Clinical Diagnosis and Management of Dry Eye and Ocular Surface

Clinical Diagnosis and Management of
DRY EYE
and
OCULAR SURFACE DISORDERS
(Xero-Dacryology)
Clinical Diagnosis and Management of
DRY EYE
and
OCULAR SURFACE DISORDERS
(Xero-Dacryology)
Editors
Ashok Garg
MS PhD FIAO (Bel) FRSM ADM FAIMS FICA
International and National Gold Medalist
Medical Director
Garg Eye Institute and Research Centre
235-Model Town, Dabra Chowk
Hisar 125005, India
John D Sheppard Eric D Donnenfeld
MD MMSc MD FACS
Clinical Director–Thomas R Lee Clinical Associate Professor
Center for Ocular Pharmacology North Shore University
Ophthalmology Program Director Hospital and Nassau County
Associate Professor of Medical Center
Ophthalmology Founding Partner
Eastern Virginia Medical School Ophthalmic Consultants of
Norfolk, Virginia 23501, USA Long Island
Rockville Center,
New York, USA
David Meyer Cyres K Mehta

M Med FCOphth PhD MS FAGE FSVH FNRERF FSEC
Professor and Head Director and Consultant
Department of Ophthalmology Ophthalmic Surgeon
Faculty of Health Sciences Dr Mehta’s International Eye
University of Stellenbosch Institute
Tygerberg, 7505 147, Shahid Bhagat Singh Road
South Africa Colaba, Mumbai 400005
India
Foreword: Juan Murube
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Clinical Diagnosis and Management of Dry Eye and Ocular Surface

Disorders (Xero-Dacryology)
© 2006, Ashok Garg, John D Sheppard, Eric D Donnenfeld, David Meyer, Cyres K Mehta
All rights reserved. No part of this publication and Interactive DVD ROM should be reproduced,
stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical,
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This book has been published in good faith that the material provided by contributors is
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editors will not be held responsible for any inadvertent error(s). In case of any dispute, all
legal matters are to be settled under Delhi jurisdiction only.
First Edition : 2006

ISBN 81-8061-775-0
Typeset at JPBMP typesetting unit
Printed at Gopsons
Dedicated to
• My Respected Param Pujya Guru Sant Gurmeet Ram Rahim Singh Ji
for his blessings and motivation.
• My Respected parents, teachers, my wife Dr Aruna Garg, son Abhishek
and daughter Anshul for their constant support and patience during
all these days of hard work.
• My dear friend Dr Amar Agarwal, a leading International
Ophthalmologist from India for his continued support and guidance.
— Ashok Garg
• My wife of 25 years, Clelia, whose understanding and patience have

allowed my time to be dedicated to the discovery of new treatments
of dry eye and other severe ocular diseases, and whose own
experience with dry eye has provided me with marvelous insight into
the human side of patient concerns.
— John Sheppard
• My wonderful wife and children who make everything possible.

— Eric Donnenfeld
• My dear wife Marita who has inspired all three our children Deidre,
Riegardt and Adelle to join me in sharing the joys of the medical
profession.
– David Meyer
• My parents for everything.

• To Vini my best friend.
— Cyres K Mehta
Contributors
Amar Agarwal MS FRCS FRC Ophth C Feinbaum MD FAAO
Consultant Spain
Dr Agarwal’s Eye Hospital
19, Cathedral Road Charlotte Wolley Dod MD
Chennai-600086 Hospital de la Santa Creu I Sant Pau
India Department of Ophthalmology
Universitat Autonoma De Barcelona
Arif Adenwala MS DNB FRCS ICO Barcelona
Consultant Ophthalmologist Spain
P Box No. 457
Zulekha Hospital Cristina Simon-Castellivi MD
Sharjah (UAE) Clinica Oftalmologica Simon
Simon Eye Clinic
A Ducasse MD Barcelona, Spain
France
Cyres K Mehta MS FSVH FAGE
Anand Shroff MS Director and Consultant
Shroff Eye Hospital Mehta International Eye Institute
222, SV Road, Bandra (W) Seaside, 147, Colaba Road
Mumbai-400050 Mumbai-400005, India
A Rahimi MD Dan Davis MD

Iran Chu Vision Institute
Edina, Minn
Ashok Garg MS PhD FRSM
Medical Director Dharmesh Kar MBBS DNB
Garg Eye Institute and Research Aditya Jyot Eye Hospital Pvt Ltd
Centre Plot No. 153, Road No. 9
235-Model Town, Dabra Chowk Major Parmeshwaran Road
Hisar-125005 (India) Opp. SIWS College, Gate No. 3
Wadala
Ashok Grover MD MNAMS FRCS Mumbai - 400031, India
Chairman, Deptt of Ophthalmology
Sir Ganga Ram Hospital David Meyer MMed FCOphth PhD
Rajinder Nagar Professor and Head
New Delhi-110060 (India) Deptt of Ophthalmology
Faculty of Health Sciences
C Baudouin MD University of Stellenbosch
France Tygerberg, 7505, South Africa
viii CLINICAL DIAGNOSIS & MANAGEMENT OF DRY EYE & OCULAR SURFACE DISORDERS
David T Vroman MD H Hoh MD

Magill Research Centre for Vision Germany
Correction, Storm Eye Institute-MUSC
Hijab Mehta MS DOMS FCPS
167, Ashley Avenue
Consultant
Charleston, South Carolina, 29425
Aditya Jyot Eye Hospital Pvt. Ltd.
USA
Plot No. 153, Road No. 9
Wadala, Mumbai-400031
D Spinelli MD
India
Italy
H Soriano MD
Eric D Donnenfeld MD FACS Argentina
Clinical Associate Professor
J Duran MD
North Shore University Hospital and
Spain
Nassau County Medical Center
2000 North Village Ave. Jessica Matsumoto MD
Rockville Center, NY 11570 Chu Vision Institute
USA Edina, Minn
Jes Mortensen MD
F Holly MD
Consultant
USA
The Eye Deptt
Orebro University Hospital
F Paulsen MD
SE-70185, Orebro, Sweden
Germany
John D Sheppard MD MMSc
Gebhard Rieger MD
Associate Professor of Ophthalmology
Paracelsus Society for Balneology and
Microbiology and Immunology
Iodine Research
Clinical Director
Bad Hall, Austria
Thomas R Lee Centre for Ocular
Pharmacology
Guillermo L Simon Castellvi MD
Eastern Virginia Medical School
Clinica Oftalmologica Simon
Norfolk, Virginia 23501
Simon Eye Clinic
USA
Barcelona
Spain
Jorge L Alio MD PhD
Instituto Oftalmologico De Alicante
G Van Setten MD
Avda. Denia 111, 03015
Sweden
Alicante
Spain
Henry D Perry MD FACS
Chief of Cornea Service
JM Benitez del Castillo MD
Nassau University Medical Center
Spain
East Meadow, New York
2000 North Village Ave
J Nemeth MD
Rockville Center, NY 11570
Hungary
USA
CONTRIBUTORS ix
Jose M Simon-Castellvi MD Kerry D Solomon MD
Anterior Segment Surgeon Magill Research Centre for Vision
Clinica Oftalmologica Simon Correction, Storm Eye Institute-MUSC
Simon Eye Clinic, Barcelona 167, Ashley Avenue
Spain Charleston, South Carolina
29425
Jose M Simon-Tor MD USA
Chairman
Glaucoma Senior Consultant L Chen Zhuo MD
Glaucoma Deptt China
Clinica Oftalmologica Simon
Simon Eye Clinic, Barcelona Luis E Fernandez de Castro MD
Spain Magill Research Centre for Vision
Correction, Storm Eye Institute-MUSC
José L Güell MD 167, Ashley Avenue
Instituto De Microcirugia Ocular (IMO) Charleston, South Carolina
Universitat Autonoma De Barcelona 29425
Barcelona USA
Spain
Marco Sales-Sanz MD
J Nepp MD Department of Ophthalmology
Austria Hospital Ramon y Cajal
Carretera de Colmenar Km 9.100
Jutta Horwath Winter MD PhD 28034-Madrid
Deptt of Ophthalmology Spain
Medical University Graz
Auenbruggerplatz 4 O Shalaby MD
8036 Graz Egypt
Austria
Oscar Gris MD
Juan Murube MD PhD Instituto De Microcirugia Ocular (IMO)
Professor of Alcala University Universitat Autonoma De Barcelona
President Barcelona, Spain
International Society of Dacryology
and Dry Eye, Moralzarzal Street 43 Otto Schmut MD
28034, Madrid Deptt of Ophthalmology
Spain Medical University Graz
Austria
Keiki R Mehta MS DO FIOS
Chairman and Medical Director P Kaynak-Hekimhan MD
Mehta International Eye Institute Turkey
147, Shahid Bhagat Singh Road
Colaba Road, Mumbai - 400005 P Raus MD
India Belgium
x CLINICAL DIAGNOSIS & MANAGEMENT OF DRY EYE & OCULAR SURFACE DISORDERS
P Sieg MD S Cervenka MD
Germany Czech Republic
Rituraj Baurah MS Shaloo Bageja MS

Consultant Consultant
Sir Ganga Ram Hospital Sir Ganga Ram Hospital
Rajinder Nagar Rajinder Nagar
New Delhi-110060, India New Delhi-110060, India
Rishi Mohan MD DNB FRCSE SH Ugurbas MD

Director Turkey
MM Eyetech
29, Link Road S Natarajan MS FRVS
Lajpat Nagar-III Chairman and Medical Director
New Delhi-24 Aditya Jyot Eye Hospital Pvt Ltd
India Plot No. 153, Road No. 9
Major Parmeshwaran Road
R Javate MD Opp. SIWS College, Gate No. 3
Phillipines Wadala, Mumbai-400031
India
Robert Latkany MD
Director Steve Pflugfelder MD
Eye Clinic NY Eye and Ear Infirmary Professor and Director of Ocular
Centre for Ocular Tear Film Disorders Surface Center, Department of
at Laser and Corneal Surgery Ophthalmology
Manhattan Baylor College of Medicine
USA 6550 Fannin, Suite 1501
Houston, Texas 77030
Rudolf Winkler MD USA
Paracelsus Society for Balneology
and Iodine Research Sunita Agarwal MS DO PSVH
Bad Hall Dr Agarwal’s Eye Hospital
Austria 19, Cathedral Road
Chennai-600086
Sabrina Shah-Desai MS FRCS India
Adnexal Associate Specialist 15, Eagle Street, Langford Town
Moorfields Eye Hospital Bangalore
City Road India
London EC 1 V2PD
UK Susmita G Shah MS DNB FICO
Consultant
Sarabel Simon-Castellvi MD Gaurav Laser Academy
Retina Vitreous Deptt 105-A, Patel Shopping Centre
Simon Eye Clinic Chandavarkar Road, Borivli (W)
Barcelona Mumbai-400092
Spain India
CONTRIBUTORS xi
Svetelana Toshniwal MBBS DNB Yogesh C Shah MS FCPS DOMS
Aditya Jyot Eye Hospital Pvt Ltd Medical Director
Plot No. 153, Road No. 9 Gaurav Laser Academy
Major Parmeshwaran Road, 105-A, Patel Shopping Centre
Opp. SIWS College Chandavarkar Road, Borivli (W)
Gate No. 3, Wadala Mumbai - 400092
Mumbai - 400031, India India
Tarjani Y Shah MBBS Y Ralph Chu MD

Gaurav Laser Academy Medical Director
105-A, Patel Shopping Centre Chu Vision Institute
Chandavarkar Road, Borivli (W) Edina
Mumbai - 400092, India Minn
Foreword
When more than three hundred million years ago
crossopterygian fish gave rise to amphibians—our
ancestors—they needed to maintain their very complex
corneo-lenticular eyes wet, not only for cornea
maintenance and metabolism, but also to allow a
smooth refractive tear film able to give the best possible
retinal images. So, they modified and developed
different glands, mainly of naso-buccal origin, to
produce tear, a complex palpebral system, to spread and protect the
lacrimal film, and a complex emunctory lacrimal pathway. Hence the first
two types of tear appeared: basal and reflex tears. Much more recently,
a third type of tear appeared in humans, the emotional tear, which was
for expressing intercommunication with other humans. How and why?
when mammals meet other animals the first thing they look at is their face.
They know that the two most important organs for forming an interrelation
are the eyes, used for observing and sizing each other up, and the mouth,
used for attacking. These two organs made the face the most important
point of their mutual attention when they met. Therefore, little by little the
face became the most important organ of interrelation, and the muscles
of the face developed a great number of contractions, mainly related with
the eyes and the mouth, in order to express hundreds of expressions:
friendship, attention, happiness, fury, sadness, anguish…. Our ancestors
manifested so many different things with different combinations of their
facial musculature, that they needed to introduce non-muscular signs to
exhibit other sentiments using mime language. So, humans, who had used
up practically all their combination of facial mimes to manifest different
expressions, began to shed emotional tears, to express an appeal for help,
or just the opposite, solidarity, offering help. The reason why they chose
this new way to express these sentiments could be that they took as point
of reference the reflex tears produced due to pain of the ocular surface as
a result of wounds or foreign bodies, as manifestation of affliction and
grief.
The complex organ of tearing has a concomitant pathology. It began
to be known little by little from the prehistory of humans, and it was
mentioned in the first written literature. As in other branches of human
xiv CLINICAL DIAGNOSIS & MANAGEMENT OF DRY EYE & OCULAR SURFACE DISORDERS
pathology, medical, psychological and surgical treatments merged in a

common profession. Ophthalmology was developed among quacks,
sorcerers, physicians and surgeons, and was mainly comprised by ocular
surface and dacryology.
Scientific medicine reached a good level and complexity in the last
centuries, as logic rejected extranatural concepts and based its conceptions
in reasonable deductions and verifiable experiences. Medicine began to
develop specialties because of the impossibility of a single person to domain
the many different fields of pathology. One of these specialties is
ophthalmology. Specialties or proto-specialties have recently become more
and more complex, and the necessity of good results, made these proto-
specialties divide into deutero-specialties or second generation specialties,
also named super-specialties, subspecialties, hyper-specialties, or ultra-
specialties, including in ophthalmology many, such as glaucomatology,
retinology, strabology, cataractology, infections … and among these in the
last years of the last century appeared the deutero-speciality of dacryology.
Deutero-specialties are gradually dividing into new branches named trito-
specialties or third generation specialties. In dacryology the two that are
clearest at this moment are xero-dacryology (Gr. xeros = dry), dedicated
to the dry eye, and odo-dacryology (Gr. odos = way) , dedicated to
lacrimal pathways.
Dry eye is the most frequent pathology of ophthalmology, that in its
mild grade of severity will affect practically 100 percent of the population.
So, xero-dacryology is becoming a ver y important branch of
ophthalmology. The present book is an expression of the increasing
interest in this condition, not only because of its topic on dry
eye, but because of the good selection of the topics, and the
efficacy and clarity with which they have been treated. In this book,
the physiology of the tear film and ocular surface has been explained, the
etiopathogenesis of the problems clearly and easily shown, and the
treatments didactically expounded with great clarity. I hope this book
by Dr Ashok Garg and Co-editors will be a landmark in the field
of xero-dacryology.
Dr Juan Murube MD PhD

Professor of Alcala University
President, International Society of Dacryology and Dry Eye
President, Spanish Society of Ophthalmology,
C / Moralazarzal Steet 43,28034, Madrid, SPAIN
Tel. 34-917350760
E-mail : murubejuan@terra.es
Preface
Tear film which covers the exposed part of the ocular globe is a complex
trilaminar structure which is clinically important for the optical integrity
and normal functions of the eye. The tear film plays an important role
in visual acuity. Decrease in quality/quantity of the tear film may introduce
optical aberrations which leads to poor retinal image quality.
Dry Eye syndrome is an extremely common and often unrecognized
disease. Due to wide variety of presentations and symptoms it often
frustrates the ophthalmologists as well as patients. Due to multifactorial
and elusive etiology it is often challenging to treat Dry Eye. Ocular surface
disorders are also clinically important to treat specially in term of visual
acuity to the satisfaction of patients.
In this International Book 32 chapters contributed by leading
International experts of this field cover all aspects of Dry Eye and Ocular
Surface disorders. New therapeutic options beyond the customary aqueous
tear replacement, latest surgical options have been included in this book
for the benefit of practising ophthalmologist. Latest amniotic membrane
transplantation techniques and stem cell surgery to treat ocular surface
disorders are added attraction of this book. An Interactive DVD ROM is
being distributed with this book showing latest surgical skills for dry eye
management by International Masters of this field.
We are highly thankful to Shri JP Vij (CEO) Jaypee Brothers Medical
Publishers, Mr Tarun Duneja (General Manager Publishing) and all staff
members of the publishing house who extended every possible help in
the preparation of this International Book at a short notice.
At the last we are quite hopeful to provide complete information on
Dry Eye and Ocular Surface Disorders (Xero-Dacryology) to our readers
in this compact and handy book.
Editors
Contents
1. Pathophysiology of Tear Film ........................................... 1
Ashok Garg (India)
2. Etiopathogenesis and Classification of Dry Eye ............. 33
Arif Adenwala (UAE)
3. The Triple Classification of Dry Eye for
Practical Clinical Use .................................................... 45
Juan Murube (Spain), et al
4. Clinical Features of Dry Eye ........................................... 60
Susmita G Shah, Tarjani Y Shah, Yogesh C Shah (India)
5. Diagnostic Tests and Principles in
Dry Eye Syndrome ......................................................... 64
David Meyer (South Africa)
6. Medical Management of Dry Eye .................................... 83
Ashok Garg (India)
7. Surgical Management of Dry Eye ................................. 100
Marco Sales Sanz, Juan Murube (Spain)
8. Pre Laser Assisted Stromal in-situ
Keratomileusis (LASIK) Investigation of Dry Eye ......... 137
Anand Shroff (India)
9. LASIK and Dry Eyes .................................................... 149
Cyres K Mehta, Keiki Mehta (India)
10. Cataract Surgery in Patients with Dry Eyes .................. 156
AK Grover, Shaloo Bageja, Rituraj Baurah (India)
11. Contact Lenses and Ocular Lubrication ....................... 163
Guillermo L Simon-Castellvi, Dra Sarabel Simon-Castellvi,
Dra Cristina Simon-Castellvi, Jose Ma Simon-Castellvi,
Jose Ma Simon-Tor (Spain)
12. Computer Vision Syndrome and Dry Eye ...................... 195
Susmita G Shah, Tarjani Y Shah, Yogesh C Shah (India)
13. Management of Dry Eye (Ocular Surface
Syndrome-OSS) after Refractive Surgery ...................... 198
Jorge L Alio, C Feinbaum (Spain)
xviii CLINICAL DIAGNOSIS & MANAGEMENT OF DRY EYE & OCULAR SURFACE DISORDERS
14. Dry Eye as Informed Consent Prior to

Refractive Surgery ........................................................ 227
Y Ralph Chu, Jessica Matsumoto, Dan Davis (USA)
15. Tear Film Function, Ocular Surface Integrity and
Corneal Sensation after Laser-assisted Subepithelial
Keratectomy ................................................................ 231
Jutta Horwath-Winter (Austria)
16. Topical Cyclosporin A—Restasis® for the Management
of Dry Eye and Ocular Surface Diseases ...................... 243
Eric Donnenfeld, Steve Pflugfelder, Henry Perry (USA)
17. Dry Eye Management in Pregnant and
Menopausal Women ..................................................... 273
John D Sheppard (USA)
18. Dry Eye and Visual Acuity ............................................ 280
Robert Latkany (USA)
19. LASIK Hinge Location and Dry Eye ............................. 286
David T Vroman, Luis E Fernandez de Castro,
Kerry D Solomon (USA)
20. Iodide Application by Iontophoresis as
Adjuvant Therapy in Dry Eye Patients .......................... 294
Jutta Horwath-Winter, Otto Schmut, Gebhard Rieger,
Rudolf Winkler (Austria)
21. Allergic Ocular Surface Diseases
and its Management ..................................................... 307
Ashok Garg (India)
22. Recent Advances in Dry Eye Management .................... 334
Rishi Mohan (India)
23. Ocular Surface Disease:
Current Management and Concepts ............................. 346
Sabrina Shah-Desai (UK)
24. Immunosuppressive Therapy for
Ocular Surface Disorders ............................................. 373
Ashok Garg (India)
25. Ocular Surface Disorders due to Drugs Toxicity ........... 380
Ashok Garg (India)
CONTENTS xix
26. Application of the Amniotic Membrane

in Ocular Surface Pathology ........................................ 430
Oscar Gris, José L Güell, Charlotte Wolley Dod (Spain)
27. Amniotic Membrane Transplantation
in Ocular Surface Disorders ......................................... 444
Dharmesh Kar, Hijab Mehta, S Natarajan (India)
28. Cultured Limbal Stem Cell Transplantation ................. 454
Hijab Mehta, Svetlana Toshniwal, S Natarajan (India)
29. Phototherapeutic Keratectomy (PTK)
in Ocular Surface Disorders ......................................... 464
Jes Mortensen (Sweden)
30. Stem Cell Surgery in Ophthalmology ........................... 486
Sunita Agarwal, Amar Agarwal (India)
31. Quick Look Ocular Lubricants and
Artificial Tear Solutions ............................................... 500
Ashok Garg (India)
32. Blepharitis and Meibomianitis ..................................... 506
Henry D Perry, Eric D Donnenfeld (USA)
Index ........................................................................................ 511

PATHOPHYSIOLOGY OF TEAR FILM 1
2 CLINICAL DIAGNOSIS AND MANAGEMENT OF DRY EYE AND OCULAR SURFACE DISORDERS
INTRODUCTION
The exposed part of the ocular globe—the cornea and the bulbar conjunctiva
is covered by a thin fluid film known as preocular tear film. Tear film is
that surface of the eye, which remains most directly in contact with
the environment. It is critically important for protecting the eye from external
influences and for maintaining the health of the underlying cornea and
conjunctiva. The optical stability and normal function of the eye depend on
an adequate supply of fluid covering its surface.
The tear film is a highly specialized and well-organized moist film which
covers the bulbar and palpebral conjunctiva and cornea. It is formed and
maintained by an elaborate system—the lacrimal apparatus consisting of
secretory, distributive and excretory parts. The secretory part includes the
lacrimal gland, accessory lacrimal gland tissue, sebaceous glands of the eyelids,
goblet cells and other mucin-secreting elements of the conjunctiva (Figure
1.1). The elimination of the lacrimal secretions is based on the movement of
tears across the eye aided by the act of blinking and a drainage system
consisting of lacrimal puncta, canaliculi, sac and nasolacrimal duct (Figure
1.2).
FIGURE 1.1: Cross-section of eye showing tear film (blue) in its natural distribution
along with tear producing glands (Courtesy Allergan India Limited)
By definition, a film is a thin layer that can stand vertically without

appreciable gravitational flow and the tear film meets this criteria very well.
FIGURE 1.2: Tear drainage system (Courtesy Allergan India Limited)
The presence of continuous tear film over the exposed ocular surface is
imperative for good visual acuity and wellbeing of the epithelium and facilitates
blinking. Tear film serves:
• An optical function by maintaining an optically uniform corneal surface
• A mechanical function by flushing cellular debris, foreign matter from the
cornea and conjunctival sac and by lubricating the surface
• A corneal nutritional function
• An antibacterial function.
The composition of the tear film must be kept within rather narrow
quantitative and qualitative limits in order to maintain the wellbeing and
proper functioning of the visual system. Abnormalities of the tear film affecting
its constituents or volume lead to serious dysfunction of the eyelids and the
conjunctiva with the concomitant loss of corneal transparency. A thin tear
film is uniformally spread over the cornea by blinking and ocular move-
ments. The tear film can be arbitrarily divided into four main parts:
• The marginal tear film along the moist portions of the eyelid which lie
posterior to the lipid strip secreted by the tarsal glands
• Portion covering the palpebral conjunctiva
• Portion covering the bulbar conjunctiva
• Precorneal tear film which covers the cornea.
FIGURE 1.3: Tear film layers (Courtesy Allergan India Limited)
The marginal, palpebral and conjunctival portions are regarded as making

the preocular tear film.
Tears refers to the fluid present as the precorneal film and in the conjunctival
sac. The volume of tear fluid is about 5 to 10 μl with normal rate of secretion
about 1 to 2 μl/minute. About 95 percent of it is produced by the lacrimal
gland and lesser amounts are produced by goblet cells and the accessory
lacrimal glands of the conjunctiva. The total mass of the latter is about one-
tenth of the mass of the main lacrimal gland.
The secretory part of the lacrimal apparatus provides the aqueous tear,
lipids and mucus all the important components of the tear film and its
boundary.
The tear film is composed of three layers (Figure 1.3).
1. Superficial Lipid Layer

The superficial layer at the air-tear interface is formed over the aqueous part
of the tear film from the oily secretions of meibomian glands and the accessory
sebaceous glands of Zeis and Moll. The meibomian gland openings are
distributed along the eyelid margin immediately behind the lash follicles.
The chemical nature of the lipid layer is essentially waxy and consists of
cholesterol esters and some polar lipids. The thickness of this layer varies
with the width of the palpebral fissure and is between 0.1 and 0.2 μm. Being
oily in nature it forms a barrier along the lid margins that retains the lid
margin tear strip and prevents its overflow on to skin. This layer is so thin that
there are no interference color patterns such as one normally sees on an oily
surface. However, if one squints, the oily layer thickness and distinct
interference colors may be seen.
While the bulk of tarsal gland secretions are nonpolar lipid compounds
which do not spread over an aqueous surface alone, many surface active
components are also present. It appears that the tarsal gland secretions which
are transported to the cornea in the tear film are massaged into the outermost
layer of corneal epithelial cells by eyelid action and then possibly are changed
by local metabolic processes in the epithelium combining with conjunctival
mucus to form a stable hydrophilic base for the precorneal tear film.
This outer lipid layer has the following main functions:
• It reduces the rate of evaporations of the underlying aqueous tear layer.
• It increases surface tension and assists in the vertical stability of the tear
film so that tears do not overflow the lower lid margin.
• It lubricates the eyelids as they pass over the surface of the globe.
2. Middle Aqueous Layer

The intermediate layer of tear film is the aqueous phase which is secreted by
the main lacrimal gland and the accessory glands of Krause and Wolfring.
This layer constitutes almost the total thickness of the tear film 6.5 to
10 μm, many times thicker than the fine superficial oily layer. This layer
contains two phases—a more concentrated and a highly dilute one. The
interfacial tension at the adsorbed mucin-aqueous layer is apt to be rather
small due to the intensive hydrogen bond formation across the interface.
This layer contains inorganic salts, water proteins, enzymes, glucose, urea,
metabolites, electrolytes, glycoproteins and surface active biopolymers.
Uptake of oxygen through the tear film is essential to normal corneal
metabolism. This layer has four main functions:
• Most importantly it supplies atmospheric oxygen to the corneal epithelium.
• It has antibacterial substances like lactoferrin and lysozyme. Therefore,
dry eye patients are more susceptible to infection than a normal eye.
• It provides smooth optical surface by removing any minute irregularities
of the cornea.
• It washes away debris from the cornea and conjunctiva.
3. Posterior Mucin Layer

The innermost layer of tear film is a thin mucoid layer elaborated by goblet
cells of the conjunctiva and also by the crypts of Henle and glands of Manz.
It is the deepest stratum of the precorneal tear film. This layer is even thinner
than the lipid layer and is 0.02 to 0.04 μm thick. This adsorbs on the epithelial
surface of the cornea and conjunctiva rendering them hydrophilic. It assumes
the ridged appearance of the microvilli of superficial epithelial cells which it
covers. The preocular tear film is dependent upon a constant supply of mucus
which must be of proper chemical and physical nature to maintain corneal
and conjunctival surfaces in the proper state of hydration. The mucous threads
present in the tear film provides lubrication allowing the eyelid margin and
palpebral conjunctiva to slide smoothly over one another with minimal energy
lost as friction during blinking and ocular rotation movements. They also
cover foreign bodies with a slippery coating thereby protecting the cornea
and conjunctiva against the abrasive effects of such particles as they are moved
about by the constant blinking movements of eyelids. The mucus contributes
stability to the preocular tear film as well as furnishing an attachment for the
tear film to the conjunctiva but not to the corneal surface. The corneal surface
is covered with a myriad of fine microvilli which provides some support for
the tear film. The mucus dissolved in the aqueous phase facilitates spreading
of the tear film by smoothening the film over the corneal surface to form a
perfect, regular refracting surface.
So the mucin layer which is a glycoprotein converts a hydrophobic surface
into a hydrophilic surface and enables the corneal epithelium to be adequately
wetted.
In addition to sufficient amounts of aqueous tears and mucin three other
important factors are necessary for effective resurfacing of the cornea by the
precorneal tear film.
• A normal blink reflex is essential to ensure that the mucin is brought from
the inferior conjunctiva and rubbed into the corneal epithelium. Patients
suffering from facial palsy and lagophthalmos therefore develop corneal
drying.
• Congruity between external ocular surface and the eyelids ensures that
the precorneal tear film shall spread evenly over the entire cornea. Patients
suffering from limbal lesions like dermoids face the problem of apposition
of the eyelids to the globe leading to local selective areas of drying.
• Normal epithelium is necessary for the adsorption of mucin on to its

surface cells. Patients suffering from corneal scars and keratinizations have
problem of interference with the corneal wetting.
The tear film is not visible apparently on the surface of the eye but at the
upper and lower lid margins a 1 mm strip of tear fluid with concave outer
surface can be seen. It is here that the oily surface prevents spillage of the
tear fluid over the lid margin. Tears forming the upper tear strip are conducted
nasally from the upper temporal fornix. At the lateral canthus the tears fall
by gravity to form the lower strip, spreading medially the upper and lower
strips reach the plica and caruncle where they join together. The tear fluid
does not flow over the eye by gravity but a thin film is spread over the
cornea by blinking and eye movements.
TEAR FILM FORMATION DYNAMICS

It is interesting to know the tear film formation. Generally during the closure
of the eyelids the superficial lipid layer of the tear film is compressed by the
eyelid edges because it is energetically unfavorable for the lipid to penetrate
under the lids into the fornix. The thickness of lipid layer therefore increases
by a factor of 1000 resulting in thickness of 0.1 mm which is easily contained
between the adjacent eyelid edges. The aqueous tear layer remains uniform
under the lids and acts as a lubricant between the eyelids and the globe. In a
complete blink phenomenon, the two tear minisci join and most of their
bulk is held at their junction to fill the slight bridge formed by the meeting
eyelids and at the canthus.
When the eyelids open, first they form an aqueous tear surface on which
the compressed lipid rapidly spread. Monomolecular lipid layer is the first to
spread at speeds limited only by the moving eyelid. Following the spread of
lipid monolayer, the excess lipid and associated macromolecules shall distribute
themselves over the tear film surface at a lower speed, usually the lipid layer
ceases within 1 second after the opening of the eye.
Under normal conditions a person blinks on an average 15 times per
minute. Some of these blinks may not be complete (the upper eyelid descends
only half way towards the lower eyelid). Normally the tear film break up
time (BUT) is longer than the interval between blinks and no corneal drying
occurs.
A deficiency in the conjunctival secretions can lead to dry eye symptoms
even in the presence of an adequate aqueous tear component (Figure 1.4).
FIGURE 1.4: Impression cytology mapping

(Courtesy Allergan India Limited)
BUT (Break up Time) is generally determined after the instillation of a

drop of fluorescein solution in the eye or after staining the tear miniscus and
the tear film by a wetted paper strip containing fluorescein. Normal BUT
value ranges from 10 to 40 seconds for normal eyes (Figure 1.5) when the
BUT is determined by a non-invasive method (e.g. by the toposcope). BUT
values of as long as 3 to 5 minutes can be recorded.
If the BUT is shorter than the average time interval between two
consecutive blinks, tear film rupture can cause pathological changes in the
underlying epithelium. The tear film breaks up prematurely over the damaged
epithelial surface thereby exacerbating the injury.
Generally there is balance between the secretion and excretion of tears
and the rate of tear drainage increases with increased tear volume.
FIGURE 1.5: Mechanism of tear film break up (Courtesy

Allergan India Limited)
NORMAL TEAR DRAINAGE

In the normal tear film between 10 and 25% of the total tears secreted are
lost by evaporation. Evaporation rate is low because of the protective oily
surface.
In the absence of the protective oily layer the rate of evaporation is
increased 10 to 20 times. Normally tear flows along the upper and lower
marginal strips and enters the upper and lower canaliculi by capillarity and
possibly by suction also. About 70% of tear drainage is via the lower canaliculus
and the remaining through the upper canaliculus. With each blink the
superficial and deep heads of pretarsal orbicularis muscle compress the
ampullae, shorten the horizontal canaliculi and move the puncta medially.
Simultaneously the deep heads of preseptal orbicularis muscle which are
attached to the fascia of the lacrimal sac contract and expand the sac. This
creates a negative pressure which sucks the tears from the canaliculi into the
sac. When the eyes are opened the muscles relax, the sac collapses and a
positive pressure is created which forces the tear down the duct into the
nose. Gravity also plays an important role in the sac emptying. The puncta
move laterally, the canaliculi lengthen and become filled with tears.
TEAR COMPOSITION
Tears contain 98.2% water and 1.8% solids. The high percentage of water in
tears is a natural consequence of the need for lubrication of the conjunctiva
and corneal surface (Tables 1.1 and 1.2). The evaporation of water between
blinks may influence the concentration of the tear film. The evaporation rate
of water from the intact precorneal tear film through the superficial lipid
layer has been shown to be 8 × 10–7 cm–2.sec–1. In a time interval of 10
seconds (between two consecutive blinks) the thickness of the tear film
decreases about 0.1 mm resulting in nearly 1 to 2% decrease in water concen-
tration. The solute concentration, however, increases about 20%.
TABLE 1.1: Relative water contents of tears and other body fluids
Fluid Percentage water
Tear 98.2
Aqueous humor 98.9
Vitreous humor 99.0
Blood 79.5
Serum 91.0
Urine 96.5
TABLE 1.2: Composition of human tears and plasma

Tears Plasma
Physical properties
pH 7.4 (7.2-7.7) 7.39
Osmotic pressure 305 mOsm/kg 6.64 atm
Equiv. 0.95% NaCl
Refractive index 1.357 1.35
Volume 0.50-0.67 g/16 hour (waking)
Chemical properties
1. General tear composition
Water 98.2 g/100 ml 98 g/100 ml
Solids (total) 1.8 g/100 ml 8.6 g/100 ml
Ash 1.05 g/100 ml 0.6-1.0 g/100 ml
2. Electrolytes
Sodium 120-170 mmol/l 140 mmol/l
Potassium 26-42 mmol/l 4.5 mmol/l
Calcium 0.3-2.0 mmol/l 2.5 mmol/l
Magnesium 0.5-1.1 mmol/l 0.9 mmol/l
Chloride 120-135 mmol/l 100 mmol/l
Bicarbonate 26 mmol/l 30 mmol/l
3. Antiproteinasis
α1-Anti trypsin(α1-at) 0.1-3.0 mg% 280 mg%
α1-Anti Chymotrypsin 1.4 mg% 24 mg%
Inter-α trypsin inhibitor 0.5 mg% 20 mg%
α2 Macroglobulin 3-6 mg% —
4. Nitrogenous substances
Total protein 0.668-0.800 g/100 ml 6.7 g/100 ml
Albumin 0.392 g/100 ml 4.0-4.8 g/100 ml
Globulin 0.2758 g/100 ml 2.3 g/100 ml
Ammonia 0.005 g/100 ml 0.047 g/100 ml
Uric acid
Urea 0.04 mg/100 ml 26.8 mg/100 ml
Total nitrogen 158 mg/100 ml 1140 mg/100 ml
Nonprotein nitrogen 51 mg/100 ml 15-42 mg/100 ml
5. Carbohydrates
Glucose 2.5 (0-5.0) mg/100 ml 80-90 mg/100 ml
6. Sterols
Cholesterol and
cholesterol esters 8-32 mg/100 ml 200-300 mg/100 ml
7. Miscellaneous
Citric acid 0.6 mg/100 ml 2.2-2.8 mg/100 ml
Ascorbic acid 0.14 mg/100 ml 0.1-0.7 mg/100 ml
Lysozyme 1-2 mg/ml —
Amino acid 7.58 mg/100 ml —
Lactate 1-5 mmol/l 0.5-0.8 mmol/l
Prostaglandin 75 pg PF/ml 80-90 pg PF/ml
300 pg PF/ml
Catecholamine 0.5-1.5 μg/ml
Complement 1:4 dilution 1.32 dilution
(Hemolytic assay) (Hemolytic assay)
PHYSICAL PROPERTIES OF TEARS

Tear pH
The pH of unstimulated tears is about 7.4 and it approximates that of blood
plasma. Although wide variations are found in normal individuals (between
5.0-8.35) the usual range is from 7.3 to 7.7. A more acidic pH of about
7.25 is found following prolonged lid closure possibly due to carbon
dioxide produced by the cornea and trapped in the tear pool under
the eyelids. Tear pH is characteristic for each individual and the normal
buffering mechanism maintain the pH at a relatively constant level during
waking hours. The permeability of the corneal epithelium does not seem to
be affected by wide variations in the pH of tear fluid.
Osmotic Pressure
The osmotic pressure in tears mainly caused by the presence of electrolytes
is about 305 mOsm/kg equivalent to 0.95% sodium chloride.
Individual values over the waking day may range from 0.90 to 1.02%
NaCl equivalents. A decrease to an average of 285 mOsm/kg equivalent to
0.89% NaCl has been reported following prolonged lid closure which
accounts for the reduced evaporation. When the aqueous component
of tears decreases, the tears become markedly hypertonic (0.97% NaCl
solution or more) and corneal dehydration results. When the eyes are closed,
there is no evaporation of tears and the precorneal tear film is in osmotic
equilibrium with the cornea. When the eyes are open evaporation takes
place, increasing the tonicity of the tear film and producing an osmotic
gradient from the aqueous through the cornea to the tear film. This direction
of flow will continue as long as evaporation maintains the hypertonicity of
the tear film. Osmotic pressure is sensitive to changes in tear flow. Reflex
stimulation of tears in early adaptation to contact lenses results in a decrease
in electrolytes and in total protein leading to hypotonicity. This relative
hypotonicity may account for the corneal edema often seen in early stages
of contact lens wearing.
Other Physical Properties of Tear (Table 1.2)

• Refractive index—1.357
• Tear volume—0.50-0.67 g/16 hr (waking).
CHEMICAL COMPOSITION OF TEAR FLUID

The chemical composition Table 1.2 of tear fluid is quite complex. The first
chemical analysis of tears was studied in 1791 by Fourcroy and Van Que Lin
Fleming (1922) and Ridley (1934) demonstrated the detailed chemical
composition of normal tears.
Immunoelectrophoretic studies have shown that tears contain lipids,
proteins, enzymes, metabolites, electrolytes and hydrogen ions, etc.
Lipids
Lipids are present in small amount in tears as they are contained only in the
very thin superficial lipid layer of the tear film. Chromatographic studies of
meibomian lipids reveal the presence of all possible lipid classes mainly waxy
esters, hydrocarbons, triglycerides, cholesterol esters and in lesser amount
diglycerides, monoglycerides, free fatty acids, free cholesterol and
phospholipid. However, great individual variations occur in lipid composition.
Cholesterol
Cholesterol has been reported to be present in tear fluid in concentrations of
about 200 mg% which is same as in the blood. Like all lipids in biological
fluids cholesterol has to be transported by α and β lipoproteins. In normal
tears the very low protein content and the absence of lipoproteins is
incompatible with a cholesterol concentration of 20 mg%.
Proteins
About 60 components to tear protein fraction have been reported which
form the first line of defense against an external infection and seen to be
more effective than systemically produced antibodies. The protein content
of tears differ from that of blood plasma in several respects. Proteins can be
divided in two groups.
Group A: Proteins which are similar to serum proteins with a low concentration
representing less than 15% of all tear proteins. Some of them are always
present in tears. Table 1.3 namely albumin, IgG, α-L antitrypsin, transferrin,
α-L antichymotrypsin and β-2 microglobulin others which appears
sporadically are ceruloplasmin, haptoglobin and Zinc α-2 glycoprotein.
Group B: Specific proteins synthesized by tear gland are RMP (rapid migration
protein) and some other proteins (Tables 1.4 and 1.5) which are also present
in other external secretions (lysozyme, lactoferrin and IgA).
TABLE 1.3: Amino acid composition of human tear lysozyme
Amino acids Residues
(gm/100 g protein)
Aspartic acid 13.23
Arginine 13.05
Glutamic acid 8.55
Tryptophane 6.89
Alanine 6.36
Leucine 6.11
Trypsin 5.65
Glycine 4.94
Lysine 4.92
Valine 4.62
Serine 4.02
Half-cysteine 4.01
Threonine 3.67
Isoleucine 3.59
Phenylalanine 1.97
Proline 1.72
Methionine 1.50
Histidine 1.01
TABLE 1.4: Relative quantity of various protein fractions in tears

Fractions Normal tears Stimulated flow
(Percentage) (Tears) Percentage
Albumin 58.2 20.2
Globulin 23.9 56.9
Lysozyme 17.9 22.9
TABLE 1.5: Origin of various tear protein fractions

Protein Lacrimal Accessory Goblet
fraction gland proper lacrimal gland cells
Lysozyme + — —
Component-I — + +
Component-II + + +
Component-III + + +
Serum albumin — — +
Tear albumin + — —
Mucin — — +
+ means fraction is present
— means fraction is absent
+ Means fraction is indifferently present
Tear Albumin
Albumin represents about 60% of the total protein in tears as it does in
plasma. Tear albumin is a unique protein fraction. It is electrophoretically a
prealbumin and migrates to a position similar to serum prealbumin. Genetic
polymorphism has been reported of the tear albumin.
Electrophoresis of tears shows several peaks of migration. These peaks
are main which correspond to proteins synthesized by the lacrimal gland—
rapid migrant proteins and lactoferrin migrating to the anode and lysozyme
migrating to the cathode.
The total tear proteins content strongly depends upon the method of
collection of tears. Small unstimulated tears show levels of about 20 mg/ml
while stimulated tears show much lower values in the range of 3 to 7 mg/ml
reflecting the level of lacrimal gland fluid.
Lysozyme
Fleming first discovered an antibacterial substance and showed that this
substance is an enzyme which he named lysozyme because of its capacity to
lyze bacteria. In normal tears concentration of lysozyme is much higher than
in any other body fluid. The normal level for human tear lysozyme (HTL) is
1 to 2 mg/ml. The enzymic activity of lysozyme is optimal at pH 5.2 and
decreases above and below this pH value.
Lysozyme is a long chain, high molecular weight proteolytic enzyme
produced by lysosomes—a known cellular ultra structure. Lysozyme acts
upon certain bacteria and dissolves them by cleaning the polysaccharide
component of their cell walls. As the function of cell wall in bacteria is to
confer mechanical support a bacterium devoid of its cell wall usually bursts
because of the high osmotic pressure inside the cell.
Lysozyme level in tears can be measured with a diffusion method or with
a spectrophotometric assay.
In addition to lysozyme, presence of other antibacterial factors in human
tears have been shown. The nonlysozymal bactericidal protein beta lysin has
been reported to be derived chiefly from platelets but it exists in higher
concentration in tears than in blood plasma. The lysozyme and beta lysin
protein fractions can be separated by filtering the tears. The antibacterial
activity of the filtrate results from lysozyme but in whole tears beta lysin is
responsible for three-fourth of the bactericidal effect. Beta lysin acts primarily
on cellular membrane while lysozyme dissolves bacterial cell walls.
The action of lysozyme depends on the pH. The optimum pH for lysis
varies with the solubility of the bacterial proteins but in general it ranges
between 6.0 and 7.4. Low salt concentrations favor lysis by increasing
solubility.
Human tear lysozyme (HTL) levels have been shown to be greatly
decreased in tears of patients suffering from Sjögren’s syndrome and ocular
toxicity from long-term use of practolol therapy thus making it a useful
diagnostic aid. Other disease states where HTL level is lowered include herpes
simplex virus infection and malnutrition in children.
Lactoferrin
It is an iron carrying protein and appears to be a major tear protein in the
intermediate fraction. Its property of iron binding (Fe III) is 300 times stronger
than the other iron binding protein (transferrin). This is probably significant
for its bacteriostatic activity in tears making essential metal ions unavailable
for microbial metabolism.
Transferrin
Transferrin has been shown to be present in tears. Transferrin along with
serum albumin and IgG can be detected only after mild trauma to the mucosal
surface of the conjunctiva or in tears.
Ceruloplasmin
Ceruloplasmin, a copper carrying protein is regularly found in tears. In
electrophoresis the migration rate of tear ceruloplasmin varies from its serum
counter part.
Immunoglobulins
Tiselius (1939) for the first time separated the plasma proteins by
electrophoresis and isolated three types of globulins—alpha, beta and gamma.
Antibody property of the immune serum resides in the gamma globulin
fraction. Immunoglobulins are elaborated by plasma cells following
transformation of antigen stimulated B-lymphocytes. This elaboration
constitutes the humoral immune system.
Five major classes of immunoglobulins have been recognized (Table 1.6).
These are:
TABLE 1.6: Immunoglobulin levels in tear and serum

Ig class Tears Serum
Total proteins 800 mg/100 ml 6500 mg/100 ml
IgA 14-24 mg/100 ml 170-200 mg/100 ml
IgG 17 mg/100 ml 1000 mg/100 ml
IgM 5-7 mg/100 ml 100 mg/100 ml
IgE 26-250 μg/ml 2000 μg/ml
Immunoglobulin A (IgA)
Immunoglobulin G (IgG)
Immunoglobulin M (IgM)
Immunoglobulin E (IgE)
Immunoglobulin D (IgD)
Immunoglobulin A (IgA): It is the major immunoglobulin present in tears,

saliva and colostrum. Almost all of the IgA have a secretory component
attached to them when they occur in external secretions. It participates in the
functioning of IgA as antibody in the external environment. The possible
functions of secretory IgA include prevention of viral and bacterial infections
that may have an access to the external secretions, e.g. tears and participate
as opsonins in the phagocytosis process.
The average levels of IgA—the predominant immunoglobulin in normal
human tear is 14 mg/dl.
In the human lacrimal gland, IgA appears to be synthesized by interstitial
plasma cells and after entry into the intercellular spaces it is coupled to SC
and secreted as secretory IgA (IgA-SC) through the blood-tear barrier involving
intracellular transport by acinar epithelial cells into the lumens. In the
conjunctiva IgA and plasma cells are located in the substantia propria. Only
in the acinar epithelium of the accessory lacrimal glands can SC material be
present indicating that these are the sites of synthesis of secretory IgA of the
conjunctival secretions. Depending upon the method of tear collection IgA
values can vary from 10 to 100 mg%.
Immunoglobulin G (IgG): It is present in very low concentrations in normal

tears. However, after mild trauma to the mucosal surface of the conjunctiva
it can be easily detected.
IgG is the most prominent circulating (serum) immunoglobulin present
in concentrations five times that of IgA. The average level of IgG in normal
human tears range from 17 to 20 mg/100 ml.
The serum level of IgG is about 1000 mg/dl. IgG molecule has a molecular
weight of about 150,000. Each molecule of IgG consists of 2 L chains and 2
H chains linked by 20-25-S-S bonds. The antigenic analysis of IgG myelomas
show four subclasses now termed as IgG1, IgG2, IgG3, and IgG4,. IgG1 is the
predominant variant and together with IgG3 possesses the ability to combine
with complement to bind to macrophages and to cross the placenta. IgG
synthesis in humans is about 35 mg/kg/d and its half-life is about 23 days.
IgG molecules are Y-shaped with a hinge region near the middle of the
heavy chain connecting the 2 Fab segments to the Fc segment.
During the secondary response, IgG is the major immunoglobulin to be
synthesized probably because of its small size, IgG diffuses more readily than
other immunoglobulins into the tears, therefore as the predominating
immunoglobulin it carries the major burden of neutralizing bacterial toxins
and of binding to microorganisms (specially streptococci, pneumococci and
staphylococci) to enhance their phagocytosis. IgG is most efficient in killing
and stopping the progress of microorganism’s invasion.
Immunoglobulin M (IgM): It is present in very low concentrations in normal
tears. The average level of IgM in normal tears range from 5 to 7 mg%.
Barnett (1968) reported first the presence of IgM in normal tears.
The serum level of IgM is about 100 mg/dl. The IgM molecule with a
molecular weight 900,000 is the largest of the immunoglobulins. Often referred
to as macroglobulin because of its size, the IgM molecule are pentamers with
a high valency or anticombining capacity. Due to its high valency IgM is
extremely efficient agglutinating and cytolytic agent and is the first type of
antibody which is formed after the initial encounter with antigen. It appears
early in response to infection and is confined mainly to the bloodstream.
Even minimum trauma to conjunctiva would cause serum proteins to
leak into the tears. There is increased concentrations of IgA, IgG and IgE in
tears. Either these immunoglobulins are selectively excreted into the tears or
they are locally synthesized. Increased concentrations of IgA, IgG and IgM
are reported in cases of blepharoconjunctivitis, herpes keratitis, vernal
conjunctivitis, acute follicular conjunctivitis, phlyctenular conjunctivitis,
keratomalacia, corneal ulcer and acute endogenous uveitis.
Immunoglobulin E (IgE): It is mostly extravascular in distribution. IgE values

ranges from 26 to 144 μg/ml in normal tears. Normal serum contains only
traces of IgE but greatly elevated levels are seen in atopic conditions.
Immunoglobulin D (IgD): IgD levels are quite low in tears as well as in serum.
It is mostly intravascular.
Complement
Complement in tears has been shown in hemolytic assays up to dilution of
1.4 whereas serum is active in this system up to 1:32.
Glycoproteins
Glycoproteins are present in the mucoid layer as well as in the tear fluid since
they are highly soluble in water. Glycoproteins contribute significantly to the
stickiness of the material forming the mucoid layer. N-acetyeneuraminic acid
(a sialic acid) has been indentified in normal tears. Glycoproteins may play a
critical role in the lubrication of the corneal surface by rendering its
hydrophobic surface more hydrophilic permitting spreading and stabilization
of the tear film. The mucus is secreted by the conjunctival goblet cells as a
solution of glycoproteins (mucoids) and this sticky mixture adheres to the
surface of the epithelium even though the glycoproteins are water soluble.
The glycoproteins are carbohydrate-protein complexes characterized by
the presence of hexosamines, hexoses and sialic acid. In normal tears relative
hexosamine content of the protein which is used as indicator for glycoproteins
varies from 0.5 to 17%, the hexosamine concentration from 0.05 to 3 g/l.
Sialic acid concentration of human tears has been reported to be 114 μmol/
100 ml.
Antiproteinases
Antiproteinases, inhibitors of proteinases are present in tears at levels much
lower than in plasma (Table 1.7).
TABLE 1.7: Antiproteinasis concentration in tears and plasma

Antiproteinasis mg percentage
Plasma Tears
α1-antitrypsin (α1at) 280 0.1-0.4
α1-antichymotrypsin 1.5
3.0
α1-antichymotrypsin 24 1.4
Inter-α-trypsin inhibitor 20 0.5
α2-macroglobulin 3
6
TABLE 1.8: Antimicrobial factors in tears

Compound Evidence
Lysozyme +
IgA +
IgG +
IgE +
IgM +
Complement +
Lactoferrin +
Transferrin +
Betalysin +
Antibiotic producing +
Commensal organism
+Present in normal tears.
+ Present in tears after stimulation (mild trauma to the conjunctiva).
These includes α1-antitrypsin, α1-antichymotrypsin, inter-α-trypsin

inhibitor and α2-macroglobulin. The source of-α1 antitrypsin is the lacrimal
gland while other antiproteinases originate from corneal and conjunctival
surfaces. In various inflammatory conditions of the eye the levels of α1-at
and α2-m in tear fluid are increased.
In bacterial and viral infections of the eye (Table 1.8) and in
corneal ulceration the levels of α1-at and α2-m in tear fluids are
increased. Using albumin as a marker protein there is evidence suggesting
that these two collagenase inhibitors are derived either from plasma by a
general increase in vascular permeability to proteins or they are produced
locally.
Metabolites
A number of metabolites have been reported to be present in normal human
tears. These include organic constituents of low molecular weight like glucose,
urea, amino acids and other metabolites like lactate, histamine, prostaglandins
and catecholamines.
Glucose
Glucose is present in minimal amounts of about 0.2 mmol/liter in tear fluids
of normal glycemic persons. This low concentration of glucose appear to be
insufficient for corneal nutrition. There is no definitive evidence that cornea
metabolizes glucose emanating from the tears.
It has been shown that some glucose in tears originates from the goblet
cells of the conjunctiva. There is corresponding rise in tear glucose level with
elevation of plasma glucose level above 100 mg%. However, there is no
significant rise in tear glucose levels in diabetics with blood glucose level of
more than 20 mmol/liter which demonstrates the barrier function of the
corneal and conjunctival epithelium against loss of glucose from the tissues
into the tear fluid. It is the tissue fluid which contributes to the tear glucose
after mechanically stimulated methods of tear collection.
Urea
Urea concentration in tear fluid and plasma have been found to be equivalent
suggesting an unrestricted passage through the blood-tear barrier in the
lacrimal gland. Urea concentration in tears decreases with increasing secretion
rate.
Amino Acids
Free amino acid concentration in tears is reported to be 7.58 mg/100 ml.
This value is 3 to 4 times higher than the free amino acid concentration in
serum.
Lactate
Lactate levels of 1 to 5 mmol/l in tears are far higher than the normal blood
levels of 0.5 to 0.8 mmol/l. Pyruvate from 0.05 to 0.35 mmol/l is about the
same as is normal for blood (0.1-0.2 mmol/l). These levels do not show
significant alterations after mechanical irritation. The epithelium does not
possess a barrier function for lactate and pyruvate.
Histamine
Histamine is present in normal tears collected from the conjunctival sac at a
level of about 10 mg/ml. In vernal conjunctivitis specifically a variable increase
up to 125 mg/ml has been observed.
Prostaglandins
Prostaglandins are present in normal tears at the level of 75 pg prostaglandin
F/ml and it is little lower than in serum. In inflammatory conditions of the eye
significant higher values are found up to 300 pg/ml of tears.
TABLE 1.9: Human tear electrolytes
Concentration in mmol/l
Na+ K+ Ca++ Mg++ Cl— HCO3—
Tears 120-170 6-26 0.5-1.1 0.3-0.6 118-138 26
145 24 0.4-1.1 0.5-1.1 106-130
134-170 26-42 0.3-2.0 120-135
Serum 140 4.5 2.5 0.9 100 30
Catecholamines, Dopamine, Noradrenaline and Dopa

Catecholamines, dopamine, noradrenaline and dopa have been found in
the tear fluid. The levels vary from 0.5 to 1.5 mg/ml. Dopamine has values
as high as 280 mg/ml.
In glaucoma patients lower values have been reported for these
compounds which reflect the diminished activity of the sympathetic innervation
of the eye. The determination of catecholamines in tears has been advocated
as a test in glaucoma diagnosis.
Electrolytes and Hydrogen Ions

The predominant positively charged electrolytes (cation) in tears are mainly
sodium and potassium while the negative ions (anions) are chloride and
bicarbonate (Table 1.9).
Sodium
Sodium concentration in tears 120 to 170 mmol/liter is about equal to
that in plasma suggesting a passive secretion into the tears. While potassium
with an average value of about 20 mmol/l is much higher than the corres-
ponding plasma concentration of about 5 mmol/l. This indicates an active
secretion of potassium into the tears. It is interesting to observe that while the
main cationic constituent of the aqueous and vitreous humor is sodium while
cornea (mainly corneal epithelium) contains a much higher concentration of
potassium than sodium. These two cations play an essential role in the osmotic
regulation of the extracellular and intracellular spaces and in general changes
in sodium level are the reverse of changes in potassium level.
Calcium
Calcium is independent of the tear production and is lower than the free
fraction of plasma. In cystic fibrosis patients have much higher calcium values.
An average of 2.5 mmol/l have been shown only at slow rates concomitant
with lower tear sodium values.
Magnesium
Magnesium in tears is little lower than corresponding serum value possibly
reflecting the free fraction of magnesium. Both calcium and magnesium play
a role in controlling membrane permeability.
Chloride
Chloride, an anion essential to all tissues also plays an important role in
osmotic regulation much like sodium and potassium. The chloride
concentration is slightly higher in tears than in serum.
Bicarbonate
The bicarbonate together with the carbonate ions in tears may be involved
in the regulation of pH. This buffer system maintains the near neutral pH of
the tear film, the surface of which is exposed to atmospheric changes.
Enzymes
Enzymes of Energy Producing Metabolisms
Glycolytic enzymes and enzymes of tricarboxylic acid cycle can be detected
in high values only in human tear samples. These enzymes form a blood-
tear barrier against penetration from the blood. The source of these enzymes
is in the conjunctiva where they are secreted in small amounts. The lacrimal
gland apparently does not secrete these enzymes. These enzymes can be
obtained during mechanical irritation.
Lactate Dehydrogenase
Lactate dehydrogenase (LDH) is the enzyme in the highest
concentration in tears. It can be separated electrophoretically into its five
isoenzymes showing a pattern with more of the slower migrating muscle type
isoenzymes. This is closely related to the distribution pattern of corneal tissue
in contrast to serum LDH where the faster migrating heart type isoenzymes
prevail.
These findings indicate that tear LDH originates from the corneal
epithelium. Therefore, in patients suffering from corneal disease, the
distribution of LDH isoenzymes in tears differs from those found in healthy
individuals. LDH isoenzymes bound to immunoglobulin have been found in

blood and it is probable that here an analogous binding takes place in tears.
Lysosomal Enzymes
Lysosomal enzymes include a number of lysosomal acid hydrolases which
are present in tears in concentration of 2 to 10 times than those in serum.
The lacrimal gland is the main source of the lysosomal enzymes but
conjunctiva may act as a second source for lysosomal enzymes after
mild trauma. The relative high values are found in tear fluid collection
where the epithelial cells of conjunctiva remain intact and contain very low
levels of lactate dehydrogenase or other cytoplasmic enzymes. Lysosomal
enzyme activities in tears are used for diagnosis and identification of carriers
of several inborn errors of metabolism.
The concentration of β-hexosaminidase in tears collected on filter paper
strips is an index for the development and prognosis of diabetic retinopathy.
The tears would reflect the decreased enzyme activity of β-hexosaminidase
and of other lysosomal glycosidases in the retina showing a negative correlation
with the increased plasma levels of these enzymes.
Amylase
Amylase is the enzyme present in tear fluid in relatively moderate levels. The
origin of this enzyme is in lacrimal gland. The reported presence of amylase
in the cornea might be due to contamination by tear fluid.
Peroxidase
Peroxidase (POD) is present in human tears originating from the lacrimal
gland and not from the conjunctiva. The level of tear POD in human tears is
103 μ/l. POD activity found in the conjunctiva is probably derived from the
tears.
Plasminogen Activator
Plasminogen activator has been demonstrated in tear fluid and corneal epithe-
lium is suggested to be the source of this urokinase-like fibrinolytic activity.
Collagenase
Collagenase has been shown to be present in tear fluid in the presence of
corneal ulceration, due to infection, chemical burn, trauma and desiccation.
Corneal collagenase is present as an inactive precursor “latent collagenase”

which can be activated with trypsin and in vivo possibly by plasmin resulting
from plasminogen activator activity in tears.
Drugs Excreted in Tears

Tears represent a potentially more stable body fluid of low protein content
and with modest variations of pH. Passage of drugs from the plasma to the
tears apparently takes place by diffusion of the non-protein bound fraction.
However, presence of tight junctions between the acinar epithelial cells in the
lacrimal gland forming a blood-tear barrier, the lipid solubility is expected to
play a major role. The blood-tear barrier shows the same characteristics as
that of cell membrane. Phenobarbital and carbamazepine are excreted in
tears in about 0.5% of corresponding plasma concentration.
Methotrexate, an antimetabolite reaches tear levels of 5% of the
corresponding plasma concentrations and is in equilibrium with the unbound
fraction in plasma. Ampicillin is present in tears in concentration of about
0.02 of the corresponding serum level.
APPLIED PHYSIOLOGY
Basic secretion of tear fluid is made up of the secretions of the lacrimal gland
and accessory lacrimal gland tissue together with the secretions of meibomian
glands and the mucous glands of the conjunctiva. Reflex secretions of tears is
hundreds time greater than basal or resting secretion. The stimulus to reflex
secretions appears to be derived from the superficial corneal and conjunctival
sensory stimulation as a result of tear break up and dry spot formation. The
secretory stimulus to the lacrimal glands is parasympathetic with reflex
secretions occurring in both eyes following superficial stimulation of one eye.
The whole mass of lacrimal tissue responds as one unit to reflex tearing.
Reflex secretion is reduced by topical corneal and conjunctival anesthesia.
HYPOSECRETION OF TEARS
Hyposecretion means decreased formation of tears.
Lacrimal hyposecretion may be congenital although not very common.
Acquired lacrimal hyposecretion may be due to:
• Atrophy and fibrosis of lacrimal tissue due to a destructive infiltration by
mononuclear cells as in keratoconjunctivitis sicca and Sjögren’s syndrome.
• Local inflammatory diseases of the conjunctiva commonly conjunctival

scarring secondary to bacterial or viral infection.
• Chronic inflammatory disease of the salivary and lacrimal glands (Mikulicz’s
syndrome).
• Damage or destruction of lacrimal tissue by granulomatous (sarcoidosis),
pseudotumor or neoplastic lesions.
• Absence of lacrimal gland.
• Blockage of excretory ducts of the lacrimal gland.
• Neurogenic lesions.
• Meibomian gland dysfunction.
Diagnostic Tests for Tear Hyposecretions (Table 1.10)

Tear Film Break-up Time (BUT)
The tear film break-up time is a simple physiological test to assess the stability
of the precorneal tear film. This test is performed by instilling fluorescein into
the lower fornix, taking precaution not to touch cornea. The patient is asked
to blink several times and then to refrain from blinking. The tear film is
scanned with a broad beam and cobalt blue filter. After an interval of time
black spots or line indicating dry spots appear in the tear film. BUT is the
interval between the last blink and appearance of the first randomly
distributed dry spot. Ideally average of three measurements is taken. A
normal BUT is more than 10 seconds and a BUT of less than 10 seconds is
considered abnormal. This test may also be abnormal in eyes with mucin or
lipid deficiency.
TABLE 1.10: Diagnostic tests and drug assays in tears

Compound Diagnosis Usefulness
Lysozyme Sjögren’s disease +
Practolol induced toxicity +
Traumatic inflammation of eye +
Lysosomal enzymes Lysosomal storage disease +
Collagenase Corneal ulceration +
α1-Antitrypsin Bacterial infections +
Glucose Diabetes mellitus +
Tear albumin Genetic marker +
Immunoglobulins Iatrogenic inflammation +
(IgA, IgG and IgM) of anterior-segment
+ Useful
+ Comparatively useful
FIGURE 1.6: Modified Schirmer’s test
Schirmer’s Test
The rate of tear formation is estimated by measuring the amount of wetting
on a special filter paper which is 5 mm wide and 35 mm long (Figure 1.6).
Previously Schirmer’s test 1 and 2 were used in diagnostic practice but
nowadays modified Schirmer-I test is employed. This test is performed as
follows.
Schirmer strips are prepared by cutting out Whatman filter paper No. 41
into the strips of 5 mm × 35 mm dimensions. A 5 mm tab is folded over at
one end. Before use, these strips are autoclaved.
The bent end is placed into lower conjunctival sac at the junction of lateral
one-third and medial two-third of the lower eyelid so that a 5 mm bent end
rests on the palpebral conjunctiva and the folding crease lies over the eyelid
margin. This test is usually performed in sitting posture in dim light.
The patient is asked to keep the eyelid open and look slightly upwards at
a fixation point. Blinking is allowed while the patient gazes at the fixation
point.
After one minute, the strips are carefully removed and moistening of the
exposed portion of the strip is measured in millimeters with the help of a
millimeter ruler.
The measurements are made from the notch at the bend of the Schirmer
strip to the distal end of the wetting on the strip (excluding the folded over
tab). The amount of wetting of the Schirmer strip in one minute is multiplied
by three to correspond roughly to the amount of wetting that would have
occurred in five minutes (Jones, 1972). It is a measure of the rate of tear

secretion in a five-minute period.
A normal eye will wet between 10 to 25 mm during that period.
Measurements between 5 and 10 mm are considered borderline and values
less than 5 mm is indicative of impaired secretion.
Vital Dye Staining

• Rose Bengal 1% has an affinity for devitalized epithelial cells and mucus in
contrast to fluorescein which remains extracellular and is more useful in
showing up epithelial defects. Rose Bengal is very useful in detecting even
mild cases of keratoconjunctivitis sicca (KCS) by staining the interpalpebral
conjunctiva in the form of two triangles with their base at the limbus.
The only disadvantage with Rose Bengal staining is that it may cause
ocular irritation specially in eyes with severe KCS. In order to reduce that
amount of irritation only a small drop should be instilled into the eye. A
topical anesthetic should not be used prior to the instillation of Rose Bengal
as it may produce a false-positive result.
• Alcian blue has similar properties as Rose Bengal and is less irritant but it
is not generally available.
Lysozyme Assay
Lysozyme assay is based on the fact that in hyposecretion of tears, there may
be reduction in the concentration of lysozyme. This test is performed by placing
the wetted filter strip into an agar plate containing specific bacteria. The plate
is then incubated for 24 hours and the zone of the lysis is measured. The zone
will be reduced if the concentration of lysozyme in the tears is decreased.
Tear Globulin Assay

Tear IgA levels are measured in this test. This test is also based on the principle
that decreased tear formation will lead to decreased IgA (immunoglobulin
A) levels in tears. This test is performed on a specific tripartigan immuno-
diffusion plates containing specific agar gel in wells (Figures 1.7 and 1.8).
20 μl of tear samples is put into these wells and plates are incubated for 48
hours. The diffusion of rings around wells are measured to the nearest 0.1
mm with a partigen ruler. The ring will be reduced if the concentration of IgA
in tears is decreased. This is a reliable test for measuring tear globulins.
FIGURE 1.7: Tear globulin assay (diagnostic test)
FIGURE 1.8: Tripartigen immunodiffusion plates

(diffusion of rings around agar wells is measured up to
0.1 mm)
Tear Osmolarity
Tear osmolarity is increased in cases of hyposecretion.
Biopsy of the Conjunctiva

Biopsy of the conjunctiva and an estimation of the number of goblet cells are
other tests which can be done. In mucin deficiency states the number of
goblet cells shall be decreased.
HYPERSECRETION OF TEARS
In practice when patient complains of a wet eye there are two possibilities of
excessive watering of the eye.
• Lacrimation from reflex hypersecretion due to irritation of cornea and
conjunctiva.
• Obstructive epiphora as a result of failure of tear drainage or evacuation
system. The main causes are lacrimal pump failure due to lower lid laxity
or weakness of the orbicularis muscle and more commonly due to
mechanical obstructions of the drainage system.
If the wet eye is caused by hypersecretion the Schirmer’s test values
(technique already mentioned) will be increased and the Jones Fluorescein
dye test will reveal normal outflow function.
Physiological Diagnostic Test for Hypersecretions

Jones I (Primary) Test
This is a physiological test which differentiates an excessive watering due to a
partial obstruction of the lacrimal passages from primary hypersecretion of
tears (Figure 1.9).
In this test 1 drop of 2% fluorescein solution is instilled into the conjunctival
sac. After about 5 minutes a cotton-tipped bud or applicator (moistened in
coccaine 4% or proparacaine 0.75%) is inserted under the inferior turbinate
at the nasolacrimal duct opening. This is situated about 3 cm from the external
nares.
The results are interpreted as follows.
• If the fluorescein is recovered from the nose on the applicator and aqueous
solution passes from the conjunctival sac to the nose in 1 minute then the
excretory system is patent and cause of watering is primary hypersecretion.
No further tests are required then and the test is inferred as positive.
FIGURE 1.9: Dye testing: Jones primary test (top) and Jones
secondary test (bottom) (Courtesy Kanski Clinical Ophthalmology
Butterworth International)
• If no dye is recovered from the nose a partial obstruction is present or

there is failure of the lacrimal pump mechanism. In this situation secondary
dye test or Jones II test is required.
Jones II (Secondary Irrigation) Test

This test helps to identify the probable site of partial obstruction.
In this procedure topical anesthesia (4% Xylocaine or 0.5% proparacaine)
is instilled into the conjunctival sac and any residual fluorescein is washed
out. The nasolacrimal system is then irrigated with normal saline. The patient
is positioned with his or her head down by about 45° so that the saline runs
out of the nose into white paper tissues and not into the pharynx.
This test is interpreted as follows.
• Positive—if fluorescein-stained saline is recovered from the nose, the dye
must have reached the lacrimal sac during the primary dye test but was
stopped from entering the nose by a partial obstruction in the nasolacrimal
duct. However, syringing of the lacrimal system had pushed the dye past
the obstruction into the nose. A positive secondary dye test indicates a
partial obstruction to the nasolacrimal duct which can be treated by a
dacryocystorhinostomy (DCR) procedure.
• Negative—if unstained saline is recovered from the nose it means that no

dye has entered the lacrimal sac during the primary dye test. This means
a partial obstruction in the upper drainage system (punctum, canaliculi
or common canaliculus) or a defective lacrimal pump mechanism. In
such a situation DCR would fail and some other operative procedure will
be required.
Fluorescein Dye Disappearance Test

An accurate status of the excretory capability of the lacrimal system can be
obtained by observing the behavior of a single drop of 2% fluorescein solution
instilled into the inferior conjunctival cul-de-sac. The color intensity after 5
minutes is measured and graded on a scale of 0 to 4+. The normal excretion
of the retained fluorescein shall be 0-1+. Any greater residual then is indicative
of impaired outflow. However, by this test one cannot distinguish between
impairment of the upper and lower segments of the system, but it may
complement the Jones tests.
• Nasal examination should be performed in order to determine the position
of normal nasal structures specially the position of the anterior end of the
middle turbinate when surgery is contemplated. It will also detect the
presence of polyps or tumors, etc.
Special Tests
Intubation Dacryocystography
The conventional method of dacryocystography consists of injecting contrast
medium into one of the canaliculi followed by the taking of posteroanterior
(PA) and lateral views, radiographs. However, far superior status of the
canalicular system can be obtained by using a technique that combines
injection of lipoidol ultra fluid through a catheter with macrography. In
common canalicular lesions, subtraction macrodacryocystography may
provide more sophisticated details.
These specific investigations are not only extremely valuable in depicting
the exact location of the obstruction but they are also of help in the diagnosis
of diverticula, fistulae, filling defects due to tumors, stones and infections by
streptothrix species.
Scintillography (Radionuclide Testing)

This test involves the labeling of tears with gamma-emitting substances such
as technetium-99m and monitoring their progress through the drainage
system. This is a sophisticated and reliable test for better understanding of

excretory physiology.
Color Doppler Scanography

Color Doppler scanography is the latest technique for evaluating the status
of the drainage system. It is a recently introduced test with accurate results.
ETIOPATHOGENESIS AND CLASSIFICATION OF DRY EYE 33
DEFINITION
Dry eye is condition produced by the inadequate inter-relation between
lacrimal film and ocular surface epithelium.
Dry eye is a general term used to describe a heterogeneous group of
diseases resulting from inadequate wetting of the cornea and conjunctiva by
the precorneal tear film (PCTF). Millions of people worldwide suffer from
dry eye.
TEAR FILM
The pre-corneal tear film consists of three layers mainly (Figure 2.1):
1. Lipid.
2. Aqueous.
3. Mucin.
FIGURE 2.1: Normal layers of the tear film
Outer Lipid Layer

The outer layer is secreted by the meibomian glands and glands of Zeiss.
Their function is:
i. To reduce the evaporation of the aqueous layer.
ii. To increase the surface tension and assist in vertical stability of the tear
film.
iii. To lubricate the eyelids.
Middle Aqueous Layer

The middle layer is secreted by lacrimal glands and has following functions:
i. To supply atmospheric oxygen to the avascular corneal epithelium
ii. Anti-bacterial functions.
iii. To reduce the irregularities of the anterior corneal surface
iv. To clean away the debris.
Inner Mucin Layer

The inner layer is secreted by the conjunctiva goblet’s cells, crypts of Henle
and glands of Manz.
It converts the corneal epithelium from hydrophobic to hydrophilic
state.
Factors responsible for good resurfacing of the corneal epithelium are:
i. Normal blink reflex
ii. Congruity between external corneal surface and eyelids
iii. Normal corneal epithelium.
The ability of the tear film to form a continuous covering over the cornea
and conjunctiva depends on the adhesion energy between the tear film and
the epithelial surfaces.
ETIOLOGY
Aging
The most common cause of severe dry eye is the normal aging process.
Aging is directly associated with a reduction in lipid production, resulting
in evaporative dry eye. Over time, your body produces less oil – 60% less at
age 65 than at age 18. With less oil to seal the watery layer, the tear film
evaporates much faster, leaving eyes feeling dry, gritty, and irritated.
The incidence of severe dry eyes over the age of 65 years is around
75%.
Excessive Use of Contact Lens

Dry eye is the most common complaint amongst contact lens wearers.
Contact lenses absorb the tear film, and rub against the conjunctiva in
the eyelids, which may cause or exacerbate dry eye. Long-term contact lens
wear may decrease epithelial nerve sensation, which would reduce the stimulus
to produce more tears (Figure 2.2).
FIGURE 2.2: Giant papillary conjunctivitis

(Courtesy Online Journal of Ophthalmology)
Systemic Diseases
• Parkinson’s disease
• Sjögren’s syndrome (an autoimmune disease)
• Autoimmune diseases (lupus, rheumatoid arthritis, Sjögren’s)
• Rheumatoid arthritis
• Lupus
• Lacrimal gland deficiency
• Diabetes
• Sarcoidosis
• Stevens-Johnson syndrome (Figure 2.3)
• Rosacea: Facial rosacea is commonly associated with ocular rosacea, which
causes conditions such as blepharitis.
FIGURE 2.3: Stevens-Johnson syndrome

(Courtesy Kanski Textbook of Clinical Ophthalmology)
FIGURE 2.4: Rosacea keratitis

Eye Injuries, Eye Surgeries

• Chemical burns (Figure 2.5)
• Laser refractive surgery, particularly LASIK which severs or ablates more
nerves than any other refractive surgery.
FIGURE 2.5: Chemical burns

Eyelid Conditions or Anatomical Features

1. Conditions which cause too much exposure of the eyes to the air (Figure
2.6):
• Incomplete closure of the lids.
• Droopy eyelid
• Bulging eye
2. Conditions resulting in tears not spreading over the eye surface adequately:
• Proptosis
• Ectropion
• Entropion
• Nocturnal Lagophthalmos
• Bell’s palsy
• Pterygium/Pingecula
• Conjunctivalchalsis
FIGURE 2.6: Trachoma

3. Conditions inhibiting the production of the lipid layer of the tear film,
resulting potentially in evaporative dry eye:
• Blepharitis
• Ocular rosacea (thought to be present in up to 75% of perimenopausal
women with facial rosacea)
• Meibomian gland dysfunction
• Climate and other environmental factors.
Outdoors and indoors, humidity levels, wind, and presence of irritants

can contribute to dry eye symptoms:
• Hot, dry and/or windy climates
• High altitudes
• Excessive sun exposure

• Central heating
• Air conditioning
• Hair dryers
• Cigarette smoke
• Air pollution
• Air travel
Hormonal Changes
• Thyroid conditions
• Hormonal changes during menopause
• Decreased production of androgen
• Estrogen supplementation.
Reduced Blinking
Blinking is a critical function in spreading tears over the eye surfaces and
stimulating tear production. A chronic low blink rate is associated with dry
eye symptoms.
Excessive use of computers most commonly associated with a low blink
rate.It can lead to common condition known as Computer Vision Syndrome.
Computer use is believed to reduce the blink rate from 22 to 7 per minute.
Drugs
Many medications can cause or exacerbate dry eye symptoms.
• Allergy medications, especially antihistamines.
• Antidepressants (e.g. amitriptyline, diazepam).
• Parkinson’s medications
• Birth control pills
• Diuretics
• Beta blockers
• Sleeping pills
• Certain medications which regulate heart rhythm irregularities
• Decongestants.
Other Causes
• Radiation (orbit) therapy
• Smoking
• Vitamin A deficiencies
• Surgery: Bone marrow transplant head and neck surgery.
• Neurological conditions like Parkinson disease Bell’s palsy, Riley Day
syndrome.
PATHOPHYSIOLOGY
Tear Dynamics
The study of tear dynamics is important to understand the pathophysiology
of dry eye.
There are four steps involved in tear dynamics:
• Production of tears by lacrimal gland.
• Its distribution by blinking.
• Evaporation from ocular surface and
• Drainage through nasolacrimal duct.
Factors involving any of the above steps can lead to dry eye.
The pathogenesis of dry eye depends on various abnormalities that can
lead to in sufficient wetting of the corneal surface. These can be divided as:
• Abnormalities of the aqueous layer
• Abnormalities of the mucin layer
• Abnormalities of the lipid layer
• Abnormalities of the corneal epithelium
• Abnormalities of the lids.
Abnormalities of the Aqueous Layer

Insufficient production of the aqueous component of the tear film is the
most common cause of dry eye. The resulting condition, known as
keratoconjunctivitis sicca (KCS), is usually due to decreased tear production
by the accessory lacrimal glands. Inflammation of the lacrimal glands may be
accompanied by inflammation and drying of other mucous membranes,
present in the mouth, vagina, and/or respiratory tract.
Abnormalities of the Mucin Layer

Deficient production of mucin interferes with the even distribution (spreading)
of the tear film across the corneal surface, resulting in a very unstable and
uneven tear film with a rapid break-up time (BUT). Abnormalities in the
mucin layer of the PCTF often occur as a result of loss of the goblet cells of
the conjunctival epithelium.
Abnormalities of the Lipid Layer

When abnormalities in the lipid layer of the PCTF occur, deficiencies in the
lipid layer result in excessive evaporation of the aqueous component of the
tear film, which in turn leads to drying of the ocular surface.
Abnormalities of the Corneal Epithelium

Alterations in the normal morphology of the corneal epithelium can adversely
affect tear film stability. Infections and trauma resulting in corneal scars and
ulcerations can damage the microvilli, causing permanent dry spots. Damage
to the corneal surface can also result from exposure to certain drugs, including
many types of general anesthesia.
Abnormalities of the Lids

Eyelids play an important role in distribution of the tear film. Normal blinking
is essential to maintaining a healthy corneal and conjunctival surface. Thus,
anything that interferes with normal blinking, or anatomic abnormalities,
which interfere with the complete closure of the eyelids during blinking, can
result in drying of the ocular surface.
In dry eye there is an abnormal, nonlubricative ocular surface that
increases shear forces under the eyelids and diminishes the ability of the
ocular surface to respond to environmental challenges.
The ocular-surface dysfunction may result from systemic autoimmune
disease or may occur locally from a decrease in systemic androgen support
to the lacrimal gland as seen in aging. This is most commonly seen in post-
menopausal female.
There is also an underlying cytokine/receptor-mediated inflammatory
process involved.
Role of Androgens
Androgens play an important role regulating tear film secretion on to the
ocular surface.
Androgen deficiency plays an important role in pathogenesis of evaporative
dry eye in women with Sjögren’s disease.
It contributes to the meibomian gland dysfunction, tear film instability,
and evaporative dry eye, which are characteristic of this autoimmune disorder.
It is also associated with significant alterations in the neutral and polar
lipid patterns of human meibomian gland secretions.
Homeostasis of the tear film involves delicate hormonal and neuronal

regulatory mechanisms. Sex hormones, particularly the androgens modulate
the immune system and tropic functions of the lacrimal glands and the
functioning of the meibomian glands.
Role of Neural Pathway

The cornea, lacrimal glands, mucous cells, and meibomian glands are all
richly innervated, indicating the importance of nervous regulation in their
function.
Parasympathetic, sympathetic, and sensory innervations play complex
stimulatory or inhibitory roles. Abnormalities at any point in these pathways
can cause overall dysregulation of lacrimal function.
Whatever the initial cause of dry eye, chronic dryness of the ocular surface
results in inflammatory reactions and gradual destruction of the lacrimal glands
and conjunctival epithelium. Once dry eye disease has developed,
inflammation is the key mechanism of ocular surface injury, as both the
cause and consequence of cell damage.
CLASSIFICATION
The Madrid Triple Classification of Dry Eye
Dry eye clinically has various combinations of anatomo-pathologic
manifestations, and different grades of severity. In order to recognize these
parameters triple classification has been elaborated.
The features of the Madrid Triple Classification are:
A. The etiologic factors are divided in to ten groups: age-related, hormonal,
pharmacologic, immunopathic, hyponutritional, dysgenetic, inflammatory,
traumatic, neurodeprivative, and tantalic. Each of these groups comprises
many variants.
B. The anatomo-pathologic factors were named as ALMEN classification
from the acronym of Aqueodeficiency, Lipodeficiency, Mucodeficiency,
Epitheliopathy, and Non-ocular exocrine affectations.
C. The severity of the dry eye was divided in to five grades:

i. Sub-clinical (symptoms only when overexposure)
ii. Mild (habitual symptoms)
iii. Moderate (symptoms plus reversible signs).
iv. Severe (symptoms plus permanent signs), and

v. Disabling (all the above, plus visual incapacity).
Recent Triple Classification of Dry Eye for Practical Clinical Use

Dry eye is a condition which can be produced by one or combined etiologic
causes, affecting one or several of the secretions of the glands serving the
ocular surface, and producing secondary manifestations of different grades
of severity”. Clinicians need a practical classification to help in the diagnosis,
prognosis and treatment.
In 8th congress of the International Society of Dacryology and Dry Eye
(Madrid, April, 2005) the previous Triple Classification of dry eye approved
in the XIV congress of the European Society of Ophthalmology (Madrid,
June, 2003) was modified.
The following classification has been established:
A. Classification of the etiopathogenesis, distributed in ten groups: age-related,
hormonal, pharmacologic, immunopathic, hyponutritional, dysgenic,
infectious/inflammatory, traumatic, neurologic and tantalic.
B. Classification of the affected glands and tissues, which under the acronym
of ALMEN includes the Aqueo-serousdeficient, Lipodeficient,
Mucindeficient and Epitheliopathic dry eyes, and the Non-dacryological
affected exocrine glands (saliva, nasal secretion, tracheo-pharyngeal
secretion, etc).
C. Classification of severity, in three grades:
i. Grade 1 or mild (symptoms without slit-lamp signs),
ii. Grade 2 or moderate (symptoms with reversible signs), and
iii. Grade 3 or severe (symptoms with permanent signs).
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THE TRIPLE CLASSIFICATION OF DRY EYE FOR PRACTICAL CLINICAL USE 45
ABSTRACT
Clinicians need a practical classification to face diagnosis, prognosis, and treatment. Dry
eyes have many etiologies and pathogenesis, different affectation of the various
dacryoglands and ocular surface epithelium, and diverse grades of severity. The specialists
in xero-dacryology must know these three parameters to evaluate any case of dry eye, and
to establish an adequate treatment. To facilitate this, an open session in the VIII congress of
the International Society of Dacryology and Dry Eye (Madrid, April, 2005) proposed
modifying the Triple Classification of Dry Eye approved in the XIV congress of the European
Society of Ophthalmology (Madrid, June 2003). The following classification has been
established: first, a classification of the etiopathogenesis, distributed in 10 groups: age-
related, hormonal, pharmacologic, immunopathic, hyponutritional, dysgenic, infectious/
inflammatory, traumatic, neurologic, and tantalic; second, a classification of the affected
glands and tissues, which under the acronym of ALMEN includes the aqueoserous deficient,
lipo deficient, mucin deficient, and epitheliopathic dry eyes, and the non-dacryologic
affected exocrine glands (i.e. saliva, nasal secretion, tracheopharyngeal secretion); third, a
classification of severity, in three grades: grade 1 or mild (symptoms without slit lamp
signs), grade 2 or moderate (symptoms with reversible signs), and grade 3 or severe
(symptoms with permanent signs). (Eur J Ophthalmol 2005; 15: 660-7).
INTRODUCTION
Dry eye is a lexicon in common use among scientists, patients, and the general
population, which like any other word may have diverse, fluctuating, and
changing meanings. The term dry eye is usually referred to a symptom, a
sign, a syndrome, and many diseases. The scientific definition of the syndrome
of the several diseases is that “dry eye is a disorder produced by the inadequate
interrelation between lacrimal film and ocular surface epithelium, caused by
quantitative and qualitative deficits in one or both of them. It can be produced
by one or combined etiologic causes, affect one or several of the secretions
of the glands serving the ocular surface, and produce secondary manifestations
of different grades of severity.”
Dry eye is one of the most frequent ophthalmologic conditions. It can be
produced by hundreds of causes. Dry eye diseases are almost always chronic,
progressive, and until the present incurable. Usually they produce mild or
moderate manifestations, but in severe cases they provoke incapacitating
discomfort and severe low vision. The prevalence of dry eye syndrome is not
well-established as it changes with sex, race, geography, epoch, sociosanitary
levels, age, and severity. By using the two last variables (severity and age) it
is possible to calculate approximately that grade 1 is present in 1% of the
population under 30 years, 20% between 30 and 60 years, and 100% over
60 years. Grade 2 is present in 0.1% of people under 30 years, 1% between
30 and 60 years, and 10% over 60 years. Grade 3 is present in 0.002% of
persons under 30 years, 0.01% between 30 and 60 years, and 0.1% over
60 years. Women are usually more precociously affected than men.
The evolution of our knowledge on dry eye was at first slow, then it
became quicker, and it is at present, vertiginous. The historical evolution can
be divided into three eras: Hippocratic (from Hippocrates to the end of the
19th century), Sjögrenic (last years of the 19th century, and 20th century),
and 21st century. The limits among these three periods are not precise and
brusque, and the two connecting periods overlap in a progressive transition.
These three periods correspond approximately with the knowledge and
evidence of severe (classical xeropthalmia), moderate (keratitis punctata,
keratopathia filamentosa, keratoconjunctivitis sicca), and mild dry eye
(symptoms of dry eye without slit lamp signs).
During the transition years between Sjögrenic and 21st century periods
many etiopathogenetic causes and combinations, glandular affectations, and
severity manifestations of clinical combinations were discovered or became
better known. It was evident that a classification for practical clinical use was
necessary. Therefore, at the XIV Congress of the European Society of
Ophthalmology, held in Madrid in June 2003, it was decided that one of the
preferential tasks of xerodacryology was to make a classification for practical
clinical use. It was presented, discussed, decided, and published as the Madrid
Triple Classification of Dry Eye.1 Two years later the 8th Congress of the
International Society of Dacryology and Dry Eye took place in Madrid, in
April 2005, and it was decided to discuss and improve the previous
classification. The results are reported in the present article.
When a clinician receives, examines, and determines the characteristics
of any dry eye, he or she needs to know several characteristics throughout
the anamnesis and examination in order to elaborate a diagnosis, prognosis,
and treatment. For practical clinical use, dry eye should be expressed by
means of three parameters: etiopathogenesis, damaged exocrine glands and
tissues, and severity.
Classification According to the Etiopathogenesis

The many causes that can produce a clinical dry eye can be distributed for
practical clinical use in 10 groups (Table 3.1). The first five groups of this
etiopathogenetic decalogue generally, but not always, affect many exocrinic
TABLE 3.1: Etiopathogenetic classification of dry eye

Pan-exocrinic Dacryo-exocrinic
1. Age-related 6. Dysgenetic
2. Hormonal 7. Infectious/inflammatory
3. Pharmacologic 8. Traumatic
4. Immunopathic 9. Neurologic
5. Hyponutritional 10. Tantalic
glands (lacrimal, salivary, nasal, vaginal, etc.) because the damage is usually
produced in cellular structures common to exocrinic glands. The last five
groups usually only affect the dacryoglands (aqueoserous, lipid, mucinic),
or even only some of them, or even only those of one eye.
Age-related
With aging, all cellular structures of the body undergo a progressive apoptotic
process. This also affects all exocrinic glands, and consequently there is
presentation of a general dryness in the body, including the dacryoglands.
The lacrimal secretion begins to diminish from the age of 30 years, but as
there is an overabundance for the normal necessities, it is only noticed by
people in situations of overexposure. The critical level between production
and necessities is reached at about 45 years. Production decreases at about
60 years, when secretion becomes insufficient for the necessities of some
normal situations. Many persons over 60 feel symptoms or signs of dry eye
in circumstances such as late afternoon or at night when the circadian rhythm
of tear production is lower, when working for a long time in front of a video
display terminal (VDT) doing convergence in horizontality, when using contact
lenses, or in drafts or dry environment, as tear evaporation leads to an increase
in tear film osmolarity.
Age-related dry eye is usually multiexocrinic (eye, mouth, nose, tracheo-
pharynx, vagina, etc.). As to the severity, it is usually grade 1, but frequently
reaches grade 2.
Hormonal
Lacrimal secretion is influenced by some endocrine gland activity, the most
important of which are androgens, estrogens, and prolactin. Dry eye is
frequently a hormone-related condition in cases of aging, castration, anti-
androgenic treatment, hypo-ovarism, ovariectomy, climacteric, menopause,
estrogenic contraceptives, and lactation. Other hormones, such as insulin
and thyroxin/thyroxamine, have no consensus in the interpretation of their

action on dry eye.
Hormonal dry eye is generally multiexocrinic. Aqueoserous and lipid
secretions are the most affected. Severity usually reaches grades 1 or 2.
Pharmacologic
Some systemic medicines have a collateral exocrinic hyposecretory effect.
Among them are antidepressants (fluoxetine, imipramine), anxiolytics
(bromazepam, diazepam, clorazepate), sleeping pills (brotizolam,
chloralhydrate, chlomethiazole), antiparkinsonians (biperiden, benztropine),
diuretics (chlorthalidone, furosemide), vascular antihypertensives
(chlorothiazide clonidine), anticholinergics (atropine, metoclopramide),
antihistaminics (dexchlorpheniramine, cetirizine), and antiarrhythmics
(disopyramide, mexiletine). Some of these drugs are mainly taken by elderly
or menopausal people, or at night, when they can aggravate the multiexocrinic
dryness. Systemic pharmacologic dry eye is generally multiexocrinic, and is
usually grade 1 or 2 severity.
Some topical collyria and ointments produce damage of the corneal
epithelium, conjunctiva, or lid margin. Among these are some preservatives
(benzalkonium chloride, thiomersal, chlorobutanol, EDTA), anesthetics
(cocaine, tetracaine, proparacaine, lidocaine), and vitamin A derivatives
(topical or systemic isotretinoin). The damage is usually restricted to the ocular
surface and related structures when the application is local. Drug-induced
adverse effects are far from being restricted to only allergic reactions and the
long-term use of eye drops has consistently been reported to induce
inflammatory ocular surface changes, causing progressive ocular discomfort
upon instillation, tear film instability, corneal surface impairment, and
subconjunctival fibrosis.
Immunopathic
Some autoimmune diseases can produce eye dryness by damaging the
dacryoglands and/or ocular surface. There are several main groups of
immunologic dry eyes: 1) those preferentially affecting the glands, as occurs
with what were known until recently as primary Sjögren’s syndromes, in
which vasculitis by immunocomplex deposits and pseudolymphomas and
lymphomas are sometimes associated; 2) those affecting the exocrine glands
and the connective tissue as in rheumatoid arthritis, systemic lupus
erythematosus, dermatomyositis, scleroderma, etc. as occurs with what were

also known until recently as secondary Sjögren’s syndromes. Today it is
preferable to use the expression “Sjögren’s syndrome associated with …,” in
order not to confuse the many different varieties of Sjögren’s syndromes;
3) those where there is an autoimmune attack of the ectodermal and
mesodermal tissues and the secondary destruction of non-attacked glands,
as occurs in the mucus membrane pemphigoids, Lyell syndromes, Stevens-
Johnson syndromes, and CREST syndrome; 4) those affecting other tissues,
which secondarily can affect the exocrinic glands and ocular surface, such as
the pluriglandular endocrine deficiencies or Schmidt’s syndrome (thyroid
and adrenal insufficiency).
Immunopathic dryness is usually multiexocrinic. It affects about 1% of
the population. Sjögren’s syndromes frequently reach grades 1 and 2, and
occasionally, grade 3. But immunopathic dry eyes of group 3 frequently
reach grade 3, with permanent ocular surface damage and sometimes
definitive decreased visual acuity.
Hyponutritional
Hypovitaminosis A was the most frequent cause of severe xerophthalmia for
millennia. It produces multiexocrinic dryness and other ophthalmic
manifestations such as Bitot’s spots in the conjunctival exposed trigoni,
keratomalacia, blepharitis, and bad scotopic adaptation. It can be produced
by severe hyponutrition or by a selective fat-free diet. It may also be due to
the intestinal malabsorption associated with Crohn’s disease, chronic
alcoholism, and intestinal resection.
Lack of omega-3 essential polyunsaturated fatty acids (alpha-linolenic
acid, EPA, and DHA) available from dark oily fish such as salmon, sardine,
and tuna produces dry eye through mechanisms that are currently being
explored.
Other controversial deficiencies with respect to their influence in dry eye
are vitamins B2, B12, and C.
Xerophthalmia by hypovitaminosis A when treated in time retrogrades
without producing sequelae, but if not treated in time, it may produce corneal
blindness or even corneal melting.
Dysgenetic
In the evolution of the medical language genetic and congenital (from Greek
geneh, birth) were applied for centuries to conditions presented at birth.
They were due to hereditary parenteral transmission, or to intrauterine

exposure to infections, toxins, traumas, mechanical factors, or unknown causes.
When genes were discovered and understood in the 20th century, genetic
also took a second meaning: expressed by anomalous genes (even when
developed in the phenotype not at birth but in childhood, puberty, or later).
In the future terminology it seems that genetic and genic will be reserved for
hereditary diseases (expressed at birth or later on), and that congenital and
connatal will be the ones appearing at birth (by gene diseases or by accidental
occasional damage to the embryo or fetus). As the future terminology is not
yet precise, in this classification we consider dysgenetic to include all genetic
and congenital diseases.
Dysgenetic dry eye can affect one or several types of dacryoglands: aqueo-
serous (alacrima, dysplasia ectodermica anhidrotica), lipid (epicanthus-
blepharophimosis syndrome, keratopathy-ichthyosis-deafness syndrome, first
branchial arc syndromes, dysplasia ectodermica anhidrotica), and mucinic
(aniridia, Bietti syndrome), or the ocular surface epithelium (Meesmann
dystrophy, Fleischer cornea verticillata, Franceschetti-Cogan microcystic
dystrophy).
Infectious/Inflammatory
Infection (from Latin inficere, filled with noxious corruption or germs) is
today applied to the contamination of the body by harmful organisms.
Inflammation (from Latin flamma, flame) had a classical definition recorded
by Celsus in the 1st century: tumor, rubor, calor, et dolor (swelling, redness,
heat, and pain). Usually inflammation was due to infection. For the last two
centuries the term inflammation has been applied to mild conditions without
some of those signs. As it has recently been discovered that proinflammatory
mediators promoting reaction and healing are present in any corporal tissue
damage, the name of inflammation may be applied to new meanings, which
can result in confusion.
Infection/inflammation of the aqueoserous dacryoglands (tuberculous,
fungic) are at present very rare. Infection/inflammation of the lipid
dacryoglands (blepharitis), both posterior (meibomitis) or anterior, usually
have a causal or secondary infectious component. The abundance of
cholesterol esters in normal meibomian secretion makes a good culture
medium for microorganisms such as Staphylococcus aureus that produces
lipases that denature the meibomian secretion and increase the evaporation
of the aqueoserous phase of the tears. About 10% of the tear of the lacrimal
basin evaporates, and this rate increases in patients with blepharitis due to
the lipid layer insufficiency of their lacrimal film.
Mucoadenitis of the conjunctiva (conjunctivitis) is highlighted by trachoma,
herpes zoster, herpes simplex, and adenoviruses. At present, aqueoserous
dacryoadenitis is very infrequent, conjunctivitis is in decreasing prevalence,
but blepharitis is very frequent.
Traumatic
The traumatic damage of dacryoglands and ocular surface may be mechanical
(surgical or accidental), chemical, or radiation induced. This damage to
dacryoglands is produced accidentally or with therapeutic aims, and may
affect the aqueoserous glands (surgical ablation, tumor radiation), the lipid
glands (lid wound, Mustardé lid reconstruction, Webster operation for
distichiasis), the mucinic glands (chemical caustication, thermic destruction,
conjunctivectomy), and the corneal epithelium (abrasion, caustication, limbal
destruction). Severity of traumatic dry eyes varies, depending on the causes,
the affected tissues, and the intensity of the destruction.
Neurologic
Lacrimal secretion is very dependent on nervous stimulation. Its influence
may be separated into three types: hypothalamic and limbic influences,
afferent neurodeprivation, and efferent neurodeprivation.
Hypothalamic and limbic influences: Hypothalamus determines a circadian

production of tear secretion that is at its maximum at morning and noon,
diminishes at sunset, and reaches its minimum at night and when sleeping.
Limbic influences such as anxiety, tiredness, psychic influences, and
somnolence diminish the basal tear secretion.
Afferent neurodeprivation: The afferent means of the reflex stimulation of

tear secretion is due to lid and eye friction, environmental temperature, and
intermittent changes of corneal thermometry when blinking, retinal light
activation, trigeminal activity, etc. Therefore, ocular surface anesthesia due
to herpetic keratitis, topical anesthetics abuse, corneal refractive surgery,
corneal transplantation, and pre- and post-semilunar trigeminal damage
diminishes lacrimal secretion.
Contact lenses, mainly hydrophilic and semipermeables, restrict the

external stimuli. Lamellar refractive surgeries (mechanical keratotomy,
femtosecond laser assisted in situ keratomileusis, etc.) produce a moderate
dry eye that is partially recoverable. The discomfort of eye dryness in persons
with altered rapid eye movement (REM) sleep becomes worse, may be
because the objective of REM sleep is to stimulate tear secretion during
prolonged sleep.
Efferent neurodeprivation: The efferent means of the reflex stimulation of

tear secretion may be damaged in the pontobulbar nuclei (nucleus salivalis
superior and lacrimalis) and their connections, nervus intermediarius and
nervus facialis pregeniculi, nervus intermedius Wrisbergi, ganglion geniculi,
nervus petrosus superficialis major, nervus canalis pterygoideisive vidianus,
ganglion pterygopalatinum Meckeli, nervus zygomaticus, ramus communicans
cum nervo lacrimale, and nervus lacrimalis. This can be produced by different
causes, such as trauma, tumors, and botulinic toxin infiltration, and may
have various collateral manifestations such as neurotrophic keratitis,
pregeniculate facial palsy, neuralgia, and crocodile tears.
Tantalic
Tantalos, son of Zeus and Pluto, offended the Olympic gods, and therefore
was condemned to live in the Tartarus lake, but when he tried to drink, the
water drew back. So, despite living in water, he suffered from thirst and
dryness. Therefore, tantalic dry eyes are those that, despite having enough
tears, have a dry ocular surface. There are three types of tantalic dry eyes:
lid-eye incongruency, epitheliopathic, and evaporation.
Lid-eye incongruency Lids cannot create, maintain, and reshape the lacrimal
film onto the ocular surface because of lid palsy, ectropion, lagophthalmos,
lid coloboma, exophthalmos, local protrusion by pterygium or dermoid cyst,
blepharochalasis, conjunctivochalasis, antimongoloid lid fissure, or half-
opened eye sleep.
Epitheliopathic: Corneal and conjunctival epithelium is hydrophobic. They

need to increase their critical surface tension with a healthy surface covered
with the appropriate mucins to make them dacryophilic, so that tear spreads
over them forming a lacrimal film. Therefore, epithelial dystrophies, limbal
deficiency, corneal conjunctivalization, keratitis-ichthyosis-deafness syndrome,
rare cases of diabetic or hypoparathyroid endocrine keratitis, corneal

caustications, corneal thesaurismosis, endothelial decompensation, and many
other causes can produce a tantalic dry eye.
Evaporation due to environmental circumstances (and not to the patient’s

condition). Among these are excessive air conditioning, fans, electric fans,
open car window, wind, running without spectacles, polluted air, or dry air.
The “Stingy taxi driver syndrome” includes dry eye and scurfy hair; it is
caused by the taxi driver lowering his window for coolness, and the back
passenger receives the draft on his/her head.
As an addendum to the decalogue of etiologic groups, it must be explained
that most of the dry eye conditions are multicausal, and sometimes the
aggressiveness of one of them puts it in a prevalent position in diagnosis,
clinical severity, and treatment. Each cause has its own evolutive characteristics:
self-limited, permanent, progressive. Most causes will last for life. Only some
of them are reversible in the present state of medicine, such as most
pharmacologic causes, and incipient hyponutritional ones.
When the underlying etiopathogenesis is identified, it can sometimes be
classified in different decalogic groups if etiology and pathogenesis are applied;
for instance, traumatic damage of the pregeniculate nervus facialis is a traumatic
and a neurodeprivative dry eye. Therefore, for descriptive purposes they
may be classified in both groups.
Each classification of the Triple Classification of Dry Eye for a patient
must be written in the patient’s chart or the sheet for the Triple Classification
of Dry Eye for the Clinical Record, which can be attached to the patient’s
chart, as seen in Table 3.2.
Classification According to the Damaged

