 39:117–128.
27. Gao H, Hollyfield JG: Basic fibroblast
growth factor (bFGF) immunolocalization in
the rodent outer retina demonstrated with
an anti-rodent bFGF antibody. Brain Res
1992; 585:355–360.
28. Nyberg F, Hahnenberger R, Jakobson AM,
et al: Enhancement of FGF-like
polypeptides in the retinae of newborn mice
exposed to hyperoxia. FEBS Lett 1990;
267:75–77.
29. Zhang NL, Samadani EE, Frank RN:
Mitogenesis and retinal pigment epithelial
cell antigen expression in the rat after

krypton laser photocoagulation. Invest
Ophthalmol Vis Sci 1993; 34:2412–2424.
30. Sivalingam A, Kenney J, Brown GC, et al:
Basic fibroblast growth factor levels in the
vitreous of patients with proliferative
diabetic retinopathy. Arch Ophthalmol
1990; 108:869–872.
31. Vlodavsky I, Folkman J, Sullivan R, et al:
Endothelial cell-derived basic fibroblast
growth factor: Synthesis and deposition
into subendothelial extracellular matrix.
Proc Natl Acad Sci USA 1987;
84:2292–2296.
32. McNeil PL, Muthukrishnan L, Warder E,
et al: Growth factors are released by
mechanically wounded endothelial cells.
J Cell Biol 1989; 109:811–822.
33. LeRoith D, Roberts CT Jr: Insulin-like
growth factors. Ann N Y Acad Sci 1993;
692:1–9.
34. Salmon WD Jr, Daughaday WH: A
hormonally controlled serum factor which
stimulates sulfate incorporation by cartilage
in vitro. J Lab Clin Med 1957; 49:825–836.
35. Poulsen JE: The Houssay phenomenon in
man. Recovery from retinopathy in a case
of diabetes with Simmonds’ disease.
Diabetes 1953; 2:7–12.
36. Grant M, Jerdan J, Merimee TJ: Insulin-like
growth factor-I modulates endothelial cell
chemotaxis. J Clin Endocrinol Metab 1987;
65:370–371.
37. Grant MB, Mames RN, Fitgerald C, et al:
Insulin-like growth factor I as an angiogenic
agent. In vivo and in vitro studies. Ann N Y
Acad Sci 1993; 692:230–242.
38. Grant M, Russell B, Fitgerald C, et al:
Insulin-like growth factors in vitreous.
Studies in control and diabetic subjects
with neovascularization. Diabetes 1986;
35:416–420.
39. Miller J, Adamis A, Aiello L: Vascular
endothelial growth factor in ocular
neovascularization and proliferative diabetic
retinopathy. Diabetes Metab Rev 1997;
13:37–50.
40. Miller JW, Adamis AP, Shima D, et al:
Vascular endothelial growth factor/vascular
permeability factor is temporally and
spatially correlated with ocular
angiogenesis in a primate model. Am J
Pathol 1994; 145:574–584.
41. Pierce EA, Avery R, Foley E, et al: Vascular
endothelial growth factor/vascular
permeability factor expression in a mouse
model of retinal neovascularization. Proc
Natl Acad Sci USA 1995; 92:905–909.
42. Dorey C, Aouididi S, Reynaud X, et al:
Correlation of vascular permeability
factor/vascular endothelial growth factor
with extraretinal neovascularization in the
rat. Invest Ophthalmol Vis Sci 1996;
114:1210–1217.
43. Stone J, Chan-Ling T, Pe’er J, et al: Roles
of vascular endothelial growth factor and
astrocyte degeneration in the genesis of
retinopathy of prematurity. Invest
Ophthalmol Vis Sci 1996; 37:290–299.
44. Adamis A, Shima D, Tolentino M, et al:
Inhibition of VEGF prevents ocular
neovascularization in a non-human primate.
Arch Ophthalmol 1996; 114:66–71.
45. Aiello L, Pierce E, Foley E, et al: Inhibition
of vascular endothelial growth factor
suppresses retinal neovascularization in
vivo. Proc Natl Acad Sci USA 1995;
92:10457–10461.
46. Aiello L, Avery R, Arrigg P, et al: Vascular
Proliferative Diabetic Retinopathy
endothelial growth factor in ocular fluid of
patients with diabetic retinopathy and other
retinal disorders. N Engl J Med 1994;
331:1480–1487.
47. Adamis AP, Miller JW, Bernal MT, et al:
Elevated vascular permeability
factor/vascular endothelial growth factor
levels in the vitreous of eyes with
proliferative diabetic retinopathy. Am J
Ophthalmol 1994; 118:445–450.
48. Malecaze F, Clamens S, Simorre-Pinatel V,
et al: Detection of vascular endothelial
growth factor messenger RNA and vascular
endothelial growth factor-like activity in
proliferative diabetic retinopathy. Arch
Ophthalmol 1994; 112:1476–1482.
49. Tolentino M, Miller J, Gragoudas E, et al:
Vascular endothelial growth factor is
sufficient to produce iris neovascularization
and neovascular glaucoma in a nonhuman
primate. Arch Ophthalmol 1996;
114:964–970.
50. Okamoto N, Tobe T, Hackett S, et al:
Transgenic mice with increased expression
of vascular endothelial growth factor in the
retina: a new model of intraretinal and
subretinal neovascularization. Am J Pathol
1997; 151:281–291.
50a. Meier M, King GL: Protein kinase C
activation and its pharmacological
inhibition in vascular disease. Vascular Med
2000; 5:173–185.
50b. Williams B: Factors regulating the
expression of vascular
permeability/vascular endothelial growth
factor by human vascular tissues.
Diabetologia 40: S118–S120, 1997
50c. Ishii H, Jirousek MR, Koya D et al:
Amerlioration of vascular dysfunctions in
diabetic rats by an oral PKC inhibitor.
Science 1996; 272:728–731
50d. Aiello LP, Bursell SE, Clermont A, et al:
Vascular endothelial growth factor-induced
retinal permeability is mediated by protein
kinase C in vivo and suppressed by an
orally effective beta-isoform-selective
inhibitor. Diabetes 1997; 46:1473–1480
50e. Suzuma K, Takahara N, Suzuma I, et al:
Characterization of protein kinase C
isoform’s action on retinoblastoma protein
phosphorylation, vascular endothelial
growth factor-induced endothelial cell
proliferation, and retinal neovascularization.
Proc Natl Acad Sci USA 2002; 99:721–726.
51. Tagawa H, McMeel J, Furukawa H, et al:
Role of the vitreous in diabetic retinopathy.
I. Vitreous changes in diabetic retinopathy
and in physiologic aging. Ophthalmology
1986; 93:596–601.
52. Foos R, Kreiger A, Forsythe A, et al:
Posterior vitreous detachment in diabetic
subjects. Ophthalmology 1980;
87:122–128.
53. Klein R, Klein B, Moss S, et al: Diabetic
retinopathy. II. Prevalence and risk of
diabetic retinopathy when age at diagnosis
is less than 30 years. Arch Ophthalmol
1984; 105:520–526.
54. Klein R, Klein B, Moss S, et al: The
Wisconsin Epidemiologic Study of Diabetic
Retinopathy. III. Prevalence and risk of
diabetic retinopathy when age at diagnosis
is 30 or more years. Arch Ophthalmol 1984;
102:527–532.
55. Aiello L, Rand L, Briones J, et al: Diabetic
retinopathy in Joslin Clinic patients with
adult-onset diabetes. Ophthalmology 1981;
88:619–623.
56. Janka H, Warram J, Rand L, et al: Risk
factors for progression of background
retinopathy in long-standing IDDM.
Diabetes 1989; 38:460–464.
57. Baker R, Rand L, Krolewski A, et al:
Influence of HLA-DR phenotype and
myopia on the risk of nonproliferative and
proliferative diabetic retinopathy. Am J
Ophthalmol 1986; 102:693–700.
58. Rand L, Krolewski A, Aiello L, et al: Multiple
factors in the prediction of risk of
proliferative diabetic retinopathy. N Engl J
Med 1985; 313:1433–1438.
59. Rand L, Krolewski A, Warram J: Late
complications: The critical period. In:
Friedman E, L’Esperance A, eds. Diabetic
Renal-Retinal Syndrome. New York: Grune
& Stratton; 1986:3.
60. Orchard T, Dorman J, Maser R, et al:
Factors associated with avoidance of
CHAPTER 135
severe complications after 25 yr of IDDM.
Pittsburgh Epidemiology of Diabetes
Complications Study I. Diabetes Care
1990; 13:741–747.
61. Kroc Collaborative Study Group: Blood
glucose control and the evolution of
diabetic retinopathy and albuminuria:
A preliminary multicenter trial. N Engl J
Med 1984; 311:365–372.
62. Dahl-Jorgensen K, Brinchmann-Hanses O,
Hanssen K, et al: Effect of near
normoglycemia for two years on
progression of early diabetic retinopathy,
nephropathy, and neuropathy: The Oslo
Study. BMJ 1986; 293:1195–1199.
63. The DCCT Research Group: Diabetes
Control and Complications Trial (DCCT):
Results of feasibility study. Diabetes Care
1987; 10:1–19.
64. Rosenlund E, Hasskens K, Brinchmann-
Hanses O, et al: Transient proliferative
diabetic retinopathy during intensified
insulin treatment. Am J Ophthalmol 1988;
105:618–625.
65. Dandona P, Bolger J, Boag F, et al: Rapid
development and progression of
proliferative retinopathy after strict diabetic
control. BMJ 1985; 290:895–896.
66. Zinman B: The physiologic replacement of
insulin, an elusive goal. N Engl J Med 1989;
321:363–370.
67. The Diabetes Control and Complications
Trial Research Group: The effect of
intensive treatment of diabetes on the
development and progression of long-term
complications in insulin-dependent diabetes
mellitus. N Engl J Med 1993; 329:977–986.
68. The Diabetes Control and Complications
Trial Research Group: Progression of
retinopathy with intensive versus
conventional treatment in the Diabetes
Control and Complications Trial.
Ophthalmology 1995; 102:647–661.
69. Cheng H, Franklin S: Treatment of cataract
in diabetics with and without retinopathy.
Eye 1988; 2:607–614.
70. Jaffe G, Burton T: Progression of
nonproliferative diabetic retinopathy
following cataract extraction. Arch
Ophthalmol 1988; 106:745–749.
71. Benson W, Brown G, Tasman W, et al:
Extracapsular cataract extraction with
placement of a posterior chamber lens in
patients with diabetic retinopathy.
Ophthalmology 1993; 100:730–738.
72. Sebestyen J: Introcular lenses and diabetes
mellitus. Am J Ophthalmol 1986;
101:425–428. 1825
 RETINA AND VITREOUS
73. Alpar J: Diabetes: Cataract extraction and
intraocular lenses. J Cataract Refract Surg
1987; 13:43–46.
74. Aiello L, Wand M, Liang G: Neovascular
glaucoma and vitreous hemorrhage
following cataract surgery in patients with
diabetes mellitus. Ophthalmology 1983;
90:814–820.
75. Hykin P, Gregson R, Stevens J, et al:
Extracapsular cataract extraction in
proliferative diabetic retinopathy.
Ophthalmology 1993; 100:394–399.
76. Lischwe T, Ide C: Predicting visual acuity
after cataract surgery using the blue field
entoptoscope and projected slides.
Ophthalmology 1988; 95:256–260.
77. Beetham W: Diabetic retinopathy in
pregnancy. Trans Ophthalmol Soc UK
1950; 48:205–216.
78. Rodman H, Singerman LJ, Aiello L, et al:
Diabetic retinopathy and its relationship to
SECTION 10
pregnancy. In: Merkaty T, Adams P, eds.
The Diabetic Pregnancy: A Perinatal
Perspective. New York: Grune & Stratton;
1979.
79. Laatikainen L, Larinkari J, Teramo K, et al:
Occurrence and prognostic significance of
retinopathy in diabetic pregnancy. Metab
Pediatr Ophthalmol 1980; 4:191–195.
80. Klein B, Moss S, Klein R: Effect of
pregnancy on progression of diabetic
retinopathy. Diabetes Care 1990; 13:34–40.
81. Laatikainen L, Teramo K, Hieta-
Heikeraninen, et al: A controlled study of
the influence of continuous subcutaneous
insulin infusion treatment on diabetic
retinopathy during pregnancy. Acta Med
Scand 1987; 221:367–376.
82. Klein B, Klein R, Meur S, et al: Does the
severity of diabetic retinopathy predict
pregnancy outcome? J Diabetes
Complications 1988; 2:179–184.
83. Janka H, Ziegler A, Valsania P, et al: Impact
of blood pressure on diabetic retinopathy.
Diabetes Metab 1989; 15:333–337.
84. Chase H, Garg S, Jackson W, et al: Blood
pressure and retinopathy in type I diabetes.
Ophthalmology 1990; 97:155–159.
85. Krolewski A, Canessa M, Warram J, et al:
Predisposition to hypertension and
susceptibility to renal disease in insulin-
dependent diabetes mellitus. N Engl J Med
1988; 318:140–145.
86. Klein R: Recent developments in the
understanding and management of diabetic
retinopathy. Med Clin North Am 1988;
72:1415–1437.
87. Petersen M, Vine A: The University of
Michigan Pancreas Transplant Evaluation
Committee: Progression of diabetic
retinopathy after pancreas transplantation.
Ophthalmology 1990; 97:496–500.
88. Ramsay R, Goetz F, Sutherland D, et al:
Progression of diabetic retinopathy after
pancreas transplantation for insulin-
dependent diabetes mellitus. N Engl J Med
1988; 318:208–214.
89. The Diabetic Retinopathy Study Research
Group: Design, methods, and baseline
results. Invest Ophthalmol Vis Sci 1981;
21:149–226.
90. Davis M: Proliferative diabetic retinopathy.
In: Ryan S, ed. Retina. St Louis: Mosby;
1989:367–402.
91. Early Treatment of Diabetic Retinopathy
Study Group: Effects of aspirin treatment
on diabetic retinopathy. Ophthalmology
1826 1991; 98:107–120.
92. Charles S: Vitreous microsurgery.
Baltimore: Williams & Wilkins;
1981:107–120.
93. Packer A: Vitrectomy for progressive
macular traction associated with
proliferative diabetic retinopathy. Arch
Ophthalmol 1987; 105:1679–1682.
94. Poulsen J: Diabetes and anterior pituitary
insufficiency. Final course and postmortem
study of a diabetic patient with Sheehan’s
syndrome. Diabetes 1966; 15:73–77.
95. Luft R, Olivecrona H, Ikkos D, et al:
Hypophysectomy in man: further
experiences in severe diabetes mellitus.
BMJ 1955; 2:752-756.
96. Sharp P, Fallon T, Brazier O, et al: Long-term
follow-up of patients who underwent yttrium-
90 pituitary implantation for treatment of
proliferative diabetic retinopathy. Diabetologia
1987; 30:199–207.
97. Beetham W, Aiello L, Balodimos M, et al:
Ruby laser photocoagulation of early
diabetic neovascular retinopathy. Arch
Ophthalmol 1970; 83:261–272.
98. Beetham W: Visual prognosis of
proliferating diabetic retinopathy. Br J
Ophthalmol 1963; 47:611–619.
98. Meyer-Schwickerath G, Schott K: Diabetic
retinopathy and photocoagulation. Am J
Ophthalmol 1968; 66:597–603.
100. Aiello L, Beetham W, Balodimos M, et al:
Ruby laser photocoagulation in treatment
of diabetic proliferating retinopathy:
Preliminary report. In: Goldberg M, Fine S,
eds. Symposium on the Treatment of
Diabetic Retinopathy. Washington, DC:
Public Health Service; 1969:437.
101. Campbell C, Koester C, Curtice V, et al:
Clinical studies in laser photocoagulation.
Arch Ophthalmol 1965; 74:57–65.
102. The Diabetic Retinopathy Study Research
Group: Four risk factors for severe visual
loss in diabetic retinopathy. The third report
from the DRS. Arch Ophthalmol 1979;
97:654–655.
103. Doft B, Blankenship G: Single versus
multiple treatment sessions of argon laser
panretinal photocoagulation for proliferative
diabetic retinopathy. Ophthalmology 1982;
89:772–779.
104. The Diabetic Retinopathy Study Research
Group: Photocoagulation treatment of
proliferative diabetic retinopathy. Clinical
application of DRS findings.
Ophthalmology 1981; 88:583–600.
105. The Diabetic Retinopathy Study Research
Group: Photocoagulation treatment of
proliferative diabetic retinopathy:
Relationship of adverse treatment effects to
retinopathy severity. Dev Ophthalmol 1981;
2:248–261.
106. Okun E, Johnston G, Boniuk I, et al: Xenon
arc photocoagulation of proliferative
diabetic retinopathy. a review of 2688
consecutive eyes in the format of the
Diabetic Retinopathy Study. Ophthalmology
1984; 91:1458–1463.
107. Plumb A, Swan A, Chignell A, et al:
A comparative trial of xenon arc and argon
laser photocoagulation in the treatment of
proliferative diabetic retinopathy. Br J
Ophthalmol 1982; 66:213–218.
108. Blankenship G: A clinical comparison of
central and peripheral argon laser
panretinal photocoagulation for proliferative
diabetic retinopathy. Ophthalmology 1988;
95:170–177.
109. Doft B, Blankenship G: Retinopathy risk
factor regression after laser panretinal
photocoagulation for proliferative diabetic
retinopathy. Ophthalmology 1984;
91:1453–1457.
110. Vine A: The efficacy of additional argon
laser photocoagulation for persistent,
severe proliferative diabetic retinopathy.
Ophthalmology 1985; 92:1532–1537.
111. Blankenship G: Red-krypton and blue-
green argon panretinal laser
photocoagulation for proliferative diabetic
retinopathy: A laboratory and clinical
comparison. Trans Ophthalmol Soc UK
1986; 134:967–1003.
112. Shea M: Early vitrectomy in proliferative
diabetic retinopathy. Arch Ophthalmol
1983; 101:1204–1205.
113. D’Amico D: Diabetic traction retinal
detachments threatening the fovea and
panretinal argon laser photocoagulation.
Semin Ophthalmol 1991; 6:11–18.
114. Early Treatment Diabetic Retinopathy Study
Group: Early photocoagulation for diabetic
retinopathy. Ophthalmology 1991;
98:766–785.
115. Ferris F: Effect of Scatter
Photocoagulation: Type I vs. Type II
Diabetes. In: Vitreoretinal Frontiers. 21st
Century. San Francisco: American
Academy of Ophthalmology; 1996:93.
116. Blondeau P, Pavan P, Phelps C: Acute
pressure elevation following panretinal
photocoagulation. Arch Ophthalmol 1981;
99:1239–1241.
117. Lobes L, Bourgon P: Pupillary
abnormalities induced by argon laser
photocoagulation. Ophthalmology 1985;
92:234–236.
117a. Shimura M, Yasuda K, Nakazawa T, et al:
Quantifying alterations of macular thickness
before and after panretinal
photocoagulation in patients with severe
diabetic retinopathy and good vision.
Ophthalmology 2003; 110:2386–2394.
118. Pender P, Benson W, Compton H, et al:
The effects of panretinal photocoagulation
on dark adaptation in diabetics with
proliferative retinopathy. Ophthalmology
1981; 88:635–638.
119. Kleiner R, Elman M, Murphy R, et al:
Transient severe visual loss after panretinal
photocoagulation. Am J Ophthalmol 1988;
106:298–306.
120. Wallow I, Johns K, Barry P, et al:
Chorioretinal and choriovitreal
neovascularization after photocoagulation
for proliferative diabetic retinopathy.
Ophthalmology 1985; 92:523–532.
121. Swartz M, Apple D, Creel D: Sudden
severe visual loss associated with
peripapillary burns during panretinal argon
photocoagulation. Br J Ophthalmol 1983;
67:517–519.
122. McCanna R, Chandra S, Stevens T, et al:
Argon laser-induced cataract as a
complication of retinal photocoagulation.
Arch Ophthalmol 1982; 100:1071–1073.
123. Lakhanpal V, Schocket S, Richards R, et al:
Photocoagulation-induced lens opacity.
Arch Ophthalmol 1982; 100:1068–1070.
124. Machemer R: Vitrectomy: A Pars Plana
Approach. New York: Grune & Stratton;
1975.
125. Aaberg T, Abrams G: Changing indications
and techniques for vitrectomy in
management of complications of diabetic
retinopathy. Ophthalmology 1987;
94:775–779.

126. Michels R: Proliferative diabetic
retinopathy: pathophysiology of extraretinal
complications and principles of vitreous
surgery. Retina 1981; 1:1–17.
127. The Diabetic Retinopathy Vitrectomy Study
Research Group: Early vitrectomy for
severe vitreous hemorrhage in diabetic
retinopathy. Arch Ophthalmol 1985;
103:1644–1652.
128. The Diabetic Retinopathy Vitrectomy Study
Group: Two-year course of visual acuity in
severe proliferative diabetic retinopathy
with conventional management.
Ophthalmology 1985; 92:492–502.
129. Koenig S, Mieler W, Han D, et al:
Combined phacoemulsification, pars plana
vitrectomy, and posterior chamber
intraocular lens insertion. Arch Ophthalmol
1992; 110:1101–1104.
130. Senn P, Schipper I, Perren B: Combined
pars plana vitrectomy, phacoemulsification,
and intraocular lens implantation in the
capsular bag: a comparison to vitrectomy
and subsequent cataract surgery as a two-
step procedure. Ophthalmic Surg Lasers
1995; 26:420–428.
131. McCuen BD, Rinkoff J: Silicone oil for
progressive ocular neovascularization after
failed diabetic vitrectomy. Arch Ophthalmol
1989; 107:677–682.
132. Abrams G, Williams G: “En bloc” excision
of diabetic membranes. Am J Ophthalmol
1987; 103:302–308.
133. Mandelcorn M, Blankenship G, Machemer
R: Pars plana vitrectomy for the
management of severe diabetic retinopathy.
Am J Ophthalmol 1976; 81:561–570.
134. Michels R, Rice T, Tice E: Vitrectomy for
diabetic vitreous hemorrhage. Am J
Ophthalmol 1983; 95:12–21.
135. Peyman G, Raichand M, Huamonte F, et al:
Vitrectomy in 125 eyes with diabetic
vitreous hemorrhage. Br J Ophthalmol
1976; 60:752–755.
136. Barrie T, Feretis E, Leaver P, et al: Closed
microsurgery for diabetic traction macular
detachment. Br J Ophthalmol 1982;
66:754–758.
137. Williams D, Williams G, Hartz A, et al:
Results of vitrectomy for diabetic traction
retinal detachments using the en bloc
excision technique. Ophthalmology 1989;
96:752–758.
138. Aaberg T: Clinical results in vitrectomy for
diabetic traction retinal detachment. Am J
Ophthalmol 1979; 88:246–253.
139. Hutton W, Bernstein I, Fuller D: Diabetic
traction retinal detachment: Factors
influencing final visual acuity.
Ophthalmology 1980; 87:1071–1077.
140. Tolentino F, Freeman H, Tolentino F: Closed
vitrectomy in the management of diabetic
traction retinal detachment. Ophthalmology
1980; 87:1078–1089.
141. Rice T, Michels R, Rice E: Vitrectomy for
diabetic traction retinal detachment
involving the macula. Am J Ophthalmol
1983; 95:22–33.
142. Rice T, Michels R, Rice E: Vitrectomy for
diabetic rhegmatogenous retinal detachment.
Am J Ophthalmol 1983; 95:34–44.
143. Miller S, Shafrin G, Bresnick G, et al:
Scleral buckling for diabetic retinal
detachments secondary to proliferative
diabetic retinopathy. Am J Ophthalmol
1980; 89:103–112.
144. Thompson J, Auer C, de Bustros S, et al:
Prognostic indicators of success and failure
in vitrectomy for diabetic retinopathy.
Ophthalmology 1986; 93:290–295.
145. Blankenship G, Machemer R: Long-term
diabetic vitrectomy results: Report of
10-year follow-up. Ophthalmology 1985;
92:503–506.
Proliferative Diabetic Retinopathy
146. Lewis H, Abrams G, Williams G: Anterior
hyaoidal fibrovascular proliferation after
diabetic vitrectomy. Am J Ophthalmol
1987; 104:607–613.
147. Lewis H, Abrams G, Foos R:
Clinicopathologic findings in anterior
hyaloidal fibrovascular proliferation after
diabetic vitrectomy. Am J Ophthalmol
1987; 104:614–618.
148. Jager RD, Aiello LP, Patel SC, et al: Risks
of intravitreous injection: a comprehensive
review. Retina 2004; 24:676–698.
149. Aiello LP, Brucker AJ, Chang S, et al:
Evolving guidelines for intravitreous
injections. Retina 2004; 24:S3–S19.
150. Bandello F, Polito A, Pognuz DR, et al:
Triamcinolone as adjunctive treatment to
laser panretinal photocoagulation for
proliferative diabetic retinopathy. Arch
Ophthalmol 2006; 124:643–650.
CHAPTER 135
151. Jonas JB, Sofker A, Degenring R:
Intravitreal triamcinolone acetonide as an
additional tool in pars plana vitrectomy for
proliferative diabetic retinopathy. Eur J
Ophthalmol 2003; 13:468–473.
152. Oshima Y, Sakaguchi H, Gomi F, et al:
Regression of iris neovascularization after
intravitreal injection of bevacizumab in
patients with proliferative diabetic
retinopathy. Am J Ophthalmol 2006;
142:155–158.
153. Spaide RF, Fisher YL: Intravitreal
bevacizumab (Avastin) treatment of
proliferative diabetic retinopathy
complicated by vitreous hemorrhage.
Retina 2006; 26:275–278.
154. Adamis AP, Altaweel M, Bressler NM, et al;
Macugen Diabetic Retinopathy Study
Group: Changes in retinal
neovascularization after pegaptanib
(Macugen) therapy in diabetic individuals.
Ophthalmology 2006; 113:23–28.
1827
 CHAPTER
136 Advanced Retinopathy of Prematurity
Peter Hovland, Shizuo Mukai, and Tatsuo Hirose
INTRODUCTION
Retinopathy of prematurity (ROP) – the proliferation of
abnormal retinal blood vessels that occurs in premature infants
and its pathologic sequelae – has been and continues to be an
important cause of childhood blindness. Since 1942 when ROP
was first recognized by Terry,1,2 advances have been made both
in understanding the etiology and characterizing the
pathological progression of ROP, as well as establishing inter-
ventions timed to prevent or even reverse visual loss. Progress
in the field has been based on key observations, well designed
studies, and improvements in surgical techniques and
technology.
The pathophysiology, diagnosis and management of acute
ROP are covered extensively in Chapter 318. In this chapter, the
concentration will be on advanced stages of ROP, including
retinal detachment and preretinal fibrovascular proliferation,
and their management.
RETINAL DETACHMENT IN ROP
Key Features: Forms of Retinal Detachment
Tractional RD – Most common form observed in acute ROP
Exudative RD – More common in chronic forms
Rhegmatogenous RD – rarely noted in acute ROP. May be
iatrogenic
Patients with ROP have an increased lifetime risk for various
forms of retinal detachment. In acute ROP, the tractional RD is
most commonly observed. Tractional RDs originate at the ridge,
at which point myofibroblasts pull centripetally and anteriorly
toward the lens in a purse-string configuration. Once retinal
detachment occurs, it can progress rapidly. Peripheral detach-
a b
ments posterior to the ridge can proceed to total retinal detach-
ment within a day, and total detachments can become closed
funnels within a week in very active vasoproliferative ROP.
Peripheral retinal cryoablation during the acute phase of ROP
appears to reduce by half the incidence of childhood RD.3
Despite prophylactic ablative therapy RD can occur. Hartnett
and McColm report4 that factors associated with progression to
stage 4 RD following laser ablative therapy included the absence
of clear vitreous, ridge elevation of at least six clock hours,
and plus disease encompassing two or more quadrants.
In contrast, exudative retinal detachments occur less
commonly in acute ROP. These occur as a result of plasma
leakage from abnormal neovascular tufts, with subsequent
subretinal fluid accumulation. Chronic vitreoretinal traction to
the retinal vessels may play some role in causing exudation.
Exudative RD may occur more frequently in the adult patient
with ROP. The fundus usually shows smooth retinal
detachment with yellow subretinal exudates. Abnormal vessels
such as small angiomas with retinal hemorrhage can be seen.
Focal and diffuse pigmentary changes indicate the chronic
nature of the detachment. Chronic exudation may result in
anterior segment pathology (ischemia, cataract, neovasculari-
zation) and posterior segment dysfunction by exudative RD or
macular edema. Shallow exudative detachments of avascular
retina anterior to the ridge do not normally require surgical
intervention.5 The abnormal neovascular tufts may be treated
with cryotherapy to reduce fluid leakage (Fig. 136.1). Newer
therapies such as intravitreal antivascular endothelial growth
factor (anti-VEGF) compounds, which decrease vessel perme-
ability may be of some use in treating this condition in
the adult.
Rhegmatogenous detachments are seen only rarely in acute
ROP and are usually iatrogenic at this age. In contrast, they are
the most common retinal detachment seen in older children
FIGURE 136.1. (a) Fundus photograph of
stage 3 moderate retinopathy of prematurity.
A large ridge with extraretinal fibrovascular
proliferation is visible. Peripheral to this ridge is
a large area of avascular retina. (b) Fundus
photograph of the same eye immediately after
ablation of the avascular retina anterior to the
ridge by diode laser coagulation. In this case,
laser coagulation was applied in three to four
contiguous rows anterior to the ridge without
treating all the way up to the ora serrata.
Treatment was as effective as cryotherapy.
1829
 RETINA AND VITREOUS
and adults with cicatricial ROP. During early adolescence,
patients may be at an increased risk of developing RD.6 Many
of these cases are long-standing and are not noticed by the
patient until subretinal fluid expands into a large enough area
to produce visual symptoms. The detached retina is usually
thin, with multiple small equatorial breaks hidden by the
vitreous membrane. These late-occurring rhegmatogenous
detachments may be repaired with scleral buckle (SB) or
vitrectomy techniques,7,8 though successful repair of late-
occurring RD is more likely to require several procedures.9
Because of the increased risk of developing RD, regular eye
examinations are recommended in high-risk or preverbal
children with a history of ROP.8
SCLERAL BUCKLING
Scleral buckling can be used to treat milder forms of traction
retinal detachment in acute ROP.10–13 Retinal detachment in
SECTION 10
posterior zone ROP in which the ridge is located very posterior
to the equator showing a large attached avascular retinal
anteriorly can not be treated with a buckle. Beyrau and Danis
reported 14 that primary scleral buckling in 22 eyes of 14 infants
with stage 4a ROP resulted in successful maintenance of
attachment of the macula in 70% initially, and useful vision in
60%. Greven and Tasman15 reported successful reattachment
with scleral buckling in 13 of 22 eyes with stage 4b and stage 5
(open–open configuration) ROP. More than 50% of patients
had satisfactory anatomic results in most other studies.5,16–18
Prost reports19 that a modified SB encircling procedure was
used in 121 eyes of 68 infants with stage 5 ROP, resulting in a
52% total (and 24% partial) reattachment rate. However, only
20% of the operated eyes were judged by the author to have
useful vision. Scleral buckling is also used in the treatment of
rhegmatogenous detachment in ROP eyes.20
The timing or even indication of surgery in the management
of stage 4a detachment is controversial because many cases of
partial nonrhegmatogenous detachments often reattach spon-
taneously particularly when there is neither active vasopro-
liferation nor plus disease. However, since the duration of
retinal detachment influences prognosis, as the retina becomes
atrophic after relatively brief periods of detachment,18 scleral
buckling should be considered early in progressive traction
detachments and in large exudative detachments. There is less
agreement about surgery in traction detachments that do not
involve the posterior pole. Until a randomized, controlled trial
of surgery for stage 4 ROP is performed, the decision to under-
take surgery in these controversial cases must be determined on
an individual basis.
Cryotherapy or laser therapy is often performed at the time
of retinal detachment surgery, especially in traction or exudative
cases with continued active neovascularization. Cryotherapy
can be applied to the active neovascular ridge if the detachment
is shallow. The scleral depression made by a cryoprobe can
reach the ridge. The laser can be applied on the ridge on the
buckle after external drainage of subretinal fluid and after the
retina is attached. Cryotherapy or laser is unnecessary if there
is no active neovascularization. When the traction is effectively
released additional treatment to create chorioretinal adhesive
force is not required (athermal buckling). A silicone band is
used to encircle the globe along the site of the ridge. External
drainage of subretinal fluid is usually necessary to indent the
sclera effectively without raising the intraocular pressure due to
the SB. Greven and Tasman15 recommended scleral dissection
in some patients and fluid drainage in nearly all patients.
The silicone band in such small eyes may impair ocular
growth. How the tightly applied band affects the intraocular
1830 circulation and future development of vision is not known. Yet
there remains disagreement as to whether to cut or remove the
band at some time after scleral buckling surgery. Machemer and
deJuan17 do not routinely remove the band unless there is cli-
nically apparent retardation of ocular growth. Greven and
Tasman15 also leave the band in place in most cases. McPherson
and coworkers18 and Orellana5 state that the band ideally
should be transected 3–6 months postoperatively to permit
normal ocular growth.
PROPHYLACTIC SB
The uniform loss of macular vision in infants who have
undergone therapeutic scleral buckling for stage 4b or stage 5
ROP has been noted by Mintz-Hittner and Kretzer.21 They
proposed two reasons for the poor outcome in these infants.
First, rapid ocular growth occurs after development of ROP in
these infants, whereas the area of vascularized retina does not
increase. The distance between the temporal optic disk and the
center of the macula remains 4 mm from preterm to adulthood.
Thus, traction is exaggerated with ocular growth. Second, the
retinal interaction with retinal pigment epithelium is critical to
normal retinal development. An interruption of the normal
configuration for even a few days may result in irreversible
dysmorphic changes. These considerations led to the proposal
that these extremely low-birth-weight infants be treated with a
prophylactic SB at the time of cryotherapy for threshold ROP.
Macular detachment or ectopia did not develop in 80% of eyes
in these infants with zone 1 disease who were treated with a
prophylactic SB. This approach to managing ROP has not
become widely adopted, however. When the ridge is located
posterior to the equator, as in zone I ROP it is better to approach
by vitrectomy.
VITRECTOMY
Vitrectomy may be considered when scleral buckling fails, a
high retinal detachment is present, media opacification by
vitreous strands or hemorrhage occurs, or a fibrous membrane
is observed behind the lens. Vitrectomy is considered as a
primary procedure for retinal detachment in posterior zone
ROP. With advances in surgical approaches to ROP, the
retina can be reattached in an apparently unsalvageable eye
(Fig. 136.2). Optimal results are achieved by meticulous
removal of proliferative membranes; this may be assisted by
intraoperative injection of triamcinolone into the eye to help in
the visualization of the vitreous and membranes. Sometimes
scleral buckling is combined with vitrectomy surgery.18,22–36
There are two distinct approaches to vitrectomy in advanced
ROP: the closed technique which is more commonly used for
stage 4a, 4b, and stage 5 when the retina is well visible; and the
‘open sky’ method which is typically reserved for stage 5 ROP
when the retina is pulled well behind the lens, including cases
with leukocoria.
CLOSED VITRECTOMY WITH LENS REMOVAL
Charles,22 Machemer and deJuan,17,23 Trese,28 and Fuchino and
associates34 pioneered closed vitrectomy (CV) techniques for
management of ROP. The small size of the eye and extensive
proliferation necessitated several modifications of the standard
closed-vitrectomy approach used in adult eyes. When the retina
is pulled so far anteriorly that it abuts the lens, the instruments
must be inserted through the iris root or anterior ciliary body
to avoid entering the subretinal space. Typically, a two-port
system is used with an irrigating light pipe in one port.
Alternatively, infusion can be placed in the anterior chamber
after removal of the lens (three-port). Machemer and deJuan17

a b
c d
recommended the corneal limbal approach to avoid tearing of
the anteriorly pulled retina by the instrument as it is inserted
through the pars plicata. This has the advantage of keeping the
anterior chamber deep and the retina back, especially when
instruments are exchanged through the surgical wound. The
disadvantage of the anterior chamber infusion is that the
infusion fluid can push the lens posteriorly and pressure the
detached retina behind it causing a retinal dialysis. Sector iridec-
tomy or iris spreading hooks may be required for visualization.
After lensectomy, the epiretinal–retrolental membrane is
dissected by delamination or segmentation with scissors or micro-
vitreoretinal (MVR) blade and removed with the vitrectomy
instrument. Additional ports may be made to allow for more
complete dissection and removal of the membranes. Hyaluronic
acid is used to aid in the dissection by Trese28 and others.
LENS-SPARING VITRECTOMY
In recent years the lens-sparing vitrectomy (LSV)37–43 technique
has been advanced in the treatment of retinal detachment,
particularly in posterior zone type ROP in which the ridge is
located posterior to the equator. It usually is performed in eyes
that have been treated previously by laser photocoagulation or
cryotherapy. The technique usually can not be applied effec-
tively in cases where the ridge is very anterior and the mem-
brane to be cut is located very peripherally. The patient benefits
by remaining phakic. This technique is more challenging if
the membrane to be cut and cleaned is anterior to the equator
due to the relatively large size of the crystalline lens at this age.
In questionable cases, one may plan the LSV to start. The
sclerotomy is through the pars plicata or pars plana and not
through ablated retina. Occasional touch of the lens with an
intraocular instrument does not lead to cataract postoperatively.
However, if the membrane could not be removed effectively
without lensectomy, the lens can be sacrificed at that point.
Despite technical difficulties, several groups have reported
successful case series. Trese and coworkers reported37a series of
Advanced Retinopathy of Prematurity
FIGURE 136.2. (a) Photograph of the eye of a
16-month-old boy with stage 5 retinopathy of
prematurity. The retina is totally detached and
pulled forward toward the lens. The vessels of
the detached retina are seen through the thin
retrolental fibrous membrane. (b) A B-scan
image of a stage 5 ROP detachment.
(c) Interpretive drawing of the B-scan.
(d) Fundus photograph of a former stage
5 ROP eye after successful open-sky
reattachment.
CHAPTER 136
successful LSV treatment of Stage 4a. They report that of 23
eyes tested in an average follow-up of 3.5 years, 83% had normal
appearance of the macula, and most patients had an average
visual acuity of 20/80. Moshfeghi and coworkers report38 that a
single LSV for treatment of stage 4a resulted in complete retinal
reattachment in 30 of 32 eyes (94%). In a nonrandomized
retrospective comparison of SB to LSV for treatment of stage 4a,
Harnett39 found that LSV was a more successful initial proce-
dure (72%), than SB (31%). Hubbard and coworkers reported40
that a two-port LSV performed in 37 eyes of 24 patients with a
stage 4 ROP resulted in complete retinal reattachment in 84%
of 4a and 92% of 4b at a median follow-up of 13 months.
Capone and Trese performed a two-port, LSV in 40 eyes of 31
patients with a reported 90% reattachment at a follow-up mean
of 12 months.41 Holz and coworkers report42 that a three-port
LSV technique allowed for a 85% successful reattachment in
108 eyes of 102 consecutive patients with stage 4a and 4b. They
also report43 94% sustained lens clarity on a mean follow-up of
32 months. Despite these successes, many of the stage 4a cases
may not advance and may not require surgery.
OPEN-SKY VITRECTOMY
The open-sky vitrectomy (OSV) technique was developed by
Schepens in 1981.25 It addresses the difficult surgical scenario
of stage 5 ROP where the retina is drawn anteriorly by the
retrolental membrane, which makes CV difficult. It also allows
for an approach to cases with corneal opacification. To initiate
the OSV, A Flieringa ring is sewn in place to preserve the shape
of the globe during surgery. Then the cornea is removed with a
7- to 8-mm trephine and stored in culture medium during
surgery.44 The eye is irrigated with chilled balanced salt solution
during the procedure to minimize fibrin formation.
Iridotomies made at the 12 and the 6 o’clock positions in the
past have been replaced by iris retractors (e.g., ‘perfect pupil’
designed by John Milverton). Intracapsular extraction of the
crystalline lens is performed using a cryoprobe. This allows 1831
 RETINA AND VITREOUS
direct visualization of the transparent anterior hyaloid and the
fibrous, white, retrolental membrane. Incision on the retro-
lental fibrous (RLF) membrane starts far in the periphery
usually in front of the ciliary body until the surface of the retina
is reached. The RLF membrane is circumcised. Then the dissec-
tion is continued centrally to the opening of the funnel of the
detachment. In order to make space inside of the funnel larger
and make the location of the adhesion of the membrane to the
retina visible hyaluronic acid is injected into the mouth of the
funnel. In order to view the inside of the funnel better, flat round
coverglass, 5 mm in diameter, is used to touch the surface of the
hyaluronic acid filling the funnel. The dissection continues
toward the disk. The fibrous mass filling the funnel of detached
retina is cut near the optic nerve head and removed en bloc.
The iridotomies, if made, are closed with 10-0 polypropylene
sutures, and the corneal button is replaced with 10-0 nylon
sutures. Hyaluronic acid is injected to deepen the anterior
chamber, as well as into the open mouth of the funnel. When
SECTION 10
the intraocular pressure goes up and the retina is found to be
still highly elevated, the subretinal fluid is drained externally
and hyaluronic acid is further injected into the vitreous cavity.
At the end of the surgery the detached retina should be placed
away from the back of the iris. No effort is made to directly
reattach the retina by intravitreous injection.
Scleral buckling was performed by Hirose and colleagues45
4–8 weeks later if the retina showed no sign of reattachment.
They reported a 39% anatomic success rate using this tech-
nique. Eyes with the closed–closed configuration had a 29%
reattachment rate; all other eyes had reattachment rates of
greater than 60%. McPherson and coworkers30 had a 22%
anatomic success rate with open funnels and an 11% success
rate with closed funnels using the open-sky technique, whereas
Tasman and associates 31 had a 35% anatomic success rate.
The preoperative presence of subretinal hemorrhage in stage
5 confers a poor prognosis. Ultrasonographic evaluation of stage
5 eyes should be performed prior to OSV. Steidl and Hirose, in
a retrospective review46 of 426 eyes of 263 patients who under-
went OSV for stage 5 ROP, identified the presence of subretinal
organization (bands, plaques, or diffuse hemorrhage) to be
associated with incomplete retinal reattachment or retinal
attachment without any useful vision.
COMPARISON OF OSV TO CV
The relative rates of success of CV versus OSV depend in part
on the selection of cases. The advantage of the closed technique
is the avoidance of removal and replacement of the corneal
button. The disadvantages include the need for a pars plicata or
iris root entry site because of the extreme anterior displacement
of the retina and the difficulty maneuvering vitrectomy
instruments within the small closed space of the premature
infant eye. The use of multiple ports may allow for more com-
plete removal of membranes. Incomplete removal of residual
peripheral membranes results in only ‘partial’ reattachment.
Reported disadvantages of the open-sky technique include
increased complexity of postoperative management because of
the need for a corneal graft, prolonged hypotony, and a longer
operating time. In experienced hands, however, operative time
is less than 2 h.45 Choroidal detachments are rare, and corneal
endothelial cell-density changes little.47 The advantages of the
open-sky technique are the excellent visualization of the
pathologic process and the direct access to the retrolental
membrane. This makes more complete removal of peripheral
membranes possible and less residual traction on the retina
when it is reattached at the posterior pole. Some cases that
would be inoperable by the closed technique can be repaired
1832 using the open-sky method. The main drawback of open-sky
vitrectomy is the difficulty in exposing the posterior pole in eyes
with a narrow funnel. The use of additional hyaluronic acid can
be helpful in these situations.
TIMING OF VITRECTOMY
The optimal timing of vitrectomy remains to be determined. In
patients with stage 5 ROP, a session of cryotherapy or laser
therapy before surgery may promote quiescence of the
vasoproliferative process, allowing earlier repair of the detach-
ment, but this is difficult to perform with the presence of partial
retinal detachment, and impossible when the detachment is
total or nearly total.48 Chong and colleagues49 recommended
operating as soon as plus disease has regressed. At this stage,
although the traction retinal detachment is typically still an
open funnel, adhesion of the membrane to the retina is very
strong, making complete removal of the fibrous tissues from the
retina extremely difficult. There is also an increased chance of
reproliferation because the membrane is still continuing to
form and there is a higher chance of hemorrhage.
Thus, the potential functional advantage of operating early
must be weighed against the increased difficulty of extracting
adherent membranes and the increased postoperative
hemorrhage and fibrin production (with development of
secondary membranes) if vitrectomy is performed too soon.
Use of the recently available anti-VEGF agents may serve as a
useful adjuvant in reducing neovascularization and vascular
permeablility prior to vitrectomy. Perhaps an approach con-
sisting of intraocular anti-VEGF injection followed few to
several days later by vitrectomy and membrane removal may
work. One must always weigh the risk of systemic absorption of
any anti-VEGF drug used in the eye.
The timing of vitrectomy in relation to the progression of
stage 4a and 4b disease is likely very important as well.
Hartnett50 identified preoperative factors which correlated with
outcome of vitrectomy and SB procedures performed on stage
4 and 5 eyes which had received previous laser ablation. In eyes
which failed first procedures, vitreous haze or organization and
plus disease were found to be significant in stage 4 eyes, while
6 clock hours of ridge elevation and plus disease were found to
be significant in stage 5 eyes. Hartnett recommends additional
laser be performed before surgery in eyes manifesting neo-
vascularization or plus disease. The optimal timing of LSV with
respect to laser ablation is unknown. An Argentine group51
reports in a small series of eight patients, that those patients
who had received laser treatment prior to LSV had more organi-
zation of the vitreous which made surgery more difficult, with
the previously untreated patients faring better.
The optimal time for surgery may be after 6 months of age
but before the patient is 1 year old. One may operate earlier if
the eye has been treated with cryotherapy or photocoagulation
and the fundus shows no sign of active vasoproliferation. Even
when surgery is delayed for years, it may be worth attempting
repair in some cases because ambulatory acuity has been
obtained postoperatively in patients with long-standing retinal
detachment up to 3 years of age.45
COMPLICATIONS OF VITRECTOMY
Iatrogenic retinal breaks produced during vitrectomy surgery are
extremely difficult to close. Some peripheral breaks may be closed
by scleral buckling, but breaks formed posterior to the ridge or
in the posterior pole in infants with ROP are impossible to close
either with scleral buckling or with air–fluid exchange and
internal drainage of subretinal fluid probably due to the inability
to completely release the traction by vitrectomy or retinal
foreshortening, or a combination of both. Other factors that can
 Advanced Retinopathy of Prematurity

make ROP surgery more difficult and associated with higher
risk include the presence of a persistent hyaloid artery,52
intraocular bleeding, multiple circular retinal folds, and tilting
of the funnel toward one quadrant.45
Although anatomic reattachment can be achieved in eyes
with severe disease using either technique, vision has been
disappointingly poor.49,53 Machemer and deJuan17 reported an
anatomic success rate of 64% and a functional success rate of
43% in stage 4 cases. Patients with stage 5 ROP do not fare as
well. Stage 5 cases with the open–open configuration have the
best prognosis; the closed–closed configuration is least likely to
result in recovery of useful vision.26,32–36 However, the limited
vision, which may detect the movement of objects, for example,
which develops after reattachment of stage 5 ROP, is very useful
for activities of daily life and as such very enhancing to the
quality of life in the affected young children.
In the cryo-ROP study, the visual outcome of infants who
progressed to stage 5 retinal detachment was studied retro-
hypotony, and vitreous hemorrhage were similar in the two
groups. Thus, although surgical approaches to ROP are meeting
with improved rates of retinal reattachment in ROP, the visual
outcomes to date indicate that the emphasis must remain on
prevention of retinal detachment.35,54
SUMMARY
Interest in ROP has grown along with the increasing incidence
of the disease resulting in many advances for treament of acute
ROP. Treatments of advanced stages of acute ROP have also
been refined, with properly timed cryotherapy or laser photo-
coagulation preventing retinal detachment and meticulous
vitrectomy techniques successfully removing traction forces.
Smaller gauge (25 G and 23 G) vitrectomy techniques are being
pioneered, yet have not been widely adapted to ROP surgery,
though ultimately they may be found to be advantageous when
operating on the smaller eyes of infants. Adjuvant to surgery

spectively.35,54 Surgery was performed by several different
surgeons using different techniques. There were no standard-
ized preoperative criteria for undertaking vitrectomy, and
patients were not randomized. The configuration of detach-
ment (open vs closed funnel) was not specified. The anatomic
success rate was 28% at 1 year and 21% at 5.5 years in operated
eyes, with a functional success rate of 1–3%. Although data
were not specified for all eyes that did not undergo vitrectomy,
one of the 10 eyes described had spontaneous resolution of the
retinal detachment. Eyes that underwent vitrectomy had a
lower incidence of glaucoma and shallow anterior chamber
compared with unoperated eyes. The rates of corneal opacity,
CHAPTER 136
such as the use of recently developed anti-VEGF agents may
make surgical success higher in addition to being potentially
useful in treating the acute stages of ROP.
The improved anatomic success rates of vitreoretinal surgery
have been confounded by disappointingly poor visual function.
Still, surgery should be pursued when indicated, as even
attaining hand-motion visual acuity allows many patients to
remain ambulatory, and anatomic success may avoid the need
for enucleation. Further modifications of treatment protocols,
with an emphasis on preventing retinal detachment, will be
necessary before significantly better acuity can be retained in
eyes with severe stages of this devastating disease.

REFERENCES
1. Terry TL: Extreme prematurity and
fibroblastic overgrowth of persistent
vascular sheath behind each crystalline
lens. I: Preliminary report. Am J Ophthalmol
1942; 25:203–204.
2. Tasman W, Patz A, McNamara JA, et al:
Retinopathy of prematurity: the life of a
lifetime disease. Am J Ophthalmol 2006;
141:167–174.
3. Cryotherapy for Retinopathy of Prematurity
Cooperative Group: Multicenter trial of
cryotherapy for retinopathy of prematurity:
ophthalmological outcomes at 10 years.
Arch Ophthalmol 2001; 119:1110–1118.
4. Hartnett ME, McColm JR: Retinal features
predictive of progressive stage 4 retinopathy
of prematurity. Retina 2004; 24:237–241.
5. Orellana J: Scleral buckling in acute
retinopathy of prematurity stages 4 and 5.
In: Eichenbaum JW, Mamelok AE, Mittl RN,
Orellana J, eds. Treatment of retinopathy of
prematurity. Chicago: Year Book Medical;
1991:194–213.
6. Palmer EA, Hardy RJ, Dobson V, et al:
Cryotherapy for Retinopathy of Prematurity
Cooperative Group 15-year outcomes
following threshold retinopathy of
prematurity: final results from the
multicenter trial of cryotherapy for
retinopathy of prematurity. Arch
Ophthalmol. 2005; 123:311–318.
7. Tufail A, Singh AJ, Haynes RJ, et al: Late
onset vitreoretinal complications of
regressed retinopathy of prematurity. Br J
Ophthalmol 2004; 88:243–246.
8. Terasaki H, Hirose T: Late-onset retinal
detachment associated with regressed
retinopathy of prematurity. Jpn J
Ophthalmol 2003; 47:492–497.
9. Kaiser RS, Trese MT, Williams GA,
Cox MS Jr: Adult retinopathy of prematurity:
outcomes of rhegmatogenous retinal
detachments and retinal tears.
Ophthalmology 2001; 108:1647–1653.
10. Topilow HM, Ackerman AL, Wang FM:
The treatment of advanced retinopathy of
prematurity with cryotherapy and scleral
buckling procedure. Ophthalmology 1985;
92:379–387.
11. Cryotherapy for Retinopathy of Prematurity
Cooperative Group: Multicenter trial of
cryotherapy for retinopathy of prematurity.
One year outcome-structure and
function. Arch Ophthalmol 1990;
108:1408–1416.
12. McPherson AR, Hittner HM: Scleral
buckling in 2- to 11-month-old premature
infants with retinal detachment associated
with acute retrolental fibroplasia.
Ophthalmology 1979; 86:819–835.
13. Ricci B, Santo A, Ricci F, et al: Scleral
buckling surgery in stage 4 retinopathy of
prematurity. Graefes Arch Clin Exp
Ophthalmol 1996; 234:S38–S41.
14. Beyrau K, Danis R:Outcomes of primary
scleral buckling for stage 4 retinopathy of
prematurity.Can J Ophthalmol 2003;
38:267–271.
15. Greven C, Tasman W: Scleral buckling in
stages 4B and 5 retinopathy of prematurity.
Ophthalmology 1990; 97:817–820.
16. Trese MT: Scleral buckling for retinopathy
of prematurity. Ophthalmology 1994;
101:23–26.
17. Machemer R, deJuan E: Retinopathy of
prematurity: approaches to surgical
therapy. Aust N Z J Ophthalmol 1990;
18:47–45.
18. McPherson AR, Hittner HM, Kretzer FL:
Treatment of acute retinopathy of prematurity
by scleral buckling. In: McPherson AR,
Hittner HM, Kretzer FL, eds. Retinopathy
of prematurity-current concepts and
controversies. Toronto: BC Decker;
1986:179–192.
19. Prost ME:Results of treatment of retinal
detachment in active stage-5 retinopathy
of prematurity. Klin Oczna 2003;
105:387–391.
20. Sneed SR, Pulido JS, Blodi CF, et al:
Surgical management of late-onset retinal
detachments associated with regressed
retinopathy of prematurity. Ophthalmology
1990; 97:179–183.
21. Mintz-Hittner HA, Kretzer FL: The rationale
for cryotherapy with a prophylactic scleral
buckle for zone 1 threshold retinopathy of
prematurity. Doc Ophthalmol 1990;
74:263–268.
22. Charles S: Vitrectomy with ciliary body entry
for retrolental fibroplasia. In McPherson AR,
Hittner HM, Kretzer FL, eds. Retinopathy
of prematurity-current concepts and
controversies. Toronto: BC Decker;
1986:225–234.
23. deJuan E, Machemer R: Retinopathy of
prematurity. Surgical technique. Retina
1987; 7:63–69.
24. Jabbour NM, Eller AE, Hirose T, et al:
Stage 5 retinopathy of prematurity.
Prognostic value of morphologic findings.
Ophthalmology 1987; 94:1640–1646.
25. Schepens CL: Clinical and research
aspects of subtotal open-sky vitrectomy.
Am J Ophthalmol 1981; 91:143.
26. Zilis JD, deJuan E, Machemer R: Advanced
retinopathy of prematurity. The anatomic 1833
 RETINA AND VITREOUS
and visual results of vitreous surgery.
Ophthalmology 1990; 97:821–826.
27. Charles S: Vitreoretinal surgery for
retinopathy of prematurity. Birth Defects
1988; 24:287–293.
28. Trese MT: Surgical results of stage V
retrolental fibroplasia and timing of surgical
repair. Ophthalmology 1984; 91:461–466.
29. Blacharski PA, Charles S: Thrombin
infusion to control bleeding during
vitrectomy for stage V retinopathy of
prematurity. Arch Ophthalmol 1987;
105:203–205.
30. McPherson AR, Hittner HM, Moura RA,
Kretzer FL: Treatment of retrolental
fibroplasia with open-sky vitrectomy. In:
McPherson AR, Hittner HM, Kretzer FL,
eds. Retinopathy of prematurity-current
concepts and controversies. Toronto:
BC Decker; 1986:225–234.
31. Tasman W, Borrone RN, Bolling J:
SECTION 10
Open-sky vitrectomy for total retinal
detachment in retinopathy of prematurity.
Ophthalmology 1987; 94:449–452.
32. Hirose T, Katsumi O, Mehta MC,
Schepens CL: Vision in stage 5 retinopathy
of prematurity after retinal reattachment by
open-sky vitrectomy. Arch Ophthalmol
1993; 111:345–349.
33. Seaber JH, Machemer R, Eliott D, et al:
Long-term visual results of children after
initially successful vitrectomy for stage V
retinopathy of prematurity. Ophthalmology
1995; 102:199–204.
34. Fuchino Y, Hayashi H, Kono T, Ohshima K:
Long-term follow-up of visual acuity in eyes
with stage 5 retinopathy of prematurity
after closed vitrectomy. Am J Ophthalmol
1995; 120:308–316.
35. Quinn GE, Dobson V, Barr CC, et al: Visual
acuity of eyes after vitrectomy for retinopathy
of prematurity: follow-up at 5 1/2 years.
Ophthalmology 1996; 103:595–600.
1834
36. Mintz-Hittner HA, O’Malley RE, Kretzer FL:
Long-term form identification vision after
early, closed, lensectomy-vitrectomy for
stage 5 retinopathy of prematurity.
Ophthalmology 1997; 104:454–459.
37. Prenner JL, Capone A Jr, Trese MT: Visual
outcomes after lens-sparing vitrectomy for
stage 4A retinopathy of prematurity.
Ophthalmology 2004; 111:2271–2273.
38. Moshfeghi AA, Banach MJ, Salam GA,
Ferrone PJ: Lens-sparing vitrectomy for
progressive tractional retinal detachments
associated with stage 4A retinopathy of
prematurity. Arch Ophthalmol 2004;
122:1816–1818.
39. Hartnett ME, Maguluri S, Thompson HW,
McColm JR: Comparison of retinal
outcomes after scleral buckle or lens-
sparing vitrectomy for stage 4 retinopathy
of prematurity. Retina 2004; 24:753–757.
40. Hubbard GB III, Cherwick DH, Burian G:
Lens-sparing vitrectomy for stage 4
retinopathy of prematurity. Ophthalmology
2004; 111:2274–2277.
41. Capone A Jr, Trese MT: Lens-sparing
vitreous surgery for tractional stage 4A
retinopathy of prematurity retinal
detachments. Ophthalmology 2001;
108:2068–2070.
42. Lakhanpal RR, Sun RL, Albini TA, Holz ER:
Anatomic success rate after 3-port lens-
sparing vitrectomy in stage 4A or 4B
retinopathy of prematurity. Ophthalmology
2005; 112:1569–1573.
43. Lakhanpal RR, Davis GH, Sun RL, et al:
Lens clarity after 3-port lens-sparing
vitrectomy in stage 4A and 4B retinal
detachments secondary to retinopathy of
prematurity. Arch Ophthalmol 2006;
124:20–23.
44. Hirose T, Lou PL: Retinopathy of
prematurity. Int Ophthalmol Clin 1986;
26:1–23.
45. Hirose T, Schepens CL, Katsumi O,
Mehta MC: Open-sky vitrectomy for severe
retinal detachment caused by advanced
retinopathy of prematurity. In: Flynn J, ed.
Retinopathy of prematurity. New York:
Springer-Verlag; 1992:95–114.
46. Steidl SM, Hirose T: Subretinal organization
in stage 5 retinopathy of prematurity.
Graefes Arch Clin Exp Ophthalmol 2003;
241:263-268; Epub 2003 Mar 18.
47. Sawa M, Hirose T, Kenyon KR: Endothelial
specular microscopy in children with
retrolental fibroplasia undergoing open-sky
vitrectomy. Jpn J Ophthalmol 1990;
34:1–14.
48. Trese MT: Surgical therapy for stage V
retinopathy of prematurity. A two-step
approach. Graefes Arch Clin Exp
Ophthalmol 1987; 225:266–268.
49. Chong LP, Machemer R, deJuan E:
Vitrectomy for advanced stages of
retinopathy of prematurity. Am J
Ophthalmol 1986; 102:710–716.
50. Hartnett ME: Features associated with
surgical outcome in patients with stages 4
and 5 retinopathy of prematurity. Retina
2003; 23:322–329.
51. Luna JD, Caribaux LJ, Reviglio VE,
Juarez CP: Lens-sparing surgery for
retinopathy of prematurity. Ophthalmology
2003; 110:1669.
52. Eller AW, Jabbour NM, Hirose T,
Schepens CL: Retinopathy of prematurity.
The association of a persistent hyaloid
artery. Ophthalmology 1987; 94:444–448.
53. Topilow HW, Ackerman AL, Wang FM,
Strome RR: Successful treatment of
advanced retinopathy of prematurity.
Ophthalmic Surg 1988; 19:781–785.
54. Quinn GE, Dobson V, Barr CC, et al: Visual
acuity in infants after vitrectomy for severe
retinopathy of prematurity. Ophthalmology
1991; 98:5–13.
 CHAPTER
137 Eales’ Disease
Marissa L. Albano and Robert P. Murphy
Key Features
• Eales’ disease is an idiopathic obliterative vasculopathy of the
peripheral retina
• Initially presents as retinal periphlebitis and later as retinal
ischemia, leading to vascular alterations, neovascularization,
and vitreous hemorrhage
• Affects persons of all ages and is usually bilateral; most
commonly affects young, healthy males in the Indian
subcontinent and Middle East
• The etiology is believed to be multifactorial
• Early manifestations include vascular sheathing and focal
occlusion of peripheral retinal vessels
• Therapy is directed toward the presenting symptoms of the
disease:
• Oral, peribulbar and intravitreal corticosteroids are used in
the active inflammatory stage
• Retinal neovascularization appears to respond well to laser
photocoagulation
• Vitrectomy for vitreous hemorrhage with or without retinal
detachment
Eales’ disease is an idiopathic obliterative vasculopathy of the
peripheral retina, initially presenting as retinal periphlebitis
and later as retinal ischemia, leading to vascular alterations,
neovascularization, and vitreous hemorrhage. It can affect per-
sons of all ages and is usually bilateral; it most commonly
affects young, healthy males in the Indian subcontinent and
Middle East. The etiology is believed to be multifactorial,
although it currently remains unclear. Recent immunological,
biochemical, and histopathological studies have implicated
Mycobacterium tuberculosis, retinal autoimmunity, human
leukocyte antigen, and free radical mediated damage in the
pathogenesis of this disease. Early manifestations include vas-
cular sheathing and focal occlusion of peripheral retinal vessels.
With progression, areas of nonperfusion can develop.
Neovascularization can occur at the junction of the perfused
and nonperfused retina, frequently resulting in recurrent
vitreous hemorrhages. As the exact etiopathogenesis remains
unclear, therapy is directed toward the presenting symptoms of
the disease. Oral, peribulbar, and intravitreal corticosteroids are
used in the active inflammatory stage, while retinal neovas-
cularization in Eales’ disease appears to respond well to laser
photocoagulation. Vitrectomy is utilized for vitreous hemor-
rhage with or without retinal detachment.
HISTORY
The disease is named after Henry Eales, an ophthalmologist
who in 1880 described a syndrome of recurrent vitreous
hemorrhages in young men with epistaxis and constipation.1
He termed this new entity primary recurrent retinal
hemorrhage. Using the newly developed direct ophthal-
moscope, Eales documented abnormal retinal veins and areas in
the peripheral retina that were free of capillaries.2 In spite of
these astute early observations, the entity he described differs
considerably from the disease that now bears his name. He did
not observe any new vessels or inflammation preceding or
accompanying the hemorrhages.
In 1887, Wadsworth described associated inflammation and
neovascularization with this disease.3 Since then, numerous
authors have grouped periphlebitis retinae and idiopathic
recurrent vitreous hemorrhages with or without retinal
perivasculitis under the term Eales’ disease.
Not all authors have believed that Eales’ disease is a specific
entity. Duke–Elder thought that Eales’ disease represented the
clinical manifestation of many diseases.4 Indeed, refined
diagnostic tests have demonstrated that many of the so-called
idiopathic hemorrhages are the result of diseases with known
causes, such as sarcoidosis, systemic lupus erythematosus, diabetes
mellitus, sickle-cell disease, and collagen vascular disease.
However, after elimination of these causes, a group of patients
remains with idiopathic peripheral nonperfusion and perivas-
culitis of the retina. Many investigators now agree that Eales’
disease is a distinct entity comprising characteristic fundoscopic
and fluorescein angiographic features.5 Although this disease has
been called periphlebitis retinae,6 emphasizing the abnorma-
lities of retinal venules, evidence suggests that the inflammation
in this disease affects both arterioles and venules.7
EPIDEMIOLOGY
Eales’ disease is uncommon in North America; however, this
disorder is responsible for widespread visual loss in the Indian
subcontinent. It often affects healthy young adults, with the
average age of onset at 20–30 years. Patients usually present
with symptoms of vitreous hemorrhage, such as floaters or
decreased vision. The majority of patients experience bilateral,
although often asymmetric, involvement.
Most reports, including Eales’ original description, indicate a
male predominance. However, Murphy and co-workers found
an equal prevalence of men and women in their study of 55
patients in North America.7
1835
 RETINA AND VITREOUS
CLINICAL FEATURES
Clinical Features of Eales’ Disease
• Vascular sheathing
• Retinal capillary nonperfusion with or without
neovascularization
• Recurrent vitreous hemorrhages
• Cystoid macular edema
INFLAMMATION
Most patients with Eales’ disease develop ocular inflammation,
especially early in its course. Vascular sheathing is seen in most
patients (Fig. 137.1). The degree of sheathing ranges from fine
white lines on both sides of the blood column to thick exudative
sheathing. The thin white lines tend to be continuous, whereas
the heavy, exudative sheathing is often segmental.
SECTION 10
Areas of vascular sheathing frequently demonstrate hyper-
fluorescence in fluorescein angiography (Fig. 137.2). However,
there is no direct correlation between the regions of sheathing
and staining. The intensity of the hyperfluorescence seen on the
fluorescein angiograms does not correlate with the intensity of
inflammation.
In the century since Eales’ observation of altered retinal
veins, many investigators have described Eales’ disease as a
primary disease of altered retinal veins. Elliot and Harris sug-
gested the term periphlebitis retinae for this disorder.6 However,
more recent studies have reported equal involvement of
arteriolar and venular sheathing.7 Because of the evidence of
arteriolar involvement (Fig. 137.1b), this disease should be
considered a retinal vasculitis or vasculopathy.
Keratic precipitates, anterior chamber cell and flare, and
vitreous cells have been observed in patients with Eales’
disease.7 Cystoid macular edema occurs in eyes with extensive
sheathing. Although the exact cause of the macular edema is
unknown, it may be associated with low-grade inflammation.
NONPERFUSION
Peripheral retinal nonperfusion is present in all patients with
this disease. The extent of the perfusion ranges from small
a b
FIGURE 137.1. (a) Thin white lines representing vascular sheathing surround a retinal venule in a patient with Eales’ disease. (a) Extensive
arteriolar sheathing with retinal vascular nonperfusion nasal to disk.
1836 (a) From Gieser SC, Murphy RP: Eales disease. In: Ryan S, ed. Retina. St Louis, MO: CV Mosby; 1989.
areas in the far periphery to massive nonperfusion extending
into the posterior pole (Fig. 137.3). The nonperfusion is
generally confluent and sharply demarcated from the posterior
perfused retina. The temporal retina is most commonly
affected.
The microvascular abnormalities may be so severe that the
fundus resembles Coats’ disease. Fine white lines representing
the remains of obliterated large vessels (ghost vessels) are often
seen in the area of nonperfusion.
Elliot8 and Spitznas and colleagues9 have documented the
vascular abnormalities at the junction of the anteroperipheral
nonperfused retina and the posterior perfused retina.
Intraretinal hemorrhages often first appear in the affected area,
followed by an increase in vascular tortuosity with frequent
collateral formation around occluded vessels (Fig. 137.3).
Microaneurysms, arteriovenous shunts, and venous beading
are commonly seen at the junction (Fig. 137.4). Fluorescein
angiography enhances these abnormalities and often demon-
strates staining at the stumps of obliterated vessels.
Patients with Eales’ disease can also experience branch vein
occlusion. The branch vein occlusion can be either single or
multiple. Unlike patients with primary branch vein occlusion,
in whom the pathologic condition is confined to one quadrant,
patients with Eales’ disease have more extensive involvement of
the peripheral retina that does not respect the horizontal
midline.
NEOVASCULARIZATION
The retinal nonperfusion leads to the eventual development of
new vessels. The neovascularization can form either on the disk
or elsewhere in the retina. Neovascularization of the iris has
also been described. These abnormal blood vessels frequently
bleed and are the major cause of visual loss in this disease.
Ischemic retina produces a diffusible substance that stimu-
lates neovascularization, vascular endothelial growth factor
(VEGF). Perentes and colleagues demonstrated a close relation-
ship between prominent neovascular proliferation and the
intense expression of VEGF via histopathological and
immunohistochemical examination of an enucleated eye from
a patient with documented Eales’ disease.10 The neovas-
cularization often occurs along the junction of perfused and

FIGURE 137.2. Fluorescein angiogram demonstrates abnormal
staining of a small retinal venule (arrows) in a patient with Eales’
disease. There was venous sheathing in this area.
FIGURE 137.3. Fluorescein angiogram of the peripheral retina
demonstrates the junction of normally perfused retinal vessels
adjacent to an area of nonperfused retina. Note the vascular
abnormalities and the small area of neovascularization at the junction.
nonperfused retina, similar to the appearance of sickle-cell
retinopathy. The neovascularization frequently has a prominent
fibrous component. Occasionally, patients have extensive
retinal and vitreal proliferation of avascular sheets and strands
of fibrous scar tissue (Fig. 137.5). The anteroposterior traction
resulting from the fibrovascular membrane places these eyes at
risk of developing traction retinal detachment. Badrinath and
colleagues found multifocal fibrous and fibrovascular
vitreoretinal adhesions in 83% of eyes undergoing vitreous
surgery for complications of Eales’ disease, in addition to noting
type II collage in the epiretinal membranes causing tangential
traction.11
Eales’ Disease
CHAPTER 137
FIGURE 137.4. Fluorescein angiogram demonstrates severe
nonperfusion of the retinal vasculature involving the macula.
FIGURE 137.5. Hypovascular fibroproliferation emanates from the
disk of a patient with advanced Eales’ disease.
VISUAL PROGNOSIS
The natural course of this disease is variable. Although the
visual acuity in patients with Eales’ disease ranges from normal
to no-light perception, most eyes retain good acuity. In spite of
extensive anteroperipheral nonperfusion, the macula is usually
spared, preserving central vision. Murphy and co-workers
reported that 67% of their patients had final visual acuity in the
better eye that ranged from 20/15 to 20/40.7 Twenty-four
percent had visual acuity that ranged from 20/50 to 20/200,
and 9% had visual acuity worse than 20/200. 1837
 SECTION 10 RETINA AND VITREOUS
a b
FIGURE 137.6. (a) Neovascularization of the disk. Note the segmental exudative arteriolar sheathing. (b) Same patient as in (a) 2.5 years later.
The patient has had total regression of the neovascularization after treatment with scatter photocoagulation of all areas of nonperfused retina.
Note that the former areas of arteriolar sheathing have resolved.
(a and b) From Gieser SC, Murphy RP: Eales disease. In: Ryan S, ed. Retina. St Louis, MO: CV Mosby; 1989.
Vitreous hemorrhage is the most frequent cause of visual
loss. Usually the hemorrhage settles to the lower portion of the
vitreous and is gradually reabsorbed within several weeks or
months, with the return of normal central vision. Severe,
permanent visual loss usually results from complications
associated with neovascularization, such as persistent vitreous
hemorrhage, retinal detachment, and neovascular glaucoma.
Occasionally, loss of vision is caused by cystoid macular edema,
macular holes, retinal telangiectasia, or epiretinal membrane.
In some patients, relentless nonperfusion progresses across the
macula (see Fig. 137.4); visual acuity in these eyes is usually
less than 20/400.
A long-term follow-up study of 130 patients with Eales’
disease showed visual acuity improved in 20%, maintained in
43%, and worsened in 37%. The complications noted after
5 years were tractional detachment, cataract, rubeosis iridis,
neovascular glaucoma, and phthisis bulbi.12
TREATMENT
Henry Eales offered his patients a mixture of laxative, digitalis,
and belladonna.1 Presumably, these remedies were not
beneficial. Lowered levels of antioxidant vitamins in patients
with Eales’ disease and consequent accumulation of oxygen and
lipid free radicals have prompted the belief that vitamins E, C,
and A may be of value.13 Bhooma and colleagues demonstrated
an increase in serum thiobarbituric acid nactine substances, an
indicator of lipid peroxidation products produced by oxygen
and free radicals.13 Some investigators believe there is an asso-
ciation of Eales’ disease with tuberculoprotein hypersensitivity,
therefore prompting the use of antituberculous therapy as
well.14–16 The benefit of these therapies is untested.
As the basic pathologic lesion of Eales’ disease is
inflammatory occlusion of retinal vessels, corticosteroids are
becoming a mainstay of treatment. For the acute inflammatory
stage, oral prednisone (1 mg/kg) is started and the dose tapered
for 6–8 weeks. If the patient is intolerant to systemic cor-
ticosteroids or if macular edema develops, periocular depot
corticosteroid/triamcinolone acetonide injections have been
found to be beneficial.17 Immunosuppressive agents are
1838 reserved for intolerance to systemic steroids or for lack of
systemic steroid efficacy. In a prospective study by Bali, pulsed
oral methotrexate therapy at a dose of 12.5 mg/week was shown
to be clinically effective within 4 weeks and is associated with
an acceptable safety profile.18 Recently, intravitreal triam-
cinolone acetonide was successfully used in three eyes of
two patients with Eales’ disease in the acute inflammatory
stage who were not responding to oral and peribulbar
corticosteroids.19
Investigators generally agree that peripheral scatter
photocoagulation of the ischemic retina is invaluable in the
treatment of neovascularization (Fig. 137.6).20,21 This is similar
to the treatment used for other vasoproliferative diseases of the
retina, such as diabetic and sickle-cell retinopathies. Several
investigators have demonstrated favorable results with light-
intensity, full-scatter argon laser photocoagulation to the
nonperfused retina and to the junction of perfusion and non-
perfusion.21 Others have used a combination of cryotherapy and
laser photocoagulation.22 Because nonperfused retina is more
fragile than perfused retina, caution should be exercised when
treating these patients. There is evidence to show that
prophylactic pan retinal photocoagulation in areas of ischemic
retina in asymptomatic fellow eyes of patients is effective in
controlling the progression and future complications of this
disease.23 Due to the intense expression of VEGF in Eales’
disease patients, anti-VEGF therapy with either Avastin or
Lucentis (Genentech Corp, San Francisco, CA) may be of some
treatment benefit, however this remains to be studied.
Vitrectomy can be employed for removing persistent vitreous
hemorrhages and fibrosis, often with good results.24 Kumar and
colleagues’ study demonstrated the importance of early vit-
rectomy for persistent hemorrhages. Delaying vitrectomy more
than 6 months is believed to allow the development of cystoid
macular edema, macular scar, and macular pucker formation
with poorer visual outcome.25 No treatment is known to
prevent or reverse the nonperfusion or capillary drop-out.
DIFFERENTIAL DIAGNOSIS AND SYSTEMIC
EVALUATION
As an idiopathic entity, Eales’ disease must first be differen-
tiated from retinal vasculopathies with known causes. Systemic
 Eales’ Disease

with Eales’ disease.14 This protein has not been seen in healthy
TABLE 137.1. Laboratory Investigations for Eales„ Disease controls or patients with diabetic retinopathy; however, it
CBC has been isolated from the serum of patients with posterior
uveitis, tuberculosis, leprosy, and rheumatoid arthritis.
Erythrocyte sedimentation rate
Immunohistochemistry on epiretinal membranes of Eales’
Reticulocyte count disease patients localized the 88-kDa protein to inflammatory
Postprandial blood sugar
cells and nonvascular endothelium.27 Further investigation is
necessary to decipher the role of this protein.
Mantoux test (tuberculosis) Electrophoretic study of serum proteins in patients with
Sickle cell preparation Eales’ disease has shown a rise in a-globulins and reduced
albumin levels.28 Isoelectric focusing of the serum samples has
Hemoglobin electrophoresis (sickle cell retinopathy)
revealed several unique proteins in these patients.13 It is
Immunoglobulin profile VDRL and Treponema pallidum possible that altered immune reactivity to an extraneous agent
Hemagglutination Test may play a role in the pathogenesis of Eales’ disease. A small
Antinuclear antibody (SLE) study by Saxena and associates found a lymphocyte proliferative
response in 6 of 24 patients against S-antigen, its uveitogenic
Serum angiotensin-converting enzyme (sarcoidosis) fragments or interphotoreceptor retinoid-binding protein,
further suggesting that retinal antigens play a role in the

Lysozyme (sarcoidosis)
X-ray chest (tuberculosis and sarcoidosis)
diseases such as diabetes mellitus, sickle-cell hemoglo-
binopathies, sarcoidosis, and systemic lupus erythematosus can
manifest retinal inflammation, nonperfusion, and neovas-
cularization. Ocular diseases such as branch and central retinal
vein occlusions, Coat’s disease, parsplanitis, dragged disk
syndrome, and macular telangiectasia.17 However, one can rule
out these conditions with a careful history and appropriate
laboratory tests (Table 137.1).
Many investigators have emphasized a relationship between
Eales’ disease and M. tuberculosis.8,9,14–17 Although there is a
higher than normal incidence of positive reaction to the
tuberculin protein, no one has demonstrated any evidence that
the ocular changes are related to infection of the eye or retina by
tuberculin bacteria. The most widely held belief is that Eales’
disease is an immune-mediated hypersensitivity process result-
ing from prior exposure to the tuberculoprotein.15 Renie and
associates noted in their group of 32 patients that 48% had
either tuberculosis or a history of exposure to tuberculosis.26
The detection of M. tuberculosis DNA by PCR in a significant
number of vitreous fluid samples and epiretinal membranes of
patients with Eales’ disease compared to normal controls
further emphasizes the association of tuberculosis with the
pathogenesis of Eales’ disease.16
Recently, a novel acute phase reactant 88-kDa protein has
been isolated in the vitreous humor and serum of patients
CHAPTER 137
pathogenesis of Eales’ disease.29
Recent evidence may suggest that HLA haplotypes have a
possible predilection for Eales’ disease. HLA phenotypes DR3,
A1, B8, B5(51), and DR15(2) occurred in the majority of cases
of Eales’ disease, while they are not found in normal controls.
HLA DQ2, DR52, and Bw6 were found in higher frequency of
Eales’ patients, and are believed to be strongly associated with
the disease.30
Some patients with Eales’ disease have a concomitant vesti-
buloauditory dysfunction. Renie and associates discovered
sensorineural hearing loss in 24% of their 35 patients with this
disease and vestibuloauditory dysfunction in 50% of their
patients.26 Wagner and Fehrmann’s case report documented a
man diagnosed with Eales’ disease presenting with concurrent
visual acuity loss and Meniere-like vestibulocochlear
symptoms, who responded well to high-dose IV corticosteroids.
They hypothesized a common pathogenic cause such as
autoimmune-mediated microvasculitis of retinal and
vestibulocochlear vessels.31
There are multiple case reports of diseases of the central
nervous system in patients with Eales’ disease, including mul-
tiple sclerosis, cerebellar ataxia, myelopathy, hemiplegia, and
stroke.32 Internuclear ophthalmoplegia33 and an internal carotid
artery aneurysm34 have also been reported in patients with
Eales’ disease. Additionally, several investigators have noted an
increased prevalence of immunologic disorders.35
Eales’ disease is a long-recognized, but poorly understood,
disorder. Until we understand more about the cause and
pathogenesis of Eales’ disease, we will continue to be able to
treat only the complications of this disorder.

REFERENCES
1. Eales H: Causes of retinal hemorrhage
associated with epistaxis and constipation.
Birm Med Rev 1880; 9:262.
2. Eales H: Primary retinal hemorrhages in
young men. Ophthalmol Rev 1882; 1:41.
3. Wadsworth OF: Recurrent retinal
hemorrhage, followed by the development
of blood vessels in the vitreous. Ophthalmol
Rev 1887; 6:289–299.
4. Duke-Elder WS: Diseases of the retina. In:
Duke-Elder WS, ed. System of
ophthalmology. St Louis, MO: Mosby; 1967.
5. Gieser SC, Murphy RP: Eales disease. In:
Ryan S, ed. Retinal disease. St Louis, MO:
Mosby; 1989.
6. Elliot AJ, Harris GS: The present status of
the diagnosis and treatment of periphlebitis
retinae (Eales disease). Can J Ophthalmol
1969; 4:117.
7. Murphy RP, Gieser SC, Fine SL, Patz A:
Retinal and vitreous findings in Eales
disease. Invest Ophthalmol Vis Sci 1986;
27:121.
8. Elliot AJ: Thirty-year observation of patients
with Eales disease. Am J Ophthalmol 1975;
80:404.
9. Spitznas M, Meyer-Schwickerath G,
Stephan B: The clinical picture of Eales
disease. Graefes Arch Clin Exp Ophthalmol
1975; 194:73.
10. Perentes Y, Chan CC, Bovey E, et al:
Massive vascular endothelium growth factor
(VEGF) expression in Eales’ disease. Klin
Monatsbl Augenheilkd 2002; 219:311.
11. Badrinath SS, Gopal L, Sharma T, et al:
Vitreoschisis in Eales’ disease: pathogenic
role and significance in surgery. Retina
1999; 19:51.
12. Atmaca LS, Batioglu F, Atmaca Sonmez P:
A long-term follow-up of Eales’ disease.
Ocul Immunol Inflamm 2002; 10:213.
13. Bhooma V, Sulochana KN, Biswas J,
Ramakrishnan S: Eales’ disease:
accumulation of reactive oxygen
intermediates and lipid peroxides and
decrease of antioxidants causing
inflammation, neovascularization and retinal
damage. Curr Eye Res 1997; 16:91.
14. McCaughan F, Holmes A, Lynn W, Friedland
JS: Mycobacterium tuberculosis infection
complicated by Eales disease with
peripheral neuropathy. Clin Infec Dis 2002;
35:89.
15. Madhavan HN, Therese KL, Doraiswamy K:
Further investigations on the association of
Mycobacterium tuberculosis with Eales’
disease. Indian J Ophthalmol 2002; 50:35.
1839
 RETINA AND VITREOUS
16. Madhavan HN, Therese KL, Gunisha P,
et al: Polymerase chain reaction for
detection of Mycobacterium tuberculosis
in epiretinal membrane in Eales’ disease.
Invest Ophthalmol Vis Sci 2000; 41:822.
17. Biswas J: Eales disease – an update.
Survey Ophthalmol 2002; 47:197.
18. Bali T, Saxena S, Kumar D, Nath R:
Response time and safety profile of pulsed
oral methotrexate therapy in idiopathic
retinal periphlebitis. Eur J Ophthalmol
2005; 15:374.
19. Agrawal S, Agrawal J, Agrawal T:
Intravitreal triamcinolone acetonide in
Eales’ disease. Retina 2006; 26:227.
20. Spitznas M, Meyer-Schwickerath G,
Stephan B: Treatment of Eales disease with
photocoagulation. Graefes Arch Clin Exp
Ophthalmol 1975; 194:73.
21. Magargal LE, Walsh AW, Magargal HO,
Robb-Doyle E: Treatment of Eales disease
SECTION 10
with scatter photocoagulation. Ann
Ophthalmol 1989; 21:300.
22. Das T, Namperumalsamy P: Combined
photocoagulation and cryotherapy in
treatment of Eales retinopathy. Indian J
Ophthalmol 1987; 35:108.
1840
23. Ishaq M, Niazi MK: Usefulness of laser
photocoagulation in managing
asymptomatic eyes of Eales’ disease.
J Ayub Med Coll Abbottabad 2002; 14:22.
24. Smiddy WE, Isernhagen RD, Michels RG,
Glaser BM: Vitrectomy for nondiabetic
vitreous hemorrhage. Retina 1988; 8:88.
25. Kumar A, Tiwari HK, Singh RP, et al:
Comparative evaluation of early vs.
deferred vitrectomy in Eales’ disease. Acta
Ophthalmol Scand 2000; 78:77.
26. Renie WA, Murphy RP, Anderson KC, et al:
The evaluation of patients with Eales
disease. Retina 1983; 3:243.
27. Rajesh M, Sulochana KN, Sundaram AL,
et al: Presence of a 88 kDa Eales protein in
uveitis, tuberculosis, leprosy and rheumatoid
arthritis. Med Sci Monit 2003; 9:95.
28. Rengarajan K, Muthukkaruppan VR,
Namperumalsamy P: Biochemical analysis
of serum proteins from Eales patients. Curr
Eye Res 1989; 8:1259.
29. Saxena S, Rajasingh J, Biswas S, et al:
Cellular immune response to retinal
S-antigen and interphotoreceptor retinoid-
binding protein fragments in Eales’ disease
patients. Pathobiology 1999; 67:39.
30. Ishaq M, Karamat S, Niazi MK: HLA typing
in patients of Eales disease. J Coll
Physicians Surg Pak 2005; 15:288.
31. Wagner W, Fehrmann A: Association of
retinal vasculitis (Eales’ disease) and
Meniere-like vestibulocochlear symptoms.
Eur Arch Otorhinolaryngol 2006; 263:100.
32. Misra UK, Jha S, Kalita J, Sharma K:
Stroke: a rare presentation of Eales’
disease. A case report. Angiology 1996;
47:73.
33. Atabay C, Erdem E, Kansu T, Eldem B:
Eales disease with internuclear
ophthalmoplegia. Ann Ophthalmol 1992;
24:267.
34. Rangasetty UC, Tyagi S, Mukhopadhyay S,
et al: Isolated extra-cranial internal carotid
artery aneurysm in a young adult with
Eale’s disease. J Assoc Phys India 2003;
51:830.
35. Muthukkaruppan V, Rengarajan K,
Chakkalath HR, Namperumalsamy P:
Immunological status of patients of Eales
disease. Indian J Med Res 1989; 90:351.
 CHAPTER

138 Retinal Arterial Macroaneurysms

Diana V. Do, Quan Dong Nguyen, and Julia A. Haller

Aneurysmal alterations of the retinal vasculature are a frequent
finding in clinical ophthalmic practice. These changes most com-
monly involve the retinal veins or capillaries and are usually
seen as a sequel to diabetes mellitus, venous occlusive disease,
sickle-cell disease, or radiation retinopathy. Less commonly,
larger aneurysms arise directly from the major retinal arteries.
Although mentioned sporadically in the earlier literature,1,2 the
entity currently known as retinal arterial macroaneurysms was
formally described in 1973 by Robertson.2
DEFINITION AND DESCRIPTION
Retinal arterial macroaneurysms may be defined as fusiform or
saccular dilatations of the retinal arteries, usually arising within
the first three orders of bifurcation. Their diameter exceeds
100 mm (arbitrarily the upper limit of typical microaneurysms)
but generally is not greater than ~250 mm. Although most cases
are unilateral, 10% of patients have bilateral disease. Multiple
aneurysms occur in ~20% of affected eyes and usually involve
different arteries in the same eye. Patients may also present
with multiple aneurysms along the same artery. The most com-
monly reported site of involvement is along the superotemporal
arcade because individuals with aneurysms at this location are
more likely to have visual symptoms.2a Rarely, macroaneurysms
can occur directly on the optic nervehead3–5 or arise from a cilio-
retinal artery.6,7 They often occur at bifurcation sites and at
arteriovenous crossings and have been seen to develop in vessels
with a documented history of embolic damage.7–9 Approximately
10% of macroaneurysms are pulsatile on initial presentation,
but the literature is discordant as to whether this is a sign of
impending rupture.10–12
Hemorrhage can also occur within the retina. Often a typical
‘hourglass hemorrhage’ occurs, consisting of simultaneous sub-
retinal and preretinal collections of blood. Serous fluid can collect
within the retina, producing diffuse, focal, or cystoid macular
edema, or it can accumulate in the subretinal space, detaching
the macula and producing a gradual diminution in visual acuity.
Lipid exudates can also cause a gradual decrease in vision by
migrating into the macula (Fig. 138.2).
Secondary epiretinal membranes may form as subhyaloid or
subinternal limiting membrane hemorrhage resorbs, and these
can cause persistent decreased visual acuity even after the macro-
aneurysm itself and bleeding/exudate caused by it have resolved.
If the macroaneurysm is large and occurs at an arteriovenous
crossing, a branch retinal vein occlusion may be produced sec-
ondarily, and symptoms may result from manifestations of the
vein occlusion or from the macroaneurysm, or both.
ANGIOGRAPHIC FINDINGS
The most common fluorescein angiographic appearance of a
macroaneurysm is uniform filling during the early arterial phase
of the angiogram. Partial filling may occur if the aneurysm is spon-
taneously involuting or is partially thrombosed (Fig. 138.3). The
late phase of the fluorescein angiogram may reveal leakage from
the macroaneurysm or staining of the vessel wall. The involved
artery is typically patent but may be narrowed proximal and
distal to the macroaneurysm, although obliteration of the distal
portion of the artery has been reported.13 The area surrounding

EPIDEMIOLOGY
The typical patient presenting with a macroaneurysm is a woman,
greater than 60 years of age, with an established history of sys-
temic hypertension. The female preponderance is on the order
of 3:1.2,10,11 Approximately 75% of patients have a history of hyper-
tension. Hypertension and arteriosclerotic vascular disease are
the only consistent disease associations in patients harboring
macroaneurysms.

FUNDUS APPEARANCE
The presentation of a patient with a macroaneurysm is variable.
Retinal arterial macroaneurysms can be found on routine exam-
ination in asymptomatic patients. Sudden, severe visual loss
may result from rupture of the aneurysm and resultant hemor-
rhage into the subretinal space, the subinternal limiting mem-
brane space, the retrohyaloid space, or the vitreous (Fig. 138.1). FIGURE 138.1. Large hemorrhage obscures the macroaneurysm. 1841
 RETINA AND VITREOUS
a b
SECTION 10
FIGURE 138.3. Fluorescein angiogram shows rapid, incomplete filling
of the macroaneurysm, which is consistent with partial thrombosis.
the macroaneurysm often shows capillary microaneurysms and
nonperfusion, intraretinal microvascular abnormalities, telang-
iectasis, and fluorescein dye leakage.
Occasionally, fluorescein angiography may not demonstrate a
macroaneurysm because of blockage by overlying hemorrhage.
A high index of suspicion combined with serial examinations and
angiography as the hemorrhage clears will result in an accurate
diagnosis. When hemorrhage prevents view of underlying struc-
tures, indocyanine green angiography may be useful in viewing the
macroaneurysm because the absorption and emission spectra of
indocyanine green are in the near-infrared range, and the dye
can often be seen through hemorrhage, allowing views of struc-
tures that would otherwise be obscured. A retrospective case
series using indocyanine green angiography in eyes with dense
preretinal and subretinal hemorrhages demonstrated that
indocyanine green angiography could correctly diagnose retinal
macroaneurysms as the cause of hemorrhage when fluorescein
angiography was inconclusive.13a
PATHOGENESIS AND PATHOLOGIC
APPEARANCE
The exact pathogenetic mechanism of macroaneurysm forma-
1842 tion is uncertain. However, several observations and associ-
FIGURE 138.2. (a and b) Peripherally located
aneurysm with lipid exudate involving the fovea.
ations have led investigators to at least three hypotheses – focal
damage to the blood vessel wall, chronic hypertensive vascular
damage, and inherent structural defects in blood vessels.
Lewis and colleagues9 observed a patient who developed
macroaneurysm at the site of a documented incomplete embolic
occlusion of a retinal artery. The authors postulated that embolic
injury results in focal damage to the blood vessel wall, causing
weakening of the wall and subsequent aneurysm formation.
Wiznia7 reported a macroaneurysm occurring in a cilioretinal
artery after an embolic occlusion of the artery. Ohga and asso-
ciates14 described a case of a macroaneurysm in an artery that
crossed over a toxoplasmosis scar. Periarteritis from the toxo-
plasmic inflammation may have caused structural damage that
weakened the arterial wall and caused an aneurysm to form.
The role of previous vascular damage was also suggested by the
study of Panton and co-workers.14a They noted a high concordance
rate between the location of macroaneurysms and that of branch
retinal vein occlusions when these occurred in the same eye.
Macroaneurysms occurred 12 times more often in the quadrant
served by the affected vein than elsewhere. In two eyes, the branch
vein occlusion was known to have preceded development of the
macroaneurysm.
Retinal arterial macroaneurysms have been noted to be
similar to intracerebral miliary aneurysms seen in elderly
hypertensive patients, especially women.2,11 Since hypertension
is commonly associated with retinal arterial macroaneurysms,
it is believed that chronic vascular wall damage caused by
hypertension and associated arteriosclerotic changes predispose
the vessels to focal dilatation in the presence of continued
increased intraluminal pressure.
Lavin and colleagues11 noted that at the point of arteriovenous
crossing, there is no adventitia and the two blood vessels share
a common coat. The arterial wall thus has less support at these
locations, and with increased intraluminal pressure in the
hypertensive patient, ectasia of the arterial wall may result.
After development of the macroaneurysm, symptoms are
produced by leakage through the thinned wall of the lesion as
well as from the surrounding microvascular alterations that are
usually present. Histopathologically, actual aneurysmal sites
show thickening of the arterial walls secondary to a fibrin-
laminated clot accompanied by hypertrophy of the muscular
layer. A thrombus will often partially or entirely fill the macro-
aneurysm. Thickened, hyalinized arterial walls are common in
adjacent arterioles. The areas surrounding the macroaneurysm,
clinically noted to show microvascular changes such as capillary
loss, telangiectasias, and products of vascular leakage, typically
show corroborating histologic findings including dilatation of
the capillary bed, hemorrhage, lipid, edema, and photoreceptor
degeneration.14b

NATURAL HISTORY
The natural history of macroaneurysms varies and is dependent
on the clinical presentation. In some patients with hemorrhage
and no involvement of the macula, the visual acuity is not affected
and the hemorrhage can resolve without any adverse effects
(Fig. 138.4).
Abdel-Khalek and Richardson10 reported the natural history
of 18 cases of macroaneurysm, segregating them by clinical
presentation into acute and chronic decompensation. Acute
decompensation was typified by hemorrhage into the retina,
subretinal space, subhyaloid space, or vitreous, and it produced
sudden visual loss. Chronic decompensation was characterized
by more gradual visual loss from the accumulation of macular
edema and lipid exudate.
After presumed aneurysmal rupture associated with the acute
decompensation category, several pathways were followed. In
some subjects, the arterial perforation closed, leaving an intact
aneurysm that could rebleed or continue to leak fluid and exudate.
Other aneurysms spontaneously closed, forming Z-shaped kinks
at the former aneurysm site (Fig. 138.5). Subjects with only an
intraretinal hemorrhage often experienced a yellow-gray, saddle-
shaped plaque centered on the macroaneurysm, with surrounding
exudate. The involved arteriole often became heavily sheathed.
a b
a b
c d
Retinal Arterial Macroaneurysms
In the group of patients with chronic decompensation, several
macroaneurysms were treated with photocoagulation because
edema and lipid exudate had already involved the central macular
area and caused decreased visual acuity. In five subjects in whom
macular function was not threatened, no treatment was under-
taken. None of these cases ever progressed to involve the macula,
although only one spontaneously closed during the study.
After closure of these chronically decompensating aneurysms,
either spontaneously or as a result of photocoagulation, kinking
occurred at the aneurysmal site. Arteriolar constriction also
occurred, usually proximal but occasionally distal to the macro-
aneurysm site. Arterial sheathing distal to the macroaneurysm
was commonly seen, but distal arterial closure was rare, even
after therapy.
These authors reported a relatively good visual prognosis
with macroaneurysms presenting with acute hemorrhage, as
have some other investigators.11,12 Of the eight patients in this
category, only two patients had a final visual acuity of 6/18 or
CHAPTER 138
worse.10 The remaining six patients had visual acuity of 6/12 or
better. Of the patients with chronic aneurysmal decompen-
sation, one patient had visual acuity of 6/60, two patients had
visual acuity of 6/36, and one patient had visual acuity of 6/18,
with only six patients arriving at visual acuity of 6/12 or better.
These authors concluded that acute hemorrhage infrequently
FIGURE 138.4. (a) Subretinal hemorrhage not
involving the fovea. (b) Same eye as in (a)
6 weeks later without treatment.
FIGURE 138.5. Spontaneous closure of the
macroaneurysm seen in Figure 138.1. (a) At
6 days. (b) At 20 days. (c) At 42 days. (d) At
close to 6 months after Figure 138.1.
(e) Fluorescein angiogram shows kinks at the
former aneurysm site.
e
1843
 RETINA AND VITREOUS
leads to marked decreases in visual acuity, whereas chronic
macular edema and exudate commonly lead to a poorer visual
outcome.
Palestine and associates12 investigated the natural course of
macroaneurysms using a similar strategy. They divided their
patients into three groups. Group A included eyes with
hemorrhage, exudate, edema, or the macroaneurysm within the
vascular arcades, accompanied by decreased visual acuity.
Group B included eyes with hemorrhage, exudate, edema, or the
macroaneurysm within the arcades, but without an effect on
visual acuity. Group C included eyes in which all the pathologic
features were peripheral to the vascular arcades. These
investigators concluded that eyes in group A could do poorly
and that the prognosis was variable. Eyes in group B did better
but needed to be observed periodically to be certain they did not
convert to the group A type of eyes. Group C eyes typically did
well without therapy. These investigators also noted that eyes
presenting with acute vitreous or subinternal limiting
SECTION 10
membrane hemorrhage tended to do well.
Cleary and co-workers13 reviewed the natural history of
macroaneurysms in 20 patients. They observed that the macro-
aneurysms almost always closed spontaneously after acute
hemorrhage, whereas the lesions rarely did so when macular
edema was the presenting pathologic condition. The authors
concluded that the prognosis was good in patients presenting
with hemorrhage and poorer in those presenting with macular
edema. Both the degree of chronicity and the severity of the
macular edema affected the prognosis.
McCabe and associates reviewed 41 patients who presented
with macular hemorrhage secondary to macroaneurysms and
were managed with observation.15 After an average follow-up of
15.7 months, a visual acuity of 20/40 was achieved in 37%,
between 20/50 and 20/100 in 29%, and 20/200 or worse in 34%.
Poorer visual acuity outcomes were associated with macular
pigmentary changes after resorption of blood.
More recently, Yang and colleagues conducted a retrospective
review of arterial macroaneurysms followed at their institution
over a 17-year period.16 The authors classified the 31 patients
in their study as having either predominantly hemorrhagic or
exudative macroaneurysms. Eyes with hemorrhagic lesions had
a greater improvement in vision after resolution of the blood
compared to eyes in the exudative cohort, and foveal exudate
was a statistically significant risk factor for final visual acuity
equal to or worse than 6/30.
Although arterial closure is not a common occurrence, some
investigators have described a significant number in their case
series. Panton and co-workers14a reported an 8% rate of branch
retinal artery occlusion in untreated cases of macroaneurysm
and a 16% incidence after treatment. There has been at least
one other case report of spontaneous branch retinal artery
occlusion.17
As already noted, a question has been raised in the literature
regarding the significance of pulsation of the macroaneurysm.
Some investigators consider this a sign of imminent
rupture,10,18,19 although others believe that it has no relation-
ship to eventual rupture and that there are no reliable signs of
impending rupture.11
DIFFERENTIAL DIAGNOSIS
In cases uncomplicated by a poor view of the fundus, the diag-
nosis of retinal arterial macroaneurysm is easily established.
Often, however, the true nature of the pathologic condition is
obscured by hemorrhage, whether in the vitreous, on the surface
of the retina, or within the retina itself. A typical hourglass type
of hemorrhage should alert the clinician to the possibility of a
1844 macroaneurysm. In addition, several entities closely resemble
retinal arterial macroaneurysms and are not always easily
distinguishable. Spalter20 called retinal arterial macroaneurysms
another ‘masquerade’ syndrome.
Microaneurysms such as those occurring secondary to
diabetes mellitus, radiation retinopathy, sickle-cell disease, and
branch retinal vein occlusion are usually not confused with
retinal arterial macroaneurysms. They are smaller and the
nature of the underlying disease is often well established.
Schulman and colleagues21 described large capillary macro-
aneurysms occurring secondary to retinal venous obstructive
disease. These were similar in size to macroaneurysms but ori-
ginated from the venous side of the capillary bed. They caused
decreased visual acuity as a result of macular edema and exudate
as well as serous elevation of the macula, mechanisms shared
in common with retinal arterial macroaneurysms. Parodi and
co-workers22 reported multiple 150–300 mm capillary macro-
aneurysms in an eye with central retinal vein occlusion.
A variety of macroaneurysms has been reported after branch
retinal vein occlusion.23,24 Cousins and associates24 reviewed
the photographs and fluorescein angiograms of patients who
participated in the Collaborative Branch Vein Occlusion Study
through the Bascom Palmer Eye Institute. They noted that four
types of macroaneurysm could be seen after branch retinal vein
occlusion. Typical retinal arterial macroaneurysms, indis-
tinguishable from the idiopathic variety, were common and
occurred within the zone of the branch retinal vein occlusion.
Venous macroaneurysms were similar in size but slower to fill
angiographically because they occurred along the obstructed
vein. Capillary aneurysms were also seen, similar to those
reported by Schulman and colleagues.21 Finally, they described a
new type of macroaneurysm that they called the collateral-
associated macroaneurysm. These were associated with clearly
identifiable dilated collateral vessels on fluorescein angiography.
All four types of these macroaneurysms were associated with
intraretinal lipid or hemorrhagic exudation, often involving the
macula. On fluorescein angiography, the macroaneurysms were
typically found to be present in areas of capillary nonperfusion.
Eighty-four percent of these eyes were classified as having severe
nonperfusion according to the criteria of the Branch Vein
Occlusion Study.
There has been one case report of a spontaneous venous
macroaneurysm occurring without an antecedent vein occlusion.
Brourman and colleagues25 described a macroaneurysm of the
proximal superotemporal vein in a patient with pericarditis.
They suggested that increased venous pressure may have been
a causative factor.
Branch retinal vein occlusions have been reported to
masquerade as retinal arterial macroaneurysms; this is known
as the Bonnet sign.26 The classic Bonnet sign consists of
intraretinal hemorrhage at an arteriovenous crossing simulating
a macroaneurysm.
There is one report of a retinal arterial macroaneurysm
presenting as a mass lesion of the optic nerve; only with serial
follow-up was the proper diagnosis ultimately made.3 There has
been one case report of Valsalva’s retinopathy occurring as the
result of a ruptured retinal arterial macroaneurysm.27
Before retinal arterial macroaneurysms became a familiar
clinical entity, they were commonly confused with retinal
telangiectasis, Leber’s miliary aneurysms, or Coats’ disease.
These patients have unilateral disease consisting of multiple
telangiectatic vessels in the midperiphery, predominantly on
the venous side of the circulation and usually present in
childhood, often with massive exudation including exudative
retinal detachment.
von Hippel’s angiomatosis usually shows a distinct genetic
component. When small, the angiomas may be confused with
macroaneurysms, but when well developed, they are typically

much larger and accompanied by large, tortuous feeder and
draining vessels. Similar-sized retinal angiomas may occur
unassociated with von Hippel’s disease; they do not have pro-
minent feeder and drainage vessels unless the tumors become
quite large.
A common presenting situation is that of an elderly patient
with an acute subretinal hemorrhage in the macula. There is
often a surrounding area of subretinal lipid exudate, and the
appearance can closely mimic neovascular age-related macular
degeneration. The macroaneurysm may be obscured by the
retinal hemorrhage. A high index of suspicion and careful
examination of the fellow eye, coupled with indocyanine green
angiography may lead to the proper diagnosis, confirmed after
hemorrhage resolution.
Since ~10% of retinal arterial macroaneurysms present with
vitreous hemorrhage, this diagnosis must be suspected when no
retinal detachment, retinal tear, or avulsed retinal vessel is
found after the vitreous hemorrhage clears. The retinal arterial
macroaneurysm may involute before adequate fundus viewing
and leave only subtle telltale signs of its presence as the cause
of the vitreous hemorrhage.
If large subretinal or subretinal pigment epithelial hemorr-
hage occurs, this presentation may be mistaken for a choroidal
melanoma (Fig. 138.6).
MANAGEMENT
Although there have been no prospective, randomized clinical
trials involving laser photocoagulation treatment of retinal
arterial macroaneurysms, empirical treatment guidelines have
been established by numerous investigators. Many investigators
apply laser photocoagulation directly to macroaneurysms
associated with exudates, macular edema, and visual acuity
decrease. Although advances in vitreous surgery and the
development of adjunctive pharmacologic agents have made the
removal of submacular hemorrhage technically feasible, and
good results with this strategy have been reported, the useful-
ness of surgical intervention has not been established as yet.
Natural history studies suggest that spontaneous resorption of
blood usually occurs with relatively good visual outcomes.28–33
Most authorities agree that a quiet macroaneurysm that is
asymptomatic without visible leakage should not be treated but
should continue to be monitored until spontaneous fibrosis
occurs. Ghost macroaneurysms (i.e., those that are already
spontaneously fibrosed and show the kinked-vessel Z-sign or
the saddle-shaped plaque) also should not be treated, as they
have run their natural course and will remain quiescent.
Similarly, macroaneurysms that have ruptured and bled acutely
rarely rebleed,34 so observation is adequate in these cases.
Aneurysms that leak fluid or exudate, or both, and threaten to
a b
FIGURE 138.6. Patient with a large subretinal and subpigment epithelial hemorrhage referred to as a choroidal melanoma. (a) At presentation.
(b) Fluorescein angiogram at presentation. (c) Appearance 5 months later.
Retinal Arterial Macroaneurysms
involve or already involve the central macula should be
considered for therapy (Fig. 138.7). Treatment has been shown
to shorten the duration of macroaneurysm patency.11 The
duration of the hemorrhage and exudate as well as its severity
will determine the ultimate visual outcome.
Abdel-Khalek and Richardson10 treated macroaneurysms with
direct photocoagulation using the argon laser and xenon arc.
Two of their patients also received perianeurysmal treatment
preceding the direct treatment. No bleeding or complications
occurred from the direct therapy. The macroaneurysms were
closed in all cases. Some investigators recommend treatment to
be undertaken early in the course of the disease because the
longer the edema and exudate are present, the less the chance
of improving the visual acuity and preventing permanent
macular damage. Closure of the macroaneurysm has been
shown to enhance the rate of resorption of retinal exudate,9
although the exudate may initially appear to worsen or increase
because of more rapid and selective resorption of retinal edema
CHAPTER 138
fluid, which may cause further precipitation of lipid exudate.
Palestine and associates12 treated several eyes with macro-
aneurysms that had produced macular edema and exudate.
They specifically advised against treating the aneurysm or the
artery directly because of the possibility of rupture of the
aneurysm, although they acknowledged that this complication
had not been reported. These investigators, as did Lewis and
colleagues,9 treated the area of the microvascular changes sur-
rounding the aneurysm and found that this predictably produced
involution of the aneurysm. They also noted an early increase
in lipid exudation, as less protein-rich fluid was initially resorbed.
Complete resolution of the exudate took several months.
Lavin and colleagues11 treated hemorrhagic and exudative
macroaneurysms when the macula was involved, with a combi-
nation of direct and perianeurysmal techniques using the argon
laser. They achieved closure of the macroaneurysms without
complications and again noted that the visual prognosis
depended on the degree of intraretinal hemorrhage and exudate
in the central macula.
Joondeph and co-workers35 treated macroaneurysms using
the yellow dye laser. They used a technique of partially over-
lapping burns applied to just the peripheral margin of the
macroaneurysm, sparing the feeding and draining arterioles.
They successfully closed all the macroaneurysms in one treat-
ment and reported no complications of therapy.
Mainster and Whitacre36 also used the yellow dye laser with
a similar technique to successfully close five macroaneurysms.
They also reported no complications. However, Russell and
Folk,37 after having successfully treated 15 macroaneurysms
with the argon laser, used the yellow dye laser on one patient
and immediately produced a branch retinal artery occlusion
after applying only four burns to the macroaneurysm. Their
c
1845
 RETINA AND VITREOUS
Arterial macroaneurysm
Exudate and macular edema Not threatening fovea
(Decreased visual acuity) (Asymptomatic)
Consider laser photocoagulation Observe
treatment technique was not well described but appeared to
involve a more direct treatment to the macroaneurysm than did
either of the previous two reports involving the yellow dye laser.
SECTION 10
Recent work by Brown and associates38 suggested that direct
laser treatment of macroaneurysms may be harmful and, in
their study, it involved a significant risk factor for poor visual
outcome. In a retrospective study, they compared the long-term
visual outcome between patients treated with direct laser photo-
coagulation and untreated patients. They treated eight eyes
with argon green and eight eyes with yellow dye lasers. Even
when statistically controlling for the effect of subfoveal hemor-
rhage and subfoveal lipid, laser photocoagulation remained the
strongest predictor for final visual acuity of less than 20/80.
They noted four cases of branch retinal artery occlusion, at least
two of which led to further foveal capillary dropout and subsequent
decreased visual acuity. They suggested that indirect treatment
may lower the complication rate and show better results.
Panton and co-workers14a observed a 16% rate of branch
retinal artery occlusion after laser photocoagulation, but noted
that none occurred with exclusively perianeurysmal treatment.
They also acknowledged that other investigators believed that
direct treatment was riskier and more likely to cause arterial
closure than were indirect techniques.
Chaum and colleagues reported the development of retino-
choroidal anastomoses and choroidal neovascularization (CNV)
in one patient after applying laser photocoagulation directly to
a macroaneurysm.38a Although the CNV was not located directly
beneath the site of the photocoagulation, the authors hypo-
thesize that the laser treatment induced changes in the blood
flow in the macula which induced retinochoroidal anastomoses
formation and CNV.
These aforementioned treatment techniques are routinely used
for managing the vision-threatening consequences of macro-
aneurysms. Ancillary techniques have been reported. Tassignon
a b
FIGURE 138.8. Patient with subretinal hemorrhage extending into the fovea. (a) Vision is counting fingers. (b) Early resorption of hemorrhage.
1846 (c) Vision is 20/40 10 weeks after (a).
FIGURE 138.7 Treatment algorithm for retinal
arterial macroaneurysm.
Hemorrhage
Into fovea
Observe
and colleagues39 used a Q-switched neodymium:yttrium–
aluminum garnet laser to release a retrohyaloid hemorrhage
resulting from a ruptured macroaneurysm, thus facilitating
more rapid resorption of the blood than would have occurred
spontaneously. Raymond40 reported two cases in which
subinternal limiting membrane hemorrhage from macro-
aneurysms was liberated into the vitreous with the same type of
laser.
Subfoveal hemorrhage, whether from a macroaneurysm or
associated with other pathology, has traditionally been believed
to have a uniformly poor prognosis for visual acuity. Advances
in vitrectomy surgery have attempted to address this problem.
Hanscom and Diddie28 first reported drainage of submacular
hemorrhage resulting from ruptured retinal arterial macro-
aneurysms in 1987. There have been numerous subsequent
reports, some of which described the adjunctive use of tissue
plasminogen activator to evacuate submacular hemorrhage in
this situation.29–33 None of these reports described more than four
eyes with subfoveal hemorrhage. Patients showed improvement
from their preoperative visual acuities, but it has yet to be deter-
mined whether this aggressive approach improves on the natural
history, even for this serious presentation of macroaneurysms.
There can be significant and sometimes marked improvement
in vision even without treatment, although natural history data
are scant. Berrocal and associates41 studied variations in the
clinical course of subfoveal hemorrhages. Two of their patients
had hemorrhage due to macroaneurysms. One did poorly, but
the other recovered to 20/30 from an initial vision of 5/200. The
authors recently observed a case of subretinal hemorrhage
extending beneath the fovea to cause counting fingers visual
acuity with eventual spontaneous recovery to 20/40 (Fig. 138.8).
Although vitreous hemorrhage from macroaneurysms typically
clears rapidly, pars plana vitrectomy surgery is effective for the
occasional case of dense, nonclearing vitreous hemorrhage.33
c
 Retinal Arterial Macroaneurysms

SUMMARY involvement with hemorrhage, exudate, edema, or serous detach-

Retinal arterial macroaneurysms are a well-defined retinal vascu-
lar disorder consisting of saccular or fusiform dilatations of the
major retinal arterioles, usually within the first three orders of
bifurcation. They usually occur in older, hypertensive women.
Diagnosis can sometimes be difficult, and a high index of
suspicion is required. Indocyanine green angiography may be
helpful in cases where hemorrhage obscures the macroaneurysm.
Their natural history is often benign, with many progressing to
spontaneous fibrosis and involution with retention of good visual
acuity. The visual acuity is decreased as the result of macular
ment or from vitreous or preretinal hemorrhage. Selected patients
may be successfully treated using laser photocoagulation, but the
visual prognosis cannot be reliably predicted in individual cases.
Key Features
• Fusiform or saccular dilation of the retinal artery
• Arises within the first three orders of artery bifurcation
• Most commonly found along superotemporal arcade
• 90% of cases are unilateral
• Often associated with hypertension and arteriosclerosis

REFERENCES
1. Rabb MF, Gagliano DA, Teske MP: Retinal 14a. Panton RW, Goldberg MF, Farber MD: 29. Peyman GA, Nelson NC, Alturki W, et al:
arterial macroaneurysms. Surv Ophthalmol Retinal arterial macroaneurysms: risk Tissue plasminogen activating factor
1988; 33:73. factors and natural history. Br J Ophthalmol assisted removal of subretinal hemorrhage.

2. Robertson DM: Macroaneurysms of the
retinal arteries. Trans Am Acad Ophthalmol
Otolaryngol 1973; 77:OP55.
2a. Moosavi RA, Fong KCS, Chopdar A.
Retinal artery macroaneurysms: clinical and
fluorescein angiographic features in 34
patients. Eye 2006; 20:1011–1020.
3. Brown GC, Weinstock F: Arterial
macroaneurysm on the optic disc
presenting as a mass lesion. Ann
Ophthalmol 1985; 17:519.
4. Kowal L, Steiner H: Arterial macroaneurysm
of the optic disc. Aust N Z J Ophthalmol
1991; 19:75.
5. Iwasawa A, Majima A, Shirai S, et al: Bilateral
prepapillary macroaneurysm. Report of a
case. Jpn J Ophthalmol 1989; 43:619.
6. Giuffre G, Montalto FP, Amodei G:
Development of an isolated retinal
macroaneurysm of the cilioretinal artery. Br
J Ophthalmol 1987; 71:445.
7. Wiznia RA: Development of a retinal artery
macroaneurysm at the site of a previously
detected retinal artery embolus. Am J
Ophthalmol 1982; 114:642.
8. El-Asrar AMA, Awad A, Tabbara KF: Retinal
artery macroaneurysm in a patient with
congenital heart disease. Br J Ophthalmol
1993; 77:606.
9. Lewis RA, Norton MH, Wise GN: Acquired
arterial macroaneurysms of the retina. Br J
Ophthalmol 1976; 60:21.
10. Abdel-Khalek MN, Richardson J: Retinal
macroaneurysm: natural history and
guidelines for treatment. Br J Ophthalmol
1986; 70:2.
11. Lavin MJ, Marsh RJ, Peart S, et al: Retinal
arterial macroaneurysms: a retrospective
study of 40 patients. Br J Ophthalmol
1987; 71:817.
12. Palestine AG, Robertson DM, Goldstein
BG: Macroaneurysms of the retinal arteries.
Am J Ophthalmol 1982; 93:164.
13. Cleary PE, Kohner EM, Hamilton AM, et al:
Retinal macroaneurysms. Br J Ophthalmol
1975; 59:355.
13a. Townsend-Pico WA, Meyers SM, Lewis H:
Indocyanine green angiography in the
diagnosis of retinal arterial
macroaneurysms associated with
submacular and preretinal hemorrhages: a
case series. Am J Ophthalmol 2000;
129:33–37.
14. Ohga H, Egi K, Katayama T, et al: A case of
retinal macroaneurysm with congenital
ocular toxoplasmosis. Folia Ophthalmol
Jpn 1990; 41:898.
1990; 74:595.
14b. Fichte C, Streeten BW, Friedman AH:
A histopathologic study of retinal arterial
aneurysms. Am J Ophthalmol 1978;
85:509.
15. McCabe C, Flynn HW, McLean WC, et al:
Nonsurgical management of macular
hemorrhage secondary to retinal artery
macroaneurysms. Arch Ophthalmol 2000;
118:780–785.
16. Yang CS, Tsai DC, Lee FL, Hsu WM:
Retinal arterial maacroaneurysms: risk
factors of poor visual outcome.
Ophthalmologica 2005; 219:366–372.
17. Oo A, Saito Y, Okamoto S, et al: Retinal
macroaneurysm and branched retinal artery
occlusion. Ther Res 1989; 10:11.
18. Psinakis A, Kokolakis PG, Theodossiadis C,
et al: Pulsatile retinal arterial macroaneurysm:
treatment with argon laser photocoagulation.
J Fr Ophtalmol 1989; 12:673.
19. Yokoi N, Tohsaka S, Yamamoto T: A case of
pulsating retinal arterial macroaneurysm.
Folia Ophthalmol Jpn 1990; 41:584.
20. Spalter HF: Retinal macroaneurysms: a
new masquerade syndrome. Trans Am
Ophthalmol Soc 1982; 80:113.
21. Schulman J, Jampol LM, Goldberg MF:
Large capillary aneurysms secondary to
retinal venous obstruction. Br J Ophthalmol
1981; 65:36.
22. Parodi MB, Bondel E, Ravalico G: Capillary
macroaneurysms in central retinal vein
occlusion. Ophthalmologica 1995; 209:248.
23. Sanborn GE, Magargal LE: Venous
macroaneurysm associated with branch
retinal vein obstruction. Ann Ophthalmol
1984; 16:464.
24. Cousins SW, Flynn HW, Clarkson JG:
Macroaneurysms associated with retinal
branch vein occlusion. Am J Ophthalmol
1990; 109:567.
25. Brourman ND, Goldberg RE, Augsburger
JJ, et al: Isolated venous macroaneurysm.
Ophthalmic Surg 1990; 21:646.
26. Kimmel AS, Magargal LE, Morrison DL,
et al: Temporal branch retinal vein
obstruction masquerading as a retinal
arterial macroaneurysm: the Bonnet sign.
Ann Ophthalmol 1989; 21:251.
27. Avins LR, Krummenacher TK: Valsalva
maculopathy due to a retinal arterial
macroaneurysm. Ann Ophthalmol 1983;
15:421.
28. Hanscom TA, Diddie KR: Early surgical
drainage of macular subretinal hemorrhage.
Arch Ophthalmol 1987; 105:1722.
CHAPTER 138
Ophthalmic Surg 1991; 22:575.
30. Moriarty AP, McAllister IL, Constable IJ:
Initial clinical experience with tissue
plasminogen activator (tPA) assisted
removal of submacular hemorrhage. Eye
1995; 9:582.
31. Lim JI, Drews-Botsch C, Sternberg P, et al:
Submacular hemorrhage removal.
Ophthalmology 1995; 102:1393.
32. Ibanez HE, Williams DF, Thomas MA, et al:
Surgical management of subretinal
hemorrhage: a series of 47 consecutive
cases. Arch Ophthalmol 1995; 113:62.
33. Brent BD, Gonce M, Diamond JG: Pars
plana vitrectomy for complications of
retinal arterial macroaneurysms – a case
series. Ophthalmic Surg 1993; 24:534.
34. Nadel AJ, Gupta KK: Macroaneurysms of
the retinal arteries. Arch Ophthalmol 1976;
94:1092.
35. Joondeph BC, Joondeph HC, Blair NP:
Retinal macroaneurysms treated with the
yellow dye laser. Retina 1989; 9:187.
36. Mainster MA, Whitacre MM: Dye yellow
photocoagulation of retinal arterial
macroaneurysms. Am J Ophthalmol 1988;
105:97.
37. Russell SR, Folk JR: Branch retinal artery
occlusion after dye yellow
photocoagulation of an arterial
macroaneurysm. Am J Ophthalmol 1987;
104:186.
38. Brown DM, Sobol WM, Folk JC, et al:
Retinal arteriolar macroaneurysms: long
term visual outcome. Br J Ophthalmol
1994; 78:534.
38a. Chaum E, Greenwald MA: Retinochoroidal
anastomoses and a choroidal neovascular
membrane in a macular exudate following
treatment for retinal macroaneurysms.
Retina 2002; 22:363–366.
39. Tassignon MJ, Stempels N, Van Mulders L:
Retrohyaloid premacular hemorrhage
treated by q-switched Nd-YAG laser.
Graefes Arch Clin Exp Ophthalmol 1989;
227:440.
40. Raymond LA: Neodymium:YAG laser
treatment for hemorrhages under the
internal limiting membrane and posterior
hyaloid face in the macula. Ophthalmology
1995; 102:406.
41. Berrocal MH, Lewis ML, Flynn HW:
Variations in the clinical course of
submacular hemorrhage. Am J Ophthalmol
1996; 122:486.
1847
 CHAPTER

139 Coats’ Disease and Retinal Telangiectasia

Grant M. Comer and Mark W. Johnson

PRIMARY OR CONGENITAL RETINAL by 20 years of age, with a median age at diagnosis of 5 years.10
TELANGIECTASIA (COATS’ DISEASE) Roughly 75% of cases occur in males, and 95% of cases are
limited to one eye with asymmetric involvement when bilateral.
Most cases are diagnosed after parents note decreased vision,
INTRODUCTION leukocoria or strabismus (Fig. 139.1).10 Milder cases may be
Coats’ disease (idiopathic retinal telangiectasia, Leber’s miliary detected at the time of routine ophthalmic examination.
aneurysms) is an idiopathic, progressive exudative retinopathy
consisting of incompetent retinal telangiectasia that results in a
variable clinical spectrum ranging from isolated vascular abnor- ETIOLOGY
malities with no exudation to extensive sub- and intraretinal Although numerous authors have described Coats’-like condi-
exudation and detachment. Initially described as separate entities, tions associated with a number of ocular and systemic diseases,
the milder (Leber’s miliary aneurysms)1 and more severe (Coats’ Coats’ disease, by definition, is isolated and idiopathic with no
disease)2,3 forms of this retinal vascular anomaly are now con- known inheritance pattern.10 One report suggested involvement
sidered by most authorities to be variable expressions of the same of the Norrie disease pseudoglioma (NDP) gene (Xp11.3), which
disease and are, therefore, currently grouped under the common produces norrin protein.13 Norrin affects retinal angiogenesis
name of Coats’ disease.4,5 by modification of endothelial cell development. Known
phenotypic manifestations of NDP gene mutations include
Norrie disease, X-linked primary retinal dysplasia, and X-linked
CLASSIFICATION exudative vitreoretinopathy, which all exhibit variable degrees of
Coats initially divided this entity into three varieties: type I congenital vascular abnormalities within the retina.14,15 Black
included cases of abnormal exudation without apparent and colleagues reported an NDP mutation in a mother with
vascular changes; type II included both exudation and abnormal Coats’ disease who gave birth to a son with Norrie disease and
vessels; and type III exhibited exudation surrounding a large suggested that a somatic NDP gene mutation may be
retinal angioma.2,3 With the advent of fluorescein angiography, responsible for Coats’ disease. They also found a mixture of
it became apparent that abnormal retinal vessels were present both normal and mutant NDP alleles within retinal tissue, but
in both types I and II. Type III was subsequently determined not nonretinal tissue, of an enucleated eye from a patient with
synonymous with von Hippel’s angiomatosis retina.6 Other Coats’ disease.13
authors6,7 have attempted to stage Coats’ disease based on
specific clinical findings at presentation.
More recently, reports have attempted to classify Coats’ disease
by associating the degree of retinal involvement with prognosis.
Cahill and associates classified Coats’ disease as severe, focal,
juxtafoveal, or associated with other diseases. While severe
Coats’ disease had a dismal prognosis, the other groups were
generally amenable to treatment with 67% achieving a visual
acuity at or better than presentation.8 Similarly, Shields and
co-authors classified Coats’ disease as: stage 1, telangiectasia only;
stage 2, telangiectasia and exudation (2A, extrafoveal; 2B foveal);
stage 3, exudative retinal detachment (3A, subtotal; 3B total);
stage 4, total detachment with secondary glaucoma; and stage 5,
advanced end-stage disease. Despite attempts at treatment,
visual prognosis decreased as the extent of retinal involvement
increased, especially once the fovea was involved.9

DEMOGRAPHICS
No strong evidence supports a specific racial or ethnic predis-
position or inheritance pattern.10 Coats’ disease has reportedly
occurred in patients ranging from 3 months of age11 to those in FIGURE 139.1. Leukocoria secondary to total exudative retinal
the eighth decade of life;12 however, the majority of cases occur detachment in a child with Coats’ disease. 1849
 RETINA AND VITREOUS
CLINICAL PRESENTATION
Although the extent and rate of development of clinical findings
are variable, the disease is usually progressive.16 Primary abnor-
malities in Coats’ disease are confined to retinal vessels, with a
spectrum of secondary findings depending on the degree and
chronicity of vascular incompetence. Abnormalities can occur
in all levels of the vasculature and include: micro- and macro-
aneurysms, capillary dilation (telangiectasis) and nonperfusion,
and saccular outpouchings of retinal venules.12,17 In mild cases,
one or more localized foci of retinal telangiectasia are noted
within the retinal capillary bed, typically in the temporal quad-
rants between the equator and ora serrata; however, all
quadrants, including the macula, can be affected (Fig. 139.2).18,19
In more advanced Coats’ disease, areas of lipoproteinaceous
exudation develop adjacent to telangiectatic vessels, which have
permeable endothelial cells, and slowly progress to involve the
entire retina (Fig. 139.3a–c).19 With accumulation of exudate, a
SECTION 10
yellow or greenish-yellow subretinal deposit may develop in
association with localized exudative retinal detachment. This
subretinal lipid may coalesce into crystalline bodies and
multiple subretinal deposits. Intraretinal macular exudation
often occurs in a stellate pattern without connection to the
peripheral telangiectasis.19 With further progression, total
exudative retinal detachment may develop.10 Although often
FIGURE 139.2. Asymptomatic focus of retinal telangiectasia in a
patient with mild Coats’ disease.
a b
FIGURE 139.3. (a) Retinal telangiectasia and exudation in the superotemporal quadrant. (b) Focal vascular incompetence and nonperfusion on
1850 composite fluorescein angiogram. (c) Subfoveal exudation extending from distant nidus of leakage as seen on optical coherence tomography.
asymptomatic in the periphery, vision usually becomes affected
with the onset of hard exudates beneath the fovea, cystoid
macular edema, or exudative macular detachment (Fig. 139.4).
Massive exudation contributes to numerous secondary abnor-
malities throughout the eye. While often normal, the anterior
segment can demonstrate corneal edema, megalocornea,
cholesterolosis in the anterior chamber, neovascularization of
the iris, cataract, peripheral anterior synechiae, angle closure,
and neovascular or secondary open-angle glaucoma.10,18,20,21
Secondary posterior segment abnormalities may include: retinal
hemorrhages, macrocysts, vasoproliferative tumors, neovascu-
larization, vitreous hemorrhage, lamellar macular holes, and
preretinal membranes.10,12,18,22,23
The clinical presentation differs in adult patients in that the
vascular abnormalities are often present in both the peripheral as
well as juxtamacular areas. In addition, adults more commonly
demonstrate localized lipid deposition, hemorrhage around
macroaneurysms, and slower disease progression.12 Long-term
surveillance is important, even after treatment, as multiple
recurrences are seen to occur in up to 33% patients with Coats’
disease.24
FIGURE 139.4. Massive lipid exudation in macula associated with
inferior exudative retinal detachment.
c

ANCILLARY TESTS
Fluorescein angiography and optical coherence tomography
provide an objective measure of disease extent. Fluorescein
angiography demonstrates areas of capillary nonperfusion,
saccular and beadlike ‘light bulb’ dilatations of larger retinal
vessels, and general dilatation (telangiectasia) of the capillary
bed (Fig. 139.5 a,b).19,25 Abnormal retinal vessels typically fill in
the late arterial or early venous phase and slowly leak
fluorescein, which may pool within the intraretinal spaces of
associated cystoid edema or within the subretinal space.19,25,26
Children as young as 11 months, under general anesthesia,27
and 4 years, unsedated,28 have tolerated optical coherence
tomography (OCT) to document and quantify subretinal fluid
and macular edema to a resolution of 10 µm.29
Additional tests help differentiate Coats’ disease from ocular
tumors such as retinoblastoma, since a definitive diagnosis
cannot be established from clinical examination alone in 20% of
cases.19,30 In A- and B-scan echography, advanced Coats’ disease
often demonstrates a narrow or closed funnel retinal detachment,
poor retinal mobility, retinal thickening, low to medium reflective
subretinal opacities with a slow convection movement, and
absence of a solid mass lesion or calcium.31 Computed tomo-
graphy demonstrates subtle homogeneous subretinal densities
without contrast enhancement. This is differentiated from retino-
blastoma which demonstrates foci of calcium and diffuse con-
trast enhancement of the mass.32 Subretinal fluid demonstrates
homogeneous hyperintensity on T2- more than T1-weighted
magnetic resonance images without further enhancement on
contrast-enhanced sequences.30,33,34 In contrast, solid intraocular
tumors greater than 2.0 mm in thickness, such as retinoblastoma,
demonstrate variable intensity on T1-weighted images and are
hypointense on T2-weighted images.30,34 Calcification is
accentuated on T2-weighted images.30 Finally, subretinal fluid
aspiration can establish a cytopathologic diagnosis characterized
by lipid-laden macrophages and cholesterol crystals.35,36
DIFFERENTIAL DIAGNOSIS
Since Coats’ disease spans a large spectrum of clinical present-
ations and ages, the differential is vast. Coats’ disease often
presents in children as leukocoria and strabismus, as such, the
differential diagnosis includes retinoblastoma, toxocariasis, per-
sistent hyperplastic primary vitreous, advanced retinopathy of
prematurity, congenital cataract, incontinentia pigmenti, endo-
phthalmitis, Norrie disease, and inflammatory uveitis.14,18,19 In
both children and adults, other retinal telangiectatic and vascular
diseases may also mimic Coats’ disease, including branch retinal
vein occlusion,37 diabetic retinopathy,38 radiation retinopathy,39
familial exudative vitreoretinopathy,18 juxtafoveal telangiectasia,40
a b
FIGURE 139.5. (a) Typical ‘light bulb’ dilations and (b) capillary nonperfusion with focal leakage in late-phase angiogram.
Coats’ Disease and Retinal Telangiectasia
TABLE 139.1 Differential Diagnosis of Coats’ Disease
Retinoblastoma
Familial exudative vitreoretinopathy
Retinopathy of prematurity
Retinal toxocariasis
Persistent hyperplastic primary vitreous
Retinal angiomatosis
Incontinentia pigmenti
Pars planitis
Congenital cataract
Malignant melanoma
Choroidal metastasis
CHAPTER 139
Choroidal hemangioma
Eccentric disciform age-related macular degeneration
Exophytic retinal capillary hemangioma
Branch retinal vein occlusion
Idiopathic acquired juxtafoveal telangiectasia
Other causes of acquired juxtafoveal telangiectasia (see Table 139.2)
Eales’ disease,41 retinal capillary hemangioma,19 retinal cavernous
hemangioma,19 and various causes of vasculitis (Table 139.1).42
Retinoblastoma, which is potentially lethal if untreated, is the
most significant condition that must be differentiated from Coats’
disease. Coats’ disease generally presents as a unilateral disorder
in older boys with no family history, whereas retinoblastoma
is more often bilateral with no sex predilection and a positive
family history.19 The presence of sub- and intraretinal calcifica-
tion strongly suggests retinoblastoma; however, limited reports
have confirmed the presence of subretinal43 and intraretinal
calcium44 in enucleated eyes found to have Coats’ disease.
True Coats’ disease is defined as an idiopathic, progressive exu-
dative retinopathy with associated retinal telangiectasia. However,
numerous reports have described predominantly nonocular dis-
orders, in which Coats’-like changes can comprise an element of
the condition, including pericentric inversion on chromosome 3,45
chromosome 13 deletion,46 fasciocapsulohumeral muscular
dystrophy,47 Turner ’s syndrome,48 Senior–Loken syndrome
(familial renal–retinal dystrophy),49 epidermal nevus syn-
drome,50 VATER association (vertebral defects, imperforate
anus, tracheoesophageal fistula, and radial and renal dysplasia),51
congenital plasminogen deficiency type I,52 Hallermann–Streiff
1851
 RETINA AND VITREOUS

FIGURE 139.6. Cholesterol crystals of

subretinal fluid aspirate in a patient with Coats’
disease as visualized with H & E staining (a)
and polarized microscopy (b).

a b

syndrome,53 Coats’ plus syndrome,54 Cornelia de Lange syn-
drome,55 Alport’s syndrome,56 renal transplantation,57 aplastic
anemia,58 multiple glomus tumors,59 and telangiectasia of the
nasal mucosa.60
Similarly, other reports have described ocular conditions
SECTION 10
cryopexy. In more advanced cases, excessive exudate may
require drainage through a sclerotomy or retinotomy to allow
for adequate treatment of the telangiectasis. As it is important
to treat the entire area of abnormal vessels, fluorescein angio-
graphy may aid in visualizing the full extent of vascular

associated with separate Coats’-like changes, including: disease.71

idiopathic retinal gliosis,61 branch retinal vein occlusion,37 Shields and associates recommend management based on
retinitis pigmentosa,62,63 morning glory optic disk,64 uveitis,65 their staging scheme. Stage 1 disease, telangiectasia only, receives
ocular toxoplasmosis,66 and retinal dysplasia.67 either periodic observation or laser photocoagulation. Stage 2,
telangiectasia and exudation, is treated with cryopexy or laser
photocoagulation. Stage 3A, subtotal detachment, requires
PATHOLOGY cryopexy or laser photocoagulation; however, 3B, total detach-
Pathologic specimens usually come from globes enucleated ment, receives cryopexy for shallow detachments and either
because of advanced disease causing a blind and painful eye or scleral buckling or pars plana vitrectomy for more extensive
when retinoblastoma could not be excluded in the diagnosis.18 involvement. Stage 4, total retinal detachment and glaucoma,
These specimens allow extensive investigation into the primary usually requires enucleation to relieve severe pain. However,
and secondary abnormalities in Coats’ disease. stage 5, advanced end-stage disease, requires no treatment
The primary mechanism underlying Coats’ disease is because the eye is usually blind but comfortable.9
abnormal permeability of the vascular endothelial cells from Reports have described resolution of exudation using xenon
hyalinization and endothelial cell separation. This vascular arc,72 argon,73 yellow-dye,74 and large spot diode75 lasers; how-
incompetence results in subsequent leakage of blood com- ever, resolution often takes months and the final visual acuity
ponents into the retinal tissue and subretinal space.68 Light is often poor. Areas of thick exudation may prevent adequate
microscopy reveals variability among the retinal vessels absorption of laser energy; in such areas, the triple freeze-thaw
including: dilation, hyaline thickening, intraluminal and peri- method of transscleral retinal cryopexy may be more effective.76
vascular gliosis, intraluminal narrowing, and aneurysms devoid Multiple treatment sessions are often necessary to accomplish
of endothelium. In addition, spindle cells, eosinophils, poly- complete vascular closure, and careful follow-up is required to
morphonuclear leukocytes, and mononuclear cells are found document regression of the abnormal vessels and to detect new
both around and within vessels.69 Electron microscopy demon- areas of telangiectasia, which have been reported to occur as late
strates intramural thickening with a basement membrane-like as 5 years after the initial treatment (Fig. 139.7).77
material, patchy absence of endothelium and pericytes, and
plasmoid and fibrinous infiltration of aneurysmal and telangi-
ectatic vessel walls.69
With breakdown of the blood–retinal barrier, massive out-
pouring of lipid-rich exudate occurs into the retina and
subretinal space. Light microscopy reveals irregular thickening
of the inner retina from cystic cavities with periodic acid-Schiff
(PAS) positive eosinophilic fluid and infiltration of foam and
‘ghost’ cells. In addition, subretinal fibrin, cholesterol crystals,
and cholesterol- and pigment-laden macrophages are observed
(Fig. 139.6).18,69,70 Electron microscopy reveals inner retina
infiltration by foam and ‘ghost’ cells, along with macrophages,
hypertrophic Muller cells, and perivascular proliferation of glial
cells. The outer retina demonstrates patchy degeneration and
atrophy of the photoreceptors. The subretinal space is generally
electron-optically empty.69 The external globe, cornea, trabecular
meshwork, iris, ciliary body, Bruch’s membrane, and choroid
are usually normal.10,69

TREATMENT
The primary goal of treatment is obliteration of the abnormal
leaking retinal vessels to allow subsequent absorption of the
lipid exudates. In mild cases, ablation of these vessels may be FIGURE 139.7. Nearly complete resolution of exudation observed in
1852 accomplished with laser photocoagulation or transscleral Figure 139.3 after laser photocoagulation.

a b
In advanced cases associated with exudative retinal detach-
ment, surgical drainage of subretinal fluid and exudate may be
necessary to allow treatment of abnormal retinal vessels with
either photocoagulation or cryopexy.72,76,77 Although scleral
buckling with external drainage remains a viable treatment
option (Fig. 139.8),6,16 accumulations of cholesterol deposits
can hinder subretinal fluid outflow at the draining sclerotomy
site, insulate retinal telangiectasia from the cryoablation, and
prevent anatomical retinal reattachment.78 Pars plana vitrec-
tomy with78,79 or without80 scleral buckling achieves anatomic
success and allows controlled subretinal fluid and cholesterol
drainage through an internal retinotomy, direct ablation of
telangiectasia with diathermy or laser, and the ability to peel
associated preretinal membranes. Although visual function may
be severely limited, particularly in cases of total retinal detach-
ment, these surgical maneuvers may stabilize the eye and
prevent the subsequent development of phthisis, painful neo-
vascular glaucoma, and the need for enucleation.16
With the recent advent of anti-vascular endothelial growth
factor (anti-VEGF) therapy, Smithen and associates12 speculate
that anti-VEGF medications may limit vascular leakage found
in Coats’ disease since VEGF injections into nonhuman
primates caused vascular changes similar to those found in
Coats’ disease.81,82 However, no published reports have evalu-
ated intravitreal VEGF levels or the use of anti-VEGF therapy in
Coats’ patients.
IDIOPATHIC MACULAR TELANGIECTASIA
Retinal telangiectasia localized to the foveal region alone in one
or both eyes is termed macular (juxtafoveal) telangiectasia.
Such changes may be congenital, and thus a mild variant of
Coats’ disease, or may be acquired and seen as an isolated
finding in middle-aged or older patients.40 These idiopathic
forms of telangiectasia must be distinguished from secondary
telangiectasia caused by other retinal vascular diseases
(Table 139.2).
Gass and Blodi classified these patients into three groups
with multiple subgroups based on historical, biomicroscopic,
and fluorescein angiographic findings.83 Recently, Yannuzzi and
associates simplified the classification scheme into two types of
idiopathic macular telangiectasia by eliminating rare forms of
the disease.84
TYPE 1 (ANEURYSMAL TELANGIECTASIS)
Also known as group 1, visible and exudative idiopathic juxtafoveal
retinal telangiectasia under the Gass and Blodi classification,
middle-aged male patients typically present with a unilateral
mild blurring of central vision.83 This form of macular telang-
iectasia is considered a form of Coats’ disease that is limited to
the macula.83,84 Biomicroscopy reveals arteriolar, capillary, and
venular aneurysms and telangiectasia which are found in both
Coats’ Disease and Retinal Telangiectasia
FIGURE 139.8. (a) B-scan ultrasound depicts
total exudative retinal detachment in a patient
with Coats’ disease. (b) This patient’s retina
was successfully reattached via pars plana
vitrectomy with internal drainage of subretinal
fluid and endolaser photocoagulation.
TABLE 139.2 Differential Diagnosis of Idiopathic Telangiectasia
Diabetic retinopathy
CHAPTER 139
Branch retinal vein occlusion/central retinal vein occlusion
Radiation retinopathy
Tapetoretinal dystrophy
Inflammatory retinopathy/Irvine–Gass syndrome
Coats’ disease
Eales’ disease
Adult-onset pseudovitelliform foveal macular dystrophy
Best’s disease
Age-related macular degeneration
Choroiditis
Sickle-cell retinopathy
Polycythemia vera retinopathy
Canthaxanthine crystalline retinopathy
Other crystalline retinopathies
Localized retinal capillary hemangioma
Hypertensive retinopathy
Ocular ischemic syndrome/carotid artery obstruction
the superficial and deep retinal capillary circulations.84 Vascular
abnormalities are noted within 2 disk diameters of the center of
the fovea, primarily along the temporal parafoveal region, and
often associated with localized capillary leakage and lipid
exudate (Fig. 139.9a,b). Visual loss in this group of patients tends
to occur with the accumulation of foveolar exudate and associated
cystoid macular edema.83,84 Despite maintenance of excellent
visual acuity for years without treatment and spontaneous reso-
lution in occasional patients, Gass and Blodi recommended early
photocoagulation when visual loss is associated with central
accumulation of yellow exudate.83
TYPE II (PERIFOVEAL TELANGIECTASIA)
Also known as group II, occult and nonexudative idiopathic
juxtafoveal retinal telangiectasia under the Gass and Blodi
classification, this is the most common form of macular telangi-
ectasia and occurs equally in both sexes. Patients typically
present in the fifth and sixth decades of life with mild blurring
of vision in one or both eyes that can progress, primarily from
foveolar atrophy or subretinal neovascularization.83 Biomicro-
scopy reveals symmetric blunting of the foveal reflex with a
mild grayish appearance of the parafoveal retina, minimal serous
exudation, and no lipid deposition.83,84 In addition, glistening 1853
 RETINA AND VITREOUS

FIGURE 139.9. (a) Unilateral type 1

aneurysmal telangiectasis. Note the aneurysms
and telangiectatic capillaries in the parafoveolar
region associated with lipid exudates.
(b) Fluorescein angiogram demonstrating
capillary telangiectasia, microaneurysms, and
leakage.

a b
SECTION 10

a c e

b d f

FIGURE 139.10. (a and b) Right and left color fundus photographs of type II idiopathic macular telangiectasia demonstrating a mild parafoveal
grayish appearance. (c and d) Classic fluoroscein staining temporal to fovea on late-phase angiogram of right and left eyes. (e and f) Horizontal
5mm optical coherence tomography scans through fovea of right and left eyes demonstrating a nearly normal appearance without fluid in areas
of staining on angiogram. There are tiny hyporeflective spaces in the foveola of each eye.

white or yellowish-white crystalline deposits may be noted in

the superficial parafoveal retina in ~40% of patients.85 In some
patients, a small, yellow lesion, 1/3 disk diameter in size,
develops within the foveal avascular zone and appears to repre-
sent an inner retinal cavitation on OCT evaluation.83,84
Initially, telangiectasis is not visible on biomicroscopy, and
fluorescein angiography shows only mild staining within
one disk diameter of the foveola, especially temporally
(Fig. 139.10a–f). With progression, these eyes may develop
dilated right-angled retinal venules and arterioles and stellate
plaques of retinal pigment epithelial hyperplasia, as well as
intra- and subretinal anastomosis and subretinal neovascular-
ization.26,40,84 Optical coherence tomography can demonstrate
hyporeflective intraretinal cavitation without foveolar thickening
(Fig. 139.11) and middle or inner layer hyperreflectivity
corresponding to areas of retinal pigment epithelial migration.86 FIGURE 139.11. Hyporeflective inner layer cavitation without retinal
When subretinal neovascularization occurs, central visual thickening on optical coherence tomography scan.
1854
 Coats’ Disease and Retinal Telangiectasia

a b c

FIGURE 139.12. (a) Color photograph of subretinal neovascularization secondary to type II idiopathic macular telangiectasia. (b) Early phase
fluorescein angiogram demonstrating subretinal neovascularization with probable retinal feeding and draining vessels. (c) Horizontal 5 mm optical
coherence tomography image demonstrating a hyperreflective subretinal focus corresponding to the area of neovascularization on clinical exam.

acuity loss may be rapid, and 81% of untreated eyes have a final
acuity of 20/200 or worse (Fig. 139.12a–c).87
Grid laser is not indicated for treatment of type II perifoveal
telangiectasia because it does not improve or stabilize long-term
visual acuity.88 In addition, laser has led to the development of
subretinal hemorrhage89 and choroidal neovascularization.88 A
variety of therapeutic modalities have been employed to treat
subretinal neovascularization complicating this disorder. Photo-
dynamic therapy90,91 and transpupillary thermotheraphy92,93
CHAPTER 139
have demonstrated efficacy; however, the subretinal neovascu-
larization in idiopathic juxtafoveal retinal telangiectasis arises
from the retina, as opposed to the choroid, and activation of
photosensitizing dye in the retinal layers may cause iatrogenic
damage.90,93 Laser photocoagulation may help stabilize central
visual acuity but induces an iatrogenic scotoma,94 and sub-
macular surgery has demonstrated poor outcomes.95 Anti-VEGF
drugs hold promise for treating neovascularization associated
with this disease.

REFERENCES
1. Leber T: Verber ein durch Yorkommen
miltipler Miliaraneurisi men Characterisierte
Form von Retinal-degeneration. Graefes
Arch Clin Exp Ophthalmol 1912; 81:1–14.
2. Coats G: Forms of retinal disease with
massive exudation. R Lond Ophthalmic
Hosp Rep 1908; 17:440–525.
3. Coats G: Ueber Retinitis exudativa (retinitis
hemorrhagiga externa). Graefes Arch Clin
Exp Ophthalmol 1912; 81:275–327.
4. Reese A: Telangiectasis of the retina and
Coats’ disease. Am J Ophthalmol 1956;
42:1–8.
5. Leber T: Retinitis exudativa (Coats),
Retinitis und Chorioretinitis Serofibrinosa
Degeraus. Graefe Saemisch Augenheikld
1915; 7:1267–1319.
6. Gomez-Morales A: Coats’ disease. Am J
Ophthalmol 1965; 60:855–864.
7. Woods A, Duke J: Coats’ disease. I.
Review of the literature, diagnostic criteria,
clinical findings, and plasma lipid studies.
Br J Ophthalmol 1963; 47:385–412.
8. Cahill M, O’Keefe M, Acheson R, et al:
Classification of the spectrum of Coats’
disease as subtypes of idiopathic retinal
telangiectasis with exudation. Acta
Ophthalmol Scand 2001; 79:596–602.
9. Shields J, Shields C, Honavar S, et al:
Classification and management of Coats
disease: the 2000 Proctor Lecture. Am J
Ophthalmol 2001; 131:572–583.
10. Shields J, Shields C, Honavar S, Demirci H:
Clinical variations and complications of
Coats disease in 150 cases. The 2000
Sanford Gifford Memorial Lecture. Am J
Ophthalmol 2001; 31:561–571.
11. Maruoka K, Yamamoto M, Fujita H, et al: A
case of Coats’ disease in a low-birth-
weight infant. Ophthalmologica 2005;
219:401–403.
12. Smithen L, Brown G, Brucker A, et al:
Coats’ disease diagnosed in adulthood.
Ophthalmology 2005; 112:1072–1078.
13. Black G, Perveen R, Bonshek R, et al:
Coats’ disease of the retina (unilateral
retinal telangiectasis) caused by somatic
mutation in the NDP gene: a role for norrin
in retinal angiogenesis. Hum Mol Gen 1999;
8:2031–2035.
14. Mintz-Hittner H, Ferrell R, Sims K, et al:
Peripheral retinopathy in offspring of
carriers of Norrie disease gene mutations.
Ophthalmology 1996; 103:2128–2134.
15. Luhmann U, Lin J, Acar N, et al: Role of
Norrie Disease Pseudoglioma gene in
sprouting angiogenesis during
development of the retinal vasculature.
Invest Ophthalmol Vis Sci 2005;
46:3372–3382.
16. Silodor S, Augsburger J, Shields J: Natural
history and management of advanced
Coats’ disease. Ophthalmic Surg 1988;
19:89–93.
17. Green W, McDonnell P, Yeo J: Pathologic
features of senile macular degeneration.
Surv Ophthalmol 1985; 92:615–627.
18. Chang M, McLean I, Merritt J: Coats’
disease: a study of 62 histologically
confirmed cases. J Pediatr Ophthalmol
Strabismus 1984; 21:163–168.
19. Shields J, Shields C: Review: Coats
disease. Retina 2002; 22:80–91.
20. Shields J, Eagle R, Fammartino J, et al:
Coats disease as a cause of anterior
chamber cholesterolosis. Arch Ophthalmol
1995; 113:975–977.
21. Eibschitz-Tsimhoni M, Johnson M, Johnson
T, Moroi S: Coats’ syndrome as a cause of
secondary open-angle glaucoma.
Ophthalmic Surg Lasers Imaging 2003;
34:312–314.
22. Machemer R, Williams J: Pathogenesis and
therapy of traction detachment in various
retinal vascular diseases. Am J Ophthalmol
1988; 105:170–181.
23. Ioannidis A, Liasis A, Sheldrick J, et al:
Lamellar macular hole as a presenting
feature in a child with Coats’ disease.
J Pediatr Ophthalmol Strabismus 2005;
42:378–379.
24. Shienbaum G, Tasman W: Coats disease.
A lifetime disease. Retina 2006; 26:422–424.
25. Theodossiadis G: Some clinical,
fluorescein-angiographic, and therapeutic
aspects of Coats’ disease. J Pediatr
Ophthalmol Strabismus 1979; 16:257–262.
26. Gass J: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 3rd edn.
St. Louis, MO: CV Mosby; 1987.
27. Chen S, Patel C: Optical coherence
tomography in uncooperative children
under general anesthesia [letter]. J Pediatr
Ophthalmol Strabismus 2005; 42:71.
28. Shields C, Mashayekhi A, Luo C, et al:
Optical coherence tomography in children:
analysis of 44 eyes with intraocular tumors
and simulating conditions. J Pediatr
Ophthalmol Strabismus 2004; 41:338–344.
29. Puliafito C, Hee M, Lin C, et al: Imaging of
macular diseases with optical coherence
tomography. Ophthalmology 1995;
102:217–229.
30. Haik B, Saint Louis L, Smith M, et al:
Magnetic resonance imaging in the
evaluation of leukocoria. Ophthalmology
1985; 92:1143–1152.
31. Atta H, Watson N: Echographic diagnosis
of advanced Coats’ disease. Eye 1992;
6:80–85.
32. Haik B, Saint Louis L, Smith M, et al:
Computed tomography of the
nonrhegmatogenous retinal detachment in
1855
 RETINA AND VITREOUS
the pediatric patient. Ophthalmology 1985;
92:1133–1142.
33. Kirath H, Eldem B: Management of
moderate to advanced Coats’ disease.
Ophthalmologica 1998; 212:19–22.
34. Potter P, Shields C, Shields J, Flanders A:
The role of magnetic resonance imaging in
children with intraocular tumors and
simulating lesions. Ophthalmology 1996;
103:1774–1783.
35. Haik B, Koizumi J, Smith M, Ellsworth R:
Fresh preparation of subretinal fluid
aspirations in Coats’ disease. Am J
Ophthalmol 1985; 100:327–328.
36. Shields J, Shields C, Ehya H, et al: Fine
needle aspiration biopsy of suspected
intraocular tumors. The 1992 Urwick
lecture. Ophthalmology 1993;
100:1677–1684.
37. Luckie A, Hamilton A: Adult Coats’ disease
in branch retinal vein occlusion. Aust N Z J
SECTION 10
Ophthalmol 1994; 22:203–206.
38. Ashton N: Studies of the retinal capillaries
in relation to diabetic and other
retinopathies. Am J Ophthalmol 1980;
90:203.
39. Hayreh S: Post-radiation retinopathy:
a fluorescence fundus angiographic study.
Br J Ophthalmol 1970; 54:705.
40. Gass J, Oyakawa R: Idiopathic
juxtafoveolar retinal telangiectasis. Arch
Ophthalmol 1982; 100:769.
41. Recine W, Murphy R, Anderson K, et al:
The evaluation of patients with Eales’
disease. Retina 1983; 3:243.
42. Ffytche T: Retinal vasculitis: a review of the
clinical signs. Trans Ophthalmol Soc UK
1977; 97:457.
43. Senft S, Hidayat A, Cavender J: Atypical
presentation of Coats disease. Retina
1994; 14:36–38.
44. Miller D, Benz M, Murray T, Dubovy S:
Intraretinal calcification and osseous
metaplasia in Coats disease. Arch
Ophthalmol 2004; 122:1710–1712.
45. Skuta G, France T, Stevens T, et al:
Apparent Coats’ disease and pericentric
inversion of chromosome 3. Am J
Ophthalmol 1987; 104:84–86.
46. Genkova P, Toncheva D, Tzoneva M:
Deletion of 13q 12.1 in a child with Coats’
disease. Acta Paediatr Hung 1986;
27:141–143.
47. Gurwin E, Fitzsimons R, Sehmi K, Bird A:
Retinal telangiectasis in
fascioscapulohumeral muscular dystrophy
with deafness. Arch Ophthalmol 1985;
103:1695–1700.
48. Cameron J, Yanoff M, Frayer W: Coats
disease and Turner’s syndrome. Am J
Ophthalmol 1974; 78:852–854.
49. Schuman J, Lieberman K, Friedman A,
et al: Senior-Loken syndrome (familial
renal-retinal dystrophy) and Coats’ disease.
Am J Ophthalmol 1985; 100:822–827.
50. Burch J, Leveille A, Morse P: Ichthyosis
hystrix epidermal nevus syndrome and
Coats’ disease. Am J Ophthalmol 1980;
89:25–30.
51. Hon C, Ko T-C: Coats disease and VATER
association in a 5-year-old boy. Arch
Ophthalmol 2004; 122:1232–1233.
52. Patrassi G, Sartori M, Piermarocchi S, et al:
Unusual thrombotic-like retinopathy (Coats’
disease) associated with congenital
plasminogen deficiency type I. J Int Med
1993; 234:619–623.
1856
53. Newell S, Hall B, Anderson C, Lim E:
Hallermann Streiff syndrome with Coats
disease. J Pediatr Ophthalmol Strabismus
1994; 31:123–125.
54. Crow Y, McMenamin J, Haenggeli C, et al:
Coats’ Plus: a progressive familial syndrome
of bilateral Coats’ disease, characteristic
cerebral calcification, leukoencephalopathy,
slow pre- and post-natal linear growth and
defects of bone marrow and integument.
Neuropediatrics 2004; 35:10–19.
55. Folk J, Genovese F, Biglan A: Coats
disease in a patient with Cornelia de Lange
syndrome. Am J Ophthalmol 1981;
91:607–610.
56. Kondra L, Cangemi F, Pitta C: Alport’s
syndrome and retinal telangiectasia. Ann
Ophthalmol 1983; 15:550–551.
57. Berger M, Lieberman K, Schoeneman M,
et al: Coats disease in a renal transplant
recipient. Nephrol Dial Transplant 1987;
2:120–123.
58. Kajtar P, Mehes K: Bilateral Coats
retinopathy associated with aplastic anemia
and mild dyskeratotic signs. Am J Med
Genet 1994; 49:374–377.
59. Bhushan M, Kumar S, Griffiths C: Multiple
glomus tumours, Coats disease and basic
fibroblast growth factor. Br J Dermatol
1997; 137:454–456.
60. Gartner J, Draf W: Leber’s miliary
aneurysms associated with telangiectasia
of the nasal mucosa. Am J Ophthalmol
1975; 79:56–58.
61. Green W: Bilateral Coats disease. Massive
gliosis of the retina. Arch Ophthalmol 1967;
77:378–383.
62. Pruett R: Retinitis pigmentosa: clinical
observations and correlations. Trans Am
Ophthalmol Soc 1983; 81:693–735.
63. Khan J, Ide C, Strickland M: Coats’-type
retinitis pigmentosa. Surv Ophthalmol
1988; 32:317–332.
64. Kremer I, Cohen S, Izhak R, Ben-Sira I:
An unusual case of congenital unilateral
Coats disease associated with morning
glory optic disc anomaly. Br J Ophthalmol
1985; 69:32–37.
65. Lim W-K, Nussenblatt R, Chan C-C:
Immunopathologic features of inflammatory
Coats disease. Arch Ophthalmol 2005;
123:279–281.
66. Frezzotti R, Berengo A, Guerra R,
Cavallini F: Toxoplasmic Coats retinitis.
Am J Ophthalmol 1965; 59:1099–1102.
67. Egerer I, Rodrigues M, Tasman W: Retinal
dysplasia in Coats disease. Can J
Ophthalmol 1975; 10:79–85.
68. McGettrick P, Loeffler K: Bilateral Coats’
disease in an infant (a clinical,
angiographic, light and electron
microscopic study). Eye 1987; 1:136–145.
69. Tripathi R, Ashton N: Electron
microscopical study of Coats’s disease.
Br J Ophthalmol 1971; 55:289–301.
70. Kremer I, Nissenhorn I, Ben-Sira I:
Cytologic and biochemical examination of
the subretinal fluid in the diagnosis of
Coats’ disease. Acta Ophthalmol (Copenh)
1989; 67:342–346.
71. Sneed S, Blodi C, Pulido J: Treatment of
Coats’ disease with the binocular indirect
argon laser photocoagulator [letter]. Arch
Ophthalmol 1989; 107:789–790.
72. Egerer I, Tasman W, Tomer T: Coats’
disease. Arch Ophthalmol 1974;
97:109–112.
73. Haik B: Advanced Coats’ disease. Trans
Am Ophthalmol Soc 1991; 89:371–476.
74. Nucci P, Bandello F, Serafino M, Wilson M:
Selective photocoagulation in Coats’
disease: ten-year follow-up. Eur J
Ophthalmol 2002; 12:501–505.
75. Couvillion S, Margolis R, Mavrofrides E,
et al: Laser treatment of Coats’ disease.
J Pediatr Ophthalmol Strabismus 2005;
42:367–368.
76. Sigelman J: Retinal diseases:
pathogenesis, laser therapy, and surgery.
Boston, MA: Little Brown & Co; 1984.
77. Chisolm I, Foulds W, Christison D:
Investigation and therapy of Coats’ disease.
Trans Ophthalmol Soc UK 1974; 94:335.
78. Yoshizumi M, Kreiger A, Lewis H, et al:
Vitrectomy techniques in late-stage
Coats’-like exudative retinal detachment.
Doc Ophthalmol 1995; 90:387–394.
79. Schmidt-Erfurth U, Lucke K: Vitreoretinal
surgery in advanced Coat’s disease. Ger J
Ophthalmol 1995; 4:32–36.
80. Kranias G, Krebs T: Advanced Coats’
disease successfully managed with vitreo-
retinal surgery. Eye 2002; 16:500–501.
81. Tolentino M, Miller J, Gragoudas E, et al:
Intravitreous injections of vascular
endothelial growth factor produce retinal
ischemia and microangiopathy in an adult
primate. Ophthalmology 1996;
103:1820–1828.
82. Tolentino M, McLeod D, Taomoto M, et al:
Pathologic features of vascular endothelial
growth factor-induced retinopathy in the
nonhuman primate. Am J Ophthalmol 2002;
133:373–385.
83. Gass J, Blodi B: Idiopathic juxtafoveolar
retinal telangiectasis. Update of
classification and follow-up study.
Ophthalmology 1993; 100:1536–1546.
84. Yannuzzi L, Bardal A, Freund K, et al:
Idiopathic macular telangiectasia. Arch
Ophthalmol 2006; 124:450–460.
85. Moisseiev J, Lewis H, Bartov E, et al:
Superficial retinal refractile deposits in
juxtafoveal telangiectasis. Am J Ophthalmol
1990; 109:604–605.
86. Gupta V, Gupta A, Dogra M, Agarwal A:
Optical coherence tomography in group 2A
idiopathic juxtafoveolar telangiectasis.
Ophthalmic Surg Lasers Imaging 2005;
36:482–486.
87. Engelbrecht N, Aaberg TJ, Sung J, Lewis
M: Neovascular membranes associated
with idiopathic juxtafoveolar telangiectasis.
Arch Ophthalmol 2002; 120:320–324.
88. Park D, Schatz H, McDonald H, Johnson R:
Grid laser photocoagulation for macular
edema in bilateral juxtafoveal
telangiectasis. Ophthalmology 1997;
104:1838–1846.
89. Friedman S, Mames R, Stewart M:
Subfoveal hemorrhage after grid laser
photocoagulation for idiopathic
juxtafoveolar retinal telangiectasis.
Ophthalmic Surg 1993; 24:551–553.
90. Potter M, Szabo S, Chan E, Morris A:
Photodynamic therapy for subretinal
neovascular membranes in Type 2A
idiopathic juxtafoveolar retinal
telangiectasis. Am J Ophthalmol 2002;
133:149–151.
91. Hershberger V, Hutchins R, Laber P:
Photodynamic therapy with verteporfin for
subretinal neovascularization secondary to
bilateral idiopathic acquired juxtafoveolar

retinal telangiectasis. Ophthalmic Surg
Lasers Imaging 2003; 34:318–20.
92. Shukla D, Singh J, Kolluru C, et al:
Transpupillary thermotherapy for subfoveal
neovascularization secondary to group 2A
idiopathic juxtafoveolar telangiectasis.
Am J Ophthalmol 2004; 138:147–149.
Coats’ Disease and Retinal Telangiectasia
93. Nachiappan K, Shanmugam M: Treatment
of CNVM secondary to idiopathic
juxtafoveal retinal telangiectasis by
transpupillary thermotherapy [letter].
Am J Ophthalmol 2005; 139:577–578.
94. Brucker A, Robinson F: Primary retinal
vascular abnormalities. In: Yannuzzi L, ed.
Laser photocoagulation of the macula.
Philadelphia, PA: Lippincott; 1989.
95. Berger A, McCuen B, Brown G, Brownlow
R: Surgical removal of subfoveal
neovascularization in idiopathic juxtafoveal
retinal telangiectasis. Retina 1997;
17:94–98.
CHAPTER 139
1857
 CHAPTER

140 Neuroretinitis
Valerie Purvin

Key Features
• Acute, painless, unilateral visual loss of variable severity
• Usually affects healthy young individuals
• Acutely: disk edema often with peripapillary serous
detachment
• Ten days later: macular hard exudates in star pattern
• Due to cat scratch disease in two-thirds of cases
• One-quarter of cases are idiopathic despite thorough
evaluation
• Generally good prognosis regardless of treatment
• Consider antibiotics for suspected bacterial infection
• Steroids may be considered as well

HISTORIC PERSPECTIVE
In 1916 Theodor Leber described a condition characterized by
acute unilateral visual loss with disk edema and macular exudates
arranged in a star pattern.1 Believing the condition to be a pri-
mary retinal disorder, he used the term ‘stellate maculopathy’.
This concept was challenged by Gass in 1977, who noted that disk FIGURE 140.1. Ophthalmoscopic appearance of idiopathic NR in a
36-year-old woman. Fundus photograph of the patient’s left eye taken
edema precedes the formation of exudates in this condition.2
1 month after onset of visual loss shows mild residual disk edema
He further demonstrated by fluorescein angiography that the with pallor and a robust macular star. Serologic testing for specfic
site of the leakage is in fact not the macula but the optic disk inflammatory diseases was unrevealing.
and suggested the term neuroretinitis (NR). In some patients a
specific infectious agent has been implicated; cases in which no
infectious etiology is identified are designated as Leber’s idio-
pathic stellate NR. The series by Dreyer et al3 and by Maitland TABLE 140.1 Etiologies
and Miller4 in 1984 furnished a description of the typical
Bartonella species (mostly B. henselae)
clinical features of this disorder. Since that time a number of
papers have reported additional cases of NR due to a wide range Spirochete: syphilis (2º or 3º), Lyme disease (stage II), leptospirosis
of infections (this is discussed in the following). Viral or postviral: mumps, chicken pox, herpes simples, herpes
zoster, HIV, hepatitis B, Coxsackie B, influenza A, Epstein–Barr,
PATHOPHYSIOLOGY cytomegalovirus
Tuberculosis
Inflammation of disk capillaries causes leakage of protein and
lipid that spreads into the peripapillary subretinal space and Toxoplasmosis
outer plexiform layer. Resorption of the serous component Nematode: Toxocara canis, DUSN
leaves lipid exudates that are subsequently ingested by
Histoplasmosis capsulatum
macrophages. Due to the loose, radial configuration of the outer
plexiform layer, a star pattern is formed5 (Fig. 140.1). This loca- Rocky Mountain spotted fever
tion of fluid accumulation has more recently been confirmed Salmonella
with ocular coherence tomography (OCT).6 It is not entirely
clear whether the disk inflammation in this disorder represents Postvaccination: Rabies
direct infection or a secondary autoimmune response. Noninfectious uveitis: sarcoidosis, inflammatory bowel disease,
periarteritis nodosa
ETIOLOGIES Uncertain mechanism: Parry–Romberg syndrome (progressive
facial hemiatrophy), IRVAN syndrome, tubulointerstitial nephritis
Cases of NR have been reported in association with a variety of and uveitis (TINU syndrome)
infectious agents (see Table 140.1).7–23 The single most 1859
 RETINA AND VITREOUS

TABLE 140.2 Differential Diagnosis for Disk Edema with

Macular Star

Hypertensive retinopathy
Papilledema (Øintracranial pressure)
Anterior ischemic optic neuropathy
Diabetic papillopathy
Branch retinal vein occlusion/papillophlebitis
Optic disk tumor: melanocytoma, juxtapapillary angioma

common of these is cat scratch disease (CSD) which accounted

for two-thirds of cases in one large series.24 Despite thorough
evaluation, approximately one quarter of cases remain idio-
pathic.24 Occasional cases are due to noninfectious forms of
uveitis such as sarcoidosis, inflammatory bowel disease, and
SECTION 10

periarteritis nodosa. NR has also been described as a part of

other retinal inflammatory disorders including idiopathic
retinal vasculitis and aneurysms (IRVAN syndrome) and diffuse FIGURE 140.2. Ophthalmoscopic appearance of NR due to CSD. The
unilateral subacute neuroretinitis (DUSN) which is caused by a patient was a 22-year-old man who developed decreased vision in the
nematode.25 Other noninflammatory conditions may also cause left eye 2 weeks after onset of fever, headache, and muscle aches.
disk edema with a macular star figure26 and it is important for Acutely the disk is swollen with nerve fiber layer hemorrhage and
the clinician to be alert to these (see Table 140.2). Notably, peripapillary serous detachment.
increased intracranial pressure (papilledema), hypertensive reti-
nopathy, ischemic optic neuropathy and diabetic papillopathy
may all cause a similar funduscopic appearance. The term NR
should be reserved for those cases in which the underlying
mechanism is inflammatory.

CLINICAL CHARACTERISTICS
NR usually affects children and young adults (average age
22–30 years) but the age range is broad.3,4 Males and females
are affected equally. Approximately 50% of affected individuals
experience an antecedent flu-like illness, usually affecting the
upper respiratory tract.3,4 In patients with cat scratch NR these
prodromal symptoms usually include sore throat, headache,
myalgias, and lymphadenopathy. Visual loss typically takes the
form of painless unilateral blurring of central vision which
progresses over several days. Visual loss is usually painless
although occasional patients experience a mild retrobulbar
ache. While mild disk edema is occasionally seen in the fellow
eye, symptomatic bilateral NR is quite unusual and should
always suggest the alternative possibility of hypertensive
FIGURE 140.3. Same patient as in Figure 140.1 but 4 weeks later.
retinopathy or raised intracranial pressure. There has been much resolution of disk edema with the new
appearance of hard exudates tracking to the macula in a star pattern.
VISUAL FUNCTION Serologic testing confirmed recent B. henselae infection.

Visual acuity is usually between 20/50 and 20/200 with a range
from 20/20 to light perception. The most common pattern of
visual field loss, found in 24 of 29 eyes in the series of Dreyer
et al, is a cecocentral or central scotoma, consistent with the
presence of edema in the papillomacular bundle.3 Other patterns
including arcuate defects and altitudinal loss are occasionally
seen. A relative afferent pupillary defect (RAPD) is often present
although not with the same constancy or magnitude as in
demyelinating optic neuritis. This difference reflects a different
mechanism of visual loss in these two conditions: visual loss
is due in large part to maculopathy in NR versus optic nerve
dysfunction in optic neuritis (ON).
FUNDUSCOPIC FINDINGS
Posterior vitreous cells are usually present; anterior chamber
1860 cell and flare are occasionally seen as well. The funduscopic
appearance depends in large part on when the patient is
examined. Isolated optic disk edema is the earliest finding
(Fig. 140.2). Disk swelling is usually diffuse but can be segmental,
a finding that may be better appreciated with fluorescein
angiography. The degree of disk edema is variable; when severe
it may be accompanied by peripapillary nerve fiber layer
hemorrhages. In most cases, disk edema is associated with
an exudative peripapillary serous retinal detachment. It takes
9–12 days for the characteristic macular hard exudates to
appear and at this stage the disk edema is usually diminishing
(Fig. 140.3). The star is initially sharply defined and spoke-like;
over time the exudates develop a more globby appearance and
eventually, after a number of months, disappear completely,
often leaving residual subfoveal RPE defects in the macula. Disk
edema resolves over 8–12 weeks in most cases.3 The disk may
eventually return to normal or may show pallor and/or gliotic
changes.

In addition to these characteristic changes involving the disk
and macula, small, discrete yellow-white chorioretinal spots are
sometimes identified.27 These spots are at the level of the deep
retina or choriocapillaris and may be seen in both symptomatic
and asymptomatic eyes. These CR lesions are especially
characteristic of patients with NR due to CSD but have also
been found in patients with other causes of NR and in those
with the idiopathic variety. Their occurrence serves as evidence
of a hematogenously spread infectious agent rather than an
autoimmune process. These spots resolve slowly, becoming
small chorioretinal scars.
ANCILLARY TESTING
Fluorescein angiography in patients with acute NR demonstrates
abnormal capillary permeability, particularly from the capillaries
deep within the optic disk. Such leakage may persist even after the
disk has returned to its normal appearance. While there may be
slight staining of peripapillary vessels, the macular vasculature is
entirely normal. Disk staining is often segmental and is found in
the contralateral (asymptomatic) eye in 10–15% of cases. Chorio-
retinal white spots, when present, show late hyperfluorescence.
OCT has shown accumulation of fluid in the outer plexiform
layer with or without serous detachment of the sensory retina.6
PROGNOSIS
Most patients with NR enjoy excellent recovery of vision
without intervention. In the series of Dreyer et al, for example,
visual acuity at last follow-up examination (median 14 months)
was 20/20 or better in 66% of cases, 20/25 to 20/40 in 31% and
remained at 20/300 in one eye.3 A repeat event either in the
previously affected or the fellow eye is unusual.
There appears to be a subset of patients, however, with a
somewhat different clinical picture in whom the prognosis is
more guarded. Two of the patients in the series of Dreyer et al
had disk-related field defects and a large relative afferent defect
and in both of these cases the visual outcome was poor.3 Of the
12 patients with NR described by Maitland and Miller, only
three failed to experience excellent recovery and in two of these
cases there was evidence of a previous similar event in the fellow
eye.4 Purvin and Chioran reported a series of seven such patients
who experienced 2–7 attacks of NR at intervals of 1–10 years
(average interval 2.7 years).28 Following repeated episodes,
visual loss is cumulative and can be quite substantial. This
variant of NR may be suspected following an initial episode by
virtue of a large relative afferent pupillary defect, disk-related
field loss and poor visual recovery. Such patients should be
considered to be at relatively high risk for a future similar event
and should be counseled accordingly. In some cases, prophy-
lactic treatment to prevent a repeat attack may be considered
(this is discussed in the following).
RELATIONSHIP TO MULTIPLE SCLEROSIS
One particular aspect of prognosis bears specific comment,
namely the possible relationship of NR to multiple sclerosis
(MS). It has been well established that patients who experience
an attack of ON are at increased risk for the future development
of MS. Insofar as NR can be considered a form of papillitis, one
might assume that patients with this condition would be at
similarly high risk. A large survey of affected patients, however,
found no such increased risk.29 This difference in prognosis is
presumably related to differences in pathophysiology in these two
conditions. In demyelinating ON the target tissue of the inflam-
matory response is the myelin sheath, whereas in NR the target
is the optic disk vasculature. However, a retrospective review of
Neuroretinitis
35 patients with NR seen in a single university-based practice
identified three patients who had already been diagnosed with
MS.30 All three of these patients were on b-interferon and the
authors suggested that perhaps this treatment influenced the
permeability of disk vessels thus affecting the funduscopic
appearance. Despite this one report, the management of patients
with NR should be clearly distinguished from those with ON.
DIFFERENTIAL DIAGNOSIS
The approach to diagnosis depends in part on when the patient
is seen in the course of the illness. When seen acutely, i.e.,
before formation of a macular star, the main alternative diag-
nosis is ON. Both NR and ON typically present as acute
monocular visual loss in a previously healthy young person and
optic disk edema is seen in both conditions. Several features are
helpful in making this distinction. The presence of eye pain in
most patients with ON is extremely helpful since this is a very
CHAPTER 140
uncommon symptom in NR. The absence of a RAPD in the
presence of monocular visual loss speaks strongly against ON
as the cause. Similarly, a disproportion between the visual loss
and the RAPD (large drop in visual acuity with only a small
RAPD) speaks in favor of NR. The presence of peripapillary
serous detachment is characteristic of NR but unexpected in
ON. Disk hemorrhages are sometimes present in NR but
extremely unusual in ON. Finally, the results of orbital MRI
scanning in ON are abnormal in 90% of cases, whereas in NR
such scans are typically normal.
When seen after appearance of the macular star the differ-
ential diagnosis is different. The first step is to decide if the
patient actually has NR or has, instead, another cause of macular
hard exudates. The presence of more extensive retinopathy
should suggest an alternative diagnosis such as CRVO or BRVO
(retinal hemorrhages predominate) or severe hypertension
(hemorrhages and exudates usually present). When these
changes are bilateral, particular attention should be directed to
the possibility of hypertensive retinopathy. In increased intra-
cranial pressure (papilledema) the findings are also typically
bilateral but the changes are usually confined to the disk and
macula. In the case of papilledema and in anterior ischemic
optic neuropathy the macular star is usually partial, seen just
on the nasal side of the macula in contrast with its appearance
360° around the macula in most cases of NR. Finally, prolonged
duration of disk edema and macular exudates should suggest a
noninflammatory disorder, specifically CRVO, papillophlebitis,
or an optic disk tumor.
EVALUATION
HISTORY AND PHYSICAL
A thorough history is important and should include the following
features: travel (particularly to areas in which Lyme disease is
prevalent), animal exposure, sexual contact, ingestion of unpas-
teurized or uncooked foods. The patient should be questioned
about systemic symptoms including fever, lymphadenopathy,
myalgias, skin rash or other skin lesions, sore throat, and
headache. Complete physical and ocular examinations are also
essential.
LABORATORY TESTING
The list of diseases that have on occasion caused NR is exten-
sive. Laboratory testing should be tailored to the individual
patient based on information obtained from the history and
physical examinations. In most cases, serologic testing should
include cat scratch titers (Bartonella species), a fluorescent 1861
 RETINA AND VITREOUS

treponemal antibody absorption (FTA-ABS) test, and a PPD. In
endemic areas and in patients with a history of tick exposure
and/or characteristic symptoms of Lyme disease, titers for these
antibodies should also be obtained. Other testing should be
obtained as indicated by specific findings from the history and
physical examination.
although the possible benefit of such treatment is unknown. In
cases with particularly severe visual loss (either idiopathic or
due to a specific organism) treatment with corticosteroids is
often advised. In patients with recurrent idiopathic NR, the
addition of long-term immunosuppression has been shown to
decrease the number of recurrences.32

TREATMENT
Treatment generally depends on the results of testing for specific
infectious agents. The most common causative organism,
Bartonella henselae, is sensitive to a variety of antibiotics and
most authors recommend treatment accordingly. There are no
controlled studies, however, comparing the results of treatment
with the natural history of the disease or comparing the efficacy
of different antibiotic regimen. A retrospective study found the
following oral medications to be of benefit: rifampin (effective
in 87% of patients), ciprofloxacin (84%), and trimethaprim-
SECTION 10
Summary: Cat Scratch NR
• Most common identifiable cause of NR
• Usually due to B. henselae
• Most often affects children
• 80% of CSD infections are self-limited
• Mild local infection is followed by tender regional
lymphadenopathy then fever, malaise, and headache
• Other ocular manifestations include conjunctivitis, anterior
uveitis, focal retinal vasculitis or choroiditis, branch retinal

artery occlusion, and peripapillary angiomatous lesions

sulfamethoxazole (58%).31 In another smaller series, patients
with NR due to CSD did well with a combination of doxycycline
100 mg and rifampin 300 mg twice daily with minimal side-
effects.9 Golnik and associates reported a similar favorable out-
Tip File
come in four patients with CSD–NR treated with ciprofloxacin
1. Other conditions besides NR can cause disk edema with
500 mg twice daily.11 Treatment is usually initiated while
macular hard exudates. Before initiating an extensive
results of serologic testing are pending and continued for any-
evaluation for specific etiologies, rule out other mechanisms
where from 10 days to 6 weeks if results confirm CSD infection.
2. Be especially cautious in cases of bilateral NR. In most cases
The use of doxycycline and ciprofloxacin should be avoided in
this clinical picture is due to hypertensive retinopathy or
children, however. Some patients are also treated with steroids
occasionally increased intracranial pressure
although there is no evidence that this addition improves the
3. NR is most common in young people. In older individuals
visual outcome. Unlike treatment considerations for demyeli-
consider the alternative possibility of anterior ischemic optic
nating ON, there is no reason to favor intravenous over oral
neuropathy
administration in this setting.
4. In cases with acute unilateral visual loss, suspect NR rather
Patients with idiopathic NR usually enjoy good visual recovery
than ON in cases with little or no RAPD
regardless of treatment. Some are treated with corticosteroids

REFERENCES
1. Leber T: Die pseudonephritischen
Netzhauterkrankungen, die Retinitis stellata:
Die Purtschersche Netzhautaffektion nach
schwerer Schadelverletzung. In: Graefe AC,
Saemische T, eds. Graefe-Saemisch
Handbuch der Augerheilkunde. 2nd edn.
Leipzig, Germany: Englemann; 1916:1319.
2. Gass JDM: Diseases of the optic nerve that
may simulate macular disease. Trans Am
Acad Ophthalmol Otolaryngol 1977;
83:766–769.
3. Dreyer RF, Hopen G, Gass JDM, Smith JL:
Leber’s idiopathic stellate neuroretinitis.
Arch Ophthalmol 1984; 102:1140–1145.
4. Maitland CG, Miller NR: Neuroretinitis. Arch
Ophthalmol 1984; 102:1146–1150.
5. Wolter JR, Philips RL, Butler GR: The star-
figure of the macular area. Arch Ophthalmol
1958; 60:49–59.
6. Stewart JW, Brazis PW, Barrett KM, et al:
Optical coherence tomography in a case of
bilateral neuroretinitis. J Neuroophthalmol
2005; 25:131–133.
7. Bar S, Segal M, Shapira R, Savir H:
Neuroretinitis associated with cat-scratch
disease. Am J Ophthalmol 1990;
110:703–705.
8. Chrousos GA, Drack AV, Young M, et al:
Neuroretinitis in cat scratch disease. J Clin
Neuroophthalmol 1990; 10:92–94.
9. Reed JB, Scales DK, Wong MT, et al:
Bartonella henselae neuroretinitis in cat
scratch disease: diagnosis, management
1862
and sequelae. Ophthalmology 1998;
105:459–466.
10. Fish RH, Hoskins JC, Kline LB:
Toxoplasmosis neuroretinitis.
Ophthalmology 1993; 100:1177–1182.
11. Golnik KC, Marotto ME, Fanous MM, et al:
Ophthalmic manifestations of Rochalimaea
species. Am J Ophthalmol 1994;
118:145–151.
12. Ulrich GG, Waecker NJ Jr, Meister SJ, et al:
Cat scratch disease associated with
neuroretinitis in a 6-year-old girl.
Ophthalmology 1992; 99:246–249.
13. Weiss AH, Beck RW: Neuroretinitis in
childhood. J Pediatr Ophthalmol
Strabismus 1989; 26:198–203.
14. Ormerod LD, Skolnick KA, Menosky MM,
et al: Retinal and choroidal manifestations
of cat scratch disease. Ophthalmology
1998; 105:1024–1031.
15. Solley WA, Martin DF, Newman NJ, et al:
Cat scratch disease: posterior segment
manifestations. Ophthalmology 1999;
106:1546–1553.
16. Johnson BL, Wisotzkey HM: Neuroretinitis
associated with herpes simplex
encephalitis in an adult. Am J Ophthalmol
1977; 83:481–489.
17. Selbst RG, Selhorst JB, Harbison JW, et al:
Parainfectious optic neuritis: report and
review following varicella. Arch Neurol
1983; 40:347–350.
18. Folk JC, Weingeist TA, Corbett JJ, et al:
Syphilitic neuroretinitis. Am J Ophthalmol
1983; 95:480–486.
19. Lesser RL, Kornmehl EW, Pachner AR,
et al: Neuro-ophthalmologic manifestations
of Lyme disease. Ophthalmology 1990;
97:699–706.
20. Mansour AM: Cytomegalovirus optic
neuritis. Curr Opinion Ophthalmol 1997;
8:55–58.
21. Fusco R, Magli A, Guacci P: Stellate
maculopathy due to Salmonella typhi.
A case report. Ophthalmologica 1986;
192:154–158.
22. Beck RW, Sergott RC, Barr CC,
Annesley WH: Optic disc edema in the
presumed ocular histoplasmosis syndrome.
Ophthalmology 1984; 91:183–185.
23. Saxena R, Sethi HS, Rai HK, Menon V:
Bilateral neuro-retinitis following chick
embryo cell anti-rabies vaccination:
a case report. BMC Ophthalmol
2005; 5:20.
24. Suhler EB, Lauer AK, Rosenbaum JT:
Prevalence of serologic evidence of cat
scratch disease in patients with
neuroretinitis. Ophthalmology 2000;
107:871–876.
25. Bird AC, Smith JL, Curtin VT: Nematode
optic neuritis. Am J Ophthalmol 1970;
69:72–77.
26. Shoari M, Katz B: Recurrent neuroretinitis
in an adolescent with ulcerative colitis.
J Neuroophthalmol 2005; 25:286–288.
 Neuroretinitis

27. Carroll DM, Franklin RM: Leber’s idiopathic
stellate retinopathy. Am J Ophthalmol 1982;
93:96–101.
28. Purvin VA, Chioran G: Recurrent
neuroretinitis. Arch Opthalmol 1994;
112:365–371.
29. Parmley VC, Schiffman JS, Maitland CG,
et al: Does neuroretinitis rule out multiple
sclerosis? Arch Neurol 1987;
44:1045–1048.
30. Williams KE, Johnson LN: Neuroretinitis in
patients with multiple sclerosis.
Ophthalmology 2004; 111:335–341.
31. Margileth A: Antibiotic therapy for
cat-scratch disease: clinical study of
therapeutic outcome in 268 patients and a
review of the literature. Pediatr Infect Dis J
1992; 11:474–478.
32. Purvin V, Ranson N, Kawasaki A: Idiopathic
recurrent neuroretinitis: effects of long-term
immunosuppression. Arch Ophthalmol
2003; 121:65–67.

CHAPTER 140

1863
 CHAPTER

141 Familial Exudative Vitreoretinopathy

Shizuo Mukai and Christopher M. Andreoli

In 1969, Criswick and Schepens1 reported on six patients with
abnormalities of the retina and vitreous that were clinically
similar to retinopathy of prematurity (ROP) but without a history
of prematurity or oxygen supplementation. Two of the patients
were related by blood, and the other four patients were members
of another family and were related by blood. Criswick and
Schepens called this entity familial exudative vitreoretinopathy
(FEVR; which is also known as Criswick–Schepens syndrome)
because of the familial and exudative nature of the disease. Both
FEVR and ROP are characterized by avascularity of the peripheral
retina, which is especially evident on fluorescein angiography.
In both diseases, reactive fibrovascular proliferations develop
that may lead to cicatricial changes and retinal traction in the
temporal periphery, resulting in dragged disks, ectopic maculae,
retinal detachments, and falciform retinal folds. Visual loss is
primarily due to retinal detachment.2
Synonyms
• FEVR
• Criswick–Schepens syndrome
CLINICAL CHARACTERISTICS
FEVR is a vitreoretinal disorder that is clinically similar to ROP,
except that there is usually a positive family history, and there
is no history of prematurity or oxygen supplementation. The
disease is often asymptomatic in the early stages and progresses
very slowly. Based on funduscopic and fluorescein angiographic
observations, Canny and Oliver3 developed a useful staging
scheme. The three stages describe mild, moderate, and severe
forms of FEVR, and each stage can be seen at any age.
• Falciform retinal fold
• Rhegmatogenous retinal detachment
• Massive intraretinal and subretinal exudation
Stage 1 describes the mild form of FEVR. Fundus examination
during this stage reveals vitreoretinal changes in the periphery
between the equator and the ora serrata, including the white-with-
pressure and white-without-pressure signs, peripheral cystoid
degeneration, and vitreous bands. There is a peripheral avascular
zone that is difficult to see clinically. Exudation, neovasculariz-
ation, and fibrovascular proliferation are not present at this
initial stage. Fluorescein angiography demonstrates the periph-
eral avascular zone clearly (Fig. 141.1) that is present in the
temporal periphery and can leak fluorescein. There is abnormal
arborization of the vessels in the periphery that terminates along
a scalloped or curvilinear border with the avascular zone. In cases
with wider zones of peripheral avascularity, a wedge-shaped area
of avascularization may be seen in the temporal meridian. Retinal
pigment epithelial changes are often associated with this V-shaped
zone of avascularization.4 In many individuals, the peripheral
avascular zone persists into adult life without regression or pro-
gression to proliferation.5 This is in contrast to ROP in which
the peripheral retina subsequently vascularizes.
It is not known why the peripheral retina does not vascularize
completely in FEVR. Whether this disease is a primary disorder

Key Features
Mild (Stage 1)
• Peripheral avascular zone
• Abnormal aborization in periphery with:
• Vascular engorgement and telangiectasia
• Capillary microaneurysms
• Arteriovenous shunts
• Straightened vessels
Moderate (Stage 2)
• Neovascularization
• Fibrovascular proliferation
• Subretinal and intraretinal exudation
Severe (Stage 3)
• Cicatricial lesion in the temporal periphery FIGURE 141.1. Fluorescein angiogram demonstrates the peripheral
• Traction retinal detachment avascular zone, vascular engorgement and telangiectasia,
microaneurysms, and shunt vessels in stage-1 disease. 1865
 RETINA AND VITREOUS

a b c
SECTION 10

FIGURE 141.2. (a) The temporal periphery in stage-2 FEVR. Fibrovascular ridge and retinal exudation are seen. (b) Early fluorescein angiogram
of the same area shows neovascularization at the vascular–avascular border. (c) Late fluorescein angiogram of the same area shows extensive
leakage of the fluorescein dye.
(a–c) Courtesy of Tatsuo Hirose, MD.

affecting retinal vessel development6,7 rather than a true vitreo-

retinopathy, as originally suggested by Criswick and Schepens,1
is still to be determined. Although congenital nonvascularization
of the retinal periphery is the most common characteristic of
the mildest phenotypes, vitreous changes are also noted in these
patients. It also remains uncertain whether a secondary vaso-
occlusive process (e.g., associated with hematologic disease)
contributes to the pathogenesis of FEVR. Laqua7 performed
extensive hematologic examinations on one of his patients with
FEVR and did not find any evidence of a hematologic disorder.
Platelet dysfunction may play a role in FEVR, but this is still
not fully determined.8–10
Stage 2 FEVR is the moderate form of the disease and
represents the proliferative and exudative stage. In addition to
the stage 1 findings already described, neovascularization, fibro-
vascular proliferation, and subretinal and intraretinal exudation
are seen, especially in the temporal periphery (Figs 141.2 and
141.3). A localized traction retinal detachment may also be
present. The fibrovascular lesions contract and exert traction on
the retina, producing ectopic maculae and dragged disks (Fig.
141.4).3 A fluorescein angiogram shows neovascularization FIGURE 141.3. The temporal periphery in stage 2 disease
developing from the retinal vessels at the vascular–avascular demonstrates intraretinal and subretinal exudation, pigmentary
border and growing anteriorly into the avascular retina. The changes, and straightening of retinal vessels.
temporal region of the retina is again the most common area for
neovascularization. There is abrupt cessation of the retinal
capillary network at the scalloped edge posterior to the fibro- constitute the major cause of visual loss in these patients. The
vascular mass. These terminal capillaries also leak fluorescein. incidence of retinal detachment ranges between 20% and
Fibrovascular masses stain with fluorescein. Large feeder vessels 32%.2,13–15 Rhegmatogenous retinal detachment is common –
may also be seen.11 between 25% and 63% of all retinal detachments in FEVR are
Stage 3 represents the advanced stage of FEVR. A cicatricial of this type. A variety of retinal breaks have been observed,
lesion in the temporal periphery pulls the retina and causes including round holes, horseshoe tears, and giant tears. Rheg-
traction retinal detachments, falciform retinal folds, and matogenous retinal detachments usually occur in the second
rhegmatogenous retinal detachments. Massive intraretinal and and third decades of life. At least in the Japanese population,
subretinal exudation is present and can result in an exudative rhegmatogenous retinal detachments from FEVR appear to
retinal detachment (Fig. 141.5). The exudative component of constitute a significant proportion of all rhegmatogenous retinal
the disease may resemble Coats’ disease and is different from detachments in this age group. Hashimoto and associates14
ROP. The degree of exudation is usually less than in Coats’ showed that in 576 consecutive cases of all rhegmatogenous
disease, and total retinal detachments from exudation are rare. retinal detachments, 5% were in FEVR patients. When these
Anterior segment changes, including cataract, iris atrophy, authors looked at all rhegmatogenous retinal detachments in
rubeosis iridis, and neovascular glaucoma, nonneovascular patients younger than 30 years of age, a surprising 12% were in
chronic angle-closure glaucoma, as well as band keratopathy patients with FEVR.
can also occur.3,12 Retinal breaks in FEVR are thought to be caused by a
1866 Retinal detachments are relatively common in FEVR and combination of vitreoretinal traction and retinal atrophy.

FIGURE 141.4. Patient with stage 2 FEVR with a dragged disk.
FIGURE 141.5. Stage 3 FEVR in a patient with retinal hemorrhage
and severe exudative retinal detachment.
Vitreous bands and adhesions are seen even in the early stages
of FEVR. Neovascularization and fibrovascular proliferation
produce additional traction. The peripheral retina in FEVR
patients is also avascular and atrophic. Atrophic holes are seen
in the periphery in many of the cases. The combination of
vitreoretinal traction and atrophic retina makes these eyes more
susceptible to retinal tears.2,15,16 The combined traction and
rhegmatogenous retinal detachments that result tend to be
surgically difficult to repair and often lead to proliferative
vitreoretinopathy and require multiple procedures.2,15,17 There
is also one reported case of significant postoperative uveitis.18
Vitreous hemorrhage in FEVR patients is rare but may be an
ominous sign; two cases described by van Nouhuys2 resulted in
rapid progression to closed-funnel retinal detachments. In
summary, the cases of retinal detachment in FEVR have many
of the difficulties seen in combined traction-rhegmatogenous
retinal detachment in young adults with predilection for pro-
liferative vitreoretinopathy.
Familial Exudative Vitreoretinopathy
Falciform retinal folds are also relatively common and are
found in 15–39% of the eyes with FEVR.2,19 The folds usually
extend from the optic nerve head to the temporal or infero-
temporal periphery, at which point there are cicatricial
connections to the mass of fibrous tissue at the peripheral
retina and lens equator.20,21 The distance between the peripheral
retina and the lens equator is very short in the neonatal eye, and
this accounts for the high frequency of adhesions anteriorly to
the lens. The folds appear to be caused by severe traction of the
retina resulting from the organization of peripheral neovas-
cularization and formation of a fibrovascular mass. The folds
usually occur in the first decade of life and do not show
progression.
Traction retinal detachments are less common and occur at a
rate of 6–10% in eyes with FEVR.2,14 They usually occur before
the age of 10 years and show very little progression. In the cases
with isolated traction retinal detachment, vitrectomy alone may
be effective.22 Massive Coats’-like exudation can cause total
CHAPTER 141
retinal detachments (Fig. 141.5),23 but in general, significant
exudative retinal detachments appear to be rare.2
DIFFERENTIAL DIAGNOSIS
Differential Diagnosis
• Retinopathy of Prematurity
• Coats’ disease
• Sickle cell trait and disease
• Other hemoglobinopathies
• Persistent hyperplastic primary vitreous/persistent fetal
vasculature
• Toxocara canis infection
• Norrie disease
• Incontinentia pigmenti
• Hereditary falciform retinal fold
• Angiomatosis of the retina
• Autosomal dominant neovascularization
• Eales’ disease
• Pars planitis
FEVR is characterized by nonvascularization of the peripheral
retina, familial occurrence (usually autosomal dominant,
X-linked, or autosomal recessive), dragged disk and macula,
retinal exudation, retinal detachment, and retinal folds. The
clinical features are most similar to those of ROP and include
peripheral nonvascularization, reactive fibrovascular prolifer-
ations, and cicatricial changes with severe traction on the retina.
Important differentiating features are a family history of the dis-
order and no history of prematurity or oxygen supplementation.
The peripheral avascular retina does not vascularize in FEVR,
as it typically does in ROP, and exudation, which is common in
FEVR, is very rare in ROP.7
In addition to ROP, possible alternative differential diagnoses
of patients having peripheral retinal nonvascularization with
neovascular proliferation include sickle-cell trait and disease as
well as other hemoglobinopathies, Eales’ disease, incontinentia
pigmenti, and autosomal dominant neovascularization as
described by Gitter and co-workers.24 Diseases causing dragged
disks, ectopic maculae, and falciform retinal folds also need
to be considered, especially hereditary falciform retinal folds,
persistent hyperplastic primary vitreous/persistent fetal
vasculature, Toxocara canis infection, Norrie disease, and
incontinentia pigmenti.19,25,26 Causes of peripheral retinal
fibrous or exudative mass lesion include Coats’ disease,
angiomatosis of the retina, Toxocara canis infection, and pars
planitis.7,16 1867
 RETINA AND VITREOUS
GENETICS
Genetics
• Genetically heterogeneous
• Autosomal dominant
• X-linked
• Autosomal recessive
• Variable clinical expression
FEVR is a genetically heterogeneous disease with autosomal
dominant, autosomal recessive, and X-linked inheritance pos-
sible with variable clinical expression. Multiple loci and genes
have been implicated. Penetrance is variable, depending on the
method of diagnosis. When using fluorescein angiography to
determine clinical status, penetrance is reported to be 100%
because all affected individuals have a sector of avascular periph-
SECTION 10
eral retina.27 When using examination of the retina with an
indirect ophthalmoscope through a dilated pupil to determine
clinical status, penetrance is considered to be ~90%.20 When
using reduced vision or other clinical symptoms to determine
clinical status, penetrance as low as 10% has been reported.
The first locus discovered, EVR1, contains the FZD-4 gene
encoding the Wnt receptor Frizzled-4.28,29 Mutations in FZD-4
are responsible for autosomal dominant forms of FEVR. This
gene maps to the long arm of human chromosome 11 at locus
11q13-23. Multiple families have been discovered to have novel
missense and nonsense mutations in this gene causing a similar
FEVR phenotype.28,30–34 The FZD-4 family of genes encode for
the Frizzled family of seven-pass transmembrane receptors that
bind to multiple ligands including the Wnt family of proteins.
This receptor–ligand pair is implicated in development, cell
proliferation, and carcinogenesis.29,35 A missense mutation in
FZD4 has been reported in a single case of advanced ROP.36
The second FEVR locus, EVR-2, has been found to contain the
same gene responsible for Norrie disease (ND) and has been shown
to be mutated in cases of X-linked FEVR.37,38 ND is clinically
characterized by bilateral retrolental grayish-yellow fibrovascular
masses. This has traditionally been thought to arise from primary
retinal dysplasia.39 With age, the disease progresses to include
cataract, posterior and anterior synechiae, iris atrophy, corneal
opacification, band keratopathy, and blindness with phthisis bulbi.
Mutations in the Norrie gene (NDP) on the human X chromo-
some at locus Xp11.4 which encodes ND protein (Norrin), have
been shown to cause a spectrum of diseases including ND
(nonsense mutation) and X-linked FEVR (missense mutations).
There are also reported cases suggesting a role of this gene in
the pathogenesis of persistent hyperplastic primary vitreous/
persistent fetal vasculature, Coats’ disease, and advanced
ROP.40 These diseases all appear to share abnormalities in
retinal vasculature.
There is some evidence that a genotype–phenotype relationship
exists with mutations in NDP. It is suggested that missense
mutations affecting the carboxy terminus of the protein result in
a less severe phenotype manisfested as X-linked FEVR.37,41 How-
ever, there is also significant phenotypic variation within families
carrying the same NDP mutation.37,42 Allen et al suggests that all
phenotypes associated with a defect in NDP should be classified
as ND with a range of expressivity, and that X-linked FEVR
should be reserved for any cases which do not involve a defect
in NDP.42
Xu et al43 established Norrin as a ligand for Frizzled-4, a pre-
sumptive Wnt receptor. They propose that Norrin–Frizzled-4
binding serves as a signaling system involved in vascular develop-
ment.43 Both FZD-4 and NDP knockout mice have been shown to
1868 display increased retinal vascular permeability with an increased
number of fenestrated blood vessels as well as persistence of
hyaloid vasculature.44,45
A third locus, EVR3, segregating with a large kindred
demonstrating autosomal dominant FEVR has been identified
on chromosome 11 at locus 11p12-13. The gene is currently
unidentified.46
A fourth locus, EVR4, contains the LRP5 gene which encodes
a Wnt co-receptor, low-density lipoprotein receptor-related
protein-5 (LRP5). Mutations in this gene cause an autosomal
dominant form of FEVR.47,48 This gene is located on
chromosome 11 at locus 11q13, distinct from EVR1 (FZD-4)
and EVR3. It has been shown that mutations in this same gene
can cause an autosomal recessive form of FEVR as well.49
Frizzled-4 and LRP5 act as a functional receptor pair in the Wnt
signaling pathway.50
Toomes has suggested a fourth autosomal dominant locus
distinct from EVR1, EVR3, and EVR4.51 Autosomal recessive
pedigrees have also been described; however, an underlying
genetic defect has not been determined.52
Genetic sequence analysis is available on a research basis for
NDP, FZD-4, and LRP. Because the autosomal dominant,
autosomal recessive, and X-linked forms of FEVR cannot be
distinguished clinically, determining the mode of inheritance
for a particular family can be difficult, and for the simplex case,
may not be possible.
PATHOLOGIC FEATURES
Histopathologic studies of six eyes enucleated for end-stage
FEVR have been reported.53–56 These eyes were enucleated for
phthisis, neovascular glaucoma, acute angle closure, and possible
retinoblastoma (in a 6-week-old infant). Many of the histo-
pathologic findings are those typically associated with chronic
retinal detachments, neovascular glaucoma, and phthisis
bulbi. This discussion concentrates on the findings unique to
FEVR. No pathology of either stage 1 or stage 2 disease is
available.
Retinal detachment and prominent preretinal and vitreal mem-
brane formation are seen in all cases. Brockhurst and colleagues55
observed a thick, acellular, preretinal membrane consisting of
amorphous material. This membrane is seen just posterior to
the ora serrata and extends posteriorly. Glazer and associates
showed by electron microscopy that the membranes consist of
fibrovascular tissue with astrocytes.57 Multiple adhesions to the
retina cause large retinal folds. Acellular fibrous membrane with
pigment is also seen in the vitreous. Van Nouhuys’54 case of the
6-week-old infant with possible retinoblastoma shows the
preretinal membrane to extend much more anteriorly and
attach to the lens capsule. Intraretinal and subretinal exudation
is also seen, but the degree of exudation and the extent of
telangiectatic vessels are less than those usually seen in Coats’
disease.56 Nicholson and Galvis53 observed areas of necrosis and
acute inflammation surrounding the fibrovascular tissue in the
temporal periphery of the retina.
PREVENTION AND TREATMENT
The major cause of visual loss in cases of FEVR is retinal
detachment. When retinal detachments occur in eyes with
FEVR, they tend to be complicated and difficult to repair, often
requiring multiple surgical procedures.2,57,58 Some of the
detachments are similar to those seen in ROP. Retinal detach-
ments are more difficult and have the worst prognosis in
younger children; rhegmatogenous retinal detachment in an
adolescent FEVR patient has high likelihood of proliferative
vitreoretinopathy and redetachment. The key to retinal
detachment repair in FEVR patients is to release the peripheral
 Familial Exudative Vitreoretinopathy

vitreoretinal traction using meticulous membrane dissection
and scleral buckling.17
As in ROP, the goal is to try to prevent the detachments of
the retina seen in stage 3, advanced FEVR. Early examination
(including dilated fundus examination with scleral depression)
of children who have a positive family history is mandatory in
identifying those with early proliferative changes. The neovascular
and fibrovascular process can then be treated by prophylactic
photocoagulation or cryotherapy. There are very few descriptions
of FEVR in neonates and infants, and early examination will
also give us a better understanding of how FEVR presents in this
population. The application of retinoablative procedures to the
avascular retina alone or together with the neovascular frond
appears to be effective in aborting the proliferative process.2,59
As in treated cases of ROP, the destruction of the proliferative
process is thought to diminish the subsequent cicatricial process
that leads to retinal detachment. A randomized study to test the
effectiveness of prophylactic cryotherapy or photocoagulation
would be difficult to carry out because of the rarity and slow
progression of the disease. It is currently not clear whether we
can prevent the retinal detachments that occur quite early in life,
since stage 3 FEVR can be already present in very young patients.60
Presence of the cicatricial process makes the direct detection
of subtle retinal detachments difficult. Vitreous cells and haze,
poor mydriasis, aqueous cells and flare, and posterior synechiae
are all signs of retinal detachment in a FEVR patient. Ultra-
sonography is an important test in the diagnosis of retinal
detachments in cases with media opacities. An increase in angle
kappa is evidence of increasing peripheral traction.2 The role of
electrophysiologic testing is uncertain.61
Treatment Options
• Photocoagulation or cryotherapy
• Scleral buckle
• Vitrectomy with meticulous membrane dissection

REFERENCES
1. Criswick VG, Schepens CL: Familial
exudative vitreoretinopathy. Am J
Ophthalmol 1969; 68:578–594.
2. van Nouhuys CE: Juvenile retinal
detachment as a complication of familial
exudative vitreoretinopathy. Fortschr
Ophthalmol 1989; 86:221–223.
3. Canny CL, Oliver GL: Fluorescein
angiographic findings in familial exudative
vitreoretinopathy. Arch Ophthalmol 1976;
94:1114–1120.
4. Miyakubo H, Hashimoto K, Miyakubo S:
Retinal vascular pattern in familial
exudative vitreoretinopathy. Ophthalmology
1984; 91:1524–1530.
5. Tasman W, Augsburger JJ, Shields JA,
et al: Familial exudative vitreoretinopathy.
Trans Am Ophthalmol Soc 1981;
79:211–226.
6. Gow J, Oliver GL: Familial exudative
vitreoretinopathy. An expanded view.
Arch Ophthalmol 1971; 86:150–155.
7. Laqua H: Familial exudative
vitreoretinopathy. Albrecht Von Graefes Arch
Klin Exp Ophthalmol 1980; 213:121–133.
8. Chaudhuri PR, Rosenthal AR, Goulstine DB,
et al: Familial exudative vitreoretinopathy
associated with familial thrombocytopathy.
Br J Ophthalmol 1983; 67:755–758.
9. Friedrich CA, Francis KA, Kim HC: Familial
exudative vitreoretinopathy (FEVR) and
platelet dysfunction. Br J Ophthalmol 1989;
73:477–478.
10. Gole GA, Goodall K, James MJ: Familial
exudative vitreoretinopathy. Br J
Ophthalmol 1985; 69:76.
11. Nijhuis FA, Deutman AF, Aan de Kerk AL:
Flourescein angiography in mild stages of
dominant exudative vitreoretinopathy. Mod
Probl Ophthalmol 1979; 20:107–114.
12. Azuara-Blanco A, Pesin SR, Katz LJ, et al:
Familial exudative vitreoretinopathy
associated with nonneovascular chronic
angle-closure glaucoma. J Glaucoma 1997;
6:47–49.
13. Miyakubo H, Inohara N, Hashimoto K:
Retinal involvement in familial exudative
vitreoretinopathy. Ophthalmologica 1982;
185:125–135.
14. Hashimoto K, Miyakubo H, Inohara N, Tada
H: Juvenile retinal detachment and familial
exudative vitreoretinopathy. Jpn J Clin
Ophthalmol 1983; 37:797–803.
15. Benson WE: Familial exudative
vitreoretinopathy. Trans Am Ophthalmol
Soc 1995; 93:473–521.
16. Dudgeon J: Familial exudative vitreo-
retinopathy. Trans Ophthalmol Soc UK
1979; 99:45–49.
17. Tano Y, Ikeda T: Treatment of familial
exudative vitreoretinopathy with pars plana
vitrectomy. Ophthalmology 1990;
97(Suppl):152.
18. Okubo Y, Okubo A, Kubono T, Shimizu H:
Familial exudative vitreoretinopathy,
rhegmatogenous retinal detachment and
postoperative uveitis with massive
subretinal exudation. Nippon Ganka Gakkai
Zasshi 1984; 88:1151–1156.
19. Nishimura M, Yamana T, Sugino M, et al:
Falciform retinal fold as sign of familial
exudative vitreoretinopathy. Jpn J
Ophthalmol 1983; 27:40–53.
20. van Nouhuys CE: Dominant exudative
vitreoretinopathy and other vascular
developmental disorders of the
peripheral retina. Doc Ophthalmol 1982;
54:1–414.
21. Campo RV: Similarity of familial exudative
vitreoretinopathy and retinopathy of
prematurity. Arch Ophthalmol 1983;
101:821.
22. Maguire AM, Trese MT: Visual results of
lens-sparing vitreoretinal surgery in infants.
J Pediatr Ophthalmol Strabismus 1993;
30:28–32.
23. Ebert EM, Mukai S: Familial exudative
vitreoretinopathy. Int Ophthalmol Clin 1993;
33:237–247.
24. Gitter KA, Rothschild H, Waltman DD, et al:
Dominantly inherited peripheral retinal
neovascularization. Arch Ophthalmol 1978;
96:1601–1605.
25. van Nouhuys CE: Congenital retinal fold as
a sign of dominant exudative
vitreoretinopathy. Albrecht Von Graefes
Arch Klin Exp Ophthalmol 1981; 217:55–67.
26. Chang-Godinich A, Paysse EA, Coats DK,
Holz ER: Familial exudative
vitreoretinopathy mimicking persistent
hyperplastic primary vitreous. Am J
Ophthalmol 1999; 127:469–471.
27. Ober RR, Bird AC, Hamilton AM, Sehmi K:
Autosomal dominant exudative
vitreoretinopathy. Br J Ophthalmol 1980;
64:112–120.
CHAPTER 141
28. Li Y, Fuhrmann C, Schwinger E, et al: The
gene for autosomal dominant familial
exudative vitreoretinopathy (Criswick-
Schepens) on the long arm of chromosome
11. Am J Ophthalmol 1992; 113:712–713.
29. Robitaille J, MacDonald ML, Kaykas A,
et al: Mutant frizzled-4 disrupts retinal
angiogenesis in familial exudative
vitreoretinopathy. Nat Genet 2002;
32:326–330.
30. Yoshida S, Arita R, Yoshida A, et al: Novel
mutation in FZD4 gene in a Japanese
pedigree with familial exudative
vitreoretinopathy. Am J Ophthalmol 2004;
138:670–671.
31. Toomes C, Bottomley HM, Scott S, et al:
Spectrum and frequency of FZD4 mutations
in familial exudative vitreoretinopathy. Invest
Ophthalmol Vis Sci 2004; 45:2083–2090.
32. Price SM, Periam N, Humphries A, et al:
Familial exudative vitreoretinopathy linked
to D11S533 in a large Asian family with
consanguinity. Ophthalmic Genet 1996;
17:53–57.
33. Kondo H, Hayashi H, Oshima K, et al:
Frizzled 4 gene (FZD4) mutations in
patients with familial exudative
vitreoretinopathy with variable expressivity.
Br J Ophthalmol 2003; 87:1291–1295.
34. Omoto S, Hayashi T, Kitahara K, et al:
Autosomal dominant familial exudative
vitreoretinopathy in two Japanese families
with FZD4 mutations (H69Y and C181R).
Ophthalmic Genet 2004; 25:81–90.
35. Huang HC, Klein PS: The Frizzled family:
receptors for multiple signal transduction
pathways. Genome Biol 2004; 5:234.
36. MacDonald ML, Goldberg YP, Macfarlane
J, et al: Genetic variants of frizzled-4 gene
in familial exudative vitreoretinopathy and
advanced retinopathy of prematurity. Clin
Genet 2005; 67:363–366.
37. Riveiro-Alvarez R, Trujillo-Tiebas MJ,
Gimenez-Pardo A, et al: Genotype-
phenotype variations in five Spanish
families with Norrie disease or X-linked
FEVR. Mol Vis 2005; 11:705–712.
38. Shastry BS, Hejtmancik JF, Trese MT:
Identification of novel missense mutations
in the Norrie disease gene associated with
one X-linked and four sporadic cases of
familial exudative vitreoretinopathy. Hum
Mutat 1997; 9:396–401. 1869
 RETINA AND VITREOUS
39. Warburg M: Norrie’s disease. A congenital
progressive oculo-acoustico-cerebral
degeneration. Acta Ophthalmol (Copenh)
1966; 89(Suppl):1–47.
40. Shastry BS, Pendergast SD, Hartzer MK,
et al: Identification of missense mutations
in the Norrie disease gene associated with
advanced retinopathy of prematurity. Arch
Ophthalmol 1997; 115:651–655.
41. Meindl A, Lorenz B, Achatz H, et al:
Missense mutations in the NDP gene in
patients with a less severe course of Norrie
disease. Hum Mol Genet 1995; 4:489–490.
42. Allen RC, Russell SR, Streb LM, et al:
Phenotypic heterogeneity associated with a
novel mutation (Gly112Glu) in the Norrie
disease protein. Eye 2006; 6:234–241.
43. Xu Q, Wang Y, Dabdoub A, et al:
Vascular development in the retina and
inner ear: control by Norrin and Frizzled-4,
a high-affinity ligand-receptor pair. Cell
SECTION 10
2004; 116:883–895.
44. Richter M, Gottanka J, May CA, et al:
Retinal vasculature changes in Norrie
disease mice. Invest Ophthalmol Vis Sci
1998; 39:2450–2457.
45. Rehm HL, Zhang DS, Brown MC, et al:
Vascular defects and sensorineural
deafness in a mouse model of Norrie
disease. J Neurosci 2002; 22:4286–4292.
46. Downey LM, Keen TJ, Roberts E, et al:
A new locus for autosomal dominant
familial exudative vitreoretinopathy maps to
chromosome 11p12-13. Am J Hum Genet
2001; 68:778–781.
1870
47. Toomes C, Downey LM, Bottomley HM,
et al: Identification of a fourth locus (EVR4)
for familial exudative vitreoretinopathy
(FEVR). Mol Vis 2004; 10:37–42.
48. Qin M, Hayashi H, Oshima K, et al:
Complexity of the genotype-phenotype
correlation in familial exudative
vitreoretinopathy with mutations in the
LRP5 and/or FZD4 genes. Hum Mutat
2005; 26:104–112.
49. Jiao X, Ventruto V, Trese MT, et al:
Autosomal recessive familial exudative
vitreoretinopathy is associated with
mutations in LRP5. Am J Hum Genet 2004;
75:878–884.
50. Pinson KI, Brennan J, Monkley S, et al:
An LDL-receptor-related protein mediates
Wnt signalling in mice. Nature 2000;
407:535–538.
51. Toomes C, Downey LM, Bottomley HM, et al:
Further evidence of genetic heterogeneity
in familial exudative vitreoretinopathy;
exclusion of EVR1, EVR3, and EVR4 in a
large autosomal dominant pedigree. Br J
Ophthalmol 2005; 89:194–197.
52. de Crecchio G, Simonelli F, Nunziata G,
et al: Autosomal recessive familial
exudative vitreoretinopathy: evidence for
genetic heterogeneity. Clin Genet 1998;
54:315–320.
53. Nicholson DH, Galvis V:
Criswick–Schepens syndrome (familial
exudative vitreoretinopathy). Study of a
Colombian kindred. Arch Ophthalmol 1984;
102:1519–1522.
54. Mintz-Hittner HA, Ferrell RE, Sims KB,
et al: Peripheral retinopathy in offspring of
carriers of Norrie disease gene mutations.
Possible transplacental effect of abnormal
Norrin. Ophthalmology 1996;
103:2128–2134.
55. Brockhurst RJ, Albert DM, Zakov ZN:
Pathologic findings in familial exudative
vitreoretinopathy. Arch Ophthalmol 1981;
99:2143–2146.
56. Boldrey EE, Egbert P, Gass JD, Friberg T:
The histopathology of familial exudative
vitreoretinopathy. A report of two cases.
Arch Ophthalmol 1985; 103:238–241.
57. Glazer LC, Maguire A, Blumenkranz MS,
et al: Improved surgical treatment of
familial exudative vitreoretinopathy in
children. Am J Ophthalmol 1995;
120:471–479.
58. Uto H, Shigeto M, Tanaka H, et al: A case
of 11q-syndrome associated with
abnormalities of the retinal vessels.
Ophthalmologica 1994; 208:233–236.
59. Bergen RL, Glassman R: Familial exudative
vitreoretinopathy. Ann Ophthalmol 1983;
15:275–276.
60. Slusher MM, Hutton WE: Familial exudative
vitreoretinopathy. Am J Ophthalmol 1979;
87:152–156.
61. Ohkubo H, Tanino T: Electrophysiological
findings in familial exudative
vitreoretinopathy. Doc Ophthalmol 1987;
65:461–469.
 CHAPTER
142 Central Serous Chorioretinopathy
Catherine B. Meyerle and Richard F. Spaide
DEFINITION
Central serous chorioretinopathy (CSC) is characterized by an
idiopathic circumscribed serous retinal detachment, usually
confined to the central macula, caused by leakage of fluid
through the retinal pigment epithelium (RPE) as defined by
fluorescein angiography. Eyes with CSC do not have signs of
intraocular inflammation, accelerated hypertension, infiltration
or infarction of the choroid or RPE. Serous detachments of the
RPE are frequently present. Although most cases are acute with
minimal sequela, some patients have a more chronic version of
the disease with poorer visual prognosis.
HISTORICAL BACKGROUND
CSC has a long history of changing names reflective of the
previous uncertainty about the etiology of the pathological pro-
cess. von Graefe first described it as a recurrent central retinitis.1
Horniker2 agreed that the pathology was localized to the retina but
thought these patients had an underlying angioneurosis causing
angiospasm and exudation. He used the name capillarospastic
central retinitis. Gifford and Marquardt3 shared Horniker’s view
and coined the term central angiospastic retinopathy. Bennet
also localized the disease to the retina and applied the name
central serous retinopathy.4 Through fluorescein angiography,
Maumenee5 changed the concept of the primary tissue affected
by describing the leak occurring at the level of the RPE. Gass6
expanded on this view with his description of the fluorescein
angiographic findings and named the condition idiopathic
central serous choroidopathy. Today, since we understand that
hyperpermeability at the choroid causes a leak through the RPE
resulting in a neurosensory retinal detachment, CSC is the
preferred term.
DEMOGRAPHICS
CSC has certain common demographic features.1–11 Historically
the mean patient age was reported as 20–45 years, but more
recent studies have not substantiated these numbers and actually
report an older mean age. In a 1996 study of 130 patients with
CSC, the mean age was 51 years.11 Two recent large retrospec-
tive case control studies concur with this older mean age. A
study of 230 patients found the mean age to be 51 years12 and
another study of 312 patients revealed a mean age of 45 years.13
If diagnosed in a patient older than 50 years of age, however,
one must carefully assess for macular degeneration or choroidal
neovascularization (CNV) before making the diagnosis of CSC.
CSC is very rare in patients less than 20 years old. Although
CSC in a 7-year-old girl has been reported, this patient may
actually have had posterior scleritis.14
In terms of gender, there is a male predilection with the
reported male:female ratio ranging from 6:1 in older studies1–10
and less than 3:1 in more recent literature.12,13 Race also plays
a role in CSC, with more whites, Hispanics, and Asians
affected. CSC has been reported as uncommon in blacks, but
some authors refute this point.15 The disease may run a more
severe course in Hispanics and Asians with extensive bullous
changes. Refractive error is significant with hyperopic or
emmetropic patients affected more in Western nations.16 This
association, however, does not hold for those in Asian regions
with a high prevalence of myopia such as in Japan.
Corticosteroids have been implicated in CSC by multiple
studies. Tittl and associates, in a retrospective case-control study
of 230 patients, found that corticosteroids (used by 9.1% of
patients) are risk factors in addition to psychotropic medications
and hypertension.12 Haimovici and co-workers13 also reported
an association of CSC with corticosteroids (used by 14.4% of
patients) in a retrospective case-control study of 312 patients.
Other risk factors, according to Haimovici13, included pregnancy,
antibiotics, alcohol, untreated hypertension, and allergic respi-
ratory disease, with the pregnancy association also reported by
Gass.17 Karadimas eventually confirmed that corticosteroids are
a risk factor for CSC in a smaller, but prospective, case-control
study.18 Systemic corticosteroid treatment in organ transplant
patients has been associated with aggressive CSC.19,20 More recent
studies have shown that fundus changes previously attributed
to organ transplantation21 were in fact most likely due to corti-
costeroid-induced CSC, as patients who never had organ trans-
plantation but were on corticosteroids had similar findings.22
Inhaled, intranasal, intramuscular, and topical dermatological23–26
corticosteroids have also been implicated in CSC pathogenesis.
There have even been isolated case reports of CSC following
vitrectomy with intravitreal triamcinolone acetonide for diabetic
macular edema27 and CSC after a periocular steroid injection
for HLA-B27-associated iritis.28 Our associates, however, have
performed hundreds of intravitreal triamcinolone acetonide
injections and have not yet observed a case of CSC. Endogenous
corticosteroids are also thought to contribute to the pathoge-
nesis of disease as many CSC patients have elevated 24-h urine
corticosteroids.29 Repeated injections of intramuscular pred-
nisolone in combination with intravenous epinephrine in a
cynomolgus monkey (Macaca irus) resulted in CSC after the
thirty-second injection.30 Some question the validity of this animal
model, however, based on the histopathology. Ultrastructural
findings of RPE degeneration with underlying damaged endo-
thelial cells within the inner surface of the choriocapillaris31 may
be more consistent with infarction seen in malignant hyperten-
sion. Yoshioka defends his CSC animal model by pointing out
that the monkeys in his study did not have any Elsching’s spots
or retinal vasculature changes consistent with hypertension.30 1871
 RETINA AND VITREOUS
Similar to corticosteroids, both exogenous and endogenous
sympathomimetic agents have been implicated in CSC. Exces-
sive use of sympathomimetic compounds has been associated
with CSC.32 Endogenous plasma concentrations of epinephrine
and norepinephrine were found to be higher among CSC
patients than in controls in one study.33 Repeated injections of
intravenous epinephrine alone in a Japanese monkey model
(Macaca fuscatus) resulted in CSC after 39 injections.30
Personality traits are thought to play a role in CSC. Patients
with CSC commonly are stressed by multiple events in their
life.34 Based on the the Jenkins Activity Survey, Yannuzzi showed
that these patients are more likely to have type A personality
characteristics when compared with controls.35 Werry and
Arends,36 using the Minnesota Multiphasic Personality Inven-
tory Test, showed that CSC patients are more likely to show
hypochondria or hysteria and have a conversional neurosis.
OCULAR SYMPTOMS
SECTION 10
Common symptoms of CSC are decreased vision with distor-
tions including metamorphopsia, micropsia, scotomas, chroma-
topsia, and prolonged after-images. The visual acuity, somewhat
improvable with mild hyperopic correction, is usually reduced
to between 20/30 and 20/60 but can decline to worse than
20/200 in severe or recurrent disease. Superior field defects can
occur in patients with inferior detachments from gravitating
fluid. Younger CSC patients usually have unilateral involve-
ment, while older patients are more likely to have bilateral
involvement.
OCULAR FINDINGS OF CLASSIC CSC
CSC can present in three different ways: classic acute chorio-
retinopathy, chronic diffuse retinal pigment epitheliopathy
a b
a b
FIGURE 142.2. (a) Red-free photograph illustrates a classic pigment epithelial detachment. (b and c) ICG angiography shows the typical early
hyperfluorescence and late hypofluorescence of the pigment epithelial detachment.
1872
(DRPE), and bullous retinal detachment. Classic or acute CSC
is the most common form, consisting of a solitary, localized
neurosensory detachment in the posterior pole. A round to oval,
well-delineated, shallow serous retinal detachment elevates the
macula and blunts the normal foveal reflex (Fig. 142.1). This
blister of clear fluid has a characteristic halo formed by light
reflexes where the sloping retina reflects light back to the observer.
The size of the detachment can vary considerably, but the average
size is 2 disk diameters. Serous retinal pigment epithelial detach-
ments (PEDs) are also commonly seen in association with CSC
(Fig. 142.2). On biomicroscopy, a PED appears as a well-
circumscribed, orange-colored elevation with a slightly darker
rim that can illuminate with a slit beam aimed from the side. A
PED forms when the RPE cells, and their associated basement
membrane, separate from the underlying Bruch’s membrane.
These detachments are often less than 0.25 disk diameter, but
can be larger. Prominent PEDs are found in two other conditions
besides CSC: CNV, particularly occult CNV, and polypoidal
choroidal vasculopathy, a variant of CNV. Therefore, if turbid
fluid or subretinal blood is noted, the macular pathology is most
likely not CSC and is rather secondary to CNV.
Some patients may have the deposition of subretinal fibrin.
The subretinal fibrin is a grayish-white sheet overlying promi-
nent leaks. Frequently, there may be a concomitant underlying
PED with the fibrin accumulating radially around the top of
the PED making a ring appearance.
FLUORESCEIN ANGIOGRAPHIC FINDINGS
OF ‘CLASSIC’ CSC
Fluorescein angiography in acute cases of classic CSC demon-
strates one or several hyperfluorescent leaks at the level of the
RPE. Early in the angiogram, there is a focal dot-like hyper-
fluorescence representing the leakage of dye from the choroid
FIGURE 142.1. (a) Red-free photography
shows a trace amount of fluid. (b) OCT better
illustrates the presence of both subretinal fluid
(asterisk) and a small pigment epithelial
detachment (arrow).
c

a b
through the RPE. Later, dye accumulates beneath the sensory
retinal detachment but does not extend outside the borders of
the detachment. Two patterns of leakage occur. First, the classic
smokestack leak described by Shimizu and Tobari in 197137
occurs in the minority of cases (10%), but has a dramatic
appearance. The leakage first arises superiorly, resembling a
smokestack, and then plumes out laterally. This pattern is
thought to be related to convection currents and a protein
gradient, with protein concentration increasing in the fluid
accumulating under the neurosensory detachment.38 Smoke-
stack leaks are usually associated with larger areas of retinal
detachment. The second and more common pattern of dye
leakage, occurring in up to 90% of cases, is manifested as a
small dot leak with a uniform filling pattern within the
detachment (Fig. 142.3).
In both types of leakage patterns, focal leaks are somewhat
more common nasally than temporally, superiorly than
inferiorly.9,39 Most leaking points are in a ring 1 mm wide,
starting 0.5 mm from the center of the fovea, but can occur
further than 3 mm from the foveal avascular zone in 11.8% of
cases. The leakage point occurs in the fovea in less than
10% of cases and within the papillomacular bundle in 20–25%
of cases. If a leakage point is not readily apparent on fluorescein
angiography, the superior extramacular area should be inspected
carefully as gravity might cause a detachment below the leak. In
some cases, a leakage point will not be found because the leak
has healed. In these cases, the detachment will usually resolve
in days to weeks. Finally, other conditions such as exudative
age-related macular degeneration (AMD) may mimic CSC
clinically, and thus a leakage point will not be found.
a b
FIGURE 142.4. (a) Early phase; (b) mid phase; (c) late phase of ICG. ICG angiography demonstrates multiple patchy areas of choroidal
hyperpermeability, best seen in mid phase (b). These hyperpermeability regions may persist in chronic central serous even when there is no
active leakage on fluorescein angiography.
Central Serous Chorioretinopathy
FIGURE 142.3. (a) The typical pinpoint leak is
present on fluorescein angiogram. (b) Magnified
view of the macula shows a pigment epithelial
detachment resulting from the leak.
INDOCYANINE GREEN ANGIOGRAPHIC
CHAPTER 142
FINDINGS OF ‘CLASSIC’ CSC
Indocyanine green (ICG) angiography demonstrates multifocal
areas of choroidal vascular hyperpermeability (Fig. 142.4).40–42
These areas are best seen in the mid-phases of the angiogram,
and appear localized within the inner choroid. With time the
liver removes the ICG from the circulation, and the dye that has
leaked into the choroid appears to disperse somewhat, parti-
cularly into the deeper layers of the choroid.42 This produces a
characteristic appearance of larger but less prominent hyper-
fluorescent patches in the choroid with silhouetting of the larger
choroidal vessels in the later phases of the ICG angiographic
evaluation. Patients with CSC can actually present with no
fluorescein leakage during a quiescent phase, but will still have
areas of underlying choroidal vascular hyperpermeability that
serves as a marker of the disease. Younger patients may have
PEDs as a forme fruste of CSC in that underlying choroidal
hyperpermeability may cause elevations of the RPE without
creating breakthrough leaks.
AUTOFLUORESCENCE PATTERNS OF
CLASSIC CSC
Autofluorescence photography is a noninvasive test that pro-
vides functional images of the fundus based on stimulated
emission of light from lipofuscin and related molecules.
Lipofuscin, found within the RPE, is a cellular waste product
containing lipid, protein, and fluorophores such as A2E. Addi-
tional sources of autofluorescence are the precursors to A2E
c
1873
 RETINA AND VITREOUS
that accumulate in the outer retina prior to phagocytosis. These
A2E precursors increase in number if the outer segments are
not being phagocytized.
Autofluorescence images can be generated by excitation of
the fluorophores with light centered at 580 nm, detection above
695 nm with a barrier filter and recording by a Topcon 50µ
fundus camera. The filter combination ensures that autofluor-
escence from the natural crystalline lens is bypassed. Alter-
natively, a Heidelberg retina angiograph (HRA) can be used with
excitation at 488 nm and detection above 500 nm. HRA is based
on confocal imaging. The advantage of the confocal aspect is
that it allows the HRA system to reject lens autofluorescence.
The disadvantage of the confocal imaging is that it collects light
only from the RPE. If there is a retinal detachment, as in CSC,
the HRA does not record the light coming from the retina. With
a fundus camera, however, it is possible to see the autofluorescence
from the RPE and outer retina simultaneously. The resulting
autofluorescence photograph obtained with the fundus camera,
SECTION 10
therefore, is a summation of the autofluorescence from the
retina and underlying RPE. Visualization of the autofluorescent
signal depends on the distribution pattern of the fluorophore-
containing lipofuscin and A2E precursors. Autofluorescence
photography is important in CSC because it provides a non-
invasive technique to study the status of both the RPE and outer
retina and to assess atrophic changes.
Von Ruckman and Bird reported abnormalities of fundus
autofluorescence in a prospective study of 69 eyes with CSC.43
In this study, acute CSC was defined by a focal leak on angio-
graphy with serous retinal detachment or pigment epithelial
detachment. In the acute CSC eyes, increased autofluorescence
noted at the leakage site and in the area of retinal detachment
was attributed to increased metabolic activity of the RPE. In
longstanding lesions of acute or classic CSC patients, decreased
or absent autofluorescence was reported to indicate reduced
metabolic activity of the RPE due to photoreceptor cell loss.
A retrospective German study of 85 patients evaluated auto-
fluorescence changes in both acute and chronic CSC patients,
with acute defined as less than 6 weeks.44 The findings for the
acute patients were that 72% had decreased autofluorescence at
the leakage site and 77% had decreased autofluorescence in the
area of the neurosensory detachment. The authors suggest that
the hypoautofluorescence in the acute stage is due to blockage
caused by edema.
Our group’s case series evaluating autofluorescence in 58
eyes with CSC expanded on these previous studies by including
optical coherence tomography (OCT) analysis and statistical
measurement of autofluorescence values.45 The acute leaks of
classic CSC, if imaged within the first month, showed no apparent
abnormal autofluorescence other than a serous detachment of
the macula. Beyond 1 month, however, the area of detachment
showed increased autofluorescence in a diffuse pattern with
some subretinal granular deposits. OCT analysis demonstrated
that the hyperautofluorescent areas had material on the outer
surface of the retina. The thickness of the outer retinal material
was proportional to the amount of hyperautofluorescence. We
hypothesize that the material on the outer surface of the retina
represents accumulated photoreceptor outer segments secondary
to lack of direct apposition and phagocytosis by the RPE. Auto-
fluorescence, therefore, is not limited to RPE cells but can include
outer retina as well. Our study also indicated that measurement
of autofluorescence of the central macula is highly correlated with
visual acuity. While a healthy macula has a relatively uniform
distribution of autofluorescence, an unhealthy macula has more
variance related to cell injury and accumulation of abnormal
amount of fluorophores.
Autofluorescence photography, therefore, provides a noninvasive
1874 assessment of the status of the RPE and outer retina in CSC
patients. This imaging technique will not only scientifically
help us better understand the pathogenesis of CSC, but will also
clinically guide us in management of individual patients.
DIFFUSE RETINAL PIGMENT
EPITHELIOPATHY
A second principal presentation of CSC shows widespread
alteration of pigmentation of the decompensating RPE in the
posterior pole that appears to be related to the chronic presence
of subretinal fluid. This variant of CSC has been termed ‘DRPE’
or ‘chronic CSC’.42 Just as CSC has had many names during its
history, so has this more chronic variant. DRPE is related to not
only a past history of CSC, but also to the age of the patient
at the time of diagnosis.11 Patients with DRPE generally have a
more pronounced loss of visual acuity, and may have perma-
nent loss of visual acuity to the level of legal blindness.
OCULAR FINDINGS OF DRPE
Patients with DRPE have widespread disease. Close examin-
ation of the retina by slit-lamp biomicroscopy may show thin-
ning of the retina and possible cystic changes within the retina.
There are often RPE alterations that are manifest in three differ-
ent ways. First, the RPE can show atrophy where there is a loss
of pigmentation and increased visibility of the underlying larger
choroidal vessels. This atrophy is readily seen with autofluor-
escence photography. Second, the RPE can have areas of focal
hyperpigmentation. Finally, some patients may have RPE hyper-
plasia to the point where they develop bone spicules. Within the
detachment, the subretinal fluid is clear, but sometimes has
flecks of subretinal lipid. This feature may suggest the presence
of occult CNV when in fact the diagnosis is CSC. Because CNV
has a different course and treatment, great care must be made
in establishing the diagnosis of CSC in an older patient with
subretinal lipid. Broad areas of detachment in the posterior pole
are present and tracts of fluid may descend inferiorly toward the
equator. Yannuzzi and colleagues7 described 25 patients with
extramacular inferior hemispheric RPE atrophic tracts related to
an antecedent retinal detachment. Five of these patients
actually had a peripheral retinal detachment.
ANGIOGRAPHIC FINDINGS OF DRPE
The various diffuse areas of altered RPE are readily apparent on
fluorescein angiography. These areas have a granular hyper-
fluorescence due to relative atrophy of the involved RPE and
associated subtle, indistinct leaks (Fig. 142.5). There may be
dependent retinal detachments into the inferior fundus with
associated atrophic tracts of the RPE.7 Capillary telangiectasis,
capillary nonperfusion,46 and secondary neovascularization
associated with the chronic detachments may occur. Because of
the widespread pigmentary alterations and chronically reduced
visual acuity, these patients are sometimes misdiagnosed as having
an inherited retinal or macular dystrophy. ICG angiography of
DRPE shows the same type of widespread choroidal vascular
hyperpermeability as patients with typical CSC have, except the
number and area of hyperpermeability seems to be greater in
patients with DRPE.
AUTOFLUORESCENCE PATTERNS OF DRPE
Autofluorescence imaging of DRPE patients varies according to
the degree of cellular injury. Von Ruckman and Bird43 concluded
in their study that decreased or absent autofluorescence within
longstanding lesions indicates reduced metabolic activity of the
RPE due to photoreceptor cell loss. A German study44 reported

a b
that the irregular and increased autofluorescence changes
observed among their chronic patients is reflective of RPE
reactive changes.
Our study of 58 eyes45 helps explain the varying patterns of
hyper- and hypo-autofluorescence seen in chronic CSC. The
descending atrophic tracts often seen in DRPE have character-
istic patterns. Tracts of more recent origin and the outer edge of
more chronic descending tracts exhibit hyperautofluorescence,
reflecting the increased lipofuscin within the RPE and A2E
products within the outer retina. Patients with a history of CSC
that has been quiescent for many years have only hypoauto-
fluorescent areas, indicative of the RPE atrophy. Autofluor-
escence photography, therefore, provides a noninvasive tool to
monitor cellular function in CSC patients and indirectly
determine visual prognosis (Figs 142.6 and 142.7).
BULLOUS DETACHMENT OF THE RETINA
SECONDARY TO CSC
There is an additional, but rare, form of CSC that causes
bullous retinal detachments. Although most patients with CSC
FIGURE 142.6. This autofluorescence photograph taken with a
Topcon 50µ camera illustrates the diffuse decompensation of the RPE
seen in chronic CSC.
Central Serous Chorioretinopathy
FIGURE 142.5. (a and b). As CSC becomes
chronic, the hyperfluorescence on fluorescein
angiography loses its pinpoint character and
becomes more diffuse.
have one to three leaks seen during fluorescein angiography,
some patients in an unusually severe variant have numerous
CHAPTER 142
exuberant leaks, multiple PEDs, and bullous retinal detach-
ments that extend into the inferior periphery of the fundus.47
These detachments are often associated with subretinal
fibrinous exudates and shifting subretinal fluid. Several reports
of this condition originated in Japan, where this variant seems
more common.41,46,48 Bullous serous retinal detachments also
have been reported in organ transplant patients.49 Patients with
bullous detachment have the same findings during ICG angio-
graphy as the patients with classic CSC and DRPE, except the
number and size of choroidal hyperpermeability areas are greater.
An observational case series of 25 patients showed that this
severe variant can occur in both healthy patients (21/25) and
patients treated with corticosteroids for metabolic or auto-
immune disease (4/25).50 Bilaterality is the norm (84%). While
some of the patients initially presented with bullous changes,
others converted from classic CSC (36%). The conversion time
ranged from 7 months to 9 years after onset. Recurrence rate
FIGURE 142.7. This autofluorescence photograph taken with a
Topcon 50µ camera shows dark hypoautofluorescent descending
tracts reflecting the atrophic patterns resulting from inferiorly
gravitating fluid. 1875
 RETINA AND VITREOUS
was as high as 52% in this study, but 80.4% recovered central
visual acuity of 20/40 or better. Those patients who experienced
visual loss greater than 20/40 had macular damage.
SUBRETINAL DEPOSITS
Patients with CSC, of any variety, may have deposition of sub-
retinal material that occurs in four forms:17,51 fibrin (see section
on Ocular Findings of Classic CSC), lipid, macrophages, and
outer photoreceptor segments. Subretinal lipid is usually found
in chronic CSC in older patients and appears as discrete, hard-
edged, subretinal accumulations typically at the borders of a
neurosensory detachment. This older age group is at risk for
CNV, which is a more common disorder causing subretinal lipid.
Because CNV has a different course and treatment, great care
must be exercised in establishing the diagnosis of CSC in an
older patient with subretinal lipid.
Diffuse deposition of macrophages and outer photoreceptor
SECTION 10
segments gives the appearance of outer retinal small dots on
ophthalmoscopy. This can be seen in almost every patient with
CSC lasting more than a few months. Pronounced accumulation
of material may even produce the appearance of diffuse yellow
flecks in some patients. Because of the subretinal deposits,
some of these patients have been initially suspected of having
retinitis, choroidal tumors, or CNV. Based on autofluorescence
studies,45 the material on the outer surface of the elevated
retina may perhaps represent an accumulation of photoreceptor
outer segments secondary to lack of phagocytosis, given that the
RPE in these cases is not in direct apposition with the retina.
Interestingly, the granular dots may vary in number, but do not
vary in size. This uniformity of size and their autofluorescent
nature suggest that these dots may be macrophages, engorged with
phagocytized outer segments. The occasional yellow fleck
appearance is explained by the lutein component of outer
photoreceptor segments.52
OPTICAL COHERENCE TOMOGRAPHY
IN CSC
OCT provides anatomical information in all types of CSC. A
Spanish study compared conventional OCT findings with
fluorescein angiographic patterns in 39 eyes with CSC.53 The
authors report that 36 eyes had an optically empty vaulted area
under the neurosensory retina consistent with detachment that
related to fluorescein-filled areas. Thirty-five eyes had highly
characteristic small bulges protruding from the RPE, angiogra-
phically related to leaking spots. Three eyes showed an almost
semicircular space under the RPE, with thinner overlying retina.
Additionally, our group’s study showed that conventional OCT
is useful for detecting subclinical cystoid macular degeneration
or foveal atrophy.54 OCT, therefore, provides a noninvasive imag-
ing test complementary to fluorescein angiography.
A study of 38 CSC eyes with OCT ophthalmoscope producing
en face OCT scans (OCT C-scans) provides information beyond
conventional OCT.55 In this study, active CSC was associated
with large neurosensory detachment (23/29), subretinal hyper-
reflective deposits (20/29), and pigment epithelial detachment
(15/29). Multiple small PEDs located both within and outside
the neurosensory detachment were detected in one-third of the
patients with either active or inactive CSC.
In a retrospective study of unilateral resolved CSC,56 the
involved eyes had a decrease in central foveal thickness which
had a statistically significant correlation with visual acuity. The
foveal thickness of the eye with resolved CSC was normalized
by dividing its thickness by that of the uninvolved eye. Addi-
tional factors on OCT associated with poorer visual acuity were
1876
the inability to visualize the external limiting membrane or the
boundary between photoreceptor bodies and outer segments.
DIFFERENTIAL DIAGNOSIS
Although the clinical and fluorescein angiographic features of
CSC are often classic, several entities should be considered in
the differential diagnosis: CNV, tumors, inflammatory disorders,
vascular pathology and rhegmatogenous retinal detachment can
sometimes have similar clinical characteristics to CSC. Careful
biomicroscopy and fundus imaging, however, allows for the
correct diagnosis.
The principal condition that needs to be differentiated from
CSC is CNV, particularly occult CNV. The ocular findings of
CNV share many similarities with those of CSC. Both groups
of patients may have neurosensory detachments, PEDs, mottled
depigmentation, hyperpigmentation, areas of RPE atrophy, and
subretinal deposits of fibrin and lipid.11 Patients with CNV,
however, have thickening at the level of the RPE, notched PEDs
and subretinal or subpigment epithelial blood. These findings
are not seen in CSC. In addition, eyes with CNV generally have
coexistent ocular findings related to the generation of new blood
vessel growth. These factors include punched-out chorioretinal
scars in ocular histoplasmosis syndrome, lacquer cracks, and
areas of choroidal atrophy in pathological myopia, breaks in
Bruch’s membrane in cases of choroidal rupture, and drusen
and pigmentary clumping in patients with age-related macular
degeneration. The CNV secondary to proximal causes such as
chorioretinal scars or choroidal ruptures generally has ‘classic’
findings on fluorescein angiography. These cases demonstrate a
lacy vascular pattern of hyperfluorescence with increasing
leakage and staining throughout a fluorescein angiographic
evaluation. Occasionally a specific feeder vessel can be seen
extending from the chorioretinal scar. The fluorescein angio-
graphic findings of exudative age-related macular degeneration
may be more difficult to differentiate from CSC because the
majority of AMD leakage is occult CNV. ICG angiography of
CSC demonstrates multifocal, and usually bilateral, choroidal
vascular hyperpermeability that has specific temporal and
topographical characteristics. The hyperpermeability in CSC is
most evident in the mid-phases of the angiographic evaluation.
The later phases of ICG angiography show dispersion of the dye
with negative staining of the larger choroidal vessels. CNV, on
the other hand, shows a unilateral, unifocal area of hyperfluor-
escence that usually shows progressively increasing contrast
with the surrounding choroid in the later phases of the angio-
gram. ICG angiography may provide important information to
help rule out the presence of occult CNV. Also, repeating the
fluorescein angiogram 2–3 weeks later may be helpful as CNV
may become more apparent with time.
Tumors and infiltrative conditions, such as leukemia, amela-
notic melanoma, or metastatic disease, can also appear similar to
CSC. Clinical examination, however, shows that these infiltra-
tive lesions generally have a different color than the surrounding
normal choroid, demonstrate thickening of the choroid by ultra-
sonography, and do not have serous PEDs. Inflammatory con-
ditions with serous retinal detachments can also masquerade as
CSC, but clinical diagnostic clues exist. For example, eyes
affected with posterior scleritis or Harada’s disease show signs
of intraocular inflammation such as iritis or vitritis, have patches
of yellowish discoloration in the posterior pole, demonstrate
staining of the optic nerve head during fluorescein angiography,
and have thickening of the choroid by ultrasonography. These
findings are not seen in CSC. Extraocular symptoms, such as
meningeal signs including headache, neck stiffness, and
vomiting, are common in Harada’s disease but not in CSC.

Anatomical changes can also complicate the picture. For exam-
ple, patients with optic nerve pits may have a serous detachment
of the macula that may appear similar to CSC. Fortunately, the
optic nerve pathology is generally readily visible. Also, the macu-
lar elevation due to optic nerve pits differs from CSC because it
is generally a bilayer detachment caused by retinoschisis in the
macula. There are no leaks from the level of the RPE during fluor-
escein angiography in patients with optic nerve pits. Another
anatomical abnormality that can mimic CSC is rhegmatogenous
retinal detachments. They may cause elevation of the macula like
CSC, but differ in that they have an associated retinal hole or tear
and do not have leaks visible during fluorescein angiography.
Vascular disorders are also in the differential diagnosis.
Malignant hypertension can produce a serous retinal detachment.
The presence of systemic hypertension, Elschnig’s spots, shifting
fluid, and choroidal or retinal vasculature changes, or both, can
distinguish it from CSC. Serous retinal detachment can occur
in toxemia of pregnancy. The systemic findings of hypertension,
proteinuria, and edema will separate this condition from CSC
seen in pregnant women. Disseminated intravascular coagulo-
pathy should also be considered in the differential diagnosis of
serous retinal detachment and can be distinguished by its sys-
temic findings.
PATHOPHYSIOLOGY
Multiple theories of pathophysiology exist and continue to
evolve as we understand the disease better. Fluorescein angio-
graphy contributed to the current pathogenesis concept. With
the advent of this retinal imaging test, ophthalmologists had a
more precise method of diagnosing and evaluating CSC. Fluor-
escein angiography demonstrates one or more sites of leakage in
cases of active CSC. With cessation of these leaks, the detach-
ment regresses. This suggested, at least to some observers, that
the leak seen during fluorescein angiography represented fluid
coming from the choroid into the subretinal space through a
precisely located defect in the RPE. The fluorescein, contained
in the choroidal fluid, was brought into the subretinal space with
the bulk fluid flow going from the choroid toward the retina.
The balance of the tissue oncotic and hydrostatic pressures
ordinarily causes fluid flow from the retina towards the choroid.
In experimental models, injury or destruction of the RPE was
seen to speed up the resorption of subretinal fluid.57 These
findings suggested that an isolated defect in the RPE could not
account for the findings seen in CSC, but rather that more
diffuse RPE abnormalities would be required to overcome the
RPE pumping function. To clarify the pathophysiology of CSC,
several newer theories were postulated based in part on findings
from animal models. One theory stated that what appeared to
be leaks at the level of the RPE were in fact not necessarily
active leaks, but were areas where dye diffused into the sub-
retinal space.58 The neurosensory detachment was thought to
be secondary to widespread areas of RPE dysfunction. This theory,
however, did not clearly elucidate why the areas of RPE dysfunc-
tion occurred or why CSC spontaneously improves, as it fre-
quently does. This theory also did not explain why patients
with CSC frequently develop PEDs, or why laser treatment to a
‘leak’ causes a rapid resolution of the neurosensory detachment.
Another theory suggested that a focus of RPE cells, losing their
normal polarity, pumps fluid from a choroid to retina direction,
causing a neurosensory detachment.59 Yet this theory could neither
explain the presence of PEDs and subretinal fibrin nor how a
few RPE cells pumping in the wrong direction could overcome
the pumping ability of broad areas of surrounding RPE cells.
Integration of the clinical findings of CSC with the ICG angio-
graphic abnormalities of the choroidal circulation in patients
Central Serous Chorioretinopathy
with CSC led to new theoretical considerations. During ICG
angiography, the choroidal circulation appears to have multi-
focal areas of hyperpermeability.40,42,60–63 These areas of hyper-
permeability may arise from venous congestion. Excessive
tissue hydrostatic pressure within the choroid from the vascular
hyperpermeability may lead to PEDs, disruption of the retinal
pigment epithelial barrier, and abnormal egress of fluid under
the retina. In past studies, leaks demonstrable at the level of the
RPE invariably are contiguous with areas of choroidal vascular
hyperpermeability.40,42,60–63 On the other hand, most areas of
hyperpermeability are not associated with actual leaks. These
areas of hyperpermeability without leaks may affect the size,
shape, and chronicity of any overlying neurosensory detachment
by inducing changes in the ability of the overlying RPE to pump.
Theoretical considerations about why the choriocapillaris
would develop increased permeability have been described else-
where. Increased circulating epinephrine and norepinephine
levels have been found in patients with CSC. Administration of
CHAPTER 142
sympathomimetic compounds has been associated with CSC in
humans. A CSC-like condition exists in monkeys given both
sympathomimetic agents and corticosteroids. It is possible to
postulate that sympathomimetic compounds or corticosteroids,
either endogenous or exogenous, alter the permeability of the
choriocapillaris directly, or through secondary means such as
affecting choroidal vasculature autoregulation. Although the rate
of developing CSC with corticosteroid use is not known, CSC is
a relatively common disease. Clearly, systemic administration
of cortiosteroids can lead to CSC, but local administration does
not appear to do so with anywhere near the same frequency.
Although there has been one isolated case report of CSC
following intravitreal triamcinolone acetonide for diabetic
macular edema,28 the author has given hundreds of intravitreal
steroid injections to patients and has not seen one case of CSC.
Perhaps systemic administration causes particular physiologic
alterations not as readily induced by local application.
HISTOPATHOLOGY OF CSC
There exists only limited histopathologic information on CSC.
Neurosensory detachment with subretinal and subpigment
epithelial deposition of fibrin has been reported. A model of
exudative detachment has been produced in monkeys with
repeated injection of corticosteroids and epinephrine.64–67 In
their monkey model of CSC, Yoshioka and Katsume31 described
a focal area of degenerated RPE with adjacent damaged chorio-
capillaris endothelial cells. These endothelial abnormalities
were sealed by platelet-fibrin clots. Some dispute the validity of
Yoshioka’s animal model and suggest the monkeys likely had
accelerated hypertension rather than just simple CSC.
OCT, thanks to its high resolution, can effectively provide
optical biopsies. Although OCT has been commonly used to
determine the presence of subretinal fluid, it can provide even
more useful information. Retinal atrophy has been seen in some
patients. In addition, the ability to visualize finer anatomic
details such as the external limiting membrane was much less
in patients with lower levels of visual acuity, suggesting that
anatomic alterations occur that are associated with decreased
acuity.56 Patients with a history of chronic detachment and poor
visual acuity after reattachment may have cystoid spaces within
the retina, a condition that has been termed cystoid macular
degeneration.54
NATURAL COURSE
Most patients with CSC spontaneously resolve and experience
an almost complete restoration of vision. In the series of Klein
1877
 RETINA AND VITREOUS
and colleagues,68 resolution was noted in all 34 eyes studied
prospectively without any treatment. The average resolution
time in this study was 3 months. All patients had visual acuity
of 20/40 or better, and 94% of the eyes had visual acuity of
20/30 or better at follow-up examination (average 23 months).
However, even if patients do recover Snellen visual acuity,
many still complain of decreased color vision, relative scotomas,
micropsia, metamorphopsia, decreased contrast sensitivity, and
nyctalopia in the affected eye. Some may even notice a slight
distortion in their central vision. Although these patients have
resolution of their neurosensory detachment, they regain only
part of their central vision because they have suffered photo-
receptor damage, atrophy, irregular RPE pigmentation, or
subretinal fibrosis.
Recurrence of CSC is a problem, affecting 40–50% of
patients.10,68 Some of these patients will go on to have recurrent
focal leaks while others will inexorably progress to the more
visually threatening DRPE. Recurrences can occur many years
SECTION 10
later. The recurrent leakage point is within 1 mm of the initial
leakage point in 80% of patients.9,l0 Secondary CNV may occur,
particularly in patients over 50 years of age.11
TREATMENT
Each treatment technique for CSC has been based to a certain
extent on proposed mechanisms of pathophysiology at the time.
The resultant treatment approaches for CSC have been varied
and have usually been examined as part of uncontrolled studies.
No medical therapy has been shown to be effective for patients
with CSC. Tranquilizers, sedatives, and barbiturates have been
advocated to decrease the psychogenic component of this dis-
order, but their efficacy has not been demonstrated. Because of
the suggestion that CSC may be related to abnormal levels of
circulating epinephrine, the use of b-blockers has been suggested
as a treatment. A small study suggested a possible benefit,69 but
the findings have not been confirmed with either a larger study
or a randomized trial. Epinephrine stimulates a and b receptors;
blocking only b receptors would allow unopposed a stimulation.
This might produce unwanted vascular constriction. If a patient
is on corticosteroids, the medical treatment includes withdrawal
of the drug. Ketoconazole has been shown to reduce endogenous
corticosteroid levels and is a theoretical treatment, but no study
regarding this treatment is published at this time. Currently, no
randomized controlled study has shown any drug to be useful in
the treatment of CSC.
PHOTOCOAGULATION THERAPY
Laser photocoagulation is the most commonly studied modality
in the treatment of CSC. The principal goal of this treatment is
to reduce the leakage through the RPE and cause resolution of
the subretinal fluid with improvement in visual acuity. Laser
photocoagulation to the site of leakage seen during fluorescein
angiography shortens the duration of macular detachment in
patients with typical CSC, but does not appear to affect the final
visual acuity.70–75 Similarly for DRPE, thermal grid laser to an
area with small leaks appeared to cause a decrease in the
amount of subretinal fluid present,76 but did not cause a long-
term change in the visual acuity. The effect of laser treatment
on the rate of recurrence is inconclusive as it reduced the rate of
recurrence in some studies,74,75 but not in others.70,71,73 For the
severe bullous variant, laser photocoagulation did not confer
any significant advantage in terms of temporal resolution of
serous retinal detachment or final visual acuity outcome.77
Potential dire side effects of photocoagulation include CNV,
scotoma, and RPE scar expansion.
1878
When is it appropriate to laser photocoagulate CSC? Because
of the unfavorable risk–benefit ratio, laser photocoagulation
generally is reserved for patients with the following criteria:
symptoms greater than 4 months, leakage sites located greater
than 375 mm from fixation, a history of CSC in the fellow eye
with an unfavorable outcome, and the need or desire for treat-
ment. If the leak is located well away from the central macula,
then there is less reason to hesitate about laser photocoagula-
tion. A detailed biomicroscopic examination and fluorescein
angiogram is essential to monitor for CNV. If laser is initiated,
it is imperative that the patient understands that treatment
only shortens the duration of the disease and does not affect the
final visual acuity or recurrence rate.
METHODS OF PHOTOCOAGULATION
Laser photocoagulation should be performed to the leakage site
with low-intensity energy. The laser is set for a spot size of
100–200 mm, power of 100–150 mW, with application time of
0.1–0.2 s. With a recent angiogram as guidance, the more
peripheral leaks are treated first. The amount of laser uptake is
affected by several variables. These include the amount of
subretinal fluid present, the degree of pigmentation of the RPE,
which is variably pigmented in areas of chronic subretinal fluid,
the degree of RPE detachment, and the wavelength of laser
used. The leakage point is treated as well as a small sur-
rounding region of normal RPE. Great care should be taken to
obtain only a dull gray coagulation to avoid the possibility of
secondary CNV.
The patient should be monitored carefully to assess for
recurrence or laser-induced complications. The subretinal fluid
generally takes a few weeks to resorb. The visual symptoms start
to abate with diminution of the subretinal fluid, but the time it
takes for the patient to regain final visual acuity seems proportional
to the amount of time the retina was detached. The initial
follow-up examinations are to evaluate the patient for CNV.
If hemorrhage, increased turbidity of the subretinal fluid, or
thickening at the level of the RPE in or adjacent to the area of
laser treatment is noted, secondary CNV should be suspected.
The patient should have a repeat fluorescein angiogram at that
point to help in establishing the diagnosis. Secondary CNV
generally causes a nodular or crescent-shaped area of hyper-
fluorescence under or adjacent to the area of previous laser photo-
coagulation. If the original site of treatment was sufficiently
extrafoveal, it is possible to discover and treat secondary CNV,
in many cases, before the neovascularization extends under the
fovea. The CNV may be treated with either thermal laser, if
sufficient room exists, or with photodynamic therapy (PDT).
PHOTODYNAMIC THERAPY
PDT is a newer treatment modality for CSC. While the thera-
peutic mechanism of PDT is known for the CNV in age-related
macular degeneration, it is not known for CSC. Studies have
shown that PDT may be useful for treatment of DRPE, and
even acute classical CSC in certain circumstances.
DRPE is a challenge to treat because of the wide distribution
of multiple indistinct leaks. Several groups have investigated
the use of PDT with verteporfin for more chronic forms of
CSC.78–80 Generally PDT causes the subretinal fluid to decrease
or resolve completely. Recurrences of subretinal fluid do occur,
but they are responsive to retreatment with PDT. Pigmentary
changes persist, however, so earlier treatment is desired.
Our group conducted a study of ICG angiography-guided
PDT of 20 chronic CSC eyes in which we found an inverse
correlation between baseline visual acuity at the time of treatment
 Central Serous Chorioretinopathy

initiation and improvement of visual acuity afterwards.79 The
location of laser light application, in our study, was based on
regions of choroidal vascular hyperpermeability seen during
ICG angiography that were responsible for the fluid leakage into
the macula. In typical clinical practice, conventional fluorescein
angiography may be used in lieu of ICG as it provides sufficient
useful information. Safety precautions include avoidance of
directly treating the central fovea to help reduce the possibility
of inducing foveal atrophy with the PDT. Although we used
the usual dose of verteporfin, it may be possible to reduce the
dosage, possibly resulting in decreased costs.
On occasion PDT has been used for typical acute leaks.
Because of the high cost of PDT, its use has typically been
limited in classic CSC to those patients with focal leaks near
the center of the fovea where laser photocoagulation may induce
excessive harm. Our group conducted a small case series of focal
RPE leaks treated with PDT.81 No areas of hyperpermeability
distant from the RPE leak were included in the treatment. All
nine eyes showed resolution of both fluorescein leakage and
anatomic macular fluid. Visual acuity improved in seven eyes
and remained the same in two eyes. There were no adverse
events. Interestingly, many of the study cases treated did not
have ICG. The leak plus 1 mm was treated in these patients
and the clinical results showed resolution of the leakage and
fluid. Therefore, it probably is not necessary to treat the hyper-
permeable area as delineated by ICG for acute leaks. Although
our case series suggests that PDT with verteporfin can lead to
resolution of focal RPE leaks in CSC, the study is limited by its
small size, retrospective nature, and lack of a control group to
help ascertain if the resolution was due to the PDT or the
natural disease course.

