Medical Retina 2017

ESASO Course Series
F. Bandello, B. Corcóstegui
Vol. 9
Medical Retina
Update 2017
Editors
F. Bandello
G. Querques
A. Loewenstein
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Singapore National Eye Centre
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Medical Retina
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Vol. 9
Series Editors
F. Bandello Milan
B. Corcóstegui Barcelona
ESASO Course Series
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Medical Retina
Update 2017
Volume Editors
Francesco Bandello Milan

Giuseppe Querques Milan
Anat Loewenstein Tel Aviv
34 figures, 26 in color, and 9 tables, 2017
Basel · Freiburg · Paris · London · New York · Chennai · New Delhi ·

Bangkok · Beijing · Shanghai · Tokyo · Kuala Lumpur · Singapore · Sydney
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Francesco Bandello Giuseppe Querques
Department of Ophthalmology Department of Ophthalmology
University Vita Salute University Vita Salute
IRCCS Ospedale San Raffaele IRCCS Ospedale San Raffaele
Via Olgettina, 60 Via Olgettina, 60
IT–20132 Milan (Italy) IT–20132 Milan (Italy)
Anat Loewenstein
Sackler Faculty of Medicine
Tel Aviv University
Department of Ophthalmology
6 Weizmann Street
IL–64239 Tel Aviv (Israel)
Library of Congress Cataloging-in-Publication Data
Names: Bandello, F. (Francesco), editor. | Querques, Giuseppe, editor. |

Loewenstein, Anat, editor. | European School for Advanced Studies in
Ophthalmology, issuing body.
Title: Medical retina / volume editors, Francesco Bandello, Giuseppe
Querques, Anat Loewenstein.
Other titles: Medical retina (Bandello)
Description: Update 2017. | Basel ; New York : Karger, 2017. | Series: ESASO
course series, ISSN 1664-882X ; vol. 9 | Includes bibliographical
references and index.
Identifiers: LCCN 2017019013 (print) | LCCN 2017018081 (ebook) | ISBN
9783318060683 (e-book) | ISBN 9783318060676 (soft cover : alk. paper) |
ISBN 9783318060683 (eISBN)
Subjects: | MESH: Retinal Diseases | Retina--physiopathology
Classification: LCC RE551 (print) | LCC RE551 (ebook) | NLM WW 270 | DDC
617.7/35--dc23
LC record available at https://lccn.loc.gov/2017019013
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and MEDLINE/Pubmed.
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of
the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or
services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or
property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord
with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations,
and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for
any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a
new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic
or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing
from the publisher.
© Copyright 2017 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed on acid-free and non-aging paper (ISO 9706)
ISSN 1664–882X
e-ISSN 1664–8838
ISBN 978–3–318–06067–6
e-ISBN 978–3–318–06068–3
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Contents
VI List of Contributors
VIII Preface
Bandello, F.; Querques, G. (Milan); Loewenstein, A. (Tel Aviv)
1 Wet Age-Related Macular Degeneration

Stanga, P.E.; Stringa, F.; Ch‘ng, S.; Chwiejczak, K.; Papayannis, A.; Tsamis, E. (Manchester)
14 A Multimodal Imaging Guide to the Evaluation and Management of Neovascular
Age-Related Macular Degeneration
Garrity, S.T. (Los Angeles, CA); Freund, K.B. (New York, NY); Sarraf, D. (Los Angeles, CA)
32 Retinal Vein Occlusion
Goldenberg, D.; Loewenstein, A. (Tel Aviv)
42 Vitreomacular Interface in Retinal Diseases
Moisseiev, E. (Tel Aviv); Moisseiev, J. (Ramat Gan/Tel Aviv)
51 Dry Macula: Essentials for Fast Diagnosis, Prognosis, and Choice of Treatment
Querques, G. (Milan); Sacconi, R. (Milan/Verona); Carnevali, A.; Rabiolo, A.; De Vitis, L.A.;
Montorio, D.; Querques, L.; Bandello, F. (Milan)
59 Diabetic Retinopathy: Essentials for Fast Diagnosis, Prognosis and Choice of Treatment
Battaglia Parodi, M.; Cicinelli, M.V.; Rabiolo, A. (Milan)
72 Pediatric Vascular Retinopathies
Caputo, G. (Paris)
83 Subject Index
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V
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List of Contributors
Francesco Bandello Maria Vittoria Cicinelli

University Vita Salute University Vita Salute
IRCCS Ospedale San Raffaele IRCCS Ospedale San Raffaele
Via Olgettina, 60 Via Olgettina, 60
IT–20132 Milan (Italy) IT–20132 Milan (Italy)
E-Mail francesco.bandello@hsr.it E-Mail cicinelli.mariavittoria@hsr.it
Georges Caputo Luigi Antonio De Vitis

Fondation Ophtalmologique A. de Rothschild Department of Ophthalmology
25 rue Manin University Vita Salute
F–75019 Paris (France) IRCCS Ospedale San Raffaele
E-Mail gcaputo@for.paris Via Olgettina, 60
IT–20132 Milan (Italy)
Adriano Carnevali E-Mail l.devitis@studenti.unisr.it
Department of Ophthalmology
University “Magna Graecia” K. Bailey Freund
Viale Europa Vitreous Retina Macula Consultants of New York
IT–88100 Catanzaro (Italy) 460 Park Ave.
E-Mail adrianocarnevali@live.it New York, NY 10022 (USA)
E-Mail kbfnyf@aol.com; kbfreund@gmail.com
Soon Ch’ng
Research Office, Purple Zone, MRI Sean T. Garrity
Central Manchester University Retinal Disorders and Ophthalmic Genetics Division
Hospitals NHS Foundation Trust Stein Eye Institute
Oxford Road David Geffen School of Medicine at UCLA
M13 9WL Manchester (United Kingdom) 100 Stein Plaza
E-Mail soon.chng@cmft.nhs.uk Los Angeles, CA 90095 (USA)
E-Mail garrity@jsei.ucla.edu
Katarzyna Chwiejczak
Research Office, Purple Zone, MRI Dafna Goldenberg
Central Manchester University Sackler Faculty of Medicine
Hospitals NHS Foundation Trust Tel Aviv University
Oxford Road Department of Ophthalmology
M13 9WL Manchester (United Kingdom) 6 Weizmann Street
E-Mail katarzyna.chwiejczak@cmft.nhs.uk IL–64239 Tel Aviv
E-Mail dafnagoldenberg@gmail.com
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VI
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Anat Loewenstein Lea Querques
Sackler Faculty of Medicine Department of Ophthalmology
Tel Aviv University University Vita Salute
Department of Ophthalmology IRCCS Ospedale San Raffaele
6 Weizmann Street Via Olgettina, 60
IL–64239 Tel Aviv IT–20132 Milan (Italy)
E-Mail anatl@tlvmc.gov.il E-Mail lea_querques@hotmail.com
Elad Moisseiev Alessandro Rabiolo

Tel Aviv Medical Center University Vita Salute
Weitzman 6 St. IRCCS Ospedale San Raffaele
IL–64238 Tel Aviv Via Olgettina, 60
E-Mail elad_moi@netvision.net.il IT–20132 Milan (Italy)
E-Mail rabiolo.alessandro@hsr.it
Joseph Moisseiev
10 Yosef Milo St. Riccardo Sacconi
IL–6964332 Tel Aviv (Israel) Department of Ophthalmology
E-Mail jetmoiss@netvision.net.il University Vita Salute
IRCCS Ospedale San Raffaele
Daniela Montorio Via Olgettina, 60
Department of Ophthalmology IT–20132 Milan (Italy)
University Vita Salute E-Mail ric.sacconi@gmail.com
Via Olgettina, 60 David Sarraf
IT–20132 Milan (Italy) Retinal Disorders and Ophthalmic Genetics Division
E-Mail da.montorio@gmail.com Stein Eye Institute
David Geffen School of Medicine at UCLA
Alessandro Papayannis 100 Stein Plaza
Research Office, Purple Zone, MRI Los Angeles, CA 90095 (USA)
Central Manchester University E-Mail dsarraf@ucla.edu
Hospitals NHS Foundation Trust
Oxford Road Paulo E. Stanga
M13 9WL Manchester (United Kingdom) Research Office, Purple Zone, MRI
E-Mail Alessandro.Papayannis@cmft.nhs.uk Central Manchester University
Battaglia Parodi Oxford Road
Department of Ophthalmology M13 9WL Manchester (United Kingdom)
University Vita Salute E-Mail Paulo.Stanga@cmft.nhs.uk
Via Olgettina, 60 Francesco Stringa
IT–20132 Milan (Italy) Research Office, Purple Zone, MRI
E-Mail battagliaparodi.maurizio@hsr.it Central Manchester University
Giuseppe Querques Oxford Road
Department of Ophthalmology M13 9WL Manchester (United Kingdom)
University Vita Salute E-Mail francesco.stringa@cmft.nhs.uk
Via Olgettina, 60 Emmanouil Tsamis
IT–20132 Milan (Italy) Research Office, Purple Zone, MRI
E-Mail querques.giuseppe@hsr.it Central Manchester University
Oxford Road
M13 9WL Manchester (United Kingdom)
E-Mail emmanouil.tsamis@manchester.ac.uk
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List of Contributors VII

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Preface
Over the past 10 years, tremendous progress has markably favorable reception of the first edition
been achieved in medical retina. This volume re- of this book encouraged us to produce this re-
flects the most relevant topics ranging from basic vised edition to include the enhanced knowledge
knowledge to the most advanced techniques. It of the past 7 years. While the number of disorders
covers the functional anatomy with medical and covered has changed only modestly, and infor-
surgical management of the retina, provides tech- mation about their etiology and pathogenesis is
niques, choices of treatments in handling intra- still limited, yet new diagnostic and management
operative and postoperative complications as well strategies have evolved and been applied to “old”
as information on high-risk retinopathy of pre- problems. The organization of this new edition is
maturity. Further contributions describe how to similar to the original. We are privileged that so
manage diabetic macular edema, retinal vein oc- many of the section editors of the first edition
clusion, age-related macular degeneration, and have shared their wisdom and experience to cre-
many other chorioretinal vascular diseases. ate this new version, and many have brought new
Well-known medical and vitreoretinal special- partners to the task.
ists share their experience in this publication, F. Bandello, Milan
making it a must-read for everyone interested to G. Querques, Milan
keep up with current treatment and surgery of A. Loewenstein, Tel Aviv
medical retina topics and procedures. The re-
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VIII
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Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.
ESASO Course Series. Basel, Karger, 2017, vol 9, pp 1–13 (DOI: 10.1159/000471824)
Wet Age-Related Macular Degeneration

Paulo E. Stanga · Francesco Stringa · Soon Ch'ng · Katarzyna Chwiejczak ·
Alessandro Papayannis · Emmanouil Tsamis
Manchester Vision Regeneration (MVR) Lab, Research Office, Purple Zone, MRI, Central Manchester University Hospitals NHS
Foundation Trust, Manchester, UK
Abstract commonly wet, AMD is the type of advanced

Age-related macular degeneration (AMD) is one of the AMD with the most rapid and severe course, it
main causes of visual deterioration in the developed na- fortunately accounts for only 10–15% of the dis-
tions. AMD comes in many forms but the most devastat- ease. According to the earliest studies (Framing-
ing form is the exudative (wet) type. Over the years, re- ham Eye Study and Beaver Dam Eye Study), wet
search into the pathophysiology of AMD has led to the AMD was estimated to affect only about 1.5% in-
discovery of multiple therapies such as the intravitreal dividuals aged 52 years or older. Nevertheless, the
injection of anti-vascular endothelial growth factor. The global prevalence is expected to increase by the
diagnostic tools to assess the type and progress of AMD year 2040 [1, 2]. This high prevalence, indeed,
have also evolved from slit lamp ophthalmoscopy exam- represents a real economic burden, leading to an
ination to high resolution imaging of the retina with opti- annual expenditure of USD 4.6 billion in the US
cal coherence tomography (OCT), fundus fluorescein an- alone [3].
giogram, and OCT angiogram. In the future, the field of The risk factors that facilitate the development
treating AMD will continue to expand with new drug of AMD can be divided in:
therapies to slow the progression of dry AMD and limit • Non-modifiable – for example, age (most im-
the retinal photoreceptor damage from wet AMD. portant), ethnicity (non-Hispanic whites),
© 2017 S. Karger AG, Basel family history (20–30%) and light;
• Modifiable – smoking, body mass index, diet
and blood lipid level [4].
Epidemiology AMD is a complex neurodegenerative disease
with intensive genetic, epidemiological and mo-
Age-related macular degeneration (AMD) is one lecular studies beginning to uncover the mecha-
of the leading causes of visual disability in indi- nism of this pathology. Various associated genes
viduals over 60 years of age in developed coun- were identified, including MMP9, CFH, CFB, C3,
tries. Although neovascular (exudative), or more ARMS2, HTRA1, and APO-E. Despite the identi-
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fication of various genetic and environmental fac- space. Studies in transgenic mice support the con-
tors involved in the development of AMD, some tetions that Bruch’s membrane disruption is re-
aspects of the pathophysiological mechanism required for the development of CNV.
main unknown. CNV Membrane Formation. Choroidal angio-
genesis is a multistep process that includes degra-
dation of vascular basement membrane, prolifer-
Pathophysiology and Natural History ation and migration of choroidal endothelial
cells, choroidal endothelial cell tube formation,
Exudative AMD is characterized by choroidal and restoration of the vascular basement mem-
neovascularization (CNV) that denotes the brane. CNV occurs when there is an imbalance
pathologic growth of new blood vessels from the between proangiogenic factors and antiangiogen-
pre-existing choroidal vessels into the subretinal ic growth factors.
space. The importance of CNV is that it is the de- Cicatricial Membrane Formation. CNV gradu-
terminant of the disciform process; the disc- ally evolve into paucicellular cicatricial mem-
shaped, subretinal, fibrovascular membrane ulti- branes. The loss of cellularity is most likely due to
mately progresses to cicatrisation, an loss of mac- apoptosis, or programmed cell death of stromal
ular function. cells [5].
The process of CNV formation in AMD can be Conditions such as inflammation, comple-
divided in 5 steps: ment activation, oxidative stress and lipid ho-
Aging and Senescence of the Retinal Pigment meostasis have also been identified to be involved
Epithelium (RPE). A decrease in lysosomal activ- in the pathogenesis of AMD [6–12].
ity of RPE accompanies aging, and age-related
progressive accumulation of lipofuscin, a byprod-
uct of photoreceptor outer-segment digestion by Classification of Neovascular AMD
lysosome. This results in disturbance of RPE
function. The hallmark of the neovascular form of AMD
RPE Basal Laminar/Linear Deposit (Drusen) is the presence of CNV. Any alteration of the
Formation. Two types of drusens have been de- BM, such as drusen, thickening of the BM’s in-
scribed: hard (nodular drusen) and soft drusen. ner aspect, or conditions similar to the non-neo-
The latter tend become confluent and, unlike vascular changes associated with AMD can di-
hard drusen, appear to be an important associat- rectly or indirectly increase the probability of
ed and predisposing feature of CNV. Deposit be- BM disruption. This consequently allows buds
tween the RPE and Bruch’s membrane may block of capillaries emerging from the choriocapillar-
the diffusion of oxygen and nutrients from cho- ies to gain access to the BM’s inner collagenous
riocapillaris to the photoreceptors. layer and/or subretinal space. Histologically,
The resulting hypoxia induces the expression CNV is classified into 3 neovascular growth
of vascular endothelial growth factor (VEGF) to patterns:
promote the formation of new blood vessels. • Type 1 neovascularization originates from the
Enzymatic and Mechanical Disruption of choriocapillaris and it is localised under the
Bruch’s Membrane. When the balance between RPE (Fig. 1).
proteolytic enzymes, such as matrix metallopro- • Type 2 neovascularization also originates from
teinases and their inhibitors favors a proteolytic the choriocapillaris but extends through the
environment the Bruch’s membrane can be dis- RPE and is localized in the subretinal space
rupted, allowing CNV to reach the sub-RPE (Fig. 2).
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2 Stanga · Stringa · Ch’ng · Chwiejczak · Papayannis · Tsamis

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a b
c d
Fig. 1. Multimodal imaging pictures of right eye type 1 CNV. a FFA shows late leakage from an
undetermined source (black arrow) as occult CNV pattern. b ICGA shows the actual CNV (white
arrow). c Infrared imaging showing OCT scan orientation and direction. d OCT B-scan reveals para-
foveal sub-RPE hyperreflective material.
• Type 3 neovascularization originates from the tending into the subretinal space and possibly
deep retinal capillary plexus and is located in communicating with a CNV. The latter, on the
the outer retina (Fig. 3). contrary, is defined as an intraretinal extension of
While the origin, anatomic location and imag- type 1 neovascularization [15, 16].
ing features of both type 1 and 2 neovasculariza-
tion are well established [13], type 3 neovascular-
ization is more controversial [14]. The term type Diagnostic and Follow-Up Tools in
3 neovascularization essentially encompass 2 pre- Neovascular AMD
viously described lesions: retinal angiomatous
proliferation (RAP) and chorioretinal anastomo- Ophthalmoscopic examination remains the first
sis. The first consists of a focal neovascular prolif- approach to patients with suspected neovascular
eration from the deep retinal capllary plexus, ex- AMD. Clinical signs may include:
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Wet AMD 3
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a b
c d
Fig. 2. Multimodal imaging pictures of right eye type 2 CNV. a Late phase FFA shows bright hy-
perfluorescence with vascular leakage, obscuring lesion’s boundaries (gray arrow head) as in clas-
sic CNV pattern. b ICGA shows the original choroidal new-vessel (white arrow head). c Infrared
imaging showing OCT scan orientation and direction. d OCT B-scan reveals intraretinal fluid, RPE
disruption and subretinal hyperreflective material.
• Subretinal fluid (SRF). Patients usually describe sudden onset of de-