Glands and Tissues (“ALMEN” Classification)
From a clinical point of view, and in order to establish a treatment, the etiologic
classification must be completed with the evaluation of the participation of
the different parts that form the lacrimal basin, i.e. the anatomic space between
the ocular surface, posterior surface of the lids, and lid rim, where the mixture
of the lacrimal sea is poured. These components of the tear may be simplified
as produced by three basic types of dacryoglands—aqueoserous, lipid, and
mucinic—with an important component of the epithelium, mainly the corneal
one. The affected parts of the lacrimal basin may be summarized in this
TABLE 3.2: Classification of dry eye for clinical use
Patient :................................................................................................
1. ETIOPATHOGENESIS
X 1. Age-related … 62 years
X 2. Hormonal … menopause
X 3. Pharmacologic … sleeping pills
4. Immunopathic
5. Hyponutritional
6. Dysgenic
X 7. Infectious/inflammatory … chronic blepharitis
8. Traumatic
9. Neurologic
10. Tantalic
2. AFFECTED GLANDS or ALMEN

X Aqueoserous deficiency ... Schirmer 5 mm, BUT 6”, osmolarity
320 mOsm/L, muramidase < 0.7 g/L
X Lipodeficiency … blepharitis, marmoreal interferometry,
318 mOsm/L
X Mucodeficiency … ferning Rolando III, BUT 6”,
low impression cytology
X Epitheliopathy … BUT 8”, fluorescein +, Bengal rose 1-1-1
X Non-lacrimal affected … mouth, vagina
exocrine glands
3. SEVERITY
Grade 1-minus
Grade 1 … dryness sensation, occasional ocular itching,
vespertinal BIVA
X Grade 2 … conjunctival redness, cornea punctata
Grade 3
Grade 3-plus
An example of the application of this Triple Classification to a patient, taken from the most
frequent profile of patients with dry eye seen in an outpatient department. The sheet is
filled with the collected tests and results. Each accurate or speculative identified
etiopathogenesis, affected glandular system, and grade of severity is marked with a cross
or mark
histopathologic classification expressed with the acronym ALMEN, in which

the A indicates the aqueoserous deficiency; L, the lipid deficiency; M, the
mucin deficiency; E, the epithelial deficiency; and N, the nondacryologic
exocrinic deficiencies.
The aqueoserous deficiency is basically produced by the damage of the
main and accessory lacrimal glands. The aqueoserous production may be
measured by the Schirmer test, tear clearance, volumetry of the lacrimal
menisci (cisterna and rivi lacrimales), lactoferrin, and other tests of
controversial value but increasing efficacy. Some of these tests such as BUT
(breakup time) or osmolarimetry do not establish the aqueo-deficiency but
only a tear film deficiency in which other deficiencies, such as lipid or mucinic,
can participate or be the primary cause. In any case, the objective of the
triple classification is not to establish the present suitable tests to determine
the deficiency, but to establish the necessity to define the dryness as aqueo-
serous deficient or not.
The lipo-deficiency is mainly due to the abnormality of the meibomian
lipid glands, and to a lesser extent of the Zeis’ glands, the pilosebaceous
gland of the eyelashes, and the fatty component of the Moll’s glands, which
participate in the anterior antievaporative lipid phase of the lacrimal film.
The deficiency is at present deduced from the presence of a blepharitis, and
the interferometry of the lipid layer, but more and more osmolarimetry, new
methods of interferometry, reflective meniscometry, evaporation test,
humidometry, lipid analysis, BUT, and others do more exact determinations.
The mucin deficiency is produced mainly by the damage of the goblet
cells of the conjunctiva, and the epithelial glycocalix, and also by lacrimal
gland participation. The most practical determination is not only by impression
cytology of the ocular surface, BUT, and vital staining of the ocular surface
epithelium, but also by the tear crystallization or ferning test, retraction of the
lacunar sulci and lower fornix conjunctival folds, and laboratory determination
of mucin MUC5AC. Some of these tests may be effective to determine the
presence of a dry eye, but are not so specific in determining the type of
ALMEN deficiency.
The corneo-conjunctival epitheliopathy is sometimes primary, but is more
frequently secondary to the other glandular deficiencies. Primary
epitheliopathies with respect to dry eye are those in which a corneal problem
not related with the tear production alters the epithelium and causes problems
in the formation of the tear film. Examples are Meesmann epithelial dystrophy,
amiodarone thesaurismosis, stromal mucopolysaccharide deposits, Fuchs
endoepitheliopathy, and corneal endothelium decompensation. Secondary
epitheliopathies produced by dry eye are those in which an aqueoserous,
lipid, or mucinic deficiency due to any dysfunction of the dacryoglands
damages the normal corneal epithelium, increasing the problem of the eye
dryness.
The affected dacryogland may be initially of one, two, or of all types. It

depends on the type of etiology. In any case, all dacryoglands and the lacrimal
basin are usually finally implicated in a vicious circle that with different
intensities affects all of them. For instance, an age-related dry eye produces
directly and with a certain synchrony a general affection of all dacryoglands.
But the extirpation or radiation of the main lacrimal gland initially only affects
the aqueoserous secretion, and little by little secondarily affects all other ocular
surface dacryoglands and the epithelium of the ocular surface.
Ocular surface epitheliopathy is diagnosed by slit lamp biomicroscopic
signs, short BUT, punctate vital staining, cellular or secretory filaments,
laboratory histopathologic tests such as impression cytology, or biochemical
tests such as low mucins MUC1, MUC4, MUC16, or aquaporin AQP5. There
is a steady advance in examination techniques.
The non-ocular exocrine glands deficiencies are an important orientation
about etiology because they can indicate if it belongs to one of the
multiexocrinic conditions, such as age-related, hormonal, pharmacologic, or
autoimmune. The more bothersome organs because of their objective or
subjective dryness manifestation are as follows:
Mouth: Oral cavity and lip dryness sensation, thirst, frequent linguo-labial
humidification movements, dense saliva, bad breath (halitosis), taste
dysfunction (dysgeusia), expulsion of saliva drops when speaking (sialo-
lalopalassia), fungal stomatitis.
Nose: Dryness sensation, dry nasal mucus, itching, impairment of the
sense of smell (dysosmia, anosmia).
Throat: Dryness sensation, thirst, need to clear the throat when talking,
dense phlegm, dense sputum, hoarseness, change of voice or raucousness
(dysphonia).
Skin: Cutaneous dryness, axillary itching.
Vagina: Pruritus, itching, painful coitus (dyspareunia), vaginitis sicca.
Seminal glands: Dense ejaculation.
Ear: Itching of the outer ear, earwax plugs. These pluri-exocrinic
manifestations are not usually of synchronic presentation, and do not all
reach the same clinical level. Frequently, the dryness of an exocrinic system
does not usually correspond with the subjective sensation of the patient. So,
a similar dryness in several exocrinic body glands is usually first noticed in the
eyes and mouth. Throat, nose, and vagina occupy an intermediate position,
followed by skin and tracheo-bronchial tract. Dryness of ear, seminal glands,

and intestinal tract are not usually noticed.
Classification According to the Severity
The clinical symptoms and signs of the many millions of patients with dry eye
can present with thousands of combinations related to etiologies, affected
types of dacryoglands and ocular surface, and severity of the damage. In
order to do a practical classification of severity capable of satisfying the clinician
it has been decided to classify them into only three grades, attending the
bases of the clinical examination, i.e. symptoms and signs: grade 1 or mild
(symptoms without slit lamp signs); grade 2 or moderate (symptoms with
reversible signs); or grade 3 or severe (symptoms with permanent signs).
Grade 1 or Mild
Patients in this grade frequently have symptoms of ocular surface dryness in
normal environmental circumstances: dryness sensation, itching, ocular
tiredness, photophobia, photo-induced cough, momentarily blurry vision
that improves with repeated blinking (BIVA: blinking-improved visual acuity),
and fissural clonic blepharospasm.
No signs related to these symptoms can be seen when fentobio-
microscopically examined at the slit lamp. Fentobiomicroscopy is the basic or
gold standard ocular surface examination used and interpreted by
ophthalmologists. With any symptom there is always a sign that sometimes
in present day medicine could be inferred or detected with analytical,
electrophysiologic, or invasive tests, such as hyperosmolarity, hypolysozyme,
or inflammatory cytokines. These non-slit lamp signs are excluded from grade
1 of this classification, which is done for practical clinical use.
In this grade 1 or mild dry eye, a previous initial period can be introduced
with the name of grade 1-minus when these symptoms appear only under
overexposure that in the same conditions do not produce symptoms in
normal persons, i.e. wind, fan, open car window, air conditioning, polluted
air, low environmental humidity, contact lens wear, or physical corporal
tiredness. Usually, in this stage of grade 1-minus the patient is not aware that
he or she has an incipient dry eye.
Grade 2 or Moderate
The patient, besides more or less evident symptoms, has reversible slit lamp
signs, such as epithelial erosion, keratopathia punctata, keratopathia
filamentosa, short BUT, hyperemia of the exposed conjunctival trigoni,

secretion sleep of the ocular surface, or marginal blepharitis.
Grade 3 or Severe
The patient, besides the symptoms of ocular dryness, has signs that have
evolved to permanent sequelae, such as corneal ulcers, nephelions and
leukomas of the cornea, corneal neovascularization, squamous epithelial
metaplasia, or retraction of the conjunctival folds of the lower cul-de-sac or
of the lacunar sulci (the first between the nasal conjunctival trigonus and the
plica semilunari, and the second between the plica semilunaris and the
caruncula).
In this grade 3 or severe dry eye a grade 3-plus may be introduced when
the keratinization, scarring, and lesions of the central cornea permanently
reduce the visual acuity. The present one is a clinical classification, and the
clinical situation and incapacity of the patient is very different from when the
lesions are in the periphery or do not diminish the visual acuity than when
they are in the center and do diminish visual acuity. For this reason grade 3
has been enriched with this more incapacitating grade 3-plus.
COMMENTS
To find a consensus in a medicine that is continuously changing and

progressing is not easy. This classification has been made not only by collecting
many opinions, but also by producing a classification of dry eye conditions
for practical clinical use that allows diagnosis, prognosis, and treatment of
patients with dry eye.
Courtesy: From Eur J Ophthalmol© 2005;15:660-667 Published

with permission from the Publisher. No Parts of this article may be
reproduced without permission from Wichtig Editore Srl.
REFERENCE
1. Murube J, Benítez del Castillo JM, ChenZhuo L, Berta A, Rolando M. The Madrid
triple classification of dry eye. Arch Soc Españ Oftalmol 2003;78:587-94.
CLINICAL FEATURES OF DRY EYE 61
INTRODUCTION
Dry eye is a disorder characterized by abnormality in the tear film associated
with ocular irritation. Various causes may lead to symptoms of ocular irritation
and feeling of dryness. Management therefore involves identification of the
cause of dry eyes so as to administer treatment directed to the cause.
Tear film abnormality can occur due to an abnormality in the composition
of tears or due to abnormality in tear surfacing. Abnormal tear composition
can occur due to abnormality in aqueous layer, lipid layer or mucin layer.
ABNORMALITIES IN TEAR FILM COMPOSITION

Aqueous Layer
Aqueous tear deficiency occurs due to decreased aqueous secretion which
can occur due to abnormality in the lacrimal gland or its nerve supply. Aqueous
tear deficiency, also called keratoconjunctivitis sicca is commonly due to
Sjögren’s syndrome which can be primary or secondary. It is also commonly
seen in postmenopausal women.
Lipid Layer
Lipid layer abnormality occurs due to abnormality in the meibomian glands
which predominantly secret lipid. Increased lipid production resulting in an
unstable tear film is found in meibomitis. Meibomian gland atrophy can also
lead to an unstable tear film due to increase in evaporative loss.
Mucin Layer
Mucin layer, which is produced by the goblet cells of the conjunctiva can be
affected by certain scarring diseases of the conjunctiva like Stevens-Johnson
syndrome, ocular cicatricial pemphigoid and chemical burns. Since mucin is
responsible for increasing the wetability of the tear film abnormal mucin
secretion leads to an unstable tear film which is clinically demonstrated by
decreased tear film breakup time. However the correlation between the
degree of goblet cell loss and severity of mucin deficiency is poor.
ABNORMALITIES IN TEAR FILM SURFACING

Tear film surfacing involves adequate spreading of the tear film over the
ocular surface. This function is facilitated by the eye lids and therefore any
abnormality in the eye lid position like ectropion, entropion, lid tumors or in
eye lid function like seventh cranial nerve palsy, symblepheron can lead to
surfacing abnormalities. Besides lid abnormalities, any abnormality of the
ocular surface contour like pterygium, filtering bleb, limbal tumor can cause
abnormality in the surfacing of the tear film.
The above mentioned classification, though extensive is not ideal for clinical
application:
The currently accepted classification of dry eye divides the condition into
two types:
1. Tear deficient dry eye
2. Tear sufficient or evaporative dry eye.
Tear deficient dry eye occurs due to either decreased secretion of tears or
inability of the secreted tears to reach the ocular surface. Decreased tear
secretion occurs in a condition called Sjögren syndrome (SS) which is a chronic
inflammatory disorder characterized by lymphocytic infiltration of exocrine
glands, especially the lacrimal and salivary glands. Sjögren’s syndrome which
may be primary or secondary. Primary Sjögren syndrome is characterized
by dry eyes with dry mouth, a positive focus score on minor salivary gland
biopsy and positive serum autoantibodies like ANA, rheumatoid factor or
Sjögren syndrome specific autoantibodies like anti-Ro (SS-A) and anti La
(anti-SS-B ). Secondary Sjögren syndrome is characterized by the presence
of systemic connective tissue disorder like rheumatoid arthritis, systemic lupus
erythematosus and scleroderma along with the features of primary Sjögren
syndrome.
The other important cause of tear deficient dry eyes is non Sjögren
syndrome (Non SS) which is not associated with any clinical manifestations
or systemic features of autoimmune disease.
In tear sufficient or evaporative dry eye, increased evaporative loss of
tears is responsible for feeling of dry eyes. Although lacrimal function, volume
and quality of tears secreted are normal, periocular disease leads to an unstable
tear film. Meibomian gland disease (MGD) and blinking disorders due to
abnormalities in the lid or its nerve supply is primarily responsible for this
type of dry eyes. MGD may be inflammatory or atrophic. Inflammatory
meibomian gland disease is characterized by meibomitis resulting in an altered
lipid layer with or without associated facial signs. In atrophic MGD, there is
acinar dropout characterized by decreased lipid secretion.
CLINICAL FEATURES OF DRY EYE 63
FIGURE 4.1: Lacrimal secretory structures
SYMPTOMS
Patients with dry eyes usually present with complains of irritation, watering,
foreign body sensation, stinging, burning, itching, redness, heaviness of lids.
Some patients may even complain of blurred vision or poor quality of vision.
The symptoms tend to get precipitated following exposure to hot and dusty
environment, prolonged use of computers, etc. Certain medications like
antihistaminics, antidepressants, oral contraceptives can also produce
symptoms of dry eyes.
DIAGNOSTIC TESTS AND PRINCIPLES IN DRY EYE SYNDROME 65
INTRODUCTION
Any practicing comprehensive ophthalmologist will confirm that dry eye is
the most common complaint of patients presenting to their offices, albeit
most frequently in a mild form. The National Eye Institute/Industry Workshop
on Clinical Trials in Dry Eyes, have formulated a “global definition” of Dry
Eye Syndrome (DES) or Keratoconjunctivitis Sicca (KCS). They suggest that
dry eye is a disorder of the tear film due to tear deficiency or excessive tear
evaporation that causes damage to the interpalpebral ocular surface and is
associated with symptoms of ocular discomfort.1 DES is a chronic condition
and currently has no real cure. It is an apparently benign condition but with
an intractable course. This is often frustrating for the sufferer and unrewarding
for the ophthalmologist. However, timely therapy after early recognition
usually helps to avert late complications. Traditional therapy has included
the long-term use of topical lubricants, but for want of a definitive causative
treatment, efficacy is usually only partial. With the increasing recognition of
ocular surface inflammation as a contributory component of DES and
the availability of new specific therapies for this condition, it has become
prudent that clinicians diagnose and objectively monitor this condition
intelligently.
CLASSIFICATION
Despite the high prevalence of this condition, it still remains remarkably under
diagnosed. This is due in part to the lack of understanding of its classification
and partly because of a lack of a single universal diagnostic test.2 There are
two clear categories of DES as proposed by the National Eye Institute, one
related to insufficient production and the other to increased evaporation of
tears. There are several subgroups in each of the two categories. Sjögren’s
and non- Sjögren’s syndrome are the two main subgroups in the insufficient
production arm whilst meibomian gland disease (MGD), exposure, blink
abnormality and contact lens wear form the essential subgroups of the
increased evaporation arm.1 Tests for one category may be positive and for
another category negative; yet, both may lead to DES. Additionally, there is
often a crossover of conditions between the two groups, e.g. (MGD), which
is the leading cause of evaporative DES, may also occur in a significant number
of cases with aqueous deficiency.3
DIAGNOSIS
Not only is there a plethora of symptoms in DES, but also numerous diagnostic
tests are available. Diagnosing the DES starts with a good clinical history and
proceeds to an applicable systemic physical examination, a complete ocular
and slit-lamp examination followed by one or more of several specific clinical
diagnostic tests. Depending on the availability, laboratory supported tests
like tear film osmolarity, tear lysozyme and lactoferrin concentrations as well
as conjunctival impression cytology may also be added to the diagnostic
routine. The average clinician generally relies on the history in conjunction
with Schirmer testing, supravital conjunctival staining, tear film break-up time,
tear fluorescein clearance, tear meniscus height, and the presence or absence
of tear film debris.
PATIENT HISTORY4
Diagnosing DES begins with the patient history, where a host of symptoms
have been ascribed to the condition. Symptoms are a hallmark of the disease,
and the most frequently encountered symptoms are dryness, foreign-body
or gritty sensation, burning and photophobia. Additional complaints may
include itching, mucus secretions, heaviness of the eyelids, inability to produce
emotional tears, pain and redness. Patients would often use the term “dryness”;
buy will have difficulty defining exactly what it means. The term “discomfort”
may be a more accurate summation of all the patient’s symptoms. Various
questionnaires have been developed to assess symptoms in DES patients.
The Ocular Surface Disease Index (OSDI)3 in Figure 5.1 lists 12 common
symptoms of dry eye patients and scores each from 1 to 4 in terms of severity.
This permits quantification of symptoms and provides a reasonably objective
approach to the evaluation of symptoms over time. These questionnaires
are valuable tools in clinical treatment trials.
A series of further specific questions during the interview may be of extreme
importance:
1. How do winds or drafts affect your eyes?
DES patients are extremely sensitive to drafts and winds, e.g. driving with
the windows down and intolerance in air conditioned surroundings. They
feel worse in a dry, cold environment with conditions of increased evaporation.
2. Does reading affect your eyes?
Reading also often elicits symptoms and many suffer because of the reduced
blink rate during periods of concentration.
FIGURE 5.1: OSDI questionnaire designed to assess DES

symptoms and severity3
3. Any problems when you awake at night?

Patients often complain that nighttime awaking is the worst part of their lives.
Sleep decreases tear production just like general anesthesia. Further reduction
in tear flow during sleep in an already compromised eye, will produce
nocturnal symptoms. Smoke produces discomfort because smoke is in reality
only a suspension of solids in air. It is valuable to determine whether symptoms
are better or worse, indoors or outdoors, at home or at work in order to
identify high-risk environments that may need modification to improve the
patient’s symptoms.
4. Do your eyes tear when you peel onions? Can you cry when you feel sad
or hurt?
Questioning patients as to their ability to produce irritant and/or emotional
tears is important. Affirmative responses suggest that at least some lacrimal
function remains, whereas negative responses would suggest the lacrimal
gland’s inability to secrete tears in response to stimuli. In patients with DES/
KCS, the ability to generate irritant tears is lost before the ability to generate
emotional tears.
5. What medications do you take?

Systemic antihistamines, antidepressants, anticholinergics, and diuretics are
notorious for reducing tear production. The use of systemic steroids, and
other immunosuppressants which may be used for the treatment of Sjögren’s
syndrome and other collagen vascular diseases should be noted. A history of
any collagen vascular disease, thyroid eye disease, lymphoma or AIDS should
be sought.
6. Can you feel saliva in your mouth? Can you swallow bread without
additional fluids?
Determining whether the patient has any associated systemic symptoms or
conditions is important. Dry mouth and dental gum disease may be pointers
to DES. Women should be asked as to noticeable decrease of vaginal
secretions.
7. Do you have any skin problems?

Looking for dermatological conditions may provided useful clues for example
scleroderma, facial rash in lupus, pemphigoid, old scars of Stevens-Johnson
syndrome and acne rosacea. Family history should be elicited as there may
be blood relatives with associated diseases.
8. What topical lubricants do you use? Are they preserved or unpreserved?

How long and how often do you use them?
Information on drops and ointments should be obtained concentrating on
type and frequency of use. Most patients will not consider topical treatment
when generally asked about medications. Most DES sufferers improve on
topical lubricant therapy. Valid deductions as to the severity of the condition
may often be made from how frequently topical lubricants are used. Patients
with severe DES will use the lubricants more often than those with mild DES.
Mild cases may be made worse when using preserved lubricants. Other non-
lubricant topical medications may be important because of the active drug

or the preservative’s (most notably benzalconium chloride) effect on the
ocular surface. Furthermore, any topical medication is potentially toxic because
of the dry eye’s inability to dilute the drug. Information about previous
temporary or permanent occlusive punctal plugs is essential. If so, was there
any improvement in symptoms or did epiphora occur?
PHYSICAL EXAMINATION
A limited physical examination before focusing on the ophthalmic examination
is advised.
Systemic Examination
The facial skin must be examined for evidence of acne rosacea or signs
of systemic lupus erythematosus (SLE) The parotid, and submandibular glands
should be palpated for presence of enlargement or masses. Thyroid gland
palpation is important in patients with thyroid eye disease (TED). Superior
limbic keratitis and Sjögren’s syndrome are both frequently seen in TED. Lid
retraction, exophthalmos and decreased blinking which occur in TED can
cause symptoms of dry eye due to increased evaporation. The mouth and
tongue are examined for the presence or absence of saliva and oral candidiasis.
The hands are assessed for joint disease. Rashes and eczema is looked for on
the extremities.
Ocular Examination
A perfectly noncontributory and normal ocular examination may be found
in cases of early or mild DES.
External Eyelid Examination

Note the presence or absence of dermatochalasis, the function of the eyelids,
completeness of the blink response as well as the blink rate should be noted.
The size of the lacrimal gland is assessed by requesting that the patient looks
down while the upper eyelid is retracted. Presence of eyelid abnormalities
like entropion, ectropion, ptosis, trichiasis, lagophthalmos, and cicatricial
conditions should be noted.
Slit-lamp Biomicroscopy (SLB)

The most characteristic finding on SLB is an abnormality of the inferior tear
meniscus. In 85% of normal subjects the height will be 0.2 to 0.3 mm.5
FIGURE 5.2: Thin and irregular tear meniscus supporting suspicion of DES.
(Courtesy: Dr Samir Al-Mansouri)
In DES, tear meniscus volume is reduced, as indicated by reduced height

and radius of curvature (Figure 5.2). Radius of curvature can be measured
by slit-lamp photography.6 Note meniscus “floaters” in dry eye cases. They
are common and are seen as tiny bits of debris suspended in the tear meniscus.
Some are dead epithelial cells that have come off the corneal surface and
some are small fibrils of lipid-contaminated mucin. Although extremely
common, these floaters are not pathognomonic for DES, as eyes with
conjunctivitis and blepharitis may also display them.
Mucous strands may be seen in the more severe cases of DES. They are
in reality strings of lipid-contaminated mucus that have been rolled up and
pushed into the cul-de-sac by the shearing action of the lids. They are
common in the aqueous-deficient states, but become extremely significant
in the mucin-deficient conditions. If mucin and excess lipid become
intermingled, mucous strands form (Figure 5.3).
Corneal filaments are commonly seen in dry eye corneas. These filaments
are < 2 mm in length and look like short “tails” that are suspended from the
surface of the cornea. The exact pathogenesis of filament formation is not
known, but these filaments are anchored to epithelial cells and pulling on
FIGURE 5.3: Mucin strand significant in mucin deficient states
them can be very painful. This is what happens during blinking, with the
resultant symptoms mimicking those of a foreign body.
Eyelid margins are to be examined for irregularity, telangiectasia,
thickening, and broken or missing eyelashes, all of which suggest chronic
blepharitis. The condition of the meibomian glands is assessed. Meibomian
gland disease (MGD) is suggested by the following: the presence of oil or
foam, pouting, plugged or missing meibomian gland orifices, and toothpaste-
like thick turbid secretions expressible from the orifices. The percentage of
meibomian gland acinar dropout can be quantified by transilluminating the
inferior tarsus with a halogen Finhoff transilluminator (Welch Allyn) as
suggested by Pflugfelder et al.7 They quantify the percentage of dropout in
the nasal and temporal halves of the lower lid by using a standardized
4-point scale: (0, no dropout; 1 = 33%; 234-66%; 3, 67-100%). They also
quantify the expressibility of meibomian gland secretions by digitally both
the upper and lower lids just above and below the lash line against the globe
over an area of five visible meibomian gland orifices. The number of
meibomian glands from which meibum can be expressed is quantified on a
four point scale as well: (0, all five glands; 1, three to four glands; 2, one to
two glands; 3, zero glands).
The bulbar conjunctiva may lose its normal luster and may become
thickened, hyperemic and edematous. Papillary conjunctivitis especially visible
on the tarsal conjunctival surfaces, representing a nonspecific reaction of the

conjunctival surface to irritation, may also be evident in DES.
CLINICAL DIAGNOSTIC TESTS

Practices of evaluating the stability of the tear film layer differ worldwide.
Entry level diagnostic tests are most often relied upon and used in practice,
but many and diverse sophisticated tests are available in larger centers. The
latter will only be referred to briefly in this discussion. Practical clinical tests
can be divided into three categories, i.e. (a) tests to assess tear film stability
(b) tests to estimate tear secretion, and (c) tests to evaluate tear film and
epithelial integrity.
Tear Film Stability Assessment

Tear Break-up Time
Tear break-up time (BUT) is the elapsed time from the blink to the first
appearance of a corneal dry spot as seen with the aid of fluorescein stain
applied to the surface of the eye. Its measurement depends on the fact that
over time the tear film thins and eventually ruptures, even in normal eyes.
Many believe that BUT is the best screening test for dry eye disease.3 If the
result of this test is abnormal, i.e. under 5 seconds, there is usually some
form of ocular surface disease; most frequently DES.
Measurement of BUT is accomplished as follows:4 flourescein is instilled
in the eye, the patient is asked to blink three times to distribute the dye, the
patient is asked to stare ahead and not blink, while the examiner scans the
cornea with the cobalt-blue light of the slit lamp, watching for an area of tear
film rupture, manifested by the appearance of a black island within the green
film of flourescein. The BUT is the time in seconds between the last blink and
the appearance of the dry spot. A mean of three trials is normally taken. A
normal BUT is 10 seconds or more.
Noninvasive break-up time (NIBUT) on the other hand is a test of tear
stability that does not involve the instillation of fluorescein dye. NIBUT is the
time between the last blink and the break-up of a reflected image of a target
on the tear film. The measurements are performed with either a xeroscope
or keratometer. Normal NIBUT is greater than 20 seconds.8
Tear Secretion Assessment

Schirmer and Jones’s Tests9
Schirmer test: The most commonly used technique for measuring aqueous
tear secretion is the Schirmer test originally described in 1903.10 It is by far
the simplest test for assessment of aqueous tear production. This test can be
performed with or without topical anesthesia. Without anesthesia the test is
know as the Schirmer 1 test. A Schirmer 1 test value of < 6 mm of strip
wetting in 5 minutes is accepted as diagnostic for aqueous tear deficiency.
The reliability of this test may be affected by environmental conditions such
as temperature and humidity.
It is recommended that the test be performed without touching the paper
strip directly with the examiner’s finger to avoid contamination with skin oils.
The strip is placed at the junction of the middle and lateral one-third of the
lower eyelid (Figures 5.4 and 5.5.) The patient is told to look forward and
blink normally. After 5 minutes strips are removed and the wetting recorded
in millimeters. The Schirmer test may be performed with the eyes open or
closed. Schirmer 1 test is recommended to determine whether any lacrimal
gland is present and functioning at all (as is the case in severe DES).
FIGURE 5.4: Schirmer-Jones’s strip placed at the junction of the

middle and lateral one-third of the lower eyelid. When performed
with local anesthetic the test is called Schirmer 1 and without local
anesthetic Jones’s test
FIGURE 5.5: A Schirmer 1 test value of < 6 mm of strip wetting in 5

minutes is accepted as diagnostic for aqueous tear deficiency
Jones’s test: In order to eliminate conjunctival reflex stimulation of tearing,

topical anesthesia is used and then the test is called the Jones’s test. This test
determines the minimum (basal) amount of tear secretion. In mild cases of
DES where it is important to determine the basal level of tear production,
Jones’s test is more appropriate.
Phenol Red Threat Test

A fine cotton threat that has been impregnated with phenol red, a pH-sensitive
substance that changes color from yellow to red on contact with the near
neutral pH of tears, is used in this test. It is placed between the eyelid and
globe, temporally and the amount of wetting over 15 seconds is measured.
Normal values are 9 to 18 mm.11
Nasal-lacrimal Reflex Tearing

The nasal-lacrimal reflex can be elicited by stimulating the nasal mucosa
under the middle turbinate with a cotton-tipped applicator. It was reported
that the nasal-lacrimal reflex is preserved in most patient with non-Sjögren’s
aqueous tear deficiency; however it is typically lost early in the course of the
disease in patients with the syndrome.12
Tear Film and Epithelial Integrity Assessment

The most commonly used methods to assess tear film and epithelial integrity
are the different vital stains (or dyes) like fluorescein, rose Bengal and lissamine
green.
Fluorescein Dye
Fluorescein stains the ocular surface epithelium by penetrating intercellular
spaces. The normal corneal epithelium does not stain with fluorescein;
however this dye readily penetrates the corneal epithelium when the mucous
layer is removed.13 Fluorescein also stains the precorneal tear film, whereas
rose Bengal precipitates at the bottom of the meniscus. Fluorescein is an
orange dye that fluoresces green when excited by blue light. It may be applied
to the eye as a 1% or 2% solution or with a fluorescein-impregnated strip
wetted with a drop of saline or balanced salt solution; the excess fluid is
shaken from the strip prior to application. The cornea is best examined 2 to
3 minutes after installation of the dye, an important fact often overlooked by
examiners in busy clinics; premature examination of the surface with a cobalt
blue light at the slit-lamp underestimates the degree of epitheliopathy.
Conjunctival fluorescein staining occurs in mild to moderate DES and
corneal staining in more severe DES cases (Figures 5.6 and 5.7). The staining
usually has a characteristic distribution, confined to the exposed interpalpebral
FIGURE 5.6
FIGURE 5.7
FIGURES 5.6 and 5.7: Fluorescein staining patterns in dry eye syndrome
area of the ocular surface; but in severe dry eye, staining may extend to the
unexposed surface of the globe, particularly the upper bulbar conjunctiva.
Sometimes fluorescein staining can be seen in normal eyes and may be
more prominent in the morning.14
Rose Bengal Dye4

Rose Bengal is a red aniline dye, a derivative from fluorescein but different
from fluorescein in several ways. Rose Bengal dye stains devitalized epithelial
cells as well as healthy epithelial cells that are not coated with mucous.15 This
allows the dye to stain living epithelial cells that would normally be protected
by mucin in the healthy eye. It appears that although stained corneal epithelial
cells are not necessarily devitalized or degenerate, they may suffer from
impaired expression of membrane-associated mucins.
Fluorescein (which readily penetrates the corneal epithelium when the
mucous layer is absent) and rose Bengal (which stains cells that are not covered
with mucin) may, therefore, be used clinically to evaluate the pre-ocular
mucin layer. It is now recognized that an intact mucous layer is a marker of
normal ocular surface epithelial function. Rose Bengal also stains lipid-
contaminated mucous strands and corneal epithelial filaments. The use of a
mixture of fluorescein and rose Bengal dyes has been reported for clinical
FIGURE 5.8
FIGURE 5.9
FIGURES 5.8 and 5.9: Staining patterns with rose Bengal vital stain.
(Courtesy: Dr Samir Al-Mansouri)
use to take advantage of the unique staining properties of both dyes with
instillation of a single drop.16 The classic location of rose Bengal staining in
aqueous tear deficiency is the interpalpebral conjunctiva. The staining appears
in the shape of two triangles with the bases to the limbus and apices to the
canthi. The conjunctiva usually shows stronger staining than the cornea, but
in severe cases of DES the entire cornea may stain with rose Bengal (Figures
5.8 and 5.9). This is also the case in cictricial pemphigoid, Stevens-Johnson
syndrome and in keratitis medicamentosa. Superior corneal and limbic staining

is seen in Superior Limbic Keratopathy (SLK). Staining of the plica semilunaris
and caruncula suggests the mucus-fishing syndrome or eye rubbing. A small
amount of stain over the body of a pterygium or pinguecula is common.
The one disadvantage of rose Bengal is the irritation it causes on instillation.
The irritation seems to depend on the amount of epithelial damage present
on the cornea. I use a drop of local anesthetic to minimize the irritation.
Using strips impregnated with rose Bengal also minimizes the amount of dye
applied.
Lissamine Green Dye

Lissamine green B dye has been reported to stain dead or degenerated cells,
and it produces less irritation after topical administration than rose Bengal.17
The dyeing quality of lissamine green is the same as that of rose Bengal. It
may be advantageous to use rather than rose Bengal as it causes so little
stinging. Its commercial availability is currently a major problem.
LABORATORY DIAGNOSTIC TESTS

Serum Antibodies
Certain diagnostic criteria for Sjögren’s syndrome require the presence of
one or more of the following serum autoantibodies: antinuclear antibodies
(ANA, titer =1:160), rheumatoid factor (titer =1:160), or Sjögren’s syndrome
specific antibodies such as anti-Ro (SS-A) or anti-La (SS-B).18 Pflugfelder
et al in a prospective evaluation of patients with Sjögren’s syndrome found
ANA positivity in 63%, rheumatoid factor in 76%, SS-A in 67%, and SS-B in
47%.9
Conjunctival Impression Cytology19

Conjunctival impression cytology is obtained by applying to the superior
bulbar conjunctiva a nitrocellulose acetate filter paper that can be either
opaque (e.g. Millipore) or transparent (e.g. Biopore). The membranes should
be removed from their packaging with sterile forceps and may not be touched
with the fingers. Each membrane is cut into two pieces, a drop of anesthetic
is instilled, and the patient is asked to down while the lid is lifted to uncover
the superior bulbar conjunctiva. The membrane is applied to the bulbar
conjunctiva. Simple contact suffices: there is no need to press the membrane
onto the eyeball. The membrane is removed immediately. A good result is
expected when the conjunctiva is lifted slightly when the filter paper is removed.
It may be necessary to transfer the cells to a transparent glass support for
immunohistological studies. The side of the membrane bearing the epithelial
cells is pressed onto the wells of a glass slide for immunofluorescent studies
or fixed in formaline or ethanol for subsequent cytological staining.
Tests to Demonstrate the Physical Characteristics of the Tear Film4

Tear Osmolarity
Normal tear osmolarity is about 302 mOsmo/L. Considerable evidence exists
suggesting that tear hyperosmolarity plays a key role in the ocular surface
damage in several forms of DES. There are various types of osmometers
available for measuring tear osmolarity. Elevated tear osmolarity indicates
an imbalance between the rate of tear secretion and the rate evaporation.
Note that reflex tear secretion at the time of sample collection can cause
false-negative results.
Ocular Ferning Test

One of the well known physical characteristics of mucus is its ability to crystallize
and form ferny patterns on a dry slide with the microscope. Utilizing this
phenomenon, Tabara and Okumoto20 developed a new qualitative teat for
the study of conjunctival mucus. Whilst microscopic ferning is observed in
normal eyes, patients with ocular pemphigoid, Stevens-Johnson syndrome,
trachoma, and alkali burns show reduced or absent ferning due to the reduced
mucus production.
Tear Film Evaporation

DES patients show an increased rate of evaporation compared to normals
(0.43 mL/min vs. 0.14 mL/min).21 The test is not specific for any particular
type of dry eye; increased evaporation is seen in KCS and many forms of
MGD and ocular surface disease.
Tear Clearance
Tear secretion, stability, and evaporation affect tear clearance. Tear clearance
is probably the best overall measure of the lacrimal gland, meibomian gland,
and ocular surface as a functional unit. Measurement of tear clearance is
helpful in the assessment and follow-up of patients with DES. When
suboptimal tear clearance is accompanied by inflammation, a vicious cycle
results. Increasing inflammation leads to further decreases in tear clearance

as well as the retention of inflammatory cytokines on the ocular surface. Tear
clearance is measured by the change in the concentration of fluorescein in
the tear film. Decreased tear clearance occurs when there is decreased tear
secretion or blinking, increased evaporation, or following punctal occlusion.
It is measured in vivo using fluorophotometric techniques.22
Tests to Measure the Chemical Composition of the Tear Film

Tear Lysozyme
Normal tear lysozyme levels are between 2 and 4 mg/ml and several assay
systems are available to determine the level of lysozyme in tears. Patients
with Sjögren’s syndrome have decreased lysozyme production.
Tear Lactoferrin
Various methods have been described to measure tear lactoferrin levels.23,24
The lactoplate test is an immunodiffusion assay performed in an agarose
gel containing rabbit antisera to human lactoferrin.23 The lactocard test is a
solid-phase enzyme-linked immunosorbent assay (ELISA) that requires only
2 μL of tears. This is a rapid, simple test that is colorimetrically measured by
a precise reflectance spectrometer.24
Tear Protein
Tear protein is analysis based on the rationale that tears from dry eye patients
may contain altered protein composition. Tear proteins can be measured
using ELISA assay. Electrophoresis can be used to separate various proteins
in tears. The electrophoretic pattern of tears from normal subjects and patients
with KCS show qualitative differences.25 Decreased levels of the goblet cell
specific mucin MUC5AC have recently been demonstrated in tears of Sjögren’s
syndrome cases.26
Tests to Measure Lipid-tear Deficiency

The diagnosis of lipid-tear deficiency is mainly indirect. Obstructive meibomian
gland disease is assessed by quantification of occluded gland orifices and
grading the quality of expressed oil secretion.27 Morphological changes of
the meibomian glands can be determined by meibography.28 Deficiency of
oil delivery onto the lid margin can be measured quantitatively by meibometry,
a technique in which samples of lid margin oil are taken from the lid with a
strip of tape and quantified by densitometry.29 Recently, a new method has

been developed that utilizes direct digitization of sequential tear interference
images for kinetic analysis.30 It is believed that kinetic analysis of tear
interference will help in devising and monitoring future therapies directed to
restoring meibomian gland functions.
CONCLUSION
If the clinician takes a good patient history, does a good physical and slit-
lamp examination of the eyes, supplemented by a few of the above specific
diagnostic tests—the diagnosis and management of this very common, but
often neglected condition may be significantly improved.
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with the severity of corneal epithelial and eyelid disease. Arch Ophthalmol
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photography of meibomian gland dysfunction. A clinical study. Ophthalmology
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of tear interference images. Arch Ophthalmol 2003;121:173-80.
MEDICAL MANAGEMENT OF DRY EYE 83
INTRODUCTION
Dry eye (keratoconjunctivitis sicca) is one of the most common causes of
chronic low-grade burning, irritation and discomfort of the eyes specially in
the elderly population. Dry eye as such is not a disease entity but a symptom
complex occurring as a sequelae to deficiency or abnormalities of the tear
film.
A reduction in tear flow in the absence of ocular disease is common in the
older age group. Pathological reduction of tear flow results in corneal drying
and this causes dry eye symptoms to develop. Dry eye is a significant clinical
problem in ophthalmology today. In more than 50 percent of elderly people,
dry eye is associated with systemic diseases particularly collagen diseases.
CAUSES OF REDUCED TEAR PRODUCTION (ETIOLOGY)

• Idiopathic Many patients with chronic low-grade mild symptoms of dry
eye shall demonstrate no systemic or ocular disease to account for the
lacrimal insufficiency. It is important to exclude drug-induced tear
hyposecretion as seen with a number of drugs specially antihistamines,
oral contraceptives, phenothiazines antihypertensives, antidepressants,
antiulcer drugs, antimuscle spasmodics, nasal decongestants and
anticholinergics.
• Aqueous tear deficiency is seen in conditions like congenital alacrimia
(although rare) and in atrophy and fibrosis of lacrimal tissue due to a
destructiveinfiltration by mononuclear cells as seen in
• Pure keratoconjunctivitis sicca (KCS) as characterized by the
involvement of lacrimal glands alone.
• Sjögren’s syndrome: It is an autoimmune disease which consists of a
triad of KCS, xerostomia and rheumatoid arthritis (Figure 6.1). It may
be associated with widespread systemic collagen diseases. Sjögren’s
syndrome is characterized by the frequent presence of hypergamma
globulinemia (50% cases), rheumatoid factor (70-90% cases) and anti-
nuclear antibody (in 80% of cases). Other findings include the presence
of antibody of DNA, salivary gland tissue, smooth muscle and gastric
parietal cells. When these features occur alone the condition is referred
as “primary Sjögren’s syndrome” or the “sicca complex” when they
are associated with connective tissue disorder the condition is known
as “secondary Sjögren’s syndrome.”
FIGURE 6.1: Keratitis filamentosa (dry eye in Sjögren syndrome

type-I (primary type)
• Damage or destruction of lacrimal tissue as a result of trauma to the

lacrimal gland may result in a loss of tear production.
• Sarcoidosis: The granuloma of lacrimal gland lead to diminished tear
secretion as seen with rose bengal staining of the conjunctiva and cornea.
• Lacrimal gland tumors may cause reduced tear secretion which is
sometimes very severe.
— Neoplastic lesions or mixed tumors which is locally invasive causes
symptoms due to its size and may displace the globe.
— Adenocarcinoma which is an invasive malignant tumor and causes
widespread local destruction of the bone and other tissues and leads
to decreased tear secretion. Chronic inflammatory (pseudotumor) also
lead to decreased tear secretion.
• Blockage of excretory ducts of lacrimal gland by scarring of the conjunctiva
also leads to decreased tear secretion. Scarring of conjunctiva is seen in
trachoma, pemphigoid and erythema multiforme—Stevens-Johnson
syndrome (Figure 6.2).
— Benign mucous membrane pemphigoid causes essential shrinkage of
conjunctiva. Chronic low-grade irritation is a common feature in this
disease. The more severe dry eye is seen late in the disease after
significant scarring of the accessory lacrimal glands and ducts has
occurred.
— The postinflammatory mucosal scarring that occurs as a result of an
acute attack of Stevens-Johnson syndrome involving the eyes can
FIGURE 6.2: Ocular cicatricial pemphigus (cicatricial dry eye)
result in chronic dry eye. Resolution of the acute mucosal necrosis

leads to symblepharon and scarring of the accessory lacrimal glands
and the ducts of the main lacrimal gland.
• Neurogenic lesions and meibomian gland dysfunction may lead to
decreased tear secretion.
• Infection of lacrimal gland (Dacryoadenitis) may cause decreased tear
secretion. It may be complication of measles or mumps.
• Both systemic and discoid lupus erythematosus can result in the complex
of keratoconjunctivitis sicca and xerostomia due to infiltration of the lacrimal
and salivary gland. Dry eye is associated with superficial punctate
epitheliopathy and corneal erosions.
• Conditions like scleroderma and periarteritis nodosa can lead to KCS as a
late development.
• Status postexcision of the lacrimal gland may lead to decreased tear
secretion.
• Mikulicz’s syndrome can result from a variety of causes like tuberculosis,
leukemia, Hodgkin’s disease, amyloid, etc.
• Other systemic diseases associated with dry eye include graft versus host,
polymyositis, post-head and post-neck radiation, HIV, hepatitis B and C,
syphilis, TBC and seventh nerve palsy.
• Mucin deficiency dry eye occurs when goblet cells are damaged as in
hypovitaminosis A (xerophthalmia) and conjunctival scarring diseases such
as erythema multiformae, trachoma, chemical burns, radiations and ocular
pemphigoid, etc.
• Lipid deficiency and abnormalities although rare but has been seen in
some cases of congenital anhydrotic ectodermal dysplasia alongwith
absence of meibomian glands.
• Ocular conditions associated with impaired eyelid function as seen in
exposure keratitis, dellen, symblepharon, pterygium, Bell’s palsy, nocturnal
lagophthalmos and ectropion.
• Epitheliopathies due to intimate relationship between the corneal surface
and the tear film affect the stability of tear film.
CLINICAL EVALUATION
Symptoms
The most common symptoms of dry eye are:
• Irritation of eyes without pain or blurred vision
• Ocular discomfort (nonspecific)
• Burning and itching sensation
• Foreign body sensation (Sandy type)
• Photosensitivity
• Grittiness
• Complaint of burning sensation when exposed to conditions associated
with increased evaporation of tears like heat, prolonged reading, air-
conditioning, etc.
• Some patients may complain of dry eye and lack of emotional tears.
Most susceptible group of patients for dry eye include:
• Postmenopausal women
• Patients of 50 years plus group
• Patients on diuretics, beta-blockers, psychotropics or oral acne medications
• Rheumatoid arthritis patients
• People exposed to heat, dust, etc.
Signs
Signs of dry eye include presence of stingy mucus and particulate matter in
the tear film, lusterless ocular surface, conjunctival xerosis, Bitot spots (Figure
6.3), reduced or marginal tear strip and corneal changes.
Precorneal Tear Film

One of the earliest signs of dry eye is the presence of an increased amount of
mucin strands and debris in the precorneal tear film. In dry eye lipid
contaminated mucin accumulates in the precorneal tear film.
FIGURE 6.3: Bitot’s spots (dry areas on the bulbar conjunctiva in

the interpalpebral fissure)
Marginal Tear Strip

In dry eye marginal tear film is reduced in height (less than 0.3 mm) and is
concave and contains mucus and debris. In severe cases of dry eye it may be
absent altogether.
Corneal Changes
In moderate to severe cases of dry eye the following corneal changes may be
present.
• Punctate epithelial erosions involving the inferior cornea which are best
shown following instillation of fluorescein into the inferior conjunctival
fornix.
• Filaments appear as small comma-shaped opacities with the free end
hanging over the cornea and moving with each blink (Figure 6.4). These
filaments are composed of central mucus core encased by epithelial cells
and are best shown on rose bengal dye staining.
• Mucus plaques appear as semitranslucent whitish grey, slightly elevated
lesions of varying shape and size. They consist of mucus, epithelial cells
and proteinaceous/lipoidal material. These plaques are usually seen in
association with corneal filaments (Figure 6.5).
FIGURE 6.4: Corneal filaments and plaques (left),

and localized area of thinning (right) (Courtesy:
Kanski Clinical Ophthalmology, Butterworth
International edition)
FIGURE 6.5: Mucous threads and corneal filaments in dry eye

(rose bengal staining) (Courtesy: Kanski Clinical Ophthalmology,
Butterworth International edition)
• Dellen unassociated with limbal elevations may be seen in cases of severe

KCS.
• Corneal thinning and rarely perforation may occur in cases of severe dry
eye.
FIGURE 6.6: Tear film break up
FIGURE 6.7: Tear film break-up mechanism

(Courtesy: Allergan India Limited)
DIAGNOSTIC TEAR FILM TESTS (FOR TEAR HYPOSECRETIONS)

Tear Film Break-up Time (BUT)
The tear break-up time is a simple physiological test to assess the stability of
precorneal tear film. This test is performed by instilling fluorescein into the
lower fornix, taking precaution not to touch the cornea. The patient is asked
to blink several times and then to refrain from blinking. The tear film is
scanned with a broad beam and cobalt blue filter. After an interval of time
black spots or line indicating dry spots appear in the tear film. BUT is the
interval between the last blink and appearance of the firm randomly distributed
dry spot (Figure 6.6). Ideally average of three measurements is taken. A
normal BUT is more than 10 seconds and a BUT of less than 10 seconds is
considered abnormal (Figure 6.7). This test may also be abnormal in eyes
with mucin or lipid deficiency.
FIGURE 6.8: Modified Schirmer’s test—diagnostic test for dry eye

(Courtesy: Garg et al internationale Ophthalmologica)
Schirmer’s Test
The rate of tear formation is estimated by measuring the amount of wetting
on a special filter paper which is 5 mm wide and 35 mm long.
Previously Schirmer’s test 1 and 2 were used in diagnostic practice but
nowadays modified Schirmer-I test is employed. This test is performed as
follows (Figure 6.8).
Schirmer strips are prepared by cutting out Whatman filter paper No. 41
into the strips of 5 mm × 35 mm dimensions. A 5 mm tab is folded over at
one end. Before use, these strips are autoclaved.
The bent end is placed into lower conjunctival sac at the junction of lateral
one-third and medial two-third of lower eyelid so that 5 mm bent end rests
on the palpebral conjunctiva and the folding crease lay over the eyelid margin.
This test is usually performed in the sitting posture in dim light.
The patient is asked to keep the eyelid open and look slightly upwards at
a fixation point. Blinking is allowed while the patient gazes at the fixation
point.
After one minute, the strips are carefully removed and moistening of the
exposed portion of the strip is measured in millimeters with the help of a
millimeter ruler.
The measurements are made from the notch at the bend of the Schirmer
strip to the distal end of the wetting on the strip (excluding the folded over
tab). The amount of wetting of the Schirmer strip in one minute is multiplied
by three to correspond roughly to the amount of wetting that would have
occurred in 5 minutes (Jones, 1972). It is a measure of the rate of tear

secretion in a 5-minute period.
A normal eye will wet between 10 mm and 25 mm during that
period. Measurements between 5 mm and 10 mm are considered
borderline and values less than 5 mm is indicative of impaired
secretion.
Vital Dye Staining

• Rose bengal 1 percent has an affinity for devitalized epithelial cells and
mucus in contrast to fluorescein which remains extracellular and is more
useful in showing up epithelial defects. Rose bengal is very useful in
detecting even mild cases of keratoconjunctivitis sicca (KCS) by staining
the interpalpebral conjunctiva in the form of two triangle with their basis
at the limbus (Figures 6.9 and 6.10).
FIGURE 6.9: Staining of conjunctiva with rose bengal
The only disadvantage with rose bengal staining is that it may cause ocular
irritation specially in eyes with severe KCS.
In order to reduce that amount of irritation, only a small drop should be
instilled into the eye. A topical anesthetic should not be used prior to the
instillation of rose bengal as it may produce a false-positive result.
• Alcian blue has the similar properties as rose bengal and is less irritant but
it is not generally available.
FIGURE 6.10: Bengal rose tincture (degenerated corneal and

conjunctival epithelial cells in the dry eye)
Lysozyme Assay
Lysozyme assay test is based on the fact that in hyposecretion of tears, there
may be reduction in the concentration of lysozyme. This test is performed by
placing the wetted filter strip into an agar plate containing specific bacteria.
The plate is then incubated for 24 hours and the zone of the lysis is measured.
The zone will be reduced if the concentration of lysozyme in the tears is
decreased.
Tear Globulin Assay

Tear IgA levels are measured in this test. This test is also based on the principle
that decreased tear formation will lead to decreased IgA (immunoglobulin
A) levels in tears (Figure 6.11). This test is performed on a specific tripartigan
immunodiffusion plates containing specific agar gel in wells. Twenty microliter
of tear samples is put into these wells and plates are incubated for 48 hours.
The diffusion of rings around wells are measured to nearest 0.1 mm with
partigen ruler. The ring will be reduced if the concentration of IgA in tears is
decreased.
This is a reliable test for measuring tear globulins.
Tear Osmolarity
• Tear osmolarity is increased in cases of hyposecretion.
FIGURE 6.11: Tear globulin assay—diagnostic test for

dry eye (Courtesy: Garg et al, Internationale
Ophthalmologica)
Biopsy of Conjunctiva
• Biopsy of the conjunctiva and an estimation of the number of goblet cells
are other tests which can be done. In mucin deficiency states, the number
of goblet cells shall be decreased.
Conjunctival Impression Cytology

Conjunctival impression cytology is a microscopic test to study the health of
conjunctival cells. In this mapping cells from the conjunctiva are directly taken
on to a slide and studied under microscope after staining. In dry eye condition
cells appear fewer, irregular in size and shape and take up straining less
uniformly confirming the condition (Figure 6.12).
MANAGEMENT OF DRY EYE

Although at present there is no satisfactory cure for dry eye, a number of
therapeutic modalities are available to relieve symptoms. Before starting the
treatment it is important to prepare the patient psychologically about the
FIGURE 6.12: Impression cytology mapping conjunctival cells

are fewer in dry eye (Courtesy: Allergan India Limited)
chronic nature of the condition, while reassuring him that with appropriate
treatment permanent damage to vision is unlikely.
Before treating, accurate diagnosis of the underlying cause is important
as it may give an indication of prognosis. Sometimes the underlying cause
may require treatment in addition to topical treatment given in dry eye cases.
Following treatment modalities are being used to treat dry eye patients.
Tear Conservation
Preservation of existing tears by reducing evaporation is initial sequence of
therapy indicated. Evaporation of tears is dependant upon temperature of
air at air-tear interface, humidity of air at the air-tear interface, air flow over
the ocular surface, surface area of the interpalpebral fissure and integrity of
the lipid layer of the precorneal tear film. Following measures may be helpful
in decreasing the evaporation of tears.
• Reduction of room temperature
• Use of a room humidifier or moist chamber
• Use of protective glasses with side pieces may protect the eye from the
effect of wind, dust, etc. in the outdoor settings
• In cases of severe KCS associated with corneal thinning partial tarsorrhaphy
may be helpful by decreasing the surface area of the interpalpebral fissure.
Tear Substitutes (Tear Replacement)

Artificial tears and lubricants are the mainstay in the treatment of dry eye.
Ophthalmic lubricants represent the cornerstone of the management of ocular
surface disease. A number of new formulations have been available

commercially which have additional advantage of limiting preservative toxicity
while enhancing epithelial cell growth.
Various tear substitutes available are as follows:
Artificial Tear Solutions (Eyedrops)

Tear substitute drops are the mainstay of treatment of mild to moderate
KCS. It is important that the patient should use these drops quite regularly
and frequently. The frequency of instillation vary on the basis of severity of
KCS signs and symptoms in the patient. In severe dry eye cases the patient is
advised to put these drops at hourly intervals while in moderate cases 4 to 6
times a day frequency is recommended. However the main drawback to
topical drops is its short duration of action. Artificial tear solutions usually
contain inorganic electrolytes, preservatives and water soluble polymeric
system. In addition to polymers, lipids and vitamin A have been added into
new ocular lubricants. Vitamin A topical preparations are shown to be effective
in severe forms of dry eye syndrome.
Following groups of topical hypotonic solutions are available for treating
dry eye cases.
Cellulose derivative: These topical hypotonic solutions contain methylcellulose

or ethylcellulose (0.1 to 1%) and 0.3 to 1 percent hypromellose.
A new topical tear solution of cellulose group commercially available
is Refresh Tears (containing 0.5% of carboxymethylcellulose sodium.) The
added advantage of this solution is that carboxymethylcellulose (CMC)
possesses strong mucoadhesive bonding which closely adheres to the epithelial
surface. Carboxymethylcellulose solution closely resembles the composition
of natural tears. It contains unique preservative sodium perborate which
breaks down to water and oxygen upon contact.
Polyvinyl alcohol base solutions: These topical solutions contain 1.4 percent
polyvinyl alcohol and 0.6 percent povidine. These two polymers enhance
comfort and maintain corneal health.
Specific properties of polyvinyl alcohol are it smoothes and cools the dry
irritated scratchy eyes, provides needed moisture to dry ocular surface and
does not blur vision. It lubricates to prevent further irritation and enhances
patient comfort.
Topical Solution Containing Longer Lasting Mucoadhesive

Topical solution containing longer lasting mucoadhesive or increased viscosity
agents like polycarbophil and dextran. On topical instillation these solutions
have better duration of action (contact time).
Polyvinyl pyrrolidone polymer base tear solution provides a longer contact

time.
Ointments
The second most common method for ocular lubricant is protrolatum, Lanolin
and mineral oil topical ointments. When instilled into the eye, they dissolve
at the temperature of the ocular tissue and disperse with tear fluids. A major
advantage of ointment is that it is retained in the cul-de-sac longer than
artificial tear solutions.
Ointment is generally applied directly to the inferior conjunctival sac (0.25-
0.50 inch ribbon) preferably at bed time. However depending upon the
severity of the conditions, it can also be used more frequently during the day
time also.
For treatment of moderate to severe dry eye a new lubricant eye gel is
commercially available which is a clear gel that liquefies and spreads rapidly
upon contact with the eye. It contains carbopal 980 (polyacryclic acid) a gel
with high water binding power that transforms gel to liquid upon contact
with the ocular tissue. It minimizes blurring and streaking common with thick
tears and ointments.
Carbomer gel is also available commercially which has markedly longer
residence time and has significant increase in the tear film break-up time at
10 minutes.
Ocular Inserts (Solid Devices)

For the relief of dry eye symptoms, preservative-free water-soluble
polymeric insert is also available. The cylindrical rod which contains 5 mg
hydroxypropylmethyl-cellulose (HPMC) (1 mm × 3 mm) is placed in
the lower cul-de-sac (slow dissolving polymers). It imbibes fluid and swells.
It starts dissolving within 6 to 8 hours releasing the polymer to the ocular
surface for 12 to 24 hours. However, patient tolerance and acceptance are
variable.
Gel Tears and Sodium Hyaluronate (0.1%)

Gel tears consist of clear, semisolid formulation of synthetic, high molecular
weight polymers of acrylic acid. This gel remains in the conjunctiva for several
hour after instillation and dissolves very slowly.
Topical sodium hyaluronate (0.1%) solution has been shown to have
properties similar to those of normal tears. This solution has a possible role in
the dry eye cases.
Soft Contact Lens Therapy

Hydrophilic bandage lenses often provide a tear reservoir but it should be
used in conjunction with replacement tears. Caution should be taken because
such patients are prone to contact lens intolerance and superinfections.
Forniceal scarring may dislodge the lenses.
Punctal Plugs (Tear Drainage Reduction)

Mechanical occlusion of the lacrimal puncta has become an accepted method
of block tear drainage and thereby prolong action of natural tears alongwith
artificial tear preparations. Two types of punctal plugs are currently used—
silicone-based plug and temporary absorbable collagen implant. Temporary
punctal occlusion can be performed by inserting 0.2 to 0.4 mm collagen
plugs. The main aim of temporary occlusion is to ensure that excessive wetness
does not occur following permanent occlusion.
Punctum silicone plugs are also available in 1.6, 2.0 and 2.8 mm sizes.
Placement of implant in all four canaliculi is recommended to prevent a
false-negative response and patient is examined after one week. If it causes
epiphora then upper plugs are removed.
Permanent punctal occlusion is recommended only in patients with severe
dry eye symptoms. Permanent occlusion should be avoided in young patients
as their tear secretion tends to fluctuate more than in the elderly patients.
Permanent occlusion is achieved by electrocautery after local anesthesia.
Following successful punctal occlusion it is important to watch for the signs of
recanalization. Argon laser canaliculoplasty is new method of permanent
occlusion which can be easily reversed.
Mucolytics
Topical 5 percent acetylcysteine drops are recommended for instillation four
times a day. It is effective in eyes with excessive mucus. It helps by dispersing
the mucous threads and decreasing tear viscosity.
Topical Retinoids
Topical retinoids have been shown to be effective in reversing the cellular
changes occurring in the conjunctiva of dry eye patients.
Systemic Therapy
Systemic corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs)
may help in low-grade inflammation of the lacrimal gland in dry eye patients.
Treatment of underlying systemic disease in patients with secondary syndrome
with corticosteroids or NSAIDs may ameliorate the symptoms of KCS.
Oral Bromhexine
Oral bromhexine (32 mg/day) has been reported to be effective in the
treatment of dry eye cases bromhexine has been clinically tried to stimulate
tear production. Such compounds require the presence of normal lacrimal
gland that responds to stimulation.
Treatment of Associated Conditions

Blepharitis
Interference with normal lubrication cleansing function of the tears as well as
the decreased lysozyme content put dry eye patients at risk for chronic low-
grade infections. Such infections of the eyelid margin can aggravate the
underlying tear deficiency. So, blepharitis should be treated with adequate
lid hygiene and antibiotic therapy when necessary.
Infections
Dry eye patients are exposed to increased risk of infection so special care
should be taken when cataract surgery is contemplated on a dry eye. Corneal
grafting is also difficult in patients with severe dry eye as is wearing of contact
lenses.
SURGICAL MANAGEMENT OF DRY EYE 101
INTRODUCTION
Surgery is usually the last step in the treatment of dry eye, although some
surgical techniques may be indicated in moderate or even mild dry eyes. We
must not forget that it must always be associated with correct psychological,
enviromental and medical treatment.
There are two possible objectives in the surgical management of these
patients:1
• Decreasing the outflow of the lacrimal sea to keep the tears or lubricants
for longer over the lacrimal basin. This can be done by lacrimal pathway
obstruction, cisternoplasty or reduction of the interpalpebral fissure.
• Increasing the inflow of lubricant into the lacrimal basin. These lubricants
can be saliva (increased by Stenon’s duct transposition or salivary gland
transplantation) or artifical tears (artificial tears reservoirs).
We include lacrimal plugs as a surgical treatment because the etiological
meaning of the word surgery is “work done with the hands” (from Greek,
cheir (hand) and érgon (work)].
Surgical treatment should begin with the less aggressive methods (such as
lacrimal plugs or canalicular occlusion) and as prevalence of very severe dry
eye is low, aggressive surgical techniques are rarely required.
DECREASING THE OUTFLOW OF THE LACRIMAL SEA

Obstruction of the Lacrimal Pathway
Under physiological conditions, the lacrimal pathway drains 90% of the
lacrimal sea, and the remaining 10% is eliminated by evaporation. These
proportions are highly variable, depending on the quantity and quality of
the tear, the effect of the lacrimal pump and several enviromental
circumstances. Environmental treatments try to decrease evaporation from
the surface and so, improve the tantalic component of dry eye. The obstruction
of the lacrimal pathway prevents the natural drainage fron the lacrimal sea,
and is nowadays the first step in the surgical treatment of dry eye.
General Considerations
Any type of dry eye may improve by occluding the lacrimal pathway,
nevertheless, it is specially indicated in aqueous-deficiency. As it only blocks
the drainage of fluid, it is advisable to have at least some amount of aqueous
secretion, even though it also increases the time that the artificial tear remains
on the surface of the eye.
There is not a formal algorithm for the treatment of dry eye. Each author
considers lacrimal occlusion on the basis of his own experience. We consider
that reversible occlusion is indicated in transient xerophthalmic conditions
(such as some pharmacological types of dry eye, like anxiolytics or estrogenic
anticonception). Permanent occlusion is considered in some patients with
symptoms but without signs for whom the use of eyedrops is restricted because
of occupational, physical or psychological limitations. It is very useful in patients
with reversible signs and compulsory in those with irreversible dry eye signs.
One or both canaliculi can be occluded. It is thought that the inferior
canaliculus drains 80% of the tear and the superior the remaining 20%.
Clinical data suggests that, in normal conditions, although both canaliculi
drain almost the same amount of fluid, the amount is slightly higher in the
inferior canaliculus. Pathologic conditions show us the great variablity in
lacrimal drainage:2-4
• The occlusion of one canaliculus (either inferior or superior) does not
usually produce epiphora.
• Patients with obstruction of one canaliculus (either superior or inferior)
and the rest of the pathway patent to irrigation may have epiphora.
The election of which canaliculus to occlude depends on the grade of dry
eye. In moderate dry eyes, we usually begin with the inferior canaliculus, not
only because it may have a slightly higher flow, but also because it is easier to
work on.5 In the case of severe dry eye, both canaliculi can be occluded, and
although this can be done simultaneously, we prefer to do the procedure in
two different surgeries to enable us to evaluate the effect of the first occlusion.
When occluding both canaliculi at the same, intermittent epiphora is more
frequent when the lacrimation reflex is stimulated, particularly in young people.
This intermittent epiphora can produce discomfort and is yet another reason
for occluding both lacrimal pathways in different surgical times.6
Benefits of lacrimal occlusion include: enlargement of the lacrimal meniscus
by increasing the aqueous component of the tear, 7 decrease of tear
osmolarity,5,8 improvement in epithelial staining, increase of mucin globet
cells,9 improvement of the symptoms and signs, and decrease in necessity of
artificial lubricants.7,12-14 All these effects improve the psychological discomfort
and improve the patient’s quality of life.15
Before performing any canalicular occlusion, a nasolacrimal duct

obstruction must be ruled out because:
• The outflow of the mare lacrimal will not decrease (it is already blocked).
• There is a high risk of complications in the form of acute dacryocystitis or
lacrimal mucocele.10,11
Although several methods have been used to block the lacrimal pathway
most of them have fallen into disuse, due to the efficacy of the lacrimal plugs
and punctal patchs.
Dacryocystectomy
Dacryocystectomy, pioneered by Beetham in 1935,12 has very few indications
in the treatment of dry eye. We only consider it in cases of eldery patients
with episodes of acute dacryocystitis asociated with dry eye symptoms. In
young patients we prefer to perform a dacryocystorhtinostomy (DCR)
associated to canalicular obstruction as it can be reverted if necessary.
Canalicular Decalage
A vertical lid incision medial to the lacrimal punctum is done, cutting the
horizontal portion of the canaliculus. Then both cruent openings are cauterized
and the lid is sutured with an offset of both cauterized portions. Frueh16
proposed this as an option when cauterization of the punctum failed on two
occasions.
Canalicular Ligature
It can be done as a temporal treatment (temporal stitch test) or as a permanent
procedure. The main use of these sutures has been as an adjuvant treatment
to cauterization.17 A transpalpebral U point is passed though the vertical
portion of the canaliculus, and tied over the skin.
Canalicular Excision
This consists in the excision of the horizontal part of the canaliculus. The first
description of this technique was made by Sysi18 in 1949. He introduced a
lacrimal probe in the canaliculus and performed a conjunctival incision parallel
to the lid margin and 2-3 mm from it. He excised the horizontal portion of
the canaliculus as medially as possible through this incision, and then sutured
the incision and cauterized the lacrimal punctum.
Another technique, described by Putterman,19 consisted in cutting the

posterior wall of the horizontal portion of the canaliculus through the
conjunctiva. When the canaliculus is opened, the punctum and canaliculus
are excised, until the lacrimal sac if the process includes both superior and
inferior canaliculi, or just to the common canaliculus if it is only done in the
inferior canaliculus. The wound is closed with a 6/0 reabsorbable suture. The
main complication of this technique is the cicatricial entropion of the medial
third of the inferior lid as this procedure is also irreversible, despite being
almost 100% effective, we prefer other methods that are less effective but
more easily reverted if necessary.
Transfer of the Punctum to Dry Dock

This was the first reversible technique described. It consisted in moving the
puctum out of the lacrimal sea, but preserving its patency. 15,20 After
identification of the vertical portion of the canaliculus with a small L-shaped
probe, a circular 2-2.5 mm incision around the punctum is done. The
dissection is extended approximately 2 mm around the vertical portion of
the canaliculus including the muscular and fibrous layers. It is very important
not to cut the horizontal portion of the canaliculus because the cicatrization
makes the technique irreversible. Once the vertical portion is dissected, the
anterior part of the cylindrical incision is opened with a postero-anterior
rectilineal cut until reaching the skin of the anterior surface of the lid. Then
the vertical portion is rotated fowards allowing the punctum to emerge between
the eyelashes, where it is sutured. The hollow left by the vertical portion is
closed with a reabsorbable suture (Figure 7.1). Retraction of the fibrous and
muscular layer of the canaliculus is frequent, and so it is difficult to revert the
procedure. This technique has fallen into disuse as nowadays there are more
simple reversible techniques such as the punctum patch technique.
Punctal Patching
This consists in changing the operculated surface of the punctum for a non
operculated one, which can be both bulbar conjunctiva or skin.1,15,21,22 This
blocks the entrance of tear to the lacrimal pathway.
The surgical technique has two main parts:
1. Exposure of the punctum and removal of its surface.
2. Covering the cruent layer with a flap or graft.
FIGURE 7.1: Punctum to dry dock. A: A circular 2-2.5 mm incision around the
punctum is done, extended approximately 2 mm around the vertical portion
of the canaliculus. B: The anterior part of the cylindrical incision is opened
with a postero-anterior rectilineal cut until reaching the skin of the anterior
surface of the lid. C: The vertical portion is rotated forwards. D: Suture of the
punctum and wound
1. We prefer to expose the punctum with an L-shaped strabismus forceps,

clamping the horizontal portion of the forceps parallel to the lid margin
about 3 mm distant from it. If the end of the forceps is in the parasagittal
plane of the punctum, when it is rotated fowards, the punctum is exposed.
This is particularly useful in the superior punctum, where more traction
over the eyelid is needed. Another way to expose the punctum is by
passing a U suture through the lid with the loop on the external surface.
The two transpalpebral sutures are passed approximately 2 mm distant
from the lid margin, and 3 and 6 mm lateral to the punctum respectively.
When the sutures are tractioned foward the punctum is exposed. When
working only over the inferior punctum, sometimes the assistant surgeon
can manage the exposure by just tractioning the medial inferior lid third
downwards with his finger or a microsponge.
Once the punctum is exposed, a 2x2 mm squared-shaped portion of
the superficial epithelium of the punctum is removed with a knife blade
(Figure 7.2).
FIGURE 7.2: A 2 × 2 mm squared-shaped portion of the superficial

epithelium of the punctum is removed with a knife blade
2. The cruent surface of the punctum can be covered in three ways:

• A free conjunctival graft1,15,22,23,24 (Figure 7.3). The graft can be
obtained from the bulbar or the cul-de-sac conjunctiva (Figure 7.3A).
A 3x3 mm square of conjunctiva is dried with a microsponge and
marked with a dermographic pencil. The use of local infiltration with
an anesthetic facilitates the incision, and the detachment of the
conjunctiva or the conjunctiva-tenon complex by blunt dissection.
Staining the epithelial surface of the conjunctiva is very useful for
identifying the external surface once the graft is removed. The fragment
of conjunctiva is placed over the cruent lid margin wound (Figure
7.3B). It is very important to keep the epithelial side exposed to the
air, so both cruent surfaces adhere together. The graft is then sutured
with four absorbable stitches, one in each corner. To avoid erosion of
the bulbar conjunctiva the posterior sutures can be buried. The suture
is removed one week later.
• An advancement cutaneous flap: With a dermographic pencil, the
tranversal borders of the punctum wound are prolonged about 6 to
8 mm on the lid skin. The skin of the anterior lamella is incised with a
knife blade and dissected over the orbicular plane, building a skin
flap. The two corners of the flap are sutured to the posterior corners
FIGURE 7.3: Mucous patch. A: An epithelial and subepithelial

2 × 2 mm piece of tissue is eliminated with a scalpel. B: A 2 × 2
quadrilateral piece of bulbar conjunctiva is taken and placed
covering the punctal wound. C: The conjunctival patch is sutured
with four 8/0 reabsorbable stitches
of the punctum wound with two absorbable buried stitches. Then

another two stitches fix the lateral portions of the flap to the adjacent
eyelid skin. It is very important that the flap does not have much
traction as it can alter the shape of the lid margin.
• A free skin graft (Figure 7.4): A square of skin from the upper eyelid
is resected under local anesthesia (Figure 7.4B). The rest of the
technique is the same as for the free conjunctival graft (Figure 7.4C).
We prefer the free skin graft, as it is simple and easy to perform, the rate
of spontaneous reopening is low, and the superior portion of the canaliculus
is kept almost intact thus making it easy to revert. It is reversible by two
different methods: By removing the patch over the punctum, or by making
a two-snip punctoplasty over the location of the vertical canaliculus.
We perform the punctum patch in patients with moderate dry eye. We
usually begin by patching only the one or the two contra-altitudinal puncta
of the driest eye so the patient can compare the result with the other eye,
and it can be decided whether or not to do the other one some weeks later.
Sometimes, if the patient has been treated with lacrimal plugs with evident
improvement of the symptoms, the patch can be placed in those puncta that
FIGURE 7.4: Cutaneous patch. A: 2 × 2 square of epithelium

surrounding the punctum is removed. B: A square of skin is taken from
superior eyelid and placed with its raw surface on the punctum wound.
C: The skin graft is sutured with 4 reabsorbable 8/0 stitches
had the plugs (after removing the plugs of course). It is also very important
to inform the patient that patching is only a symptomatic treatment, and that
the objective is to improve his condition. The patient must be aware of the
circadian rhythm of secretion, as night improvement may involve tearing in
the morning, and vice versa a good correction in the morning may imply
certain dryness at night. If there is postoperative tearing, one punctum can
be reopened.
Thermal Occlusion
Thermal energy provokes the dehydration of intra and extracellular water and
the denaturalization of tissular proteins, producing the destruction, shrinkage
and closure of the canalicular walls. There are three main methods (Table 7.1)
cautery, diathermy and laser. We will describe all the different methods with
the correct name given by its physical properties as the terms “cautery” and
“diathermy” are frequently used as synonyms. The literature about thermal
occlusion often produces confusion for the reader about the different methods.
Cautery
Cautery uses an independent source of heat to occlude the lacrimal pathway.
Although using an electrical current to produce heat, the current does not
TABLE 7.1: Methods for thermal occlusion of the
lacrimal pathway
1. Cauterization
a. Pyrocauterization
b. Galvanocauterization
2. Diathermy
a. electrocoagulation
- monopolar
- bipolar
b. electrodesiccation
c. electrofulguration
d. electrolysis
3. Laser
invade the tissues of the patient (as we will see this is the main difference with
diathermy, in which it is the current that is passed through the patient that
heats the tissues). As the source of heat is still hot after use, it must be handled
with care so as not to harm other ocular structures. There are two main types
of cauterization:
Pyrocautery (ferrum candens): It uses a red-hot probe heated by an external

flame, and was the first thermocautery described in medical history. Its main
drawback is that the probe is already warm before entering the punctum or
canaliculus, and as its temperature decreases once separated from the flame,
it is very difficult to adjust the effect of the cauterization. Nowadays it is almost
obsolete, and is only used in some underdeveloped environments.
Galvanocautery: It is based on the Joule effect. It consists of a fine U-shaped

wire through which runs a direct continuous galvanic current, delivered by a
battery that heats it. As mentioned before, the current does not pass to the
body of the patient. It applies the heat directly to the adjacent tissues and
from them, it is transmitted to deeper layers. So, to have a thermal effect on
the deeper tissues, it is necessary to overheat the superficial layers around
the cautery, which involves more risk of local necrosis.
It can be used as a temporary or permanent procedure.
The temporarly occlusion technique only cauterizes the punctum area. It
can be managed by placing the tip of the loop next to the punctum without
touching it,25 touching it lightly19,26 or introducing the tip into the first 0.25 mm
of the vertical canaliculus.27 The thermal energy is applied for around
1 second, usually until the tissue to be cauterized begins to whitening. The
results are very unpredictible, and the occlusion can last from one week to a
few hours.19,25 In very light cauterizations, the edema of the surrounding

tissues may block the canaliculus, even without an anatomical thermal
occlusion. Sometimes the hypersecretion lacrimal reflex to tissular injury may
produce tearing, giving the erroneous supposition that the canaliculus is closed.
The permanent occlusion is managed by cauterizing a more extensive
portion of the pathway. After dilating the proximal segment of the canaliculus,
the wire is introduced as far as necessary. The exact point can affect just the
punctum, or be as far as the lacrimal sac.26,28 The wire must be cold when
entering the canaliculus to avoid damage to other structures. Once in place,
the galvanocautery is activated until the whitening of the tissue for around
1 or 2 seconds. The tip can be withdrawn quickly or gradually, and it is very
common to remove the fibromuscular ring of the punctum adhered to the
tip of the cautery. Our technique is to introduce the tip just into the vertical
canaliculus, warm for 1-2 seconds until the punctum becomes white, and
remove the tip quickly so no more than the desired heat is delivered to the
tissues (Figure 7.5).
The galvanocautery is not as effective as the punctal patch.21 Its effectiveness
depends mainly on the length and depth (the more time and intensity applied,
the deeper layer reached) of the canaliculus cauterized.12,14,17,26,30 if it only
FIGURE 7.5: Galvanocautery. The cautery is introduced

into the vertical canaliculus
affects the punctum, approximately 50% of them reopen in one month after
surgery. If the cauterization includes an area of 1.5 mm from the punctum,
the rate of reopening drops to 25%. When the whole vertical portion is
cauterized only 7% reopen one month later (Table 7.2). The two main
complications besides reopening are, deformity of the eyelid margin (seldom
significant) and fistulization of the lacrimal pathway.26 Some authors agree
that deformity could even be favorable, so if the occlusion is not complete,
the injury to the lacrimal pump and the displacement of the punctum out of
the lacrimal sea, may contribute to the treatment of dry eye.14,16 We use
galvanocautery when the patient refuses the punctum patch.
TABLE 7.2: Rates of failure of galvanocautery for canalicular occlusion

Canalicular length affected Rate of reopenings at 1 month
Just the punctum 53%
1.5 mm of the vertical portion 25%
The whole vertical portion 7%
The cauterization of the vertical canaliculus, although not as easy as the

punctal patch, is also reversible. There are several ways to reopen the
canaliculus. The first option is to probe the canaliculus directly (in those cases
in which occlusion was not complete). If the canaliculus is closed firmly, this
maneuver is useless. The second step is to retrogradely probe the canaliculus
with a pig-tail from the upper punctum. As with the first step, this procedure
is seldom effective. The third and definitive step is to open a carunculo-
canalicular window. This can be managed by making a vertical incision through
the posterior lamella lateral to the vertical portion of the canaliculus, near the
caruncular tract. The horizontal canaliculus is located about 2-3 mm in depth
from the conjunctiva. If a probe can be passed retrogradely to the punctum,
a 2 snip punctoplasty can be easily made. If the canalicular scar does not let
the probe pass, a new artifical lacrimal punctum must be opened guided by
the probe with a sharp knife blade. To prevent the occlusion of the new
punctum a bicanalicular grooved stent is left for several weeks.
Diathermy
In diathermy, the heat is not produced in the probe. It uses a high frequency
electrical current that passes through the patient’s body, produces vibration
of the molecules, heating the organic hydrated tissues. So unlike cautery, the
tip of the probe always remains cold. Moreover cautery can self-sterilize by
FIGURE 7.6: Punctum diathermy
heating the tip, but diathermy can not. The electrode that contacts the
canaliculus (Figure 7.6) is the active electrode (it produces the energy) that is
spread in the patient’s tissues, and gathered by the passive electrode, located
at a distance from the active electrode on the body. This passive electrode
usually has a large surface so does not produce heating in the surrounding
tissues. The effect of the diathermy depends on the length of the active
electrode, the contact surface, the intensity of the current and the application
time. As in galvanocautery, diathermy can be used only in the lacrimal
punctum for a temporary effect, or when deeper into the canaliculus for a
permanent occlusion. Generally the tips of the diathermy have an isolating
coat that protects the surrounding tissues, so the current is only applied in
the bare last millimeter of the electrode. This helps to preserve the anatomy
TABLE 7.3: Types of diathermy

Type of Type of Active Passive
diathermy current electrode electrode
Electrocoagulation (monopolar) Alternating Fine Plate

Electrocoagulation (bipolar) Alternating Fine Fine
Electrodesiccation Alternating Fine None
Electrofulguration Alternating Fine (not None
touching tissues)
Electrolysis Direct
of the upper portion of the vertical canaliculus, so it can be more easily

reverted if needed, although in most cases, it is not possible and requires a
carunculo-canalicular vent to resolve the obstruction. The effectiveness of
diathermy is a little bit lower that galvanocautery with reopening rates of
about 20%. We prefer galvanocautery to diathermy because it is more effective
and easier to apply.
There are several forms of diathermy:
Electrocoagulation: It uses an alternating current that flows through two

electrodes. The active electrode is always a fine tip, so the current is very
condensed around it. It is located where we want to apply the diathermy. There
are two types of electrocoagulation depending on the shape of the passive
electrode: Monopolar, if it has the shape of a dispersive plate and is located
at a distance in the body of the patient, it attenuates the current without heating
the tissues next to the plate (it is also called “indifferent electrode”). And bipolar,
if the passive electrode is as fine as the active electrode. It becomes an “active
electrode”, and has to be placed very close to the other active electrode to
maintain the same surgical area. There is no clear reference to bipolar diathermy
applied to the lacrimal pathway in the literature. In most cases this is probably
a confusion of terms as we have previously mentioned.
Electrodesiccation: This is as the monopolar electrocoagulation, but without

the passive electrode (dispersive plate). The operating table and the electrical
outlet functions as a passive electrode. It has been rarely used in humans.31
Electrofulguration: This is as electrodesiccation, but the tip of the active
electrode is held away from the patient’s tissues, resulting in sparking to the
surface. Again, the terms used by the author of the only paper in which it has
been described32 are confusing, and probably electrocoagulation was used
instead of electrofulguration.
Electrolysis: This is a monopolar diathermy but uses direct electrical current
instead of alternating current. It adds an electrolytic effect to diathermy. There
are two types of electrolysis: If the active electrode is electronegative (cathode)
it attracts cations (Na+, K+, Ca2+, etc.) so the burn is alkaline, aqueous and
extensive. If the active electrode is electropositive (anode) it attract anions
(CO3-, SO4-, etc.) producing an acidic, dry and retractile burn. Again, we
have found no clear report of true electrolysis used to occlude the lacrimal
pathway.
Punctal Laser Photocoagulation

The Argon laser has been used both to close the lacrimal canaliculus and to
open occluded punctum. The results in both procedures are very variable
and unpredictable.
The main advantage of laser is that it can be managed with topical or no
anesthesia, and that we have the benefit of the magnification of the slit-
lamp. Most authors find no advantage over cautery or diathermy.28,31-33 The
parameters used to occlude the punctum vary among the authors. Herrick,34
the first using this method, applied: 400-700 μm spot size with 2 W to the
epithelium, and after cleaning the debris, he continued with a 400 μm spot
and 2 W of power in the vertical canaliculus until tissue contraction. Many
other techniques have been described with different spot sizes and power.
The effect depends on the skin color of the patient, and the punctum of
Caucasians need more power.
Canalicular Plugging
Canalicular plugs have been used with several objectives. Nowadays their
main functions are:
• To temporally block the lacrimal drainage in the treatment of dry eye
(actually this is the main way to produce a reversible block).
• To predict the effect of punctal occlusion before a definitive method is
offered.35-37
• To increase the effect of topical drugs by increasing their absorption.38-40
• To decrease the systemic effects of some topical drugs (i.e. phenylephrine).
• To determine the activity of each canaliculi separately.36,41
• To prevent punctal or canalicular occlusion after different types of palpebral
injuries.36
• As a therapy for contact lens intolerance.42
Many different material and shape implants have been assayed for
blocking the lacrimal pathway:
Absorbable Plugs
At present they are less frequently used than non-absorbable plugs. The
different materials used are: Catgut, now banned in many countries because
of Creutzfeldt-Jacob disease, N-butylcyanoacrylate glue, gelatin, collagen
implants and hydroxypropyl cellulose inserts. They are generally inserted on
the horizontal canaliculus. They usually do not block the lumen completely,37
FIGURE 7.7: Punctum plug
although enough for the temporal improvement of the dry eye or predicting
the utility of a permanent blocking.56
Nonabsorbable Plugs
The first use (Jones, 1973) of nonabsorbable implants was to determine the
contra-altitudinal canaliculus function.43 Freeman, in 1975, was the first to
block the canaliculus with nonabsorbable plugs as a treatment of dry eye.44
• Plugs for the vertical portion (Figure 7.7): Although they vary in form,
almost all have the same diabolo-like shape. They have a narrow center
cylinder to be placed in the “angustia lacrimalis” (small narrow portion of
the vertical canaliculus) to block the flow of tear, between a proximal flat
plate located over the punctum in order to prevent the intracanalicular
migration of the plug, and a distal belly-shaped dilatation that is located
in the “ampulla lacrimalis” (the angle between the vertical and horizontal
canaliculi), distal to the angustia lacrimalis, that prevents extrusion. The
first material to be commercialised was silicone (Freeman’s plug) although
the initial description published was with hydroxyethylmethacrylate of
teflon.44 This first plug had a rectilineal axis, perpendicular to the flat
plate. Hamano changed the material of the plugs to expandible
polyvinylpyrrolidone with polymethylmethacrilate,45 and Bernard and
Fayet changed the axis from perpendicular to oblique (20º).46-48
They are placed under topical anesthesia. After punctum dilatation, the
plug mounted on a loader is inserted into the vertical canaliculus leaving the
external flat plate over the punctum. Once there, one only has to push the
trigger of the loader to leave the plug in place.
This kind of plug is the most frequently used. The effective tamponade is
usually 100% if the proper size plug is chosen.54 Local discomfort only occurs
in 25% of the patients. Other complications include:5,47,48,50,51,54,55 Extrusion
of the plug, migration through the lacrimal pathway, rupture of the
fibromuscular ring of the punctum due to overdilation, erosion of the
conjunctiva or cornea (more frequently occuring in superior punctum plugs),
canaliculitis, epiphora (both beacause of tear block and hypersecretion
stimulated by a foreign body), pyogenic granuloma and canalicular stenosis
(secondary to chronic inflammation or acute canaliculitis). Punctal occlusion
may affect the ocular surface/lacrimal gland interaction, more pronounced
when both puncta are occluded. This effect normalizes in approximately 2
weeks after punctal occlusion.
Plug for the ampulla lacrimalis. An hydrophobic, thermoplastic acrylic material

is the main compound of the “Smart plug”. When introduced into the
canaliculus, the body’s temperature heats the implant over 32ºC retracting it
from a cylinder shape (8 mm long and 0.4 mm wide) to an ovoidal one
(2 mm long, 1 mm wide) that completely fills the ampulla lacrimalis (Figure
7.8). After dilatation of the punctum, 2/3 of the cylinder are placed into the
canaliculus, leaving 1/3 outside. When the implant retracts with temperature,
the external third will be dragged into the canaliculus, the whole implant
resting in the union of the vertical and horizontal canaliculus.
Plug for the horizontal portion: Herrick’s golf-tee-shaped plug (Figure 7.9) is
introduced into the horizontal canaliculus placed on the top of a probe, with
the same maneuvering as when probing tha lacrimal pathway.49,57 After
entering the vertical portion, the probe is rotated 90º and pushed through
the horizontal canaliculus. After placement, the probe is removed, leaving
the plug in the horizontal canaliculus. The main problem of this implant is
that once left in the canaliculus, it is very difficult to know if it is still in place or
not, as syringing or probing the canaliculus can dislocate a plug that was
previously well located. If it migrates into the lacrimal sac, it usually remains
asymptomatic although sometimes, mild discomfort can be produced by the
sacular foreign body. The least hyatrogenic way to remove the plug is to
push it to the lacrimal sac by probing or syringing. Retrograde probing with
FIGURE 7.8: Different sizes of a Smart Plug before and

after the contraction procedure
FIGURE 7.9: Herrick’s plug
a pig-tail can sometimes remove the plug, although there is a high-risk of

hyatrogenic damage to the canaliculus.
Cysternoplasty
The cisterna lacrimalis is the lateral part of the interpalpebral fissure, occupied
by the interpalpebral menisci. It receives the main flow of tear from the
FIGURE 7.10: Cysternoplasty
lacrimal gland, and runs along the interpalpebral fissure forming the lacrimal
film. This lacrimal cistern contains about 0.1-1 μl of fluid. The objective of
the cysternoplasty is to increase the size of the lacrimal cistern to allow it to
store more tear, thus increasing the lacrimal film and keeping it in contact
with the globe for longer (Figure 7.10). There are three surgical
techniques:1,23,52,53
Double Local Flap Cysternoplasty

After local anesthesic infiltration, a 2 mm long deep incision is made in the
posterior lamella, 1 mm away from the gray line. Two discharge transversal
incisions are made at the margins of the first one, perpendicular to it. Both
skin sheets are rotated outwards and sutured one to another with two mattress
stitches for 1-2 weeks..
Rotational Flap Cysternoplasty (Figure 7.11)

Under local anesthesia, 2-3 mm of eyelashes of the lateral lid are removed.
A 2-3 mm incision in the superior lateral lid is done, adjacent to the lid
margin. The medial part of the incision is prolonged perpendicularly with a
curved line of 5-6 mm. The lateral incision is prolonged downwards 2-3 mm
along the inferior eyelid keeping an oblique direction, to descend about 1-
2 mm from the lid margin at the same distance from the canthus as the first
incision. A fourth cut from the end of this incision is made perpendicularly to
FIGURE 7.11: Rotational flap cysternoplasty. A: A cutaneous 4 step

incision is made. B: The resulting flap of the inferior eyelid is turned
upwards and sutured to the superior lid. C: The flap of the upper eyelid
is rotated downwards to be sutured to the lower lid. D: The superior
eyelid flap covers the cruent surface of the inferior eyelid flap
the lid margin (Figure 7.11A). Two flaps are created. The first flap is obtained
from the inferior eyelid triangle formed between the third and fourth incisions
and the lid rim (Figure 7.11B). This flap is detached as thinly as possible,
rotated upwards and sutured to the medial margin of the first incision (the
cruent surface is outwards). The second flap is obtained from the two first
incisions and is brought down and sutured to the inferior cruent margin of
the inferior eyelid (the cruent surface is inwards) (Figure 7.11C). Other stitches
may be given to secure the stability of the flap (Figure 7.11D).
Rhomboid cysternoplasty (Figure 7.12): Again after local anesthesia and
plucking the same eyelashes, a 6 steps rhomboid incision is made. Two 2 mm
long incisions are made at the root of the eyelashes in both lids, without linking
them in the lateral margin. Each incision is prolonged upwards for the same
distance and height as the first ones (as the specular image of the first incisions).
Then, both incisions are linked laterally at the same distance as the first step
(Figure 7.12A). The rhomboidal flap is dissected begining from the lateral
portion, and leaving it attached to the base in the lateral cantus. The lateral half
of the rhomboid is flipped inwards to affront both cruent sides, transforming
it into a triangle (Figure 7.12B). Then, the triangle is flipped outwards to cover
FIGURE 7.12: Rhomboid cysternoplasty. A: The skin of the lateral canthus

is cut following a 6 step incision. B: The resulting rhombus is detached
from the underlying tissue, with the exception of the anterior angle. The
lateral half of the rhombus is turned inwards and sutured to the anterior
angle, transforming the rhombus into a triangle. C: The resulting skin
triangle, epithelialized on both sides is rotated fowards, its upper angle
sutured to the medial end of the superior palpebral incision, and the
lower angle sutured to the medial end of the lower palpebral incision. D:
The skin wound is closed
the lateral palpebral fissure, suturing it to the cruent margins of the first two
incision (Figure 7.12C). Only four stitches are needed, one in each vertex of
the triangle, and one in the lateral skin defect (Figure 7.12D).
Cysternoplasty techniques are easy to perform, and the resulting
cysternoplasty is difficult to notice in frontal vision, and is hidden by the
eyelashes in lateral vision. We consider this procedure in moderate dry eyes
for increasing the effect of natural or artifical tears. Residual eyelashes usually
do not disturb the patient. Rotational flap cysternoplasty is our technique of
preference.
Reduction of the Interpalpebral Fissure

Exposed ocular surface is about 2 mm in the primary gaze position, varying
from 1 mm in infraversion and 3 mm in supraversion. To diminish
spontaneous evaporation of the tear from the ocular surface, dry eye patients
usually present reflex blepharospasm (also related to superficial punctate
keratitis). Artificial reduction of the exposed ocular surface has been used in
some cases as a treatment for dry eye. There are two forms to reduce the
exposed area: with a blepharorrhaphy or with a provoked blepharoptosis.
We only consider making a blepharorrhaphy in case of severe corneal ulcers.
Blepharorrhaphy
Linkage between both contra-altitudinal lids can be managed by two
procedures:
Temporal blepharorrhaphy: By just suturing both lids together without any

cruent surface between them so no cicatrization occurs. A 6/0 silk is placed
through the gray line in both lids and tied firmly to close the palpebral fissure.
It can last approximately 2-3 weeks.
Permanent blepharorrhaphy (Tarsorrhaphy): By suturing both lids after

removing the superficial layer of the lid so cicatrization can occur between
the two cruent surfaces of the lids. First, the surface of the margin is taken
away with a knife blade. Then both palpebral lamellas are dissected and
sutured with single non-transfixiant stitches (6/0 absorbable material) to the
contra-altitudinal respective lamella.
There are four main types of blepharorrhaphy used in the treatment of
dry eye:
Lateral blepharorrhaphy: The length can be as long as needed, from 2 mm

to a complete closure. It is normally made in form of tarsorrhaphy. When
less than 2 mm, it is usually unnoticeable.
Precorneal blepharorrhaphy: Usually a temporal blepharorrhaphy used to

treat severe corneal ulcers.
Medial blepharorrhaphy: This encompases two specific techniques for dry

eye. The Prepunctal Blepharorrhaphy is a tarsorrhaphy joining the 3 mm
medial to the superior and inferior lacrimal punctal.1,23 Its effects include:
reducing the exposed ocular surface by about 25 mm2, the interpalpebral
fissure about 1 mm in the center of the cornea, and closing the lacus lacrimalis.
The main problem of medial blepharorrhaphy is the esthetic alteration which
is not accepted by all the patients. The Punctal blepharorrhaphy is a
tarsorrhaphy that includes both puncta lacrimalia (Figure 7.13).1,23 The surface
FIGURE 7.13: Punctal blepharorrhaphy
removed must include at least 1 mm of tissue arround the punctum. As both

puncta are not symmetrically placed, once sutured, the inferior punctum will
be lateral to the superior punctum. It acts as a prepunctal blepharorrhaphy
that also occludes the lacrimal pathway.
Provoked Blepharoptosis
Some authors have proposed performing a Müllerectomy to diminish the
palpebral fissure. We only use this technique for some superior eyelid
retractions, and never in the management of dry eye.
INCREASING THE INFLOW OF THE LACRIMAL SEA

Supplying Saliva
Saliva is an accessible corporal fluid, that is well tolerated by the eye.
Nevertheless it has several differences with tear (Table 7.4). Total saliva is an
admixture of several different glandular secretions. Parotid secretion is mainly
aqueoserous, submandibular glands produce a 90% aqueoserous and 10%
mucous fluid and sublingual secretions are predominantly mucous (90%
mucous, 10% aqueoserous). The minor salivary glands produce different
types of fluid depending on their location.
There are several ways for increasing the inflow of saliva to the lacrimal
basin: Stenon’s duct transposition, interocular decantation and salivary gland
transplantation (with or without vascular anastomosis).
TABLE 7.4: Differences between tear and total saliva

Tear Total salivar
Specific weight 1004-1008 1002-1012
Surface tension 40 dyne/cm 15-26 dyne/cm
Osmotic pressure 300-310 mOsm/l 200-310 mOsm/l
pH 7.47 6.75-7.25
Viscosity (at 37ºC) 1 centipoise 2-3 centipoise
Stenon’s Duct Transposition

First described by Filatov and Chevaljev in 1951,58 it consists in changing the
drainage of the parotid gland from the oral cavity to the lacrimal basin (Figure
7.14). Filatov’s original technique has been modified in two ways:82 First an
oral mucosa cylinder is retained during the dissection of the duct in order to
lengthen it, and by changing the surgical approach from the first transversal
incision, to an external periaurical incision for a transbuccal approach.
This treatment is only indicated in some severe dry eyes, mainly the dry
eye secondary to immunological diseases (Steven-Jhonson syndrome and
ocular pemphigoid).
Surgical technique: Under general anesthesia the mouth is opened with a

buccal forceps. The outlet of the Stenon’s duct is located in front of the
upper second molar. Compression of the parotid can help to identify the
FIGURE 7.14: Stenon’s duct transposition

FIGURE 7.15: Stenon’s duct prolonged with oral mucosa reaching

the inferior conjunctival fornix
outlet as saliva can be seen appearing from the duct. A 1 cm radius circle is
marked around the outlet, and incised with a sharp knife blade or scissors.
The mucosa is dissected until the external wall of the duct. The dissection is
prolonged about 3 cm, all around the Stenon’s duct, helped with a probe
inserted inside the duct. A subcutaneous tunnel is made with scissors, from
the lateral portion of the maseter muscle to a 1 cm long incision made in the
inferolateral conjunctival fornix. Four independent sutures help to manipulate
the mucosa and duct. The duct is rotated and inserted into the submucous
tunnel reaching the fornix (Figure 7.15). This maneuvering is very simple if
the four guiding sutures are clamped together with an hemostatic forceps,
and passed all together through the tunnel. The mucosal ring serves as a
prolongation of the duct, and its circumference is sutured with 8 independent
absorbable 8/0 stitches to the incision in the conjunctival fornix. The sutures
are removed one week later.
Complications of the transposition

• Eyelid movement limitation, mainly the infraduction.
• Lower lid entropion, because of both the traction from the fornix, and
cicatrization of the posterior lamella.
• Seroma secondary to Stenon’s duct section.81 This usually resolves
spontaneously, but sometimes derivative surgery is needed.
• Crocodile tears consist in the hypersalivation into the lacrimal basin when
eating or thinking of food (it is said that crocodiles cry of sorrow while
eating their victims). They usually last for life, with minimal improvement.
If the patient is dissatisfied, they may be improved by sectioning the
auriculo-temporal nerve. Some times, repositioning the duct to the oral
cavity is needed. We have treated one case with botox, with similar results
to those reported by Keegan59,60, with an effective reduction in tearing
for about 3 months.
Interocular Decantation
Interocular decantation consists in making a by-pass from one lacrimal basin
to the contralateral eye. Its objective is to transfer fluid from a wet eye to a
dry one. It has only been used on three occasions to treat severe bilateral dry
eye associated to a unilateral Stenon’s duct transposition.1
Surgical technique: Under general anesthesia the lacrimal pathway of the
donor eye is intubated. A bilateral osteotomy as that for a dacryocystor-
hinostomy is made, but it is elongated including the superior portion of the
maxillary bone in front of the nasolacrimal duct in the donor eye. Both
osteotomies are connected through the nasal septum that is perforated with
trocar and rongeur. The medial tendon of the donor eye is detached, and
the lacrimal sac and duct are blunt dissected. The nasal mucosa is incised as
low as possible, and it is kept attached to the nasolacrimal duct in order to
prolong it (as in the Stenon duct transposition). Helped by the canalicular
intubation, the sac-duct-mucosa complex is passed through the nasal septum
and the contralateral osteotomy, taking great care not to damage the
contralateral lacrimal pathway. In the recipient eye, the nasal mucosa is sutured
to the conjunctival inferomedial fornix with an absorbable 6/0 suture. The
bicanalicular intubation is maintained for 2-3 weeks, with the end of the
tubes attached to the patient’s forehead.
Salivary Gland Transplantation with Vascular Anastomosis

Surgical technique:1,61-64,66 Under general anesthesia, after temple hair shaving,
a 6 cm long incision is made in the temple at the level of the eyebrow. The
temporal vessels must be carefully dissected (they will support the anastomosis)
and clamped to avoid hemorrhage. The temporal muscle is desinserted next
to the lateral orbital wall. The wall is drilled, connecting the superolateral
FIGURE 7.16: Submandibular gland in the submandibular fossa.