REFERENCES
1. von Graefe A: Ueber centrale recidivierende
Retinitis. Graefes Arch Clin Exp Ophthalmol
1866; 12:211–215.
2. Horniker E: Su di una forma retinite
centrale di origine vasoneurotica (retinite
central capillaro spastica). Ann Ottal 1927;
55:578–600.
3. Gifford SR, Marquardt G: Central
angiospastic retinopathy. Arch Ophthalmol
1939; 21:211–228.
4. Bennett G: Central serous retinopathy.
Br J Ophthalmol 1955; 39:605–618.
5. Maumenee AE: Symposium: macular
diseases, clinical manifestations. Trans Am
Acad Ophthalmol Otolaryngol 1965;
69:605–613.
6. Gass JDM: Pathogenesis of disciform
detachment of the neuroepithelium. II.
Idiopathic central serous choroidopathy.
Am J Ophthalmol 1967; 63:587–615.
7. Yannuzzi L, Shakin J, Fisher Y, et al:
Peripheral retinal detachment and retinal
pigment epithelial atrophic tracts
secondary to central serous pigment
epitheliopathy. Ophthalmology 1984;
91:1554–1572.
8. Spaide RF: Central serous
chorioretinopathy and other causes of
serous detachment of the retina. In: Spaide
RF, ed. Diseases of the retina and vitreous.
Philadelphia, PA: W.B. Saunders Co.; 1999.
9. Spitznas M, Huke J: Number, shape, and
topography of leakage points in acute type
I central serous retinopathy. Graefes Arch
Clin Exp Ophthalmol 1987; 225:438–440.
10. Gilbert CM, Owens SL, Smith PD, Fine SL:
Long-term follow-up of central serous
chorioretinopathy. Br J Ophthalmol 1984;
68:815–820.
11. Spaide RF, Campeas L, Haas A, et al:
Central serous chorioretinopathy in younger
and older adults. Ophthalmology 1996;
103: 2070–2080.
12. Tittl MK, Spaide RF, Wong D, et al:
Systemic and ocular findings in central
serous chorioretinopathy. Am J Ophthalmol
1999; 128:63–68.
13. Haimovici R, Koh S, Gagnon DR: Risk
factors for central serous chorioretinopathy:
a case-control study. Ophthalmology 2004;
111:244–249.
14. Fine SL, Owens SL: Central serous
retinopathy in a 7-year-old girl. Am J
Ophthalmol 1980; 90:871–873.
15. Desai UR, Alhalel AA, Campen TJ, et al:
Central serous chorioretinopathy in African
Americans. J Natl Med Assoc 2003;
95:553–559.
16. Spitznas M: Central serous retinopathy. In:
Ryan SJ, ed. Retina. St Louis, MO: CV
Mosby; 1989: 217–227.
17. Gass JDM: Central serous
chorioretinopathy and white subretinal
exudation during pregnancy. Arch.
Ophthalmol 1991; 109:677.
18. Karadimas P, Bouzas EA: Glucocorticoid
use represents a risk factor for central
serous chorioretinopathy: a prospective,
case-control study. Graefes Arch Clin Exp
Ophthalmol 2004; 122:784–786.
19. Polak BC, Baarasma GS, Snyers B: Diffuse
retinal pigment epitheliopathy complicating
systemic corticosteroid treatment. Br J
Ophthalmol 1995; 79:922–925.
20. Gass JD, Little H: Bilateral bullous
exudative retinal detachment complicating
idiopathic central serous chorioretinopathy
during systemic corticosteroid therapy.
Ophthalmology 1995; 102:737–747.
21. Gass JDM, Slamovits TL, Fuller DG, et al:
Posterior chorioretinopathy and retinal
detachment after organ transplantation.
Arch Ophthalmol 1992; 110:1717–1722.
22. Iida T, Spaide RF, Haas A, et al: Leopard-
spot pattern of yellowish subretinal
deposits in central serous
chorioretinopathy. Arch Ophthalmol 2002;
120:37–42.
23. Haimovici R, Gragoudas E, Duker J, et al:
Central serous chorioretinopathy
associated with inhaled or intranasal
corticosteroids. Ophthalmol 1997;
104:1653–1660.
24. Fernandez C, Mendoza A, Arevola J:
Central serous chorioretinopathy
associated with topical dermal
corticosteroids. Retina 2004; 24:471–474.
25. Karadimas P, Kapetanios A, Bouzas E:
Central serous chorioretinopathy after local
application of glucocorticoids for skin
disorders. Arch Ophthalmol 2004;
122:784–786.
26. Williamson J, Nuki G: Macular lesions during
systemic therapy with depot tetracosactrim.
Br J Ophthalmol 1970; 54:405–409.
27. Imasawa M, Ohshiro T, Gotoh T, et al:
Central serous chorioretinopathy following
vitrectomy with intravitreal triamcinolone
CHAPTER 142
acetonide for diabetic macular oedema.
Acta Ophthalmol Scand 2005; 83:132–133.
28. Baumal C, Martidis A, Truong S: Central
serous chorioretinopathy associated with
periocular corticosteroid injection treatment
for HLA-B27-associated iritis. Arch
Ophthalmol 2004; 122:926–928.
29. Haimovici R, Rumelt S, Melby J: Endocrine
abnormalities in patients with central
serous chorioretinopathy. Ophthalmology
2003; 110:698–703.
30. Yoshioka H, Katsume Y, Akune H:
Experimental central serous
chorioretinopathy in monkey eyes:
fluorescein angiographic findings.
Ophthalmologica 1982; 185:168–178.
31. Yoshioka H, Katsume Y: Experimental
central serous chorioretinopathy. III.
Ultrastructural findings. Jpn J Ophthalmol
1982; 26(4):397–409.
32. Michael JC, Pak J, Pulido J, de Venecia G:
Central serous chorioretinopathy
associated with administration of
sympathomimetic agents. Am J
Ophthalmol 2003; 136:182–185.
33. Sun J, Tan J, Wang Z, et al: Effect of
catecholamine on central serous
chorioretinopathy. J Huazhong Univ Sci
Technolog Med Sci 2003; 23:313–316.
34. Gelber GS, Schatz H: Loss of vision due to
central serous chorioretinopathy following
psychological stress. Am J Psychiatry
1987; 144:46–50.
35. Yannuzzi L: Type A behavior and central
serous chorioretinopathy. Trans Am
Ophthalmol Soc 1986; 84:799–845.
36. Werry H, Arends C: Untersuchung zur
Objektivierung von
Personlichkeitsmerkmalen bei Patienten mit
Retinopathia centralis serosa. Klin
Monatsbl Augenheilkd 1978; 172:363–370.
37. Shimizu K, Tobari I: Central serous
retinopathy dynamics of subretinal fluid.
Mod Probl Ophthalmol 1971; 9:152–157.
38. Shimizu K, Tobari I: Central serous
retinopathy dynamics of subretinal fluid.
Mod Probl Ophthalmol 1971; 9:152–157.
39. Vukojevic N, Sikic J, Katusic D, et al: Types
of central serous retinopathy, analysis of
shape, topographic distribution and
number of leakage sites. Coll Antropol
2001; 25(Suppl):83–87.
40. Prunte C, Flammer J: Choroidal capillary
and venous congestion in central serous
1879
 RETINA AND VITREOUS
chorioretinopathy. Am J Ophthalmol 1996;
121:26–34.
41. Okushiba U, Takeda M: Study of choroidal
vascular lesions in central serous
chorioretinopathy using indocyanine green
angiography. Nippon Ganka Gakkai Zasshi
1997; 101:74–82.
42. Spaide RF, Hall L, Haas A, et al:
Indocyanine green videoangiography of
central serous chorioretinopathy in older
adults. Retina 1996; 16:78–80.
43. von Ruckmann A, Fitzke F, Fan J, et al:
Abnormalities of fundus autofluorescence
in central serous retinopthy. Am J
Ophthalmol 2002; 133:780–786.
44. Framme C, Walter A, Gabler B, et al:
Fundus autofluorescence in acute and
chronic-recurrent central serous
chorioretinopathy. Acta Ophthalmol Scand
2005; 83:161–167.
45. Spaide RF, Klancnik JM: Fundus
SECTION 10
autofluorescence and central serous
chorioretinopathy. Ophthalmolology 2005;
112:825–833.
46. Akiyama K, Kawamura M, Ogata T,
Tanaka E: Retinal vascular loss in idiopathic
central serous chorioretinopathy with
bullous retinal detachment. Ophthalmology
1987; 94:1605–1609.
47. Gass JDM: Bullous retinal detachment: an
unusual manifestation of idiopathic central
serous choroidopathy. Am J Ophthalmol
1973; 75:810.
48. Tsukahara I, Uyama M: Central serous
choroidopathy with bullous retinal
detachment. Abrecht Von Graefes Arch Klin
Exp Ophthalmol 1978; 206:169–178.
49. Friberg TR, Eller AW: Serous retinal
detachment resembling central serous
chorioretinopathy following organ
transplantation. Graefes Arch Clin Exp
Ophthalmol 1990; 228:305–309.
50. Otsuka S, Ohba N, Nakao K: A long-term
follow-up study of severe variant of central
serous chorioretinopathy. Retina 2002;
22:25–32.
51. Ie D, Yannuzzi LA, Spaide RF, et al:
Subretinal exudative depostis in central
serous chorioretinopathy. Br J Ophthalmol
1993; 77:349–353.
52. Rapp LM, Maple SS, Choi JH: Lutein and
zeaxanthin concentrations in rod outer
segment membranes from perifoveal and
peripheral human retina. Invest Ophthalmol
Vis Sci 2000; 41(5):1200–1209.
53. Montero J, Ruiz-Moreno J: Optical
coherence tomography characterisation of
idiopathic central serous chorioretinopathy.
Br J Ophthalmol 2005; 89:562–564.
54. Iida T, Yannuzzi L, Spaide R, et al: Cystoid
macular degeneration in chronic central
1880
serous chorioretinopathy. Retina 2003;
23:1–7; quiz 137–138.
55. van Velthoven M, Verbraak F, Garcia P,
et al: Evaluation of central serous
retinopathy with en face optical coherence
tomography. Br J Ophthalmol 2005;
89:1483–1488.
56. Eandi CM, Chung JE, Cardillo-Piccolino F,
et al: Optical coherence tomography in
unilateral resolved central serous
chorioretinopathy. Retina 2005;
25:417–421.
57. Negi A, Marmor MF: The resorption of
subretinal fluid after diffuse damage to the
retinal pigment epithelium. Invest
Ophthalmol Vis Sci 1983; 24:1475–1479.
58. Marmor MF: New hypotheses on the
pathogenesis and treatment of serous
retinal detachment. Graefes Arch Clin Exp
Ophthalmol 1988; 226:548–552.
59. Spitznas M: Pathogenesis of central serous
retinopathy: a new working hypothesis.
Graefes Arch Clin Exp Ophthalmol 1986;
224:321–324.
60. Hayashi K, Hasegawa Y, Tokoro T:
Indocyanine green angiography of central
serous chorioretinopathy. Int. Ophthalmol.
1986; 9:37–341.
61. Scheider A, Nasemann JE, Lund OE
Fluorescein and indocyanine green
angiographies of central serous
choroidopathy by scanning laser
ophthalmoscopy. Am J Ophthalmol 1993;
115:50–56.
62. Piccolino FC, Borgia L: Central serous
chorioretinopathy and indocyanine green
angiography. Retina 1994; 14:231–242.
63. Guyer DR, Yannuzzi LA, Slakter JS, et al:
Digital indocyanine green videoangiography
of central serous chorioretinopathy. Arch
Ophthalmol 1994; 112:1057–1062.
64. Nagayoski K: Experimental study of
chorioretinopathy by intravenous injection
of adrenaline. Acta Soc Ophthalmol Jpn
1971; 75:1720–1727.
65. Miki T, Sunada I, Higaki T: Studies on
chorioretinitis induced in rabbits by stress
(repeated administration of epinephrine).
Acta Soc Ophthalmol Jpn 1972;
75:1037–1045.
66. Yasuzumi T, Miki T, Sugimoto K: Electron
microscopic studies of epinephrine
choroiditis in rabbits. I. Pigment epithelium
and Bruch’s membrane in the healed stage.
Acta Soc Ophthalmol Jpn 1974;
78:588–598.
67. Yoshioka H, Sugita T, Nagayoski K:
Fluorescein angiography findings in
experimental retinopathy produced by
intravenous adrenaline injection. Folia
Ophthalmol Jpn 1970; 21:648–652.
68. Klein ML, van Buskirk EM, Friedman E,
et al: Experience with nontreatment of
central serous choroidopathy. Arch
Ophthalmol 1974; 91:247–250.
69. Avci R, Deutman AF: Treatment of central
serous chorioretinopathy with the beta
receptor blocker metoprolol. Klin Monatsbl
Augenheilkd 1993; 202:199–205.
70. Ficker L, Vafidis G, While A, Leaver P:
Long-term follow-up of a prospective trial
of argon laser photocoagulation in the
treatment of central serous retinopathy.
Br J Ophthalmol 1988; 72:829–834.
71. Gilbert CM, Owens SL, Smith PD, Fine SL:
Long-term follow-up of central serous
chorioretinopathy. Br J Ophthalmol 1984;
68:815–820.
72. Leaver P, Williams C: Argon laser
photocoagulation in the treatment of
central serous retinopathy. Br J Ophthalmol
1979; 63:674–677.
73. Brancato R, Scialdone A, Pece A, et al:
Eight-year follow-up of central serous
chorioretinopathy with and without laser
treatment. Graefes Arch Clin Exp
Ophthalmol 1987; 225:166–168.
74. Yap EY, Robertson DM: The long-term
outcome of central serous
chorioretinopathy. Arch Ophthalmol 1996;
114:689–692.
75. Burumcek E, Mudum A, Karacorlu S,
Arslan MO: Laser photocoagulation for
persistent central serous chorioretinopathy:
results of long-term follow-up.
Ophthalmology 1997; 104:616–622.
76. Yannuzzi LA, Slakter JS, Kaufman SR,
Gupta K: Laser treatment of diffuse retinal
pigment epitheliopathy. Eur J Ophthalmol
1992; 2:103–114.
77. Sahu DK, Namperumalsamy P, Hilton G,
et al: Bullous variant of idiopathic central
serous chorioretinopathy. Br J Ophthalmol
2000; 84:485–492.
78. Battaglia Parodi M, Da Pozzo S, Ravalico G:
Photodynamic therapy in chronic central
serous chorioretinopathy. Retina 2003;
23:235–237.
79. Yannuzzi LA, Slakter JS, Gross NE, et al:
Indocyanine green angiography-guided
photodynamic therapy for treatment of
chronic central serous chorioretinopathy:
a pilot study. Retina 2003; 23:288–298.
80. Cardillo Piccolino F, Eandi CM, Ventre L,
et al: Photodynamic therapy for chronic
central serous chorioretinopathy. Retina
2003; 23:752–763.
81. Ober M, Angelilli A, Do D, et al:
Photodynamic therapy for acute central
serous chorioretinopathy. Ophthalmology
2005; 112(12):2088–2094.
 CHAPTER

143 Genetics of Age-related Macular Degeneration

Margaret M. DeAngelis and Fei Ji

INTRODUCTION hence pharmacological targets in preventing or slowing down

progression of disease. This chapter focuses on genetic
Age-related macular degeneration (AMD) is the most common contributions to the etiology of AMD.
form of legal blindness in the United States as well as other
developed countries. The Eye Disease Prevalence Group
estimates that 1.75 million United States citizens have BACKGROUND STUDIES DEMONSTRATING
advanced AMD in at least one eye.1 Approximately 10% of the A GENETIC COMPONENT: TWIN AND
population aged 43 and older is affected with some form of the FAMILIAL AGGREGATION STUDIES
disease and 30% of the population aged 75 and older is
affected.2 As the population lives longer this number will likely AMD is a challenging disease to study from a genetic
increase. It is estimated that 2.95 million individuals in the US perspective because unlike disorders that exhibit Mendelian
will have advanced AMD by the year 2020.1 inheritance patterns (where one gene is responsible for the
Current diagnostic methods focus on the detection of phenotype observed in a given family), complex diseases like
neovascular AMD, since available treatments are directed AMD have the following characteristics. Since the disease is
against this advanced stage of the disease. Although the newest common or highly prevalent (with 1.75 million United States
treatments offer some chance of visual improvement, they citizens having advanced AMD in at least one eye),1 it is likely
require invasive delivery methods and have limited ability to that there is more than one gene or environmental factor in
prevent or reverse vision loss. Assessments of an individual's addition to the interactions of these factors that influence an
risk of developing advanced AMD are based on ocular findings individual's susceptibility to disease. AMD is also a
in those who already have the early stages.3 Methods are yet to heterogeneous disease and its many subtypes (reviewed in other
be refined that determine which individuals are at highest risk chapters in this book) present the possibility that there are
of vision loss due to AMD prior to the development of any signs different disease mechanisms and hence different genes
of the disease. responsible for each subtype.
Previous studies of genetic and epidemiologic factors have Although the causes of AMD remain elusive, there is
not been in agreement as to predictors of AMD. Cigarette evidence demonstrating that genetics plays an important role.
smoking appears to be the only epidemiologic risk factor Table 143.1 summarizes many of the studies that have
generally accepted as being associated with an increased risk for supported a role for genetics in the etiology of AMD. These
AMD,4 while an allelic variant in the complement factor H gene studies consist of data from both familial aggregation and twin
(CFH) appears to be the strongest genetic risk factor.
Specifically, several independent reports have shown the
functional polymorphism Y402H in CFH, where a tyrosine is
substituted by a histidine, to be associated with increased risk TABLE 143.1. Studies Showing Hereditability
of both early5–9 and late stages of AMD (both neovascular and
geographic atrophy).6,7,9–12 These findings further suggest that Type of Study Conclusion Authors
the histidine allele, or disease allele, contributes to almost half Monozygotic Twins shared identical Melrose et al.89,
of all cases of AMD in the population. Although having these twin case health problems and Meyers et al.90,
factors may increase one's risk of disease, there are still many report had similar features Dosso et al.91
individuals who both smoke and have the CFH-associated of AMD in
disease variant but have no signs of AMD. For this reason, the corresponding eyes
magnitude of risk for AMD probably depends on exposure to Twin study Showed higher Klein et al.92,
other environmental and genetic risk factors in combination concordance in Meyers et al.93
with smoking and CFH variation. monozygotic twins than Gottfredsdottir et al.
94
Discovering precisely which genes and environmental factors in dizygotic, confirmed Grizzard et al.
95
that stage and type Seddon et al.
contribute to the pathophysiology of AMD could provide targets 96
of AMD was similar Hammond et al.
that could be modifiable through therapeutic or behavioral between twins 2002,14
intervention, thereby reducing or preventing the incidence of
this disease. Knowing which common variants in a handful of Familial Prevalence of AMD Seddon et al.13,
aggregation was higher among Klaver et al.52,
genes may predict which individuals in the population are at study first-degree relatives Assink et al.97
greatest risk for converting to the more advanced stages of of AMD patients
AMD. These genes in turn could serve as biomarkers and 1881
 RETINA AND VITREOUS
studies. Data from the Rotterdam study showed that first-
degree relatives of affected individuals are at 25% greater risk
of developing disease than individuals in the general population
without any affected family members. It has also been shown
that AMD has a tendency to cluster or aggregate within
families.13 Further, Hammond and colleagues14 demonstrated
that monozygotic twins with AMD had a higher degree of
concordance (both members having AMD) than dizygotic
twins, 37% compared to 19%, respectively.
Key Features
A genetic component is supported by the following:
• A higher prevalence of AMD is found in identical twins
compared to fraternal twins
• A higher prevalence of AMD is found in first-degree relatives of
AMD patients compared to unrelated individuals from the
general population
SECTION 10
JUVENILE FORMS (MENDELIAN) OF
MACULAR DEGENERATION: CANDIDATE
GENES FOR AMD
Because of evidence suggesting a genetic component, some
genes known to be associated with juvenile-onset forms of
retinal degeneration have been studied for their association with
AMD. No studies to date have found an association between
mutations in vitelliform macular dystrophy 2 (VMD2) (Best
disease),15–19 tissue inhibitor of metalloproteinase–3 (TIMP–3)
(Sorsby fundus dystrophy),20,21 retinal degeneration, slow
RDS/peripherin (retinitis pigmentosa),22,23 and epidermal
growth factor-containing fibulin like extracellular martrix
protein 1 (EFEMP1) (Malattia Leventinese/Doyne honeycomb
retinal dystrophy)24–26 and any type of AMD, either early or late
stages. Table 143.2 shows the names of these genes, their
genomic locations, the retinal disease associated with the gene
and the AMD population studied. Table 143.2 also shows that
two genes, the ATP-binding cassette transporter gene, subfamily
A, member 4 (ABCA4) (autosomal recessive Stargardt disease)
and the elongation of very long chain fatty acids gene (ELOVL4)
(Stargardt disease type 3 or autosomal dominant Stargardt
disease) are inconsistent with respect to whether or not
variations in these genes are associated with AMD.
ABCA4
ABCA4 is located on the short arm of chromosome 1 (1p22.1–p21)
and functions in lipid metabolism and transport. Mutations in
ABCA4, also known as ABCR, cause Stargardt disease, a
juvenile form of macular degeneration characterized by deposits
of lipofuscin in and beneath the retinal pigment epithelium. In
1997, Allikmets et al found an association of heterozygous
ABCA4 alleles with AMD.27 In particular, G1961E (glycine is
substituted by glutamic acid) and D2177N (aspartic acid is
substituted by asparagine), the two most common variants,
along with rare variants in ABCA4 were reported to be
associated with ~4% of AMD cases (mostly the dry form).
Further, in a larger screen of more than 1200 patients with both
dry and neovascular AMD, Allikmets et al in 2000 reported that
ABCA4 variants could probably explain up to 8% of AMD.28
However, several groups have tried to replicate these findings
and were unable to conclude that variants in ABCA4 were
associated with the dry or more advanced stages of AMD.29–36 It
could be that if variation in ABCA4 increases susceptibility to
AMD, the risk of disease would only be small or modest, or
there exists multiple susceptibility genes for AMD, not
1882 necessarily expressed in every patient with AMD.
ELOVL4
Like ABCA4, the protein product of ELOVL4 is involved in lipid
transport and metabolism. Unlike ABCA4, ELOVL4 is located
in a region (6q24–q14) previously identified from genome-wide
scans to harbor AMD susceptibility genes.37,38 A five base pair
deletion in this gene has been found to be associated with
Stargardt disease 3, which has phenotypic similarity to the dry
or atrophic form of AMD. A recent report has suggested that the
M299V variant, where a methionine is substituted by a valine
in the protein sequence of ELOVL4, could increase risk of
neovascular AMD,10 although an earlier study did not find
this association for either the early or more advanced stages
of AMD.39 Similarly, a recently published study of a Finnish
population also did not find an association between the
M299V variant in ELOVL4 and patients with large drusen,
neovascular, or atrophic AMD.40 It appears that more studies
may need to be conducted before the contribution of the
ELOVL4 gene to the etiology of AMD can be confirmed.
Key Features
Of the six genes responsible for juvenile forms of retinal
degeneration (VMD2, TIMP-3, RDS/peripherin, EFEMP1, ABCA4,
ELOVL4), only ABCA4 and ELOVL4 possibly influence
susceptibility to AMD. Both ABCA4 and ELOV4L4 function in lipid
metabolism and transport
GENOME-WIDE SCANS
A genetic component is further supported by the multiple
genome-wide scans which have identified similar chromosomal
locations harboring AMD susceptibility genes. The purpose
of a genome-wide scan is to search the 22 pairs of autosomes
(no sex chromosomes) with the goal of identifying regions
significantly linked to the disease under investigation. Although
linkage studies are powerful and can uncover novel disease
genes, the significant or linked region could harbor hundreds
of these disease loci or genes making the identification of one
locus a challenge. Another disadvantage of a linkage study is
that regions that contain genes contributing modest or subtle
effects to a given phenotype may be missed.
Linkage refers to the physical proximity of the disease locus
with the marker locus. The degree of linkage is determined by
the logarithm of the odds ratio (lod score). A lod score of
3 translates to 1000 to 1 odds in favor of linkage (P = 0.0001)
and a lod score of –3 is 1000 to 1 against the genotype being
linked to the disease.
For complex diseases such as AMD generally no assumption
regarding the mode of inheritance is made a priority – this is
called model-free linkage analysis. Model-free linkage analysis
employs statistical tests that calculate the number of alleles
shared between related individuals with and without disease.
Markers called microsatellites or single nucleotide poly-
morphisms (SNPs) can be used for this purpose. A
microsatellite is a tandemly repetitive unit of base pairs in
DNA. The repetitive units usually consist of 2, 3, or 4 base
pairs and it is the number of these repetitive units that varies
between individuals. Because of the high variation or
heterozygosity in the number of these repetitive units for a
given microsatellite between individuals in a population, they
are very informative for linkage studies as they are highly
polymorphic. The disadvantage is that microsatellites are not
evenly distributed throughout the genome. An SNP is a single
base change, located every 1000–3000 base pairs in DNA
sequence and therefore they are abundant in the genome.
Over the last few years the discovery rate of SNPs throughout
 Genetics of Age-related Macular Degeneration

TABLE 143.2. Candidate Genes for AMD Derived from Juvenile Forms of Hereditary Retinal Degenerations

Gene Name Symbol Location Function Disease Association Study Population Author

Retinal RDS 6p21.2– Protein binding Retinitis pigmentosa 56 y.o. index Kemp et al.22
Degeneration, p12.3 patient w/AMD
Slow & his 41 y.o. niece,
42 y.o. index
patient w/RP
& her 15 y.o. son
3 unrelated families, Gorin et al.23
12 patients w/AMD
or peripheral retinal
degeneration, 100
related controls
Tissue TIMP3 22q12.3 Metalloendopeptidase Sorsby's fundus 68 sibpairs w/AMD De La Paz et al.20
Inhibitor of inhibitor activity dystrophy (by AREDs), mean
metallopeptidase-3 age 71.5 ±
10.2 years, 79 age,

CHAPTER 143
gender and ethnically
matched controls
143 German AMD Felbor et al.21
patients (age 48–91),
74 w/other macular
dystrophies
ATP-Binding ABCA4 1p22.1 – ATP binding, ATPase Stargardt 167 unrelated Allikmets et al.27*
Cassette, p21 activity, lipid disease patients w/drusen,
sub-family A transport GA, RPE
(ABC1), & metabolism detachment and/or
member 4 CNV, 220 racially
matched controls
182 patients w/AMD Stone et al.29
(60% w/CNV in at
least one eye),
96 unrelated
subjects expected
to develop AMD
212 patients De La Paz et al.30
w/intermediate
or large soft drusen,
RPE detachments,
GA and/or CNV
(159 familial, 53
sporadic), 56 racially
matched controls
52 unrelated French Souied et al.31
patients w/CNV, 90
French unrelated
self-reported
unaffecteds as
controls
1218 unrelated Allikmets et al.28*
patients w/dry
AMD or CNV from
North America and
Western Europe,
1258 controls
100 patients Rivera et al.32
w/GA, 100
patients w/CNV,
153 unaffecteds age
and geography-
matched controls
544 AMD patients Guymer et al.33
(mostly CNV)
from US, Australia
& Switzerland,
689 controls from
the same areas,
62 unaffected
Somalians 1883
Continued
 RETINA AND VITREOUS

TABLE 143.2. Candidate Genes for AMD Derived from Juvenile Forms of Hereditary Retinal Degenerations (Cont’d)

Gene Name Symbol Location Function Disease Association Study Population Author

182 patients Webster et al.34

w/AMD
(Int. ARM Epi.
Study Class.
System),
96 controls from
the same clinic
population as
AMD patients
26 AMD patients Bernstein et al.35
≥ grade 2 (AREDS
scale) from
15 families,
33 unaffected
siblings
SECTION 10

165 AMD patients Schmidt et al36

≥ grade 3 (Int. ARM
Study Class. System)
from 70 families,
33 unaffected
siblings, 59 unrelated
controls
Epidemial EFEMP1 2p16 Maintenance of Malattia Leventinese 494 AMD patients, Stone et al.24
Growth Factor – extracellular matrix (ML)/Doyne 56 ML/DHRD
containing integrity Honeycomb patients, 477
fibulin-like Retinal Dystrophy controls
extracellular (DHRD)
matrix protein 1
13 index patients Guymer et al.25
w/onset drusen,
15 family members,
54 familial cases of
AMD, 150 age and
ethnicity-matched
controls, all at least
50 y.o.
54 patients w/early Narendran et al.26
onset drusen, 114
unrelated controls
≥ 60 y.o.
Vitelliform VMD2 11q13 Chloride ion binding Best Disease 259 unrelated Allikmets et al.15
Macular & ion channel patients w/drusen,
Dystrophy 2 activity GA, RPE detatchment
(Best disease, and/or CNV, 30
bestrophin) patients w/other
disorders (1 w/Best)
41 unrelated Kramer et al.16
patients w/Best's
Disease, 200 AMD
patients,
140 unaffected
controls
321 patients Lotery et al.17
w/drusen and/or
atrophy of RPE,
96 unrelated
patients w/Best
disease,
192 controls
at least 40 y.o.
85 Japanese AMD Akimoto et al.18
patients, 105 age-
matched Japanese
controls

Continued

1884
 Genetics of Age-related Macular Degeneration

TABLE 143.2. Candidate Genes for AMD Derived from Juvenile Forms of Hereditary Retinal Degenerations (Cont’d)

Gene Name Symbol Location Function Disease Association Study Population Author

259 AMD patients, Seddon et al.19

28 patients
w/maculopathies
other than Best's
Elongation of ELOVL4 6q14 Lipid metabolism & Stargardt Disease, 778 AMD patients Ayyagari et al.39
very long chain transport type III (Int. Class. System),
fatty acids 551 age and race-
matched controls
992 Caucasian Conley et al.10*
patients w/extensive
drusen, pigmentary
changes, GA and/or
CNV, 120 unrelated
controls

CHAPTER 143
335 Finnish patients Seitsonen et al.40
w/more than 5 small
drusen (< 63µm),
at least 10 large
drusen (> 125µm),
GA, or CNV, of which
154 were sporadic
cases & 181 familial,
105 controls
* Denotes studies finding positive associations.
RP – Retinis Pigmentosa; y.o. – years old; AREDS – age-related eye disease study; GA – geographic atrophy; RPE – retinal pigment epithelial;
CNV – choroidal neovascularization; Int. ARM Epi. Study Class. System – International Age-Related Maculopathy Epidemiology Study Classification System;
Int. Class. System – International Classification System; ML – Malattia Leventinese; DHRD – Doyne Honeycomb Retinal Dystrophy.

the genome has accelerated, thus making them useful for
genome-wide scans; however, they are not as polymorphic
and many more are needed for linkage analysis. Almost all
of the genome-wide scans conducted to date are linkage
studies using microsatellite markers, except Klein's scan which
is an association study employing SNPs in the identification of
CFH (Fig. 143.1 and Table 143.3).
Table 143.3 illustrates results from the AMD genome-wide
scans to date including regions found to be significant, micro-
satellite markers used to identify the region, microsatellite
markers/SNPs, chromosomal band, LOD score, P value, as well
Genome-wide Scans
6 resulted in the identification of various chromosomal regions
5 across studies in definition and measurement of AMD type and
Number of Studies
as the AMD population studied. A summary of chromosomal
regions found by more than one genome-wide scan to be
significantly linked to AMD is shown in Table 143.3 and
includes 1q23.3–q31.1,6,41–46 2p25.3–p12,46,47 6q14,37,38
9q31,46,4710q26,42–46,48,49 12q23–q24.31,37,4615q13–q15,37,46
16p12–p12.1,37,38,46 17q25,42,43 and 22q12.1.45,47 A recent
pooled analysis of several of these genome-wide scans that used
linkage analysis and examined all types of AMD confirmed
two of the most consistently reported chromosomal regions
(1q23.3–q31.1 and 10q26) while identifying others that were
not initially significant in the separate studies alone.50 This
pooled analysis or meta-analysis also confirmed two regions
that had been reported to be significant by only individual
studies: 3p14.1–p25.350,51 and 4q32.44,50 Many of the AMD
genome-wide scan studies illustrated in Table 143.3 have
which have not been replicated by other studies. Differences
grade coupled with simultaneous analysis of different subtypes

4 within study populations may make it difficult to compare and

interpret findings. For example, sibling pairs with advanced
3 AMD examined from the family age-related maculopathy study
(FARMS) (Wisconsin grading scale) showed significance to
2 5q33.3, 14q32.33, 16p13.13, 19q13.31, 21q21.2,51 while other
investigators who also studied populations characterized by
1
advanced AMD did not report significant linkage to these same
regions.42–44,46 Moreover, another group's finding of a significant
association between neovascular AMD and 16p12.1 was depend-
0
1998 1999 2000 2001 2002 2003 2004 2005 2006 ent on factors such as body mass index (BMI) and hypertension,38
Year of Study
although the 16p12 region has been shown by other studies to
FIGURE 143.1. The number of genome wide scans for AMD be significantly associated with advanced AMD independent of
performed each year since the first, Klein et al, in 1998. Note that these factors.46 In summary, genome-wide scans have helped to
none were completed in 1999 nor have there been any thus far in identify candidate genes for AMD as well as to highlight the
2006. need for further evaluation of candidate regions. 1885
 RETINA AND VITREOUS

TABLE 143.3. Summary of genes uncoved by genome wide scans and candidate gene studies for AMD

Author Region Band LOD P value AMD population Grading scale

41
Klein et al. D1S466 – 1q31 3.00† 0.0001 21 individuals from a family Wis
D1S413 w/ ARMD
Weeks et al.42 D1S1660 1q31 2.46 0.0004 630 individuals w/ either GA modified
and/or CNV from 364 families
Majewski et al.44 D1S518 1q31 2.07 0.001§ 70 families w/ 258 individuals None
w/ advanced AMD, stratified
according to age and dry
vs. wet
Seddon D1S1589 1q24 1.33 0.0070 490 affected individuals AREDS
et al.45 ≥ grade 3, 608 relative pairs
Abecasis D1S549 1q41 1.55 0.0040 113 families, 331 individuals Intnl ARM Epid
et al.47 w/ any type of AMD
Iyengar et al. D1S202 1q31 1.02† 0.0149 297 individuals w/ CNV Wis
SECTION 10

or GA from 34 families,
349 sib pairs, corrected
for age
Weeks et al.43 D1S1660 1q31 2.72 0.0610 1274 individuals w/ large modified
drusen, either GA and/or
CNV from 530 families
Klein et al.6 rs380390 1q31 >5.5† 0.00000004 96 individuals w/ GA and/or AREDS
rs1329428 4.77† 0.00000140 CNV, 50 controls, all from
AREDS
Fisher 2005 D1S202 – 1q31.1 – 0.90† 0.0209 Meta-analysis of Abecasis, n/a
D1S425 q32 Iyengar, Majewski, Schick,
Seddon and Weeks
Fisher 2005 D1S2705 – 1q23.3 – 1.16† 0.0104 Meta-analysis of Abecasis, n/a
D1S202 q31.1 Iyengar, Majewski, Schick,
Seddon and Weeks
Summary region 1q23.3 – q31.1
45
Seddon et al. D2S1391 2q33 1.81 0.0020 490 affected individuals AREDS
≥ grade 3, 608 relative pairs
Abecasis et al.47 D2S1780 2p25.3 1.84 0.0020 113 families, 331 individuals Intnl ARM Epid
w/ any type of AMD (69%
w/ GA and/or CNV) - only
CNV patients
Iyengar et al. D2S1356 2p21 1.52† 0.0041 297 individuals w/ CNV or GA Wis
2004 from 34 families, 349 sib pairs,
corrected for age
Fisher 2005 D2S297 – 2p25.1 – 0.76† 0.0308 Meta-analysis of Abecasis, n/a
D2S2312 p23.2 Iyengar, Majewski, Schick,
Seddon and Weeks
Fisher 2005 D2S2312 – 2p23.2 – 0.84† 0.0244 Meta-analysis of Abecasis, n/a
D2S2251 p16.2 Iyengar, Majewski, Schick,
Seddon and Weeks
Fisher 2005 D2S2251 – 2p16.2 – 0.59† 0.0495 Meta-analysis of Abecasis, n/a
D2S139 p12 Iyengar, Majewski, Schick,
Seddon and Weeks
Summary 2p25.3 –
region p12
Majewski D3S1304 3p13 2.19 0.0007 70 families w/ 258 individuals None
et al.44 w/ advanced AMD, samples
limited to individuals w/
predominantly dry AMD
Schick et al.37 ^ D3S1763 3q26.1 1.25† 0.0081 Beaver Dam Eye Study Wis
(105 families w/ 258
individuals having scores
≥ 4.5 - No late AMD),
adjusted for age

Continued
1886
 Genetics of Age-related Macular Degeneration

TABLE 143.3. Summary of genes uncoved by genome wide scans and candidate gene studies for AMD (Cont’d)

Author Region Band LOD P value AMD population Grading scale

Summary region 6q14

Weeks et al.48 D9S925 – 9q21–q22 1.87 0.0017 212 individuals w/ either GA modified
D9S301* – and/or CNV from 225 families
D9S1120
Weeks et al.42 D9S1118 9p13 1.79 0.0020 630 individuals w/ either GA modified
and/or CNV from 364 families
Majewski et al.44 D9S934 9q33 2.07 0.0010 70 families w/ 258 individuals None
w/ advanced AMD, stratified
according to age and dry vs. wet
Abecasis et al.47 D9S938 9q31.1 1.78 0.0020 113 families, 331 individuals Intnl ARM Epid
w/ any type of AMD
Iyengar D9S1871 9p24 1.46† 0.0048 297 individuals w/ advanced Wis
et al. 2004 AMD from 34 families,

CHAPTER 143
349 sib pairs, corrected for age
Iyengar D9S938 9q31 1.26† 0.0079 297 individuals w/ advanced Wis
et al. 2004 AMD from 34 families,
349 sib pairs, corrected for age
Summary Region 9q31
48
Weeks et al. D10S1230 10q26 1.42 0.0053 212 individuals w/ either modified
GA and/or CNV from
225 families
Weeks et al.42 D10S1230 10q26 2.00 0.0400 630 individuals w/ either GA modified
and/or CNV from 364 families
Majewski et al.44 D10S1230 10q26 3.06 0.00009 70 families w/ 258 individuals None
w/ advanced AMD, stratified
according to age and dry vs. wet
Seddon et al.45 D10S1222 10q26 1.61 0.0030 490 affected individuals AREDS
≥ grade 3, 608 relative pairs
Iyengar et al. D10S1248 10q26 1.55† 0.0037 297 individuals w/ advanced Wis
2004 AMD from 34 families,
349 sib pairs, corrected for age
Kenealy et al.49 D10S1230 10q26 1.52 133 affected sib pairs modified
(graded 3, 4, or 5)
Weeks et al.43 D10S1230 10q26 1.91 0.0600 1274 individuals w/ either modified
GA and/or CNV from
530 families
Fisher 2005 D10S1690 – 10q23.33 – 1.39† 0.0057 Meta-analysis of Abecasis, n/a
D10S1483 q26.13 Iyengar, Majewski, Schick,
Seddon and Weeks
Fisher 2005 D10S1483 – 10q24.31 – 2.63† 0.0003 Meta-analysis of Abecasis, n/a
qter q26.13 Iyengar, Majewski, Schick,
Seddon and Weeks
Summary region 10q26
Fisher 2005 D12S318 – 12q23.2 – 0.76† 0.0305 Meta-analysis of Abecasis, n/a
D12S1349 q24.31 Iyengar, Majewski, Schick,
Seddon and Weeks
Schick et al.37 D12S1300 12q23– 1.35† 0.0063 Beaver Dam Eye Study Wis
12q24 (105 families w/ 258
individuals having scores
≥ 4.5 - No late AMD)
Schick et al.37 D12S346 12q22– 1.53† 0.0040 Beaver Dam Eye Study Wis
12q23 (105 families w/ 258 individuals
having scores ≥ 4.5 - No
late AMD)
Iyengar et al. D12S2078 12q23 1.88† 0.0016 297 individuals w/ CNV or Wis
2004 GA from 34 families, 349 sib
pairs, corrected for age
Iyengar et al. D12S297 12q13 1.33† 0.0066 297 individuals w/ CNV or GA Wis
2004 from 34 families, 349 sib pairs,
corrected for age
1887
Continued
 RETINA AND VITREOUS

TABLE 143.3. Summary of genes uncoved by genome wide scans and candidate gene studies for AMD (Cont’d)

Author Region Band LOD P value AMD population Grading scale

Summary region 12q23

– q24.31
Schmidt et al.38 D14S608, 14q13 3.20 0.0020 62 families: 2+ sampled relatives Wis
D14S599 w/ early or late AMD in 28
families w/ lower-than-average
IOP values
Jun et al.51 D14S1007 14q32.33 1.97† 0.0013 346 sib pairs from FARMS Wis
w/ advanced AMD
Summary: No overlapping regions found
Schick et al.37 ^ D15S659 15q11.1– 0.60† 0.0479 Beaver Dam Eye Study Wis
15q14 (105 families w/ 258 individuals
having scores ≥ 4.5 - No
late AMD)
SECTION 10

Schick et al.37 ^ D15S816 15q25– 0.63† 0.0447 Beaver Dam Eye Study Wis
15q26 (105 families w/ 258 individuals
having scores ≥ 4.5 - No
late AMD)
Iyengar et al. GATA50C03 15q14 3.94† 0.00001 297 individuals w/ advanced Wis
2004 AMD from 34 families,
349 sib pairs, corrected for age
Iyengar et al. D15S1012 15q13–15q15 5.34† 0.00000035 297 individuals w/ advanced Wis
2004 AMD from 34 families,
349 sib pairs, corrected for age
Summary region 15q13 – q15
Schick et al.37 ^ D16S769 16p12.1 1.23† 0.0086 Beaver Dam Eye Study Wis
(105 families w/ 258 individuals
having scores ≥ 4.5 - No
late AMD)
Iyengar et al. D16S769 16p12.1 1.10† 0.0120 297 individuals w/ advanced Wis
2004 AMD from 34 families,
349 sib pairs, corrected for age
Schmidt et al.38 D16S403 16p12 2.90 0.0400 32 families (late AMD) w/ higher Wis
than average BMI, SBP & IOP
values
Fisher 2005 D16S3103 –≠ 16p13 – 0.92† 0.0195 Meta-analysis of Abecasis, n/a
D16S415 q12.2 Iyengar, Majewski, Schick,
Seddon and Weeks
Fisher 2005 D16S415 – 16q12.2 – 0.94† 0.0187 Meta-analysis of Abecasis, n/a
D16S516 q23.1 Iyengar, Majewski, Schick,
Seddon and Weeks
Jun et al.51 * D16S2616 16p13.13 1.91† 0.0015 346 sib pairs from FARMS Wis
w/ advanced AMD
Summary region 16p12 – p12.1
42
Weeks et al. D17S928 17q25 3.53 0.0070 630 individuals w/ either GA modified
and/or CNV from 364 families
D17S928 17q25 1.56 0.0037 1274 individuals w/ either GA modified
and/or CNV from 530 families
Summary region 17q25
Iyengar et al. GATA178F11 18p11 1.60† 0.0033 297 individuals w/ advanced Wis
2004 AMD from 34 families, 349 sib
pairs, corrected for age
Jun et al.*51 D19S245 19q13.31 2.35† 0.0005 225 sib pairs from BDES & 346 Wis
from FARMS w/ advanced AMD
Iyengar et al. D20S451 20q13 1.42† 0.0052 297 individuals w/ advanced Wis
2004 AMD from 34 families,
349 sib pairs, corrected for age
Jun et al.51 * D21S2052 21q21.2 1.31† 0.007 346 sib pairs from FARMS Wis
w/ advanced AMD

1888 Continued

TABLE 143.3. Summary of genes uncoved by genome wide scans and candidate gene studies for AMD (Cont’d)
Author Region Band LOD
45
Seddon et al. D22S1045 22q12 – q13 2.00
Abecasis et al.47 AGAT055Z 22q12.1 2.55
Summary region 22q12 – q13
Note: All maps Marshfield unless * = not indicated and ^ = Harvard Partners, Marshfield and Weizmann.
§ indicates P value estimated by LOD score reported, † indicates LOD score estimated by P value reported.
ARMD - Age Related Macular Degeneration, Wis - Wisconsin, GA - Geographic Atrophy, CNV - Choroidal Neovascularization, AMD - Age-related Macular Degeneration,
AREDS - Age Related Eye Disease Study, Intnl ARM Epid - International Age Related Maculopathy Epidemiology, BDES - Beaver Dam Eye Study, FARMS - Family Age
Related Maculopathy Study, IOP - Intaocular Pressure, BMI - Body Mass Index, SBP - Systolic Blood Pressure, n/a - non applicable.
Key Features
Genome-wide scans can be an important tool in finding genes
associated with disease. Genome-wide scans applying either
linkage or association methods are an important approach in
finding genes associated with disease. Because AMD is
a multifactorial disease with both genetic and environmental
factors influencing susceptibility, genes with modest or subtle
effects may go undetected by linkage studies, yet may be
uncovered by an association study. For this reason, it is important
to have multiple approaches in elucidating the genetic etiology of a
complex or multifactorial phenotype such as AMD. In genome-
wide scans, there is the problem of multiple testing issue, which
can lead to false positive results. The point-wise significance level
for linkage analysis (lod = 3, P = 0.0001) and association analysis
( P = 0.05) need to be set to more stringent values to obtain a
reasonable family-wise significance.
CANDIDATE GENES
Based on the evidence for a genetic component, a variety of
candidate genes have been evaluated either for their roles in
diseases that share phenotypic similarity to AMD and/or because
they were identified in genome-wide scans that searched for
areas of the genome harboring AMD susceptibility genes as
described earlier in this chapter. The comprehensive discussion
that follows includes the genes that have been found by at least
one study to be statistically associated with either increased or
decreased risk of AMD. Table 143.4 summarizes these findings.
APOLIPOPROTEIN GENE (APOE)
Like ELOVL4, APOE functions in lipid transport and meta-
bolism. APOE was the first candidate gene investigated for a
role in AMD outside of the genes responsible for the juvenile
forms of macular degenerations. The role of apolipoprotein gene
(APOE) in susceptibility to Alzheimer's disease is well estab-
lished, i.e., APOE is a component of the amyloid plaques that
are a hallmark of this aging degenerative disease of the central
nervous system. Three alleles E2, E3, E4 (E3 is the most
frequent allele in the general population) in the last exon, exon
4, of APOE influence disease risk for Alzheimer's. The combi-
nation of these three alleles makes up six genotypes: E2/E2,
E2/E3, E2/E4, E3/E3, E3/E4, and E4/E4. The E4 allele, and in
particular the E4/E4 genotype, is thought to be associated
with increased risk of an earlier onset of Alzheimer's disease
while the E2 allele is thought to be protective for development
of Alzheimer's disease. The E4 allele of APOE was first reported
Genetics of Age-related Macular Degeneration
P value AMD population Grading scale
0.0010 490 affected individuals AREDS
≥ grade 3, 608 relative pairs
0.0003 113 families, 331 individuals Intnl ARM
w/ any type of AMD Epdiem
(69% w/ GA and/or CNV) – only
CNV patients
CHAPTER 143
by the Rotterdam group from the Netherlands in 1998 to be
associated with a 'decreased' risk of AMD.52 A trend toward
increased risk of development of AMD was observed with the
E2 allele but this finding was not statistically significant. This
study further demonstrated histologically the presence of APOE
in large soft drusen from eyes of patients with AMD as well as
the absence of this protein from small hard drusen. Many other
studies have supported the finding that the E4 allele is
associated with a decreased risk of either the early form or more
advanced stages of AMD.53–58 Although many of these studies
have shown a trend toward an association of the E2 allele with
increased risk of AMD,52,54,56 this finding did not reach
statistical significance with the exception of Baird et al who in
2004 showed that the presence of the E2 allele was statistically
significantly associated with an earlier onset of AMD in women
with the neovascular form of AMD.58 Conversely, Pang et al,59
Schmidt et al,60 Schultz et al,61 and Gotoh et al62 found no
evidence for either a protective effect of APOE E4 or a causal
effect of APOE E2 on AMD risk. Further supporting the findings
of a lack of association of APOE and AMD is that of the many
genome-wide scans conducted, none has shown the 19q13.2
region to be linked to AMD. Moreover, a study that performed
a genome-wide scan on 34 families with advanced stages of AMD
comprising 346 sibling pairs showed linkage to 19q13.31,51 a
region in close proximity to APOE, and concluded that the
signal was not due to the effect of the APOE gene. Specifically,
this group investigated all six APOE genotypes in conjunction
with the linkage findings from the FARMS cohort. This resulted
in diminished significance of the linkage peak on 19.31,
suggesting that a gene in this region, other than APOE, may be
responsible for risk of AMD. Furthermore, in a study that
examined the effects of APOE genotypes along with smoking,
APOE genotype alone was not found to influence risk of
AMD;60 however, any association observed between APOE and
AMD was dependent on smoking history. For example, risk of
neovascular AMD increased if an individual was a carrier of the
E2 allele and had a history of smoking compared to individuals
who had the E3/E3 genotype and never smoked.60 This finding
may suggest that if APOE is involved in AMD pathogenesis, it
may function as a weak modifier on risk for either early or more
advanced stages of AMD.
PAROXONASE 1 GENE (PON-1)
Paroxonase 1 gene (PON-1) like APOE encodes for a protein
that regulates both lipid metabolism and transport. The three
studies to date that have been published are not in agreement
as to the contribution of PON1 to the etiology of AMD.
Specifically the M55L (a methionine is substituted by leucine) 1889
 RETINA AND VITREOUS

TABLE 143.4. Candidate Genes for AMD

Previously
Identified
Gene name Symbol Location Function Region? Study Population Study

APOlipoprotein E APOE 19q13.2 Lipid 88 AMD patients (Int. Class. Klaver et al.52
metabolism System), 901 controls from
and transport the Netherlands ≥ 55 y.o.
116 unrelated French Souied et al.53
patients w/CNV, 168 age
and sex-matched controls
≥ 60 y.o.
39 Chinese patients w/ Pang et al.59*
disciform scarring or CNV,
133 normal controls
230 patients ≥ grade 3 by Int. Schmidt et al.55*
Class. System - 61
independent familial cases,
SECTION 10

101 sporadic cases &

68 familial cases used as
sporadic, 333 spouses
used as controls
87 Italian patients w/AMD Simonelli et al.54
(Int. ARM Epi. Study),
47 age-matched controls,
1287 individuals from
the general population
Pooled analysis of Schmidt et al.56
4 independent case-control
data sets – 377 patients
w/ any extensive,
intermediate or large soft
drusen, GA or CNV,
198 ethnically-matched
controls of similar age
259 affected in 56 families Schultz et al.61*
w/AMD, 207 unaffected
from these families,
104 unrelated affected,
88 unrelated controls
(AMD = GA, CNV and/or
extensive drusen)
322 Anglo-Celtic patients Baird et al.64
w/drusen > 63µm, CNV or
dry AMD, 123 unrelated
controls matched for
ethnicity
85 unrelated Japanese Gotoh et al.83*
patients w/CNV,
82 unrelated Japanese
controls ≥ 50 y.o.
632 white unrelated patients Zareparsi et al.57
w/GA, CNV, coarse RPE
changes or large drusen,
206 controls
992 Caucasian patients Conley et al.10*
w/extensive drusen,
pigmentary changes,
GA and/or CNV,
120 unrelated controls
377 unrelated patients Schmidt et al.60*
w/extensive intermediate
or soft drusen, GA and/or
CNV (221 ever smokers),
198 unrelated controls
(90 ever smokers)

Continued
1890
 Genetics of Age-related Macular Degeneration

TABLE 143.4. Candidate Genes for AMD (Cont’d)

Previously
Identified
Gene name Symbol Location Function Region? Study Population Study

95 patients w/white Asensio-Sanchez

drusen with or without et al. 2006
pigmentation, CNV or
geographic AMD,
65 spouses as controls
160 patients w/GA Bojanowski et al.
and/or CNV, 227 controls – 2006
133 screened unaffecteds,
94 volunteers with a
younger mean age
SuperOxide SOD2 6q25.3 Regulator 102 Japanese patients Kimura et al.67
Dismutase 2, of oxidative w/CNV, 200 controls
mitochondrial stress

CHAPTER 143
94 patients from Northern Esfandiary et al.65*
Ireland w/CNV, 95 controls
ParaoxONase 1 PON1 7q21.3 Lipid 72 unrelated Japanese Ikeda et al.63
metabolism patients w/CNV, 140 age
and transport and sex-matched controls
62 Anglo-Celtic patients Baird et al.64*
w/ late AMD (Int. ARM Epi.
Study), 115 controls
matched for age and
ethnicity
94 patients from Northern Esfandiary et al.65*
Ireland w/CNV, 95 controls
CySTatin C CST3 20p11.21 Protease 167 German patients w/ CNV Zurdel et al.68
inhibitor (Int. ARM Epi. Study),
517 unrelated controls from
Germany, Switzerland,
Italy & USA
Angiotensin I ACE 17q23.3 Regulator of 173 patients w/CNV or Hamdi et al.69
Converting systemic extensive small (< 63 µm) or
Enzyme 1 blood intermediate (>125 µm)
pressure drusen, 189 age-matched
regulation controls
992 Caucasian patients Conley et al.10*
w/extensive drusen,
pigmentary changes,
GA and/or CNV,
120 unrelated controls
Hemicentin-1 HMCN1 1q25.3 – Maintenance of Klein 1998, 100 families w/3 or more Schultz et al.61
q31.1 extracellular Weeks 2001, living AMD patients,
matrix Majewski 2003, 188 sporadic cases of AMD
integrity Seddon 2003 (Wisconsin Grading Scale),
& Iyengar 2004 174 controls matched for
age, sex and ethnicity
368 patients ≥ grade 2 Hayashi et al.77*
(Int. Class. System), equal
matched unaffected
controls
508 patients ≥ Grade 3 McKay et al.78*
(Rotterdam Study class),
25 possibly affected
and 163 controls
992 Caucasian patients Conley et al.10*
w/extensive drusen,
pigmentary changes,
GA and/or CNV,
120 unrelated controls

Continued

1891
 RETINA AND VITREOUS

TABLE 143.4. Candidate Genes for AMD (Cont’d)

Previously
Identified
Gene name Symbol Location Function Region? Study Population Study

335 Finnish patients w/large Seitsonen et al.40*

drusen, GA, or CNV,
of which 154 were sporadic
cases & 181 familial,
105 controls
Chemokine CX3CR1 3p21.3 Regulator Majewski 2003 85 patients w/GA or CNV in Tuo et al.70
(C-X3-C motif) of immune & Jun 2005 at least one eye,
Receptor 1 acute phase 105 controls (Clinically
response diagnosed group),
21 patients w/CNV,
19 w/areolar AMD &
171 controls (pathologically
diagnosed group)
SECTION 10

Fibulin-5 FBLN5 14q32.1 Maintenance of Jun 2005 402 patients w/drusen, Stone et al.79
extracellular & Schmidt disruption or atrophy of
matrix 2004 RPE or CNV, 429 controls
integrity (80% of both groups
Caucasian)
805 European patients Lotery et al.80
w/ AMD (Int. Class. System),
279 unrelated controls
≥ 65 y.o.
Toll-Like TLR4 9q32 – Regulator Majewski 667 unrelated AMD patients Zareparsi et al.81
Receptor 4 q33 of innate 2003 (Int. ARM Epi. Study),
immunity 439 unrelated controls,
all Caucasian
Complement C2 6p21.3 Regulator 898 unrelated patients Gold et al. 2005
component 2 of alternative- ≥ 60 y.o. w/AMD (Int. ARM
complement- Epi. Study), 389 unrelated
pathway age and ethnicity matched
controls, all of
European-American descent
Complement CFB 6p21.3 Regulator 898 unrelated patients Gold et al. 2005
Factor B of alternative- ≥ 60 y.o. w/AMD
complement- (Int. ARM Epi. Study),
pathway 389 unrelated age and
ethnicity matched controls,
all of European-American
descent
Complement CFH 1q32 Regulator of Klein 1998, 992 Caucasian patients Conley et al.10
Factor H alternative- Weeks 2001, w/extensive drusen,
complement- Majewski 2003, pigmentary changes,
pathway and Seddon 2003 GA and/or CNV,
innate & Iyengar 2004 120 unrelated controls
immunity
400 patients w/extensive Edwards et al.5
drusen or macular
pigmentary abnormalities,
202 controls w/no more
than 4 small, hard drusen
954 unrelated AMD patients Hageman et al.9
60 or older, 406 age- and
ethnicity-matched controls
Patients w/CNV and/or GA Jakobsdottir
– 1443 affected from et al.71
594 families, 196 sporadic
cases, 296 unrelated
controls
96 white patients with large Klein et al.6
drusen, GA and/or CNV,
50 white controls

Continued
1892
 Genetics of Age-related Macular Degeneration

TABLE 143.4. Candidate Genes for AMD (Cont’d)

Previously
Identified
Gene name Symbol Location Function Region? Study Population Study

1166 German AMD patients Rivera et al.72

(Int. Class. System),
945 unrelated controls
2 unrelated CNV groups from Souied et al.11
France, 60 sporadic and
81 familial cases compared
w/ 91 controls
616 white patients w/CNV, Zareparsi et al.81
GA and/or large drusen,
275 white controls at least
68 y.o.
The Rotterdam Study – Despriet et al.

CHAPTER 143
2387 patients, of whom 2006
49 had soft drusen, GA or
CNV, remainder controls
146 unrelated Japanese Gotoh et al.62*
patients w/CNV,
105 controls
163 Chinese patients w/CNV, Lau et al. 2006
232 age-matched controls
Patients w/soft drusen, Magnusson et al.
GA and/or CNV, 1016 from 2006
Iceland and 431 from
the US, 1108 unaffected
Icelandic relatives,
431 controls
96 Japanese patients w/CNV, Okamoto et al.
89 matched controls 2006
between 50-85 y.o.
647 patients ≥ grade 3 Postel et al. 2006
(AREDS scale) and at least
55 y.o., 163 controls grade
1 or 2
111 white males w/drusen, Schaumberg et al.
RPE changes, atrophy, 2006
hypertrophy, RPE
detachment, GA, subretinal
CNV membrane and/or
disciform scars, 401 male
controls
335 Finnish patients w/large Seitsonen et al.40
drusen, GA, or CNV, of
which 154 were sporadic
cases & 181 familial,
105 controls
443 unrelated English Sepp et al.12
patients w/GA or CNV
(mean number of pack
years of cigarette smoking
= 15.4±18.8), 262 spouses
as controls (pack years
=10.7±14.5)
104 unrelated Italian AMD Simonelli et al.
patients (Int. Class. System) 2006
and 131 unrelated controls
Very Low VLDLR 9p24 Lipid Iyengar 992 Caucasian patients Conley et al.10*
Density metabolism 2004 w/extensive drusen,
Lipoprotein and transport pigmentary changes,
Receptor GA and/or CNV,
120 unrelated controls

Continued
1893
 RETINA AND VITREOUS

TABLE 143.4 Candidate Genes for AMD (Cont’d)

Previously
Identified
Gene name Symbol Location Function Region? Study Population Study

Two independent data sets – Haines et al.66

314 affected and
97 unaffected from the
family dataset, 399 affected
and 159 unaffected from
the case-control dataset.
Affecteds had extensive
drusen ( ≥ 63–125 µm),
GA or CNV
PLEcKstrin PLEKHA1 10q26.13 Phospholipid Weeks 2001, Patients w/CNV and/or GA – Jakobsdottir
Homology domain binding Majewski 2003, 1443 affected from et al.71
containing, indirectly Seddon 2003, 594 families, 196 sporadic
family A immune Iyengar 2004 cases, 296 unrelated
(phosphoinositide response & Kenealy controls
SECTION 10

binding specific) 2004

member 1
1166 German AMD patients Rivera et al.72*
(Int. Class. System),
945 unrelated controls
810 white unrelated patients Schmidt et al.73*
w/extensive intermediate
or large (≥ 125 µm) drusen,
GA or CNV (39% reported
smokers), 259 unrelated
controls
LOC387715 LOC 10q26.13 Unknown Weeks 2001, Patients w/CNV and/or GA – Jakobsdottir
387715 Majewski 2003, 1443 affected from et al.71
Seddon 2003, 594 families, 196 sporadic
Iyengar 2004 cases, 296 unrelated
& Kenealy 2004 controls
1166 German AMD patients Rivera et al.72
(Int. Class. System),
945 unrelated controls
810 caucasion unrelated Schmidt et al.73
patients w/extensive
intermediate or large
(≥ 125 µm) drusen, GA or
CNV (39% reported smokers),
259 unrelated controls
HtrA serine HTRA1 10q26 Unknown Weeks 2001, 96 patients with neovascular Dewan et al.,
peptidase 1 Majewski 2003, AMD and 130 age-matched 2006
Seddon 2003, controls of Southeast Asian
Iyengar 2004 descent
& Kenealy 2004
442 AMD cases (265 CNV Yang et al., 2006
and 177 with soft confluent
drusen) and 309 normal
controls from a Caucasian
population in Utah
Vascular VEG-F 6p12 Regulator of Two independent data sets – Haines et al.66
Endothelial angiogenesis 314 affected and 97
Growth Factor unaffected from the family
dataset, 399 affected and
159 unaffected from the
case-control dataset.
Affecteds had extensive
drusen ( ≥ 63–≤ 125 µm),
GA or CNV

Continued

1894

TABLE 143.4 Candidate Genes for AMD (Cont’d)
Gene name Symbol Location Function
Low density LRP6 12p13 – Lipid
lipoprotein p11 metabolism
Receptor-related and transport
Protein 6
Excision ERCC6 10q11.23 DNA repair
Repair Cross-
complementing
rodent repair
deficiency,
Complementation
group 6
*Indicates no association found.
Int. Class System - International Classification System, CNV - Choroidal Neovascularization, GA - Geographic Atrophy,
Int. ARM Epi. Study - International Age Related Maculopathy Epidemiology Study, RPE - Retinal Pigment Epithelial, Int. Class. System - International Classification
System, y.o. - years old, AREDS - Age Related Eye Disease Study.
and Q192R (a glutamine is substituted by arginine) variants
were reported to be associated with neovascular AMD in
72 individuals from Japan.63 Further the affected individuals
also had significantly higher levels of low-density lipoprotein
in the plasma.63 Two other studies, however, found no
association between these variants in patients diagnosed with
late AMD of Anglo-Celtic origin64 or patients with neovascular
AMD from Northern Ireland.65 Again, it is possible that there
exists multiple susceptibility genes for AMD, that are not
necessarily expressed in every patient with AMD, possibly due
to ethnic heterogeneity.
VERY-LOW-DENSITY LIPOPROTEIN
RECEPTOR GENE (VLDLR)
Like APOE and PON-1, VLDLR is also involved in lipid meta-
bolism and transport. There is a lack of agreement between the
two studies conducted to date as to the association of VLDR
and AMD. VLDR is located on the short arm of chromosome 9
(9p24), a region found to be significantly associated with late
AMD in one genome-wide scan (Tables 143.3 and 143.4).46
While one study found a significant association of this gene
with all types of AMD in Caucasian patients including those
with large, extensive drusen, neovascularization, and geo-
graphic atrophy using SNPs,66 another large study on Caucasian
patients with similar AMD diagnosis did not find a significant
association with VLDR.10 More studies may need to be done to
validate the role of VLDR in the pathophysiology of AMD.
LOW-DENSITY LIPOPROTEIN RECEPTOR-
RELATED PROTEIN 6 GENE (LRP6)
Another gene involved in lipid metabolism and transport is
LRP6. Using a combination of linkage and association
analysis on family-based and case-control populations,
respectively, Haines et al demonstrated that LRP6 was
associated with advanced AMD in Caucasian patients.66
Although LRP6 is located in a region, 12p11–p13, yet to be
identified by genome-wide scans as significant, its recent
discovery as a candidate gene in the etiology of AMD may
warrant further study.
Genetics of Age-related Macular Degeneration
Previously
Identified
Region? Study Population Study
Two independent data sets – Haines et al.66
314 affected and
97 unaffected fromthe
family dataset, 399 affected
and 159 unaffected from
the case-control dataset.
Affecteds had extensive
drusen (≥ 63–≤ 125 µm),
GA or CNV
460 advanced AMD cases and Tuo et al.76
269 age-matched controls
CHAPTER 143
MANGANESE SUPEROXIDE DISMUTASE 2
GENE (SOD-2)
SOD2, localized to 6q25.3, encodes an enzyme with
antioxidant properties and is also expressed in the retina. The
substitution of an alanine for a valine homozygously in exon
2 of this gene was found to be associated with a 10-fold
increased risk of neovascular AMD in 102 Japanese patients
when compared to 200 ethnically matched controls.67 Like
in the case of PON1, the variant in SOD2 could not be found
in patients with neovascular AMD from Northern Ireland at
a statistically significant level when compared to controls.65
Again, it is possible that there exist multiple susceptibility
genes for AMD, not necessarily expressed in every patient with
AMD, possibly due to ethnic heterogeneity.
CYSTATIN C GENE (CST3)
CST3, similar to TIMP3 (Sorsby's fundus dystrophy), is a
protease inhibitor. CST3 is localized to 20p11.21, a region as
yet to be reported as being linked to any type of AMD. The
homozygous variant in the 5' untranslated region of CST3 state
was demonstrated to be associated with almost 7% of German
patients with neovascular AMD.68 Further study of this gene
in the etiology of AMD is warranted as this is the only
investigation to date.
ANGIOTENSIN I CONVERTING ENZYME GENE
(ACE)
The role of ACE as a regulator of blood pressure has been
established. ACE is localized to the long arm of chromosome
17 (17q23.3). The polymorphism in this gene that was found to
be associated with 'decreased' susceptibility to AMD is a
repetitive element called an Alu.69 This polymorphism was
found to be significantly associated homozygously with a
fivefold decreased risk from the early dry or atrophic forms
of AMD.69 This association was found after studying patients
with extensive small (<63 mm) drusen, intermediate (>125 mm)
drusen, geographic atrophy as well as neovascular AMD.
However, another study that examined a similar spectrum of 1895
 RETINA AND VITREOUS
AMD phenotypes concluded that there was no association of
ACE with either a decreased or increased risk of AMD.10
CHEMOKINE (C-X3-C MOTIF) RECEPTOR 1
GENE (CX3CR1)
CX3CR1 functions as a regulator of the immune response in
the acute phase.
CXCR1 is localized to the short arm of chromosome
3 (3p21.3), a region found to be significantly linked to the
advanced stages of AMD by two independent genome-wide
scans (Tables 143.3 and 143.4).44,51 Two polymorphisms
CX3CR1, V249I (a valine is substituted by isoleucine) and
T280M (a threonine is substituted by methionine), were
found both homozygously and heterozygously to be associated
with cases of advanced AMD.70 Further, this study also
demonstrated decreased level of expression of this gene in the
maculae of a patient with the T280M variation in the
SECTION 10
homozygous state, when compared to the maculae from
a control individual. Given that CX3CR1 is in a previously
linked region to AMD, the findings of a positive association
with risk of AMD and decreased level of expression of this
gene in an AMD retina should warrant further study.
PLECKSTRIN HOMOLOGY DOMAIN
CONTAINING FAMILY A (PHOSPHOINOSITIDE
BINDING SPECIFIC) MEMBER 1 GENE
(PLEKHA 1), HYPOTHETICAL LOC387715
GENE (LOC387715), AND HTRAA SERINE
PEPTODASE 1 (HTRA1)
PLEKHA1, LOC387715, and HRTA1 are localized to the long
arm of chromosome 10 (10q26.13), a region consistently found
by many genome-wide scans to be linked to both early and the
more advanced stages of AMD (Tables 143.3 and 143.4).42–46,48,49
Meta-analysis or pooled findings from six genome-wide scans
demonstrated that the 10q26 demonstrated the greatest
significance for linkage compared to other significant regions,
such as the 1q25-q32 region.50 PLEKHA1 is believed to
participate in phospholipid binding and more indirectly in the
immune response, whereas LOC387715, a gene that is not well
conserved across species, has no attributable function.
Although the function of HTRA1 is unknown, it ahs been
reported that the encoded protein is upregulated in aging and
downregulated in certain tumors. Using a combination of
linkage and association employing SNPs specific to the 10q26
region, Jakobsdottir et al demonstrated that while both
PLEKHA1 and LOC387715 were significantly associated with
both neovascular and atrophic AMD, the association was
stronger for PLEKHA1. Over 1400 affected individuals
comprised of both familial and sporadic cases of AMD were
examined.71 Rivera et al72 extended these findings by
demonstrating that a specific variant within the LOC387715
locus was associated with increased AMD risk after examining
a cohort that consisted of both early and advanced stages.
Similar findings were replicated in a Caucasian population that
consisted of advanced cases, including large drusen (=125 µm),
geographic atrophy and neovascularization.73 These two studies
concluded that LOC387715, and not PLEKHA1, was associated
with AMD. More recently, it was demonstrated that another
variant or SNP in the HTRA1 promotor, in linkage
disequilibrium (LD) with the LOC 387715 variant, is likely the
functional polymorphism responsible for increased AMD
risk.74,75 Given that 10q26 is a region that has been consistently
linked with AMD by many genome-wide scans and that
1896 PLEKHA1, LOC387715, and TRA1 are located adjacent to one
another, teasing out precisely which gene in this region is
associated with AMD may require further investigation.
VASCULAR ENDOTHELIAL GROWTH FACTOR
GENE (VEGF)
VEGF is localized to the short arm of chromosome 6 (6p12), a
region as yet to be identified in any genome-wide scan (Table
143.2). The role of VEGF as a regulator of angiogenesis is well
established. Further, VEGF is a target for therapeutic
interventions, such as Macugen and Lucentis. Only one
study to date has examined the genetic contribution of VEGF
to AMD.66
Employing a combination of linkage (family-based) and
association (sporadic) analysis using SNPs, common variation
in this gene was significantly found to be associated with
AMD.66 The affected individuals consisted of those with drusen
only (63–125 mm) geographic atrophy or neovascularization.
EXCISION REPAIR CROSS-
COMPLEMENTATION GROUP 6 GENE (ERCC6)
ERCC6 is localized to 10q11.23 and functions in the repair of
DNA as well as aging. A SNP in the 5'-untranslated region of
this gene was reported to be significantly associated in the
homozygous state with advanced AMD.76 Further, increased
expression of this gene was observed in lymphocytes from
individuals that were homozygous for his variation. To date
this is the only study showing an association of this gene
with AMD.
HEMICENTIN-1 GENE (FIBULIN 6, FIBL-6)
In 1998 Klein (Oregon) described a family linked to the long
arm of chromosome 1 (1q25–1q32).41 Subsequently, this same
region has been found by many studies to be linked or
associated with both early and advanced stages of AMD (Table
143.3).6,42–46,50 In 2003, Schultz et al analyzed this same
multigenerational family and found that a mutation in
hemicentin-1 (Fibl-6) was associated with the early stage of
AMD.77 Specifically, this group found that a Gln5345Arg
change (a glutamine is replaced by arginine) in exon 104
segregated with the disease. Based on these results, it was
suggested that hemicentin-1 was the gene responsible for the
phenotype observed in this family.76 Since this time, there
have been no other confirmatory reports that the Gln5345Arg
variant in hemicentin-1 is associated with any type of AMD
(Table 143.3).10,40,78,79 However, Iyengar et al46 reported that
this gene could be involved in the etiology of AMD because
linkage was observed for four SNPs in this gene. Iyengar then
further concluded that although they did not find the specific
Gln5345Arg that Schultz did, that maybe other variants in
FIBL-6, as yet to be discovered, could be associated with AMD.46
FIBULIN 5 (FBLN5)
FBLN5, located on the long arm of chromosome 14 (14q32.1),
was chosen as a candidate gene because of its similarity to
Fibulin 3, for which a mutation in this gene is associated with
Doyne's honeycomb dystrophy, a disease with some overlapping
phenotype to AMD (Table 143.2). More recently, the 14q32
region has been reported by one genome-wide scan to be linked
to advanced AMD.51 Like hemicentin-1, FIBLN5 is an
extracellular matrix protein that functions in maintaining the
integrity of elastic lamina, similar to what is found in Bruch's
membrane. Various mutations in FIBLN5 were reported to be
associated with AMD in 7 out of 40 AMD patients in

a case-control study.80 Phenotypically, the seven patients all had
a distinct and unusual pattern of drusen in common. Three
out of the seven patients also had neovascularization. None
of these mutations were found in unaffected individuals.
Stone et al concluded that fibulin 5 accounts for 1.7% of all
cases of AMD.80 A recent study has replicated these as well as
showed that two additional novel variants in FIBLN5 are
associated with other subtypes of AMD.80 This study further
demonstrated in vitro that there is a reduction in secretion of
FIBLN5 in COS7 cells from patients expressing these
variants.81
TOLL-LIKE RECEPTOR 4 GENE (TLR4)
TLR4 is localized to the long arm of chromosome 9 (9q32–q33)
a region previously linked to patients with the advanced forms
of AMD.44 A variant in this gene which functions in innate
immunity and lipid transport and metabolism efflux has been
SECTION 10
previously shown to be associated with a 'decreased' risk of
arteriosclerosis. This same variant, D299G (asparagine is
substituted by glycine), was found to be associated with a
2.6-fold 'increase' in risk of AMD.82 Further, this study
concluded that an individual's risk is increased even more
when this variant is present in the same individual along with
variants in APOE and/or ATP-binding cassette transporter-1
gene (ABCA1) gene. Given the suggestive findings of linkage
and association between TLR4 and AMD further studies are
warranted.
COMPLEMENT FACTOR H GENE (CFH)
The last year in the field of AMD genetics has focused on
the exciting discovery of the association of CFH with AMD
(Fig. 143.2 and Table 143.4). As stated in the beginning of
this chapter, numerous independent reports have shown that
the functional polymorphism Y402H in CFH, where a tyrosine
is substituted by a histidine, to be associated with a two- to
sevenfold increased risk of both early and/or late stages of
AMD.5–12,83 Only one study has found no association of the
CFH gene to AMD.83 This study examined the Y402 variant in
a Japanese cohort with neovascular AMD.84 This negative
finding may be possibly due to the fact that other AMD
susceptibility genes may explain the phenotype in this
Candidate Genes
18
16
14
Number of Studies
12
10
8
6
4
2 neovascular form of AMD. Genes or biological markers that
0
1998 1999 2000 2001 2002 2003
Year of Study
FIGURE 143.2. The number of studies to determine the association
between the candidate genes and AMD. With the number of
candidate genes increasing, the number of studies performed has
also increased each year. Because of recent findings of association of
AMD with the CFH gene, a large number of studies were performed in
2005 and 2006.
Genetics of Age-related Macular Degeneration
population. CFH is localized to 1q32, a region found by both
linkage6,42–46,50 and by a study of association6 to be associated
with any subtype of AMD. CFH functions in regulation of the
alternative complement pathway as well as innate immunity.
Some groups have reported that common variation in CFH,
other than Y402H, is associated with both early and advanced
forms of AMD.9,74,83 Interestingly, some of these same variants
(or a combination of them), including Y402H, are associated
with increased risk for other diseases such as myocardial
infarction,85 hemolytic uremic syndrome (HUS),86 and
membranoproliferative glomerulonephritis (MPGN).87 This by
no means indicates that CFH does not play an important role
in the pathophysiology of AMD but underscores the importance
of examining common variation in multiple susceptibility genes
as well as contributing environmental factors simultaneously to
get a better estimate of an individual's risk of AMD. Several
groups have begun to do this with respect to the contribution of
CFH along with other reported genetic and epidemiological risk
CHAPTER 143
factors for AMD. Some of these studies include, CFH,
LOC387715 and smoking,73 CFH and smoking,12 CFH,
Complement Component 2 Gene (C2), Complement Factor B
Gene (CFB),87 and CFH, C2, CFB, and LOC387715.
COMPLEMENT COMPONENT 2 GENE (C2)
AND COMPLEMENT FACTOR B GENE (CFB)
C2 and CFB are both part of a major histocompatibility com-
plex that, like CFH, regulates the alternative complement
pathway. Recently, Gold et al postulated that because
variation in CFH had been significantly associated with AMD,
genes in the alternative complement pathway may also play a
role in the pathophysiology of AMD.88 This study demonstrated
that combinations of SNPs in these two genes decreased
an individual's risk of AMD. Specifically, the protective effect
on an individual in having variation in these genes was most
significant in those who had two histidine alleles in the CFH
gene. In other words individuals who were homozygous for
the Y402H variation in exon 9 of CFH were afforded the
most protection from risk of AMD.87 These findings were
recently confirmed in a published report that examined
simultaneously CFH, C2, CFB, and LOC387715 on risk of
advanced AMD.
Key Features
• A role for Inflammation, lipid transport and metabolism as well
as oxidative stress in the pathophysiology of AMD may be
supported by findings that show that candidate genes
associated with these pathways may be involved in the early
or late stages of AMD
• The CFH Y402H variant is the most consistently associated
genetic risk factor for AMD
• Genome-wide scans and candidate gene association studies
are complementary methods
In summary, genes could potentially be used as biological
markers in the early or presymptomatic diagnosis of the
are identified can then be used as possible disease targets for
2004 2005 2006 the development of preventative therapies for AMD. Further the
findings of candidate gene associations with risk of AMD
point to possible mechanisms or pathways involved in the
etiology of AMD. Studying the hypothesized mechanisms
involving oxidative stress, inflammation, and lipid metabolism
from both an epidemiologic (reviewed in detail elsewhere in
this book) and genetic perspective is necessary to further
elucidate the role of these pathways in AMD. Given the 1897
 RETINA AND VITREOUS
multifactorial and heterogeneous nature of AMD, comple-
mentary methods are necessary to detect weak to moderate
associations to identify the contribution epidemiologic and
genetic risk factors make independently and in combination
in order to more accurately determine the overall risk of
REFERENCES
1. The Eye Diseases Prevalence Research
Group: Prevalence of Age-Related Macular
Degeneration in the United States. Arch 16.
Ophthalmol 2004; 122:564–572.
2. Klein R, Klein BE, Linton KL: Prevalence of
age-related maculopathy. The beaver dam
eye study. Ophthalmology 1992;
99:933–943.
3. Ferris FL, Davis MD, Clemons TE, et al: A
simplified severity scale for age-related 17.
SECTION 10
macular degeneration. Arch Ophthalmol
2005; 123:1570–1574.
4. Thornton J, Edwards R, Mitchell P, et al:
Smoking and age-related macular
degeneration: a review of association. Eye 18.
2005; 19:935–944.
5. Edwards AO, Ritter R III, Abel KJ, et al:
Complement factor H polymorphism and
age-related macular degeneration. Science
2005; 308:421–424. 19.
6. Klein RJ, Zeiss C, Chew EY, et al:
Complement factor H polymorphism in
age-related macular degeneration. Science
2005; 308:385–389.
7. Haines JL, Hauser MA, Schmidt S, et al:
Complement factor H variant increases the
risk of age-related macular degeneration. 20.
Science 2005; 308:419–421.
8. Zareparsi S, Branham KEH, Li M, et al:
Strong association of the Y402H variant in
complement factor H at 1q32 with
susceptibility to age-related macular 21.
degeneration. Am J Hum Genet 2005;
77:5–13.
9. Hageman GS, Anderson DH, Johnson LV,
et al: A common haplotype in the
complement regulatory gene factor H 22.
(HF1/CFH) predisposes individuals to age-
related macular degeneration. Proc Natl
Acad Sci USA 2005; 102:7227–7232.
10. Conley YP, Thalamuthu A, Jakobsdottir J,
et al: Candidate gene analysis suggests a
role for fatty acid biosynthesis and 23.
regulation of the complement system in the
etiology of age-related maculopathy. Hum
Mol Genet 2005; 14:1991–2002.
11. Souied EH, Leveziel N, Richard F, et al:
Y402H complement factor H polymorphism 24.
associated with exudative age-related
macular degeneration in the French
population. Mol Vis 2005; 11:1135–1140.
12. Sepp T, Khan JC, Thurlby DA, et al:
Complement factor H variant Y402H is a 25.
major risk determinant for geographic
atrophy and choroidal neovascularization in
smokers and nonsmokers. Invest
Ophthalmol Vis Sci 2006; 47:536–540.
13. Seddon JM, Ajani UA, Mitchell BD. Familial
aggregation of age-related maculopathy. 26.
Am J Ophthalmol 1997; 123:199–206.
14. Hammond CJ, Webster AR, Snieder H,
et al: Genetic influence on early age-related
maculopathy: a twin study. Ophthalmology 27.
2002; 109:730–736.
15. Allikmets R, Seddon JM, Bernstein PS,
et al: Evaluation of the Best disease gene
1898 in patients with age-related macular
AMD. Both population stratification between cases and
controls as well as heterogeneity in phenotype among cases, can
confound findings in analysis of data. Inconsistency in
replication of findings among studies could possibly be due to
these factors.
degeneration and other maculopathies.
Hum Genet 1999; 104:449–453.
Kramer F, White K, Pauleikhoff D, et al:
Mutations in the VMD2 gene are associated
with juvenile-onset vitelliform macular
dystrophy (Best disease) and adult
vitelliform macular dystrophy but not age-
related macular degeneration. Eur J Hum
Genet 2000; 8:286–292.
Lotery AJ, Munier FL, Fishman GA, et al:
Allelic variation in the VMD2 gene in best
disease and age-related macular
degeneration. Invest Ophthalmol Vis Sci
2000; 41:1291–1296.
Akimoto A, Akimoto M, Kuroiwa S, et al: Lack
of association of mutations of the bestrophin
gene with age-related macular degeneration
in non-familial Japanese patients. Graefes
Arch Clin Exp Ophthalmol 2001; 239:66–68.
Seddon JM, Afshari MA, Sharma S, et al:
Assessment of mutations in the Best
macular dystrophy (VMD2) gene in patients
with adult-onset foveomacular vitelliform
dystrophy, age-related maculopathy, and
bull's-eye maculopathy. Ophthalmology
2001; 108:2060–2067.
De La Paz MA, Pericak-Vance MA,
Lennon F, et al: Exclusion of TIMP3 as a
candidate locus in age-related macular
degeneration. Invest Ophthalmol Vis Sci
1997; 38:1060–1065.
Felbor U, Doepner D, Schneider U, et al:
Evaluation of the gene encoding the tissue
inhibitor of metalloproteinases-3 in various
maculopathies. Invest Ophthalmol Vis Sci
1997; 38:1054–1059.
Kemp CM, Jacobson SG, Cideciyan AV,
et al: RDS gene mutations causing retinitis
pigmentosa or macular degeneration lead
to the same abnormality in photoreceptor
function. Invest Ophthalmol Vis Sci 1994;
35:3154–3162.
Gorin MB, Jackson KE, Ferrell RE, et al:
A peripherin/retinal degeneration slow
mutation (Pro-210-Arg) associated with
macular and peripheral retinal degeneration.
Ophthalmology 1995; 102:246–255.
Stone EM, Lotery AJ, Munier FL, et al:
A single EFEMP1 mutation associated with
both Malattia Leventinese and Doyne
honeycomb retinal dystrophy. Nat Genet
1999; 22:199–202.
Guymer RH, McNeil R, Cain M, et al:
Analysis of the Arg345Trp disease-
associated allele of the EFEMP1 gene in
individuals with early onset drusen or
familial age-related macular degeneration.
Clin Exp Ophthalmol 2002; 30:419–423.
Narendran N, Guymer RH, Cain M,
Baird PN. Analysis of the EFEMP1 gene in
individuals and families with early onset
drusen. Eye 2005; 19:11–15.
Allikmets R, Shroyer NF, Singh N, et al:
Mutation of the Stargardt disease gene
(ABCR) in age-related macular
degeneration. Science 1997;
277:1805–1807.
28. Allikmets R: Further evidence for an
association of ABCR alleles with age-
related macular degeneration. The
International ABCR Screening Consortium.
Am J Hum Genet 2000; 67:487–491.
29. Stone EM, Webster AR, Vandenburgh K,
et al: Allelic variation in ABCR associated
with Stargardt disease but not age-related
macular degeneration [letter]. Nat Genet
1998; 20:328–329.
30. De La Paz MA, Guy VK, Abou-Donia S,
et al: Analysis of the Stargardt disease
gene (ABCR) in age-related macular
degeneration. Ophthalmology 1999;
106:1531–1536.
31. Souied EH, Ducroq D, Gerber S, et al:
Age-related macular degeneration in
grandparents of patients with Stargardt
disease: genetic study. Am J Ophthalmol
1999; 128:173–178.
32. Rivera A, White K, Stohr H, et al:
A comprehensive survey of sequence
variation in the ABCA4 (ABCR) gene in
Stargardt disease and age-related macular
degeneration. Am J Hum Genet 2000;
67:800–813.
33. Guymer RH, Heon E, Lotery AJ, et al:
Variation of codons 1961 and 2177 of
the Stargardt disease gene is not
associated with age-related macular
degeneration. Arch Ophthalmol 2001;
119:745–751.
34. Webster AR, Heon E, Lotery AJ, et al:
An analysis of allelic variation in the
ABCA4 gene. Invest Ophthalmol Vis Sci
2001; 42:1179–1189.
35. Bernstein PS, Leppert M, Singh N, et al:
Genotype-phenotype analysis of ABCR
variants in macular degeneration probands
and siblings. Invest Ophthalmol Vis Sci
2002; 43:466–473.
36. Schmidt S, Postel EA, Agarwal A, et al:
Detailed analysis of allelic variation in the
ABCA4 gene in age-related maculopathy.
Invest Ophthalmol Vis Sci 2003;
44:2868–2875.
37. Schick JH, Iyengar SK, Klein BE, et al:
A whole-genome screen of a quantitative
trait of age-related maculopathy in sibships
from the Beaver Dam Eye Study. Am J
Hum Genet 2003; 72:1412–1424.
38. Schmidt S, Scott WK, Postel EA, et al:
Ordered subset linkage analysis supports a
susceptibility locus for age-related macular
degeneration on chromosome 16p12. BMC
Genet 2004; 5:18.
39. Ayyagari R, Zhang K, Hutchinson A, et al:
Evaluation of the ELOVL4 gene in patients
with age-related macular degeneration.
Ophthalmic Genet 2001; 22:233–239.
40. Seitsonen S, Lemmela S, Holopainen J,
et al: Analysis of variants in the
complement factor H, the elongation of
very long chain fatty acids – like 4 and the
hemicentin 1 genes of age-related macular
degeneration in the Finnish population.
Mol Vis 2006; 12:796–801.

41. Klein ML, Schultz DW, Edwards A, et al:
Age-related macular degeneration. Clinical
features in a large family and linkage to
chromosome 1q. Arch Ophthalmol 1998;
116:1082–1088.
42. Weeks DE, Conley YP, Tsai HJ, et al:
Age-related maculopathy: an expanded
genome-wide scan with evidence of
susceptibility loci within the 1q31 and
17q25 regions. Am J Ophthalmol 2001;
132:682–692.
43. Weeks DE, Conley YP, Tsai HJ, et al: Age-
related maculopathy: a genomewide scan
with continued evidence of susceptibility
loci within the 1q31, 10q26, and 17q25
regions. Am J Hum Genet 2004;
75:174–189.
44. Majewski J, Schultz DW, Weleber RG, et al:
Age-related macular degeneration – a
genome scan in extended families. Am J
Hum Genet 2003; 73:540–550.
45. Seddon JM, Santangelo SL, Book K, et al:
A genomewide scan for age-related
macular degeneration provides evidence
for linkage to several chromosomal regions.
Am J Hum Genet 2003; 73:780–790.
46. Iyengar SK, Song D, Klein BEK, et al:
Dissection of genomewide-scan data in
extended families reveals a major locus
and oligogenic susceptibility for age-related
macular degeneration. Am J Hum Genet
2005; 74:39.
47. Abecasis GR, Yashar BM, Zhao Y, et al:
Age-related macular degeneration: a high-
resolution genome scan for susceptibility
loci in a population enriched for late-stage
disease. Am J Hum Genet 2004;
74:482–494.
48. Weeks DE, Conley YP, Mah TS, et al: A full
genome scan for age-related maculopathy.
Hum Mol Genet 2000; 9:1329–1349.
49. Kenealy SJ, Schmidt S, Agarwal A, et al:
Linkage analysis for age-related macular
degeneration supports a gene on
chromosome 10q26. Mol Vis 2004; 10:57–61.
50. Fisher SA, Abecasis GR, Yashar BM, et al:
Meta-analysis of genome scans of age-
related macular degeneration. Hum Mol
Genet 2005; 14:2257–2264.
51. Jun G, Klein BE, Klein R, et al: Genome-
wide analyses demonstrate novel loci that
predispose to drusen formation. Invest
Ophthalmol Vis Sci 2005; 46:3081–3088.
52. Klaver CC, Kliffen M, Van Duijn CM, et al:
Genetic association of apolipoprotein E
with age-related macular degeneration.
Am J Hum Genet 1998; 63:200–206.
53. Souied EH, Benlian P, Amouyel P, et al:
The e4 allele of the alipoprotein E gene as
a potential protective factor for exudative
age-related macular degeneration. Am J
Ophthalmol 1998; 125:353–359.
54. Simonelli F, Margaglione M, Testa F, et al:
Apolipoprotein E polymorphisms in age-
related macular degeneration in an Italian
population. Ophthalmic Res 2001;
33:325–328.
55. Schmidt S, Saunders AM, De La Paz MA,
et al: Association of the apolipoprotein E
gene with age-related macular
degeneration: possible effect modification
by family history, age, and gender. Mol Vis
2000; 6:287–293.
56. Schmidt S, Klaver CC, Saunders AM, et al:
A pooled case-control study of the
apolipoprotein E (APOE) gene in age-
related maculopathy. Ophthalmic Genet
2002; 23:209–223.
Genetics of Age-related Macular Degeneration
57. Zareparsi S, Reddick AC, Branham KE,
et al: Association of apolipoprotein E alleles
with susceptibility to age-related macular
degeneration in a large cohort from a single
center. Invest Ophthalmol Vis Sci 2004;
45:1306–1310.
58. Baird PN, Guida E, Chu DT, et al: The
epsilon2 and epsilon4 alleles of the
apolipoprotein gene are associated with
age-related macular degeneration. Invest
Ophthalmol Vis Sci 2004; 45:1311–1315.
59. Pang CP, Baum L, Chan WM, et al: The
apolipoprotein E epsilon4 allele is unlikely
to be a major risk factor of age-related
macular degeneration in Chinese.
Ophthalmologica 2000; 214:289–291.
60. Schmidt S, Haines JL, Postel EA, et al:
Joint effects of smoking history and APOE
genotypes in age-related macular
degeneration. Mol Vis 2005; 11:941–949.
61. Schultz DW, Klein ML, Humpert A, et al:
Lack of an association of apolipoprotein E
gene polymorphisms with familial age-
related macular degeneration. Arch
Ophthalmol 2003; 121:679–683.
62. Gotoh N, Kuroiwa S, Kikuchi T, et al:
Apolipoprotein E polymorphisms in
Japanese patients with polypoidal
choroidal vasculopathy and exudative
age-related macular degeneration. Am J
Ophthalmol 2004; 138:567–573.
63. Ikeda T, Obayshi H, Hasegawa G, et al:
Paraoxonase gene polymorphisms and
plasma oxidized low-density lipoprotein
level as possible risk factors for exudative
age-related macular degeneration. Am J
Ophthalmol 2001; 132:191–195.
64. Baird PN, Chu D, Guida E, et al:
Association of the M55L and Q192R
paraoxonase gene polymorphisms with
age-related macular degeneration. Am J
Ophthalmol 2004;138:665–666.
65. Esfandiary H, Chakravarthy U, Patterson C,
et al: Association study of detoxification
genes in age related macular degeneration.
Br J Ophthalmol 2005; 89:470–474.
66. Haines JL, Schnetz-Boutaud N, Schmidt S,
et al: Functional candidate genes in age-
related macular degeneration: significant
association with VEGF, VLDLR, and LRP6.
Invest Ophthalmol Vis Sci 2006;
47:329–335.
67. Kimura K, Isashiki Y, Sonoda S, et al:
Genetic association of manganese
superoxide dismutase with exudative
age-related macular degeneration. Am J
Ophthalmol 2000; 130:769–773.
68. Zurdel J, Finckh U, Menzer G, et al: CST3
genotype associated with exudative age
related macular degeneration. Br J
Ophthalmol 2002; 86:214–219.
69. Hamdi HK, Reznik J, Castellon R, et al:
Alu DNA polymorphism in ACE gene is
protective for age-related macular
degeneration. Biochem Biophys Res
Commun 2002; 295:668–672.
70. Tuo J, Smith BC, Bojanowski CM, et al:
The involvement of sequence variation and
expression of CX3CR1 in the pathogenesis
of age-related macular degeneration.
FASEB J 2004; 18:1297–1299.
71. Jakobsdottir J, Conley YP, Weeks DE,
et al: Susceptibility genes for age-related
maculopathy on chromosome 10q26.
Am J Hum Genet 2005; 77:407.
72. Rivera A, Fisher SA, Fritsche LG, et al:
Hypothetical LOC387715 is a second
major susceptibility gene for age-related
macular degeneration, contributing
independently of complement factor H to
disease risk. Hum Mol Genet 2005;
14:3227–3236.
73. Schmidt S, Hauser MA, Scott WK, et al:
Cigarette smoking strongly modifies the
association of LOC387715 and age-related
macular degeneration. Am J Hum Genet
2006; 78:852–864.
74. Dewan A, Liu M, Hartman S et al: HTRA1
promoter polymorphism in wet age-related
macular degeneration. Science
2006;10;314:989–992.
75. Yang Z, Camp NJ, Sun H et al: A variant of
the HTRA1 gene increases susceptibility to
age-related macular degeneration. Science
2006 November 10;314:992–993.
76. Tuo J, Ning B, Bojanowski CM, et al:
Synergic effect of polymorphisms in
ERCC6 5' flanking region and complement
CHAPTER 143
factor H on age-related macular
degeneration predisposition. Proc Natl
Acad Sci USA 2006; 103:9256–9261.
77. Schultz DW, Klein ML, Humpert AJ, et al:
Analysis of the ARMD1 locus: evidence
that a mutation in HEMICENTIN-1 is
associated with age-related macular
degeneration in a large family. Hum Mol
Genet 2003; 12:3315–3323.
78. Hayashi M, Merriam JE, Klaver CC, et al:
Evaluation of the ARMD1 locus on 1q25–31
in patients with age-related maculopathy:
genetic variation in laminin genes and in
exon 104 of HEMICENTIN-1. Ophthalmic
Genet 2004; 25:111–119.
79. McKay GJ, Clarke S, Hughes A, et al:
A novel diagnostic test detects a low
frequency of the hemicentin Gln5345Arg
variant among Northern Irish age related
macular degeneration patients. Mol Vis
2004; 10:682–687.
80. Stone EM, Braun TA, Russell SR, et al:
Missense variations in the fibulin 5 gene
and age-related macular degeneration.
N Engl J Med 2004; 351:346–353.
81. Lotery AJ, Baas D, Ridley C, et al: Reduced
secretion of fibulin 5 in age-related macular
degeneration and cutis laxa. Hum Mutat
2006; 27:568–574.
82. Zareparsi S, Buraczynska M, Branham
KEH, et al: Toll-like receptor 4 variant
D299G is associated with susceptibility to
age-related macular degeneration. Hum
Mol Genet 2005; 14:1449–1455.
83. Li M, tmaca-Sonmez P, Othman M, et al:
CFH haplotypes without the Y402H coding
variant show strong association with
susceptibility to age-related macular
degeneration. Nat Genet 2006;
38:1049–1054.
84. Gotoh N, Yamada R, Hiratani H, et al: No
association between complement factor H
gene polymorphism and exudative age-
related macular degeneration in Japanese.
Hum Genet 2006; 120:139–143.
85. Kardys I, Klaver CC, Despriet DD, et al: A
common polymorphism in the complement
factor H gene is associated with increased
risk of myocardial infarction: the Rotterdam
Study. J Am Coll Cardiol 2006;
47:1568–1575.
86. Fremeaux-Bacchi V, Kemp EJ, Goodship
JA, et al: The development of atypical
haemolytic-uraemic syndrome is influenced
by susceptibility factors in factor H and
membrane cofactor protein: evidence from
two independent cohorts. J Med Genet
2005; 42:852–856. 1899
 RETINA AND VITREOUS
87. brera-Abeleda MA, Nishimura C, Smith JL,
et al: Variations in the complement
regulatory genes factor H (CFH) and factor
H related 5 (CFHR5) are associated with
membranoproliferative glomerulonephritis
type II (dense deposit disease). J Med
Genet 2006; 43:582–589.
88. Gold B, Merriam JE, Zernant J, et al:
Variation in factor B (BF) and complement
component 2 (C2) genes is associated with
age-related macular degeneration. Nat
Genet 2006; 38:458–462.
89. Melrose MA, Magargal LE, Lucier AC:
Identical twins with subretinal
neovascularization complicating senile
macular degeneration. Ophthalmic Surg
1985;16:648–651.
SECTION 10
1900
90. Meyers SM, Zachary AA: Monozygotic
twins with age-related macular
degeneration. Arch Ophthalmol
1988;106:651–553.
91. Dosso AA, Bovet J: Monozygotic twin
brothers with age-related macular
degeneration. Ophthalmologica
1992;205:24–28.
92. Klein ML, Mauldin WM, Stoumbos VD.
Heredity and age-related macular
degeneration. Observations in monozygotic
twins. Arch Ophthalmol 1994;112:932–937.
93. Meyers SM: A twin study on age-related
macular degeneration. Trans Am
Ophthalmol Soc 1994;92:775–843.
94. Gottfredsdottir MS, Sverrisson T, Musch
DC, Stefansson E: Age related macular
degeneration in monozygotic twins and
their spouses in Iceland. Acta Ophthalmol
Scand 1999;77:422–425.
95. Grizzard SW, Arnett D, Haag SL: Twin study
of age-related macular degeneration.
Ophthalmic Epidemiol 2003;10:315–322.
96. Seddon JM, Cote J, Page WF, et al: The
US twin study of age-related macular
degeneration: relative roles of genetic and
environmental influences. Arch Ophthalmol
2005;123:321–327.
97. Assink JM, Klaver CC, Houwing-
Duistermaat JJ et al: Heterogeneity of the
genetic risk in age-related macular disease:
A population-based familial risk study.
Ophthalmology 2005;112:482–487.
 CHAPTER
Age-Related Macular Degeneration: Drusen and
144 Geographic Atrophy
Susan B. Bressler, Diana V. Do, and Neil M. Bressler

Age-related macular degeneration (AMD) is the leading cause of appear hyperfluorescent (brighter than the background fluor-
irreversible blindness in individuals age 55 and older.1 AMD escence), hypofluorescent (darker than the background fluor-
may be classified into a neovascular (exudative) form (discussed escence), or isofluorescent (unable to be distinguished from the
in Chapter 146) and a non-neovascular (nonexudative) form. background fluorescence).11 In a case series of 180 consecutive
The non-neovascular form features drusen and abnormalities eyes, small, hard drusen appeared as isofluorescent spots that
of the retinal pigment epithelium (RPE), such as geographic were difficult to discern from the background fluorescence.11
atrophy (GA), nongeographic areas of atrophy, and focal areas Small, hard drusen are not sufficient to diagnose AMD for
of hyperpigmentation within the macula. Clinical features, the following reasons:
clinicopathologic correlation, differential diagnosis, natural 1. The presence of at least one small drusen in the macula is
course, and treatment of the non-neovascular form of AMD nearly ubiquitous on fundus photographs3,6 and
are reviewed in this chapter. (The epidemiology of AMD is postmortem examination12 in individuals older than 40
discussed in Chapter 38.) years.
2. The incidence of small, hard drusen is not age-related.13
CLINICAL FEATURES AND 3. The presence of small drusen is not associated with an
CLINICOPATHOLOGIC CORRELATION increased risk of the development of the neovascular form
of AMD when compared with the risk associated with
large, soft drusen.4,14,15
DRUSEN
Multiple small, yellow-white lesions located within Bruch’s
membrane in the macula, commonly found in patients older
than 50 years, are called drusen. The term drusen is German
and is the plural for geode, a nodular stone with an interior
cavity lined with crystals.2 The relationship of drusen to AMD
may be somewhat confusing as drusen may vary greatly in
appearance and several types of yellow-white lesions may be
seen at the level of the RPE within the macula. These lesions
may be conveniently categorized into (1) small, hard drusen; (2)
large, soft drusen; and (3) cuticular (basal laminar) drusen.
Large, soft drusen, identified within two disc diameters of the
foveal center, are the form of drusen most commonly
considered to be a feature of AMD.

Small, Hard Drusen

Small drusen have been defined in most studies as having a
greatest linear dimension of less than 50 mm3,4 or less than
63 mm in diameter (Fig. 144.1).5–7 The latter definition has been
adopted, internationally, as the standard and was incorporated
into the Age-Related Eye Disease Study (AREDS) classification
of AMD.8,9 The borders of small drusen are almost always
distinct and well defined, contributing to the designation of
hard drusen.3,4
The fluorescein angiographic characteristics of drusen can
vary depending on their size, content, and RPE depigmentation
on their surface. Small drusen may appear as well-defined focal
spots of hyperfluorescence within the first few minutes of the
FIGURE 144.1. Hard drusen usually appear clinically as small yellow
angiogram.10 In the late frames these minute spots frequently punctate lesions at the level of the retinal pigment epithelium (RPE)
fade. Fluorescein angiography may also reveal the presence of with sharp discrete borders. These changes have been shown to
many more drusen than are apparent on slit-lamp bio- correspond to lipoid degeneration of a few discrete RPE cells without
microscopy. Indocyanine green angiography (ICG) of drusen evidence of diffuse thickening of the inner aspect of Bruch's
has demonstrated several patterns of fluorescence. Drusen may membrane throughout the macula. 1901
 RETINA AND VITREOUS
4. Clinicopathologic correlation demonstrates that these
small lesions represent either a lipidization of a few RPE
cells16 or a localized accumulation (nodule) of hyaline
material in the inner collagenous zone of Bruch’s
membrane,16 which can be otherwise totally normal on
either side of this nodule. The presence of these localized
accumulations in an otherwise normal Bruch’s membrane
makes it unlikely that these small, hard drusen are a
feature of a diffusely dysfunctioning RPE–Bruch’s
membrane–choriocapillaris complex.
However, many small drusen may be a precursor lesion for the
development of AMD, as the Chesapeake Bay Waterman Study
and the Beaver Dam Eye Study have each found that eyes with
numerous small, hard drusen are at increased risk of developing
soft or large drusen over time.13,17 The AREDS also reported
that roughly one-third of eyes with extensive small drusen
SECTION 10
progress to extensive numbers of medium size drusen or
develop large drusen within 5 years; thus the presence of many
small drusen do increase the chances in the long run that an eye
may develop more substantial evidence of AMD.15
Large, Soft Drusen
Large drusen have been defined in most studies as having
a dimension that is greater than or equal to 63 mm.5–8 The
borders of large drusen are generally poorly demarcated, without
sharp edges,3,5,8 contributing to the designation of soft drusen.
Soft drusen are typically indistinct (Fig. 144.2a) meaning the
density of the deposit decreases from center to periphery and
the edges are fuzzy. In contast, some large drusen may be
considered soft distinct drusen as they have a solid appearance
with distinct edges, appreciable thickness, and a more uniform
pigment distribution.
Large drusen vary in size, shape, and degree of confluence
(merging of their borders) with neighboring drusen. Sizes of
‘large’ drusen have more recently been classified into 64 to
<125 mm (medium), 125 to <250 mm (large), and ≥250 mm
(very large). Histologically, three types of soft drusen have been
identified:
1. localized detachments of RPE and basal linear deposit
(diffuse drusen) in eyes with diffuse basal linear deposits,
2. localized detachments of RPE and basal laminar deposit in
eyes with diffuse basal laminar deposits, and
a b
c d
1902
3. localized RPE detachments due to focal accumulation of
basal linear deposit in eyes without diffuse basal linear
deposits.18,19
Basal linear deposit, also known as diffuse drusen or diffuse
thickening of the inner aspect of Bruch’s membrane, lies
external to the RPE basement membrane or within the inner
collagenous zone of Bruch’s membrane, in contrast to basal
laminar deposit, which is situated between the plasma
membrane and the basement membrane of the RPE. These
deposits also differ in their ultrastructural characteristics. Basal
linear deposits consist of granular and vesicular lipid-rich
material and may contain widely spaced collagen, whereas basal
laminar deposits consist mainly of widely spaced collagen.20
Clinically, one cannot detect the diffuse thickening of the inner
aspect of Bruch’s membrane associated with basal linear or
basal laminar deposit; however, when there are areas of RPE
hypopigmentation overlying this diffusely thickened Bruch’s
membrane or when this diffuse thickening weakens the inner
aspect of Bruch’s membrane and predisposes it to separation,
or both, one recognizes these areas clinically as soft drusen
(Fig. 144.2b).
Clinically, soft drusen are believed to be a feature of non-
neovascular AMD for the following reasons:
1. The incidence and prevalence of soft drusen have been
shown to be age related among many different population-
based studies both nationally and abroad.3,6,13,17,21–25
2. Soft drusen are associated with an increased risk of
development of RPE abnormalities,13 GA,13,15 and
choroidal neovascularization (CNV).4,13–15,25,26
3. Clinicopathologic correlation demonstrates that the
presence of soft drusen represents diffuse thickening of the
inner aspect of Bruch’s membrane throughout the
macula.27,18
4. In the neovascular form of AMD (see Chapter 146)
pathologic features, including CNV or disciform scarring,
are usually noted in eyes that also have diffuse thickening
of the inner aspect of Bruch’s membrane throughout the
macular region.27,18–20
During fluorescein angiography staining of drusen (Fig. 144.2c
and 144.2d) may be noted in areas in which overlying RPE
hypopigmentation allows increased visualization of choroidal
fluorescence or in areas in which fracturing of this diffuse
FIGURE 144.2. (a) Soft drusen are seen
clinically as large yellow lesions with
amorphous, ill-defined borders (arrow) at the
level of the RPE. (b) It is suspected that the soft
drusen noted clinically usually correspond to
areas of diffuse thickening of the inner aspect
of Bruch's membrane at the point at which
focal areas of RPE hypopigmentation have
developed in areas overlying this diffuse
thickening or at the point at which fracturing of
the diffusely thickened inner aspect of Bruch’s
membrane has separated from the remaining
outer aspect of Bruch's membrane. (c) and (d)
It is suspected that drusen may stain more
intensely (arrows) in the late phases of the
angiogram when this fracturing is present,
presumably because the fluorescein molecules
collect between the detached inner aspect and
the remainder of Bruch’s membrane.
 Age-Related Macular Degeneration: Drusen and Geographic Atrophy
thickening provides a space for fluorescein molecules to pool
(Fig. 144.2d). Some investigators have suggested that the
hydrophobic or hydrophilic properties of drusen, determined by
their lipid composition, may account for hypo- or hyper-
fluorescence, respectively.28 However, this latter theory does not
as yet have direct fluoroangiographic–pathologic correlation.
Indocyanine green imaging of soft large drusen (≥125 mm) with
indistinct margins may demonstrate hypofluorescent spots with
a thin hyperfluorescent margin on the outside border of the
drusen in the early phase which persists in the late phase.11 The
thin hyperfluorescent margin may represent localization of
indocyanine green to the periphery of the drusen with poor
penetration into the substance of the drusen.
More recently, drusen have been imaged by optical coherence
tomography (OCT) and morphologic changes may be present at
the level of the external highly reflective band that represents
the RPE/Bruch’s membrane/choriocapillaris complex.29 In eyes
with soft, large drusen, OCT may demonstrate irregularity in
the contour of the external highly reflective band consistent
with accumulation of material within or beneath Bruch’s mem-
brane. In eyes with drusenoid pigment epithelial detachments,
a term generally used to describe a confluent mound of large
drusen, OCT shows focal elevation of the external highly reflective
band with moderately reflective material underneath this band.
ABNORMALITIES OF THE RPE
The development of diffuse thickening of the inner aspect of
Bruch’s membrane associated with the clinical recognition of
soft drusen may also be accompanied by abnormalities of the
RPE. These abnormalities include GA of the RPE, non-GA of
the RPE (also known as RPE depigmentation), focal hyperpig-
mentation, and dystrophic calcification of Bruch’s membrane.
Geographic Atrophy of the RPE
GA of the RPE (also called areolar atrophy) consists of one to
several areas, usually 175 mm or larger in diameter and circular,
a b
c d
of discrete absence or attenuation (depigmentation) of the RPE
overlying choriocapillaris atrophy such that larger-caliber
choroidal vessels may be seen (Fig. 144.3a). The neurosensory
retina overlying GA may appear thinned. GA represents the
most advanced form of nonneovascular AMD. Although it is far
less common than other manifestations of nonneovascular
AMD, when it involves the foveal center it accounts for 12–21%
of the cases of legal blindness attributed to AMD.30–32 Both the
incidence and the prevalence of GA are age-related.1,6,13,21,22
After the age of 70 prevalence of this nonneovascular AMD
feature rises sharply.
Clinically, four patterns have been suggested to lead to GA in
eyes that are presumed to have AMD:
1. Areas of large, soft, confluent drusen may regress and lead
to GA in multiple areas. These multifocal areas eventually
enlarge and coalesce with other similarly derived areas and
forms a ring around the fovea.
2. Alternatively, the central macula may contain tiny areas
CHAPTER 144
of reticulated hypo- and hyperpigmentation, which may
progress to one large area of GA that spreads fairly
contiguously in a horseshoe pattern around the fovea,
eventually completely surrounding it leading to a
bull’s-eye maculopathy. After many years, doughnut-
shaped areas of GA finally spread to include the foveal
center.
3. Spontaneous flattening of a serous pigment epithelial
detachment can also give rise to GA.
4. Lastly, resorption of drusenoid pigment epithelial
detachments, can evolve to GA.33 Drusenoid pigment
epithelial detachments (PEDs) may be defined as elevated
mounds of large drusen or many confluent drusen that
have coalesced. These lesions have well-defined borders,
are pale yellow to white in color, and have a minimum
diameter of 360 microns. Nearly half of the 139 eyes
monitored within AREDS that had drusenoid PEDs at or
shortly after study entry developed central GA during
follow-up of up to 9 years.
FIGURE 144.3. Abnormalities of the RPE
secondary to age-related macular degeneration.
(a) An area of GA, with well-demarcated loss of
pigmentation of the RPE and overlying thinning
of the sensory retina with more apparent
underlying choroidal vasculature. (b) Calcified
drusen that correspond histologically to
dystrophic calcification at the level of the outer
retina. (c) Focal hyperpigmentation or pigment
clumps correspond to clumps of pigment at the
level of the RPE or within the outer aspects of
the sensory retina. (d) Non-GA refers to a
finding of tiny mottled areas of hypo- and
hyperpigmentation that may show some
thinning of the overlying sensory retina.
1903
 RETINA AND VITREOUS
Clinicopathologic correlation has shown replacement of
soft drusen with fibrous tissue or dystrophic calcification.34
The RPE overlying these areas ultimately disappears, producing
small areas of GA. The underlying choriocapillaris may be
sclerosed, with thickening of the intercapillary septae.27 The
areas of GA are usually accompanied by loss of overlying photo-
receptors, accounting for the visual loss that is noted using
scanning laser ophthalmoscopy over these regions. Dystrophic
calcification may accompany GA and appears clinically as
glistening, bright yellow specks within drusen that are under-
going atrophy (Fig. 144.3b), contributing to the term calcified
drusen.
Angiography of GA demonstrates early and discrete hyper-
fluorescence of atrophic areas, presumably resulting from
increased transmission of choroidal fluorescence because of
hypopigmentation, attenuation, or lack of RPE. The chorio-
capillaris may fill slowly or may be entirely absent within
these zones, and the size and shape of these areas do not
SECTION 10
change during the study. In the late frames, persistent staining
of the areas of GA will be noted, owing to increased visibility
of the fluorescein staining of the choroidal and scleral tissue
through the atrophic RPE. OCT imaging of GA demonstrates
disruption, attenuation, or absence of the RPE/Bruch’s
membrane complex with variable thinning of the overlying
neurosensory retina due to loss of photoreceptors.29 In addition,
areas of GA have a highly reflective signal from the choroid
corresponding to enhanced penetration and reflection of the
signal from the choroid due to attenuation of the RPE/Bruch’s
membrane/choriocapillaris complex (Fig. 144.4).
Focal Hyperpigmentation
Focal hyperpigmentation of the RPE consists of areas or
clumps of increased gray or black pigmentation at the level of
the outer retina or subretinal space (Fig. 144.3c). It may be
punctate, linear, or reticular. During fluorescein angiography,
areas of focal hyperpigmentation block background choroidal
fluorescence.
The incidence and prevalence rates of focal hyperpigmen-
tation increase with age,6,13,17,21–23 and eyes with soft or large
drusen are more likely to develop increased retinal pigment
than eyes with no drusen or small drusen.13 Clinical studies
have shown that eyes with focal clumps of hyperpigmentation
identified on color fundus photographs have an increased risk
FIGURE 144.4.
(a) Fundus photograph
of GA that involves the
center of the fovea and
(b) corresponding
optical coherence
tomography
demonstrates a highly
reflective signal from
the choroid
corresponding to
enhanced penetration
and reflection of the
signal from the choroid
due to attenuation of
the RPE/Bruch's
a membrane/chorio-
capillaris complex.
b (two disc diameters using 1500–1800 mm for the standard disc).
1904
of development of soft drusen,13 GA,13 and CNV.4,14,35,36 Some
investigators hypothesized that areas of focal hyperpigmen-
tation may be associated with an increased risk of CNV because
the areas of hyperpigmentation represent disturbances of the
RPE overlying existing occult CNV.37 However, clinico-
pathologic correlation has shown that the areas of focal
pigment can correlate with areas of subretinal or intraretinal
pigment migration to the level of the photoreceptor nuclei,
overlying diffuse thickening of the inner aspect of Bruch’s
membrane without evidence of CNV.19
Nongeographic Atrophy
Non-GA of the RPE (also known as RPE degeneration or RPE
depigmentation) consists of areas of stippled, punctate hypopig-
mentation and pigment mottling in which the underlying
choroidal vessels are not more readily apparent than in areas
without non-GA, but in which the overlying sensory retina
appears to be thinned on stereoscopic examination (Fig. 144.3d).3
In comparison to GA, areas of nongeographic atophy are less
well defined, less regular in shape, and less severe. Fluorescein
angiography of these areas reveals diffuse hyperfluorescence
with a pattern of reticular or punctate blockage corresponding
to the pigment clumping. Clinicopathologic correlation has shown
mottled areas of relative RPE hypopigmentation or atrophy
overlying diffuse basal linear and basal laminar deposit.19 These
areas are similar to the pathologic correlate of large, soft
drusen identified clinically, except the areas of non-GA have
minute foci of hypopigmentation often interspersed with
clumps of hyperpigmentation, whereas clinically apparent soft
drusen have broader areas of RPE hypopigmentation, but often
do not have clumps of hyperpigmentation within the drusen.
Incidence and prevalence rates of this AMD feature are
also age dependent6,13,22,23 and eyes with large drusen are more
likely to develop this characteristic than eyes without large
drusen.13 Similarly, eyes with non-GA are more likely to develop
other features of AMD including soft drusen,13 GA,13,38 and
CNV.13,38
GRADING DRUSEN AND RPE
ABNORMALITIES AND FORMING
CLINICALLY RELEVANT CLASSIFICATION
OF AMD
The Age-Related Eye Disease Study (AREDS), a prospective
multicenter randomized clinical trial involving 4757 partici-
pants designed to evaluate the effects of high-dose vitamin and
mineral supplements on the development and progression of
AMD, has also supplied a wealth of natural history information
about AMD.9,15,38 Features of nonneovascular AMD that impart
a greater degree of risk of progression of AMD have been clearly
identified by performing detailed evaluation of baseline stereo-
scopic color fundus photographs of the macula and monitoring
patients annually with sequential color fundus photographs to
document clinically relevant outcomes of advanced AMD such
as foveal GA or CNV.
The AREDS system for classifying age-related macular
degeneration was based on reasonable quality film based
stereoscopic color fundus photographs of the disc (field 1) and
macula (field 2) of each eye of study participants.9 A standard
grid template adapted from the Early Treatment Diabetic
Retinopathy Study composed of three circles concentric with
the center of the macula was used to identify the area of
interest.39 All features of AMD found within the outer circle
were recorded. The outer circle has a radius of 3000–3600 mm
An additional standard template which consisted of a set of
 Age-Related Macular Degeneration: Drusen and Geographic Atrophy
graduated circles was used to estimate maximum drusen size,
maximum area occupied by drusen, and total area involved
by pigment abnormalities. Figure 144.5 illustrates the grading
grid and the graduated measurement circles with their
corresponding diameters.
The detailed AREDS system for classifying AMD features was
found to have good reproducibility with kappa statistics ranging
from 0.54 to 0.88; however, this system was dependent on
photographs with at least fair quality read by trained and experi-
enced readers.38 A simpler grading method to anticipate risk of
developing advanced AMD was also developed for use in clinical
practice (see section on Data from Cohorts of Participants with
Bilateral Non-Neovascular AMD and Progression to CNV or
Foveal GA).40 Nevertheless, the AREDS system for grading non-
neovascular AMD features has led to a simple classification of
AMD that can be easily adapted for clinical practice by
estimating the number of drusen of a particular size and the
presence, type, and location of pigment abnormalities.
Key Features
Age-Related Eye Disease Study Simplified Severity
Scale
No = 0
Large drusen
Yes = 1 1
Right eye
No = 0
Pigment abnormalities
Yes = 1 1 drusen.41–43 They may be differentiated from more typical soft
No = 0
Large drusen
Yes = 1 1
Left eye
No = 0
Pigment abnormalities
Yes = 1 1 soft drusen. With ICG angiography, basal laminar drusen may
兵
兵
Large drusen & pigment Patient severity scale
abnormalities = 4 risk factors
Severity Score (Risk Factors) – 5 Year Risk for Advanced
Both Eyes AMD in at Least 1 Eye
0 0.5%
1 3%
2 12%
3 25%
4 50%
Scoring System
Assess whether large drusen and pigment abnormalities are
present in each eye and add the number of risk factors. The
number of risk factors correlates with the patient’s estimated risk
of progression to advanced AMD in five years.
AREDS has provided the following clinical classification which
can be used to describe adults at risk for AMD or vision loss
from AMD:9
• No AMD. Absence of any drusen or presence of a few small
drusen (<63 mm diameter drusen occupying <125 mm
diameter circle [equivalent to 5–15 small drusen]) in the
absence of any RPE abnormalities or any later stages of
AMD.
• Early AMD. Extensive small drusen (occupies at least
125 mm diameter circle), or nonextensive medium size
drusen (63 to <125 mm diameter drusen) with or without
pigment abnormalities (increased pigment or
depigmentation) and no other later stages of AMD.
• Intermediate AMD. Extensive medium drusen (occupying
an area of at least 360 mm diameter circle, which is
equivalent to 20 drusen) if the boundaries are indistinct or
occupying an area of 656 mm diameter circle (equivalent to
65 drusen) if the boundaries are distinct or at least one
large druse (≥125 mm, approximately the width of a retinal
vein as it crosses the optic nerve) or the presence of GA
that spares the foveal center (nonfoveal GA).
• Advanced AMD. Geographic atrophy involving the center
of the fovea or CNV or disciform scar.
DIFFERENTIAL DIAGNOSIS
A variety of maculopathies might be confused with the non-
neovascular features of AMD, and they should be differentiated
from drusen or abnormalities of the RPE. These other condi-
tions often have a different prognosis from the non-neovascular
CHAPTER 144
features of AMD. A variety of factors, including demographic,
morphologic features, and distribution of the fundus and
angiographic changes, will help to differentiate these conditions
from AMD.
CUTICULAR (BASAL LAMINAR) DRUSEN
Innumerable small, uniformly sized, discretely round, slightly
raised, yellow subretinal lesions (Fig. 144.6a) that are best seen
with angiography (Fig. 144.6b) and usually present in middle
age (forties to sixties) are called cuticular (basal laminar)
drusen in that retroillumination biomicroscopically demon-
strates semitranslucency of innumerable similar–sized basal
laminar drusen, as opposed to variable–sized, more typical soft
drusen that appear opaquely yellow and are not semitranslu-
cent. During fluorescein angiography, cuticular drusen will
demonstrate early, bright, uniform hyperfluorescence compared
with the variable, less bright hyperfluorescence of more typical
appear as hyperfluorescent spots early in the study which
persist in the late phase of the angiogram.11
The term basal laminar drusen should not be confused with
the term basal laminar deposits, which refers to the
wide–spaced collagen located between the plasma membrane
and the basement membrane of the RPE, or the term basal
linear deposits, which refers to the granular, electron–dense,
lipid–rich material seen ultrastructurally external to the basement
membrane of the RPE. In fact, the term basal linear deposits
corresponds to the diffuse thickening of the inner aspect of
Bruch’s membrane, which was described previously as diffuse
drusen. Clinicopathologic correlation has shown that cuticular
drusen consist of an extremely thick inner aspect of Bruch’s
membrane with overlying nodular excrescences, all beneath the
RPE. Since no cuticle exists, and to avoid the use of the
confusing terms basal laminar and basal linear deposits, it has
been proposed that the clinical features depicted in Figure
144.6, typical of cuticular or basal laminar drusen be called
diffuse drusen with overlying nodular excrescences to more
accurately describe what they are.
Patients with this unusual form of drusen may experience
pseudovitelliform detachments consisting of yellowish material
at the level of the outer retina. The material appears to obscure
details of the RPE, suggesting that it is present between the
sensory retina and the RPE. During fluorescein angiography,
these detachments show early hypofluorescence ( Fig. 144.6b),
presumably because of the ability of the yellowish material to
block the underlying fluorescence of the choriocapillaris.
Progressive staining of the yellowish material becomes apparent 1905
 RETINA AND VITREOUS

a b

FIGURE 144.5. (a) Maculopathy grading grid used in the Age-Related Eye Disease Study. The grid is affixed to a fundus photograph of a left
eye to illustrate the three circles concentric with the center of the fovea and four radial lines in the 1:30, 4:30, 7:30, and 10:30 meridians. The
radius of the inner circle corresponds to 1/3 disc diameter (500 mm), the radius of the middle circle to 1 disc diameter (1500 mm), and the radius
of the outer circle to 2 disc diameters (3000 mm). (b) A set of standard measurement circles for estimating the area involved by various
abnormalities. Three groups of open circles are available and designated C for central, I for inner, and O for outer subfields. For each subfield,
SECTION 10

circle 1 corresponds to 1/64 of the subfield area and circle 2 to 1/16 of the area.
Reproduced from the Age-Related Eye Disease Study Research Group: The age-related eye disease study system for classifying age-related macular degeneration
from stereoscopic color fundus photographs: the AREDS report 6. Am J Ophthalmol 2001; 132:668–681.

FIGURE 144.6. Basal laminar or cuticular

drusen. (a) Color photograph shows
innumerable small, uniformly sized, discretely
round, and slightly raised yellow subretinal
lesions and dull yellow material in the central
macula referred to as a pseudovitelliform
detachment. (b) Angiogram helps highlight
basal laminar drusen. In addition,
hypofluorescence, presumably from the
associated pseudovitelliform detachment,
blocks the underlying fluorescence of the
choriocapillaris. (c) Progressive staining of the
pseudovitelliform detachment material
a b becomes apparent in the middle- and late-
transit phases of the angiogram. (d) With time,
the pseudovitelliform detachment can clear
spontaneously. Geographic atrophy will
sometimes develop with clearing.

c d

in the middle- and late-transit phases of the angiogram
(Fig. 144.6c), likely due to incompetence of the RPE’s zonula
occludens, which fails to keep fluorescein from diffusing from
the choriocapillaris to the subsensory retinal space, with
subsequent staining of the yellowish material. Pseudovitelliform
detachments appear as a mound of highly reflective material
under the neurosensory retina without any adjacent subretinal
fluid on OCT imaging.29 This highly reflective substance
appears to be located between the retina and RPE.
Since the fluorescein hyperfluorescence of a vitelliform
lesion may mimic CNV, one must recognize its appearance
in order to avoid unnecessary delivery of treatment intended
to manage CNV. The natural course of these detachments can
1906 be spontaneous clearing (Fig. 144.6d) with extremely slow
development of atrophy or rapid clearing associated with
marked GA.
These pseudovitelliform detachments should be differentiated
from true vitelliform detachments seen in Best’s disease (in
which the electrooculogram will be abnormal) and from pattern
dystrophies of the RPE that may show pseudovitelliform-like
detachments.
Patients with basal laminar or cuticular drusen have a
diseased Bruchs membrane and are at risk of development of
CNV. Therefore, careful scrutiny of any bright hyperfluores-
cence that appears to leak in these patients is needed to deter-
mine whether the features are due to the presence of CNV or to
progressive staining of the pseudovitelliform detachment.
Sometimes this differentiation is extremely difficult to make.
 Age-Related Macular Degeneration: Drusen and Geographic Atrophy
DOMINANT DRUSEN IN YOUNG INDIVIDUALS
Patients in their teens or twenties may present with large
(>63 mm), discrete nodular drusen. Typically these drusen are
bilateral and in a very symmetric distribution between the two
eyes, such as temporal to the fovea. Even the young children of
these individuals, those under age 10 years, may have discrete
drusen (Fig. 144.7). In the experience of the authors, these
patients may go years without CNV or atrophy developing
and therefore suffer no significant visual loss. When these
lesions are in the macula, they could presumably cause focal
disturbances of Bruch’s membrane and may increase the risk
of the development of CNV but there are no natural history
studies of this condition to date.
PATTERN DYSTROPHY OF THE RPE (ADULT
VITELLIFORM DYSTROPHY, ADULT-ONSET
FOVEAL PIGMENT EPITHELIAL DYSTROPHY,
BUTTERFLY-SHAPED PIGMENT DYSTROPHY,
RETICULAR DYSTROPHY OF THE PIGMENT
EPITHELIUM)
Patients with pattern dystrophy of the RPE will show a
reticulated pattern of pigmentation, usually fairly symmetric
between the two eyes and often without the presence of more
typical soft drusen (Fig. 144.8).44 These dystrophies may have a
yellow deposit at the level of the outer retina (pseudovitelliform
detachment), often with a central area of greenish hyper-
pigmentation (sometimes best seen with transillumination
of the yellowish material), and occasionally surrounded by a
petaloid pattern of hyperpigmentation, which is more obvious
on fluorescein angiography (Fig. 144.8b). These lesions have
a b
FIGURE 144.7. Dominant drusen. (a) A young woman in her twenties demonstrates typical large drusen, some of which have discrete
boundaries. Similar findings are noted in her 9-year-old son (b) and her 6-year-old son (c).
a b
been observed both within families and sporadically. Although,
they are often located in the center of the macula, they may
present eccentrically (Fig. 144.9), accounting for the variety
of appearances on presentation. The pseudovitelliform detach-
ments will not show disruption or layering of the yellow
pigment dependently, as is seen in the vitelliform lesions of
Best’s disease.
Clinicopathologic correlation of pattern dystrophies of the
RPE has shown a thick layer of slightly granular, eosinophilic,
periodic acid-Schiff (PAS)-positive material lying between a
thinned atrophic RPE and Bruch’s membrane, with central
pigment clumping from large pigment-laden cells and extra-
cellular melanin pigment lying between the sensory retina and
Bruch’s membrane.45 A recent (unpublished) clinicopathologic
correlation of an eye with pattern dystrophy and pseudovitel-
liform lesion demonstrated lipofuscin at the outer retinal level
to account for the yellow deposit. The diffuse disturbance of
Bruch’s membrane histologically presumably places these
CHAPTER 144
patients at increased risk of development of CNV through
breaks in the outer aspect of Bruch’s membrane.
More recently, OCT imaging and correlation with fluore-
scein angiographic features of eyes with pseudovitelliform
lesions has provided additional morphologic information on
the location of the yellow deposit. In sixteen eyes with adult-
onset foveomacular vitelliform dystrophy, the yellow foveal
lesion demonstrated early hypofluorescence on fluorescein
angiography with staining and absence of leakage in the late
frames.46 Corresponding OCTs in these eyes revealed a hyper-
reflective structure located between the photoreceptors and
RPE. The retina overlying the hyperreflective structure was
raised by the pseudovitelliform lesion with subsequent loss
of the normal foveal depression but the RPE layer was not
elevated. In five eyes in which fluorescein angiography
c
FIGURE 144.8. Pattern dystrophy of the RPE.
(a) Typical pattern dystrophy in which blocked
fluorescence on angiography corresponds to
pigment clumping or greenish discoloration
seen at the level of the RPE, surrounded by
hyperfluorescence corresponding to dull
yellowish material that has sometimes been
termed a pseudovitelliform detachment. (b) The
angiogram highlights not only the blocked
fluorescence but also very prominent staining
with persistent bright hyperfluorescence in the
late phase of the angiogram, but no leakage.
The absence of leakage helps confirm the
absence of choroidal neovascularization.
1907
 RETINA AND VITREOUS
SECTION 10
FIGURE 144.9. Pattern dystrophy of the RPE in which the blocked
fluorescence and hyperfluorescence occur in a multifocal distribution
outside of the foveal center.
demonstrated persistent central hypofluorescence in the late
frames corresponding to the yellow deposit, OCT revealed no
hyperreflective structure between the photoreceptors and
RPE layers. In these eyes, OCT demonstrated focal thickening
of the hyperreflective RPE layer but no distinguishable
substance between the RPE and retina. Further studies are
needed to confirm these observations.
BULL’S-EYE MACULOPATHY
A variety of conditions may produce a bull’s-eye maculopathy
(usually referring to an area of central pigmentation of the
retina surrounded circumferentially by an area of relative
hypopigmentation and sometimes surrounded, once again
circumferentially, by an area of increased pigmentation). This
condition may progress to GA of the RPE, which typically is
similar to the GA seen in AMD.47 These conditions usually
can be differentiated from GA associated with AMD. The bull’s-
eye maculopathies result in a central area of GA with no
associated soft drusen, whereas GA in AMD is usually
multifocal, with preservation of the fovea until the very late
stages. In addition, the bull’s-eye maculopathies occur in early
or midlife, whereas GA is seen most often in patients in their
late 70s and 80s, with increasing prevalence into the 90s. The
causes of some of these maculopathies include central areolar
choroidal–RPE dystrophy, the Bardet–Biedl syndrome, con-
centric annular macular dystrophy, chloroquine retinopathy,
cone dystrophy, fenestrated sheen macular dystrophy, the
Hallervorden–Spatz syndrome, and fundus flavimaculatus.
NATURAL COURSE
DRUSEN AND RPE ABNORMALITIES
The natural course of an eye with non-neovascular AMD may
ultimately lead to foveal GA, CNV, or both forms of advanced
AMD. The probability that an eye with non-neovascular
AMD will progress to CNV depends on whether the fellow
eye in that individual has non-neovascular AMD in the absence
of CNV or disciform scarring or whether the eye with drusen
or RPE abnormalities, or both, is the fellow eye of a person
whose contralateral eye has already developed the neovas-
1908 cular form of AMD.
Key Features
The Age-Related Eye Disease Study Clinical
Classification of Age-Related Macular Degeneration
(AMD)
• No AMD. Absence of any drusen or presence of a few small
drusen (<63 µm diameter drusen occupying <125 µm diameter
circle (equivalent to 5–15 small drusen)) in the absence of any
RPE abnormalities or any later stages of AMD
• Early AMD. Extensive small drusen (occupies at least 125 µm
diameter circle), or nonextensive medium size drusen
(63 to <125 µm diameter) with or without pigment
abnormalities (increased pigment or depigmentation) and
no other later stages of AMD
• Intermediate AMD. Extensive medium drusen (occupying
an area of at least 360 µm diameter circle (equivalent to
20 drusen) if the boundaries are indistinct or occupying an
area of 656 µm diameter circle (equivalent to 65 drusen) if the
boundaries are distinct) or at least one large druse (≥125 µm,
approximately the width of a retinal vein as it crosses the optic
nerve) or the presence of GA that spares the foveal center
(nonfoveal GA)
• Advanced AMD. Geographic atrophy involving the center of
the fovea or CNV or disciform scar
Data from Fellow Eye Studies and Progression
to CNV
Prior to the AREDS much of the detailed information generated
on the natural course of eyes with non-neovascular AMD had
been acquired by studying the fellow eyes of patients with
unilateral neovascular maculopathy that have participated in
the Macular Photocoagulation Study (MPS) Trials. In these
investigations, a standardized classification was used to grade
macular characteristics on the baseline fundus photographs
of the eyes with nonneovascular AMD. Fundus photograph
readers had no knowledge of the subsequent course of these
eyes. In the 5 year prospective study of fellow eyes of partici-
pants in the Extrafoveal AMD Trial of the MPS, eyes with no
large drusen and no focal hyperpigmentation were at a 10% risk
of developing CNV within 5 years.4 Eyes with large drusen or
focal hyperpigmentation had a 30% risk of developing CNV, and
eyes with both large drusen and focal hyperpigmentation had
about a 60% risk of acquiring CNV within 5 years.4 Subsequent
analyses on a larger number of fellow eyes, ~ 670, among
the individuals participating in the Juxtafoveal and Subfoveal
AMD Trials of the MPS have confirmed the heightened risk
associated with large drusen and have permitted more precise
quantification of that risk. In these subsequent studies, fellow
eyes with large drusen had a 46% chance of developing CNV,
those with focal pigment had a 38% chance, and those eyes with
both factors were at greatest risk with incidence rates of 73% at
5 years.14 Systemic hypertension and numerous drusen (≥5)
were also found to be independent risk factors; an individual
with hypertension, numerous and large drusen, and an area
of pigment had an 87% risk of progressing to CNV within
5 years.14 The development of severe visual loss in these fellow
eyes with nonneovascular AMD at baseline occurred almost
exclusively in the eyes in which CNV developed during follow-
up. Among the fellow eyes that did not develop CNV, the
average visual acuity loss over the 5 year follow-up period was
only 0.4 lines.48
In 2001, the AREDS Group reported on the risk of prog-
ression to advanced AMD among individuals who were
assigned to the placebo group.15 The risk of progression to
advanced AMD (CNV or foveal GA) within 5 years was 1.3%
for individuals with early AMD, 18% for individuals with
 Age-Related Macular Degeneration: Drusen and Geographic Atrophy
intermediate AMD, and 43% for the remaining eye
among individuals with unilateral advanced AMD (fellow
eyes). Among AREDS participants who had neovascular AMD
in their first eye affected with advanced AMD about 37%
progressed to neovascular AMD in their second eye during
a mean follow-up period of 6.2 years. Three ocular risk
factors (largest drusen size, total area occupied by drusen, and
pigmentary abnormalities) were identified as imparting
increased risk that a fellow eye would develop CNV. Logistic
regression analysis adjusted for age, gender, and AREDS
treatment assignment was used to predict development of
CNV in the second eye. The strongest predictive factor for
fellow eye CNV development was total drusen area, however,
substitution of largest drusen size and presence of focal
hyperpigment had nearly the same predictive value. Fellow
eyes with only small drusen with or without focal pigment
were at relatively low risk for CNV with rates of 5% over
5 years; whereas fellow eyes with very large drusen and
pigment were at the highest risk of approximately 50% for
incident CNV during follow-up.49 Treatment with high-dose
antioxidants and zinc resulted in an overall 25% risk
reduction for development of advanced AMD in individuals
who had intermediate or unilateral advanced AMD. The
greatest absolute reduction in risk was identified among the
fellow eyes of participants with unilateral advanced AMD.
Data from Cohorts of Participants with Bilateral
Non-Neovascular AMD and Progression to CNV
or Foveal GA
In addition to evaluating the use of micronutrient supplements
for AMD, another goal of the AREDS was to develop an AMD
severity scale that could provide baseline risk categories to
track progression of AMD in an orderly fashion to appro-
ximate risks of progression to advanced AMD. Furthermore,
development of a severity scale might aid in providing
surrogate outcomes for advanced AMD. A nine-step severity
scale was created that combines six progessive levels of total
drusen area and five progressive levels of pigmentary
abnormalities (increased pigment, depigmentation, and non-
foveal GA).38 Five-year rates of progression to advanced AMD
were as low as less than 1% in step 1 (eyes with minimal
drusen area and absence of pigment abnormalities) of the
scale to ~50% in step 9 (eyes with variable drusen area in the
presence of nonfoveal GA) of the scale. The risk of neo-
vascular AMD increased from steps 1 through 8 in the scale
and then decreased in step 9. The risk of foveal GA was low
from steps 1 through 5 and then increased steadily from steps
5 through 9, an area of the scale that is associated with a greater
degree of pigmentary abnormalities. Additional AREDS
analyses identified presence of calcified drusen as another
independent risk factor for development of GA.50
Although this nine-step severity scale may have utility in a
research setting this scale does not lend itself to use in clinical
practice. Therefore, the AREDS Group developed a simplified
scale for clinical use to predict risk for progression to advanced
AMD. The simple scale was formulated on several observa-
tions made during the construct of the research severity scale,
notably: (1) there was a strong association between drusen
area and largest drusen size; (2) there was a very low frequency
of RPE depigmentation and/or GA in the absence of increased
pigment; and (3) bilateral large drusen is a stronger risk
factor than unilateral large drusen. In the simplified scale,
clinicians are asked to assess the presence of only two
fundus characteristics: (1) large drusen and (2) pigmentary
abnormalities (hyperpigmentation or hypopigmentation, or
nonfoveal GA).40 Each eye of a person is graded separately for (1)
and (2) and for each factor present the eye receives a score of 1
(please refer to Key Features: Age-Related Eye Disease Study
Simplified Severity Scale on page 5). For example, an individual
with large drusen in the right eye and focal pigment in the left
eye would generate a person score of 2, whereas the individual
with bilateral large drusen and bilateral pigment abnormalities
would have a person score of 4. The scale can be adapted for use
in persons with unilateral advanced AMD by scoring the eye
with advanced AMD as 2 and then continuing on to the
contralateral eye to assess features (1) and (2). The range of
person scores is 0–4. The 5 year risk for developing advanced
AMD is 0.5% for individuals with a score of 0, 3% for a score of
1, 12% for a score of 2, 25% for a score of 3, and 50% for a score
of 4. The AREDS simplified scale40 and the nine-step severity
scale38 both confirm previous observations made in the MPS
fellow eye studies: drusen size and pigmentary abnormalities
are independent risk factors for progression to the advanced
stage of AMD.
In addition to the MPS and AREDS, several large population-
CHAPTER 144
based studies have also described the evolution of non-
neovascular AMD fundus manifestations. In the Beaver Dam
Study, 7–12% of eyes with intermediate or large drusen
demonstrated new areas of drusen (progression) and 10–33%
had areas of drusen disappear (regression) over a 5 year
period.13 Eyes with RPE abnormalities also showed significant
change over time with 32–39% developing additional areas of
pigment and 28% demonstrating less involvement during the 5
year period.13 The Chesapeake Bay Waterman follow-up study
had also found drusen and RPE abnormalities to progress in
some and spontaneously regress in others.17 Regarding risk
factors for progression, Beaver Dam eyes with large drusen
(≥125 mm) were more likely to develop increased drusen
area, confluence, focal hyperpigmentation, non-GA, GA, or
neovascular AMD, than were eyes with smaller drusen.13
Eyes with RPE abnormalities were more likely to develop
soft drusen, increased drusen area, confluent drusen, GA, or
neovascular AMD compared with eyes without pigmentary
abnormalities.13 Ten-year data from the Beaver Dam eye study
also confirmed that eyes with soft indistinct drusen or
pigmentary abnormalities at baseline were more likely to
develop advanced AMD at follow-up than eyes without
these lesions (15.1% vs 0.4% for soft indistinct drusen and 20%
vs 0.8% for pigmentary abnormalities).51 Therefore, charac-
teristics of large drusen and pigmentary abnormalities appear
to confer increased risk of developing more advanced AMD
and vision loss, whether found in an individuals with
bilateral nonneovascular disease or individuals with uni-
lateral neovascular maculopathy. Furthermore, these observa-
tions have been made in prospective clinical trials and
confirmed in population based studies.
The Blue Mountains Eye Study also explored the incidence
of advanced AMD among a population based sample in
Australia.52 In this cohort, the 5 year incidence of developing
neovascular AMD or GA (foveal or nonfoveal) was 1.1%. Several
ocular risk factors were associated with progression to
advanced AMD; among right eyes that had non-neovascular
AMD at baseline, the following features conveyed risk: large
drusen (≥125 mm, age-adjusted relative risk [RR] 5.7 [95%
confidence interval (CI) 3.6–9.0]), indistinct soft drusen (RR 9.9
[95% CI 6.4–15.4]), location of drusen within 1500 mm of the
foveal center (RR 11.6 [95% CI 6.7–21.1]), area involved by
large drusen equal to at least one half of the optic disc
(RR 13.5 [95% CI 8.0–22.8]), and presence of hyperpigmen-
tation (RR 8.0 [95% CI 5.4–11.9]). In addition, eyes classified
as having AREDS category 3 (intermediate AMD) or
4 (unilateral advanced AMD) at baseline were 3.9 times (95%
CI 2.3–6.7) more likely to develop advanced AMD over the
5 year period compared to eyes with category 1 or 2. 1909
 RETINA AND VITREOUS
The Rotterdam Study, another population-based cohort
performed in the Netherlands, also evaluated the incidence of
advanced AMD. The 2 year cumulative incidence of advanced
AMD (neovascular AMD or GA) was 0.2% among all study
participants, although this incidence increased to 1.8% among
participants 85 years of age and older.53 Baseline fundus
features that increased the odds that an eye would progress to
advanced AMD included more than 10% of the macular area
covered by drusen (odds ratio (OR) 5.7, 95% CI 2.9–11.3),
presence of depigmentation (OR 4.0, 95% CI 2.5–6.4), presence
of hyperpigmentation (OR 3.4, 95% CI 2.1–5.4), and ≥10%
drusen confluence (OR 2.5, 95% CI 1.7–3.8). Although the
incidence of advanced AMD is quite low in this population
given the limited 2 year follow-up, the results suggest again that
drusen area and pigmentary abnormalities are important risk
factors for progression to advanced stages of AMD.
More recently, the Copenhagen City Eye Study described the
incidence and progression of many AMD features.54 In this
SECTION 10
population-based cohort study, 359 persons of the original 946
subjects were able to participate in the 14 year follow-up
examination. Older subjects at baseline were more apt to
develop features of AMD at follow-up. Among subjects 75–80
years of age at baseline, medium size drusen were 1.8 times as
likely to develop and large drusen were 3.5 times as likely to
develop compared with subjects 60–64 years of age. In addition,
the incidence of soft drusen increased significantly with age
from 21.4% among persons aged 60–64 years to 45.2% among
persons aged 75–80 years. Pigmentary abnormalities also
increased with age such that persons aged 75–80 years were 1.8
times as likely to have hyperpigmentary abnormalities
compared to persons aged 60–64 years. The risk of developing
the advanced stage of AMD was strongly associated with the
presence of soft indistinct drusen (OR 12.2, 95% CI 3.2–47.0),
increased drusen size (63–124 mm: OR 5.0, 95% CI 1.7–14.4;
>125 mm: OR 7.6, 95% CI 1.0–20.2).
NATURAL COURSE OF GEOGRAPHIC
ATROPHY: DEVELOPMENT AND
PROGRESSION
The natural progression of non-neovascular AMD fundus
features to GA has been described in several population-based
studies (as summarized above); however, additional information
gathered from serial color fundus photographs from AREDS
participants has provided greater detail on predisposing
anatomic features and the sequence of events leading to the
formation of GA. Among a cohort of 95 eyes from two AREDS
clinical centers in which GA developed at least 4 years after
their initial study evaluation (range 4–11 years), the following
lesions were determined to have been present at the site of
future GA formation: drusen 95/95 eyes (100%), large drusen
(>125 mm) 91/95 eyes (95.8%), focal hyperpigmentation 91/95
eyes (95.8%), confluent drusen 89/95 eyes (93.7%), very large
drusen (>250 mm) 79/95 eyes (83.2%), hypopigmentation 77/95
eyes (81%), and calcification 20/57 eyes (35%).33 The average
interval from the time of appearance of these specific lesions to
the development of GA was >6.5 years for drusen or confluent
drusen, 4.0 years for hyperpigmentation, 2.3 years for hypopig-
mentation, and 1.5 years for calcification. Among this subset
of AREDS participants, the sequence of events leading to GA
appeared to be accumulation of very large, confluent drusen,
followed by hyperpigmentation appearing at the site and then
regression or fading of drusen with loss of hyperpigmentation
leading to hypopigmentation and then formation of GA.
Several authors have concentrated on eyes that already
manifest GA and monitored them prospectively to learn more
1910 about the natural course of this feature of non-neovascular
AMD. Earlier studies have tried to learn similar information by
identifying eyes with GA and evaluating case files retro-
spectively. One area of interest has been quantifying the rate of
enlargement of the atrophic areas.34,55,56 Schatz and McDonald
retrospectively reviewed 50 eyes with GA; 40% had multifocal
regions of GA to study.55 The average greatest horizontal linear
dimension of the GA was 509 mm at presentation; although the
range was 200–5300 mm. This dimension expanded at an average
rate of 139 mm/yr (~1/10 of a disc diameter). Patients under age
75 years tended to progress faster than patients 75 years and
over, but great variability was noted in both the magnitude and
the direction of progression in the cases reviewed. Sarks and
colleagues reported on a series of 208 eyes with GA.34 They
noted that GA tended to start outside the foveal center, and as
the atrophy encroached within 750 mm of the foveal center, it
approached one disc diameter. Total involvement of the fovea
occurred only in the later stages, such that the average affected
area in eyes with complete GA of the fovea measured more than
seven disc areas (DAs). Visual acuity was related to the per-
centage of fovea affected, but it varied widely, such that it was
difficult to predict visual acuity within a narrow margin of
certainty from the anatomic appearance of the atrophy alone.
Nevertheless, central fixation tended to be lost when atrophy
occupied 85% or more of the fovea.
Patients with GA often have bilateral and symmetric disease,
although there may be differences in onset and progression
rates between the two eyes.34,55,56 One-half of the subjects in
Sarks and colleagues’ study had bilateral GA,34 whereas 13% of
the Beaver Dam population-based study participants with pure
GA had bilateral involvement at baseline.6 However, individuals
with uniocular GA at baseline were at increased risk of devel-
oping GA in their fellow eye by the time of the 5 year follow-up
examination. Among the 12 patients with uniocular GA at the
initial examination, three (25%) developed GA during the 5 year
follow-up. After 10 years of follow-up, individuals with
uniocular GA at baseline were 6.3 times (95% CI 0.9–42.1) as
likely to develop advanced AMD in the uninvolved, fellow eye
as those individuals with early AMD in both eyes at baseline.
Sunness and coworkers prospectively followed 74 patients
with bilateral GA and documented median total area of
involvement of 4.4 DA at presentation (range 0.1–27.7 DA).56
There was a strong correlation between the two eyes of a patient
for the size of the atrophic area. The median rate of spread was
0.73 DA/yr, taking into account changes in all dimensions of
an atrophic area. The median absolute difference in rates of
progression between eyes of a patient was 0.38 DA/yr.
Central visual acuity loss may be gradual and progressive in
eyes with GA, with the degree of impairment directly related to
foveal involvement.57 Since GA involves the foveal center late in
the course of the disease, visual acuity is a poor guide to the
extent of the atrophy or visual impairment a patient may have.
In a study on 83 patients with bilateral GA, with a median
visual acuity of 20/54 in the better-seeing eye, the majority
reported difficulty reading, a need to use low-vision devices,
difficulty seeing in a dim environment, trouble recognizing faces,
and an awareness of a blurry area.58 These symptoms remained
frequent even in a subgroup of 39 patients with visual acuity
better than 20/50 (median 20/35). Scanning laser ophthal-
moscope testing demonstrated dense scotomas in all patients;
therefore, GA-induced scotomas may have a significant impact
on visual function even when they do not involve the foveal
center.
Although GA-induced scotomas impair visual function,
patients with GA often develop an eccentric retinal locus for
fixation. A prospective natural history study of patients with
central GA has demonstrated that 77% of eyes had an eccentric
preferred retinal locus for fixation at baseline.59 After a median
 Age-Related Macular Degeneration: Drusen and Geographic Atrophy
follow-up period of 5.3 years, 91% of eyes had an eccentric
preferred retinal locus for fixation with 81% of eyes retaining
the baseline preferred retinal locus. The most common fixation
patterns were fixation with the scotoma to the right and fixation
with the scotoma superior. Eyes that fixated with the scotoma
to the left tended to have lower reading rates (reading speed)
than eyes that fixated with right or superior patterns.
The precise rate of visual acuity loss in patients with GA has
recently been evaluated prospectively in 74 patients with visual
acuity of 20/50 or better at presentation.60 Rates of vision loss
over a 2 year period are substantial, with 50% doubling their
visual angle (a loss of three or more lines of acuity) and 25%
quadrupling their visual angle (a loss of six or more lines of
acuity). Furthermore, these patients presented with reduced
reading speeds, and this visual function significantly deteri-
orated during the 2 year follow-up period as well. Therefore, all
eyes with GA, even those with a parafoveal location, are at high
risk of significant visual impairment within a few years of
presentation.
Patients with GA report gradual progression of their vision
loss, even when a more precipitous loss of visual acuity is
documented between visits as an atrophic area enlarges and
involves more of the foveal center. Generally, patients with GA
will use central fixation if there is a small foveal region without
atrophy and eccentric fixation when the fovea is totally
involved. However, as the atrophy progressively encroaches on
the foveal center, these patients may go through a transitional
period in which they alternate between central and eccentric
fixation, and this gradual transfer of the fixation focus may
explain the lack of perception of a sudden alteration in acuity.61
Alternatively, the explanation may lie within the nature of the
residual central vision in eyes with preservation of small foveal
islands. As the foveal island progressively decreases in size, the
size of the central visual field gets progressively smaller, such
that fewer words or facets of the visual image fit into the
functional region, even though relatively good acuity with
letters may be preserved. At the point at which the patient
transfers fixation to an eccentric locus, the amount of useful
functional central retina may not provide better vision than the
eccentric region.
GA appears to act as a barrier for CNV, such that CNV does
not begin within and rarely progresses through atrophic areas.
However, CNV may occur contiguous to these regions and
course along the external perimeter of the area. Since patients
with progressive GA rarely complain of abrupt changes in visual
acuity, any such change should prompt an investigation for the
development of CNV. Forty-five to 49% of the fellow eyes with
non-neovascular maculopathy and zones of GA at study entry
into the MPS AMD trials of laser photocoagulation progress to
CNV within 5 years.14,48 Among 45 patients with unilateral GA
and a fellow eye with neovascular maculopathy followed
prospectively for natural history of GA, 23% developed CNV at
the edge of GA within 2 years, whereas CNV did not develop in
any of the 92 patients with bilateral GA during the same time
interval, suggesting that patients with bilateral GA without
evidence of CNV are at low risk for developing CNV.62
The development of subretinal hemorrhage in eyes with GA
does not necessarily imply the presence of CNV. Nasrallah and
associates reported on eight patients in whom small subretinal
hemorrhage spontaneously cleared over a 15 month period
without evidence of CNV at the time of the hemorrhage nor
evidence of CNV or disciform scarring with clearing of the
hemorrhage.63 These subretinal hemorrhages may reflect rupture
of normal choriocapillaris, as is seen in subretinal hemorrhages
occurring in myopic patients with lacquer cracks in which CNV
is not growing through the lacquer crack. However, fluorescein
angiographic signs of active CNV in patients with extensive GA
are often fairly subtle, such that careful scrutiny of these
angiograms is needed, particularly with reference to previous
studies, to determine whether or not CNV has developed.
MANAGEMENT
The risk of visual loss in eyes with drusen or pigment abnor-
malities results from the development of advanced AMD either
in the form of CNV or foveal GA. Accordingly, management is
aimed at preventing CNV or GA. There has been speculation
that ultraviolet or visible light exposure may lead to the
generation of reactive oxygen species in the outer retina,64,65
which may in turn cause lipid peroxidation of photoreceptor
outer segment membranes potentially contributing to the devel-
opment of AMD. However, observational epidemiologic studies
have failed to provide support for the theory that cumulative
sunlight exposure is associated with AMD. No association was
identified between cumulative ultraviolet or visible light
CHAPTER 144
exposure and the presence of non-neovascular AMD in the
Chesapeake Bay Waterman Study.66 However, there was a
significantly higher exposure to blue light and all wavelengths
in the visible spectrum within the 20 year period immediately
preceding study participation among the eight participants with
advanced AMD in the cohort when compared with age-matched
control subjects.67 The Eye Disorder Case-Control Study also
failed to demonstrate any positive relationship between lifetime
sunlight exposure and the presence of neovascular AMD.68 A
limited association between light and AMD was noted in the
Beaver Dam population, with increased outdoor summertime
exposure being associated with increased retinal pigment among
male subjects and late AMD in male and female subjects.69
Thus, the available data are inconsistent and inconclusive in
regard to a relationship between light and AMD. Since the
Waterman Study has shown that ultraviolet light is associated
with lenticular opacities70 and because sunglasses are inex-
pensive and associated with few side effects, it seems reasonable
not to discourage their use.
Multiple epidemiologic studies have reported positive asso-
ciations between cigarette smoking71,72 and non-neovascular
AMD, so possible prevention of AMD would seem to be yet
another reason for physicians to recommend cessation of
smoking. Although there are inconsistent data from epidemio-
logic studies with regard to an association between hyper-
tension, cardiovascular disease, and increased cholesterol and
saturated fat intake31,68,73–75 and AMD, it would seem
reasonable to recommend routine medical examinations with a
generalist physician to monitor blood pressure, cholesterol levels,
and treatable cardiovascular disease in this elderly population.
AMD has been identified as having a familial component
based on clustering of the disease within multiple family
members within different generations and greater concordance
rates among monozygotic versus dizygotic twins.76–78 These
observations fuel the search to identify specific genetic
components of AMD. Several investigators have identified a
common variant (Y402H) of the complement factor H gene
(CFH), located on chromosome 1q31, as a major AMD risk
gene.79–81 This finding further suggests that inflammation may
play an important role in the pathogenesis of AMD as CFH is a
component of the immune system. CFH helps to regulate the
body’s inflammatory response by protecting against uncon-
trolled complement activation, and the Y402H variant is located
within the binding sites for heparin and C-reactive protein.
In a retrospective case-control study, the CFH variant was
associated with an increased risk of developing GA (OR 3.22,
95% CI 1.87–5.55) as well as neovascular AMD (OR 2.50, 95%
CI 1.74–3.60) compared to controls with no AMD.82 Further
investigation is needed to determine how this gene variant may 1911
 RETINA AND VITREOUS
increase the risk of AMD. In time, this may lead to new
screening strategies to identify individuals with greater risk for
development or progression of AMD. Furthermore, identifica-
tion of the role this gene variant may play in pathogenesis may
open possibilities for new management strategies to prevent
progression.
In a small pilot trial, oral zinc administration was associated
with less vision loss in patients with non-neovascular AMD
when followed for a period of up to 2 years.83 However, a ran-
domized prospective trial evaluating oral zinc administration
versus placebo in decreasing vision loss and development of
CNV in 112 patients at risk of neovascular AMD in their
second eye did not find treatment to be beneficial.84 Exploring
the hypothesis that AMD may be caused by cumulative
oxidative insults, cross-sectional and case-control epidemiologic
investigations have evaluated blood antioxidant levels, dietary
ingestion of antioxidant-containing food sources, and uses of
micronutrient supplements.73,85–88 These studies have suggested
SECTION 10
a small to moderate protective role of antioxidants on varying
levels of AMD; however, the results for specific nutrients and
specific AMD types have been inconsistent and therefore
inconclusive. These types of studies also have several important
limitations. Blood levels may reflect recent behaviors rather
than general body stores, blood levels may not reflect tissue
levels, dietary consumption histories may be imprecise, and the
likely effects of uncontrolled confounding factors. A cause-and-
effect relationship between antioxidants and AMD cannot
be concluded from these investigations. Therefore, the AREDS
was designed to prospectively evaluate the use of antioxidants
and zinc in individuals at risk of developing advanced AMD.
The AREDS Group conducted a prospective multicenter
clinical trial to evaluate the effect of daily supplementation with
high-dose anti-oxidant vitamins and zinc supplements on the
development of advanced AMD.15 A total of 3640 subjects were
randomized to one of four treatment groups in a double masked
fashion: (1) antioxidants (500 mg vitamin C, 400 IU vitamin E,
15 mg beta carotene), (2) zinc (80 mg zinc oxide and 2 mg
cupric oxide to prevent potential anemia), (3) combination of
antioxidants and zinc, or (4) placebo. Results from the AREDS
demonstrate that the combination supplements (anti-oxidants
plus zinc) result in a 25% risk reduction for development of
advanced AMD in individuals at risk of progression and a 21%
risk reduction in rates of moderate vision loss (doubling of the
visual angle). Individuals at risk of progression are those with
intermediate AMD or unilateral advanced AMD with a fellow
eye at risk. Individuals with early AMD did not benefit from
micronutrient supplementation. Therefore, individuals should
consider taking an antioxidant and zinc supplement such as
that used in AREDS only if they meet the AREDS classification
of intermediate AMD or unilateral advanced AMD. Potential
risks associated with this daily supplementation are small and
include a mild increase in genitourinary hospitalizations in
participants taking zinc (7.5% in the zinc group vs 4.9% in the
placebo group) and a change in skin color (8.3% in the anti-
oxidant group vs 6.0% in the placebo group. Although the
AREDS type micronutrient supplementation is generally safe,
cigarette smokers have an increased risk of developing lung
cancer and increased risk of mortality when taking high doses
of beta carotene.89,90 Smokers should be counseled regarding
this increased risk and consider avoidance of high dose
betacarotene exposure. In AREDS supplementation with zinc
(in the absence of antioxidants) was found to significantly
reduce anatomic progression of AMD, and maybe considered as
an alternate treatment regimen in smokers.
A second multicenter, prospective clinical trial is now under-
way called AREDS 2. This study will evaluate additional supple-
1912 ments consisting of lutein/zeaxanthine and omega-3 poly-
unsaturated fatty acids (eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA)). Evidence supporting the perfor-
mance of AREDS 2 involves observational data from many
epidemiologic studies as well as case-control studies within
AREDS which identify individuals who consume higher amounts
of food sources rich in these ingredients to have a reduced odds
or risk of manifesting varying forms of AMD when compared to
individuals who have lower exposures. AREDS 2 is not expected
to reach any conclusions for at least 5–8 years from now. Until
AREDS 2 reports its findings, the safety and efficacy of lutein/
zeathanine and fish oil in the management of AMD will remain
unknown.
Another form of treatment that has been extensively evaluated
in the management of eyes with nonneovascular AMD to
potentially alter the course of the disease is photocoagulation,
either directly or adjacent to soft drusen. Several clinical trials
have now been completed and have not found this treatment to
be beneficial in the management of patients with soft drusen.
The Choroidal Neovascularization Prevention Trial (CNVPT),
halted recruitment when it was recognized that study eyes in
the fellow eye group randomly assigned to laser treatment had
a significantly greater rate of CNV formation within the first
2 years of follow-up when compared with the natural history
eyes.91 Another prospective study, the Prophylactic Treatment
of Age-Related Macular Degeneration Research Group (PTAMD
Study Group) found similar results in fellow eyes assigned to
grid threatment with the 810 nm diode laser.92 In this trial, the
rate of CNV development in laser treated eyes consistently
exceeded the rate found among the observation eyes. After
1 year of follow-up, 15.8% of laser-treated eyes developed CNV
compared to 1.4% of observation eyes (P = 0.05). More recently,
results from the largest investigation of prophylactic laser
treatment, the Complications of Age-Related Macular
Degeneration Prevention Trial (CAPT) demonstrated that low
intensity laser treatment to one eye of individuals with bilateral
nonneovascular AMD characterized by multiple large drusen
did not demonstrate benefit in vision or anatomic outcomes.93
The laser protocol specified 60 spots of barely visible burns in a
grid pattern within an annulus of 1500 and 2500 mm of the
foveal center. Cumulative 5 year incidence rates for develop-
ment of CNV (13.3% laser treated vs 13.3% observed) and GA
(7.4% laser treated vs 7.8% observed,) were similar between the
two groups. In addition, at 5 years the proportion of subjects
with ≥3 line loss of visual acuity from baseline was similar
between the laser treated eyes (20.5%) and observed eyes (20.5%).
Therefore, laser photocoagulation is not recommended in eyes
with bilateral large drusen since it does not alter the natural
history of AMD in these eyes.
At the present time, the most important aspect of manage-
ment in patients with drusen is education. Patients should be
informed that AMD does not, in the majority of cases, cause
legal blindness and that even in the worst cases, peripheral
vision is almost always retained. These patients are at increased
risk of acquiring CNV, especially if one eye has already been
affected, and data suggest that diagnosis at the earliest onset
of the CNV provides the greatest chance of successful
treatment.94,95 Therefore, patients should monitor their central
vision every day in each eye at risk for the development of CNV,
and they should contact their ophthalmologist promptly if they
notice any metamorphopsia or scotoma, which may suggest the
onset of CNV. Evaluation by an ophthalmologist should include
careful contact lens biomicroscopy for the presence of subretinal
fluid or hemorrhage and, if necessary, an OCT and a fluorescein
angiography to determine whether or not CNV is present.
Recently, a new perimetry device, the Preferential Hyperacuity
Perimeter (PreView PHP, Carl Zeiss Meditec, Dublin, CA) was
developed to detect metamorphopsia in patients with AMD. A
 Age-Related Macular Degeneration: Drusen and Geographic Atrophy

pilot study demonstrated that the PHP had a sensitivity of 94%
compared to 34% for the Amsler grid in detecting CNV secondary
to AMD.96 In addition, a larger clinical trial demonstrated that
the PHP has a sensitivity of 82% and a specificity of 88% in
detecting newly diagnosed CNV in a cohort of individuals com-
prised of recent-onset CNV or intermediate AMD.97 Additional
clinical trials evaluating the PHP as a screening tool in patients
with high risk macular characteristics are underway. Data from
these studies may provide information on the role of PHP
testing in the management of patients at risk of CNV.
Unfortunately, some patients develop CNV in the absence of
appreciable symptoms,98 and many ophthalmologists recommend
that patients who have drusen be followed at 6 month intervals
in the hope of detecting asymptomatic CNV that might be
amenable to treatment.99
GEOGRAPHIC ATROPHY OF THE RPE
to neovascular AMD. In addition, since extension of GA through
the foveal center can result in severe central visual loss patients
may benefit from low-vision aids. We advise patients to maintain
an open dialog with a low-vision specialist to discuss changes in
their needs and new aids that may become available.
CONCLUSIONS AND FUTURE RESEARCH
In recent years, standardized descriptions of non-neovascular
features of AMD have been developed and substantial natural
history data on AMD utilizing these standard definitions has
been accumulated. Complex and simple scales describing the
evolution of AMD have been developed. Limited information
on the cause or progression of AMD exists. It is hoped that
current and future studies will lead to better understanding of
the pathogenesis of this disease. The AREDS has confirmed
that antioxidant and zinc supplements can reduce progression
of AMD and vision loss in eyes at risk. Additional interven-

CHAPTER 144
Management of eyes with GA requires patient education, self- tional trials may allow us to gain more insight into the disease
monitoring of symptoms and vision, and routine clinical pathogenesis and reduce the burden of vision loss associated
examination by an ophthalmologist to monitor for conversion with this condition.

REFERENCES
1. Eye Diseases Prevalence Research Group:
Prevalence of age-related macular
degeneration in the United States. Arch
Ophthalmol 2004; 122:564–572.
2. Donders FC: Beitrage zur pathogischen
Anatomie des Auges. Graefes Arch
Ophthalmol 1855; 1:106.
3. Bressler NM, Bressler SB, West SK, et al:
The grading and prevalence of macular
degeneration in Chesapeake Bay
watermen. Arch Ophthalmol 1989;
107:847–852.
4. Bressler SB, Maguire MG, Bressler NM,
Fine SL: The Macular Photocoagulation
Study Group: Relationship of drusen and
abnormalities of the retinal pigment
epithelium to the prognosis of neovascular
macular degeneration. Arch Ophthalmol
1990; 108:1442–1447.
5. Macular Photocoagulation Study Group:
Persistent and recurrent neovascularization
after krypton laser photocoagulation for
neovascular lesions of age-related macular
degeneration. Arch Ophthalmol 1990;
108:825–831.
6. Klein R, Klein BEK, Linton KLP: Prevalence
of age-related maculopathy. The Beaver
Dam Eye Study. Ophthalmology 1992;
99:933–943.
7. Klein R, Davis MD, Magli YL, et al: The
Wisconsin age-related maculopathy
grading system. Ophthalmology 1991;
98:1128–1134.
8. Bird AC, Bressler NM, Bressler SB, et al:
An international classification and grading
system for age-related maculopathy and
age-related macular degeneration. Surv
Ophthalmol 1995; 39:367–374.
9. AREDS Research Group: The age-related
eye disease study system for classifying
age-related macular degeneration from
stereoscopic color fundus photographs: the
age-related eye disease study report no 6.
Am J Ophthalmol 2001; 132:668–681.
10. Gass JDM: Stereoscopic atlas of maular
diseases diagnosis and treatment. 4th edn.
St Louis: Mosby; 1997:78–79.
11. Chang AA, Guyer DR, Orlock DR, Yannuzzi
LA: Age-dependent variations in the drusen
fluorescence on indocyanine green
angiography. Clin Exp Ophthalmol 2003;
31:300–304.
12. Coffey AJH, Brownstein S: The prevalence
of macular drusen in postmortem eyes. Am
J Ophthalmol 1986; 102:164–171.
13. Klein R, Klein BEK, Jensen SC, Meuer SM:
The incidence and progression of age-
related maculopathy. The Beaver Dam Eye
Study. Ophthalmology 1997; 104:7–21.
14. Maguire MG, Bressler SB, Bressler NM,
et al: Risk factors for choroidal
neovascularization in the second eye of
patients with juxtafoveal or subfoveal
choroidal neovascularization secondary to
age-related macular degeneration. Arch
Ophthalmol 1997; 115:741–747.
15. AREDS Research Group: A randomized,
placebo-controlled clinical trial of high-
dose supplementation with vitamins C and
E, beta carotene, and zinc for age-related
macular degeneration and vision loss. Arch
Ophthalmol 2001; 119:1417–1436.
16. El Baba F, Green WR, Fleischmann J, et al:
Clinicopathologic correlation of lipidization
and detachment of the retinal pigment
epithelium. Am J Ophthalmol 1986;
101:576.
17. Bressler NM, Munoz B, Maguire MG, et al:
Five-year incidence and disappearance of
drusen and retinal pigment epithelium
abnormalities. Waterman Study. Arch
Ophthalmol 1995; 113:301–308.
18. Green WR, Enger C: Age-related macular
degeneration histopathologic studies: The
1992 Lorenz E. Zimmerman Lecture.
Ophthalmology 1993; 100:1519–1535.
19. Bressler NM, Silva JC, Bressler SB, et al:
Clinicopathologic correlation of drusen and
retinal pigment epithelial abnormalities in
age-related macular degeneration. Retina
1994; 14:130–142.
20. Sarks SH: Ageing and degeneration in the
macular region: A clinicopathologic study.
Br J Ophthalmol 1976; 60:324–341.
21. Bressler SB, Munoz B, Phillips D, West SW,
for the Salisbury Eye Evaluation Group:
Prevalence of age-related macular
degeneration in a population based study:
SEE Project. Invest Ophthalmol Vis Sci
1998; 39:S493.
22. Vingerling JR, Dielemans I, Hofman A, et al:
The prevalence of age-related maculopathy
in the Rotterdam Study. Ophthalmology
1995; 102:205–210.
23. Mitchell P, Smith W, Attebo K, Wang JJ:
Prevalence of age-related maculopathy in
Australia. Ophthalmology 1995;
102:1450–1460.
24. Klein R, Klein BEK, Knudtson MD, et al:
Prevalence of age-related macular
degeneration in 4 racial/ethnic groups in
the multi-ethnic study of atherosclerosis.
Ophthalmology 2006; 113:373–380.
25. Munoz B, Klein R, Rodriguez J, et al:
Prevalence of age-related macular
degeneration in a population-based
sample of Hispanic people in Arizona:
proyecto VER. Arch Ophthalmol 2005;
123:1575–1580.
26. Prenner JL, Rosenblatt BJ, Tolentino MJ,
et al. Risk factors for choroidal
neovascularization and vision loss in the
fellow eye study of CNVPT. Retina 2003;
23:307–314.
27. Green WR, McDonnell PH, Yeo JH:
Pathologic features of senile macular
degeneration. Ophthalmology 1985;
92:615–627.
28. Pouleikhoff D, Barondes MJ, Minassian D,
et al: Drusen as risk factors in age-related
macular degeneration. Am J Ophthalmol
1990; 109:38–43.
29. Mavrofrides EC, Villate N, Rosenfeld PJ,
Puliafito CA: Age-related macular
degeneration. In: Schuman JS, Puliafito
CA, Fujimoto JG, eds. Optical coherence
tomography of ocular diseases. 2nd edn.
Slack Inc; 2004:243–252.
30. Lebowitz HM, Krueger DE, Maunder LR,
et al: The Framingham Eye Study
Monograph VI: Macular Degeneration. Surv
Ophthalmol 1980; 24(Suppl):428–457.
31. Hyman LG, Lilienfeld AM, Ferris FL, Fine
SL: Senile macular degeneration: a case-
control study. Am J Epidemiol 1983;
118:213–227.
32. Ferris FL, Fine SL, Hyman L: Age-related
macular degeneration and blindness due to
neovascular maculopathy. Arch Ophthalmol
1984; 102:1640–1642. 1913
 RETINA AND VITREOUS
33. Klein ML, Ferris FL, Gensler G, et al:
Clinical features and natural history of
drusenoid pigment epithelial detachments
in age-related macular degeneration.
Poster presentation, ARVO annual meeting;
2004.
34. Sarks JP, Sarks SH, Killingsworth MC:
Evolution of geographic atrophy of the
retinal pigment epithelium. Eye 1988;
2:552–577.
35. Smiddy WE, Fine SL: Prognosis of patients
with bilateral macular drusen.
Ophthalmology 1984; 91:271–277.
36. Holz FG, Wolfensberger TJ, Piguet PQ,
et al: Bilateral macular drusen in age-
related macular degeneration. Prognosis
and risk factors. Ophthalmology 1994;
101:1522–1528.
37. Jampol LM: Discussion of prognosis of
patients with bilateral macular drusen.
Ophthalmology 1984; 91:276–277.
SECTION 10
38. AREDS Research Group: The age related
eye disease study severity scale for age-
related macular degeneration. Arch
Ophthalmol 2005; 123:1484–1498.
39. Early Treatment Diabetic Retinopathy Study
Research Group: Classification of diabetic
retinopathy from fluorescein angiograms.
Ophthalmology 1991; 98:807–822.
40. AREDS Research Group. A simplified scale
for age-related macular degeneration. Arch
Ophthalmol 2005; 123:1570–1574.
41. Gass JDM, Jallow S, Davis B: Adult
vitelliform macular detachment occurring in
patients with basal laminar drusen. Am J
Ophthalmol 1985; 99:445–459.
42. Kenyon KR, Maumenee AE, Ryan SJ, et al:
Diffuse drusen and associated
complications. Am J Ophthalmol 1985;
100:119–128.
43. Bressler NM, Bressler SB, Fine SL: Age-
related macular degeneration. Surv
Ophthalmol 1988; 32:375–413.
44. Gass JDM: A clinicopathologic study of a
peculiar foveomacular dystrophy. Trans Am
Ophthalmol Soc 1974; 72:139.
45. Todd K, Schatz H, Crawford JB: Pathologic
findings in pseudovitelliform macular
degeneration. Invest Ophthalmol Vis Sci
1986; 27:198.
46. Benhamou N, Souied EH, Zolf R, et al:
Adult-onset foveomacular vitelliform
dystrophy: a study by optical coherence
tomography. Am J Ophthalmol 2003;
135:362–367.
47. Gass JDM: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 3rd
edn. St Louis: Mosby; 1987:264.
48. Burgess DB, Hawkins BS, Jefferys J, et al:
Five-year follow-up of fellow eyes with
patients with age-related macular
degeneration and unilateral extrafoveal
choroidal neovascularization. Arch
Ophthalmol 1993; 111:1189–1199.
49. Bressler SB, Bressler NM, Clemons T, et al:
Ocular risk factors for developing
neovascular AMD in fellow eyes of patients
with unilateral neovascular AMD. Presented
at ARVO Annual Meeting; 2004.
50. Armstrong J, Hubbard LD, Davis MD, et al:
Association of calcified drusen with
progression of AMD in AREDS participants.
Presented at ARVO Annual Meeting; 2006.
51. Klein R, Klein BE, Tomany Sc, et al: Ten-
year incidence and progression of age-
related maculopathy; the Beaver Dam
eye study. Ophthalmology 2003;
1914 109:176–179.
52. Wang JJ, Foran S, Smith W, Mitchell P: Risk
of age-related macular degeneration in eyes
with macular drusen or hyperpigmentation.
Arch Ophthalmol 2003; 121:658–663.
53. Klaver CC, Assink JJ, van Leeuwen R,
et al: Incidence and progression rates of
age-related maculopathy: the Rotterdam
Study. Invest Ophthalmol Vis Sci 2001;
42:2237–2241.
54. Buch H, Nielson NV, Vinding T, et al:
14-year incidence, progression, and visual
morbidity of age-related maculopathy: the
Copenhagen City Eye Study.
Ophthalmology 2005; 112:787–798.
55. Schatz H, McDonald HR: Atrophic macular
degeneration: Rate of spread of geographic
atrophy and visual loss. Ophthalmology
1989; 96:1541–1551.
56. Sunness JS, Bressler NB, Tian Y, et al: The
enlargement of geographic atrophy over
time in age-related macular degeneration.
Invest Ophthalmol Vis Sci 1996; 37:S21.
57. Maguire P, Vine AK: Geographic atrophy of
the retinal pigment epithelium. Am J
Ophthalmol 1986; 102:621–625.
58. Applegate CA, Sunness JS, Haselwood
DM: Visual symptoms associated with
geographic atrophy from age-related
macular degeneration. Invest Ophthalmol
Vis Sci 1996; 37:S112.
59. Sunness JS, Applegate CA: Long-term
follow-up of fixation patterns in eyes with
central scotomas from geographic atrophy
that is associated with age-related macular
degeneration. Am J Ophthalmol 2005;
140:1085–1093.
60. Sunness JS, Ruben GS, Applegate CA,
et al: Visual function abnormalities and
prognosis in eyes with age-related
geographic atrophy of the macula and
good visual acuity. Ophthalmology 1997;
104:1677–1691.
61. Sunness JS, Bressler NM, Maguire MG:
Scanning laser ophthalmoscopic analysis
of the pattern of visual loss in age-related
geographic atrophy of the macula. Am J
Ophthalmol 1995; 119:143–151.
62. Sunness JS, Bressler NM, Marsh MJ, et al:
The development of choroidal
neovascularization in eyes with geographic
atrophy from age-related macular
degeneration. Invest Ophthalmol Vis Sci
1997; 38:S967.
63. Nasrallah F, Jalkh AE, Trempe CL, et al:
Subretinal hemorrhage in atrophic age-
related macular degeneration. Am J
Ophthalmol 1989; 107:38–41.
64. Young RW: Solar radiation in age-related
macular degeneration. Surv Ophthalmol
1988; 32:252–269.
65. Gottsch JD, Bynoe LA, Harlan JB: Light-
induced deposits in Bruch’s membrane in
protoporphyric mice. Arch Ophthalmol
1993; 111:126–129.
66. West SK, Rosenthal FS, Bressler NM, et al:
Exposure to sunlight and other risk factors
for age-related macular degeneration. Arch
Ophthalmol 1989; 107:875–879.
67. Taylor HR, Munoz B, West SK, et al: Visible
light and risk of age-related macular
degeneration. Trans Am Ophthalmol Soc
1990; 88:163–178.
68. Eye Disease Case-Control Study Group:
Risk factors for neovascular age-related
macular degeneration. Arch Ophthalmol
1992; 110:1701–1708.
69. Cruickshanks KJ, Klein R, Klein BEK:
Sunlight and age-related macular
degeneration. The Beaver Dam Eye Study.
Arch Ophthalmol 1993; 111:514–518.
70. Taylor HR, West SK, Rosenthal FS, et al:
Effect of ultraviolet radiation on cataract
formation. N Engl J Med 1988;
319:1429–1433.
71. AREDS Study Group: Risk factors for the
incidence of advanced age-related macular
degeneration in the age-related eye
disease study (AREDS). Ophthalmology
2005; 112:533–539.
72. Tomany SC, Wang JJ, van Leeuwen R et al:
Risk factors for incident age-related
macular degeneration. Ophthalmology
2004; 111:1280–1287.
73. Goldberg J, Flowerdew G, Smith E, et al:
Factors associated with AMD: analysis of
the first NHANES. Am J Epidemiol 1988;
128:700–710.
74. Klein R, Klein BEK, Franke T: The
relationship of cardiovascular disease and
its risk factors to age-related maculopathy.
The Beaver Dam Eye Study.
Ophthalmology 1993; 100:406–414.
75. Mares-Perlman JA, Brady WE, Klein R, et al:
Dietary fat in age-related maculopathy.
Arch Ophthalmol 1995; 113:743–748.
76. Hammond CJ, Webster AR, Snieder H, et
al: Genetic influence on early age-related
maculopathy: a twin study. Ophthalmology
2002; 109:730–736.
77. Seddon JM, Cote J, Page WF, et al: The
US twin study of age-related macular
degeneration: relative roles of genetic and
environmental influences. Arch Ophthalmol
2005; 123:321–327.
78. Haddad S, Chen CA, Santangelo SL,
Seddon JM. The genetics of age-related
macular degeneration: a review of progress
to date. Surv Ophthalmol 2006;
51:316–363.
79. Haines JL, Hauser MA, Schmidt S, et al.
Complement factor H variant increases the
risk of age-related macular degeneration.
Science 2005; 308:419–421.
80. Edwards AO, Ritter R III, Abel KJ, et al:
Complement factor H polymorphism and
age-related macular degeneration. Science
2005; 308:421–424.
81. Klein RJ, Zeiss C, Chew EY, et al:
Complement factor H polymorphism in
age-related macular degeneration. Science
2005; 308:385–389.
82. Postel EA, Agarwal A, Caldwell J, et al:
Complement factor H increases risk for
atrophic age-related macular degeneration.
Ophthalmology 2006; 113:1504–1507.
83. Newsome DA, Swartz M, Leone NC, et al:
Oral zinc in macular degeneration. Arch
Ophthalmol 1988; 106:192–198.
84. Stur M, Tittl M, Reitner A, Meisinger V: Oral
zinc and the second eye in age-related
macular degeneration. Invest Ophthalmol
Vis Sci 1996; 37:1225–1235.
85. Eye Disease Case-Control Study Group:
Antioxidant status in neovascular age-
related macular degeneration. Arch
Ophthalmol 1993; 111:104–109.
86. Seddon JM, Ajani UA, Sperduto RD, et al:
Dietary carotenoids, vitamins A, C, and E,
and advanced age-related macular
degeneration. JAMA 1994; 272:1413–1420.
87. West S, Vitale S, Hallfrisch J, et al: Are
antioxidants or supplements protective for
age-related macular degeneration? Arch
Ophthalmol 1994; 112:222–227.
88. Mares-Perlman JA, Brady WE, Klein R,
et al: Serum antioxidants in age-related
 Age-Related Macular Degeneration: Drusen and Geographic Atrophy
macular degeneration in a population-
based case-control study. Arch Ophthalmol
1995; 113:1518–1523.
89. Alpha-Tocopherol, Beta Carotene Cancer
Prevention Study Group: The effect of
vitamin E and beta carotene on the
incidence of lung cancer and other
changes in male smokers. N Engl J Med
1994; 330:1029–1035.
90. Omenn GS, Goodman GE, Thornquist MD,
et al: Effects of a combination of beta
carotene and vitamin A on lung cancer and
cardiovascular disease. N Engl J Med
1996; 334:1150–1155.
91. Choroidal Neovascularization Prevention
Trial Research Group: Laser treatment in
eyes with large drusen: Short-term effects
seen in a pilot randomized clinical trial.
Ophthalmology 1998; 105:11–23.
92. Friberg TR, Musch DC, Lim JI, et al:
Prophylactic treatment of age-related
macular degeneration report number 1:
810-nanometer laser to eyes with drusen.
Unilaterally eligible patients.
Ophthalmology 2006; 113:622e1.
93. Complications of Age-Related Macular
Degeneration Prevention Trial Research
Group: Laser treatment in patients with
bilateral large drusen: the complications of
age-related macular degeneration
prevention trial. Ophthalmology 2006;
113:1974–1986.
94. Bird AC: Treatment of senile macular
degeneration by photocoagulation. Br J
Ophthalmol 1974; 58:367–376.
95. Macular Photocoagulation Study Group:
Laser photocoagulation of subfoveal
neovascular lesions in age-related macular
degeneration. Results of a randomized
clinical trial. Arch Ophthalmol 1991;
109:1219–1231.
96. Loewenstein A, Malach R, Goldstein M,
et al: Replacing the amsler grid: a new
method for monitoring patients with age-
related macular degeneration.
Ophthalmology 2003; 110:966–970.
97. Preferential Hyperacuity Perimeter
Research Group: Preferential Hyperacuity
Perimeter (PreView PHP) for detecting
choroidal neovascularization study.
Ophthalmology 2005; 112:1758–1765.
98. Moisseiev J, Bressler NM: Asymptomatic
neovascular membranes in the second eye
of patients with visual loss from age-related
macular degeneration (AMD). Invest
Ophthalmol Vis Sci 1990; 31:462.
99. American Academy of Ophthalmology
Quality of Care Committee Retina Panel:
Macular degeneration. American Academy
of Ophthalmology Preferred Practice
Pattern. San Francisco: American Academy
of Ophthalmology; 1990.
CHAPTER 144
1915
 CHAPTER
Foods and Supplements in the Prevention and
145 Treatment of Age-Related Macular Degeneration
Julie A. Mares
INTRODUCTION
Food contains numerous bioactive molecules (vitamins, min-
erals, fatty acids, and other phytochemicals) that may modulate
and attenuate the multifactorial pathogenetic processes that
promote age-related macular degeneration (AMD), including
oxidative stress, inflammation, phototoxicity, and ischemia.
Nutrition may play an even larger role in preventing age-related
degenerative changes as endogenous systems to manage these
pathogenic processes become more challenged with age.
Evidence that addresses the practical importance of nutrition on
the common degenerative conditions that promote AMD has
grown over the past three decades and is the focus of the current
chapter.
Throughout the chapter, three general types of scientific
evidence that inform us about nutrition and AMD will be
discussed for each category of food component. One type of
evidence comes from studies in animals and cell systems in
which the short-term effects of nutrient deficiency or high-dose
supplementation are tested. These experiments, which push
the limits of physiological systems, elucidate the mechanisms
by which particular nutrients can exert physiological or bio-
chemical influences. These do not, however, provide insights
about the influence of more moderate variations in intake,
beyond overt deficiency states or pharmacological effects of
nutrients under isolated conditions. The results of these exper-
iments do not generally demonstrate the effect of a nutrient in
the routine context where the nutrient is one of many com-
ponents of foods consumed. Evidence for mechanisms by which
nutrients may play a role in AMD is insufficient to predict the
impact of food or supplement sources over decades.
Epidemiological studies in populations provide broader
insights about relationships between the intake of foods and
supplements under more relevant conditions in people and
over the long term. These observations illustrate how diets
that are rich in certain foods or nutrients relate to the devel-
opment of early and late stages of AMD, usually over decades,
in people possessing a variety of genetic predispositions, whose
health is influenced by a variety of medical conditions, such as
the presence of hypertension or diabetes and lifestyles such
as the use of alcohol and cigarettes. The strength of evidence
from observational studies lies in the strength and consistency
of associations across many different samples of people who
vary in the characteristics that might explain or confound these
observations, rather from any single study.
While relationships with specific nutrients or food compo-
nents to AMD are often the focus in such studies, the results
are influenced by numerous other food components that are
associated with the kind of diet that provided high levels of that
specific nutrient. For example, people who eat high levels of
the carotenoids lutein and zeaxanthin typically consume high
levels of fruits and vegetables, particularly dark leafy greens.
These foods, and foods often eaten along with them, are also
high in vitamins C and E and other carotenoids that might
also protect the retina. There is often an attempt to statistically
adjust for these other aspects of diet in order for investigators
to draw conclusions about a specific nutrient of interest. This
statistical approach is unlikely to be sufficient to fully isolate
the effects of one target nutrient with other related aspects of
diet. This is because the intake of so many of the potentially
protective ingredients in food is highly correlated, and study
samples do not include large numbers of people who have high
levels of one component and low levels of all other potentially
protective components to reliably compare risks in these
subgroups. For this reason, evidence of relationships of diets
high in certain nutrients in the diet with AMD risk cannot be
used to reliably predict the influence of supplements that con-
tain the nutrient. The relationships of certain nutrients to
AMD might also reflect the influence of other aspects of a
health-conscious lifestyle, such as physical activity and use of
protective sun gear, especially if not known or not measured
well and adjusted for. Thus, while the observations made from
epidemiological studies illustrate broad diet attributes that
associate with lower risk for AMD, they do not permit us to
generalize about the effects of single nutrients, either as distinct
from the foods that contain them, or in nutritional
supplements.
The attempt to understand the influence of particular
nutrients when consumed in isolation and at high levels drove
several decades of research using clinical trial designs. The
appeal of the results of these trials is that a specific, short-term
impact of a nutrient or combination of nutrients can be known
with a high level of certainty, and not be confounded by the
other food components or health behaviors that can influence
the results of observational studies. These trials have provided
insights about the potential for nutritional manipulation to
impact the progression of AMD. Such trials aim to test the
impact of food ingredients as medicines.
Given the limited medical approaches available to treat
AMD, nutritional supplementation options have been valued.
The specific nutrient doses and combination of ingredients is
informed by a limited state of knowledge limiting the ability to
generalize to the long-term influence of nutrients in foods or
other supplement compositions.
Despite limitations of any one type of evidence, an inte-
gration of evidence from these three scientific approaches has
provided much broader and deeper understanding with which
to counsel both patients with AMD and their families, who, due
1917
 RETINA AND VITREOUS
to genetic predispositions, might themselves be at higher risk to
develop the conditions some day. The current evidence, as well
as gaps in our existing knowledge, will be described in the
remainder of the chapter. We will conclude with a discussion
of broad dietary patterns that show promise to lower the rate
of AMD.
ANTIOXIDANTS
Oxidative damage occurs to macro molecules (such as proteins,
lipids, and DNA) when reactive oxygen species (ROS) interact
with them and compromise their function. The sources of ROS
are many and can be the result of photooxidation of lipids from
light exposure; they can also be the by-product of metabolic
events, such as oxidative metabolism or enzyme reactions that
use oxygen (such as xanthine oxidase). Alternatively, they may
be produced directly as a mechanism for biological defense, as
is the case when white blood cells respond immunologically to
SECTION 10
pathogens with an oxidant boost.
It is widely known that the retina is particularly susceptible
to oxidative stress because of its high rates of oxidative metab-
olism and light exposure, and its high concentration of lipids
with double bonds that are vulnerable to attack by free radicals.
Multiple types of oxidative stress occur in cells, and the net
damage is a function of the stressors themselves, as well as the
ability to defend against them and repair the damage done.
Food contains numerous antioxidants, such as vitamins C
and E and carotenoids, which are provided by fruits, vegetables,
nuts, and nut or vegetable oils. These are chemicals that either
directly neutralize ROS, or that are cofactors for enzyme
systems that neutralize ROS, such as zinc and selenium, which
are provided by meat, dairy, and some grains. These antioxi-
dants work in different cell compartments, and often in comple-
mentary ways. Vitamin C is the most abundant dietary
antioxidant in aqueous compartments of the cell, while vitamin
E and vitamin E-related compounds are the most abundant
lipid-phase antioxidants in foods. Other hydrocarbon plant
compounds such as carotenoids are also active in lipid-soluble
cell compartments, and may have unique function by virtue
of their ability to align in biomembranes of cells or organelles.
Foods can contain direct oxidants or substances which promote
the production of ROS (including, potentially, residual herbi-
cides and pesticides) but little is known about these effects on
the eye and they will not be discussed here.
In studies with experimental animals, deficiencies of
vitamins E and C, or nutrients such as zinc, which are
components in enzymes that protect against oxidative stress,
result in pathologic changes to the retina (as previously
reviewed1–3). Yet, antioxidants can behave as pro-oxidants under
some circumstances. Single or dual high-dose antioxidant
supplements have not been associated with lower risk of
progression of AMD.4,5 This is consistent with evidence that
oxidant defense is carried out by a highly complex system of
mechanisms, in which antioxidant effects of several different
individual antioxidant molecules have been found to be
synergistic.6–8 The type of oxidative stress that is most
damaging depends on both the cell type and intracellular
location. Retinal pigment epithelium cells, when cultured,
demonstrate different vulnerabilities to the type of oxidant
stress than do cells from other tissues, and the result of
oxidants that target the cell surface and cytosol differs from that
which targets specific organelles.9
In the Age-Related Eye Disease Study (AREDS), a 6.2 year
randomized, placebo controlled clinical trial,10 the
administering of a high dose of the antioxidants (500 mg of
vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg
1918 of zinc along with 2 mg of copper), slowed the progression of
AMD from intermediate to more advanced stages by 28%.
There is also evidence that this treatment reduces the age-
related oxidation of cysteine in the blood, which supports the
possibility that the benefit is due to an improvement in oxi-
dative stress.11 A small short-term study of men with atrophic
AMD, who received antioxidant supplements along with lutein,
also reported improved visual function in this treatment group
and not in randomized, placebo controls.12
Although the level of individual antioxidants in foods is
usually much lower than levels provided by current high-dose
antioxidant supplements, foods provide an even greater array of
antioxidants than supplements, and the impact of decades of
consuming dietary antioxidants on AMD may be substantial. In
epidemiological studies, when associations with antioxidant
nutrients are considered one at a time, low levels of one or more
antioxidants in the blood or diet have often, but not always,
been related to higher prevalence or incidence of certain age-
related changes in the macula. Antioxidant nutrients related to
lower occurrence of AMD include vitamin E13–15 and/or one
or more carotenoids or zinc.14–20 The potential impact of a
combination of dietary antioxidants was estimated in the
Rotterdam Eye Study.15 After adjusting for potential con-
founders, the 10% of participants who were consuming
antioxidant-rich diets (i.e., diets with above the median intake
of all four antioxidants in AREDS supplements) had a 35%
lower risk of incident AMD than those with more average diets
(diets with intakes of one to three antioxidants above the
median). Risk in persons with antioxidant-poor diets (with all
four antioxidant nutrients at levels below the median) was
higher, although this was not statistically significant after
adjustment for potential confounders, and larger samples would
be needed to better evaluate this trend. Overall, there is a clear
trajectory of lower risk for AMD that is associated with eating
diets higher in several antioxidants. Lowering the prevalence of
early or intermediate stages of AMD by eating antioxidant-rich
foods has the potential to prevent even more cases of advanced
AMD than does beginning supplements once intermediate
AMD becomes manifest.
Antioxidants and AMD
Summary of Evidence
Oxidative stress or deficiency of dietary antioxidants in animals
promotes degenerative changes in the retina.
In people, there is broad evidence that supports the benefit of a
combination of antioxidants in slowing early and late AMD:
• Most previous population studies indicate lower prevalence of
early AMD among persons who have diets that are high,
compared with low, in one or more antioxidant nutrients
• Multiple high-dose antioxidants in one large clinical trial
lowered the progression of intermediate to late AMD, but
single antioxidants have not lowered the incidence of AMD
• The same combination of antioxidants in foods was associated
with lower 8-year incidence of AMD in the Rotterdam Eye
Study
Bottom Line and Unanswered Questions
Foods rich in antioxidants (fruits, vegetables, and whole grains) are
often associated with lower risk of early AMD.
• The impact of diet on progression from intermediate to
advanced AMD has not been adequately studied
One specific high-dose antioxidant supplement lowers risk for
progression from intermediate to advanced AMD.
• The possibility that lower levels of antioxidants may be
effective and the long-term health influence of high-dose
antioxidants has not been tested
• The optimal combination and dose of nutrients in supplements
is unknown
 Foods and Supplements in the Prevention and Treatment of Age-Related Macular Degeneration
The number of known and unknown antioxidants in foods
exceeds that in most supplements, and foods high in
antioxidants, such as vegetables, might lower oxidative stress to
a greater degree than supplements. In a recent randomized,
cross-over trial, eating two or more cups of Brassica vegetables
(such as broccoli) lowered a urinary marker of oxidative stress,
whereas moderate levels of supplementation with antioxidants
in multivitamins did not.21 However, it is not known whether
the non-nutritive antioxidants in foods reach the retina (besides
lutein and zeaxanthin, which are discussed next) or whether
lowering the systemic level of oxidative stress by consuming
such foods influences age-related macular degeneration.
LUTEIN AND ZEAXANTHIN
The specific carotenoids lutein, and its structural isomer
zeaxanthin, may protect against the development of AMD, as
previously reviewed.22,23 These carotenoids, which comprise
macular pigment24,25 are responsible for the yellow color of the
macula lutea and must be provided by the diet, since the body
does not synthesize them. Their structure is similar to pro-
vitamin A carotenoids, like beta-carotene, but with additional
hydroxyl groups, which makes them more polar and unable to
be used in vitamin A synthesis. Lutein and zeaxanthin are
selectively concentrated into the retina and other ocular tissues
over the five other carotenoids which predominate in human
blood, and over the ~600 carotenoids present in nature.
Evidence for the existence of specific xanthophyll-binding
proteins in the vertebrate retina has been reported.26,27
Lutein and zeaxanthin may be obtained from many fruits and
vegetables, from egg yolks,28,29 or from supplements.
Particularly rich sources include dark green leafy vegetables,
such as spinach and kale, and green vegetables like broccoli,
peas, green beans, and brussels sprouts. Americans, on average,
consume 1–2 mg of these carotenoids daily.30
Lutein and zeaxanthin are found throughout the retina. The
highest density occurs in the Henle fiber and inner plexiform
layers.31 At these locations, they are likely to function as an
optical filter that absorbs short-wavelength visible (blue) light.32
These features not only may block oxidative damage due to
incident light energy, but may also improve visual resolution as
previously reviewed.33 One mechanism by which macular
pigment could protect against the development and progression
of AMD is by blocking light-induced formation of a toxic
compound, A2E; this is the principal component of lipofuscin
that accumulates in the RPE during phagocytosis of the rods
and cones, and is taken up by the lysosomes. When a critical
intracellular level of this compound has been reached, cell
damage to DNA occurs, induced by blue light irradiation.34
Because macular pigment can absorb 40–90% of incident blue
light, it could reduce the amount of A2E formed. This
possibility has not yet been tested.
The macular pigment density reduces about twofold between
the central macula, where the zeaxanthin isomer predominates,
and the periphery where the lutein isomer predominates.24 The
highest density of xanthophyll carotenoids in the peripheral
retina is in the rod outer segment membranes,35 where their
concentration is consistent with a role in oxidant defense. An
antioxidant role is supported by the presence of oxidation
products of lutein and zeaxanthin in the retina.36 These
carotenoids may also influence membrane stability by their
unique alignment in biological membranes.37
Animal models to study the impact of macular pigment on
AMD or related photoreceptor health are limited to species that
accumulate these carotenoids in their ocular tissues: primates,
and some birds such as quail. Primates fed diets deficient in
these xanthophyll carotenoids38,39 suffer a loss of retinal
pigment epithelial (RPE) cells and increased photoreceptor cell
death.40 Retinal zeaxanthin has been demonstrated to prevent
light-induced photoreceptor death in quail.41
Lower levels of lutein and zeaxanthin have been found in
autopsy specimens of donor eyes with AMD.42 Similarly, in two
cross-sectional studies, people with AMD have lower
concentrations of these carotenoids in their macula compared
to those without AMD.43,44 In contrast, in the largest such
cross-sectional study, which involved about 1700 women,
macular pigment was actually higher in those with intermediate
and advanced AMD.45 However, evidence in subgroups of
women from this study is consistent with the possibility of a
protective effect in the youngest two-thirds of the sample with
stable diets. Prospective studies of the relationships of macular
pigment to the onset of AMD are needed in order to understand
whether low macular pigment is a consequence of, or a
contributor to, AMD.
CHAPTER 145
Lutein and Zeaxanthin and AMD
Summary of Evidence
In vitro and animal studies indicate that the oxygenated
carotenoids lutein and zeaxanthin may lower oxidative stress in the
retina directly or by lowering blue light that reaches the
photoreceptor outer segments or RPE.
Lutein and/or zeaxanthin supplementation in animals lowers light-
induced damage to the retina.
The long-term intake of diets rich in lutein and zeaxanthin is often,
but not consistently, related to lower risk for AMD.
Bottom Line and Unanswered Questions
Foods rich in lutein and zeaxanthin are high in antioxidants, which
are associated with lower risk of AMD.
• The possibility that they may enhance vision by augmenting
macular pigment has not been tested
The benefit of diets or supplements rich in lutein and zeaxanthin or
high macular pigment levels on incidence and progression of AMD
has not been adequately studied.
• Benefits or safety of supplementing with L and Z has not been
studied in large trials
Results from observational studies indicate inconsistent
associations between the intake and blood levels of lutein and
zeaxanthin and the occurrence of age-related macular
degeneration. In two case-control studies, higher serum
levels46,47 and dietary intake of lutein and zeaxanthin48 were
associated with a statistically significant reduction in the risk of
neovascular/exudative AMD. Higher levels of dietary lutein and
zeaxanthin were also associated with lower prevalence of retinal
pigmentary abnormalities among Americans 40–59 years of
age, and lower rates of advanced AMD in Americans 60–79
years of age, in the Third National Health and Nutrition
Examination Survey.49 Low levels of plasma zeaxanthin19 in one
study, and both lutein and zeaxanthin in another study,16 were
associated with a higher prevalence of early and late AMD.
Other studies have either failed to find an association, or
associations did not reach statistical significance.14,50–54 It is too
early to draw conclusions from population studies because the
inconsistent observations are likely to be biased by recent diet
change, selective mortality bias or competing risk factors, or
limited to certain stages of AMD (discussed previously55). In the
recent Carotenoids in Age-Related Eye Disease Study
(CAREDS), high intake of lutein and zeaxanthin was associated
with lower odds for intermediate AMD only after excluding
persons who were likely to have had unstable diets,20 suggesting
that dietary changes contribute to inconsistent results in
epidemiological studies of AMD. A bias of selective mortality
might also explain the inconsistent results in population
studies. For example, older participants in observational studies 1919
 RETINA AND VITREOUS
may be more likely to have eaten diets rich in fruits and
vegetables over their adult lifetime than people in their birth
cohort who are no longer living, making it more difficult to
discern the effects of those diets on disease outcomes. Longer-
term prospective studies, particularly of the youngest persons at
risk for AMD, will provide more insights in years to come.
The benefits of lutein and zeaxanthin supplements on
preventing or slowing AMD are unknown. One reason is that
the ability to accumulate carotenoids with supplements appears
to be variable across individuals. Between 20% and 50% of
subjects in previous investigations have low serum and/or
retinal response to oral supplementation with these
carotenoids.56–58 In general, blood responses to oral carotenoids
vary in different people, as well.59,60 The influences on the
ability to take up carotenoids by the intestinal tract and the eye
are largely unknown. Having high levels of body fat and diabetes
is related to lower macular density.61 These conditions might
reflect levels of oxidative stress or lipoprotein distributions,
SECTION 10
which could, in turn, influence the ability to accumulate
carotenoids.
The benefit of taking lutein and zeaxanthin supplements has
not been studied in prospective studies or clinical trials. There
was, however, one very small and short-term trial in which
visual acuity improved slightly in the fewer than 30 subjects
who received exclusively lutein supplements.12 Further
information about the benefits of supplementation with lutein
and zeaxanthin (and omega-3 fatty acids) on progression of
advanced AMD may come from a large set of multicenter
clinical trials (AREDS II) that is currently underway.
Despite inconsistent data for these specific carotenoids to
date, lutein and zeaxanthin may be two of the many
components in fruits and vegetables that may slow earlier
stages of AMD. It is possible there are combinations of foods
that provide the optimal mix of nutrients that protect against
AMD. Americans who reported high intakes of vitamin A-rich
fruits and vegetables had lower prevalence of AMD.62 Low fruit
and vegetable consumption was associated with higher 5 year
incidence of large drusen in the Beaver Dam Eye Study.14 In
CAREDS, there was a strong inverse relationship between
intermediate AMD and the intake of vegetables in general, and
green vegetables, specifically, in women under 75 years of age
with stable intakes. One small study in Lithuania reported that
the consumption of fresh, uncooked vegetables at least twice per
week (compared to less than twice per week during the
winter/spring months) was inversely associated with AMD, in
women of ages age 65–74 years.63 Inverse associations with
intakes of vegetables and fruits throughout the rest of the year
were also observed, but did not reach statistical significance. In
a large prospective follow-up study of women in the Nurses’
Health Study, and men in the Health Professionals Follow-up
Study, fruit intake was inversely associated with the risk of
neovascular AMD, while overall fruit and vegetable intake were
not associated with AMD.50 Better diets and overall health
habits might explain different associations with vegetable
intake from those study samples.
In summary, while there is strong biological plausibility that
macular carotenoids might protect against AMD, the results of
existing epidemiological studies are inconsistent, and have not
addressed relationships of macular pigment, specifically, to the
progression of AMD. A large clinical trial (AREDS II) is
underway to determine the impact of lutein and zeaxanthin
supplements on the progression of advanced AMD.
The possibility that lutein and zeaxanthin are some of the
many components of fruits and vegetables that could protect
against the development of AMD seems strong. However, many
older patients who have been prescribed warfarin treatment to
1920 prevent blood clotting have been unnecessarily advised to avoid
the intake of root and leafy green vegetables because they
contain vitamin K. Vitamin K is necessary for blood clotting by
its action on the formation prothrombin, or clotting factor II. A
sudden increase in vitamin K intake can increase blood
prothrombin levels. However, patients can be advised to consult
with the physician who manages the treatment to adjust the
warfarin dose to the highest daily green vegetable intake that
the patient can consistently eat.
ZINC
Zinc may be particularly important to the retina because
concentrations of zinc in the retina exceed those elsewhere in
the body, with the exception of the prostate.64 Deficiency of zinc
in both animals and people impairs retinal functioning, as
previously reviewed.1 The mechanisms by which zinc could
influence AMD are numerous and fall into three general
categories: catalytic, regulatory, and structural.65 Zinc catalyzes
enzymatic reactions, and is a cofactor of over 100 enzymes,
some of which are involved in oxidant defense. Zinc depletion
in RPE cells has reduced levels of catalase, glutathione
peroxidase, and metallothionein, and has reduced ability to
phagocytize photoreceptor outer segments.66 Zinc performs
structural roles; its presence facilitates protein folding to
produce biologically active molecules that organize into zinc
finger-like structures. Zinc is also necessary for the DNA
binding capability of over 400 nuclear regulatory units and plays
a role in cellular signaling.67 It is involved in many homeostatic
mechanisms, including immune responses, previously
reviewed.67,68 Evidence can be found that both zinc deficiency
and excesses impair immunity.68 Zinc depletion may also
trigger apoptosis of RPE cells, or increase the vulnerability of
RPE cells to photic injury.69 However, zinc supplementation can
also enhance stress-induced effects in RPE cells.70 Thus, there
is evidence for numerous mechanisms by which zinc could
influence retinal systems that are involved in the development
of AMD.
The longer-term benefit of zinc on risk for AMD is not clear
from observational studies. In the Beaver Dam Eye Study18 high
intake of zinc from foods and supplements was related to lower
prevalence of early AMD, compared to low intake. The
association for the incidence of early AMD in that population
pointed in the same direction, but was statistically significant
only for the incidence of retinal pigment abnormalities, a less
Zinc and AMD
Summary of Evidence
Zinc availability influences retinal function in animals and humans.
Observational studies report inconsistent relationships between
moderate variation in long-term zinc intake and AMD.
High-dose zinc supplementation in one large clinical trial lowered
the progression of intermediate to late AMD. (Results of smaller
and shorter trials were inconsistent.)
Bottom Line and Unanswered Questions
Moderate intake of foods rich in zinc (dairy, meat, shellfish) might
lower risk for AMD, by virtue of the zinc they provide or because
they also contain other protective vitamins that are poorly studied.
• Can relationships of zinc intake to early AMD in some
population studies be explained by a protective influence of
other nutrients in zinc-rich diets?
• Does moderate intake of zinc from food and supplements slow
advanced AMD?
High-dose zinc supplementation may modestly slow progression
of AMD among persons who already have intermediate AMD.
• What is the long-term benefit and risk of high-dose zinc
supplementation?
 Foods and Supplements in the Prevention and Treatment of Age-Related Macular Degeneration
common and more intermediate stage of AMD.14 In a longer-
term prospective study in the Netherlands, zinc intake was
related to lower risk for incident AMD.15 In an Australian study
with a similar distribution of zinc intake, early AMD was less
prevalent among people with high zinc intake as compared to
low zinc intake, but this was not statistically significant.71
Incident AMD in the same population was unrelated to zinc
intake.51 The power to evaluate associations between the intake
of zinc and late AMD was low in these three populations.
However, zinc intake was unrelated to self-reported incident
AMD (a combination of early and late AMD) in two other large
study samples.72
By contrast, the use of high-dose zinc supplements (80 mg as
zinc oxide, along with 2 mg of cupric oxide) for 6 years, with or
without antioxidants, was associated with modestly lower
progression from intermediate to advanced AMD in the
AREDS.10 One smaller zinc supplementation trial had pre-
viously reported a benefit of zinc supplementation on vision
loss in patients with AMD,73 while another did not.74 No
serious safety issues with zinc supplementation were identified
in the 6 year AREDS study (aside from more frequent
hospitalization for genitourinary problems in men and more
frequent anemia, unsupported by differences in hematocrit) and
zinc supplementation was related to lower mortality in this
sample.75 However, the longer-term benefits and risks of zinc
supplementation at the high levels tested in AREDS are
unknown. While an enhanced immune response has been
noted in institutionalized elderly who were supplemented for 1
or 2 years with moderate levels of zinc,76 in combination with
one or more other nutrients, controversy about the long-term
safety of high-dose zinc supplementation exists77 and can only
be addressed with longer-term studies.
DIETARY FAT
There are at least three broad mechanisms by which dietary fats
might enhance or slow age-related macular degeneration. First,
because of the high caloric density of fats, eating high-fat foods
can displace other foods in the diet which have high nutrient
density that may have otherwise lowered oxidative stress, or
enhanced macular pigment or immunity. Second, eating high-
fat and low-nutrient dense foods may contribute to high body
mass, which is sometimes reported to be a risk factor for
AMD.78–80 Third, fatty acids themselves have numerous
biological effects as components of biological membranes and
regulators of biochemical pathways. Dietary fats could promote
AMD by promoting atherosclerosis, which is related to AMD
risk in some studies81,82 or parallel atherosclerosis-like
processes which result in lipid enrichment and mineralization
of the retina. Certain fatty acids can also have direct
physiological effects on the retina by modulating oxidative
stress, or by the inflammatory response which can promote
AMD pathogenesis (discussed below).
OVERALL LEVELS OF FAT
In laboratory studies of mouse models of atherosclerosis,
feeding high-fat diets resulted in the accumulation of lipid-like
droplets in the retina and degenerative changes in RPE cells and
Bruch’s membrane.83–86 In epidemiological studies, there is a
consistent relationship of high dietary fat levels to risk for early
and late AMD in observational studies. High total levels of
dietary fat have been related to higher prevalence,87–89
incidence,78,90,91 or progression92 of both early and advanced
AMD in several different study samples, even though not
always statistically significant. Some exceptions to this trend
include prevalence or short-term incidence studies with low
Dietary Fat and AMD
Summary of Evidence
High-fat diets in mouse models of AMD induce retinal pathology
thought to contribute to AMD in humans.
In population studies:
• High intakes of total fat are generally associated with risk of
early and late AMD in populations studied
• The type of fats associated with higher risk varies
considerably; there is some evidence that excess intake of
either saturated fats or omega-6 polyunsaturated fatty acids
could promote maculopathy
• The intake of fish or omega-3 fatty acids is often associated
with lower risk for AMD
The body of evidence from in vitro and in vivo animal and clinical
experiments suggest there is evidence that a protective effect of
omega-3 fatty acids in the body, in general, may involve one or
more of the following:
CHAPTER 145
• Lower oxidative stress
• Lower inflammatory cytokines
• Improved vascular integrity
• Less atherogenic blood lipid profiles
Bottom Line
Avoidance of excess fats in foods that provide few micronutrients
(processed sweet and salty snacks, and high-fat desserts) and
favoring omega-3 fatty acids over omega-6 in the diet by eating
fatty fish, leafy green vegetables, and whole grains, may lower risk
and progression of AMD.
Unanswered Questions
The benefit and safety of supplementing with fish oils to slow early
or advanced AMD is unknown.
power to evaluate associations with either early AMD91 or
advanced AMD.87–89 In one short-term prospective study,
persons with low, compared to moderate, levels of dietary fat
were at higher risk for the 5 year incidence of early AMD.91
SPECIFIC FATS
There is inconsistency across studies in the type of fat that was
most related to AMD. This suggests that these relationships
may reflect, in part, the caloric density of dietary fats that
replace other micronutrients. In some samples, high intake of
saturated fats was more strongly related to risk for AMD or
similarly to other types of fat,88–90,93 while in other studies total
intake of polyunsaturated fatty acids or monounsaturated fatty
acids78,92 was more strongly related. The intake of trans fatty
acids, provided in diets by margarines and other processed
foods, was related to higher risk for AMD in two studies.78,92
Because fat intake often changes, particularly in relation to
diagnosis for cardiovascular diseases, which can be related to
AMD, these relationships are difficult to interpret. Moreover,
there is limited ability in such studies to adjust for the
numerous other protective aspects of diet that accompany a
more moderate, as compared to high, intake of fat.
In contrast, there is more consistency in epidemiological
studies that report lower risk for AMD among people with high
intakes of fish or long-chain omega-3 polyunsaturated fatty
acids (LC omega-3 PUFAs).90–92,94 The protective influence of
omega-3 fatty acids could be somewhat dependent on the
omega-6 content of the diet. A higher ratio of omega-3 to -6
fatty acids could increase formation of antiinflammatory
eiscosanoids from omega-3 fatty acids, because the omega-6
fatty acids compete for the desaturase enzyme that creates
them95 or replace the omega-6 content of membranes. In one
past study, LC omega-3 PUFA intake was stronger among
subjects who had low intake of omega-6 PUFAs.78 1921
 RETINA AND VITREOUS
There has been interest in the health benefits of omega-3
fatty acids since the 1970s, when it was observed that
Greenland Inuit who ingested high levels of fatty fish that
contain them, had low rates of cardiovascular disease. Omega-
3 fatty acids are one of two major classes of polyunsaturated
fatty acids. Alpha linolenic acid, an omega-3 fatty acid, is one of
two essential fatty acids that must be obtained from the diet
because they cannot be synthesized by the body. In the body,
this fatty acid which is contained in leafy green vegetables and
in larger proportion in some vegetable oils (canola, soy, and
flaxseed) can be elongated to make the two major LC omega-3
PUFAs: eicosapentaenoic acid (EPA) and docosopentaenic acid
(DPA); however, the efficiency of conversion is not well
understood. Fatty fish (salmon, tuna, mackerel, and herring)
which concentrate EPA and docosahexaenoic acid (DHA) from
algae, the primary producers of these fatty acids in the
ecosystem, are concentrated dietary sources of these LC omega-
3 PUFAs. These fatty acids are also more concentrated in meat
SECTION 10
of animals fed grass-based diets than grain-based diets.96
There is general agreement that the American diet has
changed over the last century, so that the ratio of omega-6 fatty
acids (found in meat, vegetable oils such as corn, safflower, and
soy, and processed foods made with these oils) to omega-3 fatty
acids has increased. American diets provide about 10 times the
amount of omega-6 to -3 fatty acids, and there is a general
consensus that consuming more omega-3 fatty acids and less
omega-6 would be optimal for health.
LC omega-3 PUFAs, such as DHA, may be particularly
important to the health of the retina. The pathogenesis of AMD
may be influenced by atherosclerosis or involve parallel
processes.97 There is a large body of evidence to suggest that
EPA and DHA lower CVD mortality by several mechanisms: by
an improvement of blood lipids by lowering blood triglycerides,
decreasing inflammation, blood pressure, and platelet aggregation
and by improving vascular reactivity (recently reviewed).98
These may influence AMD pathogenesis directly or indirectly.
DHA is the most abundant LC omega-3 PUFA in rod outer
segment membranes99,100 at a concentration that exceeds levels
found elsewhere in the body.101 Its presence in membranes
affects their biophysical properties and may influence
membrane-bound enzymes, receptors, and transport. This is
important in visual transduction,102 but may also influence
the pathogenesis of AMD. LC omega-3 PUFAs may protect
against AMD by direct influence on retinal cell survival.103
DHA has also been demonstrated to protect RPE cells from
oxidative stress.103,104 However, high intake of this type of fat
might also lower risk for AMD because of its antiinflammatory
properties.95 Numerous cell culture studies provide clues for
possible mechanisms by which LC omega-3 PUFAs could
enhance the integrity of vascular and basement membranes and
prevent neovascularization (recently reviewed105).
Unfortunately, none of the over 100 clinical trials of LC
omega-3 PUFAs in medical research has evaluated its impact on
AMD. However, despite lack of proof of effectiveness in treating
AMD, previous clinical trials provide a large body of evidence to
support the notion that omega-3 fatty acids are potent
antiinflammatory agents and reduce the need for medications
for the chronic inflammatory disease of rheumatoid arthritis.106
Also, past clinical trials provide a history about the potential
safety of long-chain, omega-3 supplements in about 10,000
subjects of previous studies. In past studies (previously
reviewed107 in which 0.3–8 g of DHA and EPA per day was
supplemented for periods of 1 week to 7 years, no side effects
were reported in 52% of the studies. Overall, side effects were
reported in fewer than 7% of subjects and involved minor
gastrointestinal disturbances (such as diarrhea) and several
1922
cases of bleeding in trials where patients took warfarin or
aspirin daily.
In summary, at this time, most population studies to date
suggest lower early and late AMD among people who eat high
levels of fish or LC omega-3 PUFAs. The evidence for
antioxidant and antiinflammatory properties of these fatty acids
is also supportive of this possibility. However, results of
population studies may reflect other benefits of diets that are
high in fish. For example, fatty fish also provide vitamin D,
which also has antiinflammatory properties, and was recently
reported to be associated with lower risk for early AMD in one
population (discussed below). The current evidence supports
the possibility that reducing intake of omega-6 PUFAs and
increasing omega-3 PUFAs of the diet may lower risk for AMD
with little health risk. This can be achieved by eating leafy green
vegetables and fatty fish, substituting canola and olive oils for
corn and safflower oils, and avoiding processed foods, selecting
fish with low potential to contain heavy metals (for example, by
choosing wild caught rather than farm-raised fish) can minimize
potential harmful effects.
The benefit of supplementing with 1 g per day of LC omega-
3 PUFAS is currently being tested in a large clinical trial
(AREDS II).
POSSIBLE PROTECTION BY ASPECTS OF
DIET LESS WELL INVESTIGATED
VITAMIN D
Newly emerging evidence for the high prevalence of
complement H-polymorphisms among people with AMD
suggests that inflammation may play an important role in the
development of AMD.108–110 High levels of C-reactive protein (a
systemic marker of inflammation)111,112 and the use of
antiinflammatory medications113 were significantly related to
AMD, independent of other established risk factors, in some
but not all114,115 previous studies. Proteins associated with
inflammation including C-reactive protein, fibrinogen, and
complement components, as well as transcripts of these
proteins, have been observed to be entrapped within drusen,
suggesting the involvement of immunocompetent cells in
drusen biogenesis.116 Nutrients which attenuate the
inflammatory response or enhance immunity to pathogens
might protect against AMD. Vitamin D is an example of one
such food component with antiinflammatory properties.117
One form of the vitamin, vitamin D3 (cholecalciferol), is
synthesized in the skin when exposed to sufficient ultraviolet
light. The amount of ultraviolet exposure needed to elevate
blood vitamin D to recommended levels is small, ~5–15 min
per day with face and hands exposed three times per week in the
summer or on any available sunny days in the winter. However,
aging and sunscreen use can reduce synthesis.118,119 Vitamin D2
(ergocalciferol) is also provided by some foods: fortified cows
milk or soy-milk, cheese, eggs, and fatty fish. However, it has
recently been recognized that many older people obtain
inadequate levels of vitamin D, because they neither consume
the foods that contain it nor get adequate sun exposure to
manufacture it in sufficient quantities. Thirty percent of elderly
Caucasians sampled in Boston were found to be deficient in
vitamin D; the intake of this vitamin is particularly low among
men and women over 51 years of age in the United States.120
Vitamin D intake reduces C-reactive protein, a marker of
systemic inflammation.121 Low vitamin D status has been
associated with the occurrence of common chronic diseases
that are suspected to be promoted by inflammatory mecha-
nisms such as cancers, diabetes, and cardiovascular disease.117
 Foods and Supplements in the Prevention and Treatment of Age-Related Macular Degeneration
Higher blood levels of vitamin D were recently reported to be
associated with lower risk for early AMD in the Third National
Health and Nutrition Examination Survey.122 Consistent
findings in other samples are required to better evaluate this as
one of many food components that could protect against AMD.
There were too few cases of advanced AMD to reliably evaluate
relationships with blood vitamin D in this study, but vitamin D
might protect against neovascular AMD by virtue of its
antiangiogenic properties in endothelial cells.123,124 This
remains to be investigated.
In summary, vitamin D might be another of the food com-
ponents that protects the aging retina. Because this vitamin is
provided in milk and fatty fish, it might explain, in part, relation-
ships of these foods to AMD in past studies. There is currently
insufficient evidence to reliably determine whether vitamin D
status contributes significantly to protection against AMD.
Glycemic Index
The glycemic index of foods was recently introduced to be
another possible aspect of diet that could influence the
development of AMD.125 While advanced glycation end
products have been found in drusen, it is not yet known
whether they are a cause or consequence of degenerative
changes. Degeneration of the retinal vasculature is a well-
known complication of diabetes mellitus, yet, the presence of
diabetes has sometimes, but not always, been related to AMD
in epidemiological studies. The biological plausibility that
elevations in blood sugar promote AMD, particularly in the
absence of diabetes, remains untested. Nevertheless, diets with
a low glycemic index often include few refined grains and sugars
and plenty of fruits, vegetables, whole grains, legumes, and milk
which have numerous ingredients that could protect against
AMD. Thus, high-glycemic-index diets, like high-fat diets, may
be related to higher rates of AMD, in part or in whole, because
they are poorer in a wide variety of protective nutrients and
other diet components.
HERBAL SUPPLEMENTS
The use of herbal supplements has increased in the United
States. Several herbal supplements such as those containing
ginkgo biloba and bilberry have been promoted to benefit the
health of the retina. However, there are no scientific studies that
support their benefit, except one very small (20 persons) study
of ginko biloba in patients with AMD, in which improvement
in visual acuity was indicated in a preliminary report (recently
reviewed126).
LARGER DIETARY PATTERNS
There is evidence that the pathogenesis of AMD, like many
other chronic diseases of aging, is likely to involve a complex
interaction of cellular and vascular factors, which may be
promoted by light damage, oxidative stress, and inflam-
mation.127 Therefore, it comes as no surprise that numerous
nutrients and other dietary components may play multiple roles
which could be additive or complementary. In many recent
studies, specific dietary patterns, which include a high density
of fruits and vegetables and whole grains, moderate or low fat
levels, and low-fat dairy foods, such as the Mediterranean diet
and Dietary Approaches to Stop Hypertension (DASH) diet,
have been related to reduced occurrence or progression of many
chronic diseases of aging,128–132 and results support the idea that
the small effects of many individual nutrients or compounds
could add up to a stronger effect when the overall diet is
examined. For example, it was recently demonstrated that the
combination of high-fruit and -vegetable diets and low-
saturated-fat diets were more protective against coronary heart
disease mortality than was either alone.133
The possibility that certain specific diet patterns slow the
development of early or advanced AMD has not yet been
studied. There does exist evidence in mice for the cooperative
influence of dietary nutrients on the retina in mice: the
deposition of basal laminar deposits that are stimulated by diets
high in polyunsaturated fatty acids is minimized by treatment
with vitamin E.85 Because many aspects of diet have the
potential to protect against ARM, there may be important
insights to be gained by considering overall diet patterns and
their relationships to the occurrence of AMD. Certainly, the
body of evidence about specific nutrients and foods that are
related to lower occurrence of AMD support the possibility that
Mediterranean diets or DASH diets could also lower risk for
early or advanced AMD.
CHAPTER 145
CONSIDERATIONS IN USING
SUPPLEMENTS TO TREAT AMD
There has been a substantial upswing in the marketing of
vitamin and mineral supplements for aging eyes. This prompts
questions from patients who have AMD about the use of these
supplements to slow progression of this condition and about
whether their family members who may be at greater risk will
benefit from beginning supplementation to prevent or delay
getting the condition themselves. It is interesting to note that
while regular supplement use has been practiced by more than
half of Americans for decades, the prevalence of early AMD in
one primarily Caucasian American community (in Beaver
Dam, Wisconsin) was similar to the prevalence among similar,
primarily Caucasian, communities in Australia and the
Netherlands,134 where the frequency of supplement use is about
one-third that in the US community. In fact, rates of
neovascular AMD were lowest in the Dutch community. The
use of multivitamin supplements is consistently unrelated to
AMD in past epidemiological studies (previously reviewed77,126).
The evidence for benefit of supplements in treating AMD is
limited to one study (previously reviewed77,126,135). The AREDS
demonstrated that taking a high-dose combination antioxidant
supplement for 6 years resulted in a 28% reduction of risk for
progression to advanced AMD among subjects who already had
intermediate AMD.10 Given the limited treatment options for
AMD, this may have value for individual persons. It may be
that supplement use is more or less helpful in people who are
genetically prone to AMD, but this has not been tested. A
considerable public health benefit of taking the AREDS
supplements has been estimated.136 However, it is not yet
possible to weigh the costs, in terms of health risks of long-term
use and whether there would be similar or greater overall health
benefit relative to an equal amount of money spent on
consuming food sources of antioxidants. It is unknown whether
a similar benefit would accrue by the consumption of lower
levels of antioxidants. While greater benefit might be achieved
in slowing AMD with even higher doses of antioxidants, this is
not recommended because higher doses have the potential to
pose greater health risks. Results of a recent meta-analysis
suggested that intakes of vitamin E higher than the amount in
AREDS supplements (above 400 IU) was associated with higher
risk for mortality in clinical trials.137 A larger impact might be
possible with intakes over longer periods. Intakes of beta-
carotene above 20 mg have been associated with higher risk of
cancer in smokers.138,139
It is also unclear whether the results can be generalized to
other populations who are less-healthy or consume better or
1923
 RETINA AND VITREOUS
The Bottom Line: Summary of Recommendations to
Patients with Intermediate or Late AMD
Supplements
Taking the AREDS tested supplement containing 500 IU vitamin E,
15 mg beta-carotene, 500 mg vitamin C, and 80 mg zinc with
2 mg copper may reduce progression.
Caveats
• The optimal dose and combination of high-dose antioxidants is
unknown
• The benefits and safety over more than 6 years is unknown
• Individual health, diet, and genetic characteristics that enhance
or reduce the benefits and safety are unknown
Foods
The overall body of current research suggests that healthy eating
may slow the progression of AMD. (See recommendations for
patients who are at risk for AMD because of a family history of
AMD.)
SECTION 10
worse diets. People with less nutritious diets might benefit
more, but may also be at higher risk for side effects of
pharmacological doses of nutrients if diet imbalances already
exist. Insufficient numbers of people in the AREDS, or in all
trials combined, exist to determine whether the benefit (or risk)
is greater in subgroups that have other risk factors for AMD or
for specific types of AMD. There were too few people who
developed early stages of AMD to determine whether these
high-dose antioxidants had value in slowing progression of
earlier stages.
SUMMARY AND CONSIDERATIONS IN
RECOMMENDING DIETS TO LOWER RISK
OR PROGRESSION OF AMD
The knowledge base available to suggest foods that may slow
AMD at early or late stages is currently greater than for
supplements. The results of the AREDS confirmed that
nutrition is important to the health of the aging macula.
Thus, both patients who have AMD and people who might
be at high risk for AMD (perhaps because of a family history of
AMD) who inquire about what they can do to slow AMD, can
The Bottom Line: Recommendations for Patients Who
Are at Risk for AMD Because of a Family History of AMD
Supplements
There is no evidence from population studies or clinical trials that
supplement use of any kind will lower risk for developing AMD.
Foods
Current scientific evidence supports the possibility that healthy
eating is the most promising means known (besides avoiding
smoking) to lower risk for developing AMD.
Because of the broad evidence for benefits of numerous food
components, a focus on a balanced diet, rather than food
supplements, is more likely to lower risk.
Diets which show promise to lower risk for AMD include:
• An abundance of plant foods
• Fruits and vegetables of a variety of colors
• Whole grains
• A variety of daily sources of high-protein foods
• Nuts
• Fish
• Dairy foods or alternate sources of zinc (meat, shellfish)
and vitamin D (eggs, fish, and sunlight or supplements)
• A minimum of high-fat and/or highly sugared foods, especially
those made of refined grains
• A minimum of processed foods
1924
be appropriately advised by their physicians to ‘eat well’, just as
they might be cautioned to stop smoking. A full discussion of
the details of ‘eating well’ is beyond the scope of this chapter,
but suggestions in the following section summarize
recommendations, as relevant to what we currently know about
AMD, and the role of nutrition in chronic diseases of aging.
The last five decades of medical research have demonstrated
the wisdom of refraining from providing patients with
bifurcated lists of ‘good’ or ‘bad’ foods or nutrients. Over that
time, the results of studies (influenced by market forces), have
been enlisted to extol the benefits of some (margarine, beta-
carotene, vitamin E) and admonished against indulgence in
others (eggs, red meats, whole-fat dairy, high-cholesterol
shellfish) to prevent chronic diseases like cardiovascular disease
and cancer. Currently, there is a better understanding of the
complexity of roles of foods in the development of chronic
diseases and the value of traditional diets, such as the
‘Mediterranean diet’ are being considered by the medical
community. The process of adaptation has resulted in
traditional diets, specific to the availability of foods in different
regions of the world that have promoted health and longevity
over thousands of years. Evidence is mounting that certain diet
patterns, such as the Mediterranean diet, have more potential
to slow the onset, progression, and recurrence of cardiovascular
disease and this may be true for eye disease, as well. The
current consensus of medical research, together with specific
knowledge of relationships of foods and nutrients to AMD, as
reviewed in this chapter, suggests the following as
recommendations to patients to slow early and late AMD.
1. Eat an abundance of fruits and vegetables of varying colors.
Currently, the US Dietary Guidelines suggest eating three
to five vegetables per day and two to four servings of fruit
to minimize risk for a variety of chronic diseases. This
translates into ~3/4 to 1 cup of vegetables and 1/2 cup of
fruit three times a day. Choosing a variety of colors
naturally varies the nutrients supplied by them. Dark
green leafy vegetables are rich in lutein and zeaxanthin,
but are also rich in a wide variety of micronutrients such
as vitamins E, C, and other carotenoids. Yellow and orange
fruits and vegetables are often sources of vitamin A and
sources of the carotenoids beta-carotene, lutein, and
cryptoxanthin. Red fruits and vegetables often contain not
only vitamin C, but also other carotenoids, such as
lycopene. Blue and purple fruits supply other
phytochemicals such as flavonoids and anthocyanins that
have antioxidant and antiinflammatory properties.
2. Eat whole grains at most meals, as breads, cereals, or
pasta. These provide many more B vitamins, vitamin E,
and minerals (such as selenium) than refined grains. They
are also higher in fiber which can cause one to feel satisfied
sooner. The current US guidelines suggest eating from 6 to
11 servings of grains per day, depending on the calories
needed. Some controversy exists over the optimal amount
and frequency of grains needed in diets. However, there is
no controversy about the fact that whole grains are
nutritionally superior to refined grains.
3. Eat a variety of protein sources daily. Daily high-quality
protein sources are necessary. US Dietary guidelines
suggest that one should eat two to three servings of meat
or alternate protein sources (meat, fish, poultry, eggs, nuts
or legumes) and three servings of dairy each day. Many of
these have ingredients that may slow AMD, dairy products
(milk, cheese, yogurt) are one of two main sources of zinc
in the American diet and many are fortified with vitamin
D, as well. If dairy foods are not eaten, calcium and many
vitamins can be obtained from beans and other plant
foods, instead. If further research confirms a role of
 Foods and Supplements in the Prevention and Treatment of Age-Related Macular Degeneration

vitamin D in slowing AMD, as early findings suggest, then
people not eating dairy foods can receive vitamin D by
eating eggs, fatty fish from cold waters, small frequent
(three or more times/week) exposure to sunlight, or taking
multivitamins.
Zinc can be obtained from meat, shellfish, or poultry.
Grass-fed meat contains a more favorable ratio of omega-6
to omega-3 fatty acids than grain fed meat. Dark fish from
colder waters (tuna, salmon) is also a source of omega-3
fatty acids and vitamin D. Eating a variety of seafood and
concentrating on wild-caught fish reduces concern about
getting high levels of mercury or other toxins from some.
Egg yolk is an easily absorbable source of lutein and
zeaxanthin and contains vitamin D and omega-3 fats.
Nuts, another protein source, are rich in many types of
vitamin E and omega-3 fatty acids. Variety is the key to
meeting our need for protein sources, as with other types
of food.
increase omega-3 PUFA intake. Avoiding processed foods
will lower trans-fat intake; since processed foods and oils
provide ~80% of trans fats in the diet, compared to 20%,
that occur naturally in food from animal sources.
IMPORTANCE OF FOOD TO AMD PATIENTS
BEYOND NUTRIENTS
Foods nourish patients with AMD by providing numerous
bioactive chemicals that directly or indirectly slow the
pathogenesis of AMD. Additionally, the likelihood that foods
that they eat (or perhaps supplements they take if eating
healthy foods is not possible) can slow the progression of their
condition may provide a sense of hope, optimism, and self-
empowerment that cannot come from the limited medical
treatments that are currently available. The overall current
body of scientific evidence provides solid support for this,
whether or not the long-term impact of isolated components is

4. Eat moderate amounts of fat, reducing processed fats and
omega-6 fats and increasing omega-3 fatty acids. Excess fat
in the diet lowers the overall nutrient density because
high-fat foods (such as from high-fat desserts and salty
snacks) are typically low in vitamins and minerals and
replace nutrient-dense foods. However, some fat may be
part of a healthy diet for people with or at risk for AMD.
Fat is not only important in enhancing the natural flavor
of foods but also aids digestion of fat-soluble plant
pigments. For example, salads to which full-fat salad
dressings or avocados have been added raise blood
carotenoids more than eating fat-free salads that are
equally high in carotenoids.140,141 Current
recommendations to lower omega-6 and increase omega-3
fats in the diet can be achieved by reducing processed
foods, replacing corn oils and margarines with canola, nut,
and olive oils, and increasing the intake of cold-water fish,
which provide LC omega-3 PUFAs. Substituting meat that
has increasingly come from grain-fed animals, with meat
from traditional grass-fed animals, is another option to
CHAPTER 145
possible or practical to determine conclusively.
Foods can also stimulate the senses. This may be particularly
nourishing to the patient with AMD who is becoming aware
of diminished sense of sight. The role of food in connecting
the person to his or her surroundings is heightened in patients
with AMD (or any significant vision loss). Since food lies at the
center of many of the activities and rituals that bring meaning
and joy to one’s life, the smells and tastes of traditional foods
can reinforce connections to cherished past experiences.
Physicians might consider supplementing their recommen-
dations, based on evidence for the pharmacological impact of
food components on the pathogenetic process that promote
AMD, with encouragement toward a focus on enjoying
healthful eating.
Decades of medical research both inform us of the large
number of vitamins, minerals, and phytochemicals that are
currently known to contribute to retinal health, and foster
within us an appreciation of the probability that others, of
which we may not be presently aware, are likely to be elucidated
in the near future.

