Ophthalmology 7th Edition (Oftalmología 7a Edición)

Ophthalmology
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Ophthalmology
LEAD EDITORS FIFTH EDITION
Myron Yanoff, MD Jay S. Duker, MD
Chair Emeritus, Ophthalmology Director
Professor of Ophthalmology & Pathology New England Eye Center
Departments of Ophthalmology & Pathology Professor and Chairman
College of Medicine Department of Ophthalmology
Drexel University Tufts Medical Center
Philadelphia, PA, USA Tufts University School of Medicine
Boston, MA, USA
SECTION EDITORS
James J. Augsburger, MD Michael H. Goldstein, MD, MBA Alfredo A. Sadun, MD, PhD
Professor and Chairman Co-Director, Cornea and External Diseases Flora Thornton Chair, Doheny
Department of Ophthalmology Service Professor of Ophthalmology
University of Cincinnati College of Medicine New England Eye Center Vice-Chair of Ophthalmology, UCLA
Cincinnati, OH, USA Tufts Medical Center Los Angeles, CA, USA
Boston, MA, USA
Dimitri T. Azar, MD, MBA Joel S. Schuman, MD
Senior Director, Google Verily Life Sciences Narsing A. Rao, MD Professor and Chairman of Ophthalmology
Distinguished University Professor and B.A. Professor of Ophthalmology and Pathology Director, NYU Eye Center
Field Chair of Ophthalmic Research USC Roski Eye Institute Professor of Neuroscience and Physiology
Professor of Ophthalmology, Pharmacology, and Department of Ophthalmology Neuroscience Institute
Bioengineering University of Southern California NYU School of Medicine
University of Illinois at Chicago Los Angeles, CA, USA Professor of Electrical and Computer
Chicago, IL, USA Engineering
Shira L. Robbins, MD NYU Tandon School of Engineering
Sophie J. Bakri, MD Clinical Professor of Ophthalmology
Professor of Neural Science
Professor of Ophthalmology Ratner Children’s Eye Center at the Shiley Eye
Center for Neural Science, NYU
Vitreoretinal Diseases & Surgery Institute
New York, NY, USA
Mayo Clinic University of California San Diego
Rochester, MN, USA La Jolla, CA, USA Janey L. Wiggs, MD, PhD
Paul Austin Chandler Professor of
Scott E. Brodie, MD, PhD Emanuel S. Rosen, MD, FRCS, Ophthalmology
Professor of Ophthalmology FRCOphth Harvard Medical School
NYU School of Medicine Private Practice Boston, MA, USA
New York, NY, USA Case Reports Editor for Journal of Cataract &
Jonathan J. Dutton, MD, PhD Refractive Surgery
Professor Emeritus Manchester, UK
Department of Ophthalmology
University of North Carolina
Chapel Hill, NC, USA
For additional online content visit ExpertConsult.com
Edinburgh London New York Oxford Philadelphia St Louis Sydney 2019

© 2019, Elsevier Inc. All rights reserved.
First edition 1999

Second edition 2004
Third edition 2009
Fourth edition 2014
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This book and the individual contributions contained in it are protected under copyright by the Publisher
(other than as may be noted herein).
Chapter 4.29: “Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction” by
Marianne O. Price, Francis W. Price, Jr.
Marianne O. Price and Francis W. Price, Jr. retain copyright of the video accompanying this chapter.
Chapter 6.5: “Contact B-Scan Ultrasonography” by Yale L. Fisher, Dov B. Sebrow

Yale L. Fisher retains copyright of the video accompanying this chapter. The remainder of this lecture as
well as additional lectures on ophthalmology can be found at www.OphthalmicEdge.org.
Chapter 7.2: “Mechanisms of Uveitis” by Igal Gery, Chi-Chao Chan

This chapter is in the Public Domain.
Chapter 7.23: “Masquerade Syndromes: Neoplasms” by Nirali Bhatt, Chi-Chao Chan, H. Nida Sen
Chapter 11.8: “Torsional Strabismus” by Scott K. McClatchey, Linda R. Dagi

Chapter 12.16: “Aesthetic Fillers and Botulinum Toxin for Wrinkle Reduction” by Jean Carruthers,
Alastair Carruthers
Jean Carruthers retains copyright of Figures 12.16.1 & 12.16.6.
Notices
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and using any information, methods, compounds or experiments described herein. Because of
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User Guide
User Guide
COLOR CODING
Ophthalmology is organized into 12 parts, which are color-coded as follows
for quick and easy reference:
Part 1: Genetics
Part 2: Optics and Refraction
Part 3: Refractive Surgery
Part 4: Cornea and Ocular Surface Diseases
Part 5: The Lens
Part 6: Retina and Vitreous
Part 7: Uveitis and Other Intraocular Inflammations
Part 8: Intraocular Tumors
Part 9: Neuro-Ophthalmology
Part 10: Glaucoma
Part 11: Pediatric and Adult Strabismus
Part 12: Orbit and Oculoplastics
EXPERTCONSULT WEBSITE
n Full searchable text and downloadable image gallery
n Full reference lists for each chapter
n Additional online content including text, figures, & video clips
v
Video Contents Video available at
Video Contents
ExpertConsult.com
Part 3: Refractive Surgery Chapter 6.25 Coats’ Disease and Retinal Telangiectasia
Chapter 3.4 LASIK 6.25.1 Pars Plana Vitrectomy and Subretinal Fluid and Exudate Drainage Performed
for a Severe Exudative Retinal Detachment
3.4.1 iLASIK
Chapter 6.32 Macular Hole
Chapter 3.5 Small Incision Lenticule Extraction (SMILE)
6.32.1 Macular Hole Surgery
3.5.1 SMILE Instructional Video
Chapter 6.33 Epiretinal Membrane
Chapter 3.7 Phakic Intraocular Lenses
6.33.1 Epiretinal Membrane Removal
3.7.1 Cachet Lens
3.7.2 Artisan/Verisyse Lens Implantation for Hyperopia After Radial Keratotomy Chapter 6.34 Vitreomacular Traction
3.7.3 Toric Artiflex Phakic Intraocular Lens in a Patient With High Myopia and
6.34.1 Vitreomacular Traction Syndrome
Astigmatism After Deep Anterior Lamellar Keratoplasty
3.7.4 Toric Artiflex Lens Implantation in a Patient With a Previous Intracorneal Chapter 6.39 Rhegmatogenous Retinal Detachment
Ring for Keratoconus 6.39.1 Internal Limiting Membrane (ILM) Peeling for Primary Rhegmatogenous
3.7.5 ICL Implantation Repair to Reduce Postoperative Macular Pucker
3.7.6 ICL Exchange
Chapter 6.41 Choroidal Hemorrhage
Part 4: Cornea and Ocular Surface Diseases 6.41.1 Transconjunctival Trocar/Cannula Drainage of Suprachoroidal Fluid
Chapter 4.17 Noninfectious Keratitis
Chapter 6.43 Posterior Segment Ocular Trauma
4.17.1 Patient With Lax Eyelids Recommended for Sleep Study
6.43.1 Intraocular Foreign Body Removal
Chapter 4.29 Endothelial Keratoplasty: Targeted Treatment for Corneal 6.43.2 Intraocular Foreign Body Removal With Rare Earth Magnet
Endothelial Dysfunction
Part 9: Neuro-Ophthalmology
4.29.1 DSEK Pull-Through
4.29.2 DMEK Donor Preparation Chapter 9.19 Nystagmus, Saccadic Intrusions, and Oscillations
4.29.3 Descemet’s Membrane Endothelial Keratoplasty (DMEK) 9.19.1 Congenital Nystagmus
9.19.2 Oculocutaneous Albinism With Associated Nystagmus
Part 5: The Lens 9.19.3 Latent Nystagmus
Chapter 5.8 Anesthesia for Cataract Surgery 9.19.4 Spasmus Nutans
5.8.1 Standard Technique for Sub-Tenon’s Anesthesia 9.19.5 Right Internuclear Ophthalmoplegia
5.8.2 “Incisionless” Technique for Sub-Tenon’s Anesthesia 9.19.6 Convergence Retraction Nystagmus in Parinaud’s Syndrome
Chapter 5.9 Phacoemulsification Part 10: Glaucoma

5.9.1 Two Examples of “Sculpting” Using Low Flow and Vacuum but Higher Chapter 10.7 Optic Nerve Analysis
Power/Amplitude 10.7.1 Three-Dimensional Imaging of the Optic Nerve Head
5.9.2 Two Examples of Using Higher Flow and Vacuum for Nucleus Fragment
Removal Chapter 10.28 Minimally Invasive and Microincisional Glaucoma Surgeries
Chapter 5.11 Small Incision and Femtosecond Laser-Assisted 10.28.1 iStent G1 Implantation
Cataract Surgery 10.28.2 Key Steps in Trabectome Surgery
5.11.1 Unexpected Subluxation Chapter 10.29 Trabeculectomy
5.11.2 Microincision Phaco 10.29.1 Bleb Leak Detection Using Concentrated Fluorescein Dye
5.11.3 Microincision Refractive Lens Exchange 10.29.2 Trabeculectomy With Mitomycin C
5.11.4 700µ Phaco 10.29.3 5-Fluorouracil Subconjunctival Injection
Chapter 5.13 Combined Procedures Chapter 10.32 Complications of Glaucoma Surgery and Their Management
5.13.1 Combined Phacoemulsification Cataract Surgery and Descemet’s Stripping 10.32.1 Small Pupil Cataract Surgery With Use of Pupil Expansion Ring (I-Ring;
Automated Endothelial Keratoplasty (DSAEK) Beaver Visitec, Waltham, MA) and Trypan Blue Capsular Staining
5.13.2 Combined Phacovitrectomy 10.32.2 Repair of Bleb Leak
Chapter 5.16 Complications of Cataract Surgery
Part 11: Pediatric and Adult Strabismus
5.16.1 Artisan Implantation
Chapter 11.3 Examination of Ocular Alignment and Eye Movements
Part 6: Retina and Vitreous 11.3.1 Strabismus Exam Elements
Chapter 6.3 Retinal and Choroidal Circulation 11.3.2 Cover/Uncover Test
11.3.3 Exotropia
6.3.1 Fluorescein and Indocyanine Green (ICG) Video Angiogram 11.3.4 Esotropia
Chapter 6.5 Contact B-Scan Ultrasonography 11.3.5 Hypertropia
11.3.6 Prism Alternate Cover Test
6.5.1 Examination Techniques for Contact B-Scan Ultrasonography
11.3.7 Simultaneous Prism Cover Test
Chapter 6.11 Scleral Buckling Surgery 11.3.8 Exophoria
11.3.9 Alternate or Cross Cover Test
6.11.1 Scleral Buckle
6.11.2 Suture Total running time approximately 2 hours and 34 minutes
6.11.3 Drain
Chapter 6.12 Vitrectomy
6.12.1 Vitrectomy for Nonclearing Vitreous Hemorrhage
vi
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Preface
Preface
It’s been 20 years since the first edition of Ophthalmology was published. Ophthalmology was never intended to be encyclopedic, but with each
We are delighted that our textbook now has gone to a fifth edition. The lon- edition we strived to make it quite comprehensive, readable, and easy to
gevity of this title reflects the uniqueness and utility of its format; the hard access. Like the fourth edition, this edition is thoroughly revised, with new
work of our authors, editors, and publishers; and the pressing need in our section editors and many new authors. Chapters have been rewritten and
field for updated, clinically relevant information. We continue to recognize restricted to reflect the new way diseases are diagnosed, categorized, and
the advantage of a complete textbook of ophthalmology in a single volume treated. We have discarded out-of-date material and have added numerous
rather than multiple volumes. The basic visual science is admixed with new items. Extra references and other material have been moved online to
clinical information throughout, and we have maintained an entire sepa- keep the book itself as one volume.
rate section dedicated to genetics and the eye.
xii
Preface to First Edition
Preface to First Edition

Over the past 30 years, enormous technologic advances have occurred in To achieve the same continuity of presentation in the figures as well
many different areas of medicine—lasers, molecular genetics, and immu- as in the text, all of the artworks have been redesigned from the authors’
nology to name a few. This progress has fueled similar advances in almost originals, maximizing their accessibility for the reader. Each section is
every aspect of ophthalmic practice. The assimilation and integration of color coded for easy cross-referencing and navigation through the book.
so much new information makes narrower and more focused ophthalmic Despite the extensive use of color in artworks and photographs through-
practices a necessity. As a direct consequence, many subspecialty textbooks out, the cost of this comprehensive book has been kept to a fraction of the
with extremely narrow focus are now available, covering every aspect of multivolume sets. We hope to make this volume more accessible to more
ophthalmic practice. Concurrently, several excellent multivolume textbooks practitioners throughout the world.
detailing all aspects of ophthalmic practice have been developed. Yet there Although comprehensive, Ophthalmology is not intended to be encyclo-
remains a need for a complete single-volume textbook of ophthalmology pedic. In particular, in dealing with surgery, we do not stress specific tech-
for trainees, nonophthalmologists, and those general ophthalmologists niques or describe rarer ones in meticulous detail. The rapidly changing
(and perhaps specialists) who need an update in specific areas in which nature of surgical aspects of ophthalmic practice is such that the reader
they do not have expertise. Ophthalmology was created to fill this void will need to refer to one or more of the plethora of excellent books that
between the multivolume and narrow subspecialty book. cover specific current techniques in depth. We concentrate instead on
This book is an entirely new, comprehensive, clinically relevant, sin- the areas that are less volatile but, nevertheless, vital surgical indications,
gle-volume textbook of ophthalmology, with a new approach to content and general principles of surgical technique, and complications. The approach
presentation that allows the reader to access key information quickly. Our to referencing is parallel to this: For every topic, all the key references are
approach, from the outset, has been to use templates to maintain a uniform listed, but with the aim of avoiding pages of redundant references where a
chapter structure throughout the book so that the material is presented in smaller number of recent classic reviews will suffice. The overall emphasis
a logical, consistent manner, without repetition. The majority of chapters of Ophthalmology is current information that is relevant to clinical practice
in the book follow one of three templates: the disease-oriented template, superimposed on the broad framework that comprises ophthalmology as
the surgical procedure template, or the diagnostic testing template. Metic- a subspecialty.
ulous planning went into the content, sectioning, and chapter organization Essential to the realization of this ambitious project is the ream of
of the book, with the aim of presenting ophthalmology as it is practiced, Section Editors, each bringing unique insight and expertise to the book.
rather than as a collection of artificially divided aspects. Thus, pediatric They have coordinated their efforts in shaping the contents list, finding
ophthalmology is not in a separate section but is integrated into relevant contributors, and editing chapters to produce a book that we hope will
sections across the book. The basic visual science and clinical information, make a great contribution to ophthalmology.
including systemic manifestations, is integrated throughout, with only two We are grateful to the editors and authors who have contributed to
exceptions. We dedicated an entire section to genetics and the eye, in rec- Ophthalmology and to the superb, dedicated team at Mosby.
ognition of the increasing importance of genetics in ophthalmology. Optics Myron Yanoff
and refraction are included in a single section as well because an under- Jay S. Duker
standing of these subjects is fundamental to all of ophthalmology. July 1998
xiii
List of Contributors
The editor(s) would like to acknowledge and offer grateful thanks for the input of all previous editions’ contributors, without whom this new edition
would not have been possible.
Erika C. Acera, OC(C) Ferhina S. Ali, MD, MPH Steve A. Arshinoff, MD, FRCSC Nicole Balducci, MD
Clinical Orthoptist Vitreoretinal Surgery Fellow Associate Professor Consultant
Department of Ophthalmology Wills Eye Hospital University of Toronto Ophthalmology Division
Anne F. and Abraham Ratner Retina Service Department of Ophthalmology and Studio Oculistico d’Azeglio
Children’s Eye Center Mid Atlantic Retina Visual Sciences Bologna, Italy
Shiley Eye Institute Philadelphia, PA, USA Toronto, ON, Canada
University of California San Diego Piero Barboni, MD
La Jolla, CA, USA Jorge L. Alió, MD, PhD Penny A. Asbell, MD, FACS, FARVO Consultant
Professor of Ophthalmology Professor of Ophthalmology Neuro-Ophthalmology
Natalie A. Afshari, MD Miguel Hernandez University, Vissum Icahn School of Medicine at Mount Scientific Institute San Raffaele
Stuart I. Brown MD Chair in Alicante, Spain Sinai Milan, Italy
Ophthalmology in Memory of New York, NY, USA Studio Oculistico d’Azeglio
Donald P. Shiley Norma Allemann, MD Bologna, Italy
Professor of Ophthalmology Adjunct Professor Kerry K. Assil, MD
Chief of Cornea and Refractive Surgery Department of Ophthalmology and Corneal, Cataract and Refractive Cullen J. Barnett, COT, CRA, OCT-C,
Vice Chair of Education Visual Sciences Surgeon CDOS
Shiley Eye Institute University of Illinois at Chicago Medical Director Clinical Supervisor of Ophthalmology
University of California San Diego Chicago, IL, USA The Assil Eye Institute Roski Eye Institute
La Jolla, CA, USA Adjunct Professor Beverly Hills, CA, USA Keck Medicine USC
Department of Ophthalmology and Los Angeles, CA, USA
Anita Agarwal, MD Visual Sciences Neal H. Atebara, MD, FACS
Adjoint Professor of Ophthalmology Escola Paulista de Medicina (EPM) Associate Professor Soumyava Basu, MS
Vanderbilt Eye Institute Universidade Federal de São Paulo Department of Surgery Head of Uveitis Services
West Coast Retina (UNIFESP) University of Hawaii LVPEI Network
Vanderbilt University Medical Center São Paulo, SP, Brazil John A. Burns School of Medicine L V Prasad Eye Institute
San Francisco, CA, USA Honolulu, HI, USA Bhubaneswar, Odisha, India
David Allen, BSc, MB, BS, FRCS,
Joshua S. Agranat, MD FRCOphth James J. Augsburger, MD Priti Batta, MD
Resident Physician Consultant Ophthalmologist (Cataract) Professor of Ophthalmology Assistant Professor of Ophthalmology
Department of Ophthalmology Cataract Treatment Centre Dr. E. Vernon & Eloise C. Smith Chair Director of Medical Student Education
Massachusetts Eye and Ear Sunderland Eye Infirmary of Ophthalmology New York Eye and Ear Infirmary of
Harvard Medical School Sunderland, Tyne & Wear, UK College of Medicine, University of Mount Sinai
Boston, MA, USA Cincinnati New York, NY, USA
Keith G. Allman, MBChB, MD, FRCA Founding Director, Ocular Oncology &
Radwan S. Ajlan, MBBCh, FRCS(C), Consultant Anaesthetist Diagnostic Ultrasonography Service, Caroline R. Baumal, MD, FRCSC
FICO, DABO West of England Eye Unit University of Cincinnati Medical Associate Professor of Ophthalmology
Assistant Professor Royal Devon and Exeter NHS Trust Center Director ROP Service
Retina and Vitreous Exeter, Devon, UK Attending Surgeon, University of Vitreoretinal Surgery
Department of Ophthalmology Cincinnati Medical Center New England Eye Center
University of Kansas School of Nishat P. Alvi, MD Consulting Surgeon, Cincinnati Tufts University
Medicine Medical Director of Ophthalmology Children’s Hospital Medical Center School of Medicine
Kansas City, KS, USA The Vision Institute of Illinois Cincinnati, OH, USA Boston, MA, USA
Elgin, IL, USA
Anam Akhlaq, MBBS G. William Aylward, FRCS, FRCOphth, Srilaxmi Bearelly, MD, MHS
Postdoctoral Fellow Leonard P.K. Ang, MBBS, MD, FRCS, MD Assistant Professor of Ophthalmology
Center for Translational Ocular MRCOphth, MMed, FAMS Consultant Ophthalmologist Ophthalmology
Immunology Associate Professor of Ophthalmology London, UK Columbia University Medical Center
Department of Ophthalmology Medical Director, Lang Eye Centre New York, NY, USA
Tufts Medical Center Singapore Dimitri T. Azar, MD, MBA
Senior Director, Google Verily Life Jesse L. Berry, MD
Boston, MA, USA David J. Apple, MD †
Associate Director, Ocular Oncology
Sciences
Thomas A. Albini, MD Formerly Professor of Ophthalmology Distinguished University Professor Service
Associate Professor of Ophthalmology and Pathology and B.A. Field Chair of Ophthalmic Associate Residency Program Director
Department of Ophthalmology Director, Laboratories for Ophthalmic Research for Ophthalmology
Bascom Palmer Eye Institute Devices Research Professor of Ophthalmology, USC Roski Eye Institute
University of Miami John A. Moran Eye Center Pharmacology, and Bioengineering Keck School of Medicine, University of
Miami, FL, USA University of Utah University of Illinois at Chicago Illinois Southern California
Salt Lake City, UT, USA College of Medicine Attending Surgeon, Children’s Hospital
Ahmed Al-Ghoul, MD, MBA, FRCSC, Chicago, IL, USA of Los Angeles
DipABO Maria Cecilia D. Aquino, MD, MMED, Los Angeles, CA, USA
Clinical Lecturer (Ophthalmology) Sophie J. Bakri, MD
Division of Ophthalmology Resident Physician II Professor of Ophthalmology Angela P. Bessette, MD
Department of Surgery Ophthalmology/Glaucoma Vitreoretinal Diseases & Surgery Assistant Professor
University of Calgary National University Hospital Mayo Clinic Department of Ophthalmology
Calgary, AB, Canada National University Health System Rochester, MN, USA Flaum Eye Institute
Singapore University of Rochester
Laura J. Balcer, MD, MSCE Rochester, NY, USA
Anthony C. Arnold, MD Professor of Neurology
Professor and Chief Vice-Chair, Neurology
Neuro-Ophthalmology Division New York University
xiv UCLA Stein Eye Institute
Los Angeles, CA, USA
School of Medicine
†
Deceased New York, NY, USA
Nirali Bhatt, MD Igor I. Bussel, MS, MHA Chi-Chao Chan, MD Abbot (Abe) Clark, PhD, FARVO
Assistant Professor Doris Duke Clinical Research Fellow Scientist Emeritus Regents Professor of Pharmacology
Department of Ophthalmology Department of Ophthalmology Laboratory of Immunology and Neuroscience
University of Pennsylvania University of Pittsburgh School of National Eye Institute Executive Director, North Texas Eye
Perelman School of Medicine Medicine National Institutes of Health Research Institute
Philadelphia, PA, USA Pittsburgh, PA, USA Bethesda, MD, USA University of North Texas Health
Visiting Professor Science Center
Orry C. Birdsong, MD Louis B. Cantor, MD Zhongshan Ophthalmic Center Fort Worth, TX, USA
Clinical Fellow Jay C. and Lucile L. Kahn Professor Sun Yat-Sen University
Ophthalmology and Chair China Jonathan C.K. Clarke, MD, FRCOphth
Hoopes Vision Department of Ophthalmology Consultant Ophthalmologist
Draper, UT, USA Indiana University Melinda Y. Chang, MD NIHR Moorfields Biomedical Research
School of Medicine Assistant Professor of Ophthalmology Centre
Jyotirmay Biswas, MS, FMRF, FNAMS, Indianapolis, IN, USA USC Roski Eye Institute and Children’s Moorfields Eye Hospital
FIC, Path, FAICO Hospital Los Angeles UCL Institute of Ophthalmology
Director Hilda Capó, MD Keck School of Medicine of the London, UK
Uveitis and Ocular Pathology Professor of Clinical Ophthalmology University of Southern California
Department Bascom Palmer Eye Institute Los Angeles, CA, USA François Codère, MD
Sankara Nethralaya Division Chief Pediatric Associate Professor
Chennai, Tamil Nadu, India Ophthalmology and Adult Stanley Chang, MD Ophthalmology/Oculoplastic and
Strabismus KK Tse and KT Ying Professor of Orbital Surgery Section
Bahram Bodaghi, MD, PhD, FEBOphth Miller School of Medicine Ophthalmology Université de Montréal
Professor of Ophthalmology John T. Flynn Professor of Department of Ophthalmology Montréal, QC, Canada
DHU ViewRestore Ophthalmology Chair Columbia University
APHP, UPMC, Sorbonne University University of Miami New York, NY, USA Ian P. Conner, MD, PhD
Paris, France Miami, FL, USA Assistant Professor
Victoria S. Chang, MD Ophthalmology
Swaraj Bose, MD Antonio Capone, Jr., MD Assistant Professor of Clinical UPMC Eye Center
Associate Professor of Ophthalmology Professor Ophthalmology Pittsburgh, PA, USA
UCI and Attending Physician Department of Ophthalmology Ophthalmology, Cornea and External
Cedars Sinai Medical Center Oakland University Disease Peter Coombs, MD
Los Angeles, CA, USA William Beaumont Hospital Bascom Palmer Eye Institute Vitreoretinal Physician and Surgeon
School of Medicine University of Miami Utah Eye Centers
Charles S. Bouchard, MD, MA Salt Lake City, UT, USA
Professor and Chairman of Auburn HIlls, MI, USA Naples, FL, USA
Ophthalmology Alastair Carruthers, MA, BM, BCh, David G. Charteris, MD, FRCS(Ed), Zélia M. Corrêa, MD, PhD
Loyola University Health System FRCP(Lon), FRCPC FRCOphth Tom Clancy Endowed Professor of
Maywood, IL, USA Clinical Professor Professor Ophthalmology
Department of Dermatology and Skin Vitreoretinal Unit Head of Ocular Oncology and
Michael E. Boulton, PhD Echography
Susan and Dowd Ritter/RPB Endowed Science Moorfields Eye Hospital
University of British Columbia London, UK Retina Service, Wilmer Eye Institute
Chair of Ophthalmology Johns Hopkins University School of
University of Alabama Birmingham Vancouver, BC, Canada
Soon-Phaik Chee, MD Medicine
Birmingham, AL, USA Jean Carruthers, MD, FRCSC, Professor Baltimore, MD, USA
James D. Brandt, MD FRC(OPHTH) Cataract Service, Ocular Inflammation
Clinical Professor & Immunology Service Steven M. Couch, MD, FACS
Professor Assistant Professor
Department of Ophthalmology & Department of Ophthalmology Singapore National Eye Centre
University of British Columbia Singapore Department of Ophthalmology &
Vision Science Visual Sciences
Vice-Chair for International Programs Fellow
American Society for Ophthalmic John J. Chen, MD, PhD Washington University in St Louis
and New Techology Assistant Professor St Louis, MO, USA
Director - Glaucoma Service Plastic and Reconstructive Surgery
Vancouver, BC, Canada Department of Ophthalmology and
University of California Davis Neurology Stuart G. Coupland, PhD
Sacramento, CA, USA Keith D. Carter, MD, FACS Mayo Clinic Associate Professor
Lillian C. O’Brien and Dr. C.S. O’Brien Rochester, MN, USA Department of Ophthalmology
Scott E. Brodie, MD, PhD University of Ottawa
Professor of Ophthalmology Chair in Ophthalmology
Professor and Chair Xuejing Chen, MD, MS Ottawa, ON, Canada
NYU School of Medicine Clinical Fellow
New York, NY, USA Department of Ophthalmology & Claude L. Cowan, Jr., MD, MPH
Visual Sciences Retina
Ophthalmic Consultants of Boston Clinical Professor of Ophthalmology
Michael C. Brodsky, MD Carver College of Medicine Georgetown University Medical Center
Professor of Ophthalmology and University of Iowa New England Eye Center at Tufts
Medical Center Washington, DC, USA
Neurology Iowa City, IA, USA Staff Physician
Knights Templar Research Professor of Boston, MA, USA
Rafael C. Caruso, MD Surgical Service
Ophthalmology Paul T.K. Chew, MMed, FRCOphth Veterans Affairs Medical Center
Mayo Clinic Staff Clinician
National Eye Institute Director Glaucoma Division Washington, DC, USA
Rochester, MN, USA Ophthalmology/Glaucoma
National Institutes of Health E. Randy Craven, MD
Cassandra C. Brooks, MD Bethesda, MD, USA National University Hospital Singapore
Singapore Associate Professor, Glaucoma
Resident in Ophthalmology Johns Hopkins University
Duke Eye Center Harinderpal S. Chahal, MD
Oculofacial Plastic and Reconstructive Bing Chiu, MD Baltimore, MD, USA
Duke University School of Medicine Ophthalmology Resident
Durham, NC, USA Surgery Catherine A. Cukras, MD, PhD
Eye Medical Center New York University
New York, NY, USA Director, Medical Retina Fellowship
Matthew V. Brumm, MD Fresno, CA, USA Program
Ophthalmologist Clement C. Chow, MD National Eye Institute
Cataract and Refractive Surgery Wallace Chamon, MD
Adjunct Professor Partner Physician National Institutes of Health
Brumm Eye Center Retinal Diagnostic Center Bethesda, MD, USA
Omaha, NE, USA Department of Ophthalmology and
Visual Sciences Campbell, CA, USA
Linda R. Dagi, MD
Donald L. Budenz, MD, MPH University of Illinois at Chicago Mortimer M. Civan, MD Director of Adult Strabismus
Kittner Family Distinguished Professor Chicago, IL, USA Professor of Physiology and Professor Boston Children’s Hospital
and Chairman Adjunct Professor of Medicine Associate Professor of Ophthalmology
Department of Ophthalmology Department of Ophthalmology and Department of Physiology Director of Quality Assurance
University of North Carolina at Chapel Visual Sciences University of Pennsylvania Department of Ophthalmology
Hill Escola Paulista de Medicina (EPM) Perelman School of Medicine Children’s Hospital Ophthalmology
Chapel Hill, NC, USA Universidade Federal de São Paulo Philadelphia, PA, USA Foundation Chair
(UNIFESP) Harvard Medical School
São Paulo, SP, Brazil Boston, MA, USA
xv
Elie Dahan, MD, MMed, (Ophth)† Gary R. Diamond, MD† Bryan Edgington, MD Ayad A. Farjo, MD
Formerly Senior Consultant Pediatric Formerly Professor of Ophthalmology Associate Professor, Cornea Division President & Director
Ophthalmology and Glaucoma and Pediatrics Casey Eye Institute Brighton Vision Center
Department of Ophthalmology Drexel University School of Medicine Oregon Health Sciences University Brighton, MI, USA
Ein Tal Eye Hospital Philadelphia, PA, USA Staff Ophthalmologist
Tel Aviv, Israel Veterans Health Administration Eric Feinstein, MD
Daniel Diniz, MD Portland Health Care System Surgical Retina Fellow
Iben Bach Damgaard, MD Surgical Optics Fellow Portland, OR, USA Department of Ophthalmology
PhD Fellow Department of Ophthalmology & Rocky Mountain Lions Eye Institute
Department of Ophthalmology Visual Sciences Howard M. Eggers, MD University of Colorado
Aarhus University Hospital Federal University of São Paulo Professor of Clinical Ophthalmology School of Medicine
Aarhus, Denmark (UNIFESP) Harkness Eye Institute Denver, CO, USA
São Paulo, SP, Brazil New York, NY, USA
Karim F. Damji, MD, FRCSC, MBA Karen B. Fernandez, MD
Professor Diana V. Do, MD Dean Eliott, MD Consultant
Department of Ophthalmology & Professor of Ophthalmology Stelios Evangelos Gragoudas Associate Department of Ophthalmology
Visual Sciences Byers Eye Institute Professor of Ophthalmology The Medical City
University of Alberta Stanford University Harvard Medical School Pasig City, Metro Manila, Philippines
Edmonton, AL, Canada School of Medicine Associate Director, Retina Service
Palo Alto, CA, USA Massachusetts Eye & Ear Yale L. Fisher, MD
Dipankar Das, MD Boston, MA, USA Voluntary Clinical Professor
Senior Consultant & Ocular Pathologist Peter J. Dolman, MD, FRCSC Department of Ophthalmology
Uveitis, Ocular Pathology and Neuro- Clinical Professor George S. Ellis, Jr., MD, FAAP, FAAO, Bascom Palmer Eye Institute
ophthalmology Services Division Head of Oculoplastics and FACS Miami, FL, USA
Sri Sankaradeva Nethralaya Orbital Surgery Director Ophthalmology Voluntary Clinical Professor
Guwahati, Assam, India Fellowship Director Children’s Hospital New Orleans Department of Ophthalmology
Department of Ophthalmology & Associate Clinical Professor of Weill Cornell Medical Center
Adam DeBusk, DO, MS Visual Sciences Ophthalmology and Pediatrics New York, NY, USA
Instructor Division of Oculoplastics and Orbit Tulane University
Department of Ophthalmology University of British Columbia Associate Clinical Professor of Gerald A. Fishman, MD
Wills Eye Hospital Vancouver General Hospital Ophthalmology and Pediatrics Director
Sidney Kimmel Medical College Vancouver, BC, Canada Louisiana State Universities Schools of The Pangere Center for Inherited
Thomas Jefferson University Medicine Retinal Diseases
Philadelphia, PA, USA Sean P. Donahue, MD, PhD New Orleans, LA, USA The Chicago Lighthouse
Professor Professor Emeritus of Ophthalmology
Jose de la Cruz, MD, MSc Department of Ophthalmology & Michael Engelbert, MD, PhD Department of Ophthalmology &
Assistant Professor Visual Sciences Research Assistant Professor Visual Sciences
Ophthalmology, Cornea Refractive Vanderbilt University Department of Ophthalmology University of Illinois at Chicago
Surgery Service Nashville, TN, USA NYU/VRMNY College of Medicine
University of Illinois Eye and Ear New York, NY, USA Chicago, IL, USA
Infirmary Richard K. Dortzbach, MD
Chicago, IL, USA Professor Emeritus Miriam Englander, MD Jorge A. Fortun, MD
Department of Ophthalmology and Attending Surgeon Associate Professor of Ophthalmology
Joseph L. Demer, MD, PhD Visual Sciences Vitreo-Retinal Surgery Vitreoretinal Diseases and Surgery
Arthur L. Rosenbaum Chair in University of Wisconsin Ophthalmic Consultants of Boston Medical Director of Bascom Palmer
Pediatric Ophthalmology School of Medicine and Public Health Boston, MA, USA Eye Institute
Professor of Neurology Madison, WI, USA Palm Beach Gardens Bascom Palmer
Chief, Pediatric Ophthalmology and Bita Esmaeli, MD, FACS Eye Institute
Strabismus Division Kimberly A. Drenser, MD, PhD Professor of Ophthalmology University of Miami Miller School of
Director, Ocular Motility Laboratories Associated Retinal Consultants, PC Director, Ophthalmic Plastic & Medicine
Chair, EyeSTAR Residency/PhD and Department of Ophthalmology Reconstructive Surgery Fellowship Miami, FL, USA
Post-doctoral Fellowship Program in Oakland University Program, Department of Plastic
Ophthalmology and Visual Science William Beaumont Hospital School of Surgery Veronica Vargas Fragoso, MD
Member, Neuroscience Medicine Chair, Graduate Medical Education Refractive Surgery Fellow
Interdepartmental Program Royal Oak, MI, USA Committee Vissum Corporation
Member, Bioengineering University of Texas MD Anderson Alicante, Spain
Interdepartmental Program Jacob S. Duker, MD Cancer Center
University of California Los Angeles Resident Physician Houston, TX, USA Nicola Freeman, MBChB, FCOphth,
Los Angeles, CA, USA Department of Ophthalmology MMed
Bascom Palmer Eye Institute Joshua W. Evans, MD Senior Specialist
Shilpa J. Desai, MD University of Miami Assistant Professor of Ophthalmology Department of Pediatric
Assistant Professor Miami, FL, USA Division of Glaucoma Ophthalmology
Department of Ophthalmology University of Kentucky Red Cross Children’s Hospital
Tufts University Jay S. Duker, MD Lexington, KY, USA Cape Town, Western Province, South
School of Medicine Director Africa
Boston, MA, USA New England Eye Center Monica Evans, MD
Professor and Chairman Ophthalmology David S. Friedman, MD, MPH, PhD
Deepinder K. Dhaliwal, MD, L.Ac Department of Ophthalmology San Jose, Costa Rica Director, Dana Center for Preventive
Professor of Ophthalmology, University Tufts Medical Center Ophthalmology
of Pittsburgh School of Medicine Tufts University School of Medicine Daoud S. Fahd, MD Professor of Ophthalmology, Wilmer/
Director, Cornea and Refractive Boston, MA, USA Clinical Assistant Professor Glaucoma
Surgery Services Department of Ophthalmology Johns Hopkins University
Director and Founder, Center for Vikram D. Durairaj, MD, FACS Ophthalmic Consultants of Beirut Baltimore, MD, USA
Integrative Eye Care ASOPRS Fellowship Director and Jal el Dib, Metn, Lebanon
Co-Director, Cornea and Refractive Managing Partner Deborah I. Friedman, MD, MPH
Oculoplastic and Orbital Surgery Lisa J. Faia, MD Professor
Surgery Fellowship Partner, Associated Retinal Consultants
Associate Medical Director, Charles TOC Eye and Face Department of Neurology
Austin, TX, USA Associate Professor & Neurotherapeutics and
T. Campbell Ocular Microbiology Oakland University
Laboratory Ophthalmology
Jonathan J. Dutton, MD, PhD William Beaumont School of Medicine University of Texas
Medical Director, UPMC Laser Vision Professor Emeritus Ophthalmology - Retina
Center Southwestern Medical Center
Department of Ophthalmology Royal Oak, MI, USA Dallas, TX, USA
University of Pittsburgh Medical University of North Carolina
Center Chapel Hill, NC, USA Katherine A. Fallano, MD Neil J. Friedman, MD
Pittsburgh, PA, USA Department of Ophthalmology Adjunct Clinical Associate Professor
University of Pittsburgh School of Department of Ophthalmology
Medicine Stanford University School of Medicine
Pittsburgh, PA, USA
xvi †
Stanford, CA, USA
Deceased
Nicoletta Fynn-Thompson, MD Jeffrey L. Goldberg, MD, PhD Jason R. Guercio, MD, MBA Joshua H. Hou, MD
Partner Professor and Chairman Senior Resident in Anesthesiology Assistant Professor
Cornea, Cataract and Refractive Surgery Department of Ophthalmology Department of Anesthesiology Department of Ophthalmology &
Ophthalmic Consultants of Boston Byers Eye Institute at Stanford Duke University Medical Center Visual Neurosciences
Boston, MA, USA University Durham, NC, USA University of Minnesota
Palo Alto, CA, USA Minneapolis, MN, USA
Neha Gadaria-Rathod, MD Julie Gueudry, MD
Assistant Clinical Instructor Debra A. Goldstein, MD, FRCSC Senior Consultant Odette M. Houghton, MD
Department of Ophthalmology Magerstadt Professor of Ophthalmology Senior Associate Consultant
SUNY Downstate Medical Center Ophthalmology Charles Nicolle University Hospital Ophthalmology
New York, NY, USA Director Uveitis Service Rouen, France Mayo Clinic
Northwestern University Scottsdale, AZ, USA
Debora E. Garcia-Zalisnak, MD Feinberg School of Medicine Ahmet Kaan Gündüz, MD
Cornea Fellow Chicago, IL, USA Professor of Ophthalmology Kourtney Houser, MD
Department of Ophthalmology Ankara University Assistant Professor
University of Illinois at Chicago Michael H. Goldstein, MD, MBA Faculty of Medicine Ophthalmology
Chicago, IL, USA Co-Director, Cornea and External Ankara, Turkey University of Tennessee
Diseases Service Health Science Center
Gregg S. Gayre, MD New England Eye Center Joelle A. Hallak, PhD Memphis, TN, USA
Chief of Eye Care Services Tufts Medical Center Assistant Professor, Executive Director
Department of Ophthalmology Boston, MA, USA Ophthalmic Clinical Trials & Frank W. Howes, MBChB, MMed, FCS,
Kaiser Permanente Translational Center FRCS, FRCOphth, FRANZCO
San Rafael, CA, USA John A. Gonzales, MD Department of Ophthalmology & Associate Professor
Assistant Professor Visual Sciences Bond University
Steven J. Gedde, MD Francis I. Proctor Foundation and University of Illinois at Chicago Company and Clinical Director
Professor of Ophthalmology, John Department of Ophthalmology Chicago, IL, USA Cataract Refractive & Glaucoma
G. Clarkson Chair, Vice Chair of University of California San Francisco Surgery
Education San Francisco, CA, USA Julia A. Haller, MD Eye & Laser Centre
Bascom Palmer Eye Institute Ophthalmologist-in-Chief, Wills Eye Gold Coast, QLD, Australia
University of Miami Miller David B. Granet, MD, FACS, FAAp Hospital
School of Medicine Anne F. Ratner Chair of Pediatric William Tasman, MD Endowed Chair Jason Hsu, MD
Miami, FL, USA Ophthalmology Professor and Chair of Ophthalmology Co-Director of Retina Research
Professor of Ophthalmology & Sidney Kimmel Medical College at Retina Service of Wills Eye Hospital
Igal Gery, PhD Pediatrics Thomas Jefferson University Associate Professor of Ophthalmology
Scientist Emerita Director of the Ratner Children’s Eye Philadelphia, PA, USA Thomas Jefferson University
Laboratory of Immunology Center at the Shiley Eye Institute Mid Atlantic Retina
National Eye Institute University of California San Diego Pedram Hamrah, MD, FACS Philadelphia, PA, USA
National Institutes of Health La Jolla, CA, USA Director of Clinical Research
Bethesda, MD, USA Director, Center for Translational Jeffrey J. Hurwitz, MD, FRCS(C)
Matthew J. Gray, MD Ocular Immunology Professsor, Ophthalmology
Ramon C. Ghanem, MD, PhD Assistant Professor Cornea and Associate Professor, Ophthalmology University of Toronto
Director External Disease Tufts Medical Center Oculoplastic Specialist
Cornea and Refractive Surgery Department of Ophthalmology Tufts University Mount Sinai Hospital
Department University of Florida School of Medicine Toronto, ON, Canada
Sadalla Amin Ghanem Eye Hospital Gainesville, FL, USA Boston, MA, USA
Joinville, SC, Brazil Francisco Irochima, PhD
Kyle M. Green, BA David R. Hardten, MD Professor, Biotechnology
Vinícius C. Ghanem, MD, PhD Medical Student Researcher Director of Refractive Surgery Universidade Potiguar
Ophthalmologist, Medical Director Ophthalmology Department of Ophthalmology Natal, Rio Grande do Norte, Brazil
Department of Ophthalmology University of Southern California Minnesota Eye Consultants
Sadalla Amin Ghanem Eye Hospital Roski Eye Institute Minnetonka, MN, USA Jihad Isteitiya, MD
Joinville, SC, Brazil Los Angeles, CA, USA Cornea Fellow, Ophthalmology
Alon Harris, MS, PhD, FARVO Icahn School of Medicine at Mount
Saurabh Ghosh, MBBS, DipOphth, Craig M. Greven, MD Professor of Ophthalmology Sinai
MRCOphth, FRCOphth Richard G. Weaver Professor and Letzter Endowed Chair in New York, NY, USA
Consultant Ophthalmologist Chairman Ophthalmology
Cornea, Cataract, External Eye Disease Department of Ophthalmology Director of Clinical Research Andrea M. Izak, MD
Sunderland Eye Infirmary Wake Forest University Eugene and Marilyn Glick Eye Institute Post-Doctoral Fellow
Sunderland, Tyne & Wear, UK School of Medicine Indiana University Storm Eye Institute
Winston-Salem, NC, USA School of Medicine Medical University of South Carolina
Allister Gibbons, MD Charleston, SC, USA
Assistant Professor Indianapolis, IN, USA
Margaret A. Greven, MD
Bascom Palmer Eye Institute Assistant Professor Jeffrey S. Heier, MD Deborah S. Jacobs, MD
University of Miami Ophthalmology Co-President and Medical Director Associate Professor of Ophthalmology
Miami, FL, USA Wake Forest University Director, Vitreoretinal Service Harvard Medical School
School of Medicine Ophthalmic Consultants of Boston Medical Director
James W. Gigantelli, MD, FACS BostonSight
Professor Winston-Salem, NC, USA Boston, MA, USA
Needham, MA, USA
Department Ophthalmology & Visual Josh C. Gross, MD Leon W. Herndon, Jr., MD
Sciences Clinical Research Fellow Professor, Ophthalmology Sandeep Jain, MD
University of Nebraska Medical Center Ophthalmology Duke University Eye Center Associate Professor, Ophthalmology
Omaha, NE, USA Eugene and Marilyn Glick Eye Institute Durham, NC, USA University of Illinois at Chicago
Indiana School of Medicine Chicago, IL, USA
Pushpanjali Giri, BA Allen C. Ho, MD
Research Specialist Indianapolis, IN, USA Henry D. Jampel, MD, MHS
Wills Eye Hospital Director of Retina
Department of Ophthalmology Ronald L. Gross, MD Research Odd Fellows Professor of
University of Illinois at Chicago Professor and Jane McDermott Schott Retina Service Ophthalmology
College of Medicine Chair Wills Eye Hospital Wilmer Eye Institute
Chicago, IL, USA Chairman, Department of Philadelphia, PA, USA Johns Hopkins University
Ophthalmology School of Medicine
Ivan Goldberg, AM, MB, BS, FRANZCO, Christopher T. Hood, MD Baltimore, MD, USA
FRACS West Virginia University
Morgantown, WV, USA Clinical Assistant Professor
Clinical Professor Michigan Medicine Ophthalmology Lee M. Jampol, MD
University of Sydney Sandeep Grover, MD Cornea and Refractive Surgery Clinic Louis Feinberg Professor of
Head of Discipline of Ophthalmology Associate Professor & Associate Chair W.K. Kellogg Eye Center Ophthalmology
and Glaucoma Unit of Ophthalmology Ann Arbor, MI, USA Feinberg School of Medicine
Sydney Eye Hospital University of Florida Northwestern University
Director Jacksonville, FL, USA Chicago, IL, USA
Eye Associates xvii
Sydney, NSW, Australia
Aliza Jap, FRCS(G), FRCOphth, FRCS Kevin Kaplowitz, MD Jeremy D. Keenan, MD, MPH Victor T.C. Koh, MBBS, MMed(Oph),
(Ed) Assistant Professor Associate Professor of Ophthalmology FAMS
Senior Consultant Ophthalmologist Ophthalmology, VA Loma Linda Francis I. Proctor Foundation and Associate Consultant, Ophthalmology
Division of Ophthalmology Loma Linda University Department of Ophthalmology National University Hospital
Changi General Hospital, Singapore Loma Linda, CA, USA University of California San Francisco Singapore
Singapore National Eye Centre San Francisco, CA, USA
Singapore Michael A. Kapusta, MD, FRCSC Thomas Kohnen, MD, PhD, FEBO
Associate Professor Kenneth R. Kenyon, MD Professor and Director
Chris A. Johnson, PhD, DSc Director of Retina and Vitreous Surgery Clinical Professor, Ophthalmology Department of Ophthalmology
Professor Department of Ophthalmology Tufts University University Clinic Frankfurt
Department of Ophthalmology & Jewish General Hospital School of Medicine Goethe University
Visual Sciences McGill University Harvard Medical School Frankfurt am Main
University of Iowa Hospitals and Montreal, QC, Canada Schepens Eye Research Institute Germany
Clinics Boston, MA, USA
Iowa City, IA, USA Rustum Karanjia, MD, PhD, FRCSC Andrew Koustenis, BS
Assistant Professor, Ophthalmology Sir Peng Tee Khaw, PhD, FRCS, FRCP, Medical Student
Mark W. Johnson, MD University of Ottawa FRCOphth, FRCPath, FRSB, FCOptom Clinical Ophthalmology Research
Professor, Chief of Retina Section Ottawa Hospital Research Institute (Hon), DSc, FARVO, FMedSci Internship
Department of Ophthalmology & The Ottawa Hospital Professor of Glaucoma and Ocular Department of Ophthalmology
Visual Sciences Ottawa, ON, Canada Healing Eugene and Marilyn Glick Eye Institute
University of Michigan Doheny Eye Institute Consultant Ophthalmic Surgeon Indiana University
Ann Arbor, MI, USA Doheny Eye Centers Director, National Institute for Health School of Medicine
UCLA, David Geffen School of Research, Biomedical Research Indianapolis, IN, USA
T. Mark Johnson, MD, FRCS(C) Medicine Centre for Ophthalmology
Attending Surgeon, Vitreo-Retinal Los Angeles, CA, USA Moorfields Eye Hospital Stephen S. Lane, MD
Surgery UCL Institute of Ophthalmology Medical Director
Retina Group of Washington Randy H. Kardon, MD, PhD London, UK Adjunct Clinical Professor
Rockville, MD, USA Professor and Director of Neuro- Chief Medical Officer and Head Global
ophthalmology and Pomerantz Gene Kim, MD Franchise Clinical Strategy
Mark M. Kaehr, MD Family Chair in Ophthalmology Assistant Professor and Residency Associated Eye Care
Partner Ophthalmology/Neuro-ophthalmology Program Director University of Minnesota, Alcon
Associated Vitreoretinal and Uveitis Director of the Iowa City VA Center Department of Ophthalmology & Minneapolis, MN, USA
Consultants for the Prevention and Treatment of Visual Science at McGovern Medical
Assistant Clinical Professor of Visual Loss School at UTHealth Patrick J.M. Lavin, MB, MRCPI
Ophthalmology University of Iowa and Iowa City VA Houston, TX, USA Prof. Neurology and Ophthalmology
Indiana University Medical Center Neurology, Ophthalmology and Visual
Associated Vitreoretinal and Uveitis Iowa City, IA, USA Ivana K. Kim, MD Science
Consultants Associate Professor of Ophthalmology Vanderbilt University Medical Center
Indiana University Carol L. Karp, MD Retina Service, Massachusetts Eye and Nashville, TN, USA
School Of Medicine Professor of Ophthalmology Ear
Indianapolis, IN, USA Richard K. Forster Chair in Harvard Medical School Fabio Lavinsky, MD, PhD, MBA
Ophthalmology Boston, MA, USA Research Fellow
Malik Y. Kahook, MD Bascom Palmer Eye Institute NYU Langone Eye Center
The Slater Family Endowed Chair in University of Miami Alan E. Kimura, MD, MPH NYU School of Medicine
Ophthalmology Miller School of Medicine Clinical Associate Professor New York, NY, USA
Vice Chair of Clinical & Translational Miami, FL, USA Department of Ophthalmology Director, Ophthalmic Imaging
Research University of Colorado Department
Professor of Ophthalmology & Chief of Amir H. Kashani, MD, PhD Health Sciences Center Lavinsky Eye Institute
Glaucoma Service Assistant Professor of Clinical Aurora, CO, USA Porto Alegre, Brazil
Director of Glaucoma Fellowship Ophthalmology
University of Colorado University of Southern California Michael Kinori, MD Andrew W. Lawton, MD
School of Medicine Roski Eye Institute Senior Physician Director, Neuro-Ophthalmology
Aurora, CO, USA Los Angeles, CA, USA The Goldschleger Eye Institute Division
Sheba Medical Center, Tel Hashomer Ochsner Health Services
Peter K. Kaiser, MD Michael A. Kass, MD Ramat Gan, Israel New Orleans, LA, USA
Chaney Family Endowed Chair in Bernard Becker Professor,
Ophthalmology Research Ophthalmology and Visual Science Caitriona Kirwan, FRCSI(Ophth) Bryan S. Lee, MD, JD
Professor of Ophthalmology Washington University Consultant Ophthalmic Surgeon Private Practitioner
Cleveland Clinic School of Medicine Mater Private Hospital Altos Eye Physicians
Cole Eye Institute St Louis, MO, USA Dublin, Ireland Los Altos, CA, USA
Cleveland, OH, USA Adjunct Clinical Assistant Professor of
Paula Kataguiri, MD Szilárd Kiss, MD Ophthalmology
Sachin P. Kalarn, MD Research Fellow Chief, Retina Service Director Stanford University
Resident Physician Department of Ophthalmology and Clinical Research Director Stanford, CA, USA
Department of Ophthalmology & Center for Translational Ocular Tele-Ophthalmology Director
Visual Sciences Immunology Compliance Associate Professor of Daniel Lee, MD
University of Maryland Tufts Medical Center Ophthalmology Clinical Instructor, Glaucoma Service
Baltimore, MD, USA New England Eye Center Weill Cornell Medical College Wills Eye Hospital
Boston, MA, USA New York, NY, USA Philadelphia, PA, USA
Ananda Kalevar, MD, FRCSC, DABO PhD Candidate
Associate Professor, Department of John W. Kitchens, MD Gregory D. Lee, MD
Department of Ophthalmology Retina Surgeon, Partner Assistant Professor, Ophthalmology/
Ophthalmology Universidade Federal de São Paulo
University of Sherbrooke Co-Fellowship Director Retina
(UNIFESP) Retina Associates of Kentucky New York University
Sherbrooke, QC, Canada São Paulo, SP, Brazil Lexington, KY, USA New York, NY, USA
Steven Kane, MD L. Jay Katz, MD
Cornea, Cataract, and Refractive Kendra Klein, MD Olivia L. Lee, MD
Director, Glaucoma Service Faculty Physician Assistant Professor of Ophthalmology
Surgery Specialist Wills Eye Hospital
Eye Institute of West Florida Department of Ophthalmology David Geffen School of Medicine
Philadelphia, PA, USA University of Arizona University of California Los Angeles
Largo, FL, USA
Paul L. Kaufman, MD Associated Retina Consultants Los Angeles, CA, USA
Elliott M. Kanner, MD, PhD Ernst H. Bárány Professor of Ocular Phoenix, AZ, USA Associate Medical Director
Chief, Glaucoma Service Pharmacology Doheny Image Reading Center
Hamilton Eye Institute Douglas D. Koch, MD Doheny Eye Institute
Department Chair Emeritus Professor and Allen, Mosbacher, and
University of Tennessee Department of Ophthalmology & Los Angeles, CA, USA
Health Science Center Law Chair in Ophthalmology
Visual Sciences Cullen Eye Institute
Memphis, TN, USA University of Wisconsin-Madison Baylor College of Medicine
xviii School of Medicine & Public Health Houston, TX, USA
Madison, WI, USA
Paul P. Lee, MD, JD Pedro F. Lopez, MD Jodhbir S. Mehta, BSc, MD, MBBS, Majid Moshirfar, MD, FACS
F. Bruce Fralick Professor and Chair Professor and Founding Chair FRCS(Ed), FRCOphth, FAMS Professor of Ophthalmology
Director W.K. Kellogg Eye Center Department of Ophthalmology Associate Professor, Cornea and Hoopes Vision and John A. Moran Eye
Department of Ophthalmology & Herbert Wertheim College of Medicine External Disease Center
Visual Sciences Florida International University Singapore National Eye Centre Draper, UT, USA
University of Michigan Director of Vitreoretina and Macular Singapore
Heather E. Moss, MD, PhD
Ann Arbor, MI, USA Division
Luis J. Mejico, MD Assistant Professor
Center for Excellence in Eye Care
Richard M.H. Lee, MSc, FRCOphth Professor and Chair of Neurology Departments of Ophthalmology and
Miami, FL, USA
Clinical Fellow Professor of Ophthalmology Neurology & Neurological Sciences
Department of Glaucoma Mats Lundström, MD, PhD SUNY Upstate Medical University Stanford University
Moorfields Eye Hospital Adjunct Professor Emeritus Syracuse, NY, USA Palo Alto, CA, USA
London, UK Department of Clinical Sciences,
Carolina L. Mercado, MD Mark L. Moster, MD
Ophthalmology
Dawn K.A. Lim, MBBS, MRCP, Clinical Research Fellow, Director, Neuro-Ophthalmology
Faculty of Medicine
MMed(Int, Med), MMed(Ophth), FAMS Ophthalmology Fellowship
Lund University
Consultant, Ophthalmology/Glaucoma Bascom Palmer Eye Institute Professor, Neurology and
Lund, Region Skåne, Sweden
National University Hospital Miami, FL, USA Ophthalmology
Singapore Robi N. Maamari, MD Wills Eye Hospital
Ophthalmology Resident Shahzad I. Mian, MD Sidney Kimmel Medical College of
Jennifer I. Lim, MD, FARVO Department of Ophthalmology & Associate Chair, Terry J. Bergstrom Thomas Jefferson University
Marion H. Schenk Esq. Chair in Visual Sciences Professor Philadelphia, PA, USA
Ophthalmology for Research of the Washington University School of Associate Professor, Ophthalmology &
Aging Eye Visual Sciences Kelly W. Muir, MD, MHSc
Medicine in St Louis
Professor of Ophthalmology University of Michigan Associate Professor of Ophthalmology,
St Louis, MO, USA
Director of the Retina Service Ann Arbor, MI, USA Glaucoma Division
University of Illinois at Chicago Assumpta Madu, MD, MBA, PharmD Duke University
Illinois Eye and Ear Infirmary Vice Chair, Operations William F. Mieler, MD, FACS School of Medicine
Chicago, IL, USA Associate Clinical Professor of Cless Family Professor of Durham, NC, USA
Ophthalmology Ophthalmology
Ridia Lim, MBBS, MPH, FRANZCO Vice-Chairman of Education Ann G. Neff, MD
NYU School of Medicine
Ophthalmic Surgeon Illinois Eye and Ear Infirmary Dermatology Associates
NYU Langone Medical Center
Glaucoma Service University of Illinois at Chicago Sarasota, FL, USA
New York, NY, USA
Sydney Eye Hospital College of Medicine Jeffrey A. Nerad, MD
Sydney, NSW, Australia Maya H. Maloney, MD Chicago, IL, USA Oculoplastic & Reconstructive Surgery
Consultant, Medical Retina
Tony K.Y. Lin, MD, FRCSC David Miller, MD Cincinnati Eye Institute
Mayo Clinic
Assistant Professor Associate Clinical Professor of Volunteer Professor, Ophthalmology
Rochester, MN, USA
Department of Ophthalmology Ophthalmology University of Cincinnati
Schulich School of Medicine and Naresh Mandava, MD Harvard Medical School Cincinnati, OH, USA
Dentistry Professor and Chair Boston, MA, USA Neda Nikpoor, MD
Western University Department of Ophthalmology
Clinical Instructor, Ophthalmology
London, ON, Canada University of Colorado Kyle E. Miller, MD
Byers Eye Institute
School of Medicine Assistant Professor, Ophthalmology
Stanford University
John T. Lind, MD, MS Denver, CO, USA Naval Medical Center Portsmouth
Palo Alto, CA, USA
Associate Professor Portsmouth, VA, USA
Michael F. Marmor, MD
Department of Ophthalmology & Robert J. Noecker, MD, MBA
Professor Tatsuya Mimura, MD, PhD
Visual Sciences Director of Glaucoma
Department of Ophthamology Tokyo Womens Medical University
Washington University in St Louis Ophthalmic Consultants of
Byers Eye Institute Medical Center East
St Louis, MO, USA Connecticut
Stanford University Tokyo, Japan
Fairfield, CT, USA
Yao Liu, MD School of Medicine
Assistant Professor Palo Alto, CA, USA Rukhsana G. Mirza, MD Ricardo Nosé, MD
Department of Ophthalmology & Associate Professor Clinical Research Fellow
Jeevan R. Mathura, Jr., MD Department of Ophthalmology
Visual Sciences New England Eye Center
Private Practitioner and Owner Northwestern University
University of Wisconsin-Madison Tufts Medical Center
Diabetic Eye and Macular Disease Feinberg School of Medicine
Madison, WI, USA Boston, MA, USA
Specialists, LLC Chicago, IL, USA
Sidath E. Liyanage, MBBS, FRCOphth, Washington, DC, USA Annabelle A. Okada, MD, DMSc
PhD Mihai Mititelu, MD, MPH Professor of Ophthalmology
Cynthia Mattox, MD Assistant Professor
Consultant Ophthalmologist Kyorin University
Associate Professor, Ophthalmology Department of Ophthalmology &
Bristol Eye Hospital School of Medicine
Tufts University Visual Sciences
Bristol, UK School of Medicine Tokyo, Japan
University of Wisconsin-Madison
Alastair J. Lockwood, BM, BCh, Boston, MA, USA School of Medicine and Public Health Michael O’Keefe, FRCS
FRCOphth, PhD Madison, WI, USA Professor, Ophthalmology
Scott K. McClatchey, MD
Consultant, Ophthalmology Mater Private Hospital
Associate Professor, Ophthalmology Ramana S. Moorthy, MD
Queen Alexandra Hospital Dublin, Ireland
Naval Medical Center Clinical Associate Professor,
Portsmouth, Hampshire, UK San Diego, CA, USA Jeffrey L. Olson, MD
Ophthalmology
Nils A. Loewen, MD, PhD Indiana University Associate Professor
Stephen D. McLeod, MD
Associate Professor of Ophthalmology School of Medicine Department of Ophthalmology
Theresa M. and Wayne M. Caygill
Vice Chair of Electronic Health Founding Partner and CEO University of Colorado
Distinguished Professor and Chair,
Records in Ophthalmology Associated Vitreoretinal and Uveitis School of Medicine
Ophthalmology
University of Pittsburgh Consultants Denver, CO, USA
University of California San Francisco
Pittsburgh, PA, USA San Francisco, CA, USA Indianapolis, IN, USA Jane M. Olver, MB, BS, BSc, FRCS,
Reid A. Longmuir, MD Andrew A. Moshfeghi, MD, MBA FRCOphth
Brian D. McMillan, MD
Assistant Professor Director, Vitreoretinal Fellowship Consultant Ophthalmologist
Assistant Professor of Ophthalmology
Department of Ophthalmology & Associate Professor of Clinical Eye Department
WVU Eye Institute
Visual Sciences Ophthalmology Clinica London
West Virginia University
Vanderbilt University University of Southern California London, UK
School of Medicine
Nashville, TN, USA Morgantown, WV, USA Roski Eye Institute Yvonne A.V. Opalinski, BSc, MD, BFA,
Keck School of Medicine MFA
Alan A. McNab, DMedSc, FRANZCO, Los Angeles, CA, USA Clinical Associate Cardiovascular
FRCOphth
Surgery
Associate Professor and Director
Department of Cardiovascular Surgery
Orbital Plastic and Lacrimal Clinic
Royal Victorian Eye and Ear Hospital Trillium Health Partners xix
Toronto, ON, Canada
Melbourne, VIC, Australia
Faruk H. Örge, MD Alfio P. Piva, MD P. Kumar Rao, MD Damien C. Rodger, MD, PhD
William R. and Margaret E. Althans Professor of Neurosurgery and Professor of Ophthalmology and Visual Assistant Professor of Clinical
Chair and Professor Ophthalmology Science Ophthalmology
Director, Center for Pediatric University of Costa Rica Washington University Research Assistant Professor of
Ophthalmology and Adult San Jose, Costa Rica St Louis, MO, USA Biomedical Engineering
Strabismus USC Roski Eye Institute and Viterbi
Rainbow Babies, Children’s Hospital, Dominik W. Podbielski, HonBSc, MSc, Rajesh C. Rao, MD School of Engineering
UH Eye Institute MD, FRCSC Leslie H. and Abigail S. Wexner University of Southern California
Cleveland Medical Center Staff Physician, Ophthalmology Emerging Scholar Los Angeles, CA, USA
Cleveland, OH, USA Prism Eye Institute Assistant Professor, Retina Service
North Toronto Eye Care Department of Ophthalmology & Miin Roh, MD, PhD
Mark Packer, MD, FACS, CPI Toronto, ON, Canada Visual Sciences Vitreoretina Surgery Clinical Fellow
President W.K. Kellogg Eye Center Department of Ophthalmology/Retina
Mark Packer MD Consulting, Inc. Nicolas J. Pondelis, BA University of Michigan Service
Boulder, CO, USA Ophthalmic Photographer and VA Ann Arbor Health System Massachusetts Eye and Ear
Research Assistant Ann Arbor, MI, USA Boston, MA, USA
Suresh K. Pandey, MD Tufts Medical Center
Director, Ophthalmology Boston, MA, USA Sivakumar Rathinam, FAMS, PhD Shiyoung Roh, MD
SuVi Eye Institute and Lasik Laser Professor of Ophthalmology Associate Clinical Professor
Center Francis W. Price, Jr., MD Head of Uveitis Service Tufts University
Kota, Rajasthan, India President Aravind Eye Hospital School of Medicine
Visiting Assistant Professor Price Vision Group Post Graduate Institute of Vice-Chair Division of Ophthalmology
John A. Moran Eye Center Indianapolis, IN, USA Ophthalmology Vice-Chair Department of Surgery
University of Utah Marianne O. Price, PhD, MBA Madurai, Tamil Nadu, India Lahey Hospital and Medical Center
Salt Lake City, UT, USA Executive Director Peabody, MA, USA
Russell W. Read, MD, PhD
Vishal S. Parikh, MD Cornea Research Foundation of Max and Lorayne Cooper Endowed Noel Rosado-Adames, MD
Vitreoretinal Surgery Fellow, Retina America Professor in Ophthalmology Cornea and External Disease Specialist
Service Indianapolis, IN, USA Residency Training Private Practitioner
The Retina Institute Cindy Pritchard, CO University of Alabama at Birmingham OMNI Eye Specialists
St Louis, MO, USA Orthoptist Birmingham, AL, USA Baltimore, MD, USA
Louis R. Pasquale, MD, FARVO Clinical Instructor of Ophthalmology Caio Vinicius Saito Regatieri, MD, PhD Emanuel S. Rosen, MD, FRCS,
Professor of Ophthalmology Children’s Hospital of New Orleans Professor, Ohalmology FRCOphth
Harvard Medical School Tulane University Tufts Medical School Professor
Boston, MA, USA Department of Ophthalmology Boston, MA, USA Department of Vision Sciences
New Orleans, LA, USA Federal University of São Paulo University of Manchester
Sarju S. Patel, MD, MPH, MSc São Paulo, Brazil Manchester, UK
Director of Uveitis Peter A. Quiros, MD
Department of Ophthalmology Associate Professor, Ophthalmology Carl D. Regillo, MD Jonathan B. Rubenstein, MD
Weill Cornell College of Medicine University of California Los Angeles Director Retina Service Deutsch Family Endowed Chair in
New York City, NY, USA Los Angeles, CA, USA Professor of Ophthalmology Ophthalmology
Aleksandra V. Rachitskaya, MD Wills Eye Hospital Retina Service Vice-Chairman of the Department of
Vivek R. Patel, MD Thomas Jefferson University Ophthalmology
Associate Professor, Ophthalmology Assistant Professor of Ophthalmology,
Cleveland Clinic Lerner College of Philadelphia, PA, USA Rush University Medical Center
USC Roski Eye Institute Chicago, IL, USA
Keck School of Medicine Medicine of Case Western Reserve Elias Reichel, MD
Los Angeles, CA, USA University Professor and Vice Chair Richard M. Rubin, MD, LT, COL, USAF,
Vitreoretinal Staff Physician New England Eye Center MC, SFS
Carlos E. Pavesio, MD Cole Eye Institute Tufts University Neuro-Ophthalmologist and Senior
Consultant Ophthalmic Surgeon Cleveland Clinic School of Medicine Flight Surgeon
Medical Retina Cleveland, OH, USA Boston, MA, USA Departments of Ophthalmology and
Moorfields Eye Hospital Aerospace Medicine
London, UK Pradeep Y. Ramulu, MD, MHS, PhD Douglas J. Rhee, MD
Associate Professor of Ophthalmology David Grant USAF Medical Center
Chairman Travis AFB, CA, USA
Victor L. Perez, MD Chief, Glaucoma Division Department of Ophthalmology and
Professor of Ophthalmology Wilmer Eye Institute Visual Sciences Steven E. Rubin, MD
Stephen and Frances Foster Professor Johns Hopkins School of Medicine University Hospitals Case Medical Vice Chair, Residency Program
of Ophthalmology Baltimore, MD, USA Center Director and Co-Chief, Pediatric
Duke University School of Medicine Case Western Reserve University Ophthalmology
Director, Duke Center for Ocular J. Bradley Randleman, MD
Editor-in-Chief School of Medicine Hofstra North Shore–Long Island
Immunology Cleveland, OH, USA Jewish School of Medicine
Durham, NC, USA Journal of Refractive Surgery
Professor of Ophthalmology Great Neck, NY, USA
Alexander L. Ringeisen, MD
Claudia E. Perez-Straziota, MD Director, Cornea & Refractive Surgery Vitreoretinal Surgery Fellow Patrick E. Rubsamen, MD
Clinical Assistant Professor of USC Roski Eye Institute VitreoRetinal Surgery, PA Physician, Vitreoretinal Surgery
Ophthalmology Keck School of Medicine of USC Minneapolis, MN, USA Retina Group of Florida
Roski Eye Institute Los Angeles, CA, USA Boca Raton, FL, USA
University of Southern California Robert Ritch, MD, FACS
Private Practitioner Narsing A. Rao, MD Shelley and Steven Einhorn Jason D. Rupp, MD
Los Angeles, CA, USA Professor of Ophthalmology and Distinguished Chair Ophthalmology Specialist
Pathology Professor of Ophthalmology Department of Ophthalmology and
Lauren T. Phillips, MD Chief of Uveitis Service and New York Eye and Ear Infirmary of Visual Sciences
Assistant Professor, Neurology & Ophthalmic Pathology Laboratory Mount Sinai Washington University
Neurotherapeutics USC Roski Eye Institute New York, NY, USA School of Medicine
University of Texas Keck School of Medicine St Louis, MO, USA
Southwestern Medical Center University of Southern California Shira L. Robbins, MD
Dallas, TX, USA Los Angeles, CA, USA Clinical Professor of Ophthalmology Hossein G. Saadati, MD
Director of Neonatal Ophthalmology Oculofacial/Reconstructive Surgeon,
Jody R. Piltz-Seymour, MD Naveen K. Rao, MD Division of Pediatric Ophthalmology Ophthalmology
Adjunct Professor, Ophthalmology Cornea, Cataract, and Anterior and Strabismus Kaiser Permanente Medical Offices
Perelman School of Medicine Segment Surgery Ratner Children’s Eye Center at the Stockton, CA, USA
University of Pennsylvania Lahey Hospital and Medical Center Shiley Eye Institute
Glaucoma Care Center at Valley Eye Burlington, MA, USA La Jolla, CA, USA Alfredo A. Sadun, MD, PhD
Professionals, LLC Assistant Professor of Ophthalmology Flora Thornton Chair, Doheny
Glaucoma Service, Wills Eye Hospital Tufts University Professor of Ophthalmology
Philadelphia, PA, USA School of Medicine Vice-Chair of Ophthalmology, UCLA
Boston, MA, USA Los Angeles, CA, USA
xx
Osamah J. Saeedi, MD Hermann D. Schubert, MD Roni M. Shtein, MD, MS Sunil K. Srivastava, MD
Associate Professor Professor of Clinical Ophthalmology Associate Professor Staff Physician
Director of Clinical Research and Pathology Department of Ophthalmology & Cleveland Clinic
Associate Residency Program Director E.S. Harkness Eye Institute Visual Sciences Cole Eye Institute
Department of Ophthalmology & Columbia University University of Michigan Cleveland, OH, USA
Visual Sciences New York, NY, USA Ann Arbor, MI, USA
University of Maryland Brian C. Stagg, MD
Joel S. Schuman, MD Ryan W. Shultz, MD Clinical Lecturer
School of Medicine
Professor and Chairman of Ophthalmologist, Vitreoretinal Department of Ophthalmology &
Baltimore, MD, USA
Ophthalmology Diseases Visual Sciences
Daniel J. Salchow, MD Director, NYU Eye Center Colorado Permanente Medical Group University of Michigan
Professor of Ophthalmology Professor of Neuroscience and Denver, CO, USA Ann Arbor, MI, USA
Section of Pediatric Ophthalmology, Physiology
Patricia B. Sierra, MD David H.W. Steel, MBBS, FRCOphth
Strabismus and Neuro- Neuroscience Institute
Sacramento Eye Consultants Consultant Ophthalmologist and
ophthalmology NYU School of Medicine
Sacramento, CA, USA Vitreoretinal Surgeon
Department of Ophthalmology Professor of Electrical and Computer
Charité – University Medicine Berlin Engineering Brent Siesky, PhD Sunderland Eye Infirmary
Berlin, Germany NYU Tandon School of Engineering Assistant Director, Research Associate City Hospitals Sunderland NHS
Professor of Neural Engineering Ophthalmology, Glaucoma Research Foundation Trust
Sarwat Salim, MD, FACS Center for Neural Science, NYU and Diagnostic Center Sunderland, Tyne & Wear, UK
Professor of Ophthalmology New York, NY, USA Eugene and Marilyn Glick Eye Institute
Eye Institute Joshua D. Stein, MD, MS
Indiana University Associate Professor, Ophthalmology &
Medical College of Wisconsin Gary S. Schwartz, MD, MHA School of Medicine
Milwaukee, WI, USA Adjunct Associate Professor Visual Sciences
Indianapolis, IN, USA Associate Professor, Health
Department of Ophthalmology
Thomas W. Samuelson, MD University of Minnesota Paul A. Sieving, MD, PhD Management & Policy
Attending Surgeon School of Medicine Associated Eye Director University of Michigan
Glaucoma and Anterior Segment Care National Eye Institute Ann Arbor, MI, USA
Surgery Stillwater, MN, USA National Institutes of Health
Minnesota Eye Consultants, PA Mitchell B. Strominger, MD
Bethesda, MD, USA Professor of Ophthalmology and
Adjunct Associate Professor J. Sebag, MD, FACS, FRCOphth, FARVO
Department of Ophthalmology Founding Director Dimitra Skondra, MD, PhD Pediatrics
University of Minnesota VMR Institute for Vitreous Macula Assistant Professor of Ophthalmology Tufts Medical Center
Minneapolis, MN, USA Retina and Visual Science Boston, MA, USA
Huntington Beach, CA, USA Director, J. Terry Ernest Ocular Alan Sugar, MD
Simrenjeet Sandhu, MD Imaging Center
Ophthalmology Resident Dov B. Sebrow, MD Professor and Vice-Chair,
The University of Chicago Ophthalmology & Visual Sciences
University of Alberta Senior Vitreoretinal Surgical Fellow, Chicago, IL, USA
Edmonton, AL, Canada Ophthalmology/Vitreoretinal Kellogg Eye Center
Diseases Kent W. Small, MD University of Michigan
Marcony R. Santhiago, MD, PhD Edward S. Harkness Eye Institute President/Founder, Vitreo-Retinal Ann Arbor, MI, USA
Adjunct Professor of Ophthalmology Columbia University Medical Center Surgery
Refractive Surgery Department Joel Sugar, MD
Vitreous Retina Macula Consultants of Molecular Insight Research Foundation
University of Southern California Professor and Vice Head,
New York Glendale, CA, USA
Los Angeles, CA, USA Ophthalmology & Visual Sciences
Manhattan Eye, Ear and Throat William E. Smiddy, MD University of Illinois Eye and Ear
Professor of Ophthalmology Hospital
Refractive Surgery Department Professor, Ophthalmology Infirmary
New York, NY, USA Bascom Palmer Eye Institute Chicago, IL, USA
University of São Paulo
São Paulo, SP, Brazil H. Nida Sen, MD, MHS University of Miami
Yevgeniy V. Sychev, MD
Director, Uveitis Felowship Program Miller School of Medicine
Giacomo Savini, MD Senior Clinical Fellow
National Eye Institute Miami, FL, USA
Researcher Ophthalmology/Vitreoretinal Disease
National Institutes of Health Marie Somogyi, MD and Surgery
G.B. Bietti Foundation Bethesda, MD, USA
Rome, Italy Oculoplastic and Orbital Surgery Washington University
Gaurav K. Shah, MD TOC Eye and Face School of Medicine in St Louis
Ibrahim O. Sayed-Ahmed, MD Professor of Clinical Ophthalmology & Austin, TX, USA St Louis, MO, USA
Research Fellow Visual Sciences
Graduate Student in Vision Science H. Kaz Soong, MD Tak Yee Tania Tai, MD
The Retina Institute Chief of Cornea and Refractive Service Assistant Professor, Ophthalmology
and Investigative Ophthalmology Washington University
Bascom Palmer Eye Institute Co-Director of International New York Eye and Ear Infirmary of
School of Medicine Ophthalmology Mount Sinai
Miami, FL, USA St Louis, MO, USA Department of Ophthalmology & New York, NY, USA
Amy C. Scheffler, MD Carol L. Shields, MD Visual Sciences
Assistant Professor of Clinical University of Michigan James C. Tan, MD, PhD
Director, Ocular Oncology Service Associate Professor, Department of
Ophthalmology Wills Eye Hospital Ann Arbor, MI, USA
Assistant Clinical Member, Research Ophthalmology
Professor of Ophthalmology Sarkis H. Soukiasian, MD Doheny Eye Institute
Institute Thomas Jefferson University Director, Cornea and External Diseases University of California Los Angeles
Weill Cornell Medical College Philadelphia, PA, USA Director, Ocular Inflammation and Los Angeles, CA, USA
Houston Methodist Hospital Medical
Uveitis
Center Yevgeniy (Eugene) Shildkrot, MD Myron Tanenbaum, MD
Lahey Health Systems
Retina Consultants of Houston Associate Professor of Ophthalmology Voluntary Professor
Burlington, MA, USA
Houston, TX, USA Ocular Oncology and Vitreoretinal Department of Ophthalmology
Diseases and Surgery Richard F. Spaide, MD Bascom Palmer Eye Institute
Paulo Schor, MD, MSci, DSci University of Virginia Vitreous, Retina, Macula Consultants
Director of Research and Technological University of Miami
Charlottesville, VA, USA of New York Miller School of Medicine
Development New York, NY, USA
Professor of Ophthalmology Bradford J. Shingleton, MD Miami, FL, USA
Department of Ophthalmology & Clinical Associate Professor, Tatyana Spektor, MD Suphi Taneri, MD
Visual Sciences Ophthalmology Cornea and Refractive Surgery Fellow Director, Center for Refractive Surgery,
Escola Paulista de Medicina (EPM) – Harvard Medical School Department of Ophthalmology Eye Department
Universidade Federal de São Paulo Partner, Ophthalmic Consultants Baylor College of Medicine St. Francis Hospital
(UNIFESP) of Boston Houston, TX, USA Associate Professor, Eye Clinic
São Paulo, Brazil Boston, MA, USA Ruhr University Bochum
Thomas C. Spoor, MD, FACS
Private Practitioner Munster, NRW, Germany
Neuro-Ophthalmology and Oculo-
Plastic Surgery
Sarasota Retina Institute xxi
Sarasota, FL, USA
William Tasman, MD† Julie H. Tsai, MD Brian D. Walker, BS Matthew T. Witmer, MD
Formerly Professor and Emeritus Assistant Professor of Clinical Medical Student Partner Physician, Vitreoretinal Surgery
Chairman Ophthalmology McGovern Medical School Retina Associates of Western New York
Department of Ophthalmology Albany, NY, USA Houston, TX, USA Rochester, NY, USA
Wills Eye Hospital and Jefferson Clinical Instructor
Medical College Nancy Tucker, MD, FRCSC David S. Walton, MD University of Rochester Medical Center
Philadelphia, PA, USA Chief of Oculoplastics, Ophthalmology President, Children’s Glaucoma Rochester, NY, USA
University of Toronto Foundation
David G. Telander, MD, PhD Toronto, ON, Canada Clinical Professor of Ophthalmology Gadi Wollstein, MD
Clinical Professor Harvard Medical School Professor of Ophthalmology
Department of Ophthalmology Sonal S. Tuli, MD, MEd Surgeon in Ophthalmology Vice Chairman for Clinical Research
University of California Davis Professor and Chair, Ophthalmology Massachusetts Eye and Ear Infirmary Director of Ophthalmic Imaging
Davis, CA, USA University of Florida Boston, MA, USA Research Laboratory
Associate Professor Gainesville, FL, USA Director of Research Education
California Northstate Li Wang, MD, PhD NYU School of Medicine
Caroline W. Vargason, MD, PhD Associate Professor, Ophthalmology
School of Medicine Oculoplastic & Reconstructive Surgery New York, NY, USA
Sacramento, CA, USA Baylor College of Medicine
Fellow Houston, TX, USA Maria A. Woodward, MD, MS
Edmond H. Thall, MD, MS Cincinnati Eye Institute Assistant Professor of Ophthalmology
Consultant in Aerospace Cincinnati, OH, USA Michelle Y. Wang, MD & Visual Sciences
Ophthalmology Associate Physician University of Michigan
Roshni A. Vasaiwala, MD Department of Ophthalmology/
Aeromedical Consultation Service Assistant Professor of Ophthalmology Ann Arbor, MI, USA
Ophthalmology Branch Neuro-Ophthalmology
Director of Cornea Service Southern California Permanente Nicholas K. Wride, MB, ChB, FRCOphth
United States Air Force School of Loyola University Medical Center
Aerospace Medicine Medical Group Consultant Ophthalmologist
Maywood, IL, USA Los Angeles, CA, USA Sunderland Eye Infirmary
Wright–Patterson Air Force Base
Dayton, OH, USA Daniel Vitor Vasconcelos-Santos, MD, City Hospitals Sunderland
Robert C. Wang, MD Sunderland, Tyne & Wear, UK
PhD Partner
Aristomenis Thanos, MD Adjunct Professor of Ophthalmology
Retina Department Texas Retina Assoc Albert Wu, MD, PhD
Director of Uveitis Clinical Associate Professor of Associate Professor of Ophthalmology
Devers Eye Institute Universidade Federal de Minas Gerais
Portland, OR, USA Ophthalmology Icahn School of Medicine at Mount
Belo Horizonte, Minas Gerais, Brazil UT Southwestern Sinai
Christos N. Theophanous, MD Gregory J. Vaughn, MD Dallas, TX, USA New York, NY, USA
Resident Physician Consultant, Global Healthcare Practice
Department of Ophthalmology and Martin Wax, MD David Xu, MD
Spencer Stuart Chief Medical Officer and Executive Resident Physician
Visual Science Atlanta, GA, USA
University of Chicago Medicine Vice-President R&D Stein Eye Institute
Chicago, IL, USA Arthi Venkat, MD, MS, BA PanOptica, Inc. University of California Los Angeles
Staff Physician in Medical Retina and Bernardsville, NJ, USA Los Angeles, CA, USA
Benjamin J. Thomas, MD Uveitis
Physician, Vitreoretinal Surgery Joel M. Weinstein, MD Joshua A. Young, MD
Cleveland Clinic Professor of Ophthalmology and Clinical Professor
Florida Retina Institute Cole Eye Institute
Jacksonville, FL, USA Pediatrics Department of Ophthalmology
Cleveland, OH, USA Penn State University M.S. Hershey New York University
Praneetha Thulasi, MD Guadalupe Villarreal, Jr., MD Medical Center School of Medicine
Assistant Professor of Ophthalmology Attending Hershey, PA, USA Chief Ophthalmologist Correspondent
Cornea, External Diseases, and Department of Ophthalmology EyeWorld Magazine
Refractive Surgery John J. Weiter, MD, PhD Producer and Manager of Podcasting
Mid-Atlantic Permanente Medical Associate Professor of Ophthalmology
Emory University Group American Society of Cataract and
Atlanta, GA, USA Harvard Medical School Refractive Surgery
Falls Church, VA, USA Boston, MA, USA New York, NY, USA
Michael D. Tibbetts, MD Kateki Vinod, MD
Director of Retina Services Liliana Werner, MD, PhD Edward S. Yung, MD
Assistant Professor of Ophthalmology Professor of Ophthalmology & Visual
Tyson Eye Center New York Eye and Ear Infirmary of Clinical Instructor, Glaucoma
Cape Coral, FL, USA Sciences Wills Eye Hospital
Mount Sinai Co-Director Intermountain Ocular
Icahn School of Medicine at Mount Philadelphia, PA, USA
David P. Tingey, BA, MD, FRCSC Research Center
Associate Professor, Ophthalmology Sinai University of Utah Cynthia Yu-Wai-Man, PhD, FRCOphth
Western University New York, NY, USA John A. Moran Eye Center Postdoctoral Research Fellow
London, ON, Canada Jesse M. Vislisel, MD Salt Lake City, UT, USA Rescue, Repair and Regeneration
Staff Physician, Cornea & External UCL Institute of Ophthalmology
Faisal M. Tobaigy, MD Mark Wevill, MBChB, FRCSE, FCS(SA) London, UK
Associate Professor of Ophthalmology Disease Consultant Ophthalmologist
Jazan University Associated Eye Care Optegra Birmingham Eye Hospital Wadih M. Zein, MD
Jazan, Saudi Arabia Stillwater, MN, USA Birmingham, West Midlands, UK Staff Clinician
Ivan Vrcek, MD Ophthalmic Genetics and Visual
Bozho Todorich, MD, PhD Janey L. Wiggs, MD, PhD Function Branch
Staff Physician Partner, Texas Ophthalmic Plastic, Paul Austin Chandler Professor of
Reconstructive, and Orbit Surgery National Eye Institute, NIH
Pennsylvania Retina Specialists, PC Ophthalmology Bethesda, MD, USA
Camp Hill, PA, USA President, Ivan Vrcek, M.D. PA Harvard Medical School
Associate Adjunct Professor of Boston, MA, USA Ivy Zhu, MD
Stuart W. Tompson, PhD Ophthalmology and Oculoplastic Resident Physician
Associate Scientist Surgery, Texas A&M Medical School, Andrew M. Williams, MD Department of Ophthalmology &
Department of Ophthalmology & Dallas Campus Resident Visual Sciences
Visual Sciences Clinical Assistant Professor of Department of Ophthalmology Illinois Eye and Ear Infirmary
University of Wisconsin-Madison Ophthalmology and Oculoplastic University of Pittsburgh University of Illinois at Chicago
Madison, WI, USA Surgery, UT Southwestern Medical School of Medicine College of Medicine
Center Pittsburgh, PA, USA Chicago, IL, USA
James C. Tsai, MD, MBA Dallas, TX, USA
President, New York Eye & Ear George A. Williams, MD
Infirmary of Mount Sinai, Delafield- Hormuz P. Wadia, MD Chair, Department of Ophthalmology
Rodgers Professor and System Chair Assistant Clinical Professor Oakland University
Department of Ophthalmology Department of Ophthalmology William Beaumont School of Medicine
Icahn School of Medicine at Mount James A. Haley VAMC Royal Oak, MI, USA
Sinai Morsani School of Medicine
New York, NY, USA University of South Florida Eye
Institute
xxii †
Tampa, FL, USA
Deceased
Acknowledgments
Acknowledgments
We are grateful to the editors and authors who have contributed to
Ophthalmology and to the superb, dedicated Ophthalmology team at Else-
vier. We especially would like to thank Sharon Nash and Russell Gabbedy
for their tireless efforts in keeping us on track and making our job
much easier. We would also like to thank Josh Mearns, Content Coordi-
nator; Joanna Souch, Project Manager; Brian Salisbury, Designer; Karen
Giacomucci, Illustration Manager; Richard Tibbitts, Illustrator; Vinod
Kothaparamtath, Multimedia Producer; and Claire McKenzie, Marketing
Manager.
Dedication
Dedication
We would like to dedicate this book to our wives, Karin Yanoff and Julie
Starr-Duker, and to our children—Steven, David, and Alexis Leyva-Yanoff;
Joanne Grune-Yanoff; and Jake, Claire, Bear, Becca, Sam, Colette, and Elly
Duker—all of whom play such an important part in our lives and without
whose help and understanding we would have never come this far.
xxiii
Part 1 Genetics

Fundamentals of Human Genetics

Janey L. Wiggs 1.1
Definition: The central principles of human genetics with relevance to HUMAN GENOME
eye disease. Human DNA is packaged as chromosomes located in the nuclei of cells.
Chromosomes are composed of individual strands of DNA wound about
proteins called histones. The complex winding and coiling process culmi-
nates in the formation of a chromosome. The entire collection of human
chromosomes includes 22 paired autosomes and two sex chromosomes.
Women have two copies of the X chromosome, and men have one X and
Key Features one Y chromosome (Fig. 1.1.3).
• Gene structure and expression. The set consisting of one of each autosome as well as both sex chro-
• Organization and inheritance of the human genome. mosomes is called the human genome. The chromosomal molecules of
• Mutations and clinical phenotypes. DNA from one human genome, if arranged in tandem end to end, contain
• Gene-based therapies. approximately 3.2 billion base pairs (bp). The Human Genome Project was
formally begun in 1990 with the defined goals to: identify all the approxi-
mately 20,000–25,000 genes in human DNA; determine the sequences of
the 3 billion chemical base pairs that make up human DNA; store this
information in publicly available databases; improve tools for data anal-
DNA AND THE CENTRAL DOGMA OF ysis; transfer related technologies to the private sector; and address the
HUMAN GENETICS
The regulation of cellular growth and function in all human tissue is depen-
dent on the activities of specific protein molecules. In turn, protein activity
STRUCTURE OF THE DNA DOUBLE HELIX
is dependent on the expression of the genes that contain the correct DNA
sequence for protein synthesis. The DNA molecule is a double-stranded
helix. Each strand is composed of a sequence of four nucleotide bases— Sugar–phosphate backbone Separation of individual
adenine (A), guanine (G), cytosine (C), and thymine (T)—joined to a sugar and nitrogenous bases strands allows DNA replication
and a phosphate. The order of the bases in the DNA sequence forms the
genetic code that directs the expression of genes. The double-stranded helix
sugar–
is formed as a result of hydrogen bonding between the nucleotide bases of
phosphate
opposite strands.1 The bonding is specific, such that A always pairs with backbone
T, and G always pairs with C. The specificity of the hydrogen bonding is
one helical turn = 3.4 nm
the molecular basis of the accurate copying of the DNA sequence that is
required during the processes of DNA replication (necessary for cell divi-
sion) and transcription of DNA into RNA (necessary for gene expression
and protein synthesis; Fig. 1.1.1).
Gene expression begins with the recognition of a particular DNA
sequence called the promoter sequence as the start site for RNA synthe-
sis by the enzyme RNA polymerase. The RNA polymerase “reads” the
DNA sequence and assembles a strand of RNA that is complementary
to the DNA sequence. RNA is a single-stranded nucleic acid composed
of the same nucleotide bases as DNA, except that uracil takes the place
of thymine. Human genes (and genes found in other eukaryotic organ-
bases
isms) contain many DNA sequences that are not translated into polypep-
tides and proteins. These sequences are called intervening sequences or
introns. Introns do not have any known specific function, and although
they are transcribed into RNA by RNA polymerase, they are spliced out of
the initial RNA product (termed heteronuclear RNA, or hnRNA) to form
the completed messenger RNA (mRNA). Untranslated RNA may have spe-
cific functions. For example, antisense RNA and micro RNAs (miRNA) 5l 3l 5l 3l
appear to regulate expression of genes.2 The mRNA is the template for original
new chains
original
protein synthesis. Proteins consist of one or more polypeptide chains, chain chain
forming
which are sequences of specific amino acids. The sequence of bases in
the mRNA directs the order of amino acids that make up the polypeptide adenine thymine guanine cytosine
chain. Individual amino acids are encoded by units of three mRNA bases,
termed codons. Transfer RNA (tRNA) molecules bind specific amino acids
Fig. 1.1.1 Structure of the DNA Double Helix. The sugar–phosphate backbone
and recognize the corresponding three-base codon in the mRNA. Cellular and nitrogenous bases of each individual strand are arranged as shown. The two
organelles called ribosomes bind the mRNA in such a configuration that strands of DNA pair by hydrogen bonding between the appropriate bases to form
the RNA sequence is accessible to tRNA molecules and the amino acids the double-helical structure. Separation of individual strands of the DNA molecule
are aligned to form the polypeptide. The polypeptide chain may be pro- allows DNA replication, catalyzed by DNA polymerase. As the new complementary
cessed by a number of other chemical reactions to form the mature protein strands of DNA are synthesized, hydrogen bonds are formed between the 1
(Fig. 1.1.2). appropriate nitrogenous bases.
booksmedicos.org
1 CENTRAL DOGMA OF MOLECULAR GENETICS
nucleus
PACKAGING OF DNA INTO CHROMOSOMES
DNA double helix

Genetics
cytoplasm chromosome
DNA
transcription
primary
mRNA
processing
mature Nucleosome
mRNA
histone
nucleosome
translation DNA
nuclear nuclear
pore envelope
200 bp of DNA
plasma
membrane protein
Solenoid
exon intron intron spliced out
Fig. 1.1.2 The Central Dogma of Molecular Genetics. Transcription of DNA into
RNA occurs in the nucleus of the cell, catalyzed by the enzyme RNA polymerase.
Mature mRNA is transported to the cytoplasm, where translation of the code
produces amino acids linked to form a polypeptide chain, and ultimately a mature
protein is produced.
Chromosome
ethical, legal, and social issues that may arise from the project. One of chromatin loop
the most important goals, the complete sequence of the human genome, contains approximately
100, 000 bp of DNA
was completed in draft form in 2001.3 Catalogs of variation in the human
genome sequence have also been completed, with the microsatellite repeat
map in 1994,4 the release of the HapMap from the International HapMap
Consortium in 2004,5 and more recently a catalog of variants from the 1000
genomes project.6 dbSNP (https://www.ncbi.nlm.nih.gov/projects/SNP/)
is a database listing single nucleotide polymorphisms (SNPs) that are
single-letter variations in a DNA base sequence. SNPs are bound together chromatin
strand chromatid
to form haplotypes, which are blocks of SNPs that are commonly inherited
together. This binding occurs through the phenomenon of linkage disequi-
librium. Within a haplotype block, which may extend for 10,000–100,000
bases of DNA, the analysis of only a subset of all SNPs may “tag” the entire Fig. 1.1.3 The Packaging of DNA Into Chromosomes. Strands of DNA are wound
haplotype. The International HapMap project has performed an initial tightly around proteins called histones. The DNA–histone complex becomes further
characterization of the linkage disequilibrium patterns between SNPs in coiled to form a nucleosome, which in turn coils to form a solenoid. Solenoids then
multiple different populations. The SNP haplotype blocks identified can form complexes with additional proteins to become the chromatin that ultimately
be examined for association with human disease, especially common dis- forms the chromosome.
orders with complex inheritance. Knowledge about the effects of DNA
variations among individuals can lead to new ways to diagnose, treat,
and prevent human disease. This approach has been used successfully to between chromosomes by recombination (Fig. 1.1.5). The homologous
identify the risk loci for age-related macular degeneration,7–9 myopia,10,11 chromosome pairs line up on the microtubule spindle and divide such
primary open-angle glaucoma,12–14 and Fuchs’ endothelial dystrophy.15 that the maternal and paternal copies of the doubled chromosomes are
distributed to separate daughter cells. A second cell division occurs, and
Mitosis and Meiosis the doubled chromosomes divide, which results in daughter cells that have
half the genetic material of somatic (tissue) cells.
In order for cells to divide, the entire DNA sequence must be copied so
that each daughter cell can receive a complete complement of DNA. The
growth phase of the cell cycle terminates with the separation of the two
BASIC MENDELIAN PRINCIPLES
sister chromatids of each chromosome, and the cell divides during mitosis. Two important rules central to human genetics emerged from the work of
Before cell division, the complete DNA sequence is copied by the enzyme Gregor Mendel, a nineteenth century Austrian monk. The first is the prin-
DNA polymerase in a process called DNA replication. DNA polymerase is ciple of segregation, which states that genes exist in pairs and that only one
an enzyme capable of the synthesis of new strands of DNA using the exact member of each pair is transmitted to the offspring of a mating couple.
sequence of the original DNA as a template. Once the DNA is copied, the The principle of segregation describes the behavior of chromosomes in
old and new copies of the chromosomes form their respective pairs, and meiosis. Mendel’s second rule is the law of independent assortment, which
the cell divides such that one copy of each chromosome pair belongs to states that genes at different loci are transmitted independently. This work
each cell (Fig. 1.1.4). Mitotic cell division produces a daughter cell that is also demonstrated the concepts of dominant and recessive traits. Mendel
an exact replica of the dividing cell. found that certain traits were dominant and could mask the presence of a
Meiotic cell division is a special type of cell division that results in a recessive gene.
reduction of the genetic material in the daughter cells, which become At the same time that Mendel observed that most traits segregate
the reproductive cells—eggs (women) and sperm (men). Meiosis begins independently, according to the law of independent assortment, he unex-
2 with DNA replication, followed by a pairing of the maternal and paternal pectedly found that some traits frequently segregate together. The phys-
chromosomes (homologous pairing) and an exchange of genetic material ical arrangement of genes in a linear array along a chromosome is the
booksmedicos.org
MITOTIC CELL CYCLE MEIOTIC CELL CYCLE
1.1
Interphase

centrioles plasma membrane Metaphase I
nucleus cytoplasm
nucleolus
nuclear envelope
chiasmata
Daughter Anaphase I
cells Prophase
primary oocyte
bipolar primary spermatocyte
spindle
fiber
Prophase I
Telophase I
secondary oocyte
Telophase Prometaphase secondary spermatocyte
microtubule
spindle pole
Metaphase II
centromere
chromatid
Anaphase Metaphase Anaphase II
large egg and

polar bodies
spermatids of
equatorial equal size Haploid gametes
plane (meta-
phase plate)
Fig. 1.1.5 The Meiotic Cell Cycle. During meiosis, the DNA of a diploid cell is
Fig. 1.1.4 The Mitotic Cell Cycle. During mitosis, the DNA of a diploid cell is replicated, which results in the formation of a tetraploid cell that divides twice
replicated, which results in the formation of a tetraploid cell that divides to form to form four haploid cells (gametes). As a consequence of the crossing over and
two identical diploid daughter cells. recombination events that occur during the pairing of homologous chromosomes
before the first division, the four haploid cells may contain different segments of
the original parental chromosomes. For brevity, prophase II and telophase II are not
explanation for this surprising observation. On average, a recombination shown.
event occurs once or twice between two paired homologous chromosomes
during meiosis (Fig. 1.1.6). Most observable traits, by chance, are located
far away from one another on a chromosome, such that recombination is GENETIC RECOMBINATION BY CROSSING OVER
likely to occur between them, or they are located on entirely different chro-
mosomes. If two traits are on separate chromosomes, or a recombination
A a A A a a A a A a A a A a
event is likely to occur between them on the same chromosome, the resul-
tant gamete formed during meiosis has a 50% chance of inheriting differ- B b B B b b B b B b B b B b
ent alleles from each loci, and the two traits respect the law of independent
C c C C c c C C c c C C c c
assortment. If, however, the loci for these two traits are close together on
a chromosome, with the result that a recombination event occurs between D d D D d d D D d d D D d d
them only rarely, the alleles at each loci are passed to descendent gametes
E e E E e e E E e e E E e e
“in phase.” This means that the particular alleles present at each loci in the
offspring reflect the orientation in the parent, and the traits appear to be recombination
“linked.” For example, in Mendel’s study of pea plants, curly leaves were
always found with pink flowers, even though the genes for curly leaves and Fig. 1.1.6 Genetic Recombination by Crossing Over. Two copies of a chromosome
pink flowers are located at distinct loci. These traits are linked, because the are copied by DNA replication. During meiosis, pairing of homologous
curly leaf gene and the pink-flower gene are located close to each other chromosomes occurs, which enables a crossover between chromosomes to take
on a chromosome, and a recombination event only rarely occurs between place. During cell division, the recombined chromosomes separate into individual
them. Recombination and linkage are the fundamental concepts behind daughter cells.
genetic linkage analysis.
particular gene is mutated, the protein product might not be produced,
MUTATIONS or it might be produced but function poorly or even pathologically (dom-
inant negative effect). Point mutations (the substitution of a single base
Mutations are changes in the gene DNA sequence that result in a bio- pair) are the most common mutations encountered in human genetics. 3
logically significant change in the function of the encoded protein. If a Missense mutations are point mutations that cause a change in the amino
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Fig. 1.1.7 Reciprocal GENES AND PHENOTYPES
1 RECIPROCAL TRANSLOCATION Translocation Between
Two Chromosomes. The
Philadelphia chromosome
The relationship between genes and phenotypes is complex. More than
one genetic defect can lead to the same clinical phenotype (genetic het-
(responsible for chronic erogeneity), and different phenotypes can result from the same genetic
Genetics
normal 9 der (9) myelogenous leukemia) is

defect (variable expressivity). Retinitis pigmentosa is an excellent example
shown as an example of
a reciprocal chromosomal
of genetic heterogeneity, as it may be inherited as an X-linked, autosomal
translocation that results dominant, autosomal recessive, or digenic trait, and more than 200 caus-
in an abnormal gene ative genes have been identified.23 Other ocular disorders that are geneti-
product responsible for cally heterogeneous include congenital cataract, glaucoma, and age-related
a clinical disorder. In this macular degeneration. Different genes may contribute to a common phe-
case an exchange occurs notype because they affect different steps in a common pathway. Under-
between the long arm of standing the role of each gene in the disease process can help define the
chromosome 9 and the cellular mechanisms that are responsible for the disease.
normal 22 der (22) long arm of chromosome For many genes, a single mutation that alters a critical site in the
22. protein results in an abnormal phenotype. For some diseases, the resulting
phenotypes are remarkably similar regardless of the nature of the muta-
tion. For example, a wide variety of mutations in RB1 cause retinoblas-
toma. Other diseases, however, exhibit variable expressivity, in which an
individual’s mutation may be responsible for severe disease, mild disease,
or disease that is not clinically detectable (incomplete penetrance). There
are many examples of ocular disease demonstrating variable expressivity,
including Kjer’s autosomal dominant optic atrophy,24 Axenfeld–Rieger syn-
drome,25 and aniridia.26
Different mutations in the same gene can also result in different pheno-
acid sequence of the polypeptide chain. The severity of the missense muta- types (allelic heterogeneity). Allelic heterogeneity accounts for the different
tion is dependent on the chemical properties of the switched amino acids phenotypes of dominant corneal stromal dystrophies caused by mutations
and on the importance of a particular amino acid in the function of the in the TGFB1/BIGH3.27 The phenotypic expression of a mutation may
mature protein. Point mutations also may decrease the level of polypep- depend on its location within a gene. Such variable expressivity based on
tide production because they interrupt the promoter sequence, splice site the location of the mutation is exemplified by mutations in the rds gene,
sequences, or create a premature stop codon. which may cause typical autosomal dominant retinitis pigmentosa or
Gene expression can be affected by the insertion or deletion of large macular dystrophy depending on the position of the genetic defect.28
blocks of DNA sequence. These types of mutations are less common than
point mutations but may result in a more severe change in the activity
of the protein product. A specific category of insertion mutations is the
PATTERNS OF HUMAN INHERITANCE
expansion of trinucleotide repeats found in patients affected by certain The most common patterns of human inheritance are autosomal domi-
neurodegenerative disorders. An interesting clinical phenomenon, “antic- nant, autosomal recessive, X-linked recessive, and mitochondrial. Fig. 1.1.8
ipation,” was understood on a molecular level with the discovery of trinu- shows examples of these four inheritance patterns. Other inheritance pat-
cleotide repeats as the cause of myotonic dystrophy.16 Frequently, offspring terns less commonly encountered in human disease include X-linked dom-
with myotonic dystrophy were affected more severely and at an earlier inant, digenic inheritance (polygenic), pseudodominance, and imprinting.
age than their affected parents and grandparents. Examination of the Fig. 1.1.9 defines the notation and symbols used in pedigree construction.
disease-causing trinucleotide repeat in affected pedigrees demonstrated
that the severity of the disease correlated with the number of repeats found Autosomal Dominant
in the myotonic dystrophy gene in affected individuals. This phenomenon
has been observed in a number of other diseases, including Huntington’s A disease-causing mutation that is present in only one of the two gene
disease.17 copies at an autosomal locus (heterozygous) is a dominant mutation. For
Chromosomal rearrangements may result in breaks in specific genes that example, a patient with dominant retinitis pigmentosa will have a defect in
cause an interruption in the DNA sequence. Usually, the break in DNA one copy of one retinitis pigmentosa gene inherited from one parent who,
sequence results in a truncated, unstable, dysfunctional protein product. in most cases, is also affected by retinitis pigmentosa. The other copy of
Occasionally, the broken gene fuses with another gene to cause a “fusion that gene, the one inherited from the unaffected parent, is normal (wild
polypeptide product,” which may have a novel activity in the cell. Often, type). Affected individuals have a 50% chance of having affected siblings
such a novel activity results in an abnormality in the function of the and a 50% chance of passing the abnormal gene to their offspring; 50% of
cell. An example of such a fusion protein is the product of the chromo- children of an affected individual will be affected. For a dominant disease,
some 9;22 translocation that is associated with many cases of leukemia males and females transmit the disease equally and are affected equally.
(Fig. 1.1.7).18,19 True dominant alleles produce the same phenotype in the heterozy-
A set consisting of one of each autosome as well as an X or a Y chro- gous and homozygous states. In humans, most individuals affected by
mosome is called a haploid set of chromosomes. The normal complement a disease caused by a dominant allele are heterozygous, but occasionally
of two copies of each gene (or two copies of each chromosome) is called homozygous mutations have been described. In cases where the homozy-
diploidy. Rarely, as a result of abnormal chromosome separation during gous individual is more severely affected than the heterozygous individual,
cell division, a cell or organism may have three copies of each chromo- the disease is more appropriately noted to be inherited as a semidomi-
some, which is called triploidy. A triploid human is not viable, but some nant trait. For example, alleles in the PAX3 gene, causing Waardenburg’s
patients have an extra chromosome or an extra segment of a chromosome. syndrome, are semidominant, because a homozygote with more severe
In such a situation, the abnormality is called trisomy for the chromosome disease compared with their heterozygote relatives has been described.29
involved. For example, patients with Down syndrome have three copies of In some pedigrees with an autosomal dominant disease, some indi-
chromosome 21, also referred to as trisomy 21.20 viduals who carry the defective gene do not have the affected phenotype.
If one copy of a pair of chromosomes is absent, the defect is called However, these individuals can still transmit the disease gene to offspring
haploidy. Deletions of the X chromosome are frequently the cause of and have affected children. This phenomenon is called reduced pene-
Duchenne’s muscular dystrophy.21 trance. The gene responsible for retinoblastoma (RB1) is only 90% pene-
Polymorphisms are changes in DNA sequence that don’t have a signif- trant, which means that 10% of the individuals who inherit a mutant copy
icant biological effect. These DNA sequence variants may modify disease of the gene do not develop the tumor.30
processes, but alone are not sufficient to cause disease. Human DNA
sequence is highly variable and includes single nucleotide polymorphisms Autosomal Recessive
(SNPs), microsatellite repeat polymorphisms (20–50 bp repeats of CA or
4 GT sequence), variable number of tandem repeat polymorphisms (VNTR, Diseases that require both copies of a gene to be abnormal for development
repeats of 50–100 bp of DNA), or larger insertion deletions.22 are inherited as recessive traits. Heterozygous carriers of mutant genes are
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Fig. 1.1.8 Patterns of Inheritance. For pedigrees with
PATTERNS OF INHERITANCE an autosomal dominant trait, panel 1 shows inheritance
that originates from a previous generation, panel 1.1
Pedigrees with an autosomal dominant trait 2 shows segregation that originates in the second
generation of this pedigree, and panel 3 shows an