• Subretinal or sub-pigment epithelial blood. creased visual acuity (VA), metamorphopsia and
• Intraretinal hemorrhage (possible sign of paracentral scotomata. Amsler grid self-testing
RAP). by patients can be effective for detecting early
• Subretinal or intraretinal lipid. neovascular AMD.
• Subretinal pigment ring. Fundus Fluorescein Angiography (FFA) is the
• Irregular elevation of RPE. gold standard for diagnosing CNV. Two major
• Subretinal gray-white lesion (CNV lesion it- patterns are visible on FFA:
self). 1. Classic CNV, which is an area of bright, fair-
• Cystoid macular edema. ly uniform hyperfluorescence identified in the
• Sea fan pattern of subretinal vessels. early phase of the FFA that gradually increases
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a b
c d
Fig. 3. Multimodal imaging pictures of left eye type 3 CNV. a Late phase FFA of CNV type 3 shows
pooling of foveal PED and hyperfluorescence of RPE defects. b ICGA shows hypercyanescence
consistent with RAP (white arrow). c Infrared imaging showing OCT scan orientation and direction
(d) OCT B-scan reveals retinal-choroidal anastomosis (white asterisk), intraretinal cyst, subretinal
fluid, and PED at the margin of the lesion.
throughout the transit phase. Late phase is char- which is not as diffuse as that observed in clas-
acterized by leakage of dye that obscures the sic CNV.
boundaries of this area (Fig. 2). • Late leakage from an undetermined source re-
2. Occult CNV has, in turn 2 hyperfluorescent fers to regions of fluorescence at the RPE level
patterns (Fig. 1): that are best appreciated in the late phases of
• Fibrovascular Pigment Epithelium Detach- an angiographic study; they do not correspond
ment (PED) irregular elevation of the RPE, to classic CNV or to areas of irregular eleva-
best observed with stereo views on the angio- tion of the RPE during the early midphases of
gram, often stippled with hyperfluorescent the study.
dots first apparent early in the angiographic Lesions components may either block fluores-
study. Gradual leakage from these regions cence (blood, pigment or scar) or intensify hyper-
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Wet AMD 5
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fluorescence (serus PED) and thus obscure the • Central retinal thickness (CRT): this is the
underlying CNV. When determining the size of a most accessible way to quantify retinal chang-
CNV, the examiner should take into account all es. However, it is not recommended to base
areas of classic and occult CNV, as well as areas clinical decisions on retinal thickness mea-
with obscured features. surements due to lack of correlation with rel-
Other terms relevant to interpreting fluores- evant functional outcomes, and low sensitivity
cein angiography of CNV are: for subtle changes in the retinal compart-
• Predominantly classic: CNV occupies more ments.
than 50% of the lesion – including contiguous • Intraretinal cystoid fluid (ICF): it may lead to
blood, pigment, scar and dye staining. irreversible nerusensory damage. Anti-VEGF
• Minimally classic CNV: the proportion of treatment may be stopped for ICF overlying
classic CNV occupies between 1 and 49% of RPE atrophy or scarring due to its limited re-
the entire lesion. sponsiveness.
• Occult with no classic CNV: no classic CNV is • SRF: its presence usually leads to a benign dis-
present in the lesion – only occult CNV. ease course, manageable with anti-VEGF in-
• Poorly and well defined CNV: these terms de- jections.
scribe how distinct the boundaries are between • Alterations of outer retinal layers: potential
the entire CNV lesion and the unaffected retina. useful biomarker for visual function outcome
The distinction between classic and occult at the treatment-naïve stage.
CNV used to be extremely important in laser • Hypereflective loci: potential biomarker for le-
treatment and photodynamic therapy (PDT). sion activity.
Currently used therapy with anti-VEGF injec- • Outer retinal tubulation: a biomarker of
tions, however, is not dependant on the angio- chronic and irreversible photoreceptor dis-
graphic classification. There is, though, a prog- ruption associated with low visual prognosis.
nostic distinction: classic CNV tends to be more • Subretinal hyperreflective material and fi-
aggressive and rapidly progressive without brous scarring: a major risk factor related to
prompt treatment than occult CNV [17]. sustained VA loss in the treatment of neovas-
Indocyanine green videoangiography (ICGA) cular AMD.
is an adjuvant imaging modality to FFA. It has • Pigmented epithelial detachment: a biomarker
been demonstrated that ICGA can provide a of lesion activity [19].
clearer CNV image in poorly defined CNV on Recent OCT devices benefit from being paired
FFA and it is particularly useful in studying occult with swept source OCT (SS-OCT) technology,
CNV with overlying haemorrhage [18]. For these which utilizes longer wavelength infrared light
reasons, ICGA has been especially helpful in than conventional OCT and therefore has an im-
guiding laser treatment of CNV. proved penetration into tissue. This represents a
Optical Coherence Tomography (OCT) has potential advantage when imaging eyes with me-
rapidly become one of the leading diagnostic dia opacities and oedematous retinas. SS-OCT
tools in modern ophthalmology. It is a non-inva- has enabled imaging of the choroid, vitreous body
sive technique which provides high resolution to- and adjacent deep ocular structures that can be
mographic images and, therefore, has a vital role involved in the pathologic process of subfoveal
in the management and follow-up of exudative CNV [20].
AMD. The following qualitative and quantitative OCT angiography (OCT-A) is a new and
biomarkers of disease can be provided by OCT promising imaging modality that is able to depict
analysis: retinal vascular changes in patients with CNV.
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OCT-A, which does not require intravenous dye seems to be connected with the choroid through
injection, allows a sharp reconstruction of the a small vessel [24]. OCT-A can be utilized to char-
3-dimensional choroidal and retinal vascular ar- acterize the response of neovascularization to an-
chitecture by the quantification of motion con- tiangiogenic therapy.
trast between frames of corresponding pixels. It
also provides a layer-by-layer analysis through an
automated or manual segmentation of the image Differential Diagnosis of Neovascular AMD
allowing for visualization of the deep retinal cap-
illary plexus and the choroid, not readily available A variety of conditions can mimic the neovascu-
with FFA [21]. The description of retinal vascular lar changes in AMD. The following are the major
lesions on OCT-A images is based on the follow- clinical entities that can resemble neovascular
ing terminology: AMD:
• Level (depth) • Retinal arterial macroaneurysms: they can be
• Reflectance related to macular retinal hemorrhage that
• Flow, blood cell motion signal and decorrela- causes sudden vision loss, simulating hemor-
tion signal rhage from CNV. FFA and ICGA can differen-
• Morphology and architecture tiate between the 2 demonstrating the dilated
• Texture. lumen of the macroaneurysm surrounded by
OCT-A of type 1 neovascularization can pro- the hemorrhage.
vide a detailed assessment of the microvascular • Adult vitelliform dystrophy: this lesion may
morphologies of these vessel complexes, which resemble a PED. However, the presence of vi-
are typically hidden under the RPE. Also, hypo- telliform material is usually associated with
perfusion or alteration of the choriocapillaris can marked blocked fluorescence in the early
be depicted by OCT-A in association with type 1 phase of FFA.
lesions [22]. • Polypoidal choroidal vasculopathy (PCV): a
OCT-A of CNV type 2 shows 2 morphological variant of CNV type 1, PCV is characterized by
patterns, both of them located in the outer retina. polypoidal dilations and choroidal branching
• Medusa-shaped complexes are characterized vascular networks observed on ICGA. Clini-
by a well-defined oval shape, generally formed cally, it is characterized by multiple and recur-
by a very dense high-flow network at diagnosis rent serosanguineous RPE detachments, com-
because of the high activity of this kind of cho- monly in the peripapillary area. Vitreous hem-
roidal new vessel. orrhage may occur more frequently than in
• Glomerulus-shaped lesion is usually rounded, AMD and typical soft drusen of AMD are not
well defined, and full of a very dense maze of usually present [25].
small new vessels [23]. • Central serous chorioretinopathy (CSC): pa-
On OCTA, type 3 neovascularization can be tients with CSC are usually younger and do
depicted as an intraretinal anastomosis that de- not exhibit a subretinal hemorrhagic process.
velops from the deep capillary plexus, giving rise It can be further differentiate by clinical signs
to a high-flow, tuft-shaped neovascular lesion in such as patches of mottled RPE atrophy and
the segmentation corresponding to the outer ret- multiple PEDs.
inal layer, finally reaching the sub-RPE space. In • Inflammatory conditions: changes in the outer
the choriocapillaris compartment, a small clew- retina with SRF accumulation can be caused
like lesion corresponds to the abovementioned by several conditions such as posterior scleri-
tuft-shaped network. In some cases, this lesion tis, Vogt–Koyanagi–Harada syndrome, and
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Wet AMD 7
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systemic lupus erythematosus. These diseases all isoforms of VEGF-A protein and prevent-
generally have other distinguishing ocular and ing it from binding to its receptor [30].
systemic features. • Bevacizumab (Avastin® IVA), a humanized
• Choroidal tumors: they may present with a monoclonal full-length antibody against all
mass effect and occasionally CNV on the sur- isoforms of VEGF, is used off-label in ophthal-
face that resembles AMD. Ultrasonography, mology [31].
for example, can help differentiate the low re- • Aflibercept, (Eylea®, IVE) is a fusion protein
flectivity of a choroidal melanoma from the acting as a decoy receptor for VEGF, which in-
moderate/high reflectivity of a disciform scar. hibits all isoforms of VEGF-A and VEGF-B as
well as placental growth factor. It was designed
to bind stronger to VEGF, thus allowing for
Treatment increased intervals between injections [32].
First studies with IVL were completed in 2006
There were no treatment options available for exu- and proved unquestionable benefit of monthly
dative AMD until the introduction of thermal la- anti-VEGF injections over PDT and placebo
ser (Argon laser) therapy in the early 1980s. The (sham) injections [33].
treatment, however, was possible only for extrafo- Based on these results the Food and Drug Ad-
veal CNV and induced permanent negative sco- ministration (FDA) in the United States approved
toma [26]. The application of PDT in the treat- the monthly administration of IVL for treatment
ment of AMD was introduced in the end of the of wet AMD, which soon completely superseded
1990s and it was an important step forward. Its Pegaptanib (Macugen®). The CATT study pro-
main advantage is that of selectively damage part vided the basis on which 1.25 mg IVA was shown
of the CNV lesion, with energy levels far lower as equal to IVL in terms of efficacy. Moreover,
than those required for thermal destruction by Ar- between 2 and 5 years, the group assigned to IVL
gon laser. In particular, a photosensitizer com- lost more VA than the IVA group [34]. Two large
pound (Verteporfin) is administered intravenous- randomized, double-masked, active-controlled,
ly and is preferentially uptaken by dividing endo- phase 3 trials, the VIEW 1 and VIEW 2 compared
thelial cells. It is then locally activated by light IVE with IVL. Both drugs showed similar efficacy
(wavelength 689 nm) from a diode laser source; and a similar safety profile. [32].
enabling treatment of subfoveal CNV with relative
sparing of healthy tissue. It proved to be efficient
and safe in predominantly classic (smaller than Treatment Regimens
5,400 um area) CNV and became standard of
treatment for the following years [27, 28]. • Fixed dosing: Comprises monthly (IVL, IVA)
With the introduction of anti-VEGF pharma- or bi-monthly (IVE) injections, irrespective of
cotherapy patients were offered a chance for the clinical situation. This was proved effective,
first time to improve vision instead of just de- but often associated with unacceptable burden
creasing the rate of progression. The first anti- for patients and excessively high costs [35].
VEGF molecule was Pegaptanib (Macugen®), a • “Pro Re Nata” (PRN), usually conducted with
28-base ribonucleic acid aptamer [29]. Currently initial 3 monthly “loading” doses and subse-
used anti-VEGF agents were designed based on quent “as needed” retreatment, depending on
the structure of antibodies: results of OCT scanning (morphological crite-
• Ranibizumab (Lucentis®, IVL) is a humanized ria, Table 1) and changes in VA. Interestingly,
antibody Fab fragment capable of binding to risk of geographic atrophy was higher in pa-
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Table 1. Retinal morphological criteria for evaluation of pathology activity in wet AMD
Active Non-active
Abnormal retinal thickness, particularly if there is No re-appearance or further worsening of OCT

evidence of accumulated fluid, confirmed by OCT; indicators of CNV disease activity on subsequent
presence or recurrence of intraretinal and/or subretinal follow-up following recent discontinuation of
fluid or subretinal hemorrhage treatment
New or persistent leakage detected with fluorescein Absence of FFA leakage or other evidence of disease
angiography activity
Choroidal neovascular membrane growth detected No additional lesion growth or other new signs of
with fluorescein angiography VA deterioration [39, 40] disease activity on subsequent follow-up following
recent discontinuation of treatment [30]
tients treated with monthly injections. [34, of non-modifiable factors including patient’s
35]. age, lesion characteristics baseline VA and the
• Treat and extend (TREX) is a more “proac- presence of particular genotype risk alleles [41–
tive” approach: Monthly injections are given 43].
until there are no signs of activity and subse- The most frequently occurring ocular compli-
quently the intervals are extended by 2 weeks cation is an increase in intraocular pressure. Oth-
until recurrence or until maximum interval er infrequent complications (less than 1 per 100
(i.e., 12 weeks) is reached. OCT is used to de- injections) include: mild uveitis, endophthalmi-
termine time intervals between injections, not tis, retinal detachment, and intraocular haemor-
the number of injections [35, 36]. TREX rhage [44, 45] With regards to systemic complica-
proved to be equally effective as monthly regi- tions, there have been reports of nausea, chest
men in reducing CRT and improving VA with pain with acute vision loss and hypertension
decreased number of injections. Treat and ex- while more serious adverse effects include myo-
tend is reported to be the most frequently used cardial infarction, stroke or cerebral infarction,
strategy worldwide [37, 38]. transient ischemic attack, or venous thrombotic
OCT-guided strategies seem to reduce burden event. In general, reported serious ocular and
and costs of treatment without affecting efficacy. non-ocular events are very rare (below 1%) and
Currently, there is lack of evidence to recommend there is no proof confirming any difference be-
a TREX regimen over PRN, but it was shown that tween anti-VEGF’s [45].
the number of visits is lower with TREX ap- A particular category of patients are pregnant
proach, thus, it might be the most cost-effective women, where the use of anti VEGF is contro-
strategy [35]. versial – cases of miscarriage and preeclampsia
One of the main risk factors for vision loss due have been described as well as uneventful course
to neovascular AMD is the time elapsed between of pregnancy after intravitreal VEGF adminis-
the onset of visual complaints and the first diag- tration. Currently IVL, IVA, and IVE have been
nostic and treatment visit. That is why prompt categorized as Pregnancy Category C by the
diagnosis and start of treatment is vital for achiev- FDA. Every case of pregnant patient should be
ing best results. The response to anti-VEGF ther- considered individually and intraviteral treat-
apy has been found to be dependent on a variety ment only administered when there are clear
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Wet AMD 9
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benefits prevailing over risks and special multi- Decreased drug response can be related with
disciplinary attention given to the women treat- alterations of the neovascular membrane with fi-
ed [46]. brosis or in vessel wall, change of lesion type or
Response to treatment is defined as follows: in neighboring structures, systemic immune re-
• Optimal (Good) Response: Resolution of fluid sponse or development of neutralising anti-bod-
(ICF, SRF and retinal thickness, CRT), and/or ies and increased expression of VEGF (pharma-
improvement of >5 letters (subject to the ceil- codynamic tolerance) [49]. On the other hand
ing effect of good starting VA). there is no strong evidence showing an efficacy
• Poor Response: <25% reduction from the improve when the injection dose is increased
baseline in the CRT, with persistent or new [50–52]. In a case series by Tozer et al. [53] anti-
ICF, SRF or minimal or change in VA (that is, VEGF injections combined with PDT resulted in
change in VA of 0 + 4 letters). improved VA and decreased central subfoveal
• Non-Response: Increase in fluid (ICF, SRF thickness, while research with adjunct dexa-
and CRT), or increasing haemorrhage com- methasone intravitreal implant has shown sig-
pared with the baseline and/or loss of >5 let- nificant clinical effectiveness in vision stabiliza-
ters compared with the baseline or best cor- tion, reduction of fluid and retinal thickness [54,
rected vision subsequently. 55].
In eyes classified as good responders, treat- Novel Therapies. Substances that modulate
ment should be continued with the same agent complement system, such as antibodies (LFG316,
when disease activity is present or reactivation FCFD4514S, eculizumab), peptides (POT-4), ap-
occurs following temporary dose holding. In eyes tamers (ARC1905), and antibody fragments
that show partial response, treatment may be (lampalizumab) seem to be promising in AMD
continued, although re-evaluation with further therapy by halting inflammatory response [56,
imaging may be required to exclude confounding 57].
factors. Anti-VEGF might have a negative effect on at-
Where there is persistent, unchanging accu- rophy by blocking VEGF known to have neuro-
mulated fluid following 3 consecutive injections trophic activity. Thus, adjunct neuroprotection
at monthly intervals, treatment may be withheld has been also indicated as one of potential ways to
temporarily, but recommenced with the same or improve outcomes.
alternative anti-VEGF if the fluid subsequently Given the pathophysiology of the condition,
increases (lesion considered active). Shifting pa- transport, and metabolism of lipids seem to be
tients to different anti-VEGF in case of insuffi- potential targets. High-dose atorvastatin showed
cient response was shown to improve anatomical some promising results as preventive treatment
and visual outcomes. [35] Poor or non-response [58]. Recent research with the administration of
to anti-VEGF treatments requires re-evaluation platelet-derived growth factor (PDGF) antago-
of diagnosis and if necessary switch to alternative nist (E10030 – Fovista; Ophthotech, New York,
therapies. [47] With time neovascularization NY, USA) in combination with anti-VEGF could
seems to “burn out” leaving almost avascular potentially be another treatment option in the fu-
cicatrical mass. ture with phase II randomized trials reporting fa-
Presence of fluid should be analyzed cautious- vorable results and a high relative benefit.
ly, as it does not always indicate active CNV and
can be present with RPE malfunctioning as well
as over disciform scars, outer retinal tubulations
and atrophic areas [48].
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Ophthalmology 2016;123:609–616.
Prof. Paulo E. Stanga

Research Office, Purple Zone, MRI
Central Manchester University Hospitals NHS Foundation Trust
Oxford Road
Manchester M13 9WL (UK)
E-Mail Paulo.stanga@cmft.nhs.uk; mvr.lab@cmft.nhs.uk
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Wet AMD 13
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A Multimodal Imaging Guide to the Evaluation and

Management of Neovascular Age-Related Macular
Degeneration
Sean T. Garrity a · K. Bailey Freund c · David Sarraf a, b
a Stein Eye Institute, David Geffen School of Medicine at University of California Los Angeles, and b Greater Los Angeles VA
Healthcare Center, Los Angeles, CA, c Vitreous Retina Macula Consultants of New York, New York, NY, USA
Abstract Introduction
Neovascular age-related macular degeneration (AMD) is
a disease with the potential to cause significant visual im- The hallmark of neovascular age-related macular
pairment. The hallmark of this disease is the development degeneration (AMD) is the development of an-
of angiogenesis originating from the choroid or retina giogenesis originating from the choroid or retina.
leading to various, potentially blinding, complications. Associated exudative complications often result
Classification schemes of neovascular AMD have evolved in vision loss. Classification schemes of neovascu-
over the years due to major advances in retinal imaging lar AMD have evolved over the years due to major
that have provided greater understanding of the patho- advances in retinal imaging, providing greater
genic mechanisms and better guidance in developing understanding of the pathophysiology and better
treatment regimens and monitoring responses to thera- guidance in developing treatment regimens and
py. The original classification of neovascular AMD was monitoring responses to therapy. This chapter
based on fluorescein angiography while the current ana- will highlight the multimodal imaging findings of
tomic classification of neovascularization relies on a mul- neovascular AMD focusing on the evaluation and
timodal imaging approach, including spectral domain management of this disorder.
optical coherence tomography. Effective diagnosis and Classification of neovascular AMD has been
management of this disease requires a thorough under- largely based on the technology available to detect
standing of the multimodal imaging features of neovas- neovascularization (NV) and was originally de-
cularization as detailed in this chapter. Future imaging veloped during major clinical trials. The classifi-
modalities and novel biomarkers of neovascular activity cation scheme of neovascular AMD, formulated
that may enhance diagnosis and management are also during the Macular Photocoagulation Study
discussed. © 2017 S. Karger AG, Basel (MPS) in 1991, was based on fluorescein angiog-
raphy (FA) and a belief that all NV occurring in
AMD originated from the choroidal circulation.
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The MPS investigators described choroidal NV the efficacy of ablative laser therapy for the treat-
(CNV) as classic (well-defined) or occult (poorly- ment of extrafoveal, juxtafoveal, and subfoveal NV.
defined) types [1–5]. This classification system The researchers noted distinct angiographic pat-
evolved into a more complex scheme including terns of NV with variable responses to laser therapy
CNV forms referred to as predominantly classic, and proposed a classification scheme based on
minimally classic, or purely occult CNV as de- these findings. This angiographic categorization is
scribed in the Treatment of Age-Related Macular still relevant today and has been correlated with the
Degeneration with Photodynamic Therapy OCT based anatomic types of NV. Classic NV (of-
(TAP) Study Group in 1999 [6]. During this era, ten type 2 NV by OCT) demonstrates an area of
while most research efforts were focused on an bright, lacy, and well-defined choroidal hyperfluo-
angiographic-based paradigm for understanding rescence identified in the early phase that progres-
CNV, Gass proposed an anatomic-based theory sively leaks into the subretinal space during the late
for classifying CNV. Based on histopathologic re- phase of the FA. Occult NV (often type 1 NV by
sults he offered an alternative approach and OCT) may illustrate 2 forms: either a fibrovascular
coined the term type 1 CNV to represent vessels pigment epithelial detachment (PED) or late-phase
proliferating under the retinal pigment epitheli- leakage of undetermined source. Fibrovascular
um (RPE) and type 2 CNV to indicate prolifera- PEDs demonstrate early stippled hyperfluores-
tion above the RPE in the subretinal space [7]. cence (within 1 min) with late staining or leakage.
With the advent of optical coherence tomog- Late phase-leakage of undetermined source shows
raphy (OCT) providing more refined imaging speckled or stippled hyperfluorescence early with
and histopathologic-like cross sections of the ret- poorly defined borders and late pooling in the sub-
ina and choroid, a large body of evidence sup- retinal space. It should be noted that other forms of
porting Gass’ classification soon emerged. Cur- PED can be identified with FA including a serous
rent classification builds heavily upon Gass’ con- PED with uniform rapid pooling or a vascularized
cepts and is predominantly an OCT and serous PED that includes a notch or “hot spot” at
anatomic-based approach, with type 1 neovascu- the border of the PED [9].
larization (NV) identified below the RPE and type It is also now apparent that combinations of
2 NV above the RPE. More recently Freund both classic and occult patterns may be encoun-
coined the term type 3 (intraretinal) NV also tered in the same eye. Despite significant advanc-
known as retinal angiomatous proliferation es in the technology of retinal imaging, FA still
(RAP) [8] to indicate NV localized to the retina. provides substantive information for the initial
Not all NV is believed to originate in the choroid diagnosis of NV [10]. The American Academy of
and therefore the term NV (rather than CNV) Ophthalmology and the European Society of Ret-
will be used in the text that follows. Today it is ina Specialists recommend FA at initial diagnosis
recognized that classic appearing CNV on FA is and when there is a change in clinical status not
anatomically related to type 2 NV and occult ap- explained by OCT [11, 12].
pearing CNV is related to type 1 NV.
Anatomic Classification of NV
Fluorescein Angiographic Classification of NV
Based in large part upon Gass’ histologic classifi-
The original classification of neovascular AMD cation of type 1 and type 2 NV, Freund et al. [8]
was developed to describe various forms of leakage proposed a classification of NV based on the ana-
by FA in the MPS [1–5], a prospective trial to assess tomic localization in the retina vs. the choroid as
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Multimodal Imaging of Neovascular AMD 15

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a b
200 μm
Fig. 1. Multimodal imaging of type 1 neovascularization demonstrating a mixed serous and vascularized PED. The late
transit phase FA shows hyperfluorescent pooling within the serous component of the PED and a focal area of more
intense fluorescence at its nasal margin forming a “notch” (arrow) (a). The focal area of hyperfluorescence on FA cor-
responds to a focal “hot spot” on ICGA (arrow) (b) and a localized area of increased sub-RPE hyperreflectively on OCT
(c) which represents type 1 NV (arrow).
ascertained by multimodal imaging including may be associated with other disorders with dif-
FA, OCT, and when necessary indocyanine green fuse RPE/Bruch membrane abnormalities such
angiography (ICGA). FA and ICGA indicate the as cuticular drusen and malattia leventinese
presence of leakage in neovascular AMD, but [14], as well as pachychoroid spectrum disorders
these techniques do not provide depth resolved such as central serous chorioretinopathy (CSC),
anatomic information that OCT offers. Freund’s pachychoroid neovasculopathy and polypoidal
multimodal imaging approach is the most widely choroidal vasculopathy (PCV) [15]. Funduscop-
used and accepted classification of NV in AMD, ic examination may be unremarkable or may
as it allows for refinement of treatment strategies demonstrate a PED with or without a notch.
and prognosis. With FA the PED may demonstrate serous pool-
ing or stippled late staining and the occult type 1
NV may be identified as a focal area of intense
Type 1 NV fluorescence at the edge of the PED, sometimes
referred to as a “notch.” The ICGA pattern of
Type 1 NV is characterized by choroidal vessels type 1 NV presents as a “plaque” of late low-in-
proliferating under the RPE. This is the most fre- tensity hyperfluorescence [16] seen best in the
quent type of NV in neovascular AMD, identi- latter phases of the study, although a hypofluo-
fied in approximately 40% of patients [13], and rescent serous PED with a hot spot at the edge
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16 Garrity · Freund · Sarraf