REFERENCES
1. Mares-Perlman JA, Klein R: Diet and age-
related macular degeneration. In: Taylor A,
ed. Nutritional and environmental
influences on the eye. Boca Raton, FL:
CRC Press; 1999:181–214.
2. Handelman GJ, Dratz EA: The role of
antioxidants in the retina and retinal
pigment epithelium and the nature of
pro-oxidant damage. Adv Free Radic Biol
Med 1986; 2:1–89.
3. Beatty S, Koh H, Phil M, et al: The role of
oxidative stress in the pathogenesis of age-
related macular degeneration. Surv
Ophthalmol 2000; 45:115–134.
4. Teikari JM, Laatikainen L, Virtamo J, et al:
Six-year supplementation with alpha-
tocopherol and beta-carotene and age-
related maculopathy. Acta Ophthalmol
Scand 1998; 76:224–229.
5. Taylor HR, Tikellis G, Robman LD, et al:
Vitamin E supplementation and macular
degeneration: randomised controlled trial.
BMJ 2002; 325:11.
6. Stahl W, Junghans A, de Boer B, et al:
Carotenoid mixtures protect multilamellar
liposomes against oxidative damage:
synergistic effects of lycopene and lutein.
FEBS Lett 1998; 427:305–308.
7. Wrona M, Korytowski W, Rozanowska M,
et al: Cooperation of antioxidants in
protection against photosensitized oxidation.
Free Radic Biol Med 2003; 35:1319–1329.
8. Wrona M, Rozanowska M, Sarna T:
Zeaxanthin in combination with ascorbic
acid or alpha-tocopherol protects ARPE-19
cells against photosensitized peroxidation
of lipids. Free Radic Biol Med 2004;
36:1094–1101.
9. Lu L, Hackett SF, Mincey A, et al: Effects of
different types of oxidative stress in RPE
cells. J Cell Physiol 2006; 206:119–125.
10. A randomized, placebo-controlled, clinical
trial of high-dose supplementation with
vitamins C and E, beta carotene, and zinc
for age-related macular degeneration and
vision loss: AREDS report no. 8. Arch
Ophthalmol 2001; 119:1417–1436.
11. Moriarty-Craige SE, Adkison J, Lynn M, et al:
Antioxidant supplements prevent oxidation
of cysteine/cystine redox in patients with
age-related macular degeneration. Am J
Ophthalmol 2005; 140:1020–1026.
12. Richer S, Stites W, Statkute L, et al:
Double-masked, placebo-controlled,
randomized trial of lutein and antioxidant
supplementation in the intervention of
atrophic age-related macular degeneration:
the Veterans LAST study (Lutein
Antioxidant Supplementation Trial).
Optometry 2004; 75:216–2130.
13. West S, Vitale S, Hallfrisch J, et al: Are
antioxidants or supplements protective for
age-related macular degeneration? Arch
Ophthalmol 1994; 112:222–227.
14. VandenLangenberg GM, Mares-Perlman
JA, Klein R, et al: Associations between
antioxidant and zinc intake and the 5-year
incidence of early age-related maculopathy
in the Beaver Dam Eye Study. Am J
Epidemiol 1998; 148:204–214.
15. van Leeuwen R, Boekhoorn S, Vingerling
JR, et al: Dietary intake of antioxidants and
risk of age-related macular degeneration.
JAMA 2005; 294:3101–3107.
16. Delcourt C, Carriere I, Delage M, et al:
Plasma lutein and zeaxanthin and other
carotenoids as modifiable risk factors for
age-related maculopathy and cataract: The
POLA Study. Invest Ophthalmol Vis Sci
2006; 47:2329–2335.
17. Cardinault N, Abalain J-H, Sairafi B et al:
Lycopene but not lutein nor zeaxanthin
decreases in serum and lipoproteins in
age-related macular degeneration patients.
Clinica Chimica Acta2005; 357:34–42.
18. Mares-Perlman JA, Klein R, Klein BE, et al:
Association of zinc and antioxidant
nutrients with age-related maculopathy.
Arch Ophthalmol 1996; 114:991–997.
19. Gale CR, Hall NF, Phillips DI, et al: Lutein 1925
 RETINA AND VITREOUS
and zeaxanthin status and risk of age-
related macular degeneration. Invest
Ophthalmol Vis Sci 2003; 44:2461–2465.
20. Moeller SM, Mehta NR, Tinker LF, et al:
Associations between intermediate age-
related macular degeneration and lutein
and zeaxanthin in the Carotenoids in Age-
Related Eye Disease Study (CAREDS), an
ancillary study of the Women’s Health
Initiative. Arch Ophthalmol 2006; 124:1–24.
21. Fowke JH, Morrow JD, Motley S, et al:
Brassica vegetable consumption reduces
urinary F2-isoprostane levels independent
of micronutrient intake. Carcinogenesis Oct
2006; 27:2096–2102.
22. Mares-Perlman JA, Klein R: Diet and
age-related macular degeneration. In:
Taylor A, ed. Nutritional and environmental
influences on the eye. Boca Raton, FL:
CRC Press; 1999:181–214.
23. Moeller SM, Jacques PF, Blumberg JB:
SECTION 10
The potential role of dietary xanthophylls in
cataract and age-related macular
degeneration. J Am Coll Nutr 2000; 19(5
Suppl):522S–527S.
24. Bone RA, Landrum JT, Fernandez L, et al:
Analysis of the macular pigment by HPLC:
retinal distribution and age study. Invest
Ophthalmol Vis Sci 1988; 29:843–849.
25. Bernstein PS, Khachik F, Carvalho LS, et al:
Identification and quantitation of
carotenoids and their metabolites in the
tissues of the human eye. Exp Eye Res
2001; 72:215–223.
26. Yemelyanov AY, Katz NB, Bernstein PS:
Ligand-binding characterization of
xanthophyll carotenoids to solubilized
membrane proteins derived from human
retina. Exp Eye Res 2001; 72:381–392.
27. Bhosale P, Larson AJ, Frederick JM, et al:
Identification and characterization of a Pi
isoform of glutathione S-transferase
(GSTP1) as a zeaxanthin-binding protein in
the macula of the human eye. J Biol Chem
2004; 279:49447–49454.
28. Handelman GJ, Nightingale ZD,
Lichtenstein AH, et al: Lutein and
zeaxanthin concentrations in plasma after
dietary supplementation with egg yolk. Am
J Clin Nutr 1999; 70:247–2451.
29. U.S. Department of Agriculture, Agricultural
Research Service: USDA National Nutrient
Database for Standard Reference, Release
16-1. 2004 Jul 29, 2004. Available:
http://www.nal.usda.gov/fnic/foodcomp/
Data/SR16-1/wtrank/16-1w338.pdf Aug 5,
2004.
30. Mares-Perlman JA, Fisher AI, Klein R, et al:
Lutein and zeaxanthin in the diet and
serum and their relation to age-related
maculopathy in the third national health
and nutrition examination survey. Am J
Epidemiol 2001; 153:424–432.
31. Snodderly DM, Brown PK, Delori FC, et al:
The macular pigment. I. Absorbance
spectra, localization, and discrimination
from other yellow pigments in primate
retinas. Invest Ophthalmol Vis Sci 1984;
25:660–673.
32. Junghans A, Sies H, Stahl W: Macular
pigments lutein and zeaxanthin as
blue light filters studied in liposomes.
Arch Biochem Biophys 2001; 391:160–164.
33. Hammond JBR, Wooten BR, Curran-
Celentano J: Carotenoids in the retina and
lens: possible acute and chronic effects on
human visual performance. Arch Biochem
1926 Biophys 2001; 385:41–46.
34. Sparrow JR, Vollmer-Snarr HR, Zhou J,
et al: A2E-epoxides Damage DNA in
Retinal Pigment Epithelial Cells. Vitamin E
and other antioxidants inhibit A2E-epoxide
formation. J Biol Chem 2003;
278:18207–18213.
35. Rapp LM, Maple SS, Choi JH: Lutein and
zeaxanthin concentrations in rod outer
segment membranes from perifoveal and
peripheral human retina. Invest Ophthalmol
Vis Sci 2000; 41:1200–1209.
36. Khachik F, Bernstein PS, Garland DL:
Identification of lutein and zeaxanthin
oxidation products in human and monkey
retinas. Invest Ophthalmol Vis Sci 1997;
38:1802–1811.
37. Sujak A, Gabrielska J, Grudzinski W, et al:
Lutein and zeaxanthin as protectors of lipid
membranes against oxidative damage: the
structural aspects. Arch Biochem Biophys
1999; 371:301–307.
38. Malinow MR, Feeney-Burns L, Peterson
LH, et al: Diet-related macular anomalies in
monkeys. Invest Ophthalmol Vis Sci 1980;
19:857–863.
39. Leung IY, Sandstrom MM, Zucker CL, et al:
Nutritional manipulation of primate retinas,
II: effects of age, n-3 fatty acids, lutein, and
zeaxanthin on retinal pigment epithelium.
Invest Ophthalmol Vis Sci 2004;
45:3244–3256.
40. Feeney-Burns L, Neuringer M, Gao CL:
Macular pathology in monkeys fed
semipurified diets. Prog Clin Biol Res 1989;
314:601–622.
41. Thomson LR, Toyoda Y, Langner A, et al:
Elevated retinal zeaxanthin and prevention
of light-induced photoreceptor cell death in
quail. Invest Ophthalmol Vis Sci 2002;
43:3538–3549.
42. Bone RA, Landrum JT, Mayne ST, et al:
Macular pigment in donor eyes with and
without AMD: a case-control study. Invest
Ophthalmol Vis Sci 2001; 42:235–240.
43. Beatty S, Murray IJ, Henson DB, et al:
Macular pigment and risk for age-related
macular degeneration in subjects from a
Northern European population. Invest
Ophthalmol Vis Sci 2001; 42:439–446.
44. Bernstein PS, Zhao DY, Wintch SW, et al:
Resonance Raman measurement of
macular carotenoids in normal subjects
and in age-related macular degeneration
patients. Ophthalmology 2002;
109:1780–1787.
45. La Rowe TL, Snodderly DM, et al: Macular
pigment and age-related maculopathy in
the carotenoids in age-related eye disease
study, an ancillary study of the women’s
health initiative. Am J Clin Nutr Manuscript
under review, 2006.
46. Antioxidant status and neovascular age-
related macular degeneration. Eye Disease
Case-Control Study Group. Arch
Ophthalmol 1993; 111:104–109.
47. Snellen EL, Verbeek AL, Van Den Hoogen
GW, et al: Neovascular age-related macular
degeneration and its relationship to
antioxidant intake. Acta Ophthalmol Scand
2002; 80:368–371.
48. Seddon J AU, Sperduto R et al: Dietary
carotenoids, vitamins A, C, and E, and
advanced age related macular
degeneration. JAMA 1994; 272:1413–1420.
49. Mares-Perlman JA, Fisher AI, Klein R, et al:
Lutein and zeaxanthin in the diet and
serum and their relation to age- related
maculopathy in the third national health
and nutrition examination survey. Am J
Epidemiol 2001; 153:424–432.
50. Cho E, Seddon JM, Rosner B, et al:
Prospective study of intake of fruits,
vegetables, vitamins, and carotenoids and
risk of age-related maculopathy. Arch
Ophthalmol 2004; 122:883–892.
51. Flood V, Smith W, Wang JJ, et al: Dietary
antioxidant intake and incidence of early
age-related maculopathy: the Blue
Mountains Eye Study. Ophthalmology
2002; 109:2272–2278.
52. Flood V, Rochtchina E, Wang JJ, et al:
Lutein and zeaxanthin dietary intake and
age related macular degeneration. Br J
Ophthalmol 2006; 90:927–928.
53. Mares-Perlman JA, Klein R, Klein BE, et al:
Association of zinc and antioxidant
nutrients with age-related maculopathy.
Arch Ophthalmol 1996; 114:991–997.
54. Mares-Perlman JA, Brady WE, Klein R,
et al: Serum antioxidants and age-related
macular degeneration in a population-
based case-control study. Arch Ophthalmol
1995; 113:1518–1523.
55. Mares J: Carotenoids and eye disease:
epidemiologic evidence. In: Krinsky NI,
Mayne S, eds. Carotenoids in health &
disease. New York, NY: Marcel Dekker;
2003.
56. Hammond BR, Jr, Johnson EJ, Russell RM,
et al: Dietary modification of human macular
pigment density. Invest Ophthalmol Vis Sci
1997; 38:1795–1801.
57. Bone RA, Landrum JT, Guerra LH, et al:
Lutein and zeaxanthin dietary supplements
raise macular pigment density and serum
concentrations of these carotenoids in
humans. J Nutr 2003; 133:992–998.
58. Aleman TS, Duncan JL, Bieber ML, et al:
Macular pigment and lutein
supplementation in retinitis pigmentosa and
Usher syndrome. Invest Ophthalmol Vis Sci
2001; 42:1873–1881.
59. Bowen PE, Garg V, Stacewicz-Sapuntzakis
M, et al: Variability of serum carotenoids in
response to controlled diets containing six
servings of fruits and vegetables per day.
Ann NY Acad Sci 1993; 691:241–243.
60. Bowen PE, Herbst-Espinosa SM, Hussain
EA, et al: Esterification does not impair
lutein bioavailability in humans. J Nutr
2002; 132:3668–3673.
61. Mares JA, LaRowe TL, Snodderly DM, et al:
Predictors of macular pigment density in the
Carotenoids in the Age-Related Eye Disease
Study. Am J Clin Nutr 2006; in press.
62. Goldberg J, Flowerdew G, Smith E, et al:
Factors associated with age-related
macular degeneration. An analysis of data
from the first National Health and Nutrition
Examination Survey. Am J Epidemiol 1988;
128:700–710.
63. Vaicaitiene R, Luksiene DK, Paunksnis A,
et al: Age-related maculopathy and
consumption of fresh vegetables and fruits
in urban elderly. Medicina (Kaunas) 2003;
39:1231–1236.
64. Karcioglu ZA, Zinc in the eye. Surv
Ophthalmol 1982; 27:114–122.
65. Trumbo P, Yates A, Schlicker A, et al:
Scientific evaluation of dietary reference
intake. Dietry reference intakes (DRI) for
vitamin A, vitamin K, arsenic, boron,
chromium, copper, iodine, iron, maganese,
molybderum, nickel, silicon, vandadium,
and zinc. Washington DC: National
Academy Press; 2000.
 Foods and Supplements in the Prevention and Treatment of Age-Related Macular Degeneration
66. Tate DJ Jr, Miceli MV, Newsome DA:
Zinc protects against oxidative damage in
cultured human retinal pigment epithelial
cells. Free Radic Biol Med 1999;
26:704–713.
67. Mocchegiani E, Muzzioli M, Giacconi R:
Zinc, metallothioneins, immune responses,
survival and ageing. Biogerontology 2000;
1:133–143.
68. Shankar AH, Prasad AS: Zinc and immune
function: the biological basis of altered
resistance to infection. Am J Clin Nutr
1998; 68(2 Suppl):447S–463S.
69. Hyun HJ, Sohn JH, Ha DW, et al: Depletion
of intracellular zinc and copper with TPEN
results in apoptosis of cultured human
retinal pigment epithelial cells. Invest
Ophthalmol Vis Sci 2001; 42:460–465.
70. Wood JPM, Osborne NN: Zinc and energy
requirements in induction of oxidative
stress to retinal pigmented epithelial cells.
Neurochem Res 2003; 28:1525–1533.
71. Smith W, Mitchell P, Webb K, et al: Dietary
antioxidants and age-related maculopathy:
the Blue Mountains Eye Study.
Ophthalmology 1999; 106:761–767.
72. Cho E, Stampter MK, Seddon JM, et al:
Prospective study of zinc intake and the
risk of age-related macular degeneration.
Ann Epidemiol 2001; 11:328–336.
73. Newsome DA, Swartz M, Leone NC, et al:
Oral zinc in macular degeneration. Arch
Ophthalmol 1988; 106:192–198.
74. Stur M, Tittl M, Reitner A, et al: Oral zinc
and the second eye in age-related macular
degeneration. Invest Ophthalmol Vis Sci
1996; 37:1225–1235.
75. Clemons TE, Kurinij N, Sperduto RD:
Associations of mortality with ocular
disorders and an intervention of high-dose
antioxidants and zinc in the Age-Related
Eye Disease Study: AREDS Report No. 13.
Arch Ophthalmol 2004; 122:716–726.
76. Chandra RK: Effect of vitamin and trace-
element supplementation on immune
responses and infection in elderly subjects.
Lancet 1992; 340:1124–1127.
77. Mares JA, La Rowe TL, Blodi BA: Doctor,
what vitamins should I take for my eyes?
Arch Ophthalmol 2004; 122:628–635.
78. Seddon JM, Rosner B, Sperduto RD, et al
Dietary fat and risk for advanced age-
related macular degeneration. Arch
Ophthalmol 2001; 119:1191–1199.
79. Schaumberg DA, Christen WG, Hankinson
SE, et al: Body mass index and the
incidence of visually significant age-related
maculopathy in men. Arch Ophthalmol
2001; 119:1259–1265.
80. Seddon JM, Cote J, Davis N, et al:
Progression of age-related macular
degeneration: association with body mass
index, waist circumference, and waist-hip
ratio. Arch Ophthalmol 2003; 121:785–792.
81. Leeuwen VR, Ikram MK, Vingerling JR,
et al: Blood pressure, atherosclerosis, and
the incidence of age-related maculopathy:
the Rotterdam Study. Invest Ophthalmol Vis
Sci 2003; 44:3771–3777.
82. Vingerling JR, Dielemans I, Hofman A, Bots
M: Age-related Macular Degeneration is
Assoiciated with Atherosclerosis. Am J
Epidemiol 1995; 142:404–409.
83. Miceli MV, Newsome DA, Tate DJ, Jr., et al:
Pathologic changes in the retinal pigment
epithelium and Bruch’s membrane of fat-
fed atherogenic mice. Curr Eye Res 2000;
20:8–16.
84. Kliffen M, Lutgens E, Daemen MJ, et al:
The APO(*)E3-Leiden mouse as an animal
model for basal laminar deposit. Br J
Ophthalmol 2000; 84:1415–1419.
85. Espinosa-Heidmann DG, Sall J, Hernandez
EP, et al: Basal laminar deposit formation in
APO B100 transgenic mice: complex
interactions between dietary fat, blue light,
and vitamin E. Invest Ophthalmol Vis Sci
2004; 45:260–266.
86. Dithmar S, Sharara NA, Curcio CA, et al:
Murine high-fat diet and laser
photochemical model of basal deposits in
Bruch membrane. Arch Ophthalmol 2001;
119:1643–1649.
87. Heuberger RA, Mares-Perlman JA, Klein R,
et al: Relationship of dietary fat to age-
related maculopathy in the Third National
Health and Nutrition Examination Survey.
Arch Ophthalmol 2001; 119:1833–1838.
88. Mares-Perlman JA, Brady WE, Klein R,
et al: Dietary fat and age-related
maculopathy. Arch Ophthalmol 1995;
113:743–748.
89. Smith W, Mitchell P, Leeder SR: Dietary fat
and fish intake and age-related
maculopathy. Arch Ophthalmol 2000;
118:401–404.
90. Cho E, Hung S, Willett WC, et al:
Prospective study of dietary fat and the risk
of age-related macular degeneration. Am J
Clin Nutr 2001; 73:209–218.
91. Chua B, Flood V, Rochtchina E, et al:
Dietary fatty acids and the 5-year incidence
of age-related maculopathy. Arch
Ophthalmol 2006; 124:981–986.
92. Seddon JM, Cote J, Rosner B: Progression
of age-related macular degeneration:
association with dietary fat,
transunsaturated fat, nuts, and fish intake.
Arch Ophthalmol 2003; 121:1728–1737.
Erratum. Arch Ophthalmol 2004; 122:426.
93. Seddon JM, Cote J, Rosner B: Progression
of age-related macular degeneration:
association with dietary fat,
transunsaturated fat, nuts, and fish intake.
Arch Ophthalmol 2003; 121:1728–1737.
94. Seddon JM, George S, Rosner B: Cigarette
smoking, fish consumption, Omega-3
fatty acid intake, and associations with
age-related macular degeneration: The US
Twin Study of age-related macular
degeneration. Arch Ophthalmol 2006;
124:995–1001.
95. Larsson SC, Kumlin M, Ingelman-Sundberg
M, et al: Dietary long-chain n-3 fatty acids
for the prevention of cancer: a review of
potential mechanisms. Am J Clin Nutr
2004; 79:935–945.
96. Wood JD, Enser M: Factors influencing
fatty acids in meat and the role of
antioxidants in improving meat quality.
Br J Nutr 1997; 78(Suppl 1):S49–S60.
97. Snow KK, Seddon JM: Do age-related
macular degeneration and cardiovascular
disease share common antecedents?
Ophthalmic Epidemiol 1999; 6:125–143.
98. Breslow JL: n-3 Fatty acids and
cardiovascular disease. Am J Clin Nutr
2006; 83:S1477–1482.
99. Bazan NG, Scott BL: Dietary omega-3
fatty acids and accumulation of
docosahexaenoic acid in rod photoreceptor
cells of the retina and at synapses. Ups J
Med Sci 1990; 48(Suppl):97–107.
100. Fliesler SJ, Anderson RE: Chemistry and
metabolism of lipids in the vertebrate
retina. Prog Lipid Res 1983; 22:79–131.
101. Arterburn LM, Hall EB, Oken H:
Distribution, interconversion, and dose
response of n-3 fatty acids in humans.
Am J Clin Nutr 2006; 83:S1467–1476.
102. Litman BJ, Niu SL, Polozova A, et al: The
role of docosahexaenoic acid containing
phospholipids in modulating G protein-
coupled signaling pathways: visual
transduction. J Mol Neurosci 2001;
16:237–242; discussion 279–284.
103. Rotstein NP, Politi LE, German OL, et al:
Protective effect of docosahexaenoic acid
on oxidative stress-induced apoptosis of
retina photoreceptors. Invest Ophthalmol
Vis Sci 2003; 44:2252–2259.
104. Mukherjee PK, Marcheselli VL, Serhan CN,
et al: Neuroprotectin D1: a docosahexaenoic
acid-derived docosatriene protects human
retinal pigment epithelial cells from
oxidative stress. Proc Natl Acad Sci USA
CHAPTER 145
2004; 101:8491–8496.
105. SanGiovanni JP, Chew EY: The role of
omega-3 long-chain polyunsaturated fatty
acids in health and disease of the retina.
Prog Retin Eye Res 2005; 24:87–138.
106. Calder PC: n-3 polyunsaturated fatty
acids, inflammation, and inflammatory
diseases. Am J Clin Nutr 2006; 83(6
Suppl):1505S–1519S.
107. Wang C, Chung M, Lichtenstein AH, et al:
Effects of Omega-3 fatty acids on
cardiovascular disease. evidence
report/technology assessment No. 94
(Prepared by Tufts-New England Medical
Center Evidence-Based Practice Center
under contract no. 290-02-0022.) AHRQ
Publication No. 04-E013–2. Rockville, MD:
Agency for Healthcare Research and
Quality; 2004.
108. Klein RJ, Zeiss C, Chew EY, et al:
Complement factor H polymorphism in
age-related macular degeneration. Science
2005; 308:385–389.
109. Haines JL, Hauser MA, Schmidt S, et al:
Complement factor H variant increases the
risk of age-related macular degeneration.
Science 2005; 308:419–421.
110. Edwards AO, Ritter R, 3rd, Abel KJ, et al:
Complement factor H polymorphism and
age-related macular degeneration. Science
2005; 308:421–424.
111. Seddon JM, Gensler G, Milton RC, et al:
Association between C-reactive protein and
age-related macular degeneration. JAMA
2004; 291:704–710.
112. Seddon JM, George S, Rosner B, et al:
Progression of age-related macular
degeneration: prospective assessment of
C-reactive protein, interleukin 6, and other
cardiovascular biomarkers. Arch
Ophthalmol 2005; 123:774–782.
113. Clemons TE, Milton RC, Klein R, et al: Risk
factors for the incidence of advanced age-
related macular degeneration in the Age-
Related Eye Disease Study (AREDS)
AREDS report no. 19. Ophthalmology 2005;
112:533–539.
114. Klein R, Klein BE, Marino EK, et al: Early
age-related maculopathy in the
cardiovascular health study. Ophthalmology
2003; 110:25–33.
115. Klein R, Klein BE, Knudtson MD, et al:
Systemic markers of inflammation,
endothelial dysfunction, and age-related
maculopathy. Am J Ophthalmol 2005;
140(1):35–44.
116. Anderson DH MR, Hageman GS et al:
A role for local inflammation in the 1927
 RETINA AND VITREOUS
formation of drusen in the aging eye. Am J
Ophthalmol 2002; 134:411–431.
117. Holick MF, Vitamin D: importance in the
prevention of cancers, type 1 diabetes,
heart disease, and osteoporosis. Am J Clin
Nutr 2004; 79:362–371.
118. MacLaughlin J, Holick MF: Aging
decreases the capacity of human skin to
produce vitamin D3. J Clin Invest 1985;
76:1536–1538.
119. Matsuoka LY, Ide L, Wortsman J, et al:
Sunscreens suppress cutaneous vitamin
D3 synthesis. J Clin Endocrinol Metab
1987; 64:1165–1168.
120. Moore C, Murphy MM, Keast DR, et al:
Vitamin D intake in the United States. J Am
Diet Assoc 2004; 104:980–983.
121. Timms PM, Mannan N, Hitman GA, et al:
Circulating MMP9, vitamin D and variation
in the TIMP-1 response with VDR
genotype: mechanisms for inflammatory
SECTION 10
damage in chronic disorders? QJM 2002;
95:787–796.
122. Parekh N, Chappell R, Millen A, et al:
Association between Vitamin D and age-
related macular degeneration in the Third
National Health and Nutrition Examination
Survey 1988–94. Arch Ophthalmol, 2007;
125:661–669.
123. Iseki K, Tatsuta M, Uehara H, et al:
Inhibition of angiogenesis as a mechanism
for inhibition by 1alpha-hydroxyvitamin D3
and 1,25-dihydroxyvitamin D3 of colon
carcinogenesis induced by azoxymethane
in Wistar rats. Int J Cancer 1999;
81:730–733.
124. Bernardi RJ, Johnson CS, Modzelewski RA,
et al: Antiproliferative effects of 1alpha,
25-dihydroxyvitamin D(3) and vitamin D
analogs on tumor-derived endothelial cells.
Endocrinology 2002; 143:2508–2514.
125. Chiu CJ, Hubbard LD, Armstrong J, et al:
Dietary glycemic index and carbohydrate in
relation to early age-related macular
1928
degeneration. Am J Clin Nutr 2006;
83:880–886.
126. West AL, GA Oren and SE Moroi Evidence
for the Use of Nutritional Supplements and
Herbal Medicines in Common Eye
Diseases. American Journal of
Ophthalmology 2006; 141:157–166.
127. Hageman GS, Luthert PJ, Victor Chong
NH, et al: An integrated hypothesis that
considers drusen as biomarkers of
immune-mediated processes at the RPE-
Bruch’s membrane interface in aging and
age-related macular degeneration. Prog
Retin Eye Res 2001; 20:705–732.
128. Hoffmann K, Zyriax B-C, Boeing H, et al:
A dietary pattern derived to explain
biomarker variation is strongly associated
with the risk of coronary artery disease. Am
J Clin Nutr 2004; 80:633–640.
129. Moeller SM, Taylor A, Tucker KL, et al:
Overall adherence to the dietary guidelines
for americans is associated with reduced
prevalence of early age-related nuclear lens
opacities in women. J Nutr 2004;
134:1812–1819.
130. Appel LJ, Champagne CM, Harsha DW,
et al: Effects of comprehensive lifestyle
modification on blood pressure control:
main results of the PREMIER clinical trial.
JAMA 2003; 289:2083–2093.
131. Lopes HF, Martin KL, Nashar K, et al:
DASH diet lowers blood pressure and lipid-
induced oxidative stress in obesity.
Hypertension 2003; 41:422–430.
132. de Lorgeril M, Salen P, Martin JL, et al:
Mediterranean diet, traditional risk factors,
and the rate of cardiovascular
complications after myocardial infarction:
final report of the Lyon Diet Heart Study.
Circulation 1999; 99:779–785.
133. Tucker KL, Hallfrisch J, Qiao N, et al: The
combination of high fruit and vegetable and
low saturated fat intakes is more protective
against mortality in aging men than is either
alone: the Baltimore Longitudinal Study of
Aging. J Nutr 2005; 135:556–561.
134. Smith W, Assink J, Klein R, et al: Risk
factors for age-related macular
degeneration: Pooled findings from three
continents. Ophthalmology 2001;
108:697–704.
135. Evans JR, Antioxidant vitamin and mineral
supplements for slowing the progression of
age-related macular degeneration. Cochrane
Database Syst Rev 2006:CD000254.
136. Bressler NM, Bressler SB, Congdon NG,
et al: Potential public health impact of Age-
Related Eye Disease Study results: AREDS
report no. 11. Arch Ophthalmol 2003;
121:1621–1624.
137. Miller ER, 3rd, Pastor-Barriuso R, Dalal D,
et al: Meta-analysis: high-dosage Vitamin E
supplementation may increase all-cause
mortality. Ann Intern Med 2004;
142(1):37–46.
138. The effect of vitamin E and beta carotene
on the incidence of lung cancer and other
cancers in male smokers. The Alpha-
Tocopherol, Beta Carotene Cancer
Prevention Study Group. N Engl J Med
1994; 330:1029–1035.
139. Omenn GS, Goodman GE, Thornquist MD,
et al: Effects of a combination of beta
carotene and vitamin A on lung cancer and
cardiovascular disease. N Engl J Med
1996; 334:1150–1155.
140. Brown ED, Micozzi MS, Craft NE, et al:
Plasma carotenoids in normal men after a
single ingestion of vegetables or purified
beta-carotene. Am J Clin Nutr 1989;
49:1258–1265.
141. Unlu ZN, Bohn T, Clinton S, Schwartz SJ:
Enhanced carotenoid absorption in humans
from salad and salsa with addition of
avocado or avocado oil. J Nutr 2005;
135:3.
 CHAPTER
Age-Related Macular Degeneration: Choroidal
146 Neovascularization
Neil M. Bressler, Susan B. Bressler, and Evangelos S. Gragoudas
Although most patients with age-related macular degeneration
(AMD) manifest only drusen or abnormalities of the retinal
pigment epithelium (RPE), the majority of patients who are at
risk for severe loss of vision from AMD can lose vision because
of the development of choroidal neovascularization (CNV) and
related manifestations such as serous or hemorrhagic detach-
ment of the RPE and fibrovascular disciform scarring. The
pathogenesis, clinical features, differential diagnosis, impact on
quality of life, and mangement of the neovascular form of AMD
are reviewed in this chapter. (The nonneovascular form of
AMD, including drusen and abnormalities of the RPE such as
geographic atrophy, is reviewed in Chapter 144).
PATHOGENESIS
PATHOGENESIS OF DEVELOPMENT OF CNV
The understanding of the pathogenesis of the development of
CNV continues to evolve. In part, clinical1–5 and histologic
reports6–9 suggest that the presence of diffuse thickening of the
inner aspect of Bruch’s membrane (associated with large, soft
drusen clinically) predisposes Bruch’s membrane to develop
cracks through which ingrowth of new vessels from the
choriocapillaris can occur. This hypothesis is supported by the
finding of CNV in other pathologic entities in which breaks in
Bruch’s membrane occur, such as pathologic myopia10 and
angioid streaks.11 However, it is unlikely that a break in Bruch’s
membrane alone necessarily predisposes to the development of
CNV. Histologic studies have shown that in eyes with AMD,
breaks in Bruch’s membrane can be identified not only in areas
of CNV but also in areas in which no new vessels can be
identified.6
Experimental studies have also suggested that other cellular
processes may have a role in the development of the CNV
beyond merely a disturbance in Bruch’s membrane. Laboratory
studies have shown that endothelial cells can elaborate enzymes
necessary for the digestion of a basement membrane such as
Bruch’s membrane.12 This finding would support the concept
that endothelial cells from the choriocapillaris could produce a
break in Bruch’s membrane, rather than presuming that CNV
grows only through preexisting breaks in Bruch’s membrane.
Other reports have suggested that a granulomatous inflam-
matory response to degenerated Bruch’s membrane may be an
important factor in the development of CNV. In histologic
studies, eyes with AMD had an increased prevalence of
lymphocytes, macrophages, and fibroblasts within Bruch’s
membrane when compared with control eyes without AMD.13–15
These findings would suggest that a low-grade chronic
inflammatory response may be involved in the development of
AMD, although inflammation has a role in the involutionary
process of CNV (see end of this section on Pathogenesis).
Although inflammatory cells have been shown histologically
to be associated with the presence of the nonneovascular and
neovascular stages of AMD, studies have not shown that
inflammatory cells necessarily are directly linked to the devel-
opment of CNV. Therefore, these studies cannot determine
whether these inflammatory cells represent a response to existing
degenerative changes within Bruch’s membrane or whether the
inflammatory cells act as essential mediators of degeneration,
with subsequent development of CNV.
Experimentally produced CNV developing around retinal
laser burns in the monkey eye have also shown the presence of
macrophages at the site of developing CNV.16,17 Again, it is
not known whether these macrophages represent a response to
damaged retina from a laser burn or whether they act as
mediators of CNV. Also, this model of CNV differs from CNV
in AMD in that experimentally produced CNV proliferates
internal to the RPE (between the sensory retina and the RPE),16
whereas CNV associated with AMD initially proliferates
external to the RPE (within the thickened inner aspect of Bruch’s
membrane).6–8
A relationship of scleral rigidity with CNV in AMD has been
suggested in a pilot study in which increased scleral rigidity
was found to be associated with the presence of AMD.18 The
possibility of compromised blood flow in the vortex veins by
progressively increased scleral rigidity was hypothesized to
account for these findings, but further investigation is required.
Results from epidemiologic studies19 also demonstrated that
the risk of CNV is associated with low blood levels of
micronutrients with antioxidant potential, cigarette smoking,
and risk factors for cardiovascular disease. Systemic hypertension
also has been reported to be a risk factor for developing CNV in
the fellow eye of a patient who presents with CNV in the first
eye.2 Decreased risk was associated with higher levels of
carotenoids and use of postmenopausal exogenous estrogens
in women. The associations with estrogens, cigarette smoking,
and serum cholesterol are intriguing because sphingomyelins
and cholesterol esters similar to those found in arteriosclerotic
plaques are found in aging sclera.20 Perhaps these factors in
some way account for increased scleral rigidity.
PATHOGENESIS OF PROGRESSION OF CNV
While understanding the development of CNV continues to
evolve, researchers have developed a theoretical construct that
correlates the growth pattern of CNV with the pathobiologic
dynamic stages of CNV progression.21 Although no two CNV
growth patterns are identical, two distinct patterns of CNV
have been defined. The first pattern involves growth into the
plane between the RPE and Bruch’s membrane (sub-RPE, or 1929
 RETINA AND VITREOUS
type 1). The second pattern involves growth between the retina
and RPE (subretinal, or type 2). This description of CNV growth
patterns represents a spectrum, and it should be noted that
both patterns do not necessarily occur in temporal sequence,
i.e., subretinal (type 2) may precede sub-RPE (type 1). Also,
subretinal and sub-RPE CNV may be present in the same eye,
and there may be (and often are), several foci of sub-RPE CNV.21
Patients with sub-RPE CNV may have few visual symptoms, as
is most often seen in some cases imaged on fluorescein
angiography with a lesion composition described as occult CNV
or with no classic CNV (see section below describing lesion
composition on fluorescein angiography of CNV). CNV may be
difficult to detect angiographically due to the subtle patterns of
fluorescence sometimes associated with occult CNV.21 This
growth pattern is thought to provide nutrients and oxygen to
an ischemic RPE/outer retina that is expressing vascular
endothelial growth factor (VEGF) and other angiogenic
cytokines.21 The subretinal growth pattern is characterized by
SECTION 10
CNV occurring between the retina and RPE; tufts of CNV
break through Bruch’s membrane and extend laterally under
the RPE. The subretinal growth pattern of CNV typically has
one or a few ingrowth sites.21 This pattern is characterized by
a break in Bruch’s membrane, with proliferation of granulation
tissue into the subretinal space, and vascular leakage under the
RPE/outer retina, leading to relatively acute visual symptoms.21
SUMMARY OF VEGF ROLE FROM
ANGIOGENESIS/GROWTH TO INHIBITORY
(ANTIANGIOGENIC) MODE IN UNTREATED
CNV
Over time, different factors have been implicated in the
dynamic process of CNV growth. This dynamic nature is
characterized by progression from an angiogenesis/growth
promotion mode to an inhibitory (or antiangiogenic) mode, and
is incompletely understood.21 However, it is clear that growth
factors are associated with progression of CNV.22 Recent
evidence suggests a central role of VEGF (also called VEGF-A),
in the development of CNV. VEGF-A is highly regulated by
hypoxia, an important benchmark condition necessary for
vascularization in general. Experimental findings suggest that
hypoxia is involved in a feedback mechanism to accommodate
insufficient tissue oxygenation by promoting vessel formation
under normal conditions. It is hypothesized that derailment of
this feedback mechanism may lead to uncontrolled angiogenesis
in neovascular AMD.22 The vascular endothelial growth factor
family includes placenta growth factor (PIGF) VEGF-A, VEGF-
B, VEGF-C, VEGF-D, and the viral VEGF homolog VEGF-E).22
In the human, four isoforms of VEGF-A have been identified:
VEGF121, VEGF165, VEGF189, and VEGF206.22 The role of
these growth factors in AMD and tumor progression is an area
of active research. However, VEGF has been implicated in the
process of pathologic vessel growth in both experimental animal
models and in humans.23 VEGF appears to be causal for the
blood–retina barrier breakdown that accompanies neovascular-
ization, as well as that which develops independent of it.23
Other important factors implicated in neovascularization
include platelet-derived growth factor (PDGF) and the
angiopoietins.23 Evidence for the roles of these various growth
factors in neovascular AMD suggests a therapeutic use for novel
drugs aimed at these targets. Pharmaceutical companies have
already developed anti-VEGF treatments for the eye. Taken
together, research findings suggest an important role for VEGF-
A as a suitable candidate for targeted antiangiogenic therapy in
AMD patients.22
In the early stages of CNV development, VEGF is produced
1930 by the RPE and retinal photoreceptors. The RPE also produces
monocyte colonization protein (MCP) and interleukin-8 (IL-8).
Monocytes (or macrophages) express tumor necrosis factor a,
which in turn stimulates IL-8, MCP, and VEGF production by
the RPE. VEGF signaling produces other responses, including
proliferation and migration of vascular endothelium.23
Vasculogenesis may also play a role in CNV. Recent evidence
supports a role for hematopoietic stem cells (HSC) in the
pathobiology of CNV, and these stem cells express the
functional VEGF-1 receptor.21 After this initiation stage, CNV
progresses to an inflammatory active stage. At this point, CNV
digests through other tissue planes, and macrophages express
tissue factor, a protein involved in fibrogenesis, leading to a
fibrin scaffold on which CNV grows.21 Additionally, growth factors
are expressed by the RPE and vascular endothelium, including
PDGF, angiopoietins,23 aFGF, bFGF, and transforming growth
factor beta.21 During this stage, CNV stabilizes, and
equilibrium appears to be established between the various
growth and other factors that are released.21
At some point, the balance shifts toward antiangiogenic,
antiproteolytic, and antimigratory activity, resulting in the
inflammatory inactive or involutional stage of CNV. The CNV
may become collagenized and form a disciform scar.21 The
whole process may be orchestrated by the RPE, including the
initiation, stabilization, and involution of CNV, much like a
‘traffic cop’.21
Regardless of the pathogenesis of CNV in AMD, clinico-
pathologic correlative studies6–9,24 and natural history studies3,25–29
have shown that untreated CNV is often accompanied by the
ingrowth of fibrous scar tissue, eventually resulting in a
disciform scar. This CNV-scar complex may have a variety of
complex clinical and angiographic appearances. An understanding
of these clinical features (described in the next section) is
critical in the identification, proper management, and
treatment of the choroidal neovascular form of AMD.
CLINICAL FEATURES
SYMPTOMS OF CNV
CNV should be suspected in any patient (usually >65 years
with large, soft drusen) who complains of metamorphopsia,
central or paracentral scotoma, or any sudden, nonspecific
change in central vision.30,31 Any of these symptoms should
alert the ophthalmologist to look for signs of CNV, which are
outlined further on. However, not all patients with CNV will be
symptomatic32 or will note changes of metamorphopsia on
home-testing with an Amsler grid.33 Therefore, even
asymptomatic patients older than 65 years with large, soft
drusen on clinical examination should probably be scrutinized
for signs of CNV on periodic examination.
SIGNS OF CNV
In the early stages of the untreated neovascular form of AMD,
before disciform scarring has developed clinically, biomicroscopic
clues to the presence of CNV may include any or all of the
following: the presence of subretinal or intraretinal lipids,
elevation of the RPE, cystic changes in the sensory retina, or
visualization of the choroidal neovascular lesion itself. The
lesion may be seen as a yellow-green discoloration frequently
surrounded by a pigmented ring and is often visualized best
with transillumination of the RPE with a thin slit beam on
biomicroscopy. The presence of subretinal or sub-RPE blood
may be so extensive as to obscure all other signs of CNV; often
though, this blood, if present, will be along the periphery of
the CNV (Fig. 146.1). Other causes of subretinal or sub-RPE
hemorrhage should be ruled out, including macroaneurysms,
 Age-Related Macular Degeneration: Choroidal Neovascularization
FIGURE 146.1. Subfoveal choroidal neovascularization (CNV) with
contiguous blood (arrow). The boundaries of the entire lesion (the CNV
and blood) are well demarcated; the entire lesion is less than 3.5 disc
areas. The lesion would meet the eligibility criteria of the Macular
Photocoagulation Study (MPS).
From Macular Photocoagulation Study Group: Laser photocoagulation of
subfoveal neovascular lesions in age-related macular degeneration. Results of a
randomized clinical trial. Arch Ophthalmol 1991; 109:1220-1231.
lacquer cracks in pathologic myopia, traumatic choroidal
rupture, choroidal tumors, or subretinal hemorrhage within
areas of geographic atrophy when no CNV is seen on
angiography. (Presumably, the subretinal hemorrhage within
areas of geographic atrophy without CNV on angiography may
be due to CNV obscured by the hemorrhage or to disruption of
the choriocapillaris in association with the geographic
atrophy.34)
Although CNV secondary to AMD often has been described
in association with subretinal hemorrhage, many cases may
present with little or no hemorrhage, the predominant sign
being the more subtle finding of subretinal fluid. Often, one
needs a contact lens examination with biomicroscopy and a
thin slit beam to detect this subretinal fluid or evidence on
optical coherence tomography (OCT). On biomicroscopic
examination, the anterior portion of the beam will bow forward
convexly, and there will be an increased distance between the
surface of the slit beam, which is visualized on the surface of
the sensory retina, and the posterior portion of the beam, which
is visualized on the surface of the RPE. As subretinal fluid is
absorbed at the periphery of the CNV, subretinal lipid may
a b
precipitate in a circumferential pattern around the CNV and
thereby help to alert the ophthalmologist to the presence of
CNV. Other biomicroscopic signs of CNV, as already
mentioned, include the elevation of the RPE, presumably
caused by the presence of CNV and fibrovascular proliferation
beneath the RPE,24,35 pigment proliferation overlying the
CNV,36 or the actual choroidal neovascular vessels themselves
(occasionally seen when the overlying RPE pigmentation is
markedly attenuated).
If CNV secondary to AMD is suspected from symptoms or
signs, fluorescein angiography is indicated for the following
reasons: (1) to confirm the diagnosis of CNV, (2) to determine
whether treatment is indicated (as discussed further on), (3) if
treatment is indicated, to serve as a guide to treatment
response, and (4) rarely, if laser photocoagulation is indicated
for well-demarcated symptomatic extrafoveal lesions (see more
description below), to guide the placement of photocoagulation.
CHAPTER 146
FLUORESCEIN ANGIOGRAPHIC FEATURES
OF CNV
A set of photographs to facilitate the identification of the variety
of appearances of CNV secondary to AMD includes (1) a black-
and-white stereo pair of the macula obtained with green
(monochromatic) filter; (2) rapid-sequence photographs of the
macula taken during the dye transit, including at least one
stereo pair; (3) stereo pairs of the macula taken at approximately
30, 40, 60, 90, 120, and 180 s after dye injection; (4) late stereo
pairs of the macula taken at 5 and 10 min after dye injection;
and (5) stereoscopic color fundus photographs of the macula.37
Since CNV growth can be a continuous process,38,39 the size of
the CNV and the lesion composition can change within a short
time. Therefore, a fluorescein angiogram should ideally be
obtained within 2 weeks of initiation of treatment, unless laser
photocoagulation is considered, in which case angiography
should be performed ideally on the same day as any
contemplated laser treatment and probably no more than 96 h
before treatment.
Two basic angiographic patterns of CNV, recognized in the
macular photocoagulation studies37,40,41 as well as photo-
dynamic therapy trials,42 the submacular surgery trials, 43 trials
evaluating anti-VEGF treatments44–46 and described by
independent investigators,24,27,30,31,47–49 include classic and
occult CNV.
CLASSIC CNV
This condition is characterized by an area of well-demarcated
hyperfluorescence that can be discerned in the early phase of
the angiogram (Fig. 146.2a) with progressive dye leakage
pooling in the overlying subsensory retinal space (Fig. 146.2b).
FIGURE 146.2. Classic CNV. (a) Early phase of
a fluorescein angiogram of classic CNV in
which the boundaries of the neovascular lesion
are well demarcated. (b) Late phase of the
angiogram shows pooling of dye in the
subsensory retinal space, obscuring the
boundaries of CNV demarcated in the earlier
phase of the angiogram.
(a and b) From Macular Photocoagulation Study
Group: Subfoveal neovascular lesions in age-related
macular degeneration. Guidelines for evaluation and
treatment in the Macular Photocoagulation Study. Arch
Ophthalmol 1991; 109:1242–1257. Copyright 1991,
American Medical Association.
1931
 RETINA AND VITREOUS
a b
SECTION 10
The dye leakage identified by the late phase of the angiogram
will obscure the borders of the classic CNV detected in the
early phase of the angiogram. Only occasionally will fluorescein
angiography identify the actual capillary network of the CNV
secondary to AMD. This latter observation is contrary to the
widely held view that CNV presents angiographically as a lacy
network of vessels. This lacy pattern may be seen commonly in
CNV secondary to other pathologic entities, such as the ocular
histoplasmosis syndrome, but is unusual in AMD.
OCCULT CNV
This condition encompasses a variety of fluorescein angiographic
appearances that do not conform to the classic description of
CNV. The occult forms may be categorized into fibrovascular
pigment epithelial detachments (PEDs) and late leakage of
undetermined source. In fibrovascular PEDs (Fig. 146.3), areas
of irregular elevation of the RPE are often most easily detectable
on stereoscopic fluorescein angiography. These areas usually
are not as discrete or bright as areas of classic CNV in pictures
taken during the transit; by 1–2 min after fluorescein injection,
an area of stippled hyperfluorescence becomes apparent
(Fig. 146.3b). By 10 min, there is persistence of fluorescein
staining or leakage within a sensory retinal detachment
overlying this area. These fibrovascular PEDs should not be
confused with serous PEDs (discussed further on).
Late leakage of undetermined source consists of areas of late
choroidal fluorescein leakage, often appearing as speckled
hyperfluorescence, with pooling of dye in the overlying subsensory
retinal space, in which there is no discernible, discrete, well-
demarcated area of hyperfluorescence that might be considered
the source of leakage from earlier photography (Fig. 146.4).
Numerous clinicopathologic correlations on postmortem
examination8,9 or after submacular surgical removal of CNV50,51
have confirmed that all of these angiographic patterns (classic
CNV, fibrovascular PED, and late leakage of an undetermined
source) correlate with fibrovascular tissue. These studies have
not identified pathologic features to differentiate classic from
occult CNV. When adequate stereoscopic photographs are
obtained, recognizing a pattern of fibrovascular PED rather
than late leakage of an undetermined source might depend on
the thickness9 of the fibrovascular tissue, with thicker tissue
corresponding to a pattern of fibrovascular PED on fluorescein
1932 angiography.
FIGURE 146.3. Recurrent classic and occult
CNV (with fibrovascular pigment epithelial
detachment (PED)). (a) Early phase of
fluorescein angiogram shows areas of classic
CNV (small solid arrow), scar from prior laser
treatment (large solid arrow), and irregular
elevation of the retinal pigment epithelium (RPE)
with stippled hyperfluorescence (open arrows)
representing fibrovascular PED inferotemporal
to the scar. (b) One minute after fluorescein
injection, fluorescein leakage is apparent from
the classic CNV, and increased intensity of
stippled hyperfluorescence corresponding to
fibrovascular PED is noted. The boundaries of
the fibrovascular PED remain well demarcated.
At each clock hour, the boundary of the lesion
is clearly demarcated and would meet eligibility
criteria in the MPS trials.
(a and b) From Macular Photocoagulation Study
Group: Subfoveal neovascular lesions in age-related
macular degeneration. Guidelines for evaluation and
treatment in the Macular Photocoagulation Study. Arch
Ophthalmol 1991; 109:1242–1257.
ANGIOGRAPHIC FEATURES THAT
OBSCURE THE BOUNDARIES OF CNV
Three features can obscure the boundaries of CNV and are
important to recognize when attempting to delineate the
boundaries of the choroidal neovascular lesion. They include (1)
blood contiguous with the CNV that is thick enough to obscure
the normal choroidal fluorescence, (2) elevated areas of blocked
fluorescence due to hyperplastic pigment or fibrous tissue, and
(3) a serous detachment of the RPE (Fig. 146.5). The first two of
these features block the angiographic view of choroidal
fluorescence. Lesions which are predominantly hemorrhage, or
predominantly serous PED (serous PED is an area of uniform
bright fluorescence in the early phase, with staining of this
area in later phase frames) have not been subject to trials
evaluating treatments. However, often areas of occult CNV that
are irregular elevations of the RPE may be confused with a
serous PED if one does not realize that a fibrovascular PED (a
form of occult CNV) has a stippled, nonuniform fluorescence,
often not visible, and certainly not uniformly bright, in the early
phase frames. Such areas of fibrovascular PED were considered
occult CNV, not an area of serous PED, and were subjected to
trials evaluating treatments. The bright, reasonably uniform early
hyperfluorescence associated with a serous detachment of the
RPE (described further on) may obscure hyperfluorescence from
classic or occult CNV and interfere with the ability to judge
whether CNV extends under the area of the serous detachment.
Thus, lesions which were predominantly serous PED,
predominantly hemorrhage, or predominantly scar were excluded
from trials evaluating treatments for CNV and it may not be
appropriate to extrapolate results of trials that excluded these
lesions in the management of them. On the other hand, one
should include fibrovascular PEDs as occult CNV and make
treatment decisions as described for occult CNV below based on
trials evaluating treatments that included occult CNV defined
in this way.
OTHER CLINICAL AND ANGIOGRAPHIC
FEATURES OF CNV SECONDARY TO AMD
STAINING SCAR
Given variable amounts of time, as the lesion develops obvious
scarring on examination or fundus photographs, the composition
 Age-Related Macular Degeneration: Choroidal Neovascularization
a b
FIGURE 146.5. Early-phase fluorescein angiogram of a serous
detachment of the RPE. A uniform elevation of the RPE, with uniform
pooling of fluorescein dye, and a smooth contour to the surface of the
elevated RPE, with well-demarcated borders in the early phase of the
angiogram, are noted. The nasal aspect of the lesion shows irregular
elevation of the RPE with mottled and speckled fluorescence
indicative of occult CNV.
of the lesion may include staining of this scar rather than
having the scar block fluorescence when a lot of pigment or
pigment epithelium is within the scar. When a majority of the
lesion is composed of scar that stains on fluorescein
angiography, such lesion is described as being predominantly
scar and has not been subjected to trials evaluating treatments.
FADING CNV
CNV occasionally may be recognized in the early- or middle-
transit phase of the angiogram with fading in the late phase, so
that no leakage can be discerned in the area that was presumed
to harbor CNV37 (Fig. 146.6). These areas most likely represent
CNV histologically, but without evidence of subretinal fluid or
FIGURE 146.4. Occult CNV with late leakage of
undetermined source. (a) Early phase of the
angiogram. (b) Middle phase of the angiogram
shows pinpoints of speckled hyperfluorescence
and larger areas of hyperfluorescence with
accumulation of fluorescein leakage in the
overlying subsensory retinal space. The source
of the leakage cannot be discerned from earlier
phases of the angiogram. The lesion does not
meet the MPS eligibility criteria that the
boundaries of neovascularization be well
demarcated. Therefore, treatment is not
considered for this lesion.
(a and b) From Macular Photocoagulation Study
Group: Subfoveal neovascular lesions in age-related
macular degeneration. Guidelines for evaluation and
treatment in the Macular Photocoagulation Study. Arch
Ophthalmol 1991; 109:1242–1257.
CHAPTER 146
late leakage, one cannot be sure that this pattern definitively
represents CNV.
FEEDER VESSELS
These vessels may be identified as choroidal vessels apparent
during the transit phase of the angiogram connected
unequivocally to leaking choroidal capillaries (Fig. 146.7).
Although feeder vessels have been described as extending from
a laser-treated area to recurrent CNV across the perimeter of the
laser-treated area,30,37,52 feeder vessels may also be seen in
untreated eyes. In the latter situation, peripheral untreated
areas of CNV may be connected by feeder vessels to more
central areas of CNV that are evolving toward natural scar
formation.37
LOCULATED FLUID
This fluid consists of a well-demarcated area of hyper-
fluorescence that appears to represent pooling of fluorescein in
a compartmentalized space anterior to the choroidal neovascular
leakage.53 Although the loculated fluid may conform to a
pattern of typical cystoid macular edema, it can also pool within
an area deep to the sensory retina in a shape that does not bear
any resemblance to cystoid macular edema53 (Fig. 146.8).
TEARS OR RIPS OF THE RPE
An acute tear or rip of the RPE may occur spontaneously
(Fig. 146.9) or during laser photocoagulation of a choroidal
neovascular lesion.54–59 Visual acuity may fall precipitously,
especially when associated CNV has an opportunity to destroy
foveal photoreceptors. When there is no CNV, RPE tears
through the fovea may be associated with preservation of
good central visual acuity provided that the torn area, and not
the scrolled-up RPE, underlies the foveal center.60 Angiography
demonstrates early, bright, sharply demarcated hyperfluorescence
within the torn region. Blocked fluorescence corresponding to
heaped-up RPE will be noted at one side of the lesion. The
bright hyperfluorescence presumably corresponds to fluorescein
dye within the choriocapillaris that quickly leaks into the
choroidal and scleral tissues and is not blocked by pigment that
is normally otherwise present within the overlying RPE. No
leakage of dye is seen if no overlying sensory retinal detachment
is present. The lack of a sensory retinal detachment over a tear
of the RPE may be due to the higher osmotic pressure of the
choroid compared with that of the subretinal space, which
allows fluid to be removed from the subretinal space at a rapid 1933
 RETINA AND VITREOUS

a b

FIGURE 146.6. Fading fluorescence of CNV. (a) Early phase of the angiogram shows classic CNV (solid arrow) with contiguous areas of slightly
elevated hyperfluorescent RPE (open arrows), presumably representing a fibrovascular PED, and other less well demarcated areas of
hyperfluorescence nasal to fovea. (b) Later phase of the angiogram shows fluorescein leakage from classic CNV (arrow). However, areas of
SECTION 10

elevated hyperfluorescent RPE noted on the early phase of the angiogram begin to fade in the later phase. Faded areas are not considered a
lesion component to be treated in 1991 by MPS treatment protocol because hyperfluorescence does not have enough leakage or staining in the
late phase of the angiogram to be considered occult CNV. Before 1988, most ophthalmologists would have considered treatment of the classic
CNV with late leakage (arrow). By current interpretations, treatment of the area of classic CNV still might be contemplated, but ophthalmologists
would be concerned about the untreated areas of presumed occult CNV that fade in the late phase of the angiogram.
(a and b) From Macular Photocoagulation Study Group: Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in
the Macular Photocoagulation Study. Arch Ophthalmol 1991; 109:1242–1257.

rate when the tight junctions of the RPE are lacking and unable
to prevent free movement of fluid.61

DISCIFORM SCAR
The term disciform scar is used to describe the yellow-white
fibrous tissue that often accompanies CNV and is an extension
of the description of ‘scar’ above. The lesion may also contain
brown or black pigment, depending on the degree of pigment
proliferation from the RPE within the scar. The disciform
scarring may have a variety of appearances depending on its
location within the retina (sub-RPE or subretinal), the degree
of associated CNV with the scarring, the presence of
chorioretinal anastomosis within the scar, or the amount of
RPE atrophy accompanying the scar (Fig. 146.10). The natural
course of most choroidal neovascular lesions secondary to AMD
consists of scarring within the central portion of the lesion
with continued signs of active CNV at the periphery of the
lesion (including subretinal fluid, hemorrhage, or lipid).
Therefore, most disciform scars secondary to AMD could be FIGURE 146.7. Recurrent CNV with feeder vessel (arrow) as well as
termed CNV-scar when they include both a fibrous component larger choroidal vessels seen within the central portion of the scar
noted on biomicroscopy and a neovascular component from previous laser treatment.
represented by subretinal fluid-hemorrhage-lipid on biomicroscopy From Macular Photocoagulation Study Group: Subfoveal neovascular lesions in
and accompanied by leakage from CNV on angiography age-related macular degeneration. Guidelines for evaluation and treatment in the
(Fig. 146.10b). Occasionally, these disciform scars may develop Macular Photocoagulation Study. Arch Ophthalmol 1991; 109:1242–1257.
anterior to the posterior pole. These peripheral disciform scars
may become quite large with irregular shapes or they may be
accompanied by hemorrhage, leading to the suspicion of a hemorrhage. Sonographically, the posterior pole or peripheral
tumor such as a melanoma, until they are evaluated with lesion is relatively flat and broad-based, with a fairly homo-
ultrasound (see further on). geneous pattern and without signs of choroidal excavation. The
vitreous hemorrhage clears in approximately 75% of patients. If
the hemorrhage does not clear, a vitrectomy to restore
VITREOUS HEMORRHAGE peripheral vision should be considered, taking into account how
Occasionally, hemorrhage from CNV or CNV scarring extends restoration of that peripheral vision will improve the patient’s
into the vitreous space.62,63 Any patient with a massive quality of life, given the unlikelihood of restoration of central
vitreous hemorrhage in one eye and features of AMD in the vision. Whether or not submacular surgery should be considered
fellow eye should be suspected of harboring CNV in the eye to remove any subretinal hemorrhage or fibrovascular tissue
with vitreous hemorrhage. Ultrasonography should be performed identified at the time of vitrectomy probably should await
to rule out a rhegmatogenous retinal tear or detachment, results of clinical trials evaluating the benefits and risks of this
1934 choroidal melanoma, and other less common causes of vitreous intervention.
 Age-Related Macular Degeneration: Choroidal Neovascularization
a b
FIGURE 146.9. RPE tear seen on the early-transit phase of the
fluorescein angiogram demonstrates extremely sharp, well-
demarcated hyperfluorescence. Continued intense staining was seen
in the late phase of the angiogram with no leakage. An early blocked
fluorescence (arrow) presumably corresponds to the redundant,
folded, torn RPE.
From Bressler NM, Finkelstein D, Sunness JS, et al: Retinal pigment epithelial
tears through the fovea with preservation of good visual acuity. Arch Ophthalmol
1990; 108:1694–1697.
RPE DETACHMENTS IN AMD
Various changes in AMD may result in elevation or detachment
of the RPE as seen on stereoscopic biomicroscopic or
angiographic evaluation. The term RPE detachment secondary
to AMD in the ophthalmic literature remains confusing
because various RPE detachments may have quite different
prognoses and managements, and yet several series may have
included some or all of these RPE detachments in their reports.
RPE detachments secondary to AMD that may be readily
recognized and probably should be differentiated include (1)
fibrovascular PEDs, which are a subset of occult CNV
(Fig. 146.3); (2) elevated areas of RPE that block fluorescence
because of hyperplastic pigment or fibrous tissue (Fig. 146.3);
(3) serous detachments of the RPE (Fig. 146.5); (4) hemorrhagic
detachments of the RPE, in which blood from a choroidal
neovascular lesion is noted beneath or exterior to the RPE; and
(5) drusenoid RPE detachments, in which large areas of
confluent, soft drusen are noted.64
Elevated blocked fluorescence may be differentiated from
fibrovascular PEDs and serous detachments of the RPE in that
FIGURE 146.8. Example of an eye in which the
borders of loculated fluid extend beyond the
borders of CNV. In late-transit frames (a), the
area of loculated fluid (arrow) extends beyond
the area of the borders of the CNV (arrow in b)
as defined in the early-transit phase of the
angiogram.
(a and b) From Bressler NM, Bressler SB, Alexander J,
et al: Loculated fluid: A previously undescribed
fluorescein angiographic finding in choroidal
neovascularization associated with macular
degeneration. Arch Ophthalmol 1991; 109:211–215.
blocked fluorescence is noted within the area of elevated RPE
throughout the angiogram. One of the more difficult
differentiations is between fibrovascular PEDs and serous
CHAPTER 146
detachment of the RPE. Although, they probably have been
lumped together in several series that have examined RPE
detachments,65–70 some of these clinical reports have attempted
to identify certain features that might distinguish between
serous detachments of the RPE and areas of elevation of the
RPE that may harbor occult CNV.67 Using descriptions from
the Macular Photocoagulation Study (MPS), fibrovascular PEDs
(as a subset of occult CNV) have been distinguished from
classic serous detachments of the RPE in that the former have
slow filling with a stippled appearance to the surface of the RPE
by the middle phase of the angiogram and may show pooling of
dye in the overlying subsensory retinal space in the late phase,
whereas the latter show uniform, bright hyperfluorescence in
the early phase with a smooth contour to the RPE by the middle
phase and little, if any, leakage at the borders of the PED by the
late phase. As mentioned earlier, the fluorescent pattern of a
serous PED obscures the ability to determine whether classic or
occult CNV exists within the area of the serous PED.
A hemorrhagic detachment of the RPE will block choroidal
fluorescence just as blocked fluorescence from hyperplastic
pigment or fibrous tissue does. However, in hemorrhagic
detachments of the RPE, the dark appearance on biomicroscopy
caused by the mound-like collection of blood beneath the RPE
will help to differentiate it from areas of elevated blocked
fluorescence caused by hyperplastic pigment or fibrous tissue as
discussed previously. Occasionally, a hemorrhagic detachment
of the RPE may be mistaken for a choroidal melanoma, but
usually hemorrhagic detachments of the RPE will not
demonstrate low internal reflectivity, as is seen characteristically
in choroidal melanomas.
The final feature of AMD that will appear as an elevated or
detached RPE is a drusenoid RPE detachment or extensive areas
of large confluent drusen.64 Drusenoid RPE detachments can be
distinguished from serous detachments of the RPE in that
drusenoid RPE detachments will fluoresce faintly during the
transit and do not progress to bright hyperfluorescence in the
late phase of the angiogram. In contrast, serous detachments
of the RPE will fluoresce brightly in the early-transit phase and
remain brightly hyperfluorescent in the late phase. In addition,
serous detachments usually will have a smoother, sharper
boundary compared with drusenoid RPE detachments. Drusenoid
RPE detachments can be distinguished from fibrovascular PEDs
in occult CNV by noting that fibrovascular PEDs will show
areas of stippled hyperfluorescence with persistence of staining
or leakage within a sensory retinal detachment overlying the
area in the late phase of the angiogram. RPE detachments
associated with large, soft, confluent drusen are usually smaller,
more shallow, and more irregular in outline than are
fibrovascular PEDs. In addition, the drusenoid RPE detachments 1935
 RETINA AND VITREOUS

FIGURE 146.10. CNV-disciform scarring.

(a) Subretinal and sub-RPE fibrosis, as well as
subretinal fluid and hemorrhage, is seen on the
color photograph. The latter presumably are
indicative of persistent vascular tissue within
the fibrosis. (b) Fluorescein angiography of CNV
scarring demonstrates leakage toward the
periphery of the lesion, presumably from CNV
associated with the scarring.
(a and b) From Macular Photocoagulation Study
Group: Subfoveal neovascular lesions in age-related
macular degeneration. Guidelines for evaluation and
treatment in the Macular Photocoagulation Study. Arch
Ophthalmol 1991; 109:1242–1257.
a b

will often have reticulated pigment clumping overlying the

large, soft, confluent drusen, and a scalloped border. TABLE 146.1. Time Trade-off Values.4 Values Represent the
SECTION 10

Number of Years (of Every 10 Years of Remaining Life

Expectancy) That Participants Would Trade for Perfect Vision.
IMPACT OF NEOVASCULAR AMD ON QUALITY Best Corrected VA Ophthalmologists AMD
OF LIFE (n = 46) Patients (n = 72 )
Health-related quality of life (QOL), also known as patient- 20/30 to 20/50 0.3 1.9
centered QOL, refers to those aspects of life that either foster
or compromise the ability to participate fully in daily life, such 20/60 to 20/100 1.1 4.3
as driving, recognizing faces, reading small print, judging the 20/200 to 20/400 2.3 4.9
depth of stairs or curbs, or watching TV. Because patient-
Counting fingers to 3.3 6.0
centered QOL is subjective,71 AMD patients with similar visual hand motions
acuity (VA) may rate their QOL quite differently, depending
on which activities and skills are valued most.72 To
systematically measure health-related QOL, researchers have
developed standardized questionnaires that can be self-
administered or conducted as an interview. TABLE 146.2. Time Trade-off Utility Values Stratified by Level
of Vision.6

VA (n) Utility Value P value‡ P value§

WHY IS IT IMPORTANT TO EVALUATE QOL IN
AMD PATIENTS?
QOL instruments are widely used to assess patients with other
chronic diseases that are common in the population at risk
for AMD, such as arthritis, depression, cancer, hypertension,
and stroke. QOL measures are often added to clinical trials to
evaluate the cost-effectiveness and therapeutic value of new
treatments.71 Researchers and clinicians recognize the
psychosocial determinants of health, such as the skyrocketing
cost of healthcare, and patients’ desire to participate more
actively in treatment decisions.73 This has led to active
soliciting of patient input about QOL. Patient-reported visual
function can reinforce treatment decisions for practitioners,
providing evidence of treatment benefits.
Ophthalmologists may underestimate the impact that AMD
can have on patients’ health-related QOL. In one study,54
ophthalmologists were asked to imagine that they had AMD in
both eyes and were given the hypothetical scenario: regain
perfect vision by giving up some remaining lifespan.74 The same
hypothetical scenario was offered to 72 AMD patients. For
every 10 years of life remaining, AMD patients with VA of
20/30 to counting fingers would give up more years than would
ophthalmologists with the same hypothetical VA (Table 146.1).
Another way to measure patient-centered QOL is with
preference values. In the submacular surgery trials, 996
participants with subfoveal CNV were asked to pretend that
they were completely blind at their current level of general
health. Participants were also asked to pretend that they had
perfect vision and their current level of general health.75 They
rated these hypothetical situations on a scale of 0 (death) to 100
(perfect health with perfect vision). Among the 792 evaluable
1936 participants, the mean preference value assigned to current
20/200 to 0.65 0.6 µ 10 —12
0.03
20/400* (33)
LP to counting 0.47 0.007 NA
fingers* (17)
NLP† (15) 0.26 NA 0.007
LP = light perception; NLP = no light perception.
* In the better eye.
† NLP in one eye; postulated NLP in other eye.
‡ P value from Student’s t test when compared with NLP group.
§ P value from Student’s t test when compared with LP to counting fingers
group.
vision with CNV was 0.64.75 Preference values were higher in
younger patients and those with better VA, and lower in
patients with anxiety or depression.75 These mid-range values
imply that some CNV patients may consider an expensive or
potentially risky treatment to improve their QOL.75 In a utility
study, Brown and colleagues used a time trade-off method,
dividing 65 consecutive ambulatory patients into three groups.76
In the time trade-off technique, the investigator calculates each
participant’s life expectancy and then asks how many years of
remaining life expectancy an individual would be willing to
trade in return for perfect vision77 (Fig. 146.11).
One group, with no light perception (NLP) in at least one eye,
was asked to imagine that they had NLP in both eyes. One
group had bilateral vision with light perception to counting
fingers, and another group had 20/200 to 20/400 vision. Mean
utility values were lowest in the group with the worst vision.
(Table 146.2) 6 Patients in the NLP group were willing to trade
almost three out of every 4 years of remaining life expectancy in
 Age-Related Macular Degeneration: Choroidal Neovascularization
Input Variables
Participantís age
Participant’s anticipated life expectancy
How many remaining years of life would
participant trade in exchange for living without
AMD
Calculation of Time Trade-off
How many more Divide years participant
years does would trade for perfect
participant expect to vision by remaining
live? years of expected life
85 years 10 years = 0.50
20 years
-65years
20 years
Calculation of Utility Score
Subtract the time trade-off from 1.0 (the utility value for perfect health).
1.0 – 0.50 = 0.50
return for perfect vision in each eye.76 Even patients in the
20/200 to 20/400 group would trade one-third of their
remaining life expectancy for perfect vision.76
THE IMPACT OF AMD ON ACTIVITIES OF
DAILY LIVING (ADLS)
Visual changes affect physical function, even in patients with
unilateral advanced AMD. The submacular surgery trials
interviewed 789 patients with subfoveal CNV to evaluate QOL.
Investigators used the National Eye Institute Visual Function
Questionnaire (NEI-VFQ). As noted earlier, the NEI-VFQ is a
validated questionnaire that assesses physical aspects of health
(general health, visual health, pain, and near and distance vision
activities), and how visual disability affects mental health, role
difficulties, social functioning and dependency, driving, and
color and peripheral vision. Scores range from 0 (worst
functioning) to 100 (best functioning).78 Patients with bilateral
AMD scored 6–10 points lower on the NEI-VFQ than patients
with unilateral AMD even after adjusting for VA.79 Preventing
and or delaying the progression of AMD is crucial
to reducing the risk of rapidly declining QOL for patients with
vision loss.79 Cahill and colleagues evaluated patient-centered
QOL among 70 patients with bilateral severe AMD using the
NEI-VFQ. The mean QOL scores for these important quality
of vision (general vision, difficulty with distance and near tasks),
and vision-specific subscales (dependency, role difficulties, mental
health, social function limitations) were significantly worse for
patients with bilateral severe AMD than for patients with AMD
of varying severity, and persons without eye disease.80 These
data further support the assertion that visual changes affect
physical function even in patients with relatively mild AMD.
THE SOCIAL AND PSYCHOLOGICAL IMPACT
OF NEOVASCULAR AMD ON QOL
Not surprisingly, many patients with bilateral advanced AMD,
usually neovascular, are hesitant and sometimes unable to
drive.80 Among a group of patients with AMD of mixed severity,
there was a direct correlation between higher severity of AMD
and poorer scores on the driving activities subscale of the
FIGURE 146.11. Time trade-off calculation.
65 years
85 years
10 years
Subtract previous value
from 1.0
1.0 – 0.50 = 0.50
CHAPTER 146
Activities of Daily Vision Scale (ADVS), a 21-item questionnaire
about vision-specific activities, including driving in darkness
or daylight, and nondriving activities involving distance or near
vision, or glare.81 The loss of driving ability has widespread
implications: 1) a decreased ability to care for oneself (eg.,
earning a living, grocery shopping, getting to doctor appointments)
and 2) a decreased ability to care for others, such as a
chronically ill, elderly spouse.82 Data on contrast sensitivity loss
for patients with macular disease suggest that patients with
moderate visual loss (20/70 to 20/200) may have difficulty
recognizing faces.83 Patients with visual disabilities in general
are at risk of becoming socially isolated, due to difficulties with
moving around and performing ADLs. The inability to recognize
a friend or loved one would also increase feelings of social
isolation and impact functioning.84
DEPRESSION AND ANXIETY
The fear of progression and potential blindness among AMD
patients remains an important factor in patient-centered
QOL.77,85 A subgroup of patients with newly diagnosed
subfoveal CNV who participated in the Submacular Surgery
Trials had measurable anxiety and depression at baseline. In
particular, among the participants who had no prior laser
treatment in the affected eye, 60/447 (13%) were classified as
having either doubtful or definite anxiety, and 57/447 (12%) as
having doubtful or definite depression, using the Hospital
Anxiety and Depression Scale.79 In one study, patients with
severe bilateral AMD scored significantly lower in the social
and mental health domains of the NEI VFQ-25 than patients
with AMD of varying severity and persons without ocular
disease.80
MANAGEMENT OF CHOROIDAL
NEOVASCULARIZATION IN AMD
When neovascular AMD is suspected, a fluorescein angiogram
is obtained to determine the location of the lesion, and its
composition. Following the algorithm outlined in Fig. 146.12
after one determines the entire extent of the lesion, one can
determine if the most posterior extent of the lesion is 1937
 SECTION 10 RETINA AND VITREOUS

FIGURE 146.13. Proportion of eyes at each follow-up examination

FIGURE 146.12. Algorithm for management of CNV in AMD. with a decrease in visual acuity of 6 or more lines from baseline in the
Senile Macular Degeneration Study of the MPS. Dashed line indicates
eyes assigned randomly at entry to no treatment; solid line, eyes
extrafoveal (at least 200 mm from the geometric center of the
assigned at entry to laser treatment. All eyes at baseline (time zero)
foveal avascular zone). While not very common in AMD, in had well-demarcated extrafoveal CNV.
such cases, if the lesion has well-demarcated boundaries, and From Macular Photocoagulation Study Group: Argon laser photocoagulation for
the patient is symptomatic, then laser photocoagulation is neovascular maculopathy after five years. Results from randomized clinical trials.
indicated. The immediate goal of laser treatment in all clinical Arch Ophthalmol 1991; 109:1109–1114.
trials evaluating laser use for CNV38,39,86–91 was to
photocoagulate the entire area of CNV. In order to treat the
entire area of CNV, the ophthalmologist has to be able to
identify the boundaries of the choroidal neovascular lesion.
Therefore, at the present time, treatment is indicated only
when the boundaries of the CNV are well demarcated. If the
boundaries are not well-demarcated, or if one is not certain if
the lesion extends under the foveal center, or if the lesion is
so close to the foveal center that the treating ophthalmologist
believes the scotoma from treatment will outweigh any benefits
of treatment, then one could manage the lesion as if its location
were subfoveal as described below.

RISKS AND BENEFITS OF TREATMENT OF

EXTRAFOVEAL CNV (POSTERIOR BOUNDARY
OF CNV BETWEEN 200 AND 2500 µM FROM
GEOMETRIC CENTER OF THE FAZ)
In the MPS, laser treatment was beneficial at decreasing the risk
of severe visual loss in eyes with extrafoveal CNV secondary
to AMD when compared with no treatment.88 The proportion
of eyes with severe visual loss (6 lines or more of vision loss)
1 year after presenting with extrafoveal CNV was 41% in the
eyes assigned to no treatment and 24% in the eyes assigned to
laser treatment. By 3 years, 63% of the eyes assigned to no
treatment and 45% of the eyes assigned to treatment had severe
visual loss. This treatment benefit was maintained by 5 years
after treatment, at which time 64% of the eyes assigned to no
treatment and 46% of the eyes assigned to treatment had severe
visual loss92 (Fig. 146.13). The relative risk of losing 6 lines or
more of visual acuity from baseline among untreated eyes (n =
117) compared with laser-treated eyes (n = 119) was 1.5 from
6 months through 5 years after entry into the study (P =0.001).
Furthermore, after 5 years, untreated eyes had lost a mean of
7.1 lines of visual acuity, whereas laser-treated eyes had lost 5.2
lines.
Recurrent CNV was observed in 54% of laser-treated eyes by
the end of the 5 year follow-up period92 (Fig. 146.14). About
75% of all these recurrences occurred by the end of the first
year after treatment. An additional 17% of all the recurrences
1938 occurred between 1 and 2 years of follow-up. The remaining 7%
FIGURE 146.14. Cumulative proportion of laser-treated eyes ever
having recurrent CNV documented after initial laser treatment. Dashed
line indicates eyes assigned to laser treatment in the Senile Macular
Degeneration Study in which patients had extrafoveal CNV secondary
to AMD. For comparison to a cumulative proportion of recurrences
after treatment of CNV secondary to other causes, solid line indicates
eyes assigned to laser treatment in the Ocular Histoplasmosis Study,
and dotted line, eyes in the Idiopathic Neovascularization Study.
From Macular Photocoagulation Study Group: Argon laser photocoagulation for
neovascular maculopathy after five years. Results from randomized clinical trials.
Arch Ophthalmol 1991; 109:1109–1114.
of all recurrences occurred between the end of the second year
and the fifth year of follow-up (Fig. 146.14). The effect of
recurrence on visual acuity can be seen in Table 146.3; by
3 years, only 10% of the treated eyes with no recurrence had
severe visual loss compared with 80% of the treated eyes with
recurrence. At the end of the third year of follow-up, the average
visual acuity of the treated eyes with no recurrence was 20/50
and that of the treated eyes with recurrence was 20/250.92 This
 Age-Related Macular Degeneration: Choroidal Neovascularization

The term persistence was used by the MPS group to indicate

TABLE 146.3. Visual Acuity by History of Recurrence after
the presence of fluorescein leakage on the periphery of the
Laser Treatment of Extrafoveal Choroidal Neovascularization
Secondary to AMD foveal side of the laser-treated area within 6 weeks after
treatment. The investigators believed that fluorescein leakage
Years since Recurrence Number Average Eyes With within this time might represent persistence of neovascularization.
Treatment of Eyes Visual 6-Line The MPS investigators chose to use the term recurrence when
Acuity Loss n (%)
angiography confirmed no leakage for at least 6 weeks after
1 Yes 62 20/40 4 (6) treatment, with leakage subsequently noted sometime later
than 6 weeks after treatment.93 These terms were strictly
No 49 20/125 20 (41)
defined for analysis of the data from these trials. However, one
2 Yes 49 20/40 4 (8) could consider using the term recurrence whenever the
No 54 20/160 31 (57) following conditions apply: (1) leakage is seen at the periphery
of a laser-treated area and (2) one has previously documented
3 Yes 48 20/50 5 (10) unequivocal lack of peripheral leakage after treatment. A
No 46 20/250 37 (80) persistence could be defined as leakage at the periphery of the
laser-treated area without any prior unequivocal documentation
4 Yes 43 20/50 5 (12)
of lack of peripheral leakage on prior fluorescein angiograms.
No 47 20/250 37 (79) When treatments with photodynamic therapy or anti-VEGF

5 Yes 42 20/50 7 (17)
No 50 20/250 39 (78)
TABLE 146.4. Treatment Protocol for Choroidal
Neovascularization from the Macular Photocoagulation Study
All Lesions
Angiogram <96 hr old
Retrobulbar anesthesia as necessary
200–500 mm spot; 0.2–0.5 s duration
Cover entire area of neovascular lesion
Intensity sufficient to produce uniform white burn
Extrafoveal Lesions (>199 mm from Foveal Center)
Extend treatment additional 100 mm beyond any adjacent blood,
pigment ring circumferentially surrounding the lesion, or other
blocked fluorescence surrounding the lesion
Juxtafoveal Lesions (1–199 mm from Foveal Center)
Extend treatment additional 100 mm beyond the neovascular lesion
on border away from fovea
Extend treatment additional 100 mm into any blood present on the
foveal side if the hyperfluorescence from the neovascular lesion
itself is 100 mm or farther from foveal center
Subfoveal Lesions (CNV Underlies Foveal Center)
Extend treatment additional 100 mm beyond peripheral boundaries
of all lesion components except blood
Cover, but not necessarily extend 100 mm beyond areas of blocked
fluorescence into thick blood
Subfoveal Recurrent Lesions (Prior Laser Treatment with
Recurrent Lesion Underlying Foveal Center)
Extend treatment 300 mm into previous treatment scar-recurrent
neovascular lesion interface
If feeder vessels present, extend treatment 100 mm beyond lateral
borders of recurrent vessels and 300 mm radially beyond base
(origin) of feeder vessel
treatment benefit has been confirmed by two independent trials
comparing treatment and the natural course.86,87 Although, the
treatment protocol did not permit treatment of recurrences
through the foveal center in this trial, the treatment benefit for
these lesions might have been even greater if anti-VEGF
therapies now in use (see below) for subfoveal lesions had been
applied to the subfoveal recurrences that would have met
current criteria for consideration of treatment of subfoveal
lesions.
CHAPTER 146
drugs are applied, then other terms may be used to describe
angiographic appearances after treatment43 Specifically,
progression used for leakage from CNV beyond the boundaries
of the lesion identified prior to treatment. Absence of leakage
implies that there is no progression and no leakage within the
area of CNV identified prior to treatment. Minimal leakage
means that there is no progression and that less than 50%
of the area of leakage from CNV identified prior to treatment
still shows fluorescein leakage from CNV. Finally, moderate
leakage means that there is no progression and that 51-to 99%
of the area of leakage from CNV identified prior to treatment
still shows fluorescein leakage from CNV.
APPLICATION OF LASER
PHOTOCOAGULATION
Preparation
An angiogram is projected onto a screen or monitor near the
laser, so that the ophthalmologist can make rapid and repeated
extrapolations from the fluorescein’s retinal vascular landmarks
to the patient’s fundus when identifying the location of the
CNV with respect to these landmarks. Careful evaluation of
vascular landmarks in the patient’s fundus in comparison with
landmarks concurrently viewed on a projection of a fluorescein
angiogram during treatment should enable the ophthalmologist
to identify the boundaries of the lesion with confidence and
accuracy and avoid inadvertent treatment of retina that is not
involved with the lesion.
Topical anesthesia usually is sufficient if one is careful to
ensure that neither ocular motility nor patient discomfort will
compromise the success of treatment by preventing the
ophthalmologist from delivering laser of sufficient intensity
and duration of exposure to produce a uniform white treatment
burn. This is especially true when small amounts of
undertreatment may allow persistence of neovascularization93,94
or small amounts of overtreatment might obliterate foveal
structures unnecessarily.95
Treatment Parameters
Initial laser burns are placed along the boundary of the CNV
using a 200 µm spot size and 0.2–0.5 s duration. These
parameters allow the ophthalmologist to get sufficient heat to
the retina (with the long duration) without risking a sudden
break in Bruch’s membrane and to minimize the frequency of
bleeding (by spreading the intensity of the burn over a 200-µm
spot rather than a 50 or 100 µm spot). The area to be covered,
if one is following the protocol used in the MPS, differs
depending on the location of the lesion and is outlined in Table
146.4 . After the boundaries of the lesion have been treated, the 1939
 RETINA AND VITREOUS
SECTION 10
FIGURE 146.15. Treatment intensity standard. The treatment protocol
of the MPS specified a uniform, white burn at least as intense as the
treatment standard.
From Macular Photocoagulation Study Group: Persistent and recurrent
neovascularization after krypton laser photocoagulation for neovascular lesions
of ocular histoplasmosis. Arch Ophthalmol 1989; 107:344–352.
area within the boundaries is treated subsequently with burns
of the same spot size or larger, using a duration of 0.5–1 s. The
desired endpoint for the intensity of the laser lesion is to create
a uniformly relatively white lesion. The ophthalmologist can
achieve this end-point in either of the following ways: (1) by
initially applying relatively white laser burns that meet or
exceed the intensity illustrated by a standard photograph from
the MPS89 or (2) by applying lighter gray-white laser spots that
overlap again and again until the entire laser lesion is a uniform
white treatment burn at least as white as the treatment
intensity standard37 (Fig. 146.15).
Wavelength Selection
When the MPS was begun in 1978, the argon blue-green laser
was the one most commercially available to investigators. This
laser is no longer recommended for treatment within the
macular region because macular xanthophyll pigment directly
absorbs the blue light of the argon blue-green laser, thereby
inducing thermal damage to the inner retina.96 In addition, the
risk of inducing internal limiting membrane wrinkling,
although rarely of clinical significance, is probably greatest with
the argon blue-green laser.97 Subsequent trials in the MPS for
juxtafoveal lesions employed the krypton red laser because of its
theoretical advantage of penetrating through xanthophyll and
passing through thin layers of red hemorrhage, allowing the
uptake of the laser to be concentrated within the RPE and
melanocytes of the inner choroid. When the MPS trials for
subfoveal lesions were designed, eyes randomized to the
treatment group were further randomized to either the argon
green or the krypton red wavelength for treatment. None of the
findings from the subfoveal trials suggests a reason to favor
either the argon green or the krypton red wavelength.40,41 If
there were any theoretical advantage to using one wavelength
over another for treatment of CNV, one might have expected to
have detected a difference within the MPS subfoveal trials.
Although these trials did not have sufficient power to
demonstrate a small or moderate difference between the two
1940 wavelengths, a large difference has been ruled out by these
studies.40,41 Recurrence and persistence rates also were similar
between the two laser wavelengths. The recurrence and
persistence rates were similar to those observed when the
krypton red laser alone was used to treat neovascular lesions in
the MPS trial of juxtafoveal neovascularization. Thus, no visible
wavelength appears to have a significant advantage over other
wavelengths. Small differences in convenience of achieving
the endpoint of a uniform white burn might be seen with red
or yellow wavelengths when penetrating through the increased
nuclear yellow in the older age group afflicted with CNV
secondary to AMD, but any significant differences of clinical
importance have not been shown.
Special Circumstances
When treating CNV that lies under a major retinal vessel, the
laser burns should straddle the retinal vessel to reduce the
possibility of causing hemorrhage or damaging the vessel by
thermal vasculitis. There is no evidence to suggest that this
technique compromises the effectiveness of treatment.
When treating CNV that is contiguous with the optic nerve,
one must consider that laser treatment directly over the optic
nerve can cause thermal necrosis of disc tissue and nerve fiber
bundle defects.98 Therefore, one should consider refraining from
treatment within 100–200 µm of the optic nerve. Similarly,
when treating a parapapillary area of CNV, one may want to
consider treatment only when at least 1 1/2 clock hours of
papillomacular bundle on the temporal side of the disc is
uninvolved with CNV, so that at least 1 1/2 clock hours of
papillomacular bundle can be spared treatment, as was done in
several of the MPS trials.88,99 Treatment to nasal or
parapapillary lesions likely will not lead to severe visual loss
from damage to the nerve fiber layer that serves the central
macula if the treatment guidelines outlined previously are
employed.100 In these situations, the MPS group reported that
severe visual acuity loss was noted after treatment only when
recurrent CNV extended through the center of the fovea.100
This finding suggests that severe visual loss only from nerve
fiber layer damage after this treatment approach, in the absence
of subfoveal recurrence, must be a rare complication.
Certain subgroups in the various trials had different
treatment benefits, which should be considered when
determining whether treatment would be beneficial for a
particular patient.89,101 This subgroup analysis should probably
not completely sway someone in recommending or denying
treatment. Rather, the subgroup analysis data should serve as a
guideline when trying to decide whether treatment should be
recommended to a particular individual. For instance, in the
krypton trial of juxtafoveal lesions,89 patients who were
normotensive had a marked treatment benefit. Patients who
had evidence of hypertension, either by elevated systolic or
diastolic blood pressures or by the use of antihypertensive
medications, had no treatment benefit. Although similar trends
were noted in the argon trial for patients with CNV secondary
to the ocular histoplasmosis syndrome,99 similar trends were
not noted in the argon trial of CNV secondary to AMD102 nor
in the subfoveal trials in AMD.40,41 Therefore, although the
data in the juxtafoveal trial failed to detect a treatment benefit
for hypertensive patients, lack of corroboration of this finding
in two other prospective trials on CNV secondary to AMD
cautions one from withholding treatment from patients who are
hypertensive.
There is only weak evidence that laser photocoagulation of
extrafoveal fluorescent spots (‘hot spots’) on ICG angiography
or feeder vessels on high speed video ICG angiography within a
neovascular lesion leads to a better outcome than no treatment.
The lack of controls in these trials, or comparisons to anti-
VEGF treatments now used for subfoveal lesions, precludes one
 Age-Related Macular Degeneration: Choroidal Neovascularization

a b

CHAPTER 146
FIGURE 146.16. Evaluation of CNV treatment. (a) Angiogram is projected onto
an apparatus (such as a microfilm reader or slide viewer) such that the CNV and
key landmarks around the CNV such as subretinal blood, retinal vessels, and
foveal center can be drawn. (b) The foveal avascular zone (FAZ) and the foveal
center (x) are indicated. (c) A posttreatment photograph is then projected, and
the area of heavy treatment and the same landmark vessels can be outlined on
a separate piece of paper. Evaluation of photocoagulation treatment can be
determined by placing the treatment drawing (c) under the pretreatment drawing
(a) on a lightbox. The area of heavy treatment can then be traced onto the
pretreatment drawing to determine whether the treatment has entirely covered
the CNV.
(a and b) From Bressler NM, Bressler SB, Fine SL: Age-related macular degeneration. Surv
Ophthalmol 1988; 32:375–413.) Alternatively, digital imaging software can be used to overlay
the boundaries of treatment from a post-treatment photograph onto the boundaries of a
lesion from a pre-treatment frame from the fluorescein angiogram.
c

from concluding with much confidence that such treatments
should be considered. This conclusion also applies to such
fluorescent spots seen within serous RPE detachments.103
On rare occasions, a patient will present with extrafoveal
CNV contiguous to a serous detachment of the RPE in which
the serous detachment extends through the foveal center. There
have been case reports in which only the extrafoveal CNV in
these lesions is treated, resulting in prompt flattening of the
RPE detachment with improvement of vision in selected
cases.104 Nevertheless, with follow-up, many of these eyes have
acquired recurrent CNV with extensive scarring and visual loss.
The more likely situation is that the extrafoveal CNV actually
is associated with fibrovascular PED that extends through the
foveal center in which treatment of the extrafoveal CNV alone
has not been shown to be of any benefit,91 and anti-VEGF
treatment, when indicated as described below, should be
considered.
Postoperative management of laser photocoagulation
Data from the MPS group have shown that eyes in which laser
treatment did not cover the CNV completely on the foveal side
or did not meet the required level of intensity (a uniform
relatively white burn, as shown in Fig. 146.15) had ~3 times
the risk of having persistent CNV within 6 weeks after
treatment compared with eyes in which the CNV was covered
completely by intense, confluent burns.94 Because of this
information, it is essential not only to obtain a uniform
relatively white laser burn during treatment but also to ensure
that the extent of the intense confluent burns completely
covers the extent of the CNV.
When a CNV lesion is extrafoveal, it usually is not difficult
for an ophthalmologist who is experienced in treating CNV to
extend laser treatment over the entire extent of the CNV.88,99
There is probably little hesitancy in extending treatment
slightly beyond the borders of the CNV in an effort to ensure
adequate coverage when the CNV is far away from the foveal
center. Slight extension of treatment should have little effect on
the visual acuity, since the treatment in these situations will
not affect central foveal photoreceptors.
In an attempt to minimize persistent CNV caused by
inadequate coverage, one may evaluate the laser treatment by
comparing the area of laser treatment from a posttreatment
photograph to the area of the lesion to be covered from the
pretreatment angiogram.30,105,106 The MPS group has described
their methods for this evaluation.106 In step 1, the extent and
location of the CNV with respect to the vascular landmarks
(Fig. 146.16a) is traced, either on paper of a projected slide or
on available imaging software with digital imaging systems. In
step 2, immediately after treatment, a posttreatment
photograph (digitally) or Polaroid (film) is taken. The area of
heavy treatment and the same landmark vessels are outlined
on a separate piece of plain white paper (Fig. 146.16b) or with
the image software. In step 3, the treatment drawing from step
2 is placed on a light box, and the pretreatment drawing from
step 1 is placed over this, superimposing the landmark vessels,
or superimposed by digital image software. The area of heavy
treatment can then be traced onto the pretreatment drawing
to determine whether the treatment has covered the CNV in its
entirety (Fig. 146.16c). Any areas not adequately treated can be
‘touched up’ while the patient is still in the office. The MPS 1941
 RETINA AND VITREOUS
group proved the usefulness of this method using 1-day
posttreatment stereoscopic color photographs; areas of
inadequate treatment were identified, and these eyes did indeed
have a higher rate of persistent CNV in the juxtafoveal
trials,93,94 it is likely that inadequate treatment to extrafoveal
lesions would result in the same problem.
Subfoveal Lesions
For treatment of subfoveal lesions (Fig. 146.12), one first
determines if the lesion is predominantly CNV (at least 50%
of the lesion is CNV, totaling areas of any classic CNV and any
occult CNV). If the lesion is predominantly CNV, one then
determines (Fig. 146.12) if the lesion is minimally classic or
occult with no classic. If so, then one determines if the patient
has had presumed recent disease progression in this eye.
Presumed recent disease progression includes any of the
following: blood associated with the lesion, visual acuity loss
within the past 3 months, or growth of the lesion on fluorescein
SECTION 10
angiography within the last 3 months. In the absence of
presumed recent disease progression for a subfoveal lesion with
a minimally classic or occult with no classic lesion
composition, careful follow-up, perhaps at 3 week, and then 6
week, and 3 month, intervals is indicated to watch for
progression to a predominantly classic lesion (see below) or
development of presumed recent disease progression. Lesions
with these compositions were excluded from the anti-VEGF
trials described below, and may have a different natural course
from the lesions in these trials, suggesting that it would be
inappropriate to extrapolate the results of these anti-VEGF
trials to minimally classic or occult with no classic lesions in
the absence of presumed recent disease progression.
If presumed recent disease progression is noted, then
treatment with ranibizumab is considered based on the
MARINA (Minimally Classic/Occult Trial of the Anti-VEGF
Antibody Ranibizumab in the Treatment of Neovascular AMD)
trial. The MARINA trial was a Phase III study of 716 patients
with presumed recent disease progression (blood associated
with CNV, recent visual acuity loss, or recent growth of CNV on
fluorescein angiography) associated with minimally classic or
occult with no classic CNV in AMD. Participants were
randomized 2:1 to receive either ITV ranibizumab, or sham
injections. The active treatment group was further randomized
to either a 0.3-mg or 0.5 mg-dose of ranibizumab every 4 weeks
for 2 years. One-year data showed that compared with baseline,
95% (452/478) of ranibizumab-treated patients lost fewer than
15 letters of visual acuity (VA), compared with 62% (148/238)
of patients in the control group.107 Twenty-five percent (59/238)
of patients treated with 0.3 mg of ranibizumab and 34%
(81/240) treated with 0.5 mg of ranibizumab improved vision by
15 letters or more compared with approximately 5% (11/238) of
patients in the control group. Nearly 40% (188/478) of
ranibizumab-treated patients achieved a VA score of 20/40 or
better compared with 11% (26/238) in the control group. Side
effects that occurred more frequently in the ranibizumab arms
than in the control group at 1 year included mild to moderate
conjunctival hemorrhage, eye pain, and vitreous floaters.
Uveitis and endophthalmitis occurred in fewer than 1% of
patients in the ranibizumab and control groups. Serious
nonocular adverse events occurred essentially as frequently
among ranibizumab-treated patients as among controls.108
These data indicate that ranibizumab not only reduces the risk
of moderate or severe visual acuity loss, but also increases the
chance of moderate visual acuity gain. While a majority of
treated patients did not improve by 15 or more letters, patients
who do have this level of improvement following ranibizumab
treatment may regain abilities dependent on vision they had
1942 previously lost, and may be able to participate in productive and
NEI-VFQ Subscale Scores
12
9.9 Ranibizumab Sham
10
8 6.9
6 5.2
4
2
0
-2
-4 -2.6
-4.7
-6
-5.9
-8
Near activities Distance activities Dependency+
FIGURE 146.17. MARINA trial. Improvement in vision-specific QOL
following pharmacologic intervention in AMD.
enjoyable activities such as reading a newspaper or recognizing
faces in social situations.
If the lesion is predominantly classic (Fig. 146.12), one need
not have presumed recent disease progression since trials
evaluating treatments for these lesions did not include a
requirement for presumed recent disease progression. The
ANCHOR (Anti-VEGF Antibody for the Treatment of
Predominantly Classic Choroidal Neovascularization in AMD)
trial involved 423 patients with predominantly classic
neovascular AMD. This randomized, double-masked, active
treatment-controlled study compared safety and efficacy of
0.3–mg and 0.5–mg doses of ranibizumab over the course of
2 years. Results from this study showed that 94% (132/140)
of ranibizumab-treated patients assigned to 0.3 mg and 96%
(134/139) of ranibizumab-treated patients assigned to 0.5 mg
avoided 15 or more letter loss compared with 64% (92/143) of
patients assigned to verteporfin PDT (P<.0001). No additional
ocular or systemic safety problems were identified beyond the
information summarized above from the MARINA trial.109,110
Since the ranibizumab-treated subjects without PDT in
ANCHOR had similar outcomes to the predominantly classic
cases enrolled by investigators in the FOCUS trial (where
subjected were assigned randomly to verteporfin PDT with
sham injection or verteporfin PDT plus ranibizumab), it seems
unlikely that adding PDT to ranibizumab will result in better
vision outcomes for these lesions. It remains unknown at this
time if this combination therapy will lead to the need for fewer
injections, and no trial has compared PDT plus ranibizumab to
ranibizumab alone.
To examine effects of ranibizumab on patient-reported
vision-specific QOL, investigators administered the NEI VFQ-
25 to participants in both the MARINA and ANCHOR trials.
The MARINA trial demonstrated a marked increase in the
proportion of patients with clinically relevant improvement in
vision-specific QOL following pharmacologic intervention in
AMD (Fig. 146.17) (Chang TS, Fine JT, Bressler N.. Self-
reported vision-specific quality of life at 1 year in patients with
neovascular age-related macular degeneration in 2 Phase III
randomized clinical trials of ranibizumab (Lucentis). Poster
presented at: Annual Meeting of the Association for Research in
Vision and Ophthalmology, Fort Lauderdale, Fl, May 1–52006:
Poster B667) In the MARINA trial, investigators administered
 Age-Related Macular Degeneration: Choroidal Neovascularization
the NEI-VFQ 25–716 subjects with subfoveal CNV due to AMD
with minimally classic or occult with no classic types at
baseline and at months 1, 2, 3, 6, 9, and 12. MARINA patients
treated with ranibizumab 0.5 mg were more likely to improve
10 or more points on the NEI-VFQ in activities related to near
and distance vision than were patients who received sham
injections (P < 0.001), who experienced overall decreases in
their ability to perform these activities (Fig. 146.17) (Chang TS,
Fine JT, Bressler N.. Self-reported vision-specific quality of life at
1 year in patients with neovascular age-related macular
degeneration in 2 Phase III randomized clinical trials of
ranibizumab (Lucentis). Poster presented at: Annual Meeting
of the Association for Research in Vision and Ophthalmology,
Fort Lauderdale, Fl, May 1–5, 2006: Poster B667). In addition,
ranibizumab-treated patients were more likely to improve 10 or
more points in ratings of dependency on others because of
vision than were sham injection patients.
Similar benefits of ranibizumab for patients with predomi-
nantly classic lesions were confirmed in the ANCHOR trial.
Investigators administered the NEI-VFQ 25 to 418 AMD patients
with predominantly classic type at baseline and at months 1, 2,
3, 6, 9, and 12 as reported at the 2006 Annual Meeting of the
American Society of Retina Specialists, although QOL data have
not yet been published in a peer-reviewed journal.
Other treatments for subfoveal neovascular AMD
Bevacizumab was approved by the FDA for intravenous
administration to patients with metastatic colorectal cancer
in February 2004. Bevacizumab has a similar molecular
structure to ranibizumab. Initially, a report about a series of
AMD patients who were treated with systemic bevacizumab,
and one case report of bevacizumab ITV administration,
showed short-term vision and anatomic outcomes that
appeared similar to those seen with ranibizumab and unlike the
natural history of this disease. Based on these reports, some
ophthalmologists began to administer bevacizumab off-label to
treat AMD.
Specifically, an open-label, uncontrolled, clinical study
evaluated the short-term safety of systemic bevacizumab in
nine AMD patients with subfoveal CNV, with best-corrected VA
of 20/40 to 20/400. Patients received an infusion of
bevacizumab (5 mg/kg) at baseline, followed by one or two
additional doses at 2 week intervals. By 12 weeks, the median
VA scores in the study eyes increased by 8 letters (P = 0.011).
The median central retinal thickness decreased by 157 mm (P =
0.008). No serious ocular or systemic adverse events were
identified during safety assessments, which were performed at
all visits. The only treatment-related adverse event was a
treatable, reversible, mild elevation of systolic blood pressure
(+12 mm Hg; P=.035). Although, the improvements in VA,
OCT measurements, and angiography (marked improvement
in vessel leakage in all eyes) in this small sample suggest that
systemic bevacizumab may be efficacious in neovascular AMD,
a case series of nine patients does not constitute an adequate
evidence base to conclude that systemic bevacizumab®therapy
is safe and effective for neovascular AMD patients.107
The single case report of ITV bevacizumab involved a 63-
year-old woman with neovascular AMD, whose vision had
deteriorated despite treatment with PDT/triamcinolone acetate
and pegaptanib was a sentinel event leading to ophthalmologists’
use of intravitreal bevacizumab while FDA approval for
ranibizumab was pending.108 The patient received a single
1.0 mg ITV dose of bevacizumab. Within 1 week, the subretinal
fluid resolved such that the macular contour appeared normal
on OCT, and remained so for at least 4 weeks. VA remained
stable, and neither ocular inflammation nor angiographic
leakage was observed. This case report represents proof of
concept that a drug which is usually administered intravenously
to prevent neovascularization in cancer patients could be
effective and safe over the short term, administered ITV in an
AMD patient who had responded poorly to previous treatments.
The report also indicates that, although it is a larger molecule
than ranibizumab, bevacizumab apparently penetrated the
retina well enough to inhibit VEGF in the vitreous cavity. Since
then, additional reports have appeared in the literature
presenting safety evaluations of the drug when injected into the
vitreous of rabbits,109 immunofluorescent studies suggesting
the ability of bevacizumab to penetrate the retina,109 and
evidence of potential clinical efficacy.110 A large, well-designed,
clinical trial would be needed to establish more definitively the
strength of applying these results to patients with neovascular
AMD.
In summary, the strength of the evidence to warrant the tse
of ranibizumab for specific lesions described above is based on
multiple randomized clinical trials with relevant endpoints with
CHAPTER 146
respect to visual acuity and a patient’s perception of vision-
related quality of life. The strength of evidence to support use of
bevacizumab is weaker, based on case series and anecdotal
reports. It is unknown at this time if intravitreal bevacizumab
is almost as good, better, or worse than ranibizumab for
reducing the risk of visual acuity loss and increasing the chance
of visual acuity gain. However, the evidence may be strong
enough to warrant consideration of bevacizumab when
ranibizumab is not available to a patients because of regulatory
limitations (e.g., not yet approved for use in a country) or
financial limitations (since a single-use vial of ranibizumab
costs a physician approximately $2000 in 2007 compared with
approximately $50 when 1.25 mg of bevacizumab in 0.05 ml is
obtained from a compounding pharmacy making multiple doses
from a single-use vial of bevacizumab that was packaged for
intravenous use in the treatment of certain cancers).
Pegaptanib sodium
During two concurrent, 48 week, randomized, double-blind,
controlled clinical trials, patients received ITV pegaptanib in
one eye at a dosage of 0.3 mg, 1.0 mg, or 3.0 mg. The control
group was given sham injections every 6 weeks.44 The primary
outcome variable was the proportion of patients who lost fewer
than 15 letters of VA at week 54. As compared to 164 (55%) of
296 patients in the control group, 206 (70%) of 294 patients
treated with 0.3 mg pegaptanib responded (P < 0.001), as did
213 (71%) of 300 those treated with 1.0 mg pegaptanib (P <
0.001), and 193 (65%) of 296 those treated with 3.0 mg
pegaptanib (P = 0.03). The majority of patients in all three
pegaptanib groups (95–97%) and in the sham group (95%
experienced at least one adverse event.111
Vitreous hemorrhage occurred in 2% of pegaptanib-treated
eyes, endophthalmitis in 1.3%, traumatic cataract in 0.6%, and
retinal tear or detachment in 0.7%.44,111 Based on this study,
pegaptanib was approved for the treatment of neovascular
AMD and could be considered for patients with lesions similar
to those of patients enrolled in these trials. However, because
the results were far different from that obtained with
ranibizumab, most ophthalmologists would not consider the
use of pegaptanib over ranibizumab at this time.
A retrospective post hoc analysis was performed in AMD
patients with ‘early’ disease defined retrospectively in two ways:
Group 1 (n=34) characteristics include lesion size <2 disc
areas, baseline VA letter score ≥ 54, and no prior PDT or laser
photocoagulation; Group 2 (n = 30) characteristics included
occult with no classic CNV, no lipid, and VA in study eye worse
than that in fellow eye.112 It is unknown how many
combinations of characteristics were examined to form with
these groups. In pegaptanib-treated Groups 1 and 2, 26 (76%) 1943
 RETINA AND VITREOUS
and 24 (80%) of 34 and 30 subjects, respectively, lost <15
letters of VA (the primary efficacy measure), compared with 14
(50%) and 20 (57%) of 28 and 35 subjects assigned to sham
injections. In the pegaptanib Groups 1 and 2, 4 (12%; Group 1)
to 6 (20%; Group 2) of 34 and 30 subjects, respectively, gained
at least 15 letters of VA compared with 1 (4%) and none of 28
and 35 subjects, respectively, receiving sham injections. These
data suggest that pegaptanib may be more effective if treatment
is started early in the natural history of a patient’s disease. This
conclusion should be evaluated with caution, however, as based
on these small numbers, the confidence intervals surrounding
the estimated percentage values are likely to be rather wide.
While PDT with verteporfin was shown to be superior to no
treatment for predominantly classic subfoveal lesions (TAP
REPORT NO. 1 1999), its inferiority to ranibizumab in the
ANCHOR trial for these lesions suggests that few ophthal-
mologists would consider verteporfin PDT over ranibizumab in
most circumstances if both drugs are available. Similarly,
SECTION 10
although no head-to-head trial of ranibizumab to verteporfin
PDT has been done for minimally classic or occult with no
classic lesions with presumed recent disease progression, the
outcomes reported in the MARINA trial for such lesions with
ranibizumab seem far superior to those reported to verteporfin
PDT (VIP REPORT NO. 2).
With respect to safety, the risk of endophthalmitis in any
invasive ocular procedure may be minimized with proper
aseptic technique, the use of a lid speculum, careful
postinjection monitoring, and educating patients about which
postinjection symptoms to report to the physician.
Bevacizumab is not manufactured with the strict particulate
matter limits that are required for ocular drugs, such as
ranibizumab, nor does it contain preservatives. Theoretically,
when dividing bevacizumab into smaller doses required for ITV
administration, contamination could be introduced if not done
under aseptic technique, and the label currently indicates the
need to use the drug within 6 h of opening a vial.
Although it is possible that the body could develop antibodies
against VEGF inhibitors, no serum antibodies to ranibizumab
were detected in the dose-ranging trial.113 One published trial
of pegaptanib did not report evaluations of serum antibodies,114
and another reported that there were no serum antibodies or
hypersensitivity reactions to pegaptanib.44
Another potential concern is the possibility that VEGF
inhibitors may potentiate myocardial infarction and stroke, which
has occurred at higher rates in treatment than control groups in
trials of intravenous bevacizumab among cancer patients.115
Thromboembolic events have occurred among intraocular rani-
bizumab and pegaptanib trial participants, but the frequency
was not statistically different between treatment and control
groups.44 No data has been published regarding the risk of such
events following intraocular injection of bevacizumab.
In summary, based on clinical trials, ranibizumab appears to
offer the best outcome at this time in the treatment of selected
cases of neovascular AMD similar to those enrolled in
MARINA, ANCHOR, VISION, the TAP Investigation, or the
VIP Trial compared with pegaptanib or PDT with verteporfin.
Additional data are needed to determine if bevacizumab results
in similar efficacy and safety to warrant its use when ranibizumab
is available. When ranibizumab is not available because of
regulatory limitations or cost, bevacizumab might be considered.
However, the patient must be informed of the risks and benefits
of extrapolating the ranibizumab trial results to bevacizumab
based on the limited evidence published to date regarding
potential benefits of bevacizumab and the limited safety data
available compared with the more extensive safety data
available on pegaptanib or verteporfin PDT (assuming the
1944 short-term efficacy noted with bevacizumab translates to the
longer-term efficacy seen with ranibizumab, but not shown for
pegaptanib or verteporfin PDT).
The necessity for ITV administration of ranibizumab as often
as every month and pegaptanib as often as every 6 weeks is a
distinct disadvantage compared to topical applications used to
treat other eye diseases and different from the potential
disadvantages of the intravenous administration of verteporfin
PDT, with sunlight restrictions for several days and follow-up as
often as every 3 months. However, clinical trials with
ranibizumab and pegaptanib were able to successfully recruit
participants who continued treatment throughout the 2 years
of the trials, despite the administration of ITV, so it appears
to be acceptable despite the invasiveness of the procedure.
MANAGING PATIENTS AND PHYSICIANS’
EXPECTATIONS IN THE TREATMENT OF
NEOVASCULAR AMD
Ophthalmology patients’ satisfaction in care hinges on an
adequate explanation of diagnosis, treatment, and prognosis.
Based on interviews of 163 ophthalmology patients interviewed
at either a Veteran’s Administration hospital or private practice,
more than 90% of patients rate these explanations as the most
important determinant of their satisfaction with the medical
visit.116 Although all 19 ophthalmologists interviewed as part of
this study rated explanations of diagnosis and treatment as very
important to patient satisfaction, only 40% of them also rated
a discussion of prognosis as highly.Trobe Ophthalmology 1983,
P53A, T2, items 1–3 This dichotomy in expectations about
revealing prognosis indicates that patients’ expectations may be
at odds with those of their physicians on this issue.
Patients expect that their ophthalmologists will explain AMD
treatment options in ways they can understand, yet a sizable
group of patients may have problems with health literacy. In
one study of Medicare enrollees in a nationwide managed-care
system, one third of English-speaking patients, and more than
one half of Spanish-speaking patients, exhibited either marginal
or inadequate health literacy, and thus were unable to
understand consent forms or medicine labels. In addition,
health literacy tended to decline with age, with inadequate
health literacy exhibited in only 15.6% of participants 65–69
years old and increasing to 58.0% of those older than 85. If an
ophthalmologist uses the same level of language with all
patients, there is a risk, therefore, that a substantial minority
of patients will be unable to comply with treatment plans. This,
in turn, can lead to patient disappointment and ophthalmologist
frustration, since a treatment would likely be more effective if
the patient were compliant with instructions.
Those patients with AMD who are literate enough to
understand the implications of the disease process expect that
their preferences and concerns with regard to treatment options
will be considered by their ophthalmologists. They may arrive
at the ophthalmologist’s office clutching reams of printouts
from the Internet, expecting that their physician will embrace
what they have found from web sites that may or may not be
reliable.117 As a result, patients with AMD may develop
unrealistic expectations of treatment effectiveness and safety,
based on selective attention to potential positive outcomes that
are widely publicized on the Internet or in popular publications.
Patients may misunderstand and assume that positive
outcomes in a proportion of participants treated during a
clinical trial will occur to them as individuals. A patient who
has read about ranibizumab, for example, may assume that if
treated with that drug, he or she will regain vision and be able
to drive, read, and recognize faces again because ~40% of
ranibizumab-treated patients did so.118
 Age-Related Macular Degeneration: Choroidal Neovascularization
PATIENT EXPECTATIONS
In the face of AMD, a disease with uncertain outcomes, several
strategies may be useful to manage patient expectations. These
strategies, first identified among general medical practitioners,
include an honest discussion of the natural history of the
disease without treatment, the potential outcomes with
treatment, and the prognosis with or without treatment
(watchful waiting).119
The ophthalmologist should first explain that some patients
with treatment will lose vision. For example, when discussing
ranibizumab as a possible treatment with patients, it should be
explained that 5% of treated patients lost a moderate amount of
vision (15 or more letters, ~3 or more lines on the eye chart).
However, without treatment, patients should understand that
35–40% will lose at least a moderate amount of vision.
Likewise, patients should understand that treatment does not
take away one’s chance of improving, but that not all treated
patients will improve. Clinical trials suggest that few untreated
patients will improve a moderate amount (three or more lines
on an eye chart), and that with verteporfin PDT or pegaptanib
injections only ~5–10% will gain this amount of vision. With
ranibizumab, 25–40% (depending on drug dose and lesion
composition) gained three or more lines of vision by 1 year, with
the proportion of study subjects having this improvement
remaining fairly stable through 2 years. This means that a
majority of patients will not have noticeable improvement, but
it is far more likely that one will experience improvement with
ranibizumab treatment than without treatment or with other
treatments currently available.
Another strategy that is essential to managing patients’
expectations is to be sure the patient understands, and is willing
and able to comply with, the treatment plan.Hewson J Gen Int
Med 1996; P483, T1, item 5 If pegaptanib or ranibizumab is
being considered as a treatment option, for example, one should
describe the need for multiple visits, multiple imaging
procedures, and multiple injections. While it is unclear at this
time whether monthly injections (MARINA, ANCHOR) are
superior to less frequent injections (PIER), patients receiving
ranibizumab need to know that injections could be as often as
monthly for at least 2 years, and possibly for a longer time. As
more knowledge is gained regarding longer term outcomes, this
information should be shared with patients. The ophthalmologist
also must make the patient aware that there are potential risks
of treatment due to either the drug itself (none known
definitively at this time with ranibizumab) or to the administration
of the drug by injection (e.g., such as endophthalmitis or retinal
tears.120
Given the expenses of some drugs in the management of
neovascular AMD, the treating ophthalmologist should be sure
the patient understands the total expected cost of treatment
over time, and what proportions will be paid by the patient’s
third-party payer, if any, compared with those that the patient
must pay out-of-pocket. A 2 year course of pegaptanib injections
every 6 weeks, for example, may cost more than $19 000.121
The price of ranibizumab, which was administered once a
month in the pivotal trials, will be $1950 per injection to the
ophthalmologist, with an additional mark-up to the patient, for
a total of $23 000 per year to the heath care provider just for the
drug. Additional costs for visits, imaging, and mark-up on the
drug need to be explained as well.
OPHTHALMOLOGISTS’ EXPECTATIONS
The factors mentioned above that govern patient expectations
for treatment also influence their physicians. Ophthalmologists
want their patients to be satisfied with their care, and share
with them the desire for explanations of diagnosis, treatment,
prognosis that the patients can understand and apply. Most
patients will accept treatment that the physicians suggest (e.g.,
watchful waiting, surgery, photodynamic treatment, intravitreal
injection). Clinicians cannot predict which patients will benefit
from a given therapeutic intervention and which will not. Thus,
treatment decisions for AMD patients should be weighed
carefully to maximize the chances for vision retention or
improvement. One way to maximize rational treatment choice
involves the concept of the number needed to treat (NNT).
NNT is an estimate of the number of patients who need to be
treated with a given regimen (instead of the standard treatment)
for one additional patient to benefit from a specific outcome.
This benefit is often expressed as an outcome to avoid, e.g.,
three or more lines of vision loss, or a desirable outcome, e.g., 3
or more line gain. The ideal NNT would be one, meaning that
every patient treated with a given regimen would benefit.
The NNT is the reciprocal of the absolute risk reduction.
CHAPTER 146
Assuming the standard treatment is verteporfin PDT, the NNT
for ranibizumab to avoid three or more line loss is calculated as
shown in Figure 146.18, based on efficacy data from the
ANCHOR (Anti-VEGF Antibody for the Treatment of
Predominantly Classic CHORoidal Neovascularization in
AMD) Trial. If the clinician is considering ranibizumab or
pegaptanib for an AMD patient, for example, the treatment
with the lower NNT with avoidance of vision loss as the
specified outcome would be the optimal choice for the
patient.122
Ophthalmologists want to prescribe treatments that are cost-
effective for their patients. A costly intervention for AMD may
be worth the financial outlay if it truly benefits patients, as the
gift of sight may be considered priceless. The next newsletter in
this series will discuss cost-effectiveness of AMD treatments in
detail.
MANAGEMENT CONSIDERATIONS FOR
PHYSICIANS
Between one-quarter and one-half of Americans read at the
8th grade level or below, despite having graduated from high
school.123 Ideally, therefore, the ophthalmologist should
determine the patient’s health literacy level. In a research
setting, clinicians might determine the patient’s health literacy
Number Needed to Treat
Proportion with vision loss (PDT) .36
Proportion with vision loss (ranibizumab*) .04
Absolute Risk Reduction (ARR) .32
NNT = 1/ARR 1/.32=
3.125
*Dosage, ranibizumab .5mg
FIGURE 146.18. Calculation of NNT based on data from the
ANCHOR clinical trial. 1945
 RETINA AND VITREOUS
level using the Short Test of Functional Literacy in Adults,
which is available in both English and Spanish, and takes only
12 min to administer. If that is not possible in the private
setting due to time and staffing constraints, simply asking the
patient, “How often do you need to have someone help you to
read instructions, pamphlets, or other written material from
your doctor or pharmacy?” can be used as a proxy.124
The ophthalmologist should consider providing AMD
patients with recommendations for easy-to-understand
educational materials, such as those available from the
American Academy of Ophthalmology. The Medline Plus Macular
Degeneration Patient Education Page (http://www.nlm.nih.gov/
medlineplus/maculardegeneration.html) also provides reliable
material targeted to the lay public. Frequent updates may be
needed as new data are presented or published.
MONITORING PATIENTS FOLLOWING
SECTION 10
INITIATION OF RANIBIZUMAB THERAPY
FOR NEOVASCULAR AMD
Several investigators have published case series about
monitoring retinal structure with OCT following intravitreal
bevacizumab when used to treat CNV. Avery and colleagues
treated 79 patients with intravitreal bevacizumab monthly.
While they did not specify whether fluorescein angiography was
performed at each visit, patients followed for 4–15 weeks
showed a decline in central retinal thickness as measured by
OCT of at least 10% in 41 (55%) of 75 patients seen 1 week
postinjection.116 Spaide and colleagues used changes in retinal
thickness (as measured in the central subfileld on OCT) as a
primary outcome measure in a retrospective study of 266
patients who had been treated with intravitreal bevacizumab.125
Ophthalmologists for patients in this series justified performing
FA as needed, rather than at every follow-up visit, because they
deemed slit-lamp biomicroscopy and OCT adequate to measure
initial response to VEGF-inhibitor therapy.125 However,
measuring a response to therapy does not determine if
retreatment decisions based on OCT, or fluorescein angiography,
or both, lead to better outcomes than if none of these
evaluations are performed after initiating anti-VEGF therapy.
The pivotal trials leading to the FDA approval of
ranibizumab, ANCHOR (Anti-VEGF Antibody for the Treatment
of Predominantly Classic CHORoidal Neovascularization in
AMD) and MARINA (Minimally Classic/Occult Trial of the
Anti-VEGF Antibody Ranibizumab in the Treatment of
Neovascular AMD) gave monthly injections of ranibizumab
through 2 years, without considering withholding retreatment
based on OCT or fluorescein angiographic findings. Thus, these
trials do not permit one to determine if almost as good, worse,
or better outcomes would be obtained if treatment were
withheld when it was judged that there was no room for
continued improvement or when it was judged that the
condition appeared ‘stabilized’.
Although the protocols for these pivotal trials specified
follow-up visits and retreatment with ranibizumab once per
month, the possibility that the interval between ranibizumab
treatments could be extended to balance efficacy with comfort
and safety has not been determined definitively. The PIER trial
(Phase 3b, Randomized, Double-Masked, Sham Injection-
Controlled Study of the Efficacy and Safety of Ranibizumab in
Subjects With Subfoveal Choroidal Neovascularization With or
Without Classic CNV Secondary to AMD) showed that at
month 12, patients treated with ranibizumab lost 1.6 letters
and 0.2 letters (0.3 mg and 0.5 mg) compared to a loss of 16.3
letters in the sham group, on average (P < 0.0001)126 The 1 year
1946 results of PIER suggest that an initial induction with 3 monthly
ranibizumab treatments followed by quarterly injections may
confer visual acuity, FA, and OCT benefits compared with sham.
While such a regimen decreases the inconvenience and risk of
more frequent injections, it is unknown how this regimen
compares with respect to visual acuity outcomes to the monthly
treatments used in the MARINA and ANCHOR trials.
While waiting for data to determine if withholding treatment
based on parameters that indicate no room for further
improvement or a stable lesion leads to outcomes that are
almost as good, better, or worse than monthly injections of
ranibizumab or bevacizumab, and while waiting for evidence if
either retreatment approach with bevacizumab is almost as
good, better, or worse than either retreatment approach with
ranibizumab, ophthalmologists are approaching follow-up in
one of two ways.
One, they may be applying ranibizumab treatments as it was
done in the trials proving its benefits, i.e., monthly injections
for up to 2 years. Two, knowing from the PIER study that less
frequent treatments also are beneficial compared with no
treatment (although not knowing if this is almost as good,
better, or worse than monthly injections), some ophthalmologists
are withholding additional treatments when there no longer is
room for improvement or the lesion is stabilized. One might
consider that there is no longer room for improvement when
the visual acuity is as good as it could possibly be, for example,
is 20/25, taking into consideration the patient’s media
opacities, refraction, and structural damage to the macula from
atrophy or scarring or other degeneration. One might consider
a lesion stabilized when certain parameters appear absolutely
the same as the previous one or two months with respect to
symptoms, visual acuity, biomicroscopic appearance (aided by
documentation with fundus photographs), OCT, and
fluorescein angiography.
Clearly, this latter approach is more time intensive for the
patient and physician, with no strong evidence that outcomes
based on this approach are almost the same or better than those
obtained by monthly injections regardless of these parameters.
Also, while symptoms, visual acuity, and biomicroscopic
appearance add little cost to a visit, it is unknown if more costly
fundus photographs aid in determining if a lesion is stable (as
has been demonstrated with follow-up of diabetic retinopathy.127
It is also unknown if making treatment decisions based on the
increased cost of periodic OCTs are beneficial or preclude the
need for the increased cost of fluorescein angiography (with its
occasional difficulties with interpretation and its attendant side
effects of nausea, vomiting, itching, or rash),128 or making
treatment decisions based on fluorescein angiography are
beneficial or preclude the need for OCT. Since ranibizumab is
expensive to the patient and third party payers, if periodic
fundus photographs, OCT, or fluorescein angiograms were
shown to identify situations when retreatment could be
withheld with outcomes that were almost as good as monthly
injections, the cost savings on the drug could outweigh the
additional monitoring costs of fundus photographs, or OCT, or
fluorescein angiography or a combination of these. If
bevacizumab, which costs far less than ranibizumab for
intraocular injection, were shown to provide outcomes that
were almost as good or better than ranibizumab outcomes, then
avoiding the cost of a few injections might not balance the costs
of the photographs, or OCT, or angiograms.
Clearly more data is needed to make the ophthalmologist
confident that use of monitoring with one or more procedures,
including fundus photographs, OCT, and fluorescein angiograms,
to determine retreatment leads to almost as good, or better
outcomes than seen with monthly ranibizumab treatments.
Until strong evidence is available, some ophthalmologists
appropriately will apply retreatment each month for up to
 Age-Related Macular Degeneration: Choroidal Neovascularization

100
0 (n = 35)
1 (n = 105)
90 2 (n = 142) 87
3 (n = 105)
81
4 (n = 45)
Eyes with choroidal neovascularization (%)

80
72
70 68

61
60
53
50 48 49
47
44
40
40 38
36
34
32
30
30 28 28

CHAPTER 146
27
25
23 22 23 23
20 20
20 19
16
15
12 14 13 13
11
10 7 7 7 7 7 7
4 5
3 3 3
0 0 0 0 0 0
0
0 1.5 3 6 12 18 24 30 36 42 48 54 60
Follow-Up (mo)

FIGURE 146.19. Incidence of CNV by number of risk factors present including definite hypertension, 5 or more drusen, greatest linear
dimension of largest druse >63 µm, and focal hyperpigmentation.
From Macular Photocoagulation Study Group: Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal
neovascularization secondary to age-related macular degeneration. Arch Ophthalmol 115:741–747, 1997. Copyright 1997, American Medical Association.

2 years, while others will use weaker evidence (inference from
case series, biologic rationale, and experience) to consider
withholding treatment when there is no room for further
improvement or when the situation appears stabilized. A trial
announced by the National Eye Institute129 will address some
of these issues both with ranibizumab and bevacizumab.
NATURAL COURSE OF SUBFOVEAL
SUBRETINAL HEMORRHAGE IN AMD
Several reports have noted that whereas some eyes with
subfoveal subretinal hemorrhage associated with AMD have
poor outcomes, the visual acuity of other eyes do not deteriorate
or may improve spontaneously.8,130,131 Such findings underscore
the importance of evaluating the role of therapeutic interventions
for these cases, such as surgery to remove subretinal
hemorrhage,132,133 in randomized clinical trials. In one such
trial from the Submacular Surgery Trials, surgical removal of
blood and any associate neovascular lesion was not shown to
reduce the risk of vision loss in most cases and was associated
with a high risk of rhegmatogenous retinal detachments. (ref
sst report no. 13) The control group (no treatment) did note
that ~20% of predominantly hemorrhagic lesions will have a
breakthough vitreous hemorrhage. Other treatments under
investigation include the use of intravitreal ranibizumab
(although these lesions were excluded from the MARINA and
ANCHOR trials), as well as using intravitreal gas to displace
the hemorrhage.
RISK OF FELLOW EYE INVOLVEMENT WITH
SUBSEQUENT CNV SCARRING
It is important to have the patient monitor the vision in the
fellow eye if its macula does not already have CNV scarring.
The MPS group has shown that if a patient presents with CNV
in one eye and no evidence of CNV or scarring in the fellow
eye, about 40% of these eyes will have CNV in the fellow eye
within 5 years.1,2 The risk of CNV developing in these eyes
may be further specified depending on the drusen and RPE
abnormalities within 1500 mm of the foveal center present in
the fellow eye and certain patient characteristics at baseline.
2 Specific risk factors include: (1) definite hypertension (systolic
pressure ≥140 mm Hg, diastolic pressure ≥90 mm Hg, or use of
antihypertensive medications), (2) five or more drusen, (3)
greatest linear dimension of largest druse greater than 63 mm, or
(4) focal hyperpigmentation. The risk of CNV developing
within 5 years after presenting with CNV in the first eye ranged
from 7% if none of these risk factors was present to 87% if all
four risk factors were present (Fig. 146.19).2 As one might have
suspected, for the fellow eyes that had no evidence of CNV or
scarring at baseline and subsequently developed CNV within 5
years, the average visual acuity loss was eight lines of vision.141
In contrast, for the two-thirds of fellow eyes that had no
evidence of CNV or scarring at baseline and did not have CNV
within 5 years, the average visual acuity loss was less than half
a line of vision (specifically, 0.4 line).141 Therefore, the risk of
moderate or severe loss of visual acuity is highly correlated with
the development of CNV during follow-up. Eyes that do not
acquire CNV during follow-up have little or no visual acuity
loss. This finding should be considered when evaluating the role
of vitamins, minerals, or other treatment modalities in
preventing visual acuity loss for eyes with drusen or RPE
abnormalities without the presence of CNV or scarring.
If one couples this information of fellow eye involvement
with success of treatment in the first eye from the extrafoveal
argon MPS trial, one can determine the risk of legal blindness
(visual acuity of 20/200 or worse in both eyes) when treating the
first eye. The risk of legal blindness, again, is highly correlated 1947
 RETINA AND VITREOUS
with whether or not the fellow eye had CNV or scarring at
baseline. If CNV or scarring was present in the fellow eye at
baseline, it was likely that the fellow eye already had significant
loss of visual acuity and that there was a high risk of recurrence
developing in the treated eye. Forty-nine percent of patients in
the argon AMD MPS trial were legally blind within 5 years of
follow-up when the fellow eye initially had CNV or scarring,
whereas only 12% of patients were legally blind within 5 years
of follow-up when the fellow eye had no evidence of CNV or
scarring initially.134 Similar analyses currently are under way
for patients who participated in the MPS trials of juxtafoveal or
subfoveal lesions from AMD. Of course, if the visual acuity of
the fellow eye is compromised at all, and the first eye has CNV,
low-vision aids are probably indicated to assist with magnification
for near visual tasks, as are telescopic aids for spotting at
distance.
LOW-VISION AIDS
SECTION 10
Patients who have central visual impairment in both eyes
should be advised about the availability of a variety of low-vision
aids. A low-vision evaluation includes not only prescribing
appropriate lenses, magnifying aids (optical or electronic), and
other items of assistance but also properly training and
encouraging the patient to use them. Patients should also be
told of community resources available to assist them with
visual impairment such as might be obtained from the directory
of agencies serving the visually handicapped in the United
States provided by the American Foundation for the Blind. A
realistic appraisal of the prognosis coupled with appropriate
counseling and support is necessary to enable the visually
impaired patient to continue functioning as normally as possible
despite the central visual impairment. The American Foundation
for the Blind can also inform patients as to which aids, such as
talking books, large-print books, watches that ‘tell’ time, closed-
circuit television readers, and other devices, are available
through the directory of products for people with vision
problems.
Visual aids for detailed near and distance tasks, such as
reading, writing, typing, sedentary distance viewing, and
distance spotting for street signs, can be prescribed with a
thorough low-vision examination conducted in a room with
glare-free high-intensity lighting and large trial lenses to allow
for eccentric fixation. There is a wide range of magnification
levels available in the present armamentarium of low-vision
aids. Some incorporate their own illumination source. Each
aid has certain advantages and limitations, so a patient must
decide with a low-vision aid specialist what combination of
aids is best for her or his visual objectives and visual needs.
Four types of reading aids are available: reading glasses, hand-
held lenses, stand magnifiers, and electronic devices. Reading
glasses (convex lenses) provide relatively large fields of vision,
but the strongest lenses require short working distances.
Telescopic reading glasses increase the working distance;
however, they allow a relatively smaller field of view and shorter
depth of focus than a simple high plus reader of comparable
magnification. Hand-held magnifiers may suffice for quick,
simple tasks that are conducted at arm’s length, such as
adjusting a stove dial. A stand magnifier consists of a mounted
lens that will remain in focus if placed on the reading material
and held so that its focal point corresponds to the focal point of
the patient’s near correction. This device offers an alternative
to the high plus lens for the weak or tremulous patient; it is
also useful when the patient wishes an increase in working
distance or wants to have an illumination source incorporated
1948
into the magnifying system. Closed-circuit television and hand-
held electronic devices provide electronic magnification at
greater levels than is possible with optical systems. These also
provide binocular viewing and can be used at a comfortable
reading distance. Unfortunately, not all systems are readily
portable and all are quite costly. Writing assistance may be
provided with a weak hand lens or a +5.00 add-in spectacle.
Additional invaluable and simple tools to aid in writing include
signature guides, black felt-tip pens, and bold wide-ruled paper.
Distance vision may be enhanced with binocular field glasses
and opera glasses. Lightweight telescopes can be hand-held or
mounted onto spectacles. Unfortunately, these instruments
distort distances and limit peripheral vision; therefore, their
applicability is limited to tasks of sedentary distance viewing
and distance spotting.
Finally, the success of each of these aids is highly variable,
depending on the visual deficit and the motivation of the
patient. They can attempt to enhance only lighting or
magnification for the remaining vision. The patient should not
look on them as a treatment for macular degeneration nor
expect to regain central vision. Nevertheless, it is important to
give these patients every opportunity to be evaluated for and
trained in the use of optical and nonoptical systems that may
serve to improve the quality of life.
CONCLUSIONS AND FUTURE RESEARCH
The 1980s and 1990s provided enormous progress in the
management of AMD. Specifically, laser treatment has been
shown to be beneficial when compared with no treatment.
However, the fact that laser treatment is more beneficial for
preserving vision when compared with observation alone is
only a start. Successful cases of laser treatment still result in
central visual acuity loss for the patient, especially when
treatment involves the foveal center as it so often does in AMD.
Furthermore, treatment is applicable in only a minority of
cases.
Therefore, future research in the management of CNV in
AMD will have to evaluate other modalities of treatment that
do not cause destruction of the foveal center or therapies that
prevent the development of CNV in the first place.135 Such
investigations will require interdisciplinary approaches to this
problem that will probably include epidemiologists, clinicians,
psychophysicists, vitreoretinal surgeons, geneticists, and
cellular biologists. These investigations may include therapies
to prevent the development of CNV or to minimize the damage
it causes. Medical interventions that affect angiogenesis may
hold some promise. Unfortunately, one randomized clinical
trial evaluating interferon-a showed no benefit and possible
harm in the treatment of CNV from AMD.136 Surgical
interventions that could remove the neovascular process before
it destroys a large area of the central retina also may hold some
promise, especially because these interventions, as with
medical interventions, may be considered for lesions obscured
by blood or that have poorly demarcated boundaries.137 Other
currently unproven investigational therapies in the 1990s
include consideration of indocyanine green-guided laser
photocoagulation,103,138,139 radiation,140 and photodynamic
therapy.141,142 Given the variable natural history of CNV in
AMD, acceptance of any of these new therapies likely will
require therapeutic benefits proved through carefully designed
randomized clinical trials. As the number of people over the age
of 65 years in the United States and elsewhere doubles by about
2030, the importance of finding treatments for CNV in AMD
will grow tremendously.

REFERENCES
1. Bressler SB, Maguire MG, Bressler NM,
Fine SL: Macular Photocoagulation Study
Group: Relationship of drusen and
abnormalities of the retinal pigment
epithelium to the prognosis of neovascular
macular degeneration. Arch Ophthalmol
1990; 108:1442–1447.
2. Macular Photocoagulation Study Group:
Risk factors for choroidal
neovascularization in the second eye of
patients with juxtafoveal or subfoveal
choroidal neovascularization secondary to
age-related macular degeneration. Arch
Ophthalmol 1997; 115:741–747.
3. Gass JDM: Drusen and disciform macular
detachment and degeneration. Arch
Ophthalmol 1973; 90:206–217.
4. Smiddy WE, Fine SL: Prognosis of patients
with bilateral macular drusen.
Ophthalmology 1984; 91:271–277.
5. Strahlman E, Fine SL, Hillis A: The second
eye of patients with senile macular
degeneration. Arch Ophthalmol 1983;
101:1191–1193.
6. Green WR, McDonnell PH, Yeo JH:
Pathologic features of senile macular
degeneration. Ophthalmology 1985;
92:615–627.
7. Sarks SH: Ageing and degeneration in the
macular region: A clinicopathologic study.
Br J Ophthalmol 1976; 60:324–341.
8. Avery RL, Fekrat S, Hawkins BS, Bressler
NM: Natural history of subfoveal subretinal
hemorrhage in age-related macular
degeneration. Retina 1996; 16:183–189.
9. Green RW, Enger C: Age-related macular
degeneration histopathologic studies. The
1992 Lorenz E. Zimmerman Lecture.
Ophthalmology 1993; 100:1519–1535.
10. Gass JDM: Pathogenesis of disciform
detachment of the neuroepithelium.
VI: Disciform detachment secondary to
heredodegenerative, neoplastic and
traumatic lesions of the choroid. Am J
Ophthalmol 1967; 63:689.
11. Lim JI, Bressler NM, Marsh MJ, Bressler
SB: Laser treatment of choroidal
neovascularization in patients with angioid
streaks. Am J Ophthalmol 1993;
116:414–423.
12. Heriot WJ, Henkind P, Bellhorn RW, Burns
MS: Choroidal neovascularization can
digest Bruch’s membrane: A prior break is
not essential. Ophthalmology 1984;
91:1603–1608.
13. Öffler KU, Lee WR: Basal linear deposit in
the human macula. Graefes Arch Clin Exp
Ophthalmol 1986; 224:493–501.
14. Penfold PL, Killingsworth MC, Sarks SH:
Senile macular degeneration: The
involvement of immunocompetent cells.
Graefes Arch Clin Exp Ophthalmol 1985;
223:69–76.
15. Penfold PL, Provis JM, Billson FA: Age-
related macular degeneration:
ultrastructural studies of the relationship of
leucocytes to angiogenesis. Graefes Arch
Clin Exp Ophthalmol 1987; 225:70–76.
16. Ryan SJ: Development of an experimental
model of subretinal neovascularization in
disciform macular degeneration. Trans Am
Ophthalmol Soc 1979; 77:707–745.
17. Ryan SJ: Subretinal neovascularization:
natural history of an experimental model.
Arch Ophthalmol 1982; 100:1804–1809.
Age-Related Macular Degeneration: Choroidal Neovascularization
18. Friedman E, Ivry M, Ebert E, et al:
Increased scleral rigidity and age-related
macular degeneration. Ophthalmology
1989; 96:104–108.
19. Eye Disease Case-Control Study (EDCCS)
Group: Risk factors for neovascular age-
related macular degeneration. Arch
Ophthalmol 1992; 111:1701–1708.
20. Broekhuyse RM: The lipid composition of
the aging sclera and cornea.
Ophthalmologica 1975; 171:82.
21. Grossniklaus HE and Green WR: Choroidal
neovascularization. Am J Ophthalmol 2004;
137:496–503.
22. Witmer AN, et al: Vascular endothelial growth
factors and angiogenesis in eye disease.
Prog Retin Eye Res 2003; 22:1–29.
23. Adamis AP ,Shima DT: The role of vascular
endothelial growth factor in ocular health
and disease. Retina.2005; 25:111–118.
24. Bressler SB, Bressler NM, Alexander J,
Green WR: Clinicopathologic correlation of
occult choroidal neovascularization in age-
related macular degeneration. Invest
Ophthalmol Vis Sci 1991; 32:689.
25. Bressler SB, Bressler NM, Fine SL, et al:
Natural course of choroidal neovascular
membranes within the foveal avascular
zone in senile macular degeneration. Am J
Ophthalmol 1982; 93:157–163.
26. Bird AC: Macular disciform response and
laser treatment. Trans Ophthalmol Soc UK
1977; 97:490–493.
27. Bressler NM, Frost LA, Bressler SB, et al:
Natural course of poorly defined choroidal
neovascularization associated with macular
degeneration. Arch Ophthalmol 1988;
106:1537–1542.
28. Chandra SR, Gragoudas ES, Friedman E,
et al: Natural history of disciform
degeneration of the macula. Am J
Ophthalmol 1974; 78:579–582.
29. Gragoudas ES, Chandra SR, Friedman E,
et al: Disciform degeneration of the macula.
II: Pathogenesis. Arch Ophthalmol 1976;
94:755–757.
30. Bressler NM, Bressler SB, Fine SL: Age-
related macular degeneration. Surv
Ophthalmol 1988; 32:375–413.
31. Boldt C, Bressler NM, Fine SL, Bressler SB:
Age-related macular degeneration. Curr
Opin Ophthalmol 1990; 1:247–257.
32. Moisseiev J, Bressler NM: Asymptomatic
neovascular membranes in the second eye
of patients with visual loss from age-related
macular degeneration (AMD). Invest
Ophthalmol Vis Sci 1990; 31:462.
33. Fine AM, Elman MJ, Ebert JE, et al: Earliest
symptoms caused by neovascular
membranes in the macula. Arch
Ophthalmol 1986; 104:513–514.
34. Nasrallah F, Jalkh AE, Trempe CL, et al:
Subretinal hemorrhage in atrophic age-
related macular degeneration. Am J
Ophthalmol 1989; 107:38–41.
35. Small ML, Green WR, Alpar JJ, et al: Senile
macular degeneration: Clinicopathologic
correlation of two cases with
neovascularization beneath the retinal
pigment epithelium. Arch Ophthalmol 1976;
94:601–607.
36. Doyle WJ, Davidorf FH, Makley TA, Dieruf
WJ: Histopathology of an active lesion of
ocular histoplasmosis. Ophthalmic Forum
1984; 2:106–111.
37. Macular Photocoagulation Study Group:
Subfoveal neovascular lesions in age-
related macular degeneration: Guidelines
for evaluation and treatment in the Macular
Photocoagulation Study. Arch Ophthalmol
1991; 109:1242–1257.
38. Klein ML, Zorizzo PA, Watzke RC: Growth
features of choroidal neovascular
membranes in age-related macular
degeneration. Ophthalmology 1989;
96:1416–1421.
39. Vander JF, Morgan CM, Schatz H: Growth
rate of subretinal neovascularization in age-
related macular degeneration.
Ophthalmology 1989; 96:1422–1429.
40. Macular Photocoagulation Study Group:
Laser photocoagulation of subfoveal
neovascular lesions in age-related macular
CHAPTER 146
degeneration. Results of a randomized
clinical trial. Arch Ophthalmol 1991;
109:1219–1231.
41. Macular Photocoagulation Study Group:
Laser photocoagulation of subfoveal
recurrent neovascular lesions in age-related
macular degeneration. Results of a
randomized clinical trial. Arch Ophthalmol
1991; 109:1232–1241.
42. Submacular Surgery Trials Research Group:
Guidelines for interpreting retinal
photographs and coding findings in the
submacular surgery trials (SST). SST report
no. 8. Retina 2005; 25:253–268.
43. Barbazetto I, Burdan A, Bressler NM, et al:
Treatment of Age-Related Macular
Degeneration with Photodynamic Therapy
Study Group; Verteporfin in Photodynamic
Therapy Study Group. Photodynamic
therapy of subfoveal choroidal
neovascularization with verteporfin:
fluorescein angiographic guidelines for
evaluation and treatment – TAP and VIP
report no. 2. Arch Ophthalmol 2003;
121:1253–1268.
44. Gragoudas ES, Adamis AP, Cunningham
ET Jr, et al: VEGF Inhibition Study in Ocular
Neovascularization Clinical Trial Group.
Pegaptanib for neovascular age-related
macular degeneration. N Engl J Med 2004;
351:2805–2816.
45. Rosenfeld PJ, Brown DM, Heier JS,
MARINA Study Group, et al: Ranibizumab
for neovascular age-related macular
degeneration. N Engl J Med 2006;
355:1419–1431.
46. Brown DM, Kaiser PK, Michels M,
ANCHOR Study Groupet al: Ranibizumab
versus verteporfin for neovascular age-
related macular degeneration. N Engl J
Med 2006; 355:1432–1444.
47. Soubrane G, Coscas G, Francais C, Koenig
F: Occult subretinal new vessels in age-
related macular degeneration.
Ophthalmology 1990; 97:649–657.
48. Jalkh AE, Nasrallah FP, Marinelli I, Van de
Velde F: Inactive subretinal
neovascularization in age-related macular
degeneration. Ophthalmology 1990;
97:1614–1619.
49. Schatz H, McDonald HR, Johnson RN:
Retinal pigment epithelial folds associated
with retinal pigment epithelial detachments
in macular degeneration. Ophthalmology
1990; 97:658–665.
50. Grossniklaus HE, Green RW:
Histopathologic and ultrastructural findings
1949
 RETINA AND VITREOUS
of surgically excised choroidal neovascular
membranes in the submacular surgery
trials. Arch Ophthalmol 1998; 116:745–749.
51. Lopez PF, Lambert HM, Grossniklaus HE,
Sternberg P Jr: Well-defined subfoveal
choroidal neovascular membranes in age-
related macular degeneration.
Ophthalmology 1993; 100:415–422.
52. Sorenson JA, Yannuzzi LA, Shakin JL:
Recurrent subretinal neovascularization.
Ophthalmology 1985; 92:1059–1075.
53. Bressler NM, Bressler SB, Alexander J,
et al: Macular Photocoagulation Study
Reading Center: loculated fluid: A
previously undescribed fluorescein
angiographic finding in choroidal
neovascularization associated with macular
degeneration. Arch Ophthalmol 1991;
109:211–215.
54. Cantrill HL, Ramsay RC, Knobloch WH:
Rips in the pigment epithelium. Arch
SECTION 10
Ophthalmol 1983; 101:1074–1079.
55. Decker WL, Sanborn GE, Ridley M, et al:
Retinal pigment epithelial tears.
Ophthalmology 1983; 90:507–512.
56. Gass JDM: Pathogenesis of tears of the
retinal pigment epithelium. Br J Ophthalmol
1984; 68:514–519.
57. Green SN, Yarian D: Acute tear of the
retinal pigment epithelium. Retina 1983;
3:16–20.
58. Hoskin A, Bird AC, Sehow K: Tears of
detached retinal pigment epithelium. Br J
Ophthalmol 1981; 65:417–422.
59. Yeo JH, Marcus S, Murphy RP: Retinal
pigment epithelial tears: patterns and
prognosis. Ophthalmology 1988; 95:8–13.
60. Bressler NM, Finkelstein D, Sunness JS, et al:
Retinal pigment epithelial tears through the
fovea with preservation of good visual acuity.
Arch Ophthalmol 1990; 108:1694–1697.
61. Marmor MF: Mechanisms of normal retinal
adhesion. In: Ryan SJ, ed. Retina. St.
Louis: CV Mosby; 1989:76.
62. Tani PM, Buettner H, Robertson DM:
Massive vitreous hemorrhage and senile
macular choroidal degeneration. Am J
Ophthalmol 1980; 90:525–533.
63. Kreiger AE, Sterling JH: Vitreous
hemorrhage in senile macular
degeneration. Retina 1983; 3:318–321.
64. Caswell AG, Kohen D, Bird AC: Retinal
pigment epithelial detachments in the
elderly: Classification and outcome. Br J
Ophthalmol 1985; 69:397–403.
65. Bird AC, Marshall J: Retinal pigment
epithelial detachments in the elderly. Trans
Ophthalmol Soc UK 1986; 105:674–682.
66. Elman MJ, Fine SL, Murphy RP, et al: The
natural history of serous retinal pigment
epithelium detachments in patients with
age-related macular degeneration.
Ophthalmology 1986; 93:224–230.
67. Gass JDM: Serous retinal pigment epithelial
detachment with a notch. A sign of occult
choroidal neovascularization. Retina 1984;
4:205–220.
68. Poliner LS, Olk RJ, Burgess D, Gordon ME:
Natural history of retinal pigment epithelial
detachments in age-related macular
degeneration. Ophthalmology 1986;
93:543–550.
69. Teeters VW, Bird AC: The development of
neovascularization in senile disciform
macular degeneration. Am J Ophthalmol
1973; 76:1–18.
70. Singerman L: Laser photocoagulation for
1950 choroidal new vessel membrane
complicating age-related macular
degeneration associated with pigment
epithelial detachments. Retina 1988;
8:115–121.
71. Melsop KA, Boothroyd DB, Hlatky MA:
Quality of life and time trade-off utility
measures in patients with coronary artery
disease. Am Heart J 2003; 145:36–41.
72. Slakter JS, Stur M: Quality of life in patients
with age-related macular degeneration:
impact of the condition and benefits of
treatment. Surv Ophthalmol 2005;
50:263–273.
73. Sharma S, Oliver-Fernandez A: Age-related
macular degeneration and quality of life:
how to interpret a research paper in health-
related quality of life. Curr Opin Ophthalmol
2004; 15:227–231.
74. Brown GC, Brown MM, Sharma S:
Difference between ophthalmologists’ and
patients’ perceptions of quality of life
associated with age-related macular
degeneration. Can J Ophthalmol 2000;
35:127–133.
75. Bass EB, Marsh MJ, Mangione CM, et al:
Submacular Surgery Trials Research Group.
Patients’ perceptions of the value of
current vision: assessment of preference
values among patients with subfoveal
choroidal neovascularization – The
submacular surgery trials vision preference
value scale: SST report no. 6. Arch
Ophthalmol 2004; 122:1856–67.
76. Brown MM, Brown GC, Sharma S, et al:
Utility values associated with blindness in
an adult population. Br J Ophthalmol 2001;
85:327–331.
77. Stein JD, Brown GC, Brown MM, et al: The
quality of life of patients with hypertension.
J Clin Hypertens 2002; 4:181–188.
78. Mangione CM, Lee PP, Pitts J, et al:
Psychometric properties of the National
Eye Institute Visual Function Questionnaire
(NEI-VFQ). NEI-VFQ Field Test
Investigators. Arch Ophthalmol 1998;
116:1496–1504.
79. Dong LM, Childs AL, Mangione CM, et al:
Submacular Surgery Trials Research Group.
Health- and vision-related quality of life
among patients with choroidal
neovascularization secondary to age-
related macular degeneration at enrollment
in randomized trials of submacular surgery:
SST report no. 4. Am J Ophthalmol 2004;
138:91–108.
80. Cahill MT, Banks AD, Stinnett SS, Toth CA:
Vision-related quality of life in patients with
bilateral severe age-related macular
degeneration. Ophthalmology 2005;
112:152–158.
81. Mangione CM, Gutierrez PR, Lowe G, et al:
Influence of age-related maculopathy on
visual functioning and health-related quality
of life. Am J Ophthalmol 1999; 128:45–53.
82. Stevenson MR, Hart PM, Montgomery AM,
et al: Reduced vision in older adults with age
related macular degeneration interferes with
ability to care for self and impairs role as
carer. Br J Ophthalmol 2004; 88:1125–1130.
83. Peli E, Goldstein RB, Young GM, et al:
Image enhancement for the visually
impaired. Simulations and experimental
results. Invest Ophthalmol Vis Sci 1991;
32:2337–2350.
84. Rovner BW, Ganguli M: Depression and
disability associated with impaired vision:
the MoVies Project. J Am Geriatr Soc 1998;
46:617–619.
85. Krummenauer F, Braun M, Dick HB: Clinical
outcome and subjective quality of life after
photodynamic therapy in patients with age-
related macular degeneration. Eur J
Ophthalmol 2005; 15:74–80.
86. Coscas G, Soubrane G: Photocoagulation
des neovaisseaux sous-retiniens dans la
degenerescence maculaire senile par laser
a argon. Resultats de l’etude randomisee
de 60 cas. Bull Mem Soc Fr Ophthalmol
1982; 94:149–154.
87. Moorfields Macular Study Group:
Treatment of senile disciform macular
degeneration: A single-blind randomized
trial by argon laser photocoagulation. Br J
Ophthalmol 1982; 66:745–753.
88. Macular Photocoagulation Study Group:
Argon laser photocoagulation for senile
macular degeneration: results of a
randomized clinical trial. Arch Ophthalmol
1982; 100:912–918.
89. Macular Photocoagulation Study Group:
Krypton laser photocoagulation for
neovascular lesions of age-related macular
degeneration. Results of a randomized
clinical trial. Arch Ophthalmol 1990;
108:816–824.
90. Macular Photocoagulation Study Group:
Laser photocoagulation for juxtafoveal
choroidal neovascularization. Five-year
results from randomized clinical trials. Arch
Ophthalmol 1994; 112:500–509.
91. Macular Photocoagulation Study Group:
Occult choroidal neovascularization:
Influence on visual outcome in patients
with age-related macular degeneration.
Arch Ophthalmol 1996; 114:400–412.
92. Macular Photocoagulation Study Group:
Argon laser photocoagulation for
neovascular maculopathy after five years.
Results from randomized clinical trials.
Arch Ophthalmol 1991; 109:1109–1114.
93. Macular Photocoagulation Study Group:
Persistent and recurrent neovascularization
after krypton laser photocoagulation for
neovascular lesions of age-related macular
degeneration. Arch Ophthalmol 1990;
108:825–831.
94. Macular Photocoagulation Study Group:
Persistent and recurrent neovascularization
after krypton laser photocoagulation for
neovascular lesions of ocular
histoplasmosis. Arch Ophthalmol 1989;
107:344–352.
95. Macular Photocoagulation Study Group:
The influence of treatment coverage on the
visual acuity of eyes treated with krypton
laser for juxtafoveal choroidal
neovascularization. Arch Ophthalmol 1995;
113:190–194.
96. Smiddy WE, Fine SL, Quigley HA, et al:
Comparison of krypton and argon laser
photocoagulation in simulated clinical
treatment of primate retina. Arch
Ophthalmol 1984; 102:1086–1092.
97. Han DP, Folk JC: Internal limiting membrane
wrinkling after argon and krypton laser
photocoagulation of choroidal
neovascularization. Retina 1986; 6:215–219.
98. Goldberg MF, Herbst RW: Acute
complications of argon laser
photocoagulation. Arch Ophthalmol 1973;
89:311–318.
99. Macular Photocoagulation Study Group:
Argon laser photocoagulation for ocular
histoplasmosis. Results of a randomized
clinical trial. Arch Ophthalmol 1983;
101:1347–1357.

100. Macular Photocoagulation Study Group:
Laser photocoagulation for neovascular
lesions nasal to the fovea associated with
ocular histoplasmosis or idiopathic causes.
Arch Ophthalmol 1995; 113:56–61.
101. Macular Photocoagulation Study Group:
Visual outcome after laser
photocoagulation for subfoveal choroidal
neovascularization secondary to age-
related macular degeneration: The
influence of initial lesion size and initial
visual acuity. Arch Ophthalmol 1994;
112:480–488.
102. Jampol LM: Hypertension and visual
outcome in the Macular Photocoagulation
Study. Arch Ophthalmol 1991;
109:789–790.
103. Bressler NM, Bressler SB: Indocyanine
green angiography: can it help preserve the
vision of our patients? Arch Ophthalmol
1996; 114:747–749.
104. Maguire JI, Benson WE, Brown GC:
Treatment of foveal pigment epithelial
detachments with contiguous extrafoveal
choroidal neovascular membranes. Am J
Ophthalmol 1990; 109:523–529.
105. Bressler NM, Bressler SB: Laser treatment in
macular degeneration and histoplasmosis.
Ophthalmol Clin North Am 1989; 4:565–581.
106. Chamberlin JA, Bressler NM, Bressler SB,
et al: The use of fundus photographs and
fluorescein angiograms in the identification
and treatment of choroidal
neovascularization in the Macular
Photocoagulation Study. Ophthalmology
1989; 96:1526–1534.
107. Schachat AP, Chambers WA, Liesegang TJ,
Albert DA: Safe and effective.
Ophthalmology 2003; 110:2073–4.
108. Rosenfeld PJ, Moshfeghi AA, Puliafito CA:
Optical coherence tomography findings
after an intravitreal injection of
bevacizumab (Avastin) for neovascular age-
related macular degeneration. Ophthalmic
Surg Lasers Imaging 2005; 36:331–335.
109. Shahar J, Avery RL, Heilweil G, et al:
Electrophysiologic and retinal penetration
studies following intravitreal injection of
bevacizumab (Avastin). Retina 2006;
26:262–269.
110. Avery RL, Pieramici DJ, Rabena MD, et al:
Intravitreal bevacizumab (Avastin) for
neovascular age-related macular
degeneration. Ophthalmology 2006;
113:363–372.
111. Eyetech Pharmaceuticals Inc: Briefing
Document for the Dermatologic and
Ophthalmic Drugs Advisory Committee.
Pegaptanib sodium injetion in the treatment
of neovascular age-related macular
degeneration. NDA 21.756, Aug 27, 2004.
Available: http://www.fda.gov/ohrms/
dockets/ac/04/briefing/2004–4053B1_01_E
yetech-Briefing-Doc.pdf May 9, 2006.
112. Gonzales CR: VEGF Inhibition Study in
Ocular Neovascularization (VISION) Clinical
Trial Group. Enhanced efficacy associated
with early treatment of neovascular age-
related macular degeneration with
pegaptanib sodium: an exploratory
analysis. Retina 2005; 25:815–827.
113. Rosenfeld PJ, Schwartz SD, Blumenkranz
MS, et al: Maximum tolerated dose of a
humanized anti-vascular endothelial growth
factor antibody fragment for treating
neovascular age-related macular
degeneration. Ophthalmology 2005;
112:1048–1053.
Age-Related Macular Degeneration: Choroidal Neovascularization
114. Eyetech Study Group: Anti-vascular
endothelial growth factor therapy for
subfoveal choroidal neovascularization
secondary to age-related macular
degeneration: phase II study results.
Ophthalmology 2003; 110:979–986.
115. Kabbinavar F, Hurwitz H, Fehrenbacher L,
et al: Phase II, randomized trial comparing
bevacizumab plus fluorouracil
(FU)/leucovorin (LV) with FU/LV alone in
patients with metastatic colorectal cancer.
J Clin Oncol 2003; 21:60–65.
116. Trobe JD, Kraft R, Krischer JP: Doctor:
patient communication in ophthalmic
outpatient visits. Ophthalmology 1983;
90:51a-55a.
117. Taub SJ: The Internet’s role in
patient/physician interaction: bringing our
understanding in line with online reality.
Compr Ophthalmol Update. 2006; 7:25–30.
118. Genentech: Press release. Preliminary
phase III data from head-to-head study of
lucentis shows lucentis improved vision
compared to visudyne in patients with wet
age-related macular degeneration. Jan 14,
2006. Available:
http://www.gene.com/gene/news/press-
releases/display.do?method=detail&id=930
7 Jul 25, 2006.
119. Hewson MG, Kindy PJ, Van Kirk J, et al:
Strategies for managing uncertainty and
complexity. J Gen Intern Med 1996;
11:481–485.
120. Rosenfeld PJ, Heier JS, Hantsbarger G,
Shams N: Tolerability and efficacy of
multiple escalating doses of ranibizumab
(Lucentis) for neovascular age-related
macular degeneration. Ophthalmology
2006; 113:632.e1.
121. Charters L: Intravitreal anti-VEGF drugs are
step forward in AMD management.
Ophthalmology Times. Dec 15, 2005.
Available: http://www.agingeye.net/
mainnews/lucentis.php Jul 21, 2006.
122. American College of Physicians: Primer on
95% CIs for the number needed to treat.
Eff Clin Pract 1999. Available:
www.acponline.org/journals/ecp/mayjun99/
primer.pdf Jul 21, 2006.
123. Ebrahimzadeh H, Davalos R, Lee PP:
Literacy levels of ophthalmic patient
education materials. Surv Ophthalmol
1997; 42:152–156.
124. Morris NS, MacLean CD, Chew LD,
Littenberg B: The Single Item Literacy
Screener: evaluation of a brief instrument
to identify limited reading ability. BMC Fam
Pract 2006; 24;7:21.
125. Spaide RF, Laud K, Fine HF, et al:
Intravitreal bevacizumab treatment of
choroidal neovascularization secondary to
age-related macular degeneration. Retina
2006; 26:383–390.
126. Press release. PIER year 1 clinical trial
results. Available:
http://www.medicalnewstoday.com/medical
news.php?newsid=44460 Nov 7, 2006.
127. Edwards MG, Schachat AP, Bressler SB,
Bressler NM: Outcome of cataract
operations performed to permit diagnosis,
to determine eligibility for laser therapy, or
toperform laser therapy of retinal disorders.
Am J Ophthalmol 1994; 118:440–444.
128. Kwiterovich KA, Maguire MG, Murphy RP,
et al: Frequency of adverse systemic
reactions after fluorescein angiography.
Results of a prospective study.
Ophthalmology 1991; 98:1139–1142.
129. Press release. NEI Statement: NIH
Stimulates the development and testing of
new therapies for advanced AMD.
Available:
www.nei.nih.gov/news/statements/amd_the
rapy.asp Nov 7, 2006.
130. Bennett SR, Folk JC, Blodi CF, Klugman M:
Factors prognostic of visual outcome in
patients with subretinal hemorrhage. Am J
Ophthalmol 1990; 109:33–37.
131. Berrocal MH, Lewis ML, Flynn HW Jr:
Variations in the clinical course of
submacular hemorrhage. Am J Ophthalmol
1996; 122:486–493.
132. Vander JF, Federman JL, Greven C, et al.
Surgical removal of massive subretinal
hemorrhage associated with age-related
macular degeneration. Ophthalmology
1991; 98:23–27.
133. Lewis H: Intraoperative fibrinolysis of
CHAPTER 146
submacular hemorrhage with tissue
plasminogen activator and surgical
drainage. Am J Ophthalmol 1994;
118:559–568.
134. Macular Photocoagulation Study Group:
Five-year follow-up of fellow eyes of
individuals with ocular histoplasmosis and
unilateral extrafoveal or juxtafoveal
choroidal neovascularization. Arch
Ophthalmol 1996; 114:677–688.
135. Bressler NM, Bressler SB: Preventative
ophthalmology: Age-related macular
degeneration. Ophthalmology 1995;
102:1206–1211.
136. Bressler NM, Maguire MG, Murphy PL,
et al: Macular scatter (‘grid’) laser treatment
of poorly demarcated subfoveal choroidal
neovascularization in age-related macular
degeneration: results of a randomized pilot
trial. Arch Ophthalmol 1996;
114:1456–1464.
137. Bressler NM: Submacular surgery: Are
randomized trials necessary? Arch
Ophthalmol 1995; 113:1557–1560.
138. Slakter JS, Yannuzzi LA, Sorenson JA, et
al: A pilot study of indocyanine green
videoangiography-guided laser
photocoagulation of occult choroidal
neovascularization in age-related macular
degeneration. Arch Ophthalmol 1994;
112:465–472.
139. Guyer DR, Yannuzzi LA, Ladas I, et al:
Indocyanine green-guided laser
photocoagulation of focal spots at the edge
of plaques of choroidal neovascularization.
Arch Ophthalmol 1996; 114:693–697.
140. Hart PM, Chakravarthy U, Mackenzie G,
Archer DB: Telepathy for subfoveal
choroidal neovascularization of age-related
macular degeneration: Results of follow up
in a non-randomised study. Br J
Ophthalmol 1996; 80:1046–1050.
141. Gragoudas ES, Schmidt-Erfurth U,
Sickenberg M, et al: Results and
preliminary dosimetry of photodynamic
therapy for choroidal neovascularization in
age-related macular degeneration in a
phase I/II study. Invest Ophthalmol Vis Sci
1997; 38–4:S17.
142. Schmidt-Erfurth U, Miller JW, Sickenberg
M, et al: Photodynamic therapy for
choroidal neovascularization in a phase I/II
study. Preliminary results of multiple
treatments. Invest Ophthalmol Vis Sci
1997; 38–4:S17.
1951
 CHAPTER
147 Photodynamic Therapy
Deeba Husain, Evangelos S. Gragoudas, and Joan W. Miller
INTRODUCTION
Photodynamic therapy (PDT) involves the use of photo-
activatable compounds (photosensitizers) which accumulate in,
and are retained by, proliferating tissues. When these molecules
are activated by light at the appropriate wavelength, active
forms of oxygen and free radicals are generated, which result in
photochemical damage to cells in which the photosensitizer is
present. Thus PDT can be used to treat diseased areas
selectively while sparing the normal tissue. PDT has been
extensively studied in the treatment of neoplasia and more
recently for neovascularization. At this time in ophthalmology,
it is approved by the US FDA and other agencies for the
treatment of subfoveal choroidal neovascularization, and has
been used for management of other ocular neovascularization.
HISTORICAL BACKGROUND
The earliest report on the action of light-activated chemicals on
biological systems was published in 1900 by Raab, who
described the lethal effect of light on paramecium treated with
acridine dye.1 von Tappeiner in 1904 demonstrated oxygen
dependence of this photosensitization reaction and coined
the term ‘photodynamic action’.2 Meyer-Betz demonstrated
photosensitizing properties of hematoporphyrin derivative
(HPD) in 1913.3 In 1942, Aueler and Banzer for the first time
used HPD for photodynamic destruction of tumors in animals.4
Lipson and colleagues in 1961 reported on the use of HPD for
fluorescence detection of neoplastic tissue, and subsequent
treatment in patients with breast cancer.5
In 1978, Dougherty et al reported the first large series of
patients with cutaneous malignancies that exhibited partial or
complete response to photoradiation therapy using HPD and
light.6 The active components of HPD were identified to be
dihematoporphyrin ethers and esters (DHE), and the com-
mercial preparation of DHE is known as porfimer sodium or
Photofrin (PF).7 PDT with benzoporphyrin derivative (BPD) has
shown beneficial effect in preliminary trials in the treatment of
many diseases such as basal cell carcinoma, metastatic skin
lesions, and the elimination of leukemia progenitor cells in the
marrow of patients with chronic myelogenous leukemia.8 PDT
has been used for nononcological conditions outside the eye
including psoriasis, atherosclerotic plaque and restenosis, bone
marrow purging for the treatment of leukemias with autologous
bone marrow transplant, inactivation of viruses in blood or
blood products, and several autoimmune conditions including
rheumatoid arthritis.9 PDT with BPD (Verteporfin) for choroidal
neovascularization (CNV) secondary to macular degeneration
was approved by US FDA in 2000, and since then it is approved
and being used all over the world for this indication.
MECHANISM OF ACTION
PDT requires the administration, usually intravenous, of a
photosensitizer dye that accumulates in neoplastic and
neovascular tissues. The targeted tissue is then irradiated using
light of a wavelength at an absorption peak of the dye. A
photochemical reaction10 is initiated with the absorption of
light by the photosensitizer molecule in the ground state (S),
which is excited to enter a higher-energy triplet state (3S). The
triplet state molecules are short-lived reactive species that
transfer their energy via two pathways that can cause
cytotoxicity leading to physiological responses such as necrosis
and/or apoptosis. Energy can be transferred from the triplet
state photosensitizer to molecular oxygen converting it to
singlet oxygen (1O2), while returning to their ground state
(type II reaction).11 The triplet state molecules may also directly
transfer energy through a free radical mechanism to form
cytotoxic intermediates (type I reaction) (Fig. 147.1). The type
II mediated pathway accounts for the majority of tissue
destruction and is responsible for the oxygen dependence of
PDT. The extent of oxygen dependence varies somewhat among
photosensitizers; under anoxic conditions PDT effects are
abolished for Photofrin.12
PDT offers some degree of selectivity in the destruction of
tumor and neovascular tissue, with minimal local and systemic
side effects. This is due to two factors: a preferential localization
of the photosensitizer in these tissues and precise laser light
irradiation of the targeted tissue.13 The mechanism of accumu-
lation of the photosensitizer in the neovascular and neoplastic
tissue is not known, but several theories have been proposed.
Photosensitizers are taken up by most tissues of the body, but
are retained longer in neoplastic tissue, as well as in normal
liver, spleen, kidney, and wound healing tissue. Henderson et al
have suggested that pooling and retention of photosensitizers in
tumors could occur due to a larger interstitial space and poor
lymphatic network.14 The cells with high mitotic activity such
as tumor and neovascular endothelial cells were found to have
FIGURE 147.1. Schematic representation of photodynamic action.
Photons are absorbed by photosensitizer molecules in ground state (S).
This causes them to enter in a higher-energy excited triplet state (3S).
The short-lived reactive triplet state photosensitizer molecule leads to
transfer of energy causing the formation of singlet oxygen and free
radicals that cause cytotoxicity. 1953
 RETINA AND VITREOUS
TABLE 147.1. Photosensitizers in Ophthalmology
Xanthene Derivative
Rose bengal
Tetrapyrrole Derivatives
Hematoporphyrin derivative
Photofrin (dihematoporphyrin ether)
Benzoporphyrin derivative
Chlorins and Bacteriochlorins
Mono-aspartyl chlorin e6
Bacteriochlorin a
Tin etiopurpurin
ATX-S10
SECTION 10
Phthalocyanines
Chloroaluminum sulfonated phthalocyanine
Zinc phthalocyanine
a high expression of low-density lipoprotein (LDL) receptors
(e.g., the apo B/E receptor),15 which might result in more
efficient uptake of LDL-bound molecules by receptor-mediated
endocytosis.16 Therefore various methods to enhance the LDL-
mediated mechanism have been investigated, including for-
mulation of photosensitizer in liposomes, lipid-based
emulsions, as well as preincorporation with LDL. Other
techniques used are delivery with biodegradable nanospheres,
attaching photosensitizers covalently to polymers, and using
inclusion complexes such as cyclodextrins. Selective local-
ization of photosensitizers in tumors has also been improved by
binding the dye to targeting molecules such as peptides or
monoclonal antibodies (Mab) that recognize specific antigens
on tumor cells.17 Targeted PDT is a new modality to improve
the efficacy of PDT; here photosensitizer is bound to the
targeting peptide which in turn binds to VEGF receptors on
the neovascularization thus resulting in efficient localization of
the photosensitizer.18
The mechanisms of PDT-mediated tissue destruction
include cellular, vascular, and immunological damage. Direct
cellular destruction is due to the damage of cellular membranes
through lipid peroxidation and protein damage, by singlet
oxygen and free radical intermediates,7 leading to structural and
functional damage to cellular membranes. Apoptosis of the cells
has also been reported by a biomolecular cascade induced by
PDT-related damage to mitochondrion, lysosomes, and nuclear
components.19 Vascular damage is an important mechanism of
tissue destruction in PDT with certain photosensitizers, and
probably occurs secondary to endothelial damage and
subsequent platelet aggregation, and vessel thrombosis.
Eiconasoids are released following PDT including
thromboxane, histamine, and tumor necrosis factor-a and may
contribute to vascular occlusion.20 Finally, immunomodulation
may play a role in PDT-induced tissue destruction. Treatment
of various tumors with PDT has demonstrated increased tissue
levels of cytokines,21 enhanced killing activity of specific
cytotoxic T-lymphocytes,22 increased natural killer cell
activity,23 and tumor-associated macrophage accumulation in
tissue24 with TNF-a release, and macrophage- mediated
cytotoxicity. Immunomodulation following PDT is being inves-
tigated for application in organ transplantation and the
1954 treatment of autoimmune diseases.
FIGURE 147.2. Absorption spectra of selected photosensitizers that
have been used in PDT. PF, Photofrin; BPD-MA, benzoporphyrin
derivative monoacid; Ce6, Chlorin 6; CASPc, chloroaluminum
sulfonated phthalocyanine.
From Lui H. Anderson RR: Photodynamic therapy in dermatology: Recent
developments. Dermatologic Clinics 1993; 11:1–13.
CLINICALLY APPROVED
PHOTOSENSITIZERS
The effective penetration depth of the PDT treatment is dependent
on the wavelength of the light and optical properties such as
absorption and scatter of the targeted tissue. Typically, the effective
penetration depth is 2–3 mm at 630 nm and increases to 5–6 mm
at longer wavelengths (700–800 nm).25 These values can be altered
by changing the biological and physical characteristics of the
photosensitizer (Table 147.1). In general, photosensitizers with
longer wavelengths and higher molar absorption at these wave-
lengths are more efficient photodynamic agents (Fig. 147.2).10
Most clinical experience comes from the porphyrin family
of photosensitizers, including hematoporphyrin derivative
(HPD) and dihematoporphyrin ether (DHE). DHE is a complex
mixture of oligomeric esters and ethers of HPD, with inherent
variability (Fig. 147.3 ).26 The commercial preparation of DHE,
called Photofrin (Fig. 147.3a), has been used in clinical trials for
bladder, lung, stomach, and cervix cancer. The main problems
with Photofrin were prolonged skin photosensitivity and
relatively low absorption in the wavelength region of
therapeutic interest (600–1100 nm).10 This has provided an
incentive to develop second-generation photosensitizers.
The clinically tested second-generation photosensitizers
include Verteporfin (BPD-MA) (Fig. 147.3b), mono-L-aspartyl
chlorin e6 (NPe6) (Fig. 147.3c), Hypericin, protoporphyrin IX,
Foscan (mTHPC) (Fig. 147.3d), Purlytin (SnET2) (Fig. 147.3e),
5-amino-levulinic acid, ALA (Fig. 147.3f), and Lu-Tex. BPD, a
second-generation photosensitizer, is formally a chlorin, since it
has a reduced pyrrole ring as well as a fused six-membered iso-
cyclic ring (Fig. 147.3b).27 BPD has absorption maxima at 354,
418, 574, 626, and 688 nm; this allows deeper tissue penetra-
tion and effective treatment. BPD has a rapid rate of clearance,
with no significant photosensitivity after 24 h, and is meta-
bolized to inactive forms prior to excretion through the feces.28
PDT OF CHOROIDAL
NEOVASCULARIZATION
PDT is a potentially selective treatment modality for
neovascularization. It offers a treatment for CNV, where the

d
b
e
neovascularization can be occluded and the overlying neuro-
sensory retina is spared avoiding the sudden decrease of vision
seen as a complication of thermal photocoagulation of subfoveal
CNV. Several investigators have studied the efficacy of various
photosensitizers for PDT of experimental CNV.
Experimental CNV was created in a monkey model by
inducing argon laser injury to the macula, which leads to devel-
opment of CNV in 2–4 weeks (Fig. 147.4a–c).29 Thomas and
Langhofer30 in 1987 demonstrated successful thrombosis of
experimental CNV without occlusion of the choriocapillaris, in
the monkey model using DHE. Kliman et al31 studied PDT of
experimental CNV using chloroaluminum sulfonated
phthalocyanine (CASPc). These preliminary studies suggest
that closure of experimental CNV can be accomplished over a
wide range of treatment parameters, but the selectivity of effect,
and the damage to retinal structures and human safety was
not investigated. Miller and Miller32 studied the efficacy of
rose bengal, a xanthene derivative to treat experimental CNV. It
was found that PDT with rose bengal led to disruption of CNV
but did not destroy the new vessels completely, and the required
Photodynamic Therapy
FIGURE 147.3. Chemical structures of
(a) dihematoporphyrin ether, DHE;
(b) benzoporphyrin derivative monoacid,
BPD-MA; (c) mono-aspartyl chlorin e6, NP e6;
(d) meta-tetra (hydroxyphenyl) chlorin, mTHPC;
(e) tin etiopurpurin, SnET2; (f) 5-amino-levulinic
acid, ALA.
CHAPTER 147
dye dose was 27 times higher than the dose which has been
demonstrated to be safe clinically.
Preliminary work has been carried out with tin etiopurpurins
(SnET2).33 The treatment parameters include a dye dose of
1mg/kg with a light of 665 nm, an irradiance of 600 mW/cm2 and
fluence of 35–70 J/cm2. A spot size of 1200 mm was used and light
exposure lasted 60–120 s. It has been shown to be effective in
closure of experimental CNV. Clinical trials were conducted to
study the role of SnET2 (Purlytin) in the treatment of wet age
related macular degeneration (AMD). The pooled data at 2 years
showed that 58% of SnET2-treated patients lost 15 letters or less
compared to 42% of placebo patients. This effect was only seen in
lesions smaller than 3 mm and with better visual acuity (46–67
letters).34 The systemic photosensitivity lasted 4 weeks. The
drug failed to reach its efficacy end point in Phase III studies
and at this time is not used in the treatment of AMD.
Lu-Tex or lutetium texaphyrin is a water-soluble photo-
sensitizer that has an absorption peak of 732 nm. It has been
shown to localize in choroidal neovascularization in the
monkey eye. PDT using 1–2 mg/kg body weight of Lu-Tex, and 1955
 RETINA AND VITREOUS
a b
FIGURE 147.4 (a). Fundus photograph showing elevated yellow-gray areas (arrows) of choroidal neovascularization in the experimental model of
choroidal neovascularization in the monkey eye. (b) Early phase fluorescein angiogram of the eye in (a) showing the typical lacy pattern of
hyperfluorescence in areas of experimental CNV (arrow). (c) Late phase angiogram of the eye in (b) showing increasing hyperfluorescence and
fluorescein leakage by the CNV (arrows).
(a–c) From Husain D, Miller JW, Michaud N, et al: Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimental choroidal
neovascularization. Arch Ophthalmol 1996; 114:978–985.
SECTION 10
a light dose of 50–100 J/cm2 has been shown to cause closure of
CNV in the monkey eye.35 Phase I and II clinical trials with
Lu-Tex showed that the drug was effective in causing CNV
occlusion, but the drug caused peripheral parasthesias in a
significant number of patients and therefore the clinical trials
were halted.
Normal choroidal vasculature has been occluded using newer
photosensitizers and it has been extrapolated that these dyes
can potentially be used to treat CNV. Mori et al36 have
demonstrated effective and selective occlusion of choroidal
vessels in Japanese monkey eyes using 2–10 mg/kg of mono-l-
aspartyl chlorin e6 (NP e6) and 664 nm light (0.4–7.5 J/cm2).
Obana et al37 performed PDT on the retina and choroid of
monkeys using ATX-S10, a new chlorin derivative (dose of
8–12 mg/kg) using a light of 670 nm (3.5 J/cm2), 30–74 min
after the dye injection. Histopathology of these eyes demon-
strated photothrombosis of choriocapillaris and choroidal
vessels with no obvious damage to the neurosensory retina.
VERTEPORFIN PDT FOR CHOROIDAL
NEOVASCULARIZATION
Preclinical Studies
Work in our laboratory has used a tetrapyrrol derivative
benzoporphyrin derivative monoacid (BPD, Verteporfin, Visudyne).
This photosensitizer has a long absorption wavelength at
690 nm,38 therefore allowing deeper tissue penetration for effective
treatment, through blood, fluid, and fibrosis that is important in
the treatment of CNV. When injected intravenously, BPD has a
serum half-life of 30 min. The high-est tissue levels are reached in
3 h, declining rapidly and cleared in the first 24 h, therefore
reducing the risk of the systemic photosensitivity.39 It has been
found to be safe for human use, and was first studied in clinical
trials in dermatology for malignant skin tumors.40
Initial studies in experimental CNV were done using a lipo-
protein-associated preparation of BPD at doses of 1–2 mg/kg
and light of 692 nm generated from an argon/dye laser that
was delivered via a slit-lamp delivery system with a spot
size of 1250 mm. Effective vascular occlusion was seen
when irradiation was performed 1–80 min after the dye injec-
tion, with a fluence of 50–150 J/cm2 and irradiance of
150–600 mW/cm2.41 No thermal damage was seen at
irradiances as high as 1800 mW/cm2.42
Further refinement of dosimetry was carried out using the
liposomal preparation of BPD.43 The mechanism of photo-
sensitizer uptake by the neovascular tissue is not known, but it
1956 has been observed that neovascular and neoplastic tissue have
c
high density of lipoprotein receptors which may enhance
preferential uptake of the photosensitizer.44 BPD fundus
angiography has also demonstrated that liposomal BPD
accumulates in CNV.45 Dye doses of 0.25–1 mg/kg of liposomal
BPD were studied and a minimal dose of 0.375 mg/kg caused
effective closure of CNV. The optimal time for irradiation
appeared to be 20–50 min after a bolus intravenous injection
of dye with a spot size of 1250 mm at an irradiance of
600 mW/cm2 and a fluence of 150 J/cm2.43
Since damage to normal retina and choroidal structures was
difficult to assess in the experimental CNV model, selectivity
of PDT was assessed in normal retina and choroid using the
same parameters as for CNV.43 Fluorescein angiography demon-
strated early hypofluorescence in the treated areas followed by
hyperfluorescence starting at the periphery of the lesion in the
later frames of the angiogram. A grading system for assessing
damage to retina and choroid was devised. Damage to RPE and
choriocapillaris was seen in all irradiated eyes, and the grading
scheme was based on the damage to the neurosensory retina
and medium to large choroidal vessels. Some damage to the
photoreceptors was noted throughout all grades, typically mild
vacuolization and disorientation of the inner and outer
segments of the photoreceptors. When PDT was performed
with liposomal BPD doses of 0.25, 0.375, or 0.5 mg/kg, at
20–50 min after dye injection, the retinal structure was well
preserved and PDT was sufficiently selective.
Dosimetry experiments were done using a bolus intravenous
injection of liposomal BPD-MA, but liposomal drugs are typically
used clinically as an intravenous infusion, and clinical trials in
dermatology using liposomal BPD administered the dye by infu-
sion with success. Further studies were undertaken and designed to
evaluate the efficacy and parameters for PDT of experimental CNV
using an intravenous infusion of liposomal BPD.46 Infusion
(10 min) was tested and effective closure was achieved when
irradiation was performed 20–30 min from the start of infusion
using a light of spot size of 1250–3000 mm of 689 nm light at
600 mW/cm2 and 150 J/cm2. Closure of experimental CNV could
be seen by fluorescein angiography (Fig. 147.5a–c) and was con-
firmed by histopathology. Light microscopy showed occluded vessels
in the area of CNV, closure of the underlying choriocapillaris, and
the overlying retina was essentially normal. Electron microscopy of
the vessels in the CNV showed occlusion of the lumen with red
blood cells, white blood cells, and platelets, with damaged
endothelial cells showing swelling and vacuolation of the
cytoplasm, with breaks in the nuclear membrane (Table 147.2).46
Selectivity of PDT using liposomal BPD was studied by
performing light irradiation of normal monkey retina and
 Photodynamic Therapy

a b c

FIGURE 147.5. (a) Fundus photograph 24 hours after PDT with irradiation performed at the end of slow dye infusion to the foveal choroidal
neovascularization (arrow) and at the end of flush infusion to the choroidal neovascularization temporal to the fovea (arrowhead), showing mild
graying of the two treated areas. (b) Early phase fluorescein angiogram 24 h after PDT using liposomal BPD at the end of slow dye infusion
(arrow) and at the end of flush (arrowhead), illustrates hypofluorescence (occlusion of CNV) in both areas with perfusion of the overlying normal
retinal capillaries confirming occlusion of CNV. (c) Late phase angiogram of the eye in Figure 147.4, showing staining at the edge of the

CHAPTER 147
irradiated area. This most likely represents leakage from perfused choriocapillaris through damaged RPE.
(a–c) From Husain D, Miller JW, Michaud N, et al: Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimental choroidal
neovascularization. Arch Ophthalmol 1996; 114:978–985.

with optimal parameters, with histopathology showing a

TABLE 147.2. Standard Clinical Treatment Parameters for
Visudyne PDT
1. Dye dose = 6 mg/m2 body surface area
2. Intravenous infusion over 10 min
3. Treatment at 15 min after start of dye infusion
4. Laser light wavelength of at 689 nm, irradiance of 600 mW/cm2
and fluence of 100 J/cm2
choroid with the same parameters. Fundus photography was
taken 24 h after PDT and it demonstrated mild graying of the
retina at the treated areas (Fig. 147.6a). Fluorescein angiography
of these areas showed early hypofluorescence (Fig. 147.6b) with
late staining starting from the edges of the lesion (Fig. 147.6c).
Light and electron microscopy of the lesions showed occlusion
of the choriocapillaris and damage to the retinal pigment
epithelium in all cases. Most eyes showed preservation of the
medium and larger choroidal vessels, some disarray and
vacuolation of the outer segments with mild pyknosis in the
outer nuclear layer and normal inner retina.
Studies were carried out to study the long-term effect
(4 weeks follow-up) of BPD on the treated CNV.47 Persistent
closure of CNV was seen in most eyes that had been treated
fibrous scar enclosed by proliferating RPE cells with few
open capillaries. In normal eyes treated with CNV, the
choriocapillaris was re-perfused at 4 weeks. The RPE showed
presence of irregular pigmentation with liposomes, phago-
somes, and melanosomes indicating some recovery of function.
A layer of pigmented macrophages was seen over the RPE.
There was some mild disorganization of the photoreceptors.
The rest of the neurosensory retina appeared to be normal.
Therefore the damage to normal retina and retinal pigment
epithelium caused by PDT at 24 h showed histological recovery
at 4 weeks.
Long-term recurrence or persistence of CNV after PDT
may necessitate repeat treatments, so further studies were
carried out to evaluate the effect of repeat treatments on
normal monkey retina and choroid.48 Three consecutive
treatments were placed in the monkey eye, using different
doses of liposomal BPD doses (6, 12, 18 mg/m2) but constant
light dose (689 nm; 600 mW/cm2; 100 J/cm2). Treatments
were separated by an interval of 2 weeks, with histopathologic
examination at 2 and 6 weeks after the third treatment.
Minimal damage to the retina, choroid, and optic nerve was
present in animals treated at 6 mg/m2. Higher dye doses lead
to significant cumulative damage to the normal retina,
choroid, and optic nerve.

a b c

FIGURE 147.6. (a) Fundus photograph 24 hours after PDT of normal retina and choroid, showing mild graying of the areas irradiated at the end
of dye infusion (small arrow), at the end of flush (long arrow), 10 minutes after end of flush infusion (hollow arrow), and 20 minutes after the end
of flush (arrowhead). (b) Early phase fluorescein angiogram of an eye in (a), taken 24 hours after PDT of the normal retina and choroid, showing
hypofluorescence of the irradiated areas. (c) Late phase angiogram of eye in (b) showing staining of the irradiated area starting from the
periphery of the lesion. This staining is most likely occurring as described in Figure 147.4.
(a–c) From Husain D, Miller JW, Michaud N, et al: Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimental choroidal
neovascularization. Arch Ophthalmol 1996; 114:978–985.
1957
 RETINA AND VITREOUS
Clinical Trials
Phase I/II clinical trials were designed to evaluate safety and
maximum tolerated doses of verteporfin therapy for the
treatment of patients with classic CNV. Sixty-one patients were
reported in a dose escalation protocol.49,50 Dye doses were 6 or
12 mg/m2 of liposomal BPD with light of 689 nm at a fluence of
50–150 J/cm2 and an irradiance of 600 mW/cm2. Eligibility
criterion included classic CNV of less than or equal to nine
macular photocoagulation study (MPS) disc area and refracted
vision of 20/40 or worse. In a report on single treatments, the
results showed that light-activated verteporfin could cause
short-term (1–4 weeks) cessation of fluorescein leakage from
CNV without angiographic damage to retinal blood vessels or
loss of vision.51 At 12 weeks follow-up, leakage occurred in most
cases, defined as extension of the CNV beyond the original
borders. Systemic safety of verteporfin was very good in this
Phase I/II investigation (Table 147.3). Specifically, the most
frequent adverse event of this open label study was headache
SECTION 10
(4.7%). Adverse ocular side effects were noted only at the
highest light doses with a significant loss of vision in three
patients. Side effects attributed to PDT included retinal
arteriolar, venular, and capillary occlusion. Side effects which
could be attributed to the disease process itself or to PDT
included vitreous hemorrhage. The results from the Phase I/II
studies suggested that a potentially effective dose of verteporfin
to be considered for Phase III trials would be 6 mg/m2 body
surface area, which would be infused intravenously over 10 min.
Irradiation with a diode laser at 689 nm was applied 15 min
after the start of the infusion; the light dose delivered was
between 50 and 100 J/cm2 at an intensity of 600 mW/cm2 over
a period of 83 s.
A Phase III clinical trial was initiated in December 1996,
termed as the treatment of age-related macular degeneration
with photodynamic therapy (TAP). This was a randomized,
placebo-controlled, double-masked, multicentric study (19 cen-
ters in North America and Europe) designed to determine the
effect of PDT on vision in patients with subfoveal CNV
secondary to AMD. Eligibility criteria included subfoveal new or
recurrent CNV secondary to AMD with a classic component,
best corrected visual acuity of 20/40 to 20/200, and lesion size
of 5400 mm or less. Patients underwent re-treatment every
3 months if angiographic leakage was apparent on follow-up.
The proportion of eyes with at least moderate vision loss (a
decrease in the letter score of 15 letters or ~3 lines) was greater
in placebo-treated eyes than in verteporfin-treated eyes
throughout the period from examination at month 3 to the
examination at month 12. In subgroup analysis, the visual
acuity benefit of verteporfin therapy was clearly demonstrated
in eyes with classic CNV occupying at least 50% of the area
of the entire lesion (termed ‘predominantly classic’ lesions).
With respect to predominantly classic lesions, 33% of the
verteporfin-treated eyes had at least moderate vision loss at
12 months compared to 60% of the placebo-treated eyes.
Furthermore, at this time, 12% of verteporfin-treated eyes and
33% of placebo-treated eyes had severe vision loss. The results
were even greater for predominantly classic lesions and no
occult CNV; 23% of verteporfin-treated eyes had at least
moderate vision loss at 12 months compared to 73% of placebo-
treated eyes. Ten percent of the verteporfin-treated eyes had
severe vision loss compared to 41% of the placebo-treated eyes.
These results prompted the TAP Study Group to recommend
verteporfin therapy for all predominantly classic lesions that
met the eligibility criteria for the studies. Progression of classic
CNV beyond the area of the lesion identified at baseline
occurred in only 166 (46%) of 361 verteporfin-treated eyes
compared to 133 (71%) of 187 placebo-treated eyes by the
1958 month 12 examination.
TABLE 147.3. The Landmark Clinical Trials of PDT with
Verteporfin for CNV
1. The TAP (treatment of age-related macular degeneration with
photodynamic therapy) trial established the efficacy of PDT
for classic subfoveal neovascularization in AMD at 2 years
follow-up
2. The VIP (Verteporfin in photodynamic therapy) study
concentrated on subfoveal occult-only lesions not included in
the TAP study. After 2 years, treated eyes were less likely to
experience visual loss. Exploratory analyses of TAP and VIP
suggest that lesion size is a more significant predictor of the
treatment benefit than either lesion composition or visual activity
3. The VIM (Visudyne in minimally classic) trial altered the standard
PDT light fluence rate in the treatment of subfoveal minimally
classic lesions. This trial again demonstrated a beneficial effect
for those receiving treatment with PDT
4. Early retreatment (6 weeks) did not improve outcomes in the
Verteporfin in early re-treatment (VER) trial
5. The VIO (Visudyne in occult) trial, evaluating PDT in occult-only
lesions as a confirmatory study of the VIP trial, did not achieve
its primary endpoint at 2 years
Few ocular systemic adverse events judged to be of any
clinical relevance were noted in Phase III of the study.
Compared to placebo patients, verteporfin-treated patients
had more transient vision disturbances (18% vs 12%), injection
site adverse events (13% vs 3%), transient photosensitivity
reactions (3% vs 0%), and infusion-related low back pain (2%
vs 0%). However, most of these events were mild to moderate
and resolved by themselves. In summary, the TAP52 inves-
tigation showed that verteporfin therapy reduced the risk of at
least moderate vision loss compared to placebo for at least
12 months in patients with predominantly classic CNV who
presented with subfoveal lesions. In the TAP investigation, the
visual acuity results were complemented by similar outcomes
for contrast sensitivity evaluations.
The 2-year follow-up report of the TAP investigation
showed53 that the beneficial outcomes with respect to visual
acuity and contrast sensitivity noted at the month 12 exam-
ination in verteporfin-treated patients were sustained through
the month 24 examination. At the month 24 examination for
the primary outcome, 213 (53%) of 402 verteporfin-treated
patients compared to 78 (38%) of 207 placebo-treated patients
lost fewer than 15 letters. In subgroup analyses for predo-
minantly classic lesions at baseline, 94 (59%) of 159 verte-
porfin-treated patients compared to 26 (31%) of 83 placebo-
treated patients lost fewer than 15 letters at the month 24
examination. For minimally classic lesions at baseline, no
statistically significant differences in visual acuity were noted.
Few additional photosensitivity adverse reactions and injection
site adverse events were associated with verteporfin therapy in
the second year of follow-up. Therefore, this study concluded
that the visual acuity benefits of Verteporfin therapy for AMD
patients with predominantly classic CNV subfoveal lesions
are safely sustained for 2 years, providing more compelling
evidence to use Verteporfin therapy for these cases. In TAP
Report No. 5, the 36-month vision and safety results of an
open-label extension of the TAP investigation showed that the
visual outcomes for patients treated with Verteporfin with
predominantly classic lesions at baseline remained stable from
month 24 through month 36, and no additional safety
concerns.54
The role of PDT in the treatment of occult with no classic
subfoveal choroidal neovascularization was studied in 339
patients in a multicentric, placebo-controlled, double-masked

study (Verteporfin in photodynamic therapy or VIP study)
carried over 2 years.55 It showed that there was a significant
reduction in the risk of moderate to severe visual loss. The
study also suggested that greater benefit was seen in patients
with smaller lesion (4 disc area or smaller) and lower levels
of visual acuity (20/50 or less). The evidence for efficacy of PDT
in treating the occult-only subtype has weakened with the
recently completed Visudyne in occult (VIO) trial, in which the
study’s primary visual outcome was not reached at either 1 or
2 years.
A recent clinical trial was designed to compare the treatment
effect and safety of PDT with verteporfin using a standard (SF)
or reduced (RF) light fluence rate with that of placebo therapy in
patients with subfoveal minimally classic choroidal neovas-
cularization (CNV) with AMD (Visudyne in minimally classic
or VIM trial). This was a multicentric, double-masked, placebo-
controlled, randomized clinical trial. Inclusion criteria included
initial best-corrected visual acuity of at least 20/250 and a
lesion size of no greater than six MPS disc areas. One hundred
and seventeen patients were randomly assigned patients (1:1:1)
to verteporfin infusion (6 mg/m2) and light application with an
RF rate (300 mW/cm2) for 83 s (light dose of 25 J/cm2) or an SF
rate (600 mW/cm2) for 83 s (light dose of 50 J/cm2) or to placebo
infusion with RF or SF. Treatment was repeated every 3 months
if the treating physician noted fluorescein leakage from CNV on
angiography. At month 12, a loss of at least 3 lines of visual
acuity occurred in 5 (14%) of 36 eyes assigned to RF and 10
(28%) of 36 eyes assigned to SF, compared with 18 (47%) of 38
eyes assigned to placebo. At month 24, this loss occurred in 9
(26%) of 34 eyes assigned to RF and 17 (53%) of 32 assigned to
SF, compared with 23 (62%) of 37 eyes assigned to placebo.
Progression to predominantly classic CNV by 24 months was
more common in the placebo group 11 (28%) of 39 patients
compared with 2 (5%) of 38 in the RF group and 1 (3%) of 37 in
the SF group. No unexpected ocular or systemic adverse events
were identified. The study concluded that Verteporfin therapy
safely reduced the risks of losing at least 15 letters (≥3 lines) of
visual acuity, and, progression to predominantly classic CNV
for at least 2 years in individuals with subfoveal minimally
classic lesions due to AMD measuring six MPS disc areas or
less. Based on the overall evidence available on Verteporfin
therapy for these lesions, the VIM Study Group recommended
verteporfin therapy for relatively small minimally classic
lesions.56
Preliminary study57 of the treatment of CNV not related to
AMD such as myopia, histoplasmosis, angioid streaks, and
idiopathic causes, with Verteporfin therapy, achieved short-term
cessation of fluorescein leakage from CNV in a small number
of patients without loss of vision. Verteporfin therapy for
subfoveal CNV caused by pathologic myopia was studied in a
multicentric, double-masked, placebo-controlled, randomized
clinical trial in 110 patients through 2 years of follow-up.58 It
showed that PDT maintained a visual benefit compared with
a placebo therapy. Although the primary outcome was not
statistically significantly in favor of verteporfin therapy at
2 years as it had been at 1 year of follow-up, the distribution
of change in visual acuity at the month 24 examination was
in favor of the verteporfin-treated group and showed that this
group was more likely to have improved visual acuity through
the month 24 examination. The VIP Study Group recom-
mended verteporfin therapy for subfoveal CNV resulting from
pathologic myopia based on both the 1 and 2 year results of this
randomized clinical trial.
PDT of subfoveal choroidal neovascularization with
verteporfin in the ocular histoplasmosis syndrome was studied
in an uncontrolled, prospective case series of 26 patients.
A 24 month examination was completed in 22 of the 26
Photodynamic Therapy
enrolled participants (85%). At the 24 month examination,
median improvement from baseline in visual acuity of the
22 patients evaluated was six letters; median contrast sensi-
tivity improved by 3.5 letters. At the 24 month examination,
10 patients (45%) gained seven or more letters of visual acuity
from baseline, whereas four patients (18%) lost eight or more
letters, including two patients (9%) who lost at least 15 letters.
There was absence of fluorescein angiographic leakage from
classic CNV in 17 of the 20 evaluable lesions (85%), and leak-
age from occult CNV was absent in all eyes. No serious ocular
adverse events were reported, and no serious systemic event was
considered to be associated with treatment. The study59 con-
cluded that the median visual acuity improved and fluorescein
angiographic leakage decreased after verteporfin therapy in this
small, uncontrolled clinical study of patients with subfoveal
CNV resulting from OHS. Verteporfin therapy seemed to be
relatively safe in these patients.
CHAPTER 147
COMBINATION THERAPY
Preliminary study of PDT in combination with intravitreal
kenalog injection has been reported in CNV secondary to AMD
and was found to be relatively safe and had reasonable results
for lesions with some classic component.60 Subsequently, a case
series61 was reported on 26 patients with CNV secondary to
AMD treated with PDT immediately followed by intravitreal
kenalog. Elevated IOP seemed to be the most frequent early side
effect of the treatment. Although the number of patients in this
pilot study was limited, the improvement of acuity and the
reduced treatment frequency in these patients suggested that
combination therapy with PDT and intravitreal triamcinolone
acetonide, particularly when used as first-line therapy, merits
further investigation. The role of the combination of PDT
and intravitreal kenalog for nonsubfoveal choroidal neo-
vascularization was studied in another case series of 15 patients
followed over 12 months.62 This pilot study showed that
the visual acuity response and the low incidence of subfoveal
extension suggest that PDT combined with intravitreal
triamcinolone for the treatment of nonsubfoveal choroidal
neovascularization merits further investigation as a first-line
treatment. Now a clinical trial is underway to study the
combined Visudyne therapy with kenalog in CNV secondary
to AMD.
Clinical trials are also ongoing to evaluate the safety and
efficacy of combination treatment of PDT and pegaptanib
sodium (Macugen) for predominantly classic choroidal
neovascularization secondary to AMD. Preliminary preclinical
data indicate that an intravitreal ranibizumab (Lucentis)
injection in combination with verteporfin PDT causes a greater
reduction in angiographic leakage than PDT and intravitreal
vehicle injection (PDT only) in experimental choroidal
neovascularization in the monkey eye.63 Clinical trials
(FOCUS) are ongoing to compare Lucentis in combination with
PDT to PDT alone.64
Targeted PDT is a new modality to improve the efficacy of
PDT. Preclinical work has been done with Verteporfin bound to
the targeting peptide, ATWLPPR, which helps it bind to VEGF-
receptor 2. The targeted verteporfin resulted in more selective
treatment than the control conjugate or standard verteporfin.
This study provides the basis for further studies of targeted
PDT strategies and subsequent clinical trials.18
CONCLUSION
PDT causes selective damage to the proliferating tissues with
relative sparing of the surrounding tissues. This led to its vital
role in the treatment of ocular neovascularization specially 1959
 RETINA AND VITREOUS

CNV. PDT of choroidal neovascularization using verteporfin
(Visudyne) is a proven treatment modality for certain eyes with
subfoveal choroidal neovascularization secondary to age-related
macular degeneration and other causes such as myopia,
histoplasmosis, angioid streaks, and idiopathic causes. Clinical
trials have shown that it is a safe treatment with minimal
chance of transient systemic side effects. In the experimental
models, PDT has also been efficacious in the treatment of iris,
corneal neovascularization, ocular tumors, and glaucoma and it
offers an adjunctive therapy to the existing modalities for these
conditions. Further research is ongoing to determine the
suitable photosensitizer and the optimal treatment parameters
for the ocular applications of PDT. New photosensitizers that
may have improved characteristics for PDT of ocular structures
continue to be developed. Future strategies will address
improved selectivity by complexing photosensitizers to agents
that target tumors and neovasculature. Finally, PDT has a
major role in a multifaceted approach such as in combination
with antiangiogenic and immunogenic modalities.

REFERENCES
1. Raab O: Ueber die Wirkung
Fluorescierenden Stoffe Auf Infusorien.
Z Biol 1900; 39:524–546.
2. Von Tappeiner H, Jodlbauer A: Ueber
wirking der photodynamischen
(fluorescierenden) Stoffe auf Protozoan und
SECTION 10
16. Kessel D: Porphyrin–lipoprotein association
as a factor in porphyrin localization. Cancer
Lett 1986; 33:183–188.
17. Jiang FN, Allison B, Lui D, et al: Enhanced
photodynamic killing of target cells by either
monoclonal antibody or low density
29. Ohkuma H, Ryan SJ: Experimental
subretinal neovascularization in the monkey.
Arch Ophthalmol 1982; 101:1102–1110.
30. Thomas EL, Langhofer M: Closure of
experimental subretinal neovascular vessels
with dihematoporphyrin ether augmented

Enzyme. Dtsch Arch Klin Med 1904;
80:427–487.
3. Meyer-Betz F: Untersuchungen uber die
Biologische (photodynamische) Wirkung
des hamatoporphyrins und anderer
Derivative des Blut-und-Gallenfarb-stoffs.
Dtsch Arch Klin Med 1913; 112:476–503.
4. Aueler H, Banzer G: Untersuchungen uber
die rolle der Porphyrine bei
geschwulstkranken Menschen und Tieren.
Krebsforsch 1942; 53:65–68.
5. Lipson RL, Baldes EJ, Olsen EM:
Hematoporphyrin derivative for detection
and management of cancer. Proc IX internat
Cancer Congr. 1966:393.
6. Dougherty TJ, Kaufman JE, Goldfarb A,
et al: Photoradiation therapy for the
treatment of malignant tumors. Cancer Res
1978; 38:2628–2635.
7. Lui H, Anderson RR: Photodynamic therapy
in dermatology: Recent developments.
Dermatol Clin 1993; 11:1–13.
8. Levy JG: Photosensitizers in photodynamic
therapy. Sem in Oncology 1994;
21(Supp)15:4–10.
9. Richter AM, Chowdhary R, Ratkay L, et al:
Nononcologic potentials for the
photodynamic therapy. Proc Soc Photo-
Optical Instr Eng 1994; 2078:293–304.
10. Hasan T, Parish JA: Photodynamic therapy
of cancer. In: Holland JF, Frei E, et al, eds.
Cancer medicine. 4th edn. New York:
Williams and Wilkins; 1996:739–751.
11. Foote CS: Photosensitized autooxidation
and singlet oxygen: consequences in
biological systems. In: Proyer WA, ed. Free
radicals in biology. New York: Academic
Press; 1976:85.
12. Henderson BW: Probing the effects of
photodynamic therapy through in vivo in
vitro methods. In: Kessel D, ed.
Photodynamic therapy of Neoplastic
disease. Baco Raton, FL: CRC Press;
1990:169–188.
13. Fisher AMR, Murphree AL, Gomer CJ:
Clinical and preclinical photodynamic
therapy. Lasers Surg Med 1995;
17:2–31.
14. Henderson BW, Dougherty TJ: How does
photodynamic therapy work? Photochem
Photobiol 1992; 55:931–948.
15. Jori G: Low density lipoproteins–liposome
delivery system for tumor photosensitizers
in vivo. In: Handerson BW, Dougherty TJ,
eds. Photodynamic therapy, basic
principles and clinical applications.
1960 New York: Dekker; 1992:173–186.
lipoprotein mediated delivery systems.
J Control Release 1992; 19:41–58.
18. Renno RZ, Terada Y, Haddadin MJ, et al:
Selective photodynamic therapy by
targeted verteporfin delivery to experimental
choroidal neovascularization mediated by a
homing peptide to vascular endothelial
growth factor receptor-2. Arch Ophthalmol
2004; 122:1002–1011.
19. Agarwal ML, Larkin HE, Zaidi SIA, et al:
Phospholipase activation triggers
apoptosis in photosensititzed mouse
lymphoma cells. Cancer Res 1993;
53:5897–5902.
20. Fingar VH, Weiman TJ: Studies on the
mechanism of photodynamic therapy
induced tumor destruction. In: Proceedings
of the SPIC conference, ‘Photodynamic
therapy Mechanisms II’; 1990:168–177.
21. Nseyo UO, Whalen RK, Duncan MR, et al:
Urinary cytokines following photodynamic
therapy for bladder cancer: preliminary
report. Urology 1990; 36:167–171.
22. Steele JK, Lui D, Stammers AT, et al:
Suppressor deletion therapy: selective
elimination of T-suppressor cells in vivo
using Hp conjugate to a monoclonal
antibody permits animal to reject synergic
tumor cells. Cancer Immunol Immunother
1988; 26:125–131.
23. Gomer CJ, Ferrario A, Hayashi N, et al:
Molecular, and tissue response following
photodynamic therapy. Lasers Surg Med
1988; 8:450–463.
24. Evans S, Matthews W, Perry R, et al: Effect
of Photodynamic therapy on tumor necrosis
factor production by murine macrophages.
J Natl Cancer Inst 1990; 82:34–39.
25. Svaasand LO, Ellingson R: Optical
properties of human brain. Photochem
Photobiol 1983; 38:283–299.
26. Dougherty TJ, Potter WR, Weishaupt KR:
The structure of active component of
hematoporphyrin derivative. In: Doirin DR,
Gomer CJ, eds. Porphyrin localization and
treatment of tumors. New York: Alan R Liss;
1984: 304–314.
27. Richter AM, Waterfield E, Jain AK, et al: In
vitro and phototoxic properties of four
structurally related benzoporphyrin
derivatives. Photochem Photobiol 1990;
52:495–500.
28. Richter AM, Jain AK, Canaan AJ, et al:
Photosensitizing effeciency of two
regioisomers of the benzoporphyrin
derivative monoacid ring A. Biochem
Pharmacol 1992; 43:2349–2358.
argon green laser photocoagulation.
Photochem Photobiol 1987; 46:5881–5886.
31. Kliman, Puliafito CA, Stern D, et al:
Phthalocyanine photodynamic the new
strategy for closure of choroidal
neovascularization. Laser Surg Med
1994; 15:2–10.
32. Miller H, Miller B. Photodynamic therapy
of subretinal neovascularization in the
monkey eye. Arch Ophthalmol 1993;
111:855–860.
33. Baumal CR, Puliafito CA, Pieroth L, et al:
Photodynamic therapy (PDT) of
experimental choroidal neovascularization
with tin ethyl etiopurpurin. Invest
Ophthalmol Vis Sci 1996; 37:S122.
34. Thomas EL, Rosen R, Murphy R, et al:
Purlytin (SnET2)-photodynamic therapy
produces closure of subfoveal choroidal
neovascularization in humans. Invest
Ophthalmol Vis Sci 1998; 39:S242.
35. Graham KB, Arbour JD, Connoly EJ et al:
Digital angiography using Lutetium
texaphyrin in a monkey model of choroidal
neovascularization. Invest Ophthalmol Vis
Sci 1999; 40:S402.
36. Mori K, Ohta M, Katagiri T, et al:
Photodynamic therapy (PDT) with
combination of a new sensitizer: NPe6 and
a diode laser emitting at 664 nm.
Investigative Ophthalmol Vis Sci 1996;
37/3:S3177.
37. Obana A, Gohto Y, Miki T, et al: Selective
photodynamic effects of the new
photosensitizer ATX-S10(Na) on choroidal
neovascularization in monkeys. Arch of
ophthalmol 2000 ; 118:650–658.
38. Richter A, Waterfield E, Jain A, et al:
Photosensitizing potency of structural
analogs of benzoporphyrin derivative
(BPD-MA) in a mouse model. Br J Cancer
1991; 63:87–93.
39. Richter AM, Cerruti-Sola S, Sternberg ED,
et al: Biodistribution of tritiated
benzoporphyrin derivative (3H-BPD-MA),
a new photosensitizer, in normal and
tumor-bearing mice. J Photochem
Photobiol 1990; 5:231–244.
40. Lui J, Hruza L, Kollias N, et al:
Photodynamic therapy of malignant skin
tumors with benzoporphyrin derivative-
monoacid ring A (BPD-MA): Preliminary
investigations. In: Anderson RR, et al,
Chairs/eds. Proceedings of lasers in
otolaryngology, dermatology, and tissue
welding, Jan 16–18, 1993. Los Angeles CA.
Bellingham WA: SPEI, C; 1993: 147–151.

41. Miller JW, Walsh AW, Kramer M, et al:
Photodynamic therapy of experimental
choroidal neovascularization using
lipoprotein delivered benzoporphyrin. Arch
Ophthalmol 1995; 113:810–818.
42. Moulton RS, Walsh AW, Miller JW, et al:
Response of retinal and choroidal vessels
to photodynamic therapy using
benzoporphyrin derivative. Invest
Ophthalmol 1993; 34:S2294.
43. Kramer M, Miller JW, Michaud N, et al:
Liposomal benzoporphyrin derivative
verteporfin photodynamic therapy:
selective treatment of choroidal
neovascularization in monkeys.
Ophthalmology 1996; 103:427–438.
44. Allison BA, Pritchard PH, Levy JG:
Evidence of low-density lipoprotein
receptor mediated uptake of BPD. Brit J
Cancer 1994; 69:833–839.
45. Kramer M, Kenney AG, Delori F, et al:
Imaging of experimental choroidal
neovascularization (CNV) using liposomal
Benzoporphyrin Derivative mono-acid
(BPD-MA) angiography. 1995. Invest
Ophthal Vis Sci. 36/4:S236.
46. Husain D, Miller JW, Michaud N, et al:
Intravenous infusion of liposomal
benzoporphyrin derivative verteporfin for
photodynamic therapy of experimental
choroidal neovascularization. Arch
Ophthalmol 1996; 114:978–985.
47. Husain D, Miller JW, Michaud N, et al:
Long term effects of photodynamic therapy
(PDT) using liposomal benzoporphyrin
derivative (BPD) on experimental choroidal
neovascularization (CNV) and normal retina
choroid. Invest Ophthal Vis Sci 1996;
37:1013.
48. Reinke MH, Canakis C, Husain D, et al:
Photodynamic therapy retreatment o
normal retina and choroid in the primate.
Invest Ophthal Vis Sci 1997; 38:75.
49. Schmidt-Erfurth U, Miller JW, Sickenberg
M, et al: Photodynamic therapy of
subfoveal choroidal neovascularization
using benzoporphyrin derivative: first
results of multicenter trial. Invest Ophthal
Vis Sci 1996; 37:B492.
50. Miller JW, Schmidt-Erfurth U, Sickenberg
M, et al: Selected angiographic findings
following photodynamic therapy of
subfoveal choroidal neovascularization
using BPD. Invest Ophthal Vis Sci 1996;
37:1014.
51. Miller JW, Schmidt-Erfurth U, Sickenberg
M, et al: Photodynamic therapy with
verteporfin for choroidal neovascularization
caused by age-related macular
degeneration. Results of a single treatment
in a Phase 1 and 2 study. Arch Ophthalmol
1999; 117:1161–1173.
52. Treatment of Age-related Macular
Degeneration With Photodynamic Therapy
(TAP) Study Group: Photodynamic therapy
of subfoveal choroidal neovascularization in
age-related macular degeneration with
verteporfin. One-year results of 2
randomized clinical trialsTAP Report 1.
Arch Ophthalmol 1999; 117:1329–1345.
53. Bressler NM: Photodynamic therapy of
subfoveal choroidal neovascularization in
age-related macular degeneration with
verteporfin: two-year results of 2
randomized clinical trials-tap report 2. Arch
Ophthalmol 2001; 119:198–207.
54. Verteporfin Therapy for Subfoveal
Choroidal Neovascularization in Age-
Related Macular Degeneration: Four-Year
Results of an Open-Label Extension of 2
Randomized Clinical Trials: TAP Report No.
7. Arch Ophthalmol 2005; 123:1283–1285.
55. Verteporfin therapy of subfoveal choroidal
neovascularization in age related macular
degeneration: two year results of a
randomized clinical trial including lesions
with no classic choroidal
neovascularization – Verteporfin in
photodynamic therapy report 2. Am J
Ophthalmol 2001; 131:541–560.
56. Azab M, Boyer DS, Bressler NM, et al:
Verteporfin therapy of subfoveal minimally
classic choroidal neovascularization in
age-related macular degeneration: 2-year
results of a randomized clinical trial. Arch
Ophthalmol 2005; 123:448–457.
57. Sickenberg M, Schmidt-Erfurth U, Miller
JW, et al: A preliminary study of
Photodynamic Therapy
photodynamic therapy using verteporfin for
choroidal neovascularization in pathologic
myopia, ocular histoplasmosis syndrome,
angioid streaks, and idiopathic causes.
Arch Ophthalmol 2000; 118:327–336.
58. Blinder KJ, Blumenkranz MS, Bressler NM,
et al: Verteporfin therapy of subfoveal
choroidal neovascularization in pathologic
myopia: 2-year results of a randomized
clinical trial – VIP report no. 3.
Ophthalmology 2003; 110:667–673.
59. Rosenfeld PJ, Saperstein DA, Bressler NM,
et al: Photodynamic therapy with
verteporfin in ocular histoplasmosis:
uncontrolled, open-label 2-year study.
Ophthalmology 2004 Sep; 111:1725–1733.
60. Rechtman E, Danis RP, Pratt LM et al:
Intravitreal triamcinolone with
photodynamic therapy for subfoveal
choroidal neovascularisation in age-related
CHAPTER 147
macular degeneration. Br J Ophthalmol
2004; 88:344–347.
61. Spaide RF, Sorenson J, Maranan L:
Photodynamic therapy with verteporfin
combined with intravitreal injection of
triamcinolone acetonide for choroidal
neovascularization Ophthalmology 2005;
112:301–304.
62. Spaide RF, Sorenson J, Maranan L:
Combined photodynamic therapy and
intravitreal triamcinolone for nonsubfoveal
choroidal neovascularization. Retina 2005;
25:685–690.
63. Husain D, Kim I, Gauthier D et al: Safety
and efficacy of intravitreal injection of
ranibizumab in combination with
verteporfin PDT on experimental choroidal
neovascularization in the monkey. Arch
Ophthalmol 2005; 123:509–516.
64. Heier JS, Boyer DS, Ciulla TA, et al:
Ranibizumab combined with verteporfin
photodynamic therapy in neovascular age-
related macular degeneration: year 1
results of the FOCUS Study. Arch
Ophthalmol 2006; 24:1532–1542.
1961
 CHAPTER
Anti-VEGF and Other Pharmacologic Treatments
148 for Age-Related Macular Degeneration
Ivana K. Kim and Joan W. Miller
OVERVIEW
The identification of vascular endothelial growth factor (VEGF)
as a key mediator of ocular angiogenesis has led to the devel-
opment of several pharmacologic agents designed for targeted
inhibition of this molecule. Two of these agents, pegabtanib and
ranibizumab, have been proven efficacious in the treatment of
neovascular age-related macular degeneration (AMD) and are
currently available for clinical use. Additional drugs targeting
the VEGF pathway as well as other antiangiogenic compounds
are under evaluation in clinical trials and appear promising. As
options for pharmacologic therapy multiply, combination
therapy using various agents and modalities may provide
improved visual outcomes for patients with choroidal
neovascularization due to AMD.
Recent progress in the treatment of neovascular AMD has
enabled an evolution from nonspecific, ablative laser therapy
to targeted pharmacologic approaches. These new pharma-
cologic agents represent the culmination of over a decade of
investigations into the mechanisms of ocular angiogenesis.
Early observations of increased vascularity associated with
the growth of tumors gave rise to the field of angiogenesis.1
Ide and colleagues first proposed the idea of secreted factors
which could promote growth of blood vessels in 1939, based
on studies of vascular development accompanying the growth
of transplanted rabbit epithelioma.2 Similarly, in 1948,
Michaelson suggested that a diffusible ‘Factor X’ from the retina
stimulated the retinal and iris neovascularization seen in
diabetic retinopathy.3 However, many years passed before such
proposed angiogenic factors were identified.
THE ROLE OF VEGF IN OCULAR
ANGIOGENESIS
The idea of inhibiting angiogenesis was first proposed as a
strategy for treating cancer in 1971 by Judah Folkman, who
spearheaded the efforts to discover tumor angiogenesis factors.4
In 1983, Senger and colleagues discovered a protein secreted
from a guinea pig tumor cell line which was a potent inducer of
vascular leakage and named it vascular permeability factor
(VPF).5 In 1989, Napoleon Ferrara and colleagues at Genentech
identified a molecule in the conditioned media from bovine
pituitary follicular cells which promoted the proliferation of
endothelial cells and called it VEGF.6 The subsequent cloning
of these two factors demonstrated that they were the same
protein.7,8
This molecule is also known as VEGF-A, as it belongs to
a family of genes including placental growth factor (PlGF),
VEGF-B, VEGF-C,VEGF-D, and VEGF-E, a viral-derived
homolog.9 VEGF-C and -D mediate lymphangiogenesis.
Human VEGF-A is alternatively spliced into at least four active
human isoforms, consisting of 121, 165, 189, and 206 amino
acids. VEGF121 and VEGF165 are diffusible forms, although
VEGF165 retains heparin-binding ability. The other longer
isoforms remain bound to extracellular matrix. VEGF165 is the
predominant form and possesses greater mitogenic activity.
Some recent work in rodent models suggests that this isoform
may be the primary mediator of pathologic neovasculari-
zation.10 Two tyrosine kinases serve as VEGF-A receptors,
VEGFR-1 (fms-like tyrosine kinase 1, flt-1) and VEGFR-2
(kinase domain region, KDR or fetal liver kinase, flk-1). VEGFR-
2 appears to play the major role in signaling the mitogenic,
angiogenic, and permeability effects of VEGF.9
VEGF AS A MEDIATOR OF OCULAR
NEOVASCULARIZATION
It had long been appreciated that neovascularization of the
retina and iris was temporally and spatially correlated with
retinal ischemia due to various etiologies. The discovery that
hypoxia could upregulate VEGF expression made VEGF a
plausible candidate for the factor responsible for abnormal
blood vessel growth in the eye.11,12 Evidence from both clinical
and animal studies then accumulated to support the critical role
of VEGF in ocular neovascularization. VEGF expression was
shown to be correlated with iris neovascularization in a primate
model of ischemic retinal vein occlusion,13 and a similar
correlation was demonstrated in a neonatal mouse model of
retinal neovascularization.14 Additionally, injection of VEGF in
normal primate eyes produced iris neovascularization, neovas-
cular glaucoma, and retinal microangiopathy.15,16 Suppression
of neovascularization was also achieved by VEGF inhibition
through the use of neutralizing antibodies in the primate model
of iris neovascularization and chimeric proteins acting as
soluble VEGF receptors in the mouse model of retinal
neovascularization.17,18
Human clinical studies confirmed the association of VEGF
expression with pathologic ocular neovascularization. Measure-
ments of vitreous VEGF levels in patients with active prolifer-
ative diabetic retinopathy demonstrated significantly higher
VEGF concentrations when compared to patients with other
retinal disorders not characterized by abnormal blood vessel
growth.19 Another study which analyzed both aqueous and
vitreous levels of VEGF in a variety of conditions characterized
by ocular neovascularization correlated elevated ocular VEGF
concentrations to the presence of active neovascularization.
This study also demonstrated reduction of VEGF levels after
panretinal photocoagulation for retinal neovascularization.20
1963
 RETINA AND VITREOUS

TABLE 148.1. Agents Approved (*) or in Clinical Trials for Treatment of Neovascular
Macular Degeneration

Agent Target Delivery

Pegaptanib* VEGF Intravitreal

Ranibizumab* VEGF Intravitreal
Bevacizumab VEGF Intravitreal
Bevasiranib (Cand5) VEGF Intravitreal
Sirna-027 VEGFR-1 Intravitreal
VEGF Trap VEGF, PlGF Intravitreal
AdPEDF PEDF (gene transfer) Intravitreal
Anecortave acetate Proteolytic cascade leading to Juxtascleral
extracellular matrix degradation
Squalamine lactate Intracellular signaling Systemic
SECTION 10

VEGF IN CHOROIDAL NEOVASCULARIZATION 0

Mean Change in Visual Acuity

–1
–2
Although hypoxia is not clearly a stimulus for the development –3
–4
of choroidal neovascularization (CNV), VEGF does appear to –5

(no. of letters)
–6 1.0 mg Pegaptanib
–7
function in CNV formation. –8
–9 0.3 mg Pegaptanib

Overexpression of VEGF through gene transfer using viral –10

–11 3.0 mg Pegaptanib
–12
vectors induces choroidal neovascularization in rat and primate –13
–14
models.21,22 Implantation of microspheres containing VEGF –15
–16 Sham injection
–17
into the subretinal space also promotes choroidal neovasculari- 0 6 12 18 24 30 36 42 48 54

zation in primates.23 Additionally, increased VEGF expression Weeks

No. at Risk
has been demonstrated in rodent and primate models of laser- 0.3 mg Pegaptanib 294 286 289 269 273 271 265 271 266 271
1.0 mg Pegaptanib 300 292 291 291 287 285 278 270 267 275
induced CNV.24,25 Conversely, blockade of the VEGF pathway 3.0 mg Pegaptanib 296 286 283 281 283 278 273 267 259 264
Sham Injection 296 291 288 287 281 282 278 275 269 275
using monoclonal antibodies in the primate model of laser-
induced CNV26 and kinase inhibitors in a mouse model27 FIGURE 148.1. Mean change in visual acuity for all dose groups in
prevents CNV formation. This type of experimental data is also the first year of the VISION trials of pegaptanib (Macugen) for
supported by clinical evidence demonstrating the presence of neovascular AMD.
VEGF in choroidal neovascular membranes removed from From Gragoudas ES, Adamis AP, Cunningham ET, Jr, et al: Pegaptanib for
neovascular age-related macular degeneration. N Engl J Med 2004;
patients with neovascular AMD.28,29
351:2805–2816.

ANTI-VEGF AGENTS
Given such weighty evidence for VEGF as a key mediator of
ocular neovascularization, it became a prime therapeutic target
in the search for more efficacious treatments for neovascular
AMD (Table 148.1).
PEGAPTANIB
Key Features
• RNA aptamer
• Intravetreal injection
• Dosing: Every 6 weeks
• Efficacy for all lesion types
Pegaptanib sodium (Macugen) became the first anti-VEGF agent
approved by the United States Federal Drug Administration
(FDA) for ophthalmic use (0.3 mg intravitreal injection) in
December 2004. It is a modified 28-base RNA aptamer which
binds with high affinity to the 165-amino-acid isoform of
VEGF. The efficacy of pegaptanib in preventing moderate
vision loss (≥3 lines) from subfoveal CNV was demonstrated by
the VEGF Inhibition Study in Ocular Neovascularization
(VISION), two concurrent, randomized, double-masked, sham-
controlled studies involving 1186 patients, which showed a
1964 treatment benefit for all subtypes and sizes (up to 12 disc areas)
of CNV lesions due to AMD30 (Figs 148.1 and 148.2). Patients
were randomized to receive 0.3,1.0,or 3.0 mg pegpatanib intra-
vitreally or sham injection once every 6 weeks. With pegaptanib
(0.3 mg) treatment, 70% of patients avoided moderate vision loss
at 1 year versus 55% of patients in the control group. The
proportion who maintained or gained vision was 33% in the
0.3 mg pegaptanib group versus 23% of those receiving sham.
However, the number of patients who gained three or more
lines of vision was small: 6% in the pegaptanib (0.3 mg) group
versus 2% in the control group (clinical example, Fig. 148.3).
Two-year results of this study suggested that there is a benefit
to continued treatment for a second year31 (Fig. 148.4). Patients
who received pegaptanib for 2 years were less likely to lose ≥15
letters than those who discontinued treatment after 1 year. Ten
percent of patients treated with pegaptanib for 2 years gained ≥3
lines of vision. Additionally, the proportion of patients who
gained vision was higher in the group that received 2 years of
treatment than those that received usual care (Fig. 148.5).
The safety profile of pegaptanib appears quite favorable.32
The most common ocular adverse events noted during the trials
included eye pain, vitreous floaters, punctate keratitis, and
increased intraocular pressure. These symptoms were mainly
attributed to the injection procedure rather than the drug. The
serious ocular adverse events were also injection-related and
consisted of endophthalmitis (1.3%/patient in year 1), retinal
 Anti-VEGF and Other Pharmacologic Treatments for Age-Related Macular Degeneration

FIGURE 148.2. Mean changes in visual acuity

at week 54 of the VISION trials according to
baseline characteristics of (a) angiographic
subtype, (b) visual acuity, and (c) lesion size. *,
p < 0.05 for pegaptanib vs sham injection; †,
p < 0.001; ‡, p < 0.01.
From Gragoudas ES, Adamis AP, Cunningham ET, Jr,
et al: Pegaptanib for neovascular age-related macular
degeneration. N Engl J Med 2004; 351:2805–2816
Copyright © 2004 Massachussets Medical Society.
All rights reserved.

CHAPTER 148
b c

FIGURE 148.3. (a) Color photo and fluorescein angiogram of patient with occult choroidal neovascular membrane. Vision was 20/50. Patient
received pegaptanib therapy. (b) OCT scans of same patient shown in (a). The left scan was taken prior to treatment and reveals a pigment
epithelial detachment and subretinal fluid. The right scan was taken after 4 injections of pegaptanib (6 months of therapy). The subretinal fluid
had resolved and vision had improved to 20/30.

detachment (0.7%/patient in year 1), and traumatic cataract
(0.6%/patient in year 1). The incidence of these events was
similar for the second year across all cohorts. Only one of the
cases of endophthalmitis in the first year resulted in severe
vision loss, and none of the patients who developed endoph-
thalmitis in the second year experienced severe vision loss.
Clinical studies of systemically administered bevacizumab
(a monoclonal antibody directed against all VEGF-A isoforms)
in oncology patients identified hypertension, hemorrhage, and
thromboembolic events as serious systemic adverse events.33,34 1965
 RETINA AND VITREOUS

Patient Treatment Year 1 ˜ Year 2 40

50 0.3 mg ˜ 0.3 mg, N=133
Patient Treatment Year 1 ˜ Year 2
0.3 mg ˜ Discontinue, N=132
0.3 mg ˜ 0.3 mg, N=133
Usual care, N=107
45 0.3 mg ˜ Discontinue, N=132
30
Vision (letters)

Usual care, N=107

40

Percent of Patients
20
35

30
54 60 66 72 78 84 90 96 102 10
Weeks

FIGURE 148.4. Mean visual acuity from week 54 to 102 in the VISION
SECTION 10

trials.
From VISION Clinical Trial Group: Year 2 Efficacy Results of 2 Randomized 0
Controlled Clinical Trials of Pegaptanib for Neovascular Age-Related Macular ≥0 ≥1 ≥2 ≥3
Degeneration. Ophthalmology 2006 Epub July 5, 2006; 113: 1508.el–1508.e25, Lines of Vision Gained
with permission from the American Academy of Ophthamology.)

FIGURE 148.5. Proportion of patients gaining vision after 2 years in

There was no suggestion that intravitreal administration of
pegaptanib was associated with such systemic side effects
through year 2 of the VISION trials.
RANIBIZUMAB
Key Features
• Anti-VEGF antibody fragment
• Intravetreal injection
• Dosing: Every 4 weeks
• Efficacy for all lesion types
• Superior to photodynamic therapy in randomized trial
• 30–40% of patients with ≥ 3 lines visual improvement
More recently, results of Phase III trials also confirmed the
efficacy of ranibizumab (Lucentis) in neovascular AMD, with
rates of visual improvement not previously achieved. This drug
was approved by the US FDA for the treatment of neovascular
AMD in June 2006 at a dose of 0.5 mg given intravitreally.
Ranibizumab is a recombinant, humanized monoclonal anti-
body fragment (48kDa) which binds all isoforms of the VEGF-
the VISION trials.
From VISION Clinical Trial Group: Year 2 Efficacy Results of 2 Randomized
Controlled Clinical Trials of Pegaptanib for Neovascular Age-Related Macular
Degeneration. Ophthalmology 2006 Epub Jul 5, 2006; 113: 1508.el–1508.e25,
with permission from the American Academy of Ophthamology.)
A molecule (Fig. 148.6). The benefit of ranibizumab for patients
with minimally classic and occult CNV was demonstrated in
the MARINA (minimally classic/occult trial of the anti-VEGF
antibody ranibizumab) study, a randomized, multicenter,
double-masked, sham-controlled trial with an enrollment of
716 patients.35 Patients in this study were randomized to
monthly injections of either 0.3 or 0.5 mg ranibizumab or sham
injections. After 1 year, 95% of patients who were treated with
ranibizumab avoided moderate vision loss, compared to 62% of
patients who were in the control group. Thirty-four percent of
patients treated with ranibizumab 0.5 mg experienced visual
improvement of three or more lines compared to 5% of patients
receiving sham injections. The mean change in visual acuity at
the end of the first year of treatment was a gain of 7.2 letters in
the 0.5 mg ranibizumab group compared to a loss of 10.4 letters

FIGURE 148.6. Ranibizumab (Lucentis ®) is a

recombinant, humanized, monoclonal antibody
fragment with high affinity for all isoforms of
VEGF-A.
Courtesy of Genentech, Inc.

1966
 Anti-VEGF and Other Pharmacologic Treatments for Age-Related Macular Degeneration
FIGURE 148.7. Mean change in visual acuity over 2 years of the
MARINA trial of ranibizumab for minimally classic/occult CNV due to
AMD. Vertical lines are one standard error of the means. *, p < 0.001
vs sham at each month and p = 0.006 (for 0.3 mg) and 0.003 (for
0.5 mg) at day 7.
From Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY,
Kim RY; MARWA Study Group. Ranibizunab for neomuscular age-related
macular degeneration. N Engl J Med 2006; 355: 1419–1430 Copyright © 2006
Massachusetts Medical Society. All right reserved.
FIGURE 148.8. Percentage of patient achieving 20/40 or better in the
MARINA trial. Vertical lines are 95% confidence intervals. †, p < 0.001
vs sham.
From Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY,
Kim RY; MARWA Study Group. Ranibizunab for neomuscular age-related
macular degeneration. N Engl J Med 2006; 355: 1419–1430 Copyright © 2006
Massachusetts Medical Society. All right reserved.
in the sham group. Approximately 40% of patients treated with
ranibizumab achieved visual acuity of 20/40 or better at the
end of the first year versus 11% of the sham-treated group
(Fig. 148.7) The treatment benefit was sustained through 2
years. At month 24, 90% of treated patients (0.5 mg) avoided
moderate vision loss compared to 53% in the control group.
Similarly, 33% of treated patients gained three or more lines of
vision after 2 years versus 4% of the control group, and the
mean change in visual acuity was +6.6 letters in the treated
patients versus 14.9 in the control group (Fig. 148.8).
The results of the ANCHOR (anti-VEGF antibody for the
treatment of predominantly classic choroidal neovas-
cularization in AMD) trial demonstrated that ranibizumab is
superior to PDT for predominantly classic CNV. This study
randomized 423 patients to receive verteporfin PDT and sham
injection or sham PDT and ranibizumab 0.3 or 0.5 mg. The
patients received ranibizumab or sham injections monthly.
Verteporfin or sham PDT was administered upon study entry
and could be repeated every 3 months based on evidence of
leakage on angiography. The results at month 12 revealed that
96% of patients treated 0.5 mg ranibizumab avoided moderate
vision loss compared to 64% of patients treated with PDT.36
Furthermore, 40% of patients treated with ranibizumab 0.5 mg,
gained three or more lines of vision versus 6% in the PDT
CHAPTER 148
FIGURE 148.9. Mean change in visual acuity over 1 year of the
ANCHOR trial of ranibizumab compared to verteporfin PDT for
predominantly classic CNV due to AMD. Vertical bars represent one
standard error of the mean. P < 0.001 for all comparisons vs PDT at
each month.
Brown DM, Kaiser PK, Michels M, et al.; ANCHOR Study Group. Ranibizumab
versus verteporfin for neovascular age-related macular degeneration. N Eng J
Med 2006; 355: 1432–1444. Copyright © 2006 Massachusetts Medical Society.
All rights reserved.
group. The mean changes in visual acuity in the higher-dose
ranibizumab group was a gain of 11.3 letters versus a mean loss
of 9.5 letters in the PDT group (Fig. 148.9). Results of a
subgroup analysis of this data suggested a consistent benefit of
ranibizumab compared to PDT regardless of age, visual acuity,
lesion size, or presence of occult CNV at baseline.37
The safety profile of ranibizumab appears similar to that of
pegaptanib. The rates of serious ocular adverse events at month
24 of the MARINA study for ranibizumab 0.5 mg were
endophthalmitis 1.3%, uveitis 1.3%, retinal tear 0.4%, and lens
damage 0.4%.35 Similarly, at month 12 in the ANCHOR study
for the 0.5 mg ranibizumab group, the rate of endophthalmitis
was 1.4% and uveitis was seen in 0.7% of patients.36 There did
not appear to be a significant increase in systemic adverse
events such as hypertension or arterial thromboembolic events
with ranibizumab treatment in either study.
Alternative dosing regiments for ranibizumab remain under
investigation. The PIER (A Phase IIIb, multicenter, randomized,
double-masked, sham injection-controlled study of the efficacy
and safety of ranibizumab in subjects with subfoveal choroidal
neovascularization with or without classic CNV secondary to
AMD) study was designed to examine the effect of a modified
dosing regimen for ranibizumab consisting of three initial
injections at monthly intervals followed by mandated doses at
three month intervals.38 A mean gain in visual acuity was seen
in the treatment groups at month 3 (+4.3 letters in 0.5 mg
group vs 8.7 in sham group), but was not sustained through
month 12. One-year results revealed that the mean change in
visual acuity was a loss of 1.6 and 0.2 letters in patients treated
with 0.3-, and -0.5 mg of ranibizumab respectively, compared
to a loss of 16.3 letters in the control group (Fig. 148.10). More
patients treated with ranibizumab avoided moderate vision loss
(90% in 0.5 mg group versus 49% in control group), confirming
the benefit of ranibizumab treatment. However, fewer patients
gained 3 or more lines of vision (13% in 0.5 mg group vs 10%
in sham group) as compared to the pivotal Phase III trials
MARINA and ANCHOR. These results suggest that quarterly
dosing may not be as effective as monthly injections. The PIER
study remained ongoing at the time of this writing. 1967
 RETINA AND VITREOUS
FIGURE 148.10. Mean change in visual acuity over 1 year of the PIER
trial of ranibizumab for neovascular AMD which involved quarterly
SECTION 10
dosing.
From Lucentis Prescribing Information. Genentech, Inc.
The Phase I/II, open-label, single-center PrONTO
(Prospective Optical Coherence Tomography Imaging Patients
with Neovascular AMD Treated with Intraocular Lucentis)
Study conducted at the Bascom Palmer Eye Institute was also
ongoing at the time of this writing and involved a modified
dosing protocol using three initial injections of 0.5 mg
ranbizumab at monthly intervals followed by additional doses
as indicated.39 Strict criteria for additional dosing in this study
were predetermined and included visual acuity, ocular
coherence tomography (OCT), and fluorescein angiography
findings. At 1 year, patients in this study gained an average of
9.3 letters. The mean number of injections was 5.5, although
there was significant variability among patients, and the mean
time to first retreatment was 4.3 months. Although there is no
control group for comparison, these findings suggest that
a b
1968
individually tailored dosing may be similarly efficacious to
monthly dosing for ranibizumab.
BEVACIZUMAB
Key Features
• Full-length anti-VEGF antibody
• Off-label use for neovascular AMD
• Intravitreal injection
• No randomized trials for AMD completed to date
Bevacizumab (Avastin) became the first anti-VEGF drug
licensed for clinical use when it was approved for the treatment
of metastatic colorectal cancer in February 2004. It is a
humanized, full-length monoclonal antibody (149 kDa) which
binds all isoforms of VEGF-A and was developed for intra-
venous administration. Primate studies of retinal penetration
after intravitreal injection using radiolabeled antibody
preparations demonstrated that full-length antibody failed to
penetrate the internal limiting membrane while an antibody
fragment diffused through all layers of the retina40 (Fig. 148.11).
Such data indicating a molecular weight limitation for retinal
penetration as well as concerns regarding potential cytotoxicity
related to the Fc portion of antibodies provided the rationale for
the development of ranibizumab for neovascular AMD.
However, in light of positive data from clinical trials of
pegaptanib and ranibizumab for neovascular AMD, the off-label
use of bevacizumab for this condition was initiated by clinicians
prior to the approval of ranibizumab.
An early open-label, single-center study of systemically
administered bevacizumab in nine patients with neovascular
AMD suggested visual benefit with mean increase in vision at
12 weeks as well as a mean decrease in central retinal thickness
by OCT.41 There was also some improvement in these
measures noted in the fellow eyes of the study patients. A mild
FIGURE 148.11. Microautoradiographic
images of the distribution of (a) 125I-rhuMab
HER2 (full-length antibody against HER2) and
(b) 125I-rhuMab VEGF Fab (antibody fragment
against VEGF) after intravitreal injection in
rhesus monkey. In (a), the full-length antibody
remains at the level of the inner limiting
membrane. In (b), the antibody fragment
penetrates through the entire neural retina to
the level of the RPE.
Courtesy of Genentech, Inc. See Mordenti J,
Cuthbertson RA, Ferrara N, et al. Comparisons of the
intraocular tissue distribution, pharmacokinetics, and
safety of 125I-labeled full-length and Fab antibodies in
rhesus monkeys following intravitreal administration.
Toxicol Pathol. Sep–Oct 1999; 27(5):536–544.
 Anti-VEGF and Other Pharmacologic Treatments for Age-Related Macular Degeneration
RISC
siRNA
mRNA degradation
FIGURE 148.12. In the process of RNA interference, short interfering
RNAs (siRNAs) associate with RISC (RNA-induced silencing complex)
to trigger selective degradation of particular RNA transcripts.
increase in systolic blood pressure that was felt to be drug-
related was observed at 6 weeks.
Due to concerns regarding potential systemic toxicities of
intravenously administered bevacizumab, intravitreal use was
adopted. Several short term reports of intravitreal bevacizumab
for the treatment of patients with neovascular AMD suggest a
beneficial effect on visual acuity and retinal thickness.42–45 The
largest of these series was a retrospective study of 266 eyes of
266 patients, the majority (69.7%) of whom were considered to
have had an inadequate response to other treatments.44 These
patients were treated with three injections of 1.25 mg
bevacizumab at monthly intervals. Three-month follow-up
data was available for 141 eyes and revealed visual acuity
improvement (halving of the visual angle) in 38.3% of patients
as well as progressive decrease in mean central macular thick-
ness measurements by OCT (340 mm baseline to 213 mm at
month 3).
No apparent safety concerns have been detected in these
studies with intravitreal doses up to 2.5 mg. Additionally, histo-
logic and electrophysiologic studies in rabbits have shown no
evidence of toxicity after intravitreal bevacizumab in doses up
to 2.5 mg.46,47 However, longer-term, prospective, randomized
studies are necessary to fully evaluate the safety and efficacy
of bevacizumab as a treatment for neovascular AMD.
OTHER ANTI-VEGF AGENTS
RNA Interference
A powerful new technology for inhibiting the function of
selected genes known as RNA inference (RNAi) promises a
new generation of anti-VEGF drugs. This strategy exploits a
cellular phenomenon in which a small, double-stranded RNA
molecule (short interfering RNA, siRNA) associates with a
RNA–protein complex called RISC (RNA-induced silencing
complex), resulting in selective degradation of an mRNA
transcript containing a sequence homologous to the siRNA49
(Fig. 148.12). Synthesis of siRNA molecules tailored to silence
expression of chosen genes is possible and offers the potential
for a new class of therapeutic agents. Various companies have
developed siRNAs targeting VEGF or its receptors and shown
efficacy in preclinical models.
Bevasiranib sodium (formerly Cand5) is an siRNA directed
against VEGF developed by Acuity Pharmaceuticals. The Phase
I clinical trial in patients with neovascular AMD indicated that
the drug was safe and well tolerated when delivered intra-
vitreally at doses up to 3.0 mg (Prenner JL, Thompson JT, Miller
DG, et al: An open label study for the evaluation and
tolerability of five dose levels of intravitreous VEGF siRNA
(Cand5) in patients with wet age-related macular degeneration.
Paper presented at: American Academy of Ophthalmology
Annual Meeting, Chicago, IL, 14–18 Oct 2005.). The Phase II
CARE Study (Cand5 anti-VEGF RNAi Evaluation) tested three
doses of bevasiranib in 129 patients. Preliminary results sug-
gested safety as well as efficacy at all doses.49 Phase III trials are
expected to begin in 2007.
Sirna-027 is another siRNA molecule which targets vascular
CHAPTER 148
endothelial growth factor receptor-1 (VEGFR-1) developed by
Sirna Therapeutics. The Phase I dose escalation trial involved
26 patients with neovascular AMD. At 8 weeks after a single
injection, 96% of these patients showed stabilization of vision
with 23% experiencing visual improvement of three or more
lines.50 Decreases in central retinal thickness measured by
OCT were also observed. Phase II studies are anticipated.
VEGF Trap
Another novel molecule designed to block VEGF-mediated
angiogenesis is VEGF Trap (Regeneron Pharmaceuticals), which
contains immunoglobulin domains of both VEGFR-1 and
VEGFR-2 fused to the constant region of human IgG.51 It
functions as a high-affinity soluble receptor that binds and
neutralizes both VEGF and PlGF. The Phase I study involved
doses ranging from 0.05 to 4 mg which were administered as a
single intravitreal injection to 21 patients with neovascular
AMD. At 6 weeks, 95% of the patients had stabilization of
vision (loss of ≤15 letters).52 The mean change in visual acuity
for all patients was a gain of 4.8 letters at 6 weeks. In the
highest dose groups (2 and 4 mg), the mean improvement in
visual acuity was 13.5 letters. Again, the visual acuity results
were accompanied by decreases in OCT measurements of
central retinal thickness. A Phase II study is in progress.
OTHER ANTIANGIOGENIC AGENTS
ANECORTAVE ACETATE
Given the complexity of the angiogenic process, drugs which
affect an array of factors rather than one molecule may be
desirable. The degradation of capillary basement membrane
and extracellular matrix is an essential step in the migration
of endothelial cells during neovacularization and occurs
through the action of proteases such as urokinase-type plasmi-
nogen activator (uPA) and matrix metalloproteinases.53 The
angiostatic cortisene anecortave acetate (Retaane, Alcon, Inc.) is
a cortisol derivative which has been chemically modified to
eliminate all glucocorticoid activity, thereby eliminating ocular
side effects such as glaucoma and cataracts. It has been shown
to upregulate the expression of plasminogen activator inhibitor-1
(PAI-1), thereby supressing the action of uPA, which is
necessary for the activation of various other proteases.54 By
inhibition of this proteolytic cascade which is downstream of
endothelial cell stimulation, anecortave acetate may potentially
block angiogenesis initiated by a variety of signals.
In a randomized trial, three different doses (3, 15, 30 mg) of
anecortave acetate administered as a posterior juxtascleral
injection at 6 month intervals were compared to placebo in 128 1969
 RETINA AND VITREOUS
a highest studied dose and the loss of patients between the 6 and
SECTION 10
b results of the TAP (Treatment of Age-Related Macular
FIGURE 148.13. (a) Average change in logMAR visual acuity through
month 12 of patients with subfoveal neovascularization due to AMD
treated with anecortave acetate vs placebo. (b) Proportion of patients
losing <3 lines of logMAR vision.
From D’Amico DJ, Goldberg MF, Hudson H, et al: Anecortave acetate as
monotherapy for treatment of subfoveal neovascularization in age-related
macular degeneration: twelve-month clinical outcomes. Ophthalmology 2003;
110:2372–2383; discussion 2384–2375.
patients with subfoveal choroidal neovascularization due to
AMD.55 The primary outcome of change in logMAR visual
acuity at 12 months showed a statistically significant difference
favoring the 15 mg dose of anecortave acetate compared to
placebo. The mean change in the anecortave group was a loss of
1.3 lines versus 3.1 lines for the placebo group (Fig. 148.13).
Stabilization of vision (loss of <3 logMAR lines) was seen in
79% of the anecortave (15 mg) treated patients compared to
53% of those receiving placebo. A majority of patients in this
study had predominantly classic lesions (78.5% in the ane-
cortave acetate 15 mg group and 86.7% of the placebo group),
and the treatment benefit appeared slightly more pronounced
when this subgroup of patients was analyzed separately. The
difference in visual acuity was 2.4 logMAR lines in favor of
1970
anecortave acetate 15 mg versus placebo, and 84% of
anecortave-treated patients had stabilization of vision versus
50% of those in the placebo group. The results appeared
sustained through the 24 month follow-up with 73% of
anecortave-treated patients maintaining vision (<3 lines lost)
versus 47% of the placebo group (Kaiser PK, Schaffer HI, Zilliox
P, et al: Posterior juxtascleral depot of anecortave acetate for
subfoveal CNV in AMD: 24-month outcomes. Paper presented
at: American Academy of Ophthalmology Annual Meeting,
Anaheim, CA, 17 Nov 2003). No ocular or systemic safety
issues were idenitified. However, concerns regarding the results
of this trial included the decrease in apparent efficacy with the
12 month time points. Overall, 41% of patients exited the study
between 6 and 12 months, with the highest proportion of
patient dropout occurring in the 15 mg group (48.5%).
The Phase III clinical trial of anecortave acetate for neo-
vascular AMD compared the 15 mg dose to verteporfin
photodynamic therapy in 530 patients with predominantly
classic subfoveal choroidal neovascualrization.56 There was no
statistical difference between the percentage of patients losing
<3 lines of vision (responders) in the anecortave acetate
and PDT groups (45% and 49%, respectively, p = 0.43)
(Fig. 148.14). The confidence interval, however, ranged from
–13.2% favoring PDT to +5.4% favoring anecortave acetate, and
thus the results failed to meet the previously established
noninferiority margin of seven percentage points based on the
Degeneration with Photodynamic Therapy) Study. However,
an analysis of the subgroup of patients for whom drug reflux
at the time of administration was controlled and who received
the second injection within the 6 month treatment window
revealed improved outcomes which would have met the
noninferiority criterion.
Ongoing clinical trials of anecortave acetate include a study
investigating three dosage regimens (15 and 30 mg every
6 months, 15 mg every 3 months) and the Anecortave Acetate
Risk Reduction Trial (AART), which will study the efficacy of
anecortave acetate 15 mg in preventing wet AMD in patients
with high-risk dry AMD over a 4 year period.
SQUALAMINE LACTATE
Another molecule with a unique mechanism of antiangiogenic
activity is squalamine lactate (Evizon, Genaera Corp.) an
aminosterol which potently inhibits growth factor-induced
proliferation and migration of endothelial cells.57 Squalamine
has been shown to cause redistribution of calmodulin within
endothelial cells resulting in disruption of various intracellular
signaling pathways involving calcium.58 In addition to blocking
growth factor mediated signaling, squalamine may also
downregulate integrin expression and induce cytoskeletal
FIGURE 148.14. Per protocol analysis of
percentage of patients losing <15 letters in
study of anecortave acetate vs verteporfin PDT
in patients with predominantly classic CNV due
to AMD (95% confidence limits for difference
between PDT and anecortave on right).
Reprinted from Slakter JS, Bochow TW, D’Amico DJ,
et al: Anecortave acetate (15 milligrams) versus
photodynamic therapy for treatment of subfoveal
neovascularization in age-related macular
degeneration. Ophthalmology 2006; 113(1):3–13 with
permission from the American Academy of
Ophthalmology.
 Anti-VEGF and Other Pharmacologic Treatments for Age-Related Macular Degeneration
rearrangements in endothelial cells59 (Fig. 148.15). Preclinical
studies have suggested the efficacy of squalamine in inhibiting
ocular neovascularization in rodent and primate models.60,61
Several Phase II studies evaluating intravenous squalamine
treatment for wet AMD are ongoing. The largest Phase II trial
is a randomized, multi-center, double-masked, controlled study
involving 108 patients, almost half of whom had active occult
lesions.62 Two different doses of squalamine (40 and 20 mg) are
given as weekly intravenous infusions for the first 4 weeks and
monthly thereafter. PDT is permitted at the discretion of the
investigator. Preliminary results at 24 weeks revealed that 83%
of the patients receiving the 40 mg dose lost <15 letters of
visual acuity compared to 71% of the control group. Five percent
of patients in the 40 mg group and none in the control group
gained 15 or more letters. In those subjects with a fellow-
affected eye (~60%), 11% of the 40 mg group gained ≥15 letters
in the fellow eye versus none in the control group. Infusion site
reactions were the most common treatment-related adverse
events, and no ocular or systemic safety concerns have
arisen. A Phase III trial is ongoing, and another Phase II trial
investigating higher doses is planned.
PIGMENT EPITHELIUM-DERIVED FACTOR
Of the several endogenous inhibitors of angiogenesis that
have been found in ocular tissues, pigment epithelium derived
factor (PEDF) is among the most potent inhibitors of endo-
thelial cell migration in vitro.63 The downregulation of PEDF
has been demonstrated in a mouse model of ischemic
retinopathy,63 and patients with proliferative retinopathy from
diabetes or retinal vein occlusion have been shown to have
decreased vitreous levels of PEDF.64 Since PEDF also appears to
serve a neurotrophic function in the retina,65 therapeutic use of
this growth factor may have additional beneficial effects on
photoreceptor survival in AMD. Additionally, some preclinical
evidence suggests that PEDF could enhance the effect of
verteporfin photodynamic therapy by increasing endothelial
cell apoptosis within choroidal neovascular membranes.66 The
efficacy of PEDF gene transfer using an adenoviral vector in
inhibiting ocular neovascularization has been demonstrated in
FIGURE 148.15. Mechanism of action of
squalamine lactate.
Courtesy of Genaera Corp.
CHAPTER 148
animal models.67–69 Therefore, a Phase I clinical trial of PEDF
gene transfer therapy using intravitreal injection of an
adenoviral vector expressing human PEDF (AdPEDF.11) was
initiated for patients with advanced wet AMD.70 The initial
dose escalation phase has been completed with no evidence of
serious adverse events and no dose-limiting toxicities in 28
subjects. Twenty-five percent of patients experienced mild,
transient ocular inflammation and 21% had increases in
intraocular pressure which responded to topical therapy.
Additional treatment of patients with less advanced neovascular
AMD is planned.
COMBINATION THERAPY
With the availability of multiple modalities for the treatment of
wet AMD, the use of two or more of these agents in
combination is now possible. With goals of improved visual
outcomes and a reduction in frequency of treatments, several
strategies for combination therapy have been and continue to be
explored.
Increasing evidence supports inflammation as a key
component in AMD pathogenesis, providing a rationale for
the use of intravitreal triamcinolone acetonide in the treatment
of neovascular AMD. The inhibitory effect of steroids on
macrophages which secrete angiogenic factors and their ability
to reduce leukocyte adhesion and migration might have
beneficial effects in AMD.71 However, the use of intravitreal
triamcinolone as monotherapy for AMD has proved subop-
timal. In a randomized trial of a single 4 mg dose of intravitreal
triamcinolone acetonide in 151 eyes of 139 patients with neo-
vascular AMD, eyes receiving placebo were noted to have
significantly more growth of the neovascular membrane com-
pared to those receiving triamcinolone at 3 months after treat-
ment.72 However, no difference was noted at 12 months, and
there was no effect of intra-vitreal triamcinolone on visual
acuity loss at 12 months. Another prospective, nonrandomized
study using 25 mg of intravitreal triamcinolone in 115 patients
and 72 controls with exudative AMD demonstrated a visual
acuity benefit at 1 and 3 months follow-up, but not at sub-
sequent follow-ups through a mean of 6 months.73 These 1971
 RETINA AND VITREOUS

findings reveal that the effect of an intravitreally delivered

steroid when used as monotherapy is transient. However, the
use of intravitreal steroids in combination with photodynamic
therapy might have more sustained benefits.
The combination of photodynamic therapy and intravitreal
triamcinolone has shown promising results in early studies.
A small pilot study investigated verteporfin PDT immediately
followed by 4 mg of intravitreal triamcinolone in 26 patients
with neovascular AMD.74 One year results demonstrated a
mean visual acuity improvement of 2.4 lines in patients who
had not received any prior treatment, and an improvement of
0.44 lines in those patients who had been previously treated
with PDT. Retreatment rates were also low, at about 1.2 for both
groups. Ten patients (38.5%) developed an increase in intra-
ocular pressure to greater than >24 mmHg. A larger,
prospective, noncomparative case series of 184 patients with
neovascular AMD, the majority with subfoveal CNV, evaluated
the results of photodynamic therapy followed by intravitreal
SECTION 10

injection of 25 mg triamcinolone within 16 h.75 Over the mean

follow-up of 43 weeks, the mean increase in vision was 1.22
Snellen lines and the mean number of required treatments was
1.21. Topical glaucoma therapy was required in 25% of patients
and 1% required glaucoma surgery. Cataract progression was
observed in 48.73% of phakic eyes. Randomized trials studying
various doses and preparations of triamcinolone acetonide in
combination with verteporfin photodynamic therapy are
ongoing.
Evidence demonstrating increased VEGF expression after
PDT provides one explanation for improved results with PDT
combined with triamcinolone compared to PDT alone and
suggests that combining PDT with anti-VEGF agents should
have similar or superior visual results without steroid-related
side effects. Trials examining the use of anti-VEGF agents in
combination with verteporfin PDT are ongoing. The FOCUS
(RhuFab V2 Ocular Treatment Combining the Use of Visudyne
to Examine Safety) study is a Phase I/II trial investigating
the combination of ranibizumab and PDT versus PDT alone
for predominantly classic CNV76. One year results revealed that
90% of patients treated with the combination therapy avoided
moderate vision loss compared to 68% of patients treated with
PDT alone. The proportion of patients gaining 15 or more
letters was 24% in the combination group compared to 5% in
the PDT-alone group. At month 12, a mean of 0.3 additional
PDT treatments was required in the combination group versus
a mean of 2.4 additional treatments in those receiving PDT
alone.
A lyophilized preparation of ranibizumab was used for this
study and initially given at day 7 after PDT. When a higher
incidence of uveitis was detected in the combination group, the
timing of the intra-vitreal injection was moved to 30 days after
PDT. A second Phase II open-label study using the currently
approved preparation of ranibizumab 0.5 mg administered the
same day as verteprofin PDT showed no safety concerns at the
3 month time point.77 Given the proven benefit of ranibizumab
monotherapy versus PDT for predominantly classic CNV, it
possible that the favorable results of combination therapy with
ranibizumab and PDT were mainly due to ranibizumab.
Additional trials investigating pegaptanib in combination with
PDT are ongoing.
A Phase II trial of three doses of squalamine (10, 20, 40 mg)
combined with verteporfin PDT compared to PDT alone in
45 subjects also suggested an advantage to combination
therapy. At 29 weeks, 90% of patients in the 40 mg + PDT
group had stable vision (loss of ≤15 letters) compared to 71%
receiving PDT alone. The mean change in visual acuity was a
gain of 0.4 letters in the 40 mg combination group versus a loss
1972 of 4.8 letters in those treated with PDT only.78
FIGURE 148.16. Schematic showing process of angiogenesis which
involves extracellular matrix degradation, endothelial cell proliferation
and migration, tube formation, elongation, and remodeling. Numerous
mediators are involved in this cascade providing various targets for
pharmacotherapy.
FUTURE DIRECTIONS
NEW TARGETS
In addition to targeting VEGF mRNA or protein, the angiogenic
stimulus provided by VEGF may be blocked by interfering
with the signaling events induced by activated VEGF receptors
(Fig. 148.16). Various protein kinase C (PKC) isoenzymes are
activated by VEGFR binding and are important mediators in
the resulting angiogenic and permeability responses.79 PKC
inhibition has been shown to reduce retinal and CNV in both
rodent and porcine models.80,81 A PKC beta-inhibitor
ruboxistaurin mesylate (Eli Lilly and Co.) has been shown to
reduce sustained moderate vision loss in patients with
moderate to severe nonproliferative diabetic retinopathy.82
These agents may also prove to be beneficial in neovascular
AMD.
Similarly, VEGFRs belong to the family of tyrosine kinases
and inhibition of this enzymatic function disrupts the down-
stream signaling cascade. Numerous pharmacologic inhibitors
of tyrosine kinases have been synthesized and this class of
drugs has been used with great success in oncology as aberrant
tyrosine kinase activity appears to be pathogenic in certain
malignancies.83,84 Preclinical data suggest the efficacy of
tyrosine kinase inhibitors in models of ocular neovasculari-
zation.85 Vatalanib (PTK787, Novartis Pharmaceuticals) is an
orally administered tyrosine kinase inhibitor with activity
against all three VEGF receptors as well as PDGFR-b, and
c-kit.86 A Phase I/II trial of vatalanib in combination with
 Anti-VEGF and Other Pharmacologic Treatments for Age-Related Macular Degeneration
verteporfin PDT in patients with subfoveal choroidal
neovascularization due to AMD is underway.
Although VEGF certainly plays a causal role in ocular neovas-
cularization, other molecules also modulate the angiogenic
stimulus in the eye. The Tie (Tyrosine kinase with Immuno-
globulin and Epidermal growth factor homology) receptors are
also tyrosine kinase receptors expressed on endothelial cells
which play a role in vascular development.87 Their ligands
are the angiopoietins, of which there are at least four.57 The
interaction of Tie-2 and angiopoietin-1 (Ang-1) is thought to
induce maturation of vessels by promoting the association of
pericytes with endothelial cells. Ang-2 serves as an antagonist,
destabilizing vessels and allowing endothelial cells to respond to
angiogenic stimuli.88 Increased expression of Ang-2 has been
demonstrated in mouse models of retinal neovascularization89
and blockade of Tie-2 can inhibit experimental retinal
neovascularization.90 These molecules may serve as future
targets in the development of antiangiogenic drugs.
Another factor important for vessel maturation is platelet-
derived growth factor-B (PDGF-B), which has been shown to
play a critical role in the recruitment of mural cells to endo-
thelial cells.91 Preclinical studies in several models of ocular
angiogenesis have demonstrated that inhibition of PDGF-B in
addition to VEGF-A appears to be more efficacious at preventing
and regression ocular neovascularization than inhibition of
VEGF-A alone92 (Fig. 148.17). These data suggest that pericyte
loss induced by PDGF-B blockade destabilizes neovasculature
and increases susceptibility to anti-VEGF treatment. Such
combination therapy may lead to improved visual outcomes for
a broader spectrum of patients.
DRUG DELIVERY
The challenge of developing new pharmacologic agents for
the treatment of AMD lies not only in identifying efficacious
FIGURE 148.17. Results of combination
therapy with anti-VEGF aptamer (pegaptanib)
and anti-PDGFR-b antibody (APB5) in mouse
model of laser-induced CNV. Mice were treated
starting at day 7 post-injury. The combination of
VEGF and PDGF pathway inhibition resulted in
the smallest area of CNV.
Reprinted from Jo N, Mailhos C, Ju M, et al: Inhibition
of platelet-derived growth factor B signaling enhances
the efficacy of anti-vascular endothelial growth factor
therapy in multiple models of ocular
neovascularization. Am J Pathol 2006;
168(6):2036–2053 with permission from the American
Society for Investigative Pathology.
CHAPTER 148
strategies but also in creating improved delivery methods.
Repeated intra-vitreal injections present a disadvantage in
terms of risk of endophthalmitis and high frequency of
treatments. Systemic delivery of agents allows for bilateral
treatment but also substantially increases the potential for
nonocular toxicities. The juxtascleral administration of
anecortave acetate given at 6 month intervals offers an
advantage with regard to safety and convenience, and thereby
justifies its potential use in the prevention as well as treatment
of advanced AMD (Fig. 148.18).
The development of sustained-release delivery platforms for
intra vitreal or transcleral administration will provide an
increased level of safety and perhaps also efficacy as long-term,
continuous levels of therapeutic agents will be achieved. A
fluocinolone acetonide implant (Retisert, Bausch and Lomb,
Inc.) is currently available for the treatment of chronic, non-
infectious posterior uveitis,93 and injectable forms of both fluo-
cinolone and dexamethasone intravitreal implants are currently
being investigated in clinical trials. The transcleral delivery of
pegaptanib via poly(lactic-co-glycolic)acid (PLGA) microspheres
has been studied in a rabbit model.94 Biomechanical devices
for transscleral delivery are also under development. These
types of delivery methods may also allow for multiple pharma-
cologic agents to be delivered simultaneously, easily enabling
combination therapy.
The future of pharmacologic therapy for AMD appears
promising. An array of drugs is in development and in ongoing
clinical trials. Our therapeutic approach will likely become
multifaceted as treatment options increase, and combinations
of various agents lead to offer improved visual outcomes. The
identification and treatment of patients at highest risk for
vision loss early in the disease process is a goal that may be
realized soon. Continued progress in the understanding and
management of macular degeneration will one day reduce the
blinding impact of this disease. 1973
 RETINA AND VITREOUS

FIGURE 148.18. The posterior juxtascleral

injection procedure used for delivery of
anaecortave acetate.
From D’Amico DJ, Goldberg MF, Hudson H, et al:
Anecortave acetate as monotherapy for treatment of
subfoveal neovascularization in age-related macular
degeneration: twelve-month clinical outcomes.
Ophthalmology 2003; 110:2372–2383; discussion
2384–2375.
SECTION 10

REFERENCES
1. Ferrara N: VEGF and the quest for tumour
angiogenesis factors. Nat Rev Cancer
2002; 2:795–803.
2. Ide AG, Baker NH, Warren SL:
Vascularization of the Brown Pearce rabbit
epithelioma transplant as seen in the
transparent ear chamber. Am J Roentgenol
1939; 42:891–899.
3. Michaelson IC: The mode of development
of the vascular system of the retina with
some observations on its significance for
certain retinal disorders. Trans Ophthalmol
Soc UK 1948; 68:137–180.
4. Folkman J. Tumor angiogenesis:
therapeutic implications. N Engl J Med
1971; 285:1182–1186.
5. Senger DR, Galli SJ, Dvorak AM, et al:
Tumor cells secrete a vascular permeability
factor that promotes accumulation of
ascites fluid. Science 1983; 219:
983–985.
6. Ferrara N, Henzel WJ: Pituitary follicular
cells secrete a novel heparin-binding
growth factor specific for vascular
endothelial cells. Biochem Biophys Res
Commun. Jun 15 1989; 161:851–858.
7. Keck PJ, Hauser SD, Krivi G, et al: Vascular
permeability factor, an endothelial cell
mitogen related to PDGF. Science 1989;
246:1309–1312.
8. Leung DW, Cachianes G, Kuang WJ, etal:
Vascular endothelial growth factor is a
secreted angiogenic mitogen. Science
1989; 246:1306–1309.
9. Ferrara N, Gerber HP, LeCouter J: The
biology of VEGF and its receptors. Nat Med
2003; 9:669–676.
10. Ishida S, Usui T, Yamashiro K, et al:
VEGF164-mediated inflammation is
required for pathological, but not
physiological, ischemia-induced retinal
neovascularization. J Exp Med 2003;
198:483–489.
11. Plate KH, Breier G, Weich HA, Risau W:
Vascular endothelial growth factor is a
potential tumour angiogenesis factor in
human gliomas in vivo. Nature 1992;
1974 359:845–848.
12. Shweiki D, Itin A, Soffer D, Keshet E:
Vascular endothelial growth factor induced
by hypoxia may mediate hypoxia-initiated
angiogenesis. Nature 1992; 359:843–845.
13. Miller JW, Adamis AP, Shima DT, et al:
Vascular endothelial growth factor/vascular
permeability factor is temporally and
spatially correlated with ocular
angiogenesis in a primate model. Am J
Pathol 1994; 145:574–584.
14. Pierce EA, Avery RL, Foley ED, et al:
Vascular endothelial growth factor/vascular
permeability factor expression in a mouse
model of retinal neovascularization. Proc
Natl Acad Sci USA 1995; 92:905–909.
15. Tolentino MJ, Miller JW, Gragoudas ES, et
al: Vascular endothelial growth factor is
sufficient to produce iris neovascularization
and neovascular glaucoma in a nonhuman
primate. Arch Ophthalmol 1996;
114:964–970.
16. Tolentino MJ, Miller JW, Gragoudas ES, et
al: Intravitreous injections of vascular
endothelial growth factor produce retinal
ischemia and microangiopathy in an adult
primate. Ophthalmology 1996;
103:1820–1828.
17. Adamis AP, Shima DT, Tolentino MJ, et al:
Inhibition of vascular endothelial growth
factor prevents retinal ischemia-associated
iris neovascularization in a nonhuman
primate. Arch Ophthalmol 1996; 114:66–71.
18. Aiello LP, Pierce EA, Foley ED, et al:
Suppression of retinal neovascularization in
vivo by inhibition of vascular endothelial
growth factor (VEGF) using soluble VEGF-
receptor chimeric proteins. Proc Natl Acad
Sci USA 1995; 92:10457–10461.
19. Adamis AP, Miller JW, Bernal MT, et al:
Increased vascular endothelial growth
factor levels in the vitreous of eyes with
proliferative diabetic retinopathy. Am J
Ophthalmol 15 1994; 118:445–450.
20. Aiello LP, Avery RL, Arrigg PG, et al:
Vascular endothelial growth factor in ocular
fluid of patients with diabetic retinopathy
and other retinal disorders. N Engl J Med
1994; 331:1480–1487.
21. Baffi J, Byrnes G, Chan CC, Csaky KG:
Choroidal neovascularization in the rat
induced by adenovirus mediated
expression of vascular endothelial growth
factor. Invest Ophthalmol Vis Sci 2000;
41:3582–3589.
22. Lebherz C, Maguire AM, Auricchio A, et al:
Nonhuman primate models for diabetic
ocular neovascularization using AAV2-
mediated overexpression of vascular
endothelial growth factor. Diabetes 2005;
54:1141–1149.
23. Cui JZ, Kimura H, Spee C, et al: Natural
history of choroidal neovascularization
induced by vascular endothelial growth
factor in the primate. Graefes Arch Clin Exp
Ophthalmol 2000; 238:326–333.
24. Yi X, Ogata N, Komada M, et al: Vascular
endothelial growth factor expression in
choroidal neovascularization in rats.
Graefes Arch Clin Exp Ophthalmol 1997;
235:313–319.
25. Husain D, Ryan AM, Cuthbertson RA, et al:
Vascular endothelial growth factor (VEGF)
expression is correlated with choroidal
neovascularization in a monkey model
[ARVO Abstract]. Invest Ophthalmol Vis Sci
1997; 38:S501.
26. Krzystolik MG, Afshari MA, Adamis AP, et
al: Prevention of experimental choroidal
neovascularization with intravitreal anti-
vascular endothelial growth factor antibody
fragment. Arch Ophthalmol 2002;
120:338–346.
27. Kwak N, Okamoto N, Wood JM,
Campochiaro PA: VEGF is major stimulator
in model of choroidal neovascularization.
Invest Ophthalmol Vis Sci 2000;
41:3158–3164.
28. Frank RN, Amin RH, Eliott D, et al: Basic
fibroblast growth factor and vascular
endothelial growth factor are present in
epiretinal and choroidal neovascular
membranes. Am J Ophthalmol 1996;
122:393–403.
29. Lopez PF, Sippy BD, Lambert HM, et
al:Transdifferentiated retinal pigment
epithelial cells are immunoreactive for
 Anti-VEGF and Other Pharmacologic Treatments for Age-Related Macular Degeneration
vascular endothelial growth factor in
surgically excised age-related macular
degeneration-related choroidal neovascular
membranes. Invest Ophthalmol Vis Sci
1996; 37:855–868.
30. Gragoudas ES, Adamis AP, Cunningham
ET, Jr, et al: Pegaptanib for neovascular
age-related macular degeneration. N Engl J
Med 2004; 351:2805–2816.
31. VISION Clinical Trial Group:Year 2 efficacy
results of 2 randomized controlled clinical
trials of Pegaptanib for neovascular age-
related macular degeneration.
Ophthalmology 2006; 113:1508e–1508.e25.
32. D’Amico DJ, Patel M, Adamis AP, et al:
Pegaptanib sodium for neovascular age-
related macular degeneration: two-year
safety results of the two prospective,
multicenter, controlled clinical trials.
Ophthalmology 2006; 113:992–1001,
e1001–e1006.
33. Hurwitz H, Fehrenbacher L, Novotny W, et
al: Bevacizumab plus irinotecan,
fluorouracil, and leucovorin for metastatic
colorectal cancer. N Engl J Med 2004;
350:2335–2342.
34. Kabbinavar F, Hurwitz HI, Fehrenbacher L,
et al: Phase II, randomized trial comparing
bevacizumab plus fluorouracil
(FU)/leucovorin (LV) with FU/LV alone in
patients with metastatic colorectal cancer.
J Clin Oncol 2003; 21:60–65.
35. Rosenfeld PJ, Brown DM, Heier JS et al.
Marina Study Group. Ranibizumab for
neovascular age-related macular
degeneration. N Engl J Med 2006;
355:1419–1431.
36. Brown DM, Kaiser PK, Michels M et al.;
ANCHOR Study Group. Ranibizumab
versus verteporfin for neovascular age-
related macular degeneration. N Engl J
Med. 2006; 355:1432–1444.
37. Brown DM, Shapiro H, Schneider S, Group
AS: Subgroup analysis of first-year results
of ANCHOR: a Phase III double-masked,
randomized comparison of ranibizumab
and verteporfin photodynamic therapy for
predominantly classic choroidal
neovascularization related to age-related
macular degeneration. Invest Ophthalmol
Vis Sci 2006; 47:ARVO E-abstract 2963.
38. Genentech, Inc: Preliminary results from a
Phase IIIb study showed patients with wet
AMD treated with Lucentis quarterly
experienced a 16-letter benefit over the
control group at one year. Available:
http://www.gene.com/gene/news/press-
releases/display.do?method=detail&id=974
7 2 May 2006.
39. Fung AE, Lalwani GA, Rosenfeld PJ et al.
An optical coherence tomography-guided,
variable dosing regimen with intravitreal
ranibizumab (Lucentis) for neovascular
age-related macular degeneration.
Am J Ophthalmol 2007; 143:566–583
40. Mordenti J, Cuthbertson RA, Ferrara N, et
al: Comparisons of the intraocular tissue
distribution, pharmacokinetics, and safety
of 125I-labeled full-length and Fab
antibodies in rhesus monkeys following
intravitreal administration. Toxicol Pathol
1999; 27:536–544.
41. Michels S, Rosenfeld PJ, Puliafito CA, et al:
Systemic bevacizumab (Avastin) therapy for
neovascular age-related macular
degeneration twelve-week results of an
uncontrolled open-label clinical study.
Ophthalmology 2005; 112:1035–1047.
42. Avery RL, Pieramici DJ, Rabena MD, et al:
Intravitreal bevacizumab (Avastin) for
neovascular age-related macular
degeneration. Ophthalmology 2006;
113:363–372 e365.
43. Rich RM, Rosenfeld PJ, Puliafito CA, et al:
Short-term safety and efficacy of
intravitreal bevacizumab (Avastin) for
neovascular age-related macular
degeneration. Retina 2006; 26:495–511.
44. Spaide RF, Laud K, Fine HF, et al:
Intravitreal bevacizumab treatment of
choroidal neovascularization secondary to
age-related macular degeneration. Retina
2006; 26:383–390.
45. Bashshur ZF, Bazarbachi A, Schakal A, et
al: Intravitreal bevacizumab for the
management of choroidal
neovascularization in age-related macular
degeneration. Am J Ophthalmol 2006;
142:1–9.
46. Bakri SJ, Cameron JD, McCannel CA, et al:
Absence of histologic retinal toxicity of
intravitreal bevacizumab in a rabbit model.
Am J Ophthalmol 2006; 142:162–164.
47. Shahar J, Avery RL, Heilweil G, et al:
Electrophysiologic and retinal penetration
studies following intravitreal injection of
bevacizumab (Avastin). Retina 2006;
26:262–269.
48. Marano RJ, Rakoczy PE: Treatments for
choroidal and retinal neovascularization: a
focus on oligonucleotide therapy and
delivery for the regulation of gene function.
Clin Experiment Ophthalmol 2005;
33:81–89.
49. Acuity Pharmaceuticals. Acuity
Pharmaceuticals reports positive initial
Phase II results for bevasiranib (Cand5) in
wet AMD. Available:
http://www.acuitypharma.com/press/releas
e13.pdf Jun 1, 2006.
50. Sirna Therapeutics. Available:
http://www.sirna.com/wt/page/ocular Aug
4, 2006.
51. Holash J, Davis S, Papadopoulos N, et al:
VEGF-Trap: a VEGF blocker with potent
antitumor effects. Proc Natl Acad Sci USA
2002; 99:11393–11398.
52. Nguyen QD, Shah SM, Browning D, et al:
Results of a Phase I, dose-escalation,
safety, tolerability, and bioactivity study of
intravitreous VEGF Trap in patients with
neovascular age-related macular
degeneration. Invest Ophthalmol Vis Sci.
2006; 47:ARVO E-abstract 2144.
53. Das A, McGuire PG. Retinal and choroidal
angiogenesis: pathophysiology and
strategies for inhibition. Prog Retin Eye Res
2003; 22:721–748.
54. Penn JS, Rajaratnam VS, Collier RJ, Clark
AF: The effect of an angiostatic steroid on
neovascularization in a rat model of
retinopathy of prematurity. Invest
Ophthalmol Vis Sci 2001; 42:283–290.
55. D’Amico DJ, Goldberg MF, Hudson H, et al:
Anecortave acetate as monotherapy for
treatment of subfoveal neovascularization
in age-related macular degeneration:
twelve-month clinical outcomes.
Ophthalmology 2003; 110:2372–2383;
discussion 2384–2375.
56. Slakter JS, Bochow TW, D’Amico DJ, et al:
Anecortave acetate (15 milligrams) versus
photodynamic therapy for treatment of
subfoveal neovascularization in age-related
macular degeneration. Ophthalmology
2006; 113:3–13.
57. Sills AK, Jr., Williams JI, Tyler BM, et al:
Squalamine inhibits angiogenesis and solid
tumor growth in vivo and perturbs
embryonic vasculature. Cancer Res 1998;
58:2784–2792.
58. Chen Q, Williams JI, Anderson MG, et al:
Identification of the intracellular target in
endothelial cells for squalamine as
calmodulin. Available:
http://www.genaera.com/abstracts/
2000_pas_03.html.
59. Garcia CA, Quiroz-Mercado H, Uwaydat S,
et al: A Phase I/II Trial of Intravenous
Squalamine Lactate for Treatment of
Choroidal Neovascularization in Age
Related Macular Degeneration (ARMD).
Invest Ophthalmol Vis Sci 2004; 45: ARVO
E-abstract 2362.
60. Ciulla TA, Criswell MH, Danis RP, et al:
Squalamine lactate reduces choroidal
CHAPTER 148
neovascularization in a laser-injury model in
the rat. Retina 2003; 23:808–814.
61. Genaidy M, Kazi AA, Peyman GA, et al:
Effect of squalamine on iris
neovascularization in monkeys. Retina
2002; 22:772–778.
62. Genaera Corp: Genaera announces interim
Evizon Phase II (MSI-1256F–209) data.
Available: http://www.genaera.com/
pressreleases/March%201,%202006_(2).pdf
Mar 1, 2006.
63. Dawson DW, Volpert OV, Gillis P, et al:
Pigment epithelium-derived factor: a potent
inhibitor of angiogenesis. Science 1999;
285:245–248.
64. Spranger J, Osterhoff M, Reimann M, et al:
Loss of the antiangiogenic pigment
epithelium-derived factor in patients with
angiogenic eye disease. Diabetes 2001;
50:2641–2645.
65. Tombran-Tink J, Barnstable CJ: PEDF: a
multifaceted neurotrophic factor. Nat Rev
Neurosci 2003; 4:628–636.
66. Young TA, Nakazawa T, Sobrin L, et al:
Modulation of apoptosis following
combination PEDF and photodynamic
therapy for choroidal neovascularization in
the rat model. Invest Ophthalmol Vis Sci
2004; 45:ARVO E -abstract 2231.
67. Mori K, Gehlbach P, Ando A, et al:
Regression of ocular neovascularization
in response to increased expression of
pigment epithelium-derived factor. Invest
Ophthalmol Vis Sci 2002; 43:2428–2434.
68. Mori K, Gehlbach P, Yamamoto S, et al:
AAV-mediated gene transfer of pigment
epithelium-derived factor inhibits choroidal
neovascularization. Invest Ophthalmol Vis
Sci 2002; 43:1994–2000.
69. Saishin Y, Silva RL, Saishin Y, et al:
Periocular gene transfer of pigment
epithelium-derived factor inhibits choroidal
neovascularization in a human-sized eye.
Hum Gene Ther 2005; 16:473–478.
70. Campochiaro PA, Nguyen QD, Shah SM,
et al: Adenoviral vector-delivered pigment
epithelium-derived factor for neovascular
age-related macular degeneration: results
of a Phase I clinical trial. Hum Gene Ther
2006; 17:167–176.
71. Ciulla TA, Walker JD, Fong DS, Criswell
MH: Corticosteroids in posterior segment
disease: an update on new delivery
systems and new indications. Curr Opin
Ophthalmol 2004; 15:211–220.
72. Gillies MC, Simpson JM, Luo W, et al: A
randomized clinical trial of a single dose of
intravitreal triamcinolone acetonide for 1975
 RETINA AND VITREOUS
neovascular age-related macular
degeneration: one-year results. Arch
Ophthalmol 2003; 121:667–673.
73. Jonas JB, Degenring RF, Kreissig I, et al:
Exudative age-related macular
degeneration treated by intravitreal
triamcinolone acetonide. A prospective
comparative nonrandomized study. Eye
2005; 19:163–170.
74. Spaide RF, Sorenson J, Maranan L:
Photodynamic therapy with verteporfin
combined with intravitreal injection of
triamcinolone acetonide for choroidal
neovascularization. Ophthalmology 2005;
112:301–304.
75. Augustin AJ, Schmidt-Erfurth U: Verteporfin
therapy combined with intravitreal
triamcinolone in all types of choroidal
neovascularization due to age-related
macular degeneration. Ophthalmology
2006; 113:14–22.
SECTION 10
76. Heier JS, Boyer DS, Ciulla TA et al.;
FOCUS Study Group. Ranibizumab
combined with verteporfin photodynamic
therapy in neovascular age-related macular
degeneration: year 1 results of the FOCUS
Study. Arch Ophthalmol 2006;
124:1532–1542.
77. Schmidt-Erfurth UM, Gabel P, Hohman T,
Group PS. Preliminary results from an
open-label, multicenter, Phase II study
assessing the effects of same-day
administration of ranibizumab (Lucentis)
and verteporfin PDT (PROTECT study).
Invest Ophthalmol Vis Sci 2006; 47:ARVO
E-abstract 2960.
78. Genaera Corp: Genaera presents positive
prelimiary clinical results for Evizon for
treatment of age-related macualr
degeneration at the annual AAO meeting.
Available: http://www.genaera.com/
pressreleases/October%2019,%202005.pdf
Oct 19, 2005.
1976
79. Donnelly R, Idris I, Forrester JV: Protein
kinase C inhibition and diabetic
retinopathy: a shot in the dark at
translational research. Br J Ophthalmol
2004; 88:145–151.
80. Fabbro D, Ruetz S, Bodis S, et al:
PKC412—a protein kinase inhibitor with a
broad therapeutic potential. Anticancer
Drug Des 2000; 15:17–28.
81. Saishin Y, Silva RL, Saishin Y, et al:
Periocular injection of microspheres
containing PKC412 inhibits choroidal
neovascularization in a porcine model.
Invest Ophthalmol Vis Sci 2003;
44:4989–4993.
82. PKC-DMES Study Group. Effect of
ruboxistaurin in patients with diabetic
macular edema: thirty-month results of
the randomized PKC-DMES clinical
trial. Arch Ophthalmol 2007;
125:318–324.
83. Maki RG. Gastrointestinal Stromal Tumors
Respond to Tyrosine Kinase-targeted
Therapy. Curr Treat Options Gastroenterol
2004; 7:13–17.
84. O’Brien SG, Guilhot F, Larson RA, et al:
Imatinib compared with interferon and
low-dose cytarabine for newly diagnosed
chronic-phase chronic myeloid
leukemia. N Engl J Med 2003;
348:994–1004.
85. Unsoeld AS, Junker B, Mazitschek R, et al:
Local injection of receptor tyrosine kinase
inhibitor MAE 87 reduces retinal
neovascularization in mice. Mol Vis 2004;
10:468–475.
86. Thomas AL, Morgan B, Horsfield MA,
et al: Phase I study of the safety,
tolerability, pharmacokinetics, and
pharmacodynamics of PTK787/ZK 222584
administered twice daily in patients with
advanced cancer. J Clin Oncol 2005;
23:4162–4171.
87. Sato TN, Tozawa Y, Deutsch U, et al:
Distinct roles of the receptor tyrosine
kinases Tie-1 and Tie-2 in blood vessel
formation. Nature 1995; 376:70–74.
88. Hanahan D: Signaling vascular
morphogenesis and maintenance. Science
1997; 277:48–50.
89. Hackett SF, Ozaki H, Strauss RW, et al:
Angiopoietin 2 expression in the retina:
upregulation during physiologic and
pathologic neovascularization. J Cell
Physiol 2000; 184:275–284.
90. Hangai M, Moon YS, Kitaya N, et al:
Systemically expressed soluble Tie2
inhibits intraocular neovascularization. Hum
Gene Ther 2001; 12:1311–1321.
91. Hellstrom M, Kalen M, Lindahl P, et al:
Role of PDGF-B and PDGFR-beta in
recruitment of vascular smooth muscle
cells and pericytes during embryonic blood
vessel formation in the mouse.
Development 1999; 126:3047–3055.
92. Jo N, Mailhos C, Ju M, et al: Inhibition of
platelet-derived growth factor B signaling
enhances the efficacy of anti-vascular
endothelial growth factor therapy in
multiple models of ocular
neovascularization. Am J Pathol 2006;
168:2036–2053.
93. Jaffe GJ, Martin D, Callanan D, et al:
Fluocinolone acetonide implant (Retisert)
for noninfectious posterior uveitis:
Thirty-four week results of a multicenter
randomized clinical study. Ophthalmol
2006; 113:1020–1027.
94. Carrasquillo KG, Ricker JA, Rigas IK,et al:
Controlled delivery of the anti-VEGF
aptamer EYE001 with poly(lactic-co-
glycolic)acid microspheres. Invest
Ophthalmol Vis Sci 2003; 44:290–299.
 CHAPTER
Surgical Treatments of Neovascular Age-Related
149 Macular Degeneration
Sunil K. Srivastava and Cynthia A. Toth
Overview
Surgical therapy for neovascular age-related macular
degeneration (AMD) continues to evolve with refinements in
technique and integration with developments in pharmacologic
therapy. Currently available surgical treatments for neovascular
AMD may provide useful options for salvage of vision when
medical treatments are not enough. Some of the techniques
discussed such as subretinal hemorrhage displacement, and
macular translocation with 360-degree retinectomy may be
effective in restoring vision in patients with lesions not generally
treatable with medical therapy. Other therapies such as RPE
transplantation are in early stages of promising development. The
indications and techniques and evolution of the surgical
therapies for AMD are discussed in this chapter.
The treatment of neovascular age-related macular degeneration
(AMD) has included laser photocoagulation, photodynamic
therapy, radiation, use of pharmacologic agents, and in some
cases surgical intervention. Surgical therapies have been
utilized primarily for neovascular AMD and also in few cases
of geographic atrophy. The surgeries for AMD presented here:
submacular surgery, hemorrhage displacement, limited or full
macular translocation, and transplantation of retinal pigment
epithelium (RPE) will continue to evolve, affected by the rapid
evolution of novel pharmacologic therapies.
Major Complications
Submacular Surgery
Retinal detachment
Proliferative vitreoretinopathy
Vitreous hemorrhage
Cataract formation
Persistence or recurrence of CNV
Displacement of Subretinal Hemorrhage
Retinal detachment
Proliferative vitreoretinopathy
Vitreous hemorrhage
Cataract formation
Recurrence of subretinal hemorrhage
Persistence or recurrence of CNV
Limited Macular Translocation
Retinal detachment
Proliferative vitreoretinopathy
Recurrence of CNV after laser or other therapy
Cataract formation
Macular fold
Macular hole
Subretinal hemorrhage
Scleral perforation
Major Complications
Full Macular Translocation
Retinal detachment
Proliferative vitreoretinopathy
Recurrence of CNV or subretinal hemorrhage
Cystoid macular edema
Hypotony
Glaucoma
Epiretinal membrane
Keratopathy
Note that many of the more common, but not all, complications reported with
each surgery are included on this list.
SUBMACULAR SURGERY
The goal of submacular surgery is to remove the choroidal
neovascularization (CNV) and hemorrhage if present and
to re-establish the normal anatomy between retina and RPE.
The poor visual outcomes associated with the Macular
Photocoagulation Study and the encouraging results in early
submacular surgery case series generated interest in these
procedures.1–3
The surgeon considers lesion size and location when
determining a site for CNV removal through a posterior retino-
tomy. During vitrectomy the posterior hyaloid is separated. A
retinotomy is created and balanced salt solution is injected
beneath the retina or a pick may be passed over the CNV to
separate retinal connections. The surface of the membrane is
grasped with forceps and it is removed from the subretinal space
(Fig. 149.1). If the membrane is not free, attachments are cut
with a blade or scissors. Most importantly, intraocular pressure
is elevated prior to and during removal of the CNV, then
lowered once hemostasis is assured. For subretinal hemorrhage
(clot) removal, subretinal tissue plasminogen activator (tPA)
12.5–50 mg is sometimes injected for thrombolysis 30–45 min
prior to hemorrhage removal. Blood is then aspirated or pulled
from the subretinal space. A fluid to air or gas exchange is
performed and the patient is positioned upright or face down for
the first postoperative day.2–7
The Submacular Surgery Trials (SSTs), randomized prospec-
tively clinical trials, compared submacular surgery to obser-
vation for two groups of AMD patients, those with large or
poorly demarcated, new subfoveal CNV (group N)6 and those
with predominantly hemorrhagic lesions (group B).7 For group
N, at 2 years the surgery and observation groups had no
significant difference in results. A successful outcome (defined
as <1 line best corrected vision loss) occurred in 41% and 44%,
respectively. In both groups at 24 months there was a 2 line
1977
 RETINA AND VITREOUS
IOP elevated during CNV removal Subretinal
forceps
Retinotomy away from fovea
Grasp CNV Retina
beneath retina
CNV RPE
Avoid RPE-Bruchís damage by
grasping anterior surface of CNV
SECTION 10
FIGURE 149.1. Submacular surgery technique for removal of
choroidal neovascularization. The focal retinotomy is located away
from the fovea with attention to limiting subretinal instrument contact
with retinal pigment epithelium and choroid.
median vision loss and median acuity dropped from 20/100 to
20/400. Analysis of vision-related quality of life scores revealed
higher scores in the SST surgery group; however, based on
the visual acuity findings, submacular surgery could not be
recommended for patients with AMD and new subfoveal
lesions. Given these results, submacular surgery is currently
not indicated for the treatment of CNV associated with AMD.
Key Feature
Submacular surgery trials (SST) showed no visual benefit with
surgery when compared to observation for patients with new
subfoveal CNV secondary to AMD. For predominantly hemorrhagic
lesions secondary to AMD the SST found a reduced risk of severe
vision loss with surgery when compared to observation, but a high
risk of rhegmatogenous retinal detachment in the surgery group.
In SST group B (hemorrhagic lesions) the surgical technique
was similar to that described above, with both blood and CNV
removed whenever possible.7 The surgeon chose whether to
use tPA (used in 38% of Group B cases). At 24 months, the
majority, 56% of surgery eyes and 59% of observation eyes,
experienced loss of >2 lines acuity, and 18% of eyes in each
group improved at least 2 lines. In contrast to earlier case series
which had shown a trend toward better visual acuity when
subretinal blood was removed within 1 week,5 the SST did not
show improvement in acuity in the surgery group compared
to observation; however, there was no cutoff with regards to the
length of time that the hemorrhage was present, nor was there
documentation of good visual acuity before the hemorrhage.
Compared to the observation group, surgery eyes had higher
rates of retinal detachments (16% vs 2%) and of cataract surgery
(44% vs 6%), but a lower rate of severe vision loss (greater than
6 lines) (21% vs 36%).7 It is difficult to recommend submacular
surgery for submacular hemorrhage in AMD given the high rates
of complications and the pressure of other treatment options.
The observation of poor vision after intervention in both of
these AMD surgery groups in the SST is thought likely due to
damage to the retina and underlying RPE by CNV, hemorrhage,
surgical manipulation and postoperative absence of RPE in
the surgical bed.8,9 The development of alternate therapies for
neovascular AMD has further diminished interest in submacular
surgery alone.
1978
DISPLACEMENT OF SUBMACULAR
HEMORRHAGE
The prognosis for visual acuity is poor for submacular
hemorrhage associated with neovascular AMD,10–12 especially
with larger and thicker hemorrhages which cause photoreceptor
damage from clot contraction, direct iron toxicity, and the
blockade of metabolic products exchange.13,14 In light of the
potential for damage to retina and RPE during clot extraction,
even with tPA, Heriot (presentation at American Academy of
Ophthalmology Vitreoretinal Update, San Francisco, CA, 1997)
proposed subretinal hemorrhage displacement. He described
injection of tPA into the vitreous cavity, followed by injection
of a gas bubble with the goal of clot lysis and then displacement
with positioning. Although subretinal hemorrhage was suc-
cessfully displaced using this method, with some improvement
in visual acuity,15,16 it was unclear whether intravitreal tPA
reached the subretinal space, since others displaced blood with
intravitreal injections of gas alone and prone positioning.17
Alternately, Haupert et al described successful hemorrhage
displacement after pars plana vitrectomy with subretinal tPA
injection followed by fluid to air or gas exchange and prone
postoperative positioning in 11 patients.18 Two series followed
with a similar technique that added postoperative supine
positioning for the first hour and head down19 or upright
positioning for blood displacement (Fig. 149.2).20 Patients in all
three series had either partial or complete displacement of
the blood from the subfoveal space with early vision improve-
ment in the majority of eyes. With follow-up averaging from 3
to 17 months, hemorrhage recurred in 4–28% of eyes. Unlike
surgery for removal of subretinal hemorrhage, there was only
one retinal detachment in the 57 eyes in these three series.18–20
Final visual acuity decreased compared to best postoperative
acuity though some patients received photodynamic therapy or
pegaptanib sodium injection.19,20 These studies are limited by
their small numbers and lack of control group (Fig. 149.3).
In surgical therapy of subretinal hemorrhage, the earlier
submacular surgical techniques led to less invasive approaches
with the addition of adjuvants such as photodynamic or anti-
VEGF therapy after hemorrhage displacement. Submacular
surgery in randomized trials showed no significant improve-
Subfoveal blood After subretinal tPA and
before displacement fluid-air exchange
Fovea Vitreous gel Fovea Displaced Air
blood
FIGURE 149.2. Illustration of hemorrhage displacement after injection
of subretinal tPA, fluid–air exchange and upright positioning.
Hemorrhage displacement with upright positioning based on research
and diagrams presented by Marcin Stopa, MD, Duke University Eye
Center Resident’s Day, June 24, 2005.
 Surgical Treatments of Neovascular Age-Related Macular Degeneration

a b c

CHAPTER 149
d e f

FIGURE 149.3. Subretinal hemorrhage displacement. (a) Preoperative color fundus photograph
and (b) late fluorescein angiogram of an 8-day-old subretinal hemorrhage. Preoperative distance
visual acuity was 20/400 in this eye with no previous treatment. (c) Color fundus photograph and
(d) early and (e) late fluorescein angiograph 1 week after hemorrhage displacement by vitrectomy,
subretinal tPA injection and fluid–air exchange. At this exam the patient received photodynamic
therapy and subsequently this eye was treated with two injections of intravitreal bevacizumab.
Color fundus photograph (f) and late fluorescein angiogram (g) 9 months later when visual acuity
was 20/400.

ment compared to observation. Though the rate of severe vision
loss was lower with surgical removal of hemorrhage than with
observation, the rate of retinal detachment was high. Given the
poor natural history of submacular hemorrhage, and the low
rate of complications after intravitreal or subretinal injection of
tPA and air or gas displacement, this therapy is a reasonable
consideration, though timing and coordination with use of
adjuvant anti-VEGF or other therapy awaits results of further
study. A meta-analysis of submacular surgery procedures
provides a useful background for this decision making, though
techniques such as hemorrhage displacement are considered
together with hemorrhage removal in the analysis.21
MACULAR TRANSLOCATION
In contrast to submacular surgery or hemorrhage displacement,
macular translocation surgery seeks to relocate the macula to a
healthier site of RPE and choriocapillaris to prevent further
degeneration and possibly recover vision. Since the initial report
of Machemer,22 the technique of macular translocation has
evolved into two techniques: limited macular translocation
(LMT) or full macular translocation with 360o retinectomy
(MT360, also known as retinal rotation).
LIMITED MACULAR TRANSLOCATION
LMT relocates the retina by pinning detached retina against
the eye wall using a partial air or gas fill to create a downward
shift in the detached fovea and inferior retina to a site of
healthier RPE and choriocapillaris; the shift is accentuated by
also folding the choroid and sclera in the superotemporal
quadrant in the bed of the retinal detachment.23,24 Horizontal
mattress sutures preplaced in the superior temporal sclera are
tied to infold the sclera only after completion of vitrectomy and
1979
 RETINA AND VITREOUS

Scleral imbrication Translocation during upright

sutures positioning after surgery

Gas fill 1
2

Retinal fold

Translocation of fovea from

original site (1) to site 2
SECTION 10

FIGURE 149.4. Illustration of limited macular translocation technique

with partial retinal detachment and displacement of subretinal fluid
and of the fovea with partial fluid–gas exchange along with scleral
infolding.
FIGURE 149.5. Microperimetry field with good fixation (pale blue
dots) 2 years after limited macular translocation surgery and laser
treatment of the choroidal neovascular membrane (which became
juxtafoveal after the retina was shifted by the limited macular
translocation surgery).

detachment of temporal retina through injection of subretinal

fluid. Then a partial fluid to air exchange is performed.
Translocation occurs after surgery when the patient is Translocation during surgery
positioned upright. The bubble holds the retina against the Retina is detached and Fovea moved to new site 2
imbrication and subretinal fluid accumulates inferiorly shifting cut 360-degrees at the ora serrata from old site 1
the retina. After reattachment, an inferior retinal fold is seen
early in the postoperative period (Fig. 149.4).
LMT changes the CNV location from subfoveal to juxtafoveal
or extrafoveal, depending on distance of translocation, with Translocation
laser photocoagulation typically applied to the CNV early after 2
surgery (Fig. 149.5).25 Foveal displacement with LMT averages
1200–1600 mm depending on the technique and series. In the 1
largest series reported (102 patients), effective translocation off
the CNV was seen in 60% of patients and mean visual acuity
was unchanged with 40% of eyes gaining >2 Snellen lines, 29%
of eyes unchanged and 31% losing >2 Snellen lines.25 CNV
recurred in 35% of eyes after effective macular translocation and
10 eyes developed retinal detachments. A retrospective com- Subfoveal hemorrhage Hemorrhage removed
with RPE tear
parison of LMT versus photodynamic therapy found comparable
postoperative visual acuities (both 20/200) but vision loss
greater with photodynamic therapy.26 The improvement in new FIGURE 149.6. Illustration summarizing macular translocation with
therapies for subfoveal, small CNV may reduce efforts to relocate 360° retinectomy surgery. The fovea is shifted onto a new RPE bed
CNV to an extrafoveal location for treatment. If small subfoveal during surgery and is held in place with silicone oil during the early
scars persist after alternate therapy and diminish acuity, LMT postoperative period.
might then be considered for relocation of the fovea.

within months. Extraocular muscle surgery is performed at the

FULL MACULAR TRANSLOCATION WITH 360°
RETINECTOMY
Machemer initially proposed MT360 surgery in the era of
submacular surgery development. Though recognized as com-
plex surgery, MT360 allows > 3000 mm foveal movement,
enough to translocate off large hemorrhage, large CNV, or
fibrosis. The retinal rotation produces torsional diplopia,
treated by Eckardt et al with extraocular muscle surgery to
counter-rotate the globe.27 MT360 surgery currently includes a
thorough vitrectomy followed by injection of subretinal fluid
to totally detach the retina. The peripheral retina is cut at the
ora serrata, subretinal membrane and/or blood is removed, and
the retina is translocated, usually superiorly, off the CNV bed
and pinned in the new location with perfluorocarbon liquid
(Fig. 149.6). Retinectomy margins are photocoagulated and the
1980 perfluorocarbon is exchanged for silicone oil which is removed
time of translocation or in a separate surgery.
Translocation case series have included subfoveal CNV, RPE
tears, disciform scars, hemorrhages, previous photocoagulation,
and photodynamic therapy. With median follow-up ranging
from 10 to 21 months, seven of nine studies showed stabili-
zation or improvement of vision after macular translocation
surgery29 and distance acuity improved in 52–66% of patients
in three series.27,28,30,31 At 1 year after MT360, prospective studies
have also shown improvement in reading speed, color vision,
contrast, near acuity,32 critical print size,33 and in vision-related
quality of life.34
Retinal detachment rates after macular translocation were
highest in early case series (up to 43%).29 Other complications
include cystoid macular edema, CNV recurrence, hypotony,
epiretinal membranes, and keratopathy.29 In the meta-analysis
of surgery for AMD, estimated rates of complications were
 Surgical Treatments of Neovascular Age-Related Macular Degeneration

resulted in good vision recovery in patients after photodynamic

Treatment of Neovascular AMD therapy38 and after anti-VEGF therapy (Fig. 149.8).
1st eye: Is patient eligible for non-surgical treatment ?
Consider No Yes TRANSPLANTATION OF RETINAL PIGMENT
displacement of blood Non-surgical treatment EPITHELIUM
2nd eye: Is patient eligible for non-surgical treatment ? Work on transplantation of healthy RPE into the subfoveal
No space of eyes with AMD has followed from reports of poor
Yes acuity after submacular surgery and of improved acuity after
Start non-surgical treatment
macular translocation onto a healthier RPE bed. The pigment
cell transplantation techniques are combined with conventional
Is impairment visually significant
submacular surgery in eyes with neovascular AMD. In one
and not responding to treatment ?
technique, RPE cells are first harvested from irrigation of the
Yes No nasal subretinal space and are directly transplanted onto
the site of CNV removal.39 Alternately, an adjacent RPE patch
or a choroidal–RPE patch excised from the superior periphery
Consider MT360 Continue other treatment is placed beneath the fovea (Fig. 149.9).40–44 These techniques
or displacement of blood are still early in their evolution and results have been limited

FIGURE 149.7. Decision-making algorithm for treating AMD with
vision loss.
highest for macular translocation surgery.21 Despite these
complication rates, in a prospective 4 year study of 64 patients,
Toth found that acuity of 20/80 or better was maintained in
46–51% of eyes from 1 through 4 years after MT360 with RD
rate below 8% in this series.31
In light of the risks of complications, and the potential for
vision gain, the decision whether to pursue MT360 is complex.
Nonsurgical therapies now display improved results with low
rates of complications.35–37 Thus in cases where patients fail
primary therapies or when there is no effective treatment
MT360 is a reasonable salvage therapy, but one would not likely
consider surgical intervention until medical therapies have
first been utilized (Fig. 149.7), particularly since MT360 has
CHAPTER 149
with some notable recovery of acuity despite complications
such as graft failure, fibrosis, and retinal detachment. Refine-
ments in the surgery and improvements in the generation/
harvesting of RPE grafts will hopefully make this a viable
option for patients.39–44
Key Feature
In light of the complexity of surgery, macular translocation with
360° peripheral retinectomy could be considered for the second
eye with vision loss from hemorrhagic or neovascular AMD when
primary therapies fail or are ineffective.
The techniques described have been centered on manage-
ment of neovascular AMD and not geographic atrophy.
Although submacular surgery provides no advantage to eyes
with geographic atrophy, macular translocation surgery or
RPE transplantation techniques could be useful in cases of

a b c

d e f

FIGURE 149.8. Macular translocation in an eye that has already received juxtafoveal laser photocoagulation, photodynamic therapy and
pegaptanib injection. (a) Preoperative color fundus photograph, (b) late angiogram and (c) OCT scan of right eye show a fibrotic subfoveal lesion
with almost no leakage. The visual acuity at distance was 20/200, and at near was J16 with +4 add. The patient had received four treatments
with photodynamic therapy in the 20/800 fellow eye. (d) Color fundus photograph, (e) late fluorescein angiographic frame, and (f) OCT after
macular translocation surgery in the right eye. Visual acuity recovered to 20/50 distance and 20/40 near with the patient resuming normal reading
tasks. 1981
 RETINA AND VITREOUS

loss of RPE, if the retina and choriocapillaris could maintain

Site of lasered margins function or recover after the surgery. In small series, patients
excised retina RPE and choroid with geographic atrophy have recovered acuity after macular
RPE-choroid transplant
translocation, though later some eyes have developed recurrent
RPE-choroid transplant unfolded under fovea
in bed of removed CNV
geographic atrophy in a pattern echoing the preoperative
(retina discarded)
lesion.45,46 It may become possible to combine surgery –
Forceps CNV bed whether translocation or transplantation – with adjuvant
therapies to prevent recurrent atrophy in the future. Until then,
response to these therapies provides new insight into the pro-
gression of atrophic disease and should be cautiously pursued.
As treatment for neovascular AMD shifts from laser
photocoagulation to intravitreal delivery of antineovascular
drugs, long-term sustained-delivery devices will likely be
developed. Adaptation of current devices which allow sustained
delivery of corticosteroids47–49 or new devices will provide sus-
tained intravitreal delivery of pharmacologic agents for AMD
and reduce the risks associated with multiple intravitreal
injections.
SECTION 10

Enlarged retinotomy Intraoperative temporary The first line of therapy for neovascular AMD primarily
perfluorocarbon bubble involves medical and laser therapy. Surgical techniques such
Bed where CNV removed
transplant after submacular surgery
before fluid-air exchange as hemorrhage displacement, macular translocation, and RPE
cell transplantation play a role in the treatment paradigm
(Fig. 149.9) of neovascular AMD. Developments in surgical
FIGURE 149.9. Illustration of RPE–choroid transplant surgery. technique, adjuvants (such as growth factors), and drug therapy
Choroidal neovascularization is removed as in Figure 149.1. The will have a significant impact on the evolution of future surgical
RPE–choroid transplant is harvested from the mid-periphery, avoiding treatments of AMD.
large choroidal vessels with retina removed from the surface. The
transplant is placed into the subretinal space through an enlarged
retinotomy and is unrolled to flatten beneath the retina and an
intravitreal perfluorocarbon bubble.