Warthon’s duct is dissected
conjunctival fornix with the temporal fossa, at the level of the lateral
commissure. To extract the submandibular gland, a 3 cm skin incison is made
internally to the mandibular horizontal branch, next to the mandibular angle.
Dissection must be very careful in order to avoid damage to local nerves.
The posterior pole of the submandibular gland is exposed and the whole
gland dissected (Figure 7.16). The white colored submandibular ganglion is
found attached to the gland surface. A preganglionic denervation is made,
sectioning the proximal branches of the nerve, keeping the ganglion adhered
to the gland. After dissection of the gland, Wharton’s duct is dissected until
the oral cavity where it is detached with a cylinder of oral mucosa. The
dissection of the gland must finish at the main vessels of the gland. After the
artery and vein are excised, the vein is perfused with a cold solution (5ºC) of
heparin with Perfadex, and the gland is transferred to the temporal fossa
(Figure 7.17). The graft vessels are sutured to the temporal artery and vein
respectively, with about 20 independent 10/0 nylon stitches, and the vascular
clamp is removed. The glandular duct is prolonged by the cylindric oral
mucosa that is sutured through the orbital osteotomy to the superolateral
fornix with absorbable individual stitches (Figure 7.18). Both wounds, the
temporal and submandibular, are closed in two planes. Postoperatory care
includes, analgesics, antibiotics, anti-inflammatory drugs and anticoagulation
FIGURE 7.17: Submandibular transplantation with vascular anastomosis.

The gland is located in the temporal fossa
FIGURE 7.18: Salivary gland transplantation

for one month to prevent vascular occlusion.

Afferent autonomous denervation, both sympathetic and parasympathetic,
stops the circadian rhythmic and reflex secretion, producing a moderate
basal secretion.65
Salivary gland transplantation is a major procedure so it is only indicated
in severe dry eyes that have at least one submandibular gland not seriously
affected with sicca panexocrynopathy.
Salivary Gland Transplantation without Vascular Anastomosis

This process is less cruent that the previous one. In this case, one or multiple
isolated fragments of salivary gland (major or minor) are transferred to the
subconjunctival space; in the upper lid over the tarsus, and in the inferior lid
under the tarsus66-69 (Figure 7.19).The graft has no direct vascular anastomosis,
instead it is nourished by spontaneous microvascular connection with vessels
of the recipient bed, therefore a big contact surface is mandatory.
Surgery technique: The superior lid is everted with a Desmarres’ retractor,

and the conjunctiva is incised 2 cm along the superior border of the tarsus.
The conjunctiva is dissected from the Müller muscle. The inferior lid is also
everted, helped with a Desmarres’ retractor, and the conjunctiva is incised
FIGURE 7.19: Salivary gland trans-

plantation without vascular anasto-
mosis. Labial salivary gland with local
mucosa transplanted to superior and
inferior palpebral conjunctiva
and dissected from the inferior lid retractor muscle. When no vascular
anastomosis is performed, any salivary gland can be grafted. The gland is
exposed by a direct oral mucosa incision, extracting a 1-2 ml lobular block.
This glandular block is composed of several 2 × 2.5 × 3 mm lobes. The
glandular block is carefully divided into pieces, to avoid damaging the lobes.
The pieces are placed subconjunctivally with the excretory duct aimed at the
border of the tarsus. The conjunctiva is sutured into the original position.
Some glands (sublingual, labial) can be extracted with the covering oral
mucosa. In this case, the oral mucosa is sutured directly to the conjunctival
incision (Figure 7.20). Extracting the oral mucosa with the gland has the
advantage of preserving the excretory ducts of the glands connected to the
mucosa. Systemic anti-inflammatory drugs are prescribed and a therapeutical
contact lens inserted, to avoid corneal damage from the suture.
As we said before the predominant secretory compound of each gland is
different. This can be very useful when considering the different excretory
defiencies of each dry eye.
This technique is easier to perform than the vascularised graft, so it may
be indicated in less severe cases of dry eye. Again it requires moderate
conservation of the salivary gland function. This technique must be rejected
in cases of severe panexocrine disease. The activity of the grafted gland can
be evaluated both by the symptoms of the patient, and by measuring the
amylase in the mare lacrimal.70
FIGURE 7.20: Salivary gland transplantation over the superior tarsus

Transplanted salivary glands (with or without vascular anastomosis) are

denervated, have not reflex secretion, and can be stimulated with pilocarpine
ter in die.71
Supplying Tear
Cultured lacrimocyte transplantation has been assayed on different animals,
but not in humans.71-77 It may be an alternative to consider in the future.
Supplying Artificial Tear

Several types of methods have been used to automatically deliver artificial
tear to the dry eye: artificial external tear reservoirs.78 A chamber attached to
spectacles connected to the inner canthi via two tubes.79 Very uncomfortable
for little benefit.
The new dacryoreservoirs are automatic devices, placed in the abdominal
subcutaneous tissue of the patient, connected to the conjunctival superior
fornix by a subcutaneous silicone tube (Figure 7.21).80 They consist of a
60 ml compressed gas pump, that can contain artificial tears (Figure 7.22).
They produce an automated continous delivery of the content fluid (day
and night), at a rate of 1.5 ml a day. They must be refilled every 40 days by
FIGURE 7.21: Abdominal dacryoreservoir

FIGURE 7.22: Material for the dacryoreservoir.

Pump, silicone tube and trocar
FIGURE 7.23: The artificial tear reservoir is placed in the abdominal

subcutaneous tissue
percutaneous injection of artificial tear. Programmed reservoirs may also be

used.
Technical surgery: Under general anesthesia the anterolateral superior wall is
incised and dissection is made until the subcutaneous abdominal tissue, where
the reservoir is placed (Figure 7.23). The silicone tube attached to the pump
is taken subcutaneously to the superior conjunctival fornix, helped by a small
FIGURE 7.24: The silicone tube reaches the superior conjunctival fornix
cutaneous incision through the course of it. It is very imporant that the tube
is placed through the retroauricular region in order to avoid damage to the
facial nerve in front of the ear. Another critical moment is when dissecting
between the lateral portion of the eyebrow and the tragus cartilage, because
the frontal nerve can be damaged provoking an eyebrow ptosis. Once in the
orbit, the tube is taken out to the superior lateral fornix (Figure 7.24).
The main indication for dacryoreservoirs is the severe aqueodeficient dry
eye waiting for a keratoplasty. Without a constant lubrication (day and night)
the graft will fail.
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56. Altan-Yaycioglu R, Gencoglu EA, Akova YA, Dursun D, Cengiz F, Akman A. Silicone
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59. Keegan DJ, Geerling G, Lee JP, Blake G, Collin JR, Plant GT. Botulinum toxin
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(crocodile tears) with injection of botulinum toxin into the lacrimal gland. Eye
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PRE LASER ASSISTED STROMAL IN-SITU KERATOMILEUSIS (LASIK) 137
INTRODUCTION
The popularity of LASIK has grown among the youth in recent years. So has
the number of patients experiencing dry eye symptoms. According to the
2003 Refractive Surgery Survey, dry-eye symptoms are the most common
problem encountered after LASIK and occur in 15–25% of patients.1
Several factors may influence these symptoms, of which decreased corneal
sensation may play a significant role. Other potential factors include difficulty
wetting the ocular surface due to mechanical and shape factors and a loss of
neuroregulatory factors derived from the corneal nerves that promote epithelial
health.2
Particularly since the advent of the computer, dry eye symptoms resulting
from computer vision syndrome are so common, that the differentiation of
tear film abnormalities is the concern of every clinician.
The definition of an abnormal tear film and its causes has been reviewed
by many clinicians; they consider the following signs to be important when
diagnosing the condition:
1. A scanty or uneven tear meniscus.
2. The presence of excessive particulate matter.
3. The rupture of the tear film prior to a subsequent blink.
4. The production of hyperosmotic tears.
5. The abnormality or absence of the superficial lipid layer.
6. An abnormal or inadequate mucous layer.
7. The presence of an epithelial surface disorder.
A large number of clinical, experimental and research techniques have
been developed to study the tear film and its different components. The
focus here is on relevant techniques that can be applied by the clinician to
more accurately detect a dry eye.
SYMPTOMS
They vary in type and severity and are dependent on the state of instability
of the tear film and the resultant damage to the ocular surface. They include:
1. A sensation of burning in marginal cases, caused by a hypertonic shift in
the tear film
2. Tearing, as a reflex and protective mechanism, induced by external
conditions of low relative humidity, smog or air-conditioning drafts, and
associated with early break-up of the tear film.
3. Incomplete lid closure may result in difficulty in opening the eyes on

awakening.
4. Mucous discharge may indicate instability of the mucous layer and its
dehydration.
5. Foreign-body sensations may be caused by improper lubrication and
should be a warning of the possibility of a more severe tear film condition
6. Dryness itself, reported as dry, scratchy, gritty, or sandy.
7. Photophobia may occur with continuing irritation.
8. Blurred vision may occur from a non-wetting surface in Sjögren’s disease
and keratoconjunctivitis sicca.
SLIT-LAMP EXAMINATION
Assessment of Appearance of the Tear Film Meniscus
The observation of the lid meniscus height3 and its irregularity4 is a guide to
the diagnosis of dry eye. The shape of the meniscus can be observed in the
specular reflection zone of the slit-lamp as a bright central band bordered by
dark, non-reflective areas. The lower meniscus is easier to examine for
regularity, height, width and curvature. Its estimated width is 1 mm.5 A scanty
appearance or area of discontinuity is a sign of an aqueous tear deficiency or
lipid abnormality.5
An uneven border line and a height < 0.1 mm, combined with a sharp
definition of the ‘black line’ separating it from the tear film, are signs of
abnormality.
[On the corneal side of the meniscus, it is separated from the pre-ocular
tear film by a localized thinning known as the ‘black line’, which is only
visible when the film is stained with fluorescein].
Observation of Superficial Particulate Movement

Excessive particulate matter in the pre-ocular tear film and meniscus is
abnormal. It often consists of mucous strands mixed with the superficial lipid
layer. In filamentary keratitis these strands will be strongly attached to the
epithelial surface. Increased cellular debris indicates surface damage when
associated with contact lens wear or in conjunction with the use of
preservatives.6
Observation of Surface Interference Phenomena either by Simple

Specular Reflection or with the Tearscope PlusTM [Keeler Instruments]
Ehlers described the presence of embedded particles and various color
dispersion phenomena visible in the portion lying slightly outside the direct
‘mirror zone’formed by the light reflected from the cornea.7 Most of the
reflections originate from the oily layer. When the eye is opened wide, if a
petrol-like pattern appears on the precorneal tear film, the lipid layer is at
least 134 nm thick.8 If the specular reflection is colorless or presents grayish
lines, the lipid layer is thinner.
Abnormality of the lipid layer is caused by:
• An abnormal blockage of the secretion ducts8
• Poor apposition of the lid margins
• Contamination by skin lipid and/or make-up and skin lotions
• Presence of blepharitis or facial skin disorders
• Contamination by excessive or denatured mucous discharge
The Tearscope PlusTM illuminates the tear meniscus along its entire length
and permits non-invasive observation of morphological changes during the
blink sequence. In its central area of observation is a black central band
bordered by bright bands on either side. Any irregularity of the meniscus
shape caused by degenerative lid changes or meibomian gland blockage is
seen as a distortion of the central black band.
Measurement of Break-up Time [TBUT]

The pre-ocular tear film does not remain stable for long periods of time.9
When blinking is prevented, the tear film ruptures within 15 to 40 seconds.
Dry patches appear over the cornea. Reduced tear film break-up time or
limited ocular surface wetting measured with or without fluorescein staining
is one of the main signs of an abnormal tear film.
Technique
A moistened fluorescein strip is applied to the bulbar conjunctiva. After 2 to
3 blinks to spread the fluorescein evenly, the tear film is viewed with the help
of the blue filter of the slit-lamp.When a dark area appears in the uniform
green coloration, it represents a break in the tear film and the time elapsed
since the last blink is recorded as tear film break-up time (TBUT).
Factors decreasing TBUT:

• Use of local anesthetic
• Exposure to benzalkonium chloride as a preservative agent
• Presence of air convection during testing
• Forced blinking before measurement or forcing the eyelids open.
Fluorescein dyes the aqueous phase of the tear film and has little effect on
the lipid or mucous layers. In view of the limited size of the aqueous phase it
seems that a minimal amount of unpreserved dye, in an adequate concen-
tration instilled in a precise volume will improve repeatability of the test.
Measurement of Non-invasive Break-up Time [NIBUT]

Mengher developed a non-invasive technique for the assessment of preocular
tear film break-up time without the use of fluorescein.10 The method is based
on observing changes in the specular image of a grid pattern projected on
the open eye. A distortion of the grid line represents local thinning and
discontinuity represents a break in the tear film. The first discontinuity from
the last blink is taken as NIBUT. Normal values are 35 to 45 seconds.
Use of Vital Dyes to Study the Health of the Ocular Surface—

Fluorescein, Rose Bengal, Lissamine Green
Fluorescein sodium is a water-soluble yellow-green dye that can be excited
by a cobalt blue filter. The thickness and integrity of the tear film can be
assessed by the intensity of coloration on the ocular surface. Less intense
fluorescence despite repeated instillation occurs when tear volume or tear
film thickness is reduced.
Rose bengal is a water-soluble dye which stains degenerated and dead
cells and mucous fibrils. It produces a punctuate coloration along the lacrimal
rivus or line of Marx, which is probably due to pronounced cell degeneration
in this area. 1 percent concentration is preferred as irritation increases with
higher concentrations.
Conjunctival Signs
The presence of lip-like folds of the inferior conjunctiva is a sign of tear film
related ocular surface problems. Three grades of folds:11
1. The folds are barely visible in the temporal corner
2. Clearly visible in the temporal bulbar conjunctiva
3. Also visible in the conjunctiva corresponding to the inferior corneal limbus.
The folds disturb the morphology of the meniscus and its relationship
with the lid edge. The presence of folds creates abnormal reservoir
morphology, limiting the uptake of tears during a blink, decreasing the
resurfacing of the ocular surface.
Examination of the Lid Borders, the Lashes and Related Glands/

Orifices for any Signs of Blockage, Abnormality or Pathology, Such
as Blepharitis and Age-related Degenerative Changes
Blepharitis may cause secondary changes in the conjunctiva and cornea with
associated tear film instability due to the intimate relationship between the
lids and ocular surface.
The most common symptoms are burning, a foreign-body sensation,
photophobia and lid crusting.
Examination of the Meibomian Glands when the Lower Lid is Pulled

Down [using transillumination through the palpebral conjunctiva]
The meibomian orifices should be evaluated for distension or pouting caused
by internal secretion in the underlying duct, protruding filaments, foam or
bubbles surrounding the orifices or epithelial overgrowth.
Assessment of Localized Conjunctival Hyperemia, Preferably using

Grading Scales for Repeatability
Observation of the Blink Movement

Particularly observe for squeezing of eyelids during blinking and incomplete
blinks.
Tear Flow – The Schirmer’s Test

Tear flow is of prime importance in maintaining a normal, wet eye. The
Schirmer test uses a strip of filter paper 35 mm long and 5 mm wide. One
bent end is placed in the lower conjunctival sac about one-third of the palpebral
width from the temporal canthus. If anesthetic is instilled prior to the test,
only basal secretion is observed. Otherwise reflex tearing is also calculated.
Reflex lacrimation may increase the tear volume by a factor of 100. Less
than 5 mm of wetting is considered a pathological dry eye, 5-10 mm suggests
borderline dry eye and > 10 mm suggests a normal state of lacrimal secretion.
Suggested sequence of testing:
1. Comprehensive patient history and symptoms should be recorded,

preferably using a dry eye questionnaire.
2. As the tear film is very fragile, non-invasive tests should be carried out
first-first topography and aberrometry followed by NIBUT and observation
of the superficial lipid layer.
3. Slit-lamp examination of the lids for conjunctival hyperemia.
4. Perform Schirmer’s test.
5. Tests using stains should be performed last in view of their effect on tearing
and tear film composition.
6. Contact tests such as pachymetry are performed after assessment of tear
film.
MECHANISM OF DRY EYE AFTER LASIK

Dry eye after LASIK is at least partly caused by the corneal denervation
associated with LASIK. In the normal eye, a neuronal feedback loop between
the lacrimal gland and the ocular surface begins at the corneal surface and
travels via neuronal pathways that are mediated by the brain stem in a single
functional unit that is responsible for maintaining ocular surface homeostasis.
It is suggested that basal tear production does occur but ocular drying between
blinks induces subclinical corneal irritation that creates the blink reflex and
stimulates the lacrimal gland to produce tears.12 Only when ocular surface
drying becomes severe does the patient experience discomfort. In LASIK,
the corneal nerves are severed by the microkeratome and the deep corneal
nerves are photoablated at the time of laser surgery. Both processes damage
corneal innervation. The reduction in corneal neuronal feedback to the brain
stem reduces brain stem reflex mediation of the lacrimal glands, diminishing
tear production and inducing a corneal anesthesia or hypoesthesia that lasts
up to 6 months. Many patients may not have the traditional symptoms of
post-LASIK dry eye because of the lack of corneal sensation; visual fluctuation
due to damage to the ocular surface may be their only symptom.
In a subset of patients with corneal staining after LASIK, it is hypothesized
that the corneal breakdown is secondary to neurotrophic epitheliopathy in
addition to dry eye.13,14 Patients with neurotrophic keratitis with corneal
staining after LASIK have been shown to have Schirmer’s tests that are not
significantly different from those of post-LASIK patients without staining. Most
cases of neurotrophic epitheliopathy resolve by 6 months.
Laser in situ keratomileusis significantly decreases TBUT, Schirmer’s test

values, and basal tear secretion.15,16
IMPORTANCE OF HINGE LOCATION DURING THE LASIK PROCEDURE

An advantage of the hinge on the LASIK flap is that it provides a conduit for
corneal innervation. The corneal nerves that enter through the hinge are
preserved, maintaining corneal sensation in this area. Since the corneal nerves
predominantly enter the cornea at 9 o’clock and 3 o’clock,17,18 a vertical flap
(superior hinge) will transect both major areas of corneal innervation, whereas
a horizontal corneal flap (nasal hinge) will transect only 1 area. Hypothetically,
greater the loss of corneal sensation, greater is the risk for post-LASIK dry-
eye syndrome. A wide hinge will preserve a greater percentage of the corneal
neural architecture than a narrow hinge. The current data support this
hypothesis. Eyes with a narrow nasal hinge flap showed a significantly greater
loss of corneal sensation, a greater incidence of corneal and conjunctival
lissamine staining, and lower Schirmer scores than eyes with a wide nasal
hinge flap at 1 or more time intervals. Different microkeratomes cut flaps
with different thicknesses and standard deviations. Hinge width has not been
shown to affect flap thickness. The effect of flap thickness on corneal sensation
and dry eye does not appear to have been studied.
Over the past few years, there has been increased documentation of dry
eye after LASIK. There are many possible contributing factors to this, including
increased physician and patient awareness. Other factors include an increased
prevalence of superior hinge flaps, the need for larger flaps with smaller
hinges to accommodate the larger ablation zones required for hyperopic
treatments, and the larger optical and blend zones common to newer software
delivery systems. These larger ablation zones may decrease the risk for glare
and halos associated with scotopic conditions but may also be responsible
for the increased incidence of post-LASIK dry eye.19 It is recommended to
use the smallest flap necessary with the largest hinge possible to complete the
photoablation in the stromal bed without ablating the corneal hinge. Myopic
patients with mild dry eyes who have small pupils and against-the-rule
astigmatism (ablation profile is vertical) are good candidates for flaps with as
large a nasal flap as possible. Corneal sensation improves at all time intervals
but does not return to preoperative levels even 6 months postoperatively.
Associated with the corneal denervation is an immediate postoperative
increase in dry-eye syndrome signs and symptoms that improves at subsequent

visits.
Furthermore, loss of corneal sensation and dry-eye syndrome were less
pronounced in corneas with a wide nasal-hinge flap. This can be explained
anatomically by the finding that the wider hinge flap severs a smaller
percentage of the corneal innervation than a narrow hinge flap. Surgeons
operating on patients with preexisting neurotrophic corneas or dry-eye
syndrome should consider performing LASIK with as wide a nasal hinge flap
as possible.
Many LASIK patients complain of the quality of their vision despite optimal
uncorrected binocular visual acuity in the early postoperative period, related
to disturbances in the tear film as discussed above. Accuracy of treatment
may be compromised in cases with pre-existing dry eye. The stroma may be
less hydrated and result in overablation. This author20 has encountered
2 cases of overcorrection in patients with pre-existing dry eye and has evenly
spread a microdrop of BSS on the stromal bed before ablation, which resulted
in an optimal result. Both the above cases of overcorrection were enhanced
by a similar procedure.
Schirmer test scores were higher in the wide-hinge group than in the
narrow hinge group at all times, although the difference was only statistically
significant at 1 month and not at longer time intervals. There were no
significant between-group differences in TBUT.
RISK FACTORS FOR CHRONIC DRY EYE AFTER LASIK21

1. Patients developing chronic dry eye after LASIK were significantly more
likely to be female and have more dry-eye symptoms before surgery.
Longer use of contact lenses was borderline significant (P < .05).
2. Those that develop chronic dry eye also exhibit significantly greater
presurgical ocular surface staining, lower TBUT values and reduced
presurgical corneal sensation.
They also have a significantly higher attempted refractive correction
and a greater ablation depth.
3. Chronic dry eye is also associated with reduced central corneal sensation
up to 12 months after surgery.
The following guidelines should be considered by LASIK surgeons and

potential patients:22
1. Patients with dry eye before LASIK should be advised that they have a
significantly increased risk for developing chronic post-LASIK dry eye
despite comprehensive ocular surface management before, during, and
after surgery. There is also an association between chronic dry eye and
poorer refractive outcomes. Other refractive management strategies should
be discussed.
2. Women and patients requiring higher refractive corrections have an
increased risk for developing chronic dry eye and regression. Again,
alternative refractive correction options should be discussed.
3. If LASIK surgery is performed, the ocular surface and tear film must be
managed with the best available treatment options and for a sufficient
period of time. Unfortunately, corneal sensory denervation hinders the
ability to detect and treat symptoms. Therefore, routine postoperative
review in the first year after LASIK is advocated, even in asymptomatic
patients.
4. Ocular surface management strategies may accelerate the recovery of
ocular surface/lacrimal gland dysfunction after LASIK and improve visual
quality. Therefore, routine use of non-preserved artificial tears in the first
6 months after LASIK is recommended.
5. Failure to identify and treat early signs of ocular surface/lacrimal gland
dysfunction may permit a vicious cycle to occur with reduced ocular
surface sensation leading to ocular surface damage, reduced tear secretion,
and sustained reduction in corneal sensation. Regression of the refractive
result may also occur as a consequence of this chronic post-LASIK
integrated ocular surface/lacrimal gland dysfunction.
6. Enhancement surgery may exacerbate chronic post-LASIK dry eye and,
hence, may be contraindicated in patients with chronic ocular surface
dysfunction.
7. LASIK should be approached cautiously in patients with preexisting
dry eye, particularly as dry eye and associated contact lens intolerance
are significant motivating factors for patients to consider refractive
surgery.23-25
8. Patients with chronic dry-eye symptoms after surgery also have less
satisfaction with surgery.
9. Postmenopausal women on hormone replacement therapy are reported

to have significantly inferior refractive outcomes after PRK surgery
compared to age-matched controls in one study.23-25 A significant
correlation between female sex and the occurrence of corneal punctate
epitheliopathy after LASIK was reported (GL Mayo, MD, T Starck, MD,
“LASIK-Induced Neurotrophic Keratopathy: Incidence and Associated
Risk Factors,” ARVO, Ft. Lauderdale, Florida, USA, May 2002). These
results highlight the strong influence of hormone levels on the ocular
surface/ lacrimal gland function unit.
REFERENCES
1. Solomon KD, Fernańdez de Castro LE, Sandoval HP, et al. Refractive surgery
survey 2003. J Cataract Refract Surg 2004;30:1556-69.
2. Effect of hinge location on corneal sensation and dry eye after laser in situ
keratomileusis for myopia Vroman DT, Sandoval HP, Fernández de Castro LE,
Kasper TJ, Holzer MP, Solomon KD. Journal of Cataract and Refractive Surgery
2005;31(10):1881-87.
3. Baum JL. Systemic diseases associated with tear deficiencies. Int Ophthalmol Clin
1973:13157-184.
4. Rolando, M et al. Conjunctival damage distribution in keratoconjunctivitis sicca. An
impression cytology study. Ophthalmologica 1990;200:170-76.
5. Holly FJ, Lemp MA. Tear physiology and dry eyes. Surv Ophthalmol 1977;22,69-
87.
6. Bron AJ. Prospects for the dry eye. Trans Ophthalmol Soc. UK, 1985;104,801-26.
7. Ehlers N. The precorneal tear film. Biomicroscopical, histological and chemical
investigations. Acta Ophthalmol 1965;81[Suppl.],5-136.
8. Norn M.S. Semi-quantitative interference study of fatty layer of precorneal film. Acta
Ophthalmol 1979;57,766-74.
9. Holly FJ. Tear film physiology and contact lens wear. I. Pertinent aspects of tear film
physiology. Am J Optom Physiol Opt, 1981;58[4],324-30.
10. Mengher L.S. et al. A non-invasive instrument for the clinical assessment of the pre-
corneal tear film stability. Curr Eye Res 1985;4,1-8
11. Hoh et al. Lid-parallel conjunctival fold [LIPCOF] and dry eye: A diagnostic tool for
the contactologist. Contactologia, 1995;17E:104-17.
12. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the interaction
between the ocular surface and the lacrimal glands. Cornea 1998;17:584-89.
13. Wilson SE, Ambro´ sio R Jr. Laser in situ keratomileusis-induced neurotrophic
epitheliopathy. Am J Ophthalmol 2001;132:405-406.
14. Wilson SE. Laser in situ keratomileusis-induced (presumed) neurotrophic
epitheliopathy. Ophthalmology 2001;108:1082-87.
15. Yu EYW, Leung A, Rao S, Lam DSC. Effect of laser in situ keratomileusis on tear
stability. Ophthalmology 2000; 107:2131-35.
16. Toda I, Asano-Kato N, Komai-Hori Y, Tsubota K. Dry eye after laser in situ
keratomileusis. Am J Ophthalmol 2001;132:1-7
17. Mu¨ller LJ, Pels L, Vrensen GFJM. Ultrastructural organization of human corneal
nerves. Invest Ophthalmol Vis Sci 1996;37:476-88.
18. Müller LJ, Vrensen GFJM, Pels L, et al. Architecture of human corneal nerves. Invest
Ophthalmol Vis Sci 1997;38:985-94.
19. Effect of hinge width on corneal sensation and dry eye after laser in situ keratomileusis.
Donnenfeld ED, Ehrenhaus M, Solomon R, Mazurek J, Rozell JC, Perry HD.
Journal of Cataract and Refractive Surgery-April 2004 (Vol. 30, Issue 4, Pages 790-
797).
20. Shroff AA, unpublished data.
21. Chronic dry eye and regression after laser in situ keratomileusis for myopia.
Albietz JM, Lenton LM, Franzco, McLennan SG. Journal of Cataract and Refractive
Surgery-March 2004 (Vol. 30, Issue 3, Pages 675-684).
22. Toda I, Asano-Kato N, Hori-Komai Y, Tsubota K. Laser-assisted in situ keratomileusis
for patients with dry eye. Arch Ophthalmol 2002; 120:1024–28.
23. Corbett MC, O’Brart DPS, Warbuton FG, Marshall J. Biologic and environmental
risk factors for regression after photorefractive keratectomy. Ophthalmology 1996;
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24. Toda I, Yagi Y, Hata S, et al. Excimer laser photorefractive keratectomy for patients
with contact lens intolerance caused by dry eye. Br J Ophthalmol 1996;80:604-09.
25. McCarty CA, Ng I, Waldron B, et al. Relation of hormone and menopausal status to
outcomes following excimer laser photorefractive keratectomy in women. Aust NZ
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LASIK AND DRY EYES 149
INTRODUCTION
LASIK has a multipronged effect on corneal sensation, tear production and
wound healing. As the excimer laser also alters the anterior curvature of the
cornea by ablating the corneal stroma thus altering the lid interaction with
the ocular surface. Post LASIK, the cornea overlying the flap is significantly
anesthetic for in some cases upto 6 months, causing a drop in tear production.
Dry eye following LASIK is one of the most frequent problems facing
refractive surgeons today and practically all patients experience dry eye at
least transiently. Yu et al have reported that 60% of patients experienced dry
eye at 1 month following LASIK, and Hovanesian et al reported that 50% of
patients experienced symptoms related to dry eye at 6 months. Upto 5%
experience severe dry eye that lasts at least 6 months. In most patients who
are symptomatic after LASIK its found that they had a mild dry eye
preoperatively. The usual complaint following dry eye is that of fluctuating
vision due to tear film break-up. Fortunately, in Donnenfelds experience,
the great majority of patients’ dry eye symptoms resolve within a month
following surgery.
CAUSES OF DRY EYE AFTER LASIK

The etiology is multifactorial:
1. Pressure from the Suction ring at the limbus causes damage to the goblet
cells thus affecting the mucin layer of the tear film as reported by Albietz
et al.
2. Eye drops contain preservative typically benzalkonium chloride which is
epitheliotoxic.This can cause similar symptoms like those of dry eye like
grittiness and irritation
3. Its well known that corneal sensation drives tear production during
LASIK, the corneal nerve trunks are severed by the microkeratome.
The anterior stromal nerves are disrupted by photoablation. Both
processes damage corneal innervation. The reduction in corneal neuronal
feedback to the brain stem reduces brain stem innervation of the lacrimal
glands.This diminishes tear production. Perez Santonja et al showed that
as the nerves regenerate postoperatively the return of corneal sensation
takes about 6 months. This is why the dry eye recovers eventually over 6
months or so.
EFFECT OF LASIK ON CORNEAL SENSATION

Corneal sensation is provided by the long ciliary nerves of the ophthalmic
division of the fifth (trigeminal) cranial nerve. The long ciliary nerve trunk
travels in the suprachoroidal space. Here it branches several times before
entering the cornea at the limbus. The large nerves enter the limbus mainly
at the 3 o’clock and 9 o’clock positions (Figure 9.1). They then bifurcate and
move toward the 6 o’clock and 12 o’clock positions. They then undergo a
second branching and again move toward the 9 o’clock and 3 o’clock
positions. The nerves initially enter the cornea in the middle one third of the
stroma, but course anteriorly as they branch, eventually forming a plexus in
the sub- Bowman’s layer that densely innervates the central cornea. The
nerves next penetrate Bowman’s membrane and terminate in the epithelium
at the wing cell layer. Lawrenson et al using a Cohet Bonnet esthesiometer
proved that since the long ciliary nerves enter the eye at 3 and 9 o’clock
positions ,the corneal sensation is significantly greater at the temporal and
nasal limbus than inferiorly
FIGURE 9.1: Diagram of corneal innervation.

(Reprinted from Donnenfeld ED, Solomon
R, Perry HD. Prevention and management
of dry eye following LASIK, in Probst L [ed].
LASIK Advances, Controversies, and
Customs. Thorofare, NJ, SLACK Inc, 2004,
with the kind permission of Dr Donnenfeld.)
Chuck et al studied the corneal sensation post LASIK and by using the
technique of in vivo confocal microscopy showed LASIK induced alterations
in the sub-Bowman’s nerve plexus and that these alterations are directly
related to a drop in corneal sensation. In addition they found that corneal
sensation following LASIK is greatest near the hinge and decreases toward the
central cornea and the peripheral cornea away from the hinge. An advantage
of the hinge on the LASIK flap is that it provides a pathway or a “conduit” for
corneal innervation. The corneal nerves entering through the hinge are
preserved, maintaining corneal sensation in this area (Figures 9.2 and 9.3).
FIGURE 9.2: Superior hinge corneal flap

transects nasal and temporal corneal
innervation (Reprinted from Donnenfeld
ED, Solomon R, Perry HD. Prevention
and management of dry eye following
LASIK. In Probst L [Ed]: LASIK advances,
controversies, and customs. Thorofare,
NJ, SLACK Inc, 2004, with the kind
permission of Dr Donnenfeld
FIGURE 9.3: Nasal hinge corneal flap preserves nasal

innervation of cornea. (Reprinted from Donnenfeld ED,
Solomon R, Perry HD. Prevention and management of dry
eye following LASIK, in Probst L [ed]. LASIK advances,
controversies, and customs. Thorofare, NJ, SLACK Inc, 2004,
with the kind permission of Dr Donnenfeld.)
Donnenfeld et al have demonstrated in a self-controlled, masked clinical

study that eyes with a superior hinge flap had much greater loss of sensation
and significantly increased corneal lissamine green staining compared to eyes
with a nasal hinge flap. Loss of corneal sensation is always greater with a
narrow flap as the “conduit” for transmission of the corneal sensation is
narrower. In cases where dry eye was diagnosed before LASIK in some cases
positive rose Bengal staining can be demonstrated like in a neurotrophic
epitheliopathy.
MANAGEMENT OF DRY EYE AFTER LASIK

Patients who have mild dry eye symptoms can simply be treated with artificial
preferably nonpreserved tears to stabilize the ocular surface prior to surgery.
For patients who have meibomian gland dysfunction Donnenfeld et al
recommend the addition of oral doxycycline 100 mg twice a day for 2 weeks
and then daily for an additional month along with the tear substitutes.
Topical cyclosporine 0.05% in a lipid emulsion (Restasis™, Allergan) has
been found to produce significant improvement in both the signs and
symptoms of dry eye disease, as well as to produce a decrease in the levels of
inflammatory cells in the conjunctival epithelium.The connection between
inflammation and dry eye is very well known where steroid topically relieves
the symptoms of dry eye much quicker than tear substitutes alone.
Cyclosporine A offers the advantage of immunomodulation without the risk
of corticosteroid immunosuppressive side effects.
Donnenfeld et al have found that that dietary supplementation with the
omega-3 fatty acids provided by eicosapentaenoic (EPA) and doco-
sahexaenoic acid (DHA) enriched flaxseed oil is beneficial in cases of abnormal
meibomian gland secretions.
They hypothesise that dietary omega-3 fatty acids are being utilized in
the production of meibomian secretions(lipid layer of tear film) and are adding
to the tear film oil layer.
Postoperatively, the patient uses in our setup gatifloxacin eye drops and
dexamethasone eye drops post LASIK four times a day for 7 days. Any
patient complaining of grittiness or fluctuating vision is supplemented with
carboxyethylcellulose eyedrops (Refresh Liquigel). If the patient still has
symptoms of dry eye following the LASIK procedure, we an consider inserting
inferior punctal plugs (SmartPlug ) in an attempt to stabilize the ocular surface.
If meibomian gland disease is suspected we can try doxycycline tablets.If

dry eye persists for more than 3 months we start the patient on restasis.
In conclusion dry eye after LASIK is a manageable entity with fairly good
results if diagnosed and treated early and appropriately.
ACKNOWLEDGEMENT
Figures 9.1 to 9.3 reproduced with permission of Dr Donnenfeld “Donnenfeld
ED, Solomon R, Perry HD.” Prevention and management of dry eye following
LASIK, in Probst L [ed]. LASIK advances, controversies, and customs.
Thorofare, NJ, SLACK Inc, 2004).
BIBLIOGRAPHY
1. Kanellopoulos AJ, Pallikaris IG, Donnenfeld ED, et al. Comparison of corneal
sensation following photorefractive keratectomy and laser in situ keratomileusis. J
Cataract Refract Surg 1997;23:34-38.
2. Linna TU, Vesaluoma MH, Perez-Santonja JJ, et al. Effect of myopic LASIK on
corneal sensitivity and morphology of subbasal nerves. Invest Ophthalmol Vis Sci
2000;41:393-97.
3. Chuck RS, Quiros PA, Perez AC, McDonnell PJ. Corneal sensation after laser in situ
keratomileusis. J Cataract Refract Surg 2000;26:337-39.
4. Albietz JM, Lenton LM, McLennan SG. Effect of laser in situ keratomileusis for
hyperopia on tear film and ocular surface. J Refract Surg 2002;18:113-23.
5. Toda I, Asano-Kato N, Hori-Komai Y, Tsubota K. Dry eye after laser in situ
keratomileusis. Am J Ophthalmol 2001;132:1-7.
6. Yu EY, Leung A, Rao S, Lam DS. Effect of laser in situ keratomileusis on tear stability.
7. Hovanesian JA, Shah SS, Maloney RK. Symptoms of dry eye and recurrent erosion
syndrome after refractive surgery. J Cataract Refract Surg 2001;27:577-84.
8. Donnenfeld E, Solomon K, Perry H, et al. The effect of hinge position on corneal
sensation and dry eye following LASIK. Ophthalmology 2003;110:1023-9;
discussion, 1029-30.
9. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: the interaction
between the ocular surface and lacrimal glands. Cornea 1998;17:584-9.
10. Toda I, Asano-Kato N, Hori-Komai Y, Tsubota K. Laser-assisted in situ keratomileusis
for patients with dry eye. Arch Ophthalmol 2002;120:1024-8.
11. Ambrosio R Jr, Periman LM, Neto, MV, Wilson SE:Bilateral marginal sterile infiltrates
and diffuse lamellar keratitis after laser in situ keratomileusis. J Refract Surg
2003;19:154-8.
12. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies
of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to
severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology 2000;107:631-
39. Erratum in Ophthalmology 2000;107:1220.
13. Muller LJ, Pels L, Vrensen GF. Ultrastructural organization of human corneal nerves.
Invest Ophthalmol Vis Sci 1996;37:476-88.
14. Muller LJ, Vrensen GF, Pels L, et al. Architecture of human corneal nerves. Invest
15. Auran JD, Koester CJ, Kleiman NJ, et al. Scanning slit confocal microscopic obser-
vation of cell morphology and movement within the normal human anterior cornea.
16. Lawrenson JG, Ruskell GL. Investigation of limbal touch sensitivity using a Cochet-
Bonnet aesthesiometer. Br J Ophthalmol 1993;77:339-43.
17. Donnenfeld E, Ehrenhaus M, Solomon R, et al. The effect of hinge width on corneal
sensation and dry eye following LASIK. J Cataract Refract Surg, In Press.
18. Stroobants A, Fabre K, Maudgal PC. Effect of non-steroidal anti-inflammatory drugs
(NSAID) on the rabbit corneal epithelium studied by scanning electron microscopy.
Bull Soc Belge Ophthalmol 2000;276:73-81.
19. Lenton LM, Albietz JM. Effect of carmellose-based artificial tears on the ocular
surface in eyes after laser in situ keratomileusis. J Refract Surg 1999;15(2
Suppl):S227-31.
20. Albietz JM, Lenton LM, McLennan SG, Earl ML. A comparison of the effect of
Refresh Plus and Bion tears on dry eye symptoms and ocular surface health in
myopic LASIK patients. CLAO J 2002;28:96-100.
CATARACT SURGERY IN PATIENTS WITH DRY EYES 157
INTRODUCTION
Dry eye is one of the most common problems encountered by an
ophthalmologists. It is either due to decreased tear production or increase in
the evaporation resulting in ocular surface abnormality. Tear film comprises
of three layers—the inner mucin layer, middle aqueous layer and the outer
lipid layer. An abnormality of any of these layers can be the cause of dry
eye.
Dry eye patients are prone to blepharitis, conjunctivitis, punctate
keratopathy, filamentary keratitis. Sometimes corneal thinning may develop
leading to ulceration, keratinization, keratolysis. This may progress to
perforation. The visual loss occurs due to corneal involvement or due to
lenticular changes.
Cataract surgery in dry eye patients especially in those associated with
connective tissue disorders is known to be associated with various
complications.1 Mild keratoconjunctivitis sicca can become dramatically worse
after cataract extraction and result in corneal thinning and perforation. Early
recognition of the condition can prevent these complications. However, lack
of recognition may result in permanent scarring from ulceration as the
condition is slow to respond to treatment.
The patients with cataract may be diagnosed cases of dry eyes and using
tear substitutes or may present with the symptoms of irritation or gritty
sensation and lacrimation along with diminished vision.
PREOPERATIVE EVALUATION
Detailed medical history including family history and dietary habits including
alcohol consumption, smoking, or use of drugs or medications is elicited to
rule out Stevens-Johnson syndrome in relevant cases.
Complete systemic evaluation to rule out other systemic associations, signs
of Sjögren’s like dry mouth, signs of arthritis may be evaluated (Figure 10.1).
Ocular Examination
Gross examination of the eye noting lid structure, position, symmetry and
biomicroscopic examination of the lid margins, meibomian glands is carried
out.
Biomicroscopic examination of cornea may reveal lustureless cornea, rapid
tear film break up, mucus debris in the tear film, decreased tear meniscus
FIGURE 10.1: Showing hand deformity in patient of rheumatoid arthritis
height, corneal and conjunctival staining with fluorescein 1% or Rose Bengal

stain or filamentary keratitis.
The clinical diagnosis of dry eyes is based on reduced tear meniscus height,
Schirmer’s test value of less than 10 mm (Figure 10.2) or tear break up time
of less than 10 seconds,though other tests like impression cytology, salivary
gland biopsy, scintography and rheumatoid factor, fluorophotometry may be
done.
FIGURE 10.2: Schirmer’s test is being carried out

The symptoms and signs of inflammation should be controlled prior to

cataract surgery. Environmental factors contributing to dry eye should be
identified and modified or eliminated. Associated medical conditions are
identified and referred to the concerned consultant for treatment.
Preoperatively, lid hygiene should be stressed as it minimizes the effects
of altered lipid secretion. Lid hygiene reduces the possibility of secondary
infection. Blepharitis and meibomian gland dysfunction which contribute to
the mechanical trauma are managed with warm compresses, lid massage
and oral Doxycycline if required. Entropion should be surgically, corrected
and trichiatic cilia should be removed or destroyed by electrolysis. All patients
are prescribed tear substitutes The use of tear supplements can make
symptoms tolerable in the milder forms of the condition. Preservative-free
tear supplements also play a role in the relief of moderate and advanced
cases. Frequency may range from QID to 1 hrly depending on the severity
of the dry eyes. In cases of extensive corneal thinning as in cases of Stevens-
Johnson syndrome and cicatricial pemphigoid ocular surface reconstruction
with limbal stem cells and amniotic membrane transplantation should precede
cataract surgery. Non-steroidal anti-inflammatory drugs such as indomethacin
and oral steroids or antimetabolites may be prescribed to patient’s with
cicatricial keratoconjunctivitis and rheumatoid arthritis associated with active
scleritis (Figure 10.3).
FIGURE 10.3: Patient of rheumatoid arthritis with

scleritis with dellen
FIGURE 10.4: Phacoemulsification is the

procedure of choice
SURGICAL TECHNIQUE
The cataract extraction can be performed through phacoemulsification or
extracapsular technique. When the central cornea is clear enough,
phacoemulsification is the preferred technique as small incision causes least
disruption of ocular surface (Figure 10.4). The temporal incision is also
preferred in cases of symblepharon.
In cases of corneal scarring involving the visual axis, Extracapsular
technique may be preferred. In cases with peripheral thinning the scleral
incision can be used. Use of cautery should be minimized as the risk of thinning
and melting may increase.
Postoperatively, the use of steroids should be minimal and tapered along
with antibiotics. Liberal use of tear substitutes along with prophylactic
antibiotics is essential. Inflammation following surgery may be controlled with
systemic and topical immunosuppressives.
Reconstruction of ocular surface after the control of conjunctival
inflammation in patients of Stevens-Johnson syndrome facilitates successful
cataract surgery.2
Miyajima et al emphasized that small incision phacoemulsification can be
safely performed in patients with cicatricial keratoconjunctivitis, i.e Stevens-
Johnson syndrome and ocular cicatricial pemphigoid after removal of the
conjunctival and dermal tissue over the cornea before ocular surface
reconstruction by limbal allograft tissue and amniotic membrane
transplantation resulting in visual rehabilitation.3
POSTOPERATIVE COMPLICATIONS
The dry eye symptoms are known to aggravate after surgical manipulation.
Many patients with pre-existing ocular surface conditions or tear deficiency
develop severe ocular irritation after ocular surgeries. Cataract surgeries
violate the integrity of the ocular surface by creating surgical wounds. Thus
the surgery should be carried out once the inflammation has subsided. In
general, these surgical wounds heal without complications but problems
develop as a result of insufficient healing due to ocular surface
abnormalities. Corneal nerves are severed at the incision site resulting in
decreased corneal sensation. As a result of the decreased nerve impulse, the
lacrimal gland produces less reflex tears and causes inadequate lubrication of
the ocular surface.
The corneal epithelium plays a very important role in maintaining the
health of the corneal surface because of its rapid self-growing capacity. The
limbal stem cells serve as a proliferative barrier between corneal and
conjunctival epithelium, they multiply and migrate to the area of disease.
Damage to the limbal stem cells result in an invasion of conjunctival epithelium
onto the corneal surface resulting in process of conjunctivalization often with
secondary neovascularization and inflammatory cell infiltration.
Conjunctivalized tissue is prone for epithelial defects and may lead to
corneal ulceration, melting, and loss of vision due to activity of
inflammatory cells and collagenase enzymes. The patients with connective
tissue disorders are more prone to have such complications.
The development of superficial punctate keratopathy and filamentary
keratitis are managed with frequent use of preservative-free supplements
and mucolytic agents respectively. The use of steroids may trigger the
development of ulceration. Prophylactic use of antibiotics may inhibit the
normal ocular flora and prevent infections.4
The Exracapsular cataract surgery is associated with more
complications like suture abscess, infectious keratitis, peripheral keratolysis
and endophthalmitis . Jagat Ram et al reported phacoemulsification to be a
safer technique as it is associated with minimal complications postoperatively.
This is possibility due to a smaller incision resulting in less desruption of the

corneal nerves, shorter duration of surgery and minimal tear film surface
problem due to sutureless surgery.5
SUMMARY
Cataract surgery in patients with dry eyes may be associated with various
complications. It is important to diagnose keratoconjunctivitis sicca prior to
surgery and to rule out association with connective tissue disorders. With
adequate preoperative measures, use of small incision surgery, where possible
and good postoperative care, gratifying outcome can usually be achieved.
REFERENCES
1. Ram J, Sharma A, Pandav SS, Gupta A, Bambery P. Cataract surgery in patients with
dry eyes. J Cataract refract Surg 1998;28(8):1119-24.
2. Sangwan VS, Burman S. Cataract surgery in Stevens -Johnson syndrome. J Cataract
Refract Surg 2005;31:860-62.
3. Bissen-Miyajima H, Monden Y, Shimazak J, Tsubota K. Cataract surgery combined
with ocular surface reconstruction in patients with severe cicatricial
keratoconjunctivitis. J Cataract Refract Surg 2002;28:1379-85.
4. Insler MS, Boutros G, Boulware DW. Corneal ulceration following cataract surgery
in patients with rheumatoid arthritis. J Am Intraocul Implant Soc 1985;11(6):594-
97.
5. Ram J, Gupta A, Brar GS, Kaushik S, Gupta A. Outcomes of Phacoemulsification in
patients with dry eye. J Cataract Refract Surg 2002;28:1386-89.
CONTACT LENSES AND OCULAR LUBRICATION 163
Successful and problem-free adaptation of a patient to contact lenses, whether

they are hard or soft, depends upon adequate wetting of both the cornea
and the lens, and the ability of the lens to allow the necessary corneal
oxygenation. Therefore, an adequate and stable tear film layer is essential.
Tears not only lubricate the cornea, but also lubricate the opposing surfaces
of the conjunctiva (bulbar and palpebral conjunctivae). The action of the lids
is of the utmost importance, provided that the tear film is adequate in quality
and volume.
A correct fitting procedure, covered in depth in this book, include adequate
corneal, lids, and tear film evaluation at the slit-lamp.
In the USA contact lens marketplace, 82 percent wear soft lenses, 16
percent wear rigid gas-permeable (RGP), and 2 percent wear hard contact
lenses. Although very few people wear hard lenses, they are available for
people who have adapted to them and want them. Hard lenses are not the
same as RGP lenses, since they do not allow oxygen transmission through
the lens. Whichever contacts the patient uses, the reading of this chapter
should invite every practitioner to bear in mind that no contact lens patient
should be out of artificial tear lubrication. Every contact lens wearer
has tear deficiencies related to the lens. Contact lenses are like sponges, and
require considerable tear moisture to work properly: if not, they act as a
foreign body.
The purpose of contact lens fitting is to determine the type and
specifications of the most appropriate contact lenses for each individual patient.
Proper “fit” includes factors such as optimal vision correction and proper
alignment on the eye. The quality of the fit is evaluated by the prescriber in
order to ensure optimum vision and safety with contact lens wear. The choice
of the best lubricant for each patient will change with fitting experience.
Practitioners with poor contact lens fitting experience encounter some fitting
problems that would have been over-run with proper ocular lubrication.
The ocular tear film is a transient and dynamic structure (Table 11.1)
Classically, and controversially, the normal tear film has three layers (or at
least it has three major components: lipids, water and mucus). It is not perfectly
stable: each blink tends to stabilize the different layers, but this becomes
more difficult when a foreign body called contact lens is in place. Maintenance
of a healthy ocular surface depends on the amount and composition of the
tear film. The maintenance of a normal tear film depends on the maintenance
TABLE 11.1: The normal tear film
Lipid layer • Prevents rapid evaporation of the aqueous
(0.1 micron thick) component when the eye is open
• Prevents drying between blinks
• Prevents damage of the lid margin skin by tears
(prevents the overflow of tears over the skin)
forms a seal over the exposed portion of the
eye during night
• Prevents sebaceous lipids from entering the tears
Aqueous • Moisturizes and nourishes the ocular surface
Layer (10-12 (the surface of the cornea must be kept moist to
microns thick) prevent damage to the epithelium)
Mucous layer Allows the tear to spread upon the corneal
(0.6-1 micron thick) epithelium
Corneal epithelium Its microvilli anchor the mucus to the cornea
of a normal ocular surface. Therefore, the best way to prevent ocular

complications in contact lens wearers is proper lubrication.
CONTACT LENS-INDUCED CHANGES IN THE TEAR FILM

The volume and composition of tears in a contact lens wearer is clearly affected
by the contact lens wear (Table 11.2). On lens insertion, there is an increase
in tear production rate and a decline in tear tonicity levels (reaching plasma
levels). These changes come close to previous levels after about a week.
Later, in the adapted contact lens wearer, there is evidence for increased tear
osmolarity probably due to an increased tear evaporation rate, as a result of
the induced disruption of the lipid layer of the tear film and the reduced
blinking rate.
TABLE 11.2: The tear film in contact lens wearer

Lipid layer aqueous layer mucous layer
Contact lens is bathed in mucus
Mucous layer
Aqueous layer
Mucous layer
Corneal epithelium
In soft lens wearers (with a new or clean lens), the lipid layer is similar to
the non-lens wearing eye. When surface deposits or defects are present, the
tear lipid layer becomes unstable.
In hard lens wearers, the lipid layer is almost absent over the anterior
face of the contact. It is replaced by a thicker aqueous phase drying on the
lens surface. The edge of the hard lens forms a barrier to the spreading of
the lipid layer over the lens, which is surrounded by an evident amount of
lipid.
The tear film in contact lens wearer has “more” layers: Figure 11.1B
notice that the contact lens is bathed in mucus, just as happens with any
other foreign body. When the tear film breaks up, and it does so more easily
in contact lens wearers due to the contact lens, there is a loss of the mucous
barrier, and the aqueous component tends to evaporate. In such cases, the
lipid fraction and its debris come to direct contact with the contact lens,
damaging the lens material and leading to spots and deposits over its surface.
The best prevention is proper lubrication.
The fluid compartment between a hard (rigid) contact lens and the cornea
acts as a lens itself which has a refractive power independent of that of the
contact lens and that of the eye.
In soft contact lenses, the power of this fluid compartment is virtually
plano (zero) since the contact lens conforms to the exact shape of the anterior
corneal surface.
TABLE 11.3: Origin of the different components of the film layer

Lipid layer Meibomian glands (lid margins)
Glands of Zeis (sebaceous)
glands of Moll (sweat)
Aqueous layer Lacrymal glands (primarily by the lacrymal
Gland located in the superior temporal orbit,
and secondarily by the accessory glands of
Krause and Wolfring that lie in the conjunctiva)
Mucous layer Conjunctival goblet cells (distributed throughout
the bulbar and palpebral conjunctiva)
The different components of the film layer have different origins (Table
11.3): pathologic changes in the sources lead to tear film quality or quantity
loss. For instance, in giant papillary conjunctivitis, common in cases of contact
lens abuse, the conjunctival production of mucus is dramatically increased,
since extra mucus is formed in secretory vesicles of the nongoblet epithelial
cells. Clinically, the observation of increased mucus levels is one of the most
important signs in the diagnosis of giant papillary conjunctivitis.
FIGURE 11.1A: Trichiasis
FIGURE 11.1B: Pterygium
Common causes of incomplete tear film distribution:

• Contact lenses (any kind)
• Trichiasis (Figure 11.1A)
• Pterygium (Figure 11.1B)
• Corneal scars (Figure 11.1C)
• Pingueculae (Figure 11.1D)
FIGURE 11.1C: Corneal scars
FIGURE 11.1D: Pingueculae
Common methods for tear film evaluation:

1. Lacrymal lake evaluation at slit lamp
2. Corneal videokeratography (Figure 11.2)
3. Schirmer’s tests
4. BUT (tear break-up time) (Figures 11.3 and 11.4)
FIGURE 11.2: Corneal videokeratography is a useful method

for evaluation of tear film. Irregular pattern of the rings of a
Placido disk, changing between blinks, suggests a failure
in the precorneal tear film distribution
FIGURE 11.3: Measuring the tear break-up time (BUT) is a useful

method for evaluating the status of the precorneal tear film. It provides
a clinical estimation of the length of time that the tear film remains
stable and intact between blinks. The normal BUT is 10 seconds or
longer: Figure shows the broken fluorescein dye distribution in a
contact lens wearer without the contact lens, showing a fluorescent
dehydration induced staining at the superior limbus (mild punctate
keratopathy)
FIGURE 11.4: Shows the broken fluorescein dye distribution in a myopic contact
lens wearer without the contact lens, 5 seconds after the last blink, showing
a fast tear break-up time despite a good tear meniscus stained with
fluorescein. The meniscus results from excessive irritative lacrimation due
to the contact lens wear: tear film is good in quantity but not in quality. The
patient needs extra-artificial corneal lubrication to stabilize the tear film
5. Tearscope (Instrument designed by Dr Guillon and made by Keeler

Instruments,™ helps to evaluate the lipidic phase or the tear film).
Other tests for dry eye evaluation:
1. Impression cytology
2. Fluorescein and rose bengal: Hypofluorescence is a reliable indicator of
low tear volume in the resting state. A fluorescein strip touching the lower
palpebral conjunctiva after moistening with a drop of non-preserved saline
will instil a standard amount of concentrated dye, which will not fluoresce
immediately when the tear volume is low.
Roles of tear film layer and tear film substitutes in contact lens wearers:
• Provide adequate wetting of the corneal epithelium and the contact lens
surface for as long as possible (reduce corneal swelling to an extent)
• Adhesion between lens and cornea
• Optical correction of minor corneal irregularities
• Allow “friction-free” movement of hard lenses over the cornea
• Cushioning effect
• Cleaning and wetting of the lens surface
• Increase hydration of gel lenses (soft contacts)

• Prevention of infections (fungal, bacterial and parasitic)
• Removes metabolic byproducts from the cornea
• Removes toxic contact lens cleaning particles
• Disinfecting anterior segment surface
• Provide increased wearing comfort
• Improve visual acuity
• Avoids complications.
Safe contact lens wear involves using common sense. Knowing when not
to wear contact lenses is important. Patients should remove any contact lens
that is causing irritation and not reinsert the lens until the eye feels comfortable
again and the patient has consulted the ophthalmologist. The patient should
never ignore symptoms of discomfort, redness or blurred vision. Patients
should not wear their contact lenses under any of these situations, and should
immediately consult their contact lens prescriber: until then, proper lubrication
may be helpful in avoiding complications. Not all the reactions to contact
lens wear have an immunological basis: bad corneal lubrication and improper
care, or mode of usage, may be at the origin of the most common
complications.
Patients need to know that a major cause of decreased corneal sensation
is contact lens wear: sometimes, discomfort only appears when the problem
is serious.
CONTACTS AND DRY EYE SYNDROME

Tear abnormalities may be related to a problem like lagophthalmos (Figure
11.5) or blepharitis (Figures 11.6 and 11.7) or with tear volume (quantitative
abnormalities like increased tear evaporation or excess tear volume), tear
surfacing (like pterygia or pingueculae, Figure 11.8), tear wetting (like
excess of mucus in contact lens users), tear base (like abnormal corneal
epithelium in ulcerations or chemical burns) and tear lipids (like
meibomianitis in acne and blepharitis (Figures 11.9 to 11.11). The
classification of tear abnormalities according to these mechanisms provides a
rationale for therapy. Dry eye is either biological or environmental. Dry eye
(Figure 11.9) can make contact lens wear more difficult since tears may be
inadequate to keep the lenses wet and lubricated.
As we get older, we tend to produce less tears and that makes the surface
of the eye dryer. This drying effect of ageing is frequently more pronounced
FIGURE 11.5: Lagophthalmos is a rare condition in which incomplete

eye closure leads to a dry eye syndrome. Rose bengal staining
clearly shows the damaged conjunctival and corneal epithelium.
Lagophthalmos is not a contraindication for contacts, but intense
artificial moistening of the eye should be prescribed. Eye drops are
suitable during the day, while eye gels or ointments (with special
care in contact lens users) are preferred at night time
FIGURE 11.6
in women than in men, primarily due to hormonal factors. While dry eye
occurs in both women and men, it occurs more frequently in women than in
men. Now, environmental factors can influence the symptoms of dry eyes,
particularly when people are in an atmosphere in which there is movement
of air (such as wind) or when it is dry or in work conditions where there is a
FIGURE 11.7
FIGURES 11.6 and 11.7: Blepharitis is a common chronic
condition, not related to the contact lens use, but that may have
impact on contact lens wear. There are two basic types,
seborrheic and squamous. In both, staphylococcal infections
are implicated. Notice the hard-crusting scales on the anterior
lid margin. Keratoconjuctivitis sicca is present in more than 50%
of patients, and is responsible for the burning of the eyes, not
only in contact lens wearers. Artificial lubricants will improve
comfort and help avoiding the peripheral immune corneal
infiltrates, due to hypersensitivity reaction to staphylococcal
antigens (see picture), specially in contact lenses wearers
FIGURE 11.8: Minor pinguecula in a contact lens wearer is not

related to the contact lens use but may impact on contact lens
wear. Ocular lubricants are occasionally useful to avoid mechanical
trauma through lens striking the raised area. The same applies to
pterigyum
FIGURE 11.9: Examination findings that support a diagnosis of

dry eye include occluded meibomian gland orifices and small
papillae of the upper tarsal conjunctiva. Blepharitis and allergic
conjunctivitis are also contributing causes to red eye and to an
unstable tear film, which leads to excessive evaporation of tears
and dry eye
FIGURE 11.10: Conjunctival lymphatic cysts in a contact lens

wearer are not related to the contact lens use but may have
impact on contact lens wear. Ocular lubricants are occasionally
useful to avoid mechanical trauma through lens striking the
raised area. Notice the positive fluorescein staining over the cyst
due to improper lubrication
FIGURE 11.11: Large yellowish densified (or solidified) secretions in a

contact lens wearer plug the meibomian gland orifices. They are not
related to the contact lens use but may impact on contact lens wear by
modifying the tear film composition. Ocular lubricants are useful to
stabilize the precorneal film
constant flow of air across the eyes. This occurs because these conditions
facilitate evaporation and a further loss of tears.
Dry eye patients are often under the false impression that they cannot
wear contact lenses. Dry eye syndrome itself is not a contraindication for
contact lens use, but patients suffering from any of its conditions have
increased risks of complications and should be carefully instructed to the
correct use and management of contact lenses, and to the appropriate
lubrication of their eyes in order to avoid complications (Figure 11.12). Some
rare conditions which are contraindications for contact lens use: xerostomia,
erythema multiforme (Stevens-Johnson syndrome), ocular cicatricial
pemphygoid, etc.
People with inadequate tearing (dry eye syndrome) usually cannot tolerate
contacts, but only severe or extreme dry eye conditions make it preferable
to avoid the use of contact lenses. When facing a patient with dry eyes,
always try contact lens fitting after a period of proper artificial corneal
lubrication. Instruct your patient to stop the use of contacts as soon as he/she
feels any sign of complication or discomfort. In case of discomfort, contacts
should be temporarily discontinued at once. The simplest and most effective
measure to treat contact lens wear related complications is for the patient to
abandon lens wear.
FIGURE 11.12: Some soft contact lenses (like therapeutic or bandage

contacts) may prevent evaporation from the ocular surface, and provide
a benefit by moistening and covering an eroded portion of the cornea,
but may also be responsible of conjunctival erosions due to overuse
and inadequate ocular wetting. The use of an artificial tear substitute
is essential to prevent complications in contact lens users
Dry eye cannot be cured, but the eyes’ sensitivity can be lessened and
measures taken so that the eyes remain healthy by means of the use of
artificial tears or tear substitutes. In some cases, small plugs may be inserted
in the inferior lachrymal point to slow drainage and loss of tears.
Tear lysozyme and lactoferrin concentrations are decreased in dry eyes.
Although the tests are neither sensitive nor specific as a diagnostic test for
keratoconjunctivitis sicca, they are helpful in determining the bacterial
resistance of the tears. Patients with low levels of lysozyme and/or lactoferrin
have increased risk of ocular infections (conjunctivitis, corneal abscesses). In
these patients, the intermittent use of artificial tears with preservatives can
help to avoid infections.
Several varieties of contact lenses can aid in the treatment of dry eye:
hard contacts may stimulate reflex tearing and thus increase the volume of
tears. Some hard scleral contact lenses may be beneficial by preventing
evaporation from a large portion of the ocular surface. The American Food
and Drug Administration (FDA) has approved one type of contact lens for
dry eyes. This contact lens is the Proclear Lens. It is a soft lens that has some
unique properties. Not only does it have a high water content like other soft
lenses, but also has a component that retains water better than most other
soft lenses. This reduces the dehydration that occurs in most soft contact
lenses. Clinical studies have demonstrated an improvement in comfort and
in signs of dryness on the surface of the eye with this contact lens when
compared to a group of other lenses to which it was tested. Nevertheless,
contact lenses alone have no place in the treatment of dry eyes: concomitant
use of artificial teardrops (and periodic check-up) is essential.
Signs and symptoms of a contact lens wearer with a dry eye (i.e. needing
extra-lubrication)
Signs:
1. Frequent loss of the contact lenses (bad corneal adhesion)
2. Presence of bubbles between the contact lens and the cornea
3. Increased corneal deposits (Figure 11.10)
4. Conjunctival hyperemia at 3 and 9 o’clock
5. Changes in corneal thickness (frequent changes of refraction)
6. Loss of contact lens reflex.
Symptoms
1. Increased foreign body sensation
2. Increased glare (increased halos)
3. Changing visual acuity
4. Best visual acuity just after opening the eyes.
CONTACTS AND AIR CONDITIONING

Tears leave the eye via three mechanisms: (a) flow to the nasolacrymal sac
through the puncti and canaliculi, (b) evaporation and (c) conjunctival
absorption.
The rate of evaporation (approximately 3 microliter/hour at 30 percent
relative humidity) is significantly reduced in humid environments (tropical
climate) and increased in dry environments (desert environment, air dryers).
Contact lens wearers living or working under air conditioning and/or air
heating, have an increased rate of evaporation and, therefore, need extra-
artificial eye wetting via artificial tear substitutes. Direct air currents should be
avoided. The use of a humidifier is highly recommendable.
Certain working conditions, such as exposure to chemical fumes, smoke
or air conditioning, may be undesirable for contact lens wearers. Notice that
smokers are at higher risk of seeing their contacts lenses turn yellowish due
to smoke and nicotine: just as it happens to their fingers.
CONTACTS AND COMPUTER VISION SYNDROME

The use of contact lenses is no reason for stopping the use of computers.
When facing a computer monitor, the blinking rate decreases. This leads to
dry eye, responsible for most of the symptoms referred by the contact lens
user. Adequate eye lubrication with artificial tears and resting 5-10 minutes
per hour should be enough to avoid discomfort in front of the monitor.
Recent studies have shown that you can decrease the evaporation of
tears from your eyes if the computer screen is below the level of your head
by about ten inches.
Why Should We Prefer Preservative-free Artificial Tears?

Preservatives are used in most artificial tear solutions and eye medicines to
prevent bacterial contamination and to allow longer shelf-life. The most
commonly used are: thimerosal, chlorhexidine, phenylmercuric acetate,
chlorobutanol, paraben and benzalkonium chloride. Thimerosal is specially
notorious in the incidence and severity of adverse ocular effects. Contact
lens wetting solutions and artificial tear products may contain these chemicals
or preservatives which can change the tear film’s osmolarity and cause dryness
or cause an allergic reaction.
The most frequent preservative agent is benzalkonium chloride, also
known as bak, in variable amounts. Benzalkonium chloride electrostatically
binds with soft contact lens materials (hydrophilic) and can reach toxic levels.
For that reason, bak is not used as a preservative in soft lens rinsing solutions.
It is used as a preservative in rigid lens solutions, since it does not bind with
rigid lens materials as readily. Some people are very sensitive to benzalkonium
chloride, and show toxic corneal insult even at relatively low concentrations.
If the patient is using various eyedrops at a time (like glaucomatous contact
lens wearers), there may be a concern with the amount of benzalkonium
chloride they are using, because cumulative effect may result. Since
preservatives may cause toxic reactions in patients who use artificial tears
frequently, for these patients (like contact lens users), preservative-free tear
substitutes or disposable lenses are preferable. It is also possible to shorten
the wearing time for the contacts.
The ophthalmologist is sometimes also able to substitute one or more of
the ocular drops with something not preserved with benzalkonium chloride.
Contacts may be ruled out in allergy to lens-care products. When a
patient is experiencing a lot of mucus build-up, excess debris in the tear
FIGURE 11.13: Foam in the tear film is a result of meibomian gland

dysfunction, it often accumulates in the temporal canthus, flowing in
the opposite direction to tears
(Figure 11.13) film, and a viscous-appearing tear film which makes his or
her vision blurry, approximately one hour after inserting the lenses, one
possibility is that he/she has developed a sensitivity to the solution. We instruct
our patients to thoroughly moist the eyes with a preservative-free artificial
tear drops, and to try a different solution.
Contact lens wearers should monitor closely expiration dates of
preservative-free lubricants: and outdated medication should not be used.
Does Good Corneal Wetting Allow Patients to

Use Contacts Overnight (While Asleep)?
Sleeping with lenses on, in general, is not a good idea. Regardless of whether
the patient has dry eyes or not, sleeping with a lens increases the risk of
infection over ten times what it would be if the patient took the lenses out
each night.
Under normal conditions, the average person secretes about 1 g of tears
during a 24-hour period, mostly during the waking hours. At night, our eyes
produce almost no tears, so the eyes become a dry environment and can
become mildly inflamed. For these reasons, it is generally not recommended
that patients wear lenses overnight.
There are lenses approved by the FDA for overnight wearing, but we
recommend against this because there is an increased risk of infection with
overnight lens wearing.
The most serious safety concern with any contact lens is related to overnight
use. Extended-wear (overnight) contact lenses—rigid or soft—increase the
risk of corneal ulcerations that can lead to blindness.
When the eyes are open, tears carry adequate oxygen to the cornea to
keep it healthy. But while sleeping, the eye produces fewer tears, causing the
cornea to swell. With the binding down of a rigid contact lens during sleep,
the flow of tears and oxygen to the cornea is further reduced. This lack of
oxygen leaves the eye vulnerable to infection and neovascularization.
Some people believe that proper eye lubrication at daytime allows
overnight contact lens wear: this is completely false. In contact lens wearers,
proper eye lubrication reduces the risk of complications due to improper
wetting of the cornea (epithelial defects, corneal ulcers, corneal abscesses)
but does not avoid complications related to the lack of oxygen.
Generally, contacts should be removed at bedtime due to risk of infection
and risk of contact lens intolerance. Occasionally it is OK, if it is an accident.
Does good corneal wetting avoid corneal reshaping due to hard contacts?
Hard contacts and also extended-wear rigid lenses can cause unexpected,
sometimes undesirable, reshaping of the cornea (“corneal warpage”). This
phenomenon is more common with decentered contacts or in case of improper
fitting. Soft extended-wear lenses also bind down on the closed eye, but
they are porous and allow some tears through during sleep. Because they
have so little form, their binding has little effect on the shape of the eye.
Before refractive surgery is performed, if corneal reshaping is diagnosed
by means of computerized corneal topography, contacts should be
discontinued as early as possible before surgery (weeks and months before
in some cases), good corneal lubrication is mandatory until the reshaping
disappears. Corneal warpage may take months to completely disappear in a
long-term rigid contact lens user.
The FDA approved extended-wear lenses could be used up to seven
days before removal for cleaning. Still, there are risks with use of extended-
wear lenses, even if it is just one night. Daily-wear lenses are removed daily
for cleaning and are a safer choice, provided they are not worn during sleep.
Proper eye lubrication reduces but does not eliminate the risk of complications
in extended-wear lens users.
Does Good Corneal Wetting Protect from Acanthamoeba Keratitis?

Acanthamoeba keratitis is a very uncommon sight-threatening infection in
Europe. More common in the USA, it is caused by improper lens care. It is a
difficult-to-treat parasitic infection, and its symptoms are very similar to those
of corneal ulcers.
The use of home-made saline from salt tablets and water is one of the
biggest contributors to Acanthamoeba keratitis in contact lens wearers. The
use of salt tablets is not acceptable today as a correct contact lens maintenance
method. Microorganisms can also be present in distilled water, so always use
commercial sterile saline solutions to dissolve enzyme tablets. Heat disinfecting
is the only method effective against Acanthamoeba, and it also kills organisms
in and on the lens case. Proper care gives a safer contact lens wear. Good
corneal lubrication with artificial tears does not prevent from Acanthamoeba
keratitis, although artificial tear preservatives might lower the risk.
Doctor, Can I Make My Own Tear Substitute

Some patients prefer to make their own artificial tear mixtures, from a
combination of herbs (like camomile) and spring water; this practice has to
be discouraged. Sterility is of the utmost importance in contact lens users,
because Pseudomonas and Acanthamoeba are contaminants of spring
and tap water, and even distilled water may not be sterile. Osmolarity is also
important, and it cannot be easily measured at home.
Human mouth is septic; saliva should not be used for contact lens cleaning
or lubrication (yes, it happens in some countries).
Does Corneal Wetting Ease Contact Lens Fitting?

Soft lenses are much more comfortable than rigid lenses, thanks to their
ability to conform to the eye and absorb and keep water. A patient can get
used to soft lenses within days, compared with several weeks for rigid. An
added benefit is that soft lenses are not as likely as rigid lenses to pop out or
capture foreign material like dust underneath. Extra-thin soft lenses are
available for very sensitive people. Artificial tear substitutes are sometimes
useful to ease contact lens fitting, specially for those patients used to eyedrops.
CONTACT LENS MAINTENANCE AND ARTIFICIAL TEAR SUBSTITUTES

Rigid lenses generally give clearer vision, can be marked to show which lens
is for which eye, they do not rip or tear, and are easy to handle. Also, rigid
lenses do not absorb chemicals, unlike soft lenses, which are like sponges.
Soft lenses suck up any residues on your hands: soap, lotion, or whatever.
While the ability to hold water increases oxygen permeability of soft lenses, it
increases their fragility as well.
FIGURE 11.14
FIGURE 11.15
FIGURES 11.14 and 11.15: Protein and lens calculi on a soft piano therapeutic lens.
Some people build up deposits on their contact lenses, including oil and proteins,
which make it difficult for the tears to cover the contact lenses with a smooth surface.
Lids act like a windshield wiper and patients are blinking to clear it up. Deposits on
the lenses need to be cleaned or contacts need to be replaced. Deposits, like the
protein deposits shown, are more frequent in contact lens wearers with no extra-
moistening of the eyes, since cholesterol and protein concentrations are increased
(because of the decreased tear volume). This problem is worse with soft (gel) lenses.
The deposits are basically made of cells, granular and trabeculated mucus, calcium,
pigment and proteins or lipids, and provide nourishment to bacteria and fungi. The
presence of deposits on the contact lens suggests bad corneal lubrication, and may
be responsible for contact lens intolerance
Proper contact lens maintenance should include proper ocular lubrication;

in soft contact lens wearers, artificial tears help to clean any residues absorbed
by the lens (Figures 11.14 and 11.15).
Soft lenses additionally come as disposable products (defined by FDA as
used once and discarded) or as planned-replacement lenses. In such cases,
artificial ocular lubrication is not so essential, since the contact will be in place
for a short period.
For patients who produce a higher level of protein in their eyes or do not
take as good care of their lenses, it might be healthier to replace the lenses
more frequently, despite the adequate use of artificial tears.
The appropriate wearing time for each patient will depend on the type of
lens prescribed. The more the lenses are used, the more necessary good
lubrication becomes (Figure 11.17).
CONTACT LENSES AND GLAUCOMA PATIENTS

Beta-blockers are known to decrease aqueous tear secretion. If your patient
is using topical eye medication, instruct him or her to apply artificial tears
first, waiting at least 10 minutes to apply antiglaucoma topical medication.
Most lubricants may be safely used in addition to any eye care product or
medication the patient uses (suspensions or solutions).
Contact lens users, under latanoprost (alone or combined with timolol),
will feel more comfortable applying an artificial tear before latanoprost; contact
lens tolerance is increased, and eye redness and photophobia become more
rare. The same applies to other prostaglandin analogues.
GLAUCOMA FILTERING BLEBS

The filtering bleb (Figure 11.16) is a subconjunctival reservoir where remains
the aqueous that bypasses obstructed or insufficient physiological outflow
through the operative fistula. Filtering blebs may take on a wide variety of
clinical aspects. The aspect of the bleb does not always reflect its function,
though helps to establish prognosis. Most patients with a filtering bleb do
require additional lubrication, to increase comfort and to reduce the risk of
bleb infection.
FIGURE 11.16: Large or multicystic blebs really do well in IOP control,

but their paper-thin and transparent cyst walls are more prone to
leakage and infection. This kind of bleb is more common in fornix
flap-based approach. In such patients we always prescribe the
daily use of artificial tears to help avoiding bleb infection. Contact
lenses are not well-tolerated: they can erode the paper-thin walls
of the bleb resulting in bleb infection, and are easily lost by the
patient due to the bad adhesion between the contact lens and
cornea. Giant filtering blebs are contraindication for contact lenses
Normally, filtering blebs are asypmtomatic; occasionally, contact lens users

with small flat blebs may experience some discomfort, that is addressed with
topical tear substitutes. We prefer 0.18% sodium hyaluronate solution
(Vislube,™ Lab. Chemedica™—Germany, distributed by Thea™ in Spain),
two or three times-a-day.
CONTACT LENSES AND OINTMENTS

Some patients find that instillation of an ointment with a petroleum base
prevents dryness of the eyes and increases comfort. But because ointments
remain in contact with the ocular surface longer than solutions or suspensions,
sensitivity to preservatives may be increased, and contact lenses can become
greasy.
Do not use ointments with the contact lens in place. In case of severe dry
eyes, contact lenses ought better be avoided; users of contact lenses with
severe dry eyes should avoid the use of ointments; if the patient wants to
continue lens wear, instruct him or her to use ointments at night time (when
sleeping), and rinse the eye thoroughly with an artificial tear before putting
the contact lens in place. Warn your patient that using ointments makes
contact lens to be very carefully cleaned and replaced more frequently.
Some ointments may not be compatible with all contact lenses materials,
and the contact may result irreversibly damaged even by very small quantity
of product. Ask the manufacturer of the contact lens before prescribing an
ointment in a contact lens user.
THERAPEUTIC CONTACT LENSES

Correcting vision is not the only use for contact lenses. Some soft contacts
are used as bandage lenses after photorefractive keratectomy (PRK) surgery
for nearsightedness. The surgery creates a large abrasion on the eye, being
reported by the patients as “excruciatingly painful” if you do not have a
protective covering on the cornea after the anesthetic “wears off” (Figure
11.17). Providing increased comfort by means of proper corneal moistening
is always desirable.
Eye bandage lenses (like Bausch & Lomb’s “plano T” therapeutic contact
lenses) are used to relieve pain from abrasions or sores on the cornea, or
after a corneal graft, to enhance re-epithelialization. Patients feel more com-
fortable with intensive preservative-free eye moistening.
Which is Our Preferred Artificial Tear Substitute in Contact Lens Wearers?

There is not any one drop that has been proven clearly superior to all others.
Most artificial tears replace the volume of tears that are missing, however, no
artificial tear has all the ingredients that natural tears have. A number of the
artificial tears try to approximate the constituents of natural tears and some
have more ingredients than others. They all also have thickening agents in
them to make them last longer. In general, we now recommend that people
who are using eyedrops more than three or four times a day to use tears that
do not contain a preservative, as those can be irritating to the eye. The best
solutions are those that stay on the eye as long as possible; they are generally
viscid and contain mucomimetic ingredients. Nevertheless, some viscid
lubricants may precipitate on the cilia, causing some discomfort to the patient.
We always try to use the least toxic products to keep corneal epithelium
in the best condition. To keep cornea in good condition, we prescribe a
treatment with a 0,18% sodium hyaluronate solution (Vismed™ or
Vislube,™ Lab. Chemedica™—Germany, distributed by Thea™ in Spain),
two or three times-a-day. Most of our patients have a high degree of
satisfaction, and feel very comfortable with the use of sodium hyaluronate
solution.
FIGURE 11.17: Epithelial defect due to extended contact lens wear may
worsen by the long use of tear substitutes containing preservatives.
Notice the stromal and epithelial damage in a patient that used rigid
contact lenses for months without extralubrication, and without rest! If
possible, preservative-free artificial tear substitutes should be preferred
Another excellent corneal lubricant is BSS™ from Alcon™ Laboratories,

the same product we use for intraocular surgery (available in 10 ml bottles).
The eye surface depends upon the tear film’s electrolyte balance for its normal
biologic functioning. Each drop of BSS provides this balance.
Artificial tears have been a treatment mainstay for soothing dry-eye
symptoms. Some (most) are accepted in contact lens users. They lubricate
and offer temporary relief from the irritations that occur on the ocular surface.
In healthy patients, we do not prescribe artificial ocular lubrication
for treating symptoms, but to prevent them. We have a tray of artificial
tear solutions for contact lens users such as Filmabak™ (Thea) Theratears™
(Advanced Vision Research), Refresh™ and Celluvisc™ 0.5% (Allergan), Tears
Naturale™ and Bion Tears™ (Alcon), and GenTeal™ and HypoTears™
(Novartis—Ciba Vision). Patients and doctors typically go through several
brands until they find something that feels better and that is what the patient
will stick with.
Our experience shows that products have to be rotated for best
results. In that sense, we instruct our patients to use alternatively two
different artificial tear drops (two different products, once one product
and later the other one), so that the eye does not get used to the same
product. Most patients are really satisfied; they feel that relief and comfort
last longer. Good combinations are: 2% Povidone plus 0,18% sodium
hyaluronate, and polyvinyl alcohol plus 0,18% sodium hyaluronate.
Some artificial tears are delivered in single-dose preservative-free small
bottles that fit easily into the pocket or purse, and can be used quickly and
conveniently, any time and anywhere. But for daily use, at home, 10 ml
drop containers are cheaper; some modern containers, like the BAK® systems
from Thea,™ have a special filter that retains preservatives, and prevents
from external contamination.
Can We Safely Use Contacts After Refractive Surgery?

Laser surgery is an alternative to the use of lenses. The most common
procedure is LASIK (laser-assisted in situ keratomileusis). Unfortunately, for
people with dry eyes, the LASIK procedure can worsen dry eyes, at least
temporarily. This is because when the flap is made, some of the nerves to the
cornea are cut. These nerves are important in sending signals back to the
tear-producing glands, telling these glands to produce more tears. When
these nerves are cut, those signals are interrupted. The nerves eventually
grow back; but in patients in whom there is already an insufficient amount of
tears, this disruption of nerves can worsen the symptoms of dry eyes.
Although the results of radial keratotomy (RK) (Figure 11.18) and
photorefractive keratectomy (PRK) for myopia are good, some patients
still require contact lenses to optimize their postprocedure vision. Contact
lenses may provide the best vision for post-PRK and post-RK patients with
regression, anterior stromal haze, irregular astigmatism, halos and anisomet-
ropia. Modern corneal topography provides the detailed analysis necessary
to select an appropriate lens for the postsurgical patient. Contact lenses are
generally fit when corneal topography stabilizes, 3 to 6 months after RK, and
6 to 12 months after PRK. After RK and PRK, rigid gas-permeable (RGP)
lenses are more frequently fit than soft lenses, because of their superior oxygen
permeability, better movement on the altered corneal surface and good visual
acuity.
In postrefractive surgery patients, we have noticed that acuities that could
not be corrected to the preoperative level with spectacles were easily corrected
to preoperative acuities with RGP lenses. Contact lenses can be an excellent
option to optimize vision after refractive surgery if time is taken to obtain a

well-fitting lens and to counsel the patient regarding lens wear and
expectations.
Contact lenses can be effectively used after unsuccessful refractive surgery,
but care has to be taken not to worsen postoperative eye dryness. These
patients need intensive eye lubrication with preservative-free solutions.
Contacts should only be used for short periods of time.
FIGURE 11.18: Wide parallelopiped topographic view of radial keratotomy scars.