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Fig. 2. OCT B-scan demonstrates a
multi-layered PED. There is fibrovas-
cular tissue beneath the RPE overlying
organized layers of hyperreflective
fibrocellular material which form lin-
ear bands above Bruch’s membrane.
The innermost layer (yellow arrow)
may represent the fibrovascular com-
ponent of the type 1 NV and the out-
ermost layer (green arrow) may repre-
sent the fibrocellular component.
may also be identified. OCT demonstrates vari- components may also be seen [20]. Vascularized
able elevation of the RPE as a PED. Subretinal PEDs may also demonstrate a hemorrhagic or ex-
fluid may also be seen (Fig. 1). Associated cys- udative subtype [14].
toid macular edema (CME) is an adverse prog- Eyes with chronic vascularized PEDs, especial-
nostic finding that develops [17] due to perma- ly those receiving long-term intravitreal anti-vas-
nent ELM (external limiting membrane) disrup- cular endothelial growth factor (VEGF) therapy,
tion. may demonstrate a multi-layered pattern, which
PEDs can be classified as drusenoid, serous, appears on OCT as organized layers of hyperre-
vascularized, or mixed types [18]. Drusenoid flective bands between the RPE monolayer and
PEDs are primarily a feature of non-neovascular Bruch’s membrane within a vascularized PED
AMD. Approximately 1% of patients with neovas- [21, 22] (Fig. 2). Histopathological correlation
cular AMD present with a serous PED while 30% has indicated that the anterior layer of these mul-
present with a vascularized PED [19]. Serous tilayered PEDs represents the fibrovascular com-
PEDs appear as a distinct clear or yellow-orange ponent of the type 1 NV adherent to the RPE
circular or ovoid detachment of the RPE on fun- monolayer while the spindle shaped posterior
duscopic exam, while FA demonstrates a charac- layer represents the fibrocellular component [23].
teristic intense early hyperfluorescence with rapid A lower layer of hyporeflective fluid may or may
uniform pooling within the PED in a homogenous not be identified.
and well-demarcated pattern. OCT of a serous Polypoidal choroidal NV (PCN) is a variant of
PED demonstrates a sharply elevated, dome- type 1 NV seen most commonly in patients with
shaped lesion with minimal internal reflectivity PCV and neovascular AMD. PCN may also occur
and absence of subretinal or intraretinal fluid. A in other neovascular disorders including periph-
vascularized PED, originally termed a fibrovascu- eral exudative hemorrhagic chorioretinopathy
lar PED in the MPS classification [1–5], is by defi- [24]. PCV was first described as a distinct entity
nition type 1 NV. On funduscopic examination, seen in African-American and Asian patients, but
the vascularized PED can appear similar to a se- is now considered a variant of neovascular AMD
rous PED, smooth and well circumscribed, with that often occurs in eyes with pachychoroid fea-
or without a notch, or irregular in shape and tures [25]. The type 1 NV of PCN consists of a
height. On OCT the RPE may or may not be branching vascular complex associated with ter-
sharply elevated and may demonstrate an irregu- minal reddish-orange, polyp-like or aneurysmal
lar hyperreflective lesion (representing the type 1 dilations. Eyes with PCN may present with mul-
NV) on the undersurface of the RPE [8, 10]. Mixed tiple recurrent serous and serosanguineous PEDs
PEDs with drusenoid, serous, and vascularized around the optic nerve or in the central macula,
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often with prominent lipid exudation. ICGA and sociated subretinal and less typically intraretinal
OCT are the main diagnostic adjuncts used to im- fluid. Disruption of the ellipsoid zone and ELM
age PCN [26, 27]. While ICGA is the most power- is often observed [10] (Fig. 3).
ful modality to detect the characteristic polypoi-
dal aneurysms and associated branching vascular
complex, OCT may also detect aneurysmal le- Type 3 NV (RAP)
sions typically located under a PED. A character-
istic “peaked” form of PED on OCT has also been While type 1 NV and 2 NV originate from the cho-
described and noted to be very characteristic of roidal circulation, most type 3 lesions are believed
PCV [18]. to originate from the retinal circulation [13, 22,
33–35]. Type 3 NV was first identified by Hartnett
et al. [36] in 1992 who noted a retinal vascular ab-
Type 2 NV normality associated with some PEDs in eyes with
AMD. The term retinal vascular anomalous com-
Type 2 NV occurring in AMD is characterized by plex was subsequently used to describe this type 3
NV originating from the choroid that has pene- NV [37]. In 2001, Yannuzzi et al. [38] coined the
trated the RPE to proliferate in the subretinal term RAP for type 3 NV. Several hypotheses de-
space between the RPE and outer segments of the scribing the development of these lesions have
overlying retina. While early type 1 NV is often been proposed including CNV as the origin; how-
associated with subretinal fluid, type 2 NV may ever, current evidence suggests this form of NV
present with both subretinal and intraretinal flu- typically originates in the retina from the deep ret-
id, presumably due to an earlier occurrence of inal capillary plexus (DCP) [34, 35, 39]. Type 3 NV
outer retinal disruption. It is the least common is the second most common form of NV in AMD
form of NV occurring in AMD, identified in ap- after the type 1 form and is identified in approxi-
proximately 9% of patients [13]. Type 2 NV is a mately 34% of newly diagnosed patients [13].
more common in eyes with reticular pseudodru- As type 3 NV develops, vessels originating in
sen [28] and in younger patients who may lack a the DCP extend posteriorly through the outer ret-
cleavage plane between the RPE and Bruch’s ina towards the RPE [35] and may be associated
membrane [29], including disorders such as with small intraretinal hemorrhages and CME
multifocal choroiditis, pseudoxanthoma elasti- [22, 35]. Su et al. [35] have recently described an
cum, and pathologic myopia [14]. Funduscopic OCT based classification of type 3 NV. Punctate
examination may demonstrate a gray-green hyperreflective foci within the outer retina charac-
membrane with or without a pigment ring. A terize the “precursor” stage. An intraretinal hy-
classic pattern is seen with FA, with early well- perreflective density or angioma associated with
defined hyperfluorescence and intense late leak- disruption and downward deflection of the outer
age. ICGA is typically less useful in detecting type plexiform layer is identified in stage 1 with preser-
2 NV than type 1 NV [8]. A network of radiating vation of the outer retina. Associated disruption
vessels may be identified with rapid sequence an- of the inner segment ellipsoid zone and the RPE is
giography in the earliest phases of ICGA [30]. noted in stage 2. Infiltration through the RPE with
OCT imaging of these vessels may demonstrate a the development of a serous or mixed serous
hyperreflective band or plaque (a subtype of sub- drusenoid PED is noted in stage 3 and is identified
retinal hyperreflective material [SHRM]) [31, 32] in 30–67% of eyes [34] (Fig. 4). In eyes with type 3
in the subretinal space above the RPE and be- NV associated with a PED, the type 3 lesion is
neath the photoreceptor outer segments, with as- identified at the apex of the PED, unlike eyes with
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a b c
Fig. 3. Multimodal imaging of type 2 neovascularization. Color photograph shows a gray lesion with associated sub-
retinal hemorrhage (a). Early (b) and late (c) phase FA illustrates a well-defined or classic pattern of early well-demar-
cated hyperfluorescence and late intense hyperfluorescence leakage. There is blocked fluorescence nasally due to
subretinal hemorrhage. OCT (d) demonstrates SHRM (subretinal hyperreflective material) comprised of type 2 NV
above the RPE with associated subretinal hemorrhage and fluid.
type 1 lesions, in which the NV may originate at rhage, and ultimately fibrotic or disciform scar-
the margin of the PED. While the PEDs associated ring [40, 41]. The MPS group found that nearly
with type 3 NV can become very large, RPE tears 40% of untreated eyes with neovascular AMD had
rarely occur in eyes with type 3 NV [22]. significantly decreased visual acuity at 2 years [3].
Vision loss results from neovascular hemorrhage
or leakage of subretinal and/or intraretinal fluid or
Mixed Lesions SRHM, an OCT lesion that may represent fibrin,
fibrosis, or a type 2 NV [31, 32]. Hemorrhage as-
Mixed lesions in which there is more than 1 subtype sociated with NV may be sub-RPE, subretinal, in-
of NV are identified in approximately 17% of pa- traretinal, or rarely preretinal and can demon-
tients with newly diagnosed neovascular AMD [13]. strate tremendous variability in size [42]. PEDs
may develop progressive layering, including a fi-
brovascular and fibrocellular component, and be
Natural History of Neovascular AMD referred to as a multilayered PED, or may flatten
into an atrophic lesion [20]. RPE tear may compli-
The natural history of neovascular AMD can dem- cate PED development (Fig. 5), especially after an-
onstrate considerable variability but it is generally ti-VEGF therapy [43–48] and especially in eyes
remarkable for proliferation, leakage, hemor- with large PEDs greater than 500μm in height [43–
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a
Fig. 4. Multimodal imaging of stage 3 type 3

neovascularization. Color photograph illus- d
trates a subfoveal PED with overlying spot
hemorrhage and associated drusen (a). Late
phase FA (b) shows hyperfluorescent pooling
beneath the PED with more intense fluores-
cence related to intraretinal leakage at the
site of the type 3 lesion. Baseline OCT (c)
demonstrates a large type 3 lesion near the
apex of a mixed serous and drusenoid PED. e
Adjacent OCT (d) demonstrates intraretinal
fluid. Follow-up OCT (e) after a single anti-
VEGF injection illustrates near-complete res-
olution of the PED with the regressed type 3
lesion visible within an area of outer retinal
disruption.
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a b c
Fig. 5. Multimodal imaging of an RPE tear. Fundus autofluorescence (FAF) demonstrates the characteristic hypoautofluores-
cent RPE tear (a), with subsequent progression (b) then centripetal recovery (c) of autofluorescence suggestive of re-epithe-
lialization of the tear. Imaging with OCT (d) taken at the time of the first image indicates the absence of RPE (arrow) (d).
48] exhibiting signs of type 1 NV traction with Presumably, anti-VEGF therapy has substantially
OCT [47] and may be a cause of catastrophic mac- reduced this percentage [48]. Other end stage find-
ular hemorrhage and significant vision loss [49]. ings of neovascular AMD include retinal atrophy
As the neovascular complex becomes less active [52, 53], RPE and choriocapillaris (geographic) at-
over time the vascular component may regress rophy which may be promoted by long term anti-
while the fibrotic component increases, ultimately VEGF therapy [54–56], outer retinal tubulations
forming a lesion composed of fibrocellular and fi- [57], and exudative retinal detachment [14].
brovascular tissue that is commonly referred to as
a disciform scar representing the end stage of neo-
vascular AMD. This disciform scar is identified on Differential Diagnosis
OCT as a dense hyperreflective lesion with loss of
the overlying outer retinal landmarks associated A variety of conditions can mimic neovascular
with decreased visual acuity [50] (Fig. 6). Prior to AMD and typically include any disorder associ-
the introduction of anti-VEGF therapy the inci- ated with disruption of the RPE-Bruch’s complex
dence of disciform scar formation in neovascular and NV, such as the presumed ocular histoplas-
AMD was reported to be greater than 40% [51]. mosis syndrome, pathologic myopia, pachycho-
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a a
b b
c c
Fig. 6. Multimodal imaging of bilateral fibrovascular disciform scar with color photographs (a), FAF
(b), and OCT (c). Disciform scarring represents the end-stage of neovascular AMD.
roid neovasculopathy, multifocal choroiditis, Management of Neovascular AMD

choroidal rupture, angioid streaks, and idiopathic
causes. Additionally, the subretinal fluid associ- If there is clinical suspicion for neovascular AMD,
ated with CSC can be confused with the subreti- FA and OCT should be obtained. Spectral do-
nal fluid and intraretinal fluid identified in neo- main-OCT is now the most essential modality for
vascular AMD [14, 58, 59]. Pachychoroid neovas- the diagnosis and management of neovascular
culopathy is a common cause of type 1 NV and AMD, although FA is still regarded by most reti-
PCV and is not an uncommon presentation in the nal specialists as an important resource at the ini-
elderly population and can be easily confused tial assessment [62, 63].
with neovascular AMD [60, 61]. OCT evaluation Increasing knowledge of the pathogenic mech-
for a thick choroid and pachyvessels is critical to anisms responsible for neovascular growth has
exclude this common association of type 1 NV. led to an inexorable advancement of treatment
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paradigms with evolution from laser photocoag- and Pfizer Inc, New York, NY, USA) was the
ulation to photodynamic therapy (PDT) and first anti-VEGF agent approved by the US FDA
more recently to the administration of intravit- for neovascular AMD, but only reduced rates of
real agents aimed at reducing VEGF. vision loss were demonstrated and it was soon
Thermal laser photocoagulation was the first replaced by newer agents [71]. The landmark
treatment designed to halt the progression of MARINA and ANCHOR trials demonstrated
neovascular AMD dating back several decades. the efficacy of ranibizumab (Lucentis®; Genen-
As first reported in the MPS thermal laser re- tech USA Inc, San Francisco, CA, USA) with
duced severe vision loss in eyes with well defined significant reduction of vision loss and for the
classic extrafoveal, juxtafoveal, and subfoveal first time ever, average vision improvement in
CNV but results were limited by high rates of re- eyes with neovascular AMD [72, 73]. Bevaci-
currence and the development of scotomas fol- zumab (Avastin®, Genentech USA, Inc.) is a
lowing treatment and therefore this modality is much cheaper off label alternative (but related)
very rarely administered today [1–5, 64]. In 1999 therapy for neovascular AMD and it was shown
PDT emerged as a less destructive approach for to be non-inferior to ranibizumab in the Com-
the treatment of NV, featuring a low-energy laser parison of AMD Treatment Trial and Inhibition
used to excite intravenously administered verte- of VEGF in Age-related choroidal NV (CATT)
porfin dye. The resulting localized photochemi- trial [74–77]. Most recently aflibercept (Eylea®;
cal reaction can generate reactive oxygen radicals Regeneron Pharmaceutical Inc, Tarrytown, NY,
that target and damage CNV endothelial cells re- USA and Bayer Healthcare, Berlin, Germany)
sulting in thrombosis and closure of the NV was approved by the US FDA for patients with
complex. The TAP study group in 1999 and the neovascular AMD in 2011, and was non-inferior
Verteporfin In Photodynamic Therapy Study and clinically equivalent to ranibizumab in the
group in 2001 demonstrated that PDT was most VIEW 1 (VEGF Trap-Eye: Investigation of Ef-
effective in reducing vision loss in eyes with pre- ficacy and Safety in Wet AMD) and VIEW 2 tri-
dominantly classic CNV or in eyes with small als [78], even with an 8 week injection interval
purely occult CNV with no classic component. (after an every 4 week loading injection interval
These trials, however, failed to illustrate signifi- for the first 12 weeks).
cant improvement in visual acuity and PDT is no All subgroups of neovascular AMD have il-
longer employed except in recalcitrant cases or lustrated visual and anatomical benefits with
eyes with PCV/PCN [6, 65–67]. Several vitreo- any of the 3 major intravitreal anti-VEGF agents
retinal surgical approaches have been investigat- (Fig. 7), and the clinical trials discussed above
ed to manage neovascular AMD. Macular trans- have demonstrated similar outcomes with the 3
location is technically difficult with a high com- agents [22, 79]. Studies have demonstrated that
plication rate and substandard outcomes. the subtype of NV can affect prognosis and re-
Submacular surgery to remove hemorrhage and sponse to anti-VEGF therapy. Type 1 lesions
CNV has also failed to demonstrate efficacy [68]. rarely have complete and sustained regression
As a result, these procedures have never achieved of neovascular complexes [8, 22, 80], and may
mainstream clinical practice [69, 70]. be complicated by RPE tears after anti-VEGF
Currently the gold standard of care for the therapy [48], although eyes with type 1 NV may
treatment of neovascular AMD is VEGF inhibi- be more resistant to geographic atrophy [81].
tion using injected intravitreal therapies. In Early type 2 lesions may demonstrate a robust
2004, pegaptanib (Macugen®; Eyetech Pharma- response to anti-VEGF therapy while more ma-
ceuticals Inc, Palm Beach Gardens, FL, USA, ture type 2 lesions may be more resistant [8],
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Before
After
b
Before
Fig. 7. Response to anti-VEGF thera-
py (bevacizumab) in a patient with
bilateral type 3 neovascularization.
Note the presence of a stage 3 type
3 intraretinal angioma that centrally
sits atop the apex of a mixed serous c
and drusenoid PED (a). The angio- After
ma and the PED are significantly im-
proved after anti-VEGF injection (b).
CME (c) preinjection is also signifi-
cantly improved although the pre-
cipitation of exudates at the level of
the deep capillary plexus is typical
d
after antiVEGF therapy (d).
and type 2 lesions may be more prone to fibrosis may receive 1 of the 3 major intravitreal agents
and disciform scarring [82]. It has also been using a variety of dosing regimens (fixed, pro re
demonstrated that type 2 lesions can regress nata, or treat and extend) [84, 85]. Patients are
into type 1 lesions after envelopment by the RPE monitored and treatment regimens are altered
following anti-VEGF therapy [83]. Type 3 le- based on functional (visual acuity) and anatomi-
sions may be remarkably responsive to anti- cal improvement. For most physicians OCT has
VEGF therapy early in their development, re- superceded FA as the main imaging modality for
quiring fewer injections, although more mature evaluation of therapeutic efficacy [10].
type 3 lesions are more resistant [8, 22, 34, 35]. While the improved visual outcomes provid-
Type 3 lesions may also have higher rates of ed by anti-VEGF therapy are remarkable, their
macular atrophy following anti-VEGF therapy effect of reducing neovascular activity may have
[22]. long-term adverse visual and anatomical conse-
Physicians must decide which anti-VEGF quences. Many of these findings typically devel-
agent to use based on numerous additional fac- op during the natural history of neovascular
tors, including cost analysis, potential safety con- AMD but also may possibly be exacerbated by
cerns, and physician and patient preference. anti-VEGF therapy. Examples of adverse find-
Upon diagnosis of neovascular AMD patients ings include subretinal hemorrhage [86], RPE
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tear formation [43, 44, 48, 86, 87], subretinal dis- tected endothelial cells) [90, 95, 99]. Type 3 le-
ciform fibrosis, retinal disorganization, and sions, on the other hand, demonstrate more com-
macular atrophy [54, 55, 77]. plete regression of small caliber vessels and fine
vascular tufts [39, 97–99]. Type 1 complexes are
considered to be more resistant to anti-VEGF
Future Imaging Modalities therapy than type 3 lesions, perhaps reflecting the
different vascular origins and locations of these
Optical coherence tomographic angiography neovascular complexes [39].
(OCTA) is an advanced imaging modality that Current OCTA technology has limitations es-
has demonstrated power in identifying the mi- pecially motion, segmentation, and projection ar-
crovascular morphology of neovascular lesions tifacts [89, 100], and detection sensitivity may be
originating from the retina and choroid. OCTA reduced in eyes with low flow, treatment naïve and
uses amplitude or phase decorrelation technology immature lesions or eyes with large PEDs causing
with high-frequency and dense volumetric scan- signal sensitivity roll off [101]. At present the sig-
ning to detect red blood cell movement. It pro- nificance of OCTA in terms of disease prognosis
vides depth-resolved information of the micro- and treatment response is still being evaluated, and
vascular structures of the retina and choroid it now serves more as a research tool than a critical
without dye injection and has remarkable poten- component of clinical practice. Nonetheless OCTA
tial as an adjunct imaging modality for the study shows considerable promise as a practical non-in-
of neovascular AMD as it provides microvascular vasive imaging modality with rapid acquisition
details not identified with FA or OCT [88, 89]. and may replace conventional dye based angiogra-
Due to the occult nature and location under phy for the evaluation of neovascular membranes
the RPE, it has been challenging to identify type 1 as it uniquely allows for more detailed visualiza-
NV complexes with FA and OCT. OCTA, how- tion of microvascular morphology [102].
ever, has illustrated a high flow, well-organized
vascular network with outer retinal and chorio-
capillaris segmentations. Neovascular growth Imaging Biomarkers
patterns for type 1 and type 2 NV, including “me-
dusa” or “sea fan” subtypes have been described With the advent of multimodal imaging and
and include a main central core of larger vessels computerized processing, there are current ef-
with radiating branches of smaller vessels charac- forts to define which imaging features are most
teristic of a more mature lesion type [83, 88, 90– predictive of prognosis and treatment efficacy in
95]. Type 3 lesions are typically small hot spots neovascular AMD. As there is tremendous het-
with FA and ICGA but OCTA may demonstrate erogeneity in neovascular AMD and its response
a high-flow small vascular tuft in the outer retina, to treatment, elucidating prognostic imaging bio-
very similar in appearance to the histopathologic markers should improve management of the dis-
appearance of these lesions [96], sometimes ex- ease both at the individual patient and population
tending into the RPE in association with a large levels [103].
serous PED [39, 97, 98] (Fig. 8). Historically FA classification was used to de-
OCTA imaging following anti-VEGF therapy termine which patients would benefit from laser
of type 1 and 2 lesions has typically illustrated photocoagulation and PDT [1–6] but with the ad-
pruning of the smaller peripheral vessels (com- vent of OCT and anti-VEGF therapy these FA
prised of endothelial cells) but persistence of the characteristics are of less prognostic significance.
main central trunk (comprised of pericyte-pro- Prior attempts to predict visual outcomes based
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Type 1 Type 1
Type 2 Type 2
Type 3 Type 3 Type 3
Fig. 8. 3 × 3 en face OCTA images and co-registered OCT B-scans of the 3 types of NV. Type 1 and type
2 NV demonstrate a “medusa”-like mature neovascular complex (arrow type 1, outlined orange type 2)
with OCTA. Note the thick central trunk/feeder vessel, with vessels radiating in all directions from the
center of the lesion, similar in type 1 and 2 NV. Imaging of type 3 NV with OCTA illustrates a focus of
increased signal intensity in the outer retina (arrow), corresponding to a neovascular tuft.
on traditional FA classification of NV generally quantitative capability that could offer robust

have not illustrated consistent results, although predictive information on visual outcomes, al-
several studies have suggested that smaller lesion though results to date have been variable [103,
size on FA is correlated with slightly improved 104]. Intraretinal cysts/fluid have been shown to
visual outcomes after anti-VEGF therapy [76, be the single most important biomarker in terms
103]. of initial visual function and also visual outcome
OCT analysis in particular provides various after anti-VEGF therapy, with intraretinal cysts/
anatomical biomarkers, with qualitative and fluid serving as a negative prognostic factor [17,
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105], in particular for type 1 lesions associated sulting in this decreased incidence of geographic
with PED [22]. Intraretinal cysts/fluid has also atrophy [113, 114].
been associated with higher rates of geographic OCTA is still developing as an adjunct imag-
atrophy [54]. SRHM and resulting fibrous scar- ing modality but it has the potential to provide
ring are significantly associated with poor visual prognostic biomarkers. The clinical relevance of
outcomes [82, 106], although this finding is vari- the various morphologic patterns of NV seen
able [22] and may depend on the exact composi- with OCTA has yet to be determined [93, 115].
tion of SHRM. Alterations of outer retinal layers OCTA imaging of neovascular complexes after
correlate with initial visual acuity but they have treatment has demonstrated a reduction in size
less prognostic value than intraretinal cysts and of the lesion, with increased intercapillary spac-
subretinal fluid [103, 107]. Outer retinal tubula- es within the lesion and fewer smaller vessels at
tions have been found to be associated with the periphery of lesions [95, 115]. A pattern of
worse VA outcomes [108]. Other OCT biomark- mature, tangled vessels within type 1 lesions has
ers whose prognostic significance remains un- been demonstrated to be associated with lower
clear include outer retinal hyperreflective foci rates of geographic atrophy [116]. Additionally,
and choroidal thickness [103]. Subretinal fluid is the presence of secondary branching of smaller
the only pathologic marker consistently associ- vessels may be associated with active NV lesions
ated with improved visual outcomes, and may vs. quiescent [93]. Quantification of these
suggest a more benign disease course responsive changes could be used to monitor therapeutic
to therapy [105, 109]. Despite its ease of mea- responses. NV complex dimensions including
surement, central retinal thickness has been area and vessel density and fractal dimension,
shown to poorly correlate with visual outcomes and choriocapillaris structure and flow mea-
[110]. surements are parameters quantifiable on OCTA
PEDs in isolation are not associated with a that could serve as useful biomarkers [88]. Oth-
poor visual outcome, although PED in the preser new imaging modalities such as polarization-
ence of other pathologic findings particularly in- sensitive OCT and adaptive optics imaging also
traretinal cysts may be a poor prognostic sign [17, hold promise in this regard [103].
103, 104, 111] as it is typically the result of ELM
disruption. Larger PEDs (height >550 μm or PED
diameter >5 mm), the presence of a hyperfluores- Conclusion
cent ring around the PED on FA and signs of neo-
vascular traction with spectral domain OCT are Neovascular AMD is a disease with potential for
risk factors for RPE tears after anti-VEGF therapy significant visual impairment. Effective diagno-
[43, 46–48]. Larger chronic multilayered fibrosis and management relies heavily on a thorough
vascular PEDs may have a stable anatomical understanding of the many multimodal imaging
course with a good visual prognosis [21]. features discussed in this chapter. Careful inter-
The prognostic significance of lesion type has pretation of the detailed findings of neovascular
not yet been studied in large clinical trials but type AMD available with advanced multimodal reti-
1 NV has demonstrated better visual outcomes nal imaging will provide significant prognostic
than other neovascular subtypes [112]. Type 1 le- indicators of visual and anatomical outcome and
sions have also demonstrated lower rates of geo- will help guide the optimal treatment and follow-
graphic atrophy compared to other subtypes up of the patient.
[113] especially type 3 lesions [22, 54], as type 1
NV may recapitulate the choriocapillaris thus re-
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David Sarraf, MD
Retinal Disorders and Ophthalmic Genetics Division
Stein Eye Institute, David Geffen School of Medicine at UCLA
100 Stein Plaza
Los Angeles, CA 90095 (USA)
E-Mail dsarraf@ucla.edu
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Retinal Vein Occlusion

Dafna Goldenberg · Anat Loewenstein
Tel Aviv Medical Center, Department of Ophthalmology, Tel Aviv, Israel
Abstract Definition, Classification and Pathophysiology