REFERENCES
1. Macular Photocoagulation Study Group:
Laser photocoagulation of subfoveal
recurrent noevascular lesions in age-related
macular degeneration: results of a
randomized clinical trial. Arch Ophthalmol
1991; 109:1232–1241.
2. Thomas MA, Dickinson JD, Melberg NS,
et al. Visual results after surgical removal of
subfoveal choroidal neovascular membranes.
Ophthalmology 1994; 101:1384–1396.
3. Thomas MA, Grand MG, Williams DF, et al:
Surgical management of subfoveal
choroidal neovascularization.
Ophthalmology 1992; 99:952–968.
4. De Juan E, Machemer R: Vitreous surgery
for hemorrhagic and fibrous complications
of age-related macular degeneration. Am J
Ophthalmol 1988; 105:25–29.
5. Lewis H: Intraoperative fibrinolysis of
submacular hemorrhage with tissue
plasminogen activator and surgical drainage.
Am J Ophthalmol 1994; 5:559–568.
6. Submacular Surgery Trials Research Group:
Surgery for subfoveal choroidal
neovascularization in age-related macular
degeneration: ophthalmic findings: SST
report no. 11 Ophthalmology 2004;
11:1967–1980.
7. Submacular Surgery Trials Research Group:
Surgery for hemorrhagic choroidal
neovascular lesions of age-related macular
degeneration: ophthalmic findings: SST
report no. 13. Ophthalmology 2004;
11:1993–2006.
8. Grossniklaus HE, Hutchinson AK, Capone A,
et al: Clinicopathologic features of
1982 surgically excised choroidal neovascular
membranes. Ophthalmology 1994;
101:1099–1111.
9. Nasir MA, Sugino I, Zarbin MA: Decreased
choriocapillaris perfusion following surgical
excision of choroidal neovascular
rmembranes in age-related macular
degeneration. Br J Ophthalmol 1997;
81:481–489.
10. Scupola A, Coscas G, Sourbrane G,
Balestrazzi E: Natural history of macular
subretinal hemorrhage in age-related
macular degeneration. Ophthalmologica
1999; 213:97–102.
11. Avery RL, Fekrat S, Hawkins BS, Bressler
NM: Natural history of subfoveal subretinal
hemorrhage in age-related macular
degeneration. Retina 1996; 16:183–189.
12. Bennett SR, Folk JC, Blodi CF, Klugman M:
Factors prognostic of visual outcome in
patients with subretinal hemorrhage. Am J
Ophthalmol 1990; 109:33–37.
13. Glatt H, Machemer R: Experimental
subretinal hemorrhage in rabbits. Am J
Ophthalmol 1982; 94:762–773.
14. Toth CA, Morse LS, Hjelmeland LM, Lander
MBD: Fibrin directs early retinal damage
after experimental subretinal hemorrhage.
Arch Ophthalmol 1991; 109:723–729.
15. Schulze SD, Hesse L: Tissue plasminogen
activator plus gas injection in patients with
subretinal hemorrhage caused by age-
related macular degeneration: predictive
variables for visual outcome. Graefes Arch
Clin Exp Ophthalmol 2002; 240:717–720.
16. Hassan AS, Johnson MW, Schneiderman
TE, et al: Management of submacular
hemorrhage with intravitreous tissue
plasminogen activator injection and
pneumatic displacement. Ophthalmology
1999; 106:1900–1906.
17. Daneshvar H, Kertes PJ, Leonard BC,
Peyman G: Management of submacular
hemorrhage with intravitreal sulfur
hexafluoride: a pilot study. Can J
Ophthalmol 1999; 34:385–388.
18. Haupert CL, McCuen BW II, Jaffe GJ, et al:
Pars plana vitrectomy, subretinal injection
of tissue plasminogen activator and fluid-
gas exchange for displacement of thick
submacular hemorrhage in age-related
macular degeneration. Am J Ophtalmol
2001; 131:208–215.
19. Olivier S, Chow DR, Packo KH, et al:
Subretinal recombinant tissue plasminogen
activator injection and pneumatic
displacement of thick submacular
hemorrhage in age-related macular
degeneration. Ophthalmology 2004;
6:1201–1208. Erratum. Ophthalmology
2004; 9:1640.
20. Singh RP, Patel C, Sears JE: Management
of subretinal macular haemorrhage by
direct administration of tissue plasminogen
activator. Br J Ophthalmol 2006;
4:429–431.
21. Falkner CI, Leitich H, Frommlet F, et al: The
end of submacular surgery for age-related
macular degeneration? A meta-analysis.
Graefes Arch Clin Exp Ophthalmol 2007;
245:490–501.
22. Machemer R, Steinhorst UH: Retinal
separation, retinotomy and macular
relocation. II. A surgical approach for age-
related macular degeneration? Graefes
 Surgical Treatments of Neovascular Age-Related Macular Degeneration
Arch Clin Exp Ophthalmol 1993;
231:635–641.
23. De Juan E, Lowenstein A, Bressler NM,
et al: Translocation of the retina for
management of subfoveal chroidal
neovascularization. II: a preliminary report
in humans. Am J Ophthalmol 1998;
125:635–646.
24. Lewis H, Kaiser P, Lewis S, Estafanous M:
Macular translocation for subfoveal
choroidal neovascularization in age-related
macular degeneration: a prospective study.
Am J Ophthalmol 1999; 128:135–146.
25. Fujii GY, De Juan E, Pieramici DJ, et al:
Inferior limited macular translocation for
subfoveal chroidal neovascularization
secondary to age-related macular
degeneration: 1 year visual outcome and
recurrence report. Am J Ophthalmol 2002;
134:69–74.
26. Pawlak D, Glacet–Bernard A, Papp M, et al:
Limited macular translocation compared
with photodynamic therapy in the
management of subfoveal choroidal
neovascularization in age-related macular
degeneration. Am J Ophthalmol 2004;
137:880–887.
27. Eckardt C, Eckardt U, Conrad HG: Macular
rotation with and without counterrotation of
the globe in patients with age-related
macular degeneration. Graefes Arch Clin
Exp Ophthalmol 1999; 237:313–325.
28. Toth CA, Freedman SF: Macular
translocation with 360° peripheral
retinectomy: impact of technique and
surgical experience on visual outcomes.
Retina 2001; 21:293–303.
29. Cahill M, Toth CA: Macular translocation
surgery. In: Stephen JR, ed. Retina.
4th edn. Philadelphia, PA: Mosby; 2004.
30. Pertile G, Claes C: Macular translocation
with 360° retinotomy for management of
age-related macular degeneration with
subfoveal choroidal neovascularization.
Am J Ophthalmol 2002; 134:560–565.
31. Mruthyunjaya P, Stinnett SS, Toth CA:
Change in visual function after macular
translocation surgery with 360° peripheral
retinectomy for neovascular age-related
macular degeneration. Ophthalmology
2004; 111:1715–1724.
32. Toth CA, Lapolice DJ, Banks AD,
Stinnett SS: Improvement in near visual
function after macular translocation surgery
with 360o peripheral retinectomy. Graefes
Arch Clin Exp Ophthalmol 2004;
242:541–548.
33. Fujikado T, Asonuma S, Ohji M, et al:
Reading ability after macular translocation
surgery with 360o retinotomy. Am J
Ophthalmol 2002; 134:849–856.
34. Cahill MT, Stinnett SS, Banks AD, et al:
Quality of life after macular translocation
with 360 degree peripheral retinectomy for
age related macular degeneration.
Ophthalmology 2005; 112:144–151.
35. Blinder KJ, Bradley S, Bressler NM, et al:
Effect of lesion size, visual acuity, and
lesion composition on visual acuity change
with and without verteporfin therapy for
choroidal neovascularization secondary to
age-related macular degeneration: TAP and
VIP report no. 1. Am J Ophthalmol 2003;
136:407–418.
36. Gragoudas ES, Adamis AP, Cunningham ET,
et al: Pegaptanib for neovascular age-
related macular degeneration. N Engl J
Med. 2004; 351:2805–2816.
37. Heier JS, Antoszyk AN, Pavan PR, et al:
Ranibizumab for treatment of neovascular
age-related macular degeneration: a phase
I/II multicenter, controlled, multidose study.
Ophthalmology 2006; 113:633–642.e1–4.
38. Park CH, Toth CA: Macular translocation
surgery with 360o peripheral retinectomy
following ocular photodynamic therapy of
choroidal neovascularization. Am J
Ophthalmol 2003; 136:830–835.
39. Binder S, Krebs I, Hilgers RD, et al:
Outcome of transplantation of autologous
retinal pigment epithelium in age-related
macular degeneration: a prospective trial.
Invest Ophthalmol Vis Sci 2004;
45:4151–4160.
40. Stanga PE, Kychenthal A, Fitzke FW, et al:
Retinal pigment epithelium translocation
after choroidal neovascular membrane
removal in age-related macular
degeneration. Ophthalmology 2002;
109:1492–1498.
41. Van Meurs JC, ter Averst E, Hofland LJ,
et al: Autologous peripheral retinal pigment
epithelium translocation in patients with
subfoveal neovascular membranes. Br J
Ophthalmol 2004; 88:110–113.
42. Van Meurs JC, Van Den Biesen PR:
Autologous retinal pigment epithelium and
choroid translocation in patients with
exudative age-related macular
degeneration: short-term follow-up. Am J
Ophthalmol 2003; 136:688–695.
43. Stanga PE, Kychenthal A, Fitzke FW, et al:
Retinal pigment epithelium translocation
after choroidal neovascular membrane
removal in age-related macular
degeneration. Ophthalmology 2002;
109:1492–1498.
44. MacLaren RE, Bird AC, Sathia PJ,
Awylard GW: Long-term results of
submacular surgery combined with macular
translocation of the retinal pigment
epithelium in neovascular age-related
CHAPTER 149
macular degeneration. Ophthalmology
2005; 112:2081–2087.
45. Eckardt C, Eckardt U: Macular
translocation in nonexudative age-related
macular degeneration. Retina 2002;
22:786–794.
46. Cahill MT, Mruthyunjaya P, Bowes
Rickman C, Toth CA: Recurrence of retinal
pigment epithelial changes after macular
translocation with 360 degrees peripheral
retinectomy for geographic atrophy. Arch
Ophthalmol 2005; 123:935–938.
47. Jaffe GJ, Martin DF, Callanan D, et al:
Fluocinolone acetonide implant (Retisert)
for noninfectious posterior uveitis: thirty-
four week results of a multicenter
randomized clinical study. Ophthalmology
2006; 113:1020–1027.
48. Tan DT, Chee SP, Lim L, et al: Randomized
clinical trial of Surodex steroid drug
delivery system for cataract surgery:
anterior versus posterior placement of two
Surodex in the eye. Ophthalmology 2001;
108:2172–2181.
49. Srivastava S, Mruthyunjaya P, Wiser J,
et al: Intravitreal sustained-release
fluocinolone acetonide device to treat
severe experimental uveitis. Association for
Research in Vision and Ophthalmology.
Orlando, Florida; 2005:3536.
1983
 CHAPTER
150 Acute Idiopathic Maculopathy
K. Bailey Freund, Catherine B. Meyerle, and Lawrence A. Yannuzzi
BACKGROUND
Acute idiopathic maculopathy (AIM) is a rare disorder first
described by Yannuzzi and associates in 1991.1 The nine
patients in this original series experienced sudden unilateral
visual loss secondary to an exudative maculopathy following a
flu-like illness. The initial term was unilateral AIM, but further
clinical experience revealed that this entity can present
bilaterally.2 The preferred term today, therefore, is AIM.
DEMOGRAPHICS
AIM affects young adults with a mean age of 32 years (range
15–45 years) and has no sex predilection. It is uncommon, as
demonstrated by a survey of the Macula Society, with most
members of this organization seeing no more than one case per
year.3 Of reported patients, the majority are of white race.
One reported patient was seen in the first trimester of
pregnancy. Another patient was examined 4 weeks post partum.
One patient was infected with human immunodeficiency virus
but did not meet the clinical criteria for the acquired immuno-
deficiency syndrome. Of course, with small number of patients
and without a matched control group, any description of
epidemiologic features is preliminary.
CLINICAL FEATURES
AIM patients present with sudden onset of severe vision loss to
the level of 20/200 or worse with central metamorphopsia or a
central scotoma. A viral prodrome is typical and an association
between AIM and coxsackie virus has been reported.4 We have
seen an AIM patient with positive acute coxsackie titers
(unpublished data).
On examination, patients have a quiet anterior segment. In
the posterior pole, acutely, one sees a neurosensory retinal
detachment with irregular margins overlying a smaller, grayish
plaque at the level of the retinal pigment epithelium (RPE)
(Fig. 150.1). Other signs of inflammation such as vitreous cell,
papillitis, phlebitis, or intraretinal hemorrhage may also occur.
The mild vitreous cell is best appreciated with a contact lens.
Papillitis (defined as disk hyperemia and fluorescein angio-
graphic staining) has been reported in a few cases as a subtle
obscuration of the disk margins. The retinal veins in these cases
were somewhat prominent and tortuous from secondary
obstructive change or a mild phlebitis. In one case, a relative
afferent pupillary defect was noted (R Janigian and C Smith,
unpublished data, 1995). Intraretinal hemorrhage may be mis-
taken for subretinal neovascularization by the less experienced
observer. Generally, the lesion is in the foveal center, but may
present eccentrically. Patients with eccentric lesions have pre-
senting visual acuities better than those typical for AIM at the
level of 20/60 to 20/100. A subretinal exudate may be present
in some cases. In one reported patient, the exudate had a
peculiar fluffy, white appearance suggestive of inflammatory
cells or debris.5 In a second patient, the exudate had a grayish,
more solid appearance resembling subretinal fibrin seen in
central serous chorioretinopathy.
Whereas all the original cases were unilateral, three sub-
sequent cases with bilateral involvement have been reported.
In one case, macular involvement and acute loss of vision
of the fellow eye occurred bilaterally within days of the
original presentation. In the other two cases, the lesion in the
fellow eye was eccentric to the macula, smaller in size, and
asymptomatic.
The natural course of AIM for most patients is complete
resolution of the exudative changes and near-complete resto-
ration of the visual acuity (20/25 or better) within several weeks.
Stigmata of the disease process persist after its resolution in
the form of a bull’s eye type lesion. Specifically, the pigment
epithelial atrophic change corresponds to the previous neuro-
sensory detachment and the irregular hyperpigmentation is
reflective of antecedent pigment epithelial disturbance. In the
cases with subretinal exudation, this material resolved in
advance of the overlying neurosensory detachment and did not
seem to influence the natural course of the disorder. In the cases
with papillitis, this resolved in tandem with the exudative
macular changes.
To date, there have been no recurrent episodes in the cases
studied. However, the long-term visual outcome may be affected
by development of choroidal neovascularization (CNV) and
disciform scarring secondary to the retinal pigment epithelial
disturbance, which has occurred in two cases to date.
ANGIOGRAPHY
The fluorescein angiographic findings in the acute stage of
AIM characteristically demonstrate early hyperfluorescence at
the level of the RPE lesion. Late stage hyperfluorescence also
occurs, corresponding to the combined subretinal staining
external to the RPE and pooling within the overlying neuro-
sensory retinal detachment. This late stage pattern is similar
to the homogenous leakage seen beneath a serous pigment
epithelial detachment. In the resolved state, a bull’s eye pattern
of central hypofluorescence surrounded by a ring of hyperfluor-
escence is observed corresponding to the typical RPE changes of
the healed lesion. In the cases with papillitis, fluorescein
angiography revealed disk staining in all three reported cases
and mild perivenous staining in one instance.
Three cases were studied with indocyanine green angio-
graphy during the acute phase of their presentations. The studies 1985
 RETINA AND VITREOUS

a b c
SECTION 10

d e

FIGURE.150.1. (a) Color photograph shows an exudative detachment of the neurosensory retina, temporal to the center of the macula. There is
a neurosensory retinal elevation overlying an irregular thickening at the level of RPE. Visual acuity is 20/60. (b) Late fluorescein angiogram reveals
complete staining of the neurosensory retinal detachment. (c) Color photograph of the resolved state shows the characteristic atrophy of the
RPE surrounding a clump of pigment epithelial hyperplasia, corresponding to the neurosensory retinal detachment and the pigment epithelial
lesion respectively. Visual acuity is 20/20. (d) Color photograph of the fellow eye reveals a shallow alteration to the retina near the disk. There is
an irregular, grayish thickening to the underlying RPE. (e) Fluorescein angiogram of the fellow eye shows staining of the acute lesion.
(a–e) From Freund KB, Yannuzzi LA, Barile GR, et al: The expanding clinical spectrum of unilateral acute idiopathic maculopathy. Arch Ophthalmol 1996; 114:555–559.
Copyright 1996, American Medical Association.

were unremarkable except for some mild hypofluorescence
corresponding to the exudative detachment, which was seen
best in the late phase of the study. There was no late subretinal
staining suggestive of CNV in any of these patients.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of AIM includes numerous degener-
ative, infiltrative, inflammatory, and infectious disorders, such
as idiopathic CNV, serous detachment of the RPE, central serous
chorioretinopathy, Harada’s disease, serpiginous choroidopathy,
posterior scleritis, acute posterior multifocal placoid pigment
epitheliopathy (APMPPE), and secondary placoid syphilitic
retinitis. A recent case report described an acute toxoplama
retinitis masquerading as AIM,6 but the patient had satellite
lesions and a marked retinal vasculitis not typical of AIM.
Many patients with AIM are originally suspected of having
central serous chorioretinopathy or idiopathic CNV. In fact, the
authors have seen two AIM patients misdiagnosed with
idiopathic CNV and treated with photodynamic therapy. These
patients eventually did recover their central acuity to the level
typical for AIM patients, but their visual recovery was delayed
by several months. The typical flu-like illness accompanied by
evidence of inflammation (vitreous cells, papillitis) helps to
distinguish AIM from idiopathic CNV. Acute titers for
coxsackie virus also help in making the diagnosis.
Indocyanine green angiography may be useful in dis-
tinguishing AIM from other entities. Some believe that AIM, in
1986 those patients without inflammation, may represent occult
CNV that spontaneously infarcts and regresses. Indocyanine
green angiography of AIM patients, however, has not demon-
strated early vascular hyperfluorescence or late leakage con-
sistent with CNV.7 In addition, indocyanine green angiography
can help differentiate AIM from central serous chorioretino-
pathy. Indocyanine green angiography of AIM patients does not
demonstrate the mid-phase foci of choroidal hyperfluorescence
suggestive of choroidal hyperpermeability that has been
described in central serous chorioretinopathy.7
A recent case report describes the optical coherence tomo-
graphy (OCT) and multifocal electroretinogram (ERG) findings
in a patient with AIM.8 The authors conclude that the acute
OCT findings were consistent with thickening at the outer
retina and RPE, and that these outer edematous changes
resolved as visual acuity improved. Additionally, the reduced
amplitudes in multifocal ERG were suggestive of outer retinal
dysfunction as the cause of visual loss. These OCT and multi-
focal ERG findings indicative of outer retina and RPE pathology
help exclude masquerading diseases that primarily involve
inner retina.
Careful clinical biomicroscopy is essential to distinguish
AIM from masquerading APMPPE. Although AIM shares
several clinical and demographic characteristics with APMPPE,
there are many features of AIM that exclude the diagnosis of
APMPPE. These include the presence of a solitary macular lesion
with a neurosensory retinal detachment, intraretinal hemorr-
hages, and early hyperfluorescence of an acute AIM lesion on
fluorescein angiography. These features have not been reported
in APMPPE.
 Acute Idiopathic Maculopathy

TREATMENT is appropriate, and any patients presenting atypically with, for

Since this disorder is self-limited and most patients ultimately
recover excellent visual acuity, it does not appear that treatment
of the acute lesion is necessary. Perhaps of interest is that one
of the patients in the original report who was treated with
systemic corticosteroids ultimately developed milder pigmen-
tary changes in the fovea than is typical.1
CAUSE
AIM involves an inflammatory process of the RPE and, to a
lesser degree, the optic nerve. An association with coxsackie
virus has recently been reported in two patients.4 The authors
have also seen an AIM patient with positive acute coxsackie
titers (unpublished data). Of course, the clinical circumstances
of each individual case should dictate what medical evaluation
example, exuberant inflammatory findings or lack of sponta-
neous resolution should undergo appropriate diagnostic testing.
CONCLUSION
AIM is a distinct entity with characteristic clinical and angio-
graphic features. The frequent association with a flu-like illness,
vitreous cells, and in some cases, papillitis and subretinal
exudation is highly suggestive of an inflammatory disorder. The
recently reported association with coxsackie virus also suggests
an inflammatory pathogenesis. Fortunately, the natural course
of the disease is spontaneous, rapid resolution with recovery of
excellent visual acuity. The recognition of this disorder is
important to eliminate unnecessary and even potentially harm-
ful treatment such as laser photocoagulation or photodynamic
therapy of subretinal tissue misdiagnosed as CNV.

REFERENCES
1. Yannuzzi LA, Jampol LM, Rabb MF,
et al: Unilateral acute idiopathic
maculopathy. Arch Ophthalmol 1991;
109:1411–1416.
2. Freund KB, Yannuzzi LA, Barile GR, et al:
The expanding clinical spectrum of
unilateral acute idiopathic maculopathy.
Arch Ophthalmol 1996; 114:555–559.
3. Hanutsaha P, Yannuzzi LA, Freund KB:
The occurrence of uncommon intraocular
inflammatory diseases: a survey of the
Macula Society. Retina 1996;
16:437–439.
4. Beck A, Jampol L, Glaser D, et al: Is
coxsackie virus the cause of unilateral
acute idiopathic maculopathy? Arch
Ophthalmol 2004; 122:121–123.
5. Fish RH, Territo C, Anand R:
Pseudohypopyon in unilateral acute
idiopathic maculopathy. Retina 1993;
13:26–28.
6. Lieb DF, Scott IU, Flynn HW, et al: Acute
acquired toxoplasma retinitis may present
similarly to unilateral acute idiopathic
maculopathy. Am J Ophthalmol. 2004;
137:940–942.
CHAPTER 150
7. Yannuzzi LA, Slakter JS, Sorenson JA, et al:
Digital indocyanine green videoangiography
and choroidal neovascularization. Retina
1992; 12:191–223.
8. Aggio F, Farah M, Meirellee R, et al:
STRATUSOCT and multifocal ERG in
unilateral acute idiopathic maculopathy.
Graefes Arch Clin Exp Ophthalmol 2006;
244:510–516.

1987
 CHAPTER
151 Idiopathic Polypoidal Choroidal Vasculopathy
Chiara M. Eandi, Christina M. Klais, K. Bailey Freund, and Lawrence A. Yannuzzi
More than two decades ago, a peculiar hemorrhagic disorder of
the macula, polypoidal choroidal vasculopathy (PCV) was first
described (see Yannuzzi LA: Idiopathic polypoidal choroidal vascu-
lopathy. Presented at the Annual Macular Society Meeting, Miami,
FL, 1982) This entity has also been designated by Kleiner and
associates as ‘posterior uveal bleeding syndrome’1,2 and by Stern
and co-workers as ‘multiple recurrent retinal pigment epithelium
(RPE) detachments in black women’.3 In 1990, Yannuzzi and
colleagues suggested the term idiopathic polypoidal choroidal
vasculopathy (IPCV) because the pathogenesis was unknown,
the primary abnormality involved the choroidal circulation, and
the characteristic lesion was an inner choroidal vascular network
of vessels ending in an aneurismal bulge or outward projection,
visible clinically as a reddish-orange, spheroid, polyp-like struc-
ture.4 This entity has characteristic morphological features that
distinguish it from other exudative maculopathies. Clinically it
was associated with multiple, recurrent, serosanguineous
detachments of the RPE and neurosensory retina secondary to
leakage and bleeding from the peculiar choroidal vascular lesion
(Fig. 151.1).
In recent years, indocyanine green (ICG) angiography has
been used to detect and characterize the PCV abnormality with
enhanced sensitivity and specificity,5,6 expanding further the
spectrum of PCV. This allows us to describe the pathogenesis,
clinical manifestations, demographic profile, fluorescein and ICG
angiographic findings, natural course, modalities of treatment,
and visual prognosis in patients with PCV with greater detail
and precision.7,8
PATHOGENESIS
Although the pathogenesis of PCV is not completely clear, new
information is now available that might help in our under-
standing of its possible causative factor and clinical nature. PCV
has been first described in African-American females.3,9 However,
Asian patients are also at risk for developing PCV, and white
patients can definitely develop the disorder as well.7,9–11 This pre-
disposition for pigmented races contrasts the relative immunity
to age-related macular degeneration (AMD) and disciform scarring
seen in these individuals.12–14 Lafaut et al suggested a possible
coexistence of AMD and PCV, a finding certainly supported by
our own clinical experience.15 In spite of multiple, recurrent sero-
sanguineous macular detachments, significant fibrous prolifera-
tion typical of end-stage neovascularized AMD is unusual in PCV.16
Although there is no available clinical pathologic confir-
mation, in essence the vascular abnormality in PCV appears to
be a singular lesion with tubular and polypoidal components
that vary in size. The vascular lesion itself appears to be singular
and progressive. It does not occur solely in the peripapillary
region as originally believed, but it may also present as an
isolated island within the central macula. It is generally thought
that PCV originates in the inner choroid.
Lafaut et al reported light microscopic findings in submacular
tissue removed from an eye with PCV in AMD.15 They described
a sub-RPE, intra-Bruch’s fibrovascular membrane containing
several dilated thin-walled vessels under diffuse drusen. These
abnormal vessels are lined by a thin endothelium with occa-
sional pericytes. Some lesions were associated with islands of
lymphocytic infiltration.
In spite of increasing case experience, the pathogenesis of the
IPCV is still unknown. Traditionally, IPCV has not been linked
to inflammatory processes; however, Ciardella et al reported a
link between PCV and chorioretinal inflammation seen in three
cases. They identified typical clinical findings of PCV after pre-
vious inflammatory disease.8 Immunohistochemical findings in
a case with PCV demonstrated both T and B lymphocytes in the
choroid and fibrovascular tissue.17
There have been references to the association of PCV with
other ocular disorders. Ross et al reported a correlation between
retinal macroaneurysms and PCV in two hypertensive black
females.6 They proposed a relation between the retinal vascular
changes in retinal macroaneurysms and hypertensive retino-
pathy such as vascular remodeling, aneurysmal dilation, and
focal vascular constriction to the characteristic choroidal
lesions in PCV. A recent study confirmed that choroidal blood
flow increases significantly with increasing blood pressure.18
Untreated hypertension was found to be a risk factor in
development and progression of choroidal vascular pathologies.
Other potential pathogenic factors include the possibility of a
peculiar choroidal tumor, vascular malformation, or systemic
hypertension. In spite of these observations, the association of
PCV, inflammation or other ocular disorders is still inconclusive
and must be investigated further.
DEMOGRAPHIC FEATURES
AGE
PCV is usually diagnosed in patients between the age of 50 and
65 years, but the age of diagnosis can range from 20 to 80 years.
The average age of onset for all affected patients from the
literature is 60.1 years. Caucasian subjects usually present the
disease at an older age.19
SEX
Previously, it was thought that PCV exclusively affects women.
In recent studies it has been demonstrated that females are
involved predominantly over males by a ratio of approximately
4.7:1. Among Asians, men seem to be more frequently affected.16 1989
 RETINA AND VITREOUS
a b
RACE
Individuals of African-American and Asian descent are at higher
SECTION 10
risk of developing PCV.3,16 as this distinct disorder seems to
preferentially affect pigmented individuals by a ratio of 4.2:1.
However, more recent reports have shown that PCV occurs
broadly in patients of other racial descents than it has been
demonstrated in the past.16,20–23
Lafaut et al studied the prevalence of PCV in Caucasians with
occult choroidal neovascularization (CNV). In a consecutive
series of 374 eyes with occult CNV, 4% were diagnosed with
PCV by ICG angiographic findings.10 Pauleikhoff et al diagnosed
PCV in 13.9% of 101 consecutive German patients with pigment
epithelium detachment (PED).24 Other investigators diagnosed
PCV in 85% among a consecutive series of Caucasians pre-
senting with large exudative or hemorrhagic PEDs in the absence
of drusen.25 Yannuzzi et al diagnosed PCV in 13 (7.8%) of 167
consecutive Caucasian patients with presumed neovascular
AMD.19 Scassellati-Sforzolini et al found a prevalence of 9.8%
in Italian patients with newly diagnosed neovascular AMD.11
PCV has also been reported in Irish,26 French,27 and German28
subjects.
The prevalence of PCV among Chinese patients with AMD
was found to be 9.3%.29 In this patient series, the most common
clinical finding at presentation was subretinal hemorrhage
(63.6%) followed by exudative neurosensory detachment
(59.1%), and hemorrhagic PED (59.1%). There was a predo-
minance for males (68.4%). Most of the polypoidal lesions were
at the macula (63.6%) and unilateral (84%). In contrast, a
Japanese study reported a much higher prevalence of PCV
among patients with newly diagnosed neovascular AMD.30
They studied 164 eyes with PEDs and CNV and detected PCV
in 59% of the eyes. In 70% of the patients, the PED had a
hemorrhagic component. Other investigators confirmed the
predilection for male gender in the Japanese population, as well
as unilateral involvement.16
Recently, we found PCV in 14 (14%) of 100 consecutive newly
diagnosed cases with neovascular AMD. They all presented
occult or minimally classic lesion on fluorescein angiography,
but the polyp-like CNV was visible when studied with ICG
angiography (see Eandi CM, Iranmanesh R, Garuti S, et al: The
nature and frequency of neovascular age related macular
degeneration. ARVO 2005; Abstract 3311).
CLINICAL FINDINGS
PCV is a bilateral disease.4 Most patients with the evidence of
PCV in one eye eventually develop similar lesions in the fellow
eye; however, several patients with PCV have been followed up
for more than 10 years and so far demonstrate no evidence of
the condition in the other eye. The lesion is characterized by
1990 the presence of dilated, choroidal vascular channels ending in
FIGURE 151.1. (a) The fluorescein angiogram
shows a large serosanguineous detachment of
the pigment epithelium that extends in the
inter-papillo-macular region and a subfoveal
hemorrhage with an adjacent hyperfluorescent
spot (white arrow). (b) The corresponding ICG
angiogram reveals the exact location of the
vascular choroidal polypoidal abnormality in the
peripapillary area (black arrow).
orange, bulging, polyp-like dilations in the peripapillary and
macular area. Vitreous hemorrhage, relatively minimal fibrous
scarring, absence of drusen, retinal vascular disease, pathologic
myopia, and signs of intraocular inflammation are accepted
clinical features. Iida et al demonstrated that retinal micro-
angiopathy may occur in a chronic macular detachment
secondary to polypoidal CNV.31
THE VASCULAR LESION
In order to define the vascular lesion it is essential to use ICG
angiography because it images the active neovascularization,
whereas it does not show leakage at the site of serous pigment
epithelial elevations (Fig. 151.1). Although the lesion of PCV is
invariably localized to the choroidal vascular network, other
characteristics of the lesion often differ. Significant variance is
observed in size and location to the optic disk, fovea, and cross
section of the retina.
SIZE
PCV usually categorized into small, medium or large lesions.
The width of the lesions varies depending on the affected
vascular channels. With involvement of outer choroidal vessels,
the polypoidal lesions appear larger in size. Such lesions are
easily diagnosed on biomicroscopy, especially when atrophic
RPE is overlying; whereas angiography is needed to detect
vascular lesions of small dimension. Teitawa et al reported large
vascular networks expanding across the vascular arcade in 12 of
60 consecutive eyes diagnosed with PCV.32
When the middle choroidal vasculature is affected, polypoidal
lesions appear smaller. In this case it is more challenging to
diagnose on clinical examination, and the preferential method
for diagnosis is ICG angiography.4,5,33
LOCATION
Choroidal vascular lesions of PCV are usually located in the
peripapillary area (Figs 151.2 and 151.3), although recent
evidence suggests that lesions could also be found in the
central macula (Figs 151.4 and 151.5) and in the midperiphery
(Fig. 151.6).34,35 Lesions can be localized to a single location in
the fundus or can be widespread involving more than one site.
Lafaut et al detected polypoidal lesion in the macula in 22 of
45 eyes, in the peripapillary area in 16 of 45, under the
temporal vascular arcade in six of 45, and in the midperiphery
in six of 45 eyes.10 Yannuzzi and associates described a case of
PCV isolated in the midperiphery of the temporal fundus
associated with recurrent vitreous hemorrhage.35
Due to limited reports on clinocopathologic relationship
between PCV lesions and retinal layers the precise location of

a b
FIGURE 151.2. (a) Color photograph of a patient with IPCV. A choroidal abnormality in the peripapillary area shows a barely evident vascular
pattern and polypoidal changes. (b) The fluorescein angiogram reveals the vascular abnormality because of the large size of the vascular
element’s abnormality and the overlying pallor or atrophy of the pigment epithelium. (c) The corresponding ICG angiogram more clearly
delineates the vascular abnormality with branching inner choroidal vessels ending in polypoidal choroidal lesions.
b
a
c d
the polypoidal vascular lesion in the cross-sectional structure
remains unknown. Optical coherence tomography (OCT) studies
were able to localize the polypoidal lesions under Bruch’s
membrane36 but further studies are required to correlate the
histologic finding and the results of OCT imaging.
NATURAL COURSE
The natural course of PCV is becoming better understood as the
knowledge of PCV expands. This disease often follows a
remitting–relapsing course, and clinically, it is associated with
chronic, multiple, recurrent serosanguineous detachments of
the neurosensory retina and the RPE with long-term preser-
vation of good vision. Despite multiple recurrent serosangui-
Idiopathic Polypoidal Choroidal Vasculopathy
c
CHAPTER 151
FIGURE 151.3. (a) Patient with IPCV shows
the vascular abnormality, along with the
reddish-orange elevation, beneath a PED.
(b) The corresponding fluorescein angiogram
highlights the vascular lesion in the peripapillary
area and the serosanguineous detachment of
the pigment epithelium that extends to the
inferior and temporal macular area. (c) The
early ICG study accentuates the polypoidal
choroidal vascular changes. The reddish-
orange lesion is shown to represent a ring of
polypoidal lesions that project anteriorly into
the subpigment epithelial space. (d) The late-
stage ICG study shows staining of the margins
of the polypoidal lesions with relative fading of
the branching vessels (washout).
neous macular detachments, fibrous proliferation resulting in
typical plaque characteristics of end-stage neovascular AMD is
not seen in eyes with PCV. On the other hand, this may present
difficulties with the diagnosis of PCV when the lesion is
inactive. In some cases, polypoidal lesions have evolved with
resolution of the serosanguineous changes, and ICG angio-
graphy reveals a nonspecific plaque which can be interpreted as
CNV of the usual type. Still, some patients may develop chronic
atrophy and cystic degeneration of the fovea associated with
severe vision loss. Others may experience vitreous hemorrhage
or secondary CNV with disciform scarring and central vision
loss (see Yannuzzi LA: Idiopathic polypoidal choroidal vasculo-
pathy. Presented at the Annual Macular Society Meeting, Miami,
FL, 1982).2,13,17,37 Massive spontaneous choroidal hemorrhage 1991
 RETINA AND VITREOUS
a b
FIGURE 151.4. (a) Color photograph of a patient with IPCV who presented with chronic serous lipid exudation in the macula, simulating central
serous chorioretinopathy. (b) The ICG angiogram reveals the vascular abnormality and leaking polypoidal lesion. (c) The same patient after
photocoagulation of leaking polypoidal lesions shows resolution of the exudative changes.
SECTION 10
a b
a b
is a rare but severe complication. Despite immediate drainage
procedure the visual outcome is poor.38
Uyama et al followed 14 eyes of 12 consecutive patients with
PCV for at least 2 years without any treatment.16 They demon-
strated that 50% of the eyes had a favorable course. In the
remaining half, the disorder persisted for a long time with
occasional recurrent hemorrhages and leakage, resulting in
macular degeneration and vision loss. Eyes with cluster of
grape-like polypoidal dilations of the vessels had a high risk for
severe visual loss.
No underlying systemic factor has ever been associated with
this disorder, except for recent evidence suggesting a possible
1992 association of PCV to hypertension and acquired macroaneu-
c
FIGURE 151.5. (a) The red-free photograph
shows a small serosanguineous RPE
detachment in the center of the fovea with
pigmentary defects surrounding. (b) The ICG
angiogram reveals a cluster of actively leaking
polypoidal vessels in the corresponding area.
FIGURE 151.6. (a) ICG composite late
angiogram of a patient with a midequatorial
PCV lesion presenting as a subretinal
hemorrhage. (b) A magnified image of the
lesion reveals the polypoidal vascular
abnormality beneath the blood.
rysms.6 Smith et al reported a patient with PCV and concurrent
sickle cell disease.39 Other cases of PCV have been described in
eyes with melanocytoma of the optic nerve, and central retina
vein occlusion.40,41 Neither of these case reports nor our own
clinical experience demonstrates sufficient evidence finding an
association between PCV and retinal vascular ischemic diseases,
chorioretinal inflammation, or sickle cell disease.
When the lesion increases in size, it usually does so by three
proposed mechanisms. The lesion may enlarge by simple vessel
hypertrophy, by conversion of the lesion into the advancing
edge of a vascular channel, and by unfolding of a cluster of
aneurysmal elements and subsequent transformation into
enlarging, vascular, tubular components. The latter mechanism

is usually apparent on clinical examination as a large, reddish-
orange subretinal mass corresponding to a cluster of aneurysmal
elements that, on ICG angiography, project anteriorly from the
inner choroid toward the outer retina. With time, these mass-
like lesions flatten out and expand tangentially in their plane.
The overlying RPE may show signs of variable atrophy.
DIAGNOSIS
The appearance of the vessels in PCV often depends on their
location in the posterior pole. In patients with juxtapapillary
lesions, the vascular channels may follow a radial, arching
pattern and may be interconnected with smaller spanning
branches which are more evident and numerous at the edges of
the lesion. In patients with PCV limited to the macula, a
vascular network often arises in the macula and follows an oval
distribution pattern.
ICG angiography is useful to image the PCV choroidal
abnormality.5 In the initial phases of ICG videoangiograms,
when the larger choroidal vessels fill with dye, a distinct
network of vessels within the choroid becomes visible. Early in
the course of the ICG study, the larger vessels of the PCV
network start to fill before the retinal vessels, but the area
within and immediately surrounding the network is relatively
hypofluorescent compared with the uninvolved choroid. The
vessels of the network appear to fill more slowly than the retina
vessels. The network of vessels with ICG angiography generally
appear to be more numerous than one would expect from
clinical examination. Shortly after the network can be identified
on the ICG angiogram, small hyperfluorescent ‘polyps’ become
visible within the choroid.
During the mid-phase of the angiogram, however, the size of
the lesions approximates the choroidal excrescences observed
clinically. They appear to leak slowly and the surrounding hypo-
fluorescent area becomes increasingly hyperfluorescent.
The late phase of angiogram is associated with a reversal of
the pattern of fluorescence observed previously. The area sur-
rounding the lesion becomes hyperfluorescent and the center of
the lesion demonstrates hypofluorescence. The size of the lesion
seems to influence the reversal pattern. The lesions that are less
than 0.5-disk diameter in size appear to have intense uniform
fluorescence, whereas internal details seem to be visible in
larger polypoidal structures.5 These findings, in turn, suggest
presence of an internal architecture.5
The very late stages of ICG angiography demonstrate dis-
appearance of the fluorescence from the lesions thus defining
the term ‘washout’ (Fig. 151.3d). The ‘washout’ is only seen in
nonleaking lesions, whereas the leaking lesions remain
hyperfluorescent. Varying degrees of hypopigmentation of the
RPE overlying an involved area may enhance visualization of
the abnormal vessels, yet the late ICG staining results from the
intrinsic characteristics of the lesion rather than from RPE
alterations.5
OCT has also proved to be useful in the diagnosis of PCV.
Iijima and co-workers were able to demonstrate the presence of
the polypoidal lesions with OCT.36,42 They also proposed that
OCT may be able to differentiate the orange-red lesions in PCV
from serous PEDs. Otsuji et al were able to demonstrate with
OCT the presence of dome-like elevation of the RPE, and
nodular appearance beneath the RPE in 14 patients with PCV23.
Giovannini et al studied with OCT four eyes with PCV and
found in all cases a characteristic hyper-reflectivity in the
choroidal layers.43 The use of OCT is of importance in these
patients, as we recently reported. Although the polypoidal CNV
eyes seldom had associated CME (7%), a dome-like pigment
epithelium detachment was detected in 13 of 14 (93%) patients
with PCV (see Eandi CM, Iranmanesh R, Garuti S, et al: The
Idiopathic Polypoidal Choroidal Vasculopathy
nature and frequency of neovascular age related macular
degeneration. ARVO 2005; Abstract 3311).
DIFFERENTIAL DIAGNOSIS
The reddish-orange, subretinal masslike lesion seen in PCV is
composed of multiple, polypoidal elements that extend from the
PCV vascular lesion in the plane of the inner choroid, beneath
the detached pigment epithelium toward the outer retina. The
differential diagnosis of such a reddish-orange lesion under the
retina includes choroidal hemangioma, metastasis from
carcinoid syndrome, or more rarely, renal cell carcinoma, pos-
terior scleritis, choroidal osteoma, and even CNV. ICG angio-
graphy is useful in differentiating the reddish-orange mass as it
demonstrates an incomplete ring of polypoidal lesions emanating
from the PCV vascular lesion. The cluster of polypoidal
elements may be seen stereoscopically to extend toward the
overlying retina. The other mimicking orange mass-like entities
CHAPTER 151
are not associated with these dilated inner choroidal vessels
and polypoidal vascular elements beneath a pigment epithelial
detachment.
Two decades ago, PCV was considered an entity with a
distinct set of demographic characteristics, risk factors, natural
course, clinical interpretation, and outcome from AMD.
Features like Caucasian origin, macular location, presence of
drusen, frequent recurrences, rapid rate of progression, disci-
form scarring, and poor visual prognosis were considered typical
of AMD and used to differentiate the two entities.13 Since the
definition of PCV has expanded over the past two decades, the
diagnosis is no longer restricted to those specific demographic
attributes or to a specific retinal location.10,35 In addition, it
becomes more evident from the increasing volume of reports
about PCV and our own clinical experience that the patients
may have manifestations attributable to PCV and AMD. For
example, some of our patients diagnosed with AMD undergoing
ICG guided-laser treatment in the past had an exceptional and
unexpected good outcome. Later, on reviewing their records, we
determined that the patients with better results were actually
patients with PCV-type CNV rather than a typical form of
AMD.
Presently, we believe that PCV represents a subtype of CNV
in AMD. PCV has also been reported in association with dry
AMD.44 However, some characteristics distinguish PCV from
other types of CNV observed in AMD. Vascular proliferative
changes associated with nonpolypoidal CNV tend to produce
small caliber vessels that are associated with grayish colored
membrane and grayish discoloration of the overlying retina.
These vessels are not easily detected clinically.21,45 In contrast,
eyes with vascular changes typical for PCV form a network of
vessels ending with saccular polypoidal lesions which have a
redish-orange color and evident with slit lamp biomicroscopy
unless they are covered by overlying blood or exudates.4,9 Other
angiographic and histopathologic characteristics tends to
distinguish other types of CNV from PCV. AMD is associated
with diminishing choroidal thickness and with signs of stromal
fibrosis without any changes in the choriocapillaris size or
evidence of inflammatory changes.46 These findings were not
observed clinocopathological reports on PCV.15,17 Moreover,
poorly defined CNV secondary to AMD is clinically associated
with indistinct subretinal thickening and is not manifested by
the detectable choroidal vascular channels terminating in
polyp-like structures.
Fluorescein and ICG angiography can be used to distinguish
the two types of vascular abnormalities. In both, CNV is
characterized by diffuse late staining plaque.12 In contrast,
early-phase ICG angiography reveals PCV as a prominent
vascular network which becomes ‘washed out’ during the late 1993
 RETINA AND VITREOUS
phase. The late phase is also distinguished by a typical outline
of the nonleaking large choroidal vessels. If the vessels leak,
staining in the walls of aneurysmal lesions and exudation into
the surrounding choroid and subretinal space is observed.5
The natural course and clinical location of PCV are different
from those of CNV. Subfoveal CNV tends to organize into a
fibrotic or disciform scar leading to severe macular damage and
vision loss.21 PED seen in eyes with PCV virtually never forms
a fibrotic scar,4 whereas PED associated with occult CNV in
AMD usually has a poor prognosis.47 However, the spontaneously
involuted or regressed lesion looks like a well-delineated plaque
of occult CNV, even with ICG angiography.
Some eyes with PCV may present purely exudative changes
masquerading chronic decompensation of the RPE, a variant
of central serous chorioretinopathy (Fig. 151.4).33 PCV lesions
presenting with symptoms of central serous chorioretinopathy
are usually small in size. Polypoidal lesions may resemble small
PEDs clinically and on fluorescein angiography. The diagnosis
SECTION 10
becomes especially challenging in a patient with chronic central
serous chorioretinopathy presenting lipid deposits in the central
macula due to subfoveal polypoidal lesion. The principle of
differentiating a small serous PED from a polypoidal lesion
is with ICG angiography. Late staining of the PED is seen
with fluorescein angiography and hypofluorescence with ICG
imaging. In contrast, the polypoidal lesion is usually hyperfluor-
escent with ICG angiography because of its vascular nature. It
is important to consider that the PCV lesion may exist under a
PED. The portion of the PED overlying the polypoidal lesion
will be hypofluorescent, and, if there is leakage, ICG dye may
pool into the subpigment epithelial space. However, the
majority of patients with PCV present with serosanguineous
detachment of the RPE and neurosensory retina. These findings
imply the presence of new blood vessel formation or CNV as
causative factor.21
TREATMENT
Treatment for PCV is not yet well established. If the
characteristic vascular lesion of PCV is observed, a conservative
approach to management is recommended unless the lesion is
associated with persistent or progressive exudative change
threatening central vision. In this case conventional thermal
laser treatment of the leaking polypoidal choroidal abnormality
may be successful in causing resolution of the serosanguineous
manifestation.20,25,48 Yuzawa et al reported on visual
improvement after conventional laser treatment of the entire
PCV complex in nine of 10 eyes.49 However, no randomized,
controlled studies have been performed to prove the efficacy or
safety of laser treatment. Moreover, when the CNV extends
beneath the center of the fovea thermal laser treatment is not
indicated due to damage of the overlying neurosensory retina
and subsequent lead to reduced central vision.50 It is possible
that the loss of central vision due to the subfoveal treatment
may exceed the damage produced by the natural course of PCV,
although this is not known with any certainty. Conversely, it is
not uncommon for patients with untreated subfoveal involve-
ment with PCV to experience severe visual loss.
Due to limitations and uncertainty of the value of thermal
laser coagulation and the potential devastating outcome of
untreated subfoveal lesions, alternative modalities of treatment
are currently being evaluated. These include vitrectomy and
submacular removal of polypoidal vessels and subretinal blood.
In some cases, vitrectomy is required to clear the media and
recover the vision. Shiraga et al reported anatomic success in
the surgical treatment of submacular hemorrhage associated
with PCV.51 However, the value of submacular surgery has
1994 been questioned in AMD because of the recurrences and poor
vision outcomes.52–54 Macular translocation is another surgical
approach, but most patients diagnosed with PCV have relatively
large vascular lesions and the surgical procedure has a number
of serious complications.55 Low-dose external beam irradiation
does not appear to offer dramatic results, neither beneficial nor
harmful37,56; on the other hand, it has been demonstrated that
radiation therapy for AMD is a possible triggering factor for the
development of PCV.57
Transpupillary thermotherapy may show promise in treating
occult CNV,58 but the value in PCV is not known. Diode laser
photocoagulation has also been successfully used for the
treatment of PCV.20
Recent studies reported encouraging results without compli-
cations after photodynamic therapy with verteporfin in subfoveal
PCV lesions.59–65 Spaide et al reported on improvement in
visual acuity in 56% of patients undergoing photodynamic
therapy, while in 31% of the patients the vision was stable, and
in 12% a decrease in visual acuity was noted.59 Quaranta et al
found beneficial functional results in two cases of PCV treated
with PDT with verteporfin.63
We recently reported stabilization or improvement on visual
acuity in 80% of eyes with PCV treated with ICG guided PDT
treatment. In our series of 30 eyes with PCV, the PDT treat-
ment was applied only on the active lesion visible with ICG
angiography, possibly reducing the collateral damage to the
choriocapillaries. Angiographic and tomographic findings con-
firmed the resolution of the neovascular process in all cases (see
Eandi CM, Freund KB, Ober MD, et al: Minimally selective
treatment for neovascular age related macular degeneration.
Annual Meeting of the Retina Society, Coronado, CA; 2005).
Further trials of photodynamic therapy with verteporfin for PCV
are required to address long-term efficacy and safety issues.
CONCLUSION
PCV appears to be a distinct clinical entity involving the
choroidal circulation. The vascular abnormality is in the inner
choroid, composed of two fundamental elements, a dilated
network of vessels terminating in multiple areas of aneurysmal
swelling in a polypoidal configuration. The polypoidal lesion
itself accounts for the episodic leakage and bleeding seen in
these patients. In patients with serosanguineous detachment of
the pigment epithelium, particularly those with increased risk
factors like African-American or Asian race, ICG angiography
should be performed to evaluate the choroidal vascular
abnormality in an attempt to establish a more definitive
diagnosis. If the characteristic vascular lesion of PCV is seen, a
conservative approach to management should be entertained
unless there is a persistent or progressive exudative change that
is threatening central macula. In that event, there may be a
rationale for photocoagulation treatment of leaking aneurysmal
or polypoidal components within the vascular lesion, but not
the entire vascular complex. Photodynamic therapy seems to be
a promising therapeutic modality; however, randomized clinical
trials are needed to establish the efficacy and safety of the PDT
treatment in the management of these patients.
SUMMARY
PCV seems to be a distinct clinical entity that should be differ-
entiated from other forms of CNV associated with AMD and other
known choroidal degenerative, inflammatory, and ischemic dis-
orders. The principal abnormalities in PCV, notably the branching
vascular network and polypoidal structures at the borders of the
lesion, seem to be unique to this entity. In patients with sero-
sanguineous detachment of the RPE, especially in those with
increased risk factors, such as pigmented race, ICG angiography

should be performed to evaluate the choroidal vascular abnor-
mality in an attempt to establish a more definitive diagnosis.
When ICG angiography confirms the characteristic vascular
polyp-like lesion, a conservative management approach should
be considered, unless there is a persistent or progressive exudative
change threatening the fovea and the central vision. In that
REFERENCES
1. Kleiner RC, Brucker AJ, Johnson RL:
Posterior uveal bleeding syndrome.
Ophthalmology 1984; 91(Suppl 9):110.
2. Kleiner RC, Brucker AJ, Johnson RL:
Posterior uveal bleeding syndrome. Retina
1990; 10:9–17.
3. Stern RM, Zakov N, Zegarra H, et al:
Multiple recurrent serous sanguineous
retinal pigment epithelial detachments in
black women. Am J Ophthalmol 1985;
100:560–569.
4. Yannuzzi LA, Sorenson J, Spaide RF,
Lipson B: Idiopathic polypoidal choroidal
vasculopathy. Retina 1990; 10:1–8.
5. Spaide RF, Yannuzzi LA, Slakter JS, et al:
Indocyanine green videoangiography of
idiopathic polypoidal choroidal
vasculopathy. Retina 1995; 15:100–110.
6. Ross RD, Gitter GA, Cohen C, Shoemaker
KS: Idiopathic polypoidal choroidal
vasculopathy associated with retinal arterial
macroaneurysm and hypertensive
retinopathy. Retina 1996; 16:105–111.
7. Yannuzzi LA, Ciardella AP, Spaide RF, et al:
The expanding clinical spectrum of
idiopathic polypoidal vasculopathy. Arch
Ophthalmol 1997; 115:478–485.
8. Ciardella AP, Donsoff IM, Huang SJ, et al:
Polypoidal choroidal vasculopathy. Surv
Ophthalmol 2004; 49:25–37.
9. Perkovich BT, Zakov ZN, Berlin LA, et al:
An update on multiple recurrent
serosanguineous retinal pigment epithelial
detachments in black women. Retina 1990;
10:18–26.
10. Lafaut BA, Leyes AM, Snyders B, et al:
Polypoidal choroidal vasculopathy in
Caucasians. Graefe’s Arcg Clin Exp
Ophthalmol 2000; 238:752–759.
11. Scassellati-Sforzolini B, Mariotti C, Bryan
R, et al: Polypoidal vasculopathy in Italy.
Retina 2001; 21:121–125.
12. Yannuzzi LA, Slakter JS, Sorenson JA, et al:
Digital indocyanine videoangiography and
choroidal neovascularization. Retina 1992;
12:191–223.
13. Ferris FL III: Senile macular degeneration:
a review of epidemiological features. Am J
Epidemiol 1983; 118:213–221.
14. Capone A Jr, Wallace RT, Meredith TA:
Symptomatic choroidal neovascularization
in blacks. Arch Ophthalmol 1994;
112:1091–1097.
15. Lafaut BA, Aisenbrey S, van den Broecke
C, et al: Polypoidal choroidal vasculopathy
pattern in age-related macular
degeneration. A clinicopathologic
correlation. Retina 2000; 20:650–654.
16. Uyama M, Wada M, Nagai Y, et al:
Polypoidal choroidal vasculopathy: natural
history. Am J Ophthalmol 2002;
133:639–648.
17. MacCumber MW, Dastgheib K, Bressler
NM, et al: Clinicopathological correlation of
the multiple recurrent serosanguineous
retinal pigment epithelium detachments
syndrome. Retina 1994; 14:143–152.
Idiopathic Polypoidal Choroidal Vasculopathy
event, thermal lasercoagulation of leaking aneurysmal or poly-
poidal components within the vascular lesion may be a rationale.
Reports on photodynamic therapy for PCV demonstrating
encouraging results, but randomized clinical trials are required
to establish this therapeutic modality in the management of
patients with PCV.
18. Polak K, Polska E, Luksch A, et al:
Choroidal blood flow and arterial blood
pressure. Eye 2003; 17:84–88.
19. Yannuzzi LA, Wong DW, Sforzolino MS,
et al: Polypoidal choroidal vasculopathy
and neovascularized age-related macular
degeneration. Arch Ophthalmol 1999;
117:1503–1510.
20. Gomez-Ulla F, Gonzalez F, Torreiro MG:
Diode laser photocoagulation in idiopathic
polypoidal choroidal vasculopathy. Retina
1998; 18:481–483.
21. Green WR, McDonnel PJ, Yeo JH:
Pathological features of senile macular
degeneration. Ophthalmology 1985;
92:615–627.
22. Okubo A, Sameshima M, Uemara A:
Clinicopathological correlation of polypoidal
choroidal vasculopathy revealed by
ultrastructural study. Br J Ophthalmol 2002;
86:1093–1098.
23. Otsuji T, Takahasi K, Fukushima I, Uyama M:
Optical coherence tomographic findings of
idiopathic polypoidal choroidal
vasculopathy. Ophthalmic Surg Lasers
2000; 31:210–214.
24. Pauleikhoff D, Löffert D, Spital G, et al:
Pigment epithelial detachment in the
elderly. Clinical differentiation, natural
course and pathogenic implications.
Graefe’s Arch Clin Exp Ophthalmol 2002;
240:533–538.
25. Ahuja RM, Stanga PE, Vingerling JR, et al:
Polypoidal choroidal vasculopathy in
exudative and hemorrhagic pigment
epithelium detachments. Br J Ophthalmol
2000; 84:479–484.
26. Lip PL, Hope-Ross MW, Gibson JM:
Idiopathic polypoidal choroidal
vasculopathy: a disease with diverse
clinical spectrum and systemic
associations. Eye 2000; 5:695–700.
27. Mohand-Said M, Nodarian M, Salvanet-
Bouccara A: Idiopathic polypoidal choroidal
vasculopathy: 2 case report. J Fr
Ophthalmol 2002; 25:517–521.
28. Schneider U, Gelisken F, Inhoffen W:
Clinical characteristics of idiopathic
polypoidal choroidal vasculopathy.
Ophthalmologe 2001; 98:1186–1191.
29. Kwok AKH, Lai TYY, Chan CWN, et al:
Polypoidal choroidal vasculopathy in
Chinese patients. Br J Ophthalmol 2002;
86:892–897.
30. Imaizumi H, Takeda M: Knobby-like
choroidal neovascularization accompanied
with retinal pigment epithelial detachment.
Nippon Ganka Gakkai Zasshi 1999;
103:527–537.
31. Iida T, Yannuzzi LA, Freund KB, et al:
Retinal angiopathy and polypoidal
choroidal vasculopathy. Retina 2002;
22:455–463.
32. Tateiwa H, Kuroiwa S, Gaun S, et al:
Polypoidal choroidal vasculopathy with
large vascular network. Graefe’s Arch Clin
Exp Ophthalmol 2002; 240:354–361.
33. Yannuzzi LA, Freund KB, Goldbaum M, et al:
Polypoidal choroidal vasculopathy
masquerading as central serous
chorioretinopathy. Ophthalmology 2000;
107:767–777.
34. Moorthy RS, Lyon AT, Rabb MF, et al:
Idiopathic polypoidal choroidal
vasculopathy of the macula.
Ophthalmology 1998; 105:1380–1385.
CHAPTER 151
35. Yannuzzi LA, Nogueira FB, Spaide RF, et al:
Idiopathic polypoidal choroidal
vasculopathy: a peripheral lesion. Arch
Ophthalmol 1998; 116:382–383.
36. Iijima H, Iida T, Imai M, et al: Optical
coherence tomography of orange-red
subretinal lesions in eyes with idiopathic
polypoidal vasculopathy. Am J Ophthalmol
2000; 129:21–26.
37. Spaide RF, Guyer DR, McCormick B, et al:
External beam radiation therapy for
choroidal neovascularization.
Ophthalmology 1998; 105:24–30.
38. Yang SS, Fu AD, McDonald HR, et al:
Massive spontaneous choroidal
hemorrhage. Retina 2003; 23:139–144.
39. Smith RE, Wise K, Kingsley RM: Idiopathic
polypoidal choroidal vasculopathy and
sickle cell retinopathy. Am J Ophthalmol
2000; 129:105–111.
40. Bartlett HM, Willoughby B, Mandava N:
Polypoidal choroidal vasculopathy in a
patients with melanocytoma of the optic
nerve. Retina 2001; 21:396–399.
41. Katsimpris JM, Petropoulas IK,
Pharmakakis NM, Pournaras CJ: Idiopathic
polypoidal choroidal vasculopathy
associated with central retinal vein
occlusion. J Fr Ophtalmol 2003;
26:489–492.
42. Iijima H, Imai M, Gohodo T, et al: Optical
coherence tomography of idiopathic
polypoidal choroidal vasculopathy. Am J
Ophthalmol 1999; 127:301–305.
43. Giovannini A, Amato GP, D’Altobrando E,
Giuliani M: Optical coherence tomography
(OCT) in idiopathic polypoidal choroidal
vasculopathy. Doc Ophthalmol 1999;
97:367–371.
44. Lois N: Idiopathic polypoidal choroidal
vasculopathy in a patient with atrophic
age-related macular degeneration. Br J
Ophthalmol 2001; 85:1011–1012.
45. Gass JDM. Stereoscopic atlas of macular
diseases. St Louis: CV Mosby; 1997.
46. Arnold JJ, Sarks SH, Killingworth MC,
Sarks JP: Reticular pseudodrusen. Retina
1995; 15:183–191.
47. Pauleikhoff D, Radermacher M, Spital, et al:
Visual prognosis of second eyes in patients
with unilateral late exudative age-related
macular degeneration. Graefe’s Arch Clin
Exp Ophthalmol 2002; 240:539–542.
48. Guyer DR, Yannuzzi LA, Ladas I, et al:
Indocyanine green guided laser
photocoagulation of focal spots at the
edge of plaque of choroidal vascularization.
Arch Ophthalmol 1996; 114:693–697. 1995
 RETINA AND VITREOUS
49. Yuzawa M, Mori R, Haruyama M: A study
of laser photocoagulation for polypoidal
choroidal vasculopathy. Jpn J Ophthalmol
2003; 47:379–384.
50. Gass JDM: Biomicroscopical and
histopathologic considerations regarding
the feasibility of surgical excision of
subfoveal neovascular membranes. Am J
Ophthalmol 1994; 118:285–298.
51. Shiraga F, Matsuo T, Yokoe S, et al:
Surgical treatment of submacular
hemorrhage associated with idiopathic
polypoidal choroidal vasculopathy. Am J
Ophthalmol 1999; 128:147–152.
52. Merill PT, LoRusso FJ, Lomeo MD, et al:
Surgical removal of subfoveal choroidal
neovascularization in age-related macular
degeneration. Ophthalmology 1999;
106:782–789.
53. Thomas MA, Grand MG, Williams DF, et al:
Surgical management of subfoveal
SECTION 10
choroidal neovascularization.
Ophthalmology 1992; 99:952–968.
54. Yazawa M, Isomae T, Mori R, Shimade H,
Utsunomiya. I. Surgical excision versus
laser photocoagulation for subfoveal
choroidal neovascularization membranes
with age-related macular degeneration:
comparison of visual outcomes. Jpn J
Ophthalmol 2001; 45:192–198.
1996
55. Fujii GY, Pieramici DJ, Humayun MS, et al:
Complications associated with limited
macular translocation. Am J Ophthalmol
2000; 130:751–762.
56. Marcus D, Sheils W, Johnson M, et al:
External beam irradiation of subfoveal
choroidal neovascularization complicating
age-related macular degeneration: one-
year results of a prospective, double-
masked, randomized clinical trial. Arch
Ophthalmol 2001; 119:171–180.
57. Spaide RF, Leys A, Herrman-Delemazure B,
et al: Radiation associated choroidal
neovasculopathy. Ophthalmology 1999;
106:2254–2260.
58. Reichel E, Berrocal AM, Ip M, et al:
Transpupillary thermotherapy of occult
subfoveal choroidal neovascularization in
patients with age-related macular
degeneration. Ophthalmology 1999;
106:1908–1914.
59. Spaide RF, Donsoff I, Lam DL, et al:
Treatment of polypoidal choroidal
vasculopathy with photodynamic therapy.
Retina 2002; 22:529–535.
60. Silva RM, Figueira J, Cachulo ML, et al:
Polypoidal choroidal vasculopathy and
photodynamic therapy with verteporfin.
Graefes Arch Clin Exp Ophthalmol 2005;
243:973–979.
61. Chan WM, Lam DS, Lai TY, et al:
Photodynamic therapy with verteporfin for
symptomatic polypoidal choroidal
vasculopathy: one-year results of a
prospective case series. Ophthalmology
2004; 111:1576–1584.
62. Quaranta M, Mauget-Faysse M, Coscas G:
Exudative idiopathic polypoidal
vasculopathy and photodynamic therapy
with verteporfin. Am J Ophthalmol 2002;
134:277–280.
63. Hussain N, Hussan A, Natarajan S: Role of
photodynamic therapy in polypoidal
choroidal vasculopathy. Indian J
Ophthalmol 2005; 53:101–104.
64. Lee SC, Seong YS, Kim SS, et al:
Photodynamic therapy with verteporfin for
polypoidal choroidal vasculopathy of the
macula. Ophthalmologica 2004;
21:193–201.
65. Rogers AH, Greenberg PB, Martidis A,
Puliafito CA: Photodynamic therapy of
polypoidal choroidal vasculopathy.
Ophthalmic Surg Lasers Imaging 2003;
34:60–63.
 CHAPTER
152 Angioid Streaks
Eric Chen, Allen C. Ho, and David R. Guyer
HISTORICAL PERSPECTIVE
Key Features
• Angioid streaks are irregular breaks in a calcified and
thickened Bruch’s membrane
• They radiate outward from the optic nerve in a pattern similar
to retinal vasculature
• They are almost always bilateral, and there is no gender or
racial predilection
• They are not present at birth but may progress over time
• Associated findings include optic disk drusen, peau d’orange,
retinal hemorrhage, CNV, and macular degeneration
• Systemic diseases are present in 50% of patients; most
common are PXE, Paget’s disease, and the
hemoglobinopathies
Angioid streaks were first described by Doyne1 in 1889, and in
1892 Knapp2 coined the term as he thought that they resembled
blood vessels. It was not until 1917 that Kofler3 correctly stated
that the main pathologic changes were at the level of Bruch’s
membrane. This finding was confirmed histopathologically in
the late 1930s.4
The recognition of angioid streaks is important because they
can be associated with choroidal neovascularization (CNV) and
macular degeneration and can herald the presence of systemic
disorders, such as pseudoxanthoma elasticum (PXE), Paget’s
disease, and the hemoglobinopathies (Table 152.1).
TABLE 152.1 Common Systemic Findings Associated with
Angioid Streaks
Finding % and disk drusen. In one series,6 these lesions were observed in
PXE 34
Paget’s disease 10
Hemoglobinopathy 6
Idiopathic 50
From Clarkson JG, Altman RD: Angioid streaks. Surv Ophthalmol 1982;
26:235–246.
CLINICAL FINDINGS
Angioid streaks are irregular, spoke-like, and curvilinear streaks
that radiate outward from the peripapillary area in all directions
(Fig. 152.1). They are not present at birth, but have been docu-
mented as early as childhood, with subsequent growth.5 There
is no gender or racial predilection. Angioid streaks are almost
always bilateral, and can be distinguished from blood vessels as
they lie beneath the retina and above the choroidal vasculature.
Angioid streaks are within two disk diameters of the optic nerve
in 27% of cases and are widespread in 73% of patients.6 They
usually taper as they extend away from the disk, and typically
do not go past the equator. The streaks can be wide or narrow
and can vary in number from one to many. There are often
associated peripapillary chorioretinal changes.
The color of the streaks can range from red to dark brown,
and is often dependent on the pigmentation of the fundus and
degree of overlying retinal pigment epithelium (RPE) atrophy;
they can appear gray if fibrovascular tissue is present. In one
study,6 32% of streaks were gray, 23% were red, and 14% had
pigment proliferation with a blackish coloration. Hyperpigmen-
tation or atrophy of the RPE may occur at the margin of the
streak.
The streaks themselves are usually asymptomatic, but
associated complications may cause vision loss. Subretinal
hemorrhage or choroidal rupture may occur even after minor
trauma.7 However, the main cause of vision loss in these
patients is CNV, RPE detachment, and macular degeneration
(Fig. 152.2). In one series,6 macular degeneration was observed
in 40 (72%) of 56 cases; 32 patients had exudative maculopathy,
and eight patients had atrophic maculopathy. In another study
of 110 cases, the occurrence of exudative macular degeneration
was associated with the length of the streak, the distance of the
streak from the fovea, and the diffuse or ‘cracked eggshell’ type
of streak.8 A case of an RPE tear associated with angioid streaks
has also been reported.9
Other associated findings include peau d’orange changes
(Fig. 152.3), light margins along streaks, peripheral focal lesions
(salmon spots), hemorrhage, paired red spots along the streaks,
61%, 57%, 44%, 35%, 19%, and 10% of patients, respectively.
Some of these lesions, such as disk drusen, salmon spots, and
peau d’orange changes, are exclusively or more commonly
noted in cases of angioid streaks associated with PXE.
ANCILLARY TEST FINDINGS
Many authors6,10–13 have observed early hyperfluorescence of
the streaks with late staining (see Fig. 152.1). Others,6,13,14 how-
ever, have reported hypofluorescence of the streaks with hyper-
fluorescence at the margins, which stain late; hypofluorescence
is caused by separation of the underlying choriocapillaris and
subsequent nonperfusion.13 In some cases, fluorescein angio-
graphy and red-free images may reveal angioid streaks not
observed clinically.10,15 The classic findings of associated CNV,
RPE detachments, and serous or hemorrhagic detachments may 1997
 RETINA AND VITREOUS
a
c
SECTION 10
b d
a b
c d
be observed on fluorescein angiography or indocyanine green
angiography (ICGA), which may be superior in visualizing
occult CNV.16 The peau d’orange changes, which may represent
focal defects of Bruch’s membrane and the choriocapillaris,
produce hypofluorescent areas on fluorescein angiography and a
speckled pattern in the midperiphery on ICGA.13
Usually, visual fields, color testing, ERG, EOG, and dark
1998 adaptation tests are all normal.
FIGURE 152.1. (a–c) Angioid streaks are
irregular, curvilinear, reddish brown streaks that
radiate outward from the peripapillary area.
(d) Fluorescein angiography reveals
hyperfluorescence of the streaks.
FIGURE 152.2. This patient with angioid
streaks (a) has the characteristic ‘plucked-
chicken’ skin lesions (b) of PXE. (c) and (d) The
patient experienced CNV, which occurs in a
high percentage of patients with angioid
streaks.
NATURAL HISTORY
Although patients with angioid streaks are usually asymp-
tomatic early in the course of the condition, visual loss usually
occurs with time. In one report,17 vision of 20/200 or worse was
noted in most eyes after 50 years of age, while in another
series,18 greater than 50% of patients had an initial visual acuity
of 20/40 or better, but more than half of the patients were legally

a b
c d
blind at an average follow-up of 3.6 years. In another study
of 29 cases, 66% of patients had a visual acuity of 20/200
or worse.
The cause of this vision loss is macular degeneration or CNV,
or both (see Fig. 152.2). Three separate studies have reported
macular degeneration in ~70% of patients with angioid
streaks.6,19,20 Macular degeneration has even been observed in a
14-year-old patient.19
Unlike age-related macular degeneration, the exudative form
is more common than the atrophic type of maculopathy in
patients with angioid streaks.18,21 However, the exudative form
is found less frequently in patients with angioid streaks and sickle
cell disease than in patients with other associated systemic
conditions.22 Macular degeneration is not always associated
with a foveal angioid streak, and it does not occur in all patients
with a streak through the fovea.10
Piro and associates18 studied 62 patients with angioid streaks
and found that 86% had CNV in at least one eye. Bilateral CNV
was noted in 49% of patients, and 37% of patients had uni-
lateral CNV. Five fellow eyes of 22 patients with unilateral CNV
developed CNV during a mean follow-up period of 18 months.
Mansour and co-workers8 reported that the CNV was associ-
ated with streak length, streak distance from the fovea, and the
diffuse type of streak in their series.
Minor trauma may cause subretinal hemorrhage, often with
macular involvement (Fig. 152.3).4,7,10,22 Patients should be
warned to avoid trauma and contact sports and to monitor their
vision regularly with an Amsler grid for the onset of CNV.
SYSTEMIC ASSOCIATIONS
Clarkson and Altman23 found an associated systemic disease in
50% of the 50 patients in their series. PXE, Paget’s disease, and
hemoglobinopathy were diagnosed in 34%, 10%, and 6% of the
cases, respectively (see Table 152.1). Piro and associates18 noted
PXE in 61% of their patients and no systemic disease in 35%
of the patients. Federman and colleagues13 reported PXE in 30
(54%) of their 56 patients. In 1941, Scholz20 reported that 59%
Angioid Streaks
FIGURE 152.3. (a) Following trauma with a
bungee cord, a patient with angioid streaks had
multiple areas of subretinal hemorrhage with
central macula involvement, with a drop of
visual acuity to 20/200. Color montage photos
show spontaneous resolution of the
hemorrhage and unmasking of a choroidal
rupture nasal to fixation at one (b), two (c), and
3 months (d) after initial presentation, with an
ultimate improvement in vision to 20/30.
CHAPTER 152
of 131 patients with angioid streaks had PXE. Many other sys-
temic disorders have been associated with angioid streaks, but
some of these associations may be coincidental (Table 152.2).
PXE, Paget’s disease, and the hemoglobinopathies remain the
most commonly found associated systemic diseases.
PSEUDOXANTHOMA ELASTICUM
PXE is a form of systemic elastorrhexis that mainly affects the
skin, eyes, gastrointestinal system, and heart.23 Females are
affected twice as often as males. Patients usually are diagnosed
in the third to fourth decades of life. The inheritance of this rare
disorder is usually autosomal recessive but may be autosomal
dominant, and the underlying genetic defect has been localized
to chromosome 16 and a mutation in the transport protein
ABC-C6.24,25 It has been thought that the condition is caused
by elastic fiber abnormalities with secondary calcification. How-
ever, the earliest finding in PXE was determined by cytoimmuno-
chemistry and X-ray analysis to be an accumulation of
polyanions in the dermis.26 These authors speculate that the
polyanions attract calcium, which causes mineralization. Thus,
the basic defect in PXE may not be one of calcium or elastin
metabolism but rather of glycosaminoglycans and glyco-
proteins. These glycosylated molecules may attach to elastic
fibers, mineralize, and cause abnormal collagen synthesis.
The characteristic skin change in PXE is a redundant waxy,
yellow, papule-like lesion, which commonly affects the neck,
face, abdomen, axillary areas, inguinal regions, periumbilical
area, and oral mucosa (see Fig. 152.2). This skin lesion looks
like a ‘plucked chicken’. Skin biopsy results reveal elastic tissue
staining of the deep dermis, often with calcification. Lebwohl
and associates27 performed biopsies on scar and normal flexural
skin in patients suspected of having PXE without the typical
clinical skin findings. Six of 10 scar biopsy results showed
fragmentation of elastic tissue, and three normal flexural skin
biopsy results showed signs of PXE. These authors concluded
that scar biopsy is useful in suspected cases of PXE without the
characteristic clinical skin lesions. 1999
 RETINA AND VITREOUS

Strandberg syndrome in their honor. Angioid streaks are present

TABLE 152.2. Other Systemic Disorders Associated with
in ~85% of patients with PXE.19,23 The streaks usually occur
Angioid Streaks
in early adulthood but can occur in patients as young as age
Acromegaly 8 years.5
Ehlers–Danlos syndrome
The peau d’orange changes represent a diffuse mottling of
the RPE in the temporal midperiphery and consist of multiple
Facial angiomatosis yellowish RPE lesions that have the appearance of the ‘skin of
Heterotopic calcification with hyperphosphatemia an orange’ (see Fig. 152.4). These lesions may be observed
before the occurrence of the angioid streaks.31 They are usually
Idiopathic thrombocytic purpura
seen in association with PXE but occasionally can be present in
Multiple hamartoma syndrome with uterine cancer cases of Paget’s disease or sickle hemoglobinopathy.23
Ocular melanocytosis
The salmon spot31 is a multifocal, yellow, atrophic, and
peripheral RPE lesion that appears ‘punched-out’ like a
Lead poisoning histoplasmosis syndrome spot. Macular drusen and atypical
Familial polyposis drusen may be present in up to 75% of cases.21 The presence of
all five varieties of pattern dystrophy in patients with PXE and
Hypo- and abetalipoproteinemia
angioid streaks has been reported by Agarwal,32 and Kadri and
Chronic familial hyperphosphatemia colleagues15 described intraretinal bands from the optic disk,
SECTION 10

Diabetes peripheral retinal degeneration, and bilateral retinal detach-

ments in one case. Multiple small crystalline bodies may be
Hemochromatosis present in 75% of patients in the midperipheral or juxta-
Acquired hemolytic anemia papillary regions.10 These crystalline bodies are associated with
atrophic RPE changes and may resemble a comet when RPE
Hypercalcinosis
atrophy occurs in a tail-like configuration next to it. Vascular
Hyperphosphatemia abnormalities, including chorioretinal arteriovenous communi-
Myopia cations, have also been described.33
Optic disk drusen are found clinically or echographically in
Neurofibromatosis up to a quarter of patients with PXE and angioid streaks.
Senile elastosis Coleman and co-workers34 stated that the incidence of disk
drusen is 20–50 times greater in patients with PXE than in
Tuberous sclerosis
normal individuals. Shields and associates6 found disk drusen
Diffuse lipomatosis in 10% of the patients in their series, and Pierro and
Dwarfism colleagues35 observed them in 21.6% of their 58 patients.
Calcium-containing macromolecules may attach to the elastic
Epilepsy fibers at the cribriform plate, disrupt axonal flow, and produce
Nephrolithiasis disk drusen, which may be the first manifestation of ocular
PXE.34 The peau d’orange and other pigmentary lesions may
Congenital dyserythropoietic anemia (CDA III)
precede angioid streaks, which may not develop until the third
Trauma to fourth decades of life. The angioid streaks then lead to CNV,
disciform scarring, and macular degeneration.

Other systemic findings in PXE include cerebral ischemia, PAGET’S DISEASE

cerebrovascular accidents, intracranial aneurysms, claudication,
hypertension, myocardial infarction, and gastrointestinal
hemorrhage with or without ulceration. The gastrointestinal
hemorrhage may be life-threatening, can occur in up to 15% of
patients, and may occur before the skin or eye findings.
The first ocular findings in PXE were reported in 1903.28 The
first report of the association between PXE and angioid streaks
was in 1929 by Groenblad29 and Strandberg.30 The ocular and
cutaneous findings of PXE are referred to as the Groenblad–
Paget’s disease or osteitis deformans is a chronic, progressive
connective tissue disorder that involves the collagen matrix of
bone.23 Osteoclastic activity with an osteoblastic reaction
occurs. The condition may be due to a slow virus related to
measles or to the respiratory syncytial virus36 or may be trans-
mitted in an autosomal dominant manner. Males and females
are equally affected. Systemic findings include an enlarged bone
mass affecting the pelvis, skull, spine, humeri, and femora,
extraskeletal calcifications of the skin and arteries, pain,

FIGURE 152.4. (a and b) The peau d’orange

lesion is a diffuse mottling of the RPE in the
temporal midperiphery. These changes appear
as multiple, yellowish retinal pigment epithelial
lesions that have the appearance of an orange
skin ( peau d’orange).

a b
2000

secondary osteoarthritis, neurologic damage, cardiac disease,
decreased hearing, hyperparathyroidism, and claudication. The
diagnosis is made by finding an elevated serum alkaline
phosphatase level, increased urinary calcium and total peptide
hydroxyproline levels, and characteristic radiographic findings.
The first associations between Paget’s disease and angioid
streaks were made by Verhoeff in 192837 and Rowland in
1929.38 Angioid streaks are found in 8–15% of patients with
Paget’s disease.20,23 However, others have suggested that the
association may be less common. Dabbs and Skjodt39 found
only one (1.4%) of 70 patients with angioid streaks to also have
Paget’s disease.
Clarkson and Altman23 studied 50 patients with active
Paget’s disease. Angioid streaks were found in seven patients.
Those with angioid streaks were found to have had a longer
duration of Paget’s disease, a high alkaline phosphatase level,
more disease sites seen on X-ray film, and increased urinary
hydroxyproline excretion. In addition, six of the seven patients
had skull involvement.
Occasionally, patients with Paget’s disease may have peau
d’orange lesions and other RPE changes.10,23 Visual loss is
usually caused by CNV, but optic atrophy, sometimes secondary
to bony compression, may also occur.
HEMOGLOBINOPATHIES
The first association of angioid streaks with sickle cell disease
was made in 1959 by Lieb and co-workers.40 In a selected
population of patients with sickle cell disease, five (6%) of 69
patients were found to have streaks.41 Condon and Serjeant42
did not find any patients with angioid streaks in their study of
76 patients with homozygous sickle cell disease (sickle cell
anememia or hemoglobin SS disease). In another study of 124
patients with hemoglobin SS disease, no patients with streaks
were observed.43 However, five (1.4%) of 356 patients in another
series44 had angioid streaks, and in Clarkson and Altman’s
report23 six patients with hemoglobin SS disease and one
patient with hemoglobin SC disease, had angioid streaks. The
frequency of angioid streaks appears to be higher in elderly
patients45; of 60 elderly patients with hemoglobin SS disease,
13 (22%) had streaks, whereas only three (2%) of 150 younger
patients were observed to have angioid streaks.
Hamilton and associates46 reported 21 of 242 patients with
hemoglobin SS disease to have angioid streaks. Their patients
had good prognoses, as only two individuals had macular
disease.
Angioid streaks have also been reported in association with
other hemoglobinopathies besides hemoglobin SS disease, such
as hemoglobin SC disease47; hereditary spherocytosis48; sickle
trait (hemoglobin AS)49; b-thalassemia major, minor, and inter-
media50; hemoglobin H disease51; and sickle cell thalassemia.52
Overall, angioid streaks appear in 1–2% of patients with
hemoglobinopathies, with the incidence increasing with age.
Complications, such as CNV or macular degeneration, are
uncommon with angioid streaks associated with sickle cell
disease.
OTHER SYSTEMIC ASSOCIATIONS
PXE, Paget’s disease, and the hemoglobinopathies are most
commonly associated with angioid streaks. However, many
other associated systemic conditions have been reported.
Angioid streaks have been found in patients with the
Ehlers–Danlos syndrome,53 a rare autosomal dominant connec-
tive tissue disorder with hyperextensible skin and hyperflexible
joints caused by an abnormality in the synthesis and meta-
bolism of collagen. Ocular findings include high myopia, kerato-
Angioid Streaks
conus, blue sclera, ectopis lentis, and retinal detachment, while
systemic findings include cardiovascular disease, diaphragmatic
hernias, and diverticuli of the gastrointestinal and respiratory
tracts.
The other systemic conditions associated with angioid streaks
probably represent coincidental findings. These disorders include
acromegaly,54 facial angiomatosis,55 heterotopic calcification
with hyperphosphatemia,56 idiopathic thrombocytic purpura,57
multiple hamartoma syndrome with uterine cancer,58 ocular
melanocytosis,59 lead poisoning,60 familial polyposis,61 hypo-
and abetalipoproteinemia,62 chronic familial hyperphosphatemia,63
diabetes, hemochromatosis, acquired hemolytic anemia,
myopia, senile elastosis, tuberous sclerosis, hypercalcinosis,23
hyperphosphatemia,56 neurofibromatosis,64 diffuse lipomatosis,65
dwarfism,66 epilepsy,67 nephrolithiasis,68 congenital dyserythro-
poietic anemia (CDA III),69 and trauma1 (see Table 152.2).
PATHOPHYSIOLOGY
CHAPTER 152
Although the pathogenesis of angioid streaks remains con-
troversial, the elastic lamina of Bruch’s membrane seems to be
primarily affected, with secondary degeneration of the chorio-
capillaris and RPE with disease progression. In PXE and Paget’s
disease, Bruch’s membrane may become calcified and brittle.
Adelung70 studied the lines of force in the eye resulting from
traction of the ocular muscles pulling the eye around the fixed
site of the optic nerve, leading to the peripapillary origin and
radial extension of cracks occurring in a brittle Bruch’s mem-
brane. Calcification is observed in other parts of the body in
both PXE and Paget’s disease, and thus this mineralization may
be a common mechanism.
The cause of angioid streaks in sickle cell disease is even
more confusing. Calcification is not common in this disorder;
studies have conflicted as to whether a diffuse elastic degener-
ation is present in patients with sickle cell disease. Another
theory is that iron deposition in Bruch’s membrane may occur
from hemolysis. This iron deposition could cause mineraliz-
ation of Bruch’s membrane. However, only one study4
documented iron staining of Bruch’s membrane. Other studies
could not confirm these findings. Jampol and associates71 stated
that calcification may be more important than iron deposition.
Another hypothesis for the occurrence of angioid streaks in
patients with sickle cell disease stated that the lesions occur
from impaired nutrition caused by sickling and stasis.72 Small-
vessel occlusion could also be important in the pathogenesis.46
PATHOLOGIC FEATURES
The first histopathologic studies of angioid streaks were
reported in the late 1930s.4 Basophilia and calcification of a
thickened Bruch’s membrane were observed in both reports.
Breaks in Bruch’s membrane correlated with the clinical sites of
the streaks. Elastic degeneration was noted, and some breaks
were invaded by fibrovascular tissue from the choroid. Thus,
angioid streaks appear to be linear cracks in a thickened,
degenerated, and calcified Bruch’s membrane.
It appears that the histopathologic appearance is similar
regardless of the associated systemic condition.23,71 Iron
deposition has not been found in cases of associated sickle cell
disease except for one report.4,46,71,73 Dreyer and Green73 studied
the histopathologic features of 32 eyes from 21 cases. Two
patients had PXE, five patients had Paget’s disease, and 14
patients had no systemic disorder. These authors confirmed
that angioid streaks are defects in the thickened, calcified elastic
layer of Bruch’s membrane. They found that the earliest change
was a break in the elastic and collagenous layers of Bruch’s
membrane. Fibrovascular ingrowth occurred in some of the 2001
 RETINA AND VITREOUS
breaks. Secondary changes included thickening of the basement
membrane of the RPE, RPE atrophy, choriocapillaris damage,
photoreceptor loss, RPE hypertrophy or hyperplasia, serous
retinal detachment, and disciform scar formation. CNV and
serous retinal detachment were observed in two cases, and
disciform scars were present in eight eyes. Salmon spots were
found to be isolated breaks in Bruch’s membrane with fibro-
vascular ingrowth.
Jensen74 studied Bruch’s membrane in PXE using histo-
chemical, ultrastructural, and X-ray microanalytic techniques.
He found two types of calcification: hydroxyapatite and
CaHPO4. He also observed a ‘thready’ material in the mem-
brane and an increased amount of acid mucopolysaccharide.
He stated that malformed collagen may be the underlying
abnormality in PXE.
TREATMENT
SECTION 10
As even trivial trauma can precipitate hemorrhage in patients
with angioid streaks, safety glasses should be considered. In
addition, these patients should not engage in contact sports.
Low-vision aids may be useful, and in some cases, genetic
counseling should be considered. Prophylactic treatment of
angioid streaks should not be performed, as patients are
generally asymptomatic and treatment may induce CNV, but
patients should be advised to use an Amsler grid regularly to
allow early detection of CNV.
Although there have been no prospective randomized con-
trolled trials of different treatment options for CNV associated
with angioid streaks, it seems reasonable to consider treatment
of CNV to slow down progression of the CNV, decrease size of
the central scotoma, or reduce a patient’s metamorphopsia.
Successful outcomes with laser photocoagulation have been
reported with well-defined juxta- or extrafoveal CNV, although
the recurrence rate may be higher with CNV associated with
angioid streaks than with CNV associated with other macular
disorders. Singerman and Hatem75 treated eight eyes with extra-
foveal CNV with laser photocoagulation. Improved or stabilized
vision was noted in seven of the eight cases. Recurrences
occurred in four eyes. Piro and associates18 found a poor
response to laser photocoagulation in their series because of
recurrences. Brancato and colleagues76 treated 13 such eyes and
stated that laser photocoagulation should be performed. Van
Eijk and Oosterhuis77 successfully treated seven of 15 eyes.
Eight eyes had subfoveal recurrences. Gelisken and associates78
treated 30 such eyes. Sixteen of the eyes had stable or improved
vision postoperatively. Twelve of the remaining 14 cases
retained 20/200 vision or better during a mean follow-up period
of 3.4 years. Eleven untreated fellow eyes developed macular
degeneration and the loss of central vision.
In the largest series, Pece and co-workers79 treated 66 eyes
and found a significant decrease in vision in the first year, but
no significant change thereafter. They concluded laser treat-
ment could end CNV and help stabilize visual acuity or slow
down visual loss, although a high frequency of recurrences (77%
of eyes) demanded intense clinical and angiographic follow-up,
mostly in the first 3 months after treatment.
The lack of treatment for subfoveal CNV led to developments
in the surgical treatment of CNV in angioid streaks. Thomas
and associates80 first reported four eyes that underwent surgical
removal of subfoveal membranes, with a mean loss of one line
of vision and visual outcome at 20/200 or worse at 7 months;
recurrent neovascularization occurred in one eye. They pos-
tulated that diffuse abnormalities in Bruch’s membrane seen in
angioid streaks made it difficult to preserve underlying RPE
after CNV removal. Adelberg and colleagues81 reported only one
2002 eye out of five improving after surgery, with no recurrences at
follow-up up to 6 months. Fujii et al82 described inferior limited
macular translocation for angioid streak-associated subfoveal
CNV; two of four eyes had a final vision of 20/80 or better, with
one of these suffering from a retinal detachment, while another
eye had extrafoveal and subfoveal recurrence at 8 weeks and
9 months, respectively.
Photodynamic therapy (PDT), using an intravenous photo-
sensitive drug (verteporfin) that is activated with infrared laser,
is another therapeutic option with mixed results in treating
angioid streak-associated CNV. Karacorlu et al83 reported eight
eyes treated successfully, with short-term cessation of leakage
on fluorescein angiogram and no deterioration in visual acuity
over a mean of 8.7 months, while Shaikh and associates84
treated 11 eyes and found conversion of a CNV to a fibrous
disciform lesion in nine eyes and lesion enlargement in seven of
these eyes.
Menchini and colleagues85 evaluated 48 eyes with baseline
vision of 20/200 or greater and found that most had no or
limited vision loss after 1 year and suggested PDT could be used
to limit or delay visual loss, while another report by Ladas et al86
with 24 eyes found unsatisfactory anatomic and functional
results with PDT, even when re-treatments were performed
earlier than the conventional time of 3 months. Nineteen of the
24 eyes had a final best-corrected visual acuity of 20/400 or
worse. Browning and co-workers87 found PDT seemed to limit
visual loss in most patients through the first 12 months of
follow-up; in 16 eyes with subfoveal CNV, 12 lost fewer than
eight letters and 14 of the 16 lost fewer than 15 letters on
ETDRS charts.
Costa et al88 also described a novel technique of selective
occlusion of subfoveal CNV in five patients with photo-
thrombosis of the neovascular ingrowth site with large-spot,
lower-intensity 810-nm laser to ICG concentrated in vascular
lesions. They demonstrated rapid induction of CNV hypo-
perfusion within 1 h, and improvement of visual acuity and
partial restoration of retinal architecture by optical coherence
tomography up to 12 months after treatment.
DIFFERENTIAL DIAGNOSIS
Only 39% of cases in one series6 were correctly diagnosed as
having angioid streaks before referral. Twenty-three percent of
these cases were misdiagnosed as age-related macular degener-
ation. Other disorders that were confused with the angioid streaks
included choroidal sclerosis, myopia and lacquer cracks, histo-
plasmosis, toxoplasmosis, retinal vasculitis and papilledema,
and traumatic hemorrhage. Other entities to consider in the
differential diagnosis include choroidal rupture and choroidal
folds (Table 152.3).
TABLE 152.3. Differential Diagnosis of Angioid Streaks
Age-related macular degeneration
Choroidal sclerosis
Myopic lacquer cracks
Histoplasmosis
Toxoplasmosis
Retinal vasculitis and papilledema
Traumatic hemorrhage
Choroidal rupture
Choroidal folds
 Angioid Streaks

CONCLUSIONS (OR OVERVIEW)
Angioid streaks are distinctive fundus lesions that represent
breaks in a calcified and thickened Bruch’s membrane. They are
an important diagnosis for the ophthalmologist to make, as
they are associated with systemic disorders and their resultant
complications in 50% of cases; the most common diseases seen
include PXE, Paget’s disease, and the hemoglobinopathies.
Angioid streaks themselves are usually asymptomatic, but
trivial trauma can cause significant subretinal hemorrhage, and
the occurrence of CNV and macular degeneration can cause
devastating visual loss. Treatment options for angioid streaks
have shown mixed results. While laser photocoagulation,
submacular surgery, and PDT may all be attempted in an effort
to slow down progression of the CNV, decrease size of the
central scotoma, or reduce a patient’s metamorphopsia, long-
term prognosis remains guarded, as the recurrence rate with
any treatment is high.

Summary Boxes
Pseudoxanthoma Elasticum
• Usually diagnosed in the third to fourth decade of life, typically autosomal recessive, defect on chromosome 16 and protein ABC-C6
• Characteristic ‘chicken skin’ with redundant waxy, yellow, papule-like lesions
• Life-threatening complications include GI bleeding, cardiovascular and cerebrovascular disease
• Angioid streaks are present in ~85% of patients with PXE
• Other ocular associations include optic disk drusen, peau d’orange

CHAPTER 152
Paget’s Disease
• Chronic, progressive connective tissue disorder; osteoclastic bone activity with an osteoblastic reaction
• Enlargement of the skull, kyphoscoliosis, deafness, and deformities of long bones
• Angioid streaks present in <2% of patients
Hemoglobinopathies
• Angioid streaks have been found in 1–2% of patients with hemoglobinopathies, and have been observed with many varieties of
hemoglobinopathy
• Frequency of angioid streaks increases with age
• Complications such as macular degeneration and choroidal neovascular membranes are uncommon

REFERENCES
1. Doyne RW: Choroidal and retinal changes.
The result of blows on the eyes. Trans
Ophthalmol Soc UK 1889; 9:128.
2. Knapp H: On the formation of dark angioid
streaks as an unusual metamorphosis of
retinal hemorrhage. Arch Ophthalmol 1892;
21:289–292.
3. Kofler A: Beitraege zur Kenntnis der
angioid Streaks (Knapp). Arch Augenheilkd
1917; 82:134–149.
4. Hagedoorn A: Angioid streaks. Arch
Ophthalmol 1939; 21:746–774; 935–965.
5. Mansour AM, Ansari NH, Shields JA, et al:
Evolution of angioid streaks.
Ophthalmologica 1993; 207:57–61.
6. Shields JA, Federman JL, Tomer TL,
Annesley WH Jr: Angioid streaks. I.
Ophthalmoscopic variations and diagnostic
problems. Br J Ophthalmol 1975;
59:257–265.
7. Fine SL: Angioid streaks. Int Ophthalmol
Clin 1977; 17:173–182.
8. Mansour AM, Shields JA, Annesley WH,
et al: Macular degeneration in angioid
streaks. Ophthalmologica 1988; 197:36–41.
9. Lim JI, Lam S: A retinal pigment epithelium
tear in a patient with angioid streaks. Arch
Ophthalmol 1990; 108:1672–1674.
10. Gass JDM: Stereoscopic atlas of macular
diseases, diagnosis and treatment. 3rd edn.
St Louis: CV Mosby; 1987.
11. Gass JDM: Pathogenesis of disciform
detachment of the neuroepithelium. VI.
Disciform detachment secondary to
heredodegenerative, neoplastic, and
traumatic lesions of the choroid. Am J
Ophthalmol 1967; 63:689–711.
12. Smith JL, Gass JDM, Justice J Jr:
Fluorescein fundus photography of angioid
streaks. Br J Ophthalmol 1964;
48:517–521.
13. Federman JL, Shields JA, Tomer TL:
Angioid streaks. II. Fluorescein angiographic
features. Arch Ophthalmol 1975; 93:951–962.
14. Gass JDM, Clarkson JG: Angioid streaks
and disciform macular detachment in
Paget’s disease (osteitis deformans). Am J
Ophthalmol 1973; 75:576–586.
15. Kadri W, Rosen E, Harcourt B: Intraretinal
changes in the Groenblad–Strandberg
syndrome. Br J Ophthalmol 1973;
57:588–592.
16. Arvas S, Akar S, Yolar M, et al: Optical
coherence tomography (OCT) and
angiography in patients with angioid
streaks. Eur J Ophthalmol 2002
12:473–481.
17. Groenblad E: ‘Angioid streaks’ –
pseudoxanthoma elasticum.
De Zusammenhang zwischen diesen
gleichzeitig auftretenden Augen- und
Hautveran-derungen. Acta Ophthalmol
1932; 1(Suppl):1–114.
18. Piro PA, Scheraga D, Fine SL: Angioid
streaks. Natural history and visual
prognosis. In: Fine SL, Owens S, eds.
Management of retinal vascular and
macular disorders. Baltimore: Williams &
Wilkins; 1983:136–139.
19. Connor PJ, Juergens JL, Perry HO, et al:
Pseudoxanthoma elasticum and angioid
streaks. A review of 106 cases. Am J Med
1961; 30:537–543.
20. Scholz RO: Angioid streaks. Arch
Ophthalmol 1941; 26:677–695.
21. Verhoeff FH: Histological findings in a case
of angioid streaks. Br J Ophthalmol 1948;
32:531–544.
22. Archer AB, Logan WC: Angioid streaks. In:
Krill AE, ed. Hereditary retinal and choroidal
diseases. Philadelphia: JB Lippincott;
1976:851–909.
23. Clarkson JG, Altman RD: Angioid streaks.
Surv Ophthalmol 1982; 26:235–246.
24. McKusick VA: Heritable disorders of
connective tissue. 4th edn. St Louis:
CV Mosby; 1972:475–520.
25. Struk B, Cai L, Zach S, et al: Mutations of
the gene encoding the transmembrane
transporter protein ABC-C6 cause
pseudoxanthoma elasticum. J Mol Med
2000; 78:282–286.
26. Walker ER, Frederickson RG, Mayes MD:
The mineralization of elastic fibers and
alterations of extracellular matrix in
pseudoxanthoma elasticum. Arch Dermatol
1989; 125:70–76.
27. Lebwohl M, Phelps RG, Yannuzzi L:
Diagnosis of pseudoxanthoma elasticum by
scar biopsy in patients without
characteristic skin lesions. N Engl J Med
1987; 317:347–350.
28. Hallopeau L: Nouvelle note sur un cas de
pseudoxanthome elastique. Ann Dermatol
Syph (Paris) 1903; 4:595–596.
29. Groenblad E: Angioid streaks –
pseudoxanthoma elasticum; vorlaeufige
Mitteilung. Acta Ophthalmol 1929; 7:329.
30. Strandberg J: Pseudoxanthoma
elasticum. Z Haut Geschlechtski 1929;
31:689.
31. Shimizu K: Mottled fundus in association
with pseudoxanthoma elasticum. Jpn J
Ophthalmol 1961; 5:111–113.
32. Agarwal A, Patel P, Gass JD: Spectrum of
pattern dystrophy in pseudoxanthoma
elasticum. Arch Ophthalmol 2005;
123:923–928.
33. Secretan M, Zografos L, Guggisberg D:
Chorioretinal vascular abnormalities
associated with angioid streaks and
pseudoxanthoma elasticum. Arch
Ophthalmol 1998; 116:1333–1336.
2003
 RETINA AND VITREOUS
34. Coleman K, Ross MH, McCabe M, et al:
Disk drusen and angioid streaks in
pseudoxanthoma elasticum. Am J
Ophthalmol 1991; 112:166–170.
35. Pierro L, Brancato R, Minicucci M, et al:
Echographic diagnosis of Drusen of the
optic nerve head in patients with angioid
streaks. Ophthalmologica 1994;
208:239–242.
36. Altman RD: Paget’s disease. In: Talbot MD,
ed. Clinical rheumatology. 1st and 2nd
edns. New York: Elsevier/North-Holland;
1st edn, 1978:184–190; and 2nd edn,
1981:198–206.
37. Verhoeff FH: The nature and pathogenesis
of angioid streaks in the ocular fundus.
Transactions of the section on
ophthalmology of the American Medical
Association. 1928:243.
38. Rowland WD: Bilateral caerulean cataract.
Am J Ophthalmol 1933; 16:61–62.
SECTION 10
39. Dabbs TR, Skjodt K: Prevalence of angioid
streaks and other ocular complications of
Paget’s disease of bone. Br J Ophthalmol
1990; 74:579–582.
40. Lieb WA, Geeraets WJ, Guerry D III: Sickle-
cell retinopathy: ocular and systemic
manifestations of sickle-cell disease. Acta
Ophthalmol (Copenh) Suppl 1959; 58:1–45.
41. Geeraets WJ, Guerry D III: Angioid streaks
and sickle cell disease. Am J Ophthalmol
1960; 49:450–570.
42. Condon PI, Serjeant GR: Ocular findings in
homozygous sickle cell anemia in Jamaica.
Am J Ophthalmol 1972; 73:533–543.
43. Majekodunmi SA, Akinyanju OO: Ocular
findings in homozygous sickle cell disease
in Nigeria. Can J Ophthalmol 1978;
13:160–162.
44. Nagpal K, Asdourian G, Goldbaum M,
et al: Angioid streaks and sickle
haemoglobinopathies. Br J Ophthalmol
1976; 60:31–34.
45. Condon PI, Serjeant GR: Ocular findings in
elderly cases of homozygous sickle cell
disease in Jamaica. Br J Ophthalmol 1976;
60:361–364.
46. Hamilton AM, Pope FM, Condon PI, et al:
Angioid streaks in Jamaican patients with
homozygous sickle cell disease. Br J
Ophthalmol 1981; 65:341–347.
47. Condon PI, Serjeant GR: Ocular findings in
hemoglobin SC disease in Jamaica. Am J
Ophthalmol 1972; 74:921–931.
48. McLane NJ, Grizzard WS, Kousseff BG,
et al: Angioid streaks associated with
hereditary spherocytosis. Am J Ophthalmol
1984; 97:444–449.
49. Gerde LS: Angioid streaks in sickle cell trait
hemoglobinopathy. Am J Ophthalmol 1974;
77:462–464.
50. Gartaganis S, Ismiridis K, Papageorgiou O,
et al: Ocular abnormalities in patients with
b thalassemia. Am J Ophthalmol 1989;
108:699–703.
51. Daneshmend TK: Ocular findings in a case
of haemoglobin H disease. Br J Ophthalmol
1979; 63:842–844.
52. Goldberg MF, Charache S, Acadio I:
Ophthalmologic manifestations of sickle
cell thalassaemia. Arch Intern Med 1971;
128:33–39.
53. Green WR, Friedman-Kien A, Banfield WG:
Angioid streaks in Ehlers–Danlos syndrome.
Arch Ophthalmol 1966; 76:197–204.
2004
54. Howard GM: Angioid streaks and
acromegaly. Am J Ophthalmol 1963;
56:137–139.
55. Kalina RE: Facial angiomatosis with angioid
streaks. Association of angioid streaks with
a component of the Sturge–Weber
syndrome. Arch Ophthalmol 1970;
84:528–531.
56. McPhaul JJ Jr, Engel F: Heterotopic
calcification: hyperphosphatemia and
angioid streaks of the retina. Am J Med
1961; 31:488–492.
57. Yatzkan DN: Angioid streaks of the fundus
in association with posthemorrhagic
amaurosis. Am J Ophthalmol 1957;
43:219–222.
58. Allen BS, Fitch MH, Smith JG Jr: Multiple
hamartoma syndrome. A report of a new
case with associated carcinoma of the
uterine cervix and angioid streaks of the
eyes. J Am Acad Dermatol 1980;
2:303–308.
59. Awan KJ: Ocular melanocytosis and
angioid streaks. J Pediatr Ophthalmol
Strabismus 1980; 17:300–304.
60. DeSimone S, DeConciliis V: Strie angioidi
della retina. Arch Ottalmologia 1958;
62:161.
61. Awan KJ: Familial polyposis and angioid
streaks in the ocular fundus. Am J
Ophthalmol 1977; 83:123–125.
62. Duker JS, Belmont J, Bosley TM: Angioid
streaks associated with
abetalipoproteinemia. Arch Ophthalmol
1987; 105:1173–1174.
63. Iancu TC, Almagor G, Savir H: Ocular
abnormalities in chronic familial
hyperphosphatasemia. J Pediatr
Ophthalmol Strabismus 1980; 17:220–223.
64. McWilliam RJ: On the histology of angioid
streaks. Trans Ophthalmol Soc UK 1951;
71:243–249.
65. Bonamour MG: Stries angioides de la retina
et maladie de Launois–Bensaube
(lipomatose diffuse). Bull Soc Ophtalmol
1959; 406.
66. Yoneyama T, Yoneyama K: Angioid streaks
and dwarfism. J Clin Ophthalmol 1960;
14:1013–1022.
67. Blobner F: Angioid streaks and epilepsy.
Klin Monatsbl Augenheilkd 1935; 95:12.
68. Fabre B, Bayle P, Bazex J, et al:
Pseudoxanthoma elasticum and
nephrolithiasis. J Eur Acad Dermatol
Venereol 2005; 19:212–215.
69. Sandstrom H, Wahlin A, Eriksson M, et al:
Angioid streaks are part of a familial
syndrome of dyserythropoietic anaemia
(CDA III). Br J Haematol 1997;
98:845–849.
70. Adelung JC: Zur genese der angioid
streaks (Knapp). Klin Monatsbl Augenheilkd
1951; 119:241–250.
71. Jampol LM, Acheson R, Eagle RC, et al:
Calcification of Bruch’s membrane in
angioid streaks with homozygous sickle
cell disease. Arch Ophthalmol 1987;
105:93–98.
72. Hogan JF, Heaton CL: Angioid streaks and
systemic disease. Br J Dermatol 1973;
89:411–416.
73. Dreyer R, Green WR: The pathology of
angioid streaks: a study of twenty-one
cases. Trans Pa Acad Ophthalmol
Otolaryngol 1978; 31:158–167.
74. Jensen OA: Bruch’s membrane in
pseudoxanthoma elasticum. Histochemical,
ultrastructural, and X-ray microanalytical
study of the membrane and angioid streak
areas. Graefes Arch Clin Exp Ophthalmol
1977; 203:311–320.
75. Singerman LJ, Hatem GF: Laser
treatment of choroidal neovascular
membranes in angioid streaks. Retina
1981; 1:75–85.
76. Brancato R, Menchini U, Pece A, et al:
Laser treatment of macular subretinal
neovascularizations in angioid streaks.
Ophthalmologica 1987; 195:84–87.
77. Van Eijk AW, Oosterhuis JA:
Kryptonlaserbehandlung von
gefabneubildungen bei angioiden streifen.
Klin Monatsbl Augenheilkd 1987;
191:443–448.
78. Gelisken O, Hendrikse F, Deutman AF: A
long-term follow-up study of laser
coagulation of neovascular membranes in
angioid streaks. Am J Ophthalmol 1988;
105:299–303.
79. Pece A, Avanza P, Galli L, Brancato R:
Laser photocoagulation of choroidal
neovascularization in angioid streaks.
Retina 1997; 17:12–16.
80. Thomas MA, Dickinson JD, Melberg NS,
et al: Visual results after surgical removal of
subfoveal choroidal neovascular
membranes. Ophthalmology 1994;
101:1384–1396.
81. Adelberg DA, Del Priore LV, Kaplan HJ:
Surgery for subfoveal membranes in
myopia, angioid streaks, and other
disorders. Retina 1995; 15:198–205.
82. Fujii GY, Humayun MS, Pieramici DJ, et al:
Initial experience of inferior limited macular
translocation for subfoveal choroidal
neovascularization resulting from causes
other than age-related macular
degeneration. Am J Ophthalmol 2001;
131:90–100.
83. Karacorlu M, Karacorlu S, Ozdemir H,
Mat C: Photodynamic therapy with
verteporfin for choroidal neovascularization
in patients with angioid streaks. Am J
Ophthalmol 2002; 134:360–366.
84. Shaikh S, Ruby AJ, Williams GA:
Photodynamic therapy using verteporfin
for choroidal neovascularization in angioid
streaks. Am J Ophthalmol 2003; 135:1–6.
85. Menchini U, Virgili G, Introini U, et al:
Outcome of choroidal neovascularization in
angioid streaks after photodynamic
therapy. Retina 2004; 24:763–771.
86. Ladas ID, Georgalas I, Rouvas AA, et al:
Photodynamic therapy with verteporfin of
choroidal neovascularization in angioid
streaks: conventional versus early
retreatment. Eur J Ophthalmol 2005;
15:69–73.
87. Browning AC, Chung AK, Ghanchi F, et al:
Verteporfin photodynamic therapy of
choroidal neovascularization in angioid
streaks: one-year results of a prospective
case series. Ophthalmology 2005;
112:1227–1231.
88. Costa RA, Calucci D, Cardillo JA, et al:
Selective occlusion of subfoveal choroidal
neovascularization in angioid streaks by
using a new technique of ingrowth site
treatment. Ophthalmology 2003;
110:1192–1203.
 CHAPTER
153 Ocular Histoplasmosis Syndrome
Nancy M. Holekamp, Lawrence S. Halperin, Levent Akduman, and R. Joseph Olk
The ocular histoplasmosis syndrome (OHS) causes permanent
loss of central vision in 2000 young adults per year. The
organism Histoplasma capsulatum has been suspected as a
cause of granulomatous uveitis for many years. In 1951, Krause
and Hopkins1 reported a patient with atrophic chorioretinal
lesions with pigment change and hemorrhage. A histoplasmin
skin test result was positive, and a chest radiograph film
showed calcified lung nodules. In 1960, Woods and Wahlen2
published a report of a collection of patients who were residents
of an area endemic for histoplasmosis and had clear vitreous,
peripheral atrophic spots, disciform macular lesions, positive
histoplasmin skin test results, and pulmonary calcifications.
The four signs of OHS are peripheral punched-out
chorioretinal lesions, juxtapapillary atrophic pigmentary
changes, disciform macular changes, and a clear vitreous.
This chapter reviews the epidemiology, clinical findings,
evaluation, and treatment of OHS.
EPIDEMIOLOGY
Most individuals with OHS are between 30 and 40 years of age.
Fundus scars may occur with equal frequency among blacks and
whites, although maculopathy is very rare in blacks. Baskin and
associates3 reported six blacks with OHS and macular lesions,
five of whom had positive skin test results.
EPIDEMIOLOGIC STUDIES
The epidemiology of OHS has been studied by many
investigators and yet the relationship between H. capsulatum
infection and the manifestations of ocular disease remains an
enigma. A review of several of these reports provides varying
aspects of the debate.
Braunstein and co-workers4 reported 15 individuals in the
United Kingdom who had the clinical findings of OHS but in
whom all skin test results were negative. These investigators
concluded that there could be a different causative factor in the
United Kingdom.
Ellis and Schlaegel5 found the Mississippi and Ohio river
valleys to be highly infected; 80% of the adult population
had positive skin test results. This area includes 80 million
individuals, involving Missouri, Illinois, Indiana, Kentucky,
Tennessee, and Mississippi (Fig. 153.1). Wheat and colleagues6
collected worldwide patterns of skin sensitivity to histoplasmin.
Feman and associates7 noted that 60% of the Tennessee popu-
lation had positive skin test results, but only 44 new cases of
visual loss resulting from OHS occurred in a 6 month period.
Smith and Ganley and co-workers8–10 studied 842 individuals
in Walkersville, Maryland, of whom 60% had positive skin test
results. One-hundred percent of patients with highly suspicious
lesions had positive skin test results, but only 4.4% of those
who had positive results had typical fundus lesions. Only one
individual had a disciform macular lesion. We conclude that
OHS is relatively uncommon, even in endemic areas. Typically,
2–12% of the population in an endemic area has ocular findings
consistent with OHS, and only 1 in 1000 experiences
maculopathy.
Davidorf and Anderson11 examined 353 school-aged children
after an acute epidemic infection on Earth Day in 1970. Forty-
one percent of the children became acutely ill from histo-
plasmosis infection, and 85% had elevated serum titers,
compared with 10% of controls. Two years later, all children
who had the infection had a positive skin test result, compared
with 23.4% of controls. However, the incidence of fundus
lesions was similar in infected children when compared with
controls, and this brought the association of histoplasmosis
infection and OHS into question. A more likely explanation is
that a 2 year period after exposure to histoplasmosis is not suffi-
cient time to assess the occurrence of OHS lesions. Anand and
colleagues reported observation of active and inactive retinal
lesions during an outbreak of histoplasmosis (Anand R, Luby JP,
Metrikin D, et al: Acquired histoplasma chorioretinitis. Paper
presented at the Annual Meeting of the Retina Society, Santa Fe,
NM, 6–10 Sep 1995).
Feman and Tilford12 found that six of eight patients with
positive systemic histoplasmosis cultures had chorioretinal
scars consistent with OHS. This again lends support to the
concept that H. capsulatum causes OHS.
FELLOW EYE
Patients with a disciform process in one eye have posterior
atrophic lesions in the fellow eye ~25–59% of the time.13,14 If
one eye has a choroidal neovascular membrane (CNVM), and
a focal atrophic spot in the posterior pole is present in the
second eye, that eye has between 8% and 27% chance of acquir-
ing a CNVM in 3 years.13–17 More histoplasmosis spots in the
posterior pole may lead to increased chances of activation. If no
macular atrophic spot is present in the posterior pole of the
second eye, there is less than 5% chance of a CNVM developing
in 5 years; however, new spots may develop. Close follow-up is
needed for the fellow eye, especially if posterior histoplasmosis
spots are present. An individual with bilateral macular
histoplasmosis spots has 5% chance of a CNVM developing in
one eye within 5 years.
The macular photocoagulation study (MPS) showed that
there is 9% risk of CNVM formation in 5 years in the fellow eye
if a patient with OHS has an extrafoveal or juxtafoveal CNVM
in one eye.18 The study also showed that histo spots of any type
in the macula tripled the risk for later development of CNVM. 2005
 SECTION 10 RETINA AND VITREOUS
FIGURE 153.1. This world map demonstrates areas where histoplasmosis infection is endemic.
Reprinted from Ellis FD, Schlaegel TF: The geographic localization of presumed histoplasmic choroiditis. Am J Ophthalmol 1973; 75: 953–956.
Key Features
• If one eye has a CNVM, and the fellow eye has a macular histo
spot, the fellow eye has an 8 to 27% chance of developing a
CNVM in 3 years.
• CNVMs are preceded by a macular histo spot in more than
75% of cases.
• Laser photocoagulation is appropriate treatment for extrafoveal
and some juxtafoveal CNVM due to OHS, but not subfoveal
CNVM.
• The most common complication of laser photocoagulation for
CNVM due to OHS is recurrence. The recurrence rate exceeds
30%.
• No controlled trial has proven the efficacy of oral steroids in
OHS. Today, oral steroids are rarely used for CNVM.
• Subfoveal CNVM have a poor prognosis, with only 15%
spontaneously recovering visual acuity to 20/40.
• Potential treatments for subfoveal CNVM due to OHS include
photodynamic therapy, intraocular corticosteroids, submacular
surgery, and anti-VEGF drugs. They may be used alone or in
combination.
• The SST suggests that submacular surgery may be considered
for subfoveal CNVM when visual acuity is less than 20/100.
• At present, there are no published reports of anti-VEGF
therapy for CNVM due to OHS. However, this form of therapy
2006 will likely prove beneficial for this disease.
CNVMs were preceded by an atypical histo spot in the macula
in more than 75% of the cases. Eighty-one percent of all
patients in the MPS retained 20/20 vision in at least one eye in
5 years and risk of legal blindness was very low (8% in bilateral
and 1% in unilateral patients).
HISTOPATHOLOGIC FEATURES
ORGANISM AND SYSTEMIC INFECTION
H. capsulatum is a fungus that is present in its yeast form. The
fungus is carried and deposited by droppings from chickens,
pigeons, blackbirds, and bats. The birds are not infected but
carry the fungus on their feathers. Bats, however, are infected.
In humans, the fungus is first inhaled into the lungs and is
then disseminated into the blood stream. Acute pneumonitis
with fever may ensue and an acute, life-threatening disease
may rarely occur. Pulmonary granulomas form and heal with
calcification, and these may be seen on chest radiography. The
systemic forms of disease rarely have ocular manifestations.
OCULAR HISTOPATHOLOGIC FEATURES
There are several reports of H. capsulatum in eyes with OHS.19,20
However, Roth’s20 report was refuted by Gass and Zimmerman.21
 Ocular Histoplasmosis Syndrome

a b

CHAPTER 153
c d

FIGURE 153.2. Histopathology of histoplasmosis infection,

demonstrating organisms present in the cytoplasm of endothelial cells
using different staining techniques. (a) phase-contrast, (b) periodic acid
Schiff, (c) higher power of b, (d) Gomori methanamine silver, (e) Gomori
methanamine silver with 90 minute exposure.
From Scholz R, Green WR, Kutys R, et al: Histoplasma capsulatum in the eye.
Ophthalmology (1984; 91:1100–1104).

Ocular histopathologic studies have shown H. capsulatum in
disseminated histoplasmosis, often in immunocompromised
hosts (Fig. 153.2).22–26 Some of these patients exhibited clinical
signs of OHS as well.20,27 These cases and others have been well
summarized.26
Meredith and associates28 reported cracks in Bruch’s membrane
related to the growth of choroidal blood vessels into the subretinal
space. The overlying retina showed loss of outer layers and
cystic degeneration. The retinal pigment epithelium (RPE) was
lacking in the center of the lesion but was clumped at the edges.
Subretinal pigment epithelium neovascularization extended
beyond the disciform process. The juxtapapillary changes resulted
from loss of RPE, loss of photoreceptors, and discontinuities in
Bruch’s membrane. The peripheral lesions showed loss of the RPE,
scarring, and occasional lymphocytic infiltration (Fig. 153.3).
Pavan and Margo29 reported a patient with fundus findings
suggestive of OHS in which histopathologic examination of the
excised membrane revealed the following: intense staining with
visible edges in the late phases of fluorescein angiography and a
well-circumscribed granuloma containing some eosinophiles. 2007
 RETINA AND VITREOUS

EXPERIMENTAL ANIMAL MODEL

Smith and co-workers developed an experimental animal model
involving the injection of live fungus via the carotid artery.30–32
Most animals had positive skin test results and early acute
choroiditis resulting from mononuclear cell and macrophage
infiltration with phagocytosis of yeast. Lymphocytes were found
in the choroid, and damage to Bruch’s membrane occurred. Six
weeks later, yeast was rarely found. Atrophic lesions resulted
from loss of RPE associated with altered Bruch’s membrane
and lymphocytes in the choroid. Subclinical lesions occurred
in areas that were not detectable by clinical examination or
fluorescein angiography, but lymphocytes were seen under the
retina and RPE. Disappearing lesions occurred where lesions
were at one time visible but became invisible. There were lym-
phocytes in the choroid, but the RPE and retina were normal.
Chronic choroiditis occurred, with organisms disappearing in
6 weeks. This may be why amphotericin B has no effect on the
SECTION 10

disease. No macular disciform lesions developed. These

laboratory data support clinical findings. Disseminated
histoplasmosis causes acute lesions with yeast particles. Later,
chronic OHS shows lesions without yeast, but inflammatory
cells may still be present. Doubts concerning the cause and
effect of H. capsulatum and OHS could be explained by these
experimental data.

IMMUNOLOGY
Several theories exist that attempt to explain the pathogenesis
of OHS, including the following:
1. Immunologic responses to previous infection causes OHS.
The macular lesion may be a hypersensitivity reaction to
dead organisms elsewhere in the eye.
2. Macular disease in OHS is the result of re-infection with
histoplasmosis.
3. Some vascular decompensation in the choroid is
responsible for the findings in OHS.
LYMPHOCYTE HYPERREACTIVITY
Schlaegel and colleagues33 found altered skin test reactivity to
certain antigens in patients with OHS. Lymphocytes are
hyperreactive in patients with disciform lesions in OHS, and
some investigators believe there is an increased rate of macular
subretinal hemorrhage after histoplasmin skin testing.
Others34,35 found that lymphocyte transformation may corre-
late with OHS activity. Patients with disciform lesions have
stimulated lymphocytes in comparison with patients with only
peripheral scars and controls. Brahmi and associates36 found
acute histoplasmin infection to be different from OHS in terms
of T-cell studies. Lymphocyte marker CD38 was significantly
higher than controls in four patients with OHS-like syndrome
from the United Kingdom, which may correlate with poor T-cell
function in making these patients more susceptible to various
stimuli.37
HISTOCOMPATIBILITY ANTIGENS
Meredith and co-workers,38 in the Walkersville study, found
no increase in human leukocyte antigen (HLA)-B7 for peri-
pheral lesions only but did find an association with HLA-
DRw2. There was a definite association between HLA-B7 and
macular lesions. Braley and colleagues39 found that 78% of
patients with OHS and macular disciform lesions were HLA-
B7-positive compared with 20% of controls. Godfrey and associ-
ates40 found that 54.8% of macular lesions were HLA-B7
2008 positive.
FIGURE 153.3. Histopathologic specimen from a case of ocular
histoplasmosis syndrome (OHS). Discontinuities in Bruch’s membrane
(between arrows in bottom figure) allow choroidal vessels (asterisk in
bottom figure) to grow in the subretinal or subretinal pigment epithelial
space.
From Meredith TA, Green WR, Key SN, et al: Ocular histoplasmosis:
clinicopathologic correlation of 3 cases. Surv Ophthalmol 1977; 22:189, 1977.
All these studies support the concept that OHS is an
immunologic disorder. Interestingly, lymphocytes are found in
scars and lesions in OHS and they also are found in disciform
lesions of age-related macular degeneration. Age-related
macular degeneration is increasingly being thought of as arising
from an underlying chronic inflammatory disorder. Unfor-
tunately, there is no animal model for macular lesions in OHS
to study these questions further.
CLINICAL CHARACTERISTICS
See Table 153.1 for a listing of clinical characteristics of the
ocular histoplasmosis syndrome.
PUNCHED-OUT CHORIORETINAL LESIONS
Smith and co-workers41 found one to four punched-out chorio-
retinal lesions per eye, juxtapapillary changes in 28% of eyes,
and bilateral changes in 62% of patients with OHS. Macular
lesions are rare but more visually devastating.
The atrophic spots are small, irregular, roundish lesions in
the midperiphery and posterior pole. They may have pigment
on the edge or in the center and range from 0.3 to 0.7 disk
diameter. Choroidal vessels may be seen throughout the
atrophic lesions (Fig. 153.4). Watzke and Claussen42 found that
atrophic lesions change shape, size, and pigmentation over
time.
Linear streaks of chorioretinal lesions of variable length,
width, and pigmentation may form (Fig. 153.5). They are
usually equatorial, parallel to the ora, and average 3 clock hours

a b
TABLE 153.1. Clinical Characteristics of the Ocular
Histoplasmosis Syndrome
Punched-out chorioretinal lesions
Juxtapapillary chorioretinal atrophy
Choroidal neovascularization
No vitritis
No pigment epithelial detachment
Disseminated choroiditis – rare
FIGURE 153.5. Fundus photograph shows the peripheral linear streak
of histoplasmosis spots.
in length. Bottoni and colleagues43 found streaks in five patients
who also had CNVMs. Fountain and Schlaegel44 found streaks
in 5% of their patients with OHS, but this was a skewed
population.
New lesions may form in areas previously seen to be normal
on clinical examination and fluorescein angiography. Schlaegel
and associates45 said 26% of spots were newly developed over
5 years of follow-up, whereas other studies cited 9% and
16.6%.13,42,46 Gass and Wilkinson47 found only 1 out of 81
patients in whom a new peripheral lesion developed, but
Lewis and Schiffman14 re-evaluated 99 of their patients with
longer follow-up and found that 19% acquired new lesions,
Ocular Histoplasmosis Syndrome
FIGURE 153.4. (a) Fundus photograph of
peripheral, punched-out lesions typical of OHS.
(b) Fundus photograph of atrophic macular
lesions.
CHAPTER 153
FIGURE 153.6. Juxtapapillary changes include retinal pigment
epithelial hypertrophy and atrophy.
suggesting that longer follow-up leads to identification of more
new lesions.
JUXTAPAPILLARY CHORIORETINAL ATROPHY
The juxtapapillary changes in OHS are probably due to
juxtapapillary choroiditis that goes unrecognized, and this leads
to chorioretinal changes around the disk (Fig. 153.6). Various
investigators have found that 85–94% of patients with OHS
have juxtapapillary changes.13,33,48 The atrophic juxtapapillary
changes may lead to choroidal neovascularization that can
decrease central vision (Fig. 153.7).49 Lewis and co-workers48
found that 3.8% of patients with juxtapapillary changes
experienced a juxtapapillary CNVM, and Cantrill and Burgess50
found that 15% of patients with symptoms from a juxta-
papillary CNVM in one eye had a juxtapapillary CNVM in the
fellow eye. Gass and Wilkinson47 found that 10% of all CNVMs
in OHS were juxtapapillary. Gutman13 reported that 58% of
patients with these types of lesions had visual acuity of 20/200
or worse, indicating that juxtapapillary CNVM may lead to
significant central vision loss.
MACULAR LESION
The classic macular lesion associated with OHS is a well-
defined CNVM with serous detachment of the retina, a small 2009
 RETINA AND VITREOUS
a b
SECTION 10
c d
a b
amount of subretinal hemorrhage and hard lipid exudate, and a
pigment halo surrounding the active lesion (Fig. 153.8).
Symptoms of a CNVM include decreased vision, metamor-
phopsia, and blurring. Micropsia occasionally may be a
subjective complaint.
Generally, the CNVM occurs at the edge of an old healed
chorioretinal scar in the macula, termed a ‘histo spot’. Melberg
and colleagues have identified this scar as the ‘ingrowth site’ of
the neovascularization as it is associated with a discontinuity
in Bruch’s membrane on histopathologic examination.51,52
Macular lesions can develop in previously normal retina. It is
more common, however, that reactivation of old lesions
accounts for new CNVMs, with a 20–23% activation rate.47,48
CNVMs are classified by their location in relation to the
center of the foveal avascular zone (FAZ). The designations of
extrafoveal, juxtafoveal, and subfoveal are described.
Extrafoveal CNVMs
Extrafoveal CNVMs have an edge of hyperfluorescence or
2010 blockage of fluorescence, as shown on fluorescein angiography,
FIGURE 153.7. In this eye, juxtapapillary
changes led to the development of choroidal
neovascular membrane (CNVM). (a) The fundus
photograph shows evidence of gray subretinal
lesions along with subretinal blood, both of
which are signs of CNVM. (b) An early frame of
a fluorescein angiogram shows early
hyperfluorescence. (c) A later frame shows
massive leakage from the new vessel
membrane. (d) In another patient, a
juxtapapillary CNVM causes extensive retinal
striae.
FIGURE 153.8. Macular lesion of OHS.
(a) Fundus photograph of a CNVM, with a gray
membrane, subretinal hemorrhage, subretinal
fluid, and pigment ring. (b) An early frame of a
fluorescein angiogram with early
hyperfluorescence demonstrates a juxtafoveal
CNVM.
between 200 and 2500 mm from the center of the FAZ. Lewis
and co-workers48 found that 69% of patients with extrafoveal
CNVMs had visual acuity of 20/40 or better at presentation.
Juxtafoveal CNVMs
Juxtafoveal CNVMs have either a hyperfluorescent edge
1–200 mm from the center of the FAZ, with or without block-
age (blood, pigment) through the center of the FAZ, or a
CNVM 200–2500 mm from the center, with blood or blocked
fluorescence within 200 mm of the center. Lewis and co-
workers48 found that 71% of patients with juxtafoveal CNVMs
from OHS had visual acuity measuring 20/200 or worse.
Gutman13 found that if the CNVM was inside the FAZ, there
was a 63% chance that visual acuity would be less than 20/200,
but a 25% chance if the CNVM was outside the FAZ. Olk and
co-workers17 found that 65% of patients with juxtafoveal
membranes had a visual outcome of 20/200 or worse. Poor
prognostic clinical signs include subretinal blood, poor initial
vision, membrane close to the center of the FAZ, and large
CNVM size. Steroids have no effect on juxtafoveal lesions.

a b
d e
FIGURE 153.9. (a) Histoplasmic choroiditis causes yellow choroidal infiltrates with a surrounding pigment ring. Fluorescein angiography
demonstrates early blocked fluorescence (b) and the intermediate (c) and late (d) staining of the lesion. These lesions can become atrophic with
time (e) and ultimately may develop secondary reactive hyperplasia of the retinal pigment epithelium (f).
Subfoveal CNVMs
Subfoveal CNVMs have active leakage under the center of the
FAZ. Fourteen to sixteen percent of these patients recover visual
acuity of 20/40 spontaneously without laser treatment,17,48,53
and laser treatment through the center of the FAZ would almost
certainly decrease visual acuity to the 20/200 level immediately.
A pilot study of laser treatment for subfoveal neovascular
membranes in OHS has shown no benefit from the laser
treatment in eyes with new or recurrent subfoveal CNVMs
that are 3.5 disc areas or less in size and with vision between
20/40 and 20/320.54 Therefore, these patients should not be
considered for thermal laser treatment. However, untreated
50% or more of these eyes end up with very poor vision.17,47,55
A favorable natural history has been predicted by the following:
age less than 30 years, small CNVM, and good fellow eye.
A Poor prognosis untreated has been found in eyes with initially
excellent vision and a CNVM that involved more than 50% of
the FAZ. Thirty-six percent of patients less than 30 years of age
had visual acuity of 20/40 or better, establishing that the greater
the area of FAZ covered by the CNVM, or the further the CNVM
is beyond the center of the FAZ, the worse the prognosis.
VITRITIS AND OHS
The presence of vitritis almost always rules out the diagnosis of
OHS. Any time vitreous cells are present, entities other than
OHS must be considered.
PIGMENT EPITHELIAL DETACHMENTS
Gass56 and others believe that pigment epithelial detachments
are very rare in OHS. Occult and minimally classic CNVM
are also rare. The most prevalent type of CNVM in OHS is
Ocular Histoplasmosis Syndrome
c
CHAPTER 153
f
predominantly classic. There may be surrounding atrophy of
the RPE, thought to be due to chronic fluid accumulation in
untreated cases.
DISSEMINATED CHOROIDITIS
Disseminated choroiditis usually occurs in immunocom-
promised patients. The lesions present as yellow, circum-
scribed, elevated choroidal infiltrates with fuzzy edges and a
surrounding ring of pigment (Fig. 153.9). The foci of choroiditis
may develop into a CNVM, with serous retinal detachment,
hemorrhage, and retinal striae. Conway and colleagues57 have
shown that 93% of patients with macular histochoroiditis were
at least stabilized with systemic steroids.
OPTIC DISC EDEMA
Optic disc edema occurs rarely in patients with OHS.58,59 The
juxtapapillary findings in OHS may originate from undetected,
transient papillitis.
EXOGENOUS HISTOPLASMIC
ENDOPHTHALMITIS
One case of exogenous histoplasmic endophthalmitis after
cataract extraction has been reported.60
VITREOUS HEMORRHAGE
There has been one report of a patient with OHS in whom a
CNVM developed and resulted in breakthrough vitreous
hemorrhage.61 OHS can be considered in the differential
diagnosis of vitreous hemorrhage. 2011
 RETINA AND VITREOUS
a b
FIGURE 153.10. (a) Fundus photograph of a CNVM (inferior to the fovea) and histoplasmosis spots (superior to the fovea). (b) and (c)
Fluorescein angiograms of histoplasmosis spots. (b) shows early hypofluorescence and (c) shows late staining. Note how the new vessel
membrane leaks fluorescein dye and develops fuzzy margins late in the study. The histoplasmosis spots show staining of the sclera but stay
sharply demarcated.
SECTION 10
TABLE 153.2. Symptoms and Signs of Choroidal
Neovascularization
Metamorphopsia
Visual blurring
Serous detachment of retina
Subretinal hemorrhage
Hard lipid exudate
Pigment halo surrounding lesion
SUBRETINAL HEMORRHAGE
Subretinal hemorrhage from CNVM due to OHS tends to be
smaller than similar lesions from age-related macular
degeneration. Generally, they can be observed and will undergo
spontaneous resorbtion. However, subretinal hemorrhage from
a CNVM due to OHS requiring evacuation has been reported.62
FLUORESCEIN ANGIOGRAPHY
INDICATIONS
Patients with no subjective complaints or findings of peripheral
or macular chorioretinal scars do not require fluorescein
angiography. The indications for fluorescein angiography
include symptoms of a CNVM, such as visual loss, metamor-
phopsia, or blurring; clinical signs of CNVM; and the need to
evaluate the fellow eye of a patient with OHS to check for the
presence of macular chorioretinal scars that would indicate an
increased risk to that eye (Table 153.2). It is vital to obtain a
fluorescein angiogram in any patient with new symptoms.
FINDINGS
The histoplasmosis ‘spots’ show early hypofluorescence with
faint late staining (Fig. 153.10). These areas can change to early
staining with late leakage over time. Gass56 believes the
punched-out lesions fluoresce but that this is due to scleral
reflection and not actual leakage of dye. The RPE and
choriocapillaris between the histoplasmosis lesions are normal
(this is not the case in age-related macular degeneration).
Acute, yellow choroidal lesions stain with fluorescein.56
CNVM stains early in a lacy pattern and leaks late, with the
margins of the lesion becoming blurred. Subretinal fluid may
collect dye late in the study. Subretinal blood allows fluor-
2012 escence of retinal vessels but blocks fluorescence of the
c
TABLE 153.3. Differential Diagnosis of the Ocular
Histoplasmosis Syndrome
Multifocal choroiditis and panuveitis
Birdshot choroidopathy
Diffuse unilateral subacute neuroretinopathy
Acute posterior multifocal placoid pigment epitheliopathy
Vogt–Koyanagi syndrome
Behçet’s disease
choroidal vessels and CNVM. There may be a halo of hypoflu-
orescence around the CNVM which corresponds to a reactive
layer of RPE cells trying to contain or ‘cocoon’ the neovascular
tissue.
DIFFERENTIAL DIAGNOSIS
The types of differential diagnoses are listed in Table 153.3.
MULTIFOCAL CHOROIDITIS AND PANUVEITIS
(PSEUDO-PRESUMED OHS)
Dreyer and Gass63 reported on 28 patients with multifocal
choroiditis, old punched-out lesions, juxtapapillary atrophic
changes, and CNVMs. Most patients were from nonendemic
areas and had vitritis and decreased electroretinogram signals.
Of 16 patients who underwent skin testing, only 5 tested
positive for histoplasmosis. This syndrome is especially difficult
to differentiate from birdshot choroidopathy and diffuse
unilateral subacute neuroretinopathy. Deutsch and Tessler64
reported similar findings, however 43% of their patients were
black. The choroidal punched-out lesions in pseudo-presumed
OHS are smaller than those in OHS, some of the spots
represent an active choroiditis, and vitritis may be present.
Systemic steroids may help the active lesions in pseudo-
presumed OHS.
BIRDSHOT (VITILIGINOUS) CHOROIDOPATHY
Birdshot choroidopathy presents in an older age group than
does OHS. Choroidal lesions are creamy, active spots without
atrophy or pigmentation, and there are no juxtapapillary changes.
Optic disc pallor occurs, but choroidal neovascularization is
rare. The electroretinogram is depressed, and fluorescein
angiography shows disc leakage and cystoid macular edema.

DIFFUSE UNILATERAL SUBACUTE
NEURORETINOPATHY
Diffuse unilateral subacute neuroretinopathy is a unilateral
parasitic infestation. Early in the disease, there are clusters of
white spots, vitritis, and RPE changes between white lesions.
The lesions are evanescent and change with the location of the
parasite. Late in its course, optic atrophy and arterial narrowing
develop.
ACUTE POSTERIOR MULTIFOCAL PLACOID
PIGMENT EPITHELIOPATHY
Usually occurring after upper respiratory infection, acute
posterior multifocal placoid pigment epitheliopathy leads to
clustered lesions in the posterior pole, often with severe loss of
vision. The lesions disappear after a brief period, usually with
return of good vision.
VOGT–KOYANAGI SYNDROME
The Vogt–Koyanagi syndrome is a granulomatous uveitis with
infiltrative choroidal lesions. Exudative retinal detachment is
frequently present. Systemic symptoms such as tinnitus,
deafness, poliosis, vitiligo, and headache occur.
BEHÇET’S DISEASE
Behçet’s disease includes severe vasculitis with panuveitis.
Aphthous oral ulcers and genital lesions usually accompany the
attacks of uveitis.
TREATMENT
STEROIDS
No controlled trial has proven the efficacy of steroids in OHS.
Many years ago, Schlaegel and colleagues45 considered systemic
steroids to be appropriate for acute flare-ups and possibly for
long-term use to prevent visual loss. Schlaegel65,66 believed that
steroids, if used, should be given in high doses (prednisone
60–100 mg/day) and tapered very slowly over 1–2 yr. Makley
and co-workers67 found some benefit if steroids were used early
in the course of macular lesions. These studies were performed
before other treatment alternatives were available. Today,
steroids are rarely used for CNVM. However, some early cases
of OHS may present with choroditis at the site of a macular
‘histo spot’ without concomitant CNVM. It can be reasonable
to try local corticosteroids (subtenon or intravitreal) or a short
course of systemic corticosteroids in these cases, with close
follow-up looking for the development of CNVM.
DESENSITIZATION
Schlaegel and associates45 desensitized OHS patients by giving
small doses of histoplasmin antigen subcutaneously. They
found that there was no difference between treated and control
groups. Some investigators report that skin testing or
desensitization may exacerbate macular lesions in OHS.
LASER TREATMENT OF INACTIVE MACULAR
LESIONS
Gitter and Cohen68 attempted to prevent CNVM formation in
fellow eyes by laser treatment of inactive macular lesions. Their
study contained no controls, but no complications were
reported. Later, one of the patients experienced a CNVM in a
Ocular Histoplasmosis Syndrome
treated scar. Others have reported similar cases.69,70
Prophylactic laser photocoagulation is not recommended, as it
is not useful in preventing CNVM formation.
AMPHOTERICIN B
Amphotericin B has been tried in the past in an attempt to
obliterate a histoplasmosis infection. Makley and co-workers67
found no treatment benefit. Most investigators believe that
OHS lesions are probably sterile, inflammatory lesions contain-
ing no organisms, and therefore, antifungal agents play no role
in the treatment of OHS.
ANTIHISTAMINES
Antihistamines were at one time thought to play a regulatory
role for choroidal capillaries and have been tried in OHS
macular disciform lesions but without success.
CHAPTER 153
6-MERCAPTOPURINE
6-Mercaptopurine has been tried, but with no benefit.
MACULAR PHOTOCOAGULATION STUDY –
OHS AND EXTRAFOVEAL CNVM
The ocular histoplasmosis section of the MPS was a multi-
center, controlled clinical study, designed to answer specific
questions concerning whether laser treatment would prevent
visual loss from CNVMs. The CNVM includes hyperfluor-
escence, blood, pigment, and blocked fluorescence on
fluorescein angiography. Extrafoveal CNVMs are defined as
having hyperfluorescence on fluorescein angiography
200–2500 mm from the center of the FAZ (Fig. 153.11). The
diagnosis of OHS requires at least one atrophic chorioretinal
scar. Entrance into the MPS required visual acuity of 20/100 or
better. Juxtapapillary CNVMs were included in the study only if
treatment would spare at least 1.5 clock hours of nerve fiber
layer in the maculopapular bundle.
Results of the MPS71 showed that at 24 months, a 6 line
visual loss had occurred in 50% of the group receiving no
treatment and in 22% of the treated group. At 36 months, the
results were 45% for the group receiving no treatment and 10%
for the treated group.72 The effectiveness of laser treatment
when compared with controls was present in all subgroups at all
stages of follow-up. Burgess73 concluded that any CNVM
completely outside the FAZ should be treated with laser.
Brown and colleagues performed an analysis of the cost-
effectiveness of laser photocoagulation for extrafoveal CNVM
due to OHS and found it to be highly cost-effective from a
patient preference-based point of view.74
MACULAR PHOTOCOAGULATION STUDY –
OHS AND JUXTAFOVEAL CNVM
The MPS75 also looked at juxtafoveal CNVM. The results of the
juxtafoveal group of the MPS at 1 year of follow-up showed that
the risk of a six-line visual loss was 24.8% in the group who
received no treatment compared with 6.6% in the treated group.
The results were 27.9% versus 8.5%, respectively, at 5 year
follow-up.76 Untreated eyes were at much greater risk of a
six-line visual loss between 1 and 5 years of follow-up
examination than were treated eyes at an unadjusted relative
risk of 2.60 and 4.26 after adjusting for both visual acuity
and hypertension at the baseline.
Fine and associates77 separated the juxtafoveal CNVM in
the MPS study into two types defined as the following: A 2013
 RETINA AND VITREOUS

a b c
SECTION 10

d e f

FIGURE 153.11. (a) Schematic representation of an extrafoveal CNVM demonstrates the measurement from the center of the foveal avascular
zone to the edge of the CNVM, in this case 200 mm away. (b) Fundus photograph of a CNVM. (c) Fluorescein angiogram demonstrates early,
lacy hyperfluorescence. (d) Middle frame of the angiogram shows leakage of dye. (e) Posttreatment photograph. (f) Fluorescein angiogram
shows obliteration of the new vessel membrane. Note normal hyperfluorescence at the edge of a laser scar.
(a) From Poliner LS, Olk RJ: Ocular histoplasmosis syndrome. Semin Ophthalmol 1987; 2:238.

juxtafoveal CNVM was defined in this study as having a hyper-
fluorescent edge 1–200 mm from the center of the FAZ or a
CNVM 200–2500 mm from the center, with blood or blocked
fluorescence within 200 mm of the center (Fig. 153.12).
Proximity to the fovea is crucial in juxtafoveal CNVMs.
Outside the FAZ, the chances of maintaining visual acuity of
20/40 or better is 60% compared with 15% if the CNVM is
inside the FAZ. If the CNVM was within 200 mm of the center
and the foveal side was treated including 100 mm of the
uninvolved FAZ, those eyes had less risk (5% versus 25%) of
severe vision loss than those left untreated or treated with a
wider border on the foveal side.78
MACULAR PHOTOCOAGULATION STUDY –
OHS AND PERIPAPILLARY CNVM
Patients with juxtapapillary membranes could be entered into
the MPS–OHS study if treatment would allow 1.5 clock hours
of the optic disc to be left untreated. The CNVM was ineligible
if it extended under the center of the FAZ. In the group of
patients with peripapillary or large (>750 mm nasal extrafoveal
or juxtafoveal CNVMs, 14% of the treated eyes versus 41% of
the untreated eyes experienced 6 lines or more vision loss in
3 years; in those with large nasal CNVM, the numbers were 9%
versus 54%, respectively.79 This branch of the MPS used the
krypton red laser (647 nm). There are several advantages of
krypton red laser, including less lens scatter, less absorption by
xanthophyll, and less inner retina damage.80 Hemoglobin does
not absorb red laser at all. There are several disadvantages to
krypton red. This laser can crack Bruch’s membrane more
easily than can argon green, but the incidence of internal
limiting membrane wrinkling is higher with argon. These
advantages and disadvantages are created because the red laser
2014 is absorbed by melanin in the RPE and choroid.
MACULAR PHOTOCOAGULATION STUDY –
OHS (SUMMARY)
The current recommendation for the evaluation and treatment
of extrafoveal, juxtafoveal, and peripapillary (nonsubfoveal)
CNVMs resulting from OHS is to follow the guidelines from
the MPS trial. Juxtafoveal CNVMs should be treated according
to the MPS guidelines as long as a good margin of laser
(>100 mm) can be applied on the foveal edge without involving
the center of the fovea. Juxtafoveal CNVMs that would require
laser treatment into the center of the fovea should be con-
sidered for alternative treatments generally considered for
subfoveal CNVM as discussed below. CNVMs on the nasal side
of the optic nerve rarely need treatment, since they usually
undergo spontaneous involution. The most common compli-
cation of laser photocoagulation for CNVM due to OHS is
recurrence, usually attributable to inadequate coverage or
intensity of the treatment. Other complications are rare
(Table 153.4). Because the recurrence rate exceeds 30% CNVMs
treated with laser photocoagulation should be followed with
frequent examination and daily home use of the Amsler grid.
LASER TREATMENT TECHNIQUE
GENERAL GUIDELINES
There are some general rules that may guide laser
photocoagulation of choroidal neovascular membranes.
The role of anesthesia in laser photocoagulation of CNVMs
is to provide comfort during the procedure and to increase the
margin of safety when treating near the fovea. Topical
anesthesia may be adequate for treatment in the cooperative
patient with an extrafoveal CNVM. For juxtafoveal CNVMs, we
recommend retrobulbar anesthesia in all but the most

a b
c d
TABLE 153.4. Complications of Laser Treatment
Recurrence of choroidal neovascular membrane
Retinal pigment epithelial rips
Acute choroidal hemorrhage
Nerve fiber layer field defects
Premacular fibroplasia
cooperative patients. If the patient squeezes the lids, Bell’s
phenomenon can move the eye superiorly, thereby risking
photocoagulation of the fovea during treatment of a CNVM
superior to fixation. Further, juxtafoveal CNVMs should be
treated with krypton red or diode laser (805 nm), and this
frequently causes some discomfort if local anesthesia is not
given.
A recent fluorescein angiogram is essential for adequate
treatment. It has been shown that CNVMs may grow, especially
those closer to the fovea, in the course of several days. The
fluorescein angiogram being used to guide treatment should be
less than 72 h old, especially with juxtafoveal lesions. More
latitude may be taken with extrafoveal CNVMs that are greater
than 200 mm from the center of the FAZ.
The fluorescein angiogram is essential for mapping the FAZ
as well as the CNVM. The use of the aiming beam to map
fixation is not a reliable way to define the FAZ. Because of
eccentric fixation or distortion of the fovea, one may be fooled
into treating the fovea if the aiming beam is used to determine
fixation.
The following procedural details may be helpful. Both the
surgeon and the patient should be seated comfortably at the
laser. An elbow rest should be used to stabilize the surgeon’s
Ocular Histoplasmosis Syndrome
FIGURE 153.12. (a) Schematic representation
of juxtafoveal CNVM inside 200 mm from the
center of the foveal avascular zone. Photograph
(b) and angiograms (c and d) show early
(c) and middle (d) frames from the patient
shown in FIGURE 153.7 after krypton red laser
treatment. Note that choroidal vessels are
visible through the laser scar.
(a) From Poliner LS, Olk RJ: Ocular histoplasmosis
syndrome. Semin Ophthalmol 1987; 2:238.
CHAPTER 153
arm. A fixation light for the patient’s fellow eye helps to
stabilize the treatment eye. The patient should be introduced to
the sound of the laser before treatment actually begins.
Treatment should be guided by an early frame of a recent
fluorescein angiogram. One should use a computer monitor (for
digital angiograms), a table-top viewer (for film angiograms)
adjacent to the laser slit lamp.
Various fundus contact lenses are available for macular
treatment. It must be remembered that some lenses reverse and
invert the surgeon’s view of the fundus (Mainster, Rodenstock).
The fluorescein angiogram must be properly oriented so that
the surgeon does not confuse the anatomy.
If bleeding occurs during the laser treatment, intraocular
pressure should be increased with the contact lens and then
laser treatment applied over the bleeding site, preferably with
argon green.
Klein and colleagues81 did not avoid retinal vessels in the
treatment area. However, it is generally recommended that
heavy, long-duration burns not be placed directly over retinal
vessels, especially if the vessel supplies the central fovea.
Sabates and colleagues82 found that hemorrhage obscures the
complete extent of the CNVM and absorbs the laser energy,
thus sparing the CNVM. Intense treatment over areas of
subretinal hemorrhage is not indicated, as energy absorption is
quite superficial and will cause damage to the retina.
ARGON GREEN LASER FOR EXTRAFOVEAL
CNVM
First, the CNVM is outlined with burns of 100 mm size and
0.1 s duration. Gass83 recommends covering any pigment ring
and choroidal neovascularization as shown by an early frame of
the fluorescein angiogram. On the foveal side, 100–200 mm
spots of 0.2 s duration are delivered in a confluent fashion.
These should be heavy white spots. The remainder of the lesion 2015
 RETINA AND VITREOUS
a b
FIGURE 153.13. (a–c) Schematic representation of the treatment of an extrafoveal CNVM.
(a–c) From Poliner LS, Olk RJ: Ocular histoplasmosis syndrome. Semin Ophthalmol 1987; 2:238.
SECTION 10
a b
is covered confluently with heavy laser burns of 200–500 mm
spots and 0.5 s duration. The CNVM should be covered 100 mm
past the edge of the CNVM. On the foveal side, if the treatment
will not enter the FAZ, the treatment should extend 100 mm.
If the edge of the CNVM is close to the edge of the FAZ,
coverage of the CNVM by a full 100 mm beyond the edge is not
required (Fig. 153.13).
KRYPTON RED LASER FOR JUXTAFOVEAL
CNVM
The krypton red laser should be used with large spots (at least
200 mm) and long-duration (at least 0.2 s) to decrease the
chance of rupturing Bruch’s membrane. The retina will whiten
less with krypton red than with argon green. It is not necessary
to treat blood or blocked fluorescence (Fig. 153.14).
First, the foveal side of the lesion is treated with 200 mm
spots of 0.2 s duration. The remainder of the lesion is treated
with 200–500 mm confluent burns of 0.5 s duration.
1. If hyperfluorescence is more than 100 mm from the
center of the FAZ, and if blood or blocked fluorescence
is present, treatment extends 100 mm into the blocked
fluorescence, but the center of the FAZ is not treated.
2. If hyperfluorescence is within 200 mm and if no blocked
fluorescence is present, laser treatment should cover
the hyperfluorescence, and treatment does not need to
extend 100 mm past the edge.
RECURRENT CNVM IN OHS FOLLOWING
LASER PHOTOCOAGULATION
DEFINITION
After laser photocoagulation, interpretation of the post-
treatment angiogram can be one of the most challenging facets
in the treatment of macular disease.84 A persistent CNVM
shows hyperfluorescence (representing choroidal neovascular-
ization) within 6 weeks of treatment. A recurrent CNVM is
defined as leakage adjacent to or within the laser scar occurring
2016 more than 6 weeks after treatment.
c
FIGURE 153.14. (a and b) Schematic
representation of the treatment of a juxtafoveal
CNVM.
(a and b) From Poliner LS, Olk RJ: Ocular
histoplasmosis syndrome. Semin Ophthalmol 1987;
2:238.
INCIDENCE
The MPS reviewed the incidence of recurrent CNVMs.85,86 In
the OHS-juxtafoveal segment of the study, 31% of the treated
eyes had recurrent CNVMs, and 65% of these recurrences were
amenable to further treatment. The remainder were not
retreatable because of subfoveal extension of the CNVM. This
compares with 59% of treated eyes with age-related macular
degeneration and 33% of eyes with idiopathic CNVM.
Recurrence after surgical removal of CNVM in OHS has been
reported between 38 to 44%.87,88 Two-thirds of recurrences
were subfoveal and were either observed or surgically removed.
The remaining third was amenable to laser photocoagulation
(i.e., extrafoveal or juxtafoveal) and did much better than those
observed or surgically removed.
TIME COURSE
Most recurrences were noted within 12 months after treatment,
with the majority occurring within the first 6 months.
CAUSE
Several factors may contribute to the recurrence of CNVMs
after treatment: inadequate coverage or intensity of treatment,
the presence of blood or pigment within 200 mm of the center of
the FAZ, and location of the CNVM less than 200 mm from the
center. Further, the growth of an independent CNVM may occur
during the posttreatment follow-up period. This is believed to be
unrelated to treatment. Several risk factors have been statistically
associated with recurrences, including hypertension, cigarette
smoking, proximity to fovea, young age, and female gender.
In relation to the original CNVM, recurrences can occur on
the margin of the treatment, in the center of the treatment scar,
contiguous to the scar, from a feeder vessel originating from the
original CNVM, or as a completely new lesion greater than
250 mm from the margin of the laser scar (Fig. 153.15). Ninety
percent of marginal recurrences are on the foveal side of the
treatment, indicating that recurrences are largely responsible for
visual loss from OHS after laser treatment.

FIGURE 153.15. Schematic examples of locations of recurrent
CNVMs.
From Sorenson JA, Yannuzzi LA, Shakin JL: Recurrent subretinal
neovascularization. Published courtesy of Ophthalmology (1985; 92:1059–1074).
TREATMENT OF SUBFOVEAL CNVM
Laser photocoagulation of subfoveal CNVMs has been shown to
be of no benefit in a pilot study.54 Therefore, subfoveal laser
treatment of CNVMs is contraindicated.
MANAGEMENT OF SUBFOVEAL CNVM
Subfoveal CNVM has active leakage under the center of the
FAZ. Natural history studies suggest that only 14–16% of these
patients recover visual acuity of 20/40 spontaneously without
treatment.17,50,53 Laser photocoagulation is contraindicated.
Fortunately, there has been a rapid advance in recent years of
new, alternative treatments for subfoveal CNVM.
SURGICAL REMOVAL OF CNVM
Between 1992 and 1997, there were numerous reports on
surgical removal of subfoveal CNVM in OHS.62,52,89–101 Various
series reported initial visual improvement or stabilization of
visual acuity in 37–83% of the cases (Fig. 153.16).90,92,93,98,100,101
Thomas and co-workers93 reported visual acuity of 20/40 or
Ocular Histoplasmosis Syndrome
better in 31% of the cases at 10.5 months follow-up. Macular
function after removal of CNVM depends on functional
photoreceptors, RPE, and choriocapillaris. Akduman and
associates92 showed that visual improvement correlated with
perfusion of subfoveal choriocapillaris after submacular surgery
in OHS. Seventy-one percent of the eyes with perfused
subfoveal choriocapillaris had visual improvement postop-
eratively versus only 14% of those not perfused. These initially
encouraging case series led to the submacular surgery trial (SST)
for OHS.
THE SUBMACULAR SURGERY TRIALS
(GROUP H)
The SSTs were a group of randomized prospective clinical trials
funded by the National Institutes of Health whose purpose was
to determine if submacular surgery was beneficial for certain
types of CNVM. The SST Group H was designed to compare
CHAPTER 153
surgical removal versus observation of subfoveal CNVM that
were either idiopathic or associated with ocular histo-
plsmosis.102 Eligible patients had new or recurrent subfoveal
CNVM and visual acuity of 20/50 to 20/800 in the study eye.
A successful outcome was defined as a 24 month visual acuity
better or no more than one line (seven letters) worse than at
baseline.102
Of the 225 patients enrolled, 113 were assigned to observ-
ation and 112 to surgery. Forty-six percent of the eyes in the
observation arm and 55% in the surgery arm had a successful
outcome (success ratio 1.18; 95% confidence interval
0.89–1.56). Median visual acuity at the 24 month examination
was 20/250 for eyes in the observation arm and 20/160 for
eyes in the surgery arm. In a subgroup of eyes with initial
visual acuity worse than 20/100, surgery was more successful;
76% of 41 eyes in the surgery arm versus 50% of 40 eyes in the
observed arm at the 24 month examination had a successful
outcome (success ratio 1.53; 95% confidence interval
1.08–2.16)
Complications were more frequently detected in the eyes
undergoing submacular surgery. Four percent of eyes in the
surgery arm experienced rhegmatogenous retinal detachment.
Twenty-four percent of eyes developed postvitrectomy cataract,
all in patient over the age of 50 years. Recurrent CNVM
developed in 58% of surgically treated eyes by the 24 month
follow-up exam.
The SST Goup H Study Group concluded that the small
benefit of submacular surgery for CNVM due to OHS was less
than the trial was designed to detect. However, they did
recommend submacular surgery for the subgroup of eyes with
visual acuity worse than 20/100. Other factors to consider when
contemplating submacular surgery include the small risk of
retinal detachment, probably cataract among older patients, and
the need for additional treatment if recurrent CNVM were to
occur.
The SST Group H also examined the health-related quality-
of-life outcomes among patients who were randomized to
observation or surgical removal of the CNVM.103 Trained
interviewers who were masked to treatment assignment
administered three questionnaires by telephone at baseline
and 6, 12, and 24 months: The National Eye Insitute Visual
Function Questionanaire (NEI-VFQ), the 36- Item Short-Form
Health Survey (SF-36), and the Hospital Anxiety and
Depression Scale (HADS). Vision-targeted quality of life
improved more after submacular surgery than with observation,
supporting a possible small overall benefit of surgery.
Submacular surgery techniques have been successfully used
to treat nonsubfoveal CNVM due to OHS. Atebara and
colleagues104 studied results of surgical removal of large 2017
 RETINA AND VITREOUS
a b
SECTION 10
c d
non-age-related macular degeneration peripapillary CNVM,
most of which (17/19) were due to OHS. Seventy-nine percent
of those were also subfoveal. These authors reported
improvement of preoperative median visual acuity of 20/200 to
20/40 at 7 months follow-up. Submacular surgery has also been
employed to remove subfoveal hemorrhage that may occur on
rare occasions from CNVM in OHS.62
The era of submacular surgery allowed for histopathologic
analysis of the CNVM associated with OHS and increased our
understanding of the pathogenesis of non-AMD choroidal
neovascularization. The excised CNVM consists of similar
cellular and extracellular components, namely RPE cells,
vascular endothelium, erythrocytes, chronic inflammatory
cells, cells resembling fibroblasts, collagen fibrils, fibrin, and
fragments of Bruch’s membrane, as in CNVMs secondary to
other disorders, with the exception of basal laminar drusen
seen only in age-related macular degeneration.95,100 However,
clinical correlation with the histopathology in the OHS suggests
that the new vessels from the choriocapillaris grow through a
focal abnormality in Bruch’s membrane and RPE into the
subsensory retinal space, unlike age-related macular degener-
ation in which a diffuse abnormality of RPE is present and the
CNVM grows under the RPE.52 RPE is engulfed by the CNVM
in age-related macular degeneration, whereas it partially engulfs
and delineates the CNVM in OHS. Therefore, a focal rather
than a diffuse abnormality of RPE in OHS may help explain
better surgical results in OHS than other disorders associated
with CNVM formation.
PHOTODYNAMIC THERAPY FOR SUBFOVEAL
CNVM DUE TO OHS
In March 2000, Sickenberg, Schmidt–Erfurth, and Miller
published a nonrandomized, multicenter, open-label, dose-
escalation Phase I and II clinical trial of single or multiple
2018 sessions of photodynamic therapy (PDT) with verteporfin for
FIGURE 153.16. (a and b) Preoperative color
photograph and fluorescein angiogram of a
patient with subfoveal CNVM secondary to
OHS. Preoperative vision is 20/60. (c and d)
Postoperative color photograph and fluorescein
angiogram of the same patient. Postoperative
vision is 20/40.
CNVM due to causes other than AMD.105 For the 13 patients
in the study, underlying etiologies included pathologic myopia,
ocular histoplasmosis, angioid streaks, and idiopathic causes.
The authors concluded that PDT with verteporfin was well
tolerated in non-AMD eyes, and treatment could successfully
result in cessation of leakage with one or more sessions.
However, a larger, Phase III randomized, prospective, controlled
clinical trial on the use of photodynamic therapy for CNVM due
to ocular histoplasmosis was never done.
In September 2004, Rosenfeld and colleagues published the
2 year results of a prospective open-label three-center,
uncontrolled clinical study of PDT with verteporfin in patients
with CNVM due to ocular histoplasmosis.106 Twenty-six
patients with baseline visual acuity between 20/40 and 20/200
were studied. At 24 months, 22 patients were available for
examination. Median visual improvement from baseline in
visual acuity was 6 letters. Ten patients (45%) gained 7 or more
letters of visual acuity while four (18%) patients lost 8 or more
letters, including two patients (9%) who lost at least 15 letters.
There was no leakage on the fluorescein angiogram in 85% of
the evaluable lesions. No serious ocular events were noted.
The results of the above prospective study corroborated an
earlier retrospective review published by Busquets et al in June
2003.107 Thirty-eight patients with CNVM due to OHS that
were treated with PDT using verteporfin were studied. On
average, OHS patients who received treatment developed 0.88
line of visual improvement. Visual acuity improved or stayed
the same in 69% of eyes, improved by at least two lines in 44%,
and improved by more than four lines in 22%. This
retrospective series had variable follow-up and included some
eyes (38%) that had undergone prior submacular surgery.
Nevertheless, the authors concluded that PDT with verteporfin
may be beneficial in patients with CNV secondary to OHS.
Colleagues at the same institution then reported the use of
PDT with verteporfin for juxtafoveal CNVM due to OHS.108
Twenty-three eyes were retrospectively studied. With variable

a b
a b
follow-up, vision improved by more than 3 Snellen lines in
30%, remained within 2 lines of baseline in 52%, and worsened
by 3 lines or more in 18%. Other smaller retrospective case
series on PDT with Verteporfin for subfoveal and juxtafoveal
CNVM due to OHS suggested similar outcomes.109,110 In
summary, PDT with verteporfin for CNVM due to OHS is a
safe and moderately beneficial treatment option.
While PDT combined with intravitreal triamcinolone
injection has been suggested to be more beneficial than PDT
alone for CNVM due to AMD, there are no published reports in
the peer-reviewed literature of this treatment modality for
CNVM due to OHS.
INTRAOCULAR CORTICOSTEROIDS FOR
CNVM DUE TO OHS
Corticosteroids have some inherent properties which may be
considered antiangiogenic. Thus, several investigators have
looked at the effect of the intraocular use of corticosteroids for
treating CNVM due to OHS. In October 2003, Rechtman and
colleagues retrospectively reported their experience with
intravitreal triamcinolone acetonide injections for subfoveal
and juxtafoveal CNVM.111 Ten eyes (five subfoveal and five
juxtafoveal) with a mean follow-up of 17 months were treated
with one or more injections. Thirty percent of eyes gained
at least 5 letters, 20% lost 5–14 letters, and 50% maintained
stable visual acuity. Interestingly, reported side effects included
transient intraocular pressure elevation and mild cataract
development, well known complications of intravitreal
corticosteroids.
Holekamp and colleagues reported on the use of long-term
intraocular delivery of fluocinolone acetonide in treating 14
eyes with non-AMD CNVM.112 Seven eyes had ocular histo-
plasmosis. Average follow-up was 33 months. Ten of 14 eyes
demonstrated involution of CNVM or inhibition of recurrent
CNVM. Ten eyes had stable or improved visual acuity. Median
initial visual acuity was 20/64. Median final visual acuity
was 20/40. However, all eyes developed elevated intraocular
Ocular Histoplasmosis Syndrome
FIGURE 153.17. (a) A 23-year-old patient with
ocular histoplasmosis presented with a
juxtafoveal CNVM causing metamorphopsia
and visual acuity of 20/25. (b) There is late
hyperfluorescence on the fluorescein
angiogram.
FIGURE 153.18. (a) The patient refused
thermal laser and failed photodynamic therapy
and pegaptanib injection. After one injection of
bevacizumab there was complete resolution of
CHAPTER 153
symptoms, improvement of vision to 20/15, and
inactivity of the CNVM for 6 months. (b) The
fluorescein angiogram shows staining of the
inactive CNVM, but no leakage.
pressure and cataract. Complications required the removal of
the drug delivery implant in eight eyes.
Thus, it appears that intraocular corticosteroids potentially
offer stabilization and perhaps some improvement in eyes
with CNVM and OHS, but the complications of cataract and
glaucoma limit the desirability of this treatment.
ANTI-VEGF THERAPY AND CNVM DUE TO
OHS
At the time of this writing, there are no published reports of
anti-VEGF therapy for CNVM due to ocular histoplasmosis.
The authors of this chapter have anecdotal experience with
pegaptanib and bevacizumab, and believe that this form of
therapy (along with ranibizumab) will likely prove beneficial
for this disease. The following case history will serve as an
example:
Case #1. A 23-year-old white male presented with blurred
vision and distortion of 1 week duration in the left eye. He was
known to carry the diagnosis of ocular histoplasmosis. In fact,
one year ago, he presented with identical symptoms and was
felt to have choroiditis of a juxtafoveal macular histo spot. A
short course of oral steroids showed no benefit. He refused
thermal laser and subsequently underwent photodynamic
therapy with verteporfin. The symptoms resolved completely
within 2 weeks.
At this recurrence one year later, visual acuity was 20/25.
Again, there was hyperfluorescence of the juxtafoveal macular
histo spot (Fig. 153.17). PDT with verteporfin was performed
with no improvement. In order to mimic the successful result
obtained one year earlier, oral corticosteroids were started and
PDT with verteporfin was performed a second time. Because of
worsening symptoms and increased fluorecsein angiographic
leakage, an intravitreal injection of pegaptanib was given. One
week later there was continued worsening of vision and
angiographic leakage. Intravitreal bevacizumab was given.
There was immediate and complete resolution of symptoms
with 6 months follow-up (Fig. 153.18). 2019
 RETINA AND VITREOUS

FIGURE 153.19. (a) An Amsler grid is used for

diagnosis of CNVMs. This grid can be used at
home by patients at risk for the development
of new vessel membranes. (b) An artist’s
demonstration of metamorphopsia and relative
scotoma as seen by a patient with a new
CNVM.

a b
SECTION 10

CONCLUSION surgery appears to be of benefit in eyes with subfoveal CNVM

OHS is a relatively common disease in the endemic areas of the
Ohio and Mississippi river valleys. Patients with macular
chorioretinal scars are at risk for the development of choroidal
neovascularization that can threaten central vision. Individuals
with a macular ‘histo spots’ or a history of CNVM should self-
monitor vision regularly with an Amsler grid (Fig. 153.19).
Laser photocoagulation is recommended for extrafoveal and
juxtafoveal CNVMs secondary to OHS. Laser photocoagulation
is not recommended for subfoveal CNVM in OHS. Submacular
in OHS when visual acuity is less than 20/100. PDT with
verteporfin offers the possibility of stabilization and occasional
improvement in some eyes, but this has not been shown defini-
tively in a large, randomized clinical trial. Intraocular corti-
costeroids have a biologic effect on CNVM in OHS, but the
complications of glaucoma and cataract make this form of
therapy less attractive. Finally, anti-VEGF therapy has not yet
been well-studied in this disease, but is a potentially promising
treatment for the future.

REFERENCES
1. Krause AC, Hopkins WG: Ocular
manifestations of histoplasmosis. Am J
Ophthalmol 1951; 34:564.
2. Woods AC, Wahlen HE: The probable role
of benign histoplasmosis in the etiology of
granulomatous uveitis. Am J Ophthalmol
1960; 49:205.
3. Baskin MA, Jampol LM, Huamonte FU, et
al: Macular lesions in blacks with the
presumed ocular histoplasmosis syndrome.
Am J Ophthalmol 1980; 89:77.
4. Braunstein RA, Rosen DA, Bird AC: Ocular
histoplasmosis syndrome in the United
Kingdom. Br J Ophthalmol 1974; 58:893.
5. Ellis FD, Schlaegel TF: The geographic
localization of presumed histoplasmic
choroiditis. Am J Ophthalmol 1973; 75:953.
6. Wheat LJ, French MLV, Kohler RB, et al: The
diagnostic laboratory test for histoplasmosis.
Ann Intern Med 1982; 97:680.
7. Feman SS, Podgorski SF, Penn MK:
Blindness from presumed ocular
histoplasmosis in Tennessee.
Ophthalmology 1982; 89:1295.
8. Smith RE, Ganley JP: An epidemiologic
study of presumed ocular histoplasmosis.
Trans Am Acad Ophthalmol Otolaryngol
1971; 75:994.
9. Smith RE, Ganley JP: Presumed ocular
histoplasmosis. I: Histoplasmin skin test
sensitivity in cases identified during a
community survey. Arch Ophthalmol 1972;
87:245.
10. Ganley JP, Smith RE, Knox DL, Comstock
GW: Presumed ocular histoplasmosis. III:
Epidemiologic characteristic of people with
peripheral atrophic scars. Arch Ophthalmol
1973; 89:116.
11. Davidorf FH, Anderson JD: Ocular lesions
in the Earth Day histoplasmosis epidemic.
2020 Trans Am Acad Ophthalmol Otolaryngol
1974; 78:876.
12. Feman SS, Tilford RH: Ocular findings in
patients with histoplasmosis. JAMA 1985;
253:2534.
13. Gutman FA: The natural course of active
choroidal lesion in the presumed ocular
histoplasmosis syndrome. Trans Am Acad
Ophthalmol Soc 1979; 77:515.
14. Lewis ML, Schiffman JC: Long-term follow-
up of the second eye in ocular
histoplasmosis. Int Ophthalmol Clin 1983;
23:125.
15. Sawelson H, Goldberg RE, Annesley WH,
Tomer TL: Presumed ocular histoplasmosis
syndrome. Arch Ophthalmol 1976; 94:221.
16. Gass JDM: Pathogenesis of disciform
detachment of the neuroepithelium. Am J
Ophthalmol 1967; 63:661.
17. Olk RJ, Burgess DB, McCormick PA:
Subfoveal and juxtafoveal subretinal
neovascularization in the presumed ocular
histoplasmosis syndrome-Natural history.
Ophthalmology 1984; 91:1592.
18. Macular Photocoagulation Study Group:
Five-year follow-up of fellow eyes of
individuals with ocular histoplasmosis and
unilateral extrafoveal or juxtafoveal
choroidal neovascularization. Arch
Ophthalmol 1996; 114: 677.
19. Hoefnagels KLJ, Pijpers PM: Histoplasma
capsulatum in a human eye. Am J
Ophthalmol 1967; 63:715.
20. Roth AM: Histoplasma capsulatum in the
presumed ocular histoplasmosis syndrome.
Am J Ophthalmol 1977; 84:293.
21. Gass JDM, Zimmerman LE: Histopathologic
demonstration of Histoplasma capsulatum.
Am J Ophthalmol 1978; 85:725.
22. Macher A, Rodriques MM, Kaplan W, et al:
Disseminated bilateral chorioretinitis due to
Histoplasma capsulatum in a patient with
the acquired immunodeficiency syndrome.
Ophthalmology 1985; 92:1159.
23. Klintworth GK, Hollingsworth AS,
Lusman PA, Bradford WD: Granulomatous
choroiditis in a case of disseminated
histoplasmosis: histologic demonstration of
Histoplasma capsulatum in choroidal
lesions. Arch Ophthalmol 1973; 90:45.
24. Craig EL, Suie T: Histoplasma capsulatum
in human ocular tissue. Arch Ophthalmol
1974; 91:285.
25. Schwarz J, Salfelder K, Viloria JE:
Histoplasma capsulatum in vessels of the
choroid. Ann Ophthalmol 1977; 9:633.
26. Scholz R, Green WR, Kutys R, et al:
Histoplasma capsulatum in the eye.
Ophthalmology 1984; 91:1100.
27. Khalil MK: Histopathology of presumed
ocular histoplasmosis. Am J Ophthalmol
1982; 94:369.
28. Meredith TA, Green WR, Key SN, et al:
Ocular histoplasmosis: clinicopathological
correlation of 3 cases. Surv Ophthalmol
1977; 22:189.
29. Pavan PR, Margo CE: Submacular
neovascular membrane and focal
granulomatous inflammation.
Ophthalmology 1996; 103:586.
30. Smith RE: Natural history and reactivation
studies of experimental ocular
histoplasmosis in a primate pool. Trans Am
Ophthalmol Soc 1982; 80:695.
31. Smith RE, Dunn S, Jester JV: Natural history
of experimental histoplasmic choroiditis in the
primate. I: clinical features. Invest Ophthalmol
Vis Sci 1984; 25:801.
32. Smith RE, Dunn S, Jester JV: Natural
history of experimental histoplasmic
choroiditis in the primate. II:
histopathologic features. Invest Ophthalmol
Vis Sci 1984; 25:810.
33. Schlaegel TF, Weber JC, Helveston E, et al:
Presumed histoplasmic choroiditis. Am J
Ophthalmol 1967; 63:919.

34. Check IJ, Diddie KR, Jay WM, et al:
Lymphocyte stimulation by yeast phase
Histoplasma capsulatum in presumed
ocular histoplasmosis. Am J Ophthalmol
1979; 87:311.
35. Ganley JP, Nemo GJ, Comstock GW, Brody
JA: Lymphocyte transformation in
presumed ocular histoplasmosis. Arch
Ophthalmol 1981; 99:1424.
36. Brahmi Z, Wheat J, Rubin RH, et al:
Humoral and cellular immune response in
ocular histoplasmosis. Ann Ophthalmol
1985; 17:440.
37. Hodgkins PR, Lane AC, Chisholm IH, et al:
Immunophenotyping in presumed ocular
histoplasmosis-like retinopathy. Eye 1995;
9:56.
38. Meredith TA, Smith RE, Braley RE, et al:
The prevalence of HLA-B7 in presumed
ocular histoplasmosis in patients with
peripheral atrophic scars. Am J Ophthalmol
1978; 86:325.
39. Braley RE, Meredith TA, Aaberg TM, et al:
The prevalence of HLA-B7 in presumed
ocular histoplasmosis. Am J Ophthalmol
1978; 85:859.
40. Godfrey WA, Sabates R, Cross DE:
Association of presumed ocular
histoplasmosis with HLA-B7. Am J
Ophthalmol 1978; 85:854.
41. Smith RE, Ganley JP, Knox DL: Presumed
ocular histoplasmosis. II: patterns of
peripheral and peripapillary scarring in
persons with nonmacular disease. Arch
Ophthalmol 1972; 87:251.
42. Watzke RC, Claussen RW: The long-term
course of multifocal choroiditis (presumed
ocular histoplasmosis). Am J Ophthalmol
1981; 91:750.
43. Bottoni FG, Deutman AF, Aandekerk AL:
Presumed ocular histoplasmosis syndrome
and linear streak lesions. Br J Ophthalmol
1989; 73:528.
44. Fountain JA, Schlaegel TF: Linear streaks
of the equator in the presumed ocular
histoplasmosis syndrome. Arch Ophthalmol
1981; 99:246.
45. Schlaegel TF, Cofield DD, Clark G, Weber
JC: Photocoagulation and other therapy for
histoplasmic choroiditis. Trans Am Acad
Ophthalmol Otolaryngol 1968; 72:355.
46. Miller SA, Stevens TS, de Venecia G: De
novo lesions in presumed ocular
histoplasmosis-like syndrome. Br J
Ophthalmol 1976; 60:700.
47. Gass JDM, Wilkinson CP: Follow-up study
of presumed ocular histoplasmosis. Trans
Am Acad Ophthalmol Otolaryngol 1972;
76:672.
48. Lewis ML, Van Newkirk MR, Gass JDM:
Follow-up study of presumed ocular
histoplasmosis syndrome. Ophthalmology
1980; 87:390.
49. Meredith TA, Aaberg TM: Hemorrhagic
peripapillary lesions in presumed ocular
histoplasmosis. Am J Ophthalmol 1977;
84:160.
50. Cantrill HL, Burgess DB: Peripapillary
neovascular membranes in presumed
ocular histoplasmosis. Am J Ophthalmol
1980; 89:192.
51. Melberg NS, Thomas MA, and Burgess DB:
The Surgical removal of subfoveal
neovascular membranes. Ingrowth site as a
predictor of visual outcome. Retina 1996;
16:190–195.
52. Gass JD: Biomicroscopic and
histopathologic considerations regarding
the feasibility of surgical excision of
subfoveal neovascular membranes. Am J
Ophthalmol 1994; 118:285.
53. Kleiner RC, Ratner CM, Enger C, et al:
Subfoveal neovascularization in the ocular
histoplasmosis syndrome. Retina 1988;
8:225.
54. Fine SL, Wood WJ, Isernhagen RD, et al:
Laser treatment for subfoveal neovascular
membranes in ocular histoplasmosis
syndrome: results of a pilot randomized
clinical trial. Arch Ophthalmol 1993; 111:19.
55. Klein ML, Fine SL, Knox DL, Patz A:
Follow-up study in eyes with choroidal
neovascularization caused by presumed
ocular histoplasmosis. Am J Ophthalmol
1977; 83:830.
56. Gass JDM: Stereoscopic atlas of macular
disease. 3rd edn. St. Louis: CV Mosby; 1987.
57. Conway MD, Olk RJ, Burgess D, et al: Oral
steroid therapy histoplasmic choroiditis-
Natural history and visual prognosis. Paper
presented at the Sixteenth Annual Meeting
of Macula Society, Feb. 24–27. Naples, FL;
1993:78.
58. Beck RW, Sergott RC, Barr CC, Annesley
WH: Optic disc edema in the presumed
ocular histoplasmosis syndrome.
Ophthalmology 1984; 91:183.
59. Husted RC, Shock JP: Acute presumed
histoplasmosis of the optic nerve head. Br
J Ophthalmol 1975; 59:409.
60. Pulido JS, Folberg R, Carter KD, et al:
Histoplasma capsulatum endophthalmitis
after cataract extraction. Ophthalmology
1990; 97:217.
61. Kranias G: Vitreous hemorrhage secondary
to presumed ocular histoplasmosis
syndrome. Ann Ophthalmol 1985; 17:295.
62. Ibanez HE, Williams DF, Thomas MA, et al:
Surgical management of submacular
hemorrhage. A series of 47 consecutive
cases. Arch Ophthalmol 1995; 113:62.
63. Dreyer RF, Gass JDM: Multifocal choroiditis
and panuveitis. Arch Ophthalmol 1984;
102:1776.
64. Deutsch TA, Tessler HH: Inflammatory
pseudohistoplasmosis. Ann Ophthalmol
1985; 17:461.
65. Schlaegel TF: Ocular histoplasmosis. New
York: Grune & Stratton; 1977.
66. Schlaegel TF: Corticosteroids in the
treatment of ocular histoplasmosis. Int
Ophthalmol Clin 1983; 23:111.
67. Makley TA, Long JW, Suie T: Therapy of
chorioretinitis presumed to be caused by
histoplasmosis. Int Ophthalmol Clin 1975;
15:181.
68. Gitter KA, Cohen G: Photocoagulation of
active and inactive lesions of presumed
ocular histoplasmosis. Am J Ophthalmol
1975; 79:428.
69. Boucher MC, Dumas J, Labelle P, et al:
Prophylactic argon laser photocoagulation
of the second eye in presumed ocular
histoplasmosis syndrome. Can J
Ophthalmol 1987; 22:266.
70. Fine SL, Patz A, Orth DH, et al: Subretinal
neovascularization developing after
prophylactic argon laser photocoagulation
of atrophic macular scars. Am J
Ophthalmol 1976; 82:352.
71. Macular Photocoagulation Study Group:
Argon laser photocoagulation for ocular
histoplasmosis. Arch Ophthalmol 1983;
101:1347.
72. Macular Photocoagulation Study Group:
Argon laser photocoagulation for
Ocular Histoplasmosis Syndrome
neovascular maculopathy-Three-year
results. Arch Ophthalmol 1986; 104:594.
73. Burgess DB: Ocular histoplasmosis
syndrome. Ophthalmology 1986; 83:967.
74. Brown GC, Brown MM, Sharma S, et al:
Incremental cost-effectiveness of laser
therapy for choroidal neovawscularization
associated with histoplasmosis. Retina
2000; 20:331–337.
75. Macular Photocoagulation Study Group:
Krypton laser photocoagulation for
neovascular lesions of ocular
histoplasmosis. Arch Ophthalmol 1987;
105:1499.
76. Macular Photocoagulation Study Group:
Laser photocoagulation for juxtafoveal
choroidal neovascularization. Five-year
results from randomized clinical trials. Arch
Ophthalmol 1994; 112:500.
77. Fine SL, Olk RJ, Murphy RP, Hillis A:
CHAPTER 153
Current status of clinical trials to evaluate
argon (blue-green) laser and krypton (red)
laser photocoagulation in the treatment of
ocular histoplasmosis. Int Ophthalmol Clin
1983; 23:79.
78. Macular Photocoagulation Study Group:
Laser photocoagulation for neovascular
lesions nasal to the fovea. Results from
clinical trials for lesions secondary to ocular
histoplasmosis or idiopathic causes. Arch
Ophthalmol 1995; 113:56.
79. Macular Photocoagulation Study Group:
The influence of treatment extent on the
visual acuity of eyes treated with krypton
laser for juxtafoveal choroidal
neovascularization. Arch Ophthalmol 1995;
113:190.
80. Mainster MM: Wavelength selection in
macular photocoagulation. Ophthalmology
1986; 93:952.
81. Klein ML, Fine SL, Patz A: Results of argon
photocoagulation in presumed ocular
histoplasmosis. Am J Ophthalmol 1978;
86:211.
82. Sabates NF, Lee KY, Sabates R: Early
argon laser photocoagulation of presumed
histoplasma maculopathy. Am J
Ophthalmol 1977; 84:172.
83. Gass JDM: Photocoagulation of macular
lesions. Trans Am Acad Ophthalmol
Otolaryngol 1970; 75:580.
84. Sorenson JA, Yannuzzi LA, Shakin JL:
Recurrent subretinal neovascularization.
Ophthalmology 1985; 92:1059.
85. Macular Photocoagulation Study Group:
Recurrent choroidal neovascularization
after argon laser photocoagulation for
neovascular maculopathy. Arch Ophthalmol
1986; 104:503.
86. Macular Photocoagulation Study Group:
Persistent and recurrent neovascularization
after krypton laser photocoagulation for
neovascular lesions of ocular
histoplasmosis. Arch Ophthalmol 1989;
107:344.
87. Melberg NS, Thomas MA, Dickinson JD, et
al: Managing recurrent neovascularization
after subfoveal surgery in presumed ocular
histoplasmosis syndrome. Ophthalmology
1996; 103:1064.
88. Berger AS, Conway MD, Del Priore LV, et
al: Submacular surgery for subfoveal
choroidal neovascular membranes in
presumed ocular histoplasmosis. Arch
Ophthalmol 1997; 115:991.
89. Reddy VM, Zamora RL, Kaplan HJ:
Distribution of growth factors in subfoveal
neovascular membranes in age-related 2021
 RETINA AND VITREOUS
macular degeneration and presumed ocular
histoplasmosis syndrome. Am J
Ophthalmol 1995; 120:291.
90. Maas S, Deutman AF, Bandhoe F, et al:
Surgical removal of subretinal neovascular
membranes. Eur J Ophthalmol 1995; 5:48.
91. Desai VN, Del Priore LV, Kaplan HJ:
Choriocapillaris atrophy after submacular
surgery in presumed ocular histoplasmosis
syndrome. Arch Ophthalmol 1995; 113:408.
92. Akduman L, Del Priore LV, Desai V, et al:
Perfusion of the subfoveal choriocapillaris
affects visual recovery after submacular
surgery in presumed ocular histoplasmosis
syndrome. Am J Ophthalmol 1997; 123:90.
93. Thomas MA, Dickinson JD, Melberg NS, et
al: Visual results after surgical removal of
subfoveal choroidal neovascular membranes.
Ophthalmology 1994; 101:1384.
94. Bynoe LA, Chang TS, Funata M, et al:
Histopathologic examination of vascular
SECTION 10
patterns in subfoveal neovascular
membranes. Ophthalmology 1994;
101:1112.
95. Grossniklaus HE, Hutchinson AK, Capone
A Jr, et al: Clinicopathologic features of
surgically excised choroidal neovascular
membranes. Ophthalmology 1994;
101:1099.
96. Wind BE, Sobol WM: Surgical management
of a long-standing subfoveal neovascular
membrane secondary to ocular
histoplasmosis. Ophthalmic Surg 1993;
24:36.
97. Coscas G, Meunier I: Chirurgie des
membranes neovasculaires sous-
retiniennes maculaires. J Fr Ophtalmol
1993; 16:633.
98. Peyman GA, Lee KJ, Nelson NC Jr, et al:
Bimanual technique of subfoveal
neovascular membrane removal in
2022
presumed ocular histoplasmosis. Int
Ophthalmol 1993; 17:43.
99. Saxe SJ, Grossniklaus HE, Lopez PF, et al:
Ultrastructural features of surgically excised
subretinal neovascular membranes in the
ocular histoplasmosis syndrome. Arch
Ophthalmol 1993; 111:88.
100. Thomas MA, Grand MG, Williams DF, et al:
Surgical management of subfoveal
choroidal neovascularization.
Ophthalmology 1992; 99:952.
101. Berger AS, Kaplan HJ: Clinical experience
with the surgical removal of subfoveal
neovascular membranes. Short-term
postoperative results. Ophthalmology 1992;
99:969.
102. Hawkins BS, Bressler NM, Bressler SB, et
al: Surgical removal versus observation for
subfoveal choroidal neovascularization,
either associated with the ocular
histoplasmosis syndrome or idiopathic. I.
Ophthalmic findings from a randomized
clinical trial: Submacular Surgery Trials
(SST) Group H Trial: SST Report No. 9.
Arch Ophthlamol 2004; 122:1597–1611.
103. Hawkins BS, Miskala PH, Bass EB, et al:
Surgical removal versus observation for
subfoveal choroidal neovascuclarization,
etiher associated with the ocular
histoplasmosis syndrome or idiopathic. II.
Quality-of-life findings from a randomized
clinical trial: SST Group H Trial: SST Report
No. 10. Arch Ophthlamol 2004;
122:1616–1628.
104. Atebara NH, Thomas MA, Melberg NS, et al:
Surgical removal of large non-AMD
peripapillary choroidal neovascular
membranes. Ophthalmology 1996; 103:125.
105. Sickenberg M, Schmidt-Erfurth U, Miller
JW et al: A preliminary study of
photodynamic therapy using verteporfin for
choroidal neovascularization in pathologic
myopia, ocular histoplasmosis syndrome,
angioid streaks, and idiopathic causes.
Arch Ophthalmol 2000; 118:327–336.
106. Rosenfeld PJ, Saperstein DA, Bressler NM
et al: Photodynamic therapy with
verteporfin in ocular histoplasmosis:
uncontrolled, open-label 2-year study.
Ophthalmology 2004; 111:1725–1733.
107. Busquets MA, Shah GK, Wickens J et al:
Ocular photodynamic therapy with
verteporfin for choroidal neovascularization
secondary to ocular histoplasmosis
syndrome. Retina 2003; 23:299–306.
108. Shah GK, Blinder KJ, Hariprasad SM et al:
Photodynamic therapy for juxtafoveal
choroidal neovascularization due to ocular
histoplasmosis syndrome. Retina 2005;
25:26–32.
109. Postelmans L, Pasteels B, Coquelet P et al:
Photodynamic therapy for subfoveal classic
choroidal neovascularization related to
punctuate inner choroidopathy (PIC) or
presumed ocular hiestoplasmosis-like
syndrome (POHS-like). Ocul Immunol
Inflamm 2005; 13:361–366.
110. Lui JC, Boldt CH, Folk JC : Photodynamic
therapy of subfoveal and juxtafoveal
choroidal neovascularization in ocular
histoplasmosis syndrome : a retrospective
case series. Retina 2004; 24:863–870.
111. Rechtman E, Allen VD, Danis RP et al:
Intravitreal triamcinolone for choroidal
neovascularization in ocular histoplasmosis
syndrome. Am J Ophthalmol 2003;
136:739–741.
112. Holekamp NM, Thomas MA, Pearson A:
The safety profile of long-term, high-dose
intraocular corticosteroid delivery. Am J
Ophthalmol 2005; 139:421–428.
 CHAPTER
154 Pathologic Myopia
Adrienne W. Scott and Sharon Fekrat
Overview
Pathologic, or degenerative myopia, has been defined as
refractive error more negative than –6 D, and is a leading cause
of blindness in Asian countries. It is a multifactorial disorder with
genetic, environmental, and socioeconomic etiologies. The
pathogenesis of pathologic myopia is not known. Defective
collagen fibril formation results in biomechanically weak sclera
and progressive globe elongation. Numerous complications, such
as posterior vitreous detachment (PVD) and abnormal
vitreoretinal interface, retinal detachment (RD), posterior
staphyloma, macular hole, lacquer cracks (spontaneous breaks in
Bruch’s membrane), subretinal hemorrhage, lead to visual
disability. The most common visually threatening complication of
pathologic myopia is choroidal neovascularization (CNV).
Myopia-related CNV lesions are usually self-limited, and are
smaller and less exudative than CNV observed in age-related
macular degeneration (AMD). Argon laser has been used to treat
extrafoveal CNV with a high rate of posttreatment recurrence.
Photodynamic therapy (PDT) has been established as a
treatment to preserve visual acuity for subfoveal myopic CNV.
Antiangiogenic therapy is a promising treatment option.
Surgical treatments to displace the myopic CNV have also
been utilized in attempts to salvage remaining visual acuity in
these eyes.
Anticholinergic therapy is being studied as a way to slow
myopic degeneration. As yet, there is no proven method to
prevent the axial elongation and the myriad resulting posterior
segment complications described in pathologic myopia.
INTRODUCTION
Myopia, or nearsightedness, is the most common ocular con-
dition. Myopia occurs when an object image is formed anterior
to the retinal surface, due to an excessively steep corneal curva-
ture, an abnormally spherical lens, an increase in lenticular
index of refraction as in nuclear sclerosis, or more commonly,
as a result of increased axial length.1
Pathologic, myopia occurs when progressive increase in axial
length causes excessive thinning of the sclera, retina, retinal
pigment epithelium (RPE) and choroid, resulting in varying
degrees of visual disability. Pathologic myopia has been assigned
varying definitions in the ophthalmic literature. Duke-Elder
defined pathologic myopia as myopia accompanied by
degenerative posterior segment changes.2,3 Pathologic myopia
has also been defined as high myopia accompanied by visual
dysfunction.3,4 The American Academy of Ophthalmology Basic
Clinical Science Course defines pathologic myopia as refractive
error greater than ⫺6 D, with axial length in excess of
26.5 mm.5
PREVALENCE
Myopia is the most common refractive error and affects ~25% of
adults in the United States.6 Various demographic characteris-
tics have been shown to be associated with high myopia. Female
gender, younger age, earlier onset of myopia, and family history
are all risk factors found to be associated with an increased like-
lihood of progressive myopia. Increased income and educational
level have been associated with high levels of myopia, likely due
to their correlation with increased levels of near work.6
Myopia prevalence varies among racial demographics. One
study estimated prevalence of myopia in African-Americans in
the United States at 13%.7 Recently, the Los Angeles Latino Eye
Study estimated an overall prevalence of myopia in adult Latinos
in one community at 16.8%, with estimated prevalence of high
myopia in this community at 2.4%.8 A very high prevalence of
myopia has been reported among Asians. Fredrick reported the
overall prevalence of myopia to be as high as 70–90% in Asian
populations.9 While 0.2–0.4% of the US population was found to
have refractive error greater than ⫺7.9 D,7 the prevalence of
pathologic myopia in Asian countries has been reported to be as
high as 1%.4
PATHOGENESIS
It is well accepted that pathologic myopia is characterized by
progressive scleral thinning with localized ectasia. The exact
pathogenesis of pathologic myopia, however, is not entirely
understood. It is postulated that myopic sclera is biomechan-
ically weak and has been demonstrated to alter its composition
and rigidity in response to environmental and visual stimuli.
Remodeling of extracellular matrix by matrix metalloproteinases
and their tissue inhibitors leads to abnormalities in collagen
fiber bundles and a reduction in the size of individual collagen
fibers in myopic eyes.10 Myopia has been induced in animal
models by defocusing the retinal image, triggering a cascade of
events that leads to axial elongation.11 Cholinergic pathways
have been studied as mediators of scleral elongation associated
with myopia. Other neurotransmitters such as dopamine, vaso-
active intestinal peptide, and glucagon have also been implicated
as possible mediators of scleral growth.12
ASSOCIATIONS
A variety of ocular morbidities such as low-tension glaucoma,
amblyopia, strabismus, early cataract formation, image mini-
fication, decreased contrast sensitivity, and visual field defects
have all been associated to occur in association with pathologic
myopia. Stickler syndrome, Wagner syndrome, Ehlers–Danlos
2023
 RETINA AND VITREOUS
syndrome, and Marfan’s syndrome are hereditary conditions
that have been associated with axial high myopia.
COMPLICATIONS
The fundus changes observed in conjunction with pathologic myo-
pia most notably lead to visual deterioration and blindness in
highly myopic individuals. A trademark of the myopic posterior
segment clinical examination is the tessellated, or tigroid fundus,
in which choroidal vessels are evident below the thinned,
atrophic retina and RPE (Fig. 154.1). This and other abnormal
posterior segment findings in pathologic myopia were described
in a large, retrospective, histopathologic examination of enucleated
eyes with degenerative myopia by Grossniklaus and Green.13
Myopic configuration of the optic nerve head was the most fre-
quently associated finding, present in 37.7% of eyes. Posterior
staphyloma and vitreous degeneration were the next most
frequently observed findings.13
SECTION 10
Pathologic myopic retinopathy is particularly visually
devastating, as it is irreversible, often bilateral, and affects
individuals at younger ages during their productive years.14 The
major visually threatening complications of myopic retinopathy
are discussed below.
POSTERIOR VITREOUS DETACHMENT
Highly myopic eyes are characterized by premature posterior
vitreous detachment (PVD). The incidence of PVD in highly
myopic patients has been strongly correlated with increased
axial length, age, and degree of myopia compared to controls.15
A PVD is often preceded by vitreous syneresis, and the
formation of fluid pockets within the vitreous gel.1 Acute PVD
may produce photopsia and a symptomatic ‘floater’, in which
shadows are cast on the retinal surface as a result of vitreous
condensation and opacification. Detachment of the posterior
vitreous may also cause acute vitreous hemorrhage if retinal
vessels are avulsed at the time of posterior vitreous separation.
A PVD may cause retinal traction and lead to a retinal break as
well as the most common surgical complication of high
myopia-rhegmatogenous retinal detachment (RRD).
FIGURE 154.1. Typical fundus appearance of pathologic myopia. This
patient has 20/60 vision with –20 D correction. Note tilted optic nerve
with peripapillary crescent, tigroid fundus appearance, attenuated
vessels, and chorioretinal atrophy.
2024 Photo courtesy of Srilaxmi Bearelly, MD.
FIGURE 154.2. RD resulting from a macular hole (black arrow) in a
patient with pathologic myopia.
Photo courtesy of Brooks W. McCuen, MD.
RETINAL DETACHMENT
A break in the retina causes liquified vitreous fluid to travel under-
neath the retina into the subretinal space, detaching the retina.
RRD may result from a retinal tear, retinal dialysis, macular
hole, or as a result of acute PVD as described previously. In the
general population, the retinal detachment incidence is less
than 1%, RRD occurs more frequently in eyes with increased
axial length.3 This increased likelihood of RRD in high myopes
is due to peripheral retinal abnormalities such as lattice
degeneration, increased frequency of PVD, and an abnormal
vitreoretinal interface caused by increased axial length.
RRD as a result of macular hole formation is more likely to
occur in eyes with pathologic myopia (Fig. 154.2). One study
reported 6.3% of highly myopic eyes to develop an asymptomatic
macular hole, confirmed by ocular coherence tomography (OCT).16
High myopia also predisposes eyes to RRD after cataract sur-
gery. Highly myopic eyes undergoing cataract surgery are more
likely to develop a postoperative retinal detachment when
compared to controls.17 Pars plana vitrectomy (PPV) with or
without scleral buckling, with or without gas or silicone oil
tamponade may be used to repair RRD.
OPTIC NERVE
Globe elongation leads to characteristic optic nerve changes. The
tilted optic nerve is often seen in eyes with pathologic myopia.
Thinning of the retina and RPE leads to the peripapillary tem-
poral crescent observed to surround the optic nerve head (Fig.
154.1). A recently described optic nerve finding is peripapillary
detachment. Freund and colleagues reported peripapillary detach-
ment as an elevated, yellow-orange lesion inferior to the optic disk
seen in highly myopic eyes.18 OCT demonstrated a localized reti-
nal pigment epithelial detachment corresponding to the lesion.
Peripapillary detachment was not observed to be visually signifi-
cant. In another study, peripapillary detachment was present in
as many as 4.9% of highly myopic eyes and was associated with
glaucomatous optic nerve defects in 71% of eyes.19
POSTERIOR STAPHYLOMA
Localized, progressive globe elongation and resulting scleral ecta-
sia leads to the development of a posterior staphyloma, another

FIGURE 154.3. OCT in a patient with pathologic myopia. Visual acuity
is 20/200 with a spherical equivalent of –22 D. Note the posterior
staphyloma, and the hyperreflectivity of the tissues underlying the
atrophic retina. A partial PVD overlies the macula.
Photo courtesy of James Kesler, MD, FACS.
hallmark of degenerative myopia (Fig. 154.3). The prevalence of
staphyloma formation correlates with axial length. Posterior
staphyloma may cause visual field deficits, and central visual
acuity may be affected if the staphyloma involves the macula.
Increased likelihood of retinal detachment and formation of
macular hole have been associated with posterior staphyloma
formation in a study by Oie and colleagues.20
LACQUER CRACKS
Excessive tissue stress in pathologic myopia may also result in
lacquer crack formation – focal, linear breaks in Bruch’s mem-
brane. Lacquer cracks may cause spontaneous subretinal hemor-
rhage (Fig. 154.4) at the time of formation, and may produce
symptoms of acute photopsia, metamorphopsia, or scotoma.1 A
later complication of lacquer crack formation is the development
of secondary CNV.
MYOPIC CNV
Macular CNV occurs in 5–10% of eyes that are highly myopic21,22
and is the most common visually threatening complication of
pathologic myopia.3,23–25 In its later stages, CNV due to patho-
FIGURE 154.4. Subretinal hemorrhage in a myopic eye. This –11.5 D
myopic patient experienced a decrease in vision to 20/80 from
submacular hemorrhage.
Photo courtesy of Srilaxmi Bearelly, MD.
Pathologic Myopia
logic myopia may be called a Fuchs spot. Foerster also described
hemorrhagic lesions in myopic eyes which may describe a dif-
ferent stage in myopic CNV formation.26,27 It has been observed
that CNV in persons younger than 50 is seen most often in
conjunction with pathologic myopia.28
NATURAL HISTORY OF MYOPIC CNV
The natural history of myopic CNV is variable. Yoshida and col-
leagues reported a generally poor prognosis for these untreated
eyes with vision decreasing to worse than 20/200 at 10-year
follow-up.29 The same group also reported favorable character-
istics of highly myopic eyes with CNV, which include younger
age at onset, smaller CNV lesion size, and juxtafoveal location.
Degree of myopia did not appear to influence prognosis in this
study.30 Myopic CNV appears to be a self-limited process with low
activity and rapid absorption. It is, however, the development of
chorioretinal atrophy around the myopic CNV that has been
CHAPTER 154
observed to enlarge, involve the fovea in some cases, and cause
a further decrease in visual acuity.24,31
MEDICAL TREATMENTS OF MYOPIC CNV
Treatment modalities aimed toward treating CNV related to
age-related macular degeneration (AMD) have been applied to
the treatment of CNV in myopic eyes. CNV does, however,
differ between these two groups in that most CNV lesions in
association with pathologic myopia are classic, less exudative,
and smaller as compared to CNV lesions in AMD.3 Laser
photocoagulation was the primary available treatment option
for myopia-associated CNV prior to the 1990s.3,19,32–36 Laser
photocoagulation has shown short-term efficacy in limiting the
extension of the extrafoveal or juxtafoveal CNV. A long-term
study comparing the natural history of myopic CNV with laser
treatment found that the visual acuity was preserved only after
the first 2 years of follow-up.30 At 5-year follow-up, there was no
significant difference in visual acuity between treated and
untreated eyes. The CNV is subject to recur along the border of
the laser scar in treated eyes, with recurrence rates reported as
high as 31–72%.3,26–30,32–35 In addition to the immediate
scotoma formation caused by laser treatment, further loss of
central visual acuity may result in laser-treated myopic eyes
with laser scar expansion, a process known as ‘atrophic creep’.3
Photodynamic therapy (PDT) with verteporfin has been a
major treatment option in eyes with myopia-related subfoveal
CNV. PDT involves the administration of an intravenous
photosensitive verteporfin dye which selectively accumulates in
the CNV lesion.3 Diode laser is then used to activate the
accumulated dye and cause occlusion of the choroidal
neovascular vessels. Two-year data from the Verteporfin in
Photodynamic (VIP) Therapy Study Group showed maintained
visual benefit of the PDT-treated group as compared to the
placebo therapy group at 2-year follow-up.37 Other studies have
corroborated the VIP data, observing that PDT can increase the
chance of visual stabilization or improvement compared with
placebo.38 Intravitreal corticosteroids are also being considered
in myopic CNV therapy in conjunction with PDT.39 Though PDT
has been shown to have a treatment benefit in highly myopic CNV
lesions, as with thermal laser treatment, the potential exists for
posttreatment RPE damage, and posttreatment laser expansion of
chorioretinal atrophy in the myopic eye after PDT treatment.3
Angiogenic growth factors such as vascular endothelial growth
factor (VEGF) are implicated in the pathogenesis of ocular neo-
vascularization in the human eye.40,41 As in the case of neovas-
cular AMD, VEGF inhibition is being studied as a treatment
modality in myopia-related CNV.42 Clinical trials are currently
underway to evaluate anti-VEGF therapy in pathologic myopia. 2025
 RETINA AND VITREOUS

SURGICAL TREATMENTS FOR MYOPIC CNV
Surgical removal of CNV in pathologic myopia has been
performed.43,44 No significant improvement in visual acuity has
been reported, and surgical extraction of myopic CNV has been
associated with high recurrence rates and postsurgical RPE
atrophy.3,43–46
Another surgical intervention, macular translocation, is a com-
plex surgical procedure first described as a treatment for macular
degeneration by Machemer and Steinhorst.3,46 Macular trans-
location involves moving the overlying sensory retina from the
subfoveal CNV bed to a new location overlying healthy RPE.3
Proliferative vitreoretinopathy has been a frequent post-
operative complication.3 Further study is needed to establish the
role of macular translocation in the treatment of myopic CNV.
TREATMENT
SECTION 10
High myopia is a multifactorial disorder, with environmental,
socioeconomic, and genetic factors playing a role in myopic
degeneration. An X-linked form of pathologic myopia has been
described,51 and Young and associates have identified a chromo-
somal locus for autosomal dominant high myopia.52 Discovery
of other genes involved in high myopia may make gene therapy
a potential area for future treatment.
Key Features
• Tigroid, or blond fundus, with choroidal vessels visible
underneath
• Tilted optic nerve with peripapillary atrophy
• Peripapillary detachment
• Chorioretinal atrophy
• Posterior vitreous detachment
• Retinal detachment
• Lacquer cracks
• Lattice degeneration (spontaneous breaks in Bruch’s

The treatments mentioned previously are all dedicated to miti- membrane)

gating the visual disability due to complications of pathologic • Cobblestone degeneration
myopia. There is no known cure for the globe elongation respon- • Fuchs’ spot (RPE hyperplasia in response to CNV)
sible for the complications experienced by those with pathologic • Scleral thinning
myopia. Prevention of myopic degeneration has been attempted • Peripheral retinal holes
with anticholinergic agents, such as atropine47,48 and pirenzip- • Macular holes causing retinal detachment
ine,49 that have been studied as possible therapeutic agents to • Choroidal neovascularization
slow scleral growth in humans.
Scleral reinforcement surgery has been attempted to arrest the
axial globe elongation which occurs in pathologic myopia.1,50 Treatment Options for Myopic CNV
The clinical benefit of these procedures has as yet been • Observation
unproven in a randomized, controlled clinical trial. • Photodynamic therapy with or without intravitreal steroid
Refractive surgery procedures, such as laser in situ kerato- injection (FDA approved for subfoveal CNV)
mileusis (LASIK), photorefractive keratectomy (PRK), and radial • Argon laser (used for extrafoveal CNV, high rate of CNV
keratotomy (RK), have achieved emmetropia in high myopes recurrence and expansion of RPE scarring after treatment)
through alterations of corneal architecture. Phakic refractive • Transpupillary thermotherapy
lenses and cataract surgery have also been utilized to minimize • Angiogenesis inhibition
myopic refractive error. These procedures, however, do not eli- • Surgical extraction of CNV lesion
minate the myriad posterior segment complications that • Macular translocation
threaten the visual acuity of high myopes.

REFERENCES
1. Pruett RC: Pathologic myopia. In: Albert
and Jakobiec’s principles and practice of
ophthalmology. 2nd edn. Philadelphia, PA:
WB. Saunders Ca 2000; 878–882.
2. Duke-Elder S: Pathologic refractive errors.
System of ophthalmology. vol V.
Ophthalmic optics and refraction. Louis:
Mosby; 1970:297–373.
3. Tano Y: LIX Edward Jackson Memorial
Lecture. Pathologic myopia: where are we
now? Am J Ophthalmol 2002;
134:645–660.
4. Tokoro T: On the definition of pathologic
myopia in group studies. Acta Ophthalmol
1988; 66:107–108.
5. American Academy of Ophthalmology:
Pathologic myopia. In: Retina and vitreous,
basic and clinical science course, 2003;
San Francisco: American Academy of
Ophthalmology 2003; 74.
6. Eye Disease Prevalence Research Group:
The prevalence of refractive errors among
adults in the United States, Western
Europe, and Australia. Arch Ophthalmol
2004; 122:495–505.
7. Sperduto RD, Seigel D, Roberts J,
Rowland M: Prevalence of myopia in the
United States. Arch Ophthalmol 1983;
101:405–407.
2026 8. Tarczy-Hornoch K, Ying-Lai M, Varma R,
et al: Myopic refractive error in adult
Latinos: the Los Angeles Latino Eye Study.
IOVS 2006; 47:1845–1852.
9. Fredrick DR: Myopia. BMJ 2002;
324:1195–1199.
10. Rada JA, Shelton S, Norton TT: The sclera
and myopia. Exp Eye Res 2006;
82:185–200.
11. Wallman J: Retinal control of eye growth and
refraction. Prog Ret Res 1993; 12:133–153.
12. Crewther DP: The role of photoreceptors in
the control of refractive state. Prog Retina
Eye Res 2000; 19:421–457.
13. Grossniklaus HE, Green WR: Pathologic
findings in pathologic myopia. Retina 1992;
12:127–133.
14. Shih YF, Ho TC, Hsiao CK, et al: Visual
outcomes for high myopic patients with or
without myopic maculopathy: a 10-year
follow up study. Br J Ophthalmol 2006;
90:546–550.
15. Ye J, Zhou C, Du H, et al: Study on the
posterior vitreous detachment in patients
with high myopia. Zhongguo Yi Xue Ke Xue
Yuan Xue Bao 1999; 21:472–477.
16. Coppe AM, Ripandelli G, Parisi V, et al:
Prevalence of asymptomatic macular holes
in highly myopic eyes. Ophthalmol 2005;
112:2103–2109.
17. Ripandelli G, Scassa C, Parisi V, et al:
Cataract surgery as a risk factor for retinal
detachment in very highly myopic eyes.
Ophthalmology 2003; 110:2355–2361.
18. Freund KB, Ciardella AP, Yannuzzi LA, et al:
Peripapillary detachment in pathologic
myopia. Arch Ophthalmol 2003;
121:197–204.
19. Shimada N, Ohno-Matsui K, Yoshida T, et al:
Characteristics of peripapillary detachment
in peripapillary myopia. Arch Ophthalmol
2006; 124:46–52.
20. Oie Y, Ikuno Y, Fujikado T, Tano Y: Relation of
posterior staphyloma in highly myopic eyes
with macular hole and retinal detachment.
Jpn J Ophthalmol 2005; 49:530–532.
21. Curtin BJ: Basic science and clinical
management. In: Curtin BJ, ed. The
myopias. Philadelphia: Harper & Row;
1985:237–245.
22. Grossniklaus HE, Green WR: Pathologic
findings in pathologic myopia. Retina 1992;
12:127–133.
23. Avila MP, Weiter JJ, Jalkh AE, et al: Natural
history of choroidal neovascularization in
degenerative myopia. Ophthalmology 1984;
91:1573–1581.
24. Fried M, Siebert A, Meyer-Schwickerath G:
A natural history of Fuchs’ spot. A long
term follow-up study. Doc Ophthalmol
1981: 28:215–221.

25. Hampton GR, Kohen D, Bird AC: Visual
prognosis of disciform degeneration in
myopia. Ophthalmology 1983; 90:923–926.
26. Foerster R: Ophthalmologische beitrage.
Berlin: Enslin; 1862:55.
27. Soubrane G, Coscas G: Choroidal
neovascular membrane in degenerative
myopia. In: Schachat AP, Murphy RP,
Ryan SJ, eds. Retina. Los Angeles: Mosby;
1994:1149.
28. Cohen SY, Laroche A, Leguen Y, et al:
Etiology of choroidal neovascularization in
young patients. Ophthalmology 1996;
103:1241–1244.
29. Yoshida T, Ohno-Matsui K, Ohtake Y, et al:
Myopic choroidal neovascularization: a
10-year follow-up. Ophthalmology 2003;
110:1297–1305.
30. Hayashi K, Ohno-Matsui K, Yoshida T, et al:
Characteristics of patients with a favorable
natural course of myopic choroidal
neovascularization. Graefe’s Arch Clin Exp
Ophthalmol 2005; 243:13–19.
31. Kojima A, Ohno-Matsui K., Teramukai S,
et al: Factors associated with the
development of chorioretinal atrophy
around choroidal neovascularization in
pathologic myopia. Graefe’s Arch Clin Exp
Ophthalmol 2004; 242:114–119.
32. Jalkh AE, Weiter JJ, Trempe CL, et al:
Choroidal neovascularization in
degenerative myopia: role of laser
photocoagulation. Ophthalmic Surg 1987;
18:721–725.
33. Soubrane G, Pison J, Bornert P, et al:
Neovaisseaux sous-retiniens de la myopie
degerative: resultants de la
photocoagulation. Bull Soc Ophthalmol Fr
1986; 86:269–272.
34. Brancato R, Menchini U, Pece A, et al: Dye
laser photocoagulation of macular
subretinal neovascularization in
pathological myopia. A randomized study
of three different wavelengths. Int
Ophthalmol 1997; 7:339–344.
35. Pece A, Brancato R, Avanza P, et al: Laser
photocoagulation of choroidal
neovascularization in pathologic myopia:
long-term results. Int Ophthalmol 1994;
18:339–344.
36. Secretan M, Kuhn D, Soubrane G, et al:
Long-term visual outcome of choroidal
neovascularization in pathologic myopia:
natural history and laser treatment. Eur J
Opthalmol 1997; 7:307–316.
37. Verteporfin in Photodynamic Therapy (VIP)
Study Group: Verteporfin therapy of
subfoveal choroidal neovascularization in
pathologic myopia: 2- year results of a
randomized clinical trial-VIP report no. 3.
Ophthalmology 2003; 110:667–673.
38. Schnurrbusch UE, Jochmann C,
Wiedemann P, et al: Quantitative
assessment of the long-term effect of
photodynamic therapy in patients with
pathologic myopia. Graefe’s Arch Clin Exp
Ophthalmol 2005; 243:829–833.
39. Potter MJ, Szabo SM, Ho T: Combined
photodynamic therapy and intravitreal
triamcinolone for the treatment of
myopic choroidal neovascularization in a
13-year-old girl. Graefe’s Arch Clin Exp
Ophthalmol 2005; 21:1–3.
40. Adamis AP, Miller JW, Bernal MT, et al:
Increased vascular endothelial growth
factor levels in the vitreous of eyes with
proliferative diabetic retinopathy. Am J
Ophthalmol 1994; 118:445–450.
41. Aiello LP, Avery RL, Arrigg PG, et al:
Vascular endothelial growth factor in ocular
fluid of patients with diabetic retinopathy
and other retinal disorders. N Engl J Med
1994; 331:1480–1487.
42. Nguyen QD, Shah S, Tatlipinar S, et al:
Bevacizumab suppresses choroidal
neovascularization caused by pathologic
myopia. Br J Ophthalmol 2005;
89:1368–1370.
43. Ruiz-Moreno JM, de la Vega C: Surgical
removal of subfoveal choroidal
Pathologic Myopia
neovascularization in highly myopic
patients. Br J Ophthalmol 2001;
85:1041–1043.
44. Uemura A, Thomas MA: Subretinal surgery
for choroidal neovascularization in patients
with high myopia. Arch Ophthalmol 2000;
118:344–350.
45. Haemlin N, Glacet-Bernard A, Brindeau C,
et al: Surgical treatment of subfoveal
neovascularization in myopia: macular
translocation versus surgical removal. Am J
Ophthalmol 2002; 133:530–536.
46. Machemer R, Steinhorst UH: Retinal
separation, retinotomy, and macular
relocation. II. A surgical approach for
macular degeneration. Ophthalmology
1999; 101:1384–1396.
47. Bedrossian RH: The effect of atropine on
myopia. Ophthalmology 86:713–719.
48. Shih YF, Hsiao CK, Chen CJ, et al: An
CHAPTER 154
intervention trial on efficacy of atropine and
multi-focal glasses in controlling myopic
progression. Acta Ophthalmol Scand 1999;
79:233–236.
49. Siatkowski RM, Cotter S, Miller JM, et al:
US pirenzapine study group. Safety and
efficacy of 2% pirenzapine ophthalmic gel
in children with myopia: a 1-year,
multicenter, double-masked, placebo-
controlled parallel study. Arch Ophthalmol
2004; 122:1667–1674.
50. Coroneo MT, Beaumont JT, Hollows FC:
Scleral reinforcement in the treatment of
pathologic myopia. Aust N Z J Ophthalmol
1998; 16:317–320.
51. Gregg FM, Feinberg EB: X-linked
pathologic myopia. Ann Ophthalmol 1992;
24:310–312.
52. Paluru PC, Nallasamy S, Devoto D, et al:
Identification of a novel locus on 2q for
autosomal dominant high-grade myopia.
IOVS 2005; 46:2300–2307.
2027
 CHAPTER
155 Idiopathic Macular Hole
Justin L. Gottlieb
Advances in vitreoretinal imaging techniques and success in
surgical repair have stimulated great interest in the pathophysi-
ology and natural history of macular holes. In particular, optical
coherence tomography (OCT) provides unique imaging of the
vitreomacular interface that has refined the understanding of
macular hole formation. In the 25 years since Kelly and
Wendel’s landmark publication describing the successful
repair of macular holes with vitrectomy surgery,1 the surgical
technique continues to be refined with improved anatomic and
visual outcomes.
EPIDEMIOLOGY AND RISK FACTORS
Macular holes have been reported in association with many
causes, including trauma,2 laser treatment,3 retinal vascular
disease,4,5 retinal detachment repair,6,7 lightening,8 and
electrocution,9 but the vast majority of cases are age-related and
idiopathic, unrelated to other antecedent events or other ocular
disease. The Eye Disease Case-Control Study Group reported
that 72% of idiopathic holes occurred in women and more than
50% in patients 65–74 years of age10 The observed increased
risk in females is poorly understood and explanations only
speculative. Investigating the increased incidence of macular
hole in females, the case study report found that estrogen use
was protective but did not find an association with prior
hysterectomy. The observation of macular holes among siblings
within four different families has also suggested a possible
genetic component in the formation of macular holes.11
The risk of full-thickness macular hole formation in the
fellow eye is estimated to be ~10–15%.12–15 Normal fellow eyes
with posterior vitreous detachment appear to be at a very low
risk of macular hole development.14,16 However, in fellow eyes
with persistent vitreofoveal attachments (as evidenced by
optical coherence tomography) 11% of fellow eyes developed a
full-thickness macular hole over a 2 year period of observation.17
PATHOGENESIS
Theories from the early nineteenth century of the pathogenesis
of macular hole focused on trauma,18 although contemporary
reports find that greater than 80% are idiopathic.19 Early
histological description of full-thickness hole noted cystic
intraretinal changes.20,21 These changes were usually assumed
to be due to ocular trauma, supporting the prevailing theories
of the era.
Other early theories of macular hole formation suggested that
macular cysts may form atraumatically and degenerate into
macular holes.22,23 Kuhnt implicated a degenerated fovea as
the cause of macular hole and termed this disorder retinitis
atrophicans sive rarificans centralis.22 The implication of cys-
toid degeneration, coalescence of cystic spaces, and the
development of a full-thickness hole was an important develop-
ment in the understanding of macular hole development, as it
emphasized that trauma was not a necessary precedent event.24
Current concepts of macular hole formation focus on the role
of the vitreomacular interface. As early as 1924, Lister stated
the importance of the vitreous in the pathogenesis of macular
hole,25 noting traction of fibrous bands in the vitreous. How-
ever, he was puzzled by his own clinical observations of a lack
of visible tractional vitreous bands in cases of macular holes.26
Several series from the 1960s described signs of vitreomacular
traction contributing to macular hole formation.27–30
Avila and Jalkh concluded that persistent vitreous-to-macula
traction was important in the formation of macular holes, as
53% of their cases of macular holes did not have a posterior
vitreous detachment demonstrable on biomicroscopic exami-
nation.31 Similarly, Akiba et al described the progression of
premacular hole lesions to fully developed holes without the
occurrence of a posterior vitreous detachment.32 In contrast,
McDonnell et al noted a complete vitreous separation in all
macular hole cases and in all cases observed to progress from
premacular hole lesions to full-thickness macular hole,33
concluding that the act of vitreous separation from the macula
was critical to the formation of a full-thickness hole. It is
interesting that each group concluded that vitreous traction on
the macula was important in the pathogenesis of macular holes,
but arriving at this conclusion from seemingly contradicting
evidence.
The current concept of macular hole pathogenesis has grown
from the understanding that vitreofoveal traction is central to
the development of and progression to a full-thickness macular
hole. In 1988, Gass31 and Johnson and Gass35 proposed a new
hypothesis of macular hole formation, including a classification
scheme for idiopathic holes and precursor lesions. This
classification scheme has guided the description of macular hole
development and theories of pathogenesis since that time. Gass
proposed that contraction of prefoveolar cortical vitreous
resulted in tangential traction. This traction resulted in a
predictable progression through multiple stages of development
(Fig. 155.1). Stage 1 is the earliest biomicroscopic sign of an
impending macular hole and results from a foveolar or foveal
detachment. Ophthalmoscopically, it appears as a yellow dot
(stage 1a) or yellow ring (stage 1b), respectively (Fig. 155.2).
Progressive tangential traction may result in a small full-
thickness break in the neurosensory retina. These holes were
described as eccentric can-opener shaped tears or small central
defects (stage 2) (Fig. 155.3). These small holes usually prog-
ressed to larger 400-500 mm holes with or without operculum
(stage 3) (Fig. 155.4) and finally may involve the separation of
the posterior vitreous (stage 4) (Fig. 155.5). 2029
 RETINA AND VITREOUS

FIGURE 155.1. Schematic diagram of stages

VC of development of idiopathic macular hole
based on biomicroscopic observations as
proposed by Gass. See text for detail.
A. NORMAL FOVEA Reproduced from Gass JDM: Reappraisal of
biomicroscopic classification of stages of
development of a macular hole. Am J
Ophthalmol 1995; 119:752–759.