Most cases need extracorrection with time. Contact lenses can be used after
radial keratotomy, but care has to be taken not to worsen postoperative corneal
stability. These patients also need intensive eye lubrication with preservative-
free solutions, to avoid recurrent painful erosions and vision fluctuations
Lubrication with the Different Types of Contact Lenses

Is it safe to use any artificial tears with contact lenses? Most times,
there is no problem, because most brands offer preservative-free drops for
corneal lubrication. Contact lens lubricants are artificial tears that have been
tested for use with contact lenses. Basically, they are synthetic human tear
fluid with extra water. But not all are created equal; for instance, TheraTears®
is available in the USA from Advanced Vision Research, of Woburn, Mass. It
is not available in Europe at the moment these lines are written. It is the first
eyedrop for dry eye shown in preclinical studies to not only wet and lubricate
the eye, but also to promote healing and restore conjunctival goblet cells.
TheraTears® is hypotonic enough to lower elevated tear osmolarity,
rehydrating the tear film so water can move back to rehydrate the eye surface.
TheraTears® provides electrolyte balance for corneal normal biologic
functioning.
Contact lenses promote evaporation of tears from the surface of the eye.
In addition, soft contact lenses, which contain lots of water, can dehydrate
when they are on the surface of the eye. This is not a problem when people
have plenty of tears; but when a patient has marginal amounts of tears, the
stress of a contact lens and a depleted tear film can lead to a lack of comfort
and reduced wearing time of lenses.
Many types of contact lenses are available. The type of contacts prescribed
depends on every patient’s particular situation. We are able to choose from
the following types of lenses.
PMMA lenses: They were developed in the 1960s and were the first
lenses, rigid or “hard”. They are made of a type of a very durable plastic
called PMMA (polymethylmethacrylate). PMMA does not allow oxygen in
the air to directly reach the cornea. When the eye blinks, the lens moves,
allowing the oxygen dissolved in the tears to reach the cornea. Being rigid
lenses, they are the least comfortable type of contacts and are not really in
use anymore. Some people still prefer them for their durability and lower
cost.
Rigid gas-permeable lenses (Figure 11.19): These lenses are also known
as “RGPs.” They are new kind of rigid or “hard” lenses made of plastics
combined with other materials, such as silicone and fluoropolymers, which
allow oxygen in the air to pass directly through the lens. For this reason,
these are called “gas permeable (GP)”. With these lenses, a good tear film is
essential to allow “friction-free” movement over the cornea. Protein or lipid
deposits are extremely rare with this kind of contacts; they only appear in
extremely damaged surfaces (excessive use, bad maintenance). Rigid lenses
need to be soaked overnight in a wetting/soaking/disinfecting solution
(multipurpose solution, also called universal solution).
Soft contact lenses: These lenses are made of plastic materials that
incorporate water (hydrophilic). The water makes them soft and flexible,
allowing oxygen to reach the cornea diffusing through the lens. The water
content in soft contact lenses varies from 35 to 75%, being the property that
FIGURE 11.19: Once a major reason for wearing contact lenses,

correction after unilateral cataract surgery has become a rarity in the
recent years due to the use of intraocular lenses. Figure shows an
aphakic contact lens in a patient that had surgery in only one eye in the
early 1980s, and who still retains fairly normal sight in the other eye.
The contact lens prevents from aniseikonia, Without extralubrication,
patient refers foreign body sensations
determines the oxygen permeability. More than 80% of contact lens wearers
in the United States use soft lenses. Unfortunately, contact lenses with higher
water content do not work consistently for dry eye condition. These lenses
tend to be thinner, lose their integral water more readily (dehydration), and
are more likely to fold and dislodge in a patient with dry eye. New contact
lenses have recently become available that are specifically designed for patients
with dry eyes. They work by retarding the evaporation of water that is
contained within the contact lens. They are more prone to superficial deposits
that may act as food for bacteria and fungi.
Some contacts contain silicone and fluorine (hydrophobic polymers): they
have much higher oxygen permeability but need extrawetting.
Extended wear contact lenses: Made of material designed to last 2-4
weeks. Extended-wear lenses should be worn no longer than seven days.
Daily disposable lenses: Although generally more expensive, carry a lower

infection risk. A pair of contacts is used and discarded daily. Not to be used
more than 8-10 hours a day.
Toric contact lenses: They correct moderate astigmatism. They are available
in both rigid and soft materials. They are sterile, isotonic and free of particulate
matter.
Aphakic contact lenses can be used in patients with monocular or binocular
aphakia (Figure 11.19).
There are also bifocal (or multifocal) contact lenses designed to provide
good vision at a distance and for reading for people who are in an age group
who require different focusing for distance and near vision. These lenses
require that one look out of a slightly different portion of the lens for near vs.
distance vision. They come in different designs with lenses from different
companies using slightly different optical principles to provide two different
focuses. One for distance and one for reading. They need to be very carefully
fitted so that they are well centered, and they can be very effective. The
same lubricating measures apply to these lenses.
The suggested lubrication guidelines in this chapter do also apply to
cosmetic tinted contact lenses.
For soft lens care, instruct your patient to use only products designed for
soft lenses; for rigid lens care, instruct your patients to use only products
designed for rigid lenses. A good wetting solution for both soft and rigid
lenses is Liquifilm® Eye Drops from Allergan,™ a polyvinyl alcohol lubricant
solution, that can be used either as a wetting solution or as an artificial tear,
directly onto the eye.
Wetting solutions for hard lenses include methylcellulose and derivatives,
polyvinyl alcohol and povidone. Most wetting solutions for hard lenses are
preservative-free saline solutions (buffered isotonic solutions with NaCI).
Most commercially available artificial tears can be used with most contact
lenses without problems. Brand names and compositions vary widely. Some
products (like gels) can crystallize around the cilia, making the lens
wear uncomfortable.
Special directives for contact lens wearers:
1. For relief of dry eyes and contact lens irritation, apply artificial tears often,
always before contact lens insertion.
2. Lightly mist directly onto contact lenses prior to insertion.
3. Mist as often as necessary, but not in excess. Most preservative-free
products fit easily into pocket or purse and can be used quickly and
conveniently, any time, anywhere.
4. Instruct your patient to also enjoy the breath of moisture once the contact
is out.
CONTACT LENS CARE

Proper contact lens maintenance is essential for safe contact lens wear. This
starts with instruction on proper insertion and removal of contact lenses. The
contact lens prescriber will select a lens care system suited to the individual
patient’s lens type, eye health and lifestyle. Patients should consult their contact
lens prescriber before switching contact lens solution brands. Switching lens
care products can cause allergic reactions which can damage the patient’s
eyes and contact lenses. Contact lens care involves timely cleaning and
disinfecting procedures. Improper lens maintenance can decrease lens
performance and shorten lens life. The patient should always carefully wash
their hands before handling contact lenses.
Contact lens wearers who use one-step multipurpose solutions may be at
increased risk for a rare but potentially serious eye infection. That risk can be
minimized, however, by replacing storage cases frequently and following
other good lens hygiene practices, like adequate corneal moistening.
Doctor, how often should I have to put

drops in my eyes when wearing my contact lenses?
That depends on every patient’s needs. Some people do not have to put
drops in their eyes at all. It depends on the amount of tears they have and
the environmental conditions in which they are wearing the contact lenses.
For instance, being in an aeroplane, which is very dry, people always
experience more comfort if they put drops in their eyes. We always instruct
our patients to enjoy the breath of moisture always before the contact is in,
and once the contact is out. Then two or three more times-a-day may be
enough in most cases. Excessive drops (even without preservatives) may
result in paradoxical dry eye: artificial tears dilute the own lipids and mucus
of the natural tear film, thus increasing the rate of evaporation. Excessive
drops (even preservative-free ones) may result in a reduction of conjunctival
goblet cells, distorting the normal electrolyte balance of the tear film.
Doctor, one or more drops each time?

The normal eye can retain around 10 microliter of fluid (adjusted for the
effect of blinking). The conjunctival sac already contains 10 microliter. An
average dropper delivers 25 to 50 microliter per drop. The value of more

than one drop is more than questionable if it is not intended to rinse the
ocular surface. Once one exceeds the capacity of the conjunctival sac, fluid
in excess spills over the edge of the eyelid or will be drained via the punctum
into the nasolachrymal system.
If the patient is under other topical medications (like prostaglandin
analogues for glaucoma), the best interval between drops is more than 10
minutes. This interval ensures that the first drop is not flushed away by the
second or that the second drop is not diluted by the first.
Doctor, does smoking a pack of cigarettes per day make dry eyes worse?
There is no good definitive data on the roll of smoking and dry eyes. There
is no doubt—however—that the irritative effects from smoke on the eyes
certainly worsen the symptoms of dry eyes on the patients, whether they
wear contact lenses or not.
We always instruct our contact lens patients to stop smoking (or to smoke
less cigarettes) when they are at work, specially if they work with computers.
FURTHER READING
1. Albert, Daniel M, Jakobiec, Frederick A (Eds). Principles and Practice of
Ophthalmology. Second edition, Philadelphia: WB Saunders Company, 2000.
2. Bontempo A, Rapp J. Lipid deposits on hydrophilic and rigid gas permeable contact
lenses. CLAO J, 1994;20(4):242-45.
3. Brewitt H, Boushausen D, Joost P, et al. Rewetting of contact lenses: Clinical data on
efficacy and indications. Contactologia 1994; 4:15-20.
4. Duran de la Colina, Juan A, et al. Complicaciones de las lentes de contacto. Ponencia
Oficial de la Sociedad Espanola de Oftalmologia 1998, Tecnimedia Editorial, Madrid,
Spain.
5. Elie, Gabriel, Heitz, Robert. Guide de contactologie: la pratique de l’adaptation et
de la surveillance des lentilles de contact rigides et souples. Hors serie de la revue
“Contactologie”. Enke, Stuttgart (Germany), 1988.
6. Farris RL. Staged therapy for the dry eye. CLAO J 1991;37:207-15.
7. Farris RL. The dry eye: Its mechanisms and therapy with evidence that contact lens
wear is a cause. CLAOJ 1986;12:234-46.
8. Farris RL. Tear analysis in contact lens wearers. CLAO J 1986;12:106-11.
9. Fraunfelder, Frederic T, Hampton Roy F. Current Ocular Therapy. Philadelphia: WB
Saunders Company, 2000.
10. Gilbard JP, Rossi SR. An electrolyte-based solution that increases corneal glycogen
and conjunctival goblet-cell density in a rabbit model for keratoconjunctivitis sicca.
11. Hart D, Tidsale R, Sack R. Origin and composition of lipid deposits on soft contact
lenses. Ophthalmol 1986;93(4):495-503.
12. Holly FJ. Tear film physiology and contact lens wear: 1. Pertinent aspects of tear film
physiology. Am J Optom Physiol Opt 1981;58:324-30.
13. Holly FJ. Tear film physiology and contact lens wear: 11. Contact lens-tear interaction.
Am J Optom Physiol Opt 1981;58:331-41.
14. Jones Lyndon W, Jones Deborah A. Common Contact Lens Complications: Their
Recognition and Management. Oxford: Butterworth-Heinemann, 2000.
15. Larke John R. The Eye in Contact Lens Wear. London: Butterworths & Co. (Publishers)
Ltd., United Kingdom of Great Britain, 1985.
16. Lee James R. Contact Lens Handbook. Philadelphia: WB Saunders Company, 1986.
17. Lemp MA, Holly FJ, Iwata S, Dohiman CH. The precorneal tear film: 1. Factors in
spreading and maintaining a continuous tear film over the corneal surface. Arch
Ophthalmol 1970;83:89-94.
18. Lemp MA. Surfacing the precorneal tear film. Arch Ophthalmol 1973;22:165-76.
19. Lemp MA, Hamill JR. Factors affecting tear film breakup in normal eyes. Arch
Ophthalmol 1973;89:103-05.
20. Lemp MA, Holly FJ. Ophthalmic polymers as ocular wetting agents. Ann Ophthalmol
1977; 4:15-20.
21. Lemp MA. Report of the National Eye Institute/Industry Workshop in clinical trials in
dry eye. CLAO J 1995;21:221-32.
22. Maissa C, Franklin V, Guillon M, Tighe B. Influence of contact lens material surface
characteristics and replacement frequency on protein and lipid deposition. Optom
Vis Sci 1998;75(9):697-705.
23. McMonnies CW. Dry eyes and contact lens wear. In: MG Harris (Ed). Contact lenses:
Treatment Options for Ocular Disease. St Louis: Mosby, 1996;23-50.
24. Minarik L, Rapp J. Protein deposits on individual hydrophilic contact lenses: Effects
of water and ionicity. CLAO J 1989;15(3):185-88.
25. Mishima S, Gasset A, Klyce SD, Baum JL. Determination of tear volume and tear
flow. Invest Ophthalmol 1966;5:264-76.
26. Mishima S. Corneal physiology under contact lenses. In Gasset AR (Ed): Soft Contact
Lenses. St Louis: Mosby, 1972:19-36.
27. Mishima S, Maurice DM. The oily layer of the tear film and evaporation from the
corneal surface. Exp Eye Res 1961;1:39-45.
28. Murube del Castillo, Juan (Ed). Ojo seco —Dry Eye. Proceedings of the “73 Congreso
de la Sociedad Espanola de Oftalmologia”, Tecnimedia Editorial, Madrid, Spain, 1997.
29. Roth HW. Ojo seco en portadores de lentes de contacto. In El ojo seco, MA Lemp,
R Marquard (Eds): Barcelona: Springer Verlag Iberica, 1994; 221-43.
30. Simon, Jose Ma. Glaucomas: hipertensiones oculares. Editorial Jims, Barcelona,
Spain, 1973. Simon-Castellvi, Jose Ma. Los o/’os del ciudadano. Club de Autores
Ediciones, Barcelona, Spain, 2000.
31. Simon-Castellvi, Guillermo L, Simon-Castellvi, Sarabel, Simon-Castellvi, Jose Ma,
Simon-Tor, Jose Ma. Tips and tricks for successful refractive surgery. In: Refractive
Surgery. Jaypee Brothers Medical Publishers, New Delhi, India, 1998.
32. Simon-Castellvi, Guillermo L, Simon-Castellvi, Sarabel, Simon-Castellvi, Jose Ma,
Simon-Tor, Jose Ma. Assessment and management of filtering blebs. In Textbook of
Ophthalmology, vol. 3. New Delhi: Jaypee Brothers Medical Publishers, 2000.
33. M-non-Castellvi, Guillermo L, Simon-Castellvi, Sarabel, Simon-Castellvi, Jose Ma,
Simon-Castellvi, Y Cristina. Fundamentals on cornea! topography. In Lasik and
beyond Lasik: Wavefront analysis and customized ablation. Highlights of
Ophthalmology, Panama, 2001.
34. Tripathi R, Tripathi B, Silverman R. Morphology of lens deposits and causative
effects. In: Ruben M, Guillon M (Eds): Contact Lens Practice. London: Chapman
and Hall, 1994;(1):1099-1117.
35. van Bijsterveld OP. Diagnostic tests in the sicca syndrome. Arch Ophthalmol 1969;82:
10-14.
COMPUTER VISION SYNDROME AND DRY EYE 195
INTRODUCTION
Computer vision syndrome (CVS) is a condition affecting people working
on the computer monitor. Considering the undisputable invasion of
technology into our lives, this is a problem to reckon with.
Factors responsible for the development of CVS includes improper
positioning like sitting too close to the computer monitor, poor room lighting
and increased glare from the screen and infrequent blinking.
CAUSE
The prints on a computer monitor, unlike in paper is made up of pixels
which are small dots. Their edges are fuzzy giving rise to poor contrast and
indistinct margins. The eye has to constantly refocus to keep the images
sharp. This leads to strain of the eye muscles. Further, when seated to close
to the computer monitor, a lag of accomodation develops which the subject
tries to adjust for and therefore it results in eye strain. Also, letters on computer
monitors may be of variable light intensity thereby adding to the poor contrast
levels. As already mentioned, poor room lighting and glare from the monitor
also adds to the problem.
SYMPTOMS
It is characterized by symptoms of like burning, tearing, heaviness of lids, eye
pain, headaches.
PREVENTIVE MEASURES
1. Maintain a distance of 20 – 26 inches from the computer monitor.
2. Computer monitor should be placed 10 –15 degrees below eye level on
straight gaze.
3. Use of antiglare screen.
4. Glarefree room lighting.
5. Position computer to avoid falling of direct sunlight and therefore minimize
glare.
6. Take breaks from the computer screen.
7. Remember to blink at regular intervals.
8. Computer monitor may be placed horizontally on the table which will
help the subject to read with his presbyopic correction.
COMPUTER VISION SYNDROME AND DRY EYE 197
COMPUTER GLASSES
Computer glasses here actually means glasses for the intermediate working
distance where the monitor is placed. This has to be carefully determined
according to the working distance of the patient after determining the distance
and near corrections. One option would be to use a single-vision lens which
can be used only while working at the computer. However, this will cause
difficulty to the subjects when he looks around. Therefore, the other option
would be to use progressive lenses which will have corrections for distance,
near as well as for the intermediate working distance. These include lenses
like the Interview lenses, Desktop lenses, Access lenses and Technica lenses.
Coating the computer glasses could also help in improving the visual
quality. Antireflective coating is beneficial in individuals working in an
environment where the amount of lighting can be controlled. For individuals
working in offices with bright fluorescent lighting, 400nm UV coating helps
in absorbing blue light component of fluorescent light. Tinted glasses also
may be of use in reducing the brightness of harsh fluorescent light.
MANAGEMENT OF THE DRY EYE AFTER REFRACTIVE SURGERY 199
“An eye for an eye and the world would be blind.”

—Mahatma Gandhi
INTRODUCTION
Refractive surgical procedures are one of the most commonly performed
ophthalmic surgeries as of late. The technoligies have improved over the last
years and also the skill of the ophthalmic surgeons, however, complications
occur albeit at a low incidence.1
Succesful surgery is dependent on not only the measured postoperative
visual acuity or quality of vision, but also the preoperative expectations of
the patients as determinants of overall satisfaction. It is therefore crucial that
every refractive surgeon discuss the indications, methods, possible risks,
limitations, and potentional alternatives with his/her patient in advance of a
planned elective refractive procedure to accurately gauge the expectations
of the patient and recommend the best course, including possibly choosing
an alternative or abandoning surgery.
COMPLICATIONS IN REFRACTIVE SURGERY

The most common complications in refractive surgery:2
1. Overcorrection
2. Irregular astigmatism
3. Ocular surface syndrome
4. Glare
5. Difficulty with night driving
6. Corneal haze.
In this chapter, it will be dealt with the so called dry eye or better Ocular
Surface Syndrome complications and how to manage these after refractive
surgery.
The “Dry Eye” is a generic term for a group of conditions characterised
symptomatically by irritated, gritty, burning eyes and clinically by alterations
in the tear film and the anterior surface of the eye and to a certain degree
interference with innervation of the cornea after refractive procedures. In a
classic review, this syndrome was defined as “a disorder of the tear film due
to tear deficiency or excess tear evaporation which causes damage to the
interpalpebral ocular surface and is associated with symptoms of ocular
discomfort” (Lemp,1995). This general definition encompasses a range of
dry eye states with a range of etiologies.
Deficiencies or disturbances in the production, quality and replenishment

of the pre-corneal tear film will result in dry eye conditions. Such conditions
can result in ocular surface damage, and may lead to eventual corneal damage
and, ultimately a loss of viusal performance.
THE TEAR FILM

The tear film is a fluid that covers the cornea (the precorneal tear film) and
the conjunctiva (the preocular tear film). The roles of the precorneal tear
film can be summarized as follows:
1. To protect the cornea from drying
2. To maintain the refractive power of the cornea
3. To defend against eye infection
4. To allow gas to move between the air and the avascular cornea
5. To support corneal dehydration (assisted by the tear film hyperosmolality).
As well as nurturing the cornea, the preocular tear film is necessary to
protect the other epithelial tissues of the anterior surface (the bulbar and
palpebral conjunctiva) from physical damage on blinking.
Under normal conditions, the tear film is of sufficient quantity and quality
to fulfill the requirements outlined above.
Volume is an important issue: without a sufficient volume of tear fluid, a
film cannot adequately form over the ocular surface and offer protection
from exposure between blinks. An adequate volume of tears is also required
if the tear film is to provide lubrication and prevent the shear forces of blinking
from damaging the anterior eye.
Another important aspect is the tear film stability. The stability of the tear
film is the property which allows it to maintain a confluent coverage of the
ocular surface, for an adequate duration of time to protect the ocular surface
between blinks. Further the tear film must also be of a sufficient quality,
inherent of an adequate composition, to accomplish its numerous roles in
the biophysical and bacteriostatic/bacteriocidal defence of the anterior surface.
THE “DRY EYE” OR THE OCULAR SURFACE SYNDROME (OSS)

The “Dry Eye Syndromes” or better the Ocular Surface Syndromes have
been reported as being of several classifications:3
A. Aqueous deficient dry eye: This is a partial or absolute deficiency of
the aqueous phase of the tear film, and is a condition of fluctuating severity,
most commonly developing in adults (especially postmenopausal females).

Decreased aqueous production and decreased tear drainage can
compromise the anterior surface, leading to an association between
aqueous deficiency and secondary infections such as bacterial conjunctivitis
and keratitis.
B. Mucus (soluble surfactant) deficiency: Decreased quantity or quality
of surface mucus may lead to impaired surface wetting of the epithelia,
and decreased lipid trapping and masking at the epithelial interface. Mucus
deficiency is like other forms of dry eye, associated with decreased tear
stability. The majority of ocular mucus is produced by the conjunctival
goblet cells, whose numbers are reduced by vitamin A deficiency (which
promotes epithelial keritinization) and other tear deficiencies which
compromises the ocular surface.
C. Lipid abnormalities: While complete tear film lipid deficiency is not
known in man, alterations in lipid composition (as seen in chronic
blepharitis) can decrease lipid function. This can cause decreased tear
evaporation control and thus decrease tear film stability.
D. Lid surface abnormalities: When normal lid movement (blinking) is
compromised, the area of cornea and conjunctiva not adequately served
shows non-wetting. This poor wetting can lead to subsequent epithelial
desquamation. Loss of tonus or paresis of one or more eye lid muscles
may cause abnormal blinking.
E. Epitheliopathy: The normal microvillous surface of the cornea is required
to anchor the tear film (through interaction with the mucus phase). Any
pathology or disturbance adversely effecting the integrity of this epithelial
surface, decreases the tear film integrity, and thus stability.
FIGURE 13.1: The cyclic disorder by Lemp4
Further in 1995 Lemp reported two major classes of dry eye:

A. Tear deificient dry eye, where deficiencies of aqueous phase tear production
or distribution leads to the most common form of dry eye.
B. Tear sufficient (evaporative) dry eye, where sufficient tears are produced,
but tear evaporation (due to a variety of factors) mediates dry eye signs
and symptoms (Figure 13.1).
THE OCULAR SURFACE SYNDROME (OSS)

The ocular surface syndrome is a term which is now used to describe a
variety of conditions, sharing common symptomology and clinical signs,
leading to a physical and functional break-down of the tear film.
Such tear film disorders range in severity, from the borderline dry eye,
which may only be apparent under conditions such as environmental
challenge, to severe (pathological) dry eye, as often found in Sjögren´s
syndrome (Table 13.1).
TABLE 13.1: Drye eye classification after Lemp (1995)
Basic Sciences in OSS

Corneal Innervation and the Ocular Surface Syndrome (OSS)
The cornea is one of the most-densely innervated tissues in the body.
The majority of nerve fibers reaching the cornea are sensory and travel
through the trigeminal nerve (the ophthalmic division of the fifth cranial
nerve) to the long ciliary nerves; autonomic parasympathetic fibers from the
ciliary gabglion join these nerves, and a small number of sympathetic fibers
from the superior cervical ganglion are also seen.These nerves enter the
cornea at the periphery in a general distribution pattern.
The nerve bundles enter radially, running parallel to the corneal surface
at about two-thirds depth. About 60-80 in number, they course centrally as
unmyelinated nerve bundles (Descemet’s membrane and the endothelium
are not innervated). This network of fibers eventually heads toward the corneal
surface, forming a subepithelial plexus and penetrating Bowman´s membrane.
The terminal path of the corneal nerves leads to inter-and intraepithelial cell
areas.
It has been estimated that there are between 5,000 and 7,000 nerve
bundles present in the subepithelial plexus, with between 20,000 and 40,000
total axons.
The sensory receptors act as monitors directing signals via the central
nervous system to afferent nerves that terminate in the lacrimal glands, ocular
surface, lids and lacrimal drainage passages. Autonomic fibers ending within
epithelial cells are important for directing the normal turnover of epithelial
cells and cellular healing in response to injury, surgery or disease. A healthy
functioning sensory apparatus is partly essential to the maintenance of the
ocular surface, and abnormalities in neurosensory transmission can lead to
epithelial signs of dryness and an eventual breakdown of the ocular surface.5
The corneal nerves are composed of both sensory and autonomic fibers.
The sensory fibers, which, with their receptors, comprise the majority of the
corneal nerves, serve as monitors, responding to injury by initiating a protective
blink. These fibers also act as sentinels, activating the neural loop that directs
the secretory activities of the lacrimal and meibomian glands, as well as the
mucin-secreting cells of the ocular surface. The composition of the pre-ocular
tear film is determined by these signals.
The autonomic (predominantly parasympathetic) fibers direct basic cellular
activities, including cell division and maturation (differentiation).Together,
the autonomic and sensory fibers form an essential component of the tear
film—ocular surface functional unit. Nerves direct cellular turnover, and they
respond to injury by initiating changes in tear composition that promote
healing.
The OSS is characterized by multiple break-downs of inter-related aspects
of the tear film—ocular surface functional unit. Systemic initiating factors can
include hormonal changes, immunological abnormalities, genetic
predisposition, neurological lesions, and ageing. All of these can produce
destabilizing changes in the tear film including elevated tear osmolarity,
alterations in tear composition, inflammation, and refractive surgical
procedures.
Hyperosmolarity is a potent stimulator of inflammation via stress kinases
that promote an intracellular inflammatary escalation. Key to the tear film—
ocular surface functional unit´s response to these negative changes are the
sensory receptors. However, inflammation has been shown to downregulate
the receptors, in effect short-circuiting the modulating response to injury.
Deprived of a signaling pathway that could induce changes that might counter
the destructive process of the OSS, inflammation-mediated tissue damage

proceeds, leading to epithelial disruption and discomfort.
A very similar series of ocular surface events occurs in neurotrophic
keratopathy. In this case, the primary lesion involves the afferent fibers of the
ophthalmic branch of the trigeminal nerve. Clinical manifestations range from
superficial punctate keratopathy to ulceration and perforation. These profound
changes point to a central role of neural integrity in maintaining a normal
ocular surface.
Surface Properties of the Normal and the Damaged Corneal Epithelium

What triggers the corneas non-wettability by the aqueous tears in a variety of
ocular surface and tear film disorders? The answers are not straightforward
in that they involve subtle interplays of surface-chemical and physiological
factors. To adress these questions in a meaningful way, a proper understanding
of both the apolar and the polar (acid-base) surface properties of the corneal
epithelium and mucus is required. While the early approaches6,7 based on
Zisman’s method of critical surface tension8 did produce some limited insights,
it is now generally agreed that this method lacks the requisite framework to
adress the problem of polar interactions in aqueous media. Further progress
in the understanding of the cornea-tear film interactions was made possible
by the pioneering concepts of van Oss, Chaudhury and Good9,10 and their
applications to biological surfaces.11,12 These developments made it possible
for the first time to quantify the apolar and polar properties of various corneal
and tear film components and their free energies of adhesion.13
An understanding of the corneal wetting by the precorneal tear film
demands a small introduction to the structure and physiology of the corneal
surface and the tear film.
The corneal epithelium, which is the outermost covering of the cornea, is
composed of about four to six stratified cell layers, which are continously
renebwede by mitosis in the basal cell layer. The basal cells slowly move to
the progressively outer layers and differentiate, until they are shed in the tear
film from the superficial layer of highly-differentiated and sometimes
degenerating, flattened squamous cells. The surfaces of the superficial corneal
epithelial cells in contact with the tear film develop a highly-glycosylated
glycocalix14,15 which is a very hydrophilic extracellular matrix of the cell
membrane bound glycosylated glycoproteins or MUC1 mucins.16 At least
50-60% of their mass is carbohydrate. However, the less-differentiated deeper
layer cells are expected to be less-hydrophillic because they lack a mature

network of glycocalix17,18 and membrane protrusion, e.g. microvilli. The tightly
bound extracellular mucins are more properly a part of the corneal surface
than of the overlying tear film.
The tear film is most often described as a three-layered structure. The
superficial epithelial cells are covered by an intensely hydrophillic coating of
hydrated but relatively unsoluble mucous gel. Thickness of the corneal mucus
layer has been shown to be in the range of about 1 to 10 μm or even higher
by a variety of methods. The mucus gel covering the cornea has extra-corneal
origins; it is expressed by the goblet cells of the conjunctiva as a gel froming
mucin, MUC5AC19 and smeared over the cornea by the shear exerted during
blinking. Blinking assists in a slow turnover or renewal of the mucous layer
by removing small quantities of superficial mucus and replenishing it with
fresh supplies.
A 4 to 10 μm thick aqueous film containing electrolytes, soluble proteins
and mucins completely wets the mucus coated corneal surface in normal
eyes. The aqueous tears display non-Newtonian behaviour; its zero-shear
viscosity is high but declines close to that of pure water at very high shear
rates, which may be attained during a blink20 and also during de-wetting. A
high value of zero-shear viscosity is indicative of a weak network like structure
of soluble mucins in a stationary tear phase, which is readily disrupted by
flow-induced stresses. The surface tension of tears is usually found to be in
the range of 35 mN/m to 50 mN/m21 which is substantially smaller than the
surface tension of pure water.
Finally, the outermost layer at the tear-air interface consists largely of
apolar lipids such as waxy and cholesterol esters derived from the meibomian
glands. A small fraction of polar lipids such as free fatty acids are also present,
which should adsorb at the aqueous-lipid interface due to their surfactant
like properties, and assist in complete spreading of the apolar lipids on aqueous
tears. Among other things, the superficial layer greatly retards the evaporation
and flow of tears and provides a hydrophobic barrier preventing spillage of
tears at the lid margins.
The normal precorneal tear film usually remains intact between consecutive
blinks, but holes begin to appear and grow at random spots in about 20 to
60 seconds, when blinking is prevented. In the so called dry eye states, a
much more rapid breakup on the tear film during the interblink period is
usually observed, which may eventually lead to corneal dehydration and
damage. In severe cases of dry eye, a complete tear film may not even
reform after a blink, and dry corneal spots may be present immediately after
opening of the eyelids.
What are the factors that cause the wettability or nonwettability of the
corneal surface? The most popular and the earliest view of the corneal wetting
was advanced by Holly and Lemp based on the measurements of the apolar
surface properties by the then widely used critical surface tension metod of
Zisman. It was concluded that the normal corneal epithelium without mucus
is a low energy hydrophobic surface nonwettable by the aqueous tears, but
the mucous gel masks its hydrophilicity and renders it completely wettable.
However, it has since been argued and demonstrated that artifacts in the
preparation of the corneal surfaces, use of apolar diagnostic liquids and the
methods of interpretation have been responsible for these conclusions. The
particle attachment method,22 the equation method23 as well as the use of
modern “acid-base approach” have all shown the normal epithelial cells with
associated glycocalyx to be almost as hydrophillic and as wettable by the
aqueous media as the corneal mucus. Nor is this conclusion surprising,
because, like any number of cells with an extracellular coat of glycosylated
glycocalyx, the corneal epithelial cells also become wettable due to a strong
electron donor type of polarity which engenders copious amounts of
hydrogen bonding water molecules.
The corneal surface is a mosaic of cells with varying age, morphology and
degree of differentiation. The epithelial wettability should therefore also be
highly variable on the cellular level. In particular, surfaces of degenerating
and desquamating cells as well as the newly uncovered deeper layer cells
lacking a mature network of microvilli and glycocalyx, are likely to be a lot
less polar and nonwettable. The function of mucous would be to mask these
transient nonwettable sites of cellular dimensions, thereby stabilizing the tear
film. Once the mucous layer ruptures, the tear film breakup may follow on
the naturally occuring nonwettable sites, or on nonwettable sites generated
due to the epithelial contamination.
Very important though is that with increased dehydration and damage
(surgical intervention) to the epithelium, the corneal surface becomes
increasingly apolar and less hydrophillic due to the loss of its electron donating
capacity. It is likely that the individual deeper layer cells, desquamating and
degenerating cells, as well as cells with abnormalities of glycocalyx synthesis
or attachment are less polar and hydrophillic (surgical intervention or touch).
It seems that despite a diversity of the underlying causes, the loss of epithelial
polarity (and wettability) may be conceptually categorized by the following
two distinct types of epithelial alterations:
1. Alterations in the physicochemical nature and morphology of the superficial
cell surfaces. This category includes loss of surface microvilli and glycocalix,
damage/degeneration of the cell membranes, and abnromalities of cellular
differentiation leading also to keratinization in some cases. The case of
vitamin A deficiency leading to various stages of squamous metaplasia of
the corneal surface also falls in this category.24
2. Abnormal loss of superficial cells: This category includes punctate erosions
and recurrent/persistent defects of the epithelium, which may be caused
by the adhesion failure of cells, tear film and epithelial insults such as
hypersomolarity, drugs and preservatives, deficiencies of the epithelial
maintenance/turnover and surgical corneal interventions. There is evidence
that the corneal epithelial mass is maintained by a dynamic balance
between rates of basal cell mitosis, cell loss and centripetal supply of cells
from the peripheral “stem” cells located in the limbus. Thus in some cases,
reduction of the corneal epithelial mass premature exfoliation and reduced
residence time of cells and formation of superficial epithelial defects could
occur secondary to the abnormalities of centripetal supply, cell mitosis
and damage to the stem cell production. These alterations, in addition to
encouraging the loss of epithelial surface polarity, also increase
contamination of the mucous layer by the cell debris, thereby decreasing
its electron donor properties.
All the above surface chemical pathways and their probable interactions
leading to the tear film breakup in dry eyes are summarized in the Figure
9.2.25
PRESURGICAL EXAMINATIONS FOR DETERMINATION OF EVENTUAL

OSS PROBLEMS IN THE PROSPECTIVE REFRACTIVE SURGERY PATIENT
Evaluation of the prospective refarctive surgery patient for OSS includes
many of the elements of a comprehensive ophthalmological examination
and a more in-depth evaluation of the ocular surface and adnexa.26 The
evaluation for ocular surface disorders includes a carefully detailed patient
history, an assessment of associated risk factors, and an examination of the
anterior ocular structures and their functions.
FIGURE 13.2: OSS multifactorial interaction
1. Patient history: Demographic data about the patient should be collected

prior to taking the patient history. Included in the patient history is the
chief complaint, ocular history, general health history (which may include
a social history and an extended review of systems), and family ocular
and medical history. In addition, environmental factors relating to climate,
season, vocational setting, and avocational pursuits should be reviewed.
2. Ocular examination for OSS: Observations, using external ocular
examination techniques, both without magnification and with the
biomicroscope slit-lamp, show characteristic early changes of the external
eye. Evaluation for suspected ocular surface disorders should include the
following:
• External view of the eye, noting lid structure, position, symmetry, and
blink dynamics
• Biomicroscope examination of the lid margins, meibomian gland
orifices and their contents
• Biomicroscopic examination of the tear film, noting mucus, debris,
interference patterns in the lipid layer, and tear meniscus height
• Biomicroscopic examination of the cornea and conjunctiva, both with
and without sodium fluorescein and rose bengal or lissamine green
staining.
Tear quantity tests are useful in conforming the diagnosis of aqueous

deficient dry eyes. The most frequently utilized procedures are and will be
covered in more detail further in the text:
• Schirmer tear test
• Fluorescein staining
• Evaluation of the tear prism
• Debris in tear film
• Rose bengal staining.
Other tests which may be used to evaluate tear quantity include:

• Schirmer II (irritation)
• Lissamine green staining
• Tear volume measurements
• Lacrimal equilibration time
• Cotton thread test
• Phenol red test
• Fluorophotometry; fluorescein dilution
• Temporary punctal occlusion.
Several procedures are commonly used to evaluate tear film stability:

• Tear film break-up time (TBUT)
• Tear-thinning time
• Lactoferrin concentration tests: LactoPlate® and LactoCard®
• Lysozyme radial diffusion test: Quantiplate.
Other tests which may be used to evaluate the quality of the preocular tear
film (POTF) include:
• Tear osmolarity test
• Conjunctival scraping and biopsy
• Mucin test (tear ferning)
• Specular reflection of the tear surface
• Impression cytology
• Tear protein analysis
• Lipid layer interference patterns
• Enzyme-linked immunosorbent test (ELISA) tear protein profile
• Corneal topography in wet and dry state
• Corneal hysteresis
• Water content of cornea.
3. Ocular examination for blepharitis: A thorough external examination

of the lids and other parts of the adnexa, including comparison of the
eyes, helps determining the severity of the inflammation. Differentiating
among the various presentations of blepharitis requires the use of the
biomicroscope to contrast the appearance of the anterior and the posterior
lid margins. Evaluation of the patient with blepharitis should include:
• External examination of the eye, including lid structure, skin texture,
and eyelash appearance; and evaluation for clinical signs of acne
rosacea
• Biomicroscopic examination of the lid margins, the base of the lashes,
and the meibomian gland orifices and their contents
• Examination of the tear film for lipid layer abnormalities
Each type of blepharitis has specific characteristics which help in making

the diagnosis.
Tear Stability Tests

Tear film stability assessment techniques can be considered as invasive or
non-invasive. This is an important distinction, as the non-invasive techniques
are greatly superior to the invasive method.
Invasive Tear Break-up Time (TBUT, Fluorescein Break-up Time)

This test requires observing the cornea using a slit-lamp biomicroscope, with
a broad-beam cobalt-blue light source at 10 × magnification (Norn 1969,
Lemp and Hamill 1973). To view the tear film, fluorescein dye is instilled,
e.g. by wetting a dry fluorescein impregnated paper strip with a drop of
saline and placing it on the bulbar cornea for a brief moment. The dye
readily mixes in the tear fluid and after 1 or 2 blinks the tear film takes on a
uniform fluorescent appearance. Ask the patient to refrain from blinking and
in most cases within 60 seconds dark spots or streaks will form within the tear
film. These discontinuities in fluorescence are indicate breaks in the continuity
of the tear film. The time elapsing between a complete blink, and the
appearance of the first “dark spot or streak” is measured and taken to be the
break up time. Five successive measures are routinely taken, and the mean
value calculated. In dry eyes break up time is usually less than 10 seconds.27
Several workers have suggested this invasive break up time assessment to
be of poor repeatability and questionable validity,28 probably due to:
i. The destabilising effect of fluorescein on the tear film itself

ii. The volume of fluorescein added is uncontrolled and relatively large
compared with the natural tear reservoir
iii. Contact with the ocular surface will initiate some refelx lacrimation.
For these reasons many doctors have turned to the noninvasive tear film
stability assessment techniques, however, the majority of doctors do still
perform TBUT as their standard assessment of tear stability. The usefulness
of the TBUT test can be increased by minimising the amount of fluorescein
used. This has two clear advantages:
1. This prevents “quenching” of fluorescence
2. This minimizes the destabilizing effects of fluorescein, so should give more
valid assessment results.
A much smaller amount of fluorescein can be instilled using a new
fluorescein impregnated paper strip with a tapered tip (the Dry Eye test or
DET®, Ocular Research Boston, Boston, USA).
Noninvasive Tests of Tear Film Stability

The fundamental principles common to these techniques are based on the
reflective properties of the smooth, stable tear film. As the film distorts (as it
thins), its ability to reflect, undistorted, a regular optical array of pattern
diminishes. The time elapsing between a complete blink, and the appearance
of the first distortion is measured and taken to be the tear thinning time
(TTT). Five successive measures are routinely taken, and the mean value
calculated. In essence, non-invasive tests of tear stability are based on observing
the quality and stability of the first Purkinje image.29
The Bausch and Lomb keratometer can be used to measure the TTT,
using the standard mires as a light pattern source (Patel et al, 1985). However,
the mires cover a smaller total area of the cornea, and so may be more
difficult to accurately use.
Corneal topographers based on the Placido disc can also be used to
assess tear stability. The video monitor in most computerised
photokeratoscopes is used to align the instrument and record the Purkinje
images when crisp and sharp. By asking the patient to blink and observe the
time taken for part of the reflected image to break down in clarity, the tear
stability is measured and widen the the potential of the videokeratoscope.
The various non-invasive tear film stability assessment techniques can be
considered in terms of those which measure the tear thinning time (TTT),
and those which measure the noninvasive break-up time (NIBUT). NIBUT is
believed to be a measure of the time taken for a discontinuity in the superficial
lipid layer of the tear film to occur following a blink, whereas, TTT is a measure
of the time taken for the tear film to thin, following a blink. Tear thinning is
believed to occur just prior to tear break-up. For this reason, TTT and NIBUT
are taken to be similar parameters, not interchangeable or synonymous, but
both indicative of tear film stability.
Tear Volume Tests

Estimates for the volume of tears covering the ocular surface range from
b2.74 + 2 μL (Mathers et al, 1996) to 7 μL (Mishima et al 1966). The bulk
of this volume is made of fluid secreted by the main (primary) and secondary
lacrimal glands. When reading, tears are passively secreted and flowing onto
the ocular surfaces and in a few seconds there will be a blink. This will force
tear fluid towards the lacrimal puncta and via these, the tears will pass from
the ocular surface and into the lacrimal canalicuae. Intuitively, a dry eye is
one with with low tear volume. Tests for tear volume could either be invasive
or non-invasive.
Invasive Tests
Schirmer’s test: This is a strip of filter paper, (45 mm long and 5 mm wide)
which is hooked over the lower eyelid. The hook is 5 mm with a rounded
edge. On contact with the ocular surface the paper absorbs tears. The length
of paper wetted over a set time of 5 minutes is an indication of tear volume.
The paper can irritate the ocular surface initiating a reflex action whereby the
volume of tears secreted by the lacrimal glands increases. Thus, Schirmer
test is measuring both a basal and reflex tearing. By anaesthetising the ocular
surface, it is claimed the reflex stimualtion is prevented and a true measure
of basal tear secretion can be made (Jones, 1966; Lamberts, et al 1979;
Jordan and Baum; 1980; Clinch et al 1983). The Schirmer’s strip comes
into contact with not only the ocular surface but also the lid margin and
lashes. This suggests that, maybe the lid margins should also be anesthetized
if the aim is to measure basal tear secretion. Many investigators conclude,
the Schirmer’s test measures the flow of tears rather than volume and the
fact that it irritates the ocular surface is a useful adjunct. If the Schirmer’s
score is still low after irritating the ocular surface then clearly there is a dry
eye present as opposed to a marginally dry eye. Low Schirmer’s test results
are encountered when corneal sensitivity is reduced in severe dry eyes (Xu
et al 1996). Furthermore, Schirmer’s test results are low after refractive surgery
presumably because corneal sensitivity has been reduced (Ozdamar et al
1999, Aras et al 2000). The Schirmer’s test has been criticized for its low
reproducability, it is time consuming, it is irritating and has poor diagnostic
value especially when attempting to investigate the marginal dry eye (Feldman
and Wood 1979, Patel et al 1987, Cho and Yap 1993). A dry-normal cut off
value of 5 mm of wetting in 5 minutes has been used for many years but this
is not reliable because, 17% of normal eyes have a Schirmer wetting of less
than 5 mm (Wright and Meger, 1962) and 32% of dry eyes have a Schirmer’s
wetting of more than 5 mm (Farrell et al 1992). The true value of the
Schirmer’s test in the modern setting is questionable even though it is still
one of the most popular tests used by clinicians.30-33
Cotton thread test: Cotton can soak up tear fluid by capillary action. The
cotton thread (Kurihashi 1978, Hamano et al 1982) is dyed with a pH-
sensitive phenol red which changes from yellow-orange to red-orange with
contact with tears. This is useful for quickly checking the length of the wetted
thread. The volume of tears taken up by the thread depends upon the exact
type of cotton and the duration of the insertion. The Hamano thread is
inserted for 15 seconds. This thread is 70 mm long with a 3 mm hook at one
end (Zone-Quick™). The lower lid is gently depressed and the 3 mm is
placed over the lower lid margin, on to the conjunctiva about half the distance
from the centre towards the outer canthus. The patient is asked to relax and
keep looking straight ahead. Alternatively, the patient could just keep the
eyes closed. After removing the thread from the ocular surface, the soaked
up tears continue to flow along the thread. It is good paractice to measure
the length of weeting as soon as the thread is removed to reduce this effect
of systemic error. The soft thin cotton is less irritating compared with the
stiffer Schirmer test and more likely to infer basal tear volume (Hamano et al
1982). Using the thread, dry eyes tend to wet below 10 mm, averaging at
6.9 mm (Mainstone et al, 1996). Wetting values for normal eyes range from
15.4 mm (Cho and Kwang 1996) to 27.4 mm (Little and Bruce 1994). It
appears that within normals, differences in thread wetting values are related
to ethnic variations.
Does the thread measure measure tear flow or volume? A correlation
between tear flow and thread wetting has not been substantiated (Tomlinson
et al 2001). It could be, the tear fluid present at the ocular is absorbed by
when the thread is first inserted and once this is depleted to a critical mass,
reflex lacrimation is stimulated and the subsequent tears soaked up by the
thread represents the tear flow at that point in time. Exactly what the thread
measures at any moment during use is still open to question.34-37
Fluorophotometry: Fluorophotometry is a laboratory based system used to
measure tear flow and turnover rates. A controlled measure of fluorescein is
instilled in the eye and the fluorescense is gauged over time. The rate of
decay in fluorescense indicates tear flow of fluorescein instillation.
Fluorophtometric data indicates that the measurement of tears using the
phenol red cotton test is not related to tear flow (Tomlinson et al 2001). It
must be remembered, both tests are invasive and this in itself can effect the
parameter under investigation.38
Noninvasive Tests
Tear meniscus height and curvature: The tear meniscus is bound between
the ocular surface, lid margin and air. The surface exposed to the air is concave
and cylindrical. The distance from the lid margin to the boundary between
the ocular surface and the edge of the tear rivulus is the tear meniscus height
(TMH). It is claimed 75-90% of the total fluid covering the ocular surface is
contained within the upper and lower tear menisci. (Holly 1986). The volume
of fluid contained in the lower meniscus is the product of length and area if
a cross section. In turn the area of the cross section is dependant on the TMH
and the curvature of the meniscus (TMC). It follows, the height and/or
curvature of either the lower or upper tear mensicus is proportional to tear
volume. In clinical practice TMH can be measured quickly and reliably at a
magnification of 30 × or more using a graduated eyepiece. The resolution
can be improved by increasing the magnification for example using a video
capture system.
Further, measurement of TMH is a useful non-invasive technique for
investigating not only the OSS but also when the patient is complaining of
epiphoria. If the TMH is consistently high there may be a partial blockage of
the naso-lacrimal drainage system.
The subjective measure of TMH is relative, not an absolute measurement
because it depends on the observer’s interpretation of where the base of the
tear meniscus starts and where the top of the tear meniscus ends. Mainstone
et al (1996) instilled fluorescein as an aid to view the tear meniscus and

reported mean values of 0.46 mm (s.d. + 0.17 mm) in normals and 0.24 mm
(s.d. + 0.09 mm) in dry eyes.
Armed with a good slitlamp, an image recording system or eyepiece
graticule, tear volume can be clinically assessed, noninvasively and reliably,
on condition magnification is greater than 30 ×.39-41
Other Tests
Impression Cytology
Conjunctival impression cytology (CIC) is a minimally invasive technique
allowing for the investigation of of conjunctival changes at the cellular level
(Egbert et al 1977, Tseng 1985, Nelson 1988, Knop and Brewett 1992).
This technique involves pressing a piece of material, cellulose-acetate filters
being commonly used, onto the bulbar or tarsal conjunctiva. The action of
application and removal of the filter results in a fine sheet of superficial
conjunctival tissue remaining adhered to the filter. The adhered tissue can
then be fixed and stained, and the visualized cells observed directly (light
microscopy). It has been suggested, that CIC may be useful in prediciting
failure of contact lens wear (Hirji and Larke 1981), too little is yet know for
the prediction on refractive surgery. However, using CIC, the goblet cell
count in the OSS is definitely reduced.
The sensation felt when the filter is applied is similar to that experienced
on the first fitting of a contact lens (due to the presence of a foreign body
and the inability to blink), and slight irritation is felt as the filter is removed.
Topical anaesthetic can be used to minimise the discomfort. The key to good
subject tolerance of this technique lies in a confident and rapid cell collection
following a full explanation of the technique.
Goblet cell population density can be assessed by impression cytology if
the goblet cell contents are stained specifically. Alow goblet cell population
density is thought to indicate inability to produce a sufficient mucus phase of
the tear film, as the major proportion of this layer is produced by goblet cells.
Because the ocular surface and tear film are intrinsically-related, ocular
surface assessment must not be forgotten. Currently accepted techniques of
ocular surface staining assessment are quick and easy. In the future, clinicians
could routinely assess ocular surface changes at the cellular level, if impression
cytology can be adapted for clinical utility.42-45
Corneal Topography in Combination with Confocal Biomicroscopy

“The frying pan theory”
1. Examining the corneal topography carefully is a necessity for a successful
lasik procedure.
2. However, it must be understood that when per-forming a corneal
topography we are not measuring the superficial surface of the cornea
but the anterior surface of the tear film.
In the topography (Figure 13.3) one of the authors corneal topography
was taken just after blink and then 20 seconds after blink.
FIGURE 13.3: Corneal topography in combination with confocal biomicroscopy
If there is a big change from a wet cornea to a dry cornea performing

corneal topography, then an alternative refractive surgical procedure should
be a signal of contemplating a different stategy. The following problems could
occur:
1. HOA
2. Dry eye or OSS
With the confocal microscope these changes on the corneal surface will
look like this (Figure 13.4).
Like the teflon frying pan surface there is no possibility for above surface
to be wetted like an undisturbed surface since these so called “pitts” are
rather deep. The bottom line with the frying pan theory is that the surface
will not be wetted properly and this could happen after refractive surgery,
especially after the LASIK procedure.
FIGURE 13.4: Confocal biomicroscopy showing steep pits
MANAGEMENT OF THE OCULAR SURFACE SYNDROME

Stepwise determination of the minimum intervention required to achieve
results will help ensure a balance of patient compliance, long- term success
and cost-effectiveness. The management of OSS is designed to reduce
symptoms and inflammation and to re-establish a normal ocular surface.
Efforts should be aimed at maintaining or restoring the preocular tear film
and ridding the lids of potential sources of tear film destabilization. Whenever
possible, environmental factors contributing to dry eye should be identified
and either modified or eliminated. When associated medical conditions are
identified, consultation with or referral to the patient’s primary care physician
or other health care provider may be indicated.
Attempts to relieve dry eye symptoms and re-establish a normal ocular
surface have produced a myriad of possible remedies. Traditional approaches
include both tear supplementation and tear conservation measures. Several
alternatives have been used with varying degrees of clinical success:
• Ocular hygiene
• Topical treatment with tear supplements, ointments, and soluble polymeric
inserts
• Punctal occlusion.
Alternative methods for relieving symptoms specific to ocular surface

disorders include:
• Hydrophilic bandage lenses
• Moisture chamber goggles
• Tarsorrhaphy
• Estrogen replacement
• Salivary gland transplant
• Limbal grafts.
Blepharitis
Acute sequelae to blepharitis are usually the direct result of infection of the
lipid-producing glands that open to the lid margin. Their clinical presentation
includes internal and external hordeola. The treatment is relatively
straightforward. Though essential, lid hygiene alone may not resolve the
problem. Depending upon the clinical findings, an appropriate anti-infective
drug can be administered topically, systemically, or in combination. On the
other hand, chronic blepharitis is a disease for which there is no complete
cure. Aggressive therapy should initially include a minimum of 6 weeks of lid
hygiene and appropriate anti-infective medications to gain control of the
condition, followed by continuing treatment to maintain control of the chronic
blepharitis.
Because each category of blepharitis is actually a separate condition, each
has to be adressed individually:
• Staphylococcal blepharitis
• Seborrheic blepharitis
• Seborrheic/staphylococcal blepharitis
• Meibomian seborrheic blepharitis
• Seborrheic blepharitis with secondary meibomianitis
• Meibomian keratoconjunctivitis
• Angular blepharitis
• Demodicosis.
When topical treatment for OSS is prescribed, the patient should be given
the rationale for the treatment, along with specific dosages, frequency, and
duration. The patient should be made aware of the expected results and
given instructions to follow in case of adverse effects. A follow-up examination
of the patient should be scheduled to assess effectiveness.
The treatment of blepharitis require close, ongoing cooperation between

the patient and the practitioner. Thorough discussion of the causes, the
rationale for treatment and the expected results is essential in the managing
of this condition. Most patients with blepharitis have a significant improvement
in their symptoms when the appropriate hygiene, topical, and/or systemic
treatments are instituted. Since there is no cure for the chronic forms of
blepharitis, patients must actively participate in steps to control the
inflammatory process. Thorough explanation of both the chronicity of the
disease and the rationale for the therapy helps encourage patient compliance.
Specific instructions and realistic expectations for the abatement of symptoms
should be reinforced by scheduled follow-ups.46
Frequency and Composition of Evaluation and

Management Visits for OSS
Mild Induced OSS
Frequency of examination: Annual or as necessary
History: Yes
Slit-lamp biomicroscopy: Yes
Supplementary tests: Fluorescein, rose bengal or lissamine green, TBUT
Management: Unpreserved tear supplements daily
Moderate OSS
Frequency of examination: Every 6-12 months or as necessary
History: Yes
Supplementary tests: Fluorescein, rose bengal or lissamine green, TBUT,
Schirmer’s test
Management: Unpreserved tear supplements 4-5 times a day
Severe OSS
Frequency of examination: Every 3-6 months
History: Yes
Supplementary tests: Fluorescein, rose bengal or lissamine green, TBUT,
Schirmer’s test.
Management: Unpreserved tear supplements at liberty, ointment at bedtime,
punctal occlusion.
In More Detail
Artificial Tears
There are several artificial tear substitutes (ATS) formulations designed to
compensate for either lacrimal or mucous insufficiency. Most ATS act as tear
substiutes. Inter-nation variations in legislation has lead to the situation
whereby, in some countries some substitutes are on prescription only and in
others they can be sold over the counter. Most drops contain preservatives
and in many cases the drops increase symptoms because of patient
hypersensitivity to the preservatives. Single dose preservative-free drops appear
as a more expensive option, however, this is not always the case. Most
preserved drops should be discarded 28 days after opening. If the dry eye
problem is occasional, say 2 or 3 times per week, then a 20 or 30 dose pack
would last a lot longer and offer a much better cost-effective choice to the
patient. The value of artificial tears can be assessed very rapidly using one or
more of the simple tests described above for investigating the OSS.
When a single drop is instilled onto the ocular surface the bulk of its
volume rapidly drains away via the nasolacrimal duct. In effect, only a minute
amount of the initial drop is of real value in terms of ocular surface wetting
and lubrication. When using a single dose sachet, ask the patient to tilt the
head back, instill a drop on one eye, wait a few moments, and then instill on
the other eye. There will still be fluid remaining in the sachet, wait a few
moments more and repeat the procedure. This way is a useful way of making
maximum use of the drops.47
With most ATS the increase in tear stability peaks approximately 15 minutes
after instillation. Thereafter, the tear stability reduces and reaches baseline
about 90 minutes later. Many investigations claim, persistent use of drops
can produce a longer lasting improved baseline in tear stability. This could be
mediated by either:
i. a healing effect
ii. return of the epithelial to a more natural state or,
iii. gradual repopulation of active conjunctival cells.48
On instillation, ATS can momentarily blur the patient’s vision. If the drop
has a refractive index radically different from the refractive index of natural
tears and the drop mixes poorly with the tears, the instilled drop will scatter
light in the direction towards the retina. In turn this affects the quality of the
retinal image hence visual disturbances. Some patients find this disturbing at
critical viewing times. Highly viscous drops and ointments are the worse
offenders. The refractive index values of some popular ATSs are listed in the
table below. Clearly, some are more likely to affect vision than others. In
common with most other eye drops, artificial tears are buffered to maintain
a pH close to the pH of natural tears. Depending on the concentration of the
instilled drop the eye can tolerate comfortably, a
49
pH range from 6.6 to 7.8 is advisable. Thus, the pH of artificial tears
should fall within these limits. In Table 13.2 below, the measured pH of
various ATS were taken under masked randomised conditions. In theory,
some ATS will be more acceptable in terms of comfort compared with others.
(Patel 2001).
TABLE 13.2: Refractive index and pH of some artificial tears

Substitute Refractive index pH
Viva-drops 1.3354 6.7
Hypromellose 1.3347 8.2
SNO-tears 1.3357 5.3
Tears naturelle 1.3339 6.5
Isopto-plain 1.3351 7.4
Hypo-tears (UK) 1.3391 5.9
Celluvisc 1.3351 6.4
Refresh 1.3342 6.2
Visco-tears 1.3376 7.1
Clerz 1.3352 7.4
Genteal 1.3332 6.7
Ocucoat 1.3346 7.2
Hypotears (USA) 1.3393 5.5
Optifree re-wetting drops 1.3337 6.9
1. Refractive index measured using S-10 refractometer (Atago, Japan)
2. pH measured using pH meter model 10 (Corning-Eel Scientific Instruments)
3. All samples were fresh, previously unused and measured at room temperature (25
degrees).
Oral Antioxidants
The lacrimal glands, conjunctivae and meibomian glands obtain nutrients
from the vascular system. A number of quintessential anti-oxidants are
prominent in the biochemical processes leading to manufacture and secretion
of essential tear constituents. Vitamins A, C, E, zinc, selenium and
molybdenum together with other key nutrients prominently feature in tear
metabolism.
It has been shown, within a “normal, healthy, symptom-free” population

group, the blood plasma levels of essential antioxidants such as Vitamin C
can be so low, that they reach near pathological levels.50
Other than injecting nutrients directly into the blood stream we could
reach these tissues via the digestive tract. Within a “normal, allegedly healthy,
symptom-free” population group, either vitamin C (1,000 mgm/day), or
vitamin A (2250 μgm/day), or an antioxidant mixture (1 tablet/day of
Redoxan,™ La Roche) can substantially improve tear stability after 7-10 days
of treatment.51 In a controlled study featuring placebo and cross-over design,
oral ingestion of the antioxidant mixture VisionACE™ (Vitabiotics, UK) for
1 month can substantially improve both tear stability and goblet cell count in
symptomatic marginal dry eyes.52
Tear substitutes and ointments containing vitamin A (or its analogues) are
available for direct application to the ocular surface. Vitamin A is fat soluble
and therefore, it should be supplied in a suitable non-aqueous medium.
Aqueous tear drops containing vitamin A have such a low vitamin A content
that it is difficult to believe these preparations do any good other than act as
a placebo. If these drops do improve ocular surface health then the cause is
probably the lubricant vehicle not the vitamin A.
Punctal Occlusion
When the OSS is due to insufficient aqueous production and other, less
obtrusive methods have been tried and found to be insufficient, then punctal
occlusion should be attempted. Aimed at preserving the tears, several plugs
are available in various sizes, materials, construction, and they are often
supplied with an intricate method for insertion. For example, the Herrick
plug is fabricated from flexible silicone rubber, it is peg shaped and supplied
with a thin flexible wire inserter. The Freeman plug is made from a harder
polymer, is capstan shaped and has an intricate assembly which facilitates
insertion. Punctal plugs wider than the actual puncta are normally fitted to
rest tight in the lacrimal canals. If the plug is too narrow, it would simply pass
down the canals by the massaging effects produced by the lid muscles by
constant blinking and natural eye movement.
To insert a plug, simply dilate the punctum using a Foster dilator. The
sterile dilator is a tapered blunt pin. Passing it down the punctum and rotating
with the hand and gently pushing from side to side will widen the punctum.
Topical anaesthesia and a drop of lubricant can be useful. The Freeman plug
fitting assembly has a plug dilator incorporated in its design. The plug is
pushed down the punctum and turned through 90 degrees passing the apex
of the L-shaped canal. When using the Freeman plug, the plug release
assembly is pressed between the fingers, this frees the plug and the applicator
assembly is gently withdrawn from the canal. For the Herrick plug, once it is
inside the canal, the wire is gently rotated and pulled back. The fluted end of
the Herrick plug in contact with the walls of the canal is held in place by
friction as the wire is gently withdrawn.
Temporary collagen plugs should be used initially as a provocative test
which allows the clinician to assess the value of a more prolonged punctal
therapy and allows the patient a chance to experience the benefits or
otherwise. These temporary plugs are manufactured from porcine collagen
and some patients may decline these plugs on religious or other grounds.
The plug should be the same or one step wider than the punctum. The
punctum is widened as described above, the prepared sterile plugged is
gripped between the pincers of sterilised fine jeweller´s forceps, the eyelid is
pulled back to reveal a gaping punctum and the plug is inserted into the
punctum. Once the plug touches the lid margin, it soaks up tears and expands.
A swelling plug will become difficult to insert, hence it is advised to get the
plug in as a “hole-in-one.” Once inserted, the plug should be gently pushed
down into the canal until it is no longer visible to the clinician. The swelling of
the inserted plug keeps it in place and prevents extrusion. Tear stability and
meniscus height should be measured prior to punctal plugging. The collagen
plug will dissolve within a week or so, it is useful to check the patient within
48 hours. Both tear stability and meniscus height should be re-evaluated.
Patients very quickly realise if the plug is doing any good. If the patient
complains of epiphoria, then rest assured the plug will dissolve away in a few
days. Ideally, if the plug is working, patient symptoms and tear characterstics
will initially improve and fall back towards baseline as the plug gradually
dissolves.
Some clinicians prefer occluding all 4 puncta. However, in the author´s
opinion, plugging the lower puncta is sufficient in most cases because the
bulk of tears drain away to the naso-lacrimal duct via this route. Occassionally,
plugs can end up ejected from the canaliculi. After 6-14 months, in about
1% of cases the plug may pass out the punctum.53 It could be lost by passing
into the nasal cavity. In extreme cases, the puncta may be sealed with cautery
or cyanoacrylate adhesives.
Other treatment alternatives

Ointments and lubricants either prevent ocular surface friction damage,
retain fluid or maintain surface hydration. If the patient tends to sleep with
the eyes partially open, an ointment at bedtime is called for. Similarly,
ointments are useful in superficial ocualr surface damage.
Lid scrubs are useful for cleaning the lid margin at the junction between
the skin and palpebral conjunctiva, unblocking meibomian gland openings,
removing environmental debris (pollution), make-up, dry skin, denatured
skin and mucosal secretions. Scrubs are useful in cases of mild blepharitis or
meibomitis. Also, lid massaging forces fresh meibomian secretions to pass
through the duct openings.
Liposomal sprays are calimed by the manufacturers, to enhance the
skin and mucous membranes. The spary is made up microcesicles consisting
of an inner aqueous phase and outer phospholipid bi-layer floating in an
aqueous outer phase. Their use produces a refreshing sensation. No clinical
trials have been performed and the authors’ have no experience of this
product.
Lipid therapy is suitable when the OSS symptoms are of environmental
origin. Gently pinching the lower or upper lid margin will squeeze meibomian
oils out onto the ocular surface. After a few blinks, the extra lipid is spread
over the precorneal tear film, thickening the lipid layer (Craig et al 1995)
and this should in turn reduce the evaporation of tears from the ocular
surface. In cases where the meibomian secretions which are insufficiently soft
and viscous, hot compresses or hot spoon presses can soften secretions by
raising the temperature. This eases the passage of the meibomian oils to the
surface.
When the OSS is severe leading to painful ocular surface damage and
recurrent surface erosion, bandage lenses (preferably silicone-hydrogel
lenses) worn on an extended wear basis could be considered. Bandage lenses
protect the ocular surface in cases where either, blinking causes more harm
to the corneal epithelium or, the corneal epithelium is weakly fixed to the
basement membrane.
If all else fails, the patient should be referred for tarsorraphy.
REFERENCES
1. Stulting RD, Carr JD, Thompson KP, et al .Complications of laser in situ keratomileusis
for the correction of myopia. Ophthalmology 1999;106:13-20.
2. Jabbur NS, Sakatani K, O´Brien P. Survey of complications and recommendations
for management in dissatisfied patients seeking a consultation after refarctive surgery.
J Cataract Refract Surg 30: 2004;1867-74.
3. Holly FJ, Lemp MA. Wettability and wetting of corneal epithelium. Exp Eye Res
1971;11:239-250
4. Lemp MA. Report of the National Eye Institute/Industry workshop On Clinical Trials
in Drye eyes. CLAO 1995;J21:221-32.
5. Muller LJ, Marfurt CF, Kruse F, Tervo TMT. Corneal nerves: structure, contents and
function. Exp Eye Res 2003;76:521-42.
6. Holly FJ, Lemp MA. Exp Eye Res 1971;11,239.
7. Holly FJ, Lemp MA. Exp Eye Res 1973;15,515.
8. Zisman W.A. Contact angle, Wettability and Adhesion. Advances in Chemistry Series
No. 43 Am Chem Soc Washington DC 1964;1.
9. van Oss CJ, Chaudhury MK, Good RJ. Adv Colloid Interface Sci 1987;28:35.
10. van Oss CJ, Chaudhury MK. Good RJ Chem Rev 1988;88:927.
11. van Oss CJ. Cell Biophys 1989;14:1
12. van Oss CJ in Biophysics of the cell surface R.Glaser and D. Gingell (Eds): Springer
Verlag 1990;131.
13. Sharma A. In Biophys Chem 1993;47:87.
14. Tiffany JM. Lacrimal gland, tear film and dry eye syndromes. DA Sullivan (Ed):
Plenum Press, New York, 1994;231.
15. Gipson IK, Inatomi T. Paper presented at Second International Conference on the
Lacrimal Gland, tear Film and Dry Eye syndromes; Basic Science and clinical
relevance, Bermuda, 1996.
16. See ref. 14.
17. See ref. 15.
18. See ref.14.
19. See ref.15 .
20. Bron AJ, Tiffany JM. The lacrimal system. OP van Bijstervald, MA Lemp and D.
Spinelli (Eds): <kugler and Ghedini Amsterdam, 1991;27.
21. Tiffany JM, Winter N, Bliss G. Curr Eye Res 1989;8:507.
22. Tiffany JM. Acta Ophthalmol 1990;68:175.
23. Tiffany JM. Acta Ophthalmol 1990;68:182.
24. Tseng CG, Maumenee AE, Stark WJ, et al. Ophthalmology 1985;92:717.
25. Sharma A. Acid-base interactions in the cornea-tear film system; surface chemistry
of corneal wetting, cleaning, lubrication, hydration and defense. J.Dispersion Science
and technology 1998;19(6&7):1031-68.
26. American Optometric Association. Care of the patient with ocular disorders. St.
Louis (MO): American Optometric Association; 2002;59.
27. Patel S, Murray D, McKenzie A, Shearer DS, McGrath BD. Effects of fluorescein on
tear break-up time and on tear thinning time. Am J Optom Physiol Opt 1985;62:
188-90.
28. Lemp MA, Hamill JR. Factors affecting tear film breakup in normal eyes. Arch
Ophthalmol 1973;89,103-05.
29. Blades KJ, Murphy PJ, Patel S. Tear thinning time and topical anaesthesia as assesses
using the HIRCAL grid and the NCCA. Optom Vis Sci 1999;76:164-69.
30. Cho P, Yap M. Schirmer test I. A review. Optom Vis Sci 1993;70:152-56.
31. Cho P, Yap M. Schirmer test II. A clinical study of its repeatability. Optom Vis Sci
1993;70:157-59.
32. Schirmer O. Studies of the physiology and pathology of the secretion and drainage
of tears. Arch. Ophthalmol 1903;56:197-291.
33. Wright JC, Meger GE. A review of the Schirmer test for tear production. Arch.
Ophthalmol 1962;67:564-65.
34. Blades KJ, Patel S, Murphy PJ, Pearce EI. Is there a reflex component of phenol read
thread wetting? Optom Vis Sci 1999;76(suppl),228.
35. Blades KJ, Patel S. The dynamics of tear flow within a phenol red impregnated
thread. Ophthal and Physiol Opt 1996;16,409-15.
36. Cho P, Kwong YM. A pilot study of the comparative performance of two cotton
thread tests for tear volume. J Br Contact Lens Ass 1996;19,77-82.
37. Little SA, Bruce AS. Repeatability of the phenol-red thread and tear thinning time
tests for tear function. Clin Exp Optom 1994;77,64-68.
38. Tomlinson A, Blades KJ, Pearce EI. What does the phenol red thread test actually
measure? Optom and Vis Sci 2001;78,142-46.
39. Hamano H, Hori M, Mitsunaga S, Kojima S, Maeshima J. Tear secretion test (a
preliminary test) Jap. J Clin Ophthalmol 1982;32,103-107.
40. 40. Mainstone JC, Bruce AS, Golding TR. Tear meniscus measurement in the
diagnosis of dry eye. Curr. Eye Res 1996;15:653-61.
41. Oguz H, Yokoi N, Kinoshita S. The height and radius of tear meniscus and methods
of examining these parameters. Cornea 2000;19:497-500
42. Van Bijisterveld OP. Diagnostic tests in the sicca syndrome. Arch Ophthalmol 1969;
82:10-14
43. Hirji NK, Larke JR. Conjunctival impression cytology in contact lens practice. J Brit
Cont Lens Assoc 1981;4:159-161.
44. Egbert PR, Lauber S, Maurice DM. A simple conjunctival biopsy. Am J Ophthalmol
1977;84:798-801.
45. Nelson JD, Wright JC. Impression cytology of the ocular surface in keatoconjunctivitis
sicca. In the preocular tear film in health, disease and contact lens wear. 1986. Ed:
Holly FJ, Dry Eye Inst, Lubbock, Yx 140-156.
46. American Optometric Association. Care of the patient with ocular surface disorders.
St. Louis (MO): American Optometric Association 2002 Nov;59p.
47. Stevenson D, Tauber J, Reis BL. The Cyclosporin A phase 2 study group; Efficacy
and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-
severe dry eye disease. A dose-ranging, randomized trial. Ophthalmology 2000;
107:967-74.
48. Milder B. The lacrimal apparatus. In Adler´s Physiology of the eye 1975. (ed: RA
Moses). St. Louis, CV Mosby.
49. Carney LG, Fullard RJ. Ocular irritation and environmental pH. Aust J Optom
1979;62:335-36.
50. Johnston CS, Thompson LL. Vitamin C status of an outpatient population. J Am
Coll Nutr 1998;17:366-70
51. Patel S, Plaskow J, Ferrier C. The influence of vitamins and trace element supplements
on the stability of the precorneal tear film. Acta Ophthalmol 1993;71:825-29
52. Blades KJ, Patel S, Aidoo KE. Oral antioxidant therapy for marginal dry eye. Eur J
Clin Nutrition 2001;55:589-97.
53. Fayat B, Assouline M, Hanush S et al. Silicone punctal plug extrusion resulting from
spontaneous dissection of canalicular mucosa. Ophthalmology 2001;108:405-09.
DRY EYE AS INFORMED CONSENT PRIOR TO REFRACTIVE SURGERY 227
INTRODUCTION
As the first refracting surface of the eye, the ocular tear film plays a vital role
in patient satisfaction following refractive surgery. By carefully analyzing and
managing the tear film, a surgeon can have a greater degree of selectivity
with refractive candidates and ultimately success in patient satisfaction.
Several techniques are used in my office in an attempt to stabilize the tear
film perioperatively and afford the patient the fastest visual recovery possible.
I will briefly discuss our methods of evaluation and management, and highlight
aspects of patient communication of our findings.
EVALUATION
The integrity and health of the ocular surface is evaluated at the preoperative
refractive examination. Thorough attention is given to the patient’s past history
of dry eye, including contributing systemic disease, current oral and topical
medications and history of contact lens wear. It has been found that over 20
to 30% of patients who wear contact lenses have dry eye symptoms,1 usually
related to decrease in blink frequency and increased tear evaporation from
the surface.2
Evaluation of the patient’s habitual working and living environment are
also important, as low-moisture environments can contribute to evaporative
dry eye conditions.3
In my examination of the patient, we use the Schirmer II test as an
evaluation of baseline tear secretion. More specifically, the Schirmer II test
assesses basal tear secretion.4 A patient is noted to have normal tear secretion
values if the Schirmer paper strip is moistened to 10 mm or greater at
5 minutes. Values less than 10 mm are cause for initiating dry eye
management prior to considering corneal refractive surgery.
A careful examination of tear film stability is also performed at the pre-
operative refractive exam. A recent study indicated a correlation between
ocular surface discomfort and tear integrity in patients with dry eye disease.5
We use the fluorescein tear break-up time test on our patients. In those with
instable tear film, the time it takes the tear layer to thin is less than 10 seconds.
The anterior segment is also examined at the preoperative visit. Careful
attention is given to the lid margins, investigating underlying lid disease such
as meibomian gland dysfunction, which excess or deficient lipid secretion
may contribute to poor tear quality. Surface inspection of the corneal epithelial
DRY EYE AS INFORMED CONSENT PRIOR TO REFRACTIVE SURGERY 229
cells will reveal any signs of superficial punctuate keratitis in patients with dry
eye. Dry eye patients will also have low tear meniscus at the lid margin.
Staining of the bulbar conjunctival with Lissamine green will help to uncover
devitalized cells associated with dry eye syndrome.
MANAGEMENT
Our refractive patients are started on a routine regimen of nonpreservative
artificial tears four times a day and topical cyclosporin-A (Restasis®, Allergan
Inc., Irvine, CA) twice a day, at least 2 weeks prior to surgery. If initial tear
testing values (for example, Schirmer II test) were low and indicated poor
tear quantity, or slit-lamp examination revealed significant ocular surface
dryness, dry eye therapy is initiated sooner and corneal surgery is deferred
until improvement is seen in tear quantity and quality. Patients who use soft
contact lenses are advised to discontinue wear at least two weeks prior to
surgery, and those who habitually wear rigid gas-permeable lenses or soft
toric contact lenses are advised to discontinue wear at least three weeks prior
to surgery.
Postsurgically, careful examination of subjective comfort levels and objective
findings guide postoperative dry eye management. Patients are advised to
continue their regular regimen of artificial tears and topical cyclosporine at
least 6 weeks after surgery. Maintenance of a regular tear layer is important
for visual clarity in the postoperative period. In study, it was found that patients
who were symptomatic and asymptomatic for dry eye demonstrated significant
improvement in uncorrected visual acuity after the use of nonpreserved
caboxymethylcellulose (CMC).6 Thicker gel formulations are recommended
for patients with symptoms aggravated in the evening and/or waking hours.
Lid hygiene is advised for patients with chronic lid conditions such as blepharitis
or ocular rosacea. In patients who continue to have dry eye symptoms after
surgery despite the use of artificial tears and topical cyclosporin-A, the use of
punctual occlusion is introduced to the patient. For patients with tear-deficient
dry eye, the use of punctal plugs improves patient comfort as well as objective
signs.7 An evaluation studying the effectiveness of topical cyclosporin-A and
punctal plugs found that its collective use provides more protection from dry
eye disease. More specifically, there was less incidence of conjunctival staining
and less use of artificial tears when topical cyclosporin-A was used with punctal
plugs.8
COMMUNICATION AND INFORMED CONSENT

Evaluating patient expectations prior to refractive surgery is perhaps the most
critical aspect of our screening process. The benefit of spending a few extra
minutes of communication with a patient prior to surgery may prevent
significant postoperative confusion or misunderstanding.
The importance of the role the ocular surface plays after corneal refractive
surgery must be emphasized to the patient. The patient must understand
that a uniform tear layer provides optimal visual quality and its maintenance
is critical to the healing of the eye. Patients also need to be aware that they
may experience more dryness in the acute postoperative time frame and use
of artificial tears more than the required minimum will provide benefit to
visual outcome.
Patients who are symptomatic for dry eye in the postoperative period
may experience a foreign-body sensation and visual fluctuations. These
symptoms are a part of the healing process and typically resolve in the six
months following surgery. Our patients are counseled on the use of topical
cyclosporin-A preoperatively. Most of our patients continue its use for 6 weeks
after surgery. In some cases of symptomatic dry eye prior to refractive surgery,
patients are counseled on remaining on artificial tears and topical cyclosporin-
A for an extended time period until their vision is stable.
Dry eye following refractive surgery can be easily managed with proper
identification of dry eye disease prior to surgery, thorough informed consent
and realistic patient expectations.
REFERENCES
1. Bron AJ. Non-Sjogren’s dry eye: Pathogenesis, diagnosis and animal models. In:
Sullivan DA (Ed): Lacrimal Gland, Tear Film and Dry Eye Syndromes. New York:
Plenum Press, 1994;471-88.
2. Lemp MA. Surface abnormalities in the preocular tear film and dry eye syndromes.
Int Ophthalmol Clin 1973;13:191-99.
3. McMonnies CW. Key questions in a dry eye history. J Am Optom Assoc 1986;
57:512-17.
4. Schirmer O. Studien zur physiologie der tranenabsonderung und tranenabfuhr.
Graefe’s Arch Clin Exp Ophthalmol 1903;56:197-291.
5. Nally L, Ousler III GW, Albelson MA. Ocular discomfort and tear film break-up time
in dry eye patients: A correlation. Invest Ophthalmol Vis Sci 2000 Suppl; 41: S274.
6. Nilforoushan MR, Latkany RA, Speaker MG. Effect of artificial tears on visual acuity.
Am J Ophthalmol 2005; 140:830-35.
7. Albietz JM. Dry eye: An update on clinical diagnosis, management and promising
new treatments. Clin Exp Optom 2001;84:1:4-18.
8. Roberts C. Comparison of topical cyclosporin, punctal occlusion and a combination
for the treatment of dry eye disease. ARVO, 2005.
TEAR FILM FUNCTION, OCULAR SURFACE INTEGRITY & CORNEAL SENSATION AFTER LASEK 231
INTRODUCTION
Recently, a new technique called laser-assisted subepithelial keratectomy
(LASEK) has been introduced by Camellin in 1999.1 LASEK is a modification
of photorefractive keratectomy (PRK) that is based on the creation of a hinged
corneal epithelial flap after the exposure to 20% alcohol solution. This epi-
thelial flap is repositioned to its original location after anterior stromal ablation
with the excimer laser so that the stromal wound is covered immediately.1, 2
In PRK, refractive surgical ablation is performed on the corneal surface
after epithelial debridement. The disadvantage is that the epithelium is lost
during this procedure with potential problems of delayed visual improvement
caused by epithelial defects, significant postoperative pain, and formation of
stromal haze due to the healing process.3-7 These issues contribute to the lack
of acceptance of PRK.
Laser in situ keratomileusis (LASIK) is still the most common refractive
surgical procedure performed,8 because it offers prompt visual recovery,
only mild discomfort and minimal chances of corneal haze.9, 10 During LASIK,
a hinged lamellar corneal flap is raised with a microkeratome followed by
ablation in the stromal bed and repositioning of the flap. Unfortunately, the
incidence of problems related to the corneal flap can lead to complications
such as wrinkles, epithelial ingrowth and diffuse lamellar keratitis.11-15 In
addition, the corneal flap in LASIK surgery can lead to unpredictable
biomechanical corneal changes and to corneal ectasia.16, 17 These issues have
led to a regained popularity of surface ablative procedures.
LASEK has become popular for correcting refractive errors in the last
years. Advantages of this method are a smoother and more regular surface
than after the mechanical debridement in PRK18, 19 and that the ablated
corneal surface is covered by a full thickness epithelium immediately after
surgery. Combining elements of LASIK and PRK in LASEK, flap-related
complications of LASIK and the haze risk, pain, and slow visual recovery of
PRK should be avoided.
Although in several reports PRK and LASEK findings were similar in relation
to pain and visual outcomes,20-22 other clinical studies have shown a reduction
in postoperative pain, faster visual rehabilitation, and decreased haze in
LASEK-treated eyes than in PRK-treated eyes.2, 23-28
Reduced postoperative pain in LASEK is probably because the
epithelial flap protects the ablated stromal area. Retention of the epithelial
flap acts as a smooth refractive surface, allowing better visual acuity post-
surgery.23-25
The exact mechansim for less corneal haze noted in LASEK is open to
debate in the literature. It is speculated that the epithelial flap seals up the
bare surface of the stroma and prevents the influx of inflammatory cells from
tears, which reduces the initial inflammatory damage to the corneal
stroma.23,25
Various cytokines including keratinocyte growth factor and transforming
growth factor β (TGF-β) are known to regulate the corneal stromal wound-
healing process after excimer laser keratectomy. Among these cytokines,
TGF-β is proposed to be key in inducing corneal stromal fibrosis after
excimer laser keratectomy. The upregulation in the expression of TGF-β1
in the tear film in the early postoperative period induced by a greater
epithelial trauma during PRK than during LASEK29 may play a role in the
increased myofibroblast transformation observed in PRK at higher attempted
correction.
Ethanol-mediated flap repositioning during LASEK induced less keratocyte
loss and a slower wound-healing process than mechanical scraping30 and
replacement of the epithelial flap after the ablation may also decrease the
loss of stromal keratocytes.31 Zhao et al demonstrated that tears may be a
major factor in the induction of keratocyte loss after de-epithelialization in
the mouse cornea.32 In a rabbit model it was observed that in eyes with
higher attempted corrections, there was a significant increase in keratocyte
apoptosis, myofibroblast transformation and expression of chondroitin sulfate
in the PRK group compared to the LASEK-treated eyes.33
Other factors that modulate corneal wound healing and cell migration
are substance P, calcitonin gene related peptide, acetylcholine or norepinep-
hrine.34 The corneal substance-P-ergic innervation after LASEK and PRK
was investigated in rabbits.35 In the LASEK group an accelerated recovery of
substance-P-immunoreactive nerve fibers in the subepithelial layer and
anterior corneal stroma was found. This could promote wound healing in
the acute phase after laser photoablation.
According to the data of the above mentioned studies, epithelial coverage
alters the wound healing response of the cornea. Therefore, the theory that
LASEK, as a modified surface ablative procedure potentially combines the
advantages of PRK and LASIK is further supported.
TEAR FILM FUNCTION AND OCULAR SURFACE INTEGRITY

Dry eye is known to occur commonly after refractive surgery.
Several mechanisms appear responsible for tear film and ocular surface
disruption seen after this kind of surgery. Changes in the corneal curvature
alter tear wetting as the lids move over a modified ocular surface. Damage to
the ocular surface caused by epithelial toxic antibiotics and preservatives
may induce transient dry eye.
The high level of pressure induced by the suction ring during LASIK may
damage the conjunctival goblet cells, compromising the mucin layer of the
tear film.36
The most important reason leading to the development of dry eye is
consistent with the understanding that refractive surgery destroys the sensory
innervation of the cornea.
The ocular surface and lacrimal glands function as an integrated unit.
Communication between the ocular surface and lacrimal glands occurs
through a sensory/autonomic neural reflex loop.37 The sensory nerves
innervating the ocular surface connect with efferent autonomic nerves in the
brainstem that stimulate secretion of tear fluid and proteins by the lacrimal
glands.
Aqueous tear production and clearance decrease in conditions when
corneal nerves are damaged38 and may induce increased inflammation on
the ocular surface.39
Reduced corneal sensation also reduces blinking rate.40 Regular blinking
and continuous tear fluid production are vital to prevent dehydration, which
can cause damage to the cornea.41
The amputation of corneal nerves during LASIK is a risk factor for the
development of a neurotrophic keratopathy due to a loss of trophic factors
with severing of the sensory nerve trunks.42
Corneal denervation by refractive surgery not only disrupts the reflex
controlling the lacrimal gland but also disrupts the reflex controlling the
meibomian gland and, as mentioned before, eyelid blinking, the latter indirectly
controling meibom secretion.43 Lipid tear deficiency was demonstrated as a
cause of dry eye in a subgroup of patients after LASIK.43 This is in agreement
with the concept of neuroanatomic integration of external adnexa and eyelids
to maintain a stable tear film.44
Depending on the kind of the refractive surgical procedure, the effects on

tear dynamics and ocular surface may vary.
A decrease in tear flow and tear film stability was observed 6 weeks after
PRK and was found reduced up to 6 months later.45-47 LASIK has also been
shown to decrease break-up time (BUT) and Schirmer test values
significantly.38, 48-51 Basal tear secretion was reduced upto 12 months.48 BUT
was decreased 3 to 6 months after LASIK.48,51,52
In a comparative study of tear function changes after PRK and LASIK,
Lee et al showed a significant reduction in Schirmer and BUT scores and a
significant increase in tear osmolarity 6 months after both procedures.52
However, a greater decrease in these tear film factors in LASIK patients was
found.
There was a significant increase in punctate corneal fluorescein staining at
1 week after LASIK.38 Increased punctate epithelial erosions and corneal
epithelial rose bengal staining developed after LASIK within a few days to
weeks of LASIK and typically persisted for 6 to 8 months following LASIK
surgery.42
Since a modified wound healing after LASEK may also influence tear film
and ocular surface function, these factors have been studied after LASEK.53,54
The tear film breakup time was found reduced up to 1 month after LASEK
and fluorescein staining of the cornea was significantly increased 3 days and
1 week after LASEK.53, 54 Whereas Horwath-Winter et al53 did not observe a
significant decrease in reflex secretion, Hermann et al54 noted that Schirmer
test values without local anesthesia were decreased 2 and 3 months and
basal secretion was decreased 3 months after LASEK in a 6 month follow-up
period. No significant changes were found in lissamin green staining
postoperatively.53
Although there are currently no published reports detailing the course of
ocular surface integrity and tear film function after LASEK in comparison to
PRK, these studies mentioned above provide first results. LASEK induces
short-term effects on the ocular surface and tear film. Epithelial flap
repositioning in LASEK seems to have a positive influence on tear film and
ocular surface factors.
CORNEAL SENSATION
The cornea is one of the most densely innervated and highly sensitive tissues
in the body. Corneal sensation is provided by the long ciliary nerves of the
ophthalmic division of the trigeminal cranial nerve. The long ciliary nerve
trunk runs in the suprachoroidal space, where it branches several times before
entering the cornea at the limbus. The large nerves enter the limbus
predominantly at the 9 o‘clock and 3 o‘clock positions. They then bifurcate
and move toward the 12 and 6 o‘clock positions. After a second bifurcation,
they again run toward the 9 and 3 o‘clock positions. The nerves initially enter
the cornea in the middle third of the stroma, but course anteriorly as they
branch, eventually forming a plexus in the sub-Bowman‘s layer that densely
innervates the central cornea.55-57 The nerves next penetrate Bowman‘s
membrane and terminate in the epithelium at the wing cell layer.
All types of refractive surgery alter the corneal sensory nerves. The time
course and pattern of nerve regeneration after refractive surgery is expected
to depend in part on where and at which content the nerves are severed.
During PRK, those superficial nerve endings are damaged that terminate
in the corneal epithelium that is removed by mechanical scrape.
In LASIK the microkeratome makes a tangential cut through the stroma,
which induces a more proximal transection of the posterior corneal nerve
trunks that enter the cornea at the 3 and 9 o’clock positions except in the
area of the flap hinge.58 A superior hinge on the corneal flap severs both
arms of the neuroplexus, whereas a nasal hinge transects only the nerves
from the temporal side. The high level of pressure, induced perilimbally by
the suction ring may also cause trauma to the corneal nerves that diverge
just proximal to the limbus from those destined for the ciliary body, iris and
sclera. This implies that sensory deprivation could be severe after LASIK.
The pattern of nerve damage during LASEK is similar to that in PRK.
Sensory nerve endings are injured that terminate in the corneal epithelium
that is removed by topical alcohol during this procedure.
In all three refractive surgery techniques PRK, LASIK and LASEK, there
is additional damage to the nerves in the stroma removed by laser
photoablation.
Reports showed that the return to full sensitivity of the central cornea
after PRK was achieved between 3 and 12 months.59-63 In LASIK clinical
studies reported that corneal sensation after LASIK reached preoperative
levels 3 to 16 months after the procedure.38,48,58,64 The severed nerves grow
back slowly over months and up to even a year.65, 66 Evidence derived from
confocal microscopy suggests that a population of these nerves never return
to their original state.66,67
Comparing LASIK and PRK, corneal sensitivity was more depressed after
LASIK than after PRK during the first 3 months.63, 68 Studies have suggested
that the extent and duration of corneal hypoesthesia is dependent on ablation
depth.60, 61, 69-71 In contrast, Chuck et al concluded that ablation depth did
not seem to affect the initial level of decrease in corneal sensation.72
In LASEK the intraepithelial nerves are severed with lifting of the epithelium
and the superficial nerves are destroyed in the area of photoablation but the
deeper stromal nerves and their trunks are spared.
In a comparative study recovery of corneal sensitivity was faster after
LASEK (recovered at 3 months) than after LASIK in myopic eyes with less
than 6.0 diopters.73 Ablation depth was related to the recovery of corneal
sensitivity after LASEK but no correlation was found after LASIK.
As demonstrated by a study of Horwath-Winter et al, corneal sensation
recovered 3 months after LASEK in a 6 month follow-up period.53 Hermann
et al observed that during the first month after surgery the depressed corneal
sensation improved and subsequently went back to preoperative values,
staying stable 3 and 6 months after surgery.54,74 They found no significant
association between the depth of ablation and the postoperative sensation.74
Based on the findings of these studies, the restoration of corneal sensitivity
seems to be comparable53,73 to reported results or even faster54,74 after LASEK
than after PRK.
A possible reason for the faster recovery of corneal sensation after LASEK
than after PRK is the repositioned epithelial flap that may decrease
inflammation23, 25 and enhance nerve regeneration by providing a natural
matrix for the outgrowth and orientation of regenerating subepithelial nerves.
Studies in rabbits35 have shown that substance-P-ergic innervation recovers
faster in the subepithelial layer and the anterior stroma after LASEK than
after PRK. Moreover, it is possible that in the hinge of the epithelial flap some
epithelial nerves might withstand the surgical trauma and contribute to a fast
recovery of corneal sensation. Regenerating nerve fibres after refractive surgery
derive from deeper stromal nerve fibres and from the subepithelial nerve
plexus adjacent to the wound margins.
In conclusion, comparing the recovery of corneal sensation after different
kinds of excimer laser refractive surgery, the superficial ablation in PRK and
LASEK results in less damage to corneal nerves and leaves deeper stromal
nerves untouched.
CONCLUSIONS
The indications for LASEK are generally the same as those for patients with
PRK, and include patients with thin corneas, occupations that predispose to
ocular trauma, and patients with anatomic abnormalities, such as flat corneas,
steep corneas, and deep-set eyes; to those who have had filtering blebs or
retinal detachment surgery.
Because LASEK is a modified procedure of PRK the results concerning
tear film, ocular surface and corneal sensibility should be similar to PRK.
Concerning corneal sensibility the results of the above mentioned studies53,73
seem comparable to the results described in the literature60-63, 68 or even
better.54, 74 The results concerning tear film and ocular surface function53, 54
seem to be better than the results described in the literature.45,47,52 The reason
for this difference could be a modified wound healing due to the reattached
epithelial flap. LASEK surgery causes only a transient decrease of corneal
sensation, and dry eye signs revert to the preoperative level after a few months.
Therefore LASEK surgery should be considered in patients with reduced
corneal sensation and pre-existing dry eye who are undergoing refractive
surgery.
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and photorefractive keratectomy for the correction of myopia. Zhonghua Yan Ke Za
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removal in mouse cornea. Invest Ophthalmol Vis Sci 2001;42:1743-49.
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40. Collins M, Seeto R, Campell L; Ross M. Blinking and corneal sensitivity. Acta
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41. Beuerman RW, Schimmelpfennig B. Sensory denervation of the rabbit cornea
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43. Di Pascuale MA, Liu TS, Trattler W, Tseng SC. Lipid tear deficiency in persistent dry
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44. Tseng SC, Tsubota K. Important concepts for treating ocular surface and tear disorders.
45. Özdamar A, Aras C, Karakas N, Sener B, Karacorlu M. Changes in tear flow and tear
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47. Hong JW, Kim HM. The changes of tear break up time after myopic excimer laser
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48. Toda I, Asano-Kato N, Komai-Hori Y, Tsubota K. Dry Eye after laser in situ
keratomileusis. Am J Ophthalmol 2001;132:1-7.
49. Yu EY, Leung A, Rao S, Lam DSC. Effect of laser in situ keratomileusis on tear
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54. Herrmann WA, Shah CP, Winkler von Mohrenfels C, Gabler B, Hufendiek K, Lohmann
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TOPICAL CYCLOSPORIN A–RESTASIS FOR THE MANAGEMENT OF DRY EYE 243
INTRODUCTION
Dry eye disease is believed to be one of the most common ophthalmic problems
and is found with increased prevalence in older patients, postmenopausal
women, and patients with autoimmune disease.1,2 In a population-based
prevalence study, 14.6% of 2,482 patients aged 65 years or older reported
symptoms suggestive of dry eye.2,3 Based on this study, it is estimated that 4.3
million Americans experience symptoms of dry eye syndrome. In another
population-based study, 7.8% of 39,876 U.S. women reported a prevalence
of dry eye syndrome, which extrapolates to approximately 3.2 million cases
of dry eye in females aged 50 years or older.4 Remarkably, despite these large
numbers of cases, dry eye syndrome remains an under diagnosed problem.3-5
The difficulty in diagnosing dry eye syndrome is partly due to the
controversies in its classification, which is undergoing revision, and partly
due to the absence of one specific diagnostic test.6 There are two distinct
categories of dry eye syndrome, one related to insufficient production of
tears and a second, more common, category related to increased evaporation
of tears. Although both categories may lead to dry eye, tests may be positive
for one while negative for the other. To compound the confusion, there is
often a crossover of conditions between the two groups. For example,
meibomian gland dysfunction is the leading cause of evaporative dry eye
syndrome also occurs in a large number of patients with aqueous deficiency.
Topical cyclosporin A (tCSA) (Restasis®, Allergan, Inc, Irvine, CA) is a
novel and unique therapy for dry eye syndrome that holds promise for
treating both arms of the dry eye classification, aqueous deficiency and
evaporative loss. Restasis ® was approved by the US Food and Drug
Administration for the treatment of moderate and severe keratoconjunctivitis
sicca and is the first pharmaceutical agent that treats the etiology of
dysfunctional tear syndrome rather than the symptoms. In this chapter, a
brief review of the diagnosis, classification, and pathogenesis of dry eye
syndrome will be followed by an examination of the indications and use of
tCSA for the management of dry eye syndrome, meibomian gland
dysfunction, and ocular rosacea.
DIAGNOSIS OF DRY EYE SYNDROME

Diagnosing dry eye syndrome begins with the patient history, including type
and duration of symptoms, as well as the presence of any exacerbating
conditions (e.g. exposure to wind, prolonged computer work, air travel).