Generation apparent “sporadic” case, which is actually a new
I 1 2 3 mutation that arises in the most recent generation.
This mutation has a 50% chance of being passed to
II offspring of the affected individual. For pedigrees with
an autosomal recessive trait, panel 1 shows an isolated
III affected individual in the most recent generation
(whose parents are obligatory carriers of the mutant
Pedigrees with an autosomal recessive trait gene responsible for the condition), panel 2 shows a
pair of affected siblings whose father is also affected
(for the siblings to be affected, the mother must be
I 1 2 3
an obligate carrier of the mutant gene), and panel 3
II shows an isolated affected individual in the most recent
generation who is a product of a consanguineous
III marriage between two obligate carriers of the mutant
gene. For pedigrees with an X-chromosomal trait,
IV panel 1 shows an isolated affected individual whose
disease is caused by a new mutation in the gene
Pedigrees with an X-chromosomal inheritance responsible for this condition, panel 2 shows an isolated
individual who inherited a mutant copy of the gene
from the mother (who is an obligate carrier), and panel
I 1 2 3 3 shows segregation of an X-linked trait through a
multigeneration pedigree (50% of the male offspring are
II affected, and their mothers are obligate carriers of the
disease). For pedigrees with a mitochondrial trait, the
III
panel shows a large, multigeneration pedigree—men
IV and women are affected, but only women have affected
offspring.
V
Pedigrees with a mitochondrial trait
II
III
IV
affected affected unaffected unaffected male, gene unaffected unaffected female, gene
male female male carrier (heterozygous) female carrier (heterozygous)
usually clinically normal. The same recessive defect might affect both gene gene, he will be affected. If a daughter inherits the defective gene, she
copies, in which case the patient is said to be a homozygote. Different reces- will be a carrier. An important characteristic of X-linked recessive disor-
sive defects might affect the two gene copies, in which case the patient is a ders is that males never transmit the disease to sons directly (male-to-male
compound heterozygote. In a family with recessive disease, both parents are transmission).
unaffected carriers, each having one wild-type gene (allele) and one mutant Usually female carriers of an X-linked disease gene do not have any
gene (allele). Each parent has a 50% chance of transmitting the defective clinical evidence of the disease. However, for some X-linked diseases, mild
allele to a child. Because a child must receive a defective allele from both clinical features can be found in female carriers. For example, in X-linked
parents to be affected, each child has a 25% chance of being affected (50% retinoschisis, affected males are severely affected, whereas carrier females
× 50% = 25%), and 50% of the offspring will be carriers of the disease. If have a visually insignificant but clinically detectable retinal abnormality.31
the parents are related, they may be carriers of the same rare mutations, Mild phenotypic expression of the disease gene can be caused by the
and there is a greater chance that a recessive disease can be transmitted process of lyonization. In order for males (with one X chromosome) and
to offspring. Males and females have an equal chance of transmitting and females (with two X chromosomes) to have equal levels of expression of
inheriting the disease alleles. X-linked genes, female cells express genes from only one of their two X
chromosomes. The decision as to which X chromosome is expressed is
X-Linked Recessive made early in embryogenesis, and the line of descending cells faithfully
adheres to the early choice. As a result, females are mosaics, with some
Mutations of the X chromosome produce distinctive inheritance patterns, cells in each tissue expressing the maternally derived X chromosome and
because males have only one copy of the X chromosome and females the remainder expressing the paternally derived X chromosome. When
have two. Most X-linked gene defects are inherited as X-linked recessive one of the X chromosomes carries an abnormal gene, the proportion
traits. Carrier females are typically unaffected because they have both a of cells that express the mutant versus the normal gene in each tissue
normal copy and a defective copy of the disease-associated gene. Carrier can vary.
males are affected because they only have one defective X chromosome Females can also be affected by an X-linked recessive disease if the
and they do not have a normal gene copy to compensate for the defec- father is affected and the mother coincidentally is a carrier of a mutation
tive copy. All of the daughters of an affected male will be carriers of the in the disease gene. In this case, 50% of daughters would be affected,
disease gene because they will inherit the defective X chromosome. None because 50% would inherit the X chromosome from the mother carrying
of the sons of an affected male will be affected or be carriers because the disease gene, and all the daughters would inherit the X chromosome
they will inherit the Y chromosome. Each child of a carrier female has a from the father carrying the disease gene. Because most X-linked disorders 5
50% chance of inheriting the disease gene. If a son inherits the defective are rare, the carrier frequency of disease genes in the general population is
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X-Linked Dominant Inheritance
1 or
BASIC PEDIGREE NOTATION
normal female fraternal twins

This inheritance pattern is similar to X-linked recessive inheritance, except
that all females who are carriers of an abnormal gene on the X chromo-
(not identical) some are affected rather than unaffected. All of the male offspring are also
Genetics
affected. Incontinentia pigmenti is probably inherited as an X-linked dom-

or normal male
identical twins inant trait. Affected females have irregularly pigmented atrophic scars on
the trunk and the extremities and congenital avascularity in the peripheral
single bar retina with secondary retinal neovascularization.34 This and other X-linked
number of children
indicates mating 2 6 for each sex dominant disorders occur almost always in females, and it is likely that the
X chromosome gene defects causing these diseases are embryonic lethals
normal parents and darkened square or
normal offspring, two when present in males.
I circle means affected
girls and a boy, in individual; arrow (when
II birth order indicated or present) indicates the Digenic Inheritance and Polygenic Inheritance
by the numbers; I and affected individual is
1 2 3 Digenic inheritance occurs when a patient has heterozygous defects in
II indicate generations propositus, the begin-
ning of the analysis two different genes, and the combination of the two gene defects causes
single parent as disease. Individuals who have a mutation in only one of the genes are
presented means normal. Digenic inheritance is different from recessive inheritance,
partner is normal autosomal heterozygous
and because the two mutations involve different disease genes. In some retini-
or of no significance recessive
tis pigmentosa families, mutation analysis of the peripherin gene and the
to the analysis
X-linked carrier ROM1 gene showed that the affected individuals harbor specific mutations
in both genes. Individuals with a mutation in only one copy of either gene
double bar indicates dead
and were unaffected by the disease.35 Triallelic inheritance has been described
a consanguineous union
(mating between in some families affected by Bardet–Biedl syndrome (BBS). In these pedi-
close relatives) aborted or stillborn grees, affected individuals carry three mutations in one or two BBS genes
(12 BBS genes have been identified),36 and unaffected individuals have only
two abnormal alleles. In some families, it has been proposed that BBS may
not be a single-gene recessive disease but a complex trait requiring at least
Fig. 1.1.9 Basic Pedigree Notation. Typical symbols used in pedigree construction three mutant alleles to manifest the phenotype. This would be an example
are defined. of triallelic inheritance.37
If the expression of a heritable trait or predisposition is influenced by
the combination of alleles at three or more loci, it is polygenic. Because
low, and the chance that a carrier female would mate with a male affected of the complex inheritance, conditions caused by multiple alleles do not
by the same disease is quite low. demonstrate a simple inheritance pattern. These complex traits may also
be influenced by environmental conditions. Examples of phenotypes in
Mitochondrial Inheritance ophthalmology that exhibit complex inheritance because of contributions
of multiple genes and environmental factors are myopia,38 age-related
Mitochondria are small organelles located in the cytoplasm of cells. They macular degeneration,39 and adult-onset open-angle glaucoma.40
function to generate ATP for the cell and are most abundant in cells that
have high energy requirements, such as muscle and nerve cells. Mito- Imprinting
chondria have their own small chromosome—16,569 bp of DNA encoding
for 13 mitochondrial proteins, 2 ribosomal RNAs, and 22 tRNAs. Muta- Some mutations give rise to autosomal dominant traits that are transmitted
tions occurring in genes located on the mitochondrial chromosome cause by parents of either sex, but they are expressed only when inherited from a
a number of diseases, including Leber’s hereditary optic atrophy32 and parent of one particular sex. In families affected with these disorders, they
Kearns–Sayre syndrome.33 Mutations occurring on the mitochondrial chro- would appear to be transmitted in an autosomal dominant pattern from
mosome are inherited only from the mother because virtually all human one parent (either the mother or the father) and would not be transmitted
mitochondria are derived from the maternal egg. Fathers do not transmit from the other parent. Occasionally, the same mutation gives rise to a dif-
mitochondria to their offspring. ferent disorder depending on the sex of the parent transmitting the trait.
Cells vary in the number of mitochondria they contain, and when These parental sex effects are evidence of a phenomenon called imprinting.
cells divide, the mitochondria are divided randomly. As a result, different Although the molecular mechanisms responsible for imprinting are not
cells can have varying numbers of mitochondria, and if a fraction of the completely understood, it appears to be associated with DNA methylation
mitochondria contain a mutated gene, different cells will have a varying patterns that can mark certain genes with their parental origin.41
proportion of healthy versus mutant mitochondria. The distribution of
mutant mitochondria is called heteroplasmy, and the proportion of mutant
mitochondria can vary from cell to cell and can also change with age. Dif-
MOLECULAR MECHANISMS OF DISEASE
ferences in the relative proportions of mutant mitochondria can partly Autosomal Dominant
explain the observed variable severity of mitochondrial diseases and also
the variable age of onset of mitochondrial diseases. Disorders inherited as autosomal dominant traits result from mutations
that occur in only one copy of a gene (i.e., in heterozygous individuals).
Pseudodominance Usually, the parental origin of the mutation does not matter. However, if
the gene is subject to imprinting, then mutations in the maternal or pater-
This term describes an apparent dominant inheritance pattern due to reces- nal copy of the gene may give rise to different phenotypes.
sive defects in a disease gene. This situation arises when a parent affected
by a recessive disease (two abnormal copies of the disease gene) has a Haploinsufficiency
spouse who is a carrier of one abnormal copy of the disease gene. Children Under normal circumstances, each copy of a gene produces a protein
from this couple will always inherit a defective gene copy from the affected product. If a mutation occurs such that one copy of a gene no longer pro-
parent and will have a 50% chance of inheriting the defective gene copy duces a protein product, then the amount of that protein in the cell has
from the unaffected carrier parent. On average, half of the children will been reduced by half. Mutations that cause a reduction in the amount of
inherit two defective gene copies and will be affected. The pedigree would protein or lead to inactivation of the protein are called loss-of-function muta-
mimic a dominant pedigree because of apparent direct transmission of the tions. For many cellular processes, this reduction in protein quantity does
disease from the affected parent to affected children and because approxi- not have consequences, i.e., the heterozygous state is normal, and these
mately 50% of the children will be affected. Pseudodominant transmission mutations may be inherited as recessive traits (see later section). However,
6 is uncommon, because few people are asymptomatic carriers for any par- for some cellular processes there is an absolute requirement for the full
ticular recessive gene. dosage of protein product, which can only be furnished if both copies of
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a particular gene are active. Diseases that are caused by inheritance of a
GENE THERAPY USING A RETROVIRUS VECTOR
single mutation reducing the protein level by half are inherited as domi-
nant traits. 1.1
Therapeutic gene engineered into retrovirus DNA
Gain-of-Function Dominant Negative Effect

retrovirus
Autosomal dominant disorders can be caused by mutant proteins that
have a detrimental effect on the normal tissue. Mutations in one copy of a
gene may produce a mutant protein that can accumulate as a toxic product therapeutic
or in some other way interfere with the normal function of the cell. The human gene
mutant protein may also interfere with the function of the normal protein
expressed by the remaining normal copy of the gene, thus eliminating any Recombinant virus replicates in a packaging cell
normal protein activity. It is possible to have gain-of-function mutations
that can also be dominant negative because the new function of the protein replace retroviral genes
with therapeutic human gene
also interferes with the function of the remaining normal copy of the gene.
packaging cell
Autosomal and X-Linked Recessive
Recessive disorders result from mutations present on both the maternal
and paternal copies of a gene. Mutations responsible for recessive disease
typically cause a loss of biological activity, either because they create a
defective protein product that has little or no biological activity or because
they interfere with the normal expression of the gene (regulatory muta-
unpackagable virions
tions). Most individuals heterozygous for recessive disorders, both autoso-
mal and X-linked, are clinically normal. helper provirus
GENE THERAPY
Mutations in the DNA sequence of a particular gene can result in a protein
Replicated recombinant virus infects the target cell and inserts copies of the therapeutic gene
product that is not produced, works poorly, or has acquired a novel func-
tion that is detrimental to the cell. Gene-based therapies can involve deliv-
ery of a normal gene to disease tissue, replacing or augmenting protein
activity with other proteins or small molecules, decreasing abnormal gene
expression, or genome-editing techniques to repair the mutation. Thera- RNA
peutic genes can be delivered to specific tissues using modified viruses as reverse
transcription
vectors42 (Fig. 1.1.10). A successful example of this approach is the resto-
ration of vision in a canine model of Leber’s congenital amaurosis using a DNA human
recombinant adeno-associated virus carrying the normal gene (RPE65).43 target cell
Human trials using a similar approach also successfully restored vision in
patients with RPE65 mutations.44 therapeutic
gene product
Diseases caused by mutations that create a gene product that is
destructive to the cell (dominant negative or gain of function mutations)
need to be treated using a different approach. In these cases, genes or nucleus
oligonucleotides—in particular antisense molecules—that can reduce
expression of the mutated gene are introduced into the cell.45 Gene editing
using CRISPR/Cas9 (Fig. 1.1.11) is another potentially useful approach for
gain of function or loss of function mutations.46 Recent advances have pro- Fig. 1.1.10 Gene Therapy Using a Retrovirus Vector. A therapeutic gene is
duced highly potent in vivo gene therapy vectors for targeting retina.47 In engineered genetically into the retrovirus DNA and replaces most of the viral DNA
addition, new methods are emerging to introduce therapeutic genes into sequences. The “recombinant virus” that carries the therapeutic gene is allowed to
damaged tissue using nonviral mechanisms based on nanotechnology.48 replicate in a special “packaging cell“ that also contains normal virus that carries the
genes required for viral replication. The replicated recombinant virus is allowed to
infect the human diseased tissue, or “target cell.“ The recombinant virus may invade
the diseased tissue but cannot replicate or destroy the cell. The recombinant virus
inserts copies of the normal therapeutic gene into the host genome and produces
the normal protein product.
booksmedicos.org
1 GENE EDITING USING CRISPR/cas 9
Genetics
target nucleus
mutation: T2929C PAM
CGACAGGAAT T TGCAGGT
T A
5’ T G A T G A T G A T T T T G AG ACC A AC T GG AC T G T GGGG AG AGGG AG AG A A ACC A T ACC A T GG ACC T T C 3’
3’ AC T AC T AC T A A A AC T C T GG T T G ACC T G AC ACCCC T C T CCC T C T C T T T GG T A T GG T ACC T GG A AG 5’

A T
GCTGTCCT T AAACGTCCA
5’ U A GUUUUAGAGCUA G
guide CGACAGGAAUUUGCAGGU A
AA
A
GUUCAACUAUUGCCUGAUCGGAAUAAAAU CGAU sgRNA scaffold
U A
A GA
A
AAAGUGGCACCGA
G
3’ UUUUCGUGGCU
DSB repair
NHEJ HDR
C TGGAC TG T CGAC AGGA A T T TGC AGGG T A AC TGC T A TGGGGAGAGGGAGAGA A ACC A T AC A T T T TGAGACC A AC TGGAC TG T CGAC AGGA A T T TGC AG G T A TGGGGAGAGGGA
GACC TGAC AGC TG T CC T T A A ACG T CCC A T TGACGA T ACCCC T C T CCC T C T C T T TGG T A TG T A A A AC T C TGG T TGACC TGAC AGC TGT CC T T A A ACG T C C A T ACCCC T C T CCC T
GAC TG T CGAC AGGA A T T TGC AGGACCG T CCG T C A AC T T A TGGGGAGAGGGAGAGA A ACC A T TGAGACC A AC TGGAC TG T CGAC AGGA A T T TGC AGG T A TGGGGAGAGGGAGAGA A A
C TGAC AGC TG T CC T T A A ACG T CC TGGC AGGC AG T TGA A T ACCCC T C T CCC T C T C T T TGG T A AC T C TGG T TGACC T A AC AGC TG T CC T T A A ACG T CC A T ACCCC T C T CCC T C T C T T T
insertions donor template

GAGACC A AC TGGAC TG T CGAC AGGA A T T T - - - - - T A TGGGGAGAGGGAGAGA A ACC A T ACC
C T C TGG T TGACC TGAC AGC TG T CC T T A A A - - - - - A T ACCCC T C T CCC T C T C T T TGG T A TGG A T T T TGAGACC A AC TGGAC TG T CGAC AGGAAT T TGCAG GTGGGGAGAGGGAGAGA A ACC
T A A A AC T C TGG T TGACC TGAC AGC TGT CC T CCCC T C T CCC T C T C T T TGG

GAGACC A AC TGGAC TG T CGAC AGGA A - - - - - - - - - A TGGGGAGAGGGAGAGA A ACC A T ACC A
GGAT TGTCGACAGGAAT T TGC AGG T A
C T C TGG T TGACC TGAC AGC TG T CC T T - - - - - - - - - T ACCCC T C T CCC T C T C T T TGG T A TGG T T
T TGAGACC A AC A A ACG TGGA T GGGGAGAGGGAGAGA A ACC
deletions
A AC T C TGG T TGACCTAACAGCTGTCCT TAAACGTCCATACCCC T C T CCC T C T C T T TGG
A T T T TGAGACC A AC TGGA T TG T CGAC AGGA A T T TGC AGG T A TGGGGAGAGGGA
T A A A AC T C TGG T TGACC T A AC AGC TGT CC T T A A ACG T CC A T ACCCC T C T CCC T
precise repair
Fig. 1.1.11 Gene Editing Using CRISPR/Cas9. The CRISPR/Cas-DNA binding creates a double-stranded DNA break (DSB), which can be repaired through nonhomologous
end joining (NHEJ) or homology directed repair (HDR) pathways. Here, the Streptococcus pyogenes Cas9 nuclease, with a “NGG” protospacer adjacent motif (PAM) sequence,
has been directed to target the region containing the BEST1 c929T > C (Ile310Thr) mutation. The guide RNA is complementary to the non-PAM strand, and the DNA cut site
is three nucleotides from the PAM sequence. Double strand DNA breaks typically undergo repair by NHEJ, which results in deletions and insertions of variable length. DNA
nicks are generally repaired through HDR, where a donor template can be used to incorporate precise genomic modifications. (Adapted from Hung SS, McCaughey T, Swann
O, et al. Genome engineering in ophthalmology: application of CRISPR/Cas to the treatment of eye disease. Prog Retin Eye Res 2016;53:1–20.)
KEY REFERENCES Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and
refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5.
1000 Genomes Project Consortium. A map of human genome variation from population-scale Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s
sequencing. Nature 2010;467:1061–73. congenital amaurosis. N Engl J Med 2008;358:2240–8.
Bailey JN, Loomis SJ, Kang JH, et al. Genome-wide association analysis identifies TXNRD2, Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2 are
ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. Nat Genet associated with primary open-angle glaucoma. Nat Genet 2010;42:906–9.
2016;48(2):189–94. Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated
Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet
J Med 2010;363(11):1016–24. 2012;8(4):e1002654.
Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of
age-related macular degeneration. Science 2005;308:419–21.
Han J, Thompson-Lowrey AJ, Reiss A, et al. OPA1 mutations and mitochondrial DNA haplo- Access the complete reference list online at ExpertConsult.com
types in autosomal dominant optic atrophy. Genet Med 2006;8:217–25.
8
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REFERENCES 24. Han J, Thompson-Lowrey AJ, Reiss A, et al. OPA1 mutations and mitochondrial DNA
haplotypes in autosomal dominant optic atrophy. Genet Med 2006;8:217–25.
1. Watson JD, Crick FHC. Molecular structure of nucleic acids: a structure for deoxyribose
nucleic acid. Nature 1953;171:737–8.
25. Hjalt TA, Semina EV. Current molecular understanding of Axenfeld–Rieger syndrome.
Expert Rev Mol Med 2005;7:1–17.
1.1
2. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011;12(12):861–74. 26. Vincent MC, Gallai R, Olivier D, et al. Variable phenotype related to a novel PAX 6 muta-
tion (IVS4+5G>C) in a family presenting congenital nystagmus and foveal hypoplasia.

3. Wolfsberg TG, McEntyre J, Schuler GD. Guide to the draft human genome. Nature
2001;409:824–6. Am J Ophthalmol 2004;138:1016–21.
4. Murray JC, Buetow KH, Weber JL, et al. A comprehensive human linkage map with centi- 27. Schmedt T, Silva MM, Ziaei A, et al. Molecular bases of corneal endothelial dystrophies.
morgan density. Cooperative Human Linkage Center (CHLC). Science 1994;265:2049–54. Exp Eye Res 2012;95:24–34.
5. The International HapMap Consortium. The International HapMap Project. Nature 28. Stuck MW, Conley SM, Naash MI. RDS functional domains and dysfunction in disease.
2003;426:789–96. Adv Exp Med Biol 2016;854:217–22.
6. 1000 Genomes Project Consortium. A map of human genome variation from popula- 29. Wollnik B, Tukel T, Uyguner O, et al. Homozygous and heterozygous inheritance of
tion-scale sequencing. Nature 2010;28:1061–73. PAX3 mutations causes different types of Waardenburg syndrome. Am J Med Genet A
7. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk 2003;122:42–5.
of age-related macular degeneration. Science 2005;308:419–21. 30. Harbour JW. Molecular basis of low-penetrance retinoblastoma. Arch Ophthalmol
8. Seddon JM, Yu Y, Miller EC, et al. Rare variants in CFI, C3 and C9 are associated with 2001;119:1699–704.
high risk of advanced age-related macular degeneration. Nat Genet 2013;45(11):1366–70. 31. Sikkink SK, Biswas S, Parry NR, et al. X-linked retinoschisis: an update. J Med Genet
9. Fritsche LG, Igl W, Bailey JN, et al. A large genome-wide association study of age-related 2007;44:225–32.
macular degeneration highlights contributions of rare and common variants. Nat Genet 32. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve.
2016;48(2):134–43. Am J Ophthalmol 2005;140:517–23.
10. Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and 33. Schmiedel J, Jackson S, Schafer J, et al. Mitochondrial cytopathies. J Neurol 2003;250:
refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5. 267–77.
11. Verhoeven VJ, Hysi PG, Wojciechowski R, et al. Genome-wide meta-analyses of multian- 34. Shields CL, Eagle RC Jr, Shah RM, et al. Multifocal hypopigmented retinal pigment epi-
cestry cohorts identify multiple new susceptibility loci for refractive error and myopia. thelial lesions in incontinentia pigmenti. Retina 2006;26:328–33.
Nat Genet 2013;45(3):314–18. 35. Kajiwara K, Berson EL, Dryja TP. Digenic retinitis pigmentosa due to mutations at the
12. Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2 unlinked peripherin/RDS and ROM1 loci. Science 1994;264:1604–8.
are associated with primary open-angle glaucoma. Nat Genet 2010;42:906–9. 36. Sheffield VC. The blind leading the obese: the molecular pathophysiology of a human
13. Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associ- obesity syndrome. Trans Am Clin Climatol Assoc 2010;121:172–81.
ated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 37. Eichers ER, Lewis RA, Katsanis N, et al. Triallelic inheritance: a bridge between Mende-
2012;8(4):e1002654. lian and multifactorial traits. Ann Med 2004;36:262–72.
14. Bailey JN, Loomis SJ, Kang JH, et al. Genome-wide association analysis identifies 38. Hornbeak DM, Young TL. Myopia genetics: a review of current research and emerging
TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma. trends. Curr Opin Ophthalmol 2009;20:356–62.
Nat Genet 2016;48(2):189–94. 39. Deangelis MM, Silveira AC, Carr EA, et al. Genetics of age-related macular degeneration:
15. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. current concepts, future directions. Semin Ophthalmol 2011;26:77–93.
N Engl J Med 2010;363:1016–24. 40. Wiggs JL, Pasquale LR. Genetics of glaucoma. Hum Mol Genet 2017;26(R1):R21–7.
16. Lindblad K, Schalling M. Expanded repeat sequences and disease. Semin Neurol 41. Lewis A, Reik W. How imprinting centres work. Cytogenet Genome Res 2006;113:81–9.
1999;19:289–99. 42. Bennett J, Chung DC, Maguire A. Gene delivery to the retina: from mouse to man.
17. Lee JM, Ramos EM, Lee JH, et al. CAG repeat expansion in Huntington disease deter- Methods Enzymol 2012;507:255–74.
mines age at onset in a fully dominant fashion. Neurology 2012;78:690–5. 43. Acland GM, Aguirre GD, Ray J, et al. Gene therapy restores vision in a canine model of
18. Kato T, Kurahashi H, Emanuel BS. Chromosomal translocations and palindromic AT-rich childhood blindness. Nat Genet 2001;28:92–5.
repeats. Curr Opin Genet Dev 2012;22(3):221–8. 44. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s
19. Vladareanu AM, Müller-Tidow C, Bumbea H, et al. Molecular markers guide diagno- congenital amaurosis. N Engl J Med 2008;358:2240–8.
sis and treatment in Philadelphia chromosome-negative myeloproliferative disorders 45. Pelletier R, Caron SO, Puymirat J. RNA based gene therapy for dominantly inherited
(Review). Oncol Rep 2010;23:595–604. diseases. Curr Gene Ther 2006;6:131–46.
20. Roubertoux PL, Kerdelhue B. Trisomy 21: from chromosomes to mental retardation. 46. Hung SS, McCaughey T, Swann O, et al. Genome engineering in ophthalmology: appli-
Behav Genet 2006;36:346–54. cation of CRISPR/Cas to the treatment of eye disease. Prog Retin Eye Res 2016;53:
21. Soltanzadeh P, Friez MJ, Dunn D, et al. Clinical and genetic characterization of mani- 1–20.
festing carriers of DMD mutations. Neuromuscul Disord 2010;20:499–504. 47. Zinn E, Pacouret S, Khaychuk V, et al. In silico reconstruction of the viral evolutionary
22. Little PF. Structure and function of the human genome. Genome Res 2005;15:1759–66. lineage yields a potent gene therapy vector. Cell Rep 2015;12(6):1056–68.
23. Daiger SP, Sullivan LS, Bowne SJ. Genes and mutations causing retinitis pigmentosa. 48. Vasir JK, Labhasetwar V. Polymeric nanoparticles for gene delivery. Expert Opin Drug
Clin Genet 2013;84(2):132–41. Deliv 2006;3:325–44.
8.e1
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Part 1 Genetics

Molecular Genetics of Selected

Ocular Disorders 1.2
Janey L. Wiggs
trichrome and have been termed “hyalin.” In lattice dystrophy, branching

Definition: The molecular mechanisms underlying selected inherited amyloid deposits gradually opacify the visual axis. These deposits exhibit a
eye disorders as defined by the responsible genetic mutations. characteristic birefringence under polarized light after staining with Congo
red. Avellino dystrophy includes features of both granular and lattice dys-
trophies. Reis–Bücklers dystrophy appears to involve primarily Bowman’s
layer and the superficial stroma.
Key Features All four dystrophies were mapped genetically to a common interval on
• Inherited disorders affecting the ocular anterior segment. chromosome 5q31, and mutations in a single gene, TGFB1 (also known
• Genetic defects causing abnormal ocular development. as BIGH3), located in this region were found in affected individuals.2 The
• Inherited retinal degenerations. product of this gene, keratoepithelin, is probably an extracellular matrix
• Retinoblastoma. protein that modulates cell adhesion. Four different missense mutations,
• Disorders involving the optic nerve and extraocular muscles. which occur at two arginine codons in the gene, have been found (Fig.
1.2.1). Interestingly, mutations at one of these arginine codons cause lattice
dystrophy type I or Avellino dystrophy, the two dystrophies characterized
by amyloid deposits. Mutations at the other arginine codon appear to result
INTRODUCTION in either granular dystrophy or Reis–Bücklers dystrophy. The mutation
analysis of this gene demonstrates that different mutations within a single
Tremendous advances in the molecular genetics of human disease have gene can result in different phenotypes.
been made in the past 20 years. Many genes responsible for inherited The mutation that causes Avellino and lattice dystrophies abolishes a
eye diseases have been isolated and characterized, and the chromosomal putative phosphorylation site, which probably is required for the normal
location of a number of additional genes has been determined. Identify- structure of keratoepithelin. Destruction of this aspect of the protein struc-
ing and characterizing genes responsible for human disease has led to ture leads to formation of the amyloid deposits that are responsible for
DNA-based methods of diagnosis; novel therapeutic approaches, including opacification of the cornea. Consequently, the mutant protein is destructive
gene therapy; and improved knowledge about the molecular events that to the normal tissue. Mutations at the R555 (arginine at amino acid posi-
underlie the disease processes. The disorders discussed in this chapter tion 555) appear to result in either granular dystrophy or Reis–Bücklers
represent important examples of major advances in human ocular molec- dystrophy. These phenotype–genotype correlations demonstrate the vari-
ular genetics. able expressivity of mutations in this gene and the significance of alter-
Although all inherited disorders are the result of gene mutations, the ation of the arginine residues 124 and 555.
molecular consequences of a mutation are quite variable. The type of
mutation responsible for a disease usually defines the inheritance pattern.
For example, mutations that create an abnormal protein detrimental to the ANIRIDIA, PETER’S ANOMALY, AUTOSOMAL
cell are typically autosomal dominant, because only one mutant gene is
required to disrupt normal cell function. Mutations that result in proteins
DOMINANT KERATITIS
that have reduced biological activity (loss of function) may be inherited as Some cellular processes require a level of protein production that results
autosomal dominant or autosomal recessive conditions, depending on the from the expression of both copies of a particular gene. Such proteins
number of copies of normal genes (and the amount of normal protein) may be involved in a variety of biological processes. Certain disorders are
required. Disorders may be caused by mutations in mitochondrial DNA caused by the disruption of one copy of a gene that reduces the protein
that result in a characteristic maternal inheritance pattern. Also, mutations level by half. Such a reduction is also called “haploinsufficiency.”
in genes carried on the X chromosome result in characteristic inheritance
patterns.
KERATOEPITHEILIN GENE
DOMINANT CORNEAL DYSTROPHIES
The autosomal dominant corneal dystrophies are an excellent example of recognition
dominant negative mutations that result in the formation of a toxic protein. sequence for
secretory homologous
Four types of autosomal dominant dystrophies that affect the stroma of the integrins
signal domains
cornea are well characterized1:
D1 D2 D3 D4
• Groenouw (granular) type I.
• Lattice type I.
• Avellino (combined granular-lattice).
• Reis–Bücklers.
Arg124 Cys (lattice type 1) Arg 555 Trp (Groenouw 2)
Although all four corneal dystrophies affect the anterior stroma, the Arg 124 His (Avellino) Arg 555 Glu (Reis—Bücklers dystrophy)
clinical and pathological features differ. The granular dystrophies typically
form discrete, white, localized deposits that may obscure vision progres- Fig. 1.2.1 Keratoepithelin Gene. Arrows point to the location of the reported 9
sively. Histopathologically, these deposits stain bright red with Masson mutations.
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1 PAX6 GENE MYOCILIN/TIGR PROTEIN GENE
Schematic gene structure

Genetics
ATG 5a TAA 368

leucine zipper
364
437
347 504aa
1 32 117 169
1 2 3 4 5 6 7 8 9 10 11 12 13 72 179 259 501
paired box homeobox PST domain signal peptide myosin (25%) olfactomedin (40%)
200 bp
Proposed protein structure

Fig. 1.2.2 The PAX6 Gene. (Data with permission from Glaser T, et al. PAX6 gene
mutations in aniridia. In: Wiggs JL, editor. Molecular genetics of ocular disease. New
York: Wiley–Liss; 1995. p. 51–82.) 119
126
130
123
Mutations in the PAX6 gene are responsible for aniridia, Peter’s 133
anomaly, and autosomal dominant keratitis.3 Most of the mutations
responsible for these disorders alter the paired-box sequence within the 122
gene (Fig. 1.2.2) and result in inactivation of one copy of the PAX6 gene. 166 159 134
The paired-box sequence is an important element that is necessary for 169 152
the regulatory function of the protein. Losing half the normal paired-box 158
129 127
sequence, and probably other regulatory elements within the gene, appears 147 145
to be the critical event that results in the associated ocular disorders. The
protein plays an important role in ocular development, presumably by reg-
ulating the expression of genes that are involved in embryogenesis of the 118 136 138
120
eye. A reduction in the amount of active gene product alters the expression
of these genes, which results in abnormal development. The genes that
code for the lens crystallin proteins are one class of genes developmentally 131
125
regulated by the PAX6 protein.
The clinical disorders caused by mutations in PAX6 exhibit extensive
phenotypic variability. Similar mutations may give rise to aniridia, Peter’s 132 124
anomaly, or autosomal dominant keratitis. Variation in the phenotype asso-
ciated with a mutation is termed “variable expressivity” and is a common arginine
feature of disorders that arise from haploinsufficiency. It is possible that 121 128 117
leucine
the variability of the mutant phenotype results from the random activation
of downstream genes that occurs when only half the required gene product
is available.
Fig. 1.2.3 MYOC (Myocilin). The myosin-like domain, the olfactomedin-like domain,
and the leucine zipper are indicated. Amino acids altered in patients with juvenile-
RIEGER’S SYNDROME or adult-onset glaucoma are shown. (Reprinted by permission of Federation of
Rieger’s syndrome is an autosomal dominant disorder of morphogenesis the European Biochemical Societies from Orteto J, Escribano J, Coca-Prados M.
that results in abnormal development of the anterior segment of the eye. Cloning and characterization of subtracted cDNAs from a human ciliary body library
encoding TIGR, a protein involved in juvenile open angle glaucoma with homology
Typical clinical findings may include posterior embryotoxon, iris hypopla-
to myosin and olfactomedin. FEBS Lett 1997;413:349–53.)
sia, iridocorneal adhesions, and corectopia. Approximately 50% of affected
individuals develop a high-pressure glaucoma associated with severe optic
nerve disease. The cause of the glaucoma associated with this syndrome
is not known, although anomalous development of the anterior chamber
JUVENILE GLAUCOMA
angle structures is usually found. Primary juvenile open-angle glaucoma is a rare disorder that develops
Genetic heterogeneity of Rieger’s syndrome is indicated by the variety during the first two decades of life. Affected patients typically present
of chromosomal abnormalities that have been associated with the condi- with a high intraocular pressure (IOP), which ultimately requires surgical
tion, including deletions of chromosome 4 and chromosome 13. Genes for therapy. Juvenile glaucoma may be inherited as an autosomal dominant
Rieger’s syndrome are located on chromosomes 4q25, 13q14, and 6p25. trait, and large pedigrees have been identified and used for genetic linkage
Iris hypoplasia is the dominant clinical feature of pedigrees linked to the analysis. One gene responsible for this condition, MYOC, codes for the
6p25 locus, whereas pedigrees linked to 4q25 and 13q14 demonstrate the myocilin protein and is located on chromosome 1q23 (GLC1A).
full range of ocular and systemic abnormalities found in these patients. Myocilin has been shown to be expressed in the human retina, ciliary
The genes located on chromosomes 4q25 and 6p25 have been identi- body, and trabecular meshwork. The protein has several functional
fied.4 The chromosome 4q25 gene (PITX2) codes for a bicoid homeobox domains, including a region homologous to a family of proteins called
transcription factor. Like PAX6, this gene is expressed during eye devel- olfactomedins. Although the function of the protein and the olfactome-
opment and is probably involved in the ocular developmental processes. din domain is not known, nearly all the mutations associated with glau-
The chromosome 6p25 gene FOXC1 (also called FKHL7) is a member coma have been found in the olfactomedin portion of the protein (Fig.
of a forkhead family of regulatory proteins. FOXC1 is expressed during 1.2.3).5 Mutations in myocilin also have been associated with some cases of
ocular development, and mutations alter the dosage of the gene product. adult-onset primary open-angle glaucoma. Patients with only one copy of
There is some indication that the FOXC1 protein and the PITX2 protein the myocilin gene (because of chromosomal deletion removing the second
interact during ocular development. The identification of other genes copy of the gene) or without any functional myocilin (caused by homo-
responsible for Rieger’s syndrome and anterior segment dysgenesis is zygosity of a stop-codon polymorphism in the first part of the gene) do
necessary to determine whether these genes are part of a common devel- not develop glaucoma. Collectively these results suggest that mutations
10 opmental pathway or represent redundant functions necessary for eye in myocilin cause a gain-of-function or dominant negative effect rather
development. than a loss-of-function or haploinsufficiency. The role of myocilin in IOP
booksmedicos.org
elevation is not completely known, but in vitro studies show that myo- RETINITIS PIGMENTOSA
cilin mutants are misfolded and detergent resistant. Myocilin mutations
may be secretion incompetent and accumulate in the endoplasmic retic- The molecular genetics of retinitis pigmentosa (RP) is exceedingly complex. 1.2
ulum (ER) inducing ER stress. Recent studies using a transgenic mouse The disease can exhibit sporadic, autosomal dominant, autosomal reces-
model indicate that compounds that relieve ER stress can also reduce the sive, X-linked, or digenic inheritance. At least 200 genes are known to be
Molecular Genetics of Selected Ocular Disorders

mutation-associated elevation of IOP.6 associated with RP, and a number of genes have been mapped but not yet
found. Most of these genes are expressed preferentially in the retina, but
CONGENITAL GLAUCOMA some are expressed systemically. A useful resource listing genes respon-
sible for various forms of retinal diseases, including retinitis pigmentosa,
Congenital glaucoma is a genetically heterogeneous condition, with both can be found at the RetNet website (http://www.sph.uth.tmc.edu/Retnet/).
autosomal recessive and autosomal dominant forms reported. Two genes Mutations in rhodopsin can cause an autosomal dominant form of RP
responsible for autosomal recessive congenital glaucoma have been iden- that provides an interesting example of how mutant proteins can interfere
tified, CYP1B1, a member of the cytochrome P-450 family of proteins with normal cellular processes. Initially, one form of autosomal dominant
(cytochrome P-4501B1)7 and LTBP2 (latent transforming growth factor beta RP was mapped to chromosome 3q24. With a candidate gene approach,
binding protein 2).8 Mutations in CYP1B1 have been identified in patients the rhodopsin gene was identified as the cause of the disease in affected
with autosomal recessive congenital glaucoma from all over the world but families.14 Many of the first mutations detected in the rhodopsin protein
especially in areas where consanguinity is a custom.9 Responsible muta- were missense mutations located in the C-terminus of the gene (Fig. 1.2.4).
tions disrupt the function of the protein, implying that a loss of function To explore the pathogenical mechanisms of these mutations, transgenic
of the protein results in the phenotype.9 Recurrent mutations are likely to mice were created that carried mutant copies of the gene.15 Histopatho-
be the result of founder chromosomes that have been distributed to pop- logical studies of these mice showed an accumulation of vesicles that con-
ulations throughout the world.10,11 Because the defects responsible for contained rhodopsin at the junction between the inner and outer segments of
genital glaucoma are predominantly developmental, cytochrome P-4501B1 the photoreceptors. The vesicles probably interfere with the normal regen-
and latent transforming growth factor beta binding protein 2 must play a eration of the photoreceptors, thus causing photoreceptor degeneration.
direct or indirect role in the development of the anterior segment of the Because the C-terminus of the nascent polypeptide is involved in the trans-
eye. port of the maturing protein, the accumulation of rhodopsin-filled vesicles
is likely to result from abnormal transport of the mutant rhodopsin to the
NONSYNDROMIC CONGENITAL CATARACT membranes of the outer segments.
Null mutations (mutations that cause a prematurely shortened or trun-
At least one-third of all congenital cataracts are familial and are not asso- cated protein) also have been found in the rhodopsin gene in patients who
ciated with other abnormalities of the eye or with systemic abnormalities. have autosomal recessive retinitis pigmentosa (see Fig. 1.2.4).16 Mutations
A number of different genes can contribute to congenital cataract, includ- responsible for recessive disease typically cause a loss of biological activity,
ing some that code for the crystallin proteins.12 The human γ-crystallin
genes constitute a multigene family that contains at least seven highly
related members. All seven of the γ-crystallin genes have been assigned
to chromosome 2q34-q35. Of the genes mapped to this region, only two of
them, γ-C and γ-D, encode abundant proteins. Two of the genes, γ-E and TABLE 1.2.1 Web-Based Resources for
γ-F, are pseudogenes, which means they are not expressed in the normal Inherited Human Ocular Disorders
lens. A pedigree affected by the Coppock cataract, a congenital cataract that
involves primarily the embryonic lens, was shown to be linked genetically NCBI National Center for http://www.ncbi.nlm.nih.gov/
to the region that contains the γ-crystallin genes. In individuals affected by Biotechnology Information
the Coppock cataract, additional regulatory sequences have been found in OMIM Online Mendelian http://www.ncbi.nlm.nih.gov/omim
the promoter region of the γ-E pseudogene.13 This result implies that the Inheritance in Man
γ-E pseudogene is expressed in affected individuals and that expression of RetNet Retinal disease genes http://www.sph.uth.tmc.edu/Retnet/
the pseudogene is the event that leads to cataract formation. A number of Genes and Disease Systemic inherited disorders http://www.ncbi.nlm.nih.gov/books/
other genes have been associated with hereditary cataract. A useful col- (NCBI Bookshelf ) NBK22183/
lection of mutations and phenotypes can be found at the OMIM website UCSC Human genome sequence http://www.genome.ucsc.edu
(Table 1.2.1). browser
Fig. 1.2.4 Human Rhodopsin Mutations. The red

HUMAN RHODOPSIN MUTATIONS circles indicate the amino acids altered by mutations
in the gene in patients who have autosomal dominant
Autosomal dominant Autosomal recessive retinitis pigmentosa. The translational stop site that
results from a nonsense mutation is indicated as a red
circle in a patient who has autosomal recessive retinitis
C C pigmentosa.
N N
G90D P23H K296E A292E

K296M 11
booksmedicos.org
either because they create a defective protein product that has little or no atrophy, an autosomal recessive condition characterized by circular areas
1 biological activity or because they interfere with the normal expression of

the gene (regulatory mutations). Most individuals heterozygous for autoso-
mal recessive disorders are clinically normal. Unlike the missense muta-
of chorioretinal atrophy. Mutations in the gene for ornithine ketoacid ami-
notransferase mapped to chromosome 10q26 have been associated with
the disease in affected individuals.24 Most of the responsible mutations
tions responsible for the dominant form of the disease, the null mutations are missense mutations, which presumably result in an inactive enzyme.
Genetics
in rhodopsin produce an inactive protein that is not destructive to the cell. One mutation has been found in homozygous form in the vast majority of
Null mutations result in retinitis pigmentosa only when they are present apparently unrelated cases of gyrate atrophy in Finland, an example of a
in both copies of the gene. Mutations in just one copy of the gene (hetero- founder effect that produces a common mutation in an isolated population.
zygous individuals) do not have a clinically detectable phenotype. Identification of the enzyme defect responsible for this disease makes
it an interesting candidate for gene therapy. Previous studies indicated
STARGARDT DISEASE that a lower ornithine level, achieved through a strict low-arginine diet,
may retard the progression of the disease.25 Replacement of the abnormal
Stargardt disease is characterized by progressive bilateral atrophy of the gene—or genetic engineering to produce a supply of normal enzyme—
macular retinal pigment epithelium (RPE) and neuroepithelium, with the may result in a reduction of ornithine levels without dietary restrictions.
frequent appearance of orange–yellow flecks distributed around the macula.
The choroid is characteristically dark on fluorescein angiography in about
80% of cases. The disease results in a loss of central acuity that may have
COLOR VISION
a juvenile to adult onset and is inherited as an autosomal recessive trait. Defective red–green color vision affects 2%–6% of men and results from
Inactivation of both copies of the responsible gene is necessary to cause the a variety of defects that involve the color vision genes. In humans, the
disease. Mutations in a photoreceptor cell-specific ATP-binding transporter three cone pigments—blue, green, and red—mediate color vision. Each
gene (ABCA4 or ABCR) have been found in affected patients.17,18 Most visual pigment consists of an integral membrane apoprotein bound to
disease-related mutations are missense mutations in conserved amino the chromophore 11-cis retinal. The genes for the red and green pigments
acid positions. The retina-specific ABC transporter (ABCA4) responsible are located on the X chromosome, and the gene for the blue pigment is
for Stargardt disease is a member of a family of transporter proteins and located on chromosome 7. The X chromosome location of the red and green
is expressed in rod photoreceptors, which indicates that this protein medi- pigment genes accounts for the X-linked inheritance pattern observed in
ates the transport of an essential molecule either into or out of photore- red or green color vision defects.
ceptor cells. Accumulation of a lipofuscin-like substance in ABCA4-related The common variations in red or green color vision are caused by the
disease may result from inactivation of this transporter protein. loss of either the red or the green cone pigment (dichromasy) or by the
production of a visual pigment with a shifted absorption spectrum (anom-
X-LINKED JUVENILE RETINOSCHISIS alous trichromasy). A single amino acid change (serine to alanine) in the
red photopigment gene is the most common color vision variation. Among
Retinoschisis is a maculopathy caused by intraretinal splitting; the defect Caucasian men, 62% have serine at position 180 in the red pigment protein,
most likely involves retinal Müller cells. Retinoschisis is inherited as an and 38% have alanine in this position. Men who carry the red pigment
X-linked recessive trait. X-linked recessive disorders, like autosomal reces- with serine at position 180 have a greater sensitivity to long-wavelength
sive disorders, are caused by inactivating mutations. Because men have radiation than do men who carry alanine at this position.26 Recent work
only one X chromosome, one mutant copy of a gene responsible for an suggests that gene therapy could correct color vision defects.27
X-linked trait results in the disease. Usually women are heterozygous
carriers of recessive X-linked traits and do not demonstrate any clinical
abnormalities. Mutations in the gene coding for retinoschisin have been
RETINOBLASTOMA
shown to be the cause of the disease.19 The protein is involved in cell– A gene responsible for the childhood eye tumor retinoblastoma was identi-
cell interaction and may be active in cell adhesion processes during retinal fied in 1986 on chromosome 13q14.28 The gene product is involved in regu-
development. Most retinoschisis gene (XLRS1) mutations cause a loss of lation of the cell cycle. Absence of this protein in an embryonic retinal cell
protein function. results in the uncontrolled cell growth that eventually produces a tumor.29
Susceptibility to hereditary retinoblastoma is inherited as an autosomal
NORRIE’S DISEASE dominant trait. Mutations in the retinoblastoma gene result in underpro-
duction of the protein product or production of an inactive protein product.
Norrie’s disease is an X-linked disorder characterized by progressive, bilat- A retinal cell that has only one mutant copy of the retinoblastoma gene
eral, congenital blindness associated with retinal dysplasia that has been does not become a tumor. However, inactivation of the remaining normal
referred to as a “pseudoglioma.” The disease can include mental retar- copy of the retinoblastoma gene is very likely in at least one retinal cell
dation and hearing defects. Norrie’s disease is inherited as an X-linked out of the millions present in each retina. Among individuals who inherit
recessive trait, and a causative gene has been identified on the X chromo- a mutant copy of the retinoblastoma gene, 90% sustain a second hit to
some that has a tertiary structure similar to transforming growth factor-β.20 the remaining normal copy of the gene and develop a tumor (Fig. 1.2.5).30
Norrie’s disease is a member of the familial exudative vitreoretinopathy Fifty percent of the offspring of individuals affected by hereditary retino-
(FEVR) syndromes, which are genetically heterogeneous inherited blinding blastoma will inherit the mutant copy of the gene and are predisposed to
disorders of the retinal vascular system, and to date three other loci have develop the tumor. Approximately 10% of individuals who inherit a muta-
been mapped.21 Mutations in the Norrie’s disease gene have been found in tion do not sustain a second mutation and do not develop a tumor. The off-
a small subset of patients with severe retinopathy of prematurity (ROP), spring of these “carrier” individuals also have a 50% chance of inheriting
although defects in this gene do not appear to be a major factor in ROP.22 the mutant copy of the retinoblastoma gene (see Fig. 1.2.5).
SORSBY’S MACULAR DYSTROPHY ALBINISM

Sorsby’s macular dystrophy is an autosomal dominant disorder character- Autosomal recessive diseases often result from defects in enzymatic
ized by early onset bilateral and multifocal choroidal neovascularization proteins. Albinism is the result of a series of defects in the synthesis of
resulting in macular edema, hemorrhage, and exudation. The disease typ- melanin pigment.31 Melanin is synthesized from the amino acid tyrosine,
ically begins at about 40 years of age. Missense mutations in the gene that which is first converted into dihydroxyphenylalanine through the action of
codes for tissue inhibitor metalloproteinase-3 (TIMP-3) have been found in the copper-containing enzyme tyrosinase. An absence of tyrosinase results
affected individuals.23 This protein is involved in remodeling of the extra- in one form of albinism. Mutations in the gene that codes for tyrosinase
cellular matrix. Inactivation of the protein may lead to an increase in activ- are responsible for tyrosinase-negative ocular cutaneous albinism. Most of
ity of the metalloproteinase, which may contribute to the pathogenesis of the mutations responsible for this disease cluster in the binding sites for
the disease.23 copper and disrupt the metal ion–protein interaction necessary for enzyme
function.32 Both copies of the gene for tyrosinase must be mutated before a
GYRATE ATROPHY significant interruption of melanin production occurs. Heterozygous indi-
viduals do not have a clinically apparent phenotype, which suggests that
12 Hyperornithinemia results from deficiency of the enzyme ornithine one functional copy of the gene produces sufficient active enzyme for the
ketoacid aminotransferase and has been shown to be the cause of gyrate melanin level to be phenotypically normal (Fig. 1.2.6).
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LEBER’S OPTIC NEUROPATHY of the disease, all affected individuals were related through the maternal
Mutations in mitochondrial DNA are an important cause of human

lineage, consistent with inheritance of human mitochondrial DNA.
Patients affected by LHON typically present in midlife with acute or 1.2
disease. Disorders that result from mutations in mitochondrial DNA subacute, painless, central vision loss that results in a permanent central
demonstrate a maternal inheritance pattern. Maternal inheritance differs scotoma and loss of sight. The manifestation of the disease varies tremen-

from mendelian inheritance, in that men and women are affected equally, dously, especially with respect to onset of visual loss and severity of the
but only affected females transmit the disease to their offspring. The char- outcome. The eyes may be affected simultaneously or sequentially; the
acteristic segregation and assortment of mendelian disorders depend on disease may progress rapidly over a period of weeks to months or slowly
the meiotic division of maternal and paternal chromosomes found in over several years. Within a family, the disease may also vary among
the nucleus of cells. In contrast, mitochondrial DNA is derived from the affected members.
maternal egg and replicates and divides with the cell cytoplasm by simple Several factors contribute to the variable phenotype of this condition.
fission. A mutation that occurs in mitochondrial DNA is present in all cells Certain mutations are associated with more severe disease, and some
of the organism, which includes the gametes. Female eggs have abnormal mitochondrial DNA haplotypes appear to be associated with more severe
mitochondria that may be passed to offspring. Sperm contain mitochon- disease.34 Another important factor that affects the severity of the disease
dria but do not transmit mitochondria to the fertilized egg. A man who is the heteroplasmic distribution of mutant and normal mitochondria. Not
carries a mitochondrial DNA mutation may be affected by the disease, but all mitochondria present in diseased tissue carry DNA mutations. During
he cannot transmit the disease to his offspring. cell division, mitochondria and other cytoplasmic organelles are distrib-
Leber’s hereditary optic neuropathy (LHON) was one of the first dis- uted arbitrarily to the daughter cells. Consequently, the daughter cells
eases to be recognized as a mitochondrial DNA disorder.33 In familial cases are likely to have unequal numbers of mutant and normal mitochondria
(Fig. 1.2.7). Because the diseased mitochondria are distributed to develop-
ing tissues, some tissues accumulate more abnormal mitochondria than
INHERITANCE OF RETINOBLASTOMA others. Hence, some individuals have more abnormal mitochondria in the
optic nerve and develop a more severe optic neuropathy.
retina tumor CONGENITAL FIBROSIS SYNDROMES AND

DISORDERS OF AXON GUIDANCE
gametes Congenital fibrosis of the extraocular muscles and Duane’s syndrome are
inherited forms of congenital fibrosis and strabismus. At least 20 genes con-
tribute to these conditions and other disorders of axon guidance,35 with the
ARIX/PHOX2A genes causing congenital fibrosis of extraocular muscles
type 236 and the SALL4 gene causing Duane’s radial ray syndrome.37
50% 50%
retina AUTOSOMAL DOMINANT OPTIC ATROPHY

Of the inherited optic atrophies, autosomal dominant Kjer optic atrophy
gametes is the most common. This disease results in a progressive loss of visual
acuity, centrocecal scotoma, and bilateral temporal atrophy of the optic
nerve. The onset is typically in the first two decades of life. The condition
is inherited as an autosomal dominant trait with variable expressivity, and
10% 90%
mutations in OPA1 have been found in a number of affected families.38,39
no second hit second hit
OPA1 codes for a dynamin-related GTPase that is targeted to mitochon-
dria and may function to stabilize mitochondrial membrane integrity. It
normal is interesting that this gene and the gene responsible for another optic
retina atrophy, Leber’s hereditary optic atrophy (see earlier), both function in the
affected tumor
mitochondria, emphasizing the critical role of mitochondria in optic nerve
function.
Fig. 1.2.5 Inheritance of Retinoblastoma. Individuals who inherit a mutation in COMPLEX TRAITS
the retinoblastoma gene are heterozygous for the mutation in all cells of the body.
The “second hit” to the remaining normal copy of the gene occurs in a developing Human phenotypes inherited as polygenic or “complex” traits do not follow
retinal cell and leads to tumor formation (see text for explanation). the typical patterns of mendelian inheritance. Complex traits are relatively
Fig. 1.2.6 Metabolism of Tyrosine to Produce

METABOLISM OF TYROSINE TO PRODUCE MELANIN Melanin. In the final step, dopamine is converted into
an indole derivative that condenses to form the high-
molecular-weight pigment melanin.
NH3 O2 H 2O NH3 CO2
CH2CHCOO
CH2CHCOO CH2CH2NH3
melanin
OH
OH dihydrobiopterin OH OH
tetrahydrobiopterin
tyrosine tyrosine hydroxylase dihydroxyphenylalanine dopamine
13
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common disorders. Generally, DNA variants associated with these disor-
1 HETEROPLASMY IN MITOCHONDRIA ders are not causal but influence disease suspectibility.40 Environmental
factors may also contribute to complex disease risk. For example, genetic
variants in complement factor H (CFH) and LOC37718 are known to be
nucleus
major genetic risk factors for age-related macular degeneration,41–44 and
Genetics
normal mitochondrion combined with smoking the risk is increased.45 The genome-wide associa-
mutant mitochondrion tion study (GWAS) approach has also successfully identified genes contrib-
uting to other common complex ocular conditions and traits,40 including
primary open-angle glaucoma,46,47 primary angle-closure glaucoma,48 exfo-
liation syndrome and glaucoma,49,50 myopia,51,52 and Fuchs’ endothelial
cell division dystrophy.53
KEY REFERENCES
Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is
mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet
2000;26:211–15.
Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N Engl
J Med 2010;363:1016–24.
Cooke Bailey JN, Sobrin L, Pericak-Vance MA, et al. Advances in the genomics of common
eye diseases. Hum Mol Genet 2013;22(R1):R59–65.
replication and cell division Engle EC. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol
2010;2:a001784.
Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and
refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5.
Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related
macular degeneration. Science 2005;308:385–9.
Neitz J, Neitz M. The genetics of normal and defective color vision. Vision Res 2011;51:633–51.
Sergouniotis PI, Davidson AE, Lenassi E, et al. Retinal structure, function, and molecular
pathologic features in gyrate atrophy. Ophthalmology 2012;119:596–605.
Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1
gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–400.
Zode GS, Bugge KE, Mohan K, et al. Topical ocular sodium 4-phenylbutyrate rescues glau-
coma in a myocilin mouse model of primary open-angle glaucoma. Invest Ophthalmol
Vis Sci 2012;53:1557–65.
Fig. 1.2.7 Heteroplasmy in Mitochondria. Daughter cells that result from the
division of a cell that contains mitochondria with mutant DNA may contain unequal
numbers of mutant mitochondria. Subsequent divisions lead to a population of cells Access the complete reference list online at ExpertConsult.com
with different numbers of normal and abnormal mitochondria.
14
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REFERENCES 26. Neitz J, Neitz M. The genetics of normal and defective color vision. Vision Res
2011;51:633–51.
1. Musch DC, Niziol LM, Stein JD, et al. Prevalence of corneal dystrophies in the United
States: estimates from claims data. Invest Ophthalmol Vis Sci 2011;52:6959–63.
27. Mancuso K, Hauswirth WW, Li Q, et al. Gene therapy for red-green colour blindness in
adult primates. Nature 2009;461:784–7.
1.2
2. Kannabiran C, Klintworth GK. TGFBI gene mutations in corneal dystrophies. Hum 28. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the
gene that predisposes to retinoblastoma and osteosarcoma. Nature 1986;643–6.

Mutat 2006;27:615–25.
3. Kokotas H, Petersen MB. Clinical and molecular aspects of aniridia. Clin Genet 29. Manning AL, Dyson NJ. RB: mitotic implications of a tumour suppressor. Nat Rev
2010;77:409–20. Cancer 2012;12:220–6.
4. Hjalt TA, Semina EV. Current molecular understanding of Axenfeld–Rieger syndrome. 30. Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet 2012;379:1436–46.
Expert Rev Mol Med 2005;7:1–17. 31. Tomita Y, Suzuki T. Genetics of pigmentary disorders. Am J Med Genet C Semin Med
5. Hewitt AW, Mackey DA, Craig JE. Myocilin allele-specific glaucoma phenotype database. Genet 2004;131C(1):75–81.
Hum Mutat 2008;29:207–11. 32. Ray K, Chaki M, Sengupta M. Tyrosinase and ocular diseases: some novel thoughts on the
6. Zode GS, Bugge KE, Mohan K, et al. Topical ocular sodium 4-phenylbutyrate rescues molecular basis of oculocutaneous albinism type 1. Prog Retin Eye Res 2007;26:323–58.
glaucoma in a myocilin mouse model of primary open-angle glaucoma. Invest Ophthal- 33. Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with
mol Vis Sci 2012;53:1557–65. Leber’s hereditary optic neuropathy. Science 1988;242:1427–30.
7. Bejjani BA, Stockton DW, Lewis RA, et al. Multiple CYP1B1 mutations and incomplete 34. Ji Y, Zhang AM, Jia X, et al. Mitochondrial DNA haplogroups M7b1’2 and M8a affect
penetrance in an inbred population segregating primary congenital glaucoma suggest clinical expression of Leber hereditary optic neuropathy in Chinese families with the
frequent de novo events and a dominant modifier locus. Hum Mol Genet 2000;9:367–74. m.11778G→a mutation. Am J Hum Genet 2008;83:760–8.
8. Narooie-Nejad M, Paylakhi SH, Shojaee S, et al. Loss of function mutations in the gene 35. Engle EC. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol
encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary 2010;2:a001784.
congenital glaucoma. Hum Mol Genet 2009;18:3969–77. 36. Nakano M, Yamada K, Fain J, et al. Homozygous mutations in ARIX (PHOX2A) result in
9. Li N, Zhou Y, Du L, et al. Overview of cytochrome P450 1B1 gene mutations in patients congenital fibrosis of the extraocular muscles type 2. Nat Genet 2001;29:315–20.
with primary congenital glaucoma. Exp Eye Res 2011;93:572–9. 37. Al-Baradie R, Yamada K, St Hilaire C, et al. Duane radial ray syndrome (Okihiro syn-
10. Chakrabarti S, Kaur K, Kaur I, et al. Globally, CYP1B1 mutations in primary congenital drome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL
glaucoma are strongly structured by geographic and haplotype backgrounds. Invest Oph- family. Am J Hum Genet 2002;71:1195–9.
thalmol Vis Sci 2006;47:43–7. 38. Alexander C, Votruba M, Pesch UE, et al. OPA1, encoding a dynamin-related GTPase, is
11. Sena DF, Finzi S, Rodgers K, et al. Founder mutations of CYP1B1 gene in patients with mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet
congenital glaucoma from the United States and Brazil. J Med Genet 2004;41:e6. 2000;26:211–15.
12. Hejtmancik JF. Congenital cataracts and their molecular genetics. Semin Cell Dev Biol 39. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies – disease
2008;19:134–49. mechanisms and therapeutic strategies. Prog Retin Eye Res 2011;30:81–114.
13. Héon E, Priston M, Schorderet DF, et al. The gamma-crystallins and human cataracts: a 40. Cooke Bailey JN, Sobrin L, Pericak-Vance MA, et al. Advances in the genomics of
puzzle made clearer. Am J Hum Genet 1999;65:1261–7. common eye diseases. Hum Mol Genet 2013;22(R1):R59–65.
14. Dryja TP, McGee TL, Reichel E, et al. A point mutation of the rhodopsin gene in one 41. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related
form of retinitis pigmentosa. Nature 1990;343:364–6. macular degeneration. Science 2005;308:385–9.
15. Li T, Snyder WK, Olsson JE, et al. Transgenic mice carrying the dominant rhodopsin 42. Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor H polymorphism and
mutation P347S: evidence for defective vectorial transport of rhodopsin to the outer seg- age-related macular degeneration. Science 2005;308:421–4.
ments. Proc Natl Acad Sci USA 1996;93:14176–81. 43. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk
16. Rosenfeld PJ, Cowley GS, McGee TL, et al. A null mutation in the rhodopsin gene of age-related macular degeneration. Science 2005;308:419–21.
caused rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nat 44. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major sus-
Genet 1992;1:209–13. ceptibility gene for age-related macular degeneration, contributing independently of
17. Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific ATP-binding trans- complement factor H to disease risk. Hum Mol Genet 2005;14:3227–36.
porter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 45. Schmidt S, Hauser MA, Scott WK, et al. Cigarette smoking strongly modifies the
1997;15:236–46. association of LOC387715 and age-related macular degeneration. Am J Hum Genet
18. Vasireddy V, Wong P, Ayyagari R. Genetics and molecular pathology of Stargardt-like 2006;78:852–64.
macular degeneration. Prog Retin Eye Res 2010;29:191–207. 46. Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2
19. Vijayasarathy C, Ziccardi L, Sieving PA. Biology of retinoschisin. Adv Exp Med Biol are associated with primary open-angle glaucoma. Nat Genet 2010;42:906–9.
2012;723:513–18. 47. Bailey JN, Loomis SJ, Kang JH, et al. Genome-wide association analysis identifies
20. Nikopoulos K, Venselaar H, Collin RW, et al. Overview of the mutation spectrum in TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma.
familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel Nat Genet 2016;48(2):189–94.
variants in FZD4, LRP5, and NDP. Hum Mutat 2010;31:656–66. 48. Khor CC, Do T, Jia H, et al. Genome-wide association study identifies five new suscepti-
21. Toomes C, Downey LM, Bottomley HM, et al. Further evidence of genetic heterogeneity bility loci for primary angle closure glaucoma. Nat Genet 2016;48(5):556–62.
in familial exudative vitreoretinopathy: exclusion of EVR1, EVR3, and EVR4 in a large 49. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the
autosomal dominant pedigree. Br J Ophthalmol 2005;89:194–7. LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 2007;317:1397–400.
22. Hutcheson KA, Paluru PC, Bernstein SL, et al. Norrie disease gene sequence variants 50. Aung T, Ozaki M, Lee MC, et al. Genetic association study of exfoliation syndrome
in an ethnically diverse population with retinopathy of prematurity. Mol Vis 2005;11: identifies a protective rare variant at LOXL1 and five new susceptibility loci. Nat Genet
501–8. 2017;49(7):993–1004.
23. Li Z, Clarke MP, Barker MD, et al. TIMP3 mutation in Sorsby’s fundus dystrophy: 51. Solouki AM, Verhoeven VJ, van Duijn CM, et al. A genome-wide association study
molecular insights. Expert Rev Mol Med 2005;7:1–15. identifies a susceptibility locus for refractive errors and myopia at 15q14. Nat Genet
24. Sergouniotis PI, Davidson AE, Lenassi E, et al. Retinal structure, function, and molecular 2010;42:897–901.
pathologic features in gyrate atrophy. Ophthalmology 2012;119:596–605. 52. Hysi PG, Young TL, Mackey DA, et al. A genome-wide association study for myopia and
25. Caruso RC, Nussenblatt RB, Csaky KG, et al. Assessment of visual function in patients refractive error identifies a susceptibility locus at 15q25. Nat Genet 2010;42:902–5.
with gyrate atrophy who are considered candidates for gene replacement. Arch Ophthal- 53. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N
mol 2001;119:667–9. Engl J Med 2010;363:1016–24.
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Part 1 Genetics

Genetic Testing and Genetic Counseling

Janey L. Wiggs 1.3
Definition: A genetic test is any clinical or laboratory investigation Methods for DNA-Based Genetic Testing
that provides information about the likelihood that an individual is Although genetic testing can be performed using DNA, RNA, or protein,
affected with a heritable disease. The majority of genetic tests are based DNA is the easiest to work with, and most genetic tests use this as the
on molecular evaluations of genomic DNA designed to identify the DNA starting material. A biological sample from the patient is needed before
mutations responsible for the disease. genetic testing can be performed. The inclusion of family members may
help the evaluation, but they are not absolutely required. DNA for testing
can be obtained from a number of sources, including blood samples,
mouthwash samples or buccal swabs, archived pathology specimens, or
from hair.4–6
Key Features Genomic DNA sequencing is the most commonly used method to detect
• Indications and methods for genetic testing for ocular disorders. mutations. For many disorders, sequencing the entire responsible gene is
• Genetic counseling and ethical issues. necessary, including all exons, immediate flanking intron sequences with
splice signals and 5′ and 3′ flanking regulatory regions. Some disorders
are caused by a specific mutation in a gene, and genetic testing can be
limited to an evaluation of a single gene. For other diseases, however, such
as the inherited retinal degenerations, sequencing multiple genes may
GENETIC TESTING be required before a causative mutation is identified. For diseases with
Role of Genetic Testing in the Clinic many causative genes, a panel test that allows for sequencing all genes at
once is both more effective and more efficient.7 Alternatively, whole exome
DNA-based genetic tests can identify individuals at risk for disease before sequencing (WES) that captures and sequences all coding regions of the
any clinical evidence is present (presymptomatic testing).1 This informa- genome can also be a preferred approach for disorders with many possi-
tion coupled with effective genetic counseling and clinical screening can ble genetic mutations.8 Genomic DNA sequencing will not usually identify
be useful. An effective presymptomatic test needs to meet the specificity large chromosomal abnormalities, including large copy number variations
and sensitivity expectations for any clinical test. Sensitivity is the number (deletions or insertions) or chromosomal translocations. Other techniques
of affected individuals that are positive for a test compared with the total are necessary to detect large chromosomal abnormalities, including karyo-
number of affected individuals (including those that tested negative for typing and multiplex ligation-dependent probe amplification (MLPA).9,10
the test). Specificity is the number of unaffected individuals that are nega- For diseases that are caused primarily by a limited set of mutations (for
tive for the test compared with the total number of unaffected individuals example, the three mutations that commonly cause Leber’s hereditary
tested (including those that tested positive for the test) (Fig. 1.3.1). optic neuropathy (LHON),11 specific tests such as allele-specific polymerase
The identification of a mutation responsible for a disease through chain reaction (PCR) amplification or TaqMan assays can be used and can
DNA-based genetic testing can establish a molecular diagnosis. For some be more efficient than sequencing the entire gene (Table 1.3.1).
disorders, such as juvenile open-angle glaucoma caused by mutations in
MYOC,2 specific mutations have been correlated with severity of disease or Current Recommendations for Genetic Testing for
other clinical features that are useful prognostically. A molecular diagnosis
may also help guide therapy and is required before gene-based therapies Ophthalmic Diseases
can be utilized. For example, mutations in a number of different genes can Currently, genetic testing is indicated for patients with clinical evidence
cause Leber’s hereditary amaurosis, but only those patients with disease of a disorder whose causative genes have been identified and for which
due to mutations in RPE65 will benefit from novel RPE65-based therapies
using gene replacement.3
TABLE 1.3.1 Common Types of Genetic Tests
Method Indication Example
Single gene DNA Different mutations distributed Sequencing OPA1 in patients
sequencing throughout a single gene are with autosomal dominant
Fig. 1.3.1 Definition of known to cause the inherited optic neuropathy
SPECIFICITY AND SENSITIVITY Sensitivity and Specificity condition
for a Laboratory Test. Multiple gene DNA Mutations in multiple genes are Inherited retinal
Sensitivity is defined as sequencing known to cause the condition degenerations
the number of affected Multiplex ligation- Detects deletions and MLPA testing for PAX6
individuals positive for dependent probe duplications in genes known to deletions in patients with
Affected Unaffected
the test (A) divided by the amplification (MLPA) cause the condition and that aniridia
individuals individuals
total number of affected may be missed by sequence-
Individuals individuals tested (A + C). based approaches
A B Specificity is defined as TaqMan assay or Detects a single DNA base pair Three mutations commonly
positive for test
the number of unaffected allele-specific assay change and is used if a small cause Leber’s hereditary
Individuals individuals negative for set of mutations are primarily optic neuropathy (LHON)
C D the cause of the condition
negative for test the test (D) divided by the
total number of unaffected Karyotype Detects large chromosomal Down syndrome
A D individuals tested (B + D). rearrangements including
Sensitivity Specificity
A+C B+D
deletions, duplications, and
translocations
15
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the identification of the genetic mutation contributing to the disease has (3) understand the alternatives for dealing with the risk of recurrence, (4)
1 sufficient specificity and sensitivity that testing will be clinically useful.

Serious failures of a diagnostic test are false positives (individuals without
the disease who test positively) and false negatives (individuals with the
choose a course of action that seems to them appropriate in their view
of their risk, their family goals, and their ethical and religious standards
and act in accordance with that decision, and (5) to make the best possible
disease who test negatively). Although genes have been identified for adjustment to the disorder in an affected family member and/or to the risk
Genetics
some common complex disorders such as age-related macular degenera- of recurrence of that disorder.
tion, primary open-angle glaucoma, and exfoliation syndrome, in general,
testing for these mutations is not sufficiently sensitive and specific that the
test results are clinically meaningful. For example, over 90% of patients
with exfoliation syndrome carry one of two missense changes in LOXL1;
Clinical Evaluation and Family History
however, up to 80% of normal individuals also carry these same DNA An accurate diagnosis is the first step in productive genetic counseling.
sequence variants.12 Clearly the identification of these missense mutations The patient–physician discussion of the natural history of the disease and
alone is not clinically useful. Examples of genetic tests that are useful of its prognosis and management is entirely dependent on the correct
include RPE65 for Leber’s hereditary amaurosis,13 PAX6 for aniridia,14 identification of the disorder that affects the patient. Risk assessment for
MYOC for early onset primary open-angle glaucoma,15 and OPA1 for optic other family members and options for prenatal diagnosis also depend on
neuropathy,16 as well as many other genes that are known to cause inher- an accurate diagnosis. In some cases, appropriate genetic testing may help
ited ocular conditions.17 establish the diagnosis. Examination of other family members may be
indicated to determine whether a particular finding is hereditary.
CLIA Laboratories A complete family history of the incidence of the disorder is neces-
sary to determine the pattern of inheritance of the condition. The mode
Laboratories in the United States offering genetic testing must comply with of inheritance (i.e., autosomal dominant, autosomal recessive, X-linked, or
regulations under the Clinical Laboratory Improvement Amendments of maternal) must be known to calculate the recurrence risk to additional
1988 (CLIA). The Centers for Medicare and Medicaid Services administers family members, and it helps confirm the original diagnosis. For the
CLIA and requires that laboratories meet certain standards related to per- record of family information, the gender and birth date of each individual
sonnel qualifications, quality control procedures, and proficiency testing and his or her relationship to other family members are indicated using
programs in order to receive certification. This regulatory system was put in the standard pedigree symbols. It is also helpful to record the age of onset
place to encourage safe, accurate, and accessible genetic tests. In addition of the disorder in question (as accurately as this can be determined). The
to ensuring that consumers have access to genetic tests that are safe, accu- pedigree diagram must include as many family members as possible. Mis-
rate, and informative, these policies encourage the development of genetic carriages, stillbirths, and consanguineous parents are indicated.
tests, genetic technologies, and the industry that produces these products. Occasionally a patient may appear to be affected by a condition that is
A number of CLIA-certified laboratories performing genetic testing for eye known to be inherited, but the patient is unable to provide a family history
diseases exist in the United States. For a list of CLIA-certified laborato- of the disease. Several important explanations for a negative family history
ries participating in the National Eye Institute (NEI)-sponsored eyeGENE must be considered before the conclusion is made that the patient does
network, see the NEI website at http://www.nei.nih.gov. CLIA-certified lab- not have a heritable condition. First, the patient may not be aware that
oratories offering genetic testing can also be found at GeneTests: https:// other family members are affected by the disease. Individuals frequently
www.genetests.org/. are reluctant to share information about medical problems, even with close
family members. Second, many disorders exhibit variable expressivity or
Genetic Reports reduced penetrance, which means that other family members may carry a
defective gene that is not expressed or results in only a mild form of the
A genetic test report is a sensitive document that is the main form of com- disease that is not readily observed. Third, false paternity may produce an
munication between the CLIA laboratory and the physician requesting the individual affected by a disease that is not found in anyone else belonging
genetic test. Genetic test reports may be shared with the patient and with to the acknowledged pedigree. Genetic testing can easily determine the
genetic counselors. The report should include (1) the type of genetic test paternity (and maternity) of any individual if blood samples are obtained
performed (i.e., sequencing or other methodology), (2) the gene or genes from relevant family members. Fourth, a new mutation may arise that
that were evaluated, (3) the results of the testing, (4) information about the affects an individual and may be passed to offspring, even though existing
pathogenicity of the sequence variants, (5) recommendations for clinical family members show no evidence of the disease.
follow-up based on the results of testing, and (6) literature references pro-
viding additional information about the genes and mutations responsible Risk Prediction Based on Inheritance
for the disease. The report should be written clearly and have appropriate
contact information. Once the diagnosis and family history of the disorder are established, risk
Novel DNA sequence changes are frequently found as a result of prediction in other family members (existing and unborn) may be calcu-
genomic DNA sequencing. New DNA sequence changes (variants) may lated. The chance that an individual known to be affected by an autosomal
be benign polymorphisms or causative mutations. Additional studies must dominant disorder will transmit the disease to his or her offspring is 50%.
be done before the sequence change can be designated as disease causing. This figure may be modified depending on the penetrance of the condition.
Demonstrating that the mutant protein has an abnormal function or eval- For example, retinoblastoma is inherited as an autosomal dominant trait,
uation of the mutant gene in an animal model would be an ideal test of and 50% of the children of an affected parent should be affected. However,
pathogenicity, but these approaches are time consuming and may not be usually only 40%–45% of the children at risk are affected, because the pen-
possible. Current approaches to evaluate the pathogenicity of a novel DNA etrance of the retinoblastoma trait is only 80%–90%, which means that
sequence variant are based on (1) population data, (2) computational and 5%–10% of children who have inherited an abnormal copy of the retino-
predictive data from in silico estimates for pathogenicity such as SIFT18 and blastoma gene do not develop ocular tumors.
PolyPhen-2,19 (3) functional data, and (4) segregation data for families.20 An individual affected by an autosomal recessive trait will have unaf-
fected children unless he or she partners with another individual affected
GENETIC COUNSELING by the disease or with an individual who is a carrier of the disease. Two
individuals affected by an autosomal recessive disease produce only
Genetic counseling has become an important part of any clinical medicine affected offspring. (There are some rare exceptions to this rule. If the
practice. In 1975 the American Society of Human Genetics adopted this disease is the result of mutations in two different genes, it is possible for
descriptive definition of genetic counseling21: two individuals affected by an autosomal recessive trait to produce normal
children. Also, in rare cases, different mutations in the same gene may
Genetic counseling is a communication process which deals with the compensate for each other, and the resultant offspring will be normal.)
human problems associated with the occurrence or risk of occurrence of If an individual affected by an autosomal recessive disease partners with
a genetic disorder in a family. This process involves an attempt by one or a heterozygous carrier of a gene defect responsible for that disorder, the
more appropriately trained persons to help the individual or family to (1) chance of producing an affected child is 50%. Among the offspring of an
comprehend the medical facts including the diagnosis, probable course of individual affected by an autosomal recessive disease, 50% will be carriers
16 the disorder, and the available management, (2) appreciate the way heredity of the disorder. If one of these offspring partners with another carrier of
contributes to the disorder and the risk of recurrence in specified relatives, the disease, the chance of producing an affected child is 25%.
booksmedicos.org
BOX 1.3.1 Types of Clinical Genetics Services and Programs
Indications to Refer for Genetic Counseling
Center-Based Genetics Clinic
Known Inherited Condition 1.3
• Outreach clinics Genetic counseling can be useful for a family with a member affected
• Inpatient consultations by an established diagnosis. In this case the goal of the counseling is to

describe recurrence risks for other family members. For example, if a
Specialty Clinics child has retinoblastoma and a positive family history, the family may be
• Metabolic clinic referred for genetic counseling to review recurrence risks. If diagnostic
• Spina bifida clinic testing has been performed, that can also be discussed and will aid in the
• Hemophilia clinic presentation of the recurrence risks, especially if other family members
• Craniofacial clinic have been tested.
• Other single-disorder clinics (e.g., neurofibromatosis type 1 clinic)
Prenatal Diagnosis Program: Perinatal Genetics
Ocular and Systemic Congenital Anomalies
• Amniocentesis/chorionic villus sampling clinics Individuals with multiple ocular and systemic anomalies may or may
• Ultrasound program not fit into a particular syndrome. In these situations, the experience of
• Maternal serum α-fetoprotein program a geneticist in recognizing malformation patterns and understanding the
variability of genetic conditions can aid diagnosis. If an underlying cause
Genetic Screening is identified, relatives can then undergo genetic counseling.
• Newborn screening program/follow-up clinic
• Other population-screening programs (e.g., for Tay–Sachs disease) Specific Eye Diseases
Education/Training
A genetic evaluation is important for families with inherited eye diseases.
• Healthcare professional Many ophthalmological diseases have a well-documented inheritance
• General public pattern, and describing the inheritance to family members may help
• School system identify affected relatives who could be diagnosed and treated early in the
• Teratology information services course of the disease. This is especially important in families with condi-
tions such as dominantly inherited juvenile glaucoma.
Ocular Defects Associated With Genetic Diseases

Many genetic diseases have associated ocular defects. For example, a diag-
nosis of neurofibromatosis type 1 may be made in a child because Lisch
nodules were detected on a clinical examination.23 The child and family
should be referred for genetic counseling to help define the recurrence
X-linked disorders are always passed from a female carrier who has risks for other family members.
inherited a copy of an abnormal gene on the X chromosome received from
either her mother (who was a carrier) or her father (who was affected by Confidentiality
the disease). Man-to-man transmission is not seen in diseases caused
by defects in genes located on the X chromosome. Among sons born to Confidentiality is an important issue in genetic testing and genetic coun-
female carriers of X-linked disorders, 50% are affected by the disease, and seling. Confidentiality issues should be discussed before the initiation of
50% of daughters born to female carriers of X-linked disorders are carriers testing so there is consensus on how results are reported, who receives
of the disease. All the daughters of men affected by X-linked disorders are results, and where the information is documented.
carriers of the disease.
Mitochondrial disorders are inherited by sons and daughters from
the mother. The frequency of affected offspring and the severity of the
KEY REFERENCES
disease in affected offspring depend on the number of abnormal mito- Consugar MB, Navarro-Gomez D, Place EM, et al. Panel-based genetic diagnostic testing
for inherited eye diseases is highly accurate and reproducible, and more sensitive for
chondria present in the egg that gives rise to the affected child. Diseased variant detection, than exome sequencing. Genet Med 2015;17(4):253–61.
and normal mitochondria are distributed randomly in all cells of the body, Feero WG, Guttmacher AE, Collins FS. Genomic medicine – an updated primer. N Engl J
including the female gametes. As a result, not all the eggs present in a Med 2010;362:2001–11.
woman affected by a mitochondrial disorder have the same number of Kwon YH, Fingert JH, Kuehn MH, et al. Primary open-angle glaucoma. N Engl J Med
2009;360:1113–24.
affected mitochondria (heteroplasmy). Men affected by mitochondrial dis- Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s
orders only rarely have affected children, because very few mitochondria congenital amaurosis. N Engl J Med 2008;358:2240–8.
in the developing embryo are derived from the sperm used to fertilize Muto R, Yamamori S, Ohashi H, et al. Prediction by FISH analysis of the occurrence of
the egg.22 Wilms tumor in aniridia patients. Am J Med Genet 2002;108:285–9.
With careful diagnosis and family history assessment, even sporadic Sim NL, Kumar P, Hu J, et al. SIFT web server: predicting effects of amino acid substitutions
on proteins. Nucleic Acids Res 2012;40(Web Server issue):W452–7.
cases of heritable disorders are identifiable. In such cases, an estimate of Wiggs JL, Pierce EA. Genetic testing for inherited eye disease: who benefits? JAMA Ophthal-
recurrence risk can be calculated using the available pedigree and clini- mol 2013;131(10):1265–6.
cal information and the statistical principle called Bayes’ theorem. These
individuals should be referred to clinical genetics services such as those Access the complete reference list online at ExpertConsult.com
commonly found in hospital settings (Box 1.3.1).
17
booksmedicos.org
REFERENCES 12. Fan BJ, Pasquale LR, Rhee D, et al. LOXL1 promoter haplotypes are associated with
exfoliation syndrome in a U.S. Caucasian population. Invest Ophthalmol Vis Sci
1. Feero WG, Guttmacher AE, Collins FS. Genomic medicine – an updated primer. N Engl
J Med 2010;362:2001–11.
2011;52:2372–8.
13. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy for Leber congenital
1.3
2. Kwon YH, Fingert JH, Kuehn MH, et al. Primary open-angle glaucoma. N Engl J Med amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults
followed up to 3 years. Arch Ophthalmol 2012;130:9–24.

2009;360:1113–24.
3. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s 14. Zhang X, Wang P, Li S, et al. Mutation spectrum of PAX6 in Chinese patients with
congenital amaurosis. N Engl J Med 2008;358:2240–8. aniridia. Mol Vis 2011;17:2139–47.
4. Mulot C, Stucker I, Clavel J, et al. Collection of human genomic DNA from buccal cells 15. Alward WL, Kwon YH, Khanna CL, et al. Variations in the myocilin gene in patients with
for genetics studies: comparison between cytobrush, mouthwash, and treated card. J open-angle glaucoma. Arch Ophthalmol 2002;120:1189–97.
Biomed Biotechnol 2005;3:291–6. 16. Yu-Wai-Man P, Shankar SP, Biousse V, et al. Genetic screening for OPA1 and OPA3
5. Nussenzveig RH, Burjanivova T, Salama ME, et al. Detection of JAK2 mutations in par- mutations in patients with suspected inherited optic neuropathies. Ophthalmology
affin marrow biopsies by high resolution melting analysis: identification of L611S alone 2011;118:558–63.
and in cis with V617F in polycythemia vera. Leuk Lymphoma 2012;53:2479–86. 17. Wiggs JL, Pierce EA. Genetic testing for inherited eye disease: who benefits? JAMA Oph-
6. Suenaga E, Nakamura H. Evaluation of three methods for effective extraction of DNA thalmol 2013;131(10):1265–6.
from human hair. J Chromatogr B Analyt Technol Biomed Life Sci 2005;820:137–41. 18. Sim NL, Kumar P, Hu J, et al. SIFT web server: predicting effects of amino acid substi-
7. Consugar MB, Navarro-Gomez D, Place EM, et al. Panel-based genetic diagnostic testing tutions on proteins. Nucleic Acids Res 2012;40(Web Server issue):W452–7.
for inherited eye diseases is highly accurate and reproducible, and more sensitive for 19. Adzhubei IA, Schmidt S, Peshkin L, et al. A method and server for predicting damaging
variant detection, than exome sequencing. Genet Med 2015;17:253–61. missense mutations. Nat Methods 2010;7(4):248–9.
8. Green RC, Berg JS, Berry GT, et al. Exploring concordance and discordance for return of 20. Patel RY, Shah N, Jackson AR, et al. ClinGen pathogenicity calculator: a configurable
incidental findings from clinical sequencing. Genet Med 2012;14(4):405–10. system for assessing pathogenicity of genetic variants. Genome Med 2017;9(1):3.
9. Muto R, Yamamori S, Ohashi H, et al. Prediction by FISH analysis of the occurrence of 21. Epstein CJ, Erickson RP, Hall BD, et al. The center-satellite system for the wide-scale
Wilms tumor in aniridia patients. Am J Med Genet 2002;108:285–9. distribution of genetic counseling services. Am J Hum Genet 1975;27:322–32.
10. Wawrocka A, Budny B, Debicki S, et al. PAX6 3′ deletion in a family with aniridia. Oph- 22. Wallace DC. Mitochondrial DNA sequence variation in human evolution and disease.
thalmic Genet 2012;33:44–8. Proc Natl Acad Sci USA 1994;91:8739–46.
11. Tang S, Halberg MC, Floyd KC, et al. Analysis of common mitochondrial DNA muta- 23. Ruggieri M, Pavone P, Polizzi A, et al. Ophthalmological manifestations in segmental
tions by allele-specific oligonucleotide and Southern blot hybridization. Methods Mol neurofibromatosis type 1. Br J Ophthalmol 2004;88:1429–33.
Biol 2012;837:259–79.
17.e1
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Part 2 Optics and Refraction

Light
Scott E. Brodie 2.1
750 nm (red) to about 440 nm (violet). Longer wavelengths may be dis-
Definitions: cernable as heat (“infrared”) and can be detected by suitable photographic
Light – Electromagnetic energy detectable by the eye. emulsions and electronic camera chips. Shorter wavelengths (“ultraviolet”)
Geometrical Optics – The properties of light governed by propagation are sometimes visible in eyes after removal of the crystalline lens and can
in straight lines, refraction, and reflection. be seen by some insects (Fig. 2.1.1).
Physical Optics – The properties of light described by wave phenomena The behavior of light under ordinary circumstances is very familiar,
such as interference, diffraction, and polarization. but careful observations reveal important subtleties that have fascinated
Quantum Optics – The properties of light described by absorption and scientists for hundreds of years. In general, the behavior of light in detail
emission of energy in discrete quanta, proportional to frequency. depends on the scale of the objects with which it interacts.
Interactions between light and large objects (relative to the wave-
length of the light) generally follow simple geometrical rules and come
Key Features under the heading of “geometrical optics.” This is the regime of typical
• Specular Reflection – Light reflects off smooth surfaces so that the human experience—light rays travel in straight lines through homoge-
angle of incidence equals the angle of reflection. neous media but may be reflected by polished smooth surfaces or may be
• Snell’s Law – The relationship between the bending of light at an refracted (bent) as they pass from one medium to another. These interac-
interface surface to the speed of light on either side of the interface. tions of light with matter are governed by the law of (specular) reflection
• Vergence Equation – The relationship between the power of a lens and Snell’s law, respectively. Geometrical optics is the appropriate tool for
and the location of the images it forms. understanding the use of lenses for the formation of images—as in the
human eye—or as modified by lenses such as spectacles, contact lenses, or
intraocular lens implants.
INTRODUCTION When the dimensions of optical systems are comparable to the wave-
length of the light passing through them, the effects of interference
Visible light is the portion of the electromagnetic spectrum that can be become evident, demonstrating the “wave-like” properties of light. Perhaps
detected by the eye. In practice, this ranges from wavelengths of about the most common example is the diffraction of light as it passes through
Fig. 2.1.1 The Electromagnetic

THE ELECTROMAGNETIC SPECTRUM Spectrum. The pictures of mountains,
people, buttons, viruses, etc., are used to
produce a real (i.e., visceral) feeling of the
visible spectrum nm size of some of the wavelengths. In the bar
at the bottom of the figure, gray portions
radio 700 600 500 400 of the bar indicate regions of the spectrum
to which the atmosphere is transparent.
1 GHz 100 GHz
(Adapted from Zeilik M. Astronomy: the
infrared evolving universe. 3rd ed. New York:
m Harper & Row; 1982.)
AM FM
540–1650 kHz 88–108 MHz
ultraviolet
soft X-rays hard
-rays
frequency (Hz)
3 102 3 104 3 106 3 108 3 1010 3 1012 3 1014 3 1016 3 1018 31020 3 1022 3 1024
106 104 102 1 10–2 10–4 10–6 10–8 10–10 10–12 10–14 10–16
wavelength (m)
mountains factory people button point dust bacteria virus atom atomic nucleus
size
atmospheric transparency
19
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finite apertures, such as the pupil of the human eye. Because the light vacuum divided by the speed of light in the medium—the refractive index
2 bends slightly under these circumstances, diffraction limits the sharpness

of images formed through small apertures. Wave properties of light also
are seen in the phenomena of polarization and are exploited in such optical
is often denoted by the letter n, and is always greater than 1.0 for material
media, as light will always travel through a material medium more slowly
than through a vacuum. If we measure the angle between the incoming
instruments as interferometers (which accurately measure very small dis- light ray and the surface normal at the point of contact (the “angle of inci-
Optics and Refraction
tances) and clinical devices such as the optical coherence tomographer, dence”) and compare it with the angle between the surface normal and
which exploits interference between beams of light that have scattered the outgoing ray that emerges from the point of contact as the light moves
from various surfaces within the eye to provide high-resolution images of away from the interface in the second medium, we have
ocular tissues. These phenomena are discussed later under the heading of
“Wave Properties of Light.” n1 sin θ1 = n2 sin θ 2
At the smallest scales and energies, the quantum behavior of light
becomes evident. Quantum effects are responsible for the operation of where n1 and n2 are the refractive index of the first and second material,
lasers, the characteristic absorption and emission spectra of various mate- respectively, and θ1 and θ2 are the angles made by the incident and emerg-
rials, and the phenomena of fluorescence and phosphorescence. ing rays with the surface normal (Fig. 2.1.4).
In practice, if the light goes from a “rarer” medium, such as air (with a
GEOMETRICAL OPTICS greater velocity of light and thus a smaller refractive index), to a “denser”
medium (with a slower velocity of light and thus a greater refractive index),
Under ordinary conditions, light travels through homogeneous media in such as water or glass, the light will bend toward the surface normal. (Of
straight lines. This can be exploited by simple devices such as the “camera course, this use of the word “dense” has nothing to do with the specific
obscura” or pinhole camera, which forms images of bright objects by gravity of the materials.) Light that travels from a “slow” medium to a
selecting a single ray of light from each point in the source object that medium with a greater velocity of light will bend away from the surface
threads through a small aperture to form an inverted image on a conve- normal.
nient surface beyond the pinhole. Although these images enjoy an excellent The bending of light across such an interface is readily appreciated
depth of field, bringing objects both near and far into sharp focus, the small when looking at objects in a pool of water from the air above, where
aperture limits the amount of light available to form the image (Fig. 2.1.2). objects are typically seen as farther away than they really are because the
On the other hand, the paths of light rays can be altered by reflection light from the objects bends toward the observer as it passes from the
or refraction. In reflection, the incoming ray of light reverses direction to water to the air (Fig. 2.1.5).
create equal angles between the incoming ray and the exiting ray, as mea- Ordinary prisms work the same way. Light passing through a prism
sured from a line through the point of contact perpendicular to the reflect- is bent toward the base of the prism. Objects viewed through a prism are
ing surface (the “surface normal”). This is the “law of (specular) reflection.” seen displaced toward the apex. The strength of a prism is usually given in
Specular (mirror-like) reflection is seen as light encounters smoothly pol- terms of “prism diopters”—a prism that deflects a beam of light by d cm
ished surfaces, such as mirrors, and still pools of liquids, such as water at a distance 1.0 m from the prism is said to have a strength of d prism
or mercury. Flat reflecting surfaces recreate accurate reproductions of the diopters, usually abbreviated “Δ.”
source objects (with, of course, the left–right direction reversed). Curved If the angle of incidence for light going from a “slow” to a “fast”
reflecting surfaces can be used to magnify or minify the source objects, as medium exceeds the “critical angle” where sin θ = n2/n1, then Snell’s law
used for special purposes such as telescopes, shaving mirrors, or the mini- cannot be satisfied, and the light ray is reflected at the interface rather than
fying mirrors rearview mirrors used in automobiles (Fig. 2.1.3). refracted across it. This “total internal reflection” is employed by prisms in
When light traverses a boundary between two transparent media where high-quality binoculars, for example (Fig. 2.1.6).
the speed of light differs between the two materials, the path of the light When light passes through a curved surface such as the surface of
may be deflected from a straight line by the process of refraction.1 a lens, the deflection depends in detail on the shape of the surface. For
The deviation is described by “Snell’s law” as follows. First, compute lenses with spherical surfaces, for which one can determine a geometrical
the “refractive index” of each material as the ratio of the speed of light in a center of curvature, and for light rays that closely approximate the line
between the source objects and the center of curvature (the “optic axis”),
one can use Snell’s law to show that the lens will form a pointlike image of
Fig. 2.1.2 The Camera Obscura. a point source and derive simple rules relating the location of the source
(From Wikipedia “Camera Obscura”; objects, the curvature (or power) of the lens, and the location of the image
public domain.) formed by the lens. This is referred to as “stigmatic imagery” (Fig. 2.1.7).
Stigmatic imagery is strictly possible only for “paraxial” rays and lenses
with relatively small apertures (though larger than the pinhole apertures
described earlier). Nevertheless, this formulation of geometrical optics is
very useful in a wide variety of settings, even when the strict assumptions
are not met. For example, in the human eye, strict stigmatic imaging is
Fig. 2.1.3 Specular Fig. 2.1.4 Snell’s Law.