B. STAGE 1-A IMPENDING HOLE C. STAGE 1-B IMPENDING HOLE

SECTION 3

D. STAGE 1-B OCCULT HOLE E. STAGE 1-B OCCULT HOLE

F. STAGE 2 HOLE G. STAGE 2 HOLE

H. STAGE 3 HOLE I. STAGE 4 HOLE

FIGURE 155.2. (a) Color fundus photograph of

stage 1b hole. Note the central yellow ring.
(b) Optical coherence tomography of stage 1
hole. Note the foveolar detachment. Visual
acuity was 20/25. This eye later developed a
full-thickness macular hole.

a b

FIGURE 155.3. (a) Color fundus photograph of

stage 2 macular hole. The hole is full-thickness
but a diameter less than 400 mm. (b) Optical
coherence tomograph of stage 2 macular hole.
Note the vitreous traction on the operculum
which is not yet detached from the retina.

a b

Dr Gass later provided a revision and update of the bio-
microscopic classification.36 In this reappraisal, Gass proposed
that the yellow ring of a stage 1b hole is due to centrifugal
displacement of retinal receptors after a dehiscence at the
2030 umbo. The occult hole may be hidden by the semiopaque
prefoveolar condensed vitreous cortex bridging the hole. The
occult hole may then become visible after an early separation or
an eccentric can-open-like tear in the condensed prefoveolar
vitreous cortex. The prefoveolar cortex may then form a prehole
pseudo-operculum. This scheme helped to unify surgical

a b
FIGURE 155.5. Color fundus photograph of stage 4 hole. This hole
was present for at least 1 year and the visual acuity had decreased to
20/200.
observations of restoration of foveal architecture and sometimes
near normal function, which seemed at odds with the earlier
scheme of pathogenesis in which foveal opercula containing
photoreceptors were thought to develop (Fig. 155.1).
MACULAR HOLE IMAGING AND
PATHOGENESIS
The classification scheme and description of pathogenesis
provided by Dr Gass was based primarily on biomicroscopic
observations. Other diagnostic studies may be used to help
establish the diagnosis of macula hole, although the bio-
microscopic appearance remains the primary means of
diagnosis. Fluorescein angiography may show focal hyper-
fluorescence in stage 1 and stage 2 holes.34 However, a similar
pattern may be present in lesions mimicking macular holes,
such as epiretinal membrane with pseudohole. B-scan ultra-
sonography is an excellent means of imaging the posterior
vitreous hyaloid and may help determine the presence of
persistent vitreous attachment to the macula.14,37,38 It is rarely
utilized to determine the presence of macular hole in clinical
practice and except for the determination of posterior vitreous
detachment, is not useful for staging macular holes.
Ocular coherence tomography (OCT) is a medical imaging
technology that has improved the imaging of both the
neurosensory retina and vitreoretinal interface.39 OCT has
especially improved visualization of very shallow detachments
of the posterior hyaloid over the macula. Even with contact lens
biomicroscopy this shallow detachment over the parafovea and
macula is most often imperceptible. Information gained from
OCT evaluation of macular hole formation in evolution has
provided new understandings of the sequence of events leading
from vitreofoveal traction to full-thickness macular hole
formation. Gaudric et al40 utilized OCT to study eyes with
macular holes as well at the fellow eyes to detect the initial
Idiopathic Macular Hole
FIGURE 155.4. (a) Color fundus photograph of
a stage 3 hole. This hole is at least 400 mm in
diameter and has an overlying pseudo-
operculum. (b) Optical coherence tomography
of stage 3 hole. In comparison to Figure 155.3b,
the operculum is clearly detached form the
retina surface and attached to the posterior
vitreous.
stages of vitreous separation. They were able to demonstrate
initial stages of vitreous separation in the peripheral portions of
the macula which then spread throughout the macula with the
hyaloid remaining focally adherent to the foveola and the optic
disk. A distinct convexity was observed, suggesting antero-
posterior traction from the vitreous (Figs 155.2b, 155.3b, 155.4b,
CHAPTER 155
and 155.6). Other investigators have confirmed the ability of OCT
to detect the perifoveal vitreous detachment.41,42,43
Johnson and co-workers44 utilized B-scan ultrasonography
and vitreoretinal surgical observations of eyes with stage 1 or
stage 2 macular holes. They demonstrated the presence of a
shallow, localized detachment of perifoveal vitreous typically
extending to the temporal vascular arcades, supporting the
findings of Gaudric. The elegant findings of investigators using
OCT40–42 and B-scan ultrasonography14,44 suggest a modified
theory of macular hole pathogenesis implicating age-related
posterior vitreous detachment beginning in the perifoveal region
with abnormally strong persistent vitreofoveal adherence. This
theory implicates anteroposterior traction, not the tangential
traction as suggested by Gass.34,36,45 Smiddy and Flynn46
present a unifying theory incorporating observations of early
cystic degeneration, attempted wound healing by Müller and
glial cells creating tangential traction, and later anteroposterior
traction as clearly seen in OCT imaging. They suggest that it is
possible that the weakened or dehisced central fovea may be a
primary event, followed by attempted repair by focal pro-
liferation of Müller and glial cells, and persistent anteropos-
terior traction at the foveola finally resulting in an irreversible
development of full-thickness hole.
Staging systems utilizing the observations from OCT have
been developed. These generally retain the Gass biomicroscopic
stages 1A/1B through four as a basis.47
NATURAL HISTORY
There is a wide range of variation in the stated progression of
pre-hole (stage 1 or macular ‘cyst’) lesions to full-thickness hole
formation. The Vitrectomy for Prevention of Macular Hole
Study Group48 reported that 40% of eyes with stage 1 lesions
randomized to observation progressed to full-thickness macular
hole over 2 years. This occurred in an average time of 4.1
months after diagnosis. Other studies are mostly small and
retrospective. Rates of progression from premacular hole lesions
to full-thickness holes range from ~10 to 70%.35,36,48,49
Generally, spontaneous resolution of stage 1 lesions is asso-
ciated with a vitreofoveal separation with foveal reattachment
and a normal biomicroscopic appearance, or may demonstrate
an inner lamellar hole.36
Visual symptoms in stage 1 or early stage 2 lesions include
metamorphopsia and reduced visual acuity. The visual acuity of
eyes with stage 1 macular holes may help to predict the
progression to full-thickness hole formation. The visual acuity
of most stage 1 lesions ranges from 20/25 to 20/80. In one
retrospective series, if the visual acuity was 20/40 or better, 23%
progressed to a macular hole within 2 years, whereas, if the 2031
 SECTION 3 RETINA AND VITREOUS

FIGURE 155.6. Schematic diagram of macular hole formation based on

optical coherence tomography observations.
Reproduced from Gaudric A, Haouchine B, Massin P: Macular hole
formation. New data provided by optical coherent tomography. Arch
Ophthalmol 1999; 117:744–751.

visual acuity was 20/50 or worse, 89% progressed to macular
hole.19 The Vitrectomy for Prevention of Macular Hole Study
Group similarly found that stage 1 macular holes with best-
corrected visual acuity of 20/50 to 20/80 had a 66% rate of
progression, while eyes with best-corrected visual acuity of
20/25 to 20/40 had a 30% risk of progression to full-thickness
macular hole.48
The majority of stage 2 holes continue to progress to stage 3
or stage 4 holes.50,51 Stage 3 macular holes have central visual
acuity loss to the 20/80 to 20/200 level.51 There is a strong co-
relation between macular hole diameter and visual acuity.51,52
Similarly, the hole diameter (and visual acuity) is closely
correlated to duration of symptoms.
is an epiretinal membrane and pseudohole.53 Also simulating a
full-thickness macular hole may be a lamellar macular hole54 or
chronic cystic macular edema.
Premacular hole lesions are often misdiagnosed. Gass
and Joondeph55 reported that only one of 18 patients referred
with a diagnosis of stage 1 lesion actually had such a
lesion. The other misdiagnosed lesions included aborted
macular hole, stage 2 holes, stage 3 holes, and unrelated
lesions. Other lesions simulating a ‘pre-hole’ lesion may
include central serous chorioretinopathy with a central yellow
spot,55 the early yellow lesion of solar retinopathy,55 a central
druse in age-related macular degeneration,55 or a pseudo-
operculum.56

DIFFERENTIAL DIAGNOSIS MANAGEMENT OF MACULAR HOLES

Because of the preservation of peripheral vision and the relative
Key Features rarity of bilateral central visual loss, some have questioned the
• Full Thickness Hole necessity for surgical intervention for repair of macular holes.57
• Epiretinal membrane and pseudohole However, the improvements in surgical techniques and results
• Lamellar hole and a concomitant decrease in overall surgical complications of
• Cystic macular edema vitreoretinal surgery have led most vitreoretinal surgeons to
• Central serous chorioretinopathy with central yellow spot readily recommend surgical repair for affected eyes. Most retina
• Solar retinopathy specialists now recommend surgery for symptomatic stage 2, 3,
• Macular druse or 4 macular holes of limited duration with visual acuity of at
• Pseudo-operculum least 20/50 or worse.
Appreciating the role of vitreomacular traction in macular
hole formation led to the first attempts at macular hole repair
Several lesions may simulate a full-thickness macular hole or a through pars plana vitrectomy surgery. In 1991, Kelly and
precursor macular hole lesion (stage 1a or 1b). The most Wendel reported on pars plana vitrectomy, removal of the
2032 common lesion to be mistaken for a full-thickness macular hole posterior cortical vitreous, and strict facedown positioning after

gas–fluid exchange for repair of macular hole.1 The original
technique of Kelly and Wendel remains the basis of surgical
technique today.
The critical component of the surgical repair macular holes is
the induction of a posterior vitreous detachment (Fig. 155.7).
This is confirmed intraoperatively by the identification of a
Weiss ring and the visualization of the more opaque posterior
cortical vitreous face of the vitreous. The posterior cortical
vitreous may be identified with the use of a soft silicone
extrusion cannula. With gentle aspiration, the silicone tip will
engage the posterior cortical vitreous and induce a bend in the
tip similar to a ‘fish-strike’ on a fishing line.1 Many surgeons
simply use the vitrectomy cutting instrument on aspiration
mode to engage and elevate the posterior cortical vitreous, prior
to carefully completing the vitrectomy to the vitreous base.
Epiretinal membranes are then generally excised using a barbed
microvitreoretinal blade, diamond-dusted silicone scraper
and/or fine intraocular forceps. Indirect ophthalmoscopy of the
retina is performed to carefully inspect for iatrogenic retinal
tears, most often associated with the process of vitreous
separation.58 A fluid–air exchange is performed, followed by a
second fluid aspiration at least 10 min after the initial fluid–air
exchange. The second aspiration allows for removal of the
preretinal fluid accumulating from the residual vitreous skirt,
ciliary body, and anterior-segment structures.59 The air is then
exchanged with a longer acting, nonexpansile concentration of
gas. Face-down positioning is required postoperatively to
provide maximum tamponade of the gas upon the surface of the
macula and to stimulate closure of the macular hole.
In the initial report of successful macular hole surgery by
Kelly and Wendel, 58% of the holes were successfully closed and
a b
d e
Idiopathic Macular Hole
visual acuity improvement by two or more lines occurred in
42% (73% of anatomically successful eyes). In a second report,
Wendel and co-authors reported improved success with 73%
anatomic success and 55% improvement by two or more lines.60
The authors noted greater success in holes present for less than
6 months. The greater success with holes present for shorter
duration has been confirmed by a number of other authors.61,62
Most reports of visual and anatomic results are small and
uncontrolled. The definitions of anatomic and visual success
differ among the many reports. Two multicenter, randomized
clinical trials provide information regarding success rates. Kim
and colleagues reported the results of surgery for stage 2
macular holes.63 There was no statistically significant difference
in ETDRS chart visual acuity between the surgical and observed
groups. However, the Bailey–Love word-reading test did show a
significant difference between the two groups (20/78 vs 20/135,
P = 0.006).
In a second report from the Vitrectomy for Treatment of
CHAPTER 155
Macular Hole Study Group, Freeman and colleagues reported
the results of surgery versus observation for stages 3 and 4
macular holes.64 They report a 69% closure rate, as compared
with a 2% spontaneous closure rate in the observation group.
The surgically repaired eyes had a statistically significant better
visual acuity at 6 months, both by ETDRS chart testing (20/115
versus. 20/166, P ≤ 0.004) and by Bailey–Love word-reading test
(20/155 vs 20/166, P=<0.01).
A 2 year randomized clinical trial from Moorefields Eye
Hospital compared surgery to observation for full-thickness
macular holes of less than or equal to 9 months duration.65
They additionally compared whether the addition of autologous
serum improved results in the surgical arm. They reported an
c
FIGURE 155.7. Basic steps in vitrectomy
surgery for macular hole. (a) Engagement of
posterior cortical vitreous (CV) with a soft-
tipped extrusion cannula during active
aspiration – ‘the fish-strike sign’. (b) Stripping
of the CV. (c) Completion of the posterior
vitrectomy with the vitreous cutter. (d) Fluid–air
exchange. (e) Completion of fluid–air exchange
with removal of fluid over the optic nerve.
(a–e) Glaser BM, Michels RG, Kupprman BD,
et al: Transforming growth factor-b2 for the
treatment of full-thickness macular holes. A
prospective randomized study. Ophthalmology
1992; 99:1162–1173. Courtesy of
Ophthalmology
2033
 RETINA AND VITREOUS
11.5% spontaneous closure rate with little or no visual acuity
change of those eyes at 24 months. The surgical group had an
overall closure rate of 80.6%, with 45% of eyes achieving a
visual acuity of 20/40 or greater. Autologous serum did not
affect the anatomic or visual results.
CONTROVERSIES IN MACULAR HOLE
REPAIR SURGERY
SURGICAL ADJUVANTS
Most surgeons do not currently use adjuvant agents in the
surgical repair of macular holes. Such adjuvants are generally
applied to the surface of the macular hole at the conclusion of
vitrectomy surgery and fluid–air exchange and still require face-
down positioning after an initial period of prone positioning.
Glaser et al reported initial success with intravitreal trans-
forming growth factor beta (TGF-b) derived from bovine bone
SECTION 3
with higher anatomic closure rate compared with placebo.66
However TGF-b derived from recombinant DNA did not result
in similar success.67
Other blood-derived adjuvants, such as autologous
serum,65,68 autologous concentrated platelets,69 and whole
blood70 have also been utilized. Randomized clinical trials using
autologous serum have not demonstrated improved closure
rates or visual results.65,68 Similarly, platelet concentrates and
whole blood have not proven effective in clinical trials.
INTERNAL LIMITING MEMBRANE PEEL
Currently, the greatest controversy in surgical technique for
macular hole is the role of internal limiting membrane (ILM)
peeling. The necessity, preferred technique, and potential
complications, including toxicity of adjuvant agents are far from
definitively established.
Techniques for removal of the ILM involve establishing an
elevated edge of the ILM and then peeling the ILM from around
the macular hole. Establishing an initial edge may be accom-
plished with the use of a barbed microvitreoretinal blade71 or
with the use of fine intraocular end-grasping forceps to ‘pinch’
and elevate the ILM.72 The ILM peel is most often performed
in a circular motion around the hole (‘maculorhexis’) (Fig.
155.8).73
Removal of the ILM appears to increase the rate of macular
hole closure and perhaps improve the final visual acuity.
FIGURE 155.8. Peeling the internal limiting membrane with forceps in
a circular fashion around the macular hole – ‘macculorhexis’.
Reproduced from Sjaarda RN Thompson JT: Macular hole. In: Ryan SJ,
2034 Wilkinson CP, eds. Retina. 4th edn. Elsevier Moseby; 2006.
Closure rates as high as 88–100% have been reported.71–75 How-
ever, no prospective, randomized trials have been performed to
compare standard procedures with and without ILM peeling. A
retrospective comparative study of hole closure rate and
postoperative visual acuities did not demonstrate a statistical
difference in outcomes.76
The identification and peeling of the ILM is technically
challenging. Adjuvants to improve visualization of the ILM
include indocyanine green dye (ICG), trypan blue dye, and
triamcinolone acetonide.
Indocyanine green dye is instilled onto the surface of the
retina in an air-or fluid-filled eye. The ICG selectively stains the
ILM, and the ILM may be more easily identified and elevated
with the use of diamond-dusted silicone cannula or with fine
end-grasping forceps (Fig. 155.9). Retinal and retinal pigment
epithelial toxicity77–79 have been reported and questions have
arisen about potentially diminished visual acuity in eyes
exposed to intravitreal ICG dye.80 Others report excellent
results with the use of adjunctive-ICG without evidence of
toxicity.81 No randomized, prospective trials have been
performed.
Trypan blue stains both the ILM and epiretinal membranes.
The staining of the ILM is less intense than the staining
achieved with ICG.82,83 There have been no reports of toxicity
associated with trypan blue.
Triamcinolone acetonide can be injected intraoperatively
onto the surface of the macula. While it does not stain the
internal membrane, it adheres to the surface and may facilitate
identification of the ILM.84,85
DURATION OF FACE-DOWN POSITIONING
Currently most vitreoretinal surgeons recommend strict face-
down positioning for at least 1 week postoperatively. Comp-
liance with positioning seems to increase the success rates of
hole closure.60 Studies of decreased duration suggest that
successful closure of holes can occur with 0–4 days of
positioning.86,87 The shorter duration of positioning depends on
FIGURE 155.9. Intraoperative photograph of peeling of the internal
limiting membrane after staining with indocyanine green dye.
Photograph courtesy of Mathew W MacCumber, MD, PhD.
 Idiopathic Macular Hole

a very complete vitreous removal in a pseudophakic eye and ment (1–5% in most reports, but up to 14% reported).74–76,87,93,95
successful ILM peeling.87 Postoperative retinal detachments are most typically inferiorly
The use of silicone oil for postoperative tamponade has been located and associated with small retinal tears at the vitreous
advocated for patients unable to position. The visual acuity and base. Visual-field loss (up to 20%),96,97 may be due to excessive
closure rates are better among eyes undergoing surgery with gas infusion pressures and retinal dehydration during fluid–air
tamponade compared with silicone oil.88,89 exchange.98,99 Elevated intraocular pressures are common after
vitrectomy surgery with intraocular gas infusions100 and angle
closure in the unoperated eye during face-down positioning has
COMPLICATIONS OF MACULAR HOLE been reported.101
SURGERY
SUMMARY
Key Features
• Iatrogenic retinal tears Full-thickness macular holes are most often unilateral, age-
• Retinal detachment related, and idiopathic. Visual symptoms include central
• Cataract metamorphopsia and reduced visual acuity. Improved under-
• Visual-field defect standing of the pathophysiology of macular holes has occurred
• Ocular hypertension through careful biomicroscopic observations and through the
improved visualization of the vitreoretinal interface provided by

• Endophthalmitis
• Angle-closure glaucoma
The most common complication of macular hole surgery is
cataract formation.90,91,92 Phakic patients undergoing macular
hole surgery should be advised that cataract extraction surgery
will likely be required within 1–2 years after macular hole
surgery. Other surgical complications include intraoperative
iatrogenic retinal tears (3–17%),74,93,94 postoperative retinal detach-
CHAPTER 155
OCT. Vitreoretinal surgical techniques continue to evolve, and
there remain questions as to the best surgical approach to
macular holes. However, surgery most often results in suc-
cessful closure of the macular hole and improvement of visual
function. Vision-targeted health status questionnaires demon-
strate that successful macular hole closure is associated with
significant improvement in patients’ vision-related quality of
life, even when there is only modest improvement in visual
acuity.102

REFERENCES
1. Kelly NE, Wendel RT: Vitreous surgery for
idiopathic macular holes: results of a pilot
trial. Arch Ophthalmol 1991; 109:654–659.
2. Knapp H: Ueber isolerte zerreissungen der
aderhaut in folge von traumen auf dem
augapfel. Arch Augenklinik 1869; 1:6–29.
3. Vendantham V: Optical coherence
tomography findings in macular hole due to
argon laser burn. Arch Ophthalmol 2006;
124(2):287–288.
4. Cohen SM, Gass JDM: Macular hole
formation following severe hypertensive
retinopathy. Arch Ophthalmol 1994;
112:878–879.
5. Amemiya T, Yoshida H: Macular hole in
diabetic maculopathy. Ophthalmologica
1978; 177:188–191.
6. Brown GC: Macular hole following
rhegmatogenous retinal detachment repair.
Arch Ophthalmol 1988; 106:765–766.
7. Runge PE, Wyhinny GJ: Macular hole
secondary to pneumatic retinopexy: case
report. Arch Ophthalmol 1988; 106:586–587.
8. Campo RV, Lewis RS: Lightening-induced
macular hole. Am J Ophthlamol 1984;
97:792–794.
9. Chavanne H: Pseudo–trou maculaire par
electrocution. Bull Soc Ophthalmol Fr 1958;
271–275.
10. Risk factors for idiopathic macular holes.
The Eye Disease Case–Control Study
Group. Am J Ophthalmol 1994;
118:754–761.
11. Lalin SC, Chang S, Flynn H, et al: Familial
idiopathic macular holes. Am J Ophthalmol
2004; 138:608–611.
12. Ezra E, Wells JA, Gray RH, et al: Incidence
of idiopathic full-thickness macular holes in
fellow eyes. A 5-year prospective natural
history study. Ophthalmology 1998;
105:353–359.
13. Lewis ML, Cohen SM, Smiddy WE, Gass
JD: Bilaterality of idiopathic macular holes.
Graefes Arch Clin Exp Ophthalmol 1996;
234:241–245.
14. Fisher YL, Slakter JS, Yannuzzi LA, Guyer
DR: A prospective natural history study and
kinetic ultrasound evaluation of idiopathic
macular holes. Ophthalmology
1994;101:5–11.
15. Guyer DR, de Bustros S, Diener–West M,
Fine SL: Observations on patients with
idiopathic macular holes and cysts. Arch
Ophthalmol 1992; 110:1264–1268.
16. Akiba J, Quiroz MA, Trempe L: Role of
posterior vitreous detachment in idiopathic
macular holes. Ophthalmology 1990;
97:1610–1613.
17. Niwa H, Tersasaki H, Ito Y, Mikake Y:
Macular hole development in fellow eyes
with unilateral macular hole. Am J
Ophthalmol 2005; 140:370–375.
18. Kipp CJ: Macular holes: a clinical
contribution. Tran Am Ophthalmol Soc
1908; 11:518–528.
19. McDonnell PJ, Fine SL, Hillis AI: Clinical
features of idiopathic macular cysts and
holes. Am J Ophthalmol 1982; 93:777–786.
20. Fuchs E: Zur veranderung der macula lutea
nach contusion. Ztschr Augenheilk 1901;
6:181–186.
21. Coats G: The pathology of macular holes.
Roy London Hosp Report 1907; 17:69–96.
22. Kuhnt H: Ueber eine eigenthumliche
Veranderung der Netzhaut as maculam
(retinitis atrophicans sive rareficans
centralis). Z Augneheilk 1900; 3:105–112.
23. Tower P: Observations on hole in the
macula. Ophthalmologica 1954;
40(suppl):1–60.
24. Aaberg TM, Blair CJ, Gass JDM: Macular
holes. Amer J Ophthalmol 1970;
69:640–650.
25. Lister W: Holes in the retina and their
clinical significance. Br J Ophthalmol 1924;
8:1–20.
26. Aaberg TM: Macular holes: A review. Surv
Ophthalmol 1970; 15:139–162.
27. Reese AB, Jones IS, Cooper WC: Macular
changes secondary to vitreous traction. Am
J Ophthalmol 1967; 64:544–549.
28. Aaberg TM, Blair CJ, Gass JDM:
Macular holes. Am J Ophthalmol 1970;
69:555–562.
29. Yoshioka H: Clinical studies on macular
holes. III. On the pathogenesis of the senile
macular hole. Acta Soc Ophthalmol Jpn
1968; 72:575–584.
30. Jaffe, NS: Vitreous traction at the posterior
pole of the fundus due to alterations in the
vitreous posterior. Tran Am Acad
Ophthalmol Otolaryngol 1967; 71:642–652.
31. Avila MP, Jalkh AE, Murakami K, et al:
Biomicroscopic study of the vitreous in
macular breaks. Ophthalmol 1983;
90:1277–1283.
32. Akiba J, Quiroz MA, Trempe CL: Role of the
posterior vitreous detachment in idiopathic
macular holes. Ophthalmology 1990;
97:1610–1613.
33. McDonnell PJ, Fine SL, Hillis AI: Clinical
features of idiopathic macular cysts and
holes. Am J Ophthalmol 1982; 93:777–786.
34. Gass JDM: Idiopathic senile macular hole.
Its early stages and pathogenesis. Arch
Ophthalmol 1988; 106:629–639.
35. Johnson RN, Gass JDM: Idiopathic
macular holes. Observations, stages of
formation, and implications for surgical
intervention. Ophthalmology 1988;
95:917–924.
36. Gass JDM: Reappraisal of biomicroscopic
classification of stages of development of a
macular hole. Am J Ophthalmol 1995;
119:752–759.
37. Dagel PU, Smiddy WE, Byrnes SF et al:
Macular hole syndromes: echographic
findings with clinical correlation.
Ophthalmology 1994; 101:815–821. 2035
 RETINA AND VITREOUS
38. Glacet–Bernard A, Zourdani A, Perrenoud F,
et al: Stage 3 macular hole: role of optical
coherence tomography and B-scan
ultrasonography. Am J Ophthalmol 2005;
139:814–819.
39. Hee MR, Puliafito CA, Wong C et al:
Optical coherence tomography of macular
holes. Ophthalmology 1995; 102:748–756.
40. Gaudric A, Haouchine B, Massin P, et al:
Macular hole formation. New data provided
by optical coherent tomography. Arch
Ophthalmol 1999; 117:744–751.
41. Chauhan DS, Antcliff RJ, Rai PA, et al:
Papillofoveal traction in macular hole
formation: the role of optical coherence
tomography. Arch Ophthalmol 2000;
118:32–38.
42. Mori K, Abe T, Yoneya S: Dome shaped
detachment pf premacular vitreous cortex
in macular hole development. Ophthalmic
Surg Lasers 2000; 31:203–209.
SECTION 3
43. Chan A, Duker JS, Schuman JS, Fujimoto
JG: Stage 0 macular holes. Observations
by optical coherence tomography.
Ophthalmology 2004; 111:2027–2032.
44. Johnson MW, Van Newkirk MR, Meyer KA:
Perifoveal vitreous detachment is the
primary pathogenic event in idiopathic
macular hole formation. Arch Ophthalmol
2001; 119:215–222.
45. Gass JDM: Müller cell cone, an overlooked
part of the anatomy of the fovea centralis:
hypotheses concerning its role in the
pathogenesis of macular hole and
foveomacular retinoschisis. Arch
Ophthalmol 1999; 117:821–823.
46. Smiddy WE, Flynn HW Jr: Pathogenesis of
macular holes and therapeutic implications.
Am J Ophthalmol 2004; 137:525–537.
47. Altaweel M, Ip M: Macular hole: improved
understanding of pathogenesis, staging,
and management based on optical
coherence tomography. Sem Ophthalmol
2003; 18:58–66.
48.De Bustros S: Vitrectomy for prevention of
macular holes. Results of a randomized
multicenter clinical trial. Vitrectomy for
prevention of macular hole study group.
Ophthalmology 1994; 101:105–1059.
49. Guyer DR, de Bustros S, Diener–West M,
Fine SL: The natural history of idiopathic
holes and cysts. Arch Ophthalmol 1992;
110:1264–1268.
50. Hickichi T, Toshida A, Akiba J, et al:
Prognosis of stage 2 macular holes. Am J
Ophthalmol 1995; 119:571–575.
51. Kim JW, Freeman WR, Azen SP, et al:
Prospective randomized trial of vitrectomy
or observation for stage 2 macular holes.
Am J Ophthalmol 1996; 121:605–614.
52. Sjaarda RN, Frank DA, Glaser BM, et al:
Assessment of vision in idiopathic macular
hole with macular microperimetry using the
scanning laser ophthalmoscope.
Ophthalmology 1993; 100:1513–1518.
53. Allen AW, Gass JDM: Contraction of a
perifoveal epiretinal membrane simulating a
macular hole. Am J Ophthalmol 1976;
82:684–691.
54. Smiddy WE, Gass JDM: Masquerades of
macular holes. Ophthalmic Surg 1995;
26:16–24.
55.Gass JDM, Joondeph BC: Observations
concerning patients with suspected
impending macular holes. Am J
Ophthalmol 1990; 109:638–646.
56. Gass JDM, VanNewkirk M: Xanthic
2036 scotoma and yellow foveolar shadow
caused by a pseudo–operculum after
vitreofoveal separation. Retina 1992;
12:242–244.
57. Fine SL: Vitreous surgery for macular hole
in perspective. Is there an indication?
(Editorial). Arch Ophthalmol 1991;
109:635–636.
58. Sjaarda RN, Glaser BM, Thompson JT,
et al: Distribution of iatrogenic retinal
breaks in macular hole surgery.
Ophthalmology 1995; 102:1387–1392.
59. Rubin JS, Thompson JT, Sjaarda RN, et al:
Efficacy of fluid–air exchange during pars
plana vitrectomy. Retina 1995; 15:291–294.
60. Wendel RT, Patel AC, Kelly NA et al:
Vitreous surgery for macular holes.
Ophthalmology 1993; 100:1671–1676.
61. Thompson JT, Sjaarda RN, Lansing MB:
The results of vitreous surgery for chronic
macular holes. Retina 1997; 17:493–501.
62. Willis AW, Garcia–Cosio JF: Macular hole
surgery. Comparison of longstanding
versus recent macular holes.
Ophthalmology 1996; 103:1811–1114.
63. Kim JW, Freeman WR, Azen SP et al:
Prospective randomized trial of vitrectomy
or observation for stage 2 macular holes.
Vitrectomy for Macular Hole Study Group.
Am J Ophthalmol 1996; 121:605–614.
64. Freeman WR, Azen SP, Kim JW, et al:
Vitrectomy for treatment of full- thickness
stage 3 or 4 macular holes. Results of a
multicenter randomized clinical trial. The
Vitrectomy for Treatment of Macular Hole
Study Group. Arch Ophthalmol 1997;
115:11–21.
65. Ezra E, Gregor ZJ for the Moorefields
Macular Hole Surgery Group: Surgery for
idiopathic full-thickness macular hole. Two-
year results of a randomized clinical trial
comparing natural history, vitrectomy, and
vitrectomy plus autologous serum:
Moorefields Macular Hole Study Group
Report No. 1. Arch Ophthalmol 2004;
122:224–236.
66. Smiddy WE, Glaser BM, Thompson JT,
et al: Transforming growth factor-beta 2
significantly enhances the ability to flatten
the rim of subretinal fluid surrounding
macular holes: preliminary results of a
multicenter prospective randomized study.
Retina 1993; 13:296–301.
67. Thompson JT, Smiddy WS, William GA,
et al: Comparison of recombinant
transforming growth factor beta-2 and
placebo as an adjuvant for macular hole
surgery. Ophthalmology 1998;
105:700–706.
68. Banker AS, Freeman WR, Azen SP, et al:
A multicentered clinical study of serum as
adjuvant therapy for surgical treatment of
macular holes. Vitrectomy for Macular Hole
Study Group. Arch Ophthalmol 1999;
117:1499–1502.
69. Paques M, Chastang C, Mathis A, et al:
Effect of autologous platelet concentrate in
surgery for idiopathic macular hole: results
of a multicenter, double-masked,
randomized trial. Platelets in macular hole
surgery group. Ophthalmology
1999;106:932–938.
70. Hoerauf H, Kluter H, Joachimmeyer E,
et al: Results of vitrectomy and the no-
touch-technique using autologous
adjuvants in macular hole treatment. Int
Ophthalmol 2001; 24: 151–159.
71. Brooks HL Jr: Macular hole surgery with
and without internal limiting membrane
peeling. Ophthalmology 2000;
107:1939–1949.
72. Smiddy WE, Feuer W, Cordahi G: Internal
limiting membrane peeling in macular hole
surgery. Ophthalmology 2001;
108:1471–1478.
73. Mester V, Kuhn F: Internal limiting
membrane removal in the management of
full-thickness macular holes. Am J
Ophthalmol 2000; 129:769–777.
74. Park DW, Sipperly JO, Sneed SR, et al:
Macular hole surgery with internal-limiting
membrane peeling and intravitreous air.
Ophthalmology 1999; 106:1392–1397.
75. Olsen TW, Sternberg P Jr, Capone A Jr,
et al: Macular hole surgery using thrombin-
activated fibrinogen and selective removal
of the internal limiting membrane. Retina
1998; 18:322–329.
76. Margherio RR, Margherio AR, Williams GA,
et al: Effect of perifoveal tissue dissection
in the management of acute idiopathic full-
thickness macular holes. Arch Ophthalmol
2000; 118:495–498.
77. Sippy BD, Englebrecht NE, Hubbard GB,
et al: Indocyanine green effect on cultured
human retinal pigment epithelial cells :
implications for macular hole surgery. Am J
Ophthalmol 2001; 132:433–435.
78. Gandorfer A, Haritoglou C, Kampic A:
Retinal damage from indocyanine green in
experimental macular surgery. Invest
Ophthalmol Vis Sci 2003; 44:316–323.
79. Haritoglou C, Gandorfer A, Gass CA, et al:
Indocyanine green-assisted peeling of the
internal limiting membrane in macular hole
surgery affects visual outcome: a
clinicopathologic correlation. Am J
Ophthalmol 2002; 134:836–841.
80. Gass CA, Haritoglou C, Schaumberger M,
Kampic A: Functional outcomes of macular
hole surgery with and without indocyanine
green-assisted peeling of the internal
limiting membranes. Graefes Arch Clin Exp
Ophthalmol 2003: 241:716–720.
81. Da Mata AP, Burk SE, Foster RE, et al:
Long-term follow-up of indocyanine green
assisted peeling of the retinal internal
limiting membrane during vitrectomy
surgery for idiopathic macular hole repair.
Ophthalmology 2004; 111:2246–2253.
82. Li K, Wong D, Hiscott P, et al: Trypan blue
staining of internal limiting membrane and
epiretinal membrane during vitrectomy:
visual results and histopathological findings.
Br J Ophthalmol 2003; 87:216–219.
83. Azad RV, Pal N, Vashisht N, et al: Efficacy
of 0.15% trypan blue for staining and
removal of the internal limiting membrane,
epiretinal membranes, and the posterior
hyaloid during pars plana vitrectomy.
Retina 2005; 25:676.
84. Horio N, Horiguchi M, Yamamoto N:
Triamcinolone-assisted internal limiting
membrane peeling during idiopathic
macular hole surgery. Arch Ophthalmol
2005; 123:96–99.
85. Shah GV, Rosenblatt BJ, Blinder KJ, et al:
Triamcinolone-assisted internal membrane
peeling. Retina 2005; 25:972–975.
86. Krohn J: Duration of face-down positioning
after macular hole surgery; a comparison
between 1 week and 3 days. Acta
Ophthalmol Scan 2005; 83:289–292.
87. Tornambe PE, Poliner L, Grote K: Macular
hole surgery without face-down
positioning: a pilot study. Retina 1997;
17:179–185.

88. Lai JC, Stinnett SS, McCuen BW:
Comparison of silicone oil versus gas
tamponade in the treatment of idiopathic
full-thickness macular holes.
Ophthalmology 2003; 110:1170–1174.
89. Couvillion SS, Smiddy WE, Flynn HW Jr,
et al: Outcomes of surgery for idiopathic
macular hole: a case-control study
comparing silicone oil with gas tamponade.
Ophthalmic Surg Lasers Imaging 2005;
36:365–371.
90. Leonard RE II, Smiddy WE, Flynn HW Jr,
Feuer W: Long–term visual outcomes in
patients with successful macular hole
surgery. Ophthalmology 1997;
104:1648–1652.
91. Cheng L, Azen SP, El-Bradley MH, et al:
Duration of vitrectomy and post-operative
cataract in the vitrectomy for macular hole
study. Am J Ophthalmol 2001;
132:881–887.
92. Thompson JT: The role of patient age and
intraocular gas use in cataract progression
after vitrectomy for macular holes and
epiretinal membranes. Am J Ophthalmol
2004; 137:250–257.
93. Banker AS, Freeman WR, Kim JW, et al:
Vision-threatening complications of surgery
for full-thickness macular holes. Vitrectomy
for macular hole study group.
Ophthalmology 1997; 104:1442–1452.
94. Sjaarda RN, Glaser BM, Thompson JT,
et al: Distribution of iatrogenic retinal
breaks in macular hole surgery.
Ophthalmology 1995; 102:1387–1392.
95. Park SS, Marcus DM, Duker JS, et al:
Posterior segment complications after
vitrectomy for macular hole.
Ophthalmology 1995; 102:775–781.
96. Pendergast SD, McCuen BW II: Visual field
loss after macular hole surgery.
Ophthalmology 1996; 103:1069–1077.
97. Boldt HC, Munden PM, Folk JC, Mehaffey
MG: Visual field defects after macular hole
surgery. Am J Ophthalmol 1996;
122:371–381.
Idiopathic Macular Hole
98. Welch JC: Dehydration injury as a possible
cause of visual defect after pars plana
vitrectomy for macular hole. Am J
Ophthalmol 1997; 124:698–699.
99. Hirata A, Yonemura N, Hasamura T, et al:
Effect of infusion pressure on visual field
defects after macular hole surgery. Am J
Ophthalmol 2000; 130:611–616.
100. Anderson NG, Fineman MS, Brown GC:
Incidence of intraocular pressure spike and
other adverse events after vitreoretinal
surgery. Ophthalmology 2006; 113:42–47.
101. Bansal A, Salmon JF, Malhotra R, et al:
Delayed acute angle closure after macular
hole surgery. Eye 2003; 17:779–781.
102. Tranos PG, Ghazi-Nouri SMS, Rubin GS, et
al: Visual function and subjective
perception of visual ability after macular
hole surgery. Am J Ophthalmol 2004;
138:995–1002.
CHAPTER 155
2037
 CHAPTER

156 Choroidal and Retinal Folds

Thomas R. Friberg and Jenny Y. Yu

INTRODUCTION
Folds of the choroid and retina are typically a sign of an ocular
disease or disorder. Choroidal folds develop secondary to
biomechanical stresses, for instance, from an extraocular mass
in the orbit pressing upon the globe, from thickening of the
choroid from hypotony, choroidal effusion, or inflammation, or
from stresses secondary to a growing choroidal tumor. Retinal
folds may be seen over tight choroidal folds but are more
typically a result of proliferation along the superficial retinal
layers, such as seen in macular pucker, proliferative retinopathy,
or in scarring from choroidal neovascularization (CNV). Both
choroidal and retinal folds can be seen upon biomicroscopy but
fluorescein angiography outlines choroidal folds most drama-
tically. Retinal folds, on the other hand, are well demonstrated
by optical coherence tomography (OCT) or on high-power
biomicroscopy. The clinical presence of choroidal or retinal
folds needs to be explained, as the underlying disease which
created them may need to be addressed. Both types of folds can
be symptomatic with retinal folds creating metamorphopsia.
This chapter details the biomechanical principles which create
chorioretinal folds so they can be better understood.
Many disorders are associated with the formation of folds
in the choroid and retina. For descriptive purposes, folds pri-
marily involving the choroid, with the overlying retina only
secondarily affected, are classified as choroidal folds, whereas
folds occurring exclusively within the layers of the sensory
retina are termed retinal folds (Fig. 156.1). Choroidal folds are
often a sign of orbital or ocular disease, but they may develop
after surgery on the eye or orbit or may occur idiopathically.1–6
Retinal folds found without the presence of choroidal folds
develop most commonly in macular pucker, but they can also be
present in association with uveitis, in response to certain
medications,7 and as a result of proliferative vitreoretinopathy.

CHOROIDAL FOLDS DESCRIPTION,

PATHOGENESIS, AND SYMPTOMS
Choroidal folds are undulations of the choroid, Bruch’s
membrane, and pigment epithelium, with the overlying retina
wrinkled to a lesser extent.1 They develop secondary to
mechanical stresses produced within these tissues. Because the
choroid consists of a plexus of randomly oriented blood vessels,
an interstitium of connective tissue, and multiple fluid-filled
spaces, it has intrinsic elasticity and sponginess. In addition,
Bruch’s membrane and the overlying retinal pigment epithe-
lium (RPE) are firmly bonded to the inner surface of choroid at
the choriocapillaris. This architecture is roughly analogous to
that of a sponge onto which a thin elastic sheet has been fused.
FIGURE 156.1. (Top) Retinal folds involve the superficial layers of the
retina and are usually secondary to tangential forces present on the
retinal surface. The underlying RPE (cuboidal cells) and choroid are
not characteristically folded. (Bottom) Choroidal folds are
characterized by undulations of the choroid, Bruch’s membrane, and
overlying retinal pigment epithelial layers. The sensory retina is folded
in the deeper layers, but these pleats do not extend completely to the
superficial layers. Hence, retinal vessels are typically not included in
the folding process.
2039
 RETINA AND VITREOUS
FIGURE 156.2. As an analogy, the formation of choroidal folds may
be compared with folds developing along the surface of a
compressed sponge onto which an elastic membrane has been glued.
The sponge represents the choroid, whereas the membrane
represents Bruch’s membrane and the RPE.
SECTION 10
When such a sponge is compressed, folds form along its surface
(Fig. 156.2). Analogously, if compressive forces of sufficient
magnitude are induced in the choroid, it will be forced into
pleats or folds, as will Bruch’s membrane, the pigment
epithelium, and the sensory retina. Hence, choroidal folds are a
manifestation of biomechanical stresses present within the
choroid, rather than being a sign of a particular disease.2
Symptoms of choroidal folds depend on the degree of folding
of the overlying retina, particularly at the fovea, and the amount
of induced refractive error associated with the development of
the choroidal folds. Retinal folds running through the fovea in
association with choroidal folds may cause metamorphopsia
and a reduction of visual acuity that cannot be eliminated by
corrective lenses. Since choroidal folds are commonly found
when the choroid is thickened or the globe has been flattened
posteriorly, axial hyperopia is typical. If the globe is deformed
more anteriorly from an intraorbital tumor, induced astigmatic
errors along with the hyperopia are common.8 Incidental equa-
torial folds created by encircling procedures to repair retinal
detachments do not cause distortion or refractive errors them-
selves, but the scleral buckle in this situation produces relative
myopia.
a b
FIGURE 156.3. (a) Fundus appearance of choroidal folds caused by an extraconal tumor located within the superior temporal quadrant of the
orbit. (b) On fluorescein angiography, the folds are much more dramatic, appearing as alternating light and dark streaks. Note that the retinal
vessels are not distorted by the underlying choroidal folds.
2040
On funduscopic examination, choroidal folds appear as alter-
nating dark and light streaks. Often, their appearance is subtle,
especially if the fundus is lightly pigmented and the folds have
not undergone any chronic changes. Choroidal folds are best
viewed clinically by indirect ophthalmoscopy, as the field of
view is usually large enough to allow observation of the entire
fold pattern.
Histopathologic sections through choroidal folds demon-
strate the reason for their striated appearance. Typically, Bruch’s
membrane and the RPE are tightly folded within the troughs of
the folds (as viewed from the vitreous), whereas at the crests,
the change in curvature is more gradual.4 Hence, the melano-
cytes within the choroid and the RPE are compressed into a
smaller-than-normal region in the troughs, whereas over the
crest of the folds, these cells are stretched apart. This change in
pigment density across the folds creates the alternating dark
and light striae seen clinically.
FLUORESCEIN ANGIOGRAPHY AND
CHOROIDAL FOLDS
Sodium fluorescein leaks quickly out of the fenestrations of the
choroidal vessels and stains the choroid. However, because the
RPE effectively filters out most of this potential background
choroidal fluorescence, the choroid appears gray rather than
white on angiography. In the troughs of the choroidal folds in
which the RPE cells are compressed, the RPE becomes a more
efficient filter. Conversely, when the choroid and RPE are
stretched, the concentration of melanin granules per unit area
is reduced. The net effect is that choroidal folds appear
dramatically as alternating dark and light striae on fluorescein
angiography (Fig. 156.3).9
OCT AND CHOROIDAL FOLDS
OCT is a relatively new imaging tool for the posterior segment
of the eye.10 Similar to ultrasound B-mode imaging, a cross-
sectional image is generated by measuring the backscattered or
backreflected light from the tissue within the eye. Based on
the optical properties of the underlying tissue, the layers of the
retina and choroid are distinguished. The choroid appears

a
darker in comparison to the highly reflective RPE above. The
cross-section image provided by OCT can easily detect the
undulating appearance of the RPE (Fig. 156.4). The elastic
properties of the choroid are different from those of the sensory
retina. Hence the retina can, to some degree, internally adjust
(creep) along the underlying choroidal folds. This is evident on
the OCT when the inner surface of the retina is only mildly
undulating as opposed to the folds at the level of the chorio-
capillaris, Bruchs membrane, and RPE. Used in conjunction
with fluorescein angiography, OCT can differentiate retinal
folds from choroidal folds in various retinal pathology involving
the macula and periphery.11
CHOROIDAL FOLDS AND SPECIFIC
DISORDERS
CHOROIDAL TUMORS AND CHOROIDAL
DETACHMENTS
When a choroidal tumor such as a melanoma, metastatic
carcinoma, or choroidal hemangioma grows, it compresses the
adjacent choroid and may force it into folds. In this instance,
Choroidal and Retinal Folds
FIGURE 156.4. (a) Fundus photo of the right
eye in a woman with hyperopia and idiopathic
choroidal folds. (b) Cross-sectional image with
false color through the posterior pole of the
same eye. The troughs and crests of the highly
reflective RPE layer indicate choroid folds in the
macula.
Courtesy of T Friberg, MD; UPMC Eye Center.
CHAPTER 156
folds develop parallel to the boundaries of the tumor (Fig. 156.5).
Similarly, choroidal folds may develop at the edge of large
choroidal detachments. The folds in these cases are not exten-
sive because only local compressive stresses are produced. Folds
typically do not form over the tumor surface, at which point the
choroid is stretched rather than compressed. Occasionally,
however, folds develop over regions of localized choroidal
hemorrhage.12
ORBITAL TUMORS
Intraconal Orbital Tumors
Tumors located within the muscle cone, such as cavernous
hemangiomas, metastatic neoplasms, and optic nerve meningio-
mas, can press on the globe posteriorly, producing exophthalmos,
flattening of the globe, and shifting of the refractive error toward
hyperopia.8 In addition, such a tumor often displaces the optic
nerve to one side, inducing stresses within the globe at the disk
(Fig. 156.5a). The choroid on one side of the optic nerve is com-
pressed, whereas, on the opposite side, the choroid is stretched,
often resulting in a parabolic fold pattern with the nerve head
located among the folds (Fig. 156.6).8
2041
 RETINA AND VITREOUS
a b
SECTION 10
a b
Extraconal Orbital Tumors
An extraconal tumor may press directly on the extraocular
muscles and Tenon’s capsule, as well as on the sclera. The
forces generated tend to buckle the wall of the globe (see Fig.
156.6b), creating choroidal folds. Because of anterior segment
distortion, astigmatic refractive errors are commonly induced.
With respect to the fold pattern, the convex side usually points
toward the posterior pole and optic nerve, but the nerve head is
usually located outside the region of folds (Fig. 156.7 and
156.8).8 Typical extraconal tumors associated with choroidal
folds include mucoceles, dermoids, tumors of the lacrimal
gland, and orbital meningiomas.
Orbital Tumors and the Pattern of Folds
Although historically the choroidal fold pattern was said to have
no relevance in localizing a tumor within the orbit,1 in fact the
pattern of folds often reflects the location of the orbital patho-
logic condition. The tumor is often located along the axis of
symmetry drawn through the pattern of choroidal folds.8 The
location as indicated by the folds is only approximate, however,
and must be corroborated by more sophisticated evaluations,
such as computed tomography or B-scan ultrasonography.
2042
FIGURE 156.5. (a) An expanding choroidal
tumor compresses the choroid along its
boundaries, forming folds parallel to the tumor’s
perimeter. (b) Folds seldom form over the tumor
surface because the choroid is stretched
uniformly over the mass, as seen in this vertical
cross-section.
FIGURE 156.6. (a) Intraconal orbital tumors
typically displace the optic nerve, compressing
the choroid in the direction of the nerve head
displacement, and placing the choroid under
tension on the opposite side. The result is a
choroidal fold pattern, the convex side of which
is directed away from the nerve head (arrow).
(b) Extraconal tumors buckle the wall of the
globe equatorially, producing a curvilinear fold
pattern with its convex side directed toward the
optic nerve.
(a and b) From Friberg TR: The etiology of choroidal
folds. Graefes Arch Clin Exp Ophthalmol 1989;
227:459–464.
DISORDERS OF THE OPTIC NERVE HEAD
As the optic nerve head swells, it expands centrifugally, com-
pressing the peripapillary choroid and often creating choroidal
folds concentric to the disk margins (Fig. 156.9). Thus, con-
centric folds are a sign of papilledema,13 disk edema, optic nerve
head drusen, or a tumor within the nerve head. In these cases,
the abnormality of the optic nerve is usually quite obvious,
whereas the folds themselves are subtle.
SCLERAL BUCKLING PROCEDURES
Encircling scleral buckling procedures are commonly associated
with choroidal striae (Fig. 156.10a,b). In this case, the folds are
confined to the vicinity of the buckle and are oriented perpen-
dicular to the plane of the encircling element. The encirclement
reduces the surface area available to the choroid, compressing
the tissue together within the plane of the buckling element. In
addition, radial buckling elements can also produce folds by
compression (Fig. 156.10c,d). Folds associated with retinal surgery
are typically prominent during the immediate postoperative
period and fade over time. Furthermore, choroidal folds caused
by buckling are smoothed out if the intraocular pressure rises.
 Choroidal and Retinal Folds

CHAPTER 156
c

b d

FIGURE 156.7. (a and b) An intraconal tumor (in this case, an orbital hemangioma) has displaced the left globe and optic nerve superiorly
(arrow), as seen in computed tomograms. (c) The associated choroidal folds are primarily located superior to the optic nerve, whereas some
folds radiate from the disk and extend into the macula. (d) A B-scan ultrasonogram demonstrates characteristic flattening of the posterior sclera.
(a–d) From Friberg TR, Grove AS: Choroidal folds and refractive errors associated with orbital tumors. An analysis. Arch Ophthalmol 1983; 101:598–603. Copyright
1983, American Medical Association.

CHORIORETINAL SCARS AND CNV hyperopia is secondary to the development of choroidal

Dense, fibrotic chorioretinal scars from trauma or intense
choroidal inflammation contract as the scar tissue matures.
Forces from this contraction pull on the surrounding choroid
and may produce folds directed radially toward the center of the
scar (Fig. 156.11). Scarring associated with CNV can also
produce radially oriented folds.14
FOLDS ASSOCIATED WITH CHOROIDAL
THICKENING
The choroid may thicken as a result of hypotony, inflammation,
the uveal effusion syndrome, or venostasis such as that found
after a central retinal vein occlusion. As its thickness increases,
the surface area available to the choriocapillaris, Bruch’s
membrane, and the RPE is reduced because the choroid must
expand inward toward the center of the eye, being confined
by the sclera. Ultimately, the choroid may be forced into
redundant folds (Fig. 156.12). Additionally, because the internal
diameter of the globe has been decreased, the refractive error
shifts toward hyperopia. It is important to remember that this
thickening and fold formation, rather than being the cause of
the folds.
HYPOTONY
Hypotony or low intraocular pressure results in radial expan-
sion of the choroid toward the vitreous cavity. Hypotony may
result from an obvious cause such as uveitis, trauma, or filtra-
tion surgery, particularly when 5-fluorouracil or mitomycin C
are used.15,16 Choroidal folds developing shortly after anterior
segment surgery suggest a wound leak or the presence of a
cyclodialysis cleft.
INFLAMMATION
Inflammatory diseases of the orbit and sclera such as Graves’
exophthalmopathy, orbital pseudotumors, and orbital myositis
can flatten the sclera and cause scleral and choroidal thick-
ening. Choroidal compression and choroidal fold formation
may be the result. In diseases such as inflammatory bowel
2043
 RETINA AND VITREOUS

a
SECTION 10

FIGURE 156.8. (a and b) Choroidal folds caused by an extraconal tumor (in this case, a meningioma) that has displaced the left globe inferiorly
and temporally as seen on computed tomography. (c) A curvilinear fold pattern typically associated with an extraconal tumor is seen on the
fluorescein angiogram, with the convex side of the pattern directed toward the optic nerve head. (d) A B-scan ultrasonogram shows equatorial
flattening of the sclera by the meningioma.
(a–d) From Friberg TR, Grove AS: Choroidal folds and refractive errors associated with orbital tumors. An analysis. Arch Ophthalmol 1983; 101:598–603. Copyright
1983, American Medical Association.

disease, the choroid itself may show signs of inflammation

and may develop folds from uveitis.17 Sometimes, serous
retinal detachments develop in association with the folds, pre-
senting a confusing picture. Successful treatment of the
inflammatory component will lead to resolution of the folds in
most cases.

UVEAL EFFUSION
Eyes with idiopathic choroidal folds and concomitant serous
detachments may appear similar to eyes with the uveal effusion
syndrome. Typically, this syndrome is characterized by poor
vision, a thickened or detached choroid and ciliary body, and an
extensive serous retinal detachment that dominates the clinical
appearance.18 In some cases, however, the choroid may be
thickened uniformly without a significant serous detachment,
and vision may be maintained. In these cases, choroidal folds
may be the first sign of an abnormality. Decompression of the
FIGURE 156.9. Swelling of the optic nerve from papilledema or tumor vortex veins and excision of scleral flaps has, in some severe
compresses the adjacent choroid, producing choroidal folds cases, led to resolution of the choroidal detachments and folds
concentric to the disk. with improvement of visual acuity.18,19
2044
 Choroidal and Retinal Folds

CHAPTER 156
a b

c d

FIGURE 156.10. (a) Choroidal folds secondary to an encircling scleral buckle. (b) The choroid is compressed in the x direction along the plane
of the buckle and stretched in the y direction, producing folds oriented perpendicular to the induced compressive stresses. (c) A radially placed
scleral buckle element produces choroidal folds by compressing the adjacent choroid. (d) The abrupt change in scleral contour (arrow), as seen
on cross-section, creates these compressive forces.
(a and b) From Friberg TR: The etiology of choroidal folds. Graefes Arch Clin Exp Ophthalmol 1989; 227:459–464.

IDIOPATHIC FOLDS
Choroidal folds may develop in one or both eyes of a patient
with no apparent ocular or orbital disorder. These patients are
usually male and often present with acquired hyperopia of 3 D
or less. Computed tomographic findings in these eyes may
show thickening of the sclera, flattening of the posterior pole,
enlargement of the optic nerve image, and the presence of a
space seen between the optic nerve and its meninges.20 Occa-
sionally, serous retinal detachments develop (Fig. 156.13).
Patients usually retain good vision, and in some individuals the
folds disappear spontaneously.17 The cause of these alterations
is unclear. Possibly, drainage through the choroidal venous
plexus and into the vortex veins is compromised from
structural alterations within the scleral wall. In other cases,
2045
 RETINA AND VITREOUS

posterior scleritis or other local inflammation may have initially

produced the folds, which then persist long after the inflam-
mation resolves. Alternatively, idiopathic choroidal folds and
acquired hyperopia have been described in intracranial
hypertension.14

IMPLICATIONS OF CHOROIDAL FOLDS

Choroidal folds are a sign of an ocular disorder or disease.
Hence, the major consideration when presented with a patient
with choroidal folds is to determine the cause of the folds. Of
particular importance is an investigation to rule out the possi-
bility of an orbital or choroidal tumor or intracranial hyper-
tension.21 B-scan ultrasonography and computed tomography
are usually indicated, particularly in patients with unexplained
unilateral folds.
If choroidal folds remain for months, the RPE in the troughs
may undergo hypertrophy and hyperplasia from being mech-
SECTION 10

anically compacted. Even if the folds resolve, this linear

pigmentation may persist. RPE atrophy and apparent fractures
FIGURE 156.11. A dense chorioretinal scar draws the surrounding
of Bruch’s membrane may also be seen along the folds, especially
choroid inward toward its center as the scar tissue matures and
contracts. Radially oriented folds are produced.

a b

FIGURE 156.12. (a) Fluorescein angiogram of choroidal folds associated with hypotony and secondary choroidal thickening. (b) In these cases,
the choroidal fold pattern is typically random, as the folds develop secondary to rather uniform swelling of the choroid.

a b c

FIGURE 156.13. (a) Fluorescein angiogram of the right eye in a woman with mild hyperopia and acquired chorioretinal folds. (b) There is leakage
of dye from the choriocapillaris, which pools within the fovea in the late-phase films. A serous retinal detachment is present overlying the area of
2046 leakage. (c) Left eye of the same patient. Fluorescein angiography shows randomly oriented folds and retinal pigment epithelial window defects
in the peripapillary region, at the fovea, and temporal to the macula.

c
FIGURE 156.14. (a–c) Retinal pigment epithelial clumping and atrophy (arrows) can occur along choroidal folds, making the folds appear similar
to atrophic angioid streaks, both on clinical examination and particularly on fluorescein angiography.
(a–c) From Friberg TR, Grove AS: Choroidal folds and refractive errors associated with orbital tumors. An analysis. Arch Ophthalmol 1983; 101:598–603. Copyright
1983, American Medical Association.
FIGURE 156.15. CNV may develop along choroidal folds, as
demonstrated by this trapezoidal choroidal neovascular net found
along a fold running through the macula. In this case, the choroidal
folds developed secondary to an orbital tumor.
From Friberg TR, Grove AS: Subretinal neovascularization and choroidal folds.
Ann Ophthalmol 1980; 12:245–250.
Choroidal and Retinal Folds
CHAPTER 156
in older patients (Fig. 156.14). Such changes also occur along
angioid streaks, which are sometimes confused with choroidal
folds.8 As with angioid streaks, CNV can develop along
choroidal folds (Fig. 156.15).22 If CNV develops, treatment
should be initiated using strategies commonly used for neo-
vascular age-related macular degeneration. Macular folds of the
choroid should therefore be eliminated, if possible, to help avoid
permanent visual loss.
Key Features
• Undulations of the choroid, Bruch’s membrane, and pigment
epithelium as a result of compressive stresses developing
along within the plane of the choroid. Dramatic patterns of
hypo- and hyperfluorescent streaks are often seen upon
fluorescein angiography.
• Can be associated with decreased vision and the development
of CNV.
RETINAL FOLDS
Retinal folds are commonly associated with epiretinal membrane
formation. Such membranes exert stress on the underlying
retina and promote wrinkle formation, leading to macular
pucker and symptoms of metamorphopsia. These cellophane-
like membranes can best be seen on careful biomicroscopy of
the fundus. Alternatively, in certain cases of rhegmatogenous 2047
retinal detachment, proliferative membranes grow along the
 RETINA AND VITREOUS

retinal surface, creating star folds and retinal striae. In both of the sulfonamides should promote resolution of the retinal
instances, surgical removal of the membranes may be necessary. folds in these cases.6
Shallow superficial retinal folds may develop when choroidal
folds are lacking whenever there is relative choroidal thickening,
particularly in association with uveal inflammation. Reduction Key Features
of the surface area available to the retina from the radial dis- • Most typically present secondary to epiretinal membrane
placement of the choroidal surface is a likely cause. Retinal formation
folds in conjunction with transient myopia may also be associ- • May show a radial pattern if secondary to scar formation from
ated with the administration of sulfonamides. In this case, macular degeneration
swelling of the ciliary body and vitreous traction may play a • May be associated with metamorphopsia
role.6 Elimination of the uveal inflammation or discontinuation

REFERENCES
1. Newell FW: Choroidal folds. Am J
Ophthalmol 1973; 75:930–942.
2. Friberg TR: The etiology of choroidal folds.
Graefes Arch Clin Exp Ophthalmol 1989;
SECTION 10
pressure. Am J Ophthalmol 2001; 17. Ernst BB, Lowder CY, Meisler DM,
131:158–159. Gutman FA: Posterior segment
10. Norton EWD: A characteristic fluorescein manifestations of inflammatory bowel
angiographic pattern in choroidal folds. disease. Ophthalmology 1991;

227:459–464. Proc R Soc Med 1969; 62:119–128. 98:1272–1280.

3. Cangemi FE, Trempe CL, Walsh JB:
Choroidal folds. Am J Ophthalmol 1978;
86:380–387.
4. Wolter JR: Parallel horizontal choroidal
folds secondary to an orbital tumor. Am J
Ophthalmol 1974; 77:669–673.
5. Bullock JD, Egbert PR: The origin of
choroidal folds: a clinical, histopathological
and experimental study. Doc Ophthalmol
1974; 37:261–293.
6. Hertle RW, Leahey AB, Bloom S, et al:
Chorioretinal folds and a macular hole
secondary to craniofacial surgery. Ophthal
Plast Reconstr Surg 1990; 6:278–282.
7. Ryan EH, Jampol LM: Drug-induced acute
transient myopia with retinal folds. Retina
1986; 6:220–223.
8. Friberg TR, Grove AS: Choroidal folds and
refractive errors associated with orbital
tumors. An analysis. Arch Ophthalmol
1983; 101:598–603.
9. Griebel SR, Kosmorsky GS: Choroidal folds
associated with increased intracranial
11. Hee MR, Izatt JA, Swanson EA, et al:
Optical coherence tomography of the
human retina. Arch Ophthalmol 1995;
113:325–332.
12. Kokame GT, de Leon MD, Tanji T: Serous
retinal detachment and cystoid macular
edema in hypotony maculopathy. Am J
Ophthalmol 2001; 131:384–386.
13. Morgan CM, Gragoudas ES: Limited
choroidal hemorrhage mistaken for a
choroidal melanoma. Ophthalmology 1987;
94:41–46.
14. Gass JDM: Radial chorioretinal folds: a sign
of choroidal neovascularization. Arch
Ophthalmol 1982; 99:1016–1018.
15. Altan T, Temel A, Baubeck T, Kazokoglu H:
Hypotonic maculopathy after trabeculectomy
with post-operative use of 5-fluorouracil.
Ophthalmologica 1994; 208:318–320.
16. Stamper RL, McMenemy MG,
Lieberman MF: Hypotonous maculopathy
with subconjunctival 5-fluorouracil. Am J
Ophthalmol 1992; 114:544–545.
18. Schepens CL, Brockhurst RJ: Uveal
effusion: clinical picture. Arch Ophthalmol
1963; 70:189–201.
19. Ward RC, Gragoudas ES, Pon DM,
Albert DM: Abnormal scleral findings in
uveal effusion syndrome. Am J Ophthalmol
1988; 106:139–146.
20. Dailey RA, Mills RP, Stimac GK, et al:
The natural history and CT appearance of
acquired hyperopia with choroidal folds.
Ophthalmology 1986; 93:1336–1342.
21. Jacobson DM: Intracranial hypertension
and the syndrome of acquired hyperopia
with choroidal folds. J Neuroophthalmol
1995; 15:178–185.
22. Friberg TR, Grove AS: Subretinal
neovascularization and choroidal folds.
Ann Ophthalmol 1980; 12:245–250.

2048
 Acute Posterior Multifocal Placoid Pigment
CHAPTER
Epitheliopathy, Serpiginous Choroiditis, and
157 Relentless Placoid Chorioretinitis
Strutha C. Rouse, II and Lee M. Jampol
ACUTE POSTERIOR MULTIFOCAL PLACOID
PIGMENT EPITHELIOPATHY
INTRODUCTION
Acute posterior multifocal placoid pigment epitheliopathy
(APMPPE) was first described in three, otherwise healthy
women by Gass in 1968.1 Although not the first to report the
constellation of clinical findings,2 Gass gave us a definitive
description of the disease that speculated on its pathogenesis.
CLINICAL PRESENTATION
Typically, APMPPE causes central vision loss in one or both
eyes in young adults with the development of gray, white, or
yellow, flat plaques that are predominantly located in the
posterior pole at the level of the outer retina and retinal pigment
epithelium (RPE) (Fig. 157.1). Lesions are usually about one disk
diameter in size. Fresh lesions may appear for several weeks.
Resolution of the visual symptoms begins within 2–4 weeks.
The acute lesions evolve into well-demarcated, lightly pigmented
scars (Fig. 157.2). In addition, APMPPE may manifest a mild
vitreitis and occasionally mild anterior chamber inflammation.
Usually, APMPPE is a nonrecurring syndrome,3–9 although rare
a b
FIGURE 157.1. (a) Fundus photograph of the right and (b) left eye of a patient with active APMPPE demonstrating deep, white, plaque-like
lesions in the macula.
recurrent cases have been noted. These recurrent cases must be
distinguished from serpiginous choroiditis (SPC), which may
be difficult initially.
APMPPE most often affects young men and women between
the ages of 20 and 50 years.3,4 Symptoms include the rapid
onset of central or paracentral visual loss. Bilateral onset is the
rule but the second eye may be involved a few days or weeks
later. Photopsias can also be present and the visual acuity
maybe as low as counting fingers. About one-third of patients
will report an antecedent viral illness,1 often an upper respir-
atory infection. Other cases have followed vaccinations10 or
bacterial infections.11
In the great majority of patients, the visual prognosis for
APMPPE is good, with most individuals spontaneously recover-
ing vision without treatment or significant sequela. Lewis and
Gass both reported that the majority of patients regain vision
of 20/40 or better.3,4 However, residual visual complaints are
common as elucidated by two studies,12,13 retrospectively
reviewing 75 eyes. Patients described scotomas (33%), meta-
morphopsias (21%), decreased vision (16%), floaters (5%), and
chronic redness (2%). Long-term vision loss may be related to
choroidal neovascularization, extensive RPE changes, or foveal
involvement.14 Pagliarini et al12 noted features that may be
associated with poor visual outcomes in APMPPE such as foveal
2049
 RETINA AND VITREOUS

a b
SECTION 10

FIGURE 157.2. (a) Fundus photograph of the right and (b) left eye of another patient demonstrates inactive APMPPE showing well-demarcated,
lightly pigmented scars in the outer retina.

involvement at initial presentation, older age at presentation demonstrates the first signs of healing and inactivity, a trans-
(>60 years), unilateral disease, longer interval between first and mission defect without late staining. Slowly, these changes
second eye involvement (>6 months) and recurrent disease. progress to involve the center of the plaque.

FLUORESCEIN ANGIOGRAPHY INDOCYANINE GREEN ANGIOGRAPHY

Fluorescein angiography for APMPPE has a characteristic
pattern. Lesions demonstrate early hypofluorescence during
disease activity and these lesions show hyperfluorescence in the
late frames with persistent staining for 20–30 min15 (Fig. 157.3).
Rarely, large choroidal vessels can be observed under these
areas of hypofluorescence.16
The inactive, healed phase of APMPPE displays a different
angiographic pattern. Lesions show early hyperfluorescence
representing atrophic defects in the RPE with little to no
fluorescence in the later phase of the angiogram.
In 1973, Annesley et al15 studied the evolution of angiographic
changes by performing consecutive fluorescein angiograms
during follow-up visits. The peripheral portion of the lesion
Indocyanine green (ICG) angiography has been increasingly
utilized in recent years due to improvement of digital imaging
systems and enhanced image resolution. ICG has demonstrated
value in characterizing possible choroidal disorders, such as
APMPPE. Several investigators have reported the ICG charac-
teristics of APMPPE lesions, which substantiate the idea of
primary choriocapillaris involvement.7,17–21 Acute lesions of
APMPPE show early hypofluorescence during ICG angiography
with the borders of these lesions more sharply delineated in the
late phase. The lesions are rounded and tend to be confluent.
ICG angiography may demonstrate more hypofluorescent areas
than are seen on clinical examination (Fig. 157.4). Inactive,
healed lesions display early hypofluorescence on ICG with

a b

FIGURE 157.3. (a) Early phase of fluorescein angiography in acute APMPPE demonstrates blockage of fluorescence. (b) Persistent staining is
2050 present in these lesions late in the angiogram (same patient as Fig. 157.1).
 Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Serpiginous Choroiditis, and Relentless Placoid Chorioretinitis
FIGURE 157.4. ICG angiogram of the same patient in Figure 157.1,
during the active phase of APMPPE illustrates multiple
hypofluorescent areas. Although some of these spots correspond to
the photographic lesions, there are more spots apparent, during ICG
angiography.
better depiction late in the angiogram. However, these regions
are more irregularly shaped, smaller in size, and less confluent
than acute lesions.17
Persistent hypofluorescence was observed by Cimino et al22
in healed APMPPE lesions secondary to choroidal nonperfusion
and chorioretinal atrophy. These findings are consistent with
the current theory of choroidal occlusive vasculitis in APMPPE.
It is likely that nonperfusion in conjunction with blockage of
fluorescence by edematous, damaged RPE may be present in
active lesions. The inactive, healed spots are smaller in dimen-
sion and more irregular in shape. These changes would be
explained by resolution of inflammatory changes of the RPE.
OPTICAL COHERENCE TOMOGRAPHY
The novel technique of optical coherence tomography (OCT)
has been applied to patients with APMPPE. Using standard
OCT, Garg and Jampol23 documented backscatter at the outer
retina that corresponded to the placoid lesions. This case report
also described serous detachment with reflective material
within the subretinal fluid (Fig. 157.5). They proposed that this
represented proteinaceous material within the serous fluid or
damaged edematous retinal epithelium.
Scheufele et al24 illustrated similar findings in active and
healed APMPPE lesions with better clarity using ultrahigh-
resolution OCT. They observed thinning of the outer neural
b reflective material within the fluid.
a c
layer and inner and outer photoreceptor segments in healing
and inactive lesions suggesting photoreceptor damage early in
this disease course. Backscatter at the level of the outer retina
likely represents acute photoreceptor cell body swelling with
subsequent loss. Degenerative changes of the RPE and intra-
cellular edema, however, were visualized as increased back-
scatter of the underlying choroid. Similar OCT findings are
seen in patients with vascular occlusive disease. This supports
the vascular hypothesis in APMPPE, indicating intracellular
edema and inflammatory changes in the outer retina from
ischemic damage.25,26
ASSOCIATED OCULAR AND SYSTEMIC
FINDINGS
Vitreitis is seen in half the patients with APMPPE and papillitis
and retinal vasculitis have been reported.27–32 Allee and Marks33
described bilateral central retinal vein occlusions that developed
CHAPTER 157
~1 month after the onset of APMPPE. Disk edema and nerve
fiber layer hemorrhages were present 1 week prior to the vein
occlusions suggestive of a peripapillary vasculitis leading to disk
swelling and compression of the central retinal vein. De Souza
and colleagues30 reported a case of APMPPE that displayed
signs of retinal vasculitis with subsequent retinal neovascular-
ization and vitreous hemorrhage 6 years after presentation.
Other reports describe more extensive inflammatory processes,
including peripheral corneal thinning,34 corneal stromal
infiltrates,35 episcleritis, iridocyclitis,28 and choroidal vasculitis.
APMPPE has also been described with diffuse serous retinal
detachments23,36,37 and hemorrhagic retinal detachments.29
Neurological abnormalities in association with APMPPE may
include headache1,38–41,42 and cerebrospinal fluid (CSF) pleo-
cytosis,27,38–41,43–46 which usually improve spontaneously.
However, some patients can experience episodes of transient
cerebral ischemia,27,42 producing stroke-like symptoms, optic
neuritis,6,31,33,34,47 transient hearing loss,48 and permanent focal
deficits43,45 due to vasculitic changes. APMPPE has been
described in association with presumed cerebral vasculitis in a
dozen cases.27,39,42,43 Ten of these individuals suffered a stroke
and deaths have occurred. In one case, histopathology of the
brain demonstrated granulomatous inflammation of medium
size arteries49 while biopsy from the tibialis anterior muscle was
suggestive of vasculitis in another.43 Comu et al42 described
three patients with APMPPE and neurologic manifestations.
Visual disturbance and headache were shared by all three and
they had a normal radiologic scan initially but CSF pleocytosis.
One patient developed recurrent strokes involving different
vascular distributions that required immunosuppressants for
presumed cerebral vasculitis.
FIGURE 157.5. (a) Color photo and (b) OCT of
right eye of patient with APMPPE at
presentation. Note the increased reflectance at
the level of the outer retina that corresponded
to lesions seen clinically in this patient. (c) OCT
of left eye. Note serous detachment and
2051
 RETINA AND VITREOUS
APMPPE has also been associated with other systemic con-
ditions including erythema nodosum,50,51 group A streptococcal
infection,11 clear cell renal cell carcinoma,52 thyroiditis,34
pulmonary tuberculosis,53 ulcerative colitis,54 Wegener’s granu-
lomatosis,55 and systemic vasculitis.56,57 Some of these associ-
ations may be coincidental but others may indicate systemic
triggers for the APMPPE response as described below or different
manifestations of a systemic vasculitis.
The etiology of APMPPE remains a subject of debate. A viral
illness may be an immunologic trigger for some individuals.
Azar et al58 and most recently Thomson et al59 both described
cases of APMPPE occurring with culture-proven adenovirus
infections. Recombinant hepatitis B vaccination, reported by
Brezin,10 caused two patients to develop APMPPE between
3 days and 2 weeks after a booster shot. Despite the lack of
histologic evidence, the possibility of a virus or vaccination
causing APMPPE supports an immune-mediated scheme. Some
investigators have speculated that molecular mimicry could
SECTION 10
play a significant role in damage to the RPE or occlusion of the
choriocapillaris. In a patient who is genetically predisposed to
immune dysregulation, environmental triggers may precipitate
APMPPE. A case of atypical APMPPE occurred in a patient with
clear-cell renal-cell carcinoma; high levels of circulating
immune complexes accompanied the fundus findings.52 This
possibly implicates immune complexes in tandem with the
complement cascade in the development of choroidal vascular
occlusions. This theory is reinforced by a documented case of
APMPPE after acute group A streptococcal infection with an
observed rise in anti-DNAase B antibody titers.11 Interestingly,
a patient with APMPPE in the course of ulcerative colitis was
documented in 2001.54 Mathura et al described a patient who
had an episode of APMPPE and then, years later, developed
multifocal choroiditis, distinctly different from the earlier
lesions.60 Thus, a patient with immune (or genetic) dysregula-
tion may manifest at different times as different white spot
syndromes.
Human leukocyte antigens (HLAs) B7 and DR2 have been
associated with APMPPE.61 Two cousins were described with
recurrent APMPPE and both were found to have HLA DR2,
promoting the concept of an inherent propensity to acquire this
disease.62 Undoubtedly, other immune regulatory genes will be
involved.63
PATHOPHYSIOLOGY
Gass believed that the abnormalities in APMPPE were at the
level of the RPE.1 He felt that the early blockage of fluorescein
was due to acute physiologic alterations in the RPE that
accounted for the opalescent appearance. The late staining
typical of this disorder could be explained by the uptake of
fluorescein into damaged pigment epithelium. The RPE
eventually recovers along with some of the photoreceptors,
allowing the return of visual function, despite areas of signifi-
cant pigment clumping or atrophy.
Others agreed that edematous RPE cells absorb the under-
lying choroidal fluorescence but hypothesized that, during the
acute process, an infectious or immunologic insult occludes the
choriocapillaris, sparing the larger vessels.27
Further supporting the idea of a primary RPE process, the
electroculogram (EOG) findings are remarkably impaired during
the acute phase of the disease. However, the electroretinogram
(ERG) responses are normal. Fishman concluded that these
findings demonstrated RPE dysfunction.5 If the choriocapillaris
were primarily involved, both EOG and ERG responses would
be extinguished.
At the present time, most investigators currently attribute
2052 the hypofluorescence to hypoperfusion of the choroid. There is
substantial evidence of APMPPE-like changes in association
with ocular and systemic vasculitic conditions, which impli-
cates an inflammatory process of the choriocapillaris. Diseases
like Wegener’s granulomatosis55 and ulcerative colitis54 have
both been reported in association with APMPPE-like changes.
Van Buskirk et al50 first reported the fluorescein angiographic
changes of APMPPE as a primary vascular abnormality of the
choroid. They described the hypofluorescence as impaired
filling of the choriocapillaris. Many investigators who support
this idea feel the placoid lesions represent focal infarcts of the
RPE caused by choroid vascular disease. Hayreh’s studies of
the choroidal vasculature support the hypothesis of a vascular
pathologic process.64 He believed the angiographic appearance
of APMPPE lesions denoted occlusions of precapillary choroidal
arterioles.
Deutman and colleagues16 reported the appearance of large
choroidal vessels seen under areas of hypofluorescence. This
evidence suggested that diseased RPE could not fully account for
the lack of choroidal fluorescence but rather suggested chorio-
capillaris nonperfusion. They surmised that APMPPE lesions
signify choroidal ischemia with subsequent RPE involvement.
MANAGEMENT/THERAPY
No therapy has been proven to affect the short-term or long-
term outcome of APMPPE. Corticosteroids are sometimes used
with the rationale that this may reduce the impairment of
central vision and speed healing. This has not been proven.
However, in cases where central nervous system inflammation
is present with APMPPE, immunosuppressive agents have been
utilized to treat these patients with success in some cases.42–44
DIFFERENTIAL DIAGNOSIS
The majority of patients with APMPPE are easily diagnosed
based on the classic clinical findings and course. However,
other inflammatory processes of the choroid should be con-
sidered when contemplating the diagnosis of APMPPE. Serpiginous
choroiditis (SPC), multifocal choroiditis, multiple evanescent
white dot syndrome, relentless placoid chorioretinitis (RPC),
diffuse unilateral subacute neuroretinitis, choroidal neoplasms,
birdshot chorioretinopathy, and others can resemble APMPPE.
Additionally, infections like syphilis and granulomatous diseases
like sarcoidosis can resemble APMPPE lesions. The individual,
acute lesions of APMPPE, serpiginous, and relentless are not
clearly distinguishable at times. However, the clinical course
and setting usually allows diagnosis.
CONCLUSION
APMPPE presents typically in early adulthood and affects the
central vision. The visual symptoms begin to resolve over
2–4 weeks. APMPPE has a characteristic fluorescein angio-
graphic pattern and clinical course. The prognosis for visual
recovery is good and the exact pathologic process involved is
still debatable. To date, there is no proven treatment.
SERPIGINOUS CHOROIDITIS
INTRODUCTION
SPC is a rare, chronic, recurring, usually bilateral disease,65–69
which has also been called geographic choroiditis,70,71 geographic
choroidopathy,70,72 geographic helicoid peripapillary choroido-
pathy,65,69,70,73 helicoid peripapillary chorioretinal degeneration,72
and macular geographic helicoid choroidopathy.74 The disease
has been reported in whites,75 Asians,74 African-Americans,76
 Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Serpiginous Choroiditis, and Relentless Placoid Chorioretinitis

and Hispanics.66 Men are affected slightly more frequently than
women.77 The onset of SPC is usually between ages 30 and
70 years,68,78 although affected patients in their 20s have
occasionally been reported.76,79
CLINICAL PRESENTATION
Patients with SPC usually report painless blurring of
vision.76,79,80 Vision loss can vary, depending on the affected
area, and visual field examination reveals small, central or para-
central scotomas, either absolute or relative.80 In the early stages
of the episode, the scotomas are more frequently absolute.76
Amsler grid visual field testing reveals scotomas that correspond
precisely with the clinical lesions.73 Acute peripapillary or
macular geographic lesions appear clinically as gray to grayish-
yellow placoid lesions, owing to outer retinal or retinal pigment
epithelial thickening with translucency (Figs 157.6 to 157.8).80
Peripapillary lesions, when present, are discoid, often showing

FIGURE 157.6. (a) Active focus of recurrent

SPC (arrows). (b) Late-phase angiogram shows
leakage from two foci of choroiditis.
From Jampol LM, Orth D, Daily MJ, Rabb MF:
Subretinal neovascularization with geographic
[serpiginous] choroiditis. Am J Ophthalmol 1979;
88:683–689.

CHAPTER 157
a b

a b

FIGURE 157.7. (a) Active initial lesion of macular SPC. (b) Same patient 3 years and several recurrences later with serpentine extension.
From Mansour AM, Jampol LM, Packo KH, Hrisomalos NF: Macular serpiginous choroiditis. Retina 1988; 8:125.

a b c

FIGURE 157.8. (a) Unusual-shaped lesion of macular SPC. (b) Early-phase angiogram shows hypofluorescence. (c) Late-phase angiogram
shows staining of lesion.
Courtesy of Kirk Packo, MD. 2053
 SECTION 10 RETINA AND VITREOUS

FIGURE 157.9. End-stage scarring of inactive SPC.

FIGURE 157.10. Inactive lesion of macular SPC.
From Mansour AM, Jampol LM, Packo KH, Hrisomalos NF: Macular serpiginous
choroiditis. Retina 1988; 8:125.
multiple confluent old scars and finger-like projections
(Fig. 157.9; see also Figs 157.6 and 157.7).81 These projections
may completely envelop small areas with normal appearance.
The EOG is unaffected.82,83 When extensive disease is
present,83 however, ERG values have been shown to fall to
70–80% of normal for total retinal illumination and to 20–30%
of normal for local macular illumination.82
Individual acute lesions normally last from weeks to
months.68,80 Resolution of the lesion results in either pigmen-
tary loss or hyperplastic mottling of the RPE, variable atrophy of
the choriocapillaris and large choroidal vessels, and scarring
(Figs 157.10 to 157.12; see also Figs 157.6 to 157.9).69,81
Characteristically, patients show evidence of multiple recur-
rences at intervals of several months to years during follow-
up.66,80 Recurrent lesions most frequently spread centrifugally
from the disk, preferentially moving toward the macula (see
Figs 157.6, 157.7, 157.10, and 157.11), although some cases
spread from the macula to the disk.69,78,80 New lesions are
often, but not always, contiguous with the borders of previous
scars.69,78,80 These new lesions are believed to be genuine recur-
rences rather than a simple progression of previous lesions,
owing to the prolonged period between the resolution of one
episode and the subsequent recurrence.69,78,80
Although blurred vision is usually the patient’s chief com-
plaint, this is frequently not noticed until the fovea becomes
involved.73,74,76,81 Many patients show evidence of previous
lesions at the time of their first examination, representing extra-
foveal disease that was previously active.66,73,76 For the patient FIGURE 157.11. Finger-like inactive lesion that eventually reached the
presenting with foveal involvement, vision may be rapidly and fovea.
permanently lost; finger-counting vision is frequently encoun- From Jampol LM, Orth D, Daily MJ, Rabb MF: Subretinal neovascularization with
tered in these patients.69,78 geographic [serpiginous] choroiditis. Am J Ophthalmol 1979; 88:683–689.
Commonly, lesions may present in the macula without pre-
ceding peripapillary activity, a variant known as macular SPC
(see Figs 157.7 to 157.9). These cases characteristically present
early in their course, owing to the early loss of central vision.66 FLUORESCEIN ANGIOGRAPHY
Other portions of the posterior pole, and even the periphery, are During the early phase of fluorescein angiography, the lesions
uncommon but occasional sites of involvement.78 are hypofluorescent (see Fig. 157.8b).65,73,80,82 The borders of
Virtually all patients eventually show bilateral disease; how- these lesions may hyperfluoresce throughout the angiography,
ever, it is uncommon to see bilateral simultaneous onset of representing leakage from the surrounding choriocapillaris. The
the disease.69 Additionally, the course and complications of the hypofluorescence of the interior represents either blockage by
disease are not necessarily the same for both eyes; one eye may swollen RPE cells or nonperfusion of the choriocapillaris, or a
show primary peripapillary involvement, whereas the other may combination of the two. Later in the angiogram, the inner
2054 show macular SPC.73 portions of a lesion may show spotty hyperfluorescence, which
 Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Serpiginous Choroiditis, and Relentless Placoid Chorioretinitis
a b
FIGURE 157.12. (a) Peripapillary SPC with choroidal neovascularization at its temporal margin. (b) Angiography shows choroidal neovascular
membrane.
From Jampol LM, Orth D, Daily MJ, Rabb MF: Subretinal neovascularization with geographic [serpiginous] choroiditis. Am J Ophthalmol 1979; 88:683–689. Reprinted
from Elsevier Science.
with time becomes more intense and may spread within the
previously hypofluorescent regions (see Figs 157.6b and
157.8c).82,84 The areas of active inflammation eventually stain.73
Over a period of several weeks, the active lesion shows pig-
mentary atrophy and clumping, with variable destruction of the
choroid. The atrophy is usually much more pronounced than
APMPPE. Angiography shows mottled hyperfluorescence due to
pigment clumping.78 Late staining, representing leakage of dye
from damaged choriocapillaris at the periphery of the lesion, is
also observed.85–88
ICG ANGIOGRAPHY
Ciulla and Gragoudas have reported the results of ICG angio-
graphy in one patient with an acute lesion in one eye and an
inactive lesion in the fellow eye.89 Their findings were similar
to those with fluorescein angiography, except that the borders of
both active and inactive lesions were less well defined and did
not show late staining.
Giovanni and associates reported their findings in 17 patients
with SPC.90 In one patient, they found evidence of a possible
active area of choroidal involvement extending beyond the
borders of a lesion noted clinically and by fluorescein angio-
graphy. Additionally, resolution of choroidal late staining in
subacute lesions was noted before this resolution on fluorescein
angiography. In contrast to the findings of Ciulla and
Gragoudas,89 the healed lesions behaved similarly on both ICG
and fluorescein angiography, although the authors found clearer
delineation of the atrophic choroid with ICG.90
Giovanni and associates also noted two cases with possible
de novo lesions in patients with dormant SPC.90 In one, multi-
focal hyperfluorescent lesions were seen bilaterally on ICG,
although one eye had not shown clinically active disease. In the
second patient, ICG revealed late hypofluorescent spots; this,
however, could represent blockage. These authors did not change
their treatment strategy based on the findings in these two
patients and noted that further follow-up would be required to
determine if these lesions represent early disease activity.90
CHAPTER 157
ASSOCIATED OCULAR AND SYSTEMIC
FINDINGS
Vitreitis is seen in up to a one-third of individuals with
SPC.69,78,80 A mild, nongranulomatous, anterior uveitis has been
reported but is much less common.91
Generally, the optic nerve is not affected,69,73 although Wu and
colleagues described a patient with temporal sectorial atrophy of
the optic nerve.81 However, photocoagulation had been per-
formed in this patient. Fujisawa and co-workers reported a
patient with evidence of recurrent disease who developed ‘optic
neuritis’.84
Choroidal neovascularization is a common complication of
SPC, and it may be more common in women than in men (see
Fig. 157.12).77 In a 1982 study of 53 patients, Blumenkranz and
associates reported that 13% (seven patients) had active choroidal
neovascularization.77 Five of these patients demonstrated bilat-
eral SPC, but only two showed evidence of bilateral choroidal
neovascularization, demonstrating that the course of the
disease can vary between eyes in the same patient. Since then,
Gass has reported that the incidence of choroidal neovascular-
ization may be as high as 25%,69 although Nussenblatt has
reported an incidence of just 10%.92
The time course for the development of the choroidal neo-
vascularization is uncertain; the asymptomatic nature of SPC
before foveal involvement often allows the disease to progress,
so that neovascularization may be seen at the first examination.68
Neovascular membranes have been reported to occur as soon as
7 months after presentation with acute SPC.93 As with other
entities, hemorrhage, exudate, and retinal thickening may be
associated with choroidal neovascularization in SPC. Some of
these neovascular membranes have been treated successfully
with thermal laser photocoagulation or surgery (see section
on Management/Therapy), whereas others have shown spon-
taneous regression.93
Retinal and optic disk neovascularization has been reported
with SPC.77,93–95 Retinal edema and localized serous detach-
ment (usually in association with choroidal neovascularization) 2055
 RETINA AND VITREOUS
of the neurosensory retina may occasionally be seen.68,69,91
Wojno and Meredith also reported localized RPE detachment.94
Their proposed mechanism suggests that irritation of the RPE
and Bruch’s membrane decreases the adherence of the two
layers, allowing fluid buildup beneath the RPE. The detached
RPE cells may then show pump dysfunction, resulting in a
serous retinal detachment. These serous detachments overlie
RPE detachments and extend slightly beyond their borders.94
Macular involvement is one of the most common compli-
cations of SPC; the disease may originate in the macula,66 or a
peripapillary lesion may spread to the macula.69,78,80 Foveal
involvement causes a rapid decrease in central vision and has a
poor prognosis for recovery. Disciform macular scars, with or
without active subretinal membranes, have been reported in as
many as 26% of patients.77
Retinal vasculitis, usually in the form of periphlebitis, has
been observed in patients with SPC.76,80,91,96 Occasional branch
vein77,96 or combined branch vein and artery occlusions have
SECTION 10
been described.91 In one report of a patient with SPC and asso-
ciated branch vein occlusion with retinal periphlebitis, the patient
had ipsilateral optic nerve head drusen; the authors speculated
that the drusen could have contributed to venous stasis and
subsequent vein occlusion.96 The retinal vasculitis and vascular
occlusion could be secondary to a spillover of choroidal inflam-
mation or an antigen-antibody reaction of the retinal vessel wall.
Erkkila and associates reported a 54.5% prevalence of
HLA-B7 in Finnish patients with SPC,95 which is greater than
that of the general Finnish population (24.3%).79,97 HLA-B7 was
found in all three patients with choroidal neovascularization
and in one patient who showed neovascularization of the disk.95
Other HLA associations have not be proved.79,95 One case of
familial SPC has been reported that demonstrated autosomal
dominant inheritance with complete penetrance.94
In most reports, no systemic disease has been detected in
patients with SPC.76,79,91,95 Some studies, however, have found
singular associated systemic manifestations, many of which are
probably chance associations.
Edelston and colleagues have reported two cases of biopsy-
proven sarcoidosis in patients who developed acute lesions
resembling those of SPC late in the course of their disease
(21 and 51 years after diagnosis of sarcoidosis).98 In one patient,
the episode represented apparent reactivation of choroiditis
in one eye, which had been quiet from age 29 until age
70 years. The lesions in these patients showed the
characteristic changes of SPC on fluorescein angiography and
demonstrated the typical helicoid progression of SPC during
follow-up.98
Richardson and colleagues report a case of SPC and nongenetic
dystonia (simultaneous contraction of antagonistic muscle
groups) believed to be acquired secondary to remote trauma, an
unknown degenerative process, or microinfarction secondary to
migraine.72 These authors cited two other cases that may
suggest a predisposing degenerative link between SPC and
neurologic disorders, including a young man with SPC and a
relative absence of arm swing during walking and an SPC
patient whose sister had multiple sclerosis.72
A case of celiac disease associated with SPC and autoimmune
thrombocytopenic purpura has been reported.99
Vascular endothelial injury releases von Willebrand factor
(vWF), which complexes with factor VIII. Factor VIII is necess-
ary for normal clotting cascade activity; its deficiency results in
hemophilia. vWF increases platelet adhesion. Elevated levels of
vWF have been associated with several disorders that manifest
vascular occlusion as a primary component, including poly-
myalgia rheumatica, Raynaud’s phenomenon, and scleroderma.
King and associates reported elevated factor VIII-vWF antigen
2056
in eight patients with SPC. None of the patients was found to
have rheumatologic or vascular disorders on follow-up.67
HISTOPATHOLOGY
Histopathologic findings, including atrophy of the chorio-
capillaris, photoreceptors, and RPE, were reported by Wu and
colleagues.81 Fibrocellular scars lined the inner portion of
Bruch’s membrane in the regions of RPE and photoreceptor cell
atrophy. The choriocapillaris was acellular. A diffuse and focal
infiltration of lymphocytes was seen in the choroid. Infiltration
was most prominent at the borders of RPE atrophy and
lymphocytic infiltration was also present in the venous walls.81
ETIOLOGY
Maumenee, in his 1970 Edward Jackson Memorial Lecture to
the American Academy of Ophthalmology and Otolaryngology,
stated that the entity of SPC ran a spectrum that included as its
two end points vascular abiotrophy and choroidal inflamma-
tion.100 Since then, the theory of vascular abiotrophy, perhaps
genetic and similar to various hereditary choroidal atrophies,
has not been substantiated. As recently as 1981, however,
Richardson and colleagues suspected a degenerative cause in
their analysis of a case of SPC associated with nongenetic
unilateral extrapyramidal dystonia.72
Compelling evidence supporting an inflammatory cause of
SPC has been set forth by Baarsma and Deutman82 in support
of Schlaegel (1969)71: an edematous zone surrounds the active
lesion, and lesions expand through this edematous zone. The
variable time course of bilateral involvement suggests that SPC
is not of a degenerative origin. Degenerative disorders rarely
show restoration of eyesight to any marked degree, unlike that
sometimes seen in SPC. Familial occurrence of SPC is rare.82
The inflammatory etiology is supported by the occasional
presence of anterior uveitis, retinal vasculitis, vitreitis,68 and
optic disk neovascularization.94
An immune response induced by a tissue or microbial antigen
could play a role in this inflammatory etiology. Recurrences
could be caused by reactivation of the immunologic reaction95
or by an underlying infection.
In support of an immunologic etiology, Erkkila and associates
discovered an increased prevalence of HLA-B7 (previously dis-
cussed).95 These authors have also described a decline in com-
plement factor C3 in two patients.95 Broekhuyse and colleagues
described the presence of immune responsiveness of SPC
patients to retinal photoreceptor protein.101 Immune reactivity
may depend on release of autoantigens and leakage of S-antigen
through the blood–retina barrier at the level of the RPE.
Attempts to demonstrate a microbial cause of SPC have been
unrevealing. An infectious etiology or trigger remains appealing,
however, because recurrences could indicate reactivation of
the infection, as seen with toxoplasmosis or herpesviruses. A
tubercular allergic cause has been proposed for patients with a
history of tuberculosis or a positive Mantoux reaction.80 Schatz
and co-workers reported a single case of active SPC lesions
concurrent with both maxillary sinusitis and ‘influenza’.65
Laatikainen and Erkkila noted one patient who had viral
meningitis before the first attack and three patients with
increased antistreptolysin titers but without evidence of focal
infection.80 One patient had been receiving estrogen-type
hormonal therapy for menopausal symptoms for 2 years before
onset of symptoms.80 These four patients were part of a group
of nine for whom systemic antibody titers were negative for a
variety of viruses or other infectious entities. Mansour and
colleagues also found no evidence of preceding viral illnesses.66
 Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Serpiginous Choroiditis, and Relentless Placoid Chorioretinitis
To the contrary, Gass described one patient who developed
bilateral SPC after herpes zoster ophthalmicus.102 Yet, Akpek
and colleagues cited postmortem histologic findings of an eye
with a long history of SPC and were unable to isolate herpetic
viral genomic fragments (herpes simplex, Epstein–Barr virus,
cytomegalovirus, and herpes zoster) in the infiltrating lympho-
cytes or choroidal tissues, using PCR amplification.103
Friberg has reported elevated Toxoplasma gondii titers in a
patient with SPC with branch vein occlusion and bilateral
periphlebitis, but he was cautious in pointing out that serum
Immunoglobulin (Ig) levels are often elevated for months to
years after an active toxoplasmosis infection and that serum
IgM levels, which would have been indicative of an active
primary infection, were not obtained.96
PATHOPHYSIOLOGY
Choroidal vascular occlusion could be the mechanism through
which either an autoimmune disease or an infectious agent
could incite inflammation and tissue damage. Although King
and associates did not find an immunologic association for
SPC, they suggested that vascular occlusion is the most
probable mechanism of tissue damage. Areas of normal retina
can be found immediately adjacent to affected areas, which is
suggestive of a precisely defined loss of choroidal filling. This
cannot be explained by blockage of fluorescence from inflam-
mation at choroid or RPE alone.67 Mansour and colleagues,
however, found evidence of hyperfluorescence in an atrophic
laser spot in an active lesion of macular SPC.66 The laser spot,
from treatment of previous subretinal neovascularization,
provided a window defect through involved RPE and suggested
intact underlying choroidal fluorescence.66 Thus, the hypofluor-
escence seen in the angiogram of an active lesion may be due at
least in part to RPE opacity and not to underlying choroidal
vascular occlusion.66
DIFFERENTIAL DIAGNOSIS
APMPPE and SPC both present as flat geographic yellowish
white lesions of the outer retina and RPE with similar fluor-
escein angiographic patterns. Most notably, hypofluorescence
during the acute stages of the disease is seen with both
lesions.66,82,96,104 In APMPPE, however, most lesions largely
resolve within weeks,69 and recurrences are uncommon more
than several months after disease onset. A viral prodrome is
often seen before ocular manifestations in patients with
APMPPE. SPC invariably shows recurrences over periods of
many months or years after disease onset,66,73,82 and a viral
prodrome is not seen. The scarring in APMPPE is generally
limited to pigment mottling.80,82,104 Choroidal atrophy is
usually not prominent in APMPPE;66,80,83 it is the rule with
SPC. Patients with APMPPE and macular involvement have a
much more favorable visual outcome.66,73,105 Visual acuity, even
after foveal involvement, often recovers dramatically in patients
with APMPPE (although this may be delayed), but recovery is
rare in patients with SPC.73 APMPPE patients are generally
younger, with simultaneous multifocal bilateral involvement
throughout the posterior pole;66,73 in contrast, SPC patients are
most frequently middle-aged, with activity of the disease in
each eye generally occurring sporadically. Choroidal neovas-
cularization has been seen in APMPPE, but it occurs much less
frequently than with SPC.73
Like those of SPC, the recurrent lesions of retinal toxoplas-
mosis usually begin at the margin of an inactive scar.96 How-
ever, only one-third of SPC patients show evidence of vitreous
cells, whereas patients with acute toxoplasmosis usually show
marked infiltration of the vitreous. Visual loss with toxoplas-
mosis may be secondary to direct foveal involvement, macular
edema, or media opacities.96 Toxoplasmosis may be seen any-
where in the fundus. Additionally, the scars of toxoplasmosis
are much more atrophic than those of SPC, indicating more
extensive destruction of the retina, RPE, and choriocapillaris.96
Systemic diseases may cause choroidal ischemia in the pos-
terior pole. These include hypertensive vascular disease, systemic
lupus erythematosus, polyarteritis nodosa, preeclampsia,
eclampsia, disseminated intravascular coagulation, and throm-
botic thrombocytopenic purpura.66 The fluorescein pattern in
these conditions may resemble that of SPC, but the clinical course
is different. Marked atrophy of the RPE and choroid as seen with
SPC does not occur with these choroidal ischemic syndromes.
MANAGEMENT/THERAPY
Various antiinflammatory and immunosuppressive agents have
CHAPTER 157
been used to treat SPC. Most efforts do not appear to halt
recurrence of the disease,76 although these therapies may be
tried when macular vision is threatened. Systemic prednisone,
60–80 mg/day, is a commonly prescribed therapeutic regimen,
but it has not been proved to affect the recurrence rate or the
long-term outcome of the disease.76,80 Many experienced
observers, including one of the authors (LMJ), believe that the
acute lesions of SPC heal more rapidly with systemic,
periocular, or intraocular corticosteroids and that maintenance
steroids can prevent recurrences.
Araujo et al used oral cyclosporine at 3–5 mg kg–1 day–1 along
with varying doses of prednisone to treat seven patients with
active SPC and to analyze the effects on the rate of recur-
rence.106 The median duration of treatment was 3 years, ranging
from 1.3 to 5 years; five patients demonstrated remission and
avoided recurrences while on this regimen. However, only two
of the seven patients actually achieved drug-free remissions (2.5
and 1.6 years) after cyclosporine therapy for 3.5 and 2.5 years,
respectively. There were no serious complications reported in
this series related to the long-term use of cyclosporine.
Hooper and Kaplan described triple immunosuppressive
therapy, with low doses of azathioprine (Imuran), cyclosporine,
and prednisone in combination.107 All five of their patients
showed resolution of active choroidal infiltrates within 2 weeks
of beginning therapy. Recurrence was immediate in one patient
when therapy was discontinued but ceased when the therapy
was resumed. The authors suggest a synergistic effect between
the three agents used. Nussenblatt, however, remarked in his
discussion of the article that although this regimen may be
effective for long-term immunosuppression, the short-term
effects demonstrated may be due to the effects of the steroids
alone or may even represent the natural resolution of the
disease.108 Alkylating agents, such as cyclophosphamide or
chlorambucil, in conjunction with oral steroid seemed effective
at controlling the acute inflammation and allowing long-term
drug-free remission in another report.109 Seven of the nine
patients managed to reach a drug-free remission after 15–96
months of treatment (median, 78 months). However, the side
effects were considerable, including nausea, and fatigue. One
patient developed transitional epithelial carcinoma of the
bladder 3 years after succession of treatment, related to the
cyclophosphamide therapy.
Secchi and co-workers have reported improved visual acuity
in seven patients treated with cyclosporine as monotherapy,
with recurrence in one of three patients in whom therapy was
discontinued.110 Using similar doses of cyclosporine as Secchi’s
group, Leznoff and colleagues treated 18 patients with
nonmicrobial uveitis. Of these, three carried a diagnosis of SPC.
2057
 RETINA AND VITREOUS
Two showed no improvement after 4 months of therapy each,
despite the addition of prednisone and azathioprine in one
patient and prednisone in the second. The third patient showed
dramatic improvement after the addition of prednisone and
azathioprine. This patient had the shortest duration of disease
(0.2 years vs 1 and 2 years in the nonresponders).111
The long-term outcome of five patients treated with
interferon alpha-2a was described by Sobaci and colleagues.112
The eight eyes in this report had vision-threatening SPC that
failed to respond to steroid-cyclosporine or chlorambucil. The
authors found that all lesions were quiescent after this
treatment and no recurrences were noted during the follow-up
period (16–48 months). Early flu-like symptoms were the only
adverse reaction observed and recovery of vision or stability of
useful vision was documented. This suggests that interferon
alpha-2a may be an option for the treatment of SPC but further
studies are necessary.
Cases of SPC complicated by extrafoveal choroidal neovas-
SECTION 10
cular membranes with attendant hemorrhage, exudate, or
serous retinal detachment have been successfully treated with
laser photocoagulation.66,68 For subfoveal choroidal neovascular
membranes, present management could include photodynamic
therapy, intraocular triamcinolone, or antivascular endothelial
growth factor agents. Improvement in visual acuity may occur
after treatment, but lesions located in the foveal avascular zone
have a poor prognosis with treatment.77 Schatz and McDonald
noted that new lesions in patients with SPC should be assessed
carefully to determine whether they represent fresh inflam-
mation or choroidal neovascular membranes.73 Navajas et al
cited treatment of a peripapillary choroidal neovascular mem-
brane secondary to SPC utilizing ICG-mediated photothrombosis
with intravitreal triamcinolone. This case report demonstrated
recovery of vision from 20/200 to 20/20 over a 10-week course,
which was maintained up to 1 year of follow-up.113
Surgical removal of choroidal neovascular membranes, either
peripapillary or submacular, has shown some benefit in specific
groups of patients but has never been systematically studied in
SPC because of its rare nature. Given the extensive RPE and
choroidal damage from SPC, it would unlikely be of much
benefit.
MONITORING DISEASE ACTIVITY
Amsler grid testing is an excellent means for assessing the
activity of SPC or the effectiveness of therapy in patients with
SPC because scotomas can be mapped precisely on the grid.114
Activity of the disease or secondary choroidal neovascular-
ization may affect the Amsler test.
RELENTLESS PLACOID CHORIORETINITIS
INTRODUCTION
RPC is a newly recognized disease process that resembles
APMPPE and SPC in many respects.115 Unlike these two
diseases, RPC shows a progressive, relentless course with the
widespread development of dozens to hundreds of inflamma-
tory areas. Previous cases, called multifocal SPC,116 ampiginous
choroiditis,92,117 or recurrent APMPPE,8 may represent RPC.
CLINICAL PRESENTATION
Patients with RPC develop multiple placoid, white lesions at the
level of the outer retina and RPE115 (Fig. 157.13). Over the
course of several weeks, the acute lesions first grow in size and
then evolve to inactive pigmented chorioretinal scars. However,
2058 all the patients demonstrate a recurrent, recalcitrant course that
includes the development of multiple, new lesions, growth of
previous lesions and continued inflammation of some older
lesions over many months (5–24 months). The disease process
eventually involves all areas of the retina, including anterior to
the equator.
RPC affects patients between 20 and 50 years old. Concurrent
inflammation of both eyes occurs in the majority of patients
with frequent foveal involvement. Central vision can be poor
but recovery is sometimes seen, despite foveal RPE changes.115,116
Only two out of 11 eyes, in Jones and associates’ case series,
had a final vision worse than 20/40.115 No gender predilection
was noted.
The individual lesions of RPC are similar to those seen with
APMPPE. However, the lesions demonstrate growth in size and
contiguous relapses over several months.115 Recurrence is a
classic feature of SPC in which a serpentine extension of existing
lesions is routinely seen. For APMPPE, recurrences have been
clearly documented but remain a rare clinical finding.8
FLUORESCEIN ANGIOGRAPHY
The fluorescein angiography of patients with RPC resembles
those of APMPPE or SPC. Lesions are hypofluorescent in the
early phase due to blockage or choriocapillaris nonperfusion.
Later, hyperfluorescence develops, starting at the borders of the
lesion, with uniform late staining of the underlying fibrotic scar
and sclera.20
ICG ANGIOGRAPHY
ICG angiography findings reported with RPC are again similar
to APMPPE or SPC.20,90,117,118–122 The ICG angiographic pattern
is characterized by hypofluorescent areas initially that persist
into the late phase.
ASSOCIATED OCULAR AND SYSTEMIC
FINDINGS
Vitreitis is a frequent manifestation seen with RPC. Both Lyness’
and Jones’ description of this entity reported that over half of
their patients presented with vitreitis.8,115 Also noted were
episcleritis,115 keratic precipitates,115 and optic disk swelling,33
all of which support an inflammatory process at least within the
ocular tissues if not a more global inflammatory disease.
No consistent systemic disorder has been demonstrated in
patients with RPC. However, one of Jones’ patients had herpes
keratitis.115 Some patients who subsequently developed RPC
had upper respiratory tract infections that were treated with
antibiotics. A case series in 1984 by Lyness et al described
‘recurrent APMPPE’ in seven patients; three of these individuals
used antimicrobial agents on multiple occasions with con-
current episodes of blurred vision and characteristic lesions
consist with RPC. The authors concluded that an antibiotic
could possibly act as an antigenic trigger for this disease.8 Other
systemic findings seen in association with RPC included
erythema nodosum, thyroiditis, and aseptic meningitis, which
all have been previously described with APMPPE or recurrent
APMPPE.8,38,34,50,51,58,80,115
PATHOPHYSIOLOGY
The individual lesion of RPC resembles APMPPE and SPC.
Fluorescein and ICG angiography both suggest an element of
nonperfusion of the choriocapillaris and the ERG and EOG were
extinguished in one patient with RPC.115 Choroidal ischemia
from an unknown trigger is the most widely accepted theory for
both APMPPE and SPC and may also be involved in RPC.
 Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Serpiginous Choroiditis, and Relentless Placoid Chorioretinitis

CHAPTER 157
b
a

c d

FIGURE 157.13. (a) Fundus photograph demonstrating the acute

presentation of RPC with multiple deep retinal lesions. (b) Within
weeks, new lesions appeared and growth of old lesions was apparent.
(c and d) Photos show light pigmentation of the outer retinal scar
around the fovea. (e) Months later, there is subretinal fibrosis and
atrophic scarring throughout the fundus.

2059
 RETINA AND VITREOUS

MANAGEMENT/THERAPY
With only limited experience to date, the best management for
RPC patients is not known. Corticosteroids have been used
with rapid resolution of active lesions and improvement in
vision. Yet, it is difficult to conclude that steroids affected the
long-term outcome, given the natural history of spontaneous
healing of individual lesions. Antiviral agents also have been
tried in a small number of patients but without obvious benefit
to date. Other immunosuppressive agents, such as cyclosporine,
have also been used,115 but recurrence often is seen after
immunosuppression is tapered.
DIFFERENTIAL DIAGNOSIS
See sections on APMPPE and/or Serpiginous Choroiditis.
CONCLUSION
APMPPE, SPC, and RPC all represent idiopathic outer retinal
and choroidal inflammatory processes. They are usually clini-
cally distinguishable based on specific characteristics including
age of onset, course, visual outcome, systemic associations,
and recurrence patterns. Given the clinical and angiographic
similarities among these entities, they may share a common
immune dysregulation.
ACKNOWLEDGMENTS
Charles J Bock Jr, MD assisted with the earlier version of the chapter
on SPC.
The present work was supported in part by an unrestricted grant from
Research to Prevent Blindness, Inc, New York City.

REFERENCES
SECTION 10

1. Gass JDM: Acute posterior multifocal
placoid pigment epitheliopathy. Arch
Ophthalmol 1968; 80:177.
2. Bonnin P, Lavat P: In connection with a
case of Gass placoid epitheliopathy in
1860. Bull Soc Ophthalmol Fr 1983; 83:49.
3. Gass JDM: Acute posterior multifocal
placoid pigment epitheliopathy:
a long-term follow-up study. In: Fine SL,
ed. Management of retinal vascular and
macular disorders. Baltimore: Williams &
Wilkins; 1983.
4. Lewis RA, Martonyi CL: Acute posterior
multifocal placoid pigment epitheliopathy: a
recurrence. Arch Ophthalmol 1975; 93:235.
5. Fishman GA, Rabb MF, Kaplan J: Acute
posterior multifocal placoid pigment
epitheliopathy. Arch Ophthalmol 1974;
92:173.
6. Kirkman TH, Ffytche TJ, Sanders MD:
Placoid pigment epitheliopathy with retinal
vasculitis and papillitis. Br J Ophthalmol
1972; 56:875
7. Bohlender T, Weindler J, Ratzkova A:
Indocyanine green angiography in acute
posterior multifocal placoid pigment
epitheliopathy. Klin Monatsbl Augenheilkd
1998; 212:170.
8. Lyness AL, Bird AC: Recurrences of acute
posterior multifocal pigment epitheliopathy.
Am J Ophthalmol 1984; 98:203.
9. Damato BE, Nanjiani M, Foulds WS: Acute
posterior multifocal placoid pigment
epitheliopathy: a follow up study. Trans
Ophthalmol Soc UK 1983; 103:517.
10. Brezin AP, Massin-Korobelnik P, Boudin M,
et al: Acute posterior multifocal placoid
pigment epitheliopathy after hepatitis B
vaccine. Arch Ophthalmol 1995; 113:297.
11. Lowder CY, Foster RE, Gordon SM, et al:
Acute posterior multifocal placoid pigment
epitheliopathy after acute group A
streptococcal infection. Am J Ophthalmol
1996; 122:115.
12. Pagliarini S, Piguet B, Ffytche TJ, et al:
Foveal involvement and lack of visual
recovery in APMPPE associated with
uncommon features. Eye 1995; 9:42.
13. Vianna R, van Egmond J, Priem H, et al:
Natural history and visual outcome in
patients with APMPPE. Bull Soc Belge
Ophthalmol 1993; 248:73.
14. Quillen DA, Davis JB, Gottlieb JL, et al: The
white dot syndromes. Am J Ophthalmol
2060 2004; 137:538.
15. Annesley WH, Tomer TL, Sheilds JA:
Multifocal placoid pigment epitheliopathy.
Am J Ophthalmol 1973; 76:511.
16. Deutman AF, Lion F: Choriocapillaris
nonperfusion in acute multifocal placoid
pigment epitheliopathy. Am J Ophthalmol
1977; 84:652.
17. Schneider U, Inhoffen W, Gelisken F:
Indocyanine green angiography in a case of
unilateral recurrent posterior acute
multifocal placoid pigment epitheliopathy.
Acta Ophthalmol Scand 2003; 81:71.
18. Dhaliwal RS, Maguire AM, Flower RW,
et al: Acute posterior multifocal placoid
pigment epitheliopathy. An indocyanine
green angiographic study. Retina 1993;
13:317.
19. Howe LJ, Woon H, Graham EM, et al:
Choroidal hypoperfusion in acute posterior
multifocal placoid pigment epitheliopathy.
An indocyanine green angiography study.
Ophthalmol 1995; 102:790.
20. Van Liefferinge T, Sallet G, De Laey JJ:
Indocyanine green angiography in cases of
inflammatory chorioretinopathy. Bull Soc
Belge Ophthalmol 1995; 257:73.
21. Yuzawa M, Kawamura A, Matsui M:
Indocyanine green videoangiographic
findings in acute posterior multifocal
placoid pigment epitheliopathy. Acta
Ophthalmol 1994; 72:128.
22. Cimino L, Auer C, Herbort CP: Sensitivity
of indocyanine green angiography for the
follow-up of active inflammatory
choriocapillaropathies. Ocul Immunol
Inflamm 2000; 8:275.
23. Garg S, Jampol LM: Macular serous
detachment in acute posterior multifocal
placoid pigment epitheliopathy. Retina
2004; 24:650.
24. Scheufele TA, Witkin AJ, Schocket LS, et al:
Photoreceptor atrophy in acute posterior
multifocal placoid pigment epitheliopathy
demonstrated by optical coherence
tomography. Retina 2005; 25:1109.
25. Lofoco G, Ciucci F, Bardocci A, et al:
Optical coherence tomography findings in a
case of acute multifocal posterior placoid
pigment epitheliopathy (AMPPPE). Euro J
Ophthalmol 2005; 15:143.
26. Cruz-Villegas V, Puliafito CA, Fujimoto JG:
Retinal vascular diseases. In: Schuman JS,
Puliafito CA, Fujimoto JG, eds. Optical
coherence tomography of ocular diseases.
Thorofare, NJ: Slack incorporated; 2004.
27. Holt WS, Regan CDJ, Trempe C: Acute
posterior multifocal placoid pigment
epitheliopathy. Am J Ophthalmol 1976;
81:403.
28. Gass JDM: Inflammatory diseases of the
retina and choroid. In: Stereoscopic atlas of
macular diseases: diagnosis and treatment.
3rd edn. St Louis: CV Mosby; 1987.
29. Isashiki M, Koide H, Yamashita T, et al:
Acute posterior multifocal placoid pigment
epitheliopathy associated with diffuse
retinal vasculitis and late haemorrhagic
macular detachment. Br J Ophthalmol
1986; 70:255.
30. De Souza S, Aslanides IM, Altomare F:
Acute posterior multifocal placoid pigment
epitheliopathy associated with retinal
vasculitis, neovascularization, and
subhyaloid hemorrhage. Can J Ophthalmol
1999; 34:343.
31. Abu El-Asrar AM, Aljazairy AH: Acute
posterior multifocal placoid pigment
epitheliopathy with retinal vasculitis and
papillitis. Eye 2002; 16:642.
32. Hector RE: Acute posterior multifocal
placoid pigment epitheliopathy. Am J
Ophthalmol 1978; 86:424.
33. Allee SD, Marks SJ: Acute posterior
multifocal placoid pigment epitheliopathy
with bilateral central retinal vein occlusion.
Am J Ophthalmol 1998; 126:309.
34. Jacklin HN: Acute posterior multifocal
placoid pigment epitheliopathy and
thyroiditis. Arch Ophthalmol 1977; 95:995.
35. Oh KT, Park DW: Acute posterior multifocal
placoid pigment epitheliopathy with corneal
stromal infiltrates. Am J Ophthalmol 1998;
125:556.
36. Bird AC, Hamilton AM: Placoid pigment
epitheliopathy presenting with bilateral
serous retinal detachments. Br J
Ophthalmol 1972; 56:881.
37. Wright BE, Bird AC, Hamilton AM:
Placoid pigment epitheliopathy and
Harada’s disease. Br J Ophthalmol 1978;
62:609.
38. Savino PJ, Weinberg RJ, Yassin JG, et al:
Diverse manifestations of acute posterior
multifocal placoid pigment epitheliopathy.
Am J Ophthalmol 1974; 77:659.
39. Sigelman J, Behrens M, Hilal S: Acute
posterior multifocal placoid pigment
epitheliopathy associated with cerebral
vasculitis and homonymous hemianopia.
Am J Ophthalmol 1979; 88:919.
 Acute Posterior Multifocal Placoid Pigment Epitheliopathy, Serpiginous Choroiditis, and Relentless Placoid Chorioretinitis
40. Bullock JD, Thomas ER, Fletcher RL:
Cerebrospinal fluid abnormalities in acute
posterior multifocal placoid pigment
epitheliopathy. Am J Ophthalmol 1977; 84:45.
41. Fishman GA, Baskin M, Jednick N: Spinal
fluid pleocytosis in acute posterior
multifocal placoid pigment epitheliopathy.
Ann Ophthalmol 1977; 9:33.
42. Comu S, Verstraeten T, Rinkoff JS, et al:
Neurological manifestations of acute
posterior multifocal placoid pigment
epitheliopathy. Stroke 1996; 27:996.
43. Bewermeyer H, Nelles G, Huber M, et al:
Pontine infarction in acute posterior
multifocal placoid pigment epitheliopathy.
J Neurol 1993; 241:22.
44. Althaus C, Unsold R, Figge C, et al:
Cerebral complications in acute posterior
multifocal placoid pigment epitheliopathy.
Ger J Ophthalmol 1993; 2:150.
45. Smith CH, Savino PJ, Beck RW, et al:
Acute posterior multifocal placoid pigment
epitheliopathy and cerebral vasculitis. Arch
Neurol 1983; 40:48.
46. Ryan SJ, Maumenee AE: Acute posterior
multifocal placoid pigment epitheliopathy.
Am J Ophthalmol 1972; 74:1066.
47. Jenkins RB, Savino PJ, Pilkerton AR:
Placoid pigment epitheliopathy with
swelling of the optic discs. Arch Neurol
1973; 29:204.
48. Clearkin LG, Hung SO: Acute posterior
multifocal placoid pigment epitheliopathy
associated with transient hearing loss.
Trans Ophthalmol Soc UK 1983; 103:562.
49. Wilson CA, Choromokos EA, Sheppard R:
Acute posterior multifocal placoid pigment
epitheliopathy and cerebral vasculitis. Arch
Ophthalmol 1988; 107:796.
50. Van Buskirk EB, Lessell S, Friedman E:
Pigment epitheliopathy and erythema
nodosum. Arch Ophthalmol 1972; 85:369.
51. Deutman AF, Oosterhuis JA, BoenTan TN,
et al: Acute posterior multifocal placoid
pigment epitheliopathy: pigment
epitheliopathy or choriocapillaritis. Br J
Ophthalmol 1972; 56:863.
52. Parmeggiani F, Costagliola C, D’Angelo S,
et al: Clear cell renal cell carcinoma
associated with bilateral atypical acute
posterior multifocal placoid pigment
epitheliopathy. Oncology 2004; 66:502
53. Anderson K, Patel KR, Webb L, et al:
Acute posterior multifocal placoid pigment
epitheliopathy associated with pulmonary
tuberculosis [letter]. Br J Ophthalmol 1996;
80:186.
54. Di Crecchio L, Parodi MB, Saviano S, et al:
Acute posterior multifocal placoid pigment
epitheliopathy and ulcerative colitis: a
possible association. Acta Ophthalmol
Scand 2001; 79:319.
55. Chiquet C, Lumbroso L, Denis P, et al:
Acute posterior multifocal placoid pigment
epitheliopathy associated with Wegener’s
granulomatosis. Retina 1999; 19:309.
56. Hsu CT, Harlan JB, Goldberg MF, et al:
Acute posterior multifocal placoid pigment
epitheliopathy associated with a systemic
necrotizing vasculitis. Retina 2003; 23:64.
57. Matsuo T, Horikoshi T, Nagai C: Acute
posterior multifocal placoid pigment
epitheliopathy and scleritis in a patient with
pANCA-positive systemic vasculitis. Am J
Ophthalmol 2002; 133:566.
58. Azar P, Gohd RS, Waltman D, et al: Acute
posterior multifocal placoid pigment
epitheliopathy associated with an
adenovirus type 5 infection. Am J
Ophthalmol 1975; 80:1003.
59. Thomson SPS, Roxburgh STD: Acute
posterior multifocal placoid pigment
epitheliopathy associated with adenovirus
infection. Eye 2003; 17:542.
60. Mathura JR, Jampol LM, Daily MJ:
Multifocal choroiditis and acute posterior
multifocal placoid pigment epitheliopathy
occurring in the same patient. Arch
Ophthalmol 2004; 122:1881.
61. Wolf MD, Folk JC, Panknen CA, et al:
HLA-B7 and HLA-DR2 antigens and acute
posterior multifocal placoid pigment
epitheliopathy. Arch Ophthalmol 1990;
108:698.
62. Kim RY, Holz FG, Gregor Z, et al: Recurrent
acute multifocal placoid pigment
epitheliopathy in two cousins. Am J
Ophthalmol 1995; 119:660.
63. Jampol LM, Becker KG: White spot
syndromes of the retina: a hypothesis
based on the common genetic hypothesis
of autoimmune/inflammatory disease. Am J
Ophthalmol 2003; 135:376.
64. Hayreh SS: Segmental nature of the
choroidal vasculature. Br J Ophthalmol
1975; 59:631.
65. Schatz H, Maumenee AE, Patz A:
Geographic helicoid peripapillary
choroidopathy: clinical presentation and
fluorescein angiographic findings. Trans Am
Acad Ophthalmol Otolaryngol 1974; 78:747.
66. Mansour AM, Jampol LM, Packo KH,
Hrisomalos NF: Macular serpiginous
choroiditis. Retina 1988; 8:125.
67. King DG, Grizzard WS, Sever RJ, Espinoza
L: Serpiginous choroidopathy associated
with elevated factor VIII-von Willebrand
factor antigen. Retina 1990; 10:97.
68. Jampol LM, Orth D, Daily MJ, Rabb MF:
Subretinal neovascularization with
geographic (serpiginous) choroiditis. Am J
Ophthalmol 1979; 88:683.
69. Gass JDM: Specific choroidal diseases
causing disciform macular detachment. In:
Gass JDM, ed. Stereoscopic atlas of
macular diseases: diagnosis and treatment.
3rd edn. St Louis: CV Mosby; 1987:136.
70. Green WR: The uveal tract. In: Spencer
WH, ed. Ophthalmic pathology: an atlas
and textbook. 3rd edn. Philadelphia: WB
Saunders; 1986:1994.
71. Schlaegel TF Jr: Metastatic nonsuppurative
uveitis. In:Schlaegel TF Jr, ed. Essentials of
uveitis. Boston: Little Brown; 1969:77.
72. Richardson RR, Cooper IS, Smith JL:
Serpiginous choroiditis and unilateral
extrapyramidal dystonia. Ann Ophthalmol
1981; 13:15.
73. Schatz H, McDonald HR: Geographic
helicoid peripapillary choroidopathy
(serpiginous choroiditis). In: Ryan SJ,
Schachat AP, Murphy RB, Patz A, eds.
Retina. St Louis: CV Mosby; 1989:705.
74. Hardy RA, Schatz H: Macular geographic
helicoid choroidopathy. Arch Ophthalmol
1987; 105:1237.
75. Sveinsson K: Helicoidal peripapillary
chorioretinal degeneration. Acta
Ophthalmol 1979; 57:69.
76. Weiss H, Annesley WH Jr, Shields JA, et al:
The clinical course of serpiginous
choroidopathy. Am J Ophthalmol 1979;
87:133.
77. Blumenkranz MS, Gass JDM, Clarkson JG:
Atypical serpiginous choroiditis. Arch
Ophthalmol 1982; 100:1773.
78. Jampol LM: The retina: inflammatory
diseases. In: Miller S, ed. Clinical
ophthalmology. Bristol: Wright; 1987:186.
79. Laatikainen L, Erkkila H: A follow-up study
on serpiginous choroiditis. Acta Ophthalmol
1981; 59:707.
80. Laatikainen L, Erkkila H: Serpiginous
choroiditis. Br J Ophthalmol 1974; 58:777.
81. Wu JS, Lewis H, Fine SL, et al:
Clinicopathologic findings in a patient
with serpiginous choroiditis and treated
choroidal neovascularization. Retina 1989;
9:292.
82. Baarsma GS, Deutman AF: Serpiginous
(geographic) choroiditis. Doc Ophthalmol
1976; 40:269.
83. Chisholm IH, Gass JDM, Hutton WL: The
late stage of serpiginous (geographic)
choroiditis. Am J Ophthalmol 1976; 82:343.
84. Fujisawa C, Fujiwara H, Hasegawa E, et al:
CHAPTER 157
The cases of serpiginous choroiditis
[Japanese, English abstract]. Nippon
Ganka Gakkai Zasshi 1978; 82:135.
85. Deutman AF: Choriocapillaris filling
patterns in health and disease. Trans
Ophthalmol Soc UK 1968; 100:553.
86. Fitzgerald PJ, Robertson DM: Acute
posterior multifocal placoid pigment
epitheliopathy. Arch Ophthalmol 1973;
89:373.
87. Alvi NP, Fishman GA: Granulomatous
uveitis presenting with acute posterior
multifocal placoid pigment epitheliopathy.
Doc Ophthalmol 1995; 89:347.
88. Dick DJ, Newman PK, Richardson J, et al:
Acute posterior multifocal placoid pigment
epitheliopathy and sarcoidosis. Br J
Ophthalmol 1988; 72:74.
89. Ciulla TA, Gragoudas ES: Serpiginous
choroiditis. Int Ophthalmol Clin 1996; 36:135.
90. Giovanni A, Ripa E, Scassellati-Sforzolini B,
et al: Indocyanine green angiography in
serpiginous choroidopathy. Eur J
Ophthalmol 1996; 6:299.
91. Masi RJ, O’Connor R, Kimura SJ: Anterior
uveitis in geographic or serpiginous
choroiditis. Am J Ophthalmol 1978; 86:228.
92. Nussenblatt RB, Whitcup SM, Palestine
AG: Serpiginous choroidopathy. In: Uveitis:
fundamentals and clinical practice. 2nd
edn. St Louis: CV Mosby; 1996:364–370.
93. Laatikainen L, Erkkila H: Subretinal and
disc neovascularization in serpiginous
choroiditis. Br J Ophthalmol 1982; 66:326.
94. Wojno T, Meredith TA: Unusual findings in
serpiginous choroiditis. Am J Ophthalmol
1982; 94:650.
95. Erkkila H, Laatikainen L, Jokinen E:
Immunological studies on serpiginous
choroiditis. Graefes Arch Clin Exp
Ophthalmol 1982; 219:131.
96. Friberg TR: Serpiginous choroiditis with
branch vein occlusion and bilateral
periphlebitis. Arch Ophthalmol 1988;
106:585.
97. Huuskonen MS, Tilikainen A, Alanko K:
HLA-B18 antigens and protection from
pulmonary fibrosis in asbestos workers.
Br J Dis Chest 1979; 73:253.
98. Edelston C, Stanford MR, Graham EM:
Serpiginous choroiditis: an unusual
presentation of ocular sarcoidosis.
Br J Ophthalmol 1994; 78:70.
99. Mulder CJJ, Pena AS, Jansen J,
Oosterhuis JA: Celiac disease and
geographic (serpiginous) choroidopathy
with occurrence of thrombocytopenic
purpura. Arch Intern Med 1983; 143:842. 2061
 RETINA AND VITREOUS
100. Maumenee AE: Clinical entities in uveitis:
an approach to the study of intraocular
inflammation. XXVI Edward Jackson
Memorial Lecture. Am J Ophthalmol
1970; 69:1.
101. Broekhuyse RM, Van Herck M, Pinckers
AJ, et al: Immune responsiveness to retinal
S-antigen and opsin in serpiginous
choroiditis and other retinal diseases. Doc
Ophthalmol 1988; 69:83.
102. Gass JDM: Serpiginous choroiditis. In:
Gass JDM, ed. Stereoscopic atlas of
macular diseases: diagnosis and treatment.
4th edn. St Louis: Mosby-Year Book;
1997:158–165.
103. Akpek EK, Chan CC, Shen D, et al: Lack of
herpes virus DNA in choroidal tissues of a
patient with Serpiginous choroiditis.
Ophthalmology 2004; 111:2071.
104. Neetens A, Burvenich H: Presumed
inflammatory maculopathies. Trans
SECTION 10
Ophthalmol Soc UK 1978; 98:160.
105. Pham-Duy T, Miszalok V: Choroiditis
geographica. Klin Monatsbl Augenheilkd
1983; 183:278.
106. Araujo AA, Wells AP, Dick AD, et al: Early
treatment with cyclosporine in serpiginous
choroidopathy maintains remission and
good visual outcome. Br J Ophthalmol
2000; 84:979.
107. Hooper PL, Kaplan HJ: Triple agent
immunosuppression in serpiginous
choroidopathy. Ophthalmology 1990;
97(Suppl):109.
108. Nussenblatt RB: Discussion of Hooper PL,
Kaplan HJ: triple agent immunosuppression
2062
in serpiginous choroiditis. Ophthalmology
1991; 98:951.
109. Akpek EK, Jabs DA, Tesseler HH, et al:
Successful treatment of serpiginous
choroiditis with alkylating agents.
Ophthalmology 2002; 109:1506.
110. Secchi AG, Tognon S, Maselli C:
Cyclosporine-A in the treatment of
serpiginous choroiditis. Int Ophthalmol
1990; 14:395.
111. Leznoff A, Shea M, Binkley KE, et al:
Cyclosporine in the treatment of
nonmicrobial inflammatory ophthalmic
disease. Can J Ophthalmol 1992; 27:302.
112. Sobaci G, Bayraktar Z, Bayer A: Interferon
alpha-2a treatment for serpiginous
choroiditis. Ocular Immunol Inflam 2005;
13:59.
113. Navajas EV, Costa RA, Farah ME, et al:
Indocyanine green-mediated
photothrombosis combined with intravitreal
triamcinolone for the treatment of choroidal
neovascularization in serpiginous
choroiditis. Eye 2003; 17:563.
114. Duke-Elder S, Perkins E: Inflammations of
the uveal tract: uveitis. In: Duke-Elder S,
ed. System of ophthalmology. Diseases of
the uveal tract. St Louis: CV Mosby;
1966:246.
115. Jones EB, Jampol LM, Yanuzzi LA, et al:
Relentless placoid chorioretinitis: a new
entity or an unusual variant of serpiginous
chorioretinitis? Arch Ophthalmol 2000;
118:931.
116. Gupta V, Agarwal A, Gupta A, et al: Clinical
characteristics of serpiginous
choroidopathy in North India. Am J
Ophthalmol 2002; 134:47.
117. Bouchenaki N, Cimino L, Auer C, et al:
Assessment and classification of choroidal
vasculitis in posterior uveitis using
indocyanine green angiography. Klin
Monatsbl Augenheilkd 2002; 219:243.
118. García-Sáenz MC, Gili Manzanaro P,
Bañuelos J, et al: Indocyanine green
angiography in chorioretinal inflammatory
diseases. Arch Soc Esp Oftalmol 2003;
78:675.
119. Giovannini A, Mariotti C, Ripa E, et al:
Indocyanine green angiography findings in
serpiginous choroidopathy. Br J
Ophthalmol 1996; 80:536.
120. Salati C, Pantelis V, Lafaut BA, et al:
A 8 months indocyanine green
angiographic follow-up of a patient with
serpiginous choroidopathy. Bull Soc Belge
Ophtalmol 1997; 265:29.
121. Squirrell DM, Bhola RM, Talbot JF:
Indocyanine green angiographic findings in
serpiginous choroidopathy: evidence of a
widespread choriocapillaris defect of the
peripapillary area and posterior pole. Eye
2001; 15:336.
122. Vabres G: Study of an atypical unilateral
choroidopathy of the posterior pole with
centrifugal serpiginous development
(clinical, angiofluorographic and functional
aspects). Ann Ocul (Paris) 1972; 205:927.
 CHAPTER
158 Multiple Evanescent White Dot Syndrome
Howard F. Fine, Antonio P. Ciardella, and John A. Sorenson
INTRODUCTION
The multiple evanescent white dot syndrome (MEWDS) was
first described in 1984 by Jampol and associates.1 Within the
same year, Takeda and co-workers independently reported in the
Japanese literature, the clinical findings of four patients with
presentations indistinguishable from MEWDS; they proposed
the term acute disseminated retinal pigment epitheliopathy.2
The subjective, demographic, clinical, fluorescein angiographic,
and electrophysiological findings of MEWDS represent a dis-
tinct clinical entity.
SUBJECTIVE COMPLAINTS
The usual presenting symptom is the acute onset of decreased
or blurred vision often accompanied by dark or black spots in
the periphery. Virtually all patients also note photopsia,
described as flickering or shimmering lights. The photopsia
sometimes seems to originate from temporal scotomas. Com-
monly, patients describe a preceding ‘flu-like’ illness.3,4 Rarely,
patients report headaches5 accompanying the visual symptoms
or ocular discomfort.6
a b
c d
DEMOGRAPHICS
Most patients are myopic7 females in roughly the third decade
of life. The reported age range of cases is 108 to 679 years old.
MEWDS does not appear to have a racial predilection.
CLINICAL FINDINGS
The presenting visual acuity ranges from 20/20 to 20/400.
Some patients may have an afferent papillary defect. The ante-
rior segment examination is normal except for the occasional
presence of mild iritis. The most striking findings on posterior
slit-lamp biomicroscopic examinations are numerous small
white spots, ~100–200 mm in size and located at the level of the
retinal pigment epithelium (RPE) or deep retina. They are most
prominently seen encircling the posterior pole and in the
perifoveal region, but the fovea is spared (Figs 158.1 to 158.3).
The spots are discrete and are not associated with overlying
exudative changes. They are sometimes migratory, clearing in
one area while appearing in another, over a period of several
days. If spots are large in size, the center of the spot may resolve
before the periphery.10 Usually, the lesions resolve entirely,
FIGURE 158.1. (a) Color photograph of the
fundus in a patient with MEWDS. Note the
scattered deep retinal spots in the posterior
pole. (b) Color photograph of the nasal
posterior retina of the same patient. Additional
spots are evident extending toward the
midperipheral retina. (c) Early fluorescein
angiogram reveals multiple pinpoint dots, most
of which correspond to the white lesions.
(d) The late-stage angiogram reveals no
significant leakage associated with the
punctate hyperfluorescent dots. Disk edema is
evident. The left eye was completely normal
clinically and angiographically.
2063
 RETINA AND VITREOUS

FIGURE 158.2. (a) Color photograph of a

patient with MEWDS reveals scattered lesions
in the posterior pole, most prominently evident
in the inferior and superior nasal juxtapapillary
regions. There were a few cells in the posterior
vitreous. (b) Color photograph of the same
patient 4 days later. Note the disappearance of
the white spots in the nasal juxtapapillary
regions and the appearance of new spots in the
temporal macula. No vitreous cells were noted
at this time.
a b

FIGURE 158.3. (a) Color photograph of a

patient with MEWDS. Note the prominent deep
retinal or retinal pigment epithelial lesions, or
both. These are more conspicuously evident
SECTION 10

than in the patient in Figure 158.1. (b) A

monochromatic photograph of the same
patient highlights the white spots in the fundus.
(c) Early fluorescein angiogram in this patient
reveals the characteristic hyperfluorescent dots
in the region of the pigment epithelium.
(d) Late-stage fluorescein angiogram reveals
staining of the RPE and outer retina. In this
patient, there has been alteration of the
b posterior blood–retinal barrier from extensive
a neuroretinitis involving the pigment epithelium.

c d

leaving behind a characteristic foveal RPE granularity in most

cases (Fig. 158.4). Other findings sometimes include a few cells
in the posterior vitreous,11 mild blurring of the disk margin, and
isolated areas of perivascular sheathing. When seen, the cellular
reaction in the posterior vitreous is mild and transient in the
early stages of the disease.

ATYPICAL MANIFESTATIONS
While atypical, cotton wool spots have been noted in
MEWDS.12 Prior to the typical appearance of macular spots,
MEWDS rarely may first manifest with a large peripapillary
outer retinal lesion13 or geographic circumpapillary discolora-
tion.14 MEWDS can result in midperipheral, peripapillary, and
even macular chorioretinal scarring, typically in patients with
recurrent or bilateral disease. One report describes a patient
diagnosed with MEWDS who developed transient reddish-
brown spots after resolution of the acute MEWDS lesions.15
MEWDS can occasionally be seen with multiple, large lesions, FIGURE 158.4. Color photograph of a patient with MEWDS. Note the
up to 1000 mm in size, and granular, pigmented, placoid lesions granular appearance of the macula, which is characteristic of this
in association with a panuveitis.16 Patients with recurrent disease and is exceedingly prominent in this patient.
2064

a b
MEWDS can develop choroidal neovascularization.17,18 This
may cause some diagnostic confusion with multifocal choroidi-
tis (MFC), especially after the acute phase of the disease has
resolved.19
VISUAL FIELDS
The visual field findings are variable in MEWDS, ranging from
normal to a generalized depression (Fig. 158.5). Large blind
spots are a frequent finding. In his original description, Jampol
noted optic nerve edema clinically in some patients. Arcuate
scotomas, cecocentral scotomas, and central depression have also
been reported.20 The field loss is sometimes exaggerated when
compared with the clinical findings in the retina and at the disk.
FLUORESCEIN ANGIOGRAPHY
The fluorescein angiography findings in MEWDS are charac-
terized by early punctate hyperfluorescent spots, 50–500 mm in
diameter, at the level of the RPE, often corresponding to the
white dots observed clinically.21 Classically, these punctate
spots assume a wreath-shaped pattern. The late-phase fluores-
cein angiogram reveals staining in the area of the spots and the
optic nerve head (Figs 158.1c,d and 158.3c,d). Late capillary
leakage in the perifoveal area and focal areas of vasculitis are
occasionally noted. Capillary leakage of the optic nerve head
can be present. The spots often resolve angiographically within
4–6 weeks and are thought to represent inflammatory lesions at
the level of the photoreceptors, RPE, and choroid.
INDOCYANINE GREEN ANGIOGRAPHY
On indocyanine green (ICG) angiography, hypofluorescent spots
are seen (Fig. 158.6), which may be more extensive and may
persist longer than spots observed on fluorescein angiography.
Peripapillary hypofluorescence on ICG may account for the
enlarged blind spot and other field abnormalities observed
secondary to choroidal hypoperfusion of the optic nerve and
peripapillary area.22 In an evidence-based review of chorioretinal
diseases, the use of ICG for the diagnosis and management of
MEWDS was ‘recommended with moderately strong supporting
evidence’.23 ICG may be particularly useful in cases with subtle
clinical findings and absent fluorescein angiographic changes.
ICG can also be used to follow the clinical course.24
ELECTROPHYSIOLOGY
The electrophysiologic findings were described for three of the
original patients reported to have MEWDS.25 During the acute
Multiple Evanescent White Dot Syndrome
FIGURE 158.5. (a) Humphrey’s visual field of a
24-year-old woman with MEWDS involving the
left eye 1 week after the onset of symptoms.
The field demonstrates marked visual loss in
the entire visual field, most profound temporally
(giant blind spot). The visual acuity was 20/40.
(b) Visual field of the same patient 4 months
later. The field is now nearly normal, although
the patient still complained of dim vision. The
visual acuity had returned to 20/20 and the
white spots were completely gone. Eight
months after the initial onset of symptoms, this
patient still complained of dim vision in the left
eye.
phase of the illness, the Ganzfield electroretinogram (ERG)
CHAPTER 158
a-wave and early receptor potential amplitudes were profoundly
decreased. This suggests that photoreceptors are involved
during active disease. These normalize with resolution of the
disease.26 Additionally, S-cone reductions are more pronounced
than in the L- or M-cone systems on Ganzfield ERG.27 The
multifocal ERG, which reflects the cone activity of the central
retina, demonstrates a supranormal response in acute disease of
less than 2 weeks duration, which may become subnormal or
normalize subsequently. Similar multifocal ERG findings have
been observed in other deep retinal inflammatory conditions.28
Electrooculography results have also been reported to be mildly
abnormal, suggesting involvement of the RPE during acute
disease.29 Abnormal foveal densitometry has been reported for a
patient with MEWDS who had normal ERG findings.30
CLINICAL COURSE
Most patients with MEWDS experience a relatively short course
with recovery of vision within 3–10 weeks. Usually, the vision
returns to 20/30 or better, with the majority of patients regain-
ing 20/20 vision. The white spots also disappear during this
time; however, the orange foveal granularity usually persists.
Some patients will have visual symptoms for much longer
periods following resolution of the white spots. Even though
visual acuity returns, some patients are aware of visual field
defects, photopsia, or dim vision for extended periods.
Bilateral involvement is uncommon31–33 and has been re-
ported as late as 4 years after initial presentation in the con-
tralateral eye.34 When both eyes are involved, one eye is usually
involved minimally and is asymptomatic. One reported patient
was symptomatic in both eyes simultaneously.35 This patient
experienced visual loss in the right eye after 7 weeks of vision
loss in the left eye. Recurrences of MEWDS are uncommon.36
Choroidal neovascularization is a rare but potential late
sequelae.37,38
PATHOPHYSIOLOGY
MEWDS is a distinct clinical syndrome. Since it has an acute
onset and is sometimes preceded by a ‘flu-like’ illness, a viral
cause seems likely. As Gass proposed for acute zonal occult
outer retinopathy, the disease may manifest first at the optic
nerve margin due to the lack of surrounding neuroepi-
thelium.39,40
Clinically and angiographically, the disease process involves
the RPE and outer retina. ICG findings suggest that early MEWDS
involves the RPE and photoreceptors, but with periphlebitis, all
layers of the retina may be involved.41 The ERG abnormalities
2065
 RETINA AND VITREOUS
a b
SECTION 10
d e
g h
i j
suggest a metabolic disturbance of the RPE–photoreceptor
complex.
One case has been described with increased serum levels of
total IgG and IgM during the acute phase.42 MEWDS has been
reported in association with recent varicella infection,43
increased CSF protein levels,44 and vaccinations for hepatitis
A45 and B.46 One study documented a 3.7-fold increase in
association with HLA-B51.47 Hormonal factors play a role in
pathogenesis, owing to the gender imbalance and high rate of
2066 oral contraception usage.48
c
f
FIGURE 158.6 (a) Color photograph of a
patient with acute onset MEWDS. Only a few
yellowish spots are visible temporally. (b) The
spots are seen better with a red-free light.
(c) Midphase fluorescein angiography
demonstrates a few hyperfluorescent spots and
staining of the disc margin. (d) Late-phase
fluoroscein angiography shows marked staining
of the optic nerve. (e) Late-phase indocyanine
green (ICG) study shows a hypofluorescent ring
around the optic nerve. (f and g) There is also
evidence of multiple hypofluorescent spots at
the posterior pole and in the midperiphery.
(h) Goldmann’s visual field demonstrates an
enlarged blind spot. (i) Late-phase ICG study
4 months later demonstrates resolution of the
hypofluorescent ring aroung the optic nerve.
(j) Goldmann’s visual field on the same day
shows resolution of the enlarged blind spot.
From Yannuzzi LA, Flower WR, Slakter JS (eds):
Indocyanine Green Angiography. St Louis, Mosby Year
Book, 1997.
DIFFERENTIAL DIAGNOSIS
MEWDS must be differentiated from other inflammatory dis-
orders of the RPE, choroid, or retina. The primary differential
diagnosis includes the white dot syndromes: MFC, punctate
inner choroidopathy (PIC), acute idiopathic blindspot enlarge-
ment syndrome (AIBSE), acute posterior multifocal placoid
pigment epitheliopathy (APMPPE), acute retinal pigment epi-
theliitis (ARPE), birdshot retinochoroidopathy, toxoplasmosis,
diffuse unilateral subacute neuroretinitis (DUSN), acute

macular neuroretinopathy (AMN), and primary intraocular
lymphoma. In most instances, the diagnosis of MEWDS can be
made confidently on clinical and angiographic examination,
and other disorders can be excluded.
MFC AND PIC
Several papers have described a group of patients that can
probably best be lumped together as cases of MFC. They include
the following: PIC,49 MFC and panuveitis,50 MFC associated
with subretinal fibrosis,51 and recurrent MFC. The patients
described in these papers are similar. As in MEWDS, they are
usually young females who present with acute visual loss in one
eye and spots in the fundus. Gass and Callanan posited that
MEWDS, MFC, PIC, and AIBES are, in fact, manifestations of
a single disease spectrum.52
PIC was described by Watzke and associates in 1984. Ten
moderately myopic women (aged 21–37 years) presented with
blurred vision, paracentral scotomas, or light flashes. The
characteristic fundus lesions are small gray-yellow spots
~100–200 mm in diameter at the level of the RPE and inner
choroids scattered throughout the posterior pole. Many lesions
had an overlying serous detachment. Neither vitreous nor
anterior chamber inflammation is present. The fluorescein
angiogram reveals early hyperfluorescence and late staining or
leakage into an overlying sensory retinal detachment. Eight of
10 patients had bilateral involvement, although symptoms were
usually unilateral. The lesions developed into atrophic scars.
Some scars became pigmented over time. Four of 10 patients
eventually experienced subretinal neovascularization in
association with perifoveal scars. Dreyer and Gass described 28
patients with MFC and panuveitis.53 Besides the characteristic
RPE lesions resembling those seen in the presumed ocular
histoplasmosis syndrome, these patients also had vitreous cells
and anterior segment inflammation. Many of these patients
experienced peripapillary or subfoveal subretinal neovas-
cularization. Cantrill and Folk reported five female patients in
whom progressive subretinal fibrosis developed in association
with MFC.54 Doran and Hamilton55 and Palestine and co-
workers56 had previously reported similar cases. Morgan and
Shatz described a similar group of female patients with MFC
who had multiple recurrences.57
All these papers describe a MFC that is generally seen in
young myopic females. The disorder can be chronic and
recurrent. Although often presenting with unilateral symptoms,
findings are usually bilateral. The RPE and inner choroidal
spots vary in size but are generally larger than those seen in
MEWDS. Papillitis, retinal phlebitis, vitritis, anterior uveitis,
cystoid macular edema, and subretinal neovascularization can
all be part of the disease process. One or more of these
manifestations may predominate in a given patient. Following
resolution of the spots in the acute stage, there is some degree
of permanent RPE and choroidal damage, which can be
atrophic, pigmentary, or cicatricial in nature. Since many
disorders may mimic this idiopathic condition, a full medical
work-up is needed, especially to rule out treatable infectious or
inflammatory conditions such as syphilis or sarcoidosis.
A common host susceptibility factor or even a common
pathogenesis may exist between MEWDS and the MFC
spectrum of disease. Several cases have been observed
of patients with MEWDS who subsequently develop MFC,58–60
and several cases are described of patients with a previous
diagnosis of MFC who develop MEWDS. Both MEWDS and
MFC typically affect young myopic women. However, unlike
MEWDS, MFC is usually associated with bilateral involvement,
deep choroidal inflammatory (rather than deep retinal/RPE)
lesions, prominent vitritis and anterior chamber reaction, and
Multiple Evanescent White Dot Syndrome
early hypofluorescent spots which stain late on fluorescein
angiography.61
ACUTE IDIOPATHIC BLIND SPOT
ENLARGEMENT
Fletcher and colleagues described a syndrome occurring
primarily in young females consisting of blind spot enlargement
without optic disk edema.62 The acute idiopathic blind spot
enlargement (AIBSE) syndrome has features suggesting retinal
dysfunction as its cause, including the presence of the scotoma,
steep borders of the scotoma, and prolonged recovery time with
photostress testing. Hamed and colleagues suggested that
patients with AIBSE represent a subset of those with MEWDS,
presenting for examination after the retinal spots have faded.63
More recently, Singh and associates suggested that MEWDS is
one of several conditions that may be characterized by blind
spot enlargement.64 Some cases of AIBSE, but not all, may be
CHAPTER 158
due to MEWDS. Volpe and colleagues reviewed 27 cases of
AIBSE and suggest that the primary factor that distinguishes
AIBSE from MEWDS is that the visual field abnormalities do
not resolve in AIBSE.65 Patients with AIBSE can present with
photopsia; visual field defects; and have abnormal funduscopic,
angiographic, and electroretinographic findings.
ACUTE POSTERIOR MULTIFOCAL PLACOID
PIGMENT EPITHELIOPATHY
APMPPE can also present with rapid loss of vision in a young
patient.66 However, this condition is usually bilateral and the
fundus lesions are characteristic. Multiple, flat gray-white
lesions are present at the level of the RPE. These lesions are
much larger than the spots of MEWDS. The lesions are hypo-
fluorescent in the early-stage fluorescein angiogram and stain
late. Extensive RPE alterations develop as lesions resolve.
ACUTE RETINAL PIGMENT EPITHELIITIS
ARPE was described by Krill and Deutman in 1972.67 Chittum
and Kalina more recently reported the findings of eight patients
with ARPE.68 This condition is also characterized by acute loss
of vision in a young patient. The ages of the first nine reported
patients ranged from 18 to 45 years.69 Three of the nine
patients had bilateral involvement. The acute findings have
been described as discrete clusters of dark spots surrounded by
hypopigmented halos. These spots are localized to the peri-
foveal region. Fluorescein angiography can reveal blockage of
choroidal fluorescence from the pigmented center with a
surrounding zone of hyperfluorescence corresponding to the
hypopigmented halo. Gradual resolution of the fundus findings
with complete recovery of vision within 7–10 weeks is typical.
Subtle RPE alterations may remain.
BIRDSHOT RETINOCHOROIDOPATHY
Birdshot retinochoroidopathy or vitiliginous chorioretinitis is
characterized by white or depigmented spots at the level of the
RPE scattered throughout the fundus.70,71 The older age at
presentation, chronic course, bilateral involvement, and signi-
ficant vitreous involvement all help to easily distinguish this
syndrome from MEWDS.
TOXOPLASMOSIS
Another cause of retinochoroiditis that must be differentiated
from MEWDS is toxoplasmosis. Ocular toxoplasmosis can
present with multifocal gray-white lesions at the level of the 2067
 RETINA AND VITREOUS

deep retina and RPE, with little or no overlying vitreous
reaction.72 These lesions typically resolve slowly and can recur.
The diagnosis of punctate outer retinal toxoplasmosis is dif-
ficult to confirm. The presence of satellite lesions and positive
serologic findings for toxoplasmosis can help to make the
diagnosis in the appropriate clinical setting.
DIFFUSE UNILATERAL SUBACUTE
NEURORETINITIS
The early stage of DUSN can be characterized by recurrent
crops of evanescent gray-white lesions at the level of the outer
retina and RPE.73 The chronic course of DUSN with eventual
development of visual loss, optic atrophy, diffuse RPE de-
generation, and retinal vessel narrowing easily differentiates
this disorder from MEWDS. DUSN is caused by a nematode
that can sometimes be visualized in the subretinal space.74
SECTION 10
who initially presented with transient lesions of the posterior
pole, simulating MEWDS. Eventually, these patients were
diagnosed with primary intraocular lymphoma due to the
persistence or expansion of retinal lesions or of vitreous cellular
infiltration.78,79
CONCLUSIONS
In summary, MEWDS is a unilateral, idiopathic, and inflam-
matory disease with a constellation of well-described subjective,
clinical, fluorescein angiographic, and electrophysiologic
features. It occurs most often as a unilateral phenomenon,
predominantly in young, myopic females. The most charac-
teristic manifestation is that of outer retinal or superficial
pigment epithelial white spots, often 100–200 mm in size, and
usually confined to the posterior pole or midretinal areas. These
fleeting disturbances are migratory in nature and evident on
fluorescein angiography with a wreath-like distribution of early

punctate hyperfluorescent spots which stain late. A persistent

ACUTE MACULAR NEURORETINOPATHY
AMN is another cause of loss of vision and paracentral
scotomas in young patients.75,76 This disorder can be bilateral
and is characterized by cloverleaf, wedge-shaped, grayish lesions
in the macular area, probably in the outer retinal layers. Interes-
tingly, patients have been reported with AMN and MEWDS in
the same eye, suggesting some similarity in their origins.77
PRIMARY INTRAOCULAR LYMPHOMA
Primary intraocular lymphoma is well known to masquerade as
numerous other ocular inflammatory syndromes, and MEWDS
is no exception. Several cases have been reported of patients
orange foveal granularity and mild papillitis are hallmarks of
the disorder. Similarly, there are characteristic electroretino-
graphic findings and visual field loss. The field changes exceed
what might be expected on the bases of the clinical findings in
the retina and at the optic nerve. The natural course is generally
benign with spontaneous disappearance of the lesions and
improvement of the visual function. MEWDS is often clinically
differentiated from other categorized intraocular inflammatory
diseases. Although there is considerable information available
on the subjective, demographic, clinical, angiographic, and
electrophysiologic features of this disease, a causative agent is
still unknown. Further clinical research is needed to identify the
precise pathogenesis.

REFERENCES
1. Jampol LM, Sieving PA, Pugh D, et al:
Multiple evanescent white dot syndrome.
I. Clinical findings. Arch Ophthalmol 1984;
102:671–674.
2. Takeda M, Kimura S, Tamiya M: Acute
disseminated retinal pigment
epitheliopathy. Folia Ophthalmol Jpn 1984;
35:2613.
3. Jampol LM, Sieving PA, Pugh D, et al:
Multiple evanescent white dot syndrome.
I. Clinical findings. Arch Ophthalmol 1984;
102:671–674.
4. Slusher MM, Weaver RG: Multiple
evanescent white dot syndrome. Retina
1988; 8:132–135.
5. Meyer RJ, Jampol LM: Recurrences and
bilaterality in the multiple evanescent
white-dot syndrome. Am J Ophthalmol
1986; 101:388–389.
6. Kimmel AS, Folk JC, Thompson HS,
Strnad LS: The multiple evanescent white-
dot syndrome with acute blind spot
enlargement. Am J Ophthalmol 1989;
107:425–426.
7. Asano T, Kondo M, Kondo N, et al: High
prevalence of myopia in Japanese patients
with multiple evanescent white dot
syndrome. Jpn J Ophthalmol 2004;
48:486–489.
8. Olitsky SE: Multiple evanescent
white-dot syndrome in a 10-year-old child.
J Pediatr Ophthalmol Strabismus 1998;
35:288–289.
9. Lim JI, Kokame GT, Douglas JP: Multiple
evanescent white dot syndrome in older
patients. Am J Ophthalmol 1999;
2068 127:725–728.
10. Huang J, Spaide R: Appearance of brown
areas after resolution of the acute phase of
multiple evanescent white dot syndrome.
Retina 2004; 24:814–816.
11. Gass JD, Hamed LM: Acute macular
neuroretinopathy and multiple evanescent
white dot syndrome occurring in the same
patients. Arch Ophthalmol 1989;
107:189–193.
12. Dodwell DG, Jampol LM, Rosenberg M,
et al: Optic nerve involvement associated
with the multiple evanescent white-dot
syndrome. Ophthalmology 1990;
97:862–868.
13. Ray S, Loewenstein J: Atypical
manifestation of multiple evanescent white
dot syndrome with large peripapillary
lesion. Arch Ophthalmol 2003;
121:1794–1796.
14. Luttrull JK, Marmor MF, Nanda M:
Progressive confluent circumpapillary
multiple evanescent white-dot syndrome.
Am J Ophthalmol 1999; 128:378–380.
15. Huang J, Spaide R: Appearance of brown
areas after resolution of the acute phase of
multiple evanescent white dot syndrome.
Retina 2004; 24:814–816.
16. Khurana RN, Albini T, Dea MK, et al:
Atypical presentation of multiple
evanescent white dot syndrome involving
granular lesions of varying size. Am J
Ophthalmol 2005; 139:935–937.
17. Wyhinny GJ, Jackson JL, Jampol LM,
Caro NC: Subretinal neovascularization
following multiple evanescent white-dot
syndrome. Arch Ophthalmol 1990;
108:1384–1385.
18. Oh KT, Christmas NJ, Russell SR: Late
recurrence and choroidal neovascularization
in multiple evanescent white dot syndrome.
Retina 2001; 21:182–184.
19. Kozielec GF, Wyhinny GJ, Jampol LM:
Evolution of distinct chorioretinal scars in
recurrent MEWDS. Retina 2001;
21:180–182.
20. Nakao K, Isashiki M: Multiple evanescent
white dot syndrome. Jpn J Ophthalmol
1986; 30:376–384.
21. Gass JDM: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 3rd edn.
St Louis: Mosby; 1987:510–511.
22. Yen MT, Rosenfeld PJ: Persistent
indocyanine green angiographic findings in
multiple evanescent white dot syndrome.
Ophthalmic Surg Lasers 2001; 32:156–158.
23. Stanga PE, Lim JI, Hamilton P: Indocyanine
green angiography in chorioretinal
diseases: indications and interpretation: an
evidence-based update. Ophthalmology
2003; 110:15–21.
24. Cimino L, Auer C, Herbort CP: Sensitivity
of indocyanine green angiography for the
follow-up of active inflammatory
choriocapillaropathies. Ocul Immunol
Inflamm 2000; 8:275–283.
25. Sieving PA, Fishman GA, Jampol LM,
Pugh D: Multiple evanescent white dot
syndrome. II. Electrophysiology of the
photoreceptors during retinal pigment
epithelial disease. Arch Ophthalmol 1984;
102:675–679.
26. Slusher MM, Weaver RG: Multiple
evanescent white dot syndrome. Retina
1988; 8:132–135.

27. Yamamoto S, Hayashi M, Tsuruoka M, et al:
S-cone electroretinograms in multiple
evanescent white dot syndrome. Doc
Ophthalmol 2003; 106:117–120.
28. Feigl B, Haas A, El-Shabrawi Y: Multifocal
ERG in multiple evanescent white dot
syndrome. Graefes Arch Clin Exp
Ophthalmol 2002; 240:615–621.
29. Laatikainen L, Immonen I: Multiple
evanescent white dot syndrome. Graefes
Arch Clin Exp Ophthalmol 1988;
226:37–40.
30. Keunen JE, van Norren D: Foveal
densitometry in the multiple evanescent
white-dot syndrome. Am J Ophthalmol
1988; 105:561–562.
31. Aaberg TM, Campo RV, Joffe L:
Recurrences and bilaterality in the multiple
evanescent white-dot syndrome. Am J
Ophthalmol 1985; 100:29–37.
32. Jost BF, Olk RJ, McGaughey A: Bilateral
symptomatic multiple evanescent white-dot
syndrome. Am J Ophthalmol 1986;
101:489–490.
33. Meyer RJ, Jampol LM: Recurrences and
bilaterality in the multiple evanescent
white-dot syndrome. Am J Ophthalmol
1986; 101:388–389.
34. Hernandez Artola F, Garay Aramburu G,
Llorca Pellicer S: Multiple evanescent
white-dot syndrome: bilateralization four
years later. Arch Soc Esp Oftalmol 2002;
77:393–396.
35. Jost BF, Olk RJ, McGaughey A: Bilateral
symptomatic multiple evanescent white-dot
syndrome. Am J Ophthalmol 1986;
101:489–490.
36. Aaberg TM, Campo RV, Joffe L:
Recurrences and bilaterality in the multiple
evanescent white-dot syndrome. Am J
Ophthalmol 1985; 100:29–37.
37. Wyhinny GJ, Jackson JL, Jampol LM,
Caro NC: Subretinal neovascularization
following multiple evanescent white-dot
syndrome. Arch Ophthalmol 1990;
108:1384–1385.
38. Oh KT, Christmas NJ, Russell SR: Late
recurrence and choroidal neovascularization
in multiple evanescent white dot syndrome.
Retina 2001; 21:182–184.
39. Gass JD, Agarwal A, Scott IU: Acute zonal
occult outer retinopathy: a long-term
follow-up study. Am J Ophthalmol 2002;
134:329–339.
40. Ray S, Loewenstein J: Atypical
manifestation of multiple evanescent white
dot syndrome with large peripapillary
lesion. Arch Ophthalmol 2003;
121:1794–1796.
41. Ikeda N, Ikeda T, Nagata M, et al: Location
of lesions in multiple evanescent white dot
syndrome and the cause of the
hypofluorescent spots observed by
indocyanine green angiography. Graefes
Arch Clin Exp Ophthalmol 2001;
239:242–247.
42. Chung YM, Yeh TS, Liu JH: Increased
serum IgM and IgG in the multiple
evanescent white-dot syndrome. Am J
Ophthalmol 1987; 104:187–188.
43. Laatikainen L, Immonen I: Multiple
evanescent white dot syndrome. Graefes
Arch Clin Exp Ophthalmol 1988;
226:37–40.
Multiple Evanescent White Dot Syndrome
44. McCollum CJ, Kimble JA: Peripapillary
subretinal neovascularization associated
with multiple evanescent white-dot
syndrome. Arch Ophthalmol 1992;
110:13–14.
45. Fine L, Fine A, Cunningham ET Jr: Multiple
evanescent white dot syndrome following
hepatitis A vaccination. Arch Ophthalmol:
2001; 119:1856–1858.
46. Baglivo E, Safran AB, Borruat FX: Multiple
evanescent white dot syndrome after
hepatitis B vaccine. Am J Ophthalmol
1996; 122:431–432.
47. Borruat FX, Herbort CP, Spertini F,
Desarnaulds AB: HLA typing in patients
with multiple evanescent white dot
syndrome (MEWDS). Ocul Immunol
Inflamm 1998; 6:39–41.
48. Gass JD, Hamed LM: Acute macular
neuroretinopathy and multiple evanescent
white dot syndrome occurring in the same
patients. Arch Ophthalmol 1989;
107:189–193.
49. Watzke RC, Packer AJ, Folk JC, et al:
Punctate inner choroidopathy. Am J
Ophthalmol 1984; 98:572–584.
50. Dreyer RF, Gass DJ: Multifocal choroiditis
and panuveitis. A syndrome that mimics
ocular histoplasmosis. Arch Ophthalmol
1984; 102:1776–1784.
51. Cantrill HL, Folk JC: Multifocal choroiditis
associated with progressive subretinal
fibrosis. Am J Ophthalmol 1986;
101:170–180.
52. Callanan D, Gass JD: Multifocal choroiditis
and choroidal neovascularization
associated with the multiple evanescent
white dot and acute idiopathic blind spot
enlargement syndrome. Ophthalmology
1992; 99:1678–1685.
53. Dreyer RF, Gass DJ: Multifocal choroiditis
and panuveitis. A syndrome that mimics
ocular histoplasmosis. Arch Ophthalmol
1984; 102:1776–1784.
54. Cantrill HL, Folk JC: Multifocal choroiditis
associated with progressive subretinal
fibrosis. Am J Ophthalmol 1986;
101:170–180.
55. Doran RM, Hamilton AM: Disciform
macular degeneration in young adults.
Trans Ophthalmol Soc UK 1982; 102(Pt
4):471–480.
56. Palestine AG, Nussenblatt RB, Parver LM,
Knox DL: Progressive subretinal fibrosis
and uveitis. Br J Ophthalmol 1984;
68:667–673.
57. Morgan CM, Schatz H: Recurrent multifocal
choroiditis. Ophthalmology 1986;
93:1138–1147.
58. Callanan D, Gass JD: Multifocal choroiditis
and choroidal neovascularization
associated with the multiple evanescent
white dot and acute idiopathic blind spot
enlargement syndrome. Ophthalmology
1992; 99:1678–1685.
59. Kozielec GF, Wyhinny GJ, Jampol LM:
Evolution of distinct chorioretinal scars in
recurrent MEWDS. Retina 2001;
21:180–182.
60. Oh KT, Christmas NJ, Russell SR: Late
recurrence and choroidal
neovascularization in multiple evanescent
white dot syndrome. Retina 2001;
21:182–184.
61. Bryan RG, Freund KB, Yannuzzi LA, et al:
Multiple evanescent white dot syndrome in
patients with multifocal choroiditis. Retina
2002; 22:317–322.
62. Fletcher WA, Imes RK, Goodman D,
Hoyt WF: Acute idiopathic blind spot
enlargement. A big blind spot syndrome
without optic disc edema. Arch Ophthalmol
1988; 106:44–49.
63. Hamed LA, Schatz NJ, Glaser JS, Gass JD:
Acute idiopathic blind spot enlargement
without optic disc edema. Arch Ophthalmol
1988; 106:1030–1031.
64. Singh K, de Frank MP, Shults WT,
Watzke RC: Acute idiopathic blind spot
enlargement. A spectrum of disease.
Ophthalmology 1991; 98:497–502.
65. Volpe NJ, Rizzo JF 3rd, Lessell S: Acute
idiopathic blind spot enlargement
syndrome: a review of 27 new cases.
CHAPTER 158
Arch Ophthalmol 2001; 119:59–63.
66. Gass JDM: Acute posterior multifocal
placoid pigment epitheliopathy. Arch
Ophthalmol 1968; 80:177.
67. Krill AE, Deutman AF: Acute retinal pigment
epitheliitus. Am J Ophthalmol 1972;
74:193–205.
68. Chittum ME, Kalina RE: Acute retinal
pigment epitheliitis. Ophthalmology 1987;
94:1114–1119.
69. Deutman AF: Acute retinal pigment
epitheliitis. Am J Ophthalmol 1974;
78:571–578.
70. Ryan SJ, Maumenee AE: Birdshot
retinochoroidopathy. Am J Ophthalmol
1980; 89:31–45.
71. Gass JD: Vitiliginous chorioretinitis. Arch
Ophthalmol 1981; 99:1778–1787.
72. Doft BH, Gass DM: Punctate outer retinal
toxoplasmosis. Arch Ophthalmol 1985;
103:1332–1336.
73. Gass JD, Scelfo R: Diffuse unilateral
subacute neuroretinitis. J R Soc Med 1978;
71:95–111.
74. Gass JD, Braunstein RA: Further
observations concerning the diffuse
unilateral subacute neuroretinitis syndrome.
Arch Ophthalmol 1983; 101:1689–1697.
75. Bos PJ, Deutman AF: Acute macular
neuroretinopathy. Am J Ophthalmol 1975;
80:573–584.
76. Rush JA: Acute macular neuroretinopathy.
Am J Ophthalmol 1977; 83:490–494.
77. Gass JD, Hamed LM: Acute macular
neuroretinopathy and multiple evanescent
white dot syndrome occurring in the same
patients. Arch Ophthalmol 1989;
107:189–193.
78. Fahim DK, Bucher R, Johnson MW: The
elusive nature of primary intraocular
lymphoma. J Neuroophthalmol 2005;
25:33–36.
79. Shah GK, Kleiner RC, Augsburger JJ, et al:
Primary intraocular lymphoma seen with
transient white fundus lesions simulating
the multiple evanescent white dot
syndrome. Arch Ophthalmol 2001;
119:617–620.
2069
 CHAPTER
159 Acute Zonal Occult Outer Retinopathy
Alan C. Bird
INTRODUCTION
The condition was probably reported initially by neuro-
ophthalmologists when patients were recognized as having a big
blind spot without disk swelling or any other retinal abnor-
malities.1,2 The field loss was reported to be persistent over
many months. It was then identified that in some, it was
progressive over a period extending temporally around the
macula. Electro-physiological testing showed that the loss was
due to retinal dysfunction.
Gass was the first to recognize and characterize the nature
of the disorder which he named acute zonal occult outer
retinopathy (AZOOR) which he described in 1993 in his
Donder’s lecture.3 He reported 13 patients, mostly young
women, who had rapid self limited loss of visual fields,
photopsia, minimal ophthalmoscopic changes. Spontaneous
recovery could occur during the first 5 years, but in its absence
signs of retinal degeneration developed. The evidence that the
loss was due to outer retinal dysfunction was based on the
interpretation of electrophysiological (ERG) abnormalities.
Gass, and subsequently others, described AZOOR as being
associated with various inflammatory inner choroidal inflam-
matory disease and retinopathies of unknown etiology
including the multiple evanescent white dot syndrome
(MEWDS),3–8 acute macular neuroretinopathy (AMN),9–11
multifocal choroidopathy,12–13 punctate inner choroidopathy
(PIC)14,15 or pseudopresumed ocular histoplasmosis syndrome
(pseudo-POHS),16–18 PIC being the most common. It is con-
sidered that AZOOR was a complication of disorders that cause
inner choroidal inflammation rather than being intrinsic to the
primary disorder.
CLINICAL PRESENTATION
The vast majority of patients are female, healthy, in their
mid-thirties although the condition has been reported in the
seventh decade of life. The sex predilection is determined by
that of the precipitating disorders. The condition presents with
progressive visual loss over a period of weeks or a few months.
The visual field loss most frequently involves blind spot
enlargement extending in an arcuate manner into the superior
and inferior temporal quadrants. Photopsia extending over the
whole of the affected field is a prominent symptom described
as ‘scintillating’ or ‘shimmering’ lights. The visual acuity may
or may not be affected. The severity is variable and visual acuity
as bad as counting fingers has been recorded. The field defect
increases in size within a few weeks or months before
stabilizing. In most cases, the visual field loss and decrease in
visual acuity are asymmetric and some have unilateral
symptoms only.
CLINICAL FINDINGS
Characteristically, the fundus changes are those of the
precipitating disorder, with inner choroidal infiltrates or
scarring if it is PIC. In some cases, the fundi may be normal and
it is assumed that MEWDS was the cause given and the retinal
changes may be very limited in this disorder even a few weeks
after its onset. Evidence of MEWDS may be evident on ICG
angiography when the fundus appears to be normal on
ophthalmoscopy. In the area of field loss, the retina appears
normal including autofluorescence imaging. Visual fields show
the characteristic loss.19,20 Both rod and cone sensitivities may
be reduced without there being an increase of time to recovery
from bleach.
ERG FINDINGS
ERG tests show that retinal dysfunction accounts for the field
loss.21,19 The most sensitive test in flicker ERG in which the
implicit time is invariably prolonged. The additional changes
include photopic transient ERGs with abnormal b-wave ampli-
tude and increased implicit time the reduced scotopic rod
responses were abnormal in nine eyes, and abnormal pattern
ERG. The light induced rise of ocular potential on electro-
oculography (EOG) is usually reduced to an extent not
explained by reduced photoreceptor responses.
CLINICAL COURSE
The long term course has been well recorded.21 Those who
present with unilateral AZOOR may have affection of the other
eye after weeks. Progression of the deficit has been recorded by
both psychophysics and ERG testing over a period of a few
weeks followed by stability.
In a proportion of cases, there is recovery of function over a
period of months or years shown both on visual field and ERG
testing although recovery is rarely complete. If after 5 years
there is no recovery, widespread retinal changes occur that
correspond with the field loss with retinal thinning and changes
at the level of the retinal pigment epithelium (RPE).
PATHOGENESIS
The abolished EOG light rise and reduced photoreceptor cell,
responses on ERG testing show that the abnormality is largely
at the level of the RPE–photoreceptors complex. The greater
reduction in EOG’s light rise than is easily explained by photo-
receptor functional loss implies the RPE affection is likely to be
intrinsic to the disorder. Autofluorescence images obtained with
a scanning laser ophthalmoscope are derived from lipofuscin 2071
 RETINA AND VITREOUS

in the retinal pigment epithelium.22,23 The presence of
lipofuscin is thought to reflect the metabolic activity of the RPE
which is determined largely by the rate of turnover of photo-
receptor outer segments. The finding of normal autofluor-
escence distribution early in disease implies that there is no
significant loss of photoreceptors, and the presence of normal
outer segment and retinoid turnover. That the loss is due to cell
dysfunction and not cell loss might be expected from the
normal appearance of the retina on clinical examination. The
loss of b-wave amplitude in some cases that is greater than
a-wave loss suggest that, in these, there is posttransduction
abnormality as well.
The mechanism leading to malfunction of the retinal
RPE–photoreceptor–epithelium complex in AZOOR and the
causal relationship between the initiating event and the
widespread function loss are still unknown. Why patients with
multifocal choroiditis or punctate inner choroidopathy,15
presumed ocular hystoplasmosis syndrome (POS), MEWDS are
SECTION 10
firmed by Spaide et al.25 Candida famata was isolated from
conjunctival exudates of a patient diagnosed with AZOOR.26
Immunological tests revealed the presence of antigen-specific
T lymphocytes by using C. famata as a challenge, and enzyme-
linked immunosorbent assay (ELISA) analysis showed the
presence of specific antibodies against this yeast in the patient’s
blood. Delayed hypersensitivity by use of a skin test was also
positive.
Alternatively, it was considered that antibodies to retina may
have been induced either by the infective agent or by release
of antigens from the retina. However, Jacobson found no
indication that patients with AZOOR as a group have auto-
antibodies that recognize a specific cell type in sections of
human or rat retina. None of the AZOOR sera/IgGs produced
specific labeling of rat retinal cells.20 No similar antibodies
reactive with a specific retinal antigen were found in AZOOR.
TREATMENT

at high risk of developing AZOOR is not understood. An

autoimmune etiology or toxic mechanism precipitated possibly
by a virus has been proposed by some. It was suggested that
persistence of virus may be the cause. Tiedeman24 found
evidence of persistent EBV infection in 10 patients with multi-
focal choroiditis and panuveitis. His findings were not con-
As a result of finding hypersensitivity to C. famata antifungal
treatment was tried and it was reported that there were
improvements in several clinical symptoms, including
fundoscopic analysis. This observation has not been repeated,
and the general view is that treatment is unhelpful.21

REFERENCES
1. Rosenberg ML, O’Connor P, Carter J:
Idiopathic unilateral disk edema. The big
blind spot syndrome. J Clin
Neuroophthalmol 1984; 4:181–184.
2. Fletcher WA, Imes RK, Goodman D,
Hoyt WF: Acute idiopathic blind spot
enlargement. A big blind spot syndrome
without optic disk edema. Arch Ophthalmol
1988; 106:44–49.
3. Gass JDM: Acute zonal occult outer
retinopathy. J Cl Neuro-ophthalmology
1993; 13:79–97.
4. Jampol LM, Sieving PA, Pugh D, et al:
Multiple evanescent white dot syndrome.
I. Clinical findings. Arch Ophthalmol 1984;
102:671–674.
5. Sieving PA, Fishman Ga, Jampol LM,
Pugh D: Multiple evanescent white dot
syndrome. II. Electrophysiology of the
photoreceptors during retinal pigment
epithelial disease. Arch Ophthalmol 1984;
102:675–679.
6. Aaberg TM, Campo RV, Joffe L: Recurrence
and bilaterality in the multiple evanescent
white dot syndrome. Am J Ophthalmol
1985; 100:29–37.
7. Callanan D, Gass JDM: Multifocal choroiditis
and choroidal neovascularisation
associated with the multiple evanescent
white dot and acute idiopathic blind spot
enlargement syndrome. Ophthalmology
1992; 99:1678–1685.
8. Hamed LM, Glaser JS, Gass JDM,
Schatz NJ: Protracted enlargement of the
blind spot in multiple evanescent white dot
syndrome. Arch Ophthalmol 1989;
107:194–198.
9. Singh K, de Frank M, Shults WT, Watzke RK:
Acute idiopathic blind spot enlargement: a
spectrum of disease. Ophthalmology 1991;
98:497–502.
10. Bos PJM, Deutman AF: Acute macular
neuroretinopathy. Am J Ophthalmol 1975;
80:573–584.
11. Gass JDM, Hamed L: Acute macular
neuroretinopathy and multiple evanescent
white dot syndrome occurring in the same
patients. Arch Ophthalmol 1989;
107:189–193.
12. Khorram KD, Jampole LM, Rosenberg MA:
Blind spot enlargement as a manifestation
of multifocal choroiditis. Arch Ophthalmol
1991; 109:1403–1417.
13. Morgan CM, Schatz H: Recurrent multifocal
choroiditis. Ophthalmology 1986;
93:1138–1147.
14. Watzke RC, Packer AJ, Folk JC, et al:
Punctate inner choroidopathy. Am J
Ophthalmol 1984; 98:572–584.
15. Eldem B, Cumhur S: Punctate inner
choroidopathy and its differential diagnosis.
Ann Ophthalmol 1991; 23:153–159.
16. Gass JDM, Wilkinson CP: Follow-up study
of presumed ocular histoplasmosis. Trans
Am Acad Ophthalmol Otolaryngol 1972;
76:672–694.
17. Gutman FA: The natural cause of active
choroidal lesions in the presumed ocular
histoplasmosis syndrome. Trans
Ophthalmol Soc 1979; 777:515–541.
18. Elliott JH, Jackson DJ: Presumed
histoplasmatic maculopathy: clinical course
and prognosis in nonphotocoagulated
eyes. Int Ophthalmol Clin 1975; 15:29–30.
19. Francis PJ, Marinescu A, Fitzke FW, et al:
Acute zonal occult outer retinopathy:
towards a set of diagnostic criteria. Br J
Ophthalmol 2005; 89:70–73.
20. Gass JD, Agarwa A, Scott IU: Acute zonal
occult outer retinopathy: a long-term
follow-up study. Am J Ophthalmol 2002;
134:329–339.
21. Jacobson SG, Morales DS, Sun XK, et al:
Pattern of retinal dysfunction in acute zonal
occult outer retinopathy. Ophthalmology
1995; 102:1187–1198.
22. von Rückmann A, Fitzke FW, Bird AC:
Distribution of fundus autofluorescence
with a scanning laser ophthalmoscope.
Br J Ophthalmol 1995; 79:407–412.
23. von Rückmann A, Fitzke FW, Bird AC:
In vivo fundus autofluorescence in macular
dystrophies. Arch Ophthalmol 1997;
115:609–615.
24. Tiedeman JS: Epstein Barr viral antibodies
in multifocal choroiditis and panuveitis.
Am J Ophthalmol 1987; 103:659–663.
25. Spaide RF, Sugin S, Yannuzzi LA,
DeRosa JT: Epstein Barr virus antibodies in
multifocal choroiditis and panuveitis.
Am J Ophthamol 1991; 112:410–413.
26. Carrasco L, Ramos M, Galisteo R, et al:
Isolation of Candida famata from a patient
with acute zonal occult outer retinopathy.
J Clin Microbiol 2005; 43:635–640.

2072
 CHAPTER
160 Macular Epiretinal Membranes
Darin R. Haivala and David W. Parke II
INTRODUCTION
Iwanoff first described the abnormal proliferation of cellular
membranes on the inner retinal surface in 1865.1 Since this
initial description, surface proliferation in the macular region
has been subsequently described as epimacular membrane,
macular pucker, cellophane maculopathy, preretinal macular
fibrosis, wrinkling of the internal limiting membrane, among
others.2–8 Although histologically similar to epiretinal prolifera-
tion elsewhere associated with proliferative vitreoretinopathy, it
is clinically considered a separate entity based on its location,
clinical features, and clinical course. Most commonly, macular
epiretinal membranes (ERMs) are asymptomatic or cause mild
symptoms of metamorphopsia and/or modest decreased central
acuity. A minority of these membranes can cause sufficient
macular distortion and macular edema to induce clinicians to
recommend ERM removal via pars plana vitrectomy (PPV).
EPIDEMIOLOGY
While ERM formation has been associated with and results
from a variety of primary intraocular diseases, the vast majority
are considered to be idiopathic, unassociated with other sys-
temic or ocular disease. They are found most frequently over
the age of 50, and several large clinical studies have noted a
clinical prevalence of between 7% and 11.8%.9,10 Most of these
are asymptomatic, with many being extrafoveal in location.
There appears to be no significant gender predilection and
20–30% are bilateral. Posterior vitreous detachments are
present in up to 90% of clinically significant ERMs. (The
absence of a posterior vitreous detachment in the presence of an
‘ERM’ should alert the clinician to the probability of the
vitreomacular traction syndrome). Second eye involvement was
a b
reported in the Blue Mountains Eye Study to occur in 13.5% of
patients over a 5 year time period.11
Nonidiopathic ERMs have been associated with a wide
variety of vitreo-retinal diseases including retinal vascular
disease, vitreo-retinal inflammatory conditions, postoperative
(particularly scleral buckle) and posttraumatic states, inherited
and congenital posterior segment anomalies and syndromes,
and intraocular tumors. Inflammation and/or vascular leakage
appear to be common mediators. Retinal vascular diseases
associated with increased vascular permeability and ERMs
include diabetic and hypertensive retinopathy, venous occlusive
disease, angiomas, telangiectasis, as well as others (Fig. 160.1).12–23
Intraocular inflammation resulting in an inflammatory cellular
infiltrate in the vitreous may also be associated with ERM
formation. Any infectious or noninfectious ocular condition
resulting in intermediate or posterior uveitis may be causative.
Common examples include both toxoplasmosis and pars planitis
(Fig. 160.2).13,24-29 Ocular trauma, including both blunt and
penetrating injuries, particularly if there is associated vitreous
hemorrhage (as well as nearly all ocular surgery) may lead to
ERM formation or to worsening of preexisting ERMs.30–38
Although cataract surgery has been reported to be associated
with new ERMs in 9% of eyes, it is likely that a substantial per-
centage of these membranes were preexisting and undetected,
or were preexisting and worsened during the perioperative
period.
Epiretinal membrane formation is not uncommon following
successful retinal detachment surgery, occurring in 4–8% of
eyes. Retinal breaks both before and after laser or cryo-
retinopexy are frequently associated with subsequent retinal
surface membrane proliferation (Fig. 160.3).4,30–38 Among the
less common associations with ERM are retina tumors
(particularly vascular tumors) and retinitis pigmentosa.
FIGURE 160.1. (a) Acute CRVO. (b) ERM
development 1 year later.
2073
 RETINA AND VITREOUS

PATHOGENESIS AND PATHOLOGY

The cellular origin of epiretinal membranes has long been
debated, and almost every possibility has been considered. Iwanoff,
in 1865, implicated the endothelial cell in the formation of the
membranes.1 Manschot, in 1958, believed that the membrane
was an extension of the Müller cell processes,39 whereas Wolter
considered the cells to originate from fibroblasts in the vascular
connective tissue.40 Smith suggested that the cells in the mem-
brane originated from the pigmented or nonpigmented cells of
the pars ciliaris, retinal pigment epithelium (RPE) cells, meso-
dermal elements of the vascular system, normal vitreous cells,
inflammatory cells within the vitreous, or retinal glial cells.41 In
1962, Kurz and Zimmerman believed that the cells originated
from migration of RPE cells.42 Ashton later suggested that the
cells originated from a transformation of vascular mesenchymal
cells into fibroblasts,43 and in 1969, von Gloor proposed that
hyalocytes were the cells of origin.44
SECTION 10

The advent of vitreous surgery has provided an opportunity

to advance our understanding of the clinicopathologic relation-
ships of epiretinal membranes. Numerous authors have
attempted to characterize the cells of origin and correlate this
FIGURE 160.2. ERM after exogenous endophthalmitis. with the ERM etiology. Many studies have determined that the
predominant cells types in idiopathic ERMs removed at surgery
include glial cells or fibrous astrocytes and (particularly with
clinically severe membranes) elements of retinal pigment
epithelial cells, fibrocytes, and macrophages. This is consistent
Key Features with a theory of idiopathic ERM pathogenesis first advanced by
Causes of Macular ERMs Roth and Foos.
• Idiopathic Foos suggested that the glial cells found in the thin,
• Retinal vascular disease idiopathic membranes were derived from the glial cells of the
• Diabetic retinopathy superficial retina (fibrous astrocytes and Muller cells) that had
• Retinal vein occlusion migrated through breaks in the internal limiting membrane
• Perifoveal telangiectasia syndrome (ILM) to proliferate on the retinal surface.45 These ILM breaks
• Other were hypothesized to be associated with acute separation of the
• Posterior segment inflammatory disease posterior vitreous from the macular region (where it has rela-
• Idiopathic posterior uveitis tively tight adherence). This hypothesis was subsequently sup-
• Sarcoidosis ported by Bellhorn and associates.46
• Pars planitis ERMs occurring following retinal breaks and detachment are
• Other felt to have a different pathogenesis. In these situations, retinal
• Posttraumatic pigment epithelial (RPE) cells gain access to the vitreous cavity
• Postoperative through the retinal break and settle on the macular surface,
• Retinal reattachment surgery subsequently developing a membrane. These membranes are
• Treatment of retinal break architecturally enhanced by the presence of fibrocytes and macro-
• Retinal break phages, stimulated in part by the inflammation associated with
• Intraocular tumors vitreous hemorrhage and/or surgical repair.
• Angiomas Most published reports on the ultrastructure of epiretinal
• Other macular membranes have been on vitrectomy specimens in
• Miscellaneous elderly patients. Vinores and colleagues studied the ultra-
• Retinitis pigmentosa structural and electron immunocytochemical characterization
• Combined hamartoma of the RPE of cells in epiretinal membranes. Their work suggests that both
RPE cells and retinal glial cells are most likely to be the major

FIGURE 160.3. (a) ERM following cryotherapy

of a peripheral retinal break. (b) OCT showing
highly reflective ERM, corrugation of retinal
surface, loss of foveal depression, and
increased central macular thickness.

a b

2074

participants in the pathogenesis of epiretinal membranes.47
Smiddy and co-workers reported on membranes removed in
children and young adults. They noted that myofibroblasts,
myoblastic differentiation of RPE cells and fibrous astrocytes,
and new collagen formation tended to be found more frequently
in younger patients.48 The progressive tangential and antero-
posterior traction exerted by ERMs is likely due to the myofibro-
plast characteristics of the membrane which have been
determined on immunohistochemical staining to contain actin,
transforming growth factor, and fibronectin.49
The dispersion of RPE cells on the retinal surface has been
demonstrated clinically and experimentally in cases of retinal
breaks and detachment.50–54 However, the finding of RPE cells
in idiopathic membranes is more difficult to explain. Smiddy
and colleagues suggested that the RPE cells gain access to the
retinal surface by various methods including migration through
occult breaks, by inactivation of developmental rests of RPE
cells already on the surface of the retina, through transforma-
tion from other cell types, or via transretinal migration.55 The
exact mechanism or combination of mechanisms is yet to be
elucidated. Stern and co-workers56 suggested that the contrac-
tive forces of the membranes were related to their constituent
cell types and not dependent on intercellular collagen, as sug-
gested by previous investigators.57
Collagen is a component of all surgically removed epiretinal
membranes. The abundance of collagen in some membranes
and the presence of fibrocytic and macrophage-like cells suggest
that vitreous hyalocytes may be a significant premetaplasia cell
of origin in these collagen membranes.58
CLINICAL FINDINGS: SYMPTOMATOLOGY
Symptoms associated with epiretinal membrane formation vary
greatly depending on the location and characteristics of the
membrane as well as the amount of underlying macular archi-
tectural disruption. Patients with membranes that are very thin
or outside the central macula are oftentimes completely asymp-
tomatic. It is not uncommon for these patients to have normal
or near-normal visual acuity. Subtle complaints of blurring of
vision or metamorphopsia may develop with increasing trac-
tion, membrane opacification, or macular edema, and the onset
is often insidious. These patients typically remain very stable
with only 10–25% of patients losing one or two lines of vision
over a 2 year time period.11,23,59–62 Of those patients with idio-
pathic membranes, two-thirds will have 20/30 or better vision
and 85% will display a visual acuity of 20/70 or better.8,63 At the
opposite end of the spectrum are those patients with very thick
central membranes associated with significant underlying
retinal architectural distortion, subtle detachment of the
posterior pole, and/or macular edema. Visual acuity at or below
a b
Macular Epiretinal Membranes
the 20/200 level may be seen in a small number of patients
(~5%).64–66 Other complaints may include monocular diplopia
and macro or micropsia.
Clinicians will encounter cases of patients with substantially
decreased vision but clinically unimpressive ERMs. In such
situations, substantial macular edema or (more rarely) a lamellar
or full-thickness macular hole may be present. On the other
hand, a clinically impressive ERM but with a central pseudo-
hole may result in preservation of good central visual acuity.
Optical coherence tomography (OCT) assists substantively in
the evaluation of these patients.
CLINICAL ASSESSMENT
Evaluation of an eye with a suspected ERM begins first with
testing of central visual acuity and central visual fields (such as
via an Amsler grid). Retinal distortion or macular heterotopia
may induce metamorphopsia and Amsler grid abnormalities.
CHAPTER 160
Indirect ophthalmoscopy and slit-lamp biomicroscopy consti-
tute the next major element in the evaluation process. The
clinical findings differ greatly depending on the severity of the
membrane and whether it has undergone significant contrac-
tion. The membrane may be very fine and translucent without
an identifiable edge. These may be identifiable only on careful
contact lens biomicroscopy and can be as subtle as a fine ‘sheen’
in the macular region. There may be blunting or an irregularity
of the foveal light reflex. These finding may be best appreciated
on red-free or monochromatic green or blue light. Vascular
tortuosity may be more evident on fluorescein angiography than
on clinical inspection (Fig. 160.4). In such cases, visual acuity
may be determined principally by the amount of associated
macular edema or macular detachment.
More extensive membranes may take on an opaque appear-
ance and obscure underling retinal vasculature. They may be
pigmented, particularly in the case of membrane formation
following the treatment of a retinal break or retinal detachment,
severe intraocular inflammation, or vitreous hemorrhage.67–69
More severe membranes may be contractile and result in iden-
tifiable striae at the level of the internal limiting membrane and
inner retina, or true retinal folds. The contraction of the mem-
brane may also result in traction on surrounding retinal vessels
resulting in abnormal distortion and a tethering effect. It is
not uncommon for the major vasculature to have a more
‘straightened’ appearance than that of the fellow eye. Contrac-
tion may also result in macular ectopia and traction. The
resulting macular heterotopia may cause diplopia. Contraction
may also lead to foveolar detachment.
Small intraretinal hemorrhages as well as evidence of pre-
sumed axoplasmic stasis or ischemia may be seen as a result of
ERM-induced vascular traction. The axoplasmic stasis can
FIGURE 160.4. (a) Idiopathic ERM.
(b) Fluorescein image demonstrating
combination of vascular tortuosity and
straightening.
2075
 RETINA AND VITREOUS

manifest itself as cotton-wool spots as well as larger areas of

Key Features
inner retinal whitening.70 Additional biomicroscopic findings
Value of OCT in Macular ERMs
may include macular edema with cystic changes, subfoveal
• Diagnostic confirmation
retinal pigment epithelial changes, and macular pseudoholes
• Poor visualization
which have been reported in up to 8–20% of eyes with epiretinal
• Topographic localization
membranes.71–74 Epiretinal membranes are found in up to 30%
• Vitreoretinal relationships
of patients with true full-thickness macular holes and these
• Associated vitreomacular traction
must be differentiated from pseudoholes.23,75
• Points of attachment
A posterior vitreous separation is present in up to 80–90% of
• Multilaminar membranes
patients with epiretinal membrane, but the true vitreoretinal
• Identify coincident pathology
relationships may be difficult to discern clinically.8,23,59,60,63,66,76
• Macular holes
Margherio et al noted that the vitreoretinal interface relation-
• Macular pseudoholes
ships were more accurately evaluated at the time of vitrectomy
• Macular edema
surgery by observing the effects of surgical manipulation on the
• Age-related macular degeneration
underlying retina.77 In some cases, large areas of vitreous col-
• Assist in preoperative patient counseling
lapse noted intraoperatively with an adherent posterior hyaloid
• Evaluation of postoperative status
were misinterpreted as a true vitreous separation preoperatively.
• Macular thickness
In eyes with a partial vitreous separation, spontaneous mem-
SECTION 10

• Membrane regrowth
brane avulsion with the complete detachment of the posterior
vitreous has been reported.78 The spontaneous ‘peeling’ of an
epiretinal membrane has also been described in patients with a can assist in postoperative management by assessing macular
complete vitreous separation. An edge of the ERM may ‘scroll’ thickness and membrane re-growth.
upon itself, contracting to the other edge of the membrane Fluorescein angiography, although still useful in evaluating
resulting in spontaneous visual improvement.23,79 selected ERM cases, has been partially supplanted by OCT. The
Any eye with an ERM and without evidence of a clear pos- principal utility of angiography in the setting of an ERM is to
terior vitreous separation must be carefully inspected clinically rule out the concomitant presence of retinal vascular disease or
and by OCT for evidence of the vitreomacular traction syn- of underlying pigment epithelial pathology. In some ERM cases
drome (VMTS) (Fig. 160.5). In the VMTS, a partially detached with intraretinal hemorrhages, it may be impossible to rule out
posterior hyaloid retains attachments in the posterior pole an associated small branch retinal vein occlusion by ophthal-
resulting in traction upon the macular region. VMTS frequently moscopy alone. Similarly, it may be necessary to perform
coexists with an epiretinal membrane. Complete surgical fluorescein angiography to rule out the presence of a choroidal
management therefore requires not only removal of VMTS- neovascular membrane in the patient with substantial intra-
induced traction, but also removal of any associated epiretinal retinal and/or submacular fluid. Finally, stereo fundus photo-
tissue. graphy and angiography may assist in delineation of vitreoretinal
Attention must always be paid to the peripheral retina as relationships, ERM borders, and degree of retinal vascular dis-
well. The new diagnosis of an ERM, particularly if purely uni- tortion in the difficult-to-examine patient.
lateral, pigmented, or associated with pigmented vitreous cells,
must stimulate a careful examination for a peripheral retinal
break. This is not only an etiologic consideration, but impor-
tant in ultimate management plans.
OCT can play an important role in the clinical assessment of
eyes with ERMs (Fig. 160.6). OCT can not only detect ERMs,
but also assist in topographic localization, identification of
vitreoretinal relationships (such as in the vitreomacular traction
syndrome), detection of macular holes, and quantitation of
macular thickness and macular volume. In addition to value in
clinical characterization, OCT has therapeutic value in pre-
operative planning. The co-existence of a macular hole, the
presence of a bilaminar ERM, or knowledge of substantive
macular edema may lead the surgeon to modify his or her FIGURE 160.6. OCT showing typical ERM features including highly
approach. It also has considerable prognostic value in coun- reflective ERM, multiple points of retinal attachment, loss of foveal
seling patients as to the eye’s likely visual potential. Finally, it depression, and increased retinal thickness.

FIGURE 160.5. (a) Fundus photograph

demonstrating loss of central foveal depression.
(b) OCT demonstrating central vitreomacular
traction and traction retinal elevation.

a b
2076

TREATMENT
The vast majority of patients who present with epiretinal mem-
brane will remain stable if observed over a period of time.11,60,66,80
From the standpoint of the surgeon and the patient, this is
characteristically not an inexorably progressive disease.
However, visual function may progressively deteriorate in some
patients, due to progressive membrane thickening, retinal
distortion, macular edema, lamellar hole formation, or retinal
pigment epithelial change. Episodes of intraocular inflammation
or intraocular surgery may be followed by alterations in ERM
architecture or the amount of associated macular edema.
Therefore, it is impossible to predict for any patient what will
be the course of any specific ERM. This renders decisions
difficult regarding surgery and the timing of surgery. In cases
with significant or progressive vision loss, debilitating
metamorphopsia or diplopia, surgical intervention should be
considered. Most surgeons reserve surgery for those patients with
vision reduction at least to the 20/50–20/60 level, although
earlier surgery may be considered for those with debilitating
symptoms or specific visual needs. The goals of surgical
intervention include the removal of all epimacular tissue and
relief of all macular traction with the subsequent resolution of
underlying-traction-induced retinal folds, macular edema, as
well as traction-induced axoplasmic stasis.81
Once the surgeon and the patient have elected to proceed
with surgery, conventional 20-, 23-, or 25-gauge vitrectomy is
carried out. A core vitrectomy is completed and the posterior
cortical vitreous should be elevated and excised in those cases
where a complete vitreous separation is not present. (As noted
earlier, posterior vitreous separation is present in the vast
majority of ERM cases. Anteroposterior traction indicates that
the vitreomacular traction syndrome is present.) Attention is
then turned to the macular surface. A prominent edge of the
epiretinal tissues can often be identified and this provides a con-
venient location in which to engage the ERM. Using a barbed
micro-vitreoretinal blade, bent 25-gauge needle, or retinal pick,
the edge of the membrane can be ‘engaged’ in a tangential,
‘dragging’ fashion, elevating the membrane edge. An alternative
method involves using an intraocular diamond dusted or end-
grasping forceps to ‘pinch’ the membrane and initiate removal.
In cases where a defined edge is not identifiable, the same
‘dragging’ maneuver can be used to ‘snag’ the membrane
resulting in the elevation of a piece of the membrane that can
be further advanced. Additional tools, such as the Tano Diamond
Dusted Membrane Scraper,82,83 can be very helpful in ‘snagging’
the membrane in cases where an identifiable edge is not present.
Recently, the use of surgical adjuncts to help visualize the mem-
a b
FIGURE 160.7. (a) ERM following treatment of a retinal detachment. (b) Fluorescein angiography showing ERM and retinal edema.
(c) Appearance following vitrectomy with removal of ERM.
Macular Epiretinal Membranes
brane has gained popularity. Indocyanine green, trypan blue,
and triamcinolone acetonide have been used to help visualize
epiretinal tissue to facilitate its complete removal.84-91
Once an edge has been elevated, the ‘peeling’ of the tissue can
be advanced using intraocular forceps, regrasping the mem-
brane near the retinal surface while advancing across the pos-
terior pole. This should be carried out in a tangential fashion,
limiting anterior traction. Care should be taken to minimize
traction on a very cystic macula to mitigate the risk of ‘unroofing’
a large central cyst. It is not uncommon for a seemingly
localized ERM to extend well beyond the major vascular arcades.
The extent of more peripheral membranectomy should depend
on ease of removal and associated pathology. After the mem-
brane has been elevated, it is not uncommon to see superficial
retinal whitening in the area where the membrane has been
removed. It is important to differentiate this whitening from
residual epiretinal tissue in the cases of multilayered mem-
branes. As always, care should be taken to ensure that peri-
CHAPTER 160
pheral or mid-peripheral retinal breaks have not occurred with
instrument changes or with traction on the retina by extensive
membranes.
RESULTS OF SURGERY
In a majority of patients, the macular surface architecture is
greatly improved in the immediate postoperative period, though
short-term vision reduction beyond the preoperative level is not
uncommon (Figs 160.7 and 160.8). While immediate and signifi-
cant improvement in acuity may occur, it often takes 4–6 weeks
for the patient’s vision to return to the preoperative level, with
subsequent improvement over the ensuing 3-6 months. This
course can be modulated by factors most commonly including
cystoid macular edema, cataract formation, and ERM regrowth.
Numerous authors have attempted to identify prognostic
indicators of postoperative vision in vitrectomy for treatment of
ERMs. Indicators that have been mentioned are (1) preoperative
visual acuity, (2) duration of diminished acuity before surgery,
(3) the presence of preoperative cystoid macular edema, (4) the
age of the patient, (5) the thickness of the epiretinal membrane,
(6) idiopathic versus nonidiopathic epiretinal membranes, and
(7) the presence of RPE window defects on fluorescein angiography.
Trese and colleagues reported that transparent membranes had
a better visual prognosis than opaque ones. They also believed
that the presence of cystoid macular edema was a poor prog-
nostic sign.62 However, Rice and associates found that eyes with
thin, transparent membranes had a poorer prognosis than eyes
with thicker membranes.92 Several additional studies found no
association between the transparency of the membrane and the
c
2077
 RETINA AND VITREOUS
a b
SECTION 10
final postoperative vision.69 (Ferencz JR, Mussbaum JJ,
Richards SC, et al: Predictive variables in vitrectomy for idio-
pathic epimacular membranes. Presented at Schepens Alumni
Meeting, Boston, MA, 9 Jun 1990.) Other studies have also
suggested that the presence of cystoid macular edema is a poor
prognostic sign.62,92,93,94,95,96 However, larger series have shown
no relationship between the presence of preoperative cystoid
macular edema and the ultimate visual prognosis.97,98,99,100 Two
studies have suggested that even in eyes with severe degrees of
macular edema, epiretinal membrane peeling may significantly
improve visual acuity.101,102
It is worth noting that all of these series were performed
before the advent of intravitreal triamcinolone acetonide
injection, which is utilized as a surgical adjunct by many
surgeons when substantial preoperative cystoid macular edema
is identified. It is well recognized that even total removal of
ERMs (clinically and by postoperative OCT) may not achieve
normal macular thickness in all eyes.
The presence of portions of the internal limiting membrane
in surgical specimens has been evaluated as a possible prognos-
tic factor in epiretinal macular membrane surgery. Sivalingam
and associates found that surgical specimens from eyes con-
taining long segments of internal limiting membrane had a less
favorable visual prognosis.103 Other series did not find a similar
correlation.104,105 Some surgeons prefer to remove ILM as a
routine part of ERM surgery cases, with one preliminary study
suggesting a lower incidence of membrane recurrence.106
Nonidiopathic ERMs (particularly those following retinal
reattachment surgery) have been demonstrated to have an over-
all worse prognosis than idiopathic ERMs. This is correlated
with antecedent macular damage related to underlying pathol-
ogy such as a prior macula off retinal detachment or macular
ischemia or severe cystoid macular edema secondary to retinal
vascular disease. A recent paper studying ERM removal in eyes
following retinal detachment repair by Council and co-authors
noted that 88% of eyes experienced an improvement in acuity
postoperatively with 65% of eyes 20/60 or better; 6.7% of eyes
had a recurrent retinal detachment.107
In those patients undergoing surgery for removal of idiopathic
ERMs, 80–90% of patients will gain 2 Snellen lines.93,108,99 A
2 line gain was seen in 65–80% of patients with membranes
associated with previous retinal tear or detachment.108,99,109 While
the Snellen acuity improvement may be limitied in some, the
metamorphopsia is improved in most. In a series of 328 eyes,
Margherio, Cox, and Trese demonstrated visual acuity improve-
ment of at least 2 lines in 74% of patients. Twenty-four percent
were unchanged, and 2% were noted to have a reduction in their
preoperative visual acuity level.99 Twenty-five to fifty percent of
2078 eyes will achieve a final acuity of 20/40 or better.93,99,109,96
FIGURE 160.8. (a) Idiopathic ERM before
surgery. (b) Idiopathic ERM after vitrectomy
showing mild residual retinal fold.
Thompson, in a recent review of eyes with 20/50 or better
preoperative acuity, reported that mean postoperative
pseudophakic acuity improved to 20/32.110 Some patients will
describe a relief of metamorphopsia or diplopia which appears
more rewarding to them than their return of Snellen acuity.111
SURGICAL COMPLICATIONS
The most common postoperative complication following
vitrectomy for epiretinal membrane is progressive nuclear
sclerotic cataract in the phakic patient. This has been reported
in 12% to nearly 70% of patients.93,99,109,94,95,100,96,112 It is not
uncommon for patients to experience a gradual improvement in
vision follow vitrectomy surgery, followed by an insidious
decline as the nuclear sclerosis progresses. The final best-
corrected visual acuity may very well be following cataract
extraction. For this reason, some surgeons routinely recom-
mend combined phacoemulsification, posterior chamber
intraocular lens implantation and ERM removal in patients
with any preexisting nuclear sclerosis. The cataract surgery is
performed first, followed by the vitrectomy surgery. Even
patients without preexisting nuclear sclerosis are generally told
to expect more rapid progression of lens changes with a likeli-
hood of cataract surgery within several years.
From the opposite perspective, patients with visually signifi-
cant cataracts and ERMs judged to be clinically insignificant
should be informed that cataract surgery may carry with it a
higher postoperative incidence of cystoid macular edema and
worsening of the ERM.
Peripheral retinal tears are encountered in up to 6% of
cases.38,93,108,99,109,96 Tears are likely related to the insertion of
instruments through the vitreous base with resultant peripheral
retinal traction. In cases where the posterior cortical vitreous
remains attached, inducing a vitreous separation can also lead
to peripheral retinal tears. When identified, these tears should
be treated with either transcleral cryotherapy or laser photo-
coagulation, and occasionally fluid–air or gas exchange.
Posterior retinal breaks resulting from iatrogenic traction are
uncommon. Late retinal detachments have been reported in up
to 7% of patients undergoing vitrectomy surgery and are largely
related to missed peripheral tears or subsequent contraction of
the vitreous base or incarcerated vitreous with resultant tear
formation.93,108,112
The recurrence of significant epiretinal tissue following
vitrecomy is seen in up to 5% of patients, depending on the
underlying etiology.93,108,99,96 Whether the use of dyes and
substances to identify the membrane and/or internal limiting
membrane peeling will reduce this risk of recurrence is unclear.
Only a small percentage of membrane regrowths become visually
 Macular Epiretinal Membranes

significant. Other complications including endophthalmitis,
retinal phototoxicity, choroidal neovascularization, macular
hole, and visual field defects have also been described.113
CONCLUSION
Macular epiretinal membranes most commonly represent an
idiopathic growth of transparent tissue across the macular
region. The majority of these membranes are not visually sig-
nificant and do not require treatment. A minority of ERMs are
associated with a wide variety of ocular conditions generally
involving inflammation or retinal vascular leakage or prior
retinal detachment. Surgical intervention should be considered
when warranted by visual symptomatology. A discussion
regarding realistic postsurgical outcomes and well as the
potential risk of vitrectomy needs to be carried out prior to
proceeding with surgery. Vitrectomy with membrane removal
results in symptomatic improvement in a vast majority of
patients and plays a very important role in managing patients
with this relatively common condition.

REFERENCES
1. Iwanoff A: Beitrage zur normalen und
pathologischen anatommie des auges.
Grafes Arch Clin Exp Ophthalmol 1865;
11:135–170.
2. Roth AM, Foos RY: Surface wrinkling
vitrectomy. Trans Ophthalmol Soc UK 1985;
104:285–296.
17. Carney MD, Jampol LM: Epiretinal
membranes in sickle cell retinopathy.
Arch Ophthalmol 1987; 105:214–217.
32. Winthrop SR, Cleary PE, Minckler DS et al:
Penetrating eye injuries: a histopathological
review. Br J Ophthalmol 1980; 64:809–817.
33. Green WR, Kenyon KR, Michels RG et al:
Ultrastructure of epiretinal membranes

retinopathy in eyes enucleated at autopsy.
Trans Am Acad Ophthalmol Otolaryngol
1971; 75:1047–1059.
3. Francois J, Verbraeken H: Relationship
between the drainage of the subretinal
fluid in retinal detachment surgery and
the appearance of macular pucker.
Ophthalmologica 1979; 179:111–114.
4. Tanenbaum HL, Schepens CL, Elzeneiny I,
Freeman HM: Macular pucker following
retinal detachment surgery. Arch
Ophthalmol 1970; 83:286–293.
5. Tannenbaum HL, Schepens CL,
Elzeneiny I, Freeman HM: Macular pucker
following retinal detachment surgery.
A biomicroscopic study. Can J Ophthalmol
1969; 4:20–23.
6. Jaffe NS: Macular retinopathy after
separation of vitreoretinal adherence.
Arch Ophthalmol 1967; 78:585–591.
7. Maumenee AE: Further advances in the
study of the macula. Arch Ophthalmol
1967; 78:151–165.
8. Wise GN: Preretinal macular fibrosis (an
analysis of 90 cases). Trans Ophthalmol
Soc UK 1972; 92:131–140.
9. Mitchell P, Smith W, Chey T et al:
Prevalence and associations of epiretinal
membranes. The Blue Mountains Eye Study,
Australia. Ophthalmology 1997; 1022–1040.
10. Klein R, Klein BE, Wang Q et al: The
epidemiology of epiretinal membranes.
Trans Am Ophthalmol Soc 1994; 92:
403–425.
11. Fraser-Bell S, Guzowski M, Rochtchina E
et al: Five-year cumulative incidence and
progression of epiretinal membranes: the
Blue Mountains Eye Study. Ophthalmology
2003; 110:34–40.
12. Lyle DJ: Detachment of the internal limiting
membrane of the retina (hyaloid
membrane). Trans Am Ophthalmol Soc
1934; 39:201–217.
13. Appiah AP: Secondary causes of
premacular fibrosis. Ophthalmology 1989;
96:389–392.
14. Wise GN: Macular changes after venous
obstruction. Arch Ophthalmol 1957;
58:544–557.
15. Tang S, Le-Ruppert KC, Gabel VP:
Proliferation and activation of vascular
endothelial cells in epiretinal membranes
from patients with proliferative diabetic
retinopathy. An immunohistochemistry and
clinical study. Ger J Ophthalmol 1994;
3:131–136.
16. Barry PJ, Hiscott PS, Grierson I et al:
Reparative epiretinal fibrosis after diabetic
18. Laatikainen L, Immonen I, Summanen P:
Peripheral retinal angioma-like lesion and
macular pucker. Am J Ophthalmol 1989;
108:563–566.
19. McDonald HR, Schatz H, Johnson RN et al:
Vitrectomy in eyes with peripheral retinal
angioma associated with traction macular
detachment. Ophthalmology 1996;
103:329–335; discussion 34–35.
20. Moriarty BJ, Acheson RW, Serjeant GR:
Epiretinal membranes in sickle cell disease.
Br J Ophthalmol 1987; 71:466–479.
21. Nicoletti VG, Nicoletti R, Ferrara N et al:
Diabetic patients and retinal proliferation:
and evaluation of the role of vascular
endothelial growth factor (VEGF).
Exp Clin Endocrinol Diabetes 2003;
111:209–214.
22. Schwartz PL, Fastenberg DM, Shakin JL:
Management of macular puckers
associated with retinal angiomas.
Ophthalmol Surg 1990; 21:550–556.
23. Gass JDM: Stereoscopic atlas of macular
disease. St Louis: Mosby; 1997.
24. Augustin AJ, Spigtznas M, Koch F et al:
Indicators of oxidative tissue damage
and inflammatory activity in epiretinal
membranes of proliferative diabetic
retinopathy, proliferative vitreoretinopathy,
and macular pucker. Ger J Ophthalmol
1995; 4:47–51.
25. Charteris DG, Hiscott P, Grierson I et al:
Proliferative vitreoretinopathy. Lymphocytes
in epiretinal membranes. Ophthalmology
1992; 99:1364–1367.
26. Kiryu J, Kita M, Tanabe T et al: Pars plana
vitrectomy for epiretinal membrane
associated with sarcoidosis. Jpn J
Ophthalmol 2003; 47:479–483.
27. McDonald HR, De Bustros S, Sipperley JO:
Vitrectomy for epiretinal membrane with
Candida chorioretinitis. Ophthalmology
1990; 97:466–469.
28. Naoi N, Sawada A: Effect of vitrectomy on
epiretinal membranes after endogenous
fungal endophthalmitis. Jpn J Ophthalmol
1996; 40:434–438.
29. Repka MX, Green WR: Epiretinal
membrane: an unusual complication of
childhood optic neuritis. J Pediatr
Ophthalmol Strabismus 1996; 33:124–127.
30. Hagler WS, Aturaliya U: Macular puckers
after retinal detachment surgery. Br J
Ophthalmol 1971; 55:451–457.
31. Michels RG, Gilbert HD: Surgical
management of macular pucker after retinal
reattachment surgery. Am J Ophthalmol
1979; 88:925–929.
CHAPTER 160
causing macular pucker after retinal
reattachment surgery. Trans Am
Ophthalmol Soc 1979; 99:63–77.
34. Jahn CE, Minich V, Moldaschel S et al:
Epiretinal membranes after extracapsular
cataract surgery. J Cataract Refract Surg
2001; 27:753–760.
35. Saran BR, Brucker AJ: Macular epiretinal
membrane formation and treated retinal
breaks. Am J Ophthalmol 1995;
120:480–485.
36. Lincoff HA, McLean JM: Cryosurgical
treatment of retinal detachment. Am J
Ophthalmol 1966; 61:1227–1234.
37. Lobes LAJ, Burton TC: The incidence of
macular pucker after retinal detachment
surgery. Am J Ophthalmol 1978; 85:72–77.
38. Michels RG: Vitretomy for macular pucker.
Ophthalmology 1984; 91:1384–1388.
39. Manschot WA: Persistent hyperplastic
primary vitreous: special reference to
preretinal glial tissue as a pathological
characteristic and to the development of
the primary vitreous. Arch Ophthalmol
1958; 59:188.
40. Wolter JR: Glia of human retina. Am J
Ophthalmol 1959; 48:370.
41. Smith TR: Pathologic findings after retina
surgery. In: Schepens C, ed. Importance
of the vitreous body in retina surgery with
special emphasis on reoperations.
St Louis: Mosby; 1960.
42. Kurz GH, Zimmerman LE: Vagaries of the
retinal pigment epithelium. Int Ophthalmol
Clin 1962; 2:441.
43. Ashton N: Oxygen and the growth and
development of retinal vessesl: in vivo and
in vitro studies. The XX Francis I. Proctor
Lecture. Am J Ophthalmol 1966; 62:412.
44. von Gloor BP: Mitotic activity in the
cortical vitreous cells (hyalocytes) after
photocoagulation. Invest Ophthalmol 1969;
8:633
45. Foos RY: Vitreoretinal juncture-Simple
epiretinal membranes. Graefes Arch CLin
Exp Ophthalmol 1974; 189:231–250.
46. Bellhorn MB, Friedman AH, Wise GN,
Henkind P: Ultrastructure and
clinicopathologic correlation of idiopathic
preretinal macular fibrosis. Am J
Ophthalmol 1975; 79:366–373.
47. Vinores SA, Campochiaro PA, Conway BP:
Ultrstructural and electron
immunocytochemical characterization of
cells in epiretinal membranes. Invest
Ophthalmol VIs Sci 1990; 31:14–28.
48. Smiddy W, Michels RG, Gilbert HD, Green
WR: Clinicopathologic study of idiopathic 2079
 RETINA AND VITREOUS
macular pucker in children and young
adults. Retina 1992; 12:232–236.
49. Hui YN, Goodnight R, Zhang HJ et al:
Glial epiretinal membranes and contraction.
Immunohistochemical and morphological
studies. Arch Ophthalmol 1988; 106:
1280–1285.
50. Campochiaro PA, Kaden IH, Vidaurri-Leal J,
Glaser BM: Cryotherapy enhances
intravitreal dispersion of viable retinal
pigment epithelial cells. Arch Ophthalmol
1985; 103:434–436.
51. Machemer R, Laqua H: Pigment epithelium
proliferation in retinal detachment (massive
preretinal proliferation). Am J Ophthalmol
1975; 80:1–23.
52. Machemer R, Van Horn D, Aaberg TM:
Pigment epithelial proliferation in human
retinal detachment with massive periretinal
proliferation. Am J Ophthalmol 1978;
85:181–191.
SECTION 10
53. Newsome DA, Rodrigues MM,
Machemer R: Human massive periretinal
proliferation. In vitro characteristics of
cellular components. Arch Ophthalmol
1981; 99:878–880.
54. Wallo IHL, Miller SA: Preretinal membrane
by retinal pigment epithelium. Arch
Ophthalmol 1978; 96:1643–1646.
55. Smiddy WE, Maguire AM, Green WR, et al:
Idiopathic epiretinal membranes.
Ophthalmology 1989; 96:811–821.
56. Stern WH, Fisher SK, Anderson DH, et al:
Epiretinal membrane formation after
vitrectomy. Am J Ophthalmol 1982;
93:757–772.
57. Daicker B, Guggenheim R:
Rasterelektronenmikroskopische
untersuchungen an fibrosen und fibro-
gliosen epiretinalen fibrplasien. Graefes
Arch Clin Exp Ophthalmol 1978;
207:229–242.
58. Trese MT, Chandler DB, Machemer R:
Macular pucker II. Ultrastructure. Graefes
Arch Clin Exp Ophthalmol 1983; 221:16–26.
59. Scudder JM, Eifrig DE: Spontaneous
surface wrinkling retinopathy. Ann
Ophthalmol 1975; 7:333–341.
60. Sidd RJ, Fine Sl, Owens SL et al: Idiopathic
preretinal gliosis. Am J Ophthalmol 1982;
94:44.
61. Spitznas M, Leuenberger R: Die primare
epiretinale gliose. Klin Monatsbl Augeneilkd
1977; 171:410.
62. Trese MT, Chandler DB, Machemer R:
Macular pucker. Prognostic criteria.
Graefes Arch Clin Exp Ophthalmol 1983;
221:12–15.
63. Hirokawa H, Jalhk AE, Takahashi M et al:
Role of the vitreous in idiopathic preretinal
macular fibrosis. Am J Ophthalmol 1986;
101:166–169.
64. Kuriyama S, Matsumura M, Harada T et al:
Surgical techniques and reattachments
rates in retinal detachment due to
macular hole. Arch Ophthalmol 1990;
1089:1559.
65. Wise GN: Clinical features of idiopathic
preretinal macular fibrosis. Am J
Ophthalmol 1975; 79:349.
66. Wiznia RA: Natural history of idiopathic
preretinal macular fibrosis. Ann Ophthalmol
1982; 14:876–878.
67. Dellaporta A: Macular pucker and
peripheral retinal lesions. Trans Am
Ophthalmol Soc 1973; 71:329–340.
68. Laqua H: Pigmented macular pucker. Am J
2080 Ophthalmol 1978; 86:56–58.
69. Robertson DM, Buettner H: Pigmented
preretinal membranes. Am J Ophthalmol
1977; 83:824–829.
70. Arroyo JG, Irvine AR: Retinal distortion and
cottonwool spots associated with epiretinal
membrane contraction. Ophthalmology
1995; 102:662–668.
71. Klein BR, Hiner CJ, Glaser BM et al:
Fundus photographic and fluorescein
angiographic characteristics of
pseudoholes of the macula in eyes with
epiretinal membranes. Ophthalmology
1995; 102:768–774.
72. Martinez JM, Smiddy WE, Kim J et al:
Differentiating macular holes from macular
pseudoholes. Am J Ophthalmol 1994;
762–767.
73. Massin P, Paques M, Masri H et al: Visual
outcome of surgery for epiretinal
membranes with macular pseudoholes.
Ophthalmology 1999; 106:580–585.
74. Smiddy WE, Gass JDM: Masquerades of
macular holes. Ophthalm Surg 1995;
26:16–24.
75. Johnson RN, Gass JDM: Idiopathic
macular holes: observations, stages of
formation, and implications for surgical
intervention. Ophthalmology 1988;
95:917–924.
76. Fine S: Idiopathic preretinal macular
fibrosis. Int Ophthalmol Clin 1977;
17:183–189.
77. Margherio RR, Trese MT, Margherio AR,
Cartright K: Surgical management of
vitreomacular traction syndromes.
Ophthalmology 1989; 96:1437–1445.
78. Greven CM, Slusher MM, Weaver RG:
Epiretinal membrane release and posterior
vitreous detachment. Ophthalmology 1988;
95:902–905.
79. Mulligan TG, Daily MJ: Spontaneous
peeling of an idiopathic epiretinal
membrane in a young patient. Arch
Ophthalmol 1992; 110:1367–1368.
80. Noble KG, Carr RE: Idiopathic preretinal
gliosis. Ophthalmology 1982; 89:521–523.
81. Reeser FH, Aaberg TM: Vitreous humor.
In: Records RE, ed. Physiology of the
human eye and visual system. Hagerstown,
MD: Harper and Row; 1979.
82. Johnston RL: Modification of the Tano
diamond dusted scraper. Retina 2000;
20:427.
83. Kuhn F, Mester V, Berta A: The Tano
diamond dusted membrane scraper:
indications and contraindications.
Acta Ophthalmol Scand 1998;
76:754–755.
84. Sakamoto H, Yamanaka I, Kubota T, et al:
Indocyanine green assisted peeling of the
epiretinal membrane in proliferative
vitreoretinopathy. Graefes Arch Clin Exp
Ophthalmol 2003; 241: 204–207.
85. Perrier M, Sebag M: Epiretinal membrane
surgery assisted by trypan blue. Am J
Ophthalmol 2003; 135:909–911.
86. Fraser EA, Cheema RA, Roberts MA:
Triamcinolone acetonide-assisted peeling
of retinal internal limiting membrane for
macular surgery. Retina 2003; 23:883–884.
87. Kimura H, Kuroda S, Nagata M:
Triamcinolone acetonide-assisted peeling
of the internal limiting membrane. Am J
Ophthalmol 2004; 137:172–173.
88. Burk SE, Da Mata AP, Snyder ME et al:
Indocyanine green assisted peeling of the
retinal internal limiting membrane.
Ophthalmology 2000; 107:2010–2014.
89. Feron EJ, Veckeneer M, Parys-van
Ginderdeuren R et al: Trypan blue staining
of epiretinal membranes in proliferative
vitreoretinopathy. Arch Ophthalmol 2002;
120:141–144.
90. Hillenkamp J, Saika P, Gora F et al:
Macular function and morphology after
peeling of idiopathic epiretinal membrane
with and without the assistance of
indocyanine green. Br J Ophthalmol 2005;
89:437–443.
91. Haritoglou C, Eibl K, Schaumberger M
et al: Functional outcome after trypan
blue-assisted vitrectomy for macular
pucker: a prospective, randomized,
comparative trial. Am J Ophthalmol
2004; 138(1):1–5.
92. Rice TA, de Bustros S, Michels RG, et al:
Prognostic factors in vitrectomy for
epiretinal membranes of the macula.
Ophthalmology 1986; 93:602–610.
93. McDonald HR, Verre WP, Aaberg TM:
Surgical management of idiopathic
epiretinal membranes. Ophthalmology
1986; 93:978–983.
94. Michels RG: Vitreous surgery for macular
pucker. Am J Ophthalmol 1981;
92:628–639.
95. Michels RG: A clinical and hisopathologic
study of epiretinal membranes affection the
macula and removed by vitreous surgery.
Trans Am Ophthalmol Soc 1982;
100:580–656.
96. de Bustros S, Thompson JT, Michels RG
et al: Vitrectomy for idiopathic epiretinal
membranes causing macular pucker.
Br J Ophthalmol 1988; 72:692–695.
97. Margherio RR: Epiretinal membrane.
(Discussion). Ophthalmology 1984;
91:1387–1388.
98. von Gunten S, Pournaras CJ, de Gottrau P,
Brazitikos P: Facteurs prognostiques du
traitement chirurgical des membranes
epiretiniennes. Klin Monatsbl Augenheilkd
1994; 204:309–312.
99. Margherio RR, Cox MS Jr, Trese MT et al:
Removal of epimacular membranes.
Ophthalmology 1985; 92:1075–1083.
100. Pesin SR, Olk RJ, Grand MG et al:
Vitrectomy for premacular fibroplasia.
Prognostic factors, long-term follow-up,
and time course of visual improvement.
Ophthalmology 1991; 98:1109–1114.
101. Maguire AM, Margherio RR, Dmuchowski C:
Preoperative flourescein angiographic
features of surgically removed idiopathic
epiretinal membranes. Retina 1994;
14:411–416.
102. Ma SS, Barloon S, Maberley AL, Kestle J:
Effect of macular edema on surgical visual
outcome in eyes with idiopathic epiretinal
membrane. Can J Ophthalmol 1996;
31:183–186.
103. Sivalingam A, Eagle RC Jr, Duker JS, et al:
Visual prognosis correlated with the
presence of internal-limiting membrane in
histiophathologic specimens obtained from
epiretinal membrane surgery.
Ophthalmology 1990; 97:1549–1552.
104. Kampik A, Green WR, Michels RG,
Nase PK: Ultrastructureal features of
progressive idiopahtic epiretinal
membrane removed by vitreous
surgery. Am J Ophthalmol 1980;
90:797–809.
105. Smiddy WE, Maguire AM, Green WR, et al:
Idiopathic epiretinal membranes.
Ophthalmology 1989; 96:811–821.

106. Park DW, Dugel PU, Garda J et al: Macular
pucker removal with and without internal
limiting membrane peeling : pilot study.
Ophthalmology 2003; 110: 62–64.
107. Council MD, Shah GK, Lee HC et al: Visual
outcomes and complications of epiretinal
membrane removal secondary to
rhegmatogenous retinal detachment.
Ophthalmology 2005; 112: 1218–1221.
108. de Bustros S, Rice TA, Michels RG et al:
Vitrectomy for macular pucker after
treatment of retinal tears or retinal
detachment. Arch Ophthalmol 1988;
106:758–760.
109. Poliner LS, Olk RJ, Grand MG et al:
The surgical management of premacular
fibroplasia. Arch Ophthalmol 1988;
106:761–764.
110. Thompson JT: Epiretinal membrane
removal in eyes with good visual acuities.
Retina 2005; 25: 875–882.
111. Ghazi-Nouri SM, Tranos PG, Rubin GS
et al: Visual function and quality of life
following vitrectomy and epiretinal
Macular Epiretinal Membranes
membrane peel surgery. Br J Ophthalmol
2006; 90: 559–562.
112. de Bustros S, Thompson JT, Michels RG
et al: Nuclear sclerosis after vitrectomy for
idiopathic epiretinal membrane. Am J
Ophthalmol 1988; 105:160–164.
113. McDonald HR, Johnson RN, Ai E, et al:
Macular epiretinal membrane. In: Ryan SJ,
ed. Retina 4th edn. Philadelphia, PA
Mosby; 2006.
CHAPTER 160
2081
 CHAPTER

161 Acute Macular Neuroretinopathy

Lucy H. Y. Young and Donald J. D’Amico

Acute macular neuroretinopathy was first described in 1975 by
Bos and Deutman.1 In their six patients, this entity was charac-
terized by a sudden onset of paracentral scotomas and the
presence of cloverleaf, wedge-shaped, darkish red lesions centered
around the fovea. Only a small number of cases have been
added subsequently.
Characteristically, visual acuity remains normal or is slightly
reduced.1–22 The chief complaint is usually related to the sudden
appearance of paracentral scotomas. This rare macular disease
can occur unilaterally or bilaterally, and the majority of patients
are young adults, mostly women. Many of these patients are
taking birth control pills.1,3–5,11–15,17–20 The visual disturbance is
often preceded by a bout of a flu-like syndrome, such as influenza,
pharyngitis, or enteritis.1,4,5,9,11,12,14,19–22
When patients are tested with the Amsler grid, they can
usually outline parafoveal negative scotomas, frequently in the
shape of teardrops, corresponding exactly with the fundus
lesions (Fig. 161.1).9,11–13,16 In patients whose fundus lesions are
less prominent, examination with red-free light may be useful
in highlighting the lesions. As mentioned by Guzak and
colleagues,4 this enhancement is probably related to the color of
the lesion rather than to the surface changes in the retina.
Although Bos and Deutman1 suggested that the fundus lesions
seen in their six patients were located in the inner retina,
thus the name acute macular neuroretinopathy, subsequent
reports relying on biomicroscopic examination, stereophoto-
graphs, fluorescein angiography, and electrodiagnostic testing
indicate that the acute macular neuroretinopathy lesions are

a b

c d e

FIGURE 161.1. This 42-year-old woman presented with a 3-week history of a flu-like syndrome before the onset of paracentral scotomas in the
left eye. Her past medical history was significant, for she had undergone hysterectomy and oophorectomy 2 years previously and had since
been using estradiol transdermal (Estroderm) patch. Her visual acuity was 20/20 in the left eye. (a) Note the darkish red lesions centered around
the fovea. (b) These lesions are better appreciated with red-free light. (c and d) Angiography results were normal. (e) Amsler grid testing showed
two paracentral scotomas.
(a–e) Courtesy of Jack F. Bowers, MD. 2083
 RETINA AND VITREOUS

located in the outer retinal layers.9,11,13 Scanning laser ophthal-
moscopy has been shown to be useful in enhancing the visibility
of the macular lesions.17,18 In addition to the deep, reddish
brown lesions, a few small, superficial retinal hemorrhages may
be present in the macula.2,9 The retinal vasculature, nerve fiber
layer, retinal pigment epithelium, and optic disk are normal,
and there are no vitreous cells. In symptomatic patients with
normal fundus examination, it is important to bear in mind
that the onset of visual symptoms of acute macular neuro-
retinopathy may occur few days before retinal lesions can be
visualized and thus close observation can be helpful.19
Fluorescein angiography studies are essentially normal.
Questionably dilated perimacular capillaries without leakage
and subtle hypofluorescence corresponding to the fundus lesions
have been reported.1,2,9 Similarly, no abnormalities are observed
with indocyanine green angiography.20 In two case reports,
optical coherence tomography (OCT) demonstrated a band of
hyperreflectivity at the outer retinal layer.21,22
SECTION 10
fosfestrol (an estrogen preparation) for a prostatic carcinoma at
the time of the onset of visual symptoms.6
O’Brien and co-workers8 reported three patients in whom
acute macular neuroretinopathy developed after acute hyper-
tension caused by intravenous sympathomimetics. Guzak and
colleagues4 reported two cases, and both of their patients experi-
enced macular neuroretinopathy after intravenous injections of
epinephrine for adverse reactions to contrast agents. However,
blood pressure readings were not reported in these two cases.
The temporal relationship between the development of acute
macular neuroretinopathy and the use of intravenous epine-
phrine suggests an association with either the hypertensive epi-
sodes or the sympathomimetics themselves. However, this would
not explain the other cases reported to date. Acute macular
neuroretinopathy has also been reported in two patients treated
with epinephrine for acute shock.23 In another case report
associated with epinephrine administration, multiple blood
pressure recordings were taken and they were all normal.16

Electrical testing, such as electroretinogram and electroocu- Gass and Hamed3 reported acute macular neuroretinopathy
logram studies, of patients afflicted with acute macular neuro- and multiple evanescent white dot syndrome occurring in the
retinopathy is normal.1,7,9,12 This is not unexpected because same patients. They compared the clinical features of acute
both tests measure mass physiologic responses and are not macular neuroretinopathy and multiple evanescent white dot
sensitive to pathologic processes confined to the macula alone. syndrome and suggested that these two rare syndromes may be
To address this issue, Sieving and associates13 recorded the early related pathogenetically and causally.
retinal potential responses from the posterior fundi in one The milder forms of acute macular neuroretinopathy, i.e.,
patient with unilateral acute macular neuroretinopathy. The when the characteristic macular lesions are not prominent, may
early retinal potential is generated in the photoreceptor outer be mistaken for acute retinal pigment epitheliitis24–27 because
segments, and by restricting the recording to the posterior both entities cause loss of central vision in young adults.
fundus, the investigators made the recording more sensitive to Table 161.1 lists the differential diagnostic features of these two
localized lesions in the macula. They found a reduced ampli- entities. The peculiar macular lesions may also be mistaken for
tude in the affected eye when compared with the normal fellow subretinal hemorrhage; this is probably what happened in the
eye. This recording was done 13 months after the initial onset case reported by Weinberg and Nerney.15 No recurrence of this
of visual disturbances. A follow-up early retinal potential entity has been reported.
measurement 7 months later, or 20 months after the onset of
symptoms, showed similar amplitude reduction. Their findings
TABLE 161.1 Differential Diagnostic Features of Pigment
would suggest that the abnormality is located in the outer Epitheliitis and Acute Macular Neuroretinopathy
segments. Multifocal electroretinogram (ERG) has been shown
to be more useful in the evaluation of acute macular neuro- Feature Pigment Acute Macular
retinopathy and its findings support an outer retinal layer Epitheliitis24–27 Neuroretinopathy
involvement.20–22 Ophthalmoscopy Clusters of round, Red-brown
Although acute macular neuroretinopathy is associated with dark lesions wedges
minimal, if any, decline in visual acuity, patients with this surrounded by
disorder rarely report improvement of symptoms. The para- hypopigmented halos
central scotomas may become less dense but usually persist Lesion distribution Macular Macular
despite resolution of the fundus lesions. Most of the follow-up
examinations reported to date range from months to a few years Location Retinal pigment Sensory retina
epithelium
only.1,2,4–6,9,11–16,22 However, one patient5 with bilateral involve-
ment was followed up for 9 years. This patient had resolution Laterality Usually unilateral Either
of paracentral scotomas in the right eye but persistence of a Associated vitritis None None
large scotoma in the left eye 2 years later. During the following
7 years, the large paracentral scotoma remained but slowly Diminished visual Moderate Mild
acuity
became smaller.
Both the histopathologic features and the pathogenesis of Sex predilection None Female
these rare macular lesions are unknown. Although a large Age of onset Young adults Young adults
number of reported patients experienced a flu-like syndrome
before the onset of their visual symptoms, a relationship to viral Associated None Often preceded
infection has not yet been established. It has also been sug- by a flu-like
systemic
gested that there is an association with oral contraceptives infection
because the condition affects predominantly healthy young syndrome
women, many of whom are taking this medication. However,
since the majority of women with this condition are of child- Visual recovery Complete in Minimal
7–10 weeks
bearing age, it is highly likely that the use of birth control pills
is merely coincidental; in addition, cases have been reported Cause Unknown Unknown
without birth control pill use. Furthermore, acute macular Fluorescein Normal or halos of Normal
neuroretinopathy has been reported in male patients, although angiography hyperfluorescence
it is interesting to note that one of them was being treated with
2084

REFERENCES
1. Bos PJM, Deutman AF: Acute macular
neuroretinopathy. Am J Ophthalmol 1975;
80:573.
2. Gass JDM: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 2nd edn.
St Louis: CV Mosby; 1977:304.
3. Gass JDM, Hamed LM: Acute macular
neuroretinopathy and multiple evanescent
white dot syndrome occurring in the same
patients. Arch Ophthalmol 1989; 107:189.
4. Guzak SV, Kalina RE, Chenoweth RE:
Acute macular neuroretinopathy following
adverse reaction to intravenous contrast
media. Retina 1983; 3:312.
5. Miller MH, Spalton DJ, Fitzke FW, Bird AC:
Acute macular neuroretinopathy.
Ophthalmology 1989; 96:265.
6. Nagasawa N, Hommura S: A case of acute
macular neuroretinopathy: an optical
consideration on the peculiar features of
fundus oculi. Acta Soc Ophthalmol Jpn
1982; 86:2044.
7. Neetens A, Burvenich H: Presumed
inflammatory maculopathies. Trans
Ophthalmol Soc UK 1978; 98:160.
8. O’Brien DM, Farmer SG, Kalina RE, Leon JA:
Acute macular neuroretinopathy following
intravenous sympathomimetics. Retina
1989; 9:281.
9. Priluck JA, Buettner H, Robertson DM:
Acute macular neuroretinopathy. Am J
Ophthalmol 1978; 86:775.
10. Putteman A, Toussaint D, Deutman AF:
Neuroretinopathie maculaire aigue. Bull
Soc Belge Ophtalmol 1982; 199-200:35.
11. Rait JL, O’Day J: Acute macular
neuroretinopathy. Aust N Z J Ophthalmol
1987; 15:337.
12. Rush JA: Acute macular neuroretinopathy.
Am J Ophthalmol 1977; 83:490.
13. Sieving PA, Fishman GA, Salzano T,
Rabb MF: Acute macular neuroretinopathy:
early receptor potential change suggests
photoreceptor pathology. Br J Ophthalmol
1984; 68:229.
14. van Herck M, Leys A, Missotten L: Acute
macular neuroretinopathy. Bull Soc Belge
Ophtalmol 1984; 210:119.
15. Weinberg RJ, Nerney JJ: Bilateral
submacular hemorrhages associated with
an influenza syndrome. Ann Ophthalmol
1983; 15:710.
16. Desai UR, Sudhamathi K: Intravenous
epinephrine and acute macular
neuroretinopathy. Arch Ophthalmol 1993;
111:1206.
17. Tingsgaard LK, Sander B, Larsen M:
Enhanced visualization of acute macular
neuroretinopathy by spectral imaging. Acta
Ophthalmol Scand 1999; 77:592.
18. Gandorfer A, Ulbig MW: Scanning laser
ophthalmoscope findings in acute macular
neuroretinopathy. Am J Ophthalmol 2002;
133:413.
Acute Macular Neuroretinopathy
19. Douglas IS, Cockburn DM: Acute macular
neuroretinopathy. Clin Exp Optom 2003;
2:121.
20. Amin P, Cox TA: Acute macular
neuroretinopathy. Arch Ophthalmol 1998;
116:112.
21. Feigl B, Haas A: Optical coherence
tomography (OCG) in acute macular
neuroretinopathy. Acta Ophthalmol Scand
2000; 78:714.
22. Chan WM, Liu DTL, Tong JP, et al:
Longitudinal findings of acute macular
neuroretinopathy with multifocal
electroretinogram and optical coherence
tomography. Clin Exp Ophthalmol 2005;
33:439.
23. Leys M, Van Slycken S, Koller J, Van de
Sompel W: Acute macular neuroretinopathy
CHAPTER 161
after shock. Bull Soc Belge Ophtalmol
1991; 241:95.
24. Krill AE, Deutman AF: Acute retinal pigment
epitheliitis. Am J Ophthalmol 1972; 74:193.
25. Deutman AF: Acute retinal pigment
epitheliitis. Am J Ophthalmol 1974; 78:571.
26. Friedman MW: Bilateral recurrent acute
retinal pigment epitheliitis. Am J
Ophthalmol 1975; 79:567.
27. Eifrig DE, Knobloch WH, Moran JA: Retinal
pigment epitheliitis. Ann Ophthalmol 1977;
9:639.
2085
 CHAPTER
162 Toxoplasmosis
Neal P. Barney, Timothy J. Daley, and C. Stephen Foster
Toxoplasmosis is one of the leading causes of infectious retinitis.1
It is produced by the coccidian parasite Toxoplasma gondii, and
the cat is its definitive host. Humans and other animals act as
intermediate hosts. Toxoplasmosis infection is particularly
serious and potentially fatal in congenital disease as well as in
immunocompromised patients.
T. gondii is ubiquitous in nature. The parasite has three forms:
tachyzoite, bradyzoite, and sporozoite.2 The tachyzoite is the
infectious form of the parasite; it multiplies intracellularly and
causes host cell death and the release of more tachyzoites. The
host’s immune response causes the tachyzoite to transform into
the slowly dividing bradyzoite, the encysted intracellular form
of the parasite found in tissue cysts. These cysts may remain in
any tissue, such as the retina, for years without provoking an
immune response in the host. When the cysts rupture, parasites
are released into the surrounding tissues, resulting in a recur-
rence of clinical disease. The sporozoite forms from oocysts,
which are produced exclusively in the intestinal enterocytes of
cats. Millions of oocysts are released into the environment for
2–3 weeks after primary infection until the cat becomes
immune.3 The oocysts undergo sporulation within a few days
and may remain infectious for up to 2 years.
Human infection may occur by either the congenital or the
acquired route. The acquired disease can occur by the ingestion
of either sporozoites or tissue cysts in inappropriately cooked
infected meat and is usually asymptomatic in immuno-
competent persons. Infected livestock are a prominent source of
infection for humans. Recent evidence also suggests the disease
can be acquired through inhalation of spores and ingestion of
contaminated drinking water. Infection can also be acquired
through contaminated blood transfusions and organ trans-
plants.4 Congenital infection occurs through transplacental
transmission of tachyzoites from a mother infected just before
or during pregnancy to the developing fetus.5 The severity of
congenital infection is highest when acquired during the first
trimester of pregnancy, although the frequency of transmission
to the fetus is greatest during the third trimester when contact
of the maternal and fetal circulations is more likely to occur.
Once maternal immunity has developed, it is believed that all
future fetuses are protected from the development of congenital
toxoplasmosis.
CLINICAL FEATURES
The majority of cases of ocular toxoplasmosis are congenital. In
one study of 300 cases of congenital toxoplasmosis in newborns,
ocular lesions were present in 76%, neurologic involvement was
present in 51%, intracranial calcifications were present in 32%,
and microcephaly or hydrocephalus was present in 26%.6 Among
the clinical manifestations of congenital ocular toxoplasmosis
Key Features
1. The majority of cases of ocular toxoplasmosis are congenital.
2. The diagnosis is based on clinical findings.
3. The definitive diagnosis requires demonstration of tachyzoites
in ocular tissues
4. Numerous treatment protocols have been used with success.
Most utilize two antimicrobial drugs.
5. Complications include:
• Choroidal neovascularization
• Retinochoroidal vascular anastamosis
• Branch retinal vein occlusion
• Cystoid macular edema
• Retinal detachment
• Cataracts
• Glaucoma (most common complication)
reported in infants are microphthalmia, enophthalmos, ptosis,
nystagmus, choroidal colobomas, and strabismus.7
Several reports of acquired ocular toxoplasmosis suggest that
this route may actually be more important and more prevalent
than previously thought.8–11 A population study in southern
Brazil reported a high prevalence of acquired ocular toxoplas-
mosis in subjects older than 12 years.12 Similarly, a study after
an outbreak of toxoplasmosis on Victoria Island, in British
Columbia, Canada reported that 21% of confirmed cases of new
infection had ocular disease.13
Ocular toxoplasmosis frequently presents as a focal necro-
tizing retinitis, usually adjacent to a large, atrophic chorio-
retinal scar (Fig. 162.1), which is often located in the macula
in congenital cases. The scar is typically yellow-white and
unevenly pigmented. Acquired cases of toxoplasmosis may
present as a unilateral focal chorioretinitis with no preexisting
retinal scars in either eye.14 The areas of retinitis are the result
of tissue cysts bursting and releasing bradyzoites that transform
into tachyzoites, which in turn invade neighboring cells. These
destructive lesions are usually larger than one disk diameter
and appear as soft, white, fluffy infiltrates surrounded by retinal
edema with subjacent choroiditis.15 When the tachyzoites come
under increasing attack by the host’s immune response, they
gradually transform back into bradyzoites. Inflammatory
cells will be found in the vitreous overlying the active lesion
(Fig. 162.2). Perivascular inflammatory exudates are frequently
present around retinal vessels peripheral to an area of active
inflammation. In cases where the retinal vessel transverses the
active toxoplasmic lesion, regression of the vascular infiltrates
may take longer to recede or may even fail to disappear.16
Patients will often complain of pain, blurred vision, floaters,
and photophobia. More than a third of patients with active
ocular toxoplasmosis will have macular involvement resulting 2087
 SECTION 10 RETINA AND VITREOUS
FIGURE 162.1. Atrophic chorioretinal scar with surrounding retinal
pigment epithelial proliferation; a chorioretinal scar quite typical of
Toxoplasma chorioretinitis. However, note also the fresh satellite lesion
at the edge of the pigmented chorioretinal scar (at the 11 o’clock
position) threatening the fovea.
FIGURE 162.2. Multiple atrophic and hyperpigmented chorioretinal
scars from previous toxoplasmosis. Note the fresh area of
chorioretinitis with overlying vitreal inflammatory cells and vitreal
‘haze’.
in severe visual loss.17,18 Ocular toxoplasmosis may also present
as gray-white punctate lesions in the outer retina and retinal
pigment epithelium (Fig. 162.3).19 Occasionally, patients will
present initially with severe unilateral papillitis, macular hard
exudates distributed in a star fashion, and vitreal inflammation
(Fig. 162.4).20,21 Abnormal intraocular pressure has also been
associated with active disease.22 Active toxoplasmosis
simultaneously involving both the retina and the optic nerve is
unusual but has been documented clinically in an immuno-
competent patient using magnetic resonance imaging.21 There
has also been a report of active ocular toxoplasmosis presenting
as hemorrhagic retinochoroiditis in an otherwise healthy
2088 adult.23
FIGURE 162.3. Toxoplasma retinitis without typical choroidal
involvement. Note the multifocal nature of the lesions, with an area of
active retinitis at the 11 o’clock position. Note also the associated
vasculitis.
FIGURE 162.4. Toxoplasma papillitis with vitreal inflammatory cells
anterior to the optic nerve, making visualization of the optic nerve
slightly difficult. The ELISA for Toxoplasma antibodies gave the
following results: The IgG titer was 1:496; the IgM titer at the time this
photograph was taken was 1:64; 2 weeks later, the anti-Toxoplasma
IgM antibody titer was 1:256.
COMPLICATIONS
Secondary complications arising from ocular toxoplasmosis
include choroidal neovascularization,24 retinochoroidal vascular
anastomosis,25 and branch retinal artery26 and vein occlusion,27,28
cystoid macular edema, retinal detachment, cataracts, secondary
glaucoma, and optic atrophy.17 The most frequent complication
is secondary glaucoma. There is a well-known association
between Fuchs’ heterochromic iridocyclitis and ocular toxo-
plasmosis, but the reasons for this are unclear.29
HISTOPATHOLOGIC AND IMMUNOLOGIC
FEATURES
Histopathologically, there is necrosis of the involved retina
with destruction of the retinal architecture and the underlying
choroid.30 Since the parasite has a propensity for attacking
neural tissue, tissue cysts and trophozoites are usually found in

the superficial layers of the retina within the area of necrosis
(Figs 162.5 and 162.6). The infiltrate consists predominantly of
lymphocytes, macrophages, and epitheloid cells, with plasma
cells found in the periphery of the lesion.
Cell-mediated immunity is felt to be the major defense
mechanism against Toxoplasma infection.31 Several purified
antigens from tachyzoites have been identified, including the
major surface protein antigen p30, which can participate
in antibody-dependent complement-mediated lysis of the
tachyzoite.32,33 In patients with ocular toxoplasmosis, the
cellular immune response appears to be directed predominantly
against the cell surface protein p22.34 Additionally, gamma
interferon and tumor necrosis factor both appear to play an
important role in inducing and maintaining the interconversion
of the organism’s tachyzoite form to the bradyzoite form during
active infection.35 When neutralizing doses of antibodies to
either gamma interferon or tumor necrosis factor are given to
animal models with chronic infection, free tachyzoites and an
increased number of cysts are observed.36 However, some evi-
dence also indicates that part of the disease may be mediated by
an autoimmune mechanism directed against certain retinal
antigens.
The role of the humoral response to toxoplasmosis is unclear.
Whereas an intact cellular component of the immune system is
FIGURE 162.5. Toxoplasma feline retinochoroiditis. Histopathologic
appearance of the retina and choroid. Note the Toxoplasma cysts
(arrowheads).
FIGURE 162.6. Same specimen as in Figure 162.5. Note the
Toxoplasma cyst (arrowhead).
Toxoplasmosis
necessary for the resolution of active disease, antibody may be
important in establishing a state of immunity in the host.37
Antibodies directed against the cytoplasmic protein F3G338 can
protect passively immunized mice from a lethal challenge of
T. gondii.39
OCULAR TOXOPLASMOSIS IN THE
IMMUNOCOMPROMISED HOST
Although T. gondii is a common opportunistic pathogen with a
penchant for attacking the central nervous system in immuno-
compromised patients,40–42 including those with acquired
immunodeficiency syndrome (AIDS),43–45 ocular toxoplasmosis
appears to be uncommon. Ocular toxoplasmosis occurs in ~1%
of patients with AIDS.46 Systemically, these patients are prone
to the development of Toxoplasma encephalitis, myocarditis, or
pneumonitis.
AIDS-related Toxoplasma retinochoroiditis has several
CHAPTER 162
atypical clinical manifestations, including bilateral involvement
and single or multifocal discrete lesions47–49 or diffuse areas of
retinal necrosis (Fig. 162.7).50 Furthermore, unlike immuno-
competent individuals, who rarely have more than one focus of
active retinal disease, even if there are multiple retinochoroidal
scars, immunocompromised individuals can have multiple
active lesions in one or both eyes.51 Vascular sheathing may be
present, and prominent inflammatory reactions in the vitreous
and anterior chambers are common (Fig. 162.8). Lesions may
occur adjacent to retinal blood vessels and are usually not asso-
ciated with preexisting retinochoroidal scars. These findings
suggest that the ocular lesions in AIDS patients may be the
result of newly acquired disease or from organisms that have
disseminated to the eye from extraocular sites. The retina can
be infected simultaneously by both T. gondii and cytomegalo-
virus in patients with AIDS.52,53 Anti-Toxoplasma immuno-
globulin G (IgG) antibodies are present in these patients,
although IgM antibodies against Toxoplasma are uncommon.
Infection usually produces a full-thickness retinal necrosis,
but early necrosis may be confined to either the inner or the
outer layers. Large numbers of trophozoites and cysts with
scanty inflammatory reaction are seen within the necrotic
retina and optic nerve head. Although T. gondii organisms may
involve anterior segment structures and uveal tissue in patients
with AIDS, parasites are rarely found in these structures in
FIGURE 162.7. Diffuse retinitis with probable underlying choroiditis in
an immunocompromised patient with toxoplasmosis. Note the
overlying vitreal inflammatory cellular response with vitreal ‘haze’. 2089
 RETINA AND VITREOUS
SECTION 10
FIGURE 162.8. Fluorescein angiogram in a patient with active
toxoplasmosis. Note not only the dye accumulation in the two foci
representing the areas of active Toxoplasma chorioretinitis but also the
papillitis with dye staining of the nerve head and the associated retinal
vasculitis with late vascular staining.
otherwise healthy patients.54 Toxoplasma retinochoroiditis may
rarely progress to panophthalmitis and orbital cellulitis in
patients with AIDS.55 Finally, not only do patients with AIDS
develop more extensive disease, but lesions are more likely to
reactivate if treatment is discontinued.56
DIAGNOSIS
The definitive diagnosis of ocular toxoplasmosis requires the
demonstration of tachyzoites in ocular tissues.57 Cytologic
evaluation of vitrectomy specimens to detect the presence of
Toxoplasma organisms is especially useful in patients with
necrotizing retinitis where the cause for the retinitis is
uncertain.58 The presence of cysts in tissue samples, however,
only suggests, but does not prove acute infection. Toxoplasma
retinochoroiditis is, therefore, usually a clinical diagnosis based
on a compatible lesion in the fundus and positive serologic
results for anti-Toxoplasma antibodies. Additionally, other causes
of focal exudative retinitis, including syphilis, tuberculosis,
sarcoidosis, cytomegalovirus, and fungal infections, must be
excluded.
Because of their ease of performance and their relatively high
sensitivity and specificity, serologic methods are often preferred
for the diagnosis of toxoplasmosis. Serologic diagnosis is com-
plicated by the high prevalence of T. gondii-specific antibodies
in the human population persisting for years and therefore
frequently reflecting past infection. Classic serodiagnosis of an
acute systemic infection requires the demonstration of a
seroconversion, a significant rise in specific antibody titers in
paired sera taken 4–6 weeks apart, or the presence of anti-
Toxoplasma IgM antibody in a single serum sample. If
retinochoroiditis develops subsequently, it is presumed to be
acquired. However, because systemic toxoplasmosis infection is
often subclinical in its manifestations, the diagnosis of acquired
ocular toxoplasmosis may be missed or confused with
reactivation of the congenital type if ocular involvement occurs
months or years after a systemic infection. Because sera are
often submitted late after infection, it is difficult to detect an
antibody titer rise. Establishing the presence of Toxoplasma
antibodies in a patient’s serum is considered essential in the
diagnosis of Toxoplasma retinochoroiditis. In this case, any titer
2090 of antibody is significant because no correlation exists between
the serum level of anti-Toxoplasma titers and the activity of the
ocular disease in recurrent ocular toxoplasmosis.59
The most widely used serologic methods for detecting anti-
Toxoplasma antibodies are the Sabin–Feldman test, the
complement fixation test, the agglutination tests, the indirect
immunofluorescence assay (IFA), and the enzyme-linked
immunosorbent assay (ELISA). Although the Sabin–Feldman
dye test represents the standard against which all other tests are
measured, it is no longer performed routinely because it requires
the constant maintenance of virulent organisms in the
laboratory with the associated risks to laboratory personnel.
The IFA test, which has largely replaced the Sabin–Feldman
dye test, has become the most widely used test for the detection
of anti-Toxoplasma IgG or IgM antibodies.60 Although it is easy
to perform, the interpretations of its results can be misleading.
False-negative IgM titers may occur because of competitive
inhibition by anti-Toxoplasma IgG if present simultaneously.61
False-positive IgM titers can occur because of the presence of
rheumatoid factor.62 Rheumatoid factor, an anti-IgG IgM
antibody, can bind to specific anti-Toxoplasma IgG. Finally, the
presence of antinuclear antibody may produce false-positive
IgM and IgG titers.63 This occurs because Toxoplasma organ-
isms possess antigens that are indistinguishable from those
found in human leukocyte nuclei using immunologic laboratory
testing techniques. Because IgM titers in ocular toxoplasmosis
become significant only in cases of acquired retinochoroiditis,9,64
the specificity limitations of the IFA tests are restricted, for
practical purposes, to false-positive IgG titers produced by the
presence of antinuclear antibodies.
Commercially available IFA tests for Toxoplasma begin with
a 1:16 serum dilution because specificity decreases when more
concentrated dilutions are used. Since any titer of antibody is
considered significant in establishing the diagnosis of
Toxoplasma retinochoroiditis, it is logical to expect a significant
percentage of false-negative titers using this serologic method.
One report cited three documented cases of Toxoplasma
retinochoroiditis with positive Sabin–Feldman dye titers and
negative immunofluorescent titers (titer <1:16).65
The double-sandwich ELISA for anti-Toxoplasma antibodies
eliminates IgM specificity problems associated with the IFA
test.66,67 False-positive reactions resulting from rheumatoid
factor and false-negative reactions because of competing IgG are
avoided because only IgM of the test serum adheres to plates
precoated with anti-IgM antiserum. The ELISA for anti-
Toxoplasma antibodies is as specific and sensitive as the
Sabin–Feldman dye test. Therefore, in cases where ocular toxo-
plasmosis is strongly suspected despite negative immunofluo-
rescent titers, a Sabin-Feldman titer or an ELISA titer should be
obtained before excluding the diagnosis of toxoplasmosis.
Some experts advocate measuring anti-Toxoplasma antibody
titers in intraocular fluids,68 or even tears,69 but this has not
been widely adopted at the present time. Polymerase chain
reaction (PCR) techniques have been used to detect the presence
of toxoplasma genes in ocular tissues and fluids.70,71 However,
its precise role in the diagnosis of ocular toxoplasmosis remains
to be defined by controlled clinical trials. It is quite expensive,
not widely available, and requires special equipment and highly
specialized technical skills to perform properly. Although, with
the advent of real-time PCR and its advantages of higher sensi-
tivity, improved quantitation, and fewer manual manipulations
required, it could prove to be useful in determining disease
burden, therapy efficacy, and epidemiology of the disease.72
THERAPY
Since available agents against T. gondii are ineffective against
tissue cysts, the major aim of therapy has been to stop the

multiplication of tachyzoites during episodes of active retino-
choroiditis. It is important for the clinician to realize this
and to inform the patient that drug therapy does not totally
eradicate the parasite.
Complicating matters is that little is known about the
natural history of active disease. There have been surprisingly
few prospective, randomized, placebo-controlled clinical trials
for the treatment of ocular toxoplasmosis in immunocompetent
individuals. Interestingly, none of them demonstrated that
short-term drug therapy was effective in treating active toxo-
plasmic retinochoroiditis, reducing recurrent disease, or
shortening duration of disease.73
This is in contrast to numerous animal studies, which have
found antimicrobial agents to be highly efficacious for active
toxoplasmosis treatment. In fact, some newer drugs such as
atovaquone and azithromycin, have even been shown to reduce
the number of tissue cysts in animal models.74 Furthermore,
while treatment efficacy has been difficult to determine in
immunocompetent patients, antimicrobial therapy can be highly
effective in patients with AIDS. Long-standing active infections
rapidly become inactive with treatment in these individuals.
Finally, observational experience suggests that therapy is
beneficial in immunocompetent patients, despite difficulties to
quantify their efficacy. Most clinicians agree that antimicrobial
therapy is warranted in active disease.
Toxoplasma organisms lack the transmembrane transport
systems for physiologic folates and thus synthesize this sub-
stance instead. Folic acid antagonists inhibit this biochemical
pathway and prevent the organism from replicating by
impairing DNA synthesis.75 A combination of sulfadiazine
(1 g PO qid for first day, then 500 mg PO qid for 2–8 weeks)
with pyrimethamine (50 mg PO bid for first day, then 25 mg PO
qid for 2–8 weeks) and folinic acid (5 mg PO three times a week)
has classically been considered to be the most effective treatment
for toxoplasmosis.76 If necessary, repeated courses of drugs may
be administered. However, many toxic side effects occur with
this regimen, most notably bone marrow depression with
subsequent hematologic complications. Weekly white blood cell
counts and platelet counts are therefore mandatory in these
patients.
A less toxic means of treatment consists of clindamycin
(300 mg PO tid or qid) in combination with sulfadiazine
(500 mg PO qid). Patients are generally treated for 4–6 weeks on
this drug regimen. However, diarrhea, colitis, and pseudomem-
branous colitis remain potential problems with clindamycin use.
Co-trimoxazole (trimethoprim 160 mg with sulfamethoxazole
800 mg) given twice daily for 2–6 weeks either alone or in
combination with clindamycin (300 mg PO qid) has also been
suggested for the treatment of toxoplasmosis in humans.77,78
The side effects are similar to those of the sulfonamides.
Anterior uveitis associated with ocular toxoplasmosis may be
treated with topical corticosteroids and cycloplegic agents along
with concurrent systemic antitoxoplasmosis therapy. Increased
intraocular pressure can be managed with standard glaucoma
medical therapy.
The addition of systemic corticosteroids to the therapeutic
regimen may diminish the degree of collateral damage from the
inflammatory response. Some experts advocate adding pred-
nisone 12–24 h after initiating the antiparasitic therapy if the
Toxoplasma lesion is in the posterior pole, threatening the optic
nerve head, or if the vitreal response is extreme, starting with
40–80 mg of prednisone with breakfast daily for 1 week, then
rapidly tapering the prednisone before discontinuing the anti-
toxoplasmosis therapy. Under no circumstances, however,
should systemic corticosteroids be used without concurrent
antitoxoplasmosis therapy, nor should they be used in patients
with necrotizing retinitis where the diagnosis of ocular
Toxoplasmosis
TABLE 162.1. Recommended Therapy for Ocular
Toxoplasmosis
Clinical Features Recommended Treatment
Peripheral lesion: Clindamycin, 300 mg PO tid or qid
mild to moderate and
vitreal cells sulfadiazine, 1 g initially then
500 mg PO qid
Peripheral lesion: As above
moderate to severe plus
vitreal cells prednisone 1 mg/kg PO/day with
taper based on clinical response
Juxtamacular lesion Clindamycin and sulfadiazine as above
plus
pyrimethamine, 50 mg bid during the
first day then 25 mg PO/day
plus
folinic acid, 5 mg PO three times a week
CHAPTER 162
prednisone use based on vitreal cells,
as in the case of peripheral lesions
toxoplasmosis has not been ruled out. Several cases of
fulminant ocular toxoplasmosis have been described after the
use of corticosteroids alone.79,80 Other recommendations for
ocular toxoplasmosis therapy in various situations are
summarized in Table 162.1.
Standard antitoxoplasmosis drug regimens can usually
control AIDS-related ocular lesions. Treatment is given until
4–6 weeks after resolution of all signs and symptoms. However,
as many as 20% of immunocompromised patients with toxo-
plasmosis may fail to respond to medical therapy.43 A
combination of pyrimethamine and clindamycin was reported
to be more effective than either pyrimethamine alone or in
combination with sulfadiazine for patients with AIDS.81
Toxoplasmosis in patients with AIDS frequently recurs when
medical treatment is discontinued.49,82,83 It may be necessary to
continue treatment indefinitely to maintain control of the
disease, but adequate maintenance treatment regimens have
not been established. Zidovudine (azidothymidine (AZT) anta-
gonizes the anti-Toxoplasma activity of pyrimethamine both
in vivo and in vitro and may have to be discontinued.84 Co-
trimoxazole has been employed in AIDS patients sensitive to
pyrimethamine, but this has been reported to be associated with
treatment failure.85 Comanagement with an infectious disease
specialist is recommended when treating these patients.
Atovaquone (Mepron), 750 mg tid, plus clarithromycin (Biaxin),
500 mg bid, has been used for long-term suppressive therapy of
recurrent toxoplasmosis in selected individuals with AIDS,
especially in the context of sensitivity to the more classic anti-
toxoplasma agents. Azithromycin (Zithromax) and Spiramycin
(Rovamycine) are additional agents with antitoxoplasma
activity that have had limited use thus far with promising
results.86,87
The role of laser photocoagulation in the treatment of active
ocular toxoplasmosis and for prophylaxis against the spread of
lesions is limited.88 Although photocoagulation can destroy
Toxoplasma cysts and tachyzoites, Toxoplasma cysts can reside
in ophthalmoscopically normal-appearing retina. Furthermore,
photocoagulation of active lesions can be complicated by retinal
or vitreous hemorrhage or even by retinal detachment.
Vitrectomy and lensectomy can be performed to remove vitre-
ous and lens opacities in these patients.89 Patients undergoing
surgery should probably be treated preoperatively with anti-
Toxoplasma agents, and the medications should be continued
postoperatively. 2091
 RETINA AND VITREOUS
REFERENCES
1. Perkins, ES: Ocular toxoplasmosis. Br J
Ophthalmol 1973; 57:1–17.
2. Krick JA, Remington JS: Toxoplasmosis in
the adult – an overview. N Engl J Med
1978; 298:550–553.
3. van Knapen F: Toxoplasmosis, old stories
and new facts. Int Ophthalmol 1989;
13:371–375.
4. Holland GN: Reconsidering the
pathogenesis of ocular toxoplasmosis.
Am J Ophthalmol 1999; 128:502–505.
5. Swartzberg JE, Remington JS:
Transmission of toxoplasma. Am J Dis
Child 1975; 129:777–779.
6. Couvreur J, Desmonts G: Congenital and
maternal toxoplasmosis. A review of 300
congenital cases. Dev Med Child Neurol
1962; 4:519–530.
SECTION 10
7. de Jong PT: Ocular toxoplasmosis;
common and rare symptoms and signs.
Int Ophthalmol 1989; 13:391–397.
8. Teutsch SM, Juranek DD, Sulzer A, et al:
Epidemic toxoplasmosis associated with
infected cats. N Engl J Med 1979;
300:695–699.
9. Akstein RB, Wilson LA, Teutsch SM:
Acquired toxoplasmosis. Ophthalmology
1982; 89:1299–1302.
10. Silveira C, Belfort R, Jr., Burnier M, Jr., et al:
Acquired toxoplasmic infection as the cause
of toxoplasmic retinochoroiditis in families.
Am J Ophthalmol 1988; 106:362–364.
11. Couvreur J, Thulliez P: Acquired
toxoplasmosis of ocular or neurologic site:
49 cases. Presse Med 1996; 25:438–442.
12. Glasner PD, Silveria C, Kruszon-Moran D,
et al: An unusually high prevalence of
ocular toxoplasmosis in southern Brazil.
Am J Ophthalmol 1992; 114:136–144.
13. Burnett AJ, Shortt SG, Isaac-Renton J,
et al: Multiple cases of acquired
toxoplasmosis retinitis presenting in an
outbreak. Ophthalmology 1998;
105:1032–1037.
14. Ronday MJ, Luyendijk L, Baarsma GS,
et al: Presumed acquired ocular
toxoplasmosis. Arch Ophthalmol 1995;
113:1524–1529.
15. Tabbara KF: Ocular toxoplasmosis:
toxoplasmic retinochoroiditis. Int
Ophthalmol Clin 1995; 35:15–29.
16. Theodossiadis P, Kokolakis S, Ladas I,
et al: Retinal vascular involvement in acute
toxoplasmic retinochoroiditis. Int
Ophthalmol 1995; 19:19–24.
17. Friedmann CT, Knox DL: Variations in
recurrent active toxoplasmic
retinochoroiditis. Arch Ophthalmol 1969;
81:481–493.
18. Stanford MR, Tomlin EA, Comyn O,
et al: The visual field in toxoplasmic
retinochoroiditis. Br J Ophthalmol 2005;
89:812–814.
19. Doft BH, Gass JD: Outer retinal layer
toxoplasmosis. Graefes Arch Clin Exp
Ophthalmol 1986; 224:78–82.
20. Folk JC, Lobes LA: Presumed toxoplasmic
papillitis. Ophthalmology 1984; 91:64–67.
21. Borruat FX, Kapoor R, Sanders MD:
Simultaneous retinal and optic nerve
lesions in toxoplasmosis: the advantages of
magnetic resonance imaging. Br J
Ophthalmol 1993; 77:450–452.
22. Westfall AC, Lauer AK, Suhler EB, et al:
Toxoplasmosis retinochoroiditis and
2092
elevated intraocular pressure: a
retrospective study. J Glaucoma 2005;
14:3–10.
23. Baglivo E, Safran AB: Haemorrhagic
toxoplasmic retinochoroiditis: description of
an unusual clinical presentation. Br J
Ophthalmol 2003; 87:1051–1052.
24. Fine SL, Owens SL, Haller JA, et al:
Choroidal neovascularization as a late
complication of ocular toxoplasmosis. Am
J Ophthalmol 1981; 91:318–322.
25. Kennedy JE, Wise GN: Retinochoroidal
vascular anastomoses in uveitis. Am J
Ophthalmol 1971; 71:1221–1225.
26. Braunstein RA, Gass JD: Branch artery
obstruction caused by acute toxoplasmosis.
Arch Ophthalmol 1980; 98:512–513.
27. Rose GE: Papillitis, retinal neovascularisation
and recurrent retinal vein occlusion in
toxoplasma retinochoroiditis: a case report
with uncommon clinical signs. Aust N Z J
Ophthalmol 1991; 19:155–157.
28. Gentile RC, Berinstein DM, Oppenheim R,
et al: Retinal vascular occlusions
complicating acute toxoplasmic
retinochoroiditis. Can J Ophthalmol 1997;
32:354–358.
29. Toledo de Abreu M, Belfort R Jr, Hirata PS:
Fuchs’ heterochromic cyclitis and ocular
toxoplasmosis. Am J Ophthalmol 1982;
93:739–744.
30. Jabs DA: Ocular toxoplasmosis. Int
Ophthalmol Clin 1990; 30:264–270.
31. Williams DM, Grumet FC, Remington JS:
Genetic control of murine resistance to
toxoplasma gondii. Infect Immun 1978;
19:416–420.
32. Kasper LH, Crabb JH, Pfefferkorn ER:
Purification of a major membrane protein of
toxoplasma gondii by immunoabsorption
with a monoclonal antibody. J Immunol
1983; 130:2407–2412.
33. Kasper LH, Crabb JH, Pfefferkorn ER:
Isolation and characterization of a
monoclonal antibody-resistant antigenic
mutant of toxoplasma gondii. J Immunol
1982; 129:1694–1699.
34. Nussenblatt RB, Mittal KK, Fuhrman S,
et al: Lymphocyte proliferative responses
of patients with ocular toxoplasmosis to
parasite and retinal antigens. Am J
Ophthalmol 1989; 107:632–641.
35. Bohne W, Heesemann J, Gross U:
Induction of bradyzoite-specific
toxoplasma gondii antigens in gamma
interferon-treated mouse macrophages.
Infect Immun 1993; 61:1141–1145.
36. Denkers EY, Gazzinelli RT: Regulation and
function of T-cell-mediated immunity during
toxoplasma gondii infection. Clin.
Microbiol. Rev 1998; 11:569–588.
37. Hafizi A, Modabber FZ: Effect of
cyclophosphamide on toxoplasma gondii
infection: reversal of the effect by passive
immunization. Clin Exp Immunol 1978;
33:389–394.
38. Naot Y, Remington JS: Use of enzyme-
linked immunosorbent assays (ELISA) for
detection of monoclonal antibodies:
experience with antigens of toxoplasma
gondii. J Immunol Methods 1981;
43:333–341.
39. Sharma SD, Araujo FG, Remington JS:
Toxoplasma antigen isolated by affinity
chromatography with monoclonal antibody
protects mice against lethal infection with
toxoplasma gondii. J Immunol 1984;
133:2818–2820.
40. Cohen SN: Toxoplasmosis in patients
receiving immunosuppressive therapy.
JAMA 1970; 211:657–660.
41. Ruskin J, Remington JS: Toxoplasmosis in
the compromised host. Ann Intern Med
1976; 84:193–199.
42. Ryning FW, Mills J: Pneumocystis carinii,
toxoplasma gondii, cytomegalovirus and
the compromised host. West J Med 1979;
130:18–34.
43. Wong B, Gold JW, Brown AE, et al:
Central-nervous-system toxoplasmosis in
homosexual men and parenteral drug
abusers. Ann Intern Med 1984; 100:36–42.
44. Luft BJ, Brooks RG, Conley FK et al:
Toxoplasmic encephalitis in patients with
acquired immune deficiency syndrome.
JAMA 1984; 252:913–917.
45. Araujo FG, Remington JS: Toxoplasmosis
in immunocompromised patients. Eur J
Clin Microbiol 1987; 6:1–2.
46. Jabs DA, Green WR, Fox R, et al: Ocular
manifestations of acquired immune
deficiency syndrome. Ophthalmology 1989;
96:1092–1099.
47. Friedman AH: The retinal lesions of the
acquired immune deficiency syndrome.
Trans Am Ophthalmol Soc 1984;
82:447–491.
48. Schuman JS, Friedman AH: Retinal
manifestations of the acquired immune
deficiency syndrome (AIDS):
cytomegalovirus, candida albicans,
cryptococcus, toxoplasmosis and
Pneumocystis carinii. Trans Ophthalmol
Soc UK 1983; 103(Pt 2):177–190.
49. Heinemann MH, Gold JM, Maisel J:
Bilateral toxoplasma retinochoroiditis in a
patient with acquired immune deficiency
syndrome. Retina 1986; 6:224–227.
50. Parke DW 2nd, Font RL: Diffuse
toxoplasmic retinochoroiditis in a patient
with AIDS. Arch Ophthalmol 1986;
104:571–575.
51. Holland GN: Ocular toxoplasmosis: a
global reassessment. Part II. Disease
manifestations and management. Am J
Ophthalmol 2004; 137:1–17.
52. Cochereau-Massin I, LeHoang P, Lautier-
Frau M, et al: Ocular toxoplasmosis in
human immunodeficiency virus-infected
patients. Am J Ophthalmol 1992;
114:130–135.
53. Pivetti-Pezzi P, Accorinti M, Tamburi S,
et al: Clinical features of toxoplasmic
retinochoroiditis in patients with acquired
immunodeficiency syndrome. Ann
Ophthalmol 1994; 26:73–84.
54. Zimmerman LE: Ocular pathology of
toxoplasmosis. Surv Ophthalmol 1961;
6:832–856.
55. Moorthy RS, Smith RE, Rao NA:
Progressive ocular toxoplasmosis in
patients with acquired immunodeficiency
syndrome. Am J Ophthalmol 1993;
115:742–747.
56. Holland GN, Engstrom RE, Jr., Glasgow BJ,
et al: Ocular toxoplasmosis in patients with
the acquired immunodeficiency syndrome.
Am J Ophthalmol 1988; 106:653–667.
57. Remington JS, Miller MJ, Brownlee I:
IgM antibodies in acute toxoplasmosis.