Retinal vein occlusion is an obstruction of the retinal ve-
nous system by thrombus formation. It is the second The European Consensus Document defined
most common retinal vascular disease after diabetic reti- RVO as a “retinal vascular disorder characterized
nopathy affecting nearly 16 million adults. Careful diag- by engorgement and dilatation of the retinal veins
nosis, categorization, and treatment may minimize per- with secondary, mostly intraretinal hemorrhages
manent damage. Identification and modification of and intraretinal edema, retinal ischemia includ-
underlying systemic risk factors help to minimize sight ing cotton wool spots, retinal exudates and macu-
threatening complications. Ophthalmologic manage- lar edema” [3].
ment includes the use of anti-VEGF agents and steroids RVO is an obstruction of the retinal venous
to promote reabsorption of macula edema and delay or system by thrombus formation. The anatomic
halt the development of neovascularization. classification of RVO is derived from the fundu-
© 2017 S. Karger AG, Basel scopic appearance of the eye and includes 3 main
groups depending on the site of the vein obstruc-
tion: central RVO (CRVO), branch RVO (BRVO)
Retinal vein occlusion (RVO) is the second most and hemi RVO (HRVO).
common cause of retinal vascular disease after di- CRVO occurs due to thrombus within the cen-
abetic retinopathy [1, 2]. It is a sight-threatening tral retinal vein when it passes through the lamina
condition that usually affects middle-aged to old- cribrosa of the optic nerve, leading to involve-
er people (older than 50 years). ment of the entire retina. There are a number of
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factors that may be involved in the pathogenesis non-perfusion with profoundly reduced visual
of CRVO. The central retinal vein and artery acuity, usually to the level of counting fingers or
share a common fibrous coat, with changes in the less. Cotton wool spots are typically seen, as are
arterial wall causing compression of the vein. relative afferent pupillary defects. Visual field
Changes in the venous wall due to inflammatory testing generally shows significant defects, and
or degenerative disease may contribute to venous there is a high risk of subsequent intraocular neo-
occlusion, as well as blood viscosity changes such vascularization.
as in blood dyscrasias. Systemic hypertension is Non-ischemic RVO is associated with much
another potential factor in the pathogenesis of less retinal ischemia and capillary non-perfusion
CRVO. Any one or more of these predisposing and few or no cotton wool spots. Intraocular neo-
factors may produce slowing and turbulence of vascularization does not generally occur. Visual
blood flow in the vein which in turn leads to for- acuity is often reduced by the macular edema,
mation of a thrombus. The resulting clinical fea- which accompanies the vein occlusion, but the
tures are widespread involving the disc and the degree of visual loss is generally not as severe as in
entire retina [3–5]. ischemic RVO [2].
BRVO most commonly occurs at an arterio-
venous (AV) crossing where an artery and vein
share a common vascular sheath. The occlusion Prevalence
involves the venous branches distal to the AV
crossing. In most cases, the artery lies anterior to RVO affects approximately 16 million adults
the vein, making the vein vulnerable to compres- worldwide with an estimated prevalence of 0.5–
sion by the artery, resulting in turbulent flow, 0.7% in adults 49–60 years of age, and 4.6% after
which in turn leads to a predisposition toward the age of 80 [2, 3]. The prevalence of RVO in-
endothelial damage and thrombus formation. creases with age and is similar between men and
This process is exacerbated in the presence of ar- women [1]. BRVO occur 2–3 times more often
teriosclerosis. The clinical features are confined than CRVO. The overall estimated prevalence for
to the fundus portion drained by the affected vein BRVO and CRVO is 0.6 and 0.2% respectively [3].
[3–5].
HRVO occurs when the thrombus is in a vein
that drains the superior or inferior hemi-retina, Risk Factors
leading to involvement of one-half of the retina.
The presumed site of the occlusion is 1 of the 2 There are several systemic risk factors associated
trunks of the intraneural central retinal vein when with RVO, mainly hypertension and hyperlipid-
this congenital abnormality exists. The clinical emia. In addition, renal dysfunction and less
features are confined to 2 altitudinal quadrants commonly diabetes are also risk factors. RVO is
(the nasal and temporal aspect) of the involved associated with elevated plasma homocysteine
hemisphere. It is not clear whether HRVO is an levels and low serum folate levels. However, there
entity in itself or a subtype of CRVO [3–5]. is no association for serum vitamin B12 levels and
It is important to distinguish CRVOs from thermolabile MTHFR genotype. Open angle
BRVOs because they have different risk factors, glaucoma is the most common ocular risk factor
prognosis, and treatments. for RVO [6–8].
We further distinguish between ischemic and An increased risk of CRVO was found in per-
non-ischemic retinal vein occlusions. Ischemic sons with systemic hypertension, diabetes melli-
RVO demonstrates significant retinal capillary tus, and open-angle glaucoma [8–11].
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Retinal Vein Occlusion 33

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An increased risk of BRVO was found in per- local ocular conditions such as retinal vasculitis,
sons with a history of systemic hypertension, a glaucoma, and trauma [2, 13, 14].
history of cardiovascular disease, high body mass Evaluation of RVO patients for underlying
index, a history of glaucoma, and higher serum predisposing systemic disorders is very impor-
levels of alpha 2-globulin [11, 12]. tant, since treating these systemic disorders may
help prevent further ocular venous occlusive epi-
Open Angle Glaucoma sodes as well as systemic complications [3].
The increased intraocular pressure is thought to
compromise retinal vein outflow and produce
stasis. It is more associated with CRVO than Natural History
BRVO [3].
Visual Acuity
Hypertension The prognosis for visual acuity loss depends
More than 64% of RVO patients in the age group largely on the type and location of RVO.
over 50 are hypertensive, and it is a predominant Patients with CRVO generally have a poor vi-
finding in recurrent RVO (88%) This major risk sual outcome. The visual acuity at presentation is
factor is more prevalent in patients with BRVO the major predictive factor for final visual acuity.
than in those with CRVO [3]. Eyes presenting with an initial VA of 6/12 or better
are more likely to have a good outcome compared
Hyperlipidemia to those presenting with visual acuity less than
This is the predominant risk factor for RVO in 6/12. In contrast, when initial visual acuity is less
patients under 50 years old. It is also found in up than 6/60, 80% will either remain at this level or
to 50% of older patients. continue to lose vision. Patients with ischemic
CRVO are at high risk for poor visual acuity at ini-
Diabetes Mellitus tial presentation and over the long-term, com-
This risk factor is significantly associated with pared to those with non-ischemic CRVO. The
CRVO. However, it was not found to be an inde- Central Vein Occlusion Study (CVOS) Group
pendent risk factor for BRVO [3]. found visual acuity of less than 6/12 in 63% of non-
ischemic eyes. The Standard Care vs. Corticoste-
RVO of the Young roid study (SCORE) found a visual acuity of 20/40
Hypertension is considered the major risk factor or worse in at least 75% of eyes with both ischemic
for CRVO in older patients, while hypercoagula- and non-ischemic CRVO patients observed for 12
blity is a major risk factor for RVOs in younger months. The Ozurdex GENEVA study found a
patients. gain of at least 15 letters from baseline after 30 days
Thus, evaluation of RVO in younger patients of treatment in only 7.5% of patients in the obser-
includes tests for hyperviscosity or hypercoagula- vation group of both ischemic and non-ischemic
bility such as polycythemia or leukemia, cryofi- CRVO patients. A report by McIntosh et al. [16]
brinogenemia, multiple myeloma, decreased lev- found a mean decrease in VA of 35 letters after 12
els of antithrombin III, elevated platelet count, or months or longer follow-up for ischemic CRVO,
abnormal platelet function. Other factors predis- while patients with non-ischemic CRVO had an
posing to RVO in younger patients include both average visual acuity decrease of only 3 letters with
systemic diseases such as collagen vascular disor- a follow-up of at least 12 months [3, 15–17].
ders, systemic medications such as diuretics, Patients with BRVO not involving the macula
sympathomimetics, and oral contraceptives, and are usually asymptomatic with no loss of visual
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34 Goldenberg · Loewenstein
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acuity. Patients with macular edema from BRVO emic CRVO. According to the CVOS, the stron-
may have spontaneous visual acuity improve- gest predictors of NVI/NVA were initial visual
ment in the first 3 months after onset of symp- acuity and the area of retinal capillary non-perfu-
toms. After 3 months, the likelihood of spontane- sion as determined by fluorescein angiography
ous improvement in visual acuity diminishes. Ini- (FA). For eyes initially categorized as non-per-
tial visual acuity in eyes with BRVO is generally fused or indeterminate CRVO, 35% developed
worse than 6/12. The Branch Vein Occlusion NVI/NVA, compared with 10% of those initially
Study (BVOS) found significant visual deteriora- categorized as perfused [3, 15, 16].
tion over time in 20% of untreated eyes. Approx- Conversion from non-ischemic to ischemic
imately 50% of untreated eyes with BRVO main- CRVO has been reported to be 34% over 3 years.
tain a visual acuity of 6/12 or better, while final
vision was less than 6/60 in 25% of cases [3, 18, Macular Edema
19]. Macular edema is a major complication of both
ischemic and non-ischemic CRVO and is likely to
Neovascularization present at baseline. The reported incidence rate
Neovascularization of the iris (NVI), anterior ranges from 0 to 73% for the ischemic type, and
chamber angle (NVA), and retina are important about 30% for the non-ischemic type over 2–15
complications of CRVO. While retinal neovascu- months [2, 3]. Chronic macular edema is associ-
larization may occur after a major BRVO, ante- ated with a worse visual prognosis, and thus mac-
rior segment neovascularization is very unusual. ular edema needs to be treated early. Prompt in-
Neovascularization of the retina can lead to vitre- tervention is justified by the finding that the lon-
ous hemorrhage and traction retinal detachment, ger the duration of edema, the greater the
while anterior segment neovascularization can likelihood of structural damage to the fovea.
result in neovascular glaucoma. Vitreous hemor- Macular edema may develop in 5–15% of eyes
rhage can be associated with visual disturbances associated with BRVO. The Ozurdex GENEVA
such as severe floaters, intermittent visual obscu- study showed greater likelihood of improvement
rations, and varying degrees of visual loss. Devel- of the macular edema within a shorter duration in
opment of neovascular glaucoma may result in both treatment and sham groups.
significant ocular morbidity, such as pain, chron-
ic ocular redness, unremitting intraocular pres- Fellow Eye Involvement
sure elevation, and profound visual loss that is of- The existence of systemic risk factors makes the
ten unresponsive to anti-glaucoma drops or sur- fellow eye similarly vulnerable. Approximately
gery. NVI/NVAs are considered harbingers of 5–10% of CRVO cases were reported to develop
neovascular glaucoma, and are most likely to oc- RVO in the fellow eye over a 1-year period. The
cur in eyes with ischemic CRVO [5]. BVOS reported a rate of 9% of bilateral involve-
In BRVO, neovascularization is uncommon, ment whereas cross-sectional population data
except where more than one-third of the fundus suggest a 5% bilateral involvement [3].
is involved by capillary non-perfusion. Neovascu-
lar glaucoma is rare. In CRVO, the incidence of
neovascularization has been reported in up to Diagnostic Evaluation
60% of cases. The incidence of neovascularization
secondary to non-ischemic CRVO has been The evaluation of RVO, like other retinal diseas-
found to vary from 0 to 33% over 12–15 months, es, begins with a history and complete ophthal-
whereas it reaches 60% over 6–12 months in isch- mologic examination. Other testing such as FA
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and optical coherence tomography (OCT) may
be performed to confirm the diagnosis, assess ret-
inal capillary non-perfusion, and follow disease
progression or response to treatment.
Clinical Manifestations
Retinal vein occlusions produce a typical fundu-
scopic picture with darker, dilated retinal veins,
with retinal hemorrhages and edema, cotton wool
spots, retinal exudates, and macular edema [2].
CRVO is seldom asymptomatic, with patients
initially reporting a monocular painless acute on-
set of decreased vision. BRVO may be asymptom-
Fig. 1. Large superotemporal branch retinal vein occlu-
atic and may be diagnosed on routine ophthal-
sion with wedge-shaped pattern of intraretinal hemor-
mologic examination. More commonly, patients rhages.
describe a visual field deficit or scotoma with
blurred vision corresponding to the area of the
occluded retinal vein. Patients with BRVO in- Fluorescein Angiography
volving the macula typically complain of blurred FA is very important both in diagnosing RVOs
central vision. and in distinguishing ischemic from non-isch-
In patients presenting with chronic RVO, emic subtypes. The CVOS Group classified
there may be additional findings. NVI and the CRVOs into perfused, non-perfused, or indeter-
NVA can lead to the development of neovascular minate types depending on the amount of retinal
glaucoma. In addition to decreased vision, these capillary non-perfusion on wide-field FA. The
patients may complain of a red, painful eye sec- classification scheme is based on disc areas, which
ondary to elevated intraocular pressure [5]. represent the surface area of the optic nerve head.
In patients with BRVO, the area containing the If the area of retinal capillary non-perfusion is less
retinal hemorrhages are focal or wedge-shaped, than 10 disc areas, it is classified as “perfused =
with the apex situated at the offending AV cross- non-ischemic CRVO”. If the area of retinal capil-
ing (Fig. 1). Variable amounts of retinal edema are lary non-perfusion is greater than10 disc areas, it
present within this region. The distribution cor- is classified as “non-perfused = ischemic CRVO.”
responds to the area that is served by the affected If the extent of capillary non-perfusion cannot be
retinal vein. There may also be venous dilatation determined because of extensive intraretinal
extending peripherally from the AV crossing hemorrhage, it is classified as “indeterminant”
where the vein occlusion occurred (Fig. 2). CRVO [2, 5].
In patients with CRVO, the retinal hemor- In cases of long-standing CRVO, FA may dem-
rhage is scattered and diffuse, with optic disc ede- onstrate additional findings such as the presence
ma in some patients. Dilated and tortuous veins of collateral vessels in or on the optic disc, which
are seen throughout the fundus. All 4 quadrants divert blood from the occluded retinal circulation
have intraretinal hemorrhages (Fig. 4). Cotton to the choroidal circulation. These vessels are larg-
wool spots are observed in approximately half of er in caliber than neovascularization and do not
patients with CRVO. The arterioles may be atten- leak in late frames of the angiogram. Retinal ve-
uated, indicating generalized arteriosclerotic dis- nous collaterals may also be seen, connecting the
ease. occluded retinal veins to nearby patent ones [2, 5].
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a b
Fig. 2. a, b Fluorescein angiogram frame depicts dilated superotemporal retinal vein.
Fig. 3. OCT image shows macular edema with sub retinal fluid.
Optical Coherence Tomography different vascular diseases including RVO. It

OCT has become an essential part of the initial seems there is a reduction of foveal and parafo-
examination and routine follow up of RVO pa- veal retinal superficial and deep vascular density
tients. It assists in diagnosis including baseline as- and choriocapillaris density compared to normal
sessment, guiding clinical practice, analyzing the subjects [20–23].
progression of RVO and response to treatment.
Its main use in RVO is in quantifying retinal
thickening (Fig. 3, 5). Treatment
OCT angiography provides non-invasive im-
aging of the superficial and deep retinal capillary The European Consensus Document and the Pre-
network with detailed foveal avascular zone visu- ferred Practice Pattern of American Academy of
alization and vessel density evaluation useful in Ophthalmology set out practical guidelines for
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a b
Fig. 4. a, b Intraretinal hemorrhages and cotton wool spots in all 4 quadrants on funduscopic examination in CRVO.
Fig. 5. OCT image shows macular edema with foveal sub-retinal fluid.
the management of RVO [3, 4, 24]. The manage- patient for glaucoma as it has been proved to be
ment of RVO is aimed at identification and man- associated with RVO.
agement of modifiable risk factors and of sight- The ophthalmological management of RVO
threatening complications. has dramatically evolved and changed over the
It is critical to identify and to manage systemic last 3 decades. Two studies provided the guide-
risk factors such as hypertension, cardiovascular lines for treatment for many years. In 1984, the
disease, diabetes mellitus, hyperlipidemia, and BVOS Group reported the benefits of grid laser
hypercoagulable states. Their treatment is impor- photocoagulation and it used to be the gold stan-
tant to reduce the risk of venous occlusion in the dard for treating BRVO. In 1997, the CVOS
fellow eye and the development of systemic com- Group reported the very limited effect of grid la-
plications such as coronary artery occlusion and ser photocoagulation on reducing macular edema
strokes. In addition it is important to evaluate the after CRVO, although pan-retinal laser photoco-
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agulation helps to reduce the progress of neovas- evaluated intravitreal Aflibercept vs. grid-laser in
cular complications [4, 15, 18]. patients with BRVO-related macular edema [2–
Over the last decade, there have been multiple 4].
well-controlled studies, which demonstrated new Many uncontrolled case series have reported
and effective treatments for RVO. The treatment that bevacizumab (Avastin) intravitreal adminis-
of RVO has been revolutionized by the intravit- tration can lead to a VA improvement and resolu-
real injection of sustained-released steroids and tion of macular edema in RVO. There is, howev-
anti-VEGF agents. These are mostly targeted on er, no randomized clinical trial involving bevaci-
enhancing the resorption of macular edema and zumab (Avastin) in RVO [3].
stopping the progression of neovascularization
[4]. Anti-Inflammatory Therapies
Steroids are known to reduce inflammation, ves-
Anti-Vascular Endothelial Growth Factor sel permeability, edema, and angiogenesis. This
Therapy has led to the use of intravitreal steroids in the
Studies showed that the vitreous level of VEGF is treatment of RVO. The most obvious benefit of
significantly higher in CRVO and BRVO patients steroid use is a decrease in macular edema. Fur-
than in controls. This is the rationale for anti- thermore, biodegradable intravitreal implants
VEGF therapy in RVO. Anti VEGF drugs include provide some potential advantages over tradi-
ranibizumab (Lucentis), bevacizumab (Avastin), tional intravitreal injections by delivering a
and aflibercept (Eylea). known dose of drug directly at the site of action,
Ranibizumab proved to be effective for treat- amplifying the drug’s half-life, reducing peak
ing macular edema in the CRUISE trial for CRVO plasma levels, and avoiding the side effects associ-
patients and in the BRAVO trial for BRVO pa- ated with repeated intravitreal injections [2, 3].
tients up to 12 months. Long-term treatment out- Two major studies evaluated steroid efficacy
comes were provided in the HORIZON cohort up in treating RVO. The SCORE study aimed at ex-
to 24 months and the RETAIN study up to 4 years amining the effect of intraocular triamcinolone as
in which patients from the CRUISE and BRAVO treatment of ME in patients with CRVO and with
were recruited. BRVO. The standard care in CRVO was observa-
The SHORE study compared monthly vs. PRN tion whereas the standard care in BRVO was grid
ranibizumab dosing in BRVO/CRVO and sup- laser photocoagulation. The SCORE CRVO study
ports flexible dosing of ranibizumab for both has confirmed the beneficial effect of the intravit-
BRVO and CRVO [2–4]. real drug for the treatment of macular edema as-
Aflibercept demonstrates a longer duration of sociated with non-ischemic CRVO. The SCORE
activity by exhibiting a higher binding affinity for BRVO trial concluded that there was no differ-
VEGF-A, VEGF-B, and placental growth factor. ence identified in VA at 12 months for the stan-
The longer duration of action brings with it the dard care group compared with the triamcino-
potential to reduce the dosing intervals. It proved lone groups [2, 3, 25].
to be effective for treating macular edema related The GENEVA trial evaluated the safety and ef-
to both BRVO and CRVO. GALILEO and CO- ficacy of the biodegradable dexamethasone intra-
PERNICUS were 2 sister studies. They were phase vitreal implant (Ozurdex) compared with sham
III randomized double-masked multicenter clini- treatment in eyes with RVO-related ME. It re-
cal studies that aimed to evaluate intravitreal cruited patients with either BRVO or CRVO. The
Aflibercept vs. sham in patients with CRVO-re- mean VA for patients with BRVO (but not those
lated macular edema. VIBRANT was a study that with CRVO) improved significantly. Retinal
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thickness was significantly greater for the whole the development of ocular neovascularization. In
study population. The only prominent complica- less severe cases, scatter treatment directed at the
tions observed over the 12 months of follow-up non-perfused areas may be sufficient. Patients
were cataract progression and a limited rise in in- with ischemic CRVO without neovascularization
traocular pressure [2, 3, 26]. should be followed up closely. Whenever NVI/
NVA is identified, evidence-based medicine sup-
Management of Peripheral Non-perfusion and ports the administration of PRP. In cases of
Neovascularization BRVO with peripheral neovascularization, intra-
Ischemic CRVO is usually characterized by pe- vitreal therapy should be initiated, followed by
ripheral retinal non-perfusion greater than 10 scatter laser aimed at the area of the occluded vein
disk diameters, as evaluated by FA examination. [3].
Development of ocular neovascularization is di-
rectly related to the extent of non-perfusion. Cas- Radial Optic Neurotomy
es with extensive retinal non-perfusion, or with Radial neurotomy (RON) has been suggested as a
limited compliance regarding follow-up exami- therapy for CRVO. However, randomized pro-
nations, may be considered for early panretinal spective trials have not yet shown beneficial ef-
photocoagulation (PRP) in an attempt to block fects of RON in the treatment of CRVO [3].
References
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retinal vein occlusion: pooled data from molabile MTHFR genotype as risk fac- 15 Natural history and clinical management
population studies from the United tors for retinal vascular occlusive dis- of central retinal vein occlusion. The
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20 Coscas F, et al: Optical coherence to- 23 Rodolfo M, Lisa T, Luca DA, Enrico B, 25 Ip MS, Scott IU, VanVeldhuisen PC, et
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Dafna Goldenberg
Department of Ophthalmology, Tel Aviv Medical Center
6 Weizmann Street
E-Mail dafnagoldenberg@gmail.com
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Vitreomacular Interface in Retinal Diseases

Elad Moisseiev a, c · Joseph Moisseiev b, c
a Departmentof Ophthalmology, Tel Aviv Medical Center, Tel Aviv, b Department of Ophthalmology, Sheba Medical Center,
Ramat Gan, and c Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Abstract ermost “shell” of the vitreous body is known as

The vitreoretinal interface is known to play a role in the the vitreous cortex, and has the highest concen-
pathogenesis of many retinal diseases. This chapter will tration of both collagen and HA [1].
discuss the properties of the vitreoretinal interface, the The vitreomacular interface (VMI) lies be-
macular conditions caused by abnormalities of this inter- tween the posterior vitreous cortex and the inner
face, their characteristic presentation on optical coher- surface of the internal limiting membrane (ILM).
ence tomography, and their management. An updated These 2 structures are very different, as the for-
review of the relevant current literature will also be pro- mer contains mostly type II collagen fibers and
vided. The chapter will focus on posterior vitreous de- the latter is comprised mostly of type IV collagen
tachment, vitreoretinal traction, epiretinal membrane, fibers [1].
full-thickness macular hole, lamellar macular hole, and The VMI is best demonstrated by optical co-
the role of the vitreoretinal interface in age-related mac- herence tomography (OCT). With recent ad-
ular degeneration and diabetic macular edema. Finally, it vances in imaging techniques, it has been shown
will also review the literature on the management of vit- to play an important role in the pathogenesis of
reous floaters. © 2017 S. Karger AG, Basel several retinal diseases.
The Vitreomacular Interface Posterior Vitreous Detachment
The vitreous is composed of approximately 98% The vitreous undergoes progressive liquefaction,
water and 2 other major components: collagen with gradual weakening of the vitreoretinal adhe-
and hyaluronan (HA). It is actually a dilute mesh- sion. This process is physiologic and age-related,
work of collagen fibrils (types II, V/XI and IX) and most significant over the posterior pole,
that create a scaffold-like structure that is inter- where the premacular liquefied vitreous pocket
spersed with HA, which is hydrophilic. The out- enlarges and the vitreous cortical layer overlying
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the macular area becomes extremely thin. It has Vitreomacular Traction
been shown that liquefaction of the vitreous be-
gins as early as at 4 years of age, and advances Since the vitreoretinal interface is best imaged by
throughout life [2]. OCT, its appearance is generally classified using
Posterior vitreous detachment (PVD) is de- this modality. The recent International Vitreo-
fined as a complete separation of the vitreous ma- macular Traction (VMT) Study group has cre-
terial from the retinal surface. This process typi- ated several definitions to describe these condi-
cally begins in the perifoveal region where vitre- tions in a uniform manner [6]. Vitreomacular
ous is more loosely attached, and then extends to adhesion (VMA) has been defined a perifoveal
areas where the ILM is thinner and the attach- separation of the cortex from the retina, but with
ment is stronger, including the foveola, along no separation form the fovea or midperipheral
large retinal vessels, the optic disc margin and the retina and no change in the foveal contour. This
vitreous base. PVD usually presents with flashes is generally asymptomatic, and equivalent to
and floaters, and can be complicated by retinal stage 1 PVD. VMT has been defined as perifo-
breaks, vitreous hemorrhage, rhegmatogenous veal separation of the cortex from the retina, with
retinal detachment, and retinal or optic disc hem- no separation form the fovea or midperipheral
orrhages [2]. retina, but with associated distortion of the fo-
The progression of PVD has been divided into veal surface or intraretinal structure. Although
4 stages. In stage 1, the vitreous remains attached this condition may be asymptomatic, it can cause
to the fovea and is only detached in the perifoveal reduced visual acuity or metamorphopsia. In
area. In stage 2, it is detached from the fovea but VMT, broad (>1,500 μm) areas of attachment
still attached to the midperipheral retina and op- with traction can cause generalized thickening of
tic disc. In stage 3, the vitreous has also detached the macula, vascular leakage on FA, macular
from the midperipheral retina but is still attached schisis, and cystoid macular edema (CME). Focal
to the optic disc. In stage 4 the vitreous is com- areas of vitreous attachment with traction tend to
pletely detached from the inner retina including distort the foveal surface, elevate the foveal floor,
the disc [2, 3], and remains attached only at the and form pseudocysts within the central macula
vitreous base. It has been shown that at age 80, (Fig. 1).
about 60% of patients have complete PVD (stage Although VMT can resolve spontaneously,
4) and the majority of the remaining patients have this can take a very long time and can be visually
partial PVD. The rate of complete PVD was about significant for the patients. There are several
twice as high in women than in men [4]. treatment options for VMT:
In a subset of eyes, remnants of cortical vitre- 1. Ocriplasmin (Jetrea, ThromboGenics NV,
ous remain attached to the ILM in areas of firm Leuven, Belgium) is a recombinant truncated
vitreoretinal adhesion. This is considered an form of human plasmin with a molecular weight
anomalous PVD, in which the liquefied vitreous of 27.2 kDa, which has potent proteolytic activity
body collapses without sufficient dehiscence at against major components of the vitreoretinal in-
the vitreoretinal interface and with a split within terface, including fibronectin, collagen IV and
the posterior vitreous cortex (vitreoschisis), leav- laminin. It induces both liquefaction and vitre-
ing the outermost layer of the posterior vitreous ous detachment and is capable of chemically sep-
cortex attached to the macula. This has been im- arating the vitreoretinal adhesion. Ocriplasmin
plicated in a variety of vitreoretinal interface dis- has been shown to be able to release VMT within
orders, such as macular hole (MH) and epiretinal 28 days of a single injection (125 μg/0.1 μL) in
membrane (ERM) formation [5]. 26.5% of symptomatic patients compared to
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Vitreomacular Interface in Retinal Diseases 43