SPECULAR REFLECTION Reflection. (From SNELL’S LAW (From Wikipedia, “Snell’s
Wikipedia, “Specular Law; public domain.)
Reflection”; available for
P
normal
mirror unrestricted use from

Creative Commons.)
P θ1
interface n1 v1
normal θi
O n2 v2
θr
θ2
Q
Q
20
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possible only when the pupil is fairly small, but because awareness of For thin lenses, the power of two lenses placed in contact with
the sharpness of the image formed on the retina by the optics of the eye
is dominated by the image presented to the fovea, the paraxial regime
each other and used as a single lens system is approximately additive:
P = P1 + P2. 2.1
remains an adequate description and is routinely used to guide the pre- Lenses can also be fabricated with concave surfaces. These lenses,
scription of spectacle lenses and contact lenses. which are assigned powers less than 0, do not form images by themselves
Light
but can be used to adjust the power of convex lenses by means of the addi-
BASIC STIGMATIC OPTICS tion formula above. Placing such a lens adjacent to an existing lens system
can reduce the effective power, for example, pushing an image farther to
A convex lens will image the light from an infinitely distant object (such the right, as described earlier.
as a star) at a finite distance, say f, from the lens on the side opposite from If light approaches or leaves a lens through a medium other than air
the source. This distance is referred to as the focal length of the lens and or a vacuum (with n = 1.0), the equation (*) must be modified as follows:
is measured in meters. The “power” of the lens, P, is given by the equation
P = 1/f. In this context, the units for lens power are referred to as “diopters” n1 u + P = n2 v
and abbreviated “D.” For objects closer than infinity, the image location is
determined by the relation where n1 and n2 are the refractive indices of the media to the left and right
of the lens, respectively.
1 u + P = 1 v , (*) If lenses are used in combination but spaced apart, the image formed
by the first lens encountered by the light becomes the source for the next
where u is the distance in meters from the lens to the source object (objects lens in sequence, and the effect of each lens in the sequence is thus ana-
to the left of the lens are considered to be at distances less than 0); and v lyzed in turn.
is the distance from the lens to the image. This formula is referred to as For example, in a myopic eye, the optical power of the cornea and
the vergence equation. In practice, if an image is formed to the right of lens system is too great for the axial length of the eye, and images of
such a lens, increasing the power P will pull the image closer to the lens; distant objects are formed in front of the retina. A correcting concave
reducing the power P will push it farther away.2 (minus-power) lens placed in front of the eye will move the image farther
away from the anterior segment, placing it on the fovea, allowing for clear
vision and normal acuity. In a hyperopic eye, the optical power of the ante-
rior segment is too little for the axial length of the eye, and so additional
plus-lens power is placed in front of the eye to pull the image forward and
Fig. 2.1.5 Refraction at an clarify the vision. See Section 2.4 for further details.
Air–Water Interface. The If light passes through the periphery of a thin lens, it encounters
portion of the soda straw seen inclined surfaces resembling those of a prism, oriented base-inward for a
through the surface of the convex lens or base-outward for a concave lens. In general the deflection is
water is closer than it appears. proportional to the power of the lens and the distance of the incident ray
(After Wikipedia, “Refraction”; from the optical center.
available for unrestricted
use from Creative Commons;
original figure has been
truncated.)
Fig. 2.1.7 Image Formation by a Biconvex Lens. (After Wikipedia, “Lens [Optics]”;
available through Creative Commons; original figure has been truncated.)
Fig. 2.1.6 Total Internal Reflection. (From Wikipedia,

TOTAL INTERNAL REFLECTION “Refraction”; available for unrestricted use from Creative
Commons.)
critical angle total internal reflection
air
θ2
y
ra
n2
d
cte
ra
ref
y
n1
t ra
den
θ2 θ2 θ2
inci
θ2
water
21
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Comparison between the definition of the prism diopter and the defini- diffraction, polarization, and dispersion. These phenomena are readily
2 tion of dioptric power for lenses yields the “Prentice rule”: The prismatic
effect of lens decentration is given by the formula d (Δ) = P•r, where d is
the prismatic effect in prism diopters, P is the power of the lens in diop-
understood in terms of the classical Maxwell equations of electricity and
magnetism but are reasonably appreciated with less detailed descriptions,
which simply identify light with a single transverse wave (that is, a wave
ters, and r is the distance from the optical axis of the lens to the incident that oscillates in a direction perpendicular to the propagation of the light)4
ray of light in centimeters. (Fig. 2.1.10).
ASTIGMATIC OPTICS Interference

Lens surfaces with more complex shapes than the spherical surfaces dis- Suppose monochromatic light passes through a narrow slit and then in
cussed earlier cannot form simple point images. The simplest case is turn through one of two narrow slits separated by a small distance and
that of “toric surfaces” resembling the surface of the side of a rugby ball, is then allowed to land on a screen. Instead of two stripes, one for each
an American football, or the outer rim of an automobile tire inner tube of the final slits, the light creates a pattern of alternating bright and dark
(Fig. 2.1.8). stripes. This is apparently due to the variation in the path length from the
Such a surface has different degrees of curvature in different directions two slits to each image point on the screen, so that the waves emanating
at each point. Typically, the maximal and minimal curvatures occur in per- from each slit alternately reach the image screen so that the peaks coincide
pendicular directions at each location. If the surface is sufficiently regular, (producing a bright stripe—“constructive interference”) or so that a peak
it can be characterized as equivalent to a spherical refracting surface taken from one slit coincides with a trough from the other slit (producing a dark
together with a cylindrical surface, with maximal refracting power in one stripe—“destructive interference”). As the observation point on the screen
direction and no power in the perpendicular direction. Such lenses form moves to one side, the relative distance from each of the final slits varies.
a complex image of a source object point consisting of two perpendicular When the distances differ by exactly one wavelength, the pattern repeats
“focal lines” at the two distances corresponding to the optical powers of the (Fig. 2.1.11).
steepest and flattest meridians of the surface (Fig. 2.1.9).
In practice, such a lens can produce stigmatic imagery with the addi-
tion of a correcting cylinder oriented to compensate for the variation in Fig. 2.1.10
power of the original lens. ELECTROMAGNETIC WAVE Electromagnetic Wave.
More complex surfaces and their optical effects are discussed in Section An electromagnetic wave
2.6 on Wavefront Optics and Optical Aberrations of the Eye.3 consists of an oscillating
electric field perpendicular
to an oscillating magnetic
WAVE PROPERTIES OF LIGHT field. Both fields are
perpendicular to the
In the nineteenth century, it was realized that light exhibits behaviors sug- direction of propagation.
gestive of wave propagation, which cannot be incorporated into the simple
geometrical framework described earlier. These include interference,
Fig. 2.1.8 Toric Surface. (From

Wikipedia, “Toric Lens”; available under
GNU Free documentation license.)
CONOID OF STURM TWO-SLIT EXPERIMENT
astigmatic lens focal lines

X
interval of Sturm θ
P
cross sections:
circle of least confusion
Fig. 2.1.9 Conoid of Sturm. Astigmatic imaging of a point source by a toric

lens forming a complex figure between two perpendicular focal lines. ([From
AccessLange: General Ophthalmology / Printed from AccessLange (accesslange.
22 accessmedicine.com). Chapter 20, Optics and refraction, Paul Riordan-Eva] Copyright Fig. 2.1.11 The “two-slit experiment.” (From Wikipedia “Double-slit experiment”;
©2002–2003 The McGraw-Hill Companies. All rights reserved.) licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license.)
booksmedicos.org
Fig. 2.1.12 The Airy disc. (From
RESOLUTION OF DIFFRACTION PATTERNS
Wikipedia, “Airy disk”; public domain.)
OF TWO OBJECT SOURCES OF LIGHT 2.1
Light
Production of Light intensity Appearance of
diffraction patterns distribution light distribution
S2 S1 central maxima + second minima
Similar patterns can be seen with light passing through a single slit or
round aperture, as the light coming from the edge of the aperture inter- central maxima + first minima
feres with the light coming from the opposite edge, as if the edges were (angle of
the “slits” in a two-slit experiment. In the case of a circular aperture, the separation)
stripes take the form of concentric rings. The central spot in the pattern is
known as the “Airy disc” (Fig. 2.1.12).
In general, the spacing between interference fringes will vary with the merge to one image
wavelength of the source illumination—shorter wavelengths give rise to
more narrowly spaced fringes. Narrow slits or spacing between the slits
leads to wider spacing between fringes, as greater angles are needed to
create path length differences of a half wavelength.
Nearly monochromatic light is needed to observe these effects, so as to
produce consistent patterns of peaks and troughs.
Mosaic of retinal cones

Diffraction
(angle of
As described earlier, interference of portions of a light beam passing near resolution)
the opposite edges of a small aperture creates a pattern of fringes that
extends beyond the geometrical shadow of the aperture on the screen. In intensity
this context, the apparent “spreading out” of the light beyond the geomet-
rical limits of the expected image is referred to as “diffraction.” In most
contexts, it is sufficient to consider the diameter of the Airy disc as a useful
S1 S2
description of the magnitude of this effect. For monochromatic light of
wavelength λ, the angular extent of the Airy disc is given by
sin θ = 1.22 λ d ,
Fig. 2.1.13 Resolution of Diffraction Patterns of Two Object Sources of Light.
where d is the diameter of the aperture. For the human eye, this is Two object sources of light (S1 and S2) cannot be resolved if their diffraction patterns
comparable to the diameter of a single foveal cone, suggesting that the (Airy discs) overlap substantially. Two refraction patterns are produced by a circular
optics of the eye have evolved to approach “diffracted limited” resolution aperture placed between two lenses, and resultant patterns of the light intensity
(Fig. 2.1.13). distribution and appearance are shown. The central maxima of one diffraction
pattern falls on the second minima of the diffraction pattern from the second
source; the central maxima of one diffraction pattern falls on the first minima of the
Polarization diffraction pattern from the second source, and the two images can just be resolved
(Rayleigh criterion); the two images merge as one. Bottom right, mosaic of retinal
The association of an oscillation perpendicular to the direction of propaga- cones with the diffraction pattern superimposed. (Adapted from Jenkins FA, White
tion of a light beam endows it with a specific orientation. If this orientation HE. Fundamentals of optics. New York: McGraw-Hill; 1950. p. 290–3; and Emsley HH.
is consistent across the beam of light, it is said to exhibit “polarization.” Visual optics. London: Hatton Press; 1950. p. 47.)
In practice, polarization is demonstrated by the interactions of light with
materials that exhibit a particular, consistent molecular organization, such
as certain (“birefringent”) crystals or manufactured materials (Polaroid
filters) (Fig. 2.1.14). POLARIZATION
Polarized light can also occur in nature when light is reflected from
a suitable surface, such as a flat pool of water. The preferred direction of Horizontally Vertically
polarization is parallel to the reflecting surface, in this case horizontal. polarized polarized
Sunglasses containing filters that preferentially transmit vertically polar-
ized light will selectively block these reflections, which make up the bulk
of the annoying stray light seen when driving or boating.
Polarized light filters also are useful in certain eye examinations. Ste-
reoscopic depth perception tests are designed to create separate images for
the two eyes, each polarized in one of two perpendicular directions. When
viewed through glasses with polarized filters placed perpendicular to each
other, each eye can see only one of the test targets, creating a stereoscopic
3-D image. Similar strategies can be used to control which eye sees partic-
ular acuity targets to reveal possible malingering.
Dispersion
Visible light varies in wavelength from red (with the longest wavelengths)
to blue and violet (with the shortest wavelengths). All wavelengths travel
through a vacuum or through air at the same velocity. However, material
media may transmit light at different velocities depending on its wave- Fig. 2.1.14 Polarization. Both transverse waves propagate in the same direction but
length. This phenomenon is referred to as “dispersion,” and it accounts oscillate in different planes. Here, only the scalar wave approximation is adopted, 23
for the ability of prisms to break up white light into its constituent colors, and only the electric field is shown.
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Fig. 2.1.16 Energy
2 energy
FLUORESCENCE Levels in a Hypothetical
Fluorescent Molecule.
A relatively high-energy
photon raises an electron
to the highest level. The

electron drops to a nearby
nonradiative
level by nonradiative
transition
means and then drops
to its original low level
emitting a lower energy
photon than the one
stimulating emitted originally absorbed.
photon “fluorescent”
photon
Fluorescence and Phosphorescence

In some cases, the energy absorbed by a molecule will be dispersed in
stages, initially dropping from one state to a nearby state (the energy
released in the form of thermal energy of the molecule, rather than
released as a photon), and subsequently the remaining energy released as
a photon as the electron returns to its initial base level. In such an event,
the energy of the photon that is emitted will be less than that of the photon
that was initially absorbed, and so will necessarily be seen as a photon
of a different wavelength, shifted toward the red end of the spectrum
(Fig. 2.1.16).
Fig. 2.1.15 Dispersion of White Light by a Prism. (From Wikipedia “Prism”; licensed If this transition occurs promptly, the effect is referred to as fluores-
under the Creative Commons Attribution-Share Alike 3.0 Austria license.) cence. For example, the dye molecule fluorescein, frequently used as a
disclosing agent in ophthalmology, absorbs photons in the blue portion of
the spectrum but fluoresces a yellow–green color. If the intermediate level
is more stable, the intermediate energy state can persist for many hours,
as light of each color is refracted by a prism to slightly different degree resulting in a prolonged release of the light energy as the final energy tran-
(Fig. 2.1.15). sition occurs over an extended period. In this case the process is known as
In most optical devices, this effect is something of a nuisance, produc- phosphorescence.
ing colored fringes at the edge of images. In practice this is corrected in
high-quality optics by using lenses of different types of glass in such a way Lasers
as to cause their dispersion effects to cancel out. In the human eye, this The operation of laser devices is another important manifestation of a
effect is referred to as “chromatic aberration,” which is the basis of the quantum effect. In this case a working medium is “pumped” into a meta-
“duochrome” test used to refine measurements of refractive error. stable state by absorbing energy from an external source, often a flash
of light from an ordinary source.6 This produces an “inversion,” with an
Quantum Effects excess of electrons at an elevated energy state. The probability of such
electrons dropping to their base energy level is enhanced by interaction
At the smallest scales, the quantum-mechanical nature of the interactions with another photon of the same energy as the latent transition—this is
between light and matter become evident. These effects reflect the observa- referred to as “stimulated emission of radiation.”
tion that an energy transfer between light and matter occurs only in fixed In practice, the working medium is contained in a cylindrical cavity
amounts (“quanta”) with energy proportional to the frequency of the light, with a reflecting mirror at one end and a partially reflecting mirror at the
according to Planck’s equation: E = hν, where h is Planck’s constant.5 other. After creation of the inversion, as electrons revert to their base level,
For example, the electrons in a molecule transition between various photons of an energy corresponding to this transition start to bounce back
energy states by exchanging light energy (“photons”) with the environ- and forth between the two mirrors, stimulating more photon emissions
ment. As the various available energy states form a series of discrete of precisely the same energy. The corresponding light beams accumu-
values, the energy of the various possible transitions can take only certain late homogeneously in the laser cavity, and eventually the excess energy
discrete values. These are appreciated as the emission lines seen in the emerges through the partially silvered mirror as a highly monochromatic
spectrum when such a material is heated to incandescence, which are beam of light with a very high degree of coherence (all waves with peaks
characteristic of the material, or as absorption lines seen when broadband and troughs aligned parallel to the laser cavity mirrors). The resulting laser
light passes through a gaseous medium, absorbing only light of the fre- light can be very accurately collimated into a beam with little angular diver-
quencies (colors) corresponding to permissible transitions of electrons gence, suitable for applications from photocoagulation of retinal lesions to
between allowed energy levels. serving as a lecture pointing device (Fig. 2.1.17).
24
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Fig. 2.1.17 Gas Laser. A typical design consists of a
GAS LASER DESIGN gas-filled cavity, external optical pumping lights, and a
resonator that comprises partially and totally reflecting 2.1
Initial state mirrors. Without optical pumping, most of the gas
atoms are in lower energy states and incapable of
Light
light for undergoing either spontaneous or stimulated emission.
optical pumping With optical pumping, photons from the external lights
totally reflecting are absorbed by the gas atoms, which raises the energy
partially reflecting mirror of the atoms and makes them capable of undergoing
mirror spontaneous or stimulated emission. Ultimately,
laser cavity the majority of atoms are in excited states—a
light for population inversion. One of the higher energy atoms
optical pumping spontaneously emits a photon that produces stimulated
emissions as it passes by other high-energy atoms. As
Optical pumping on the photons are reflected back and forth across the
cavity multiple times, a chain reaction of stimulated
emissions is produced.
Spontaneous emission
KEY REFERENCES Lipson A, Lipson SG, Lipson H. Optical physics. 4th ed. Cambridge: Cambridge University
Press; 2011.
Basic and Clinical Science Course, Section 3, “Clinical Optics,” American Academy of Oph- Milonni PW, Eberly JH. Laser physics. Hoboken: Wiley; 2010.
thalmology, 2017–2018. Rubin ML. Optics for clinicians. 25th ed. Gainesville: Triad Publishing; 1993.
Feynman RP. QED: The strange theory of light and matter. Princeton: Princeton University
Press; 2014. Access the complete reference list online at ExpertConsult.com
Hecht E. Optics. 5th ed. Essex: Pearson Education Limited; 2014.
25
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REFERENCES 4. Lipson A, Lipson SG, Lipson H. Optical physics. 4th ed. Cambridge: Cambridge Univer-
sity Press; 2011.
1. Rubin ML. Optics for clinicians. 25th ed. Gainesville: Triad Publishing; 1993.
2. Hecht E. Optics. 5th ed. Essex: Pearson Education Limited; 2014.
5. Feynman RP. QED: The strange theory of light and matter. Princeton: Princeton Univer-
sity Press; 2014.
2.1
3. Basic and Clinical Science Course, Section 3, “Clinical Optics,” American Academy of 6. Milonni PW, Eberly JH. Laser physics. Hoboken: Wiley; 2010.
Light
Ophthalmology, 2017–2018.
25.e1
booksmedicos.org

Optics of the Human Eye

Daniel Diniz, Francisco Irochima, Paulo Schor 2.2
survey of normal eyes shows that almost every human eye has a base-
Definition: The classic optics of the eye are best understood in terms line corneal astigmatism of at least 0.25–0.50 D.6 Spherical aberration is
of the optical characteristics of its components—the cornea, pupil, caused by the radius of curvature of the corneal surface changing (gener-
crystalline lens, and retina—and how they function in combination. ally increasing) with distance from the center of the pupil to the pupillary
margin. Several devices based on Placido’s ring principle provide quan-
titative data on corneal aberrations.7 The amount of spherical aberration
contributed by the cornea varies with pupillary aperture and individual
corneal shape. For a pupil 4 mm in diameter, spherical aberration varies
Key Features from +0.21 D to +1.62 D, depending on the specific corneal form.8
The quality and characteristics of the different optical components and
the combination are described in these terms:
• Cornea. PUPIL
• Pupil. The iris expands or contracts to control the amount of light admitted to the
• Lens. eye. The pupil can range in diameter from 8 mm in very dim light down
• Accommodation. to about 1.5 mm under very bright conditions.9 A strong association exists
• Scattering. between visual acuity and pupillary diameter. For example, visual acuity
• Aberrations. has been shown to improve steadily as background illumination increases
• Retina. up to a value of 3400 cd/m2.10 This improvement is due to blockage of
• Resolution and focal length. paraxial aberrant rays and brain compensation for the resulting dimming
• Depth of focus. of retinal illumination. To deliver more light (larger pupil) without aberra-
• Refractive errors. tion it is necessary to control the peripheral shape of the cornea.
Retinal image quality, as determined by optical aberrations such as
spherical aberration, tends to improve with decreasing pupil diameter,
INTRODUCTION because peripheral optical aberrations decrease with decreasing pupil size.
On the other hand, retinal image quality is limited by diffraction, which
Each optical component of the eye contributes to image formation on the tends to improve with increasing pupil diameter. For most eyes the best
retina and its brain interpretation. In order to discuss these components, retinal images are obtained when the pupil diameter is about 2.4 mm,
we must first define the limits of normality considering the best image which is the diameter at which the effects of aberration and diffraction
quality that can be produced by an emmetropic eye (an eye without refrac- are balanced optimally. Thus the optimal pupillary size seems to be deter-
tive error). The determination of these limits is important, as they serve mined by several influences. In fact, Campbell and Gregory have shown
as guides for intervention on clinical practice. This chapter discusses indi- that pupil size tends to be adjusted automatically to give optimal visual
vidual optical variables that characterize the normal human eye as well acuity over a wide range of luminance.11
abnormal conditions of the refracting apparatus of the eye, also called
ametropia. LENS
CORNEA The crystalline lens, which has about one-third of the eye’s refractive power,
enables the eye to change focus. When the eye views nearby objects, the
The cornea’s anterior surface is approximately spherical, with a radius of ciliary muscle changes the shape of the crystalline lens by making it more
curvature that is typically a bit less than 8 mm. This surface is responsi- bulbous and, consequently, optically more powerful. The lens of a young
ble for about two-thirds of the eye’s refractive power. Technology based in adult can focus over a range greater than 10 D. Presbyopia, which begins
the Scheimpflug principle allows for the detailed analysis of each interface at about 40 years of age (depending on the environmental factors such as
together with the local thickness in estimating the total corneal power for temperature),12 is the inability of the eye to focus (accommodate) due to
an individual eye before and after corneal surgery.1 The corneal stroma hardening of the crystalline lens with age. Experiments that disrupt the
must be transparent for high-quality image formation on the retina, yet the hard collagen within the lens are ongoing and may provide new insights in
normal human cornea scatters 10% of the incident light.2 By comparison, presbyopia correction.13 When the eye can no longer accommodate at the
the corneal stroma of the eagle is almost as transparent as glass.3 This reading distance, positive spectacle lenses of about 1.5–3 D are prescribed
factor (along with the larger pupil size and finer cone diameter) is why the to correct the difficulty.
resolution of the eagle eye is better than 120 cycles per degree, which is The normal 20-year-old crystalline lens scatters about 20% of the inci-
equivalent to a Snellen acuity of 20/5 (6/1.5).4 dent light. The amount of scatter is more than double this in the normal
The aspherical shape of the cornea’s anterior surface affects the quality 60-year-old lens.14 Such scatter significantly diminishes contrast sensitiv-
of the retinal image. Normal corneas have a flatter periphery and steeper ity.15 Also, the normal 20-year-old lens absorbs about 30% of incident blue
center, counteracting the effect of paraxial light that tends to bend more light. At age 60, this absorption increases to about 60% of the incident
at peripheral areas. The “Q” factor, also named asphericity or eccentric- blue light.16 The increase of blue light absorption with age results in subtly
ity factor, quantifies this central-periphery flattening and averages −0.25 decreased color discrimination and decreased chromatic aberration. It is
in normal eyes. A more negative number means that this cornea is steeper possible that this increased absorption helps to reduce the amount of UV
than normal (i.e., central keratoconus), and less negative “Qs” are seen, for light reaching the older retina, protecting it from oxidative damage, which
example, in postrefractive myopic procedures. Such knowledge was built is seen in age-related macular degeneration.
into equipment for new refractive surgeries that allows for the control of The variation in index of refraction of the crystalline lens (higher index
final “Q” factor, aiming for better contrast definition after surgery.5 in the nucleus, lower index in the cortex) is responsible for neutralization
26 Corneal astigmatism is caused by this surface having different radii of of a good part of the spherical aberration caused by the human cornea. A
curvature along different meridians (directions in the coronal plane). A progression toward positive spherical aberration throughout life due to the
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2.2

A B
Fig. 2.2.1 Spherical Aberrations Produced by Lenses of the Same Shape. (A) A glass lens. (B) A fish lens. The variation in index of refraction is responsible for the
elimination of spherical aberration in the fish lens. (Reproduced from Fernald RD. Vision and behavior in an African Cichlid fish. Am Sci 1984;72:58–65.)
Fig. 2.2.2 Accommodation by von Helmholtz Model.

ACCOMMODATION BY HELMOLTZ MODEL (Courtesy Francisco Irochima, MD.)
crystalline lens has been described.17 Fig. 2.2.1 shows how this variation of
index of refraction in the spherical fish lens almost eliminates its spherical ZONULES AND LENS DETAILS ON ACCOMMODATION
aberration compared with a spherical glass lens.18
ACCOMMODATION
In a convergent optical system, as an object approaches, its formed image
moves away from its original position, that is, farther away from the lens.
Accommodation is a complex mechanism involving sensory and neuro-
muscular phenomena by which the human eye, through contraction of the
ciliary muscle, changes the optical power of the lens to assist the conver-
gence of the image to the retina, adjusting the focus to different distances
between the object of regard and the eye.
According to the von Helmholtz model (the most widely held theory),
when the visual target approaches nearer to the eye, there is a stimulus to
the contraction of the ciliary muscle that leads to a relaxation of the sus-
pensory ligaments of the lens, increasing its anterior–posterior diameter,
and a forward shift of the lens, and, consequently, its dioptric power19,20
(Figs. 2.2.2 and 2.2.3). The opposite occurs when relaxation of this mus-
culature occurs.
The precise details of the mechanism of accommodation remain Fig. 2.2.3 Zonules and Lens Details as Described by von Helmholtz. Contraction
unclear to this day. Discussion of the various hypotheses currently under of ciliary muscle leading to relaxation of the zonules and acommodation. (Courtesy
investigation is beyond the scope of this chapter. Francisco Irochima, MD.)
The ability of the lens to change its shape is called physical accom- 27
modation, whereas the contraction capacity of the ciliary muscle is called
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physiological accommodation. Both alter the refractive power of the system point, as we saw before, the added refractive power of the system is 10 D.
2 and can be measured. If the lens becomes stiffer and unsightly, unable to
alter its shape, physical accommodation is impaired even with the strength
of the preserved ciliary muscle. A similar process may occur with physio-
The amplitude of accommodation will be the difference of the power in
the two points, that is, A = P − R = 10 − 5 = 5 D. Notice that a 5 D myopic
eye accommodates 5 D to focus an image at 10 cm. Therefore, although
logical accommodation if weakness of the ciliary muscle21 exists. myopes cannot see objects at distance clearly, they have the advantage of
being able to see objects at closer range with a smaller effort of accommo-
Range and Amplitude dation (Fig. 2.2.5).
The greatest distance an object can be clearly seen by the eye with relaxed
accommodation is called the “far point.” The nearest point at which an
SCATTERING
object can be clearly seen is called the “near point,” which is the loca- Another significant optical factor that degrades vision is intraocular light
tion of the focus obtained with maximum accommodation. The range scatter. The mechanism of light scatter is different from the aberrations
of accommodation, by definition, is the distance between these two discussed earlier, each of which deviates the direction of light rays coming
points. The amplitude, measured in diopters, refers to the refractomet- from points in object space to predictable and definite directions in image
ric difference between the eye in maximum relaxation and maximum space. With light scattering, incoming light rays are deflected from their
accommodation. initial (i.e., prescattered) direction into random (postscattered) directions,
which generally lie somewhere within a cone angle of approximately
• Far point: The greatest distance at which an object can be seen clearly
a degree or so. Therefore a dioptric value cannot be placed on the blur
in the absence of accommodation.
caused by light scatter. A glaring light worsens the effect of light scatter on
• Near point: The closest distance at which an object can be seen clearly vision. Thus a young, healthy tennis player may not see the ball when it is
when maximum accommodation is used.
nearly in line with the sun. Light scattering is the mechanism associated
• Range of accommodation: Distance between the far point and the near with most cataracts and causes significant degradation of vision due to
point.
image blur, loss of contrast sensitivity, and veiling glare.
• Amplitude of accommodation: Difference in dioptric power between
the eye at rest and the fully accommodated eye.
The amplitude of accommodation can be measured directly by the
ABERRATIONS
method of spheres. In this method, we ask the patient to look at an object Aberrations are changes in image formation that do not occur in a clas-
40 cm away and change his/her need for accommodation with the addi- sically paraxial system.22 In other words, in specific situations, such as
tion of lenses. By adding negative lenses, the accommodation is stimulated when light incidence occurs at an angle far above the reference axis of
until the image begins to blur. For example, suppose the patient accepts the system, no formation of an image exists at a single point. In practice,
−2 D with clear vision. As we add positive lenses, the accommodation an optical system never makes a perfect point image and this does not
will relax until the image begins to blur again. Suppose in this situation, depend only on the regularity of the surface. With the advent of wavefront
the lens used was +3 D. In this case the patient has a 5 D amplitude of aberrometry, several new types of aberrations—especially those of high
accommodation. orders—can be classified and today become major challenges for optical
Further information can be obtained with simple examination. Placing system manufacturers and refractive surgeons.
an object at the nearest point where the patient can obtain sharp vision will The aberrations are divided into monochromatic and chromatic. The
determine the near point. Moving away the object, we define the far point. monochromatic aberrations can be further subdivided into several types:
In the case of a patient with 3 D of amplitude: If he or she is emmetropic, astigmatism, defocus, tilt, spherical aberration, among others.
the far point will be in infinity and the near point will be to 33 cm. If the
patient is a 3 D hyperope, the near point will be at infinity, because all Monochromatic Aberrations
the accommodation must be used to clarify the acuity at distance. If the Monochromatic aberrations of a geometrical nature are also called figure
patient has a myopia of 3 D, the near point will be 16.7 cm because the aberrations. In spherical aberration, for example, light rays that refract at
accommodation together with the refractive error amounts to a total of 6 D the extreme periphery of a convergent lens have a different focus from
of refractive power. those that enter the eye more centrally, better aligned with the optical axis.
In a hyperope, the accommodation necessary to see clearly at a distance Thus between them, many of the rays will cross at intermediate points,
is the same diopters of the magnitude of their hypermetropia. However, degrading the nominal point image (see Fig. 2.2.1). A comet-like tail
to see a near object 10 cm from the eye, as we saw before, 10 diopters (D) or directional flare appearing in the retinal image is a manifestation of
should be added to this value. another aberration called coma. This occurs due to the obliquity of the
In hyperopia, there is no object distance for which a clear retinal image system, resulting from misalignment of the various refracting surfaces in
can be obtained without accommodation (or optical correction)—the the eye. A large amount of coma (0.3 µm of coma alone) may point to
optical apparatus of the eye has too little dioptric power at rest to focus an specific corneal diseases such as keratoconus or a decentered intraocular
object on the retina. In this case we may define the far point of the eye as lens. Several other forms of monochromatic aberrations are induced by
the (virtual) point, located behind the eye, which is imaged by the relaxed differences in the axial curvature of the lens and inclination of the light
optics of the eye on the retina. Additional plus lens power, either from beams, among others.
accommodation or supplied by a spectacle lens, is necessary to obtain a
clear image. Chromatic Aberrations
For example, assuming a 4 D hyperope with amplitude of accommo- Because the index of refraction of the ocular components of the eye varies
dation of 8 D, the (virtual) far point is at 25 cm behind the eye. With an with wavelength, colored objects located at the same distance from the eye
accommodating effort of 4 D, the parallel rays from an object at infinity are imaged at different distances with respect to the retina. This phenom-
converge to the retina. Note that with an 8 D effort, this hyperope can con- enon is called axial chromatic aberration. In the human eye the magni-
verge divergent rays from a point 25 cm away from the eye. Assuming that tude of chromatic aberration is approximately 3 D.23 However, significant
this is the maximum available accommodation, by definition this is the colored fringes around objects generally are not seen because of the pref-
near point (Fig. 2.2.4). It is important to note that this hyperope needs to erential spectral sensitivity of human photoreceptors. Studies have shown
accommodate between 4 D and 8 D to see objects ranging from infinitely that humans are many times more sensitive to yellow–green light with a
distant to the near point. In other words, in some situations, the hyperope central wavelength at 560 nm than to red or blue light.8 Amber spectacles
can have the same range as an emmetrope but the required amplitude of used to enhance night vision partially block the blue light, lowering the
accommodation is necessarily greater, that is, the hyperope needs a greater effect of chromatic aberration.
accommodative effort. The prescription of lenses for this patient should The specific types of each monochromatic and chromatic aberration are
take into account maintaining a more physiological accommodative effort. discussed in Chapter 2.6.
This process is discussed in the next chapter.
In myopes, the far point is at a finite distance in front of the eye. In a
myopic eye that sees objects at most up to 20 cm distant from the eye, a
RETINA
myopia of 1/0.2 = 5 D exists. Remember that the accommodation of an eye An image may be considered as made up of an array of pointlike regions.
28 when viewing an object at the far point is fully relaxed. If the near point is When a picture on the video screen is viewed with a magnifying glass,
at 10 cm, the accommodation range will be α = 20 − 10 = 10 cm. As at this these small regions, called pixels, are seen clearly. Technological evolution
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A 4 D HYPEROPIC EYE
2.2
1,24mm

FP
+4 D
+8 D
NP
25 cm
Fig. 2.2.4 A 4 D Hyperope Eye. (A) The far point (FP) is at 1.24 mm behind the retina. (B) The image focus on retina after 4 D of accommodation. (C) The near point (25 cm)
after maximum accommodation of 8 D. (Courtesy Francisco Irochima, MD.)
has produced screen resolution above the human vision threshold in the and absorbs scattered light, which is predominantly of shorter wavelength
new generation of smartphones or monitors with so-called retina display. (i.e., the blue end of the spectrum).
Likewise, the pixel elements comprising a retinal image are the cone and
rod photoreceptors. It is the finite size of these photoreceptors that ulti-
mately determines the eye’s ability to resolve fine details.
RESOLUTION AND FOCAL LENGTH
The finest details in a retinal image can be resolved only within the A derivation of the theoretical diffraction-limited resolution of a normal
foveal macular area. This elliptical zone of about 0.1 mm in maximal width emmetropic human eye must consider the eye’s optimal pupil diameter, its
(Fig. 2.2.6)24 has an angular size of approximately 0.3° about the eye’s focal length, which is associated with its axial length, and the anatomical
visual axis. It contains about 30,000 tightly packed light-sensitive cones. size of the photoreceptors. A point object imaged by a diffraction-limited
The cones themselves have diameters of 1–2 µm (a dimension comparable optical system has an angular diameter in radians (diameter at one-half the
to 3–4 wavelengths of green light) and are separated by about 0.5 µm.25 peak intensity of the Airy disc) given by Eq. 2.2.1.
Cone size is an important factor in determining the ultimate resolution of
the human eye. No nerve fiber layer, ganglion cell layer, inner plexiform 1.22 ( wavelength)
Angular diameter = Equation 2.2.1
layer, or inner nuclear layer is present in much of the fovea, and in the pupil diameter
very center of the fovea no outer nuclear layer is present. Only the so-called
Henle’s fiber layer, consisting of the axons between the cones and their In Eq. 2.2.1, let pupil diameter be 2.4 mm, which for a normal eye is
synaptic pedicles, and the cones themselves are found. the largest pupil diameter for which spherical aberration is insignificant,
Another important aspect of the cone receptors is their orientation. and let the wavelength be 0.00056 mm (yellow–green light) to find the
Each cone functions as a “light pipe” or a fiber optic that is directed to diffraction-limited angular diameter = 0.00028 radians (or, equivalently,
the second nodal point of the eye (Fig. 2.2.7). This orientation optimally 0.98 minutes of arc). Note that this angular diameter matches the angular
receives the light that forms an image and, together with the black pigment resolution of an eye with 20/20 Snellen acuity, because the black-on-white
epithelium of the retina, partially prevents this light from scattering to bands of the letter E on the 20/20 line of the Snellen chart are spaced 1
neighboring cones.26 Müller cells may also be considered living optic fibers minute of arc apart.
in the retina,27 preventing light scatter. The spatial diameter in millimeters of the diffraction-limited Airy disc
Another retinal factor that helps to improve vision is the configuration on the retina is found by multiplying the angular diameter, given by Eq.
of the foveal pit, which is a small concavity in the retina. This recessed 2.2.1, by the effective focal length of the eye.
shape acts as an antiglare device in which the walls of the depression
prevent stray light within the internal globe of the eye from striking the
Spatial diameter = (angular diameter )
cones at the center of the depression. Finally, the yellow macular pigment Equation 2.2.2 29
may be considered to act as a blue filter that limits chromatic aberration × (effective focal length)
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2
A MYOPIC EYE OF 5 D
1,33mm
FP
FP
B
20 cm
+5 D
NP
10 cm
Fig. 2.2.5 A Myopic Eye of 5 D. (A) Far point is situated at 1.33 m in front of the retina. (B) At 20 cm distance, the image focus on retina without accommodation.
(C) Maximum accommodation of 5 D and the near point at 10 cm. (Courtesy Francisco Irochima, MD.)
ORIENTATION OF PHOTORECEPTORS
Fig. 2.2.6 Retinal Mosaic (Rhesus Monkey) in an Area Adjacent to the Fovea.
The large circles are rods and the clusters of small circles are cones. This section
gives a perspective of the different receptor sizes. (From Wassle H, Reiman HJ. The
mosaic of nerve cells in mammalian retina. Proc R Soc Lond B 1978;200:441–61.)
Fig. 2.2.7 Orientation of the Photoreceptors. They all point toward the second
nodal point of the eye. (Courtesy Francisco Irochima, MD.)
Using the angular diameter found from Eq. 2.2.1 and a value of 17 mm
for the eye’s effective focal length (i.e., second nodal point to retina dis-
tance) in Eq. 2.2.2 results in the diffraction-limited spatial diameter = that the foveal cones are approximately 1.5 µm in diameter and are sep-
0.0048 mm (i.e., 4.8 µm). arated by about 0.5 µm of space, then the distance between neighboring
It is interesting to use our results to make a comparison with cones is 2.0 µm. We estimate the number of receptors covered by the Airy
30 Kirschfield’s estimate that about five receptors are needed to scan the Airy disc by calculating in Eq. 2.2.3 the ratio of the area of the Airy disc to the
disc to obtain the maximal visual information available.28 If we assume area occupied by a single cone.
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(spatial diameter of disc)2
Number of cones covered by Airy disc = AMETROPIAS
(distance between cones)2 2.2
Equation 2.2.3

Using Eq. 2.2.3 we find that approximately six receptors are covered
by the Airy disc in close accord with Kirschfield’s estimate of five. Thus
given an eye with maximal sensitivity to yellow light and an optimal pupil
size of 2.4 mm, we find that the human eye’s 17 mm effective focal length
and, correspondingly, its 24 mm axial length are properly sized to achieve
optimal resolution for the cone sizes present. The higher resolution of the
eagle’s eye compared with the human’s eye probably results from a larger
pupil size-to-focal-length ratio, cones of smaller diameter, and a clearer
cornea and lens.3 A
REFRACTIVE ERRORS
In an emmetropic eye, parallel light rays that come from infinity, after
refracting on the cornea and lens of an eye at rest, converge on the retina.
Refractive errors, or ametropias, are anomalies of the optical state of the
eye that cause imperfect focus on the retina, leading to a poor quality of
the final image.
Refractive errors can occur for several reasons:
Change in Size or Position or Absence of Optical Elements B

A major cause of ametropia is a mismatch between the axial length and
the refractive power of the optical elements of the eye, for example in an
enlarged eye the image is formed in front of the retina—this is referred
to as axial myopia. Similarly, on an eye with reduced anterior–posterior
diameter, the image is formed behind the retina, referred to as axial hyper-
metropia (Figs. 2.2.8 and 2.2.9).
If the lens is positioned more anterior or posterior than the normal
range, similar refractive errors occur. If the lens is displaced anteri-
orly, myopia results. Conversely, if the lens is displaced posteriorly, this
causes hypermetropia. The lens may also be subluxated or tilted, causing
astigmatism.
The absence of the lens, or aphakia, reduces the high power of conver- C
gence of the optical system, producing high hypermetropia.
Change in the Shape of Optical Elements

Irregularities on the surface of the cornea can occur with the formation of
images in two different planes, instead of a single point, causing astigma- Fig. 2.2.8 Ametropias. (A) Emmetropic eye. (B) Myopic eye. (C) Hyperopic eye.
tism. If the curvature is regular but steep, it causes refractional myopia. If (Courtesy Francisco Irochima, MD.)
it’s more flat, it causes refractional hyperopia. These types of ametropia are
widely seen in clinical practice in various corneal diseases, such as kerato-
conus, marginal pellucid degeneration, and keratoglobus.
Change in Refractive Indexes Myopia

The refractive power created at a tissue interface is proportional to the dif-
ference in the refractive indices of the two tissues. If, as a consequence of Myopia is the condition in which parallel light rays from infinity, as they
some pathology, the index of refraction of the aqueous humor increases, refract on cornea and lens, converge at a focus in front of the retina. There
the negative power of the interface between the cornea and aqueous the light rays cross, forming a “blur circle” for each point of the source
humor will be decreased, causing index myopia. Index hyperopia occurs if object. The image that projects itself into the retina thus corresponds to
it is decreased. The opposite occurs with changes in the refractive index of the sum of the blur circles, causing poor image quality.
the vitreous body. If the refractive index of the vitreous increases, becom- Only diverging rays from nearby objects naturally converge to a sharp
ing closer to that of the lens, light will be refracted less at the lens–vitreous focus on a myopic eye’s retina. Due to the high positive power, parallel rays
interface, causing index hyperopia. Index myopia occurs if the refractive from infinity or convergent rays tend to converge until they reach a focus
index of the vitreous is decreased. Such changes in the index of aqueous in front of a retinal point. Therefore it is common to see a myopic person
and vitreous are seldom observed (except following surgical procedures, bringing objects near the eye to improve the quality of the image, so that
which may temporarily replace these tissues with air or silicone oil). It the rays of light leaving the object diverge. Another method of correction
is believed that during aging, with the formation of nuclear cataract, the is the prescription of negative lenses, which cause the parallel rays from
lens nucleus increases its refractive index, producing mild myopia. Some- an object at infinity to diverge as they enter the eye, allowing a sharp focus
thing similar happens with cortical cataract, which with aging approaches on the retina.
the index of refraction of the nucleus, causing mild hypermetropia. Such In myopia the distance from the nodal point (optic center) to the retina
ametropic effects of lens aging are often the presenting signs of cataract is greater than is found in a typical “normal” eye, and, therefore, the pro-
formation and may be mistaken for “improvement” of presbyopia (“second jected image will be larger than normal, unlike hyperopes, in whom the
sight”). Frequently, further lens changes eventually degrade image quality, optics project a smaller image.
necessitating cataract extraction surgery. The far point in myopia is at a finite distance in front of the eye. As seen
It is important to note that there often appears to be a coordination previously, the emmetropic eye has the far point at infinity. In myopes, the
between the axial growth of the eye and the evolving refractive power of distance to the far point is inversely proportional to the ametropia. For
the anterior segment, so that the net refractive error is typically less severe example, a myope of 0.25 D has its far point in 1/0.25 = 4 m
than might be expected if these structures developed independently—a On the other hand, the myope needs less accommodative effort for
phenomenon referred to as “emmetropization.” Thus one cannot accu- near vision. Thus the accommodation, if used in its entirety, can main-
rately predict the refractive error simply knowing only the axial length or tain an object in good definition even at small distances, smaller than 31
refractive power of the eye in isolation.21 those accepted by the emmetrope. For example, a 4 D myopic patient who
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2 REFRACTIVE ERRORS
A A
B D
C E
Fig. 2.2.9 Refractive Errors. (A) Emmetropic eye. (B) Axial myopia. (C) Axial hyperopia. (D) Index myopia (nuclear cataract). (E) Aphakia. (Courtesy Francisco Irochima, MD.)
accommodates up to 8 D will have its far point at 25 cm, that is, without hyperope (Fig. 2.2.10). Because not enough convergence exists to see objects
accommodation, he or she will see an object clearly at this distance, acting at a distance, positive dioptric power must be added, which is usually done
like an emmetropic accommodating 4 D. His or her near point will be through prescription of converging lenses, artifical corneal steeping by
100 / (4 + 8) = 8.3 cm, because at this distance the eye resembles that of an refractive surgery, or by the physiological mechanism of accommodation
emmetropic accommodating 12 D but with less effort. itself. For eyes with the same amplitude of accommodation, the hyperope
has its near point at a greater distance, because part of its accommodation
Hypermetropia is already used to converge parallel rays from infinitely distant sources,
unlike in myopia (Fig. 2.2.11).
Hypermetropia, or hyperopia, is the condition in which parallel light rays Hyperopia can be divided into latent and manifest hyperopia. Ideally, a
from infinity converge on a focus behind the retina after refracting on the clinical refraction is performed with the eye in a state of complete relax-
cornea and lens. What is projected into the retina thus corresponds to ation of accommodation. Such a state is artificially induced by cycloplegic
blur circles formed before the light rays converge to a point, causing poor eyedrops and does not occur in an eye in its natural state. Thus, if the ame-
image quality. tropia measured during cycloplegia were used as the prescribed correction,
Contrary to common belief, there are more hyperopes in the world this would likely be uncomfortable and not generate the best quality of
population than myopes. However, many do not manifest it until the age vision for the patient, who would probably continue to exhibit some degree
of 40, as their refractive errors are typically neutralized by accommoda- of accommodative tone after the cycloplegia wears off.
tion without spectacle correction. After age 40 years, the amplitude of Indeed, the normal tonus of the ciliary body obscures a latent hypero-
accommodation decreases, generating presbyopia, which will be further pia, that is, an accommodation that is present even with the eye adjusted
discussed later. to fix a distant image, using the least possible accommodative effort. Latent
At birth the human eye usually has a hyperopia of + 2.25 D that hyperopia usually is around 1 D, and its understanding is important in daily
increases and peaks at approximately 8 years of age. After this age, the practice for prescribing a more physiological refraction to the patient.30
eye will progressively become more myopic, reaching emmetropia in The manifest hyperopia is the amount of diopter power required to
adulthood.29 Growth of the eye during development is a complex process, reach emmetropia after minimal (latent) accommodation. Taking into
usually accompanied by changes in corneal curvature and in the dioptric account that in that state, there is still available some power of accommo-
power of the lens. Hyperopia occurs when there is an imbalance between dation, one may subdivide the manifest hyperopia in two facultative and
these mechanisms, such as the axial diameter decreasing relative to the absolute hypermetropia. The facultative is that part of manifest hyperopia
refractive power of the other elements of the eye, as discussed previously. that can be overcome by accommodation. Thus the absolute is the remain-
Generally the shortening of the eye does not exceed 2 mm. Each millime- ing refraction error after maximum accommodative effort (Fig. 2.2.12).
ter of shortening of the diameter corresponds to about 3 D of refractive
error. Therefore, excluding pathological abnormalities such as microph-
thalmia, few hyperopic eyes exceed a refractive error of 6 D.21
Astigmatism
32 In hyperopia the far point is a virtual point located behind the retina, Astigmatism is a condition in which the light rays, after refracting, do not
because only converging rays can focus on the retina of an uncorrected converge to a single point. Due to variations in the curvatures of the cornea
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FAR POINT
2.2

FP =
FP
FP
Fig. 2.2.10 Far point on (A) emmetropic eye, (B) myopic eye, (C) hyperopic eye. (FP) Far point. (Courtesy Francisco Irochima, MD.)
or the lens in different axes, instead of focusing the light from a point (an eye with astigmatism). Thus with the spherical equivalent of optical
source to a single point, the image consists of two lines, separated from correction, which places this circle on the retina, we will have the best
each other. image that can be obtained by correcting an astigmatism with only spher-
When the light from the main meridians that focus on the system in ical lenses.
this optical condition are at right angles to each other, this is referred to Although no eye is perfectly free from astigmatism, in practice it is nec-
as regular astigmatism. If, however, these principal meridians form a right essary to correct astigmatic refractive errors only when patients experience
angle but not oriented horizontally and vertically (at 90° and 180°), the con- symptoms such as decreased visual acuity or eye fatigue from constantly
dition is described as oblique astigmatism. If the cornea or lens are so adjusting accommodation to optimize the seeing between the two focal
irregular that they do not form well-defined meridians, the condition is lines.
described as irregular astigmatism.
In regular astigmatism, depending on where the two lines focus, one Presbyopia
may specify further subtypes. If both are in front of the retina, the refrac-
tive state is compound myopic astigmatism. Similarly, if both are behind, As seen earlier, manifest hyperopia has its facultative and absolute com-
a compound hypermetropic astigmatism results. If one line focuses on the ponent. The facultative component, which can be compensated by accom-
retina but the other line is in front or behind, one obtains a simple myopic modation, decreases progressively with age, so the absolute hyperopia will
or simple hypermetropic astigmatism, respectively. If one line focuses in eventually become evident in those hyperopes that did not exhibit this com-
front and the other behind the retina, the condition is called mixed astig- ponent earlier in life (when hyperopia is totally neutralized by accommo-
matism (Fig. 2.2.13). dation). In such symptomatic patients, absolute hyperopia increases and
In the space between the two focal lines, the light rays determine a symptoms become more evident around the age of 40, requiring greater
characteristic geometrical figure called the conoid of Sturm (Fig. 2.2.14). optical correction. Myopes, as they have the near point at a shorter dis-
The spacing of these focal lines (i.e., the size of the conoid) is a measure tance, usually have a “natural protection” against presbyopia. Myopes with
of astigmatism, and its correction is based on merging the focal lines small refractive errors, however, will also require positive diopter power for
into one, collapsing the conoid of Sturm to a single point. If the error near objects after a more significant progression of presbyopia.
is not corrected, the projected image on the retina within this space will Fisher31 published an important paper in 1988 breaking previous par-
form circles, ellipses, or lines, but never a single point, causing a blurred adigms, such as those published by von Helmholtz32 that presbyopia was
image. Note, however, that cylindrical lenses apply their power under the due to lenticular sclerosis and by Donders,33 who argued that the loss of
rays to 90° from the plane of their axis, not altering the rays on their own strength of the contraction of the ciliary muscle was the main cause.
axis. Thus correction with cylindrical lenses can only be done in regular In his article, Fisher states that at the beginning of presbyopia, there
astigmatism. is in fact hypertrophy of the ciliary muscle as a compensatory form to the
In the center of the conoid, there is a region where the image is closest greater difficulty of lenticular diameter alteration. This difficulty, however,
to forming a point, a circular region (due to the pupil shape) called the was not due to sclerosis but rather to the stiffening of the lens capsule
circle of least confusion. The circle of least confusion is the “best” image associated with changes in the zonule structure, which became more 33
after light passes through an optical system with sphero-cylindrical power compact.31
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2
NEAR POINT
NP
NP
NP
Fig. 2.2.11 Near point on (A) emmetropic eye, (B) myopic eye, (C) hyperopic eye. (NP) Near point. (Courtesy Francisco Irochima, MD.)
34
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2.2

HYPEROPIA
II
I II
M L
Fig. 2.2.12 Hyperopia. (I) Absolute hyperopia—fraction of the hyperopia that cannot be corrected by accommodation. (II) Facultative hyperopia—can be measured by
divergent lenses. M—Manifest hyperopia. L—Latent hyperopia, detected with cycloplegic eyedrops. (∞ - infinite). (Courtesy Francisco Irochima, MD.)
35
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2
TYPES OF ASTIGMATISM
A B
C D
E F
Fig. 2.2.13 Types of Astigmatism. (A) Simple myopic astigmatism. (B) Compound myopic astigmatism (notice that both of lines are in front of the retina). (C) Simple
hypermetropic astigmatism. (D) Compound hypermetropic astigmatism. (E) Equidistant mixed astigmatism. (F) Nonequidistant mixed astigmatism. (Courtesy Francisco
Irochima, MD.)
36
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Fig. 2.2.14 Sturm’s Conoid Formed by
STURM’S CONOID Two Perpendicular Cylinders (A and
B). (A) 180° axis cylinder. (B) 90° axis 2.2
cylinder. (1) Focal line from cylinder A.
(2) Less confusion circle. (3) Focal line

from cylinder B. (Courtesy Francisco
Irochima, MD.)
B
A
1
entire accommodative power, because maximal prolonged accommodative

ACCOMMODATION X AGE effort is usually only one-third to one-half the total amplitude. Thus in a
comfortable and tolerable way, the routinely available accommodation at
that age usually is less than 1 D, which means that optical corrections will
18
usually be necessary for near vision in a previously emmetropic patient
17
(Fig. 2.2.15).
16 The treatment of presbyopia is performed with the use of convex
15 lenses, bringing the near point to a region of comfortable working dis-
14 tance that is compatible with the patient’s needs. With advancing age, the
13 depth of focus through a presbyopic correction will decrease, potentially
12 creating a gap between the closest focus with the distance correction, and
accommodation (D)
11 the most distant focus available through the reading correction. If this is
10 bothersome, the patient may be helped by a prescription for trifocals, with
9 an intermediate presbyopic correction zone, or progressive lenses, which
8 provide a continuous transition between distance and near corrections.
7
6
5 KEY REFERENCES
4
Borish IM. Clinical refraction. 3rd ed. Chicago: Professional Press; 1970.
3 Campbell FW, Gregory AH. Effect of pupil size on visual acuity. Nature 1960;208:191–2.
A
2 B Donders FC. On the anomalies of accommodation and refraction of the eye: with a prelimi-
1 C nary essay on physiological dioptrics. London: The New Sydenham Society; 1864.
Duane A. Normal values of the accommodation at all ages. JAMA 1912;59:1010–13.
0 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 Enoch JM. Vertebrate rod receptors are directionally sensitive. In: Snyder A, Menzel R,
age editors. Photoreceptor optics. Berlin: Springer-Verlag; 1975. p. 17–37.
Hartridge H. Helmholtz’s theory of accommodation. Br J Ophthalmol 1925;9(10):521–3.
Hemenger RP. Intraocular light scatter in normal lens with age. Appl Opt 1984;23:1972–4.
Fig. 2.2.15 Accommodation (D – diopters) X Age (years), according to Duane.34 Miller D, Benedek GB. Intraocular light scattering. Springfield: CC Thomas; 1973.
(A) Minimum values, (B) medium values, (C) maximum values. (Courtesy Francisco Miller D, Scott CA. Epidemiology of refractive errors. In: Yanoff M, Duker JS, Augsburger JJ,
Irochima, MD.) editors. Ophthalmology. 3rd ed. Edinburgh: Mosby Elsevier; 2009. p. 61–3.
Oliveira CM, Ferreira A, Franco S. Wavefront analysis and Zernike polynomial decompo-
sition for evaluation of corneal optical quality. J Cataract Refract Surg 2012;38:343–56.
Later, it was proved that the role of the stiffening of the crystalline Owsley C, Sekuler R, Siemsen D. Contrast sensitivity throughout adulthood. Vision Res
nucleus itself would also play a part in the phenomenon. Thus aging 1983;23:689–99.
would be associated with complex physical and optical changes in the crys- Reymond L. Spatial visual acuity of the eagle Aquila audax: a behavioral, optical and ana-
tomic investigation. Vision Res 1985;25:1477–91.
talline structure responsible for changes not only limited to loss of accom- Tsubota K, Boxer Wachler BS, Azar DT, et al. Hyperopia and presbyopia. New York: Marcel
modation and cataract.30 Dekker; 2003.
With the loss of amplitude of accommodation during aging, therefore, von Helmholtz H. Treatise on physiological optics, translated from the 3d German ed., vol.
the near point gradually recedes, making it harder to see near objects with 1. JPC Southall, ed. Handbuch der physiologischen Optik. (English). Rochester: The
Optical Soc America; 1924.
clarity. This phenomenon should not be seen as pathological, but rather as
a normal—indeed inevitable—consequence of aging.
Note that at age 45 the range of accommodation is around 2 D. In prac- Access the complete reference list online at ExpertConsult.com
tice, this does not mean that the patient will be able to routinely exert this 37
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REFERENCES 17. Borja D, Manns F, Ho A, et al. Optical power of the isolated human crystalline lens.
Invest Ophthalmol Vis Sci 2008;49:2541–8.
1. Sónego-Krone S, López-Moreno G, Beaujon-Balbi OV, et al. A direct method to measure
the power of the central cornea after myopic laser in situ keratomileusis. Arch Ophthal-
18. Fernald RD. Vision and behavior in an African Cichlid fish. Am Sci 1984;72:58–65.
19. Hartridge H. Helmholtz’s theory of accommodation. Br J Ophthalmol 1925;9(10):521–3.
2.2
mol 2004;122:159–66. 20. Azar DT. Refractive surgery. 2nd ed. St Louis: Mosby; 2006.
21. Sir Stewart D-E. The practice of refraction. 8th ed. St Louis: CV Mosby; 1969. ISBN

2. Miller D, Benedek GB. Intraocular light scattering. Springfield: CC Thomas; 1973.
3. Miller D. The eye of the eagle. Eur J Implant Refractive Surg 1991;3:71–3. 0-7000-1410-1.
4. Reymond L. Spatial visual acuity of the eagle Aquila audax: a behavioral, optical and 22. Clinical Optics. American Academy of Ophtalmology, Section 3 2007-2008.
anatomic investigation. Vision Res 1985;25:1477–91. 23. Wald G, Griffin DR. The change in refractive power of the human eye in dim and bright
5. Randleman JB, Loft ES, Banning CS, et al. Outcomes of wavefront-optimized surface light. J Opt Soc Am 1947;37:321–36.
ablation. Ophthalmology 2007;114:983–8. 24. Wassle H, Reiman HJ. The mosaic of nerve cells in mammalian retina. Proc R Soc Lond
6. Borish IM. Clinical refraction. 3rd ed. Chicago: Professional Press; 1970. B Biol Sci 1978;200:441–61.
7. Oliveira CM, Ferreira A, Franco S. Wavefront analysis and Zernike polynomial decompo- 25. Gregory RL. Eye and brain. New York: World University Library McGraw-Hill Book
sition for evaluation of corneal optical quality. J Cataract Refract Surg 2012;38:343–56. Company; 1973.
8. Bennett AG, Rabetts RB. Clinical visual optics. 2nd ed. London: Butterworths; 1988. 26. Enoch JM. Vertebrate rod receptors are directionally sensitive. In: Snyder A, Menzel R,
9. Kaufman S, editor. IES lighting handbook. 4th ed. New York: Illumination Engineering editors. Photoreceptor optics. Berlin: Springer-Verlag; 1975. p. 17–37.
Society; 1966. p. 2–10. 27. Franze K, Grosche J, Skatchkov SN, et al. Müller cells are living optical fibers in the
10. Foxell CAP, Stevens WR. Measurement of visual acuity. Br J Ophthalmol 1955;39: vertebrate retina. Proc Natl Acad Sci USA 2007;104:8287–92.
513–33. 28. Kirschfield K. The resolution of lens and compound eyes. In: Zettler F, Weiler R, editors.
11. Campbell FW, Gregory AH. Effect of pupil size on visual acuity. Nature 1960;208: Neural principles of vision. Berlin: Springer-Verlag; 1976. p. 354–69.
191–2. 29. Slataper FJ. Age norms of refraction and vision. Arch Ophthalmol 1950;43:466–81.
12. Miller D, Scott CA. Epidemiology of refractive errors. In: Yanoff M, Duker JS, Augs- 30. Tsubota K, Boxer Wachler BS, Azar DT, et al. Hyperopia and presbyopia. New York:
burger JJ, editors. Ophthalmology. 3rd ed. Edinburgh: Mosby Elsevier; 2009. p. 61–3. Marcel Dekker; 2003.
13. Schumacher S, Oberheide U, Fromm M, et al. Femtosecond laser induced flexibility 31. Fisher RF. The mechanics of accommodation in relation to presbyopia. Eye (Lond)
change of human donor lenses. Vision Res 2009;49:1853–9. 1988;2:646–9.
14. Hemenger RP. Intraocular light scatter in normal lens with age. Appl Opt 1984;23: 32. von Helmholtz H. Treatise on physiological optics, translated from the 3d German ed.,
1972–4. vol. 1. JPC Southall, ed. Handbuch der physiologischen Optik. (English). Rochester: The
15. Owsley C, Sekuler R, Siemsen D. Contrast sensitivity throughout adulthood. Vision Res Optical Soc America; 1924.
1983;23:689–99. 33. Donders FC. On the anomalies of accommodation and refraction of the eye: with a
16. Said FS, Weale RA. The variation with age of the spectral transmissivity of the living preliminary essay on physiological dioptrics. London: The New Sydenham Society; 1864.
human crystalline lens. Gerontologia 1959;3:213–31. 34. Duane A. Normal values of the accommodation at all ages. JAMA 1912;59:1010–13.
37.e1
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Clinical Refraction
Albert Wu 2.3
Definition: The neutralization of an individual’s refractive error using HISTORY
a variety of tests in which the patient’s responses determine the lens Spectacles were first described during the Middle Ages. In 1266 Roger
power that best produces a sharply focused image on the retina. Bacon magnified print in a book using a segment of a glass sphere. A
painting completed in 1352 shows a prelate wearing lenses in a mounting.
In the late fifteenth century, merchants sold spectacles to buyers who chose
them on the basis of their own judgment of how vision improved. As the
Key Features trade of lens-making proliferated throughout Europe, it became organized
• The selection of a prescription for corrective lenses that balances into a guild. Although cylindrical lenses had been manufactured since
optical clarity with other important physical and psychological 1827, it was not until Donders published his methods of refraction that
factors, such as equality of magnification, single vision, and comfort. correcting astigmatism became an exact science. In 1893 when American
• The determination of the most appropriate form of optical correction Optical developed the trial case of lenses, opticians—rather than spectacle
based on the patient’s visual needs and on environmental factors. peddlers—became the primary providers of eye examinations.1 Although
instrument-makers have dramatically improved the ability of examiners to
provide accurate and repeatable lens prescriptions, most subjective tech-
niques still rely on a comparison of views through different lenses.
INTRODUCTION
Many people equate an eye examination with a refraction test for glasses.
VISUAL ACUITY
The confusion is understandable because for the vast majority, especially The idea that the minimal separation between two point sources of light
those in the preretirement age group, eyeglasses or contact lenses resolve was a measure of vision dates back to Hooke in 1679, when he noted,
the main complaints they have about their eyes. Also, refraction is almost “tis hardly possible for any animal eye well to distinguish an angle much
always part of a comprehensive eye examination, not only to provide a pre- smaller than that of a minute: and where two objects are not farther distant
scription for corrective lenses but also to determine the best acuity that an than a minute, if they are bright objects, they coalesce and appear as one.”2
eye can achieve. In the early nineteenth century, Purkinje and Young used letters of various
Refraction is only one of the many methods used to determine the func- sizes for “judging the extent of the power of distinguishing objects too
tion and health of the visual system. Because of the value of the results, it near or too remote for perfect vision.” Finally, in 1863, Professor Hermann
is important to develop an efficient and accurate basic refractive technique Snellen of Utrecht developed his classic test letters. He quantitated the
that can be modified when unusual variations present themselves. lines by comparison of the visual acuity of a patient with that of his assis-
Although often relegated as a purely technical task in the spectrum of tant, who had perfect vision. Thus 20/200 (6/60) vision meant that the
high-technology examination and treatment procedures that characterize patient could see at 20 ft (6 m) what Snellen’s assistant could see at 200 ft
contemporary ophthalmic practice, refraction provides relief for one of the (60 m).3
world’s most common physical defects. An understanding of the concepts The essence of correct identification of the letters on the Snellen chart
used to identify and measure refractive errors is the basis for prescribing is to see the clear spaces between the black elements of the letter. Thus in
individual corrections that offer patients improved quality of life. Fig. 2.3.1, the angular spacing between the bars of the C is 1 minute for the
Fig. 2.3.1 Spacing of Gap in the Letter “C.” This letter

SPACING OF THE LETTER ”C ” is used to determine the minimal separable spacing or
resolution of the eye at the retina. The gap in the letter
C subtending 1 minute, when imaged on the retina,
0.67 inches 20 ft
has a dimension (Y) representing the resolution of the
eye where tan (1 minute) = Y/0.67 (with Y in inches);
therefore, Y = 0.00019 inches (or 4.8 m). The overall size
of the letter is X = 0.349 inches, and the gap dimension
is 0.070 inches (see text).
Y inches
1m
inu
te
1 minute
38
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20/20 (6/6) letter. The entire letter has an angular height of 5 minutes. To to use the Landolt ring test in which circles of decreasing size, each with
calculate the height, x, of a 20/20 (6/6) letter, use Eq. 2.3.1. an open gap, are used in successive lines, with the orientation of the gaps
in the circles randomly changing. 2.3
xfeet The 20/20 (6/6) Snellen line represents the ability to resolve 1 minute
tan(5 minutes) = Equation 2.3.1
of arc, which is close to the theoretical diffraction limit, but the occasional
Clinical Refraction
20
patient can see the 20/15 (6/4.5) or, rarely, 20/10 (6/3) line. Four expla-
From Eq. 2.3.1, x = 0.0291 ft (0.349 in). In like manner, the 20/200 nations suggest themselves. First, some individuals may have cone outer
(6/60) letter is 10 times taller, or 3.49 in (8.87 cm) high. segment diameters of less than 1.5 µm, which would give a finer-grain
mosaic having cone separations of less than 1 minute of arc. Second,
Testing Distance longer eyes provide slightly magnified retinal images, thereby tending
to yield better acuities. Third, some eyes may have less aberration than
The Snellen acuity test traditionally is done at a distance of 20 feet (6 m). others, which would allow them to function optimally with larger pupils
At this distance, very little accommodation is required by the patient. For having, consequently, better diffraction-limited performance. Finally, our
hospital patients, testing must often be carried out in a smaller room. If the experience with a small aperture corneal inlay has taught us that brain
doctor stands at the foot of the bed and the patient sits propped up at the processing cancels much of the diffraction noise for apertures between
head of the bed, the distance between them is about 5 feet (1.5 m). Thus 1.5 mm to 2.0 mm (US PATENT # 4955904, Atebara, Miller. US PATENT
the classic Snellen chart, with its conventional notations, may be used if #5245367, Miller/Meshel. US PATENT #6899424, Miller, Blanco).
the chart is reduced to one-fourth its original size. Admittedly, a test at 5 ft
(1.5 m) requires the emmetropic patient to accommodate 0.67 diopters (D). Contrast Sensitivity
Visual acuity testing is relatively inexpensive, takes little time to perform,
Other Considerations and describes visual function with one notation, such as 20/40 (6/12).
Over the years, it has become apparent that projection of the Snellen chart Best of all, for more than 150 years it has provided an end point for the
onto a screen in a darkened examination room does not give an accurate correction of a patient’s refractive error. Yet contrast sensitivity testing, a
replication of “everyday” visual function. For example, the high contrast time-consuming test born in the laboratory of the visual physiologist and
black-on-white letters do not represent the contrast of most objects seen described by a graph rather than a simple notation, has become a popular
in everyday life. The dark examination room, which is devoid of glare clinical test recently. It describes a number of subtle alterations of vision
sources, also is not representative of most daytime visual tasks. not accounted for by the visual acuity test. Thus it more accurately quan-
As the projector bulb ages or collects dirt, and as the projection lens tifies the loss of vision in cataracts, corneal edema, neuro-ophthalmic dis-
becomes dusty, the contrast of the letters projected on the chart decreases. eases, and certain retinal diseases. Although these advantages have been
Thus a change in readings between patient visits may not always arise known for a long time, the recent enhanced popularity has arisen because
from a significant change in the visual status of the patient. At present, of patients with cataracts. As lifespan increases, more patients who have
British standards require 480 to 600 lux to illuminate distant wall charts cataracts request medical help. Very often, their complaints of objects that
and 1200 lux to illuminate projected charts.4 appear faded or objects that are more difficult to see in bright light are
As the letters become smaller on the Snellen chart, the number of not described accurately by their Snellen acuity scores. Contrast sensitivity
letters per line increases. Thus one error per line means a different degree tests and glare sensitivity tests do quantitate many of these complaints.
of impairment for each line. It is necessary, therefore, to establish criteria Contrast sensitivity testing is similar to Snellen visual acuity testing in
by which it can be agreed that a patient has seen the line. Some clinicians that it tests using several different sized letters or grid patterns. However,
credit a patient if more than one-half the letters are identified correctly. it is different from visual acuity testing because the letters (or grid pat-
Others require identification of all the letters before credit is given. Also terns) are displayed in six or more shades of gray instead of the standard
remember that no orderly progression of size change exists from line to black letters of the Snellen chart. Thus contrast sensitivity testing reports
line. Thus a two-line change on the Snellen chart going from the 20/200 show a contrast threshold (i.e., lightest shade of gray just perceived) for
(6/60) line to the 20/80 (6/24) line represents an improvement of visual each of several letter (or grid pattern) sizes.
acuity by a factor of 2.5, whereas a two-line change going from the 20/30
(6/9) line to the 20/20 (6/6) line represents an improvement by only a Contrast
factor of 1.5. The components of a conventional newspaper photo consist of various
Another problem is that the identification of different letters of the regions associated with the scene where each region is filled in with a defi-
same size has been shown to vary in difficulty. Thus A and L are easier to nite density of black dots depicting that region’s contrast or level of gray.
identify than E. The Bailey–Lovie chart (Fig. 2.3.2), designed by two Aus- Such newspaper photos may have over 100 half-tone levels (i.e., densities
tralian optometrists5 and modified by Ferris et al.6 in 1982, uses 10 letters of black dots) to represent the different contrast levels in the scene.
of similar difficulty with five different letters per line and has uniform Whereas a black letter on a white background is a scene of high con-
proportional size change between neighboring lines. Another approach is trast, a child crossing the road at dusk and a car looming in a fog are
scenes of low contrast. The contrast of a target on a background is defined
by Eq. 2.3.2.
target luminance − background luminance

VISUAL ACUITY CHARTS contrast = Equation 2.3.2
target luminance + background luminance
Standard Snellen chart Bailey–Lovie chart
As an example, suppose a photometer measures the luminance of a
target at 100 units of light and the luminance of the background at 50 units
of light. Substitution into Eq. 2.3.2 gives Eq. 2.3.3.
100 − 50
contrast = = 0.33 (or 33%) Equation 2.3.3
100 + 50
Suppose the contrast of a target of a certain size is 0.33, which also

may represent a particular older patient’s threshold, which means that
this patient cannot detect similar-sized targets of lower contrast. The older
patient’s contrast sensitivity (CS) is the reciprocal of the contrast, namely
CS = 3.0. On the other hand, a young, healthy subject viewing a target of
the same size may have a contrast threshold of 0.01 with a corresponding
CS = 100. Occasionally subjects (for certain-size targets) have even better
contrast thresholds. A subject could have a contrast threshold of 0.003,
which converts into a CS of 333. In the visual psychology literature, CS 39
Fig. 2.3.2 Visual Acuity Charts. Standard Snellen and Bailey–Lovie charts. often is described in logarithmic terms. For example, associated with CS
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= 10 is log(CS) = 1, with CS = 100 is log(CS) = 2, and with CS = 1000 is
2 log(CS) = 3, and so on.
Targets 1000
CONTRAST FUNCTIONS
Both the visual scientist and the optical engineer use a series of alternating
black and white bars as targets. The optical engineer describes the fineness
of a target by the number of line pairs per millimeter (a line pair consists 100
of a dark bar with a white space next to it). The higher the number of line
pairs per millimeter, the finer is the target. For example, about 82 line
pairs per millimeter imaged on the retina of an eye with a focal length 10
of 21 mm is equivalent to a periodic black–white target in object space,
where the white space between two black spaces subtends approximately a
minute of arc (like the letter E of the Snellen chart viewed at 20 ft). Equiva- 0
lently, with a Snellen chart viewed at 20 ft, 109 line pairs per millimeter on 0.1 1 10 100
the retina is equivalent to the 20/15 (6/4.5) letters. spatial frequency (cycles/degree)
The vision scientist generally describes a periodic bar pattern in terms retinal testing function (RTF)
of its spatial frequency as perceived at the test distance—the units are contrast sensitivity function (CS)
cycles per degree (cpd). A cycle is a black bar and a white space. To convert modulation transfer function (MTF)
Snellen units into cpd at the 20 ft (6 m) testing distance, the Snellen Fig. 2.3.3 Contrast Functions. The human eye’s contrast sensitivity (CS) function
denominator is divided into 600 (180). For example, 20/20 (6/6) converts is the product of the contrast transfer function of the purely optical contribution,
into 30 cpd. Likewise, 20/200 (6/60) converts into 3 cpd. called the modulation transfer function (MTF), and the contrast sensitivity function
of the purely neuroretinal contribution, called the retinal testing function (RTF).
Sine Waves The MTF is magnified 10× in the graph. (Redrawn from Mainster MA. Contemporary
So far, targets have been described as high-contrast dark bars of different optics and ocular pathology. Surv Ophthalmol 1978;23:135–42.)
spatial frequency against a white background. These also are known as
square waves or Foucault gratings. However, in optics very few images can
be described as perfect square waves with perfectly sharp edges. Diffrac- EFFECT OF BRAIN'S CONTRAST ENHANCEMENT FUNCTION
tion tends to make most edges slightly fuzzy, as do spherical aberration
and oblique astigmatism, particularly in the case of the optics of the eye. If
the light intensity is plotted across a strongly blurred image of a Foucault
grating, a sine wave pattern results. Sine wave patterns have great appeal
because they can be considered the essential elements from which any
pattern can be constructed. The mathematician can break down any alter-
nating pattern, be it an electrocardiogram or a trumpet’s sound wave, into
a unique sum of sine waves. This mathematical decomposition of patterns
into sinusoidal components is known as a Fourier transformation. Fouri-
er’s theorem describes the way that any pattern may be written as a sum of
sine waves that have various spatial frequencies, amplitudes, and phases.
Also, it is thought that the visual system of the brain may operate by
breaking down observed patterns and scenes into sine waves of different
frequencies. The brain then adds them up again to produce the mental
impression of a complete picture. Fourier transformations may be the
method the visual system uses to encode and record retinal images. It has
been shown that different cells or “channels” occur in the retina, lateral
geniculate body, and cortex that selectively carry different spatial frequen-
Fig. 2.3.4 Effect of Brain’s Contrast Enhancement Function. One gray circle is
cies.7 So far, six to eight channels have been identified. It also has been seen against a black background and one against a white background. The brain’s
shown that all channels respond to contrast—the cortex shows a linear contrast enhancement function makes the gray look lighter against the dark
relationship between the amplitude of the neuronal discharge and the background and darker against the light background.
logarithm of the grating contrast. Consequently, many contrast sensitivity
tests are based on sine wave patterns rather than square wave patterns.
which is expressed by Eq. 2.3.4, the so-called Campbell–Green relation,11
Recording Contrast Sensitivity and is illustrated in Fig. 2.3.3. The Campbell–Green relation has been
Fig. 2.3.3 shows a number of functions, including the contrast sensitiv- demonstrated in clinical studies.12
ity testing function for a normal subject. The shape of the human eye’s
contrast sensitivity function is different from that of an inanimate optical CS = RTF × MTF for all frequencies Equation 2.3.4
imaging systems in which the function generally decreases continuously
from very low to very high spatial frequencies. For the normal human eye, Differences in the contrast sensitivity function are expected among dif-
the contrast sensitivity generally increases from very low frequencies to ferent subject groups. For example, contrast sensitivity decreases with age,
about 6 cpd and then decreases with increasing frequency beyond 6 cpd. for which two factors appear to be responsible. First, the normal crystalline
The decrease of the contrast sensitivity with frequency above 6 cpd is due lens scatters more light with increasing age,13 which thus blurs the edges
to the influence of diffraction and aberrations, which make the detection of of targets and degrades the contrast. Second, the retina–brain processing
finer details more difficult. The increase of the contrast sensitivity with fre- system itself loses its ability to enhance contrast with increasing age.
quency up to 6 cpd is due to the retina–brain processing system, which is The contrast sensitivity function also is an accurate method by which
programmed to enhance our contrast sensitivity in the range of 2 to 6 cpd. to follow certain disease states. For example, the contrast sensitivity func-
Receptor fields, on–off systems, and lateral inhibition are the well-known tion of a patient who has a cataract is diminished, as it is in another
physiological mechanisms that influence the different spatial frequency light-scattering lesion, corneal edema. Because the contrast sensitivity
channels and are responsible for such enhancement. In Fig. 2.3.3, the function is dependent on central nervous system processing, it is not sur-
plot labeled retinal testing function (RTF) represents the retinal–neural prising that conditions such as optic neuritis and pituitary tumors also
system’s contrast sensitivity performance.8–10 A striking proof of brain characteristically have diminished contrast sensitivity functions.
enhancement of contrast is given in Fig. 2.3.4. The contrast sensitivity of patients also decreases as the illumination
Also shown in Fig. 2.3.3 is the plot labeled modulation transfer func- decreases.14 Thus contrast sensitivity for a spatial frequency of 3 cpd typ-
tion (MTF), which represents the sinusoidal components of the object-to- ically drops from 300 to 150 to 10 as the retinal luminance drops from 9
image transfer function for the purely optical portion of the visual system trolands to 0.09 trolands to 0.0009 trolands. (The troland is a psychophys-
40 (cornea, lens).11 The MTF is described more completely in the next section. ical unit. One troland is the retinal luminance produced by the image of
A significant mathematical relationship exists among the three functions, an object, the luminance of which is 1 lumen/m2 (1 lux) for an area of
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AN UNCORRECTED ASTIGMATIC EYE WITH THE CIRCLE OF LEAST CONFUSION ON THE RETINA
2.3
Clinical Refraction
point source circle of
of light at least confusion
Fig. 2.3.5 An Uncorrected Astigmatic Eye With the Circle of Least Confusion on the Retina. The horizontal and vertical focal lines are dioptrically equal in front of and
behind the retina.
the entrance pupil of 1 mm2.) Therefore, when careful contrast sensitivity Practically speaking, the spherical equivalent is useful for prescribing a
function comparisons are made, the illuminance of the test targets must spherical contact lens to a patient with a low level of astigmatism. It also is
be kept at the recommended value. useful when prescribing astigmatic contact lens to an individual with high
astigmatism beyond the maximum cylinder correction of −2.75 commonly
SPHERICAL EQUIVALENT offered by many contact lens companies. As a result, one might prescribe
the lesser amount of astigmatism and correct the spherical power based
There are three basic components in the specification of a spectacle lens: on the spherical equivalent. Another similar use of spherical equivalent
the spherical power, the astigmatic cylinder axis, and the cylinder power. An would be when prescribing glasses to a patient with high astigmatism
accurate determination of the spherical component is predicated on having and reducing the full cylinder correction to help the patient adjust to their
fully corrected the astigmatic error to ensure that a point focus is obtained prescription.
with the final correcting lens. Therefore subjective examinations proceed
in that order. In eyes with astigmatism, each of the principal meridians
produces a linear image at its focal distance. In the space between foci—
DETECTING ASTIGMATISM
the interval of Sturm—the image has a progressive change in its elliptic One of the most common reasons that patients seek eye care is to obtain
profile. At the focal distance of the dioptric average of the two principal correction of their refractive error. However, refraction is also a diagnostic
powers, the image is round and is called the circle of least confusion. In tool used to differentiate decreased acuity caused by uncorrected or incom-
an eye uncorrected for astigmatism, the best acuity occurs when the circle pletely corrected refractive error from blurred vision related to eye disease.
of least confusion falls on the retina (Fig. 2.3.5). At all other points within In most cases the final determination of the refractive correction is
the astigmatic pencil, the image is distorted along the principal meridi- based on the patient’s appreciation of the lens power that provides the
ans whereby each point source produces an oval image.3 The oval images clearest vision at the desired viewing distance. This procedure, subjective
of two or more adjacent point objects overlap along one of the principal refraction, is a time-honored combination of the technical skill required
meridians and appear darker along their long axes. Some refractive tech- to select a lens that produces a sharply focused image on the retina tem-
niques use this effect to neutralize the astigmatic focus subjectively. pered with the fine art of determining the best overall correction incorpo-
Spherical equivalent is an important optical concept that is applicable rating other factors such as the balance between the two eyes, the patient’s
in the dispensing of contact lenses and glasses. It is defined as the spher- visual needs, the patient’s age, and the rate of change of the refractive
ical power whose focal point coincides with the circle of least confusion, error. The concepts and procedures described here refer to neutralization
where one would see minimal blurring in their vision. To calculate the of the refractive error with spectacles, but most of these principles and
spherical equivalent, disregard the axis and add half the cylinder power to techniques also apply to correction using contact lenses.
the sphere power. This is the algebraic sum of the value sphere and half
the cylinder value, representing the average of the two powers that make Utility of the Test
up spherocylinder.
A plus cylinder example: Subjective refraction is usually performed after an in-depth history has been
obtained, which includes ascertaining that clear vision has been achieved
+2.00 + 3.00 × 120 previously in both eyes, describing visual symptoms and any relief pro-
vided with the current correction, and specific visual requirements related
The spherical equivalent is: to work and avocations. It should be performed before any other test that
might alter the patient’s responses because of physical changes to the eye,
+2.00 + (+3.00 2) = +3.50 such as Goldmann tonometry and gonioscopy. Any examination procedure
that uses bright lights, such as ophthalmoscopy or slit-lamp evaluation,
A minus cylinder example: can produce a photostress response. Refraction should be done either
before these tests are performed or after an appropriate recovery period.
+2.00 − 3.00 × 120
The spherical equivalent is:

Procedure
Although a totally subjective test is possible, most examiners use a 41
+2.00 + (−3.00 2) = +0.50 baseline starting point, such as an evaluation of the patient’s previous
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2 THE PRINCIPAL MERIDIANS OF THE CLOCK CHART
A B C
Fig. 2.3.6 The Principal Meridians of the Clock Chart. (A) As seen by an eye with uncorrected astigmatism in which each image appears as a vertical oval. The overlapping
ovals make the vertical line darker. (B) The same eye when the correct amount of cylinder is in place and the fogging lens has not been removed. Each image appears as a
blurred circle so that all the lines appear equally dark. (C) The same eye with the full spherocylindrical correction in place. Each image appears as a sharp point, giving an
even, well-focused appearance to the chart.
eyeglasses, retinoscopy, or the results of an automated refraction, which toric lens is interposed along the appropriate axis, each image is circular
they then refine to meet the patient’s requirements. In general, the goal and all of the radii appear equally dark (Fig. 2.3.6). The starting point of
is to determine the maximum plus-lens (or minimal minus-lens) power the test is to have sufficient plus lens power in the tentative correction so
correction that provides clear far vision while minimally exerting accom- that the focal points of both principal meridians are anterior to the retina
modation, and a near correction that provides clear vision at the desired yet are recognizable. This “fogging” technique serves to inhibit the natural
distances. Many methods have been developed to determine the “best” cor- accommodative response to blur; any focusing effort only further blurs the
rection, any of which an adept refractionist can call on to resolve a specific image. In practice, the initial starting sphere (obtained by omitting the
refractive quandary. For the purposes of this chapter, only the most widely minus cylinder from the net retinoscopy result, the previous spectacle cor-
accepted methods are described. rection, or the autorefraction result) is placed before the eye under test.
For an eye correctable to 20/20 (6/6), sufficient plus lens power is added to
blur the 20/40 (6/12) line of letters, usually at least 1.00 D.
Instrumentation In eyes with more astigmatism, enough plus power must be added to
As with most healthcare procedures, many levels of sophistication in fog the least myopic or the most hyperopic meridian. The clock chart is
the instruments are available to perform this technique. They range projected and the patient is asked, “Which, if any, spokes on the wheel
from highly automated scanners and analyzers that provide an objec- are darker?“ Because the details of the chart are standardized at the 20/30
tive measure of the eye’s refractive error in seconds to the centuries-old level, incremental reductions in plus power are required until some of
method of placing loose lenses by hand into a trial frame worn by the the lines are clear. If no astigmatism is present, all of the spokes remain
patient. Each method has its proponents and in particular situations, each equally blurred as plus power is reduced. In astigmatic eyes, the focal
method has its advantages. line produced by the flatter principal meridian is closer to the retina and
Automated refractors analyze the focal power of emitted light from the appears darker or bolder. With high values of astigmatism, one or two lines
eye and convert it into a dioptric correction. They are very fast, require are prominent, whereas at lower values several lines may initially appear
minimum skill levels to operate, and are fairly accurate. They also are very equally dark. The center of the group is identified by the patient. A direct
expensive. Certain high-end models have subjective refraction capabil- method of communicating the correct axis is to have the patient point
ity so that the correction can be refined in the instrument. Portable and out the darkest meridian with a laser pointer.15 The axis of the correcting
hand-held automated refractors now are available. minus cylinder is placed at 90° to this line.
Most practitioners rely on the manually operated refractor or phorop- Another simple method is to use the lowest “clock time” of the darkest
ter that contains a battery of lenses arranged in geared wheels that can line and multiply by 30. For example, if the vertical line were darkest, the
be positioned in front of the patient’s eyes. The lenses can be changed patient would respond, “The 6 o’clock/12 o’clock line.” The correcting
quickly to provide a wide array of plus and minus spherical lenses as well cylinder should be placed at axis 180° (6×30). Minus cylinder lenses are
as a range of cylindrical lenses, available in either minus cylinder and plus then added in 0.25 D increments until all the spokes are equally dark. To
cylinder configurations, that can be rotated to the appropriate axis. maintain the refractive fog, a +0.25 D sphere is added for each −0.50 D of
A trial frame can be used to mount loose trial lenses in front of the cylinder that is added. When equality of the spokes is reported, the process
patient’s eyes. Trial frame refraction is a time-consuming procedure, and should be continued until reversal occurs to ensure that the full cylinder
because of the thickness of individual lenses, especially at stronger powers, power has actually been identified.
a power shift is induced when several lenses are stacked together. This Because the meridians on the clock chart are 30° apart, the true axis
error can be minimized by placing the strongest spherical lens in the rear may lie between them. There are several other commonly used charts that
well closest to the patient’s eye. A variation of this technique is to use a can refine the axis more precisely. The sunburst chart has radial lines that
clip-on trial lens holder, which can be mounted on the patient’s current are only 15° apart, but it is often difficult to communicate the precise axis
glasses or on a “loaner” pair of glasses made up in a spherical power close to the examiner because of fluctuations in response related to minor head
to the patient’s required correction. This works exceptionally well when the movements. The Paraboline rotary slide (Fig. 2.3.7) has two symmetrical
existing eyeglasses contain a strong spherical or cylindrical component. parabolic arcs whose asymptotic ends approximate the image of an arrow-
The most practical use of a trial frame or clip-ons is to allow the patient head.16 With the eye in a “fogged” state, the slide is rotated until both halves
to experience the change in correction before investing in a new pair of of the arrowhead appear equally dark. The axis can be read from a protrac-
glasses. tor projected onto the screen. Along the principal axes of the pattern is a
cross of dotted lines, which is then used as described before to determine
Determination of the Cylinder Axis the correct cylinder power.
The Jackson cross-cylinder (JCC) test is perhaps the most commonly
42 The “clock dial,“ a standard target in most ophthalmic projector systems, is used method for subjectively determining the presence of astigmatism and
a circular chart with radii drawn at 30° intervals. When the correct power for refining the power and axis of a refractive cylinder. It relies on the
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THE PARABOLINE ROTARY PROJECTION CHART
2.3
90 75
60
Clinical Refraction
Fig. 2.3.7 The Paraboline Rotary Projection Chart. The axis of the correcting lens Fig. 2.3.9 The refractor-mounted Jackson cross-cylinder is in place to check for axis
is determined by rotating the slide until both arms of the pattern appear equally orientation of a cylinder of axis 90°.
dark.
JCC is aligned along the minus axis of the spectacle lens, placing the JCC’s
principal meridians each 45° away. Using a target one line larger than the
best acuity obtained through the tentative correction, the examiner flips
the JCC and asks the patient the famous question, “Which is better—one
or two?” The endpoint is the answer, “They are equally blurred.” If one
position of the JCC produces a better image, the axes of both the tentative
correcting lens and the JCC are moved 5° in the direction of the red dots
on the JCC (if using minus-cylinder trial lenses—if using plus-cylinder
trial lenses, rotate the tentative correcting lens toward the preferred orien-
tation of the white dots). In most refractor models, the cylinder axis and the
JCC rotate together. The lens is flipped again and the patient is given the
opportunity to compare the image through each lens. At the axis at which
equality of blur is located, the lenses should be rotated another 5° in the
same direction. If the previous response was accurate, the new position
should produce a reversal in direction.
Determination of Cylinder Power

To determine the correct minus cylinder power, the JCC is rotated until
one set of principal meridians overlies the minus axis of the correcting
lens. The handle of the manual JCC is now 45° away. On the refractor
Fig. 2.3.8 The Handheld Jackson Cross-Cylinder. Note the red circles at the ends units, the position is marked by a click-stop detent. Using the same line
of the minus axis. (Courtesy Scott Brodie.) of letters, the JCC is flipped and again the patient is asked to choose the
better of the two images. If the JCC’s minus axis, marked by the red dots,
is aligned with the cylinder axis, a cylinder of 0.25 D more minus power
principle of placing the circle of least confusion on the retina. A crossed is added to the correction. If the better image is produced when the plus
cylinder is a lens whose principal powers are equal and opposite in sign. axis, marked by the white dots, is aligned, the cylinder power is adjusted
Each end of the minus axis is marked with a red dot, whereas the plus axis by adding +0.25 D. To ensure that the circle of confusion remains on the
has white dots. The rotating handle in the manual lens and the pivot axis retina, for each 0.50 D of cylinder that is added, a 0.25 D sphere of the
in the refractor-mounted JCC is 45° away from the principal meridians to opposite power should be added. The procedure is repeated until the two
allow the lens to be flipped quickly into two primary positions. When the images are equally blurred. Going one lens past to reversal ensures that
circle of least confusion lies on the retina, meridians are equally out of the correct lens is selected.
focus (see Figs. 2.3.8, 2.3.9).
A cylindrical lens whose minus axis is lined up exactly along the astig- Rechecking the Sphere
matic plus axis of the eye produces a resultant spherocylinder whose axis
is also coincident. However, if the correcting lens axis is not aligned with Once the proper cylindrical correction has been established, the final
the astigmatic axis of the eye, the resultant cylinder’s axis lies oblique to sphere needs to be determined. One simple technique is to “refog” the
the other two axes. The power of the resultant cylinder varies in proportion eye using plus lenses to minimize the effects of uncontrolled accommoda-
to the amount of axial rotation between the axis of the eye and the axis of tion. Obviously, this is more of an issue in younger individuals who have
the lens. The JCC is used to determine the correct axis and power of the a large accommodative reserve. Using the line of expected best acuity, the
correcting lens by producing larger or smaller circles of least confusion on power is reduced by 0.25 D at a time with a sufficient intervening pause
the retina in each of its flipped positions. The correcting cylinder can be to allow the patient to attempt to interpret the letters. Once the letters are
changed until the sizes of the blur circles are equal. As in all astigmatic identified, the next smaller line is presented. If these letters are not clearly
correction techniques, the cylinder axis needs to be established before the recognized, power is reduced by another 0.25 D. If the letters are still not
power can be determined. clear, the previous lens probably produces the sharpest unaccommodated
When the JCC is used to locate the correcting axis, the images are equally focus. If the letters are seen, the process is repeated with the next smaller
blurred when the principal meridians of the JCC are equally misaligned line. Many individuals have the capability to see details smaller than those
with the true correcting axis of the eye. To refine the astigmatic correction, on the 20/20 line. It is important to record the best acuity to establish a 43
the starting point correction is placed before the eye. The handle of the baseline for future comparisons.
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more clearly. The lens is removed and the process repeated for the other
2 eye. Adjustments are made until the images are as equally blurred as pos-
sible. If there is no pair of lenses that produces an equality of blur between
the two eyes, the pair that gives the slightly better image in front of the
dominant eye is often preferred.
The best acuity line is then isolated on the chart. The fogging lenses
are reduced from both eyes by 0.25 D at a time, allowing sufficient time
between stages for the patient to adjust to the lens change. In the same
way as with the monocular subjective test, the lens power that gives best
acuity without inducing accommodation is usually the final choice. The
duochrome test offers an alternative method of determining the lens
powers that produce a sharp unaccommodated retinal image.
The same technique can be employed with eyes that have a moderate
discrepancy in best-corrected vision, either from amblyopia or from some
other abnormality. The lens powers can be balanced using a larger line
of letters, for example the 20/80 (6/24) line, and then reduced to the best
binocular acuity, which is that of the better eye. This solves the dilemma
of trying to determine the best monocular subjective correction in an eye
with poor visual discrimination.
Binocular refraction is an infrequently used technique in which both
eyes are fixating while the monocular refraction is measured. Most con-
Fig. 2.3.10 When letters on the green side of the chart are clearer, more spherical temporary devices use some form of vectographic separation in which a
plus power needs to be added. polarized target is presented to each eye through interposing polarized
analyzers with a different axis in front of each eye. This has the advantage
Another technique commonly used to refine the final sphere is the of mimicking the normal form of seeing, incorporating all of the patient’s
duochrome test, which makes use of the chromatic aberration of the binocular efforts including horizontal and vertical phorias. In addition,
eye.17 White light entering the eye is refracted according to its component this method offers the only way to identify a cyclophoria in which the astig-
wavelengths. In an emmetropic eye, blue light focuses about 1 D myopic, matic axes of the eyes are different under binocular conditions from when
whereas red light focuses about 0.5 D hyperopic but equidistant from the observed monocularly.20
retina. The duochrome test uses a pair of colored filters built into the pro- Trial frame confirmation of the final prescription is often overlooked
jector chart, the peak transmission of one at 530 µm (green) and of the but is an extremely valuable verification of the comfort and acuity of the
other at 670 µm (red) (Fig. 2.3.10). In corrected emmetropia, a matched new lens power. Although an examination room of length 20 ft (6 m) is
presentation of letters is equally blurred on each side of the chart. With considered to be the equivalent of optical infinity, 0.17 D of accommoda-
the best spherocylindrical correction, the patient is asked to look at the tion is still required at that distance. It is psychologically reassuring for
letters on the green side. They remain in focus only when accommoda- the patient to step out of the examination room and view the end of the
tion is relaxed. Because the letters on the red side can be made clearer by hallway or, better still, the other side of the street, through the new lenses.
accommodating for them, the patient is asked to look quickly at the letters This small investment of time may save lengthy follow-up visits that could
on the red side and then back at the green and compare their clarity. If the result from miscommunication in the examination room.
letters on the green side are clearer, the correcting sphere is changed by If the cylinder correction is similar to that of the patient’s old glasses,
0.25 D in the plus direction. If the letters on the red side are clearer, 0.25 D it is relatively straightforward to have the patient hand-hold spherical trial
is added in the minus direction. This test is sensitive enough for 0.25 D to lenses in front of the glasses and compare vision with and without the
cause a reversal in clarity. change in prescription. This is a simple way to determine which is the more
satisfactory lens correction when a discrepancy exists between the mon-
Final Checks ocular subjective and the binocular subjective tests. As the monocular
subjective test’s endpoint is best acuity and the binocular subjective test’s
Accommodation endpoint is equality of accommodation, some patients may have a slight
Cycloplegic eyedrops can be used to eliminate accommodation during difference in right and left eye acuities through the binocular prescrip-
the examination. In most cases, the results of a cycloplegic refraction are tion. This refinement offers them the opportunity to observe the difference
not prescribed as a correction. Rather, this type of examination is used in between the two corrections and to make a practical choice between them.
selected circumstances to determine the baseline refractive status of the If there is some doubt about the visual comfort of the change, the lenses
eye. There are two common situations in which this is valuable: can be held in position with a clip-on lens holder while the patient takes
the opportunity to walk around and adjust to the difference. In some cases,
• In young individuals who are suspected of accommodative spasm, espe-
it may be beneficial to allow patients to borrow the lenses and holders
cially when it is accompanied by esophoria or esotropia, it is important
overnight to evaluate the lens changes in their own environment. It is
to prescribe the strongest plus power correction in order to relax accom-
important to mark the right and left lenses and, if cylinders are required,
modation. A follow-up examination not under cycloplegia is usually
to provide a sketch to help align the axis marks.
required to determine the maximum amount of lens power that can be
A similar procedure can be used when the change in correction is a
tolerated in the natural state.
spherocylinder. It is unwieldy to place and remove more than one lens in
• Protocols for refractive surgery usually dictate that the cycloplegic front of the patient’s glasses. If the new cylinder axis is different from that
refractive power of the eyes be determined before the procedure.18
of the old eyeglasses, a calculation of resultant cylinder axis and power is
required to determine the appropriate lens to hold in front of the glasses.
Binocular Balance In such a situation, it is more practical to place the new correction in a trial
The entire procedure is repeated for each eye to produce two monocular frame and to let the patient alternately view at a distance through the trial
subjective prescriptions. Assuming that the patient has clear, single binoc- frame and the old glasses. The trial frame interpupillary distance, the ver-
ular vision, the effects of compensating for an existing heterophoria or the tical lens position, and the pantoscopic angle should be adjusted correctly,
effects of summation of vision from both eyes may alter the lens powers especially with strong lens powers.
chosen for the binocular subjective prescription.19 The process is usually
accomplished in two steps.
The first is to ensure that equal accommodative effort is present between
REFRACTING AT NEAR
the two eyes. If the best-corrected vision is approximately the same in each The near correction is the distance correction with sufficient plus addi-
eye, vision is fogged with +0.75 D lenses. Sufficient vertical prism is placed tional power (the “add”) to satisfy individual needs for clear, comfortable
in front of each eye to produce two separate images of the isolated 20/40 single vision at a desired near point. Although there are normative tables
(6/12) line. The patient is asked to compare the clarities of the upper line for determining an add according to the patient’s age, these simply func-
44 and the lower line. If they appear equally blurred, +0.25 D is added to one tion as benchmarks to help the examiner recognize a potential overcor-
eye and they are compared again. The other eye should now see slightly rected or undercorrected condition. This is an important time to listen to
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your patient. Although patients are notoriously inaccurate when estimat- presbyopic correction to have lenses held in place to demonstrate that their
ing their working distances, the description of how they use their eyes at
near helps to determine not only the strength of the lens power required
near correction will, of necessity, blur their distance vision.
In situations where an anisometropic distance correction is required, 2.3
for tasks at near, but also the form in which the correction will be most it is wise to measure the ranges monocularly to account for any optical
effective. For example, a presbyope who requires a +2.00 D add for reading effects related to the unequal strength of the lenses.23 Unequal adds may
Clinical Refraction
may be very satisfied with a bifocal correction for most activities but be prescribed in certain other situations to keep the near and far points
may require a +1.25 D add in single vision lenses to work at a computer of the ranges at similar distances. As with any significant change, a trial
terminal. frame evaluation of the new correction may help to identify any potential
One rule of thumb that has gained wide acceptance is that the near difficulties before glasses are fabricated. In some cases of anisometropia,
add at a given distance should allow half of the patient’s accommodative bifocals may produce reading discomfort because of an induced vertical
amplitude to remain in reserve. The amplitude is determined by measur- prismatic effect in the reading position of gaze. Specially designed slab-off
ing the closest point at which an individual can maintain focus through lenses or single-vision reading glasses may be required.
the distance correction. For a prepresbyope, this simply means measuring Patients who require higher bifocal adds may not have sufficient
the distance at which a fine line of print can no longer be focused. This accommodation to overlap their distance and near ranges of vision. This
distance, measured in centimeters, is divided into 100 to convert it into “dead zone” is problematic in certain jobs and avocations. An accountant
amplitude of accommodation. A presbyope needs to place a plus lens over may not be able to see a calculator clearly in its normal desktop position,
the distance correction to be able to see the fine print. The closest distance and a violinist may have difficulty reading from a music stand. Although
to which the print can be moved before blurring is again converted into trifocals or progressive lenses may be satisfactory, special use lenses may
diopters and the power of the interposed lens subtracted to give the ampli- be required, such as low-add bifocals with a high segment line.
tude (Box 2.3.1, Fig. 2.3.11). Computer users who must also read place a unique set of demands
A clinical method commonly used to measure the near add is the fused on their glasses. The video screen is usually just below eye level at arm’s
cross-cylinder test. A cross made up of multiple horizontal and vertical length or slightly closer, whereas reading material and the keyboard are
lines is presented to the patient at a distance of 40 cm. A JCC with its positioned lower and somewhat closer. It is often worthwhile to have
minus axis vertical is placed in front of the distance correction. The patient patients adjust one of the computer terminals in the examiner’s office to
is asked to compare the boldness of the horizontal and vertical lines of simulate their workstation conditions.24 Eye-to-screen and eye-to-keyboard
the cross. If no add is required, the lines are equally dark. If the horizon- measurements can be used to determine the necessary add powers. Many
tal lines are darker, plus power is added binocularly in 0.25 D increments presbyopic computer operators have occupational bifocals in which the top
until the lines are equally black or until the vertical lines become more section of the lenses has the intermediate correction and the lower portion
prominent. This lens power becomes the tentative add.21 is set for the keyboard distance. When the operator leaves the worksta-
The final add is determined by verifying that the add is appropriate tion, these glasses are left at the terminal and a conventional correction
for the patient’s visual needs. The range of clear near vision is the linear is used. Progressive lenses often work very well at the computer, though
distance between the far point of the near lens (usually the reciprocal of the patient should be warned that the greater magnification at the bottom
the add power) and the near point of accommodation through the add. of the lenses will make the computer screen appear trapezoidal in shape.
Because the range of vision is inversely proportional to the power of the The vast majority of presbyopic refractive errors are now corrected
lens, many experienced refractionists prescribe the weakest add that meets using multifocal progressive lenses. The continuity of focus that can be
the patient’s demands.22 For most individuals, having a larger range in achieved by slight shifts in vertical head position combined with the lack
which objects are clear overrides the desire to see extremely fine print at of a visible line in the lens identifying the wearer as “older” has made this
a close distance. It is often helpful to patients who are receiving their first the default presbyopic lens design in affluent countries. In recent years,
special use lenses have proliferated offering even more comfort and func-
tionality for those who spend considerable time in activities with a high
BOX 2.3.1 Calculated Near “Add” at Any Distance Should visual demand at near or intermediate distances.
Keep Half of the Patient’s Accommodative Amplitude
in Reserve ADDITIONAL SUBJECTIVE TECHNIQUES
With an extra +1.50 D lens the near point of accommodation is 40 cm Bedside examinations, nursing home visits, and equipment failure are
(2.50 D). examples of situations that require skill in trial frame refraction. When
The patient’s amplitude is 1.00 D (2.50 D − 1.50 D). poorly controlled ambient lighting exists, retinoscopy is often an estimate
For a working distance of 50 cm, 2.00 D of accommodation is required. at best. A retinoscopy rack made up of a battery of spherical lenses (Fig.
Therefore the patient’s “add” for that distance is +1.50 D [2.00 D − 1 2 2.3.12) arranged in ascending order of power can be used to determine the
(1.00) D].
Fig. 2.3.11 A near card is placed in front of the phoropter and slid back and forth to Fig. 2.3.12 Plus and minus racks of spherical lenses, normally used for retinoscopy
determine the closest distance at which the print can be seen before blurring takes screening, are also useful to determine an approximate subjective spherical 45
place. equivalent lens.
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subjective spherical equivalent. Using this power as the initial trial frame essence of retinoscopy is captured. The red reflex is produced when the
2 starting lens, a handheld JCC can be used to determine the presence of

any astigmatism. The handle is positioned along a true oblique meridian
(45° or 135°) so that the principal powers are along the horizontal and ver-
flash lamp is positioned close to the optical axis of the camera.
The source of the red reflex is the aerial image of the blood-filled
choroid superimposed on the pupil. Because the image is very small, it
tical meridians. The lens is flipped and the patient is asked whether either is seen only if the optical systems of the subject’s eye and the camera,
position is better. If not, the handle is repositioned horizontally so that respectively, are close to alignment. Because the aerial image cannot be
the principal powers now lie along the 45° and 135° meridians and the in the plane of the pupil, it must always be out of focus when the plane of
procedure is repeated. If again there is no preference, there is no clinically the face or eye is in sharp focus. Von Helmholtz realized that the origin of
significant astigmatism in that eye. If the patient indicates a preference in the reflex must be the fundus itself and developed the ophthalmoscope to
any of those positions, the JCC tests proceed as described earlier. focus on the details of the fundus.26,27 Thus the position of the aerial image
Some examiners locate the axis of a tentative cylinder by rotating the of the fundus is determined by the optical components of the eye. There-
lens and asking the patient to indicate the position where vision is the fore determination of the position of the image can lead to determination
clearest. For strong cylinders, this is an accurate and repeatable technique. of the refractive error of the eye. Cuignet, a French army ophthalmologist
However, for low-power cylinders a range of axis positions exists that who measured the refractions of a large number of army recruits, must be
produce clear vision for most observers.25 A modification of this test to credited with the development of a better way to define the position of the
increase its accuracy is to rotate the lens until a small line of letters first aerial image.28 His method always brought the aerial image to the same
blurs noticeably then rotate the lens back in the opposite direction to first location in space, at the examiner’s eye, a principle employed by most
blur. The midposition is the correcting axis. This test is highly dependent contemporary retinoscopists. Subtraction of the dioptric-value equivalent
on an acutely observant patient. of the “working distance” determined the power of the lens required to
One drawback of the JCC is its reliance on the patient’s visual memory correct the refractive error.
to determine preferences. Modifications of the refractor-mounted versions
exist that use split prisms to produce a simultaneous presentation of both Optics of Retinoscopy
positions of the JCC. The lens and device can be rotated together until the The essence of retinoscopy is to illuminate the retina and then locate
images are equally blurred to locate the cylinder axis. In the same way, the the image of the retina in space. Thus the retinoscope combines a light
power can be determined by changing the correcting cylinder power until source with an observation aperture (i.e., peephole). The position of the
both images appear equal. retinal image is called the far point. Its position in dioptric units is equal to
In situations where vision in an eye is very poor and no other instru- the refractive error. Thus the eye may be considered as an element in an
ments are available, the stenopeic slit can be used to screen for a high optical bench. When the light rays that leave the eye are made visible, the
degree of astigmatism. It functions as a series of pinholes along a merid- far point can be located and the refractive error calculated. Unfortunately,
ian. A trial frame or clip-on device is used to place the trial lens stenopeic a side-view analysis of the human eye as though it is on an optical bench
slit in the lens cell and rotate it slowly. If there is a position that produces cannot be done. However, with this side-view analysis in mind, the mech-
improved vision, it is treated as a principal meridian of the eye. With the anism of retinoscopy can be understood.
slit still in place, spherical plus and minus lenses are positioned in front For the purposes of this description, it is assumed that a side-view anal-
of it. A convenient method is to use the retinoscopy rack. When the lens ysis is possible. The retinoscopist places lenses in front of the patient’s
power that gives the most improvement has been established, the steno- eye so that the patient’s far point is focused at the peephole of the retino-
peic slit is rotated 90° and the procedure repeated. The two spherical scope. For example, the emmetrope’s far point is at infinity. If the retinos-
lens powers are considered to be the correcting lens powers for each of copist works at a distance of 25 inches (66 cm) from the patient (called
the principal meridians. The powers are combined in a spherocylinder the working distance), a +1.50 D lens brings parallel light to a focus at
lens that is placed in the trial lens cell. If vision is improved sufficiently, 25 inches (66 cm) from the patient’s eye. The far point of the myope lies
it may be possible to refine the correction using conventional methods between the examiner and the patient (Fig. 2.3.14). A minus lens of the
(Fig. 2.3.13). appropriate power brings the image to the peephole of the retinoscope.
The refractive error equals the dioptric power of the minus lens needed
less that of the working-distance lens (+1.50 D). Thus, if a −5.00 D lens is
RETINOSCOPY needed to bring the far point to the examiner, then the refractive error is
Retinoscope −5.00 D + 1.50 D = −3.50 D. The far point of the hyperope is theoretically
behind the head of the patient. A plus lens of the appropriate power brings
Every time a close-up photograph is taken of the face of a subject and a the far point to the peephole of the examiner. Thus, if a +5.00 D lens is
vivid red pupil (called red eye) seen instead of the usual black pupil, the needed to bring the far point to the examiner, then the refractive error is
5.00 + 1.50 D = +6.50 D.
Neutrality
Cuignet found the position of the far point by using a version of the Foucalt
knife-edge test. Imagine a thin, sharp knife that moves across the beam of
light that leaves the patient’s eye. If the knife edge passes across the point
of focus, then the knife edge blocks all the light for an instant, after which
all the light reappears; the edge of the peephole of the retinoscope may
Fig. 2.3.13 A Stenopeic Slit Is in Place to Check Along the 135th Meridian. Once
the spherical power has been determined, the lens should be rotated 90° and
46 the spherical power measured along the 45th meridian. The two powers can be Fig. 2.3.14 The Far Point of the Myopic Eye Lies Between the Patient and the
combined into a spherocylindrical lens. Retinoscopist.
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be considered such a knife edge. If the far point is brought to a focus at at 7.5 inches (20 cm), the amount of myopia is 5.00 D (no working distance
the peephole, then the focused light appears to vanish and reappear with
a slight side-to-side motion of the peephole. This situation is called neu-
compensation is needed).
2.3
trality and represents the endpoint of retinoscopy. It is at this endpoint Astigmatism
that the power of the lens in front of the patient’s eye minus the +1.50 D To determine the presence of astigmatism, simply sharpen the streak and
Clinical Refraction
working lens yields the value of the refractive error. slowly rotate it to 360°. If little or no astigmatism exists, the retinoscopic
streak reflex always is parallel to the intercept. A break phenomenon
With and Against Motion occurs when the reflex is not in perfect alignment with the intercept as the
The image that emerges from the patient’s eye before neutrality is reached streak is rotated. The orientation of the streak reflex when it lies parallel to
is significant. In a myopic eye, as the examiner moves the illumination the intercept indicates the direction of one of the major meridians of the
light upward, the retina is illuminated in an upward direction. The real, astigmatism. The examiner must find the lens of neutrality for a side-to-
inverted image of the retina is focused between the patient and examiner, side movement along that meridian and establish neutrality for the merid-
and the retinal image appears to move downward in a direction opposite ian 90° away. For example, assume that the maximum break phenomenon
to the movement of the retinoscope. This is called against motion. Minus is along the 90° meridian. Rotate the streak into a horizontal position and
lenses are placed in front of the patient’s eye until the focus is brought to move the retinoscope up and down (along the 90° meridian). Imagine
the plane of the peephole, at which point neutrality is seen. In a hyperopic that a +4.50 D sphere neutralizes the vertical movement. Now rotate the
eye, as the beam from the retinoscope moves upward, the retina is illu- streak vertically and move it side to side along the 180° meridian. With
minated in an upward direction. The virtual, upright image of the retina the +4.50 D sphere in place, a −2.00 D cylinder of axis 90° neutralizes the
appears illuminated in an upward direction. Because the image moves in side-to-side movement. Subtraction of the +1.50 D power of the working
the same direction as the retinoscope, the motion is called a with motion. distance lens from the dioptric power of the sphere yields a +2.00 D sphere
Plus lenses are placed in front of the patient’s eye, the image is moved to with a −2.00 D cylinder of axis 90°.
the plane of the retinoscopic pinhole, and neutrality is seen.
Other Clues KEY REFERENCES