II. Prevalence and significance in
acquired cases. J Lab Clin Med 1968;
71:855–866.
58. Greven CM, Teot LA: Cytologic
identification of toxoplasma gondii from
vitreous fluid. Arch Ophthalmol 1994;
112:1086–1088.
59. Schlaegel TF Jr: Ocular toxoplasmosis and
par planitis. New York: Grune & Stratton;
1978:138–172.
60. Kelan AE, Ayllon-Leindl L, Labzoffsky NA:
Indirect fluorescent antibody method in
serodiagnosis of toxoplasmosis. Can J
Microbiol 1962; 8:545.
61. Pyndiah N, Krech U, Price P, et al: Simplified
chromatographic separation of
immunoglobulin M from G and its
application to toxoplasma indirect
immunofluorescence. J Clin Microbiol
1979; 9:170–174.
62. Fuccillo DA, Madden DL, Tzan N, et al:
Difficulties associated with serological
diagnosis of toxoplasma gondii infections.
Diagn Clin Immunol 1987; 5:8–13.
63. Araujo FG, Barnett EV, Gentry LO, et al:
False-positive anti-toxoplasma fluorescent-
antibody tests in patients with antinuclear
antibodies. Appl Microbiol 1971;
22:270–275.
64. Asbell PA, Vermund SH, Hofeldt AJ:
Presumed toxoplasmic retinochoroiditis in
four siblings. Am J Ophthalmol 1982;
94:656–663.
65. Weiss MJ, Velazquez N, Hofeldt AJ:
Serologic tests in the diagnosis of
presumed toxoplasmic retinochoroiditis.
Am J Ophthalmol 1990; 109:407–411.
66. Naot Y, Desmonts G, Remington JS: IgM
enzyme-linked immunosorbent assay test
for the diagnosis of congenital toxoplasma
infection. J Pediatr 1981; 98:32–36.
67. Tomasi JP, Schlit AF, Stadtsbaeder S:
Rapid double-sandwich enzyme-linked
immunosorbent assay for detection of
human immunoglobulin M anti-toxoplasma
gondii antibodies. J Clin Microbiol 1986;
24:849–850.
68. Davis JL, Feuer W, Culbertson WW, et al:
Interpretation of intraocular and serum
antibody levels in necrotizing retinitis.
Retina 1995; 15:233–240.
69. Lynch MI, Cordeiro F, Ferreira S, et al:
Lacrimal secretory IgA in active posterior
uveitis induced by toxoplasma gondii. Mem
Inst Oswaldo Cruz 2004; 99:861–864.
70. Aouizerate F, Cazenave J, Poirier L, et al:
Detection of toxoplasma gondii in aqueous
humour by the polymerase chain reaction.
Br J Ophthalmol 1993; 77:107–109.
71. de Boer JH, Verhagen C, Bruinenberg M,
et al: Serologic and polymerase chain
reaction analysis of intraocular fluids in the
diagnosis of infectious uveitis. Am J
Ophthalmol 1996; 121:650–658.
72. Contini C, Seraceni S, Cultrera R, et al:
Evaluation of a real-time PCR-based assay
using the lightcycler system for detection
of toxoplasma gondii bradyzoite genes in
blood specimens from patients with
toxoplasmic retinochoroiditis. Int J Parasitol
2005; 35:275–283.
73. Stanford MR, See SE, Jones LV, et al:
Antibiotics for toxoplasmic
retinochoroiditis: an evidence-based
systematic review. Ophthalmology 2003;
110:926–931; quiz 931–932.
74. Huskinson-Mark J, Araujo FG, Remington
JS: Evaluation of the effect of drugs on the
cyst form of toxoplasma gondii. J Infect Dis
1991; 164:170–171.
75. Giles CL: Pyrimethamine (Daraprim) and
the treatment of toxoplasmic uveitis.
Surv Ophthalmol 1971; 16:88–91.
76. Smith RL, Nozik RA: Toxoplasmic
retinochoroiditis. In: Smith RE, Nozik RA,
eds. Uveitis: a clinical approach to
diagnosis and management. Baltimore:
Williams & Wilkins; 1989:128–134.
77. Norrby R, Eilard T, Svedhem A, et al:
Treatment of toxoplasmosis with
trimethoprim–sulphamethoxazole. Scand J
Infect Dis 1975; 7:72–75.
78. Opremcak EM, Scales DK, Sharpe MR:
Trimethoprim–sulfamethoxazole therapy for
Toxoplasmosis
ocular toxoplasmosis. Ophthalmology
1992; 99:920–925.
79. Nicholson DH, Wolchok EB: Ocular
toxoplasmosis in an adult receiving long-
term corticosteroid therapy. Arch
Ophthalmol 1976; 94:248–254.
80. Sabates R, Pruett RC, Brockhurst RJ:
Fulminant ocular toxoplasmosis. Am J
Ophthalmol 1981; 92:497–503.
81. Rolston KV, Hoy J: Role of clindamycin in
the treatment of central nervous system
toxoplasmosis. Am J Med 1987;
83:551–554.
82. Luft BJ, Conley F, Remington JS, et al:
Outbreak of central-nervous-system
toxoplasmosis in western Europe and
North America. Lancet 1983; 1:781–784.
83. Levy RM, Bredesen DE, Rosenblum ML:
Neurological manifestations of the acquired
immunodeficiency syndrome (AIDS):
CHAPTER 162
experience at UCSF and review of the
literature. J Neurosurg 1985; 62:475–495.
84. Israelski DM, Tom C, Remington JS:
Zidovudine antagonizes the action of
pyrimethamine in experimental infection
with Toxoplasma gondii. Antimicrob Agents
Chemother 1989; 33:30–34.
85. Holliman RE: Toxoplasmosis and the
acquired immune deficiency syndrome.
J Infect 1988; 16:121–128.
86. Chang HR: The potential role of
azithromycin in the treatment of
prophylaxis of toxoplasmosis. Int J STD
AIDS 1996; 7(Suppl 1):18–22.
87. Hacker M, Richter R, Gumbel H, et al:
Toxoplasmosis retinochorioiditis, a therapy
comparison between spiramycin and
pyrimethamine/sulfadiazine. Klin Monatsbl
Augenheilkd 1998; 212:84–87.
88. Ghartey KN, Brockhurst RJ:
Photocoagulation of active toxoplasmic
retinochoroiditis. Am J Ophthalmol 1980;
89:858–864.
89. Fitzgerald CR: Pars plana vitrectomy for
vitreous opacity secondary to presumed
toxoplasmosis. Arch Ophthalmol 1980;
98:321–323.
2093
 Retinal Manifestations of the Acquired
CHAPTER
Immunodeficiency Syndrome: Diagnosis and
163 Treatment
Michelle Tarver-Carr, M.D., Ph.D. and James P. Dunn, M.D.
OVERVIEW
Acquired immunodeficiency syndrome (AIDS) is a potentially
fatal multisystem disorder in which immunity is severely
compromised as a result of infection with the human
immunodeficiency virus (HIV). AIDS is defined by the Centers
for Disease Control as a CD4+ T-lymphocyte count of less
than 200 cells/mL or specific opportunistic disease, including
cytomegalovirus (CMV) retinitis.1 According to the World
Health Organization, ~ 38 million people worldwide were
infected with HIV in a cross-sectional analysis in 2003. In 2004
alone, 4.8 million new infections developed.2
This chapter will focus on the retinal manifestations of AIDS,
particularly noninfectious microvasculopathy and CMV retinitis.
Other less common viral, bacterial, parasitic, and fungal infec-
tions affecting the retina will also be discussed. Lastly, diag-
nostic methods in cases in which the cause of the ocular disease
is not clinically evident will be described, along with current
treatments for the opportunistic infections and HIV itself.
EPIDEMIOLOGY OF HIV INFECTION
AND AIDS
In 2004, there were 38 730 new cases of HIV with 14.1 cases of
AIDS per 100 000 in the United States. There are currently ~
950 000 individuals with AIDS living in the US, translating to
a prevalence rate of 136.7/100 000 of HIV and 168.8/100 000 of
AIDS or HIV.1 The number of HIV cases in the United States
has increased linearly over time with almost half of the patients
being diagnosed with AIDS within 12 months after becoming
HIV seropositive.3 HIV is transmitted by (1) sexual contact,
(2) inoculation from infected sources (especially the sharing of
contaminated needles by injection drug users), and (3) exposure
to infected blood, tissues, and milk in utero, during or after
birth. At 2–4 weeks after infection many patients are
asymptomatic; however, ~ 50–70% of patients develop an acute
retroviral syndrome typified by myalgias, lymphadenopathy,
diarrhea, and other viral symptoms.4
Viral invasion and replication occur through attachment of
HIV to the CD4+ receptors on CD4+ T-lymphocytes,
macrophages, and other dendritic cells. The viral envelope fuses
with the cellular membrane, leading to insertion and uncoating
of the viral nucleocapsid. HIV reverse transcriptase forms a
complementary DNA strand from HIV RNA which inserts into
the host genome using HIV integrase. Activation of the CD4+
T-lymphocyte causes transcription and translation of viral
proteins and viral assembly. The viral particles bud from the cell
surface and mature upon cleavage of viral polyproteins by HIV
protease. This process promotes apoptosis of CD4+ cells,
decreasing the number of T-lymphocytes available to mount a
defense against infections. Macrophages, however, are not lysed
in the viral cycle but instead escort the virus to vulnerable host
tissues such as the central nervous system.5
HIV infection is diagnosed by assaying viral p24 anti-
genemia, viral culture, or amplification of viral nucleic acids by
polymerase chain reaction. People with suspected HIV infection
are screened with enzyme-linked immunosorbent assay
(ELISA), which detects core HIV proteins and surface
glycoproteins. While the ELISA is very sensitive, a positive
result must be confirmed by Western blot analysis. Moreover,
disease progression is monitored by the viral load of HIV since
the HIV-1 RNA assay has been shown to predict the clinical
progression of HIV-associated disease.6 Advanced HIV disease
is associated with many ocular and systemic manifestations.
NONINFECTIOUS RETINAL
VASCULOPATHY
BACKGROUND AIDS RETINOPATHY
Noninfectious HIV microangiopathy, also called ‘background
HIV retinopathy’, is the most common ophthalmic manifes-
tation of HIV/AIDS. It is uncommon in those with CD4+ cell
counts greater than 200 cells/mL but occurs in a majority of
patients with CD4+ counts less than 50 cells/mL, and therefore
serves as a marker for advanced immunosuppression.7
The retinopathy is characterized by cottonwool spots
(Fig. 163.1), which occur in 25–50% of patients with AIDS,
intraretinal hemorrhages, white-centered hemorrhages, retinal
capillary microaneurysms, telangiectasias, and capillary
nonperfusion.8 Affected patients are usually asymptomatic.
Cotton-wool spots are a result of microinfarctions and edema in
the retinal nerve fiber layer; the histopathologic findings (cytoid
bodies) correspond to the reversible feathery whitening seen
clinically. They are not pathognomonic, since they also occur in
other conditions such as hypertension, diabetes, severe anemia,
lupus, and leukemia.9 As in diabetes, the earliest histopatho-
logic finding in noninfectious HIV-related microvasculopathy is
loss of capillary pericytes. Vascular sludging from hypergamma-
globulinemia, immune complex deposition on the vascular
walls, and local release of cytotoxic substances have all been
postulated as causative factors for the hemorrhages.10 The
cotton-wool spots occur in the posterior pole, often near the
optic disc. There is no associated vitritis or increased vascular
permeability. The time to regression is 6–12 weeks.11
Cumulative loss of retinal ganglion cells manifests itself as an
asymptomatic decrease in visual acuity, color vision, and
contrast sensitivity.12,13 With highly active antiretroviral
therapy (HAART), the lesions can disappear, leaving a normal-
appearing fundus, although studies of patients with AIDS show 2095
 RETINA AND VITREOUS
SECTION 10
FIGURE 163.1. HIV microvasculopathy. Note the cottonwool spots
and intraretinal hemorrhage in the right eye of this 36-year-old woman
with AIDS and a CD4+ count persistently below 10 cells/mL. She had
CMV retinitis in the fellow eye.
a global decrease in the number of optic nerve fibers resulting
from axonal degeneration in the absence of infection.
The retinal hemorrhages in background retinopathy may
appear as including flame-shaped, dot-blot or punctuate
peripheral intraretinal hemorrhages; occasionally Roth spots
(hemorrhages with a white central region) are seen. The hemor-
rhages are not associated with a coagulopathy or a bleeding
diathesis. Fluorescein angiography may reveal areas of micro-
aneurysms, telangiectasias, and capillary loss.
RETINAL MACROVASCULOPATHY
Branch or central retinal vein occlusions, branch retinal artery
occlusion, and ischemic maculopathy have all been described in
the literature in persons with HIV/AIDS.14–17 In one study of
nearly 2500 consecutive persons with HIV infection, 1.3% of
patients were noted to have retinal vascular occlusion, of whom
48% had central retinal vein occlusion (CRVO), 27.3% branch
retinal vein occlusion (BRVO), 12.1% hemitretinal vein
occlusion (HRVO), and 3% central retinal artery occlusion. The
presence of microvasculopathy was associated with a higher risk
of macrovasculopathy.18 In contrast to noninfectious micro-
vasculopathy, visual loss from these macrovasculopathies can
be severe and permanent. The risk of retinal vein occlusion in
those with HIV-infection is significantly higher than in their
age-matched healthy peers. The cause of the retinal
macrovasculopathy is unclear; however, it is presumed that
abnormalities of retinal blood are contributing factors.19,20
CYTOMEGALOVIRUS RETINITIS
Human cytomegalovirus (CMV) is an enveloped, double-
stranded DNA herpes virus. It is most often transmitted by
contact with persons shedding the virus in their urine, sputum,
breast milk, semen, or cervical secretions. The virus can also be
transmitted by solid organ or bone marrow transplantation or
through blood transfusions. Between 40 and 100% of healthy
adults have antibodies to CMV, confirming prior exposure.
Primary CMV infection is usually asymptomatic, although 5%
of newly infected individuals may manifest a mononucleosis-
like syndrome.21 The virus is latent in immunocompetent
2096 individuals with residence in the bone marrow. In immuno-
70
Incidence per 1,000 person years
60
50
40
30
20
10
0
1992 1993 1994 1995 1996 1997
Calendar Year
FIGURE 163.2. Incidence of CMV retinitis over time standardized by
age, race, and CD4+ T-lymphocyte distribution.
Reference: CDC Surveillance for AIDS-defining opportunistic illnesses, 1992–97.
compromised patients, reactivation may lead to clinically
significant disease following hematogenous dissemination. The
retina is the most commonly affected tissue, occurring in
75–80% of patients with reactivation22,23; the gastrointestinal
tract, lung, adrenal glands, and nervous system are also
common sites of clinical disease. Most patients with AIDS-
related CMV retinitis have CD4+ count less than 50 cells/mL.24
Histological samples of CMV retinitis demonstrate intra-
cytoplasmic inclusion bodies in vascular endothelial cells.25
The infection appears to spread by cell-to-cell transmission.
CMV retinitis was one of the first opportunistic infections
reported as a complication of AIDS. In the era before HAART,
up to 30% of patients with AIDS developed CMV retinitis.23
In patients taking HAART, the incidence of CMV retinitis has
declined dramatically to ~ 20–25% of the pre-HAART era rate
(Fig. 163.2).26
DESCRIPTION
In untreated patients, CMV retinitis spreads relentlessly
throughout the retina, causing full- thickness necrosis and
blindness. Lesions may be single or multiple and unilateral or
bilateral, affecting any part of the retina. Symptoms may
include visual field loss, decreased visual acuity, floaters, and
photopsias, but it is not uncommon for patients to be
completely asymptomatic.27,28 The presence of subjective
scotomata varies with the location of the lesions. In patients
with CD4+ counts of less than 50 cells/mL, the prevalence of
previously undiagnosed CMV retinitis detected on screening
has been reported to be as high at 13–18%.24 Eye pain and
redness are not typical features. CMV retinitis may appear as
intraretinal yellow necrotic lesions with retinal hemorrhages
(fulminant/edematous retinitis), as less densely necrotic
without hemorrhage (indolent/granular retinitis), or some
combination of the two. Both types, however, are characterized
by a dry-appearing, granular border (Fig. 163.3). There is often
a mild vitritis and anterior chamber inflammation.27 The
disease progresses outward in a brushfire pattern, leaving
behind an atrophic, avascular, full-thickness retinal necrosis.
The disease is described according to the location within the
retina: zone 1 is within 3000 mm of the center of the fovea or
1500 mm of the optic nerve, zone 2 is located from the periphery
of zone 1 to the ampulla of the vortex veins, and zone 3 from
the periphery of zone 2 to the ora serrata. Zone 1 lesions are
generally considered immediately sight-threatening and usually
require more urgent therapy than do more peripheral lesions.
 Retinal Manifestations of the Acquired Immunodeficiency Syndrome: Diagnosis and Treatment
FIGURE 163.3. CMV retinitis with granular appearance.
Natural History
If CMV retinitis remains untreated, the lesions spread
inexorably to cause total retinal necrosis. The borders of the
lesion advance on average one disc diameter every 6 weeks in a
centrifugal pattern.29 The older portion of the advancing lesion
becomes gliotic scar tissue. Optic atrophy can also be observed
late in the disease from the diffuse retinal damage. Vision loss
may occur from retinal necrosis involving the macula,
rhegmatogenous retinal detachment, secondary optic nerve
involvement, or exudative swelling along an active border
adjacent to the fovea.
DIFFERENTIAL DIAGNOSIS
In the early stage of CMV retinitis it may be difficult to
distinguish cottonwool spots from foci of viral infection.
Cottonwool spots do not cause blurred vision, floaters, or
photopsias and are not associated with vitritis or anterior
uveitis; they usually have a feathery border rather than the
granular border of CMV retinitis. Repeating the ophthalmic
exam after 1-2 weeks will aid in making the diagnosis, as
cotton-wool spots will not progress in size.
As CMV retinitis progresses, it may resemble other infec-
tions of the retina. Toxoplasmic retinochoroiditis can mimic
CMV retinitis, but usually presents with a creamy border,
prominent vitritis, and the absence of intralesional hemor-
rhages. Herpetic infections of the retina (e.g., acute retinal
necrosis and progressive outer retinal necrosis) are less common
than CMV retinitis and have a clinical appearance that is
distinctly different. Bacterial and fungal infections, including
syphilitic retinitis and aspergillosis or candida retinitis, may
also mimic CMV retinitis. Finally, intraocular lymphoma
a b
should be considered in the differential diagnosis of CMV
retinitis, especially in patients with neurologic abnormalities.
DIAGNOSIS
CMV retinitis is usually diagnosed clinically. The presence of
antibodies to CMV indicates prior infection but is neither
indicative of concurrent clinical disease nor predictive of future
disease. Reactivation of CMV is confirmed by positive cultures
for CMV from blood, urine, or throat washings or from
polymerase chain reaction (PCR) amplification of CMV DNA.30
An elevated CMV viral load may be the most predictive risk
factor for end-organ disease. In atypical cases, endoretinal
biopsy taken at the junction of necrotic and actively infected
tissue may be necessary. The pathognomonic finding is the
presence of intranuclear and intracytoplasmic inclusion bodies
with an ‘owl’s eye’ appearance, or positive CMV staining by
immunohistochemistry; electron microscopy demonstrates
CHAPTER 163
viral particles.
COMPLICATIONS
Retinal Detachment
Untreated CMV retinitis causing full-thickness retinal necrosis
may result in a retinal detachment within 3–6 months of
diagnosis.29 In the pre-HAART era, rhegmatogenous retinal
detachment occurred at a rate of 25% per patient-year in
patients treated with anti-CMV therapy, and detachments
remain a major cause of vision loss in CMV retinitis. Lesions
located at the peripheral retina where the vitreous body is
adherent to the retina are more likely to be associated with a
retinal detachment than those lesions located in the posterior
pole. Eyes with larger lesions and a longer duration of active
retinitis also have a higher risk of retinal detachment. While the
retina can usually be reattached surgically, the ultimate visual
acuity is usually worse than the preoperative vision before the
detachment. It is presumed that vitreous fluid egresses through
the breaks in the necrotic retina, rendering photocoagulation
ineffective at promoting adhesion between the retina and the
choriocapillaris. Scleral buckling and vitrectomy with gas
tamponade are often ineffective in treating CMV-related
detachments. Long-term tamponade with oil is often necessary
due to the number of holes in atrophic or gliotic retina.31,32
Exudative retinal detachments are observed in eyes with
involvement of zone 1 and peripapillary lesions.27 These
detachments usually resolve with treatment of the retinitis and
vision may improve substantially (Fig. 163.4).33
Immune Recovery Uveitis
Immune recovery uveitis (IRU), also known as immune
recovery vitritis, was first described in patients with inactive
CMV retinitis who had immune reconstitution following
initiation of HAART. The reported incidence ranges widely from
FIGURE 163.4. CMV retinitis with exudative
retinal detachment (a) before and (b) after
treatment.
2097
 RETINA AND VITREOUS
0.109 cases per person-year to 0.83 cases per person-year.34,35
While differences in the case definition partially explain the
difference in incidence, another factor is thought to be changes
in the treatment of CMV retinitis; patients initially treated with
cidofovir may be at higher risk for IRU. Immune recovery
uveitis usually occurs 2–16 weeks after the elevation of the
CD4+ lymphocyte counts, which typically is noted 2.5–8
months after starting HAART.36
Affected patients develop a painless decrease in visual acuity
and floaters without any redness. The vision loss is generally
mild, in the range of 20/40 to 20/80. The symptoms often begin
within a few weeks or months after the CD4+ counts increase
above 100 cells/mL.37 Examination reveals moderate to severe
vitritis, papillitis, cystoid macular edema, and/or epiretinal
membranes. Uncommon complications include vitreous hemor-
rhage, retinal neovascularization, optic disc neovascularization,
vitreomacular traction syndrome, proliferative vitreoretino-
pathy, posterior and anterior subcapsular cataracts, posterior
SECTION 10
synechiae, and angle closure glaucoma.38,39 The clinical findings
may vary depending on ocular co-morbidities; for instance, eyes
that have had a vitrectomy with silicone oil tamponade will not
have visible vitritis but instead will have cystoid macular edema
or spillover cells in the anterior chamber.37
The cause of immune recovery syndrome is not known.
Immune reconstitution is thought to occur after depletion of
CD4+ lymphocytes is halted, allowing the surviving clones to
expand their population.40 It has been suggested that the
recovering immune system reaches a threshold above which the
body is able to mount an ocular inflammatory response to CMV
antigens in the eye. Some patients, however, may lack the
clones capable of responding to cytomegalovirus even though
they have elevated CD4+ T-lymphocyte counts. Eyes with
inactive retinitis involving over 30% of the retinal area are at a
higher risk of developing immune recovery uveitis when
compared to eyes with less extensive involvement, presumably
because those eyes with a larger area of CMV retinitis may
generate a greater antigenic stimulus, prompting a more
aggressive inflammatory response.41 This reaction is analogous
to the necrotizing lymphadenitis observed with Mycobacterium
avium-complex infections after the initiation of HAART
therapy.42 As immune recovery progresses, the production of
CMV antigens stops and the inflammatory reaction subsides.40
Limited histologic and immunohistochemical studies of epi-
retinal membranes found in this syndrome have shown a
predominately T-lymphocyte population. Surprisingly, higher
levels of CD4+ T-lymphocyte levels were not associated with
the severity of the inflammation. Some investigators have
suggested that variations in the incidence of IRU may also be
due to different virus strains which may stimulate different
degrees of inflammation or have different replication rates.
There may also be differences in the number of clones capable
of responding to CMV, even if the CD4+ counts are the same.43
Vision loss typically results from the cystoid macular edema
or the formation of epiretinal membranes and vitreomacular
traction. Less commonly, branch retinal vessel occlusion and
retinal neovascularization are the cause. Successful treatment
of IRU has not been demonstrated in a randomized clinical
trial; however, a few small cohort studies and case reports have
shown that treatment with periocular or systemic corticos-
teroids may result in improved vision.41,44 On the other hand,
Zegans found that the vitreous cells resolved and the vision
improved within 6 weeks with or without antiinflammatory
therapy.37 Re-activation of CMV retinitis following corticos-
teroid therapy appears to be very rare. It is unclear whether
resumption of anti-CMV therapy or longer use of anti-CMV
therapy prior to discontinuation in patients with immune
2098 recovery reduces the risk of IRU.
TREATMENT OPTIONS
CMV Retinitis Treatment Overview
Screening
• Patients with CD4<100 cells/mL for periodic opthalmological
evaluation; more urgent in patients with visual symptoms
Diagnosis
• Clinical presentation: single or multiple lesions with dry,
granular-appearing border; can occur with or without retinal
hemorrhage
Management
• Zone 1 disease: treat urgently with intravenous anti-CMV agent
• Insertion of ganciclovir implant in those with lesions
immediately adjacent to the optic nerve or fovea
• Monitor renal function, hematological indices, and toxicity
profiles to determine appropriate treatment
• Patients with CMV retinitis (even if inactive) and persistent
immunosuppression should be examined monthly
Prevention
• HAART for patients with CD4+ count less than 200 cells/mL
to reduce the risk of CMV retinitis
• Secondary prophylaxis with valganciclovir in those with
CMV retinitis until CD4 counts consistently higher than
100 cells/mL while on HAART
It is essential to realize that CMV retinitis is part of systemic
CMV and HIV infection and that treatment must take into
account the nonocular effects of disease; the best outcome is
obtained in patients treated with both anti-CMV therapy as
well as HAART. In the pre-HAART era, patients with AIDS with
cytomegaloviremia had a higher risk of end-organ CMV disease
and mortality.45,46 The mechanisms by which CMV increases
mortality includes transactivation of HIV, altering the tropism
of HIV, production of interleukins, chemokine receptors, and
interference with natural killer cells, thereby inhibiting the
host’s ability to clear viruses.47 Kempen et al showed ~30%
reduction in mortality in patients treated with systemic anti-
CMV therapy, after adjusting for HAART.48 The widespread use
of HAART has not only changed the course of AIDS, but has
also reduced the rates of vision loss in those with CMV retini-
tis. Those with HAART-induced immune recovery have half the
risk of visual acuity loss.49 This decrease has been attributed to
a reduction in progression (96% reduction), contralateral eye
involvement (82%) and associated retinal detachments (88%) in
the HAART era.50–52 Patients with unilateral CMV retinitis are
at a significantly higher risk of developing second-eye retinitis
of the order of 26.1% per person-year, almost all within the first
few months after diagnosis, despite systemic CMV treatment.
Those on treatment with anti-CMV therapy and HAART with
immune recovery are significantly less likely to develop
contralateral eye involvement.53 However, cytomegalovirus
infection worsens the prognosis in patients with AIDS; CMV
viral load and active disease are associated with an increased
mortality despite the use of HAART.54
There are four drugs that have been FDA approved for the
treatment of CMV retinitis-ganciclovir, valganciclovir, f os-
carnet, and cidofovir. All of these drugs work by inhibiting the
activity of CMV DNA polymerase that is essential for
replication of the virus (a fifth approved drug, fomvirsen, is an
antisense oligonucleotide that works by a different mechanism,
but the drug was voluntarily taken off the market in 2003 due
to poor sales). All of these drugs are virostatic, not virocidal.
The dosing strategy for systemic medications involves an
induction period of 2–3 weeks, followed by indefinite, lower-
 Retinal Manifestations of the Acquired Immunodeficiency Syndrome: Diagnosis and Treatment

TABLE 163.1. Medication Regimen for the Treatment of CMV Retinitis.

Drug Induction Maintenance Laboratory Tests Toxicity Considerations

Ganciclovir
Intravenous 5 mg/kg IV bid 5 mg/kg IV qd Complete blood Anemia, Dose adjustment for
(Cytovene) µ 14 days count twice a thrombocytopenia, renal disease
not used for 1 g po tid week during neutropenia Avoid other bone marrow
induction 2000 g induction, weekly suppressing
Oral N/A per 0.1 mL during maintenance medications
(Cytovene) 2000 mg intraocular Serum creatinine Cytokine support)
Implant per 0.1mL injection monthly (granulocyte colony-
(Vitrasert) intraocular qweek Complete blood stimulating factor)
Intraocular injection twice count every for neutropenia
injections weekly 1–2 weeks; serum (absolute neutrophil
creatinine monthly count <500/mm3)
None for intraocular
or implant
administration
alone

CHAPTER 163
Valganciclovir 900mg po 900 mg po Complete blood Bone marrow Avoid other bone
(Valcyte) bid µ 21 days qday count weekly suppression, marrow suppressing
nausea, diarrhea medications
Cytokine support for
neutropenia
Foscarnet 90 mg/kg bid 90–120 mg/kg Serum creatinine, Nephrotoxicity, Dose adjustment for
Intravenous µ 14 days or qday potassium, hypokaemia, renal disease
(Foscavir) 60 mg/kg tid 2400 g magnesium, hypocalcemia, IV prehydration with 1
Intraocular 2400 mg qweek calcium, hypomagnesemia, L 0.9% NaCl
injections biweekly phosphorous genital ulcers, Slow infusion if
biweekly during anemia, headache hypocalcemia
induction, weekly symptoms
during maintenance; Electrolyte replacement
hemoglobin
Cidofovir 5 mg/kg qweek 3–5 mg/kg IV Serum creatinine, urinary Nephrotoxicity, IV prehydration with 1 liter
Intravenous µ 14days q2weeks protein, complete proteinuria, Fanconi- 0.9% NaCl
(Visitide) blood count before like syndrome, Oral probenecid 2 g po
each infusion hypocalcemia, 3 h before, 1 g po 2 h
neutropenia, uveitis, after and 1g 8 h after
hypotony dose
Discontinue if IOP < 50%
of baseline
Discontinue if dipstick
proteinuria > 2+ or
serum Cr increases by
0.5 mg/dL
Fomvirsen 330 g 330 mcg None Increased IOP, uveitis Withdrawn from the
(Vitravene) intraocular intraocular market as of 2003
qweek

frequency maintenance therapy that must be lifelong in
patients with persistent immunosuppression (Table 163.1).
In patients with immune recovery (generally defined as a
recovery in the CD4+ count by more than 50 cells/mL or to a
level greater than 100 cells/mL for at least 3–6 months), discon-
tinuation of maintenance therapy in those with inactive CMV
retinitis is usually possible, thereby avoiding the cost and
toxicity of treatment.55,56 Some investigators have suggested
that HIV viral load is a better predictor of progression than
CD4+ counts.57 In light of these findings, there is no consensus
on when the maintenance therapy can be discontinued.
Ganciclovir is the most commonly used medication for the
treatment of CMV retinitis and can be administered intra-
venously, orally, or intraocularly via an injection or an implant.
Activation of ganciclovir requires initial phosphorylation by a
CMV-encoded kinase produced by the UL97 gene, followed by
additional phosphorylation by host cellular enzymes to the
active drug, ganciclovir triphosphate, that inhibits CMV DNA
polymerase. In 80–90% of patients, the intravenous adminis-
tration of ganciclovir at a dosage of 5 mg/kg twice a day during
the induction period initially halts retinal cell necrosis and
reduces the viral load of CMV. Maintenance therapy at a dosage
of 5 mg kg–1 day–1 is then continued, but the need for daily
intravenous mandates the need for a permanent indwelling
catheter and the associated risks of line infection and sepsis.
Maintenance therapy with oral ganciclovir was effective in
controlling retinitis temporarily and obviated the need for
permanent catheterization,58 but bioavailability is poor (less
than 7%) and the risk of progression of retinitis is high.
Consequently, vision-threatening lesions (e.g., zone 1 disease)
are poor candidates for oral maintenance therapy.
Valganciclovir is an oral prodrug which is hydrolyzed to
ganciclovir in the gastrointestinal mucosa and has better bio-
availability (61%) than oral ganciclovir. The plasma levels
obtained with valganciclovir are comparable to that obtained
with intravenous ganciclovir, making it a viable option for both
induction and maintenance therapy at dosages of 900 mg twice
a day and 900 mg once daily, respectively.59,60 2099
 RETINA AND VITREOUS
FIGURE 163.5. Placement of ganciclovir implant in the vitreous cavity.
SECTION 10
The ganciclovir implant is a surgically-implanted, sustained-
release, 4.5 mg ganciclovir pellet attached to a nonerodable
strut. The pellet is coated with polyvinyl alcohol (which is
permeable to ganciclovir) and ethylene vinyl acetate (which is
impermeable). The release rate of about 2 mg/h is determined
by the thicknesses of the coatings of the two polymers,
providing release of drug for about 7–8 months. The implant is
placed in the vitreous cavity through a 5.5 mm pars plana
incision made 3.5–4 mm posterior to the limbus; prolapsed
vitreous is excised, but an internal vitrectomy is not
necessary.61 The strut attached to the implant is trimmed to a
length of about 2 mm and a hole is placed in the end of the strut
with a 27- or 30-gauge needle. A double-armed 8–0 nylon or
prolene suture is placed through this hole and the device is
centered in the wound (Fig. 163.5). A stable intraocular con-
centration of ganciclovir is obtained within 24–48 h and is
roughly fourfold higher than that obtained with intravenous
therapy. In a randomized clinical trial of 188 patients with
active CMV retinitis and AIDS, the sustained release
ganciclovir implant decreased the risk of progression threefold
when compared to intravenous ganciclovir. However, the risk of
systemic CMV disease as well as involvement of the con-
tralateral eye was significantly higher than that observed in
patients receiving intravenous therapy.62 The implantation
procedure typically causes a transient decrease in visual acuity
from astigmatism to 20/80 on average which resolves within
the first 4 weeks of treatment. The most significant risks are
associated with the surgical complications. The presence of
silicone oil does not appear to interfere with the functioning of
the ganciclovir implant.63
Following ganciclovir implant placement, the risk of retinal
detachment was 11.9%, endophthalmitis was 1.7%, and
vitreous hemorrhage was 7.8%.62,64 Endophthalmitis may occur
through introduction of organisms into the eye at the time of
surgery or subsequently through incomplete wound closure at
the intrascleral location of the suture tab. Because of these
potential complications, the implant is avoided if immune
reconstitution is expected unless zone 1 is involved.
Foscarnet, a pyrophosphate analog, also inhibits CMV DNA
polymerase but does not require phosphorylation. It is compa-
rably effective to ganciclovir in the treatment of CMV retinitis.
However, its tedious intravenous administration schedule
coupled with its side effect profile, especially nephrotoxicity, has
made it a less desirable first-line therapy. Because foscarnet does
not require phosphorylation, it may be effective in the treat-
ment of CMV retinitis resistant to ganciclovir as a result of
2100 mutations in the UL97 gene.
Intravitreous injections of both ganciclovir and foscarnet
have been used off-label to treat CMV retinitis. The usual
dosage for ganciclovir is 2 mg in 0.1 ml and for foscarnet
2400 mg in 0.1 mL. The injections must be given twice weekly
as induction therapy and once weekly thereafter, a regimen that
is usually not practical for patients in the long term. As with the
ganciclovir implant, the use of intravitreal injections does not
prevent second-eye or visceral CMV disease. On the other hand,
intravitreal injections can be very useful in obtaining rapid
control of zone 1 retinitis before more definitive therapy can be
instituted, and can serve as a bridge between systemic therapies
when toxicity requires temporary cessation. Risks include
subconjunctival hemorrhage, pain, acute glaucoma, infection,
vitreous hemorrhage, endophthalmitis, and retinal detachment.
Cidofovir is an acyclic nucleotide analog that was found in a
series of clinical trials to be effective at preventing the prog-
ression of CMV retinitis. Its activity is 10–100 times greater
than other available anti-CMV medications. The induction
regimen is 5 mg/kg once a week for 2 weeks, followed by
3–5 mg/kg every two weeks. Its prolonged antiviral effect allows
for intermittent intravenous administration to control the
disease, so that permanent catheterization is not needed.
However, the use of cidofovir is limited by potentially
irreversible nephrotoxicity through dose-dependent damage to
proximal tubular cells of the kidney and by the development of
anterior uveitis in 24–59% of patients receiving the drug.65–67
Another 25% of patients developed hypotony presumed to be
secondary to changes in the ciliary epithelium and a reduction
of aqueous humor production. Injections of intravitreous
cidofovir may result in irreversible hypotony and for this reason
should never be used. The anterior uveitis is characterized by
pain, ciliary injection, posterior synechiae formation, and
decreased visual acuity, and occurs on average after approx-
imately five doses of the medication. The uveitis usually
responds to topical steroids and cycloplegia.65 The risk of
anterior uveitis appears to be reduced by the concomitant use of
probenecid, which is thought to inhibit secretion of cidofovir by
the ciliary body and therefore decreased intraocular drug levels.
Clinical resistance to anti-CMV therapy is estimated to occur
in 20–30% of patients after one year of therapy. Mutations at
the level of the UL97 gene result in the reduced uptake of
phosphorylated ganciclovir into host cells and cause low-level
resistance that is often responsive to foscarnet or cidofovir.
Mutations at the level of the UL54 gene cause high level resist-
ance that may be resistant to all three medications. Resistance
was associated with prior intravenous cidofovir use or prior oral
ganciclovir use.68 Phenotypic resistance is determined by
analysis of viral cultures, whereas genotypic resistance is deter-
mined by the use of PCR techniques using blood or vitreous
specimens; there is a good correlation between resistance
determined from blood specimens and those obtained from the
vitreous. It is important to distinguish resistant CMV retinitis
from progression of disease due to poor compliance or
inadequate drug penetration because the former is associated
with reduced survival and poorer visual outcomes.69
Treatment Effectiveness
Resolution of CMV retinitis is recognized by the loss of satellite
lesions, disappearance of vascular sheathing, and the formation
of a well-demarcated lesion borders. Systemic therapy may take
several weeks or more to control retinitis and therefore may not
be adequate in the initial treatment of lesions near the fovea or
optic nerve. In these cases, immediate intravitreous injections
of ganciclovir or foscarnet, followed by placement of a gan-
ciclovir implant, may be more effective. Secondary prophylaxis
with valganciclovir is then indicated to reduce the risk of
second-eye and visceral CMV disease. In all patients with CMV
 Retinal Manifestations of the Acquired Immunodeficiency Syndrome: Diagnosis and Treatment
retinitis, initiation or maximization of HAART is critical in
achieving long-term control of retinitis.
Studies have shown that plasma CMV loads >400 copies/mL
and leukocyte CMV loads >400 copies/106 leukocytes are
associated with an increased risk of CMV retinitis progression.
Unfortunately, the sensitivity and positive predictive value for
these markers were low, limiting their global clinical utility.70
Measurement of the CMV plasma load may aid in rapidly
excluding CMV resistance and identifying those patients
requiring more detailed and time-consuming resistance testing.
Salvage Therapy
Over time, most patients with CMV retinitis relapse with
progression of the disease when treated with systemic therapy
alone. Progression is much less common in eyes treated with
the ganciclovir implant because of the high-intraocular levels
obtained, but will invariably occur when the implant is
exhausted of drug after 7–8 months if immune recovery is not
established. Therefore, the use of HAART in all patients with
CMV retinitis is highly desirable. Reactivation is documented
with the reappearance of opacification of the border of the lesion
and advancement of the lesion borders or the development of
new lesions. Predictors of clinical relapse include HAART
failure, weak lymphoproliferative responses to CMV, and a low
nadir HIV viral load.71 Progression of previously inactive lesions
(‘breakthrough’ or ‘relapse’) in the first year of treatment is most
likely due to poor intraocular drug levels as a result of re-
establishment of the blood–retinal barrier. Subsequent
progression may be due to drug resistance. Various strategies
have been used to manage the relapse but there is limited
evidence to guide the clinician. Reinduction therapy with a
higher dose of drug or by switching from one drug to another,
combined therapy with intravenous ganciclovir and foscarnet
has been shown to be twice as effective as either drug alone in
delaying further progression72; however, the added toxicity of
the second drug makes combination therapy difficult to
administer and reduces quality of life. In cases in which drug
resistance is the cause of progression, a change from ganciclovir
to foscarnet or cidofovir may be necessary. In patients who are
unable to tolerate systemic treatment, intravitreal injections or
the ganciclovir implant are options. The ganciclovir implant
produces intravitreous drug levels high enough to overcome
some cases of low-level ganciclovir resistance (UL97 mutations)
but will not control retinitis with UL54 mutations.
INVESTIGATIONAL AGENTS
The dramatic drop in the incidence of CMV retinitis has
reduced the interest in developing new anti-CMV agents;
nonetheless, several drugs are being examined in early clinical
trials. Maribavir is a proposed drug that inhibits the UL97 gene
product prohibiting terminal DNA processing and hence
arresting nuclear egress of CMV particles. It has shown activity
in vitro in suppressing CMV retinitis. The drug does not need
intracellular activation and shows promise for retinitis resistant
to ganciclovir or foscarnet. Some of the side effects include
headache, dysgeusia, diarrhea, and nausea which are dose
related. Tomeglovir another orally administered drug still in the
early trial phase has also proven to have efficacy against
resistant strains of CMV.73
PREVENTION
The inhibition of viral replication instigated by HAART coupled
with the reconstitution of the immune system of patients with
AIDS has led to a dramatic decrease in morbidity and mortality.
Periodic CD4+ counts must be monitored in these patients
with resumption of secondary prophylaxis in the presence of
immunological failure (generally considered a decrease in the
CD4+ count to less than 75 cells/mL). Routine use of primary
prophylaxis with anti-CMV therapy, including valganciclovir, is
not recommended because of the high cost, potential toxicity,
and concerns about the development of drug-resistant disease.
OTHER VIRAL INFECTIONS
PROGRESSIVE OUTER RETINAL NECROSIS
Progressive outer retinal necrosis (PORN) was the second most
common infectious retinopathy in patients with AIDS before
the advent of HAART, occurring in 2% of patients with AIDS
with a median CD4+ count of 21 cells/mL.74 It is generally
associated with reactivation of herpes zoster virus, although
herpes simplex virus (HSV-1) has also been reported to cause
PORN (Fig. 163.6). The retinitis can start in the macula or in
CHAPTER 163
the periphery with patchy, multifocal outer retinal lesions
coalescing rapidly throughout the retina in the absence of
vascular or vitreous inflammation. Severe visual loss from the
diffuse retinal necrosis, optic atrophy, and retinal detachment
occurs in up to 70% of patients.75 Progression is extremely
rapid, occurring over days or even hours. Some patients have
severe vision loss despite minimal or absent retinitis as a result
of early optic nerve involvement; in these patients, the onset of
pain with vision loss may be a key finding. Treatment with
intravenous acyclovir alone results in a final vision of no light
perception (NLP) in 67% of affected eyes within 1 month.74
While there is no standard recommendation for treating PORN,
combination therapy appears to result in better visual out-
comes. A regimen of intravitreal foscarnet and ganciclovir as
well intravenous administration of both drugs was associated
with 45% of patients having a vision of 20/80 or better. This
same study suggested that laser demarcation may result in
better outcomes as well due to a lower risk of retinal detachment.76
Indefinite maintenance therapy with valacyclovir is necessary
in patients with persistent immunosuppression. However, as
with CMV retinitis and all viral retinitides, the development of
immune recovery by HAART is probably the most important
factor in maintaining long-term control of the disease.
ACUTE RETINAL NECROSIS
Acute retinal necrosis (ARN) is an aggressive and devastating
retinitis characterized by a fulminant panuveitis with well-
demarcated confluent areas of full-thickness retinitis, choroiditis,
FIGURE 163.6. PORN radiating in posterior pole. 2101
 RETINA AND VITREOUS
TABLE 163.2. American Uveitis Society Criteria for Diagnosing
ARN
Required Clinical Criteria
Rapid progression of disease in absence of therapy
One or more foci of retinal necrosis with discrete borders in
peripheral retina
Circumferential spread
Evidence of occlusive vasculopathy and arteriolar involvement
Prominent vitreous inflammation and anterior chamber reaction
Supporting Clinical Criteria
Optic neuropathy/ atrophy
Scleritis
pain
SECTION 10
and papillitis. Varicella zoster virus and herpes simplex virus
have both been associated with this disease. The retinitis is
marked by deep retinal whitening, limited hemorrhage hemor-
rhage, and a rapid progression over days to weeks. Dense vitritis
produces fibrotic bands that exert traction on necrotic retina
leading to complex retinal detachments in 75% of patients and
blindness in 64% of patients within 2–3 months. Unlike
PORN, the CD4+ count is usually greater than 60 cells/mL in
these patients. The American Uveitis Society has criteria
established for making the diagnosis of ARN (Table 163.2).77
Late in the course of the disease, retinal breaks and detach-
ments in the area of necrosis are common. Proliferative vitreo-
retinopathy often accompanies the retinal atrophy in the
end-stages of the disease. The treatment for ARN in AIDS
patients is similar to that advocated in non-HIV patients.
Therapy includes intravenous acyclovir followed by indefinite
oral therapy with acyclovir, valacyclovir, or famciclovir. While
those immunocompetent patients with ARN are sometimes
treated with oral corticosteroids to reduce vitreous inflam-
mation, this approach is controversial in HIV patients because
of concerns about additional immunosuppression; short-term
prednisone therapy probably does not put the patient at
significant risk. Laser demarcation along the posterior border of
the retinitis is indicated to reduce the risk of retinal
detachment.
NONVIRAL RETINAL INFECTIONS
PARASITIC INFECTIONS
Pneumocystis carinii Pneumonia
Pneumocystis carinii pneumonia (PCP) was in the pre-HAART
era the most common AIDS-defining condition in HIV-infected
patients, usually developing in patients with a CD4+ count less
than 200 cells/mL. Patients at risk for developing PCP are placed
on prophylactic therapy with trimethoprim-sulfmethoxazole
(TMP-SMX), or dapsone, or dapsone plus leucovorin and aero-
solized pentamidine. Prophylactic treatment with aerosolized
pentamidine alone is associated with an increased risk of
Pneumocystis carinii choroidopathy, characterized by pale,
multifocal, cream- to orange-colored plaques ranging in size
from 300–3000 mm deep in the mid-peripheral and posterior
choroid.78 Except in some cases of subfoveal involvement,
vision is typically preserved because neither the retina nor the
vitreous are involved.79 Histopathologically, the choroidopathy
is characterized by eosinophilic, acellular, frothy, vacuolated
2102
infiltrates within choroidal vessels. The choroiditis takes from
6 weeks to 4 months to resolve after treatment with double
strength trimethoprim-sulfmethoxazole. It is usually a marker
for disseminated pneumocystosis. In the era of HAART and
systemic prophylaxis with systemic therapy such as TMP-SMX,
P. carinii choroidopathy has virtually disappeared.
Toxoplasmosis Retinochoroiditis
Toxoplasmosis retinochoroiditis was the third most common
infectious retinopathy of AIDS in the pre-HAART era, occurring
in 1% of patients.7 The retinitis is characterized by yellow-white
areas of retinal necrosis with smooth, nongranular borders most
often involving the posterior pole in the absence of hemorrhages.
It is associated with a severe vitritis. In immunocompromised
patients, ocular involvement is much less common than central
nervous system toxoplasmosis. The ocular involvement is often
atypical in patients with AIDS. The various presentations range
from acute anterior uveitis to panophthalmitis with a secondary
orbititis.80 Lesions are more frequently multifocal and bilateral
than in immunocompetent. Those who are infected have IgG
antibodies to T. gondii at the time of diagnosis. Treatment con-
sists of trimethoprim-sulfmethoxazole; maintenance therapy is
required because recurrences are frequent in patients without
immune recovery but may be discontinued in patients whose
CD4+ count is consistently above 200 cells/mL. For patients
allergic to sulfa drugs, azithromycin, atovaquone, and clinda-
mycin with pyrimethamine/leucovorin may be effective.81,82
Primary prophylaxis for toxoplasmosis with TMP-SMX is given
to those with CD4+ counts less than 200 cells/mL.
FUNGAL DISEASE
Endogenous endophthalmitis can be caused by a number of
fungal infections.
Cryptococcus Neoformans
Cryptococcus neoformans is a common cause of meningitis
with central nervous system disease in patients with AIDS.
Chorioretinitis and endophthalmitis are both thought to result
from direct invasion of the organism usually through neural
tissue (e.g., optic nerve). Ocular symptoms often precede the
neurological disease.83 Treatment consists of amphotericin B
during the induction phase and oral fluconazole for mainte-
nance therapy. Although many patients with AIDS also use
illegal drugs intravenously and Candidal infections are
associated with intravenous drug use, Candida endophthalmitis
is uncommon in AIDS patients. Endogenous endophthalmitis
caused by Aspergillus fumigatus is also very rare in the AIDS
population.84 A systematic review of 77 AIDS patients with
coccidiomycosis also found no cases of endogenous
endophthalmitis.85
In 1987, the Centers for Disease Control (CDC) modified the
case definition for AIDS to include extrapulmonary histo-
plasmosis in a person who is HIV positive. Most cases of
histoplasmosis in immunosuppressed individuals are dissemi-
nated. The chorioretinitis that results is characterized by
perivascular retinal lesions with minimal inflammation.
Choroidal infection with H. capsulatum is rare.86
Paracoccidioidomycosis
Paracoccidioidomycosis is a granulomatous infection pro-
minent in Latin America. Although, it is the most frequent
systemic mycosis in Brazil, it is infrequently seen in patients
with AIDS. The disease characteristically begins in the
oropharynx and disseminates to lymphoid tissue. In immuno
compromised patients, it can result from reactivation of a
 Retinal Manifestations of the Acquired Immunodeficiency Syndrome: Diagnosis and Treatment
quiescent lesion since cell-mediated immunity keeps the
infection dormant. Choroidal granulomas and endophthalmitis
have been described. This fulminant infection can cause a total
retinal detachment with marked vitritis and iridocyclitis and in
one case resulted in enucleation.87
In general, the treatment for fungal endophthalmitis is
intravenous amphotericin B since most patients also have
systemic fungemia. Because intravenous amphotericin has poor
intravitreal penetration, vitrectomy and intravitreal ampho-
tericin B are recommended adjunct therapy for sight-
threatening endophthalmitis.
BACTERIAL
Syphilitic (luetic) retinitis is a complication of central nervous
system involvement not exclusive to patients with AIDS.
However, it may have a very fulminant course in patients with
patients with AIDS, resulting in blindness from retinal
necrosis, vasculitis, and papillitis. The retinitis can manifest as
a localized large, pale yellow, placoid subretinal macular lesion
or as a necrotizing retinitis resembling CMV retinitis, ARN and
toxoplasmosis retinitis.88 The diagnosis is based on the clinical
appearance and positive serology. Because HIV-positive patients
frequently have a false-negative serum rapid plasma reagin
(RPR) test, the more specific fluorescent treponemal antibody
absorbed (FTA-ABS) test should also be drawn.88 The treatment
consists of 4 weeks of intravenous penicillin, with the same
dosage used for treatment of neurosyphilis.
Hematogenous dissemination of Mycobacterium tuberculosis
to the choroid results in single or multiple round, yellow-white
elevated lesions with indefinite borders ranging from 0.5 to
3.0 mm in diameter in the posterior pole and midperiphery
(Fig. 163.7). Only a few cases have been described in the
literature.89 The diagnosis is difficult to establish the diagnosis
in the absence of systemic disease, and treatment is often
undertaken presumptively, based on the clinical appearance, the
patient’s history of TB exposure and treatment even in the
absence of a positive chest radiograph. Tuberculous choroiditis
responds well to systemic therapy with rifampin, ethambutol,
isoniazid, and pyrazinamide.
TUMORS
HIV-associated primary lymphoma of the choroid is extremely
rare. In the reported cases, it appears as a confluent yellowish-
white retinochoroidal infiltrate with perivascular sheathing that
FIGURE 163.7. Tuberculosis nodule in the choroid.
can mimic CMV retinitis.90 The diagnosis may be made by
endoretinal biopsy but more often treatment is initiated based
on a systemic workup, including spinal tap, neuroimaging, and
brain biopsy. Survival is poor in affected patients.
DIAGNOSTIC TECHNIQUES FOR
DETERMINING CAUSE OF RETINAL
LESIONS
In complex cases, where the clinical picture is atypical for any
disease, a diagnostic biopsy of the choroid, vitreous, or retina
may be necessary. Vitreous sampling is most appropriate if
there is a brisk vitritis. At the time of a pars plana vitrectomy,
the vitreous washings in the cassettes can be plated for cultures
and cytology to further tailor treatment. If there is a choroidal
infiltrate, a choroidal biopsy can be performed. In the operating
room, a complete peritomy is performed with isolation of the
CHAPTER 163
four recti muscles. A half-thickness scleral trapdoor dissection
is performed with preplaced sutures, allowing rapid closure of
the wound, and is surrounded by cautery. Choroid only is
removed and the wound is then closed. Some advocate per-
forming a pars plana vitrectomy prior to choroidal sampling to
aid in the maintenance of intraocular pressure. Endoretinal
biopsy can be performed at the time of repair of rhegma-
togenous retinal detachment in patients with viral retinitis. The
sample is taken from the margin of healed and active retinitis.
The need for these surgical diagnostic techniques is fortunately
uncommon, as most retinal manifestations of AIDS are
diagnosed clinically (Fig. 163.8).
DRUG TREATMENT
HIV THERAPY
The goals for therapy of HIV include suppression of viral
replication, preservation of immune function, with main-
tenance of quality of life without sacrificing a reduction in HIV-
related morbidity and mortality. The Department of Health and
Human Services recommends treatment of HIV with a
combination of a nonnucleoside reverse transcriptase inhibitor
or protease inhibitor with two nucleoside reverse transcriptase
inhibitors for the initiation of therapy in treatment-naïve
patients. This regimen has been termed highly active anti-
retroviral therapy (HAART). Treatment for HIV using HAART
FIGURE 163.8. Toxoplasmosis scar, inactive.
2103
 RETINA AND VITREOUS

Non-nucleoside Reverse Transcriptase Inhibitors

TABLE 163.3. Antiretroviral Regimens Recommended for
Treatment of HIV Infection in Anti-Retroviral Naïve Patients
(Reference: JAMA (2004) 292: 251-65.)
Recommended Components
Non-nucleoside reverse
transcriptase inhibitors
Protease inhibitors
Nucleoside reverse
transcriptase inhibitors
Alternative Components
Protease inhibitors
Nucleoside reverse
SECTION 10
Efavirenz
Nevirapine
Lopinavir + ritonavir
Atazanavir + low-dose ritonavir
Saquinavir + low-dose ritonavir
Indinavir + low-dose ritonavir
Zidovudine or tenofovir) +
(lamivudine or emtricitabine)
Didanosien + emtricitabine
Fosamprenavir + low-dose
ritonavir
Non-nucleoside reverse transcriptase inhibitors are a struc-
turally diverse group of agents that function as noncompetitive
inhibitors of HIV-1 reverse transcriptase and do not exhibit
activity against HIV-2 strains. These agents are associated with
a hypersensitivity reaction that affects the entire class of agents.
These medications also interfere with the cytochrome P450
metabolic pathways.
Protease Inhibitors
In 1995, inhibitors of HIV protease were first introduced and
completely altered the natural history of HIV by decreasing
morbidity and mortality when combined with other anti-
retrovirals.94 Because of their short half-life, co-administration
of ritonavir, which inhibits the cytochrome P450-mediated
metabolism of these compounds, is advised. Protease inhibitors
are often associated with gastrointestinal intolerance and
metabolic abnormalities.

transcriptase inhibitors Atazanavir

Nelfinavir
Abacavir + lamivudine
Didanosine + lamivudine
Didanosie + tenofovir
Stavudine + lamivudine
Zidovudine + abacavir
Reference: JAMA (2004) 292: 251–65.
Fusion Inhibitors
This is the newest class of antiretroviral agents that works by
blocking cellular invasion. It inhibits fusion of the viral envelope
glycoprotein (gp41) with the host cell membrane. There is only
one fusion inhibitor presently approved for HIV infection treat-
ment and it is administered as repeated subcutaneous injections.

OCULAR COMPLICATIONS OF OTHER

detailed in Table 163.3 is typically initiated when CD4+ cell
counts drop below 200 cells/mL or constitutional symptoms
develop. No conclusive benefit has been demonstrated for
starting the medication at CD4+ counts above 300 cells/mL. By
tracking the CD4+ count as well as the HIV-RNA viral load,
response to HAART can be determined. Current treatment
recommendations are specified below.91
Nucleoside Reverse Transcriptase Inhibitors
These were the first agents used to treat HIV infection and
remain integral to the management. They are competitive
inhibitors of reverse transcriptase, active against HIV-1 and
HIV-2, prohibiting budding of the virus from the cell. The
agents must be phosphorylated by host cell enzymes in the
cytoplasm to become active. Once active they are incorporated
into the proviral DNA and cause termination of the chain.
These compounds have a narrow therapeutic index secondary
to their affinity for DNA polymerases. Currently, there are eight
available agents. They are associated with myopathy, hepatic
steatosis, and polyneuropathy. Macular edema has been
described in a patient treated with zidovudine.92 Didanosine
has been linked to optic neuritis and atrophy of the retinal
pigment epithelium especially in children. Hence, quarterly
indirect ophthalmoscopy should be performed in children on
this medication.93
MEDICATIONS IN HIV
Treatment of the opportunistic infections associated with AIDS
may cause ocular side effects. Rifabutin, cidofovir, and
fomivirsen may all induce uveitis.95 Ethambutol, used to treat
tuberculosis and Mycobacterium avium infections, may cause
optic neuropathy. Finally, AIDS neuropathy can affect sexual
function, necessitating the use of phosphodiesterase inhibitors
(e.g., sildenafil) for erectile dysfunction. These drugs cause
inhibition of the nitrous oxide pathway and have been linked to
anterior ischemic optic neuropathy.96
SUMMARY
AIDS is a syndrome that affects all organ systems with frequent
retinal findings. In particular, CMV retinitis is an AIDS-
defining illness as well as a prognostic indicator for mortality in
patients with AIDS. While CMV retinitis is the most common
opportunistic infection in patients with AIDS, noninfectious
retinal microvasculopathy is the most prevalent finding. Other
opportunistic pathogens can destroy retinal and/or choroidal
tissue. Aggressive treatment with specific antiviral, antibiotic,
antifungal, or antiparasitic drugs and HAART have resulted in
reduced ocular morbidity and, in some cases, reduced mortality.
Nonetheless, visual loss remains a major cause of impaired
quality of life in these patients.

REFERENCES
1. CDC: HIV/AIDS surveillance report. Atlanta,
Georgia: US Department of Health and
Human Services, Public Health Service:
CDC; 1997:(Vol 9, no. 1).
2. UNAIDS: 2004 Report on the Global AIDS
Epidemic: executive summary. Joint United
Nations Programme on HIV AIDS; 2004.
3. CDC: HIV/AIDS surveillance report 2004.
Vol. 16. Atlanta, Georgia: US Department of
Health and Human Services: CDC; 2005.
4. Sooqoor M, Daar ES: Primary human
immunodeficiency virus type 1. Curr
2104 HIV/AIDS Rep 2005; 2:55–60.
5. Pantaleo G, Graziosi C, Fauci AS: New
concepts in the immunopathogenesis of
human immunodeficiency virus infection.
N Engl J Med 1993; 328:327–335.
6. Vlahov D, Graham N, Hoover D, et al:
Prognostic indicators for AIDS and
infectious disease death in HIV-infected
injection drug users: plasma viral
load, CD4+ cell count. JAMA 1998;
279:35–40.
7. Jabs DA: Ocular manifestations of HIV
infection. Trans Am Ophthalmol Soc 1995;
93:623–683.
8. Freeman WR, Lerner CW, Mines JA, et al:
A prospective study of the ophthalmologic
findings in the acquired immune deficiency
syndrome. Am J Ophthalmol 1984;
97:133–142.
9. Rosenberg PR, Uliss AE, Firedland GH, et al:
Acquired immunodeficiency syndrome:
ophthalmic manifestations in ambulatory
patients. Ophthalmology 1983; 90:874–878.
10. Engstrom RE, Holland GN, Hardy WD,
et al: Hemorheologic abnormalities in
patients with human immunodeficiency
virus infection and ophthalmic
 Retinal Manifestations of the Acquired Immunodeficiency Syndrome: Diagnosis and Treatment
microvasculopathy. Am J Ophthalmol 1990;
109:153–161.
11. Mansour AM, Li H, Segal E: Picture
resembling hemicentral retinal vein
occlusion in the acquired immunodeficiency
syndrome: is it related to cytomegalovirus?
Ophthalmologica 1996; 210:108–111.
12. Quiceno JI, Capparelli E, Sadun AA, et al:
Visual dysfunction without retinitis in
patients with acquired immunodeficiency
syndrome. Am J Ophthalmol 1992;
113:8–13.
13. Sadun AA, Pepose JS, Madigan MC,
et al: AIDS-related optic neuropathy :
a histological, virological and ultrastructural
study. Graefes Arch Clin Exp Ophthalmol
1995; 233:387–398.
14. Yassur Y, Biedner B, Fabrikant M: Branch
retinal-artery occlusion in acquired
immunodeficiency syndrome prodrome.
Ann Ophthalmol 1988; 20:191–195.
15. Friedman SM, Mrgo CE: Bilateral central
retinal vein occlusions in a patient with
acquired immunodeficiency syndrome.
Clinicopathologic correlation. Arch
Ophthalmol 1995; 113:1184–1188.
16. Mansour AM, Rodenko G, Dutt R: Half-life
of cotton wool spots in the acquired
immunodeficiency syndrome. Int J STD
AIDS 1990; 1:132–33.
17. Park KL, Marx JL, Rao NA: Noninfectious
branch retinal vein occlusion in human
immunodeficiency virus-positive patients.
Retina 1997; 17:162–165.
18. Dunn JP, Yamashita A, Kempen JH, Jabs
DA: Retinal vascular occlusion in patients
infected with human immunodeficiency
virus. Retina 2005; 25:759–766.
19. Yung CW, Harris A, Massicotte S, et al:
Retinal blood flow indices in patients
infected with human immunodeficiency
virus. Br J Ophthalmol 1996; 80:723–727.
20. Dejaco-Ruhswurm I, Kiss B, Rainer G, et al:
Ocular blood flow in patients infected with
human immunodeficiency virus. Am J
Ophthalmol 2001; 132:719–725.
21. Horwitz CA, Henle W, Henle G, et al:
Heterophil-negative infectious
mononucleosis and mononucleosis-like
illnesses. Laboratory confirmation of 43
cases. Am J Med 1977; 63:947–957.
22. Hoover DR, Peng Y, Saah A, et al:
Occurrence of cytomegalovirus retinitis
after human immunodeficiency virus
immunosuppression. Arch Ophthalmol
1996; 114:821–827.
23. Gallant JE, Moore RD, Richman DD, et al:
Incidence and natural history of
Cytomegalovirus disease in patients with
advanced human immunodeficiency virus
disease treated with zidovudine. The
Zidovudine Epidemiology Study Group.
J Infect Dis 1992; 166:1223–1227.
24. Baldassano V, Dunn JP, Feinberg J,
Jabs DA: Cytomegalovirus retinitis and low
CD4 T-lymphocyte counts. New England J
Med 1995; 333:670.
25. Egbert PR, Pollard RB, Gallagher JG,
et al: Cytomegalovirus retinitis in
immunosupressed hosts. II. Ocular
manifestations. Ann Intern Med 1980;
93:664–670.
26. Jacobson MA, Stanley H, Holtzer C,
et al: Natural history and outcome of new
AIDS-related cytomegalovirus retinitis
diagnosed in the era of highly active
antiretroviral therapy. Clin Infect Dis 2000;
30:231–233.
27. Studies of Ocular Complications of AIDS
Research Group in collaboration with the
AIDS Clinical Trials Group:
Foscarnet–ganciclovir cytomegalovirus
Retinitis Trial 5. Clinical features of
cytomegalovirus retinitis at diagnosis. Am J
Ophthalmol 1997; 124:141–157.
28. Wei LL, Park SS, Skiest DJ: Prevalence of
visual symptoms among patients with
newly diagnosed cytomegalovirus retinitis.
Retina 2002; 22:278–282.
29. Holland GN, Pepose JS, Pettit TH, et al:
Acquired immune deficiency syndrome.
Ocular manifestations. Ophthalmology
1983; 90:859–873.
30. McCann JD, Margolis TP, Wong MG, et al:
A sensitive and specific polymerase chain
reaction-based assay for the diagnosis of
cytomegalovirus retinitis. Am J Ophthalmol
1995; 120:219–226.
31. Davis JL, Serfass MS, Lai MY, et al:
Silicone oil in repair of retinal detachments
caused by necrotizing retinitis in HIV
infection. Arch Ophthalmol 1995;
113:1401–1409.
32. Azen SP, Scott IU, Flynn HW Jr, et al:
Silicone oil in the repair of complex retinal
detachments. A prospective observational
multicenter study. Ophthalmology 1998;
105:1587–1597.
33. Gangan PA, Besen G, Munguia D et al:
Macular serous exudation in patients with
acquired immunodeficiency syndrome and
cytomegalovirus retinitis. Am J Ophthalmol
1994; 118:212–219.
34. Karavellas MP, Plummer DJ, MacDonald JC,
et al: Incidence of immune recovery vitritis
in cytomegalovirus retinitis patients
following institution of successful highly
active antiretroviral therapy. J Infect Dis
1999; 179:697–700.
35. Kempen JH, Min YI, Freeman WR, et al:
Risk of immune recovery uveitis in patients
with AIDS and cytomegalovirus retinitis.
Ophthalmology 2006; 113:684–694.
36. Karavellas MP, Lowder CY, MacDonald JC,
et al: Immune recovery vitritis associated
with inactive cytomegalovirus retinitis.
A new syndrome. Arch Ophthalmol 1998;
116:169–75.
37. Zegans ME, Walton RC, Holland GN, et al:
Transient vitreous inflammatory reactions
associated with combination antiretroviral
therapy in patients with AIDS and
cytomegalovirus retinitis. Am J Ophthalmol
1998; 125:292–300.
38. Karavellas MP, Song M, MacDonald JC,
et al: Long-term posterior and anterior
segment complications of immune recovery
uveitis associated with cytomegalovirus
retinitis. Am J Ophthalmol 2000; 130:57–64.
39. Nguyen QD, Kempen JH, Bolton SG, et al:
Immune recovery uveitis in patients with
AIDS and cytomegalovirus retinitis after
highly active anti-retroviral therapy. Am J
Ophthalmol 2000; 129:634–639.
40. Nussenblatt RB, Lane HC: Human
immunodeficiency virus disease: changing
patterns of intraocular inflammation. Am J
Ophthalmol 1998; 125:374–382.
41. Karavellas MP, Azen SP, MacDonald JP, et
al: Immune recovery vitritis and uveitis in
AIDS: clinical predictors, sequelae , and
treatment outcomes. Retina 2001; 21:1–9.
42. Llatjos M, Romeu J, Clotet B, et al: A
distinctive cytologic pattern for diagnosing
tuberculous lymphadenitis in AIDS. J AIDS
1993; 6:1335–1338.
43. Holland GN: Immune recovery uveitis. Ocul
Immunol Inflamm 1999; 7:215–221.
44. Henderson HWA, Mitchell SM: Treatment of
immune recovery vitritis with local steroids.
Br J Ophthalmol 1999; 83:540–545.
45. Spector SA, Hsia K, Crager M, et al:
Cytomegalovirus (CMV) DNA load is an
independent predictor of CMV disease and
survival in advanced AIDS. J Virol 1999;
73:7027–7030.
46. Jabs DA, Gilpin AMK, Min Y-I, et al: For
studies of ocular complications of aids
research group. HIV and CMV viral lad and
clinical outcomes in patients with AIDS and
CMV retinitis: the Monoclonal Antibody
Cytomegalovirus Retinitis Trial. AIDS 2002;
16:877–887.
47. Griffiths PD: CMV as a cofactor enhancing
progression of AIDS. J Clin Virol (2006)
35: 489–92.
CHAPTER 163
48. Kempen JH, Jabs DA, Wilson LA, et al:
Mortality risk for patients with
cytomegalovirus retinitis and acquired
immune deficiency syndrome. Clin Infect
Dis 2003; 37:1365–1373.
49. Thorne JE, Jabs DA, Kempen JH, et al:
Incidence of and risk factors for visual
acuity loss among patients with AIDS and
cytomegalovirus retinitis in the era of highly
active antiretroviral therapy. Ophthalmology
2006; 113:1432–1440.
50. Kempen JH, Jabs DA, Dunn JP, et al:
Retinal detachment risk in cytomegalovirus
retinitis related to the acquired immune
deficiency syndrome. Arch Ophthalmol
2001; 119:33–40.
51. Jabs DA, Van Natta ML, Thorne JE, et al:
Course of cytomegalovirus retinitis in the
era of highly active antiretroviral therapy. 1.
Retinitis progression. Ophthalmology 2004;
111:2224–2231.
52. Jabs DA, Van Natta ML, Thorne JE, et al:
Course of cytomegalovirus retinitis in the
era of highly active antiretroviral therapy. II.
Second eye involvement and retinal
detachment. Ophthalmology 2004;
111:2232–2239.
53. Kempen JH, Jabs DA, Wilson LA, et al:
Incidence of cytomegalovirus (CMV)
retinitis in second eyes of patients with the
acquired immune deficiency syndrome and
unilateral CMV retinitis. Am J Ophthalmol
2005; 139:1028–1034.
54. Jabs DA, Holbrook JT, Van Natta ML, et al:
Risk factors for mortality in patients with
AIDS in the era of highly active antiretroviral
therapy. Ophthalmology 2005;
112:771–779.
55. Whitcup SM, Fortin E, Lindblad AS, et al:
Discontinuation of anticytomegalovirus
therapy in patients with HIV infection and
cytomegalovirus retinitis. JAMA 1999;
282:1633–1637.
56. Wohl DA, Kendall MA, Owens S, et al: The
safety of discontinuation of maintenance
therapy for cytomegalovirus (CMV) retinitis
and incidence of immune recovery uveitis
following potent antiretroviral therapy. HIV
Clin Trials 2005; 6(3):136–146.
57. Lin DY, Warren JF, Lazzeroni LC, et al:
Cytomegalovirus retinitis after initiation of
highly active antiretroviral therapy in HIV
infected patients: natural history and clinical
predictors. Retina 2002; 22:268–277.
58. Drew WL, Ives D, Lalezari JP, et al: Oral
ganciclovir as maintenance treatment for
cytomegalovirus retinitis in patients with
AIDS. New Engl J Med 1995; 333:615–620. 2105
 RETINA AND VITREOUS
59. Martin DF, Sierra-Madero J, Walmsley S,
et al: A controlled trial of valganciclovir as
induction therapy for cytomegalovirus
retinitis. N Engl J Med 2002;
346:1119–1126.
60. Lalezari J, Lindley J, Walmsely S, et al:
A safety study of oral valganciclovir
maintenance treatment of cytomegalovirus
retinitis. J Acquir Immune Defic Syndr
2002; 30:392–400.
61. Sandorn GE, Anand R, Torti RE, et al:
Sustained-release ganciclovir therapy for
treatment of cytomegalovirus retinitis:
use of an intravitreal device. Arch
Ophthalmol ;992) 110:188–195.
62. Musch DC, Martin DF, Gordon JF, et al:
Treatment of cytomegalovirus retinitis with
a sustained release ganciclovir implant.
N Engl J Med 1997; 337:83–90.
63. Martidis A, Danis RP, Ciulla TA: Treating
cytomegalovirus retinitis-related retinal
SECTION 10
detachment by combining silicone oil
tamponade and ganciclovir implant.
Ophthalmic Surg Lasers 2002; 33:135–139.
64. Charles NC, Freisberg L: Endophthalmitis
associated with extrusion of a ganciclovir
implant. Am J Ophthalmol 2002;
133:273–275.
65. Ambati J, Wynne KB, Angerame MC,
Robinson MR: Anterior uveitis associated
with intravenous cidofovir use in patients
with cytomegalovirus retinitis. Br J
Ophthalmol 1999; 83:1153–1158.
66. Akler ME, Johnson DW, Burman WJ, et al:
Anterior uveitis and hypopyon after
intravenous cidofovir for the treatment of
cytomegalovirus retinitis. Ophthalmology
1998; 105:651–657.
67. Davis JL, Taskintua I, Freeman WR, et al:
Iritis and hypotony after treatment with
intravenous cidofovir for cytomegalovirus
retinitis. Arch Ophthalmol 1997;
115:733–737.
68. Smith IL, Taskintuna I, Rahhal FM, et al:
Clinical failure of CMV retinitis with
intravitreal cidofovir is associated with
antiviral resistance. Arch Ophthalmol 1998;
116:178–185.
69. Jabs DA, Martin BK, Formann MS, et al:
Cytomegalovirus resistance to ganciclovir
and clinical outcomes of patients with
cytomegalovirus retinitis. Am J Ophthalmol
2003; 135:26–34.
70. Jabs DA, Martin BK, Forman MS, Ricks
MO: Cytomegalovirus (CMV) blood DNA
load, CMV retinitis progression, and
occurrence of resistant CMV in patients
with CMV retinitis. JID 2005; 192:640–649.
71. Torriani FJ, Freeman WR, MacDonald JC,
et al: CMV retinitis recurs after stopping
treatment in virological and immunological
2106
failures of potent antiretroviral therapy.
AIDS 2000; 14:173–180.
72. Combination foscarnet and ganciclovir
therapy vs monotherapy for the treatment
of relapsed cytomegalovirus retinitis in
patients with AIDS: The Cytomegalovirus
retreatment trial. The studies of ocular
complications of AIDS research group in
collaboration with the AIDS clinical trials
group. Arch Ophthalmol 1996; 114:23–33.
73. Emery VC, Hassan–Walker AF: Focus on
new drugs in development against human
cytomegalovirus. Drugs 2002;
62:1853–1858.
74. Engstrom RJ, Holland GN, Margolis TP,
et al: The progressive outer retinal necrosis
syndrome. A variant of necrotizing herpetic
retinopathy in patients with AIDS.
Ophthalmology 1994; 101:1488–1502.
75. Ciulla TA, Rutledge BK, Morley MG, et al:
The progressive outer retinal necrosis
syndrome: successful treatment with
combination antiviral therapy. Ophthalmic
Surg Lasers 1998; 29:198–206.
76. Scott IU, Luu KM, Davis JL: Intraviteal
antivirals in the management of patients
with acquired immunodeficiency syndrome
with progressive outer retinal necrosis.
Arch Ophthalmol 2002; 120:1219–1222.
77. Holland GN: Standard diagnostic criteria
for the acute retinal necrosis syndrome.
Executive Committee of the American
Uveitis Society. Am J Ophthalmol 1994;
117:663–667.
78. Shami MJ, Freeman WR, Friedberg D, et al:
A multicenter study of pneumocystis
choroidopathy. Am J Ophthalmol 1991;
112:15–22.
79. Rao NA, Zimmerman PL, Boyer D, et al:
A clinical, histopathologic, and electron
microscopic study of Pneumocystis carinii
choroiditis. Am J Ophthalmol 1989;
107:218–228.
80. Fardeau C, Romand S, Rao NA, et al:
Diagnosis of toxoplasmic retinochoroiditis
with atypical clinical features. Am J
Ophthalmol 2002; 134:196–203.
81. Bosch–Driessen LH, Verbraak FD,
Suttorp–Schulten MSA, et al: A prospective,
randomized trial of pyrimethamine and
azithromycin vs pyrimethamine and
sulfadiazine for the treatment of ocular
toxoplasmosis. Am J Ophthalmol 2002;
134:34–40.
82. Kovacs JA: Efficacy of atovaquone in
treatment of toxoplasmosis in patients
with AIDS. The NIAID-Clinical Center
Intramural AIDS Program. Lancet 1992;
340:637–638.
83. Crump JRC, Elner SG, Elner VM, et al:
Cryptococcal endophthalmitis : case report
and review. Clin Infect Dis 1992;
14:1069–1073.
84. Denning DW, Follansbee SE, Scolaro M,
et al: Pulmonary aspergillosis in the
acquired immunodeficiency syndrome.
N Engl J Med 1991; 324:654–662.
85. Fish DG, Ampel NM, Galgiani JN, et al:
Coccidioidomycosis during human
immunodeficiency virus infection: a review
of 77 patients. Medicine 1990; 69:384–391.
86. Macher A, Rodrigues MM, Kaplan W, et al:
Disseminated bilateral chorioretinitis due to
histoplasma capsulatum in a patient with
the acquired immunodeficiency syndrome.
Ophthalmology 1985; 92:1159–1164.
87. Finamore LP, Muccioli C, Martins MC, et al:
Ocular and central nervous system
paracoccidioidomycosis in a pregnant
woman with acquired immunodeficiency
syndrome. AJO 2002; 134:456–459.
88. McLeish WM, Pulido JS, Holland S, et al:
The ocular manifestations of syphilis in
the human immunodeficiency virus type
1-infected host. Ophthalmology 1990;
97:196–203.
89. Recillas-Gispert C, Ortega-Larrocea G,
Arrelanes-Garicia L, et al: Chorioretinitis
secondary to Mycobacterium tuberculosis
in acquired immune deficiency syndrome.
Retina 1997;: 17:437–439.
90. Matzkin DC, Samovits TL, Rosenbaum PS:
Simultaneous intraocular and orbital non-
Hodgkin lymphoma in the acquired immune
deficiency syndrome. Ophthalmology 1994;
101:850–855.
91. Rathbun RC, Lockhart SM, Stephens JR:
Current HIV treatment guidelines-An
overview. Current Pharmaceutical Design
2006; 12:1045–1063.
92. Lafeuillade A, Aubert L, Chaffanjon P, et al:
Optic neuritis associated with
dideoxinosine. Lancet 1991; 337:615.
93. Whitcup SM, Butler KM, Caruso R, et al:
Retinal toxicity in human immunodeficiency
virus-infected children treated with
2,3-dideoxinosine. Am J Ophthalmol 1992;
113:1–7.
94. Palella FJ, Delaney KM, Moorman AC, et al:
Declining morbidity and mortality among
patients with advanced human
immunodeficiency virus infection. HIV
Outpatient Study Investigators. N Engl J
Med 1998; 338:853–860.
95. Arevalo JF, Russack V, Freeman WR: New
ophthalmic manifestations of presumed
rifabtin-related uveitis. Opthalmic Surg
Lasers 1997; 28:321–324.
96. Egan R, Pomeranz H: Sildenafil (Viagra)
associated anterior ischemic optic
neuropathy. Arch Ophthalmol 2000;
118:291–292.
 CHAPTER
164 Acute Retinal Necrosis
Janet L. Davis, Gregory M. Fox, and Mark S. Blumenkranz
Initially described in Japan in 1971 by Urayama and colleagues
and termed Kirisawa’s uveitis, acute retinal necrosis (ARN) is a
dramatic uveitic syndrome that presents with vitreous inflam-
mation, retinal periarteritis, optic neuropathy, and confluent
peripheral necrotizing retinal infiltrates.1–7 This important
clinical syndrome has since been documented to represent the
consequences of acute infection of the retina and associated
ocular tissues by certain types of Herpesvirus hominis.8,9 In
order to promote clarity of definition, the American Uveitis
Society has suggested that the term acute retinal necrosis be
used to designate only those cases that conform to a well-
described clinical syndrome, characterized by peripheral retinal
necrosis with discrete borders, rapid progression with circum-
ferential spread in untreated eyes, occlusive vasculopathy with
arteriolar involvement, and prominent inflammation in the
vitreous and anterior chamber. Optic neuropathy or atrophy,
scleritis, and pain are well-described features in some patients
but are not necessary to make the diagnosis.2,10
The demonstration of a viral cause for this syndrome has
led to the important development of specific pharmacologic
therapies; however, late retinal detachment continues to be a
serious complication.11,12 Fortunately, modern vitreoretinal
surgical techniques continue to improve the prognosis for
retinal reattachment and for recovery of visual acuity.14 Prompt
treatment with antiviral agents and prophylactic retinal photo-
coagulation may also lessen the risk of disease in the fellow eye
and the incidence of late retinal detachment in the initially
involved eye.15,16 Experimental animal studies have shed further
light on the mode of viral transmission between the eye and the
central nervous system and on the contribution of immuno-
regulatory events to the pathophysiology of this disease.17,18
In selected cases in which optic neuropathy seems to be
responsible for the large proportion of visual-field and visual-
acuity loss, optic nerve sheath decompression has been reported
to be worth considering.19
Since the original descriptions of ARN, atypical cases of
herpetic retinitis have also been described that do not fit the
classic syndrome, including more indolent forms of necrotizing
retinitis in some patients with varicella.20–22 The American
Uveitis Society suggests that any cases of herpetic retinitis that
do not fit the clinical syndrome of ARN be designated as
necrotizing herpetic retinopathy. If the specific viral cause is
known, the causative viral name can be added as a modifier.10
Although typical features of ARN have been reported in patients
with human immunodeficiency virus (HIV) infection, herpetic
retinitis in patients with the acquired immunodeficiency syn-
drome (AIDS) frequently present with atypical features. An
important devastating syndrome of necrotizing retinitis in
patients with AIDS has been described by the term progressive
outer retinal necrosis (PORN). Believed to be largely caused by
retinal infection with varicella-zoster virus, PORN is charac-
terized by the initial appearance of multifocal areas of outer
retinal opacification (with little other intraocular inflam-
mation), rapid progression of the lesions to confluence with
full-thickness retinal necrosis, and poor response to antiviral
therapy.23,24
Terminology
• ARN syndrome
• Peripheral retinal necrosis
• Rapid, circumferential spread
• Occlusive vasculopathy
• Optional: optic neuropathy, vitreitis or iritis, episcleritis, or
pain
• Necrotizing herpetic retinopathy
• Retinal necrosis due to herpes simplex or varicella-zoster
virus
• Not necessary to meet criteria for ARN syndrome
• Specify virus if known
• Progressive outer retinal necrosis
• Colloquial term for necrotizing herpetic retinopathy with a
paucity of inflammatory signs
• Usually in immunocompromised patients
• ARN-like retinitis
• Features of ARN syndrome
• Causative agent is cytomegalovirus, toxoplasmosis,
Epstein–Barr virus, or syphilis
• Other infectious and noninfectious causes of confluent
retinal inflammation
EPIDEMIOLOGY
Initially described in Asia,2 ARN has also been documented
in both Europe3,20–22 and North America.4–9 Limited prevalence
data are available for this disease, but the incidence does appear
to be rising. There were no reported cases before 1971, although
it now seems likely that previously cases either were not
recognized or were misclassified as other forms of posterior
uveitis. By 1982, there were 41 cases reported in the world
literature,6 and by 1996, more than 150 articles had been
devoted to the syndrome. An epidemiologic study of uveitis in
Switzerland found that cases of ARN represented 2.5% of cases
of uveitis seen at the uveitis clinic of the Hospital Jules Gonin
between January 1990 and March 1993. The incidence of ARN
for the referral area studied was calculated to be 4.25 per
1 000 000 inhabitants per year.25
Men contract ARN more often than women, and more adults
are affected than children. In one report, 63% of patients were 2107
 RETINA AND VITREOUS
male and 37% were female; none was younger than 13 years of
age.6 Since that report, an 11-year-old girl with HIV infection,
acquired at birth from her infected mother developed an
atypical case of necrotizing retinitis after contracting chicken-
pox.26 The disease may affect one or both eyes, with the initial
presentation being unilateral in approximately two-thirds of
cases.6,27 When the involvement is bilateral, there is generally
a delay between involvement of the first and the second eyes,
ranging from 1–6 weeks.2,28 The timing of involvement of the
second eye is consistent with the theories on the propagation
and transfer of virus from one eye to another via the optic nerve
and central nervous system. Delays as long as 3028 and 3429
years between involvement of the first and the second eye have
been reported in patients not treated with acyclovir during
involvement of the first eye. The risk of development of disease
in the fellow eye in patients not treated with intravenous
acyclovir has been estimated to be as high as 65% 2 years after
the onset of the disease.15
SECTION 10
The disease was initially described in otherwise healthy
patients,1–7 and immunocompetence has been judged to be one
criterion for establishing the diagnosis.13 This characteristic has
distinguished ARN from other forms of opportunistic retinitis
in patients with incompetent immune systems or in those with
concurrent herpetic disease of the central nervous system.30,31
Subsequent reports have documented that immunosuppressed
patients may experience a clinical syndrome of ARN that is
identical to that seen in immunocompetent patients and is
readily distinguished from other types of opportunistic retinitis,
including cytomegalovirus (CMV) retinitis.32–34
HOST FACTORS
Most cases of ARN probably represent primary infection of the
retina with virus reactivated from dormant sites, including gan-
glionic tissue. Serum neutralizing antibodies to the herpes zoster
varicella virus group are present in up to 95% of adults,1,35 and
it is likely that host factors predispose certain individuals to the
development of the syndrome of ARN. For example, although in
excess of 3 million persons each year experience chickenpox, to
date there have been 10 patients reported with ARN as a
short–term complication of varicella.20,21,26,36 Similarly, although
ARN has been reported to occur as an early complication of
herpes zoster in a small number of patients, this is also believed
to be an extremely infrequent problem in immunocompetent
patients with cutaneous herpes zoster.37,38 In one prospective
randomized series of patients with herpes zoster ophthalmicus
(HZO), none of the 71 patients treated with either acyclovir or
placebo experienced ARN, although in another large series,
10–33% of patients with HZO demonstrated other forms of
viral dissemination.39 In contrast, the risk of a patient with HIV
infection and HZO developing ARN is likely substantial. Sellitti
and associates40 cited an incidence of ARN in 17% of patients
with HIV infection and HZO. The majority of these patients
developed bilateral retinal necrosis, and all patients presented
with retinal necrosis within 9 months of the onset of HZO.
It is likely that patients who experience ARN may have an
underlying immunogenetic predisposition to the disease. Holland
and colleagues41 demonstrated a statistically significant increase
in the frequency of human leukocyte antigen (HLA) -DQw7 in
patients with ARN (55%) versus control patients (19%) (P
< 0.0004; relative risk 5.2). In this study, the HLA phenotype
Bw62,DR4 was also more frequent than in the controls (16% vs
2.6%; relative risk 7.49). Moreover, the HLA phenotypes of
patients may have some effect on the severity of the clinical
disease. Matsuo and Matsuo42 measured an increased frequency
of HLA-DR9 in their patients with fulminant ARN (50%) as
2108 compared with their patients with mild ARN (0%) (P < 0.05).
However, the difference does not retain statistical significance
after analysis in a chi-squared test with Yates correction for the
number of HLA antigens that were tested.42 Klok and asso-
ciates43 identified the presence of anticardiolipin antibodies
in the sera of seven out of 24 patients with ARN versus 10%
of healthy control patients. The importance of anticardiolipin
antibodies in the pathogenesis of ARN in these patients is
uncertain.
In addition to differences in underlying genetic predisposition, it
is likely that other host factors and viral factors may play a role in
the development of ARN and may influence the incidence of
unfavorable clinical outcomes. Recent periocular trauma has been
reported to precede the onset of ARN in a few patients.44,45 Clinical
signs such as diffuse arteritis, at the optic disc or beyond the area
of retinitis, reduced electroretinographic a- and b-waves, elevated
levels of circulating immune complexes, and larger zones of
necrosis and exudation are associated with an especially poor
prognosis, suggesting that the immunologic response to the
virus or intrinsic factors may strongly affect the outcome.46
CLINICAL FEATURES
Although the most dramatic and visually devastating aspect of
this disease is the confluent necrotizing retinitis from which the
syndrome draws its name, most ocular tissues are concurrently
affected. The disease can be divided into two different phases:
(1) the acute herpetic phase, which lasts ~4–8 weeks; and (2)
the late cicatricial phase, occurring after the onset of the disease
and characterized by the organization of the vitreous and devel-
opment of large retinal tears, retinal detachment, and pro-
liferative vitreoretinopathy (PVR).
DISEASE TYPES
Increased awareness and recognition of ARN have enabled
clinicians to make increasingly subtle distinctions between
ARN, as defined by the American Uveitis Society,10 and other
variants of necrotizing retinitis. These variants include a ‘mild
form which is more indolent in character and not associated
with retinal detachment’,46 and a severe, rapidly progressive
syndrome of outer retinal necrosis associated with little vitritis,
seen in patients with HIV infection, that is distinct from CMV
retinitis.23,24,34,47 Moreover, there is some evidence to suggest
that the disease course and clinical profile of patients with ARN
may differ, depending on whether the causative agent is herpes
simplex virus (HSV) or the herpes varicella virus group.22
ACUTE HERPETIC PHASE
Presenting Symptoms
The onset of ARN is frequently heralded by the development
of ocular pain, diminished vision, floaters, and external ocular
injection. The patient may give a history of recent or remote
herpes zoster or varicella infection in the majority of cases or
may occasionally volunteer no history of prior herpetic infection.
Anterior Segment Examination
The conjunctiva is invariably injected with limbal flush, epis-
cleritis, or scleritis. Anterior chamber cell and flare are frequent
in conjunction with granulomatous keratinous precipitates (Fig.
164.1). Although a plasmoid aqueous or mild fibrin strands
may be seen, iris nodules or hypopyon rare. One clinical feature
that may assist in the differentiation of the early phase of ARN
from other causes of acute granulomatous anterior uveitis is the
frequent occurrence of ocular hypertension, which is also seen
in herpes zoster keratouveitis. Herpetic corneal epithelial
dendrites or disciform corneal lesions are not encountered,

FIGURE 164.1. Granulomatous keratic pzrecipitates are seen in a slit-
lamp photomicrograph of a middle-aged man with the early phases of
acute retinal necrosis (ARN).
although some patients with concurrent HZO may
demonstrate typical vesicular lesions in the distribution of the
affected fifth dermatome. The lens is typically unaffected aside
from the presence of inflammatory precipitates on its surfaces,
which are responsive to steroid therapy. If untreated, posterior
synechiae and pupillary seclusion may occur in addition to
complicated cataract formation.
Vitreous Examination
Vitreous cellular infiltration and protein exudation are charac-
teristic features of the acute phases of the syndrome. In the
earliest stages, the inflammatory infiltrate in the vitreous may
be relatively mild, increasing as cellular immunity to the virus
develops. The vitreous cellular infiltrate is composed predomi-
nantly of mononuclear cells including lymphocytes and plasma
cells, paralleling the infiltrates seen in other ocular tissues.1 A
viral cytopathic effect has been demonstrated from culture of
vitreous specimens obtained at the time of enucleation during
the acute phase of the disease.8,74 Polyclonal anti-HSV
antibodies have been identified from vitrectomy specimens in
patients with the active phase of the disease.13 Aqueous
specimens from patients with the disease similarly demonstrate
antibodies to either HSV-1 and the herpes zoster varicella virus
group in ratios suggesting local intraocular antibody
production.8,13,14,70,72,90 High levels of cytokines such as
interleukin (IL)-6 have also been found in the vitreous in
patients with ARN.48
Retina Examination
Retina examination may reveal two characteristic features:
confluent zones of opaque necrotizing retinitis predominantly
involving the periphery and generalized retinal arteritis asso-
ciated with capillary vasoocclusion.
Necrotizing retinitis
The earliest retinal lesions are subtle, isolated retinal opacities
that may assume a patchy, granular or nummular configura-
Acute Retinal Necrosis
CHAPTER 164
FIGURE 164.2. Nummular lesion of ARN superonasal and inferonasal
to the optic nerve in a middle-aged man with associated herpes
zoster involving the upper extremity.
tion, depending on their stage of evolution. Although usually
seen in the mid-periphery and preequatorial regions, small
nummular lesions may also be seen in the posterior retina,
generally sparing the macula (Fig. 164.2). In distinction to the
granular white dots frequently associated with CMV inclusion
disease of the retina, the earliest lesions of ARN are not
prominently associated with venules or perivenous hemorrhage.
With progression of the syndrome, the granular and nummular
lesions increase in size and coalesce to form confluent zones of
full-thickness retinal necrosis. These lesions, which are
typically situated in the retinal periphery, may occupy as little
as 1–2 clock hours or may extend to completely encircle the
retina over 360° (Fig. 164.3). The mature lesions have a yellow
to white homogeneous color with a somewhat jagged or dentate
posterior border in portions extending more posteriorly (Fig.
164.4). They obstruct visualization of the underlying retinal
pigment epithelium and choroid. The lesions end abruptly at
the ora serrata anteriorly and do not appear to parallel or
otherwise respect the retinal vasculature, as is frequently seen
in CMV inclusion disease. The retinal lesions that are seen
early in the disease arise abruptly and may progress in size and
number over approximately a 2-week period in untreated patients.
The lesions then begin a period of regression characterized by
loss of retinal opacification, thinning, and pigmentary scarring
(Fig. 164.5). The loss of opacification, which correlates with the
resolution of the inflammatory and viral infiltration of the
retina, may initially be seen as perivascular curvilinear lucencies
within zones of confluent necrosis. This has been termed a
Swiss-cheese appearance (Fig. 164.6). Over the course of several
ensuing weeks, these zones of retinal lucency enlarge in
conjunction with the development of pigmentary changes in the
retinal pigment epithelium and neural retina.
The pigmentary changes that characterize the convalescent
phase of ARN are most prominent initially at the posterior
margins of the lesions and progress outward in a centrifugal
fashion coincident with the development of lucencies. The
character of the pigmentary response associated with the 2109
 SECTION 10 RETINA AND VITREOUS
FIGURE 164.3. Typical lesions of ARN involving the periphery. Note
the confluent white–yellow appearance with an irregular scalloped
posterior margin and a sharp transition between involved and
uninvolved portions.
FIGURE 164.4. Area of confluent necrotizing retinitis with early
depigmentation at the posterior margin signifies the beginning of the
resolution phase.
resolution of ARN is similar to that associated with other forms
of viral retinitis, including rubella and CMV, and is distinct
from either the heavily pigmented hyperplastic response typical
of toxoplasmosis or the atrophic scalloped appearance asso-
ciated with ocular histoplasmosis. In zones in which there has
been particularly severe retinal inflammation and underlying
choroidal inflammation, the degree of postnecrotic thinning
and retinal pigment epithelial atrophy may be prominent. In
some patients in the convalescent phase, giant retinal pigment
epithelial tears can develop, leaving large areas devoid of retinal
pigment epithelium.49 In other zones in which the necrotizing
retinitis was more mild, it may be difficult to identify the
original margins of involvement in the later phases of the
disease. In some instances, the acute phase of the disease may
be accompanied by the development of a peripheral exudative
retinal detachment. This may be distinguished from a rheg-
2110 matogenous or complex detachment by the lack of retinal holes,
FIGURE 164.5. The same region as shown in Figure 164.4, ~4 months
later, demonstrates clearing of ocular media opacity and better
visualization of retinal vascular detail. Note the atrophic pigmented
zone corresponding to the area of prior necrosis with some fibroglial
proliferative change overlying the center of scar.
FIGURE 164.6. Midresolution phase of ARN with the development of
curvilinear perivascular lucencies within zones of necrosis before the
development of late pigmentary changes (Swiss-cheese appearance).
its presence beneath areas of opaque retina, and the presence
of shifting subretinal fluid or xanthochromia.
Retinal vasculitis
The second major feature of retinal involvement in this disorder
is the development of severe vasoocclusive changes predomi-
nantly involving the arterial system. The presence of arteritis,
rather than phlebitis, and the associated peripheral vaso-
occlusion seen in this disease help to distinguish it from CMV
infection of the retina on ophthalmoscopic grounds. Although
occasionally seen in ocular toxoplasmosis and syphilis, retinal
arteritis is particularly striking and severe in ARN and was
recognized to be a characteristic feature of herpes zoster infec-
tion of the retina even before the widespread recognition of the
syndrome ARN in the English-language literature (Fig. 164.7).50
 Acute Retinal Necrosis

CHAPTER 164
FIGURE 164.8. Patient with confirmed herpes zoster infection of the
retina producing ARN. Note the prominent hemorrhagic component
FIGURE 164.7. Artist’s representation of a patient with the classic suggestive of concomitant retinal venous obstruction.
features of ARN, including confluent necrotizing retinitis, posterior
nummular infiltrates, and retinal arteritis (with involved vessels seen in
yellow).

Fluorescein angiographic and histopathologic studies on eyes

with ARN confirm that the arteritis is not confined to the
retinal vessels and may be seen in virtually all tissues studied,
including the iris, ciliary body, choroid, and optic nerve. The
ophthalmoscopic features of retinal periarteritis include
opacification and refractile changes in the walls of the larger
retinal arterioles; ophthalmoscopically visible nonperfusion and
obliteration of the smaller, more distal ramifications; and retinal
capillary nonperfusion best demonstrated by fluorescein
angiography.
The retinal opacification seen in this syndrome is distinct
from the cloudy swelling commonly associated with retinal
arteriolar obstruction, although the latter may contribute to this
phenomenon in addition to the cellular infiltration seen
histopathologically. Despite the presence of peripheral retinal
capillary nonperfusion, retinal, optic nerve, and iris neovascu-
larization are distinctly uncommon in this disease, as con-
trasted with other forms of vasoocclusive retinopathies.51,52 The
FIGURE 164.9. Fluorescein angiogram of a patient with ARN.
reasons for this observation are unknown but may reflect the
Courtesy of Jay Duker.
concurrent development of retinal and retinal pigment epithelial
necrosis in conjunction with nonperfusion, resulting in
decreased production of intraocular angiogenic factors. Although
large zones of intraretinal hemorrhage are not a characteristic (Fig. 164.10). To date, despite the early marked inflammatory
feature of ARN, they may occur in patients in association with changes seen in the choroid, herpesvirus particles have been
zones of phlebitis or frank venous occlusion. Rarely, the fundus identified only within the choriocapillaris and choroid by in situ
appearance may be that of a combined central retinal artery and DNA hybridization and immunohistochemical stains in a blind
vein occlusion when there has been severe involvement of the eye with burned-out disease.53 Thus, the majority of early
optic nerve and associated vasculature (Fig. 164.8). choroidal changes are likely immunocytopathologic rather than
the effect of direct viral infection.
Choroidal Involvement
The choroidal vasculature is actively involved in this syndrome. Optic Nerve Examination
Before the development of opaque confluent retinal lesions, it is Optic neuropathy is a frequent and serious complication of
possible to identify more subtle opacifications in the outer retina ARN. Some degree of optic disk swelling is seen in most cases
and underlying choroid and pigment epithelium. Early frame and may be associated with engorgement of the disk capillaries,
angiograms document the presence of focal areas of choroidal swelling of the neural tissue, and distention of the optic nerve
hypoperfusion with intense late staining suggestive of infil- sheath (Fig. 164.11).19,54 In some instances, this may result in
tration and ischemia (Fig. 164.9). These frequently presage profound vision loss. The mechanism of vision loss associated
overlying zones of necrotizing retinitis. In histopathologic with optic neuropathy in ARN remains somewhat uncertain. It
specimens, the choroidal thickness may be increased three- to may reflect one of multiple causes, including direct viral infec-
fourfold in conjunction with diffuse plasma cell, macrophagic, tion of the optic nerve,8,17,19 optic nerve ischemia secondary to
and lymphocytic stromal infiltrates and perivascular cuffing vasooclusion,8 or the result of compression by distention of the 2111
 RETINA AND VITREOUS
SECTION 10
FIGURE 164.10. Histopathologic specimen demonstrates marked
choroidal stromal thickening and lymphocytic infiltration including
larger choroidal vessels. H & E µ100.
FIGURE 164.11. Photographs of severe optic nerve involvement in a
patient with ARN. Visual acuity is reduced to light perception despite
the lack of obvious macular involvement. Media opacity secondary to
vitritis is not consistent with the level of vision dysfunction.
nerve sheath.19 Optic nerve sheath fenestration has been
proposed as a method of therapy for patients who demonstrate
optic nerve sheath distention by neuroradiologic imaging studies.
This has been associated with dramatic visual improvement in
some instances. In one clinical series, 47% of eyes in patients
with ARN demonstrated neuropathy severe enough to warrant
consideration of surgical intervention.54 Optic neuropathy in
ARN that is sufficiently severe to warrant consideration of
surgical optic sheath decompression has been defined as (1) the
presence of an afferent pupillary defect not consistent with
retinal findings, (2) poor correlation between retinal findings
and visual acuity and visual field, and (3) sudden deterioration
of visual acuity not corresponding to retinal changes.
CICATRICIAL PHASE
With or without therapy, ARN appears to be a self-limited disease,
2112 with resolution of the acute inflammatory changes occurring
Key Features: Signs and Symptoms of Acute Phase of
ARN
• Symptoms: Pain, blurred vision, floaters, constricted field
Signs:
• Anterior segment hyperemia and iritis
• Vitreous cells and flare
• Peripheral confluent retinal necrosis
• Satellite lesions
• Optic nerve edema or pallor
• Retinal vascular occlusions
• Associated findings
• RPE scarring anterior to the active border
• Serous retinal detachment
• Rhegmatogenous retinal detachment (uncommon)
• Recent or current meningitis or encephalitis
over the course of 1–3 months, depending on the severity of the
initial infection and other factors. After resolution of the active
phase of the disease, secondary cicatricial changes occur, which
frequently lead to the development of late retinal tears, retinal
detachment, and loss of useful visual function.
The phase of active viral replication is believed to be controlled
by normal host humoral and cellular immune mechanisms. In
patients not treated with oral acyclovir, corticosteroids, or other
pharmacologic agents, the time course for resolution of the
active phase may be 6–12 weeks. In patients treated with oral
acyclovir, this time phase may be shortened to 4–6 weeks,
although to date no prospective studies confirming this have
been performed. It is believed that the breakdown in the
blood–ocular barrier and secondary cellular and humoral infil-
tration of the vitreous contribute to the development of late
organizational changes in the vitreous body. Collagenous and
cellular membranes develop, composed of pigment epithelial
cells and fibroblastic elements develop (Fig. 164.12).28,55
Additionally, secondary growth of pigment epithelial, glial, and
fibroblastic membranes on the surface of the retina and con-
tinuous with the organized vitreal membranes occurs in the
periphery. The concurrence of peripheral retinal thinning,
membrane formation, and vitreous contraction contributes to
the development of severe PVR frequently seen in patients in
the cicatricial stages of ARN (Figs 164.13 and 164.14).
Irrespective of acyclovir therapy, late retinal detachment occurs
in 75–86% of eyes with ARN.7,11
Prophylactic photocoagulation during the acute phase of the
disease may reduce the risk of late retinal detachment in some
patients.13,14,17 Although retinal detachment in this condition
has been associated with a generally unfavorable prognosis,2,14
vitreoretinal surgical therapy has improved the outlook (see
section on Management of Retinal Detachment). Other late
cicatricial complications of the syndrome include iris atrophy,
cataract, ciliary body fibrosis and hyposecretion, visually signi-
ficant vitreous opacities, macular pucker, and giant tears of the
retinal pigment epithelium.49
OTHER TYPES OF NECROTIZING RETINITIS
Necrotizing Herpetic Retinopathy, Varicella
Associated
In addition to the classic form of ARN, patients may exhibit
both more benign and more fulminant degrees of ocular invol-
vement in retinal infections caused by the varicella-zoster
group. Matsuo and co-workers46 described six patients with
isolated mid-peripheral nonconfluent retinal infiltrates and
serologic evidence of herpes zoster varicella infection in whom

FIGURE 164.12. Zone of retinal pigment epithelial proliferation and
migration underlying thinned necrotic peripheral retina. Note the
presence of the nonpigmented epiretinal membrane on the surface of
the necrotic retina. H & E µ250.
FIGURE 164.13. Large tear in the inferior posterior retina of a patient
with ARN.
the ocular involvement did not progress to retinal detachment.
In these patients, the role of early acyclovir treatment in the
prevention of more severe phases of the disease is unclear. More
indolent manifestations of retinal involvement have also been
reported in other patients with varicella.20,21,56–58 Necrotizing
herpetic retinopathy associated with varicella appears to be
limited predominantly to adults rather than children who
contract the disease despite more than 90% of all cases of
varicella occuring between the ages of 1 and 14 years.58
Necrotizing herpetic retinopathy associated with varicella
occurs within 3 months of the onset of primary infection
(ranging from 5 to 40 days) and is believed to be limited
primarily to adults, to involve fewer quadrants, to have less
vitritis, and infrequently to lead to retinal detachment.21
Acute Retinal Necrosis
CHAPTER 164
FIGURE 164.14. Retinal folds in stage C2 proliferative
vitreoretinopathy associated with ARN. Note the pigmented epiretinal
membranes in the lower left corner.
Acute Retinal Necrosis Associated with Cutaneous
Herpes Zoster
Typical ARN has also been associated with cutaneous herpes
zoster, reflecting reactivation of latent virus rather than primary
infection as in varicella. In contrast to necrotizing herpetic
retinopathy associated with varicella, patients with ARN and
cutaneous herpes zoster demonstrate typical features including
confluent peripheral necrosis, severe vitritis, optic nerve invol-
vement, and late retinal detachment.37–40 The time interval
between cutaneous eruption and ARN ranges from 5 days to
3 months and has been unilateral in eight of nine cases reported
in immunologically competent patients to date. Slightly less
than half of the cases reported to date have involved cranial
nerve V or VII, with the remainder of sites being remote from
the eye. However, in patients with AIDS, five cases have been
reported of ARN in patients with AIDS and history of prior
HZO. The time interval between cutaneous eruption and ARN
in these patients has ranged between 0 and 9 months, and four
out of five patients developed bilateral ARN.40 Patients with
AIDS and cutaneous zoster remote from the eye have also been
reported to develop typical ARN.59
Progressive Outer Retinal Necrosis
Although typical ARN has been reported in immunocompro-
mised patients, including those with AIDS,33–35 a subgroup of
patients experience a more fulminant, rapidly progressive
necrotizing retinopathy, distinct from either CMV retinitis or
typical ARN and consistent with herpes zoster infection of the
retina. Early disease in PORN syndrome is characterized by
multifocal deep retinal opacifications. These lesions quickly
coalesce and progress to total full-thickness retinal necrosis over
a short period, and early retinal detachment develops in the
majority of patients. In patients with PORN, little or no inflam-
matory reaction is seen in the vitreous and the anterior chamber,
and occlusive vasculitis is generally not seen. Fluorescein angio-
graphy demonstrates full-thickness retinochoroiditis with
associated choroidal leakage, pruning of the retinal vasculature
and zones of frank nonperfusion.60
PORN can be easily distinguished from CMV retinitis. CMV
retinopathy is characterized by slow progression, and the visual
loss associated with CMV corresponds directly with the area
of retina involved with the infection or with direct optic nerve
involvement. In contrast, the lesions in PORN are rapidly 2113
 RETINA AND VITREOUS

progressive and are multifocal in presentation, and the retinal
dysfunction in PORN syndrome is widespread, leading to severe
visual loss. The role of varicella-zoster virus group in patients
with PORN is strongly suggested by the frequent history of
cutaneous herpes zoster infection in affected patients. In one
report, antecedent cutaneous zoster occurred in 67% of patients
for whom a history was available, and oral acyclovir was being
taken by 32% for active cutaneous disease or for antiviral
prophylaxis at the time PORN was diagnosed.61 DNA ampli-
fication using the polymerase chain reaction of a paraffin-
embedded transscleral eyewall biopsy specimen and an
enucleation specimen from a patient with PORN has successfully
identified herpes zoster virus DNA, and histologic studies
showed intranuclear inclusion in choroidal cells consistent with
viral particles.62 Despite the apparently clear viral cause of this
syndrome, potent antiviral medications have failed to preserve
visual acuity for most of these patients. Some case reports have
described success in treatment of patients with PORN syndrome
SECTION 10
including the herpes zoster varicella virus group,1,24,69,76 herpes
simplex, types 1 and 2,1,44,47,70 and CMV in several, rare, single
case reports.75–78 The herpes zoster varicella virus group is believed
to account for the majority of cases and the typical syndrome.
Herpesvirus hominis organisms, although exhibiting different
immunocytochemical staining characteristics, appear morpho-
logically similar by electron microscopy. The herpes zoster
varicella viruses are relatively large, measuring ~150–200 nm
when fully enveloped by an outer lipid coat with a central core
of double-stranded DNA measuring ~100 nm. The central core
is covered by an icosahedral capsid composed of 162 tubular
capsomers, which, in turn, are covered by the lipid bilayered
envelope (Figs 164.15 and 164.16). The DNA contains
~125 000 bp and weighs 80 MDa. At least five families of
varicella-zoster virus glycoproteins have been identified by
immunohistochemical studies that represent the primary
markers for both humoral and cell-mediated immunity. The
varicella-zoster group is highly cell associated and spreads from

using several combinations of antiviral medications, including cell to cell by direct contact. These viruses are fastidious and are
intravenous ganciclovir and oral acyclovir,63 intravitreal
ganciclovir and oral sorivudine,64 lifelong high-dose intravenous
foscarnet alone,65 or intravenous foscarnet and ganciclovir.66
Overall, the visual prognosis is poor. Unlike other patients with
ARN and like patients with CMV retinitis, patients with PORN
often develop disease reactivation along edges of previous
retinal infection, even in those who show some initial response
to antiviral medications.67 Laser prophylaxis may be of some
benefit.68 The overall poor visual prognosis for patients with
PORN is attributable to a variety of factors, including frequent
total necrosis of the retina, retinal detachments, and optic
neuropathy. Intravitreal administration of antiviral medication
may improve prognosis.80

Key Features: Signs and Symptoms of the Cicatricial

Phase of ARN
• Symptoms: Reduced vision, persistent floaters, constricted
visual field
• Signs:
• Retinal atrophy
• Scarring of RPE and choroid
FIGURE 164.15. Transmission electron micrograph of viral particles in
• Vascular nonperfusion the necrotic retina of a middle-aged man with ARN. Note the
• Optic atrophy complete and incomplete viral particles, including the central
• Epiretinal membrane nucleocapsid and outer lipid envelope. µ87 000.
• Rhegmatogenous retinal detachment (common)

PATHOPHYSIOLOGY

VIRAL CAUSE
Although initial reports noted the similarities between the
clinical findings of ARN and those of both Behçet’s disease and
certain viral infections, the viral cause of this syndrome was not
definitively established until 1982.8 Several lines of evidence
implicate the Herpesvirus hominis class of viral infection as
the cause of this syndrome. These data include direct viral
culture,7,59,69,74 detection of viral antigens in intraocular fluid
specimens by direct or indirect immunofluorescence,34,65
elevated or serially increasing intraocular or serum antibody
titers to herpesviruses,70–72 immunocytochemical staining of
viral antigens in fixed tissue from biopsy or enucleation
specimens,8,23,72,73,74 Herpesvirus hominis particles in
gluteraldehyde-fixed retinal tissue,8,12,24,25,75 herpesvirus DNA
amplified by polymerase chain reaction,25 and clinical disease
coincident with or immediately following herpes infection in FIGURE 164.16. Another portion of the retina seen in Figure 164.15
other sites.21–23,39 Several members of the Herpesvirus hominis demonstrates a large number of tightly packed viral particles in
2114 family have been implicated in the pathogenesis of this disease, varying stages of assembly. µ30 000.

difficult to culture, having been successfully transferred from
ocular specimens to human embryonal lung fibroblasts and
human embryonal kidney cells in vitro.1,36,79
HSV-1 and -2 are responsible for oral and genital ulcerations
in humans. The virus is also transmitted by direct contact
between skin surfaces and mucous membranes. The virus
consists of four major components, a centrally located core
surrounded by three concentric structures; capsid, tegumen,
and envelope. The fully enveloped particle has an approximate
diameter of 150–200 nm, with the envelope composed of lipid
and protein components conveying the antigenicity of the virus
and thereby dictating the host immunologic responses.
Both the herpes zoster varicella virus group and the HSVs
code for two unique herpes-specific enzymes, an isofunctional
deoxynucleoside kinase (herpes-specific thymidine kinase) and
a herpes-specific DNA polymerase. These enzymes are coded by
the herpesvirus genome and are not normally encountered in
mammalian cells.80 Acyclovir (9(2-hydroxy-ethoxy)methylgua-
nine) is selectively phosphorylated by the herpes-coded thymidine
kinase to its monophosphate form. Mammalian cellular enzymes
are then capable of converting acyclovir monophosphate to
acyclovir triphosphate. This represents the active antiviral form
of the drug, which becomes a selective substrate and inhibitor
of herpesviral DNA polymerase. As a result, acyclovir inhibits
viral replication in two ways: first, by prevention of the incorpo-
ration of deoxynucleotide triphosphates into herpesvirus DNA
and, second, by the incorporation of altered nucleotide analogs
(Fig. 164.17). Since uninfected mammalian cells do not contain
the virus-specific enzyme that converts acyclovir to its
monophosphate form, this sequence of inhibitory events is not
initiated in nonvirally infected cells, and the drug is therefore
relatively nontoxic contrasted with other antiviral agents such
as adenine arabinoside.107
HISTOPATHOLOGY
Histopathologic studies in the acute phases of ARN have been
performed on a relatively small number of eyes, either after
enucleation or on retinal biopsy specimens taken during
vitrectomy.1,24,35,76,77 Initial reports based on eyes undergoing
either vitrectomy for late retinal detachment or enucleation for
FIGURE 164.17. Structural formula of acyclovir, a substituted purine
nucleoside that is active against various members of the Herpesvirus
hominis family.
Acute Retinal Necrosis
intractable pain with chronic retinal detachment demonstrated
extensive atrophy and degeneration of the outer retinal layers
and pigment epithelium, occlusion of the retinal blood vessels,
and massive choroidal lymphocytic infiltration and engorgement.
Membranes associated with PVR demonstrated a prominent
pigment epithelial component with intraretinal and subretinal
cysts and subretinal ossification. No viral particles were
identified.28,55
Eyes in the acute phases of the disease show widespread pro-
found changes in virtually all ocular structures. Granulomatous,
keratic precipitates line the corneal endothelium, and chronic
and acute inflammatory cells infiltrate the iris and ciliary body,
in which perivascular lymphocytic cuffing is evident in con-
junction with focal edema of the iris root and adjacent ciliary
muscle. Chronic inflammatory cells are seen infiltrating the
sclera, accounting for the pain and scleral injection commonly
seen clinically. The histopathologic hallmarks of ARN are (1)
retinal vasoocclusion, (2) sharply demarcated zones of necrotizing
CHAPTER 164
retinitis, (3) choroidal lymphocytic infiltration and thickening,
and (4) optic neuropathy.
RETINAL VASOOCCLUSION
Both large- and small-caliber arterioles demonstrate perivascular
cuffing, endothelial cell swelling, and fibrinoid or thrombotic
occlusion to varying degrees.1 In some instances, the lumina
may be nearly or totally occluded through a combination of
endothelial swelling, red blood cell and platelet thrombi, and
fibrin (Figs 164.18 and 164.19). Despite the fact that the retinal
and choroidal vascular changes are a conspicuous feature of the
disease, to date no viral particles or antigen has been detected
within retinal vessel walls, suggesting that the changes seen are
immunologically mediated.
CONFLUENT NECROTIZING RETINITIS
Another characteristic feature of ARN is the abrupt demar-
cation of necrotic and normal retina. Areas of relatively well
preserved retina containing inflammatory infiltrates and
hemorrhages in the inner and outer layers may be immediately
FIGURE 164.18. Histophathologic specimen of thrombotic vascular
occlusion in ARN. Note engorgement of the underlying choroidal
vessel as well as severe perivascular cuffing and occlusion of the
lumen in the vessel by erythrocytes. H & E µ25. 2115
 SECTION 10 RETINA AND VITREOUS
FIGURE 164.19. Cowdry’s A intranuclear eosinophilic nuclear inclusions
in the retina in a zone of severe necrosis. Note the marked swelling of
endothelial cells and the encroachment on lumen by fibrinoid change
seen adjacent to a zone of inclusion bodies. H & E µ400.
adjacent to other zones of full-thickness necrosis with partial or
complete obliteration of the normal retinal architecture. High-
power views disclose the presence of eosinophilic intranuclear
inclusion bodies in infected retinal cells characteristic of herpes
infection. These changes, termed Cowdry A inclusions, contain
complete and incomplete viral particles and marginally displace
the host nuclear chromatin, which is basophilic in H & E-
stained sections. The pigment epithelial proliferation and
migration from the normal monolayer through necrotic retina
and onto the surface are frequently associated with reactive
gliosis and epiretinal membrane formation. These represent the
sites of future retinal tears in response to contracting preretinal
and transvitreal membranes. Pigmented macrophages are
commonly encountered, and cytomegaly is not a conspicuous
feature.
CHOROIDAL THICKENING AND
LYMPHOCYTIC INFILTRATION
Another feature that differentiates ARN from CMV retinitis
histologically is the relatively severe thickening and lympho-
cytic infiltration of the choroid seen in the former condition.
The infiltrate is mononuclear, consisting predominantly of
lymphocytes and plasma cells with associated occlusion of the
choriocapillaris and, to a lesser extent, the larger choroidal
vessels. Areas of granulomatous inflammation may be seen as
well. In a blind eye with ARN, varicella-zoster virus DNA was
detected in the choroid and choriocapillaris by in situ hybridiza-
tion and by immunohistochemical stains in mononuclear cells
with eosinophilic inclusions.53
OPTIC NEUROPATHY
Involvement of the optic nerve is variable, ranging from patchy
areas of chronic inflammation along the pia to broad zones of
neuronal necrosis, plasma cell infiltration, and vascular
occlusion (Fig. 164.20). To date, viral particles have not been
identified in the optic nerves available for study, although there
is experimental evidence to suggest that transmission from
one eye to another in bilateral cases may occur via the optic
2116 nerve.17,18
FIGURE 164.20. Cross-section of the optic nerve from a patient with
ARN. Note the central zone of necrosis. H & E µ100.
ELECTRON MICROSCOPIC AND
IMMUNOCYTOLOGIC FEATURES
Viral particles found within individual retinal cells demonstrate
nucleocapsids of 80–100 nm, which can be seen undergoing
assembly within retinal cell nuclei to form poorly enveloped
virus. These measure 150–200 nm in diameter and are adherent
to retinal cell membranes (Figs 164.15 and 164.16). The virus
appears most abundant in the inner retinal layers and in the
transition zone between necrotic and preserved retina. In areas
of greatest cytopathic effect, there is marked disruption of
retinal tissue, with bare nuclei and fragmented cell membranes
present. Viral antigens have been identified by immunocyto-
chemical techniques employing a variety of murine monoclonal
antibodies and avidin–biotin–peroxidase methods specific for
the major GP98/GP62 varicella-zoster glycoprotein complex.
Viral antigens have been detected in transitional zones between
normal and necrotic retina, retinal pigment epithelial cells, and
inner and outer retinal cells, but not in retinal vascular endo-
thelium, ciliary body, or optic nerve. However, immunoglobulins
G and M, fibrinogen, and complement component C3c have
been detected in retinal arteriolar walls and in surrounding
retinal tissue adjacent to zones of zoster antigens.76
EXPERIMENTAL ACUTE RETINAL
NECROSIS IN AN ANIMAL MODEL
Although it is well established that the primary pathogenetic
event of ARN is Herpesvirus hominis infection of the retina, a
number of issues remain unresolved, including the route of
transmission to the eye, the mechanism of bilateral disease in
some patients, and the underlying mechanisms responsible for
the variability and severity of the disease. The development of a
murine model of herpes simplex retinitis has provided some
insights into these questions.17,18,81,82
It has been shown that intracameral injection of HSV-1 (KOS
strain) in BALB/c mice produces the picture of acute hemor-
rhagic necrotizing retinitis. Interestingly, the retinitis does not
occur in the injected eye but rather in the contralateral (non-
injected) eye 9–10 days after injection and is completed over the
course of 12–48 h.82,83 ARN develops only in immunocompetent
animals and only when viral titers in the contralateral eye
exceed a threshold level (4 log10 plaque-forming units). This
confirms that viral infection is essential for the development of
this syndrome. After injection into the anterior chamber of one
eye, HSV reaches the contralateral eye in two waves. The first,

which fails to replicate, arrives within 24 h. The second arrives
within 5–7 days and reaches the eye after retrograde spread
down the optic nerve from the brain. Within 24–48 h of the
arrival of the second wave of replicating virus, the characteristic
picture of hemorrhagic and necrotizing retinitis develops.83
In this murine model, in addition to viral infection,
immunologic factors play an important role in the development
of ARN. It is known that, paradoxically, immunocompetence is
a prerequisite for the development of ARN in several different
regards. First, immunoincompetent mice (athymic) do not
develop the characteristic fundus picture of ARN, although viral
replication takes place in the contralateral eye at a comparable
time and in similar quantity to immunocompetent animals.
Second, ARN does not develop unless there is suppression of
virus-specific delayed hypersensitivity. This phenomenon is
termed anterior chamber-associated immune deviation and is
genetically determined in certain strains of mice in which
humoral antiviral antibody production remains unaffected.
These findings are consistent with a report on a patient with
ARN caused by HSV who had documented evidence of bilateral
high-intensity optic tract lesions involving the lateral geniculate
ganglia, temporal lobes, and midbrain seen on magnetic
resonance imaging (MRI). This, along with concurrent gene-
ralized malaise and fever, suggests a neural route of spread.1
The requirement for immunocompetence appears to be based
on the participation of precursor cytotoxic T cells in the
development of retinal necrosis. T cells harvested from lymph
nodes ipsilateral to the injected eye and from the contralateral
eye proliferate in vitro when exposed to viral antigens and are
believed to mediate the destruction of retinal cells infected by
HSV.18 It has also been shown that HSV-specific effector T cells,
when promptly injected into the contralateral eye of animals
undergoing intracameral injection of HSV, will prevent the
development of ARN, although injection of effector cells delayed
by more than 1 day after virus injection will not. Moreover,
HSV-1-specific immune effector cells restimulated with virus in
vitro are more effective in producing cytotoxicity to HSV-1-
infected target cells than are HSV-1-specific immune effector
cells that are not restimulated.83
DIFFERENTIAL DIAGNOSIS
OPHTHALMOSCOPY
Because of its characteristic fundus appearance, the diagnosis
of ARN can be established in the healthy immunocompetent
patient on ophthalmoscopic grounds, which include (1) the
presence of granulomatous anterior uveitis, (2) vitreous cellular
reaction, (3) retinal arteritis, (4) multiple patchy or confluent
areas of necrotizing retinitis with or without associated
hemorrhage predominantly located in the retina periphery, and
(5) optic disk swelling of variable degree.
The conditions to be considered in the differential diagnosis
of ARN are listed in Table 164.1. The clinical syndromes most
commonly misdiagnosed as ARN in healthy patients are syphilitic
neuroretinitis and acute multifocal hemorrhagic retinal
vasculitis.51,84 The former can be distinguished on the basis of
appropriate serologic testing, and the latter by the presence of a
greater degree of retinal hemorrhages, initial venous involve-
ment, and a subsequent clinical course that includes a failure to
respond to acyclovir, a failure to develop retinal detachment,
and the likelihood of ocular neovascularization. In some
instances, the differentiation between ARN and CMV retinitis
or toxoplasmic retinochoroiditis may be problematic in
immunocompromised patients. PORN can be readily distin-
guished from ARN syndrome because of the absence of vitritis
and anterior chamber inflammation, the extremely rapid
Acute Retinal Necrosis
TABLE 164.1. Differential Diagnosis of Acute Retinal Necrosis
Syphilitic neuroretinitis
Cytomegalovirus retinitis
Epstein–Barr virus retinitis
Toxoplasmic retinochoroiditis
Candida albicans endophthalmitis
Acute multifocal hemorrhagic retinal vasculitis
Behçet’s disease
Sarcoidosis
Progressive outer retinal necrosis
Primary intraocular lymphoma
CHAPTER 164
progression from multifocal areas of deep retinal opacification
to complete retinal necrosis, and the commonly very poor
response to antiviral therapies seen in patients with PORN.
Sarcoidosis, Candida albicans endophthalmitis, and Behçet’s
disease can generally be distinguished from ARN by the clinical
history. It has been recognized that some patients with
intraocular lymphoblastic lymphoma may present with retinal
hemorrhages, pseudovasculitis, and infiltrates mimicking
ARN.85–87 Bilateral retinal necrosis has also been described
as a complication of X-linked lymphoproliferative disease, and
Epstein–Barr virus genomic DNA within the eye was shown by
the polymerase chain reaction.88
LABORATORY EVALUATION
Baseline laboratory examination of patients with suspected
ARN can help establish the diagnosis and facilitate treatment.
Suggested studies are outlined Key Features: Diagnosis. Patients
should have a complete blood count, sedimentation rate
determination, and basic serologic studies, including a Venereal
Disease Research Laboratory (VDRL) test, fluorescent tre-
ponemal antibody absorption test, and rheumatoid factor and
antinuclear antibody determinations to exclude systemic
vasculitis or coagulopathy. Consideration should be given to
serologic testing for HIV infection. Abnormal platelet hyper-
aggregation in response to adenosine diphosphate admini-
stration has been detected in patients with ARN.89 Quantitative
antibody level testing for herpesvirus in acute and chronic sera
from patients with ARN is relatively unhelpful in determining
a specific causative diagnosis in this syndrome. In one study,
only 39% of cases had a diagnostic increase or decrease in
herpes group viral antibody levels on serial sampling.90 Serum
creatinine, blood urea nitrogen determinations, as well as
urinalysis, should be performed to determine the patient’s
suitability for acyclovir administration, and a chest radiograph
study and a purified protein derivative test should be performed
to exclude tuberculous disease, which could contraindicate oral
corticosteroid therapy.
Optional studies should be performed in specialized
circumstances, including a computed tomography (CT) scan or
MRI study in patients with clinical evidence of severe optic
nerve dysfunction or central nervous system symptoms such
as headache, meningismus, or altered mental status. MRI evi-
dence of optic nerve tract, ganglionic, or cerebral disease may
have an impact on the dosage and duration of acyclovir therapy.
Consideration should be given to lumbar puncture in patients
with either neurologic symptoms or an abnormal neuroradiologic
imaging study. Appropriate cerebrospinal fluid cultures, antibody 2117
 RETINA AND VITREOUS
testing, and cytologic studies should be performed only in rare
instances to exclude other causes of central nervous system
disease and retinal infiltration such as syphilis or lymphoblastic
lymphoma.
Anterior chamber or vitreous specimens have been obtained
in patients with ARN that helped to determine the causative
viral agent. Assays are used to detect viral antibody levels in the
intraocular fluids with appropriate recalculations for serum
antibody levels by the Goldmann–Wittmer coefficient.23,70,71,91–95
In one study, the rate of identifying viral cause in ARN via
intraocular antibody production determinations was 89%.96
However, the detection of multiple positive quotients for anti-
bodies within a single eye can make interpretation problematic.96
The detection of herpesviral DNA in specimens from eyes with
ARN and eyes with PORN has also been reported utilizing the
polymerase chain reaction to amplify minute quantities of viral
DNA from specimens as small as 50 mL.63,97–101 When available
and when intraocular surgery is otherwise warranted, these
SECTION 10
tests on intraocular fluids are certainly indicated. Rarely, in
complex cases – such as in patients with underlying
immunocompromise or atypical findings, or in those refractory
to antiviral therapy – diagnostic vitrectomy or retinal biopsy, or
both, may be indicated. In addition to conclusively establishing
the diagnosis, this may permit testing for antiviral
sensitivities.1,24,48,70,73,102 Diagnostic vitrectomy has been combined
with infusion of intravitreal acyclovir in a concentration of
10–40 mg/mL.12
Key Features: Diagnosis
• Ophthalmoscopy
• Serology: limited benefit due to high exposure in general
population
• MRI with contrast: perform if encephalitis suspected
• Lumbar puncture: perform if meningitis suspected; include viral
diagnostic studies
• Intraocular diagnostics: perform to discriminate between
herpes simplex and varicella zoster; include CMV,
toxoplasmosis, Epstein–Barr virus, if atypical
• PCR: best in first 2 weeks of disease
• Antibodies: permit diagnosis in some cases after 2 weeks
• HIV test
• Syphilis serology
CURRENT THERAPY
Current management of ARN consists of five primary com-
ponents in the acute phase of the disease, in addition to
treatment of retinal detachment if it occurs in the cicatricial
phase of the disease. These five components are (1) antiviral
therapy, (2) antiinflammatory therapy, (3) antithrombotic therapy,
(4) retinal detachment prophylaxis, and (5) possible optic nerve
therapy.
ANTIVIRAL THERAPY
The demonstration of herpesvirus particles in eyes with ARN
facilitated the development of specific treatment regimens. Both
intravitreal12,80 and intravenous acyclovir12,16 have been
reported to be of benefit in the treatment of this disorder.
Acyclovir
Acyclovir remains the drug of choice for the initial treatment of
ARN and has selective advantages over other purine and
pyrimidine nucleoside antimetabolites with antiviral activity in
vitro, including phosphonoformate, bromovinyldeoxyuridine,
2118 and fluoroiodoaracytosine.69 Because of the relative sensitivity
of HSV (ED50 of 0.1–1.6 mM) and, to a lesser extent, the herpes
zoster varicella group (ED50 of 3–4 mM) to acyclovir, the drug
theoretically is effective in ARN associated with either agent.104
Because ARN is generally not believed to be caused by strains of
CMV, which is typically more resistant to acyclovir (ED50 of
200 mM), more toxic agents, including vidarabine104 and
ganciclovir104 or foscarnet,105 are not generally required, unless
there is evidence of drug resistance or associated HIV infection.
After intravenous administration of 5 mg/kg of acyclovir in
humans, peak plasma levels of 30–40 mM are reached with a
half-life of 2–4 h. These levels contrast with a peak concen-
tration of 8.7 mM in the serum and 3.3 mM in the aqueous
humor after five oral 400–mg doses in volunteers undergoing
cataract extraction.106,107 Because there is a significant corre-
lation between plasma and aqueous concentrations of the drug,
it can be inferred that intraocular concentrations of acyclovir
are considerably higher after intravenous administration than
after oral administration. At present, initial therapy with intra-
venous acyclovir for a minimum of 1 week is recommended.
Because active viral particles have been identified in eyes with
ARN subsequent to intravenous acyclovir therapy,11 and the
greatest period of risk for involvement of the fellow eye is within
the first 6 weeks after presentation of the first eye, oral acyclovir
should be administered at a dosage of 2–4 g daily for 4–12 weeks
after completion of intravenous acyclovir as a precautionary
measure. The role of oral acyclovir in higher dose ranges (4 g
daily) as an alternative treatment to intravenous acyclovir
remains unsettled and awaits further study.
Intravenous acyclovir is generally administered at a total
dosage of 1500 mg m–2 day–1 based on calculation of the body
index in square meters from the height and weight; 500 mg m–2
day–1 is administered every 8 h. Oral acyclovir is available in
either 200-mg or 800-mg strength, which is administered five
times daily in dosages ranging from 1000 mg to 4 g daily,
depending on the severity of the disease process and the age and
weight of the patient. Studies of antiviral sensitivities of the
herpes zoster varicella virus group isolated from the vitreous
of a patient with ARN indicated in vitro susceptibility of the
isolate to both acyclovir (ED50 of 5.3 mM) and dehydroxy-
phenylglycol (ED50 of 4.7 mM).
Acyclovir has a large therapeutic index, and complications
reported to date have been relatively minor. They include local
irritation at the intravenous entry site and, rarely, reversible
elevation of serum creatinine concentration, presumably
through crystallization. Central nervous system toxic reactions,
including delirium, tremors, abnormal electroencephalograms,
as well as elevation of liver transaminase levels, have been re-
ported, although also rarely and in complex cases in which a
causal relationship has not been clearly established. To date,
acyclovir has not been found to be carcinogenic, mutagenic, or
teratogenic.107
In one clinical series, treatment of patients with ARN with
1500 mg m–2 day–1 of acyclovir in conjunction with aspirin and
corticosteroids resulted in regression of active retinal lesions
of presumed viral origin beginning, on average, 3.9 days after
initiation of therapy. Lesions completely regressed on an
average of 32.5 days after initiation of therapy, and no eye
developed new retinal lesions or progressive optic nerve
involvement 48 h or more after initiation of therapy. Acyclovir
treatment does not appear to ameliorate vitritis or retard the
rate of retinal detachment in advanced cases, although it may
do so in cases treated at an earlier time, before the development
of severe confluent lesions.11,46 Retrospective analysis of
patients treated both before the era of acyclovir therapy and
subsequent to the induction of acyclovir suggests a benefit of
treatment with regard to prevention of new lesions in the fellow
eye. Of 31 patients treated with acyclovir, 87.1% were disease-

free in the fellow eye at the time of last examination, in contrast
to only 30.4% of fellow eyes in patients not treated with
acyclovir. Two years after treatment using multivariate
methods, the cumulative proportion of patients who remained
disease-free in the fellow eye was 75.3% for the group treated
with acyclovir and 35.1% for the group not treated with
acyclovir.15 Since the patients involved in this study were
evaluated retrospectively and treated at different times and at
multiple different institutions, these data should be interpreted
with appropriate caution (Figs 164.21 and 164.22).
FIGURE 164.21. Life table analysis of lesions treated with and
without acyclovir and the resultant cumulative risk of disease
development in the fellow eye. The broken line represents untreated
patients with unilateral disease over time. The group of patients
treated with acyclovir is less likely than the group not treated to
develop ARN in the fellow eye (P = 0.0013).
Reprinted with permission from Elsevier Science Palay DA, Sternberg P, Davis J,
et al: Decrease in the risk of bilateral ARN by acyclovir therapy. Am J Ophthalmol
1991; 112:250–255.
FIGURE 164.22. The same region as shown in Figure 164.2 after
10 days of intravenous administration of acyclovir. Note the nearly
complete resolution of nummular lesions nasal to the optic nerve.
Acute Retinal Necrosis
In patients who are unable to tolerate acyclovir or who
demonstrate clinical disease progression suggestive of acyclovir
drug resistance, consideration may be given to administration
of intravenous ganciclovir as an alternative form of therapy.
Recommended guidelines for treatment with ganciclovir at
present are 5 mg/kg every 12 h for 7 to 14 days by intravenous
infusion. Patients undergoing ganciclovir administration should
have a twice-weekly complete blood count with differential and
platelet count to identify early signs of hematopoietic sup-
pression. The dosage of ganciclovir should be reduced in
patients with evidence of impaired creatinine clearance, and the
drug should be discontinued on signs of severe leukopenia
(<1000 cells/mL) or thrombocytopenia.78,104,108
In addition to oral and intravenous routes, acyclovir may also
be administered as an intravitreal infusate during the course of
vitrectomy. Concentrations of 10–40 mg/mL have been reported to
be safe.12,108 This form of treatment may be effective as an adjunct
to oral and intravenous therapy in patients requiring vitrectomy
CHAPTER 164
during the acute phase of viral replication within the eye. Direct
intravitreal injection of ganciclovir 2 mg or foscarnet 2.4 mg
during the acute phases of the disease appears to improve outcome
compared to treatment with systemic medication only.80
Other Antiviral Agents
Famciclovir
Recently, congeners of acyclovir have been developed that have
more favorable pharmacokinetic parameters after oral adminis-
tration. Famciclovir is a synthetic acyclic guanine derivative
prodrug that is metabolized to penciclovir after oral adminis-
tration. Penciclovir is active against HSV and herpes zoster
virus and has been used successfully in immunocompetent
patients with shingles and recurrent genital infection (Fig.
164.23).109
Valacyclovir
Valacyclovir is the L-valyl ester of acyclovir, which is given as an
oral prodrug that undergoes rapid first-pass metabolism to yield
acyclovir and L-valine. Its principal advantage over oral
acyclovir is its greater bioavailability (Fig. 164.24). Three daily
1000-mg doses of valacyclovir are believed to be as effective
as five daily 800-mg doses of acyclovir in the treatment of
cutaneous herpes zoster infection.110 There remain few
published data on the effectiveness of either famciclovir or
valacyclovir in the treatment of ARN, but anecdotal data seem
promising.
ANTIINFLAMMATORY THERAPY
Inflammatory cells, including cytotoxic lymphocytes, are
believed to play a major role in both the primary phases of the
syndrome, when they may contribute to both retinal necrosis
and vasculitis,17,18,111–114 and secondarily, when vitreous cellular
infiltrates contribute to organization of the vitreous that
predisposes to late retinal detachment.1–9 As a result, anti-
inflammatory therapy is an important component of treatment
for this disease. Administration of oral prednisone or equivalent
corticosteroids in doses of 0.5–1.5 mg kg–1 day–1 is recommended
in the acute phases of the syndrome during the period of
greatest intraocular inflammation. Because steroids are known
to enhance viral replication under selected conditions, the
initiation of steroid therapy should be delayed 24–48 h after
administration of intravenous acyclovir. However, in cases in
which the severity of intraocular inflammation is great,
particularly with optic nerve involvement, consideration may
be given to earlier institution and increase of the dosage to
2 mg kg–1 day–1 of steroid therapy. The exact duration of steroid 2119
 RETINA AND VITREOUS

N O
N
O N
NH
NH2

O N O N
H3C N NH2 O
N NH2

O
Valacyclovir
O CH3 Hydrolysis by
valacyclovir hydrolase

O O

N
Famciclovir NH
SECTION 10

NH2

OH HO N N NH2
O
O
O

N L-valine Aciclovir
NH
FIGURE 164.24. Structural formula of valacyclovir, a prodrug
converted to acyclovir and L-valine by hydrolase.

HO N N NH2

markedly swollen, nearly obliterating the vascular lumina in

HO
Penciclovir
FIGURE 164.23. Structural formula of famciclovir and its active
metabolite penciclovir.
therapy is dictated by the severity of the intraocular inflam-
mation and any associated complications of therapy. In patients
in whom there is no contraindication to steroid therapy,
treatment with prednisone should continue for 6–8 weeks, with
gradual tapering of the dose in order to reduce both the anterior
and the posterior segment intraocular inflammation. At present,
no other form of antiinflammatory therapy, including
cyclosporine or various antimetabolites, has been shown to be
of benefit in this syndrome. Topical treatment with pred-
nisolone in conjunction with cycloplegic agents should also be
given with dosage dictated by the severity of anterior segment
inflammation. No benefit has been demonstrated for the use of
topical acyclovir in this syndrome.
ANTITHROMBOTIC THERAPY
Periarteritis and intraluminal narrowing are conspicuous
features of ARN on both clinical and histopathologic studies.
Viral particles have not been demonstrated in the retinal
2120 vascular endothelial cells, although the cells themselves may be
some patients.1,76 These events are believed to be secondary to
humoral and cell-mediated mechanisms and contribute to
stasis and vascular thrombosis in patients with ARN. This may
result in vision loss from both optic nerve dysfunction and
retinal infarction. In addition to treatment with antiinflam-
matory agents, both antiplatelet agents and anticoagulation
have been previously recommended.11,115 Platelet hyper-
aggregation has been detected in patients with ARN and may be
treated with aspirin, 500–650 mg daily. The benefits of more
aggressive forms of anticoagulation, including both heparin and
warfarin, do not at present appear to warrant the use of such
forms.
RETINAL DETACHMENT PROPHYLAXIS
Retinal detachment continues to be the most serious late
complication of ARN, even with the prompt administration of
acyclovir and steroid therapy. Peripheral argon laser photo-
coagulation to demarcate zones of retinitis during the acute
phase of the disease has been recommended as a potentially
effective prophylactic measure if the media will permit such
treatment.16,68 In one retrospective clinical series,16 12 eyes in
10 patients underwent prophylactic laser photocoagulation and
two (17%) retinal detachments developed. During the same
time, four of six (66%) patients not receiving photocoagulation
experienced retinal detachment as a complication of ARN.
Because it is likely that eyes with less severe forms of ARN have
the clearest media and are therefore more likely to be able to
undergo prophylactic photocoagulation when compared with
more severely affected eyes, it cannot be definitively concluded
that the difference in these two rates is solely the result of
photocoagulation. Nonetheless, it seems likely that photoco-
 Acute Retinal Necrosis

agulation does have some prophylactic value against the devel-

opment of retinal detachment and it should be administered
in all patients at the earliest possible stage. Recommended
treatment guidelines at present include the placement of three
rows of argon, krypton, or dye laser at the junctional zones
demarcating peripheral confluent necrosis from normal retina.
When possible, photocoagulation should be extended into zones
of necrosis, in which the retina tears usually occur. The benefit
of photocoagulation in isolated thumbprint lesions in the
posterior segment is less certain. In some instances, longer
wavelengths and retrobulbar anesthesia may be helpful in
permitting successful applications in eyes with media opacities.
Despite photocoagulation, it can be estimated that up to 50% of
eyes with ARN will develop retinal detachment.
One alternative strategy for retinal detachment prophylaxis
has been the use of vitrectomy combined with endophoto-
coagulation and scleral buckling.12,14,114 One difficulty encoun-
tered in the performance of a vitrectomy in such eyes is the
MANAGEMENT OF RETINAL DETACHMENT
Retinal detachment continues to be a difficult problem in
patients with late-stage ARN. In initial series of patients treated
appropriately with acyclovir, corticosteroids, and aspirin, 11 of
13 eyes experienced retinal detachment (84.6%).11 This is com-
parable to a 75% rate of retinal detachment seen before the
introduction of acyclovir therapy.7
Retinal detachment complicating ARN is particularly severe.
The majority of retinal detachments occur within 3 months
of the onset of symptoms. In one review, 41 of 55 eyes (75%)
affected by the virus experienced retinal detachment. The time
interval ranged from 1 to 10 months, with only four of 41 eyes
experiencing a retinal detachment more than 3 months after
the onset of the syndrome.9 In a series of 12 patients (13 eyes)
treated with intravenous acyclovir, 83.6% of eyes experienced
retinal detachment an average of 59 days after initiation of
therapy, with a range of 30–145 days.11 Eyes with retinal

CHAPTER 164
tight adherence between the nondetached vitreous gel and the detachment complicating ARN have a more unfavorable visual
atrophic, necrotic peripheral retina. Additionally, eyes with and anatomic prognosis for several reasons. The retinal breaks
ARN-associated severe intraocular inflammation may develop contributing to the rhegmatogenous components of these
severe postoperative ocular hypertension, fibrin response, and detachments are often multiple, large, and posteriorly located,
choroidal detachment after vitrectomy and scleral buckling.115 either in necrotic retina or at the junction between normal and
The prophylactic benefit of combined vitrectomy and scleral necrotic retina (Figs 164.25 and 164.13). PVR is frequent, and
buckling with endolaser remains uncertain.12,14,117,118 In one eyes that demonstrate severe preexisting intraocular inflam-
series, three of four eyes undergoing such prophylactic surgery mation and vascular compromise are predisposed to fibrin
experienced retinal detachment despite this therapy and appeared response, choroidal detachment, and ocular hypertension (Fig.
to have a more unfavorable course than eyes not undergoing 164.14).5,15,118
prophylactic vitrectomy and photocoagulation.118 PVR is a frequent occurrence in eyes with ARN that expe-
rience retinal detachment. In one series, 72.7% of eyes with
retinal detachment demonstrated stage C1 or greater PVR.12
TREATMENT OF ACUTE OPTIC NEUROPATHY The high frequency with which PVR occurs in this group of
In addition to the zones of frank neural necrosis seen histopatho- patients can be understood in view of the pathophysiology of
logically,19,54 it has been suggested that in some instances optic
nerve sheath distention and compression of the optic nerve may
contribute to the visual dysfunction associated with ARN. In
one series, eight eyes in six patients with optic neuropathy
believed to be secondary to ARN underwent optic nerve sheath
decompression in addition to intravenous acyclovir therapy.
These patients had a more favorable long-term visual prognosis
than did patients with lesser degrees of neuropathy not under-
going decompression.54 Clinical experience with this form of
therapy remains limited, but it appears to be a potentially useful
way to reduce visual disability in this condition in conjunction
with appropriate antiviral, antiinflammatory, and antithrombotic
therapy. This diagnosis may be established on the basis of CT
or MRI scanning in patients with clinical or visual evidence of
optic neuropathy in association with ARN.

Key Features: Treatment

• Antiviral therapy
• Intravenous acyclovir*
• Oral valacyclovir†
• Intravitreal ganciclovir and/or foscarnet*‡
• Combination antiviral therapy with intravenous foscarnet
plus intravenous acyclovir or intravenous ganciclovir*‡
• Or, appropriate treatment for atypical cases:
cytomegalovirus, toxoplasmosis
• Antiinflammatory treatment
• Oral or extraocular corticosteroids* FIGURE 164.25. Artist’s representation of retinal detachment in a
• Retinal detachment prophylaxis patient with ARN, including a large superior retinal tear at the junction
• Laser demarcation* of involved and noninvolved retina as well as multiple smaller pinpoint
• Early vitrectomy, membrane peeling and endolaser† defects in areas of postnecrotic zones. Note the presence of fixed
*Case series support use. folds radiating through the posterior pole from the periphery
†
Case reports support use. superotemporally. Reprinted from Blumenkranz MS, Clarkson J, Culbertson
‡ W, et al: Vitrectomy for retinal detachment associated with ARN. Am J
Recommended in patients who are immunocompromised.
Ophthalmol 1088; 106:426–429. 2121
 RETINA AND VITREOUS

the disease, including marked thinning of the peripheral retina

and migration of pigment epithelial cells through necrotic
retina onto the retina surface associated with metaplasia and
epiretinal membrane formation. These changes occur in
conjunction with cellular infiltration and secondary fibrotic
changes in the vitreous, including adherence to the peripheral
retina. It is known that the breakdown of the blood–ocular
barrier encountered in patients with uveitis contributes to the
development of PVR, through liberation of serum-derived growth
factors within the eye.119 It is also known that fibrin, which is
known to be more common in eyes undergoing retinal reattach-
ment surgery for ARN,118 is capable of producing mesenchymal
transformation of pigment epithelial cells, which may further
contribute to the development of PVR.120 As a result of these
factors, retinal detachment repair in patients with ARN has
been more difficult than other forms of retinal reattachment,
although success rates appear to be improving with improved
vitreoretinal surgical techniques.
SECTION 10

Before 1982, retinal reattachment was attempted in only 18

of 41 eyes, with only four of 18 procedures being successful
(22%).7 Employing a combination of scleral buckling and
vitrectomy in selected instances, Clarkson and colleagues118
reported an improved success rate, with 13 of 16 eyes that
experienced retinal detachment from ARN requiring operation
and seven retinas remaining reattached (53.8%). Similar results
have been reported by other authors employing a combination FIGURE 164.26. Artist’s representation of peripheral demarcating
of vitreoretinal surgery and scleral buckling.121 photocoagulation, after vitrectomy and fluid–gas exchange in a patient
with retinal holes and detachment secondary to ARN, seen in
Other reports suggest that a combination of vitrectomy,
Figure 164.25.
lensectomy, internal fluid–gas exchange, and endolaser treatment Reprinted from Blumenkranz MS, Clarkson J, Culbertson W, et al: Vitrectomy for
without scleral buckling may provide a more favorable anatomic retinal detachment associated with ARN. Am J Ophthalmol 1988; 106:426–429.
and visual outcome in eyes with retinal detachment com-
plicating ARN (Fig. 164.26).14 In one series, eyes undergoing this
procedure were compared with eyes undergoing conventional
scleral buckling in association with vitrectomy. Overall, a com-
bined final success rate of 93.8% (15 of 16 eyes) was reported.
Complete retinal reattachment with one operation was
achieved for all eyes not previously subjected to a prophylactic
procedure.14,118 In this series of patients, perioperative com-
plications, including ocular hypertension (75%), fibrin response
(87.5%), and choroidal detachment (62.5%), were common in
patients undergoing scleral buckling (Fig. 164.27). Without
scleral buckling and cryotherapy, only one of eight eyes (12.5%)
experienced fibrin response and none had choroidal detachment
or ocular hypertension (intraocular pressure greater than 35
mm Hg). The rate of reoperation and the final visual-acuity rate
also appeared to be more favorable in those patients undergoing
vitrectomy without scleral buckling, with 87.5% of patients
achieving a visual acuity of 20/200 or better and 62.5%
achieving a visual acuity of 20/70 or better. These visual-acuity
results contrasted with only 25% of patients undergoing scleral FIGURE 164.27. Slit-lamp photograph of a pupillary fibrin response in
buckling combined with vitrectomy achieving a visual acuity of a patient who underwent lensectomy, vitrectomy, scleral buckling, and
20/200 or better. This may be related to the higher rate of need endolaser treatment for an ARN-related retinal detachment.
for retinal reoperation and use of silicone oil in this group.118
Silicone oil, or other tamponades, and retinotomy may be
required in some eyes with severe proliferative retinopathy.
However, the use of silicone oil in primary retinal detachment
associated with ARN does not seem necessary in the majority
of cases.

REFERENCES
1. Lewis ML, Culbertson WW, Post JD, et al:
Herpes simplex virus type I. A cause of the
ARN syndrome. Ophthalmology 1989;
96:875–878.
2. Uragama A, Yamada N, Sasaki Y,
et al: Unilateral acute uveitis with
2122 retinal periarteritis and detachment.
Jpn J Clin Ophthalmol 1971;
25:607–619.
3. Wilkerson D, Aaberg TM, Reeser FH:
Necrotizing vaso-occlusive retinitis. Am J
Ophthalmol 1977; 84:209–219.
4. Young NJA, Bird AC: Bilateral ARN. Br J
Ophthalmol 1978; 62:581–590.
5. Price FW, Schlaegel TF: Bilateral ARN. Am
J Ophthalmol 1980; 89:419–424.
6. Sternberg P, Knox DL, Finkelstein D, et al:
Acute retinal necrosis syndrome. Retina
1982; 2:145–151.
7. Fisher JP, Lewis ML, Blumenkranz MS,
et al: The acute retinal necrosis syndrome.

Part 1. Clinical manifestations.
Ophthalmology 1982; 89:1309–1316.
8. Culbertson WW, Blumenkranz MS, Haines H,
et al: The acute retinal necrosis syndrome.
Part 2. Histopathology and etiology.
Ophthalmology 1982; 89:1317–1325.
9. Gorman BD, Nadel AJ, Coles RS: Acute
retinal necrosis. Ophthalmology 1982;
89:809–814.
10. Holland GN, the Executive Committee of
the American Uveitis Society: Standard
diagnostic criteria for the acute retinal
necrosis syndrome. Am J Ophthalmol
1994; 117:663–667.
11. Blumenkranz MS, Culbertson WW,
Clarkson JG, et al: Treatment of the ARN
syndrome with intravenous acyclovir.
Ophthalmology 1986; 93:296–300.
12. Peyman GA, Morton FG, Uninsky E, et al:
Vitrectomy and intravitreal antiviral drug
therapy in ARN syndrome. Arch
Ophthalmol 1984; 102:1618–1621.
13. Culbertson WW, Clarkson JG, Blumenkranz
MS, Lewis ML: Acute retinal necrosis. Am J
Ophthalmol 1983; 96:683–685.
14. Blumenkranz MS, Clarkson JG, Culbertson
WW, et al: Vitrectomy for retinal
detachment associated with ARN. Am J
Ophthalmol 1988; 106:426–429.
15. Palay DA, Sternberg P, Davis J, et al:
Decrease in the risk of bilateral ARN by
acyclovir therapy. Am J Ophthalmol 1991;
112:250–255.
16. Sternberg P, Han DP, Yeo JH, et al:
Photocoagulation to prevent retinal
detachment in ARN. Ophthalmology 1988;
95:1389–1393.
17. Atherton SS, Kanter MY, Streilein JW: ACAID
requires early replication of HSV-1 in the
injected eye. Curr Eye Res 1990; 10:75–80.
18. Streilein JW, Igietseme JU, Atherton SS:
Evidence that precursor cytotoxic T cells
mediate acute necrosis in HSV-1 infected
retinas. Curr Eye Res 1990; 10:81–86.
19. Sergott RC, Belmont JB, Savino PJ, et al:
Optic nerve involvement in the ARN
syndrome. Arch Ophthalmol 1985;
103:1160–1162.
20. Culbertson WW, Brod RD, Flynn HW, et al:
Chickenpox-associated ARN syndrome.
Ophthalmology 1991; 98:1641–1646.
21. Matsuo T, Kuyama M, Matsuo N: Acute
retinal necrosis as a novel complication of
chickenpox in adults. Br J Ophthalmol
1990; 74:443–444.
22. Matsuo T, Morimoto K, Matsuo N: Factors
associated with poor visual function in
ARN. Br J Ophthalmol 1991; 75:450–454.
23. Margolis TP, Lowder CY, Holland GN, et al:
Varicella-zoster retinitis in patients with the
acquired immunodeficiency syndrome. Am
J Ophthalmol 1991; 112:119–131.
24. Forster DJ, Dugel PU, Frangieh GT, et al:
Rapidly progressive outer retinitis in
patients with the acquired
immunodeficiency syndrome. Am J
Ophthalmol 1990; 110:341–348.
25. Tran VT, Auer C, Guex-Crosier Y, et al.
Epidemiological characteristics of uveitis in
Switzerland. Int Ophthalmol 1994–1995;
18:293–298.
26. Friedman SM, Mames RN, Sleasman JW,
Whitcup SM: Acute retinal necrosis after
chickenpox in a patient with acquired
immunodeficiency syndrome. Arch
Ophthalmol 1993; 111:1607–1608.
27. Saari KM, Boke W, Manthey KF, et al: Bilateral
ARN. Am J Ophthalmol 1982; 93:403–411.
28. Ezra E, Pearson RV, Etchells DE, Gregor
ZJ: Delayed fellow eye involvement in
acute retinal necrosis syndrome. Am J
Ophthalmol 1995; 120:115–117.
29. Falcone PM, Brockhurst RJ: Delayed onset
of bilateral acute retinal necrosis syndrome:
a 34-year interval. Ann Ophthalmol 1993;
25:373–374.
30. Egbert P, Pollard RB, Galligher JG, Merigan
T: Cytomegalovirus retinitis in
immunosuppressed hosts. Natural history
and effects of treatment with adenine
arabinoside. Ann Intern Med 1980;
93:655–664.
31. Bloom JN, Katz JI, Kaufman HE: Herpes
simplex retinitis and encephalitis in an adult.
Arch Ophthalmol 1977; 95:1798–1799.
32. Friberg TR, Jost BF: Acute retinal necrosis
in an immunosuppressed patient. Am J
Ophthalmol 1984; 98:515–517.
33. Jabs DA, Schachat AP, Liss R, et al:
Presumed varicella-zoster retinitis in
immunocompromised patients. Retina
1987; 7:9–13.
34. Chambers RB, Derick RJ, Davidorf FH,
et al: Varicella-zoster retinitis in human
immunodeficiency virus infection. Arch
Ophthalmol 1989; 107:960–961.
35. Englund JA, Balfour HH: Varicella and
herpes zoster. In: Hoeprich PD, Jordan MC,
eds. Infectious diseases. 4th edn.
Philadelphia: JB Lippincott; 1989.
36. Matsuo T, Ohno A, Matsuo N: Acute retinal
necrosis following chickenpox in pregnant
woman. Jpn J Ophthalmol 1988; 32:70–74.
37. Browning DJ, Blumenkranz MS, Culbertson
WW, et al: Association of varicella-zoster
dermatitis with ARN syndrome.
Ophthalmology 1987; 94:602–606.
38. Yeo JH, Pepose JS, Stewart JA, et al:
Acute retinal necrosis syndrome following
herpes zoster dermatitis. Ophthalmology
1986; 93:1418–1422.
39. Cobo LM, Foulks GN, Liesegant T, et al:
Oral acyclovir in the treatment of acute
herpes zoster ophthalmicus.
Ophthalmology 1986; 93:763–770.
40. Sellitti TP, Huang AJ, Schiffman J, Davis JL:
Association of herpes zoster ophthalmicus
with acquired immunodeficiency syndrome
and acute retinal necrosis. Am J
Ophthalmol 1993; 116:297–301.
41. Holland GN, Cornell PJ, Park MS, et al: An
association between retinal necrosis
syndrome and HLA-DQw7 and phenotype
Bw62,DR4. Am J Ophthalmol 1989;
108:370–374.
42. Matsuo T, Matsuo N: HLA-DR9 associated
with the severity of acute retinal necrosis.
Ophthalmologica 1991; 203:133–137.
43. Klok AM, Geertzen R, Rothova A, et al:
Anticardiolipin antibodies in uveitis. Curr
Eye Res 1992; 11:209–213.
44. Thompson WS, Culbertson WW, Smiddy
WE, et al: Acute retinal necrosis caused by
reactivation of Herpes simplex virus type 2.
Am J Ophthalmol 1994; 118:205–211.
45. Rosenbaum JT, Tammaro J, Robertson JE
Jr: Uveitis precipitated by nonpenetrating
ocular trauma. Am J Ophthalmol 1991;
112:392–395.
46. Matsuo T, Nakayama T, Koyama T, et al: A
proposed mild type of ARN syndrome. Am
J Ophthalmol 1988; 105:579–583.
47. Duker JS, Nielsen JC, Eagle RC, et al:
Rapidly progressive ARN secondary to
herpes simplex virus, type I.
Ophthalmology 1990; 97:1638–1643.
Acute Retinal Necrosis
48. deBoer JH, van Haren MA, de Vries
Knoppert WA, et al: Analysis of IL-6 levels
in human vitreous fluid obtained from
uveitis patients, patients with proliferative
intraocular disorders and eye bank eyes.
Curr Eye Res 1992; 11:181–186.
49. Fox GM, Blumenkranz MS: Giant retinal
pigment epithelial tears in acute retinal
necrosis. Am J Ophthalmol 1993;
116:302–306.
50. Brown RM, Mendis U: Retinal arteritis
complicating herpes zoster ophthalmicus.
Br J Ophthalmol 1973; 57:344–346.
51. Blumenkranz MS, Kaplan HJ, Clarkson JG,
et al: Acute multifocal hemorrhagic retinal
vasculitis. Ophthalmology 1988;
95:1663–1672.
52. Han DP, Abrams GW, Williams GA:
Regression of disc neovascularization by
photocoagulation in the ARN syndrome.
CHAPTER 164
Retina 1988; 8:244–246.
53. Rummelt V, Wenkel H, Rummelt C, et al:
Detection of varicella zoster virus DNA and
viral antigen in the late stage of bilateral
acute retinal necrosis syndrome. Arch
Ophthalmol 1992; 110:1132–1136.
54. Sergott RC, Anand R, Belmont JB, et al:
Acute retinal necrosis neuropathy. Clinical
profile and surgical therapy. Arch
Ophthalmol 1989; 107:692–696.
55. Topilow H, Nussbaum JJ, Freeman HM,
et al: Bilateral ARN. Clinical and
ultrastructural study. Ophthalmology 1982;
100:1901–1908.
56. Barondes MJ, Tellez F, Siegel A: Acute
retinal necrosis after chickenpox in a
healthy adult. Ann Ophthalmol 1992;
24:335–336.
57. Ehongo-Bidime A, Perleux A, Zanen A:
Post-varicella acute retinal necrosis. Bull
Soc Belge Ophthalmol 1995; 255:61–68.
58. Blumenkranz MS: Discussion of
chickenpox-associated ARN syndrome.
Ophthalmology 1991; 98:1645–1646.
59. Hellinger WC, Bolling JP, Smith TF,
Campbell RJ: Varicella-zoster virus retinitis
in a patient with AIDS-related complex:
case report and brief review of the acute
retinal necrosis syndrome. Clin Infect Dis
1993; 16:208–212.
60. Walton R, Byrnes G, Chan C, et al:
Fluorescein angiography in the progressive
outer retinal necrosis syndrome. Retina
1996; 16:393–398.
61. Engstrom RE, Holland GN, Margolis TP,
et al: The progressive outer retinal necrosis
syndrome. A variant of necrotizing herpetic
retinopathy in patients with AIDS.
Ophthalmology 1994; 101:1488–1502.
62. Greeven CM, Ford J, Stanton C, et al:
Progressive outer retinal necrosis
secondary to varicella zoster virus in
acquired immune deficiency syndrome.
Retina 1995; 15:14–20.
63. Morley MG, Duker JS, Zacks C: Successful
treatment of rapidly progressive outer
retinal necrosis in the acquired
immunodeficiency syndrome. Am J
Ophthalmol 1994; 117:264–265.
64. Pinnolis MK, Foxworthy D, Kemp B:
Treatment of progressive outer retinal
necrosis with sorivudine. Am J Ophthalmol
1995; 119:516–517.
65. Holland GN: The progressive outer retinal
necrosis syndrome. Int Ophthalmol 1994;
18:163–165.
66. Moorthy R, Weinberg D, Teich S, et al:
Management of varicella zoster virus 2123
 RETINA AND VITREOUS
retinitis in AIDS. Br J Ophthalmol 1997;
81:189–194.
67. Johnston WH, Holland GN, Engstrom RE,
Rimmer S: Recurrence of presumed
varicella-zoster virus retinopathy in patients
with acquired immunodeficiency syndrome.
Am J Ophthalmol 1993; 116:42–50.
68. Cooper H, Beek P: Spontaneous regression
and successful laser prophylaxis in
progressive outer retinal necrosis syndrome.
Am J Ophthalmol 1996; 121:723–724.
69. Pepose JS, Biron K: Antiviral sensitivities of
the ARN syndrome virus. Curr Eye Res
1987; 6:201–205.
70. Sarkies N, Gregor Z, Forsey T, Darougar S:
Antibodies to herpes simplex virus type I in
intraocular fluids of patients with ARN. Br J
Ophthalmol 1986; 70:81–84.
71. Margolis T, Irvine AR, Hoyt WF, Hyman R:
Acute retinal necrosis syndrome presenting
with papillitis and arcuate neuroretinitis.
SECTION 10
Ophthalmology 1988; 95:937–940.
72. Suttorp-Schulten MS, Zaal MJ, Luyendijk
BS, et al: Aqueous chamber tap and
serology in ARN. Am J Ophthalmol 1989;
108:327–328.
73. Souchi S, Ozawa H, Matsuhashi M, et al:
Demonstration of varicella-zoster virus
antigens in the vitreous aspirates of
patients with ARN syndrome.
Ophthalmology 1988; 95:1394–1398.
74. Culbertson WW, Blumenkranz MS, Pepose
JS, et al: Varicella-zoster is a cause of the
ARN syndrome. Ophthalmology 1986;
93:559–569.
75. Rochat C, Herbort CP: Acute retinal
necrosis syndrome. Klin Monatsbl
Augenheilkd 1994; 204:440–449.
76. Rugger-Brandle E, Roux L, Leuenberger
PM: Bilateral ARN: identification of the
presumed infectious agent. Ophthalmology
1984; 91:1648–1658.
77. Madhavan HN, Biswas J, Gopal L, Sharma
T: Investigations in the virological etiology
in acute retinal inflammation. Indian J Med
Res 1995; 101:233–237.
78. Schmitz K, Fabricius EM, Popescu M:
Cytomegalovirus retinitis in AIDS.
Effectiveness and complications of long-
term therapy [German with English abstract].
Ophthalmologe 1992; 89:416–426.
79. Whitley RJ: Varicella-zoster virus. Infectious
diseases and their etiologic agents. Part III.
In: Mandell GL, Goudlas RG, Bennet JE,
eds. Principles and practice of infectious
diseases. 3rd edn. New York: Churchill
Livingstone; 1991:1153–1159.
80. Scott IU, Luu KM, Davis JL.
Clinicopathologic reports, case reports,
and small case series: Intravitreal antivirals
in the management of patients with aquired
immunodeficiency syndrome with
progressive outer retinal necrosis. Arch
Ophthalmol 2002; 20:1219–1222.
81. Whittum JW, McCulley JP, Niederkorn JT,
Streilein JW: Ocular disease induced in
mice by anterior chamber inoculation of
herpes simplex virus. Invest Ophthalmol Vis
Sci 1984; 25:1065–1073.
82. Cousins SW, Gonzalez A, Atherton S:
Herpes simplex retinitis in the mouse:
clinicopathologic correlations. Invest
Ophthalmol Vis Sci 1989; 30:1485.
83. Igietseme JU, Streilein JW, Miranda F, et al:
Mechanisms of protection against herpes
simplex type 1-retinal necrosis by in vitro-
activated T lymphocytes. J Virol 1991;
2124 65:763–768.
84. Duker JS, Blumenkranz MS: Diagnosis and
management of the ARN syndrome. Surv
Ophthalmol 1991; 35:327–343.
85. Ridley ME, McDonald HR, Sternberg P,
et al: Retinal manifestations of ocular
lymphoma (reticulum cell sarcoma).
Ophthalmology 1992; 99:1153–1160.
86. Kohno T, Uchida H, Inomata H: Ocular
manifestations of adult T-cell leukemia/
lymphoma. A clinicopathologic study.
Ophthalmology 1993; 100:1794–1799.
87. Gass JD, Trattler HL: Retinal artery
obstruction and atheromas associated with
non-Hodgkin’s large cell lymphoma
(reticulum cell sarcoma). Arch Ophthalmol
1991; 109:1134–1139.
88. Grossniklaus HE, Aaberg TM, Purnell EW,
et al: Retinal necrosis in X-linked
lymphoproliferative disease. Ophthalmology
1994; 101:705–709.
89. Ando F, Kato M, Goto S, et al: Platelet
function in bilateral ARN. Am J Ophthalmol
1983; 96:27–32.
90. Pepose JS, Flowers B, Stewart JA, et al:
Herpesvirus antibody levels in the etiologic
diagnosis of the acute retinal necrosis
syndrome. Am J Ophthalmol 1992;
113:248–256.
91. Carney MD, Peyman GA, Goldberg MF,
et al: Acute retinal necrosis. Retina 1986;
6:85–94.
92. Matsuo T, Nakayama T, Koyama T, et al:
Cytological and immunological study of the
aqueous humor in acute retinal necrosis
syndrome. Ophthalmologica 1987;
195:38–44.
93. Matsuo T, Nakayama T, Koyama T, et al:
Mild type acute retinal necrosis syndrome
involving both eyes at three-year interval.
Jpn J Ophthalmol 1987; 31:455–460.
94. Immunen I, Laatikainen L, Linnanvuori K:
Acute retinal necrosis syndrome treated
with vitrectomy and intravenous acyclovir.
Acta Ophthalmol 1989; 67:106–108.
95. de Boer JH, Luyendijk L, Rothova A, et al:
Detection of intraocular antibody
production to herpesviruses in acute retinal
necrosis syndrome. Am J Ophthalmol
1994; 117:201–210.
96. Davis JL, Feuer W, Culbertson WW,
Pflugfelder SC: Interpretation of intraocular
antibody levels in necrotizing retinitis.
Retina 1995; 15:233–240.
97. Kumano Y, Manabe J, Hamamoto M, et al:
Detection of varicella-zoster virus genome
having a Pst1 site in the ocular sample
from a patient with acute retinal necrosis.
Ophthalmic Res 1995; 27:310–316.
98. Sado K, Kimura T, Hotta Y, et al: Acute
retinal necrosis syndrome associated with
herpes simplex keratitis. Retina 1994;
14:260–263.
99. Thompson WS, Culbertson WW, Smiddy
WE, et al: Acute retinal necrosis caused by
reactivation of herpes simplex virus type 2.
Am J Ophthalmol 1994; 118:205–211.
100. Mitchell SM, Fox JD, Tedder RS, et al:
Vitreous fluid sampling and viral genome
detection for the diagnosis of viral retinitis
in patients with AIDS. J Med Virol 1994;
43:336–340.
101. Pavesio CE, Mitchell SM, Barton K, et al:
Progressive outer retinal necrosis (PORN) in
AIDS patients: a different appearance of
varicella-zoster retinitis. Eye 1995;
9:271–276.
102. Rutzen AR, Ortega-Larrocea G, Dugel PU,
et al: Clinicopathologic study of retinal and
choroidal biopsies in intraocular
inflammation. Am J Ophthalmol 1995;
119:597–611.
103. Hirsch MS, Schooley RT: Treatment of
herpes virus infections (second of two
parts). N Engl J Med 1983; 309:1034–1039.
104. Holland GN, Sakamoto MJ, Hardy D, et al:
CMV Retinopathy Study Group: treatment
of cytomegalovirus retinopathy in patients
with acquired immunodeficiency syndrome.
Arch Ophthalmol 1984; 104:794.
105. Jacobson MA, Drew WL, Feinberg J, et al:
Foscarnet therapy for ganciclovir-resistant
cytomegalovirus in patients with AIDS.
J Infect Dis 1991; 163:1348–1351.
106. Hung SO, Patterson A, Rees PJ:
Pharmacokinetics of oral acyclovir (Zovirax)
in the eye. Br J Ophthalmol 1984;
68:192–195.
107. Laskin OL: Acyclovir. Pharmacology and
clinical experience. Arch Intern Med 1984;
144:1241–1246.
108. Pulido JS, Palacio MN, Peyman GA, et al:
Toxicity of antiviral drugs. Ophthalmic Surg
1984; 15:666–669.
109. Perry C, Wagstaff A: Famciclovir: a review
of its pharmacologic properties and
therapeutic efficacy in herpesvirus
infections. Drugs 1995; 50:396–415.
110. Perry C, Faulds D: Valaciclovir: a review of
its antiviral activity pharmacokinetic
properties, and therapeutic efficacy in
herpesvirus infections. Drugs 1996;
52:754–772.
111. Whittum JW, McCulley JP, Niederkorn JT,
Streilein JW: Ocular disease induced in
mice by anterior chamber inoculation of
herpes simplex virus. Invest Ophthalmol Vis
Sci 1984; 25:1065–1073.
112. Cousins SW, Gonzalez A, Atherton S:
Herpes simplex retinitis in the mouse:
clinicopathologic correlations. Invest
Ophthalmol Vis Sci 1989; 30:1485.
113. Igietseme JU, Calzada PJ, Gonzalez AR,
et al: Protection of mice from herpes
simplex virus-induced retinitis by in vitro-
activated immune cells. J Virol 1989;
63:4808–4813.
114. Igietseme JU, Streilein JW, Miranda F, et al:
Mechanisms of protection against herpes
simplex virus type I-retinal necrosis by in
vitro-activated T lymphocytes. J Virol 1991;
65:763–768.
115. Ando F, Kato M, Goto S, et al: Platelet
function in bilateral ARN. Am J Ophthalmol
1983; 96:27–32.
116. Carney MD, Peyman GA, Goldberg MF, et al:
Acute retinal necrosis. Retina 1984; 6:85.
117. Blumenkranz MS, Clarkson J, Culbertson
WW, et al: Visual results and complications
after retinal reattachment in the ARN
syndrome: the influence of operative
technique. Retina 1989; 9:170–174.
118. Clarkson JG, Blumenkranz MS, Culbertson
WW, et al: Retinal detachment following the
ARN syndrome. Ophthalmology 1984;
91:1665–1668.
119. Campochiaro P, Jerdan JA, Glaser BM:
Serum contains chemoattractants for
human retinal pigment epithelial cells. Arch
Ophthalmol 1984; 102:1376–1379.
120. Vidaurri JS, Glaser BM: Effect of fibrin on
retinal pigment epithelial cells. Arch
Ophthalmol 1984; 102:1376–1379.
121. McDonald HR, Lewis H, Kreiger AE, et al:
Surgical management of retinal detachment
associated with the ARN syndrome. Br J
Ophthalmol 1991; 75:455–458.
 CHAPTER
165 Ocular Syphilis
C. Stephen Foster and Richard R. Tamesis
Syphilis is a sexually transmitted, chronic, systemic infection
caused by the spirochete Treponema pallidum. Primary
infection is followed by an incubation period of ~3 weeks,
usually succeeded by the appearance of a primary skin or
mucous membrane lesion, the chancre. This lesion, which may
appear from 8 days to 6 weeks after infection with T. pallidum,
is usually painless and associated with regional lymph node
enlargement. The chancre typically heals within a few weeks.
The secondary stage of syphilis ensues. Symptoms of this stage
(fever, malaise, headache, generalized lymph node enlargement,
and rash) generally appear within a few weeks or, at most, a few
months after the primary chancre has disappeared. This
spirochetemic stage of the disease then subsides, even without
antibiotic therapy, and the infection becomes ‘latent’.
Individuals with historic or serologic evidence of syphilis but
with no clinical manifestations by definition have latent
syphilis. Secondary syphilitic relapses may develop during this
state of latency. Approximately one-third of untreated cases will
progress to tertiary syphilis, with syphilitic inflammatory
lesions of the heart, aorta, brain, kidney, bone, eye, or skin.
CAUSE
The organism responsible for syphilis, T. pallidum, was
discovered by Schaudinn and Hoffman of Hamburg in 1905 in
inflammatory lesions from a patient with syphilis. This
organism is a thin, spiral-shaped parasite for whom the only
known natural host is Homo sapiens. Other mammals can be
infected with the organism. The origins are unknown, and
several hypotheses exist regarding the development of syphilis
in humans. Two main theories, one tracing the development
from the tropics and the other tracing the development from
native Americans, are most commonly espoused. The first clear
descriptions of clinical evidence of syphilis were recorded at the
end of the fifteenth century, when a pandemic known as the
Great Pox, as distinguished from smallpox, swept over Europe
and Asia.1 Warfare in the fifteenth century, including the seige
of Naples by Charles VIII of France, was associated with the
spread of what today is known as syphilis among soldiers,
prostitutes, and other women who followed the warriors. The
disease became known as the French disease among Italians
and the Italian disease among the French. It supposedly
received its present name from a poem written in 1530 by
Fracastoro about an infected shepherd named Sifilis.2
EPIDEMIOLOGY
TRANSMISSION
With the notable exception of transplacental transmission from
an infected mother to her fetus, the transmission of T. pallidum
is almost exclusively sexual. Transmission requires a break in
the skin, but T. pallidum can penetrate intact mucous mem-
branes. The primary mode of transmission is through sexual
intercourse, but transmission during oral sexual practices may
also occur. Transmission after blood transfusions is, in essence,
unheard of in civilized societies today because of the screening
of blood and blood products for transfusion. The likelihood of
transmission of an infectious dose of T. pallidum from an
infected to a noninfected individual during sexual intercourse is
undoubtably multifactorial. One study based on a placebo-
controlled trial of antibiotic efficacy in aborting syphilis in
known contacts, however, suggested a 30% incidence of trans-
mission with a single sexual encounter.3 Few organisms are
needed to survive, proliferate, and produce disease. It is
estimated that the ID50 inoculum is 57 spirochetes.4
INCIDENCE
With the exception of two periods of a rising incidence of
syphilis, the incidence of this disease has been steadily
decreasing since 1940. Infant deaths resulting from syphilis
and new admissions of patients with syphilitic psychoses have
fallen 99% since 1940 in the United States, and the total
number of cases of late and latent syphilis has fallen 98% since
1943. A decrease of 98% in the number of congenital syphilitic
cases has occurred since 1941.1 An increase in the incidence
of syphilis in World War II was noted in all Western countries;
this incidence rapidly fell in the 1950s. A smaller rise occurred
between 1971 and 1980, which can be accounted for primarily
by the increasing incidence of syphilis in the homosexual
community. By 1988, there were 40 275 new cases of primary
and secondary syphilis reported in the United States. That
number had fallen to 16 500 in the 1995 Summary of
Notifiable Diseases, and to 7980 in 2004.4,5 Age-related data
show early syphilis to be concentrated in young adults, with
many more male than female cases reported.2 The reported
incidence is higher among nonwhites than among whites,
higher in urban areas than in rural areas, higher in the southern
and southwestern United States, and higher in those states
with large urban populations. Grassly and coworkers used
time series of annual disease reports for 68 US cities to
demonstrate marked 8–11 year cycles in syphilis incidence from
the 1980s, which had previously been attributed to changes
in sexual behavior.6 Instead, they showed that the dynamics
of syphilis infection can be explained by the ‘susceptible–
infected–recovered’ (SIR) model for microparasitic infections.7,8
Syphilis stimulates significant but imperfect immunity
following recovery from infection. In the SIR model, oscillations
in incidence of disease are produced by prolonged immunity
following infection combined with a short infection period. 2125
Cycles occur because major epidemics exhaust their supply of
 RETINA AND VITREOUS
FIGURE 165.1. Iris nodule, syphilitic uveitis. Note the true mass in the
SECTION 10
substance of the iris periphery at the 8–9 o’clock position.
susceptible individuals. The number of individuals in at-risk
groups then gradually increases, eventually providing enough
numbers for the next major outbreak.
OCULAR MANIFESTATIONS
UVEA
Syphilis was believed to be a common cause of iritis before the
antibiotic era. In the decade from 1970 to 1980 in a large
referral uveitis practice, Schlaegel and Kao estimated that only
1.1% of their uveitis cases were secondary to syphilis.9 However,
they emphasized one of the most important points for
ophthalmologists to remember; they did not initially suspect
syphilis in most of their 28 patients who were ultimately shown
to have this disease, and many of their patients had a
nonreactive Venereal Disease Research Laboratory (VDRL) test.
The authors emphasized, once again, the ‘great imitator’
capabilities of syphilis and also stressed the importance of the
fluorescent treponemal antibody absorption (FTA-ABS) test in
the routine screening of all patients with intraocular
inflammation. If this test had not been used in their inves-
tigations, three-fourths of their syphilitic iritis cases would have
gone undiagnosed. This point is reemphasized as a result of an
experience with 25 of 1020 new uveitis referral cases seen
between 1 Jan 1983, and 30 Jan 1989.10 This 2.45% portion of
new uveitis referral population had previously undiagnosed
syphilis as the cause of their chronic or recurrent intraocular
inflammation. More than one-third of these patients had a
nonreactive serum VDRL test; all had a positive FTA-ABS test
and, on further testing, a positive microhemagglutination assay-
T. pallidum (MHA-TP) test. All had total resolution of their
uveitis with systemic intravenous penicillin therapy at doses
adequate for neurosyphilis.
The iritis of syphilis has no remarkably distinguishing
features. Although some authors have stated that ocular mani-
festations of syphilis are more likely to arise in the secondary
stage of acquired syphilis, it is emphasized that in almost every
instance in a referral practice, the patients have had latent
syphilis with no clinical manifestations prompting a suspicion
of this disease. In addition, although the older literature divided
syphilitic iritis into three types according to iris features, that in
only one of the cases showed an iris pathologic condition that
prompted a specific suspicion for syphilis. It is suspected that
2126 iritis roseati (with small dilated collections of capillaries in the
FIGURE 165.2. Sector retinitis, syphilitic uveitis, retinal vasculitis, and
retinitis. Note the sector of the retina, beginning at the disk and
extending superiorly, with infiltrate retinitis and associated retinal
vasculitis.
iris), iritis papulosa (with the iris roseati increasing in size to
resemble a papule), and iritis nodosa (with increasing size of iris
papulosa forming a yellow–red nodule) may be relatively restric-
ted to cases of syphilitic uveitis that are associated with classic
secondary syphilis with extraocular manifestations. Although it
is typically thought of syphilis as being a ‘granulomatous’ dis-
ease and, hence, imagine that the iritis of syphilis should be
a ‘granulomatous’ one with mutton-fat keratic precipitates on
the corneal endothelium, in fact approximately half of the
patients exhibit no keratic precipitates or fine keratic preci-
pitates on the endothelium. One case with iritis nodosa has
previously been reported,10 and the iris lesion in the right eye of
this patient, shown in Figure 165.1, is a good example of
syphilitic uveitis nodosa.
Inflammatory cells may accumulate in the vitreous body to
varying degrees (including nearly to the point of vitreal
opacification) in syphilitic panuveitis or posterior uveitis. It
may be difficult to evaluate the choroid and retina in such
instances, but if and when the retina can be seen, sectors or
foci of active choroiditis will usually be found. Placoid
chorioretinitis may occur in immunocompetent11,12 or in
human immunodeficiency virus (HIV)-infected individuals.13
The outer retina, retinal pigment epithelium, and choroid
are affected, and the lesions tend to present in the posterior
pole. Vitreal cells are typical, and a serous detachment
secondary to an outpouring of serum and inflammatory cells
may produce the unusual appearance of a macular or retinal
‘pseudohypopyon’.12 A diffuse retinitis or neuroretinitis without
choroiditis can also occur, as can papillitis. Disk edema in a
patient with periphlebitis and cells in the vitreous,14 central
retinal vein occlusion with disk edema,15 or even simple disk
edema (caused by a gumma of the optic nerve)16 should
probably be sufficient reason for considering the possibility of
syphilis and requesting an FTA-ABS test. Indeed, a healthy
dictum for all ophthalmologists to follow would be that any
patient with iritis and papillitis should be considered to have
syphilis unless proved otherwise. An example of sectoral
neuroretinitis secondary to undiagnosed syphilis is shown in
Figure 165.2, and an example of undiagnosed syphilitic
multifocal chorioretinitis is shown in Figure 165.3. Figure
165.4 depicts syphilitic uveitis and associated papillitis.
 Ocular Syphilis

TABLE 165.1. Causes of Interstitial Keratitis

Bacterial
Syphilis
Leprosy
Tuberculosis
Chlamydia
Lyme agent
Protozoal
Acanthamoeba
Malaria
Trypanosomiasis
Leishmaniasis

CHAPTER 165
FIGURE 165.3. Syphilitic multifocal choroiditis. Multifocal Other
chorioretinal lesions, now healed, with scarring in a patient with Cogan’s syndrome
previous active syphilis with multifocal choroiditis.
Sarcoidosis
Lymphoma
Viral
Herpes simplex
Herpes zoster
Epstein–Barr virus
Rubella
Rubeola
Vaccinia
Variola
Mumps
Helminthic
Cysticercosis
Onchocerciasis

FIGURE 165.4. Syphilitic uveitis with papillitis. Note the swelling of

the optic nerve and the hazy view of the nerve secondary to the
associated inflammatory cells in the vitreous anterior to the disc.
NEUROOPHTHALMIC MANIFESTATIONS
In addition to the possibility of papillitis previously described,
optic neuritis,17–19 optic perineuritis,20,21 and papilledema22
have been described as ocular manifestations in patients with
ocular syphilis. Zambrano and associates reported the
occurrence of bilateral syphilitic optic neuritis in a bisexual man
with AIDS; this patient’s visual acuity deteriorated over a period
of ~12 h from 20/20 bilaterally to total bilateral blindness.23
Toshniwal reported optic perineuritis, characterized by swollen
optic discs without raised intracranial pressure and visual dys-
function, in a patient with secondary syphilis and a complaint
of recurrent headache.21
CORNEA AND SCLERA
Syphilis can cause corneal inflammation, and unlike the multi-
faceted uveitis presentations possible with syphilis, syphilitic
keratitis is typically an interstitial keratitis (i.e., a nonulcerative
and nonsuppurative inflammation of the corneal stroma).
Untreated, this stromal keratitis is frequently accompanied
by stromal neovascularization. A variety of agents may cause
interstitial keratitis (Table 165.1), but syphilis may be the
second most common cause after herpes simplex virus.24
Approximately 10% of cases of interstitial keratitis secondary
to syphilis are associated with acquired syphilis; 90% are seen
with congenital syphilis. Syphilitic interstitial keratitis may be
diffuse and generalized, or it may be localized. When localized,
the area affected is commonly a sector of cornea (Fig. 165.5).
The keratitis may be subtle, and in the photophobic patient
with minimal circumlimbal injection, patience and practice are
required to discover the subtle, diffuse patina of tiny, tan
inflammatory cells in the affected area of the corneal stroma. As
the inflammatory process increases, the density of the
inflammatory cell population rises, and the ‘infiltrate’ is easier
to see, as is the associated corneal edema. An associated iritis
with or without keratic precipitates may develop, and peripheral
corneal neovascularization may ensue. Untreated, the keratitis
may progress to involve the entire cornea, with progressive
neovascularization of the stroma, enormous photophobia, and
discomfort and decreased visual acuity for the patient. The
inflammatory process may slowly regress over the ensuing
2 years, leaving a scarred cornea with emptied or ‘ghost’ stromal
vessels (Fig. 165.6). One or both eyes may be affected. In
congenital syphilitic keratitis, both eyes are affected, either
simultaneously or sequentially, in more than 75% of patients.18 2127
 SECTION 10 RETINA AND VITREOUS

FIGURE 165.5. Sector interstitial keratitis and luetic, old, inactive

sector interstitial keratitis with stromal scarring in the inferonasal
quadrant in a patient with previously treated syphilis.

Syphilitic scleritis may be nodular or diffuse. We have never

seen a case of necrotizing scleritis secondary to syphilis.
Syphilitic scleritis has no distinguishing features and, hence, is FIGURE 165.6. Luetic sector interstitial keratitis with ghost vessels in
diagnosed only because the ophthalmologist has cleverly the deep corneal stroma (extremely difficult to capture on film and
included, as routine, an FTA-ABS test as part of the diagnostic reproduce).
survey in all patients with scleritis, interstitial keratitis, or
uveitis.

DIAGNOSIS
Syphilis may be definitively diagnosed by direct or indirect
techniques. Direct techniques include the darkfield exam-
ination, in which exudate from a suspected syphilitic lesion
is examined by microscopy with a darkfield technique. The
corkscrew-shaped T. pallidum motile organisms are seen
directly. Fluorescein-labeled anti-T. pallidum antibodies may
be used in an immunofluorescence analysis of exudate or
material taken from a suspected syphilitic lesion. The antibody
will stick to syphilitic organisms in the exudate or specimen
and will be seen by the characteristic apple-green fluorescence
when the specimen is examined under the fluorescence
microscope. Detection of spirochetes in tissue specimens can
be accomplished through special staining techniques, including
the Warthin–Starry method. The spirochetes are seen directly in
the tissue specimens as shown in Figure 165.7.
Indirect techniques depend on serologic studies, including FIGURE 165.7. Spirochetes (arrow) in the cornea, as demonstrated
Treponema-specific and nontreponemal tests. These nontre- by silver stain, after penetrating keratoplasty in a patient with
ponemal tests detect antibodies directed against lipoidal secondary syphilis and active interstitial keratitis.
antigens. The primary nontreponemal test used in the United
States is the VDRL. This test is typically positive in patients
with active syphilis and negative in patients with successfully opinion, lies in monitoring the response to treatment. A
treated syphilis. In patients with latent syphilis, however, the persistent fall in VDRL titers after treatment provides essential
serum VDRL test is only ~70% sensitive. As discussed before, evidence of an adequate response to therapy. Polymerase chain
35% of Schlaegel and Kao’s cases of ocular syphilis would have reaction (PCR) testing for T. pallidum DNA is the most
been misdiagnosed if the authors had relied solely on the VDRL sensitive and specific test, but it is currently not economically
as the diagnostic test for syphilis.8 More than a third of the feasible for routine analyses.25
patients have nonreactive serum VDRL tests.9 These findings
dramatically emphasize the importance of never relying on the
VDRL as the sole screening test for the possibility of ocular EVALUATION FOR ASYMPTOMATIC
syphilis. The standard treponemal tests for syphilis in the NEUROSYPHILIS
United States are the FTA-ABS and the MHA-TP. The FTA-ABS Patients with positive serologic tests for syphilis should have
test is 98% sensitive, even in latent syphilis. This test will their cerebrospinal fluid (CSF) examined for VDRL titers, total
remain positive for life, regardless of whether the patient has protein, and cell counts including a differential count. Without
been treated. The VDRL titer, in contrast, reflects the systemic a positive CSF VDRL test, an elevated white blood cell count
2128 activity of the disease, and hence, its major value, in our with a predominance of lymphocytes in the CSF or an elevated
 Ocular Syphilis

total protein level is indicative of neurologic involvement, and
the patient should be treated accordingly as for neurosyphilis.
EVALUATION FOR HIV
There are reports in the literature of HIV-positive young adult
patients with concurrent ocular syphilis.26 This is not sur-
prising given the similar mode of transmission in both disease
entities. There is evidence that syphilis may pursue a more
aggressive course in patients who are concurrently infected with
HIV, rendering standard therapy for primary and secondary
syphilis inadequate.27 In view of these reports, we believe that
all patients with ocular syphilis should now be evaluated for
HIV and vice versa. The Centers for Disease Control recom-
mends that an asymptomatic patient with a positive tre-
ponemal confirmatory test and whose VDRL titer exceeds 1:32
or alternatively whose CD4 Th count is below 350 should be
evaluated for neurosyphilis.28 HIV-infected patients and those
patients with ocular syphilis should be hospitalized and treated
using 18-24 million units per day of intravenous aqueous
crystalline penicillin G (3–4 million units every 4 h or con-
tinuous infusion) for 10–14 days. An alternative regimen con-
sisting of 10–14 days of procaine penicillin 2.4 million units IM
once daily with plus probenecid 500 mg orally four times a day
can be used if compliance with therapy can be ensured. Some
infectious disease specialists also administer benzathine
penicillin 2.4 million units IM once a week up to 3 weeks after
completion of these neurosyphilis treatment regimens. The
Jarisch–Herxheimer reaction, which is due to lysis of spiro-
chetes and release of endotoxin-like antigens triggering an
autoimmune crisis, can develop in HIV-positive and secondary
stage patients. Patients should be informed about this possible
adverse reaction. An acute febrile reaction frequently accom-
panied by headache, myalgia and other flu-like symptoms
occurs within the first 24 h after any therapy for syphilis and
may induce early labor or cause fetal distress in pregnant

patients with ocular, tertiary and neurosyphilis should have
a reassessment of the CSF by VDRL every 3 months. A source
of substantial concern arises with reports of proven29 or sus-
pected syphilis30 in seronegative HIV-infected individuals.
Clinical suspicion and penicillin therapeutic trials have been
enlightening in these instances. Emergence of molecular diag-
nostic techniques (e.g., polymerase chain reaction technology)
makes it possible now to more definitively establish evidence of
microbial causes of uveitis,31 and we believe increasing use of
this technology on aqueous and vitreous specimens will clarify
the cause as microbial in many instances of unusual or atypical
ocular inflammation.
TREATMENT
PATIENTS WITHOUT PENICILLIN ALLERGY
Patients with ocular syphilis should be treated in the same way
that patients with tertiary syphilis are treated. This philosophy
has been adopted for two reasons: (1) the blood–ocular barrier is
as much a hindrance to adequate spirocheticidal doses of
penicillin as is the blood–brain barrier and (2) some evidence
exists suggesting that patients with syphilitic ocular inflam-
mation may have central nervous system syphilis without
VDRL-positive CSF. We therefore recommend that the assist-
ance of an infectious disease expert be obtained and that all
CHAPTER 165
women. This concern should not, however, prevent or delay
therapy. The use of aspirin or steroids may prevent this.32
Patients can become re-infected. For this reason, all sexual
partners must be screened and treated. HIV testing and sexually
transmitted disease counseling should also be offered.
PATIENTS WITH PENICILLIN ALLERGY
Some authors have recommended doxycycline,33 tetracycline,
or erythromycin in the treatment of penicillin-allergic patients
with syphilis. It is as yet unclear whether this therapeutic
approach is sufficient therapy in most patients with neuro-
syphilis, and little to no experience exists with these treatment
regimens in patients with ocular syphilis. Some investigators
believe that ‘penicillin-allergic’ patients should be carefully
evaluated and possibly desensitized and then treated with
penicillin. Many patients with penicillin ‘allergy’ in fact do not
have a true allergy at all. Careful allergy testing is advocated in
patients with syphilis who claim to have a penicillin allergy.
Such patients who have negative skin test results can safely
undergo the aforementioned penicillin treatment program with
close in-hospital monitoring. In addition, although penicillin
allergy desensitization can be lengthy, costly, and complex, this
alternative for treating the individual with ocular syphilis or
neurosyphilis who has been proved to be allergic to penicillin is
not without merit.

REFERENCES
1. Poitevin M, Collart P, Bolgert M: Syphilis in
1986. J Clin Neuroophthalmol 1987; 7:11.
2. Fracastoro: Le mal franais ou syphilis.
Extrait du livre de ‘contagionibus et
contagiosis morbis’ (1546) avec
commentaires de A. Fournier. 1869.
3. Martin JP: Conquest of general paresis.
BMJ 1972; 2:159.
4. Centers for Disease Control and Prevention:
Summary-Cases of specified notifiable
disease-United States. MMWR 1996;
44:11.
5. Centers for Disease Control and Prevention:
Primary and secondary syphilis – United
States, 2003-2004. MMWR 2006; 55;10:
269–273.
6. Grassly NC, Fraser C, Garnett GP: Host
immunity and synchronized epidemics of
syphilis across the United States. Nature
2005; 433:417.
7. Anderson RM, May RM: Infectious diseases
of humans: dynamics and control. Oxford
University Press; 1992.
8. Grenfell BT, Bjørnstad ON, Kappey J:
Travelling waves and spatial hierarchies in
measles epidemics. Nature 2001; 414:695.
9. Schlaegel TF Jr, Kao SF: A review (1970–
1980) of 28 presumptive cases of syphilitic
uveitis. Am J Ophthalmol 1982; 93:412.
10. Tamesis RR, Foster CS: Ocular syphilis.
Ophthalmology 1990; 97:1281.
11. Gass JDM, Braunstein RA, Chenoweth RG:
Acute syphitic posterior placoid
choridretinitis. Ophthalmology 1990;
97:1288.
12. Ouano DP, Brucker AJ, Saran BR: Macular
pseudohypopyon from secondary syphilis.
Am J Ophthalmol 1995; 119:372.
13. Dodds EM, Lowder CY, Boskovich SA,
et al: Simultaneous syphilitic necrotizing
retinitis and placoid chorioretinitis in
acquired immune deficiency syndrome.
Retina 1995; 15:354.
14. Halperin LS, Berger AS, Grand MG:
Syphilitic disc edema and periphlebitis
[photo essay]. Retina 1990; 10:223.
15. Primo S: Central vein occlusion in a young
patient with seropositive syphilis. J Am
Optom Assoc 1990; 61:896.
16. Smith JL, Byrne SF, Cambron CR:
Syphiloma/gumma of the optic nerve and
human immunodeficiency virus
seropositivity. J Clin Neuroophthalmol 1990;
10:175.
17. Graveson GS: Syphilitic optic neuritis.
J Neurol Neurosurg Psychiatry 1950; 13:216.
18. Walsh FB: Syphilis of the optic nerve.
Ophthalmology 1956; 60:39.
19. Weinstein JM, Lexow SS, Ho P, Spickards
A: Acute syphilitic optic neuritis. Arch
Ophthalmol 1981; 99:1392.
20. Rush JA, Ryan EJ: Syphilitic optic
perineuritis. Am J Ophthalmol 1981; 91:404.
21. Toshniwal P: Optic perineuritis with
secondary syphilis. J Clin Neuroophthalmol
1987; 7:6.
22. Schatz NJ, Smith JL: Non-tumor causes of
the Foster-Kennedy syndrome. J Neurosurg
1967; 27:37. 2129
 RETINA AND VITREOUS
23. Zambrano W, Perez GM, Smith JL: Acute
syphilitic blindness in AIDS. J Clin
Neuroophthalmol 1987; 7:1.
24. Duke-Elder SS, Leigh AG: Diseases of the
outer eye. System of ophthalmology series.
St Louis: CV Mosby; 1965:790.
25. Noordhoek GT, Wolters EC, de Jonge MEJ,
van Embden JDA: Detection by polymerase
chain reaction of Treponema pallidum in
cerebrospinal fluid from neurosyphilis
patients before and after antibiotic
treatment. J Clin Microbiol 1991; 29:1976.
26. Passo MS, Rosenbaum JT: Ocular syphilis in
patients with human immunodeficiency virus
infection. Am J Ophthalmol 1988; 106:1.
SECTION 10
2130
27. Johns DR, Tierney M, Felsenstein D:
Alteration in the natural history of
neurosyphilis by concurrent infection with
the human immunodeficiency virus. N Engl
J Med 1987; 316:1569.
28. Marra CM, Maxwell CL, Smith SL, et al:
Cerebrospinal fluid abnormalities in
patients with syphilis: association with
clinical and laboratory features. J Infect Dis
2004; 189:369.
29. Hicks CB, Benson PM, Lypton GP, et al:
Seronegative secondary syphilis in a
patient infected with the human
immunodeficiency virus with Kaposi
sarcoma. Ann Intern Med 1987; 107:492.
30. Halperin LS: Neuroretinitis due to
seronegative syphilis associated with
human immunodeficiency virus. J Clin
Neuroopthalmol 1992; 12:171.
31. deBoer JH, Verhagen C, Bruinenberg M,
et al: Serologic and polymerase chain
reaction analysis of intraocular fluids in the
diagnosis of infectious uveitis. Am J
Ophthalmol 1996; 121:650.
32. Brown ST. Adverse reactions in syphilis
therapy. J Am Venere Dis Assoc 1967;
3:172.
33. Tramont EC: Syphilis in the AIDS era.
N Engl J Med 1987; 316:1600.
 CHAPTER
166 Subretinal Fibrosis and Uveitis Syndrome
Tina Scheufele, Jay S. Duker, David R. Guyer, and Evangelos S. Gragoudas
HISTORICAL PERSPECTIVE
The subretinal fibrosis and uveitis syndrome is a rare distinct
posterior uveitis, which was first described by Palestine and
associates in 1984.1 These authors described three patients
with the unusual findings of progressive subretinal fibrosis and
uveitis. The condition most commonly occurs in healthy,
young, myopic females, usually with only minimal signs of
ocular inflammation. Early in the disorder, multiple small,
whitish-yellow retinal pigment epithelial or choroidal lesions
are observed in the posterior pole and mid-periphery. In the
later stages of the disease, progressive subretinal fibrosis occurs.
The condition usually becomes bilateral, but often initially
presents unilaterally. The first histopathologic and immuno-
histopathologic features of this condition were subsequently
described by the same group.2,3
When it was first being described, the subretinal fibrosis and
uveitis syndrome was given many different names and was
often grouped together with other chorioretinal inflammatory
diseases. Most commonly, it was grouped with multifocal
choroiditis, with some believing that this was a rarely observed
late stage in the spectrum of this disease.4–6 It was also
classified as a ‘disciform macular degeneration of young adults’
by Doran and Hamilton.7 However, in retrospect, many of these
patients probably had choroidal neovascular membranes that
lead to disciform scarring, rather than the subretinal fibrosis
syndrome.7 Now, it is considered a distinctly separate entity
from multifocal choroiditis, punctate inner choroidopathy, and
other chorioretinal inflammatory diseases.
PATIENT CHARACTERISTICS
The subretinal fibrosis and uveitis syndrome occurs predomi-
nantly in young, healthy, myopic females. The patients are
usually less than 35 years of age.1–11 In one series of 11 patients,
the age range was 24–43 years, with a mean age of 30.2 years.8
The disease has been described in patients as young as 6 years
and as old as 76 years.4,5,9 In several series, all of the patients
were female,1,2,6,8,10 although a meta-analysis of all large
published series found that 86% of all reported cases were
female.11 The patients usually have a myopic refractive
error.7,9,11 In Morgan and Schatz’s series,8 10 of 11 patients were
myopic, with a range of –2.75 to –8.50 D. No racial predilection
has been identified.11 Systemic evaluation of these patients is
almost always unremarkable.1–9 Cases have been reported in
patients with Reiter’s syndrome; migraine; atopy; schizoid syn-
drome; gastric bypass surgery; positive skin, serologic, and
biopsy findings of histoplasmosis; and a positive purified
protein derivative test for tuberculosis.1–9 In one series, six of 11
patients were taking oral contraceptives.8 However, all of these
associations are probably unrelated to the ocular condition.
SYMPTOMS
Patients usually complain of acute vision loss, often with meta-
morphopsia. Scotomas and photopsias also may be reported.
OBJECTIVE FINDINGS
The vision loss may be very mild or severe, depending on
the stage of the disease at which the patient presents (see
Table 166.1). Early in the disease course, the visual acuity can
range from 20/20 to 20/400.6,8 As the disease progresses and
subretinal fibrosis develops, the visual acuity may be decreased
severely to counting-fingers, light perception, or even no light
perception.10–13 The condition is usually bilateral (45–100% of
cases)1–11; however, the fellow eye is often asymptomatic
initially and may not become involved until months later. For
example, in one series of five patients, one case remained
unilateral, one case presented with bilateral involvement, and
three cases that were initially unilateral involved the second eye
within 3–6 months.6
Slit-lamp examination may reveal an anterior or posterior
uveitis (Fig. 166.1).1–11 Usually, however, the inflammation is
mild when present. A mild chronic vitritis is often associated
with transient, multiple, small (100–500 mm), round, discrete,
yellowish white lesions of the retinal pigment epithelium
or choriocapillaris in the posterior pole and mid-periphery
(Fig. 166.1).1–11 These lesions may fade or enlarge and coalesce
to create multiple areas of whitish subretinal fibrosis
(Fig. 166.2; see also Fig. 166.1).1–11 The progression of
TABLE 166.1. Findings in the Subretinal Fibrosis and Uveitis
Syndrome
Anterior uveitis
Vitritis
Multifocal choroiditis
Subretinal fibrosis
Optic disc edema
Serous and hemorrhagic macular detachment
Cystoid macular edema
Choroidal neovascularization
2131
 RETINA AND VITREOUS
a b
FIGURE 166.1. This 26-year-old woman presented with decreased vision, redness, and pain in both eyes. (a) Slit-lamp examination revealed
conjunctival injection, anterior chamber reaction, posterior synechiae, and a cataract. (b and c) Examination of the fundus showed subretinal
fibrosis.
SECTION 10
a b
c d
subretinal fibrosis may occur over months to years, and relapses
and recurrences are common.
Other findings may include optic disk edema, serous and
hemorrhagic macular detachment, macular hole, cystoid
macular edema, and choroidal neovascularization (CNV).1–11
CNV may occur in up to 44% of patients at some time during
the course of the disease.5,6,8,11 In one study, CNV occurred 2–6
months after the onset of the disease, during the fibrotic stage
of the disease.5–8
FLUOROANGIOGRAPHIC AND
ELECTROPHYSIOLOGIC FINDINGS
Retinal pigment epithelial window defects or mottled hyper-
fluorescence of the acute lesions are observed by fluorescein
2132 angiography in the early stages of this disorder.1–11 The
c
FIGURE 166.2. (a–d) The extensive subretinal
fibrosis that occurs in this syndrome is
illustrated in this patient.
Courtesy of Robert Nussenblatt, MD.
subretinal fibrosis shows late staining.1,2,6 Optic disk leakage
and macular edema may be present. CNV is commonly
observed later in the disease course.5,6,8,11
Electroretinographic signals may be depressed.1,2 The
electrooculogram may be markedly decreased1,2 or normal.6,8
Three patients in one series8 had normal color vision testing
results.
NATURAL HISTORY
In all but one series,8 the visual prognosis of these patients was
poor. Many of these patients had final visual acuities of 20/200
to counting-fingers in the more severely affected eye.5,6,8,10,11
Two case reports documented visual decline to no light
perception.12,13 This poor visual prognosis was confirmed in all
of the other reports except for the series of Morgan and Schatz.8

a b
These authors noted a final vision of 20/20 to 20/70 in patients
treated with oral or periocular corticosteroids and vision of
20/400 in patients who were not treated. The beneficial effect of
steroids or other immunosuppressants is still controversial.
Although some have noted an improvement in vision and
halting of the fibrotic response when steroids were started early
in the disease course, most authors agree that once subretinal
fibrosis occurs, the response to corticosteroids is minimal at
best and the visual prognosis is generally poor.5,6,10,11 The eye
affected first usually has the worst final visual acuity, except in
cases where a subfoveal CNV develops in the second eye.5,6,10
Recurrences are common in this disorder and have been
documented to range from two to seven recurrences per patient.
HISTOPATHOLOGIC AND
IMMUNOHISTOPATHOLOGIC FINDINGS
Histopathologic studies of chorioretinal biopsies from patients
with this condition demonstrated a uveal inflammatory infil-
trate, retinal gliosis, and subretinal fibrosis (Fig. 166.3). 2,3,12,13
The inflammatory infiltrate was composed of plasma cells and
lymphocytes.2,3,12 The subretinal space and choroid contained
complement C3, immunoglobulin G, epithelioid histiocytes,
multinucleated giant cells, noncaseating granulomas, and
fibrin.2,3,12 Stains for bacteria and fungi were negative, and
polymerase chain reaction (PCR) did not detect any herpes
viruses.3,12
Whereas T-cells normally make up 90% of the peripheral
blood lymphocytes, T- and B-cells were found in equal numbers
in the iris, ciliary body, and choroid of patients with this
condition, indicating a large increase in the number of B-cells.3
Within the T-cell population, there was a relative increase in
the number of T-helper cells, whose functions include B-cell
recruitment and granuloma formation.3 Some authors have
proposed an association of the subretinal fibrosis and uveitis
syndrome with sympathetic ophthalmia, on the basis of
histologic similarities.12,13 However, the predominance of
T-cells in sympathetic ophthalmia and B-cells in the subretinal
fibrosis syndrome argues against a close association.12,13
By light microscopy, the retina was gliotic and markedly
attenuated due to loss of photoreceptors and thinning of the
bipolar cell layer.3 The Müller cells were thickened and
expressed class II antigen, suggestive of active proliferation.3
The retinal pigment epithelium was absent and replaced by
amorphous connective tissue.3 Electron microscopy showed
that this subretinal tissue contained retinal pigment epithelial
cells.3 It has been proposed that both the retinal pigment
epithelial cells and the Muller cells are responsible for the
subretinal fibrosis.3
Subretinal Fibrosis and Uveitis Syndrome
FIGURE 166.3. (a) This 18-year-old woman
presented with the subretinal fibrosis and
uveitis syndrome and underwent a chorioretinal
biopsy. (b) Histopathologic examination
revealed a thickened choroid that contained
numerous lymphocytes and plasma cells.
Connective tissue replaced the normal retina.
(c) Histopathologic study in another patient
with the subretinal fibrosis and uveitis
syndrome revealed thick, fibrous tissue
interposed between the markedly gliotic retina
and the choroid.
Courtesy of Chi-Chao Chan, MD and Robert
Nussenblatt, MD.
c
CHAPTER 166
PATHOPHYSIOLOGY
This condition is probably due to a localized autoimmune
antibody-mediated inflammatory process that destroys the
retinal pigment epithelium and may cause massive subretinal
fibrosis.1–3,6,12 These patients have no evidence of systemic
disease. Antibodies against the photoreceptors and the retinal
pigment epithelium have been detected in the serum of affected
patients.12 These antibodies, likely produced by the infiltrating
plasma cells, lead to destruction of the retinal pigment
epithelium and formation of fibrotic tissue.3,12 Activated Müller
cells likely stimulate retinal gliosis and further subretinal
fibrosis.3
TREATMENT
Once subretinal fibrosis occurs, there appears to be no beneficial
treatment.6,10,11 Although controversial, steroids may be useful
early in the disease. Some have documented visual
improvement and halting of the fibrotic response when steroids
were started during the acute phase.5,6,8 However, many more
cases have been reported where patients showed no improve-
ment and their disease continued to progress.10–13 In one series,
there was a dramatic response to systemic and periocular
corticosteroids.8 All nine treated patients showed visual
improvement after treatment (final visual acuity 20/20 to
20/70), whereas the two untreated patients had a poor visual
prognosis (visual acuity of 20/400).8 In this same series, one
patient developed a CNV that appeared to respond to steroid
treatment. In another case series, six of 18 patients responded
with an improvement in visual acuity after treatment with
steroids, but steroids failed to prevent the subfoveal progression
of CNV in the one patient who declined laser treatment for
an extrafoveal CNV.5 Thus, it seems reasonable to consider
steroid treatment for acute cases but not for cases in which
subretinal fibrosis has already occurred.10 Other immuno-
suppressants have been tried as well, but experience using these
for the subretinal fibrosis and uveitis syndrome is limited.
Cyclophosphamide and azathioprine have each been used in
one reported case, but failed to halt the progression of disease in
these two patients, who both already had extensive subretinal
fibrosis at the time of treatment.3,13
DIFFERENTIAL DIAGNOSIS
The acute phase of this condition can mimic many entities,
although the disease is easy to identify once progressive
subretinal fibrosis occurs (Table 166.2). Acutely, the differential
diagnosis includes sarcoidosis, presumed ocular histoplasmosis 2133
 RETINA AND VITREOUS

acute retinal pigment epitheliitis, acute macular neuro-

TABLE 166.2. Differential Diagnosis in the Subretinal Fibrosis
retinopathy, and inflammatory pseudohistoplasmosis. Recently,
and Uveitis Syndrome
a few authors proposed that this condition may, in fact, be a
Sarcoidosis variant of sympathetic ophthalmia based on histopathologic
Presumed ocular histoplasmosis syndrome
similarities; however, the immunohistopathology is very
different in these two conditions and both of the patients
Tuberculosis described in these case reports had prior intraocular surgery.12,13
Syphilis The clinical history, inflammatory reaction, and progression to
subretinal fibrosis can distinguish the subretinal fibrosis and
Birdshot chorioretinopathy
uveitis syndrome from each of these conditions. In the later
Toxoplasmosis stages of this disease, choroidopathies with CNV and disciform
Fungal infections
scarring, such serpiginous choroidopathy, may be confused with
this entity.
Acute posterior placoid pigment epitheliopathy
Serpiginous choroidopathy CONCLUSIONS
Multiple evanescent white dot syndrome
The subretinal fibrosis and uveitis syndrome is a condition that
Diffuse unilateral subacute neuroretinitis generally affects young, otherwise healthy, myopic females in
SECTION 10

Punctate outer retinal toxoplasmosis
Sympathetic ophthalmia
Acute retinal pigment epitheliitis
Acute macular neuroretinopathy
Inflammatory pseudohistoplasmosis
syndrome, tuberculosis, syphilis, birdshot chorioretinopathy,
toxoplasmosis, fungal infections, acute posterior multifocal
placoid pigment epitheliopathy, serpiginous choroidopathy,
multiple evanescent white dot syndrome, punctate inner
choroidopathy, diffuse unilateral subacute neuroretinitis,
punctate outer retinal toxoplasmosis, sympathetic ophthalmia,
which progressive subretinal fibrosis occurs some time after the
onset of a posterior uveitis and choroiditis. CNV and macular
edema may also occur. The visual prognosis is generally poor.
Corticosteroid treatment may be beneficial during the acute
stages of the disorder, and chemotherapy may be considered in
severe cases. However, once subretinal fibrosis occurs, the
visual prognosis and response to treatment is generally poor.
The disease is probably caused by a localized autoimmune
reaction in which antibodies destroy the retinal pigment
epithelium and produce subretinal fibrosis. The condition is
now considered a distinctly separate entity from multifocal
choroiditis and panuveitis, punctate inner chorioretinopathy,
and other chorioretinal inflammatory diseases. Although the
acute stages of this condition may be confused with other types
of choroiditis, the progressive subretinal fibrosis observed
during the late stages distinguishes this disorder from most
other diseases.

REFERENCES
1. Palestine AG, Nussenblatt RB, Parver LM,
Knox DL: Progressive subretinal fibrosis
and uveitis. Br J Ophthalmol 1984;
68:667–673.
2. Palestine AG, Nussenblatt RB, Chan CC,
et al: Histopathology of the subretinal
fibrosis and uveitis syndrome.
Ophthalmology 1985; 92:838–844.
3. Kim MK, Chan CC, Belfort R, et al:
Histopathologic and immunohistopathologic
features of subretinal fibrosis and uveitis
syndrome. Am J Ophthalmol 1987;
104:15–23.
4. Gass JDM, Margo CE, Levy MH:
Progressive subretinal fibrosis and
blindness in patients with multifocal
granulomatous chorioretinitis. Am J
Ophthalmol 1996; 122:76–85.
5. Dreyer RF, Gass JDM: Multifocal choroiditis
and panuveitis: a syndrome that mimics
ocular histoplasmosis. Arch Ophthalmol
1984; 102:1776–1784.
6. Cantrill HL, Folk JC: Multifocal choroiditis
associated with progressive subretinal
fibrosis. Am J Ophthalmol 1986;
101:170–180.
7. Doran RML, Hamilton AM: Disciform
macular degeneration in young adults.
Trans Ophthalmol Soc UK 1982;
102:471–480.
8. Morgan C, Schatz H: Recurrent multifocal
choroiditis. Ophthalmology 1986;
93:1138–1143.
9. Nozik RA, Dorsch W: A new
chorioretinopathy associated with anterior
uveitis. Am J Ophthalmol 1973;
76:758–762.
10. Brown J, Folk JC, Reddy, CV, et al: Visual
prognosis of multifocal choroiditis,
punctuate inner choroidopathy, and the
diffuse subretinal fibrosis syndrome.
Ophthalmology 1996; 103:1100–1105.
11. Kaiser PK, Gragoudas, ES: The subretinal
fibrosis and uveitis syndrome. Int
Ophthalmol Clinics 1996; 36:145–152.
12. Wang RC, Zamir E, Dugel PU, et al:
Progressive subretinal fibrosis and
blindness associated with multifocal
granulomatous chorioretinitis.
Ophthalmology 2002; 109:1527–1531.
13. Lim W, Chee S, Sng I, et al:
Immunopathology of progressive subretinal
fibrosis: a variant of sympathetic
ophthalmia. Am J Ophthalmol 2004;
138:475–477.

2134
 CHAPTER

167 Diffuse Unilateral Subacute Neuroretinitis

J. Michael Jumper, H. Richard McDonald, Robert N. Johnson, Arthur D. Fu, and
Everett Ai

INTRODUCTION In the nearly three decades since the original description,

As he did with many other retinal inflammatory diseases,
J Donald M Gass meticulously investigated and described the
condition he would eventually name diffuse unilateral sub-
acute neuroretinitis (DUSN). For 15 years prior to the ground-
breaking paper in 1978, he and his colleagues had recognized a
“unilateral retinal wipe-out syndrome” in which healthy young
individuals developed: “(1) insidious, usually severe loss of
peripheral and central vision; (2) vitritis; (3) diffuse and focal
pigment epithelial derangement with relative sparing of the
macula; (4) narrowing of the retinal vessels; (5) optic atrophy;
(6) increased retinal circulation time; and (7) subnormal
electroretinographic findings.”1 Further observation led to the
discovery of the earlier findings including: “mild optic nerve
head edema, multifocal areas of active chorioretinitis and
occasionally, iridocyclitis.”1 Later that year, Dr Gass and
colleagues described 12 additional cases of DUSN, two in
whom a motile subretinal nematode was observed.2 Over the
next 5 years, he further studied his and other reported cases3–6
which led to the hypothesis that at:
(1) at least two different nematodes can cause this
syndrome
(2) there are endemic geographic regions for the different sized
nematodes and
(3) laser photocoagulation of the worm can halt disease
progression.7
dozens of papers have been written to identify the likely
pathogens, report cases in other regions of the world and
describe the findings of newer diagnostic tests performed
on patients with DUSN. However, the observations of
Dr Gass and his colleagues have withstood the test of time.
EPIDEMIOLOGY
There have been over 200 cases of DUSN published in the
literature to date, in the form of six case series each containing
4–78 patients with the rest being case reports of one to three
patients (Table 167.1). DUSN is a rare condition and incidence
data is not available. It has been described to occur in the
Southeast,2,6 upper Midwest,5,8 Northeast9,10 and Northwest11,12
United States. Other countries with reported cases include
Canada,13 France,14 Scotland,15 Switzerland,16 Germany,17,18
Senegal,19 Liberia,20 India,21 and China.22 de Souza and
coworkers from Brazil were the first to report cases outside of
the United States or Caribbean Islands.23 Recently, large series
have been published from Venezuela and Brazil.24–26
Meta-analysis of the peer-reviewed literature (209 patients,
216 eyes) reveals an average age at diagnosis of 17.5 years (range
2–84 years) with slight male predominance (60%). Sixty-six
percent of patients are Latino, 27% are Caucasian, 5% are Black
and 2% are Asian. In 53% of cases, the right eye is involved.
Bilateral disease has been reported in 7 patients (4%).2,24,27,28

TABLE 167.1. Meta-Analysis of Diffuse Unilateral Subacute Neuroretinitis

Author No. of Patients M:F Ratio Average Age Worm

(No. of Eyes) (Range) Identified

Gass et al2 37 (38) 22:15 16 (8–41) 2/38

7
Gass and Braunstein 10 6:4 25.5 (13–65) 10/10
Gass et al45 4 2:2 10.5 (4–16) 1/4
24
Cortez et al 78 (82) 45:33 16.7 (7–64) 33/82
25
Souza et al 12 8:4 15.4 (7–36) 4/12
de Garcia et al26 22 12:10 15.6 (5–37) 22/22
Garcia et al43 4 4:0 14.2 (9–23) 4/4
Case reports* 42 (44) 26:16 23.9 (2–84) 38/44

Total 209 (216) 125:84 17.5 years (2–84) 114/216 (52%)

*References 3–6, 8–13, 16, 17, 19, 20, 22, 23, 27, 28, 30–32, 35, 37, 38, 42, 44, 46–49.
2135
 RETINA AND VITREOUS
TABLE 167.2. Clinical Features of Diffuse Unilateral Subacute
Neuroretinitis
Early Stage
Vision loss
Afferent pupillary defect
Anterior chamber cells
Hypopyon (rare)
Vitritis
Optic disk swelling
Optic atrophy (rare)
Retinal arterial narrowing
Intraretinal perivascular exudation
Multifocal evanescent gray-white outer retinal lesions
SECTION 10
Localized serous retinal detachment (rare)
Focal intraretinal hemorrhage (rare)
Choroidal neovascularization (rare)
Subretinal or intraretinal tracks
Motile worm: preretinal (rare), intraretinal, or subretinal
Late Stage
Severe vision loss
Central scotoma
Peripheral visual field abnormalities
Relative afferent pupillary defect
Optic atrophy
Retinal vascular attenuation with or without sheathing
Retinal pigment epithelial derangement
Subretinal macular or peripapillary mass from choroidal
neovascularization (rare)
CLINICAL FEATURES
DUSN typically affects children or young adults (see
Table 167.2). Usually, there are no associated systemic symptoms
although cutaneous and neural larva migrans have been
described in a few patients.8,29 The vision loss, while profound,
is often found incidentally due to the insidious nature of the
disease. In Gass and associates’ original series, half of patients
are unaware of vision loss until the late stages of the disease.2
Of symptomatic patients, the presenting complaint is often
vision loss, central or paracentral scotoma.2 Ocular discomfort
is a less common complaint. The occurrence of symptoms have
been reported to range from 1 day to 4 years prior to
presentation.3,26 The clinical features of DUSN manifest as
early and late stages.
EARLY STAGE
Visual acuity in the early stage of DUSN ranges from 20/20 to
hand motions, the majority being 20/200 or worse. The vision
loss is often out of proportion to the visible changes of the optic
nerve or retina. An afferent pupillary defect was present in 36 of
37 patients in Gass’ original series, regardless of stage.2
In the early stage of DUSN, the external and slit-lamp eye
examination is often normal. Ciliary flush, keratic precipitates,
anterior chamber cell and flare have been described. Two
2136 patients presented with hypopyon.2,30 Vitreous inflammation
FIGURE 167.1. Outer retinal whitening, retinal vasculitis and arteriolar
narrowing in a patient with early stage DUSN.
from mild to severe is always present. Half of patients have mild
optic disk swelling. Optic atrophy has also been described in
the early stage of DUSN.
Early fundus features include retinal arteriole narrowing,
intraretinal perivascular exudation, pigment epithelial depig-
mentation and recurrent, multifocal evanescent gray-white
lesions in the outer retina (Fig. 167.1). Lesions vary in size
from 100 to 1200 mm. The retinitis is typically found in one
sector of the fundus and has been attributed to an inflammatory
reaction against byproducts of the worm. These lesions can
provide a clue as to the worm’s location. The retinitis resolves
in 7–10 days with minimal or no residual retinal changes. The
presence and amount of retinal whitening is dependent on
the activity of the organism. Localized serous retinal detach-
ment, choroidal neovascularization, cystoid macular edema
and focal intraretinal hemorrhages have been described but are
less common.2 Progressive arteriolar narrowing, optic atrophy,
vitreous degeneration and pigment epithelial changes (that
can simulate multifocal choroiditis or an inherited retinal
degeneration) follow in the subacute phase.
A motile intraretinal, subretinal and, in rare cases, intra-
vitreal worm has been described in 52% of all cases in the
literature (Fig. 167.2). These are commonly of two different
lengths depending on the region of the world the disease is
contracted. In the Southeastern United States, Caribbean,
Africa, and South America, the worm is usually 400–1000 mm
in length whereas longer (1500–2000 mm) organisms are found
in the upper Midwest United States, Canada, China, and
Europe. The diameter of the worm typically measures one-
twentieth of its length but an organism measuring 550 mm by
150 mm has been described.12 It is usually nonsegmented,
white, glistening and tapered at both ends. Exposure to the
examination light can cause movement in which the worm is
propelled by coiling and uncoiling or wriggling in a snake-like
manner. The worm often disappears and reappears over time.
More than one worm has been identified in the same eye.24
Living organisms have been identified in the eye several years
after onset of symptoms and a thorough search for a worm
should be carried out on all patients. Occasionally, the worm is
only identified with fundus photography.
 Diffuse Unilateral Subacute Neuroretinitis

a b c

FIGURE 167.2. The 42-year-old Caucasian man from the upper Midwest United States with a 1 month history of blurred left vision (20/100)
presented with (a) mild vitritis, deep retinal gray-white lesions and a motile, subretinal worm measuring 1000 mm in length located inferotemporal
to the fovea (black arrow). (b) Fluorescein angiography revealed multiple hyperfluorescent spots corresponding to areas the worm was seen

CHAPTER 167
migrating. (c) The patient was treated with argon laser photocoagulation (white arrow). Vision returned to 20/30 and remained stable.
Photographs courtesy of George A Williams, MD.

LATE STAGE
In the late or inactive stage of DUSN, vision is typically 20/200
or worse with a dense central scotoma. Visual field deficits can
include the periphery. Optic atrophy and vascular attenuation
(with or without sheathing) are prominent features (Fig. 167.3).
There can be little correlation between the optic nerve changes
and vision such that some patients with severe atrophic
changes can maintain good vision and vice versa. The severity
of arterial and optic nerve changes are usually consistent with
one another. Vascular changes and pigment epithelial alteration
can vary between different quadrants of an eye. While pigment
epithelial disruption is a common feature of DUSN, pigment
migration into the retina (bone spicules) is less common and
not widespread when present. Greater pigment epithelial
alteration has been attributed to the larger worm. A subretinal
mass associated with choroidal neovascularization has been
described in the macula and around the optic nerve.2

DIAGNOSTIC FEATURES
ANGIOGRAPHY
Fluorescein angiography in the early stage of DUSN reveals
normal retinal and choroidal blood flow (see Table 167.3). Optic
disk leakage is often present in eyes with nerve swelling on
clinical examination. Peripheral retinal vascular changes are
rarely seen in patients with active retinitis. Cystoid macular
edema has been described. The focal grey-white retinal lesions
are hypofluorescent in the early phase of the angiogram and
stain later in the course of the study. Pigment epithelial
alterations are visible as window defects but may be subtle
and detected only when comparing the diseased to normal eye
(Fig. 167.4).
In the late stage of DUSN, retinal circulation times may be
delayed. The hyperfluorescence from pigment epithelial atrophy
is most prominent around the optic nerve and in the
midperipheral retina. The macula usually only demonstrates
mottled hyperfluorescence except in cases of disciform scar
formation.
Serial indocyanine green (ICG) angiographic findings have
been described in one patient with DUSN in which a worm was
identified.31 Findings in both the early and late stage of the
disease include hypofluorescence of the clinically visible lesions
in the early and intermediate phases of the study with per-
sistent changes of only a few of the lesions in the late frames of
FIGURE 167.3. Optic atrophy and vascular narrowing in a patient
with 3/200 visual acuity due to late stage DUSN.
Table 167.3. Angiographic Features of Diffuse Unilateral
Subacute Neuroretinitis
Normal retinal and choroidal vascular filling times in the early stage
Delayed retinal circulation time in the late stage
Optic disk leakage
Early blockage and late staining of focal retinitis when present
Window defect from pigment epithelial alterations
Cystoid macular edema (rare)
the study. There was also ill-defined hyperfluorescence in the
macular area in both phases of the disease. The authors suggest
that choroidal infiltration was the cause of the angiographic
pattern.
ELECTROPHYSIOLOGY
Electroretinographic (ERG) abnormalities of only the affected
eye were present in all but one patient in Gass and Scelfo’s 2137
 RETINA AND VITREOUS
a b
original series.1 The unaffected eye is normal in all electro-
physiologic parameters. In the affected eye, both rod and cone
function is typically abnormal, with a reduction of the b:a-wave
ratio, suggestive of proportionately inner retinal injury.
SECTION 10
Electrooculography was noted as subnormal in 16 of 29 in the
original series.
Electrophysiologic deterioration is progressive as suggested
by a case report of a 9-year-old Caucasian boy with serial
electrophysiologic testing over 4 years.32 In this patient (who
had poor vision at presentation), pattern visual-evoked potential
and pattern ERG, indicators of visual pathways and macular
photoreceptor function, respectively, both progressed from
nearly extinguished to undetectable over a year. Full-field ERG
demonstrated progressive inner retinal dysfunction as suggested
by reduced b-wave amplitudes and additional photoreceptor
involvement, but, in keeping with Gass and associates’ findings,
never became completely extinguished.32
Multifocal electroretinography (mfERG) was described in one
patient in early stage DUSN with good vision.9 The decreased
foveal response density as well as the increased parafoveal and
perifoveal waveform amplitudes fully recovered after successful
laser ablation of the parasite.
OTHER STUDIES
There has been no consistently positive serum, urine or stool
assays in patients with DUSN. In an analysis by Gass and
coworkers, serum antibody titers to Toxocara canis by enzyme-
linked immunosorbent assay (ELISA) was present in five of 14
eyes in which the smaller worm was identified.7 None of these
titers met the Centers for Disease Control definition of a
positive test. Eosinophilia is rare in DUSN.
Scanning laser ophthalmoscopy (SLO) has been used to study
four eyes of three patients with DUSN.28 The authors used the
argon blue (488 nm wavelength) laser to provide high contrast
for identification of the worm and helium–neon (633 nm) laser
energy to perform perimetry and identify scotoma associated
with damage associated with the worm. They suggest that SLO
may be more sensitive and better tolerated than clinical
examination or fundus photography in detecting the often
elusive parasite.28
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for DUSN is broad and varies
depending on the stage at presentation. In the early stage of
the disease, optic nerve swelling and vitritis may mimic
intermediate uveitis or optic neuritis. The outer retinal lesions
can be mistaken for multiple evanescent white dot syndrome,
acute posterior multifocal placoid pigment epitheliopathy,
multifocal choroiditis and panuveitis, serpiginous choroiditis,
multifocal outer retinal toxoplasmosis, sarcoidosis, syphilis,
2138 Behçet’s disease or large-cell lymphoma.
FIGURE 167.4. Color fundus photograph
(a) and fluorescein angiogram (b) of retinal
pigment epithelial changes due to subretinal
movement of a worm in a case of DUSN.
In the late stages of the disease when pigment epithelial
derangement, vascular narrowing and optic atrophy are the
predominant features of the disease, the differential diagnosis
includes multifocal choroiditis with panuveitis, central or
ophthalmic artery obstruction, optic neuropathy from a com-
pressive orbital lesion, Behçet’s disease, large cell lymphoma,
inactive acute retinal necrosis, atypical retinitis pigmentosa,
retained ferrous-containing metallic foreign body or post-
traumatic chorioretinopathy. Careful history and serial
ophthalmic examinations will help to differentiate the
conditions listed above from DUSN.
PATHOPHYSIOLOGY
It is accepted that DUSN is a form of ocular larval migrans and
that vision loss is associated with the parasite movement
through and under the retina. The clinical and electrophy-
siology data suggest damage to both the retina and optic
nerve.32 Proposed mechanisms of vision loss include: (1) direct
toxic effects of the worm’s excretory–secretory proteins or
(2) a result of the host inflammatory reaction to the parasite
(3) mechanical damage caused by movement of the worm or
(4) an autoimmune reaction somehow initiated by the
infection.2,7,32
The toxic effect of the worm has been described as both local
and diffuse. The local effects are manifest in the focal, evane-
scent retinal lesions that seem to coincide with the worm’s
migration while the diffuse effects are manifest in the rapid
vision loss and global retinal and optic nerve dysfunction.7
While no specific causative toxin has been identified in DUSN,
eosinophil-derived neurotoxin and major basic protein have
been implicated in neural larval migrans with Baylisascaris
procyonis.33
The exact identity of the parasite in most cases is not known.
Multicellular parasites exist in two distinct phyla: nemahel-
minthes (roundworms or nematodes) and platyhelminthes
(flatworms, containing classes trematoda and cestoda). A large
number of helminthes have the potential to cause ocular
larval migrans. Species implicated in DUSN include several
nematodes: Toxocara canis, Baylisascaris procyonis, Ancylostoma
caninum, Ascaris lumbricoides and Dirofilaria spp.8,29,34–38 One
trematode, Alaria mesocercaria, has been identified as causing
DUSN.12
At least two distinct worms are responsible for DUSN.
Investigators have speculated that the smaller (400–1000 mm)
worm found in Southeast US, the Caribbeans, and South
America is Toxocara canis or Ancylostoma caninum. While
serologic evidence supports the diagonis of T. canis in some
cases, the majority do not have positive serology, eosinophilia or
granuloma characteristic of toxocariasis.6,7,37
Baylisascaris procyonis has been implicated in DUSN due to
the larger (1500–2000 mm) nematode found in the upper
Midwest US, Canada, China and Europe. Investigators have

found retinal lesions consistent with DUSN in animal models
experimentally infected with B. procyonis eggs.39,40 Goldberg
and coworkers describe a case of DUSN in which the patient
had serologic evidence of Baylisascaris exposure and necropsy
of several raccoons around the patient’s home revealed adult
B. procyonis in the intestines and infective eggs in the feces of
8/12 (67%) animals tested. Concurrent ocular and neural larval
migrans have been described in two children with a history of
pica living in an area endemic for raccoons. Both had high
cerebrospinal fluid and serum titers to B. procyonis.
The parasite has been successfully removed via eye wall
resection41 and vitrectomy12,35,38 in a total of four patients.
Identification of surgically removed specimens has proven chal-
lenging. Gass described features of Ancylostoma caninum but
exact identification could not be made. de Souza and coworkers
described the findings of a 630 µ 30 mm worm with morphologic
features most consistent with T. canis but because of poor
fixation, the definite identification remains uncertain.35 Others
who have reviewed photomicrographs of this case have
suggested the organism is Ancylostoma.29 A larger worm
measuring 4500 mm was lost in transport to the parasitology
lab.38 McDonald and coworkers removed and identified a
pathogen as Alaria mesocercaria.12 This is clearly not the cause
of the majority of DUSN cases as the shape (550 µ 190 mm) and
movement differs greatly.
TREATMENT
Laser photocoagulation of the motile worm has been shown to
halt disease progression in DUSN.5,7,10,12,17,20,23,42–44 In 1978,
Raymond and coworkers were the first to report the use of
xenon (one patient) and argon (one patient) laser photo-
coagulation to destroy a motile worm. Vision improvement and
resolution of inflammation was noted in both patients.5
Improved visual acuity with laser photocoagulation has since
been confirmed in early stage DUSN. Garcia reported four
cases treated with laser relatively early in the course of the
disease. The two patients treated within a month of symptom
onset had the best outcomes.43 In a large series of patients
with late stage DUSN, vision stabilization was achieved in 19
of 22 patients, with improvement in only one.26 There have
been no reported complications of laser for DUSN. While
confluent treatment of the larvae has most often been
employed, treatment of the advancing end of the worm has been
a b
FIGURE 167.5. The 29-year-old Caucasian man from Northern California with a 3 week history of right transient visual obscurations. Initial vision
was 20/20 in the right eye with optic nerve swelling and a trace afferent pupillary defect. Serial examination over 6 weeks led to the discovery of
a (a) motile subretinal worm within the macula (magnified in inset). (b) Examination after initial thermal laser phototcoagulation (white arrow)
revealed the worm had moved superotemporal to the fovea. A second session of laser (black arrow) was performed. The motile tail end of the
worm was not treated due to proximity to the fovea. (c) After destruction of the worm, the vision stabilized at 20/25.
Diffuse Unilateral Subacute Neuroretinitis
successful in a case when treatment of the entire worm would
jeopardize the fovea (Fig. 167.5).21
Medical therapy for DUSN has produced mixed results.
Rubin was the first to report using a combination of oral
prednisone (40 mg/day for 3 weeks) and thiabendazole (2 g/day
for 5 days) in a 31 year-old woman with early stage DUSN and
progressive vision loss.6 Three months after treatment the
vision improved from 20/200 to 20/60 and there was reduction
of scotoma size and intraocular inflammation. Subsequently,
Gass and Braunstein reported patients treated with thiaben-
dazole (with or without steroids) or diethylcarbamazine citrate
in which the worm remained viable. They postulated that the
drug could not cross the blood–retinal barrier at larvacidal
concentrations. A later study by Gass and coworkers suggest
that thiabendazole could be effective in some patients,
especially those with moderate or severe vitritis.45 One patient
treated with ivermectin had continued nematode movement
and subsequently required laser photocoagulation.42
CHAPTER 167
Recently, success has been achieved with a 1 month course
of high dose (400 mg/day) albendazole (without corticosteroids)
in patients with the small worm variant of DUSN.25 The
authors report improved inflammation, stable or improved
vision and resolution of worm motility. Cortez and colleagues
treated six patients in which a motile worm was identified
with a 10-day course of albendazole (600 mg/day). The worm
remained viable in half (three) of the patients, necessitating
laser.
CONCLUSION
DUSN represents a form of ocular larva migrans that is likely
caused by many different helminthes and leads to global retinal
and optic nerve dysfunction. Early recognition of the disease is
essential to maintaining, and in some cases, improving vision.
A detailed search for the motile larvae (including serial
biomicroscopy and color fundus photography) should be carried
out in all stages of the DUSN as destruction of the worm can
halt disease progression. While most patients are otherwise
healthy, cutaneous, visceral or neural larva migrans may occur.
Laser photocoagulation should be considered as first-line
therapy in patients in whom the motile larvae are identified,
provided treatment will spare the central macula. For the 50%
of patients in whom a worm cannot be found, a month-long
course of albendazole should be considered.
c
2139
 RETINA AND VITREOUS
REFERENCES
1. Gass JD, Scelfo R: Diffuse unilateral
subacute neuroretinitis. J R Soc Med 1978;
71:95–111.
2. Gass JD, Gilbert WR Jr, Guerry RK,
Scelfo R: Diffuse unilateral subacute
neuroretinitis. Ophthalmology 1978;
85:521–545.
3. PARSONS HE: Nematode chorioretinitis;
report of a case, with photographs of a
viable worm. AMA Arch Ophthalmol 1952;
47:799–800.
4. Price JA Jr, Wadsworth JA: An intraretinal
worm. Report of a case of macular
retinopathy caused by invasion of the retina
by a worm. Arch Ophthalmol 1970;
83:768–770.
5. Raymond LA, Gutierrez Y, Strong LE, et al:
Living retinal nematode (filarial-like)
SECTION 10
destroyed with photocoagulation.
Ophthalmology 1978; 85:944–949.
6. Rubin ML, Kaufman HE, Tierney JP,
Lucas HC: An intraretinal nematode
(a case report). Trans Am Acad Ophthalmol
Otolaryngol 1968; 72:855–866.
7. Gass JD, Braunstein RA: Further
observations concerning the diffuse
unilateral subacute neuroretinitis syndrome.
Arch Ophthalmol 1983; 101:1689–697.
8. Mets MB, Noble AG, Basti S, et al: Eye
findings of diffuse unilateral subacute
neuroretinitis and multiple choroidal
infiltrates associated with neural larva
migrans due to Bbaylisascaris procyonis.
Am J Ophthalmol 2003; 135:888–890.
9. Martidis A, Greenberg PB, Rogers AH,
et al: Multifocal electroretinography
response after laser photocoagulation of a
subretinal nematode. Am J Ophthalmol
2002; 133:417–419.
10. Sivalingam A, Goldberg RE, Augsburger J,
Frank P: Diffuse unilateral subacute
neuroretinitis. Arch Ophthalmol 1991;
109:1028.
11. Goldberg MA, Kazacos KR, Boyce WM,
et al: Diffuse unilateral subacute
neuroretinitis. Morphometric, serologic, and
epidemiologic support for Baylisascaris as
a causative agent. Ophthalmology 1993;
100:1695–1701.
12. McDonald HR, Kazacos KR, Schatz H,
Johnson RN: Two cases of intraocular
infection with Alaria mesocercaria
(Trematoda). Am J Ophthalmol 1994;
117:447–455.
13. Yuen VH, Chang TS, Hooper PL: Diffuse
unilateral subacute neuroretinitis syndrome
in Canada. Arch Ophthalmol 1996;
114:1279–1282.
14. Salvanet-Bouccara A, Troussier H: Diffuse
unilateral subacute neuroretinitis. Apropos
of a case. J Fr Ophtalmol 1987;
10:667–672.
15. Kinnear FB, Hay J, Dutton GN, Smith HV:
Presumed ocular larva migrans presenting
with features of diffuse unilateral subacute
neuroretinitis. Br J Ophthalmol 1995;
79:1140–1141.
16. Bernasconi OR, Piguet B. Unilateral diffuse
subacute neuroretinitis. Klin Monatsbl
Augenheilkd 1997; 210:327–328.
2140
17. Kuchle M, Knorr HL, Medenblik-Frysch S,
et al: Diffuse unilateral subacute
neuroretinitis syndrome in a German most
likely caused by the raccoon roundworm,
Baylisascaris procyonis. Graefes Arch Clin
Exp Ophthalmol 1993; 231:48–51.
18. Meyer-Riemann W, Petersen J, Vogel M:
An attempt to extract an intraretinal
nematode located in the papillomacular
bundle. Klin Monatsbl Augenheilkd 1999;
214:116–119.
19. Rasquin F, Waterschoot MP, Termote H,
Carlier Y: Diffuse unilateral subacute
neuroretinitis in Africa. Ocul Immunol
Inflamm 2006; 14:59–62.
20. Carney MD, Combs JL. Diffuse unilateral
subacute neuroretinitis. Br J Ophthalmol
1991; 75:633–635.
21. Myint K, Sahay R, Mon S, et al: ‘Worm in
the Eye’ – The Rationale for treatment of
DUSN in South India. Br J Ophthalmol 2006;
90:1125–1127.
22. Cai J, Wei R, Zhu L, et al: Diffuse unilateral
subacute neuroretinitis in China. Arch
Ophthalmol 2000; 118:721–722.
23. de Souza EC, da Cunha SL, Gass JD.
Diffuse unilateral subacute neuroretinitis in
South America. Arch Ophthalmol 1992;
110:1261–1263.
24. Cortez R, Denny JP, Muci-Mendoza R,
et al: Diffuse unilateral subacute
neuroretinitis in Venezuela. Ophthalmology
2005; 112:2110–2114.
25. Souza EC, Casella AM, Nakashima Y,
Monteiro ML: Clinical features and
outcomes of patients with diffuse unilateral
subacute neuroretinitis treated with oral
albendazole. Am J Ophthalmol 2005;
140:437–445.
26. de Garcia CA, Gomes AH, Vianna RN,
et al: Late-stage Diffuse Unilateral
Subacute Neuroretinitis: Photocoagulation
of the Worm does not Improve the Visual
Acuity of Affected Patients. Int Ophthalmol
2006; 26:39–42.
27. de Souza EC, Abujamra S, Nakashima Y,
Gass JD: Diffuse bilateral subacute
neuroretinitis: first patient with documented
nematodes in both eyes. Arch Ophthalmol
1999; 117:1349–1351.
28. Moraes LR, Cialdini AP, Avila MP,
Elsner AE: Identifying live nematodes in
diffuse unilateral subacute neuroretinitis by
using the scanning laser ophthalmoscope.
Arch Ophthalmol 2002; 120:135–138.
29. Gass JDM: Stereoscopic atlas of macular
diseases. 4th edn. St Louis: Mosby;
1997:622–628.
30. Muccioli C, Belfort R Jr: Hypopyon in a
patient with presumptive diffuse unilateral
subacute neuroretinitis. Ocul Immunol
Inflamm 2000; 8:119–121.
31. Vianna RN, Onofre G, Ecard V, et al:
Indocyanine green angiography in diffuse
unilateral subacute neuroretinitis. Eye 2006;
20:1113–1116
32. Audo I, Webster AR, Bird AC, et al:
Progressive retinal dysfunction in diffuse
unilateral subacute neuroretinitis. Br J
Ophthalmol 2006; 90:793–4.
33. Moertel CL, Kazacos KR, Butterfield JH,
et al: Eosinophil-associated inflammation
and elaboration of eosinophil-derived
proteins in 2 children with raccoon
roundworm (Baylisascaris procyonis)
encephalitis. Pediatrics 2001; 108:E93.
34. Ashton N: Larval granulomatosis of the
retina due to Toxocara. Br J Ophthalmol
1960; 44:129–148.
35. de Souza EC, Nakashima Y: Diffuse
unilateral subacute neuroretinitis. Report of
transvitreal surgical removal of a subretinal
nematode. Ophthalmology 1995;
102:1183–1186.
36. Kazacos KR, Vestre WA, Kazacos EA,
Raymond LA: Diffuse unilateral subacute
neuroretinitis syndrome: probable cause.
Arch Ophthalmol 1984; 102:967–968.
37. Oppenheim S, Rogell G, Peyser R: Diffuse
unilateral subacute neuroretinitis. Ann
Ophthalmol 1985; 17:336–338.
38. Yamamoto S, Hayashi M, takeuchi S:
Surgically removed submacular nematode.
Br J Ophthalmol 1999; 83:1088.
39. Akao N, Hayashi E, Sato H, et al: Diffuse
retinochoroiditis due to Baylisascaris
procyonis in Monglian gerbils. J Parasitol
2003; 89:174–175.
40. Kazacos KR, Raymond LA, Kazacos EA,
Vestre WA: The raccoon ascarid.
A probable cause of human ocular larva
migrans. Ophthalmology 1985;
92:1735–1744.
41. Gass JDM: Stereoscopic atlas of macular
diseases. 3rd edn. St Louis: CV Mosby;
1987:474–475.
42. Casella AM, Farah ME, Belfort R Jr:
Antihelminthic drugs in diffuse unilateral
subacute neuroretinitis. Am J Ophthalmol
1998; 125:109–111.
43. Garcia CA, Gomes AH, Garcia Filho CA,
Vianna RN: Early-stage diffuse unilateral
subacute neuroretinitis: improvement of
vision after photocoagulation of the worm.
Eye 2004; 18:624–627.
44. Matsumoto BT, Adelberg DA, Del Priore LV:
Transretinal membrane formation in diffuse
unilateral subacute neuroretinitis. Retina
1995; 15:146–149.
45. Gass JD, Callanan DG, Bowman CB: Oral
therapy in diffuse unilateral subacute
neuroretinitis. Arch Ophthalmol 1992;
110:675–680.
46. Myint K, Sahay R, Mon S, et al: The Indian
case of live worm in Diffuse Unilateral
Subacute Neuroretinitis. Eye 2006;
20:612–613.
47. Cialdini AP, de Souza EC, Avila MP:
The first South American case of diffuse
unilateral subacute neuroretinitis caused by
a large nematode. Arch Ophthalmol 1999;
117:1431–1432.
48. Harto MA, Rodriguez-Salvador V, Avino JA,
et al: Diffuse unilateral subacute
neuroretinitis in Europe. Eur J Ophthalmol
1999; 9:58–62.
49. Gass JD: Subretinal migration of a
nematode in a patient with diffuse unilateral
subacute neuroretinitis. Arch Ophthalmol
1996; 114:1526–1527.
 CHAPTER
168 Frosted Branch Angiitis
George N. Papaliodis, Carol M. Lee, and Henry J. Kaplan
Key Features
• Rare clinical entity without an established cause which must
be distinguished from secondary frosted branch angiitis with
identifiable etiologies
• Bilateral retinal vasculitis with profound vascular sheathing
found in young, otherwise healthy patients
• Treatment of choice (after excluding infectious etiologies) is
oral corticosteroids with improvement in vascular sheathing
and resultant visual acuity
INTRODUCTION
Frosted branch angiitis was first described in 1976 by Ito and
co-workers in a 6-year-old healthy boy with severe sheathing of
all the retinal vessels, resembling the frosted branches of a tree.1
Between 1976 and 2005 there have been 57 total cases2–9
reported in the literature with some degree of uncertainty to the
absolute number, given the confusion in the literature regard-
ing the use of the term ‘frosted branch angiitis’.2–29 The initial
clinical presentation of this rare entity may be similar to that
of other more common retinal vasculitides,30–33 and the term
‘frosted branch angiitis’ has been utilized to describe any con-
dition which manifests with severe retinal vascular sheathing.
It is unclear if this condition represents a distinct clinical
syndrome or a sign of severe vasculitis/phlebitis.72 The term
‘frosted branch angiitis’ has been used synonymously with
‘diffuse acute retinal periphlebitis’.6
CLINICAL CHARACTERISTICS
Acute frosted branch angiitis is most commonly a bilateral
retinal vasculitis seen in young, otherwise healthy patients in
the age range of 3–36 years and present with a chief complaint
of decreased visual acuity. Unilateral cases have similarly been
reported in the literature.14,15,20,29 Vision is usually profoundly
affected, with the majority of reported cases presenting with
20/200 vision or worse (range 20/20 to light perception). An
antecedent viral illness has been reported in some cases. On
examination, both anterior chamber and vitreous inflammation
are present in almost all cases without pars plana deposits. The
appearance of bilateral retinal phlebitis and arteritis extending
from the posterior pole to the periphery with uninterrupted
severe sheathing of all the vessels, established the term ‘frosted
branch angiitis’ (Fig. 168.1). Prominent sheathing of the retinal
veins is characteristic of this entity, but the retinal arteries may
similarly be involved (more commonly noted in younger
patients).
Patients with frosted branch angiitis as described by Ito were
young and otherwise healthy. This is in contrast to patients
with ‘frosted branch like appearance’ of the retinal vasculature
in patients with lymphomas or leukemias, and similarly distinct
from patients with an associated viral or autoimmune disease
in which the frosted branch appearance is a clinical sign of
disease severity.72
DIAGNOSTIC TESTS
Fluorescein angiography shows normal blood flow without
evidence of occlusion or stasis but with late staining and leakage
of dye from affected vessels (Fig. 168.2). Additional fundus
findings may include intraretinal hemorrhages, punctate hard
exudates, macular edema, and serous exudative detachments
of the macula or periphery. The retina can appear diffusely
thickened and edematous. It is postulated that these thick
perivascular infiltrates may be a result of immune complex
deposition along the vessel walls.29,34,35
Electrophysiologic testing shows a reduction in the amplitude
of the electroretinogram, which remains reduced even after
convalescence. In contrast, the visual-evoked response is initially
reduced but may return to normal.5,8 Visual-field testing reveals
concentric constriction or relative central defects that improve
after clinical resolution of the vasculitis.
Laboratory investigations have not revealed a single causative
agent in this disease. Moreover, as this entity must be dis-
tinguished from pathologic processes which present as an
exaggerated sheathing of retinal vessels, any condition which
can cause a retinal vasculitis should be included in the differ-
ential diagnosis. Included among the normal laboratory studies
from case reports in the literature were: complete blood cell
count and differential; erythrocyte sedimentation rate; skin test
for tuberculin delayed-type hypersensitivity; determination of
serum antibodies for syphilis, Lyme, toxoplasmosis, human
immunodeficiency virus (HIV), herpes simplex, herpes zoster,
and cytomegalovirus (CMV); urine and blood cultures for
both bacteria and virus; antinuclear antibody determination;
rheumatoid factor; serum protein electrophoresis; immuno-
electrophoresis; and determination of serum angiotensin-
converting enzyme levels. Chest radiograph films, lumbosacral
X-ray films, cerebrospinal fluid examinations, and computed
tomographic scans or magnetic resonance imaging of the head
and orbits have all been normal. One patient demonstrated an
increased serum antistreptolysin O titer.6
MANAGEMENT RECOMMENDATIONS
Frosted branch angiitis responds to systemic steroids with a
rapid resolution of the vascular sheathing, retinal hemorrhages,
and exudative neurosensory retinal detachment (Fig. 168.3).
Systemic steroids (initial dose 80–100 mg oral prednisone in 2141
 RETINA AND VITREOUS

a b
SECTION 10

c d

FIGURE 168.1. (a and b) The most frequent presentation of frosted branch angiitis is bilateral extensive venous sheathing, resembling the
frosted branches of a tree. There is mild pallor of the left optic disk. (c and d) Bilateral retinal phlebitis extends from the posterior pole to the
periphery with uninterrupted severe sheathing of all the vessels. Extensive perivenous exudates associated with intraretinal hemorrhage are
noted in this patient. (Left figures, right eye; right figures, left eye.)

FIGURE 168.2. The fluorescein angiogram

demonstrates normal venous flow in the early
phase (left), with diffuse staining of the vein
walls in the late phase (right).

adults for 10 days) should be initiated once treatable causes in
the differential diagnosis are excluded (most notably infectious
etiologies which may worsen in the context of steroid therapy).
The steroids should subsequently be tapered over several weeks.
Funduscopic sequelae include attenuation of both the arteries
and the veins, the development of sharply demarcated atrophic
lesions in the periphery, and the deposition of yellow subretinal
deposits in areas of previously detached retina.
Recovery to normal vision usually occurs, with a range of
2142 20/15 to –20/40, the majority of cases improving to 20/20 or
better within 2–3 weeks after initiation of treatment. Others
have reported complications prohibiting full visual recovery
including a fibrotic macular scar,6 and central retinal vein
occlusion.19 Remote sequelae have included a horseshoe tear in
one patient and multiple bilateral branch vein occlusions in
another. It is not known whether these complications are
adverse sequelae of frosted branch angiitis or are fortuitous in
their occurrence.6
The natural history of the disease without the use of oral
steroids is not known. One report has shown that the frosted

FIGURE 168.3. Systemic steroids are associated with the rapid resolution of the vascular sheathing, intraretinal hemorrhages, and exudative
neurosensory retinal detachments. A residual scar in the right macula (left figure) of this patient resulted in a permanent decrease in vision to
20/300.
branch angiitis resolved spontaneously without the use of oral
agents and with only topical steroid drops for an anterior uveitis
over a course of 1 week without any permanent retinal sequelae.7
DIFFERENTIAL DIAGNOSIS
Although no specific causative agent has been identified in
frosted branch angiitis, treatable causes of retinal vasculitis
should be excluded before the initiation of corticosteroid treat-
ment (Table 168.1). Conditions associated with a predominant
periphlebitis include tuberculosis, Eales’ disease, sarcoidosis,
multiple sclerosis, and HIV infection, whereas systemic lupus
erythematosus (SLE) and syphilis have been associated with a
predominant inflammation of the arterial tree. Retinal vasculitis
has been reported as a consequence of Lyme borreliosis.30 A
workup for a presumed diagnosis of frosted branch angiitis
revealed ultimately a diagnosis of ocular large cell lymphoma in
TABLE 168.1 Differential Diagnosis of Frosted Branch Angiitis
Disease Laboratory Tests
Sarcoidosis Chest radiograph film, serum calcium and
phosphorus levels, serum angiotensin
converting enzyme determination
Multiple sclerosis Magnetic resonance imaging, cerebrospinal
fluid examination
Pars planitis
Eales’ disease
Tuberculosis Chest radiograph film, tuberculin skin test
Syphilis Venereal Disease Research Laboratory test,
fluorescent treponemal antibody test
Lyme disease Lyme serology, ELISA, Western blot analysis
Systemic lupus Antinuclear antibody, anti DNA determinations
erythematosus
AIDS HIV antibody determination
Bone marrow Complete blood count with differential,
tumefaction vitreous biopsy, cerebrospinal fluid
examination, magnetic resonance imaging
Abbreviations: ELISA, enzyme linked immunosorbent assay; AIDS, acquired
immunodeficiency syndrome; HIV, human immunodeficiency virus.
Frosted Branch Angiitis
CHAPTER 168
one case.31 Another study reported a case of frosted branch
angiitis due to a relapsing acute lymphoblastic leukemia involv-
ing the central nervous system that resolved with appropriate
systemic chemotherapy and local radiotherapy.36 Case reports
have similarly described secondary frosted branch angiitis in
patients with Behçet’s disease,10 herpes simplex virus (types 1
and 2),12,24 CMV retinitis,33–35 toxoplasmosis,13 Harada’s
disease,16 rapidly progressive glomerulonephritis,17 aseptic
meningitis,25 and Crohn’s disease.27
The ocular manifestations of sarcoidosis occur in 15–33% of
cases.36–39 Posterior segment involvement is seen frequently
(14–28%), usually in association with anterior segment disease.
The perivascular sheathing of ocular sarcoid is seen in the
midperiphery, usually without vascular occlusion, and affects
mainly the veins. Severe perivascular sheathing appears as
‘candle wax drippings’. Acute periphlebitis may be accompanied
by intraretinal hemorrhages and edema. Occasionally, branch or
central retinal vein occlusion may occur, with subsequent
peripheral retinal or disk neovascularization.
The vitritis of sarcoidosis consists of clumps of vitreal inflam-
matory cells – ’snowballs’ or ‘strings of pearls’. These clumps of
cells may remain adherent to the posterior vitreous face and
may appear as a sheet. Sarcoid granuloma can be seen in the
deep retina or choroid or on the optic nerve head. Although
the diagnosis of sarcoid should be excluded by a chest CT scan
and determinations of serum angiotensin-converting enzyme
and serum calcium, the associated ophthalmic findings should
help differentiate ocular sarcoidosis associated vasculitis from
frosted branch angiitis.
Retinal venous sheathing is observed in 10–20% of patients
with multiple sclerosis40–45 and is seen either as active periph-
lebitis, with white patchy cuffs surrounding the blood vessel, or
as venous sclerosis. Periphlebitis in multiple sclerosis is occa-
sionally accompanied by pars planitis and frequently resolves
spontaneously without visual symptoms or hemorrhages. Rarely,
severe periphlebitis can lead to peripheral retinal ischemia and
neovascularization. The perivascular infiltrates have been ident-
ified histopathologically to be composed of segmental lympho-
plasmacytic infiltrates within and around the retinal veins.40,44
The diagnosis of multiple sclerosis can be made readily by
magnetic resonance imaging or cerebrospinal fluid examination
with oligoclonal banding. Additionally, the fluffy perivenous
cuffs in multiple sclerosis are quite small, focal, and inter-
rupted, in contrast to the widespread sheathing of the vessels in
frosted branch angiitis. 2143
 RETINA AND VITREOUS
Retinal periphlebitis can be found in association with
peripheral uveitis or pars planitis.46–48 Snowbanks consisting of
fibroglial proliferation and vascular exudation are seen over a
broad area of the inferior peripheral retina; retinal edema,
premacular fibroplasia, and cystoid macular edema are also
observed. The peripheral terminal branches of the retinal veins
are cuffed with white inflammatory material, differentiating
this entity from the diffuse periphlebitis of frosted branch
angiitis.
Tuberculosis commonly produces focal perivenous sheathing
in the peripheral venules, which only occasionally involves
the central retinal vein.49,50 Eales’ disease, which has been
associated with tuberculosis,51 characteristically produces early
capillary closure in the periphery of multiple quadrants of the
retina, with sheathing of the peripheral retinal veins and intra-
retinal hemorrhages. Neovascularization of the retinal periphery
results from the ensuing ischemia, usually at the clearly defined
border between perfused and nonperfused retina. The charac-
SECTION 10
teristic picture of extensive peripheral capillary nonperfusion in
Eales’ disease and the focal perivenular sheathing in tuber-
culosis should help differentiate these entities from frosted
branch angiitis.
The vasculitis of ocular syphilis is generally a periarteritis
with arteriolar sheathing, exudates, and intraretinal and pre-
retinal hemorrhages,52–55 although isolated venous periphlebitis
has also been described.55 The arteriolitis may become occlu-
sive, with eventual sclerosis of the involved arterioles and the
development of peripheral retinal neovascularization. Other
more common manifestations of posterior syphilis include
neuroretinitis, chorioretinitis, and papillitis. The course of ocular
syphilis has been noted to be more aggressive in patients with
associated HIV disease, and as such it is recommended that
patients being evaluated or treated for ocular syphilis be tested
for HIV infection.53,56 Because ocular syphilis can mimic many
diseases, patients with a vasculitis resembling frosted branch
angiitis should have antibody tests for syphilis (the Venereal
Disease Research Laboratory test and the fluorescent trepo-
nemal antibody test).
Retinal periphlebitis has also been described in patients with
Lyme borreliosis.30,57 Lyme disease is a tick-borne infection that
causes a constellation of systemic complaints and manifes-
tations usually within the dermatologic, rheumatologic, cardiac,
and central nervous systems.30,57–61 Ocular manifestations are
generally uncommon, and these usually present in patients
with either established systemic disease or systemic complaints
referable to Lyme disease. The most frequent signs include
conjunctivitis, optic neuritis and neuropathy, papilledema, and
interstitial keratitis.58–61 In the reported cases of retinal vascu-
litis with Lyme disease, the arteries and veins were sheathed but
a b
FIGURE 168.4. (a) Severe sheathing of the vessels is present adjacent to a patch of CMV retinitis along the superotemporal arcade of the left
eye. (b) This sheathing extends to the periphery, giving a frosted branch appearance. (c) Two weeks after induction with antiviral medications,
2144 the sheathing is resolving.
they also appeared occluded and extremely attenuated. This
obliterative feature was confirmed on fluorescein angio-
graphy.30,57 In the laboratory workup, patients seronegative for
Lyme disease may have positive results with the more sensitive
Western blot analysis.57 A careful history should be taken to
identify any exposure to ticks or to reveal any systemic com-
plaints. The presence of associated systemic findings, in areas
endemic for Lyme disease, and the more occlusive nature of the
periphlebitis should help in differentiating this from frosted
branch angiitis.
Retinal vasculitis is a common ophthalmic manifestation of
SLE. Although the most common findings are cotton-wool
spots with or without intraretinal hemorrhages, almost 30% of
patients with SLE will have retinal vasculitis with micro-
angiopathic small-vessel occlusion most often affecting the
arterioles.62 Occasionally, severe retinal occlusive disease can
occur, affecting both the arteries and the veins in association
with anticardiolipin antibodies,63 with subsequent peripheral
retinal neovascularization. Retinal arterial inflammation is also
seen in segmental periarteritis of the retina, in which whitish
plaques are scattered along the main arterial branches.
Surprisingly, fluorescein leakage is seen from the venous but not
from the arterial wall.64 It can be distinguished from frosted
branch angiitis by the generally more limited involvement of
the retinal vascular tree.
The perivasculitis in acquired immunodeficiency syndrome
(AIDS) retinopathy should also be included in the differential
diagnosis of frosted branch angiitis.65–69 Diffuse perivasculitis of
the far-peripheral veins and focal periarteritis can be seen in
patients with AIDS or AIDS-related complex67,68,70 without
concomitant infectious retinopathy. These conditions are more
commonly seen, however, with an associated infectious com-
ponent such as CMV retinopathy (Fig. 168.4).33,35,66 Frosted
branch angiitis has been described in AIDS patients accompany-
ing small areas of CMV retinopathy. Classically, CMV lesions
appear as creamy yellow-white retinal opacifications generally
following the vessel walls and often accompanied by variable
amounts of intraretinal hemorrhage. The vessel walls may be
narrowed, sheathed, or occluded.60 In these patients, treatment
for CMV infection provided resolution of the vasculitic com-
ponent of their retinopathy. The perivascular infiltrates seen in
CMV-related frosted branch angiitis may be due to direct
infection by the CMV of the retinal vessel walls.34 However, this
infiltrate may also be a result of immune complex deposition
within the vascular wall similar to that hypothesized in
conventional cases of frosted branch angiitis.
A case of endogenous Fusarium endophthalmitis diagnosed
by vitrectomy was reported in an intravenous drug user who
initially presented with frosted branch angiitis and vitritis.71 In
c
 Frosted Branch Angiitis

this case, the presence of worsening vitritis and the social
history were helpful in obtaining a correct diagnosis.
Secondary vasculitis with frosted branch appearance has been
described in patients with ocular toxoplasmosis.13,14,21 The
vasculitis from toxoplasmosis is more commonly an arteritis in
the vicinity of the active focus of retinitis.
Finally, bone marrow tumefactions such as leukemia and
non-Hodgkin’s lymphoma (i.e., reticulum cell sarcoma) should
be considered in the presence of diffuse retinal vascular
sheathing.31,32 Intraretinal hemorrhages and cotton-wool spots
are more frequently seen in leukemia, whereas retinal cell
sarcoma can present as a diffuse vitritis, often with accompany-
ing retinal pigment epithelial abnormalities such as multifocal,
yellow, subretinal infiltrates or pigment epithelial detachments.
Underlying the vitreal inflammation may be a diffuse retinal
vasculitis resembling frosted branch angiitis. The diagnosis can
be established by a vitreous biopsy if there is no obvious
systemic evidence of disease.
CONCLUSIONS
In summary, frosted branch angiitis is a bilateral inflammation,
in healthy young individuals, of the retinal arteries and veins,
with the veins being more severely affected. Unilateral cases
have been also described. No cause has been identified which is
distinctly different from patients who have a frosted branch
like appearance from underlying infectious or autoimmune
mediated diseases. Vision is profoundly diminished in the acute
phase, with dramatic improvement after oral corticosteroid
administration. The differential diagnosis is extensive, but
frosted branch angiitis can frequently be distinguished by its
unique clinical presentation and course.