Ocular history includes contact lens wear, eyelid surgery, allergic conjunctivitis,
and ocular surface inflammatory disease (e.g. ocular cicatricial pemphigoid,
Stevens Johnson syndrome) and topical medications (e.g. antihistamines,
vasoconstrictors, corticosteroids, glaucoma medications, artificial tears).
Systemic history should include details about dermatological diseases (e.g.
rosacea), atopy, menopause, autoimmune disease (e.g. Sjögren’s syndrome,
rheumatoid arthritis, systemic lupus erythrematosus), and systemic medications
(diuretics, hormones, antihistamines, antidepressants).
A variety of symptoms have been associated with dry eye syndrome.
These symptoms have been quantified by a questionnaire entitled the Ocular
Surface Disease Index (OSDI). This questionnaire (Figure 16.1) lists 12
common symptoms of dry eye patients and scores each on a scale of 1 to 4
in terms of severity. This survey permits quantification of symptoms and
enables categorization of dry eye syndrome as mild, moderate, or severe.
Numerous diagnostic tests are available for the evaluation of dry eye.
Examination with slit lamp biomicroscopy should particularly focus attention
to the tear film, eye lashes, anterior and posterior lid margins, puncta, inferior
fornix, tarsal and bulbar conjunctiva, cornea, height of tear meniscus (marginal
tear strip) (Figure 16.2), and the presence or absence of tear film debris. To
make the diagnosis of dry eye, the clinician generally relies on the clinical
history and slit lamp biomicroscopy findings in conjunction with Schirmer
testing (with or without anesthesia), supravital conjunctival staining, tear film
break-up time, and tear fluorescein clearance. Delayed tear fluorescein
clearance is reported to show better correlation with the severity of ocular
irritation symptoms and keratoconjunctivitis sicca than the Schirmer 1 test.6,7
The tear break-up time is the best screening test for dry eye syndrome. If
the result of this test is abnormal, i.e. under 5 seconds, there is usually some
form of ocular surface disease, most commonly dry eye syndrome. At this
point, the clinician can help confirm the diagnosis of dry eye with the use of
supravital staining. Lissamine green (Figure 16.3) is a new supravital stain
that combines the diagnostic advantages of fluorescein and rose bengal.
Lissamine green stains healthy epithelial cells when they are not protected by
a mucin layer in a manner similar to rose Bengal (Figure 16.4). In addition,
lissamine green, like fluorescein, stains dead or degenerated cells as fluorescein
does.8-10 Lissamine green is extremely helpful in diagnosing dry eye. Its main
advantage is that it avoids the ocular discomfort associated with the use of
FIGURE 16.1: Ocular surface disease index for evaluation of dry eye patients
rose bengal, which can be very troublesome for patients with

keratoconjunctivitis sicca.8,11,12 Its main disadvantage is that it is little less
sensitive, more transient, and somewhat more difficult to see on slit lamp
examination than rose bengal. In the evaluation of refractive surgery
candidates, supravital staining can reduce the risk of complications and wound
FIGURE 16.2: Clinical photograph of marginal tear strip
FIGURE 16.3: Clinical photograph demonstrating lissamine green staining

pattern of the interpalpebral conjunctiva and cornea in a patient with severe dry
eye syndrome
FIGURE 16.4: Clinical photograph demonstrating rose bengal staining pattern

of the interpalpebral conjunctiva and cornea in a patient with severe dry eye
syndrome
healing problems related to poor outcomes by identifying high-risk patients

before surgery.13 Tear film osmolarity, tear lysozyme and tear lactoferrin
concentrations, and conjunctival impression cytology are helpful tests that
are rarely used outside of a research setting.
Severe untreated chronic dry eye syndrome can result in poor lubrication
(Figure 16.5A), altered barrier function (Figure 16.5B), sterile melting (Figure
16.5C), and even bacterial keratitis (Figure 16.5D). Therefore, to prevent
these potentially serious complications, it is extremely important to understand
and treat dry eye syndrome.
CLASSIFICATION SYSTEMS
Dry Eye Syndrome versus Dysfunctional Tear Syndrome
In the early 1990s the National Eye Institute (NEI) proposed a classification
system for dry eye based on the differentiation between deficient aqueous
production and evaporative tear loss. Although there is often significant
crossover between the two groups in addition to multiple sub-groups in each
category, the classification system provides a starting point for a rational
treatment plan for dry eye syndrome. Traditional therapy has included the
FIGURES 16.5A to D: Severe untreated chronic dry eye syndrome can result
in poor lubrication (Figure 16.5A), altered barrier function (Figure 16.5B),
sterile melting (Figure 16.5C) and even bacterial keratitis (Figure 16.5D)
use of artificial tears to supplement the patient’s own tear production.

Preserved artificial tears have been effective for mild dry eye, while non-
preserved unit dose packs have gained widespread acceptance for severe
dry eye. Recently, transiently preserved artificial tears, in which the preservative
is dissipated upon exposure to air, have been developed. For patients in
whom artificial tears are not sufficient, punctal occlusion, either temporary
or permanent, with plugs or cautery, may be effective for both preserving
the patient’s own natural tears and prolonging the effect of artificial tears.14
The NEI classification does not address the inflammatory component of
dry eye syndrome. Employing the Delphi consensus approach to develop
current treatment recommendations for dry eye syndrome, an international
panel of experts on dry eye syndrome created a practical treatment algorithm
TABLE 16.1: Dysfunctional tear syndrome—progression of severity levels

(from Behrens et al)
Level 1 Mild to moderate symptoms, no corneal signs
Mild to moderate conjunctiva signs
↓
Level 2 Mild to severe symptoms
Tear film signs, visual signs
Mild corneal punctate staining
Conjunctival staining
↓
Level 3 Severe symptoms
Marked corneal punctate staining
Central corneal staining
Filamentary ketatitis
↓
Level 4 Extremely severe symptoms/altered lifestyle
Severe corneal staining, erosions
Conjunctival scarring
TABLE 16.2: Dysfunctional tear syndrome severity levels and

treatment algorithm levels (from Behrens et al)
Patient education
Environmental modifications
Control systemic medications
↓
Level 1 If no
improvement,
add level 2 Preserved tears
treatments Allergy control
↓
Level 2 If no Unpreserved tears Cyclosporin A
improvement, Gels/night time ointments Topical steroids
add level 3 Nutritional support Secretagogues
treatments
↓
Level 3 If no Tetracyclines
improvement Punctal plugs (control inflammation 1st)
add level 4
treatments
↓
Level 4 Systemic anti-inflammatory therapy
Acetylcysteine
Moisture goggles
Surgery (punctal cautery)
in an attempt to cover gaps in the available literature. A new term for the
disease was proposed, dysfunctional tear syndrome. Dysfunctional tear
syndrome may be diagnosed as one of four severity levels and treatment
recommendations were made for each level (Tables 16.1 and 16.2). Treatment
recommendations were based primarily on patient symptoms and specific
clinical signs. Diagnostic tests were deemed secondary in the election of
therapy. Algorithms were developed depending on the presence or absence
of lid margin disease, and disease severity (mild 1-2, moderate 3-4, and
severe > 4) was assessed according to use of tear substitutes, ocular fatigue
and discomfort, and visual disturbances.15,16
Since the abstracts re-classifying dry eye syndrome as dysfunctional tear
syndrome have not yet been published and the entity is still more commonly
referred to as dry eye syndrome, for the remainder of this chapter we will
refer to the entity according to the NEI classification.
COMMUNICATION BETWEEN THE OCULAR SURFACE AND THE

LACRIMAL GLANDS IN THE PATHOGENESIS OF DRY EYE SYNDROME
One major advance in dry eye over the past decade is the understanding
that the ocular surface and lacrimal glands function as an integrated unit. A
sensory/autonomic neural reflex loop facilitates communication between the
lacrimal glands and the ocular surface. The sensory nerves innervating the
ocular surface and nasal mucosa synapse with efferent autonomic nerves in
the brainstem that stimulate secretion of tear fluid and proteins by the lacrimal
glands. Ocular surface sensitivity has been found to decrease as aqueous
tear production and clearance of tears from the ocular surface decrease. This
decrease in surface sensation in turn exacerbates dry eye because of a decrease
in sensory-stimulated reflex tearing and decrease in the ability of the lacrimal
glands to respond to ocular surface injury. This creates a self-perpetuating
cycle of continuing inflammation mediated by tears produced by lacrimal
gland tissue heavily infiltrated with T cell lymphocytes that constantly secrete
inflammatory mediators and cytokines that bathe the ocular surface.17-19
The importance of inflammation in the pathogenesis of dry eye in people
65 years of age or older has also been elucidated over the past decade and
is now being taken into account in the classification of the dry eye disorder.20
It has been found that decreased tear production and tear clearance lead to
chronic inflammation of the ocular surface. This inflammatory response consists
of inflammatory cell infiltration of the ocular surface, activation of the ocular

surface epithelium with increased expression of adhesion molecules and
inflammatory cytokines, increased concentrations of inflammatory cytokines
in the tear fluid, and increased activity of matrix degrading enzymes such as
matrix metalloproteinase-9 in the tear fluid.21 A significant positive correlation
has been observed between the levels of inflammatory cytokines in the
conjunctival epithelium and the severity of ocular irritation symptoms and
corneal fluorescein staining. The inflammatory cytokines and other
inflammatory mediators also correlate positively to the severity of conjunctival
squamous metaplasia in patients with Sjögren syndrome keratocon-
junctivitis.17,18
TOPICAL CYCLOSPORIN A–RESTASIS®

For years, dry eye patients have had their symptoms treated with artificial
tears, gels, ointments, steroids, punctual plugs, nonsteroidal anti-inflammatory
agents, etc., but nothing provided more than symptomatic relief until the
breakthrough development of the pharmacologic agent, Restasis®. Restasis®
is a 0.05% emulsion of the active ingredient cyclosporin A formulated in a
castor oil-based topical emulsion vehicle containing glycerin, polysorbate 80,
carbomer 1342, purified water and sodium hydroxide.22 TCSA is the first
FDA approved medication indicated to increase tear production in patients
who do not produce sufficient tears due to ocular inflammation associated
with chronic dry eye syndrome.
Cyclosporin A is a cyclic polypeptide (Figure 16.6) produced as a
metabolite by the fungus Beauveria nivea, which is well known for its anti-
inflammatory and immunomodulatory properties. It is most commonly used
systemically to prevent rejection of transplanted tissues.23 In addition, it is
used systemically to treat psoriasis 24 and rheumatoid arthritis. 25 The
mechanism of action of cyclosporine on inflammatory disease processes arises
from its ability to inhibit T cell activation and thus T cell-mediated inflammation.
TCSA is advantageous in blocking T cell activation because activated T cells
produce cytokines that may result in recruitment of additional T cells, increased
cytokine production, neural signal to the lacrimal gland that disrupts
production of natural tears, which leads to a decrease in quality and quantity
of tears, and damage in lacrimal gland tissue and the ocular surface.
TCSA prevents activation of T cells by cytokines and other agents of
inflammation and normalizes effects of chronic dry eye syndrome processes
FIGURE 16.6: Schematic diagram of cyclic polypeptide of topical cyclosporin A.
of T cells and lacrimal gland acinar cells. Activated T cells are responsible for
the production of inflammatory cytokines and other inflammatory mediators.
These mediators lead to tissue damage, activation of more T cells, and the
production of more inflammatory mediators.
It is important to note that tCSA has no effect on intraocular pressure
(IOP) and does not inhibit the phagocytic system as greatly as do
corticosteroids, allowing the antimicrobial arm of the immune system to fight
infection. Furthermore, tCSA does not inhibit wound healing or produce
lens changes. This creates a wide safety profile for this drug.26 FDA guidelines
indicated two contraindications for the use of tCSA, which are active ocular
infection and any previously demonstrated hypersensitivity to the active
molecule or any of the ingredients in the formulation.
Composition and Appearance of Restasis® with Slit-lamp

Biomicroscopy
Restasis® appears as a white to slightly translucent oil slick or micellar aggregate
(Figure 16.7).22 The micellar aggregate phenomena observed under the slit
lamp in the tear film of patients using tCSA may be seen because tCSA is
formulated as an emulsion, i.e. a medication containing two immiscible liquids
in which one is dispersed, in the form of very small globules or droplets
(internal phase), throughout the other (external phase) [e.g. oil in water
(milk) or water in oil (mayonnaise)].27,28
FIGURE 16.7: Slit lamp examination of the tear film demonstrating an

accumulation of tiny droplet material with lucent centers and white looking
surrounds. (Image from Solomon R, Perry HD, Donnenfeld ED, Greenman
HE. Slit-lamp biomicroscopy of the tear film of patients using topical Restasis
and Refresh Endura. J Cataract Refract Surg. 2005;31:661-63.)
The size of a micelle in tCSA is about one or two microns in diameter.

When first applied, the initial micelles are too small to be seen even under
the magnification of the slit lamp, but what can be appreciated is a general
hazy texture to the tear film. If the emulsions in either formulation were
examined with a slit lamp at highest magnification, one would appreciate the
uniform hazy fluid, or oil slick due to light scatter, with no visible structure
except occasional air bubbles floating at the top.
The microscopic micelles of the emulsion change over time and break
apart as micelles are destabilized. The micelles are destabilized as the emulsion
is diluted by tears and the viscosity of the emulsion drops. Salts enhance this
destabilization process and the sodium in the fluorescein may speed the pace
of the micellar destabilization. After the micelles are destabilized, they release
oil and polymeric emulsifying agents into the tear film, and a portion of these
may reform and coalesce into the visible aggregates described previously in
this paper.22 Tear components may participate in the formation of this
aggregate, and may add bulk, increasing visibility. In general, when emulsions
begin to break up, it is possible for larger temporary features to form. These
features might look like oil droplets or may have a creamy or foamy whitish
appearance if many were trapped together. The micellar aggregates also
appear white because the light shown on the tear film (the “blue” cobalt
light) contains sufficient other wavelengths to appear white when reflected.
Enough blue is absorbed by the miceller aggregate so that the reflected mix
appears white, at least by contrast with the surrounding much bluer tissue.
Emulsifying agents are added to stabilize the emulsion and prevent
coalescence of the dispersed drops.27 The findings of micellar aggregates are
specific for topical ophthalmic emulsion agents. Emulsions are advantageous
as a drug delivery system because they offer the ability to deliver lipid-soluble
drugs in a liquid aqueous like form. This produces enhanced bioavailability,
protection of drugs susceptible to oxidation or hydrolysis, and patient
acceptability in instances where the free drug is irritating.27
Careful examination under the slit lamp of patients applying Restasis®
can help to confirm patient compliance with the drug. We estimate the duration
of time the micellar aggregates are visible to be hours based on what we
have observed in patients using these emulsion agents. Break up of the micelles
is necessary to release the suspended cyclosporin A to the ocular surface.
This technique may help quantitate the stability of this agent on the ocular
surface and help determine whether an increase or decrease in dosing is
required.
Indications and Uses of Topical Cyclosporin A–Restasis®

We will limit our discussion to the studies evaluating tCSA in dry eye syndrome
and to disorders that may be associated with dry eye syndrome,29-31 including
posterior blepharitis, 32 meibomian gland dysfunction, 33 and ocular
rosacea.34,35
TCSA has been successfully used or has shown promise in the management
of many other ophthalmologic conditions. These off-label uses for tCSA,
some of which were tried prior to the release of commercially available
Restasis®, include vernal keratoconjunctivitis,36 Thygeson’s superficial punctate
keratitis,37,38 superior limbic keratoconjunctivitis,39 improvement of LASIK
outcomes in patients with dry eye,40 postkeratoplasty glaucoma,26 post-
keratoplasty glaucoma with corticosteroid- induced ocular hypertension,26,41
HSV stromal keratitis,42 steroid-resistant atopic keratoconjunctivitis,43
keratoconjunctivitis sicca in secondary Sjögren’s syndrome,44 as an adjunct

to antifungal treatment in nonresolving severe keratomycosis,45 inhibition of
fungal growth,46 synergistically with punctual plugs in the treatment of dry
eye syndrome,47 prevention of corneal graft rejection,37,48,49 50 dysthyroid
ophthalmopathy, 51 allergic conjunctivitis, 52 severe allergic kerato-
conjunctivitis,53 phlyctenular keratoconjunctivitis,54 graft-versus host disease,55
treatment of necrotizing scleritis and corneal melting in patients with
rheumatoid arthritis,56 prevention of pterygium recurrence along with
thiotepa,57 the prevention of limbal allograft rejection,58 in the management
of therapeutic keratoplasty for mycotic keratitis,59 treatment of contact lens
intolerance,60 stimulation of neovascularization in sterile rheumatoid central
corneal ulcers as the first sign of a favorable clinical response,61 and Mooren’s
ulcer.62
Restasis® and Dry Eye Syndrome–

Phase III Studies and Other Dry Eye Investigations
Early studies suggesting its utility in dry eye syndrome came from dog studies
in which topical application of cyclosporine ophthalmic emulsion twice daily
reduced lymphocyte infiltration in the lacrimal glands and conjunctiva.63-65
Cyclosporin A also was associated with reduced apoptosis of lacrimal glands
and conjunctival epithelial cells in dogs, effects that contribute to reduced
inflammation and clinical improvement of dry eye.64 The earliest human
studies in keratoconjunctivitis sicca revealed that topical eye treatment with
cyclosporin A relieved the signs and symptoms of the disease.44,66,67
More recent data from a large, multicenter, double-masked, parallel,
randomized 6-month trial evaluating three treatment groups: 0.05%
cyclosporine in vehicle, 0.1% cyclosporine in vehicle, and vehicle all given 1
drop twice daily involving 877 patients, was the basis for approval of
Restasis®.29 This study established the efficacy, safety, and anti-inflammatory
activity of cyclosporin A ophthalmic emulsion compared with castor oil-based
topical emulsion vehicle alone in patients with moderate to severe dry eye
syndrome.29
Patient demographics in each group were as follows: 82%, 84% and
31% were female, Caucasian and Sjögren’s syndrome patients, respectively.
The age range was 22 - 90 years (mean: 60 years). There were no statistically
significant differences between treatment groups in any demographic variable.
No statistically significant differences in prior therapy or types of concomitant
medications used during study for other conditions were observed. At baseline,
patients were using artificial tears as required. In the 0.05% cyclosporine
group, the average baseline use was 6.25 times daily. In the 0.1% cyclosporine
group, the average baseline use was 5.56 times daily. These patients had
been previously treated unsuccessfully – sometimes for decades – with multiple
products and practices.
The study evaluated several primary and secondary variables. The four
primary efficacy variables included two objective: corneal staining and
Schirmer test with anesthesia; and two subjective: reliance on artificial tears
and blurred vision. Six secondary efficacy variables included: photophobia,
sandy/gritty feeling, burning or stinging, itching, feeling of dryness, and pain.
Several tertiary laboratory variables to assess immune involvement included
the following: presence of inflammatory markers, goblet cell density, and
status of pathological apoptosis. These were performed on conjunctival biopsy
tissue obtained before and after treatment.
The rationale behind this study was the theory that insufficient ocular
lubrication increases corneal abrasion of the superficial epithelium. Abraded
corneal epithelium readily accepts stain. However, although corneal staining
is an indirect measure of inflammation and immunoreactivity, it is a commonly
used diagnostic test for chronic dry eye syndrome and is considered clinically
important. Significant differences relative to the vehicle were seen for corneal
staining for both the 0.05% and 0.1% cyclosporine at month 4.
Significant differences relative to the vehicle were seen for 0.05%
cyclosporine at month 6, with a trend towards significance for the 0.1%
emulsion. With the 0.05% emulsion, both patients showed statistically and
clinically significant mean reductions of > 30% versus baseline in corneal
staining at all time points.
Changes also occurred from baseline blurred vision. Blurring of vision
occurs in chronic dry eye syndrome because of desiccation of corneal epithelial
cells causing them to shrink, crease, and opacify. This makes a reduction in
blurred vision an important efficacy measure. The 0.05% cyclosporine-treated
patients exhibited statistically and clinically significant reductions versus baseline
and vehicle in complaints of blurred vision at all time points. At six months,
44% of the 0.05% cyclosporine-treated patients experienced a mean
improvement in blurred vision of 24%, indicating a significant difference in
normalizing ocular surface improvement compared to the vehicle at months
1, 3, 4 and 6.
Reliance on the administration of artificial tears was also tested, whereby

a reduction in the volume of artificial tears used can be a gauge of symptomatic
relief. Patients in all study groups were allowed to instill artificial tears between
study medication doses throughout the trial. A trend towards decreased
artificial tear use in all groups was observed. After 6 months, a reduction in
artificial tear use was seen in all cyclosporine groups versus baseline. The
decrease was statistically significant for the 0.05% cyclosporine group at month
6. A total of 33% of patients reduced concomitant tear use by at least five
times daily. A total of 51% reduced tear use by at least three times daily. The
overall use of artificial tears fell by one-third at month 6. These data indicate
that the condition of the patients’ eyes was improving.
Clinical presentation of dry eye syndrome can have significant variation.
Patients range from mildly to extremely symptomatic, and staining can be
very mild or pronounced. One patient may have severe corneal staining and
a very low Schirmer score, whereas another with severe corneal staining
may have a normal Schirmer score. Therefore, the need for laboratory
assessments is vital as there is currently no good, single test in order to assess
function or even, that which correlates well with common complaints.
Severe dry eye may have no effect on vision in one patient, whereas
another might complain of blurring despite only minor corneal staining. The
condition may have just reached clinical level, or it may be severe end stage
disease with complete lacrimal gland shutdown and severe corneal and
conjunctival signs. Signs and symptoms may be the result of the primary
disease, or they may be secondary to autoimmune disorder, trauma, or
other factors. All these factors warrant the performance of laboratory
assessments, which include the following: CD3 levels (staining for immune T-
lymphocyte cell marker CD3 in chronic dry eye syndrome patients both in
non-Sjögren and Sjögren’s syndrome). Comparing baseline to 6-month values
in a Sjögren’s patient, a significant decrease is again seen in the number of
CD3-positive T cells in the conjunctiva with 0.05% cyclosporine. Similar results
occurred in non-Sjögren’s patients (Figure 16.8).
Consistent with a similar path physiology for both conditions, there was a
reduction in the inflammatory markers, HLA-DR and CD11a, determined
by conjunctival biopsy. Baseline values were found to be significantly elevated
in both Sjögren’s and non-Sjögren’s patients in the pivotal clinical trials, as
well as a separate biopsy study performed by Allergan in collaboration with
the National Eye Institute. After 6 months of 0.05% cyclosporine treatment,
FIGURE 16.8: Immunofluorescence showing dramatic decrease in total

lymphocytes in Sjögren’s and non-Sjögren’s patients after 6 months of
topical Restasis® therapy
Sjögren’s patients:
Top) At baseline, 3965 cells/mm2 ± 1837.3 (n = 4)
Bottom) After 6 months, 819 cells/mm2 ± 396.1 (n = 4)
Non-Sjögren’s syndrome patients:
Top) At baseline, 2291 cells/mm2.
Bottom) After 6 months, 762 cells/mm2
statistically significant decreases in the levels of HLA-DR and CD11a were

seen, compared with increases in the vehicle group.
The final laboratory efficacy measure, goblet cell density, may be the
most sensitive measure of overall ocular surface health. The number of mucin-
producing goblet cells is decreased in patients with moderate-to-severe chronic
dry eye syndrome. As goblet cells die, their density decreases, resulting in
decreased mucin production, which further destabilizes tear film. Increases
in goblet cell density indicate a normalization of the ocular surface.
Cyclosporine treatment resulted in a significant increase in goblet cells. The
increase over the 6-month treatment period was 191% in the cyclosporine-
treated patients, compared with only 13% in the vehicle-treated group (p =
0.013). The vehicle provided only symptomatic relief and had no effect on
goblet cell density.
These clinically relevant findings indicate that cyclosporine affects the
underlying pathology of chronic dry eye syndrome. These data further suggest
that the use of 0.05% cyclosporine results in normalization of the ocular

surface, permitting the return of a stable and healthy tear film. The Restasis®
vehicle also contributes to this efficacy. The vehicle is a low-viscosity oil-based
emulsion that includes a water-soluble polymer, oil and an emulsifying agent,
which lubricates and moisturizes, providing immediate palliative relief. The
oil component remains on the tear-film surface for up to several hours and
may decrease aqueous evaporation. The vehicle alone, while not treating
the disease directly, provides substantial symptomatic relief. All statistically
significant results favored Restasis® over its vehicle. The vehicle alone showed
no significant benefit for any measured inflammatory marker.
Adverse events were monitored. Blood chemistry and hematology tests
were carried out in order to monitor changes in renal and hepatic function.
No significant adverse events were reported. All adverse events were local,
mild, and unrelated to administration of the drop medications. This is a
significant finding because these are patients who usually tend to react
significantly to any form of topical medication. Transient burning, usually of
mild or moderate severity, was reported in 14.7% of the 293 0.05% cyclo-
sporine-treated patients, and was the main adverse event recorded. Other
ocular adverse events reported were stinging, discharge, and foreign-body
sensation in 3-6% of the 0.05% cyclosporine treated patients. Differences in
the incidence between 0.05% cyclosporine and vehicle groups were negligible.
Serious adverse events (5.8% of 293 patients in the 0.05% cyclosporine
group and 4.8% of the 292 patients in the vehicle group) were considered
unrelated or unlikely to be related to study medications. Treatment
discontinuation rates due to adverse events were low and comparable – 6.5
versus 4.5% for 0.05% cyclosporine and vehicle, respectively. There were
no clinically significant differences between the 0.05% cyclosporine- and the
vehicle-treated group in visual acuity, changes in IOP, or biomicroscopy. There
were no cases of ocular infection in the cyclosporine-treated groups, although
there were in the vehicle-treated group. Additional results support the excellent
safety profile of topical cyclosporine. There were no cyclosporine-related
ocular infections in either the phase II or III studies. No clinically significant
changes were seen in blood chemistry or hematology values (including hepatic
and renal function). No patients experienced adverse effects related to blood
chemistry or hematology. Furthermore, there were no treatment-related
changes in IOP, visual acuity, or biomicroscopy, and there was no overgrowth
of microbial organisms.
Other studies further confirmed these findings by showing a significant

decrease in the levels of both inflammatory cells and markers in the conjunctival
epithelium, while allowing for a dramatic increase in the number of goblet
cells.68,69 There were no systemic side effects from the tCSA and no detectable
serum levels in the trial.29,30 In addition, it has been determined that treatment
of dry eye syndrome with topical cyclosporine significantly reduced the
numbers of activated lymphocytes within the conjunctiva.70
Most of these studies have been done in patients who have moderate to
severe dry eye syndrome. In a prospective study of 158 consecutive patients
with dry eye syndrome unresponsive to artificial tear therapy that assessed
all three levels of dry eye syndrome, (mild, moderate and severe) it was
demonstrated that patients who have dry eye symptoms and are refractory
to standard artificial tear therapy benefit from tCSA in helping to alleviate
their complaints.71 The study participants were prescribed tCSA twice daily.
The patients underwent a subjective evaluation with the OSDI and an
objective evaluation with TBUT, fluorescein staining, histamine green staining,
and Schirmer testing (basic secretion). Patients were divided into three groups
(mild, moderate, and severe) and were followed for 3 to 16 months.
It was worthwhile to note that in regards to the patient characteristics,
there was a three times greater prevalence of patients with thyroid
autoimmune disease than would be expected in an age-matched population.
Interestingly, the greatest symptomatic benefit actually occurred in the mild
patient group, suggesting that patients treated earlier in the disease may
show the greatest symptomatic improvement. The authors have also
demonstrated that over 70% of patients starting therapy with tCSA for dry
eye unresponsive to artificial tears will have a positive response to treatment,
regardless of the severity of their disease. Additional studies have confirmed
the beneficial use of tCSA for keratoconjunctivitis sicca.72,73
Restasis® and Posterior Blepharitis—Meibomian Gland Dysfunction

Not only has inflammation been linked to aqueous deficiency dry eye
syndrome, but also to that of evaporative loss. The most common cause of
evaporative loss dry eye syndrome is posterior blepharitis or meibomian
gland dysfunction (Figure 16.9). The abnormalities of the lipid layer cause
an unstable tear film and prevent the eye from always being wet.
In a prospective study of 33 patients with symptomatic meibomian gland
dysfunction, an evaluation was performed comparing tCSA to artificial
FIGURE 16.9A to D: Clinical photos of eyelids in patients with

meibomian gland dysfunction
tears.33,74 This study demonstrated that tCSA could be of benefit in the

treatment of meibomian gland dysfunction.33 At the 3-month follow-up visit
following initiation of treatment, many objective clinical findings were
significantly better in the tCSA group than in the placebo group, notably
meibomian gland inclusions, lid margin vascular injection, tarsal telangiectasis,
and fluorescein staining. In addition, there was a trend toward significant
prolongation of the tear film break-up time in the tCSA group.
The reason that tCSA may ameliorate posterior blepharitis is because
underlying the pathophysiology of posterior blepharitis is meibomian gland
dysfunction. The signs and symptoms of this disease are exacerbated by
abnormalities in the lipid layer of the tear film, which is produced by the
meibomian glands. Obstruction of the meibomian ducts causes accumulation
of meibomian secretions known as meibum. Accumulation of meibum within
the meibomian gland can lead to inflammation of the gland and bacterial
colonization.1,3,68,75-79 The colonizing bacteria have lipases that break the
nonpolar wax and sterol esters into triglycerides and free fatty acids (polar
lipids), thus altering the normal composition of the meibum.33,80 The polar
lipids diffuse more easily through the aqueous layer and contaminate the
mucin layer, making it hydrophobic.81 This causes the tear film to become
unstable, and the surface of the eye becomes unwettable. The abnormal
meibum has a melting point above the ocular surface temperature, in contrast
to normal meibum, which has a melting point equal to or lower than the
ocular surface temperature.75,79,82 The abnormal meibum therefore solidifies
and obstructs the ducts, leading to further inflammation and perpetuating
the vicious cycle. TCSA, as a highly specific immunomodulator that affects
primarily T-lymphocytes, may decrease the inflammation of the meibomian
glands and thus reduce their plugging and dysfunction.
Restasis® and Ocular Rosacea

Rosacea is a common oculodermal disorder, primarily affecting the sebaceous
glands of the face and the meibomian glands of the eyelids. Recent studies
estimate the prevalence of potentially blinding ocular pathology to be between
6% and 18% of patients with acne rosacea (Figure 16.10).83 Ocular signs
and symptoms are common and include foreign body sensation, photophobia,
lid margin telangiectasia, meibomian gland inflammation and inspissation,
decreased tear break-up time, conjunctival hyperemia, and marginal corneal
ulcers and vascularization. In addition, this autoimmune disease routinely
produces tear film abnormalities, which result in complaints of blurred vision,
FIGURE 16.10: Clinical photograph of severe effects of ocular rosacea

tearing, and burning. Tear film instability, characterized by rapid tear break-
up time, leads to decreased tear production and function.84 As a result, the
corneal and conjunctival epithelium of these patients often exhibits significant
pathology compared with normal subjects.85 Artificial tears have been used
for chronic management of dry eye symptoms; however, these drops provide
insufficient long-term symptomatic relief in most patients and fails to address
the underlying pathology. Traditional treatment for ocular rosacea has included
lid hygiene with warm salt-water soaks, use of the oral tetracycline family of
antibiotics, application of topical antibiotics to lid margins, or short courses of
corticosteroids.
Two recent studies were performed examining the role of tCSA in the
management of ocular rosacea. One investigation was a retrospective chart
review that surveyed patients with chronic ocular rosacea, refractory to
traditional treatments, who were subsequently administered cyclosporine
0.05% ophthalmic emulsion.86 The second recent study investigated the
efficacy of tCSA compared to an artificial tear solution (Refresh Plus®, Allergan,
Inc.) used as a control, for the treatment of rosacea-associated eyelid and
corneal pathology.87
In the first study, a retrospective chart review of patients diagnosed with
ocular rosacea, all patients had active inflammation of lids and ocular surface
(many for several months prior to the study). All patients from a large group
practice treated with cyclosporine ophthalmic emulsion over a 17-month
period were included, and they all failed to respond to other currently available
treatments (including oral tetracycline, warm soaks with lid hygiene, topical
antibiotics, or short courses of topical steroids).
The treatment regimen for the initial 1 to 2 weeks consisted of loteprednol
etabonate 0.5% (Lotemax, ® Bausch and Lomb, Tampa, FL) or
fluorometholone 0.1% ophthalmic suspension (FML;® Allergan, Inc.) twice
daily, oral tetracycline (250 mg) or doxycycline (100 mg) once daily, and
gatifloxacin 0.3% ophthalmic solution (Zymar;® Allergan, Inc.) four times
daily if conjunctivitis were present. The treatment regimen thereafter consisted
of tCSA twice daily. After starting cyclosporine, oral tetracycline/doxycycline
was continued, while loteprednol or fluorometholone tapered off over 2
weeks.
Evaluation of treatment efficacy consisted of a patient symptom
assessment, clinical examination, including supravital staining with lissamine
green and/or fluorescein, and follow-up for at least 6 months.
The results of the study showed that 18% (10/55) of patients with ocular
rosacea refractory to other treatments showed complete resolution when
treated with cyclosporine 0.05% ophthalmic emulsion, 31% (17/55) showed
significant improvement, 31% (17/55) experienced mild (4) to moderate
(13) relief of symptoms and improved clinical signs, 4% (2/55) had recurrence
of symptoms while on treatment, despite initial improvement, and 20% (11/
55) of patients showed poor response to the treatment and withdrew before
6 months. At last follow-up visit, 5% of the patients who responded to
cyclosporine (2/44) were able to discontinue all medications without
recurrence of rosacea. TCSA was sufficient to control ocular rosacea in 68%
of responsive patients (30/44). They required no additional medications 27%
(12/44) and continued low-dose tetracycline along with topical cyclosporine.
This study demonstrated that tCSA effectively treated signs and symptoms
of ocular rosacea in patients who failed to respond to other treatments. The
majority of patients were able to discontinue oral tetracyclines, but most
required continued treatment with cyclosporine 0.05% to manage the
condition.
In the second investigation, a double-masked clinical trial of 37 patients
with rosacea-associated eyelid and corneal changes were enrolled in a study
comparing the efficacy of tCSA with artificial tear solution in treating rosacea
associated eyelid and corneal pathology. Patients were enrolled after any
active infections were treated with lid scrubs and antibiotics. Once the infection
was clinically controlled, patients were randomized to cyclosporine or artificial
tears for 3 months. All patients were withdrawn from oral doxycycline for at
least 2 weeks prior to study, and patients with eyelid defects or lagophthalmos
were excluded.
At each visit, patients were assessed by the OSDI questionnaire, Schirmer’s
testing with anesthesia, measurement of corneal staining, and TBUT. The
number of meibomian glands expressed (due to inspissation) and the quality
of the excreta were also evaluated at each study visit. Changes from baseline
were described at follow-up visits, and final patient success was evaluated at
the month 3 visit. Patients who were still symptomatic after their initial regimen
(at the month 3 evaluation) were offered a switch to the alternate regimen
and returned for a follow-up assessment after 1 month.
The results of the study demonstrated that tCSA provided statistically
significantly greater improvements in Schirmer’s scores, TBUT, corneal staining,
and OSDI scores compared with artificial tears after 3 months of treatment.
TCSA produced a statistically significant increase in Schirmer’s (with anesthesia)

scores of 2.7 ± 2.2 mm after 3 months of treatment (p < .001). Conversely,
Schirmer’s scores worsened in the artificial tears group, with a mean decrease
of 1.4 ± 4.6 mm (p = .271). Similarly, the mean TBUT score also significantly
improved in the cyclosporine-treated patients (a mean increase of 3.56 ±
1.5 seconds, p < .001) but worsened in the control group (a mean decrease
of 0.04 ± 1.6 seconds, p = .929). Cyclosporine-treated patients exhibited a
significantly greater mean reduction in corneal staining (-1.3 ± 0.53)
compared with artificial tears (-0.2 ± 0.83) after 3 months of treatment
(p < .001). Moreover, tCSA provided significantly greater improvement in
OSDI scores than did artificial tears (mean reduction of 11.5 ± 8.8 with
cyclosporin versus a mean decrease of 2.9 ± 11.6 with artificial tears, p =
.022). The study demonstrated that tCSA is superior to artificial tears for the
treatment of rosacea-associated lid and corneal changes.
Recommended Topical Cyclosporin A Regimen

The recommended dosing for tCSA is 1 drop in each eye every 12 hours. It
is important to inform patients: do not use “as needed” like traditional drops.
Patients may concomitantly use aqueous tears. Nonpreserved tears were
used in clinical trials. Patients should allow a 15-minute interval between
instillations and realize that additional application of a topical emulsion agent
may be poorly tolerated. For patients who wear contact lenses, they should
be instructed to remove their contact lenses before administering tCSA, and
to wait 15 minutes before replacing the lenses.
While it is common to advise patients that it may take three months to see
an improvement in symptoms after starting tCSA, a recent study has
demonstrated that a positive effect may be seen after only a few weeks of
therapy72 to 30 days of therapy.88 However, to ensure patient compliance, it
is important to caution patients that it could take as much as 90 days of
continual use of tCSA to experience improvement.
Patients should be informed that the most common adverse event reported
following tCSA use was ocular burning (17%). Other ocular adverse events
reported by 1% to 5% of cyclosporine patients included conjunctival
hyperemia, discharge, epiphora, eye pain, foreign-body sensation, stinging,
and visual disturbance. To increase patient comfort, ketorolac 0.4% (Acular
LS®, Allergan, Inc.) could be applied 10 minutes preceding instillation of
tCSA and has been demonstrated to increase patient comfort and improve
patient compliance in the induction phase of using tCSA (first six weeks).89
Long-term treatment with tCSA over a period of up to 3 years has been
demonstrated to be well tolerated, and not associated with systemic side
effects.90
SUMMARY
Topical cyclosporin A ophthalmic emulsion (Restasis®) is the first treatment
that targets an underlying pathological mechanism for chronic dry eye:
immune-mediated inflammation. Furthermore, it is the only purpose-
designed topical drug therapy for chronic dry eye syndrome. Restasis® has
been demonstrated to be safe and effective in animal and human clinical
trials. TCSA reduces signs and symptoms of dry eye syndrome, has a favorable
pharmacokinetic profile, and is well tolerated, with few and minor ocular
adverse effects.
TCSA has no effect on IOP and does not inhibit the phagocytic system as
greatly as do corticosteroids, allowing the antimicrobial arm of the immune
system to fight infection. Furthermore, tCSA does not inhibit wound healing
or produce lens changes. These characteristics create a wide safety profile for
this drug.26 There were no systemic side effects from the topical Restasis,®
and no detectable serum levels in the phase III trial.
No microbial overgrowth or ocular infections occurred during clinical
studies. Restasis® is well-accepted by patients, and they can expect results in
3 to 6 months of treatment. Most importantly, this agent provides rational
pharmacological therapy where none currently exists.
CONCLUSION
In conclusion, the difficulty of diagnosing and treating dry eye syndrome
remains problematic. However, a breakthrough in our understanding of the
pathogenesis of dry eye syndrome has led to the first drug therapy aimed at
treating the cause of dry eye, rather than merely signs or symptoms. Restasis®
is also useful for a variety of disorders related to dry eye disease, including
posterior blepharitis and ocular rosacea. In addition, Restasis® has been
demonstrated to be effective or has shown promise in the treatment of
management of a wide variety of additional ophthalmic disorders. Restasis®
offers the advantage of immunomodulation without the risk of corticosteroid
side effects.
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DRY EYE MANAGEMENT IN PREGNANT AND MENOPAUSAL WOMEN 273
INTRODUCTION
Dry eye is an extremely common and often unrecognized disease. Due to a
wide variety of presentations and symptoms, dry eye syndrome frustrates
doctors as well as patients. The etiology is both elusive and multivariate.
Because it is difficult to successfully identify a cause, it is also challenging to
find efficacious therapy. New therapeutic options beyond the customary
aqueous tear replacement so long the standard for ophthalmologists,
optometrists, and rheumatologists has rendered the field of dry eye more
exciting for clinicians. Since not all dry eye results from a lack of tears, but
rather from instabilities in the tear film, even more therapeutic options excite
pharmaceutical development teams.
Many factors can affect dry eye, including environment, eyelid problems,
oral medications, age, heredity, cigarette and multivitamin use, arthritis,
hormone replacement therapy, and most importantly sex: dry eye is far
more common in females than males due to hormonal differences.
The tear film, which consists of the lipid, aqueous, and mucin layers,
performs a specific role in protecting the ocular surface. If one component is
deficient, then the tear film destabilizes more rapidly than normal, resulting
in exposed ocular surface epithelium or basement membrane. Prolonged or
repeated exposure creates the uncomfortable symptoms of dry eye as well
as damaged conjunctival and corneal epithelium. The entire treatment strategy
revolves around preservation of the intact ocular surface unit, which consists
of several important components, including the tears, the corneal surface,
the lids, and the lashes. An extremely important factor in maintaining an
adequate ocular surface is the presence of normal androgen levels, which
are found in both sexes albeit in far higher concentration in males. With
aging, all hormone levels decrease, and androgens reach critically low levels
in females at a far younger age than males. Thus, the remarkably earlier
onset of dry eye in the female population.
PREGNANCY AND DRY EYE

Pregnancy changes everything, since all hormone levels are markedly elevated
during gestation. This is generally a very healthy state, full of anticipation and
very important bodily changes. The high levels of hormones circulating during
pregnancy, particularly in the last trimester, can create accentuated hormone
levels and marked alterations in the estrogen to androgen ratio, effectively
decreasing androgen effect upon the ocular surface. Androgens may actually
be decreased during pregnancy and lactation thereafter.
Thus, the pregnant female should be well aware of dry eye symptoms,
particularly if she has had dry eye before or suffers from any of the other risk
factors for dry eye. The greatest danger may occur in contact lens wearers,
who are already at increased risk of corneal infections. Further drying due to
pregnancy may add to this infection risk.
Currently available tear substitutes replicate and replace tears, but their
use is only palliative, helping manage dry eye through short-term symptomatic
relief. Anti-inflammatories reduce ocular surface effects of the underlying
cause of dry eye, thereby for the first time treating the disease and not the
symptoms. Secretagogues address specific deficiencies in the tear film. In
addition, other classes of treatments include nutritionals, hormonal agents,
anti-evaporatives, mucomimetics and improved polymers. Thus, numerous
strategies are involved with the treatment of chronic dry eye disease and,
while treatment algorithms and priorities differ between patients and
practitioners, the approximate order of intervention presents as follows:
1. Preserved artificial tear substitutes.
2. Vanishing preservative tear substitutes.
3. Preservative-free tear substitutes (in Single Dose Units, or SDUs).
4. Environmental control (wind, humidity, allergens, fumes, smoke, vapors).
5. Ocular surface anti-inflammatory (Restasis, Loteprednol etabonate).
6. Systemic medication control (less diuretics, anti-histamines, anti-
depressants, HMG co-A Reductase inhibitors).
7. Punctal occlusion (collagen, plastic or silicone, cautery).
8. Oral secretagogues (Pilocarpine, Salagen, Evoxac).
9. New medication categories (Androgens, Diquafosol, 5-HETE).
Chronic dry eye disease is highly heterogeneous. Therefore, patients
present in many different ways. For example, patients with severe symptoms
may reveal minimal signs upon examination, while patients with a multitude
of seemingly significant findings at the slit lamp may have minimal complaints.
These guidelines reflect a universal acceptance of dry eye by clinicians —
alone or in combination with other conditions — as an inflammatory ocular
surface disorder that can be a cause of visual morbidity and may compromise
the results of corneal surgery, cataract surgery, or other ocular surface
procedures. The symptoms of dry eye often improve with treatment, but the
disease usually is not curable. Many of the ocular surface changes associated
with KCS can be reversed with specific treatment.
Improvement and preservation of vision, prevention or minimization of
structural damage to the ocular surface, and alleviation of patient discomfort
are key to therapeutic success. Thus, clinicians must be aggressive both in
diagnosing possible underlying systemic inflammatory disease and in making
ocular surface anti-inflammatory therapy a key component of their
therapeutic approach. Environmental control as well as a careful evaluation
of systemic medications may also be key to clinical improvement.
Patients with a clinical diagnosis of mild dry eye may also benefit from
behavioral and environmental modification, such as learning to take breaks
while reading, lowering the computer monitor to decrease lid aperture, and
humidification of the environment. Because dry eye also can be an iatrogenic
disease, elimination of exacerbating exogenous medical factors, such as
prescription regimens that include ocular topical preservatives or systemic
antihistamines or diuretics, may also help.
For patients with mild disease, use of tear substitutes is indicated. As the
severity of dry eye increases, nonpreserved tear substitute emulsions, gels,
and ointments may be used instead of a conventional preserved tear substitute.
Noninvasive therapies such as spectacle side shields, moisture inserts, and
moisture chambers are appropriate for more severe disease, but these
therapies tend to be unpopular among patients for cosmetic reasons.
Moderate dry eye sufferers generally fare better on non-preserved tears,
supplied in individual single dose units which are disposed of after each use.
Specially prepared tears with a vanishing preservative like Refresh tears allow
multiple doses from a standard dropper bottle, providing the convenience
of continuous use from the bottle with the benefits of preservative free
solutions on the ocular surface.
A newer medication, Restasis, or topical cyclosporine emulsion, has
revolutionized the treatment and prevention of dry eye. This medication
actually reduces ocular surface inflammation while allowing the patient to
make more of their own tears. Restasis is useful not only for severe dry eye,
but also especially beneficial to patients with moderate disease otherwise
destined to worsening symptoms.
Patients with systemic disease such as primary Sjögren’s syndrome or
connective tissue disease such as rheumatoid arthritis should be managed in
conjunction with the appropriate medical specialist. Anti-inflammatory/

immunosuppressive therapy may be appropriate for patients with a systemic
disease such as rheumatoid arthritis.
Surgical treatment is generally reserved for patients with symptomatic,
moderate, or severe disease, and for whom medical treatment has been
inadequate or impractical. This consists of either dissolving or permanent
plastic plugs in the canaliculus, or tear drain, thus preserving tears secreted
onto the ocular surface and preventing their loss into the nose via the
nasolacrimal duct.
Dry eye as well as many other ocular surface diseases produce similar
symptoms, such as foreign-body sensation, mild itching, burning, blurred
vision, irritation, and soreness. The initial evaluation of a patient presenting
with symptoms that are suggestive of dry eye should include those features
of the comprehensive adult eye evaluation relevant to dry eye.
Diagnosis of mild dry eye is often difficult to diagnose, because of the
inconsistent correlation between reported symptoms and clinical signs and
the relatively poor sensitivity and/or specificity of existing diagnostic tests.
When exacerbating environmental and other potential causes of ocular
irritation have been eliminated from consideration, patients with suggestive
symptoms who do not have overt signs of disease should be placed on trial
treatments, such as artificial tears or, where appropriate, trial discontinuation
of systemic antihistamines. Significant deleterious environmental factors
include air travel, riding in convertibles or on motorcycles, exposure to air
conditioning, and contact lens use. Activities that may exacerbate dry eye
disease include reading, night-shift work, computer work, and living within a
poorly humidified work space or home. Important exogenous irritants include
cigarette smoke, dust, allergens, chemicals, fertilizers, and various perfumes.
Pregnancy can be a wonderful time in any family’s life. If complicated by
worsening dry eyes, or potentially vision threatening problems resulting from
contact lens use on a drying ocular surface, the picture can be far more
dismal.
MENOPAUSAL WOMEN AND DRY EYE

For women in menopause, in addition to the hot flashes and mood swings,
dry-eye syndrome is often one more thing with which to contend, as many
women develop dry eye during this time.
The vast majority of the patients with dry eye are women and the vast
majority of those are in menopause, or are postmenopausal.
That’s due to a hormonal component at work. Surprisingly, it is not likely
diminishing estrogen levels that tip the scale toward dry eye, but androgen
levels—hormones that are present in both men and women, but which are
higher in men.
Androgen levels circulating in the blood stream stimulate lacrimal secretion
result in the normal turnover of cells on the surface of the eye. These cells
decline with age and so the female androgen levels (which start lower) reach
the critical threshold below which the ocular surface begins to show signs of
tear-deficiency syndrome, low secretion, and increased inflammation.
Some women, however, are more prone to the condition than others,
likely due to heredity.
Additional Factors to Consider

In addition, other standard factors that contribute to dry eye may also be
important. These include contact-lens use, concomitant lid disease or allergy,
as well as medication that can dry the mucous membranes.
It would also include antihistamines and antidepressants, diuretics, and
the usual allergy medicines and even cholesterol medicines.
The type of hormone medication women opt for may also have an impact.
The estrogen only caused more dry eye than the estrogen and progesterone,
which suggests that progesterone may have had a little bit of a protective
effect.
Treating Menopausal Dry Eye

When treating menopausal women for dry eye, meticulous recording the
medical history can be key.
It’s important to ask in the history if there may be an underlying
autoimmune disease, because in some of those cases, a drug like Restasis
(cyclosporine ophthalmic, emulsion, allergan, irvine, calif) can help because
of the anti-inflammatory mechanism.
For menopausal women that wear contact lenses punctal plugs can help
to increase lubrication. While there is no out-of-the-ordinary dry eye therapy
for this population, often, postmenopausal women need a more aggressive
regimen because of the severity of the dry eye.
I recommends the use of preservative-free tears in conjunction with agents

such as Restasis that boost patient’s own natural tear production.
Natural tears produced by the patient have all of the beneficial substances
that promote healing and protection on the surface of the eye, whereas
artificial tears only provide water and electrolytes..
DRY EYE AND VISUAL ACUITY 281
INTRODUCTION
The tear film plays an important role in visual acuity. The tear film is the most
anterior surface of the eye and has the greatest change in refractive index.
Insufficient quality and/or quantity of the tear film may introduce aberrations
into the optical system.1 These aberrations contribute to a reduction in retinal
image quality.1-6
Dry eye syndrome has been defined as an insufficient quantity or quality
of tears on the ocular surface causing a variety of signs and symptoms, one
of which but rarely discussed is blurry vision. This may be due to the poor
correlation between signs and symptoms in dry eye patients.7
Even from a therapeutic standpoint, the armamentarium against dry eye
syndrome is lacking. Up until recently, most of the therapy involved temporary
relief from an artificial tear substitute rather than therapeutic agents that
address the root of the cause.
While artificial tears are certainly not the cure, there are at least some
clear benefits seen with their use.
Artificial tears can correct corneal topographic surface irregularities, contrast
sensitivity, glare disability, visual acuity and wavefront aberrations in dry eye
patients.8-15 Therefore, those dry eye patients who complain of visual
disturbances may see an improvement with a stable and healthier tear film.
The trick is figuring out an artificial tear composition that improves visual
acuity and lasts an extended period of time.
Artificial tears can, albeit temporarily, improve visual acuity.8,11,14 In a
study looking at 40 eyes of symptomatic dry eye patients and 40 eyes of
asymptomatic dry eye patients, artificial tears improved the uncorrected
distance vision in both groups for up to 4 minutes (p=0.002, p < 0.001
respectively).14 This improvement in visual acuity may be due to the reduction
of aberrations and surface irregularities on the ocular surface.11
Most refractive surgeons would agree that a fair number of their patients
have fluctuating vision in the first few postoperative days following refractive
surgery. It is common knowledge that these patients are typically dry in their
early postoperative period, and in some, the dryness may persist. This happens
because of the severing of the superficial nerves and possibly a reduction in
the number of goblet cells due to intraoperative trauma.16 The slight blur
that these postrefractive surgery patients experience early on in their vision
seems to either resolve eventually with time or temporarily resolves with the
instillation of a nonviscous artificial tear drop.
Although artificial tear drops appear to improve vision, it is not practical

to use them every few minutes to achieve this result. There are, however,
some useful points to this short-lived benefit. The Tear film Normalization
Test (TNT) evaluates for the presence of dry eyes (p < 0.0001).17 A patient’s
uncorrected distance vision is recorded using Snellen vision charts before
any eye drops are placed in their eyes and any slit lamp exam is performed.
The smallest line read correctly in its entirety is recorded as the best
uncorrected visual acuity. One drop of a nonviscous artificial tear drop is
instilled in each eye and the uncorrected distance vision is rechecked starting
at the smallest line read correctly. The patient is told not to blink excessively
after each drop in order to not “blink” out the additional tears. If a tight
squeezing blink is noted, an additional artificial tear drop is instilled in the
eye. In some patients, after drop instillation, a few seconds of waiting may be
necessary in order to “normalize” the tear film. The vision in each eye is
rechecked. When the patient’s visual acuity improves by one line the test has
a 95% sensitivity, and a 70% specificity, and if their vision improves by two
lines the test has a 82.5% sensitivity, and a 100% specificity for detecting dry
eyes. Basically TNT can be used as a screening test when looking at one line
of visual improvement; as it detects 95% of all patients with dry eyes. And
100% of patients who have at least a two line improvement of vision will
have dry eyes. The test can easily be performed by a technician and any of
a number of non-viscous artificial tears can be used for instillation.
Other methods of improving visual acuity involve the use of Punctal plugs.
Occluding the drainage site of the nasolacrimal apparatus will delay tear
clearance and therefore increase the quantity of tears in the eyes.18 Punctal
plugs have been shown to improve visual acuity in dry eye patients.13,18 One
possible concern is the potential of a limited long term benefit.19
It is well known that the majority of dry eye patients are over the age of
40 as the condition worsens with age.20 The incidence of dry eyes has been
estimated to be up to 77 million Americans by a 2002 Gallup poll. The true
incidence varies depending on the study which may be due to the fact that
the condition has historically been difficult to diagnose due to the
inconsistencies of some of the available diagnostic tests and the lack of
correlation of signs and symptoms.
Given that a large number of people over the age of 40 have dry eyes,
there may be an additive effect of dry eyes on presbyopia. 20 patients over
the age of 40 evaluated the uncorrected near vision before and after the use
of an artificial tear drop were evaluated. 14 There was a statistically

significant improvement (p < 0.001) of uncorrected near vision in these
patients. Since the visual improvement returns to baseline by a few minutes,
the true practical benefit is unrealistic. However, another study looking at the
use of punctal plugs in presbyopic dry eye patients showed a statistically
significant improvement of uncorrected near visual acuity as well (p
< 0.0001)21 (Fig. 18.1) As the follow-up on these patients was only one
month the long-term benefits need to be evaluated.
When evaluating patients with blurry vision, the possibility of dry eyes
should not be overlooked. As treatment options are all for the most part
conservative, a diagnosis of dry eyes should be ruled out before any more
aggressive surgical option is pursued such as cataract or laser refractive surgery.
The same applies to ruling out any more serious cause of blurry vision and
performing possibly unnecessary neurological testing such as radiological
imaging, visual field testing, or retinal studies. The time it takes to perform
TNT or a combination of other diagnostic tests such as the Schirmer test, or
tear film break-up time is minimal and should be done first. In addition it
would be wise to manage a dry eye patient before any ocular surgery as
their outcome will probably improve and the possibility of reducing any side
effects should increase.
FIGURE 18.1: Visual acuity 1 month after punctal plug placement

The contribution of dry eyes to poor visual acuity continues to become

more apparent.
The likelihood of even more sensitive and specific dry eye diagnostic
tools to surface in the near future is high and a more readily available means
of assessing a patient’s visual acuity should go beyond Snellen vision testing.
The black on white contrast rarely mimics our typical daily lives. We have all
encountered an unhappy 20/20 patient and with newer more available means
of assessing acuity this may help distinguish the true cause of their complaints.
Functional visual acuity is one possible new method of assessing vision as it
typically shows visual impairment while gazing for 10 to 20 seconds in only
dry eye patients.22
As the forecast for the treatment of dry eyes looks promising, we should
not only see an overall reduction in the commonly associated burning, redness,
foreign body sensation and dryness symptoms but we will also hope to see
an accompanying improvement in vision. We have many more treatment
options on the horizon and more will follow as dry eye syndrome continues
to get the attention it deserves.
REFERENCES
1. Albarran C, Pons AM, Lorente A, et al. Influence of the tear film on opitical quality of
the eye. Contact Lens Anterior Eye 1997;20:129-35.
2. Thibos LN, Hong X. Clinical applications of the shack Hartmann aberrometer.
Optom Vis Sci 1999; 76:817-25.
3. Montes-Mico R, Alio JL, Munoz G, et al. Post blink changes in total and corneal
aberrations. Ophthalmology 2004;111:758-67.
4. Tutt R, Bradley A, Begley C, et al. Optical and visual impact of tear break-up in
human eyes. Invest Ophthalmol Vis Sci 2000;41:4117-23.
5. Koh S, Maeda N, Kuroda T, et al. Effect of tear film break-up on higher order
aberrations measaured with a wavefront sensor. Am J Ophthalmol 2002; 134:115-
17.
6. Rieger G. The importance of the precorneal tear film for the quality of optical
imaging. Br J Ophthalmol 1992;76(3):157-58.
7. Nichols KK, Nichols JJ, Mitchell L. The lack of association between signs and
symptoms in patients with dry eye disease. Cornea 2004;23:762-70.
8. Montes-Mico R, Araceli Caliz, Alio JL. Changes in ocular aberrations after installation
of artificial tears in dry eye patients 2004;30:1649-52.
9. Novak, K, Kohnen T, Chang-Godinich A, et al. Changes in computerized video
keratography induced by artificial tears. J Cataract Refract Surg. 1997; 23:1023-28.
10. Albarran C, Pons AM, Lorente, et al. Influence of the tear film on the optical quality
of the eye. Contact Lens and Anterior Eye 1997;20:129-35.
11. Liu Z, Pflugfelder SC. Corneal surface regularity and the effect of artificial tears in
aqueous tear deficiency. Ophthalmology May 1999;106:939-43.
12. Pavlopoulos GP, Horn J, Feldman ST. The effect of artificial tears on computer-
assisted corneal topography in normal eyes and after penetrating keratoplasty. Am
J Ophthalmol 1995;119:712-22.
13. Huang B, Mirza MA, Qazi MA, et al. The effect of punctal occlusion on wavefront
aberrations in dry eye patients after laser in situ keratomileusis. Am J Ophthalmol
2004;137:52-61.
14. Nilforoushan M, Latkany R, Speaker MG. Effect of artificial tears on visual acuity.
15. Huang F, Tseng S, Shih M, et al. Effect of artificial tears on corneal surface regularity,
contrast sensitivity, and glare disability in dry eyes. 2002;109(10):1934-40.
16. Wilson SE. Laser in situ kertaomileusis-induced (presumed) neurotrophic
epitheliopathy. Ophthalmology 2001;108(6):1082-87.
17. Latkany R, Speaker MG. Tear Normalization Test. ASCRS 2005.
18. Goto E, Yagi Y, Kaido M, et al. Improved functional visual acuity after punctal
occlusion in dry eye patients. Am J Ophthalmol 2003;135:704-05.
19. Yen MT, Pflugfelder SC, Feuer WJ. The effect of punctal occlusion on tear production,
tear clearance, and ocular surface sensation in normal subjects. Am J Ophthalmol
2001; 131(3):314-23.
20. Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eye syndrome
among US women. Am J Ophthalmol 2003;136(2):318-26.
21. Latkany R, Speaker MG. Punctal plugs and presbyopia. ASCRS 2005.
22. Goto E, Yagi Y, Matsumoto Y, et al. Impaired functional visual acuity of dry eye
patients. Am J Ophthalmol 2002; 133(2):181-86.
LASIK HINGE LOCATION AND DRY EYE 287
INTRODUCTION
Normal tear function is essential for maintaining corneal function and structure.
As the popularity of LASIK has grown, the number of patients experiencing
dry eye symptoms has grown as well. According to the 2004 Refractive
Surgery Survey, 1 dry eye symptoms are the most common problem
encountered after LASIK and occur in 15 to 25% of patients. The dry eye
symptoms range from a mild irritation and foreign body sensation to pain,
photophobia and decreased visual acuity with visual fluctuation. There may
be several factors that influence these symptoms, but decreased corneal
sensation may play a major role.
The cornea is innervated by sensory nerve fibers originating from the
ophthalmic division of the trigeminal nerve, and by sympathetic nerves. It is
the tissue most densely innervated in the body. Corneal sensation is essential
to maintaining the integrity of the ocular surface. Neurotrophic keratitis can
result from common ocular disorders such as herpes simplex or herpes zoster
infections or from uncommon insults affecting the fifth cranial nerve such as
tumor, irradiation, or strokes.2 In its early stages, neurotrophic keratopathy
can manifest as an interpalpebral punctate keratitis and visual fluctuation and
can progress to loss of epithelial integrity and corneal stromal melting.3
Experimental and clinical studies have demonstrated that corneal nerve damage
alters the metabolism and vitality of the epithelium, impairs epithelial healing,
and is responsible for trophic ulceration.4 Corneal surgical procedures may
disrupt the normal organization of corneal innervation, including refractive
surgery, which has been shown to cause decreased corneal sensation. This has
been documented after epikeratophakia,5 radial keratotomy,6 photorefractive
keratectomy (PRK),7 and laser in situ keratomileusis (LASIK).8-11 A number of
possible etiologies explaining the appearance of dry eye following LASIK have
been proposed. These include damage of the globlet cells by the pressure
generated by the suction ring, alteration of the corneal curvature affecting tear
stability, and medications that can induce transient dry eye symptoms.12 More
significant is the transection of a significant number of afferent sensory nerves
in the cornea during the formation of the flap and, therefore, interruption of
the cornea-trigeminal nerve-brain stem-facial nerve-lacrimal gland reflex arc
that influences both basal and stimulated tear production.8,13-18
Damage to the corneal nerves has a direct effect on the health of the
epithelium. In diseases where the trigeminal nerve has been damaged, a
non-healing epithelial defect can occur. This epithelial breakdown may be

due to poor blinking, decreased tear production, or by loss of direct
neurotrophic effects on the epithelium. In some patients with dry eye after
LASIK, there are signs of dryness with relatively few symptoms and ample
tear production. These patients may be suffering from the loss of the direct
effects that the corneal nerves may have in maintaining a healthy epithelium.
The subject of corneal innervation has gained importance in recent years
due to the observation that corneal nerves are routinely injured following
modern refractive surgical procedures. An example is LASIK surgery where
a microkeratome is used to create a hinged lamellar corneal flap, disrupting
the normal organization of corneal innervation. This damage can lead to
transient or chronic neurotrophic deficits.12,13 Some authors suggest the corneal
nerves predominantly enter the cornea at the 9 and 3 o’clock position. Thus,
creating a LASIK flap with a hinge provides a potential conduit for superficial
innervation. A vertical flap (superior hinge) would transect both of the major
areas of corneal innervation, while a horizontal flap (nasal hinge) would
transect only one of these areas.14 This suggests that a nasally hinged corneal
flap may cause less loss of sensation than a superior hinge.14-16,19 Descriptions
of the anatomy of the mammalian corneal innervation are numerous;
nevertheless many aspects of corneal nerve architecture remain incompletely
understood. The true distribution of corneal nerves is controversial and it is
still being elucidated.
To determine whether patients undergoing LASIK might actually have
dry eye, we conducted a prospective, randomized, masked study to determine
the effects of hinge position (superior vs nasal hinge) on corneal sensation
and dry eye signs and symptoms after LASIK.20 The study included 47 patients
undergoing bilateral myopic LASIK surgery. The first eye was randomly
assigned to have a nasal or superior hinge flap; the fellow eye had the alternate
location. Visual acuity, contrast sensitivity, corneal sensation, basic secretion
test (BST), tear film break-up time (TBUT), conjunctival and corneal staining,
and a subjective questionnaire were evaluated preoperatively and
postoperatively at 1 week, 1, 3 and 6 months. We observed a decrease in
central corneal sensation at all time point in both eyes compared to baseline
(Figure 19.1). The improved nasal sensation did not seem to change the
clinical outcome (Figure 19.2). Dry eye occurred with the same frequency
and there were no differences in the questionnaire. We observed a decrease
FIGURE 19.1: Illustrates the mean central corneal sensation (Cochet-Bonnet) in

nasal and superior hinge groups when compared to preoperative values (*p < .01)
FIGURE 19.2: Illustrates the mean nasal corneal sensation (Cochet-Bonnet) in eyes
with the nasal hinge when compared to those with the superior hinge (*p <. 01)
in BST at the first week visit in our patients. We also established that dry eye
and decreased corneal sensitivity affect many LASIK patients postoperatively
and that even six months following surgery, corneal sensitivity was significantly
decreased compared to preoperative measurements.
Our study showed that central corneal sensation was significantly depressed
in both groups for the entire six month duration of the study as illustrated in
Figure 19.1. This is compatible with results from several other studies.15,16,18,21
Figure 19.3 demonstrates a decrease in tear production at one week that
increased to normal levels at one month. The tear break-up time was also
reduced at the one week and one month visits (Figure 19.3). These alterations
FIGURE 19.3: Illustrates the mean basal secretion test and tear break-up
time scores, in nasal and superior hinge groups when compared to
preoperative values (*p <.05)
were shown to be subjectively important as patients reported increased dryness

using the subjective questionnaire at 1, 3 and 6 month postoperative visits.
Differences between nasal and superior hinge in corneal sensation and
dry eye have been previously studied,14,19 showing nerve fibers oriented in a
9-3 hour (temporal-to-medial) orientation. Our study demonstrated an
improved nasal corneal sensation at one month in the nasal hinge group but
found no difference in dry eye. This agrees with recent studies using in vivo
confocal microscopy that show that subbasal nerve fibers run in a 6-12 hour
(superior-to-inferior) orientation. Müller et al22 reported finding that leashes
extend across the corneal apex preferentially in the 6-12 direction while
other leashes approach the apex in the 5-11, 7-1, 9-3, 2-8 and 4-10 hour
direction.
The current description is that nerve bundles enter the cornea at the
periphery in a radial fashion parallel to the corneal surface. The majority of
the stromal nerve fibers are located in the anterior third of the stroma; however,
thick stromal nerve trunks move from the periphery towards the center below
the anterior third of the stroma due to the organization of the collagen
lamellae.22 Eventually the stromal nerve fibers turn abruptly 90° and proceed
toward the corneal surface. The nerves penetrate Bowman’s layer throughout
the peripheral and central cornea.23 After penetrating the Bowman’s layer,
the large nerve bundles divide into several smaller ones. Each small nerve
bundle then turns abruptly once more at 90° and continues parallel to the
cornea surface. The exact orientation and the depth of the deep nerve fiber
bundles is not entirely known and may be variable between patients.22-25
There is also a question as to how the nerves regenerate. Will nerve fibers
reinnervate the central cornea by growing up from underlying stroma, or
will peripheral nerves grow centrally? The pattern of regrowth could affect
the speed of reinnervation as well as our understanding of the potential
benefits of certain hinge locations. A potential important feature of LASIK is
that it spares the epithelium, the Bowman layer, a considerable proportion
of the anterior stromal nerve plexus and the corneal nerves in the hinge
region. Furthermore, the flap contains the original Schwann cell pathways,
which might facilitate the process of nerve recovery. Examination of the
regeneration of the subepithelial nerve plexus after LASIK has showed that
regenerating fibers appears first as short sub-basal leaches. Then by 3 months
they are elongated, but interconnections are not observed before the sixth
postoperative month.26 A prospective 5-year study demonstrated that sub-
basal nerve density in the central cornea, measured by confocal microscopy,
did not recover to near preoperative densities until 5 years after LASIK.27
Factors such as flap size, hinge width and depth of the flap play an
important role in the health of the corneal surface. Lamellar cutting of the
cornea during LASIK impairs corneal sensitivity and depth of the corneal
ablation affects the extent of loss of corneal sensitivity and recovery.26
Furthermore, the diameter of the flap and the ablation area may also have
an effect on the degree of corneal sensation loss and time for its recovery.
Deeper and wider ablation as well as a wider flap may cause a greater reduction
in corneal sensation.
CONCLUSION
It is important that surgeons avoid inducing dry eye after LASIK. To do this,
the entire corneal surface must be evaluated preoperatively including tear
secretion, mucous layer, and the meibomian glands. Each of these
components is essential for a healthy tear film and must be maximized prior
to surgery. Therefore, any treatment available for dry eye should be used
preoperatively to minimize this common finding postoperatively.
Successful surgery is dependent on not only the measured postoperative
visual acuity or quality of vision, but also the preoperative expectations of
the patient as determinants of overall satisfaction. It is therefore crucial that

every refractive surgeon discuss the indications, methods, possible risks,
limitations, and potential alternatives with his/her patient in advance of a
planned elective refractive procedure to accurately gauge the expectations
of the patient and recommend the best course, including possibly choosing
an alternative or deferring surgery.28
REFERENCES
1. Sandoval HP, Fernández de Castro LE, Vroman DT, Solomon KD. Refractive surgery
survey 2003. J Cataract Refract Surg 2005;31:221-33.
2. Martin X, Safran AB. Corneal hypoesthesia. Surv Ophthalmol 1988;33:28-40.
3. Lambiase A, Rama P, Aloe L, Bonini S. Management of neurotrophic keratopathy.
Curr Opin Ophthalmol 1999;10:270-6.
4. Joo MJ, Yuhan KR, Hyon JY, et al. The effect of nerve growth factor on corneal
sensitivity after laser in situ keratomileusis. Arch Ophthalmol 2004;122:1338-41.
5. Koenig SB, Berkowitz RA, Beuerman RW, et al. Corneal sensitivity after
epikeratophakia. Ophthalmology 1983;90:1213-8.
6. Shivitz IA, Arrowsmith PN. Corneal sensitivity after radial keratotomy.
Ophthalmology. 1988;95:827-32.
7. Kanellopoulos AJ, Pallikaris IG, Donnenfeld ED, et al. Comparison of corneal
sensation following photorefractive keratectomy in laser in situ keratomileusis. J
8. Matsui H, Kumano Y, Zushi I, et al. Corneal sensation after correction of myopia by
photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg
2001;27:370-73.
9. Patel S, Perez-Santonja JJ, Alio JL, et al. Corneal sensitivity and some properties of
the tear film after laser in situ keratomileusis. J Refract Surg 2001;17:17-24.
10. Benitez-del-Castillo JM, del Rio T, Iradier T, et al. Decrease in tear secretion and
corneal sensitivity after laser in situ keratomileusis. Cornea 2001;20:30-2.
11. Chuck RS, Quiros PA, Perez AC, et al. Corneal sensation after laser in situ
12. Wilson SE, Ambrosio R. Laser in situ keratomileusis-induced neurotrophic
epitheliopathy. Am J Ophthalmol. 2001;132:405-6.
14. Donnenfeld ED, Solomon KD, Perry HD, et al. The effect of hinge position on
corneal sensation and dry eye after LASIK. Ophthalmology 2003;110:1023-30.
15. Kumano Y, Matsui H, Zushi I, et al. Recovery of corneal sensation after myopic
correction by laser in situ keratomileusis with nasal or superior hinge. J Cataract
Refract Surg 2003;29:757-61.
16. Nassaralla BA, McLeod SD, Nassaralla JJ. Effect of myopic LASIK on human corneal
sensitivity. Ophthalmology 2003;110:497-502.
17. Lemp MA. Report of the National Eye Institute/Industry workshop on clinical trials
in dry eyes. CLAO J 1995;21:221-32.
18. Battat L, Macri A, Dursun D, et al. Effects of laser in situ keratomileusis on tear
production, clearance, and the ocular surface. Ophthalmology 2001;108:1230-
35.
19. Lee KW, Joo CK. Clinical results of laser in situ keratomileusis with superior and
nasal hinges. J Cataract Refract Surg 2003;29:457-61.
20. Vroman DT, Sandoval HP, Fernández de Castro LE, et al. Effect of hinge location on
corneal sensation and dry eye alter laser in situ keratomileusis for myopia. J Cataract
Refract Surg 2005;31:1881-87.
21. Toda I, Asano-Kato N, Komai-Hori Y, et al. Dry eye after laser in situ keratomileusis.
22. Muller LJ, Marfurt CF, Kruse F, et al. Corneal nerves: Structure, contents and function.
Exp Eye Res. 2003; 76:521-42.
23. Müller LJ, Pels L, VrensenGF. Ultrastructural organization of human corneal nerves.
24. Kim J, Foulks GN. Evaluation of the effect of lissamine green and rose bengal on
human corneal epithelial cells. Cornea 1999;18:328-32.
25. Müller LJ, Vrensen GF, Pels L, et al. Architecture of human corneal nerves. Invest
26. Bragheeth MA, Dua HS. Corneal sensation after myopic and hyperopic LASIK:
clinical and confocal microscopic study. Br J Ophthalmol 2005;89:580-85.
27. Erie JC, McLaren JW, Hodge DO, Bourne WM. Recovery of corneal subbasal nerve
density after PRK and LASIK. Am J Ophthalmol 2005;140:1059-64.
28. Jabbur NS, Sakatani K, O’Brien TP. Survey of complications and recommendations
for management in dissatisfied patients seeking a consultation after refractive surgery.
IODIDE APPLICATION BY IONTOPHORESIS AS ADJUVANT THERAPY IN DRY EYE PATIENTS 295
INTRODUCTION
Dry eye or tear film and ocular surface disorders are among the most frequent
ophthalmologic conditions. Approximately upto 20% of adults aged 45 years
or older report typical symptoms.1 In the United States the prevalence of
mild to moderate dry eye is approximately 10 million.2,3
Dry eye is related to a pathologic condition of anyone of the parts of a
functional unit including the tear film, the ocular surface (cornea, conjunctiva,
accessory lacrimal glands, and meibomian glands), the main lacrimal glands
and the interconnecting neural reflex loops.4 The origin of this disease is
believed to be multifactorial.5
The prevalence of dry eye has increased in recent years due to the general
aging of the population.2 This may also be due to additional factors, which
have exerted an increasing influence on the population. A lot of new medicines
such as antihypertensives, antihistamines, psychotropic drugs, and hormonal
replacement therapy are known to provoke or intensify tear film and ocular
surface disorders.6-8 Visual display terminal work leads to a reduction of the
blinking rate and thus to dry eye conditions.9 Poor indoor-air-quality such as
low humidity caused by fan heaters, air conditioning, and central heating
lead to an increase in the evaporation of tear fluid thus potentially damaging
the anterior part of the eye.10,11
Other studies revealed that dry eye was found more often outdoors in
polluted areas. Tear film abnormalities are present in a large number of people
staying within the metropolis of New Delhi.12 Versura et al observed a
relationship between ocular surface inflammation and urban pollution in
patients with typical dry eye symptoms.13
The increased air pollution in the course of the past 20 years may therefore
lead to the conclusion that oxidative reactions due to environmental
aggression are directly related to the pathogenesis of dry eyes.12-15
The depleted ozone layer is no longer able to act as an effective filter
against ultraviolet (UV)-light, allowing intensive UV-rays to reach the earth‘s
surface (Figure 20.1). Oxidative reactions induced by UV-light occur either
via a type I reaction, in which an excited irradiated sensitizer in the triplet
state directly reacts with a biological substrate by abstracting a proton or by
transferring an electron, or via a type II reaction in which the sensitizer reacts
with oxygen, thereby inducing a highly reactive excited singlet state oxygen,
or a superoxide ion.16 These factors may result in alterations of the eye surface
FIGURE 20.1: The depleted ozone layer allows intensive UV-rays to reach
the earth’s surface. In combination with exhaust fumes ground level
ozone is generated
and possibly in DNA changes of the conjunctival and corneal cells, thus leading
to their involution, to enzyme alterations, and finally to the development of
ocular surface disease.17-23
Tear fluid consists of a mucous layer, an aqueous layer and a lipid layer.
The interaction of all these components produces a stable tear film as needed
by the anterior part of the eye. Hyaluronate, a component of the mucous
layer of tear fluid and of tissues of the anterior part of the eye,24,25 is degraded
upon irradiation with UV-light.15,26 In this process, the macromolecule is
degraded to fragments of low molecular weight. Hyaluronate is not only
destroyed by UV-light, a change of the structure of the hyaluronate molecule
can also be observed by other oxidative systems such as ozone and cigarette
smoke.26,27
Also the proteins of the tear fluid are destroyed by ozone and UV-light,
whereby ozone and UV-light are especially aggressive in a combined form.15,28
Other pollutants containing damaging components such as cigarette smoke
and car exhaust fumes react in a similar way.29 Since lipids are also extremely
sensitive to oxidative reactions,30,31 all components of the tear fluid are
degraded by free radicals. Changes in the composition of the tear fluid caused
by high-energy ultraviolet light, ozone and other free radical producing agents
affect the interaction of tear fluid components so that the tear film ultimately
loses its stability.
Therefore, among a lot of different causes related to the development of

dry eye, oxidative reactions on the ocular surface may take part in the
pathogenesis of this disorder.14,15,32
It is well-established that inflammation itself such as occurring in dry eye
disease is also associated with a production of free radicals. Activated
leukocytes to which the conjunctiva and the cornea are exposed during
inflammation are known to produce large amounts of O2-. and H2O233 and
in the presence of iron the extremely toxic OH radical can be formed.34 In
addition, these free radicals play a significant role in the intensification or the
perpetuation of inflammation due to the generation of chemotactic factors.35
Reactive oxygen species (ROS) stimulate TNF-α synthesis21,36 an important
pro-inflammatory cytokine over-expressed in dry eye. ROS also activate
apoptosis.37-39 An apoptosis imbalance may also play an important role in
tear film and ocular surface disorders.40-42 These observations demonstrate
the close interaction between inflammation, apoptosis and oxidative reactions
on the ocular surface.
ANTIOXIDATIVE PROTECTIVE MECHANISMS

The eye protects itself from radical injury by endogenous antioxidant enzymes,
such as superoxide dismutase, catalase, and glutathione peroxidase.43,44 Also
lactoferrin and lysozyme show antioxidative activities.45-47 Further antioxidants
such as uric acid and ascorbic acid are present in tear fluid.48
If the eye is exposed to excessive oxidative stress, the scavengers normally
present in the tear fluid are exhausted and apparently no longer capable of
preventing damage. Therefore, increasing the antioxidative capacity of the
ocular surface and the tear film by supporting the natural defence mechanisms,
additional antioxidants might be of interest in dry eye patients. Ophthalmic
hydrogels possess antioxidant properties and reduce ROS.49 Artificial tear
preparations containing a mixture of vitamin A, C and E as well as iodide
also confirmed the efficacy of preparations containing free radical scavengers.50
The polysaccharide from the plant Tamarindus indica protects cultured corneal-
derived cells from oxidative damage caused by ultraviolet rays.51
IODIDE
Iodide, a reducing agent and electron donor has been demonstrated acting
as an oxygen-free-radical-scavenger in vitro and in vivo.52-58
For the eye, iodide-containing brine has been used in Bad Hall (Austria)
against different eye diseases, including chronic conjunctivitis and incipient
cataract for many years.
In vitro, iodide has been shown to provide a significant protection of
hyaluronate, a component of tear fluid and tissues of the anterior part of the
eye against UVB-light-induced oxidative degradation.59
Also injury of human conjunctival cells can be prevented by incubation
with iodide before UVB irradiation as shown by the preservation of the
mitochondrial activity with the MTT assay.59
Peroxidase activity, which can scavenge H2O2 in the presence of a suitable
substrate, has been detected in human tears.14 Iodide has been found to
increase peroxidase activity.55
The mechanism of protection by iodide is likely to include an antioxidative
action as discussed by several authors.52,53,55,57
For therapeutic management iodide containing eye drops, eye baths,
aerosols, and especially iontophoresis can be used.
IONTOPHORESIS
In dry eye disease, instillation of artificial tears is the most frequent prescribed
therapy, but topically applied substitutes are rapidly eliminated from the
precorneal area. In addition, the cornea is the major pathway for penetration
of topically applied drugs, but the epithelium is an effective barrier to prevent
accumulation of active substances. To reduce the frequency of instillation
without lack of therapeutic effects would increase the comfort of the patients.
Modification of the formulation of the artificial tears, plugging of the lacrimal
puncta or the utilization of reservoir systems increase the duration of the
contact to the cornea.
Iontophoresis utilizes a low current to drive charged molecules across
tissue barriers for delivery of therapeutic drug concentrations to the inner
eye and to facilitate ion penetration into tissues (Figure 20.2).60
Several applications of iontophoresis in experimental and clinical ophthal-
mology, particularly for the treatment of bacterial or viral infections, and
inflammations have been reported.61-66
Transcorneal and trans-scleral iontophoresis of antibacterial, antifungal,
anti-inflammatory and antiangiogenetic agents have been performed.61-67
FIGURE 20.2: Scheme of the iontophoresis device
Studies demonstrated that increased amounts of iodide can be transferred

into all ocular tissues by means of iontophoresis, especially to the anterior
segment.68-71
The optimal values of current and time for iontophoresis are still on debate.
Several variables, including the charge of the molecule, the molecular weight
of the drug and its lipid solubility are of importance in enhancing penetration
of the ionised drug into the tissue during iontophoresis. Other important
variables are the current density, the duration of the procedure, and the
concentration of the drug in the solution.60,72 Using controlled iontophoretic
parameters and a low current density side effects can be avoided.73
Other biological effects of iontophoresis are still unknown. Iontophoretic
application may influence the metabolic processes in the ocular tissues. There
are clinical observations demonstrating that the application of exogenous
electric fields enhances wound healing. It is known that many types of cells
respond to weak direct-current electric fields with a cellular reorientation and
migration.74
CLINICAL STUDIES
In a current study we investigated the capability of iodide to influence dry
eye syndrome in an iontophoresis system and in a control group of iodide
application without current.75
This prospective study evaluated 56 eyes of 28 consecutive patients with
moderate to severe dry eye disease with and without Sjögren’s syndrome
before and after iodide treatment with a 3-month follow-up period. Sixteen
patients received iodide treatment with current (iontophoresis) and 12 patients
without (mock iontophoresis). A 0.5% sodium iodide solution at pH 8.0 was
used. The ocular surface applicator of the iontophoretic apparatus (Erbe,
Tübingen, Germany) was used as the cathode as iodide is negatively charged.
A platinum electrode is in contact with the iodide solution but not with the
surface of the eye. An eye probe was used which covers the cornea, the
conjunctiva and the lids (Figure 20.3).
The positive pole (anode), which is the indifferent or ground electrode, is
held in one hand of the patient. The iontophoresis protocol of this study was
FIGURE 20.3: The ocular surface

applicator of the iontophoretic
apparatus
based on the protocol used by Pommer and Trichtel.70,71 Iontophoresis was

applied at a constant direct current of 0.2 mA for 7 minutes. Ten treatments
were applied to both eyes over a 2-week period. Mock iontophoresis was
applied under the same conditions but no current was passed.
During the application of sodium iodide solution with the iontophoresis
apparatus the eyes of the patients could easily kept open in the solution. Slit-
lamp examination after iodide treatment showed slight conjunctival injection
in all eyes immediately after removal from the eyecup. The injection
disappeared within one hour. No corneal edema or increase in epithelial
damage was observed during any examination period after iontophoresis.
A reduction in subjective symptoms, frequency of artificial tear substitute
application and an improvement in tear film and ocular surface factors could
be observed in both groups. A stronger positive influence of iodide was seen
after the application of iodide with current (iontophoresis) as observed in a
distinctly higher improvement in break-up time, fluorescein and rose bengal
staining and in a longer duration of this improvement as compared with the
non current group.
Although a low level of passive diffusion of iodide application without
current may occur, our results suggest the clinical advantage that the dosage
is apparently much more consistent when iodide is transferred into the eye
with the use of the electric potential. Iodide delivered with iontophoresis
penetrates into deeper layers, can increase the amount of iodide in the tissues
of the ocular surface, and may result in a depot effect explaining the sustained
improvement seen after a longer period of up to 3 months.76 The longer
duration of clinical efficacy in our patients after iontophoretic delivery may
indicate that iodide binds to some of the tissue components such as collagen.
Patients with typical dry eye symptoms reported an improvement in their
subjective conditions and a reduction of the frequency of tear substitution
after taking a course of iodide treatment including iontophoresis in Bad Hall
(Austria).77,78
We assume that iodide application might contribute to the antioxidant
potential in tear fluid and in ocular tissues. This was confirmed by measuring
the antioxidative status in human tears. An increase of the antioxidative status
in tear fluid was observed in patients receiving a 3-week iontophoresis
treatment with iodide containing brine.57 This increase was still evident
6 months after therapy.79
Summarizing, iodide has shown a positive influence in patients with dry

eye disease. Further investigations regarding the biological properties and
efficacy of iodide applications are in progress.
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ALLERGIC OCULAR SURFACE DISEASES AND ITS MANAGEMENT 307
INTRODUCTION
Allergic ocular disease is one of the most common problems seen by
ophthalmologists worldwide. The allergic disease can involve several type of
reactions which varies from mild intermittent tearing characteristics of seasonal
and perennial allergic conjunctivitis (SAC) to more constant itching and mucoid
discharge of vernal keratoconjunctivitis (VKC) and ultimately to the vision
threatening corneal scarring of atopic keratoconjunctivitis (AKC). New and
effective treatment of allergic conjunctivitis depends on clear understanding
of the underlying pathophysiology. Ocular allergy respresents a variety of
problems that are primarily type-1 hypersensitivity reactions (IgE mediated)
with the cell mediated or type IV hypersensitivity response playing a role in
some of these disorders. Patients with atopic disease may also have deficient
immunoregulation with depressed T cell function that results in systemic
involvement. Appropriate treatment should be prescribed to the ocular and
systemic involvement and should consider this underlying defect in T cell
function.
Histamine release can cause a variety of uncomfortable symptoms and
sometime life-threatening complications. Drug therapy is successful in
satisfactorily relieving associated signs and symptoms when ocular tissues are
affected. Pathophysiology of allergic ocular diseases is being mentioned here
for better understanding of ocular allergy and antiallergy medication.
TYPE-1 HYPERSENSITIVITY REACTIONS

It is also known as anaphylactic, immediate or IgE mediated reactions which
occur when an antigen such as a pollen, drug is reintroduced into the individual
who has been previously exposed to the antigen. Upon initial exposure to
antigen, IgE antibodies are produced which get attached to mast cells and
make the cells susceptible to rupture when the patient is again exposed to
same antigen. Disruption of mast cells cause a release of large quantities of
inflammatory mediators including histamine and histamine activates H1
receptors on blood vessels causing vasodilation. These dilated vessels leak
fluid causing tissue to swell. Common clinical signs and symptoms of type-1
reaction include redness swelling and itching. Such reactions occur in allergic
conjunctivitis. The following ophthalmic diseases are characterized by type-1
hypersensitivity reactions.
Clinical Response
Seasonal Allergic Conjunctivitis
Seasonal allergic conjunctivitis is a recurrent condition that occurs secondarily
to the contact with allergens present in the air such as pollen grasses, trees,
house dust, mites, etc. It can be associated with systemic conditions like hay
fever. This is the classical type I hypersensitivity. It presents in any age but it is
more common in adulthood. Increased number of eosinophils and mast
cells is seen in predisposed patients. The allergen in contact with IgE antibodies
in the conjunctiva attached to the mast cell and induce its degranulation
releasing multiple mediator such as: histamine, prostaglandin, leukotrienes
and platelet activating factor.
The symptoms are itching which is the most prominent, chemosis, dilated
conjunctival vessels, burning and lid edema (Figure 21.1). An Acute reaction
can present with clear or white exudate, whereas a chronic reaction may be
characterized by mucopurulent exudate. A papillary conjunctival reaction
associated or not with punctate keratitis may occur.
The diagnosis is made with detailed anamneses, family history, and careful
examination. Many are mild and can be misdiagnosed. A conjunctival smear
shows the presence of eosinophils and raised tear or serum total IgE can be
seen.
The treatment includes avoidance of the causing allergen when possible
and desensitization. Symptomatic treatment is done with topical antihistamines,
mast cell stabilizers, and nonsteroidal anti-inflammatory drugs. In mild cases
FIGURE 21.1: Seasonal allergic conjunctivitis

a vasoconstrictor associated with an anti-histamine may give good result. To

decrease the recurrence of the disease the use of mast cell stabilizer before
the allergic season are useful. Systemic antihistamine can give a symptomatic
treatment in selected cases.
Vernal Keratoconjunctivitis (VKC)

Vernal conjunctivitis is a disease seen more often in males than females with
an onset between the ages of five to ten years old with a range from 3 to 25.
It is more common in warm climates and usually there is a personal and
family history of atopy. Patients can present symptoms during the whole
years with a worsening in the spring and summer. Both type I and IV reactions
are involved in the pathophysiology.
The clinical signs include itching, tearing, burning, photophobia, ptosis,
blepharospasm, redness, chemosis, and papillae often giant in the upper
tarsus. There is three type of clinical presentation: palpebral, limbic and mixed.
In the palpebral form, the presence of cobblestone papillae in the upper
tarsus is a frequent sign (Figure 21.2). It is a proliferative disease with the
formation of hyaline and hyperplastic tissue. A sign of worst prognosis is the
occurrence of papillae in the lower tarsus. Fibrin formation and symblepharon
are seen in severe cases. The bulbar form may present with thickness and
enlargement of the limbus with the presence of gelatinous nodules in the
palpebral fissure and superior limbus, which we are, called Trantas dot. A
mixed form with signs of both palpebral and limbic is seen. The limbic form
is more common in pigmented people and palpebral in white people. Mild
FIGURE 21.2: Vernal keratoconjunctivitis

corneal involvement like a superficial keratitis, usually superior, is often seen.