The retinoscopist must be aware of other subtle clues that differentiate Azar D. Refractive surgery. Stamford: Appleton & Lange; 1997. p. 118–19.
fine with and against motions from neutrality. For example, the aerial Borish IM. Clinical refraction. Chicago: Professional Press; 1970. p. 722–3.
image becomes larger the closer it is to the examiner’s eye. A closer aerial Borish IM. Subjective testing of refraction. In: Miller D, editor. Optics and refraction: a
image also appears to move faster because more of the closer image fills user-friendly guide, vol. I. Textbook of ophthalmology. New York: Gower Medical; 1991.
p. 9.8, 9.26.
the peephole than does a smaller, more distant aerial image. A small move- Borish IM. Benjamin WJ, editor. Borish’s clinical refraction. 2nd ed. St Louis: Butterworth–
ment of the peephole crosses a larger percentage of the aerial image and Heinemann; 2006. p. 801, p. 833.
gives the appearance of a faster movement. The closer to neutrality, the Carlson NB, Kurtz D. Clinical procedures for ocular examination. 3rd ed. New York:
faster is the movement of the reflex. In a similar vein, the brighter the McGraw-Hill; 2004. p. 146–8.
Carter JH. On the significance of axis error. Alumni Bull Pa Coll Optom 1966;20:6–8.
reflex, the closer it is to neutrality. Here again, the closer the aerial image Gettes BC. Refraction. Boston: Little Brown; 1965. p. 343–5.
is to the retinoscopist (Newton’s law), the brighter it is. Rutstein RP, Eskridge JB. The effect of cyclodeviations on the axis of astigmatism. Optom
Vis Sci 1990;67:803.
Myopia Estimation Scheiman M. Accommodative and binocular vision disorders associated with video display
If the initial retinoscopic movement is slow and dull, with movement, then terminals: diagnosis and management issues. J Am Optom Assoc 1996;67:531–9.
Werner DL. Clinical pearls in refractive care. Boston: Butterworth–Heinemann; 2002. p. 155,
high myopia is present. To estimate quickly the amount of myopia without p. 318.
using trial lenses, simply move toward the patient and simultaneously
move the retinoscope slowly from side to side. As the far point is reached,
the endpoint of neutrality is given. The distance from the patient is the far Access the complete reference list online at ExpertConsult.com
point and must be converted into diopters. Thus, if neutrality takes place
47
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REFERENCES 15. Borish IM. Subjective testing of refraction. In: Miller D, editor. Optics and refraction: a
user-friendly guide, vol. I. Textbook of ophthalmology. New York: Gower Medical; 1991.
1. Gettes BC. Refraction. Boston: Little Brown; 1965. p. 343–5.
2. Ronchi L, Fontana A. Laser speckles and the depth of field of the human. Opt Acta
p. 9.8.
16. Borish IM. Clinical refraction. Chicago: Professional Press; 1970. p. 722–3.
2.3
(Lond) 1975;22:243–6. 17. Borish IM. Benjamin WJ, editor. Borish’s clinical refraction. 2nd ed. St Louis: Butter-
worth–Heinemann; 2006. p. 833.
Clinical Refraction
3. Levene JR. Clinical refraction and visual science. London: Butterworths; 1977.
4. Bennett AG, Rabetts RB. Clinical visual optics. 2nd ed. London: Butterworths; 1988. 18. Azar D. Refractive surgery. Stamford: Appleton & Lange; 1997. p. 118–19.
5. Bailey IL, Lovie JE. New design principles for visual acuity letter charts. Am J Optom 19. Borish IM. Subjective testing of refraction. In: Miller D, editor. Optics and refraction: a
Physiol Opt 1976;53:740–5. user-friendly guide, vol. I. Textbook of ophthalmology. New York: Gower Medical; 1991. p.
6. Ferris FL, Kassoff A, Bresnick GH, et al. New visual acuity charts for clinical research. 9.26.
Am J Ophthalmol 1982;94:91–6. 20. Rutstein RP, Eskridge JB. The effect of cyclodeviations on the axis of astigmatism.
7. Maffei L, Fiorentin A. The visual cortex as a spatial frequency analyzer. Vision Res Optom Vis Sci 1990;67:803.
1973;13:1255–67. 21. Carlson NB, Kurtz D. Clinical procedures for ocular examination. 3rd ed. New York:
8. Mainster MA. Contemporary optics and ocular pathology. Surv Ophthalmol 1978;23: McGraw-Hill; 2004. p. 146–8.
135–42. 22. Werner DL. Clinical pearls in refractive care. Boston: Butterworth–Heinemann; 2002.
9. Campbell FW, Robson JG. Application of Fourier analysis to the visibility of gratings. J p. 155.
Physiol 1968;197:551–66. 23. Werner DL. Clinical pearls in refractive care. Boston: Butterworth–Heinemann; 2002.
10. Campbell FW, Gubisch RW. Optical quality of the human eye. J Physiol 1966;186:558–78. p. 318.
11. Campbell FW, Green DG. Optical and retinal factors affecting visual resolution. J Physiol 24. Scheiman M. Accommodative and binocular vision disorders associated with video
1965;181:576–93. display terminals: diagnosis and management issues. J Am Optom Assoc 1996;67:531–9.
12. Balaram M, Ragavan A, Tung W, et al. Testing the Campbell–Green Equation using 25. Carter JH. On the significance of axis error. Alumni Bull Pa Coll Optom 1966;20:6–8.
MTF and CS data from normal and cataractous eyes. Opt Soc Am Tech Dig Vis Sci Appl 26. Rucker CW. A history of ophthalmology. Rochester: Whiting Printers and Stationers;
1998;1:82–5. 1971. p. 57–62.
13. Hemenger RP. Intraocular light scatter in normal lens with age. Appl Opt 1984;23:1972–4. 27. von Helmholtz H. Ueber eine neue einfachste Form des Augenspiegel. Arch Physiol
14. Van Nes FL, Bouman MA. Spatial modulation transfer in the human eye. J Opt Soc Am Heilbron 1852;2:827–40.
1967;57:401–6. 28. Duke-Elder S. System of ophthalmology, vol. 4. St Louis: CV Mosby; 1949. p. 4391–3.
47.e1
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Correction of Refractive Errors

Bing Chiu, Joshua A. Young 2.4
Definition: Refractive errors may be corrected by means of spectacles, SPECTACLE CORRECTION
contact lenses, orthokeratology, intraocular lens implants, and Evidence of spectacle use dates to at least the late thirteenth century.
keratorefractive surgery. Although this certainly implies that people with refractive errors could
seek no remedy for the countless millennia that preceded the invention of
spectacles, it has been suggested that ametropia, particularly myopia, was
far less common in the ancient world than it is at present.
Key Features
• Spectacle lens advantages: inexpensive; suitable to correct Spectacle Material
myopia, hyperopia, astigmatic refractive errors, and presbyopia; no Whether a person wears glasses for correction of refractive error, pro-
permanent ocular alterations. Drawbacks: some patients may reject tection of eyes, or for cosmetic reasons, the materials of the lenses can
for cosmetic reasons; may cause image jump, object displacement, play a significant role. For the patient who desires the best optical quality
and alter retinal image size. throughout her or his visual field, a thin lens with significant peripheral
• Contact lens advantages: excellent cosmetic appearance, free from blurring might be a poor choice. Likewise, for the patient for whom impact
prismatic effects, minimize astigmatic distortions and problems with protection is paramount, a glass lens that can easily break and shatter
alterations in retinal image size. Drawbacks: correction of astigmatic would be unsuitable.
errors and presbyopia may be difficult; expose patients to risk of Spectacle lenses are manufactured from a variety of materials1 with
corneal oxygen deprivation and corneal infections. characteristics that can be condensed into a few properties that describe
• Orthokeratology advantages: patients may be able to function the optical quality, strength, and density. The ideal material would be
without glasses or contact lenses during daytime. Drawbacks: require thin, lightweight, impact and scratch resistant, inexpensive, and devoid
nighttime contact lens wear; correction may wane during daytime of optical distortion. The variety of available materials may be seen as a
hours. demonstration that no single optimal material exists. One unwanted prop-
• Intraocular lens implant advantages: preferred correction for aphakia; erty of lens material is the tendency to disperse white light into its com-
may allow for correction of extreme myopia in phakic patients. ponent wavelengths. Rainbows are pretty in the sky but the color fringing
Drawbacks: limited correction of presbyopia, astigmatism; phakic that results from wavelength dispersion in spectacles is distracting and
intraocular lenses may induce cataract formation. degrades image quality. This wavelength dispersion is referred to as chro-
• Keratorefractive surgery advantages: may eliminate need for glasses. matic aberration, and the degree to which materials disperse wavelengths
Drawbacks: less predictable for correction of larger refractive errors; is quantified as the Abbe number or V-number. Materials that minimize
may destabilize cornea; risk of complications (small). chromatic dispersion—those with higher Abbe numbers—are generally
more desirable.
Of course, the primary reason for which lenses are designed is to bend
INTRODUCTION or refract light. The degree to which a spectacle lens bends light is a func-
tion of its curvature and of the material from which it is made. For any
In an ideal eye, the combined optical contribution of the front of the eye given shape, certain materials will bend light more than others. The degree
focuses incoming rays of light onto the retina to produce a clear image. If to which a material can bend or refract light is a function of the speed of
this optically ideal eye requires no aid or accommodation to focus distant light through that material. We generally think of the speed of light as
objects onto the retina, the eye is said to be emmetropic. Conversely, if an the immutable value c or 299,792,458 m/s, but of course this is the speed
eye in its relaxed, nonaccommodating state and devoid of other pathol- of light through a vacuum. Through any other medium, light propagates
ogy fails to produce a clear image on the retina from rays of light of a at a velocity lower than c. Media through which light moves especially
distant object, the eye is said to be ametropic. Ametropia encompasses slowly have the greatest ability to refract. The degree to which a material is
a wide range of optical imperfections including myopia (nearsightedness capable of refracting light is given by the ratio of c over the speed of light
or shortsightedness), hyperopia (farsightedness or long-sightedness), and through the material. This ratio is called the index of refraction, and higher
astigmatism, itself a collection of different optical imperfections. Indeed, values indicate a greater ability of a material to refract light. Because a lens
an almost limitless number of optical abnormalities exist beyond these, with greater intrinsic ability to refract light requires a less curved surface
but such optical aberrations are not amenable to correction by spectacles, to achieve the desired refraction, high refractive index lenses can be made
and discussion of these will be limited in this chapter. thinner than low refractive index lenses. For this reason, patients with
In addition to the very obvious disadvantage of reducing visual clarity, high degrees of ametropia often opt for high index lenses.
ametropia may be an indicator of more serious ophthalmic disease. An Spectacles also serve as a barrier between the environment and the eyes.
adult whose previously stable refraction has begun to demonstrate increas- For some patients—those who are monocular or amblyopic and those who
ing myopia may be demonstrating the refractive effect of a maturing are engaged in work in which ocular trauma is possible—the strength of
nuclear cataract. A 20-year-old whose astigmatism has begun to worsen the lens material may be its most important property.2 Standards are set
may be suffering from progressive keratoconus, a disease of ectasia of the by the US Food and Drug Administration (FDA) and American National
most refractively important part of the eye, the cornea. The highly hyper- Standards Institute (ANSI) for resistance of a material to penetration or
opic middle-aged woman is at substantial risk of angle-closure glaucoma shattering. Although glass lenses offer excellent optical quality and scratch
for precisely the same reason for which she is hyperopic, a small and resistance at a low cost, glass has fallen out of favor because of its poor
therefore crowded eye. impact resistance and high specific gravity, making it a heavy material.
A number of clinical modalities exist to correct ametropia. Each of Plastic, also known as hard resin or Columbia resin (CR-39), has become
these has limitations, and different types of correction are advantageous the most common material for spectacles. It is light, impact resistant,
48 for different clinical settings. The simplest of these and the only method and versatile, naturally UV blocking, and can be easily tinted or treated
without medical risk is spectacle correction. to be scratch resistant. However, plastic has a low index of refraction and
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a thicker lens is therefore required. A stronger material, polycarbonate, spectacle lens. This produces a type of distortion characteristic to each
is commonly used in protective wear. Originally made for aerospace and
used in helmet visors and space shuttle windshields, this petroleum deriv-
type of lens.
Spectacles to correct myopia employ minus-powered lenses. These 2.4
ative plastic polymer has a high refractive index and low specific gravity lenses produce minification and, because the periphery of the image is
with very high impact resistance. Although these lenses are thin and light- minified to a greater extent, produce a sort of distortion in which the

weight, polycarbonate has a relatively low Abbe number, and so high chro- periphery of the image is rendered at a smaller scale than the center. This
matic dispersion results. Polycarbonate is also prone to scratches, making is referred to as “barrel distortion.” Such distortion is readily observed
scratch-resistant coating essential. when looking into a convenience store mirror, when looking at one’s self
For high refractive errors, high refractive index materials can be benefi- in a mirrored sphere like a ball bearing, or viewing a scene through a
cial, although not without costs—both optical and financial. Plastic or glass fisheye lens.
materials that are made with higher index of refraction (i.e., over 1.6) are Similarly, plus-powered spectacles for the correction of hyperopia
lighter and thinner but are also prone to more chromatic aberration and produce distorted images in which the periphery is more magnified than
distortion at the periphery of the lens. They also tend to be less impact and the center. This “pin-cushion distortion” also may be observed when using
scratch resistant. a magnifying glass3 (Fig. 2.4.1).
Perhaps the most disturbing sort of asymmetrical magnification
Monofocal Spectacles induced by spectacle lenses is the meridional magnification intrinsic to
astigmatic lenses. In this case the meridian of highest plus power pro-
Monofocal spectacles correct for spherical refractive errors such as myopia duces relative magnification compared with the meridian of highest minus
and hyperopia, astigmatic refractive errors, and for combinations of spher- power. The net result is to produce images that are short and fat, tall and
ical and astigmatic errors. For patients incapable of any degree of accom- skinny, or magnified obliquely. This is especially disturbing when, as is
modation, for example patients who have undergone cataract extraction, often the case, astigmatic axes are oblique and at mirror-image orienta-
these spectacles bring clear focus to objects at only a defined distance from tions in the two eyes. Oppositely oriented meridional magnification may
the eye. For example, monofocal distance spectacles would not bring near be misinterpreted as distortion in depth perception and can make specta-
objects into clear focus for such a patient. In clinical practice, monofocal cles intolerable even if the right and left lenses are of equal dioptric power.
lenses are prescribed to young, nonpresbyopic patients for all tasks and for
presbyopic patients for limited tasks. For emmetropic presbyopic patients, Bifocals
those with naturally good distance vision but for whom accommodation is
inadequate, monofocal reading glasses often are prescribed. Traditional bifocal and trifocal lenses have been largely displaced by pro-
Clinicians prescribing monofocal spectacles specify only three param- gressive lenses. Still, these older forms remain in wide use and in some
eters for each eye: the power of the spherical correction, the power of the clinical settings have advantages over the newer progressive designs. Bifocal
astigmatic correction, and the orientation (axis) of the astigmatic correc- lenses are distinguished by discrete segments for distance and for near
tion. Although this prescription may compensate for the patient’s refrac- with an abrupt transition between the two4 (Fig. 2.4.2). Unlike monofocal
tive error, a number of factors other than these determine whether the
patient will tolerate the prescribed lenses. These factors have in common
the drawback that image distortion is intrinsic to spectacle correction. Most DISTORTION TYPES
important, distortions arise from asymmetrical image magnification and
may be illustrated in this thought experiment: Imagine an emmetropic
patient looking through a telescope at a distant object. The telescope, a Gal-
ilean telescope in this case, consists of a plus-power or converging objective
(the lens at the large end of the telescope) and a minus-power or diverging
eyepiece. For this experiment, let’s imagine that the minus-power eyepiece
is a contact lens. Indeed, the telescope would exhibit the same degree of
magnification if the eyepiece were a conventional lens or a contact lens.
If we further imagine that our patient, rather than being emmetropic,
has instead a refractive error equivalent to the contact-lens eyepiece, she
or he would experience the same degree of magnification as our original
emmetrope. Our ametropic patient is hyperopic. We know this because
the correcting lens (i.e., the objective of the telescope) is plus powered and
thus we see that hyperopes corrected with plus spectacles experience a
degree of image magnification. The case of the myope is identical in every
barrel distortion pincushion distortion
regard except that the “telescope” is now oriented backward and produces
object minification.
The magnification produced by spectacles is generally tolerated well Fig. 2.4.1 Types of Distortion Induced by Spectacle Lenses. (Courtesy Joshua
Young and Wikipedia, “Barrel distortion”; public domain.)
by patients as long as its magnitude is similar in each eye. However,
asymmetrical magnification of only a few percent can produce symptoms
sufficient to make spectacle correction intolerable. The degree of magni-
fication is a function of two variables: the dioptric power of the spectacle BIFOCAL SEGMENT TYPES AND THEIR OPTICAL CENTERS
lens (equivalent to the telescope’s object lens) and the distance between the
spectacle lens and the eye, known as the vertex distance (and equivalent to round-top segment flat-top segment
the length of the telescope’s tube).
The condition of perceived difference in image size between right and
left eyes is called aniseikonia. As a general rule, adults who are unaccus-
tomed to large differences in prescriptions between right and left eyes
will tolerate no more than 3 or 4 diopters of asymmetry in spectacles.
This challenge arises clinically in the case of patients who are develop-
ing an asymmetrical increase in myopia from a maturing nuclear cataract
(so-called myopic shift) or after cataract surgery if the refractive errors are
substantially asymmetrical postoperatively.
Symptoms attributable to asymmetrical magnification are not limited
to aniseikonia from asymmetrical spectacles. Asymmetrical magnifica-
tion also can produce symptoms monocularly. Because the degree of
magnification produced by a spectacle lens is dependent partly on the optical center of the distance lens optical center of the bifocal segment
distance between the lens and the eye, the degree of magnification or
minification is least at the center of the spectacle lens where the lens is Fig. 2.4.2 Bifocal Segment Types and Their Optical Centers. (Courtesy Joshua 49
closest to the cornea and increases farther away from the center of the Young.)
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lenses, the prescriptions for which are ground into the back surface of worse, the choice of this type of bifocal represents a missed opportunity to
2 the lens, bifocal segments are applied to the front surface. Bifocal designs
take a number of forms, and the appropriate choice of bifocal segment is a
function of the lens to which it is applied.
make the image displacement better.
All bifocal segments are plus-dioptric powers. As such, they may be

Progressive Spectacles
thought of as portions of a larger plus-powered lens. The round-type Progressive spectacles or progressive-addition lenses (PAL) hold a number
bifocal would then derive from the top of a plus-powered lens and the of advantages over traditional bifocal and trifocal lenses. PAL spectacles
flat-top from the bottom of a plus-powered lens. This is highly significant appeal to patients because they are without visible lines and so do not
because each type of bifocal adds a certain degree of prism to the bottom
of the spectacles and produces a certain amount of discontinuity at the line
of transition between the distance and near portions of the lens. The dis- ROUND-TOPS INCREASE IMAGE
continuity of the image produced at the line between the distance and the DISPLACEMENT IN MINUS LENSES
near portion of the lens is called “image jump.” The degree of image jump
is a function of the power of the reading add and of the distance between
-5.0D
the optical center of the reading add and the top of the reading segment.
By Prentice rule, discussed earlier in this volume, the amount of prism
induced at the top of the bifocal segment is proportional to the distance
between the optical center of the segment and the top of the segment.
Round-top bifocals have the largest distance between these two points and
therefore will produce the largest image jump for any given bifocal power.
Traditional flat-top bifocals have only a small distance between the optical
center and the top of the bifocal segment and produce only a very small
amount of image jump.
Although image jump may be annoying to patients, it is not the chief
determinant in choosing the appropriate bifocal segment design. Rather,
the bifocal design is chosen in an effort to minimize the total amount of
prismatic power induced at the bottom of the patient’s spectacle. All spec-
tacles, even those without bifocal segments, demonstrate prismatic power
for all locations away from the optical center. The amount of prismatic Fig. 2.4.4 The Round-Top Bifocal Segment Increases Image Displacement in
power at the bottom of the spectacle lens is important because the shift in Myopic Spectacles. (Courtesy Joshua Young.)
the image induced by this prism may cause patients to miss obstacles on
the ground or misjudge the location of curbs or steps. It is advantageous
to choose a bifocal design that will incorporate a prism of opposite orienta- FLAT-TOPS DECREASE IMAGE
tion to that already existing in the patient’s spectacles. In the case of hyper- DISPLACEMENT IN MINUS LENSES
opic patients who are wearing spectacles that already incorporate a base
up prism in the bottom portion of the lens, the appropriate bifocal choice
would be one that demonstrates a base down prism (Figs. 2.4.3 and 2.4.4). -5.0D
This is necessarily a round-top bifocal segment. Such a choice will min-
imize the total prismatic power at the bottom of the patient’s spectacles
and make it less likely that the patient will miss obstacles in his path. Keep
in mind that this is the appropriate choice despite the fact that round-top
bifocals produce more substantial image jump than flat-top type bifocals.
In the case of the myope who demonstrates a base down prism in the
bottom portion of her or his spectacle lens, a base up bifocal design will
prove complementary, and therefore a flat-top bifocal is the appropriate
choice for this patient (Figs. 2.4.5 and 2.4.6).
Currently, choices exist beyond simple round-top and flat-top designs.
Some flat-top shaped bifocals known as C-designs and D-designs actually
extend above the optical centers of the reading segment. This results in
only a small amount of induced prism over much of the area of the bifocal
segment. Therefore this may be an acceptable design even in the case of
Fig. 2.4.5 The Flat-Top Bifocal Segment Decreases Image Displacement in
hyperopic patients. It must be remembered that although this design does
Myopic Spectacles. (Courtesy Joshua Young.)
not make the image displacement produced by the total prism materially
FLAT-TOPS INCREASE IMAGE

ROUND-TOPS DECREASE IMAGE DISPLACEMENT IN PLUS LENSES DISPLACEMENT IN PLUS LENSES
round-tops decrease image displacement in plus lenses +5.0D

+5.0D
50 Fig. 2.4.3 The Round-Top Bifocal Segment Decreases Image Displacement in Fig. 2.4.6 The Flat-Top Bifocal Segment Increases Image Displacement in
Hyperopic Spectacles. (Courtesy Joshua Young.) Hyperopic Spectacles. (Courtesy Joshua Young.)
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lenses were oriented in the horizontal or coronal plane, the spectacle lens
ANATOMY OF A PROGRESSIVE LENS would be farther from the eye in downgaze than in primary gaze. To com-
pensate for this, spectacles incorporate a tilt to the lens about the hori- 2.4
zontal axis. This pantoscopic tilt keeps the vertex distance (the distance
between the cornea and the lens) more consistent in primary and down-

gaze. An additional benefit is that the patient gains a larger field of vision
in the reading portion of the lens because it is closer to the eye. A similar
distance
tilt may be incorporated along the vertical axis. This is referred to as Z-tilt
or as the wrap angle of the lens.
blend
inter-
blend
Base Curve and Center Thickness
mediate
A number of other variables influence the degree of magnification pro-
duced by spectacle lenses. Because myopic spectacles induce a degree of
near minification, parameters such as base curve (or back curve) and center
lens thickness may be altered to reduce this minification. Increasing the
convexity of the back surface of the lens and increasing the thickness of
the center of the lens will produce a small degree of magnification. In
practice, these may be difficult to implement because increasing the thick-
ness of the already thick lens of a high myope will make the spectacle
Fig. 2.4.7 Parts of a Progressive Addition Lens (PAL). (Courtesy Joshua Young.) heavy and less attractive and because increasing the back curve tends to
increase the vertex distance of the lens.6a
reveal that the patient is of presbyopic age. The lenses have several func-
CONTACT LENSES
tional advantages as well. Because no discrete interface exists between Although the idea of contact lenses dates at least to a sixteenth-century
the distance and near portions, no image jump occurs. Image displace- suggestion by Leonardo da Vinci, it was not until 1887 that a wearable
ment is not an independent variable in this type of lens design, and so contact lens was developed. This lens, made of blown glass, was much
no choices need be made by the prescribing physician to minimize image larger than the majority of modern contact lenses and was tolerated for no
displacement either. Progressive lenses incorporate variable dioptric power more than a couple of hours at a time.
between the distance portion in primary and upgaze and the reading Contact lenses of a modern design were introduced in the late 1940s
portion at the bottom of the lens. Because the lens powers are graduated, and were made of polymethyl methacrylate (PMMA). These hard contact
there is at least some portion of the spectacle lens that will bring objects at lenses are still encountered in clinical practice, but the majority of patients
intermediate distance into focus.5 who report wearing “hard contact lenses” are not wearing these oxygen
Progressive lenses vary substantially in design, but all share a number impermeable plexiglass lenses but rather lenses of rigid gas permeable
of features. From primary gaze through the center of the lens to the top material. Beginning in the 1970s, rigid gas permeable lenses were intro-
of the frame, progressive lenses provide a single correction for distance duced. Soft hydrogel contact lenses were developed in the 1960s and newer
vision. The bottom of the lens contains a region of single power for silicone hydrogel contact lenses in the late 1990s.
reading. These two regions are connected in a narrow-waist corridor. The Contact lens wear is associated with a number of risks and hygiene
regions to the right and left of the corridor (looking down and to either requirements that are more burdensome than simple spectacle wear.6b
side) do not provide clear focus at any distance because of the aberrations These risks will be discussed later in this chapter, but it bears discuss-
necessary to produce the graduated power along the centerline of the lens. ing the advantages to contact lenses that offset these risks and cleaning
These afocal areas are called blend zones and are the source of complaints requirements. The cosmetic advantage of forgoing spectacles is the most
from patients who find it difficult to adapt to progressive lenses (Fig. 2.4.7). obvious benefit to contact lens wear, but several optical benefits also accrue.
The width of the corridor and the amount of the lens devoted to The pincushion and barrel distortions as well as the astigmatic distortions
intermediate vision vary by the particular lens design and manufacturer. induced by meridional magnification are greatly minimized by the use of
Because sufficient room in the spectacle frame must exist beneath primary contact lenses. Additionally, much more substantial anisometropia is toler-
gaze for the graduation to incorporate an adequate reading portion, some ated with contact lens wear than with spectacles. Indeed, aniseikonia that
frames are unacceptably short for the incorporation of a progressive lens. would otherwise prohibit the correction of monocular aphakia is gener-
ally tolerated in contact lenses. Symptoms of anisometropic anisophoria
Occupational Bifocals resulting from asymmetrical prismatic power induced by Prentice rule are
completely negated with contact lens wear because the optical center of
Before the advent of desktop computers, bifocal spectacles were probably the contact lens moves with the patient’s eye. Different types of contact
adequate to most patients’ needs. The distinguishing feature of desktop lenses hold different advantages, and each major type of contact lens will
computers is that their screens represent an intermediate distance task be discussed in the section that follows.
that is performed in primary (i.e., straight-ahead) gaze or slightly below
primary gaze. Because it is impossible to prescribe spectacles that have Vertex Correction
two different prescriptions in primary gaze, dedicated computer glasses
are often warranted. Progressive spectacles may provide a useful solu- Because patients are aware that their prescriptions for spectacles do not
tion if the computer screen can be placed so as to intercept the zone of vary with the type of frame they choose, it is not unreasonable for them to
intermediate-add correction. If the screen is placed too high for the patient assume that the prescriptions are also identical for contact lenses. This is
to view the computer screen, he must adopt a chin-up position. This is not the case, primarily because contact lenses are positioned at a different
inadvisable for lengthy computer use. distance from the eye from spectacles. The distance between the correcting
Another solution is to prescribe either single-vision spectacles for the lens and the cornea is referred to as the vertex distance, and this distance
computer distance—often 21 or 22 inches from the patient’s eyes—or to must be accounted for when the contact lens prescription is given.
prescribe glasses that are indeed bifocal but incorporate only the computer As the vertex distance decreases, the myopic correction must decrease
distance and reading distance without having any portion dedicated to far as well. In the case of hyperopic patients, the hyperopic correction is higher
distance vision. These are called occupational bifocals and allow the patient in contact lenses than in spectacles. Similarly, myopic patients generally
to see the computer screen in primary gaze and to bring printed copy to will have a contact lens prescription with a lower number than their pre-
the closer reading position in downgaze. scription for spectacles. The difference produced by the change in vertex
distance is small for low-to-moderate myopes and at least in theory should
Pantoscopic Tilt and Wrap Angle yield no difference for myopic or for hyperopic corrections with an abso-
lute value of less than four diopters. In practice, it is generally beneficial to
In the course of normal activities, people tend to employ either primary refract the patient with contact lenses on the eye and to adjust the contact 51
gaze or downgaze. Few of our tasks require substantial upgaze. If spectacle lens by the power of this “overrefraction.” A number of other parameters
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must be considered when prescribing rigid gas permeable contact lenses maintains centration and comfort for central fit. The diameter of the RGP
2 to account for the effect of the tear lens, the shape of the tear film between
the posterior surface of the contact lens, and the anterior surface of the
patient’s cornea.
lens is fit usually to 2 mm less than the corneal diameter. Similar to steep-
ening the base curve, increasing the diameter of a lens also will increase
the central vault or sagittal depth of the lens. If the lens is fit too tightly,
insufficient lens movement will be observed with each blink. The base
Rigid Contact Lenses curve then may be flattened or sagittal depth may be decreased by decreas-
ing the diameter of the lens. Likewise, increasing the diameter or steep-
Rigid contact lenses are made from a number of materials, the salient ening base curve can tighten the fit of a lens that demonstrates excessive
features of which can be distilled into a few characteristics.7,8 The rigid- movement on blink.
ity of the material plays a major role in the function of the lenses and
determines their flexibility and durability. The oxygen permeability or Dk, Special Purpose Contact Lenses
where D is the diffusion coefficient and k the solubility constant of oxygen
in the material, describes the amount of oxygen that can penetrate through A number of conditions exist for which rigid gas permeable contact lenses
the lens to reach the corneal surface. Wetting angle is the angle created by may be of benefit and also for which standard rigid gas permeable contact
placing a bead of water against a flat surface of the material and measur- lenses cannot be fit. The most important pathology that presents this clin-
ing the tangential surface of the bead of water to the horizontal surface, ical scenario is a condition of corneal ectasia called keratoconus. Patients
describing the tendency for water to spread on the lens surface.9 A lower with keratoconus experience thinning and steepening of the cornea with
wetting angle indicates more spread of water and suggests the lens mate- the apex of the steepness often outside of the geometrical center of the
rial will be more comfortable and offer better optics. cornea. This steepness and asymmetry often make conventional rigid gas
Historically, contact lenses were made from PMMA, a hard and durable permeable contact lenses inappropriate. Special rigid contact lenses are
material that had very low oxygen permeability but offered sharp optics. designed to accommodate the conical shape of the pathological cornea.
Beginning in the late 1970s, silicone has been incorporated into contact These contact lenses generally are smaller and steeper and more expensive
lens material to increase oxygen permeability through its bulky molecular than conventional rigid gas permeable contact lenses.
structure. As such, most rigid gas permeable (RGP) lenses today are made Patients who have undergone corneal transplantation may have irregu-
from silicone acrylate, which allows for the required rigidity and durabil- lar corneas that warrant rigid contact lens correction. These postoperative
ity while facilitating good oxygen permeability. Silicone does have a ten- corneas are sufficiently different in shape from the surgically naïve cornea
dency to be more bioreactive, binding other hydrophobic substances on its that conventional rigid contact lenses cannot be fit. Special contact lens
surface, including lipid-containing mucus. The addition of fluorine may fitting techniques are often warranted in this setting.
counteract this tendency and increase biocompatibility while also increas- Although the intention of keratorefractive surgery is to reduce depen-
ing the gas solubility. dence upon external refractive correction, some patients still require spec-
RGP lenses, unlike most soft contact lenses, must be fit to the individ- tacles or contact lenses. In the case of myopic keratorefractive surgery, the
ual patient’s eye, making this a more laborious process. The fit is first opti- most common sort, the postoperative cornea is flatter centrally than it is
mized with a set of trial lenses and then the power of the lens is further in the midperiphery. This is exactly opposite to the case of the surgically
refined. The base curve of the lens retains its shape, and the space between naïve cornea and often requires contact lenses that are flat centrally as
the cornea and back surface of the lens is filled in with tears, creating a well. Such unconventional contact lenses are available and require special
tear lens (Fig. 2.4.8). This tear lens can add plus power (when base curve is fitting techniques.
steeper than cornea curvature) or minus power (when base curve is flatter
than cornea curvature). Because the tear film fills in any corneal surface Contact Lens Complications
irregularities, rigid contacts correct irregular corneal astigmatism better
than soft lenses. Contact lens wear generally is a safe option but it is not without risk.
The most common placement position for RGP is apical alignment, Corneal pathology is dealt with elsewhere in this volume, but a brief review
in which the upper edge of the lens fits under upper eyelid, allowing lens of contact lens–associated complications is worthwhile. Adverse events
to move with each blink, minimizing discomfort and circulating tears. associated with contact lenses can be divided into contact lens intolerance
Another position, the central fit, may be used instead, where the lens rests and true contact lens complications. Intolerance to contact lenses may be
at the center of the cornea between upper and lower lids. With this fit, the result of ocular surface disease as is often observed in patients with
the eyelids strike the lens with each blink, resulting in increased lens sen- dry eyes. Patients with substantial atopy are often poor contact lens candi-
sation. This position is useful for patients who have large interpalpebral dates and can exhibit both exaggeration of pre-existing ocular allergies and
openings, astigmatism greater than 1.75 D, and corneas steep in the hori- de novo reactions such as giant papillary conjunctivitis.3,4,10 Patients with
zontal meridian. hypoesthesia either from previous injury or insult or as a result of herpetic
A few other parameters can affect the fit of RGP lenses. Thickness and infection are often poor contact lens candidates.
peripheral curves are typically standardized by the manufacturer. The edge Genuine complications arising from contact lens wear may be sterile
thickness of the lens can affect positioning. A thicker edge maintains the or infectious. Sterile infiltrates of the cornea may arise from hypoxia or
lens position under the lid in apical alignment, whereas a thinner edge immunological reactions to bacterial endotoxins.11 These sterile ulcers are
often difficult to distinguish from true infectious ulcers, and prudence
dictates the treatment with antibiotic therapy even if the chief suspicion
is that the ulcer is noninfectious. Bacterial keratitis is the most common
serious complication arising from contact lens wear.12 Even though the
“TEAR LENS” BENEATH RIGID CONTACT LENS ulcer may be small, the development of a central corneal scar can produce
a debilitating effect on the patient’s vision, and the irregular topography
contact lens tear lens that may result after healing of an ulcer may preclude successful spectacle
wear. The risk of recalcitrant amoebic keratitis has prompted clinicians to
tear film cornea insist that patients avoid exposing contact lenses and contact lens cases to
tap water and to avoid at all costs exposure to outside bodies of water such
as lakes, streams, and swimming pools.
Contact lenses may also produce transient effects on the cornea. Cornea
molding, the deformation of the topography of the cornea, is a transient
feature that may be observed in soft contact lens wear and is almost
ubiquitous in rigid contact lens wear.13,14 Patients with underlying corneal
disease may experience corneal edema with contact lens wear, and even
patients with otherwise healthy corneas may exhibit edema in the context
of corneal hypoxia.15 Chronic corneal hypoxia may induce the formation of
corneal neovascularization, a condition called pannus. Pannus and corneal
limbal stem cell pathology may be signs that the patient is wearing the
52 Fig. 2.4.8 The Space Between the Cornea and Back Surface of the Lens Is Filled contact lens in a manner not tolerated by the eye and that modification or
in With Tears, Creating a Tear Lens. (Courtesy Joshua Young.) cessation of contact lens wear is indicated.
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Soft Contacts Orthokeratology is the use of purpose-made rigid gas permeable contact
Although the practice of contact lens fitting is beyond the scope of this
lenses to temporarily reshape the cornea to reduce refractive errors such
as myopia, hyperopia, or astigmatism.17 Typically worn overnight, these 2.4
chapter, the differences between fitting soft contact lenses and rigid contact reverse geometry contact lenses temporarily flatten the cornea centrally
lenses are worth mentioning. In contrast to case of rigid contact lenses, the for myopic patients, which leads to central corneal epithelial thinning

tear film between the soft contact lens and the cornea is optically neutral. and steepening of the midperiphery, which in turn leads to midperiph-
Therefore any astigmatic correction must occur in the contact lens itself. eral epithelial and stromal thickening. This results in correction of central
Because the orientation of astigmatism correction is of great importance, refractive error while leaving peripheral myopic blur that may act to drive
toric soft contact lenses are designed with a variety of mechanisms to slowing of myopic progression. Younger children are often treated with the
sustain the correct orientation. These include ballast weighting and lens intention of reducing the axial elongation, but the FDA has not approved
edge modulation that, in interaction with the lid margin, maintains the its use for this purpose.
appropriate orientation of the lens. Because these lenses are worn at night and do not move on the cornea,
The primary consideration when fitting soft contact lenses is to achieve most individuals report no significant discomfort while wearing the lenses.
good approximation to the anterior surface of the cornea while avoiding However, these same properties create increased susceptibility to infec-
such tight adherence of the contact lens to the surface of the eye that the tion of the cornea, an especially concerning condition in a young child in
contact lens does not move on blink.16a Contact lens movement is import- whom amblyopia may be induced. In an attempt to mitigate the risk of
ant to circulate the tear film underneath the contact lens. On the other infection and decreased oxygen tension at night, these rigid contact lenses
hand, a contact lens that is too loose is uncomfortable for the patient. A are made with high DK values close to 100 to allow for more oxygenation.
raised edge of such a lens may cause other wear complications.
The primary distinction between different sorts of soft contact lens
materials is between hydrogel and silicone hydrogel. The former are
INTRAOCULAR LENSES
older materials and are less oxygen permeable. Although the newer sil- Intraocular lenses (IOLs) are discussed in the context of cataract surgery
icone hydrogel contact lenses enable the movement of oxygen through elsewhere in this volume, but it is worthwhile to discuss here the role that
the contact lens, they generally exhibit poorer wetting than older hydrogel IOLs play in the correction of refractive errors. IOLs are broadly separated
materials. into categories based on their materials and the refractive errors that they
correct. IOL materials include PMMA, silicone, and hydrophilic and hydro-
Contact Lens Correction of Presbyopia phobic acrylic.18 Even within each of these categories, the optical properties
of materials produced by different manufacturers vary in important ways.
Presbyopia is the condition of loss of accommodation that arises with The Abbe numbers, discussed in the section on spectacle materials, vary
increasing age. Presbyopia is a result of increasing rigidity of the crystal- by material, and this is relevant in the chromatic aberration produced by
line lens and of changes in the ciliary body musculature and as such is not different intraocular lenses. Similarly, different materials pose different
directly correctable by any external optical device. Although contact lenses biocompatibility challenges.
cannot increase the flexibility or the range of accommodation of the pres- Functionally, IOLs can be divided into monofocal, toric, and a variety
byopic eye, a number of strategies have been developed to alleviate some of presbyopia-correcting designs. In their surgical roles, IOLs are catego-
of the symptoms of presbyopia. Several multifocal soft contact lenses have rized as anterior chamber, iris plane, sulcus lenses, and posterior chamber
been developed using refractive rather than diffractive optics in contrast to “in-the-bag” lenses. IOLs are primarily employed in cataract surgery as
the optical strategies developed for intraocular lenses. replacement for the crystalline lens removed during surgery but may also
Although multifocal contact lenses may provide focus for both distance be used in patients who remain phakic, purely for refractive correction.
and near, they do so with compromise to visual function. Patient dissat- Additionally, more than one IOL may be inserted into a single eye to
isfaction with multifocal contact lenses arises chiefly from decrease in achieve a particular refractive affect. When a second IOL is placed on top
optical quality. These lenses necessarily produce stray rays of light as light of another IOL, this second lens is referred to as a “piggyback lens.”
from distant objects encounters the near portion of the contact lens and
vice versa. Monofocal Intraocular Lenses
An alternative to multifocal contact lenses is to employ a monovision
strategy whereby one eye is fit with a distance contact lens and the other Monofocal IOLs have the broadest range of designs, including lenses
eye with a near-focus contact lens. Each of these lenses is monofocal and designed for anterior chamber placement, sulcus and iris plane placement,
may be spherical or astigmatic. Although this may seem to be a less phys- piggyback, phakic, and one-piece and three-piece posterior chamber IOLs
iological approach than multifocal contact lenses that allow for a degree of designed for placement within the capsule bag. Monofocal lenses are also
fine stereopsis, monovision contact lenses are generally tolerated very well. available in spherical and aspherical designs produced to decrease spheri-
As a rule, the patient’s dominant eye is chosen for distance vision and the cal aberration created by the optics of the front of the eye. Monofocal IOLs
nondominant eye is set for either an intermediate distance as would be also hold the advantage of enhanced visual quality compared with the mul-
appropriate for use with a computer or for a reading distance requiring tifocal lenses described later. This is perceived by the patient as higher
more disparity between the eyes. contrast sensitivity.
Ocular dominance may be assessed in a number of ways, but one of the An important consideration in choosing the appropriate power of an
easiest is to cut a small hole in a piece of cardboard and have the patient IOL is its intended postoperative location within the eye. This is referred
fixate at an object while holding the cardboard at arm’s length. Having to as the effective lens position or ELP.19 As is the case with contact lenses
the patient bring the cardboard toward the face while maintaining fixation described earlier, the anteroposterior position of the IOL changes its
of the object forces the patient to choose one eye over the other, because refractive effect. To achieve the same refractive effect, lenses with a more
the cardboard necessarily occludes the fellow eye. Patients perform this posterior position require higher plus dioptric powers. This is important
task without realizing that they are forced to make a choice between clinically not only in the context of preoperative IOL calculation but in the
the eyes. event that the surgeon chooses to place a lens in the ciliary sulcus that
was originally intended for placement within the capsular bag. This con-
Orthokeratology tingency may arise in the context of certain surgical complications, most
commonly rupture of the posterior lens capsule.20
Myopia, or nearsightedness, is the most common eye disorder in the
world, affecting over 85% of young adults in some Asian countries, with a Toric IOLs
natural tendency to progress with rates of 12% in preschool children that
increases to over 50% by preteenage years. With high degrees of myopia, Pre-existing astigmatism may be addressed during cataract surgery
there are increased risks of blinding complications including glaucoma, by incisional keratotomy, described elsewhere in this chapter, and by
retinal detachment, and myopic degeneration. A variety of interventions employing an astigmatism-correcting IOL. These toric IOLs differ from
have been studied to slow progression of myopia. Although interventions astigmatism-correcting contact lenses in that they incorporate no special
such as undercorrection, bifocals, progressive lenses, and contact lenses elements to establish the orientation of the lens. Therefore IOLs are pro-
likely do not slow progression, several interventions, including atropine duced in different spherical and astigmatic powers but not in different
eyedrops and orthokeratology, do seem to have some effect in reducing axes. The axis of orientation is of great import to achieve the desired refrac- 53
myopic progression.16b tive result,21 and many methods—from marking the cornea with a pen to
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automated computer-based corneal registration—have been employed to Lenses designed to demonstrate functional vision over a range of dis-
2 ensure the appropriate toric IOL orientation.

Although toric are of immense value in clinical practice, their benefit is
contingent on a number of factors.22 Typically, the astigmatism of a nonop-
tances have been introduced recently. These are generally referred to as
extended depth of focus (EDOF) lenses. Although these lenses may provide
a more uniform visual quality between far and intermediate distances, the
erated eye is primarily of corneal origin. However, the crystalline lens may visual quality is diminished across all distances compared with monofocal
itself be tilted, and this lenticular astigmatism is not amenable to correc- IOLs.
tion with a toric IOL. Irregular astigmatism also is not completely correct- An early attempt to design an accommodating IOL was approved for
able with a toric IOL, and caution must be exerted when employing a toric clinical use in the United States.27 However, this design yields insufficient
IOL in the context of keratoconus. presbyopia correction to replace reading glasses and is often referred to as
Even small misorientations of a toric IOL can produce clinically signif- a “pseudoaccommodative intraocular” lens.
icant diminutions of the ability of the IOL to correct the patient’s astigma-
tism. Each degree of misorientation will produce a diminution of effect
of 3.3% and a rotation of the patient’s axis of astigmatism. A misorienta-
KERATOREFRACTIVE SURGERY
tion of 30° completely negates the reduction of absolute astigmatism while The idea of refractive surgery is not a new one and dates to at least the late
simultaneously rotating the astigmatic access to an orientation to which nineteenth century. Although refractive surgery may be undertaken to any
the patient is unaccustomed. of the optical surfaces of the front of the eye, the most fruitful approach
has been the intentional modification of the shape of the cornea. The ante-
Presbyopia Correcting Intraocular Lenses rior surface of the cornea accounts for the great majority of the refractive
power of the eye, and fractional modification of the surface curvature may
Because presbyopia is the result of loss of accommodation, the obvious produce tremendous refractive change.
surgical solution would be the implantation of an accommodating intra- Discussion in this section will center on corneal refractive surgery or
ocular lens. Such accommodating intraocular lenses are in clinical trials, keratorefractive surgery, but it bears mentioning that intraocular refrac-
but no truly accommodating intraocular lens has been approved to date for tive surgery also is performed. Removal of the noncataractous crystalline
clinical use in the United States. lens and replacement with an IOL—so-called clear lens extraction—may
A number of alternatives to this ideal are available. It must be remem- be performed successfully for higher refractive errors at the expense of the
bered that in addition to the out-of-pocket cost associated with these loss of accommodation. This procedure is identical to conventional cat-
premium lenses, there is an optical cost that must be paid to achieve both aract surgery. Additionally, an IOL may be inserted into the eye without
distance and near vision. The first and optically simplest manner in which removal of the patient’s own crystalline lens. This is referred to as phakic
to address presbyopia during cataract surgery is to employ monofocal lens implantation or implantable collamer lens (ICL) surgery.28-31
IOLs in a monovision strategy as is discussed in the section on contact The majority of patients who undergo refractive surgery are undergo-
lens correction of presbyopia.23 Of course, a risk of this strategy is that ing some modification of the shape of the anterior cornea. Initially, this
the patient may not tolerate monovision or may only tolerate the degree was performed by making incisions in different patterns on the corneal
of monovision that allows for intermediate (e.g., computer) use and does surface. Radial incisions in the cornea cause circumferential flattening.
not yield the ability for closer reading without spectacles. The advantage Thereby myopic correction is achieved through the creation of a series
of this strategy is that contrast sensitivity and overall visual quality is not of radial incisions centering about the central cornea but, of course, not
diminished in either eye individually. passing through the corneal center. This is the basis of radial keratotomy,
Multifocal IOLs are designed to project both distance and near images a procedure that can successfully correct substantial degrees of myopia32
onto the patient’s retina.24 This is generally done by employing a refractive (Fig. 2.4.10). Although nomograms were developed for titratable correction
lens for the distance focus and a diffractive lens for reading (Fig. 2.4.9). of various degrees of myopia, radial keratotomy incisions proved to have
The combination of refractive and diffractive elements holds the advantage an unstable effect for many patients over the long term. Patients who were
of decreasing the overall chromatic aberration because short wavelength initially corrected to emmetropia sometimes demonstrated a progressive
light converges to a greater degree than long wavelength light in refrac- increase in the degree of corneal flattening over many years postopera-
tive lenses, and the opposite is true in diffractive lenses. However, the tively. These formerly myopic patients experience a trend toward increas-
rings employed in diffractive designs cause visual symptoms that disturb ing hyperopia over time.33 Radial keratotomy also carries the additional
some patients.25,26 Also, visual quality is poorer in multifocal lenses than concern of globe rupture with blunt trauma, even years after the surgery,
in monofocal spherical or toric lenses. The degree to which these visual because the structural integrity of the cornea has been violated and never
degradations are tolerated is impossible to predict preoperatively with cer- completely recovers.
tainty, and a higher number of multifocal lenses require explantation for In a manner similar to the myopic correction achieved by radial kera-
reason of bothersome visual symptoms than is the case with monofocal totomy, astigmatic correction is achievable through tangential or arcuate
IOLs. incisions of the midperipheral or peripheral cornea. These incisions need
Fig. 2.4.10 In Radial Keratotomy (RK) Surgery, Flattening Perpendicularly to

54 Fig. 2.4.9 A Type of Multifocal Intraocular Lens (IOL) With Refractive and the Radial Incisions Reduces the Average Refractive Power of the Cornea and
Diffractive Elements. (© 2017 Novartis.) Corrects for Myopia. (Courtesy Joshua Young.)
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not be made as deep, and are generally fewer in number than those of
radial keratotomy and so pose less of a structural risk to the eye. In the
past, radial and arcuate incisions were combined to correct for myopic 2.4
astigmatism.
Although radial incisions have largely been displaced by laser ablative

surgery as discussed later, arcuate incisions continue to play a role for cor-
rection of low degrees of astigmatism during cataract surgery. Arcuate ker-
atotomy has morphed into the limbal relaxing incisions (LRI) performed
during cataract surgery.
Historically, myopic correction could be performed by the removal of a
lenticule of corneal stromal tissue. This was performed using a motorized
blade in a miniaturized device looking something like a wood plane. Auto-
mated lamellar keratectomy, ALK as it was called, formed the mechanical
foundation of the microkeratome, the device created to produce corneal
flaps for laser in situ keratomileusis (LASIK) surgery.
Incisional keratotomy may correct myopia and astigmatism, but the
correction of hyperopia is not achievable in this manner. In order to
steepen the central cornea, surgeons sought to create a zone of contraction
of corneal tissue paracentrally. One approach to this was conductive kera-
toplasty (CK), in which heating was induced focally in a number of spots
surrounding the center of the cornea.
In the mid-1990s, the excimer laser was introduced to clinical practice
Fig. 2.4.11 The KAMRA Inlay Implanted Within the Cornea to Alleviate
to perform athermal ablation of corneal tissue to reshape the cornea to Symptoms of Presbyopia. (December 2016 EyeWorld REFRACTIVE SURGERY
produce the desired refractive effect. Excimer ablation holds the advan- section.)
tages of great precision without substantial compromise to the mechan-
ical integrity of the cornea. However, ablation through the anterior layers
of the corneal stroma, termed Bowman’s layer, resulted in the creation of inlays approved for use in the United States are the KAMRA and the
symptomatic corneal haze in some patients. Today this haze may be dealt Raindrop devices. The KAMRA inlay is a small opaque disc with an even
with by using mitomycin C to modulate postoperative healing or may be smaller aperture in the center that functions as a as an optical pinhole.
avoided altogether through the creation of an anterior corneal flap under This inlay increases depth of field while reducing the amount of light that
which the laser treatment is performed. The combination of ablation plus enters the eye. This increase in depth of field gives patients some degree of
a flap is what it has been termed laser in situ keratomileusis. LASIK flaps near vision. The KAMRA inlay is implanted in only one eye35 (Fig. 2.4.11).
may be produced by means of femtosecond laser rather than by mechan- The Raindrop inlay is no longer available as of publication. It is a small
ical microkeratome. The advantages of the flap are faster visual recovery, clear lenticule and is also implanted in only one eye. Corneal inlays are
less corneal haze, and greater patient comfort. The disadvantage of the flap introduced underneath a corneal flap or in a corneal pocket and sit within
is that adhesion of the flap to the underlying cornea is not as strong as the the corneal stroma.36,37
shear resistance of the surgically naïve corneal tissue. Therefore even very
late term shear stress, such as may be experienced with ocular injury, can
dislodge a LASIK flap. KEY REFERENCES
Although ablative keratorefractive surgery caries risk, it must be Atchison DA. Spectacle lens design: a review. Appl Opt 1992;31:3579–85.
remembered that contact lens wear also carries risk that is cumulative over Calladine D, Evans JR, Shah S, et al. Multifocal versus monofocal intraocular lenses after
the many years a patient may wear contact lenses. For many patients, the cataract extraction. Cochrane Database Syst Rev 2012;(9):CD003169.
de Vries NE, Nuijts RM. Multifocal intraocular lenses in cataract surgery: literature review of
risk of a keratorefractive procedure is comparable to the risk of contact benefits and side effects. J Cataract Refract Surg 2013;39(2):268–78.
lens wear and represents an acceptable alternative. Doan KT, Olson RJ, Mamalis N. Survey of intraocular lens material and design. Curr Opin
Both spherical errors and astigmatic errors are correctable with ablative Ophthalmol 2002;13(1):24–9.
keratorefractive surgery. Different refractive errors are corrected by altering Fonn D, Dumbleton K, Jones L, et al. Silicone hydrogel material and surface properties.
Contact Lens Spectrum 2002;3:24–8.
the ablation pattern.34 The correction of myopia is achieved by the simple Holden BA, Mertz GW, McNally JJ. Corneal swelling responses to contact lenses worn under
ablation of a lenticule from the center of the cornea. Because tissue cannot extended wear conditions. Assoc Res Vision Ophthalmol 1983;24:218–26.
be added by the excimer laser, however, steepening the central cornea as is Kessel L, Andresen J, Tendal B, et al. Toric intraocular lenses in the correction of astigma-
required for the correction of hyperopia necessitates a more complicated tism during cataract surgery: a systematic review and meta-analysis. Ophthalmology
ablation pattern. A torus (think of a doughnut or bagel sliced in half) is 2016;123(2):275–86.
Koffler BH, Sears JJ. Myopia control in children through refractive therapy gas permeable
ablated from just outside of the center of the cornea to produce steepen- contact lenses: is it for real? Am J Ophthalmol 2013;156(6):1076–81.
ing centrally. However, the zone of uniform curvature, the optical zone, is Mimura T, Fujimura S, Yamagami S, et al. Severe hyperopic shift and irregular astigmatism
necessarily smaller in a hyperopic treatment than in a myopic treatment. after radial keratotomy. Eye Contact Lens 2009;35(6):345–7.
The femtosecond laser may be used to carve a lenticule from the central Naroo SA, Bilkhu PS. Clinical utility of the KAMRA corneal inlay. Clin Ophthalmol 2016;10:
913–19.
cornea in a manner reminiscent of automated lamellar keratectomy. This Norrby S. Sources of error in intraocular lens power calculation. J Cataract Refract Surg
lenticule is then withdrawn through a channel also carved into the cornea 2008;34(3):368–76.
by the femtosecond laser. This procedure is known as small incision lenti- Waring GO 3rd, Lynn MJ, McDonnell PJ. Results of the prospective evaluation of radial
cule extraction or SMILE surgery and is relatively new. keratotomy (PERK) study 10 years after surgery. Arch Ophthalmol 1994;112(10):1298–
308.
White P. Disposable and programmed replacement soft contact lenses. Contact Lens Spec-
CORNEAL INLAYS trum 1994;8:40–52.
Whitman J, Hovanesian J, Steinert RF, et al. Through-focus performance with a corneal
While the correction of presbyopia is not directly achievable by means of shape-changing inlay: one-year results. J Cataract Refract Surg 2016;42:965–71.
refractive surgery, a number of procedures have been introduced to alle-
viate some presbyopia symptoms. These procedures have in common the Access the complete reference list online at ExpertConsult.com
introduction of an implant into the substance of the cornea. Two corneal
55
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REFERENCES 19. Plat J, Hoa D, Mura F, et al. Clinical and biometric determinants of actual lens position
after cataract surgery. J Cataract Refract Surg 2017;43(2):195–200.
1. Atchison DA. Spectacle lens design: a review. Appl Opt 1992;31:3579–85.
2. Hoskin AK, Philip S, Dain SJ, et al. Spectacle-related eye injuries, spectacle-impact per-
20. Norrby S. Sources of error in intraocular lens power calculation. J Cataract Refract Surg
2008;34(3):368–76.
2.4
formance and eye protection. Clin Exp Optom 2015;98(3):203–9. 21. Felipe A, Artigas JM, Díez-Ajenjo A, et al. Residual astigmatism produced by toric intra-
ocular lens rotation. J Cataract Refract Surg 2011;37(10):1895–901.

3. Allansmith MR, Greiner JV, Covington HI. Surface morphology of giant papillary con-
junctivitis in contact lens wearers. Am J Ophthalmol 1978;85:242–9. 22. Kessel L, Andresen J, Tendal B, et al. Toric intraocular lenses in the correction of astig-
4. Allansmith MR, Greiner JV, Korb DR. Giant papillary conjunctivitis in contact lens matism during cataract surgery: a systematic review and meta-analysis. Ophthalmology
wearers. Am J Ophthalmol 1977;86:697–706. 2016;123(2):275–86.
5. Jaschinski W, König M, Mekontso TM, et al. Comparison of progressive addition lenses 23. Zhang F, Sugar A, Arbisser L, et al. Crossed versus conventional pseudophakic monovi-
for general purpose and for computer vision: an office field study. Clin Exp Optom sion: patient satisfaction, visual function, and spectacle independence. J Cataract Refract
2015;98(3):234–43. Surg 2015;41(9):1845–54.
6a. Brown WL. The importance of base curve in the design of minus iseikonic lenses. 24. Calladine D, Evans JR, Shah S, et al. Multifocal versus monofocal intraocular lenses after
Optom Vis Sci 2006;83(11):850–6. cataract extraction. Cochrane Database Syst Rev 2012;(9):CD003169.
6b. White P. Disposable and programmed replacement soft contact lenses. Contact Lens 25. de Silva SR, Evans JR, Kirthi V, et al. Multifocal versus monofocal intraocular lenses after
Spectrum 1994;8:40–52. cataract extraction. Cochrane Database Syst Rev 2016;(12):CD003169.
7. Coletta N. Correcting higher-order aberrations: implications for clinical practice. Contact 26. de Vries NE, Nuijts RM. Multifocal intraocular lenses in cataract surgery: literature
Lens Spectrum 2005;11:42–7. review of benefits and side effects. J Cataract Refract Surg 2013;39(2):268–78.
8. Fonn D, Dumbleton K, Jones L, et al. Silicone hydrogel material and surface properties. 27. Ong HS, Evans JR, Allan BD. Accommodative intraocular lens versus standard mono-
Contact Lens Spectrum 2002;3:24–8. focal intraocular lens implantation in cataract surgery. Cochrane Database Syst Rev
9. Read ML, Morgan PB, Kelly JM, et al. Dynamic contact angle analysis of silicone hydro- 2014;(5):CD009667.
gel contact lenses. J Biomater Appl 2011;26(1):85–99. 28. Domínguez-Vicent A, Ferrer-Blasco T, Pérez-Vives C, et al. Optical quality comparison
10. Silbert JA. The role of inflammation in contact lens wear. In: Silbert JA, editor. Ante- between 2 collagen copolymer posterior chamber phakic intraocular lens designs. J Cat-
rior segment complications of contact lens wear. New York: Churchill Livingstone; 1994. aract Refract Surg 2015;41(6):1268–78.
p. 123–42. 29. Eissa SA. Management of pseudophakic myopic anisometropic amblyopia with piggy-
11. Gordon A, Kracher GP. Corneal infiltrates and extended-wear contact lenses. J Am back Visian implantable collamer lens. Acta Ophthalmol 2017;95(2):188–93.
Optom Assoc 1985;56:198–201. 30. Hassan AH, Sayed KM, ElAgooz M, et al. Refractive results: safety and efficacy of sec-
12. Mondino BJ, Weisman BA, Farb MD, et al. Corneal ulcers associated with daily-wear and ondary piggyback Sensar™ AR40 intraocular lens implantation to correct pseudophakic
extended-wear contact lenses. Am J Ophthalmol 1986;102:58–65. refractive error. J Ophthalmol 2016;2016:4505812.
13. Schoessler JP. Corneal endothelial polymegathism associated with extended wear. Int 31. Lee J, Kim Y, Park S, et al. Long-term clinical results of posterior chamber phakic intra-
Contact Lens Clin 1983;10:148–56. ocular lens implantation to correct myopia. Clin Exp Ophthalmol 2016;44(6):481–7.
14. Zantos SG. Cystic formations in the corneal epithelium during extended wear of contact 32. Waring GO 3rd, Lynn MJ, McDonnell PJ. Results of the prospective evaluation of radial
lenses. Int Contact Lens Clin 1983;10:128–35. keratotomy (PERK) study 10 years after surgery. Arch Ophthalmol 1994;112(10):1298–308.
15. Holden BA, Mertz GW, McNally JJ. Corneal swelling responses to contact lenses worn 33. Mimura T, Fujimura S, Yamagami S, et al. Severe hyperopic shift and irregular astigma-
under extended wear conditions. Assoc Res Vision Ophthalmol 1983;24:218–26. tism after radial keratotomy. Eye Contact Lens 2009;35(6):345–7.
16a. Grohe RM, Bennett ES. Problem solving. In: Bennett ES, Weissman BA, editors. Clini- 34. Motwani M. A protocol for topographic-guided corneal repair utilizing the US Food and
cal contact lens practice. Philadelphia: Lippincott; 1991. p. 1–16. Drug Administration-approved Wavelight Contoura. Clin Ophthalmol 2017;11:573–81.
16b. World Society of Pediatric Opthalmology & Strabismus. Myopia Consensus Statement. 35. Naroo SA, Bilkhu PS. Clinical utility of the KAMRA corneal inlay. Clin Ophthalmol
2016. 2016;10:913–19.
17. Koffler BH, Sears JJ. Myopia control in children through refractive therapy gas perme- 36. Whitman J, Hovanesian J, Steinert RF, et al. Through-focus performance with a corneal
able contact lenses: is it for real? Am J Ophthalmol 2013;156(6):1076–81. shape-changing inlay: one-year results. J Cataract Refract Surg 2016;42(7):965–71.
18. Doan KT, Olson RJ, Mamalis N. Survey of intraocular lens material and design. Curr 37. Yoo A, Kim JY, Kim MJ, et al. Hydrogel inlay for presbyopia: objective and subjective
Opin Ophthalmol 2002;13(1):24–9. visual outcomes. J Refract Surg 2015;31(7):454–60.
55.e1
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Ophthalmic Instruments
Neal H. Atebara, David Miller, Edmond H. Thall 2.5
and the accommodation of each, its total power provides only a rough esti-
Definition: From the earliest optical devices to the latest mate of the patient’s refractive state. The magnitude of a large amount of
computerized imaging systems, technology has aided the clinician in the astigmatism may actually be estimated if the lens is focused on a blood
diagnosis and treatment of ocular disease. vessel that travels parallel to the foveal reflex and then refocused on a
vessel that travels perpendicular to the first vessel.2
Probably the most important advance in direct ophthalmoscopy was
the use of the halogen tungsten bulb,3 which has a number of advantages
Key Features over the older tungsten bulb. A quartz jacket can withstand higher tem-
peratures than can the glass jacket, thus the filament temperature may be
• The ability of a transparent medium to bend a ray of light is the basis raised higher than that in the conventional tungsten bulb to produce an
for most of the instruments used in ophthalmology today.
increased lumen output.
• Spherical lenses, prisms, mirrors, slit-shaped illumination, The field of view of the modern direct ophthalmoscope averages about
astronomical and Galilean telescopes, and a multitude of other
10° and is limited by the most oblique pencil of rays that can pass from
optical components—both simple and complex—have been devised
the outer edge of the observer’s pupil to the opposite outer edge of the
and manufactured for more than two centuries in order to study the
patient’s pupil. To enlarge the field of view of the direct ophthalmoscope,
human eye and its function.
the investigator’s eye must be brought closer to the patient’s eye with the
patient’s pupils dilated.
Because the enlargement capacity of any magnification lens usually is
INTRODUCTION defined as one-fourth of the lens power, the retinal image in the typical
emmetropic eye of 60 D may be considered to be magnified by 60/4, or
In this chapter, the basic principles that underlie some of the more ×15. In aphakic eyes, from which a 20 D natural lens has been removed,
common instruments used in ophthalmology will be reviewed, including: the magnification for the observer is reduced to about 40/4 or ×10.
• Direct ophthalmoscope.
• Binocular indirect ophthalmoscope. BINOCULAR INDIRECT OPHTHALMOSCOPE
• Fundus camera.
Compared with the direct ophthalmoscope, the binocular indirect oph-
• Optical coherence tomograph.
thalmoscope gives a wide field of view, a stereoscopic impression, and an
• Slit-lamp biomicroscope.
image of high contrast. Of course, a small price must be paid for these
• Slit-lamp fundus lenses.
advantages. The patient’s pupil must be dilated, the instrumentation is
• Goldmann applanation tonometer.
larger, heavier, and more expensive, and the illumination is almost pain-
• Specular microscope.
fully bright for the patient.
• Operating microscope.
• Keratometer and corneal topographer.
• Lensmeter (also known as lensometer). Illumination System
• Automatic refractor.
In order to avoid corneal and lens reflection and scatter, the observation
• Magnifying devices.
beam and the illumination beam is separated at the corneal and lens
plane,4 requiring a dilated pupil (Fig. 2.5.2). The filament of the bulb is
DIRECT OPHTHALMOSCOPE actually brought to a focus in a portion of the patient’s pupil. To minimize
the loss of light, the condenser lens brings the observer’s pupil to a focus
The entire retina, if spread out and flattened, is about the size of a large
postage stamp. The important structures themselves are rather small.
For example, the optic nerve is 1.5 mm in diameter, and the major blood
vessels are only 0.1–0.2 mm in diameter. Significant papilledema, with OPTICS OF THE DIRECT OPHTHALMOSCOPE
an elevation of the nerve head of 3.00 D, is equivalent to only a 1 mm
change in elevation. Most of the important red and yellow details, includ- observer patient
ing blood vessels, hemorrhages, and exudates, are seen against the light
red background of the blood-filled choroid. Subtle changes in the pinkish
white backscattered light of the optic disc announce major glaucomatous
or neuro-ophthalmic alterations. The presence of the corneal reflection and
the usual backscattered light of the healthy cornea and lens make the eval-
uation of fundus changes even more difficult.
In the face of these obstacles, it seems almost miraculous that the exam-
iner is able to make a significant number of diagnoses using the direct partial mirror
ophthalmoscope. Fig. 2.5.1 illustrates how the ophthalmoscope directs the
light rays of illumination and observation coaxially, while the observation
system is essentially a peephole.1 The lens and cornea of the patient’s eye light source
actually create the retinal image. Thus the observer does not really see the
retina of the patient but an optical image of the retina.
To bring the red fundus reflex into sharp focus for the viewer, the Fig. 2.5.1 Optics of the Direct Ophthalmoscope. With use of a mirror (either half-
56 modern ophthalmoscope has a disc of lenses. Because the compensating silvered or one that has a central aperture), the directions of the light of observation
lens neutralizes the refractive error of both the physician and the patient and the light incident to the patient are made concentric (coaxial).
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THEORETICAL OPTICS OF THE INDIRECT OPHTHALMOSCOPE ZEISS FUNDUS CAMERA
2.5
observer's eye patient's eye eyepiece
objective lens aerial image holed mirror
mirror
pupil retina
camera
lens
entering illumination beam light incandescent
exiting observation beam source lamp
fixation beam splitter
Fig. 2.5.2 Theoretical Optics of the Indirect Ophthalmoscope. The illumination pointer
beam enters a small part of the pupil and does not overlap with the observation flash
beam, and thus minimizes bothersome reflection and backscatter. lamp
FIELD OF VIEW OF THE INDIRECT OPHTHALMOSCOPE

Fig. 2.5.4 Zeiss Fundus Camera. See text for the description. (Adapted from
14 D lens lesion image American Academy of Ophthalmology. Home study course, optics and refraction.
San Francisco, CA: American Academy of Ophthalmology; 1990.)
Thus a 20 D lens of 3 cm diameter yields almost the same field of view as
a 30 D lens of 2 cm diameter.
Magnification
Fig. 2.5.3 shows the chief ray that passes from the edge of the fundus view
Retinal lesion size Lesion image size
through the nodal point of the eye to the aerial image. The ratio of the
Width 1 mm Width 4 mm fundal object to the aerial image is proportional to the ratio of the focal
retinal lesion
Depth 1 mm Depth 16 mm length of the patient’s eye to the focal length of the condenser lens, or
inversely proportional to the power (F) of the eye (60 D) and the handheld
lens. Thus for an emmetropic eye and a 20 D lens, the magnification =
Fig. 2.5.3 Field of View, Indirect Ophthalmoscope. The focal length of the 60 D/20 D = ×3; for a 30 D lens, the magnification = 60 D/30 D = ×2.
handheld lens determines the distance from the patient’s eye at which to hold the Ultimately, the distance of this mildly magnified aerial image from the
lens. The tangent of the angle of field of view equals the lens diameter divided by observer determines the total magnification. If the observer has a large
the focal length. amplitude of accommodation, the aerial image is brought closer and its
overall magnification increased.
in the patient’s pupil. With patient and observer pupils conjugate, loss of Stereopsis
light is minimized, and field of view is maximized. The light beam that emerges from the patient’s dilated pupils is directed
through the handheld lens and into the two eyepieces (separation usually
15 mm) of the binocular indirect ophthalmoscope. Prisms then redirect
Observation System the two beams into the examiner’s eyes. A smaller distance between the
Contrast two eyepieces than the interpupillary distance reduces the stereopsis
Because the observation beam path is different from the illumination appreciated by an observer (interpupillary distance of 60 mm) by about
beam path, glare degradation from reflection and backscatter is minimized one-fourth. However, axial magnification (which equals one-fourth of the
and subtle details are seen more easily. The observer must learn to tilt the square of lateral magnification) augments the stereoscopic appearance.
handheld lens strategically to avoid reflection from the surface of the lens If the lateral magnification of a 20 D lens is ×3, the axial magnification
itself. This reflection is minimized (from about 4% of incident light to 1%) equals 9/4 or ×2.25. Thus the ophthalmoscopic view through the handheld
by a lens that has an antireflection coating. lens amplifies small changes in retinal topography. Using a lower power
hand lens further increases this effect: for example, a 15 D lens results in
Inverted Image transverse magnification of 60/15 = 4×, but axial magnification of 16/4 =
The handheld condenser lens creates a real, inverted aerial image of the 4-fold.
illuminated patient’s fundus, as expected from a positive lens. Thus the Variations of indirect ophthalmoscopy include the scanning laser oph-
examiner must learn to reorient details from where they appear to be to thalmoscope and various analyzers of the optic nerve head.
where they actually are located.
Field of View FUNDUS CAMERA

Fig. 2.5.3 illustrates how the handheld lens produces the aerial image of
the fundus. Rays that pass through the nodal point of the patient’s eye and
Lighting
the edge of the handheld lens determine the size of the field of view. The The present illumination system of the Zeiss fundus camera is shown in
distance of the handheld lens from the patient’s eye also determines the Fig. 2.5.4.5,6 Light from the incandescent lamp (for observation) and the
angular subtense of the patient’s fundus caught by the lens. This distance flash lamp (for photography) is superimposed by means of the beam split-
is optimal if it equals the focal length of the lens. Thus the field of view is ter, so that the light from the flash travels along the same path as that of
determined by the expression d/F, where d is the diameter and F the focal the observation light. The lamp filaments are imaged in the vicinity of the
length of the handheld lens. holed mirror, which deflects the light toward the eye. The holed mirror is
For example, given equal diameters, stronger lenses (e.g., F = 30 D, f = similar to the mirrors used in many retinoscopes, with a central hole to
3.3 cm) provide larger fields of view. However, a weaker lens may be made allow observation. In contrast to the retinoscope arrangement, the holed 57
with a larger diameter because it is less vulnerable to spherical aberration. mirror in the fundus camera is imaged onto the plane of the patient’s
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pupil by the objective lens to ensure the necessary separation of illumi-
2 nation and observation pathways at the pupil. The objective lens corre-
sponds to the condenser lens in the indirect ophthalmoscope; both lenses
are designed with aspherical surfaces to provide the best possible image
TIME-DOMAIN OCT
9
movable 8 mirror
quality over a wide field of view.
7
mirror 6 position
Photographing through an undiluted pupil was achieved by observation 5
4
of the fundus using infrared light, which does not stimulate the retina. In 3
such a system, the infrared light penetrates the 4–5 mm diameter pupil
in a dark setting, is reflected off the retina, and is displayed on a monitor.
reference beam
Once the retina has been focused and framed, an electronic flash illumi- retina
nates the retina before the pupil constricts.
Reducing Reflections From the Cornea

and Instrument
Anyone who has tried to evaluate subtle macular detail using a direct oph- object beam
thalmoscope is familiar with the annoyance of corneal reflection. Gull- light
strand’s table-mounted ophthalmoscope embodied his principle that the source
illumination system should not intersect the cornea in the same area as
the rays that come from the observation system. In the Zeiss system, this retinal layer
principle is satisfied by a mirror that has a central hole. The mirror reflects corresponding
3456 7 89
to mirror position
a circle of light through the pupillary periphery while the fundus is viewed
through the central hole of the mirror. Although such a system is not able
to completely eliminate ocular and camera lens reflections, it successfully
reduces them to a significant degree.
output of light source
lateral scan position

of objective beam
The Observation System
Fig. 2.5.4 illustrates all the elements of the fundus camera. As noted
before, light from the incandescent lamp and that from the flash lamp are
folded into a common path, which ultimately strikes the holed mirror and 345 67 89 345 67 89
is reflected into the patient’s eye. This illumination system and the obser- light detector position of position of
vation system are very similar to those of the indirect ophthalmoscope. movable mirror movable mirror
In the case of the fundus camera, light reflected from the patient’s retina
passes through the hole in the mirror and focuses a real image in the film A-scan B-scan
plane of the camera. A beam splitter diverts a portion of the light directed
to the camera and sends it to the eyepiece. In essence, the eyepiece is like a Fig. 2.5.5 Optical Coherence Tomography (OCT). Based on the principle of
simple microscope. It receives the real image of the fundus and processes the Michelson interferometer, OCT analyzes the interference patterns between a
reference beam and the object beam to create a precise cross-sectional reflectivity
it such that parallel light exits for the observer.
map of the internal retina.
Field of View white light is split into two beams moving in perpendicular directions. The
In theory, a 180° aerial image of the retina can be captured, even through beams are reflected back to, and recombine at, the beam splitter. When the
a small pupil. In practice, however, because the rays from the equator exit beams recombine, interference fringes are observed, provided that the dif-
the pupil at a very sharp angle, the collection of these rays can be accom- ference in optical path length (OPL) between the two arms of the interfer-
plished only by a lens held very close to the pupil or a lens of very wide ometer is less than the coherence length of the light utilized. Michaelson
diameter. Of course, although wide-diameter lenses produce a greater field used white light with a coherence length of 1–2 µm. One arm of the device
of view, they also introduce significant spherical aberration. For fields had a fixed, known length, and the length of the other arm was varied until
of view greater than 100°, therefore, the only sensible way to collect the interference fringes were observed, at which point the difference in OPL
sharply bent rays that come from the retinal periphery is to move the front between the two arms had to be less than 2 µm. Submicron accuracy could
lens close to the pupil. Thus in the equator-plus camera, the front lens be achieved by counting fringes.
of the system is a contact lens. Because the aerial image of such a large If this technique were directly applied to retinal imaging, only a single
expanse of retina follows the globe’s curvature, special lenses must be layer’s thickness could be measured because of the low coherence of white
introduced into this system to flatten the image. light. However, if a laser is used, the coherence length is too long and the
To photograph different fields of view, three different focal length lenses position of a retinal layer could be localized only to within a few centi-
are used, much as the ophthalmologist might switch between +14 D, meters. The OCT utilizes a superluminescent diode that operates in the
+20 D, and +28 D handheld lenses. The lens system that has the longer near-infrared and has a bandwidth of about 50 nm or about six times more
focal length (less dioptric power) produces a more magnified image. Thus coherent than white light but far less than the coherence of a laser.
the amount of field captured in a frame is smaller than that produced by The original clinical instruments incorporated two moving mirrors.
the more powerful, shorter focal length lens. Theoretically, both the larger One varied the length of one arm of the interferometer and was used every
field and higher magnification could be obtained if the size of the film time the device scanned a narrow section of retina (Fig. 2.5.5). After a
could be doubled. single scan was completed, the other mirror shifted the beam to the neigh-
Portions of the retina can be photographed beyond the traditional central boring section of the retina and the next scan was repeated. An import-
30° if the camera is directed to the peripheral area of interest. However, a ant limitation was the amount of time required to complete a scan. The
camera aimed off axis by 30° or more with the 60 D ocular optical system time required to scan a single line of retina a few millimeters in length
induces 10–15 D of oblique astigmatism and results in fuzzy pictures.7 far exceeded even the best patient’s fixation. Moreover, the eye itself is
Fortunately, well-designed fundus cameras anticipate off-axis photography not dimensionally stable due to choroidal blood flow that varies with the
and include a large range of cylindrical corrections with which to sharpen cardiac cycle. Sophisticated software can overcome some fixation require-
the peripheral views. ments, but limitations exist to this technique.
In spectral domain instruments one of the mirrors (which scans the
OPTICAL COHERENCE TOMOGRAPHY reference arm) is replaced by a spectrometer that measures the reflection
from each wavelength simultaneously, producing a much faster scan that
Optical coherence tomography (OCT) is based on the Michaelson inter- not only improves accuracy but also enables a larger region of retina to
58 ferometer invented in the late 1800s. Originally the instrument was used be interrogated. It is important to realize that OCT measures optical path
to make extremely accurate measurements of length. A single beam of length not physical thickness. The presence of edema or other pathologies
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Fig. 2.5.6 The Slit Lamp. (A) Some slit lamps first bring
SLIT-LAMP OPTICS the light to a sharp focus within the slit aperture, and
the light within the slit is focused by the condensing 2.5
lens on to the patient’s eye. The observation system of a
modern slit lamp has many potential reflecting surfaces;
antireflection coatings on these surfaces help reduce
loss of light. (B) Slit-lamp apparatus. (Modified from
condensing Spalton DJ, Hitchings RA, Hunter PA. Atlas of clinical
lens ophthalmology. New York: Gower Medical; 1984. p. 10.)
slit
filter/tray
slit image
mirror
microscope
A B
that differ in refractive index from the retina can distort the apparent • Specular reflection: In this technique the angle of observation is set to
thickness of the pathology, leading to imaging artifacts that can complicate equal the angle of illumination. In this way, the structure of the front
interpretation of OCT images. surfaces of the cornea (i.e., ulcers, dry areas) and the rear surfaces
(endothelial pattern) may be assessed.
SLIT-LAMP BIOMICROSCOPE • Proximal indirect illumination: In this technique a moderately wide
beam is directed to the areas adjacent to the area of interest. Against
The slit lamp is the piece of equipment most frequently used by the oph- a dark background, the backscattered light from the lesion yields a
thalmologist.8 With the addition of auxiliary lenses, it can give unique, higher contrast, which often allows the observer to see the borders of
magnified views of every part of the eye. In conjunction with auxiliary the lesion more precisely. For example, when this technique is used,
devices it can be used to take photographs and to make quantitative mea- subtle corneal edema—with its minute pools of fluid—stands out more
surements, including intraocular pressure, endothelial cell counts, pupil distinctly against a dark pupil.
size, corneal thickness, anterior chamber depth, and others. • Sclerotic scatter: With the slit illuminator offset from its isocentric posi-
tion, light is directed to the limbus. The light then follows the cornea as
Illumination if it were a fiberoptic element and reaches the other side of the limbus.
However, if a lesion or particles within the cornea exist, the backscat-
The modern slit lamp produces an intensity of about 200 mW/cm2. When tered light from the lesion or particles is seen clearly against the dark
operated at the rated voltage, halogen lamps have a higher luminance and pupillary background.
color temperature than do conventional incandescent lamps. For slit-lamp • Retroillumination from the fundus: Light sent through the pupil to the
work, a high color temperature (e.g., a greater amount of blue light) is fundus is reflected and yields an orange background. Holes in the iris
useful. Because many of the ocular structures are seen via light scatter, or subtle wrinkles in the cornea become silhouetted and much easier
and because the shorter wavelengths are scattered most, a light with a high to see.
blue component illuminates the structures best. The light is first brought
to a focus at the slit aperture (Fig. 2.5.6), and the light within the slit is Observation System
focused by the condensing lens onto the patient’s eye.
The observation system of the slit-lamp biomicroscope has a long working
distance of about 3.9 inches (10 cm), which is about 100 times longer than
Improving Tissue Contrast that of a laboratory microscope. Prisms take the divergent rays from the
One of the great strengths of the modern slit lamp is the way in which patient’s eye and force them to emerge as parallel pencils from each eye-
contrast can be improved by various maneuvers: piece. Thus a stereoscopic appreciation of the patient’s eye is achieved
without convergence of the observer’s visual axis. Most slit-lamp micro-
• Optical sectioning: As the beam is narrowed, the scattered light of adja- scopes offer magnifications between ×5 and ×50, with ×10, ×16, and
cent tissue is removed and greater detail of the optical section is seen. ×25 being the most popular. Image resolution is ultimately limited by
• Tangential illumination: When the light is brought in from the side, diffraction.
highlights and shadows become stronger, and the texture (i.e., eleva-
tions and depressions) is seen better.
• Pinpoint illumination: The cells and flare in the anterior chamber in SLIT-LAMP FUNDUS LENSES
a patient who has iritis are best seen using a narrow beam focused
into the aqueous, so that the black pupil becomes the background. Because the cornea has such a high refractive power, the slit-lamp micro-
The combination of the narrow beam and the dark pupillary back- scope can view only the first one-third of the eye.9 Special lenses, in con-
ground eliminates any extraneous light that would reduce contrast. The junction with the slit-lamp microscope, can be used to view the posterior
same principle holds when the examiner pushes the lower lid up to vitreous and the posterior pole retina. The two ways to overcome the high
examine the tear meniscus. For example, the stagnant cell pattern of an corneal refractive power are (1) nullifying the corneal power, or (2) utilizing
obstructed tear duct is best seen using a narrow beam with the dark iris the power of the cornea as a component of an astronomical telescope in a 59
in the background. manner similar to that exploited by the indirect ophthalmoscope.
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Fig. 2.5.7 The Goldmann fundus contact lens, or
2 GOLDMANN FUNDUS CONTACT LENS any similar plano-concave contact lens, nullifies the
refractive power of the cornea, thereby moving the
retinal image close to the pupillary plane and into the
focal range of the slit-lamp microscope. The image
virtual upright image formed is virtual, erect, and diminished in size.
Goldmann
contact lens
patient's eye
Fig. 2.5.8 The concave Hruby lens, when placed close in

CONCAVE HRUBY LENS front of the patient’s eye, forms a virtual, erect image of
the illuminated retina that lies within the focal range of
the slit-lamp microscope.
virtual upright image
Hruby
lens
patient's eye
Fig. 2.5.9 The 60 D, 78 D, and 90 D lenses produce

60 D, 78 D, AND 90 D LENSES inverted, real images of the retina within the focal range
of the slit-lamp microscope in a fashion similar to that
employed by the indirect ophthalmoscope.
real,
inverted
images
patient's eye +78 D lens
The Goldmann contact lens (Fig. 2.5.7) and other similar lenses work The Quadraspheric, SuperQuad, and similar lenses are corneal contact
in conjunction with the slit-lamp microscope to nullify the dioptric power lenses (Fig. 2.5.11).
produced by the corneal curvature and to bring the retina into the focal A real, inverted aerial image of the fundus is formed a few millime-
range of the slit-lamp microscope. These plano-concave contact lenses are ters outside the large aspherical condensing lens, which is within the focal
placed on the cornea, forming virtual, erect, and diminished images of the range of the slit-lamp microscope. Because the condensing lens is so close
illuminated retina near the pupillary plane within the focal range of the to the eye and has such a high power, the field of view is very wide, making
slit-lamp microscope. these lenses specially suited for a wide-angle view of the posterior pole and
The Hruby lens is a powerful plano-concave lens, −58.6 D in power. It midperipheral fundus.
is held immediately in front of the cornea, forming a virtual, erect, and
diminished image of the illuminated retina near the pupillary plane, bring-
ing it within focal range (Fig. 2.5.8).
GOLDMANN APPLANATION TONOMETER
The 60 D, 78 D, and 90 D funduscopic lenses (Fig. 2.5.9) use a different The applanation tonometer (Fig. 2.5.12) is used to measure intraocular
approach to view the posterior vitreous and posterior pole retina. These pressure. It relies on an interesting physical principle. For an ideal, dry,
lenses act as high-powered, biconvex, condensing lenses, projecting an thin-walled sphere, the pressure inside a sphere is proportional to the
inverted, real image in front of the lens within focal range. This is the force applied to its surface. Unlike an ideal sphere, however, the human
same optical principle used by the indirect ophthalmoscope: the higher the eye is not thin-walled and it is not dry, producing two confounding forces:
power of the lens, the lower the magnification of the image. (1) a force produced by the eye’s scleral rigidity (because the eye is not
The Goldmann three-mirror contact lens (Fig. 2.5.10), as its name thin-walled), directed away from the globe; and (2) a force produced by
implies, incorporates three internal mirrors. The contact lens nullifies the the surface tension of the tear film (because the eye is not dry), directed
refractive power of the patient’s cornea, and the three mirrors then reflect toward the globe (Fig. 2.5.13). Goldmann determined that when a flat
light from the patient’s midperipheral retina, peripheral retina, and the surface is applied to the cornea with enough force to produce a circular
iridocorneal angle, respectively. The posterior pole of the fundus can be area of flattening 3.06 mm in diameter, then the force caused by scleral
60 visualized, also, in a manner similar to that of the Goldmann posterior rigidity exactly cancels out the force caused by surface tension. Therefore it
pole contact lens. is a very useful fact that the applanating force required to flatten a circular
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Fig. 2.5.10 The contact lens of the Goldmann lens
EFFECT OF GOLDMANN LENS AND MIRRORS nullifies the refractive power of the patient’s cornea,
while the three mirrors then reflect light from the 2.5
patient’s peripheral retina (orange ray) and iridocorneal
angle (green ray). The posterior pole of the fundus also
can be visualized in a manner similar to that of the
equator Goldmann posterior pole contact lens (blue ray).
posterior pole
angle
GOLDMANN APPLANATION TONOMETER
Fig. 2.5.12 Photograph of a Goldmann applanation tonometer in working position

on a slit-lamp microscope.
tonometer (multiplied by a factor of 10) represents the intraocular pressure

in millimeters of mercury (Fig. 2.5.16).
Specular Microscope
A number of significant obstacles stand in the way of easy microscopical
observation of the living corneal endothelium. First, the reflection from
the front corneal surface interferes with a sharp view of the endothelium.
Fig. 2.5.11 The QuadrAspheric lens consists of a corneal contact lens and a high- Second, the intervening stromal layers backscatter light, which decreases
powered, highly aspherical condensing lens. A real, inverted image of the fundus is the contrast of the endothelial details. In addition, when the stroma
formed, which is within the focal range of the slit-lamp microscope. (Courtesy Volk becomes thick and edematous, the views of the endothelium become hazy.
Optical.) Finally, because of the small difference in index of refraction between the
cornea (1.376) and the aqueous (1.336), only 0.02% of the incident light (for
area of cornea exactly 3.06 mm in diameter is directly proportional to the most angles of incidence) is reflected from the interface between corneal
intraocular pressure. Specifically, the force (measured in dynes) multiplied endothelium and aqueous.10
by 10 is equal to the intraocular pressure (measured in millimeters of To eliminate the bothersome reflection from the front corneal surface,
mercury). two approaches are used. An increase in the angle of incidence moves
How does the observer know when the area of applanation is exactly the anterior reflection to the side so it covers less of the specular reflec-
3.06 mm in diameter so that the intraocular pressure can be measured? tion from the endothelium. This approach alone is used in the noncontact
The applanation tonometer is mounted on a biomicroscope to produce technique. If the cornea could be thickened artificially (without an increase
a magnified image. When the cornea is applanated, the tear film, which in light scatter), this would move the surface reflection further to the side.
rims the circular area of applanated cornea, appears as a circle to the With use of a contact lens that has a coupling fluid of index of refraction
observer. The tear film often is stained with fluorescein dye and viewed similar to that of the cornea, the surface reflection is eliminated and the
under a cobalt-blue light to enhance the visibility of the tear film ring. corneal thickness may be assumed to include the contact lens thickness
Higher pressure from the tonometer head causes the circle to have a wider also. The reflection from the surface of the contact lens replaces that of the
diameter because a larger area of cornea becomes applanated (Fig. 2.5.14). corneal surface. However, because of the thickness of the contact lens, the
Split prisms, each mounted with their bases in opposite directions, are surface reflection is moved well over to the side (Fig. 2.5.17).
mounted in the applanation head, creating two images offset by exactly The magnification needed to yield important details about the shape
3.06 mm. The clinician looks through the applanation head and adjusts and size of the endothelial cells lies between a magnification of ×80 and
the pressure until the half circles just overlap one another (Fig. 2.5.15). At ×250. Of course, a lower magnification photograph may allow an accurate 61
this point, the circle is exactly 3.06 mm in diameter, and the reading on the count of the endothelium. In normal individuals the number of endothelial
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Fig. 2.5.13 Effect of Force on Cornea. (A) When a flat
2 EFFECT OF FORCE ON CORNEA surface is applied to the cornea with enough force
(w) to produce a circular area of flattening greater
than 3.06 mm in diameter, the force caused by scleral
rigidity (r) is greater than that caused by the tear
film surface tension (s). (B) When the force of the flat
surface produces a circular area of flattening exactly
3.06 mm in diameter, the confounding forces caused
w w by scleral rigidity and tear film surface tension cancel
each other. The applied force (w) then becomes directly
proportional to the intraocular pressure (p).
r s r s
p p
A B
Fig. 2.5.14 Fluorescein-Stained Tear Film. When

FLUORESCEIN-STAINED TEAR FILM viewed through a transparent applanation head, the
fluorescein-stained tear film appears as a circular ring
(A). Greater applanation pressure causes the ring to
increase in diameter (B).
Fig. 2.5.15 Effects of Applanation on Split Prism. The

EFFECTS OF APPLANATION ON SPLIT PRISM split prism in the applanation head creates two images
offset by 3.06 mm, allowing greater ease in determining
when the circular ring is exactly 3.06 mm in diameter.
applanation applanation applanation When the area of applanation is smaller than 3.06 mm,
area too small area too large area correct the arms of the semicircles do not reach each other (A).
When the area of applanation is greater than 3.06 mm,
the arms of the semicircles reach past each other (B).
When the area of applanation is exactly 3.06 mm, the
arms of the semicircles touch each other (C). This is
the endpoint at which the intraocular pressure can be
measured.
A B C
62 3.06 mm
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LOW APPLANATION PRESSURE OPTICS OF ENDOTHELIAL SPECULAR
MICROSCOPY USING A CONTACT LENS 2.5
A immersion
cap
Fig. 2.5.17 Optics of Endothelial Specular Microscopy Using a Contact Lens.