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a
Fig. 1. Vitreomacular traction. a Fo-

cal vitreomacular adhesion with
traction causing flattening of the
foveal contour and small intrareti-
nal cysts. b A more severe case in
which the traction resulted in more
significant distortion of the retina
with formation of an impending
b
macular hole.
10.1% of patients injected with placebo for con- retinal detachment, vitreous hemorrhage, intra-
trol [7], and has been approved by the FDA for ocular pressure changes, cataract progression and
the treatment of this condition. Further analysis endophthalmitis.
has showed that resolution of VMA was achieved
more often in younger patients (<65 years), pa-
tients without ERM at baseline, patients with full Epiretinal Membrane
thickness MH (FTMH) at baseline, phakic pa-
tients, and patients with a VMA diameter under ERM is a common cause of visual impairment,
1,500 mm [8]. Therefore, careful patient selec- which occurs in about 7% of the population,
tion is recommended when considering ocriplas- with an incidence that rises with age [11, 12].
min treatment. ERM consist of fibrocellular proliferation found
2. A simple alternative treatment for symp- at the vitreoretinal interface, which may be com-
tomatic VMT is pneumatic vitreolysis. It has been pletely asymptomatic when the membrane is
shown that injecting a small amount of expansile thin and translucent, but can progress to a semi-
gas (such as C3F8 or SF6) can achieve release of translucent, thick, and contractile membrane
VMT in approximately 85% of cases [9, 10]. This resulting in macular distortion, thus inducing
is a safe, simple and cheap procedure, which ap- decreased visual acuity and metamorphopsia
pears to be highly effective. [13].
3. An additional therapeutic option is pars pla- Anomalous PVD has been recognized as a pre-
na vitrectomy (PPV), which will release the VMT disposing factor for ERM formation [5]. The pro-
in all cases, but may also be associated with a gression of an ERM toward a contractile mem-
small risk of postoperative complications such as brane is related to the transdifferentiation of its
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44 Moisseiev · Moisseiev
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a
Fig. 2. Epiretinal membrane. a The epiretinal membrane is demonstrated by optical coherence tomography as a hy-
per-reflective layer overlying the retina. Note the irregular surface of the inner retina, with a “saw-tooth” pattern.
b A more severe case in which an epiretinal membrane resulted in more significant distortion of the retinal architec-
ture with diffuse retinoschisis.
cellular components toward myofibroblasts, amination of the macula in a patient with an

which are responsible for excessive collagen pro- ERM. It appears as a discrete, reddish, round or
duction and deposition and contraction of the oval lesion in the fovea similar in appearance to a
membrane. The accumulation of advanced glyca- small or medium FTMH. Slit-lamp examination
tion end products, which is an age-related phe- of the macula can result in a false diagnosis of
nomenon, has been implicated in both the patho- FTMH, hence the term pseudo-hole. The ERM
genesis of anomalous PVD as well as increased on the surface of the macula distorts the foveal
stiffness of ERMS [13]. contour into a shape with a steep slope that mim-
On OCT, an ERM appears as a highly reflec- ics a hole but contains no actual loss of foveal tis-
tive layer. It may cause the macular contour to sue [6] (Fig. 3a).
become flattened, or create irregularities in the An ERM may appear as adherent to the reti-
inner retinal surface contour, such as ILM folds na or separated from the inner retina, and needs
or a “saw-tooth” pattern. Additional findings may to be distinguished from a detached posterior
include macular schisis, intraretinal fluid cysts, or hyaloid surface. It is very important to evaluate
a pseudo-hole (Fig. 2). A pseudo-hole is a clinical the integrity of the outer retinal layer, as numer-
diagnosis based on slit-lamp biomicroscopic ex- ous studies have reported it to be a major deter-
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a
Fig. 3. Types of macular holes. a A pseudohole with an associated epiretinal membrane. b A lamellar macular hole.
c A full-thickness macular hole.
minant of the postoperative visual acuity [14– tion is excellent, with very low rates of complica-
16]. tions reported with the use of small-gauge instru-
The only effective treatment for ERM is PPV mentation.
with membrane peeling. It is recommended to
consider surgery when there is an indication of
progression, with objective and/or subjective Macular Hole
worsening of visual acuity and metamorphopsia.
It has been shown that surgery for ERM removal As was first hypothesized by Gass [18], MHs are
is effective also in eyes with very good preopera- caused by anteroposterior and tangential vitreous
tive VA [17]. The safety profile of this interven- traction on the macula during the course of PVD.
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The classic classification categorized MH into 4 ers, and the photoreceptor layer at the base is in-
stages. In stage 1, also called “impending MH”, tact [6] (Fig. 3b).
there is a foveal cyst within the retina with no full A LMH is believed to be caused by an abortive
thickness defect. In stage 2, there is a full thick- process of MH formation, with de-roofing of an
ness hole which is under 400 μm diameter with intraretinal cyst with preservation of foveal base.
persistent vitreous adhesion. In stage 3, the hole It may also be a complication of chronic CME. A
is over 400 μm in diameter, and in stage 4 it is also LMH is essentially different from a pseudo-hole,
accompanied by a complete PVD [18, 19]. A new- in which there is no loss of tissue but rather a
er classification based on OCT has been recently change in the foveal contour and a concomitant
suggested, in which MHs are defined as a full ERM with a central opening [6]. In contrast to
thickness foveal defect that interrupts all layers FTMH, in both of these conditions there is a neg-
from the ILM to the retinal pigment epithelium ative Watzke-Allen sign. The differentiation be-
(Fig. 3c), and are further classified by size (small tween them is based on their appearance in OCT
under 250 μm, medium between 250 and 400 μm and the presence of an ERM.
and large over 400 μm) and the presence or ab- LMHs are known to be a stable macular condi-
sence of VMT [6]. tion, and generally do not require any interven-
PPV (with or without ILM peeling) and gas tion. PPV should be considered only in the pres-
tamponade has been the standard treatment of ence of progressive thinning of foveal thickness
MHs for over 2 decades, with anatomical closure and/or decrease of visual acuity during the fol-
rates of 85–100% and significant visual improve- low-up of the disease [24].
ment in as much as 85–95% of patients [20, 21]. It
is important to note that intravitreal injection of
ocriplasmin was found to achieve about 40% clo- Diabetic Macular Edema
sure of stage 2 MHs [7]. Although this finding is
impressive and suggests that MH closure can be The pathophysiology of diabetic macular edema
achieved without surgery, it should be noted that (DME) is known to be complex, and involves
these results are only achieved in a small subset of multiple pathways such as inflammation, vascu-
patients. In fact, a retrospective study of a cohort lar dysfunction and oxidative stress. In addition
of patients with MH revealed that only 6.7% were to these biological processes, the VMI has also
compatible with the strict criteria for ocriplasmin been implicated as a causative factor in DME.
use [22]. Additionally, it should be noted that the Lewis et al. [25] were the first to describe a thick-
success rates are significantly better with PPV ened taut posterior hyaloid in patients with
than with ocriplasmin, and that due to the high DME, and postulated that it caused macular
cost of this agent, PPV is a more cost-effective traction resulting in thickening and edema. They
treatment option [23]. were also the first to perform vitrectomy for the
treatment of DME, and achieved visual improve-
ment in 9 of the 10 patients in their series [25].
Lamellar MH Later studies using OCT imaging showed that
patients with DME have VMI abnormalities
A lamellar MH (LMH) is defined as an irregular [26–29]. Also, it has been shown that the pres-
foveal contour, with a defect in the inner fovea ence of PVD was significantly associated with
that may not represent actual loss of tissue. There lack of macular edema [30], and that vitreomac-
can be intraretinal splitting (schisis), typically be- ular separation was significantly associated with
tween the outer plexiform and outer nuclear lay- its resolution [31]. Histologic studies of eyes
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with diffuse DME have reported them having live with them. Therefore, they are generally ob-
vitreoschisis, which was responsible for contin- served with no intervention.
ued macular traction [32, 33]. It is important to Although not commonly used, Nd:YAG laser
note that a recent study reported that the pres- has been shown to be successful in eliminating
ence of VMA in patients with DME was associ- floaters, and it is capable of cutting vitreous
ated with a greater potential for improvement in strands [36, 37]. Nd:YAG laser vitreolysis causes
visual outcomes with anti-vascular endothelial lysis of fibers and rhexis of aggregates, followed
growth factor therapy [34]. Therefore, the pres- by displacement of the vitreous floaters out of the
ence of VMA or VMT should not preclude treat- visual axis. There is a concern that the laser may
ment with intravitreal injections. However, in damage the retina or the lens, and possible com-
persistent and refractive cases of DME, perform- plications include retinal holes, chorioretinal
ing PPV is an appropriate treatment option to bleeding, vitreous hemorrhage, CME, and intra-
consider. ocular pressure elevation. For this reason, this
treatment is generally not offered to patients
[38].
Age-Related Macular Degeneration The severity of symptoms associated with vit-
reous floaters should not be underestimated just
The VMI may also play a role in the pathogenesis because there is no common treatment to offer
of exudative age-related macular degeneration these patients. In fact, it has been reported that
(AMD). It has been found that persistent attach- patients with floaters were willing to trade off an
ment of the posterior vitreous cortex to the mac- average 1.1 years out of every 10 years of their re-
ula was significantly more common in eyes with maining life to get rid of the symptoms associated
exudative AMD than in eyes with non-exudative with floaters, and were also willing to take, on av-
AMD, and its presence has been implicated as a erage, an 11% risk of death and a 7% risk of blind-
risk factor for exudation. It has been proposed ness to get rid of symptoms relating to floaters
that the persistent vitreoretinal traction may in- [39]. For this reason, some experts feel that per-
duce chronic low-grade inflammation, allow for forming PPV for the removal of vitreous floaters
continued macular exposure to cytokines or free (“floaterectomy”) is justified. Although this is a
radicals in the vitreous gel, and interfere in trans- simple and effective surgery, especially when per-
vitreous oxygenation and nutrition of the macula formed with small-gauge instrumentation, there
[35]. It has also been suggested that induction of are still possible complications that should be tak-
PVD may offer some protection against the pro- en into consideration. One recent publication re-
gression of AMD to exudation. ported the results of a limited vitrectomy with re-
moval of floaters from the central vitreous, with-
out induction of PVD, peripheral shaving of the
Vitreous Floaters vitreous or retrolental vitrectomy [40]. Although
rates of cataract progression and other complica-
The most common symptom of PVD are floaters. tions were very low, it is possible that the remain-
The majority of eyes with vitreous floaters are still ing vitreous over the macula will lead to later vit-
phakic, healthy, and with an excellent visual acu- reoretinal interface disorders such as ERM or MH
ity. The floaters can interfere with daily activities formation. Therefore, PPV for this indication re-
and may have a negative impact on quality of life, mains a controversial issue.
but the symptoms are often temporary, and most
patients adapt to persistent floaters and learn to
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Elad Moisseiev, MD
Department of Ophthalmology, Tel Aviv Medical Center
Weitzman 6 St.
E-Mail elad_moi@netvision.net.il
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Dry Macula: Essentials for Fast Diagnosis,

Prognosis, and Choice of Treatment
Giuseppe Querques a · Riccardo Sacconi a, b · Adriano Carnevali a ·
Alessandro Rabiolo a · Luigi Antonio De Vitis a · Daniela Montorio a ·
Lea Querques a · Francesco Bandello a
a Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, and b Department of Ophthalmology,
University of Verona, University Hospital of Verona, Verona, Italy
Abstract tools available for the fast diagnosis and prognosis of

Age-related macular degeneration (AMD) is a leading d-AMD and on current data of drugs that are under inves-
cause of vision impairment in elderly people and is be- tigation in the treatment of this disease.
coming a public health problem of great proportions in © 2017 S. Karger AG, Basel
Western society. AMD is classified in dry AMD (d-AMD)
and neovascular AMD depending on the presence of cho-
roidal neovascularization. The term “dry AMD” is com- Introduction
monly used to cover a range of different stages of the
disease, in which geographic atrophy (GA) represents the Age-related macular degeneration (AMD) is a
most advanced and debilitating stage. In the last years, major cause of vision impairment in elderly peo-
the development of several non-invasive tools, in partic- ple in Western society [1, 2]. AMD is a multifac-
ular fundus autofluorescence, optical coherence tomog- torial pathology, in which genetic and environ-
raphy (OCT), and OCT angiography, allowed the ophthal- mental risk factors play a crucial role [3]. In addi-
mologists to better understand the natural course of the tion to age, many other factors were associated
disease and to follow-up better AMD patients with a mul- with the development of AMD, such as cigarette
timodal imaging approach. At the same time, no existing smoking, one of the major risk factors of the dis-
approved therapy for GA is available because no treat- ease, blood hypertension or pulse pressure, high
ment is able to repair damages of retinal pigment epithe- lipid levels and dietary fat, abdominal obesity and
lium or photoreceptors. For this reason, all treatments are low physical activity, and cataract surgery [4–9].
intended to prevent or stop the progression of the atro- Nevertheless, the exact pathophysiological mech-
phy. However, several drugs are under evaluation with anisms behind AMD remain to be determined,
promising results. In this chapter, we focus on the new and several pathways are under investigation.
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a b c
Fig. 1. Multimodal imaging evaluation of a patient with drusen. a–c Multicolor imaging, infrared reflectance, and fun-
dus autofluorescence showing the presence of drusen in the macular area. d Optical coherence tomography B-scan
passing through the fovea showing small deposits under the RPE, above the Bruch’s membrane. e, f Choriocapillaris
segmentation on 3 × 3 optical coherence tomography angiography and corresponding B-scan with flow showing a
general reduction in choriocapillary density with some focal areas of choriocapillaris loss.
The Age-Related Eye Disease Study Group patients with a multimodal imaging approach. At
(AREDS) has classified AMD into 2 different cat- the same time, no existing approved therapy for
egories, dry form of AMD (d-AMD) and exuda- GA is available because no treatment is able to re-
tive or neovascular form of AMD (n-AMD) [10, pair damages of RPE and photoreceptors. New
11]. The hallmark of n-AMD is the presence of treatments for d-AMD are under investigation
choroidal neovascularization (CNV). d-AMD is with the intent to prevent or stop the progression
classified in 3 main stages: in the early and inter- of the atrophy.
mediate stages there are deposition of drusen be- This chapter focuses on the fast diagnosis and
tween the Bruch’s membrane and the retinal pig- prognosis of patients affected by d-AMD and on
ment epithelium (RPE) and RPE alterations in current data about drugs under investigation in
the macular area. The late stage of d-AMD is the treatment of dry form of AMD.
characterized by geographic atrophy (GA) [5].
Reticular pseudodrusen represent an additional
phenotype and are associated with worse visual Diagnosis and Prognosis
function from early stage, and an overall higher
likelihood of progression to both forms of late Drusen are usually the earliest clinical finding in
AMD (n-AMD and GA) [12–14]. dry form of AMD. Most commonly they are
In the last years, the development of many new found in the posterior pole but they can occur
non-invasive tools, such as fundus autofluores- throughout the retina. Clinically, on fundus bio-
cence (FAF), optical coherence tomography microscopy, drusen appear as yellow or white
(OCT) and OCT angiography (OCT-A), allowed spots deep to the retina, specifically between RPE
the ophthalmologists to follow-up better AMD and Bruch’s membrane (Fig. 1). Drusen are clas-
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52 Querques · Sacconi · Carnevali · Rabiolo · De Vitis · Montorio · Querques · Bandello