In worse cases, a shield ulcer with indolent course characterized by sharp
edges, a gray color is usually seen in the superior cornea. Because patients
often rub their eyes energycally, vernal conjunctivitis is also related with
keratoconus. Severe VKC in developing countries is a potentially blinding
disease. Visual loss is associated with corneal complications, like scar,
astigmatism and keratoconus, as well as complications of topical corticosteroids.
Many cases of vernal keratoconjunctivitis have a spontaneous resolution
if we avoid iatrogenic conditions and possible allergens. Moving to cooler
climate or using air-conditioning is useful in many cases. The use of cold
compresses is recommended in all cases. Prolonged use of topical mast cell
stabilizer is useful to prevent recurrence. In acute phases the use of topical
antihistamine, topical nonsteroidal antiinflammatory drugs (NSAIDs) and in
selected cases steroids are important. In refractory or chronic cases topical
cyclosporine A 2% could be sight saving. Cases with shield ulcer should be
treated and followed carefuly. Sometimes bandage contact lens, papillae
resection or tarsorrhaphy is needed.
Atopic Keratoconjunctivitis (AKC)

Usually associated with systemic atopy (rhinitis, asthma, and eczema), atopic
keratoconjunctivitis is more frequent in males and occurs in adulthood with
the peak ranging from 30 to 50 years old. It is a disease that has a potential
for blindness. It is mainly a Th2 response to allergens (airborne, foods, etc)
and there is an imbalance between Th1 and Th2 lymphocytes.
Atopic keratoconjunctivitis shares many features with vernal
keratoconjunctivitis however may present more fibrosis. It is characterized
by atopic dermatitis of the lid, papillary conjunctivitis, disruption of corneal
epithelium and in severe cases corneal and conjunctival scarring and
vascularization (Figure 21.3). The skin of the lid is thickened. Cicatrization of
the skin and lid margin and symblepharon formation could occur. AKC is
associated with cataract, often steroid induced, and keratoconus. Patients
usually complain about acute and bilateral itchiness, burning, tearing,
photophobia and blurred vision. Transtas dot, blepharitis and inflammation
of the meibomian gland may be present. Tearing can be secondary to punctual
occlusion and loss of the inferior cul-de-sac. Mucopurulent discharge is often
present, especialy when a secondary staphylococcal infection is present. Patients
with AKC have an increased susceptibility to develop herpes simplex infection,
FIGURE 21.3: Atopic keratoconjunctivitis
as there is an imbalance between Th1 and Th2 cells, with a predominance of

Th2 response.
To prevent iatrogenic disease and to release symptoms appropriate
treatment should be given. Systemic and topical antihistamine, cold compress,
artificial tears may control the symptoms howeveer topical or systemic steroids
are needed in severe cases and should be used only for a short period of
time to avoid iatrogenic complication. Topical cyclosporine A could be used
in severe cases much more rarely. Mucolytic agents are useful in cases of
severe mucus production.
Giant Papillary Conjunctivitis

Giant papillary conjunctivitis (GPC) is most often associated with contact lens
wear, but has also been described in patients with ocular prosthesis and
corneal sutures. There is a strong association with hydrogel contact lens
presence of atopy and is more common in younger patients. GPC results
from mechanical and immune mechanisms to substances that are deposited
on the surface of the foreign body. The immune mechanism is far from
being understood, however both type I and IV (delayed type) hypersensitivity,
contribute to the pathogenesis of giant papillary conjunctivitis. Increased level
of leukotrienes C4 (LTC4) and decreased level of lactoferrin in tears is seen in
patients with GPC.
Symptoms can vary from mild to intense like mild hyperemia of the upper
tarsal conjunctiva with strands of mucus streaking the otherwise smooth
conjunctival surface, to the presence of milky-white discharge covering broad
FIGURE 21.4: Giant papillary conjunctivitis
areas of giant papillae (Figure 21.4). As the disease progresses, infiltration by

inflammatory cells continues and the conjunctiva acquires a more opaque
appearance. Signs such as abnormal large conjunctiva papillae, excess mucus
production and hyperemia are usually present. An obvious sign is the presence
of enlarged papillae, usualy greater than 0.3 mm in diameter, on the upper
conjunctiva.
The frequency at which patients replace their contact lens appears to be
an important variable in developing GPC. Although frequent replacements
do not eliminate this condition, patients on one day to three weeks
replacement cycle has significantly lower risk to develop GPC.
In most of the cases, it is not necessary to discontinue the use of contact
lens. Just removing the causing agent, eliminates the symptoms, however in
the cases of contact lens wearers and in cases secondary to prosthesis, the
main goal is to decrease and control the symptoms. In the case of contact
lens wearers, one option is to change the material to rigid contact lens that
has lower risk in developing GPC. Improvement in methods of cleaning is
another step, changing for a solution without preservatives. The use of topical
mast cell stabilizer and topical NSAIDs could increase the tolerance.
HYPERSENSITIVITY REACTION TO DRUGS

Allergic or hypersensitivity reaction to a drug or its metabolites is an immune-
mediated reaction that requires previous exposure to the same or chemically
related drug and it can develop rapidly after exposure. It occurs in a small
number of patients and can produce clinical syndromes that are commonly
associated with immune reaction.
The sensitization can occur by any route of administration. Topical
administration has the greatest risk and favors the production of delayed
type hypersenstivity (Th1). On the other hand, oral and nasal has the lower
risk and favors the production of Th2 response. Many topical drugs can
cause allergic reaction in the eye such an anesthetics, antibiotics, autonomic,
antihistamine, steroids, metals, antiseptic, preservatives, vehicles, in short,
practically anything.
Ocular allergy related to drugs is mediated by Th1 and also by Th2 cells.
Th1 related is a relative common cause of drug inducing keratoconjunctivitis.
Patients complain of itching (but no as prominent as in Th2 related) and
tearing. The conjunctivitis is characterized by papillary reaction with the
presence of mucus or mild mucopurulent discharge. Initially the conjunctivitis
is worse inferonasally and inferior, where drugs tend to accumulate, but it
become diffuse after a time. The cornea usually shows punctate epithelial
keratitis and erosions. It may be diffuse but are usually worst in the lower
two-third of the cornea. Marginal ulcer rarely occurs, when present is close
to the limbus and is characterized by cellular infiltrate in the superficial stroma.
In severe cases the conjunctiva may develop mild keratinization. Punctal
edema, stenosis and occlusion may also occur.
Th2 related disease may also occur. It may be acute or chronic. The acute
form is characterized by rapid onset and consists of tearing, itching, redness
and burning. The conjunctiva is chemotic and hyperemic. The chemosis
may be so prominent as to obscure the hyperemia, so that the over all
appearance is one of milky edema rather than redness. Mucus discharge
appears rapidly. On the other hand, the chronic form manifests the same
signs and symptoms, except that they are less impressive and usually mild.
Mild papillary hypertrophy may appear and the discharge occassionally
became mildly mucopurulent. The cornea is rarely involved.
It is important to know that a prolonged allergic reaction may cause scaring
and cicatrization of the conjunctiva, and, therefore, it is of great importance
to identify the process as early as possible, especially in cases where nature of
the ophthalmologic problem precludes the discontinuation topical therapy.
Present day, ophthalmologists and their patients have a great variety of
topical medications for the treatment of a wide diversity of ocular diseases,
but these drugs should be regarded without judgement. Many of these drugs
can cause annoying, clinically confusing, and sometimes serious adverse effects.
Rational prescription must be based on specific diagnosis and indication (as
opposed to “shotgun therapy”). The indiscriminate use of medication is
appropriate to do more harm than good.
ANTIALLERGY MEDICATION
Since much of the symptomatic picture of type-1 hypersensitivity reactions is
caused by histamine release from mast cells, antihistaminics are usually
effective in relieving annoying symptoms. These agents are usually given
with decogestants and are given topically or systemically depending upon
the degree of involvement. Mast cell stabilizers are also very effective and
can be given prophylactically.
Current treatment options include non-drug therapy, pharmacotherapy
and immunotherapy. Initially attention is directed at identifying the offending
allergen and eliminating it whenever possible.
Mild symptoms of itching and discomfort can be relieved with cool
compresses and artificial tear/saline irrigation of the eyes (nondrug therapy).
More intense signs and symptoms usually require pharmacotherapy,
immunotherapy or both.
Current ocular therapy emphasises the use of topical medication to alter
mediator production, release or end organ. Although more potent mediator
antagonists are becoming available, simultaneous control of all mediators is
difficult. The antiallergy medication is broadly classified into following
categories:
1. Topical mast cell stabilizers
2. Antihistamines combinations
i. Topical antihistamines—vasoconstrictor
ii. Topical high potency antihistamines
iii. Oral antihistamines
3. NSAIDs
i. Topical NSAIDs
ii. Systemic NSAIDs
4. Topical steroids
5. Topical immunosuppressors.
TOPICAL MAST CELL INHIBITORS

Topical mast cell inhibitors are one of the most commonly used antiallergy
agent in the ophthalmology worldwide.
Mast cell stabilizers act by preventing calcium influx into the mast cells
and basophills thus preventing the cascade that results in degranulation.
These are potent H1 receptor antagonists. Once these mast cell inhibitors
are bound to a membrane receptor, they prevent IgE cross linking and thus
stabilizes the entire excitation process. Their mechanism of action also involve
increasing intracellular cyclic adenosine monophosphate levels thereby
reducing calcium influx or by inhibiting the enzyme nucleosides disphosphate
kinase in the cytoplasm.
Mast cell stabilizers can also act by inhibiting the release of neuropeptides
from sensory nerve endings. The various agents of this group used in
ophthalmology are as follows:
Cromolyn Sodium (Sodium Cromoglycate)

Indications: In the treatment of allergic ocular disorders including vernal
keratoconjunctivitis giant papillary conjunctivitis, vernal keratitis and allergic
keratoconjunctivitis.
Cromolyn sodium inhibits the degranulation of sensitized mast cells and
basophills which occur after exposure to specific antigens thus inhibiting the
release of histamine and SRS-A (slow reacting substance of anaphylaxis)
from the mast cell. It has no intrinsic vasoconstrictors, antihistamines or anti-
inflammatory activity (Figure 21.5).
Cromolyn sodium is poorly absorbed and approximately 0.03% of
cromolyn is absorbed following topical administration to the eye. Systemically
absorbed drug is excreted unchanged in the urine.
Contraindications: Hypersensitivity to cromolyn or to any component of its

product. Patients are advised not to wear soft contact lenses during cromolyn
sodium treatment.
Dosage: It is available as topical ophthalmic solution in strength of 2% and

4% (in 5 ml and 10 ml vials) usual dosage is to instill 1-2 drops in each eye
4-6 times a day at regular intervals till the desired effect is obtained. It is
effective alone or in combination with other antiallergy drugs (Topical or
systemic).
FIGURE 21.5: Mechanism of action of sodium cromoglycate
Symptomatic response to the therapy is usually evident within few days

but treatment should be given upto 6 weeks or more. Effect of therapy
depends upon administration at regular intervals. Continue therapy as long
as needed to sustain clinical improvement. Topical corticosteroids can be
used concomitantly with cromolyn sodium.
Adverse reactions: The most frequent adverse reaction reported is ocular

stinging or burning sensation upon instillation which usually regresses with
continued use. So patient should be initially warned about this reaction before
starting the treatment. Other adverse effects reported are conjunctival injection,
watery, itchy and puffy eyes, dryness around eyes, irritation styes.
Disodium Cromoglycate
Disodium cromoglycate (DSCG) is the prototype mast cell stabiliser. It is
used widely and is effective to varying extents in different ophthalmic allergic
disorders. In vernal keratoconjunctivitis DSCG is more effective in treating
signs and symptoms in children and adults. This agent is also effective in
other forms of allergic conjunctivitis (GPC and AKC). It is safe and well-
tolerated. It is given topically.
It has been shown that DSCG can prevent the reflex stimulation of primary
afferent nerve fiber endings initiated by capsaicin a compound capable of
causing the release and depletion of neuropeptides. DSCG is also known to
inhibit activation of neutrophils, eosinophils and monocytes and to prevent
neutrophil chemotaxis.
Lodoxamide
It is most potent topical mast cell inhibitor. Lodoxamide is 2500 times more
potent than cromolyn sodium. It effectively prevents histamine release from
mast cells during immediate hypersensitivity reactions.
Lodoxamide significantly reduces recruitment of neutrophils and
eosinophils and prevents mast cell degranulation. Inhibition of leukocyte,
monocyte and eosinophils activation by mast cell stabilizers is important in
modifying the allergic inflammatory response. It stabilises the mast cell response
in vernal conjunctivitis and has dual mechanism of action.
Indications: It is highly effective in treatment of vernal keratoconjunctivitis

(VKC), giant papillary conjunctivitis (GPC) and atopic keratoconjunctivitis
(AKC). Lodoxamide is more efficacious than DSCG with earlier improvement
of signs and symptoms. It is most effective in VKC and for sustained relief of
signs and symptoms and treatment of corneal complications.
Dosage: It is available as 0.1% ophthalmic suspension (Lodoxamide

tromethamine) usual dosage is to instill 1-2 drops in the affected eyes 4 times
a day throughout the year.
Adverse reactions: No serious adverse effects have been reported with topical
lodoxamide use except for transient burning and stinging sensation, ocular
itching, dry eye, blurred vision tearing/discharge, hyperemia, crystalline
deposits, foreign body sensation, rarely chemosis, corneal abrasion, keratitis,
blepharitis, allergy, etc. which regresses with regular and continuous use of
lodoxamide. Topical preparation should be instilled at regular intervals for
better response.
Other new mast cell inhibitors that are on trials and shall be available
commercially shortly.
Nedocromil
It is a disodium salt of pyranoquinoline dicarboxylic acid.
It has been reported more effective in vernal keratoconjunctivitis.
Nedocromil prevents chemotactic and inflammatory mediator release from
the effector cells such as granulocytes, monocytes, macrophages and mast
cells. In comparison to DSCG, nedocromil is more effective in controlling
symptoms of VKC and SAC. In GPC nedocromil is effective in reducing
itching and mucous discharge.
It is tried in conc of 1% to be given 1-2 drops 4 times a day. No serious

side effects have been reported with the use of this drug.
Ketotifen Fumarate
Ketotifen is a relatively selective, noncompetitive histamine antagonist (H1
receptor and mast cell stabilizer). Ketotifen inhibits the release of mediators
from cells involved in hypersensitivity reactions. Decreased chemotaxis and
eosinophil activation have also been shown.
Indications: It is indicated for the treatment of allergic conjunctivitis of diverse

etiology.
Dosage: It is available as 0.025% topical solution (0.25-0.345 mg/ml ketotifen

fumarate) in 5 and 7 ml packs.
Recommended dose is to instill one drop in each affected eye every 8-12
hours. This solution is for topical ophthalmic use only. It is not recommended
for injection or oral use.
It is contraindicated in patients who are hypersensitive to any component
of the product.
Adverse reactions: Generally topical ketotifen solution is safe for ophthalmic

use. However, in less than 5% of patients following ocular adverse affects
may appear.
Burning or stinging sensation, allergic reaction, conjunctivitis, discharge,
dry eyes.
Keratitis, lacrimation disorder, photophobia and rash. General adverse
effects may include flu syndrome, pharyngitis.
In pregnant, lactating mothers and children below 3 years of age its use is
not generally recommended.
Olopatadine Hydrochloride
Olopatadine is a new agent that exerts both mast cell stabilization effect and
an antihistaminic effect. It is highly potent and a relatively selective H1-receptor
antagonist that inhibits in vivo and in vitro the type-I immediate hypersensitivity
reaction. It has no effect on alpha-adrenergic dopamine muscarinic type-1
and 2 and serotonin receptors.
Olopatadine has been reported to have low systemic exposure following
topical ocular administration. Clinical trials have shown that it has more than
90% inhibition of basophil and mast cell degranulation and histamine-induced

conjunctival vascular permeability.
Olopatadine is indicated for the treatment of allergic conjunctivitis of
diverse etiology.
Dosage and administration: Olopatadine is available as 0.1% topical

ophthalmic solution in 5 ml vial. The recommended dose is 1-2 drops in
each affected eye 3-4 times per day (every 6-8 hours).
Olopatadine ophthalmic solution is available for topical use only. Not for
injection. It is contraindicated in those patients who are hypersensitive to any
component of this product.
Patients are instructed not to wear contact lenses during treatment with
olopatadine. In pregnant, lactating mothers and children below 3 years of
age, its use is not generally recommended.
Adverse reactions: Ophthalmic adverse effects reported are burning or stinging

sensation, dry eye, foreign body sensation, hyperemia, keratitis, lid edema
and pruritus.
Systemic effects include headache, asthenia, cold syndrome, pharyngitis,
sinusitis and taste perversion.
Azelastine Hydrochloride
Azelastine is a phthalazinone derivative of noval with histamine H1-receptor
antagonist activity which also inhibits mast cell histamine release, has some
leukotriene and platelet aggregating factor (PAF) antagonistic activity and
inhibits IgE-mediated inflammation in vivo.
While the inhibition of itching of the eyes in allergic patients by azelastine
eyedrops is certainly due to inhibition of the release and actions of histamine,
the inhibition of conjunctival redness is likely to be the result of a combination
of the various anti-inflammatory actions of azelastine. Due to its multiple
activities azelastine is classified as an antiallergic and anti-inflammatory agent
rather simply as an antihistamine.
Azelastine is a highly selective H1-receptor blocker with a very low affinity
for both β-receptors and muscarinic receptors. Topical azelastine reduces the
neutrophil and eosinophil infiltrate following a single antigen challenge in
patients with seasonal allergic diseases. Interleukocyte adhesion molecule-1
(ICAM-1) expression is also reduced on epithelial cells.
Desmethyl azelastine, a metabolite of azelastine is pharmacologically active

and probably contributes to the activity of the parent compound.
Indications: Azelastine is indicated for the treatment of seasonal allergic

conjunctivitis.
Dosage and administration: It is available as 0.05% topical ophthalmic solution

in 5 ml vial.
Recommended dosage is to instill one drop in each affected eye twice
daily. Dose can be increased to 4 times a day depending upon the severity of
the condition. Topical azelastine is generally not recommended for pregnant,
lactating mothers and children.
Adverse reactions: Local adverse effects include burning and tingling sensation,
local irritation, etc.
Systemic effects include metallic or bitter taste in mouth (dysgeusia), hot
flushes, epistaxis, etc. bitter taste may disappear quickly.
The other mast cell inhibitors that are on ophthalmic clinical trials are:
• Nicotinamide
• Picumast
• Calmodulin antagonists.
Hopefully these compounds shall appear in commercial market shortly.
The other mast cell inhibitors that are on ophthalmic clinical trials are:
• Nicotinamide
• Picumast
• Calmodulin antagonists.
Hopefully these compounds shall appear in commercial market shortly.
ANTIHISTAMINES
Antihistamines are histamine H1-receptor antagonists and cause sympatho-
mimetic vasoconstriction. First and second generation antihistamines are being
used either topically or systemically in the treatment of various ocular allergic
disorders.
H2 receptors have also been indentified on the ocular surface.
H1 receptors are involved primarily with neuronal tissue and H2 receptor
with vascular tissue, thus combination drops containing both H1 and H2
receptor antagonists have been found more useful in treatment of allergic
eye diseases.
Various topical antihistamine available in combination for ophthalmic use

are pheniramine maleate, pyrilamine maleate, antazoline and levocabastine.
1. Pheniramine maleate 0.3% ophthalmic solution in combination with
0.025% naphazoline HCl (in 10 ml and 15 ml packs).
2. Pheniramine maleate 0.5% ophthalmic solution with 0.125%
phenylepherine HCl (in 10 ml and 15 ml packs).
3. Pyrilamine maleate 0.1% ophthalmic solution with 0.12% phenylephrine
HCl and 0.1% antipyrine (in 10 ml and 15 ml packs).
4. Antazoline 0.5% ophthalmic solution with 0.05% naphazoline HCl (in 15
ml packs).
5. Antazoline 0.5% ophthalmic solution with 0.05% naphazoline HCl (in 15
ml packs).
6. Topical Levocabastine HCl 0.05% ophthalmic suspension available without
decongestant.
7. Tetrahydozoline 0.05% ophthalmic solution with zinc sulphate (0.25%).
8. Emedastine difumarate topical ophthalmic solution (0.05%).
Usual dosage for various topical antihistamines combinations is to instill
1-2 drops in the affected eyes 3-4 times daily till the desired response is
obtained.
Levocabastine Hydrochloride
Levocabastine is a potent, selective histamine H1-receptor antagonist for topical
ophthalmic use. It has rapid onset and long duration of action.
It has been shown to effectively control the symptoms of allergic
conjunctivitis. It is 15000 times more potent than pheniramine and more
effective than cromolyn sodium. It provides relief within minutes and block
histamine the primary mediatory for type, response to allergy and is safe and
comfortable.
It is indicated for use in the treatment of seasonal allergic conjunctivitis.
Dosage and administration: Levocabastine is available as 0.05% ophthalmic

suspension in 2.5, 5 and 10 ml bottles. The recommended dosage is to
instill one drop in the affected eye 4 times daily. Treatment may be
continued upto 2 weeks. Levocabastine instilled 4 times daily is significantly
more effective than its vehicle in reducing ocular itching associated with allergic
conjunctivitis.
In pregnant, lactating mothers and in children below 12 years topical

levocabastine is generally not recommended.
Adverse reactions: The most frequent ocular adverse reactions reported with
it are mild transient stinging and burning sensation, visual disturbances, eye
pain or eyelid edema.
Systemic effects include headache, dry mouth, fatigue, pharyngitis, cough,
nausea and dyspnea.
Emedastine Difumarate
Emedastine is a relatively selective histamine H1 antagonist. Clinical studies
have shown concentration dependent inhibition of histamine induced increase
in conjunctival vascular permeability in the conjunctiva following topical ocular
administration.
Following topical administration emedastine has low systemic exposure.
Indications: Emedastine is indicated for topical use in the treatment of allergic

conjunctivitis.
Dosage and administration: Emedastine is available as topical 0.05%

ophthalmic solution in 5 ml opaque plastic dispenser.
Recommended dosage is to instill one drop in the affected eye four times
a day.
It is generally not recommended for use in pregnant, lactating mothers
and children below 3 years of age.
Adverse reactions: Headache, asthenia, blurred vision, burning or stinging

sensation, corneal infiltrates, corneal staining, discomfort, dry eyes, keratitis,
pruritus, sinusitis and hyperemia.
Topical impiramine which has H1 and H2 receptor blocking activity is on
trials. It has been shown to be highly effective in reducing signs and symptoms
in the conjunctival challenge test in patients with seasonal allergic conjunctivitis.
A variety of topical antihistamine and decongestant (vasoconstrictor)
combinations are available. But with the emergence of high potency H1-
receptor antagonists, these agents are playing a lesser role in the treatment
of allergic eye diseases. Before discussing systemic antihistamines it is
worthwhile to discuss decongestants used in treating allergic disorders in
combination with topical antihistamines.
Decongestants
These are adrenergic agonists with direct vasoconstrictive activity. This
vasoconstrictor effect (Phenylephrine and imidazole derivatives) makes them
useful as topical ocular decongestants. Following instillation, the conjunctival
vessels constrict within minutes causing the eye to normal white color.
Due to relatively low concentrations required for ocular decongestion,
phenylephrine and imidazole derivatives generally do not cause systemic
side effects.
Phenylephrine
It is a synthetic amine structurally similar to epinephrine and is present in
several topical commercial preparations. Concentration of 0.12 or 0.125%
cause vasoconstriction with little or no pupillary dilation in eyes with intact
corneal epithelium.
Phenylephrine is contraindicated in eyes predisposed to angle closure
glaucoma. Prolonged or excessive use may result in rebound conjunctival
hyperemia. Phenylephrine solution can exhibit variable effectiveness since
they are subject to oxidation on exposure to air, light or heat. Antioxidants
like sodium bisulfite may be added to it prolong shelf life.
Imidazole Derivatives
The imidazoline derivatives used topically are naphazoline, tetrahydrozoline
and oxymetazoline differ structurally from phenylephrine by replacement of
benzine ring with an unsaturated ring. Concentrations used for ocular
vasoconstriction do not alter pupil size or raise IOP in the normal eye.
These agents are generally more stable in solution than phenylephrine
and have a longer shelf life and longer duration of action. Following instillation,
the balancing effect, occurs within minutes and may last upto several hours.
The solutions may sting upon initial instillation.
In addition to vasoconstrictor substances, ocular decongestants may also
contain antihistamines, viscosity increasing agents, preservative, buffers and
astringents. Various topical combination products with antihistamines as
already mentioned are available commercially (Table 21.1).
Individual drug monograph of various decongestants is as follows:
Phenylephrine HCl: Used as a decongestant either alone or in combination

with topical antihistamine to provide relief from symptoms of mild ocular
TABLE 21.1: Ophthalmic decongestants

Vasoconstrictor Concentration Duration (hr)
(%)
Epinephrine 0.1 1-3
Phenylephrine 0.12 0.5-1.5
Oxymetazoline 0.025 < 6 hours
Naphazoline 0.012-0.1 2-3
Tetrahydrozoline 0.05 2-3
allergy disorder (relief of eye irritation caused by hay fever, colds, dust, wind,
sun, smog or hard contact lenses).
Contraindications: Hypersensitivity to any of its components, narrow angle
glaucoma because the mydriatic action of phenylephrine may precipitate
angle block.
Dosage: It is available as topical ophthalmic solution in strength of 0.125-
0.12% usual dosage is to instil 1-2 drops of 0.12% solution in eyes 2-4 times
daily.
Adverse reactions: On topical use it may cause transitory stinging on initial

instillation, blurring of vision, rebound miosis and decreased mydriatic
response to therapy.
Naphazoline HCl: It is used as topical vasoconstrictor to soothe, refresh,

moisturize and removes redness due to mild ocular allergic disorder or minor
eye irritation.
Dosage: It is available in various topical ophthalmic preparations in

concentrations varying from 0.012 to 0.1%. It is also available as topical
ophthalmic solution alone.
Usual dosage is to instill 1-2 drops into the conjunctival sac of the affected
eyes every 2-4 hours.
Contraindications: Like phenylephrine it is also contraindicated in patients

with narrow angle glaucoma, unstable systemic hypertension and individuals
using MAO inhibitors. Over use can produce rebound hyperemia.
Adverse reactions are similar to those mentioned in phenylephrine section.
Tetrahydrozine HCl: It is also used as topical ocular decongestant. It is

available as topical ophthalmic solution either alone or in combination with
antihistamines in the strength of 0.05%. Usual dosage is to instill 1-2 drops
into the affected eyes 2-4 times a day.
Adverse reactions and contraindications are similar to as described in

phenylephrine section.
Oxymetazoline HCl: It is a imidazoline derivative and is sympathomimetic

drug that acts to constrict blood vessels. Its effect is due to direct action of the
drug upon the alpha (postsynaptic) receptors of vascular smooth muscles.
Oxymetazoline is characterized by an early onset of action, a relatively long
duration of action and a low tendency to rebound congestion.
Indications: It is indicated for use as a long-acting topical ocular vasoconstrictor

for symptomatic relief of allergic conjunctivitis, non-infectious conjunctivitis
and ocular congestion caused by conditions such as allergy, dry eyes,
swimming, smog, contact lens wear and eye strain.
Contraindications: It is contraindicated in patients in whom pupillary dilation

should be avoided, e.g. angle closure glaucoma or those with critically narrow
angles and hypersensitivity to the drug.
It should be used with caution in patients using systemic MAO inhibitors
as an increase in blood pressure may occur. In children it may cause sedation
and hence use with caution.
Dosage: It is available as liquifilm sterile ophthalmic solution in conc of 0.025%

usual dosage is 1-2 drops in the affected eyes every 8 hourly.
Adverse reactions: Pupillary dilation may occur in susceptible individuals and

may be associated in IOP rise. Other ocular effects are transient burning and
stinging sensation.
Oxymetazoline is best topical decongestant of this group which has been
shown to be more potent and effective than naphazoline HCl, tetrahydro-
zoline HCl and xylometazoline HCl.
Oxymetazoline slow elimination rate ensures that more drug stays in contact
with superficial blood vessels for longer time period.
It produces a marked and prolonged reduction of hyperemia with the
onset of effect occurring with in 1-5 minutes of instillation.
Its liquifilm character protects the tear film and prevents development of
an iatrogenic dry eye. Liquifilm soothes and comforts inflamed ocular tissue.
It has no systemic side effects.
Rose petal aqueous infusion: It is also used to provide relief from mild
ocular allergic irritation of the eye. It is available as topical solution (aqueous
influsion in 7.5 ml with 0.01% thiomersal) usual dosage is to instill one drop
in the affected eye twice-thrice a day. If irritation persists or increases,
discontinue the use of infusion immediately.
Oral Pseudoephedrine (30 and 60 mg oral tablets) and topical ephedrine

solution (0.05%) are also used in relieving ocular irritation.
Emedastine: It is a benzimidazole derivative and is a new high potency, high

affinity H1 selective histamine receptor antagonist that effectively inhibited
allergic conjunctivitis in trial patients.
It displays a rapid onset and good duration of action. Its action starts within
10 minutes of topical instillation and effect last for 4 hours. This agent appears
to be a promising new drug for the treatment of ocular allergic diseases.
Oral Antihistamines
Oral antihistamines are prescribed in conjunction with topical antiallergy agents
in severe cases of ocular allergic disorders where topical therapy alone is
insufficient to achieve desired effects.
Although systemic antihistamines such as chlorpheniramine, clemastine,
dex-chlorpheniramine, diphenhydramine, promethazine and triprolidine
relieve ocular allergic symptoms but they have greater CNS pene-tration
and increased anticholinergic side effects like dryness and drowsiness. While
second generation H1-receptor antagonists such as terfenadine, fexofenadine,
astemizole, cetrizine and loratadine do not cross blood- brain barrier to any
appreciable extent and thus are minimally sedating.
In addition to blocking H1-receptors, terfenadine and loratadine have
been found to inhibit histamine release.
Astemizole and cetrizine have been found to be effective in reducing
symptoms of seasonal allergic conjunctivitis. Loratadine has been found to
protect against the clinical and cellular early phase and late phase reactions.
The onset of action of these oral antihistamines is approximately 1 hour
after administration but maximal antagonism at their sites of action takes
several hours longer.
These agents are useful in ocular allergic disorders specially when eyelid
edema and chemosis are significant.
The various systemic antihistamines given orally are always prescribed in
conjunction with standard topical anti-allergy agents to be more effective in
relieving the symptoms.
Levocetrizine
It is a new highly effective and well tolerated antihistamine. Levocetrizine
being the potent single isomer of cetrizine binds twice as strongly to histamine
H1 receptors and has a highly consistent and predictable antihistamine action.
It is available as 5 mg tablet.
Dosage: 5 mg orally once or twice daily. It is indicated for the treatment of

allergic conjunctivitis.
Desloratidine
It is active metabolite of loratidine and is indicated for use in seasonal allergic
conjunctivitis. Desloratidine possesses pharmacodynamic activity similar to
that of loratidine but has a relative potency 10-20 times greater than loratidine.
It is available as 5 mg tablet. Dosage is 5 mg orally once daily.
The dosage of various systemic antihistamines is given in Table 1.2.
Although second generation H1-receptor antagonist antihistamines are
relatively free of systemic adverse reactions yet rare adverse effect of
ventricular tachycardia can occur with terfenadine and astemizole if their
metabolism is inhibited by hepatic disease or drugs such as erythromycin
and certain antifungal agents.
Fexofenadine
It is a newer second generation nonsedating specific antihistamine (H1
blocker). It is a hydrochloride salt of terfenadine active metabolites.
It has been shown to have a good clinical efficacy and tolerability in the
treatment of vernal keratoconjunctivitis and seasonal allergic conjunctivitis.
Fexofenadine is truly non-sedating and safe antihistamine.
Dosage: It is available as 60 and 120 mg tablets. Usual dosage is 60 mg twice

a day or 120 mg OD for 14-21 days till the desired response is obtained.
It is usually given in combination with topical antiallergy drops.
Adverse reactions: Generally the drug is well-tolerated. However, the common

adverse effects seen are headache, throat irritation, viral infection, nausea,
dysmenorrhea, drowsiness, dyspepsia and fatigue.
Drug interactions: Fexofenadine is least likely nonsedating antihistamines to

interact with other medications.
TABLE 21.2: Oral antihistamine dosages
Drug name Dose (mg) Dose interval Max daily Antihistamine
(h) dose (mg) activity
Chlorpheniramine 4 4-6 24 Moderate
Dexchlorpheniramine 2 4-6 12 High
Clemastine 1 12 08 Moderate
Diphenhydramine 25-50 6-8 400 Moderate
Promethazine 12.5-25 6-24 100 High
Triprolidine 2.5 4-6 10 High
Astemizole 10 24 10 High
Brompheniramine 04 4-6 24 High
Cetrizine 10 24 10 High
Loratadine 10 24 10 High
Pyrilamine 25-50 6-8 200 Moderate
Terfenadine 60 12 120 High
Fexofenadine 60 12 120 High
Tripelenamine 25-50 4-6 300 Moderate
Hydroxazine 50 mg 6-8 400 High
Fexofenadine does not impair driving performance, a usual precaution

advised with other antihistamines.
NSAIDS (ANTIPROSTAGLANDIN THERAPY)

One of the oral non-steriodal anti-inflammatory drugs (NSAIDs), aspirin (a
cyclooxygenase inhibitor) has been proved effective in controlling symptoms
in patients of vernal keratoconjunctivitis (VKC) unresponsive to DSCG and
corticosteroids. Clinical studies have shown dramatic improvement in
conjunctival and episcleral redness limbal infiltration and epithelial keratitis
with systemic aspirin therapy. Standard oral dosage of aspirin is 0.5-1.5 gm
daily for 4-6 week period. With oral aspirin there is marked symptomatic
improvement, e.g. reduced palpebral papillae size, decreased punctate
keratopathy and decreased limbal inflammation.
Topical NSAIDs which are effective in ocular allergy are as follows:
1. Topical suprofen (1%) is effective in managing the signs and symptoms of
giant papillary conjunctivitis and vernal keratoconjunctivitis. Usual dosage
is to instill 1-2 drops in the affected eye three times a day for 4-6 weeks.
2. The most effective topical NSAIDs used commonly in treating ocular allergic
disorder is: topical ketorolac tromethamine solution (0.5%). Topical
ketorolac is the itch buster in allergic conjunctivitis.
The salient features of topical ketorolac solution is:

• It stops allergic itch prompty—start immediately after instillation.
• Provides relief from allergic symptoms—itching, tearing, redness and
swelling.
• Breaks the itch-rub cycle. It inhibits prostaglandin formation by blocking
enzyme cyclooxygenase putting an end to further cycle of irrtation and
discomfort.
• Provides relief from acute flare ups with no need for prophylactic use.
The recommended dosage is to instill one drop in the conjunctival sac
four times a day for relief of ocular itching due to seasonal allergic
conjunctivitis.
• In patients with allergic conjunctivitis the most frequent adverse effect
reported with the use of topical ketorolac solution is transient burning
and stinging sensation on instillation. Otherwise it is a safe medication in
ocular allergy disorder.
TOPICAL STEROIDS
Glucocorticoids exert a potent anti-inflammatory effect in allergic ocular
disorders but are reserved for refractory cases unresponsive to other
know antiallergy agents because of their potential side effects specially risk of
cataract formation, steroid induced glaucoma and decreased resistance to
infection.
Topical loteprednol (0.5%), rimexolone (1%), fluorometholone FML
(0.3%) are new potent steroid with marked anti-inflammatory properties
but with a reduced propensity to elevate intraocular pressure (an important
side effect with previous generation topical steroids, e.g. dexamethasone,
betamethasone, hydrocortisone and prednisolone).
• Topical loteprednol, rimexolone and FML effectively suppresses
inflammation in allergic conjunctivitis.
• They inhibit leukocyte accumulation better than dexamethasone.
• Microfine suspension helps in uniform distribution and rapid absorption
• Proven safety in children also.
TOPICAL IMMUNOSUPPRESSORS
Topical immunosuppressor therapy in ocular allergic disorders is recently
introduced anti-allergy agent with promising results.
Cyclosporine
It is a cyclic peptide that exerts a potent immunosuppressive effect by acting
specifically on lymphocytes particularly CD4+ T cells. Cyclosporine inhibits
transcription of interleukin-2 (IL-2) as well other cytokines such as interferon,
gamma and other interleukins. Decreased IL-2 production by CD4+ cell results
in decreased activation and in decreased levels of cytokines which in turn
results in inhibition of cell mediated immunity.
Topical cyclosporine 2% has been clinically tried with a dosage of (instill
one drop in the affected eye four times a day) in patients of vernal
keratoconjunctivitis and atopic keratoconjunctivitis (AKC). There was complete
improvement in symptoms of ocular allergic disorders in 6 weeks of treatment
in more than 80% of patients. Cyclosporine is also effective in reducing signs
and symptoms of atopic keratoconjunctivitis. In a recent study topical
cyclosporine therapy was correlated with a significant reduction in numbers
of T-cells and plasma cells in the conjunctiva of patients with vernal
keratoconjunctivitis.
Unlike systemic cyclosporine, topical preparation is relatively free of adverse
effects and holds a promising future in the treatment of various ocular allergic
disorders.
RECENT ADVANCES IN IMMUNOSUPPRESSIVE THERAPY

a. Active research is going on competitive inhibition of IgE binding to effector
cells using Fc fragments from human IgE. Isolation of the specific binding
site and fragment production with recombinant DNA technology may
allow selective inhibition of mast cells or eosinophils in ocular allergic
disorders.
b. Adhesion molecules are proteins that allow cells to interact with one
another. In patients of SAC and VKC therer is a marked increase in
conjunctival expression of ICAM-1, ICAM-3 and other adhesion molecules
when compared to normal.
Intensive efforts are going on in developing specific therapeutic agents
that can modulate these adhesion molecule (proteins) and diminish the
allergic response.
c. Clinical trials are going on in development of suitable therapeutic agents
that could modulate the actions of cytokines such as IL-3, IL-5 and GM-
CSF suppressing aspects of the immune response that are not strongly
affected by current available medications. A better clinical understanding

of the role of specific cytokines in the different ocular allergic disorders
shall stimulate the development of tailoring therapeutic agents to each of
these entities.
Liposomes
New drug delivery systems may offer advantages in future therapy for ocular
allergic disorders. Liposomes are vesicles consisting of lipid bilayers alternating
with aqueous compartments. They may provide several advantages over
current therapeutic modalities in ocular diseases.
• These allow prolonged contact between the medication and ocular tissue
by preventing excessive rapid drug removal via tears.
• Changes in lipid composition and liposome structure can alter the amount
of intraocular drug absorption.
• Incorporation of monoclonal antibodies into outer lipid bilayer of the
liposome would transport the liposome to the target tissue or cell type
where the drug is required.
A safe liposome system is now available for ocular use. Cationic lipids
such as BDSA can be added to the outer surface of liposomes thereby
increasing the contact time of medication with ocular tissues. This liposome
system cause minimal eye irritation and may prove valuable in clinical
treatment of ocular allergy.
BIBLIOGRAPHY
1. Agarwal Amar. Textbook of Ophthalmology (1st edn). New Delhi: Jaypee Brothers
Medical Publishers, 2002.
2. Bartlett JD. Clinical Ocular Pharmacology (4th edn). Boston: Butterworth-
Heinemann, 2001
3. Bartlett JD. Ophthalmic Drug Facts, Lippincott-William and Wilkins 2001.
4. Bartlett JD, Ross RN. Primary Care of Ocular Allergy. J Am Optom Assoc 1990;
61,S3-46.
5. Ciprandi G, et al. Drug Treatment Allergic Conjunctivitis: Drugs 1992;43:154.
6. Crick RP, Trimble RB. Textbook of Clinical Ophthalmology, Hodder and Stoughton,
1986.
7. Duane TD. Clinical Ophthalmology (4th edn). Butterworth-Heinemann, 1999.
8. Duvall. Ophthalmic Medications and Pharmacology, Slack Inc, 1998.
9. Ellis PP. Ocular Therapeutics and Pharmacology (7th edn). CV Mosby, 1985.
10. Fechner. Ocular Therapeutics, Slack Inc., 1998.
11. Fraunfelder. Current Ocular Therapy (5th edn). WB Saunders, 2000.
12. Garg Ashok. Current Trends in Ophthalmology (1st edn). New Delhi: Jaypee
Brothers Medical Publishers, 1997.
13. Garg Ashok. Manual of Ocular Therapeutics (1st edn). New Delhi: Jaypee Brothers
14. Garg Ashok. Ready Reckoner of Ocular Therapeutics (1st edn). New Delhi: 2002.
15. Goodman LS, Gilman A, Pharmacological Basis of Therapeutics (7st edn). New
York: Macmillan, 1985.
16. Havener’s. Ocular Pharmacology (6th edn). CV Mosby, 1994.
17. Kanski. Clinical Ophthalmology (4th edn). Butterworth-Heineman, 1999.
18. Kershner. Ophthalmic Medications and Pharmacology, Slack. Inc., 1994.
19. Olin BR, et al. Drugs Facts and Comparisons: Facts and Comparisons, St. Louis,
1997.
20. Onofrey. The Ocular Therapeutics; Lippincott-William and Wilkins, 1997.
21. Rhee. The Wills Eye Drug Guide, Lippincott-William and Wilkins, 1998.
22. Steven Podos. Textbook of Ophthalmology, New Delhi: Jaypee Brothers Medical
Publishers, 2001.
23. Zimmerman. Textbook of Ocular Pharmacology, Lippincott and William and Wilkins,
1997.
RECENT ADVANCES IN DRY EYE MANAGEMENT 335
INTRODUCTION
The management of dry eye states depends on the following approaches:
1. Lubrication of the ocular surface
2. Reduction of evaporation losses
3. Lacrimal occlusion
4. Adjunctive treatments
5. Surgical treatments
6. Treatment of underlying disease.
Although the basic concepts of managing dry eyes have not changed,
there have been significant advances in our understanding of the
pathophysiology in recent years. This has led to newer modalities of treatment,
other than the conventional methods.
LUBRICANTS
The two major advances in the formulation of ocular lubricants have been in
the field of polymer technology and in the development of topical solutions
that are preservative-free.
Preservatives are chemical additives to the formulation that prevent
microbial spoilage. Additionally, there are ‘stabilizing agents’ in the formulations
which protect the drug against physical-chemical degradation. There are also
buffers, osmolarity adjusting agents and excipients such as chelating agents,
surfactants and stabilizers, etc. Detergent preservatives such as benzalkonium
chloride (BAK) alter cell membrane permeability causing cell lysis. Mammalian
cells cannot neutralize these chemicals and they incorporate into the cell and
cause damage and produce clinical signs of toxicity.
Oxidative preservatives such as sodium perborate and stabilized oxychloro
complex penetrate cell membranes but since mammalian cells are equipped
with antioxidants, oxidases and catalases, low level oxidants are neutralized
and there is negligible toxicity. Purite™ is a proprietary, non-sensitizing oxidative
preservative which is safe, gentle and labile on use. It is activated by acidic
environment due to microbial action and converts to sodium chloride and
water in the eye.
Prolonged and frequent use of preserved tear substitutes can produce
irritation and inflammation of the conjunctival surface, reduced goblet cell
density and damage to the corneal epithelial barrier. It has long been
recommended by clinicians that mild cases of dry eye, which require tear
substitutes less than four times daily may be treated with preserved tears.
However, patients with moderate disease requiring lubricant eye drops more
frequently should be treated with non-preserved tears.
The costs of using preservative-free artificial tear drops can be prohibitive.
These are single use disposable units, have a short shelf-life (typically less
than one year) are expensive to produce and not freely available. Moreover,
they may have to be used very frequently, thereby substantially increasing
the cost of daily treatment.
A viable medium has been the development of labile or ‘disappearing’
preservatives. These are transiently preserved artificial tears drops. The
stabilized oxychloro complex which is the preservative used has been described
above. Sodium perborate, derived from contact lens saline products, has
been very useful in this regard. It preserves the formulation through the
effect of hydrogen peroxide and degrades to water on contact with the eye.
Research in polymer technology has bought in newer products. Polymers
are complex molecules which have mucoadhesive properties (they bind to
conjunctival mucin via non-covalent bonds) and significantly increase
retention time in the eye. They are broadly classified as natural, semi-synthetic
cellulose derivatives, synthetic polyvinyl polymers or viscoelastic agents. The
important considerations for the use of ophthalmic polymers are their viscosity,
ocular retention time, water retention, tissue compatibility and surfactant
behavior. The recognized ophthalmic demulcents are carboxymethyl cellulose
(CMC), hydroxypropylmethyl cellulose (HPMC), hydroxyethylcellulose,
Dextran 70, gelatin, liquid polyols such as glycerine, polyethylene glycol
(PEG), polysorbates and propylene glycol, Povidone (PVP) and polyvinyl
alcohol (PVA).
Different polymers have different complex properties. These are influenced
by many factors such as chemical structure, charge, molecular size and
concentration in the solution. Each product is optimized for specific properties
and there is a balance achieved between retention and visual blurring.
The cellulose derivatives are semisynthetic substituted cellulose ethers and
are the most widely used tear substitutes. Their viscous properties and their
relative lack of toxicity have a beneficial effect on tear film stability. HPMC,
and more recently, CMC are the two most commonly used.
Newer molecules are being introduced as tear substitutes.
Sodium Hyaluronate
Sodium hyaluronate as a tear substitute has been shown to offer subjective
and objective improvements in patients with KCS. It has been shown to
improve ocular surface damage as evidenced with impression cytology
scores2.
According to Prof Juan Murube, the treatment of dry eye problems has
five aspects: psychological, environmental, physical, medical and surgical.3
He opines that the patient must be explained that this is a chronic problem
and though it cannot be cured, it can be relieved. This would psychologically
help the patient to live and adapt to his disease and search for practical
solutions.
Environmentally, the patient should be in quiet, humid and clean air.
“Quiet” implies relatively still air, i.e. low-flow air conditioners, ventilators,
fans at low speed, windows rolled up while in the car or coach and protective
eyewear which cuts down air flow around the eyes.
Humidified air is found in saunas or with the use of a humidifier in the
home/office or with special semi-closed eyewear that retains the eyes moisture
in a humidified microclimate in front of the eye. Clean air is free from smoke
from tobacco, fireplaces, kitchen, barbeques, etc. and from chemical fumes
as from pollution, fresh paint, furniture, flooring, etc. Protective eyewear
prevents air currents and maintains greater humidity in front of the eyes and
is divided into three types: Type I (normal glasses), Type II (glasses with lateral
panels) and Type III (hermetic eyewear of the type worn in swimming
underwater). These protective glasses capture the evaporation of the tear
film and create a humid ambience.
Amongst the physical treatments suggested are lid massage with or without
warm compresses for meibomian gland dysfunction. Warm compresses
produce a temporary thickening of the oil layer of the tear film4 and reduce
the evaporation. Patients should be advised to use warm compresses on
waking up in the morning and in the mid afternoon. Strongly squeezing the
lids also helps express meibomian lipids. Corneal contact lenses with very
frequent instillation of drops can be used as bandage lenses where there is
an epithelial abrasion caused by excessive dryness.
Newer propositions such as radiation and laser over the region of the
lacrimal gland to stimulate secretion have been suggested for specific cases
and treatments that combine medical radiation with iodide iontophoresis are
being tested.
Nutritional Supplements
Oxholm et al found that in Sjogren’s syndrome (SS) the higher the level of
dietary long-chain omega 3 fatty acids in the serum and cell membrane, the
less severe the dry eye.5 It was found that the higher the dietary omega 3
fatty acids, the lower the risk of having a clinically diagnosed dry eye.6 Boerner
et al found 98% patients reported improvement in the symptoms with omega
3 supplementation.7 Omega 3 fatty acids suppress inflammation by generating
anti-inflammatory eicosanoid acid and blocking the gene expression of pro-
inflammatory cytokines.
Tear Stimulants (Secretagogues)

Diquafosol
Diquafosol tetrasodium is a uridine nucleotide analogue that acts as a P2Y2
receptor agonist. P2Y2 belongs to a family of G-coupled protein receptors
present on the ocular surface, conjunctiva and other mucous membranes.
Diquafosol increases water transport via chloride channel activation and
enhances nonglandular secretion of tear fluid. It increases the mucin
production by the conjunctival goblet cells8 and also the meibomian lipid
production.8
In a large randomized, double-masked, placebo-controlled trial, it was
found that 2% diquafosol significantly improved corneal and conjunctival
staining scores and Schirmer’s test values with improvements beginning to
appear in the 2nd week.9 The benefits started to disappear a week after
discontinuation which would suggest that treatment may need to be given
for long periods. The drug has been approved by the FDA but a confirmatory
phase III trial is to be undertaken.
Pilocarpine
A naturally occurring plant alkaloid, pilocarpine is a cholinergic
parasympathetomimetic that binds to muscarinic M3 receptors and stimulates
the salivary and lacrimal glands. Pilocarpine tablets at doses of 5 mg TDS are
used in dry eyes patients. A study by Vivino et al showed its superiority over
artificial tear substitutes or punctal occlusion in terms of subjective global
assessment of dry eye symptoms. Rose bengal scores improved significantly,
however, Schirmer’s test values did not differ significantly from the other
treatment groups.10 In many, the benefits were noted after 2 months of
therapy. Significant side effects of sweating, headache, ‘flu’ symptoms, nausea

and rhinitis were reported. Only 2%, however, withdrew from the study due
to side effects.
Cevimeline
Cevimeline is an acetylcholine analogue and has high affinity for the muscarinic
M3 receptors of the salivary and lacrimal glands. There are many clinical
trials supporting the use of cevimeline for the dry eyes and mouths of patients
with Sjögren’s syndrome.11 There was improvement in global assessments of
dry eye symptoms with doses of 20 to 30 mg thrice daily. The results of
changes in objective measures, however, were not uniform. Although
efficacious, there are frequent side effects reported such as sweating, nausea,
diarrhea, headache, arrhythmia, etc. There was a high rate of withdrawal of
14-19% from these studies owing to drug-related adverse effects.11
Eledoisin
Eledoisin is an endecapeptide extracted from the salivary gland of octopus
species. When applied locally it has a secretostimulant effect which lasts 30
minutes.
Mucinous Stimulators
Bromhexine and n-acetylcysteine are stimulants of mucin production
generally. They are not mucolytics as they do not polymerize mucus already
formed but cause the secretion of new mucus. More recently, topically applied
medicines such as geranyl farnesylacetate and hydroxyeicosatetraenoic acid
15-(S)-HETE have been introduced which improve the epithelium and
stimulate the goblet or caliciform cells, especially MUC-1.
Anti-inflammatory Therapy
The role of inflammation in the pathogenesis of KCS has been well-
documented.12 There are multiple mechanisms of inflammation which include
an increased production of pro-inflammatory cytokines such as interleukin,
an increase in secretion of proteolytic enzymes (matrix metalloproteases
MMPs), decreased secretion of anti-inflammatory proteins such as lactoferrin
and activation of cytokines and proteases which are latent in the tear film.
There is resultant loss of the normal corneal barrier function with
corneal erosions and surface abnormalities. Agents that have been used
for anti-inflammatory properties are the corticosteroids, NSAIDs and

cyclosporin A.
Corticosteroids
Corticosteroids have many diverse actions by which they bring about their
anti-inflammatory activity. They decrease inflammatory cytokine production
as well as that of chemotactic factors, reduce cell adhesion, decrease lipid
inflammatory mediators and increase lymphocyte apoptosis.
Because of their wide spectrum of anti-inflammatory activity, they also
produce significant side effects such as cataract and increased intraocular
pressure. Since dry eye syndrome and especially Sjogren’s syndrome (SS)
require extensive periods of treatment, the routine use of full strength topical
steroids is not recommended.
NSAIDs
Topical NSAIDs have been compared with topical corticosteroids in the
treatment of dry eyes.13 There was no benefit recorded with the use of NSAIDs
in comparison with artificial tears substitutes, either in symptom severity scores
or ocular staining scores with rose bengal or fluorescein. In another study for
treatment of corneal filamentary keratitis, in comparison with 5% NaCl drops
there was no advantage seen with 0.1% topical diclofenac.
Cyclosporin A
Cyclosporin A is a potent immunosuppressive peptide which inhibits the
nuclear translocation of transcription factor NF-AT leading to reduced
transcription of many inflammatory cytokines such as IL-2, IL-3 and IL-4
and TNF. It inhibits the activation of T cells.
Kaswan et al demonstrated its ability to increase tear secretion in both
normal animals and dogs with KCS.14 When administered in doses of 0.05%
ophthalmic emulsion twice daily, it increases the conjunctival goblet cell density
in both SS and non-SS patients of KCS. In patients with SS, it reduces the
number of conjunctival CD4(+) cells as well as the cells expressing the
activation marker CDIIa.15,16
Many clinical trials have conclusively shown that in moderate-severe dry
eye disease there is significant improvement in both subjective and objective
outcome measures.17,18 There were marked improvements in corneal and
conjunctival staining scores and Schirmer’s test results and blurred vision
scores. The benefits were appreciable by the end of the 1st month of treatment
and increased progressively. There were no significant blood levels achieved
after topical treatment.
0.05% cyclosporin A was confirmed to be safe and effective for the
management of moderate to severe dry eye.
Autologous Serum Drops

The serum contains numerous substances and factors such as epidermal
growth factor (EGF), transforming growth factor, fibronectin and vitamin A
which are found in normal tears but are lacking in KCS. This forms the
rationale for treating severe dry eyes with autologous serum. Though initially
suggested in 1984, it was only recently that there was a renewal in interest
with the demonstration of autologous serum as a safe and effective treatment
for dry eyes and that it may be superior to conventional treatment.19 Tsubota
et al showed that autologous serum upregulated mucin expression on cultured
conjunctival cells.20 The preparation of autologous serum drops is a tedious
process, however, and labor intensive. There are also problems of microbial
contamination and risks of disease transmission. The use of serum drops,
therefore, has not got universal acceptance clinically in the treatment of mild
and moderate disease.
Interferon
In a pilot study on patients with SS, administration of interferon-? showed
significant changes in ocular and mouth dryness without any drug-related
adverse reactions.21
Hormones
Cermak et al recently found that women with primary and secondary SS are
androgen deficient.22 They showed that androgens regulate meibomian gland
function, control the quantity and quality of lipids produced and promote
the formation of the tear film lipid layer. Due to a drop in androgen synthesis
(e.g. in SS, menopause, with ageing, complete androgen insensitivity
syndrome, etc.) there will be meibomian gland dysfunction (MGD) and an
evaporative dry eye. The authors suggest that topical testosterone may be
helpful in treating dry eye in SS and MGD. A non-virilizing androgen may
prove useful as adjunctive therapy in dry eye syndrome.
Surgical Treatments
Many methods to retain the tears and reduce evaporative losses as well as
methods to provide tear substitutes to the eye have been described.
Punctal Occlusion
In moderate to severe dry eyes, increasing the retention of tears by occluding
the puncta and canaliculi by plugs or cauterization, is an effective way to
improve the subjective and objective parameters of dry eye. The efficacy has
been established by a number of clinical trials. Temporary (dissolving) and
non-dissolving punctual plugs produce an improvement in symptoms,
decrease staining scores, increase TBUT and increase the number of goblet
cells.23 However, there is a relatively high rate of loss of the plugs and other
complications such as epiphora and erosions can also occur.
It is important to consider punctual occlusion only after sufficient control
of the conjunctival inflammation the inflammatory cytokines and other
chemical mediators be retained in the conjunctival sac, thereby worsening
the condition of the ocular surface. It is often useful to perform plugging
after initial therapy with conventional lubricants and anti-inflammatory
agents.
Plugging can be performed with reabsorbable materials such as collagen,
gelatin or chromic catgut or thermophilic acrylic. Permanent occlusion by
lasers, electrocauterization or a conjunctival patch autograft can be done.
Cisternoplasty
Creating an additional skinfold at the outer angle of the eye which acts as a
natural reservoir for the tears helps patients with mild to moderate dry eye.
The procedure is simply performed and is cosmetically acceptable.
Tarsorrhaphy/Blepharorrhaphy
A lateral or medial 3 mm blepharorrhaphy reduces the surface evaporation
of the eye and is justifiable in moderate to severe disease.
Blepharoptosis
Inducing an upper lid blepharoptosis of about 1 mm decreases the surface
are for evaporative loss by about 30 mm2 and can be considered for severe
dry eye states.
Transposition of Salivary Ducts

The duct of the parotid salivary gland can be transposed subcutaneously
into the inferior fornix of the conjunctival sac. Used only in the severest
cases, it has the problems of ‘crocodile tears’ formation.
Transplantation of Salivary Glands

The submandibular salivary gland can be transplanted into the temporal
fossa and the vascular supply anastomosed to the superficial temporal artery.
The submandibular duct can be passed through an opening in the lateral
orbital wall and opened into the lateral fornix.
Smaller pieces can also be implanted in the subconjunctival areas of the
upper and lower lids without having to anastomose the blood supply. Gland
transplants are denervated and therefore, provide only basal secretion and
not reflex. They may be stimulated with oral/topical pilocarpine. They can
also be useful only in patients with normal salivary secretion.
Tear Pumps
A tear pump device implanted under the skin in the abdominal wall can
slowly release upto 1.5 ml of tears daily. The tube has to extend subcutaneously
through the chest, neck and head till it is brought into the superolateral
fornix under the upper lid. The reservoir has to be filled every few weeks
with a needle-stick. Freon gas provides the emptying mechanism. In a pilot
study, there was significant improvement in the sign and symptoms with
good tolerance to the device.24
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Cornea 2003;22:516-21.
23. Tai MC, Cosar CB, Cohen EJ, et al. The clinical efficacy of silicone punctual plug
therapy. Cornea 2002;21:135-39.
24. Murube J, Murube E, ChenZhuo L, Rivas L. Subcutaneous abdominal artificial
tears pump-reservoir for severe dry eyes. Orbit 2003;22:29-40.
OCULAR SURFACE DISEASES: CURRENT MANAGEMENT AND CONCEPTS 347
INTRODUCTION
Chronic ocular surface disease (OSD) may be a difficult clinical problem to
manage, with varied treatment options available for the care of such patients.
Conventional treatment strategies include the use of lubricant eyedrops,
punctal occlusion, therapeutic contact lenses, penetrating keratoplasty,
conjunctival flaps, buccal mucous membrane grafts, and keratoprosthesis.
The various methods of caring for these problems, suggests a lack of any
one totally satisfactory method of treatment, prompting the use of a
multidisciplinary approach with techniques of stem cell transplantation,
amniotic membrane transplantation and use of topical autologous serum,
vitamin A and cyclosporin.
OCULAR SURFACE DISEASE

The current definition of the ocular surface includes mainly the cornea and
conjunctiva with support from the main and accessory lacrimal glands and
meibomian glands. Also included is the connective tissue of the conjunctiva,
as Plugfelder has suggested that the underlying subepithelial tissues and the
interconnecting innervation acts as one biologic continuum. Thus when any
one portion of the ocular surface is compromised, normal lacrimal support
of the ocular surface can be impaired.1
Ocular surface disease (OSD) has been defined by John Dart et
2
al as a group of disorders of diverse pathogenesis in which disease
results in failure of mechanisms that maintain a healthy ocular
surface.
ETIOLOGY
Ocular surface disease is seen in the following conditions (Table 23.1):
Dry eye syndromes, ocular cicatricial pemphigoid (OCP), chemical and
thermal injuries, herpes simplex and zoster, atopic keratoconjunctivitis,
trachoma, contact lens-induced keratopathy, secondary to multiple surgeries
or cryotherapies to the limbal regions and the chronic use of topical
medications.3 Eyelid abnormalities (involving eyelashes, lid position and lid
closure) can affect the integrity of the ocular surface. Limbal stem cell deficiency
forms a part of the spectrum of ocular surface disease (Table 23.2).
The normal ocular surface is maintained by the corneal and conjunctival
epithelium, which is nonkeratinized and stratified. Although corneal and
TABLE 23.1: Causes of ocular surface disease

Disorders of the tear film
1. Aqueous deficiency
• Congenital—Riley-Day syndrome, congenital alacrimia
• Acquired—chemical burns
• Graft versus host disease (GVHD)
• Postirradiation atrophy, postdacryoadenitis
• Sjogren’s syndrome
• Systemic medications—psychotropics, antihistamines, etc.
2. Lipid deficiency
• Congenital—congenital anhydrotic ectodermal dysplasia
• Acquired—meibomian gland dysfunction
Contact lens wear
3. Mucin deficiency
• Hypovitaminosis A
• Ocular cicatricial pemphigoid (OCP)
• Erythema multiforme
• Chemical burns
• Trachoma
• Sjogren’s syndrome
4. Lid tear resurfacing abnormalities
• Facial paresis
• Exposure keratitis
• Dysthyroid eye disease
• Pterygium
5. Ocular surface epithelial disorders
• Anaesthetic cornea
• Keratitis
• Keratinization
6. Lid disorders
• Blepharitis
• Trichiasis
• Entropion and ectropion
conjunctival epithelia are intrinsically different, both of them together

contribute to the health of the ocular surface. The integrity of the ocular
surface is greatly affected by the quality of the epithelia and overlying tear
film. Goblet cells in the conjunctival epithelium provide the primary source
of ocular mucin and along with the corneal epithelium play an important
role in stabilizing the preocular tear film.
Most dry eye symptoms result from an abnormal nonlubricative ocular
surface that increases shear forces under the eyelids and diminishes the ability
of the ocular surface to respond to environmental challenges.
Tear film instability secondary to aqueous or mucin deficiency produces
tissue destruction as a result of a nonwettable ocular surface.4, 5 The destructive
TABLE 23.2: Causes of limbal deficiency
A. Primary causes—destruction of limbal stem cells
• Chemical or thermal injuries
• Iatrogenic—multiple surgeries or cryotherapies of the limbus
• Autoimmune— Ocular cicatricial pemphigoid (OCP),
Stevens- Johnson syndrome (SJS),
Atopic keratoconjunctivitis and Sjogren’s syndrome
• Contact lens-induced keratopathy
• Severe microbial infection
B. Secondary causes—dysfunction of stromal microenvironment of limbal epithelial
stem cells
• Aniridia
• Keratitis associated with multiple endocrine deficiencies (hereditary)
• Neurotrophic keratopathy (neuronal or ischemic)
• Chronic limbitis or peripheral corneal ulceration
• Pterygium and pseudopterygium
• Idiopathic keratopathy
loss of stem cells or dysfunction of limbal stroma, results in a destruction of

the basement membrane and fibrous tissue ingrowth on histopathology.6
The resultant poor epithelialization, chronic stromal inflammation, corneal
vascularization and conjunctival epithelial ingrowth (conjunctivalization) can
present as chronic ocular discomfort and cause corneal scarring, perforation
and permanent loss of vision.7
Limbal Stem Cell Hypothesis

Thoft and Friend8 proposed the X, Y, Z hypothesis that normal corneal
epithelial mass is maintained by continuous centripetal movement of
peripheral corneal epithelium towards the visual axis.The X, Y, Z hypothesis
of corneal epithelial maintenance stated that there was a balance of three
FIGURE 23.1: X, Y, Z hypothesis of corneal epithelial maintenance

separate variables that were responsible for the maintenance of the ocular
surface (Figure 23.1).
• X represents basal cell proliferation—limbal basal epithelium (stem cells)
• Y represents centripetal movement—basal corneal epithelium (transient
amplifying cells)
• Z represents loss of cells from corneal surface—suprabasal corneal
epithelium (terminally differentiated cells).
The maintenance of the corneal epithelium depends on a delicate balance
between cellular proliferation and differentiation. Cellular proliferation of all
self-renewing epithelia originates from stem cells, which are undifferentiated
and mitotically quiescent under normal conditions. Upon demand for tissue
regeneration, stem cells differentiate into transient amplifying cells (TACs),
which cycle rapidly and can amplify the total cell number before they become
postmitotic and, eventually, terminally differentiated.9
The half-time of corneal epithelial replacement is 9 weeks, while the time
required for 95 to 99% replacement is 9 to 12 months. Although the limbal
area is only 24% of the total cornea, limbal cells can spread sufficiently to
cover a total corneal epithelial defect. Additionally limbal epithelium, unlike
conjunctiva, has no goblet cells.10
Numerous studies have supported the hypothesis that centripetal
movement of cells from the peripheral cornea, limbus, or conjunctiva is
responsible for normal and post-traumatic replacement of corneal
epithelium.11
The morphological and biochemical transformation called transdifferen-
tiation, where conjunctival epithelium seemed to transform into corneal
epithelium is controversial and disputed, with evidence to suggest that
complete transdifferentiation of conjunctival epithelium is rarely, if ever
complete. If limbal stem cell loss is complete, severe superficial pannus occurs,
often in association with stromal vascularization, resulting in complete
conjunctival phenotype.12
Clinically it is well-established that the resurfacing of the cornea with
conjunctival epithelium is associated with delayed epithelialization, superficial
and deep stromal vascularization, persistence of goblet cells within the corneal
epithelium, and recurrent epithelial erosions due to abnormal basement
membrane epithelial adhesion.
Tseng and Kenyon demonstrated evidence of restoration of corneal
phenotype after limbal transplantation, but not after bulbar conjunctival
transplantation.13 They proposed that limbal stem cells are the most qualified
cells to restore functional competence after extensive ocular surface and limbal
stem cell injury.
SIGNS OF OCULAR SURFACE DISEASE

Aqueous tear deficiency leads to dry eye (keratoconjunctivitis sicca—KCS),
increases tear evaporation and leads to ocular surface disease. Primary
inflammatory diseases (e.g. Sjogren’s, OCP) cause cellular metaplasia, whilst
meibomian gland dysfunction, neurotrophic keratitis and thyroid eye disease,
increase tear evaporation thus causing OSD.14 Ocular surface dysfunction
may also occur from a decrease in systemic androgen support to the lacrimal
gland as seen in aging, most commonly in the menopausal female.15 The
balance of cytokines in the tear fluid and conjunctival epithelium has been
found altered in Sjogren’s syndrome. Thus it has been hypothesized that
common to all ocular surface disease is an underlying cytokine receptor-
mediated inflammatory process.16
The tear film can be examined by Schirmer’s test and by assessing the
height of marginal tear strip and tear break-up time. The lid margins and
eyelid position should be noted as ocular surface abnormalities may be exacer-
bated by symblepharon and eyelid abnormalities.
The conjunctiva should be assessed for papillae and scarring, and fornices
examined to detect significant scarring and foreshortening. Scarring of the
lacrimal ductules and conjunctiva can cause reduction in tear secretion and
dry eye. Diagnostic aids include vital stains like rose bengal, lissamine green
and fluorescein.
Other causes of ocular surface disease that may coexist like lagophthalmos,
blepharitis, atopic keratoconjunctivitis or toxic keratoconjunctivitis should be
excluded.
There are three types of ocular surface failure:
• Limbal stem cell deficiency
• Squamous metaplasia
• Carcinoma in situ.
Conjunctivalization of the cornea (Figure 23.2) is a sign of limbal
deficiency, whilst skin-like changes of the conjunctiva and cornea (Figure
23.3) indicates squamous metaplasia. Squamous metaplasia is a process of
abnormal epithelial differentiation and transformation from a nonkeratinized
epithelium complimented with goblet cells into a keratinized nonsecretory
FIGURE 23.2: Conjunctivalization of the ocular surface
FIGURE 23.3: Squamous metaplasia with keratinization

of the ocular surface
epithelium. Ocular surface squamous neoplasia presents as a spectrum from

simple dysplasia to carcinoma in situ to invasive squamous cell carcinoma. It
most commonly arises in the limbal region in elderly patients exposed to
high levels of ultraviolet light.17
Conjunctival epithelial ingrowth, manifests as poor epithelial integrity,
irregular epithelium (whorl pattern), persistent and recurrent corneal epithelial
defects, corneal melts (Figure 23.4) and corneal filaments.
Pannus or superficial corneal vascularization, inflammatory infiltrates,
fibrous tissue ingrowth and basement membrane destruction are all sequelae
of limbal deficiency.
FIGURE 23.4: Persistent epithelial defect with stromal melt

secondary to ocular surface disease
The state of limbal deficiency is best determined by impression cytology

for goblet cells.18 There are no reliable markers for limbal stem cells, however,
cytokeratin markers have been used to support the theory of stem cells.19
GOALS OF THERAPY
Major goals of therapy include:
• Supplementation of a deficient tear film
• Re-establishment of lid motility with normal lid-corneal congruity
• Supplementation of limbal tissue containing epithelial stem cells for the
management of epithelial disease of the cornea
• Improvement or supplementation of a basement membrane substrate
• Restoration of clear visual axis.
It is important to place realistic expectations and agree on treatment
strategies with the patients. These patients need close monitoring and care
must be taken to avoid iatrogenic disease by limiting damage.
Remember the dictum for ocular surface disease management “less is more”.
TREATMENT GUIDELINES
Medical
Avoid using toxic medications and preservatives. Consider stopping all topical
medication, it usually takes 2 to 3 weeks for all the toxic effect to wash off. If
there is an increased frequency of drops, use nonpreserved medication. Treat

coexisting lid disease like blepharitis, trichiasis and meibomian gland
dysfunction. Occlude the puncti in aqueous deficiency, consider topical steroids
if indicated and use bandage contact lens to preserve the existing delicate
ocular surface. Fujishia et al advocate a conservative approach if there is
partial limbal stem cell deficiency with some transient amplifying cells (TACs)
remaining on the central cornea.20
Tear Substitutes and Lubricants

The basis of lubricant therapy is to employ physical means to protect a
compromised ocular surface from desiccation and lid irritation. In dry eyes
treatment with preserved artificial tears may lead to a objective improve-
ment in corneal surface disease, but the preservatives like benzalkonium
chloride may counteract the benefit,21 having been found to cause toxic or
allergic reactions with secondary changes of scarring and vascularization.22 A
guide to various types of therapy for specific tear film abnormalities23 is listed
in Table 23.3.
TABLE 23.3: A guide to various types of therapy for

specific tear film abnormalities
Abnormality Forms of therapy
Aqueous tears Artificial tears, lubricating ointment
Punctal occlusion, tarsorrhaphy
Avoid antihistamines, diuretics
Moist chamber spectacles
Tear mucin Artificial tears /lubricating ointment
Acetylcysteine
Immunosuppressants for pemphigoid
Vitamin A ointment
Tear lipids Lid hygiene, warm compresses
Oral tetracycline and other antibiotics
Tear spreading/ Artificial tears/lubricating ointment
Lid problems Taping lids, tarsorrhaphy
Other lid surgeries
Tear base (epithelial) Artificial tears/lubricating ointment
Therapeutic soft contact lens
Anterior stromal puncture/excimer PTK
for anterior basement abnormalities
Modified from “Punctal occlusion for dry eye—A three year revision”, American Academy
of Ophthalmology. Ophthalmology 1997;104(9):1521-24.
The key points to remember are the liberal use of artificial tears,
preservative-free lubricants are preferable although more expensive. Lubricant
ointment is good for night time use. Conserve the existing tears with punctal
occlusion or spectacles fitted with side shields. Tsubota24,25 recommends a
combination of lubricants, autologous serum (discussed later), punctal
occlusion, and protective eyeglasses with moist inserts and side panels as his
strategy to control the dry eye.
Suppression of Inflammation
Corticosteroids
Ocular surface defect characterized by intense inflammation is benefitted by
the use of topical corticosteroids to limit stromal destruction and suppress
anterior segment inflammation.26 The anti-inflammatory effect of cortico-
steroids are mediated through stabilization of the cytoplasmic and lysosomal
membranes, thereby reducing the release of inflammatory mediators and
inhibiting the chemotaxis of leukocytes.
For patients suffering from Sjögren’s related keratoconjunctivitis sicca,
topical nonpreserved methylprednisolone has been reported to be an effective
treatment option, as inflammation may be a key pathogenic factor in this
condition. However, careful monitoring is essential in dry eye patients treated
with corticosteroids for more than 2 weeks because steroid-related
complications like increased intraocular pressure (IOP) and cataract formation
have been observed. Hence it is more appropriate to use steroids as a short-
term pulse treatment for exacerbation of keratoconjunctivitis sicca.27
Like nonsteroidal anti-inflammatory agents (salicylates, indomethacin and
flurbiprofen), progestational steroids share the important pharmacological
effect of reducing inflammation without suppressing wound repair.28 The
incidence of perforation and deep ulceration of the alkali-burned rabbit cornea
was substantially reduced by topical or parenteral administration of
medroxyprogesterone. The mode of action of the hormone is probably at
least in part related to its suppressive effects on production of tissue collagenase,
as indicated by the considerable reduction in collagenolytic activity by living
explants of the treated corneas.29
Immunosuppressives
Certain disorders of autoimmune origin result in chronic ocular inflammation
with progressive destruction of ocular tissue. Immunosuppression with
antimetabolites or high-dose systemic corticosteroids have been effective in

managing conditions like rheumatoid arthritis, systemic lupus erythematosus
(SLE) and ocular cicatricial pemphigoid.30 There are many systemic immuno-
suppressives effective in controlling the clinical symptoms and arresting the
disease process, however, close monitoring of hematopoietic functions and
systemic toxicities in concert with a hematologist or rheumatologist is
mandatory.
Limitation of Tissue Destruction

Tissue Adhesives
Tissue adhesives, particularly isobutylcyanoacrylate have been used as an
adjunct to management of corneal ulceration and perforation.31
Its most important function is of structural support, alone or with a glued
on contact lens, it can further arrest stromal loss by excluding intrastromal
and tear polymorphonuclear leukocytes. It also has an antibacterial action
and promotes neovascularization.32
Early application of tissue adhesive in the management of stromal melts,
can postpone or reduce the need for keratoplasty or conjunctival flaps.
Mechanical Protection of the Corneal Epithelium

It is important not to overlook some simple and direct mechanical approaches
to assist epithelial healing. Temporary closure of the eyelid with patch or tape
or tarsorrhaphy are useful as they reduce the zone of exposure. Alternatives
like botulinum-induced ptosis to afford eyelid cover should be considered.
Therapeutic Contact Lens

The application of a therapeutic bandage contact lens to protect the loosely
adherent remaining transient amplifying cells or regenerating epithelium from
the action of blinking eyelids, has significantly improved the management of
persistent epithelial defects.33 Frequent irrigation and lubrication of the eye,
prophylaxis with antibiotic solutions and close follow-up are crucial especially
with dry eyes which are prone to develop infectious infiltrates and ulcers.
Soft contact lenses are undesirable in dry eye patients because of the
high risk of infection, whilst thin high water content lenses may fail because
of rapid water evaporation, further compounding the hypertonicity-induced
surface damage in the dry eye.34 Only silicone provides adequate oxygen
transmission for continuous eye wear, however, Omafilcon A (proclear ), a
novel biomimetic, 59% water content hydrogel soft contact lenses for daily
wear has been found to give better comfort, less on-eye dehydration and
less fluorescein staining than other soft daily wear contact lenses in subjects
with mild to moderate dry eye.35
In extremely dry eyes the use of non-hydrophylic silicone rubber lenses
may be an alternative to circumvent problems encountered with hydrogel
lenses.36 Rigid lenses can be used for exposure and protection. A high oxygen-
permeable scleral contact lens has been reported to provide a physiological
condition of the cornea by creating a moist atmosphere in front of the cornea
with dry eye circumstances.37
Experimental Treatment Modalities

Promotion of Epithelial Wound Healing and Differentiation
Topical autologous serum drops have been shown to keep the ocular surface
moist and provide necessary tear proteins such as epidermal growth factor
(EGF), vitamin A, transforming growth factor-beta (TGF-β), fibronectin and
various other cytokines, despite loss of endogenous tears, because all these
proteins are present in serum.38 The effect of EGF seems to be primarily on
epithelial wound healing, whereas fibronectin appears to be involved in stromal
healing. Epidermal growth factor enhances the rate of healing and induces
hyperplasia in the cornea. Tsubota has reported that topical autologous serum
drops used 6 to 8 times/day, are a safe and efficient way of providing essential
components to the ocular surface in treatment of dry eyes.39
Topical retinoids are essential for epithelial growth and differentiation. All
transretinoic acid 0.05% in Vaseline applied twice daily has been shown to
increase the epithelial healing rate.40 Retinol plamitate ophthalmic solution
has also shown an increase in goblet cells and an increase in nonkeratinized
cells.41
Topical trisodium citrate(10%) and sodium ascorbate (10%) have been
found to reduce the incidence of ulceration and perforation in the immediate
treatment of alkali-injured eyes.42
Topical 0.05% and 0.1% cyclosporin A have been recently reported
beneficial in managing dry eyes. 43 Its efficacy may be due to an
immunomodulatory and anti-inflammatory effect on the ocular surface, thus
facilitating ocular surface healing.
Surgical
There are many surgical approaches for treating ocular surface disease (the
eyelids, conjunctiva and cornea), but these are rarely used alone.
It is important to control inflammation before surgery, correct the
precipitating problem and give prophylaxis for postoperative inflammation.
Preoperatively epithelial stability must be improved by either a temporary
tarsorrhaphy, botulinum toxin-induced ptosis or therapeutic contact lens.
Associated eyelid malposition and trichiasis also need to be treated to
avoid continuous damage to the ocular surface by mechanical forces.
Methods to restore the ocular surface epithelium include limbal stem cell
transplantation and conjunctival transplantation. Amniotic membrane
transplantation (AMT) has been used to restore the stromal environment by
replacing basement membrane for epithelial cells and stromal matrix for
mesenchymal cells. Other strategies to improve the basement membrane
include anterior stromal puncture, excimer phototherapeutic keratectomy,
and corneal grafting (lamellar or penetrating). This discussion will be limited
to a few, namely limbal stem cell transplantation, amniotic membrane
transplantation with a brief mention of other procedures.
Limbal Stem Cell Transplantation

As there are multiple procedures which share the common goal of providing
a new source of epithelium, a standard classification has been proposed by
Holland EJ et al for epithelial transplantation of the ocular surface.44
Conjunctival transplantation—where conjunctival tissue is transplanted
includes:
Conjunctival autograft (CAU), cadaveric conjunctival allograft (c-CAL)
and living-related conjunctival allograft (Lr-CAL).
Limbal transplantation—where limbus or conjunctiva are mainly
transplanted includes:
Conjunctival limbal autograft (CLAU), cadaveric conjunctival limbal
allograft (c-CLAL), and living-related conjunctival limbal allograft (Lr-CLAL).
Keratolimbal allograft (KLAL) provides limbal or corneal tissue from a cadaveric
eye.
Holland and Tsengs recommendations for epithelial transplantation are
as follows:46
For patients with unilateral cicatrizing conjunctival disease, the first option
should be a conjunctival autograft (CAU), with unilateral limbal deficiency, a
conjunctival limbal autograft (CLAU) is the procedure of choice.
FIGURE 23.5: Peritomy and removal of pannus prior to allograft

transplantation
In bilateral disease, a living-related conjunctival allograft (Lr-CLAL) should

be considered first, if this procedure is not available then a keratolimbal
allograft (KLAL) is warranted. Dua and Forrester recommend debridement
of conjunctival epithelium that has migrated onto the corneal surface in partial
focal limbal deficiency, so as to encourage gradual reoccupation of the corneal
territory by corneal transient amplifying cells.47
The principle of limbal transplantation involves first a 360° peritomy with
removal of abnormal corneal epithelium and pannus (Figure 23.5).
In conjunctival limbal auto-or allografts, two strips of conjunctival tissue,
each lenticule approximately measuring 4 clock hours are harvested from
the donor and sutured to cover the area of limbal deficiency in the recipient.
In keratolimbal allograft transplantation, individual lenticules of limbal
tissues are harvested from a cadaveric eye (Figure 23.6). These can then be
used to cover the area of limbal deficiency. For total limbal deficiency, a ring
of limbal lenticules (Figure 23.7) or a doughnut-shaped 360° limbal graft
(Figure 23.8) is recommended.
A sufficient portion of limbal stroma should be included in the graft which
is fixed at its scleral and conjunctival margins. From this ring of limbal tissue,
transient amplifying cells are generated which migrate onto the denuded
corneal surface of the host (Figure 23.9). After successful transplantation the
host’s cornea should be covered by epithelium from the donor.45
Transplantation of limbal tissue from live-related donors in HLA-matched
recipients has been reportedly successful in reconstructing the ocular surface.48
FIGURE 23.6: Harvestation of a keratolimbal lenticule

from a cadaveric eye
FIGURE 23.7: Keratolimbal lenticules sutured around the

limbus, to treat total stem cell deficiency
The related donors need to be screened for potential blood-borne infectious

diseases including hepatitis B and C and human immunodeficiency virus 1
and 2. Human leukocyte antigen (HLA) typing is performed preoperatively
to find the best match.
The postoperative regimen includes use of preservative-free topical
corticosteroids three to four times a day to control inflammation, and topical
antibiotics till the epithelium has healed (roughly 1-3 weeks). Most patients
are maintained on a tapered dose of topical corticosteroids and topical
lubricants and also receive systemic prednisolone, 1 mg/kg/day, with a slow
taper over 3 to 6 months.
FIGURE 23.8: Postoperative day 4, demonstrating transient

epithelial cell waves originating from keratolimbal grafts
FIGURE 23.9: Ring-shaped keratolimbal allograft, with concomitant

penetrating keratoplasty
In patients with living-related allografts or keratolimbal allografts, rejection

of the allografts results in a breakdown of the ocular surface, therefore systemic
immunosuppression has been advocated with oral cyclosporin A.49 Recent
claims regarding the efficacy of topical 2% cyclosporin A in preventing rejection
of the allografts50 need further investigations. Systemic immunosuppression
with FK 506 has also been reported.51
Recurrence of vascularization on follow-up probably results from

inadequate stem cell transfer, immune-mediated stem cell damage or both.52
Although lamellar and penetrating keratoplasty are established procedures
for the opaque cornea, in stem cell failure, they may not be successful in the
long-term as they only provide transient amplifying cells and not corneal
stem cells.53
Using techniques of fluorescence in situ hybridization (FISH), polymerase
chain reaction (PCR) and restriction fragment length polymorphism (RLFP)
analysis, it has been found that donor-derived cells survived much longer
after limbal allograft transplantation (LAT) than those after a penetrating
keratoplasty.54
However, re-establishment of limbal stem cells by transfer in conjunction
with large diameter penetrating keratoplasty, may facilitate development of
intact, phenotypically correct corneal epithelium.55 In severe corneal thinning
or impending perforations, concomitant lamellar or penetrating keratoplasty
may be required. Prior to a second surgical intervention such as lamellar or
penetrating keratoplasty for complete visual rehabilitation, it is preferable to
keep an interval after limbal transplantation to allow for stabilization of the
ocular surface.56
Amniotic Membrane Transplantation

The technique of amniotic membrane transplantation was first used as a
biological dressing to promote wound healing.57 De Rotth in 1940, first
reported the use of fetal membranes for the plastic repair of conjunctival
symblepharon and defects, claiming that the embryonal tissues used had a
property of being transformed to conjunctiva. The epithelium of the
membrane excised two and four months after transplantation showed the
same histological structure as the epithelium of the bulbar conjunctiva.58
Sorsby later showed impressive results in the early treatment of chemical
injuries to the eye.59 Recently there has been a revival in the use of amniotic
membrane for ocular surface reconstruction. It has been postulated that
cultured conjunctival epithelial cells can express a corneal type keratin pair
when grown on a corneal basement membrane substrate. Although the
concept of transdifferentiation was controversial, it was postulated that corneal
surface reconstruction could be facilitated by the use of basement membrane
and amniotic membrane was chosen as it contained a thick basement
membrane.60 Kim and Tseng reported that transplantation of the basement
membrane-containing human amniotic membrane lead to successful

reconstruction of damaged corneal surface, with the return of a cornea-like
epithelial phenotype in 30% of rabbits tested, and wondered if the loss of
corneal epithelial phenotype is related to a loss of a basement membrane.61
However, it has been subsequently reported that there is a return of
conjunctival epithelial phenotype after amniotic membrane transplantation
for reconstructing the ocular surface. The lack of corneal epithelial phenotype
even on an avascular corneal stroma supports the concept that conjunctival
transdifferentiation does not occur in vivo, and indicates that additional limbal
stem cell transplantation is needed for ocular surface reconstruction in patients
with limbal deficiency.62
Tseng postulated that amniotic membrane transplantation (AMT) could
help in restoring the stromal environment by replacing basement membrane
for epithelial cells and stromal matrix for mesenchymal cells, AMT has been
shown to facilitate epithelialization, help in maintenance of normal conjunctival
phenotype, and reduce inflammation, vascularization and scarring of the
ocular surface.60
Tseng has recommeded that in ocular surface reconstruction for partial
limbal deficiency with superficial involvement, AMT alone is sufficient and
superior to limbal transplantation because there is no need to administer
systemic cyclosporine.
For total limbal deficiency, additional limbal transplantation is needed,
and AMT helps reconstruct the perilimbal stroma, with reduced inflammation
and vascularization, which collectively may enhance the success of limbal
transplantation62 and reduce the amount of further surgery.
Amniotic membrane has been used with success as an adjunct for
reconstructing the ocular surface along with limbal allografts, and it has been
used alone, either as a first stage procedure before the use of limbal allograft63
or as a patch graft in the treatment of persistent corneal epithelial defects.64
Amniotic membrane transplantation can be considered an alternative
substrate for conjunctival surface reconstruction during removal of pterygium,
large tumors, disfiguring scars or symblepharon, especially for those whose
surrounding conjunctival tissue remains relatively normal.65
Principal steps for amniotic membrane transplantation are: for small
persistent epithelial defects, the base of the defect is scraped clean. A hand-
held trephine of the appropriate size is used to punch a circular disk of the
amniotic membrane or a free hand graft is sutured to cover the epithelial
FIGURE 23.10: Amniotic membrane used as a patch graft for

treatment of persistent epithelial defect
defect (Figure 23.10). Re-epithelialization generally occurs over 1 to 2 weeks

(Figures 23.11 to 23.13).
For reconstructing the ocular surface, the recipient eye undergoes a
superficial keratectomy in the area of stem cell deficiency with removal of
pannus and a peritomy. The amniotic membrane is secured to the
keratectomized corneal surface and fixed in the fornices with fixation sutures
(Figure 23.14).
Topical postoperative regimen is essentially the same as for limbal stem
cell transplantation, and has been discussed earlier. General care has to be
FIGURE 23.11: Epithelium growing over amniotic membrane

(postoperative day 2)
FIGURE 23.12: Fluorescein staining showing re-epithelialization

of the amniotic membrane (postoperative day 4)
FIGURE 23.13: Fluorescein staining showing completely re-

epithelialized amniotic membrane (postoperative day 7)
taken to protect the regenerating epithelium with either a therapeutic contact

lens or lateral tarsorrhaphy.
Conjunctival Flap
In situations like neurotrophic keratitis, where the conjunctiva is fairly normal,
a conjunctival flap may supply the necessary vascularity to prevent stromal
FIGURE 23.14: Operative view of amniotic membrane used in

ocular surface reconstruction
ulceration and support repair.66 In situations of sterile stromal ulceration related

to a severe chemical burn, involving cornea, limbus and conjunctiva with
vascular ischemia, advancement of the conjunctiva or Tenon’s tissue or
autologous limbal transplantation,67 may establish the necessary vascular
supply to reverse such ischemia-related complications.
Buccal Mucous Membrane Transplantation

It is a popular technique of correcting eyelid position anomalies caused by
cicatrizing conjunctival disorders.68 It is also used to reconstruct bilateral fornix
obliteration, and eyelid margin keratinization69 in relationship to cicatrizing
disorders like SJS and OCP. Fairly good results have been reported for
inactive, late stage disease, however, with immunosuppression, in OCP, there
has been substantial success of buccal mucous membrane grafting.70
Complications include breakthrough trichiasis, surface keratinization of the
graft, ptosis, incomplete eyelid closure, persistent epithelial defects and
submucosal abscess formation.
Keratoprosthesis
Artificial corneas are recommended for use in heavily scarred and vascularized
corneas, in severely dry blind eyes. Most widely used are collar-button or
nut-bolt prosthesis. Various designs have reported benefits, however, the
problem related to extrusion of the implants, often secondary to lack of
incorporation of the prosthesis to surrounding tissues has been reportedly

addressed by the osteo-odontokeratoprosthesis (OOKP). OOKP surgery
performed in 2 stages spaced 2 to 4 months apart, has shown fair results.71
However, it is complex and requires meticulous follow-up. Oral structures
have to be sacrificed, patients experience glare and restricted field of vision,
and management of glaucoma and retinal detachment is difficult.72 It is an
option for desperate cases of corneal blindness not amenable to conventional
corneal surgery.
Excimer Laser Phototherapeutic Keratectomy (PTK)

A common problem in ocular surface disease is recurrent corneal erosions
and persistent corneal epithelial defects. Excimer laser PTK has been reported
beneficial in treating these disorders by improving the basement membrane.73
In some cases of ocular surface disease, with problems of surface irregularity,
epithelial defects and scarring, PTK may offer a better treatment option in
comparison to corneal transplantation for visual rehabilitation.74
Cultured Corneal Epithelium: A New Strategy

Autologous transplantation of cultured corneal epithelium feasible by using
either a collagen shield, soft contact lens or acellular amniotic membrane as
a carrier, has been reported as a promising new procedure, offering hope to
patients with severe ocular surface disease.75, 76 From the limbal region of the
uninjured eye a small biopsy of corneal epithelial cells is taken and cultured
in a laboratory environment on a carrier. After 2 weeks a confluent primary
culture of limbal corneal cells is established and the recipient eye is grafted
with this. The corneal epithelium repopulates the ocular surface and has
been reported to adhere tightly to the underlying stroma by hemides-
mosomes77, 78
The cultivation of corneal epithelium might offer a alternative to patients
with unilateral lesions and a therapeutic chance to patients with bilateral
limbal epithelial defects.
CONCLUSION
Patients with ocular surface disease are challenging to treat, requiring an
armamentarium of medical and surgical procedures. The accompanying
conditions of ocular surface disease, including severe dry eye, lack of corneal
stem cells, eyelid abnormalities and persistent ocular surface inflammation

render treatment with procedures like corneal grafting alone unsuccessful.
The investigation of corneal stem cells has significantly enhanced our
understanding of ocular surface disorders and has led to the development of
new therapeutic procedures. A wide body of experimental and clinical data
support the model of limbal location of corneal epithelial stem cells. One of
the concerns is that almost nothing is known about the regulation of the self-
renewal of stem cells and their resistance to differentiation inducing agents.
The lack of a suitable model system as well as the enormous complexity of
the regulatory mechanisms have precluded investigation of these important
questions. An increasing number of cytokines are being studied and
investigation of the interaction of various cell types (stromal and epithelial
cells) might eventually enable the identification of an environmental niche
that governs the regulatory stem cells. The identification of factors that prevent
the differentiation of stem cells and allows their amplification has enormous
clinical potential. Such factors could allow for a conservative treatment of
ocular surface disorders, and help in overcoming the limitations of current
management options.
CURRENT RECOMMENDATIONS FOR MANAGEMENT

Treatment of dry eye with use of nonpreserved lubricants, topical autologous
serum, cyclosporin A and vitamin A drops. Tear conservation by occlusion of
puncti and spectacles. Treatment of lid diseases like blepharitis, trichiasis and
meibomitis.
Protection of the corneal epithelium from mechanical damage by the use
of therapeutic contact lenses and/or tarsorrhaphy. Control of inflammatory
disease with the help of systemic and topical steroids and cyclosporin A drops.
Conjunctival autograft or an amniotic membrane graft in those
circumstances where there is a localized need to replace abnormal or absent
conjunctival tissue (e.g. after pterygium excision) or to restore more normal
conjunctival anatomy and function (e.g. cicatricial fornix reconstruction). In
bilateral cases (e.g. ocular cicatricial pemphigoid), buccal mucous membrane
may be substituted.
Partial limbal deficiency can be treated by amniotic membrane
transplantation alone, and in situations with widespread limbal stem cell
destruction, a limbal autograft (unilateral cases) or allograft (bilateral cases),
with or without an amniotic membrane transplantation should be considered.
More evidence on limbal transplantation procedures needs to be gathered,

especially concerning their long-term stability, the role of immunosuppression
and limbal graft rejection. Newer strategies in developing the ideal tear and
the judicious use of amniotic membrane to rehabilitate the ocular surface,
along with further research in expansion of single stem cells in culture may
provide more satisfactory clinical outcomes and substantially reduce the
necessity of high-risk surgical interventions.
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IMMUNOSUPPRESSIVE THERAPY FOR OCULAR SURFACE DISORDERS 373
INTRODUCTION
Immunosuppressive drugs should be prescribed by ophthalmologist preferably
with greater caution and in concert with an oncologist.
Till date there appears to have been very low incidence of severe
complications from the combined regimen of cortico steroids and immuno
suppressive agents probably because of lower dosage use and better general
health of ophthalmic patients receiving them. Patients should be fully informed
as to potential risks and benefits.
SELECTION OF PATIENTS
• Selection involves those patients who have progressive, usually bilateral
vision threatening disease
• Failed to respond to conventional corticosteroid therapy or have
unacceptable side effects from them
• Have Wegener’s granulomatosis, polyarteritis nodosa or Behcet’s disease
(Drugs of first choice)
• Have adequate follow-up
• Good compliance about following instructions
• Are ready to undergo therapy voluntarily with knowledge of potential
side effects
• May benefit certainly from the use of the drugs
• Have no primary contraindication like active tuberculosis, toxoplasmosis
or other infectious process.
Immunosuppressive agents used in ocular inflammatory diseases are
classified into three groups:
a. Alkylating agents
b. Antimetabolites
c. Antibiotics.
Alkylating Agents
Common alkylating agents used in ophthalmic conditions are cyclophos-
phamide and chlorambucil. They work by suppression of lymphocyte T cell
(cell-mediated immunity) and to lesser extent B cell (antibodies) function.
Clinical Indications
Behcet’s disease, sympathetic ophthalmia, rheumatoid arthiritis, polyarteritis
nodosa, Wegner’s granulomatosis, relapsing poly chondritis, bulluous

pemphigoid and malignancy.
Dosage
1. Cyclophosphamide: In adult patients start at 150-200 mg/day (1-2 mg/
kg/day) taken empty stomach. A white blood count (WBC) is taken at
day 1 and after every 2-3 days until at about 7 days. At this point dosage
is reduced by 25-50 mg to stabilize the WBC at about 3000 cells/μl. WBC
and CBC with differential are than followed weekly and fortnightly once
stabilized.
2. Chlorambucil dosage: In adult patients start at 0.1-0.2 mg/kg/day and
increased every 3-4 days to total dosage of 10-12 mg/day if there is no
idiosyncratic reaction. The WBC and CBC with DLC are followed as for
cyclophosphamide.
Adverse Reactions
Adverse side effects of alkylating agents include:
• Thrombocytopenia
• Anemia and oppurtunistic infections
• GIT disturbances
• Alopecia, jaundice
• Pulmonary interstitial fibrosis
• Renal toxicity and testicular atrophy
• Hemorrhagic cystitis is an indication for discontinuing the medication.
There is report of increased incidence of myeloproliferative and
lymphoproliferative malignancy in patients on these drugs.
The Antimetabolites
The antimetabolites used in ophthalmology are:
1. Azathioprine which interfers with purine metabolism.
2. Methotrexate which interfers with folate action.
Both functions are essential for nucleic acid synthesis.
• In rheumatoid arthiritis, pemphigoid and regional ileitis.
• Sympathetic ophthalmia and VKH syndrome.
• Pars planitis and Behcet’s disease.
• Recalcitrant cases of intermediate uveitis.
Dosage
1. Azathioprine dosage starts at 1-2 mg/kg/day gradually increasing to
2.5 mg/kg/day. The usual dose range is 100-200 mg/day in one or divided
doses. Patient WBC, CBC with differential are taken at regular intervals.
Adverse reaction:
• Uncontrolled leukopenia
• Thrombocytopenia
• Hyper uricemia
• GIT disturbances.
2. Methotrexate dosage is variable due to high drug toxicity. Generally for
1-4 weeks oral, IM or IV dose of 2.5-15 mg is given over 36-48 hours
until a therapeutic response is noted and then maintained as per
hematologic (weekly) and renal and hepatic (monthly) monitoring.
Adverse effects of methotrexate:

• Leukopenia and thrombocytopenia
• Hepatic and renal toxicity
• GIT disturbances
• Interstitial pneumonitis
• CNS toxicity and sterility.
Hematological monitoring (WBC, CBC with differential) is similar to that
of cyclophosphamide.
The Antibiotic Cyclosporin A

It probably interfers with T cell lymphocyte activation and interleukin activity
and Dapsone may work by lysosomal stabilization.
• Behcet’s disease (for which corticosteroids are contraindicated).
• Birdshot chorioretinopathy
• Sarcoid, VKH and sympathetic ophthalmia.
Relative indications are:

All non-infectious cases of uveitis unresponsive to maximum tolerated steroid
therapy.
• Eale’s disease
• Retinal vasculitis (non-infectious)
• Serpiginous choroiditis.
• Anterior segment diseases include pemphigoid, Mooren’s ulcer, high-risk

corneal transplant rejection and cataract surgery in uveitis patients.
Dosage
2.5-5 mg/kg/day given orally in an olive oil – ethanol solution with milk or
juice. Maximum dose is 10 mg/kg/day.
- It is also available as 0.05% ophthalmic emulsion for topical use in dry eye
disorders.
Adverse Effects
• Systemic hypertension
• Partially reversible renal toxicity
• Oppurtunistic infections
• Hyperuricemia
• Hepatotoxicity.
Monthly and if required weekly blood tests (CBC with differential and
WBC) should monitor these effects:
I. A combination of steroid and cyclosporine A therapy augment each
other such that addition of prednisone (10-20 mg/day) or short-term
1 mg/kg/day may allow a lowering of the cyclosporine A dosage.
(4-6 mg/kg/day) with no loss of therapeutic efficacy.
II. Chlorambucil or cyclophosphamide and steroid management module
It involves initial treatment with prednisone 1 mg/kg/day along with
cytotoxic drug at an appropriate dose. This treatment should be continued
for 4 weeks until the disease is suppressed than steroids are tapered and
stopped over 2 months. The cytotoxic drug dose is adjusted to keep the
WBC at 3000-4000/μl and continued for one year to induce remission
before being stopped. Monitor the CBC and urine analysis weekly until
stable than at every 2 weeks.
OCULAR DRUG TOXICITY OF IMMUNOSUPPRESSIVE AGENTS

USED IN OPHTHALMIC CONDITIONS
• Decrease in vision
• Visual hallucinations
• Lids or conjunctiva—redness, conjunctivitis, subconjunctival hemorrhage
and hypertrichosis
• Eyelashes or brow losses

• Retinal hemorrhages
• Retinal pigment epithelium disturbances
• Cortical blindness (cyclosporine).
RECENT ADVANCES IN IMMUNOSUPPRESSIVE THERAPY

a. Active research is going on competitive inhibition of IgE binding to effector
cells using Fc fragments from human IgE. Isolation of the specific binding
site and fragment production with recombinant DNA technology may
allow selective inhibition of mast cells or eosinophils in ocular allergic
disorders.
b. Adhesion molecules are proteins that allow cells to interact with one
another. In patients of SAC and VKC therer is a marked increase in
conjunctival expression of ICAM-1, ICAM-3 and other adhesion molecules
when compared to normal.
Intensive efforts are going on in developing specific therapeutic agents
that can modulate these adhesion molecule (proteins) and diminish the
allergic response.
c. Clinical trials are going on in development of suitable therapeutic agents
that could modulate the actions of cytokines such as IL-3, IL-5 and GM-
CSF suppressing aspects of the immune response that are not strongly
affected by current available medications. A better clinical understanding
of the role of specific cytokines in the different ocular allergic disorders
shall stimulate the development of tailoring therapeutic agents to each of
these entities.
Liposomes
New drug delivery systems may offer advantages in future therapy for ocular
allergic disorders. Liposomes are vesicles consisting of lipid bilayers alternating
with aqueous compartments. They may provide several advantages over
current therapeutic modalities in ocular diseases.
• These allow prolonged contact between the medication and ocular tissue
by preventing excessive rapid drug removal via tears.
• Changes in lipid composition and liposome structure can alter the amount
of intraocular drug absorption.
• Incorporation of monoclonal antibodies into outer lipid bilayer of the
liposome would transport the liposome to the target tissue or cell type
where the drug is required.
A safe liposome system is now available for ocular use. Cationic lipids
such as BDSA can be added to the outer surface of liposomes thereby
increasing the contact time of medication with ocular tissues. This liposome
system cause minimal eye irritation and may prove valuable in clinical
treatment of ocular allergy.
BIBLIOGRAPHY
1. Agarwal Amar. Textbook of Ophthalmology (1st edn). New Delhi: Jaypee Brothers
2. Bartlett. JD, Clinical Ocular Pharmacology (4th edn). Boston: Butterworth-
Heinemann, 2001
3. Bartlett JD. Ophthalmic Drug Facts, Lippincott-William and Wilkins, 2001.
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S3-46.
5. Ciprandi G, et al. Drug Treatment Allergic Conjunctivitis: Drugs, 1992; 43: 154.
6. Crick RP, Trimble RB, Textbook of Clinical Ophthalmology, Hodder and Stoughton,
1986.
9. Ellis PP Ocular Therapeutics and Pharmacology (7th edn): CV Mosby, 1985.
11. Fraunfelder. Current Ocular Therapy, (5th edn). WB Saunders, 2000.
15. Goodman LS, Gilman A, Pharmacological Basis of Therapeutics (7th edn). New
York: Macmillan, 1985.
17. Kanski. Clinical Ophthalmology (4th edn). Butterworth-Heineman, 1999.
19. Olin BR, et al. Drugs Facts and Comparisons: Facts and Comparisons, St. Louis,
1997.
Publishers, 2001.
23. Zimmerman. Textbook of Ocular Pharmacology, Lippincott and William and Wilkins,
1997.
OCULAR SURFACE DISORDERS DUE TO DRUGS TOXICITY 381
INTRODUCTION
Ocular tissue undesired side effects have been seen by every ophthalmologists
in their practice involving various drugs used topically and systemically for
the treatment of various ocular problems. An adverse drug reaction (ADR) is
an undesirable response to a drug occurring during or following a course of
therapy. The types of adverse effects of drugs on the eye may be mild and
transient like temporary decrease in vision, abnormal pupillary responses,
accommodation impairment, color vision disturbance, abnormal eye
movements to serious side effects like cataract, glaucoma and retinal damage
which may seriously disrupt in ocular functions.
It is essential for every ophthalmologist to have complete insight to
recognize and prevent vision threatening complications from adverse effects
of drug reactions. It is essential for the ophthalmologist to obtain a careful
history with special attention to particular medication used. The clinicians
shall be fully aware of certain oculotoxic drugs and their side effects to detect
the drug-related ocular disorder.
Before going into details of complications of various topical ocular
formulations, let me remind you that for certain drugs with potential ocular
toxicity a careful pre-treatment examination should be performed before
the drug is administered specially if:
a. The drug shall be used for a long period of time.
b. It is known to have established severe toxic effects.
Patients taking such drugs should undergo frequent monitoring
examinations so that if the symptoms do arise, the drugs can be withdrawn
immediately.
Often reversible effects are observed while the patient is off the drug and
later after resolution of the effects, the drug regimen may be restarted at a
lower dose. The pre-treatment examination should include following
parameters:
Visual acuity: Check visual acuity for near and distance vision with and without
pin hole testing and spectacles (if required).
Pupillary responses: Check pupil size, briskness of reactions (direct and

consensual) to light and convergence reflex.
Ocular motility examination: Check complete motility in all field directions of

gaze with ductions, versions and convergence.
Intraocular pressure monitoring: Periodic tonometry should be done as intra-

ocular pressure rise is sensitive adverse effect of certain topical formulations.
Slit lamp examination: It is essential as certain drugs affect the conjunctiva,

cornea and lens.
Ophthalmoscopy: Perform ophthalmoscopy (direct and indirect) with dilation

as certain drugs may produce changes in the retina, macula and the optic
nerve.
Specific retinal function examinations: These examinations include:

• Electroretinography (ERG)
• Fundus photography
• Visual field analysis
• Color vision tests
• Visual evoked potential (VEP)
• Fluorescein angiography.
Generalized ocular manifestations of drug toxicity:

• Reduced visual acuity due to transient changes in refractive errors, anterior
and posterior segment toxicity.
• Blurring of vision may be caused by mydriasis and cycloplegia as well as
anterior and posterior segment toxic changes.
• Color vision disturbances that may include hallucination, altered
perception and diminished sensitivity.
• Ocular movement abnormalities include neuromuscular myesthenic block,
paralytic strabismus, diplopia and oculogyric crisis.
• Severe conjunctival inflammation and corneal opacification.
• Glaucoma
• Cataract development
• Optic nerve pathology (optic neuritis).
• Exophthalmos, retinal hemorrhage, vasculopathy, retinal pigment
epitheliopathy and macular edema.
Ocular adverse drug reactions (OADR) may be predictable and
unpredictable. In 80-90% of cases OADR caused by drugs can lead to complete
loss of vision also. The causes of adverse drug reactions are summarised as
follows:
• Exaggeration of intended pharmacological effects
• Concomitant administration of drugs with synergistic effects

• Immunological mechanism
• Idiosyncratic reactions
• Cytotoxic reactions
• Genetically determined enzymatic defects
• Error in self-administration of the drugs.
Here in this chapter I shall discuss the main systemic and local complications
due to the use of various topical ocular formulations and ocular surgery
adjuncts prescribed by ophthalmologists in their day-to-day practice. In
modern high tech scenario it is important to have complete insight into the
complications of prescribing ophthalmic formulations.
COMPLICATIONS OF TOPICAL ANTIMICROBIAL AGENTS

Topical antimicrobial drugs—antibiotics, antifungals, antivirals and anti-
parasitics are the most common drugs prescribed by ophthalmologists. These
drugs used to treat a wide variety of infectious diseases ranging from mild
conditions to vision threatening infections such as corneal ulceration and
endophthalmitis. Topical antimicrobial agents are often used in postocular
surgical phase for the prophylasis of infections. Although these drugs are
effective, however, in some cases complications may arise from their use. In
this chapter the common and serious complications of the use of topical
antimicrobial drugs are reviewed.
Systemic Complications
A major advantage of the topical use of drugs is that high local drug level can
be achieved with minimal systemic absorption. However, idiosyncratic and
immunological reactions can occur with exposure to minute quantities of
drugs. One such reaction that may occur related to the use of topical
antimicrobial drugs is Stevens-Johnson syndrome.
Stevens-Johnson Syndrome
It is an acute dermatitis with severe mucous membrane involvement that
most commonly occurs in association with Mycoplasma pneumoniae infection
or as a reaction to variety of drugs. In the milder form of disease there is
symmetrical involvement with skin lesions affecting mainly the extremities.
Mucous membrane involvement is mild and generally limited to one surface.
The disease generally resolves in 1 to 4 weeks without imp. sequelae.
In major form cutaneous eruptions are more variable in morphological

features, area of extent of involvement.
Lesions may become confluent, bullar may form and there may be toxic
epidermal necrolysis.
Drug-induced cases of STS generally occur after 7-14 days of drug therapy
but may occur within hours if patients had previous exposure to the drug.
Sulfonamides are the drugs most commonly complicated as causes of SJS
followed by pencillins.
Phenylbutazone and barbiturates. Patients should be questioned about
previous exposure to sulfonamides and specially about any reaction to these
drugs before ophthalmic sulphonamide preparations are prescribed.
Local Complications
Most of the complications of topical antimicrobial drugs affect only local
structure. They may be immunological or allergic in origin, related to toxicity
of the drug or reflect a lack of specificity of effect against the organism being
treated. Local side effects may be caused by preservatives which are combined
in commercially available antimicrobials.
Nonspecific Local Complications

Contact Dermatoconjunctivitis
It is a cell-mediated reaction and most commonly related to the use of topical
ophthalmic medications. Patients are usually sensitized to previous exposure
to the drug. Because of popularity of topical neomycin-polymixin B-bacitracin
combination, many individuals are sensitized to neomycin, a common cause
of this condition. This disease begins 24-72 hours following repeated instillation
of the drug.
The patient complains of itching. Chronic changes include thickening of
skin and hyperpigmentation and sometimes mild ectropion may occur.
Initially findings will be more apparent in the lower conjunctiva and eyelid
but eventually the entire eye and upper lid are involved in the process.
Conjunctival involvement takes the form of papillary conjunctivitis.
The diagnosis of contact dermatoconjunctivitis is generally made on the
basis of clinical appearance of the patient. In patients taking several topical
ophthalmic drugs, the specific offender can be identified by cutaneous patch
testing.
In addition to neomycin other drugs that may cause CDC are topical
gentamicin, tobramycin, idoxuridine, trifluridine, natamycin, atropine and
commonly used preservatives like thiomersal and EDTA. The treatment of
CDC requires identification and discontinuation of the offending agent.
Chronic Follicular Conjunctivitis

CFC may occur as a complication of the long-term topical use of the drug.
Affected patients complain of chronic redness and mild discharge. In general
follicular reaction involves both the upper and lower palpebral conjunctiva
but it is most apparent in the lower fornix.
Drug-related CFC is a diagnosis of exclusion.
Idoxiuridine is the most common cause of CFC among the antimicrobial
drugs. Sulfonamides are also another cause for CFC. The conjunctivitis resolve
in 6 weeks after discontinuation of offending drug.
Punctate Marginal Keratitis

It occurs either during the acute stages of infectious conjunctivitis or as a
hypersensitivity reaction to topical drugs. The most common topical
antimicrobial drug implicated is gentamicin but several other drugs like
atropine, mydriatics and epinephrine may also cause.
PKM treatment involves the discontinuation of the offending agent. In
addition topical steroids may be useful.
Keratitis Medicamentosa
It refers to corneal epitheliopathy related to the use of certain topical
medications. In milder form KM may affect only the lower cornea. In more
severe forms, the entire corneal epithelium may become involved. The
epithelium may slough and superficial stromal edema and necrosis may lead
to corneal scarring and vascularization. KM must be suspected in any patient
with epithelial keratitis of any degree. The antivirals appear to be most common
cause of medication-induced epithelial keratitis. A 2-week course of idoxuridine
or trifluridine will nearly always cause KM. Among the antibiotics the
aminoglycoside, neomycin, gentamicin and tobramycin appears to be drugs
that may cause KM. Preservative benzalkonium commonly used in prep of
topical antibiotics may also cause desquamation of the outer two layers of
the corneal epithelium.
The treatment of KM is discontinuation of all topical medications. Early

recognization of the problem is essential since advanced disease may take 2-
3 months to clear. The use of nonpreserved artificial tears may ameliorate
symptoms. In extreme causes, use of bandage soft contact lenses may relieve
pain until the epithelium begin to heal. Patient should understand the nature
of disease as prolonged time may be required for disease resolution.
Inhibition of Epithelial Wound Healing

Antimicrobial drugs exert their effects by one of two broadly defined
mechanisms of action: (i) disruption of cell wall (ii) inhibition of intracellular
metabolic process.
To heal an epithelial defect, the bordering epithelium must replicate and
slide to fill the defect. In addition epithelial defects may persist following any
type of corneal infection and antibiotics, antifungals or antivirals may be
used beyond the period that is needed to eradicate the infecting organisms.
Antimicrobial drugs that inhibit intracellular metabolic processes may have a
deleterious effect on healing of corneal epithelium.
Although topical antimicrobials may not have an appreciable effect on
the healing of healthy epithelium following a mechanical injury but these
agents may have a markedly deleterious effect on the healing of persistent
epithelial defects that occur in neurotrophic, postsurgical and postinfections
corneas and in corneas that have suffered chemical injuries.
The first step in treating such cases is to assess the patients topical
medications and to eliminate or reduce to lowest possible level of all those
might interfere with epithelial healing.
Specific Local Complications

Sulfonamides
Calcific band-shaped keratopathy has been reported with use of topical
sulfonamides. This was most likely complication caused by the preservative
since band keratopathy is known to be caused by chronic exposure to organic
mercurials.
Amphotericin B
Salmon colored subconjunctival nodules have been seen following S/C
injection of amphotericin B in doses greater than 5 mg. Histological
examination of nodules revealed numerous histiocytes in an area of fibrosis
in addition to lymphocytes and plasma cells. The lesions eventually resolved

but permanent yellowing of conjunctiva remains.
Idoxuridine
IDU has been reported to cause punctal or canalicular stenosis. It has been
attributed to cicatricial changes occurring in patients who have had a CFC
related to the drug.
Propamidine
Propamidine isoethionate is a nonspecific conjunctivitis remedy. It can cause
intraepithelial microcystic lesions related to the use of topical preparation.
The lesions are asymptomatic and resolved without sequelae following
discontinuation of the drug.
COMPLICATIONS OF STEROIDS
Corticosteroids are important therapeutic agents that are used to treat ocular
inflammation commonly.
Complications of steroids are related to dose and duration of therapy.
The clinician must consider all the possible complications when counseling
and treating patients with vision-threatening disease.
Corticosteroids
Few adverse effects of steroids occur with short-term therapy. Most problems
occur with long-term therapy. However, long-term and short-term adverse
effects are grouped together. In general, the lower the maintenance dose,
lesser the side effects. These adverse effects are produced both by topical
and systemic steroid therapy.
Topical Steroids
Dermatitis
Periocular dermatitis resulting from long-term use of fluorinated steroid drops
or ointment have been reported. This dermatitis is similar to perioral dermatitis
and should not be confused with allergic contact dermatitis.
Infection and Ulceration

Inappropriate use of topical steroids by patient and registered medical
practitioners lead to infectious keratitis specially herpetic keratitis. Reactivation
of herpes simplex virus in patients who have undergone penetrating

keratoplasty is specially common in patients who were previously treated
with steroid antibiotic combination.
Delayed Wound Healing

Corneal wound healing may be inhibited by proliferation of fibroblasts and
new vessels. Ocular surgery may be carried out but the surgeon may use
interrupted suture techniques and delay suture removal for few weeks.
Periocular Steroids
One of the rare but most dangerous complications of injections behind Tenon’s
capsule is penetration of globe and accidental intraocular injection, substantial
retinal damage has also been reported when the vehicles in which steroids
are commonly packed react. The preservatives and the osmolality of the
vehicle can cause retinal degeneration, pre-retinal membrane formation,
cataract formation. Other complications of injection itself includes retrobulbar
hemorrhage, proptosis of globe and fibrosis of extraocular muscles.
Increased IOP may also occur with depot injections of long-acting steroids.
Injections of long-acting steroids are not indicated in patients with episcleritis
and scleritis.
Systemic Steroids
Systemic steroids affect patients in many ways. A number of side effects
seem to occur early on, in the treatment. The classical clinical triad that
contributes to the moon-face appearance of some patients using systemic
steroids comprises ptosis, chemosis and swelling of the periorbital tissues.
Various Adverse Effects

Abnormalities of the hypothalmic-pituitary adrenal axis: Soon after start of
steroid therapy abnormalities of hypothalmic-pituitary gland adrenal axis
including decreased cortisol, adrenal axis response to ACTH and blunted
response to insulin-induced hypoglycemia can occur. Long-term therapy
may blunt this effect.
However, low dose maintenance and alternate day therapy will minimize
this effect.
Steroids should be withdrawn slowly as quick tapering often result in
flare-up of ophthalmic disease and can leave the patients with adrenal
FIGURE 25.1: Fluorescein stain of dendritic ulcer with

numerous branches made worse by the use of topical steroid
eyedrops
FIGURE 25.2: Steroid-induced dendritic keratitis.