(Adapted from Bigar F. Specular microscopy of the corneal endothelium. In: Straub
W, editor. Developments in ophthalmology, vol. 6. Basel, Switzerland: Karger; 1982.
p. 1–88.)
Fig. 2.5.18 External Photograph of an Operating Microscope.
(1) astronomical telescope, (2) inverting prism, (3) Galilean telescope, (4)
objective lens, (5) light source, and (6) binocular viewing system (Fig.
C
2.5.19). Unlike the slit-lamp microscope, the operating microscope’s illu-
mination source is not slit-shaped, and the working distance for the oper-
Fig. 2.5.16 Low Applanation Pressure. When the applanation pressure is too low ating microscope (the distance from the objective lens to the patient’s eye)
(1.0 dyne in this illustration) the circular ring is smaller than 3.06 mm in diameter, is longer to accommodate the specific requirements of ocular surgery.
and the arms of the ring do not reach each other in the split image (A). When the The working distance of this microscope is equal to the focal length of
applanation pressure is too high (3.0 dynes in the illustration) the circular ring is the objective lens. Commonly used objective focal lengths in ophthalmic
larger than 3.06 mm in diameter, and the arms of the ring stretch past each other surgery are 150 mm, 175 mm, and 200 mm. Use of the proper working
in the split image (B). When the applanation pressure creates a circular ring exactly
distance can greatly lessen back and neck strain on the surgeon, especially
3.06 mm in diameter, the arms of the ring just reach each other in the split image
(C). In this illustration, the endpoint is reached at 2.0 dynes of applanation pressure,
during lengthy operations. A difference of 25 mm often can affect body
which corresponds to an intraocular pressure of 20 mm Hg. comfort and the positioning of the surgeon’s arms and hands.
The total magnification of the operating microscope is equal to the
product of the magnifications of its various components. Because several
cells per square millimeter decreases with age, while the size of the cells different lenses are available for the objective and the eyepiece, magnifica-
increases with age. tion can be controlled. Smoothly variable magnification changers (zoom
Galilean telescopes) are now incorporated into many operating micro-
OPERATING MICROSCOPE scopes. The ×12.5 eyepiece is the most popular choice for ophthalmic
surgery, with magnification from ×6 to ×40.
The operating microscope (Fig. 2.5.18) works on principles similar to those Various illumination systems are available, but the most important 63
of the slit-lamp microscope. Both have the following optical components: system for ophthalmic surgery is known as coaxial illumination. This
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from the shape of the mires. Implicit in all corneal measuring instruments
2 OPERATING MICROSCOPE SCHEMATIC based on Scheiner’s method are two assumptions: (1) that the cornea is
restricted to a specific geometrical class, and (2) that the instrument is
aligned on the corneal axis. In many cases, at least one of the assumptions
(and often both) is invalid.
Consider the simple case of a rotationally symmetrical cornea that can

be described by two parameters: vertex curvature and eccentricity. Vertex
curvature is directly proportional to power, and eccentricity describes how
quickly the cornea flattens to influence aberrations. The two variables are
independent, e.g., a 45.00 D hyperboloid can have many different eccen-
tricities, and a hyperboloid of a given eccentricity can have many different
powers. Thus to describe the shape and optical properties of a hyperboloid
it is necessary to measure both eccentricity and power, but ophthalmom-
eters such as the Bausch & Lomb keratometer or Javal–Schiotz measure
neither.
Instead ophthalmometers assume the cornea is spherical. Under the
spherical constraint the only remaining question is what is the radius of
the sphere? The keratometer gives the radius of the sphere that produces
the same mires as those produced by a hyperboloidal cornea. Two corneas
with the same power but different eccentricities will produce different
K-readings. Likewise, corneas of different power may produce the same
K-readings.
It is important to realize that the keratometer was not intended to
measure corneal shape or optical properties. The device was introduced
shortly after World War II and was originally designed to assist in fitting
rigid contact lenses that had spherical posterior surfaces, so the assumption
of a spherical cornea was reasonable for the intended purpose. Originally,
contact lens base curves had to be specified as a radius (in millimeters), so
the keratometer was calibrated in millimeters. Some clinicians preferred
to specify base curves in diopters, so later instruments were calibrated in
diopters using the conversion formula:
337.5
Diopters =
Radius (mm )
This conversion formula is not optically correct because it assumes

the corneal refractive index is 1.3375, not the correct value of 1.376. The
conversion underestimates the power of the anterior cornea and tear film.
However, because the posterior corneal surface has negative power, this
formula is a better estimate of overall corneal power. This was of no conse-
Fig. 2.5.19 Schematic Diagram of an Operating Microscope. The major quence at the time, because the only purpose of this formula was to allow
components include: the eyepiece, an astronomical telescope system, which laboratories to convert base curves specified in diopters into millimeters
provides most of the magnification (a); an inverting prism, such as a Porro– for purposes of fabrication. This formula had the advantage of making a
Abbe prism, to correct for the inverted image produced by the eyepiece (b); a radius of 7.5 mm exactly equal to 45 D. Today, ophthalmometers are avail-
magnification changer, such as a Galilean telescope system, in which different lenses able that give K-readings in millimeters, diopters, or both.
can be introduced in order to change the degree of magnification (c); and the With the general acceptance of intraocular lenses (IOLs) in the
objective lens, which adjusts the working distance (d). Two parallel optical systems, mid-1970s, ophthalmometers gained a new clinical role for which they
each a mirror image of the other, provide a stereoptic view of the patient’s eye. are not ideally suited—the estimate of corneal power to calculate implant
power. Theoretical formulas incorporated K-readings as if they were actu-
ally accurate measurements of corneal power. It is fair to say that most
system is especially useful for visualization of the posterior capsule and for of the clinical community did not fully appreciate the distinction between
vitreous surgery. Fiberoptic delivery systems reduce heat near the micro- K-readings and corneal power. According to theory, if corneal power
scope and facilitate the changing of bulbs during surgery. changes by 1.00 D, implant power should change by more than one diopter.
It came as a complete surprise when the SRK equation—the first formula
KERATOMETER AND CORNEAL TOPOGRAPHER based on statistics rather than theory—suggested that a 1.00 D change in
K-readings should change the implant power by only 0.9 D. This result
In the early 1600s Christopher Scheiner sat a person opposite a window. proves that K-readings are not a measurement of corneal power.
The subject’s anterior corneal surface with its overlying tear film acted Nevertheless, the SRK equation proved that corneal power and
as a convex mirror and produced a small image of the window. Today K-readings are correlated. The spherical aberration of a hyperboloidal
we refer to that image as the first Purkinje image or simply the mire or cornea can be eliminated with the right eccentricity. Indeed, the eccentric-
mires. Scheiner compared the corneal mire to similar images produced by ity of most human corneas varies over a narrow range that is quite close to
glass spheres of differing sizes and concluded the cornea had about the the optimal (spherical aberration free) value. Because corneal eccentricity
same shape as the sphere that produced the image most closely matching normally varies over a limited range, K-readings correlate with—but are
the mire. not measurements of—corneal power.
The technique has been greatly refined. Today the mires are measured The success of the SRK formula should have alerted the clinical com-
by an electronic camera, but the same basic principle introduced four munity to the limitations of the Scheiner approach, but it did not. With the
centuries ago remains fundamentally unchanged. An object of known advent of refractive surgery, ophthalmometers were again used to correlate
dimensions is placed in front of the cornea, which like any convex mirror changes in refractive error to K-readings. Again, it was soon found that
produces a virtual erect image of the object. The dimensions of the mires K-readings did not correlate with changes in refractive error. The reason
are measured, and from this information an attempt is made to infer for the poor correlation is that keratorefractive surgical procedures change
corneal shape and optical properties. corneal eccentricity, destroying the statistical relationship that normally
The basic problem, however, is that there is no definite relationship exists between power and eccentricity. The result is that K-readings no
between the dimensions of the mires and the shape of the cornea.11 Put longer reflect corneal power in a predictable way.
64 another way, there are infinitely many corneas that can produce identical Refractive surgeons quickly recognized the shortcomings of ophthal-
mires. Consequently, it is impossible to derive the shape of the cornea mometers but did not understand the underlying reason. Many believed
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that the single circular mire interrogated only a small region of the cornea proportional to the power of the unknown lens (an example of Badal’s
and additional rings would overcome the problem, but they do not. The
fundamental problem, as stated before, is that no definite relationship
principle). Such an arrangement allows the instrument’s linear scale to be
read in diopters. 2.5
exists between the mires and corneal shape, even when multiple rings are To determine the power of each principal meridian of an unknown
used. lens, the lens simply is inserted into the lensmeter, the principal merid-
Alignment is another critical factor affecting the “accuracy” of corneal ian located, the target lines focused sharply, and the power recorded.
topography systems. Most algorithms assume the instrument’s optical axis The second target, set 90° from the first, is refocused and the new power
coincides with the corneal axis, but it does not. The early corneal topog- recorded. Once the powers in the two principal meridians and the axes are
raphy instruments lacked any alignment method, which led to unrepro- known, the final prescription is calculated.
ducible results. Repeated measurements on the same patient were often The automatic device rapidly measures the powers in all meridians,
wildly different, which obviously cast serious doubt on the reliability of selects the meridians with the greatest difference in power between them,
these devices. Later instruments used the pupil, not the corneal vertex, and designates these as the major meridians of the lens. The device is pro-
for alignment. A consistent alignment procedure produced reproducible grammed to calculate the prescription and print out the result. The entire
but not necessarily accurate measurements. Inappropriate alignment even procedure takes less than 1 minute from spectacle insertion to printout.
in today’s instruments can produce artifacts that have been mistakenly The main advantage of the automated lensmeter is its elimination
attributed to early keratoconus.12 of human error. In today’s busy ophthalmic office, in which technicians
Despite their failings, most corneal measurement systems in clini- and doctors juggle many mental tasks at the same time, a clear advantage
cal use are based on the Scheiner principle. Clinicians should use these exists to a device that does not need to be focused, have numbers written
systems with an appreciation for their limitations. Fundamentally, no rela- down, or require calculations to be made.
tionship exists between the mires and corneal shape, because infinitely If an automated lensmeter does not focus a sharp image, how does it
many different corneas can produce identical mires. However, the cornea work? It simply measures the deflection of a fixed number of light rays
is not infinitely variable, so correlations occur between the mires and the produced by the unknown lens. To do this, the direction of the rays must
cornea that make it possible to use ophthalmometers and video keratos- be known before they enter the lens. The easiest way to accomplish this is
copy to calculate IOL power and assist in other clinical evaluations. Clini- to have them all enter parallel to one another. Fig. 2.5.21 shows a beam of
cians should be aware, however, that the more irregular or misaligned the collimated green light (which eliminates chromatic aberration) incident to
corneal and instrument axes, the more likely that the data are unreliable. the unknown lens. Thus a circle of light of a known dimension strikes the
lens. The refracted light is passed through a ring aperture to tailor the size
LENSMETER of the new beam to the size of the board of light detectors. By deflection of
the parallel beam in its unique manner, the unknown lens produces a new
For most of the twentieth century, the lensmeter (also known as the lensom- pattern (i.e., a smaller or larger circle or an ellipse), which is detected and
eter or vertex meter) changed very little. However, in the 1970s a number carefully measured by an array of photodiodes. These measurements yield
of automatic lens analyzers appeared that eliminated almost all human deflection information that is fed into a small computer that calculates
involvement and quickened the determination of new prescriptions. the lens parameters (powers, axis, adds, prisms), and a printer creates a
In this chapter, the basic principles of the traditional lensmeter are record of the parameters. Because these devices measure ray deflections,
reviewed to outline its strengths and weaknesses and thus help to appreci- if the lenses in the lensmeter are tipped at all, the deflection is altered and
ate the usefulness of the automatic devices. erroneous results are produced.
The lensmeter does not measure the focal length of the unknown Another small error arises in the measurement of the add of a bifocal.
lens. It measures the vertex power, which is the reciprocal of the distance All automated lensmeters are designed to measure the vergence of the
between the back surface of the lens and its secondary focal point; this light that exits a lens when parallel light enters it. However, light that
distance is known as the back focal length. enters the add when worn by a patient is typically divergent (i.e., originates
A simple lensmeter (Fig. 2.5.20) is an optical bench that consists of an at 16 inches [40 cm] or the reading distance from the spectacle plane). The
illuminated, movable target, a powerful fixed-field lens, and a telescope error is significant only in high-powered lenses, such as for an aphakic
eyepiece focused to infinity.13 The key element is the field lens; without correction. To minimize this error, the distance and near powers are mea-
this, to measure the merest 0.25 D lens would require a lensometer of sured using the back surface of the lens (in the position usually occupied
the optical bench type to be over 4 m long. The fixed-field lens is situated by the front surface).
so that its focal point is on the back surface of the unknown lens being Accurate measurement of the progressive multifocal lens presents a
analyzed, which, in turn, sends parallel light to the observation telescope. problem with many lensmeters. The operator must first align the lens to
Thus the small movement of the target is amplified optically and in such measure the distance correction, bind then find and realign, and measure
a way that the distance between the target and field lens always is directly the area of the lens with the maximum add.
OPTICS OF A TYPICAL AUTOMATED LENSMETER

LENSMETER
fixed
position of illuminated fixed field unknown mirror
target image movable lens lens telescope
by field lens target
green beam-forming small beam-forming white light
filter optics aperture optics source
lens
ring aperture which
beam pattern in
F defines detected rays
F detector plane
fixed linear array

mirror photo-detector
(position 1)
beam-forming image of (position 2)
back focal length of unknown lens lens ring aperture
Fig. 2.5.20 The Lensometer Resembles an Optical Bench. The movable

illuminated target sends light to the field lens, with the target in the endpoint Fig. 2.5.21 Optics of a Typical Automated Lensometer. Parallel light strikes the
position. Because the focal point of the field lens coincides with the position of the unknown lens. The refracted light rays (which are confined to a pencil beam within 65
unknown lens, all final images are the same size (Badal principle). an annulus) ultimately strike an array of electronic photoreceptors.
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AUTOMATED REFRACTOR Fig. 2.5.22
2 Any clinician who has asked enough patients “Is it better with lens 1 or
lens 2?” must have dreamed of an automated refractor.14 After all, the eye
Emmetropia
PRINCIPLE OF SCHEINER'S DISC Principle of
Scheiner’s Disc.
Light enters the
is a partial optical bench. The fundus can be a serviceable target if illumi- two pinholes and
produces two
nated. The cornea and lens make a passable aspherical focusing system.
images on the
To complete the optical bench, a positive lens needs to be placed before retina until the
the eye to form a real aerial image of the fundus, as in indirect ophthal- light is brought to
Emmetropia
moscopy. Except that distances are not standardized and calibration is not a focus. (Adapted
present, an indirect ophthalmoscope has most of the essential elements of from Guyton DL.
an objective refractor. Automated clinical
Modern instruments have two sources of light. First, the target is illu- refraction. In:
minated with visible light for fixation and accommodation control and, Duane T, editor.
second, a low-intensity infrared or near-infrared source sends light into Myopia Clinical refraction,
the patient’s eye, which is “seen” by a sensor. The optometer must use vol. 1. Baltimore,
“invisible” (or at least dim, unobtrusive) light for measurement to preclude MD: Harper & Row;
an unwanted stimulus to accommodation and to allow comfortable fixa- 1987. p. 1–43.)
tion. These two (visible and infrared) systems usually are derived from a
single incandescent lamp by the use of filters. For example, a cut-off filter Hyperopia
of 800 nm allows only infrared light to enter the system.
The area of retina irradiated by infrared radiation produces a real image
within the optometer. This image is analyzed by photoelectric means
using an infrared-sensitive device. The use of infrared for focus evalua-
tion presents a few problems. For example, an examiner cannot calibrate
the focusing system “by eye” but must use an indirect method. In terms
of accuracy, the eye’s chromatic aberration is a problem. Anyone familiar
with the duochrome (red–green) test knows that the human eye focuses
light of various wavelengths differently. Because the goal is to learn the
eye’s refractive error in visible (yellow) light, a correction factor of about
1.00 D must be built into any infrared device.
It is valuable to consider some problems that had to be solved in the of-focus candle is seen double when viewed through paired apertures
design of modern objective refractors: accommodation, subjective align- separated by a distance slightly less than the diameter of the pupil. An
ment, and focusing. automatic focusing device that uses Scheiner’s disc principle divides the
Accommodation. Accommodation associated with the use of a target that rays that emerge from a subject’s eye into two bundles and then seeks the
is optically distant but objectively near may induce errors in the measure- point at which these intersect. For example, a photoelectric sensing device
ment of refraction. Modern devices use a fogging lens through which the might register an endpoint for a particular meridian under the condition
fixation target is viewed. The subject hopefully learns that accommoda- that all the light falls on one sensing element rather than two. The 6600
tion tends to make the visible target even more blurred and thus relaxes Autorefractor16 is an example of an instrument that operates on Scheiner’s
accommodation. Occasional failure of accommodation to relax under a fog principle (Fig. 2.5.22).
is presumed to occur because of an awareness that the target is not truly Grating-focus principle. In the grating-focus method, an image of a lumi-
distant. This phenomenon has been termed instrument myopia. nous target grating is formed on the retina. The sharpness of the aerial
Subjective alignment. It is almost paradoxical to request a subject to image of the illuminated “retina grating” is assessed continuously, usually
simultaneously look at a fixation target and not attempt to clear it by by a scanning process. A high-speed servomechanism varies the focusing
accommodation. These divergent responses are required, however, if lenses until the actual grating image is as sharp as a standard in-focus
refraction is to be measured accurately for foveal vision. Accordingly, when image provided by the device.
the examiner aligns the optometer with respect to the subject’s pupil as
the subject fixates the target, proper overall alignment must be ensured.
At the same time, a fogging lens provides a disincentive to accommodate.
MAGNIFYING DEVICES
Focusing. Modern objective refractors are focused automatically, which Angular Magnification
eliminates the variability otherwise introduced by examiner accommoda-
tion. Automatic focusing for various meridians is accomplished swiftly, In addition to transverse and axial magnification, angular magnification
with the number and locations of meridians actually scanned depending is another parameter used to characterize the performance of optical
on the method of image evaluation and on the approach to refractive error instruments. All focal optical systems (i.e., those with first order properties
analysis used in the particular instrument. The computational power of described by three pairs of points—focal, principal, and nodal) have an
the microprocessors found in today’s automated refractors allows refrac- angular magnification of 1. Afocal systems such as telescopes that do not
tion to be calculated within 10 seconds or less. This high speed tends to have focal, nodal, or principal points can have angular magnifications that
negate one of the major problems associated with older manual devices, differ from 1.
such as momentary changes in fixation or accommodation or both that
may take place during the course of measurement. Magnifying Glass
Most objective optometers use one of three methods for focus analysis:
the retinoscopic principle, Scheiner’s disc principle, or the grating focus The simplest way to make an object appear larger is to move it closer to the
principle. eye, increasing the angular subtense of the retinal image (measured with
Retinoscopic principle. Bausch and Lomb’s Ophthalmetron was the respect to the eye’s posterior nodal point). The fundamental limitation to
first clinical automated refractor to utilize the retinoscopic principle.15 No this approach is the eye’s near point, determined by accommodation. With
longer commercially available, this instrument used paired light sensors placement of a single positive ancillary lens between the object and eye,
to register movement of the retinoscopic reflex. For example, if sensor 1 the angular subtense can be increased beyond what can be achieved by
was stimulated before sensor 2, an analog of a retinoscopic “with” existed. accommodation alone. How much magnification is produced by a lens of
Conditions that gave rise to a retinoscopic “against” caused sensor 2 to be a given power? The answer depends on where the object is placed relative
stimulated first. In any event, a servomechanism found the focus in one to the ancillary lens.
meridian and attempted to maintain focus as each meridian was scanned The following analysis is based on paraxial optics, which is to say that
in turn. The Ophthalmetron produced a graph that displayed the refraction all angles are small and aberrations are not involved. If the patient has A
in each meridian. Modern automated refractors are much more rapid and diopters of accommodation then in the unaided eye the object of height h
display refractive data directly in numeric form. at the near point subtends an angle of
66 Scheiner’s disc principle. In the early seventeenth century, Fr. Christopher
Scheiner observed that an in-focus candle is seen singly, whereas an out- α = h( A ).
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If an auxiliary positive thin lens of power P (the magnifier) is placed in
GALILEAN TELESCOPE
front of the eye such that the object is in the magnifier’s front focal plane
the angular subtense of the retinal image becomes 2.5
α ′ = h(P ). fo
The ratio (α′/α) compares the angular subtense of the retinal image
when a magnifier is used divided by the image subtense without a magni-
fying lens and is the angular magnification. fe
Ma = α ′ α = (P A )
y1
By convention, it is often assumed that the patient has 4 diopters of
residual accommodation, so the formula becomes
Ma = (P 4)
The last equation is the standard formula often quoted in textbooks,

but since accommodation varies from patient to patient, the last equation
does not reflect the correct value in many cases. By preserving the patient’s
Fig. 2.5.23 A Galilean Telescope. Note the objective lens takes parallel light and
accommodation as a variable, the equation Ma = P/A more accurately places a real image at the focal point of the negative eyepiece. The eyepiece takes
reflects the magnification produced by a simple magnifier for a specific the incident convergent light and renders rays parallel.
patient.
When the object is placed in the front focal plane of the auxiliary lens,
however, the patient’s accommodation is completely relaxed, which wastes
some power that could be used for further magnification. The maximum SIMPLE MICROSCOPE
amount of angular magnification is achieved when the ancillary lens pro-
duces a virtual image at the near point of accommodation. In which case
the angular magnification becomes
y
Ma = 1 + P A
or using the conventional value for A = 4.00 D
Ma = 1 + P 4 fw
which is another formula often cited in textbooks. Again, a more versatile

equation is obtained by preserving the patient’s accommodation as a vari- hand magnifier telescope
able. In any case, the lower the patient’s accommodation, the greater the
benefit of the simple magnifier.
Fig. 2.5.24 A Simple Microscope. A positive lens (working distance lens) is placed
Galilean Telescope in front of a Galilean telescope. This lens takes light from an object located at
its focal point and renders the rays parallel for the Galilean telescope part of the
To calculate the magnification of a telescope, the angle of incident parallel device.
light is compared with the angle of the parallel rays of emergent light.
From Fig. 2.5.23, the entrance angle is given by y1/fo (where fo is the focal
length of the objective lens), the emergent angle is given by y1/fe (where Simple Microscope (Operating Loupe)
fe is the focal length of the eyepiece lens), and the magnification is given
by Eq. 2.5.1. The principles of this device are similar to those of a Galilean telescope,
even though it works only if it receives parallel light and a microscope is
y1 − fe −Fe used to look at close objects.
= Equation 2.5.1
y1 fo Fo However, if a magnifying lens (Fw) is added, the focal length of which
is the working distance, then the magnifying lens introduces parallel light
For example, if a Galilean telescope has an angular magnification of ×3 to the telescope, as shown in Fig. 2.5.24, and the total magnification is
and the eyepiece is −12 D, the power of the objective is given by Eq. 2.5.2. given by Eq. 2.5.4.
12
3= Fw Fe
Fo Equation. 2.5.2 × Equation 2.5.4
4 Fo
Fo = 4 D
As another example, for a telescope of magnification ×3 and tube length For example, for a loupe with a ×3 telescope and a +8D working lens
(L), the distance between objective and eyepiece, of 22 cm, fo, and fe are (reading cap) the magnification = (8/4) ⋅ 3 = ×6.
given by Eq. 2.5.3.
KEY REFERENCES
fo American Academy of Ophthalmology. Basic and clinical science course section 3—Clinical
−3 = optics. San Francisco: American Academy of Ophthalmology; 2012.
− fe American Academy of Ophthalmology. Home study course, optics and refraction. San Fran-
−3 fe = fo cisco: American Academy of Ophthalmology; 1990.
Doss JD, Hutson RL, Rowsey JJ, et al. Method of calculation of corneal profile and power
L = fo − fe distribution. Arch Ophthalmol 1981;99:1261–5.
Equation 2.5.3 Duke-Elder S. System of ophthalmology, vol. 4. St Louis: CV Mosby; 1949. p. 4391–3.
22 = −3 fe − (− fe) Tage GW, Safir A. The slit lamp; history, principles and practice. In: Duane TD, editor. Clin-
22 = −2 fe ical ophthalmology, vol. 1. New York: Harper & Row; 1980.
− fe = −11 cm
Access the complete reference list online at ExpertConsult.com 67
fo = 3.3 cm
m
booksmedicos.org
REFERENCES 8. Gullstrand A. Demonstration der Nerstspattlempe. Heidelberg: Heidelberger Bericht;
1911.
1. Albert DM, Miller WH. Jan Purkinje and the ophthalmoscope. Am J Ophthalmol 1973;76:
494–500.
9. Tage GW, Safir A. The slit lamp; history, principles and practice. In: Duane TD, editor.
Clinical ophthalmology, vol. 1. New York: Harper & Row; 1980.
2.5
2. Kent PR. The foveal light reflex and its use as an objective test for astigmatism. Am J 10. Laing RA, Sandstrom MM, Leibowitz HM. Clinical specular microscopy. I: Optical prin-
ciples. Arch Ophthalmol 1979;97:1714–19.
Optom Arch Am Acad Optom 1960;37:304–10.
3. GTE Sylvania Lighting Center. Tungsten-halogen lamps. Sylvania Engineering Bulletin 11. Doss JD, Hutson RL, Rowsey JJ, et al. Method of calculation of corneal profile and power
O-349. Danvers: GTE Sylvania Lighting Center; 1970. distribution. Arch Ophthalmol 1981;99:1261–5.
4. Gullstrand A. Neue Methoden der reflexlosen Ophthalmopskiepie. Ber Disch Ophthal- 12. Doyle SJ, Hynes D, Naroo S, et al. PRK in patients with a keratoconic topography picture.
mol Ges 1910;30:36–75. The concept of a physiological “displaced apex syndrome.” Br J Ophthalmol 1996;80:
5. American Academy of Ophthalmology. Basic and clinical science course section 3— 25–8.
Clinical optics. San Francisco: American Academy of Ophthalmology; 2012. 13. Rubin M. Optics for clinicians. Gainesville: Triad Publications; 1993.
6. American Academy of Ophthalmology. Home study course, optics and refraction. San 14. Duke-Elder S. System of ophthalmology, vol. 4. St Louis: CV Mosby; 1949. p. 4391–3.
Francisco: American Academy of Ophthalmology; 1990. 15. Safir A. Automatic measurement of the refractive properties of the eye. Med Res Eng
7. Busse BJ, Mittleman D. Use of the astigmatism correction device on the Zeiss fundus 1972;2:12–18.
camera for peripheral retina photography. In: Justice J, editor. Ophthalmic photography. 16. Guyton DL. Automated clinical refraction. In: Duane T, editor. Clinical refraction, vol. 1.
Int Ophthalmol Clin 1976;16:63–75. Baltimore: Harper & Row; 1987. p. 1–43.
67.e1
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Wavefront Optics and Aberrations of

the Eye 2.6
Edmond H. Thall
diagrams show that a stigmatic focus occurs about one-third of a milli-

Definition: An aberration is any deviation of the path of a ray of light meter anterior to the retina. The size of the spot diagram increases as the
from geometrically ideal behavior. pupil enlarges, but the location of the stigmatic focus (and, therefore, the
power of the corrective spectacle lens) does not change with pupil size, so
the aberration is said to be pupil independent. Likewise, regular astigma-
tism is also pupil independent, which is why it is unnecessary to check
Key Features pupil size to prescribe spectacles. The aberration known to lens designers
• Aberration theory is strictly confined to geometrical optics and as defocus encompasses both myopia and hyperopia.
ignores any aspects of physical optics such as diffraction and In 1857 Ludwig von Seidel described five basic monochromatic ray aber-
interference. rations of rotationally symmetrical optical systems.5 When studied indi-
• Originally, wave aberrations were applied only to symmetrical vidually, each aberration can be easily identified by its characteristic spot
optical systems, and each aberration was represented by a unique diagram. However, virtually all optical systems have many different aberra-
polynomial. tions. The spot diagrams of actual optical systems are a complex combina-
• Today other expansions, particularly the Zernike polynomials, are tion of several aberrations. It is difficult to identify and quantify the many
most commonly used, and usually each polynomial is a combination individual aberrations from spot diagrams of actual optical systems.
of pure aberrations. In the early 1950s HH Hopkins developed a different, wavefront-based
• In any case, after defocus and regular astigmatism, the most approach that simplified the definition, identification, and quantification
important aberrations are coma and spherical aberration. of aberrations.6 The two approaches, ray and wavefront, are not mutually
exclusive but rather complementary.
INTRODUCTION THE WAVEFRONT APPROACH TO ABERRATIONS

From a clinical perspective, aberration theory is simply an extended treat- Aberration theory falls within the discipline of geometrical optics,7 so dif-
ment of refractive error. Only hyperopia, myopia, and regular astigmatism fraction and other wave phenomena are completely ignored. In aberration
are correctable by spectacles,1 so in the past these were the only aberrations theory, light propagation obeys the basic laws of reflection, refraction, and
of clinical interest. The existence of other refractive errors was certainly rectilinear propagation. All three laws are encompassed by Fermat’s princi-
recognized,2 but because they were not correctable, clinicians had no need ple, which states that between any two points light travels the fastest path.
to study them in depth. Instead, the many aberrations not correctable by Ideally, a pencil of rays filling the entrance pupil of an optical system
spectacles were relegated to a single broad category—irregular astigma- emerges from the exit pupil as a pencil converging to a perfect image
tism. It is probably fair to say that even today many clinicians believe irreg- point,8 i.e., a stigmatic focus. The reference sphere is an imaginary spher-
ular astigmatism exists only in pathological cases and is not present in ical surface centered on the ideal (paraxial) image point and intersecting
normal eyes.
For centuries, designers of optical instruments (e.g., telescopes, micro-
scopes) had methods of correcting aberrations that could not be imple- RAY ABERRATION AND SPOT DIAGRAMS
mented clinically. Consequently, engineers have carefully characterized the
individual aberrations that clinicians refer to collectively as irregular astig-
matism.3 With the advent of keratorefractive surgery came the intriguing
possibility of correcting at least some refractive errors not correctable by
spectacles. Keratorefractive surgery also brought the disconcerting compli-
cation of increased irregular astigmatism in some cases.4 For the first time
it was necessary for clinicians to explore irregular astigmatism more thor-
oughly. Fortunately, rather than reinvent the wheel, ophthalmologists can
turn to the already well-developed aberration theory used by lens designers.
RAY ABERRATIONS
Aberrations can be described by two different but closely related methods: object
ray and wave aberrations. When a ray is precisely traced through an optical point
ideal image
system using the laws of geometrical optics (e.g., Snell’s law) it is found
point
that usually the ray does not exactly intersect the ideal image point. The
displacement of the actual ray from the image point is the ray aberration.
Fig. 2.6.1 Ray Aberration and Spot Diagrams. In principle, the image ray should
When a pencil of rays (by definition all originating from a single object intersect the ideal image point but usually does not. The separation between any
point) are traced, the result is a spot diagram (Fig. 2.6.1). ray and the ideal image point is the ray aberration (for that particular ray). A spot
For a specific and familiar example, consider the spot diagram for the diagram shows the intersection of multiple rays (from a single object point) in
axial object point at infinity of a theoretical eye with a 4 mm pupil and any plane perpendicular to the axis. Through-focus spot diagrams are a set spot
−1.00 D of myopia and no other aberrations. A spot diagram can be calcu- diagrams in the vicinity of the ideal image point showing the position of the best
68 lated anywhere within an optical system, and typically several are calculated focus. In this case (but not usually), the best focus is stigmatic but in front of the
in the vicinity of the theoretical image plane. The set of through-focus spot ideal image point.
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THE WAVE ABERRATION MYOPIA
2.6
exit pupil
Wavefront Optics and Aberrations of the Eye

aberrated
wavefront
reference
sphere RAW myopic image
point
optical axis
ideal image
point
RRS
Fig. 2.6.3 Myopia. In myopia, the aberrated wavefront is spherical but has a shorter
radius (RAW ) than the reference sphere (RRS).
Returning to the example of a theoretical eye with −1.00 D of myopia,

Fig. 2.6.2 Definition of Wave Aberration. The reference sphere is centered on the
the reference sphere is centered on the ideal image point. As shown earlier,
desired image point and intersects the center of the exit pupil (shown top, in red).
An ideal optical system would produce an actual wavefront that coincides with the in myopia, the image is stigmatic but anterior to the ideal image point.
reference sphere. A real optical system produces a wavefront that does not coincide The wavefront emerging from the exit pupil therefore also is spherical but
with the reference sphere (shown top, in blue). The difference between the actual centered on a point anterior (i.e., to the left) of the ideal image point. The
wavefront and the reference sphere is the wave aberration (shown bottom, in green). difference between the actual wavefront and reference sphere is the wave
aberration surface (Fig. 2.6.3). It is worth noting that the maximum sepa-
ration between the reference sphere and the wavefront is a mere 1.5 µm,
the center of the exit pupil.9 According to Fermat’s principle, to achieve which is at the edge of the pupil. For midperipheral and central rays the
a stigmatic focus, all light radiating from the object point at a particular wave aberration is less.
instant must arrive simultaneously at the image point, or equivalently, When wave aberrations are displayed on a graph, the optical axis is
must cross the reference sphere simultaneously. rotated 90° from horizontal to vertical. The wave aberration produced by
In most cases, image rays do not emerge from the exit pupil as a pencil myopia has a bowl shape.13 All myopias, whether large or small, have the
converging to a single point but rather converge to a small irregularly same characteristic bowl shape. The amount of myopia changes the bowl’s
shaped region.10 In other words, the focus is not stigmatic. It always is depth and steepness of its edges but does not change its basic bowl shape.
possible to draw a surface through the center of the exit pupil that all rays The wave aberration for hyperopia also is bowl shaped but the bowl is
cross simultaneously, and when the focus is not stigmatic, that surface— inverted (i.e., spills water). As both refractive errors have the same fun-
called the actual wavefront—is not spherical. The difference between the damental shape, lens designers classify them as the single aberration,
reference sphere and actual wavefront is the wave aberration (Fig. 2.6.2).11 defocus just as clinicians use “sphere” to specify either myopic or hyper-
The wavefront and reference sphere are both surfaces, and the difference opic correction when writing prescriptions. However, positive defocus is
between these two surfaces, the wave aberration, is likewise a surface. To myopia and negative defocus is hyperopia, which may be counterintuitive
give an analogy, consider the Earth’s surface as the actual wavefront and to clinicians. The difference arises because lens designers classify defocus
sea level as the reference sphere. Height above (or below) sea level is anal- by the shape of the wave aberration, whereas clinicians think in terms of
ogous to the wave aberration. the power of the correcting lens.
The word wavefront is perhaps an unfortunate choice, suggesting that
it is somehow related to the wave nature of light. However, as noted, aber-
ration theory is based on geometrical optics that by definition ignores the
SPHERICAL ABERRATION
wave properties of light. A pencil of object rays entering the optical system In spherical aberration (SA), rays near the center of the lens focus at or
upon emerging from the exit pupil always “reaches” the wavefront simul- close to the ideal image point, whereas more peripheral rays focus in a
taneously, so the wavefront is a surface of equal time. Arguably, the term different location. In positive SA, peripheral rays focus in front of the ideal
isochrone (equal time) is more descriptive, but wavefront is too entrenched image point, and the more peripheral the ray the more anterior its focus
to change. (Fig. 2.6.4). In negative SA, peripheral rays focus behind the ideal image
It is a common misconception that there is only one set of aberrations point and, again, the more peripheral the rays, the more posterior their
for each optical system. In fact, there is a different set of aberrations for focus. The wave aberration representing SA also has a bowl shape.14 In fact,
every object point. This discussion began with a single pencil of object SA looks more like a bowl than does defocus. Compared with defocus, the
rays by definition from a single object point. Each object point produces its wave aberration of SA has a flatter broader center and the edges become
own pencil, and each object pencil has its own unique set of aberrations, much steeper than the bowl representing defocus.
although nearby object points have very similar aberrations. When SA is present, the location of the best focus is no longer at the
Stigmatic focus means image rays converge to a perfect point either at ideal image point predicted by the vergence equation (U + P = V). Positive
the ideal image point or elsewhere.12 Because of diffraction, the focus can SA shifts the best focus toward myopia, whereas negative SA shifts the
never be stigmatic, but geometrical optics ignores diffraction. Using only focus toward hyperopia. However, even at the best position the focus is
refraction, reflection, and rectilinear propagation, focus can, in theory, be not stigmatic.
stigmatic. Some use the term “astigmatism” to refer to any focus that is SA is strongly pupil dependent, because the position of best focus
not stigmatic, but the word astigmatism also has several other more spe- changes with pupil size. In positive SA, myopia increases as the pupil
cific meanings. To avoid confusion in this chapter, “nonstigmatic” refers enlarges, which explains the uncommon clinical condition known as night
to any focus that is not stigmatic. The term astigmatism is reserved for myopia. In patients with a large amount of positive SA the increase in
regular astigmatism or astigmatism of oblique incidence. When the focus myopia under low light conditions is typically about −0.50 D and produces
is nonstigmatic, rays do not converge to a perfect point even at the best symptoms of blurred vision and halos. The condition can be treated by a
possible focus. As in defocus, aberrations can still exist even when the second pair of spectacles or clip-ons with an extra −0.50 D over the daytime
image is stigmatic. If rays converge to a perfect point but the image point correction for night use.
is not at the position predicted by the vergence equation, then an aberra- SA can be reduced by aspherical refracting surfaces that flatten periph- 69
tion is present. erally, which is typical of most corneas. Indeed, the cornea can flatten so
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Fig. 2.6.6 Coma Spot
2 SPHERICAL ABERRATION COMA SPOT DIAGRAM Diagram. Coma causes

light from a single object
point to flare out in
the image giving the
best focus
appearance of a comet’s
tail.
paraxial (ideal)
focus
Fig. 2.6.4 Positive Spherical Aberration. Central rays (red) focus at the paraxial
(ideal) image point but peripheral rays focus anteriorly. The more peripheral the
ray, the more anterior its focus. In negative spherical aberration peripheral rays
focus posterior to the ideal image point. Notice that spherical aberration shifts the
position of the best focus.
COMA DISTORTION
Fig. 2.6.5 Coma. When rays are incident on a lens at an angle the focus flares out in Fig. 2.6.7 Distortion. The original object consists of straight lines (left). Barrel
a pattern suggestive of a comet’s tail. distortion (middle) causes the lines to curve outward. Pincushion distortion (right)
causes the lines to curve inward.
much that it overcompensates, producing negative SA. Theoretically, large

amounts of negative SA would cause a hyperopic shift in low light condi- Clinically, coma rarely produces recognizable symptoms. However,
tions, but this is rarely if ever seen clinically. The Stiles–Crawford effect15 coma can be symptomatic if there is a large amount present, which can
(see later) also reduces the effect of SA on vision. The fact that refractive occur (along with other higher-order aberrations) in off-axis keratorefrac-
error usually does not fluctuate with pupil size in most eyes suggests that tive surgery, dislocated or tilted crystalline lens or implant, or when the
SA is adequately compensated over the typical range of pupil sizes. corneal vertex of a full-thickness graft is displaced by an unusual amount.21
It has been claimed that the crystalline lens compensates for corneal
SA, and when the crystalline lens is removed, it should be replaced by an
SA-compensating implant. However, studies that have measured SA in the
DISTORTION
cornea and crystalline lens separately have not found any tendency for the Ideally, the image is geometrically similar to the object, which is to say
crystalline lens to compensate for corneal SA.16 Also, corneal SA varies that the image is a scale model of the object with all image distances pro-
from person to person,17 so an implant that corrects a fixed amount of SA portional to corresponding object distances. Distortion is absent when the
is unlikely to benefit all patients. The patient’s corneal SA should be mea- transverse magnification is constant over the entire image plane.
sured preoperatively to properly compensate corneal SA with an implant, In pincushion distortion the transverse magnification increases as
and an implant should be selected not only by its power but also by the distance from the optical axis increases (Fig. 2.6.7). In barrel distortion
amount of SA corrected, which is not current clinical practice.18 Raytracing magnification decreases as distance from the axis increases. Distortion is
data on model eyes show that the amount of SA corrected by an implant similar to defocus in that rays still focus stigmatically but in the wrong
varies substantially if the anterior chamber depth changes by tenths of mil- place. In defocus, rays focus stigmatically but in front or behind the ideal
limeters or if the implant is tilted or decentered.19 Refractive error rarely image point. In distortion, rays also focus stigmatically and in the same
fluctuates with pupil size,l suggesting SA is not a problem in patients with plane as the ideal image but too far (or too close) to the optical axis.
conventional implants. SA increases depth of focus, so reducing it is not Pincushion distortion occurs in practically all spectacle-corrected,
always desirable. aphakic patients22 and is occasionally seen in high myopes after clear lens
extraction. Originally, one of the major reasons for the use of intraocular
COMA lens implants was to overcome the distortion suffered by spectacle-corrected
aphakes. Once common, distortion is now rare since the introduction of
Coma causes a pencil of rays to “flare out” from the image point in a intraocular lenses, although there has been a minor resurgence in patients
fashion reminiscent of a comet’s tail (Figs. 2.6.5 and 2.6.6). The shape of undergoing clear lens extraction.
the wave aberration resembles a lounge chair.
Coma is increased when multiple optical elements do not share the
same optical axis. Howland showed that after best spectacle correction,
FIELD CURVATURE (FC)
coma accounts for most of the residual aberration in otherwise normal Ideally a flat object perpendicular to the optical axis is imaged as a flat
70 eyes,20 which is not surprising because none of the ocular media share a object perpendicular to the axis. When field curvature is present, the object
common axis. is imaged onto a curved surface (as in an IMAX theater). Field curvature
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does not become significant until the image is outside the fovea, where (Fig. 2.6.9). Although the chromatic aberration of the eye is significant,
retinal acuity is too low to detect the blurring produced by this aberration. color effects are rarely noticeable because of visual processing. Occasion-
ally patients notice colored fringes around the edges of objects or letters 2.6
OBLIQUE ASTIGMATISM (OA) when reading; these are usually produced by spectacle lenses made from
highly dispersive materials. The problem generally is transient, but if

Oblique astigmatism is not to be confused with regular astigmatism. Seidel not, can be overcome by using lenses fabricated from less dispersive (i.e.,
only considered rotationally symmetrical optical systems, which excludes higher Abbe number) materials.
regular astigmatism. Like field curvature, oblique astigmatism does not
become significant until the image is outside the fovea where retinal acuity
is too low to detect the blurring produced by this aberration.
MEASUREMENT OF OCULAR ABERRATIONS
In 1896 Tscherning was the first to observe irregular astigmatism (in his
HIGHER-ORDER ABERRATIONS (HOA) own eyes).23 A small, distant source is viewed through a grid of pinhole
apertures placed in front of an eye that is or has been rendered myopic
When the importance of aberration theory began to be appreciated, it was (perhaps by fogging with, for example, +5.00 D lens). The grid divides the
initially thought that understanding in detail the unique characteristics of light into parallel pencils that focus in front of the retina then diverge,
many individual aberrations would be helpful. Theoretically, an infinite forming a pattern on the retina that is essentially the physical embodi-
number of aberrations exist, so how many aberrations do clinicians really ment of a spot diagram. The grid will not be regularly spaced if aberra-
need to understand thoroughly? tions (other than defocus) are present. If one draws the appearance of the
Lens designers have found empirically that 36 aberrations adequately grid, ocular aberrations can be estimated. Readers can easily reproduce
describe the imaging properties of even very complex optical systems. The this experiment for themselves just as Tscherning did.
number of aberrations required for clinical purposes is uncertain but is As a method for measuring aberrations, the Tscherning aberrometer
probably much less. However, lacking clear evidence to the contrary, many suffers from the obvious limitation that it is subjective, relying on the
authors have adopted the use 36 polynomials based on engineering, not patient’s ability to observe and accurately locate the displaced pencils.
clinical experience. Nonetheless, it is a useful conceptual tool. The subjective limitations of
The order of an aberration is defined rigorously later, but basically an Tscherning’s approach can be overcome by photographing the grid on the
order is a family of aberrations. The clinical triad of myopia, hyperopia, retina. However, photography introduces another problem—double pass.
and regular astigmatism all belong to the family of second order wave To be photographed, each grid spot on the retina acts as a light source,
aberrations. The five Seidel aberrations (coma, SA, FC, distortion, OA) are which passes through the eye, suffering its aberrations a second time. The
all fourth order aberrations. As the order increases so does the number of second pass complicates the analysis of aberrations, although the Alle-
aberrations belonging to the order. gretto Wave Analyzer is based on this approach.24
It now appears that besides a general familiarity with aberration theory, There are several ways to overcome the double pass problem. One
a thorough understanding of just a few specific aberrations is sufficient. In approach is to focus a laser (at low power of course) on the retina.25 Since
addition to defocus and regular astigmatism, the Seidel aberrations of SA the laser traverses only a small amount of the pupil, it is essentially unaf-
and coma and perhaps a few others in specific cases are all that need to be fected by ocular aberrations; practically speaking, this is a single pass
understood in depth. technique. The small area of laser illuminated retina becomes a source
The situation has returned somewhat, but not completely, to the idea of from which light emerges from the eye. If the eye is aberration-free, the
lumping many aberrations into a single category. Whereas irregular astig- emerging light will have planar wavefronts, otherwise aberrations distort
matism refers to any aberration higher than second order, “higher-order the wavefront shape.
aberrations” generally refers to sixth order and above and thus excludes Using an approach suggested by Shack, the wavefront is sampled using
the Seidel aberrations. a lenslet array that focuses small areas of the wavefront onto a detector.
In any case, it is clear that typically coma and SA account for most of the Each lenslet produces a small dot image on the detector that is displaced
eye’s irregular astigmatism, with only small amounts of other aberrations depending on the wavefront’s shape. The full wavefront is reconstructed
contributing to the total irregular astigmatism. Higher-order aberrations from the displaced position of dots. The Hartman–Shack, as it is called
may be increased in pathological cases or after some refractive procedures, today, is probably the most reliable way of measuring small amounts
particularly keratorefractive surgery. of higher-order aberration in an otherwise well-corrected eye or optical
system. The technique is not as well suited to the measurement of large
CHROMATIC ABERRATION amounts of low-order aberrations.26 Recent modifications of the technique
improve the performance for low-order aberrations. Many aberrometers
Wave aberration theory usually adopts the simplifying assumption that the utilize some variation of the Hartmann–Shack approach.
light traversing the optical system is monochromatic. However, chromatic Automated retinoscopy is another means of measuring aberrations and
aberration has a significant effect on the image. is incorporated into the ARK 10000 (Nidek). The Tracey uses the Tschern-
Longitudinal chromatic aberration (LCA) is the difference in image ing approach but performs it sequentially by scanning a single laser beam
location between short and long wavelength light measured along the over the pupil and observing the beam’s deviation on the pupil.27 Besides
optical axis (Fig. 2.6.8). LCA is the basis for the duochrome test. The green being essentially a double pass system, movements during data acquisition
half of the chart focuses anterior to the red half, and the power of the cor- are a potential problem.
recting sphere is adjusted until both sides appear equally sharp. In most It is important to realize that just because an instrument claims to
cases there is about 0.50 D of separation between the two images. measure aberrations does not mean it actually does so. It is very difficult
Transverse chromatic aberration (TCA) is the difference in image loca- to verify the accuracy of an aberrometer. Ocular aberrations, especially
tion between short and long wavelength light measured in the image plane higher-order aberrations, change with the slightest change in tear film
LONGITUDINAL CHROMATIC ABERRATION

TRANSVERSE CHROMATIC ABERRATION (TCA)
TCA
Fig. 2.6.8 Longitudinal Chromatic Aberration. The image formed by short

wavelength light is anterior to the image formed by longer wavelengths. This is the Fig. 2.6.9 Transverse Chromatic Aberration (TCA). Highly dispersive materials 71
basis for the duochrome test used in subjective refraction. may produce colored fringes at the image.
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thickness, or changes in choroidal thickness that occur during the cardiac Infinitely, many Zernike polynomials exist, but as a rule, the higher
2 cycle, accommodation, hippus, ocular movement, head movement, or fix-

ation change. The active optics photographic system that captures high
resolution fundus images requires a bite bar for adequate head stabiliza-
the order of an aberration, the less it contributes to the total aberration.
Usually there is no need to consider aberrations higher than a certain
order. How many orders of Zernike polynomials must be calculated to
tion,28 which no clinical aberrometer utilizes. Too often reproducibility is obtain a reasonably accurate description of an optical system’s aberrations?
considered indicative of accuracy, but a stopped watch gives highly repro- There is no definite answer, but lens designers have found empirically that
ducible yet useless results. Accuracy cannot be inferred simply because a 36 Zernike polynomials are sufficient for most purposes. Consequently,
device gives reproducible results. Given the number of factors that affect clinical aberrometers usually calculate 36 Zernike polynomials, but this
ocular aberrations, an instrument that gives highly reproducible results, is probably excessive. Lens designers usually deal with optical systems far
especially for higher-order aberrations, is suspect. Keep in mind that with more complicated than the eye. It is likely that far fewer aberrations are
all the advances in the clinical measurement of aberrations, there is still required for clinical work, although the precise number is not known, and
no objective measurement of hyperopia, myopia, or regular astigmatism currently no standard exists.
that is consistently superior to subjective refraction. If low-order aberra-
tions cannot be measured satisfactorily by objective methods, good reason
exists to suspect that objective measurements of higher-order aberrations AN OVERALL PERSPECTIVE ON
are somewhat inaccurate.
Regardless of the method used, all clinical measurements produce a
ABERRATION THEORY
set of discrete data points. The wavefront’s shape between data points With the emergence of keratorefractive surgery came the possibility of
is not known. Mathematics, no matter how sophisticated, cannot create correcting aberrations uncorrectable by spectacles. Initially some overly
information beyond that present in the data. To summarize, the mathe- optimistic claims were made, including the possibility of achieving 20/6
matical techniques do not find the actual wavefront, only the most likely acuity.30 These claims were based on an incomplete understanding of aber-
wavefront given the data values, regardless of how the data were acquired ration theory as well as other optical and nonoptical factors limiting acuity.
(e.g., Hartman–Shack, Tscherning). More data points, provided they are It is impossible to correct all aberrations by sculpting a single surface.
accurately measured, and the more Zernike polynomials considered, the Lens designers have known for centuries that correcting multiple aberra-
more likely the computed wavefront is a reasonable representation of the tions requires multiple lenses. For this reason, high-quality optical systems
actual wavefront. corrected for many aberrations contain multiple lenses. At best, shaping
just the anterior corneal surface can correct defocus, regular astigmatism,
Mathematical Considerations and SA. Correcting coma by keratorefractive surgery would probably be
unwise even if it were possible, because coma is the result of misalign-
There is no need to be intimidated by the mathematical aspects of aber- ment between cornea and lens. The misalignment changes with age and
ration theory. Just as a spectacle lens is a combination of spherical and following cataract surgery and could leave pseudophakic patients worse off.
cylindrical contributions, total aberration is the combination of individual Wave aberration data measures the entire eye, but keratorefractive
aberrations. The only difference is that in aberration theory several more surgery alters only the anterior corneal surface. Wavefront guided abla-
individual aberrations occur, and they are less familiar to clinicians. tion attempts to improve outcomes by combining aberration data with
An individual aberration can be specified by a graph or its associated corneal topography to improve visual results. However, corneal topography
formula. As noted, when displayed graphically, the optical axis is rotated data has an accuracy of only ±5 µm, whereas the wavefront optimization
90° from horizontal to vertical. Zernike polynomials are the formulas rep- requires accuracy better than 1 µm. It appears that at this time corneal
resenting each individual graph. topography data is not sufficiently accurate to reap the theoretical benefits
Every Zernike polynomial has the same structure consisting of a coeffi- of wavefront guidance. Wavefront optimized ablation does not incorporate
cient that specifies the amount of the aberration (analogous to power, but patient-specific data but simply flattens the ablation profile peripherally to
in units of distance, not diopters), a radial polynomial, and usually a sine reduce SA. As noted, corneal SA is patient specific, so results will vary.
or cosine function. For instance, Altering the shape of just the anterior corneal surface cannot, correct
all ocular aberrations. No matter how technically advanced keratorefractive
Secondary Astigmatism X = Z11(4 ρ 4 − 3ρ2 )Cos 2θ surgery becomes (and it still has a long way to go),31 it will not be possi-
ble to eliminate all aberrations by this method. Even if it were possible to
The coefficient’s subscripts (shown in purple) identify the individual eliminate (or reduce to insignificance) all aberrations, other factors such as
aberration, the radial polynomial is (4ρ4 − 3ρ2), is multiplied by a cosine diffraction and intraocular light scattering would limit vision.
function. The order of a Zernike polynomial is the sum of the largest expo- As noted, aberration theory is strictly limited to geometrical optics,
nent in the radial polynomial (red) and the coefficient of θ (blue). Thus completely ignoring diffraction, light scattering, and many other phenom-
secondary astigmatism is a sixth order aberration. ena that affect visual function. After the correction of defocus and RA, for
Most Zernike polynomials come in pairs. For instance there is another pupils smaller than about 2.5 mm, acuity is limited by diffraction not aber-
sixth order Zernike polynomial: rations.32 Consequently, the correction of higher-order aberrations would
not lead to further visual improvement in patients with smaller pupils.
Secondary Astigmatism Y = Z12 (4 ρ 4 − 3ρ2 )Sin 2θ Aberration theory also ignores intraocular light scattering, which can pro-
foundly affect acuity.33
Note the difference in the coefficient subscripts. The shapes of these Although incompletely understood, neural mechanisms doubtless play
polynomials are identical except rotated around the vertical axis (i.e., the an important role. It is speculative, but patients who have had uncorrected
optical axis) by 90°. aberrations their entire lives may develop a form of refractive amblyopia,
A few Zernike polynomials are symmetrical about the optical axis and so again correction of irregular astigmatism in adults may not improve
consequently have no trigonometric factor. For instance, fourth order vision. Visual processing can decrease the influence of some aberrations
primary spherical aberration is represented by the Zernike polynomial: but not all. The large amount of chromatic aberration present in most eyes
is largely neutralized by visual processing.
Primary Spherical Aberration = Z 08 (1 − 6 ρ2 + 6 ρ 4 ) In most cases the rays near the edge of the pupil are the most aber-
rant, in other words, focus farthest from the ideal image point. Wavefront
Zernike polynomials have only even orders (0, 2, 4, etc.). An order is a apodization is a general term for any technique that diminishes the effect
family of aberrations. For Zernike polynomials the number of aberrations of peripheral rays on the image reducing the influence of aberrations. For
within an order is always one more than the order itself. Thus there is example, rays striking the retina parallel to the photoreceptor outer seg-
one 0th order aberration, three 2nd order aberrations, five 4th order aber- ments produce more of a response than oblique incident rays (the Stiles–
rations, and so forth. The variables ρ and θ identify the position of a ray Crawford effect).34 The Stiles–Crawford effect mitigates the influence SA
in the exit pupil, but it is important to understand the overall concepts and many higher-order aberrations.
without dwelling on mathematical detail. For various reasons, apodization also can diminish image quality. Apo-
A Zernike polynomial calculator is available on the Internet.29 Users dization is helpful provided the improvement in image quality gained by
choose the amount of each individual Zernike aberration and the total decreasing the influence of aberrations exceeds the loss of image quality
72 aberration is calculated and displayed, which is a useful tool for those who produced by the apodization itself. Given the natural retinal apodiza-
wish to explore aberration theory in greater detail. tion, the advantages of wavefront apodized IOLs may not be significant
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or even beneficial. Keratorefractive surgery often increases HOA. The Carroll J, Neitz M, Hofer H, et al. Functional photoreceptor loss revealed with adaptive
optics: an alternate cause of color blindness. Proc Natl Acad Sci USA 2004;101:8461–6.
Stiles–Crawford effect may to some extent reduce the effect of HOA on
vision-improving refractive outcomes.
Guirao A, Miller DT, Williams DR, et al. Ocular aberrations and their measurement. Adap-
tive Opt Vis Sci Astron 1995;7:75–92.
2.6
Clinicians should be aware that irregular astigmatism is not uncom- Hopkins HH. Wave theory of aberrations. Oxford: Clarendon Press; 1950.
mon but actually ubiquitous. All eyes have a large amount of uncorrected Howland HC. The history and methods of ophthalmic wavefront sensing. J Refract Surg

chromatic aberration. Considering only monochromatic aberrations, after 2000;16:S552–3.
http://wyant.optics.arizona.edu/zernikes/zernikes.htm. Accessed June 16, 2017.
correction of sphere and cylinder, almost all eyes will have some residual Kingslake R. History of the photographic lens. New York: Academic Press; 1991.
uncorrected irregular astigmatism. In most cases, coma is the dominant Lipshitz I. Thirty-four challenges to meet before excimer laser technology can achieve super
uncorrected aberration followed by SA to a lesser extent. vision. J Refract Surg 2002;18:740–3.
Aberration theory and wavefront methods were developed in the hope Millodot M, Sivak J. Contribution of the cornea and lens to the spherical aberration of the
eye. Vision Res 1979;19:685–7.
of improving the visual outcomes of keratorefractive surgery by correct- Oshika T, Klyce SD, Applegate RA, et al. Comparison of corneal wavefront aberrations
ing higher-order aberrations. Ironically, wavefront measurements have after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol
shown that more often than not keratorefractive surgery introduces more 1999;127:1–7.
higher-order aberration than it corrects.35–37 Shack RV, Platt BC. Production and use of a lenticular Hartmann screen. J Opt Soc Am
1971;61:656–60.
Tasman W, Jaeger EA, editors. Clinical ophthalmology: glare and contrast sensitivity testing.
New York: Lippincott, Williams, & Wilkins; 2006.
Welford WT. Aberrations of optical systems. New York: Adam Hilger; 1997.
KEY REFERENCES Westheimer G. Directional sensitivity of the retina: 75 year of Stiles-Crawford effect. Proc
Biol Sci 2008;275:2777–86.
Applegate RA, Howland HC. Refractive surgery, optical aberrations, and visual performance.
J Refract Surg 1997;13:295–9.
Brint SF. Higher order aberrations after LASIK for myopia with alcon and wavelight lasers: Access the complete reference list online at ExpertConsult.com
a prospective randomized trial. J Refract Surg 2005;21:S799–803.
73
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aberrations of human eyes as a function of accommodation by the Howland aberroscope
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defects of vision connected with it. London: J. Churchill; 1854. formance of aspheric intraocular lenses in a model eye. J Cataract Refract Surg
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3. Kingslake R. History of the photographic lens. New York: Academic Press; 1991.
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9. Hopkins HH. Wave theory of aberrations. Oxford: Clarendon Press; 1950. 27. Rozema JJ, Van Dyke DE, Tassignon MJ. Clinical comparison of 6 aberrometers. Part 2:
10. Conrady AE. Applied optics and optical design, vol. 1. New York: Dover; 1957. statistical comparison in a test group. J Cataract Refract Surg 2006;32:33–44.
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14. Kingslake R, Johnson RB. Lens design fundamentals. 2nd ed. London: Elsevier Science; 31. Lipshitz I. Thirty-four challenges to meet before excimer laser technology can achieve
2009. super vision. J Refract Surg 2002;18:740–3.
15. Welford WT. Useful optics. Chicago: University of Chicago; 1991. 32. Wyant JC, Creath K. Basic wave aberration theory for optical metrology. Appl Optics Opt
16. Millodot M, Sivak J. Contribution of the cornea and lens to the spherical aberration of the Eng 1991;30:27–40.
eye. Vision Res 1979;19:685–7. 33. Tasman W, Jaeger EA, editors. Clinical ophthalmology: glare and contrast sensitivity
17. Howland B, Howland HC. A subjective method for the measurement of monochromatic testing. New York: Lippincott, Williams, & Wilkins; 2006.
aberrations of the eye. J Opt Soc Am 1977;67:1508–17. 34. Westheimer G. Directional sensitivity of the retina: 75 year of Stiles-Crawford effect. Proc
18. Scholz K, Eppig T, Messner A, et al. Topography-based assessment of anterior corneal Biol Sci 2008;275:2777–86.
curvature and asphericity as a function of age, gender, and refractive status. J Cataract 35. Brint SF. Higher order aberrations after LASIK for myopia with alcon and wavelight
Refract Surg 2009;35:1046–54. lasers: a prospective randomized trial. J Refract Surg 2005;21:S799–803.
19. Eppig T, Scholz K, Loffler A, et al. Effect of tilt and decentration on the optical per- 36. Applegate RA, Howland HC. Refractive surgery, optical aberrations, and visual perfor-
formance of aspheric intraocular lenses in a model eye. J Cataract Refract Surg mance. J Refract Surg 1997;13:295–9.
2009;35:1091–100. 37. Oshika T, Klyce SD, Applegate RA, et al. Comparison of corneal wavefront aberrations
20. Howland B, Howland HC. Subjective measurement of high-order aberrations of the eye. after photorefractive keratectomy and laser in situ keratomileusis. Am J Ophthalmol
Science 1976;193:580–2. 1999;127:1–7.
73.e1
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Part 3 Refractive Surgery

Current Concepts, Classification, and

History of Refractive Surgery 3.1
Suphi Taneri, Tatsuya Mimura, Dimitri T. Azar
Definition: Refractive surgery is the surgical correction of refractive MYOPIC PHOTOREFRACTIVE KERATECTOMY
errors of the eye such as myopia, hyperopia, astigmatism, and
presbyopia.
Key Features
• Established subspecialty of ophthalmology.
• Growing variety of well-established procedures.
• Adequate understanding of potential surgical complications,
limitations, and alternatives.
• Blurring boundary with cataract surgery.
Associated Features
• Alterations in optical aberrations after surgery.
• Mean uncorrected visual quality after modern procedures similar to
preoperative spectacle correction.
INTRODUCTION
Refractive surgery is one of the most rapidly evolving fields in ophthal-
mology. The introduction of the excimer laser, for example, has replaced
corneal incisions for routine cases in a very short time. Additionally, over Fig. 3.1.1 Photorefractive Keratectomy (PRK). After removal of the corneal
epithelium, the excimer laser is used to reprofile the anterior curvature of the
the past decade the femtosecond laser for laser-assisted in situ keratomile-
cornea, which changes its refractive power.
usis (LASIK) has added to the ease, safety, and efficacy of refractive proce-
dures. Today, the femtosecond laser also is used for:
• Incisional refractive surgery. improved clinical outcomes.4 The advent of wavefront measurement tech-
• Corneal tunnels or pockets for the insertion of ring segments or
nology also enabled the quantification of ocular aberrations.5
disc-shaped implants into the stroma.
• Lamellar or penetrating corneal transplantations.
• Removal of corneal stromal lenticule to change the refraction of the eye Laser Ablation Profiles
small incision lenticule extraction (SMILE).
The excimer laser can be used to flatten or steepen differentially the
• (Refractive) lens exchange surgery. corneal meridians and hence to treat compound myopic and compound
Many new approaches to correct presbyopia have been introduced in hyperopic astigmatism. Mixed astigmatism can be treated by flattening the
the last couple of years, including laser ablation profiles and intracorneal refractively more powerful meridian or by steepening the weaker one.
and intraocular implants. The greatest paradigm shift may have been the There are currently several ablation profiles available for laser vision
Nobel prize–winning method for adjusting the refractive power of an intra- correction. Challenging cases include high and mixed astigmatism, higher
ocular lens (IOL) after implantation into the eye by targeted radiation with degrees of defocus, large pupil size, higher amounts of higher-order
UV light. Corneal cross-linking for the treatment of keratoconus is now a aberration (HOA) or specifically spherical aberrations, thin corneas, pre-
Food and Drug Administration (FDA)–approved treatment that also may existing corneal opacification, or night driving problems. Assessment and
have some potential as a refractive procedure. treatment of an eye may be complicated by previous corneal or lenticular
In this chapter, we discuss excimer laser and ablation profiles; the clas- surgery leading to false measurements or an unpredicted response to the
sification of the different refractive surgery procedures, their utilization, ablation. Moreover, a refractive procedure may have therapeutic aspects in
advantages, and limitations; and briefly describe new procedures. recurrent erosion syndrome.
Existing laser ablation profiles include6:
EXCIMER LASER AND ABLATION PROFILES • Munnerlyn’s formula.7
Excimer laser corneal surgery was introduced as a precise tool for linear
• Wavefront-guided ablation.
keratectomies by Trokel et al.1 in 1983 but was later used for corneal repro-
• Wavefront-optimized or aspherical or Q factor–adjusted laser profile.
filing or photorefractive keratectomy (PRK) in 1988.2 The ultraviolet laser
• Topography-guided ablation.
(193 nm excimer or 213 nm solid state) allows the anterior corneal surface
• Presbyopia correcting profiles.
to be reshaped precisely to change its radius of curvature3 (Fig. 3.1.1). In addition, combinations of these existing variants have been intro-
Numerous technological developments—such as flying-spot lasers, duced recently, and even more are announced for the future (for example, 75
eye trackers, and use of femtosecond lasers for flap preparation—have ray-tracing optimized ablations).8 Ablation profiles in corneal laser surgery
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can be divided into those based on the total optical system and those based In theory, the higher the amount of HOA, the greater the benefit of
3 on the cornea.9 performing a wavefront-guided ablation. However, wavefront-sensing may

be negatively affected by the use of mydriatic eyedrops.11 Furthermore,
new HOA are induced by the laser treatment itself even if the radial loss
Munnerlyn’s Formula of efficacy is compensated by less than perfect alignment of the ablation
Refractive Surgery
The classic ablation profile for the correction of myopia and myopic astig- pattern on the cornea12 and less than perfect eye-tracking,13 including cyclo-
matism is based on Munnerlyn’s formula,7 which removes a convex– torsional movements14 before and during ablation. In addition, aberrations
concave lenticule of corneal tissue with spherocylindrical surfaces to are induced when a LASIK flap is created.
remodel the corneal curvature. The laser profile is based only on subjec- Lenticular aberrations increase with age, whereas corneal aberrations
tive and objective measurements of refraction. It does not take spheri- remain fairly stable throughout our lives in the absence of anterior corneal
cal aberrations into account, which may lead to an increase of spherical disease or dry eye.
aberration, resulting in an oblate cornea. Munnerlyn’s formula does not
compensate for the loss of fluence in the periphery of the ablation zone, Topography-Guided Ablation
which occurs because the energy of a laser pulse is spread out over a larger
area (i.e., an oval rather than a circle), nor the increased reflectance of the Based on topography measurements by different topographers, includ-
laser beam due to an oblique angle of incidence when the laser is not ing the Orbscan IIz (Fig. 3.1.3), the Pentacam (Fig. 3.1.4), and others, the
targeting the corneal apex.10 Moreover, the reduction in tissue removal elevation profile of the anterior corneal surface is calculated. The desired
is greater than the reduction in fluence. These three laser-related factors corneal surface is determined with the goal of correcting the refractive
together with different biomechanical and wound-healing responses in the error and HOA induced at the cornea. The difference between the preexist-
periphery are now compensated for by algorithms proprietary to the laser ing surface and the desired surface is used to calculate the ablation profile.
manufacturer. Because of the calculated wavefront component of the cornea in this laser
profile, the term corneal wavefront ablation is sometimes imprecisely used.
Wavefront-Guided Ablation Topography-guided ablations have their greatest theoretical superiority
in cases in which the problem is clearly located in the anterior cornea,
The principles of wavefront deformation measurements are discussed in like consequences of earlier surgery.15,16 Examples include decentered laser
greater detail in Chapter 3.6. In a perfect optical system, all the refracted ablations,17 corneal grafts,15 and corneal scars.18 The reason is that a corneal
rays are focused on a single plane (wavefront). Optical aberrations induce topographer has a much higher resolution than wavefront sensors. A
deformations on this plane and can be quantified. They represent the corneal topographer may evaluate the whole cornea, whereas ocular aber-
optical performance of the entire visual system, not only the anterior ration measurements are only possible over the entrance pupil. Finally,
surface of the cornea, as in corneal topography. The lower-order optical a topographer directly evaluates the surface on which there are imper-
aberrations (sphere and astigmatism) can be corrected with spherocylin- fections. Topography-guided ablations that were combined with collagen
drical glasses. The HOA (including spherical aberration and coma) cor- cross-linking were introduced in the treatment of keratoconus19 or forme
respond to what is clinically known as irregular astigmatism (Fig. 3.1.2). fruste keratoconus.20
Fig. 3.1.2 Wavefront Measurements Over a Pupil Size

of More Than 6 mm in a Myopic Astigmatic Eye.
76
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Fig. 3.1.3 Orbscan Examination. Including anterior and
posterior float, corneal topography, and pachymetry
preoperatively in a 30-year-old patient. 3.1
Current Concepts, Classification, and History of Refractive Surgery

CONCEPTS IN DEVELOPMENT
An online pachymetry-guided ablation could aid in removing the anterior
portion of the cornea without perforating Descemet’s layer before a lamel-
lar graft is transplanted.
In routine laser vision correction, the combination of existing prin-
ciples will bring even better outcomes than we are used to today. Such
a combination of a wavefront-guided ablation with an aspherical profile
according to the cornea’s preoperative asphericity has delivered excel-
lent results in our hands.33 Optical ray-tracing algorithms, on the other
hand, may allow the highest degree of customization. The idea behind ray
tracing is that no single measurement of an eye can provide all the data
required to achieve utmost individualization of the ablation. Therefore the
information of several types of measurements such as ocular wavefront,
corneal topography including the topography of the cornea’s back surface,
corneal thickness, anterior chamber depth, lens thickness, and axial
length may be considered. The systematic induction of HOA by means of
wavefront-guided treatments may be overcome by such a method.8
Fig. 3.1.4 Pentacam Examination of a Keratoconic Eye Showing Inferno-Nasal

Steepening and Central Thinning of the Cornea.
CLASSIFICATION OF REFRACTIVE PROCEDURES
The refractive power of an optical system, such as the eye, can be modified
by changing the curvature of the refractive surfaces, the index of refraction
Wavefront-Optimized21/Aspherical22/ of the different media, or the relative location of the different elements of
Q-Factor-Adjusted23–25 Laser Profiles the system.
Several classifications of keratorefractive surgery have been proposed
The term wavefront-optimized refers to laser treatment software that has based on the mechanisms of action of the surgery34 or on the type of
been designed with certain corrections preprogrammed, although a true surgery.35 A simplified classification in which the site of action of the
and customized wavefront plan is not employed. Spherical aberrations surgery on the cornea—either over the optical zone or peripheral to it—
are the most disturbing optical imperfections after the lower-order terms is matched against the four different mechanisms of action of corneal
sphere and cylinder. Because standard spherocylindrical excimer ablations surgery: addition, subtraction, relaxation, and coagulation–compression.
induce positive spherical aberrations,26,27 wavefront-optimized laser pro- The procedures that act on the optical zone are further subdivided into
files have been developed to preserve the eye’s pre-existing optical aberra- superficial or intrastromal (Table 3.1.1). In addition to keratorefractive
tions without introducing new aberrations.28,29 surgery, the use of intraocular implants is the second class of procedures
The aim of preserving the natural cornea shape of each patient is propa- to modify the ocular refraction.
gated by other companies as aspherical or Q factor–adjusted ablation. This
treatment is designed to improve the eye’s optical quality by optimizing Cornea
the asphericity of the cornea. The Q-factor is a measure of the asphericity
of the cornea. In the normal population, the mean Q-factor is −0.25, which Approximately two-thirds of refraction occurs at the air–tear–corneal
indicates a slightly prolate shape. After determining the ideal asphericity interface, which generally parallels the anterior surface of the cornea.
of the cornea in a model, some researchers have suggested the optimum The cornea is readily accessible, and its curvature can be modified as an
Q-factor should be around −0.4 or −0.5.30 extraocular procedure. Most keratorefractive procedures to date modify the
radius of curvature of the anterior surface of the cornea.36
Presbyopia Correction Central Cornea
Presbyopia correction can be attempted by creating multifocal corneas31 Most procedures used to modify the corneal optical zone, or central cornea,
or hyperprolate corneas when aiming for a postoperative Q-factor close to change the relationship between its anterior and posterior surfaces; the
−1.0. Attempts to address presbyopia by corneal ablation date back to the thickness of the cornea is also modified. The central cornea may be modi- 77
last millennium.32 fied either on the surface or intrastromally.
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3
TABLE 3.1.1 Proposed Classification of Keratorefractive Surgical Procedures
Optical Zone Addition Subtraction Relaxation Coagulation–Compression
Superficial Epikeratophakia PRK, LASEK, epiLASIK, epi-Bowman keratectomy Corneal molding
Refractive Surgery
Synthetic epikeratophakia
Intrastromal Keratophakia LASIK, Femto-LASIK Lamellar keratotomy
Intracorneal lenses Keratomileusis in situ
Intracorneal transplants Keratomileusis
SMILE
Peripheral cornea Intracorneal ring segments Wedge resection Radial keratotomy Thermokeratoplasty
Hexagonal keratotomy Compression sutures
Arcuate keratotomy
LASEK, Laser subepithelial keratomileusis; LASIK, laser-assisted in situ keratomileusis; PRK, photorefractive keratectomy; SMILE, small incision lenticule extraction.
effect or focal topographical abnormalities; it peaks in humans 3–6 months

after the operation and disappears after 1 year for most patients. Many sur-
geons now use mitomycin-C prophylactically during the initial treatment
to prevent haze formation or therapeutically to remove haze.43
Laser Subepithelial Keratomileusis. LASEK involves cleaving the epi-
thelial sheet at the basement membrane or at the junction of the epithe-
lium to Bowman’s membrane with dilute alcohol, applying the laser as
in conventional PRK, and repositioning the epithelium afterward.44,45 The
first LASEK procedure was performed by Azar.46,47 The term LASEK was
coined by Massimo Camellin, who also popularized this method of surface
ablation.
EpiLASIK. EpiLASIK is an abandoned surface ablation procedure
designed to create an epithelial flap with an epikeratome that is equipped
with a blunt separator instead of a sharp blade, as in microkeratomes used
during LASIK.
Epi-Bowman Keratectomy (EBK). Epi-Bowman keratectomy was
recently introduced and does not employ a metallic blade but a soft instru-
ment to manually remove the epithelium before stromal ablation.
Corneal Stroma: Subtraction

Keratomileusis. The term keratomileusis refers to the technique of
Fig. 3.1.5 Subepithelial Haze 3 Months After LASEK in a 28-Year-Old Man.
“carving” (Greek smileusis) the cornea. Dr. José I. Barraquer first reported
clinical results with the technique in 1964.48
Corneal Surface: Addition Classic keratomileusis involves the excision of a lamellar button of par-
Epikeratophakia. Epikeratophakia (also known as epikeratoplasty and allel faces from the cornea with a microkeratome, freezing and reshaping
onlay lamellar keratoplasty) was introduced by Werblin et al.37 It involves the lamellar button, and replacing it in position with sutures. The proce-
removal of the epithelium from the central cornea and preparation of a dure was modified by Krumeich and Swinger, who reshaped the disc with
peripheral annular keratotomy. A lyophilized donor lenticule (consisting a second microkeratome pass without having to freeze it, in a procedure
of Bowman’s layer and anterior stroma) is reconstituted and sewn into the known as BKS (Barraquer–Krumeich–Swinger) keratomileusis. Ruiz and
annular keratotomy site. Rowsey49 made further modifications by applying the second microker-
Use of epikeratoplasty for the general treatment of myopia and atome pass to the stromal bed instead of the resected disc, in a proce-
hyperopia has been abandoned largely because of the potential loss of dure called in situ keratomileusis. Even though the refractive cut with the
best-corrected visual acuity due to complications like irregular astigma- microkeratome gave a disc of parallel surfaces with no optical power, a
tism, delayed visual recovery, and prolonged epithelial defects. dioptric effect was achieved because of the remodeling of corneal tissue,
Synthetic materials38 and improved means of attaching the lenticule to as described by Barraquer50 in the law of thickness. The development of
the cornea may allow epikeratoplasty to become a more useful refractive a mechanized microkeratome, or automatic corneal shaper, provided a
technique in the future. more consistent thickness and diameter of the corneal disc and improved
the predictability of the procedure. This procedure is known as automated
Corneal Surface: Subtraction lamellar keratoplasty (ALK). The fact that the corneal cap does not have
The surface ablation procedures PRK, laser subepithelial keratomileusis to be modified led to the use of a hinged flap instead of a free cap. This,
(LASEK), and epiLASIK have excellent results in terms of safety, efficacy, in turn, led to sutureless repositioning of the flap, which simplified the
and stability with low-to-moderate myopic astigmatic corrections.39 In pro- procedure further.
spective trials, no clinically significant superiority of any of these three Laser-Assisted in situ Keratomileusis. LASIK refractive correction is
methods could be established regarding epithelial closure time, pain per- the most commonly performed refractive surgery in the world today. The
ception, haze formation, safety, and efficiency.40 Epi-Bowman keratectomy early model was first performed in rabbits by Pallikaris et al.51 in a mod-
(EBK) is the latest variant of these surface ablation techniques. ification of Ruiz’s keratomileusis in situ (Fig. 3.1.6). Buratto and Ferrari52
Photorefractive Keratectomy. In PRK, the epithelium is removed by first performed this procedure in humans after inadvertently obtaining a
mechanical scraping, utilizing ethanol or with an excimer laser ablation, thin resection with the microkeratome while performing a modification of
before the stroma is ablated to correct the ametropia. The stroma is even- Barraquer’s classic keratomileusis using the excimer laser instead of the
tually covered by the epithelium, which heals from the periphery toward cryolathe to modify the corneal cap.
the center in about 4 days. After PRK, the corneal epithelium undergoes a In PRK, LASEK, and epiLASIK the laser is applied directly to Bowman’s
hyperplastic phase in which the refractive status of the eye may be mod- layer, whereas in LASIK it is applied to the midstroma after a flap has
ified.41 The deposition of new collagen and glycosaminoglycans42 by acti- been lifted from the cornea. The flap is then replaced. LASIK causes a
vated stromal keratocytes after PRK is a common phenomenon after deep minimal degree of epithelial hyperplasia (much less than PRK) that causes
ablations and in younger individuals (Fig. 3.1.5) and manifests as corneal regression of the effect.53 No visually significant haze follows uncompli-
haze or subepithelial scarring. The activation of the keratocytes seems to cated LASIK,54 but when the flap is too thin, haze may occur, suggesting
stem from interaction of epithelial cells and raw corneal stroma as the that a critical amount of unablated flap keratocytes is needed to inhibit
epithelium migrates to cover the defect or from activation of keratocytes haze formation after routine LASIK.
78 by soluble tear factors that percolate through the initial epithelial defect Femto-LASIK. Traditionally, the corneal flap cut during LASIK was
after PRK. The haze may be associated with regression of the refractive created with a microkeratome blade. In contrast, Femto-LASIK uses the
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Corneal Stroma: Addition
Lenticle removed using laser light
Keratophakia. Keratophakia is the technique by which a corneal lens
is inserted to change the shape of the cornea and modify its refractive 3.1
power.55 Traditionally, a lamellar keratectomy was performed with a micro-
keratome on the recipient’s cornea. A fresh or preserved donor cornea also

underwent a lamellar keratectomy. A stromal lens was created from the
donor cornea and placed intrastromally in the recipient. In the future, lent-
icules obtained during a SMILE procedure may be reshaped according to
the refractive needs of the recipient cornea and implanted in an intrastro-
mal interface created by a femtosecond laser.
Intracorneal Inlays. Intracorneal inlays may prove beneficial in the
treatment of various refractive errors. Barraquer, working in Bogotá,
Colombia, performed experiments with corneal implants as early as 1949.
Early inlays were composed of flint glass and Plexiglas for the correction
of aphakia and high myopia. Claes Dohlman first described the use of a
Flap repositioned permeable lenticule in 1967 in Boston. Hydrogel inlays were developed so
as not to impede metabolic gradients across the stroma, including nutrient
flow to the anterior cornea.
Today, corneal inlays mainly are designed to treat presbyopia. The
mechanisms behind the current generation of inlays can be divided into
three categories:
• Small-aperture corneal inlays that increase the depth of focus.
• Space-occupying inlays that create a hyperprolate and thus multifocal
cornea.
• Refractive annular addition lenticules that work as bifocal optical inlays
to create separate distance and near focal points.
Fig. 3.1.6 Laser-Assisted in situ Keratomileusis (LASIK). A flap with parallel sides
is lifted using the microkeratome. The excimer laser is used to remove an exactly Corneal Stroma: Relaxation
planned amount of tissue from the exposed corneal stroma. The flap, with its intact Lamellar Keratotomy (Hyperopic Automated Lamellar Keratoplasty).
epithelium, is then folded back, and as it drapes over the modified stromal surface, In deep lamellar keratotomy (hyperopic ALK), a microtome performs a
the refractive power of the anterior corneal surface is modified. The dotted area in deep keratectomy to elevate a corneal flap that is replaced without addi-
the bottom panel corresponds to the stromal tissue that was removed. No sutures tional surgery. The stromal bed then develops ectasia under the flap.
are required. Hyperopic ALK works best for low levels of hyperopia, but the predict-
ability is low, and the risk of progressive ectasia ended the use of this
procedure.
femtosecond laser, which is coupled to the patient’s eye with an interface
fixated by suction. The femtosecond laser beam separates the corneal tissue Peripheral Cornea
by causing numerous microexplosions at a preprogrammed depth and Several keratorefractive procedures are used to change the shape of the
position. The remaining tissue bridges between these cavitation bubbles central cornea through their action on the peripheral cornea. This is
are then bluntly dissected using spatula-like instruments. As no actual cut achieved without changing the thickness or the relationship between the
is performed with the femtosecond laser, in the rare event of a suction anterior and posterior surfaces over the corneal optical zone.
loss during flap preparation, a second attempt can be done immediately.
This is not possible after a suction loss of a mechanical microkeratome, Peripheral Cornea: Addition
which necessitates changing to a surface ablation or waiting for approxi- Intracorneal Rings. Krumeich56 introduced the concept of titanium
mately 3 months. This feature is a clear advantage to mechanical micro- rings to alter the corneal curvature in keratoconic eyes or in combina-
keratomes, but other flap-related complications like buttonholed flaps, flap tion with corneal transplant surgery (Fig. 3.1.8). In keratoconic eyes,
striae, flap dislocation, and keratectasia may still happen. Transient light first, a dedicated trephination system (GTS) is used to create a circular
sensitivity—a new complication seen with initial femtosecond flap makers groove in which the ring is placed and secured with a double running
that occurred in some patients and resolved spontaneously after a couple antitorque suture. The suture may be removed after completion of wound
of weeks—seems to be overcome with state-of-the-art femtosecond lasers healing. The rings may be inserted in the interface of corneal transplants.
by reducing the amount of energy delivered into the cornea. The idea was to modify corneal curvature by altering the shape of the
Intrastromal Laser Ablation. Intrastromal, solid-state, picosecond implanted ring with special instruments. However, this concept yielded
lasers are being developed that are more compact and portable than no sufficiently predictable effect, and extrusion of the rings has been
excimer lasers. Intrastromal ablation is made to flatten the central cornea, observed.
the epithelium and Bowman’s layer are spared, and thus fewer keratocyte Intracorneal Ring Segments. Intracorneal ring segments are placed in
fibroblastic responses are seen. the peripheral cornea and take advantage of the fact that the arc of the
Intrastromal Lenticule Extraction. A new procedure, small incision cornea remains constant at all times, so when the anterior surface is
lenticule extraction (SMILE), takes place entirely within the cornea and is lifted focally over the ring, a compensatory flattening of the central cornea
performed exclusively with a femtosecond laser system, that is, no excimer occurs (Fig. 3.1.9). An advantage of intracorneal segments over other
laser is needed. The SMILE procedure consists of these steps (Fig. 3.1.7): refractive surgical techniques is removability as opposed to reversibility, as
at least the tunnel preparation is permanent. The main drawbacks are the
• The femtosecond laser is used to outline a small lens-shaped segment
limited range of correction and poor predictability compared with excimer
of tissue (lenticule) within the center of the cornea and a small incision
laser ablative procedures. As a result, intracorneal ring segments today are
in the midperiphery of the cornea.
almost solely used for high cylindrical corrections in keratoconic corneas
• The lenticule is removed through this self-sealing incision and and may be combined with corneal cross-linking.
discarded.
The removal of the lenticule reduces the curvature of the cornea, Peripheral Cornea: Subtraction
thereby reducing myopia. Without a corneal flap, SMILE causes less Wedge Resection. Troutman developed the use of wedge resections and
postsurgical dry eye and may pose less risk for ectasia than LASIK. Also, resuturing in the flat meridian, often with relaxing incisions in the steep
without a corneal flap, no risk exists of flap displacement from trauma to meridian. Although the procedure effectively decreases astigmatism, clin-
the eye after surgery. SMILE has recently been approved by the FDA for ical results are highly unpredictable and it is now reserved for the cor-
the correction of myopia and myopic astigmatism and may soon become a rection of postkeratoplasty astigmatism of high degree. The use of the
popular alternative to LASIK for vision correction. However, currently it is femtosecond laser to facilitate wedge resection surgery has been shown to 79
not possible to perform SMILE for hyperopia. be effective for postkeratoplasty astigmatism.
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SMILE INSERTION OF INTRACORNEAL RING
Flap lenticle prepared using femto-laser light from eye Intracorneal ring
flattening of
Refractive Surgery
anterior lamellae
Lenticle extracted using forceps
Fig. 3.1.9 Intracorneal Ring Segments. After a peripheral circular lamellar

dissection, two polymethyl methacrylate ring segments of predetermined diameter
and thickness are inserted. The midperipheral anterior lamellae are lifted focally by
the ring segments, which results in a compensatory flattening of the central anterior
lamellae and hence a decrease in the refractive power of the central cornea.
RADIAL KERATOTOMY
Partial-thickness incisions
Cornea remodeled
incisions
Fig. 3.1.7 Small Incision Lenticule Extraction (SMILE). A femtosecond laser

fashions as an intrastromal corneal lenticule. This lenticule is extracted through
a small incision that flattens the anterior corneal surface. No flap and sutures are Compensatory flattening of the central cornea
required.
Fig. 3.1.10 Radial Keratotomy. Partial-thickness incisions result in limited ectasia of

the paracentral cornea and compensatory flattening of the central cornea.
astigmatism, and myopia. The procedure was abandoned because of the

long-term complication of bullous keratopathy secondary to endothelial
cell loss.58 Anterior RK was performed by several ophthalmologists in the
former Soviet Union in the early 1970s and was later popularized by Fyo-
dorov and Durnev.59 RK has been performed in the United States since
1978.60
The stability of refraction after RK is lower than with many other refrac-
Fig. 3.1.8 Intracorneal Titanium Ring as Devised by Krumeich.
tive surgical procedures. Therefore RK has been replaced by excimer laser
procedures.
Peripheral Cornea: Relaxation Hexagonal Keratotomy. Proposed by Gaster and Yamashita in 1983,
Radial Keratotomy. Radial keratotomy (RK) for myopia involves deep, hexagonal keratotomy, first performed in humans by Mendez in 1985, con-
radial corneal stroma incisions that weaken the paracentral and periph- sists of making circumferential, hexagonal, peripheral cuts around a clear
80 eral cornea and flatten the central cornea (Fig. 3.1.10). Sato et al.57 in Japan optical zone. It “uncouples” the central cornea from the periphery, which
used anterior and posterior corneal radial incisions to treat keratoconus, allows the cornea to bulge or steepen, thereby decreasing hyperopia. The
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procedure has been largely abandoned because of the complications of high refractive errors by clear lens extraction. Because of retinal problems
poor healing and irregular astigmatism.61
Astigmatic Keratotomy. The first modern cataract extraction through a
in high myopes, the procedure seems safer in high hyperopes73 For young
patients, one major drawback is the loss of accommodation. To date, a 3.1
corneal incision, performed by David in France in 1747, introduced oph- variety of methods to restore near vision are available after lens removal,
thalmologists to surgically induced astigmatism. Several investigators in including correction with glasses and contact lenses, monovision, scleral

the latter part of the nineteenth century, including Snellen, Schiotz, and expansion techniques, and various IOLs. However, none of them is perfect.
Bates, attempted to correct corneal astigmatism with transverse relaxing
corneal incisions. The first systematic study of the correction of astigma- Toric Intraocular Lenses
tism was performed by Lans62 in 1898. Intraocular lenses with a toric or bitoric surface with corrections of up to
Astigmatic keratotomy (AK) involves making transverse cuts in an 5 D to correct even high amounts of astigmatism are available. They have
arcuate or straight fashion perpendicular to the steep meridian of astig- demonstrated reasonable rotational stability.
matism to produce localized ectasia of the peripheral cornea and central
flattening of the incised meridian, thereby decreasing the astigmatism. Multifocal Intraocular Lenses
Although important in its time, AK is no longer used except during a Pseudoaccommodative bifocal or trifocal lenses with a refractive and/
corneal graft. or diffractive design have been in routine refractive surgical use for the
For cataract surgery, limbal-relaxing incisions have gained popularity last couple of years. For acceptable correction of presbyopia, the achieved
because they are more comfortable for the patient than are arcuate or refractive error must be negligible. However, this is often not the case
transverse midperipheral incisions, although their effect is smaller as they after lens exchange alone even with toric multifocal IOLs, and the use of
are farther away from the corneal center.63 However, today limbal-relaxing modern biometry devices, as well as sophisticated lens power calculation
incisions are inferior to the implantation of toric IOLs during cataract formulae. Then an enhancement with an excimer laser may be an option.
surgery. However, even if emmetropia is achieved, compromises in night vision,
glare, and halos remain inherent drawbacks of this approach.
Peripheral Cornea: Coagulation–Compression
Thermokeratoplasty. Radial intrastromal thermokeratoplasty shrinks Potentially Accommodative Intraocular Lenses
the peripheral and paracentral stromal collagen to produce a peripheral An alternative approach to a true accommodative IOL is to use the “focus
flattening and a central steepening of the cornea to treat hyperopia. Unable shift” principle produced by an increase in effective lens power with
to produce satisfactory results with relaxing incisions, Lans used cautery forward movement of the optic.74–76 The haptics of the accommodative IOL
to selectively steepen a corneal meridian in rabbits. It was not until 1914 fixate in the capsular bag and allow the optic to move in reaction to the
that Wray performed the procedure in humans in a case of hyperopic contraction of the ciliary muscle so that the patient can focus on nearby
astigmatism. The procedure was later modified to correct hyperopia and objects (Fig. 3.1.11). However, based on simple calculations, the forward
popularized by Fyodorov. Although an initial reduction in hyperopia was shift possible in the capsular bag on its own is not sufficient to allow for
observed, the lack of predictability and significant regression are persistent the restoration of a reasonable amount of accommodation of 2–3 D for a
problems. single optic lens.
The solid-state infrared laser holmium:yttrium–aluminum–garnet Another variant is to combine two optics that move relative to each
(Ho:YAG) laser has been used in a peripheral intrastromal radial pattern other within the capsular bag into a single IOL (Synchrony dual-optic
(laser thermokeratoplasty) to treat hyperopia of 2.50 diopters (D) and less.64 lens, Abbot Medical Optics, AMO, Santa Ana, CA). Using this intraocu-
The long-term refractive stability of Ho:YAG laser thermokeratoplasty is lar telescope effect, small excursions may allow for sufficient accommo-
poor. A handheld radiofrequency probe to shrink the peripheral collagen dative response. The FluidVision IOL (PowerVision, Belmont, CA) uses
also has been employed. liquid channels to harness the accommodative forces from the ciliary body
Microwave-Induced Thermokeratoplasty: Keraflex Procedure. During an expressed through the capsule similar to the crystalline lens. The NuLens
investigational Keraflex procedure, a microwave generator delivers a single (NuLens, Ltd., Herzliya Pituah, Israel) is a two-piece IOL that is placed
low-energy microwave pulse lasting less than 1 second. Energy is applied outside the capsular bag. With the Tetraflex lens (Lenstec, St Petersburg,
to the cornea using a dielectrically shielded microwave emitter that con-
tacts the epithelial surface. Through capacitive coupling, the single pulse
raises the temperature of the selected region of corneal stroma to approx-
imately 65°C, shrinking the collagen and forming a toroidal lesion in the
upper 150 µm of the stroma. The lesion created is intended to flatten the
central cornea to achieve myopic correction without compromising the
biomechanical integrity of the cornea.
Circular Keratorrhaphy. A suture placed in a circular fashion on the
peripheral cornea to constrict the cornea and steepen the central cornea
was first attempted by Krasnov in Russia in 1985 to treat hyperopia and
aphakia. The principal problems are the development of irregular astigma-
tism by differential tension and loss of the effect as the suture elongates
and “cheese-wires” through the tissue.
Peripheral Cornea: Oppression

Orthokeratology. Orthokeratology is used as a nonsurgical option for
the correction of myopia. An orthokeratology lens is flatter, looser, and
larger than a conventional lens. Theoretically, the lens mechanically alters
the central corneal contour over time.65,66 Because of safety concerns,
orthokeratology did not gain widespread acceptance.
Reverse-geometry lenses are fitted with a base curve flatter than the
central corneal curvature to apply pressure to a central corneal zone that
flattens during wear to reduce the myopic refractive error. The current
approach to orthokeratology using reverse-geometry lens designs results
in rapid reductions in myopic refractive error.67–71
Intraocular Lenses and Refractive Lensectomy

Refractive Lens Exchange
Extraction of the clear lens to correct high myopia was performed by
Fukala72 in Germany in 1890. The procedure was later abandoned because Fig. 3.1.11 Potentially Accommodative Intraocular Lens, “Crystalens.“ The IOL
of an unacceptably high rate of complications. With more sophisticated is fixated in the capsular bag. Forward movement or change in shape of the IOL in 81
operative techniques, recently there has been renewed interest in managing reaction to the contraction of the ciliary muscle may have an accommodative effect.
booksmedicos.org
3
Refractive Surgery
Fig. 3.1.13 Endothelial Cell Loss 4 Years After Implantation of an Iris-Claw Lens
in a 29-Year-Old Woman.
Long-term follow-up is needed for all types of phakic IOLs regarding

Fig. 3.1.12 Angle-Supported Anterior Chamber Phakic Lens (© 2017 Novartis). endothelial cell loss (Fig. 3.1.13), glaucoma, iris abnormalities, and cataract
formation.
FL) the rationale is that accommodation results from an increase in HOA Add-on Intraocular Lenses in Pseudophakic Eyes
caused by deformation of the IOL through ciliary muscle contraction and/ In contrast to obsolete “piggyback” procedures in which two IOLs were
or increased vitreous pressure analogous to the natural lens. However, no implanted in the capsular bag, the “add-on” concept involves placement
long-term data are available yet for any of these potentially accommodating of an additional IOL in the sulcus ciliaris after routine implantation of
IOLs. another lens into the capsular bag. The first “add-on” lens (HumanOp-
tics, Germany) was first implanted in 2000. An add-on IOL can be per-
Light-Adjustable Intraocular Lenses formed immediately following cataract surgery in a single session or years
The Light Adjustable Lens (LAL, Calhoun Vision, Pasadena, CA) utilizes later. Its indications include correction of residual ametropia after cataract
a Nobel prize–winning technology that allows it to change its refractive surgery (spherical and/or cylindrical) and the treatment of pseudophakic
power after implantation in the eye. The LAL has properties similar to presbyopia. This method avoids the risk and hazards of IOL explantation
standard monofocal IOLs, but it differs with the special macromers incor- from the capsular bag. The exchangeability of the additional IOL may be
porated in the makeup of the lens. These macromers are sensitive to light advantageous in cases with expected change of refraction as in kerato-
of a certain wavelength. When irradiated by such light, the macromers are plasty patients, in pediatric patients after cataract surgery, and for refractive
photopolymerized. power compensation in vitrectomized eyes filled with silicone oil.
After LAL implantation using a standard cataract surgery technique,
allowing 2–3 weeks for corneal incisions to heal and refraction to stabilize, New or Alternative Approaches
the lens in the eye will be irradiated for approximately 2 minutes with a
digital light delivery device specially designed to deliver the exact dose and Photorefractive Intrastromal Cross-Linking (PiXL)
profile of light onto the lens. This light exposure is limited to certain por- Corneal collagen cross-linking, recently FDA approved to halt progres-
tions of the lens and lets the macromers form an interpenetrating network sive ectatic disorders, uses UV light and a photosensitizer (riboflavin) to
via photopolymerization. Over the next 1–2 days, unreacted macromers strengthen chemical bonds in the cornea. A mild flattening of the corneal
from the nonexposed areas physically migrate to the irradiated areas, thus curvature and a tendency toward centration of the apex are observed. Clin-
re-establishing a chemical equilibrium. This physical diffusion causes the ical studies in low myopic eyes have shown promising early results.
irradiated parts to swell and change their curvature, which results in a
change of refractive power. Myopia, hyperopia, and astigmatism may be LASIK Extra
corrected by customized irradiation patterns. Even multifocal treatments The most common form of ectasia is naturally occurring keratoconus.
or the induction of positive or negative asphericity are thus possible. Once However, corneal ectasia is also feared as a rare but potentially devas-
the targeted power adjustment is achieved, the entire lens is irradiated to tating complication after laser vision correction such as LASIK. Corneal
polymerize the remaining unreacted macromers. cross-linking has been reported to be beneficial for this condition. Recently
it was proposed to prophylactically apply corneal cross-linking immediately
Phakic Intraocular Lenses following LASIK.
In the 1950s, the use of phakic IOLs was attempted first by Strampelli
and Barraquer but abandoned at that time because of multiple compli- Prophylactic
cations. Improvements in IOLs have renewed interest in the procedure. In the future, it may be possible to prevent the development of corneal
The iris-claw lens originally devised by Worst for the correction of aphakia astigmatism or corneal ametropia by cross-linking, even when performed
was later modified by Fechner et al.77 to correct high myopia in phakic on nonectatic corneas with different parameters than used today for ectatic
patients. It is enclaved in the midperipheral, less mobile iris and presently diseases.
requires a 6.0-mm incision for its insertion. The angle-supported phakic
IOL was introduced by Baikoff and Joly78 for the correction of myopia and IntraCor
has gone through several modifications (Fig. 3.1.12). Long-term follow-up IntraCor was a minimally invasive femtosecond laser procedure for the
has reported progressive pupil ovalization with an older model.79 treatment of presbyopia. The laser formed a series of concentric rings
The posterior chamber phakic IOL was introduced by Fyodorov et al.80 within the stroma, which caused a central steepening of the cornea to treat
in 1990. Several new models have been developed since. They must accom- the presbyopia (Fig. 3.1.14).
modate to the space between the posterior iris and the crystalline lens.
Sizing is crucial. If the IOL vaults too much, pigment dispersion and even Ciliary Muscle–Zonular Complex
82 papillary block glaucoma can result. If it lies against the anterior surface of Attempts have been made to treat presbyopia based on an alternative
the crystalline lens, cataract can result. theory of its pathogenesis: relaxation of the equatorial zonules. These
booksmedicos.org
SUMMARY
Refractive surgery is an established subspecialty of ophthalmology with 3.1
a rapidly growing choice of long-term proven and novel procedures. The
responsible and caring refractive surgeon much choose the procedure that

best fits the needs and expectations for each particular patient from among
all the techniques described in Part 3 Refractive Surgery. The patient
should be fully aware of all the risks and benefits as well as all the optical
alternatives to the proposed procedure, especially if a novel procedure is
recommended. Presbyopia correction is targeted with multiple approaches,
but to date none is perfect.
KEY REFERENCES
Azar DT, Ang RT, Lee JB, et al. Laser subepithelial keratomileusis: electron microscopy
and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol
2001;12:323–8.
Azar DT, Primack JD. Theoretical analysis of ablation depths and profiles in laser in situ
keratomileusis for compound hyperopic and mixed astigmatism. J Cataract Refract Surg
2000;26:1123–36.
Baikoff G, Joly P. Comparison of minus power anterior chamber intraocular lenses and
Fig. 3.1.14 Intrastromal Rings. Rings formed by femtosecond laser bubbles 6
myopic epikeratoplasty in phakic eyes. Refract Corneal Surg 1990;6:252–60.
months after IntraCor placement in the nondominant eye. The patient perceived the Basuk WL, Zisman M, Waring GO 3rd, et al. Complications of hexagonal keratotomy. Am J
rings without upset. Ophthalmol 1994;117:37–49.
Hettlich HJ, Lucke K, Asiyo-Vogel MN, et al. Lens refilling and endocapsular polymerization
of an injectable intraocular lens: in vitro and in vivo study of potential risks and benefits.
J Cataract Refract Surg 1994;20:115–23.
Kezirian GM. Q-factor customized ablations. J Cataract Refract Surg 2006;32:1979–80, author
reply 1980–1.
zonules have been made taut by either scleral expansion or infrared laser Mrochen M, Bueeler M, Donitzky C, et al. Optical ray tracing for the calculation of optimized
application. However, this theory of accommodation is not supported by corneal ablation profiles in refractive treatment planning. J Refract Surg 2008;24:S446–51.
Munnerlyn CR, Koons SJ, Marshall J. Photorefractive keratectomy: a technique for laser
independent studies. The studies undertaken all support the classic accom- refractive surgery. J Cataract Refract Surg 1988;14:46–52.
modative mechanism described by Helmholtz. Roberts C. Future challenges to aberration-free ablative procedures. J Refract Surg
2000;16:S623–9.
Axial Length Taneri S, Oehler A, Azar D. Influence of mydriatic eye drops on wavefront sensing with the
Zywave aberrometer. J Refract Surg 2011;27:678–85.
Presently, procedures that modify the axial length of the eye—by either Taneri S, Oehler S, MacRae S. Aspheric wavefront-guided versus wavefront-guided LASIK for
resection of the sclera or reinforcement of the posterior pole in cases of myopic astigmatism with the Technolas 217z100 excimer laser. Graefes Arch Clin Exp
high myopia—have a role in the management of staphyloma but not in the Ophthalmol 2013;251:609–16.
management of refractive error. Taneri S, Stottmeister S. Aspheric ablation for the correction of myopia: clinical results
after LASIK with a Bausch & Lomb 217 Z 100 excimer laser. Klin Monbl Augenheilkd
2009;226:101–9 [in German].
Refractive Indexes Taneri S, Weisberg M, Azar DT. Surface ablation techniques. J Cataract Refract Surg
Although not intended to be a refractive procedure, the use of compounds 2011;37:392–408.
with a different index of refraction during retinal surgery must be consid- Thompson KP, Hanna K, Waring GO 3rd. Emerging technologies for refractive surgery:
laser-adjustable synthetic epikeratoplasty. Refract Corneal Surg 1989;5:46–8.
ered. In an aphakic eye, a convex bubble of silicone oil (with a higher index Trokel SL, Srinivasan R, Braren B. Excimer laser surgery of the cornea. Am J Ophthalmol
of refraction) will act as a positive IOL, rendering the eye more myopic 1983;96:710–15.
while the oil stays in place. A gas bubble with a lower index of refraction
will act as a diverging IOL, rendering the eye hyperopic while the gas stays Access the complete reference list online at ExpertConsult.com
in place.
83
booksmedicos.org
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31. Telandro A. Pseudo-accommodative cornea: a new concept for correction of presbyopia. 73. Cohn J, Robinet A, Cochener B. Retinal detachment after clear lens extraction for high
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32. Bauerberg JM. Centered vs. inferior off-center ablation to correct hyperopia and presby- 74. Hettlich HJ, Lucke K, Asiyo-Vogel MN, et al. Lens refilling and endocapsular poly-
opia. J Refract Surg 1999;15:66–9. merization of an injectable intraocular lens: in vitro and in vivo study of potential risks
33. Taneri S, Oehler S, MacRae S. Aspheric wavefront-guided versus wavefront-guided and benefits. J Cataract Refract Surg 1994;20:115–23.
LASIK for myopic astigmatism with the Technolas 217z100 excimer laser. Graefes Arch 75. Nishi O, Nishi K. Accommodation amplitude after lens refilling with injectable silicone
Clin Exp Ophthalmol 2013;251:609–16. by sealing the capsule with a plug in primates. Arch Ophthalmol 1998;116:1358–61.
34. Waring GO 3rd. Making sense of keratospeak IV: classification of refractive surgery. Arch 76. Nishi O, Nishi K, Mano C, et al. Lens refilling with injectable silicone in rabbit eyes. J
Ophthalmol 1992;1992:1385–91. Cataract Refract Surg 1998;24:975–82.
35. Barraquer JI. Cirugia refractiva de la cornea. Bogotá, Colombia: Instituto Barraquer de 77. Fechner PU, van der Heijde GL, Worst JGF. The correction of myopia by lens implanta-
America 1989;67–85. tion into phakic eyes. Am J Ophthalmol 1989;107:659–63.
36. Barraquer JI. Queratoplastia refractiva. Estudio Inform Oftalmol Inst Barraquer 78. Baikoff G, Joly P. Comparison of minus power anterior chamber intraocular lenses and
1949;10:2–10. myopic epikeratoplasty in phakic eyes. Refract Corneal Surg 1990;6:252–60.
37. Werblin TP, Kaufman HE, Friedlander MH, et al. A prospective study of the use of 79. Alió JL, de la Hoz F, Pérez-Santonja JJ, et al. Phakic anterior chamber lenses for the
hyperopic epikeratophakia grafts for the correction of aphakia in adults. Ophthalmology correction of myopia: a seven year cumulative analysis of complications in 263 cases.
1981;88:1137–40. Ophthalmology 1999;106:458–66.
38. Thompson KP, Hanna K, Waring GO 3rd. Emerging technologies for refractive surgery: 80. Fyodorov SN, Suyev VK, Tumanyan ER, et al. Analysis of long-term clinical and func-
laser-adjustable synthetic epikeratoplasty. Refract Corneal Surg 1989;5:46–8. tional results of posterior chamber intraocular lenses in high myopia. Ophthalmic Surg
39. Taneri S, Weisberg M, Azar DT. Surface ablation techniques. J Cataract Refract Surg 1990;4:3–6.
2011;37:392–408.
83.e1
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Preoperative Evaluation for

Refractive Surgery 3.2
Praneetha Thulasi, Joshua H. Hou, Jose de la Cruz
Definitions: BOX 3.2.1 Systemic Contraindications to Photorefractive

• Wavefront aberrometry is the measurement of the wavefront that Keratectomy and Laser-in Situ Keratomileusis
emerges from an eye as a result of light reflecting from a focused
light spot on the fovea. Application of Zernike polynomials allows Immunological Disease
characterization of a reconstructed estimated wavefront. • Autoimmune
• Videokeratography is the computerized measurement of variation • Collagen vascular
in curvature and dioptric power across the corneal surface that is • Immunodeficiency
typically based on the corneal reflection of the Placido pattern. Pregnancy or Nursing (not absolute contraindication)
• Pachymetry is the measurement of corneal thickness.
Abnormal Wound Healing
• Keloids (contraindicated for PRK only)
• Abnormal scars
Key Features Diabetes Mellitus (if corneal sensation is not intact)
• Preoperative evaluation for refractive surgery should involve
documentation of refractive stability, review of both systemic and Interference from Systemic Medications
ophthalmic contraindications, manifest refraction, cycloplegic • Isotretinoin
refraction, pupil measurements, pachymetry, wavefront analysis, • Amiodarone hydrochloride
corneal topography, slit-lamp examination, and dilated fundus
examination.
• Care should be taken to identify patients at risk for postoperative expect better vision than with glasses or contacts, or who have unrealistic
corneal ectasia. expectations are likely not good candidates for refractive surgery. Appro-
• Patient counseling is an important part of preoperative testing before priate counseling becomes even more important in patients between 40
refractive surgery. and 50 years of age as presbyopia sets in and monovision may need to
be a consideration. Another aspect to consider is a patient’s occupation
and hobbies. Those who perform activities that may put them at risk for
INTRODUCTION flap dislocations should not be offered laser-assisted in situ keratomileusis
(LASIK).
Comprehensive preoperative evaluation of patients considering refractive
surgery is often preceded by a brief screening examination to eliminate
patients who are clearly not candidates for refractive surgery. Although it Systemic Contraindications to
can help identify patients who would not benefit from refractive surgery, Keratorefractive Surgery
it also helps the surgeon plan the operative technique and further recom-
mendations for a patient. A thorough medical history should be obtained from all patients consider-
ing refractive surgery. In particular, patients with a history of diabetes mel-
General Considerations litus, pregnancy, autoimmune disease, collagen vascular disorders, thyroid
disease, or abnormal wound healing may be at risk for poor outcomes
Age postoperatively and should be identified before proceeding with surgery
Laser corrective surgery is approved for those over 18 years of age who (Box 3.2.1).
have had a stable refractive error over the previous 1–2 years. Although
laser corrective surgery may be indicated in younger patients who are oth- Diabetes Mellitus
erwise intolerant of traditional therapy, care must be taken because refrac- Uncontrolled diabetes not only leads to unstable refractions but also
tive error at this age often is unstable. A stable refractive error generally is causes poor wound healing, persistent epithelial defects, and neurotrophic
defined as a ±0.5 diopter (D) change in refraction over the past 1–2 years. changes after laser surgery. A high risk of complications has been reported
Every patient presenting to a screening examination should be asked to in the literature, including poor healing, worse refractive outcomes, and
discontinue all contact lens wear (1 week for soft nontoric lenses, 2 weeks epithelial ingrowth.1,2 Other studies did not show a significant complica-
for toric lenses, and at least 3 weeks for rigid lenses) and asked to bring tion rate in diabetes patients with well-controlled blood glucose.3,4 There-
their previous spectacles for assessment of refractive stability. fore it is recommend that refractive surgery be performed only in diabetes
patients with tight blood glucose control (Hb A1c <7.9%) over the previous
Degree of Correction year, normal corneal sensation, and no signs of diabetic retinopathy.5
Although different laser platforms are approved for various thresholds
of refractive correction, most surgeons opt to limit myopic correction to Pregnancy and Lactation
−10 D and hyperopic and astigmatic correction to +4 D to prevent postop- Refractive surgery during pregnancy is contraindicated because pregnancy
erative corneal ectasia and haze and to avoid the unpredictability of correc- can lead to transient changes in refractive error and cornea curvature and
tion at these higher refractions. changes in tear quality. In addition, there are risks of fetal or infantile
exposure to topical and systemic medications. There are multiple case
Patient Expectations reports of pregnancy-induced keratectasia following LASIK; it is import-
84 Perhaps the most important aspect of refractive surgery is appropriate ant to counsel young female patients regarding this possibility.6–8 Sharif
counseling to set realistic expectations. Patients who are risk averse, who reported a greater risk for corneal haze and myopic regression in women
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who became pregnant within 5 months of photorefractive keratectomy
TABLE 3.2.1 Ophthalmic Contraindications to
(PRK). Starr also reported the case of a pregnant patient in whom overcor-
rection was induced and haze formation occurred.9,10 It is recommended Photorefractive Keratectomy 3.2
that patients wait 3 to 6 months after pregnancy and cessation of lactation Relative Contraindications Absolute Contraindications
before undergoing refractive surgery.
Preoperative Evaluation for Refractive Surgery

Ocular surface Mild dry eye Severe dry eye
disease Lid disorders that affect • Keratoconjunctivitis sicca
Autoimmune Diseases the tear layer • Exposure keratitis
Uncontrolled collagen vascular disease is an absolute contraindication to • Lid disorders that affect the tear
undergoing laser refractive surgery, as it can lead to corneal melts and layer
irregular healing. Patients with Sjögren’s disease and thyroid-associated Neurotrophic keratitis
eye disease are predisposed to tear film irregularities and dry eyes.11 Disorders that may Herpes zoster Herpes zoster ophthalmicus/herpetic
Although most surgeons would agree that PRK will lead to poor healing be exacerbated ophthalmicus/herpetic keratitis (especially if active during
in these patients, the debate is still ongoing whether patients with inactive by photorefractive keratitis (if inactive for the previous 6 months)
keratectomy >1 year—unproved) Uncontrolled glaucoma
or well-controlled collagen vascular disease can safely undergo LASIK.12
Multiple studies have shown no additional complications with LASIK Abnormalities of Shape changes induced Corneal ectasia
corneal shape by contact lens • Keratoconus
in patients with inactive disease and a normal ocular surface.3,13–15 Case Mild irregular astigmatism • Pellucid marginal degeneration
reports of severe complications also exist, however.11,16–19 Appropriate coun- • Keratoglobus
seling must be done in any patient with a collagen vascular disease inter- High, irregular astigmatism
ested in pursuing laser refractive surgery. Other ophthalmic Posterior corneal Uveitis
disorders dystrophies Diabetic retinopathy
Dermatological Keloid Progressive retinal disease
Although dermatological keloid is listed as a precaution for LASIK and
PRK, several studies have demonstrated good results without any addi-
tional complications after both PRK and LASIK.3,20,21 Most surgeons at this
point do not consider this a concern with laser surgery. for postrefractive ectasias, but the key factors include abnormal topogra-
phy, percent of tissue altered, thin corneal thickness, thin residual stromal
Human Immunodeficiency Virus bed, young age, and high myopia. Key elements of history such as rapidly
A theoretical risk exists of transmission of human immunodeficiency changing refraction or a family history of ectasia can be helpful. Imaging
virus (HIV) through laser plumes, but no reported cases have occurred using Placido-slit topography or Scheimpflug tomography can often iden-
to date that have shown such transmission. Nevertheless, adequate pre- tify suspicious changes in the anterior and posterior cornea.
cautions must be taken while operating on patients with HIV. Hagen
et al. used culture plates, and an excimer laser was used to ablate infected Ocular Surface Disease
tissue.22 None was culture positive. These patients also have a theoretical Dry eyes are the most commonly experienced side effect after LASIK. Pre-
higher risk of infectious complications. Therefore only those on appropri- operative dry eye symptoms are at risk for worsening after laser surgery.
ate therapy and with adequate CD4 cell counts should be considered for It is important to optimize the ocular surface before refractive surgery.
refractive surgery. Although artificial tears are the mainstay of treatment, punctal plug place-
ment during the LASIK procedure can decrease dry eye symptoms after
Medications LASIK.31 Use of medications such as cyclosporine A after LASIK, while
Multiple medications delay or inhibit wound healing after laser refractive not significantly changing patient symptoms,32 may improve refractive
surgery. Of these, amiodarone and isotretinoin need to be carefully con- predictability.33 Similarly, uncontrolled ocular allergy symptoms can lead
sidered before refractive surgery. Amiodarone is used to treat arrhythmias to increased risk of perioperative complications; systemic treatment can
and can lead to multiple ocular side effects, including optic neuropathy, decrease the risk of complications.
corneal and lenticular deposits, and halos around lights. Although there
are reports of no increased complications, patients must be appropriately Herpes Reactivation
screened.23,24 Isotretinoin is used to treat acne and can lead to dry eyes, Excimer laser treatment can lead to reactivation of herpes keratitis in both
blepharoconjunctivitis, and photosensitivity, all of which can complicate animal models and humans. Therefore refractive surgery was considered a
recovery.25 Sumatriptan was previously considered to delay wound healing. contraindication. Recently however, de Rojas et al. presented a study in 48
However, recent reports do not show any significant adverse effects.26 patients who had inactive herpes keratitis for at least 1 year and in whom
Various other systemic medications can exacerbate dry eye symptoms, and LASIK was performed while they were on oral and topical antiviral prophy-
therefore patients on these should be appropriately counseled and treated. laxis without any reactivation postoperatively.34 The authors suggest careful
patient selection, with inactive disease for at least 1 year, normal corneal
Ophthalmic Diseases sensitivities, and normal corneal parameters before proceeding. Given the
risk of potentially devastating scarring if reactivation does occur, caution
Multiple ophthalmic conditions necessitate special attention. Of note are must be used while considering refractive surgery in this population.
disorders that lead to tear film deficiency, corneal dystrophies and ectasias,
glaucoma, and other retinal and intraocular disorders (Table 3.2.1). Glaucoma
Laser refractive surgery poses multiple complexities in patients with glau-
Corneal Dystrophy coma. Although uncontrolled intraocular pressure is a contraindication for
Any form of anterior corneal dystrophy is a contraindication for excimer refractive surgery, patients with well-controlled glaucoma may be candi-
laser use because this may lead to increased deposits.27 Patients with epi- dates. However, these patients often have ocular surface diseases that can
thelial basement membrane disease may benefit from PRK, as this can complicate healing for LASIK or PRK. In addition, a change in corneal
treat both the refractive error and the underlying pathology.28 LASIK is thickness can falsely change intraocular pressure measurements. Case
contraindicated in patients with Fuchs’ dystrophy because of the risk of reports exist of visual field, optic nerve, and nerve fiber layer changes occur-
corneal decompensation and potential for overestimation of corneal thick- ring during the acute intraocular pressure elevation involved in LASIK flap
ness in subclinical edema. There are case reports of safe performance of creation,35,36 and surface ablation procedures may be better suited in these
LASIK and PRK for posterior polymorphous corneal dystrophy.29,30 Family patients. Another aspect to consider is the prolonged use of corticoster-
history should be especially noted to ensure that any subtle changes of oids in patients undergoing PRK, which may lead to corticosteroid-induced
familial dystrophies are not missed. intraocular pressure elevation, which occurs more commonly in patients
predisposed to glaucoma.
Corneal Curvature
Corneal curvature must be carefully examined because corneal ectasia Other Considerations
after refractive surgery is a feared complication that can lead to severe loss Patients with visually significant or incipient cataracts must not undergo
of vision. Any signs or symptoms of corneal ectasia like keratoconus or laser refractive surgery. Similarly, patients with significant retinal disease,
pellucid marginal degeneration are a contraindication for laser refractive latent strabismus, and monocular patients should not undergo laser refrac- 85
surgery. There are multiple criteria to evaluate and identify eyes at risk tive surgery.
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degeneration, unrecognized diabetic retinopathy or myopic degeneration,
3 BOX 3.2.2 Ophthalmic Examination