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a b c
Fig. 2. Multimodal imaging evaluation of a patient affected by geographic atrophy (GA). a–c Multicolor imaging, in-
frared reflectance, and fundus autofluorescence showing the large area of GA, partially sparing the fovea. d Optical
coherence tomography B-scan passing through the fovea showing central retinal atrophy with backscattering.
e, f Choriocapillaris segmentation on 3 × 3 optical coherence tomography angiography and corresponding B-scan
with flow showing the atrophy of the choriocapillaris layer in the area affected by GA and thus the direct visualization
of underlying choroidal vessels.
sified based on their size in drupelets (small dru- shaped band within the limits of the OPL) that
sen <63 μm), medium drusen (between 63 and appear approximately 1 year before the develop-
125 μm), and large drusen (>125 μm) [11]. ment of atrophy visible on color fundus photog-
Drupelets are small, common in normal eyes, raphy [15, 16]. Nascent GA and drusen-associat-
and do not carry an increased risk for the devel- ed GA can be considered direct precursors of ex-
opment of neovascular AMD; they are included tensive GA, the late stage of d-AMD [15, 17]. GA
in the normal aging changes. Soft drusen are me- is clinically observed as areas of hypopigmenta-
dium to large in size, may have nondiscrete bor- tion or depigmentation of the RPE and repre-
ders or be confluent, and are associated with an sents areas of outer retinal loss (Fig. 2). Visual
increased risk of progression to neovascular acuity can be significantly affected if the damage
AMD or progressive atrophy [11]. Moreover, extends through the fovea and often these GA ar-
drusen do not cause decreased central vision, but eas occur in a site of previous drusen.
patients may have mildly impaired contrast sen- Color fundus photography, FAF, OCT, fluo-
sitivity, metamorphopsia, and difficulty with rescein angiography (FA), indocyanine green an-
light adaptation and reading. The development giography (ICGA) and OCT-A are useful tools to
of drusen regression was associated with high classify and to diagnose different stages of d-
risk of drusen-associated atrophy. This stage was AMD. Color fundus photography documents the
defined as nascent GA, which is characterized by presence of drusen, RPE irregularity as well as ar-
specific OCT features (the subsidence of the out- eas of GA. Moreover, color fundus photography
er plexiform layer and inner nuclear layer, and/or is used in d-AMD to follow the progression of the
the development of a hyporeflective wedge- disease over time. OCT is the main tool used to
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Dry Macula: Essentials for Fast Diagnosis, Prognosis and Choice of Treatment 53
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evaluate patients with macular degeneration. report any changes in visual acuity immediately
Drusen can be visualized as small deposits under to their ophthalmologist, as this could signal a
RPE cells into Bruch’s membrane and GA is also conversion to n-AMD.
visualized on OCT scans with absence of the out-
er layers of the retina and with presence of the
typical backscattering effect. Furthermore, the Choice of Treatment
absence of subretinal or intraretinal fluid is im-
portant to rule out the conversion to n-AMD. No existing therapy is able to repair damaged RPE
Also FA and ICGA are important tools to verify or photoreceptors and no therapy is currently ap-
the presence of a CNV and thus the n-AMD. FAF proved for the treatment of GA.
may highlight areas of sick or atrophic RPE, In the last years, several approaches have been
which appears as a hypoautofluorescent area, studied considering the pathogenesis of d-AMD
also demonstrates the presence of drusen that ap- and many drugs are under evaluation. The main
pear hyperautofluorescent. Areas of GA show areas of research are the oxidative stress, the neu-
very low to extinguished FAF due to the loss of roprotection, the chronic inflammation and the
RPE and lipofuscin. Finally, OCT-A, a new non- complement activation, the accumulation of lipo-
invasive imaging tool able to characterize and fuscin, the choroidal blood flow insufficiency,
quantify the vascular network, has added more and the stem cell-based therapy.
data characterizing all stages of d-AMD. In early In this section, we briefly report the main
and intermediate stages, characterized by drusen drugs under evaluation in each category.
and pigmentary abnormalities of RPE, OCT-A
suggests that there are no significant changes in Nutritional Supplementation
retinal vasculature but there is a general reduc- The role of nutrition is very important in several
tion in choriocapillary density compared to age- diseases, including AMD. The daily intake of spe-
matched normal controls, with some focal areas cific food components is able to decrease the rate
of choriocapillaris loss or flow impairment. GA is of progression of d-AMD in selected patients.
associated with loss of choriocapillaris lying un- The AREDS formula supplementation (a daily
der the area of retinal atrophy and asymmetric dose of 80 mg zinc oxide, 2 mg cupric oxide, 15
alteration of choriocapillaris at the margin of GA mg β-carotene, 500 mg vitamin C and 400 IU vi-
[18]. tamin E) has proven efficacy in patients with
Between all these useful tools, FAF is currently high-risk affected by d-AMD, significantly reduc-
considered as the gold standard in monitoring ing the risk of AMD progression [21]. However,
progression of atrophic areas [19]. Sunness et al. it was not proven whether this formula supple-
[20] report the enlargement rate of GA over time mentation is also effective in patients affected by
using FAF, with the median overall enlargement GA or by the earliest stages of d-AMD. Interest-
rate of 2.1 mm2/year. Eyes with larger areas of at- ingly, the authors reported that patients with GA
rophy at baseline tended to have larger enlarge- involving the central area of the retina, similarly
ment rates, but knowledge of prior rates of en- to patients affected by intermediate d-AMD [22],
largement was the most significant factor in pre- had a beneficial effect from AREDS supplementa-
dicting subsequent enlargement rates [20]. tion due to the lower rate of progression to n-
Finally, patients with d-AMD should be fol- AMD.
lowed every 3–6 months depending on the clini- A following study (AREDS2) demonstrated
cal status, and suggested to use an Amsler grid that the elimination of β-carotene or lower-dose
regularly at home. They should also be advised to zinc did not change the rate of progression to late
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AMD [23]. This result is very important in clinics which when combined with CNTF in a sustained-
because it was proven that β-carotene intake in- release platform (NT-501), releases the substance
creases the incidence of lung cancer in smokers for more than 1 year [28]. A phase II, random-
[24]. Moreover, also AREDS2 study reported a ized, double-masked, clinical trial (NCT00447954)
great incidence of lung cancer in d-AMD patients evaluates the efficacy of NT-501 implant in GA
treated with AREDS supplementation vs. patients patients with promising results at 1-year follow-
treated with AREDS2 supplementation, mostly in up. Zhang et al. [29] showed a dose-dependent
former smokers [23]. stabilization of visual acuity and a relation with
In the last years, with the genetic risk profiling the retinal thickness increase at structural OCT.
for prediction of AMD, many researchers are High-dose CNTF patients showed a loss of <15
evaluating the association between the vitamin letters on the ETDRS chart in 96.3% of cases com-
supplements and the genetic risk profile with pared with 83.3% in low-dose CNTF patients and
promising results [25]. 75% in sham treatment patients.
In conclusion, AREDS and AREDS2 supple-
mentation have been proven effective in reducing Anti-Inflammatory Agents
the rate of progression of d-AMD patients and Chronic inflammation plays an important role in
thus they are habitually used in clinics but the nu- AMD pathogenesis and corticosteroids are
tritional supplementation is still an active scien- known for their antiangiogenic and anti-inflam-
tific research field. matory effects [30, 31]. On the basis of this ratio-
nale, many clinical trials are ongoing to evaluate
Neuroprotection the role of these drugs in the treatment of AMD.
The neuroprotection is thought to be crucial in In a phase II study (NCT00695318), 40 patients
the treatment of d-AMD. Brimonidine in an α-2 affected bilaterally by GA were recruited and
agonist that showed a neuroprotective effect on treated by Iluvien (Alimera Sciences, Alpharetta,
retinal cells in rats [26]. It is generally used in GA, USA), a sustained-release formulation of
glaucoma patients, but currently is under evalua- fluocinolone acetonide. The study was complet-
tion in patients affected by d-AMD. A phase II ed, but the results are not yet available.
randomized study (NCT00658619) evaluated the In addition to corticosteroids, a few comple-
efficacy and the safety of brimonidine adminis- ment inhibitors are being studied to treat GA
tered by an intravitreal biodegradable polymer with promising results. Several authors demon-
matrix similar to the dexamethasone intravitreal strated the role of different complement com-
implant model (Ozurdex; Allergan, Irvine, CA, plexes in patients with GA and in the pathogen-
USA) in 119 patients with bilateral GA. Since the esis of this disease [32, 33]. Lampalizumab
results were controversial, a second multicenter (FCFD4514S; Genentech/Roche, San Francisco,
trial (NCT02087085) was designed to evaluate the CA, USA), a humanized monoclonal antibody, is
GA area change from baseline to 24-month fol- the first complement inhibitor to demonstrate a
low-up. The results will be available in 2019. positive effect in slowing the progression of GA
A second neuroprotective drug, ciliary neuro- with a phase II clinical trial (NCT02288559). Cur-
trophic factor-501 (CNFT), is under evaluation. rently, 2 different phase III trials, Chroma
CNFT is a interleukin 6 family cytokine and it (NCT02247479) and Spectri (NCT02247531),
has been shown to have a protection effect in ani- have begun to evaluate the long-term efficacy and
mal models [27]. Neurotech Pharmaceuticals safety of lampalizumab injections.
(Cumberland, RI, USA) developed a well-tolerat- Another promising drug is glatiramer acetate
ed intraocular encapsulated cell technology, (Copaxone; Reva Pharmaceuticals, Kfar-Saba,
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Israel), an immunomodulatory that influence T- crease the choroidal blood flow and delay the pro-
cell differentiation. In a phase I clinical trial gression of d-AMD.
(NCT00541333), subcutaneous Glatiramer injec- Alprostadil (UCB Pharma, Berkshire, UK)
tions was proven effective in reducing the drusen and MC-1101 are the 2 most promising drugs of
area of patients with drusen after 12 weeks. A this category. Alprostadil was superior to placebo
phase II/III study (NCT00466076) is underway to therapy in the treatment of d-AMD patients.
evaluate the long-term efficacy and safety. In a phase III, randomized clinical trial
Two different drugs targeting C5 are under (NCT00619229), patients treated with this drug
evaluation. ARC1905 (Zimura; Ophthotech showed a BCVA superior to placebo group after
Corp., Princeton, NJ, USA) was demonstrated 6 months of treatment [36]. MC-1101, a new va-
safe in a phase I study (NCT00473928), but a sodilator, has been shown to increase choroidal
phase II clinical trial would be required to prove blood flow and to have an anti-inflammatory and
the safety and efficacy of this drug in d-AMD. Ec- an antioxidant effect in a small clinical trial
ulizumab (Soliris; Alexon Pharmaceuticals, (NCT01922128). However, further trials are rec-
Cheshire, CT, USA) showed no reduction of GA ommended to evaluate the long-term safety and
progression over 6 months in the COMPLETE effects of both these drugs and thus to establish
study [34]. their role in the treatment of d-AMD.
Also POT-4 (Potentia Pharmaceuticals, Moxaverine, a nonselective phosphodiesterase
Louisville, Ky., USA and ALcon, Hünenberg, inhibitor, and Sildenafil (Viagra; Pfizer Inc, New
Switzerland), a C3 inhibitor administered by in- York, NY, USA) showed contradictory results in
travitreal injection, completed the phase I study different studies, and thus their future in the
(NCT00473928) without safety concerns but a treatment of d-AMD is still unclear [37–39].
phase II clinical trial is required to evaluate its role
in the treatment of d-AMD. Accumulation of Lipofuscin and Visual Cycle
Since amyloid-beta may play a role in AMD Inhibitors
progression, 2 humanized monoclonal antibodies Accumulation of lipofuscin has been observed to
targeting amyloid-beta, RN6G (Pfizer, New York, be phototoxic and play a role in the RPE atrophy
NY, USA) and GSK933776 (GlaxoSmithKline, [40]. For this reason, visual cycle inhibitors have
Brentford, UK), have been studied in phase II been proposed in the treatment of patients affect-
clinical trials (NCT01577381 and NCT01342926, ed by GA. Two main drugs were studied with un-
respectively), but results are not available. clear results. In a phase II clinical trial
(NCT00429936), fenretinide (Sirion Therapeu-
Choroidal Blood Flow Restoration Agents tics, Tampa, FL, USA) did not reduce the growth
In recent years, an increasing role in AMD patho- rate of GA in patients treated with 100 and 300
genesis has been attributed to vascular factors. mg daily drug.
Choroidal circulation plays an important role in Downregulation of photoreceptors activity is
providing nutrients and removing wastes from also being investigated using emixustat (ACU-
the RPE and retina layers [35]. Thus, another tar- 4489, Acucela, Seattle, WA, USA). It is a non-ret-
get for a new therapy could also be increasing the inoid visual cycle modulator of the isomerase
blood flow of the choroid, which is diminished in (RPE65) that reduces the accumulation of lipo-
thickness in older age patients. Therapies cur- fuscin. A phase IIa trial (NCT01002950) showed
rently in clinical trials include vasodilators such a biological effect in GA eyes, and thus a phase II/
as alprostadil, MC-1101, moxaverine, and silde- III study (NCT01802866) was conduced but re-
nafil with the rationale that these drugs may in- sults are not yet available.
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Stem Cell-Based Therapy In the last years, the development of several
Stem cell therapy represents an emerging therapy new non-invasive tools, in particular FAF, OCT
for d-AMD. Human pluripotent stem cells, em- and OCT-A, has allowed us to better understand
bryonic or induced are currently being investigat- the natural course of the disease and to carefully
ed in clinical trials for AMD [41–43]. The patho- follow-up patients affected by d-AMD. However,
physiologic rationale is that RPE and photorecep- the pathogenesis of the disease is not completely
tors are primarily affected in GA, and thus their clarified yet, and further studies are recommend-
restoration by cell transplantation seems a possi- ed to understand all mechanisms related to d-
ble new approach. AMD. There is no approved therapy for GA, the
However, stem-cell-based disease modeling late form of d-AMD, but there are several drugs
and transplantation requires a long-term and under evaluation with promising results. Proba-
multi-disciplinary method. bly, only a few of these drugs will confirm the pre-
liminary results and will be available in the near
future for clinical practice.
Conclusions
AMD is becoming a public health problem of Disclosure Statement

great proportions; Klein et al. [44] reported that
the 15-year cumulative incidence of early and late No competing interests were disclosed.
form of AMD was 24 and 8%, respectively.
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Prof. Giuseppe Querques

Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele
Via Olgettina 60
E-Mail giuseppe.querques@hotmail.it
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Diabetic Retinopathy: Essentials for Fast

Diagnosis, Prognosis and Choice of Treatment
Maurizio Battaglia Parodi · Maria Vittoria Cicinelli · Alessandro Rabiolo
Department of Ophthalmology, University Vita-Salute, Ospedale San Raffaele, Milan, Italy
Abstract According the most recent statistics, one-third

The management of diabetic retinopathy (DR) has sig- of diabetic patients suffer from diabetic retinopa-
nificantly improved over the past decade. New imaging thy (DR) and 10.2% feature vision-threatening
techniques along with more appropriate and tailored DR [3, 4]. DR is one of microvascular complica-
treatments have been introduced in an attempt to sim- tion of DM, as the consequence of chronic hyper-
plify the diagnostic and therapeutic pathways of patients glycemia on retinal neuronal and endothelial
affected by DR. Although the rate of involvement will in- cells. It represents the main cause of vision loss in
crease in the near future, we hope that an improved ap- people between 25 and 74 years old in developed
proach can provide helpful answers to the remaining clin- countries, being diabetic macular edema (DME)
ical and therapeutic questions. the major cause of visual impairment [3, 4]. Oth-
© 2017 S. Karger AG, Basel er causes of visual loss may be related to vitreous
hemorrhage (VH), retinal detachment (RD), or
neovascular glaucoma (GNV). A comprehensive
Introduction diagnostic and therapeutic approach should
match with any of these specific manifestations of
The World Health Organization estimates that DR, in addiction to strict systemic glycemic con-
the number of people with diabetes mellitus (DM) trol.
has risen from 108 million in 1980 to 422 million The recent advances in understanding the
in 2014 and the global prevalence of DM among pathophysiology of DR have led to important im-
adults over 18 years of age has risen from 4.7% in provements in the therapeutic approach, that
1980 to 8.5% in 2014 [1, 2]. Clearly, these trends now include focal/grid laser photocoagulation,
predict an increase in the associated costs for vitreo-retinal surgery, and intraocular injections
health care and in the burden of disability associ- of anti-vascular endothelial growth factor (VEGF)
ated with DM and its complications. and steroids molecules [5–8].
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Classification mary care physicians caring for patients with
DM, an International Clinical Disease Severity
The earliest clinically visible manifestations of DR Scale has been developed for DR and DME
include microaneurysm and intraretinal hemor- (Tables 1, 2).
rhages. However, defects in neurosensory function The Early Treatment Diabetic Retinopathy
have been demonstrated in patients with DM even Study Group (ETDRS) defined clinically signifi-
prior to the onset of the detectable vascular lesions cant diabetic macular edema (CSME) as:
[9, 10]. Non-proliferative retinopathy (NPDR) is 1. Retinal thickening at or within 500 μm or
characterized by retinal capillary nonperfusion, 1/3 disc diameter of the macular center.
cotton wool spots, dot, blot or flame hemorrhages, 2. Hard exudates at or within 500 μm of macu-
venous beading, and intraretinal microvascular ab- lar center with adjacent retinal thickening.
normalities (IRMA). If left untreated, very severe 3. Retinal thickening greater than 1 disc diam-
NPDR may evolve to proliferative retinopathy eter in size within 1 disc diameter from the center
(PDR), characterized by the development of abnor- of the macula.
mal neovascularization (NV) in response to angio- This classification is essentially based on fun-
genic growth factors (VEGF and other molecules) dus stereophotographs, and even though widely
upregulated by non-perfused retina. Proliferation applied for research purposes, is not often em-
of NV occurs on the disc (NVD), retina (NVE), iris, ployed in the common clinical practice [11].
and in the filtration angle, leading to GNV. Therefore, a simplified DME classification has
Endothelial walls of NV are more fragile than been proposed, including 4 main forms [7]:
normal vessel, and can easily break down, causing • Vasogenic DME, characterized by the biomi-
pre-retinal or VH, or subsequent fibrous prolif- croscopic identification of retinal thickening
eration leading to tractional RD. When VH oc- with vascular dilations, often associated with
curs, or when new vessels at the optic disc occupy hard exudate deposition;
greater than or equal to about one-quarter to one- • Non-vasogenic DME, defined by retinal thick-
third disc area, even in the absence of VH, PDR is ening without identifiable vascular dilations;
considered high-risk (HR-PDR). • Tractional DME, due to alteration at the vit-
DME is the result of complex pathogenetical reomacular interface;
alterations involving the blood-retinal barrier • Mixed DME, when tractional DME is associ-
disruption (BRB) and inflammatory process, and ated with vasogenic or non-vasogenic leakage.
it may arise in the setting of both non-prolifera- This classification provides a practical guide
tive and proliferative DR [5]. A variety of bio- for the choice of treatment; patient characteriza-
chemical alterations have been implicated in tion by means of biomicroscopy and multimodal
DME pathogenesis, including expression of in- imaging is mandatory to proper identify the clin-
flammatory mediators (i.e., intercellular adhe- ical category of each patient.
sion molecule-1, tumor necrosis factor-α, inter-
leukin-6 and VEGF), recruitment and adhesion
of leukocytes to vascular endothelium, and loss of Diagnosis and Imaging
endothelial tight junction proteins [8]. Increased
vasopermeability results in retinal thickening Diagnosis and prognosis of DR has been revolu-
(edema) and/or extracellular protein leakage that tionized in the past years with the advent of opti-
lead to hard exudates deposition. cal coherence tomography (OCT), ultra-wide
In an attempt to improve communication field (UWF) imaging and OCT angiography
worldwide between ophthalmologists and pri- (OCT-A).
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60 Battaglia Parodi · Cicinelli · Rabiolo

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Table 1. International clinical disease severity scale
Disease severity level Findings observable upon dilated ophthalmoscopy
No apparent retinopathy No abnormalities

Mild NPDR Microaneurysms only
Moderate NPDR More than just microaneurysms but less than severe NPDR
Severe NPDR (4-2-1 rule)
U.S. Definition Any of the following and no signs of proliferative retinopathy:
– Severe intraretinal hemorrhages and microaneurysms in each of four quadrants
– Definite venous beading in two or more quadrants
– Moderate IRMA in one or more quadrants
International definition Any of the following and no signs of proliferative retinopathy:
– More than 20 intraretinal hemorrhages in each of four quadrants
– Definite venous beading in two or more quadrants
– Prominent IRMA in one or more quadrants
Very severe NPDR Any patient with two or more of the characteristics of severe NPDR
PDR One or both of the following:
– Neovascularization
– Vitreous/preretinal hemorrhage
High-risk PDR One or both of the following:
– Neovascularization at disc greater than or equal to about one-quarter to one-
third disc area
– New vessels elsewhere at least one-half disc area in size
– Vitreous hemorrhage
IRMA, intraretinal microvascular abnormalities; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative dia-
betic retinopathy (adapted from Wilkinson et al. [90]).
Table 2. International clinical disease severity scale
Proposed disease Findings observable upon dilated ophthalmoscopy*