Fluorescein stain of dendritic ulcer
suppression. Too rapid a decrease in steroids can also result in pseudorheu-

matism. Systemic steroids can also cause retardation of growth in children
and secondary amenorrhea in females.
Ophthalmic changes: Studies have shown the presence of exophthalmos

induced by exogenous steroids. Other ocular effects are:
• Ocular palsy due to extraocular muscles myopathy
• Thining and thickening of sclera
• Refractive changes due to electrolyte and water shifts
FIGURE 25.3: Steroid-induced dendritic keratitis, dendritic ulcer

under magnification with fluorescein stain (Courtesy: Kanski
Clinical Ophthalmology, Butterworth International Edition)
FIGURE 25.4: Steroid-induced fungal keratitis (Courtesy: Kanski

Clinical Ophthalmology, Butterworth International Edition)
• Posterior subcapsular cataracts

• Elevation of IOP
• Papilledema, visual fields changes like scotoma, constriction and glaucoma
field defects
• Ptosis, subconjunctival hemorrhage
• Visual hallucinations, mydriasis, ciliary body epithelial microcysts
• Color vision defects, myopia, diplopia
• Myesthenic block and toxic amblyopia
• Central serous retinopathy
• Herpes keratitis activation

• Retinal hemorrhages, edema, abnormal ERG and VEP.
• Pseudotumor cerebri.
COMPLICATIONS OF TOPICAL OCULAR ANESTHETIC AGENTS

Topical ocular anesthetics play an important role in the diagnosis and treatment
of ocular diseases. Although these anesthetics are generally safe, complications
do arise from their use. In addition the potential for their abuse exists, causing
significant ocular morbidity. The complications of topical anesthetics must be
recognized because such complications often can be treated or reversed proper
recognization of these complications may reduce the incidence of ocular
morbidity. The ophthalmologist must be aware of the possibilities for
complications both ocular and systemic and how to deal with those that
arise.
Adverse Effects
Direct Corneal Effects
Topical anesthetic agents can affect the eye in many ways, including the
alteration of lacrimation and tear film stability and direct epithelial toxicity.
Endothelial toxicity may occur in cases of perforating injury. Moreover, agent
and its vehicle may serve as reservoir of microbial contamination with the
potential for causing an infection.
Alteration of lacrimation: Topical anesthetics can cause decreased stability of

tear film and decreased aqueous reflex tear production by virtue of their
own properties or properties of preservatives. Anesthetics by disrupting the
surface microvilli of the epithelial cells cause a decrease in mucous adherence,
poor wettability of cornea and shortening of tear break up time. Ocular
surface anesthesia block conduction in the different loop of reflex tearing
pathway causing decreased aqueous tear production in response to noxious
stimuli. Further these agents cause the blink rate to decrease. All these factors
cause an increased rate of tear evaporation facilitating deterioration of the
ocular surface.
Epithelial toxicity: Direct epithelial toxicity can occur when an epithelial defect
is present, topical ocular anesthetics slow down the healing process. Chronic
use of topical ocular anesthetics causes delayed healing of epithelial defects
by mechanism of disruption of the vinculin-based epithelial cell motility

complexes. In the intact epithelium topical proparacaine 0.5% has been shown
to increase the sloughing rate of epithelial cells.
Endothelial toxicity: Endothelial toxicity may be caused by exposure to

topically applied anesthetic agents when a transcorneal portal of entry
(perforating injury) is present. Intracameral BAC the primary preservatives
used in topical anesthetics (0.025-0.05%) causes irreversible corneal edema
data on individual toxicities of topical agents to the endothelium are not
available yet.
Microbial contamination: The possibility of multidose vial contamination has

been reported in some cases. The squeeze bottles of topical anesthetic agents
had recoverable bacterial contamination in the cap areas.
Secondary Adverse Effects

Interference with Diagnostic Tests
Hypofluoroscence of fluorescein: All ocular surface anesthetics can cause
interference with and distoration of diagnostic test results. It can cause decrease
in the fluoroscence of sodium fluorescein. Use of artificial tears solutions, or
sterile sodium chloride as a vehicle for the fluorescein will avoid this decrease
in fluorescence.
Variability in Schirmer’s Testing

The use of topical anesthetic agents diminishes the reliability of Schirmer’s
testing. This effect is due to fact that variability in the density of anesthesia
may cause a variability of reflex tearing. One can avoid this condition by
increasing the density of anesthesia.
Reduction of Microbial Recovery

Topical anesthetic drugs have been reported to decrease the recoverability
of organisms in ocular surface culturing.
Preclusion of Sequential Testing

Topical agents may preclude necessary diagnostic testing. In case of disorders
such as Horner’s syndrome, the use of topical anesthetic agents can distort
the results of subsequent cocaine and hydroxyamphetamine testing. In diseases
caused by herpes zoster or simplex, with strong neurotrophic components,
topical anesthetic may mask significant diagnostic clues. The order of

instillation of drops in diagnostic testing must be carefully planned.
Surface Keratopathy
Punctate keratitis is a hypersensitivity reaction caused by topical anesthetic
agents themselves.
Topical agents precipitate intraepithelial proteins or globulins.
This punctate keratitis is frequently absent immediately after the instillation
of topical anesthetic agent, but it may appear about 5-20 minutes later.
Alterations of Ocular Response to Other Topical Agents

Changes in Epithelial Permeability
Topical anesthetics may cause the eye to respond differently to other topically
applied agents by changing the permeability of the ocular surface to such
agents altering their bioavailability. The alteration in permeability of the ocular
surface to various agents may involve a direct effect on the epithelium. These
agents cause a loosening of the desmosomal area of cell to cell adhesion.
When this condition occurs other pharmaceutical agents are more able to
penetrate this normally poorly permeable layer.
Prolonged Surface Contact

The bioavailability of topically applied agents may be altered by an additional
mechanism. Anesthetics decrease the reflex secretion of tears causing an
increase in length of time required for tear wash out. This allows topically
applied agents to be in contact with the epithelial surface for a prolonged
period of time.
Abuse of topical ocular anesthetics: Topical ocular anesthetic abuse is a serious

disorder causing keratitis and persistent epithelial defect. It is generally accepted
that frequent use of topically applied agents cause poor healing of epithelial
defects, leading to corneal stromal infiltration. This infiltrate appears ring-
shaped. The presence of a prolonged epithelial defect may also give rise to
an increased susceptibility to secondary infections.
Various ocular adverse effects reported with topical anesthetic agents are
summarized as below:
• Mild stinging and burning sensation
• Vasodilation
• Shortening of tear break-up time

• Decreased blinking
• Corneal edema
• Decreased epithelial mitosis and migration
• Slow epithelial healing
• Punctate epithelial keratitis
• Epithelial desquamation
• Allergic reactions of lid and conjunctiva
• Iritis.
TOXICITY OF SURGICAL SOLUTIONS

Surgical solutions play an important role in many aspects of anterior and
posterior segment ocular surgery. They include preoperative antiseptics,
irrigating solutions viscoelastic substances, mydriatics and miotics and a number
of other agents designed to enhance intraocular operations. All surgical
solutions and additives have the potential for injuring the tissues they contact
like cornea, lens, trabecular meshwork, uvea, vitreous and retina. This potential
for injury is more when solution is used inside the eye rather than applied
externally because the concentration to which the sensitive intraocular tissues
are exposed are much higher. Because of potential for toxicity there should
always be specific indication for the use of an intraocular solution or
medication.
Antiseptic Solutions
Cleaning of periocular skin area with an antiseptic scrubbing solution is a
routine step in the preparation of the eye for operation and is designed to
reduce the risk of bacterial contamination. Toxicity of these solutions is related
to inherent toxicity of the antiseptic itself, concentration, presence of a
detergent and contact time.
Recent reports of keratitis resulting from accidental exposure to
chlorhexidine highlight the potential for toxicity of the scrubbing solution is
allowed to enter the cojunctival sac.
Pain and decreased vision following chlorhexidine exposure, this was
associated with:
• A large corneal epithelial defect
• Punctate keratitis
• Stromal edema and vascularization

• Intrastromal hemorrhages
• Irreversible bullous keratopathy.
In chlorhexidine exposure limited to epithelial involvement, the patients
recovered without sequelae within 5 days.
The adverse effects have also been seen following use of following
antiseptics:
• Tincture of iodine
• Hexachlorophene 3% with detergent
• 70% ethanol
• 7.5% povidone iodine with detergent (Betadine).
Toxicity of these antiseptics can lead to:

• Marked corneal de-epithelialization
• Conjunctival chemosis
• Anterior stromal edema.
Corneal toxicity is a potential for corneal exposure to scrubbing solution
cannot be completely eliminated. It is advised to use 10% povidone iodine
solution without detergent (Betadine solution). This solution is germicidal
against a broad range of gram-positive and gram-negative bacteria, yeast,
fungi and protozoa.
In addition conjunctival sac can be irrigated with BSS after the skin has
been prepared.
Irrigating Solutions Toxicity

An essential component in most intraocular surgical procedures is a safe
irrigating solution. The irrigants keep the globe inflated and maintains normal
pressure volume relationships intraoperatively. The increase in the number
of intraocular surgical procedures being performed over the last decade has
been paralleled by an increase in the number of commercially available
irrigating solutions.
The potential for damage to the corneal endothelium and other tissues is
related to the chemical composition, pH and osmolality of the solution that
bathes those tissues.
The most physiological solution is the one that most closely matches the
chemical composition of human aqueous humor. BSS plus is an ideal solution.
Endothelial barrier and pump functions both may be adversely affected by
nonphysiological solutions. The key advantage of BSS plus lie in its

physiological bicarbonate buffer and the presence of glucose and glutathione.
Patients at Increased Risk

Patients with low cell densities or morphological abnormalities of the
endothelium (diabetes, endothelial dystrophies) are known to be more
susceptible to surgical trauma and other stresses such as contact lens wear
that might result in corneal decompensation. Diabetics are also more likely
than others to require cataract extraction or vitrectomy.
A physiological irrigating solution becomes even more important as
intraocular manipulations become more complex and the duration and
volume of irrigation increases.
Formulation Problems and Toxicity

There have been reports of irrigating solution toxicity most of which are
related to microbial contamination, indequate packaging or improper
formulation. Filamentous fungi yeasts and anerobic bacteria have been
isolated from various irrigating solutions and corneal stroage media in recent
years.
Container failures and manufacturing errors have been implicated as source
of contamination.
A single lot of contaminated irrigating solutions can result in widely dispresed
cases of postoperative endophthalmitis many of which may be delayed in
onset or difficult to diagnose.
Poor packaging of irrigating solutions can result in widely dispressed cases
of postoperative endophthalmitis many of which may be delayed in onset or
difficult to diagnose.
Poor packaging of irrigating solutions may lead to corneal decompensation.
Improper formulation and variations in quality control result in
intraoperative endothelial cell edema and temporary corneal clouding.
Reuse
I strongly advise against reuse of irrigating solution because of the increased
risk of contamination. Irrigating solutions contain no preservatives, and designed
to be used once after opening. Reuse contradicts all standard infection control
principles and increase the chances of error in the operation theater.
Viscoelastic Solutions
Viscoelastic solutions are used increasingly for protection of corneal
endothelium and manipulation of tissues during anterior segment surgery.
Generally these solutions are effective and well-tolerated in most instances.
Clinical problems associated with these solutions have been related to increased
intraocular pressure formulation problems and intraocular inflammation as
well as corneal edema and corneal decompensation.
Formulation Problems and Toxicity

Currently available viscoelastics solution are formulated in phosphate buffered
saline and non-buffered saline (Amvisc). All appear nontoxic to the
endothelium. However, calcium precipitation due to excessive phosphate
concentration in the viscoat vehicle have been seen.
Intraocular Inflammation
Commercially available, highly purified viscoelastic solutions are non-
antigenic in human beings. However, in some cases postoperative
intraocular inflammation has been seen (iritis and hypopyon). It is probably
due to the presence of endotoxins or other protein impurities in the viscoelastic
material.
New Viscoelastic Solutions

A host of new viscous solution based on sodium hyaluronate, chondroitin
sulphate, hydroxypropyl methyl cellulose, polyacrylamide and collagen are
being developed. An ideal viscoelastic solution should effectively protect and
manipulate tissues. It should be uniform, inexpensive and easy to manufacture
and purify. It also should not contain antigenic proteins. Finally it should be
formulated in a BSS that resembles as closely as possible the composition of
aqueous humor.
Mydriatics and Miotics

Control of pupil during intraocular surgery can be accomplished using a
variety of mydriatics and miotics. Almost all drugs formulated for topical,
intravenous use contains preservatives and other chemicals that are toxic to
the endothelium or that may adversely affect the physiological balance of
the ocular irrigant.
Mydriatics
A well-dilated pupil facilitates many surgical maneuvers. Intraocular
epinephrine has been the mydriatic of choice for most ophthalmologists.
Studies have shown the corneal edema after intraocular administration of
epinephrine. Toxicity of 1:1000 and 1:10000 solutions is due to sodium
bisulfite (preservative), an acidic pH and nonphysiological citrate buffer.
Miotics
A miotic pupil facilitates corneal trephine centration, peripheral iridectomy,
anterior chamber lens insertion and a variety of other intraocular
manipulations. Most surgeons prefer a miotic pupil at the end of cataract
surgery to ensure lens centration and to protect the endothelium from the
lens implant. Pilocarpine is toxic to the endothelium, so its intraocular use
should be avoided. Currently available intraocular miotics include acetylcholine
chloride (miochol) and carbachol.
Some reports have shown the corneal swelling and endothelial changes
during perfusions of human cornea with miochol. When carbachol use may
lead to reversible corneal swelling.
Other Agents
Preservatives
Preservatives like sulfites, parabens, benzalkonium, benzyl alcohol,
chlorhexidine and thiomersal have been shown to affect endothelial structure
and function adversely and their use should be avoided benzalkonium
chloride is particularly toxic.
Another potential source of preservative toxicity is reuse of instruments
and irrigating tubings. Ethyline oxide gas sterilization of plastics may cause
release of complex compounds that can combine with sterilant residues,
resulting in toxicity or inflammation. Iritis and corneal decompensation have
been reported as a result of toxicity from thiomersal residues in reused
viscoelastic cannulas.
Thrombin
Commercial preparations of bovine thrombin designed for topical application
have been added to irrigating solutions and used during vitrectomy for diabetic
retinopathy and trabeculectomy for neovascular glaucoma. These thrombins
have been shown with 20% incidence or severe postoperative inflammation

with sterile hypopyon formation and fibrin deposition.
Alpha Chymotrypsin
It is a proteolytic enzyme mainly used for enzymatic zonulysis for intracapsular
lens extraction specially in young patients.
The adverse effects reported with alpha chymotrypsin include transient
rise in IOP, corneal edema, striation, moderate uveitis, delayed healing of
incisions, wound disruption and vitreous loss.
Hyaluronidase
The enzyme hyaluronidase is commonly used in conjunction with local
anesthetic (lignocaine 2% with adrenaline) for infiltration and regional local
anesthesia.
Hyaluronidase is antigenic and may sometimes produce allergic reactions.
Because of danger of spreading infection the enzyme should not be injected
into or around an infected area.
COMPLICATIONS OF CONTACT LENS SOLUTIONS

Todays contact lens professionals have not only many different lenses at their
disposal but also a great number of sophisticated contact lens solutions. Recent
datas for possible sources of eye irritation, increased incidence of allergic
sensitivity, chemical and physical changes in lens integrity and discoloration
or lens spoilage have been traced to problems related to contact lens solutions.
The most prominent complications are related to:
• Solution stability
• Patient sensitivity
• Chemical and lens binding
• Product compatibility.
Solution Stability
The composition of contact lens solutions are from simple salt solutions to
complex disinfecting formulas. The possibility of complications with their use
is always present in the hands of typical contact lens wearer.
Many of the ingradients of the contact lens solutions change with time
and precipitate undesirable reaction. An example of an undesired reaction
in contact lens solutions is changed in sorbic acid, a popular preserative for
such solutions which when in fresh state performs satisfactorily but when
allowed to degrade produces mixed aldehyde that can discolor protein
deposits on the lenses. Consequently, the useful life is shortended. Many
contact lens solution can develop physical stability problems, i.e. precipitates,
unnatural odor or color, evaporation under a variety of conditions. Both hot
and cold weather are responsible in this process.
Sensitivity
Sensitivity reactions can be grouped as allergic responses to either specific
chemicals or contact lens deposits. The typical sensitivity to thiomersal has
been well-documented.
Once a contact lens wearer recognizes his or her sensitivity to thiomersal,
the wearer should avoid products containing this preservative.
Most wearers can tolerate sorbic acid preserved products much better
than thiomersal preserved products. From the first day, they are worn, contact
lenses collect deposits consisting of complex mixtures of protein, lipid and
mucin. Workers have shown that giant papillary conjunctivitis is an
autoimmune response of the conjunctiva to contact lens deposits. This
condition is a significant contributor to the contact lens drop out rate.
Binding
Some of the ingradients of contact lens solutions are attracted to external
and internal surfaces of the lenses. This phenomenon severily limits the types
of chemicals for contact lens formulations.
Benzalkonium chloride (BAC) is the most widely used preservative of
ophthalmic and hard contact lens solutions. In soft lens reaction BAC was
found to bind very strongly to HEMA material. This binding leads to
concentration of BAC in the lenses which then renders the lenses potentially
damaging to the eye.
This complications lead to search for low binding/non-binding chemicals.
Chlorhexidine, an antibacterial disinfecting and preservative agent was found
to have a much lower binding to HEMA than BAC. As a result chlorhexidine
is widely used as both preservative and a disinfecting agent for soft contact
lenses but the accumulative binding of chlorhexidine to protein deposits is
undesirable. Thus regular cleaning of HEMA lenses become specially
important.
This leads to the use of hydrogen peroxide (H2O2). The chemical

degradation route of H2O2 is very well-defined.
The advantage of H2O2 for soft contact lenses is that there is no undesirable
action.
Compatibility
Contact lens wearers have too many care products from which to choose many
wearers mixing and matching these products indiscriminately. For example a
wearer might use a clearner of one company and disinfecting solution from
other company. Although many contact lens solutions are reasonably
compatible with other company products. The use of combinations of contact
lens solutions may lead to variety of problems ranging in severity from minor
to major. Further failure of the user to read directions for use, carefully and
to comply with these directions can lead to unfortunate circumstances.
Recently Bausch and Lomb and Allergan have come up with an excellent
multipurpose solution for soft and RGP lenses which contains no chlorhexidine
and thiomersal. It can be used safely for cleaning, rinsing, disinfecting and
storing soft lenses without any side effects. Compatibility and stability of
solution is very good. There is no binding and sensitivity reactions reported
with multipurpose solution.
DRUG-INDUCED OCULAR CICATRIZATION

Drug-induced ocular pemphigoid or drug-induced cicatrization of the
conjunctiva is clinically identical to this disease and occurs secondary to long-
term use of topical ocular medications. Topical ocular therapy can produce
many side effects, i.e. scarring with shrinkage of conjunctiva although less
common, but is a deleterious complication of long-term use of certain topical
ocular medications. Drugs that have been shown to produce such effect
include epinephrine, pilocarpine, idoxuridine, timolol, echothiophate iodide,
demecarium bromide and various preservatives in topical eyedrops.
Kristensen and Norn were first to suggest an association between long-term
topical drug use and ocular cicatrization.
Clinical Manifestations
Differential Diagnosis
The early diagnosis of drug-induced ocular cicatrization is difficult. The early
manifestations—chronic conjunctivitis with irritation, burning and tearing are
FIGURE 25.5: Drug-induced ocular cicatricial pemphigus
FIGURE 25.6: Drug-induced Stevens-Johnson syndrome
similar to those of ocular cicatrical pemphigoid. Later on dry eye symptoms

develop. Corneal dessication leads to foreign body sensation, photophobia
and reduced visual acuity from scarring. Terminal stage disease is characterized
by ocular surface keratinization and ankyloblepharon. The diagnosis is missed
unless the fornices of patients using long-term topical medications are
examined for shortening or shrinking. The diagnosis of drug-induced ocular
pemphigoid is made both by excluding other causes of conjunctival shrinkage
and by obtaining a thorough history of topical medication use. The differen-
tial diagnosis of ocular scarring and shrinkage must be kept in the mind.
These can be:
• Chemical, thermal or radiation burns
• Severe membranous conjunctivitis
• Stevens-Johnson syndrome
• Sjögren’s syndrome
• Sarcoidosis
• Trachoma
• Bullous pemphigoid
• Pemphigus.
Ocular cicatrical pemphigoid is a chronically progressive disease and if
untreated can have a variable and asymmetrical course that may or may not
be progressive. It can occur as nonprogressive toxic reaction that is self-
limiting once the offending topical medication is stopped or it can be
relentlessly progressive. In progressive cases an immunological factors has
been suggested.
Disease Stages
Although there is no uniformly accepted classification for ocular cicatrical
pemphigoid, yet Foster has described following four stages:
Stage I: It consists of conjunctival inflammation, mucoid discharge, rose bengal

staining of the conjunctival epithelium and subepithelial fibrosis with fine
white subepithelial striae.
Stage II: It continues with conjunctival shrinkage and foreshortening of the

inferior fornix.
Stage III: It includes frank symblepharon and a wide variety of other ocular
changes including keratopathy, corneal neovascularization, trichiasis and tear
insufficiency.
Stage IV: It is end stage disease marked by severe sicca syndrome, ocular
surface keratinization and ankyloblepharon.
Drug-induced ocular pemphigoid appears pathologically identical to

idiopathic, ocular cicatrical pemphigoid. There is chronic conjunctival
subepithelial inflammation with an invasion of the submucosal tissue by newly
formed connective tissue which subsequently contracts. Ocular cicatrical
pemphigoid is associated with a diminished and unstable tear film caused by
destruction of conjunctival goblet cells. The chronic dry eye condition and
exposure results in keratinization of the ocular surface.
Treatment
The treatment criteria to patients with ocular irritation and conjunctival
shortening of recent onset should be careful and methoidical with primary
stoppage of all topical medications. Every effort should be made to eliminate
other causes of conjunctival cicatrization. Patients with ocular irritation may
need only artificial tear lubricants and mild topical steroids for comfort. If
preservatives are potential cause of cicatrization then preservative-free artificial
tear should be prescribed.
In addition to it, a soft bandage contact lens can be given to keep patients
comfortable by protecting the cornea from excessive drying. Topical all
transretinoic ointment can be given to reverse the surface disorder specially
keratinization.
All patients must be followed regularly for disease progression.
Reduction in tear flow with an accumulation of thick stingy discharge
leads to blepharitis in many patients. Such patients are managed with frequent
warm eyelid scrubs with mild soap followed by application of antibiotic
ointment.
Secondary bacterial conjunctivitis is known to occur in this condition. If
suspected then following culture test, treat specific pathogens with suitable
antibiotic drops.
If the conjunctival scarring and shrinkage progress ectropion and trichiasis
may occur. Trichiasis can be controlled by electrolysis or cryotherapy. Surgical
eyelid procedures should be avoided because of poor results and the risk of
exacerbating the condition. Systemic steroids have been found helpful in the
treatment of acute exacerbations of ocular cicatrical pemphigoid.
Systemic immunosuppressive therapy consisting of cyclophosphamide
or azathioprine both with or without prednisone has been used with success.
Cytotoxic therapy is indicated for those patients with documented progressive
conjunctival shortening which can lead to symblepharon and total blindness.
SYSTEMIC DRUGS CAUSING OCULAR SURFACE TOXICITY

The eye due to relatively small size, multiple tissue characteristics and rich
blood supply are highly vulnerable to toxic substances. Systemically
administered medications have potential to produce adverse ocular effects
and almost all the structures of the eye are susceptible. Although list of
systemically administered drug is very big here in this section, I shall describe
the most common used systemic drugs that have been reported to cause
ocular toxicity, giving in nutshell the salient features of ocular adverse effects.
Antimalarial Drugs
Chloroquine, quinacrine and hydroxychloroquine on prolong use can cause
following changes in the cornea:
• In early phase diffuse punctate deposits develop in the corneal epithelium
and later these deposits aggregate to form curved lines which converge
and coalesce below the central cornea.
• Corneal changes lead to visual symptoms like halos around light, glare
and photophobia.
• On discontinuation of drug therapy these objective and subjective corneal
signs disappear.
• Other adverse effects include night blindness, visual hallucinations, cataract
(posterior subcapsular, optic neuritis/atrophy and toxic amblyopia).
Chlorpromazine
Out of phenothiazine derivatives chlorpromazine is the only drug that produce
changes in cornea and lens.
These changes include:
• Lenticular pigmentation which may vary from fine dot-like opactics on
anterior lens surface to central pearl-like light pigmented aggregation
surrounded by small pigment clump.
• Corneal pigment changes may also develop in those patients who have
concomitant lens opacities. Corneal pigmentation is noticed at the level
of endothelium and Descemet’s membrane in interpalpebral fissure area.
• Such patient may complain of glare, halos around bulb and hazy vision.
• On discontinuation of drug therapy these pigment deposits remain static
and irreversible.
• Other effects include discoloration of conjunctiva and sclera.
Analgesics
Analgesics are most commonly used in diverse conditions of systemic disorders.
Non-narcotic analgesics may produce following adverse ocular effects:

• Decrease in visual acuity and color vision
• Lid/conjunctival irritation, edema

• Mydriasis.
Narcotic analgesics may produce:
• Diplopia, myopia, photophobia and color vision defects
• Lid edema
• Dry eyes
• Mydriasis or anisocoria
• Accommodative paralysis
• Optic atrophy
• Nystagmus and visual field scotomas.
Antiarthritic Drugs
Gold salts: Following prolonged administration gold salts can be deposited in
various tissues of body including eye, known as chrysiasis.
Ocular chrysiasis can involve the conjunctiva, cornea and lens. Various
ocular adverse effects are:
• Gold deposits (red, brown or violet) in lid, conjunctiva, pancorneal and
lens
• Diplopia
• Extraocular muscles paresis
• Ptosis
• Myasthenic block
• Iritis
• Papilledema and retinal hemorrhages.
Antigout:
• Decreased visual acuity
• Scleritis
• Corneal: Keratitis, ulcers, scarring, dellen
• Macular edema and retinal hemorrhages
• Diplopia
• Extraocular muscle paresis.
Corticosteroids
Systemic steroids can produce posterior subcapsular cataracts (PSC) that are
clinically difficult to distinguish from complicated cataracts and age-related
PSC cataracts.
These cataracts remain unchanged even on discontinuation or decrease
in the dose of the drug. Other adverse effects include:
• Decreased vision
• Myopia, diplopia
• Color vision defects
• Delayed wound healing
• Mydriasis
• Retinal hemorrhages and edema
• Papilledema
• Exophthalmos
• Extraocular muscle paralysis
• Toxic amblyopia
• Visual fields scotomas
• Glaucoma.
NSAIDs (Nonsteroidal Anti-inflammatory Drugs)

These include:
• Red green color vision defect
• Myopia, photophobia
• Diplopia and extraocular muscle paralysis
• Dry eye
• Keratitis
• Mydriasis
• Serous retinopathy
• Corneal deposits
• Macular edema, papilledema
• Optic neuritis/atrophy
• Toxic amblyopia and nystagmus.
General Anesthetic Agents

General anesthesia is given in a wide variety of surgeries. It is important to
know the ocular adverse effects of general anesthetic agents (commonly
used drugs include chloroform, ether, ketamine, methoxyflurane, nitrous
oxide, trichloroethylene, halothane).
The ocular adverse effects reported are:
• Diplopia and color vision defects
• Mydriasis (on light anesthesia)
• Miosis (on deep anesthesia)
• Eso or exotropia
• Nystagmus
• Scotomas.
Antihistamines
H1 antihistamines have varying degree of atropine like actions including the
ability to alter tear film integrity. Both aqueous and mucin production may
decrease with use of systemic antihistamines. Other adverse effects include:
• Diplopia
• Dry eyes
• Anisocoria
• Mydriasis
• Nystagmus
• Retinal hemorrhages.
Anti-infective Agents
Systemic Antibiotics
Systemic antibiotics are widely prescribed both in medical and surgical
conditions of diverse etiology.
Aminoglycosides: They may produce:
• Diplopia
• Ptosis
• Brow loss
• Papilledema and retinal hemorrhages
• Optic neuritis
• Toxic amblyopia
• Pseudotumor cerebri
• Scotomas.
Cephalosporins
• Diplopia
• Corneal peripheral edema
• Subconjunctival hemorrhage
• Papilledema
• Nystagmus.
Chloramphenicol
• Decrease vision and color vision defects
• Lid or conjunctival allergy
• Mydriasis
• Retinal edema, hemorrhages
• Optic atrophy
• Toxic amblyopia
• Retrobulbar or optic neuritis.
Erythromycin and related drugs
• Retinal hemorrhage
• Extraocular muscle paralysis.
Colistin
• Diplopia
• Mydriasis
Nitrofurantoins (Nalidixic acid)

• Glare
• Scintillating scotomas
• Mydriasis
• Papilledema
• Lid or conjunctival photosensitivity
• Nystagmus.
Penicillins
• Diplopia, blepharoconjunctivitis
• Ptosis
• Edema
• Allergy.
Antifungals
Penicillin derivatives (Griseofulvin)
• Keratitis, ulcers, scarring
• Macular edema
• Scleritis
• Ulceration.
Polyenes derivatives
• Retinal exudates/hemorrhages
• Optic neuritis
• Diplopia.
Imidazoles
• Photophobia
• Shimmering lights
• Diplopia
• Corneal vortex whorls
• Superficial punctate keratitis
• Iritis
• Optic neuritis or atrophy
• Oculogyric crisis.
Antileprosy Drugs
Phenazines
• Corneal polychromatic crystals
• Macular retinal pigment epithelium mattle
• Hyperpigmentation
• Decrease in vision.
Sulfones
• Lid edema
• Optic atrophy
• Decrease in vision.
Antiparasitics
Amebicides
• Corneal opacities
• Diplopia
• Optic atrophy/neuritis
• Macular degeneration
• Macular edema
• Toxic amblyopia.
Antihelminthics
• Variable color vision
• Flashing lights
• Dry eyes and punctate keratitis
• Corneal multicolor deposits

• Nonreactive pupils
• Iritis
• Chorioretinitis
• Scotomas
• Mydriasis
• Yellow sclera
• Yellow or black pigmentation of conjunctiva
Antituberculosis Drugs
Ethambutol
• Visual field constriction
• Hemianopia
• Retinal or macular edema
• Vascular dilation
• Photophobia
• Scotomas: annular, central, cecocentral
• Color vision defects.
Para-aminosalicylates
• Red green color defect
• Scotomas
• Lid inflammation, edema.
Cycloserine
• Flickering vision
• Retinal hemorrhage.
Isoniazid,ethionamide
• Keratitis
• Mydriasis
• Retrobulbar neuritis
• Red green color defects
• Diplopia, photophobia
• Extraocular muscle paresis
• Visual field hemianopia
• Nystagmus.
Rifampicin, capreomycin
• White vision
• Angioneurotic edema
• Flashing lights
• Conjunctival hyperemia
• Iritis
• Blepharoconjunctivitis.
Antivirals (Systemic)
• Lid spasm
• Erythema
• Decreased visual acuity.
Antineoplastic Drugs
Alkaloids
• Nonspecific pain, burning
• Lid edema
• Dry eyes
• Photophobia
• Eyelash or brow loss
• Papilledema.
Antibiotics – Antineoplastics
• Photophobia
• Toxic amblyopia
Antimetabolites
• Lid edema, pain, cicatricial ectropion
• Nystagmus
• Ulcer
Thiotepa
• Lid edema
• Iritis
Folic acid antagonists

• Keratitis
• Periorbital edema
Heavy metals
• Oculogyric crisis
• Orbital pain
• Cortical blindness
• Hemianopia
Interferon
• Abnormal oculography
• Eyelash or brow growth
• Papilledema
Nonsteroidal antiestrogens (e.g. tamoxifen, temorifen)

• White or yellow refractile opacities in the macular and paramacular area
• Reduced visual acuity
• Abnormal visual fields
• Subepithelial corneal whorl opacities
• Paracentral scotomas
• Retinal pigment epithelium disturbances.
Vinca alkaloids (e.g. vinblastine, vincristine)

• Corneal ulcers or deposits
• Decreased dark adaptation
• Iritis, scleritis
• Hemianopia
• Central or paracentral scotomas
• Nystagmus.
Antianginal Drugs
These agents may produce:
• Photophobia, halos
• Myopia, diplopia, reduced visual acuity
• Yellow or blue vision due to nitrates
• Color vision defect
• Dry eys
• Corneal ulcers
• Periorbital edema
• Papilledema and optic neuritis
• Nystagmus
• Lid edema, eyelashes loss
Antiarrhythmics
Anticholinergics
• Dryness of mucous membrane
• Marked mydriasis
• Pupillary dilatation and cycloplegia
• Dry eyes
• Photophobia, diplopia
• Reduced vision
• Visual hallucinations.
Beta-adrenergic blockers
• Reduced tear secretion
• Photophobia
• Ptosis
• Conjunctival edema
• Decreased corneal sensation
• Severe dry eye
• Yellow or white corneal stromal opacities
• Ocular pain
• Ocular pseudotumor
• Accommodative paralysis.
Quinidine
• Night blindness
• Dry eyes
• Iritis
• Mydriasis
• Optic neuritis
• Toxic amblyopia
• Reduced vision.
Antihypertensives
Alpha-adrenergic agonists
• Lid edema
• Toxic miosis
• Retinal or macular degeneration

• Visual hallucinations.
Beta-adrenergic blockers
• Dry eyes
• Hemianopia
• Extraocular muscles paralysis
• Reduced vision
• Ocular pain and subconjunctival hemorrhage.
Angiotension-converting enzymes inhibitors

• Lid edema, brow discoloration
• Reduced vision.
Ganglionic blockers
• Ptosis
• Dry eyes
• Conjunctival edema
• Mydriasis
• Macular edema
• Optic atrophy
• Retinal vasodilation.
Monoamine oxidase inhibitors

• Reduced vision, photophobia
• Diplopia, nystagmus
• Blepharospasm, dry eyes
• Toxic amblyopia, oculogyric crisis.
Rauwolfia alkaloids
• Yellow vision and reduced vision
• Tearing
• Mydriasis, iritis
• Abnormal conjugate gaze
• Jerky pursuit.
Antimigraine Agents
• Visual hallucinations and reduced vision
• Miosis
• Retinal vascular spasm
• Optic neuritis
• Lid edema
• Scotomas, hemianopia.
Peripheral Vasodilators
• Ptosis
• Miosis
• Lid edema.
Bronchodilators
• Reduced vision
• Photophobia and diplopia
• Mydriasis
• Rebound redness
• Hemianopia
• Horizontal nystagmus.
Alcohols
• Miosis/mydriasis
• Tearing
• Ptosis, diplopia
• Nystagmus
• Blue vision
• Toxic amblyopia
• Strabismus oscillopsia
• Central scotomas.
Anorexiants (Amphetamines)
• Reduced vision
• Blue vision
• Eyelash loss
• Blepharospasm
• Mydriasis
• Decreased pupil reflex and convergence
• Retinal vein occlusion
• Nystagmus.
Muscles Relaxants (Benzodiazepines)

• Decreased depth perception
• Reduced vision
• Diplopia, visual hallucinations
• Nystagmus
Anticonvulsants
• White snow vision
• Night blindness
• Diplopia, photosensitivity
• Scotomas, nystagmus
Antidepressants
• Impaired vision
• Diplopia
• Jerky pursuit, tearing
• Blepharospasm
• Dry eyes
Antipsychotics and Tranquilizers

• Night blindness
• Color halos
• Yellow or brown vision
• Corneal hyperpigmentation
• Miosis/mydriasis
• Cataract, diplopia
• Nystagmus, oculogyric crisis
• Papilledema
• Optic atrophy
• Scotomas
• Exophthalmos.
Psychedelic Drugs
• Yellow or violet vision
• Flashing colored lights
• Prolonged after images
• Ptosis
• Miosis, anisocoria.
Sedatives and Hypnotics

• Reduced vision and color vision defects
• Yellow or green vision
• Blepharoclonus
• Oscillopsia
• Vertical gaze palsy
• Dry eyes
• Anisocoria, miosis
• Optic neuritis, papilledema
• Toxic amblyopia
• Optic atrophy.
Dermatological Preparations
Hexachlorophene
• Reduced vision, diplopia
• Mydriasis/miosis
• Absent pupil light reflex
• Papilledema, optic atrophy
Chrysarobin
• Ocular irritation (nonspecific)
• Brown violet lid discoloration
• Keratoconjunctivitis
• Gray corneal opacities.
Retinoids
• Impaired vision
• Myopia
• Dry eyes
• Decreased dark adaptation
• Lid inflammation, edema
• Corneal opacities
• Papilledema and optic neuritis.
Psoralen therapy
• Photophobia
• Dry eyes
• Keratitis
• Pigmentary glaucoma
• Central scotomas
• Photosensitivity.
Diuretics
Spironolactone
• Reduced vision
• Myopia
• Lid redness.
Ethacrynic acid
• Impaired vision
• Nystagmus.
Sulfonamides
• Yellow vision
• Photophobia
• Contact lens intolerance.
Thiazides
• Myopia, yellow vision
• Dry eyes
Hyperosmotics
• Impaired vision
• Nystagmus
• Lid edema
• Decreased IOP.
Gastrointestinal Drugs
Antacids
Bismuth salts may produce:
• Toxic impaired vision
• Lid blue discoloration.
Histamine H2 blockers may produce:
• Mydriasis
• Decreased pupil light reflex
Antiemetics
• Impaired vision
• Tearing
• Lid edema
• Mydriasis
• Strabismus.
Antispasmodics
• Micropsia
• Flashing lights
• Dry eyes
• Mydriasis
• Red vision
• Eyelash loss.
Hormonal Drugs
Androgens
• Cataract
• Papilledema
• Visual field defects
• Impaired vision, diplopia.
Corticosteroids
• Cataract (Posterior subcapsular)
• Glaucoma
• Myopia, diplopia
• Delayed wound healing
• Ciliary body microcysts
• Retinal edema and hemorrhage
• Papilledema
• Exophthalmos
• Toxic amblyopia
• Visual field defects (scotomas)
• Myasthenic block.
Antihyperglycemics
Insulin
• Mydriasis
• Absent pupil light reflex
• Strabismus
• Nystagmus
• Decreased vision, diplopia.
Sulfonylureas
• Central or cecocentral scotomas
• Retrobulbar or optic neuritis.
Antithyroid Drugs
Iodines
• Impaired vision
• Green vision, visual hallucination

• Mydriasis
• Hypopyon, iritis
• Vitreous floaters
• Retinal or macular degeneration
• Exophthalmos
• Toxic amblyopia
• Retrobulbar neuritis.
Thiouracils
• Conjunctival depigmentation
• Dry eyes, keratitis
• Exophthalmos
• Nystagmus
Thyroid replacement therapy

• Cataract
• Papilledema
• Impaired vision
• Central scotomas
• Hemianopias.
Oral Contraceptives
Estrogen-progesterone combination
• Impaired vision, diplopia, myopia, color vision defects blue vision, colored
halos
• Dry eyes, iritis
• Mydriasis, anisocoria
• Cataract
• Retinal vascular occlusion
• Macular edema
• Optic or retrobulbar neuritis

• Papilledema
• Scotomas
• Nystagmus
Nonsteroidal antiestrogens
• Flashing or colored lights
• Glare image distortion
• Phosgene stimulation
• Prolonged after images
• Posterior subcapsular cataracts
• Retinal vasospasm
• Optic neuritis
• Visual field constriction.
Immunosuppressant drugs
• Hypertrichosis.
Neuromuscular Drugs
Polyalcohols
• Impaired vision
• Diplopia
• Ptosis, ciliary flush
• Nystagmus
• Extraocular paralysis.
Anticholinergics
• Impaired vision
• Mydriasis
• Retrobulbar neuritis.
Baclofen
• Impaired vision, diplopia
• Lid photosensitivity
• Corneal edema, punctate keratitis
• Mydriasis, miosis
• Strabismus
• Oculogyric crisis.
Myasthenia Gravis Drugs

• Impaired vision, diplopia
• Miosis
• Ptosis
• Blepharoclonus
• Tearing.
Vaccines (DPT, Polio, Measles, Mumps-rubella,

Smallpox, Rabies, Tetanus)
• Iritis, mydriasis
• Papilledema
• Optic neuritis
• Nystagmus
• Scotomas
Vitamins
Vitamin A
• Diplopia, yellow vision
• Red dyschromatopsia
• Calcium deposits in conjunctiva, cornea and sclera
• Miosis
• Retinal hemorrhages, optic atrophy

• Papilledema, exophthalmos
• Strabismus, nystagmus
• Scotomas
Vitamin D
• Diplopia
• Calcium deposits in cornea, sclera
• Cataract
• Papilledema
• Optic atrophy/neuritis
• Small optic disc
• Strabismus
• Narrowed optic foramina
• Nystagmus
• Hemianopia
• Extraocular muscle paresis.
Isotretinoin
• Impaired dark adaptations
• Glare sensitivity
• Blepharoconjunctivitis
• Dry eye
• Contact lens intolerance
• Subepithelial corneal opacities.
Amiodarone
• Optic neuropathy or optic neuritis
• Visual impairment
• Keratopathy
• Bilateral corneal deposits
• Whorl like corneal opacity
• Lenticular opacity
• Glare and halos around light.
BIBLIOGRAPHY
1. Agarwal Amar. Textbook of Ophthalmology (1st edn), New Delhi: Jaypee Brothers
2. Bartlett JD. Clinical Ocular Pharmacology (4th edn). Boston: Butterworth-
Heinemann, 2001.
3. Bartlett JD. Ophthalmic Drug Facts, Lippincott-William and Wilkins, 2001.
4. Crick RP, Trimble RB. Textbook of Clinical Ophthalmology, Hodder and Stoughton,
1986.
7. Ellis PP. Ocular Therapeutics and Pharmacology (7th edn). CV Mosby, 1985.
9. Fraunfelder. Current Ocular Therapy (5th edn). WB Saunders, 2000.
13. Goodman LS, Gilman A, Pharmacological Basis of Therapeutics, ed. 7, New York:
Macmillan, 1985.
15. Kanski. Clinical Ophthalmology (4th edn). Butterworth-Heinemann, 1999.
17. Olin BR, et al. Drugs Facts and Comparisons: Facts and Comparisons, St Louis,
1997.
Publishers, 2001.
21. Zimmerman. Textbook of Ocular Pharmacology, Lippincott-William and Wilkins,
1997.
APPLICATION OF THE AMNIOTIC MEMBRANE IN OCULAR SURFACE PATHOLOGY 431
HISTORY
Searching the medical literature we find that the first studies documented
using fetal membranes were carried out almost 100 years ago. Davis,1 in
1910, was the first to use fetal membranes in skin grafting. Later, in 1913,
Stern 2 and Sabella3 used the amniotic membrane to treat cutaneous
ulcerations and burns. Whilst using the amniotic membrane as a substitute
for skin grafts, there was an absence of infections of clean wounds, an
important decrease in the pain experienced, and an increase in the speed of
re-epithelialization of the wound. Some later authors used the amniotic
membrane in the reconstruction of skin wounds from trauma or burns4 with
good results, and others5-7 demonstrated in their studies that such membranes
produced equivalent results to skin autografts and improved on allografts.
However, during this period the amniotic membrane was not only utilized in
trauma and plastic surgery, but also within other medical specialties as well.
Such applications include: in the reconstruction of the vagina after caustic
burns or vaginectomy,8 as a peritoneal substitute in abdominal surgery and
pelvic reconstruction,9 in reconstruction following total glossectomy,10 as a
biological cover for omphaloceles,11 etc.
In ophthalmology, De Rotth in 194012 was the first to use fetal membranes.
Fresh amnion and the chorion were used as grafts for the reconstruction of
the ocular surface, however with only one successful result out of the six
cases treated. These poor results were probably due to the inclusion of chorion
in the graft. Later, Sorsby et al13,14 successfully treated chemical ocular burns
with the amniotic membrane. Despite Sorsby´s favorable results in 1947, no
further studies were published using the amniotic membrane for almost 50
years, probably due to the difficulties in processing and storage of the tissue.
In 1995, Kim and Tseng15 reintroduced the preserved amniotic membrane
graft for the treatment of ocular surface pathology, and with them the interest
in the use of this material was reborn.
HISTOLOGY
The amniotic membrane, or amnion, is the most internal “layer” of the
placenta, and is composed of a monolayer of epithelial cells, a thick basal
membrane and an avascular stromal matrix.
The cells of the epithelial monolayer vary in form and height depending
on the anatomical area, so that, in the placental amnion they are cylindrical
whilst in the extraplacental amnions they are flatter, more cuboid in shape.16
Numerous microvilli can be found on all the epithelial cells on both the
surface and lateral sides. These epithelial cells contain a large quantity of
growth factors that favor epithelialization and tissue repair after amniotic
membrane grafting.
The thick, resistant basal membrane is found beneath the epithelium.
The basal membrane is an excellent substratum for the epithelialization of
the tissues, and its resistance aids in the manipulation and fixation of the graft
during surgery. Finally, we have the inferior layer consisting of the stromal
matrix, which varies greatly in thickness between different placentas and
indeed between different areas of the same placenta. The stroma is completely
avascular and very rich in collagen and mucopolysaccharides. In its interior a
few fibroblasts can be identified. In Figure 26.1 there are two fragments of
amniotic membrane, in apposition, as a result of a folded amnion. In the
center are the two epithelial layers, with the corresponding basal membrane
and stromal matrix on either side.
FIGURE 26.1: Histopathological section of amniotic membrane illustrating

the monolayer of epithelial cells, the thick basal membrane, and the avascular
stromal matrix
IMMUNOLOGY
On analysis of the fetal membranes it can be seen that immunologically, the
amnion and chorion behave in a completely different manner. The amniotic
membrane or amnion shows very weak antigenicity, such that severe immune
responses after grafting have never been described. There are some studies17
that have demonstrated that human amniotic epithelial cells do not express
the surface antigens HLA-A,B,C or DR. The amniotic membrane used as an
autograft in the same newborn donor, remains permanently integrated with
the receptor tissues without producing any significant rejection.18 If amniotic
membrane is implanted subcutaneously in another receptor, it behaves in
the same way during the first 15 days. However, henceforth the membrane
is progressively reabsorbed,19 with only a mild infiltration of round cells
identifiable at 20 to 30 days.
On the contrary, the chorion exhibits high antigenicity and, when it is
grafted, either as an autograft or as an allograft it produces a severe
immunological rejection.20 The considerable antigenicity of this tissue mounts
an intense cellular response, mixed with a lesser humoral component
mediated by antibodies.
EXTRACTION AND PRESERVATION

The placenta is obtained from elective cesarean sections. Prior to aquisition
of the placenta, a written authorization from the mother is required, and the
same protocols are followed as those used in the donation of other tissues. In
order to avoid the possible transmission of infectious diseases to the host,
serological studies on the donor are performed for human immunodeficiency
virus, hepatitis B, hepatitis C and syphilis. As a live donor is in question, it is
necessary to cover the window periods for these diseases. Therefore, the
donor is tested at the time of the birth, and afterwards, at least three months
if using serological tests, or a minimum of 10 days if using polymerase chain
reaction (PCR).
Once obtained, in sterile conditions, the placenta is washed in an antibiotic
solution containing penicillin, streptomycin, neomycin, and amphotericin-B.
The amnion is separated from the placenta using blunt dissection (Figure
26.2) and is mounted on fragments of nitrocellulose paper, with the epithelium
uppermost and the stromal surface in contact with the paper (Figure 26.3).
The fragments of amniotic membrane are preserved in separate containers
at –80°C, along with a cryopreservative substance. We, as do other authors,21
use glycerol and a culture media in a proportion of 1:1. However, other
cryopreservative substances can be used, such as dimethylsulfoxide.22
FIGURE 26.2: Blunt dissection of the amniotic membrane

from the rest of the placenta
FIGURE 26.3: Prepared fragments of amniotic membrane on

nitrocellulose paper disks, in a container with antibiotic solution
With this method the amniotic membrane can be frozen and available
for use for a minimum of 12 months, although its viability can probably be
guaranteed for longer. When required it need only be taken from the freezer
10-15 minutes before the intended intervention, as it quickly thaws at room
temperature.
CLINICAL PROPERTIES
In the various studies performed in recent years the different therapeutic
effects of the amniotic membrane have been observed which are summarized
in Table 26.1. The main clinical property it possesses, and indeed its main
clinical indication, is that it favors tissue epithelialization.
Table 26.1: Clinical properties of the amniotic membrane

• Aids tissue epithelialization (maintaining the epithelial phenotype)
• Reduces inflammation
• Reduces scarring
• Reduces vascularization
• Diminishes pain
• (Protects against infection?)
Once the amniotic membrane is grafted on a tissue defect it acts as a

basal membrane, and an excellent substrate for the epithelialization over it.
Also, the amniotic membrane contains a large number of growth factors
which further aid the epithelial growth. For these reasons it greatly enhances
tissue regeneration, maintaining the pre-existing epithelial phenotype. This
concept is of utmost importance since the epithelium is generated from stem
cells present in this zone, without cellular transdifferentiation. Therefore, if
the amniotic membrane is used to treat a corneal epithelial defect in a patient
with a total deficit of corneal stem cells, the result is an epithelialization of the
cornea from the surrounding tissue, thus with conjunctival phenotype cells.
Another clinical property of the amniotic membrane is a marked reduction
in inflammation. The amnion also contains a large number of substances
that inhibit different inflammatory mediators. This reduction in inflammation
is achieved, not only in the tissues immediately beneath the graft, but also in
the immediate uncovered areas. This reduction in inflammation in itself favors
the epithelialization, as the environment of the stem cells and thus their activity
is improved (Figures 26.4A to C). The amniotic membrane graft also reduces
scar tissue formation during the regeneration process. This is achieved by the
inhibition of fibroblast differentiation, which permits tissue regeneration with
a minimum of scarring after extensive conjunctival resections.
Finally, other clinical properties of amniotic membrane grafts include a
reduction in neovascularization, a decrease in pain experienced, and a possible
protection against infection.
FIGURE 26.4A: Salzmann’s nodular degeneration preoperatively
FIGURE 26.4B: The same eye, one day after superficial

keratectomy and amniotic membrane implantation
INDICATIONS
The ophthalmological indications of the amniotic membrane can be divided
into two large groups: (i) pathologies that require reconstruction of the
conjunctival surface, and (ii) those pathologies that require reconstruction of
the corneal surface (Table 26.2). At the conjunctival level the amniotic
membrane can be used to reconstruct the ocular surface after the resection
of extensive conjunctival lesions, like tumors or intraepithelial neoplasias,21
pterygium, 23 conjunctivochalasis, 21 or conjunctival scarring and
FIGURE 26.4C: Two months after surgery, a reduction in conjunctival

injection with normal corneal epithelialization is observed
TABLE 26.2: Indications of the amniotic membrane

• Reconstruction of the conjunctival surface
• After the resection of extensive lesions (tumors, scars...)
• Symblepharon reconstruction
• Reconstruction of the corneal surface
• Persistent epithelial defects—ulcers
• Partial limbal insufficiency
• Total limbal insufficiency (associated with a limbal graft)
simblepharon.21 The amniotic membrane graft facilitates epithelialization,

maintaining the normal epithelial phenotype (with calciform cells), and
reducing inflammation, vascularization, and scarring. After resection of the
conjunctival lesion (for example, a tumor), an area of uncovered sclera
remains, which if extensive can lead to abundant scarring, or indeed problems
of scleral necrosis. Until recently the alternatives were using buccal mucosa
grafts, or conjunctival autografts to cover the defect, although the former
poses esthetic problems and the latter necessitates graft extraction from the
contralateral eye. Now, the preferred technique after resection of large
conjunctival lesions is with an amniotic membrane graft, thus providing a
rapid epithelialization with minimum scarring and without the necessity to
extract a graft from the buccal mucosa or the contralateral eye. Some studies
have shown that the amniotic membrane is useful as a graft after resections,
especially when involving primary pterygium. However, the conjuncival

autograft continues to have a lower rate of recurrences after the resection of
primary or recurrent pterygium.23
Finally, the amniotic membrane has demonstrated its use after the resection
of simblepharon and conjunctival scars, in cases of ocular pemphigoid or
Stevens-Johnson syndrome24 and those following burns.25
With regards to the cornea the amniotic membrane has shown to be
useful, in both the treament of corneal epithelial defects22, 26 (with or without
stromal ulceration), and in some cases of limbal stem cell deficiency.27 In
chronic epithelial defects that have not responded satisfactorily to medical
treatment, the amniotic membrane acts as a basement membrane that aids
epithelialization (Figures 26.5A to C). In cases of epithelial defect with deep
stromal ulceration a multilaminated graft can be employed (with various
layers of amniotic membrane),28 in order to promote more stable deep
stromal healing (Figure 26.6). Some authors29 have also employed the
amniotic membrane to reduce pain in cases of bullous keratopathy and in
those cases where penetrating keratoplasty are not indicated or were not
possible. Although esthetically this option is superior to that with conjunctival
grafting, probably, the long-term results are better with total conjunctival
grafting.
Finally, amniotic membrane grafts can be useful in cases of limbal
insufficiency. Confronted with a possible stem cell deficit it is recommendable
FIGURE 26.5A: Amniotic membrane implantation in a diabetic

patient with post-vitrectomy long-standing epithelial defect
FIGURE 26.5B: The same eye one month later, previously to

suture extraction. Observe the absence of conjunctival redness
and complete epithelial healing (with mild residual haze)
FIGURE 26.5C
to study the corneal surface using impression cytology30 to provide a diagno-

sis, and to quantify the severity of the deficit. In cases of partial insufficiency
or hypofunction of the stem cells the amniotic membrane can sufficiently
stimulate the activity of these cells, by the mechanisms already discussed,
enough to improve the clinical situation. On the other hand, if there is a total
stem cell deficit an auto- or allo-limbal graft is required in order to obtain
satisfactory reults. However, in these cases, a combined amniotic membrane
and limbal graft, can improve the final result,27 by reducing inflammation,
FIGURE 26.6: One day after surgery in a patient with stromal

ulceration. A multilayer amniotic membrane transplantation has
been performed
vascularization and by improving the perilimbal state and the activity of the
stem cells.
LIMITATIONS
The amniotic membrane also has its limitations, in which acting alone it is
unable to produce the desired results (Table 26.3). The first of these limitations
is when an absolute deficit of stem cells at the limboscleral level is involved.
We have already commented on how the amniotic membrane graft does
not produce tissue transdifferentiation, so that in these cases the tissue
phenotype that will grow over the cornea will be conjunctival. A limbal graft
is the necessary treatment in these cases, although an associated amniotic
membrane graft could improve the results ( by reducing inflammation and
improving the stromal environment thus helping limbal stem cell function).
Although the amniotic membrane graft works in many cases of neurotrophic
ulcer, in eyes with severe trophic changes, and in those with severe stromal
necrosis the amniotic membrane may not be sufficient. In the same way, in
eyes with extreme ischemia or absence of tear film the amniotic membrane
will not be able to re-establish the ocular surface, and, in some cases,
postoperative infections could occur (it should not be forgotten that these
patients lack the defense mechanisms provided by the tear film and blood
components). Finally, even though the amniotic membrane significantly
reduces inflammation, this can fail on occasions due to severe inflammation

of the eye surface.
TABLE 26.3: Limitations of the amniotic membrane

• Absolute deficit of limbal stem cells
• Severe stromal necrosis
• Severe neurotrophic changes
• Severe ischemia
• Absence of tear film
SURGICAL TECHNIQUE
Surgery is performed under peribulbar or retrobulbar anesthesia, on patients
previously tested serologically for hepatitis-B, hepatitis-C, human
inmunodeficiency virus and syphilis. The choice of surgical technique depends
on the pathology to be treated.31
In those patients with extensive conjunctival lesions the resection is
performed using standard techniques later covering the resected area with
the fragment of amniotic membrane (Figure 26.7). Reabsorbable 8-0 suture
is used in these cases, to suture a fragment of amniotic membrane graft
slightly larger than that of the area resected, since a discrete retraction of the
graft is to be expected in the postoperative period.
In patients with corneal trophic ulcers unresponsive to medical treatment,
the surgery starts with a thorough cleaning of the base and edges of the
FIGURE 26.7: Amniotic membrane implantation after resection of

an extense nevus in the superior and nasal bulbar conjunctiva
ulcer, including the edges of the de-epithelialized zone. Next, the amniotic
membrane is grafted and sutured using separate stitches of nylon 10-0, burying
the knots within the stroma. When there is profound stromal ulceration various
layers of amniotic membrane are used, one on top of the other, to fill in the
existing space.28 When amniotic membrane grafts are used for corneal lesions
a therapeutic contact lens is indicated to prevent spontaneous loss of the
graft.
In cases of limbal insufficiency the amniotic membrane should cover both
the cornea and the limbal region. If there are severally affected areas at the
limbus or areas of scarred conjunctiva (for example, following burns) a
peritomy must be carried out 2 to 3 mm from the limbus, with the complete
elimination of scarred areas or destructed limbus. Finally, in cases of an
absolute stem cell deficit an additional auto- or allo-limbal graft must be
used.25, 27
REFERENCES
1. Davis JW. Skin transplantation with a review of 550 cases at The Johns Hopkins
Hospital. Johns Hopkins Med J 1910;15:307.
2. Stern M. The grafting of preserved amniotic membrane to burnt and ulcerated
surfaces, substituting skin grafts. JAMA 1913;60:973.
3. Sabella N. Use of the fetal membranes in skin grafting. Med Rec NY 1913;83:478.
4. Kubanyi A. Trapianto d’amnion sterile ottenuto dal teglio cesareo. Ann Ital Chir
1948;25:10.
5. Robson MC, Samburg JL, Krizek TJ. Quantitative comparison of biological dressings.
Surg Forum 1972;23:503.
6. Robson MC, Krizek TJ, Koss N, et al. Amniotic membranes as a temporary wound
dresssing. Surg Gynecol Obstet 1973;136:904.
7. Robson MC, Krizek TJ. Clinical experiences with amniotic membranes as a temporary
biologic dressing. Conn Med 1974;38:449.
8. Tancer ML, Katz M, Perez Veridiano N. Vaginal epithelialization with human amnion.
Obstet Gynecol 1979;54:345-49.
9. Trelford-Sauder M, Trelford JD. Replacement of the peritoneum with amnion
following pelvic exanteration. Surg Gynecol Obstet 1977;145:699.
10. Kothary P. Total glossectomy and repair with amniotic membrane (preliminary
observations). Indian Med Assoc J 1974;62:87.
11. Seashore JH, MacNaughton RJ, Talbert JR. Treatment of gastroschisis and
omphalocele with biological dressings. J Pediatr Surg 1975;10:9.
12. De Rotth A. Plastic repair of conjunctival defects with fetal membrane. Arch
Ophthalmol 1940;23:522-25.
13. Sorsby A, Symons HM. Amniotic membrane grafts in caustic burns of the eye. Br J
Ophthalmol 1946;30:337-45.
14. Sorsby A, Haythorne J, Reed H. Further experience with amniotic membrane grafts
in caustic burns of the eye. Br J Ophthalmol 1947;31:409-18.
15. Kim JC, Tseng SCG. Transplantation of preserved human amniotic membrane for
surface reconstruction in severely damaged rabbit corneas. Cornea 1995;14:473-
84.
16. Van Herendael BJ, Oberti C, Brosens I. Microanatomy of the human amniotic
membranes. Am J Obstet Gynecol 1978;131:872-80.
17. Goodfellow PN, Barnstable CJ, Bodmer WF, et al. Expression of HLA system antigens
in placenta. Transplantation 1976;22:595-603.
18. Trelford JD, Hanson FW, Anderson DG, et al. Amnion autografts, permanent
structure. J Med1975; 6:243.
19. Trelford JD, Hanson FW, Anderson DG, et al. Implanted amniotic membrane as an
autograft and as an allograft. J Med 1975;6:169.
20. Douglas B, Conway H, Stark RB, et al. The fate of homologous and heterologous
chorionic transplants as observed by the transparent tissue chamber technique in
the mouse. Plast Reconstr Surg 1954;13:125.
21. Tseng SCG, Prabhasawat P, Lee SH. Amniotic membrane transplantation for
conjunctival surface reconstruction. Am J Ophthalmol 1997;124:765-74.
22. Azuara-Blanco A, Pillai CT, Dua HS. Amniotic membrane transplantation for ocular
surface reconstruction. Br J Ophthalmol 1999;83:399-402.
23. Prabhasawat P, Barton K, Burkket G, et al. Comparison of conjunctival autografts,
amniotic membrane grafts and primary closure for pterygium excision.
in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J
25. Shimazaki J, Yang HY, Tsubota K. Amniotic membrane transplantation for ocular
surface reconstruction in patients with chemical and thermal burns. Ophthalmology
1997;104:2068-76.
26. Lee SH, Tseng SCG. Amniotic membrane transplantation for persistent epithelial
defects with ulceraction. Am J Ophthalmol 1997;123:303-12.
27. Tseng SCG, Prabhasawat P, Barton K, et al. Amniotic membrane transplantation
with or without limbal allografts for corneal surface reconstruction in patients with
limbal stem cell deficiency. Arch Ophthalmol 1998;116:431-41.
28. Kruse FE, Rohrschneider K, Völcker HE. Multilayer amniotic membrane
transplantation for reconstruction of deep corneal ulcers. Ophthalmology 1999;106:
1504-11.
29. Pires RTF, Tseng SCG, Prabhasawat P, et al. Amniotic membrane transplantation for
symptomatic bullous keratopathy. Arch Ophthalmol 1999;117:1291-97.
30. Puangsricharern V, Tseng SCG. Cytologic evidence of corneal diseases with limbal
stem cell deficiency. Ophthalmology 1995;102:1476-85.
31. Gris O, Güell JL, López-Navidad A, et al. Application of the amniotic membrane in
ocular surface pathology. Annals of Transplantation 1999;4(3-4):71-73.
AMNIOTIC MEMBRANE TRANSPLANTATION IN OCULAR SURFACE DISORDERS 445
INTRODUCTION
In the advancing world of ophthalmology the use of Amniotic membrane
transplantation becoming wider day by day. Amniotic membrane
transplantation (AMT) has been used in many different types of reconstructive
surgery. The ophthalmic uses of human amniotic membrane for
transplantation are many and its rediscovery has greatly improved our ability
to treat debilitating ocular surface disease. Its rebirth for ophthalmic use has
been likened to the in vivo studies and new technology. In ophthalmology,
AMT has been used as graft with its epithelium up when it is expected to
become covered by host conjunctival or corneal epithelium; as a protective
patch with its epithelium down, which facilitates trapping of inflammatory
cells in stroma, reducing inflammation; and in a combination of both, one
used as a graft and the other as a patch.
HISTORY
Davis in 1910 reported the use of fetal membranes as a skin substitute. In
1940, De Roth used a fresh fetal membrane (i.e. both amnion and chorion)
as a graft for conjunctival surface reconstruction with limited success . Sorsby
et al in 1946 and 1947 reported the successful use of amniotic membrane as
a patch graft in the treatment of acute ocular burns. Interest in AMT then
waned and it was not until Kim and Tseng successfully reintroduced the
concept after successful reconstruction of severely damaged rabbit cornea.
HISTOLOGY
Amniotic membrane is the innermost layer of the fetal membranes. It consist
of a single layer of epithelial cells attached to a thick basement membrane,
and an avascular stromal matrix. Being fetal tissue it is immunologically inert
and possess several clinically useful physiological properties, viz. inhibition of
scarring, inflammation, and angiogenesis, and providing a substrate for
epithelial cell growth and attachment both in vivo and in vitro. The amniotic
membrane consists of a single layer of cuboidal epithelial cells, a thick basement
membrane and an avascular stromal matrix, loosely attached to the chorion.
One placenta provides amniotic membrane for ophthalmic use—sufficient
for 20 to 30 transplants. In addition, amniotic membrane can be easily stored.
PREPARATION
Amniotic membrane is obtained under sterile conditions after elective cesarean
delivery from a seronegative donor .Two similar methods of tissue preparation
have been described. (A) Under a lamellar flow hood, the placenta is first
washed free of blood clots with balanced saline solution containing 5 0 μg/
ml of penicillin, 50 μg/ml of streptomycin, 100 μg/ml of neomycin, and
2.5 μg/ml of amphotericin B. The inner amniotic membrane is separated
from the rest of the chorion by blunt dissection (through the potential spaces
between these two tissues). The membrane is then flattened onto a
nitrocellulose paper, with the epithelium/basement membrane surface up.
The membrane with the paper is cut into 4 × 4 cm pieces and placed in a
sterile vial containing Dulbecco’s modified Eagle’s medium and glycerol at a
ratio of 1:1 (vol/vol). The vials are frozen at –80°C. The membrane is defrosted
immediately before use by warming the container to room temperature for
10 minutes. (B) After washing with physiological saline or 0.01 M phosphate
buffered saline (PBS) containing 100 mg of dibekacin sulphate, the amniotic
membrane with the chorion is separated from other uterus tissue by blunt
dissection. The membrane is then cut into pieces measuring 5 × 5 cm and
rinsed three times in 0.01 M PBS. Each piece is rinsed in 0.5 M DMSO
dissolved in PBS, then in 1.0 M and 1.5 M DMSO in PBS, for 5 minutes
each. The membrane is placed in a plastic container and preserved at –80°C
until use. The container with amniotic membrane is warmed to room
temperature preoperatively, and the membrane is rinsed three times in saline,
then once in saline containing 100 mg of dibekacin sulphate. At the time of
surgery the amniotic membrane is separated bluntly from the underlying
chorion with forceps.
CLINICAL EFFECTS AND MECHANISMS OF ACTION

Amniotic membrane has been found to:
• Facilitate epithelialization
• Maintain a normal epithelial phenotype
• Reduce inflammation
• Reduce scarring
• Reduce the adhesion of tissues
• Reduce vascularisation
• Reduce apoptosis.
A number of cytokines, growth factors, such as IL-4 and 6; EGF, FGF,
TGF, HGF, and 2-macrobulin, have been found in cryopreserved amniotic
membranes. The presence, concentration and action of these substances
may account for most of the observed clinical effects and its mechanisms of
action such as:
• Exclusion of inflammatory cells with anti-protease activities
• Suppression of TGF-signalling system and myofibroblast differentiation
of normal fibroblasts
• Prolongation of the life span and clonogenicity of epithelial progenitor
cells
• Promotion of non-goblet cells epithelial differentiation
• Promotion of goblet cell differentiation when combined with conjunctival
fibroblast.
CLINICAL USE IN OPHTHALMOLOGY

• Corneal reconstruction
— Limbal Stem cell deficiency
– Partial
– Total
— Limbal stem cell autograft or allografts
— Cultivated limbal stemcells
— Ulcers/perforations
— Bullous keratopathy
— Chemical burn
— Persistent epithelial defect
• Conjunctival reconstruction
— Pterygium
— Tumors
— Symblepharon
— Conjunctival cicatrisation / scar
— Stevens-Johnson syndrome
• Miscellanous
— Patch
– Acute inflammatory conditions
— Band keratopathy
— Conjunctivochalasis
— Vernal conjunctivitis
— Glaucoma surgery/complications
Limbal Stem Cell Deficiency

Excellent results are observed with the use of amniotic membrane for partial
limbal stem cell deficiency. Even for total limbal stem cell deficiency, successful
outcomes varying between 60-70% of the cases. In total limbal stem cell
deficiency the result will be more successful when used with limbal stem cell
autograft or allografts or cultivated limbal stem cells compared to only amniotic
membrane transplantation.
The eyes in patients with Stevens-Johnson syndrome, dry eye,
keratinization and eye lid abnormalities that received allogeneic conjunctival
limbal transplant developed graft failure more frequently. Preoperative dry
eye was the most important prognostic factor for limbal conjunctival graft
survival. Future directions include the refinements of the culture system,
genetic manipulation and the use of other sources of autologous stem cells.
Corneal Ulcers and Perforations

One or multiple layers of amniotic membrane have been used for the
treatment of corneal ulcers and corneal perforations of different sizes. Multi-
layered amniotic membrane transplantation is effective for treating corneal
perforations with diameter less than 1.5 mm. Fibrin glue and amniotic
membrane used together in the management of different types of corneal
ulcers and in corneal perforations upto 3 mm.
Bullous Keratopathy
Amniotic membrane transplantation done in case of symptomatic bullous
keratopathy, which gives complete corneal epithelial healing and pain relief.
Chemical Burn
Amniotic membrane transplantation in acute stage of chemical burn patients
can be done to prevent complications such as symblepharon. But in sever
stage of chemical burn (grade III or IV) with ischemic component the results
are not very good.
Conjunctival Reconstruction
Pterygium
AMT represents a new, safe, and cosmetically pleasing modality of treatment
for both primary and recurrent pterygium. It achieves success rates that are
comparable to those of conjunctival autograft, and therefore, may be

considered the first line treatment choice for advanced primary pterygium in
which the involvement is diffused, and for recurrent pterygium in which the
conjunctival graft has already been performed and there is limited availability
of healthy conjunctiva.
Tumors
AMT has been used successfully in the treatment of ocular surface neoplasia
including conjunctival intraepithelial neoplasia, primary acquired melanosis,
and malignant melanoma, that was followed by adjunctive cryotherapy.
Symblepharon
AMT can be done for fornix reconstruction in a variety of ocular surface
disorders. In case of surrounding host tissue with inflammatory activity, sub-
conjunctival injections of long acting triamcinolone acetonide can be given
along the edges of the excised conjunctiva. AMT with intraoperative use of
mitomycin-C also improve the results.
Miscellaneous
It is possible that the association of amniotic membrane graft with
ethylenediamine tetra-acetate 3% calcium chelation, phototherapeutic
keratectomy with the excimer laser (PTK), or both might improve the results.
AMT also can be used successfully to cover large conjunctival defects after
resection of the conjunctiva in conjunctivochalasis. In severe vernal
conjunctivitis, amniotic membrane transplantation can be used successfully
as a patch or a graft, in the treatment of shield ulcer, or as a tarsal conjunctival
substitute after resection of giant papillae.
Amniotic membrane also may be used in glaucoma as an adjunct to
reduce scarring or to treat conjunctival complications after glaucomatous
filtrating surgery, such as leaking blebs, or to cover valve implants and scleral
patches.
SURGICAL TECHNIQUE
At the time of surgery, the container with amniotic membrane is thawed at
room temperature just before its use, and the membrane is rinsed three
times in BSS. The membrane is then gently separated from the nitrocellulose
paper with blunt forceps. AMT is not performed in a universal manner. There
have been contradictory reports concerning the right way to place the amnion
on the ocular surface. The membrane can be sutured to the ocular surface
with its epithelium-basement membrane side up and the stromal side in
contact with the eye (preferred technique) or stromal side up, away from the
eye. The stromal side of the membrane is sticky, similar to vitreous and the
epithelial basement membrane side is shiny and nonsticky. The amniotic
membrane is then gently spread on to the ocular surface and trimmed to the
appropriate shape and size. In cases of corneal pathologies (e.g. persistent
epithelial defect) the membrane is secured in place using 10-0 nylon
interrupted sutures to the cornea. There is a consensus that in corneal/limbal
diseases (e.g. chemical injury) a membrane much larger than the affected
area is needed. In these cases, a combination of interrupted 10-0 nylon
sutures to the conjunctiva/episclera and a 10-0 nylon continuous suture (i.e.
purse string bedding suture just outside the limbus) is usually required,
although 8-0 Vicryl suture can also be used. In conjunctival surgery the amnion
is used as a substrate to cover the defect after removal of the affected tissue.
In those circumstances where reconstruction of the conjunctival fornices is
needed, a spacer (e.g. retinal band) is used to maintain the fornices until
epithelialization has occurred. Amniotic membrane becomes indistinguishable
from conjunctival tissue once covered by the epithelium. The mechanism by
which it facilitates epithelial healing may vary depending on the technique
used at the time of amniotic membrane transplant surgery: inlay vs. overlay
technique. AM may also be used in a “filling” technique. The inlay technique
involves placement of the amniotic membrane graft into the corneal ulcer
secured into place by interrupted sutures without extending beyond the edge
of the epithelial defect. The amniotic membrane thus acts as a basement
membrane to which epithelialization may take place over it from the
surrounding epithelium. Therefore, persistent corneal defects or ulceration
may be treated prior to or after perforation. Larger AMT used for treatment
of symptomatic bullous keratopathy by leaving peripheral cornea uncovered
to promote epithelialization over the graft. In using this technique, however,
the amniotic membrane graft becomes trapped under the healed corneal
epithelium and may limit corneal transparency for several months or more
affecting vision.
In the overlay technique, the entire corneal surface including the limbus
is covered with the amniotic membrane graft. Here the amniotic membrane
FIGURE 27.1: Upper and lower eyelid symblepheron with

total loss of fornices with vascularized corneal scar following
chemical injury
FIGURE 27.2: Three months postoperative following

symblepheron release and forniceal reconstruction with
amniotic membrane
functions primarily as a biological contact lens. The graft protects regenerating

epithelium from the frictional forces of the eyelid and palpebral conjunctiva
while at the same time appears to allow adequate oxygen permeability and
moisture to the epithelium. Corneal transparency remains when the graft
eventually detaches or dissolves. This method has been used successfully in

cases of stem cell deficiency of various causes and in cases of persistent epithelial
defect unresponsive to medical therapy and surgically induced epithelial
defects. This is a safe alternative that some patients may prefer over
tarsorrhaphy when medical treatment has failed. Both the inlay and overlay
techniques may be used together.
A large therapeutic contact lens is routinely used, at the end of the
operation, to protect and keep the amniotic membrane in place and also for
comfort. Occasionally, a tarsorrhaphy may also offer additional protection.
The sutures and contact lens are often removed after 2 to 4 weeks.
Recommended postoperative topical treatment consists of preservative free
antibiotic and corticosteroid drops.
POSTOPERATIVE COMPLICATION
AMT has been successfully used in ophthalmic surgery, but not without
complications. Postoperative infection, although rare, is one of the risks
associated with this procedure. The amnion can also become loose or
dislocated as a result of loose/broken sutures. Hemorrhage under the
membrane and early disintegration of the membrane have also been
observed. Lack of its beneficial effect may also occur possibly related to
problems with processing.
CONCLUSION
The use of amniotic membrane in ophthalmic surgery has been shown to
provide an alternative for corneal and conjunctival reconstruction in many
clinically challenging situations. Nevertheless, it is has its limitations and is not
universally successful for every indication. The indication for its use are ever
increasing. The collective global experience with the membrane is now vast,
and the field should now move into proper randomized controlled studies to
evaluate its true potential.
BIBLIOGRAPHY
1. Amniotic membrane use in ophthalmology. Jose AP Gomes, Andre Romano, Myrna
S Santos, Harminder S Dua (Eds): Current Opinion in Ophthalmology
2005;16;233-40.
2. Amniotic membrane transplantation. Harminder S Dua (Eds): British Journal of
Ophthalmology 1999;83;748-52.
3. Management of primary and recurrent pterygium using amniotic membrane
transplantation. Seng-Ei Ti, Scheffer CG Tseng (Eds): Current Opinion in
4. The amniotic membrane in ophthalmology. Dua HS, Gomes JA, King AJ, Maharajan
VS (Eds): Surv Ophthalmology 2004;49;51-77.
5. Amniotic membrane transplantation for reconstruction of corneal epithelial surface
in cases of partial limbal stem cell deficiency. SangwanVS, Matalia HP, Vemuganti
GK, Rao GN (Eds): Indian J Ophthalmology 2004;52:281-85.
6. Davis JW. Skin transplantation with a review of 550 cases at the Johns Hopkins
Hospital. Johns Hopkins Med J 1910;15:307-96.
7. De Rotth A. Plastic repair of conjunctival defects with fetal membranes. Arch
Ophthalmol 1940;23:522-25.
8. Kim JC, Tseng SCG. Transplantation of preserved human amniotic membrane for
surface reconstruction in severely damaged rabbit cornea. Cornea 1995;14:473-
84.
9. Tseng SCG, Prabhasawat P, Lee SH. Amniotic membrane transplantation for
conjunctival surface reconstruction. Am J Ophthalmol 1997;124:765-74.
10.Shimazaki J, Yang HY, Tsubota K. Amniotic membrane transplantation for ocular
surface reconstruction in patients with chemical and thermal burns. Ophthalmology
1997;104:2068-76.
11. Tseng SCG, Prabhasawat P, Barton K, et al. Amniotic membrane transplantation
with or without limbal autografts for corneal surface reconstruction in patients with
limbal stem cell deficiency. Arch Ophthalmol 1998;116:431-41.
in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J
Ophthalmol 1996;122:38-52.
CULTURED LIMBAL STEM CELL TRANSPLANTATION 455
INTRODUCTION
Corneal and conjunctival epithelial stem cells are responsible for the
homeostasis and regeneration of the ocular surface epithelium. The
proliferative capacity of limbal stem cells is now being explored to reconstitute
the damaged or completely depleted corneal epithelium after transplantation.
Normal ocular surface consists of corneal, limbal, conjunctival epithelium,
preocular tear film.
The repair of severe ocular surface disease has been a long-standing
challenge and has generated a substantial variety of medical techniques and
surgical procedures for repair with only limited success. There is no magic
formula for many of these severe surface problems that bedevil the patient
and the physician alike.
WHAT ARE LIMBAL STEM CELLS

Limbal stem cells are slow cycling cells, which have a longer life span, but
when enticed, they have a high capacity for self-renewal. They are poorly
differentiated cells with primitive cytoplasm and have the ability to grow into
different tissues. Limbal epithelial stem cells are responsible for corneal
epithelial renewal, normal and injured state. Hence any dysfunctional deficient
stem cell condition will lead to a diseased state, i.e. Limbal Stem Cell Deficiency
(LSCD).
WHAT IS LIMBAL STEM CELL DEFICIENCY (LSCD)

Healing of limbus occurs by preferential circumferential migration of
sheets of epithelial cells arising from either side of remaining intact
epithelium. Once the healing is complete centripetally migrating sheets of
corneal epithelial cells appear from healed limbus to cover the epithelial
defect.
In LSCD the conjunctival epithelium reaches and crosses the limbus thus
preventing the circumferentially migrating limbal sheets from covering the
deficiency. Constant vertical movement of limbal cells normally prevents this
horizontal conjunctival epithelial growth. The conjunctival encroachment has
to be prevented and treated at every stage of LSCD management.
CAUSES OF LSCD
Kruse Classification of Caused of LSCD
Primary cause: In absence of necessary external factors and insufficient
microenvironment to support the proliferation of limbal stem cells.
1. Aniridia
2. Multiple endocrine deficiency
3. Neurotrophic keratopathy.
Secondary cause: due to destruction of these cells by external sources.
1. Chemical and Thermal injury
2. Stevens-Johnson syndrome
3. Ocular cicatricial pemphigoid
4. Contact lens
5. Microbial infestations leading to extensive infection
6. Multiple ocular surgeries
7. Cryo therapy.
CLINICAL FEATURES
Patient can present with:
1. Photophobia
2. Watering
3. Redness
4. Diminish of vision
5. Recurrent attacks of pain due to epithelial breakdown
Hallmark signs are:

1. Conjunctivalization of cornea.
2. Superficial corneal vascularization.
3. Chronic inflammation.
4. Persistent epithelial defects.
5. Dull and irregular corneal reflex.
6. Variable thickness of epithelium.
7. Decreased transparency and loss of limbal palisades of Vogt.
8. There can be persistent epithelial defect, scarring, ulceration and melting
of cornea.
DIAGNOSIS
1. Conjunctivalization confirmation is provided by imprint cytology based
on the presence of goblet cells.
2. Immunofluorescent staining with monoclonal antibodies can prove the
conjunctival source of epithelial ingrowth.
3. Due to the increased permeability of conjunctival epithelium, stippled
staining by fluorescein is one of the clinically useful ways to demonstrate
the conjunctival epithelial ingrowth.
MANAGEMENT
Conservative approach is taken in a patient with good visual acuity and
when corneal epithelial cells cover the central corneal visual axis. Topical
lubricants preferably preservative free can be used with discretion.
In patients with poor visual acuity, limbal stem cell transplant can be done.
All stem cell transplants finally have a common goal, i.e. transplantation of a
new source of corneal epithelium and removal of altered damaged host’s
corneal epithelium and pannus.
With the realization that limbal stem cells are present in and can be
harvested from the conjunctiva and limbus, lot of research is done on isolation
and cultivation of stem cells in culture and subsequent transplantation on
needy ocular surface.
The various procedures that have been proposed to correct such
problems were doomed to failure until we better understood the role of the
corneal epithelial stem cell in the homeostasis of the corneal surface. This
understanding has allowed for the autologous or even allogeneic
transplantation of such presumed stem cells and bioengineered composite
tissues have been viewed as the logical extension of such reparative surgery
and may represent the future of ocular surface.
With the accumulating evidence of the 1980s and 1990s suggesting that
corneal epithelial stem cells resided at the limbus of each cornea, investigators
began to consider that complete autologous limbal stem transplantation could
be used to resurface eyes in a patient with unilateral surface problems. With
this knowledge surgeons started transplanting autologous limbal tissues to
include nearly 180 degree of the limbus from a healthy eye to a diseased
contralateral eye in victims of unilateral ocular surface pathology.
Conjunctival limbal autografts have shown dramatic success in patients

with severe problems. With this patients did show Visual Acuity improvement,
rapid surface healing, stable epithelial adhesions and no recurrent erosion or
persistent epithelial defects. Corneal neovascularization stopped or regressed.
Nonetheless there were potential problems with this approach. The technique
is restricted to unilateral disease and the donor eye has to be normal. And
not all patients are willing to risk their uninvolved and healthy eye. In such
cases, as well as those with bilateral injuries, it becomes necessary to consider
other alternatives including the use of allografts.
Bilateral severe ocular surface injury or disease led investigators to consider
the treatment with the use of conjunctival limbal allografts using donor tissue
from siblings or other relatives. But for this transplant, the donor must provide
almost half his or her limbal tissue. This donation may represent a majority
of corneal epithelial stem cells because using superior and inferior limbus,
has the largest number of stem cell concentration. This donor location may
leave the donor at higher risk of future epithelial surface disease because
much of the limbal epithelial stem cell complement may be removed.
To circumvent this are autologous or allogenic bio-engineered graft.
Using this technique it is possible to culture stem cells using a small amount
of tissue expanding them on amniotic membrane for recontruction of ocular
surface without compromising donor eye there by theoretically reducing a
potential risk to the donor surface.
Since the antigen presenting cells and vascular tissue are excluded from
transplantation, risk of rejection is virtually nullified in allogenic cultured tissue.
The results of cultured autologous corneal epithelial cells in two patients
followed-up for more than two years as described first by Pellegrini. Penetrating
keratoplasty was done in one patient after 4 months and vision improved to
6/24. In the other it was counting fingers at one meter without additional
surgery. There was no recurrence of conjunctivalization and the surface
remained stable. Corneal biopsies in both eyes approximately 11/2 years
after limbal transplantation were positive for cornea specific keratin K3.
Sangwan et al have reported the successful use of autologus cultured
limbal and conjunctival epithelium in a patient with bilateral ocular surface
damage induced by acid injury.
Tsai et al studied 6 total patients who received autologus composite grafts
consisting of en bloc limbal tissues grown on amniotic membrane. They
reported successful re-epithelialization of 4 of these 6 with follow-up of up to

15 months at the same time Schwab et al reported 10 patients who had
received composite bio-engineered autologus grafts and 4 patients who
received composite bio-engineered allogeneic grafts. The donated stem cells
for the allogeneic graft were obtained from living related donors. 10 of these
14 patients had a successful result, which was defined as restoration or
improvement of vision, along with maintenance of corneal re-epithelialization
and absence or recurrence of surface diseases. Follow-up ranged from 6 to
19 months with a mean of 13 months.
Currently, culturing corneal epithelial stem cells is the most exciting and
promising technique in limbal transplantation.
It is possible to culture stem cells using a small amount of tissue
thereby minimising the damage to the donor surface and the potential limbal
epithelial exhaustion. Since only epithelial cells without Langerhan’s cells and
blood vessels are transplanted, theoretically it is possible that the incidence of
rejection may also be reduced in homologous cultured limbal stem cell
transplantation in bilateral ocular surface disease. The concept of culturing
stem cells was derived from the use of cultured human epidermal cells as
autologous grafts in burns patients and in plastic and reconstructive surgery.
It was established as a human epidermal keratinocyte-culturing method
involving the use of 3T3 feeder layers. This was subsequently applied to
limbal stem cells.
If other procedures offer the patient an improved prognosis, ex vivo
composite grafting should probably not be done, reserving this procedure
for only those with few other alternatives.
Cultured limbal stem cell transplantation is what we shall discuss in
detail.
Current Indications of Cultured Stem Cell Transplant

Ocular surface diseases such as Stevens-Johnson syndrome, toxic epidermal
necrolysis, chemical and thermal burns, medication toxicity, recurrent pterygia,
certain infections diseases, ocular tumors, immunologic conditions, radiation
injury, inherited and congenital syndromes such as aniridia.
Cultured Stem Cell Grafting can be considered for all these conditions.
This procedure could still be considered investigational; it is ideal for unilateral
involvement where the other eye is normal.
Contraindications
These techniques require a great deal of preparation and expense and should
not be used in patients who have a healthy stem cell population or even a
partially healthy stem cell population. Composite bio-engineered limbal tissue
grafting is in its infancy and should not be considered for patients where
other techniques will have a satisfactory prognosis.
The general principals of culturing stem cells are-
• Harvesting the limbal tissue
• Selecting the appropriate carrier which may be a sheet of multi layered
epithelium, human amniotic membrane, collagen shields or contact lens.
• Preparation of human corneal epithelial medium
• Explant cultures and transplantation.
Confirmation of growth is done by various methods including –direct
observation, whole mount stained preparation, histopathology examination,
immunohistochemistry study, thymidine incorporation and by flow cytometry
using markers for cell cycle.
Preoperative Considerations
The procedure is done in two stages. At first visit the limbal biopsy is planned
and tissue is harvested. The patient is called again after at least two weeks for
transplantation of the cultured tissue and followed-up to assess the surface
stability.
The donor eye should be healthy without a history or physical signs of
injury.
As with any surgical procedure, the patient should be in as good general
health as possible, although this procedure is generally done under local
anesthesia even when combined with a corneal transplantation. If the corneal
transplant is to be combined with the composite graft, and the corneal
transplant involves anterior segment reconstruction, then general anesthesia
should be considered because of the length of the surgical procedure.
Technique
Human amniotic membrane (HAM) is prepared by obtaining placenta from
the cesarean deliveries after screening the donor for HIV, HBsAg, VDRL.
The specimen is washed with antibiotic solutions till sterile. AM is peeled,
separating amnion and chorion. The AM pieces are mounted on nitrocellulose
paper and inserted in vials. It is believed that the amniotic membrane also
acts as a barrier to immune cells decreases the immune response by inhibiting
IL-1β and IL8 expression and produces antiangiogenic proteins. All these
properties are beneficial to limbal stem cell transplantation; whether the
concomitant use of amniotic membrane may help reduce the risk of rejection
in allo-transplantation is yet undetermined. Fibrin substrate has also been
used to culture limbal stem cells. For limbal biopsy, under local anesthesia,
the conjunctiva of the eye is incised 1-2 mm behind the limbus at 12 o’ clock
position and dissected towards limbus and into the clear cornea up to 1mm.
2 mm 2 biopsy is harvested and placed in a transport medium for
transportation to the laboratory. If the expanded tissue is allogenic, the
recipient should be immunosuppressed prior to the transplantation.
Cyclosporin A is the prototype immunosuppressive agent with the dosage of
2-5 mg/kg-body weight.
The limbal cells are grown on de-epithelialized amniotic membrane. The
limbal tissue collected in the human corneal epithelium medium is then
shredded into tiny bits using sterile surgical blade and then the tissue bits are
picked-up and explanted on to the denuded amniotic membrane.
The culture system is maintained for 14-28 days.
At the time of surgery, all of the abnormal tissue is removed and the
conjunctiva is resected and recessed. The amniotic membrane carrier with
expanded corneal epithelial cells was placed atop the defect, and the corneal
edge is sewn to the peripheral cornea with 10-0 nylon. The posterior
peripheral edge of the amniotic membrane is sewn to the peripheral recessed
or resected conjunctiva with 8-0 vicryl and a bandage contact lens was placed
to prevent lid trauma. The contact lens is left for approximately three months.
During this time, the amniotic membrane gradually dissolves and the
peripheral conjunctival sutures disintegrate.
Postoperative Management
A therapeutic contact lens is placed at the end of the procedure to help
ensure that the cells remain in place. Epithelial cell adherence takes weeks, if
not months to complete attachment of hemidesmosomes. Bandage contact
lens is left in place for 8-12 weeks to help assist these cells in adhering
Amniotic membrane will dissolve within a matter of weeks although in
some cases fragments may persist for 3-4 months. Systemic immuno-
suppression may be continued in case of allografts with cyclosporin or a
similar agent for at least a year. Topical treatment with corticosteroids and
antibiotics such as a fluoroquinolone is indicated for a period of 4-6 weeks.
Vigilant observation is essential as these patients are at high-risk for infectious
keratitis. Intraocular pressure should be monitored for steroid response.
CONCLUSION
Ocular surface reconstruction has been evolving as this understanding
improves. Most evidence suggests that corneal epithelium stem cells are
necessary to create normal epithelial cells, at least for a prolonged period of
time. The number of corneal epithelial stem cells is clearly finite, and a donor
cannot part with all these cells, although it is unclear what percentage of the
original stem cell population is necessary to maintain a normal ocular surface.
If progress is to be made in the resurfacing of eyes with damaged stem cells,
donor stem cells must be used.
While the results are very promising in selected cases, there are several
unanswered questions regarding the nature of cells on the surface and the
strength of their adherence to the stroma, whether they return to their niche
at the limbus, and their long-term survival.
Cultured ocular surface grafting is a nascent technology that is potentially
a powerful tool for ocular surfaced repair.
BIBLIOGRAPHY
1. Kenyon KR,Tseng SCG. Limbal autograft transplantation for ocular surface disorders.
Ophthalm 1989;96:683-87.
2. Coster DJ, Aggarwal RK, Williams KA. Surgical management of ocular surface
disorders using conjunctival and stem cell allografts. Br J Ophthalmol 1995;79:977-
82.
3. Tsubota K, SatakeY, Ohyamam M, et al. Surgical reconstruction of the ocular surface
in advanced ocular cicatricial pemphigoid and stevens – Johnson syndrome. Am J
Ophthalmol 1996122:38-52.
4. Tsubuta K, Toda I, Saito H, et al. Reconstruction of the corneal epithelium by libla
allograft transplantation for sever ocular surface disorder. Ophthalmol 1995;
102:1486-96.
5. Shimazaki J, Yanghy, Tsubota K. Limbal autograft transplantation for recurrent and
advanced petryjia. Ophthalmic surge lasers 1996;27:917-23.
6. Pellegrini G, Travesrso CE, Franziat et al. Long-term restoration of damage corneal
surfaces with autologus cultivated corneal epithelium. Lanset 1997;349:990-93.
7. Tsai RJF. Corneal surfaces reconstruction by amniotic membrane with cultivated
autologus limbo-corneal epithelium. Invest Ophthalmol Vissci 1998;39:S429.
8. Tsai RJF, Li LM, Chen JK. Reconstruction of damage cornea by transplantation of
autologus limbal epithelial cells. NEJM 2000;343:86-93.
9. Schwab IR, Isseroff RR, Reyes M. Successful transplantation of bio-engineer tissue
replacements in patients with ocular surface diseases. Cornea 2000;343:86-93.
10. Sangwan VS, Vemuganti GK, Iftekhar G, Bansal AK, Rao GN. Use of autologous
cultured limbal and conjunctival epithelium in a patient with severe bilateral ocular
surface disease induced by acid injury: A case report of unique application Cornea.
2003;22(5):478-81.
PHOTOTHERAPEUTIC KERATECTOMY (PTK) IN OCULAR SURFACE DISORDERS 465
INTRODUCTION
In 1983, Professor Steven Trokel suggested the use of the excimer laser in
ophthalmic surgery. Since then, thousands of patients have been treated
successfully, mostly in the refractive area, at first myopia and astigmatism
and now hyperopia. The exact edging capability of the excimer laser has
been found useful in treating superficial corneal opacities, corneal scars,
dystrophies and irregularities. This part of the excimer laser use is commonly
referred to as phototherapeutic keratectomy (PTK). This chapter is based on
the author’s experience in treating PRK and PTK for over seven years. More
than 3000 patients have been treated at the author’s clinic and at least 400/
500 PTK cases among those. Until January 1998 the author has been using
the VISX B 2020 laser and after January 1998 the VISX Star laser. The VISX
B 2020 laser is a broad beam laser which is able to treat PTK and myopia
with or without astigmatism. The VISX Star is able to treat PTK, myopia,
astigmatism and hyperopia using a scanning mode. The author believes that
the function of the excimer laser is so well known that instead of going into a
deeper aspect his technique is discussed in this chapter.
As mentioned, about 500 patients have been treated by PTK at the
author’s clinic during the last seven years. The follow-up has not been very
easy as many patients have been treated from a broad area from almost the
whole of Sweden, but the author has been able to locate 369 records, and
among those 293 patients have had a follow-up time which can give some
indications of the achieved results.
Before you start treating with the excimer laser you have to
remember that it is a surgical device and that you can only remove
tissue, you can never add tissue. So, you really have to be sure what you
intend to do, therefore do a thorough investigation, not only with a slit-
lamp, but also with videokeratography and pachymetry, especially if you are
to treat thin corneas. Of course, you should also try to arrive at the right
diagnosis so that you can fully discuss the prognosis for the achieved result
with the patient.
As said, you can only remove tissue, never add. The cornea has a given
thickness. The more you treat the cornea [and it is especially worth giving a
thought to this when you are to treat diseases that you are not able to cure,
and diseases that might recur as dystrophies and band keratopathies] the
less you will be able to repeat the treatment in the future. Irregularities of the
surface remain irregularities after treating if you are not using a masking
technique to smooth the surface. Do be very careful when you are to treat
very dry eyes, postherpetic eyes or eyes with some blinking defect, and never
treat a denervated cornea.
Now the author gives a little menu, so to speak, of the diagnoses he has
been treating and further on he will discuss more thoroughly about the results
for each group.
It has not been very easy to decide how to group the different treatments.
The author has chosen to group them according to the different diagnoses,
but you could even choose to group them according to what symptoms you
have treated.
Back to the author’s database: band keratopathy, primary keratoconus,
recurrent erosion, pterygium, dystrophies (lattice, geographic, fingerprint,
Reis-Bückler, Groenouw), astigmatism, anisometropia, corneal scars.
RECURRENT EROSION
First described by Hansen in 1972, causes episodes of acute pain, lacrimation
and photophobia on waking. There may be a history of previous ocular
trauma, or it may occur spontaneously—probably in association with some
base membrane degeneration and often seen with different dystrophies.
The recurrent erosion group is the largest and includes 80 eyes. We found
the results very good and consider PTK as a cure for that disease today.
Many of the patients have had a long history for several years with problems
that more or less have disabled them for long periods. Today, we find that
PTK at our clinic is the preferred choice of treatment with recurrent erosion,
and as we have not seen any complications we treat very liberally.
In the group of 80 eyes we found that 81 percent of the eyes only needed
one treatment, 19 percent had a new episode of recurrent erosion, often
because the whole area with the disease was not covered. Three eyes had to
be treated three times.
How we treated:
If the patient did not have any epithelial defect we chose to treat
transepithelially, 45 to 50 μ followed by 5 μ. If the patient had any erosion
or we found the epithelium very loose we scraped the epithelium away from
the affected area and treated 5 to 8 μ through the Bowman’s membrane. A
point you should be very careful about is not to treat too much especially if
you have an emmetropic or hyperopic patient, for otherwise you might end
up with unintended hyperopia and not a very satisfied patient. The size of
the spot can be adjusted to the size of the area. Videokeratography can often
help if you are not able to localize the erosion at the moment of healing, as
it will often show irregularity of the affected area. If the erosions are near the
visual axis the treatment should always be properly centered to omit any
irregularity of the surface that could disturb the visual acuity or visual quality
of the eye.
Postoperatively the patients were given painkillers orally and antibiotic
ointment as recommended treatment. The author would recommend that
you treat 48 m transepithelially followed by 10 m using a masking agent.
Summary
PTK is safe treating recurrent erosions. After repeated treatment, our success
rate was 100 percent, after one treatment 81 percent were cured. The risk of
inducing hyperopia can be minimized if the ablation depth is restricted to
within the Bowman’s membrane.
ANISOMETROPIA DUE TO IATROGENICALLY-PRODUCED REFRACTIVE ERRORS

Iatrogenically-produced refractive errors are not uncommon but are
decreasing in number due to modern phacoemulsification techniques, at
least in the group submitted by the surgeons for cataract. This group consists
of patients from surgery for, cataract, secondary IOL-implantation and PKP
without cylinder. The PKP group will be discussed more thoroughly further
on, because the biggest problem in that group is often astigmatism, not
anisometropia.
The group comprised 42 eyes, the largest number coming from cataract
surgery. The group’s mean refractive error before treatment: –6.05 D ×
–1.29 D (spherical equivalent:–6.69 D), after treatment: –0.8 D –1.01 D
(spherical equivalent: –1.31 D). The results are as good as the results you get
when treating with PRK.
Treatment
The group was treated as a PRK group. We have changed our approach
when removing the epithelium. First we scraped off the epithelium with a
knife and then we used a brush. Today, we ablate the epithelium with the
excimer laser.
Conclusion
Anisometropia due to iatrogenically-produced refractive errors is not
uncommon, but it is a decreasing group which can easily be treated with the
same good results as you get after PRK. In this group, we have not included
patients with high astigmatism after PKP (that group will be evaluated later).
KERATOCONUS
Treating keratoconus with the excimer laser has been regarded as
contraindicated until we started treating primary keratoconus in 1992. In the
two articles* treating keratoconus is not contraindicated and we find that
keratoconus can safely be treated by the excimer laser.
The keratoconus group has been evaluated after treating 5 eyes, then 24
and now in this chapter 40 eyes. The success rate of the first published group
was that 4 eyes out of 5 improved (80%), the second follow-up study of 24
treated eyes showed that 14 eyes improved and now in the group of 40 eyes
22 eyes improved (55%).
The success rate is bound to reduce as time goes by due to the nature of
the keratoconus disease. What the author postulated, and in his opinion
succeeded in proving, was that it is not harmful to treat keratoconus as no
acceleration of the disease was seen, and that they succeeded in increasing
the time until penetrating keratoplasty (PKP) might be needed. The author
knows that some keratoconus patients will never need PKP though he is not
able to predict which patients will be in that group, and he is not able to tell
if he in the long run could increase that group, but what he does know is that
he surely can postpone the need of PKP for several years for some of the
patients.
New lenses have been introduced since he started: the scleral lens and
the Rose K Lens, and perhaps this together with the excimer laser treatment
can reduce the need for PKP in the future.
Evaluation
The patients should have a lengthy history of keratoconus and not be able to
wear a contact lens. The refraction should be rather stable for the last year.
* 1. Mortensen J, Öhrström A. Excimer laser photorefractive keratectomy for treatment

of keratoconus. J Refract Corneal Surg 1994;10:368-72.
* 2. Mortensen J, Carlsson K, Öhrström A. Excimer laser surgery for keratoconus. J
Refract Corneal Surg 1998;24:893-89.
The corneal thickness at the apex of the cone was required to be more than
half the peripheral thickness, evaluated by optical estimation with the slit-
lamp biomicroscopy, excessive scarring of the cone involving the stroma was
contraindicated. Further evaluation by the videokeratography was done
(Topographic Modeling System [TMS-1], computed anatomy, Inc). The
biggest obstacle to success is irregularity of the surface, not major ametropia.
The surgery was done by the old workhorse, the VISX 2020 B system with
spherical ablation, cylinder ablation or both. The spherical ablation was
decentered to cover the steepest part of the cone.
The videokeratographic charts of the keratoconus can vastly differ in
appearance—most of the surface being normal with an inferior cone
peripherally, the whole central surface can be engaged with the topographic
picture looking very much like an astigmatic cornea, and the center can be
irregular. The type with the inferior cone can be viewed like the picture that
is seen after decentration and should be treated the same way—decenter
the spherical ablation over the cone, look at the dioptric power and treat
approximately two-third of the value (9 diopters gives a treatment of 6
diopters). Measure the distance from the visual axis to the center of cone
from the videographic picture, and mark the measured distance on the cornea
before treating.
Treatment
Figure 29.1 shows a videokeratography of a keratoconus eye with a typically
inferior cone. Treatment was done transepithelially 52 μ, followed by 5 D in
a 4 mm zone that was decentered approximately 2 mm inferiorly to cover
the cone. Five diopters was chosen as the cone was approximately 7 diopters
over the center. Preoperative change of refraction: +4.0 sphere × –3 cyl ×
110°, after 4 months +2.75 sphere –0.5 × 40°. Best spectacle-corrected
visual acuity (BSCVA) preoperatively 0.5, postoperatively BSCVA 0.6 and
0.5 without SC. Was the patient satisfied? No. The result was quite good, but
the expectation of the patient exceeded the achieved result, so far.
Figure 29.2 shows the videokeratography of a binocular keratoconus
with heavy irregularity. Preoperatively right eye BSCVA:0.13 (+2.0 sphere
–6.0 cyl × 140°). Postoperatively right eye BSCVA: 0.25 (–2.0 sphere).
Treatment was done with –7 diopters in a 5 mm zone decentered).
Left eye was treated –6 diopters in a 4 mm zone not decentered.
Preoperatively BSCVA: 0.17 (–3, sphere –6 cyl × 70°).
FIGURE 29.1: Videokeratography showing a keratoconus

eye with a typically inferior cone
FIGURE 29.2: Videokeratography of a binocular keratoconus

with heavy irregularity
Postoperatively BSCVA: 0.17 (–1.0 sphere). The patient was not satisfied
and later had PKP. This illustrates irregularity as the major obstacle to success;
today, the author would not have treated that patient.
Figure 29.3 shows the videokeratography of a keratoconus type not
uncommonly called globus type. The patient was treated transepithelially
60 μ (–2 diopters sphere –6 cyl × 180°). Preoperatively BSCVA: 0.5 (–10
sphere –8 cyl × 180°). Follow-up 11 months, (Figure 29.4) BSCVA: 0.5 (0
sphere –4.5 × 90°), the patient was very satisfied.
FIGURE 29.3: Videokeratography showing a keratoconus type not

uncommonly called globus type before PTK
Conclusion
Keratoconus has been considered a contraindication to excimer laser surgery
because of the fear of accelerating the disease and the fear that the epithelium
might not heal. The author has been treating primary keratoconus for the
past seven years, and the author has not been able to confirm these fears.
You have to carefully evaluate the eye before treating. We did not find any
changes in the cornea that should negatively influence the possibility to affecting
a successful PKP if this should be needed in the future. We believe that
earlier surgery could be an advantage in some cases. The irregularity of the
FIGURE 29.4: Videokeratography showing a keratoconus type not

uncommonly called globus type at follow-up 11 months
surface of the cornea is the biggest obstacle, not the ametropia. Never
promise the patient that you can arrest or heal his or her keratoconus.
What you might do for him or her is to extend the period till he or
she might need PKP.
ASTIGMATISM
Most astigmatism treated by the author was iatrogenic. The author has chosen
to deal with that problem in this session.
The group consisted of 37 eyes, 25 eyes after PKP and 12 eyes after
cataract surgery or surgery for corneal trauma. Most of the PKP was due to
keratoconus. The reason for making this division is the difference in achieved
results with PKP. Treating astigmatism after PKP is somewhat like treating a
jelly, it seems stable but in the next second has changed. It was very difficult
to predict the results, and the achieved results were unstable. Laser in situ
keratomileusis (LASIK) might be the solution to this problem, Professor
McGhee, Dublin, told the author that he had obtained very good and stable
results after LASIK treatments of astigmatism after PKP.
In the first group of 25 eyes the preoperative mean refraction was: +1.77
sphere –7.55 cylinder, postoperative refraction: +0.39 sphere –3.33 cyl.
Remarkable results were seen, but overall, most treatments were not stable.
Twelve eyes were treated in the other group with a much better outcome.
Preoperative mean:–0.35 sphere –4.60 cyl.
Postoperative mean:+0.54 sphere –1.60 cyl. These are acceptable results.
When you are treating an eye that has had PKP you always give
corticosteroids in high dosage orally, to avoid rejection of the graft. In the
group we saw one rejection after PTK-treatment.
Conclusion
Astigmatism can successfully be treated with the excimer laser and the result
will certainly be better in the future with the new lasers. Treating astigmatism
after PKP was and still is a problem—predictability is low, and we get quite
unstable results. LASIK might be the answer to the problems.
CORNEAL SCARS
Corneal scars group is very heterogenous consisting of eyes with:
• Corneal dystrophies (Reis-Bückler, lattice dystrophy, Meesmann’s
dystrophy, granular dystrophy)
• Traumatic scars
• Scars after keratitis (Virogen, bacterial).
Before treating, you have to evaluate what you want to accomplish with
the treatment—reducing pain, increasing visual acuity, cosmetic reasons or
help the eye to tolerate a contact lens.
Evaluation
To understand the disease behind the scar is very important. The evaluation
is done by videokeratography and slit-lamp microscopy. If the cause is a
dystrophy, it is important to understand the anatomy of the disease and
even its nature, is it slowly progressive, affecting the Bowman’s membrane,
the stroma, the epithelium, does it cause recurrent erosion, irregularity of
the surface or is it a dense central macula that causes the bad visual acuity?
Again, if you have a dystrophy try to treat as little as possible so that you
can repeat the treatment in the future if so required without causing a major
change in the refraction. Dystrophies from the Bowman’s membrane and in
the epithelium are treated as recurrent erosion. If the major optical problem
comes from irregularity use a masking agent, even if you have a combination
of dense macula and surface irregularity, try firstly to smooth the surface,
then evaluate the result after that.
Traumatic macula can be very deep and produces a major change in the
refraction. Again, be careful first to smooth the surface and after that go for
the change of refraction, and inform the patient that you may need to do
more sessions. Always try to remember that what has been removed by the
excimer laser, will not come back. If you treat a myopic patient or a patient
who later will have a cataract operation, you can of course treat more deeply
without inflicting harm to the patient. Irregularity of the surface is still
irregularity after the treating surface if you do not use a masking agent. New
agents are coming. Masking is an art, using the epithelium, masking with
paper, contact lens and different floating agents (balanced salt solution—
BSS, methylcellulose, LaserVis).
If you are uncertain as to what caused the macula, always suspect virus
and then give systemic antivirus medication to prevent a recurrence of the
infection that could be devastating for the result.
Do remember to carefully evaluate the sensibility of the cornea, if you
are treating a cornea with a diminished sensibility you could have a big
problem. The same applies if the lacrimation is in any way adversely affected
owing to reduced production or corrupted lubricating ability. Sjögren’s
syndrome and postherpetic scars are relatively contraindicated in the author’s
opinion. Careful evaluation of the blinking ability and the state of the palpebrae
are also of major importance.
Treatment
As you will understand from the above, there is no easy menu program
giving all the answers, but again first of all try to treat as little as possible, at
least at the first session, then you can come back if needed. We did most
treatments transepithelially with 50 to 70 μ followed by 20 μ using a masking
agent. When you are smoothing the surface, try also to use the biggest zone
you can get from the laser beam. Try to avoid inducing irregularity. In the
very early days the author treated a patient who was bothered by a halo
from a paracentral macula caused by a metal splinter, uncorrected visual
acuity (UCVA) 1.3. The author intended to remove the macula as he thought
that the unclarity of the cornea caused the patient’s problems. He treated in
a 2 mm zone 40 μ and changed the refraction from 0.75 sphere –0.75 cyl ×
75° to +1.25 sphere –0.5 × 85° and alas the visual acuity diminished to
0.65 giving severe halo and glare even after 2 years. That patient was not
very satisfied. What would the author do to day? First, wait up to 2 years
after the trauma to see what nature will do, if by then the patient still has
problems, he should treat with the 6 mm spot transepithelially 45 microns
and additionally 10 to 15 microns masked by some masking agent and wait
for at least 6 months for a new evaluation.
You can obtain really remarkable results when treating the dystrophies
affecting the Bowman’s membrane and the epithelium. Again, first try to
smooth and do the treatment in more sessions, and be very careful.
We even have happy stories to tell—a 29-year-old man woke up after he
had been wearing his contact lenses for at least 24 hours, he did not really
remember as he had been celebrating. His problem was that he did not see
anything so he was led to the author’s clinic. Evaluation showed finger counting
both eyes, the spectacles he wore showed that he was –18 diopters in both
eyes. He could even tell that he had low vision on his left eye since childhood.
Slit-lamp microscopy showed contact lenses “glued” to the epithelium, heavy
edema of both corneas. The contact lenses were removed, resulting in almost
total removal of the epithelium. At first severe infection was suspected, but
this could not be confirmed. The corneas were cloudy and had severe edema.
The diagnosis of severe ischemia of the corneas was proposed. The patient
stayed for three weeks and he slowly regained some vision, the epithelium
healed with severe scarring and irregularity. Visual acuity at best was 0.2 in
his right eye and finger counting left eye. The author waited for one year
and then the right eye was treated 50 μ transepithelially and he tried to
smooth the surface. The result was 0.5 with contact lenses. The patient was
very happy after that (Figures 29.5 and 29.6).
CORNEAL DYSTROPHIES
The evaluation is very important to get to the right diagnosis. The dystrophies
are often assessed anatomically into pre-Bowman’s layer, Bowman’s layer,
anterior stromal and stromal. The dystrophies are congenital and will recur,
so the PTK treatment cannot be considered as a cure for the future problems
caused by the dystrophies, that again points up the need to cause as little
impact to the cornea as possible to relieve the problem of the patient, so that
the procedure may be repeated in the future.
FIGURE 29.5: Videokeratography showing severe scarring and

irregularity of the right eye
FIGURE 29.6: Videokeratography showing severe scarring

and irregularity of the left eye
Generally, the problems most often seen with dystrophies are recurrent
erosion and irregularity of the surface. The cloudiness of the stroma is more
seldom the cause that reduces the visual acuity.
The dystrophies treated were: lattice dystrophy, map-dot-fingerprint,
Meesmann’s dystrophy, Reis-Bückler’s dystrophy, granular dystrophy
(Groenouw type I), endothelial dystrophies and dystrophies of uncertain
diagnosis.
The author’s treatment strategy was to inflict as little change to cornea as
was needed. In this group he found 20 eyes where PTK treatment was done
transepithelially followed by 20 micron in the stroma, often using a masking
agent. Three eyes had the diagnosis of lattice dystrophy whose pathology is
caused by accumulation of amyloid material subepithelial in the stroma,
causing recurrent erosion and irregularity of the surface. Mean age was 33
years. They were treated transepithelially followed by 15 to 27 micron, visual
acuity increased in all eyes (Table 29.1).
TABLE 29.1: Lattice dystrophy, 3 eyes visual acuity pre- and postoperatively and
stromal ablation
Va Prop Sph Cyl Axis Stromal Va Postop Sph Cyl Axis
0.25 0.50 –1.00 80 25 0.80 1.75 –2.25 100
0.10 6.00 –3.00 0 20 0.50 6.00 –3.00 0
0.25 –3.00 –1.00 90 50 1.00 –1.50 –0.75 60
Two eyes had the diagnosis Groenouw type I. The lesions are sharply-
demarcated confined to the axial portion of the cornea, usually beginning in
the most superficial portion of the stroma. The deposit is believed to come
from the epithelium—recurrence and irregularity often the biggest problem.
Those eyes were treated like recurrent erosion, transepithelial followed
by 10 micron in one eye and the other eye was “polished” 20 micron using
methylcellulose as a masking agent. The results were very good—both patients
got rid of the erosions and even gained in visual acuity (Figures 29.7A to D).
One eye had the Meesmann dystrophy caused by small cysts looking
gray-white in the rim area. The cysts are seen at the level of the Bowman’s
membrane. The complain is often a foreign body sensation and recurrent
erosion and may even be decreased visual acuity. The author’s patient was
treated transepithelially 50 microns, followed by 30 microns in a 6 mm zone
masked by methylcellulose. Visual acuity was preoperatively 0.5 and post-
operatively 1.0.
FIGURES 29.7A and B: Cornea with Groenouw

dystrophy pre-and postoperative, difficult to tell
the difference
One eye with map-dot-fingerprint dystrophy disorder involving the

epithelium and the basement membrane had problems caused by recurrent
erosion.
The patient was treated transepithelially 50 microns followed by 11 microns.
The patient had one relapse after 6 months but after that no problems.
Reis-Bücklers dystrophy is symmetric, evident in early childhood as
recurrent erosive episodes. Patients develop decreased vision due to anterior
scarring and irregularity of the corneal surface.
FIGURES 29.7C and D: Videokeratographies of the eye in Figures 29.7A and

B. Visual acuity preoperative—0.4 8–1.5 sphere –1.5 cylinder in 35 degrees.
Postoperative—0.7 –0.75 sphere –2.25 in 25 degrees
FIGURES 29.8A and B: Immigrant from Ethiopia with unknown corneal

dystrophy pre- and postoperative
Two patients were found with the diagnosis and one patient was treated
transepithelially 50 microns followed by 100 micron masked by tetracaine.
The patient did not improve and had PKP. The patient was 63-year-old and
had developed excessive scarring.
The other patient was 49-year-old and was treated 50 microns
transepithelially followed by 10 microns ablation of the stroma (Figures 29.8A
and B). The result was very good, visual acuity went from 0.2 to 0.6 and was
still stable after 14 months.
The rest of the group was classified as having corneal dystrophies with
anterior involvement. As you can see from the Table 29.2, the whole group
had an increase of visual acuity, but also a shift of refraction to hyperopia in
spite of the cautious treatments.
Conclusion
PTK treatment of different corneal dystrophies often gives very good results,
especially if the problem is due to recurrent erosion and not to severe
irregularity of the surface of the cornea. Try to treat as little as possible to
obtain the desired result, as the dystrophy can often give similar problems in
the future.
BAND KERATOPATHY
The group consisted of 16 eyes. Most eyes had severely impaired function
due to severe diseases.
Five treatments were carried out to improve visual acuity, one treatment
esthetic the rest was to relieve pain.
TABLE 29.2: Corneal dystrophies with anterior involvement. The whole group had an increase of visual acuity, but
also a shift of refraction to hyperopia in spite of the cautious treatments
Visual Acuity Preoperative Ablation Ablation Visual Acuity Postoperative
Preoperative sphere Cylinder Axis Micron Method Postoperative sphere Cylinder Axis
0.65 2.25 –0.75 85 20 Transepithelial 50
micron 0.65 2.75 –0.75 85
micron 0.90 1.75 –2.25 100
micron 1.30 –0.50 –1.00 120
micron +
masking 0.65 1.75 –3.00 83
micron +
masking 0.80 2.50 –4.00 160
0.40 0.00 –5.00 160 33 Transepit 70 μ +
33 μ + –4 cyl 0.80 2.50 –4.00 160
micron +
PHOTOTHERAPEUTIC KERATECTOMY (PTK) IN OCULAR SURFACE DISORDERS
masking 1.00 3.00 –1.00 10

481
FIGURES 29.9A and B: Band keratopathy in an eye

operated with silicon IOL, pre- and postoperative
The treatment were transepithelially followed by ablation from 18 to 200

microns to polish the surface, often using a masking agent. With the rough
type of band keratopathy you might need to remove the dense calcification
manually before doing the smoothing. You might even try ethylene diamine
tetraacetic acid (EDTA) before continuing with the excimer laser (Figures
29.9A and B).
Conclusion
Developing band keratopathy often indicates severe disease of the eye. The
treatment can often relieve or diminish pain caused by recurrent erosion or
irregularity of the surface. Is it better than EDTA? The outcome is not certain,
but the author has seen less complication and pain for the patients, as the
epithelium will heal much faster and the treatment is often chosen by the
patient as the much the easier one to endure.
PTERYGIUM
We meant to abolish or diminish the recurrence of the pterygium. The
pterygium was surgically excised and after that the denuded area was polished,
often under masking of methylcellulose, by the excimer laser. Central macula
or irregularities of the cornea were treated as earlier described. Did we see
any success in the group of 13 eyes? Yes, if visual acuity was diminished due
to central irregularity of the cornea the success rate was high, but we did not
see any indication that polishing after surgical removal would minimize the
recurrence of the pterygium compared with only surgical excision (Figure
29.10).
Conclusion
We did not see that any beneficial effect obtained from polishing the denuded
area by the excimer laser as compared to only surgical excision of the
pterygium. Treating macula of the central cornea was successful.
FIGURE 29.10: Pterygium recurs after 2 months in spite of

polishing with the excimer laser
SUMMARY
PTK is still in it is infancy. The author used the old broad beam excimer laser:
VISX B 2020. New scanning lasers will certainly improve the possibility of
treating irregularity of the corneal surface and the results will be further
improved through new masking agents. Videokeratographically-guided
scanning lasers are now being developed and perfected. The LASIK method
has a great potential used as a PTK instrument for example when treating
high astigmatism after PKP. Only the future will show whether LASIK could
be used to treat other diseases of the cornea.
BIBLIOGRAPHY
1. Algawi K, Goggin M, O’Keefe M. 193 nm excimer laser phototherapeutic keratectomy
for recurrent corneal erosions. Eur J Implant Ref Surg 1995;7:11-13.
2. Belin MW, Fowler WC, Chambers WA. Keratoconus—evaluation of recent trends in
the surgical and nonsurgical correction of keratoconus. Ophthalmology 1988;
95:335-38.
3. Campos M, Hertzog L, Garbus J et al. Phototherapeutic keratectomy for severe
postkeratoplasty astigmatism. Am J Ophthalmol 1992;114:429-36.
4. Campos M, Lee M, McDonnell PJ. Ocular integrity after refractive surgery—effects of
photorefractive keratectomy, phototherapeutic keratectomy, and radial keratectomy.
Ophthalmic Surgery 1992;23:598-602.
5. Durrie DS, Schumer DJ, Cavanaugh T. Phototherapeutic keratectomy—the summit
experience. In Salz JJ (Ed): Corneal Laser Surgery CV Mosby: St Louis, 1995.
6. Gibralter R, Trokel SL. Correction of irregular astigmatism with the excimer laser.
7. Hersh PS, Wagoner MD. Excimer Laser Surgery for Corneal Disorders Thieme:
New York 1998.
8. John ME, Martines E, Cvintal T et al. Phototherapeutic keratectomy following
penetrating keratoplasty. J Refract Corneal Surg , 1994;10:S296-S10.
9. Kasti PR, Donzis PB, Cole HP III et al: A 20-year retrospective study of the use of
contact lenses in keratoconus. CLAOJ 1987;13:102-04.
10. Kornmehl EW et al: A comparative study of masking fluids for excimer laser
phototherapeutic keratectomy. Arch Ophthalmol 1991;109:860-63.
11. McDonald MB, Kaufman HE, Durrie DS et al: Epikeratophakia for keratoconus—
the nationwide study. Arch Ophthalmol 1986;104:1294-1300.
12. McDonnell PJ, Seiler T: Phototherapeutic keratectomy with excimer laser for Reis-
Buckler’s corneal dystrophy. Refract Corneal Surg 1992;8:306-10.
13. McGhee CNJ, Hugh Taylor, Gartry DS et al: Excimer Lasers in Ophthalmology:
Principles and Practice, Butterworth-Heinemann: Boston, 1997.
14. Mortensen J, Carlsson K, Ohrstrom A: Excimer laser surgery for keratoconus. J
Refract Corneal Surg 1998;24:893-98.
15. Mortensen J, Ohrstrom A: Excimer laser photorefractive keratectomy for treatment
of keratoconus. J Refract Corneal Surg 1994;10:368-72.
16. O’Brart DP, Garty DS, Lohmann CP et al: Treatment for band keratopathy by excimer
laser phototherapeutic keratectomy—surgical techniques and long-trem follow-up.
Br J Ophthalmol 1993;77:702-08.
17. Seiler T, Bende T, Wollensack J: Ablation rate of human corneal epithelium and
Bowman’s layer with the excimer laser (193 nm). Refract Corneal Surg 6: 99-102,
1990.
18. Seiler T, Schnelle B, Wollensak J: Pterygium excision using 193-nm excimer laser
smoothing and topical mitomycin C. German J Ophthalmology 1: 429-31, 1992.
19. Trokel SL, Srinivasan R, Braren B: Excimer laser surgery of the cornea. Am J
Ophthalmol 96: 710-15, 1983
20. Vinciguerra P et al: A new strategy in excimer laser PTK—use of sodium hyaluronate
solution as masking fluid. Inv Ophthalmol and Visual Sci 35(4): 1300, 1994.
STEM CELL SURGERY IN OPHTHALMOLOGY 487
INTRODUCTION
The corneal epithelium continuously sheds its surface epithelium, and is
replaced by stem cells originating from beneath and peripheral to the central
desquamating epithelium.1,2 Stem cells are the ultimate source of the rapidly
self-renewing corneal epithelium and are located in the basal layer of the
limbal epithelium.3-5 They are present in the crypts of Vogt or the palisades
of Vogt, which are principally located at the sclerocorneal limbus.6 These
cells, like all stem cells are poorly-differentiated7-10 and have a low mitotic
rate and asymmetrical DNA segregation. They have the potential for
clonogenic cell division and are essential for the maintenance of a healthy
corneal surface. Limbal stem cells evolve into the transiently amplifying cells
(TAC). Both of these undergo cell division and remain in the poorly
differentiated stage. They are both located in the limbal region, with the
stem cells in the basal epithelium7,11, 12 and TAC occurring in the basal and
suprabasal levels, extending up to the superficial layers. These cells divide
into the non-dividing post-mitotic cells (PMCs), which then undergo terminal
differentiation and migrate onto the central cornea as terminally differentiated
cells (TDCs) to form the new corneal epithelium.
LIMBAL STEM CELL DEFICIENCY

Loss of limbal stem cells, or corneal stem cell deficiency, can be partial or
total, unilateral or bilateral. The absence or malfunction of corneal stem
cells, either primary (aniridia, congenital erythrokeratoderma, etc.) or
secondary (chemical burns, Steven Johnson syndrome, ocular cicatricial
pemphigoid (Figure 30.1), etc.8,12,13, results in loss of the regenerative capacity
of the corneal epithelium. This results in “transdifferentiated” conjunctivally-
derived epithelium surfacing the cornea or, sometimes, failure to resurface at
all leading to a persistent epithelial defect, with corneal neovascularization
(Figure 30.2) and scarring, melting, ulceration and perforation of the cornea,
corneal calcification, and band keratopathy.14-19 The patient may complain
of decreased vision, photophobia, tearing, blepharospasm, and recurrent
episodes of pain, as well as a history of chronic inflammation with redness.
A keratoplasty in these patients, whether lamellar or penetrating, is generally
not successful as the host’s corneal epithelium is only temporarily replaced
and the limbal function continues to remain poor.20-21 Limbal stem cell
transplantation is a surgical modality, described by Kenyon and Tseng, to
FIGURE 30.1: Pemphigoid (Courtesy-Guilermo Simon-Castellvi, Spain)
FIGURE 30.2: Patient with dry eye, corneal vascularization and epithelial defect
replenish or repopulate the ocular surface epithelium in an eye with limbal

stem cell deficiency. Limbal transplantation for these patients restores the
corneal limbal stem cells and long term corneal epithelial healing may be
achieved.22 -29 A keratoplasty may be combined with this or done at a later
sitting. Any underlying primary problem should also be corrected.
LIMBAL STEM CELL TRANSPLANTATION

A variety of techniques of limbal transplantation have been reported. 30-41 All
these procedures remove the host’s altered corneal epithelium and pannus
and provide a new source of epithelium for a diseased ocular surface. From
the donor tissue, transient amplifying cells are generated which migrate onto
the denuded corneal surface of the host. A successful transplantation leads to
the host’s cornea (or grafted cornea) being permanently covered by epithelium
from the donor. The donor tissue can be obtained from the other eye (limbal
autograft) in cases of unilateral disease. In case of bilateral disease, cadaveric
whole globe or corneoscleral rim of a living relative (limbal allograft) can
be used. Limbal transplantation procedures may also be classified depending
on the carrier tissue used for the transfer of the limbal stem cells. Either
conjunctiva (conjunctival limbal graft) or corneal/limbal stroma
(keratolimbal graft) have been used as carrier tissue for limbal stem cells.36
PREOPERATIVE PREPARATION
Any pre-existing problem such as dry eye, corneal anaesthesia, conjunctival
scarring, corneal epithelial keratinisation, mucous depletion, meibomitis,
entropion, ectropion, trichiasis etc. should be taken care of. Procedures like
punctal occlusion, autologous serum eye drops, lid margin eversion, scleral
contact lens and topical retinoid acid ointment may be used preoperatively
to augment ocular surface defense. The patient (Figure 30.3) can be put on
preoperative steroids and immunosuppressives to decrease coexisting
inflammation. In case of allograft, HLA typing and matching can be done.
SURGICAL TECHNIQUE FOR LIMBAL ALLOGRAFT

From Cadaver Eye
As success depends on transplantation of healthy limbal stem cells, fresh
donor eyes are preferred. In case of cadaver eye, whole globe is preferred as
it provides better stability while dissecting the donor tissue. Several variations
of limbal autografts30-37and allografts32-41 have been reported. Dua HS, Azuara-
Blanco et al have described a modified procedure for limbal allograft.42 The
eye is first made tense by injecting air into the vitreous cavity through the
optic nerve using a 26 guage needle and the nerve is clamped. The eye is
held in a Tudor Thomas stand. A trephine 3 mm smaller than the corneal
diameter is used to make a well centered, superficial, partial thickness cut in
FIGURE 30.3: Patient to undergo limbal stem cell

transplantation. Note the corneal vascularization and
corneal opacity
the donor tissue (approximately 150 μm depth). The cornea peripheral to

the cut is then dissected using a bevel up dissector. The dissection is carried
all the way through the limbus into a small peripheral rim of sclera,
approximately 1mm, any conjunctiva, if present being retained. This
corneoscleral rim is then cut free from the cadaver globe. The recipient bed
is prepared by doing a 360 degree peritomy, and removing the conjuctivalized
epithelium and underlying scar tissue off the cornea by blunt dissection.
The donor graft is then placed at the host limbus and sutured in place using
10-0 nylon. Any gap is filled with a “spacer” made from donor corneal stroma
or a piece of donor limbal tissue from the other eye of the same donor. The
host conjunctiva is reapproximated to the limbus using interrupted sutures.
If required, a tarsorrhaphy can be done.
The advantages of cadaver eye are that a 360-degree limbal graft can be
taken, thus providing more limbal stem cells. The larger graft also acts as a
barrier for migration of conjunctivally derived epithelium over the cornea.
The disadvantage is that there is a greater chance of rejection of the graft and
the patient may even be required to be put on immunosuppressives for his
lifetime.
FIGURE 30.4: Dissection done in the live related donors eye to get a
limbal graft
FIGURE 30.5: Limbal graft dissection complete
From Live Related Donor

Here, the procedure followed is the same as limbal autograft (explained
next) except that the donor tissue is taken from a live, related donor (Figures
30.4 and 30.5) , preferably after HLA typing and matching. This is done in
case of bilateral limbal stem cell deficiency. Even though this theoretically
FIGURE 30.6: Dissection done in the recipient eye and graft kept over
the area for suturing to start
decreases the chances of rejection as compared to cadaver graft, yet

postoperative systemic immunosuppressive therapy may be required for the
patient’s lifetime.
RECIPIENT EYE
The recipient bed is then prepared by doing a peritomy in the involved area
and removing the conjuctivalized epithelium and underlying scar tissue off
the cornea by blunt dissection. A bed is prepared for the graft by excising a
rim of corneolimbal tissue corresponding in size to the donor. A thin rim of
conjunctiva is also excised. The donor graft is then kept in place (Figure
30.6) and sutured in place using 10-0 nylon (Figure 30.7). The host
conjunctiva is approximated to the donor conjunctiva using interrupted
sutures. If required, a tarsorrhaphy can be done. At the end if necessary an
amniotic membrane transplantation can also be done (Figure 30.8).
AMNIOGRAFT
Amniotic membrane can be got from a maternity ward. This way one can
use fresh amniotic membrane. One can also use Amniograft (Bio-tissue Inc,
Miami, USA). Amniograft is the brand name from Bio-tissue. This has been
recovered aseptically from a donated placental tissue through elective cesarian
section delivery and processed under class 100 condition. The donor is
FIGURE 30.7: Suturing done of the limbal graft
FIGURE 30.8: Amniotic membrane transplantation done
screened for H1V, HBsAg, etc. Amniograft is preserved in a validated and

patented storage medium made of Dulbecco’s modified eagle medium and
glycerol (1:1) with antiobiotics. No preservatives or additives are added. The
tissue is stored at –80°C prior to distribution.
Amniograft is attached to a white nitrocellulose paper with the stromal

(sticky) side adherent to the filter paper, and the basement membrane side
away from the paper. If orientation is questionable after detaching the
membrane from the paper, one can use a dry Weckcel or cotton tip to check.
Weckcell will only adhere to the (sticky) stromal side.
Bio-tissue have also brought out Prokera which is a clinically proven
amniograft which is mounted on a corneal shaped ring so that you can use a
sutureless graft for ocular surface reconstruction. This way there is quicker
healing, no scars and it takes less time.
SURGICAL TECHNIQUE FOR LIMBAL AUTOGRAFT

Here, the donor tissue is taken from the same or the opposite eye.43,44 Hence,
it can be performed only in conditions with limited or unilateral limbal stem
cell deficiency 22. The advantage is that the risk of graft rejection is very low.
Dua HS, Azuara-Blanco et al have described a modified procedure for
limbal allograft.22 The donor tissue is taken from the contralateral eye and
transplanted onto the diseased eye. It may also be taken from a different site
on the same eye in case of localized disease. Approximately 2 o’ clock hours
of the donor tissue consisting of 2 mm of superficial (about 150 μm)
peripheral cornea, limbus and 3 mm of conjunctiva is dissected from the
donor eye.
The number of grafts taken depends on the severity and extent of
involvement of the diseased eye. A maximum of upto 180 degrees of limbal
tissue may be excised from the donor eye without inducing iatrogenic limbal
stem cell deficiency.
LIMBAL STEM CELL TRANSPLANTATION WITH KERATOPLASTY

In case of both allografts and autografts, if a penetrating keratoplasty is also
planned for the same sitting, it is done after the limbal grafts are sutured in
place. The corneal graft has generally to be kept to within 7 mm in size to
avoid encroaching onto the limbal graft.
LIMBAL STEM CELL TRANSPLANTATION WITH AMNIOTIC MEMBRANE GRAFT

Limbal stem cell transplantation can be combined with an amniotic membrane
graft in severe cases (Figure 30.8). Amniotic membrane graft may be sufficient
by itself in cases with partial limbal stem cell deficiency but in cases with total
stem cell deficiency, it is combined with limbal stem cell transplantation.
Amniotic membrane serves as a “transplanted basement membrane.” It

facilitates migration of epithelial cells and reinforces epithelial cell adhesion. It
provides a potential substrate and is a source of various growth factors that
promote epithelialisation and enhance wound healing. 13, 23,24
POSTOPERATIVE COURSE
The patients should be on frequent follow up until epithelialization is complete.
Generally, the epithelium starts growing from the graft within two to three
days and becomes complete within two weeks.42 If at any stage, conjunctival
epithelium is seen to grow over the limbus or cornea again, it is scraped off
to allow the epithelialization to occur from the graft. The signs which are
indicative of graft rejection include graft edema, graft neovascularization,
vascularization over the graft onto the cornea, focal conjunctival injection, or
focal corneal epithelial defect in the sector of rejection.
POSTOPERATIVE DRUG THERAPY

Postoperatively, the patient is maintained on topical antibiotic steroid drops
and preservative-free artificial tears. Autologous serum eye drops are also
seen to be useful. In case of allografts, steroids may be continued for a longer
period at a low dosage (one drop per day). Immunosuppressive therapy is
also given postoperatively for allografts.
SUCCESS RATES
Tsubota and coauthors45 in 1999, published a large case series in the New
England Journal of Medicine, where they used a cadaver source for the
donor LSC, and all patients underwent concomitant amniotic membrane
grafting. Success rates as denoted by successful epithelialization with
phenotypic corneal epithelium, presence of a clear cornea, and visual acuity
were 71%, 50%, and 0.04 (count fingers) respectively in burn patients and
were lower: 50%, 28%, and 0.02 (hand motion) respectively in ocular
cicatricial pemphigoid / Steven Johnson syndrome group. Their conclusion
was that limbal stem cell transplantation with amniotic membrane grafting
was successful in certain patients. These results, though not as satisfactory
from the point of final visual acuity are acceptable as the only other alternative
for these patients would be a keratoprosthesis.
RECENT ADVANCES
Transplantation of Ex Vivo Expanded Limbal Epithelial Stem Cells
Using Collagen shield as Transfer Substrate
He and Macully46documented that limbal epithelial stem cells can be grown
in vitro and stratified on collagen gel substrate. They transferred these collagen
shields with epithelial cells to denuded ex vivo human corneal stroma in
organic cultures. The 3T3 coculture system allows clonal growth of corneal
epithelial cells and maintains them in the relatively undifferentiated state.47
Using Amniotic Membrane as Transfer Substrate

Pellegrini et al 25 transplanted a sheet of in-vitro cultured autologous limbal
corneal epithelial cell layer to stem cell deficient cornea and reported successful
long-term restoration of the corneal epithelial surface in two cases. A small
piece of limbal tissue obtained from a biopsy from the contralateral eye was
digested enzymatically and the epithelium was then expanded in special
medium. Three weeks later the confluent epithelial sheet was grafted to the
diseased cornea. They found difficulties in handling this fragile sheet of
epithelium and hence the search for a suitable carrier was begun, the role
being fulfilled by amniotic membrane. When the expanded cell population
reached 40-50% confluence, they were passed on to human amniotic
membrane and allowed to attach to the AM for 10-14 days. This was then
used for limbal stem cell transplantation. The biopsy can be taken from the
same patient in case of unilateral or limited disease and from a living related
donor or a cadaver eye 28, 48 in case of bilateral total involvement. Culturing
the cells takes three to four weeks. It may then be cryo-preserved for any
length of time in liquid nitrogen. In case of allografts, the patient may need
to be placed on immunosuppressive therapy postoperatively.
Using Fibrin as Transfer Substrate

Limbal stem cells can be cultured using fibrin as a medium and can be
transferred to the eye.49
Gene Therapy
Genes expressing anti inflammatory proteins or growth factors can be used
to prevent inflammation and to supply components for healthy epithelial
turn over.50
KEY POINTS
1. The corneal epithelium continuously sheds its surface layers, and is replaced
by epithelial cells beneath and peripheral to the central desquamating
epithelium. The origin of these cells is thought to be from the crypts of Vogt
or the palisades of Vogt located at the sclerocorneal limbus, where the stem
cells reside.
2. These cells have the potential for clonogenic cell division and are essential
for the maintenance of a healthy corneal surface.
3. In patients with limbal stem cell deficiency, limbal autotransplantation or
allotransplantation should be considered for corneal surface reconstruction.
This may be combined with or followed by keratoplasty.
4. The donor tissue can be obtained from the fellow eye (limbal autograft) in
cases of unilateral disease. Cadaveric whole globe or corneoscleral rim of a
living relative (limbal allograft) can be used when both eyes are affected.
5. Limbal transplantation procedures vary depending on the carrier tissue used
for the transfer of the limbal stem cells. Carrier tissue is needed in limbal
transplantation because it is not possible to transfer limbal stem cells alone.
Either conjunctiva (conjunctival limbal graft) or corneal/limbal stroma
(keratolimbal graft) have been used as carrier tissue for limbal stem cells.
6. The future lies in transplanting ex vivo expanded limbal epithelial stem
cells using a suitable transfer substrate. Gene therapy can be implemented
by incorporating suitable genes into these cells to decrease inflammation or
to express growth factors.
7. Amniotic membrane can be got from a maternity ward. This way one can
use fresh amniotic membrane. One can also use Amniograft (Bio-tissue Inc,
Miami, USA).
REFERENCES
1. Maumenee A, Scholz R. Histopathology of the ocular lesions produced by the
sulphur and nitrogen mustards. Johns Hopkins Hospital Bull 1948;82:121-47.
2. Buschke W. Morphologic changes in cells of corneal epithelium in wound healing.
Arch Ophthalmol 1949;41:306-16.703.
3. Kinoshita S, Friend J, Thoft RA. Biphasic cell proliferation in transdifferentiation of
conjunctival to corneal epithelium in rabbits. Invest Ophthalmol Vis Sci 1983;24:
1008-14.
4. Lajtha LG. Stem cell concepts. Differentiation 1979;14:23-34.
5. Potten CS, Morris RJ. Epithelial stem cells in vivo. J Cell Sci 1988;10 (Suppl): 45-
62.
6. Davanger M, Evensen A. Role of the pericorneal papillary structure in renewal of
corneal epithelium. Nature 1971;229:560-1.
7. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling
limbal epithelial basal cells that can be preferentially stimulated to proliferate:
implications on epithelial stem cells. Cell 1989;57:201-9.
8. Tseng SC. Regulation and clinical implications of corneal epithelial stem cells. Mol
Biol Rep 1996;23:47-58.
9. Ebato B, Friend J, Thoft RA. Comparison of central and peripheral human corneal
epithelium in tissue culture. Invest Ophthalmol Vis Sci 1987;28:1450-6.
10. Pellegrini G, Golisano O, Paterna P, et al. Location and clonal analysis of stem cells
and their differentiated progeny in the human ocular surface. J Cell Biol 1999;145:
769-82.
11. Kruse FE, Volcker HE. Stem cells, wound healing, growth factors, and angiogenesis
in the cornea. Curr Opin Ophthalmol 1997;8:46-54.
12. Kruse FE. Stem cells and corneal epithelial regeneration. Eye 1994;8:170-83.
13. Dua HS, Azuara-Blanco A. Limbal stem cells of the corneal epithelium. Surv
Ophthalmol 2000;44:415-25.
14. Chen JJY, Tseng SCG. Corneal epithelial wound healing in partial limbal deficiency.
15. Huang AJW, Tseng SCG. Corneal epithelial wound healing in the absence of limbal
epithelium. Invest Ophthalmol Vis Sci 1991;32:96-105.
16. Kenyon KR, Bulusoglu G, Ziske JD. Clinical pathologic correlations of limbal
autograft transplantation. Am J Ophthalmol 1990;31:1.
17. Kinoshita S, Kiorpes T, Friend J, et al. Limbal epithelium in ocular surface wound
healing. Invest Ophthalmol Vis Sci 1982;23:73-80.
18. Nishida K, F S, Ohashi Y, et al. Ocular surface abnormalities in aniridia. Am J
Ophthalmol 1995;120:368-75.
19. Tseng SCG. Concept and application of limbal stem cells. Eye 1989;57:201-209.
20. Brown SI, Bloomfield SE, Pearce DB. Follow-up report on transplantation of the
alkali burned cornea. Am J Ophthalmol 1974;77:538-42.
21. Abel R Jr, Binder PS, Pilack FM, et al. The results of penetrating keratoplasty after
chemical burns. Trans Am Acad Ophthalmol Otolaryngol 1975;79:584-95.
22. Dua HS, Azuara-Blanco A. Autologous limbal transplantation in patients with
unilateral corneal stem cell deficiency. Br J Ophthalmol 2000;84:273-78.
23. Azuara-Blanco A, Pillai CT, Dua HS. Amniotic membrane transplantation for ocular
surface reconstruction. Br J Ophthalmol 1999;83:399-402.
24. Dua HS, Azuara-Blanco A. Amniotic membrane transplantation. Br J Ophthalmol
1999;83:748-52.
25. Pellegrini G, Traverso CE, Franzi AT, Zingirian M. Long term restoration of damaged
corneal surface with autologous cultivated corneal epithelium. Lancet 1997;349:
990-93.
26. Schwab IR. Cultured corneal epithelia for ocular surface disease. Trans Am
Ophthalmol Soc 1999;97:891-986.
27. Schwab IR, Isseroff RR. Bioengineered corneas–the promise and the challenge. N
Engl J Med 2000;343:136-38.
28. Schwab IR, Reyes M, Isseroff RR. Successful transplantation of bioengineered tissue
replacements in patients with ocular surface disease. Cornea 2000;19:421-26.
29. Tsai RJ, Li LM, Chen J-K. Reconstruction of damaged corneas by transplantation of
autologous limbal epithelial cells. N Engl J Med 2000;343:86-93.
30. Copeland RA, Char DH. Limbal autograft reconstruction after conjunctival squamous
cell carcinoma. Am J Ophthalmol 1990;110:412-15.
31. Jenkins C, Tuft S, Liu C, et al. Limbal transplantation in the management of chronic
contact-lens associated epitheliopathy. Eye 1993;7:629-33.
32. Pfister R. Corneal stem cell disease: concepts, categorization, and treatment by
auto- and homotransplantation of limbal stem cells. CLAO J 1994;20:64-72.
33. Kwitko S, Marinho D, Barcaro S, et al. Allograft conjunctival transplantation for
bilateral ocular surface disorders. Ophthalmology 1995;102:1020-25.
34. Kenyon KR, Rapoza PA. Limbal allograft transplantation for ocular surface disorders.
Ophthalmology 1995;102 (suppl):101-02.
35. Holland EJ. Epithelial transplantation for the management of severe ocular surface
disease. Trans Am Ophthalmol Soc 1996;94:677-43.
36. Holland EJ, Schwartz GS. The evolution of epithelial transplantation for severe
ocular surface disease and a proposed classification system. Cornea 1996;15:549-
56.
37. Tan DTH, Ficker LA, Buckley RJ. Limbal transplantation. Ophthalmology
1996;103:29-36.
38. Tsai RJF, Tseng SCG. Human allograft limbal transplantation for corneal surface
reconstruction. Cornea 1994;13:389-400.
39. Tsubota K, Toda I, Saito H, et al. Reconstruction of the corneal epithelium by limbal
allograft transplantation for severe ocular surface disorders. Ophthalmology
1995;102:1486-96.
40. Sundmacher R, Reinhard T. Central corneolimbal transplantation under systemic
ciclosporin A cover for severe limbal stem cell insuficiency. Graefes Arch Clin Exp
Ophthalmol 1996;234 (suppl):s122-s125.
41. Tseng S, Prabhasawat P, Barton K, et al. Amniotic membrane transplantation with or
wihout limbal allografts for corneal surface reconstruction in patients with limbal
stem cell deficiency. Arch Ophthalmol 1998;116:431-41.
42. Harminder S Dua, Augusto Azuara-Blanco. Allo-limbal transplantation in patients
with limbal stem cell deficiency Br J Ophthalmol 1999;83:414-19.
43. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders.
Ophthalmology 1989;96:709-22; Discussion 722-3.
44. Kenyon KR. Limbal autograft transplantation for chemical and thermal burns. Dev
45. Tsubota K, Satake Y, Kaido M, et al. Treatment of severe ocular-surface disorders
with corneal epithelial stem-cell transplantation. N Engl J Med 1999;340:1697-
703.
46. He YG, McCulley JP. Growing human corneal epitheli-um on collagen shield and
subsequent transfer to de-nuded cornea in vitro. Curr Eye Res 1991; 10: 851-63.
47. Rheinwald JG, Green H. Serial cultivation of strains of human epidermal
keratinocytes: the formation of kera-tinizing colonies from single cells. Cell 1975;6:
331-43.
48. Koizumi N, Inatomi T, Suzuki T, Sotozono C, Kinoshita S. Cultivated corneal epithelial
transplantation for ocular sur-face reconstruction in acute phase of Stevens-Johnson
syndrome. Arch Ophthalmol 2001;119:298-300.
49. Rama P, Bonini S, Lambiase A, et al. Autologous fibrin-cultured limbal stem cells
permanently restore the corneal surface of patients with total limbal stem cell
deficiency. Transplantation 2001;72:1478-85.
50. Hauswirth WW, Beaufrere L. Ocular gene therapy: quo vadis? Invest Ophthalmol
Vis Sci 2000;41:2821-26.
QUICK LOOK OCULAR LUBRICANTS AND ARTIFICAL TEAR SOLUTIONS 501
OCULAR LUBRICANTS AND ARTIFICIAL TEAR SOLUTIONS

Methylcellulose and Ethylcellulose Base
Hydroxypropylmethyl i. Solution containing In 10,15 ml
Cellulose (HPMC) 0.5 or 1% HPMC and dropper vials
0.01% Benzalkonium
chloride
ii. Solution containing In 10,15 and 30 ml
0.5%, HPMC, Gelatin A, vials
Chlorbutanol 0.5%,
NaCl and polysorbate 80
iii. Solution containing In 15 ml vials
0.5% HPMC, boric acid,
NaCl, KCl, Phosphoric
Acid and sodium
Perborate
iv. Solution containing In 10 and 15 ml
0.5% HPMC, Dextran vials
40 (0.1%).
0.01% Benzalkonium Cl
EDTA, NaCl and Boric
acid solution
v. 0.5% HPMC, Dextran In 15 ml vials
70 (0.1%) Benzalkonium
Chloride (0.01%)
EDTA
vi. Solution: HPMC 1%, In 10 and 15 ml vials
Propyleneglycol, NaCl,
Boric acid and paraben
vii. Solution: 0.8% HPMC, Preservative free in
0.1% Dextran 70, 0.5 ml single dose
Sodium Phosphate, containers (28s)
KCl, NaCl, Dextrose
viii. Solution: 0.3% Preservative free
HPMC 2910, in single use 0.45 ml
0.1% Dextran 70, packs (28s)
NaCl, KCl Sodium
Bicarbonate
ix. Solution : 0.4% HPMC In 15 ml

2910, Diabasic dropper vials
phosphate, potassium
chloride, NaCl and 0.01%
Benzalkonium Cl.
x. Solution: 0.3% HPMC In 15 and 30 ml
2910, 0.1% Dextran, dropper vials
0.01% polyquarterrnium-1
NaCl, KCl, sodium borate
Hydroxyethyl cellulose i. Solution containing In 10 and 15 ml vials

(HEC) 0.5% hydroxyethyl
cellulose (HEC), 1.67%
povidone with water
soluble polymers,
Thimerosal 0.004% and
EDTA(1%)
ii. Solution: 0.5% HEC, In 15 ml vials
polyvinyl alcohol 1% and
0.01% Benzalkonium
chloride, EDTA and NaCl
iii. Solution: 0.5% HEC In 10 and 15 ml vials
in a hypertonic base,
0.25% sorbic acid 0.01%
EDTA
iv. Solution: 0.5% HEC In 10 and 15 ml vials
0.44% NaCl
Carboxy methylcellulose i. Solution containing Preservative free
(CMC) 1% CMC, NaCl, KCl and in 0.3 ml unims
sodium lactate (30 single dose pack)
ii. Solution: 0.25% Preservative free
sodium carboxymethyl- in 0.6 ml single
cellulose, NaCl, KCl and dose containers
sodium phosphate
iii. Solution : 0.5% CMC, Preservative free
KCl, NaCl in 0.3 ml single use
Containers
iv. Solution : 0.5% CMC, In 15 ml vial
boric acid, CaCl, KCl, NaCl
and magnesium chloride
Polyvinyl Alcohol Base Solutions

i. Solution containing In 15 ml vials
1.4% Polyvinyl alcohol
(PVA) and 0.6% Povidine,
0.5% chlorbutanol and NaCl
ii. Solution: 1.4%, 0.6% In 15 ml dropper
Povidone, retinyl palmi- vials
tate, boric acid, 0.09%
EDTA, 0.001% WSCP,
NaCl, KCl
iii. Solution : 1% PVA, In 15 and 30 ml vials
PEG-400, 1% Dextrose,
0.01% Benzalkonium,
EDTA
iv. Solution : 1.4% PVA, In 15 × 30 ml vials
0.5% Chlorbutanol,
NaCl
v. Solution: 0.5% PVA, In 15 and 30 ml vials
0.6% Povidone,
Benzalkonium Cl,
Dextrose, EDTA, NaCl,
Sodium bicarbonate and
Sodium phosphate.
vi. Solution: 1.4% PVA, Preservative free
0.6% povidone and NaCl in 0.3 ml single
dose containers
(30 and 50 UD)
vii. Solution : 3% PVA, In 15 ml vial
0.002% Thimerosal, NaCl
and EDTA
Miscellaneous Artificial Tear Solutions

i. Solution: Polysorbate Preservative free in
80, Sodium chloride, 10 and 15 ml packs
EDTA, Retinyl palmitate,
Mannitol, Sodium citrate
and pyruvate
ii. Solution: 0.3% Preservative free
Glycerin, NaCl, KCl, in 0.3 ml (UD 32s)
Sodium citrate and
Sodium phosphate
iii. Solution: 0.25% In 15 ml vial
Glycerin, EDTA,
Sodium chloride and
Benzalkonium Cl
iv. Adsorbonac NaCl In 5 and 10 ml vials
2% or 5% solution
OINTMENTS
i. Ointment containing Preservative free
petrolatum (55.5%) in 3.5 and 5 g tubes
Lanolin (2% and mineral
Oil (42.5%)
ii. Ointment :2% HPMC, Preservative free in
NaCl, KCl, CaCl, MgCl, 3.5 and 5 g tubes
Sodium acetate and
Sodium citrate
iii. Lubricant gel In 5 g tube

Carbopal 980 (Poly-
acryclic acid) which
Transforms from gel
to liquid in contact
with ocular tissue
iv. Gel : 0.3% HPMC In 10 ml pack
v. Ointment: 56.8% In 3.5 and 7 g tubes
white petrolatum,
42.5% mineral oil,
Chlorobutanol, Lanolin
alcohols
vi. Ointment: White Preservative free
petrolatum in 0.5 gm pack
vii. Ointment: 55% In 3.5 g tube

white petrolatum,
32% mineral oil,
boric acid, Stearic acid
and wheat germ oil
OCULAR INSERTS
Lacriset Polymeric insert having Preservative free in
5 mg of HPMC 60s with applicator
PUNCTAL PLUGS
Collagen implant Intra canalicular In a pack of 10 or
Collagen implant 72 plugs with
Consists of 0.2, 0.3, inserter tool
0.4, 0.5 and 0.6 mm
diameter inserts pack-
ed at the edge of a
foam strip
Silicone plugs Punctum silicone In a pack of

Plug in 1.6, 2 and 2.8 mm 2 or 10 plugs with
sizes inserter tool
LUBRICANT FOR ARTIFICIAL EYES

Solution containing In 15 ml dropper
0.25% Tyloxapol and vials
0.02% Benzalkonium
chloride
Solution containing In 15 ml dropper
2.5% HPMC with vials for gonioscopic
0.004 Thimerosal examination
and 0.1% EDTA
Topical Cyclosporine 0.05% Ophthalmic In single use unims

Eye Drops emulsion and In 5 ml poly
dropper vials
BLEPHARITIS AND MEIBOMIANITIS 507
INTRODUCTION
Blepharitis is an acute or chronic inflammatory process involving the eyelids
that is frequently associated with conjunctivitis. There are many forms of
blepharitis, including bacterial, parasitic, seborrheic, eczematoid, and
neoplastic. Generally speaking, blepharitis may be divided into anterior and
posterior forms.1,2 Anterior blepharitis may be associated with staphylococcal
infection and seborrheic dermatitis. Posterior blepharitis is associated with
various disorders of the meibomian glands, known collectively as meibomian
gland dysfunction.3-5
Meibomian gland dysfunction, a condition associated with obstruction
and inflammation of the meibomian glands, is a widespread and chronic
problem. It may be the most common cause of dry eye.1,3-7 Other sequelae
which confront the ophthalmologist include chalazia, punctuate keratopathy,
pannus, phlyctenules, recurrent conjunctivitis, and in severe cases, even
corneal ulceration and endophthalmitis. Although blepharitis, in its many
clinical forms, is one of the most common diseases seen by ophthalmologists,
it remains a diagnostic and therapeutic challenge.8 The management of
blepharitis is time consuming and frequently ineffective in part because little
is known about the underlying pathophysiology of the condition, and in part
because of the difficulty in categorizing an entity that frequently coexists with
other ocular conditions, including ocular rosacea and keratoconjunctivitis
sicca. Current treatment for meibomian gland dysfunction includes lid hygiene,
oral tetracycline, doxycycline or minocycline, topical erythromycin or
bacitracin, and topical corticosteroids.1,3,7,9,10
Dietary supplementation with omega-3 fatty acids and their metabolites
can play a significant therapeutic role in dry eye and meibomian gland
dysfunction.
Underlying the pathophysiology of posterior blepharitis is meibomian
gland dysfunction. The signs and symptoms of this disease are exacerbated
by abnormalities in the lipid layer of the tear film, which is produced by the
meibomian glands. Obstruction of the meibomian ducts causes accumulation
of meibomian gland secretions, known as meibum. Accumulation of meibum
within the meibomian gland can lead to inflammation of the gland and bacterial
colonization.1,3,11,12 The colonizing bacteria have lipases that break the non-
polar wax and sterol esters into triglycerides and free fatty acids (polar lipids),
thus altering the normal composition of the meibum.13 The polar lipids diffuse
TABLE 32.1: Mean total ocular symptoms scores at each visit for the tCSA and
Refresh groups. t-test on means was utilized
Visit tCSA Refresh P value
Baseline 17.7 (n=16) 18.4 (n=17) 0.68
1 month 8.9 (n=15) 9.9 (n=16) 0.63
2 months 6.3 (n=13) 8.1 (n=15) 0.42
3 months 5.8 (n=12) 9.3 (n=14) 0.21
TABLE 32.2: Meibomian gland inclusions, fluorescein staining, tear break-up time,
and Schirmer scores at each visit for the tCSA and Refresh groups. t-test on means
was utilized. Data used is from the worse eye
Visit tCSA Refresh P value
Mean number of meibomian gland inclusions
Baseline 26.0 23.8 0.54
1 month 19.3 22.0 0.38
2 months 14.3 21.5 0.02
3 months 12.2 23.9 0.001
Mean fluorescein staining scores

Baseline 3.3 4.4 0.23
3 months 1.3 3.9 0.01
Mean tear break-up time (in seconds)

Baseline 9.9 7.4 0.40
1 month 11.2 5.3 0.24
2 months 10.3 6.4 0.19
3 months 10.8 6.1 0.08
Mean Schirmer scores (in millimeters of wetting at 5 minutes)

Baseline 14.2 11.6 0.31
3 months 11.5 11.2 0.92
TABLE 32.3: Number of patients in each lid margin vascular injection category at
each visit for the tCSA and Refresh groups. Fisher’exact test was utilized after the
table was collapsed for analysis. Data used is from the worse eye
tCSA Refresh
Visit None Mild Moderate Severe None Mild Moderate Severe P value
Baseline 0 2 8 6 0 3 2 12 0.34
1 month 1 4 3 7 0 2 5 9 0.14
2 months 0 4 4 5 0 2 4 9 0.20
3 months 3 4 2 3 0 0 5 9 0.001
BLEPHARITIS AND MEIBOMIANITIS 509
TABLE 32.4: Number of patients with presence or absence of tarsal telangiectasis at
each visit in the tCSA and Refresh groups. Fisher’s exact test was utilized. Data used
considers both eyes
tCSA Refresh P value
Visit present Absent Present Absent
Baseline 16 0 16 1 0.52
1 month 15 0 16 0 —
2 months 13 0 13 2 0.28
3 months 8 4 14 0 0.03
Need to streamline the tables
more easily through the aqueous layer and contaminate the mucin layer,
making it hydrophobic.14 This causes the tear film to become unstable, and
the surface of the eye becomes unwettable. The abnormal meibum has a
melting point above the ocular surface temperature, in contrast to normal
meibum, which has a melting point equal to or lower than the ocular surface
temperature.15 The abnormal meibum therefore solidifies and obstructs the
ducts, leading to further inflammation and perpetuating the vicious cycle.
Blepharitis and Meibomianitis are two of the most common forms of
ocular surface dysfunction. Their sequelae may lead to breakdown of the
ocular surface including dry eye symptoms which are usually worse in the
morning than in the evening. In addition these entities may be associated
with staphylococcal immune disease such as cattarhal ulcers, phlyctenules,
and inferior corneal staining. The lid manifestations include chalazia and
hordeolum. Meibomianitis and blepharitis are chronic diseases which often
require long-term therapy. A comprehensive approach in conjunction with a
dermatologist may be necessary.
REFERENCES
1. Smith RE, Flowers CW. Chronic blepharitis: A review. CLAO J 1995;21:200-07.
2. McCulley JP, Dougherty JM, Deneau DG. Classification of chronic blepharitis.
3. Driver PJ, Lemp MA. Meibomian Gland Dysfunction. Surv Ophthalmol
1996;40:343-67.
4. Bron AJ, Benjamin L, Snibson GR. Meibomian gland disease. Classification and
grading of lid changes. Eye 1991;5:395-411.
5. Mathers WD, Shields WJ, Sachdev MS, et al. Meibomian gland dysfunction in
chronic blepharitis. Cornea 1991;10:277-85.
6. Shimazaki J, Sakata M, Tsubota K. Ocular surface changes and discomfort in patients
with meibomian gland dysfunction. Arch Ophthalmol 1995;113:1266-70.
7. Gilbard JP. Dry eye, blepharitis and chronic eye irritation: Divide and conquer. J
Ophthalmic Nurs Technol 1999;18:109-15.
8. McCulley JP, Shine WE. Changing concepts in the diagnosis and management of
blepharitis. Cornea 2000;19:650-08.
9. Perry HD, Serniuk RA. Conservative treatment of chalazia. Ophthalmology
1980;87:218-21.
10. Dougherty JM, McCulley JP, Silvany RE, et al. The role of tetracycline in chronic
blepharitis. Inhibition of lipase production in staphylococci. Invest Ophthalmol Vis
Sci 1991;32:2970-75.
11. Zengin N, Tol H, Gunduz K, et al. Meibomian gland dysfunction and tear film
abnormalities in rosacea. Cornea 1995;14:144-46.
12. McCulley JP, Shine WE. Meibomian secretions in chronic blepharitis. Adv Exp Med
Biol 1998;438:319-28.
13. Shine WE, Silvany R, McCulley JP. Relation of cholesterol-stimulated staphylococcus
aureus growth to chronic blepharitis. Invest Ophthalmol Vis Sci 1993;34:2291-96.
14. Shine WE, McCulley JP. Keratoconjunctivitis sicca associated with meibomian
secretion polar lipid abnormality. Arch Ophthalmol 1998;116:849-52.
15. Shine WE, McCulley JP. Meibomian gland triglyceride fatty acid differences in chronic
blepharitis patients. Cornea 1996;15:340-46.
Index
A tetrahydrozine HCI 325
Acanthamoeba keratitis 180 immunosuppressive therapy 331
Afferent neurodeprivation 52 liposomes 332
Allergic ocular disease 308 NSAIDs [antiprostaglandin therapy]
atopic keratoconjunctivitis 311 oral antihistamines 327
giant papillary conjunctivitis 312 desloratidine 328
seasonal allergic conjunctivitis 309 levocetrizine 328
vernal keratoconjunctivitis 310 phenylephrine 324
Alpha chymotrypsin 399 topical immunosuppressors 330
Amniograft 492 cyclosporine 331
Amniotic membrane transplantation 362, topical mast cell inhibitors 316
431, 445 azelastine hydrochloride 320
clinical effects 446 cromolyn sodium 316
clinical properties 435 disodium cromoglycate 317
clinical use in ophthalmology 447 ketotifen fumarate 319
bulous keratopathy 448 lodoxamide 318
chemical burn 448 nedocromil 318
conjunctival reconstruction 448 olopatadine hydrochloride 319
corneal ulcers and perforations 448 topical steroids 330
symblepharone 449 Anti-inflammatory therapy 339
extraction and preservation 433 autologous serum drops 341
histology 431, 445 corticosteroids 340
history 445 cyclosporin A 340
immunology 432 hormones 341
indications 436 interferon 341
limitations 440 NSAIDs 340
mechanisms of action 446 Artificial tear 281
preparation 445 drops 187
surgical technique 441, 449 preservative-free tears 178
postoperative complication 452 solution 96
Anisometropia 467 substitute 181, 185, 220
Antiallergy medication 315 Astigmatism 472
anthihistamines 321
emedastine difumarate 323
B
levocabastine hydrochloride 322 Band keratopathy 480
antiallergy medication 315 Blepharitis 99, 173, 218, 261, 507
decongestants 324 Blepharoptosis 122, 342
fexofenadine 328 Blepharorrhaphy 121, 342
imidazole derivatives 324 Buccal mucous membrane
emedastine 327 transplantation 366
naphazoline HCI 325 Bullous keratopathy 448
oral pseudoephedrine 327
oxymetazoline HCI 326 C
phenylephrine HCI 324 Cataract surgery in dry eye 157
contact lens induced changes proteins 12

hard lens 166 transferrin 15
soft lens 165 urea 20
contact lens maintenance 181 Complications in refractive surgery 199
contact lenses and glaucoma patients Computer glasses 197
183 Computer vision syndrome 178, 196
contact lenses and ointments 184 cause 196
contacts and air conditioning 177 preventive measures 196
contacts and computer vision symptoms 196
syndrome 178 Confocal biomicroscopy 216
contacts and dry eye syndrome 171 Conjunctival flap 365
incomplete tear film distribution 167 Conjunctival impression 215
postoperative complications 161 cytology 78, 94
preoperative evaluation Contact lens care 192
ocular examination 157 Corneal dystrophies 475
surgical technique 160 Corneal scars
Chemical composition of tear fluid 12 evaluation 473
electrolytes and hydrogen lons 21 treatment 474
bicarbonate 22 Corneal sensation 235, 287, 289
calcium 21 Corticosteroids 355
chloride 22 Cotton thread test 213
magnesium 22 Cultured corneal epithelium 367
sodium 21 Cysternoplasty 117, 118, 342
enzymes 22
amylase 23 D
collagenase 23 Dacryocystography 31
energy producing 22 Depleted ozone layer 296
lactate dehydrogenase 22 Dermatoconjunctivitis 384
lysosomal enzymes 23 Diathermy 111
peroxidase 23 forms 113
plasminogen activator 23 Drug toxicity 383
lipids 12 contact lens solutions 399
albumin 14 binding 400
amino acids 20 compatibility 401
antiproteinases 18 sensitivity 400
catecholamines 21 solution stability 399
ceruloplasmin 15 drug-induced ocular cicatrization 401
cholesterol 12 steroids
complement 18 corticosteroids 387
dopa 21 systemic steroids 388
dopamine 21 topical steroids 387
glucose 19 systemic drugs 404
glycoproteins 18 alcohols 418
histamine 20 amiodarone 428
immunoglobulins 15 analgesics 405
lactate 20 anorexiants 419
lactoferrin 15 antianginal drugs 415
lysozyme 14 antiarrhythmics 415
metabolites 19 antiarthritic drugs 406
noradrenaline 21 anticonvulsants 419
prostaglandins 20 antidepressants 419
INDEX 513
antifungals 410 classification
antihistamines 408 Madrid triple classification 42
antihyperglycemics 424 recent triple classification 43
antihypertensives 416 clinical evaluation
anti-infective agents 408 signs 87
antileprosy drugs 411 symptoms 87
antimalarial drugs 405 diagnostic tear film tests 90
antimigraine agents 418 etiology 35
antineoplastic drugs 413 aging 35
antiparasitics 411 drugs 39
antipsychotics and tranquilizers 420 excessive use of contact lens 35
antithyroid drugs 424 eye injuries, eye surgeries 37
antituberculosis drugs 412 eyelid conditions 37
antivirals 413 hormonal changes 39
bronchodilators 418 reduced blinking 39
chlorpromazine 405 systemic diseases 36
corticosteroids 407 management 94
dermatological preparations 421 associated conditions 99
diuretics 422 mucolytics 98
gastrointestinal drugs 423 oral bromhexine 99
general anesthetic agents 408 punctal plugs 98
hormonal drugs 423 soft contact lens therapy 98
hyperosmotics 422 systemic therapy 99
isotretinoin 428 tear conservation 95
muscles relaxants 419 tear substitutes 95
myasthenia gravis drugs 427 topical retinoids 99
neuromuscular drugs 426 pathophysiology 40
NSAIDs 407 role of androgens 41
oral contraceptives 425 role of neural pathway 42
peripheral vasodilators 418 tear dynamics 40
psychedelic drugs 420 symptoms 138
sedatives and hypnotics 420 Dry eye after LASIK 143, 150
vaccines 427 effect on corneal sensation 151
vitamins 427 hinge location 144
topical antimicrobial agents 383 management 153
local complications 384 risk factors 145
nonspecific local 384 Dry eye syndrome 65, 171, 244, 248,
specific local 386 256, 281
systemic complications 383 classification 65
topical ocular anesthetic agents classification systems 248
advrese effects 391 clinical diagnostic tests 72
ocular response 393 tear film epithelial integrity
secondary adverse effects 392 assessment 75
toxicity of surfical solutions tear film stability assessment 72
antiseptic solutions 394 tear secretion assessment 73
irrigating solutions toxicity 395 diagnosis 66, 244
mydriatics and miotics 397 laboratory diagnostic tests 78
viscoelastic solutions 397 characteristics of the tear film 79
Dry eye 34, 46, 84 chemical composition of the tear
causes 84 film 80
conjunctival impression cytology 78 device 299

lipid-tear deficiency 80 Jones’s test 74
serum antibodies 78
ocular examination 69 K
external eyelid 69 Keratitis medicamentosa 385
slit-lamp biomicroscopy 69 Keratoconjunctivitis sicca 65
pathogenesis 251 Keratoconus
patient history 66 evaluation 468
physical examination 69 treatment 469
systemic examination 69 Keratolimbal lenticule 360
Dysfunctional tear syndrome 248 Keratoprosthesis 366
E L
Electrocoagulation 113 Lacrimal pathway 101
Electrolysis 113 Lagophthalmos 172
Epithelial wound healing 386 Laser in situ keratomileusis 287
Excimer laser phototherapeutic Laser-assisted subepithelial keratectomy
keratectomy 367 232
Lid scrubs 224
F Limbal stem cell deficiency 448, 455, 487
Filtering bleb 183 causes 456
Fluorescein break-up time 210 clinical features 456
Fluorescein dye 75 diagnosis 457
Fluorophotometry 214 management 457
Follicular conjunctivitis 385 contraindications 460
Frying pan theory 216 indication of transplantation 459
postoperative management 461
G preoperative considerations 460
Galvanocautery 110 technique 460
Limbal stem cell transplantation 358, 489
H postoperative course 495
Hyaluronidase 399 postoperative drug therapy 495
Hypersensitivity reactions 308, 313 preoperative preparation 489
Hypofluoroscence of fluorescein 392 recent advances 496
Ex vivo expanded limbal epithelial
I stem cells 496
Immunosuppressive drugs gene therapy 496
alkylating agents 374 success rates 495
antibiotic cyclosporin A 376 surgical technique for imbal autograft
antimetabolities 375 494
liposomes 378 with amniotic membrane graft 494
ocular drug toxicity 377 with keratoplasty 494
recent advances 378 surgical technique for limbal allograft
Immunosuppressives 355 489
Interocular decantation 125 from cadaver eye 489
Intraocular inflammation 397 from live related donor 491
Iodide 297 Limbal stem cells 455
Iontophoresis 298 Liposomal sprays 224
clinical studies 300 Lissamine green dye 78
INDEX 515
Lubricants 335, 354 artificial tears 220
Lysozyme assay 27, 93 lipid therapy 224
ointments and lubricants 224
M oral antioxidants 221
Meibomian gland dysfunction 261, 507 punctal occlusion 222
Menopausal women and dry eye 277 presurgical examinations 207
treatment 278 corneal topography 216
Mikulicz’s syndrome 86 impression cytology 215
noninvasive tests 211
N noninvasive tests 214
Nasal-lacrimal reflex tearing 74 ocular examination 208
Neurotrophic keratitis 287 tear stability tests 210
New viscoelastic solutions 397 tear volume tests 212
Nutritional suplements 338 surface integrity 234
surface properties 204
O Ointments 97
Ocular ferning test 79
Ocular lubricants and artificial tear
P
solutions 501 Phenol red threat test 74
artificial tear solutions 503 Phototherapeutic keratectomy 465
lubricant for artificial eyes 504 Pinguecula 173
methylcellulose and ethyl cellulose Pregnancy and dry eye 274
base 501 Pterygium 483
ocular inserts 504 Punctal laser photocoagulation 114
ointments 503 Punctal occlusion 342
polyvinyl alcohol base solutions 502 Punctate marginal keratitis 385
punctal plugs 504
topical cyclosporine eyedrops 505 R
Ocular rosacea 263 Recipient eye 492
Ocular surface disease 347 Recurrent erosion 466
current recommendations for Refractive surgery 228
management 368 communication and informed
etiology 347 consent 230
limbal stem cell hypothesis 349 evaluation of the patient’s 228
goals of therapy 353 management 229
index 246 Ring verification 169
signs 351 Rose bengal dye 76
treatment 353
experimental treatment modalities S
357 Salivary gland transplantation 125, 127,
limitation of tissue diestruction 356 128, 129
mechanical protection 356 Schirmer’s test 26, 73, 91, 142, 212, 392
medical 353 Scintillography 31
suppression of inflammation 355 Sjogren’s syndrome 84
surgical 358 Slit-lamp examination 139
tear substitutes and lubricants 354 conjunctival signs 141
Ocular surface syndrome 200, 202 measurement of break-up time 140
basic sciences measurement of non-invasive break-
corneal innervation 202 up time 141
management of 217 observation of the blink movement 142
particulate movement 139 formation dynamics 7

surface interference phenomena 140 function 3, 234
tear film meniscus 139 layers 4
tear flow 142 middle aqueous 5, 35
Sodium hyaluronate 337 posterior mucin 6, 35
Stenon’s duct transposition 123 superficial lipid 4, 34
Surface keratopathy 393 main parts 3
Surgical treatment of dry eye 101 normalization test 282
canalicular decalage 103 surfacing 61
canalicular excision 103 symptoms 63
canalicular ligature 103 Tear pumps 343
canalicular plugging Tear stimulants 338
absorbable 114 cevimeline 339
nonabsorbable 115 diquafosol 338
cysternoplasty 117 eledoisin 339
double local flap 118 pilocarpine 338
rhomboid 119, 120 Tear substitutes and lubricants 354
rotational flap 118 Therapeutic contact lenses 185, 356
dacryocystectomy 103 Tissue adhesives 356
punctal patching 104 Topical cyclosporin A-Restasis® 252
reduction of the interpalpebral fissure composition and appearance 253
120 indications and uses 255
thermal occlusion recommended dosing 266
cautery 108 Transplantation of salivary glands 343
diathermy 111 Transposition of salivary ducts 343
transfer of the punctum to dry dock 104 Triple classification of dry eye 47
Symblepharon 449 according to the damaged glands and
tissues 54
T according to the etiopathogenesis 47
Tarsorrhaphy 342 age-related 48
Tear 9 dysgenetic 50
applied physiology 24 hormonal 48
hypersecretion 29 hyponutritional 50
hyposecretion 24 immunopathic 49
composition 9, 10 infectious/inflammatory 51
drainage 9 neurologic 52
drugs excreted 24 pharmacologic 49
fluid 296 tantalic 53
globulin assay 27, 93 traumatic 52
physical properties 11 according to the severity
osmolarity 79, 93 grade 1 or mild 58
osmotic pressure 11 grade 2 or moderate 58
pH 11 grade 3 or severe 59
Tear drainage system 3, 9 Types of contact lenses 188
Tear film 2, 34, 200
abnormality 61 V
break up time 8, 25, 72, 90, 120 Visual acuity 280, 283, 381
composition 61 Vital dye staining 27, 92

Clinical Diagnosis and Management of Dry Eye and Ocular Surface

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Clinical Diagnosis and Management of Dry Eye and Ocular Surface

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Clinical Diagnosis and Management of

David Meyer Cyres K Mehta

Foreword: Juan Murube

Clinical Diagnosis and Management of Dry Eye and Ocular Surface

First Edition : 2006

• My wife of 25 years, Clelia, whose understanding and patience have

• My wonderful wife and children who make everything possible.

• My parents for everything.

A Rahimi MD Dan Davis MD

David T Vroman MD H Hoh MD

Rituraj Baurah MS Shaloo Bageja MS

Rishi Mohan MD DNB FRCSE SH Ugurbas MD

Tarjani Y Shah MBBS Y Ralph Chu MD

pathology, medical, psychological and surgical treatments merged in a

Dr Juan Murube MD PhD

14. Dry Eye as Informed Consent Prior to

26. Application of the Amniotic Membrane

Index ........................................................................................ 511

By definition, a film is a thin layer that can stand vertically without

FIGURE 1.2: Tear drainage system (Courtesy Allergan India Limited)

FIGURE 1.3: Tear film layers (Courtesy Allergan India Limited)

The marginal, palpebral and conjunctival portions are regarded as making

1. Superficial Lipid Layer

2. Middle Aqueous Layer

3. Posterior Mucin Layer

• Normal epithelium is necessary for the adsorption of mucin on to its

TEAR FILM FORMATION DYNAMICS

FIGURE 1.4: Impression cytology mapping

BUT (Break up Time) is generally determined after the instillation of a

FIGURE 1.5: Mechanism of tear film break up (Courtesy

NORMAL TEAR DRAINAGE

TABLE 1.2: Composition of human tears and plasma

PHYSICAL PROPERTIES OF TEARS

Other Physical Properties of Tear (Table 1.2)

CHEMICAL COMPOSITION OF TEAR FLUID

TABLE 1.4: Relative quantity of various protein fractions in tears

TABLE 1.5: Origin of various tear protein fractions

TABLE 1.6: Immunoglobulin levels in tear and serum

Immunoglobulin A (IgA): It is the major immunoglobulin present in tears,

Immunoglobulin G (IgG): It is present in very low concentrations in normal

Immunoglobulin E (IgE): It is mostly extravascular in distribution. IgE values

TABLE 1.7: Antiproteinasis concentration in tears and plasma

TABLE 1.8: Antimicrobial factors in tears

These includes α1-antitrypsin, α1-antichymotrypsin, inter-α-trypsin

Catecholamines, Dopamine, Noradrenaline and Dopa

Electrolytes and Hydrogen Ions

individuals. LDH isoenzymes bound to immunoglobulin have been found in

Corneal collagenase is present as an inactive precursor “latent collagenase”

Drugs Excreted in Tears

• Local inflammatory diseases of the conjunctiva commonly conjunctival

Diagnostic Tests for Tear Hyposecretions (Table 1.10)

TABLE 1.10: Diagnostic tests and drug assays in tears

FIGURE 1.6: Modified Schirmer’s test

occurred in five minutes (Jones, 1972). It is a measure of the rate of tear

Vital Dye Staining

Tear Globulin Assay

FIGURE 1.7: Tear globulin assay (diagnostic test)

FIGURE 1.8: Tripartigen immunodiffusion plates

Biopsy of the Conjunctiva

Physiological Diagnostic Test for Hypersecretions

• If no dye is recovered from the nose a partial obstruction is present or

Jones II (Secondary Irrigation) Test

• Negative—if unstained saline is recovered from the nose it means that no