Visual Acuity
and other pathologies that preclude photoablative treatment.
• Distance with and without correction ANCILLARY TESTING

• Reading with and without correction
Refractive Surgery
Refraction
Wavefront Measurement (Aberrometry)
• Current spectacle correction Recent advances in wavefront aberrometry have allowed for refined abla-
• Manifest refraction tion profiles that correct for both higher- and lower-order aberrations in
• Cycloplegic refraction with cyclopentolate 1% appropriate patients. Benefits to wavefront-guided LASIK include improved
Topographical Analysis
contrast sensitivity, reduced incidence of postoperative glare and halos,
• Keratometry (measures central 3 mm) and reduced postoperative higher-order aberations.39,40 Wavefront testing
• Computerized videokeratography should be the first examination performed before the eye is manipulated
in any way. Any application of drops or tonometry can alter the results and
Intraocular Pressure Measurement thus should be avoided before testing. While waiting, patients should avoid
External Examination
reading magazines or other materials in the waiting room to minimize
• Ocular motility accommodation and dessication of the ocular surface. In all cases, wave-
• Ocular dominance front measurements should be compared with the manifest and cyclople-
• Gross external examination measurements in bright and dim light gic refractions to confirm consistency. Higher-order aberration indices,
such as vertical coma, should be further reviewed for evidence suggestive
Slit-Lamp Examination of subclinical keratoconus.41
• Fluorescein stain
• Vital stain (if symptoms warrant) Computerized Videokeratography
Dilated Funduscopy
Computerized videokeratography is crucial in the preoperative evaluation
Jones’ Basal Tear Secretion Rate (if symptoms/signs warrant) of patients for refractive surgery. Postoperative ectasia remains the most
Pachymetry
feared complication of photorefractive surgery; appropriate screening with
corneal topography is absolutely essential. In any preoperative evaluation
for refractive surgery, one must maintain a high degree of suspicion for
ectatic disorders.
OPHTHALMIC EXAMINATION Care should be taken to establish the stability of patient corneal topog-
raphy before surgery. Progressive changes in corneal topography may be
The preoperative ophthalmic examination consists of determining patients’ indicative of ectatic disease or corneal molding (warpage) due to rigid or
manifest and cycloplegic refraction, pupil diameter, ocular dominance, soft contact lens wear. Because distortion from long-term contact lens wear
wavefront aberrometry measurement, corneal topography, pachymetry, may persist for a long time, patients should discontinue all contact lens
slit-lamp examination, and dilated funduscopy (Box 3.2.2). Special care wear before the preoperative examination. Prolonged contact lens cessa-
is required when manifest refraction is performed to avoid any errors. tion is warranted in patients who demonstrate poor stabilization of their
Cycloplegic refraction with 1% cyclopentolate is mandatory, especially in corneal topography.42,43
younger patients, to accurately measure refractive error in the absence of
accommodation and to avoid myopic overcorrection. Pachymetry
A complete slit-lamp examination is important to identify problems
with the lids, conjunctiva, cornea, or lens, which may lead to complica- Pachymetry must be performed in all patients before LASIK. It is manda-
tions postoperatively. Eyelid malpositions, lagophthalmos, proptosis, and tory that the postablation corneal bed following LASIK be at least 250 µm
other external conditions that predispose the cornea to exposure must be in thickness to avoid iatrogenic corneal ectasia and refractive instability.
recognized and treated before refractive surgery is attempted. Small inter- Residual bed thickness can be estimated from the baseline corneal pachym-
palpebral fissures should be noted if LASIK is planned because of the etry, the anticipated flap thickness, and the expected depth of ablation.
difficulty in inserting the suction ring. Blepharitis and meibomian gland
dysfunction should be treated aggressively before photoablation to reduce Counseling
the risk of bacterial superinfection, to improve the quality of the tear film, Not all patients who meet medical and ophthalmic criteria for refractive
and to prevent meibomian gland secretions and lash debris from becom- surgery are necessarily good candidates for the procedure. Patients with
ing lodged in the interface between the flap and the corneal stroma. unrealistic expectations are likely to be dissatisfied after surgery. Appro-
Patients affected by significant corneal neovascularization extending priate counseling regarding the risks of over- or undercorrection, post-
within 1 mm of the ablation zone should be excluded from treatment. operative dry eye, or postoperative glare and halos should be performed
Extensive peripheral pannus should be noted and may be associated with routinely. Patients should be informed of the potential need for spectacles
bleeding following the keratectomy. Adequacy of the tear film should be after surgery for certain tasks such as driving at night. High hyperopes
assessed based on the Schirmer’s test or tear meniscus height (approxi- should be made aware of the decreased predictability of photoablative
mately 0.3 mm) and tear-film breakup time (≥10 sec). treatments in hyperopic cases. Presbyopic myopes should be made aware
An accurate preoperative measure of pupillary diameter in dim light that the removal of distance glasses to achieve better near vision would no
should be obtained using an infrared pupillometer. Patients with scotopic longer be possible after refractive surgery.
pupil sizes 6.5 mm should be warned about the risks of night glare and The preoperative evaluation of the patient for refractive surgery is
halos following surgery, although the risk is lower with modern laser algo- lengthy and must be performed in an unrushed manner. However, it is
rithms and blended ablation zones.37,38 time well spent because the best treatment for complications and disap-
In patients aged over 45 years, or those nearing the presbyopic age, pointment is avoidance.
a discussion regarding the postoperative need for reading glasses or the
option for monovision correction should be discussed. Patients who are
motivated to pursue monovision therapy should have ocular dominance KEY REFERENCES
assessed and should consider a trial of a monovision contact lens before
surgery. Standard practice is to correct the dominant eye for distance and Alfawaz AM, Algehedan S, Jastaneiah SS, et al. Efficacy of punctal occlusion in management
of dry eyes after laser in situ keratomileusis for myopia. Curr Eye Res 2014;39(3):257–62.
the nondominant eye for near sight in appropriate patients. Cobo-Soriano R, Beltran J, Baviera J. LASIK outcomes in patients with underlying systemic
Keratometry should be measured to assess the power of the central contraindications: a preliminary study. Ophthalmology 2006;113(7):1118.e1111–18.
cornea, to gauge the quality of the mires, and to provide a basis for later de Rojas Silva V, Rodriguez-Conde R, Cobo-Soriano R, et al. Laser in situ keratomileusis
intraocular lens calculations. Tonometry, as part of a thorough examina- in patients with a history of ocular herpes. J Cataract Refract Surg 2007;33(11):1855–9.
Hagen KB, Kettering JD, Aprecio RM, et al. Lack of virus transmission by the excimer laser
tion, should also be obtained. plume. Am J Ophthalmol 1997;124(2):206–11.
86 Dilated funduscopy should be performed to identify patients affected Halkiadakis I, Belfair N, Gimbel HV. Laser in situ keratomileusis in patients with diabetes.
by progressive retinal disease, retinal holes, tears, or atypical lattice J Cataract Refract Surg 2005;31(10):1895–8.
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Li Y, Li HY. [Analysis of clinical characteristics and risk factors of corneal melting after laser Tsai PS, Dowidar A, Naseri A, et al. Predicting time to refractive stability after discontin-
in situ keratomileusis]. [Zhonghua yan ke za zhi] Chinese Journal of Ophthalmology uation of rigid contact lens wear before refractive surgery. J Cataract Refract Surg
2005;41(4):330–4.
Padmanabhan P, Radhakrishnan A, Natarajan R. Pregnancy-triggered iatrogenic (post-laser
2004;30(11):2290–4.
Zhang J, Zhou YH, Wang NL, et al. Comparison of visual performance between con-
3.2
in situ keratomileusis) corneal ectasia—a case report. Cornea 2010;29(5):569–72. ventional LASIK and wavefront-guided LASIK with iris-registration. Chin Med J
Simpson RG, Moshirfar M, Edmonds JN, et al. Laser in situ keratomileusis in patients 2008;121(2):137–42.

with collagen vascular disease: a review of the literature. Clin Ophthalmol 2012;6:
1827–37.
Smith RJ, Maloney RK. Laser in situ keratomileusis in patients with autoimmune diseases. Access the complete reference list online at ExpertConsult.com
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3. Cobo-Soriano R, Beltran J, Baviera J. LASIK outcomes in patients with underlying sys- 27. Wan XH, Lee HC, Stulting RD, et al. Exacerbation of Avellino corneal dystrophy after
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with collagen vascular disease: a review of the literature. Clin Ophthalmol 2012;6:1827–37. terior polymorphous dystrophy. Cornea 2005;24(2):230–2.
6. Hafezi F, Koller T, Derhartunian V, et al. Pregnancy may trigger late onset of keratectasia 30. Bower KS, Trudo EW, Ryan DS, et al. Photorefractive keratectomy in posterior poly-
after LASIK. J Refract Surg 2012;28(4):242–3. morphous dystrophy with vesicular and band subtypes. J Cataract Refract Surg
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Ophthalmol 2011;25(3):225–30. 31. Alfawaz AM, Algehedan S, Jastaneiah SS, et al. Efficacy of punctal occlusion in man-
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J Refract Surg 1997;13(5 Suppl.):S445–6. photorefractive keratectomy and laser in situ keratomileusis. J Cataract Refract Surg
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with development of systemic lupus erythematosus. J Refract Surg 2002;18(6):750–2. in patients with a history of ocular herpes. J Cataract Refract Surg 2007;33(11):1855–9.
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atomileusis in patients positive for human leukocyte antigen-B27. J Cataract Refract Surg 37. Chan A, Manche EE. Effect of preoperative pupil size on quality of vision after wave-
2008;34(7):1110–13. front-guided LASIK. Ophthalmology 2011;118(4):736–41.
16. Aman-Ullah M, Gimbel HV, Purba MK, et al. Necrotizing keratitis after laser refractive 38. Schallhorn S, Brown M, Venter J, et al. The role of the mesopic pupil on patient-re-
surgery in patients with inactive inflammatory bowel disease. Case Rep Ophthalmol 2012; ported outcomes in young patients with myopia 1 month after wavefront-guided LASIK.
3(1):54–60. J Refract Surg 2014;30(3):159–65.
17. Li Y, Li HY. [Analysis of clinical characteristics and risk factors of corneal melting after 39. Moussa S, Dexl AK, Krall EM, et al. Visual, aberrometric, photic phenomena, and patient
laser in situ keratomileusis]. [Zhonghua yan ke za zhi] Chinese Journal of Ophthalmol- satisfaction after myopic wavefront-guided LASIK using a high-resolution aberrometer.
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18. Lahners WJ, Hardten DR, Lindstrom RL. Peripheral keratitis following laser in situ ker- 40. Zhang J, Zhou YH, Wang NL, et al. Comparison of visual performance between con-
atomileusis. J Refract Surg 2003;19(6):671–5. ventional LASIK and wavefront-guided LASIK with iris-registration. Chin Med J 2008;
19. Diaz-Valle D, Arriola-Villalobos P, Sanchez JM, et al. Late-onset severe diffuse lamellar 121(2):137–42.
keratitis associated with uveitis after LASIK in a patient with ankylosing spondylitis. 41. Jafri B, Li X, Yang H, et al. Higher order wavefront aberrations and topography in early
J Refract Surg 2009;25(7):623–5. and suspected keratoconus. J Refract Surg 2007;23(8):774–81.
20. Artola A, Gala A, Belda JI, et al. LASIK in myopic patients with dermatological keloids. 42. Tsai PS, Dowidar A, Naseri A, et al. Predicting time to refractive stability after discon-
J Refract Surg 2006;22(5):505–8. tinuation of rigid contact lens wear before refractive surgery. J Cataract Refract Surg
21. Lee JY, Youm DJ, Choi CY. Conventional Epi-LASIK and lamellar epithelial debridement 2004;30(11):2290–4.
in myopic patients with dermatologic keloids. Korean J Ophthalmol 2011;25(3):206–9. 43. Wang X, McCulley JP, Bowman RW, et al. Time to resolution of contact lens-induced
22. Hagen KB, Kettering JD, Aprecio RM, et al. Lack of virus transmission by the excimer corneal warpage prior to refractive surgery. CLAO J 2002;28(4):169–71.
laser plume. Am J Ophthalmol 1997;124(2):206–11.
23. Mantyjarvi M, Tuppurainen K, Ikaheimo K. Ocular side effects of amiodarone. Surv Oph-
thalmol 1998;42(4):360–6.
87.e1
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Excimer Laser Surface Ablation:

Photorefractive Keratectomy (PRK), 3.3
Laser Subepithelial Keratomileusis
(LASEK), and Epi-LASIK
Sandeep Jain, David R. Hardten, Leonard P.K. Ang, Dimitri T. Azar
Other corneal surface ablative procedures include laser-assisted subepi-

Definitions: thelial keratomileusis (LASEK) and epi-LASIK. In principle, they combine
• Photorefractive keratectomy (PRK) is a procedure in which the cornea the advantages of both LASIK (laser-assisted in situ keratomileusis) and
is reshaped using an excimer laser. PRK involves epithelial removal PRK, while at the same time overcoming some of their problems.8–18
and photoablation of Bowman’s layer and anterior corneal stromal LASEK was first conceived independently in 1996 by Azar,9 as well as
tissue. In contrast to laser-assisted in situ keratomileusis (LASIK), there Cimberle and Camellin.10 LASEK involves creating an epithelial flap with
is no need for flap creation with a microkeratome. dilute alcohol solution and repositioning this flap after laser ablation, thus
• Laser subepithelial keratomileusis (LASEK) and epi-LASIK are corneal eliminating any inherent flap complications. Epi-LASIK makes use of a
surface ablative refractive procedures. motorized epithelial separator to mechanically separate the corneal epithe-
• LASEK involves creating an epithelial flap with dilute alcohol and lium in toto from the stroma without the use of alcohol or chemicals.14,15
repositioning this flap after laser ablation. This device makes use of a proprietary oscillating blade that separates the
• Epi-LASIK involves the use of a motorized epithelial separator to epithelial layer at the layer of Bowman’s membrane without dissecting the
mechanically separate the corneal epithelium from the stroma. corneal stroma.
Development of excimer lasers began in 1975 when Velasco and Setser19
noted that metastable rare gas atoms such as xenon (Xe) could react under
Key Features high pressures with halogens such as fluorine (F) to produce unstable
compounds such as XeF.20 These compounds rapidly dissociated to the
• Excimer laser surface ablation results in removal of a precise amount ground state of the individual molecules associated with the release of an
of tissue from the anterior cornea. The central cornea is reprofiled to
energetic ultraviolet photon and could be made to undergo light ampli-
achieve myopic, hyperopic, or astigmatic correction.
fication by stimulated emission when they were excited by an electron
• The refractive result is related to the depth of ablation and the beam, with the argon-fluorine (ArF) molecule emitting light with a wave-
diameter of the optical zone.
length of 193 nm.21 The ablation thresholds, ablation rates, and healing
• Preoperative assessment plays a key role in determining a safe and patterns for different excimer wavelengths were described by Krueger and
effective outcome. It includes corneal pachymetry, topography, and
Trokel.22–24 The ablation threshold for the cornea is the fluence at which
cycloplegic refraction.
tissue removal begins, which is approximately 50 mJ/cm2 for 193 nm. The
• Mitomycin-C is useful to prevent corneal haze and scarring in high 193 nm light has very low tissue penetrance, enabling the laser to operate
myopic corrections.
on the surface of the corneal tissue with precision and safety.
• Wavefront guided ablations result in higher percentage of patients Large-area ablation with resculpting of the cornea to correct refractive
achieving uncorrected visual acuity of 20/20 or better compared with
errors is termed laser keratomileusis. Tissue is removed with great preci-
conventional ablations.
sion, and the corneal epithelium heals over the ablated area to create a
• PRK, LASEK and epi-LASIK are considered in patients with thin, steep, smooth surface. About 0.24 µm of tissue is removed with each laser pulse.
or flat corneas and in patients predisposed to flap trauma in thinner
Corneal epithelium ablates at a slightly faster and more irregular rate
corneas, where creation of LASIK flap may leave less tissue than
than corneal stroma, which is the reason that the epithelium is typically
desired (usually 250 µm of corneal tissue) remaining to the posterior
removed mechanically before ablation of the stroma for the PRK proce-
stroma.
dure. Bowman’s layer ablates about 30% slower than the stroma, and fluo-
• Postoperative complications of PRK, LASEK, and epi-LASIK include rescein decreases the ablation rate by about 40%.
epithelial healing, pain, infiltrates and infection, dry eye, and corneal
haze.
• LASEK-related intraoperative complications include alcohol leakage, ABLATION PROFILES
incomplete epithelial detachment, and laser-related complications.
Munnerlyn25 described the direct relation between the amount of tissue
• Epi-LASIK–related intraoperative complications include flap-related that must be removed to produce a certain refractive result and the optical
complications (when these occur the procedure may be converted to
zone size. The relationship can be simplified to:
PRK) and laser-related complications.
Depth of ablation (µm) = [diameter of optical zone (mm)]2
INTRODUCTION × 1 3 power (D)
The surgical treatment of myopia, hyperopia, and astigmatism has As the optical zone is increased, the ablation depth needs to be
made great strides over time, with the introduction and advancement of increased. The optical zone size and depth are optimized to reduce exces-
the excimer laser PRK followed by LASIK surgery. Ultraviolet radiation sive wound healing seen in deep ablations and the excessive halos, edge
at 193 nm wavelength utilized by the excimer laser can remove precise glare, and irregular astigmatism seen with small optical zones.26
amounts of tissue from the anterior cornea. Use of the excimer laser In correction of spherical hyperopia, the cornea needs to be reshaped
88 for the treatment of myopia, hyperopia, and astigmatism is now well into a steeper convex structure. This can be achieved by a peripheral
established.1–7 annular ablation with peripheral flattening creating central corneal
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steepening. Generally, a larger (9–9.5 mm) ablation diameter is required
BOX 3.3.1 Indications and Cautions
to achieve permanent steepening of the cornea. It is more challenging to
deliver larger-diameter hyperopic ablations than the equivalent myopic Potential Preference of PRK Over LASIK
3.3
correction. • Thin corneal pachymetry
Excimer laser surgical correction of astigmatism requires that the • Epithelial irregularities/dystrophies
Excimer Laser Surface Ablation: Photorefractive Keratectomy (PRK), Laser Subepithelial Keratomileusis (LASEK), and Epi-LASIK
cornea be ablated in a cylindrical or toric pattern. In the early excimer • LASIK complications in the contralateral eye
systems, the excimer laser beams were passed through a set of parallel • Predisposition to trauma
blades that gradually open as directed by the computer algorithm. The ori- • Low myopia
entation and speed of opening depends on the orientation and amount of • Irregular astigmatism
astigmatism to be corrected. Flattening occurs perpendicular to the long • Dry eyes
axis of the slits. No change in power occurs along the axis of the slits.
Another method of creating a toric ablation utilizes an ablatable mask. The Cautions
laser first ablates the thinnest areas of the mask, thus allowing greater • Postoperative pain intolerance/concern
treatment of the cornea in areas where the mask is thinnest.27 Any pattern • Keratoconus
can be created by differential protection of the cornea from treatment. • Glaucoma
A computer-controlled scanning beam can be utilized to treat astig- • Pregnancy
matism. The size of the beam can be varied to create a transition zone, • Advanced diabetes
preventing a steep step off at the edges of treatment. With this method, • Collagen vascular disease
it is possible to steepen, rather than flatten an axis, thus allowing for a • Previous herpes (simplex or zoster) infection
more direct and tissue-conserving treatment of hyperopic astigmatism. • Severe dry eye
Wavefront-guided customized corneal ablation profiles have been intro- • Untreated blepharitis
duced for correction of irregular astigmatism (higher-order aberrations) as • Neurotrophic cornea
well as spherocylindrical refractive errors. • Peripheral ulcerative keratitis
• Patients on isotretinoin (Accutane), amiodarone (Cordarone), or
sumatriptan (Imitrex)
INDICATIONS
PRK, LASEK, and epi-LASIK surface ablation may be performed in patients
who are at low risk for subepithelial haze with low to moderate myopia and
myopic astigmatism. The ideal candidates for LASEK and epi-LASIK are
those with mild to moderate myopia up to −7.00 diopters (D).12,17 LASEK inferior half of the cornea, as often occurs after anesthetic drops have been
has also been shown to be effective for hyperopia up to +4.00 D.28 instilled, can lead to increased thinning inferiorly.
Surgeons should consider these surface ablative refractive procedures The epithelium is marked with a 7- or 8-mm optical zone marker cen-
for patients whose corneal characteristics render them at greater risk for tered on the pupil for myopia or a 9- or 10-mm marker for hyperopia or
LASIK, such as those with thin corneas where less than 250 µm of resid- wavefront correction. It is helpful to remove a 1-mm larger area of epi-
ual stromal bed would be left and those with steep or flat corneas. These thelium than the planned ablation. Mechanical epithelial removal involves
would also be the preferred surgical procedures in patients with lifestyles the use of a Tooke knife, disposable excimer spatula, or rotating brush.
or professions that predispose them to flap trauma. LASEK may also be a Alternatively, alcohol (18%–25% ethanol for 21–30 seconds) can be used
better choice for patients with narrow palpebral fissures where the micro- to loosen the epithelium or excimer laser for partial or complete removal.
keratome cannot be well applied. The laser is typically set to a depth of approximately 45 µm, and the epithe-
Contraindications for these procedures include exposure keratopathy, lium being ablated by the laser beam can be visualized under blue fluores-
neuropathic keratopathy, severe dry eye (Sjögren’s syndrome), keratoco- cence. The ablation is stopped when a change from a fluorescent pattern to
nus, central or paracentral corneal scars, unstable myopia, and irregular a dark pattern is seen, indicating that the epithelium has been ablated. If
astigmatism.11,12 fluorescence persists across the whole area after a 50 µm ablation has been
performed, an additional depth of 25 µm should be set for the laser. It may
PREOPERATIVE EVALUATION be helpful to scrape the remaining epithelium. It is important to remove
the epithelium totally. Any residual epithelium will create an uneven abla-
As for any refractive procedure, the preoperative workup for PRK, LASEK, tion and irregular astigmatism. Also, epithelial removal should be quick to
and epi-LASIK includes uncorrected and best-corrected distance and near avoid corneal hydration changes.
visual acuities with a manifest and cycloplegic refraction. Ocular domi-
nance testing, anterior segment and posterior segment examinations, Stromal Ablation
keratometry, tonometry, pachymetry, aberrometry, and computerized
topographical analysis are other important parts. A careful systemic and The ablation should promptly follow epithelial removal to prevent drying,
ocular history and examination is necessary to look for conditions that may which can lead to increased haze and scarring.29–30
require preoperative management or contraindicate the procedure (Box Centration is rechecked after epithelial removal. For astigmatic cor-
3.3.1). For example, mild degrees of dysfunctional tear syndrome or dry rections, alignment on the proper axis should be verified by marking the
eye (Fig. 3.3.1) can be managed preoperatively with lid hygiene, artificial patient’s limbus at the 12 and 6 o’clock positions with gentian violet dye
tears, and topical cyclosporin for better early postoperative recovery. Metic- on a Sinskey hook at the slit lamp before the procedure. The ultraviolet
ulous preoperative counseling is also a very important aspect, as for any excimer lasers used have wavelengths outside the visible spectrum; an
refractive procedure. auxiliary aiming device that is coaxial to the ablating laser is required to
make certain the laser is centered on the eye. Helium–neon lasers, laser
diodes, or a coaxial aiming target are commonly used for this. In auto-
PRK SURGICAL TECHNIQUE mated systems with eye trackers, this is used only for initial alignment,
Patient Preparation and Epithelial Removal but in manually controlled systems, it is used to align the eye during the
entire procedure.
The initial patient preparation is similar to all the three surface ablation The ablation is begun, centered over the pupil with the patient looking
procedures. The patient is positioned under the microscope, and the head at the fixation light. Eye movements should be minimized during the
is carefully aligned to make sure that the iris plane is perpendicular to the ablation to reduce irregular surfaces. The use of an eye tracker is helpful
laser beam. After topical anesthesia (0.5% proparacaine or tetracaine), the in maintaining centration.31–32 It is important to make certain that the
eyelids and periocular skin are prepped with dilute povidone–iodine (Beta- hydration status of the corneal stroma is uniform during the procedure.
dine) solution. A lid speculum is placed to provide adequate exposure of If excess fluid is detected, the procedure should be paused and the excess
the globe. Careful centration with the eye aligned in the x-, y-, and z-planes fluid removed by using a cellulose sponge to dry the cornea (Fig. 3.3.2).
is crucial. Likewise, if the cornea becomes too dry, a cellulose sponge can be used to
It is important to perform the treatment as soon as possible after the evenly hydrate it. Inadequate or excessive tissue hydration leads to more or
proparacaine or tetracaine drops are instilled or have the patient close less tissue ablation per pulse, resulting in an overcorrection or undercor- 89
their eyes to prevent exposure keratitis from poor blinking. Drying of the rection, respectively.
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Fig. 3.3.1 Inferior Steepening and
3 Irregularity of the Topography Is Seen

in This Young Patient With Dry Eye
and Blepharitis. This patient improved
significantly with lid hygiene, artificial
Refractive Surgery
tears, and topical cyclosporin 0.05% for 1

month.
Fig. 3.3.2 A the cornea while the barrel of the marker is filled with two drops of 18%
REMOVAL OF EXCESS MOISTURE Merocel Sponge ethanol. After 25–35 seconds, the ethanol is absorbed using an aspiration
Can Be Used to hole followed by dry sponges (Weck-cel or Merocel, Xomed, Jacksonville,
Remove Excess FL), to prevent alcohol spillage onto the epithelium outside the marker
epithelial cornea wetter Merocel Moisture in a barrel. The ethanol application may be repeated for an additional 10–15
edge in some areas sponge Uniform Fashion. seconds.
Maintaining proper One arm of a modified curved Vannas scissors or a jeweler’s forceps is
central corneal
inserted under the epithelium and traced around the delineated margin
hydration may
improve results.
of the epithelium, leaving 2–3 clock hours of intact margin, preferably
at the 12 o’clock position. The loosened epithelium is peeled as a single
sheet using a jeweler’s forceps, spatula, or a Merocel sponge, leaving a flap
of epithelium with the hinge still attached. The ablation is then initiated
immediately using an excimer laser.
After ablation, a 30-gauge anterior chamber cannula is used to hydrate
the stroma and epithelial sheet with balanced salt solution. The epithe-
lial sheet is replaced on the stroma using the straight part of the cannula
under intermittent irrigation. The epithelial flaps are realigned using the
previous marks. The flap is then allowed to dry for 2–5 minutes.
A bandage contact lens is placed on the operated eye at the end of the
procedure.
Epi-LASIK Surgical Technique (Fig. 3.3.4)

The corneal epithelium is dried with sponges after proper positioning
LASEK Surgical Technique (see Fig. 3.3.3) and ocular surface irrigation with balanced salt solution using an ante-
rior chamber cannula. The cornea is marked with a standard LASIK
Patient is prepared and eye aligned as described earlier. Just before surgery, marker.
topical broad-spectrum antibiotics (e.g., tobramycin or a fluoroquinolone) The subepithelial separator is applied to the eye and suction is activated
may be applied prophylactically. Some surgeons use topical nonsteroidal by a foot pedal. The oscillating blade separates the epithelium leaving a
anti-inflammatory drugs (NSAIDs) for pain relief. Dilute ethanol at a con- 2–3-mm nasal hinge, the suction is released, and the device is removed
centration of 18% is prepared by drawing 2 mL of dehydrated alcohol into from the eye. The epithelial sheet is reflected nasally using a moistened
a 12 mL syringe and diluting it with sterile water to 11 mL.9,12 Merocel sponge or a spatula. Laser ablation is then initiated immediately,
The cornea is marked with 3-mm circles around the corneal periphery with use of an excimer laser. The cornea then is irrigated with balanced salt
to allow the surgeon to have the precise reference points to realign the solution. The epithelial sheet is carefully repositioned using the straight
flap over the corneal bed. An alcohol dispenser consisting of a customized part of the cannula. The replaced corneal epithelial sheet is left to dry for
7- or 9-mm semisharp marker (ASICO, Westmont, IL) attached to a hollow 2–3 minutes to allow adhesion to the underlying corneal stroma. Some
metal handle serves as a reservoir for the 18% alcohol. surgeons may choose to discard the epithelial flap instead. In this situa-
Firm pressure is exerted on the central cornea and a button is pushed tion, the subepithelial separator would then simply remove the epithelium
on the side of the handle, releasing the alcohol into the well of the marker. before the laser ablation.
90 Alternatively, a 7-mm optical marker (Storz, St Louis, MO) is used to At the end of the procedure, a bandage contact lens is placed on the
delineate the area centered on the pupil. Gentle pressure is applied on operated eye.
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3.3
A B C
D E F
G H I
Fig. 3.3.3 Our Current LASEK Technique. (A) Multiple marks are applied around the corneal periphery, simulating a floral pattern. (B) An alcohol dispenser consisting of
a customized 7- or 9-mm semisharp marker attached to a hollow metal handle serves as a reservoir for 18% alcohol. Firm pressure is exerted on the cornea, and alcohol is
released into the well of the marker. (C) After 25–30 seconds, the ethanol is absorbed using a dry cellulose sponge. (D) One arm of a modified Vannas scissors (note knob
at tip of lower arm) is then inserted under the epithelium and traced around the delineated margin of the epithelium, leaving a hinge of 2–3 clock hours of intact margin,
preferably at the 12 o’clock position. (E) The loosened epithelium is peeled as a single sheet using a Merocel sponge or the edge of a jeweler’s forceps, leaving it attached at
its hinge. (F) After laser ablation is performed, an anterior chamber cannula is used to hydrate the stroma and epithelial flap with balanced salt solution. (G) The epithelial
flap is replaced on the stroma using the cannula under intermittent irrigation. (H) Care is taken to realign the epithelial flap using the previous marks and to avoid epithelial
defects. The flap is allowed to dry for 2–5 min. Topical corticosteroids and antibiotic medications are applied. (I) A bandage contact lens is placed. (Reproduced from Azar DT,
Taneri S. LASEK. In: Azar DT, Gatinel D, Hoang-Xuan T, editors. Refractive surgery. 2nd ed. Philadelphia: Elsevier; 2007. p. 239–47.)
Surface Ablation With Mitomycin-C application for 2 minutes on the exposed stromal bed has been used suc-
cessfully to treat central subepithelial fibrosis after radial keratotomy (RK)
In refractive surgery, patients with high myopia are at a higher risk of or PRK.40–42 It also has a role in prevention of corneal haze formation after
haze formation.4,33–35 Early haze formation has been more common with PRK for treatment of myopia and hyperopia.43 The typical application times
higher attempted corrections, smaller ablation zones (<4.5 mm), male range between 1 and 2 minutes, although as little as a 12-second applica-
gender, ablations deeper than 80 µm, and discontinuation of topical tion of 0.02% MMC has been found effective for prevention of corneal
corticosteroids.36–37 Subepithelial stromal tissue reformation following pho- haze.44 Application is performed immediately after the laser ablation. The
torefractive ablation is attributable to abnormal activation or proliferation corneal surface and the entire conjunctiva are then vigorously irrigated
of stromal keratocytes following surgical trauma to Bowman’s layer.38–39 with 20 mL of cold normal saline to remove any residual MMC.
Mitomycin-C (MMC) is an alkylating antibiotic substance with anti- PRK with MMC application may offer a good alternative for patients 91
proliferative and antifibrotic actions. Topical MMC 0.02% (0.2 mg/mL) with high refractive error, where the cornea is not thick enough for a safe
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3
Refractive Surgery
A B C
D E F
G H I
Fig. 3.3.4 The Epi-LASIK Technique. (A) Marks are applied around the corneal periphery. (B,C) The epikeratome is applied to the eye with suction; the oscillating blade
separates the epithelium. Once the separator reaches its final position, suction is released and the device is removed from the eye. (D) With the use of either a moistened
Merocel sponge or a metallic spatula, the epithelium is reflected to reveal the corneal stroma. (E) Laser ablation is performed. (F,G) The cornea is irrigated with balanced
salt solution and the epithelial sheet is carefully repositioned. (H,I) The replaced corneal epithelial sheet is left to dry for 2–3 minutes, and a bandage contact lens is placed.
(Reproduced with permission from Azar DT, editor, Ghanem RC, DVD editor. Refractive surgery. 2nd ed. St Louis: Mosby Elsevier; 2006.)
LASIK procedure or if LASIK is contraindicated for other reasons. It has computer-generated, complex patterns of ablation are delivered in an
also been tried in post keratoplasty, post RK, and immediately after the attempt to decrease the pre-existing HOA as well.
occurrence of the LASIK flap buttonhole with successful results.45–47
Wavefront-Guided Surface Ablation RESULTS

Conventional laser treatments tend to increase the higher-order aberra- Photorefractive Keratectomy for Myopia
tions (HOA) in an attempt to treat the lower-order aberrations by altering
the corneal shape from its normal prolate to a more oblate configuration.
and Astigmatism
Spherical aberration is the most common of these, causing mainly loss Outcomes have improved over time as techniques and lasers have evolved
of contrast sensitivity rather than Snellen visual acuity.48 Wavefront-guided based on the experience gained from early studies. Treatments limited
laser utilizes the preoperative wavefront of the patient and compares it to low myopia (less than −6.00 D) have achieved a final mean spherical
92 to the desired postoperative wavefront. The difference is used to gener- equivalent refraction between −0.04 D and −0.44 D postoperatively. Over
ate a three-dimensional map of the planned ablation. Thus customized, various studies, 25.9%–80% of patients have achieved a postoperative
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uncorrected visual acuity (UCVA) of 20/20 or greater, whereas about COMPLICATIONS
82%–91.5% of patients received a best-corrected visual acuity (BCVA)
of 20/40 or greater. Loss of BCVA, a measure of safety, is typically General Complications for All Surface 3.3
2%–4% but rises significantly in studies treating high and very high Ablation Procedures
myopia.13,49–53
The numbers for high myopia fall to about 27%–30% of patients achiev- Undercorrection or Overcorrection
ing 20/40 or better vision for more than −10.00 D of myopia, with 39% of Corneal wound healing response after surface ablation is more complex
these within 1.00 D of emmetropia.34,54 Another study reported 42.9% of than after LASIK for the same amount of correction.72 Therefore compli-
eyes within 1.00 D of intended correction 6–9 years after PRK for myopia cations such as regression, overcorrection, and haze are more common.
≥6.00 D.55 Refractive regression is a manifestation of postoperative stromal keratocyte
From the 1.5- and 6-year follow-up studies it was reported that all myopic healing or, less importantly, epithelial hyperplasia. Excessive fluid or desic-
PRK ablations were accompanied by a hyperopic shift that increased with cation of the corneal stroma intraoperatively can result in an undercorrec-
the magnitude of myopic correction followed by a period of regression that tion or overcorrection.
compensated for the hyperopic shift, finally stabilizing in 3–6 months. In cases of undercorrection with residual myopia, the simplest form
The standard deviation of the postoperative endpoint increased with an of management is to use spectacles or contact lenses. Contact lens use
increase in attempted correction. No significant regression occurred after can be highly successful after surface ablation. An attempt can be made
1.5 or after 6 years.2,56–57 Refractive stability, in fact, continues for up to 12 to reduce wound healing in patients with mild undercorrection by using
years, as reported by Rajan et al.58 corticosteroids; mixed results have been reported with this technique.
It has been shown that refractive results in flap-based and PRK-based Residual myopia also can be managed by further refractive surgery, includ-
procedures are comparable in mild-to-moderate myopia patients but are ing additional PRK or LASIK.
better in high-myopia patients.59 Visual rehabilitation after PRK is slower Overcorrection is a desired result in the first few months after surface
than after LASIK. A recent report comparing the two procedures showed ablation, as there is usually regression of 5%–10%. If the patient has a
similar visual acuity efficacy in the treatment of eyes with high myopia (≥ greater degree of overcorrection than is expected at 1 month or longer
−10.00 D) in the long term, with LASIK having superior efficacy and safety after surgery, an attempt may be made to increase wound healing by taper-
over PRK within the first 2 years after surgery.60 ing the corticosteroids rapidly. If additional stromal remodeling occurs
Astigmatism correction is more complicated than myopia or hypero- during this corticosteroid taper, a decrease in the amount of hypero-
pia correction because it involves both the amount and the orientation of pia will occur. A rapid taper of corticosteroids may induce corneal haze
the astigmatism. More recent trials have shown promising results in treat- in some patients, so monitoring is important. Also, as previously men-
ing astigmatism. In general, results in those with low and moderate levels tioned, refractive modulation with corticosteroid therapy is not always
of astigmatism have greater predictability and safety than those with high successful.
astigmatism. PRK for the correction of mixed astigmatism is a useful tech-
nique in terms of efficacy, safety, and predictability with conventional as Epithelial Problems
well as customized ablation techniques.61 Hyperopic ablation is limited by the large epithelial defect created. Nor-
mally, the defect heals in 3–4 days. Inadequate healing can lead to per-
Photorefractive Keratectomy for Hyperopia sistent epithelial defects. Pre-existing dry eye, autoimmune connective
tissue disease, or diabetes mellitus predispose to it. Medication toxicity can
The treatment of hyperopia with excimer laser PRK has lagged behind lead to superficial punctate keratitis (SPK). Discontinuation of such medi-
that of myopia. Reproducible steepening of the cornea has been more cation can be considered along with use of preservative-free artificial tears.
difficult to obtain than flattening, and regression has been more of a Persistent defects need to be treated aggressively with pressure patching,
problem. autologous serum, punctual occlusion, or cyclosporine as per the individ-
Hyperopic PRK shows good predictability and safety in those with low ual case. This is necessary to avoid corneal haze, scarring, and a possible
and moderate hyperopia; results for high hyperopes are less impressive. risk of infection.
In a study by Pacella et al.,59 including hyperopia up to +4.75 D, 100% of
patients achieved 20/30 acuity or better and the mean postoperative spher- Corneal Haze/Scar Formation
ical equivalent was −0.01 D. In contrast, for patients with between +11.00 Transient haze after surface ablation, which can be visually significant
and +16.00 D of hyperopia, only 37% had a spherical equivalent within 1 D and can cause loss of BCVA (Fig. 3.3.5), may result from the corneal
of emmetropia.62 wound-healing process. The haze formation can be visually significant and
The long-term efficacy and stability of spherical and astigmatic PRK cause loss of BCVA (see Fig. 3.3.5). In most cases, it appears within a few
have been found to be similar to LASIK.63 Nevertheless, the epithelial weeks as a mild, diffuse, whitish anterior stromal opacity, which increases
healing time was predictably longer for the PRK group. Eyes that under- in severity for 2–4 months and then fades. Late-onset haze is defined as
went LASIK experienced less pain/discomfort and faster visual recovery. haze presenting 4–14 months postoperatively.73 It has been linked to ultra-
Mitomycin-C has been shown to prevent haze formation and improve pre- violet exposure; patients should be cautioned to always wear ultraviolet
dictability and efficacy of PRK.64 protection when outdoors for the first few years following the procedure.
Corneal scar development may be prevented by the prophylactic use of
Wavefront-Guided PRK mitomycin-C 0.02% in patients with higher spherical equivalent correc-
tions.44 Surgical removal of the scar with the excimer laser can improve
Custom PRK has been shown to be safe and effective for the correction of visual function in these patients.
low to moderate and high myopia, compound myopic astigmatism, and
hyperopia. In a recent study, the mean refractive spherical equivalent was Dry Eyes
−0.16 ± 0.45 1 year after custom myopic PRK, with 96.6% of eyes within Dry eye symptoms are thought to be less common following surface abla-
±1.00 D of intended correction. In another study, 80% of eyes achieved tion procedures compared with LASIK. The reinervation process is speed-
uncorrected distance visual acuity (UDVA) of 20/20.65–67 A randomized, ier after these, because the ablated nerve endings are located close to the
prospective, contralateral eye study comparing custom and conventional epithelial surface.74
PRK showed that the mean uncorrected and corrected visual acuity did
not differ significantly in the two groups. Higher order aberration was less Infectious Keratitis
in the custom group, but this did not seem to correlate with clinical out- Although rare, infectious keratitis can be a devastating complication of any
comes.68 We must realize that it is not possible to totally eliminate these refractive surgery. The breakdown of the corneal epithelium as a barrier
HOA with wavefront treatment either.69 and the use of an extended wear bandage contact lens are predisposing
Compared with wavefront-guided LASIK, wavefront-guided PRK factors for development of corneal infection. In addition, the use of topical
had similar efficacy, predictability, safety, and contrast sensitivity. In corticosteroids may suppress the immune response to infection. Staphy-
one study, wavefront-guided PRK induced statistically fewer HOA than lococcus species have been noted as the most common causative organ-
wavefront-guided LASIK.53,66,70 Wavefront-guided PRK with MMC has been isms and streptococcus species as the next, with Pseudomonas aeruginosa
used to successfully treat residual myopia/hyperopia in eyes with prior RK, also causing bacterial keratitis.75 Opportunistic organisms such as Myco-
with a mean improvement of three lines of uncorrected acuity in both the bacterium chelonae and fungal infections have been reported. Prophylactic 93
groups.71 broad-spectrum antibiotics such as fourth-generation fluoroquinolones
booksmedicos.org
remaining epithelium may be scraped off and the procedure easily con-
3 verted to PRK.
Specific Intraoperative Complications Related

Refractive Surgery
to Epi-LASIK
The major difference between LASEK and epi-LASIK is that the separa-
tion of the epithelial sheet is performed mechanically without exposing
the cornea to alcohol or other chemical agents that may be toxic to the
epithelial cells.76,77 The use of a motorized epithelial separator, however,
creates a different set of flap-related problems, such as a free or incom-
plete epithelial flap and tearing, fragmentation, or buttonhole of the flap.
However, unlike the flap-related complications of LASIK, when these
occur in epi-LASIK, the residual epithelium may be removed mechanically
and the procedure easily converted to a standard PRK with equally good
results. This is where epi-LASIK offers advantages over LASIK, where the
corneal flap-related complications often require that the LASIK procedure
be abandoned.
CONCLUSIONS
A The excimer laser surface ablation procedures include PRK, LASEK, and
epi-LASIK. The techniques are still developing, and there will certainly be
significant advances in the future. Developments of customized corneal
ablation using wavefront analysis, laser registration systems, and use of
mitomycin-C have been the most recent significant achievements to date
in laser vision correction. Although LASIK continues to be the preferred
surgical procedure in most situations, PRK, LASEK, and epi-LASIK are
useful alternatives in patients with thin corneas and in patients prone to
flap dislocation such as military personnel or contact sports athletes. An
increased understanding of the optics of refractive surgery and the corneal
wound-healing response may help us to improve our results and modulate
the patient’s postoperative healing to further our goal of predictable, safe
refractive surgery.
KEY REFERENCES
Azar DT, Ang RT. Laser subepithelial keratomileusis: evolution of alcohol assisted flap
surface ablation. Int Ophthalmol Clin 2002;42:89–97.
Azar DT, Ang RT, Lee JB, et al. Laser subepithelial keratomileusis: electron microscopy
B and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol
2001;12:323–8.
Camellin M. Laser epithelial keratomileusis for myopia. J Refract Surg 2003;19:666–70.
Fig. 3.3.5 Corneal Haze After PRK in a Patient With Prior LASIK When No Carones F, Vigo L, Scandola E, et al. Evaluation of the prophylactic use of mitomycin-C
Mitomycin-C Was Used. (A) Slit beam of subepithelial haze. (B) Haze evident over to inhibit haze formation after photorefractive keratectomy. J Cataract Refract Surg
area of photoablation. 2002;28:2088–95.
Cimberle M, Camellin M. LASEK technique promising after 1 year of experience. Ocular
currently are the most commonly prescribed to try to reduce the potential Surg News 2000;18:14–17.
for infection in the postoperative period. Heitzman J, Binder P, Kasser B, et al. The correction of high myopia using the excimer laser.
Arch Ophthalmol 1993;111:1627–34.
Krueger RR, Trokel SL. Quantitation of corneal ablation by ultraviolet laser light. Arch Oph-
thalmol 1985;103:1741–2.
Specific Intraoperative Complications Related Krueger RR, Trokel SL, Schubert HD. Interaction of ultraviolet laser light with the cornea.
Invest Ophthalmol Vis Sci 1985;26:1455–64.
to LASEK Munnerlyn CR, Koons SJ, Marshall J. Photorefractive keratectomy: a technique for laser
refractive surgery. J Cataract Refract Surg 1988;14:46–52.
Alcohol Leakage During Surgery Pallikaris IG, Kalyvianaki MI, Katsanevaki VJ, et al. Epi-LASIK: preliminary clinical results of
Alcohol leakage may occur during LASEK and spill over to the limbal and an alternative surface ablation procedure. J Cataract Refract Surg 2005;31:879–85.
conjunctival epithelium. When this happens, it should be immediately Pallikaris IG, Katsanevaki VJ, Kalyvianaki MI, et al. Advances in subepithelial excimer refrac-
tive surgery techniques: epi-LASIK. Curr Opin Ophthalmol 2003;14:207–12.
absorbed with a sponge and the area irrigated thoroughly with balanced Rajan MS, Jaycock P, O’Brart D, et al. A long-term study of photorefrective keratecomy
salt solution. No significant long-term complications are likely to occur if 12-year follow-up. Ophthalmology 2004;111:1813–24.
prompt irrigation is performed. Schwiegerling J, Snyder RW. Corneal ablation patterns to correct for spherical aberration in
photorefractive keratectomy. J Cataract Refract Surg 2000;26:214–21.
Taneri S, Feit R, Azar DT. Safety, efficacy and stability indices of LASEK correction in moder-
Incomplete Epithelial Detachment ate myopia and astigmatism. J Cataract Refract Surg 2004;30:2130–7.
Insufficient alcohol exposure and poor surgical technique may lead to Taneri S, Zieske JD, Azar DT. Evolution, techniques, clinical outcomes, and pathophysiology
incomplete epithelial detachment. This may in turn result in tearing of of LASEK: review of the literature. Surv Ophthalmol 2004;49:576–602.
the flap, fragmentation, or creating a buttonhole. If epithelial detachment
is difficult, additional application of alcohol usually is sufficient to facili- Access the complete reference list online at ExpertConsult.com
tate complete detachment of the epithelial sheet. If this still fails, then the
94
booksmedicos.org
REFERENCES 42. Spadea L, Verrecchia V. Effectiveness of scraping and mitomycin C to treat haze after
myopic photorefractive keratectomy. Open Ophthalmol J 2011;5:63–5.
1. Puliafito CA, Steinert RF, Deutsch TF, et al. Excimer laser ablation of the cornea and
lens: experimental studies. Ophthalmology 1985;92:741–8.
43. Carones F, Vigo L, Scandola E, et al. Evaluation of the prophylactic use of mitomycin-C
to inhibit haze formation after photorefractive keratectomy. J Cataract Refract Surg
3.3
2. Gartry DS, Kerr Muir MG, Marshall J. Excimer laser photorefractive keratectomy: 2002;28:2088–95.
44. Virasch VV, Majmudar PA, Epstein RJ, et al. Reduced application time for prophylactic
18-month follow-up. Ophthalmology 1992;99:1209–19.
3. Sher NA, Chen V, Bowers RA, et al. The use of the 193-nm excimer laser for myopic mitomycin C in photorefractive keratectomy. Ophthalmology 2010;117:885–9.
photorefractive keratectomy in sighted eyes: a multi-center study. Arch Ophthalmol 45. Ghanem RC, Ghanem VC, Ghanem EA, et al. Corneal wavefront-guided photorefractive
1991;109:1525–30. keratectomy with mitomycin-C for hyperopia after radial keratotomy: two-year follow-up.
4. Sher NA, Barak M, Daya S, et al. Excimer laser photorefractive keratectomy in high J Cataract Refract Surg 2012;38:595–606.
myopia: a multi-center study. Arch Ophthalmol 1992;110:935–43. 46. Hodge C, Sutton G, Lawless M, et al. Photorefractive keratectomy with mitomycin-C
5. Sher NA, Hardten DR, Fundingsland B, et al. 193-nm excimer photorefractive keratec- after corneal transplantation for keratoconus. J Cataract Refract Surg 2011;37:1884–94.
tomy in high myopia. Ophthalmology 1994;101:1575–82. 47. Kymionis GD, Portaliou DM, Karavitaki AE, et al. LASIK flap buttonhole treated imme-
6. Talley AR, Hardten DR, Sher NA, et al. Results one year after using the 193-nm excimer diately by PRK with mitomycin C. J Refract Surg 2010;26:225–8.
laser for photorefractive keratectomy in mild to moderate myopia. Am J Ophthalmol 48. Schwiegerling J, Snyder RW. Corneal ablation patterns to correct for spherical aberration
1994;118:304–11. in photorefractive keratectomy. J Cataract Refract Surg 2000;26:214–21.
7. Jackson WB, Casson E, Hodge WG, et al. Laser vision correction for low hyperopia. An 49. Fernández AP, Jaramillo J, Jaramillo M. Comparison of photorefractive keratectomy and
18-month assessment of safety and efficacy. Ophthalmology 1998;105:1727–37, discussion laser in situ keratomileusis for myopia of −6 D or less using the Nidek EC-5000 laser. J
1737–8. Refract Surg 2000;16:711–15.
8. Azar DT, Ang RT. Laser subepithelial keratomileusis: evolution of alcohol assisted flap 50. el Danasoury MA, el Maghraby A, Klyce SD, et al. Comparison of photorefractive keratec-
surface ablation. Int Ophthalmol Clin 2002;42:89–97. tomy with excimer laser in situ keratomileusis in correcting low myopia (from −2.00 to
9. Azar DT, Ang RT, Lee JB, et al. Laser subepithelial keratomileusis: electron microscopy −5.50 diopters). A randomized study. Ophthalmology 1999;106:411–20, discussion 420–1.
and visual outcomes of flap photorefractive keratectomy. Curr Opin Ophthalmol 51. Tole DM, McCarty DJ, Couper T, et al. Comparison of laser in situ keratomileusis and
2001;12:323–8. photorefractive keratectomy for the correction of myopia of −6.00 diopters or less. Mel-
10. Cimberle M, Camellin M. LASEK technique promising after 1 year of experience. Ocular bourne Excimer Laser Group. J Refract Surg 2001;17:46–54.
Surg News 2000;18:14–17. 52. Moshirfar M, Schliesser JA, Chang JC, et al. Visual outcomes after wavefront-guided
11. Taneri S, Feit R, Azar DT. Safety, efficacy and stability indices of LASEK correction in photorefractive keratectomy and wavefront-guided laser in situ keratomileusis: prospec-
moderate myopia and astigmatism. J Cataract Refract Surg 2004;30:2130–7. tive comparison. J Cataract Refract Surg 2010;36:1336–43.
12. Taneri S, Zieske JD, Azar DT. Evolution, techniques, clinical outcomes, and pathophysi- 53. O’Doherty M, Kirwan C, O’Keeffe M, et al. Postoperative pain following epi-LASIK,
ology of LASEK: review of the literature. Surv Ophthalmol 2004;49:576–602. LASEK, and PRK for myopia. J Refract Surg 2007;23:133–8.
13. Lee JB, Seong GJ, Lee JH, et al. Comparison of laser epithelial keratomileusis and 54. McCarty CA, Alfred GE, Taylor HR. Comparison of results of excimer laser correction of
photorefractive keratectomy for low to moderate myopia. J Cataract Refract Surg all degrees of myopia at 12 months postoperatively. The Melbourne Excimer Laser Group.
2001;27:565–70. Am J Ophthalmol 1996;121:372–83.
14. Pallikaris IG, Katsanevaki VJ, Kalyvianaki MI, et al. Advances in subepithelial excimer 55. Dirani M, Couper T, Yau J, et al. Long-term refractive outcomes and stability after
refractive surgery techniques: epi-LASIK. Curr Opin Ophthalmol 2003;14:207–12. excimer laser surgery for myopia. J Cataract Refract Surg 2010;36:1709–17.
15. Pallikaris IG, Kalyvianaki MI, Katsanevaki VJ, et al. Epi-LASIK: preliminary clinical results 56. Stephenson CG, Garty DS, O’Brart DP, et al. Photorefractive keratectomy. A 6-year fol-
of an alternative surface ablation procedure. J Cataract Refract Surg 2005;31:879–85. low-up study. Ophthalmology 1998;105:273–81.
16. Katsanevaki VJ, Kalyvianaki MI, Kavroulaki DS, et al. One-year clinical results after epi- 57. Van Gelder RN, Steger-May K, Yang S, et al. Comparison of photorefractive keratectomy,
LASIK for myopia. Ophthalmology 2007;114:1111–17. astigmatic PRK, laser in situ keratomileusis, and astigmatic LASIK in the treatment of
17. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy for myopia: two-year fol- myopia. J Cataract Refract Surg 2002;28:462–76.
low-up. J Cataract Refract Surg 2003;29:661–8. 58. Rajan MS, Jaycock P, O’Brart D, et al. A long-term study of photorefrective keratecomy
18. Claringbold TV 2nd. Laser-assisted subepithelial keratectomy for the correction of 12-year follow-up. Ophthalmology 2004;111:1813–24.
myopia. J Cataract Refract Surg 2002;28:18–22. 59. Pacella E, Abdolrahimzadeh S, Mollo R, et al. Photorefractive keratectomy in the man-
19. Velasco JE, Setser DW. Bound-free emission spectra of diatomic xenon halides. J Chem agement of refractive accommodative esotropia in young adult patients. J Cataract Refract
Phys 1975;62:1990–1. Surg 2009;35:1873–7.
20. Searles SK, Hart GA. Stimulated emission at 281 nm XC. Br Appl Phys Lett 1975;27: 60. Spadea L, D’Alessandri L, Necozione S, et al. Three different techniques for pho-
243–5. torefractive keratectomy for mixed astigmatism. Ophthalmic Surg Lasers Imaging
21. Hoffman JM, Hays AK, Tisone GC. High-power UV noble gas-halide lasers. Appl Phys 2007;38:307–13.
Lett 1976;28:538–9. 61. Rosman M, Alió JL, Ortiz D, et al. Comparison of LASIK and photorefractive keratec-
22. Krueger RR, Trokel SL. Quantitation of corneal ablation by ultraviolet laser light. Arch tomy for myopia from −10.00 to −18.00 diopters 10 years after surgery. J Refract Surg
Ophthalmol 1985;103:1741–2. 2010;26:168–76.
23. Krueger RR, Trokel SL, Schubert HD. Interaction of ultraviolet laser light with the 62. Dausch J, Klein R, Schroder E. Excimer laser photorefractive keratectomy for hyperopia.
cornea. Invest Ophthalmol Vis Sci 1985;26:1455–64. Refract Corneal Surg 1993;9:20–8.
24. Trokel SL, Srinivasan R, Braren B. Excimer laser surgery of the cornea. Am J Ophthalmol 63. Settas G, Settas C, Minos E, et al. Photorefractive keratectomy (PRK) versus laser assisted
1983;96:710–15. in situ keratomileusis (LASIK) for hyperopia correction. Cochrane Database Syst Rev
25. Munnerlyn CR, Koons SJ, Marshall J. Photorefractive keratectomy: a technique for laser 2012;(6):CD007112.
refractive surgery. J Cataract Refract Surg 1988;14:46–52. 64. Leccisotti A. Mitomycin-C in hyperopic photorefractive keratectomy. J Cataract Refract
26. Barraquer JI. Keratomileusis. Int Surg 1967;48:103–17. Surg 2009;35:682–7.
27. Maloney RK, Friedman M, Harmon T, et al. A prototype erodible mask delivery system 65. George MR, Shah RA, Hood C, et al. Transitioning to optimized correction with the
for the excimer laser. Ophthalmology 1993;100:542–9. WaveLight ALLEGRETTO WAVE: case distribution, visual outcomes, and wavefront
28. Autrata R, Rehurek J. Laser-assisted subepithelial keratectomy and photorefractive kera- aberrations. J Refract Surg 2010;26:S806–13.
tectomy for the correction of hyperopia. Results of a 2-year follow-up. J Cataract Refract 66. Randleman JB, White AJ Jr, Lynn MJ, et al. Incidence, outcomes, and risk factors for
Surg 2003;29:2105–14. retreatment after wavefront-optimized ablations with PRK and LASIK. J Refract Surg
29. Netto MV, Mohan RR, Ambrosio R Jr, et al. Wound healing in the cornea: a review of 2009;25:273–6.
refractive surgery complications and new prospects for therapy. Cornea 2005;24:509–22. 67. Bababeygy SR, Manche EE. Wavefront-guided photorefractive keratectomy with the VISX
30. Shahinian L Jr. Laser-assisted subepithelial keratectomy for low to high myopia and astig- platform for myopia. J Refract Surg 2011;27:173–80.
matism. J Cataract Refract Surg 2002;28:1334–42. 68. Mifflin MD, Hatch BB, Sikder S, et al. Custom vs conventional PRK: a prospective, ran-
31. Anderson NJ, Beran RF, Schneider TL. Epi-LASEK for the correction of myopia and domized, contralateral eye comparison of postoperative visual function. J Refract Surg
myopic astigmatism. J Cataract Refract Surg 2002;28:1343–7. 2012;28:127–32.
32. Chalita MR, Tekwani NH, Krueger RR. Laser epithelial keratomileusis: outcome of initial 69. Mrochen M, Kaemmerer M, Seiler T. Clinical results of wavefront-guided laser in situ
cases performed by an experienced surgeon. J Refract Surg 2003;19:412–15. keratomileusis 3 months after surgery. J Refract Surg 2001;27:201–7.
33. Heitzman J, Binder P, Kasser B, et al. The correction of high myopia using the excimer 70. Randleman JB, Perez-Straziota CE, Hu MH, et al. Higher-order aberrations after wave-
laser. Arch Ophthalmol 1993;111:1627–34. front-optimized photorefractive keratectomy and laser in situ keratomileusis. J Cataract
34. Carson CA, Taylor HR. Excimer laser treatment for high and extreme myopia. Arch Oph- Refract Surg 2009;35:260–4.
thalmol 1995;113:431–6. 71. Koch DD, Maloney R, Hardten DR, et al. Wavefront-guided photorefractive keratectomy in
35. Maldonado MJ, Arnau V, Navea A, et al. Direct objective quantification of corneal eyes with prior radial keratotomy: a multicenter study. Ophthalmology 2009;116:1688–96.
haze after excimer laser photorefractive keratectomy for high myopia. Ophthalmology 72. Mohan RR, Hutcheon AE, Choi R, et al. Apoptosis, necrosis, proliferation, and myofibro-
1996;103:1970–8. blast generation in the stroma following LASIK and PRK. Exp Eye Res 2003;76:71–87.
36. Caubet E. The course of subepithelial corneal haze over 18 months after photorefractive 73. Lipshitz I, Loewenstein A, Varssano D, et al. Late onset corneal haze after photorefractive
keratectomy for myopia. Refract Corneal Surg 1993;9(Suppl.):S65–70. keratectomy for moderate and high myopia. Ophthalmology 1997;104:369–73, discussion
37. Braunstein RE, Jain S, McCally RL, et al. Objective measurement of corneal light scatter- 373–4.
ing after excimer laser keratectomy. Ophthalmology 1996;103:439–43. 74. Kauffmann T, Bodanowitz S, Hesse L, et al. Corneal reinervation after photorefractive
38. Chang SW, Benson A, Azar DT. Corneal light scattering with stromal reformation after keratectomy and laser in situ keratomileusis: an in vivo study with a confocal videomi-
laser in situ keratomileusis and photorefractive keratectomy. J Cataract Refract Surg croscope. Ger J Ophthalmol 1996;5:508–12.
1998;24:1064–9. 75. Donnenfeld ED, O’Brien TP, Solomon R, et al. Infectious keratitis after photorefractive
39. Chang SW, Ashraf FM, Azar DT. Wound healing patterns following perforation sus- keratectomy. Ophthalmology 2003;110:743–7.
tained during laser in situ keratomileusis. J Formos Med Assoc 2000;99:635–41. 76. Kim SY, Sah WJ, Lim YW, et al. Twenty percent alcohol toxicity on rabbit corneal epithe-
40. Majmudar PA, Forstot SL, Dennis RF, et al. Topical mitomycin-C for subepithelial fibro- lial cells: electron microscopic study. Cornea 2002;21:388–92.
sis after refractive corneal surgery. Ophthalmology 2000;107:89–94. 77. Abad JC, An B, Power WJ, et al. A prospective evaluation of alcohol-assisted versus
41. Vigo L, Scandola E, Carones F. Scraping and mitomycin C to treat haze and regression mechanical epithelial removal before photorefractive keratectomy. Ophthalmology
after photorefractive keratectomy for myopia. J Refract Surg 2003;19:449–54. 1997;104:1566–74, discussion 1574–5.
94.e1
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LASIK
Patricia B. Sierra, David R. Hardten 3.4
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Within a few years, advances in instrumentation allowed for the lamel-

Definition: Laser-assisted in situ keratomileusis (LASIK) is a form of lar keratoplasty to be performed with greater accuracy of the resections;
lamellar corneal surgery that employs an excimer laser ablation of the this became known as automated lamellar keratoplasty (ALK). Results of
corneal stroma beneath a hinged corneal flap. ALK for myopia showed improvement over previous lamellar techniques
but still were far from predictable, with significant induction of irregular
astigmatism and reduction of best-corrected visual acuity (BCVA).7
The introduction of the excimer laser has had a greater impact on the
practice of refractive surgery than any other event in the past 25 years.6
Trokel et al. suggested PRK after studying the effect of the excimer laser
Key Features on animal corneas in 1983.8 It was later revealed that in myopia greater
• Combines lamellar surgery with the accuracy of the excimer laser. than 6.00 diopters (D), PRK resulted in significant central corneal haze,
• Hinged flap may be created either with a microkeratome or a regression of the refractive effect, and poor predictability.
femtosecond laser, however, femtosecond lasers produce thinner, Buratto reported the use of the excimer laser in situ after a cap of
more predictable flaps with fewer complications. corneal tissue was removed.9 In a further improvement of his technique,
• Most widely used refractive surgery technique. Pallikaris came up with the idea of combining the precision of PRK with
• Excellent option for refinement of refractive errors in pseudophakes the technique of ALK and creating a hinged flap that was replaced after
especially with presbyopic and toric lenses. treatment of the lamellar bed with the laser.10–12 In this way LASIK was
• Recent advances including wave-front guidance, wavefront introduced, designed, and developed at the University of Crete and the
optimization, and topography guidance improve visual results and Vardinoyannion Eye Institute of Crete, Greece.12 LASIK avoided the inac-
predictability. curate positioning of the corneal cap, which produced significant irregular
• Recent rates of ectasia continue to fall due to better pre-operative astigmatism. Guimaraes et al. then reported that suturing could be elimi-
screening and awareness. nated by briefly drying the flap.13,14
In summary, it was the combination of an old technique (keratomil-
eusis) with new technology (excimer laser) that redefined corneal refrac-
tive surgery at the close of the twentieth century.9 Buratto9 and Pallikaris12
are credited with combining lamellar surgical techniques developed by
Associated Features Barraquer2,5 and excimer laser technology in a procedure they termed
laser-assisted in situ keratomileusis.
• PRK and other surface procedures are an alternative for patients in
whom LASIK may not be ideal.
• Intraoperative ablation and postoperative complications. LASIK
• LASIK in complex cases: after radial keratotomy (RK), PRK, and LASIK combines lamellar corneal surgery with the accuracy of the excimer
penetrating keratoplasty.
laser. It involves the excimer laser ablation of the corneal stroma beneath a
• IOL after LASIK. hinged corneal flap that is created with a microkeratome or a femtosecond
laser.
LASIK has been used to correct up to 15.00 D of myopia, 6.00 D of
hyperopia, and up to 6.00 D of astigmatism. The range of corrections
HISTORICAL REVIEW utilized has not been clearly defined, and many surgeons have treated
patients beyond these ranges with success. The results in the clinical eval-
Refractive corneal surgery principles date back at least to the nineteenth uation of the procedure as far as predictability (percentage of eyes within
century.1 However, lamellar refractive surgery was not described until 1949, a given postoperative target, i.e., ±0.5 D), efficacy (percentage of eyes with
when Dr. José I. Barraquer realized that the refractive power of the eye loss of best-corrected vision postoperatively, i.e., loss of two or more lines),
could be altered by subtraction or addition of corneal tissue.2 The term ker- stability (evaluation of stability of refraction at a certain interval postopera-
atomileusis, which is derived from the Greek roots keras (hornlike = cornea) tively), and quality of vision (incidence of adverse visual phenomena, such
and mileusis (carving), was used to describe the lamellar techniques.3–5 as halos, glare, etc.) have been better in lower ranges than in higher ranges
Unfortunately, there were many disadvantages to the procedure (i.e., of correction.15 Most surgeons now limit their levels of correction to less
complex instrumentation, steep learning curve, high rate of complications, than 8.00–10.00 D of myopia and 4.00 D of hyperopia.16
and corneal scarring4), and the initial enthusiasm soon dissipated. The normal cornea has a prolate shape (greater curvature centrally
It was not until Dr. Luis Ruiz turned to keratomileusis in situ that than peripherally). Laser vision correction procedures for myopia reverse
the technical difficulties of the previous techniques were overcome. The this natural prolate shape of the cornea and decrease the central corneal
introduction by Ruiz in the early 1980s of a microkeratome propelled by curvature to create an oblate shape (Fig. 3.4.1). Corneal surgery for hyper-
gears was a significant milestone for the development of modern refractive opia differs in several important respects from surgery for myopia. The
surgery. Dr. Leo Bores in 1987 performed the first keratomileusis in situ in corneal refractive power must be increased to treat hyperopia, whereas it
the United States. This technique was still difficult to perform and had a must be decreased to treat myopia. Excimer laser ablations for treatment of 95
significant complication rate.5,6 hyperopia are applied in the midperiphery and result in steepening of the
booksmedicos.org
Fig. 3.4.1 Postmyopic LASIK With Scheimpflug
3 Imaging. Note the central corneal flattening on

sagittal curvature and anterior elevation maps with
corresponding thinning on pachymetry map.
Refractive Surgery
of the flat meridian. Cylindrical ablation patterns for correction of mixed

astigmatism include the bitoric and the cross-cylinder techniques. The
bitoric LASIK technique consists of flattening the steep meridian with a
cylindrical ablation in combination with a paracentral ablation over the flat
meridian to steepen this axis. The cross-cylinder technique corrects astig-
matism by dividing the cylinder power into two symmetrical parts. Half of
the correction is treated on the negative meridian, and half is treated on
the positive meridian.
Excimer Lasers
The excimer laser is used to reshape the surface of the cornea by removing
anterior stromal tissue. The process by which the excimer laser removes
corneal tissue is nonthermal ablative photodecomposition.17
Laser delivery patterns include broad beam, scanning slit, and flying
spot. Some lasers have a combination of mechanisms that allow for large
and small treatment areas through a system termed variable spot scan-
ning. This combines the advantage of a shorter treatment time by treating
large areas all at once and the flexibility of treating smaller areas asymmet-
rically when needed with a small-diameter beam.18
There are four basic types of excimer laser treatment profiles: conven-
tional, wavefront-optimized, wavefront-guided, and topography-guided.
Conventional LASIK, also called standard or traditional LASIK, was the
first profile to receive Food and Drug Administration (FDA) approval and
still is used commonly today. Conventional LASIK applies a simple sphero-
Fig. 3.4.2 Posthyperopic LASIK Imaging on Placido Disc Topography. Note cylindrical correction obtained through a manifest refraction and based on
central corneal steepening. the removal of tissue using Munnerlyn’s equation.19 However, conventional
LASIK to treat myopia induces positive spherical aberration dependent on
the amount of attempted correction.20
central cornea and relative flattening of the periphery with minimal abla- In standard treatments, the best point to use for centration during the
tion occurring at the center of the cornea (Fig. 3.4.2). Effective treatments refractive procedure is still not clear, with the options of the corneal inter-
for hyperopia have a larger ablation diameter than those for myopia. cept of the visual axis, the entrance pupil, or the corneal light reflex.21,22
96 Hyperopic astigmatism treatment is accomplished with the excimer Eye-tracking devices rely on infrared lasers or cameras to follow small eye
laser by removing tissue along the paracentral area, promoting steepening movements and move the laser ablation beam accordingly.
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Studies have shown improvements in uncorrected visual acuity (UCVA),
BCVA, and centration with eye-tracking devices.23,24 Larger ablations and
blend zones may reduce the incidence of glare and halos.25 3.4
Wavefront-guided (WFG) LASIK, also called custom LASIK, is a varia-
tion in which the excimer laser ablates a sophisticated pattern based on
LASIK
measurements from an aberrometer. The goal of WFG LASIK is to achieve
an improved ablation based on the optical aberrations measured with the
wavefront aberrometer, not just sphere and cylinder (lower-order aberra-
tions). There are other types of optical aberrations in the visual pathway
of the eye, such as coma and spherical aberration, collectively called
higher-order aberrations (HOA). Wavefront technology measures both the
lower-order aberrations and HOA,26,27 improving the precision of refraction
to 0.1 D or smaller. There are several methods that can be used to measure
the wavefront: Tscherning, dynamic skiascopy, ray tracing, and Hartmann–
Shack. All methods evaluate how light is modified as it passes through the
lens and cornea, and a wavefront is constructed by analyzing the exiting
light rays. The shape of the wavefront describes the total aberration of the
eye. The size of the wavefront (cross-sectional area) is determined by the
size of the entrance pupil.
The first step in the wavefront-based LASIK technique is an examina-
tion with a wavefront device that measures the aberrations. The profile to A
correct these aberrations is created and imported into an excimer laser
and used to guide the ablation during LASIK. (Fig. 3.4.3A). As the abla-
tion patterns and treatments become more complex and more specific for WAVEFRONT OPTIMIZED
the individual, the importance of precise registration of these patterns on
the cornea increases. Significant cyclorotation could introduce significant
postsurgical aberrations.22,28,29 Iris registration is able to compensate for
pupil centroid shifts due to variable illuminations and pupil sizes by ref-
erencing to the outer iris boundary with improved centration of wavefront
ablations.30
The wavefront data can provide useful information in the postoperative
setting, where it can be used to identify and describe specific HOA that
may be consistent with a patient’s subjective visual symptoms.
Wavefront-optimized treatment profiles are population-based correc-
tions designed to reduce or eliminate the induced spherical aberration of
conventional LASIK.31 The wavefront-optimized treatment is based on a normal ablation
spherocylindrical correction that is adjusted by an internal algorithm to
remove additional tissue in the periphery of the ablation zone, thereby cre-
circular in the center reflection
ating a more prolate corneal shape.
In traditional myopic corrections, laser pulses at the peripheral cornea
have a diminished effect due to the oblique angle of the laser beam,
which induces spherical aberration. To compensate for this effect in a reduced ablation, low fluence
wavefront-optimized ablation, extra laser pulses are applied to the corneal B
periphery (Fig. 3.4.3B).32,33
Topography-guided LASIK uses information from both the corneal shape
and the refractive spherocylindrical correction to determine the excimer
laser ablation profile (Fig. 3.4.3C).
Topographers, which are not limited by pupil size, can measure greater
and wider points of curvature on the cornea compared with wavefront
devices. Topography-guided treatments can be used successfully for highly
aberrated eyes (such as corneas with opacities or irregular astigmatism)
and are not affected by the state of accommodation, early cataracts, or vit-
reous opacities.34
Patient Selection
Preoperative Evaluation and Diagnostic Approach
The first step in the evaluation should be to determine the goals of the
patient in seeking refractive surgery and assess whether the patient has
realistic expectations. Patients should understand the risks, benefits, and
alternatives to the LASIK procedure. A stable refraction is important. Most
surgeons now limit the upper range of correction to treatment of 8–10 D of
myopia even though the lasers are capable of treating higher corrections.
Also important is a review of ocular and systemic conditions. Visual
acuity is measured using manifest and cycloplegic refraction. The refrac- C
tion is compared with prior spectacle corrections to assess the stability of
refraction for the given eye. In addition, the wavefront refraction can be Fig. 3.4.3 Wavefront-Guided, Wavefront-Optimized Ablations, and Topography-
used as the baseline to obtain the wavefront-adjusted manifest refraction Guided Lasik. (A) Wavefront-guided treatment plan based on aberrometry
(WAMR). Pupil size, ocular dominance testing, and distance and near demonstrating lower and higher aberrations. Note: eye with significant degree
vision with and without correction should also be documented. Anterior of higher order aberrations despite low refractive error. (B) Wavefront-optimized
and posterior segment examinations are performed to rule out other con- treatments deliver additional pulses to the peripheral cornea to compensate for
ditions that may adversely affect the surgical result. energy loss (beam ovalization and reflection) and decrease spherical aberration.
Measurement of the central corneal thickness is an important element (C) Topography-guided ablation. Overview display of patient’s topographical data
of the preoperative evaluation. WFG and optimized procedures usually utilized to guide excimer laser treatment. Data include reduced camera image of
measurement, keratometer data, color coded topographical image, and values.
97
remove more stromal tissue compared with conventional treatments. An
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estimated residual stromal bed is needed for surgical planning, because and sounds of the procedure, serves to maximize comfort and minimize
3 it is one factor that may predict postoperative ectasia. It is computed by

subtracting the anticipated flap thickness and maximum ablation depth
from the central corneal thickness measurement. The minimal residual
anxiety. Approximately 5–10 minutes before the procedure, a mild sedative
can be given to the patient to alleviate the anxiety of undergoing the proce-
dure and to help them sleep postoperatively.
bed for LASIK remains controversial, although 250–300 µm is generally When performing a WFG LASIK procedure, obtaining an accurate
Refractive Surgery
recognized as a minimum. capture of ocular aberrations is critical to ensure accurate measurements

Ectasia can occur with even thick residual stromal beds in eyes with and optimal results (Fig. 3.4.3A).
keratoconus features. To account for variations in actual flap thickness, the
stromal bed can be measured after the flap has been retracted to allow for Microkeratome Surgical Technique
a more precise determination of the residual bed. A percentage of ante- Topical anesthesia is applied to the eye. The eyelids are prepared with
rior tissue depth altered (PTA) ≥40 at the time of LASIK was significantly dilute povidone–iodine solution. A lid speculum is inserted to open the
associated with the development of ectasia in a study of eyes with normal eyelids. Eyelashes should be kept away from the surgical field by the use of
preoperative topography.35 adhesive drapes or a closed bladed lid speculum. The contralateral eye is
Computer-assisted videokeratoscopy, corneal tomography, and Scheimp- taped shut to prevent cross-fixation and drying. The microkeratome should
flug imaging are now available and used routinely in the preoperative and be inspected for any defects in the blade or function of the moving parts.
postoperative assessments of refractive surgery patients. These tools can It is vital to confirm that the excimer laser will be able to deliver treatment
help to screen for subclinical keratoconus or other corneal diseases. after the corneal flap is reflected.
Rigid contact lens wearers should remove their lenses for 3–4 weeks The cornea can be marked with ink before creating the corneal flap
before examination, and soft contact lens wearers should have 2 weeks with the microkeratome to more easily realign the corneal flap in the event
without lenses. that a free flap is created.
The possibility of monovision should be discussed with patients near The suction ring is placed using a bimanual technique in which the
or of presbyopic age; the discussion should include glare and halos, the shaft of the suction ring is held in the fingers of one hand and a finger
possibility of under- and overcorrection, and any special considerations. from the other hand provides additional support on the ring itself. Once
Appropriate reading materials are helpful for patient education. adequate placement has been achieved, the suction is engaged by foot
Informed consent should include a discussion of the most frequent control (usually done by the technician). Adequate intraocular pressure
side effects and potential risks involved with the surgery. (above 65 mm Hg) is then verified, with one useful method being an appla-
Alternative refractive treatments such as PRK should be discussed and nation lens (Barraquer tonometer). When adequate suction is achieved, the
may be preferred to LASIK in patients with anterior basement membrane patient will confirm the temporary loss of visualization of the fixation light.
dystrophy (ABMD), thin corneas, small and deep-set orbits, anterior scleral Before the pass of the microkeratome, several drops of artificial tears
buckles, glaucoma after trabeculectomy, optic nerve disease, a risky occu- are placed on the cornea. This lubrication reduces the likelihood of a
pation or activity, and corneal ectasia.36,37 corneal epithelial defect occurring during the microkeratome pass. If
The option of phakic IOL implantation can be offered to patients with using a two-piece microkeratome, the head is slid onto the post of the
high myopic corrections, very thin corneas, or abnormal corneal topogra- suction ring and advanced until the gear on the microkeratome head
phy and/or tomography. Natural lens replacement is an option for patients engages the track. It is important to again verify that the suction ring is
nearing cataract age or requiring higher hyperopic corrections. still firmly attached to the globe at this point by gently lifting the suction
ring upward, making sure that the suction is not lost. The surgeon then
Limitations and Contraindications activates the microkeratome using forward and reverse foot control, the
Laser vision correction may have a higher risk in patients with collagen suction is turned off after the microkeratome pass, and then the suction
vascular disease,38 patients with autoimmune or immunodeficiency dis- ring can be carefully removed. Prompt attention at this point is extremely
eases, women who are pregnant or nursing, patients with signs of kera- important in the case that a free cap or buttonhole has been created. In
toconus, and those taking isotretinoin or amiodarone. Other conditions cases in which the stromal bed is too small or irregular for a good result,
potentially associated with more adverse outcomes include Fuchs’ corneal the laser ablation should not be performed, and the flap should be placed
dystrophy, strabismus, ophthalmic herpes simplex or herpes zoster, and carefully back into position.
other systemic diseases likely to affect healing, such as diabetes and atopic Before the flap is lifted, a wet cellulose sponge is used to prevent any
disease.17,39-41 Caution should be exercised for patients with abnormal cells, debris, or excess fluid from getting onto the stromal bed. With use
corneal topographies or with ocular abnormalities as well as systemic con- of a flat cannula, iris sweep, or smooth forceps, the flap can be lifted and
ditions that are likely to affect wound healing. directed toward the hinge. Assessment of the thickness of the residual
corneal bed may be performed by using ultrasound pachymetry. Microker-
Microkeratomes and Femtosecond Lasers atome flap thickness may vary, with differences in thickness occurring even
with the same microkeratome, making this measurement more important
A critical step in LASIK is the creation of the corneal flap. Several differ- in eyes that may require a deeper ablation with the excimer laser, thus
ent microkeratomes are available for use in LASIK, ranging from modern leaving less tissue in the residual corneal bed.
automated steel microkeratomes to femtosecond lasers.42 The choice
depends on the surgeon’s access and preference. In the past decade, the Femtosecond Laser Flap Creation
femtosecond laser has gained popularity and is replacing mechanical The femtosecond laser is a highly precise, computer-guided laser that
microkeratomes for LASIK flap creation in the United States.43,44 Femto- enables surgeons to program flap parameters, such as diameter, depth,
second lasers use laser pulses to cause microcavitation bubbles at a preset hinge location, and edges, based on patients’ anatomical characteristics or
depth in the corneal stroma. The cavitation bubble is composed primar- surgeons’ preferences (Video 3.4.1). Flap parameters such as pattern, hinge
ily of water and carbon dioxide. Multiple cavitation bubbles coalesce, and position, flap depth, flap diameter, bed energy and spot separation, side cut
See clip:
an intrastromal cleavage plane is created. Hinge placement, flap diame- angle and energy, hinge angles, and pocket parameters need to be carefully 3.4.1
ters, and flap thickness can be set to exact specifications. The chance of programmed or reviewed by the surgeon before the surgical procedure is
a flap buttonhole or incomplete, decentered, or free flap appears to be initiated.
reduced. Flaps are thinner and of uniform thickness from the center to A suction ring is applied to the eye with slight downward pressure, and
the periphery. Femtosecond flap creation is very precise and flap thick- suction is then enabled to affix the ring firmly to the eye. Proper centration
ness is usually within ±14 µm of the intended result.43–45 These differences is extremely important and is a critical step that ensures greater accuracy
in flap creation between femtosecond lasers and mechanical microker- of all subsequent steps of flap creation (Fig. 3.4.4). With the eye fixated,
atomes are thought to be responsible for better LASIK outcomes with the the cornea is then fully applanated. Centration and flap size should be
femtosecond laser. confirmed on the monitor before the laser is initialized for treatment. It is
critical to instruct the patient to abstain from eyelid squeezing during this
Operative Technique step to prevent suction loss (Fig. 3.4.5A).
Once the procedure is complete, suction can be released and the same
Careful candidate selection, as discussed earlier, is critical for optimal technique can be repeated on the contralateral eye.
outcomes. Surgeon preparation, including a thorough knowledge of the Lifting femtosecond flaps can be quite different from lifting a micro-
98 patient, procedure, parameters, and equipment, is essential. Patient prepa- keratome flap and is rather a blunt dissection, best accomplished with the
ration, including preoperative explanation regarding the steps, sights, use of a spatula (Fig. 3.4.5B). The spatula should be entered near the hinge
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LASIK
Fig. 3.4.4 Suction Ring Centration Is a Critical Step That Ensures Accuracy of All Fig. 3.4.6 Patient Fixation on Target Light Under Laser and Tracker Fixation on
Subsequent Steps of Femtosecond Laser Flap Creation. Pupil Width Should Be Maintained at All Times During Excimer Treatment.
and gently elevated in one to four swipes. The flap is then reflected, and
the surgeon can proceed with excimer laser treatment.
Excimer Laser Ablation

The patient should be positioned under the microscope with the head
carefully aligned to make sure that the iris is perpendicular to the laser
beam. Careful centration with the eye aligned in the x, y, and z planes
is crucial. Alignment is even more critical with wavefront-guided laser
treatments because most HOA are not radially symmetrical. Torsional
misalignment—either cyclotorsion or head tilt—during surgery can result
in undercorrection of the aberration or even in the induction of additional
aberrations. The most basic technique to ensure alignment is to mark
the limbus, typically at the 3 and 9 o’clock positions, immediately before
surgery while the patient is seated. These marks are then used to align the
head when the patient is lying under the laser. Most modern laser systems
are now equipped with either pupil tracking or iris registration.
The surgeon should always verify the entered computer data before
starting the ablation. The microscope should be adequately focused on the
corneal surface. A dry cellulose sponge is then used to carefully remove
any excess fluid from the stromal surface. Hydration of the stromal bed
needs to be adjusted evenly and consistently in all cases. It is important
at this point to minimize the procedure time in order to prevent stromal
dehydration and subsequent overcorrection. Uneven hydration can lead to
central islands and/or irregular astigmatism. Excess pooling of fluid often
can be found near the hinge after folding back the flap and should be
A
wicked away. The patient should be instructed to fixate on the target light.
Adequate centration over the pupil should be reassessed (Fig. 3.4.6).
The laser eye tracker and iris registration are activated, and the laser
ablation initiated. If fluid starts accumulating over the stromal surface, the
laser ablation can be halted, and the fluid should be removed with a cel-
lulose sponge. The hinge should be protected if it is within the ablation
zone.
After the ablation, the flap is then repositioned onto the bed using
an irrigation cannula or an iris sweep. Saline solution is used to remove
debris from the interface (Fig. 3.4.7). A wet cellulose sponge is then used
to realign the flap. Sweeping movements should be performed from the
hinge toward the periphery of the flap.
Good adhesion of the flap is verified by stretching the flap toward the
gutter. If good adhesion is present, there is minimal space in the gutter
and no movement of the flap occurs when stroking the flap with a dry
sponge. When the flap is felt to be securely in position, a drop of an antibi-
otic, a corticosteroid, and a lubricating agent may be applied to the cornea
before removal of the speculum. If bilateral LASIK will be performed, the
operated eye is covered and the procedure repeated in the contralateral
eye. Both eyes are then protected with transparent plastic shields until the
following day.
B
Postoperative Care
Fig. 3.4.5 Raster pattern flap creation with Intralase femtosecond laser (A). Postoperative care of the typical patient who has undergone LASIK is still 99
Femtosecond flap dissection with blunt spatula. (B). quite important. Generally, some tearing and burning occurs immediately
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Fig. 3.4.7 Irrigation Under the Flap Can Remove Debris From the Interface. Care
must be taken not to overirrigate, as this can increase the risk of flap striae from Fig. 3.4.8 Opaque Bubble Layer (OBL). Note gas bubbles trapped inside the
overhydration. stoma. The OBL can make lifting of the flap difficult and, if over the pupillary area,
may interfere with an eye-tracking mechanism during excimer laser ablation.
after surgery, for which it is recommended that the patient take a 2-hour
nap. The patient is placed on topical prophylactic antibiotics and topical photoablation. Care must be taken to reposition the cap into the same ori-
corticosteroids four times per day for 1–2 weeks. Preservative-free lubri- entation after the ablation. Adequate drying time should be allowed for the
cating drops are helpful in most patients for the first several weeks after cap to adhere without sutures. The most frequent cause of a free cap is a
surgery, and frequent use should be encouraged. flat or small cornea in which there is less tissue to be brought forward into
On the first postoperative day, careful evaluation of the corneal flap the microkeratome. Poor suction also can cause small free flaps. Marking
should be performed at the slit lamp. The patient may resume most activ- of the cornea before flap creation can facilitate alignment in the event of
ities if the postoperative examination is normal. Instructions not to rub a free cap.
the eyes or swim underwater should be reinforced to prevent flap displace- Epithelial defects can be prevented with adequate lubrication of the
ment or infectious keratitis. cornea before the microkeratome pass. Also, toxic anesthetics should be
kept to a minimum before the procedure. If a large epithelial defect occurs
Complications during the microkeratome pass, the ablation should be aborted in the
affected eye. It is not recommended to proceed with flap creation in the
Intraoperative Complications contralateral eye, as the same complication is likely to occur. On the other
An incomplete flap may result from the premature termination of the hand, if the epithelial defect is small, a contact lens can be placed over
microkeratome advancement or ineffective passes or suction loss during a the cornea to decrease significant discomfort to the patient. An epithelial
femtosecond flap creation. Reasons for a microkeratome incomplete pass defect may lead to greater flap edema with poorer adherence in the area of
include inadequate globe exposure due to interference of eyelid, lashes, the defect, increasing the risk of epithelial ingrowth and diffuse lamellar
speculum, and/or drape as well as loss of suction during the pass. If there keratitis.
is not enough room beneath the flap to perform the ablation, then the Epithelial breakthrough is a rare complication during femtosecond laser
surgeon should reposition the flap and abort the surgery. Incomplete corneal flap creation and is generally observed in patients with prior corneal
flaps also can result when the femtosecond laser cannot photodisrupt the incisions in the ablation zone. In these situations, increasing femtosecond
corneal stroma in portions of the intended interface or if there is resistance energy or microkeratome flap creation should be considered. In patients
within the interface from scar tissue. Typically, surface laser treatment with with severe corneal scars that obscure visualization of anterior segment
mitomycin-C can be used later to complete the refractive correction.46,47 structures, femtosecond flap creation should be avoided. It is important
When suction loss occurs during a femtosecond LASIK flap creation, to be attentive for this complication intraoperatively and to abstain from
resulting in an incomplete flap, a second femtosecond pass can create an lifting the flap to prevent more serious flap problems such as buttonholes
intact flap. Tomita and colleagues reported successful immediate lamel- or flap tears.55
lar recut in their series of eyes with suction loss.48 Some controversy An opaque bubble layer (OBL) and anterior chamber gas bubbles can
surrounds the rationale for immediate recut, as other authors have demon- present during corneal flap creation with a femtosecond laser. An OBL
strated the potential for creating new cleavage planes if immediate recut is forms when gas bubbles created by laser photocavitation are trapped inside
undertaken.49 When suction loss occurs during the side cut or just before the stoma. Gas also can appear in the anterior chamber and persist up
starting the side cut, a repeat side cut can be performed with a smaller to several minutes or even hours. The OBL can make lifting of the flap
diameter. difficult, and care must be taken to perform a gentle blunt dissection to
A flap buttonhole is one of the most serious flap complications, and the prevent a flap tear in the area of the OBL. If the OBL or anterior chamber
excimer laser ablation should be aborted. The flap should be repositioned bubbles are over the pupillary area, they may interfere with an eye-tracking
and smoothed into place. Treatment of the second eye is not advisable at the mechanism during excimer laser ablation. In these situations, it is usually
same setting, as the same complication is likely to happen in the presence recommended to wait for bubbles to dissipate before proceeding with laser
of a steep cornea or poor suction. However, these almost always occur in treatment.56 Other factors associated with increased frequency of OBL
the second eye with a thinner flap in mechanical microkeratomes.50,51 Fem- include steeper, thicker corneas and a hard docking technique. Although
tosecond laser flaps also are prone to similar complications, albeit usually the OBL makes the LASIK procedure more difficult, it does not appear
from a different mechanism: vertical gas breakthrough.52 Epithelial ingrowth to affect the postoperative optical quality and visual outcome (Fig. 3.4.8).57
or haze may occur in the area of the buttonhole and may require further
intervention. Typically, retreatment can be performed immediately or later Ablation Complications
with phototherapeutic keratectomy (PTK)/PRK and mitomycin-C.53,54 Central islands are small central elevations in the corneal topography
A free cap can occasionally occur when using a microkeratome to create that may occur for a variety of reasons.58,59 Beam profile abnormalities,
a flap, and the surgeon should be prepared to deal with this problem. If the increased hydration of the central corneal stroma, or particulate material
cap is small and/or decentered, it should be replaced without ablation and falling onto the cornea may block subsequent laser pulses. This was more
100 the procedure aborted. If it is well centered and of adequate size, the cap is common with broad-beamed lasers.60 Typically these central islands resolve
typically placed on the conjunctiva with the epithelial side down during the with time as epithelial remodeling fills in the surrounding area.
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Fig. 3.4.9 Superior Decentration on Scheimpflug
Imaging Following Myopic Excimer Ablation.
3.4
LASIK
Decentration (Fig. 3.4.9) can result from poor fixation and alignment, sponge can minimize persistent folds in the flap and properly line up the
eye movement during the laser procedure, significant pupil shift with cap with the bed.
light, or asymmetrical hydration of the cornea. The higher the myopic cor- Punctate epithelial keratopathy (dry eye) is the most frequent complication
rection, the greater the risk of a decentered ablation, which can result in of LASIK.68 Several possible mechanisms contributing to LASIK-induced
glare, irregular astigmatism, and a decrease in BCVA.22,61,62 Low-contrast dry eye have been proposed. The mechanisms include injury to the affer-
visual acuity is a more sensitive measurement of visual function than ent sensory nerve fibers, a reduction in neurotrophic influences on epi-
high-contrast Snellen acuity and can be used to assess these patients more thelial cells, a decreased blinking rate, decreased tear production, altered
accurately.63 Decentration may be decreased with the use of current lasers tear-film stability and distribution, increased tear evaporation, and injury
with incorporated eye-tracking systems and iris registration, yet careful to limbal goblet cells. The preponderance of data supports the hypothesis
attention must still be paid to patient fixation.64 Typically, if the ablation that the most important factor in the pathophysiology of LASIK-induced
is more than 1 mm decentered, the irregular astigmatism that occurs is dry eye is the transection of afferent sensory nerves in the anterior third
symptomatic. Management of decentration by treatment based on wave- of the stroma during the lamellar cut.69,70 The disorder tends to be more
front or topographical information may decrease symptoms in patients common and more severe in the context of underlying chronic dry eye. It
with an unsatisfactory outcome with the first procedure.65 has become evident, however, that the disorder is multifactorial.71,72 Studies
Under- and overcorrection may result from errors of refraction, improper in patients in whom the flap was created with a microkeratome showed
surgical ablation, malfunctioning of the excimer laser, abnormal corneal significantly more signs and symptoms of LASIK-induced dry eye than
hydration status, or an excessive or inadequate wound-healing response. those in which a femtosecond laser was used for flap creation.73 Treatment
It is crucial to maintain consistent hydration of the cornea, because exces- involves frequent lubrication of the ocular surface with artificial tears,
sive fluid on the cornea results in an undercorrection. If desiccation of topical anti-inflammatory therapy, and punctual plugs; management of any
the corneal stroma is present, then overcorrection and haze may occur. eyelid disorder also may be of benefit.
The higher the refractive error, the greater the chance of regression.63 Diffuse lamellar keratitis (DLK), also known as Sands of Sahara syndrome,
Many surgeons find that adjusting the amount of treatment using a is an interface inflammatory process that occurs in the early postopera-
nomogram based on their actual surgical results improves their refractive tive period after LASIK (Fig. 3.4.10).74 Patients are initially asymptomatic
outcomes. and often have no visual impairment. A fine granular-appearing infiltrate
that looks like dust or sand typically presents initially in the interface
Postoperative Complications periphery. If left untreated, the inflammation can progressively worsen
Interface debris is common even with aggressive interface irrigation. The and may lead to corneal scarring with resultant irregular astigmatism. The
most frequent source of debris is meibomian gland material from the lids cause of DLK is likely multifactorial. Bacterial toxins or antigens, debris
that is trapped in the interface. Careful draping of lashes and cleaning of on the instruments, eyelid secretions, or other factors may play a role.74–77
the flap interface with balanced salt solution before and after the flap is Femtosecond LASIK flap creation has been associated with a higher risk
floated into position can help to reduce the incidence of this problem.66 for DLK than microkeratome flap creation.78 Studies suggest that newer
Flap displacement usually occurs in the first 24 hours postoperatively. generation femtosecond lasers with higher frequency are associated with
When a flap displacement occurs, it should be lifted and repositioned as decreased DLK rates because lower energy settings are used in creating
soon as possible.67 The epithelium at the flap edge grows remarkably fast LASIK flaps.
to cover the stromal bed. Care must be taken to clean the bed and back Treatment involves frequent topical corticosteroids, and if severe 101
of the flap of debris and epithelial cells. Stroking the cap with a cellulose enough, interface irrigation.79,80 However, some authors have reported
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Refractive Surgery
Fig. 3.4.10 Diffuse Lamellar Keratitis (DLK). The image shows stage II DLK,
and identification of this should be followed by increased topical corticosteroid
administration and close follow-up.
excellent results in the treatment of severe DLK with high-dose topical and
oral corticosteroids without flap lifting and interface irrigation.81
Flap striae and microstriae are common complications after LASIK. Most
striae are asymptomatic and can be visualized if the flap is carefully exam-
ined with retroillumination.66 When microstriae occur over the pupil or
when macrostriae exist, irregular astigmatism with visual aberrations and
monocular diplopia may result. In such cases, the flap should be lifted
again, hydrated, and stretched back into position.
Epithelial ingrowth into the interface between the flap and the stromal
bed occurs in up to 3% of patients following myopic LASIK surgery (Fig.
3.4.11). Known risk factors for this complication include epithelial defects
at the time of surgery, history of recurrent corneal erosions, corneal base- B
ment membrane epithelial dystrophy, history of ingrowth in the other eye,
hyperopic LASIK correction, flap striae or folds (as when the flap dislocates Fig. 3.4.11 (A) Central epithelial ingrowth under LASIK flap following traumatic flap
after surgery because of trauma or poor adhesion), flap instability, type 1 displacement. (B) Peripheral epithelial ingrowth with associated flap melting.
diabetes, and repeated LASIK surgeries.82,83 Rarely, the epithelial ingrowth
progresses into the central visual axis, causing irregular astigmatism and
loss of BCVA. In some cases, the epithelial cells will block nutritional
support for the overlying stroma and lead to flap melt.66 If this is the case, should also be taken for Gram, Giemsa, and Calcofluor white stains as well
the flap should be lifted, and careful scraping of the epithelium should as Ziehl–Neelsen for acid-fast bacteria.
be performed at the stromal bed as well as under the flap. In recurrent The mycobacteria species associated with keratitis following LASIK
cases, suturing or flap gluing may help to reduce the incidence of recur- belong to the nontuberculous mycobacteria group. These species are resis-
rent epithelial ingrowth.84 Nd:YAG laser application has been described as tant to chemical disinfectants such as chlorine, which is probably why
a technique for the treatment of epithelial ingrowth after LASIK surgery.85 such infections may occur after surgical procedures. Clarithromycin and
Corneal haze can occur following LASIK. With fears of corneal ectasia amikacin are the antibiotics of choice, but poor penetration of topical med-
following LASIK, surgeons continue to aim for thinner flaps. Although ications leads to persistent infection. Early flap lifting and soaking of the
thin-flap LASIK has been reported to be successful,86 there have been flap and bed with amikacin 0.08% and/or clarithromycin 1% followed by
reports of interface haze formation with thin-flap femtosecond LASIK aggressive topical therapy leads to the best results.92
(<90 µm), especially in young patients87 and could be related to focal Perhaps the most important factor within our control is prevention.
disruptions of the Bowman’s layer and injury to the epithelial basement Meibomian gland disease should be treated before LASIK. Instruments
membrane.88 must be properly sterilized, and intraoperative sterile techniques should
Infectious keratitis after LASIK is a devastating, vision-threatening be employed, including the use of sterile gloves and drapes and disinfec-
complication. Fortunately, the estimated incidence is low and reported to tion of the skin and eyelids with povidone–iodine. During the procedure,
be between 1 in 1000 and 1 in 5000 procedures.89,90 Reported organisms instruments should be sterile and sterile plastic bags used for the nonster-
include Mycobacterium spp., fungi, Nocardia spp., Staphylococcus aureus, ile portions of the laser. Efforts should be made to avoid irrigating meibo-
Streptococcus viridans, coagulase-negative Staphylococcus spp., and Strepto- mian secretions into the interface. Suction lid specula may be helpful in
coccus pneumoniae.91 The most common organism cultured in a worldwide removing excessive fluids and debris. Postoperatively, the patient should
survey was methicillin-resistant Staphylococcus aureus (MRSA).93 Symp- be instructed to wear shields and not to rub the eye. Prophylactic antibiot-
toms may include pain, photophobia, watering, decreased visual acuity, ics should be used for 1 week postoperatively.
ghost images, and halos. Slit-lamp examination may reveal ciliary injec-
tion, epithelial defect, anterior chamber reaction, and hypopyon. In the Keratectasia
case of mycobacteria and fungi, presentation is usually delayed several Retrospective analysis of patients with ectasia suggests the following risk
weeks after the LASIK procedure and then has a smoldering course. Clin- factors for progression of ectasia after laser vision correction: (1) abnormal
ically, the mycobacteria and fungi usually are seen in the interface, often preoperative topography, (2) low residual bed thickness, (3) young age, (4)
with a feathery or indistinct margin. Gram-positive infections are usually low preoperative corneal thickness, and (5) high myopia.94,95 General agree-
seen shortly after the procedure, often at the flap margin, and usually have ment exists on leaving 250–300 µm of untouched posterior cornea stroma.
distinct, sharp margins. Ablation below that limit may cause biomechanical weakening, causing
It is important to maintain a high suspicion for atypical organisms. The the cornea to bulge forward.96 Another important cause of iatrogenic ker-
102 flap should be lifted and cultures should be inoculated on blood, chocolate, atectasia is LASIK performed on unrecognized keratoconus suspects.97
Sabouraud and Lowenstein–Jensen agar, and blood–heart infusion. Smears Videokeratographic clues for a keratoconus suspect may include steep
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keratometry, inferior steepening of the cornea, asymmetry of the corneal lines of BCVA at 1 year.122 For higher levels of correction, the predictability
curvature, or nonorthogonal astigmatism. Iatrogenic keratectasia has been
reported as early as 1 week and as late as 2 years postoperatively.98
within ±1 D of attempted correction decreases to approximately 50%–80%,
and the loss of BCVA generally ranges from 0% to 7%. However, LASIK 3.4
Although ectasia is rare after laser vision correction, many manage- for hyperopia greater than +5.00 D is not recommended, as it may result
ment options are available. Most are similar to those available for naturally in a loss of BSCVA in a significant number of eyes (13%–15%).123–128
LASIK
occurring keratoconus. Most patients can still function well with nonsurgi- Multicenter clinical trials of wavefront-guided LASIK for the correc-
cal options, such as contact lenses.99,100 Intracorneal ring segments may be tion of hyperopia and hyperopic astigmatism demonstrated significant
used to manage patients with ectasia after refractive surgery.101–103 Corneal improvements compared with traditional LASIK. Mean preoperative
collagen crosslinking (CXL) with riboflavin and ultraviolet-A (UVA) radi- spherical error was +1.67±1.00 (up to +4.59 D), the average astigmatism
ation is now being used to treat keratoconus and post-LASIK ectasia; the was +0.65±0.48 D (up to +2), and MRSE was +1.99±1.00 D (up to 4.84 D).
principal goal of the technique is to stabilize the progression of these At 6 months, 95% of the eyes had a UCVA of 20/40 or better, 62% were at
corneal diseases.104,105 In previous studies of CXL outcomes, patients had 20/20 or better, and 20% were at 20/16 or better. The UCVA at 9 months
improvement in corrected distance visual acuity (CDVA), uncorrected dis- was 20/16 or better in 24% of eyes and 20/20 or better in 72% of eyes.120
tance visual acuity (UDVA), maximum and average keratometry (K) values, For mixed astigmatism, multicenter trials for custom wavefront LASIK
several corneal topography indices, and corneal and optical HOA.106–108 results 6 months after surgery were a UCVA of 20/40 or better in 96% of
Although corneal transplantation (penetrating or lamellar) is not often eyes and 20/20 or better in 60% of eyes.120
required, transplantation does have a high rate of success in eyes with ker- Wavefront-guided and wavefront-optimized procedures attempt
atoconus and would likely yield similarly good results in eyes with ectasia to minimize induced aberrations in different ways. Aspherical or
after refractive surgery.109,110 wavefront-optimized ablation profiles have been developed to avoid induc-
ing spherical aberrations.129,130 Stonecipher and Kezirian reported 3-month
Results results of an FDA trial for LASIK with the Allegretto Wave comparing
wavefront-optimized versus wavefront-guided LASIK for myopic astig-
The efficacy and predictability of laser refractive surgery have greatly matism, finding no statistically significant differences between either
improved in recent years, even with standard conventional techniques. treatment group in regard to visual acuity and refractive outcomes. They
Most of this improvement is due to the development of flying spot stated that 93% of patients in each group had achieved 20/20 vision or
lasers,18,111 tracking systems,112,113 and 8- to 9-mm transition zones that allow better.131 These results are comparable to those reported in a prospective,
for blending the steep step at the periphery of the ablation zone.114,115 randomized study by Miraftaf et al., who compared wavefront-guided and
With traditional LASIK, the accuracy is greater for lower degrees of wavefront-optimized LASIK in contralateral eyes with myopia up to 7.00 D
myopia. In one study of 130 eyes with an average preoperative spheri- and astigmatism up to 3.00 D, also reporting no statistical differences in
cal equivalent (SE) of −3.61 D followed for 12 months after LASIK, 98% the UCVA, BCVA, or contrast sensitivity between both groups with 20/20
obtained a correction within ±1 D from target and 93% obtained 20/40 or vision or better in 83.8% of the wavefront-optimized eyes and 89.2% of the
better UCVA.116 wavefront-guided eyes.132
Another study showed that in low myopia (−0.75 D to −6.00 D of Stonecipher and Kezirian concluded in their study that wavefront-guided
myopia and 0–0.75 D of preoperative astigmatism), 50% of eyes achieved treatments may be considered if the magnitude of preoperative root mean
20/25 or better and 90% of eyes achieved 20/40 or better at 1 month post- square (RMS) HOA is >0.35 µm, and in their study population, 83% of
operatively, and the SE was within ±1.00 D of emmetropia in 89% of the eyes had preoperative RMS HOA of <0.3 µm.131
patients. In high myopia (−6.00 to −20.00 D of myopia and 0 to 4.5 D of Studies using topography-guided LASIK have been encouraging. A
preoperative astigmatism), at 1 month, 35% of eyes were 20/25 or better prospective study of topography-guided LASIK using the WaveLight Alle-
and 71% of eyes were 20/40 or better, and the mean SE was within ±1.00 D gretto Wave Eye-Q Laser included 249 eyes of patients with up to –9.00 D
of emmetropia in 63%.117 The results of this and other studies suggest of SE myopia at the spectacle plane with up to 6.00 D of astigmatism.
more predictable results for low myopia without astigmatism than for high Topography-guided treatment resulted in a significant reduction in MRSE
myopia correction or in eyes requiring astigmatic correction.118,119 and cylinder, reaching stability at 3 months after treatment. The mean
Data obtained from multicenter trials on wavefront-guided LASIK abla- MRSE was 0.06±0.33 D at 3 months and 0.00±0.27.00 D at 1 year. At 1 year,
tion for low to moderate myopia and astigmatism revealed that 98% of 94.8% of eyes were within 0.50 D of plano. At 1 year, 15.7% of eyes saw
eyes achieved 20/20 UCVA, and 71% were at 20/16 or better uncorrected. 20/10 or better without correction; 34.4% of eyes saw 20/12.5 or better;
What is even more impressive is the fact that postoperative UCVA was 64.8% of eyes saw 20/16 or better; 92.6% of eyes saw 20/20 or better; and
better than the preoperative best corrected results in 47% of patients.120,121 96.5% of eyes saw 20/25 or better. Eyes treated with topography-guided
Ongoing improvements in the custom wavefront treatments have treatment achieved an improvement in UCVA compared with preoperative
resulted in more precise treatments and postoperative results even for BSCVA, with 29.6% of eyes gaining one or more lines of UCVA and 89.9%
higher corrections. The results achieved with VISX Star S4 laser (Advanced of eyes seeing at least as well without correction postoperatively as they did
Medical Optics, Inc.; Santa Ana, CA) treatment of high myopia and astig- with best spectacle correction preoperatively.133
matism with Custom Vue customized ablations were remarkable. The In a comparative study, both topography-guided and wavefront-optimized
mean preoperative refractive spherical error was −8.00 D (±1.4 D, range LASIK for myopia in virgin eyes provided excellent results. However,
−5.5 to −11.3 D). The average cylinder was −1.00 D (±1.00, range 0.0 to topography-guided LASIK was associated with better contrast sensitivity,
−5.3 D). The manifest refraction spherical equivalent (MRSE) was −8.5 D lower induction of HOA, and a smaller amount of tissue ablation.134
(±1.3, range −6.4 to −11.8 D). At 6 months, 98% of the eyes were seeing With regard to patient satisfaction following LASIK, a comprehensive
20/40 or better uncorrected, 84% were 20/20 or better, and 65% were literature review was conducted in 2008 by the Joint LASIK Study Task
20/16 or better. Three quarters had the same or better postoperative UCVA Force. The results showed that 95% of patients were satisfied with their
compared with their preoperative best spectacle-corrected visual acuity visual outcome after myopic and hyperopic LASIK.135
(BSCVA). Among the spherical myopes, 99% were at 20/20 or better Modern LASIK outcomes support the safety, efficacy, and patient satis-
uncorrected, with 84% at 20/16 or better at 6 months. Patients’ satisfaction faction of the procedure and appear better than those reported in summa-
with their quality of vision was also high. This demonstrated that the cus- ries of the safety and effectiveness of earlier laser refractive surgery systems
tomized approach offers excellent quantity as well as quality of vision even approved by the FDA. In a recent literature review of LASIK articles pub-
for higher corrections.120 lished between 2008 and 2015, the aggregate loss of two or more lines of
Low to moderate levels of spherical hyperopia, simple hyperopic astig- corrected distance visual acuity was 0.61% (359/58 653). The overall per-
matism, and compound hyperopic astigmatism can be effectively and centage of eyes with a UCVA better than 20/40 was 99.5% (59 503/59 825).
safely corrected with LASIK. The results of a study evaluating patients The SE refraction was within ±1.00 D of the target refraction in 98.6% of
with primary and secondary hyperopia who underwent traditional LASIK eyes (59 476/60 329), with 90.9% (59 954/65 974) within ± 0.50 D. In studies
demonstrated that patients with primary hyperopia and a mean man- reporting patient satisfaction, 1.2% (129/9726) of patients were dissatisfied
ifest SE of +1.73±0.79 D before surgery obtained a postoperative SE of with LASIK.136
−0.13±1.00 D at 6 months after surgery and an SE of −0.18±1.08 D at 1 In addition, Price et al. compared visual satisfaction between LASIK
year after surgery. At 6 months, 84% of patients with secondary hyperopia and contact lens wear over a 3-year period. Current LASIK technology
had a UCVA of 20/40 or better; 76% were within ±1 D of emmetropia. At improved ease of night driving, did not significantly increase dry eye
1 year, 85% had a UCVA of 20/40 or better and 85% were within ±1 D symptoms, and resulted in higher levels of satisfaction at 1, 2, and 3 years 103
of emmetropia. No patients with secondary hyperopia lost two or more of follow-up.137
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LASIK ENHANCEMENTS group of patients, and it has been proven to be a safe, effective, and pre-
3 The initial consideration when deciding to perform a LASIK enhance-