severity level
Mild DME Retinal thickening or hard exudates in posterior pole but distant from the center of the macula
Moderate DME Retinal thickening or hard exudates approaching the center of the macula but not involving the
center
Severe DME Retinal thickening or hard exudates involving the center of the macula
(Adapted from Wilkinson et al. [90]).
Optical Coherence Tomography nal layers) and quantitative (i.e., macular volume,
Since its introduction in 1991, OCT gained a pri- central [CRT] and sectorial retinal thickness)
mary role in DR management by revealing patho- fashion [12–14].
logical changes both in qualitative (i.e., DME pat- Beyond diabetic maculopathy, OCT individu-
tern, presence and aspects of intraretinal cysts, ates several other lesions occurring in the setting
fluid localization, integrity and reflectivity of reti- of either non-proliferative (i.e., hyperreflective
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spots, micropseudocysts, hard exudates, micro- retinal surface [21]. When compared to 7SF,
aneurysm, cotton-wool spots) or proliferative UWF retinography exhibits a substantial agree-
(i.e., NV, vitreoschisis, tractional RD, pre-retinal ment in grading DR severity [22]. UWF retinog-
hemorrhage) retinopathy. OCT provides valu- raphy, however, increases the detection rate of
able information also on vitreo-retinal interface, DR by 10% compared to 7SF, revealing addition-
retinal nerve fiber layers (RNFL), ganglion cell al peripheral diabetic retinal pathology, known as
complex (GCC) and choroid. Recent studies have “predominately or only present outside 7SF le-
demonstrated early neurodegeneration in diabet- sions” (PPLs), which include retinal hemorrhage/
ic patients, expressed as reduction of RNFL and microaneurysms, IRMA and NVE [23, 24]. Pres-
GCC thickness, even before DR onset [15–17]. ence and progression of PPLs conferee higher risk
Choroidal thickness in DR is controversial, but of DR worsening, independently from baseline
probably is not different with respect normal eyes DR severity or HbA1c levels [24]. Since UWF ret-
[18–20]. inography augments the rate of DR detection by
10%, reduces the percentage of ungradable image
UWF Retinography of more than 70%, decreases image assessment
Color fundus photography (CFP) has been the time of 25%, allows to identify more diabetic and
most important test in DR diagnosis, classifica- nondiabetic retinal pathology, its role in telemed-
tion and management for many years. Most of the icine has been advocated [22–25].
concepts applied in the everyday clinical practice
are actually based on high-quality clinical trials UWF Fluorescein Angiography
conducted more than 25 years ago, including the Fluorescein angiography (FA) is a useful test in
ETDRS. In those trials, DR presence and grading DR to assess the status of BRB and the presence of
was assessed using a traditional fundus camera, non-perfused areas, vascular leakage, microvas-
which captures 30° of retinal surface at once, and cular abnormalities and NVs. Widefield and
combining 7 shots in established position (i.e., 4 UWF fluorescein angiography (UWFA) systems
around the optic nerve, 3 across the macula). This have been employed to overcome pitfalls of tradi-
was referred as “ETDRS 7 standard fields (7SF) tional FA and 7SF protocol. UWFA capacity to
protocol” which is still considered the gold stan- image more retinal surface, peripheral non-per-
dard. However, 7SF has several limitations infusion, NV and laser panretinal photocoagulation
cluding need of mydriasis, high skilled operators, (PRP) could help in screening, diagnosis, moni-
patient collaboration, and incapability to image toring, treatment and prognosis of DR [26–28].
the entire retina at the same. In addition, 7SF pro- Novel angiographic entities have been individu-
vides information only on the central posterior ate using UWFA, including peripheral vascular
90°, corresponding to less than 30% of all retinal leakage (PVL) and white dots. PVL has been de-
surface. In order to overcome these pitfalls, wide scribed as late leakage of dye from retinal vessels
field and ultra-widefield technologies have been reflecting impairment of BRB in setting of acute
developed. Optos UWF camera (Optos, PLC, DR and correlates to peripheral ischemia, macu-
Scotland) is a confocal scanning laser ophthalmo- lar leakage and NVs [29]. White dots have been
scope equipped with an ellipsoid mirror with 2 linked to capillary nonperfusion and DR severity
focal points that captures the 82% of retinal sur- [30]. In order to objectively quantify the amount
face (200°) in a single shot with no need of my- of retinal non-perfusion, ischemic index, defined
driasis or contact lens. Photomontage of images as the ratio between nonperfused areas and total
acquired in different steering position can further retinal surface, has been introduced and correlat-
widen the field of view, imaging almost the entire ed to presence and severity of DME [31, 32], DMI
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[33], VH [34], and oxygen saturation of retinal well detected using both OCT-A and FA [42].
arteries [35]. OCT-A is not only able to identify epiretinal NV,
Although UWFA main application relies on but also evaluates their activity. Active NV are
its diagnostic potential, it has also a role in DR characterized by large trunk vessels accompanied
therapy. UWFA-guided targeted laser photoco- by irregular proliferation of fine vessels, called
agulation (TRP) aims to selectively treat ischemic exuberant vascular proliferation (EVP) at OCT-
areas sparing perfused retina. Recent studies sug- A; conversely, inactive NV are defined by fila-
gest that TRP is not inferior to PRP in inducing mentous vessels without EVP [43]. In addition to
NV regression, but has less effect on central mac- diagnostic information, OCT-A has also a prog-
ular thickness (CMT) [36, 37]. nostic value. Both FAZ area and vessel density
have been correlated to visual acuity (VA) [44,
OCT Angiography 45]. Moreover, it has been observed that patients
OCT-A is a novel, dye-less, non-invasive test that with DME and disruption of DCP are less prone
permits the visualization of retinal and choroidal to respond to anti-VEGF than those with pre-
vasculature. Differently from FA, OCT-A is able served deep plexus [46].
to investigate superficial capillary plexus (SCP)
and deep capillary plexus (DCP) in a separate
fashion. Although several algorithms have been Treatment of DR
developed, OCT-A technology relies on the
“decorrelation principle,” which states that in a Laser Photocoagulation
static eye the only structure in motion is the blood Laser photocoagulation has been considered the
flowing inside vessels and contrast is generated by standard of care for both PRD and DME for the
the difference between moving cells in the vascu- past decades [11, 47]. The mechanism of action of
lature and motionless surrounding tissue [38]. laser is mainly based on destruction of retinal
OCT-A reveals several pathological changes cells, leading to improved inner retinal oxygen-
in DR, including enlargement of FAZ area, capil- ation, reduced production of pro-angiogenetic
lary abnormalities and NV. FAZ area is enlarged factors and greater release of NV inhibitors from
and irregular at both SCP and DCP as a conse- retinal pigment epithelium (RPE) cells. Different
quence of micro-infarctions in the surrounding types of laser can be used: Argon green (514 nm)
vascular arcades [39, 40]. Interestingly, enlarge- or dye yellow (577 nm) lasers are the convention-
ment and irregularity of FAZ area can be appre- ally used wavelengths, but krypton red (647 nm)
ciated also in diabetic patients with no DR and, and diode (810 nm) lasers have also been effec-
thus, OCT-A has been advocated as screening tively employed [48, 49].
test to detect early microcirculatory disturbances In 1976, the Diabetic Retinopathy Study set
[41]. By separating SCP from DCP and being free the standards for argon PRP and demonstrated
from leakage phenomena, OCT-A is highly suit- that PRP reduced the risk of severe visual loss
able to inquiry for capillaries abnormalities, as (SVL) in eyes with PDR by 50 percent or more
reduction in vessel density, which is present also during a 5-year period of follow-up compared
in diabetics with no DR and is associated to DR with no treatment [50, 51]. ETDRS demonstrated
grade. OCT-A displays microaneurysms as sac- that early treatment was associated with a smaller
cular outpouchings originating along ectasic incidence of SVL compared to deferred laser
capillaries and permits to define their origin (su- treatment, achieving NV regression in 60% of pa-
perficial or deep), despite being inferior to FA in tients after 3 months [52]. Longer-term reports
their detection [42]. On the contrary, IRMAs are showed that long-lasting effectiveness of PRP
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treatment is dose related, and supplemental ad- cant VA gain in eyes with DME, reduced risk of
ministration is often required following primary progression toward more advanced forms of reti-
treatment in order to achieve complete disease re- nopathy and increased chances of regression of
gression. DR lesions [64–67]. In addition, anti-VEGF ap-
Laser photocoagulation plays a fundamental proach has shown favorable results also in the
role also in the treatment of DME: focal treatment management of proliferative DR, as demonstrat-
is directly addressed to individual leakage points ed by DR Clinical Research Network’s (DRCR.
(microaneurysms, IRMA or short capillary seg- net) in Protocol S [68]. In particular, ranibizumab
ments) especially in vasogenic DME; grid treat- is noninferior to PRP with regard to VA out-
ment, instead, is applied to areas of diffuse thick- comes at 2 years in patients with proliferative DR
ening. The ETDRS reported the standard guide- (+2.8 letters from baseline in the ranibizumab
lines for macular argon photocoagulation, stating group compared with +0.2 letters from baseline
that prompt laser treatment reduced the risk of in the PRP group), peripheral visual field (213 dB
moderate VA loss (loss of >15 letters) at 3 years in the ranibizumab group vs. 531 dB in the PRP
by 50%, compared with deferred treatment [53]. group), and vitrectomies (15% of eyes requiring
Advantages of laser are fewer costs and long- vitrectomy compared with 4% of eyes in the ra-
lasting effects. Complications are progressive re- nibizumab group).
striction of visual field, color vision, night vision, Disadvantages of intravitreal anti-VEGF mol-
and contrast sensitivity impairment, as burn-in- ecules are shorter duration of action compared to
duced scars tend to expand over time [54]. Other laser treatment and higher recurrence rate of the
side effects may include subretinal fibrosis, cho- disease. This leads to more frequent treatment,
roidal NV, VH, DME worsening and epiretinal with consequent increased risk of adverse events
membrane (ERM) formation [55–57]. related to intraocular injections, including endo-
Innovative laser technologies have been pro- phthalmitis, retinal tears and holes, and VH.
posed, differing in pulse power, time of exposure, Moreover, anti-VEGF should be avoided in pa-
spot size, or pattern distribution from conven- tients with cardiovascular disease, for increased
tional treatment, in order to selectively target RPE risk of cerebral accidents.
and spare surrounding tissue [58]. For example, Overall, anti-VEGF therapy shows a favorable
micropulse diode laser technique, using a train of tolerability profile in diabetic patients, even
repetitive short laser pulses, has been shown to be though patients with DME and co-existing prolif-
as effective as conventional argon laser, without erative DR may have an increased risk of traction-
scar development [59, 60]. Nowadays, common al RD secondary to fibrosis. VEGF-inhibitors that
clinical practice relies on the pattern Scan Laser have been studied for DR are pegaptanib, ranibi-
(PASCAL) system, especially if guided by UWF zumab, bevacizumab, and aflibercept [68].
imaging [36, 37, 61, 62].
Corticosteroids
VEGF Inhibitors Due to anti-VEGF limitations, corticosteroids
On the basis of the evidence that laser alone im- have been gaining great interest in DME manage-
proves vision only in a small group of eyes and ment [69, 70]. These molecules have shown ca-
many patients report visual loss despite treat- pacity to inhibit leukostasis, adhesion, and trans-
ment, the first line treatment for DME has been migration of leukocytes and to downregulate ex-
shifted to anti-VEGF injections [63]. Several ran- pression of prostaglandins, cytokines, and growth
domized, multicenter clinical studies demon- factors, especially VEGF in both in vitro and in
strated that VEGF inhibitors result in a signifi- vivo settings [71]. In addition to their anti-in-
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flammatory function, corticosteroids may have a 70% of patients achieving ≥10-letter improve-
neuroprotective effect on the retina [72]. ment and 10–40% of patients achieving ≥15-let-
Three fluorinated synthetic corticosteroids terimprovement in best-corrected VA (BCVA)
lacking mineralocorticoid activity – triamcino- after 1 year of treatment [64–67].
lone acetonide, dexamethasone phosphate, and Nevertheless, an appreciable proportion of pa-
fluocinolone acetonide – have been used for the tients with DME respond suboptimally to medi-
treatment of DME. They differ according to their cal therapy: it has been estimated that 35% of pa-
glucocorticoid-receptor binding affinities (dexa- tients with DME fail to achieve ≥10-letter im-
methasone > triamcinolone > fluocinolone), du- provement in BCVA and more than 55% fail to
ration of action (from nearly a month to 3 years), achieve ≥15-letter improvement after 2 years of
and their lipophilicity (triamcinolone > fluocino- first-line anti-VEGF therapy.
lone > dexamethasone), characteristics that may This heterogeneity of response is expressed in
partially explain their relative potencies (triam- terms of visual gain, number of injection or effect
cinolone = 5, dexamethasone = 25, fluocinolone = of different molecules. Identification of clinical
25, compared to cortisol = 1) [73]. Relevant side and anatomical predictors for better visual gain
effects of steroids are related to increase of intra- has been attempted by several studies: high base-
ocular pressure (IOP) and progression of cataract. line VA, absence of cardiovascular disease, no
Absolute contraindications for the insertion of history of PRP, and male gender have been asso-
dexamethasone implants include advanced or un- ciated with better outcome after treatment [74,
controlled glaucoma, local infection or communi- 75]. OCT biomarkers (as CMT, disorganization
cation with the anterior chamber. Patients con- of the retinal inner layers [14, 76], integrity of the
sidered at risk for potentially infective chorioreti- ellipsoid zone and of the cone outer segment tips,
nopathies should have these conditions excluded and presence of taut internal limiting membrane
prior to considering intravitreal steroid therapy. [ILM], ERM, and vitreomacular traction) and
novel OCT-A features (as DMI, enlarged FAZ
Pars Plana Vitrectomy [40, 45]) have also been analyzed by different
Surgical approach, including pars plana vitrecto- studies [77, 78]. Among these elements, CMT ap-
my (PPV), is generally used to manage tractional pears to be the least important, as persistent mac-
DME and severe complications of DR such as ular edema (defined as failure to achieve a central
non-clearing VH, severe fibrovascular prolifera- subfield thickness <250 μm and at least a 10% re-
tion, and RD. It is considered an option also for duction from the 24-week visit on at least 2 con-
patients with refractory DME or PDR not re- secutive study visits) is associated with similar
sponding to laser photocoagulation. Cataract, ret- long-term improvement in VA showed by pa-
inal or choroidal detachment, VH, endophthalmi- tients in which DME does not persist [79].
tis, increased IOP, rubeosis iridis, and GNV are the The EARLY (Early Anti-VEGF Response and
most common postoperative complications. Long-term efficacY) program, a series of post hoc
analyses of data from the DRCR.net Protocol I,
found significant correlation between early
Prognosis BCVA gain and long-term visual prognosis in the
majority of patients [80, 81]. However, approxi-
Intravitreal anti-VEGF agents and corticoste- mately one-third of the patients with poor func-
roids, as monotherapy or in association with laser tional recovery after ranibizumab loading phase
photocoagulation, currently constitute first-line (i.e., <5-letter improvement in BCVA at 12 week)
therapy for most patients with DME, with 30– subsequently achieved a BCVA gain of ≥10 letters
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after 3 years of treatment. The reason for this de- with severe NPDR develop PDR within 1 year,
layed improvement is still unclear. On the con- and 15% will have high-risk PDR (Table 3). The
trary, OCT-defined anatomic response (≥20% ETDRS suggested that PRP should not be recom-
CRT reduction) at 12 weeks showed an inconsis- mended for eyes with mild or moderate NPDR,
tent and weak association with long-term VA provided that follow-up could be maintained
outcome, as reported before [74, 81]. [47]. If the patient cannot be followed closely or if
In essence, the precise classification of DME is there are associated medical conditions such as
critical in clinical decision-making and requires a impending cataract surgery or pregnancy, early
combination of biomicroscopic, OCT and func- treatment may be warranted. On the contrary, la-
tional data. Moreover, individualized treatment ser photocoagulation represents the treatment of
strategy on the basis of specific patient’s DME choice for more severe stages of DR.
characteristics and early identification of subopti- Anti-VEGF therapy and PRP may also be ad-
mal responders to anti-VEGF facilitates timely ministered concomitantly. If anti-VEGF therapy
consideration of additional/alternative treatments. can completely replace laser treatment in the
management of PDR is still matter of scientific
debate. Very recently, the DRCR.net study proto-
Choice of Treatment col S has demonstrated the non-inferiority at 2
years follow up of intravitreal ranibizumab com-
Latest evidences in the diagnosis and in manage- pared with PRP for VA outcomes in patients with
ment of DR support the application of a personal- PDR. In addition, superior vision over the course
ized patient-based approach rather than a stan- of 2 years (area under the curve) was achieved in
dard fixed protocol. An assessment of patients’ the ranibizumab group, with reduces incidence of
systemic risk factors before treatment adminis- DME at 2 years, less peripheral visual field loss,
tration, including baseline blood pressure, lipid and fewer need of vitrectomy. Intravitreal ranibi-
panel, and glycated hemoglobin levels, usually zumab may be preferred as the initial treatment
through correspondence with the primary care approach for patients who have both PDR and
physician, has a primary role, since maintaining DME; however, further studies are required to
near-normal glucose levels and near-normal determine the long-term implications of using
blood pressure lowers the risk of retinopathy de- anti-VEGF monotherapy [68–88].
velopment and/or progression [83]. Management In patients presenting with CSME, initial laser
recommendations for patients with DR vary ac- photocoagulation is recommended in eyes with
cording to severity of the retinopathy and the circumscribed, non center-involving edema with-
presence and the location of DME [87]: out any sign of ERM. Treatment should be direct-
Patients with no or minimal NPDR should be ed to microaneurysms and other treatable lesions
followed annually, as 5–10% of them will develop within the area of edema and the burn intensity
DR within 1 year. Existing retinopathy will wors- titrated to achieve mild blanching, as per the
en by a similar percentage [84]. modified ETDRS guidelines. Alternatively, sub-
Patients with mild to moderate NPDR should threshold laser can be performed, covering the
be re-examined within 6–12 months. The natural DME area with confluent spots. On the other
history of type 1 diabetic patients suggests that hand, center-involving DME and center-threat-
approximately 16% of patients with mild NPDR ening edema should be managed with intravitreal
progress to proliferative stages within 4 years. anti-VEGF (Fig. 1). Treatment regimen with anti-
Patients with severe NPDR should be re-ex- VEGF therapy should be guided by patient’s clin-
amined within 2–4 months, as half of patients ical response, with possible additional focal laser
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Table 3. Management recommendations for patients with diabetes
Severity of retinopathy Presenceof Follow-up, Panretinal Focal and/or Intravitreal

macular edema months photocoagulation grid laser anti-VEGF therapy
(Scatter) laser
Normal or minimal NPDR No 12 No No No

Mild NPDR No 12 No No No
ME 4–6 No No No
CSME 1 No Sometimes Sometimes
Moderate NPDR No 12‡ No No No
ME 3–6 No No No
CSME 1 No Sometimes Sometimes
Severe NPDR No 4 Sometimes No No
ME 2–4 Sometimes No No
CSME 1 Sometimes Sometimes Sometimes
Non-high-risk PDR No 4 Sometimes No No
ME 2–4 Sometimes No No
CSME 1 Sometimes Sometimes Sometimes
High-risk PDR No 4 Recommended No Alternative
ME 4 Recommended Sometimes Usually
CSME 1* Recommended Sometimes Usually
Anti-VEGF, anti-vascular endothelial growth factor; CSME, clinically significant macular edema; ME, non-clinically significant
macular edema; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy (Adapted from [87]).
DME
No centre Centre
involvement involvement
Treat according to Vision loss due

No vision loss
ETDRS guidelines to DME
Observe and treat

Ranibizumab
according to
monotherapy*
ETDRS guidelines
Fig. 1. Practical management od diabetic macular edema. DME, diabetic macular edema; Anti-VEGF, anti-vascular
endothelial growth factor (modified from Bandello et al. [7]).
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to decrease the need for repeated injections. Fi- Conclusions
nally, the choice of the anti-VEGF molecule
should be driven by the initial VA: as demonstrat- Over the past decade, great strides have been
ed by the DRCR.net protocol T, aflibercept is pre- made in the management of DR. It is also clear
ferred at worse levels of initial VA (20/50 or that DR is a chronic disease with variable clinical
worse) over the other anti-VEGF agents [88]. manifestations, and therefore, a single treatment
In patients who remain unresponsive to anti- cannot be enough for the entire course of the dis-
VEGF and are pseudophakic and at low risk for ease. Metabolic control is the first way to prevent
glaucoma or who have significative cardiovascu- the incidence and to slow-down progression of
lar risk profile, treatment with intraocular steroids RD. Specific treatment should combine different
is suggested, especially to achieve an initial treat- approaches, such as laser, surgery, and medical
ment associated with fewer intravitreal injections. therapy, in order to act on all the different patho-
In those cases refractory to medical treatment, genetic mechanisms. New drugs are under inves-
the next step in the therapeutic algorithm is PPV tigations and further results are expected from
with ILM removal, especially in eyes with vitreo- the future trials, trying to give an answer to the
macular pathology. Postoperatively, vitrecto- clinical open questions, regarding the doses, the
mized eyes with persistent edema can be man- frequency, and the correct regimen of each treat-
aged with laser or intraocular corticosteroid, ment.
based on the guidelines discussed previously.
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Maurizio Battaglia Parodi

Department of Ophthalmology, Ospedale Ospedale San Raffaele, University Vita-Salute San Raffaele
Via Olgettina 60
E-Mail battagliaparodi.maurizio@hsr.it
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Pediatric Vascular Retinopathies

Georges Caputo
Fondation Ophtalmologique A. de Rothschild, Paris, France
Abstract Acquired Vascular Retinopathies:

Pediatric vascular retinopathies involve children from Retinopathy of Prematurity
their birth through their whole lifespan. They include ac-
quired retinopathies like retinopathy of prematurity Introduction
(ROP), congenital lesions like Coats disease, and genetic Retinopathy of prematurity (ROP) was first de-
vasculopathies as in familial exudative vitreoretinopathy, scribed in 1942 by Terry, with the survival of pre-
incontinentia pigmenti, or Norrie’s disease. The latter all mature babies. It was only in the 1950s that the
share a common pathophysiological mechanism impli- role of oxygen was identified, leading to the mon-
cating the WNT signaling pathway. They are dominated itoring of oxygen therapy in premature infants.
by ROP and its devastating consequences if not properly After a phase of increased mortality due to oxy-
addressed. Differential diagnosis can be challenging: gen restriction in the 1960s, a careful monitoring
medical history, family history are fundamental elements, of oxygen administration resulted in reduced
and clinical characteristics need to be detailed with wide mortality in the eighties, but persistent ROP; the
field angiography. The most effective treatment is laser use of artificial surfactant and maternal steroids
ablative therapy of the ischemic retina or vascular anom- have significantly diminished the rate of severe
alies in early stages of these diseases, vitrectomy surgery retinopathies. This trend is counter balanced by
addressing the most severe ones with a poorer anatomi- the survival of extremely premature infants and
cal and functional prognosis. Anti-vascular endothelial always lower birth weights.
growth factor is a helpful tool in these conditions, but It is responsible for over 50,000 cases of blind-
should be used with caution in developing children. ness worldwide and is the leading cause of treat-
© 2017 S. Karger AG, Basel able blindness in developed countries [1]. With
increased survival of premature infants in devel-
oping countries, a new epidemic is taking place in
In this article, we will focus on pediatric vascular these regions.
retinopathies that can benefit from an effective
treatment allowing resolution and conservation Pathophysiology
of the visual function. The classification of reti- The normal development of retinal vessels is cen-
nopathies is presented in Table 1. trifugal and takes place from 16 weeks gestation
up to the term. In premature infants, the vessel
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Table 1. Vascular pediatric retinopathies Zone 2: circled zone centered by the disk up to
the nasal ora serrata
Acquired retinopathies
Retinopathy of prematurity
Zone 3: up to the temporal ora serrata.
Congenital retinopathies
Coat’s disease Evolutivity
Inherited retinopathies It is defined as “plus” disease. This term charac-
Familial exudative vitreoretinopathy (FEVR)
terizes dilation of retinal veins and arterial tortu-
Incontinentia pigmenti
Norrie disease osity as the disk margin in 2 quadrants or more:
these clinical features are evaluated in compari-
son to a picture of the CRYO-ROP study defining
plus disease [4].
development is not finished and immature sub- A particular form of severe retinopathy has
ject to the influence of general and local factors been defined as “aggressive posterior retinopa-
[2]; it goes through 3 phases after birth: thy” (APROP; Fig. 6): it develops in zone 1 with
1. Interruption of vascular development due to no thick ridge but a wide anastomotic neovascu-
oxygen administration lar meshwork, which is sometimes difficult to
2. Relative hypoxia due to metabolic demand identify when optical media are not clear.
(infection, general status)
3. Abnormal and abundant vascular development Treatment
due to high levels of induced angiogenesis factors The large CRYO-ROP randomized studies con-
(IGF1, vascular endothelial growth factor, VEGF) ducted in the 1980’s have shown the benefit of
ablating the peripheral non vascularized retinal
Classification zones [4]. The “threshold” stage was defined as
The classification of ROP has been revised in 2005 having a 50% risk of retinal detachment, and cor-
by the international committee for ROP and takes responds to stage 3 retinopathy with plus disease
in account the vascular status, the geographical in 5 contiguous meridians (Table 2). Laser thera-
extent, and the evolutivity of the retinopathy [3]. py has replaced cryo therapy and holds less side
effects leading to earlier treatment of patients [5].
Vascular Status The “early treatment ROP” study published in
Stage 1: demarcation line 2003 [6] is now the reference for indication of la-
Stage 2: ridge (intraretinal neovascularization; ser treatment in ROP. It defined 2 types of ROP
Fig. 1) outlining the evolutivity of the retinopathy: type 1
Stage 3: thickened ridge and extraretinal neo- had a 15% risk or higher of unfavorable outcome
vascularization (Fig. 2) as opposed to type 2, having a lower than 15% risk
Stage 4: partial retinal detachment (Table 3).
Stage 4A: macula preserved ETROP type 1: zone 1, any plus disease or
Stage 4B: macula involved (Fig. 3) stage 3; and zone 2, stage 2 or 3, with plus disease.
Stage 5: total retinal detachment (open funnel ETROP type 2: zone 1, any stage without plus
or closed funnel; Fig. 4) disease; and zone 2, stage 2 or 3 without plus disease.
Geographical Extent Laser Treatment

Zone 1: posterior retina, zone seen with a 28 or Laser ablation of the non vascularized peripheral
30D lens centered on the disc (2 disc to fovea retina is performed in type 1 ETROP eyes. Under
radius; Fig. 5). general anesthesia, laser is applied nearly conflu-
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Pediatric Vascular Retinopathies 73

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Fig. 1. Stage 2 ROP zone 2. Fig. 2. Stage 3 ROP, zone 1.
Fig. 3. Dry retinal fold, stage 4B ROP. Fig. 4. Stage 5 ROP.
12 h
Field of a 28D lens
Ora Ora
serrata III II I serrata
temporal nasal
Fig. 5. 3 zones defining the extent 6h

of ROP.
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74 Caputo
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Table 2. Results of the CRYO-ROP study
Anatomical failure, % VA <20/200, %

3 months 1 year 5 years 10 years 5 years 10 years
Control 51.4 47.4 45.4 47.9 45.4 62.1

Treated 31.1 25.7 26.9 27.2 26.9 44.4
Table 3. Results of the ETROP study
Anatomical failure, Functional failure at 6 years

at 6 years (type 1), % (<1.85 c/day) (type 1), %
Threshold treated 15.2 32.8

Number 303 204
ETROP 8.9 (p < 0.001) 25.1 (p < 0.001)
Number 305 203
Other complications of the treatment include

induced Myopia (15% compared to 50% in the
CRYO-ROP study), cataracts (0.5%) [5].
Anti-Vascular Endothelial Growth Factor

VEGF is a major factor involved in retinal angio-
genesis and high concentrations have been iden-
tified in severe retinopathy cases.
Mercado first used Anti-VEGF for the
treatment of severe ROP without any adverse
effects.
A randomized control study in 2011, showed
the superiority of half adult dose of Bevacizumab
Fig. 6. APROP.
in APROP and posterior severe retinopathy over
conventional laser treatment, allowing regres-
sion of the ridge and almost normal peripheral
ent by indirect ophthalmoscope or threw microvascular growth compared to the large scarring
scope laser adapter and wide angle contact lens of the posterior retina after laser ablation [7].
(pediatric quadraspheric lens). Although no adverse report has been presented
Regression of the retinopathy takes place in with the use of Anti-VEGF, the latter has to be
the following days in 90% of the cases, allowing used with caution in infants, because of the role of
preservation of the posterior pole. VEGF in normal central nervous system and lung
Failure of the treatment is due to untreated development and maturation. Sato has shown that
ischemic retinal areas, or mostly to APROP intravitreal injection of half-dose of bevacizumab
cases. leads to systemic drop in VEGF concentration for
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Table 4. ROP incidence
Author Year Country Period GA, weeks Weight, g ROP, % ROP >3, %
Chiang 2004 USA 1996–2000 <1,200 27.30 9.50