REFERENCES

1. Ito Y, Nakano M, Kyu N, et al: Frosted
branch angiitis in a child. Jpn J Clin
Ophthalmol 1976; 30:797.
2. Sakanishi Y, Kanagami S, Ohara K: Frosted
retinal angiitis in children. Jpn J Clin
Ophthalmol 1984; 38:803.
3. Yamane S, Nishiuchi T, Nakagawa Y, et al:
A case of frosted branch angiitis of the
retina. Folia Ophthalmol Jpn 1985;
36:1822.
4. Higuchi K, Maeda K, Uji T, et al: A case of
infantile uveitis with frosted branch angiitis.
Jpn Rev Clin Ophthalmol 1985; 79:2660.
5. Watanabe Y, Takeda N, Adachi-Usami E:
A case of frosted branch angiitis. Br J
Ophthalmol 1987; 71:553.
6. Kleiner RC, Kaplan HJ, Shakin JL, et al:
Acute frosted retinal periphlebitis. Am J
Ophthalmol 1988; 106:27.
7. Vander JF, Masciulli L: Unilateral frosted
branch angiitis [letter; comment]. Am J
Ophthalmol 1991; 112:477.
8. Hamed LM, Fang EN, Fanous MM, et al:
Frosted branch angiitis: the role of
systemic corticosteroids. J Pediatr
Ophthalmol Strabismus 1992; 29:312.
9. Nakai A, Saika S: A case of frosted branch
retinal angiitis in a child. Ann Ophthalmol
1992; 24:417.
10. Reynders S, Dewachter A, de Vriese AS:
A case of secondary frosted branch angiitis
in Behçet’s disease. Bull Soc Belge
Ophthalmol 2005; 298:41.
11. Liu Y, Ma Z, Tso MO, Zhang Q: Frosted
branch angiitis secondary to macular
choroidal neovascularization in a Chinese
woman. Jpn J Ophthalmol 2005; 49:228.
12. Shenoy R, Elagib EN, Al-Siyabi H:
Frosted retinal branch angiitis in an
immunocompetent adult due to herpes
simplex virus. Indian J Ophthalmol 2001;
49:56.
13. Oh J, Huh K, Kim SW: Recurrent secondary
frosted branch angiitis after toxoplasmosis
vasculitis. Acta Ophthalmol Scand 2005;
83:115.
14. Diaz-Valle D, Diaz-Rodriguez E, Diaz-Valle T,
et al: Frosted branch angiitis and later
peripheral retinochoroidal scar in a patient
with acquired toxoplasmosis. Eur J
Ophthalmol 2003; 13:726.
15. Agrawal S, Agrawal J, Agrawal TP:
Unilateral frosted branch angiitis with
vitreous hemorrhage. Indian J Ophthalmol
2001; 49:269.
16. Matsuo T, Kanata N, Itami M: Frosted
branch angiitis associated with Harada
disease-like manifestations recurs
10 years later. Jpn J Ophthalmol
2002; 46:682.
17. Gupta A, Narang S, Gupta V, et al: Frosted
branch angiitis associated with rapidly
progressive glomerulonephritis. Indian J
Ophthalmol 2002; 50:317.
18. Huerva V, Puig T, Sanchez MC, et al: A new
case of acute idiopathic frosted branch
angiitis in Europe. Eur J Ophthalmol 2002;
12:127.
19. Kaburaki T, Nakamura M, Nagasawa K,
et al: Two cases of frosted branch angiitis
with central retinal vein occlusion. Jpn J
Ophthalmol 2001; 45:628.
20. Fine HF, Smith JA, Murante BL, et al:
Frosted branch angiitis in a child with
HIV infection. Am J Ophthalmol 2001;
131:394.
21. Ysasaga JE, Davis J: Frosted branch
angiitis with ocular toxoplasmosis. Arch
Ophthalmol 1999; 117:1260.
22. Biswas J, Raizada S, Gopal L, et al:
Bilateral frosted branch angiitis and
cytomegalovirus retinitis in acquired
immunodeficiency syndrome. Indian J
Ophthalmol 1999; 47:195.
23. Luo G, Yang P, Huang S, et al: A case
report of frosted branch angiitis and its
visual electrophysiology. Doc Ophthalmol
1998–99; 97:135.
24. Markomichelakis NN, Barampouti F,
Zafirakis P, et al: Retinal vasculitis with a
frosted branch angiitis-like response due to
herpes simplex virus type 2. Retina 1999;
19:455.
25. Johkura K, Hara A, Hattori T, et al: Frosted
branch angiitis associated with aseptic
meningitis. Eur J Neurol 2000; 7:241.
26. Seo MS, Woo JM, Jeong SK, et al:
Recurrent unilateral frosted branch angiitis.
Jpn J Ophthalmol 1998; 42:56.
27. Sykes SO, Horton JC: Steroid responsive
retinal vasculitis with a frosted branch
appearance in Crohn’s disease. Retina
1997; 17:451.
28. Quillen DA, Stathopoulos NA,
Blankenship GW, et al: Lupus associated
frosted branch periphlebitis and exudative
maculopathy. Retina 1997; 17:449.
29. Sugin SL, Henderly DE, Friedman SM:
Unilateral frosted branch angiitis. Am J
Ophthalmol 1991; 111:682.
CHAPTER 168
30. Smith JL, Winward KE, Nicholson DF, et al:
Retinal vasculitis in Lyme borreliosis. J Clin
Neuroophthalmol 1991; 11:7.
31. Ridley ME, McDonald HR, Sternberg P, et al:
Retinal manifestations of ocular lymphoma
(reticulum cell sarcoma). Ophthalmology
1992; 99:1153.
32. Kim TS, Duker JS, Hedges TR: Retinal
angiopathy resembling frosted branch
angiitis in a patient with relapsing acute
lymphoblastic leukemia. Am J Ophthalmol
1994; 117:806.
33. Geier SA, Nasemann J, Klauss V, et al:
Frosted branch angiitis in a patient with the
acquired immunodeficiency syndrome. Am
J Ophthalmol 1992; 113:203.
34. Spaide RF, Vitale AT, Toth IR, et al: Frosted
branch angiitis associated with
cytomegalovirus retinitis. Am J Ophthalmol
1992; 113:522.
35. Rabb MF, Jampol LM, Fish RH, et al:
Retinal periphlebitis in patients with
acquired immunodeficiency syndrome with
cytomegalovirus retinitis mimics acute
frosted retinal periphlebitis. Arch
Ophthalmol 1992; 110:1257.
36. Obenauf CD, Shaw HE, Sydnor CF, et al:
Sarcoidosis and its ophthalmic
manifestations. Am J Ophthalmol 1978;
86:648.
37. Jabs DA, Johns CJ: Ocular involvement in
chronic sarcoidosis. Am J Ophthalmol
1986; 102:297.
38. Spalton DJ, Sanders MD: Fundus changes
in histologically confirmed sarcoidosis. Br J
Ophthalmol 1981; 65:348.
39. Smith JA, Foster CS: Sarcoidosis and its
ocular manifestations. Int Ophthalmol Clin
1996; 1:109.
40. Arnold AC, Pepose JS, Hepler RS, et al:
Retinal periphlebitis and retinitis in multiple
sclerosis. Ophthalmology 1984; 91:255.
41. Barnford CR, Ganley JP, Sibley WA, et al:
Uveitis, perivenous sheathing and multiple
sclerosis. Neurology 1978; 28:119.
42. Rucker CW: Sheathing of the retinal veins
in multiple sclerosis: review of the pertinent
literature. Mayo Clin Proc 1972; 47:335.
43. Vine AK: Severe periphlebitis, peripheral
retinal ischemia, and preretinal
neovascularization in patients with multiple
sclerosis. Am J Ophthalmol 1992; 113:28.
44. Kerrison JB, Flynn T, Green WR: Retinal
pathologic changes in multiple sclerosis.
Retina 1994; 14:445.
2145
 RETINA AND VITREOUS
45. Birch MK, Barbosa S, Blumhardt LD, et al:
Retinal venous sheathing and the blood-
retinal barrier in multiple sclerosis. Arch
Ophthalmol 1996; 114:34.
46. Brockhurst RJ, Schepens CL, Okamura ID,
et al: Uveitis II. Peripheral uveitis: clinical
description, complications, and differential
diagnosis. Am J Ophthalmol 1966;
49:1257.
47. Wetzig RP, Chan CC, Nussenblatt RB, et al:
Clinical and immunopathological studies of
pars planitis in a family. Br J Ophthalmol
1988; 72:5.
48. Malinowski SM, Pulido JS, Folk JC: Long-
term visual outcome and complications
associated with pars planitis.
Ophthalmology 1993; 100:818.
49. Fountain JA, Werner RB: Tuberculous
retinal vasculitis. Retina 1984; 4:48.
50. Helm CJ, Holland GN: Ocular tuberculosis.
Surv Ophthalmol 1993; 38:229.
SECTION 10
51. Renie WA, Murphy RP, Anderson KC, et al:
The evaluation of patients with Eales’
disease. Retina 1983; 3:243.
52. Crouch ER, Goldberg MF: Retinal
periarteritis secondary to syphilis. Arch
Ophthalmol 1975; 93:384.
53. Tamesis RR, Foster CS: Ocular syphilis.
Ophthalmology 1990; 97:1281.
54. Schlaegel RF, Kao SF: A review
(1970–1980) of 28 presumptive cases of
syphilitic uveitis. Am J Ophthalmol 1982;
93:412.
2146
55. Lobes LA, Folk JC: Syphilitic phlebitis
simulating branch vein occlusion. Ann
Ophthalmol 1981; 13:825.
56. McLeish WM, Pulido JS, Holland S, et al:
The ocular manifestations of syphilis in the
human immunodeficiency virus type
I-infected host. Ophthalmology 1990;
97:196.
57. Karma A, Seppala I, Mikkila H, et al:
Diagnosis and clinical characteristics of
ocular Lyme borreliosis. Am J Ophthalmol
1995; 119:127.
58. Winward KE, Smith JL, Culbertson WW,
et al: Ocular Lyme borreliosis. Am J
Ophthalmol 1989; 108:651.
59. Winterkorn JMS: Lyme disease: neurologic
and ophthalmic manifestations. Surv
Ophthalmol 1990; 35:191.
60. Rosenbaum JT, Rahn DW: Prevalence of
Lyme disease among patients with uveitis.
Am J Ophthalmol 1991; 112:462.
61. Breeveld J, Kuiper H, Spanjaard L, et al:
Uveitis and Lyme borreliosis. Br J
Ophthalmol 1993; 77:480.
62. Lanham JG, Barrie T, Kohner EM, et al:
SLE retinopathy: evaluation by fluorescein
angiography. Ann Rheum Dis 1982; 41:473.
63. Jabs DA, Fine SL, Hochberg MC, et al:
Severe retinal vaso-occlusive disease in
systemic lupus erythematosus. Arch
Ophthalmol 1986; 104:558.
64. Orzalesi N, Ricciardi L: Segmental retinal
periarteritis. Am J Ophthalmol 1971; 72:55.
65. Holland GN, Pepose JS, Pettit TH, et al:
Acquired immune deficiency syndrome –
ocular manifestations. Ophthalmology
1983; 90:859.
66. Jabs DA, Green WR, Fox R, et al: Ocular
manifestations of acquired immune
deficiency syndrome. Ophthalmology 1989;
96:1092.
67. Kestelyn P, Van de Perre P, Rouvroy D, et al:
A prospective study of the ophthalmologic
findings in the acquired immune deficiency
syndrome in Africa. Am J Ophthalmol 1985;
100:230.
68. Kestelyn P, Lepage P, Van de Perre P:
Perivasculitis of the retinal vessels as an
important sign in children with AIDS-related
complex. Am J Ophthalmol 1985; 100:614.
69. Holland GN: Acquired immunodeficiency
syndrome and ophthalmology: the first
decade. Am J Ophthalmol 1992; 114:86.
70. McClusky PJ, Wakefield D: Posterior uveitis
in the acquired immunodeficiency system.
Int Ophthalmol Clin 1995; 35:1.
71. Gabriele P, Hutchins RK: Fusarium
endophthalmitis in an intravenous drug
abuser. Am J Ophthalmol 1996; 122:119.
72. Kleiner RC: Frosted branch angiitis: clinical
syndrome or clinical sign? Retina 1997;
17:370.
 CHAPTER
169 Retinal Manifestations of the Rheumatic Diseases
Amitabh K. Bharadwaj, Carl D. Regillo, and E. Mitchel Opremcak
Rheumatologic disorders are a collection of inflammatory
diseases which are typically multisystemic with protean mani-
festations. Rheumatologic diseases include the arthritides, the
connective tissue diseases, and the vasculitides (Table 169.1).
Despite the many clinical and pathologic presentations which
exist, these diseases are so named because of the involvement
of these supportive structures. It is not uncommon for the eyes
to be inflamed in many of these rheumatologic syndromes;
indeed, ocular inflammation is often considered a major diag-
nostic criterion for establishing a clinical diagnosis in several of
these disorders.
An accurate understanding of the connective tissue proper is
required to appreciate ocular involvement in rheumatic diseases.
Connective tissues and structures are the matrix that support
individual cells, tissues, and organs. This ground substance is
produced by specialized connective tissue cells that secrete
various fibers (collagens, reticulin, and elastin), as well as a group
of mucopolysaccharides called proteoglycans.1 Hyaluronic acid,
chondroitin sulfate, dermatan sulfate, keratan sulfate, and
heparin sulfate are the common polysaccharides found in the
connective tissue proteoglycans.2 Collagen fibers can also be
further subdivided by their polypeptide structure into six types
(collagen types I to VI).3 Each tissue and organ maintains a
distinct connective tissue environment by varying these
individual components, thereby effecting optimal structure and
TABLE 169.1. Rheumatic Diseases With Ocular Involvement
Arthritides
Rheumatoid arthritis
Seronegative spondyloarthropathies (HLA-B27 associated)
Ankylosing spondylitis
Reiter’s syndrome
Psoriatic arthritis
Inflammatory bowel disease
Juvenile rheumatoid arthritis
Connective Tissue Diseases
Systemic lupus erythematosus
Progressive systemic sclerosis
Polymyositis and dermatomyositis
Sjögren’s syndrome
Relapsing polychondritis
Vasculitides
Polyarteritis nodosa
Churg–Strauss syndrome
Wegener’s granulomatosis
Hypersensitivity vasculitis
Lymphomatoid granulomatosis
Giant-cell arteritis
Behçet’s disease
function. In rheumatologic diseases, inflammation of these
supportive structures and milieu results in tissue and organ
dysfunction.
The eye, perhaps more than any other organ, maintains a
unique connective tissue environment. Corneal keratocytes
secrete both type II and type IV collagen, as well as chondroitin
and keratan sulfate.1,4 This connective tissue combination
results in strong tissue that becomes transparent as a result of
unique lamellar fiber orientation and active endothelial cell
dehydration. Hyalocytes in the vitreous produce hyaluronic acid
and type II collagen, which forms a clear gel, allowing
transmission of light, and provides support for the globe and
retina.1,5 The retina and choroid possess connective tissue and
a complex vascular system that is composed of type III and type
IV collagen.1 These circulations are critical for retinal function
and general nutrition of the eye. Each of these ocular tissues
performs critical functions in the visual system and is
exquisitely sensitive to inflammation.
Different connective tissues and structures within the eye
can become inflamed in the various rheumatic diseases.
Wegener ’s granulomatosis, rheumatoid arthritis (RA), and
polyarteritis nodosa (PAN) can affect the cornea and produce
peripheral ulcerative keratopathy. Reiter’s syndrome is defined
by the triad of urethritis, arthritis, and inflammation of the
conjunctiva and iris. Ankylosing spondylitis, Reiter’s syndrome,
psoriatic arthritis, and the chronic inflammatory bowel diseases
produce an acute iridocyclitis. Juvenile rheumatoid arthritis
(JRA) commonly produces a chronic iridocyclitis. It is
important, therefore, to evaluate all patients who present with
ocular inflammation for symptoms and signs of an underlying
rheumatologic disease.
Often, rheumatic diseases present in the eye before the onset
of significant systemic involvement. The eye may even be the
primary target of several diseases such as Behçet’s syndrome,
Reiter’s disease, and ankylosing spondylitis. The importance of
performing a careful review of systems and physical examin-
ation cannot be underestimated. Particular attention should be
paid to the skin, joints, central nervous system, lungs, gastro-
intestinal tract, and kidneys. Often, involvement of these
systems can lead the ophthalmologist to establish the existence
of an underlying rheumatic disease as the cause for the ocular
inflammation. For example, iritis in a patient complaining of
large-joint arthritis could represent JRA, systemic lupus erythe-
matosus (SLE), Wegener’s granulomatosis, or Behçet’s disease.
Oral ulcers, malaise, skin rash, and uveitis may be found in
SLE, Behçet’s disease, and sarcoidosis. Genital–urethral pain
and uveitis may represent Behçet’s disease, PAN, or Reiter’s
syndrome. Laboratory evaluation and consultation with an
internist or a rheumatologist can help confirm the presence of
a rheumatologic disease and result in diagnosis and the 2147
 RETINA AND VITREOUS
initiation of proper systemic therapy. Local ocular therapy in
rheumatic disorders without attention to the underlying
systemic process universally results in suboptimal control of the
ocular inflammation and risks potentially life-threatening
complications of uncontrolled systemic disease.
In summary, rheumatic diseases provide an opportunity for
the ophthalmologist to interface with both the patient and the
internist. The expertise of the ophthalmologist in determining
the specific ocular tissue involved and the rheumatologist’s
knowledge of the systemic manifestations can not only
facilitate the proper diagnosis but can also provide optimal care
for these diseases of vision, which are often life-threatening.
RHEUMATOID ARTHRITIS
Key Features
• Chronic idiopathic systemic inflammatory disease
SECTION 10
• More common in females
• Malaise, fatigue, weight loss, and arthralgia
• Typically involves small joints of the wrist and hand
• Anterior segment findings more common
• Posterior scleritis may secondarily cause retinal striae and
exudative retinal detachment
RA is a chronic systemic inflammatory disease of unknown
cause, producing a distinct form of polyarticular and symmetric
arthritis. It is more common in women (3:1) and typically
begins between the ages of 30 and 40 years.6 RA is thought to
have a strong autoimmune pathogenesis. Patients with RA have
immunoglobulin (Ig) M, IgG, and IgA antibodies that are
directed against the Fc portion of IgG.7 The resulting immune
complexes are postulated to mediate both the articular and the
extraarticular manifestations of the disease through activation
of complement.
Patients with RA complain of malaise, fatigue, weight loss,
and arthralgia. The joint disease is symmetric and often involves
the small joints of the wrist and hand, excluding the distal
interphalangeal joints.1 Morning stiffness is characteristic.
Extraarticular involvement in RA, including pleurisy, neuro-
pathy, and ocular inflammation, is thought to be secondary to
systemic vasculitis and may represent a change from a local
joint disease to a more serious systemic form of RA.
The most common anterior segment findings in RA are
keratoconjunctivitis sicca, marginal keratitis, peripheral ulcer-
ative keratopathy, and anterior scleritis.8 Uveitis and direct
involvement of the retina are rare. The retina can, however, be
involved secondarily after the development of posterior scleritis.
Forty-six percent of patients with scleritis will have an
a b
2148
associated underlying rheumatic disease.9 While the differential
diagnosis also includes conditions such as Wegener’s granulo-
matosis, relapsing polychondritis, and PAN, up to 30% of such
patients will have RA.
Posterior scleritis is not as common as anterior scleral
inflammation. This condition is defined as scleritis posterior to
the equator of the eye, and in one series accounted for only 2%
of all cases.10,11 It is important to recognize, however, that
posterior scleritis is much more difficult to detect than anterior
scleritis. In one report of 30 eyes enucleated for ocular inflam-
mation, 40% had previously undetected posterior scleritis.12
Posterior scleritis can be unilateral and is often associated
with a profound decrease in visual acuity. There is pain and
tenderness with motion or palpation. On biomicroscopic
examination, the anterior segment is often normal or may show
only a narrow angle resulting from displacement by the
posterior structures.
The fundus examination in posterior scleritis reveals
choroidal thickening or choroidal nodules overlying the area of
scleritis. Secondary choroidal folds and effusions may develop.
The retina may demonstrate secondary striae and exudative
retinal separations (Fig. 169.1).11 A high index of suspicion is
often required to make a clinical diagnosis of posterior scleritis.
Ultrasonography or computed tomography can support this
diagnosis by showing thickening of the sclera and choroid.
There may be fluid in the contiguous Tenon space. Fluorescein
angiography illustrates the choroidal and retinal striae. A
characteristic linear pattern of alternating hypo- and hyper-
fluorescent streaks can be seen as a result of folds in the retinal
pigment epithelial layer (see Fig. 169.1b). Multifocal, punctate,
hyperfluorescent choroidal lesions can also be noted and may
evolve into areas of exudative retinal detachment. The retinal
circulation is typically unaffected.
Once a clinical diagnosis of posterior scleritis is established,
a search for an underlying cause is in order. A general physical
examination and review of systems can help establish extra-
ocular involvement. Patients with the characteristic deforming
arthritis associated with RA seldom present a diagnostic
challenge. Mild anemia, elevation of the erythrocyte sedimenta-
tion rate (ESR), and a positive result for rheumatoid factor in
serum may support the clinical diagnosis. Without obvious
systemic findings, scleritis may be the initial manifestation of
occult rheumatic disease.
Therapy for rheumatoid scleritis should be directed at
controlling the underlying systemic disease.10 Local ocular
therapy and regional steroids should be used with caution and
only as adjuncts to systemic treatment. Regional steroids
should be used only in extenuating circumstances, as they have
been reported to cause scleral melting and ocular perforation.
Mild cases can often be effectively managed by nonsteroidal
FIGURE 169.1. Posterior scleritis in a patient
with rheumatoid arthritis with secondary
thickening of the choroid in the posterior pole
and peripapillary area. (a) Chorioretinal striae in
the macula. (b) Alternating hypofluorescent and
hyperfluorescent linear streaks correspond to
folding of the retinal pigment epithelium.

antiinflammatory agents. Indomethacin (50–150 mg/day) has
been reported to be particularly effective for scleritis.9 The goal
of early aggressive therapy is to prevent permanent damage
from the disease. In more severe cases, immunosuppressive
drugs such as methotrexate, azathioprine, or one of the newer
biologic agents should be considered. The biologic agents are
designed to block cytokines or cytokine receptors, and include
medicines that decrease the activity of tumor necrosis factor-
alpha (etanercept, adalimumab, and infliximab) and an
interleukin-1 receptor antagonist (anakinra).13,14 Oral prednisone
may be used adjunctively as a bridge to a steroid-sparing agent.
The ocular and systemic prognoses depend in part on
establishing the proper diagnosis and detecting the underlying
rheumatic disease. In a report by Foster and associates, the
development of necrotizing scleritis forbode a more severe form
of RA.15 They noted an 8-year mortality rate of 20% in patients
with this extraarticular involvement.
SERONEGATIVE
SPONDYLOARTHROPATHIES
(HLA-B27-ASSOCIATED)
Key Features
• Ankylosing spondylitis, Reiter’s syndrome, psoriatic arthritis,
and arthritis associated with inflammatory bowel disease
• Acute, recurrent, anterior uveitis
• Posterior segment findings: vitritis, papillitis, cystoid macular
edema, vasculitis, and epiretinal membrane
The group of collagen vascular diseases have in common
spondylitis and a strong association with HLA-B27. Ankylosing
spondylitis, Reiter’s syndrome, psoriatic arthritis, and arthritis
associated with chronic inflammatory bowel disease (Crohn’s
disease and ulcerative colitis) compose this group. Patients with
these disorders experience an acute, alternating, recurrent,
nongranulomatous iridocyclitis. This anterior segment inflam-
mation can be severe, with hypopyon and posterior synechiae
formation. Secondary glaucoma and cataract are not uncommon.
These collagen vascular diseases do not have marked posterior
segment involvement in the form of primary choroiditis,
retinitis, or retinal vasculitis. Cystoid macular edema can occur
with prolonged or severe cases of anterior uveitis, and this may
respond to therapies designed to address the iridocyclitis.
Crohn’s disease has been reported with uveitis and severe
bilateral obliterative retinal vasculitis.16–18 In one series, 29 of
166 (17%) patients with HLA-B27-associated uveitis had
posterior segment manifestations including vitritis (93%),
papillitis (83%), vasculitis (24%), cystic macular edema (38%),
and epiretinal membrane (17%).19 In this report, the retinal
vasculitis was responsive to corticosteroids or cyclophospha-
mide therapy, or a combination of these medicines.
JUVENILE RHEUMATOID ARTHRITIS
Key Features
• Childhood disease with multisystemic involvement
• Ocular inflammation may precede or follow arthritis
• Chronic, bilateral iridocyclitis
• Pauciarticular arthritis is a risk factor for development of ocular
inflammation
• Cyclitic membranes may form after standard cataract surgery
JRA is a multisystemic childhood disease associated with
chronic arthritis. JRA is much more common in girls and
Retinal Manifestations of the Rheumatic Diseases
occurs typically between the ages of 2 and 5 years. The cause of
JRA is unknown, but it is thought to be a primary autoimmune
disease. Children with the pauciarticular form of JRA have the
highest risk for the development of ocular inflammation.20 Over
80% of such children are ANA positive.
Chronic iridocyclitis develops in 5–17% of children with
JRA.21 Eye disease may precede the development of arthritis by
several years. Ocular involvement may be insidious because of
the lack of symptoms and ocular signs early in the disease. JRA-
associated iridocyclitis is typically chronic and bilateral (70%).
The inflammation is usually nongranulomatous and involves
primarily the iris and ciliary body. Chronic inflammation
commonly results in band keratopathy (41%), posterior
synechiae, glaucoma (19%), and cataract formation (42–92%).22
In JRA the retina and choroid are involved to a much lesser
extent than the anterior segment. Cystoid macular edema may
develop in patients with JRA. As a result of chronic cyclitis,
organization and fibrosis of the anterior vitreous may occur,
CHAPTER 169
resulting in further media opacification. Cyclitic membrane
formation and ocular hypotony can develop spontaneously after
standard cataract surgery. True retinitis, retinal vasculitis, or
choroiditis is uncommon in JRA.
JRA can be diagnosed in children with a characteristic arthritic
and ocular picture. The diagnosis can be further supported by
documenting a positive antinuclear antibody (ANA) level (79%)
and a negative result for rheumatoid factor in serum.23 Topical
corticosteroids and cycloplegics are the mainstay of therapy for
children with JRA-associated ocular inflammation. Oral
nonsteroidal antiinflammatory agents are useful in controlling
both the ocular and systemic symptoms.24 Regional corti-
costeroids can be used for ocular inflammation but are difficult
to deliver in this age group and often require general anesthesia.
Methotrexate, cyclosporine, or other immunosuppressive agents
should be considered in patients whose eyes cannot be quieted
by the above methods. Oral corticosteroids (1 mg kg–1 day–1)
may be helpful while transitioning to a steroid-sparing agent.
Due to the monitoring that is needed while on, immuno-
suppressive agents these potentially toxic medicines should be
used under the direction of physicians who have experience
with their use.
The overall visual prognosis in JRA is poor. Seventy-five
percent of children with JRA have moderate or severe
inflammation with loss of vision due to glaucoma, cataract, or
phthisis.1,25 Lens and vitreous opacification should be
addressed, preferably via pars plana lensectomy and vitrectomy,
to afford better control of the inflammation and prevent cyclitic
membrane formation and hypotony.15,26
SYSTEMIC LUPUS ERYTHEMATOSUS
Key Features
• Most patients are women around child-rearing age
• Malaise, fatigue, anorexia, and lowgrade fever
• Arthritis, facial rash, Raynaud’s phenomenon, and oral ulcers
may be present
• Anterior findings: keratoconjunctivitis sicca, scleritis, and
keratitis
• Posterior findings: cotton wool spots, vascular occlusions,
retinal vasculitis, neovascularization, choroidopathy
SLE is a collagen vascular disease with protean manifestations.
Ninety percent of patients with SLE are women at or around
child-rearing age.27 The pathogenesis of SLE appears to be an
autoimmune systemic necrotizing vasculitis. Patients with SLE
have ANAs and elevated levels of circulating immune com-
plexes that appear to play a role in the disease.27 Immune 2149
 RETINA AND VITREOUS
complexes composed of these autoantibodies and DNA have
been found in the walls of inflamed blood vessels and in the
areas of fibrinoid necrosis.
Clinically, patients with SLE present with malaise, fatigue,
anorexia, and low-grade fever. On examination, they may have
arthritis, facial rash, alopecia, and pleurisy.28 Raynaud’s pheno-
menon, oral ulcers, and central nervous system complaints are
also common. Laboratory evaluation may reveal anemia, an
elevated ESR, the presence of ANAs, proteinuria, and a false-
positive Venereal Disease Research Laboratory (VDRL) result.
Lupus nephritis and central nervous system involvement
represent serious and potentially fatal complications of SLE.
SLE may involve the eye in up to 50% of cases, depending on
the series and the nature of the clinic reporting the findings.29
Anterior segment findings include keratoconjunctivitis sicca,
scleritis, and keratitis. The retina and choroid may be primarily
involved; however, it is important to separate lupus-associated
retinal vasculitis from the secondary retinal and choroidal
SECTION 10
changes of SLE-mediated hypertension and anemia. Severe
hypertension can occur in lupus as a result of nephritis.
Arteriolar narrowing, intraretinal hemorrhages, exudate, and
disk edema are characteristic of hypertensive retinopathy.
The mechanism of primary lupus retinopathy is unknown
but is thought to be secondary to circulating immune com-
plexes found in the disease. Ten percent of patients with SLE
also have lupus anticoagulant antibodies that are known to
increase the incidence of thrombosis. The relationship between
this factor and lupus retinopathy is unclear but provocative.30
Retinal manifestations of SLE are a result of focal ischemia and
necrotizing retinal vasculitis. Three fundus presentations have
been described.31–33 The most common form is focal ischemia
resulting in multiple cotton wool spots. Intraretinal hemorr-
hages and mild disk edema can also be associated with this
form of lupus retinopathy. A second form of retinopathy noted
in SLE is a severe retinal vasoocclusive disease without evidence
of retinal vasculitis.32 Retinal infarction and hemorrhage can
result in severe and sudden loss of vision. The third form
of retinopathy in SLE is proliferative lupus retinopathy
(Fig. 169.2a,b). Retinal vasculitis and secondary ischemia
produce neovascularization of the optic nerve and elsewhere in
the retina.33 This neovascularization can result in vitreous
hemorrhage and even retinal detachment.
The choroidal circulation may be involved in this process as
well (see Fig. 169.2c,d).34,35 Choroidal infarction, exudative
changes, central serous chorioretinopathy, and subretinal
neovascular membranes have been reported with SLE. Focal
choroidal vessel injury with secondary dysfunction of the
overlying retinal pigment epithelial cells is believed to be one of
the mechanisms in this form of ocular disease.35
SLE is a clinical diagnosis. The American Rheumatologic
Association defines the disease by the presence of four of the 14
major symptoms and signs. Laboratory testing may support the
clinical diagnosis by revealing the presence of ANAs, elevated
circulating immune complexes, proteinuria, anemia, and a
false-positive VDRL test result. Fluorescein angiography may
help define the extent of retinal involvement and may assist in
differentiating secondary hypertensive retinopathy from the
true retinal vasculitis noted in lupus retinopathy.
Therapy for SLE varies according to the severity of the
systemic symptoms. It is important to note that lupus may
present in the eye 1–5 years before the onset of other systemic
findings.36 Lupus retinopathy may respond to systemic therapy,
including nonsteroidal antiinflammatory agents, oral corti-
costeroids, hydroxychloroquine, gold, and cyclophosphamide.37
Proliferative lupus retinopathy can be treated with panretinal
laser ablation to help control the consequences of ocular
2150 neovascularization.
PROGRESSIVE SYSTEMIC SCLEROSIS
Key Features
• Autoimmune disorder with multisystemic fibrosis
• Often women in the fourth decade of life
• Anterior segment findings are most frequent, including
keratoconjunctivitis sicca
• Posterior findings similar to those in SLE
Progressive systemic sclerosis (PSS), or scleroderma, is a chronic
autoimmune disorder resulting in inflammation and fibrosis of
the skin and other organs. Women in the fourth decade of life
are affected more often than men (4:1).38 The immune defect in
PSS is not completely understood, but circulating immune
complex deposition, vasculitis, and secondary fibrosis of the
vessels are thought to produce the typical clinical picture.
Clinically, patients may present with scleroderma or may
manifest other symptoms of the CREST syndrome (calcinosis,
Raynaud’s phenomenon, esophageal symptoms, sclerodactyly,
and telangiectasia).
The eye is commonly involved in scleroderma. Keratocon-
junctivitis sicca occurs in up to 70% of patients with PSS as a
result of lacrimal gland fibrosis.39 Filamentary keratitis, eyelid
edema, and conjunctival shrinkage can also be noted. Patients
with PSS have also been seen to have fundus findings similar to
those in SLE. Intraretinal hemorrhages, cotton wool spots, and
retinal vasculitis, as well as choroidal infarctions, have been
reported.40
The diagnosis can be established by the characteristic clinical
picture of the scleroderma, with or without the other CREST
findings. These systemic findings in association with retinal
microvascular infarctions and retinal vasculitis support the
clinical diagnosis. Laboratory testing may reveal the presence of
ANAs with a speckled pattern. Fluorescein angiography can be
used to document the cotton wool spots and define the extent
of choroidal nonperfusion. Long-term systemic therapy has not
been useful in controlling PSS, and therapy is chiefly sup-
portive.41 Localized scleroderma has a relatively good prognosis.
Systemic involvement has a worse prognosis, with an 80%
10-year mortality rate.
DERMATOMYOSITIS AND POLYMYOSITIS
Key Features
• Diffuse inflammatory myopathies
• Children and adults may be affected
• In dermatomyositis, lilac discoloration and edema of eyelids
• Cotton wool spots, intraretinal hemorrhages, venous
engorgement, disk edema, and optic atrophy have been
reported in dermatomyositis
Dermatomyositis and polymyositis are autoimmune forms of
inflammatory diffuse myopathy. The pathogenesis of these
diseases appears to be mediated via microvascular damage from
immune complex formation. Patients with dermatomyositis
show ischemic necrosis and loss of capillary beds in the
perifascicular region of the involved muscles.42 Both children
and adults are affected by this disease.
Ocular involvement in dermatomyositis includes a lilac
discoloration and edema of the eyelids, conjunctivitis, iritis,
blepharoptosis, scleritis, uveitis, and extraocular muscle
paralysis.43 Cotton wool spots, intraretinal hemorrhages, venous
engorgement and disk edema, and optic atrophy have been
observed primarily in childhood dermatomyositis.44

a b
c d
Corticosteroids (1 mg kg–1 day–1) have proved helpful in
managing these diseases. Methotrexate and azathioprine have
been used for refractory cases or when complications of steroid
use develop.45 The prognosis is better for childhood forms of the
disease, with a 90% 5-year survival rate.1 Adult-onset disease
fares worse, with a 53% survival at 5 years.
SJÖGREN’S SYNDROME
Key Features
• Key findings are keratoconjunctivitis sicca and xerostomia
• More common in postmenopausal women
• Anterior segment findings are typical
• Chorioretinal involvement is unclear
Sjögren’s syndrome is a constellation of clinical disorders that
have in common keratoconjunctivitis sicca and xerostomia.46
Twenty-five percent to 50% of patients with RA have Sjögren’s
syndrome. This syndrome is more common in postmenopausal
women. Exocrine glands, including the lacrimal gland, demon-
strate infiltration with lymphocytes and secondary fibrosis.
These patients have antinucleoprotein antibodies; anti-SSA
(anti-Ro) and anti-SSB (anti-La).
Patients with Sjögren’s syndrome complain of dryness of the
mouth and eyes. Other manifestations of primary Sjögren’s
syndrome include pneumonitis, renal tubular acidosis, poly-
myositis, and gastritis.
Keratoconjunctivitis sicca is the most common ocular
finding.47 Secondary filamentary keratitis can also be
problematic. In one series, eight patients with a clinical picture
compatible with Sjögren’s syndrome had anterior or inter-
mediate uveitis but did not have chorioretinal involvement.48 In
another report, two patients with progressive retinal vasculitis
were found to have anti-SSA antibodies, suggesting a Sjögren-
like syndrome.49 Their disease was unresponsive to cortico-
steroid, immunosuppressive, and panretinal photocoagulation
therapy.
Retinal Manifestations of the Rheumatic Diseases
FIGURE 169.2. (a and b), Peripheral retinal
vasculitis in a patient with systemic lupus
erythematosus with areas of intraretinal
hemorrhage, retinal nonperfusion, and
neovascularization on fluorescein angiography.
(c and d) Another patient with systemic lupus
erythematosus with focal areas of serous
elevation of the retinal pigment epithelium and
sensory retina as a result of lupus-associated
choroidopathy.
CHAPTER 169
RELAPSING POLYCHONDRITIS
Key Features
• Collagen vascular disease involving cartilaginous tissues
• Bilateral ear pinna inflammation and nasal cartilage destruction
• Anterior segment findings: episcleritis, scleritis, or conjunctivitis
• Anterior uveitis common
• Posterior scleritis may secondarily affect retina and choroid
Relapsing polychondritis is a collagen vascular disease affecting
primarily the cartilaginous tissues. The cause is unknown but
appears to be an autoimmune disease directed against type II
collagen.50 Patients with polychondritis have circulating anti-
type II collagen antibodies. These autoantibodies are thought to
play a mediating role in the recurrent, granulomatous inflam-
mation noted in this disease. Relapsing polychondritis occurs in
adults aged 20–60 years and affects both men and women.
Systemically, patients will have bilateral ear pinna inflam-
mation and nasal cartilage destruction (72%).51 Nasal septal
damage typically results in a saddle nose deformity. Secondary
otitis, vertigo, tinnitus, and deafness may be noted. A non-
erosive polyarthralgia may also bring the patient to medical
attention. Laryngeal and tracheal ring cartilage may be involved
and can cause acute respiratory distress as a result of upper
airway collapse.
Ocular involvement in relapsing polychondritis may occur in
as many as 20–50% of cases.52 This involvement is typically in
the form of episcleritis, scleritis, or conjunctivitis. Anterior
uveitis can be found in 20% of patients. Primary retinal or cho-
roidal involvement is unusual. Retinal pigment epithelial and
sensory retinal detachments as well as choroidal thickening can
be noted as a result of localized posterior scleritis.53
The diagnosis can be established by the pathognomonic
bilateral ear pinna inflammation. Biopsy of involved cartilage
demonstrates the characteristic granulomatous chondritis.
Relapsing polychondritis is a potentially fatal disease with a
30% mortality rate.54 Dapsone (50–200 mg/day) is often used
first in patients with mild symptoms and no cardiac or 2151
 RETINA AND VITREOUS
pulmonary involvement. Prednisone (0.5–1 mg kg–1 day–1) is
highly effective, and may be added in cases that do not respond
well to dapsone alone. Dapsone does not appear to be as
effective in patients with severe necrotizing forms of scleritis.54
Destructive changes in the cartilage are not reversible, and the
goal of therapy should be to limit further disease progression.
POLYARTERITIS NODOSA
Key Features
• Multisystemic disease associated with a necrotizing vasculitis
• Fatigue, myalgia, weight loss, fever, arthralgia, and testicular
pain
• Peripheral ulcerative keratitis and mild iritis can occur
• Most common ocular findings are choroidal and retinal
vasculitis
• High mortality rate if not treated early
SECTION 10
PAN is a multisystemic disease associated with a necrotizing
vasculitis. Medium- to small-sized vessels are characteristically
affected with all stages of necrosis noted in the involved
tissues.55 The cause of PAN is unknown. Thirty percent to 70%
of patients with PAN have antihepatitis B antibodies.56 The
significance of this virus in the pathogenesis has not been
established. This is a rare disease that affects 20- to 50-year-old
adults. Men are affected more frequently than are women (3:1).
Systemically, patients with PAN may note fatigue, myalgia,
weight loss, fever, arthralgia, and testicular pain. The kidneys,
liver, and gastrointestinal and central nervous systems are
commonly involved. Renal involvement is one of the more
serious and potentially fatal complications of PAN. Abdominal
pain from intestinal infarction and headaches from central
nervous system vasculitis are also serious and potentially life-
threatening complications of this disease.
Ten to 20% of patients with PAN will have ocular
involvement.57 Peripheral ulcerative keratitis and mild iritis can
be found in this disease. A mild vitritis may also be noted. The
most common ocular findings in PAN are choroidal and retinal
vasculitis.58 Fundus examination will show retinal vasculitis
with associated intraretinal hemorrhages, cotton wool spots,
and retinal edema (Fig. 169.3). Central retinal artery occlusion
and optic atrophy have also been reported in PAN. Patients with
PAN may also experience anterior or posterior scleritis.
Posterior scleritis will manifest with pain and chorioretinal
folds similar to those in RA.
Any patient with occlusive retinal vasculitis should be
examined for evidence of systemic findings that may help
establish the presence of a collagen vascular disease. Often, a
biopsy of an involved artery or lesion will demonstrate a
hemorrhagic vasculitis and fibrinoid necrosis and establish the
a b
2152
diagnosis. Laboratory tests may show elevated white blood cell
and eosinophil counts, decreased complement, elevated
circulating immune complexes, and negative rheumatoid factor
and ANA determinations. Hepatitis B surface antigen has been
found in up to 70% of patients with PAN. Angiography in
patients with abdominal pain may reveal aneurysmal dilatation
of the hepatic and renal arteries.
PAN is a potentially fatal disease. Without therapy, it carries
an 80–90% 5-year mortality rate. Corticosteroids reduce this
mortality rate to 50%.59 The combination of corticosteroids
with cyclophosphamide (1–2 mg kg–1 day–1) results in an 80% 5-
year survival rate. After disease control is achieved, the steroid
may be tapered. Patients may require high doses of intravenous
steroids and cyclophosphamide early in the course to gain
control of severe disease.60
WEGENER’S GRANULOMATOSIS
Key Features
• Necrotizing granulomatous vasculitis
• Epistaxis, rhinorrhea, sinusitis, otitis, chronic cough, and
saddle nose deformity
• Pulmonary, renal, and CNS lesions possible
• Most common ocular findings are proptosis and orbital pain
• Scleritis, peripheral ulcerative keratitis, conjunctivitis, or
dacryocystitis may occur
• Posterior scleritis may cause secondary chorioretinal
thickening
Wegener’s granulomatosis is a multisystem disease associated
with a necrotizing granulomatous vasculitis.61 The cause is
unknown. It is uncommon and occurs between the ages of 40
and 50 years. Men are affected more often than are females
(3:2). Immune complex formation and deposition are thought
to result in vasculitis of small- to middle-sized vessels. Acute
and chronic lesions can be found simultaneously in the
involved tissues and organs.
Characteristically, Wegener’s granulomatosis involves the
upper and lower respiratory tracts.62 Epistaxis, rhinorrhea,
sinusitis, otitis, chronic cough, and saddle-nose deformity are
frequently observed. Chronic pulmonary infiltrates, nodules,
and cavitary lesions are found in the lungs. Wegener’s granu-
lomatosis also commonly affects the kidneys and the central
nervous system. A granulomatous glomerulitis can be found in
80% of patients with this collagen vascular disorder.
Wegener’s granulomatosis may involve the eye in 40–50% of
cases.63 Eye involvement may precede other organ involvement.
Proptosis and orbital pain from a pseudotumor are the most
common findings. Scleritis, peripheral ulcerative keratitis, con-
junctivitis, and dacryocystitis are also frequently noted ocular
FIGURE 169.3. (a) Localized area of
necrotizing retinal vasculitis associated with
polyarteritis nodosa. (b) The patient refused
immunosuppressive therapy and lost central
acuity in the left eye over a 5-month period
because of progressive ischemic retinal
vasculitis. Note the development of vitritis as
well as further retinal involvement.

manifestations of Wegener’s vasculitis. Posterior scleritis in
Wegener’s granulomatosis behaves similarly to scleritis in other
rheumatologic disorders and presents with decreased vision and
pain. Secondary chorioretinal thickening and striae can be seen
both clinically and on fluorescein angiography. Although uveitis,
retinitis, and retinal vasculitis have been reported, intraocular
disease is rare. Retinitis and retinal vasculitis in Wegener’s
granulomatosis may present as a geographic area of retinal
edema and intraretinal hemorrhage (Fig. 169.4), which may
increase in size and can be difficult to distinguish from a
secondary opportunistic or viral retinitis.
Wegener’s granulomatosis should be suspected in patients
with these ocular findings and respiratory, renal, or central
nervous system involvement. The diagnosis can be supported
by finding pneumonitis or cavitary lesions on chest radiograph
film. Laboratory testing will demonstrate an elevated white
blood cell count, ESR, and serum IgA. Antineutrophilic cyto-
plasmic antibodies (ANCAs) have been found in this disease
and have proved useful in advancing a diagnosis of Wegener’s
granulomatosis.64 Although failure of ANCA to return to
normal may predict an unfavorable clinical course, absolute
titers do not appear to correlate with disease severity.65 Biopsy
of the involved tissue often establishes the diagnosis by
revealing a granulomatous vasculitis.
Wegener’s granulomatosis is a serious and potentially fatal
disease. Therapy should be designed to address both the ocular
and the systemic inflammation. Without therapy, the average
survival is 5 months, with an 80% mortality rate by 1 year.66
Corticosteroids prolong survival to 12.5 months. Cyclophos-
phamide (1–2 mg kg–1 day–1) in combination with corti-
costeroids is the treatment of choice, with a 90% remission rate.
Maintenance therapy may be required for 1–2 years.
GIANT-CELL ARTERITIS
Key Features
• Medium- to large-vessel systemic vasculitis
• Average age 70 years
• Fever, weight loss, malaise, headaches, jaw claudication
• Most common ocular manifestation is ischemic optic
neuropathy
• Less commonly branch or central retinal artery occlusion
Giant-cell arteritis (GCA), or temporal arteritis, is a systemic
vasculitis that involves medium- to large-sized muscular
arteries.67 The cause is unknown. GCA affects an older popula-
tion with an average age of 70 years. The pathophysiology of
this collagen vascular disease appears to be a panarteritis.
Affected blood vessels demonstrate a mononuclear cell infiltra-
tion and giant-cell formation within the vessel wall, with
a b
Retinal Manifestations of the Rheumatic Diseases
subsequent destruction and fragmentation of the internal
elastic membrane.
Patients with GCA commonly complain of fever, weight loss,
malaise, and headaches. Jaw claudication may occur. The most
common ocular complication of GCA is ischemic optic
neuropathy.68 The larger vessels supplying the optic nerve
become inflamed and effect an infarction of the optic nerve.
Rarely, the retinal vessels may be involved, producing a branch
or central retinal artery occlusion.69 Attenuation of the retinal
arterioles, disk pallor, and optic atrophy may develop late.
Primary uveitis or retinitis is uncommon.
The diagnosis can be made in the clinical setting of an older
patient with malaise, fever, weight loss, headache, and sudden
loss of vision in one or both (65%) eyes as a result of ischemic
optic neuropathy. The diagnosis can be supported by finding a
markedly elevated ESR and/or C-reactive protein level. A
temporal artery biopsy will demonstrate a granulomatous
vasculitis with infiltration of the vessel wall with mononuclear
CHAPTER 169
cells, histiocytes, and giant cells and loss of the internal elastic
membrane.
Untreated, this disease has a poor prognosis with irreversible
loss of vision secondary to ischemic optic neuropathy and death
from coronary or cerebral vasculitis.70 Therapy should be
initiated as soon as GCA is suspected in order to prevent
bilateral optic nerve involvement. Prednisone (1 mg kg–1 day–1)
is the treatment of choice in GCA, and maintenance doses may
be required for 1–2 years when the disease may remit.
BEHÇET’S DISEASE
Key Features
• Systemic necrotizing vasculitis
• Most prevalent in Asia and the Middle East
• Chronic prodrome of malaise, fever, and sore throat may occur
• Classic triad: recurrent aphthous oral ulcers, genital ulcers,
and uveitis
• Erythema nodosum is common
• Typical occlusive retinal vasculitis with intraretinal hemorrhage
and edema
Behçet’s disease is a systemic necrotizing vasculitis with diverse
manifestations. The cause is unknown but is thought to have a
strong autoimmune component. Human leukocyte antigen
(HLA) associations have been established in other countries for
Behçet’s disease but have not proved useful in the United
States.71 HLA-B51, HLA-B12, and HLA-B27 have all been
associated with certain forms of Behçet’s disease. The disease is
much more common in Asia and the Middle East.72 In the
United States, there is an equal gender distribution, and the
disease is found in 20- to 40-year-old adults.
FIGURE 169.4. (a) An area of retinitis and
retinal vasculitis associated with biopsy-proven
Wegener’s granulomatosis. (b) The fluorescein
angiogram illustrates an area of segmental
vascular staining and leakage of dye into the
vitreous.
2153
 RETINA AND VITREOUS
Behçet’s vasculitis involves small- to medium-sized vessels.
A perivascular infiltrate with polymorphonuclear neutrophils
and mononuclear cells can be found around the veins and
arteries. This is often associated with vessel thrombosis and
tissue hemorrhage.
Clinically, there may be a 6- to 10-year prodrome with
recurrent or chronic malaise, fever, and sore throat.73 The
classic triad of recurrent aphthous oral ulcers (100%), genital
ulcers (84%), and uveitis (66%) establishes the clinical diagnosis
of Behçet’s disease. Erythema nodosum (66%), arthritis (66%),
and meningoencephalitis (22%) are also common. The gastro-
intestinal, renal, pulmonary, and cardiovascular systems may
also be involved and are considered ‘minor’ findings in this
syndrome.
The eye may be the first or predominant organ involved in
Behçet’s disease. More characteristically, uveitis follows the
other systemic findings by 1–3 years. Systemic and ocular
symptoms typically wax and wane. Patients will often present
SECTION 10
with an acute loss of vision associated with a bilateral (80%)
uveitis.74 The ocular inflammation may be severe and relapsing.
A nongranulomatous iridocyclitis with hypopyon, posterior
synechiae, and hyphema is common. On fundus examination,
there may be a severe vitritis, disk edema, and attenuation of
the arterioles.75 An essential finding in Behçet’s disease is the
presence of an occlusive retinal vasculitis with surrounding
intraretinal hemorrhage and retinal edema (Fig. 169.5). Cystoid
macular edema, cataract, glaucoma, and retinal detachment can
occur as secondary complications of the uveitis and retinal
vasculitis.76
The complete form of Behçet’s disease consists of oral ulcers,
genital ulcers, uveitis, and nonulcerative skin lesions. Several
systems have been proposed for diagnosing partial or
incomplete forms of Behçet’s disease.77 Behçet’s disease is more
prevalent in Japan, leading the Japanese to classify this disease
into four forms: (1) complete-all four major findings,
(2) incomplete-three major findings or uveitis with one other
major finding, (3) suspect-two major findings, and (4) possible-
one major finding.
The presence of other minor findings associated with the
multisystemic involvement can assist in the diagnosis.
Laboratory testing may help by demonstrating an elevated ESR,
elevated levels of C-reactive protein, immune complexes, and a
positive ANA determination. HLA typing can also be helpful in
incomplete forms of Behçet’s disease. Properdin factor B, serum
lysozyme, and a1-acid glycoprotein are also elevated in Behçet’s
disease.78 Pathergy and dermatographia, although much extolled,
have not proved to be helpful measures for detecting Behçet’s
disease in the United States. Fluorescein angiography can be
employed to help document the ischemic retinal vasculitis and
follow up response to therapy. Cystoid macular edema and disk
a b
2154
edema often result from the chronic inflammation. Choroidal
vessels may be involved and show delayed filling or localized
choroidal infarction.
Treatment of Behçet’s disease is characteristically challenging.
The disease is relapsing and may persist for many years.
Behçet’s disease can have explosive exacerbations after periods
of relative inactivity or remission. Central nervous system
involvement may be fatal in up to 40% of treated cases. Mild
forms may be controlled initially with prednisone and
colchicine (0.6 mg PO bid).79 Usually, Behçet’s disease requires
more aggressive therapy. Periocular steroids can assist in
controlling severe bouts of ocular inflammation. Chlorambucil
(0.1–0.15 mg kg–1 day–1) or cyclophosphamide (1–2 mg kg–1
day–1) has been the mainstay of therapy.80 Cyclophosphamide
has fewer systemic side effects and therefore has been in favor
for the treatment of ocular Behçet’s disease in the United
States. Cyclosporine (4 mg kg–1 day–1), alone or in combination
with low-dose corticosteroid therapy, has also proved effective in
controlling this disease and has become the treatment of choice
at some centers.81,82 Therapy may be required for several years.
Careful monitoring for side effects and complications of
immunosuppressive therapy is required. Even with treatment,
up to 74% of patients lose useful visual acuity.
SUMMARY
The rheumatic diseases are a collection of inflammatory
disorders that have multisystemic involvement and protean
manifestations. Ocular inflammation may occur in many of
these syndromes. The retina and choroid may be affected
primarily as a result of retinal or choroidal vasculitis. Retinal
ischemia, cotton wool spots, intraretinal hemorrhages, retinal
edema, and retinal vasculitis are the typical findings in many of
these diseases. Posterior scleritis may result in secondary
chorioretinal involvement.
The ophthalmologist should be aware of the association
between ocular inflammation and the various rheumatologic
disorders. Many of these diseases either involve the eye
primarily or present initially in the eye, and can precede the
involvement of other organ systems by several years. A careful
review of systems and general physical examination should be
performed to ascertain systemic involvement. The prognosis for
many of these vision- and life-threatening disorders depends on
accurate diagnosis and the institution of appropriate therapy.
Until the pathophysiology and exact causes of the rheuma-
tologic diseases are defined, antiinflammatory and immuno-
suppressive agents remain the mainstays of therapy. As such,
the rheumatic diseases are best managed by a multidisciplinary
approach, not infrequently negotiated by the ophthalmologist
and the temper of the eye.
FIGURE 169.5. (a and b) Two patients with
Behçet’s disease illustrate the profound
involvement of the retinal vessels. A bilateral
occlusive retinal vasculitis results in intraretinal
edema, hemorrhage, and retinal nonperfusion.
Progressive damage to the sensory retina
results in marked attenuation of the arterioles.

REFERENCES
1. Rodnan GP, Schumacher RH: The
connective tissues: structure, function and
metabolism. In: Rodnan GP, Schumacher
RH, eds. Primer on the rheumatic diseases.
8th edn. Atlanta: Arthritis Foundation; 1983.
2. Hascall VC, Hascall GK: Proteoglycans. In:
Hay ED, ed. Cell biology of extracellular
matrix. New York: Plenum; 1981.
3. Sanberg LB, Gray WR, Franzblau C, eds:
Elastin and elastic tissue. New York:
Plenum; 1977.
4. Friend J: Physiology of the cornea. In:
Smolin G, Thoft RA, eds. Cornea. 2nd edn.
Boston: Little, Brown; 1987.
5. Fine BS, Yanoff M: The vitreous body. In:
Fine BS, Yanoff M, eds. Ocular histology.
2nd edn. New York: Harper & Row; 1979.
6. Kelgren HJ: Epidemiology of rheumatoid
arthritis. In: Dutker JJR, Alexander WRM,
eds. Rheumatic diseases. Baltimore:
Williams & Wilkins; 1968.
7. Torrigiana G, Roitt IM: Antiglobulin factors
in sera from patients with rheumatoid
arthritis and normal subjects. Ann Rheum
Dis 1977; 3:315.
8. Barr CC, Davis H, Culbertson WW:
Rheumatoid scleritis. Ophthalmology 1981;
88:1269.
9. Waston PG, Hayreh SS: Scleritis and
episcleritis. Br J Ophthalmol 1976; 60:163.
10. Benson WE, Sheilds JA, Tasman W, et al:
Posterior scleritis: a cause of diagnostic
confusion. Arch Ophthalmol 1979;
97:1482.
11. Singh G, Guthoff R, Foster CS: Observation
on long-term follow-up of posterior
scleritis. Am J Ophthalmol 1986; 101:570.
12. Fraunfelder FT, Watson PG: Evaluation of
eyes enucleated for scleritis.
Br J Ophthalmol 1976; 60:227.
13. O’Dell JR: Therapeutic strategies for
rheumatoid arthritis. N Engl J Med 2004;
350:2591.
14. Olsen NJ, Stein CM: New drugs for
rheumatoid arthritis. N Engl J Med 2004;
350:2167.
15. Foster CS, Forstot SL, Wilson LA: Mortality
rate in rheumatoid arthritis patients
developing necrotizing scleritis or
peripheral ulcerative keratitis.
Ophthalmology 1984; 91:1253.
16. Salmon JF, Wright JP, Bowen RM, et al:
Granulomatous uveitis in Crohn’s disease.
Arch Ophthalmol 1989; 107:718.
17. Duker JS, Brown GC, Brooks L: Retinal
vasculitis in Crohn’s disease.
Am J Ophthalmol 1987; 103:664.
18. Ruby AJ, Jampol LM: Crohn’s disease and
vascular disease. Am J Ophthalmol 1990;
110:349.
19. Rodriguez A, Akova YA, Pedroza-Seres M,
Foster CS: Posterior segment ocular
manifestations in patients with
HLA-B27-associated uveitis.
Ophthalmology 1994; 101:1267.
20. Kanski JJ: Juvenile arthritis and uveitis.
Surv Ophthalmol 1990; 34:253.
21. Kanski JJ, Shun-Shin GA: Systemic uveitis
syndromes in childhood: an analysis of
340 cases. Ophthalmology 1984; 91:1247.
22. Giles CL: Uveitis in childhood. Part I:
anterior. Ann Ophthalmol 1989; 21:13.
23. Kanski JJ: Anterior uveitis in juvenile
rheumatoid arthritis. Arch Ophthalmol 1977;
95:1794.
Retinal Manifestations of the Rheumatic Diseases
24. Olson NY, Lindsley CB, Godfrey WA:
Nonsteroidal anti-inflammatory drug
therapy in chronic childhood iridocyclitis.
Am J Dis Child 1988; 142:1289.
25. Kanski JJ: Uveitis in juvenile rheumatoid
arthritis: incidence, clinical features and
prognosis. Eye 1988; 2:641.
26. Diamond JG, Kaplan HL: Lensectomy and
vitrectomy for complicated cataract
secondary to uveitis. Arch Ophthalmol
1978; 96:1798.
27. Mintz G, Fraga A: Arteritis in systemic
lupus erythematosus. Arch Intern Med
1965; 116:55.
28. Estes D, Christian CL: The natural history
of systemic lupus erythematosus by
prospective analysis. Medicine 1971; 50:85.
29. Baehr G, Klemperer R, Schifrin A: A diffuse
disease of the peripheral circulation (usually
associated with lupus erythematosus and
endocarditis). Trans Assoc Am Phys 1935;
50:139.
30. Levine SR, Crofts JW, Lesse GR, et al:
Visual symptoms associated with the
presence of a lupus anticoagulant.
Ophthalmology 1988; 95:686.
31. Gold DH, Morris DA, Henkind P: Ocular
findings in systemic lupus erythematosus.
Br J Ophthalmol 1972; 56:800.
32. Gold D, Feiner L, Henkind P: Retinal arterial
occlusive disease in systemic lupus
erythematosus. Arch Ophthalmol 1977;
95:1580.
33. Vine AK, Barr CC: Proliferative lupus
erythematosus. Arch Ophthalmol 1988;
106:230.
35. Cunningham ET Jr, Alfred PR, Irvine AR:
Central serous chorioretinopathy in patients
with systemic lupus erythematosus.
Ophthalmology 1996; 103:2081.
36. Wong K, Everett A, Jones JV, et al: Visual
loss as the initial symptom of systemic
lupus erythematosus. Am J Ophthalmol
1981; 92:238.
37. Neumann R, Foster CS: Corticosteroid-
sparing strategies in the treatment of retinal
vasculitis in systemic lupus erythematosus.
Retina 1995; 15:206.
38. Maricq HR, LeRoy EC: Progressive
systemic sclerosis: disorders of the
microcirculation. Clin Rheum Dis 1979;
5:81.
39. Horan EC: Ophthalmic manifestations of
progressive systemic sclerosis.
Br J Ophthalmol 1969; 53:388.
40. Pollack IP, Becker B: Cytoid bodies of the
retina in a patient with scleroderma.
Am J Ophthalmol 1962; 54:655.
41. Medsger TA, Masi AT, Rodnan GP, et al:
Survival with systemic sclerosis
(scleroderma): a life-table analysis of 309
patients. Ann Intern Med 1971; 75:369.
42. Kissel JT, Mendell JR, Rammohan KW:
Microvascular deposition of complement
membrane attack complex in
dermatomyositis. N Engl J Med 1986;
314:329.
43. Harrison SM, Frenkel M, Grossman BJ, et al:
Retinopathy in childhood dermatomyositis.
Am J Ophthalmol 1973; 76:786.
44. Bruce GM: Retinitis in dermatomyositis.
Trans Am Ophthalmol Soc 1938; 36:282.
45. Oddis, CV: Idiopathic inflammatory
myopathies: a treatment update. Curr
Rheumatol Rep 2003; 5:431.
46. Manthorpe R, Frost-Larson K, Isager H,
et al: Sjögren’s syndrome. Allergy 1981;
36:139.
47. Brown SI, Grayson M: Marginal furrows: a
characteristic corneal lesion of rheumatoid
arthritis. Arch Ophthalmol 1968; 79:563.
48. Rosenbaum JY, Bennett RM: Chronic
anterior and posterior uveitis and primary
Sjögren’s syndrome. Am J Ophthalmol
1987; 104:346.
49. Farmer SG, Kinyoun MD, Nelson JL, et al:
Retinal vasculitis associated with autoan-
tibodies to Sjögren’s syndrome A antigen.
Am J Ophthalmol 1985; 100:814.
50. Foidart JM, Abe S, Marin GR, et al:
Antibodies to type II collagen in relapsing
polychondritis. N Engl J Med 1978;
299:1203.
CHAPTER 169
51. McAdam LP, O’Hanllan MA, Bluestone R,
et al: Relapsing polychondritis: prospective
study of 23 patients and a review of the
literature. Medicine 1976; 55:193.
52. Isaak BL, Liesang TJ, Michet CJ: Ocular
and systemic findings in relapsing
polychondritis. Ophthalmology 1986;
93:681.
53. Magargal LE, Donoso LA, Goldberg RE,
et al: Ocular manifestations of relapsing
polychondritis. Retina 1981; 1:96.
54. Hoang-Xuan T, Foster CS, Rice BA:
Scleritis in relapsing polychondritis:
response to therapy. Ophthalmology 1990;
97:892.
55. Christain CL, Sargent JS: Vasculitis
syndromes, clinical and experimental
models. Am J Med 1976; 61:385.
56. Gocke DJ, HSU K, Morgan C, et al:
Association between polyarteritis and
Australia antigen. Lancet 1970;
2:1149.
57. Stillerman ML: Ocular manifestations of
diffuse collagen disease. Arch Ophthalmol
1951; 45:239.
58. Goar EL, Smith LS: Polyarteritis nodosa
of the eye. Am J Ophthalmol 1952;
35:1619.
59. Fauci AS, Doppman JL, Wolff SM:
Cyclophosphamide-induced remissions in
advanced polyarteritis nodosa. 1978;
Am J Med 64:890.
60. Colmegna I, Maldonado-Cocco JA:
Polyarteritis nodosa revisited. Curr
Rheumatol Rep 2005; 7:288.61. Goodman
GC, Churg J: Wegener’s granulomatosis:
pathology and review of the literature. Arch
Pathol 1954; 58:533.
62. Robin JB, Schanzlin DJ, Meisler DM, et al:
Ocular involvement in the respiratory
vasculitides. Surv Ophthalmol 1985;
30:127.
63. Bullen CL, Liesegang TJ, McDonald TJ,
et al: Ocular complications of Wegener’s
granulomatosis. Ophthalmology 1983;
90:279.
64. Pulido JS, Goeken JA, Nerad JA, et al:
Ocular manifestations of patients with
circulating antineutrophilic cytoplasmic
antibodies. Arch Ophthalmol 1990;
108:845.
65. Power WJ, Rodriguez A, Neves RA, et al:
Disease relapse in patients with ocular
manifestations of Wegener granulomatosis.
Ophthalmology 1995; 102:154.
66. Fauci AS, Haynes BF, Katz P: The
spectrum of vasculitis: clinical, pathologic, 2155
 RETINA AND VITREOUS
immunologic and therapeutic
considerations. Ann Intern Med 1978;
89:660.
67. Huston KA, Hunder GC, Lie JT, et al:
Temporal arteritis. A 25-year
epidemiological, clinical and pathological
study. Ann Intern Med 1978; 88:162.
68. Keltner JL: Giant-cell arteritis.
Ophthalmology 1982; 89:1101.
69. Whitfield JH, Bateman M, Cooke WT:
Temporal arteritis. Br J Ophthalmol 1963;
47:555.
70. Cullen JF, Colier JA: Ophthalmic
complications of giant cell arteritis. Surv
Ophthalmol 1976; 20:247.
71. Numaga J, Kazumasas M, Mochizuki M,
et al: An HLA-D region restriction fragment
associated with refractory Behçet’s
disease. Am J Ophthalmol 1988;
105:528.
SECTION 10
2156
72. Aoki K, Fujioka K, Katsumata H, et al:
Epidemiologic studies on Behçet’s disease
in Hokkaido district. [Japanese]
J Clin Ophthalmol 1971; 25:2239.
73. Chajek T, Fainaru M: Behçet’s disease:
report of 41 cases and a review of the
literature. Medicine 1975; 54:179.
74. Michelson JB, Chisari VF: Behçet’s
disease. Surv Ophthalmol 1982; 26:190.
75. James DG, Spiteri MA: Behçet’s disease.
Ophthalmology 1982; 89:1279.
76. Colvard DM, Robertson DM, O’Duffy JD:
The ocular manifestations of Behçet’s
disease. Arch Ophthalmol 1977; 95:1813.
77. Behçet’s Disease Research Committee of
Japan: Behçet’s disease: guide to
diagnosis of Behçet’s disease.
Jpn J Ophthalmol 1974; 18:291.
78. Lehner T, Adinolfi M: Acute phase proteins,
C9, factor B and lysozyme in recurrent oral
ulceration and Behçet’s syndrome.
J Clin Pathol 1980; 33:269.
79. Hijakata K, Masuda K: Visual prognosis in
Behçet’s: effects of cyclophosphamide
and colchicine. Jpn J Ophthalmol 1978;
22:506.
80. O’Duffy JD, Robertson DM, Goldstein NP:
Chlorambucil in the treatment of uveitis and
meningoencephalitis of Behçet’s disease.
Am J Med 1984; 76:75.
81. Nussenblatt RB, Palastine AG, Chan CC:
Effectiveness of cyclosporin therapy in
Behçet’s disease. Arthritis Rheum 1985;
28:671.
82. Whitcup SM, Salvo EC Jr, Nussenblatt RB:
Combined cyclosporine and corticosteroid
therapy for sight-threatening uveitis in
Behçet’s disease. Am J Ophthalmol 1994;
118:39.
 CHAPTER
170 Retinopathy Associated with Blood Anomalies
John I. Loewenstein and Demetrios Vavvas
ANEMIA
Key Features
• Superficial flame-shaped hemorrhages and cotton wool spots
are typically seen
• Approximately one-third of anemic patients may have some
retinopathy
• Prevalence of retinopathy increases with severity of anemia or
thrombocytopenia
• Retinal abnormalities in anemia without accompanying
thrombocytopenia are less common, unless the anemia is
profound.
• The combination of thrombocytopenia and anemia makes
retinopathy more likely.
• Vision is not affected unless macula is involved
• Treat the underlying condition
Fundus findings in anemia may include hemorrhages, cotton wool
spots, and retinal edema. The hemorrhages are typically super-
ficial and flame shaped, but they may also have a white center
(Figs 170.1 and 170.2). Rarely, preretinal or vitreous hemor-
rhage or a macular star may occur. The retinal vessels are
usually normal, although pale arterioles and dilated veins may
be seen.1 Fluorescein angiography may reveal an increased retinal
transit time.
FIGURE 170.1. Intraretinal hemorrhages and cotton wool spots in a
case of severe anemia.
Vision is not affected unless there are changes at the macula,
and such changes are unusual. Retinopathy resolves with
treatment of the underlying anemia.
The picture as a whole is suggestive, but not diagnostic, of
anemia. It usually is not possible to determine the type of
anemia from the fundus findings. Some authors feel that white-
centered hemorrhages are more common in pernicious anemia
than in other types of anemia2; others state that a picture of
numerous preretinal hemorrhages, together with white-centered
hemorrhages, is characteristic of aplastic anemia,3 but systematic
quantitative studies have not been undertaken. Two case reports
link moderately severe iron deficiency anemia and retinal
arterial occlusive events.4,5 With only two cases, it is difficult to
prove causality. One case of Fanconi anemia, a rare chromosomal
abnormality, has been reported with widespread vasculopathy,
including areas of central and peripheral leakage, areas of
nonperfusion and neovascularization.6 Angioid streaks have
been reported to occur with familial dyserythropoietic anaemia
type III.7 Anemia associated with malaria has been reported to
have high incidence of retinopathy, but cerebral malaria without
anemia can also have fundus changes, and the severity of
fundus changes may be a predictor of worse outcome.8
There is controversy in the literature regarding the most
important factors related to the prevalence of retinopathy in
anemia. Age, sex, type of anemia, hematocrit values, and platelet
counts have all been invoked, but only a few quantitative studies
have been performed. Foulds3 studied 30 cases of pernicious
FIGURE 170.2. Intraretinal hemorrhages, white-centered hemorrhage,
and cotton wool spots in a case of aplastic anemia. 2157
 RETINA AND VITREOUS
anemia. He found retinopathy in all patients with a hemoglobin
concentration of less than 5 g/dL, in one-third of patients with a
hemoglobin concentration of 5–6 g/dL, and in no patients with a
hemoglobin concentration of greater than 6 g/dL. On this basis,
he states that retinopathy is most likely associated with a
hemoglobin concentration of less than 6 g/dL. Wise and
colleagues1 stated that a hemoglobin concentration of 2.5 g/dL
or less is usually associated with retinopathy. Merin and Freund9
studied 89 patients with anemia in Africa. The majority of their
patients had anemia secondary to nutritional deficiency and
hookworm infestation. None of their patients with a hemo-
globin level greater than 8 g/dL had retinopathy, whereas 46%
of those with a hemoglobin concentration of less than 8 g/dL
showed hemorrhages or ‘exudates’, or both. Aisen and
associates10 examined 35 anemic patients and 35 age- and sex-
matched controls. Twenty percent of the anemic patients had
hemorrhages or cotton wool spots, but there was no correlation
with the hematocrit value. Rubenstein and co-workers11 studied
SECTION 10
two groups of patients with anemia. Group 1 consisted of
67 patients, each having a hemoglobin concentration of less
than 12 g/dL or a platelet count of less than 100 000, or both. A
variety of diseases was present in this group, including many
cases of leukemia. Some of the leukemic patients were receiving
chemotherapy. It was demonstrated in these patients that, for a
given platelet level, a lower hematocrit value was more likely to
be associated with retinal hemorrhages. Similarly, for a given
hemoglobin concentration, more severe thrombocytopenia was
more likely to be associated with retinal hemorrhage. The data
for group 1 are summarized in Table 170.1.
Group 2 consisted of 123 hemophiliacs and 42 patients with
Cooley’s anemia. All patients in this group had a hemoglobin
concentration of less than 8 g/dL at some point in the course of
disease, but none had thrombocytopenia. No patient in this
group had retinal hemorrhages. Not all members of group 2 had
a dilated fundus examination by an ophthalmologist, whereas
all members of group 1 did have such an evaluation. It is
therefore possible that the number of retinal hemorrhages in
the patients in group 2 was underestimated. Since many
leukemic patients were included in group 1, it is not possible to
determine from their data whether the relationship among
anemia, thrombocytopenia, and retinopathy holds true for
nonleukemic cases. Holt and Gordon-Smith12 examined a large
number of patients with a variety of blood diseases. They
studied 33 patients with leukemia and found that 18 of them
had retinopathy, which was more likely with increasing anemia
and thrombocytopenia. These authors did not report platelet
levels in their other cases of anemia, but they did give the
impression that the combination of anemia and thrombo-
TABLE 170.1. Data for Group 1 in Rubenstein and Co-Workers'
Study
Hemoglobin Patients Patients with
Platelets/mm2 g/dL (n) Retinal Hemorrhage
<50 000 <8 10 7
8–12 14 5
>12 1 0
50 000–100 000 <8 7 3
8–12 8 2
>12 5 0
>100 000 <8 19 2 •
8–12 3 0
Data from Rubenstein RA, Yanoff M, Albert DM: Thrombocytopenia, anemia,
and retinal hemorrhage. Am J Ophthalmol 1968; 65:435.
2158
cytopenia was more likely to yield retinopathy. They found that
more profound anemia was required to produce cotton wool
spots than was required to produce hemorrhages.
Carraro and associates13 studied 226 consecutive patients with
anemia alone, thrombocytopenia alone or both. They excluded
patients with leukemia, diabetes and hypertension and liver
cirrhosis. All patients had dilated eye exams by ophthalmologists.
Most common fundus findings were superficial flame-shaped or
discrete hemorrhages. There were few patients with subhyaloid
hemorrhages and one with disk edema. As a whole, 28% of the
patients had retinopathy findings. Among patients with both ane-
mia and thrombocytopenia the incidence of retinopathy ranged
from ~10% with the presence of mild anemia and thrombocyto-
penia and increased to 100% in the presence of combined severe
anemia and severe thrombocytopenia. In severe anemia (less than
8 g/dL) only, 70% of patients had retinopathy findings, and in
severe or very severe thrombocytopenia alone (<50 µ 109/L),
45% of patients (four of nine) had retinopathy findings.
Merin and Freund,9 in their study of anemia in Africa, could
find no cases of retinopathy in children, despite very low hemo-
globin levels. This has led to speculation that age is a factor in
the prevalence of retinal abnormalities in anemia. Aisen and
associates,10 however, could not confirm a correlation between
age and retinopathy in their population. These two studies also
suggested that hemorrhages and cotton wool spots in anemia were
more common in males than in females. Aisen and associates
subjected this hypothesis to statistical analysis and failed to find
significance despite the trend. The Carraro et al study,13 which is
the largest and most carefully performed to date, failed to find
an association between age or sex and retinopathy in multi-
variate analysis. They did not, however, include children.
In summary, a precise level of anemia at which retinal abnor-
malities will occur cannot be given. Several studies have shown
that prevalence of retinopathy increases with severity of anemia.
Retinal abnormalities in anemia without accompanying thrombo-
cytopenia are less common, unless the anemia is profound. The
combination of thrombocytopenia and anemia makes retino-
pathy more likely. Young children may be less likely to show
retinal changes with anemia, unless it is caused by leukemia.
Venous tortuosity may be a feature of anemic retinopathy,10
but there is no correlation with the hematocrit value.14
The pathophysiology of retinopathy in anemia is poorly under-
stood. It is possible that dilatation of retinal vessels occurs as a
response to retinal hypoxia in profound anemia. The resulting
increase in transmural pressure, or perhaps the hypoxia itself, may
damage vascular walls. Thrombocytopenia might contribute by
retarding healing. This scheme might explain vascular leakage
that produces hemorrhage and edema. Cotton wool spots are
infarcts of the nerve fiber layer of the retina. It is possible that
they are produced by relative hypoxia in anemia; vascular spasm
might explain their focal nature.
LEUKEMIA
Key Features
• Up to 40% of the patients may have ocular findings
• Hemorrhages (flame, white-centered, preretinal, and vitreous)
and cotton wool spots are the most common findings
• Venous dilatation, irregularity, and vessel sheathing may be seen
• Leukemic infiltrates can occur (white clumps or masses in the
retina/optic nerve)
Microaneurysms and retinal neovascularization are sometimes
seen in chronic leukemia
• Serous detachment of the retina may occur as a result of
choroidal infiltration

• Retinopathy is more common in adults than in children and
more prevalent in myeloid leukemia versus lymphoid
• HTLV-1 leukemia has a somewhat different clinical picture that
includes pigmentary retinopathy, lymphoma-like picture, uveitis,
and vasculitis
• Treat underlying pathology
The fundus in leukemia may show venous dilatation, tortuosity,
and irregularity, and vessels may show abnormal color and
sheathing. Flame, white-centered, preretinal and vitreous hemor-
rhages; cotton wool spots; and leukemic infiltrates may occur
(Figs 170.3 to 170.5). The latter appear as white clumps or
masses in the retina. Microaneurysms, venous occlusions, and
neovascularization are sometimes seen, typically in chronic
FIGURE 170.3. Large leukemic infiltrate.
From Schachat AP, Markowitz JA, Guyer DR, et al: Ophthalmic manifestations of
leukemia. Arch Ophthalmol 1989; 107:698. Copyright 1989, American Medical
Association.
a b
FIGURE 170.4. (a) Intraretinal and preretinal hemorrhages in a case of acute lymphatic leukemia. Right eye. (b) Left eye of the patient in (a).
Retinopathy Associated with Blood Anomalies
leukemia. Serous detachment of the retina may occur as a result
of choroidal infiltration.15–17
In general, the presence of retinal abnormalities in leukemia
has not been well correlated with the white cell count. Autopsy
studies show a high agonal white cell count in patients with
leukemic infiltration,18 but the relationship between the white
cell count and infiltration was difficult to demonstrate in most
clinical studies. A recent study of leukemic patients in Malaysia
however, demonstrated an association between hemorrhages
with white centers and the white blood count, whereas hemor-
rhages without white centers were found to correlate with low
platelet counts.19
The anemia, thrombocytopenia, and hyperviscosity that may
accompany leukemia probably account for many of the retinal
findings. Retinal hemorrhages are likely the result of anemia
and thrombocytopenia. As discussed in the section on anemia,
for a given platelet level, a lower hematocrit value is more likely
to be associated with retinal hemorrhages.11,12 Similarly, for a
CHAPTER 170
given hemoglobin level, more severe thrombocytopenia is more
likely to be associated with retinal hemorrhage. A prospective
study of retinopathy in leukemia by Guyer and colleagues20 as
well as a study by Reddy and Jackson19 demonstrated signifi-
cantly lower platelet counts in patients with retinal hemorrhages
in comparison with those without such lesions, regardless of
the type of leukemia. In these studies, patients with acute
lymphocytic leukemia and retinal hemorrhages showed lower
hematocrit levels than did those without retinal hemorrhages.
This relationship was not demonstrated in patients with myeloid
leukemia. In patients with acute nonlymphocytic leukemia, the
presence of anemia was related to the presence of white-centered
hemorrhages in Guyer’s study20 but not in Reddy and Jackson’s.19
Hemorrhages (with or without white centers) and cotton wool
spots were more common in adults than in children in Guyer’s
study but not in Reddy and Jackson’s. There was no correlation
between fundus findings and mean leukocyte counts in Guyer’s
study. Karesh and co-workers,21 in a prospective evaluation of
the fundi of patients with myeloid leukemia, demonstrated
significantly lower platelet counts in patients with retinopathy
than in those without fundus lesions. They found no difference
in hematocrit levels and white cell counts in groups with and
without retinopathy. They did not do a separate analysis for
different types of retinal lesions. Most of their patients with
retinopathy had retinal hemorrhages.
Venous dilatation, tortuosity, and irregularity seen in leukemia
may be caused by a combination of anemia and hyperviscosity.
2159
 SECTION 10 RETINA AND VITREOUS

a b

FIGURE 170.5. (a) Retinal vascular dilatation and tortuosity in a case of secondary polycythemia. Right eye. (b) Left eye of the patient in (a).

Venous occlusions are likely to result from hyperviscosity. Cotton serous retinopathy cases represented a chance occurrence of two
wool spots are caused by occlusion of precapillary arterioles, conditions, a manifestation of leukemia, or were limited presen-
but the reason for these occlusions in leukemia has not been tations of serous retinal detachment secondary to infiltration
established. Ischemia secondary to anemia, direct occlusion by of the choroid. Kuwabara and Aiello34 described the pathologic
leukemic cells, occlusion by platelet-fibrin aggregates, or sludging findings in a case of leukemic miliary nodules of the retina.
resulting from hyperviscosity may all be factors. In their prospec- Human T-cell lymphotropic virus type 1 (HTLV-1) is a retro-
tive study, Guyer and colleagues20 did not find an association virus that can cause leukemia. The virus is endemic in southwest
between hematologic variables and cotton wool spots. Japan, some Caribbean countries, sub-Saharan Africa, and parts
Microaneurysms are seen in cases of chronic leukemia and of the Middle East. It has been seen in Melanesia, the south-
may be related to hyperviscosity.22,23 In Jampol and colleagues’23 eastern United States, and South America. Transmission of the
study of 25 patients with chronic leukemia, eight individuals virus is similar to that of human immunodeficiency virus.
had microaneurysms. Infection with HTLV-1 may produce several clinical pictures.35
Neovascularization may also be seen in cases of chronic The most common are transverse myelopathy and leukemia/
leukemia.24 It is usually accompanied by capillary closure.25 lymphoma. It may also produce pulmonary alveolitis, Sjögren’s
The white centers of some hemorrhages seen in leukemia may syndrome, and polymyositis.
consist of leukemic cells and debris, platelet-fibrin aggregates, About 10% of patients with transverse myelopathy and HTLV-1
or septic emboli.26 infection have a pigmentary retinopathy.36,37 Some of these
The prevalence of retinal involvement in leukemia varies widely cases show a progressive, widespread retinal degeneration indis-
in the literature. Almost all studies suffer from their retrospective tinguishable from retinitis pigmentosa. The electroretinogram
nature and a variety of selection biases. Schachat and associates27 in these cases is markedly abnormal. Other patients have a
performed a prospective ophthalmic study of patients with
newly diagnosed leukemia. A summary of the prevalence of retinal
findings in their patients is given in Table 170.2. They found a 5% TABLE 170.2. Prevalence of Retinal Findings in Schachat and
prevalence of visual loss caused by vitreoretinal disease in those Associates’ Study
patients in whom a reliable acuity determination was possible.
Another prospective study of 288 patients found similar results, Retinal Finding Myeloid Lymphoid Total
with about a third of the patients showing retinal findings. A low Patients (%) Patients (%) Affected (%)
percentage (~ 1.5%) had neuro-ophthalmic findings. Ocular Intraretinal 33 13 24
findings were more common in adults than in children (50% vs hemorrhage
16%) and more prevalent in myeloid leukemia versus lymphoid Cotton wool 24 6 16
(40% vs 30%).28 Karesh and co-workers21 prospectively evaluated spot
the fundi of patients with myeloid leukemia and found that 53%
of their subjects had retinopathy. Five of 53 patients in their White-centered 13 8 11
hemorrhage
study had visual loss in one or both eyes related to macular
hemorrhage. Central vein 7 0 4
Alterations in the retinal pigment epithelium caused by occlusion
leukemia have been reported by several authors.29–32 The appear- Vitreous 4 0 2
ance is one of pigment clumping or a reticular pattern of pigment hemorrhage
change. Pathologic examination demonstrates leukemic infiltra-
Leukemic 3
tion of the choroid and retina, with destruction and hyperplasia infiltrate
of the pigment epithelium.
From Schachat AP, Markowitz JA, Guyer DR, et al: Ophthalmic manifestations of
There are reports of bilateral central serous retinopathy in leukemia. Arch Ophthalmol 1989; 107:697. Copyright 1989, American Medical
acute lymphocytic leukemia as well as other serous retina Association.
2160 detachments.15–17,33 It is difficult to know whether the central

sectoral or regional atrophy of the retina and choroid that is
nonprogressive. Fukushima and associates38 demonstrated that
T cells responsive to HTLV-1-infected cells are cross-reactive
with retinal antigens, suggesting a possible mechanism for the
retinal degeneration.
Retinal infiltration similar to that seen in large-cell lym-
phoma may occur with HTLV-1 leukemia/lymphoma. Kumar
and colleagues39 described such a patient who presented with
deep retinal and subretinal infiltrates. Chorioretinal biopsy
demonstrated large atypical mononuclear cells located primarily
in the retinal pigment epithelium, but focally involving the
neurosensory retina.
HTLV-1 infection has been associated with anterior uveitis,
vitreous infiltration, and uveitis with retinal perivasculitis.40,41 Evi-
dence that the virus may be causative of these forms of uveitis
is presented in two studies. Nakao and co-workers42 demonstrated
that 41% of patients with nonspecific uveitis had positive titers
to HTLV-1, compared with ~23% of patients with other ocular
disorders. The latter percentage did not differ significantly from
the general population in this endemic area.
Mochizuki and associates43 found a 35% seroprevalence of
HTLV-1 in nonspecific uveitis patients in an endemic area,
versus 16% in patients attending the eye clinic who did not have
uveitis. The typical clinical picture included iritis, midvitreous
inflammation, and retinal vasculitis. In this study, proviral DNA
was detected by polymerase chain reaction in inflammatory cells
from the anterior chambers of seven of nine seropositive patients
with uveitis. The inflammatory cells from patients with other
forms of uveitis were tested, and none were positive.
A mother and son who were both infected with HTLV-1 devel-
oped white-yellow intraretinal lesions and vitreous opacities
without vitreous cells or anterior uveitis. The lesions did not
respond to systemic steroid administration, but later resolved
spontaneously.44
Cotton wool spots and Cytomegalovirus infection of the
retina have also been reported with this virus.40 A compre-
hensive review of the ocular findings in HTLV-1 can be found
in Buggage.45
POLYCYTHEMIA
Foulds2 pointed out that whole-blood viscosity is considerably
influenced by the number of red cells present. He found that
a b
FIGURE 170.6. (a) Retinal vascular dilatation and tortuosity, with intraretinal hemorrhage, in a case of hyperviscosity due to dysproteinemia.
Right eye. (b) Left eye of the patient in (a). There is disk hyperemia in addition to vascular dilatation, tortuosity, and intraretinal hemorrhage.
Retinopathy Associated with Blood Anomalies
clinical signs of hyperviscosity begin with a hematocrit value
greater than 50%. Wise and colleagues1 noted that there is a
linear relationship between viscosity and hematocrit value up
to a hematocrit of 50%. When the level is greater than this,
viscosity increases exponentially with the rising hematocrit
value. Blood flow in retinal vessels is typically laminar, and
Foulds noted that this may be responsible for the proportion-
ality of whole-blood viscosity to the shear rate; thus, whole-blood
viscosity is greater when blood flow is slower, and hyper-
viscosity, therefore, results in greater changes in the venous
system.
In polycythemia, the fundus typically shows dark, dilated,
tortuous veins (Figs 170.6 and 170.7). The disk is usually hyper-
emic and swollen, intraretinal hemorrhages are frequently seen,
and there may be retinal edema. Central or branch vein retinal
occlusions may occur. Patients may lose vision because of retinal
edema or vein occlusion. Abnormalities are almost always
present in both eyes; the patient with a central vein occlusion
CHAPTER 170
in one eye and a normal fellow eye rarely has underlying
polycythemia.
Bilateral vein occlusion in polycythemia secondary to
Eisenmenger syndrome has been reported.46 However, primary
polycythemia is more likely to produce retinopathy than is
secondary polycythemia, probably because of higher red cell
counts and hyperviscosity in the former.1 Treatment will reverse
most of the findings unless venous occlusion has occurred.
DYSPROTEINEMIAS
Key Features
• Retinopathy is usually bilateral
• Veins are dark, dilated, and tortuous; disk is hyperemic
• Intraretinal hemorrhages and cotton wool spots are seen
• Central or branch vein retinal occlusion may be found, as in
polycythemia
• Neovascularization of the retina or iris and neovascular
glaucoma can occur
• May also see serous retinal detachments and Purtscher-like
retinopathy
• A paraneoplastic degenerative retinopathy has been described
in Waldenström’s macroglobulinemia
2161
 RETINA AND VITREOUS
a b
SECTION 10
FIGURE 170.7. (a) Waldenström’s macroglobulinemia with venous dilatation and beading, as well as intraretinal hemorrhage. Right eye. (b) Left
eye of the patient in (a).
Dysproteinemia that results in hyperviscosity of the serum
from a variety of causes can produce a dramatic retinopathy.47
Carr and Henkind47 reported similar retinal findings in cases of
hyperviscosity caused by cryomacroglobulinemia, hypergam-
maglobulinemia, Waldenström’s macroglobulinemia, chronic
lymphoctyic leukemia with macroglobulinemia, and multiple
myeloma with hyperglobulinemia. Waldenström’s macroglobu-
linemia may be the most likely dysproteinemia to produce reti-
nopathy, possibly because the large size of the protein molecules
in this condition lead to very high viscosity levels.1 Holt and
Gordon-Smith,12 however, found no correlation between total
serum protein and retinopathy in their series. Rather, they
thought that the presence of retinopathy correlated with the
degree of anemia found in their patients. They noted that their
patients, as well as others reported in the literature with
Waldenström’s macroglobulinemia and retinopathy, exhibited
severe anemia.
In retinopathy of dysproteinemia, the retinal veins are dark,
dilated, and tortuous; intraretinal hemorrhages and cotton wool
spots are seen; and the disk is hyperemic. The retinal hemorrhages
may be of the superficial flame or deep punctate type and extend
to the periphery. Retinal edema may occur. Central or branch
vein retinal occlusion may be found, as in polycythemia. Visual
loss may be due to vascular occlusion or retinal edema. Abnor-
malities are usually found bilaterally.
Retinal microaneurysms may be seen in more chronic cases.48
Exudative retinal detachment has been described in multiple
myeloma.49,50 Neovascularization of the retina or iris with vitreous
hemorrhage or neovascular glaucoma can occur. Fibrous
proliferation has been described.
Retinopathy may be reversible with treatment of the underlying
disease if frank vein occlusion has not occurred.51
More recently a paraneoplastic retinopathy in a patient with
Waldenström’s macroglobulinemia has been reported with findings
of deteriorating vision, declining electroretinogram and presence
of serum antibodies against photoreceptor proteins.52
Cases of serous detachment of the retinal pigment epithelium
and neurosensory retina have been reported in patients with
paraproteinemia.53–55 The relationship of the paraproteinemia
to development of these serous leaks is uncertain since patients
were on steroids.
Purtscher-like retinopathy picture has also been reported in
hepatitis C-associated cryoglobulinemia.56
2162
HEMORRHAGIC DISORDERS
The retina is not typically involved in hemorrhagic disorders
unless there is ocular trauma. Thrombocytopenia is an exception,
particularly if there is accompanying anemia (as described earlier).
Idiopathic thrombocytopenic purpura rarely results in retino-
pathy.7 Thrombotic thrombocytopenic purpura may cause retinal
hemorrhages and serous retinal detachment; the relative roles of
thrombosis, hypertension, and renal disease in producing the reti-
nal findings are uncertain.57,58 Fundus appearance compatible
with Purtscher’s retinopathy has been reported in patients with
thrombotic thrombocytopenic purpura.59
APPROACH TO THE PATIENT WITH
RETINAL HEMORRHAGES OF UNKNOWN
CAUSE
The patient who presents with retinal hemorrhages can be a diag-
nostic dilemma, as the list of conditions involved in the differ-
ential diagnosis is long. The first task is to decide whether the
hemorrhages are intraretinal, subretinal, or preretinal. Intraretinal
hemorrhages are of two types: dot and blot, and flame. Dot and
blot hemorrhages are located deep in the retina and are confined
by the anteroposterior orientation of the rods and cones, bipolar
cells, and Müller’s cells. When viewed end-on through the ophthal-
moscope, they appear as round, red dots or somewhat larger
round ‘blots’. Flame hemorrhages are located in the superficial
retina and are confined by the mediolateral, arcing orientation
of the nerve fiber layer. When viewed with the ophthalmoscope,
they are flame shaped, with feathery borders. Flame hemorrhages
tend to occur mainly in the posterior portion of the retina. In
the periphery, hemorrhages appear as dots and blots regardless
of their level in the retina.60 Intraretinal hemorrhages occur in
a wide variety of disorders, including many systemic diseases and
retinal venous occlusions. Subretinal hemorrhages are amorphous
in shape and are deep to the retinal vessels. These hemorrhages
occur in trauma or with subretinal neovascularization (e.g., from
age-related maculopathy). Preretinal hemorrhages may also be
amorphous, or they may be boat shaped, with a horizontal
upper border and a curved lower border (caused by settling of red
cells). These hemorrhages cover retinal vessels. Preretinal hemor-
rhages occur with retinal neovascularization (e.g., in diabetic
retinopathy or sickle cell disease), vitreous detachment or retinal
 Retinopathy Associated with Blood Anomalies

breaks, and trauma. Occasionally, they are seen in other dis-
orders (e.g., vein occlusion without neovascularization, leukemia,
or subarachnoid hemorrhage).
Bilateral intraretinal hemorrhages pose the greatest challenge
to the differential diagnosis. Unilateral intraretinal hemorrhages
are most frequently due to venous occlusive disease. Bilateral
findings suggest systemic disease as the cause. The distribution
of the hemorrhages may be helpful. If they occur mainly in the
posterior fundus, systemic disease is likely. Extension to the far
periphery suggests venous occlusive disease. Confinement to
the peripapillary retina suggests optic nerve disease (including
papilledema). Accompanying findings may be helpful in the
differential diagnosis. Venous dilatation suggests obstructed
flow, which may be due to venous occlusion or hyperviscosity.
Microaneurysms are the hallmark of diabetic retinopathy, but
they occur with hypertension, venous occlusion, leukemia, and
other disorders. They are, however, a sign of chronicity. Arteriolar
narrowing and sclerotic changes suggest systemic hypertension.
Flame hemorrhages are more frequent in hypertension, with dot
and blot lesions more common in diabetes, but both lesions
occur in either disorder as well as in vein occlusion and retino-
pathy associated with blood disorders. Cotton wool spots or
white-centered hemorrhages often accompany retinal hemor-
rhages, and they may be seen in so many disorders that they are
of little help in the differential diagnosis. A thorough medical
history, general physical examination, complete blood count,
and blood glucose determination will reveal the cause of
bilateral, posterior intraretinal hemorrhages in the majority of
cases. Study of serum protein levels may be useful when hyper-
viscosity is suspected. Fluorescein angiography may be useful in
demonstrating subtle abnormalities of the retinal and choroidal
vasculature.

REFERENCES

1. Wise GN, Dollery CT, Henkind P: The retinal
circulation. New York: Harper & Row; 1971.
2. Foulds WS: Blood is thicker than water.
Some haemorrheological aspects of ocular
disease. 50th Bowman lecture. Eye 1987;
1:343.
3. Foulds WS: The ocular manifestations of
blood diseases. Trans Ophthalmol Soc UK
1963; 83:345.
4. Imai E, Kunikata H, Udono T, et al: Branch
retinal artery occlusion: a complication of
iron-deficiency anemia in a young adult
with a rectal carcinoid. Tohoku J Exp Med
2004; 203:141–144.
5. Matsuoka Y, Hayasaka S, Yamada K:
Incomplete occlusion of central retinal
artery in a girl with iron deficiency anemia.
Ophthalmologica 1996; 210:358–360.
6. Bahar I, Weinberger D, Kramer M, Axer-
Siegel R: Retinal vasculopathy in Fanconi
anemia: a case report. Retina 2005;
25:799–800.
7. Sandstrom H, Wahlin A, Eriksson M, et al:
Angioid streaks are part of a familial
syndrome of dyserythropoietic anaemia
(CDA III). Br J Haematol 1997; 98:845–849.
8. Beare NA, Southern C, Chalira C, et al:
Prognostic significance and course of
retinopathy in children with severe malaria.
Arch Ophthalmol 2004; 122:1141–1147.
9. Merin S, Freund M: Retinopathy in severe
anemia. Am J Ophthalmol 1968; 66:1102.
10. Aisen ML, Bacon BR, Goodman AM, et al:
Retinal abnormalities associated with
anemia. Arch Ophthalmol 1983; 101:1049.
11. Rubenstein RA, Yanoff M, Albert DM:
Thrombocytopenia, anemia, and retinal
hemorrhage. Am J Ophthalmol 1968; 65:435.
12. Holt JM, Gordon-Smith EC: Retinal
abnormalities in diseases of the blood. Br J
Ophthalmol 1969; 53:145.
13. Carraro MC, Rossetti L, Gerli GC:
Prevalence of retinopathy in patients with
anemia or thrombocytopenia. Eur J
Haematol 2001; 67:238–244.
14. Fletcher ME, Farber MD, Cohen SB, et al:
Retinal abnormalities associated with
anemia. [letter] Arch Ophthalmol 1984;
102:358.
15. Kincaid MC, Green WR, Kelley JS: Acute
ocular leukemia. Am J Ophthalmol 1979;
87:698.
16. Paydas S, Soylu MB, Disel U, et al: Serous
retinal detachment in a case with chronic
lymphocytic leukemia: no response to
systemic and local treatment. Leuk Res
2003; 27:557–559.
17. Miyamoto K, Kashii S, Honda Y: Serous
retinal detachment caused by leukemic
choroidal infiltration during complete
remission. Br J Ophthalmol 2000;
84:1318–1319.
18. Robb RM, Ervin LD, Sallan SE: A
pathologic study of eye involvement in
acute leukemia of childhood. Trans Am
Ophthalmol Soc 1978; 76:90.
19. Reddy SC, Jackson N: Retinopathy in
acute leukaemia at initial diagnosis:
correlation of fundus lesions and
haematological parameters. Acta
Ophthalmol Scand 2004; 82:81–85.
20. Guyer DR, Schachat AP, Vitale S, et al:
Leukemic retinopathy. Ophthalmology
1989; 96:860.
21. Karesh JW, Goldman EJ, Reck K, et al: A
prospective ophthalmic evaluation of
patients with acute myeloid leukemia:
correlation of ocular and hematologic
findings. J Clin Oncol 1989; 7:1528.
22. Duke JR, Wilkinson CP, Sigelman S: Retinal
microaneurysms in leukemia. Br J
Ophthalmol 1968; 52:368.
23. Jampol LM, Goldberg MF, Busse B:
Peripheral retinal microaneurysms in
chronic leukemia. Am J Ophthalmol 1975;
80:242.
24. Morse PH, McReady JL: Peripheral retinal
neovascularization in CML. Am J
Ophthalmol 1971; 72:975.
25. Schachat AP: The leukemias and
lymphomas. In: Ryan SJ, Ogden TE,
Schachat AP, eds. Retina. St Louis:
CV Mosby; 1989.
26. Kincaid MC, Green WR: Ocular and orbital
involvement in leukemia. Surv Ophthalmol
1983; 27:211.
27. Schachat AP, Markowitz JA, Guyer DR, et al:
Ophthalmic manifestations of leukemia.
Arch Ophthalmol 1989; 107:697.
28. Reddy SC, Jackson N, Menon BS: Ocular
involvement in leukemia – a study of 288
cases. Ophthalmologica 2003; 217:441–445.
29. Clayman HM, Flynn JJ, Koch K, et al:
Retinal pigment epithelial abnormalities in
leukemic disease. Am J Ophthalmol 1972;
74:416.
30. Jakobiec F, Behrens M: Leukemic retinal
pigment epitheliopathy, with report of a
unilateral case. J Pediatr Ophthalmol 1975;
12:10.
CHAPTER 170
31. Inkeles DM, Friedman AH: Retinal pigment
epithelial degeneration, partial retinal
atrophy and macular hole in acute
lymphocytic leukemia. Graefes Arch Clin
Exp Ophthalmol 1975; 194:253.
32. Verbraak FD, van den Berg W, Bos PJM:
Retinal pigment epitheliopathy in acute
leukemia. Arch Ophthalmol 1991; 111:111.
33. Burns CA, Blodi FC, Williamson BK: Acute
lymphocytic leukemia and central serous
retinopathy. Trans Am Acad Ophthalmol
Otolaryngol 1965; 69:307.
34. Kuwabara T, Aiello L: Leukemic miliary
nodules in the retina. Arch Ophthalmol
1964; 72:494.
35. Spalton DJ, Nicholson F: HTLV-I infection in
human disease. Br J Ophthalmol 1991;
75:174.
36. Nakao K, Ohba N, Isahiki M, et al:
Pigmentary retinal degeneration in patients
with HTLV-1 associated myelopathy. Jpn J
Ophthalmol 1989; 33:383.
37. Ohba N, Nakao K, Isahiki Y: HTLV-1
associated retinochoroidal degeneration.
Jpn J Ophthalmol 1996; 40:71.
38. Fukushima A, Veno H, Fujimoto S: HTLV-1
and retinal antigens recognized by T cells.
Nippon Ganka Gakkai Zasshi 1994; 98:157.
39. Kumar SR, Gill PS, Wagner DG, et al:
Human T-cell lymphotrophic virus type
1-associated retinal lymphoma. A
clinicopathologic report. Arch Ophthalmol
1994; 112:954.
40. Ohba N, Matsumoto M, Sakeshima M,
et al: Ocular manifestations in patients
infected with human T-lymphotrophic
virus type 1. Jpn J Ophthalmol
1989; 33:1.
41. Sasaki K, Morooka I, Inomata H, et al:
Retinal vasculitis in human T-cell
lymphotrophic virus type I associated
myelopathy. Br J Ophthalmol 1989; 73:812.
42. Nakao K, Matsumoto M, Ohba N:
Seroprevalence of antibodies to HTLV-1 in
patients with ocular disorders. Br J
Ophthalmol 1991; 75:76.
43. Mochizuki M, Watanabe T, Yamaguchi K,
et al: Uveitis associated with human T-cell
lymphotrophic virus type I. Am J
Ophthalmol 1992; 114:123.
44. Hayasaka S, Takatori Y, Noda S, et al:
Retinal vasculitis in a mother and her son
with human T-lymphotrophic virus type 1
associated myelopathy. Br J Ophthalmol
1991; 75:566.
2163
 RETINA AND VITREOUS
45. Buggage RR: Ocular manifestations of
human T-cell lymphotropic virus type 1
infection. Curr Opin Ophthalmol 2003;
14:420–425.
46. Rodriguez N, Eliott D: Bilateral central
retinal vein occlusion in Eisenmenger
syndrome. Am J Ophthalmol 2001;
132:268–269.
47. Carr RE, Henkind P: Retinal findings with
serum hyperviscosity. Am J Ophthalmol
1963; 56:23.
48. Gates RF, Richards RD: Macroglobulinemia
with unusual vascular changes. Arch
Ophthalmol 1960; 77:64.
49. Ashton N: Ocular changes in multiple
myelomatosis. Arch Ophthalmol 1965;
73:487.
50. Franklin RM, Kenyon KR, Green WR, et al:
Epibulbar IGA plasmacytoma occurring in
multiple myeloma. Arch Ophthalmol 1982;
100:451.
SECTION 10
2164
51. Schwab PJ, Okun E, Fahey JL: Reversal of
retinopathy in Waldenström’s
macroglobulinemia by plasmapheresis.
Arch Ophthalmol 1960; 64:515.
52. Sen HN, Chan CC, Caruso RC, et al:
Waldenstrom’s macroglobulinemia-
associated retinopathy. Ophthalmology
2004; 111:535–539.
53. Cohen SM, Kokame GT, Gass JDM:
Paraproteinemias associated with serous
detachments of the retinal pigment
epithelium and neurosensory retina. Retina
1996; 16:467.
54. Zamir E, Chowers I: Central serous
chorioretinopathy in a patient with
cryoglobulinaemia. Eye 1999;
13(Pt 2):265–266.
55. Ogata N, Ida H, Takahashi K, et al: Occult
retinal pigment epithelial detachment in
hyperviscosity syndrome. Ophthalmic Surg
Lasers 2000; 31:248–252.
56. Myers JP, Di Bisceglie AM, Mann ES:
Cryoglobulinemia associated with
Purtscher-like retinopathy. Am J
Ophthalmol 2001; 131:802–804.
57. Lambert SR, High KA, Cotlier E, et al:
Serous retinal detachments in thrombotic
thrombocytopenic purpura. Arch
Ophthalmol 1985; 103:1172.
58. Percival SPB: Ocular findings in thrombotic
thrombocytopenic purpura (Moschcowitz’s
disease). Br J Ophthalmol 1970; 54:73.
59. Power MH, Regillo CD, Custis PH:
Thrombotic thrombocytopenic purpura
associated with Purtscher retinopathy. Arch
Ophthalmol 1997; 115:128.
60. Ballantyne AJ, Michaelson IC: Textbook of
the fundus of the eye. 2nd edn. Baltimore:
Williams & Wilkins; 1970.
 CHAPTER
171 Posterior Segment Sarcoidosis
Anita G. Prasad, Daniel Wee, and Russell N. Van Gelder
Overview
Sarcoidosis is a multiorgan inflammatory disease of unknown
etiology that is a frequent cause of ocular inflammation. The
histologic hallmark of disease is the noncaseating granuloma.
Posterior segment findings include vitritis, choroiditis, vasculitis,
retinal ischemia, and retinal neovascularization. The differential
diagnosis for sarcoidosis is broad; definitive diagnosis requires
biopsy, although certain laboratory tests such as CT scanning,
gallium scanning, and ACEs have adjunctive diagnostic value.
Treatment requires corticosteroid medications and/or
immunomodulation, and frequently requires systemic treatment,
particularly if organs besides the eye are involved.
Key Features
• Vitritis
• Choroiditis
• Vasculitis
• Retinal ischemia
• Retinal neovascularization
Sarcoidosis is a chronic, multiorgan inflammatory disease of
unknown etiology. Sarcoidosis can be a very frustrating disease
for the patient and clinician alike. The pathogenesis of the
disease is largely unknown, risk factors for its acquisition are
not well understood, its clinical manifestations are protean,
clinical diagnosis is challenging, treatments are nonspecific,
and prognosis is variable. As sarcoidosis is a relatively common
cause of uveitis (in both the anterior and posterior segment), it
belongs on the differential diagnosis in many cases. It is
important for the clinician to be aware of the varied clinical
appearances of sarcoidosis and to be facile with the diagnostic
workup and management of this disease.
EPIDEMIOLOGY
The incidence and prevalence of sarcoidosis vary markedly with
geographic location. Because strict diagnostic criteria are not
always followed in epidemiologic studies of sarcoidosis, accurate
estimates of disease rates are not available. Older data from the
United States suggest an annual incidence in African-Americans of
82 per 100 000 person-years, compared with 8 per 100 000 person-
years in the Caucasian population.1 It is believed that Latino-
Americans are more commonly affected than Caucasians. The
disease is also common in northern Europe, with an incidence
of 20 per 100 000 in the United Kingdom, and 24 per 100 000
in Sweden.2 There is no firm consensus on the relative rates of
disease between the genders; some studies have suggested a female
preponderance up to 2:1, while others report equal incidence
between the genders. The disease is most typically diagnosed in
the third decade.2
Several studies have attempted to identify risk factors for
development of sarcoidosis. The predominant risk factor in the
Isle of Man study was living in close proximity to an individual
with known sarcoidosis.3–6 Husband–wife pairs with disease have
been identified frequently. There is a familial association in
first- and second-degree blood relatives as well, although this
appears stronger in Caucasian cases than in African-American
cases.7 Nurses have a sevenfold higher lifetime risk of sarcoidosis
than the average population.8 These findings suggest a trans-
missible agent responsible for at least triggering, if not causing,
chronic disease. Consistent with this, organ transplantation
studies have suggested that the disease may be transferred with
diseased organs.9–11 In one study, an individual with a known
history of sarcoidosis served as a bone marrow donor for his
brother, who did not have disease. Despite aggressive immuno-
modulation post-transplant, the sibling developed sarcoidosis
within several weeks of the transplant. Sarcoidosis has also
been associated with cardiac transplantation from an affected
donor. Interestingly, sarcoid-positive recipients typically redevelop
disease in naïve organs.12 The estimated rate of redevelopment
of pulmonary sarcoidosis in lung transplant recipients is close
to 80%.
Several candidate pathogens have been proposed as causative
for sarcoidosis. L-form mycobacteria are cell wall-less bacteria
that have been found in a subset of lymph nodes affected with
sarcoidosis13; myobacterial DNA has been detected sporadically
in lymph nodes from confirmed sarcoidosis cases as well.14,15
Other studies have suggested an association with human herpes
virus 8 (HHV-8) with sarcoidosis in Europe,16 although this asso-
ciation has not been confirmed in several other populations.17,18
Most recently, members of the genus Propionibacterium, particu-
larly Propionibacterium granulosum, have been found with high
frequency in lymph node biopsies of patients with proven sar-
coidosis.15,19 To date, however, Koch's postulates have not been
fulfilled for any infectious organism in sarcoidosis.
In addition to sporadic cases, familial variants of sarcoidosis
(with juvenile onset) are well documented. Blau syndrome is a
multisystem granulomatous disease presenting in childhood.
Unlike sarcoidosis, Blau syndrome typically spares the lungs; how-
ever, uveitis can be a presenting complaint and the clinical appear-
ance of Blau syndrome can be identical to sarcoidosis. Patients
will often present with juvenile arthritis. Recently, Blau syndrome
has been shown to be due to mutations in CARD15/NOD2, a
gene involved in regulation of inflammation and apoptosis (and
also associated with Crohns’ disease).20,21 However, sarcoidosis
(and in particular the uveitis associated with sarcoidosis) does
not appear to be associated with these mutations.22,23 2165
 RETINA AND VITREOUS
SECTION 10
FIGURE 171.1. Sarcoid granulomas in the choroids from an
enucleated eye.
HISTOPATHOLOGY
The defining feature of sarcoidosis is the formation of the non-
caseating granuloma (Fig. 171.1). These granulomas may be found
in nearly any organ of the body, but typically target the lungs,
thoracic lymph nodes, skin, and eyes. The granulomas are pre-
dominantly composed of epithelioid multinucleated giant cells,
which are essentially aggregated macrophages. The predominant
lymphocytic cell type is the CD4+ T-cell, which is found in the
periphery of the granuloma. Smaller numbers of CD8+ T-cells
and B-cells are also present within the granuloma. The histo-
pathology is consistent with an exaggerated immune response
in target organs. The predominant inflammatory response is
Th1 mediated, with a preponderance of interferon gamma and
interleukin-2, as well as production of tumor necrosis factor
and interleukin-6 by macrophages. Progression of granulomas
culminates in tissue damage, fibrosis, and end organ destruction.
The noncaseating granuloma is not specific for sarcoidosis,
however. Noncaseating granulomas can also be seen in response
to hypersensitivity pneumonitis (including berylliosis, asbestosis,
or silicosis), mycobacterial infections, or fungal infection. Diag-
nosis is considered definitive when the noncaseating granuloma
is seen in the setting of characteristic clinical findings.
SYSTEMIC CLINICAL FINDINGS
Sarcoidosis can affect nearly any organ in the body. The lung is
the most frequently involved organ, with greater than 90% of
patients affected. The next most commonly affected organs
include the lymph nodes, skin, eyes, and liver, each affected in
approximately one-quarter of patients.24 Pulmonary findings range
from asymptomatic discovery on routine chest radiograph, to
severe pulmonary fibrosis and restrictive lung disease. A stand-
ardized staging scheme is employed in the reading of chest radio-
graphs of patients with sarcoidosis. Bilateral hilar adenopathy
constitutes stage 1 disease. Parenchymal involvement with hilar
adenopathy defines stage 2; in stage 3 disease, parenchymal
involvement is seen without hilar adenopathy. In stage 4 disease,
pulmonary fibrosis is seen, which may be accompanied by
bronchiectasis.
The skin is involved in an estimated 18–32% of cases. The
most typical skin lesion is erythema nodosum. These are typi-
cally elevated red lesions often found on the lower extremity
(such as the shins). These are a nonspecific finding and can be
identified in a number of hypersensitivity conditions. Since these
2166 lesions do not contain granulomas, it is not worthwhile to biopsy
them to make a diagnosis; biopsy will typically demonstrate
septal panniculitis.
Central nervous system sarcoidosis occurs in ~5% of patients
with systemic sarcoidosis, and is most commonly associated with
cranial neuropathy, which may be multiple or bilateral. Facial
nerve involvement is most common. Optic neuropathy occurs in
~3% of patients with systemic sarcoidosis. Rarely, more gener-
alized aseptic meningitis may be the presenting sign of sarcoidosis.
In addition to these chronic presentations of sarcoidosis, the
disease can occasionally present acutely. Lofrgren syndrome is
characterized by acute fever, arthralgias, erythema nodosum, and
bilateral hilar adenopathy. Heerfordt–Waldenström syndrome
(also called uveo-parotid fever) is the combination of fever, parotid
enlargement, and uveitis.
RETINAL INVOLVEMENT
In most studies, the eye is reported to be involved in ~20–25%
of cases of sarcoidosis,25 although some studies suggest rates as
high as 60%. Of those patients with ocular involvement, posterior
segment disease is thought to occur in ~25%.26 Sarcoidosis is
thought to be responsible for between 4% and 8% of uveitis cases
in referral centers.27,28 Ocular involvement may be the initial
manifestation of sarcoidosis, and patients may present with
classic uveitic symptoms of redness, pain, photophobia, floaters,
or scotomas, or they may be asymptomatic.29,30 There are no
specific signs unique to the eye; the disease can present in the
anterior segment, as intermediate uveitis, in the posterior pole,
or as panuveitis. Although posterior segment disease is typically
associated with anterior segment inflammation, retinal findings
may occur in isolation. Anterior segment disease can present as
nongranulomatous or granulomatous inflammation. The latter
is typified by large, ‘mutton fat’ keratic precipitates as well as iris
nodules. Posterior synechia are commonly seen. The anterior
segment can show significant ciliary flush or conjunctival injec-
tion; it can also be relatively quiet even with active anterior
segment disease.
The most common posterior segment findings in sarcoidosis are
vitritis, choroidal punched-out lesions, snowball lesions, cystoid
macular edema, periphlebitis, and epiretinal membrane.29 In cases
associated with ischemia, neovascularization can develop. Isolated
or optic nerve granulomas are also typical of the disease.
The intermediate uveitis associated with sarcoidosis can be
isolated, or can be associated with punched-out choroidal lesions
or retinal granulomas. Approximately 10% of sarcoidosis presents
as an isolated intermediate uveitis,31 and this entity must be
considered in the differential diagnosis of isolated intermediate
uveitis.
The choroidal lesions are often the principal posterior segment
finding in sarcoidosis. The lesions may be large, isolated granu-
lomas (Fig. 171.2), or can be small, clustered yellowish lesions
(Fig. 171.3). The lesions are most commonly found in the
inferior equatorial retina. By themselves, these lesions rarely lead
to visual dysfunction unless they are localized to the macula. They
may be associated, however, with panuveitis, vitritis, or cystoid
macular edema. Angiographically, the lesions will typically show
early blockade of fluorescence, with late staining, typical of
inflammatory lesions in the posterior pole. Resolved lesions
may show only RPE window defects (Fig. 171.4). With treatment,
choroidal granulomas secondary to sarcoidosis can resolve com-
pletely, without pigment epithelial change; however, chronic
lesions may show evidence of scarring (Fig. 171.4). Rarely,
sarcoidosis lesions may resemble serpiginous choroiditis lesions.32
Retinal vasculitis may be the predominant finding in sarcoi-
dosis involving retina. Vasculitis is typically limited to the venous
system, with sparing of the arteries, although arterial involvement
has been reported. The location can be peripheral, or can be in
 Posterior Segment Sarcoidosis

the posterior pole (Fig. 171.5). Extensive perivascular exudates

are called candle wax drippings or ‘taches de bougies’. In severe
cases, the vasculitis can lead to branch retinal vein occlusions
which, in turn, may lead to ischemia and neovascularization.
Complications from ocular manifestations of posterior segment
sarcoidosis are common. Cystoid macular edema has been noted
in approximately three-fourths of patients with posterior seg-
ment sarcoidosis, cataract in about half, and glaucoma in about
one-third. Retinal ischemia and neovascularization are reported
to occur in 16% and 11%, respectively.29

DIFFERENTIAL DIAGNOSIS
The differential diagnosis for posterior segment inflammation
containing features seen in sarcoidosis is remarkably broad. Iso-
lated intermediate uveitis may be due to Lyme disease, syphilis,
tuberculosis, pars planitis, multiple sclerosis, or intraocular
lymphoma. Disease associated with retinal or choroidal granu-

FIGURE 171.2. Resolving solitary choroidal granuloma in a patient
with sarcoidosis.
CHAPTER 171
lomas has a similar differential diagnosis, but also includes bird-
shot chorioretinopathy, multifocal choroiditis with panuveitis,
acute posterior multifocal placoid pigment epitheliopathy
(APMPPE), cat scratch disease, toxoplasmosis, toxocariasis,
Vogt–Koyanagi–Harada syndrome, sympathetic ophthalmia, bru-
cellosis, Whipple's disease, and ocular candidiasis. With marked
phlebitis, collagen vascular diseases (including Wegener’s granulo-
matosis, systemic lupus erythematosus, Behcet’s disease, Eales'
disease, and frosted branch angiitis) should also be considered. If
the patient is immunocompromised, cytomegalovirus (CMV)
retinitis and other HIV-associated diseases must be considered.

LABORATORY TESTING
Unfortunately, there is no highly specific and sensitive labora-
tory test for the diagnosis of sarcoidosis, except for tissue
biopsy. It is always worth examining the conjunctiva carefully
for the presence of granulomas, which have been reported to
occur in as many as 40% of sarcoidosis patients.26 In older
patients with either chest radiograph abnormalities or elevated
angiotensin converting enzyme (ACE) levels, the yield on
nondirected conjunctival biopsy may exceed 50%33; in other
populations, the yield is lower.34 Probably, the most effective
means for finding tissue to make a definitive biopsy is
performing CT scan of the chest; in one recent series of elderly
women with uveitis typical for either sarcoidosis or lymphoma,
FIGURE 171.3. Multiple small granulomas associated with 57% had hilar adenopathy on CT scan, and 82% of these were
sarcoidosis. found to have sarcoidosis on biopsy or bronchoscopy. However,

a b

FIGURE 171.4. (a,b) Inactive peripheral choroidal lesions with window retinal pigment epithelial defects secondary to sarcoidosis. 2167
 RETINA AND VITREOUS
SECTION 10
FIGURE 171.5. Circinate subretinal granulomas with focal
periphlebitis (taches du bougie).
before commencing with this test, one should consider carefully
whether one is prepared to follow the CT with bronchoscopy or
mediastinoscopy; in many cases, it may not be essential to
make a definitive diagnosis in order to guide therapy.
The ACE test measures serum levels of the hydrolase enzyme
involved in blood pressure regulation. It is present on the
luminal surface of vascular endothelial cells, as well as in cells
of the macrophage–monocyte system. The ACE level is thought
to be a measure of total granuloma load on the body. The test,
unfortunately, is neither highly sensitive nor highly specific.
Sensitivity varies in different studies between approximately
40% and 80%.35–38 The specificity is somewhat higher, and has
been estimated to be as high as 90%. This yields a positive
predictive value for an elevated ACE level of ~84–90%. However,
negative predictive values are very poor. In addition, patients
who are taking ACE inhibitors will have depressed levels, as will
patients who are already on anti-inflammatory (such as corti-
costeroid) treatment. Other diseases to consider in the setting
of elevated ACE level include miliary tuberculosis, atypical
mycobacterial infections, asbestosis and silicosis, primary biliary
cirrhosis, and hyperthyroidism.
A number of other tests have been advocated for the diagnosis
of sarcoidosis, including serum lysozyme, serum calcium, and
cutaneous anergy. All suffer from low sensitivity and specificity.
Human Leukocyte Antigen (HLA) typing is not useful in the
diagnosis of sarcoidosis, although weak disease susceptibility has
been associated with HLA-B8 and HLA-DRB1.39–41 Gallium
scanning measures the uptake of gallium-67, which localizes to
areas of active inflammation. This may be useful in distinguish-
ing lymphoma from sarcoidosis; in the former, peripheral lymph
node uptake is increased, while in the latter bilateral hilar uptake
is noted. The finding of increased uptake in the lacrimal and
parotid glands (the panda sign) has been seen between 60% and
87% of the time in sarcoidosis patients.35,36 Specificity is
relatively high. The combination of a positive gallium scan and
elevated ACE level has high specificity (>90%) for sarcoidosis;
however, this does not serve as a substitute for tissue biopsy for
definitive diagnosis.
The older literature refers to the Kveim–Siltzbach reaction.42
In this test, intradermal injection of a tissue suspension derived
from the spleen of a sarcoidosis patient results in local develop-
ment of sarcoid granuloma. The lesions typically form 2–6 weeks
after injection. The inciting antigen in this preparation is
unknown. The test is not used in routine clinical settings.
In cases where sarcoidosis is clinically suspected, the following
2168 approach may be considered. First, common or medically
threatening conditions with similar clinical appearances are ruled
out. This will typically involve placing a PPD and obtaining a
chest radiograph for evaluation of tuberculosis, testing FTA-ABS
and/or RPR for syphilis, and possibly other serologic or blood tests
for specific infections such as Lyme disease, toxoplasmosis, or
toxocariasis. A careful examination for conjunctival granulomas
or enlarged lacrimal gland should be performed; if found, this
may be the easiest site for biopsy. If this workup is negative,
consideration may be given to chest CT to identify hilar adeno-
pathy; alternatively, ACE and gallium scanning may be per-
formed (although the negative predictive value for such testing
may be limited). In the setting of abnormal ACE or gallium scan,
a nondirected conjunctival biopsy may be acquired.
If a diagnosis of sarcoidosis is made in the setting of positive
chest radiograph, positive chest CT, or positive review of systems
for shortness of breath or chronic cough, consideration should
be given to obtaining pulmonary function tests. Given a positive
workup, a complete blood count and comprehensive metabolic
panel including hepatic and renal function tests should be
obtained, both to seek possible signs of systemic sarcoidosis and
to help tailor therapy.
Specific ocular testing may be required to fully characterize
the ophthalmic manifestations of disease. Fluorescein angiogra-
phy and optical coherence tomography may be of great value in
characterizing and following cystoid macular edema. Angiography
can also indicate areas of occult vasculitis, and can demonstrate
optic nerve head leakage. ICG angiography reveals several potential
patterns of choroidal disease, including focal hypo- and hyper-
fluorescence and late choroidal vessel leakage which are relatively
nonspecific but may be useful in following disease activity.43,44
TREATMENT
Treatment Options
• Local
• Topical corticosteroids (i.e., prednisolone acetate)
• Periocular corticosteroids (i.e., triamcinolone acetonide)
• Cycloplegics (homatropine 5%, scopolamine 0.25%)
• Systemic
• Corticosteroids
• Methotrexate
• Azathioprine
• Cyclosporin A
• Infliximab
• Adalimumab
• Alkylating agents (cyclophosphamide, chlorambucil)
In initiating therapy for posterior segment sarcoidosis, the primary
consideration is whether the patient has systemic involvement
warranting treatment; this will dictate whether the first approach
must include systemic medication. Typically, pulmonologists
will not treat stage 1 disease but will treat stage 2 or higher dis-
ease. The mainstay of treatment of sarcoidosis is corticosteroid
therapy; for posterior segment disease, the treatment options
include systemic administration, periocular injection, and intra-
ocular administration. For bilateral or sight-threatening disease,
systemic corticosteroids are frequently employed, unless the
patient has absolute contraindications to this treatment (such as
brittle diabetes or severe psychiatric disease). Cycloplegia should
be employed to reduce the risk of posterior synechia formation.
With rare exceptions, posterior segment sarcoidosis will not
respond to topical medication; however, topical corticosteroids are
a mainstay of treatment for the anterior segment inflammation
that often accompanies posterior segment inflammation. Peri-
ocular corticosteroids (typically triamcinolone acetonide admin-
 Posterior Segment Sarcoidosis

istered 20–40 mg either applied beneath Tenon’s capsule or
retroseptally through inferior or superior approaches) offer the
benefits of sustained continuous release and high intraocular con-
centrations. However, this approach is associated with iatrogenic
cataract formation, steroid responsive ocular hypertension, cos-
metic concerns, and rarely injury to the globe or its circulation.
Recently, intravitreal corticosteroid administration has been used
in small numbers of patients for the treatment of refractory
cystoid macular edema and isolated choroidal granulomas asso-
ciated with sarcoidosis, with encouraging short-term results.45,46
The recently approved fluocinolone acetonide intravitreal implant
releases a constant dose of corticosteroid intraocularly for over
2 years, and may be appropriate for patients with chronic pos-
terior segment inflammation.47,48
As sarcoidosis is typically a chronic condition, patients will
frequently require long-term treatment, which may require
initiation of treatment with steroid sparing agents. All classes of
immunomodulatory drugs, including antimetabolites (methotrex-
ate, mycophenolate mofetil, and azathioprine), anti-T-cell activa-
tion factors (cyclosporine A, tacrolimus), biologics (infliximab and
adalimumab), and alkylating agents (cyclophosphamide and
chlorambucil), have been utilized.49–51 Unfortunately, no well-
controlled prospective clinical trials on the efficacy of these treat-
ments has been performed to date.

REFERENCES
1. Bresnitz EA, Strom BL: Epidemiology 16. Di Alberti L, Porter SR, Piatelli A, et al: 32. Edelsten C, Stanford MR, Graham EM:
of sarcoidosis. Epidemiol Rev 1983; Human herpesvirus 8 and sarcoidosis. Serpiginous choroiditis: an unusual
5:124–156. Lancet 1998; 351:1589–1590. presentation of ocular sarcoidosis. Br J

2. Milman N, Selroos O: Pulmonary
sarcoidosis in the Nordic countries
1950–1982. Epidemiology and clinical
picture. Sarcoidosis 1990; 7:50–57.
3. Ayres JG: Epidemiology of sarcoidosis in
the Isle of Man. Thorax 1987; 42:911–911.
4. Hills SE, Parkes SA, Baker SB:
Epidemiology of sarcoidosis in the Isle of
Man. 2. Evidence for space-time clustering.
Thorax 1987; 42:427–430.
5. Parkes SA, Baker SB, Bourdillon RE, et al:
Epidemiology of sarcoidosis in the Isle of
Man. 1. A case controlled study. Thorax
1987; 42:420–426.
6. Parkes SA, Baker SB, Bourdillon RE, et al:
Incidence of sarcoidosis in the Isle of Man.
Thorax 1985; 40:284–287.
7. Rybicki BA, Iannuzzi MC, Frederick MM,
et al: ACCESS Research Group Familial
aggregation of sarcoidosis. A case-control
etiologic study of sarcoidosis (ACCESS).
Am J Respir Crit Care Med 2001;
164:2085–2091.
8. Edmondstone WM: Sarcoidosis in nurses:
is there an association? Thorax 1988;
43:342–343.
9. Burke WM, Keogh A, Maloney PJ, et al:
Transmission of sarcoidosis via cardiac
transplantation. Lancet 1990;
336:1579–1579.
10. Heyll A, Mecjenstock G, Aul C, et al:
Possible transmission of sarcoidosis via
allogeneic bone marrow transplantation.
Bone Marrow Transplant 1994; 14:161–164.
11. Padilla ML, Schilero GJ, Teirstein AS:
Donor-acquired sarcoidosis. Sarcoidosis
Vasc Diffuse Lung Dis 2002; 19:18–24.
12. Muller C, Briege J, Haller M, Vogelmeier C,
Bittman I, Welz A Furst H, Dienemann H,
et al: Sarcoidosis recurrence following lung
transplantation. Transplantation 1996;
61:1117–1119.
13. Cantwell AR, Jr.: Histologic observations of
variably acid-fast pleomorphic bacteria in
systemic sarcoidosis: a report of 3 cases.
Growth 1982; 46:113–125.
14. Ikonomopoulos JA, Gourgoulis VG,
Zacharatos PV, et al: Multiplex polymerase
chain reaction for the detection of
mycobacterial DNA in cases of tuberculosis
and sarcoidosis. Mod Pathol 1999;
12:854–862.
15. Ishige I, Usui Y, Takemura T, Eishi Y:
Quantitative PCR of mycobacterial and
propionibacterial DNA in lymph nodes of
Japanese patients with sarcoidosis. Lancet
1999; 354:120–123.
17. Knoell KA, Hendrix JD, Jr., Stoler MH, et al:
Absence of human herpesvirus 8 in
sarcoidosis and crohn disease granulomas.
Arch Dermatol 2005; 141:909–910.
18. Maeda H, Niimi T, Sato S, et al: Human
herpesvirus 8 is not associated with
sarcoidosis in Japanese patients. Chest
2000; 118:923–927.
19. Hiramatsu J, Kataoka M, Nakata Y, et al:
Propionibacterium acnes DNA detected in
bronchoalveolar lavage cells from patients
with sarcoidosis. Sarcoidosis Vasc Diffuse
Lung Dis 2003; 20:197–203.
20. Wang X, Kuivaniemi H, Bonavita G, et al:
CARD15 mutations in familial
granulomatosis syndromes: a study of the
original Blau syndrome kindred and other
families with large-vessel arteritis and
cranial neuropathy. Arthritis Rheum 2002;
46:3041–3045.
21. Miceli-Richard C, Lesage S, Rybojad M,
et al: CARD15 mutations in Blau syndrome.
Nat Genet 2001; 29:19–20.
22. Schurmann M, Valentonyte R, Hampe J,
et al: CARD15 gene mutations in
sarcoidosis. Eur Respir J 2003; 22:748–754.
23. Martin TM, Doyle TM, Smith JR, et al:
Uveitis in patients with sarcoidosis is not
associated with mutations in NOD2
(CARD15). Am J Ophthalmol 2003;
136:933–935.
24. Siltzbach LE, James DG, Neville E, et al:
Course and prognosis of sarcoidosis
around the world. Am J Med 1974;
57:847–852.
25. Jabs DA, Johns CJ: Ocular involvement in
chronic sarcoidosis. Am J Ophthalmol
1986; 102:297–301.
26. Obenauf CD, Shaw HE, Sydnor CF,
Klintworth GK: Sarcoidosis and its
ophthalmic manifestations. Am J
Ophthalmol 1978; 86:648–655.
27. Rodriguez A, Calonge M, Pedroza-Seres M,
et al: Referral patterns of uveitis in a tertiary
eye care center. Arch Ophthalmol 1996;
114:593–599.
28. Perkins ES: Epidemiology of uveitis. Trans
Ophthalmol Soc UK 1976; 96:105–107.
29. Rothova A: Ocular involvement in
sarcoidosis. Br J Ophthalmol 2000;
84:110–116.
30. Rothova A, Alberts C, Glasius E, et al: Risk
factors for ocular sarcoidosis. Doc
Ophthalmol 1989; 72:287–296.
31. Graham EM, Edelsten C: Intermediate
uveitis and sarcoidosis. Dev Ophthalmol
1992; 23:106–110.
CHAPTER 171
Ophthalmol 1994; 78:70–71.
33. Hershey JM, Pulido JS, Folberg R, et al:
Non-caseating conjunctival granulomas in
patients with multifocal choroiditis and
panuveitis. Ophthalmology 1994;
101:596–601.
34. Spaide RF, Ward DL: Conjunctival biopsy in
the diagnosis of sarcoidosis. Br J
Ophthalmol 1990; 74:469–471.
35. Power WJ, Neves RA, Rodriguez A, et al:
The value of combined serum angiotensin-
converting enzyme and gallium scan in
diagnosing ocular sarcoidosis.
Ophthalmology 1995; 102:2007–2011.
36. Baughman RP, Shipley R, Eisentrout CE:
Predictive value of gallium scan,
angiotensin-converting enzyme level, and
bronchoalveolar lavage in two-year follow-
up of pulmonary sarcoidosis. Lung 1987;
165:371–377.
37. Lieberman J, Sastre A: An angiotensin-
converting enzyme (ACE) inhibitor in human
serum. Increased sensitivity of the serum
ACE assay for detecting active sarcoidosis.
Chest 1986; 90:869–875.
38. Klech H, Kohn H, Kummer F, Mostbeck A:
Assessment of activity in sarcoidosis.
Sensitivity and specificity of 67gallium
scintigraphy, serum ACE levels, chest
roentgenography, and blood lymphocyte
subpopulations. Chest 1982; 82:732–738.
39. Dubaniewicz A, Szczerkowska Z, Hoppe A:
Comparative analysis of HLA class I
antigens in pulmonary sarcoidosis and
tuberculosis in the same ethnic group.
Mayo Clin Proc 2003; 78:436–442.
40. Hedfors E, Lindstrom F: HLA-B8/DR3 in
sarcoidosis. Correlation to acute onset
disease with arthritis. Tissue Antigens
1983; 22:200–203.
41. Olenchock SA, Heise ER, Marx JJ Jr, et al:
HLA-B8 in sarcoidosis. Ann Allergy 1981;
47:151–153.
42. Teirstein AS: Kveim antigen: what does it
tell us about causation of sarcoidosis?
Semin Respir Infect 1998; 13:206–211.
43. Matsuo T, Itami M, Shiraga F:
Choroidopathy in patients with sarcoidosis
observed by simultaneous indocyanine
green and fluorescein angiography. Retina
2000; 20:16–21.
44. Wolfensberger TJ, Herbort CP: Indocyanine
green angiographic features in ocular
sarcoidosis. Ophthalmology 1999;
106:285–289.
45. Larsson J, Hvarfner C, Skarin A: Intravitreal
triamcinolone in two patients with refractory 2169
 RETINA AND VITREOUS
macular oedema in sarcoid uveitis. Acta
Ophthalmol Scand 2005; 83:618–619.
46. Chan WM, Lim E, Liu DT, et al: Intravitreal
triamcinolone acetonide for choroidal
granuloma in sarcoidosis. Am J Ophthalmol
2005; 139:1116–1118.
47. Jaffe GJ, Ben-Nun J, Guo H, et al:
Fluocinolone acetonide sustained drug
delivery device to treat severe uveitis.
Ophthalmology 2000; 107:2024–2033.
SECTION 10
2170
48. Jaffe GJ, Martin D, Callanan D, et al:
Fluocinolone Acetonide Uveitis Study
Group Fluocinolone acetonide implant
(Retisert) for noninfectious posterior uveitis
thirty-four-week results of a multicenter
randomized clinical study. Ophthalmology
2006; 113:1028–1034.
49. Baughman RP, Lower EE: Steroid-sparing
alternative treatments for sarcoidosis. Clin
Chest Med 1997; 18:853–864.
50. Callejas-Rubio JL, Ortego-Centeno N,
Lopez-Perez L, Benticuaga MN: Treatment
of therapy-resistant sarcoidosis with
adalimumab. Clin Rheumatol 2006;
25:596–7.
51. Sweiss NJ, Welsch MJ, Curran JJ,
Ellman MH: Tumor necrosis factor inhibition
as a novel treatment for refractory
sarcoidosis. Arthritis Rheum 2005;
53:788–791.
 CHAPTER
172 Sickle-Cell Retinopathy
Fina C. Barouch, George K. Asdourian, and John I. Loewenstein
Sickling hemoglobinopathies are caused by the presence of one
or a combination of abnormal hemoglobins in red blood cells.
Normal hemoglobin, which is referred to as hemoglobin A
(HbA), is composed of two a-peptide and two b-peptide chains.1
A mutation can lead to a single amino acid substitution in the
sixth position of the b-chain (valine for glutamic acid),
producing hemoglobin S (HbS), whereas a different substitution
at the same position (lysine for glutamic acid) will produce
hemoglobin C (HbC). The various hemoglobins can occur in
combinations resulting in hemoglobins such as hemoglobin AS
(sickle-cell trait), hemoglobin SS (sickle-cell disease or anemia),
hemoglobin SC (sickle-cell hemoglobin C disease), and others.
A mutation can also induce failure or inadequate production of
one of the two peptide chains (a or b) (a- and b-thalassemia),
which in combination with sickle hemoglobin, leads to sickle-
cell thalassemia (S-thal) disease. Sickle cell is the most common
hemoglobinopathy affecting humans, with ~8% of African–
Americans having the gene for HbS. Other less common geno-
types of sickle-cell disease have also been described.
Normal red blood cells are round or oval, flexible, and can
squeeze through capillaries. Under conditions of hypoxia and
other metabolic conditions (pH, temperature), the red blood
cells containing HbS become rigid and adopt an elongated
sickle-shaped configuration.1 This occurs because of the
formation of intracellular aggregates of long polymers in a
crystalline gel. With recurring sickling, the membranes of the
red blood cells become damaged and can no longer assume a
normal configuration on reoxygenation and become irreversibly
sickled. As the sickle cells increase in number in the circulation,
they increase the viscosity of the blood and lead to sluggish
blood flow, erythrocytic aggregation, increased adhesion to the
vascular endothelium, and eventual vasoocclusion of the vessel.
In the fundus, the peripheral retina and the macula are the
areas most susceptible for vascular occlusions. The vascular
occlusions usually occur in the arterioles, especially in patients
with a large number of irreversibly sickled cells, since these rigid
red blood cells cannot enter the capillaries. Using fluorescein
angiography, prolonged transition times of blood have been well
documented in the peripheral retina of sickle-cell patients.2,3
The systemic and ocular manifestations of the different
hemoglobinopathies do not go hand in hand. Although patients
with hemoglobin SS disease manifest the worst systemic symp-
toms, patients with hemoglobin SC and hemoglobin S-thal
hemoglobinopathies exhibit the most severe ocular complica-
tions. The reason for this discrepancy is poorly understood.
The sickling process can produce vasoocclusion and second-
ary tissue changes in all the vascular structures of the eye,
including the conjunctiva (conjunctival sickling sign),4–6 the iris
(iris atrophy and neovascularization),7,8 the choroid (occlusion
of the posterior ciliary vessels),9–12 the optic disk,13 and the
retina. The constellation of retinal abnormalities observed in
these patients constitutes the retinopathy of sickle cell.4,14–24
The posterior segment abnormalities can be divided into the
following categories:
• Optic disk changes
• Posterior retinal and macular vascular occlusions
• Chronic macular changes
• Choroidal vascular occlusions
• Nonproliferative retinal changes
• Proliferative retinal changes
OPTIC DISK CHANGES
Similar to vascular occlusions elsewhere, the small vessels on
the surface of the optic disk can exhibit intravascular occlusions
(disk sign of sickling).13 These occlusions are seen ophthal-
moscopically as dark red intravascular spots (Fig. 172.1) and
probably represent plugs of deoxygenated erythrocytes occurring
in the small surface vessels of the disk. Fluorescein angiography
(Fig. 172.2) shows linear or Y-shaped segments of hypofluores-
cence corresponding to these red spots but does not reveal any
substantial impairment of blood flow in these vessels.
These occlusions are transient and do not produce clinically
detectable visual impairment. Although disk changes have been
found in patients with hemoglobin SS, hemoglobin SC, and
hemoglobin S-thal diseases, they are most common in patients
with hemoglobin SS disease (29%).13
Key Features
• Disk sign of sickling,
• vascular occlusions,
• “salmon patch” hemorrhages,
• “black sunbursts,”
• “iridescent spots,”
• neovascularization,
• vitreous hemorrhage
Optic disk neovascularization is uncommon in patients with
sickle-cell retinopathy but has been documented in patients with
SC disease, hemoglobin SS, and hemoglobin SA.25,26 Scatter
peripheral retinal photocoagulation has been found to be effec-
tive in stimulating regression of disk neovascularization.25
POSTERIOR RETINAL AND MACULAR
VASCULAR OCCLUSIONS
Acute major retinal vascular occlusions – central and branch
retinal artery occlusions and peripapillary and macular arte- 2171
 RETINA AND VITREOUS

riolar occlusions – although infrequent, have been reported

(Fig. 172.3).27–36 These occlusions occur more commonly in
patients with hemoglobin SS disease, although their occurrence
in various other sickling genotypes has been reported. The occlu-
sions can occur in one eye or simultaneously in both eyes and
result in complete loss of vision or debilitating central and para-
central scotoma. Arterial occlusions in sickle-cell patients have
also been reported as a complication of retrobulbar anesthesia,29,37
after ocular compression during photocoagulation,38 during air-
plane travel,18 after trauma,39 and with extreme dehydration.11
Retinal venous occlusions – central and branch retinal vein
occlusions – are very uncommon in patients with sickle-cell
disease and one should suspect other underlying causes for their
occurrence in these patients.

CHRONIC MACULAR CHANGES (SICKLING

FIGURE 172.1. The disk sign of sickling. Blocked small vessels are MACULOPATHY)
SECTION 10

seen as dark spots or lines.

From Goldbaum MH, Jampol LM, Goldberg MF: The disk sign in sickling
Apart from the acute vascular occlusions of the macular region,
hemoglobinopathies. Arch Ophthalmol 1978; 96:1597. Copyright 1978, American chronic vascular changes of the posterior pole have been
Medical Association. reported in patients with hemoglobin SS, hemoglobin SC,
hemoglobin S-thal, and hemoglobin AS diseases. They occur in
~30% of patients with sickle-cell disease.19–21,40–43 These
occlusions are insidious, progressive, and clinically difficult to
detect. They consist of alterations in the normal architecture of
FIGURE 172.2.
Fluorescein the fine vasculature of the macula, perimacular region, and
angiography of the region of the horizontal raphe lying temporal to the macula.
optic disk shows They may be transient with a continuous remodeling of the
several plugged macular vasculature. Careful direct ophthalmoscopy, contact
vessels (arrows). lens examination, and fluorescein angiography are necessary to
From Goldbaum MH, detect these abnormalities. Microaneurysms, dark and enlarged
Jampol LM, Goldberg MF: segments of terminal arterioles representing occluded
The disk sign in sickling precapillary arterioles, hairpin-shaped vascular loops, an
hemoglobinopathies. Arch
abnormal foveal avascular zone (FAZ) with adjacent areas of
Ophthalmol 1978;
96:1599. Copyright 1978,
capillary nonperfusion (pathologic avascular zones (PAZs)), and
American Medical areas of retinal depression (Figs 172.4 and 172.5) may be seen.44
Association. Sanders and co-workers found the mean largest diameter of the
FAZ in patients with hemoglobin SC and hemoglobin SS disease
to be 1.0 mm compared with 0.61 mm in normal subjects.40
However, there was no significant difference in the FAZ
diameters within the sickle-cell group in regard to the degree of
retinopathy, type of sickle-cell disease, or the visual acuity. The
areas of retinal depression are best seen by direct ophthal-
moscopy and are thought to be the result of atrophy of the inner
retina (secondary to capillary closures) (Fig. 172.6). These
depressed areas produce a concavity that appears as a dark
retinal area with a bright central reflex.

FIGURE 172.3. (a) Several cotton wool spots

in a patient with sickle-cell disease. (b) Macular
infarction in a patient with sickle-cell
thalassemia.
(b) From Asdourian GK, Goldberg MF, Rabb MF:
Macular infarction in sickle cell B+ thalassemia. Retina
1982; 2:155.

a b
2172

FIGURE 172.4. The left macula of a patient with sickle-cell
hemoglobin C (SC) disease with an enlarged FAZ.
Even when the innermost arcades of the FAZ are occluded,
patients are usually asymptomatic and the visual acuity, color
vision, and central visual fields may be normal. However, with
more sophisticated clinical tests and static perimetry, absolute
and relative scotomas can be detected that correspond to these
areas of vascular abnormalities. Furthermore, these macular
vascular changes may be the cause of unexplained visual loss or
amblyopia in young patients with sickle-cell disease.
CHOROIDAL VASCULAR OCCLUSIONS
Choroidal vascular occlusions are reported to occur in patients
with sickle hemoglobinopathies, but their occurrence is rare and
clinically difficult to document. Condon and colleagues described
three patients with unusual chorioretinal degeneration and
suggested that this may be the sequelae of posterior ciliary
artery occlusions.12 Dizon and associates reported on the
clinical findings of a patient with hemoglobin SS disease that
suggested a posterior ciliary artery occlusion.9 They also reported
the histopathology of three eyes in patients with hemoglobin SS
and hemoglobin SC disease that may have sustained small
posterior ciliary artery occlusions. Clinically, acute posterior
ciliary vessel occlusions appear as white, circumscribed
triangular patches at the level of the retinal pigment epithelium
(RPE). Eventually, these areas heal with a mottled appearance of
the RPE. Acute choroidal infarctions have been well docu-
mented after feeder vessel laser photocoagulation of peripheral
retinal neovascularization.45
Peripheral spontaneous chorioretinal neovascularization has
also been reported. Liang and Jampol reported a patient with
hemoglobin SS anemia who developed peripheral chorioretinal
neovascularization in the center of a black sunburst that was
thought to be the result of massive mid-peripheral retinal
hemorrhage.46 Choroidal neovascularization has also been
implicated in the formation of angioid streaks and black
sunbursts,10 although the evidence to support the relationship
is not very strong.
Sickle-Cell Retinopathy
NONPROLIFERATIVE RETINAL CHANGES
Changes in the retina referred to as nonproliferative or back-
ground sickle retinopathy include venous tortuosity; salmon-
patch hemorrhage, schisis cavity, and iridescent spots; the black
sunburst; and other nonproliferative sickle changes.
VENOUS TORTUOSITY
Although venous tortuosity (Fig. 172.7) was one of the first
ophthalmoscopic signs of sickling to be described, it is neither
pathognomonic nor of any diagnostic value, since it occurs in a
great number of other ocular diseases. It has been reported in up
to 47% of patients with hemoglobin SS disease and 32% of
patients with hemoglobin SC disease.18 The tortuosity may
be due to arteriovenous shunting that occurs in the retinal
periphery of these patients.
CHAPTER 172
SALMON-PATCH HEMORRHAGE, SCHISIS
CAVITY, AND IRIDESCENT SPOTS
Salmon-patch hemorrhages are preretinal or superficial intra-
retinal hemorrhages that occur mainly in the mid-peripheral
retina, adjacent to a retinal arteriole.47 Because of their
peripheral location, they do not produce any visual symptoms.
These hemorrhages are thought to occur after sudden arteriolar
occlusions, with subsequent ‘blowout’ of the vessel wall,
presumably from ischemic necrosis.29 These hemorrhages are
round or oval and are initially bright red (Fig. 172.8). Over
several days, however, they acquire an orange-red coloration and
have been referred to as salmon patches or salmon hemorrhages
(Fig. 172.9). Histologic studies have shown these hemorrhages
to be limited by the internal limiting membrane, although some
may dissect internally into the vitreous cavity or into the retina
and the subretinal space (Fig. 172.10).48 With the resorption of
the hemorrhages, the retina may resume a normal appearance
at the site of the hemorrhage, may be marked by a subtle retinal
dimple (usually highlighted by the light reflection from the
internal limiting membrane), or more frequently, may show a
schisis cavity with multiple glistening yellow spots (Fig. 172.11).
The schisis cavity represents the space created by the resorption
of the intraretinal portion of the hemorrhage, whereas the
glistening refractive bodies in the schisis cavity, referred to as
iridescent spots, represent macrophages that are filled with iron
and blood breakdown products (Fig. 172.12).
THE BLACK SUNBURST
Round or ovoid black chorioretinal scars, ranging in size from
0.5 to 2 disk diameters and characteristically located in the equa-
torial fundus, are called black sunbursts (Fig. 172.13).2,18,21,49
They usually have stellate or spiculate borders caused by peri-
vascular accumulation of pigment. They are sometimes associ-
ated with iridescent spots. Because of their peripheral location,
these lesions do not produce any visual symptoms.
On fluorescein angiography, these lesions are hypo- and
hyperfluorescent, denoting changes in the RPE (Fig. 172.14).
Histologically, these scars represent focal areas of RPE hyper-
trophy, hyperplasia, and migration (Fig. 172.15).48 Occasionally,
there is a distinct perivascular localization of the pigment in the
sensory retina.
OTHER NONPROLIFERATIVE SICKLE CHANGES
Mottled geographic flat, dark brown areas have been reported in
the posterior pole and the fundus periphery (Fig. 172.16).21,50
These lesions are not associated with any hemorrhagic changes 2173
 RETINA AND VITREOUS

a b
SECTION 10

c d

FIGURE 172.5. (a) Fluorescein angiography of the macular area shows an occluded vessel. (b) Fluorescein angiography shows a PAZ, as well
as microaneurysmal formation of the perifoveal capillaries. (c) Fluorescein angiography shows an enlarged FAZ. (d) Fluorescein angiography of
the macular area shows an enlarged FAZ, microaneurysmal formation, and hairpin loops.
(a–c) From Asdourian GK, Nagpal KC, Busse B, et al: Macular and perimacular vascular remodeling in sickling hemoglobinopathies. Br J Ophthalmol 1976; 60:431.)

or vascular occlusions, are transient, and disappear over a
period of time. Angioid streaks have also been reported to occur
in 22% of adult patients with hemoglobin SS disease and less
frequently in patients with hemoglobin SC disease.51–53 Their
presence is age dependent, occurring in less than 2% of hemo-
globin SS patients less than 40 years of age.22 They are rarely
associated with loss of central vision secondary to choroidal
neovascularization. Epiretinal membranes54 and macular holes55
have also been reported.
PROLIFERATIVE RETINAL CHANGES
Proliferative sickle retinopathy (PSR) is the most severe ocular
complication of sickle-cell disease, since it can lead to severe
visual disability secondary to vitreous hemorrhage or retinal
detachment. Although neovascularization of the disk and the
temporal macula have been reported,26,56 PSR is over-
whelmingly a peripheral retinal disease. PSR occurs more
frequently in the temporal retina and tends to be more rapidly
progressive in children and adolescents than adults. It is more
prevalent in patients with hemoglobin SC and hemoglobin
S-thal disease than in those with hemoglobin SS disease. In a
2174 study of selected patients from Jamaica, the incidence of PSR
was reported to be 2.6% in SS patients,21 14% in S-b-thal
patients,19 and 32.8% in SC patients.20 The development of PSR
is also age dependent, with the highest risk period of 20–34
years in SC disease and 40–50 years in SS disease.22 PSR has
also been reported in patients with other hemoglobinopathies
such as hemoglobin AS24 and AC.23
The development of PSR follows a relatively orderly
sequential course. On the basis of longitudinal clinical studies
and with serial fluorescein angiographies, the development
of PSR has been classified by Goldberg14 into five stages
(Fig. 172.17):
1. Peripheral arteriolar occlusions
2. Peripheral arteriolar–venular anastomoses
3. Neovascular proliferation
4. Vitreous hemorrhage
5. Retinal detachment
STAGE I: PERIPHERAL ARTERIOLAR
OCCLUSIONS
Stage I is the earliest abnormality that can be visualized in the
fundus periphery and can be seen even in children with no other
evidence of PSR. These occlusions are arteriolar rather than

FIGURE 172.6. Color photograph of the right macula shows the
retinal depression sign.
FIGURE 172.7. The left fundus of patient with sickle-cell (SS) disease
shows vascular tortuosity.
venular and result in the failure of the dependent capillary bed
to fill with resultant anteriorly located avascular zones. The
occluded arterioles can be seen as dark red lines but eventually
turn into white ‘silver-wire’ vessels (Fig. 172.18). Fluorescein
angiography clearly delineates the occluded vessels and the
surrounding avascular and abnormal capillary bed (Fig. 172.19).
Sickle-Cell Retinopathy
CHAPTER 172
FIGURE 172.8. Acute preretinal hemorrhage. The hemorrhage is
bright red. Anterior to the hemorrhage, a black sunburst lesion is seen.
FIGURE 172.9. Same lesion as in Figure 172.8, 4 weeks later. The
hemorrhage is pink (salmon patch) with a surrounding schisis cavity.
STAGE II: PERIPHERAL ARTERIOLAR-
VENULAR ANASTOMOSES
With the arteriolar occlusions, a vascular remodeling process
ensues, with some vessels remaining occluded and others
demonstrating partial or complete reopening. As the blood is
diverted from the occluded arterioles to the nearest venules,
arteriolar–venular anastomoses develop. Anterior to these 2175
 RETINA AND VITREOUS
SECTION 10
FIGURE 172.10. Histopathologic appearance of an acute superficial
retinal hemorrhage (salmon patch).
From Romayananda N, Goldberg MF, Green RW: Histopathology of sickle cell
retinopathy. Trans Am Acad Ophthalmol Otolaryngol 1973; 77:OP652-OP676.
FIGURE 172.11. Same lesion as in Figure 172.8, 6 weeks later. A
schisis cavity is seen with multiple iridescent spots.
arteriolar–venular changes, the retina remains devoid of any
perfusion. On fluorescein angiography, there is no evidence of
any leakage of dye from these anastomoses, since they do not
represent true neovascularization (Fig. 172.20).
STAGE III: NEOVASCULAR PROLIFERATION
At the interface of vascular and avascular retina, new blood
vessels arise from the arteriolar–venular anastomoses and grow
peripherally into the preequatorial ischemic retina. The growth
of these new blood vessels is thought to be in response to
2176
growth factors such as vascular endothelial growth factor and
basic fibroblast growth factor.57,58 These neovascular fronds
initially are small, lie flat on the surface of the retina, may be
mistaken for microaneurysms or telangiectasia, and are difficult
to detect ophthalmoscopically (Fig. 172.21). With time, these
neovascular tufts grow, acquire a characteristic fan-shaped
appearance resembling the marine invertebrate Gorgonia
flabellum, and are known as sea fan neovascularization
(Fig. 172.22).18
Small sea fans usually have a single feeding arteriole and a
draining venule. As they grow in size and number they acquire
additional feeding and draining vessels and may show pro-
gressive circumferential growth leading to neovascularization of
the entire retinal periphery. Fluorescein angiography shows
leakage of dye from these tufts (Fig. 172.23).
With time, these neovascular tufts may become fibrotic and
can be pulled into the vitreous cavity, appearing as elevated
neovascular tissue.
STAGE IV: VITREOUS HEMORRHAGE
Peripheral neovascular tufts can bleed spontaneously or second-
ary to a variety of conditions such as trauma. Spontaneous
bleeding occurs secondary to contraction of the vitreous adja-
cent to the neovascular tufts or due to traction of vitreous bands
and membranes resulting from previous vitreous hemorrhages.
With PSR, the risk factors for vitreous bleeding are hemoglobin
SC disease, more than 60° of perfused sea fans, and the
presence of old blood in the vitreous.59
STAGE V: RETINAL DETACHMENT
Vitreous traction and fibrous membranes can also produce
traction on the sea fan and adjacent retina, resulting in traction
retinal detachment or traction retinoschisis.60 Localized
traction detachments may remain stationary or may progress
posteriorly. Full-thickness retinal breaks can occur due to
traction and lead to total rhegmatogenous retinal detachment.
Exudative retinal detachments are rare and may resolve after
photocoagulation of the neovascularization.61
PSR may progress rapidly in some patients, however in a
majority of patients PSR appears to progress slowly and severe
visual dysfunction is relatively uncommon. This may be due to
the tendency of the neovascular tufts to involute or undergo
autoinfarction62 (reported to occur in 20–60% of eyes with PSR)
(Fig. 172.24). Involution may occur because of strangulation of
the neovascular tufts by fibroglial tissue, whereas autoinfarction
is thought to be secondary to a spontaneous occlusion of the
arteriolar feeding vessel.
Because PSR is progressive and is the major cause of visual
morbidity in these patients (12% of eyes showing evidence of
visual disability), especially in young persons, obliteration of the
neovascular tissue should be accomplished before a major
vitreous hemorrhage has occurred.63
TREATMENT OF PSR
The aim of therapy is to eradicate new vessels, thus eliminating
the complications of vitreous hemorrhage and retinal detach-
ment.64 The mainstay of treatment is argon laser photocoag-
ulation64–68 although cryotherapy may be useful when vitreous
hemorrhage prevents visualization of the retina. Fluorescein
angiography may be useful to localize areas of peripheral leakage
prior to treatment.
The neovascular tufts can be directly treated with photo-
coagulation if the neovascularization is flat on the retina.

FIGURE 172.12. Histopathologic appearance of a schisis cavity containing proteinaceous material and hemosiderin-laden macrophages (clinical
iridescent spots).
From Romayananda N, Goldberg MF, Green RW: Histopathology of sickle cell retinopathy. Trans Am Acad Ophthalmol Otolaryngol 1973; 77:655.
FIGURE 172.13. The black sunburst sign.
From Goldberg MF: Retinal vaso-occlusion in sickling hemoglobinopathies. Birth
Defects 1976; 12:475.
Another technique favored in the past that has been shown to
reduce vitreous hemorrhage and visual loss is feeder vessel
treatment, whereby the feeder arterioles and subsequently the
draining venules of the neovascularization are directly photo-
coagulated until the blood flow is obliterated (Fig. 172.25).65
Feeder vessel treatment is now rarely performed due to com-
plications such as choroidal hemorrhages, choroidal ischemia,
and choroidal neovascularization that are associated with the
intense burns needed to obliterate the vessels (Fig. 172.26).45,69,70
Most physicians currently favor scatter photocoagulation
applied in either a localized area68 – confined to the area
anterior to perfused neovascular fronds (Fig. 172.27) – or in
Sickle-Cell Retinopathy
CHAPTER 172
FIGURE 172.14. Fluorescein angiogram of a black sunburst shows
areas of focal hyperfluorescence and hypofluorescence.
From Asdourian G, Nagpal KC, Goldbaum M, et al: Evolution of the retinal black
sunburst in sickling hemoglobinopathies. Br J Ophthalmol 1975; 59:715.
a 360° peripheral circumferential manner (Fig. 172.28).66,67,71
Both of these techniques show evidence of neovascularization
regression with minimal complications.
Patients with nonclearing vitreous hemorrhages, tractional or
rhegmatogenous retinal detachments, or epiretinal membranes
can be treated with vitrectomy or scleral buckling.72,73 However,
these surgical procedures can be associated with both ocular and
systemic complications. Ocular complications include, anterior
segment ischemia (particularly from encircling scleral buckles)74
and intraoperative hemorrhages with secondary glaucoma.
These complications have stimulated the preoperative use of
prophylactic exchange transfusions or erythrophoresis.75 How-
2177
 SECTION 10 RETINA AND VITREOUS

FIGURE 172.16. Fundus photograph shows a mottled brown area.

ever, the risks involved with these transfusion procedures –

acquired infections (human immunodeficiency virus, non-A,
non-B hepatitis) – have stimulated a reevaluation of this rou-
tine. At present, improved vitreoretinal techniques and the use
of pre- and postoperative oxygen and intraoperative measures
(avoiding excessive manipulation of extraocular muscles,
avoiding encircling scleral buckles, limiting the use of intra-
ocular gases) to reduce complications have almost eliminated
the need for preoperative exchange transfusions. Systemic
complications include thromboembolic complications such as
pulmonary or cerebral embolism or thrombosis. Patients who
need vitreoretinal surgery should be evaluated by experienced
medical personnel to decrease the systemic complications of
surgery.

FIGURE 172.15. Histopathologic appearance of a black sunburst

shows marked proliferation of the RPE.
From Romayananda N, Goldberg MF, Green RW: Histopathology of sickle cell
retinopathy. Trans Am Acad Ophthalmol Otolaryngol 1973; 77:657.

2178
 Sickle-Cell Retinopathy

CHAPTER 172
FIGURE 172.18. Stage I PSR. Peripheral arteriolar occlusions are
seen as ‘silver-wire’ vessels.

FIGURE 172.17. Classification of PSR.

From Goldberg MF: Classification and pathogenesis of proliferative sickle
retinopathy. Am J Ophthalmol 1971; 71:654. Copyright from Elsevier Science.

FIGURE 172.19. Stage I PSR. Fluorescein angiography shows the

occluded peripheral vessels with the adjacent avascular retina.

2179
 SECTION 10 RETINA AND VITREOUS

FIGURE 172.21. Early retinal neovascularization, which may be

FIGURE 172.20. Stage II PSR. Fluorescein angiography shows the
mistaken for microaneurysms or telangiectasia.
arteriolar–venular anastomoses with the adjacent avascular retina.

FIGURE 172.22. (a) Fluorescein angiography

of characteristic sea fan neovascularization.
(b) The sea fan neovascularization shows
evidence of leakage of dye. Inferior to the
neovascularization, the arteriolar–venular
anastomosis is seen with early
neovascularization.

a b

FIGURE 172.23. (a) Sea fan neovascularization

with a single feeder vessel and two draining
venules. (b) Sea fan neovascularization with
multiple feeder arterioles and draining venules.

a b

2180
 Sickle-Cell Retinopathy

FIGURE 172.24. (a and b) Autoinfarcted sea

fan neovascularization. (c) A perfused, leaking
sea fan neovascularization. (d) Same area
several days later shows lack of perfusion.
(c and d) From Nagpal KC, Patrianakos D, Asdourian
GK, et al: Spontaneous regression (autoinfarction) of
PSR. Am J Ophthalmol 1975; 80:886. Copyright from
Elsevier Science.

a b

CHAPTER 172
c d

FIGURE 172.25. Feeder vessel photocoagulation. Both feeder

arterioles and draining venules have been photocoagulated. The
neovascular tuft is not treated.

2181
 RETINA AND VITREOUS

FIGURE 172.26. (a) Feeder vessel

photocoagulation. A localized hemorrhage is
noted adjacent to the sea fan
neovascularization. (b) Anteriorly located
triangular gray areas represent areas of
choroidal ischemia. (c) Heavy treatment has
resulted in breaks in Bruch’s membrane (dark
areas in the center of photocoagulation spots).
(d) Same patient as in (c). Choroidal
neovascularization has occurred at the site of
the break in Bruch’s membrane. (e–h) Same
patient as in (c). Rapid-sequence fluorescein
angiography shows choroidal
neovascularization occurring after heavy
photocoagulation, which resulted in breaks in
Bruch’s membrane. Center arrows show filling
a b of main choroidal vascular trunk before retinal
arterial filling (open arrows). Lower arrows show
another but smaller neovascular tuft.
(e–h) From Galinos SO, Asdourian GK, Woolf MB,
SECTION 10

et al: Choroido-vitreal neovascularization after argon

laser photocoagulation neovascularization. Arch
Ophthalmol 1975; 93:524. Copyright 1975, American
Medical Association.

c d

e f

g h

2182
 Sickle-Cell Retinopathy

FIGURE 172.27. (a) Fluorescein angiogram

demonstrates a leaking sea fan
neovascularization. (b) Complete regression of
the lesion occurred after scatter
photocoagulation.
(a and b) Reprinted from Rednam KR, Jampol LM,
Goldberg MF: Scatter retinal photocoagulation for
proliferative sickle cell retinopathy. Am J Ophthalmol
1982; 93:594. Copyright from Elsevier Science.

a b

CHAPTER 172
FIGURE 172.28. Fundus drawing illustrates the technique of
peripheral circumferential retinal scatter photocoagulation.
From Cruess AF, Stephens RF, Magargal LE, et al: Peripheral circumferential
retinal scatter photocoagulation for treatment of proliferative sickle retinopathy.
Ophthalmology 1983; 90:273.

2183
 RETINA AND VITREOUS
REFERENCES
1. Beutler E: Disorders of hemoglobin
structure: sickle cell anemia and related
abnormalities. In: Lichtman MA, Beutler E,
Kipps TJ, et al, eds. Williams Hematology.
7th edn. New York: McGraw-Hill;
2006:668–700.
2. Goldberg MF: Retinal vaso-occlusion in
sickling hemoglobinopathies. Birth Defects
Orig Artic Ser 1976; 12:475–515.
3. Welch RB: Fluorescein angiography in
sickle-cell retinopathy and von
Hippel–Lindau disease. Int Ophthalmol Clin
1977; 17:137–154.
4. Goodman G, Von Sallmann L, Holland MG:
Ocular manifestations of sickle-cell
disease. AMA Arch Ophthalmol 1957;
58:655–682.
5. Paton D: The conjunctival sign of sickle-cell
SECTION 10
disease. Arch Ophthalmol 1961; 66:90–94.
6. Paton D: The conjunctival sign ox
sickle-cell disease. Further observations.
Arch Ophthalmol 1962; 68:627–632.
7. Galinos S, Rabb MF, Goldberg MF, Frenkel M:
Hemoglobin SC disease and iris atrophy.
Am J Ophthalmol 1973; 75:421–425.
8. Goldberg MF, Tso MO: Rubeosis iridis and
glaucoma associated with sickle cell
retinopathy: a light and electron
microscopic study. Ophthalmology 1978;
85:1028–1041.
9. Dizon RV, Jampol LM, Goldberg MF, Juarez
C: Choroidal occlusive disease in sickle cell
hemoglobinopathies. Surv Ophthalmol
1979; 23:297–306.
10. McLeod DS, Goldberg MF, Lutty GA:
Dual-perspective analysis of vascular
formations in sickle cell retinopathy. Arch
Ophthalmol 1993; 111:1234–1245.
11. Stein MR, Gay AJ: Acute chorioretinal
infarction in sickle cell trait. Report of
a case. Arch Ophthalmol 1970;
84:485–490.
12. Condon PI, Serjeant GR, Ikeda H: Unusual
chorioretinal degeneration in sickle cell
disease. Possible sequelae of posterior
ciliary vessel occlusion. Br J Ophthalmol
1973; 57:81–88.
13. Goldbaum MH, Jampol LM, Goldberg MF:
The disc sign in sickling hemoglobinopathies.
Arch Ophthalmol 1978; 96:1597–1600.
14. Goldberg MF: Classification and
pathogenesis of proliferative sickle
retinopathy. Am J Ophthalmol 1971;
71:649–665.
15. Goldberg MF: Sickle cell retinopathy.
In: Tasman W, Jaeger EA, eds. Duane’s
clinical ophthalmology. Philadelphia:
Lippincott Willaims & Wilkins; 2004:1–45.
16. Goldberg MF: Natural history of untreated
proliferative sickle retinopathy. Arch
Ophthalmol 1971; 85:428–437.
17. Penman AD, Talbot JF, Chuang EL, et al:
New classification of peripheral retinal
vascular changes in sickle cell disease.
Br J Ophthalmol 1994; 78:681–689.
18. Welch RB, Goldberg MF: Sickle-cell
hemoglobin and its relation to fundus
abnormality. Arch Ophthalmol 1966;
75:353–362.
19. Condon PI, Serjeant GR: Ocular findings in
sickle cell thalassemia in Jamaica. Am J
Ophthalmol 1972; 74:1105–1109.
20. Condon PI, Serjeant GR: Ocular findings in
hemoglobin SC disease in Jamaica. Am J
Ophthalmol 1972; 74:921–931.
2184
21. Condon PI, Serjeant GR: Ocular findings in
homozygous sickle cell anemia in Jamaica.
Am J Ophthalmol 1972; 73:533–543.
22. Condon PI, Serjeant GR: Ocular findings of
elderly cases of homozygous sickle-cell
disease in Jamaica. Br J Ophthalmol 1976;
60:361–364.
23. Moschandreou M, Galinos S, Valenzuela R,
et al: Retinopathy in hemoglobin C trait
(AC hemoglobinopathy). Am J Ophthalmol
1974; 77:465–471.
24. Nagpal KC, Asdourian GK, Patrianakos D,
et al: Proliferative retinopathy in sickle cell
trait. Report of seven cases. Arch Intern
Med 1977; 137:325–328.
25. Kimmel AS, Magargal LE, Tasman WS:
Proliferative sickle retinopathy and
neovascularization of the disc: regression
following treatment with peripheral retinal
scatter laser photocoagulation. Ophthalmic
Surg 1986; 17:20–22.
26. Ober RR, Michels RG: Optic disk
neovascularization in hemoglobin SC
disease. Am J Ophthalmol 1978;
85:711–714.
27. Asdourian GK, Goldberg MF, Rabb MF:
Macular infarction in sickle cell B+
thalassemia. Retina 1982; 2:155–158.
28. Merritt JC, Risco JM, Pantell JP: Bilateral
macular infaction in SS disease. J Pediatr
Ophthalmol Strabismus 1982; 19:275–278.
29. Jampol LM, Condon P, Dizon-Moore R, et al:
Salmon-patch hemorrhages after central
retinal artery occlusion in sickle cell disease.
Arch Ophthalmol 1981; 99:237–240.
30. Fine LC, Petrovic V, Irvine AR, Bhisitkul RB:
Spontaneous central retinal artery
occlusion in hemoglobin sickle cell disease.
Am J Ophthalmol 2000; 129:680–681.
31. Al-Abdulla NA, Haddock TA, Kerrison JB,
Goldberg MF: Sickle cell disease
presenting with extensive peri-macular
arteriolar occlusions in a nine-year-old boy.
Am J Ophthalmol 2001; 131:275–276.
32. Conrad WC, Penner R: Sickle-cell trait and
central retinal-artery occlusion. Am J
Ophthalmol 1967; 63:465–468.
33. Kabakow B, Van Weimokly SS, Lyons HA:
Bilateral central retinal artery occlusion;
occurrence in a patient with cortisone-
treated systemic lupus erythematosus,
sickle cell trait, and active pulmonary
tuberculosis. AMA Arch Ophthalmol 1955;
54:670–676.
34. Acacio I, Goldberg MF: Peripapillary and
macular vessel occlusions in sickle cell
anemia. Am J Ophthalmol 1973;
75:861–866.
35. Khwarg SG, Feldman S, Ligh J,
Straatsma BR: Exchange transfusion in
sickling maculopathy. Retina 1985;
5:227–229.
36. Weissman H, Nadel AJ, Dunn M:
Simultaneous bilateral retinal arterial
occlusions treated by exchange
transfusions. Arch Ophthalmol 1979;
97:2151–2153.
37. Roth SE, Magargal LE, Kimmel AS, et al:
Central retinal-artery occlusion in
proliferative sickle-cell retinopathy after
retrobulbar injection. Ann Ophthalmol 1988;
20:221–224.
38. Klein ML, Jampol LM, Condon PI, et al:
Central retinal artery occlusion without
retrobulbar hemorrhage after retrobulbar
anesthesia. Am J Ophthalmol 1982;
93:573–577.
39. Sorr EM, Goldberg RE: Traumatic central
retinal artery occlusion with sickle cell trait.
Am J Ophthalmol 1975; 80:648–652.
40. Sanders RJ, Brown GC, Rosenstein RB,
Magargal L: Foveal avascular zone
diameter and sickle cell disease. Arch
Ophthalmol 1991; 109:812–815.
41. Asdourian GK, Nagpal KC, Busse B, et al:
Macular and perimacular vascular
remodelling sickling haemoglobinopathies.
Br J Ophthalmol 1976; 60:431–453.
42. Lee CM, Charles HC, Smith RT, et al:
Quantification of macular ischaemia in
sickle cell retinopathy. Br J Ophthalmol
1987; 71:540–545.
43. Stevens TS, Busse B, Lee CB, et al:
Sickling hemoglobinopathies; macular and
perimacular vascular abnormalities. Arch
Ophthalmol 1974; 92:455–463.
44. Goldbaum MH: Retinal depression sign
indicating a small retinal infarct. Am J
Ophthalmol 1978; 86:45–55.
45. Goldbaum MH, Galinos SO, Apple D, et al:
Acute choroidal ischemia as a complication
of photocoagulation. Arch Ophthalmol
1976; 94:1025–1035.
46. Liang JC, Jampol LM: Spontaneous
peripheral chorioretinal neovascularisation
in association with sickle cell anaemia. Br J
Ophthalmol 1983; 67:107–110.
47. Gagliano DA, Goldberg MF: The evolution
of salmon-patch hemorrhages in sickle cell
retinopathy. Arch Ophthalmol 1989;
107:1814–1815.
48. Romayanada N, Goldberg MF, Green WR:
Histopathology of sickle cell retinopathy.
Trans Am Acad Ophthalmol Otolaryngol
1973; 77:OP642–OP676.
49. Asdourian G, Nagpal KC, Goldbaum M,
et al: Evolution of the retinal black sunburst
in sickling haemoglobinopathies. Br J
Ophthalmol 1975; 59:710–716.
50. Nagpal KC, Goldberg MF, Asdourian G,
et al: Dark-without-pressure fundus lesions.
Br J Ophthalmol 1975; 59:476–479.
51. Nagpal KC, Asdourian G, Goldbaum M, et al:
Angioid streaks and sickle
haemoglobinopathies. Br J Ophthalmol
1976; 60:31–34.
52. Hamilton AM, Pope FM, Condon PI, et al:
Angioid streaks in Jamaican patients with
homozygous sickle cell disease. Br J
Ophthalmol 1981; 65:341–347.
53. Paton D: Angiod streaks and sickle cell
anemia: a report of two cases. Arch
Ophthalmol 1959; 62:852–858.
54. Carney MD, Jampol LM: Epiretinal
membranes in sickle cell retinopathy.
Arch Ophthalmol 1987; 105:214–217.
55. Raichand M, Dizon RV, Nagpal KC, et al:
Macular holes associated with proliferative
sickle cell retinopathy. Arch Ophthalmol
1978; 96:1592–1596.
56. Frank RN, Cronin MA: Posterior pole
neovascularization in a patient with
hemoglobin SC disease. Am J Ophthalmol
1979; 88:680–682.
57. Cao J, Mathews MK, McLeod DS, et al:
Angiogenic factors in human proliferative
sickle cell retinopathy. Br J Ophthalmol
1999; 83:838–846.
58. Kim SY, Mocanu C, McLeod DS, et al:
Expression of pigment epithelium-derived

factor (PEDF) and vascular endothelial
growth factor (VEGF) in sickle cell retina
and choroid. Exp Eye Res 2003;
77:433–445.
59. Jacobson MS, Gagliano DA, Cohen SB,
et al: A randomized clinical trial of feeder
vessel photocoagulation of sickle cell
retinopathy. A long-term follow-up.
Ophthalmology 1991; 98:581–585.
60. Goldberg MF: Retinal detachment
associated with proliferative retinopathies
(sickle cell disease, retrolental fibroplasia
and diabetes mellitus). Isr J Med Sci 1972;
8:1447–1457.
61. Durant WJ, Jampol LM, Daily M: Exudative
retinal detachment in hemoglobin SC
disease. Retina 1982; 2:152–154.
62. Nagpal KC, Patrianakos D, Asdourian GK,
et al: Spontaneous regression
(autoinfarction) of proliferative sickle
retinopathy. Am J Ophthalmol 1975;
80:885–892.
63. Stephens RF: Proliferative sickle cell
retinopathy: the disease and a review of its
management. Ophthalmic Surg 1987;
18:222–231.
64. Goldberg MF: Treatment of proliferative
sickle retinopathy. Trans Am Acad
Ophthalmol Otolaryngol 1971; 75:532–556.
65. Condon P, Jampol LM, Farber MD, et al:
A randomized clinical trial of feeder vessel
photocoagulation of proliferative sickle cell
retinopathy. II. Update and analysis of risk
factors. Ophthalmology 1984; 91:1496–1498.
66. Farber MD, Jampol LM, Fox P, et al:
A randomized clinical trial of scatter
photocoagulation of proliferative sickle cell
retinopathy. Arch Ophthalmol 1991;
109:363–367.
67. Jampol LM, Farber M, Rabb MF,
Serjeant G: An update on techniques of
photocoagulation treatment of
proliferative sickle cell retinopathy. Eye
1991; 5(Pt 2):260–263.
68. Rednam KR, Jampol LM, Goldberg MF:
Scatter retinal photocoagulation for
proliferative sickle cell retinopathy. Am J
Ophthalmol 1982; 93:594–599.
69. Condon PI, Jampol LM, Ford SM, Serjeant
GR: Choroidal neovascularisation induced
by photocoagulation in sickle cell disease.
Br J Ophthalmol 1981; 65:192–197.
Sickle-Cell Retinopathy
70. Galinos SO, Asdourian GK, Woolf MB, et al:
Choroido-vitreal neovascularization after
argon laser photocoagulation. Arch
Ophthalmol 1975; 93:524–530.
71. Cruess AF, Stephens RF, Magargal LE,
Brown GC: Peripheral circumferential retinal
scatter photocoagulation for treatment of
proliferative sickle retinopathy.
Ophthalmology 1983; 90:272–278.
72. Jampol LM, Green JL Jr, Goldberg MF,
Peyman GA: An update on vitrectomy
surgery and retinal detachment repair in
sickle cell disease. Arch Ophthalmol 1982;
100:591–593.
73. Morgan CM, D’Amico DJ: Vitrectomy
surgery in proliferative sickle retinopathy.
Am J Ophthalmol 1987; 104:133–138.
74. Ryan SJ, Goldberg MF: Anterior segment
ischemia following scleral buckling in sickle
cell hemoglobinopathy. Am J Ophthalmol
CHAPTER 172
1971; 72:35–50.
75. Koshy M, Weiner SJ, Miller ST, et al:
Surgery and anesthesia in sickle cell
disease. Cooperative study of sickle cell
diseases. Blood 1995; 86:3676–3684.
2185
 CHAPTER
173 Traumatic Retinopathy
Melvin D. Rabena, Dante J. Pieramici, and Mark W. Balles
The retina, marvelous in its design and function, is a fragile
tissue, easily injured and possessing only modest capabilities
for repair. The mechanisms of traumatic injury of the retina are
numerous and can be categorized into those associated with
blunt force (contusion/rupture), those resulting from sharp or
lacerating forces, those resulting from acceleration/deceleration
forces, and other more complex mechanisms. The most com-
mon injuries of the retina involve contusion related trauma
(closed globe) and to understand the diffuse nature of these
injuries requires an appreciation of the mechanical changes the
globe undergoes following blunt impact (Fig. 173.1).
Our ability to manage severe ocular injuries has certainly
improved in the past 50 years; however, involvement of the
retina continues to be an ominous sign, portending a poor
visual prognosis.
CONTUSION (BLUNT, CLOSED GLOBE)
When a blunt force strikes the eye, the eyeball is shortened in
the anteroposterior dimension and elongated equatorially. As
the lens–iris diaphragm and the anterior vitreous base are
anchored to the eyewall, portions of these structures are forced
posteriorly, while their sites of attachment to the eyewall move
equatorially. This results in additional forces generated at the
attachment sites leading to characteristic contusion injuries
such as a retinal dialysis. More complex less well understood
interactions between the movement of the eyewall and the
vitreous gel lead to posteriorly located retinal injuries such as
a traumatic macular hole or choroidal rupture.
a b
Key Features: Contusion (Closed Globe Injuries)
• When a blunt force strikes the eye the globe undergoes
mechanical changes in its anteroposterior and equatorial
dimension
• Forces generated at attachment sites cause retinal dialysis,
tears, and detachments
CHOROIDAL RUPTURE
A choroidal rupture is a tear in the choroid, Bruch’s membrane,
and retinal pigment epithelium (RPE)1 and was first described
by von Graefe in 1854.2 Choroidal ruptures may occur
anteriorly, where they are usually parallel to the ora serrata, or
posteriorly, where they are usually crescentic and oriented
around the optic nerve (Fig. 173.2). Anterior choroidal ruptures
are thought to occur directly at the site of impact, while
posterior pole choroidal ruptures result indirectly from the
movements of the eyewall.
Identification of a choroidal rupture acutely may be difficult
because of co-existing anterior segment or vitreous opacities
(i.e., hyphema). Even in cases of clear ocular media, posterior
segment hemorrhage, which may be subretinal, retinal, or
preretinal, is often present obscuring the rupture (Fig. 173.3). In
such cases, one or more ruptures are almost always present,
only to be identified with subsequent clearing of the blood or
with fluorescein angiographic testing.
Most patients presenting with choroidal ruptures do not
regain vision to the 20/40 level.3 Visual outcome is often
FIGURE 173.1. Closed globe injury.
(a) Dimensional changes in the eye following
contusion (blunt) injury. The anteroposterior
dimension of the globe shortens (large arrow)
as it expands equatorially (smaller arrows).
(b) Forces generated at the lens–iris diaphragm
and vitreous base attachment site at the point
of maximum equatorial expansion.
2187
 RETINA AND VITREOUS
b
a
SECTION 10
c d
a b
difficult to predict at presentation but poor final vision is
associated with foveal location of the rupture, multiple rup-
tures, and poor presenting visual acuity.3 Choroidal ruptures
heal with time through the process of fibrous and fibrovascular
proliferation. Choroidal neovascularization may be a late com-
plication of a choroidal rupture occurring months or years
following the initial injury. The development of choroidal neo-
vascularization is associated with more posteriorly located
choroidal ruptures and older aged patients. Laser photo-
coagulation,4 photodynamic therapy,5 or anti-VEGF therapy of
choroidal rupture-associated choroidal neovascularization
can be beneficial in minimizing visual loss.
Key Features: Choroidal Rupture
• Characterized by a tear in the choroid, Bruch’s membrane,
retinal pigment epithelium
• Anterior choroidal ruptures are parallel to the ora serrata
• Posterior choroidal ruptures are crescentic oriented around the
optic nerve
• Poor final visual outcome is associated with fovea location of
rupture, multiple ruptures and poor presenting visual acuity
• Choroidal neovascularization can be a late complication
(months or years later) of choroidal ruptures
2188
FIGURE 173.2. Choroidal rupture.
(a) Fundus photograph showing multiple
concentric choroidal ruptures, one through the
fovea. (b–d) Corresponding red-free fundus
photograph, late-phase fluorescein angiogrpahy
and ocular coherence tomography.
FIGURE 173.3. Choroidal rupture. (a) Acutely
after injury, retinal and subretinal hemorrhage
and commotio retinae obscure the peripapillary
choroidal rupture from view. (b) The same
patient, 2 months later. After clearing of the
hemorrhage, the peripapillary, concentric
choroidal rupture can be seen.
COMMOTIO RETINAE
First described in 1873,6 commotio retinae (Berlin’s edema)
occurs after blunt injury to the eye and is characterized by
decrease in central and/or peripheral vision and a transient gray-
white patchy discoloration and opacification of the outer
neurosensory retina (Fig. 173.4). The opacification may be
accompanied by retinal, subretinal, or preretinal hemorrhage
and choroidal rupture.7 Central and peripheral vision tends to
improve as the retinal whitening resolves; however, in other
cases, central vision loss may be permanent, associated with
RPE changes and pigment migration.8 The peripheral pigmentary
changes when present, can mimic retinitis pigmentosa.9,10
Fluorescein angiography typically shows no alteration in
retinal vascular permeability.11,12 Experimentally produced
commotio retinae in owl monkeys has shown disruption of the
photoreceptor outer segments and acute damage to the
photoreceptor cells.13 This was followed by pigment migration
to the ganglion cell layer and, in severe injuries, thinning of the
outer plexiform and outer nuclear layers with variable loss of
the photoreceptor outer segments. No evidence of intracellular
or extracellular retinal edema was seen in this model, which
appears clinically identical to human patients with this
condition.
The visual prognosis is good in extrafoveal or mild injuries
and the vision tends to recover in a vast majority of cases

FIGURE 173.4. Commotio retinae in the extramacular retina. The
retinal whitening affects the outer retina and is seen in this patient in
association with retinal hemorrhage. One month later, the retinal
whitening had resolved with some pigment migration into the
neurosensory retina.
(60%).14 Permanent vision loss may occur if there is significant
damage in the fovea or there are associated retinal injuries such
as a choroidal rupture or macular hole formation. There is no
treatment of proven benefit for this condition.
Key Features: Commotio Retinae
• Transient gray-white patchy discoloration and opacification of
outer neurosensory retina
• Commotio retinae is not associated with extracellular edema
but with disruption of photoreceptor outer segments
• Visual acuity tends to recover except in cases where there is
significant damage to the fovea
TRAUMATIC MACULAR HOLE
Trauma is the mechanism of macular hole formation in ~10%
of cases.15 Macular holes may be present immediately following
the contusion injury or may take days to weeks to form. The
pathophysiologic mechanism(s) underlying traumatic macular
hole formation are unclear but in most cases, traumatic holes
probably result from similar, albeit more abrupt, tractional
vitreofoveal interface changes similar to idiopathic macular
holes.16 Traumatic macular holes range in size from 0.2 to 0.5
disk diameters and may be round or oval in appearance
a b
FIGURE 173.5. Traumatic macular hole. (a) Color fundus photograph and (b) ocular coherence tomography revealing small full-thickness
macular hole less than 500 mm in diameter caused by contusion injury to the eye. (c) Anterior segment photograph shows zonular fiber dialysis.
Traumatic Retinopathy
(Fig. 173.5). Ocular coherence tomography reveals findings
similar to nontraumatic holes, although at times, a more
ragged/irregular appearance to the edges of the hole are present.
Sometimes, traumatic macular holes may close spontaneously,
particularly in younger patients, and a period of observation is
reasonable before deciding on surgery in these cases. Vitrectomy
with or without peeling of the internal limiting membrane
(ILM) can result in hole closure in over 90% of the cases with
visual improvement of two or more lines in more than three out
of four patients and more than half of the patients achieving
20/50.17 Eyes with associated macular RPE atrophy or choroidal
injury have a poorer visual prognosis and may have only limited
improvement after surgery.18,19 Progression to retinal
detachment rarely occurs as macular holes are usually stable
lesions.20
Key Features: Traumatic Macular Hole
CHAPTER 173
• Accounts for less than 10% of macular hole cases
• Traumatic macular holes typically ranges in size from 0.2 to 0.5
disk diameters
• Vitrectomy with or without ILM peeling can result in hole
closure (90% of cases) and improvement in visual acuity
• Progression to retinal detachment is unlikely
• Spontaneous closure of traumatic macular holes has been
reported, suggesting a role for initial observation
CHORIORETINITIS SCLOPETARIA
Chorioretinitis sclopetaria is characterized by a rupture of the
retina and choroid after nonpenetrating ocular trauma in which
a high-velocity projectile usually a shotgun or BB pellet, strikes
or passes tangential to the globe.21 The first case caused by a
shotgun, was described by Goldzeiher22 in 1901. The concus-
sive force of the injury causes full-thickness rupture of the
retina, Bruch’s membrane, and choroid with associated
hemorrhage and is followed by retraction of these tissues to
expose the bare sclera (Fig. 173.6).21 It is relatively rare,
especially during peacetime, as it is most often the result of gun
related injuries.23
Both the posterior pole and the peripheral retina may be
involved, with marked choroidal and retinal hemorrhages
associated with tears in these layers. The sclera remains intact
and may be visible on ophthalmoscopy but may be obstructed
acutely by overlying vitreous hemorrhage and intraretinal and
subretinal hemorrhage. Retinal detachment occurs only rarely,
and with resolution of the hemorrhage the lesion typically heals
and develops irregular border with the formation of white
fibrous scars and associated pigment migration and
proliferation.24 The visual prognosis is usually poor owing to
the initial severity of the injury, however cases of excellent
visual return have been reported.25 Vitrectomy may be used to
c
2189
 RETINA AND VITREOUS
a b
SECTION 10
c d
remove nonclearing vitreous hemorrhage26 or repair retinal
detachment; however, surgery is not often required.
Key Features: Chorioretinitis Sclopetaria
• Nonpenetrating ocular trauma in which a high velocity
projectile (i.e., shotgun or BB pellet) strikes or passes
tangential to the globe
• Concussive force causes a full-thickness rupture of the retina,
Bruch’s membrane and choroid
• Lesions typically heal spontaneously and only rarely lead to
retinal detachment
TRAUMATIC RETINAL TEARS, DIALYSIS, AND
DETACHMENT
As mentioned above movement of the eyewall relative to the
vitreous following blunt trauma creates tractional forces at
the vitreous base and pars plana. Blunt trauma to the eye can
cause retinal tears, dialysis, and retinal detachment. Traumatic
retinal detachments account for ~15% of all detachments
and tend to occur in a much younger patient population than
do nontraumatic detachments. Traumatic detachment is
four times more common in males than in females, compared
with a similar incidence between the sexes for nontraumatic
detachments.27,28
Retinal dialysis is the most common type of retinal break
associated with traumatic retinal detachment. It occurs most
commonly in the inferotemporal quadrant (66% of detachments)
followed by the superonasal quadrant (14% of detachments). A
retinal dialysis is characterized by a break or separation at the
anterior edge of the ora serrata and it differs from a retinal tear
as the vitreous remains attached to the posterior edge of the
dialysis.29,30 In the same series, giant retinal tears accounted for
16% of detachments, retinal flap tears accounted for 11%, and
2190 tears in an area of lattice accounted for 8% of detachments.28
FIGURE 173.6. Chorioretinitis sclopetaria.
(a) This 16-year-old boy noted decreased vision
after being shot with a BB gun from 4 ft away.
Vision was 8/200. Note the entry wound in the
left lower lid just above the inferior orbital rim.
Subconjunctival hemorrhage is also visible.
(b) Fundus photographs of the inferonasal
quadrant in this patient show the acute
appearance of choroidal and retinal rupture
with preretinal hemorrhage typical in
chorioretinitis sclopetaria. The sclera remains
intact. (c) Computed tomography scan shows
the location of the BB at the orbital apex. Note
that the globe appears intact, without the ‘flat
tire’ sign seen in perforating injuries of the
globe. (d) Seven months later, the patient’s
vision has improved to 20/70. The retina has
remained attached without surgical
intervention, and a white scar with pigment
proliferation and intraretinal pigment migration
along its margins is present in the inferonasal
quadrant.
Avulsion of the anterior vitreous base in association with
detachment always indicates a history of significant ocular
trauma. Retinal detachments associated with retinal dialysis
and other traumatic retinal breaks tend to progress slowly and
may not present for months or years following the injury.
Retinal tears associated with ocular trauma may be treated
with cryoretinopexy or laser retinopexy. Traumatic retinal
detachments can be treated using scleral buckling or vitrectomy
techniques. Proliferative vitreoretinopathy (PVR) is the most
common reason for surgical failure in the management of
trauma related retinal detachment. Cases of retinal detachment
associated with PVR generally require more advanced vitreo-
retinal surgical techniques including; vitrectomy, membrane
dissection, retinectomy, and use of long-active intraocular gases
or silicone.
Key Features: Traumatic Retinal Tears, Dialysis, and
Detachment
• Retinal dialysis is characterized by a break or separation at the
anterior edge of the ora serrata and are most common in the
inferotemporal quadrant
• Retinal detachments following trauma may occur months to
years following the trauma
• PVR is the most common reason for surgical failure in the
management of trauma related retinal detachment
ACCELERATION/DECELERATION INJURY
OPTIC NERVE EVULSION
Evulsion of the optic nerve is the rarest form of traumatic optic
neuropathy. The optic nerve may be partially or completely
separated from the globe. In total evulsion the vitreous and
retina separate from the optic disk and the lamina cribosa is
detached from the choroid and sclera. Partial evulsion involves
 Traumatic Retinopathy

partial disruptions of laminar–scleral connections. Cases can resolve quickly and are generally gone by 1 month following
involve severe orbital trauma;31,32 however, other cases of partial birth.40 They can mimic retinal hemorrhages seen in the shaken
evulsion have been reported after seemingly minor trauma.33,34 baby syndrome and should be considered in the differential
Fundus examination shows total or partial absence of the optic diagnosis.
disk however immediately after injury the disk is often obscured
by overlying vitreous hemorrhage. Partial evulsion may mimic RETINAL TRAUMA ASSOCIATED WITH
an optic nerve pit in appearance. Serous macular detachment OPEN GLOBE INJURIES
has been reported after partial evulsion injury.33
Fluorescein angiography may demonstrate either normal, Open globe injuries (full-thickness eyewall defect present) are
partial, or absent retinal vascular filling. Anterior segment neo- classified as lacerating if they are the result of sharp force
vascularization may develop in rare cases as a result of posterior
segment ischemia. Computed tomography or magnetic reso-
nance imaging usually demonstrates an intact nerve sheath.26
Presumed mechanisms of injury include extreme rotation
and anterior globe displacement, sudden marked increase in
intraocular pressure after traumatic compression in which the
optic nerve is pneumatically disinserted and sudden elevation of
intraorbital pressure stretches optic nerve until it is evulsed

CHAPTER 173
from its scleral insertion.35

Key Features: Optic Nerve Evulsion

• In total evulsion the vitreous and retina separate from the optic
disk and the lamina cribrosa is detached from the choroid and
sclera
• Partial evulsion involves partial disruptions of laminar–scleral
connections.
• Presumed mechanisms of injury include:
• Extreme rotation and anterior globe displacement
• Sudden increase in intraocular pressure after traumatic
compression
• Sudden elevation of intraorbital pressure
FIGURE 173.7. Shaken baby syndrome. This 1-month-old child was
hospitalized in the neonatal intensive care unit with subarachnoid and
SHAKEN BABY SYNDROME subdural hemorrhages due to child abuse. The fundus photograph of
the right eye taken at that time demonstrates a large, bean-shaped
Shaken baby syndrome presents as retinal hemorrhages and macular subinternal limiting membrane hemorrhage. A glistening light
cotton-wool spots in an abused infant who may have sustained reflex is present on its surface, and white, intraretinal patches are seen
violent shaking; direct eye, head, or chest trauma; or in the macula temporal to the hemorrhage. Similar findings were
choking.6,36 Papilledema and vitreous hemorrhage may occur in present in the fellow eye.
association, along with subdural or subarachnoid hemorrhage
or cerebral contusion. Ocular injury may be present in up to
30–40% of abused children.36–38 Retinal manifestations are
most common (Fig. 173.7) and may appear similar to Terson’s
syndrome, Purtscher’s retinopathy, or central retinal vein occlu-
sion.6 Other rare retinal manifestations include; subhyaloidal
hemorrhage (hemorrhagic macular cyst) and circular perima-
cular folds. The prognosis is poor, with children suffering from
the sequelae of their intracranial injuries as well as ocular visual
loss, which may be secondary to macular scarring, vitreous
hemorrhage, retinal detachment,39 or from amblyopia. Retinal
reattachment surgery or vitrectomy for nonclearing vitreous
hemorrhage may be beneficial.26
Intraretinal, subretinal, pretinal, and vitreous hemorrhages
may occur following either vaginal or caesarean birth in over
one-third of newborns (Fig. 173.8). These hemorrhages tend to

Key Features: Shaken Baby Syndrome

• Characterized by retinal hemorrhages and cotton wool spots
• Papilledema, vitreous hemorrhage, subarachnoid hemorrhage
or cerebral contusion may also occur
• Prognosis is poor, with children suffering from intracranial
injuries and ocular visual loss
• Intraretinal, subretinal, pretinal, and vitreous hemorrhages may
occur following either vaginal or caesarean birth in over 1/3 of
newborns but these tend to resolve by the first month FIGURE 173.8. Intraretinal hemorrhages following birth. Fundus
following birth photograph of newborn with multiple intraretinal hemorrhages some
with white centers. 2191
 RETINA AND VITREOUS

(i.e., nail injury) or rupture if the eyewall opens as a result of

blunt force.41
A ruptured globe occurs when a blunt object of significant
force strikes the eyewall. This causes typical deformation
changes in the eyewall and marked increase in the intraocular
pressure. When significant blunt force is applied, or in cases of
inherent or acquired eyewall weakness and lesser forces, the
eyewall will rupture or burst at its weakest points. The most
common locations are just posterior to the rectus muscle
insertions where the sclera is thinnest, at the equator, at the site
of previous surgical incisions, or at the limbus. Ruptured globes
carry a poor prognosis as the injuries typically result in diffuse
ocular trauma with posteriorly located wounds.42
Lacerating open globe trauma is sub-classified into penetrat-
ing, perforating, and intraocular foreign body (IOFB) injuries.
Penetrating wounds are the result of sharp forces that result in
full-thickness defect entrance wounds. They tend to carry a
favorable prognosis unless the wounds are large and extend
SECTION 10

posteriorly. IOFB injuries are essentially penetrating injuries in

which the lacerating object remains lodged into the eye. They
also may carry a favorable prognosis if the foreign body is small
and sharp in nature. IOFB injuries must be identified acutely as
they carry a higher risk of traumatic endophthalmitis,
particularly if the IOFB is not removed urgently. CT scan and/or
B-scan testing should be performed in all cases of open globe
injury when one cannot visualize the posterior segment.
Perforating injuries are through-and-through injuries of the eye
(Fig. 173.9). They are often the result of missile injuries and the
perforating object generally comes to rest in the orbit. The exit
site for perforating injuries is often the posterior segment of the
eye, and these injuries carry a very poor prognosis.
Key Features: Open Globe Injuries
• Open globe injuries are classified as lacerating if they are the
result of sharp force (i.e., nail injury) or rupture if the eyewall
opens as a result of blunt force
• Ruptured globes carry a poor prognosis
• Lacerating open globe trauma is subclassified into penetrating,
perforating, and intraocular foreign body (IOFB) injuries
FIGURE 173.9. Perforating intraocular foreign body injury. This
patient suffered perforating pellet injury to the left eye. An intraocular
foreign body (pellet) lodged in the orbit resulting after passing through
the globe causing diffuse injury. Note the intraocular air (closed arrow)
and foreign body (open arrow).
endothelial damage,44,45 complement-induced granulocyte
aggregation,46 air embolism associated with crushing chest
injuries,44 and fat embolism associated with long bone frac-
tures47 have all been proposed as possible mechanisms. Patients
with acute pancreatitis may have associated fat emboli and
present with a Purtscher-like retinopathy.48 The complement
system is also activated in acute pancreatitis, as well as in
severe trauma,26 which lends support to the theory of retinal
intravascular clotting as the mechanism of Purtscher ’s
retinopathy.

Key Features: Purtscher’s Retinopathy

MISCELANEOUS MECHANISM OF RETINAL
INJURY
PURTSCHER’S RETINOPATHY
Purtscher described patches of superficial retinal whitening,
intraretinal hemorrhages, and disk edema in five patients after
severe compression injury to the head in 1910.43 The charac-
teristic fundus changes may be seen immediately and may
continue to progress for 1–2 day following trauma.21 Presenting
visual acuity may range from 20/20 to count fingers and
findings typically are bilateral although unilateral cases have
been described.21
The characteristic retinal findings in Purtscher’s retinopathy
are multiple patches of superficial retinal whitening and retinal
hemorrhages surrounding the optic nerve. The disk may appear
normal initially, but an afferent pupillary defect may be present,
and later optic disk edema followed by atrophy may develop.
Fluorescein angiography may show leakage of dye in the region
of the white retinal patches, retinal and disk edema, venous
staining, and areas of capillary nonperfusion. The retinal
hemorrhages and white patches resolve over several months,
although the patient may be left with some loss of vision
secondary to pigmentary macular changes and optic atrophy.44
Several theories have been advanced to explain the patho-
2192 genesis of Purtscher’s retinopathy. Retinal vascular injury with
• Characterized by multiple patches of superficial retinal
whitening and retinal hemorrhages surrounding the optic nerve
• Theories to explain the pathogenis of Purtscher’s retinopathy
include:
• Retinal vascular injury with endothelial damage
• Complement-induced granulocyte aggregation
• Air embolism associated with crushing chest injuries
• Fat embolism associated with long bone fractures
TERSON’S SYNDROME
Terson’s syndrome is the term used to describe the association
of retinal and vitreous hemorrhage with subarachnoid and
subdural hemorrhage, first described by Terson in 1900.49
Approximately 20% of patients with spontaneous or
posttraumatic subarachnoid hemorrhage will present with
intraocular hemorrhage.50 These hemorrhages are typically
located between the ILM and the rest of the neurosensory retina
and may occasionally break into the vitreous cavity. The blood
usually clears spontaneously; however, in cases of nonclearing
vitreous hemorrhage, vitrectomy may be beneficial.51
The mechanism of intraocular hemorrhage in Terson’s
syndrome is thought to be due to significant hemorrhage from
epipapillary and peripapillary capillaries that rupture after a
sudden increase in venous pressure resulting from acute
 Traumatic Retinopathy

elevation of intracranial pressure after intracranial hemor-

Key Features: Valsalva Retinopathy
rhage.49 The hemorrhage may spread to the subretinal space,
• Retinal hemorrhages observed in association with heavy lifting,
within the retina, the subretinal limiting membrane space, the
coughing, vomiting, vigorous sexual activity or straining during
subhyaloid space, or vitreous cavity.52–55
bowel movement
• Characterized by well-circumscribed, round or dumbbell-
shaped red elevation beneath the internal limiting membrane or
Key Features: Terson’s Syndrome intraretinal hemorrhage in or near the fovea
• Term used to describe retinal and vitreous hemorrhage
associated with subarachnoid and subdural hemorrhage
• Hemorrhages are located between the internal limiting
membrane and the neurosensory retina but may break into the
vitreous cavity
• Prognosis for visual return is generally good, however,
vitrectomy may be indicated for some cases

VALSALVA RETINOPATHY

CHAPTER 173
Duane first used the term Valsalva hemorrhagic retinopathy
in 197256 to describe the retinal hemorrhages observed in
association with heavy lifting, coughing, vomiting, vigorous
sexual activity or straining during bowel movement.57
Patients may note a sudden decrease in vision associated with
these activities resulting in Valsalva retinopathy. Typical fundus
findings include a well-circumscribed, round or dumbbell-
shaped red elevation beneath the ILM or intraretinal
hemorrhage in or near the fovea. There may be associated
vitreous hemorrhage or dissection of blood beneath the retina.
The blood is initially bright red with a prominent light reflex
on the surface, but it may turn yellow after several days or
weeks (Fig. 173.10). A fluid level may develop early with settling FIGURE 173.10. Valsalva maculopathy. This 22-year-old man noted
of red blood cells.6 The visual prognosis is good, with most decreased vision and a central scotoma immediately after a coughing
episode 3 weeks before presentation. Visual acuity was 20/50. Note
patients returning to normal vision.
the bilobed appearance of the preretinal hemorrhage, now yellow
The presumed mechanism of retinal hemorrhage is rupture because of hemolysis. Along the inferior margin of the hemorrhage,
of superficial retinal capillaries owing to a sudden increase in blood can be seen breaking through the internal limiting membrane
retinal venous pressure after the rapid increase in intrathoracic and extending into the vitreous cavity inferiorly. One month later, the
or intraabdominal pressure associated with a Valsalva hemorrhage had almost completely resolved, and vision improved
maneuver, such as coughing or vomiting. to 20/20.

REFERENCES
1. Aguilar JP, Green WR: Choroidal rupture.
A histopathologic study of 47 cases. Retina
1984; 4:269–275.
2. von Graefe A: Zwei Falle von Ruptur der
Choroidia. Graefes Arch Ophthalmol 1854;
1:402.
3. Ament CS, Zacks DN, Lane AM, et al:
Predictors of visual outcome and choroidal
neovascular membrane formation after
traumatic choroidal rupture. Arch
Ophthalmol 2006; 7:957–66.
4. Fuller B, Gitter KA: Traumatic choroidal
rupture with late serous detachment of the
macula: Report of successful argon laser
treatment. Arch Ophthalmol 1973;
89:354–355.
5. Harissi-Dagher M, Sebag M, Gauthier d,
Marcil G, et al: Photodynamic therapy in
young patients with choroidal
neovascularization following traumatic
choroidal rupture. Am J Ophthalmol 2005;
139:726–8.
6. Berlin R: Zur sogenannten Commotio
retinae. Klin Monatsbl Augenheilkd 1873;
1:42–78.
7. Gass JDM: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 3rd edn.
St Louis: CV Mosby, 1987:170, 552–565.
8. Duke-Elder S: System of ophthalmology.
St Louis: CV Mosby, 1972:165.
9. Bastek JV, Foos RY, Heckenlively J:
Traumatic pigmentary retinopathy. Am J
Ophthalmol 1981; 92:621–624.
10. Cogan DG: Pseudoretinitis pigmentosa:
report of two traumatic cases of recent
origin. Arch Ophthalmol 1969; 81:45–53.
11. Pulido JS, Blair NP: The blood–retinal barrier
in Berlin’s edema. Retina 1987; 7:233–236.
12. Hart JCD, Frank HJ: Retinal opacification
after blunt non-perforating concussional
injuries to the globe: A clinical and retinal
fluorescein angiographic study. Trans
Ophthalmol Soc UK 1975; 95:94–100.
13. Sipperley JO, Quigley HA, Gass JD:
Traumatic retinopathy in primates: The
explanation of commotio retinae. Arch
Ophthalmol 1878; 96:2267–2273.
14. Eagling EM: Ocular damage after blunt
trauma to the eye: its relationship to the
nature of the injury. Br J Ophthalmol 1974;
58:126–140.
15. Aaberg TM: Macular holes. Surv
Ophthalmol 1970; 15:139:162.
16. Gass JDM: Stereoscopic atlas of macular
diseases. St Louis: CV Mosby; 1970:94–96.
17. Johnson RN, McDonald HR, Lewis H, et al:
Traumatic macular hole: observations,
pathogenesis and results of vitrectomy
surgery. Ophthalmology 2001;
108:853–857.
18. Rubin JS, Glaser BM, Thompson JT,
et al: Vitrectomy, fluid-gas exchange and
transforming growth factor beta-2 for
the treatment of traumatic macular
holes. Ophthalmology 1995;
102:1840–1845.
19. Garcia-Arumi J, Corcostegui B, Cavero L,
et al: The role of vitreoretinal surgery in the
treatment of posttraumatic macular hole.
Retina 1997; 17:372–377.
20. Aaberg TM, Blair CJ, Gass JDM:
Macular holes. Am J Ophthalmol 1970;
69:555–562.
21. Elliot D, Avery RL: Issues in ocular trauma-
Nonpenetrating posterior segment trauma.
Ophthalmol Clin North America 1995;
8:647–667
22. Goldzieher W: Beitrag zur Pathologie der
orbitalen Schussverletzungen. Z Augenh
1901; 6:277.
23. Richards RD, West CE, Meisels AA:
Chorioretinitis sclopetaria. Trans Am
Ophthalmol Soc 1968; 66:214–232.
24. Richards RD, West CE, Meisels AA:
Chorioretinitis sclopetaria. Am J
Ophthalmol 1968; 66:852–860.
25. Martin DF, Awh CC, McCuen BW, et al:
Treatment and pathogenesis of traumatic
chorioretinal rupture sclopetaria. Am J
Ophthalmol 1994; 117:190–200. 2193
 RETINA AND VITREOUS
26. Williams DF, Mieler WF, Williams GA:
Posterior segment manifestations of ocular
trauma. Retina 1990; 10:S35–S44.
27. Cox MS, Schepens CL, Freeman HM:
Retinal detachment due to ocular
contusion. Arch Ophthalmol 1966;
76:678–685.
28. Goffstein R, Burton TC: Differentiating
traumatic from nontraumatic retinal
detachment. Ophthalmology 1982;
89:361–368.
29. Ross WH: Traumatic retinal dialyses.
Arch Ophthalmol 1981; 99:1371–1374.
30. Scott JD: Retinal dialysis. Trans
Ophthalmol Soc UK 1997; 97:33–35.
31. Lister W: Some concussive changes met
with in military practise. Br J Ophthalmol
1924; 8:305.
32. Caiger H: Ocular injuries resulting from the
war. Trans Ophthalmol Soc UK 1941;
61:54–73.
SECTION 10
33. Delaney WV, Geiss M: Partial evulsion of
the optic nerve. Ann Ophthalmol 1988;
20:371–372.
34. Chow AY, Goldberg MF, Frenkel M:
Evulsion of the optic nerve in association
with basketball injuries. Ann Ophthalmol
1971; 72:969–971.
35. Assaf AA: Traumatic retinal detachment.
J Trauma 1985; 25:1085–1089.
36. Harley RD: Ocular manifestations of child
abuse. J Pediatr Ophthalmol Strabismus
1980; 17:5–13.
37. Friendly DS: Ocular manifestation of the
physical child abuse. Trans Am Acad
Ophthalmol Otolaryngol 1971; 75:318–332
38. Jensen AD: Ocular clues to child abuse.
J Pediatr Ophthalmol 1971; 8:270.
2194
39. Harcourt B, Hopkins D: Permanent
chorioretinal lesions in childhood of
suspected origin. Trans Ophthalmol Soc
UK 1973; 93:199–205.
40. Emerson MV, Pieramici DJ, Stoessel KM,
et al: Incidence and rate of disappearance
of retinal hemorrhage in newborns.
Ophthalmology 2001; 108:36–39.
41. Kuhn F, Morris R, Witherspoon CD:
Birmingham eye trauma terminology
(BETT): terminology and classification of
mechanical eye injuries. Ophthalmol Clin
North Am 2002; 15:139–143.
42. Pieramici DJ, Au Eong KG, Sternberg P Jr,
et al: The prognostic significance of a
system for classifying mechanical injuries
of the eye (globe) in open-globe injuries.
J Trauma 2003; 54:750–54.
43. Purtscher O: Angiopathia retinae
traumatica. Lymphorrhagien des
Augengrundes. Graefes Arch Clin Exp
Ophthalmol 1912; 82:347–371.
44. Burton TC: Unilateral Purtscher’s
retinopathy. Ophthalmology 1980;
87:1096–1105.
45. Kelley JS: Purtscher’s retinopathy related
to chest compression by safety belts:
Fluorescein angiographic findings. Am J
Ophthalmol 1972; 74:278–283.
46. Jacob HS, Craddock PR,
Hammerschmidt DE, Moldow CF:
Complement induced granulocyte
aggregation. An unsuspected mechanism
of disease. N Engl J Med 1980;
302:789–794.
47. Urbanek J: Uber Fettembolie des Auges.
Graefes Arch Clin Exp Ophthalmol 1934;
131:147–173.
48. Inkeles DM, Walsh JB: Retinal fat emboli as
a sequelae to acute pancreatitis. Am J
Ophthalmol 1975; 80:935–938.
49. Terson A: De l’hemorrhagie dans le corps
vitre au cours de l’hemorrhagie cerebrale.
Clin Ophthalmol 1900; 6:309.
50. Shaw HE Jr, Landers MB III, Sydnor CF:
The significance of intraocular
hemorrhages due to subarachnoid
hemorrhage. Ann Ophthalmol 1977;
9:1403–1405.
51. Clarkson JG, Flynn HW Jr, Daily MJ:
Vitrectomy in Terson’s syndrome. Am J
Ophthalmol 1980; 90:549–552.
52. Khan SG, Frenkel M. Intravitreal
hemorrhage associated with rapid increase
in intracranial pressure. J Neurosurg 1974;
41:167–176.
53. Muller PJ, Deck JHN: Intraocular and optic
nerve sheath hemorrhage in cases of
sudden intracranial hypertension.
J Neurosurg 1974; 41:160–166.
54. Toosi SH, Malton M: Terson’s syndrome-
significance of ocular findings. Ann
Ophthalmol 1987; 19:7–12.
55. Weingeist TA, Goldman EJ, Folk JC, et al:
Terson’s syndrome. Clinicopathologic
correlations. Ophthalmology 1986;
93:1435–1442.
56. Duane TD: Valsalva hemorrhagic
retinopathy. Trans Am Ophthalmol Soc
1972; 70:298–313.
57. Markovits AS: Sudden visual loss
associated with sexual activity. Arch
Ophthalmol 1996; 114: 106.
 CHAPTER

174 Photic Retinopathy

Martin A. Mainster and Michael E. Boulton

Light can cause photomechanical, photothermal, or photo-

Spectral dependence of phototoxicity or absorption

chemical retinal damage.1–4 Photochemical (actinic) retinal 1
injury occurs at retinal temperature elevations too low for tissue
UV-blue phototoxicity
coagulation (photocoagulation).5–10 It is generally termed photic Lipofuscin
retinopathy or retinal phototoxicity when it occurs without 0.8 All-trans-retinal
exogenous photosensitizers. Photic retinopathy is produced Cytochrome c
experimentally by prolonged intense light exposures ranging Porphyrin
0.6
from seconds to hours at illuminances exceeding normal Xanthophyll
environmental levels that would probably be well tolerated if
experienced only briefly. Solar eclipse and welding arc injuries 0.4 Blue-green phototoxicity
are caused by retinal phototoxicity. Photochemical retinal
damage has also provided valuable insight into the molecular
biology of retinal degeneration.11,12 This chapter summarizes 0.2 Melinin

current understanding of the pathogenesis and clinical con-

sequences of photic retinopathy.
OPTICAL INTERACTIONS AND
PROTECTION
Key Features
• Thermal (photocoagulation) and photochemical (phototoxicity)
effects can damage the retina
• Absorption spectra describe how effectively chromophores
such as melanin or lipofuscin absorb light of different
wavelengths
• Action spectra describe the relative effectiveness of
wavelengths in causing acute retinal phototoxicity
• Photosensitizers are molecules that generate reactive oxygen
species upon light absorption
• The cornea and crystalline lens shield the retina from UV
radiation
The retina is potentially vulnerable to damage from ultraviolet
radiation (UV; l < 400 nm), visible light (400 nm < l < 700 nm),
and infrared radiation (IR; l > 700 nm). Violet (400–440 nm)
and blue (440–500 nm) light comprise the shorter wavelength
portion of the visible spectrum.13,14 Retinal effects depend on
the wavelength (nm), power (W), duration (s), lateral extent
(cm), and location (macular vs elsewhere) of optical radiation
exposures.9,10,15–17 Photochemical effects also depend on oxygen
tension18,19 and body temperature.7,20,21 The magnitude of a
retinal exposure is usually specified in terms of its irradiance
(power density in W/cm2) or fluence (energy density in J/cm2).
Thermal and photochemical retinal damage occur when pho-
tons are absorbed by chromophores, the light absorbing com-
ponents of biomolecules. Melanin, hemoglobin, and macular
xanthophyll are the most effective retinal light absorbers. Other
0
UV Violet Blue Green Yellow Orange Red
<400 400-440 440-500 500-570 570-590 590-610 610-700
350 400 450 500 550 600 650 700
Wavelength (nm)
FIGURE 174.1. Acute UV-blue type,9,55,245 lipofuscin,24,57 and all-trans-
retinal phototoxicity rise rapidly in the violet (400–440 nm) part of the
spectrum, where porphyrin24,246 and cytochrome c oxidase24,247
phototoxicities peak and macular xanthophyll protection declines.248
The action spectrum of the blue-green type retinal phototoxicity peaks
at 500 nm, similar to scotopic luminous efficiency (sensitivity),
because rhodopsin mediates both processes. The absorption spectra
of rhodopsin in rod photoreceptors and melanopsin in light-sensitive
ganglion cells are similar in form but peak at ~500 nm249 (blue-green)
and 480 nm (blue),67–69 respectively. Blue-green type phototoxicity in
experimental studies occurs at lower retinal irradiances than UV-blue
type phototoxicity.26 The absorption spectrum for xanthophyll
decreases rapidly with decreasing wavelength from its peak
absorption at 460 nm.44–47 Melanin absorption, shown for adults over
50 years of age, increases with decreasing wavelength in the visible
and near-UV part of the spectrum, similar to that of lipofuscin
absorption.22–24 The spectral dependence of phototoxicity and
absorption are shown, but ordinate (y-axis) units are arbitrary, so the
relative magnitudes of different curves are not directly comparable in
this figure.
retinal light absorbers include lipofuscin, rhodopsin, cone photo-
pigments, melanopsin, porphyrins, and cytochrome c oxidase.
Absorption spectra describe how effectively tissue chromo-
phores capture photons at different wavelengths. Absorption
spectra for molecules such as hemoglobin or rhodopsin have
peaks at specific wavelengths, with lower absorption at adjacent
wavelengths. Alternatively, absorbers such as melanin and lipo-
fuscin have absorption spectra that increase steadily with
2195
 RETINA AND VITREOUS
decreasing wavelength (increasing photon energy).22–24 Figure
174.1 presents examples of both patterns. When photon
absorption induces damaging reactive oxygen species, spectra
that describe the effectiveness of photon capture at different
wavelengths are known as action spectra. Action spectra charac-
terize how effectively different optical radiation wavelengths
produce photochemical effects.25
Photon absorption excites electrons in target molecules to
higher energy states. Excited molecules release their excess
energy in different ways. Energy can be converted into increased
average molecular vibrational motion, raising retinal tempera-
ture and causing photocoagulation when tissue temperature
elevation is sufficiently high.4 Vibrational energy transferred to
neighboring molecules diffuses heat beyond the directly irradiated
area in a process known as heat conduction. Alternatively, if
photon energy is coupled effectively to chemical bonds in target
molecules, excess molecular electronic energy from photon
absorption can break those bonds, producing photochemically
SECTION 10
induced structural changes in the molecules.26
Reactive oxygen species in the eye can be formed as a result
of (1) the interaction of ionizing radiation with biological
molecules, (2) an unavoidable byproduct of cellular respiration,
(3) synthesis in phagocytic cells such as neutrophils and macro-
phages, or (4) a respiratory burst during phagocytosis. Reactive
oxygen species are highly reactive oxygen radicals with the
capacity to modify and damage cell membranes, proteins,
carbohydrates, and nucleic acids. Most reactive oxygen species
(e.g., hydroxyl radicals, superoxide anions, and lipid hydro-
peroxides) have an unpaired electron in their outer orbital and
are referred to as free radicals. In addition, there are oxygen
species in which electron pairing is normal but the molecule is
in an excited state (e.g., singlet oxygen and hydrogen peroxide).
Singlet oxygen is the lowest excited state of the di-oxygen
molecule, its lifetime in solution is in the microsecond range,
and it reacts readily with membrane lipids. Reactive oxygen
species can react either directly with target tissues (type-1
photochemical or free radical reactions) or with molecular
oxygen to produce singlet oxygen or superoxide which then
reacts with target tissues (type-2 photochemical or photo-
dynamic reactions).26–28 Molecules that produce reactive oxygen
species upon light absorption are referred to as photosensitizers.
Photochemical damage to retinal cells can lead to cellular
dysfunction or death. The latter normally occurs by a process
termed apoptosis, which is a common cell death pathway not only
for photic retinopathy but also conditions such as age-related
macular degeneration (AMD) and retinitis pigmentosa.11 Nor-
mal cellular homeostasis balances cell proliferation and death.
Apoptosis removes unneeded, injured, or diseased cells, span-
ning a broad complex of interrelated mechanisms for signaling
and producing cell death.11,29 Analyses of molecular mechan-
isms of rodent retinal phototoxicity provide insights into the
genetics of inherited retinal disorders.11,12
Ocular media protect the retina from potentially harmful
optical radiation. The cornea shields internal ocular structures
by blocking UV radiation below 300 nm.30 The crystalline
lens protects the retina from UV radiation between 300 and
400 nm,30–32 except in young eyes with clear crystalline lenses
that transmit some UV around 320 nm to the retina.30 The
aging crystalline lens attenuates an increasing amount of visible
light, particularly at shorter violet and blue wavelengths.30–34
Additional extraretinal protection is provided by eyebrow sha-
dowing, corneal reflection of light not incident perpendicular to
its surface (Fresnel’s law), and pupillary, aversion, squint, and
blink responses.35,36
Macular xanthophyll is a yellowish pigment in the cone axon
and inner plexiform layers of the macula that reduces the
2196 short wavelength light exposure of photoreceptors and retinal
pigment epithelium (RPE) cells.37,38 It is composed of the
carotenoid pigments lutein and zeaxanthin, which can limit
photosensitization reactions in the macula either by reducing
the amount of incoming short wavelength light or by directly
quenching reactive oxygen species generated by optical
radiation.38–40 Xanthophyll density declines rapidly with
increasing retinal eccentricity from its foveolar peak, except for
a ring of increased extrafoveolar density that is more common
in women and may be related to the anatomy of the foveolar
depression.37,41–43 Light absorption by xanthophyll also decreases
rapidly with decreasing wavelength from its peak absorption
at 460 nm.44–47 Thus, macular xanthophyll protection is least
effective in the potentially hazardous violet and UV parts of the
spectrum,14,48 an issue of increased significance when the
crystalline lens is removed in cataract surgery. Studies of how
macular xanthophyll varies with retinal aging and AMD have
produced inconsistent results.49–52
MECHANISMS OF PHOTIC INJURY
Key Features
• Photic retinopathy is mediated by either retinal photopigments
(rod, cone or ganglion) or retinal photosensitizers (such as
lipofuscin, cytochrome c oxidase and all-trans-retinal)
• The action spectrum of blue-green phototoxicity peaks around
500 nm (blue-green) because it is mediated by the rod
photopigment rhodopsin
• UV-blue phototoxicity increases with decreasing wavelength,
so UV radiation is more hazardous than violet light which is
more hazardous than blue light
• UV-blue phototoxicity requires 100 times more retinal
irradiance (power density) than blue-green phototoxicity
• International light hazard standards incorporating photic
retinopathy are based on acute UV-blue phototoxicity
CLASSIC PHOTOTOXICITIES
There are two classic types of photic retinopathy. Blue-green
retinal phototoxicity in rodents was discovered by Werner Noell
in 1966.5,20 Its action spectrum is similar to scotopic visual
sensitivity,53,54 which peaks at 500 nm (blue-green), because
rhodopsin mediates both processes. Blue-green phototoxicity
is also termed ‘class 1’, ‘Noell-type’ or ‘white light’ photic
retinopathy. Damage is typically located in the photoreceptor
layer or both the photoreceptor and RPE layers.5
The second classic type of phototoxicity was discovered in
young primates by William Ham and his colleagues in
1976.9,16,26,55–57 UV-blue phototoxicity has an action spectrum
that increases with decreasing wavelength, similar to that of
lipofuscin which may be one of its primary mediators.23,24,57
Thus, UV radiation is more hazardous than violet light, which
in turn is more hazardous than blue light. UV-blue photo-
toxicity is also termed ‘class 2’, ‘Ham-type’, or ‘blue light
hazard’ retinal phototoxicity. Damage is typically located in the
RPE or both the RPE and photoreceptor layers.9,58
UV-blue phototoxicity requires ~100 times more retinal
irradiance than blue-green phototoxicity.16,26,59,60 UV-blue photo-
toxicity is the basis for the international consensus standard
Al phototoxicity function used to estimate acute industrial
retinal phototoxicity risks.61 Blue-green and UV-blue photic
retinopathies are archetypes of photopigment-mediated and
photosensitizer-mediated retinal photoxicity damage mech-
anisms, respectively.9,16,20,26,59 Figure 174.1 illustrates the action
spectra of the classic retinal phototoxicities.

PHOTOPIGMENT-MEDIATED DAMAGE
There are three types of retinal photopigments: (1) cone photo-
receptor photopigments that provide photopic (bright light) and
mesopic (intermediate light) vision,62,63 (2) rhodopsin in rod
photoreceptors responsible for mesopic and scotopic (dim light)
vision,53,54 and (3) melanopsin in blue-light sensitive retinal
ganglion cells that modulate circadian photoentrainment,
pupillary function, and possibly conscious vision.64–67 Cone
photoreceptors in humans have absorption maxima around
426 nm (blue), 530 nm (green), and 552 or 557 nm (red).62,63
Rod and light-sensitive retinal ganglion photoreceptors have peak
spectral sensitivities of ~ 500 nm (blue-green)53,54 and 480 nm
(blue),67–69 respectively.
A photoreceptor photopigment consists of an 11-cis retinal
chromophore molecule bound to a transmembrane opsin
protein in a photoreceptor outer segment disk.70 Differences
in rod, cone, and retinal ganglion photopigment absorption
maxima results from different amino acid sequences in the
opsin molecule adjacent to the 11-cis retinal binding site.71
When a photopigment molecule absorbs a photon, 11-cis retinal
is converted to all-trans retinal, initiating a conformational
change in opsin and a sequence of transient photopigment
states that include metarhodopsin II (activated rhodopsin).70,72
Metarhodopsin II catalyzes the activation of transducin, which
continues the phototransduction cascade that converts absorbed
photon energy into neurochemical signals.73 Metarhodopsin II
decays through hydrolysis, releasing all-trans retinal from its
opsin binding site. All-trans-retinal is reduced to all-trans-
retinol, and then re-isomerized and oxidized back to its original
11-cis retinal in a complex series of steps involving the RPE for
rods and Muller cells for cone photoreceptors.74,75 In general, a
functional retinoid cycle is needed for both retinal photorecep-
tion and phototoxicity.
Most experimental studies of photopigment-mediated retinal
phototoxicity use rodent models and protocols that differ in
retinal irradiance, exposure duration, source wavelength, animal
species, antioxidant status, and circadian timing.5,11,12,20,71,76,77
Studies using knockout mice have demonstrated apoptotic
pathways for photic damage that may or may not involve
phototransduction.78,79
Light damage in mice requires effective retinoid recycling.
The RPE65 protein is needed for the production of 11-cis
retinal. RPE65–/– knockout mice without this protein are pro-
tected against photic retinopathy.11,71 Photochemical damage
thresholds depend on RPE65 protein levels in mice but not in
rats.12 The susceptibility of rats to photic injury has a circadian
rhythm, with dark adaptation increasing the risk of damage.80
Many other molecular, pharmacological, and environmental
factors influence rodent retinal phototoxicity.11,71
Most rodent retinas adapt to ambient illumination, a
phenomenon known as photostasis.81–84 For example, changing
from bright to dim environments upregulates rhodopsin and
increases rod rhodopsin regeneration rates, rod outer segment
lengths, and rhodopsin concentration in rod outer segments.82
The reverse is true for changes from a dim to a bright environ-
ment. A significant finding is that local rhodopsin concentra-
tion across a rodent retina is inversely proportional to local
illuminance.82 Autophagic degradation of opsin may contribute
to downregulation of rhodopsin when ambient illumination is
increased, possibly reducing the risk of retinal phototoxicity.85
Bleached rhodopsin is more thermally labile than the
unbleached photopigment, so bright sustained illumination
that increases the percentage of bleached photopigment could
contribute to increased opsin misfolding86 and phototoxic
injury.8
Cone photopigment-mediated phototoxicity data are limited.
Experimental studies have shown that cones have lower photo-
Photic Retinopathy
toxicity susceptibility than rods in rodents87 and greater suscep-
tibility in pigeons and primates.15,88 These latter observations
are not consistent with the greater resistance of cones than rods
to photic injury in a histopathologic study of human solar
retinopathy,89 possibly because of the relatively small number of
photoreceptors per RPE cell in the primate foveola.90 Repeated
intermittent blue or green light stimulation in primates causes
selective blue or green cone damage, respectively.91 Photo-
sensitive retinal ganglion cells which modulate circadian
rhythmicity92–95 may also be susceptible to phototoxicity
mediated by their photopigment melanopsin.4
PHOTOSENSITIZER-MEDIATED DAMAGE
The retina is vulnerable to oxidative stress because of its high
oxygen and light levels. Its internal defenses include: (1) circadian
shedding of damaged photoreceptor outer segment disks,
(2) enzymatic antioxidants, such as superoxide dismutase,
CHAPTER 174
catalase, and glutathione peroxidase, (3) nonenzymatic anti-
oxidants including a-tocopherol, ascorbate, lutein, and zeaxanthin,
and (4) light-absorbing molecules such as melanin in the
RPE and choroid or macular xanthophyll in the inner
retina.16,24,26,77,96–98 Retinal phototoxicity may be mediated by
photosensitizers such as lipofuscin, all-trans-retinal, cyto-
chrome c oxidase, and the porphyrins.24,99–101 As shown in
Figure 174.1, absorption spectra for these photosensitizers
increase with decreasing wavelength or peak typically in the
near-UV or violet part of the spectrum.
Lipofuscin accumulates with aging in the RPE because
undegradable endproducts of either photoreceptor phagocytosis
or autophagy of spent intracellular organelles such as mito-
chondria and endoplasmic reticulum cannot be removed effec-
tively from cells. Lipofuscin may impair antioxidant activity,
produce phototoxic damage or mechanically compromise
cellular function.24,102,103 It is a photoinducible generator of
reactive oxygen species that can damage RPE cells.24 Lipofuscin
is comprised of many fluorophores, including the pyridinium
bisretinoid A2E, which has received considerable recent
attention. A2E is a retinoid cycle byproduct, formed from
phosphatidylethanolamine and two molecules of all-trans-
retinaldehyde.104 The action spectrum of A2E peaks around
430 nm in the violet part of the spectrum. (cf Fig. 174.1)104,105
A2E and its derivatives are only weakly photoreactive compared
to lipofuscin and thus account for only a small fraction of the
total photoreactivity of lipofuscin.57,106
All-trans-retinal is a potent intraretinal photosensitizer
produced during the normal retinoid cycle. It plays an essential
role in A2E and lipofuscin formation.71 Increased all-trans-
retinal concentration during prolonged bright light exposure107
may cause photic retinopathy.71 Other potential intraretinal
photosensitizers include porphyrin containing molecules such
as hemoglobin and enzymes, including cytochrome c oxidase.
Cytochrome c oxidase is an important respiratory chain enzyme
located in mitochondria and photoreceptors and may contribute
to short wavelength light-induced mitochondrial damage in
the RPE.108 The role of melanin as a photosensitizer or
photoprotective agent in the RPE remains unclear but there is
evidence that it can become a photosensitizer in older
adults.24,60,109–111
CLINICAL SYNDROMES
Solar and operating microscope exposures performed on eyes
prior to enucleation for malignant melanoma have proven that
these light sources can cause phototoxic injuries89,112,113 at retinal
temperature elevations too low for thermal damage.4,114–116
Welding arc and solar maculopathies are similar, as are operating 2197
 SECTION 10 RETINA AND VITREOUS

FIGURE 174.3. Welding arc injuries typically produce yellowish-white

FIGURE 174.2. An acute solar injury produces a yellowish-white
foveolar lesions similar to those seen in solar maculopathy, as
foveola lesion, as seen in this 15-year-old female with 20/70 visual
illustrated in this 17-year-old male 3 days after a welding arc
acuity.
exposure.
Photograph courtesy of Raj Lucas, MD and the Medical Photographic Imaging
Centre, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia.

Key Features
• Clinical photic retinopathy is an acute injury that occurs when
retinal defenses are overwhelmed by brilliant light exposures
• The four well identified clinical examples of photic retinopathy
are solar, welding, operating microscope and endoilluminator
injuries
• Solar and welder’s maculopathies share similar clinical
features, as do operating microscope and endiolluminator
injuries
• The primary sites and mediators of clinical photic injuries are
as yet undetermined
• Most large epidemiologic studies fail to support a significant
role for environment light exposure in AMD
• Minimizing the duration and intensity of operating microscope
and endoilluminator exposures reduces the risk of photic
retinopathy

microscope and endoilluminator injuries.4 The role of light in
AMD has yet to be proven despite decades of investigation.4,48
SOLAR AND WELDER’S MACULOPATHY
The solar disk forms a 160 mm diameter retinal image, ~20%
of the area of the 350 mm diameter foveola.114,117 Unassisted
observation of the sun at its zenith with a 3 mm pupil diameter
produces only a 4°C retinal temperature rise, well below the
10°C temperature elevation needed for threshold retinal
photocoagulation.114,118 Thus, solar retinopathy is usually
caused by retinal phototoxicity, not photocoagulation. Solar
observation with a dilated 7 mm pupil or telescope-assisted
solar inspection can cause significantly higher retinal tem-
perature increases and photocoagulation injuries.1,114,118
Solar injuries can be severe or mild.119,120 Visual acuity is
typically decreased after an injury to 20/40 to 20/200, usually
returning to 20/20 to 20/40 over 6 months.121,122 Injuries have
been reported after sungazing during drug abuse123,124 and
hypoglycemia.125 They can occur with or without eclipses.4
Pupil dilation during an eclipse makes eclipse observation
particularly hazardous.1 There are several safe methods for
viewing solar eclipses.1,117
Acute solar injuries produce yellowish-white foveolar lesions,
2198 as illustrated in Figure 174.2.112,121 Lesions gradually fade over
FIGURE 174.4. Optical coherence tomograms after welding arc and
solar injuries typically show foveal abnormalities affecting the outer
neural retina and RPE, as seen in this 17-year-old male with a
localized hyporeflective defect 8 months after a welding arc exposure.
Photograph courtesy of Raj Lucas, MD., and the Medical Photographic Imaging
Centre, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia.
several weeks. Months later, there may be foveal distortion,
lamellar defects, pigment mottling, a macular hole or no appa-
rent damage.121 Lesion severity depends on viewing circum-
stances and an individual’s defense mechanisms. The worst
injuries occur with prolonged observation and good fixation, as
when the solar disk is foveated through a defective optical filter.
Foveal RPE defects can be demonstrated on fluorescein angio-
grams after severe solar injuries, but angiograms are often
normal.121,126 Optical coherence tomography typically shows
foveal abnormalities affecting the outer neural retina and
RPE.124,126–128
Histopathologic studies of the eyes of volunteers who gazed
at the sun prior to ocular enucleation for choroidal melanoma
show predominantly rod and cone photoreceptor damage,
including vesiculation and fragmentation of outer segment
lamellae, mitochondrial swelling and nuclear pyknosis.89,112
Cones are more resistant to damage than rods, perhaps
accounting for good visual acuity after many solar injuries.89

FIGURE 174.5. The endoilluminator lesion in the temporal macula of
this 68-year-old male is accompanied by cystoid macular edema after
epiretinal membrane surgery.
Fluorescein angiographic image courtesy of Giovanni Staurenghi, MD,
Department of Clinical Science Luigi Sacco, University of Milan, Italy.
RPE damage can be extensive112 or limited and scattered.89
Combined clinical and histopathological evidence to date does
not permit determination of whether solar/welding arc
maculopathy is a photoreceptor versus RPE injury or a
photopigment-mediated versus photosensitizer-mediated
process.
The term foveomacular retinitis was originally used to describe
foveal abnormalities resembling solar retinopathy. These
conditions include whiplash and blunt ocular injuries,129–131
although similar findings have been reported in people with no
prior history of photic or mechanical trauma.132,133 Foveo-
macular retinitis was first described during World War II, with
additional reports between 1966 and 1973.134–137
Experimental photic retinopathy is enhanced by higher core
body temperatures,7,20,21 so the risk of retinal phototoxicity may
be increased by light exposures associated with exercise, infec-
tion, or warm environments. Increased chorioretinal pigmenta-
tion increases chorioretinal temperature elevations from solar
observation, perhaps increasing the risk or extent of photic
injury. High local irradiance from direct sungazing places the
foveola at greatest risk for damage from solar observation,
but solar retinopathy can occur in young sunbathers who
deny sungazing,138,139 possibly due to Henle layer fiberoptic
channeling of short-wavelength photons from perifoveal regions
to the center of the fovea.46 Fiberoptic transmission increases
and xanthophyll protection decreases below 450 nm where the
risk of UV-blue type retinal phototoxicity increases.45,46
Photokeratitis is a common welding arc accident, but a foveal
injury as shown in Figures 174.3 and 174.4 is rare.1,115,140
Welding arc maculopathy has the same clinical appearance and
course as solar retinopathy.115,141–143 Welder’s maculopathy usually
occurs in young workers at risk for retinal injury because of
clear ocular media, occupational inexperience, and inadequate
protective filters. Violet and blue light from a welding arc may
cause most damage, but 320 nm UV transmitted through the
crystalline lens of younger eyes may contribute to the
Photic Retinopathy
damage.30,144 UV may also be responsible for the retinal injury
from an intense flash due to a short-circuiting high-tension
electric circuit.145
OPERATING MICROSCOPE AND
ENDOILLUMINATOR MACULOPATHY
Intense visible light from operating microscopes can produce
retinal lesions that are usually oval shaped and 1–2 optic disk
diameters in lateral extent.146,147 The long axis of the lesion
often has the same orientation as the filament of the operating
microscope’s lamp.148 During cataract surgery, lesions typically
occur in the inferior macula because of microscope tilt and
illumination positioning.149,150 Injuries occur after cataract,
cornea, glaucoma, and retinal procedures.146,147,151–155 Fiberoptic
endoilluminators in vitreoretinal surgery can produce similar
lesions in different retinal locations,21,156,157 as shown in
Figure 174.5.
CHAPTER 174
Operating microscope maculopathy rates have declined with
improved, faster cataract surgery techniques, but injuries can
still occur in brief procedures.158 Acute lesions usually have a
yellowish-white appearance that fades quickly over several days.
They can be associated with a transient serous detachment of
the neural retina. Pigment mottling, RPE degeneration, and
occasionally choroidal neovascularization may develop over
months to years at injury sites.4,159 Fluorescein angiography is
useful when a lesion is suspected but not ophthalmoscopically
apparent.4 Damage was present in the RPE and photoreceptor
layers of a volunteer’s eye after it was exposed to an intense
operating microscope exposure before ocular enucleation for a
choroidal melanoma.113 Experimental primate studies have
reported similar findings.160–162 Combined clinical and histo-
pathological evidence to date does not permit determination of
whether operating microscope/endoilluminator maculopathy is
a primarily photoreceptor versus RPE injury or a photopigment-
mediated versus photosensitizer-mediated process.
The size, location, and severity of operating microscope
lesions determine their visual effects.4,159 Immobilization and
higher blood oxygen levels potentially increase the risk of retinal
injuries in patients undergoing general rather than local
anesthesia.18,163 The hazard of a particular light exposure is also
higher with (1) elevated core body temperature,7 (2) increased
chorioretinal pigmentation (absorption of light by pigmented
tissues potentially elevates local chorioretinal temperature),
and (3) systemic photosensitizing medications,164,165 including
hydroxychloroquine, hydrochlorothiazide, furosemide, allopurinol,
and the benzodiazepines.166 Diabetes mellitus and hypertension
may also increase injury risks.148,167
Operating microscope hazard can be decreased by reducing
illumination, minimizing coaxial exposure duration, and dis-
continuing systemic photosensitizing medications preoper-
atively, when possible.116,160,165,168–170 Positioning a patient’s eye
in downgaze is potentially useful,165 as is tilting the operating
microscope appropriately,150 using corneal occluders,171–173 and
avoiding supplemental oxygen usage and/or elevated patient
core body temperatures.
Operating microscopes produce little UV radiation,116,174,175
so UV-blocking filters are of limited value in reducing injury
risks.176 Some microscopes produce more short wave-
length visible light than others,116 increasing the risk of
photosensitizer-mediated UV-blue type phototoxicity. Filtering
out light with wavelengths below 450 nm reduces the risk of
acute UV-blue type photic retinopathy,168,170,177 but some blue
light is useful for surgery and detecting inner retinal
abnormalities.168,178–180 Filtering out wavelengths greater than
700 nm eliminates unnecessary IR that could thermally
enhance photochemical damage.168,181 2199
 RETINA AND VITREOUS
Studies of the relationship between cataract surgery and
AMD have produced differing results.182–192 Positive
studies189,191,192 may have been confounded by the possibility
that cataract surgery was performed for vision loss due to
AMD rather than cataract.191,193 The AREDS study found no
correlation between cataract surgery and AMD after checking
for the retinal status of all subjects prior to surgery.193,194 If there
is a correlation between AMD and cataract surgery, it is
probably due to trauma or other sequellae of intraocular surgery
and operating microscope illumination on aged susceptible
maculas.189,191,192
AGE RELATED MACULAR DEGENERATION
Geographic RPE atrophy and choroidal neovascularization cha-
racterize the nonneovascular ‘dry’ and neovascular ‘wet’ forms
of AMD, respectively. RPE lipofuscin accumulation increases
with aging in a spatial pattern consistent with rod photo-
SECTION 10
receptor density, possibly contributing to the pathogenesis of
both types of AMD.195–197 Increased lipofuscin may (1) com-
promise RPE cell function mechanically, (2) promote expression
of angiogenic factors, or (3) act as a photoinducible generator of
reactive oxygen species.24,102,103 Lipofuscin accumulation and
photic retinopathy both probably involve direct and indirect
oxidative stress.24,57,198,199
Rod photoreceptors and RPE cell numbers gradually decline
with retinal aging,102,195 accompanied by increasing thickness
and hydraulic resistance of Bruch’s membrane200 and decreas-
ing choriocapillaris vascular diameter.201 Rod photoreceptor loss
is more prominent in retinal aging and AMD than cone
loss.202–204 The density of RPE cells in the peripheral/equatorial
retina decreases with increasing age, but the RPE appears to be
relatively protected in the macular region.205 Anatomic and
physiologic factors beyond ordinary aging conspire to cause
AMD, which is a complex multifactorial process affected by many
factors including nutrition, smoking, and genetics.202,206–211.
Oxidative stress may injure the RPE and choriocapillaris in
AMD and possibly aging, potentially producing chronic local
inflammation.207
Phototoxicity from environmental light exposure is a poten-
tial but unproven cause of AMD.16,24,57,77,103,212–216 One origin
for this phototoxicity-AMD hypothesis is a 1920 study which
reported that AMD occurred less frequently in cataractous
eyes.212 Later studies showed, however, that the risk of AMD is
increased in cataractous eyes.189,192 It has been speculated that
if light is a factor in the pathogenesis of AMD, then blue-green
type phototoxicity is more likely to be involved than UV-blue
phototoxicity because photopigment-mediated damage occurs
at lower retinal irradiances.217 There are many other theories
for the pathogenesis of AMD, including those positing the
primary mechanism to be (1) RPE dysfunction with subsequent
basal laminar deposits,206 (2) impaired choroidal perfusion,218
(3) genetic defects,219 and (4) retinoid deficiency.204,220 These
theories are of course not mutually exclusive.
The phototoxicity-AMD hypothesis remains popular despite
its limitations. (1) Retinal illumination studies show that cen-
tral retinal exposure is higher than peripheral exposure under
Ganzfield illumination conditions221 and that superior peri-
pheral retinal illumination is higher than inferior peripheral
retinal exposure in bright environments.222 Retinal damage is
worst centrally in people with AMD,204 but there is no signi-
ficant difference between superior and inferior retinal photo-
receptor loss with aging,203 and age-related photoreceptor loss
is most pronounced adjacent to rather than in the center of
the retina (possibly due to protective macular pigment).202–204,223
(2) Lipofuscin accumulates with aging in the RPE, increasing
2200 the risk of retinal phototoxicity in older adults.102,224,225
Additionally, in vivo fundus autofluorescence measurements of
patients with nonneovascular AMD and retinitis pigmentosa
show focal regions of lipofuscin hyperfluorescence prior to the
occurrence of RPE atrophy.197 Nonetheless, lipofuscin concen-
trations are highest adjacent to rather than in the center of the
retina, where age-related photoreceptor loss but not AMD is
most prominent.196,223 (3) There are striking similarities in the
retinal abnormalities caused by AMD and repetitive
experimental acute phototoxicity.213 214,226,227 This similarity is
not surprising, however, because the retina and choroid have
only a limited repertoire of responses to injury, inflammation,
and senescence.
An important failing of the phototoxicity-AMD hypothesis is
the lack of supportive epidemiological evidence despite two
decades of careful investigation. Two large population-based
studies did find a weak correlation,228,229 but four other large
studies did not,208,230–232 including a recent study by Taylor,208
who had initially identified an association between light expo-
sure and AMD in the Waterman study.228 Additionally, three
large case-control studies failed to show that AMD is correlated
with environmental light exposure,233–235 one of which actually
found sunlight exposure to be lower in AMD subjects than
controls.234 This lack of evidence is due either to (1) difficulty in
accurately estimating a subject’s cumulative light exposure,
retrospectively, (2) variability in genetic susceptibility, (3) poten-
tially obfuscating factors such as differences in the age at which
subjects experience bright environmental light exposure, or
(4) the possibility that phototoxicity is not a significant factor in
retinal aging or AMD.
Most ocular UV exposure comes from reflective terrain below
or viewing the horizontal sky.25,236 There is strong evidence that
environmental UV exposure is a significant risk factor for
cataractogenesis.237–239 There is additional evidence that UV
exposure, particularly in early life, may increase the risk of
ocular melanoma.240–242 Using UV-blocking sunglasses and
IOLs as well as brimmed hats reduces both those risks242,243
Photocarcinogenesis differs from retinal phototoxicity because
it involves primarily UV-B (280 < l < 315 nm) induced damage
to DNA molecules240,244 that is not induced by the longer wave-
length UV-A (315 < l < 400 nm) and visible optical radiation
that causes retinal phototoxicity.
If sunlight is a risk factor in retinal aging and AMD, groups
that might potentially benefit from wearing sunglasses and
brimmed hats include: (1) young, lightly pigmented people,
particularly in warm climates, (2) individuals taking photo-
sensitizing medications, (3) people with malabsorption
syndromes or other problems contributing to malnutrition, and
(4) aphakes or pseudophakes. Contemporary IOLs that block
UV or UV+visible light provide adequate photocarcinogenic
protection against ocular melanoma. Conversely, they provide
20% less acute phototoxicity protection than a 53-year-old
crystalline lens that does not prevent AMD.48 Thus, if retinal
phototoxicity is a retinal aging or AMD risk factor, pseudo-
phakes should wear sunglasses in bright environments regard-
less of their IOL chromophores.48 Conventional sunglasses are
not safe for directly viewing the sun.117,168
CONCLUSION
Experimental studies have identified photopigment-mediated
(e.g., Noell-type blue-green) and photosensitizer-mediated (e.g.,
Ham-type UV-blue) photic retinopathies. Clinical photo-
toxicities can be divided into solar/welding arc and operating
microscope/endoilluminator injuries. Injuries localized pri-
marily to the RPE or photoreceptor layers have been observed,
but clinical phototoxicity studies often show that both layers are
affected, due either to multifocal nature of photic effects or the
 Photic Retinopathy

suprathreshold exposure of one layer that directly or indirectly
damages the other. Photopigments and photosensitizers are
distributed throughout the retina, so clinical injuries currently
cannot be reliably classified as being due to photopigment-
mediated or photosensitizer-mediated processes.
Photopigment-mediated photic retinopathies have been
studied most extensively in nocturnal rodent models, where the
primary photopigment is rhodopsin. Nonetheless, it is possible
that cone photopigments and light-sensitive ganglion cell
melanopsin may cause clinical phototoxic damage during
bright, sustained exposures. Lipofuscin in the RPE, all-trans-
retinal in the photoreceptor layer and mitochondrial enzymes
throughout the retina such as cytochrome c oxidase may be
responsible for photosensitizer-mediated retinal phototoxicities.
International standards for light exposure in older adults may
need to be reconsidered because they are based largely on light
exposure studies performed in young primates.
Appropriate protective measures are available for solar and
welding arc maculopathies. Minimizing the intensity and dura-
tion of operating microscope and endoilluminator exposures
reduces the risk of patient injuries. There is no proof at this
time that environmental light exposure is a significant risk fac-
tor in AMD, but UV exposure is implicated in cataractogenesis
and possibly ocular melanoma so it is prudent to wear sun-
glasses and a brimmed hat in bright environments such as
beaches and skiing slopes.

REFERENCES

1. Sliney DH, Wolbarsht ML: Safety with
lasers and other optical sources: a
comprehensive handbook. New York:
Plenum; 1980.
2. Mainster MA: Finding your way in the
photoforest: laser effects for clinicians.
Ophthalmology 1984; 91:886–888.
3. Marshall J: Structural aspects of laser-
induced damage and their functional
implications. Health Phys 1989; 56:617–624.
4. Mainster MA, Turner PL: Retinal injuries
from light: mechanisms, hazards and
prevention. In: Ryan SJ, Hinton DR,
Schachat AP, Wilkinson P, eds. Retina. 4th
edn. London: Elsevier; 2006:1857–1870.
5. Noell WK: Possible mechanisms of
photoreceptor damage by light in
mammalian eyes. Vision Res 1980;
20:1163–1171.
6. Kuwabara T, Gorn RA: Retinal damage by
visible light. An electron microscopic study.
Arch Ophthalmol 1968; 79:69–78.
7. Friedman E, Kuwabara T: The retinal
pigment epithelium. IV. The damaging
effects of radiant energy. Arch Ophthalmol
1968; 80:265–279.
8. Mainster MA: Destructive light adaptation.
Ann Ophthalmol 1970; 2:44–48.
9. Ham WT Jr, Mueller HA, Sliney DH: Retinal
sensitivity to damage from short
wavelength light. Nature 1976;
260:153–155.
10. Lawwill T: Three major pathologic
processes caused by light in the primate
retina: a search for mechanisms. Trans Am
Ophthalmol Soc 1982; 80:517–579.
11. Wenzel A, Grimm C, Samardzija M,
Reme CE: Molecular mechanisms of light-
induced photoreceptor apoptosis and
neuroprotection for retinal degeneration.
Prog Retin Eye Res 2005; 24:275–306.
12. Reme CE: The dark side of light: rhodopsin
and the silent death of vision the proctor
lecture. Invest Ophthalmol Vis Sci 2005;
46:2671–2682.
13. Pokorny J, Smith VC, Verriest G, Pinckers
AJLG: Congenital and acquired color vision
defects. New York: Grune & Stratton; 1979.
14. Mainster MA: Intraocular lenses should
block UV radiation and violet but not blue
light. Arch Ophthalmol 2005; 123:550–555.
15. Sykes SM, Robison WG Jr, Waxler M,
Kuwabara T: Damage to the monkey retina
by broad-spectrum fluorescent light. Invest
Ophthalmol Vis Sci 1981; 20:425–434.
16. Mainster MA: Light and macular
degeneration: a biophysical and clinical
perspective. Eye 1987; 1:304–310.
17. Sliney DH, Mellerio J, Gabel VP,
Schulmeister K: What is the meaning of
threshold in laser injury experiments?
Implications for human exposure limits.
Health Phys 2002; 82:335–347.
18. Crockett RS, Lawwill T: Oxygen
dependence of damage by 435 nm light in
cultured retinal epithelium. Curr Eye Res
1984; 3:209–215.
19. Ruffolo JJ Jr, Ham WT Jr, Mueller HA,
Millen JE: Photochemical lesions in the
primate retina under conditions of elevated
blood oxygen. Invest Ophthalmol Vis Sci
1984; 25:893–898.
20. Noell WK, Walker VS, Kang BS, Berman S:
Retinal damage by light in rats. Invest
Ophthalmol 1966; 5:450–473.
21. Rinkoff J, Machemer R, Hida T, Chandler D:
Temperature-dependent light damage to the
retina. Am J Ophthalmol 1986; 102:452–462.
22. Boulton M, Docchio F, Dayhaw-Barker P,
et al: Age-related changes in the
morphology, absorption and fluorescence
of melanosomes and lipofuscin granules of
the retinal pigment epithelium. Vision Res
1990; 30:1291–1303.
23. Rozanowska M, Jarvis-Evans J,
Korytowski W, et al: Blue light-induced
reactivity of retinal age pigment. In vitro
generation of oxygen-reactive species.
J Biol Chem 1995; 270:18825–18830.
24. Boulton M, Rozanowska M, Rozanowski B:
Retinal photodamage. J Photochem
Photobiol B 2001; 64:144–161.
25. Sliney DH:. How light reaches the eye and
its components. Int J Toxicol 2002;
21:501–509.
26. Mellerio J: Light effects on the retina. In:
Albert DM, Jakobiec FA, eds. Principles
and practice of ophthalmology.
Philadelphia: W. B. Saunders Company;
1994: 1326–1345.
27. Girotti AW: Photodynamic lipid peroxidation
in biological systems. Photochem
Photobiol 1990; 51:497–509.
28. Glickman RD: Phototoxicity to the retina:
mechanisms of damage. Int J Toxicol 2002;
21:473–490.
29. Leist M, Jaattela M: Four deaths and a
funeral: from caspases to alternative
mechanisms. Nat Rev Mol Cell Biol 2001;
2:589–598.
30. Boettner EA, Wolter JR: Transmission of
the ocular media. Invest Ophthalmol 1962;
1:776–783.
31. van Norren D, Vos JJ: Spectral
transmission of the human ocular media.
Vision Res 1974; 14:1237–1244.
CHAPTER 174
32. Mellerio J: Yellowing of the human lens:
nuclear and cortical contributions. Vision
Res 1987; 27:1581–1587.
33. Weale RA: Age and the transmittance of
the human crystalline lens. J Physiol 1988;
395:577–587.
34. Xu J, Pokorny J, Smith VC: Optical density
of the human lens. J Opt Soc Am A 1997;
14:953–960.
35. Sliney DH: Eye protective techniques for
bright light. Ophthalmology 1983;
90:937–944.
36. Stamper DA, Lund DJ, Molchany JW,
Stuck BE: Human pupil and eyelid
response to intense laser light: implications
for protection. Percept Mot Skills 2002;
95:775–782.
37. Snodderly DM, Auran JD, Delori FC: The
macular pigment. II. Spatial distribution in
primate retinas. Invest Ophthalmol Vis Sci
1984; 25:674–685.
38. Beatty S, Boulton M, Henson D, et al:
Macular pigment and age related macular
degeneration. Br J Ophthalmol 1999;
83:867–877.
39. Kirschfeld K: Carotenoid pigments: their
possible role in protecting against
photooxidation in eyes and photoreceptor
cells. Proc R Soc Lond B Biol Sci 1982;
216:71–85.
40. Khachik F, Bernstein PS, Garland DL:
Identification of lutein and zeaxanthin
oxidation products in human and monkey
retinas. Invest Ophthalmol Vis Sci 1997;
38:1802–1811.
41. Berendschot TT, van Norren D: Macular
pigment shows ringlike structures. Invest
Ophthalmol Vis Sci 2006; 47:709–714.
42. Liew SH, Gilbert CE, Spector TD, et al:
Central retinal thickness is positively
correlated with macular pigment optical
density. Exp Eye Res 2006; 82:915–920.
43. Delori FC, Goger DG, Keilhauer C, et al:
Bimodal spatial distribution of macular
pigment: evidence of a gender relationship.
J Opt Soc Am A Opt Image Sci Vis 2006;
23:521–538.
44. Pease PL, Adams AJ, Nuccio E: Optical
density of human macular pigment. Vision
Res 1987; 27:705–710.
45. Werner JS, Donnelly SK, Kliegl R: Aging
and human macular pigment density.
Appended with translations from the work
of Max Schultze and Ewald Hering. Vision
Res 1987; 27:257–268.
46. Mainster MA: Henle fibers may direct light
toward the center of the fovea. Lasers Light
Ophthalmol 1988; 2:79–86. 2201
 RETINA AND VITREOUS
47. Handelman GJ, Snodderly DM, Krinsky NI,
et al: Biological control of primate macular
pigment. Biochemical and densitometric
studies. Invest Ophthalmol Vis Sci 1991;
32:257–267.
48. Mainster MA: Violet and blue light blocking
intraocular lenses: photoprotection versus
photoreception. Br J Ophthalmol 2006;
90:784–792.
49. Beatty S, Murray IJ, Henson DB, et al:
Macular pigment and risk for age-related
macular degeneration in subjects from a
Northern European population. Invest
Ophthalmol Vis Sci 2001; 42:439–446.
50. Delori FC, Goger DG, Hammond BR, et al:
Macular pigment density measured by
autofluorescence spectrometry:
comparison with reflectometry and
heterochromatic flicker photometry. J Opt
Soc Am A Opt Image Sci Vis 2001;
18:1212–1230.
SECTION 10
51. Berendschot TT, van Norren D: On the age
dependency of the macular pigment optical
density. Exp Eye Res 2005; 81:602–609.
52. Berendschot TT, Willemse-Assink JJ,
Bastiaanse M, et al: Macular pigment and
melanin in age-related maculopathy in a
general population. Invest Ophthalmol Vis
Sci 2002; 43:1928–1932.
53. Wald G: Human vision and the spectrum.
Science 1945; 101:653–658.
54. Griswold MS, Stark WS: Scotopic spectral
sensitivity of phakic and aphakic observers
extending into the near ultraviolet. Vision
Res 1992; 32:1739–1743.
55. Ham WT Jr, Ruffolo JJ Jr, Mueller HA,
Guerry D 3rd: The nature of retinal radiation
damage: dependence on wavelength,
power level and exposure time. Vision Res
1980; 20:1105–1111.
56. Reme CE, Grimm C, Hafezi F, et al: Why
study rod cell death in retinal
degenerations and how? Doc Ophthalmol
2003; 106:25–29.
57. Margrain TH, Boulton M, Marshall J,
Sliney DH: Do blue light filters confer
protection against age-related macular
degeneration? Prog Retin Eye Res 2004;
23:523–531.
58. Ham WT Jr, Ruffolo JJ Jr, Mueller HA, et al:
Histologic analysis of photochemical
lesions produced in rhesus retina by short-
wave-length light. Invest Ophthalmol Vis
Sci 1978; 17:1029–1035.
59. Kremers JJ, van Norren D: Two classes of
photochemical damage of the retina.
Lasers Light Ophthalmol 1988; 2:41–52.
60. ACGIH Gorgels TG, Van Norren D: Two
spectral types of retinal light damage occur
in albino as well as in pigmented rat: no
essential role for melanin. Exp Eye Res
1998; 66:155–162.
61. ACGIH Threshold limit values for chemical
substances physical agents: biological
exposure indices. Cincinnati: American
Conference of Governmental Industrial
Hygienists; 1997.
62. Merbs SL, Nathans J: Absorption spectra
of human cone pigments. Nature 1992;
356:433–435.
63. Stockman A, Sharpe LT, Merbs S, Nathans
J: Spectral sensitivities of human cone
visual pigments determined in vivo and in
vitro. Methods Enzymol 2000;
316:626–650.
64. Brainard GC, Hanifin JP, Greeson JM, et al:
Action spectrum for melatonin regulation in
2202 humans: evidence for a novel circadian
photoreceptor. J Neurosci 2001;
21:6405–6412.
65. Thapan K, Arendt J, Skene DJ: An action
spectrum for melatonin suppression:
evidence for a novel non-rod, non-cone
photoreceptor system in humans. J Physiol
2001; 535:261–267.
66. Hankins MW, Lucas RJ: The primary visual
pathway in humans is regulated according
to long-term light exposure through the
action of a nonclassical photopigment.
Curr Biol 2002; 12:191–198.
67. Dacey DM, Liao HW, Peterson BB, et al:
Melanopsin-expressing ganglion cells in
primate retina signal colour and irradiance
and project to the LGN. Nature 2005;
433:749–754.
68. Hattar S, Lucas RJ, Mrosovsky N, et al:
Melanopsin and rod-cone photoreceptive
systems account for all major accessory
visual functions in mice. Nature 2003;
424:76–81.
69. Qiu X, Kumbalasiri T, Carlson SM, et al:
Induction of photosensitivity by
heterologous expression of melanopsin.
Nature 2005; 433:745–749.
70. Burns ME, Baylor DA: Activation,
deactivation, and adaptation in vertebrate
photoreceptor cells. Annu Rev Neurosci
2001; 24:779–805.
71. Rozanowska M, Sarna T: Light-induced
damage to the retina: role of rhodopsin
chromophore revisited. Photochem
Photobiol 2005; 81:1305–1330.
72. Wenzel A, Oberhauser V, Pugh EN Jr, et al:
The retinal G protein-coupled receptor
(RGR) enhances isomerohydrolase activity
independent of light. J Biol Chem 2005;
280:29874–29884.
73. Arshavsky VY, Lamb TD, Pugh EN Jr: G
proteins and phototransduction. Annu Rev
Physiol 2002; 64:153–187.
74. Saari JC: Biochemistry of visual pigment
regeneration: the Friedenwald lecture. Invest
Ophthalmol Vis Sci 2000; 41:337–348.
75. Lamb TD, Pugh EN Jr: Dark adaptation and
the retinoid cycle of vision. Prog Retin Eye
Res 2004; 23:307–380.
76. Rapp LM: Retinal phototoxicity. In:
Chang LW, Dyer RS, eds. Handbook of
neurotoxicology. New York: Dekker; 1995.
77. Reme C, Reinboth J, Clausen M, Hafezi F:
Light damage revisited: converging
evidence, diverging views? Graefes Arch
Clin Exp Ophthalmol 1996; 234:2–11.
78. Hao W, Wenzel A, Obin MS, et al: Evidence
for two apoptotic pathways in light-induced
retinal degeneration. Nat Genet 2002;
32:254–260.
79. Jacobson SG, McInnes RR: Blinded by the
light. Nat Genet 2002; 32:215–216.
80. Vaughan DK, Nemke JL, Fliesler SJ, et al:
Evidence for a circadian rhythm of
susceptibility to retinal light damage.
Photochem Photobiol 2002; 75:547–553.
81. Penn JS, Williams TP: Photostasis: regulation
of daily photon-catch by rat retinas in
response to various cyclic illuminances.
Exp Eye Res 1986; 43:915–928.
82. Williams TP, Squitieri A, Henderson RP,
Webbers JP: Reciprocity between light
intensity and rhodopsin concentration
across the rat retina. J Physiol
1999; 516(Pt 3):869–874.
83. Williams TP, Webbers JP, Giordano L,
Henderson RP: Distribution of photon
absorption rates across the rat retina.
J Physiol 1998; 508(Pt 2):515–522.
84. Daly GH, DiLeonardo JM, Balkema NR,
Balkema GW: The relationship between
ambient lighting conditions, absolute dark-
adapted thresholds, and rhodopsin in black
and hypopigmented mice. Vis Neurosci
2004; 21:925–934.
85. Reme CE, Wolfrum U, Imsand C, et al:
Photoreceptor autophagy: effects of light
history on number and opsin content of
degradative vacuoles. Invest Ophthalmol
Vis Sci 1999; 40:2398–2404.
86. Surgucheva I, Ninkina N, Buchman VL,
et al: Protein aggregation in retinal cells
and approaches to cell protection. Cell Mol
Neurobiol 2005; 25:1051–1066.
87. Cicerone CM: Cones survive rods in the
light-damaged eye of the albino rat.
Science 1976; 194:1183–1185.
88. Marshall J, Mellerio J, Palmer DA: Damage
to pigeon retinae by moderate illumination
from fluorescent lamps. Exp Eye Res 1972;
14:164–169.
89. Hope-Ross MW, Mahon GJ, Gardiner TA,
Archer DB: Ultrastructural findings in solar
retinopathy. Eye 1993; 7(Pt 1):29–33.
90. Snodderly DM, Sandstrom MM, Leung IY,
et al: Retinal pigment epithelial cell
distribution in central retina of rhesus
monkeys. Invest Ophthalmol Vis Sci 2002;
43:2815–2818.
91. Sperling HG, Johnson C, Harwerth RS:
Differential spectral photic damage to
primate cones. Vision Res 1980;
20:1117–1125.
92. Provencio I, Jiang G, De Grip WJ, et al:
Melanopsin: an opsin in melanophores,
brain, and eye. Proc Natl Acad Sci USA
1998; 95:340–345.
93. Van Gelder RN: Non-visual ocular
photoreception. Ophthalmic Genet 2001;
22:195–205.
94. Berson DM, Dunn FA, Takao M:
Phototransduction by retinal ganglion cells
that set the circadian clock. Science 2002;
295:1070–1073.
95. Menaker M: Circadian rhythms. Circadian
photoreception. Science 2003; 299:213–214.
96. Feeney L, Berman ER: Oxygen toxicity:
membrane damage by free radicals. Invest
Ophthalmol 1976; 15:789–792.
97. Ham WT Jr, Mueller HA, Ruffolo JJ Jr, et al:
Basic mechanisms underlying the
production of photochemical lesions in the
mammalian retina. Curr Eye Res 1984;
3:165–174.
98. Snodderly DM: Evidence for protection
against age-related macular degeneration
by carotenoids and antioxidant vitamins.
Am J Clin Nutr 1995; 62:1448S-1461S.
99. Pautler EL, Morita M, Beezley D:
Hemoprotein(s) mediate blue light damage
in the retinal pigment epithelium.
Photochem Photobiol 1990; 51:599–605.
100. Gorgels TG, van Norren D: Ultraviolet and
green light cause different types of damage
in rat retina. Invest Ophthalmol Vis Sci
1995; 36:851–863.
101. Grimm C, Wenzel A, Williams T, et al:
Rhodopsin-mediated blue-light damage to
the rat retina: effect of photoreversal of
bleaching. Invest Ophthalmol Vis Sci 2001;
42:497–505.
102. Feeney-Burns L, Hilderbrand ES, Eldridge S:
Aging human RPE: morphometric analysis
of macular, equatorial, and peripheral cells.
Invest Ophthalmol Vis Sci 1984; 25:195–200.
103. Marshall J: The ageing retina: physiology or
pathology. Eye 1987; 1(Pt 2):282–295.