ment is to determine the possible reason for failure of the prior procedure.
dictable procedure for treating eyes with no or low haze after PRK.162 Some
surgeons suggest that the postoperative care should be the same as after
primary PRK, with prolonged use of topical corticosteroids.163
Errors may be related to inadequate preoperative refraction, improper laser In most cases, though, because of the underlying process that led the
Refractive Surgery
ablation, abnormal corneal hydration during the procedure, an excessive or surgeon to decide on PRK in the first procedure (thin corneas, ABMD), the
inadequate healing response, or induced corneal ectasia. A careful analysis authors typically utilize PRK for enhancement procedures.
of anterior and posterior corneal elevation maps should be performed to
rule out a decentered ablation or iatrogenic corneal ectasia.138,139 LASIK After Penetrating Keratoplasty
Patient selection and appropriate timing are key for a successful LASIK
enhancement. It is recommended to wait at least 3 months before con- Residual refractive errors after penetrating keratoplasty (PKP) are usually
sidering an enhancement.140 Patients with refractive instability should not responsible for decreased visual acuity despite a clear graft. The mean
undergo an enhancement procedure. amount of astigmatism that has been reported after PKP for keratoconus is
Another important consideration is the measurement of the central usually between 2 and 6 D with only 15% >5.00 D.164 Visual rehabilitation
corneal thickness. If less than 250–300 µm of residual untouched stromal with spectacles or contact lenses should be considered initially, followed by
bed will be available after the enhancement laser ablation or PTA is less the possibility of incisional refractive surgery if the patient is intolerant to
than 40%, the risk of inducing corneal ectasia probably outweighs the either of these alternatives.
benefit of the procedure.35 Several studies have shown that LASIK has significant advantages over
Regarding the decision of whether to recut the cornea versus lift the other surgical procedures in the management of refractive errors after
flap, studies have shown the effectiveness and predictability of using differ- PKP.165–170
ent techniques.141,142 Flap lifting is probably the preferred method in most LASIK should be delayed at least 12 months after PKP because of the
patients.143 The flap edge can be marked at the slit lamp and lifted before risk of corneal dehiscence during the creation of the flap. Although the
the laser ablation. Unfortunately, this method requires flap manipulation precise safety interval between PKP and LASIK has not been established,
and has been reported to be associated with a higher risk for epithelial some surgeons have performed LASIK as early as 8 months after PRK,171
ingrowth.143,144 Flap recutting, however, may be associated with a higher risk while others advise a minimum period of 2–3 years.167,168 All sutures should
of an inadequate flap or in loose lamellar wedges of stromal tissue. There- be removed before performing the lamellar surgery.
fore it is recommended to relift a flap when performing early enhance- LASIK is more effective in treating myopia than astigmatism after PKP.
ments in most patients. Some surgeons, however, advocate a deeper cut to In a study by Donnenfeld et al., the mean SE of patients before surgery of
avoid the previous interface.145 −7.58±4.42 D improved to −1.57±1.20 D at 12 months after LASIK. Also, the
Femtosecond laser-created flaps are significantly stronger than mean cylinder of 3.64±1.72 D before surgery improved to 1.29±1.04 D by 12
microkeratome-created flaps and may be associated with increased diffi- months after. SE anisometropia was reduced from a mean of 6.88±4.4 D
culty of flap lift and a higher risk of complications.146,147 To avoid these dif- to 1.42±1.05 D at the final examination. BCVA remained the same or
ficulties and possible complications of relifting or recutting LASIK flaps, improved in 21 of 23 eyes and decreased by one and three lines in two
a newer alternative is to utilize a femtosecond laser for the creation of a patients.171
second side cut, within the border of the original LASIK flap (i.e., smaller Our experience in 57 eyes treated for myopia and astigmatism after PKP
than the original flap diameter).148 Despite some reports of good results, was a mean SE decrease from −4.19±3.38 D (range, −0.75 D to −15.25 D)
epithelial ingrowth or irregular flaps can still result, and therefore most preoperatively to −0.61±1.81 D 2 years after LASIK. The mean preoperative
surgeons do not utilize these techniques. refractive astigmatism decreased from 4.51±2.2 D (range, 0.5–10.00 D) to
A third alternative to flap lifting or recutting is PRK with the use of 1.0±1.35 D for the 28 eyes with follow-up. The UCVA was 20/40 or better
mitomycin-C on the LASIK flap.149 This is a less invasive technique for in 12 eyes (43%), and the BCVA was 20/40 or better in 86%.169 These
the correction of residual refractive errors in patients with low residual results are very similar to those of a recent study by Malecha et al. in which
stromal bed or in patients seeking an enhancement 2 or more years after the preoperative SE was reduced by 3.93 D and the mean cylinder was
the initial LASIK procedure, even though it is associated with a longer reduced by 2.83 D from the preoperative values at the last follow-up visit.
recovery.150,151 The UCVA was 20/40 or better in 73.7% of the eyes after LASIK.172 The
long-term results also appear to be quite stable in most eyes.171
In conclusion, LASIK after PKP is in general less predictable than in
LASIK IN COMPLEX CASES eyes with no history of surgery, partly because of larger corrections and the
LASIK After Radial Keratotomy effect of the graft–host interface.171 Still, significant improvement in uncor-
rected vision as well as anisometropia make this treatment attractive for
Various studies have proven LASIK to be safe and effective in treating patients with a healthy endothelium and a transplant large enough to place
residual myopia and RK-induced hyperopia.152,153 the ablation within the transplanted cornea. It is important to remember
A stable refraction for at least 6 months before LASIK is mandatory. that the realistic goals of LASIK after PKP are to decrease the degree of
A careful evaluation of the RK incisions is mandatory because the pres- anisometropia and ametropia to levels at which spectacle correction or
ence of epithelial inclusion cysts can predispose the patient to subse- contact lenses can be tolerated.
quent epithelial ingrowth after LASIK; LASIK should be avoided in these
patients.
During the LASIK procedure, the flap should be manipulated with LASIK After Intraocular Lens Implantation
extreme care to prevent the RK incisions from splaying.154 Careful obser-
vation of the patient during the postoperative period should be granted, and Bioptics
as the risk of epithelial ingrowth is higher in this group of patients.155 Bioptics, popularized by Roberto Zaldivar, is the planned combination of
The epithelial ingrowth can be particularly difficult to manage and may phakic or aphakic IOL surgery with corneal surgery to correct large refrac-
even require fibrin glue for effective treatment.84 With the availability of tive errors.173 Typically the maximum IOL power is used, and the residual
mitomycin-C to reduce haze in patients having PRK after prior surgery, refractive error is corrected by corneal ablation surgery (PRK or LASIK).
many surgeons are now using PRK to treat patients with residual refractive The surgeries can be staged, with the lens surgery performed first followed
errors after RK.156–158 later by PRK or LASIK. Alternatively, the LASIK flap can be made before
the time of the lens surgery and lifted several weeks or months later for
LASIK After Photorefractive Keratectomy the laser ablation. Bioptics can be performed with either phakic or aphakic
IOLs to correct any residual refractive error. Bioptics is especially useful
PRK has been proven to be a safe and effective method for treating low to in high myopia with astigmatisms, and it is preferable to laser corneal
moderate myopia.159 Regression as well as the development of corneal haze ablation alone because of the reduced risk of visual aberrations, contrast
are the main limiting factors in the correction of higher refractive errors, loss, glare, and halos that are associated with extremely large myopic laser
which are greater in patients treated for more than 6.00 D of myopia. ablations.174,175
PRK retreatment for undercorrections should be approached with Similarly, LASIK can be extremely useful in treating ametropia after
104 caution because there is a risk of further regression, increased haze, and clear lens extraction or cataract surgery with multifocal IOL implantation
loss of visual acuity.160,161 LASIK appears to be a better approach in this with good refractive outcomes and improved patient satisfaction.176,177
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Intraocular Lens Calculations After LASIK SUMMARY
Postrefractive surgery patients who develop a cataract expect excellent LASIK is an extremely useful technique that combines safety, rapid visual 3.4
UCVA after cataract surgery, just like after their previous refractive pro- recovery, and flexibility in its ability to be enhanced or combined with other
cedure. Experience with eyes after myopic refractive procedures indi- procedures. As the techniques continue to improve, with newer advances
LASIK
cates that use of postoperative average standard keratometric readings in in femtosecond and excimer lasers, refractive surgery will continue to
standard IOL power predictive formulas frequently results in substantial evolve and will change the way we assess our refractive expectations and
refractive errors, hyperopia being the unexpected surprise in patients who outcomes.
undergo myopic refractive procedures, and myopia in those undergoing
hyperopic procedures.178–180
Calculation of IOL power in cataract surgery is based on the measure- KEY REFERENCES
ments of corneal power/radius of curvature, axial length, and estimation of Chernyak DA. From wavefront device to laser: an alignment method for complete registra-
postoperative anterior chamber depth (effective lens position, ELP). tion of the ablation to the cornea. J Refract Surg 2005;21:463–8.
The main reason for underestimation of IOL power after refractive Davis EA, Hardten DR, Lindstrom M, et al. LASIK enhancements: a comparison of lifting to
recutting the flap. Ophthalmology 2002;109:2308–13.
corneal surgery lies in the inaccurate determination of keratometric Davis EA, Hardten DR, Lindstrom RL. LASIK complications. Int Ophthalmol Clin
power.181 The keratometer is inaccurate in this setting, because it measures 2000;40:67–75.
only four points of the cornea in a paracentral region, ignoring flatter (after Durrie DS, Vande Garde TL. LASIK enhancements. Int Ophthalmol Clin 2000;40:103–10.
myopic refractive surgery) or steeper (after hyperopic refractive surgery) Haft P, Yoo SH, Kymionis GD, et al. Complications of LASIK flaps made by the IntraLase
15- and 30-kHz femtosecond lasers. J Refract Surg 2009;25:979–84.
more central regions.182 Computerized videokeratography (CVK) overcomes Kezirian GM, Stonecipher KG. Comparison of the IntraLase femtosecond laser and mechan-
some of these limitations. However, both keratometry and CVK are inaccu- ical keratomes for laser in situ keratomileusis. J Cataract Refract Surg 2004;30:804–11.
rate in eyes that have had myopic PRK or LASIK, because the standardized Lindstrom RL, Hardten DR, Chu YR. Laser in situ keratomileusis (LASIK) for the treatment
value for the corneal index of refraction (1.3375) used in both devices is of low, moderated and high myopia. Trans Am Ophthalmol Soc 1997;95:285–306.
not valid for measuring these corneas.180,183,184 A second important factor Lindstrom RL, Linebarger EJ, Hardten DR, et al. Early results of hyperopic and astig-
matic laser in situ keratomileusis in eyes with secondary hyperopia. Ophthalmology
accounting for inaccuracies when using conventional IOL calculations is 2000;107:1858–63.
the ELP, or predicted position of the IOL along the axial length of the eye. Mrochen M, Donitzky C, Wullner C, et al. Wavefront-optimized ablation profiles: theoretical
Because preoperative data frequently are not available, and perfor- background. J Cataract Refract Surg 2004;30:775–85.
mance of IOL calculations can be time consuming using various indi- Muravchik J. Keratectasia after LASIK. J Cataract Refract Surg 2000;26:629–30.
Pallikaris IG, Papatzanaki ME, Stathi EZ, et al. Laser in situ keratomileusis. Lasers Surg Med
vidual methods, the American Society of Cataract and Refractive Surgery 1990;10:463–8.
developed an online Internet-based IOL power calculator to assist sur- Probst LE, Machat JJ. Epithelial ingrowth following LASIK. In: Machat JJ, Slade SG, Probst
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tive surgery. Ophthalmology 2008;115:37–50.
this online IOL power calculator after previous myopic LASIK or PRK. Sandoval HP, Donnenfeld ED, Kohnen T, et al. Modern laser in situ keratomileusis out-
Methods using surgically induced change in refraction as well as methods comes. J Cataract Refract Surg 2016;42:1224–34.
using no previous data gave better results than methods using pre-LASIK/ Slade SG. The use of femtosecond laser in the customization of corneal flaps in laser in situ
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As with all refractive procedures and because of the possibility of resid-
ual refractive errors, it is important that the patient should have realistic Access the complete reference list online at ExpertConsult.com
expectations and that the desired target refraction be discussed beforehand.
105
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170. Chang DH, Hardten DR. Refractive surgery after corneal transplantation. Curr Opin 182. Wang L, Jackson DW, Koch DD. Methods of estimating corneal refractive power after
Ophthalmol 2005;16:251–5. hyperopic laser in situ keratomileusis. J Cataract Refract Surg 2002;28:954–61.
171. Donnenfeld ED, Kornstein HS, Amin A, et al. Laser in situ keratomileusis for cor- 183. Maeda N, Klyce SD, Smolek MK, et al. Disparity between keratometry-style read-
rection of myopia and astigmatism after penetrating keratoplasty. Ophthalmology ings and corneal power within the pupil after refractive surgery for myopia. Cornea
1999;106:1966–74. 1997;16:517–24.
172. Malecha MA, Holland EJ. Correction of myopia and astigmatism after penetrating kera- 184. Hugger P, Kohnen T, La Rosa FA, et al. Comparison of changes in manifest refraction
toplasty with laser in situ keratomileusis. Cornea 2002;21:564–9. and corneal power after photorefractive keratectomy. Am J Ophthalmol 2000;129:68–75.
173. Zaldivar R, Davidorf JM, Oscherow S, et al. Combined posterior chamber phakic intra- 185. Wang LI, Hill WE, Koch DD. Evaluation of intraocular lens power prediction methods
ocular lens and laser in situ keratomileusis: bioptics for extreme myopia. J Refract Surg using the American Society of Cataract and Refractive Surgeons post-keratorefractive
1999;15:299–308. intraocular lens power calculator. J Cataract Refract Surg 2010;36:1466–73.
105.e3
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Small Incision Lenticule

Extraction (SMILE) 3.5
Iben Bach Damgaard, Jodhbir S. Mehta IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Definition: Small incision lenticule extraction (SMILE) is a laser TREATMENT RANGE FOR SMILE
refractive procedure in which a corneal stromal lenticule is created with SMILE with VisuMax is approved outside the United States for myopia
a femtosecond laser and removed though a small incision in order to up to −10.00 diopters (D) in sphere and up to 5.00 D of cylindrical com-
correct the refractive error. ponent. SMILE for myopia and astigmatism with VisuMax was Confor-
mité Européenne (CE) marked in 2009. In 2016, the US Food and Drug
Administration (FDA) approved VisuMax for myopia from −1.00 D and
up to −8.00 D in sphere and astigmatism of 0.50 D or less. Patients with
more than −10.00 D in sphere still remain a surgical challenge. For now,
VisuMax does not have an approved algorithm for treating hyperopia.
Key Features Initial studies have tested an improved lenticule shape that removes more
• SMILE preserves the corneal integrity better than laser-assisted in tissue in the midperiphery than in the center. Although the technique is
situ keratomileusis (LASIK) with its flap-free design eliminating risk of promising, it still needs refinement to be on par with the state-of-the-art
microfolds and flap dislocation. excimer laser treatments for low to moderate hyperopia.8–10
• Perioperative complications include epithelial abrasions, suction
loss during femtosecond laser application, and minor tears of the
lenticule or incision edges during lenticule removal.
PATIENT EVALUATION
• Corneal haze is the most common early postoperative Patients referred to SMILE should preferably be 18 years or older with
complication. a stable refraction for more than 2 years. Standard preoperative evalua-
• Early dry eye symptoms can occur, although it spares the subbasal tion includes uncorrected and corrected distance visual acuity, pupil size,
nerve density better than flap-based LASIK, with faster sensitivity tonometry, pachymetry, tomography, slit-lamp examination, and dilated
recovery. funduscopy. Tomographic measurements of the corneal front and back
• Enhancements can be performed with the CIRCLE procedure, where curvature should be carefully examined to exclude irregular tomographic
the cap is converted to a flap and followed by excimer ablation of the patterns or subclinical keratoconus. The patient should not wear contact
stromal bed or with surface ablation. lenses 2 days (soft lenses) or 2 weeks (hard lenses) before tomographic
evaluation. Contraindications for SMILE include corneal scars, corneal
dystrophies, and severe dry eyes. Very anxious patients may not be can-
didates for SMILE, due to the increased risk of perioperative suction loss.
LASIK is still the chosen technique to achieve monovision in presbyopic
INTRODUCTION patients, as they often require surgical enhancements, which are done
more easily after a flap-based procedure.11 SMILE may be preferred over
Over the past decade, femtosecond laser-assisted in situ keratomileusis LASIK in patients who are involved in contact sports or perform jobs with
(FS-LASIK) has become a well-established technique for correcting myopic increased risk of eye trauma, because there is no risk of traumatic flap
refractive errors. Femtosecond laser technology allows a more reproducible displacement or dislodgement. Studies suggest that SMILE may also be
corneal flap of predetermined thickness, compared with microkeratome.1 the best option for moderate to high myopic correction due to higher pre-
Femtosecond lenticule extraction (FLEX) was later introduced as an alter- dictability than after LASIK.12
native to FS-LASIK after development of the VisuMax femtosecond laser
(Carl Zeiss Meditec, Jena, Germany). FLEX still required a corneal flap to
enter the corneal stroma, as with LASIK. However, FLEX allowed corneal
SURGICAL PROCEDURE
tissue removal by creating a stromal lenticule instead of laser ablation. It SMILE can be performed under topical anesthesia. Bilateral sequential
proved beneficial to further improve on this and develop a laser refrac- treatment is usually performed. The patient is positioned supine under the
tive technique that did not require use of a corneal flap, minimizing the femtosecond laser, and the untreated eye is covered and taped to prevent
trauma on the corneal surface and removing the risk of microfolds or flap corneal dehydration. Two drops of 0.8% oxybuprocaine tetrachloride are
dislocation.2,3 applied 5 minutes before operation and again just before the lid specu-
Small incision lenticule extraction (SMILE) was introduced as a lum is installed. A contact glass interface that consists of a peripheral ring
next-generation stromal lenticule refractive procedure, further optimizing of small suction ports is attached to the femtosecond laser. The curved
FLEX.4,5 As a flap-free technique, an instrastromal lenticule was cut by a contact glass ensures precise contact to the corneal surface during laser
femtosecond laser and removed through a small corneal incision. With use application and is available in various sizes (S, M, L, and type KP). The
of only a small incision (2–4 mm in width) for removal of the lenticule, the size of the contact glass should correspond to the white-to-white distance
corneal integrity was left almost intact. of the patient. A small (S)-sized contact glass is generally preferred, espe-
cially in Asian patients with small white-to-white distances. The patient is
FEMTOSECOND LASER SYSTEM positioned under the laser head. It is important to dry the ocular surface,
especially the inferior fornix, with a sponge to remove any excess tear fluid
The femtosecond laser (10−15 seconds) that is used for SMILE is a Nd:YAG or ocular surface secretions. This can be performed by placing a dispos-
106 solid-state laser that emits energy into a focal point with a 1043 nm wave- able sponge in the inferior fornix while the patient is being aligned to
length and has been discussed in previous sections in this chapter. the interface cone. Some surgeons advocate the use of a speculum with a
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suction device to remove excess tear fluid. Once the patient is under the twice a day for 2 weeks.16 The patient should use lubricating drops hourly
laser head, the bed is elevated to allow contact with the interface and the
anterior corneal surface. Before contact the patient is asked to fixate on a
for the first week to ease the discomfort in the postoperative period. Daily
activities can be performed, but the patient should avoid swimming pools 3.5
green light from the femtosecond laser for accurate centration. The bed and extensive eye rubbing during the first 2 weeks. Slit-lamp examination
then is elevated further to allow complete contact with the corneal surface. should be performed 1 day, 1 week, and 1 and 3 months after the operation.
Small Incision Lenticule Extraction (SMILE)

The degree of contact with the ocular surface can be ascertained by the We normally assess refractive outcome with formal refraction at 1 and 3
spread of the tear fluid meniscus. In most cases when the tear fluid has months.
spread to three quarters of the width of the cornea, suction is applied.
Following suction, the patient is still able to fixate on the green light due
to a low intraocular pressure rise.13,14 Good centration is important because
COMPLICATIONS
no built-in tracker exists.15 Patients who have high astigmatism treatments SMILE has an advantage over LASIK; flap dislocation and detachment are
should be marked in the horizontal axis on the slit lamp before the laser not seen because of the flap-free approach. Nevertheless, specific compli-
procedure. Once under the interface and suction applied, the interface can cations related to the lenticule cutting and removal do occur. Before oper-
be rotated to ensure that the marked horizontal axis on the eye is in align- ation, the surgeon should be aware of how to avoid and manage the most
ment with that of the horizontal meridian through the right eyepiece in frequent peri- and postoperative complications (Table 3.5.1).20
the microscope of the laser, to counter any cyclotorsion.14
Perioperative Complications
Femtosecond Laser Application Epithelial abrasions (5.2%) are the most common complication after SMILE
SMILE is performed with four sequential laser cuts to create a corneal but rarely cause sequelae. Central abrasions (0.2%) can be treated with a
lenticule and a tunnel incision4: (1) a posterior lenticule surface cut in a bandage lens for few days. Epithelial abrasions have been associated with
spiral-in pattern (refractive cut), (2) a vertical cut along the circumference an increased risk of postoperative interface inflammation. Intensive treat-
of the lenticule, (3) an anterior lenticule surface cut in a spiral-out pattern ment with topical dexamethasone every hour eases the inflammation.21,22
(corneal cap), and (4) a superiorly placed 2–4 mm tunnel vertical incision Incisional abrasions may be seen more commonly in older patients (e.g.,
cut that gives access to the lenticule from the corneal surface (Fig. 3.5.1). in their 40s).
We prefer to rotate the incision to the superior temporal side in the right Minor and major tears (1.8%) of the lenticule or incision edges are a
eye and superior nasal in the left eye to ease the access for a right-handed common complication after SMILE and depend on the width of the inci-
surgeon and to avoid any superior pannus and intraoperative bleeding, sion (Fig. 3.5.3A). Small tears will normally heal with minor scar forma-
which maybe be common in patients who wear contact lenses. tions outside the optical zone. Nevertheless, they should be avoided to
The spiral-in pattern of the posterior lenticule cut maximizes the reduce the risk of postoperative epithelial ingrowth. The incision width
time the patient can focus on the fixation target and minimizes the risk should be altered depending on the surgeon’s experience, usually 2–3 mm
of suction loss due to eye movements. Cutting the posterior surface first for experienced surgeons but up to 5 mm for inexperienced. Minor tears
ensures that the gas bubbles do not block the laser application of the ante- in the lenticule edge most commonly occur in thin lenticules and after
rior surface cut. The spiral-in and spiral-out laser firing sequence has also uneven laser application (opaque bubbles or “black areas” where energy
been shown to cause minimal disruption to the collagen lamellae.7 The was not transferred to the stromal tissue due to opacities).
laser refractive application takes approximately 20–25 seconds depending Lenticule extraction difficulties (1.6%) may occur after inadequate laser
on the laser settings. Suction is released automatically after treatment. cutting and/or dissection. Difficulties with lenticule removal may increase
The following laser settings can be altered by the surgeon and to deter- the risk of tearing the lenticule, with lenticule tags left in the stromal
mine the lenticule thickness and treatment zone. For the lenticule: lenti- pocket (0.04%) leading to induced postoperative irregular astigmatism. In
cule diameter, minimum lenticule thickness, and lenticule side cut angle. those cases, the original incision may be used to remove the lenticule tag.23
For the corneal cap: cap thickness, cap diameter, incision position, incision Adequate dissection to remove any remaining stromal bridges anterior and
width, and incision side cut angle. The laser settings are determined by posterior to the optical zone (see earlier) can avoid this complication. The
the preoperative refractive status, together with the preference and experi- most common reason that may lead to difficulty with removal of the lent-
ence of the surgeon. Surgeons starting with SMILE should perform cases icule occurs when the dissection is performed inadvertently on the pos-
with lenticule thickness of above 70 µm (minimum lenticule thickness of terior surface first. This pushes the anterior surface of the lenticule up
15 µm) because it will be easier to perform the removal.16 Surgeons with against the cap, which if unrecognized can cause difficulties in removal.
more experience with the procedure may perform treatments of −1 D. This is particularly common when performing corrections for low myopia.
Adequate delineation of the anterior and posterior surfaces of the lenti-
Lenticule Removal cule at the beginning of the procedure—and custom-made instruments
that allow removal of the lenticule from the posterior surface—can help
Lenticule removal includes several key stages (Fig. 3.5.2) (Video 3.5.1). in this situation.24 Prolonged stromal manipulation may lead to delayed
See clip:
3.5.1
The eye can be fixated with a pair of forceps to avoid sudden eye move- postoperative visual quality.
ments during the intrastromal maneuvers. The incision is opened with Intraoperative suction loss (1%) with detachment of the contact glass
a Sinskey hook. The two lenticule planes are identified in each corner of may occur at any time throughout the procedure and will automatically
the incision. The remaining tissue bridges of the upper surface are broken terminate laser application. Common reasons for suction loss include eye
with a blunt spatula and the lenticule is separated from the cap. The blunt squeezing or head movements, often seen in anxious patients, or excess
spatula should be gently maneuvered over the lenticule with no major tearing on the ocular surface.20,21,25,26 Detailed counseling of what visually
resistance from the remaining tissue bridges. A gentle sweeping move- to expect during the laser application are important. Hence, the surgeon’s
ment is advocated ensuring that the dissection passes over the complete experience with the technique and patients’ counseling may decrease the
area of the anterior surface of the lenticule. The same maneuver is per- risk of suction loss.27 Increased tear production or local anesthesia can
formed on the posterior surface of the lenticule. The lenticule then can be induce fluid ingress and detachment between the contact glass and cornea.
removed through the incision using a pair of forceps. Some surgeons flush Small palpebral apertures and a large cap diameter also increase the risk
the intrastromal pocket with balanced salt solution to remove remaining of suction loss.26,27
debris and minimize the risk of epithelial ingrowth. However, the fluid If suction loss occurs before completion of the posterior surface, the
may possibly induce small fluid pockets in the interface and can delay the surgeon will not be allowed to complete the SMILE procedure, but is
immediate visual recovery.17 After lenticule removal, the cap can be mas- given the option to convert to FS-LASIK. The option then is to convert to
saged with a sponge to remove residual tension folds to the periphery, to FS-LASIK. Retreatment can be performed after a few minutes or postponed
minimize irregularities and microfolds on the visual axis when correcting to another day. If suction loss appears after completing the vertical lenti-
highly myopic patients.18,19 One drop of fluoroquinolone and corticosteriod cule side cut, the surgeon can aim to redock and complete the procedure.
are then applied at the end of the procedure. However, it can be problematic to achieve the exact alignment because
of the gas bubble layer obscuring the pupil. Gentle compression on the
Postoperative Management ocular surface with a wet sponge will allow dispersion of the cavitation
bubbles and improve visualization for the patient. Increasing the anterior
A postoperative regimen may include a combination of topical dexameth- cap diameter following suction loss will help ensure adequate alignment 107
asone and antibiotics, typically 4 times a day for 2 weeks, then tapered to during redocking to repeat the anterior cut. In a study of suction loss
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Refractive Surgery
A B
C D
Fig. 3.5.1 Laser Firing Sequence. (A) Fixation during infrared illumination. The
patient is instructed to look at the green fixation light before suction is applied.
E (B) Posterior lenticule surface cut in a spiral in pattern. (C) Lenticule edge cut.
(D) Anterior lenticule surface cut in a spiral out pattern. (E) Incision cut.
and redocking during SMILE, uncorrected distance visual acuity (UDVA) Postoperative Complications
was 20/30 or better in 73% of the patients after 3 months (mean preop-
erative sphere of −5.81 D and cylinder up to 1.09 D).25 In a paired-eyed Corneal haze (5.6%) is a well-known early postoperative complication after
case study of 35 patients with suction loss in one eye, corrected distance almost all laser refractive procedures and is associated with corneal kerato-
visual acuity (CDVA) was significantly worse after 1 week in the compli- cyte apoptosis and wound healing.28,29 The corneal haze usually decreases
108 cated eye but with no significant differences in UDVA and CDVA after over time. In cases with moderate corneal haze, CDVA had normalized
3 months.21 within 2 years after the operation.21
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3.5

A B
C D
E F
Fig. 3.5.2 Lenticule Dissection and Removal. (A) Opening of the side cut incision with a Sinskey hook. (B) Demarcation of the anterior lenticule surface. (C) Demarcation of
posterior lenticule surface. (D) Dissection of the anterior surface. (E) Dissection of the posterior surface. (F) Peripheral dissection of posterior lenticule surface. (G) Dissection
of the edge, ensuring the lenticule is detached. (H) Removal of the lenticule with a pair of forceps.
Continued
109
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Refractive Surgery
G H
Fig. 3.5.2, cont’d
A B
Fig. 3.5.3 (A) Minor tear at the incision edge are a common complication after SMILE. Usually, they will heal with minor scar formations and no influence on the visual
outcome. Nevertheless, they should be avoided due to increased risk of epithelial ingrowth. (B) Epithelial ingrowth 6 weeks after operation due to seeding of epithelial cells
through the incision. The epithelial ingrowth was left untouched because it was located outside the visual axis and the patient did not have any visual complaints. (Courtesy
Dr. C Chan.)
The epithelial islands may be left alone if no progression is observed. They

TABLE 3.5.1 Incidence of Peri- and Postoperative also can be scraped off the border of the incision using a pocket epithe-
Complications Following SMILE.20 lial remover or treated with Nd:YAG laser. Only in very severe cases with
epithelial ingrowth to the interface center does it become visually signif-
Perioperative Complications Postoperative Complications
icant.34 In such situations if the epithelium cannot be removed through
Peripheral (5.2%) and central (0.2%) epithelial Corneal haze/nontransparency (5.6%)
the small incision, an alternative option would be to perform a conversion
abrasions
of the pocket to a flap to allow a more extensive irrigation of the stromal
Minor and major tears (1.8%) Dry corneal surface, day 1 (3.2%)
interface.
Lenticule extraction difficulties (1.6%) Epithelial ingrowth (0.5%) Diffuse lamellar keratitis (DLK) (0.2%), also known as Sands of Sahara
Suction loss (1%) Irregular corneal topography (0.5%) or interface inflammation, typically appears after 1–3 days, accompanied
Fiber in interface (0.2%) Visually insignificant microstriae (0.4%) by decreased visual acuity, pain, and photophobia.35 High laser energy set-
Remaining lenticule remnant (0.04%) Diffuse lamellar keratitis (0.2%) tings during photodisruption increase the risk of diffuse lamellar kerati-
Monocular ghost images (0.2%) tis.36 Thin stromal lenticules may increase the risk of DLK, because gas
bubbles after photodisruption accumulate within a small stromal area and
Early dry eyes (3.2%) at day 1 may be seen in combination with corneal provoke a strong inflammatory response.35 DLK is frequently reported in
haze. In several studies, the flap-free approach has been shown to pre- conjunction with central aberrations and postoperative epithelial defects.21
serve the subbasal nerve layer density better after SMILE compared with DLK may be successfully treated with topical corticosteroids or flushing
FS-LASIK in both short- and longer-term studies.30–32 Corneal sensitivity the interface in some cases. In rare cases, a bacterial or fungal organism
recovery has been shown to be faster after SMILE. However, early postop- can be the cause of the inflammation and should always be considered if
erative dry eye symptoms are comparable with flap-based procedures.30,33 the patient does not respond to the treatment.37 From the authors’ experi-
Tear break-up time (TBUT), Schirmer’s test, and tear meniscus height ence a higher incidence of DLK has been reported when the interface has
were similar after SMILE and FLEX up to 6 months after operation in a not been irrigated following the procedure.
contralateral eye study.30
Epithelial ingrowth (0.5%) is seen when epithelial cells proliferate at the
incision site or are displaced into the interface during lenticule removal
HIGHER-ORDER ABERRATIONS
(Fig. 3.5.3B). Epithelial ingrowth to the interface is more rarely seen after Increased postoperative higher-order aberrations (HOAs) may promote
110 SMILE than after LASIK. Epithelial islands may be spotted at the incision visual complaints such as glare, halos, reduced contrast sensitivity, and
site, often in relation to a minor tear after lenticule removal difficulties. poor night vision.
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Preoperative patient evaluation includes pupil size and should be taken of attempted correction after 12 months.65,66 Postoperative undercorrection
into consideration when the lenticule diameter is determined for the oper-
ation. Patients with large pupils may be more troubled by postoperative
tended to increase with higher attempted astigmatic correction and may be
taken into consideration if the surgeon chooses to personalize the nomo- 3.5
spherical aberrations if a small lenticule diameter is chosen. In particular, gram for astigmatic treatments.67
spherical aberrations may induce halos and decreased night vision due to

the myopic shift with a large pupil (night myopia). However, a large lent-
icule diameter requires a thick lenticule to gain the same amount of cor-
RETREATMENTS
rection and may not be acceptable when correcting highly myopic patients. With improvement of the VisuMax nomogram, SMILE has proven to
Coma may increase after decentered laser treatment and can lead to be accurate and predictable for correcting myopia and myopic astigma-
symptoms of halos and monocular diplopia. In contrast to state-of-the-art tism.5,6,45,68,69 Still there is a risk of postoperative under- or overcorrection,
excimer lasers, the VisuMax laser lacks an eye-tracking system. The but it does not seem to be related to the intended refractive correction.6
alignment relies on the patient’s cooperation and the surgeon’s objective Furthermore, the minor but significant myopic drift may require further
adjustment. Nevertheless, VisuMax is on par with the MEL 90 laser used enhancements years after SMILE.45,63,64 It raises the question of how to
for LASIK when it comes to centration during surgery.38,39 Studies have correct patients already treated with SMILE. After LASIK or FLEX, the
reported an increase in coma and HOAs but not in spherical aberrations surgeon would simply lift the flap and perform excimer reshaping in the
after SMILE.40–44 A minor decrease is seen years after the operation, prob- earlier treated zone. Several techniques for postoperative enhancement
ably explained by remodeling of the epithelial layer.45 Corneal aberrations have been suggested, and the chosen technique should always be based
after SMILE have been shown to be less than after FS-LASIK,42–44 although on an extensive evaluation of the postoperative tomography, the degree of
one study reported a similar shift in aberrations after SMILE and LASIK.46 correction required, and the visual complaints of the patient.70
In the CIRCLE procedure available with VisuMax, the corneal cap can
BIOMECHANICAL STABILITY be converted to a flap with use of the previous upper surface and lenticule
edge cuts.71,72 With the femtosecond laser, the surgeon creates a circular
In contrast to a flap-based LASIK procedure, SMILE involves the creation incision in relation to the edge of the previous cap and leaves a hinge
of a cap. Thus SMILE may be able to better preserve the corneal tectonic in the superior position. A lamellar cut connects the new circular cut
integrity because the small incision leaves most of the anterior corneal with the previous SMILE optical zone. Lifting the flap gives access to the
collagen intact. Most of the corneal strength is located in the anterior third stromal bed, where reshaping can be done with excimer laser. The visual
of the cornea and is crucial to withstand the intraocular pressure.47 From and refractive outcomes after the CIRCLE procedure followed by excimer
earlier ex vivo studies of the depth-dependent tensile strength, Reinstein laser surgery have proven to be reliable. Reportedly, 95.8% of patients
et al.48 developed a mathematical model to predict the tensile strength fol- with emmetropia as target refraction reached a UDVA of 20/20 or better
lowing SMILE, LASIK, and photorefractive keratectomy (PRK). The model 3 months after the CIRCLE procedure, with a residual refractive error of
demonstrated greater postoperative tensile strength after SMILE than after 0.10 D (mean preoperative SE: −0.74 D, range −2.98 D–0.38 D).71 Another
LASIK and PRK, due to the creation of the corneal cap. Several studies technique involves topography-guided PRK in patients with postoperative
have assessed the postoperative corneal biomechanical properties in vivo irregular topography.73 Corneal haze has been reported after the PRK treat-
after SMILE and LASIK by using the Ocular Response Analyzer and Corvis ment even after minimal ablation depths. Perioperative mitomycin-C may
ST (Scheimpflug-based tonometry). In a randomized pair-eyed study of be beneficial to prevent postoperative haze. In one case study, enhance-
SMILE and LASIK, both corneal hysteresis (CH) and corneal resistance ment was performed with SMILE using the original cap. The laser appli-
factor (CRF) decreased after operation, but with no significant differences cation was stopped after the new lower surface and lenticule edge was cut,
between the two methods.49 Likewise, a randomized pair-eyed study of and the new lenticule was removed though the original incision.74
SMILE and FLEX reported no significant differences in terms of CH and
CRF between the two methods after 6 months.50 For now, no studies have CONCLUSIONS
performed a randomized pair-eyed study with Corvis ST. Retrospective
studies using the Corvis ST on LASIK, FLEX, and SMILE reported similar SMILE has emerged as a new technique for correcting myopia and astig-
reduction in the corneal biomechanical properties with regard to the defor- matism. SMILE preserves the corneal integrity by creating a corneal cap
mation pattern during the airpulse.51,52 with no risk of flap displacement as may be seen after LASIK and FLEX.
Iatrogenic ectasia with corneal protrusion and decreased visual acuity is Several studies have shown SMILE to have high efficacy, predictability,
a rare but severe complication after LASIK (0.05%).53 The general recom- stability, and safety with fewer postoperative HOAs than after LASIK.
mendation for preventing ectasia is a minimum residual bed thickness of In future, the development and refinement of SMILE may open up new
300 µm in LASIK. The use of the same recommendations in SMILE has ways of correcting hyperopia by removal of a piece of tissue that flattens
been a topic of discussion because the cornea may be more biomechani- the corneal curvature. Until then, LASIK and PRK are the recommended
cally robust with less risk of iatrogenic ectasia.48 Nevertheless, a few cases corneal treatment for correcting low hyperopia.
of iatrogenic ectasia have been reported after SMILE, although the preop-
erative evaluation of the patients may have shown abnormal preoperative
topographical patterns.54–58
KEY REFERENCES
Hjortdal JO, Vestergaard AH, Ivarsen A, et al. Predictors for the outcome of small-incision
lenticule extraction for myopia. J Refract Surg 2012;28:865–71.
REFRACTIVE AND VISUAL OUTCOME Ivarsen A, Asp S, Hjortdal J. Safety and complications of more than 1500 small-incision
lenticule extraction procedures. Ophthalmology 2014;121:822–8.
SMILE has shown to be comparable with LASIK in terms of efficacy, predict- Liu YC, Koh J, Rosman M, et al. Enhancement following small incision lenticule extraction
ability, stability, and safety.21,42,43,59,60 However, the learning curve of SMILE (SMILE): incidence, risk factors and outcomes. Ophthalmology 2017;124:813–21.
Liu YC, Teo EP, Lwin NC, et al. Early corneal wound healing and inflammatory responses
is likely to affect the postoperative results in the early phase.6,27,60 This can after SMILE: comparison of the effects of different refractive corrections and surgical
possibly be avoided with proper supervised training and earlier experience experiences. J Refract Surg 2016;32:346–53.
with corneal surgery.61 In a study of SMILE for low myopia (mean spheri- Reinstein DZ, Carp GI, Archer TJ, et al. Outcomes of small incision lenticule extraction
cal equivalent [SE] of −2.61 D and cylinder up to 1.50 D), UDVA was 20/20 (SMILE) in low myopia. J Refract Surg 2014;30:812–18.
or better in 96% of the patients after 1 year.62 In terms of CDVA, 9% lost Riau AK, Angunawela RI, Chaurasia SS, et al. Early corneal wound healing and inflamma-
tory responses after refractive lenticule extraction (ReLEx). Invest Ophthalmol Vis Sci
one Snellen line but no eyes more than two. Postoperative SE was within 2011;52:6213–21.
±0.50 D and ±1.00 D in 84% and 89%, respectively. Minor regression was Sekundo W, Kunert KS, Blum M. Small incision corneal refractive surgery using the small
reported from 3 to 12 months, where SE changed more than 0.5 D in 8% incision lenticule extraction (SMILE) procedure for the correction of myopia and myopic
of the patients. A study of SMILE for moderate to high myopia (mean SE astigmatism: results of a 6 month prospective study. Br J Ophthalmol 2011;95:335–9.
Shah R, Shah S, Sengupta S. Results of small incision lenticule extraction: all-in-one femto-
of −7.18 D and cylinder up to 1.50 D), UDVA was 20/40 or better in 97% second laser refractive surgery. J Cataract Refract Surg 2011;37:127–37.
of the patients after 3 months.6 CDVA improved slightly but significantly Vestergaard AH, Grønbech KT, Grauslund J, et al. Subbasal nerve morphology, corneal sen-
from baseline to 3 months, and with 2.4% loss in CDVA of two Snellen sation, and tear film evaluation after refractive femtosecond laser lenticule extraction.
lines or more. In eyes with emmetropia as target refraction, 80% and 94% Graefe’s Arch Clin Exp Ophthalmol 2013;251:2591–600.
Wong JX, Wong EP, Htoon HM, et al. Intra-operative centration during small incision lenti-
were within ±0.50 D and ±1.00 D, respectively. Studies with up to 5 years cule extraction (SMILE). Medicine (Baltimore) 2017;96(16):e6076.
of follow-up report stable visual outcomes but a minor myopic regression
of 0.48 D.45,63,64 A study of SMILE for astigmatism (1.81 D in mean cylin- Access the complete reference list online at ExpertConsult.com 111
der, range 0.75 D–4.00 D) reported an astigmatic undercorrection of 11%
booksmedicos.org
REFERENCES 38. Reinstein DZ, Gobbe M, Gobbe L, et al. Optical zone centration accuracy using corneal
fixation-based SMILE compared to eye tracker-based femtosecond laser-assisted LASIK
1. Kezirian GM, Stonecipher KG. Comparison of the IntraLase femtosecond laser
and mechanical keratomes for laser in situ keratomileusis. J Cataract Refract Surg
for myopia. J Refract Surg 2015;31:586–92.
39. Lazaridis A, Droutsas K, Sekundo W. Topographic analysis of the centration of the treat-
3.5
2004;30:804–11. ment zone after SMILE for myopia and comparison to FS-LASIK: subjective versus
objective alignment. J Refract Surg 2014;30:680–6.

2. Galvis V, Tello A, Guerra AR, et al. Risk factors and visual results in cases of LASIK flap
repositioning due to folds or dislocation: case series and literature review. Int Ophthal- 40. Tan DKL, Tay WT, Chan C, et al. Postoperative ocular higher-order aberrations and con-
mol 2014;34:19–26. trast sensitivity: femtosecond lenticule extraction versus pseudo small-incision lenticule
3. Amoils SP, Deist MB, Gous P, et al. Iatrogenic keratectasia after laser in situ keratomile- extraction. J Cataract Refract Surg 2015;41:623–34.
usis for less than −4.0 to −7.0 diopters of myopia. J Cataract Refract Surg 2000;26:967–77. 41. Ang M, Farook M, Htoon HM, et al. Simulated night vision after small-incision lenticule
4. Sekundo W, Kunert KS, Blum M. Small incision corneal refractive surgery using the extraction. J Cataract Refract Surg 2016;42:1173–80.
small incision lenticule extraction (SMILE) procedure for the correction of myopia 42. Ganesh S, Gupta R. Comparison of visual and refractive outcomes following femtosec-
and myopic astigmatism: results of a 6 month prospective study. Br J Ophthalmol ond laser-assisted LASIK with SMILE in patients with myopia or myopic astigmatism. J
2011;95:335–9. Refract Surg 2014;30:590–6.
5. Shah R, Shah S, Sengupta S. Results of small incision lenticule extraction: all-in-one 43. Lin F, Xu Y, Yang Y. Comparison of the visual results after SMILE and femtosecond
femtosecond laser refractive surgery. J Cataract Refract Surg 2011;37:127–37. laser-assisted LASIK for myopia. J Refract Surg 2014;30:248–54.
6. Hjortdal JO, Vestergaard AH, Ivarsen A, et al. Predictors for the outcome of small-inci- 44. Gyldenkerne A, Ivarsen A, Hjortdal JO. Comparison of corneal shape changes and aber-
sion lenticule extraction for myopia. J Refract Surg 2012;28:865–71. rations induced By FS-LASIK and SMILE for myopia. J Refract Surg 2015;31:223–9.
7. Riau AK, Angunawela RI, Chaurasia SS, et al. Effect of different femtosecond laser-firing 45. Pedersen IB, Ivarsen A, Hjortdal J. Three-year results of small incision lenticule extraction
patterns on collagen disruption during refractive lenticule extraction. J Cataract Refract for high myopia: refractive outcomes and aberrations. J Refract Surg 2015;31:1–7.
Surg 2012;38:1467–75. 46. Kamiya K, Shimizu K, Igarashi A, et al. Comparison of visual acuity, higher-order aber-
8. Liu YC, Ang HP, Teo EPW, et al. Mehta, wound healing profiles of hyperopic-small inci- rations and corneal asphericity after refractive lenticule extraction and wavefront-guided
sion lenticule extraction (SMILE). Sci Rep 2016;6:29802. laser-assisted in situ keratomileusis for myopia. Br J Ophthalmol 2013;97:968–75.
9. Sekundo W, Reinstein DZ, Blum M. Improved lenticule shape for hyperopic femtosec- 47. Randleman JB, Dawson DG, Grossniklaus HE, et al. Depth-dependent cohesive tensile
ond lenticule extraction (ReLEx FLEx): a pilot study. Lasers Med Sci 2016;31:659–64. strength in human donor corneas: implications for refractive surgery. J Refract Surg
10. Blum M, Kunert KS, Vossmerbaumer U, et al. Femtosecond lenticule extraction 2008;24:S85–9.
(ReLEx) for correction of hyperopia – first results. Graefes Arch Clin Exp Ophthalmol 48. Reinstein DZ, Archer TJ, Randleman JB. Mathematical model to compare the relative
2013;251:349–55. tensile strength of the cornea after PRK, LASIK, and small incision lenticule extraction.
11. Braun EH, Lee J, Steinert RF. Monovision in LASIK. Ophthalmology 2008;115:1196–202. J Refract Surg 2013;29:454–60.
12. Gazieva L, Beer MH, Nielsen K, et al. A retrospective comparison of efficacy and safety 49. Agca A, Ozgurhan EB, Demirok A, et al. Comparison of corneal hysteresis and corneal
of 680 consecutive LASIK treatments for high myopia performed with two generations resistance factor after small incision lenticule extraction and femtosecond laser-assisted
of flying-spot excimer lasers. Acta Ophthalmol 2011;89:729–33. LASIK: a prospective fellow eye study. Cont Lens Anterior Eye 2014;37:77–80.
13. Vetter JM, Faust M, Gericke A, et al. Intraocular pressure measurements during flap 50. Vestergaard AH, Grauslund J, Ivarsen AR, et al. Central corneal sublayer pachymetry and
preparation using 2 femtosecond lasers and 1 microkeratome in human donor eyes. J biomechanical properties after refractive femtosecond lenticule extraction. J Refract Surg
Cataract Refract Surg 2012;38:2011–18. 2014;30:102–8.
14. Ang MM, Charurasia SS, Angunawela RI, et al. Femtosecond lenticule extraction (FLEx): 51. Pedersen IB, Bak-Nielsen S, Vestergaard AH, et al. Corneal biomechanical properties
clinical results, interface evaluation, and intraocular pressure variation. Invest Ophthal- after LASIK, ReLEx flex, and ReLEx smile by Scheimpflug-based dynamic tonometry.
mol Vis Sci 2012;53:1414–21. Graefe’s Arch Clin Exp Ophthalmol 2014;252:1329–35.
15. Wong JX, Wong EP, Htoon HM, et al. Intraoperative centration during small incision 52. Wang D, Liu M, Chen Y, et al. Differences in the corneal biomechanical changes after
lenticule extraction (SMILE). Medicine (Baltimore) 2017;96(16):e6076. SMILE and LASIK. J Refract Surg 2014;30:702–7.
16. Liu YC, Teo EP, Lwin NC, et al. Early corneal wound healing and inflammatory responses 53. Moshirfar M, Smedley JG, Muthappan V, et al. Rate of ectasia and incidence of irregular
after SMILE: comparison of the effects of different refractive corrections and surgical topography in patients with unidentified preoperative risk factors undergoing femtosec-
experiences. J Refract Surg 2016;32:346–53. ond laser-assisted LASIK. Clin Ophthalmol 2014;8:35–42.
17. Liu YC, Jayasinghe L, Ang HP, et al. Effect of intraoperative corneal stromal pocket irri- 54. Mastropasqua L. Bilateral ectasia after femtosecond laser-assisted small-incision lenticule
gation in small incision lenticule extraction. Biomed Res Int 2015;2015:928608. extraction. J Cataract Refract Surg 2015;41:1338–9.
18. Shroff R, Francis M, Pahuja N, et al. Quantitative evaluation of microdistortions in Bow- 55. El-Naggar MT. Bilateral ectasia after femtosecond laser-assisted small-incision lenticule
man’s layer and corneal deformation after small incision lenticule extraction. Transl Vis extraction. J Cataract Refract Surg 2015;41:884–8.
Sci Technol 2016;5:12. 56. Mattila JS, Holopainen JM. Bilateral Ectasia after femtosecond laser-assisted small inci-
19. Luo J, Yao P, Li M, et al. Quantitative analysis of microdistortions in Bowman’s layer sion lenticule extraction (SMILE). J Refract Surg 2016;32:497–500.
using optical coherence tomography after SMILE among different myopic corrections. J 57. Sachdev G, Sachdev MS, Sachdev R, et al. Unilateral corneal ectasia following small-inci-
Refract Surg 2015;31:104–9. sion lenticule extraction. J Cataract Refract Surg 2015;41:2014–18.
20. Moshirfar M, McCaughey MV, Reinstein DZ, et al. Small-incision lenticule extraction. J 58. Wang Y, Cui C, Li Z, et al. Corneal ectasia 6.5 months after small-incision lenticule
Cataract Refract Surg 2015;41:652–65. extraction. J Cataract Refract Surg 2015;41:1100–6.
21. Ivarsen A, Asp S, Hjortdal J. Safety and complications of more than 1500 small-incision 59. Liu M, Chen Y, Wang D, et al. Clinical outcomes after SMILE and femtosecond laser-as-
lenticule extraction procedures. Ophthalmology 2014;121:822–8. sisted LASIK for myopia and myopic astigmatism: a prospective randomized compara-
22. Shah MN, Misra M, Wihelmus KR, et al. Diffuse lamellar keratitis associated with tive study. Cornea 2016;35:210–16.
epithelial defects after laser in situ keratomileusis. J Cataract Refract Surg 2000;26: 60. Vestergaard A, Ivarsen AR, Asp S, et al. Small-incision lenticule extraction for moderate
1312–18. to high myopia: predictability, safety, and patient satisfaction. J Cataract Refract Surg
23. Dong Z, Zhou X. Irregular astigmatism after femtosecond laser refractive lenticule 2012;38:2003–10.
extraction. J Cataract Refract Surg 2013;39:952–4. 61. Pradhan KR, Reinstein DZ, Carp GI, et al. Quality control outcomes analysis of small-in-
24. Liu YC, Pujara T, Mehta JS. New instruments for lenticule extraction in small incision cision lenticule extraction for myopia by a novice surgeon at the first refractive surgery
lenticule extraction (SMILE). PLoS ONE 2014;9:e113774. unit in Nepal during the first 2 years of operation. J Cataract Refract Surg 2016;42:267–74.
25. Wong CW, Chan C, Tan D, et al. Incidence and management of suction loss in refractive 62. Reinstein DZ, Carp GI, Archer TJ, et al. Outcomes of small incision lenticule extraction
lenticule extraction. J Cataract Refract Surg 2014;40:2002–10. (SMILE) in low myopia. J Refract Surg 2014;30:812–18.
26. Liu M, Wang J, Zhong W, et al. Impact of suction loss during small incision lenticule 63. Han T, Zheng K, Chen Y, et al. Four-year observation of predictability and stability of
extraction (SMILE). J Refract Surg 2016;32:686–92. small incision lenticule extraction. BMC Ophthalmol 2016;16:149.
27. Osman IM, Awad R, Shi W, et al. Suction loss during femtosecond laser-assisted small-in- 64. Blum M, Taubig K, Gruhn C, et al. Five-year results of small incision lenticule extraction
cision lenticule extraction: incidence and analysis of risk factors. J Cataract Refract Surg (ReLEx SMILE). Br J Ophthalmol 2016;100:1192–5.
2016;42:246–50. 65. Pedersen IB, Ivarsen A, Hjortdal J. Changes in astigmatism, densitometry, and aberra-
28. Riau AK, Angunawela RI, Chaurasia SS, et al. Early corneal wound healing and inflam- tions after SMILE for low to high myopic astigmatism: a 12-month prospective study. J
matory responses after refractive lenticule extraction (ReLEx). Invest Ophthalmol Vis Sci Refract Surg 2017;33:11–17.
2011;52:6213–21. 66. Zhang J, Wang Y, Wu W, et al. Vector analysis of low to moderate astigmatism with small
29. Dupps WJJ, Wilson SE. Biomechanics and wound healing in the cornea. Exp Eye Res incision lenticule extraction (SMILE): results of a 1-year follow-up. BMC Ophthalmol
2006;83:709–20. 2015;15:8.
30. Vestergaard AH, Grønbech KT, Grauslund J, et al. Subbasal nerve morphology, corneal 67. Ivarsen A, Hjortdal J. Correction of myopic astigmatism with small incision lenticule
sensation, and tear film evaluation after refractive femtosecond laser lenticule extraction. extraction. J Refract Surg 2014;30:240–7.
Graefe’s Arch Clin Exp Ophthalmol 2013;251:2591–600. 68. Sekundo W, Gertnere J, Bertelmann T, et al. One-year refractive results, contrast sen-
31. Li M, Niu L, Qin B, et al. Confocal comparison of corneal reinnervation after small sitivity, high-order aberrations and complications after myopic small-incision lenticule
incision lenticule extraction (SMILE) and femtosecond laser in situ keratomileusis extraction (ReLEx SMILE). Graefe’s Arch Clin Exp Ophthalmol 2014;252:837–43.
(FS-LASIK). PLoS ONE 2013;8:e81435. 69. Vestergaard AH, Grauslund J, Ivarsen AR, et al. Efficacy, safety, predictability, contrast
32. Mohamed-Noriega K, Riau AK, Lwin NC, et al. Early corneal nerve damage and recovery sensitivity, and aberrations after femtosecond laser lenticule extraction. J Cataract Refract
following small incision lenticule extraction (SMILE) and laser in situ keratomileusis Surg 2014;40:403–11.
(LASIK). Invest Ophthalmol Vis Sci 2014;55:1823–34. 70. Liu YC, Koh J, Rosman M, et  al. Enhancement following small incision lenticule extraction
33. Reinstein DZ, Archer TJ, Gobbe M, et al. Corneal sensitivity after small-incision lenticule (SMILE): incidence, risk factors and outcomes. Ophthalmology 2017;124:813–21.
extraction and laser in situ keratomileusis. J Cataract Refract Surg 2015;41:1580–7. 71. Chansue E, Tanehsakdi M, Swasdibutra S, et al. Safety and efficacy of VisuMax® circle
34. Thulasi P, Kim SW, Shetty R, et al. Recalcitrant epithelial ingrowth after SMILE treated patterns for flap creation and enhancement following small incision lenticule extraction.
with a hydrogel ocular sealant. J Refract Surg 2015;31:847–50. Eye Vis (Lond) 2015;2:21.
35. Zhao J, He L, Yao P, et al. Diffuse lamellar keratitis after small-incision lenticule 72. Riau AK, Ang HP, Lwin NC, et al. Comparison of four different VisuMax circle patterns
extraction. J Cataract Refract Surg 2015;41:400–7. for flap creation after small incision lenticule extraction. J Refract Surg 2013;29:236–44.
36. Choe CH, Guss C, Musch DC, et al. Incidence of diffuse lamellar keratitis after LASIK 73. Ivarsen A, Hjortdal JO. Topography-guided photorefractive keratectomy for irregular
with 15 KHz, 30 KHz, and 60 KHz femtosecond laser flap creation. J Cataract Refract astigmatism after small incision lenticule extraction. J Refract Surg 2014;30:429–32.
Surg 2010;36:1912–18. 74. Donate D, Thaeron R, Thaëron R. Preliminary evidence of successful enhancement after 111.e1
37. Chehaibou I, Sandali O, Ameline B, et al. Bilateral infectious keratitis after small-inci- a primary SMILE Procedure with the Sub-Cap-Lenticule-Extraction technique. J Refract
sion lenticule extraction. J Cataract Refract Surg 2016;42:626–30. Surg 2015;31:708–10.
booksmedicos.org

Wavefront-Based Excimer Laser

Refractive Surgery 3.6
Faisal M. Tobaigy, Daoud S. Fahd, Wallace Chamon
entirely dependent on the diameter of the pupil; a larger diameter leads to

Definition: Wavefront-customized excimer laser refractive surgery a larger wavefront error (Fig. 3.6.1).4,7,8
corrects pre-existing lower- and higher-order aberrations. Wavefront-
optimized treatments preserve pre-existing corneal optical aberrations
(customizing for spherical aberration). HIGHER-ORDER ABERRATIONS
HOA are monochromatic refractive disorders that may limit the vision
of healthy eyes to less than the retinal detection threshold. HOA cannot
be corrected with spherocylindrical lenses or with standard refractive
Key Features surgery.5,8 They have been categorized using Zernike polynomials by radial
• Zernike polynomials and Fourier transforms are used to represent order and by angular frequency, with third order and higher constituting
and analyze the ocular wavefront. HOA.5 The higher the order, the less visually significant the aberration.
• Optical properties influence image quality. The two most frequently discussed aberrations are spherical aberration
• Different devices measure ocular aberrations differently. (which causes halos and night vision disturbances) and coma (which is
• Wavefront-customized and wavefront-optimized ablations result in associated with monocular diplopia).4,9 The wavefront in spherical aberra-
better visual acuity and mesopic contrast sensitivity. tion is spherical in the center of the pupil but changes its curvature toward
the edge of the pupil, giving concentric rings of focus that result in point
images with halos. In coma, the wavefront is asymmetrical, producing a
INTRODUCTION comet-shaped pattern (Fig. 3.6.2). Trefoil, quadrifoil, pentafoil, and second-
ary astigmatism are other HOA (see Fig. 3.6.2).
The eye is a complex, imperfect optical system. As light rays from distant
objects pass through the optical components of the eye, they refract at the
tear film and at corneal and crystalline lens interfaces. Any deviation from
IDEAL CORNEAL SHAPE
a perfectly focused optical system is referred to as aberration. Most of these The shape of the cornea is prolate (more curved in the center) to allow
aberrations reflect myopia, or hyperopia, and regular astigmatism, known for a lower total HOA.10 The Q-value of the central cornea (5–7 mm) in
as lower-order aberrations (LOA), which can be corrected with spherocy- a normal population varies from −0.21 to −0.27, meaning that the central
lindrical spectacles.1 Other optical aberrations are commonly referred to as cornea has a stronger curvature than the periphery.11 This aspherical shape
irregular astigmatism and include spherical aberration, coma, trefoils, and allows for focusing of rays coming from the periphery and those coming
quadrifoils. Irregular astigmatism encompasses higher order aberrations from the center on one point, correcting for inherent spherical aberra-
(HOA). tion of spherical lenses. Any change in the average prolate corneal shape
HOA may decrease the quality of vision and cause symptoms in up to toward a more oblate profile (less curved in its center) leads to induction
15% of the general population.2 Rigid contact lenses can correct HOA that of spherical aberrations and consequently a decrease in night vision and
are generated at the anterior corneal surface. More advanced treatments contrast sensitivity.
involve the use of a personalized wavefront-guided laser refractive tech-
nique to reshape the surface of the cornea that leads to a more optically
desired outcome.1 MEASUREMENTS OF
A customized corneal shaping requires wavefront analysis of the eye
(aberrometry). For reproducibility, the waveform can be decomposed into
WAVEFRONT ABERRATIONS
components, using either Zernike polynomials or Fourier analysis.3–5 The Zernike polynomials and Fourier transforms are used to analyze the
wavefront map is digitally interfaced with an excimer laser to control the detected ocular wavefront.5,12 Zernike polynomials are a sequence of poly-
delivery of a laser beam across the cornea in a customized fashion. nomials based on a radial model, whereas Fourier transforms represent
In the majority of the population, other noncustomized treatments may nonradial mathematical functions of frequency. Most aberrometers used
use epidemiological data to predefine ablation profiles that may be suitable for customized laser surgery rely on Zernike polynomials to decompose
to improve high-order aberration, especially spherical aberration. Although the wavefront aberrations (Fig. 3.6.2). They can, in principle, measure an
these treatments are not personalized for each patient, they are based on infinite number of aberration orders. Clinically, data up to the Zernike
epidemiological information of wavefront analyses and are commonly fifth order capture nearly all the aberration variance typically found in
known as wavefront optimized treatments.6 normal human eyes.7,8 The Fourier analysis can decompose an image
into spatial frequency components with a higher resolution of the surface
WAVEFRONT OPTICS (Fig. 3.6.3).
The measured wavefront errors are represented as root mean square
The wavefront is the locus of points in an optical pathway having the same deviations (RMS), which are correlated to the absolute deviation of an ideal
phase. If all incoming rays are parallel, and the eye is free from any aberra- wavefront. Applegate and colleagues4,5 evaluated the effect of individual
tions, the resultant emerging wavefront is a perfectly flat surface. In other Zernike modes on visual quality and noted large differences in their sub-
words, all light rays coming from a point source located at infinity focus at jective impact, with those in the middle of a given Zernike order influenc-
a single point on the retina. In reality, though, the focusing properties of a ing vision more than those at the periphery. For example, in the second
real eye are not completely uniform: Some areas bend light more strongly radial order, defocus degrades vision more than astigmatism. Similarly, in
112 than others. The wavefront aberration is the deviation of a particular eye’s the third and fourth order, coma and spherical aberration degrade vision
wavefront from the ideal wavefront in the pupillary plane. Its magnitude is more than trefoil and quadrifoil, respectively (see Fig. 3.6.2).
booksmedicos.org
Fig. 3.6.1 Aberrations of the Eye With Different Pupil
IDEAL EYE WITH DIFFERENT PUPIL SIZES Sizes. (A) In an ideal eye with no ocular aberrations,
a point source of light focuses on the retina. Image 3.6
quality is not influenced by pupil size. (B) In an eye
with an error of refraction (here with axial myopia),
Wavefront-Based Excimer Laser Refractive Surgery

pupil size plays an important role in image quality. Rays
striking the cornea further away from the center are
bent differently from those striking the corneal center
due to the intrinsic corneal shape. The formed aberrated
wavefront is greater in the dilated eye compared with
the miotic eye.
MYOPIC EYE WITH DIFFERENT PUPIL SIZES
QUALITY OF VISION AND MEASURES OF Standard approaches to quantification of the optical quality of the eye
OPTICAL QUALITY describe either the optical properties of the eye (aberration maps, wavefront
error maps) or the effect these properties have on image quality (abnormal-
Visual assessment has two parts, acuity (quantity) and quality. A good ity of an image of a point light source or of a sinusoidal grating).13
visual acuity can be achieved on a high-contrast eye chart by correcting Aberration maps measure the undulating wavefront from an aberrated
LOA using the standard refractive ablation. Vision quality refers to all fine eye at the pupillary plane; they are quantified by the RMS wavefront error.
details, colors, and shades of images after they are in focus—it is especially Despite the fact that RMS wavefront error is not a good predictor of the
compromised in dim light. It can manifest as double vision, ghosting, subjective impact of aberrations on vision, it usually gives a rough estimate 113
glare, halos, starbursts, and reduced contrast sensitivity. of the overall aberrations of the eye.10,13,14
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Fig. 3.6.2 Zernike Pyramid. The defocus, coma, and
3 ZERNIKE PYRAMID spherical aberration are located in the middle of the

second, third, and fourth order, respectively. The middle
aberrations affect vision more.
f = angular frequency
Z(r n,fΘ)=Zfn
Refractive Surgery
n = radial order
4 3 2 1 0 +1 +2 +3 +4
(2, 2) (2, 0) (2, 2)
astigmatism defocus astigmatism

(3, 3) (3, 1) (3, 1) (3, 3)
trefoil coma coma trefoil

(4, 4) (4, 2) (4,0) (4, 2) (4, 4)
tetrafoil secondary astig. spherical aberration secondary astig. tetrafoil
Fig. 3.6.3 The Basis of Fourier Analysis. Any periodic

THE BASIS OF FOURIER ANALYSIS signal (red line) can be broken down into fundamental,
selectively weighted harmonics (green, purple, and
pink lines). Conversely, the addition of the weighted
fundamentals allows reconstruction of the original
0.4
signal. (Reproduced from Gatinel D. Wavefront analysis.
complex signal In: Azar DT, Gatinel D, Hoang-Xuan T, editors. Refractive
0.3
surgery. 2nd ed. Philadelphia: Elsevier; 2007. p. 117–45.)
0.2
0.1
°
(degrees) Coefficients Harmonics
0
50 100 150 200 250 300 350
0.1
0.1 × sin
0.2
0.3 × sin 2
0.3
0.08 × sin 3
-0.4
0.3
a mplitude
Fourier spectrum
0.1
0.08
frequency
Image plane metrics quantify the quality of the retinal image for both to the image is called the modulation transfer function (MTF) and phase
a point source of light (the point spread function, PSF) and a sinusoidal transfer function (PTF), respectively. The eye’s OTF includes both the MTF
grating (optical transfer function, OTF). The theoretical retinal image of and PTF.13,14
any object can be obtained by a convolution process based on the PSF. Any
object can be thought of as a collection of points of light, each of which
produces its own blurred image. The retinal image of the object is then the
sum of these blurred images. An optical system can affect the quality of a
WAVEFRONT-MEASURING DEVICES
114 sinusoidal grating by reducing its contrast or by causing a phase-shift. The Several methods for assessing the wavefront aberrations in human eyes
ability of an optical system to transfer contrast and phase from the object are currently available. Each method has its own way of measuring the
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Fig. 3.6.4 VISX WaveScan Map Showing
a High Amount of Coma.
3.6

displacement of a ray of light from its ideal position. They can be generally
classified as outgoing or ingoing aberrometers.
WAVEFRONT-BASED SURGERY
Devices based on the Hartmann–Shack principle are currently the most The aim of wavefront custom ablation, in addition to spherocylindrical cor-
widely used. These devices analyze an outgoing light that emerges or is rection, is to adjust for the pre-existing aberrations and those that may be
returned from the retina and passes through the optical system of the induced by conventional laser vision correction.20,21 To achieve this aim,
eye.15,16 A narrow beam of light is projected onto the retina, and its image preoperative ocular higher-order aberration wavefront measurements
passes through the lens and the cornea and exits the eye. The Hartmann– should be accurate, and the laser ablation profiles should be precise—
Shack sensor has a lenslet array that consists of a matrix of small lenses.15,16 hence efficient eye-registration and tracking devices, a small laser spot
The light that emerges from the eye is focused on a charge-coupled device size, and a sufficient corneal bed thickness become paramount for achiev-
(CCD) camera through each lenslet to form a spot pattern. The spot ing superior clinical results.
pattern of an ideal subject with a perfect wavefront will be exactly the same Wavefront measurements should be accurate; the alignment of the line
pattern as the reference grid; a distorted wavefront will create an irregular of sight is important to avoid artifacts. Common clinical conditions, such
spot pattern. Displacement of lenslet images from their reference position as tear film abnormalities or opacities, may present challenges to wave-
is used to calculate the shape of the wavefront. The advantages of this front measurements.15 Eyes with small-diameter pupils may be difficult
system include the fact that it measures wavefront in one shot; hence it is to measure and provide information beyond the 3-mm optical zone and
faster, leading to a higher resolution and a higher repeatability (Figs. 3.6.4 therefore require pharmacological dilatation. However, some variations in
and 3.6.5). the wavefront maps have been seen with some pharmaceutical agents. It
Tscherning aberrometry analyzes the ingoing light that forms an has been reported that cyclopentolate eyedrops lead to a significant dif-
image on the retina.17 A grid pattern formed by multiple spots is projected ference in the preoperative refractive error wavefront compared with the
through the optical system of the eye and forms an image on the retina. subjective refraction, whereas Neo-Synephrine does not significantly influ-
This image is observed, evaluated, and captured on a CCD similar to a ence measurements.22 An eye with marked aberrations such as scars or
fundus camera. The distortion of the grid pattern enables calculation of keratoconus may be difficult to measure because of complete light scatter
the aberrations of the optical system of the eye.17 and the inability of the source testing light to reach to the retina and reflect
Ray-tracing aberrometry measures ingoing light that passes through back to the CCD camera.15
the optical system of the eye and forms an image on the retina.17 It mea- The algorithm for converting measurements into an ablation profile
sures rays sequentially making it much slower (the total time of scanning should be faithful to the original maps. It should be optimized to provide
is 10–40 milliseconds) and decreasing its precision. The iTrace aberrometer the best optical quality over the optical zone and tapering of the ablation in
(Tracey Technologies, Houston, TX) is the only one based on the retinal the surrounding zone (Figs. 3.6.6 and 3.6.7).
ray-tracing technology and is not currently linked to any customized laser Another important issue for successful custom ablation surgery is eye
platform.18 registration and eye tracking during corneal laser ablation. The wavefront
The scanning slit refractometer is a double-pass aberrometer (slit ski- data must be transferred to the laser machine and applied to the same loca-
oloscopy) that is based on retinoscopic principles.19 Both the projecting tion on the eye from which they were captured. A small misalignment in
system—consisting of an infrared light source—and the receiving system the axis can have significant impact on the results of the procedure. It may
rotate at high speed around the optical axis synchronously, with 360° actually cause new HOA due to misalignment of the pattern of treatment
meridians measured in 0.4 seconds. A group of photodetectors is located to the actual wavefront error on the eye. It is common to have 5°–7° of
above and below the optical axis at 2.0, 3.2, 4.4, and 5.5 mm, and they cyclotorsion when changing from sitting position to supine position. It has
detect the time needed for reflected light to reach them. The time differ- been reported that 50% of the visual benefit correction of HOA is lost with
ence depends on the type and amount of refractive error and is converted a 250 µm decentration or a 10° eye rotation.23 Ideally the wavefront must
into the refractive power.19 This principle is used in the ARK 10000 Optical be centered and registered with respect to a fixed ocular structure to avoid 115
Path Difference Scanning System (OPD-Scan) distributed by Nidek. misalignment between the captured wavefront and the delivered laser. No
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Fig. 3.6.5 VISX WaveScan Map Showing
3 High Amount of Trefoil.

Refractive Surgery
TABLE 3.6.1 Table Comparing Different Available Wavefront Platforms for Customized Lasik Treatment
Aberrometer Manufacturer Wavefront Sensor Minimum Resolution (Points per mm2) FDA Approved CE Approved
Wavelight Allegro Analyzer Alcon Tscherning 3.3 Yes Yes
Zywave 3 Bausch & Lomb Hartmann–Shack 10.7 Yes Yes
OPD Scan III Nidek Dynamic skiascopy 35.5 No Yes
Schwind Peramis Schwind Hartmann–Shack 572.9 No Yes
Itrace Tracey Technologies Ray tracing 6.6 Yes Yes
IDesign Abbott Vision Hartmann–Shack 31.2 Yes Yes
confusion should exist regarding axis alignment of wavefront-based treat- less SE achieved UCVA of 20/20 or better, as did 91% of patients with
ments. Considering that they are based on a detailed map of the entrance preoperative SE of −2.00 to −4.00 D. A marked difference in 20/20 or
pupil, centration of the treatment is unquestionably done over the pupil. better postoperative UCVA was seen between the wavefront-customized
All concerns about kappa angle or centration on different axes only apply and conventional LASIK treatments. In wavefront LASIK, 89% of myopic
to noncustomized treatments. patients achieved this level of vision, whereas 72% of patients treated
Two main methods of using wavefront information in refractive surgery with conventional treatment achieved 20/20 or better. Feng et al. did a
are wavefront-optimized ablation and wavefront-customized ablation. meta-analysis comparing 458 eyes with wavefront-customized and 472 eyes
Wavefront-optimized ablation aims at preserving the eye’s pre-existing with wavefront-optimized LASIK treatments for myopia (SE between −0.25
optical aberrations using adjustments based on population averages and at and −9.75 D).24 No statistically significant difference was detected in eyes
optimizing the asphericity of the cornea. The ablation profile is based on achieving 20/20 UCVA or better, nor in eyes achieving postoperative SE
an ideal model without evaluating the patient’s own aberrometry, therefore within ±0.50 D, nor in the average change in HOA. No eye lost two or
it is not a customized treatment. Wavefront-customized ablation leads to more lines of BSCVA.24
having an individual treatment ablation profile based on the patient’s own
aberrometry; therefore it would be able to correct for pre-existing HOA.
WAVEFRONT PLATFORMS (TABLE 3.6.1)
RESULTS
Sakimoto et al. reviewed the outcomes for wavefront-customized LASIK
in low to moderate myopia using three separate laser platforms.21 The
CONCLUSIONS
postoperative manifest spherical equivalent (SE) was within ±1.00 diopters Knowledge of ocular aberrations can lead to better understanding of the
(D) in 96% of eyes and within ±0.50 D in 81%. Ninety-eight percent of quality of vision. Adequate interpretation of ocular wavefront maps can
patients had postoperative uncorrected visual acuities (UCVA) better than help in planning for custom LASIK treatment. Our quest for achieving
20/40, and 89% had UCVA equal to or better than 20/20. A loss of best perfect vision following laser vision correction is still ongoing. Despite
spectacle-corrected visual acuity (BSCVA) of more than two lines was seen falling short of the high expectations of supervision with wavefront-guided
116 in 0.5% of patients. Wavefront-customized LASIK seems to be most suc- ablations promised by earlier studies, wavefront-based treatments still
cessful in patients with low myopia: 95% of the patients with −2.00 D or shows superiority over conventional treatment profiles.
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3.6

A
Fig. 3.6.7 Left Eye of a Patient After Radial Keratotomy (RK). Scheimpflug
C image–based axial map of anterior cornea (A); high definition Hartman–Shack
aberrometry (B) demonstrating high-order aberrations (inferior left), placido disc
axial map (superior right), and high-order point spread function (PSF, inferior
Fig. 3.6.6 Right Eye of a Patient After Radial Keratotomy (RK). Scheimpflug right); and treatment plan (C) for a wavefront customized surgery. Notice the
image–based axial map of anterior cornea (A); high definition Hartman–Shack preponderance of trefoil aberration caused by the RK incisions and the appropriate
aberrometry (B) demonstrating high-order aberrations (inferior left), placido disc treatment plan, solely based on wavefront.
axial map (superior right), and high-order point spread function (PSF, inferior
right); and treatment plan (C) for a wavefront customized surgery. Notice the
preponderance of quadrifoil aberration caused by the RK incisions and the
appropriate treatment plan solely based on wavefront. 117
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KEY REFERENCES Krueger R, Applegate R, MacRae S, editors. Wavefront customized visual correction: the
3 Applegate RA. Limits to vision: can we do better than nature? J Refract Surg 2000;16:S547–51.
Applegate RA, Ballentine C, Gross H, et al. Visual acuity as a function of Zernike mode and
level of root mean square error. Optom Vis Sci 2003;80:97–105.
quest for super vision II. Thorofare: Slack; 2003.
Maeda N. Evaluation of optical quality of corneas using corneal topographers. Cornea
2002;21(Suppl. 7):S75–8.
Sakimoto T, Rosenblatt MI, Azar DT. Laser eye surgery for refractive errors. Lancet
2006;367:1432–47.
Refractive Surgery
Applegate RA, Thibos L, Williams DR. Converting wavefront aberration to metrics predic-
tive of visual performance. Invest Ophthalmol Vis Sci 2003;44(Suppl.):ARVO E-Abstract Thibos LN. Principles of Hartmann–Shack aberrometry. J Refract Surg 2000;16:S563–5.
2124.
Chalita MR, Krueger RR. Correlation of aberrations with visual acuity and symptoms. Oph-
thalmol Clin North Am 2004;17:135–42, v–vi. Access the complete reference list online at ExpertConsult.com
Feng Y, Yu J, Wang Q. Meta-analysis of wavefront-guided vs. wavefront-optimized LASIK for
myopia. Optom Vis Sci 2011;88:1463–9.
Huang D. Physics of customized corneal ablation. In: MacRae S, Kreger R, Applegate R,
editors. Customized corneal ablation: the quest for supervision. Thorofare: Slack; 2001.
p. 51–62.
118
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REFERENCES 12. Applegate RA, Thibos L, Williams DR. Converting wavefront aberration to metrics pre-
dictive of visual performance. Invest Ophthalmol Vis Sci 2003;44(Suppl.):ARVO E-Ab-
1. Applegate RA. Limits to vision: can we do better than nature? J Refract Surg
2000;16:S547–51.
stract 2124.
13. Cheng X, Thibos LN, Bradley A. Estimating visual quality from wavefront aberration
3.6
2. Thibos LN, Hong X, Bradley A, et al. Statistical variation of aberration structure and measurements. J Refract Surg 2003;19:S579–84.
14. Guirao A, Williams DR. A method to predict refractive errors from wave aberration data.

image quality in a normal population of healthy eyes. J Opt Soc Am A Opt Image Sci Vis
2002;19:2329–48. Optom Vis Sci 2003;80:36–42.
3. Maeda N. Evaluation of optical quality of corneas using corneal topographers. Cornea 15. Thibos LN, Hong X. Clinical applications of the Shack–Hartmann aberrometer. Optom
2002;21(Suppl. 7):S75–8. Vis Sci 1999;76:817–25.
4. Applegate RA, Sarver EJ, Khemsara V. Are all aberrations equal? J Refract Surg 16. Thibos LN. Principles of Hartmann–Shack aberrometry. J Refract Surg 2000;16:S563–5.
2002;18:S556–62. 17. Mrochen M, Kaemmerer M, Mierdel P, et al. Principles of Tscherning aberrometry. J
5. Applegate RA, Ballentine C, Gross H, et al. Visual acuity as a function of Zernike mode Refract Surg 2000;16:S570–1.
and level of root mean square error. Optom Vis Sci 2003;80:97–105. 18. Molebny VV, Panagopoulou SI, Molebny SV, et al. Principles of ray tracing aberrometry.
6. Stojanovic A, Wang L, Jankov MR, et al. Wavefront optimized versus custom-Q treat- J Refract Surg 2000;16:S572–5.
ments in surface ablation for myopic astigmatism with the WaveLight ALLEGRETTO 19. Mierdel P, Kaemmerer M, Mrochen M, et al. Ocular optical aberrometer for clinical use.
laser. J Refract Surg 2008;24:779–89. J Biomed Opt 2001;6:200–4.
7. Huang D. Physics of customized corneal ablation. In: MacRae S, Kreger R, Applegate R, 20. Marcos S. Aberrations and visual performance following standard laser vision correction.
editors. Customized corneal ablation: the quest for supervision. Thorofare: Slack; 2001. J Refract Surg 2001;17:S596–601.
p. 51–62. 21. Sakimoto T, Rosenblatt MI, Azar DT. Laser eye surgery for refractive errors. Lancet
8. Williams D, Yoon GY, Porter J, et al. Visual benefit of correcting higher order aberrations 2006;367:1432–47.
of the eye. J Refract Surg 2000;16:S554–9. 22. Giessler S, Hammer T, Duncker GI. Aberrometry due to dilated pupils – Which mydri-
9. Chalita MR, Krueger RR. Correlation of aberrations with visual acuity and symptoms. atic should be used? Klin Monatsbl Augenheilkd 2002;219:655–9.
Ophthalmol Clin North Am 2004;17:135–42, v–vi. 23. Guirao A, Williams DR, Cox IG. Effect of rotation and translation on the expected benefit
10. Williams DR. What adaptive optics can do for the eye. Rev Refract Surg 2002;3:14–20. of an ideal method to correct the eye’s higher-order aberrations. J Opt Soc Am A Opt
11. Yazdani N, Shahkarami L, OstadiMoghaddam H, et al. Topographic determination of Image Sci Vis 2001;18:1003–15.
corneal asphericity as a function of age, gender, and refractive error. Int Ophthalmo 24. Feng Y, Yu J, Wang Q. Meta-analysis of wavefront-guided vs. wavefront-optimized LASIK
2017;37(4):807–12. for myopia. Optom Vis Sci 2011;88:1463–9.
118.e1
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Phakic Intraocular Lenses

Ramon C. Ghanem, Vinícius C. Ghanem, Norma Allemann, Dimitri T. Azar 3.7
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Fig. 3.7.1 Angle-

Definition: Phakic intraocular lenses (IOLs) are artificial lenses supported Baikoff
implanted in the anterior or posterior chamber of the eye to correct ZB5M (left) and
refractive errors. They preserve the natural crystalline lens to maintain the NuVita MA20
accommodation. (right).
Key Features
• Three models of phakic IOLs are described: anterior chamber
angle-supported, anterior chamber iris-fixated, and posterior
chamber IOLs.
• Improved IOL designs and better preoperative screening are
providing increased safety and efficacy for the correction of severe
ametropias.
Associated Features
• Early models of phakic IOLs were made of rigid polymethyl
methacrylate (PMMA). Newer lenses are foldable, requiring a smaller
incision and providing a faster visual recovery.
• Complications are IOL specific and include over- and undercorrection, and 1990s several PMMA angle-supported AC phakic IOLs were intro-
glare and halos, endothelial cell loss, glaucoma, pigment dispersion, duced, but subsequently discontinued due to the same complications. The
and cataract formation. most important were the Baikoff3,4 lens, ZB and ZB5M models (Fig. 3.7.1),
• Surgical peripheral iridectomy or preoperative YAG laser iridectomies which were based on the multiflex Kelman anterior chamber IOL and the
are necessary to avoid postoperative pupillary-block glaucoma in ZSAL-4 (Morcher GmbH, Stuttgart, Germany).3,5–9 The ZB5M was later
most IOL models. modified to implement thinner optics, greater effective optic diameter,
flatter anterior face, and improved loop profile to reduce angle trauma. It
was called NuVita MA20 (Bausch & Lomb, Rochester, NY) (see Fig. 3.7.1).
INTRODUCTION The first iris-fixated lenses were sutured to the iris stroma. The claw
fixation method rendered iris stitching unnecessary. Worst introduced his
If high ametropia occurs, laser corneal refractive surgery (photorefrac- final conceptual model of the midperipheral fixation iris-claw lens for sec-
tive keratectomy [PRK] and laser-assisted in situ keratomileusis [LASIK]) ondary lens implantation. For many years, the iris-claw lens was used as
is limited by decreased safety, predictability, and efficacy of postoperative a primary implant after intracapsular and extracapsular cataract extraction
results. Now a growing interest exists in the use of phakic intraocular because of good tolerance and refractive results; it is still used today as
lenses (IOLs) to correct these refractive errors. Phakic IOL implantation a standby lens in cases of posterior capsule rupture. In 1986 Worst and
has the advantage of preserving the architecture of the cornea. Addition- Fechner10,11 modified this IOL to a biconcave AC lens for the correction
ally, it may provide more predictable refractive results and better visual of myopia. To increase the safety of this IOL and minimize the possibil-
quality than surgical techniques that manipulate the corneal curvature. ity of IOL–cornea contact, the biconcave design was changed in 1991 to a
convex–concave model with a lower shoulder, a thinner periphery, and a
HISTORY OF PHAKIC LENSES larger optic diameter (Fig. 3.7.2). This lens was called the Worst myopia
claw lens. The name of the lens then was changed to the Artisan–Worst
Clear lens extraction for the correction of myopia was a concept introduced lens (Ophtec BV, Groningen, Netherlands) and Artisan–Verisyse lens
in the early 1800s, becoming increasingly popular from 1850 to 1900.1 After (Abbott Medical Optics, Inc., Abbott Park, IL).
the discovery of sterilization in 1889, a rush for myopia correction by In the mid-1980s, the implantation of posterior chamber IOLs in
clear lens extraction was started by Fukala in Austria/Germany (“Fukala phakic eyes was reported by Fyodorov.12 The original lens design was a
surgery”) and Vacher in France.1 It was not until the end of the nineteenth “collar-button” type, with the optic located in the anterior chamber and the
century, however, that complications of this operation (e.g., retinal detach- haptics behind the iris plane. The design, modified by Chiron-Adatomed
ment and choroidal hemorrhage) began to be reported, and the technique to produce a silicone elastomer posterior chamber lens, was reported to
largely fell out of favor. have a high incidence of cataract formation.13 Further modification, the
In the 1950s, an emergence of the idea of correcting myopia by insert- phakic refractive lens (PRL) (Ioltech/CIBA Vision, La Rochelle, France)
ing a concave lens into the phakic eye was seen. At this time, Stram- (Fig. 3.7.3), had a greater vaulting, decreasing the incidence of cataract but
pelli, Barraquer,2 and Choyce experimented with anterior chamber (AC) causing zonular lesions.14 Currently, the implantable collamer lens (ICL)
angle-fixed lenses, which they eventually abandoned because of corneal (STAAR Surgical Co., Monrovia, CA) is the only posterior chamber phakic 119
edema, chronic iritis with pupil ovalization, and iris atrophy. In the 1980s IOL available (Fig. 3.7.4).
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3 BOX 3.7.1 General Criteria for Implanting Phakic IOLs
• Age >21 years
• Stable refraction (less than 0.50 D change) for 1 year
• Clear crystalline lens
Refractive Surgery
• Ametropia not suitable/appropriate for excimer laser surgery

• Unsatisfactory vision with/intolerance of contact lenses or spectacles
• Functional and occupational requirements
• Anterior chamber depth (measured from endothelium)*
Artisan–Verisyse / Artiflex–Veriflex: ≥2.7 mm
ICL: ≥2.8 mm for myopia, ≥3.0 mm for hyperopia
• A minimum endothelial cell density of:
≥3000 cells/mm2 at 21 years of age
≥2000 cells/mm2 at 45 years of age or more
Fig. 3.7.2 Iris-fixated Verisyse Lens in situ.
• No ocular pathology (corneal disorders, iris or pupil anomaly,
glaucoma, uveitis, maculopathy, etc.)
*Güell JL, Morral M, Kook D, Kohnen T. J Cataract Refract Surg. 2010;36:1976–93.
Fig. 3.7.3 Posterior

Chamber Phakic INDICATIONS OF PHAKIC LENSES
Refractive Lens (PRL) Regardless of the type of phakic IOL, careful patient selection is critical for
for Myopia (top) and
successful outcomes. General criteria should be followed (Box 3.7.1).
Hyperopia (bottom).
Moderate and High Myopia

Patients who are poor candidates for laser correction may be candidates
for phakic IOL. Food and Drug Administration (FDA)–approved excimer
lasers can treat myopia of up to −12.00 diopters (D). However, the higher
the intended correction, the thinner and flatter the cornea will be postop-
eratively. For LASIK surgery, one must preserve a safe residual corneal
stromal bed of at least 250 µm. A more conservative value would be 300 µm
and a percentage of tissue altered (PTA) no more than 40%.15,16 There is a
limit to the amount of central flattening one can induce in the cornea,
which is usually around 35.00 to 36.00 D (final keratometry). Beyond these
limits, there is an increased risk of developing corneal ectasia due to thin
residual stromal bed and loss of visual quality and night vision problems
due to excessive corneal flattening. It was shown that LASIK also induces
significant spherical and coma aberrations compared with phakic IOLs
for high myopia.17 Because of these risks, a current trend exists toward
reducing the upper limits of LASIK and PRK to around −8.00 to −10.00 D.
Above these limits, and in cases of keratoconus or keratoconus-suspect, or
the cornea is too thin or too flat for laser surgery, phakic IOLs become the
major alternative.
Most phakic IOLs for myopia can correct up to around −20.00 D
(Table 3.7.1). In 2004 the FDA approved the first phakic IOL designed to
correct high myopia. The Verisyse (AMO/Ophtec, USA Inc.), also known
as Artisan–Worst iris-claw lens, was approved for myopia ranging from
−5.00 to −20.00 D with astigmatism less than or equal to 2.50 D. In 2005 a
second phakic IOL was approved by the FDA. The Visian ICL was approved
for myopia ranging from −3.00 to −20.00 D with astigmatism less than or
equal to 2.50 D.
High Hyperopia
The upper limits for hyperopic laser surgery are around +5.00 to +6.00 D.
Higher attempted corrections can cause excessive steepening of the cornea
(above 50.00 D), usually with a small optical treatment zone, leading to
induced aberrations, especially spherical and coma aberrations and degra-
dation of optical quality. Phakic IOLs may be indicated for the correction
of hyperopia up to +22.00 D (see Table 3.7.1). In many cases, however, these
eyes have insufficient AC depth, limiting its implantation. For hyperopia,
refractive lens exchange (refractive lensectomy) with IOL implantation is
the main alternative for laser surgery in the presbyopic age group.18,19
High Astigmatism
LASIK is the treatment of choice for astigmatism of up to around
5.00–7.00 D. One may consider implanting toric phakic IOLs in cases of
120 Fig. 3.7.4 Posterior Chamber Sulcus-Supported Implantable Collamer Lens (ICL) high degrees of astigmatism whether associated with myopia or hyperopia
in situ. (see Table 3.7.1). Both spherical and cylindrical corrections can be combined
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TABLE 3.7.1 Current Phakic IOLs, Either FDA Approved or With European Conformity Mark
Type of Lens Name/Model Power Range (D) Optic Size (mm) Length (mm) Incision Size (mm) Material Manufacturer
3.7
AC Angle-Supported Kelman Duet (two parts) −8.00 to −20.00 5.5 12.5–13.5 (0.5 steps) 2.0 (foldable) Silicone optic TEKIA

PMMA haptic
Acrysof Cachet −6.00 to −16.5 6.0 12.5–14.0 (0.5 steps) 2.0 (foldable) Hydrophobic Alcon
Acrylic
AC Iris-Fixated Artisan 202 Pediatric −3.00 to −23.5 5.0 7.5 5.2 PMMA Ophtec/Abbott
Artisan 203 Hyperopia +1.00 to +12.00 5.0 8.5 5.2 PMMA Ophtec/Abbott
Artisan Toric +6.5 to −23.00 Cyl +1.00 to +7.5 5.0 8.5 5.2 PMMA Ophtec/Abbott
Artisan 204 Myopia −1 to −15.5 6.0 8.5 6.2 PMMA Ophtec/Abbott
Artisan 206 Myopia −1.00 to −23.5 5.0 8.5 5.2 PMMA Ophtec/Abbott
Artiflex/Veriflex −2.00 to −14.5 6.0 8.5 3.2 (foldable) Polysiloxane optic Ophtec/Abbott
PMMA haptics
Artiflex/Veriflex Toric −1.00 to −13.5 Cyl +1.00 to +5.00 6.0 8.5 3.2 (foldable) Polysiloxane optic Ophtec/Abbott
PMMA haptics
PC Sulcus-Supported ICL −23.00 to + 22.00 4.65–5.5 11.0–13.0 (0.5 steps) 3.0 (foldable) Collamer STAAR
Cyl + 1.00 to + 6.00
AC, Anterior chamber; FDA, Food and Drug Administration; ICL, implantable collamer lens; IOLs, intraocular lenses; PC, posterior chamber, PMMA, polymethyl methacrylate.
TABLE 3.7.2 Advantages and Disadvantages of Phakic IOLs