Teed 2009 USA 2003–2007 <25 87 23
25–27 62 9
Hoogewerf 2010 Holland 1991–1995 <1,500 40.90 3.30
2001–2005 <1,500 23.30 1.20
1991–1995 <1,000 67 8.10
2001–2005 <1,000 41.80 3
Austeng 2009 Sweden 2004–2007 <27 35 19.60
Beby 2004 France <32 <1,500 22.30 1
Slidsborg 2008 Denmark 1996–2000 <32 1.30
2001–2005 <32 3.50
Vatavu 2010 Rumania 2002–2007 <34 <2,000 55 15.20
Fortes 2009 Brazil 2002–2006 1,000–1,500 18.20 2.30
<1,000 48.90 17
Wani 2010 India 2001–2003 <34 <1,500 38.90 7.80
Shreshta 2010 Nepal 12 months <36 <2,000 29.50 3.80
over 2 weeks and simultaneous raise in Anti- and allows around 60% success rate with poste-
VEGF serum level for the same period of time [8]. rior pole flattening. Functional results are far less
Anti-VEGF allows quick neovessel regression, encouraging, partially due to central nervous im-
permitting earlier surgery for active stage 4 and 5 pairment present in 50% of these patients [12].
retinopathies avoiding, secondary bleeding.
Schapiro et al. reported the need for prolonged Late Complications
surveillance of patients treated with Anti VEGF, Myopia is less common in laser treated compared
because of the risk of late recurrence of stage 3 to cryo-treated eyes. Macular ectopia and dry ret-
retinopathy; the median recurrence delay was 50 inal folds can be observed secondary to the tem-
weeks, up to 70 weeks after birth [9]. poral extraretinal proliferation. The peripheral
retrocrystalline fibrous tissue can lead to second-
Surgery: Vitrectomy ary closed angle glaucoma a few years later and
In case of stage 4 or 5, with retinal detachment, careful and prolonged follow-up is necessary.
surgery is the only alternative.
Although buckling has given some positive Screening Recommendations
results in advanced cases, vitrectomy has shown Screening is the milestone to preventing blind-
far less adverse effects. Lens sparing vitrectomy ness due to ROP.
in stage 4 has a high success rate and better func- Recommendations have to be adapted to the
tional outcome [10, 11]. In case of stage 5, lens standards of the neonatal care in the selected
ablation through a limbal approach is necessary country, as shown in Table 4.
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76 Caputo
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Table 5. Screening schedule Conclusion
ROP represents the main cause of treatable blind-
AG, weeks First fundus ex
ness in developed countries; the raising survival
<28 31 of premature babies induces a new epidemic
28 32 worldwide in smaller babies in high income coun-
29 33 tries and in older babies in emerging countries. A
30 34
well organized screening is the key to prevent
31 35
blindness due to ROP; surgery of advanced cases
is palliative although results have been improving
with small gauge and lens sparing vitrectomy.
The American society of Ophthalmology rec- Anti-VEGF treatment is an answer to the most
ommends ROP screening in children under vascular active and posterior forms of ROP, al-
1,500 g birth weight and 31 weeks gestation. In lowing neovessels regression and earlier interven-
England and recently in France, the threshold of tion, but insufficient safety data are available to
the birth weight for screening was lowered to generalize this approach.
1,250 g unless unfavorable general clinical out-
come; the first fundus examination is to be per-
formed between 4 and 6 weeks post birth accord- Congenital Retinopathies: Coats Disease
ing to the term.
Winrop algorithm uses the weight gain during History and Introduction
the first weeks of life to identify high risk children In 1908, Coats described for the first time this dis-
for developing severe ROP. Weight gain has been ease which clinical features include retinal exuda-
correlated to serum levels of IGF1. This algorithm tion and aneurysmal vascular dilations. He de-
available on line has been validated in popula- scribed the severe form of retinal detachment of-
tions of neonates in developed countries but does ten seen in children. Coats disease is characterized
not apply reliably in developing countries. The by the presence of subretinal exudation, periph-
use of this tool enables to diminish the number of eral aneurysmal vascular dilation and rarefaction
necessary fundus examinations. of the capillary meshwork which is often too well
The standard screening procedure uses indi- seen in angiography.
rect ophthalmoscopy with a 28 to 30 D lens ac-
cording to the schedule presented in Table 5. Diagnosis and Epidemiology
Dilation is obtained by tropicamide repeated Boys are affected in 80% of the cases, and pre-
instillation and one epinephrine 2.5% instillation. sentation is unilateral although, some mild vas-
A lid speculum is recommended, topical anesthe- cular anomalies can be seen in 20% of the fellow
sia and glucose sucking prior to examination. eyes.
The use of a wide field retinal camera is be- It is non genetic, but can be associated with
coming the standard procedure, allowing docu- some general involvement and coats like lesions
mentation, collective picture analysis and treat- have been reported in scapulohumeral dystro-
ment decision making; fundus pictures can be phy, leukoencephalopathy with dilation and
taken by a trained technician or nurse and sent cysts [14], Senior–Loken and Cornelia Delange
through a network allowing in an anyway, any- syndromes.
where, anytime an expert assessment. It has prov- Patients present with leukocoria, strabismus
en to be as effective as indirect ophthalmoscopy or loss of vision due to macular involvement. An-
to detect stage 2 and above ROP [13]. terior segment is unremarkable, and fundus ex-
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amination finds retinal exudates, peripheral ves-
sel aneurysmal dilations, and exudative retinal
detachment in evolved cases (Fig. 7). Retinal wide
field angiography localizes vascular anomalies
and distended capillary meshwork.
The earlier the age at presentation, the more
severe is the anatomical and functional prognosis
[15].
Classification
Shields presented a classification in 2001:
Stage 1: vascular dilations.
Stage 2: vascular anomalies and exudation.
Fig. 7. Total retinal detachment due to Coats disease:
Stage 3: exudative retinal detachment. vessel dilations are clearly visible.
Stage 4: neovascular glaucoma.
Stage 5: phthisis bulbi.
Differential Diagnosis Anti-VEGF have been proposed as adjunctive

Differential diagnosis is essentially retinoblasto- treatment of Coats disease; VEGF was found in
ma in young children presenting advanced stages aqueous humor and subretinal fluid [16], but no
of the disease. Ultrasound examination rules out controlled randomized study has shown any ben-
a tumor and associated microcalcifications. Vas- efit of this treatment. In case of ischemia and sec-
cular anomalies are well identified by the angiog- ondary neovascularization, it can be suggested
raphy. [17].
can be suggested when vitreous involvement and Conclusion
preretinal neovascularization is present at initial Coats disease is an exudative disease limited to
presentation in untreated eyes. the eye, unilateral in 80% of the case and affects
essentially boys. The treatment is challenging in
Treatment young patients with severe forms of the disease
The standard treatment is photocoagulation of that have poor functional results because of mac-
the vascular anomalies by transpupillary argon ular involvement. Laser is the standard treatment.
laser using long delivery and non explosive spots. Anti-VEGF can be an adjunct in case of ischemia.
Sessions need to be repeated and will be per-
formed under general anesthesia in children. In
case of extensive retinal detachment and non vis- Inherited Vascular Retinopathies
ible dilations, external drainage followed by
cryotherapy can be applied. Once retina is reat- Familial Exudative Vitreoretinopathy
tached, photocoagulation is extended in the non
perfused areas induced by initial vascular occlu- Introduction and Genetics
sion treatment (Fig. 8). In case of treatment fail- FEVR is a vascular proliferative genetic retinal
ure, vitrectomy, external drainage and tampon- disorder. The transmission is mostly dominant,
ade silicone can allow to preserve the eye ana- but can be X-linked or autosomal recessive. FZD4,
tomically. LRP5, TSPAN 12, NDP, ZNF408 genes have been
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78 Caputo
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a b
c d
Fig. 8. Stage 2 coats disease: fundus photograph (a), retinal angiography (b), just after laser ablation (c), laser scarring
and partial exudate resorption 4 months later (d).
implicated in this disorder that has an incidence with no history of prematurity and a longer time
of 1 per 5,000 births; all of these gene products are span of evolution. Strong stage asymmetry be-
involved in the WNT signaling pathway implicat- tween both eyes is another common feature of the
ed in angiogenesis [18]. disease (Fig. 9) [19].
Diagnosis Classification
In the most advanced stages, patients present Trese’s classification was published in 1998 [20]:
with both exudative and tractional retinal detach- Stage 1: avascular retina
ment due to preretinal neovascular proliferation Stage 2: avascular retina and extraretinal ves-
often developed in the peripheral temporal retina. sels
Early stages show zone 3 peripheral avascular ret- Stage 3: retinal detachment sparing the macula
ina, only visible in wide-field angiography. Age of (Fig. 10)
onset can be from birth to adulthood [19]. The A: non exudative
clinical presentation is similar to retinopathy B: exudative
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Fig. 9. FEVR patient with stage 5B in right eye and 1 in left eye (wide field angiography).
Stage 4: retinal detachment involving the mac-

ula
A: non exudative
B: exudative
Stage 5: total retinal detachment
A: non exudative
B: exudative
Differential Diagnosis
Differential diagnosis of FEVR is all retinopathies
presenting with the following features separately
or all together: retinal ischemia (ROP), retinal ex-
udation (Coats), retinal fold and retinal detach-
Fig. 10. FEVR patient with stage 3AB already partially
ment (Norrie’s disease and persistent fetal vascu- treated by laser ablation.
larization) [21]. Despite the clinical elements, age,
medical and familial histories play a key role in
guiding the diagnosis. angiography along the years is recommended
to identify new retinal zones that need to be
Treatment treated.
Laser ablation of the avascular retinal areas is
the treatment FEVR in stage 2 disease. Vitrec-
tomy is indicated in case of retinal detach- Incontinentia Pigmenti
ment, and anti-VEGF can be an adjunctive
agent when rubeosis is present [22]. In case of Genetics and Presentation
severe thickening of the neovascular peripher- Incontinentia pigmenti is a dominant genetic dis-
al fibrosis, careful cryotherapy can allow treat- ease linked to chromosome X, lethal for boys. Ret-
ment of the anterior retina. Repeated wide field inal ischemia develops during the first year of life,
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80 Caputo
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Fig. 11. Tractional retinal detachment due in an eye
with incontinentia pigmenti.
a b
Fig. 12. A 2-year-old boy with Norrie disease: preoperative fundus examination (a), postoperative (b).
and usually affects only one eye due to lionization Norrie Disease
of chromosome X. Advanced disease will lead to
tractional retinal detachment (Fig. 11). Other spe- Genetics and Presentation
cific features of this disease are the dermatological Norrie disease is an X-linked disease affecting
lesions in pigmented skin lesions on the legs that boys; the gene involved is NDP coding for Nor-
are visible during the first months of life [23]. rin implicated in the WNT signaling pathway
[24].
Treatment Hearing impairment and autistic disorder can
Laser ablation of the non perfused retinal zones is be associated in 20% of the cases.
the treatment of early stages of the disease; it is Clinical presentation can range from a dry
guided by wide field angiography. In case of reti- retinal fold to a total retinal detachment with se-
nal detachment, vitrectomy is performed with vere retinal dysplasia and vascular immaturity
poorer results in the involved eyes. [25].
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Treatment rior vitrectomy to release fibrous traction can be
Treatment is surgical, and consists of removing performed in more localized presentations with a
the lens to avoid corneal apposition and second- retinal fold (Fig. 12) [26].
ary opacification in the most severe cases; poste-
References
1 Blencowe H, Moxon S, Gilbert C: Update 8 Sato T, et al: Serum concentrations of 16 Zhao Q, et al: Vascular endothelial
on blindness due to retinopathy of pre- bevacizumab (avastin) and vascular en- growth factor in Coats’ disease. Acta
maturity globally and in India. Indian dothelial growth factor in infants with Ophthalmol 2014;92:e225–e228.
Pediatr 2016;53(suppl 2):S89–S92. retinopathy of prematurity. Am J Oph- 17 Grosso A, et al: Pearls and pitfalls in
2 Hartnett ME, Penn JS: Mechanisms and thalmol 2012;153:327–333.e1. diagnosis and management of coats dis-
management of retinopathy of prematu- 9 Hu J, et al: Reactivation of retinopathy ease. Retina 2015;35:614–623.
rity. N Engl J Med 2013;368:1162–1163. of prematurity after bevacizumab injec- 18 Gilmour DF: Familial exudative vitreo-
3 International Committee for the Classi- tion. Arch Ophthalmol 2012;130:1000– retinopathy and related retinopathies.
fication of Retinopathy of Prematurity: 1006. Eye (Lond) 2015;29:1–14.
The International Classification of Reti- 10 Hartnett ME, et al: Comparison of reti- 19 Ranchod TM, et al: Clinical presentation
nopathy of Prematurity revisited. Arch nal outcomes after scleral buckle or of familial exudative vitreoretinopathy.
Ophthalmol 2005;123:991–999. lens-sparing vitrectomy for stage 4 reti- Ophthalmology 2011;118:2070–2075.
4 Cryotherapy for Retinopathy of Prema- nopathy of prematurity. Retina 2004;24: 20 Pendergast SD, Trese MT: Familial exu-
turity Cooperative Group: Multicenter 753–757. dative vitreoretinopathy. Results of sur-
Trial of Cryotherapy for Retinopathy of 11 Prenner JL, Capone A Jr, Trese MT: Vi- gical management. Ophthalmology
Prematurity: ophthalmological out- sual outcomes after lens-sparing vitrec- 1998;105:1015–1023.
comes at 10 years. Arch Ophthalmol tomy for stage 4A retinopathy of prema- 21 Nishina S, et al: Clinical features of con-
2001;119:1110–1118. turity. Ophthalmology 2004;111: genital retinal folds. Am J Ophthalmol
5 Shalev B, Farr AK, Repka MX: Random- 2271–2273. 2012;153:81–87.e1.
ized comparison of diode laser photoco- 12 Seaber JH, et al: Long-term visual results 22 Fei P, et al: Surgical Management of Ad-
agulation versus cryotherapy for thresh- of children after initially successful vit- vanced Familial Exudative Vitreoreti-
old retinopathy of prematurity: rectomy for stage V retinopathy of pre- nopathy with Complications. Retina
seven-year outcome. Am J Ophthalmol maturity. Ophthalmology 1995;102: 2016;36:1480–1485.
2001;132:76–80. 199–204. 23 Holmstrom G, Thoren K: Ocular mani-
6 Early Treatment for Retinopathy of Pre- 13 Wang SK, et al: SUNDROP: six years of festations of incontinentia pigmenti.
maturity Cooperative Group: Revised screening for retinopathy of prematurity Acta Ophthalmol Scand 2000;78:348–
indications for the treatment of retinop- with telemedicine. Can J Ophthalmol 353.
athy of prematurity: results of the early 2015;50:101–106. 24 Wu WC, et al: Retinal phenotype-geno-
treatment for retinopathy of prematu- 14 Romaniello R, et al: Cerebroretinal mi- type correlation of pediatric patients
rity randomized trial. Arch Ophthalmol croangiopathy with calcifications and expressing mutations in the Norrie dis-
2003;121:1684–1694. cysts associated with CTC1 and NDP ease gene. Arch Ophthalmol 2007;125:
7 Mintz-Hittner HA, et al: Efficacy of in- mutations. J Child Neurol 2013;28: 225–230.
travitreal bevacizumab for stage 3+ reti- 1702–1708. 25 Goldberg MF, Custis PH: Retinal and
nopathy of prematurity. N Engl J Med 15 Sigler EJ, et al: Current management of other manifestations of incontinentia
2011;364:603–615. Coats disease. Surv Ophthalmol 2014; pigmenti (Bloch-Sulzberger syndrome).
59:30–46. Ophthalmology 1993;100:1645–1654.
26 Walsh MK, et al: Early vitrectomy effec-
tive for Norrie disease. Arch Ophthal-
mol 2010;128:456–460.
Dr. Georges Caputo

Fondation Ophtalmologique A. de Rothschild
25 rue Manin
FR–75019 Paris (France)
E-Mail gcaputo@for.paris
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Subject Index
Age-related macular degeneration (AMD) AMD, see Age-related macular degeneration

classification 52 ARC1905, dry age-related macular degeneration
dry form management 56
diagnosis 52–54
prognosis 54 Branch retinal vein occlusion, see Retinal vein
prospects for study 67 occlusion
treatment Bruch’s membrane, disruption in age-related macular
anti-inflammatory agents 55, 56 degeneration 2
choroidal blood flow restoration agents
56 β-Carotene, dry age-related macular degeneration
neuroprotection 55 management 54, 55
nutrition 54, 55 Central retinal vein occlusion, see Retinal vein
stem cell therapy 57 occlusion
visual cycle inhibitors 56 Choroidal neovascularization (CNV), age-related
epidemiology 1, 2 macular degeneration 2, 3, 14–19
risk factors 51 Ciliary neurotrophic factor (CNFT), dry age-related
vitreomacular interface 48 macular degeneration management 55
wet form CNFT, see Ciliary neurotrophic factor
anatomic classification of neovascularization CNV, see Choroidal neovascularization
mixed lesions 19 Coats disease
overview 15, 16 classification 78, 79
type 1 16–18 diagnosis 77, 78
type 2 18 differential diagnosis 78
type 3 18, 19 epidemiology 77
choroidal neovascularization classification 2, 3, historical perspective 77
14–19 treatment 78
diagnosis and follow-up 3–7 Corticosteroids
differential diagnosis 7, 8, 21, 22 diabetic retinopathy management 64, 65
imaging dry age-related macular degeneration
biomarkers 25–27 management 55
prospects 25 retinal vein occlusion management 39, 40
natural history 2, 19, 21
pathophysiology 2 Diabetes, retinal vein occlusion risks 34
treatment 8–10, 22–25 Diabetic macular edema (DME)
Alprostadil, dry age-related macular degeneration pathophysiology 60
management 56 vitreomacular interface 47, 48
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83
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Diabetic retinopathy (DR) Incontinentia pigmenti
classification 60 clinical presentation 80, 81
diagnosis and imaging 60–63 treatment 81
epidemiology 59 Indocyanine green angiography, age-related macular
prognosis 65, 66 degeneration 6, 16, 18
treatment
corticosteroids 64, 65 Lamellar macular hole (LMH) 47
laser photocoagulation 63, 64, 66 Lampalizumab, dry age-related macular degeneration
pars plana vitrectomy 65 management 55
selection of treatment 66–68 Laser photocoagulation, diabetic retinopathy
vascular endothelial growth factor management 63, 64, 66
inhibitors 64–66 LMH, see Lamellar macular hole
DME, see Diabetic macular edema
DR, see Diabetic retinopathy Macular edema, retinal vein occlusion association
Drusen, age-related macular degeneration 2, 35
52, 53 Macular hole 46, 47
Moxaverine, dry age-related macular degeneration
Emixustat, dry age-related macular degeneration management 56
management 56
Epiretinal membrane (ERM) 44–46 NCT02087085, dry age-related macular degeneration
ERM, see Epiretinal membrane management 55
Norrie disease
FA, see Fluorescein angiography clinical presentation 81
FAF, see Fundus autofluorescence treatment 82
classification 79, 80 Ocriplasmin, vitreomacular traction management 43,
diagnosis 79 44
differential diagnosis 80 OCT, see Optical coherence tomography
genetics 78, 79 Optical coherence tomography (OCT)
treatment 80 age-related macular degeneration
FEVR, see Familial exudative vitreoretinopathy dry form 52, 53
Floaters, vitreous 48 wet form 6, 7, 9, 16–19, 25–27
Fluorescein angiography (FA) diabetic retinopathy 61–63
age-related macular degeneration retinal vein occlusion 37
dry form 53, 54
wet form 4–6, 15, 25, 26 Pars plana vitrectomy (PPV)
diabetic retinopathy 62, 63 diabetic retinopathy management 65
retinal vein occlusion 35, 36 epiretinal membrane management 45
Fundus autofluorescence (FAF), dry age-related macular hole management 47
macular degeneration 52–54 vitreomacular traction management 44
PED, see Pigment epithelial detachment
Glatiramer acetate, dry age-related macular Pigment epithelial detachment (PED), age-related
degeneration management 55, 56 macular degeneration 5, 15–20, 27
Glaucoma, retinal vein occlusion risks 34 Posterior vitreous detachment (PVD) 42, 43,
48
Hemi retinal vein occlusion, see Retinal vein POT-4, dry age-related macular degeneration
occlusion management 56
Hyperlipidemia, retinal vein occlusion risks 34 PPV, see Pars plana vitrectomy
Hypertension, retinal vein occlusion risks 34 PVD, see Posterior vitreous detachment
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84 Subject Index
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Radial neurotomy (RON), retinal vein occlusion Sildenafil, dry age-related macular degeneration
management 40 management 56
Retinal vein occlusion (RVO)
classification 32, 33 Ultra-wide field (UWF) imaging, diabetic
clinical manifestations 36 retinopathy 62, 63
definition 32 UWF imaging, see Ultra-wide field imaging
fluorescein angiography 35, 36
natural history Vascular endothelial growth factor (VEGF), inhibitors
fellow eye involvement 35 Coats disease management 78
macular edema 35 diabetic retinopathy management 64–66
neovascuarization 35 familial exudative vitreoretinopathy
visual acuity 34, 35 management 80
optical coherence tomography 37 retinal vein occlusion management 39
pathophysiology 32, 33 retinopathy of prematurity management 75, 76
prevalence 33 wet age-related macular degeneration
risk factors 33, 34 management 8–10, 21, 24, 26, 27
treatment 37–40 VEGF, see Vascular endothelial growth factor
Retinopathy of prematurity (ROP) Vitamin C, dry age-related macular degeneration
classification 73, 74 management 54
historical perspective 72 Vitreolysis, vitreomacular traction management 44
late complications 76 Vitreomacular interface (VMI)
pathophysiology 72, 73 age-related macular degeneration 48
screening 76, 77 diabetic macular edema 47, 48
treatment epiretinal membrane 44–46
laser ablation 73, 75 macular hole 46, 47
vascular endothelial growth factor overview 42
inhibitors 75, 76 posterior vitreous detachment 42, 43
vitrectomy 76 vitreomacular traction 43, 44
RON, see Radial neurotomy vitreous floaters 48
ROP, see Retinopathy of prematurity VMI, see Vitreomacular interface
RVO, see Retinal vein occlusion
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Subject Index 85
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ESASO Course Series
F. Bandello, B. Corcóstegui
ISSN 1664–882X
6 Cornea
Editor: J.L. Güell, Barcelona
VIII + 128 p., 85 fig., 81 in color, 9 tab., soft cover, 2015. ISBN 978–3–318–05452–1
7 Ocular Tumors
Editors: A.D. Singh, Cleveland, Ohio; S. Seregard, Stockholm
8 Glaucoma
Editors: C.E. Traverso, Genoa; I. Stalmans, Leuven; F. Topouzis, Thessaloniki;
L. Bagnasco, Genoa
9 Medical Retina
Update 2017
Editors: F. Bandello, Milan; G. Querques, Milan; A. Loewenstein, Tel Aviv
In the ‘ESASO Course Series’ the essentials of the courses of the European School for Ad-
vanced Studies in Ophthalmology (ESASO) are made available to interested ophthalmolo-
gists, optometrists, technicians, and residents all over the world.
In the seven years since the first edition of this book was published, major advances in
diagnostics and management strategies of retinal diseases have evolved.
This updated and revised edition takes this into account and focuses on the significant
developments of preferred practice for diabetic retinopathy and dry and neovascular AMD.
It further discusses pathology, imaging, and visualization of retinal diseases. In addition it
considers biologic disease markers and new drugs being developed.
Medical retina specialists who wish to stay abreast of the constantly changing world of
medical retina will find this publication a must-read.
Cover illustration: An epiretinal membrane causing distortion of the retinal architecture with diffuse
retinoschisis. For details see chapter by Moisseiev and Moisseiev, pp. 42–50.
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ESASO Course Series

129.126.182.195 - 12/26/2019 4:49:58 AM

Francesco Bandello Milan

34 figures, 26 in color, and 9 tables, 2017

Basel · Freiburg · Paris · London · New York · Chennai · New Delhi ·

Library of Congress Cataloging-in-Publication Data

Names: Bandello, F. (Francesco), editor. | Querques, Giuseppe, editor. |

1 Wet Age-Related Macular Degeneration

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Francesco Bandello Maria Vittoria Cicinelli

Georges Caputo Luigi Antonio De Vitis

Elad Moisseiev Alessandro Rabiolo

List of Contributors VII

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Wet Age-Related Macular Degeneration

Abstract commonly wet, AMD is the type of advanced

2 Stanga · Stringa · Ch’ng · Chwiejczak · Papayannis · Tsamis

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

• Subretinal fluid (SRF). Patients usually describe sudden onset of de-

4 Stanga · Stringa · Ch’ng · Chwiejczak · Papayannis · Tsamis

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

6 Stanga · Stringa · Ch’ng · Chwiejczak · Papayannis · Tsamis

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

8 Stanga · Stringa · Ch’ng · Chwiejczak · Papayannis · Tsamis

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Abnormal retinal thickness, particularly if there is No re-appearance or further worsening of OCT

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

10 Stanga · Stringa · Ch’ng · Chwiejczak · Papayannis · Tsamis

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

12 Stanga · Stringa · Ch’ng · Chwiejczak · Papayannis · Tsamis

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Prof. Paulo E. Stanga

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

A Multimodal Imaging Guide to the Evaluation and

Multimodal Imaging of Neovascular AMD 15

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

16 Garrity · Freund · Sarraf

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Multimodal Imaging of Neovascular AMD 17

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

18 Garrity · Freund · Sarraf

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Multimodal Imaging of Neovascular AMD 19

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Fig. 4. Multimodal imaging of stage 3 type 3

20 Garrity · Freund · Sarraf

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Multimodal Imaging of Neovascular AMD 21

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

roid neovasculopathy, multifocal choroiditis, Management of Neovascular AMD

22 Garrity · Freund · Sarraf

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Multimodal Imaging of Neovascular AMD 23

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

24 Garrity · Freund · Sarraf

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Multimodal Imaging of Neovascular AMD 25

Bandello F, Querques G, Loewenstein A (eds): Medical Retina. Update 2017.

Type 3 Type 3 Type 3

on traditional FA classification of NV generally quantitative capability that could offer robust