104. Sparrow JR, Nakanishi K, Parish CA: The
lipofuscin fluorophore A2E mediates blue
light-induced damage to retinal pigmented
epithelial cells. Invest Ophthalmol Vis Sci
2000; 41:1981–1989.
105. Sparrow JR, Parish CA, Hashimoto M,
Nakanishi K: A2E, a lipofuscin fluorophore,
in human retinal pigmented epithelial cells
in culture. Invest Ophthalmol Vis Sci 1999;
40:2988–2995.
106. Lamb LE, Simon JD: A2E: a component of
ocular lipofuscin. Photochem Photobiol
2004; 79:127–136.
107. Mainster MA: Retinol transport and
regeneration of human cone photopigment.
Nat New Biol 1972; 238:223–224.
108. Godley BF, Shamsi FA, Liang FQ, et al:
Blue light induces mitochondrial DNA
damage and free radical production in
epithelial cells. J Biol Chem 2005;
280:21061–21066.
109. Lawwill T: Effects of prolonged exposure of
rabbit retina to low-intensity light. Invest
Ophthalmol 1973; 12:45–51.
110. Hoppeler T, Hendrickson P, Dietrich C,
Reme C: Morphology and time-course of
defined photochemical lesions in the rabbit
retina. Curr Eye Res 1988; 7:849–860.
111. Rozanowska M, Korytowski W,
Rozanowski B, et al: Photoreactivity of
aged human RPE melanosomes: a
comparison with lipofuscin. Invest
Ophthalmol Vis Sci 2002; 43:2088–2096.
112. Tso MO, La Piana FG: The human fovea
after sungazing. Trans Am Acad Ophthalmol
Otolaryngol 1975; 79:OP788–OP795.
113. Green WR, Robertson DM: Pathologic
findings of photic retinopathy in the human
eye. Am J Ophthalmol 1991; 112:520–527.
114. White TJ, Mainster MA, Wilson PW, Tips JH:
Chorioretinal temperature increases from
solar observation. Bull Math Biophys 1971;
33:1–17.
115. Naidoff MA, Slinkey DH: Retinal injury from
a welding arc. Am J Ophthalmol 1974;
77:663–668.
116. Sliney DH, Armstrong BC: Radiometric
analysis of surgical microscope lights for
hazards analyses. Appl Opt 1986;
25:1882–1889.
117. Mainster MA: Solar eclipse safety.
Ophthalmology 1998; 105:9–10.
118. Mainster MA, White TJ, Tips JH, Wilson PW:
Retinal-temperature increases produced by
intense light sources. J Opt Soc Am 1970;
60:264–270.
119. Dhir SP, Gupta A, Jain IS: Eclipse retinopathy.
Br J Ophthalmol 1981; 65:42–45.
120. Jacobs NA, Headon M, Rosen ES: Solar
retinopathy in the Manchester area. Trans
Ophthalmol Soc UK 1985; 104(Pt
6):625–628.
121. Gass JDM: Stereoscopic atlas of macular
diseases. 3rd edn. St Louis: Mosby-Year
Book; 1987.
122. MacFaul PA: Visual prognosis after solar
retinopathy. Br J Ophthalmol 1969;
53:534–541.
123. Schatz H, Mendelblatt F: Solar retinopathy
from sun-gazing under the influence of
LSD. Br J Ophthalmol 1973; 57:270–273.
124. Steinkamp PN, Watzke RC, Solomon JD:
An unusual case of solar retinopathy. Arch
Ophthalmol 2003; 121:1798–1799.
125. Aiello LP, Arrigg PG, Shah ST, et al: Solar
retinopathy associated with hypoglycemic
insulin reaction. Arch Ophthalmol 1994;
112:982–983.
126. Kaushik S, Gupta V, Gupta A: Optical
coherence tomography findings in solar
retinopathy. Ophthalmic Surg Lasers
Imaging 2004; 35:52–55.
127. Garg SJ, Martidis A, Nelson ML,
Sivalingam A: Optical coherence
tomography of chronic solar retinopathy.
Am J Ophthalmol 2004; 137:351–354.
128. Jorge R, Costa RA, Quirino LS, et al:
Optical coherence tomography findings in
patients with late solar retinopathy. Am J
Ophthalmol 2004; 137:1139–1143.
129. Grey RH: Foveo-macular retinitis, solar
retinopathy, and trauma. Br J Ophthalmol
1978; 62:543–546.
130. Kelley JS, Hoover RE, George T: Whiplash
maculopathy. Arch Ophthalmol 1978;
96:834–835.
131. Abebe MT, De Laey JJ: Foveomacular
retinitis as a result of ocular contusion. Bull
Soc Belge Ophtalmol 1992; 243:171–175.
132. Kuming BS: Foveomacular retinitis. Br J
Ophthalmol 1986; 70:816–818.
133. Jacobs NA: Foveomacular retinitis. Br J
Ophthalmol 1987; 71:563.
134. Cordes FC: A type of foveomacular retinitis
observed in the US Navy. Am J Ophthalmol
1944; 27:803–816.
135. Ritchey CL, Ewald RA: Sun gazing as the
cause of foveomacular retinitis. Am J
Ophthalmol 1970; 70:491–497.
136. Kerr LM, Little HL: Foveomacular retinitis.
Arch Ophthalmol 1966; 76:498–504.
137. Marlor RL, Blais BR, Preston FR,
Boyden DG: Foveomacular retinitis, an
important problem in military medicine:
epidemiology. Invest Ophthalmol 1973;
12:5–16.
138. Gladstone GJ, Tasman W: Solar retinitis
after minimal exposure. Arch Ophthalmol
1978; 96:1368–1369.
139. Yannuzzi LA, Fisher YL, Krueger A, Slakter J:
Solar retinopathy: a photobiological and
geophysical analysis. Trans Am Ophthalmol
Soc 1987; 85:120–158.
140. Terrien F: De trouble visuel provoqué par
l’électricité. Arch Ophthalmol 1902;
22:692–696.
141. Uniat L, Olk RJ, Hanish SJ: Welding arc
maculopathy. Am J Ophthalmol 1986;
102:394–395.
142. Fich M, Dahl H, Fledelius H, Tinning S:
Maculopathy caused by welding arcs.
A report of 3 cases. Acta Ophthalmol
(Copenh) 1993; 71:402–404.
143. Lucas RS, Harper CA, McCombe MF,
et al: Optical coherence tomography
findings in Welder’s maculopathy. Retina
2007; 27 (in press).
144. Sliney DH: Defining biologic exposures to
light. In: Cronly-Dillon J, Rosen ES,
Marshall J, eds. Hazards of light. New York:
Pergamon; 1986.
145. Gardner TW, Ai E, Chrobak M, Shoch DE.
Photic maculopathy secondary to
short-circuiting of a high-tension electric
current. Ophthalmology 1982;
89:865–868.
146. Fishman GA: Light-induced maculopathy
from surgical microscopes during cataract
surgery. In: Ernest JT, ed. The 1985 year
book of ophthalmology. St Louis: Mosby-
Year Book; 1985:177–180.
147. Michels M, Sternberg P, Jr: Operating
microscope-induced retinal phototoxicity:
pathophysiology, clinical manifestations
and prevention. Surv Ophthalmol 1990;
34:237–252.
Photic Retinopathy
148. Khwarg SG, Linstone FA, Daniels SA, et al:
Incidence, risk factors, and morphology in
operating microscope light retinopathy. Am
J Ophthalmol 1987; 103:255–263.
149. Brod RD, Olsen KR, Ball SF, Packer AJ:
The site of operating microscope light-
induced injury on the human retina. Am J
Ophthalmol 1989; 107:390–397.
150. Pavilack MA, Brod RD: Site of potential
operating microscope light-induced
phototoxicity on the human retina during
temporal approach eye surgery.
Ophthalmology 2001; 108:381–385.
151. Boldrey EE, Ho BT, Griffith RD: Retinal
burns occurring at cataract extraction.
Ophthalmology 1984; 91:1297–1302.
152. Brod RD, Barron BA, Suelflow JA:
Phototoxic retinal damage during refractive
surgery. Am J Ophthalmol 1986; 102:121–123.
153. Khwarg SG, Geoghegan M, Hanscom TA:
CHAPTER 174
Light-induced maculopathy from the
operating microscope. Am J Ophthalmol
1984; 98:628–630.
154. Robertson DM, Feldman RB: Photic
retinopathy from the operating room
microscope. Am J Ophthalmol 1986;
101:561–569.
155. Mares-Perlman JA, Brady WE, Klein BE,
et al: Diet and nuclear lens opacities. Am J
Epidemiol 1995; 141:322–334.
156. Fuller D, Machemer R, Knighton RW:
Retinal damage produced by intraocular
fiber optic light. Am J Ophthalmol 1978;
85:519–537.
157. Michels M, Lewis H, Abrams GW, et al:
Macular phototoxicity caused by fiberoptic
endoillumination during pars plana
vitrectomy. Am J Ophthalmol 1992;
114:287–296.
158. Kleinmann G, Hoffman P, Schechtman E,
Pollack A: Microscope-induced retinal
phototoxicity in cataract surgery of short
duration. Ophthalmology 2002;
109:334–338.
159. Postel EA, Pulido JS, Byrnes GA, et al:
Long-term follow-up of iatrogenic
phototoxicity. Arch Ophthalmol 1998;
116:753–757.
160. Irvine AR, Wood I, Morris BW: Retinal
damage from the illumination of the
operating microscope. An experimental
study in pseudophakic monkeys. Arch
Ophthalmol 1984; 102:1358–1365.
161. Jaffe GJ, Wood IS: Retinal phototoxicity
from the operating microscope: a
protective effect by the fovea (letter). Arch
Ophthalmol 1988; 106:445–446.
162. Parver LM, Auker CR, Fine BS:
Observations on monkey eyes exposed to
light from an operating microscope.
Ophthalmology 1983; 90:964–972.
163. Jaffe GJ, Irvine AR, Wood IS, et al: Retinal
phototoxicity from the operating
microscope. The role of inspired oxygen.
Ophthalmology 1988; 95:1130–1141.
164. Mauget-Faysse M, Quaranta M, Francoz N,
et al: Incidental retinal phototoxicity
associated with ingestion of
photosensitizing drugs. Graefes Arch Clin
Exp Ophthalmol 2001; 239:501–508.
165. Manzouri B, Egan CA, Hykin PG:
Phototoxic maculopathy following
uneventful cataract surgery in a
predisposed patient. Br J Ophthalmol
2002; 86:705–706.
166. Ferguson J: Photosensitivity due to drugs.
Photodermatol Photoimmunol Photomed
2002; 18:262–269. 2203
 RETINA AND VITREOUS
167. Li S, Lam TT, Fu J, Tso MO: Systemic
hypertension exaggerates retinal photic
injury. Arch Ophthalmol 1995; 113:521–526.
168. Mainster MA, Ham WT Jr, Delori FC:
Potential retinal hazards. Instrument and
environmental light sources.
Ophthalmology 1983; 90:927–932.
169. McIntyre DJ: Phototoxicity. The eclipse
filter. Ophthalmology 1985; 92:364–365.
170. Landry RJ, Miller SA, Byrnes GA: Study of
filtered light on potential retinal photic
hazards with operation microscopes used
for ocular surgery. Appl Opt 2002;
41:802–804.
171. O’Brien DP, Francis IC: The corneal quilt:
a protective device designed to reduce
intraoperative retinal phototoxicity.
Ophthalmic Surg 1994; 25:191–194.
172. Kraff MC, Lieberman HL, Jampol LM,
Sanders DR: Effect of a pupillary light
occluder on cystoid macular edema.
SECTION 10
J Cataract Refract Surg 1989; 15:658–660.
173. Nevyas HJ, Nevyas JY: Surgical corneal
light occluder made of black HEMA.
Ophthalmic Surg 1985; 16:696–698.
174. Jampol LM, Kraff MC, Sanders DR, et al:
Near-UV radiation from the operating
microscope and pseudophakic cystoid
macular edema. Arch Ophthalmol 1985;
103:28–30.
175. Keates RH, Genstler DE: UV radiation.
Ophthalmic Surg 1982; 13:327.
176. Robertson DM, McLaren JW: Photic
retinopathy from the operating room
microscope. Study with filters. Arch
Ophthalmol 1989; 107:373–375.
177. Keates RH, Armstrong PF: Use of a short
wavelength filter in an operating
microscope. Ophthalmic Surg 1985;
16:40–41.
178. Delori FC, Gragoudas ES, Francisco R,
Pruett RC: Monochromatic
ophthalmoscopy and fundus photography.
The normal fundus. Arch Ophthalmol 1977;
95:861–868.
179. Ducrey NM, Delori FC, Gragoudas ES:
Monochromatic ophthalmoscopy and
fundus photography. II. The pathological
fundus. Arch Ophthalmol 1979;
97:288–293.
180. James RH, Bostrom RG, Remark D,
Sliney DH: Handheld ophthalmoscopes for
hazard analysis: an analysis. Appl Opt
1988; 27:5072–5076.
181. Michels M, Dawson WW, Feldman RB,
Jarolem K: Infrared. An unseen and
unnecessary hazard in ophthalmic devices.
Ophthalmology 1987; 94:143–148.
182. Oliver M: Posterior pole changes after
cataract extraction in elderly subjects. Am
J Ophthalmol 1966; 62:1145–1148.
183. Blair CJ, Ferguson J Jr: Exacerbation of
senile macular degeneration following
cataract extraction. Am J Ophthalmol 1979;
87:77–83.
184. van der Schaft TL, Mooy CM, de Bruijn WC,
et al: Increased prevalence of disciform
macular degeneration after cataract
extraction with implantation of an
intraocular lens. Br J Ophthalmol 1994;
78:441–445.
185. Pollack A, Marcovich A, Bukelman A,
Oliver M: Age-related macular degeneration
after extracapsular cataract extraction with
intraocular lens implantation.
Ophthalmology 1996; 103:1546–1554.
186. Pollack A, Bukelman A, Zalish M, et al:
2204 The course of age-related macular
degeneration following bilateral cataract
surgery. Ophthalmic Surg Lasers 1998;
29:286–294.
187. Shuttleworth GN, Luhishi EA, Harrad RA:
Do patients with age related maculopathy
and cataract benefit from cataract surgery?
Br J Ophthalmol 1998; 82:611–616.
188. Wong TY: Cataract surgery in patients with
cataract and age related macular
degeneration: do the benefits outweigh the
risks? Br J Ophthalmol 2000;
84:1337–1338.
189. Klein R, Klein BE, Wong TY, et al: The
association of cataract and cataract
surgery with the long-term incidence of
age-related maculopathy: the Beaver Dam
eye study. Arch Ophthalmol 2002;
120:1551–1558.
190. Armbrecht AM, Findlay C, Aspinall PA, et al:
Cataract surgery in patients with age-
related macular degeneration: one-year
outcomes. J Cataract Refract Surg 2003;
29:686–693.
191. Wang JJ, Klein R, Smith W, et al: Cataract
surgery and the 5-year incidence of late-
stage age-related maculopathy: pooled
findings from the Beaver Dam and Blue
Mountains eye studies. Ophthalmology
2003; 110:1960–1967.
192. Freeman EE, Munoz B, West SK, et al:
Is there an association between cataract
surgery and age-related macular
degeneration? Data from three population-
based studies. Am J Ophthalmol 2003;
135:849–856.
193. Ferris FL 3rd: Discussion of a model of
spectral filtering to reduce photochemical
damage in age-related macular
degeneration. Trans Am Ophthalmol Soc
2004; 102:95.
194. Martin DF, Gensler G, Klein BEK, et al: The
effect of cataract surgery on progression to
advanced AMD (abstract number 1907).
ARVO annual meeting. Ophthalmology
AfRiVa, translator. FL: Fort Lauderdale;
2002:76.
195. Dorey CK, Wu G, Ebenstein D, et al:. Cell
loss in the aging retina. Relationship to
lipofuscin accumulation and macular
degeneration. Invest Ophthalmol Vis Sci
1989; 30:1691–1699.
196. Delori FC, Goger DG, Dorey CK: Age-
related accumulation and spatial
distribution of lipofuscin in RPE of normal
subjects. Invest Ophthalmol Vis Sci 2001;
42:1855–1866.
197. Sparrow JR, Boulton M: RPE lipofuscin and
its role in retinal pathobiology. Exp Eye Res
2005; 80:595–606.
198. Winkler BS, Boulton ME, Gottsch JD,
Sternberg P: Oxidative damage and age-
related macular degeneration. Mol Vis
1999; 5:32.
199. Beatty S, Koh H, Phil M, et al: The role of
oxidative stress in the pathogenesis of age-
related macular degeneration. Surv
Ophthalmol 2000; 45:115–134.
200. Hillenkamp J, Hussain AA, Jackson TL,
et al: The influence of path length and
matrix components on ageing
characteristics of transport between the
choroid and the outer retina. Invest
Ophthalmol Vis Sci 2004; 45:1493–1498.
201. Ramrattan RS, van der Schaft TL, Mooy CM,
et al: Morphometric analysis of Bruch’s
membrane, the choriocapillaris, and the
choroid in aging. Invest Ophthalmol Vis Sci
1994; 35:2857–2864.
202. Curcio CA, Millican CL, Allen KA, Kalina
RE: Aging of the human photoreceptor
mosaic: evidence for selective vulnerability
of rods in central retina. Invest Ophthalmol
Vis Sci 1993; 34:3278–3296.
203. Panda-Jonas S, Jonas JB, Jakobczyk-
Zmija M: Retinal photoreceptor density
decreases with age. Ophthalmology 1995;
102:1853–1859.
204. Curcio CA: Photoreceptor topography in
ageing and age-related maculopathy. Eye
2001; 15:376–383.
205. Del Priore LV, Kuo YH, Tezel TH: Age-
related changes in human RPE cell density
and apoptosis proportion in situ. Invest
Ophthalmol Vis Sci 2002; 43:3312–3318.
206. Spraul CW, Lang GE, Grossniklaus HE,
Lang GK: Histologic and morphometric
analysis of the choroid, Bruch’s membrane,
and retinal pigment epithelium in
postmortem eyes with age-related macular
degeneration and histologic examination of
surgically excised choroidal neovascular
membranes. Surv Ophthalmol 1999;
44(Suppl 1):S10–S32.
207. Zarbin MA: Current concepts in the
pathogenesis of age-related macular
degeneration. Arch Ophthalmol 2004;
122:598–614.
208. McCarty CA, Mukesh BN, Fu CL, et al: Risk
factors for age-related maculopathy: the
Visual Impairment Project. Arch Ophthalmol
2001; 119:1455–1462.
209. Seddon JM, Ajani UA, Sperduto RD, et al:
Dietary carotenoids, vitamins A, C, and E,
and advanced age-related macular
degeneration. Eye Disease Case-Control
Study Group. Jama 1994; 272:1413–1420.
210. Tso MO: Pathogenetic factors of aging
macular degeneration. Ophthalmology
1985; 92:628–635.
211. van Leeuwen R, Ikram MK, Vingerling JR,
et al: Blood pressure, atherosclerosis, and
the incidence of age-related maculopathy:
the Rotterdam Study. Invest Ophthalmol Vis
Sci 2003; 44:3771–3777.
212. van der Hoeve J: Eye lesions produced by
light rich in ultraviolet rays: senile cataract,
senile degeneration of the macula. Am J
Ophthalmol 1920; 3:178–194.
213. Ts’o MO, La Piana FG, Appleton B:
The human fovea after sungazing. Trans
Am Acad Ophthalmol Otolaryngol 1974;
78:OP-677.
214. Mainster MA: Solar retinitis, photic
maculopathy and the pseudophakic
eye. J Am Intraocul Implant Soc 1978;
4:84–86.
215. Young RW: A theory of central retinal
disease. In: Sears ML, ed. New directions
in ophthalmic research. New Haven, CT:
Yale University Press; 1981:237–270.
216. Burkle A: Mechanisms of ageing. Eye 2001;
15:371–375.
217. van Norren D, Vos H: Sunlight and age-
related macular degeneration. Arch
Ophthalmol 1990; 108:1670–1671.
218. Friedman E: A hemodynamic model of the
pathogenesis of age-related macular
degeneration. Am J Ophthalmol 1997;
124:677–682.
219. Fan BJ, Tam PO, Choy KW, et al: Molecular
diagnostics of genetic eye diseases. Clin
Biochem 2006; 39:231–239.
220. Curcio CA, Owsley C, Jackson GR: Spare
the rods, save the cones in aging and age-
related maculopathy. Invest Ophthalmol Vis
Sci 2000; 41:2015–2018.

221. Pflibsen KP, Pomerantzeff O, Ross RN:
Retinal illuminance using a wide-angle
model of the eye. J Opt Soc Am A 1988;
5:146–150.
222. Sliney DH: Geometrical gradients in the
distribution of temperature and absorbed
ultraviolet radiation in ocular tissues. Dev
Ophthalmol 2002; 35:40–59.
223. Jackson GR, Owsley C, Curcio CA:
Photoreceptor degeneration and
dysfunction in aging and age-related
maculopathy. Ageing Res Rev 2002;
1:381–396.
224. Feeney-Burns L, Berman ER, Rothman H:
Lipofuscin of human retinal pigment
epithelium. Am J Ophthalmol 1980;
90:783–791.
225. Weiter JJ, Delori FC, Wing GL, Fitch KA:
Retinal pigment epithelial lipofuscin and
melanin and choroidal melanin in human
eyes. Invest Ophthalmol Vis Sci 1986;
27:145–152.
226. Marshall J: Ageing changes in human cones.
Acta XXIII Concilium Ophthalmologicum
(Kyoto) 1978; 1:375–378.
227. Borges J, Li ZY, Tso MO: Effects of repeated
photic exposures on the monkey macula.
Arch Ophthalmol 1990; 108:727–733.
228. Taylor HR, West S, Munoz B, et al: The
long-term effects of visible light on the eye.
Arch Ophthalmol 1992; 110:99–104.
229. Tomany SC, Cruickshanks KJ, Klein R,
et al: Sunlight and the 10-year incidence of
age-related maculopathy: the Beaver Dam
Eye Study. Arch Ophthalmol 2004;
122:750–757.
230. Hirvela H, Luukinen H, Laara E, et al: Risk
factors of age-related maculopathy in a
population 70 years of age or older.
Ophthalmology 1996; 103:871–877.
231. Delcourt C, Carriere I, Ponton-Sanchez A,
et al: Light exposure and the risk of age-
related macular degeneration: the
Pathologies Oculaires Liées à l’Age (POLA)
study. Arch Ophthalmol 2001;
119:1463–1468.
232. Clemons TE, Milton RC, Klein R, et al:
Risk factors for the incidence of Advanced
Age-Related Macular Degeneration in the
Age-Related Eye Disease Study (AREDS)
AREDS report no. 19. Ophthalmology 2005;
112:533–539.
233. Risk factors for neovascular age-related
macular degeneration. The eye disease
case – Control Study Group. Arch
Ophthalmol 1992; 110:1701–1708.
234. Darzins P, Mitchell P, Heller RF: Sun
exposure and age-related macular
degeneration. An Australian case-control
study. Ophthalmology 1997; 104:770–776.
235. Khan JC, Shahid H, Thurlby DA, et al: Age
related macular degeneration and sun
exposure, iris colour, and skin sensitivity to
sunlight. Br J Ophthalmol 2006; 90:29–32.
236. Sliney DH: Photoprotection of the eye – UV
radiation and sunglasses. J Photochem
Photobiol B 2001; 64:166–175.
237. Midelfart A: Ultraviolet radiation and
cataract. Acta Ophthalmol Scand 2005;
83:642–644.
238. McCarty CA, Taylor HR: A review of the
epidemiologic evidence linking ultraviolet
radiation and cataracts. Dev Ophthalmol
2002; 35:21–31.
239. Delcourt C, Carriere I, Ponton-Sanchez A,
et al: Light exposure and the risk of
cortical, nuclear, and posterior subcapsular
cataracts: the Pathologies Oculaires Liees
a l’Age (POLA) study. Arch Ophthalmol
2000; 118:385–392.
Photic Retinopathy
240. Singh AD, Rennie IG, Seregard S, et al:
Sunlight exposure and pathogenesis of
uveal melanoma. Surv Ophthalmol 2004;
49:419–428.
241. Li W, Judge H, Gragoudas ES, et al:
Patterns of tumor initiation in choroidal
melanoma. Cancer Res 2000;
60:3757–3760.
242. Vajdic CM, Kricker A, Giblin M, et al: Sun
exposure predicts risk of ocular melanoma
in Australia. Int J Cancer 2002;
101:175–182.
243. Rosenthal FS, Phoon C, Bakalian AE,
Taylor HR: The ocular dose of ultraviolet
radiation to outdoor workers. Invest
Ophthalmol Vis Sci 1988; 29:649–656.
244. Gilchrest BA, Eller MS, Geller AC, Yaar M:
The pathogenesis of melanoma induced by
ultraviolet radiation. N Engl J Med 1999;
340:1341–1348.
CHAPTER 174
245. ACGIH: Threshold limit values and
biological eposure indices. Cincinnati, OH:
American Conference of Governmental
Industrial Hygienists; 2000.
246. Anderson HL: Building molecular wires
from the colours of life: conjugated
porphyrin oligomers. Chem Commun 1999;
9:2323–2330.
247. Kaderbhai MA, Hopper DJ, Akhtar KM,
et al: A cytochrome c from a lupanine-
transforming Pseudomonas putida strain is
expressed in Escherichia coli during
aerobic cultivation and efficiently exported
and assembled in the periplasm. Appl
Environ Microbiol 2003; 69:4727–4731.
248. Wyszecki G, Stiles WS: Color Science. 2nd
ed. New York: Wiley; 1982.
249. Wald G, Brown PK: Human rhodopsin.
Science 1958; 127:222–226.
2205
 CHAPTER
175 Radiation Retinopathy
Sayjal J. Patel and Andrew P. Schachat
Key Features
• Retinopathy is typically delayed. If it occurs, the onset is
typically in the first 1–3 years after treatment
• Retinal manifestations of radiation vary with dose of radiation
used, fraction number, size of tumor, location of tumor, and the
use of external beam versus plaque therapy
• Early histological findings are usually focal loss of capillary
endothelial cells and pericytes with subsequent areas of retinal
capillary nonperfusion that can lead to neovascularization
INTRODUCTION
Radiation has been used therapeutically for the treatment of
neoplastic lesions for over 100 years. According to del Regato, in
1896, 3 weeks after reading about Roentgen's discovery of ‘X-rays’,
Grubbe was the first to use radiation to treat breast cancer.1 In the
1930s, Moore and Stallard began using radiation for the treat-
ment of ocular tumors.2,3 Ocular complications following radia-
tion were described by Stallard in 1933 subsequent to treatment for
retinoblastoma and retinal capillary hemangioma.3 He described
retinal hemorrhages, exudative changes in a circinate pattern,
optic disk edema and optic atrophy occurring over a period of
~20 months postradiation. Since these early reports, many
reports of retinopathy following radiation to various tumors of
the head and neck have been described.4–16
The onset of radiation retinopathy is usually delayed and
generally does not appear for months or years after initial expo-
sure to radiation. Characteristics of radiation retinopathy include
retinal microaneurysms and intraretinal hemorrhages, telangiec-
tasia, perivascular sheathing, cotton wool spots, exudate, macular
edema, retinal pigment epithelial atrophy, optic disk edema and
atrophy. The appearance can mimic diabetic retinopathy and there
is a similar underlying cause – microvascular leakage and occlu-
sion. Areas of ischemia can lead to retinal, optic disk or iris
neovascularization which can further develop into vitreous hemor-
rhage, retinal detachment or glaucoma. The primary cause of
vision loss is usually due to exudative or ischemic maculopathy
or optic neuropathy. The severity, although multifactorial, is largely
dependent on dose, frequency, location as well as total area treated.
Patients with diabetes or patients undergoing chemotherapy are
at increased risk for developing radiation retinopathy.11,12
PATHOPHYSIOLOGY
Ionizing radiation can be used therapeutically in two general
forms: external beam radiation (teletherapy, or radiation from a
distance) and plaque radiation (brachytherapy, or radiation from
a nearby source). Many variables may have an effect on the
ocular manifestations of radiation therapy. Total dose, fraction
number and size, as well as location most likely have a large
influence. Normal eyes indirectly or directly exposed to radia-
tion for nonocular tumors may manifest different effects of radia-
tion compared to eyes with tumors being treated directly. Local
damage due to the effects of the tumor may be difficult to differen-
tiate from radiation damage alone. Chemotherapy used concur-
rently with radiation or systemic diseases such as diabetes can
further confound the interpretation of retinopathy seen after
radiation.
Studies using angiography and histopathology have been pivotal
in an attempt to understand the effects of radiation on the retina.
Most of these studies have concentrated on findings after external
beam radiation, presumably since external beam radiation is
most common. The doses used in these studies vary and there-
fore the dose–effect relationship findings are difficult to
compare and interpret.
In 1958, histologic studies of primate eyes previously exposed
to external beam radiation by Cibis et al showed the acute
sequelae of radiation therapy primarily involved the outer reti-
nal layer and the photoreceptors, specifically the rods, and the
delayed sequelae involved the inner retina and retinal vascula-
ture.4 The acute changes were noted as early as 19 min following
radiation exposure. The dose used in this study is much higher
than the typical doses used today.
In 1970, Hayreh was the first to describe the fluorescein charac-
teristics of radiation retinopathy followed over time in three
patients with choroidal melanoma.15 All three patients had been
treated with plaque radiation at a dose of 80 Gy to the tumor
apex. Over a 22 month to 4 year follow-up, he noted a variety
of changes in the inner and outer retina including obliteration
of retinal capillary vessels and the choriocapillaris as well as
areas of retinal ischemia.
In 1980, Egbert et al described the histological changes seen
in 17 human eyes with retinoblastoma after receiving 35–60 Gy
of external beam radiation.17 They described the arteriolar and
capillary walls as thickened due to a fine fibrillary material with
fibrin deposition within the walls and outside the vessel walls.
They postulated that the occlusion of the vessels could be due to
narrowing of the vessel lumen. Brown et al, in 1982, found areas
of retinal capillary obliteration in all eyes studied with fluorescein
angiography after cobalt-60 plaque radiation and external beam
radiation.12 They suggested the diagnosis of radiation retino-
pathy should be questioned if retinal capillary nonperfusion is
not demonstrated.
In 1987, Irvine et al reported the clinical and histological
changes seen in 11 primates after radiation levels of up to 35 Gy.18
Early findings were focal loss of capillary endothelial cells and
pericytes. As more capillaries became incompetent, areas of retinal
capillary nonperfusion followed. Nonperfusion led to intra-
retinal neovascularization and eventual neovascular glaucoma. 2207
 RETINA AND VITREOUS
Elevated levels of a vasoproliferative factor were found in an eye
with rubeosis while lower levels were found in an eye without
rubeosis. Interestingly, intravitreal proliferative retinopathy was
not noted.
In 1991, Archer et al described their observations after
enucleating seven human eyes that had received external beam
radiation for various head and neck tumors with radiation levels
up to 55 Gy.13 With the help of trypsin digest and electron
microscopy, a preferential loss of vascular endothelial cells and
preservation of pericytes was demonstrated. Early structural
changes in capillaries such as outpouchings, fusiform dilations,
and microaneurysms were described. With further damage,
fenestrated endothelial cells were seen in both the small caliber
and larger caliber vessels. There was atrophic retinal parenchyma
surrounding these vessels with hypertrophy of glial cells and
degeneration of neurons. They postulated that endothelial cell
damage from radiation and free radical exposure was the inciting
factor leading to a chain of events. These events included the
SECTION 10
activation of the clotting cascade, capillary occlusion and forma-
tion of incompetent capillary collaterals.
In 1992, Krebs et al described their histological findings after
examining an eye that had been enucleated 13 years following
60 Gy of external beam radiation and subsequent chemotherapy
for embryonal rhabdomyosarcoma.19 ERG studies done prior to
enucleation showed severely reduced cone responses and no rod
responses. They concluded that radiation damage enhanced by
chemotherapy may have damaged the retinal vasculature and
pigment epithelium with a secondary loss of photoreceptors.
They noted that rods seemed to be more affected than cones.
Histologic studies of three primate eyes previously treated with
iodine-125 brachytherapy were done in 1999 by Robertson et al.20
A theoretical choroidal tumor with apical height of 5 mm was
assumed so that 80 Gy was to be delivered to the apex. Revised
dose calculations revealed 5 mm apical doses ranged from 64 to
82 Gy and the inner scleral doses ranged from 280 to 420 Gy.
Their findings showed an atrophic retina, retinal pigment epithe-
lium, and choroid with macrophage invasion of the tissues in the
area overlying the site of the radioactive plaque. Trypsin digest
studies further confirmed capillary remodeling with loss of
endothelial cells and pericytes.
In 2003, Sefau et al described the histopathologic changes in
the choroidal circulation seen in three enucleated human eyes
from three patients after external beam radiation.21 The dose for
the first patient treated for congenital hemangioma was unknown.
In the second patient, the total dose used was 57.6 Gy followed
with chemotherapy to treat malignant mesenchymoma. The third
patient had retinoblastoma initially treated with 36 Gy and a
year later with 30 more Gy due to persistence of the tumor.
Findings similar to those seen in paving stone degeneration such
as extensive loss of the retinal pigment epithelium and chorio-
capillaris with adhesion of the degenerated retina to Bruch's
membrane were noted.
CLINICAL FEATURES
NONPROLIFERATIVE RADIATION
RETINOPATHY
Most cases of radiation retinopathy are diagnosed between 1
and 3 years after treatment with rare cases reported as early as
1 month and as late as 15 years. The most common time of
onset is of course dose related but changes are infrequent before
a year and often become apparent at 18–24 months.9,11,12,22 In
general, the nonproliferative manifestations of radiation retino-
pathy consist of focal capillary closure, irregular dilation of sur-
rounding vessels, microaneurysms, intraretinal hemorrhages,
2208 cotton wool spots, retinal exudates, retinal edema, nerve fiber layer
infarctions, and focal retinal pigment epithelial changes.9–12,14 If
any of these findings are within 3 mm of the foveola, the term
radiation maculopathy is used.9 In patients with choroidal
melanoma, local tumor effects may resemble changes similiar
to radiation related retinopathy such as macular edema and intra-
retinal hemorrhages. The similarity in findings may make it
difficult to distinguish between these two possible causes.
Just as the manifestations of radiation vary with dose, fraction
number, size, location, and external beam versus plaque therapy, so
does the incidence. In one study of 96 patients with large uveal
melanoma who underwent plaque radiation, the 5-year incidence
of maculopathy was 52%.5 Gunduz et al studied 1300 patients
treated with plaque radiation for posterior uveal melanoma.9
Their overall incidence of radiation maculopathy was 43%. A 5%
incidence of nonproliferative retinopathy was seen after 1 year
and 42% after 5 years. The most important predictor of nonprolif-
erative retinopathy in their study was the posterior location of
the tumor. Guyer et al reported a radiation maculopathy incidence
of 89% in their study of 218 patients who had received external
beam radiation for paramacular choroidal melanomas.10 The
earliest and most common sign was macular edema, found in
61% of the patients at 1 year and 87% at 3 years. In their study of
32 patients with radiation retinopathy, Brown et al found hard
exudates in 85% of those treated with plaque radiation compared
to 38% in those treated with external beam radiation.12 The pos-
sibility of leakage of serum products from necrotic tumor tissue
as a cause of the disparity in incidence could not be excluded. In
the group treated with plaque radiation, microaneurysms were seen
in 75%, intraretinal hemorrhages were seen in 65%, telangiectasia
were seen in 35%, cotton wool spots were seen in 30% and 20%
had vascular sheathing. In the group treated with external beam
radiation, microaneurysms and intraretinal hemorrhages were
seen in 81% and 88% respectively, 38% had telangiectasia and
cotton wool spots, and vascular sheathing was seen in 25%.
In addition to the previously mentioned manifestations of radia-
tion retinopathy, other rare presentations of radiation retinopathy
including central retinal artery occlusion or central retinal vein
occlusion have also been reported.12,15 Maberley et al have also
postulated that radiation may be a contributing factor to
idiopathic perifoveal telangiectasia.23
PROLIFERATIVE RADIATION RETINOPATHY
The proliferative manifestations of radiation retinopathy include
any neovascularization of the retina or optic disk. Brown et al
reported a higher rate of neovascularization after treatment with
external beam radiation (43%) compared to plaque radiation
(5%).12 Subsequent reports have not shown this disparity. Guyer
et al reported an incidence of 6% after external beam radiation
and Gunduz et al observed a proliferative retinopathy incidence
of 1% at 1 year and 8% at 5 years after plaque radiation.9,10 In a
study of 558 patients treated with external beam radiation for
choroidal melanoma, Gragoudas et al reported a proliferative
retinopathy incidence of 3%.8 In addition to the possible manifes-
tations described above, an atypical case of subretinal neovascu-
larization originating from telangiectatic vessels has been
reported.24 Spaide et al have also identified unusual vascular,
bleb-like choroidal complexes located at the outer border of
choroidal neovascularization.25 They have proposed the term
'radiation-associated choroidal neovasculopathy' (RACN) to
identify their observations.
DOSIMETRY
Dosimetry varies widely based on the method of radiation
delivery (plaque versus external beam), the type of lesion, and
location of therapy. Standard fractionation for external beam

radiation is typically 1.8–2.0 Gy of radiation in single daily
doses until the total dose desired is achieved. The benefits of
fractionated radiation therapy had been established a few years
prior to Moore and Stallard's use of radiation to treat ophthalmic
tumors.1 Hyperfractionation refers to even smaller fractions
applied more than once daily over the same treatment time.
The theoretical benefits of hyperfractionation for the retina are
to allow normal retinal tissue to repair single-strand DNA
breaks and limit late damage to double-strand breaks.22 There
is also a potential to deliver a higher total radiation dose which
may limit late sequelae. Randomized trials have not been
undertaken to prove any clinical benefit of this approach.
Reports of the incidence of retinopathy vary from 35% to 56%
with doses above 45 Gy.8,12,16,22 Brown et al have reported an
incidence of 85% with doses between 70 and 80 Gy.12 A specific
threshold dose that will result in retinopathy has not been
determined. Factors such as varying radiation fractionation and
hyperfractionation techniques, retinal dose measurement tech-
niques and co-morbid disease make establishing this threshold
difficult.
In a review of patients who had undergone external beam
radiation with varying fractionation schedules for various head
and neck tumors, Amoaku et al reported the threshold dose for
radiation retinopathy was between 25 and 30 Gy.11 The mean
follow-up was 8 years. Parsons et al investigated radiation-induced
retinopathy according to total radiation dose and fraction size
both retrospectively from data in the literature and also prospec-
tively in 64 patients receiving external beam radiation for various
extracranial head and neck tumors.16 A sigmoid dose–response
curve was created indicating that with fraction sizes less than or
equal to 2 Gy, total dose of 30 Gy seemed to be the threshold
prior to the development of retinopathy. In a prospective study
of 42 patients with Graves ophthalmopathy, Robertson et al
observed the development of retinopathy in three patients
within 3 years.7 The dose received by all patients was 20 Gy
delivered in 10 doses of 2 Gy. Their results were confounded by
the fact that retinal microvascular abnormalities were observed
prior to radiation in one patient and the other two had factors
known to be associated with retinopathy such as uveitis, systemic
hypertension and abnormal glucose levels. More recently, Monroe
et al identified 186 patients undergoing external beam radiation
for various head and neck tumors and followed them prospec-
tively for a median of 6.7 years.22 Their studies indicated the
threshold for retinopathy was 40 Gy with standard fractionation.
The threshold for retinopathy was 50 Gy with a hyperfraction-
ation schedule. Hyperfractionation reduced the incidence of
retinopathy by more than half compared to standard fractionation
(13% vs 37%) in those patients who received more than 50 Gy.
In the Brown et al study of radiation retinopathy, 20 eyes had
been treated with plaque radiation and 16 eyes with external
beam radiation.12 They reported a higher mean dose of radiation
with plaque radiation was needed compared to external beam
radiation therapy to produce foveopathy. The mean dose with
plaque radiation was 150 Gy, whereas a mean of 49 Gy was
needed with external beam radiation. In their study of plaque
radiation therapy for posterior melanoma, Gunduz et al found a
significantly higher risk for nonproliferative retinopathy with
doses above 57 Gy to the fovea.9 The median dose to the fovea
in those developing retinopathy was 70 Gy.9
OTHER ASSOCIATIONS
Independent factors thought to exacerbate radiation retinopathy
are chemotherapy and systemic conditions such as diabetes,
hypertension and collagen diseases.11 These conditions may
decrease the threshold dose required to develop radiation
retinopathy. For example, Brown et al found radiation retinopathy
Radiation Retinopathy
in four of seven eyes that had received chemotherapy in
addition to external beam radiation.12 All four eyes progressed
to total blindness. Parsons et al observed four of 10 patients
treated with external beam radiation that developed radiation
retinopathy compared to two of two that were treated with
external beam radiation in addition to chemotherapy.16
With regard to diabetes and radiation retinopathy, Brown et
al observed the only patient to develop proliferative retinopathy
in the plaque radiation group was known to have diabetes. The
minimal dose shown to induce foveal damage was 45 Gy,
whereas excluding this patient would have raised the minimal
dose to 100 Gy.12 Parsons et al described a diabetic patient with
no evidence of retinopathy and normal visual acuity prior to
treatment for advanced skin cancer of the central face with
external beam radiation.16 He subsequently developed radiation
retinopathy in both eyes resulting in hand-motion vision by 47
months after treatment. Other large studies following plaque
therapy for melanoma have supported the theory that diabetes
CHAPTER 175
increases the risk of retinopathy following radiation.9
DIFFERENTIAL DIAGNOSIS
Because the clinical features of radiation retinopathy are similar
to those seen in other retinal vasculopathies, it is important to
elicit a thorough history and review any prior medical records
available. If a history of radiation exposure is obtained, impor-
tant details such as the date, dose, frequency and area of radiation
should be reviewed. Information about the fields will allow an
estimate of whether the eye was or was not likely included in
the field or radiation.
The clinical manifestations of diabetic retinopathy and hyper-
tensive retinopathy can be difficult to distinguish from radiation
retinopathy. Other retinal vascular abnormalities such as arterial
or venous occlusive disease and telangiectasia must be differ-
entiated. Ocular ischemic syndrome can also mimic radiation
retinopathy although the intraretinal hemorrhages are generally
found in the midperipheral retina whereas in radiation retinopa-
thy, intraretinal hemorrhages are generally found diffusely
throughout the retina or in the localized area of treatment.
TREATMENT
The natural history of radiation maculopathy is characterized
by progressive retinal damage with eventual resolution of edema
as ischemia develops. Proliferative retinopathy can result in
vitreous hemorrhage, retinal detachment or neovascular glaucoma
and loss of vision is often due to ischemia or optic neuropathy.
The optimal treatment of radiation retinopathy is not well
established. Because of the similarities to diabetic retinopathy
and branch vein occlusion, data from the Branch Retinal
Vein Occlusion Study (BRVO) and Early Treatment Diabetic
Retinopathy Study (ETDRS) has been extrapolated to study the
use of laser photocoagulation for the treatment of macular
edema and proliferative retinopathy after radiation.26–28
Hykin et al retrospectively studied the effect of focal laser- on
radiation-induced macular edema with a treatment group of 19
patients and a matched observation group of 23 patients.27 Their
results showed an initial 6-month modest improvement in
visual acuity and resolution of macular edema in the treatment
group; however, at 2-year follow-up, no significant difference in
visual acuity was found compared to the observation group.
Other techniques to treat radiation maculopathy have been
proposed such as the use of oral pentoxifylline to treat capillary
nonperfusion, intravitreal triamcinolone acetonide or verteporfin
photodynamic therapy, and hyperbaric oxygen.29–32 These treat-
ments have either been described in small cases series or have
not proven to have lasting effects. 2209
 RETINA AND VITREOUS

In a retrospective study of 14 eyes of 10 patients with

TABLE 175.1. Finger Classification of Radiation Retinopathy
proliferative radiation retinopathy, Kinyon et al reported a
91% rate of resolution after panretinal photocoagulation for Stage 1 (Findings Are Limited to Outside the Macula)
proliferative radiation retinopathy.28 The visual acuity, however,
went from an initial median of 20/90 to 20/400 after an average Cotton wool spots
follow-up of 75 months. Significant contributing factors to Retinal hemorrhages
visual loss included optic neuropathy, macular ischemia, and Retinal microaneursyms
vitreous hemorrhage.
Recently, Finger et al have proposed a four-stage classification Ghost vessels
for radiation retinopathy (Table 175.1).26 Based on this classi- Exudate
fication, they studied the effects of sector scatter laser photoco-
Uveal effusion
agulation through an interventional case series in two groups of
patients that had been previously treated with plaque radiation Choroidal atrophy
for posterior choroidal melanoma. The first group of 45 patients Choroidopathy
had signs of radiation retinopathy and the second group of 16
patients did not have any clinical evidence of radiation Retinal ischemia <5 DA
retinopathy but were considered 'high risk' based on the Stage 2 (Findings from Stage 1 but Found Within the Macula)
posterior location of the tumor.26 Radiation retinopathy in the
SECTION 10

Stage 3 (Any Stage 1–2 in Addition to the Following)

first group was defined as any iris or retinal neovascularization
or any stage-1 finding, with the exception of isolated ghost
vessels, uveal effusion, or chorioretinal atrophy. They reported
a regression rate (defined as disappearance or regression of
initial treatment indications) of 64% and a loss of three lines or
more in visual acuity in 47% after a mean follow-up of 48
months. In a third of the patients who lost three lines of vision,
the cause was due to maculopathy. In the second group, three
patients developed radiation retinopathy which regressed with
further treatment. No patients lost more than three lines of
vision due to radiation maculopathy. The authors suggested
that sector scatter laser photocoagulation may regress radiation
retinopathy under their proposed classification and preserve
vision. The findings, however, were not statistically significant
and further prospective studies were recommended.
With new treatments targeting vascular endothelial growth
factors now available, perhaps future studies will involve the
Retinal vascularization
Macular edema
Stage 4 (Any Stage 1–3 in Addition to the Following)
Vitreous hemorrhage
Retinal ischemia >5 DA
use of these growth factor inhibitors to treat permeability-
related pathology in radiation retinopathy, or to achieve
regression of new vessels. However, it is not likely to alter the
tendency to develop progressive ischemia or optic neuropathy,
so the vision outcomes may not be good. Prospective studies
will be necessary.

REFERENCES
1. del Regato JA: The unfolding of American
radiotherapy. Int J Radiat Oncol Biol Phys
1996; 35:5–14.
2. Moore RF: Choroidal sarcoma treated by
the intraocular insertion of radon seeds.
Br J Ophthalmol 1930; 14:145–152.
3. Stallard HB: Radiant energy as (a) a
pathogenic (b) a therapeutic agent in
ophthalmic disorders. Br J Ophthalmol
Monograph Suppl 1933; VI:70.
4. Cibis PA, Brown DVL: Retinal changes
following ionizing radiation. Am J
Ophthalmol 1955; 49:84–88.
5. Puusaari I, Heikkonen J, Kivela T: Ocular
complications after iodine brachytherapy
for large uveal melanomas. Ophthalmology
2004; 111:1768–1777.
6. Subramanian PS, Bressler NM, Miller NR:
Radiation retinopathy after fractionated
stereotactic radiotherapy for optic nerve
sheath meningioma. Ophthalmology 2004;
111:565–567.
7. Robertson DM, Buettner H, Gorman CA,
et al: Retinal microvascular abnormalities in
patients treated with external radiation for
Graves ophthalmopathy. Arch Ophthalmol
2003; 121:652–657.
8. Gragoudas ES, Li W, Lane AM, et al: Risk
factors for radiation maculopathy and
papillopathy after intraocular irradiation.
Ophthalmology 1999; 106:1571–1578.
9. Gunduz K, Shields CL, Shields JA, et al:
Radiation retinopathy following plaque
2210
radiotherapy for posterior uveal melanoma.
Arch Ophthalmol 1999; 117:609–614.
10. Guyer DR, Mukai S, Egan KM, et al:
Radiation maculopathy after proton beam
irradiation for choroidal melanoma.
Ophthalmology 1992; 99:1278–1285.
11. Amoaku WMK, Archer DB: Cephalic
radiation and retinal vasculopathy. Eye 1990;
4:195–203.
12. Brown GC, Shields JA, Sanborn G, et al:
Radiation retinopathy. Ophthalmology
1982; 89:1494–1501.
13. Archer DB, Amoaku WM, Gardiner TA:
Radiation retinopathy – clinical,
histopathological, ultrastructural and
experimental correlations. Eye 1991;
5:239–251.
14. Amoaku WM, Archer DB: Fluorescein
angiographic features, natural course and
treatment of radiation retinopathy. Eye
1990; 4:195–203.
15. Hayreh SS: Post radiation retinopathy:
a fluorescence fundus angiographic study.
Br J Ophthalmol 1970; 54:705–714.
16. Parsons JT, Bova FJ, Fitzgerald CR, et al:
Radiation retinopathy after external beam
irradiation: analysis of time-dose factors. Int
J Radiat Oncol Biol Phys 1994; 30:765–773.
17. Egbert PR, Donaldson SS, Moazed K,
Rosenthal AR: Visual results and ocular
complications following radiotherapy for
retinoblastoma. Arch Ophthalmol 1978;
96:1826–1830.
18. Irvine AR, Wood IS: Radiation retinopathy
as an experimental model for ischemic
proliferative retinopathy and rubeosis iridis.
Am J Ophthalmol 1987; 103:790–797.
19. Krebs IP, Krebs W, Merriam JC, et al:
Radiation retinopathy: electron microscopy
of retina and optic nerve. Histol Histopathol
1992; 7:101–110.
20. Robertson DM, Garretson BR, de Venecia GB,
et al: Clinicopathologic correlation of
radiation retinopathy in the rhesus monkey
induced by iodine-125 episcleral plaque.
Ophthalmic Pract 1999; 17:86–92.
21. Sefau SO, Dorey MW, Brownstein S, et al:
Radiation-induced chorioretinal degeneration:
a clinicopathological report of three cases.
Can J Ophthalmol 2003; 38:57–62.
22. Monroe AT, Bhandare N, Morris CG,
Mendenhall WM: Preventing radiation
retinopathy with hyperfractionation. Int J
Radiat Oncol Biol Phys 2005; 61:856–864.
23. Maberley DAL, Yannuzzi LA, Gitter K, et al:
Radiation exposure: a new risk factor for
idiopathic perifoveal telangiectasis.
Ophthalmology 1999; 106:2248–2253.
24. Boozalis GT, Schachat AP, Green WR:
Subretinal neovascularization from the
retina in radiation retinopathy. Retina 1987;
7:156–161.
25. Spaide RF, Leys A, Herrmann-Delemazure B,
et al: Radiation-associated choroidal
neovasculopathy. Ophthalmology 1999;
106:2254–2260.

26. Finger PT, Kurli M: Laser photocoagulation
for radiation retinopathy after ophthalmic
plaque radiation therapy. Br J Ophthalmol
2005; 89:730–738.
27. Hykin PG, Shields CL, Shields JA,
Arevalo JF: The efficacy of focal laser
therapy in radiation-induced macular
edema. Ophthalmology 1998;
105:1425–1429.
28. Kinyoun JL, Lawrence BS, Barlow WE:
Proliferative radiation retinopathy. Arch
Ophthalmol 1996; 114:1097–1100.
Radiation Retinopathy
29. Gupta P, Meisenberg B, Amin P, 32. Stanford MR: Retinopathy after irradiation
Pomeranz HD: Radiation retinopathy: the and hyperbaric oxygen. J R Soc Med 1984;
role of pentoxifylline. Retina 2001; 77:1041–1043.
21:545–547.
30. Shields CL, Demirci H, Dai V, et al:
Intravitreal triamcinolone acetonide for
radiation maculopathy after plaque
radiotherapy for choroidal melanoma.
Retina 2005; 25:868–874.
31. Bakri SJ, Beer PM: Photodynamic therapy
for maculopathy due to radiation
retinopathy. Eye 2005; 19:795–799.
CHAPTER 175
2211
 CHAPTER

176 Retinal Toxicity of Systemic Medications

Patrick D. Williams and David Callanan

Key Features: BOX 176.1 Systemic medications that cause retinal

• Systemic medications can produce posterior segment toxicity toxicity
through varying mechanisms
• Phenothiazines
• Direct toxicity to the retina
• Direct toxicity to the RPE • Thioridazine
• Vascular damage • Chlorpromazine
• Accumulation in tissue • Quinolines
• Cystoid macular edema • Chloroquine
• The American Academy of Ophthalmology has issued
• Hydroxychloroquine
recommendations for hydroxychloroquine screening
(see Box 176.2) • Drugs that cause crystal deposition
• Documented toxicity is rare • Talc
• Tamoxifen
• Canthaxanthine

INTRODUCTION • Methoxyflurane
• Cisplatin
Medications that are toxic to the retina can produce variable • Interferon
presentations and clinical courses. The retinal changes can be
• Didanosine
subtle or dramatic, and the damage can be benign or devas-
tating. The retina can demonstrate toxicity in numerous ways, • Niacin
including cystoid macular edema, damage to the retinal pigment • Clofazamine
epithelium (RPE), damage directly to the retina, and accumula- • Desferoxamine
tion of the substance in tissue. Knowledge of the known toxi- • Methanol
cities can help the practitioner to decipher the sometimes
• Quinine
unusual clinical presentations and treat patients accordingly.
• Antiepileptics
• Vigabatrin
PHENOTHIAZINES • Lamotrigine

The phenothiazine class of compounds is used to treat

psychiatric conditions such as acute psychosis. Chlorpromazine
(Thorazine) and thioridazine (Mellaril) are known to cause
retinopathy with the high doses sometimes used to treat acutely
psychotic patients. Chlorpromazine is used to treat intractable
hiccoughs as well as psychiatric diseases.
THIORIDAZINE
GENERAL INFORMATION
Thioridazine has been used for acute psychosis since the 1950s.
A dose of greater than 800 mg/day of thioridazine is more likely
to produce toxicity, and 2 weeks of high-dose therapy is com-
monly required for retinopathy.1 A high daily dosage is
considered to be a greater risk factor than cumulative dosage.
Although toxicity has been reported with chronic use at doses
less than 800 mg/day, the incidence is extremely low.2
CLINICAL FEATURES
Patients typically complain of blurred vision, dyschromatopsia
(brownish or reddish vision), and nyctalopia with acute
thioridazine toxicity.3–5 The visual symptoms can be variable,
and acute toxicity may present with a normal retina or a granular
stippling of the RPE with or without pigment clumping. More
chronic disease can cause patients to develop geographic
‘nummular’ areas of atrophy of the RPE and retina (Fig. 176.1).1
Early cessation of the medication may allow for some return of
visual acuity.6 The retina and RPE changes usually progress,
suggesting atrophy of previously damaged cells.1,6
ANCILLARY TESTING
Ancillary testing can confirm thioridazine toxicity, although it
is unclear if it can reveal preclinical disease. The fluorescein
angiogram shows irregularity of the RPE initially, with severe
atrophy of the RPE and choriocapillaris in the late stages of
2213
 RETINA AND VITREOUS
FIGURE 176.1. Right eye of patient that used Mellaril (thioridazine) for
SECTION 10
many years with nummular areas of hypopigmented RPE.
1
toxicity. Fluoroscein angiogram changes can be more striking
than clinical findings. Visual fields, electroretinogram, and
electrooculogram are variably affected. Visual fields can have
varying ring or paracentral scotomata or constriction.4 Electro-
retinography can be normal or can have photopic and scotopic
amplitude reductions.6,7 Electroretinography changes, like visual
symptoms, are reversible with quick cessation of medication.
PATHOPHYSIOLOGY
The toxicity of thioridazine may be due to its piperidyl side
chain. The only other phenothiazine with a piperidyl side chain
was NP-207, a drug never marketed. Severe retinopathies,
similar to thioridazine toxicity, were found in early clinical
trials.8 Pathology specimens of eyes with thioridazine toxicity
show initial atrophy and disorganization of the photoreceptors
followed by loss of the choriocapillaris and RPE.9 Both
thioridazine and chlorpromazine bind to melanin and show
accumulation in the melanin granules of pigmented tissues.10–12
Phenothiazine toxicity may involve dopamine metabolism in
the eye.13 Dopamine regulates melatonin, which is involved in
retinal physiology and prevents light toxicity.
CHLORPROMAZINE
CLINICAL FEATURES
Chlorpromazine causes hyperpigmentation of tissues, including
sun-exposed skin and conjunctiva.14–16 Corneal deposits and a
characteristic cataract can develop. Retinopathy associated with
chlorpromazine is rare. When it occurs, it presents as a diffuse
hyperpigmentation of the RPE. The changes are finer and more
diffuse than those of thioridazine toxicity. Patients may have
arteriolar attenuation and optic nerve pallor. Alternatively,
chlorpromazine toxicity may present with more well-defined
patches of depigmentation.17 Very large doses (~1–2 g/day) are
required for retinopathy.14–16
QUINOLINES
GENERAL INFORMATION
The quinoline derivative antimalarials include both chloro-
quine and hydroxychloroquine (Plaquenil). Chloroquine was
first used to treat malaria in the mid-twentieth century. It
2214 was first discovered in Germany in 1934, but was not used
extensively until after World War II. The toxic side effects of
chloroquine and hydroxychloroquine became apparent with the
increasing use for rheumatoid diseases, as these diseases
required higher doses and chronic treatment. The first reported
case of chloroquine retinopathy was a case report of pigmentary
retinopathy of unknown origin associated with systemic lupus
erythematosus.18
CHLOROQUINE
Chloroquine can cause retinal damage with long-term daily use.
Daily doses exceeding 250 mg and cumulative doses between
100 and 300 g are typically required to affect the posterior
segment.19 The daily dose may be more important than the
cumulative dose. Doses at or below 3–3.5 mg kg–1 day–1 appear
to prevent toxicity.20,21 Maintaining a low daily dose appears to
control the risk of toxicity, even with very high cumulative
doses.22
HYDROXYCHLOROQUINE
Hydroxychloroquine has largely supplanted chloroquine for the
treatment of rheumatoid diseases, in no small part due to its
improved safety profile. Although hydroxychloroquine toxicity
has been well documented, the incidence of hydroxychloroquine
retinal toxicity is much lower than that of chloroquine.23–25 The
accepted safe dose is regarded as 6.5 mg kg–1 day–1. Below this
threshold, the incidence of retinopathy is rare, but it has been
reported.26 At doses below 6.5 mg kg–1 day–1, 6 years of treat-
ment is typically required before any retinopathy is appreciated.
The most recent estimate of the incidence of toxicity at normal
doses for greater than 6 years duration was 0.5%.27 Patients
using low-dose hydroxychloroquine therapy with massive
cumulative doses can still avoid retinopathy.28
CLINICAL FEATURES
The most common early symptoms of toxicity are paracentral
scotomata. As toxicity progresses, patients can also report a loss
of acuity, nyctalopia, and photophobia. Dyschromatopsia can
occur as well.29 Toxicity is not limited to the retina. Poliosis,
subepithelial corneal deposits, decreased corneal sensitivity, and
even sixth cranial nerve palsies may develop.29 These findings
were much more common with chloroquine than what is
reported now with hydroxychloroquine.
Early disease may not reveal retinal changes on biomicro-
scopy. The earliest signs include loss of the foveal reflex and
nonspecific changes in the macular RPE.30 In the later stages,
there is granularity of the RPE in the classic bull’s-eye pattern.31
Bull’s-eye maculopathy consists of a circular area of RPE hyper-
pigmentation centered on the fovea. An oval area of RPE hypo-
pigmentation around the circle creates the appearance of a bull’s
eye (Fig. 176.2). Subsequent arteriolar narrowing, optic disk
pallor, and peripheral RPE degeneration develop as well, giving
an appearance similar to retinitis pigmentosa (Fig. 176.3).
There is no treatment besides drug cessation. Unfortunately,
the toxicity can often progress even after the drug is stopped. It
will eventually stabilize, but the central acuity can be sig-
nificantly affected. In some cases of early toxicity, visual acuity
has improved after stopping therapy.
ANCILLARY TESTING
There is still controversy about whom and how to monitor
these patients for early signs of toxicity. As stated above,
hydroxychloroquine toxicity is exceedingly rare in doses under
6.5 mg kg–1 day–1 and less than 5 years duration. Other factors,
 Retinal Toxicity of Systemic Medications

toxicity.34,35 The standard Pseudoisochromatic Plates part 2

and the AO HRR tests are more reliable predictors of retinal
toxicity.35 A baseline color vision examination may be beneficial
in males to later differentiate inherited color deficiencies from
equivocal cases of toxicity. Also, color vision testing can be use-
ful in elderly patients, in which accurate perimetry is difficult.

Amsler Grid
The Amsler grid is widely used for evaluation of early hydroxy-
chloroquine toxicity, and is recommended by the AAO.32 It is
inexpensive and easy to administer, making it ideal for clinic
and home use. The scotomata produced on Amsler grid cor-
relate well with those found on perimetry.36 In patients with
normal perimetry, the Amsler grid can sometimes reveal relative
scotomata.37
Modifications in the Amsler grid may improve its sensitivity.
Red Amsler grid testing yields a higher incidence of scotomata,
FIGURE 176.2. Classic bull’s-eye pattern of retinopathy due to
but the sensitivity is questionable due to a lack of confirmation

CHAPTER 176
chloroquine toxicity.
of many positive tests.38,39 These may be early toxic changes or
may be false-positive results. Recently, the threshold Amsler
grid has been proposed as a test more sensitive than even the
red Amsler grid.38 The patient looks through cross-polarizing
filters at a standard Amsler grid, thereby reducing contrast sen-
sitivity and eliciting milder relative scotomata. The sensitivity
of threshold Amsler grid testing is much higher than that of
either the standard Amsler grid or the red Amsler grid.38 As
with the red Amsler grid, the true specificity is difficult to
ascertain.

Perimetry
Perimetry has become commonplace in the evaluation of
hydroxychloroquine patients. Both kinetic (Goldmann) and
static (Humphrey) perimetry have been used to evaluate
hydroxychloroquine and chloroquine toxicity. Humphrey 10–2
visual fields allow focused examination of macular function.40
The sensitivity and specificity of Humphrey static perimetry
has been evaluated and is accepted as reasonable for decisions
FIGURE 176.3. Advanced chloroquine toxicity mimicking retinitis whether to continue or withdraw medication.41 Red target peri-
pigmentosa with bone spicules and arteriolar narrowing.
metry appears to be more sensitive than white target perimetry
(91.3% and 78%, respectively), but the specificity of red target
perimetry is worse (57.8% and 84%, respectively). The AAO
however, can influence the risk of toxicity. In 2002, the currently recommends either Amsler grid testing or Humphrey
American Academy of Ophthalmology (AAO) published a 10–2 perimetry to monitor patients taking hydroxychloroquine.32
guideline for hydroxychloroquine screening.32 Not only do dose
and duration of therapy affect toxicity risk, but liver or renal Fluoroscein Angiogram
disease, obesity, concomitant retinal disease, and age over 60 Fluoroscein angiography can highlight the changes seen on
may play a role. Liver or renal disease can affect chloroquine ophthalmologic exam (Fig. 176.4). It is not mandatory for
and hydroxychloroquine levels because these drugs are cleared
by both organs. Obesity is a risk factor because neither drug
is stored in fat cells. People in which fat contributes a large
percentage of total body weight must be placed on relatively
lower doses.
The clinical examination is the basis of all ophthalmologic
testing for chloroquine and hydroxychloroquine toxicity.32 The
AAO recommends a baseline examination, although the efficacy
has not been proven. Routine examinations should be main-
tained based on risk stratification. Unfortunately, early toxicity
may be missed by only relying on clinical examination. Con-
sidering the rare incidence of hydroxychloroquine toxicity, there
has been much debate over the costs and benefits of extensive
ancillary screening.

Color Vision
There are no changes in color vision specific to chloroquine or
hydroxychloroquine retinopathy, but nonspecific changes may
occur with disease.33 In general, Ishihara color plates and the FIGURE 176.4. Fluoroscein angiogram highlighting bull’s eye
Farnsworth D-15 panel have poor sensitivity for early retinopathy due to chloroquine toxicity. 2215
 RETINA AND VITREOUS

routine evaluation, but can help differentiate toxicity from other

maculopathies.32 BOX 176.2 Screening for hydroxychloroquine toxicity
• Dosage less than 6.5 mg/kg lean body weight considered
Electrooculogram safe for 5 years
Early reports suggested that the electrooculogram (EOG) may be • Risk factors for retinopathy include:
a useful tool in chloroquine toxicity screening.42,43 An Arden • Liver or renal disease
ratio of less than 1.85 appeared to signify toxicity. EOG has a
poor specificity, however, and active episodes of rheumatologic • Obesity
disease can also alter the EOG.44 The most recent review of • Concomitant retinal disease
EOG findings suggested a sensitivity of 50% and a specificity • Use greater than 5 years
of 54%.45 • Age greater than 60 years
• Recommended ancillary testing:
Multifocal Electroretinogram
Multifocal electroretinogram (mfERG) is a newer screening • Amsler grid or 10–2 perimetry for everyone screened
modality for hydroxychloroquine toxicity. Decrease in mfERG • Red test objects can improve sensitivity but may
amplitudes have been demonstrated in documented hydroxy- reduce specificity
chloroquine toxicity, consistent with the decline in visual • Fluoroscein angiography can assist when concomitant
acuity.46 More interestingly, changes in mfERG have been noted retinal disease is present
SECTION 10

in patients with no other evidence of toxicity.47–49 The signifi- • Baseline color vision testing can separate congenital
cance of these changes is unknown, as there is no comparison deficits from acquired retinopathy
to known parameters. Abnormalities were noted in patients
• mfERG can confirm retinopathy
with less than 5 years of hydroxychloroquine use, suggesting an
early subclinical toxicity that was reversible with discontinua- • May reveal preclinical disease
tion of the medication. Normal mfERG examinations have also
been found in patients taking the medication for over 10 years,
however.49 Therefore, there are likely some individual differ-
TALC
ences in mfERG responses, just as there are individual dif- General Information
ferences in frank toxicity. Multifocal ERG may become standard Talc is the common name for hydrous magnesium silicate. It is
in hydroxychloroquine screening, but more information is an inert filler used in oral medication such as methylphenidate
needed to interpret abnormal results when no other abnor- (Ritalin) and can cause crystalline retinopathy in intravenous
malities are found. drug abusers.55–57 With intravenous injection, crystals smaller
than 7 mm can pass through the lungs. The large talc crystals
are trapped in the lungs, but pulmonary shunt vessels develop
PATHOPHYSIOLOGY with repeated injections.57 The crystals can then enter the
The pathophysiology of chloroquine and hydroxychloroquine arteriolar system and embolize to the eye. This likely explains
toxicity is, for the most part, unknown.50 Chloroquine is con- why chronic intravenous drug abuse is usually required before
centrated in the RPE and uvea and is bound by melanin. Due to retinopathy develops.
the fact that the toxicity appears to be concentrated in the
macula, some have hypothesized a direct effect on cone cells. Clinical Features
Chloroquine toxicity affects lysosomal metabolism in the Patients can be asymptomatic with talc crystalline retino-
neurosensory retina and RPE.51 In a rat model, lysosomal pH pathy.56 The crystals appear reflective and migrate to the end
rises with in vivo administration of chloroquine. Numerous arterioles (Fig. 176.5). With persistent crystal deposition, an
membranous cytoplasmic bodies can be seen in retinal neurons, ischemic retinopathy develops.56,58,59 Ischemia is confined to
including cone cells but not rod cells. RPE metabolism is areas with capillary nonperfusion due to emboli. Other sequelae
affected, with increase in lysosomal associated organelles and of ischemia, such as microaneurysms, cotton wool spots, and
lysosomal accumulation of rod outer segments. The difference collateral vessels may also be present. Neovascularization of the
in toxicity between chloroquine and hydroxylchloroquine may
be due to the difference in effect on lysosomal metabolism.52 In
vitro administration of chloroquine to RPE cells causes greater
accumulation of lipofuscin than does administration of
hydroxychloroquine. Lipofuscin accumulation is increased by
elevated lysosomal pH and oxidative breakdown of phago-
cytosed material.
Changes in lipid metabolism are also present in the neuro-
sensory retina.53,54 An accumulation of lipids, which can cause
direct neuronal damage, has been documented with chloro-
quine toxicity. Based on comparisons to electroretinographic
findings in a rat model, lipidosis is not likely the direct cause of
toxicity.

CRYSTALLINE RETINOPATHIES
Several chemicals can cause deposition of crystals in the retina.
These include talc, tamoxifen, canthaxanthin, and methoxy-
flurane. In the majority of these cases, the patient is unaware of FIGURE 176.5. Talc crystals in the right eye of a patient with chronic
the presence of these crystals and they are found on a routine intravenous drug use. The patient had developed severe hypertension
2216 dilated retinal exam. and suffered an intracranial hemorrhage as well.

disk or elsewhere can develop, leading to vitreous hemorrhage
and retinal detachment.58 Vision loss can also occur due to
macular fibrosis.60 Animal model of talc retinopathy suggests
that the ischemic response is similar to other vascular diseases
such as diabetes and sickle cell retinopathy.61–63 Retinal photo-
coagulation to the ischemic retina can prevent complications of
proliferative disease, just as in other vascular retinopathies.64
TAMOXIFEN
General Information
Tamoxifen is an estrogen receptor antagonist typically used in
treating estrogen-receptor positive breast cancer. The number of
cases with tamoxifen retinopathy has greatly declined since the
daily dose was lowered to 10–20 mg/day, but retinopathy is still
possible.65–67 The classic descriptions of tamoxifen retinopathy
were associated with doses of 180 mg/day in the treatment of
metastatic disease.68,69 While tamoxifen retinopathy can
happen at standard doses, it is rare. There is no evidence to
support routine screening of patients taking tamoxifen at
standard doses.70,71 Even if patients develop retinal crystals,
there is typically little change in retinal function.
Clinical Features
Patients develop white, glistening crystals in the inner plexi-
form layer and nerve fiber layer. Varying degrees of pigmentary
changes may also be present. With high doses, patients may
lose vision due to direct retinal toxicity as well as macular
edema and optic neuropathy.72 Patients can have improvement
in vision with termination of tamoxifen therapy.73
Ancillary Testing
Electroretinography demonstrates a decrease in the photopic
and scotopic a- and b-wave amplitudes.73 Fluoroscein
angiography can highlight the cystoid macular edema. Optical
coherence tomography also demonstrates the cystoid spaces as
well as photoreceptor disruption.74
Pathophysiology
Small intracellular lesions (3–10 mm in diameter) in the macula
and larger extracellular crystals in the paramacular region
(30–35 mm in diameter) have been described by electron
microscopy.69 These lesions were assumed to be the clinically
apparent crystals and seemed to represent the products of
axonal degeneration.
CANTHAXANTHINE
General Information
Canthaxanthine has been used as an oral tanning agent, but its
use seems to have diminished since the reports of deposits in
the retina. It is a naturally occurring carotenoid also used to
treat vitiligo and disorders involving photosensitivity. It also can
be found in common foods and has been suggested to be toxic
with large dietary ingestion.75 The first reports of retinopathy were
in the European literature.76–79 In cumulative doses greater than
60 g, a majority of patients have clinically apparent retinopathy.79,80
Clinical Features
In high doses for chronic use, canthaxanthine produces a cha-
racteristic crystalline retinopathy with an annular distribution
of glistening crystals.76–78,80,81 The ring of crystals is localized in
the macula and is centered on the fovea (Fig. 176.6). Most
patients with clinically apparent crystals are asymptomatic.
Patients can, however, develop metamorphopsia or decreased
vision. The retinopathy is reversible, with slow resolution of the
crystals over years.82
Retinal Toxicity of Systemic Medications
FIGURE 176.6. Right eye of a patient that used canthaxanthin for
CHAPTER 176
several months. There are numerous tiny crystals that are extremely
reflective around the fovea.
Photo courtesy of Barbara Blodi, MD.
Ancillary Testing
Ten-degree static perimetry can show reduced sensitivity in
patients with retinopathy, but patients taking canthaxanthine
without clinical toxicity have normal visual fields.83 Electro-
physiology studies have not been consistent across studies, but
some alterations have occurred clinically and in animal
models.84–87
Pathophysiology
Based on histopathology, the crystals settle in the nerve fiber
layer and can be found throughout the retina, even though
clinically they are only apparent in the macula.88 The crystals
are actually canthaxanthine–lipoprotein complexes in which
only the central portion can be appreciated clinically.
METHOXYFLURANE
Methoxyflurane is an inhalational anesthetic that metabolizes
into oxalate crystals. With extended use, renal failure ensues
due to the oxalate deposition in the kidney. A flecked retinal
appearance with copious small yellow-white punctate lesions in
the posterior pole and mid-periphery has been described
(Fig. 176.7).89 Toxicity due to chronic illicit abuse of
methoxyflurane has also been reported.90 Cotton wool spots,
large retinal crystals in a periarteriolar pattern, and crystals in
the RPE were clinically apparent. Histopathology has
demonstrated oxalate crystals in the inner retina and RPE, as
well as throughout the body.91
The relationship between retinal changes in methoxyflurane
toxicity and primary oxaluria is unknown. Both flecked retina
and crystalline retinopathy have been reported in primary
disease.92–95 Unlike methoxyflurane toxicity, pigmented patches
in the RPE have been described in primary oxaluria.
CISPLATIN
Cisplatin has been used for the treatment of malignant nervous
system tumors as well as metastatic breast cancer and is
commonly used in concert with other chemotherapeutic agents.
It binds directly to DNA to inhibit normal DNA functioning.
Nephrotoxicity, ototoxicity, and peripheral neuropathy are all
common. Transient blurred vision is also common in high-dose
intravenous infusion.96
The platinum in cisplatin is believed to cause direct retinal
toxicity when administered directly into the carotid artery.97–99 2217
 RETINA AND VITREOUS
FIGURE 176.7. Left eye of a patient with retinal oxalosis due to
SECTION 10
methoxyflurane anesthesia.
Photo courtesy of Daniel Albert, MD.
It has also been documented in an inadvertently high dose given
intravenously.100 These patients can develop a pigmentary
retinopathy with severe vision loss in the eye ipsilateral to the
carotid infusion.97,98 The a-wave is attenuated and the b-wave
is lost on electrophysiology. Histopathology reveals normal
photoreceptors, but a splitting of the outer plexiform layer,
which may explain the loss of the b-wave on ERG.100
Another form of retinopathy associated with cisplatin use
involves an ischemic maculopathy and optic neuropathy.97,99
Patients can present with arteriolar attenuation, cotton wool
spots, retinal hemorrhages, and macular exudates. Optic nerve
head edema may be present, and these patients can have
significant visual loss. Permanent vision loss may be due to
the optic nerve disease, as patients with only retinopathy
had improvement in both symptoms and signs.99 BCNU
(carmustine) may account for some of the toxicity, as it can
produce a similar retinopathy without concomitant cisplatin
treatment.97,101
INTERFERON
GENERAL INFORMATION
Interferon alpha is a common adjuvant in the treatment of
malignant melanoma as well as renal cell carcinoma,
lymphoma, and leukemia. Alone or in combination with
ribavirin, interferon is now the standard of care for treatment of
hepatitis C. An ischemic retinopathy can develop in patients
taking interferon, in some cases causing serious visual decline.
Many of the descriptions of interferon retinopathy are in the
Japanese language literature.102
CLINICAL FINDINGS
The earliest reports of interferon retinopathy in the English
literature were in cancer patients receiving combination chemo-
therapy.103 Patients developed common sequelae of retinal
ischemia, including capillary nonperfusion, cotton wool spots,
retinal hemorrhages, and occlusive disease (Fig. 176.8). Sub-
sequently, corroborating reports have described ischemic retino-
pathy in both cancer treatment and hepatitis C treatment.104–107
A similar retinopathy develops in patients undergoing treat-
ment for hepatitis C, suggesting that the pathophysiology is
2218 similar regardless of the underlying disease.104,106 Retinopathy
FIGURE 176.8. Left eye of a patient treated with interferon for
hepatitis C. Cotton wool spots are apparent.
begins within the first few months of therapy and the retinal
signs fade with cessation of interferon.103–110 Cystoid macular
edema has been reported and severe, permanent vision loss can
occur due to arteriolar occlusion.108,109 Retinal changes
commonly occur in asymptomatic patients, suggesting the need
for ophthalmologic screening concurrent with therapy.106,110
PATHOLOGY
Based on analysis of intravitreal interferon in the rabbit eye,
interferon retinopathy appears to have an immune-mediated
etiology.111 Complement pathway activation and immune
complex deposition may be the underlying cause.
DIDANOSINE
The 2„,3„ dideoxyinosine (didanosine) is an antiretroviral
medication used in the treatment of HIV. Pancreatitis and
peripheral neuropathy are well described complications.112 It
can cause peripheral RPE atrophy in children without changes
in central visual acuity.113–115 The toxicity appears to be dose
dependent and is common in the pediatric population (7.0%).113
Didanosine is also associated with visual field deficits in
adults.116 In a report of two cases, an annular scotoma occurred
in one patient and a mild increase in the physiologic blind spot
occurred in the other. Both patients had abnormal EOG (Arden
ratio < 1.6 in both eyes of both patients), suggesting diffuse
RPE dysfunction.
Histopathologic examination has revealed loss of the RPE
with surrounding hypertrophy or hypopigmentation.114 Partial
loss of the choriocapillaris and neurosensory retina were present
in the areas of RPE loss. Electron microscopy demonstrated
lamellar inclusion and cytoplasmic bodies in the RPE, sug-
gesting that the primary toxicity is at the level of the RPE.
NIACIN
GENERAL INFORMATION
Nicotinic acid (Niacin) is both a vitamin and a medication that
reduces cholesterol levels when ingested orally in large doses.117

It causes spectrum alterations in both lipid and cholesterol
metabolism and is relatively inexpensive. Common side effects,
such as flushing, rise in uric acid levels, and gastritis have
curtailed its use in exchange for other cholesterol reducing
medications.118 An extended-release formulation of nicotinic
acid (Niaspan) has been introduced as an alternative for
lowering of cholesterol levels.119 The side effect profile is
improved in comparison to Niacin, and no reports of macular
edema have been published.
CLINICAL FEATURES
Cystoid macular edema is a rare but well known complication
of high-dose niacin use and can be associated with blurred
vision.112–123 Most reports have documented CME associated a
dosage of 3 g/day, but CME has been reported with as little as
1.5 g/day.124 The clinical appearance of CME is similar to the
edema caused by numerous other etiologies, however no other
retinal changes are typically found with niacin maculopathy.
The edema rapidly improves after discontinuation of niacin
with resolution and improvement in vision commonly within
2 weeks.120–123
ANCILLARY TESTING
Fluoroscein angiography does not reveal any leakage.120–123
Thus, nicotinic acid maculopathy fits with retinitis pigmentosa
and Goldman–Favre disease as causes of ‘angiographically
negative’ cystoid macular edema. Optical coherence tomo-
graphy does, however, demonstrate cystoid spaces in the outer
plexiform layer.125 The author postulated that this finding con-
firms the cystic nature of the toxicity and makes other possible
etiologies, such as muller cell engorgement, less likely. Minor
disruptions in the blood-ocular barrier may cause leakage too
slow for fluoroscein angiography, but still result in edema.
CLOFAZIMINE
GENERAL INFORMATION
Clofazimine is one of a class of drugs known as rimino-
phenazines.126 This type of drug was developed for treatment of
Mycobacterium tuberculosis. They have since been tried in
other mycobacterial diseases, including Mycobacterium leprae
and Mycobacterium avium complex (MAC).127,128 Clofazimine
has been approved by the World Health Organization for the
treatment of leprosy and in particular dapsone-resistant cases.
It is currently under increased study for use in multidrug
resistant tuberculosis as well as systemic or discoid lupus
erythematosus.129,130
CLINICAL FEATURES
The most common side-effect is a brownish discoloration of the
skin that occurs in 75–100% of patients after a few weeks of
treatment. It also causes brownish discoloration of the
conjunctiva, tears, and thin superficial lines in the cornea.131,132
There are only a few brief reports of pigmentary retinal changes
in patients with leprosy treated with clofazimine.132–134 There
are three reports of a bull’s eye type of retinopathy in patients
treated with clofazimine.135–137 All of these occurred in HIV
positive individuals. At least one eye in these patients had
evidence of an infectious retinitis. All of the patients died
within months of the detection of the retinopathy and there was
no pathologic specimen obtained. Patients that are HIV positive
and treated with clofazimine may have an increased risk for
retinal toxicity and should be monitored. There are other
Retinal Toxicity of Systemic Medications
riminophenazines being studied now as possible new agents for
use in leprosy and tuberculosis.126
ANCILLARY TESTING
The angiogram in the above mentioned HIV patients shows an
annular area of RPE depigmentation in the macula. Electro-
retinography shows a decrease in the amplitude of the b-wave
under both scotopic and photopic conditions. There is also a
delay in the implicit time.135,136
PATHOPHYSIOLOGY
Riminophenazines accumulate in the intracellular space of
mononuclear phagocytic cells and also in adipose tissue. The
mechanism of injury to the RPE or retina is unknown. In two
of the well documented cases, the patients received more than
40 g total of clofazimine. The dosage used was 200 mg/day in
CHAPTER 176
one patient and 300 mg/day in the other.135,136
DEFEROXAMINE
GENERAL INFORMATION
This drug is most commonly used for treatment of
hemosiderosis. Excessive levels of iron can lead to cardiac
failure; so the treatment is often life-saving. The most common
predisposing factor is repetitive blood transfusions in patients
with thalassemia or aplastic anemia.138–141 The drug chelates or
binds copper, iron, aluminum, and zinc. The iron present in
normal hemoglobin is not chelated. Patients with renal failure
and high aluminum levels are also sometimes treated with
deferoxamine.142,143 Deferoxamine can be given subcutaneously,
intramuscularly, or sometimes intravenously.
CLINICAL FEATURES
Patients present with an acute onset of decreased vision,
nyctalopia, ring scotoma, or color vision abnormalities as early
as 7–10 days after treatment.144–148 Patients can also develop
symptoms after several months of treatment. The fundus may
appear normal initially, but later develops a salt and pepper-like
RPE abnormality (Fig. 176.9). Haimovici et al and Gass have
reported a loss of transparency or opacification of the outer
retina and RPE in the early stages of toxicity.144,149 This is
FIGURE 176.9. Right eye of patient with aplastic anemia. After
receiving multiple transfusions, the patient developed hemosiderosis
treated with deferoxamine. Mottling of the RPE is shown. 2219
 RETINA AND VITREOUS
accompanied by late hyperfluorescent staining in the macula.
This then progresses to RPE hypopigmentation and mottling on
the angiogram and a decrease in the late hyperfluorescence.
Haimovici also reported patients with peripapillary, papillo-
macular, and paramacular changes similar to those described
above. Gonzalez and co-workers reported two patients treated
with deferoxamine who presented with vitelliform lesions.150 It
is not known whether the vitelliform lesions were present prior
to treatment with deferoxamine. Both patients were 70 years
old so a preexisting condition can not be ruled out. Neither
patient improved after discontinuation of deferoxamine. One of
the patients had an abnormal ERG and showed more typical
RPE mottling 1 year after the drug was stopped. Patients can
also develop a high-frequency sensorineural hearing loss.146,147
The visual symptoms and hearing loss often diminish when
the drug is stopped, but not all patients fully recover. Optic
neuropathy has been reported as well.144,145,147,151
SECTION 10
ANCILLARY TESTING
The ERG is often abnormal with increased implicit times and
a- and b-wave diminution under either scotopic or photopic
conditions.144,152,153 The EOG shows a reduced light peak to
dark trough or Arden ratio. The EOG may serve as an early
detector of toxicity or monitoring test.153 An audiogram often
shows high-frequency loss.146,147 The ERG and EOG changes
can also improve following discontinuation of deferoxamine.
PATHOPHYSIOLOGY
Light and electron microscopy evaluation of the eyes from a
patient with deferoxamine toxicity showed RPE degeneration.154
The patient had decreased vision and a subnormal EOG. The
changes in the RPE included loss of microvilli from the apical
surface, patchy depigmentation, vacuolation of the cytoplasm,
and swelling with calcification of mitochondria. Bruch’s mem-
brane overlying these degenerated RPE cells was abnormally
thickened with accumulation of elastic fibers and collagen. At
least two teams of investigators have suggested that deferoxamine
may increase the transport of copper, out of cells and raise the
extracellular concentration of copper.151,155 Measurements of
copper levels in the cerebrospinal fluid of a few patients are
compatible with this hypothesis. A model of deferoxamine
toxicity in the albino rat demonstrated increased toxicity with
light and oxygen exposure.156 This was postulated to be related
to increased free radical production. There is no further
evidence to support this hypothesis. The exact cause of the RPE
toxicity from deferoxamine remains unknown. It may be a
direct effect of the drug or a secondary effect from chelation of
divalent metal ions. One study in albino rats showed a
reduction in toxicity as measured by electrophysiology when it
was conjugated with hydroxyethyl starch.157 There are at least
two new agents, deferiprone and deferasirox, under study as
replacements for deferoxamine or as combination therapy.138,139
The use of these chelating agents is necessary to prevent the
dire consequences of iron overload. It is hoped that their side
effects can be minimized. Any patient treated with deferoxamine
should be carefully monitored for visual changes.
METHANOL
GENERAL INFORMATION
Methanol toxicity is commonly due to accidental poisoning in
alcoholics. Improper distillation allows for methanol formation
as well as ethanol. Inhalation and skin contact can also induce
2220
methanol toxicity. When methanol is ingested, an anion gap
metabolic acidosis occurs with acute renal failure. Fomepizole is
a competitive alcohol dehydrogenase inhibitor with demonstrated
efficacy in methanol poisoning.158 Electophysiologic testing sug-
gests that it benefits retinal toxicity as well as systemic toxicity.159
CLINICAL FEATURES
Patients develop blurred vision and scotomata within hours of
ingestion.160,161 Optic nerve hyperemia and posterior retinal
edema are present. If the toxicity is not reversed, permanent
vision loss and optic atrophy ensue.
PATHOPHYSIOLOGY
Methanol metabolizes into formic acid, which is the cause of
the neurotoxicity.162,163 It is a mitochondrial toxin that causes
direct damage to the ganglion cells and optic nerve. Electro-
physiologic and histopathologic examinations have suggested a
direct effect to the RPE as well as the neurosensory retina.
QUININE
Quinine is an antimalarial now used in the treatment of muscle
cramps and restless leg syndrome. It is the active ingredient in
tonic water, which was used by sailors as a malaria prophylactic.
Toxicity can be both acute and chronic.164–167
The syndrome of acute toxicity is known as cinchonism,
from the natural source of quinine – the cinchona bark.
Cinchonism consists of headache, dizziness, hearing loss,
nausea, and tremor.168 The pupils can be poorly responsive
during unconsciousness, and vermiform movements of the
pupils have been described.166 Patients can lose consciousness
and, if they survive, awake blind. While vision may return,
patients may be left with permanent, severe visual field con-
striction. During the acute phase, the retinal arterioles can be
normal with mild venous distention. Within weeks to months,
the arterioles become severely constricted and the optic nerve
becomes atrophic.
There has been some debate regarding the mechanism of
retinal toxicity. The classic theory included ischemia due to
vascular constriction.165–167 More recent studies have suggested
a direct retinal toxicity, however.165–169 Electrophysiology,
including ERG, EOG, and VEP, can be abnormal in the acute
phase of toxicity, and ERG and histopathology are suggestive of
diffuse damage to neurosensory retina. Even without signs of
quinine toxicity, ERG demonstrates a transient decrease in
photoreceptor function at therapeutic doses.170
Despite the evidence of direct retinal toxicity, recent reports
have proposed the treatment of blindness due to cinchonism
with vasodilating agents.171 The results have not been tested in
comparative trials.
ANTIEPILEPTICS
VIGABATRIN
Vigabatrin is an irreversible inhibitor of GABA transaminase
used in the treatment of pediatric and adult seizures.172,173 It is
known to cause visual field defects at therapeutic doses.174–176
The peripheral retina can be atrophic and the optic disk can
exhibit nasal or diffuse pallor.177,178 The visual loss can be
transient or permanent. Toxicity can occur within the first few
years of therapy. Although a dose dependent toxicity was found
in one study, no dose response or risk factors for retinopathy
were found in another.179,180

Visual field changes can be asymptomatic, and, in children,
accurate peripheral visual testing can be dfficult.181 ERG, EOG,
and VEP changes correlate with the visual field changes,
however, and can be used for routine evaluation.182–184 Reduc-
tions in the cone b-wave and oscillatory potentials are well
documented.
REFERENCES
1. Meredith TA, Aaberg TM, Willerson WD:
Progressive chorioretinopathy after receiving
thioridazine. Arch Ophthalmol 1978; 96:1172.
2. Hamilton JD: Thioridazine retinopathy
within the upper dosage limit.
Psychosomatics 1985; 26:823.
3. Weekley RD, Potts AM, Reboton J, et al:
Pigmentary retinopathy in patients receiving
high doses of a new phenothiazine. Arch
Ophthalmol 1960; 64:65.
4. Connell MM, Poley BJ, McFarlane JR:
Chorioretinopathy associated with
thioridazine therapy. Arch Ophthalmol
1964; 71:816.
5. Siddall, JR: The ocular toxic findings with
prolonged and high dosage chlopromazine
intake. Arch Ophthalmol 1965; 74:460.
6. Marmor MF: Is thioridazine retinopathy
progressive? Relationship of pigmentary
changes to visual function. Br J
Ophthalmol 1990; 74:739.
7. Miyata M, Imai H, Ishikawa S, et al:
Changes in human electroretinography
associated with thioridazine administration.
Ophthalmologica 1980; 181:175.
8. Goar EL, Fletcher MC: Toxic
chorioretinopathy following the use of
NP 207. Trans Am Ophthalmol Soc 1956;
54:129.
9. Miller, FS III, Bunt-Millam AH, Kalina RE:
Clinical-ultrastructural study of thioridazine
retinopathy. Ophthalmology 1982; 89:1478
10. Potts AM: The concentration of
phenothiazines in the eye of experimental
animals. Invest Ophthalmol 1962; 1:522.
11. Potts AM: Further studies concerning the
accumulation of polycyclic compounds on
uveal melanin. Invest Ophthalmol 1964;
3:399.
12. Potts AM: The reaction of uveal pigment in
vitro with polycyclic compounds. Invest
Ophthalmol 1964; 3:405.
13. Fornaro P, Calabria G, Corallo G, Picotti GB:
Pathogenesis of degenerative retinopathies
induced by thioridazine and other
antipsychotics: a dopamine hypothesis.
Doc Ophthalmol 2002; 105:41.
14. DeLong SL, Poley BJ, McFarlane JR:
Ocular changes associated with long-term
chlorpromazine therapy. Arch Ophthalmol
1965; 73:611.
15. Siddal JR: The ocular toxic findings with
prolonged and high dosage chlorpromazine
intake. Arch Ophthalmol 1965; 74:460.
16. Oshika T: Ocular adverse effects of
neuropsychiatric agents: incidence and
management. Drug Safety 1995; 12:256.
17. Zelickson AS, Zeller HC: A new and
unusual reaction to chlorpromazine. JAMA
1964; 188:394.
18. Cambiaggi A: Unusual ocular lesions in a
case of systemic lupus erythematosus.
Arch Ophthalmol 1957; 57:451.
19. Tobin DR, Krohel GB, Rynes RL:
Hydroxychloroquine: seven-year
experience. Arch Ophthalmol 1982; 100:81.
Retinal Toxicity of Systemic Medications
LAMOTRIGINE
Lamotrigine is another antileptic with documented changes
in electrophysiology.185 No clear cases of toxicity have been
identified, but one patient on high-dose lamotrigine therapy had
transient visual field changes.
20. Mackenzie AH: Dose refinements in long-
term therapy of rheumatoid arthritis with
antimalarials. Am J Med 1983; 75:40.
21. Ochsendorf FR, Runne U: Chloroquine:
consideration of maximum daily dose
(3.5 mg/kg ideal weight) prevents
retinopathy. Dermatology 1996; 192:382.
22. Mackenzie AH, Scherbel AL: A decade of
chloroquine maintenance therapy: rate of
administration governs incidence of
retinotoxicity. Arthritis Rheum 1968; 11:496.
23. Weiner A, Sandberg MA, Gaudio AR, et al:
Hydroxychloroquine retinopathy. Am J
Ophthalmol 1991; 112:528.
24. Coyle JT: Hydroxychloroquine retinopathy.
Ophthalmology 2001; 108:243.
25. Levy GD, Munz SJ, Paschal J, et al:
Incidence of hydroxychloroquine
retinopathy in 1207 patients in a large
multicenter outpatient practice. Arthritis
Rheum 1997; 40:1482.
26. Mavrikakis M, Papazoglou S, Sfikakis PP,
et al: Retinal toxicity in long-term
hydroxychloroquine treatment. Ann Rheum
Dis 1996; 55:187.
27. Mavrikakis I, Sfikakis PP, Mavrikakis E, et al:
The incidence of irreversible retinal toxicity
in patients treated with hydroxychloroquine:
a reappraisal. Ophthalmology 2003;
110:1321.
28. Johnson MW, Vine AK: Hydroxychloroquine
therapy in massive total doses without
retinal toxicity. Am J Ophthalmol 1987;
104:139.
29. Bernstein HN: Ophthalmic considerations
and testing in patients receiving long-term
antimalarial therapy. Am J Med 1983;
75:25.
30. Henkind P, Carr RE, Siegel IM: Early
chloroquine retinopathy: clinical and
functional findings. Arch Ophthalmol 1964;
71:157.
31. Easterbrook M: Chloroquine retinopathy.
Arch. Ophthalmol 1991; 109:1362.
32. Michael F M, Carr RE, Easterbrook M, et al:
Mieler and American Academy of
Ophthalmology: recommendations on
screening for chloroquine and
hydroxychloroquine retinopathy: a report by
the American Academy of Ophthalmology.
Ophthalmology 2002; 109:1377.
33. Easterbrook M: Ocular effects and safety of
antimalarial agents. Am J Med 1988; 85:23.
34. Carr RE, Henkind P, Rothfield N, Siegel IM:
Ocular toxicity of antimalarial drugs. Long-
term follow-up. Am J Ophthalmol 1968;
66:738.
35. Vu BL, Easterbrook M, Hovis JK: Detection
of color vision defects in chloroquine
retinopathy. Ophthalmology 1999; 106:1799.
36. Easterbrook M: The use of Amsler grids in
early chloroquine retinopathy.
Ophthalmology 1984; 91:1368.
37. Easterbrook M: The sensitivity of Amsler
grid testing in early chloroquine retinopathy.
Trans Ophthalmol Soc UK 1985; 104:204.
38. Almony A, Garg S, Peters RK, et al:
Threshold Amsler grid as a screening tool
for asymptomatic patients on
Hydroxychloroquine therapy. Br J
Ophthalmol 2005; 89:569.
39. Pluenneke AC, Blomquist PH: Utility of red
amsler grid screening in a rheumatology
clinic. J Rheumatol 2004; 31:1754.
40. Hart WM Jr, Burde RM, Johnston GP,
CHAPTER 176
Drews RC: Static perimetry in chloroquine
retinopathy. Perifoveal patterns of visual
field depression. Arch Ophthalmol 1984;
102:377.
41. Easterbrook M, Trope G: Value of
Humphrey perimetry in the detection of
early chloroquine retinopathy. Lens Eye
Toxic Res 1989; 6:255.
42. Arden GB, Friedmann A, Kolb H:
Anticipation of chloroquine retinopathy.
Lancet 1962; 1:1164.
43. Kolb H: Electro-oculogram findings in
patients treated with antimalarial drugs.
Br J Ophthalmol 1965; 49:573.
44. Reijmer CN, Tijssen JG, Kok GA,
van Lith GH: Interpretation of the electro-
oculogram of patients taking chloroquine.
Doc Ophthalmol 1980; 48:273.
45. Neubauer AS, Samari-Kermani K, Schaller U,
et al: Detecting chloroquine retinopathy:
electro-oculogram versus colour vision.
Br J Ophthalmol 2003; 87:902.
46. So SC, Hedges TR, Schuman JS,
Quireza ML: Evaluation of
hydroxychloroquine retinopathy with
multifocal electroretinography. Ophthalmic
Surg Lasers Imaging 2003; 34:251.
47. Lai TY, Chan WM, Li H, et al: Multifocal
electroretinographic changes in patients
receiving hydroxychloroquine therapy. Am J
Ophthalmol 2005; 140:794.
48. Teoh SC, Lim J, Koh A, et al: Abnormalities
on the multifocal electroretinogram may
precede clinical signs of
hydroxychloroquine retino-toxicity. Eye
2006; 20:129.
49. Maturi RK, Yu M, Weleber RG: Multifocal
electroretinographic evaluation of long-term
hydroxychloroquine users. Arch
Ophthalmol 2004; 122:973.
50. Bernstein H, Zvaifler N, Rubin M, et al:
The ocular deposition of chloroquine.
Invest Ophthalmol 1963; 2:384.
51. Mahon GJ, Anderson HR, Gardiner TA, et al:
Chloroquine causes lysosomal dysfunction
in neural retina and RPE: implications for
retinopathy. Curr Eye Res. 2004; 28:277.
52. Sundelin SP, Terman A: Different effects of
chloroquine and hydroxychloroquine on
lysosomal function in cultured retinal
pigment epithelial cells. APMIS 2002;
110:481.
53. Duncker G, Schmiederer M, Bredehorn T:
Chloroquine-induced lipidosis in the rat
retina: a functional and morphological
study. Ophthalmologica 1995;
209:79. 2221
 RETINA AND VITREOUS
54. Duncker G, Bredehorn T: Chloroquine-
induced lipidosis in the rat retina: functional
and morphological changes after
withdrawal of the drug. Graefes Arch Clin
Exp Ophthalmol 1996; 234:378.
55. Atlee WE: Talc and cornstarch emboli in
eyes of drug users. JAMA 1972; 219:49.
56. Tse DT, Ober RR: Talc retinopathy. Am J
Ophthalmol 1980; 90:624.
57. Schatz H, Drake M: Self-injected retinal
emboli. Ophthalmology 1979; 86:468.
58. Brucker AJ: Disk and peripheral retinal
neovascularization secondary to talc and
cornstarch emboli. Am J Ophthalmol 1979;
88:864.
59. Friberg TR, Gragoudas ES, Regan CDJ:
Talc emboli and macular ischemia in
intravenous drug abuse. Arch Ophthalmol
1979; 97:1089.
60. Sharma MC, Ho AC: Macular fibrosis
associated with talc retinopathy. Am J
SECTION 10
Ophthalmol 1999; 128:517.
61. Jampol LM, Setogawa T, Rednam KRV, et al:
Talc retinopathy in primates: a model of
ischemic retinopathy. I. Clinical studies.
Arch Ophthalmol 1981; 99:1273.
62. Kaga N, Tso MOM, Jampol LM, et al: Talc
retinopathy in primates: a model of
ischemic retinopathy. II. A histopathologic
study. Arch Ophthalmol 1982; 100:1644.
63. Kaga N, Tso MOM, Jampol LM: Talc
retinopathy in primates: a model of
ischemic retinopathy. III. An electron
microscopic study. Arch Ophthalmol 1982;
100:1649.
64. Hanscom TA: Indirect treatment of
peripheral retinal neovascularization. Am J
Ophthalmol 1982; 93:88.
65. Pavlidis NA, Petris C, Briassoulis E, et al:
Clear evidence that long-term, low-dose
tamoxifen treatment can induce ocular
toxicity. A prospective study of 63 patients.
Cancer 1992; 69:2961.
66. Chang T, Gonder JR, Ventresca MR: Low-
dose tamoxifen retinopathy. Can J
Ophthalmol 1992; 27:148.
67. Noureddin BN, Seoud M, Bashshur Z, et al:
Ocular toxicity in low-dose tamoxifen: a
prospective study. Eye 1999; 13:729.
68. Kaiser-Kupfer MI, Lippman ME: Tamoxifen
retinopathy. Cancer Treat Rep 1978;
62:315.
69. Kaiser-Kupfer MI, Kupfer C, Rodrigues MM:
Tamoxifen retinopathy. A clinicopathologic
report. Ophthalmology 1981; 88:89.
70. Heier JS, Dragoo RA, Enzenauer RW, et al:
Screening for ocular toxicity in
asymptomatic patients treated with
tamoxifen. Am J Ophthalmol 1994;
117:772.
71. Noureddin BN, Seoud M, Bashshur Z, et al:
Ocular toxicity in low-dose tamoxifen: a
prospective study. Eye 1999; 13:729.
72. Ashford AR, Donev I, Tiwari RP, et al:
Reversible ocular toxicity related to
tamoxifen therapy. Cancer 1988; 61:33.
73. McKeown CA, Swartz M, Blom J, et al:
Tamoxifen retinopathy. Br J Ophthalmol
1981; 65:177.
74. Martine MF, Joel G, Maddalena QE: Optical
coherence tomography in tamoxifen
retinopathy. Breast Cancer Res Treat 2006;
99:117.
75. Sharkey JA: Idiopathic canthaxanthine
retinopathy. Eur J Ophthalmol 1993; 3:226.
76. Cortin P, Corriveau LA, Rooseau AP, et al:
Maculopathie en pailletes d’or. Can J
2222 Ophthalmol. 1982; 17:103–106.
77. Boudreault G, Cortin P, Corriveau LA, et al:
La rétinopathie à la canthaxanthine. I.
Etude clinique de 51 consommateurs.
Can J Ophthalmol 1983; 18:325
78. Cortin P, Boudreault G, Rousseau AP, et al:
La rétinopathie à la canthaxanthine. 2.
Facteurs prédisposants. Can J Ophthalmol
1984; 19:215.
79. Metge P, Mandirac-Bonnefoy C, Bellaube P:
Thésaurismose rétinienne à la
canthaxanthine. Bull Mem Soc Fr
Ophtalmol 1984; 95:547.
80. Ros AM, Leyon H, Wennersten G:
Crystalline retinopathy in patients taking an
oral drug containing canthaxanthine.
Photodermatol 1985; 2:183.
81. Lonn LI: Canthaxanthin retinopathy. Arch
Ophthalmol 1987; 105:1590.
82. Harnois C, Samson J, Malenfant M, et al:
Canthaxanthine retinopathy: anatomic and
functional reversibility. Arch Ophthalmol
1989; 107:538.
83. Harnois C, Cortin P, Samson J, et al:
Static perimetry in canthaxanthin
maculopathy. Arch Ophthalmol 1988;
106:58.
84. Goralczyk R, Barker FM, Buser S, et al:
Dose dependency of canthaxanthin
crystals in monkey retina and spatial
distribution of its metabolites. Invest
Ophthalmol Vis Sci 2000; 41:1513.
85. Weber U, Kern W, Novotny GE, et al:
Experimental carotenoid retinopathy. I.
Functional and morphological alterations of
the rabbit retina after 11 months dietary
carotenoid application. Graefes Arch Clin
Exp Ophthalmol 1987; 225:198.
86. Weber U, Michaelis L, Kern W, Goerz G:
Experimental carotenoid retinopathy. II.
Functional and morphological alterations
of the rabbit retina after acute
canthaxanthin application with small
unilamellar phospholipid liposomes.
Graefes Arch Clin Exp Ophthalmol 1987;
225:346.
87. Arden GB, Oluwole JO, Polkinghorne P,
et al: Monitoring of patients taking
canthaxanthin and carotene: an
electroretinographic and ophthalmological
survey. Hum Toxicol 1989; 8:439.
88. Daicker B, Schiedt K, Adnet JJ,
Bermond P: Canthaxanthin retinopathy.
An investigation by light and electron
microscopy and physicochemical analysis.
Graefes Arch Clin Exp Ophthalmol 1987;
225:189.
89. Bullock JD, Albert DM: Fleck retina:
appearance secondary to oxalate crystals
from methoxyflurane anesthesia. Arch
Ophthalmol 1975; 93:26.
90. Novak MA, Roth AS, Levine MR: Calcium
oxalate retinopathy associated with
methoxyflurane abuse. Retina 1988; 8:230.
91. Albert DM, Bullock JD, Lahav M, et al:
Flecked retina secondary to oxalate
crystals from methoxyflurane anesthesia:
clinical and experimental studies. Trans Am
Acad Ophthalmol Otolaryngol 1975; 79:817.
92. Wells CG, Johnson RJ, Qingli L, et al:
Retinal oxalosis: a clinicopathological
report. Arch Ophthalmol 1989; 107:1638.
93. Meredith TA, Wright JD, Gammon JA, et al:
Ocular involvement in primary
hyperoxaluria. Arch Ophthalmol 1984;
102:584.
94. Fielder AR, Garner A, Chambers TL:
Ophthalmic manifestations of primary
oxalosis. Br J Ophthalmol 1980; 64:782.
95. Zak TA, Buncic R: Primary hereditary
oxalosis retinopathy. Arch Ophthalmol
1983; 101:78.
96. Wilding G, Caruso R, Lawrence TS, et al:
Retinal toxicity after high-dose cisplatin
therapy. J Clin Oncol 1985; 3:1683.
97. Miller DF, Bay JW, Lederman RJ, et al:
Ocular and orbital toxicity following
intracarotid injection of BCNU (carmustine)
and cisplatinum for malignant gliomas.
Ophthalmology 1985; 92:402.
98. Kupersmith MJ, Seiple WH, Holopigian K,
et al: Maculopathy caused by intra-
arterially administered cisplatin and
intravenously administered carmustine.
Am J Ophthalmol 1992; 113:435.
99. Khawly JA, Rubin P, Petros W, et al:
Retinopathy and optic neuropathy in bone
marrow transplantation for breast cancer.
Ophthalmology 1996; 103:87.
100. Katz BJ, Ward JH, Digre KB, et al:
Persistent severe visual and
electroretinographic abnormalities after
intravenous cisplatin therapy.
J Neuroophthalmol 2003; 23:132.
101. Shingleton BJ, Bienfang DC, Albert DM,
et al: Ocular toxicity associated with high-
dose carmustine. Arch Ophthalmol 1982;
100:1766.
102. Hayasaka S, Nagaki Y, Matsumoto M,
Sato S: Interferon associated retinopathy.
Br J Ophthalmol 1998; 82:323.
103. Guyer DR, Tiedeman J, Yannuzzi LA, et al:
Interferon-associated retinopathy. Arch
Ophthalmol 1993; 111:350.
104. Kawano T, Shegehira M, Uto H, et al:
Retinal complications during interferon
therapy for chronic hepatitis C. Am J
Gastroenterol 1996; 91:309.
105. Schulman JA, Liang C, Kooragayala LM,
et al: Posterior segment complications in
patients with hepatitis C treated with
interferon and ribavirin. Ophthalmology
2003; 110:437.
106. Esmaeli B, Koller C, Papadopoulos N,
Romaguera J: Interferon-induced
retinopathy in asymptomatic cancer
patients. Ophthalmology 2001;
108:858.
107. Hejny C, Sternberg P, Lawson DH, et al:
Retinopathy associated with high-dose
interferon alfa-2b therapy. Am J
Ophthalmol 2001; 131:782.
108. Tokai R, Ikeda T, Miyaura T, et al:
Interferon-associated retinopathy and
cystoid macular edema. Arch Ophthalmol
2001; 119:1077.
109. Kiratli H, Irkee M: Presumed interferon-
associated bilateral macular arterial branch
obstruction. Eye 2000; 14:920.
110. Jain K, Lam WC, Waheeb S, et al:
Retinopathy in chronic hepatitis C patients
during interferon treatment with ribavirin.
Br J Ophthalmol 2001 85:1171.
111. Kertes PJ, Britton WA, Addison DJ, et al:
Toxicity of intravitreal interferon alpha-2b
in the rabbit. Can J Ophthalmol 1995;
30:355.
112. Perry CM, Balfour JA: Didanosine. An
update on its antiviral activity,
pharmacokinetic properties and therapeutic
efficacy in the management of HIV disease.
Drugs 1996; 52:928.
113. Whitcup SM, Butler KM, Caruso R, et al:
Retinal toxicity in human immunodeficiency
virus-infected children treated with 2„,3„-
dideoxyinosine. Am J Ophthalmol 1992;
113:1.

114. Whitcup SM, Butler KM, Pizzo PA,
Nussenblatt RB: Retinal lesions in children
treated with dideoxyinosine. N Engl J Med
1992; 326:1226.
115. Whitcup SM, Dastgheib K, Nussenblatt RB,
et al: A clinicopathologic report of the
retinal lesions associated with didanosine.
Arch Ophthalmol 1994; 112:1594.
116. Cobo J, Ruiz MF, Figueroa MS, et al:
Retinal toxicity associated with
didanosine in HIV-infected adults. AIDS
1996; 10:1297.
117. Parsons WB Jr, Flinn JH: Reduction in
elevated blood cholesterol levels by large
doses of nicotinic acid: preliminary report.
JAMA 1957; 165:234.
118. Carlson LA: Nicotinic acid: the broad-
spectrum lipid drug. A 50th anniversary
review. J Intern Med 2005; 258:94.
119. Capuzzi DM, Guyton JR, Morgan JM, et al:
Efficacy and safety of an extended-release
niacin (Niaspan): a long-term study. Am J
Cardiol 1998 82:74U.
120. Gass JDM: Nicotinic acid maculopathy.
Am J Ophthalmol 1973; 76:500.
121. Millay RH, Klein ML, Illingworth DR:
Niacin maculopathy. Ophthalmology 1988;
95:930.
122. Jampol LM: Niacin maculopathy.
Ophthalmology 1988; 95:1704.
123. Callanan D, Blodi BA, Martin DF: Macular
edema associated with nicotinic acid
(niacin). JAMA 1998; 279:1702.
124. Fraunfelder FW: Ocular side effects from
herbal medicines and nutritional
supplements. Am J Ophthalmol 2004;
138:639.
125. Spirn MJ, Warren FA, Guyer DR, et al:
Optical coherence tomography findings in
nicotinic acid maculopathy. Am J
Ophthalmol 2003; 135:913.
126. Reddy VM, O’Sullivan JF, Gangadharam
PR: Antimycobacterial activities of
riminophenazines. J Antimicrob Chemother
1999; 43:615.
127. Biswas SK: Chemotherapy of leprosy.
J Indian Med Assoc 2004; 102:695.
128. Tomioka H: Present status and future
prospects of chemotherapeutics for
intractable infections due to
Mycobacterium avium complex. Curr Drug
Discov Technol 2004; 1:255.
129. Bezerra EL, Vilar MJ, da Trindade Neto PB,
Sato EI: Double-blind, randomized,
controlled clinical trial of clofazimine
compared with chloroquine in patients with
systemic lupus erythematosus. Arthritis
Rheum 2005; 52:3073.
130. Schraufnagel DE: Tuberculosis treatment
for the beginning of the next century. Int J
Tuberc Lung Dis 1999; 3:651.
131. Kaur I, Ram J, Kumar B, et al: Effect of
clofazimine on eye in multibacillary leprosy.
Indian J Lepr 1990; 62:87.
132. Walinder PE, Gip L, Stempa M: Corneal
changes in patients treated with
clofazimine. Br J Ophthalmol 1976; 60:526.
133. Ohman L, Wahlberg I: Letter: ocular side-
effects of clofazimine. Lancet 1975; 2:933.
134. Yawalkar SJ, Vischer W: Lamprene
(clofazimine) in leprosy. Basic information.
Lepr Rev 1979; 50:135.
135. Craythorn JM, Swartz M, Creel DJ:
Clofazimine-induced bull’s eye retinopathy.
Retina 1986; 6:50.
136. Cunningham CA, Friedberg DW, Carr RG:
Clofazimine-induced generalized retinal
degeneration. Retina 1990; 10:131.
Retinal Toxicity of Systemic Medications
137. Forster DJ, Causey DM, Rao NA: Bull’s eye
retinopathy and clofazimine. Ann Intern
Med 1992; 116:876.
138. Greenberg PL: Myelodysplastic syndromes:
iron overload consequences and current
chelating therapies. J Natl Compr Canc
Netw 2006; 4:91.
139. Kattamis A, Ladis V, Berdousi H, et al: Iron
chelation treatment with combined
therapy with deferiprone and
deferioxamine: a 12-month trial. Blood
Cells Mol Dis 2006; 36:21.
140. Pippard MJ: Iron metabolism and iron
chelation in the thalassaemia disorders.
Haematologica 1990; 75(Suppl 5):66.
141. Silliman CC, Peterson VM, Mellman DL,
et al: Iron chelation by deferoxamine in
sickle cell patients with severe transfusion-
induced hemosiderosis: a randomized,
double-blind study of the dose-response
relationship. J Lab Clin Med 1993; 122:48.
142. Simon P, Ang KS, Cam G, et al:
Desferrioxamine, aluminium, and dialysis.
Lancet 1983; 2:1489.
143. Yokel RA, Ackrill P, Burgess E, et al:
Prevention and treatment of aluminum
toxicity including chelation therapy: status
and research needs. J Toxicol Environ
Health 1996; 48:667.
144. Haimovici R, D’Amico DJ, Gragoudas ES,
Sokol S: The expanded clinical spectrum of
deferoxamine retinopathy. Ophthal 2002;
109:164.
145. Lakhanpal V, Schocket SS, Jiji R:
Deferoxamine (Desferal)-induced toxic
retinal pigmentary degeneration and
presumed optic neuropathy.
Ophthalmology 1984; 91:443.
146. Olivieri NF, Buncic JR, Chew E, et al: Visual
and auditory neurotoxicity in patients
receiving subcutaneous deferoxamine
infusions. N Engl J Med 1986; 314:869.
147. Orton RB, de Veber LL, Sulh HM: Ocular
and auditory toxicity of long-term, high-
dose subcutaneous deferoxamine therapy.
Can J Ophthalmol 1985; 20:153.
148. Rubinstein M, Dupont P, Doppee JP, et al:
Ocular toxicity of desferrioxamine. Lancet
1985; 1:817.
149. Gass JDM: Stereoscopic atlas of macular
diseases: diagnosis and treatment. 4th edn.
Mosby, St Louis; 1997.
150. Gonzales CR, Lin AP, Engstrom RE,
Kreiger AE: Bilateral vitelliform maculopathy
and deferoxamine toxicity. Retina 2004;
24:464.
151. Blake DR, Winyard P, Lunec J, et al:
Cerebral and ocular toxicity induced by
desferrioxamine. Q J Med 1985; 56:345.
152. Arden GB, Wonke B, Kennedy C,
Huehns ER: Ocular changes in patients
undergoing long-term desferrioxamine
treatment. Br J Ophthalmol 1984; 68:873.
153. Hidajat RR, McLay JL, Goode DH,
Spearing RL: EOG as a monitor of
desferrioxamine retinal toxicity. Doc
Ophthalmol 2004; 109:273.
154. Rahi AH, Hungerford JL, Ahmed AI: Ocular
toxicity of desferrioxamine: light
microscopic histochemical and
ultrastructural findings. Br J Ophthalmol
1986; 70:373.
155. Pall H, Blake DR, Winyard P, et al: Ocular
toxicity of desferrioxamine – an example of
copper promoted auto-oxidative damage?
Br J Ophthalmol 1989; 73:42.
156. Good PA, Claxson A, Morris CJ, Blake DR:
A model for desferrioxamine-induced
retinopathy using the albino rat.
Ophthalmologica 1990; 201:32.
157. Gehlbach PL, Purple RL, Hallaway PE,
Hedlund BE: Polymer conjugation reduces
deferoxamine induced retinopathy in an
albino rat model. Invest Ophthalmol Vis Sci
1993; 34:2871.
158. Megarbane B, Borron SW, Trout H, et al:
Treatment of acute methanol poisoning
with fomepizole. Intensive Care Med 2001;
27:1370.
159. Essama Mbia JJ, Guerit JM, Haufroid V,
Hantson P: Fomepizole therapy for reversal
of visual impairment after methanol
poisoning: a case documented by visual
evoked potentials investigation. Am J
Ophthalmol 2002; 134:914.
160. Krolman GM, Pidde WJ: Acute methyl
alchohol poisoning. Can J Ophthalmol
1968; 3:270.
CHAPTER 176
161. Ingemansson SO: Clinical observations on
ten cases of methanol poisoning. Acta
Ophthalmol 1984; 62:15.
162. Murray TG, Burton TC, Rajani C, et al:
Methanol poisoning. A rodent model with
structural and functional evidence for
retinal involvement. Arch Ophthalmol 1991;
109:1012.
163. Treichel JL, Murray TG, Lewandowski MF,
et al: Retinal toxicity in methanol poisoning.
Retina 2004; 24:309.
164. Horgan SE, Williams RW: Chronic retinal
toxicity due to quinine in Indian tonic water.
Eye 1995; 9:637.
165. Bacon P, Spalton DJ, Smith SE: Blindness
from quinine toxicity. Br J Ophthalmol
1988; 72:219.
166. Canning CR, Hague S: Ocular quinine
toxicity. Br J Ophthalmol 1988; 72:23.
167. Brinton GS, Norton EW, Zahn JR,
Knighton RW: Ocular quinine toxicity. Am J
Ophthalmol 1980; 90:403.
168. Wolf LR, Otten EJ, Spadafora MP:
Cinchonism: two case reports and review
of acute quinine toxicity and treatment.
J Emerg Med 1992; 295.
169. Buchanan TAS, Lyness RW, Collins AD,
et al: An experimental study of quinine
blindness. Eye 1987; 1:522.
170. Lochhead J, Movaffaghy A, Falsini B, et al:
The effect of quinine on the electroretino-
grams of children with pediatric cerebral
malaria. J Infect Dis 2003; 187:1342.
171. Barrett NA, Solano T: Quinine ocular
toxicity: treatment of blindness using
therapy for vasospasm. Anaesth Intensive
Care 2002; 30:234.
172. Uldall P, Alving J, Gram L, Hogenhaven H:
Vigabatrin in childhood epilepsy: a 5-year
follow-up study. Neuropediatrics 1995;
26:253.
173. The Canadian Vigabatrin Study Group,
Guberman A, Bruni J: Long-term open
multicentre, add-on trial of vigabatrin in
adult resistant partial epilepsy. Seizure
2000; 9:112.
174. Eke T, Talbot JF, Lawden MC: Severe
persistent visual field constriction
associated with vigabatrin. BMJ 1997;
314:180.
175. Lawden MC, Eke T, Degg C, et al: Visual
field defects associated with vigabatrin
therapy. J Neurol Neurosurg Psychiatry
1999; 67:716.
176. Wild JM, Martinez C, Reinshagen G,
Harding GF: Characteristics of a unique
visual field defect attributed to vigabatrin.
Epilepsia 1999; 40:1784. 2223
 RETINA AND VITREOUS
177. Buncic JR, Westall CA, Panton CM, et al:
Characteristic retinal atrophy with
secondary ‘inverse’ optic atrophy identifies
vigabatrin toxicity in children.
Ophthalmology 2004; 111:1935.
178. Russell-Eggitt IM, Mackey DA, Taylor DS,
et al: Vigabatrin-associated visual field
defects in children. Eye 2000; 14:334.
179. Malmgren K, Ben-Menachem E, Frisen L:
Vigabatrin visual toxicity: evolution and
dose dependence. Epilepsia 2001; 42:609.
180. Kinirons P, Cavalleri GL, O’Rourke D, et al:
Vigabatrin retinopathy in an Irish cohort:
SECTION 10
2224
lack of correlation with dose. Epilepsia
2006; 47:311.
181. Daneshvar H, Racette L, Coupland SG,
et al: Symptomatic and asymptomatic
visual loss in patients taking vigabatrin.
Ophthalmology 1999; 106:1792.
182. Besch D, Kurtenbach A, Apfelstedt-Sylla E,
et al: Visual field constriction and
electrophysiological changes associated
with vigabatrin. Doc Ophthalmol 2002;
104:151.
183. Comaish IF, Gorman C, Brimlow GM, et al:
The effects of vigabatrin on
electrophysiology and visual fields in
epileptics: a controlled study with a
discussion of possible mechanisms. Doc
Ophthalmol 2002; 104:195.
184. Harding GF, Spencer EL, Wild JM,
et al: Field-specific visual-evoked
potentials. Identifying field defects in
vigabatrin-treated children. Neurology
2002; 58:1261.
185. Arndt CF, Husson J, Derambure P, et al:
Retinal electrophysiological results in
patients receiving lamotrigine monotherapy.
Epilepsia 2005; 46:1055.
 CHAPTER
177 Retinitis Pigmentosa and Allied Diseases
Eliot L. Berson
Retinitis pigmentosa (RP) is the name applied to a group of
hereditary retinal degenerations that affect ~1 in 4000 people
worldwide.1–6 In the state of Maine in the United States, genetic
types by families were found to be 19% autosomal dominant,
19% autosomal recessive, 8% X-chromosome-linked, 8%
undetermined, and 46% isolates with only one affected member
in a given family.5 In England, the X-linked type has been
reported to account for 16% of families and the autosomal
recessive type for 7%.4 The condition can rarely be inherited by
a digenic or mitochondrial mode of transmission and uni-
parental isodisomy has also been reported.7–10 Taking into
account that most isolate cases are inherited by an autosomal
recessive mode but some are X-linked and that most dominant
and X-linked families have two or more affected members, one
can estimate that 30–40% of cases are inherited as an auto-
somal dominant trait, 50–60% as an autosomal recessive trait,
and ~10–15% as an X-linked trait in North America.
To understand the functional abnormalities that occur in
these diseases, it is first important to know that the normal
human retina has ~120 million photoreceptors; ~93% are rods
and 7% are cones. Although cone density is highest in the
central macula (Fig. 177.1), more than 90% of the cones are
outside the central 10°. A patient with normal cone function
and absent rod function has normal visual acuity and a full
visual field even with a small (I-4e) white test light in the
Goldmann perimeter. A patient with absent cone function and
normal rod function has reduced visual acuity with a 1.2°
diameter central scotoma but still retains a full peripheral visual
field with a I-4e white test light. A patient with RP with a mid-
peripheral scotoma has, by definition, lost both cone and rod
function in the area of the scotoma. When a patient reports
‘night blindness’ in the era of the electric light bulb, most often
this symptom is related to impaired cone function. Because the
cones are used most of the time, patients can lose all their rod
function and not be aware of visual loss unless they are trying
to see under starlight or moonlight conditions.11
The rapid expansion of knowledge about RP and allied night-
blinding diseases precludes a comprehensive review in a single
chapter. This chapter provides a framework for evaluating
patients with these diseases (Table 177.1), information on some
of the genes that, when mutated, cause these diseases, and a
summary of treatments for some forms.
SYMPTOMS AND SIGNS
Key Features: Retinitis Pigmentosa – Clinical Findings
• Estimated prevalence – 1 in 4000 worldwide.
• Modes of transmission – dominant, recessive, X-linked,
digenic, mitochondrial, uniparental isodisomy.
• Symptoms – abnormal adaptation, night blindness, loss of
mid-peripheral and then far-peripheral visual field, tunnel
vision, eventual loss of visual acuity.
• Signs on ocular examination – posterior subcapsular cataracts,
vitreous cells, attenuated retinal vessels, bone spicule pigment
around the mid-periphery, waxy pallor of the optic discs,
cystoid macular edema in some cases.
• Reduced and delayed full-field electroretinograms.
FIGURE 177.1. Distribution of rods and cones
in the normal human retina. Corresponding
perimetric angles from the fovea at 0° are
given.
After Osterberg: From Pirenne MH: Vision and the Eye.
London, Chapman & Hall, 1967.
2225
 RETINA AND VITREOUS
Patients with RP characteristically develop night blindness and
difficulty with mid-peripheral visual field in adolescence; as their
condition progresses, they develop a tendency to blue blindness,
TABLE 177.1. Retinitis Pigmentosa and Some Allied Diseases
Autosomal dominant forms of retinitis pigmentosa
Autosomal recessive forms of retinitis pigmentosa
Sex-linked (X-chromosome-linked) forms of retinitis pigmentosa
Isolated (simplex) forms of retinitis pigmentosa
Progressive cone–rod degeneration
Atypical retinitis pigmentosa including sector, pericentral,
paravenous, and unilateral forms
Some syndromes or diseases of which retinitis pigmentosa is a
part
Bassen–Kornzweig syndrome (abetalipoproteinemia)
Refsum disease
Familial isolated vitamin E deficiency
SECTION 10
Usher syndrome types I, II, and III
Laurence–Moon and Bardet–Biedl syndromes
Kearns–Sayre syndrome
Hereditary cerebroretinal degenerations including Batten disease
Olivopontocerebellar atrophy
Cockayne syndrome
Alström disease
Congenital amaurosis of Leber
Choroideremia
Gyrate atrophy of the choroid and retina
Retinitis punctata albescens
Clumped pigmentary retinal degenerations (enhanced S-cone
syndrome in some cases)
Stationary forms of night blindness
a b
d e
2226
lose far-peripheral field, and eventually lose central vision often
by age 60. Signs on ocular examination include narrowed retinal
vessels, depigmentation of the retinal pigment epithelium, intra-
retinal bone spicule pigmentation, waxy pallor of the optic
disks, and vitreous cells.12–20 Posterior subcapsular cataracts
develop in many cases,21 and some patients show cystoid macular
edema.22,23 Refractive errors, including astigmatism and myopia,
are common.24,25 The characteristic bone spicule pigment is
typically distributed around the mid-peripheral fundus (Fig.
177.2a) in the zone where rods are normally in maximal con-
centration. Histopathologic studies of autopsy eyes have shown
loss of photoreceptors as well as photoreceptors with shortened
or absent outer segments.26–30
ELECTRORETINOGRAMS
In 1945, Karpe discovered that patients with advanced RP had
very small or nondetectable (<10 mV) ERGs.31 Subsequently, it
was shown that patients with early RP could have subnormal
but easily detectable ERGs.32–35 Responses were not only reduced
in amplitude but also delayed in b-wave implicit times,36–39 and
these ERG changes could be detected in some instances many
years before diagnostic abnormalities were visible on fundus
examination.20,37 Figure 177.3 illustrates representative full-field
ERGs from a normal subject and four children ages 9–14 years
with early RP. Rod responses to dim blue light under dark-
adapted conditions (left column) are reduced in all genetic types
and when detectable are delayed in b-wave implicit times, as
designated by horizontal arrows. Cone responses to 30-cps (i.e.,
30 Hz) white flickering light (right column) are normal or
reduced in amplitude and normal or delayed in b-wave implicit
c
FIGURE 177.2. Fundus
photographs of
moderately advanced
retinitis pigmentosa (a),
moderately advanced
choroideremia (b), gyrate
atrophy of the choroid
and retina (c), Oguchi
disease without dark
adaptation (d), and
fundus albipunctatus (e).

FIGURE 177.3. Electroretinogram (ERG) responses for a normal
subject and four patients with retinitis pigmentosa (RP) (ages 13, 14,
14, and 9 years). Responses were obtained after 45 min of dark
adaptation to single flashes of blue light (left column) and white light
(middle column). Responses (right column) were obtained to a 30-cps
(or 30-Hz) white flickering light. Calibration symbol (lower right)
signifies 50 msec horizontally and 100 mV vertically. Rod b-wave
implicit times in column 1 and cone implicit times in column 3 are
designated with arrows. Auto. Rec., autosomal recessive. a, peak of
cornea-negative a-wave; b, peak of cornea-positive b-wave.
Modified from Berson EL: Retinitis pigmentosa and allied diseases:
Electrophysiologic findings. Published courtesy of Trans Am Acad Ophthalmol
Otolaryngol 81:OP659-OP666, 1976.
times. In most cases, cone b-wave implicit times (displayed by
arrows in the right column) are so delayed that a phase shift
occurs between the stimulus artifacts (designated by the vertical
lines) and the corresponding response peaks. Each stimulus flash
elicits the next-plus-one response in contrast to the normal. In
the mixed cone–rod responses to single flashes of white light
under dark-adapted conditions (middle column), the cornea-
negative a-wave generated by the photoreceptors is reduced in
amplitude in all genetic types, pointing to the involvement of
the photoreceptors in these early stages.37
The subnormal responses with delayed b-wave implicit times
seen in widespread progressive forms of RP contrast with the
subnormal responses with normal b-wave implicit times seen
in self-limited sector RP (Fig. 177.4). For example, a father and
son with dominantly inherited sector RP, separated in age by
almost 30 years, have comparably reduced amplitudes and
normal b-wave implicit times. These patients usually have an
area of intraretinal pigment confined to one or two quadrants in
the periphery of each eye, with loss of peripheral rods and cones
and consequent reductions in both rod and cone amplitudes.
Rod b-wave implicit times are within the normal range (desig-
nated by the vertical bars), and cone b-wave implicit times are
also within the normal range, as each stimulus elicits the suc-
ceeding response, as seen in the normal. The ERGs recorded
from patients with sector RP are comparable to those recorded
from patients with large peripheral chorioretinal scars.36,38
Retinitis Pigmentosa and Allied Diseases
CHAPTER 177
FIGURE 177.4. ERG responses of a normal subject and four patients
with sector or stationary retinal disease. Horizontal arrows (column 1)
designate the range of normal rod b-wave implicit times, and the
vertical bar defining this range (mean ± SD) has been extended
through responses of patients with sector retinitis pigmentosa (RP).
Responses (middle column) from a patient with Oguchi’s disease are
interrupted by reflex blinking, so the latter part cannot be illustrated.
Cone implicit times in column 3 are designated with arrows. SNB,
stationary night blindness.
From Berson EL: Retinitis pigmentosa and allied diseases: Electrophysiologic
findings. Published courtesy of Trans Am Acad Ophthalmol Otolaryngol
81:OP659-OP666, 1976.
Studies of patients with widespread progressive forms of RP
with detectable rod ERGs and delayed cone b-wave implicit
times have demonstrated that cone b-wave implicit time to
white flicker is inversely proportional to the log amplitude of
the dark-adapted rod b-wave to blue light. In these patients,
cone b-wave implicit time did not vary with the amplitudes of
the dark-adapted cone b-waves. A 10-fold reduction in rod
amplitude was associated with ~5.5 msec slowing in cone
b-wave implicit times.39 These results would suggest that it is
the loss of rod photoreceptors among remaining cones that
apparently leads to abnormal rod–cone interaction,40 which can
account in large part for the delays in cone b-wave implicit
times seen in progressive forms of RP.
The ERG can be used to identify not only which patients
have widespread progressive forms of RP but also which
patients are normal. Relatives of patients with RP, age 6 years or
over, with normal rod and cone ERG amplitudes and implicit
times have not been observed to develop this disease at a later
time.20,37,38,41
CARRIERS OF X-LINKED RP
Female carriers of X-linked RP can show a patch of bone spicule
pigmentation in the periphery or an abnormal tapetal reflex in
the macula; among carriers of childbearing age, less than half
show diagnostic abnormalities on fundus examination. ERG 2227
 RETINA AND VITREOUS
testing can be used as an aid in detecting female carriers of
X-linked RP.42,43 ERG testing of obligate carriers has shown that
more than 90% have abnormal responses that either are
reduced in amplitude to single flashes of blue or white light
under dark-adapted conditions or are delayed in cone b-wave
implicit times, or both, in one or both eyes. A few older obligate
carriers with visual symptoms have had very small or even
nondetectable full-field ERGs (Fig. 177.5).42 Daughters of
obligate carriers have had either normal ERGs or abnormal
ERGs similar to those recorded from obligate carriers.
The abnormal ERGs of carriers of X-linked RP contrast with
the normal full-field ERG amplitudes and normal fundi observed
in obligate female carriers of autosomal recessive disease.42
Once carrier females of X-linked RP have been detected by
ophthalmoscopy or full-field ERG testing, or both, they would
know that they have a 50% chance of having an affected son and
a 50% chance of having a carrier daughter with each childbirth.
Female carriers of X-linked RP can have a slowly progressive
SECTION 10
retinal degeneration, although the natural course remains to be
defined. Some female carriers have had considerable loss of
visual field and substantial reductions in ERG amplitudes by
age 70 years.
NATURAL COURSE OF RP
The ERG provides a quantitative measure of remaining retinal
function and therefore can aid in defining the natural course
FIGURE 177.5. ERG responses from a normal subject and four
obligate carriers of sex-linked retinitis pigmentosa (RP). Pt (patient) 15,
age 39 years; Pt 8, age 41; Pt 4, age 51; Pt 22, age 70. Stimulus
onset is designated by ‘vertical hatched lines’ for columns 1 and 2
and ‘vertical shock artifacts’ for column 3. Cornea-positivity is upward
deflection. Arrows in column 3 designate cone b-wave implicit times.
Reprinted from Am J Ophthalmol, vol 87, Berson EL, Rosen JB, Simonoff EA,
Electroretinographic testing as an aid in detection of carriers of X-chromosome-
2228 linked retinitis pigmentosa, pp 460–468, Copyright 1979, from Elsevier Science.
of RP. For example, full-field ERGs have been recorded over a
20-year interval in young patients in a family with a dominant
form. Amplitudes decreased over this period, and patients age
13 years or under with normal fundi and abnormal ERGs in
1967 showed fundus changes of RP and further reductions in
their ERG amplitudes in 1977 (Fig. 177.6).44 Examination of
some members of this family showed further loss in 1987.38
Signal averaging with a bipolar artifact reject buffer and
bandpass filtering has extended the range of detectability of
responses from affected patients. ERGs can now be recorded
that are as low as 1 mV to 0.5-Hz flashes of white light with
signal averaging alone and, with bandpass filtering and signal
averaging, as low as 0.05 mV to 30-Hz white flicker. Full-field
ERG function could be monitored with at least one test
criterion in 90% of an outpatient population with a visual-field
diameter greater than 8°, thereby making this technique useful
in defining the natural course of the disease. ERGs in an adult
male with X-linked RP are illustrated to show changes in ERG
function over a 2-year period (Fig. 177.7).20,45,46
Among 94 patients, ages 6–49 years, with the common forms
of RP, full-field ERGs declined significantly over a 3-year
interval in 66 of 86 patients (77%) with detectable responses at
baseline. Patients lost on average 16% of remaining full-field
ERG amplitude per year to single flashes of white light (95%
confidence limits 13.1–18.6%) and 18.5% of remaining ampli-
tude per year to 30-Hz white flicker (95% confidence limits
15.1–21.5%). Patients lost on average 5.2% of remaining foveal
cone ERG amplitude per year, indicating that loss of retinal
function was primarily extrafoveal in these patients. They lost
on average 4.6% of remaining visual-field area per year in the
Goldmann perimeter with a V-4e white test light, whereas
visual acuity and dark-adaptation thresholds remained rela-
tively stable. Bone spicule pigment increased in 54% of patients
for whom comparisons could be made over a 3-year interval,
suggesting that observation of increased pigmentation as a
means of following this condition was not as sensitive as full-
field ERG testing.45
Caution must be exercised in applying these population ERG
results to predict longitudinal patterns in individual patients,
since standard deviations derived from standard errors
indicated considerable variation around the mean for these
patients.45 However, these results, describing the natural course
on a quantitative basis, provide a frame of reference for
planning interventions in similar populations to stabilize or
slow the course of RP, particularly if monitored with full-field
ERG testing.
ABNORMAL ROD ERG DIURNAL RHYTHM
IN RP
The changes that occur in RP can be considered not only in
terms of the course over years but also in terms of abnormalities
in rod function that can occur over the course of a day.
Abnormal rod ERG diurnal rhythms have been observed in
light-entrained patients with dominant RP; these patients had
abnormal reductions in rod b-wave sensitivity 11⁄2 h and 8 h
after light onset (Fig. 177.8). The abnormal reductions in rod
b-wave sensitivity at 9:30 a.m. and 4:00 p.m. raised as one
possibility that these patients with dominant RP shed
abnormally large fractions of rod outer segments throughout the
light period and that their rods were slow to renew their pre-
light-onset outer segment length. Abnormal diurnal rhythms
have also been reported in patients with autosomal recessive
and isolate forms of RP. The pathogenetic mechanism that
leads to these abnormal rod ERG diurnal rhythms remains to
be defined.47
 Retinitis Pigmentosa and Allied Diseases

1967 1977

Blue-Green White White (30 cps) Blue-Green White White (30 cps)

Normal Normal

V1-92, age 6 V1-92, age 15

V1-90, age 11 V1-90, age 20

CHAPTER 177
V1-86, age 13 V1-86, age 22

V1-84, age 17 V1-84, age 26

a b

FIGURE 177.6. (a) ERGs recorded in 1967 for a normal subject and four affected members from a family with dominant retinitis pigmentosa
with reduced penetrance. One to three responses to the same stimulus are represented. Stimulus onset is designated by ‘vertical hatched lines’
in columns 1 and 2 and ‘vertical shock artifacts’ in column 3; cornea-positivity is upward deflection; arrows in column 3 designate cone implicit
times. Calibration symbol (lower right) designates 50 msec horizontally for columns 1 and 2 and 25 msec for column 3 and 50 mV vertically for
column 1 and 100 mV for columns 2 and 3. (b) ERGs recorded in 1977 for a normal subject and four affected members from the same family as
in a for comparison with the ERGs recorded in 1967. Calibration symbol (lower right) designates 50 msec horizontally and 100 mV vertically for all
tracings.
(a and b) From Berson EL, Simonoff EA: Dominant retinitis pigmentosa with reduced penetrance: Further studies of the electroretinogram. Arch Ophthalmol
97:1286–1291, 1979. Copyright 1979, American Medical Association.

MOLECULAR GENETIC STUDIES OF RP
Key Features: Retinitis Pigmentosa – Summary of
Molecular Genetic Findings
• Most frequent known causes – mutations in the rhodopsin,
USH2A, or RPGR gene.
• Variable severity of disease at a given age among patients with
the same gene defect.
• Causative genes broadly classified – those affecting the
phototransduction cascade, the retinoid cycle, photoreceptor
structure, or other aspects of photoreceptor and retinal
pigment epithelial cell biology.
• Some 40–50% of cases have an unknown molecular genetic
basis.
More than 100 gene loci that cause RP have been mapped or
identified; a current list of genes responsible for this group of
diseases is maintained on the RetNet site at http://www.sph.
uth.tmc.edu/Retnet/sum-dis.htm. Estimated proportions of
cases of RP, excluding syndromic RP other than Usher syn-
drome, caused by identified genes are listed in Table 177.2. The
most common forms of RP are due to either mutations in
the rhodopsin gene, the Usher IIA gene, or the RPGR gene. The
genes listed in this table account for ~50–60% of the cases of
RP in North America.
The first gene abnormality found to cause RP was a single-
base substitution in codon 23 of the rhodopsin gene found
among 17 of 148 unrelated patients with autosomal dominant
RP from across North America (Fig. 177.9). The nucleotide base
change was a cytosine-to-adenine transversion (i.e., CCC to
CAC) in codon 23, corresponding to a substitution of histidine
for proline in the twenty-third amino acid of rhodopsin. Only
clinically affected relatives showed this gene defect in the
families studied. These results, coupled with the fact that
proline-23 is highly conserved among normal opsins, suggested
that this point mutation affected a critical amino acid in
rhodopsin and that this mutation could be the cause of one
form of autosomal dominant RP. This mutation was designated
as rhodopsin, proline-23-histidine (i.e., Pro23His).48
Subsequent studies have revealed more than 100 additional
mutations in the rhodopsin gene.49–50 Only one mutation has
been found in a given family, and each mutation has segregated
perfectly with the disease in the families so far studied. All
patients with rhodopsin gene mutations so far tested have had
abnormal rod ERGs. None of these mutations has been found
in unrelated normal subjects.
The site of the mutation in the rhodopsin gene has impli-
cations with respect to the clinical severity of the disease. A
group of 17 patients from separate families with Pro23His
(mean age 37 years) retained a mean visual acuity of 20/26,
compared with 20/37 for the group of eight patients from
separate families with Pro347Leu (mean age 32 years). Visual-
field area was on average 3463 deg2 in the Pro23His group to a
V-4e white test light (normal >11 399 deg2) and 1224 deg2 in
the Pro347Leu group. Mixed cone plus rod ERG responses to 2229
 RETINA AND VITREOUS

TABLE 177–2. Estimated Proportions of Cases of Retinitis

Pigmentosa (RP) Caused by Identified Genes
(Excluding Syndromic RP Except for Usher Syndrome)
(Genes currently identified account for 50–60% of cases of RP)

Inheritance Pattern/Gene Percent of all RP (including

Usher Syndrome)

Autosomal Dominant (~40% of all cases of RP)

1. RHO (rhodopsin) (3q) 10%
2. RP1 (8q) 2.2%
3. PRPF31 (19q) 2.0%
4. PRPF3 (1q) 1.6%
5. peripherin/RDS (6p) ~1%
6. FSCN2 (17q) ~1%
7. PRPF8 (17p) 0.8%
8. IMPDH1 (7q) 0.8%
9. NRL (14q) 0.4%
FIGURE 177.7. Computer-averaged full-field ERGs from a 26-year-old 10. CRX (19q) 0.4%
man with X-linked retinitis pigmentosa obtained in response to 11. CA4 (carbonic anhydrase) ? frequency in USA (~2% in UK)
SECTION 10

10-msec flashes of white light at 16 000 ftL presented at 0.5 Hz (17q)

(n = 64), 30 Hz (n = 256), and 42 Hz (n = 256) at baseline (year 0) and 12. PAP1 (7p) <1%
at 2-year follow-up (year 2). Three consecutive response averages are 13. SEMA4A (semaphorin) (1q) <1%
superimposed in each case. ‘Vertical broken lines’ denote flash onset Autosomal Recessive (~50% of all cases of RP, including
for the 0.5-Hz condition and the onset of one of the trains of flashes isolates)
for the 30-Hz and 42-Hz conditions. 14. usherin (1q) ~10% (based on analysis of all
Reprinted from Am J Ophthalmol, vol 99, Berson EL, Sandberg MA, Rosner B, 72 exons in USH2A gene)
et al, Natural course of retinitis pigmentosa over a three-year interval, 15. PDE6B (4p) 2%
pp 240–251, Copyright 1985, from Elsevier Science. 16. PDE6A (5q) 1.5%
17. CNGA1 (4p) 1%
18. RPE65 (1p) 1%
19. myosin VIIa (11q) ~1% (Usher IB)
20. LRAT (4q) <1%
21. NR2E3 (15q) <1%
22. MERTK (2q) <1%
23. harmonin (11p) <1% (Usher IC)
24. CDH23 (10q) <1% (Usher ID)
25. PCDH15 (10q) <1% (Usher IF)
26. VLGRI (5q) <1% (Usher IIC)
27. clarin-1 (3q) <1% (Usher IIIA)
28. SAG (arrestin) (2q) ~0.5%
29. CRALBP (15q) ~0.5%
30. RHO (rhodopsin) (3q) ~0.5%
31. TULP1 (6q) ~0.5%
32. ABCA4 (i.e., ABCR) (1p) <1%
33. RGR (10q) <1%
34. CRB1 (1q) <1%
35. CERKL (2q) <1%
36. CNGB1 (16q) <1%
37. SANS (17q) <1% (Usher 1G)
39. RP1 (8q) <1%
X-linked (~10% of all cases of RP)
39. RPGR (Xp21.1) 8% (RPGR and RP2 combined
40. RP2 (Xp11.3) account for ~90% of XLRP)
Digenic (only a few families described to date)
41. ROM1 (11q) and <1%
peripherin/RDS (6p)
Mitochondrial (only one family, with Usher type III, described to
date)
42. MTTS2 <1%
Note: Percentages are approximate and are based on the breakdown of RP
cases according to genetic type reported by Fishman (Arch Ophthalmol
96:822–826, 1978.), Macrae (Birth Defects: Original Article Series 18:175–185,
1982), and Bunker et al. (Am J Ophthalmol 97:357–365, 1984) and on the
FIGURE 177.8. Mean log Ithreshold–1 of rod b-wave V = kl n function assumptions that all isolate cases are autosomal recessive and that about one
versus time of day for 5 light-entrained normal subjects and 5 light- third of cases of Usher syndrome type I (approximately 6% of all cases of RP)
entrained patients with dominant retinitis pigmentosa (RP). Subjects are caused by defects in myosin VIIa. The values are calculated based on
were dark-adapted for 1 h before 9:30 a.m., 4 p.m., and 9 p.m. test frequency of cases in a published series multiplied by the proportion of RP with
sessions. log Ithresholds–1 were based on criterion amplitudes averaging that inheritance pattern (e.g., dominant rhodopsin mutations were found in
90/363 cases of ADRP; ADRP accounts for about 40% of all cases of RP;
28.8 mV for normal subjects and 10.6 mV for patients with retinitis
accordingly, the percentage of cases caused by dominant rhodopsin mutations
pigmentosa. ‘Error bars’ designate ±SEM derived from pooled is 90/363 = 24.8% µ 0.4 = 9.92 ≈ 10%). Table prepared 4/15/06. A current
estimates of population variances obtained from analyses of variance. listing of genes causing retinitis pigmentosa and allied hereditary retinal
From Sandberg MA, Baruzzi CM, Hanson AH III, Berson EL: Rod ERG diurnal diseases can be accessed on the world-wide web
rhythm in some patients with dominant retinitis pigmentosa. Invest Ophthalmol at:http://www.sph.uth.tmc.edu/RetNet.
2230 Vis Sci 29:494, 1988. © Association for Research in Vision and Ophthalmology.
 Retinitis Pigmentosa and Allied Diseases

CHAPTER 177
FIGURE 177.9. Nucleotide sequence of codons 20–26 of the human rhodopsin gene derived from leukocyte DNA of a normal individual (N79)
and of five representative patients with autosomal dominant retinitis pigmentosa included in this study and identified by their molecular genetic
numbers AD12, AD160, AD133, AD87, and AD126. The normal subject and patient AD12 show the normal sequence, whereas the other four
patients are heterozygous for the cytosine-to-adenine transversion within codon 23 (CCC to CAC). In these four patients with this mutation, the
single base change can be seen as a band marked in brackets.
From Berson EL, Rosner B, Sandberg MA, et al: Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect [Pro23His].
Arch Ophthalmol 109:92, 1991. Copyright 1991, American Medical Association.

single 0.5-Hz flashes of white light were on average 14.4 mV in
the Pro23His group, almost 10-fold larger when compared with
the mean amplitude of 1.7 mV in the Pro347Leu group. Cone
isolated responses to 30-Hz flicker were also 10-fold larger on
average for the Pro23His group (i.e., 5.5 mV) compared with the
Pro347Leu group (i.e., 0.5 mV). The ERG and other clinical
findings taken together would support the idea that patients
with Pro23His have on average a less severe disease at a given
age than those with rhodopsin, Pro347Leu.51 A study of the
longitudinal course of the disease among patients with these
mutations has shown that patients with Pro23His have, on
average, a slower course than patients with Pro347Leu.52
Although patients with the Pro23His mutation retain more
retinal function on average than patients with the Pro347Leu
mutation, considerable variability in clinical expression exists
at a given age among patients with these mutations, particularly
among the group with Pro23His. This variability in clinical
expression among patients with the same gene defect has raised
the possibility that some factor or factors other than the gene
defect itself are responsible for the expression of this condition.
This could be the result of a modifier gene or environmental
factors, or both. Risk factor analyses of patients with a given
mutation and varying severity of disease may help to identify
ameliorating or aggravating factors that may be affecting the
course of this condition with possible implications for therapy.20
The rhodopsin (RHO) gene is ~7 kilobases (kb) in length
with five exons; the gene normally encodes 348 amino acids
in the rhodopsin protein. Normal rhodopsin molecules are
thought to traverse the rod outer segment membrane seven
times (Fig. 177.10) and are folded in three dimensions, with the
first and seventh transmembrane segments in close proximity.
Loops on the intradiscal side near the amino terminal tail are
thought to be involved in the folding of the molecule, whereas
some loops on the cytoplasmic side appear to interact with
transducin as the first step in the phototransduction cascade.
The normally folded rhodopsin molecule forms a pocket for
vitamin A, which is bound to a lysine residue at position 296,
designated by the letter K in the seventh transmembrane
segment (Fig. 177.11). Mutations resulting in abnormal amino
acids in the intradiscal or intramembranous domain (e.g.,
Pro23His) may interfere with the folding of rhodopsin and
thereby modify the capacity of the pocket to hold vitamin A
with consequent instability of opsin in the outer segment
membranes. Mutations involving the intracytoplasmic domain
(e.g., Pro347Leu) may result in abnormal transport of nascent
rhodopsin to the outer segments. The reason mutations involv-
ing the rod system eventually also lead to cone photoreceptor
cell death is not known. Studies of transgenic mice with these
mutations as well as evaluation of cultured cell systems with
these mutations should help to define the mechanisms by
which these mutations lead to photoreceptor cell death.53
Mutations in the human retinal degeneration slow (RDS)
gene on the short arm of chromosome 6 have been reported in
other families with autosomal dominant RP.54,55 All patients so
far studied have had abnormal rod and cone ERGs. This gene
encodes for the protein peripherin, thought to help maintain
normal outer segment structure.56 An abnormality in this gene
is also known to be responsible for a retinal degeneration in a 2231
 RETINA AND VITREOUS
SECTION 10
FIGURE 177.10. Model of the normal rhodopsin protein in a rod outer
segment disk membrane. Each letter signifies an amino acid residue,
using the standard single-letter code. A, alanine; R, arginine;
N, asparagine; D, aspartic acid; C, cysteine; E, glutamic acid;
Q, glutamine; G, glycine; H, histidine; I, isoleucine; L, leucine;
K, lysine; M, methionine; F, phenylalanine; P, proline; S, serine;
T, threonine; W, tryptophan; Y, tryosine; V, valine. The protein, which
contains 348 amino acids, traverses the outer segment disk
membrane seven times, so that different portions of the molecule are
in the cytoplasm, within the outer segment membrane, or in the
intradiscal space. The lysine residue (K) in the seventh transmembrane
domain is covalently bound to vitamin A aldehyde (i.e., 11-cis-retinal).
Glycosylation sites are labeled near the N-terminal of the protein. A
disulfide bond between two cysteines in separate intradiscal loops is
indicated by a line.
Reprinted from American Journal of Ophthalmology, Vol III, Berson EL, Rosner
B, Sandberg MA, et al: Ocular findings in patients with autosomal dominant
retinitis pigmentosa and rhodopsin, proline-347, pp 614–623, Copyright 1991,
from Elsevier Science.
FIGURE 177.11. Schematic representation of a normal rhodopsin
molecule folded in three dimensions to form a pocket to hold the
vitamin A-derived chromophore (11-cis-retinal), which is covalently
attached to a lysine residue, designated by the letter K in the seventh
transmembrane segment.
Modified from Applebury ML: Molecular genetics. Insight into blindness.
Reprinted by permission from Nature vol 343, pp 316–317; Copyright © 1990
2232 Macmillan Magazines Limited.
mouse model called rds. Abnormalities in the human RDS gene
have been reported to be a cause not only of RP but also of
retinal pattern dystrophy, retinitis punctata albescens, macular
dystrophy, butterfly shaped macular dystrophy, and cone-rod
dystrophy.57–60 Even among relatives who share the same
mutant RDS allele various phenotypes have been reported,
including RP, pattern dystrophy, and fundus flavimaculatus.60
Phenotypic variability may be due to an unexplained variation
in the relative involvement of rods and cones and in the
presence of yellow or yellow–white deposits at the level of the
retinal pigment epithelium seen in only some patients.
Genes that cause RP can be subclassified into those that
affect (1) the phototransduction cascade (RHO, PDE6A, PDE6B,
CNGA1, CNGB1, and SAG), (2) the retinoid cycle (ABCA4,
RLBP1, RPE65, LRAT, and RGR), (3) photoreceptor structure
(RDS/peripherin, ROM-1, FSCN2, TULP1, CRB1, RP1, and
USH2A), (4) cell–cell interactions (SEMA4A, CDH23, PCDH15,
USH1C, MASS1, USH3A, and RP2), (5) RNA intron-splicing
factors (PRPF31, PRPF8, PRPF3, and PAP1), (6) intracellular
transport of proteins (MYO7A and SANS), (7) maintenance of
cilia or ciliated cells with possible role in trafficking (BBS1,
BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, PTHB1, and
RPGR), (8) regulation of carbon dioxide/bicarbonate balance
(CA4), (9) phagocytosis (MERTK), and (10) other yet-to-be-
defined functions of the photoreceptors and retinal pigment
epithelium (CERKL, BBS10, and IMPDH1).61
TREATMENT OF THE COMMON FORMS
OF RP
Key Features: Retinitis Pigmentosa – Treatment of
Common Forms
• Vitamin A palmitate 15 000 IU/day for nonpregnant adults with
normal liver function.
• Avoidance of high dose vitamin E supplementation such as
400 IU/day.
• Adults already taking vitamin A palmitate should also eat
1–2 three-ounce servings per week of omega-3 rich fish (i.e.,
salmon, tuna, mackerel, herring, or sardines) of which DHA is a
major constituent.
• Adults taking vitamin A for the first time should take DHA
supplementation (1200 mg/day) for 2 years to shorten the
interval for vitamin A to achieve its benefit. After 2 years, they
should continue vitamin A palmitate, stop DHA gelcaps, and
eat 1–2 three-ounce servings per week of omega-3 rich fish.
• Potential treatment effect – 20 additional years of vision for the
average patient who starts this regimen in their mid-30s.
• Beta-carotene is not a suitable substitute for vitamin A
palmitate in the context of this treatment as it is not
predictably converted into vitamin A.
Many treatments have been attempted without proven benefit
for the common forms of RP.62–69 These include various vita-
mins and minerals, vasodilators, tissue therapy with placental
extract, cortisone, cervical sympathectomy, injections of a
hydrolysate of yeast RNA, ultrasound, transfer factor, dimethyl
sulfoxide, ozone, muscle transplants, and subretinal injections
of fetal retinal cells. A study of patients evaluated before and
after receiving electrical stimulation, autotransfused ozonated
blood, and ocular surgery in Cuba showed that this intervention
provided no benefit; the results raised the possibility that this
intervention was aggravating the course of the disease.69
Claims of success with one or another treatment by patients
with RP that are based solely on subjective reporting of
improved visual function should be interpreted with caution.
 Retinitis Pigmentosa and Allied Diseases

Spontaneous fluctuations in acuity and field are well known in
this condition. Given the slow course of the disease without
treatment, it will usually require several years to assess whether
or not any proposed treatment has an effect on stabilizing or
slowing the course of the disease. The problem of assessing
treatments may be further complicated by the genetic hetero-
geneity of this condition and the stage of disease at which treat-
ment is initiated.
None of these attempts at treatment was conducted with a
randomized, controlled, double-masked protocol, which is
necessary to avoid possible patient or examiner biases. Most of
these studies were performed without ERG data as an end-point
for evaluating efficacy, so that the amount of remaining retinal
function could not be quantitated in an objective manner.
Preliminary data obtained while conducting a natural history
study of the course of RP revealed that those patients self-
treating with a separate capsule of vitamin A or vitamin E or
both were losing less retinal function than those not self-
Rates of decline for visual field area both for all randomized
patients and for the higher-amplitude cohort showed similar
trends (see Table 177.3), although the differences were not
statistically significant. No significant differences were observed
among groups with respect to rates of decline of visual acuity.
For a subset of 125 patients with the lowest intervisit variability
(i.e., ≤5%), mean rates of decline of remaining visual field area
per year were group A, 3.4%; group trace, 7.3%; group A + E,
4.0%; and group E, 5.3%. Comparisons of specific groups
showed that the rate of decline of visual field area for group A
differed significantly (p=0.03) from that of group trace, whereas

CHAPTER 177
treating with these supplements.70 This prompted a random-
ized, controlled, double-masked trial among 601 adult patients
to determine whether supplementation with vitamin A or
vitamin E, alone or in combination, would halt or slow the
progression of the common forms of RP including Usher syn-
drome type II. Patients were randomly assigned to one of
four treatment groups, as follows: vitamin A, 15 000 IU/day
plus vitamin E, 3 IU/day (Group A); vitamin A, 75 IU/day plus
vitamin E, 3 IU/day (Group Trace); vitamin A, 15 000 IU/day
plus vitamin E, 400 IU/day (Group A + E); and vitamin A,
75 IU/day plus vitamin E, 400 IU/day (Group E). The main
outcome variable was the 30-Hz cone flicker ERG.70–72
Mean annual rates of decline of remaining ERG amplitude
were slowest for the group taking 15 000 IU/day of vitamin A
and fastest for the group taking 400 IU/day of vitamin E. These
rates were observed among all randomized patients as well as
among a subgroup of 354 patients with slightly higher initial
ERG amplitudes (i.e., ≥ 0.68 mV) who could be followed more
reliably and who were designated ‘the higher amplitude cohort’.
Mean annual rates of decline of remaining 30-Hz ERG ampli-
tude among this cohort were as follows: group A, 8.3%; group
trace, 10%; group A + E, 8.8%; and group E, 11.8%. These
results are summarized in Table 177.3. The treatment effect is
plotted by year in Figure 177.12. Comparison of those taking
vitamin A 15 000 IU/day versus those not on this dose revealed
that the beneficial effect of vitamin A was significant at the
P =.01 level for all randomized patients and at the P <.001
level for the higher-amplitude cohort. Comparison of those
taking vitamin E 400 IU/day versus those not on this dose
revealed no significant treatment effect among all randomized
patients but did show an adverse effect among those in the
higher amplitude cohort (p=0.04).

TABLE 177.3. Mean Rates of Decline in Visual Function by

Treatment Group Among Patients with the Common Forms of
Retinitis Pigmentosa Supplemented with Vitamins A and E*
FIGURE 177.12. Mean change from baseline over 6 years in 30-Hz
All Randomized Patients Higher Amplitude Cohort ERG amplitude in the higher amplitude cohort by treatment group
Test A Trace A+E E A Trace A+E E (top), by vitamin A main effect (middle); and by vitamin E main effect
30 Hz* 6.1 7.1 6.3 7.9 8.3 10.0 8.8 11.8 (bottom). Sample sizes for years 1 through 6, respectively, were
n = 171, n = 167, n = 168, n = 164, n = 123, and n = 59 for patients
0.5 Hz* 8.7 9.6 9.1 10.6 8.1 9.4 8.4 10.9 receiving vitamin A, 15 000 IU/day; and n = 178, n = 182, n = 172,
n = 171, n = 125, and n = 64 for patients receiving vitamin A,
Field Area* 5.6 5.9 6.2 6.3 6.3 7.2 7.3 7.8
75 IU/day. Sample sizes for years 1-6, respectively, were n = 178,
†
Visual Acuity 1.1 0.9 0.7 0.9 0.8 0.8 0.7 0.7 n = 177, n = 173, n = 168, n = 122, and n = 61 for the patients on
vitamin E, 400 IU/day; and n = 171, n = 172, n = 167, n = 167,
*Percent decline in remaining function per year
†
Letters lost per year n = 126, and n = 62 for patients receiving vitamin E, 3 IU/day.
(Modified from Berson EL, Rosner B, Sandberg MA, et al.: Arch Ophthalmol From Berson EL, Rosner B, Sandberg MA, et al: A randomized trial of vitamin A
1993; 111:761–772; copyright 1993, American Medical Association. and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol
111:761–772, 1993. Copyright 1993, American Medical Association. 2233
 RETINA AND VITREOUS
the rates of decline of the A + E and E groups did not differ
significantly from that of the group trace. Therefore, for this
subset of 125 patients representing all genetic types, a
significant beneficial effect of vitamin A supplementation on
visual field area could be detected.73
The optimal total intake of vitamin A appeared to be
~18 000 IU/day; that is, a supplement of 15 000 units plus a
regular diet of ~3500 units of vitamin A per day resulted in the
smallest ERG decline (Fig. 177.13). Vitamin A intake greater
than 18 380 IU/day provided no greater benefit. Vitamin A
intake of 25 000 IU/day or greater is potentially toxic over the
long term.74–76
No case of toxicity in adults in good general health on this
dose has been reported.70–77 No significant differences in treat-
ment effects were noted among different genetic types. The pre-
cise mechanism by which vitamin A supplementation provides
its benefit is not known. It has been speculated that vitamin A
rescues remaining cones, thereby explaining how one supple-
SECTION 10
ment may help a group of patients many of whom have dif-
ferent rod-specific gene defects. Vitamin E may lead to an
adverse effect on the course of RP by inhibiting the absorption
or transport of vitamin A.70
Based on the results of this trial, it is recommended that
most adults with the common forms of RP should take 15 000
units of vitamin A palmitate daily under the supervision of their
ophthalmologists and avoid high-dose supplements of vitamin
E such as the 400 units used in this trial. It is also recom-
mended that patients continue on a regular diet without
specifically selecting foods containing high levels of preformed
vitamin A. The palmitate form of vitamin A is recommended,
as this was the form used in this study. Other forms might be
suitable, but some are probably not, for example beta-carotene,
which is not predictably converted to vitamin A from one
patient to another.
As a precaution, patients should be advised to have a
pretreatment assessment of fasting serum vitamin A and liver
function and annual evaluations thereafter. Because of the
potential for birth defects, women who are pregnant or planning
to become pregnant are advised not to take this dose of vitamin
A. Because patients under 18 years were not evaluated, no formal
recommendation for patients under this age can be made.70
FIGURE 177.13. Mean ± SE decline from baseline in 30-Hz ERG
amplitude by total vitamin A intake (diet plus capsules) irrespective of
randomization assignment for all patients in the higher-amplitude
cohort. The mean decline was calculated as the mean of screening
and baseline minus the mean of all follow-up visits by quintile of total
vitamin A intake averaged over all visits. Sample sizes were 69, 72,
74, 65, and 74 for the lowest to highest quintiles of total vitamin A
intake. Vertical bars indicate SEs.
From Berson EL, Rosner B, Sandberg MA, et al: A randomized trial of vitamin A
and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol
2234 111:761–772, 1993. Copyright 1993, American Medical Association.
In older adults, long-term vitamin A supplementation has
been associated with a decrease in bone density and up to a 1%
increased risk of hip fractures.78,79 Therefore, postmenopausal
women and men aged 49 and over who are taking vitamin A
should be advised to consult with their physician about their
bone health and be followed regularly in this regard. Vitamin A
should not be given to patients with RP who have had renal
transplants as they have excessive renal re-absorption of vitamin
A and, therefore are more susceptible to toxicity. Patients on chronic
doxycycline should not take vitamin A because the combination
has been associated with increased intracranial pressure.
While conducting the clinical trial on vitamins A and E, data
were obtained raising the possibility that docosahexaenoic acid
(DHA) in addition to vitamin A could further slow the course of
RP. This led to a second randomized, controlled, double-masked
trial for the typical forms of RP. Patients were randomly assigned
to DHA capsules (1200 mg/day) or control fatty acid capsules;
all participants were given vitamin A palmitate 15 000 IU/day.
In this trial the main outcome variable was the total point score
for the 30–2 program of the Humphrey field analyzer. Among all
participants taken together, DHA supplementation by capsules
did not, on average, slow the course of RP over a 4-year
interval.80 However, a subgroup analysis showed that those
already taking vitamin A who also ate an omega-3 rich diet
(≥0.2 g/day) of which DHA is a major constituent, had a
40–50% slowing of annual decline in visual field sensitivity.81
This omega-3 rich diet consisted of two or more 3-ounce
servings of oily fish per week (i.e., salmon, tuna, herring,
mackerel, or sardines). DHA is thought to facilitate the release
of vitamin A from its carrier protein (interphotoreceptor
retinoid binding protein, IRBP) in the subretinal space. It has
been estimated that an average patient age 37 with typical RP
already on vitamin A palmitate 15 000 IU/day who maintains
this oily fish DHA-rich diet would be expected to lose virtually
all central visual field sensitivity by age 78, whereas an average
patient who eats less than two servings per week would be
expected to lose all central visual field sensitivity by age 59.81 In
summary, whereas vitamin A alone is thought to provide seven
additional years of vision, vitamin A with an oily fish diet
provides almost 20 years of visual preservation for the average
patient with RP who starts this regimen in their mid-30s.
About 3 months after starting an oily fish diet (thereby
allowing sufficient time for red blood cell (RBC) turnover),
patients with RP should have a measurement of their fasting
RBC DHA to confirm that the RBC DHA level is at least 4% of
total RBC fatty acids as it has been reported that such patients
have, on average, a slower rate of decline of visual field
sensitivity than those with lower levels.81 If the RBC DHA level
is not at least 4%, patients should be advised to consult with
their physician on how to best reach this level through food. If
the level is 4% or greater, this test should be repeated annually
thereafter.
Although high DHA supplementation (1200 mg/day) has no
benefit over a 4-year interval among patients taking vitamin A,80
it has been reported that this dose can shorten the interval for
vitamin A to achieve its benefit among those taking vitamin A
for the first time.81 Therefore, adults with RP starting vitamin
A for the first time should be advised to take vitamin A
palmitate 15 000 IU/day and DHA capsules 600 mg twice per
day for 2 years (i.e., three 200 mg capsules both morning and
night with meals). After 2 years, patients should discontinue
DHA supplementation by capsules because no evidence was
found for continued benefit and because a slight tendency
toward adversity on ocular function was observed over the long-
term among patients on high DHA with vitamin A.81 After
stopping DHA capsules after 2 years, patients should continue
the vitamin A and eat two 3-ounce servings per week of omega-

3 rich fish. About 3 months thereafter, RBC DHA levels should
be checked as described above. It should be noted that com-
bining an omega-3 rich diet with DHA capsules did not provide
any additional benefit.
Sources of vitamin A palmitate and DHA capsules as well as
laboratories that perform measurements of RBC DHA are main-
tained on the website of the Foundation Fighting Blindness
(www.blindness.org).
RP ASSOCIATED WITH HEREDITARY
ABETALIPOPROTEINEMIA
Key Features: Retinitis Pigmentosa – Treatment of Rare
Forms
• Hereditary abetalipoproteinemia (Bassen–Kornzweig syndrome)
– low-fat diet and vitamins A, E, and K.
• Refsum disease – low-phytol, low-phytanic acid diet while
maintaining body weight.
• Familial isolated vitamin E deficiency – oral vitamin E
supplementation.
In 1950, Bassen and Kornzweig described an 18-year-old girl,
born of first cousins, who had a malabsorption syndrome, a
generalized retinal degeneration, a diffuse neuromuscular
disease similar to Friedreich ataxia, and a peculiar crenation of
the RBCs, now called acanthocytosis. In 1956, low serum
cholesterol (<50 mg/dL) was observed.82–86 Soon thereafter, an
absence of low-density plasma lipoproteins or so-called beta-
lipoproteins was found, and the term abetalipoproteinemia was
assigned to this recessively inherited disorder.87–89 Other classes
of lipoproteins have also been found to be abnormal.90
Patients with hereditary abetalipoproteinemia can assimilate
fat into the intestinal mucosa, but a defect exists in its removal
from this site because of the lack of chylomicra. Intestinal
biopsies have revealed normal-sized villi filled with lipid
droplets that are essentially triglycerides. Mutations in the gene
encoding a microsomal triglyceride transfer protein have been
found in patients with this condition.91 It appears that the liver
and then the retina become depleted of vitamin A. Abnormal
ERGs have been reported in children in whom the fundi were
still normal.92 The original case described by Bassen and
Kornzweig showed multiple white dots in the early stages, but
by age 31 years, the patient developed multiple areas of pigment
epithelial cell atrophy. In other cases, the typical intraretinal
pigment associated with RP has been noted in the retinal
periphery.
Retinitis Pigmentosa and Allied Diseases
Patients with this condition are treated with a low-fat diet
and supplements of the fat-soluble vitamins A, E, and K.
Vitamin A supplementation has been shown to restore elevated
dark-adaptation thresholds and reduced ERG responses to
normal in two patients in the early stages (Fig. 177.14).93,94
More advanced cases have not responded, but in one such case,
in which the retina was examined after the death of the patient,
widespread loss of photoreceptor cells was observed.95 Vitamin
A therapy may not maintain retinal function over the long
term, as patients have been reported in whom vitamin A levels
have been restored to normal and yet the retinal degeneration
has appeared to progress.96 Since these patients have low serum
vitamin E levels, supplementation with vitamin E in addition to
vitamin A has been advocated with reported stabilization of
retinal function.97–101
RP ASSOCIATED WITH REFSUM DISEASE
CHAPTER 177
Refsum disease is a recessively inherited condition in which the
patient accumulates exogenous phytanic acid.102,103 Findings
include a peripheral neuropathy, ataxia, an increase in cerebro-
spinal fluid protein with a normal cell count, and RP. All
patients have elevated serum phytanic acid. Some cases have
anosmia, neurogenic impairment of hearing, electrocardiogram
abnormalities, and skin changes resembling ichthyosis. The
fundus can appear granular with areas of depigmentation
around the periphery with a subnormal ERG in the early stages
or can show more typical RP with a nondetectable ERG in more
advanced stages.104
A defect exists in the conversion of phytanic acid to ∂-hydroxy
phytanic acid, specifically in the introduction of a hydroxyl
group on the ∂-carbon of phytanic acid (Fig. 177.15).105 The
pathogenesis appears to involve accumulation of phytanic acid
in a variety of tissues, including the retinal pigment epithelium.106
Treatment consists of restricting not only animal fats and
milk products (i.e., foods that contain phytanic acid) but also
green leafy vegetables containing phytol.107 Success of treat-
ment depends on the patient’s maintaining his or her body
weight; if body weight becomes reduced, phytanic acid is
released from tissue stores, resulting in an increase of phytanic
acid in serum and exacerbation of symptoms. Refsum reported
two patients whose serum phytanic acid levels were lowered to
normal and who showed improvement in motor nerve conduc-
tion velocity, some relief of ataxia, and return of the cerebro-
spinal fluid protein to normal. Moreover, the RP and hearing
impairment did not progress; one of these patients was followed
for 10 years and the other for many years.108 One young adult
with a mild form of this disorder has been followed on a low-
FIGURE 177.14. Full-field ERGs to red (top)
and blue (middle) light, equal for rod vision, and
brighter white stimulus (bottom) from a patient
with hereditary abetalipoproteinemia (dark-
adapted). Responses in the left column were
obtained before vitamin A therapy, those in
middle column at 6 h, and those on right at 24 h
after vitamin A therapy. Two to three responses
to the same stimulus are superimposed. Light
stimulus begins with each trace. Calibration
(lower right) signifies 0.06 mV vertically and 60
msec horizontally.
From Gouras P, Carr RE, Gunkel RD: Retinitis
pigmentosa in abetalipoproteinemia: Effects of vitamin
A. Invest Ophthalmol Vis Sci 10:784, 1971. ©
Association for Research in Vision and Ophthalmology.
2235
 RETINA AND VITREOUS
SECTION 10
FIGURE 177.15. Phytanic acid, its immediate precursors and
metabolites, and site of enzyme defect in Refsum disease (Rd).
From Eldjarn L, Stokke O, Try K: Biochemical aspects of Refsum disease and
principles for the dietary treatment. In Vinken PJ, Bruyn GW [eds]. Handbook of
Clinical Neurology. Amsterdam, North Holland, 1976, pp 519–541.
phytol, low-phytanic acid diet for 4 years; full-field ERGs,
reduced ~75% below normal before commencement of this diet,
have remained about the same over this period (Fig. 177.16).
Long-term effects of this diet on retinal function continue to be
studied.38
FAMILIAL ISOLATED VITAMIN E
DEFICIENCY
Another rare recessively inherited form of ataxia associated
with RP has recently been termed familial isolated vitamin E
deficiency. These patients present in adulthood with Friedreich-
like ataxia, dysarthria, hyporeflexia, and decreased propriocep-
tive and vibratory sensation as well as markedly decreased
serum vitamin E levels. In later stages, patients can develop the
fundus changes of RP and abnormal ERGs. Molecular genetic
analysis has revealed a mutation in the alpha-tocopherol-
transfer protein (alpha-TTP) gene. Oral administration of
vitamin E restored serum vitamin E levels to normal and
appeared to halt or slow the progression of the neurologic
abnormalities and RP in three patients followed for 1, 4, and
2236 10 years, respectively.109,110
FIGURE 177.16. Full-field ERGs from a normal subject and a patient
with a mild form of Refsum disease before and 4 years after treatment
with a low-phytol, low-phytanic acid diet. Pretreatment responses
were recorded at age 31 years.
From Berson EL: Electroretinographic findings in retinitis pigmentosa. Jpn J
Ophthalmol 31:327, 1987.
OTHER FORMS OF RP
Some 15–20% of individuals with RP have associated hearing
loss, sometimes referred to as Usher syndrome in recognition of
the British ophthalmologist, C. H. Usher, who observed that
this condition was recessively inherited.111,112 Patients with
Usher syndrome type I typically have night blindness in the first
or second decade of life, profound congenital deafness (i.e.,
>70 dB loss at all frequencies) with unintelligible speech, and
vestibular ataxia, whereas those with Usher syndrome type II
usually report night blindness in the second to fourth decades,
have a partial high-tone hearing loss with intelligible speech,
and do not show ataxia.113 Patients with Usher syndrome type
II have abnormalities in the cilia of sperm and in the connecting
cilia in many remaining photoreceptors in autopsy eyes.114,115
Patients with Usher syndrome type III have RP with onset of
hearing loss in mid-adulthood that can progress to profound
deafness; some have vestibular ataxia.116 All forms of Usher
syndrome appear to be slowly progressive over the long term.
Patients with Usher syndrome type II were included in the clinical
trial of vitamin A70 and DHA80,81 and, therefore, adult patients
are being treated with vitamin A palmitate 15 000 IU/day and
an omega-3 rich diet as described earlier in this chapter.
Molecular genetic analyses have revealed gene loci for Usher
syndrome type I (further subdivided into forms B through F); for
Usher syndrome type II (forms A through D); and for Usher
syndrome type III (form A only so far detected) (see Table
177.2). The authors who originally reported Usher syndrome
type IA have subsequently found that this form does not exist
as initially described.117
Some 2–6% of congenitally deaf children will develop Usher
syndrome type I. If a child presents with profound deafness and
a balance disorder manifested by late onset of walking, usually
after 15 months of age, the possibility of Usher syndrome type
I should be considered.118 The diagnosis of RP as part of Usher
syndrome can be made in early life with ERG testing. No tests
of retinal function are yet available to identify carriers of Usher
syndrome.
The Laurence–Moon–Bardet–Biedl syndrome includes RP,
mental retardation, polydactylism, truncal obesity, and hypo-
gonadism as the most frequent features.119–122 Some authors
have subdivided this syndrome into two disorders: poly-
dactylism is found primarily in patients with the Bardet–Biedl

form, whereas neurologic findings are typically observed in
patients with the Laurence–Moon form.123–124 However, some
patients have been described with both polydactylism and
neurologic abnormalities and therefore would seem to qualify
for inclusion in both syndromes.125,126 Variability of clinical
expression is well known, and some patients may have this
condition without mental retardation or polydactylism.127
Genetic heterogeneity also exists, as the condition is caused by
at least 12 different genes (BBS1, BBS2, ARL6, BBS4, BBS5,
MKKS, BBS7, TTC8, PHTB1, BBS10, BBS11, and BBS12). These
genes in the aggregate account for only about half of the cases
of this syndrome. Renal disease can be a part of this
syndrome,127 and therefore, patients should have their blood
pressure and urine checked periodically, with appropriate
treatment instituted for their renal disease if detected.
Retinal degeneration is the most common feature of the
Laurence–Moon–Bardet–Biedl syndrome, occurring in ~90% of
cases.127 The macula is often involved early, leading to the
suggestion that these patients have an inverse form of RP. The
fundus in early life may be granular without pigment formation,
so that the diagnosis is established only after ERG testing.128 A
child born with polydactylism to normal parents should be a
suspect for this syndrome. Once this syndrome is identified in
one individual, parents would know that they have as much as
a 25% chance with each succeeding childbirth of having another
child with this condition. The inheritance of the Bardet–Biedl
syndrome can be unusual as mutations in two unlinked
Bardet–Biedl genes at one locus have been detected in some
families and expression of this condition may be modified by
a mutation at a second locus that may not alone cause
disease.129–131 No treatment is currently known for the retinal
degeneration associated with this syndrome.
Congenital amaurosis of Leber is an autosomal recessive
disorder associated with severe reduction in vision near birth
and very reduced ERGs.132–133 Patients characteristically have
hyperopia and nystagmus, and fundus examination reveals
granularity, white flecks, or intraretinal bone spicule pigment,
or some combination of these. Carrier parents have a 25%
chance with each childbirth of having a child affected with this
condition. Mental retardation has been reported in some
patients, possibly secondary to visual impairment. Leber con-
genital amaurosis involving the retina and pigment epithelium
should not be confused with Leber optic atrophy, a maternally
inherited condition involving the optic nerve associated in some
families with an abnormality in mitochondrial DNA.134,135
Abnormalities in 12 genes have been so far identified as
causes of Leber congenital amaurosis. Genes so far implicated
are GUCY2D, CRB1, IMPDH1, RPE65, AIPL1, RDH12,
RPGRIP1, CRX, TULP1, LRAT, CEP290, and LCA5. These
genes account for more than half of the known cases. In one
form of this condition mutations in GUCY2D (retinal guanylate
cyclase 1) suggest that cGMP production in photoreceptors is
abolished. Consequently, photoreceptor excitation would be
expected to be impaired due to closure of cGMP-gated cation
channels with hyperpolarization of the photoreceptors. It has
been proposed that the cGMP concentration in photoreceptor
cells cannot be restored to the dark level, leading to a situation
equivalent to constant light exposure during photoreceptor
development.136 A model for this disease exists in the rd/rd
chicken, which is functionally blind at hatching, with an
extinguished ERG, absent guanylate cyclase activity, and a
mutation in the guanylate cyclase gene.137 Mutations in
another gene, designated as RPE65, affect vitamin A
metabolism in the retinal pigment epithelium.138,139 A canine
model of this condition with an RPE65 gene deficiency has been
rescued with subretinal injection of the RPE65 gene carried by
an attenuated adenoviral (AAV) vector.140 Another model of
Retinitis Pigmentosa and Allied Diseases
Leber congenital amaurosis has been produced in mice with
knockout of the RPGRIP1 gene, and rod structure and function
have been restored with subretinal injection of the RPGRIP1
gene also carried in an AAV vector.141 It remains to be
established whether gene therapy can be safely used to reverse
retinal malfunction in humans with Leber congenital
amaurosis with remaining photoreceptor cells.
Retinitis punctata albescens can be associated with some
signs and symptoms characteristic of RP.142 Patients usually
present with profound adaptational problems and gradual loss
of peripheral vision. Examination with a direct ophthalmoscope
reveals multiple punctate white deposits in the macula and
around the mid-periphery at the level of the pigment epithe-
lium, for which this condition was named. Patients have retinal
arteriolar attenuation and some develop round areas of atrophy
of the retinal pigment epithelium as well as intraretinal bone
spicule pigment in the midperiphery. This raises the possibility
that this condition is a variant of RP.143 This form of retinal
CHAPTER 177
degeneration may affect the eyes of a patient asymmetrically;
therefore, these patients often receive a neurologic evaluation in
search of an intracranial abnormality before it is realized that
the visual loss is due to a widespread retinal degeneration. Full-
field ERGs of such patients are invariably abnormal with reduc-
tions in amplitude and delays in implicit times. The condition
is usually slowly progressive, although the course appears to
vary from one individual to another. This condition has been
thought to be inherited by an autosomal recessive mode, but a
dominant mode of transmission can occur. Therefore, ERG
testing of relatives of affected patients is recommended to help
establish the mode of transmission. A null mutation in the
peripherin/RDS gene has been reported in one family with this
condition with a dominant mode of transmission144; other
families with an autosomal recessive mode of transmission
have shown mutations in the cellular retinaldehyde-binding
protein (CRALBP) gene.145–147
Another atypical form of RP has been designated as
“progressive cone–rod degeneration.”148 Patients with this form
present with reduced visual acuity, photophobia, color deficiency,
and night deficiency and show signs of macular degeneration,
retinal arteriolar attenuation, and in some cases, intraretinal
bone spicule pigment in the peripheral fundus. Dark-adaptation
testing shows elevated final dark-adaptation thresholds across
the fundus, and full-field ERGs show a profound loss of cone
function and some reduction in rod function. This condition is
usually inherited by an autosomal recessive mode but can also
be inherited by an autosomal dominant mode. Mutations have
been found in the retina-specific ATP-binding cassette trans-
porter (ABCA4) gene,149 the same gene that has been found to
be abnormal in patients with juvenile macular degeneration
(Stargardt disease).150–152 No treatment is yet known for pro-
gressive cone–rod degeneration.
Other atypical forms of RP include pericentral, paravenous,
or unilateral RP. The pericentral form is characterized by a near
mid-peripheral scotoma extending from the 5–30° isopter (Fig.
177.17) (in contrast to typical RP where the field loss initially
extends from the 20–40° isopter), single flash (0.5 Hz) ERGs
greater than 100 mV and 30-Hz cone ERGs greater than 15 mV
initially (Fig. 177.18), and a normal or nearly normal final dark
adaptation threshold in the periphery. This form progresses at a
slower rate than typical RP; in later life they can lose central
vision but they retain considerable peripheral vision.153 The
paravenous form is usually characterized by slightly reduced
full-field ERGs and intraretinal pigment and atrophy of the
pigment epithelium confined to the distribution of the retinal
veins in each eye. In some cases the macula degenerates as well
(Fig. 177.19). Patients with paravenous disease may lose central
vision but, like pericentral RP, they retain peripheral vision into 2237
 RETINA AND VITREOUS

FIGURE 177.17. Fundus photographs for a

patient with pericentral retinitis pigmentosa to
show an increase in pericentral bone-spicule
pigmentation over an 18-year interval.
Reprinted from Am J Ophthalmol, vol 140, Sandberg
MA, Gaudio AR, Berson EL. Disease course of patients
with pericentral retinitis pigmentosa, pp 100–106,
Copyright 2005 from Elsevier Science.

FIGURE 177.18. Visual fields to the V-4e white

test light and full-field electroretinograms to
0.5 Hz and 30 Hz flashes spanning 22 years
from a patient with pericentral retinitis
pigmentosa to illustrate disease progression.
Reprinted from Am J Ophthalmol, vol 140, Sandberg
SECTION 10

MA, Gaudio AR, Berson EL. Disease course of patients

with pericentral retinitis pigmentosa, pp 100–106,
Copyright 2005 from Elsevier Science.

FIGURE 177.19. Fundus photographs of the right eye of a patient at age 22 years (left) and at age 39 years (right) with pigmented paravenous
retinochoroidal atrophy. At age 22 years, the fundus showed paravenous intraretinal bone spicule deposits overlying areas of pigment epithelial
and choroidal atrophy with some disturbance of the retinal pigment epithelium in the macula. At age 39 years, progression can be seen with
more paravenous pigment and some clumped pigment in the macula.
Reprinted from Am J Ophthalmol, vol 141, Choi JY, Sandberg MA, Berson EL. Natural course of ocular function in pigmented paravenous retinochoroidal atrophy,
pp 763–765, Copyright 2006 from Elsevier Science.

later life.154 Unilateral RP is characterized by fundus changes of
RP in one eye with no evidence of RP in the fellow eye. Full-field
ERGs are substantially reduced in the affected eye and normal
in the fellow eye. Patients with unilateral RP have progressive
disease in the affected eye but have not been observed to develop
a generalized form of RP in the fellow eye at a later time.
Pericentral RP can be inherited by a recessive or dominant mode
while paravenous and unilateral RP have been found charac-
2238 teristically in patients with no family history of this condition.
No evidence exists that patients with pericentral, paravenous,
or unilateral RP will benefit from vitamin A treatment.
An estimated 0.5% of patients with RP have a clumped pat-
tern of pigmentation in the mid-peripheral fundus, sometimes
referred to as ‘clumped pigmentary degeneration’. These patients
characteristically have hyperopia, night blindness, and reduced
and delayed full-field ERGs. Humphrey static perimetry with
blue stimuli on a yellow background to evaluate short-wave (S)
blue-cone function and white stimuli on a white background to

evaluate function mediated by all three cone types has revealed
that some of these patients with clumped pigment have rela-
tively enhanced blue-cone function and such patients are
therefore considered to have the enhanced S-cone syndrome.155
Molecular genetic analyses have revealed mutations in the
NR2E3 gene which is thought to encode a ligand-dependent
transcription factor156 or in the NRL gene which encodes a basic
motif-leucine zipper protein.157 Patients with enhanced S-cone
syndrome have been shown to have shared mutations in the
NR2E3 gene with patients with Goldmann–Favre syndrome.
Patients with NR2E3 mutations appear to inherit this condition
by an autosomal recessive mode while those with NRL muta-
tions can inherit this condition by a dominant or recessive
mode. Patients with the enhanced S-cone syndrome appear to
have a slowly progressive disease with gradual loss of peripheral
field. No treatment is yet known.
CHOROIDEREMIA
Young males with choroideremia characteristically have normal
visual acuities, minimally increased dark-adaptation thresholds,
and full visual fields to large test lights at a time when granu-
larity and depigmentation of the retinal pigment epithelium are
seen around the fundus periphery. ERGs are reduced in ampli-
tude with delays in b-wave implicit time (Fig. 177.20). In more
advanced stages in adulthood, dark-adaptation thresholds are
FIGURE 177.20. ERG responses of four males with choroideremia.
Cone flicker responses to white 30-cps flicker remained detectable in
the oldest male when rod responses to blue light were not detectable.
Normal responses are shown for comparison. Time of stimulus onset
is designated by ‘vertical hatched lines’ in columns 1 and 2 and
vertical shock artifacts in column 3. Arrows and vertical bar on rod
responses to blue light show the range of normal b-wave implicit
times. Responses to single flashes of white light show reduced a- and
b-wave amplitudes in all males. Arrows on white flicker responses
show delayed implicit times in the affected males.
Reprinted from Sieving PA, Niffenegger AB, Berson EL, Am J Ophthalmol,
vol 101, Electroretinographic findings in selected pedigrees with choroideremia,
pp 361–367, Copyright 1986, from Elsevier Science.
Retinitis Pigmentosa and Allied Diseases
further increased and the visual fields become constricted at a
time when ERGs are profoundly reduced or nondetectable and
extensive choroidal atrophy and clumped pigment are visible
around the peripheral fundus (see Fig. 177.2b). Males usually
retain little, if any, central vision beyond the age of 60 years.158,159
Obligate female carriers of this X-linked disease may demon-
strate fundus changes that include patchy depigmentation of
the retinal pigment epithelium and coarse pigment granularity
or even pigment clumps in the periphery. However, carriers
typically retain normal visual acuities and normal final dark-
adapted rod thresholds.159–161 Generally, carriers have been thought
to have a nonprogressive course, but carriers with severe disease
have been described.159 In contrast to the carrier state of
X-linked RP, ERGs of carriers of choroideremia usually are
normal,159 although reduced amplitudes have been reported in
some cases.159,161
Study of a patient with choroideremia with a large deletion
helped to assign the choroideremia gene to a small segment of
CHAPTER 177
the long arm of the X-chromosome, specifically in the Xq21
band.162,163 The gene (CHM) responsible for this condition,
encodes Rab escort protein 1 (REP-1).164 Many mutations in this
gene have been described subsequently.165,166 Loss of the REP-1
protein is thought to compromise Rab protein prenylation; the
lack of prenylation, in turn, would affect protein trafficking
inside the retinal pigment epithelium or choroidal cells triggering
the degenerative process in this condition.167–169 An animal
model of this condition has been created and is under study.170
Interfamilial and intrafamilial variability of clinical expres-
sion is known to exist in this disease. The natural course of
choroideremia on a year-to-year basis is being investigated.
Correlations, if any, between specific mutations and clinical
expression of the disease remain to be completed. No treatment
is yet known.
GYRATE ATROPHY OF THE CHOROID AND
RETINA
Key Features: Gyrate Atrophy of the Choroid and Retina
– Diagnosis and Management
• Symptoms – night blindness, loss of peripheral field, eventual
loss of visual acuity.
• Ocular findings - myopia, peripheral chorioretinal atrophy,
reduced electroretinograms.
• Biochemical findings - hyperornithinemia, hyperornithinuria,
hypolysinemia.
• Treatment – low-protein, low-arginine diet in all cases; vitamin
B6 supplementation for the B6-responsive form.
Gyrate atrophy of the choroid and retina is a rare chorioretinal
degeneration inherited by an autosomal recessive mode of
transmission.171,172 Patients usually report night deficiency and
loss of peripheral vision in adolescence. Ocular findings include
myopia, constricted visual fields, elevated dark-adaptation
thresholds, very small or nondetectable ERG responses, and
chorioretinal atrophy distributed circumferentially around the
peripheral fundus (see Fig. 177.2c) and sometimes near the
optic disk. In addition to the ocular findings, abnormalities in
electroencephalograms, muscle and hair morphology, and
mitochondrial structure in the liver have been reported.173
Enlargement, coalescence, and posterior extension of areas of
atrophy have been observed in young patients within 2 years.174
Patients develop cataracts in young adulthood and often require
surgery. If untreated, patients usually become virtually blind
between the ages of 40 and 55 years as a consequence of
extensive chorioretinal atrophy.175 2239
 RETINA AND VITREOUS
Patients with this condition have plasma ornithine concen-
trations elevated 10- to 20-fold above normal176,177 due to a
deficiency of ornithine aminotransferase (OAT) activity (Fig.
177.21).178–180 Affected individuals cannot convert ornithine to
pyrroline-5-carboxylic acid (PCA); this deficiency can be
detected in extracts of cultured skin fibroblasts. Patients have
virtually no OAT activity in contrast to normal persons, where-
as carrier parents have a partial deficiency. Cultured cells from
some patients have shown increased OAT activity when the
cofactor for OAT, namely pyridoxal phosphate or vitamin B6, is
added to the media in increased concentration. Plasma lysine181
and glutamate and glutamine,182 as well as serum and urine
creatine,183 have also been found to be reduced. More than
60 mutations have been discovered in the OAT gene on
chromosome 10 in affected patients.184
Since arginine is a precursor of ornithine, and since arginine,
but not ornithine, is a constituent of food protein, it has been
suggested that dietary restriction of protein and arginine will
SECTION 10
reduce plasma ornithine levels in these patients.185 OAT-
deficient mice produced by gene targeting develop a retinal
degeneration over several months that is amenable to treatment
postweaning with an arginine-restricted diet.186
The hyperornithinemia associated with human disease has
been lowered toward normal with a low-protein, low-arginine
diet in all cases so far studied185,187,188 and with vitamin B6 (300
to 500 mg/day) in some cases.189–191 However, extreme protein
restriction (10–15 g/day) with substantial lowering of plasma
ornithine, accomplished under supervision in the hospital, has
been difficult to achieve at home, and therefore, many of the
patients have followed modified (20–35 g/day) protein restric-
tion with slight rises in their plasma ornithine levels. Some
investigators have reported improvements in visual acuity,
visual fields, dark-adaptation thresholds, or ERGs in patients
with gyrate atrophy after onset of either the diet or vitamin
B6,187 whereas others have not documented any significant
improvement in visual function despite substantial reductions
in plasma ornithine concentrations.191 Improvement in muscle
morphology after creatine supplementation has been reported
in several patients.192
The effect of severe arginine restriction has been evaluated in
two pairs of siblings younger than 10 years who were followed
for 5–7 years.193 The plasma ornithine levels were reduced to
approximately the normal range (106 and 121 mmol/L) in one
pair of siblings and reached twice the upper limit of normal
2240
(251 and 313 mmol/L) in the other pair. These younger siblings
had significantly less atrophy than their elder siblings when
they reached or approached the same age at which their elders
had begun the diet. Thus, there is evidence that a low-protein,
low-arginine diet can slow progression of the chorioretinal
degeneration, but only a few patients have so far been studied.
The goal of treatment is to maintain plasma ornithine levels
as close to normal as possible. Since some patients may respond
to supplementation with pyridoxine (vitamin B6), all patients
are initially given a trial of this vitamin to determine to what
extent, if any, it will lower plasma ornithine levels. Both
pyridoxine-responsive and nonresponsive patients are then
placed on a low-protein, low-arginine diet. Based on plasma
ornithine levels, biochemical control has been classified as good
to excellent (<200 mmol/L), fair (200 to 400 mmol/L), or poor
(>400 mmol/L). In the management of children, expertise is
required to be certain that growth and development remain
normal while lowering ornithine levels with a low-protein diet.
An arginine-free essential amino acid mixture (e.g., Cyclinex-1
or -2 [Ross Laboratories], depending on the patient’s age) is used
to provide sufficient nitrogen and meet essential amino acid
requirements. In adults, a low-protein diet is also likely to result
in amino acid deficiency. Thus, adults should also be placed on
an arginine-free essential amino acid mixture. Lysine supple-
mentation may be necessary, depending on plasma levels. As a
precaution, all patients are placed on a multivitamin prepara-
tion with minerals. In addition to a regular ocular examination,
all patients on this treatment regimen should have their amino
acid and protein levels monitored periodically.194
OTHER RETINAL DEGENERATIONS
Retinal degenerations involving the photoreceptors across the
retina can exist in association with other systemic findings. If a
patient presents with ophthalmoplegia and retinal degeneration,
the Kearns–Sayre syndrome should be considered. Abnormalities
include ptosis, chronic progressive external ophthalmoplegia, a
disturbance of the retinal pigment epithelium, ERGs usually
reduced in amplitude, and respiratory distress. Some patients
develop heart block and may require a pacemaker.195,196 The
diagnosis is confirmed by the observation of ragged red fibers on
muscle biopsy. This syndrome has been associated with mito-
chondrial DNA mutations; treatment of one patient with
coenzyme Q10 and succinate resulted in clinical improvement
FIGURE 177.21. Pathways of ornithine
metabolism.
From Weleber RG, Kennaway GN, Buist NR: Gyrate
atrophy of the choroid and retina. Int Ophthalmol
4:23–32, 1981. Reprinted by permission of Kluwer
Academic Publishers.

of respiratory distress.197 The value, if any, of this treatment for
retinal malfunction remains to be established.
Patients who present with a widespread loss of photoreceptor
function with abnormal ERGs and symptoms of cerebral
deterioration may have a cerebroretinal degeneration, grouped
under the overall heading of neuronal-ceroid lipofuscinosis, or
Batten disease. This group of diseases, which are recessively
inherited, is characterized by accumulation of lipopigments
(lipofuscin and ceroid) in neurons and other cell types. Batten
disease can be subdivided into an infantile form (psychomotor
deterioration by age 2 years, ataxia, microcephaly, granular
inclusions on conjunctival biopsy), a late-infantile form (seizures,
rapid mental deterioration in early childhood, curvilinear inclu-
sions on biopsy), a juvenile form (mental deterioration begin-
ning around age 6 years, bull’s-eye maculopathy, fingerprint
inclusions on conjunctival biopsy), and an adult-onset form
(seizures, slow dementia, abnormal inclusions best seen on
muscle biopsy).
Molecular genetic studies have revealed that the juvenile
onset form of Batten disease results from defects in the CLN3
gene on chromosome 16p; the majority of patients have a 1.2-kb
deletion in this gene on at least one chromosome.198 The gene
encodes a novel protein of unknown function. Studies have
suggested that the mechanism of apoptosis is involved in the
demise of both neurons and photoreceptors.199 No treatment
exists for the retinal degeneration in this condition.
Patients with olivopontocerebellar atrophy can present with a
history of tremors, ataxia, and dysarthria and show findings of
oculomotor impairment and retinal degeneration. This con-
dition is inherited by a dominant mode with variable pene-
trance. Some patients have retinal arteriolar attenuation, a
diffuse disturbance of the retinal pigment epithelium, and
very reduced ERGs. Some patients may show only neurologic
findings and have normal fundi and normal retinal function,
whereas others have had abnormal ERGs with no diagnostic
findings on fundus examination and no history of neurologic
disease. Of all the known forms of spinocerebellar atrophy, if
there is associated photoreceptor degeneration, almost all are
due to mutations in the SCA-7 gene. In general, each succeeding
generation is more severely affected and has an earlier onset
and increase in severity is more common if the condition
is inherited from the father. This condition is presently
untreatable.200–202
Other rare syndromes associated with retinal degeneration
include Alström disease and Cockayne syndrome. Patients with
Alström disease have RP with profound loss of vision in the first
decade of life and very reduced ERGs. Systemic findings include
diabetes mellitus, obesity, deafness, renal failure, baldness, and
hypogenitalism.203,204 Patients with Cockayne syndrome show
extensive loss of vision by the second decade of life and have RP,
dwarfism, deafness, mental deterioration, and premature aging.
No treatments are known for these conditions.205,206
STATIONARY FORMS OF NIGHT
BLINDNESS
Key Features: Stationary Forms of Night Blindness
• Inherited by a dominant, recessive, or X-linked mode.
• Clinical findings – normal appearing fundi or golden brown
fundi (Oguchi disease) or white deposits around the mid-
periphery (fundus albipunctatus).
• Electroretinograms – impaired rod function after 45 min of dark
adaptation, normal or nearly normal cone function.
• Long-term visual prognosis relatively good compared to
retinitis pigmentosa.
Retinitis Pigmentosa and Allied Diseases
Stationary night blindness can be inherited by an autosomal
dominant, autosomal recessive, or X-linked mode. Some patients
can have a normal fundus appearance. Two forms, Oguchi disease
and fundus albipunctatus, have characteristic fundus abnor-
malities (see Fig. 177.2d and e). It is the normality or near-
normality of the cone system in the full-field ERGs that allows
separation of most stationary forms of night blindness from
practically all forms of night blindness associated with the early
stages of RP (see Fig. 177.4).
The original classification of these diseases was based on the
family of origin (e.g., Nougaret type) or by the initial description
of the ERG waveforms associated with the condition (e.g., Riggs
or Schubert–Bornschein type), or by the ophthalmologist who
first described the disease (e.g., Oguchi disease). These diseases
are now being reclassified by molecular genetic analysis.207
Missense mutations in three different genes encoding mem-
bers of the rod phototransduction cascade have been reported to
cause dominantly inherited stationary night blindness. Specifi-
CHAPTER 177
cally, the mutations are the Ala292Glu and Gly90Asp muta-
tions in the rhodopsin gene;208,209 the His258Asp mutation in
the beta-subunit of rod phosphodiesterase gene;210 and the
Gly38Asp mutation in the alpha-subunit of rod transducin
gene.211 The latter mutation has been seen only in the descen-
dants of Jean Nougaret. Whereas the Ala292Gly rhodopsin
mutation apparently causes a complete loss of rod function (i.e.,
Riggs type),208 the other mutations cause an incomplete loss of
rod function.211,212
Some evidence exists from psychophysical and ERG testing
that the rods are constitutively active in the dark in some forms
of stationary night blindness. In the rhodopsin, Gly90Asp
mutation, psychophysical measures with Stiles two-color incre-
ment threshold technique show the equivalent of light adapta-
tion in the dark owing to rhodopsin activation in darkness.208
The ERG abnormalities in patients with the Gly38Asp muta-
tion in the alpha-subunit of rod transducin can be simulated by
light-adapting the normal retina, compatible with the idea that
these patients have mutant rod transducin that is constitutively
active in the dark.212 Evidence that patients with stationary night
blindness have rod photoreceptors despite their night blindness
is supported by fundus reflectometry studies that have shown
normal levels of rhodopsin and normal rhodopsin kinetics.213
Oguchi disease is a recessively inherited form of stationary
night blindness. Patients usually require 2–12 h to attain nor-
mal dark-adapted rod thresholds and show a characteristic
change from a golden brown color of the fundus in the light-
adapted state (see Fig. 177.2d) to a fundus of normal color in
the dark-adapted state (the ‘Mizuo phenomenon’). After 1 h of
dark adaptation, patients with Oguchi disease have no rod
b-wave in response to dim blue light flashes, a cornea-negative
response to white light, and a normal cone response to 30-Hz
white flicker. Following complete dark-adaptation after 12 h,
some patients have a normal rod b-wave amplitude and normal
rod b-wave implicit time, but only in response to one or two
flashes of light.214 Apparently, the test flash used to elicit the
ERG, although relatively dim, can be intense enough to light-
adapt the rod system. Molecular genetic analyses have shown a
null mutation, Asn309(1-bp del), in the gene encoding arrestin
in some patients of Japanese descent.215 Several null mutations
have also been described in the gene encoding rhodopsin kinase
in some patients of Eastern European descent.216 Both arrestin
and rhodopsin kinase participate in the deactivation of photo-
activated rhodopsin. The lack of either arrestin or rhodopsin
kinase would be expected to have the same physiologic effect,
namely the prolongation of photoactivated rhodopsin with a
consequent abnormality in rod sensitivity.
Fundus albipunctatus is another form of recessively inherited
stationary night blindness.217,218 Patients have yellow-white 2241
 RETINA AND VITREOUS

deposits in the deep retina outside the macula (see Fig. 177.2e).
Some develop macular degeneration in later life. Patients with
fundus albipunctatus have a delay in rod visual pigment and
foveal cone pigment regeneration as monitored with fundus
reflectometry.217,219 Changes in visual pigment levels parallel
the prolonged cone and rod limbs of the dark-adaptation curve.
Full-field ERGs have been found to be normal with respect to
both cone and rod amplitudes and b-wave implicit times after
full dark-adaptation.218 The findings in fundus albipunctatus
suggest an abnormality in visual pigment regeneration second-
ary to some abnormality in the relationship between the photo-
receptors and the pigment epithelium. The composition of the
yellow–white lesions and their relationship to the abnormality
in visual pigment regeneration are not known. Mutations in the
RDH5 gene compromising the function of 11 cis-retinol-dehydro-
genase have been found to be the cause of this condition.220,221
Another form of stationary night blindness is congenital
nyctalopia with myopia. This condition (i.e., Schubert–
SECTION 10
axial myopia as the only finding.225 Patients with X-linked
congenital nyctalopia have been further subdivided into the
complete or incomplete form. In the complete form, the rod a-
wave is normal and the rod b-wave is absent and responses are
mediated by the cone system. This form appears to be caused
by abnormalities in the NYX gene, whose gene product appears
to be involved in ON-bipolar cell signaling.226,227 In the incom-
plete form rod ERG responses, although reduced in amplitude,
are still measurable to dim blue light, and the cone ERG is also
subnormal. The incomplete form appears due to mutations in
the CACNAIF gene; patients with this condition have ERG
abnormalities due to malfunction of both the ON- and OFF-
bipolar pathways. Whereas patients with the complete form have
moderate or high myopia, those with the incomplete form are
thought to have mild myopia or slight hyperopia.228 Whereas
the complete form appears to be stationary, the long-term course
of patients with the incomplete form remains to be established.
Congenital night blindness associated with a negative ERG

Bornschein type) is inherited by either an X-linked or an
autosomal recessive mode.222–224 The extent of the myopia is
characteristically –3.5 to –14.5 D. Patients cannot attain
normal dark-adapted rod thresholds and have fundus findings
of myopia. Their rod ERG b-wave responses to dim blue light
are nondetectable, and they show a characteristic cornea-
negative response to white light in the dark-adapted state and
normal or nearly normal cone responses to 30-Hz white flicker
(see Fig. 177.4). The preservation of the a-wave from the rod
photoreceptors with loss of the b-wave from neurons proximal
to the photoreceptors suggests some abnormality in intraretinal
transmission of the response from the rod photoreceptors to
proximal retinal cells. ERG amplitudes are reduced in
congenital nyctalopia with myopia compared with those from
normal emmetropes; this probably occurs because of the known
reductions of ERG amplitude seen in patients with moderate
waveform has also been described in some patients with
mutations in the GRM6 gene encoding the glutamate receptor
mGluR6. This receptor is present only in the synapses of the
ON-cell bipolar dendrites and it mediates synaptic transmission
from rod and cone photoreceptors to this second order neuron.
Patients are night blind at an early age and have acuities that are
normal or slightly reduced. In addition to reduced b-waves, ERG
responses to saw-tooth flickering light indicate a reduced ON-
response and a nearly normal OFF-response. The condition
appears inherited by an autosomal recessive mode and is
thought to be stationary or very slowly progressive.229
The ERG abnormality in congenital nyctalopia with myopia
has been reported as an acquired defect in patients with
cutaneous malignant melanoma, who report an acute onset of
night blindness with selective reduction in the rod b-wave
response (Fig. 177.22).230 Development of an antibody to the

FIGURE 177.22. Full-field ERG responses from a normal subject, from the right (OD) and left (OS) eyes of a patient with malignant melanoma,
and from a patient with congenital stationary night blindness with myopia (CSNB). Stimulus onset is designated by the ‘vertical hatched lines’ in
columns 1, 2, and 3 and the ‘vertical lines’ superimposed on the responses in column 4. Two or three consecutive responses are illustrated, and
cornea-positivity is an upward deflection. The peak of the cornea-negative a-wave, generated by photoreceptors, and the peak of the cornea-
positive b-wave, generated by activity of cells proximal to the photoreceptors, are designated in the response of the normal subject to single
flashes of white light. Calibration symbol (lower right) designates 50 msec horizontally, 200 mV vertically for the top recording in column 3, and
100 mV vertically for all other tracings. Both patients lack the cornea-positive b-wave from the rod system in columns 1, 2, and 3 in contrast to
the normal, while retaining normal cone amplitudes (≥50 mV) in their responses to 30-Hz white flickering light in column 4.
Reprinted from Berson EL, Lessell S, Am J Ophthalmol, vol 106, Paraneoplastic night blindness with malignant melanoma, pp 307–311, Copyright 1988, from Elsevier
2242 Science.

melanoma that also reacts to retinal cells with an interruption
in rod signal transmission has been considered as a probable
mechanism to account for the sudden onset of night blindness
in these patients.
Another form of congenital night blindness is that seen in
patients with impaired cone adaptation and elevated final rod
thresholds which has been termed ‘bradyopsia’.231 Patients with
this condition have mutations in the genes encoding RGS9 or
its anchor protein R9AP with consequent slow photoreceptor
deactivation. RGS9 specifically deactivates the G-proteins
(transducins) in the rod and cone phototransduction cascades.
It is anchored to photoreceptor membranes by the transmem-
brane protein R9AP which enhances RGS9 activity up to
70-fold. Patients present in childhood with photophobia and
have difficulty adapting to sudden changes in luminance levels
under photopic conditions. Visual acuity is either normal or
moderately subnormal and can fluctuate. Patients have diffi-
culty seeing moving objects especially with low contrast despite
full visual fields. Fundus findings are unremarkable. Diminu-
tion in cone 30-Hz flicker ERG responses to successive flashes
of light should suggest the possibility of this condition. Findings
in patients followed for as long as 25 years suggest that this
condition is stationary.
It is of interest that stationary forms of night blindness, with
impaired rod function in early life but no evidence of rod cell
death, are not associated with intraretinal pigment migration or
attenuation of the retinal vessels, whereas these latter findings
are characteristically seen in patients with rod cell degeneration
and RP. Although the stationary or near stationary forms of
night blindness are rare, it is important to identify these con-
ditions when patients present with night blindness on a retinal
basis, as the long-term prognosis in these patients is relatively
good, in contrast to the progressive retinal degeneration of rods and
cones seen in patients with night blindness associated with RP.
APPROACH TO THE PATIENT
Patients with known or suspected RP or an allied disease should
be asked to provide a history of the age of onset of night blind-
ness, visual-field loss, and loss of visual acuity. Often symptoms
of night blindness reflect problems in adaptation under dim
photopic conditions, and therefore suggest cone malfunction.
Patients with a sudden onset of night blindness, particularly
after the age of 50 years, should be considered suspects for
a paraneoplastic process (i.e., nonocular malignancy with
associated retinal malfunction), or so-called cancer-associated
retinopathy.232–234 Difficulties in reading may reflect a general-
ized loss of cone function or loss of cone function confined to
the macula.
The medical history should include information on
operations and illnesses as well as current medications and
nutritional supplements. Intestinal surgery or liver disease may
have affected the absorption or metabolism of vitamin A.
Chronic intake of some medications (e.g., hydroxychloroquine,
phenothiazines) may have compromised retinal function. The
medical history should include information on the status of
hearing, as some 10–15% of patients with RP have a high-tone
partial hearing loss, and some 5% have profound congenital
deafness. A history of polydactyly, mental retardation, or renal
disease, if elicited, should raise the possibility of an association
of these abnormalities with a retinal degeneration. A detailed
family history is always warranted to determine whether other
members of the family are affected with the retinal degeneration
and to determine whether or not consanguinity exists in the
parents, as this raises the likelihood of a hereditary disease.
The ocular examination should include a refraction; some
50% of patients with RP have 1 or more diopters of astigmatism
Retinitis Pigmentosa and Allied Diseases
in the less astigmatic eye.25 Uncorrected myopia can be a cause
of night blindness, and therefore it is important to establish
that the patient has the correct prescription. Reading vision
should be tested and lenses prescribed as needed to ensure that
the patient can read at least 8-point print. After an assessment
of acuity and refractive error, a visual field should be performed
with either the Goldmann perimeter or the Humphrey field
analyzer. If the Goldmann perimeter is used, it is recommended
to test with both a small (e.g., I-4e or II-4e) and large (e.g., IV-4e
or V-4e) white test light, as many patients do not have sufficient
remaining function to detect the small light. If the Humphrey
field analyzer is used, use of the size III or size V white target is
advised using both the 30–2 and 60–2 programs to assess the
central and the mid-peripheral visual fields. Color vision testing
should then be performed, preferably without dilation and
under standard lighting conditions. The Farnsworth panel D15
and the Ishihara plates are adequate for initial screening for red
and green color deficiencies; a tritan axis of confusion (i.e., blue
CHAPTER 177
blindness) can occur in patients with RP. After these tests,
applanation pressures are measured; elevated pressures (>35
mm Hg) can result in diminished ERG amplitudes.
Pupils are then maximally dilated with phenylephrine hydro-
chloride and cyclopentolate hydrochloride and the patient patched.
After 30–45 min of dark adaptation, final dark-adaptation
thresholds are measured to establish whether the patient has
impaired rod function. After dark-adaptation testing, full-field
ERG testing is performed. If the responses are easily detected
without computer averaging, the test can be accomplished
within 10–15 min per eye; if computer averaging is required, the
testing may take 20–30 min per eye. This sequence of
evaluations helps to ensure that the patients have their dark-
adaptation and ERG testing before more extensive light
exposure associated with ophthalmoscopy that might light-
adapt the patient and thereby affect the dark-adaptation and
ERG measurements.
After the results of dark-adaptation and ERG testing are
obtained, patients are examined with pupils fully dilated, at
which time the refractive error can be confirmed by retinoscopy
and glasses modified, if necessary. A slit-lamp examination and
direct and indirect ophthalmoscopy are performed; fine retinal
deposits (as, e.g., those seen in retinitis punctata albescens) and
slight retinal arteriolar attenuation may be appreciated with
direct but not indirect ophthalmoscopy. In the case of patients
with cataracts, a retinal acuity can be obtained with a retinal
potential acuity meter or equivalent instrument to compare
retinal acuity with distance acuity.
In the case of isolate males with RP when X-linked disease is
suspected, the patient’s mother should be evaluated, if possible,
with both a fundus examination and ERG testing, to determine
whether she shows signs of a carrier state of X-linked disease
and, if affected, how much retinal function remains. Carriers of
X-linked RP have abnormal full-field ERGs in one or both eyes
in more than 90% of cases, whereas carriers of autosomal reces-
sive disease have normal fundi and normal ERG amplitudes.
Establishment of a diagnosis of X-linked disease can be helpful
in determining the visual prognosis of a male patient with RP,
since untreated males with X-linked disease often become vir-
tually blind by age 30–45 years, whereas males with autosomal
recessive disease often become virtually blind after age 50–60 years.
If the diagnosis of a common form of RP is established, adult
patients should be advised that their condition is treatable with
vitamin A palmitate.70–73 Before treatment is initiated, eligible
patients should have a fasting serum vitamin A level and liver
function profile performed to be certain these values are normal
before starting vitamin A. Information should be provided as to
available sources of the correct dose of vitamin A palmitate (i.e.,
15 000 IU/day for adults). (For current sources of vitamin A 2243
 RETINA AND VITREOUS
palmitate see www.blindness.org). The patient should be
advised that higher doses provide no additional benefit and that
doses of 25 000 IU/day or greater are potentially toxic over the
long term. All patients should be advised of the possible adverse
effect of high-dose (i.e., ≥ 400 IU/day) vitamin E supplemen-
tation.70 Adult patients already taking vitamin A should be
advised to eat two 3-ounce servings of oily fish per week of
which DHA is a major constituent. Adult patients starting
vitamin A for the first time should be encouraged to take DHA
gelcaps 600 mg twice a day for 2 years at which time they
should stop the DHA supplement, continue to take vitamin A,
and begin to eat two 3-ounce servings of oily fish (e.g., salmon,
tuna, mackerel, or sardines of which DHA is a major con-
stituent) per week. Once oily fish is begun, they should have a
fasting red blood cell DHA (RBC DHA) level 3 months after
starting consumption of oily fish (i.e., to give time for the red
blood cells to renew themselves) to confirm that this level is at
least 4% of total RBC fatty acids. Patients should have a fasting
SECTION 10
serum vitamin A, liver function profile, and RBC DHA
annually thereafter. Whereas vitamin A alone is thought to slow
the annual rate of decline of remaining retinal function by 20%,
the combination of vitamin A plus an oily fish diet is thought
to slow the amount of remaining function by an additional
40–50%.81 Precautions with regard to the safe use of vitamin A
are reviewed earlier in this chapter in the section on The
Treatment of Retinitis Pigmentosa.
At the initial examination, every effort should be made to
establish the diagnosis; consider the best possible optical devices
to maximize remaining vision; explain the genetic implications,
where indicated; and offer referral to appropriate psychologic,
social, and community resources. In most cases, follow-up
examinations are conducted every 2 years to help determine the
course of the disease as monitored by visual acuity, visual fields,
and ERGs (computer averaged in most cases); to adjust glasses
and provide low-vision aids, if required; and to consider whether
cataract surgery is indicated. Cataract surgery is usually
deferred in the case of RP until a time when the patient can-
not read with either eye. A trial with dilating drops (e.g.,
homatropine 2% taken at dusk) may be attempted to see
whether the patient can meet her or his visual needs without
surgery. Cataract extraction has the greatest potential for
improving vision among those patients who have large enough
cataracts to impair visualization of the fundus with the
ophthalmoscope, detectable ERGs with computer averaging as a
measure of some remaining retinal function, and evidence of
retinal acuity that is better than distance acuity.
Key Features: Retinitis Pigmentosa – Other Treatment
Considerations
• Cataracts – surgical removal when patient can no longer read
with the better eye.
• Cystoid macular edema – oral Diamox, Acular drops,
dorzolamide drops, intravitreal steroids in some cases.
• Reduced doses of vitamin A palmitate for children aged
6–18 years.
• Night deficiency – night vision pocketscope to alleviate the
symptom of night blindness.
• Other optical aids – closed circuit television in selected cases,
avoidance of bifocals in patients with constricted visual fields.
Some 10–25% of patients with RP develop cystoid macular
edema. In some cases the edema can be subclinical and only
detected with optical coherence tomography (OCT). Acetazo-
lamide and Acular drops have been advocated for patients with
RP with cystoid macular edema; some given these medications
2244 have shown an improvement in acuity and others have claimed
subjective improvement without measurable change in acuity
within 1 month. Topical dorzolamide 2% can provide benefit.
Intravitreal steroid injections have also been used for severe
edema. The value of these treatments over the longer term for
such patients remains to be established.235,236
For patients under age 40 years with autosomal recessive RP,
serum lipoprotein electrophoresis and serum phytanic acid can
be assessed after fasting for 12 h if Bassen–Kornzweig syndrome
or Refsum disease is suspected. A fasting serum vitamin A level
can be obtained if nutritional deficiency or intestinal malabsorp-
tion is suspected. A serologic test for syphilis should be performed
if this diagnosis is suspected, as RP has been associated with
this disease. A fasting serum vitamin E level should be
considered in patients with the signs of RP who also report the
onset of ataxia in adulthood, as some success has been reported
with vitamin E supplementation for this rare disorder.
Discussion of results of the ocular examination with the
patient, and with the patient’s family if indicated, must be
individualized for each case; but in any event, every effort
should be made to answer the patient’s questions faithfully and
provide a clear description of not only what abnormalities exist
but also how much function remains. In this regard, the
measurement of any ERG function is an advantage, as the
patient can be shown in positive terms how much function
remains. The use of computer averaging and narrow bandpass
filtering is particularly important, as most patients with
remaining vision have detectable cone ERGs with use of this
specialized technology (which can detect responses as low as
0.05 mV) but will show nondetectable responses with conven-
tional full-field ERG systems (which can detect responses only
as low as 10 mV). The demonstration of remaining retinal func-
tion has prognostic implications. For example, assuming an
exponential rate of decline of remaining cone ERG function, the
average patient with 1.3 mV at age 32 would be expected to
retain some useful vision (i.e., greater than or equal to 0.05 mV)
until age 63 without treatment or until age 83 with vitamin A
supplementation plus an oily fish diet. A patient with 2.6 mV at
age 32 would be expected to retain useful vision until age 69
without treatment or until age 89 with vitamin A and oily fish.
Knowledge of the amount of remaining cone function quan-
tified by full-field ERG testing is therefore helpful in estimating
the long-term visual prognosis.237
It is important to impress on the patient that these con-
ditions in general progress at a very slow rate. Remarks such as
“Your vision may last for 2 years or 30 years” should be avoided,
as the patient hears only the more severe prognosis and does
not understand that in most instances he or she may well retain
vision for 20 to 40 years or more after the initial evaluation,
particularly in the case of RP or choroideremia. It is often useful
to hear what the patient believes he or she was told previously
and to try to address any misconceptions. For example, some
patients believe that retinal dystrophy and degeneration are
‘different diseases’ and erroneously conclude that none of the
physicians agree on the diagnosis.
Literature provided to the patient at the time of the visit is
extremely important, as most patients cannot assimilate all the
information given to them verbally. Printed information
describing their condition, patterns of inheritance, reasons why
they should be followed up over time by their ophthalmologist,
the significance of molecular genetic studies, and the like
should be available for distribution in the office. Patients may
wish to receive copies of the results of their ocular examin-
ations; visual displays of their ERG responses as part of this
report can be helpful in demonstrating to patients the amount
of retinal function remaining.
When a child is detected with RP or an allied retinal degen-
eration, parents should be provided with a full written report. If
 Retinitis Pigmentosa and Allied Diseases

the parents agree, then the child should be provided with sufficient
verbal information at the time of the examination to allow the
child to understand her or his own symptoms. For example, if
the child is night deficient, the child should be advised to be
careful when engaging in activities under conditions of dim
illumination. If the child has a deficiency in side vision, the
child should be advised that it may be difficult if not unsafe to
play certain sports (e.g., baseball or hockey). A child may well be
legally blind due to loss of acuity and yet still be able to read
with magnifying lenses; if this child has sufficient visual field,
he or she may well be able to continue functioning in a regular
school. It is psychologically helpful to both the child and the
parents to emphasize how much visual function remains rather
than how much has been lost and to defer conclusions about
long-term visual prognosis until the child has been examined
several times over 2-year intervals. In the case of children aged
6–18 years with the common forms of RP and normal serum
vitamin A and liver function, reduced doses of vitamin A

CHAPTER 177
palmitate adjusted for age and weight may be considered on a
trial basis with the agreement of the parents and close follow-up
by the pediatrician and ophthalmologist. As a general guideline,
for children above the fifth percentile in weight for a given age,
sex, and height, 5 000 IU/day of vitamin A palmitate may be
tried for those between ages 6 and 10 years, 10 000 IU/day for
those between 10 and 15 years of age, and 15 000 IU/day
thereafter. Sources of reduced doses of vitamin A palmitate can
be found at www.blindness.org. As noted earlier in this chapter
in the section on treatment of RP, beta-carotene is not a suitable
substitute for vitamin A palmitate in the context of this
treatment as it is not predictably converted into vitamin A.
Children should also be encouraged to eat 1–2 servings of oily
fish per week. However, it must be re-emphasized that patients
younger than age 18 were not included in our randomized trials
and therefore no formal recommendations can be made.

NIGHT VISION POCKETSCOPE

Advances in electro-optical technology have resulted in night
vision devices that allow patients with RP, choroideremia,
stationary night blindness, and allied diseases to use their cones
to function under scotopic (starlight or moonlight conditions)
or, if necessary, under dim photopic conditions that exist at
night near streetlights or in a slightly darkened room.238,239
These light-amplifying devices have been incorporated into a
monocular pocketscope or binoculars that can be used as an aid
to alleviate the symptom of night blindness. The instruments
contain bright-point-source protection so that a patient can
view a dimly illuminated scene in the presence of automobile FIGURE 177.23. Top, Model LV6015 night vision pocketscope
headlights or street lights. Figure 177.23 illustrates a hand-held adapted for patients with night blindness (top and left). The instrument
monocular pocketscope. The instrument provides a patient can also be used when held in the hand (right). Middle, Schematic
with a 40-degree field of view and gives the patient her or his diagram of a generation III night vision pocketscope. The pocketscope
best daylight vision at night in one eye. contains a light-emitting diode to provide supplementary illumination
Candidates for these devices should have a best-corrected within 3 m and is powered by two AA batteries. It weighs 13.8 oz and
vision of better than 20/200 and a central visual-field diameter is 4.5 inches long µ 2 inches wide µ 2.25 inches high. Bottom, Single-
stage image intensifier tube, 3 cm in length, contained in the night
of greater than 20° in at least one eye. Patients considering a
vision pocketscope.
monocular device should also have good mobility in daylight Top, From ITT Night Vision, Inc., Roanoke, VA. Middle and bottom, from Berson
with one eye patched. Patients who depend heavily on a far- EL: In Faye EE [ed]: Clinical Low Vision. Boston, Little, Brown, 1976.
temporal crescent for mobility are not good candidates; nor are
patients who, because of a central scotoma, cannot view the
output screen in these devices. Patients should be advised to particularly since patients can view the reading material as
assess the value of the device for their routine activities before white on a black background, thereby reducing glare. For those
making a decision as to whether or not to obtain it. who have difficulty tracking a line, a ruler or cutout window
may be of value. Patients with night deficiency should be
OTHER OPTICAL AIDS encouraged to carry a small penlight. Magnifying lenses put
into a glasses frame are also helpful. Bifocals are to be avoided
Some patients with RP have reduced acuity. A closed-circuit in patients with very constricted visual fields, as the lower
television for magnification is helpful in many instances, segment may cut the visual field such that patients find them 2245
 RETINA AND VITREOUS
less than useful. In the author’s experience, field wideners have
had limited if any value for patients with RP and allied
conditions.
GENETIC COUNSELING
If RP is dominantly inherited (i.e., three consecutive genera-
tions with father-to-son transmission), each affected patient has
a one in two chance with each childbirth of having a child of
either sex with this condition. If RP is inherited by an autosomal
recessive mode (i.e., at least two comparably affected female
siblings or male and female siblings comparably affected, with
normal parents, or an isolate case with a family history of
consanguinity), an affected patient has about a one in 80 chance
of marrying a carrier with this condition and the carrier has a
one in two chance of passing on the abnormal gene. Therefore,
the chance of a patient with an autosomal recessive form of RP
having an affected child is ~1 in 160 with each childbirth (1/80
SECTION 10
µ 1/2). If a male has X-linked RP or choroideremia, all of his
sons will be normal and all of his daughters will be carriers. If a
woman is a carrier of X-linked RP or choroideremia, she has a
50% chance of having an affected son and a 50% chance of
having a carrier daughter with each childbirth. Patients with
isolate (simplex) RP (i.e., no known affected family members)
can be considered to be recessive, although exceptions exist. All
offspring of males or females with autosomal recessive RP are
carriers of this condition; carriers enjoy normal vision but have
about a one in 320 chance of having an affected child with each
childbirth (i.e., one in 80 chance of marrying a carrier and, if
married to a carrier, one in four chance of having an affected
child; 1/80 µ 1/4 = 1/320). In the case of Usher syndrome type
I, Usher syndrome type II, Leber congenital amaurosis, or other
autosomal recessive diseases, once a couple has one affected
child they have a one in four chance with each succeeding child-
birth of having another affected child.
In families with only one affected male, RP can be inherited
by an autosomal recessive or X-linked mode; ERG testing and
fundus examination of the mother can help to determine
whether she is a carrier of X-linked disease. A careful family
history and examination of relatives of an affected patient with
ERG testing can aid in establishing this mode of transmission.
It is important to recognize that RP may skip generations and
yet be transmitted by a dominant mode; the dominant mode
with variable penetrance should be suspected in patients who
have large cone ERGs with substantial delays in implicit time
under age 20 years.
If a pedigree with multiple affected members is inconclusive
as to whether the disease is transmitted by a recessive or a
dominant mode, a digenic mode of inheritance should be con-
sidered. In digenic transmission, two unlinked mutations (neither
of which results in RP) cause this disease in patients with both
mutations. Affected individuals can have asymptomatic parents
but a 25% chance of having an affected child with each birth.
The first example of digenic transmission of RP involved a muta-
tion in the peripherin/RDS gene on chromosome 6 (Leu185Pro)
and one or another mutation in the rod outer segment mem-
brane 1 (ROM1) gene on chromosome 11; both genes encode
proteins responsible for maintaining photoreceptor outer
segment structure. The discovery of this mode of transmission
provides an explanation on a molecular genetic basis for the
pattern of inheritance described clinically as dominant RP with
reduced or incomplete penetrance.7
Patients often state that their children have had normal
routine eye examinations and therefore must not have RP or an
allied disease. Some young people may have these diseases and
yet appear normal on routine ocular examination. By age
2246 30 years, more than 90% of patients can be diagnosed with the
ophthalmoscope, but under age 30 years, ERG testing is indi-
cated if the patient wants to be certain whether any relatives are
affected. The ERG identifies those who are affected and those
who are normal; in families with RP, patients aged 6 years and
over with normal ERGs would not be expected to develop the
condition at a later time.
Recent advances with molecular genetic techniques
undoubtedly will facilitate genetic counseling. For example,
some 20–25% of patients with autosomal dominant RP in the
United States have rhodopsin gene mutations detectable
through analysis of leukocyte DNA. Patients identified through
analysis of DNA would have an ocular examination including
ERG testing to confirm the diagnosis and to determine the
amount of remaining retinal function, as variable clinical
expression at a given age is known to exist among patients with
the same rhodopsin gene mutation. Patients with dominant RP
due to rhodopsin Pro23His can differ by up to 1000-fold in their
ERG amplitudes at a given age; therefore definition of severity
of disease cannot be determined simply by a molecular genetic
analysis. Leukocyte DNA analysis should be considered not
only for families with a known dominant mode of transmission
over three consecutive generations but also for families with
transmission over two consecutive generations or for isolate
cases with presumably normal parents. Some of these patients
may have a rhodopsin gene mutation described in dominant
pedigrees, thereby helping to establish that the mode of
inheritance is dominant. It is important to establish the correct
genetic type in families with RP, not only for the sake of
providing accurate genetic counseling but also as a guideline in
establishing long-term visual prognoses of affected patients, as
patients with dominantly inherited disease generally retain
vision longer than those with autosomal recessive or X-linked
disease.
PSYCHOLOGIC AND VOCATIONAL
COUNSELING
Patients identified with progressive retinal degenerations often
need psychologic counseling to help adjust to the knowledge
that they can expect to lose their vision over time. Initial
expressions of anger, frustration, despair, or depression are nor-
mal reactions in such patients, and they may need counseling
in order to come to terms with their disease. Similarly, parents
of affected patients may feel profound guilt when they learn
about the genetic implications of the disease and may need
psychologic counseling. Patients and their family members
frequently benefit from a support group where they can talk to
others who have similar problems. Patients may also need
guidance in selecting an appropriate vocation that they can
pursue with their present vision and can continue to pursue in
the event their vision fails. To this end, guidance provided by a
trained specialist can be extremely helpful. It is very important
that the patient be advised to return every 1–2 years to see an
ophthalmologist. Patients with these diseases need periodic
contact with their ophthalmologists to receive information on
the course of their disease, particularly if they are being treated
with vitamin A plus an omega-3 rich fish diet; to obtain,
wherever possible, optical aids to maximize use of remaining
vision; and in some cases, to receive psychologic support.
SUNGLASSES
General agreement exists that patients with hereditary degen-
erations of the retina should avoid excessive exposure to bright
sunlight outdoors until more is known about whether light
stress will modify the course of these conditions.240,241 Two
patients with RP who wore an opaque scleral contact lens over
 Retinitis Pigmentosa and Allied Diseases

one eye for 8–10 h per day for 5 years showed comparable
degeneration in both eyes, suggesting that this type of protec-
tion from light did not alter the course of their disease.241 Some
patients have expressed a preference for orange photochromic
sunglasses (e.g., Corning CPF 550) with tinted side shields or
dark amber sunglasses (e.g., NoIR brand worn over an existing
prescription) with tinted side shields. However, no particular
type of sunglasses has been shown to alter the course of retinal
degeneration. Until more is known, patients should be advised
to select sunglasses for outdoor use that provide maximal com-
fort without compromising vision.
SOME FUTURE DIRECTIONS WITH
REGARD TO THERAPY
Key Features: Retinitis Pigmentosa – Some Future
Directions that May Lead to Treatments
example a deficiency in the RPE65 gene results in loss of the
isomerase needed for production of 11-cis-retinal in the retinal
pigment epithelium; this deficiency leads to a form of Leber
congential amaurosis or early onset recessive RP. Gene therapy
has been achieved in animal models of this condition140,246,247
and trials of human therapy have begun. In dominantly
inherited mutations or so-called ‘gain of function mutations’,
the encoded amino acid sequence is altered and can result in
accumulation of abnormal proteins leading to toxicity in retinal
cells. In this instance treatment is aimed at eliminating the
mutant gene with the expectation that the normal copy of the
gene will encode sufficient normal protein. Research is being
done involving ribosome-based or RNAi-based therapy to reduce
expression or inactivate specific abnormal alleles.248 With appro-
priate preliminary data continued study of nutritional interven-
tions is also warranted.
Other strategies to promote photoreceptor survival include
attempts to interfere with apoptosis and thereby prevent

• Gene therapy for early stages of Leber congenital amaurosis.
• Neuroprotection with intravitreal administration of ciliary
neurotrophic factor.
• Treatment with channel blockers or drugs that interfere with
apoptosis.
• Microchip implant technology.
• Stem cell therapy.
• Risk factor analyses of genetically defined populations
followed over time may reveal additional ameliorating factors
with possible implications for treatment.
Some preliminary evidence exists that neuroprotection with a
ciliary neurotrophic growth factor (CNTF) will substantially
slow the course of retinal degeneration in animal models of RP.
A phase I study in humans with RP that used encapsulated cell
technology with intravitreal sustained release of CNTF showed
that CNTF could be well-tolerated over 6 months with a few
patients reporting improved vision.242 This has set the stage for
a phase II–III study. Preliminary work has also been done with
implantation of light sensitive microchips on or under the retina
in patients with advanced RP; it is not yet established whether
patients can achieve useful vision with these devices.243,244
Retinal transplantation of photoreceptor cells under the retina
has also been advocated, but no convincing data exists that the
transplanted cells form viable synaptic connections with the
inner retina.245
Increased knowledge of the gene abnormalities and
biochemical defects involved in these conditions provide new
opportunities to discover additional therapies for hereditary
retinal diseases. In the case of recessively inherited mutations
which usually result in ‘loss of function’, patients typically develop
disease due to loss of a critical protein, and gene replacement
therapy could result in restoration of the missing protein. For
CHAPTER 177
photoreceptor degeneration or use of a calcium channel blocker
to counter the effects of cyclic GMP elevation that occurs in
some degeneration with consequent opening of cGMP-gated
channels. In the former case some success has been achieved
with animal models249,250 but none so far in humans. In the
latter case an initial claim of success with a calcium channel
blocker in an rd mouse model of retinal degeneration251 was not
confirmed by further studies of this channel blocker, namely
D-cis-diltiazem, in this and other animal models.252–254 Some
research has been done with embryonic stem cells in mice and
rats that were found to integrate into the host retina with
reported protection of host retinal neurons.255,256 It is not
known whether stem cells will have clinical applications in the
treatment of these diseases.
ERG testing, using computer averaging and narrow bandpass
filtering, provides a basis for objectively monitoring the course
of retinal degeneration in most patients with RP and allied
diseases. Variability of clinical severity at a given age among
patients with the same gene defects suggests that a modifier
gene or some factor(s) other than the gene defects alone may be
involved in the clinical expression of some forms of these
diseases.257 Evaluation of subgroups of patients with known
gene defects prospectively over a period of years may reveal
ameliorating or aggravating factors with possible implications
for therapy. Collaborations between scientists and clinicians
should enhance the likelihood of developing new treatments for
these diseases.258
ACKNOWLEDGMENTS
This work is supported in part by the National Eye Institute, EY00169,
Bethesda, MD and in part by the Foundation Fighting Blindness, Owings
Mills, MD.

REFERENCES
1. Ammann F, Klein D, Franceschetti A:
Genetic and epidemiological investigation
of pigmentary degeneration of the retina
and allied disorders in Switzerland.
J Neurol Sci 1965; 2:183–196.
2. Boughman JA, Conneally PM, Nance WE:
Population genetic studies of retinitis
pigmentosa. Am J Hum Genet 1980;
32:223–235.
3. Hu DN: Genetic aspects of retinitis
pigmentosa in China. Am J Med Genet
1982; 12:51–58.
4. Jay M: On the hereditary of retinitis
pigmentosa. Br J Ophthalmol 1982;
66:405–416.
5. Bundy S, Crews SJ: Wishes of patients
with retinitis pigmentosa concerning
genetic counseling. J Med Genet 1982;
19:317–318.
6. Bunker CH, Berson EL, Bromley WC, et al:
Prevalence of retinitis pigmentosa in Maine.
Am J Ophthalmol 1984; 97:357–365.
7. Kajiwara K, Berson EL, Dryja TP: Digenic
retinitis pigmentosa due to mutations at the
unlinked peripherin/RDS and ROM1 loci.
Science 1994; 264:1604–1608.
8. Mansergh FC, Millington-Ward S, Kennan
A, et al: Retinitis pigmentosa and
progressive sensorineural hearing loss
caused by a C12258A mutation in the
mitochondrial MTTS2 gene. Am J Hum
Genet 1999; 64:971–85.
9. Rivolta C, Berson EL, Dryja TP: Paternal
uniparental heterodisomy with partial
isodisomy of chromosome 1 in a patient
with retinitis pigmentosa without hearing
loss and a missense mutation in the Usher
syndrome type II gene USH2A. Arch
Ophthalmol 2002; 120:1566–1571.
10. Thompson DA, McHenry CL, Li Y, et al:
Retinal dystrophy due to paternal isodisomy
for chromosome 1 or chromosome 2, with
homoallelism for mutations in RPE65 or
MERTK, respectively. Am J Hum Genet
2002; 70:224–229.
2247
 RETINA AND VITREOUS
11. Berson EL: Visual function testing: clinical
correlations. In: Tasman W, Jaeger E, eds.
Foundations of clinical ophthalmology.
Philadelphia: J.B. Lippincott; 1991:1–10;
reprinted in J Clin Neurophys 11:472–481,
1994; updated Vol. 2, Chapter 14.
Hagerstown, MD: Lippincott Williams &
Wilkins; 2001: 1–12.
12. Donders FC: Beiträge zur pathologischen
Anatomie des Auges. Graefes Arch Clin
Exp Ophthalmol 1855; 1:139; 1857;
2:106–118.
13. Leber T: Die Pigmentdegeneration der
Netzhaut und mit ihr verwandte
Erkrankungen. In: Graefe A, Saemisch T,
Hess C, eds. Handbuch der Gesamten
Augenheilkunde, 2nd edn. Leipzig:
W Engelmann; 1916:1076–1225.
14. Bell J: Retinitis pigmentosa and allied
diseases of the eye. In: Pearson K, ed.
Treasury of human inheritance. London:
SECTION 10
Cambridge University; 1922; 2:1–28.
15. Franceschetti A, François J, Babel J:
Les Héredodégenerescences Chorio-
rétiniennes. Paris: Masson; 1963.
16. Duke-Elder S, Dobrie JH: Diseases of the
retina, Vol. 10. In: Duke-Elder S, ed.
System of ophthalmology. St. Louis: CV
Mosby; 1967.
17. Marmor MF, Aguirre G, Arden G, et al:
Retinitis pigmentosa, a symposium on
terminology and methods of examination.
Ophthalmology 1983; 90:126–131.
18. Pruett RC: Retinitis pigmentosa: Clinical
observations and correlations. Trans Am
Ophthalmol Soc 1983; 81:693–735.
19. Heckenlively JR: Retinitis pigmentosa.
Philadelphia: JB Lippincott; 1988.
20. Berson EL. Retinitis pigmentosa. The
Friedenwald lecture. Invest Ophthalmol Vis
Sci 1993; 34:1659–1676.
21. Heckenlively JR: The frequency of posterior
subcapsular cataract in the hereditary
retinal degenerations. Am J Ophthalmol
1982; 93:733–738.
22. Fetkenhour CL, Choromokos E, Weinstein
J, et al: Cystoid macular edema in retinitis
pigmentosa. Trans Am Acad Ophthalmol
Otolaryngol 1977; 83:515–521.
23. Fishman GA, Maggiero JM, Fishman M:
Foveal lesions seen in retinitis pigmentosa.
Arch Ophthalmol 1977; 95:1993–1996.
24. Sieving PA, Fishman GA: Refractive errors
of retinitis pigmentosa patients. Br J
Ophthalmol 1978; 52:625–633.
25. Berson EL, Rosner B, Simonoff EA: Risk
factors for genetic typing and detection in
retinitis pigmentosa. Am J Ophthalmol
1980; 89:763–775.
26. Kolb H, Gouras P: Electron microscopic
observations of human retinitis pigmentosa
dominantly inherited. Invest Ophthalmol Vis
Sci 1974; 13:487–498.
27. Szamier RB, Berson EL: Retinal
ultrastructure in advanced retinitis
pigmentosa. Invest Ophthalmol Vis Sci
1977; 16:947–962.
28. Szamier RB, Berson EL, Klein R, et al: Sex-
linked retinitis pigmentosa: ultrastructure of
photoreceptors and pigment epithelium.
Invest Ophthalmol Vis Sci 1979;
18:145–160.
29. Bunt-Milam AH, Kalina RE, Pagon RA:
Clinical-ultrastructural study of a retinal
dystrophy. Invest Ophthalmol Vis Sci 1983;
24:458–469.
30. Ben-Arie-Weintrob Y, Berson EL, Dryja TP:
2248 Histopathologic-genotypic correlations in
retinitis pigmentosa and allied diseases.
Ophthalm Genet 2005; 26:91–100.
31. Karpe G: The basis of clinical
electroretinography. Acta Ophthalmol 1945;
23(Suppl):1–118.
32. Goodman G, Gunkel RD: Familial
electroretinographic and adaptometric
studies in retinitis pigmentosa. Am J
Ophthalmol 1958; 46:142–172.
33. Gouras P, Carr RE: Electrophysiological
studies in early retinitis pigmentosa. Arch
Ophthalmol 1964; 72:104–110.
34. Berson EL, Gouras P, Gunkel RD: Rod
responses in retinitis pigmentosa, dominantly
inherited. Arch Ophthalmol 1968; 80:58–67.
35. Berson EL, Gouras P, Gunkel RD, et al:
Dominant retinitis pigmentosa with reduced
penetrance. Arch Ophthalmol 1969;
81:226–234.
36. Berson EL, Gouras P, Hoff M: Temporal
aspects of the electroretinogram. Arch
Ophthalmol 1969; 81:207–214.
37. Berson EL: Retinitis pigmentosa and allied
diseases: Electrophysiologic findings. Trans
Am Acad Ophthalmol Otolaryngol 1976;
81:659–666.
38. Berson EL: Electroretinographic findings in
retinitis pigmentosa. Jpn J Ophthalmol
1987; 31:327–348.
39. Birch DG, Sandberg MA: Dependence of
cone b-wave implicit time on rod amplitude
in retinitis pigmentosa. Vision Res 1987;
27:1105–1112.
40. Sandberg MA, Berson EL, Effron MH:
Rod-cone interaction in the distal human
retina. Science 1981; 212:829–831.
41. Berson EL: Retinitis pigmentosa, the
electroretinogram, and Mendel’s laws.
Trans Pa Acad Ophthalmol Otolaryngol
1973; 26:109–113.
42. Berson EL, Rosen JB, Simonoff EA:
Electroretinographic testing as an aid in
detection of carriers of X-chromosome-
linked retinitis pigmentosa. Am J
Ophthalmol 1979; 87:460–468.
43. Fishman GA, Weinberg AB, McMahon TT:
X-linked recessive retinitis pigmentosa:
Clinical characteristics of carriers. Arch
Ophthalmol 1986; 104:1329–1335.
44. Berson EL, Simonoff EA: Dominant retinitis
pigmentosa with reduced penetrance:
Further studies of the electroretinogram.
Arch Ophthalmol 1979; 97:1286–1291.
45. Berson EL, Sandberg MA, Rosner B, et al:
Natural course of retinitis pigmentosa over
a three-year interval. Am J Ophthalmol
1985; 99:240–251.
46. Andréasson SOL, Sandberg MA, Berson
EL: Narrow-band filtering for monitoring
low-amplitude cone electroretinograms in
retinitis pigmentosa. Am J Ophthalmol
1988; 105:500–503.
47. Sandberg MA, Baruzzi CM, Hanson AH III,
et al: Rod ERG diurnal rhythm in some
patients with dominant retinitis pigmentosa.
Invest Ophthalmol Vis Sci 1988; 29:494–498.
48. Dryja TP, McGee TL, Reichel E, et al: A
point mutation of the rhodopsin gene in
one form of retinitis pigmentosa. Nature
1990; 343:364–366.
49. Dryja TP, McGee TL, Hahn LB, et al:
Mutations within the rhodopsin gene in
patients with autosomal dominant retinitis
pigmentosa. N Engl J Med 1990;
323:1302–1307.
50. Berson EL, Rosner B, Sandberg MA, et al:
Ocular findings in patients with autosomal
dominant retinitis pigmentosa and a
rhodopsin gene defect (Pro23His). Arch
Ophthalmol 1991; 109:92–101.
51. Berson EL, Rosner B, Sandberg MA, et al:
Ocular findings in patients with autosomal
dominant retinitis pigmentosa and
rhodopsin, proline-347-leucine. Am J
Ophthalmol 1991; 111:614–623.
52. Berson EL, Rosner B, Weigel-DiFranco C,
et al: Disease progression in patients with
dominant retinitis pigmentosa and
rhodopsin mutations. Invest Ophthalmol Vis
Sci 2002; 43:3027–3036.
53. Hargrave PA, O’Brien PJ: Speculations on
the molecular basis of retinal degeneration
in retinitis pigmentosa. In: Anderson RE,
Hollyfield JG, LaVail MM, eds. Retinal
degenerations. Boca Raton, FL; CRC;
1991:517–518.
54. Farrar GJ, Kenna P, Jordan S, et al: A
three-base-pair deletion in the peripherin-
RDS gene in one form of retinitis
pigmentosa. Nature 1991; 354:478–480.
55. Kajiwara K, Hahn L, Mukai S, et al: Mutations
in the human retinal degeneration slow
gene in autosomal dominant retinitis
pigmentosa. Nature 1991; 354:480–483.
56. Molday RS: Peripherin/rds and rom-1:
Molecular properties and role in
photoreceptor cell degeneration. In:
Osborne N, Chader G, eds. Progress in
retinal and eye research. Oxford:
Pergamon; 1994:271–299.
57. Weleber RG, Carr RE, Murphey WH, et al:
Phenotypic variation including retinitis
pigmentosa, pattern dystrophy, and fundus
flavimaculatus in a single family with a
deletion of codon 153 or 154 of the
peripherin/RDS gene. Arch Ophthalmol
1993; 111:1531–1542.
58. Fossarello M, Bertini C, Galantuomo MS,
et al: Deletion in the peripherin/RDS gene
in two unrelated Sardinian families with
autosomal dominant butterfly-shaped
macular dystrophy. Arch Ophthalmol 1996;
114:448–456.
59. Nakazawa M, Kikawa E, Chida Y, et al:
Autosomal dominant cone-rod dystrophy
associated with mutations in codon 244
(Asn244His) and codon 184 (Tyr184Ser) of
the peripherin RDS gene. Arch Ophthalmol
1996; 114:72–78.
60. Apfelstedt-Sylla E, Theischen M, Rüther K,
et al: Extensive intrafamilial and interfamilial
phenotypic variation among patients with
autosomal dominant retinal dystrophy and
mutations in the human RDS/peripherin
gene. Br J Ophthalmol 1995; 79:28–34.
61. Hartong D, Berson EL, Dryja TP: Retinitis
pigmentosa. Lancet 2006; 368:1795–1809.
62. Biro I: Therapeutic experiments in cases of
retinitis pigmentosa. Br J Ophthalmol 1939;
23:332–342.
63. Gordon DM: The treatment of retinitis
pigmentosa with special reference to the
Filatov method. Am J Ophthalmol 1947;
30:565–580.
64. Campbell DA, Harrison R, Tonks EL:
Retinitis pigmentosa: Vitamin A serum
levels in relation to clinical findings. Exp
Eye Res 1964; 3:412–426.
65. Chatzinoff A, Nelson E, Stahl N, et al:
Eleven-CIS vitamin A in the treatment of
retinitis pigmentosa: A negative study. Arch
Ophthalmol 1968; 80:417–419.
66. Bergsma DR, Wolf ML: A therapeutic trial of
vitamin A in patients with pigmentary retinal
degeneration: A negative study. In: Landers
MA, Wolbarsht ML, Laties AM, et al, eds.

Retinitis pigmentosa. New York: Plenum;
1976; 197–209.
67. Katznelson LA, Khoroshilova-Maslova IP,
Eliseyeva RF: A new method of treatment
of retinitis pigmentosa/pigmentary
abiotrophy. Ann Ophthalmol 1990;
22:167–172.
68. Duke-Elder S, Dobrie JH: System of
ophthalmology. In: Duke-Elder S, ed.
Diseases of the retina. St. Louis: CV
Mosby; 1967; 10:574–622.
69. Berson EL, Remulla JFC, Rosner B, et al:
Evaluation of patients with retinitis
Retinitis Pigmentosa and Allied Diseases
85. Jampel RS, Falls HF: Atypical retinitis
pigmentosa, acanthocytosis and
heredodegenerative neuromuscular
disease. Arch Ophthalmol 1956;
59:818–820.
86. Salt HB, Wolff OH, Lloyd JK, et al: On
having no betalipoprotein. A syndrome
comprising A-beta-lipoproteinemia,
acanthocytosis and steatorrhea. Lancet
1960; 2:325–329.
87. Druez G, Lamy M, Frézal J, et al:
L’acanthocytose: Ses rapports avec
l’absence congénitale de
103. Klenk E, Kahlke W: Über das Vorkommen
der 3,7,11,15-tetramethylhexadecansäure
(Phytansäure) in den Cholesterinestern und
anderen Lipoidfraktionen der Organe bei
einem Krankheitsfall unbekannter Genese:
Verdacht auf Heredopathia atactica
polyneuritiformis (Refsum syndrome).
Hoppe Seylers Z Physiol Chem 1963;
333:133–139.
104. Berson EL: Nutrition and retinal
degenerations: Vitamin A, taurine, ornithine
and phytanic acid. Retina 1982; 2:236–255.