Advantages Disadvantages
• Preserves corneal architecture • Potential risks of an intraocular procedure
• Potential to treat a large range of (e.g., endophthalmitis)
myopic, hyperopic, and astigmatic • Nonfoldable models require large incision
refractive error that may result in significant residual
• Allows the crystalline lens to postoperative astigmatism
retain its function, preserving • Highly ametropic patients may require
accommodation additional laser surgery (bioptics) for fine-
• Excellent visual and refractive tuning the refractive outcome
results (induces less coma and • May cause irreversible damage (e.g.,
spherical aberration than LASIK) endothelial cell loss, cataract formation,
• Removable and exchangeable glaucomatous optic neuropathy)
• Frequently improve BSCVA in • Implantation in hyperopic patients is limited
myopic eyes by eliminating by shallow anterior chambers and can be
minimization effect of glasses followed by loss of BSCVA due to loss of
• Results are predictable and stable magnification effect of glasses
• Flat learning curve for some models • Other complications are not rare: pupil
ovalization, induced astigmatism, chronic
uveitis, pupillary block, pigment dispersion
BSCVA, Best spectacle-corrected visual acuity; IOLs, intraocular lenses; LASIK, laser-assisted in
situ keratomileusis.
Fig. 3.7.5 Toric Artiflex to Correct Residual Myopic Astigmatism After 6-mm
Intracorneal Ring Segment Implantation in a Patient With Keratoconus.
Sizing the Phakic IOLs

in these lenses, which aims to correct the total refractive error, but to date, The eye’s anterior segment anatomy differs significantly among individu-
only spherical corrections are FDA approved. The sum of minus sphere als, affecting the indications of phakic IOLs in different refractive errors.22
and cylinder cannot exceed −14.50 D with Artiflex toric and −23.00 D with Most of the complications of these lenses are related to inappropriate
Artisan toric. sizing and inaccurate measurements of the AC dimensions.
With irregular astigmatism or if toric models are not available, astigma- For the iris-fixated phakic IOLs (i.e., Artisan and Artiflex), sizing is
tism can be reduced with relaxing procedures such as limbal relaxing inci- not an issue because these IOLs are fixated to the midperipheral iris, not
sions, arcuate keratotomy, intrastromal rings20 (Fig. 3.7.5), and with toric the angle or sulcus, having the advantage of being one-size-fits-all length
pseudophakic IOLs in cases where the crystalline lens is opaque. LASIK or (8.5 mm).
PRK could be performed after phakic IOLs to correct residual ametropia For the sulcus-supported phakic IOLs (i.e., implantable collamer lens),
(myopia, hyperopia, and/or astigmatism), also called bioptics (discussed different sizes of overall length are manufactured to suit normal variations
later in the chapter). in intraocular anatomy (e.g., 12.1, 12.6, 13.2, and 13.7 mm). The relation-
ship of the selected overall diameter of the implanted lens to the dimen-
sions of the posterior chamber represents an important determinant of
ADVANTAGES AND DISADVANTAGES the achieved postoperative vault, which is the term used to describe the
OF PHAKIC IOLS measurable distance between the anterior capsule of the crystalline lens
and the posterior surface of the ICL (Fig. 3.7.6).23
For the advantages and disadvantages of phakic IOLs, see Table 3.7.2. The white-to-white (WTW) diameter (external measurement from
limbus to limbus) is the most important factor in determining the ICL
INTRAOCULAR LENS POWER CALCULATION size. It provides an approximate estimation of the AC (angle-to-angle [ATA])
and sulcus-to-sulcus (STS) diameters. The WTW is usually measured with
Van der Heijde21 proposed the theoretical basis for IOL power calculations the IOLMaster or the Lenstar biometers and checked with manual cali-
based on studies of patients implanted with a Worst and Fechner lens, pers between the 3 and 9 o’clock meridians. Alternative methods include
which are directly applicable to other phakic IOLs. The power calculation tomographers such as the Galilei (Ziemer), Pentacam (Oculus), and the
is independent of the axial length of the eye. Instead it depends on: (1) Orbscan IIz (Bausch & Lomb). Most studies have used the WTW measure-
central corneal curvature (power)−keratometry (K); (2) AC depth; and (3) ment plus 0.5 mm, rounded to the nearest 0.5 mm increment.12,24
patient refraction (preoperative spherical equivalent). With current IOL for- The WTW measurement, however, is well known to suffer from signif- 121
mulas and nomograms great accuracy occurs on IOL power calculations. icant inaccuracies.25,26 In a study comparing vertical and horizontal WTW
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3
Refractive Surgery
A
A
Fig. 3.7.6 (A) ICL-V4 in a patient with previous deep anterior lamellar keratoplasty. B
Observe adequate vaulting (arrow). (B) ICL vault measured with anterior segment
OCT. (Courtesy João Marcelo Lyra, MD, Maceió, Brazil.) Fig. 3.7.7 (A) Artemis High-Frequency (50 MHz) 3D-Digital Ultrasound Imaging of
the Anterior Segment. Red arrows indicate angle-to-angle distance; yellow arrows
indicate sulcus-to-sulcus distance. (B) UBM Vumax II (50 MHz transducer) of a
myopic ICL in the posterior chamber. Sulcus-to-sulcus measurement: 12.22 mm. STS
diameter measurement is important to determine adequate sizing of the phakic IOL.
measurements with direct anatomical measurements (postfixation) in
postmortem eyes, there was no correlation between the horizontal WTW
distance and the AC angle diameter; nor was there correlation between ANTERIOR CHAMBER ANGLE-SUPPORTED
either technique of external measurement and the ciliary sulcus diameter.26 PHAKIC INTRAOCULAR LENSES
High-frequency ultrasound biomicroscopy (35 to 60 MHz) has been
used to directly measure the STS diameter. It was not until recently, After the development of foldable AC angle-supported phakic IOLs, the
however, that more adequate devices for imaging and measuring the ante- rigid PMMA IOLs were almost abandoned, including the NuVita MA20,
rior segment became available. The wide-angle high-frequency (50 MHz) ZSAL-4 (Morcher GmbH) and Phakic 6 H2 (Ophthalmic Innovations
ultrasound systems (Eye Cubed, Ellex; VuMAX II, Sonomed; Aviso, Quantel International). Later, due to safety concerns related to endothelial cell loss,
Medical; Artemis, Ultralink LLC; among others) (Fig. 3.7.7) currently are the the NewLife and Vivarte (both from IOLTech–Zeiss Meditec) (Fig. 3.7.8)
best tools to measure the STS distance. Although the FDA-approved tech- and the Icare (Corneal Inc.) were also withdrawn from the market.31,32
nique for measurement remains WTW, growing evidence demonstrates A few years ago the AcrySof Cachet (Alcon Laboratories, Inc., Fort Worth,
that direct sulcus measurement using any of these methods is superior TX) phakic lens was approved by the FDA. The Cachet is a single-piece,
and minimizes the risk of incorrect ICL sizing.
Despite there being no consensus in the literature regarding the upper
and lower limits of safe vault, the lens manufacturers suggest that an Fig. 3.7.8 Foldable
acceptable amount of vaulting of the lens optic over the crystalline lens Hydrophilic Acrylic Angle-
is 1.00 ± 0.5 corneal thicknesses (approximately 250–750 µm). The clini- Supported Vivarte Lens.
cal significance of vault outside of the range of safety resides in the risk
of specific adverse events, including pupillary block, anterior subcapsular
cataract, pigment dispersion, and glaucoma.23
VISUAL OUTCOMES
Phakic IOLs are the most predictable and stable of the refractive methods
for preserving the crystalline lens in high myopia. New improved designs
and current methods for sizing and power determination are providing
increasing safety and efficacy for the correction of severe ametropias.
In high myopia correction, significant postoperative gain of best-
corrected visual acuity (BCVA) over the preoperative levels likely occurs as
a result of a reduction in the image—the minimization that is present with
spectacle correction of high myopia. A loss of BCVA is uncommon. The
loss of contrast sensitivity observed after LASIK for high myopia does not
occur after phakic IOL.27,28 In fact, with phakic IOLs an increase in contrast
sensitivity occurs in all spatial frequencies compared with preoperative
levels with best spectacle correction.29 Even for moderate myopia (between
−6.00 and −9.00D) phakic IOLs provide better CDVA, contrast sensitivity
122 at high spatial frequencies, and higher percentage of eyes gaining lines of
CDVA compared with femtosecond laser-assisted LASIK.30
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ACRYSOF CACHET DIAGRAM
3.7

A
Fig. 3.7.9 AcrySof Cachet Diagram. A single-piece, foldable, soft hydrophobic

acrylic phakic IOL.
Fig. 3.7.11 Anterior Segment OCT Use in Pre and Postoperative Assessment of a
Highly Myopic Eye. (A) Preoperative measurement of the internal anterior chamber
diameter at axis 180 = 11.68 mm. This measurement can be used to determine the
total diameter of the phakic implant. (B) Anterior segment OCT in the postoperative
assessment of Cachet phakic IOL in a highly myopic eye with angle supported
haptics (left and right) and central distance to endothelium: 2.06 mm.
Complications
Pupillary Ovalization
Ovalization of the pupil, one of the most prevalent complications of
angle-supported phakic IOLs, has a reported incidence of between 7% and
22%.5,6,9,37–40 Pupillary abnormalities tend to be progressive, being more
frequent with longer follow-up visits.6,9 The most accepted mechanism is
Fig. 3.7.10 Biomicroscopy Photograph of the AcrySof Cachet Phakic IOL related to haptic compression of the angle structure due to an oversized
Implant for High Myopic Correction. (Courtesy Wallace Chamon, MD, São Paulo, lens causing inflammation of the angle, peripheral synechia formation,
Brazil.) and pupillary ovalization. This mechanism was believed to be associated
with iris ischemia.5,41 Iris hypoperfusion was confirmed using indocyanine
green angiography (ICGA).40
Another associated complication is iris retraction and atrophy6; the
foldable, soft hydrophobic acrylic phakic IOL (Fig. 3.7.9). Four models were atrophy usually occurs in the iris sector affected by ovalization. Total sector
available, each with a different overall length. The haptics were designed iris atrophy can occur after progressive pupil ovalization in long-standing
to allow compression within the angle for IOL stability without creating cases (Fig. 3.7.13).
excessive force that could cause angle tissue damage or pupil ovalization.
The vault of the IOL was designed to provide optimal central clearance Endothelial Damage
distance between the IOL and the cornea and the natural crystalline lens Endothelial damage was the main reason for recalling several AC phakic
(Video 3.7.1) (Figs. 3.7.10 and 3.7.11).33 The 3-year findings from pooled IOLs from the market.42
See clip:
3.7.1 global studies (United States, Canada, and the European Union) showed Two different mechanisms have been proposed to explain the ECL: the
favorable refractive results and acceptable safety in patients with moder- excessive proximity of the IOL parts to the corneal endothelium, which
ate to high myopia.34,35 Recently, however, its distribution was placed on may intermittently or permanently be in contact with the posterior cornea43
hold due to a significant late-term endothelial cell loss (ECL) in a subset or the presence of inflammatory cytokines in the aqueous humor produced
of patients, especially in those with small eyes and patients self-identified by trauma to uveal structures.44 A follow-up study of more than 15 years of
to be of Asian race. Data predict that eyes need to be monitored frequently an angle-supported phakic intraocular lens model (ZB5M) for high myopia
because ~30% of eyes are at risk of early explantation based on the observed found a median coefficient of ECL of 17.5% with a rate of 0.97% every year,
ECL rates, and 5% have loss rates higher than 3.9% per year. These rates twice the physiological loss. Careful long-term follow-up of each patient
can accelerate suddenly. with an AC phakic IOL is necessary to identify patients who may need
The Kelman Duet (Tekia, Inc., Irvine, CA) consists of a duet of an inde- explants of the IOL.
pendent PMMA tripod haptic and a silicone optic (Fig. 3.7.12). The haptic
is implanted first in the AC through a 2.5-mm incision. The optic is then Elevation of Intraocular Pressure
inserted using an injector system. Finally, the optic is fixated in the AC by
the optic eyelets and haptic tabs using a Sinskey hook. At 12 months, 17% Elevation of intraocular pressure (IOP) usually occurs transiently during
of eyes had more than 15% ECL.36 No mid- or long-term data of endothelial the early postoperative period but may become chronic due to periph- 123
cell loss have been reported to date. The Duet is not FDA approved. eral synechiae, which affects 2%–18% of patients.3,5,6,37,38 Another risk is
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Fig. 3.7.12 Foldable “two
3 parts” (silicone optic/

PMMA haptics) Kelman
Duet lens (A). The haptics
are implanted initially
Refractive Surgery
through a small incision

(B), then the optic is
injected (C). The optic-
haptics are assembled
inside the anterior
chamber (D).
A B
C D
A B
Fig. 3.7.13 Pupil ovalization 2 years after implantation of an angle-supported phakic IOL (A). At 5 years, progressive ovalization was observed and the lens was explanted (B).
(Courtesy Emir Amin Ghanem, MD, Joinville, Brazil)
acute glaucoma secondary to pupillary block in the absence of adequate pupil ovalization, iris atrophy, and other complications, such as glaucoma,
iridectomies. cataract, or anterior synechiae.
Uveitis Cataract
Chronic uveitis can be observed after angle-supported IOLs, with rates from Cataract after an AC lens—less common than with posterior chamber
1% to 5%.3,5,6,37,38 An oversized lens can be a potential cause, compressing IOLs—can still occur, mainly due to chronic uveitis and other compli-
124 the angle structures and altering the blood–aqueous barrier (BAB) perme- cations. A meta-analysis of cataract development after AC phakic IOL
ability. The chronic inflammation may continue for several years, inducing implantation found an incidence of 1.29%.45
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3.7

A
Fig. 3.7.14 Artisan/Verisyse Lens. Detail of the midperipheral iris stroma

enclavated by the haptic claw.
IRIS-FIXATED PHAKIC INTRAOCULAR LENSES

The Artisan iris-claw (Ophtec)/Verisyse (Abbott Medical Optics, Inc.) lens
is fixated to the anterior iris surface by enclavation of a fold of iris tissue
into the two diametrically opposed “claws” of the lens (Fig. 3.7.14). The fix-
ation sites are located in the midperiphery of the iris, which is virtually
immobile during pupillary movements. The optic vaults approximately
0.87 mm anterior to the iris, providing good clearance from both the ante-
rior lens capsule and the corneal endothelium. The distance from the optic
edge to the endothelium ranges from 1.5 to 2.0 mm, depending on the
dioptric power, AC anatomy, and optic diameter.
The Artisan/Verisyse has a fixed overall length of 8.5 mm (7.5 mm
for pediatric implantations or small eyes), which means a great advan-
tage to the surgeon for not dealing with sizing measurements. Another
major advantage of these IOLs is that they can be properly centered over B
the pupil, even when the pupil is off-center, a relatively common situation
among people with high ametropia.32 Off-center pupils cannot be used as Fig. 3.7.15 Artisan/Verisyse Lens. FDA-approved models (A) 204 (6.0 mm optic)
a reference for centration of symmetrical IOLs such as angle-supported and (B) 206 (5.0 mm optic) for the correction of myopia.
and sulcus-fixated IOLs.32 Additionally, the fixation system inhibits IOL
movement,46 which warrants the correction of astigmatism and may help
to correct other vectorial or asymmetrical aberrations in the future.32 Pupil
size in scotopic conditions should be equal or less than body size of IOL
+ 1.0 mm to reduce the risk of glare and halos (e.g., if the IOL has a body
size of 6 mm, the scotopic pupil can be up to 7 mm). A convex, bulging, or
volcano shaped iris, usually found in hyperopes, is a contraindication for
its implantation. Currently, this lens is mainly used to treat high primary
myopia (FDA approved–Models 204 and 206; Fig. 3.7.15), hyperopia (Fig.
3.7.16),47 and astigmatism48–50 in adults. Other indications include:
• Treatment of refractive errors after penetrating keratoplasty.51–54

• Treatment of anisometropic amblyopia in children.55,56
• Secondary implantation for aphakia correction.57–59
• Treatment of refractive errors in patients with keratoconus.60
• Correction of progressive high myopia in pseudophakic children61 and Fig. 3.7.16 Anterior Segment Optical Coherence Tomography of an Artisan
postoperative anisometropia in unilateral cataract patients with bilateral Phakic IOL to Correct High Hyperopia. The posterior vault is 0.57 mm (distance
high myopia.62 from the IOL to the lens) and the distance of the anterior surface of the IOL optic to
the endothelium (safety distance) at the center is 1.75 mm.
The foldable model (Artiflex/Veriflex, Ophtec) is approved in Europe
and is now under clinical investigation for FDA approval. This lens is a outflow), a peripheral iridectomy during surgery is mandatory. Alterna-
convex–concave three-piece phakic IOL with a hydrophobic polysiloxane tively, a neodymium:YAG (Nd:YAG) laser can be used preoperatively to
6-mm optic and PMMA haptics. The toric model of the Artiflex is also create one or two small iridectomies (Videos 3.7.2, 3.7.3, and 3.7.4) See clip:
3.7.2
available in Europe.63 Various incision techniques (e.g., corneal, limbal, or scleral tunnel inci- to
sion) can be used, usually with peribulbar anesthesia, but topical anesthe- 3.7.4
Surgical Procedure sia also can be used. Usually a superior limbal or clear-corneal incision is
used. Depending on the diameter of the lens used—5.0 mm or 6.0 mm—
Preoperative application of topical pilocarpine for miosis is mandatory to the incision should be at least 5.2 mm or 6.2 mm, respectively, to avoid
form a protective shield for the natural lens during the insertion and fixa- difficulties with IOL insertion. The incision is usually located on the steep
tion of the iris-claw lens. A constricted pupil facilitates proper centration of corneal meridian, minimizing postoperative astigmatism.
the lens. Although a very low risk of pupil-block glaucoma exists (because The “claw” haptics are fixated to the iris by a process called enclavation, 125
the vaulted configuration of the Artisan lens ensures a normal aqueous and specially designed bent needles are used. Another option to facilitate
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Refractive Surgery
A B
C D
E F
G H
Fig. 3.7.17 Toric Artiflex Implantation Technique. (A) A 3-mm clear corneal incision is created. (B) Two paracentesis are created parallel to the limbus, oriented toward the
enclavation site. (C) Lens is removed from package and held with special forceps. (D) The Artiflex is mounted in the implantation spatula. (E) The optic edge bends downward
during the lens insertion. (F) and (G) Lens is rotated, centered on the pupil and positioned according to the preoperative markings on the cornea (toric model). The superior
claw is grasped and the enclavation is performed with the VacuFix. (H) Cohesive viscoelastic material is removed and peripheral iridectomy is performed. Main incision is
closed.
controlled and reproducible enclavation in the exact desired spot is the rotated and centered in front of the pupil with the haptics at 3 and 9 o’clock
VacuFix (Ophtec) (Fig. 3.7.17). This is especially important for the toric positions. When using toric models, the correct axis of implantation will
models, to facilitate cyclotorsion control. be calculated preoperatively. Limbal marks at the slit-lamp or iris marks
126 Two 1.0-mm side-port incisions at 10 and 2 o’clock positions are required with Nd:YAG should be done in the axis of implantation helping to control
for enclavation. The lens is implanted vertically through the incision, then cyclotorsion and increasing axis enclavation precision.
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3.7

Fig. 3.7.18 Blunt Iris Entrapment Needles Can Be Used to Create a Fold of Fig. 3.7.19 Inadequate Iris Enclavation (arrow) increases the risk of focal iris
Midperipheral Iris Tissue Through Vertical Movement of the Needle. atrophy, uveitis, and dislocation of the IOL.
The AC is filled with cohesive viscoelastic material, usually high-viscosity

sodium hyaluronate injected through one of the puncture incisions to
create a deep AC to maintain working space in the AC. If additional visco-
elastic material needs to be injected during surgery, care should be taken
not to let it slip under the IOL. It should be used as a stabilizing agent that
presses the implant onto the iris surface.
Centration and fixation of the IOL are probably the most critical steps of
the procedure, and their accuracy influences the postoperative results. The
pupil is used as a reference for centration. Fixation is performed by gently
creating an iris fold under the claw and then entrapping the iris fold into
the claw (Fig. 3.7.18). If adjustment of the lens is needed after fixation, the
iris must first be released before the lens is moved. At the end of surgery,
it is not unusual to have mild ovalization of the pupil due to the effect of
the miotic agent.
The number of stitches depends on the type of incision. Watertight
wound closure is of paramount importance to prevent a shallow AC from
leading to IOL–endothelial contact in the immediate postoperative period.
A small incision will help minimize surgically induced astigmatism and
inflammation.
When the foldable Artiflex is used, a small 3.2-mm clear cornea inci-
sion may be preferred. A special Artiflex implantation spatula and a lens
holder are necessary. The lens should be held by the haptics as the optic is Fig. 3.7.20 Nonpigmented (cellular) Deposits on the Posterior Surface an
made of polysiloxane and should not be touched during surgery. Artiflex Lens.
The viscoelastic material should be completely removed, preferably
with automated irrigation/aspiration system as it may induce an early post-
operative IOP rise. 3% of cases.65 In the FDA trial, iritis was observed in 0.5% of cases and
Topical corticosteroids and antibiotics are usually prescribed for 2–4 poor fixation in 2.1%.
weeks after surgery. Regular follow-ups are recommended, in particular With the Artiflex, Tehrani et al.69 observed an increased incidence of
long-term evaluations of the corneal endothelium. Correct timing of suture pigment dispersion (12.2%), believed to be due to a slight step within the
removal is critical in reducing residual astigmatism. implant in the area of the connection of the foldable silicone optic to the
rigid haptic (claw), which may have caused iris pigment abrasion during
Complications pupillary movement. Another complication in about 12% of patients is a
nonpigment deposition on the polysiloxane optic of the Artiflex lens. Treat-
Glare and Halos ment, which is successful in almost all cases, is with topical corticoste-
The incidence of glare and halos is greater with the 5.0-mm than with roids.70a The deposits tend to diminish after the third month and usually
the 6.0-mm optic diameter.64,65 The general incidence has varied from 0 disappear after 12 months, even when not treated with corticosteroids. In
to 8.8%. In the FDA prospective study, as many as 13.5%–18.2% of the one of our cases, surface IOL cleaning was needed once topical treatment
patients had glare and halos postoperatively, but approximately 10%–13% was not successful (Fig. 3.7.20).70b A re-enclavation or even an explantation
had these symptoms preoperatively with an improvement after surgery. can be considered if the deposits recur.
Pupils larger than 5.5 mm are at a significantly increased risk for glare
and halos.66 Endothelial Cell Loss
Intraoperative trauma is considered the main cause of early cell loss. Inves-
Anterior Chamber Inflammation/Pigment Dispersion tigators have found an acceptable mean endothelial loss of 2.8%–9.2% 2
Cases of severe iritis are rarely observed after surgery but can occur after years following iris-claw phakic lens implantation,47,65,69,71,72 which is similar
repeated traumatic attempts at iris enclavation or occasionally without any to results of posterior chamber IOL implantation.73 Menezo et al.65 noted
predisposing factors.67,68 Pigment dispersion syndrome has occasionally endothelial cell loss of 13.4% at 4 years, without morphometric changes.
been observed. A known mechanism is poor fixation/enclavation of the The largest cell loss was observed in the first 6 months after surgery.
IOL to the iris with subsequent pseudophakodonesis (IOL movement), In the FDA trial, a mean corneal endothelial cell change of 4.8% was
which may cause chronic inflammation with the need for reintervention observed 3 years after surgery.66 Artisan phakic IOLs implanted in eyes with 127
for refixation (Fig. 3.7.19). Poor fixation has been observed in as many as AC depths less than 3.2 mm exhibited the greatest cumulative endothelial
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cell loss (9%) at 3 years. The FDA panel then contraindicated the use of
3 this lens for patients with an AC depth of less than 3.2 mm. Morral et al.74
observed that Artisan/Artiflex implantation did not produce significant
ECL up to 10 years after surgery compared with corneal refractive surgery
and unoperated eyes. Patients should never rub their eyes and never press
Refractive Surgery
them against the pillow at night.
Glaucoma
Postoperative glaucoma after Artisan lens implantation can occur due
to residual ophthalmic viscosurgical device in the AC, dispersion of iris
pigment during surgery with partial occlusion of the trabecular meshwork,
use of topical corticosteroids, and postoperative inflammation.65,68,72 Tem-
porary ocular hypertension was demonstrated in a prospective study of 100
eyes with Artisan IOL. IOP showed a mean increase of 2.1 mm Hg at 3
months after surgery but a return to preoperative levels by 6 months.75
In the same study, one lens was explanted due to chronic high IOP at 11
months. In the FDA study, no case of raised IOP requiring treatment was
observed.
Iris Atrophy or Dislocation A

Despite successful implantation of an Artisan lens, there is a risk of sub-
sequent IOL dislocation. In the FDA trial, IOL dislocation occurred in five
cases (0.8%) at 3 years. IOL dislocation can occur due to iris atrophy at the
site of enclavation, usually when a small amount of tissue is entrapped,
or due to blunt ocular trauma, as reported previously in two cases76,77 (Fig.
3.7.21). Repositioning of the lens may be done with an excellent visual
outcome in most cases.
Cataract
Nuclear cataract (NC) developed in 7 of 231 eyes (3%) with an Artisan lens
after 8 years follow-up in one study.78 Patients older than 40 years of age at
implantation of the IOL and axial length greater than 30 mm were factors
significantly related to NC formation.78 A meta-analysis of cataract after
iris-fixated phakic IOL implantation found an incidence of 1.11%.45 In the
FDA trial, the cumulative incidence of lens opacity was 4.5% (49/1088 eyes). B
The majority of these opacities were not visually significant. During the
study, four opacities were determined to be visually significant and three
required cataract extraction. The authors pointed out that the rate of cata-
ract surgery in the general population over 40 years of age is 1.7%–10.8%.66
Other Complications
Other complications include hyphema,71 intermittent myopic shift (of
4.00 D),79 retinal detachment, and giant retinal tears.71,80,81
POSTERIOR CHAMBER PHAKIC

INTRAOCULAR LENSES C
Since 1986, when Fyodorov first implanted a phakic IOL in the prelen-
ticular space to correct high myopia, several posterior chamber phakic Fig. 3.7.21 (A) Artisan Dislocation After Blunt Trauma. Note the avulsion of iris
IOLs of his derivation have been developed.12,82 Results with phakic IOL stromal tissue in the site of enclavation. (B) and (C) Anterior segment OCT of a
materials and designs used to date suggest that both biocompatibility with dislocated Artisan intraocular lens. IOL optic touch to endothelium (left in both
and adequate spacing from sensitive intraocular structures are required figures) and correspondent thickening of the cornea (edema).
for improved safety in all patients. For implantation of a phakic IOL in
the prelenticular space, we would ideally desire materials that would allow
permeability of nutrients and circulation of aqueous humor and would not Collamer is a hydrophilic flexible material with a high biocompatibility and
cause crystalline lens or zonular trauma. permeability to gas (oxygen) and metabolites.88 These features and the free
Until recently, two models of posterior chamber phakic IOLs were avail- space left between the IOL and the crystalline lens, named “vault,” should
able on the market, the phakic refractive lens and the implantable colla- allow the crystalline to have a normal metabolism and thus avoid the
mer lens. Despite initial promising results with the PRL, it was withdrawn development of cataracts. Yet cataract formation, pigment dispersion, and
from the market due to safety concerns. glaucoma still are the main complications.91–93 The FDA-approved model
The PRL (IOLTech/CIBA Vision) (see Fig. 3.7.3), a model based on pre- of the ICL—the Visian ICL V4 (Fig. 3.7.22A), a rectangular single-piece
vious work by Fyodorov et al.,12,13,24 was a silicone single-piece plate design IOL, 7 mm wide, with greater vaulting than the V2 and V3 models—has
IOL that had a concave posterior base curve mimicking the anterior cur- been associated with a decrease in the frequency of lens opacification.94,95 A
vature of the crystalline lens. Earlier designs of this IOL caused cataract newer design, currently available outside the United States, the V4c Visian
because of mechanical touch, impermeability of nutrients, and stagnation ICL with Aquaport (Fig. 3.7.22B), incorporates a 0.36-mm diameter port
of aqueous flow without the elimination of waste products.13,14,83 Further in the center of the optic. The presence of this port obviates the need for
improvements in the vaulting reduced the incidence of cataract, but UBM preoperative iridotomies.
studies documented that the PRL was located on the zonules in most
cases.84 After reports of PRL decentration and dislocation into the vitreous Surgical Technique
cavity the lens was withdrawn from the market.85–87
ICL: In 1993, a posterior chamber phakic IOL made of Collamer A combination of topical mydriatics (e.g., cyclopentolate 0.75% and phen-
(0.2% collagen and 60% hydroxylethyl methacrylate copolymer) was ylephrine 2.5%) is applied three times 30 minutes before surgery to obtain
128 developed.88–90 The ICL (STAAR Surgical Co.); Fig. 3.7.22 is designed to good pupil dilation. For toric cases the 0° and 180° horizontal corneal axis
be implanted in the posterior chamber supported in the ciliary sulcus. are marked while the patient is sitting upright to control cyclotorsion while
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A B C
D E
Fig. 3.7.22 (A) ICL V4 and (B) V4c toric with central Aquaport. (C–E) Myopic ICL. (C) Biomicroscopic slit demonstrating the distance ICL to the crystalline lens. (D) UBM (50
MHz) quantitatively assessing lens vault (distance ICL to lens) = 590 microns; and (E) UBM showing the proximity of the ICL haptic to the ciliary processes and zonulae.
Fig. 3.7.23 A Posterior Chamber Lens (ICL) Is Inserted Through a Small Incision Fig. 3.7.24 After the Lens Unfolds, the Footplates Are Placed Underneath
With an Injector. (Courtesy Glauco R. Mello, MD, Curitiba, Brazil.) the Iris.
lying supine. Topical or peribulbar anesthesia are usually preferred. A 2.7- induced by the implant also may be partially responsible for cataract
or 3.0-mm temporal clear corneal tunnel, and two paracentesis are created. formation.
Following the placement of cohesive viscoelastic, the posterior chamber A meta-analysis of cataract development after different posterior
IOL is introduced into the AC using an injector (Fig. 3.7.23) (Video 3.7.5). chamber phakic IOLs found that 223 of 1210 eyes developed new-onset
See clip:
3.7.5 While the IOL unfolds, its proper orientation must be checked. Each cataract.45 Of these, 195 were anterior subcapsular. The overall incidence
footplate then is placed one after the other beneath the iris with use of of cataract formation was 9.6%. In the ICLV4 FDA trial with a mean
a specially designed, flat, nonpolished manipulator, without placing pres- follow-up of 4.7 years, a cumulative probability estimate of 6%–7% of ante-
sure on the crystalline lens (Fig. 3.7.24). The surgeon should avoid contact rior subcapsular opacities was found more than 7 years after implantation
with the central 6.0 mm of the lens, as any contact might damage the thin of the Visian ICL.96
lens optic. Except for the newest model (V4c), a small peripheral iridec- In a more recent meta-analysis comprising 2592 eyes, the occurrence
tomy should be performed to prevent pupillary block. Then the viscoelastic of cataract formation with the V4 ICL models was 5.2%. Of those, 43.4%
material is removed with irrigation–aspiration, and acetylcholine (Miochol) were reported within 1 year, 15.4% between 1 and 3 years, and 35.3% ≥3
is injected. Corticosteroid–antibiotic eyedrops are prescribed for 4 weeks. years after ICL implantation.97 In a retrospective review of 133 consecutive
eyes implanted with the V4 ICL model, the observed rate of phacoemul-
Complications sification increased from 4.9% at 5 years to 18.3% at 10 years after ICL
implantation, and 13% of eyes developed ocular hypertension that required
Cataract topical therapy at 10 years. A smaller vault height was associated with the
Cataract is the most crucial concern for the future of posterior chamber development of lens opacity.98 Another study with 84 eyes with V4 ICL
phakic IOLs (Fig. 3.7.25). Cataract may form as a result of trauma to the reported a rate of phacoemulsification of 17% at 10 years.99
crystalline lens during the implantation procedure or due to long-term The treatment of cataract in patients implanted with posterior chamber 129
contact between the IOL and the crystalline lens. Metabolic disturbances phakic IOLs is not difficult. Explantation of the ICL is easily performed
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Refractive Surgery
Fig. 3.7.25 Anterior Cortical Cataract 1 Year After ICL-V4 Implantation in a

Patient With Previous Intracorneal Ring Segment for Keratoconus. (Courtesy
João Marcelo Lyra, MD, Maceio, Brazil).
through the same incision. Phacoemulsification and posterior chamber

IOL implantation can be done in a routine fashion.100
ICL Replacement
ICL exchange for insufficient or excessive vault is an uncommon compli-
cation. In a cohort of 616 eyes implanted with V4 ICLs sized according to
WTW and ACD measurements, 16 eyes (2.6%) had lens replacement.101
Eight surgeries (50%) were performed because of low vaulting (≤100 µm) B
and another 8 (50%) because of too high vaulting (≥1000 µm). In the US
FDA trial using the same sizing methodology, ICL replacement for insuf-
ficient or excessive vault was reported in five of 526 eyes (1.0%).102 In the
absence of complications, however, ICL replacement remains a matter of
medical judgment. On the other hand, excessive vault in the presence of
compromised AC angle function (Fig. 3.7.26) (Video 3.7.6) and insufficient
See clip:
3.7.6 vault in the presence of visually significant cataract are indications for sur-
gical intervention.23
Pigmentary Dispersion and Elevated Intraocular Pressure

Pigmentary dispersion syndrome occurs when the iris is abraded and
releases pigments into the aqueous humor. Because of the close position
to the iris and ciliary sulcus, the placement of posterior chamber phakic
IOLs may increase the risk of pigmentary dispersion14,24,92103 (Fig. 3.7.27).
Pigmentary reaction has been described with rates between 0% and 15.5% C
with posterior chamber phakic IOLs and is frequently associated with
elevated IOP. Sanders et al.102 reported two eyes out of 526 (0.4%) with Fig. 3.7.26 (A) Anterior chamber angle closure and excessive vault after ICL V4
increased IOP requiring treatment at 3 years postoperative. Guber et al.98 implantation in a patient with high myopic astigmatism after previous deep
reported that at 10 years, 12 eyes (12.9%) had developed ocular hyperten- anterior lamellar keratoplasty. (B) The ICL was replaced for a smaller size through
sion that required topical medication, which raises some concern about a microincision (arrow). (C) After replacement, a normal vaulting was observed.
the long term. (Courtesy Walton Nosé, MD, PhD, São Paulo, Brazil.)
Endothelial Cell Damage

Although endothelial cell loss is a major concern with AC IOLs, it is not This two-step technique was called adjustable refractive surgery (ARS) by
such an important problem with posterior chamber phakic IOLs. In the Guell.105 The rationale for performing the flap first is to avoid any possibil-
ICL FDA trial, cumulative cell loss over the first three postoperative years ity of contact between the endothelium and the IOL during the suction and
was 8.4%–9.7%, depending on the method of analysis.94 Most loss occurred cut for the LASIK procedure. Most authors believe that the corneal flap can
in the first year and is considered to be due to surgical trauma. be created despite the presence of an AC phakic IOL. The combination of
phakic IOLs and LASIK is a safe, effective, predictable, and stable proce-
BIOPTICS dure for the correction of high myopia and hyperopia.
Zaldivar et al.104 introduced the term “bioptics” in the late 1990s to describe
the combination of phakic IOL implantation followed by LASIK in patients
CONCLUSION
with extreme myopia, high levels of astigmatism, and in patients whose The field of phakic IOLs has greatly progressed in recent years. The
lens power availability was a problem. The concept of first implanting increased knowledge on anterior segment anatomy and the availability of
a phakic IOL to reduce the amount of myopia and then fine-tuning the better imaging technologies along with improved IOL designs and mate-
residual correction with LASIK has gained appeal. rials and surgical techniques have led to higher success rates with these
When an AC phakic IOL combined with LASIK is planned, the corneal lenses. Compared with corneal refractive surgery, phakic IOLs compete
130 flap can be created just before the insertion of the lens. Then, usually after favorably for the correction of high ametropias with increasing predictabil-
1 month, the flap is lifted for laser correction of the residual ametropia. ity, efficacy, safety, and quality of vision.
booksmedicos.org
KEY REFERENCES
Budo C, Hessloehl JC, Izak M, et al. Multicenter study of the Artisan phakic intraocular lens.
3.7
Chen L-J, Chang Y-J, Kuo JC, et al. Meta-analysis of cataract development after phakic intra-

ocular lens surgery. J Cataract Refract Surg 2008;34:1181–200.
Dick HB, Alió J, Bianchetti M, et al. Toric phakic intraocular lens: European multicenter
study. Ophthalmology 2003;110:150–62.
Fernandes P, González-Méijome JM, Madrid-Costa D, et al. Implantable collamer poste-
rior chamber intraocular lenses: a review of potential complications. J Refract Surg
2011;27(10):765–76, Review.
Ghoreishi M, Agherian R, Peyman AR, et al. Flexible toric iris claw phakic intraocular lens
implantation for myopia and astigmatism. J Ophthalmic Vis Res 2014;9(2):174–80. (FFF)
– For results table.
Guber I, Mouvet V, Bergin C, et al. Clinical outcomes and cataract formation rates in eyes 10
years after posterior phakic lens implantation for myopia. JAMA Ophthalmol 2016;doi:
10.1001/jamaophthalmol.2016.0078.
Güell JL, Morral M, Kook D, et al. Phakic intraocular lenses part 1: historical overview, current
models, selection criteria, and surgical techniques. J Cataract Refract Surg 2010;36:
1976–93, Review.
Güell JL, Vazquez M, Gris O. Adjustable refractive surgery: 6-mm Artisan lens plus laser in
situ keratomileusis for the correction of high myopia. Ophthalmology 2001;108:945–52.
Kohnen T, Kook D, Morral M, et al. Phakic intraocular lenses part 2: results and complica-
Fig. 3.7.27 Pigmentary Deposits Are Seen in the Angle in an Eye With a tions. J Cataract Refract Surg 2010;36:2168–94, Review.
Lane SS, Waycaster C. Correction of high myopia with a phakic intraocular lens: interim anal-
Posterior Chamber Phakic Intraocular Lens. (From Arné JL, Hoang-Xuan T. ysis of clinical and patient-reported outcomes. J Cataract Refract Surg 2011;37:1426–33.
Posterior chamber phakic IOL. In: Azar DT, editor. IOLs in cataract and refractive Malecaze FJ, Hulin H, Bierer P, et al. A randomized paired eye comparison of two tech-
surgery. Philadelphia: WB Saunders; 2001. p. 267–72.) niques for treating moderately high myopia: LASIK and Artisan phakic lens. Ophthal-
mology 2002;109:1622–30.
Packer M. Meta-analysis and review: effectiveness, safety, and central port design of the intra-
ocular collamer lens. Clin Ophthalmol 2016;10:1059–77, Review.
Stulting RD, John ME, Maloney RK, Verisyse Study Group, et al. Three-year results of
Artisan/Verisyse phakic intraocular lens implantation. Results of the United States Food
and Drug Administration clinical trial. Ophthalmology 2008;115:464–72.
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131
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131.e2
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Astigmatic Keratotomy: The

Transition from Diamond Blades 3.8
to Femtosecond Lasers
Kerry K. Assil, Joelle A. Hallak, Pushpanjali Giri, Dimitri T. Azar
Definitions: SURGICAL TECHNIQUES FOR ASTIGMATIC AND

• Astigmatic keratotomy (AK) is an incisional procedure in which a RADIAL KERATOTOMY
diamond blade or a femtosecond laser is used for the correction of
astigmatism. The surgical techniques for AK and RK1–4 (rarely used today) have many
• Radial keratotomy (RK) is a procedure in which radial incisions common aspects. AK remains a surgical option for correcting high astig-
are used to correct myopic spherical refractive error. The lower matism (e.g., postkeratoplasty astigmatism) that is beyond excimer laser
predictability and higher complication rates of RK relative to laser correction or for the correction of smaller degrees of astigmatism in
refractive surgery have reduced its utility for the correction of patients undergoing cataract surgery. Femtosecond AK has increased the
myopia. predictability and improved the safety of AK.5,6,7 Although limbal relax-
ing incisions have become popular as well, they do not have the tensile
strength of Descemet’s membrane, which fortifies a corneal incision.
Key Features
Preoperative Considerations
• The effect of incisional keratotomy is influenced by corneal wound Patient Selection
healing and patient age. In selecting patients for AK, the surgeon must screen surgical candidates
• For astigmatic keratotomy, the surgeon must screen surgical for myopic or planospherical equivalents. AK does not, as a general rule,
candidates for myopic or planospherical equivalents. benefit patients who have hyperopic astigmatism in which the spherical
• The axis of astigmatism is important for the placement of AK equivalents are relatively unaffected or associated with a further hyperopic
incisions. Sound clinical judgment is needed when disparity occurs shift.
between corneal topography and clinical refraction. Ideal candidates for AK, in addition to having a myopic or planospher-
• Complications of incisional keratotomy may be reduced by adequate ical equivalent, have no keratoconus, are intolerant of contact lenses, and
marking of the visual axis, adequate corneal incision shape and experience meridional magnification and distorted peripheral vision with
depth, and avoidance of corneal perforations. high-cylinder spectacles.
• Postoperative complications include progressive hyperopia,
progressive wound gaping, induced astigmatism, and contact lens Visual Axis Determination and Marking
intolerance. The use of scanning slit topography or Scheimpflug-based topogra-
• Femtosecond laser arcuate keratotomy (femtosecond AK) is phy along with clinical refraction will help confirm the positioning of
an effective alternative to AK. Laser arcuate resection (LAR) is the planned AK incisions. Modern topographers provide an estimate of
an effective alternative to manual wedge resection for high pachymetry at the location of the intended AK incision sites.8,9
postkeratoplasty astigmatism. A corneal light reflex used to guide procedure centration serves only
to approximate the physiological visual axis location, because a coaxially
aligned light reflex corresponds to the center of the corneal optical system
and not the true visual axis. Studies have demonstrated this site to be asso-
ciated most closely with the physiological visual axis.10
HISTORICAL REVIEW For marking of the visual axis, the administration of a drop of fluid
Incisional Keratotomy over the corneal apex may enhance an otherwise dull corneal light reflex.
A Sinskey hook is used to indent gently the epithelium that overlies the
The diamond knife, although still in use today, is being replaced in many visual axis. If the epithelial indentation is not visualized readily, a Weck
centers by the femtosecond laser with its ultrashort pulses capable of chis- cell may be applied to the central epithelium, which enhances the central
eling precise incisions on the cornea. Femtosecond lasers have garnered epithelial mark.
acclaim in terms of generating corneal incisions with greater precision, Treatment alignment is important for successful correction of astigma-
accuracy, safety, predictability, and reproducibility. tism. The results of vector analysis have indicated that treatment decen-
Incisional keratotomy now is mainly limited to astigmatic keratotomy tration by 5°, 15°, and 30° corresponds to losses of the flattening effect by
at the time of cataract surgery and, rarely, to two-incision radial keratotomy 1.5%, 13.4%, and 50%, respectively. Moreover, complete loss of the flatten-
(RK) for patients with low-grade myopic astigmatism who are not good ing effect is seen with treatment misalignment of 45°.11
candidates for laser in situ keratomileusis (LASIK) and photorefractive ker-
atectomy (PRK). Intraoperative Corneal Pachymetry
Several options are available today for femtosecond laser AK: femto- The paracentral corneal thickness (1.5 mm from the visual center, at the
second laser astigmatic keratotomy (femtosecond AK) and intrastromal 3-mm central clear zone) is measured at both the temporal site and the
astigmatic keratotomy (ISAK). Methods for astigmatism correction can be thinnest paracentral site, as previously established by pachymetry at
performed alone or in combination with other procedures such as cataract the screening examination. Most often, this thinnest paracentral site coin-
132 surgery. Further, the correction can be done for natural or surgery-induced cides with the paracentral temporal (or inferotemporal) site as the region
astigmatism such as postkeratoplasty astigmatism. closest to the anatomical corneal center. If the two sites do not coincide,
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the diamond blade is set to 100% of the thinner of the two intraoperatively spot sizes smaller. This way the spots never really connect, which reduces
measured sites using a calibration microscope. the effectiveness of the femtosecond laser–created AK incision compared
with those created using the diamond blade. However, the incision is made 3.8
Incision Technique tighter, ensuring that it does not open immediately. The laser pulses are
typically placed around 3 µm on both the spot and layer separations.
Astigmatic Keratotomy: The Transition from Diamond Blades to Femtosecond Lasers

Astigmatic incisions, either arcuate or tangential, produce maximal flatten-
ing in the meridian of the incision when they are placed within 2.5–3.5 mm Femtosecond Intrastromal Astigmatic Keratotomy (ISAK)
of the visual axis, which also is within the 5–7 mm optical zone. Inci- Intrastromal incision is conceptually different from a manual LRI or full
sions made closer than the 5-mm optical zone cause visual disturbances. penetration astigmatic incision in that there is no breakage of Bowman’s
Incisions beyond 7 mm (such as limbal relaxing incisions [LRIs]) have a layer during the procedure. Compared with penetrating AK incisions, the
diminished effect on central corneal flattening. optical zone is made a little smaller and the arc angle is made a little longer
When arcuate incisions are lengthened, increasingly greater degrees of in ISAK.16 The complete intrastomal nature of the incision allows the
astigmatic correction are provided, up to an arc length of 90°. Beyond an healing of the realigned stroma without wound gaping or epithelial plug
arc length of 90°, no reliable additional flattening occurs. Stacking mul- formation. To ensure proper alignment, limbal marks can be made with a
tiple rows of astigmatic incisions is neither productive nor advised. Inci- sterile pen placed at the 3 o’clock and 9 o’clock positions at the slit lamp
sions carried out at progressively smaller optical zones may result in global just before the procedure. The incision details such as the depth, optical
corneal flattening. Such incisions may be associated with increased inci- zone, and arc length can be preprogrammed into the femtosecond laser
dence of irregular astigmatism. post limbal marking, after which the procedure can be carried out in a very
similar manner to LASIK flap creation with the femtosecond laser. Patients
Diamond Blade–Assisted AK with mixed astigmatism with a plano spherical equivalent will best benefit
The diamond blade–assisted AK procedure is a manual process that from the ISAK procedure, because the AK incisions are neutral in relation
requires marking the optical zone of the desired incision, marking the to myopia or hyperopia.17 Thus, ISAK is a great additional potential option
steep axis of astigmatism according to the appropriate arc length, and available for femtosecond laser users, especially for astigmatism ranging
then determining the corneal thickness at the optical zone with ultrasound from 0.50 to 2.75 D of cylinder.
pachymetry before inserting the blade into the cornea to make the inci- The variables in performing ISAK incisions are arc length on the nomo-
sion. A sterilized diamond knife blade then is mounted onto the sterile grams and the surgical platform. As for femtosecond AK, Donnenfeld,
mounting block of the calibration microscope with the knife footplates set Nichamin LRI, and modified Lindstrom nomograms are used as starting
to zero and the diamond either extended to 550 mm or set at the thinnest points for performing ISAK. However, additional nomograms have been
paracentral screening pachymetric reading. Once real-time, intraoperative determined for ISAK incisions combined with other procedures such as
ultrasonic pachymetry is obtained, the diamond-tip extension is adjusted phacoemulsification.18 The surgeons suggest an incision depth of 80% or
to the newly selected level. In this way, a minor adjustment is generally 90%.
all that is needed, and it can be carried out in only a few seconds. When ISAK confers a unique advantage to the process of astigmatism cor-
LRIs are being applied during cataract surgery, a preset blade is often used rection by virtue of its intrastromal nature. The intrastromal incisions can
without the need for precalibration.12,13 be titrated easily by opening of the incision, and they can be performed
Although this AK procedure has the potential to reduce high degrees of easily in a minor procedure room or right at the slit lamp.17 It is easiest to
astigmatism, the postoperative outcomes are often accompanied by com- open the incision if the anterior edge of the incision is left just under the
plications such as wound gape, perforation, skin lesions, epithelial inclu- Bowman’s layer.
sion, higher order aberrations, and poor predictability. LRIs have become
popular as well, but the tensile strength of Descemet’s membrane that Wedge Resection Using Laser Arcuate Resection (LAR)
strengthens a corneal incision is absent in laser arcuate resection (LAR). LAR is a standardized technique in which intersecting arcuate cuts are
used to perform a wedge resection for the correction of high astigmatism
Full Penetrating Femtosecond AK through corneal steepening. The arcuate wedges to be excised are placed
Femtosecond AK corneal surgery creates arcuate incisions to flatten the in the flat meridian. A simple formula is used to estimate the relative size
cornea. AK incisions are generally placed in the steep corneal meridian and location of the arcuate cuts based on the radii of curvature and desired
and result in flattening of the steep meridian (often associated with a wedge width to be resected. The feasibility of the procedure was estab-
compensatory steepening “coupling” effect of the orthogonal flat merid- lished in porcine corneas before treatment of a patient with 20.00 D of
ian). A coupling ratio is defined as the ratio of the values of the flattening postkeratoplasty astigmatism.13 The astigmatism was reversed (Fig. 3.8.1),
of the steep meridian and the steepening of the orthogonal flat meridian and suture removal resulted in a 14.5 D reduction of astigmatism. LAR
after placement of AK incisions.14 A coupling ratio equal to 1 indicates an can be an effective alternative to manual wedge resection, allowing easier,
unchanged spherical equivalent (SE) after the procedure due to equal flat- more controlled, and more precise excision of tissue in width, length,
tening and steepening of the two meridians. A coupling ratio less than 1 and depth.13
indicates a SE shift toward myopia, and conversely, a coupling ratio greater
than 1 indicates a SE shift toward hyperopia. Corneal topography or tomog- Surgical Protocol
raphy, along with refraction, are performed in planning the femtosecond
AK incisions.15 Nomograms are then used to determine the arc length and When AK is planned, careful attention to quantitative keratography
the optical zone to achieve the desired astigmatism correction. (corneal topography) may be valuable, because paired incisions based on
Although prior nomograms existed, developing their own nomogram either the standard keratometer measurements or the refraction alone may
based on a series of cases was important for each surgeon as demonstrated be inaccurate. If a manifest refraction fails to yield the patient’s potential
by the different surgery results of the femtosecond procedure experienced acuity, irregular astigmatism may be present, and a topographical analysis
by some surgeons compared with the manual AK technique. Donnenfeld is useful.
and Nichamin LRI nomograms were most commonly used as the baseline The visual axis is determined first, followed by selection of the appro-
for the laser nomograms. Some surgeons altered both the blade nomo- priate optical zone, incision number, and length, as directed by the
gram and the laser’s power output to come up with an effective approach nomogram.
for using the IntraLase laser. The modified Lindstrom nomogram is the
most widely implemented nomogram for planning femtosecond AK inci- Axis of Astigmatism
sions. Usually, when using the modified Lindstrom nomogram, surgeons When disparity occurs between corneal topography and clinical refrac-
recommend adding 0.05 diopters (D) to the planned astigmatism correction, the surgeon needs sound clinical judgment on a case-by-case basis.
tion per year for patients less than 30 years old and subtracting 0.02 D In such circumstances, if topographical analysis demonstrates orthogonal
per year for patients over 30 years old. Additional nomograms have been astigmatism, the surgeon may proceed according to the manifest refrac-
developed for femtosecond AK as well. tion, as this provides the physiological combined (lenticular plus corneal)
When femtosecond laser incisions are made, a series of spherical spots astigmatism. Alternatively, in cases of nonorthogonal astigmatism (when
are created adjacent to each other tightly so that the final effect is similar the two steep hemimeridians differ by any angle other than 180°), if the
to a wide-open incision made using the traditional diamond blade. Alter- spherocylindrical reconstruction of the topographical pattern is con-
natively, this process can be adjusted by altering the laser energy and the sistent with the refraction, the incisions are placed as indicated by the 133
spot size. Lowering the laser energy creates a weaker shot, making the topographical map.
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C
D
Fig. 3.8.1 (A) Preoperative corneal topography of the right eye demonstrated 20.0 D of post-PKP astigmatism. (B) Intraoperative view during wedge tissue removal (0.5 mm
width) after LAR. The tissue was easily peeled off the wound. (C) Single 10–0 nylon sutures were placed. (D) Biomicroscopy appearance 1 month following LAR. (E) At 4
months, the corneal topography showed a decrease in topographical astigmatism to 6.3 D. (Reproduced with permission from Ghanem RC, Azar DT. Femtosecond-laser
arcuate wedge-shaped resection to correct high residual astigmatism after penetrating keratoplasty. J Cataract Refract Surg 2006;32:1415–19.)
Once the desired axis of astigmatic correction has been determined, at eye level and from head-on provides a virtual image of the light filament,
this needs to be translated onto the cornea. Because the astigmatic axis which falls at the center of the corneal optical system and closely approx-
is defined so carefully with the patient in an upright position without imates the visual axis. The epithelium is abraded at the outer margins
sedation or a lid speculum, one must not estimate the surgical axis intra- along the long axis of the beam using a Sinskey hook.
operatively with the patient in a supine position or sedated or with a lid After true 90° or 180° is marked precisely at the slit lamp, the true
speculum in place. Cyclotorsional rotation of the globe may occur and visual axis is determined in the operating room under the operating micro-
introduce significant error. scope. With the 90° (or 180°) position determined precisely (reference
For control, with the patient seated at the slit lamp, epithelial marks are axis), any desired axis may be marked using an axis marker and a surgical
placed on either the vertical or horizontal axis. Using the slit beam for cen- marking pen.
134 tration and with the contralateral eye covered, the patient fixates straight After appropriate marking of the astigmatic axis, pachymetry is carried
ahead first on the slit-lamp light source. Fixation on the slit-lamp filament out at the selected optical zone over the incision sites. The diamond blade
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is set at 100% of the measurement at the thinner of the two sites. With the
BOX 3.8.1 Potential Complications of Astigmatic and
globe fixated, the corneal marks are incised.
The use of guarded diamond knife blades is advisable. The conjunctiva Radial Keratotomy 3.8
is grasped close to the limbus, where it fuses with Tenon’s capsule and
Self-Limited
enables stable fixation; this region also is anesthetized more deeply than

Halo effect
are the posterior conjunctiva and sclera.
Starburst effect
The surgeon needs patience when secondary enhancements to AK are
Diurnal visual fluctuation
planned and performed. AK incisions require more time to stabilize than
Early regression
do radial incisions, so enhancement should be deferred for a minimum
of 6 weeks after the primary procedure. A computerized videokeratogra- Intraoperative
phy system is indispensable when the enhancement of an AK procedure is Marking
carried out. Caution is advised in treating overcorrected AK patients. If the • inaccurate visual axis marking
resultant refractive error is one of hyperopic astigmatism, the original inci- Incisions
sions may be reopened, the fibrous plug removed, and the wound margins • incision invading optical zone
approximated using a 10–0 nylon suture. Likewise, if an astigmatic inci- • incision beyond clear cornea
sion is placed incorrectly in the flat axis, the wound margins are approx- • intersecting incisions
imated using 10–0 nylon suture. Alternatively, if the residual refractive Perforations
error is myopic astigmatism, further astigmatic incisions may be placed • corneal perforation
in the newly defined, steep hemimeridian. Such incisions are shorter than • lens capsule perforation
otherwise indicated, because the cornea has now demonstrated an exces- Associated with retrobulbar anesthetic
sive response to the initial incisions and could respond in like fashion to • optic nerve damage
any further astigmatic incisions. • globe penetration/retinal detachment
Miscellaneous
Postoperative Protocol • diamond blade chip
Postoperative
At the termination of the procedure, diclofenac sodium, mild corticoste-
Non-sight-threatening complications related to refractive changes
roid, and anti-infective agent drops (such as tobramycin, ciprofloxacin,
ofloxacin, or norfloxacin) can be given. The diclofenac drops are discon-
• undercorrection
tinued on postoperative day 2 to avoid masking early keratitis and to min-
• overcorrection
imize the risk of a toxic response.
• regression
• progression
• induced irregular astigmatism
Miscellaneous non-sight-threatening complications
OUTCOME COMPARISON FOR VARIOUS • contact lens intolerance
ASTIGMATISM CORRECTION METHODS • epithelial basement membrane disorders
In 2008, Harissi-Dagher and Azar5 first reported the outcomes of high
• epithelial inclusion cysts
astigmatism correction in postkeratoplasty patients treated with femtosec-
• foreign particles within grooves
ond laser–assisted paired arcuate keratotomies. The report included two
• epithelial iron lines
patients whose outcome measures included best-corrected visual acuity
• diminished corneal strength
(BCVA), refraction, keratometry, and topography findings. The patients’
• endothelial cell loss
Sight-threatening complications
BCVA improved from 20/100 and 20/200 to 20/30 and 20/60, respectively,
without any postprocedure complications such as microperforations, graft
• stromal melting
rejection, or graft failure.
• infectious keratitis
Newer versions of femtosecond laser platforms utilize both static Therapy-related
and real-time optical coherence tomography (OCT) imaging systems to Pharmacological
provide better accuracy and precision for the determination of planned • drug toxicity
AK incisions. LenSx is an example of a new generation femtosecond laser Chronic corticosteroid use
platform that has a video microscope and OCT integrated to facilitate visu- • cataracts
alization of detailed corneal structures in real time. Significant successes • glaucoma
in the reduction of high residual astigmatism have been reported with this Contact lens wear
AK technique because of the production of precise and reproducible inci- • keratitis
sional cuts with proper depth, length, and curvature. Some examples of • neovascularization
such success include astigmatism reduction rates of 36% by Kumar et al.,19 • late progression of effect
47% by Buzzonetti et al.,20 54% by Cleary et al.,21 55% by Hoffart et al.,6 and Retrobulbar injection
65.5% and 89.42% by Viswanathan et al.15 • optic atrophy
The efficacy of the astigmatic incisions has been shown to be depen- • globe penetration/retinal detachment
dent on the depth and length of the incisions, the optical zone, and the age
and gender of the patient. These reports have been made based on studies
on both live patients and on cadaver eyes. Incisions can be arcuate or intraoperatively, those that occur postoperatively, and those that are associ-
beveled, full penetrating or intrastromal. Clearly et al.21 performed paired ated with adjunctive therapy (Box 3.8.1).
femtosecond AK incisions at a bevel angle of 135° at a depth of 65%–75%, A number of potential complications may develop intraoperatively as
and with arc length of 60°–90°. The outcomes of these beveled incisions a result of deviations from prescribed surgical protocols or faulty surgical
were compared with a case of perpendicular femtosecond AK incision. technique. Such complications can generally be avoided by diligent train-
They reported an astigmatism reduction rate of 54%, which is comparable ing, literature review, detailed preparation, and adherence to proper surgi-
or better than those achieved with vertical incisions at similar depths. The cal protocols. In the unusual event that a complication does occur, sound
major advantage observed from the beveled incision technique compared judgment generally can remedy the problem.
with the regular perpendicular incision technique was the lack of wound
gaping. Complications Related to Corneal Incisions
Incision Beyond Clear Cornea
COMPLICATIONS AND MANAGEMENT OF Extension of incisions beyond the clear cornea onto the corneoscleral
ASTIGMATISM CORRECTION METHODS limbus or onto limbal vascular arcades must be avoided to prevent subse-
quent vascular ingrowth. Incisions that invade the limbus may render the
The complications associated with incisional keratotomy may be cat- patient intolerant to subsequent contact lens use because of the associated 135
egorized into those that are self-limited side effects, those that occur vascularization of the incision grooves. Fibrovascular ingrowth may result
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Fig. 3.8.2 Corneal Perforation. The risk of corneal perforation has been minimized
greatly through recent developments (see text). The horizontal slit shows mild Fig. 3.8.3 Fibrovascular Tracks. The postoperative development of fibrovascular
leakage of fluorescein. tracks within incision grooves is most often associated with chronic irritation or
hypoxia.
in corneal destabilization over time, with large diurnal fluctuation and pro-
gression of refractive effect. Postoperative Complications
Optical Zone Invasion Progressive Hyperopia
Optical zone invasion as a result of spontaneous patient eye movement or Risk factors associated with postoperative progressive hyperopia include
lack of surgical control represents one of the more worrisome potential multiple enhancement procedures, peripheral redeepening procedures,
complications of centripetal incisions. Patient education or globe fixation lack of preoperative cycloplegic refraction (latent hyperopia), postoperative
may reduce—but not entirely eliminate—the potential for optical zone contact lens wear, and postoperative ocular massage. The surgeon may
invasion. The combined (Genesis) incision technique was designed to wish to consider these factors when patient management strategies are
address this and other potential complications. Because the uphill margin determined.
of the blade cuts only along its distal portion, the diamond cannot produce
deep incisions outside the previously incised groove. Once the central zone Induced Astigmatism
has been reached and intentionally slightly undermined, continued pres- Induced regular or irregular astigmatism may occur if fewer incisions
sure must not be applied against the optical zone as the diamond is lifted are placed, if the incisions are placed asymmetrically about the visual axis
from the groove. or are of variable depth, or if the optical zone is decentered with respect
to the visual axis. The great majority of these refractive aberrations are
Complications Related to Corneal Perforations self-limited and spontaneously improve within the first 6 postoperative
weeks. Thus wait until the refraction and surface topography have stabi-
The risk of corneal perforation (Fig. 3.8.2) has been reduced with the advent lized before placing additional incisions.
of screening and real-time pachymetry, the availability of microscopes for
precise diamond knife calibration, and the adherence to protocols suggest- Contact Lens Intolerance
ing incision of the thinnest corneal zones first and the use of diamonds Newly designed rigid, gas-permeable lenses that have peripheral curves
not set at substantially more than 100% of paracentral pachymetry. The to match the patient’s preoperative parameters are recommended to over-
use of the femtosecond laser for AK reduces the complications related to come postoperative lens intolerance. The risk of lens-associated corneal
corneal perforations, although it does not eliminate them entirely. The best vascularization is reduced by a shorter incision that does not extend to
way to prevent the development of a self-sealing perforation into a more the limbus. The fibrovascular tracks within the incision sites are associ-
serious perforation is to operate on a relatively dry field so that any leakage ated most often with chronic irritation and hypoxia from subsequent soft
of aqueous humor is detected readily. contact lens wear (Fig. 3.8.3). To diminish the risk of this complication, RK
Early recognition of a self-sealing perforation, by operating on a rel- incisions are stopped approximately 1 mm short of the limbus. Chronic
atively dry field (no tear pooling within the cul-de-sac), prevents its contact lens wear may provide a direct compressive effect, with associated
extension into a nonsealing perforation. Patients who have self-sealing wound stretching and progressive hyperopia.
perforations are managed using cycloplegia (for dilatation and prevention
of iris adherence to the self-sealing perforation site), topical aqueous sup- Stromal Melting
pressants such as beta-blockers, a loading dose of topical antibiotics such Stromal melting often develops in patients who have crossed incisions.
as polymyxin and ofloxacin every 5 minutes for three doses, and an ocular Thus this complication can be prevented by taking great care to avoid
shield over the eye. The eye must not be patched, as this compresses the crossed incisions during surgery. Corneal stromal melt is also associated
corneal apex, bows open the incisions, and retards healing. The use of with patients who have rheumatoid arthritis or other collagen vascular dis-
collagen shields is not recommended. Incision of the thinnest quadrant eases and concomitant severe keratoconjunctivitis sicca with diffuse punc-
first greatly reduces the risk of a self-sealing perforation, as the cornea tate epitheliopathy (Fig. 3.8.4). Patients affected by such advanced disease
continues to thin throughout the procedure. If the diamond penetrates the are not viable candidates for incisional keratotomy. For patients who have
globe on the first incision or on the centrifugally directed component of significantly diminished tear production, it may be necessary to perform
any incision, the operation may be terminated and completed at a later punctal occlusion before considering incisional keratotomy.
time, with repeated pachymetry and diamond calibration. The surgeon
cannot determine intraoperatively the degree to which the diamond has Infectious Keratitis
been overextended or whether pathological corneal thinning exists. Although its incidence is lower than that observed in contact lens wearers,
In the event of a nonsealing perforation, it is prudent to place a single this disorder generally develops in the perioperative period, although
(or multiple) interrupted 10–0 or 11–0 nylon suture to seal the wound and delayed cases in association with contact lens wear have been reported.
prevent any of the sequelae of hypotony or of an open wound. Indeed, the only two cases of keratitis reported in the PERK study23
Early detection of the corneal perforation is important. When a perfora- occurred in association with postoperative contact lens wear.
tion occurs, air bubbles, indicating the invasion of endothelium and/or epi- Intensive, broad-spectrum antibiotic therapy is instituted. An aggres-
thelium integrity, can typically be observed in the anterior chamber.22 Care sive protocol may include fortified cefazolin (50 mg/mL), fortified tobra-
136 should be taken because sometimes the perforation can go undetected, mycin (14 mg/mL), and fourth-generation fluoroquinolone–gatifloxacin on
which may lead to postoperative corneal infection and/or endophthalmitis. an hourly basis, with rotation every 20 minutes, while waiting for culture
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after penetrating keratoplasty or for the correction of smaller degrees of
astigmatism within the framework of cataract surgery. The use of the fem-
tosecond laser to create AK incisions has increased the applicability of AK 3.8
to correct high and asymmetrical astigmatism, singly or in conjunction
with other procedures, although the combined therapy outcomes need to

be explored further.
KEY REFERENCES
Abbey A, Ide T, Kymionis GD, et al. Femtosecond laser-assisted astigmatic keratotomy in
naturally occurring high astigmatism. Br J Ophthalmol 2009;93:1566–9.
Amesbury EC, Miller KM. Correction of astigmatism at the time of cataract surgery. Curr
Opin Ophthalmol 2009;20:19–24.
Assil KK, Kassoff J, Schanzlin DJ, et al. A combined incision technique of radial keratotomy:
a comparison to centripetal and centrifugal incision techniques in human donor eyes.
Ophthalmology 1994;101–7.
Cherfan DG, Melki SA. Corneal perforation by an astigmatic keratotomy performed with
an optical coherence tomography-guided femtosecond laser. J Cataract Refract Surg
2014;40(7):12224–7.
Cleary C, Tang M, Ahmed H, et al. Beveled femtosecond laser astigmatic keratotomy for
the treatment of high astigmatism post-penetrating keratoplasty. Cornea 2013;32:54–62.
Fig. 3.8.4 Chronic Stromal Melting. Serious complications as a result of chronic Ghanem RC, Azar DT. Femtosecond-laser arcuate wedge-shaped resection to correct
stromal melting may occur in the setting of crossed incisions. high residual astigmatism after penetrating keratoplasty. J Cataract Refract Surg
2006;32:1415–19.
Harissi-Dagher M, Azar DT. Femtosecond laser astigmatic keratotomy for postkeratoplasty
results. A combination of 0.4 mL cefazolin (250 mg/mL) and 0.4 mL tobra- astigmatism. Can J Ophthalmol 2008;43:367–9.
Hoffart L, Proust H, Matonti F, et al. Correction of postkeratoplasty astigmatism by fem-
mycin (40 mg/mL) mixed with 0.1 mL lidocaine 2% may be administered tosecond laser compared with mechanized astigmatic keratotomy. Am J Ophthalmol
further as a subconjunctival injection to the affected quadrant on a daily 2009;147:779–87, 787.e1.
basis until culture results are available. Kubaloglu A, Coskun E, Sari ES, et al. Comparison of astigmatic keratotomy results in deep
anterior lamellar keratoplasty and penetrating keratoplasty in keratoconus. Am J Oph-
thalmol 2011;151:637–43.e1.
CONCLUSIONS Pande M, Hillman JS. Optical zone centration in keratorefractive surgery: entrance pupil
center, visual axis, coaxially sighted corneal reflex, or geometric corneal center? Ophthal-
The use of incisional keratotomy has declined over the past decade as laser mology 1993;100:1230–7.
vision correction has gained popularity (due to superior predictability). Vaddavalli PK, Hurmeric V, Yoo SH. Air bubble in anterior chamber as indicator of full
thickness incisions in femtosecond-assisted astigmatic keratotomy. J Cataract Refract
RK was the most common form of surgical correction of myopia from Surg 2011;37:1723–5.
the 1970s through the early 1990s. It was an important milestone in the Verity SM, Talamo JH, Chayet A, et al. The combined (genesis) technique of radial keratot-
history of refractive surgery. In the early 1990s, at the 10-year follow-up of omy: a prospective, multi-center study. Ophthalmology 1995;102:1908–17.
the PERK study, concerns arose about the lack of predictability and stabil- Vickers LA, Gupta PK. Femtosecond laser-assisted keratotomy. Curr Opin 2016;27(4):277–84.
Viswanathan D, Kumar NL. Bilateral femtosecond laser-enabled intrastromal astigmatic ker-
ity of RK. There were no identifying risk factors to predict those at risk atotomy to correct high post-penetrating keratoplasty astigmatism. J Cataract Refract
for the hyperopic shift and the diurnal change in refraction. This is in Surg 2013;39(12):1916–20.
contrast to the safety, efficacy, and predictability of excimer laser ablation.
Incisional keratotomy continues to be an important surgical method for
correcting high astigmatism, which, for example, may occur iatrogenically
137
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REFERENCES 12. Amesbury EC, Miller KM. Correction of astigmatism at the time of cataract surgery. Curr
Opin Ophthalmol 2009;20:19–24.
1. Assil KK, Schanzlin DJ, editors. Radial keratotomy surgical technique and protocol. In:
Radial and astigmatic keratotomy: a complete handbook for the successful practice of
13. Ghanem RC, Azar DT. Femtosecond-laser arcuate wedge-shaped resection to correct
high residual astigmatism after penetrating keratoplasty. J Cataract Refract Surg
3.8
incisional keratotomy using the combined technique. Thorofare: Slack; 1994. p. 87–110. 2006;32:1415–19.
14. Faktorovich EG, Maloney RK, Price FW Jr. Effect of astigmatic keratotomy on spher-

2. Assil KK, Kassoff J, Schanzlin DJ, et al. A combined incision technique of radial keratot-
omy: a comparison to centripetal and centrifugal incision techniques in human donor ical equivalent: results of the astigmatism reduction clinical trial. Am J Ophthalmol
eyes. Ophthalmology 1994;101:746–54. 1999;127(3):260–9.
3. Assil KK. Genesis technique of radial keratotomy: Initial clinical experience. Presented at 15. Viswanathan D, Kumar NL. Bilateral femtosecond laser-enabled intrastromal astigmatic
the American Society of Cataract and Refractive Surgery Summer Symposium on Refrac- keratotomy to correct high post-penetrating keratoplasty astigmatism. J Cataract Refract
tive Surgery, August 1993, Los Angeles. Surg 2013;39(12):1916–20.
4. Verity SM, Talamo JH, Chayet A, et al. The combined (genesis) technique of radial kera- 16. Bethke W. Femtosecond AK: how to make the cut. Rev Ophthalmol. 2013.
totomy: a prospective, multi-center study. Ophthalmology 1995;102:1908–17. 17. Blanton CL. The art and science of titrating incisions. CRSTEurope. 2015.
5. Harissi-Dagher M, Azar DT. Femtosecond laser astigmatic keratotomy for postkerato- 18. Vickers LA, Gupta PK. Femtosecond laser-assisted keratotomy. Curr Opin
plasty astigmatism. Can J Opthhalmol 2008;43(3):367–9. 2016;27(4):277–84.
6. Hoffart L, Proust H, Matonti F, et al. Correction of postkeratoplasty astigmatism by 19. Kumar NL, Kaiserman I, Shehadeh-Mashor R, et al. IntraLase-enabled astigmatic ker-
femtosecond laser compared with mechanized astigmatic keratotomy. Am J Ophthalmol atotomy for post-keratoplasty astigmatism: on-axis vector analysis. Ophthalmology
2009;147(5):779–87, 787.e1. 2010;117:1228–35.
7. Abbey A, Ide T, Kymionis GD, et al. Femtosecond laser-assisted astigmatic keratotomy in 20. Buzzonetti L, Petrocelli G, Laborante A, et al. Arcuate keratotomy for high postop-
naturally occurring high astigmatism. Br J Ophthalmol 2009;93:1566–9. erative astigmatism performed with the IntraLase femtosecond laser. J Refract Surg
8. Kubaloglu A, Coskun E, Sari ES, et al. Comparison of astigmatic keratotomy results in 2009;25:709–14.
deep anterior lamellar keratoplasty and penetrating keratoplasty in keratoconus. Am J 21. Cleary C, Tang M, Ahmed H, et al. Beveled femtosecond laser astigmatic keratotomy for
Ophthalmol 2011;151:637–43.e1. the treatment of high astigmatism post-penetrating keratoplasty. Cornea 2013;32:54–62.
9. Vaddavalli PK, Hurmeric V, Yoo SH. Air bubble in anterior chamber as indicator of 22. Cherfan DG, Melki SA. Corneal perforation by an astigmatic keratotomy performed
full-thickness incisions in femtosecond-assisted astigmatic keratotomy. J Cataract Refract with an optical coherence tomography-guided femtosecond laser. J Cataract Refract Surg
Surg 2011;37:1723. 2014;40(7):12224–7.
10. Pande M, Hillman JS. Optical zone centration in keratorefractive surgery: entrance pupil 23. Waring GO 3rd, Lynn MJ, McDonnell PJ. Results of the prospective evaluation of radial
center, visual axis, coaxially sighted corneal reflex, or geometric corneal center? Ophthal- keratotomy (PERK) study 10 years after surgery. Arch Ophthalmol 1994;112(10):1298–308.
mology 1993;100:1230–7.
11. Chan TC, Cheng GP, Wang Z, et al. Vector analysis of corneal astigmatism after com-
bined femtosecond-assisted phacoemulsification and arcuate keratotomy. Am J Ophthal-
mol 2015;160(2):250–5.
137.e1
booksmedicos.org

Intrastromal Corneal Ring Segments

and Corneal Cross-Linking 3.9
Claudia E. Perez-Straziota, Marcony R. Santhiago, J. Bradley Randleman
parameters such as corneal hysteresis and corneal resistance factor, and in

Definitions: younger patients ICRS outcomes have regressed in long-term follow-up,7
• Corneal cross-linking (CXL) is a procedure combining corneal suggesting the underlying biomechanical failure in keratoconus has been
saturation with riboflavin and exposure to UV light to increase the left untreated.
amount of links between collagen fibers in the corneal stroma,
thereby increasing its tensile strength.
• Intracorneal ring segments (ICRS) are semi circularly shaped Corneal Cross-Linking (CXL)
polymethyl methacrylate (PMMA) segments that are inserted into the In 1998, Spoerl et al. published their findings after collagen cross-linking of
paracentral region of the anterior corneal stroma to flatten the center porcine corneas, establishing riboflavin as a safe and effective component
of the cornea and induce a hyperopic shift. of the treatment.8 The first clinical results after CXL in human keratoconic
• CXL is used to halt progression of corneal ectasias, whereas ICRS are corneas were published in 2003.9 In the photochemical reaction, riboflavin
used in patients with moderate to advanced stable keratoconus to acts as a photosensitizer that absorbs UV-A energy and excites into a triplet
counterbalance the myopic shift induced by corneal steepening. state. This triplet can undergo an aerobic (type 2) or anaerobic (type 1)
reaction, both of which create oxygen species that induce covalent bonds
between collagen molecules and between proteoglycans and collagen. The
depth of this effect is thought to be seen in the demarcation line on optical
Key Features coherence tomography (OCT) images of post-cross-linking corneas, usually
• Preoperative evaluation and topographical assessment is necessary at 300–350 µm of depth.10 Long-term follow-up of cross-linked corneas has
to select the appropriate ICRS size and positioning. demonstrated that in contrast to ICRS, CXL affects the biomechanical
• The flattening effect of ICRS can be potentiated by the combination properties of the cornea and halts the progression of the disease with only
with cross-linking. mild and refractive changes.
• Careful selection of patients for combined ICRS and CXL is
imperative to increase the chances of success and reduce the risk of CXL Plus
postoperative complications. The lack of significant refractive impact of CXL stimulated the develop-
• There is currently no consensus regarding timing of combined ment of treatment protocols combining CXL with a variety of techniques
procedures. Inserting the ICRS before CXL may optimize the impact (CXL Plus), including phakic intraocular lens (IOL) implantation and
of ring segment insertion, whereas CXL alone may be sufficient to selective excimer laser ablation and CXL combined with ICRS.11–15
halt progression and improve corneal shape, thereby obviating the The rationale behind the combination of ICRS and CXL seems to be
need for a combined procedure. the symbiosis that occurs when combining the mechanical and refractive
changes induced by the segments with the biomechanical changes induced
by CXL and their benefits in halting disease progression.
INTRODUCTION
For the majority of patients seeking refractive surgery, the best, most effec-
SURGICAL PROCEDURE: ICRS
tive treatment will be laser ablation as highlighted in the previous chap- Patient Selection
ters. However, for patients with ectatic corneal disease, ICRS and CXL play
a prominent role in halting disease progression and improving acuity. The primary indication for ICRS implantation in ectatic patients include
moderate to advanced stages of disease, with clear corneas and unsatis-
INTRACORNEAL RING SEGMENTS factory corrected near visual acuity (CDVA) or contact lens intolerance,16
steepest keratometry less than 58 diopters (D), no corneal scarring or
Intracorneal ring segments add volume peripherally by changing the arc opacities, and at least 450 µm thickness at the 7-mm diameter where the
length of the anterior corneal curvature and redistributing the posterior segments are to be placed.17 The flattening effect of ICRS becomes more
corneal tissue.1 This shortens the posterior lamellae and flattens the cornea robust in advanced stages of ectasia.
centrally, correcting myopia.2,3
Intracorneal ring segments received European Conformité Européene
certification in 1996 and US Food and Drug Administration (FDA) approval
Preoperative Considerations
in 1999. However, the initial enthusiasm for the correction of myopia faded Preoperative refraction, aberrometry, and corneal topography are import-
due to a limited range of correction, less predictability, induced astigma- ant factors to consider in surgical planning. Topographical features are rel-
tism, and slower visual recovery. evant in the selection of the segments and their location in asymmetrical
The idea of using intrastromal rings in the treatment of keratoconus corneas, with thicker and longer segments placed in the area just below
was proposed in 2000 by Colin et al.4 Since then their use has evolved into the cone. Single versus paired segment implantation appear to be equiva-
an important therapeutic intervention in corneal ectatic diseases.4,5,6 Intacs lent in terms of refractive results,18 and the decision should be made on a
received FDA approval for the use in the treatment of keratoconus in 2004 case-by-case basis using the manufacturer’s ICRS nomograms.
for rings 0.25–0.35 mm and in 2010 for 0.4–0.45 mm.
In patients with ectatic disease, ICRS induce morphological changes
by flattening the steepest meridian and decreasing the cone location mag-
ICRS Selection
138 nitude index (CLMI) and the mean curvature in the 2-mm area over the There are currently three main types of ICRS: Intacs (Addition Technology,
cone. They do not induce significant changes in biomechanical corneal Sunnyvale, CA), with a hexagonal transverse shape, and Intacs SK, with
booksmedicos.org
Fig. 3.9.1 Topographical Flattening
After Intacs Segment Placement.
Note the reduction in size and maximal 3.9
steepness in the right image (after segment
implantation) compared with the left image
Intrastromal Corneal Ring Segments and Corneal Cross-Linking

(before segment implantation).
an oval cross-section shape; Ferrara, with triangular shape, and Kerarings

(both from Mediphacos, Belo Horizonte, Brazil), with almost identical
design to Ferrara rings, but different arc lengths and internal diameters.
Intacs are the only FDA-approved ICRS for the reduction or elimination
of myopia and astigmatism in normal patients or those with keratoconus
and are available in 0.25, 0.30, and 0.35 mm. The 0.4-mm Intacs and the
Ferrara rings are available only in European countries and South America.
The effect of the implantation of an ICRS correlates directly to its thick-
ness and inversely to its distance from the visual axis, or optical zone, with
thicker implants and smaller optical zones resulting in greater flattening
effect and reduction of coma-like aberrations.1,19,20
Single Versus Paired ICRS

In cases of peripheral steepening, where the main issue is irregular astig-
matism, implanting a single segment may provide better results than two
segments, whereas in central cones, where the high myopic refractive
error is the main issue, two segments or a longer continuous segment
with a simple nomogram using keratometry readings only are a better
alternatives because they target a larger change in spherical equivalent.21–24
ICRS Surgical Technique

Intrastromal corneal ring segments are placed within the peripheral stroma
at approximately two-thirds of the stromal depth, outside the central optical Fig. 3.9.2 Late-Onset Corneal Haze After Intracorneal Ring Segment
zone, to reshape the anterior corneal surface while maintaining the posi- Implantation.
tive asphericity of the cornea.25–32
There are no significant differences in refractive outcomes of ICRS
between femtosecond laser and manual spreader. When using femto- abnormalities, with reported significant changes in spherical equivalent
second laser, the efficacy in creation of an intrastromal channels can be (SE), (average 4.0 D reduction in SE), manifest astigmatic error and UCVA,
affected by previous cross-linking treatment, perhaps due to changes in with the most significant improvement in the first 64 and 9 months.5,6
the optical quality of the anterior stroma that interfere with laser tracking.
Therefore even though femtosecond laser is associated with fewer com- Postoperative Complications
plications compared with the mechanical spreader,33 manual dissection
of the channels may be considered in patients that have been previously The overall reported adverse event rate after ICRS is 1.1% including infec-
cross-linked. tious keratitis (0.2%), shallow placement (0.2%), loss of two lines of best
After channel formation, the segments are introduced with forceps into spectacle-corrected visual acuity (BSCVA) (0.2%), and anterior chamber
the channels. In their final position, the segments should be located 3 mm perforation during initial and exchange procedures (0.4%).35,36 Reduced
apart superiorly. Once the segments have been inserted, each segment has central corneal sensation can occur up to 6 months after surgery and can
a small positioning hole at the superior end to aid with surgical manipu- persist up to 12 months in 5.5% of cases. Some patients experience diffi-
lation for proper positioning, after which the incision site is hydrated and culty with night vision (4.4%), blurry vision (2.9%), diplopia (1.6%), or glare
closed with 10–0 nylon sutures.25 and halos (1.3%),35 which accounts for an explantation rate of 8.7%, mostly
due to glare, halos, and difficulty with night vision as well as dissatisfaction
Clinical Outcomes with refractive results. Late onset corneal haze is another potential compli-
cation (Fig. 3.9.2).
ICRS flatten the cornea permanently, but the major shifts in refraction
and topographical findings after ICRS implantation usually occur in the
first 6 months of postoperative period34 with some fluctuations during the
SURGICAL PROCEDURE: CXL
first month (Fig. 3.9.1). Even though late postoperative variations proba- The procedure for CXL involves three essential steps: epithelial removal
bly occur due to intrinsic biomechanical changes in those with unstable (9 mm debridement), riboflavin saturation of the corneal stroma, and
disease, the difference in CDVA and keratometry between month 6 and stromal irradiation with UV-A light (Fig. 3.9.3). These elements can be
month 36 is not significant. combined in varying intensities and times. For CXL, after complete UVA
The results of ICRS in patients with corneal ectasia are encourag- irradiation, a bandage soft contact lens is typically placed and left in place 139
ing, especially in decreasing astigmatism and improving topographical until complete epithelization is achieved.
booksmedicos.org
achieved only when corneal epithelium is removed.48 To date, long-term
3 clinical results of transepithelial CXL have failed to find equivalency with

the standard protocol.
CXL CLINICAL OUTCOMES

Refractive Surgery
Results from the first US-based prospective clinical trial for cross-linking
demonstrated improvement in visual acuity and reduction in Kmax in
patients with ectatic disease either LASIK induced or from keratoconus,
with greater flattening in keratoconus compared with post-LASIK ectasia
patients.49 These changes continued over time, resulting in progressive
improvement of uncorrected and corrected distance visual acuities and
reduction in higher order aberrations up to 4 years postprocedure, which
do not necessarily correlate with the topographical changes observed.50
Failure to halt progression has been seen in approximately 2%–4% of
eyes treated, with up to 2% of eyes losing lines of Snellen visual acuity.51
These failures were initially associated with older age (beyond 35 years
old), thinner corneas (<400 µm), preoperative CDVA better than 20/25,
and Kmax >58.00 D. These risk factors were not confirmed in prospective
trials.
Postoperative Complications
Fig. 3.9.3 Corneal Cross-Linking Procedure. After riboflavin saturation, the UV light can have deleterious effects within the corneal stroma. Standard
cornea is exposed to UV-A light. The red lines are guidance beams to ensure proper epi-off riboflavin/UVA treatments trigger a temporary UVA dose-dependent
treatment centration. keratocyte apoptosis response approximately at 300 µm deep that typically
resolves with nerve regeneration and stromal keratocyte repopulation 4–6
weeks after the procedure. Endothelial damage is possible, but avoidable
by maintaining a safe stromal thickness of 400 µm during treatment.
Monitoring corneal thickness throughout the procedure with use of iso-
osmolar riboflavin solution to minimize stromal thinning along with use
of hypo-osmolar riboflavin solutions to temporarily thicken the cornea
all reduce the risk of endothelial cell damage in patients with thinner
corneas.
The corneal wound-healing process after epithelial removal increases the
risk of delayed re-epithelialization, sterile and infectious stromal infiltrates,
corneal haze, and scarring. Matrix metalloproteinases (MMPs)–mediated
activation of keratolysis, caused by nonsteroidal anti-inflammatory drugs
(NSAIDs), also can induce corneal melting. For this reason the use of
NSAIDS in the early postprocedure period after CXL is controversial. The
disruption of corneal epithelium also increases the risk of infectious ker-
atitis. CXL may lead to the reactivation of herpes simplex keratitis. Sterile
stromal infiltrates rarely occur; these usually are asymptomatic and not
visually significant. Persistent stromal haze correlated with advanced ker-
atoconus (steeper keratometric values and/or thinner corneas) and older
age (beyond 35 years old) at the time of treatment can become visually
significant and affect final outcomes after CXL.
Fig. 3.9.4 Corneal Demarcation Line Following CXL With the Standard Protocol.
Note the prominent demarcation line at approximately 300 µm depth.
COMBINING ICRS WITH CXL
Due to potential optical changes in the corneal stroma after CXL that could
The standard protocol delivers 3 mW/cm2 of energy for 30 minutes for interfere with laser tracking, inserting the ICRS before CXL when using
a total energy dose (fluence) of 5.4 J/cm2, resulting in up to 70% increase the femtosecond laser appears optimal. Refractive outcomes appear better
in cornea rigidity compared with controls using porcine and human when ICRS are implanted before cross-linking, possibly due to reduced
cadaver eyes.8,37 Accelerated protocols, still with a total dose of 5.4 J/cm2, mechanical effect from ICRS after CXL, but some concerns remain about
have been derived from the Bunson–Roscoe law of reciprocity of photo- the impact of CXL on the PMMA material of the ICRS.
chemistry, which states that the photochemical effect of ultraviolet light is Timing of treatment is undetermined, with some advocating for waiting
proportional to the total amount of energy delivered and should be equiv- 3–6 months between treatments, while others advocate for implantation
alent for equivalent total doses regardless of the relative irradiation time of ICRS with intrastromal injection of riboflavin through the ring chan-
and intensity for each protocol.38 These accelerated protocols have been nels, followed immediately by CXL treatment.52 Comparative studies are
evaluated with mixed results. warranted to determine whether simultaneous treatments are superior to
The demarcation line, evident after cross-linking with the standard sequential treatments.
protocol (Fig. 3.9.4) and typically approximately 300 µm deep, is thought
to represent the depth of cross-linking treatment and thereby serves as a
surrogate of biomechanical impact.39–44 In accelerated protocols and ion-
CONCLUSIONS
tophoresis CXL, the demarcation line is less dense, less uniform, and Epithelium-off CXL using the standard protocol has been proven to
demonstrably present in fewer cases.40,45,46 Recently a modified accelerated effectively flatten the steepest regions of the cornea in patients with
protocol of 9 mW/cm2 for 14 minutes has been proposed by Kymionis and progressive ectatic disease, halting the progression of disease, reduc-
colleagues with no difference in the demarcation line compared with stan- ing the need for corneal transplantation, and improving visual acuity
dard CXL protocol.44 and quality of life. ICRS also play a role in management of ectatic
Transepithelial (epi on) CXL has also been reported, but while corneal corneal disease, with surgical techniques advancements resulting from
confocal microscopy alterations are similar in the subbasal nerve plexus the advent of the femtosecond laser. The preservation of the prolate
and anterior stromal keratocytes between standard and accelerated cornea and the reversibility of the procedure are major advantages of
140 (30 mW/cm2 for 3 minutes) protocols, no changes are seen after trans- ICRS implants, and their mechanical effect can have a symbiotic effect
epithelial approaches.47 Effective riboflavin concentration seems to be with CXL.
booksmedicos.org
KEY REFERENCES Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res
1998;66(1):97–103.
Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J
Cataract Refract Surg 2009;35(8):1358–62.
Touboul D, Efron N, Smadja D, et al. Corneal confocal microscopy following conventional,
transepithelial, and accelerated corneal collagen cross-linking procedures for keratoco-
3.9
Kymionis GD, Grentzelos MA, Plaka AD, et  al. Correlation of the corneal collagen cross-linking nus. J Refract Surg 2012;28(11):769–76.
Vega-Estrada A, Alio JL, Brenner LF, et al. Outcome analysis of intracorneal ring segments

demarcation line using confocal microscopy and anterior segment optical coherence
tomography in keratoconic patients. Am J Ophthalmol 2014;157(1):110–115.e111. for the treatment of keratoconus based on visual, refractive, and aberrometric impair-
Kymionis GD, Grentzelos MA, Portaliou DM, et al. Corneal collagen cross-linking (CXL) ment. Am J Ophthalmol 2013;155(3):575–84.e571.
combined with refractive procedures for the treatment of corneal ectatic disorders: CXL Vinciguerra P, Randleman JB, Romano V, et al. Transepithelial iontophoresis corneal colla-
Plus. J Refract Surg 2014;30(8):566–76. gen cross-linking for progressive keratoconus: initial clinical outcomes. J Refract Surg
Kymionis GD, Siganos CS, Tsiklis NS, et al. Long-term follow-up of Intacs in keratoconus. 2014;30(11):746–53.
Am J Ophthalmol 2007;143(2):236–44. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced collagen crosslinking for
Kymionis GD, Tsoulnaras KI, Grentzelos MA, et al. Evaluation of corneal stromal demar- the treatment of keratoconus. Am J Ophthalmol 2003;135(5):620–7.
cation line depth following standard and a modified-accelerated collagen cross-linking Wollensak G, Spoerl E, Seiler T. Stress-strain measurements of human and porcine
protocol. Am J Ophthalmol 2014;158(4):671–5.e671. corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg
Rabinowitz YS. INTACS for keratoconus and ectasia after LASIK. Int Ophthalmol Clin 2003;29(9):1780–5.
2013;53(1):27–39.
Randleman JB, Khandelwal SS, Hafezi F. Corneal cross-linking. Surv Ophthalmol
2015;60(6):509–23. Access the complete reference list online at ExpertConsult.com
Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea
2006;25(9):1057–9.
141
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tion in paracentral keratoconus with coincident topographic and coma axis. J Cataract
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Refract Surg 2009;35(10):1761–7. ness on corneal flattening in human eyes. Refract Corneal Surg 1991;7(1):46–50.
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for the treatment of keratoconus. Am J Ophthalmol 2003;135(5):620–7. corneas after riboflavin-ultraviolet-A-induced cross-linking. J Cataract Refract Surg
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2015;60(6):509–23. 38. Gatzioufas Z, Richoz O, Brugnoli E, et al. Safety profile of high-fluence corneal collagen
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Cornea 2007;26(7):891–5. 39. Seiler T, Hafezi F. Corneal cross-linking-induced stromal demarcation line. Cornea
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sisted keratoplasty for keratoconus. Eur J Ophthalmol 2012;22(2):274–7. 40. Bouheraoua N, Jouve L, El Sanharawi M, et al. Optical coherence tomography and con-
13. Kymionis GD, Grentzelos MA, Portaliou DM, et al. Photorefractive keratectomy followed focal microscopy following three different protocols of corneal collagen-crosslinking in
by same-day corneal collagen crosslinking after intrastromal corneal ring segment implan- keratoconus. Invest Ophthalmol Vis Sci 2014;55(11):7601–9.
tation for pellucid marginal degeneration. J Cataract Refract Surg 2010;36(10):1783–5. 41. Doors M, Tahzib NG, Eggink FA, et al. Use of anterior segment optical coherence
14. Kremer I, Aizenman I, Lichter H, et al. Simultaneous wavefront-guided photorefractive tomography to study corneal changes after collagen cross-linking. Am J Ophthalmol
keratectomy and corneal collagen crosslinking after intrastromal corneal ring segment 2009;148(6):844–51.e842.
implantation for keratoconus. J Cataract Refract Surg 2012;38(10):1802–7. 42. Kymionis GD, Grentzelos MA, Plaka AD, et al. Evaluation of the corneal collagen
15. Kymionis GD, Grentzelos MA, Portaliou DM, et al. Corneal collagen cross-linking (CXL) cross-linking demarcation line profile using anterior segment optical coherence tomog-
combined with refractive procedures for the treatment of corneal ectatic disorders: CXL raphy. Cornea 2013;32(7):907–10.
Plus. J Refract Surg 2014;30(8):566–76. 43. Kymionis GD, Grentzelos MA, Plaka AD, et al. Correlation of the corneal collagen
16. Giacomin NT, Mello GR, Medeiros CS, et al. Intracorneal ring segments implantation for cross-linking demarcation line using confocal microscopy and anterior segment optical
corneal ectasia. J Refract Surg 2016;32(12):829–39. coherence tomography in keratoconic patients. Am J Ophthalmol 2014;157(1):110–
17. Rabinowitz YS. INTACS for keratoconus and ectasia after LASIK. Int Ophthalmol Clin 15.e111.
2013;53(1):27–39. 44. Kymionis GD, Tsoulnaras KI, Grentzelos MA, et al. Evaluation of corneal stromal demar-
18. Yeung SN, Ku JY, Lichtinger A, et al. Efficacy of single or paired intrastromal corneal ring cation line depth following standard and a modified-accelerated collagen cross-linking
segment implantation combined with collagen crosslinking in keratoconus. J Cataract protocol. Am J Ophthalmol 2014;158(4):671–5.e671.
Refract Surg 2013;39:1146–51. 45. Vinciguerra P, Randleman JB, Romano V, et al. Transepithelial iontophoresis corneal col-
19. Alfonso JF, Fernandez-Vega Cueto L, Baamonde B, et al. Inferior intrastromal corneal lagen cross-linking for progressive keratoconus: initial clinical outcomes. J Refract Surg
ring segments in paracentral keratoconus with no coincident topographic and coma axis. 2014;30(11):746–53.
J Refract Surg 2013;29(4):266–72. 46. Vinciguerra P, Rechichi M, Rosetta P, et al. High fluence iontophoretic corneal col-
20. Vega-Estrada A, Alio JL, Brenner LF, et al. Outcome analysis of intracorneal ring seg- lagen cross-linking: in vivo OCT imaging of riboflavin penetration. J Refract Surg
ments for the treatment of keratoconus based on visual, refractive, and aberrometric 2013;29(6):376–7.
impairment. Am J Ophthalmol 2013;155(3):575–84.e571. 47. Touboul D, Efron N, Smadja D, et al. Corneal confocal microscopy following conven-
21. Alió JLAA, Hassanein A, Haroun H, et al. One or 2 Intacs segments for the correction of tional, transepithelial, and accelerated corneal collagen cross-linking procedures for ker-
keratoconus. J Cataract Refract Surg 2005;31:943–53. atoconus. J Refract Surg 2012;28(11):769–76.
22. Fahd DCAR, Nasser M, Awwad ST. Refractive and topographic effects of single-segment 48. Leccisotti A, Islam T. Transepithelial corneal collagen cross-linking in keratoconus. J
intrastromal corneal ring segments in eyes with moderate to severe keratoconus and Refract Surg 2010;26(12):942–8.
inferior cones. J Cataract Refract Surg 2015;41:1434–40. 49. Hersh PS, Stulting RD, Muller D, et al. United States crosslinking study G. United States
23. Yeung SNKJ, Lichtinger A, Low SA, et al. Efficacy of single or paired intrastromal corneal multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Oph-
ring segment implantation combined with collagen crosslinking in keratoconus. J Cata- thalmology 2017;124(9):1259–70.
ract Refract Surg 2013;39:1146–51. 50. Greenstein SA, Fry KL, Hersh PS. Corneal topography indices after corneal collagen
24. Jabbarvand MHH, Mohammadpour M, Khojasteh H, et al. Implantation of a com- crosslinking for keratoconus and corneal ectasia: one-year results. J Cataract Refract Surg
plete intrastromal corneal ring at 2 different stromal depths in keratoconus. Cornea 2011;37(7):1282–90.
2014;33:141–4. 51. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking.
25. Schanzlin DJ, Asbell PA, Burris TE, et al. The intrastromal corneal ring segments. Phase J Cataract Refract Surg 2009;35(8):1358–62.
II results for the correction of myopia. Ophthalmology 1997;104(7):1067–78. 52. Kilic A, Kamburoglu G, Akinci A. Riboflavin injection into the corneal channel for com-
26. Nose W, Neves RA, Burris TE, et al. Intrastromal corneal ring: 12-month sighted myopic bined collagen crosslinking and intrastromal corneal ring segment implantation. J Cata-
eyes. J Refract Surg 1996;12(1):20–8. ract Refract Surg 2012;38(5):878–83.
141.e1
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Surgical Correction of Presbyopia

Veronica Vargas Fragoso, Jorge L. Alió 3.10
Definition: Presbyopia is an age-related condition that enables the TABLE 3.10.1 Advantages and Disadvantages of LASIK Monovision
patient to perform near visual tasks due to the decay of accommodation.
Good far and near outcomes Reduction of stereopsis
Reversible Slight reduction in contrast sensitivity
Key Features Easy to perform surgically Not all patients are good candidates
• Presbyopia starts affecting people around 40 years of age. Asthenopia
• Its surgical correction may be performed at the cornea, lens, or sclera.
• Corneal procedures like monovision have good visual outcomes, but
some stereopsis may be lost. monovision depends on interocular blur suppression, and an assumption
• Multifocal intraocular lenses (IOLs) have a high rate of spectacle exists that it is easier to suppress blur in the nondominant eye.4,5 However,
independence, but the appearance of glare and halos are an pseudo-phakic crossed monovision (nondominant eye is corrected for far
important drawback. and the dominant eye for near vision) has had similar outcomes to con-
• Not all commercially available accommodative IOLs have proved to ventional monovision.3,4
really restore accommodation. There is a correlation between the degree of anisometropia and the
• Surgical correction of presbyopia with the restoration of improvement of near and intermediate distance acuity; the greater the
accommodation is still a challenge for all refractive surgeons. anisometropia, the better the near visual outcome.6 At the same time,
the greater the anisometropia, the greater the loss of stereopsis.6,7 Also,
an increased time for neuroadaptation is required,7 and a major risk for
INTRODUCTION monofixation syndrome (loss of foveal fusion which manifests as a facul-
tative absolute scotoma in the fovea of the nonfixating eye) exists.8 Thus,
Presbyopia is an age-related condition characterized by the loss of accom- the anisometropia should not be more than 1.5 diopters (D) because it
modation, enabling the patient not to perform near visual tasks, decreas- has been reported for good spectacle independence in patients with mini
ing the quality of life.1 monovision, in which the target for the nondominant eye is −1.00 to
Its correction remains a challenge for the refractive surgeons; although −1.25 D and that for the dominant eye is plano.9 In this way, stereopsis is
many procedures to restore near vision are available, not all of them really maintained.
restore accommodation (with the exception of some accommodative IOLs). Patient selection is important as in every other surgical procedure,
Accommodation is the change of power of the crystalline lens that and monovision is generally contraindicated for the following patients:
allows us to change the point of focus from far to near. airplane pilots,3,10 truck or taxi drivers,6,10 and patients with strong ocular
During accommodation, there is a contraction of the ciliary muscle, dominance,3,11,12 strabismus,3,12 or exophoria of more than 10.0 Δ.3,4,6,10
which releases the zonular tension, allowing the anterior and posterior Good near and distance outcomes have been reported for LASIK mono-
surfaces of the lens to increase in curvature, increasing the optical power vision. Spectacles for night driving were used in only 16.2% of patients,
of the lens (Helmholtz theory). and there was a slight decrease in contrast sensitivity and stereopsis13
This is accompanied by the accommodative triad: accommodation, con- (Table 3.10.1).
vergence, and miosis,2 and there is also an increase in negative aberration Pseudo-phakic monovision has a success rate of approximately 80%,12,14
of the eye. and the advantage over multifocal IOLs is the lower cost.14 Although the
Most of the presbyopia treatments induce pseudo-accommodation, rate of spectacle independence is higher with multifocal IOLs, they induce
which improves near vision through multifocality or increasing the depth more dysphotopsia.15a
of field, not by a change of the optical power of the eye sustained by the Monovision is one of the most popular presbyopia treatments among
active action of the ciliary body.2 refractive surgeons; it also offers the possibility of reversal in case of
Presbyopia can be corrected at the cornea, lens, or sclera or treated with patient dissatisfaction. LASIK monovision is ideal for presbyopic patients
topical medication; all therapeutic options come with pros and cons. over 40 years of age, and in pseudo-phakic monovision for patients with
In this chapter, we will discuss all of the current treatment options for cataract in whom a multifocal or accommodative IOL is contraindicated.
presbyopia correction.
Presby-LASIK
PRESBYOPIA CORRECTION AT THE Presby-LASIK is a surgical technique that employs the principles of LASIK
CORNEAL LEVEL to create a multifocal corneal surface.
There are three main types of multifocal corneal excimer laser profiles:
Correction at the cornea can be achieved by monovision, presby-LASIK, (1) multifocal transition profile (no longer in use because it induced signif-
and corneal inlays. icant levels of vertical coma), (2) central presby-LASIK, and (3) peripheral
presby-LASIK (Fig. 3.10.1). The principles of each algorithm are based on
Monovision the dioptric power of refractive error and presbyopia correction calculation,
corneal asphericity quotient (Q-value), and changes in higher-order spheri-
Correction with monovision was first described in 1958 by Westsmith with cal aberrations or optical and transition zone manipulation.
contact lenses wearers.3,4
It can be achieved through contact lenses, LASIK, or pseudo-phakia. Central Presby-LASIK
In monovision, an intended anisometropia is induced in order to This technique was first described by Ruiz in 1996.15b It creates a hyper-
142 provide near and distance vision. Usually, the nondominant eye is cor- positive area for the near vision at the center, and the periphery is left for
rected for near vision and the dominant eye for far vision. This is because far vision.
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The main disadvantage of presby-LASIK is the lack of long-term results
ABLATION DIFFERENCES BETWEEN CENTRAL AND PERIPHERAL PRESBY-LASIK (beyond 3-year outcomes), and having a multifocal cornea can be a limita-
tion for further multifocal IOL implantation. 3.10
central model peripheral model Intracorneal Inlays

Historical Background
distance vision zone In 1964 Barraquer developed keratophakia, a lamellar refractive proce-
dure in which an alloplastic lenticule is placed at the interface of the free
near vision zone corneal cap and the stromal bed.29a The difficulty of the surgical procedure
and the unpredictability of the refractive results meant that few surgeons
transition zone adopted keratophakia.29b
Early corneal implants were made of polymethylmethacrylate or poly-
untreated cornea
sulfone, and although they corrected the refractive error, they produced
corneal necrosis and implant extrusion.30 Nowadays, the material used
in corneal inlays allow sufficient nutrient flow; a very important feature
Fig. 3.10.1 Ablation Differences Between Central and Peripheral Presby-LASIK. because interruption of the nutrient flow can cause loss of transparency,
In the peripheral model, the center of the cornea is modified for distance vision; in
corneal thinning, epithelial and stromal decompensation, and melting.31
the central model, the center of the cornea is modified for near vision.
The permeability of the hydrogel material used in the inlays is similar to
that of the corneal stroma, allowing to some extent the exchange of nutri-
ents32,33 such as glucose and oxygen.
Corneal inlays have several advantages: There is no need to remove
It is pupil dependent, and an advantage is that it can be performed at corneal tissue, the surgical technique is relatively easy and minimally inva-
the center of the cornea in myopic and hyperopic profiles as well as in sive, and the inlays are all removable.9,34,35
emmetropes with minimal corneal excision. Adequate centration is crucial There are three types of corneal inlays9,34:
for having a controllable result.
Its main limitation is the lack of adequate alignment among the line of
• Corneal reshaping inlays
They enhance near and intermediate vision through a multifocal effect.
sight, the central pupil, and the corneal vertex, which leads to the induc-
There’s a reshape of the anterior curvature of the cornea (hyperpro-
tion of coma aberrations.
late region of increased power).34,35
These are the platforms available for central presby-LASIK:
• Refractive inlays
• AMO VISX hyperopia–presbyopia multifocal approach steepens the An alteration of the refractive index occurs with a bifocal optic.34
central zone to improve near vision and the peripheral zone for distance • Small aperture inlays
vision. It is for hyperopic patients with astigmatism up to +4.00 D and There is an improvement of depth of focus.34
–2.00 D.
The inlays are implanted in the nondominant eye within a corneal
• SUPRACOR (Technolas Perfect Vision GmbH, Munich, Germany) is pocket made by a femtosecond laser or under a stromal flap (the pocket
an aberration-optimized presbyopic algorithm. The SUPRACOR creates
is preferred because it might decrease the incidence of dry eye).31 The
a hyperpositive area in the central 3.0 mm zone, and the treatment
depth depends on the inlay.35 Inlays that alter the curvature of the cornea
targets 0.50 D of myopia in both eyes.16 It treats hyperopic presbyopia
are implanted more superficially; inlays with small aperture or those that
and minimizes the aberrations normally induced during treatment.
have a different index of refraction are implanted deeper to avoid changes
• PresbyMAX (SCHWIND eye-tech-solutions GmbH, Kleinostheim, in the cornea curvature and to allow a proper diffusion of nutrients in
Germany, Dr Jorge Alió’s trademark) is based on the creation of a
the corneal stroma.31 The inlays must be centered on the first Purkinje
biaspheric multifocal corneal surface with a central hyperpositive area
reflex.
to achieve +0.75 to +2.50 D of near vision correction, surrounded by an
There are currently four corneal inlays available on the market:
area in which the ablation is calculated to correct the distance refractive
error.17,18 It can be performed in hyperopes and myopes. • KAMRA Vision (AcuFocus Inc., Irvine, CA, USA). Small aperture
• In peripheral presby-LASIK, the center of the cornea is left for distance inlay.
and the periphery is ablated in a way that a negative peripheral asphe- • Raindrop (ReVision Optics Inc., Lake Forest, CA, USA). Corneal reshap-
ricity is created to increase the depth of field. ing inlay.
However, when positive spherical aberration is present, if the pupil
• Flexivue Microlens (Presbia Cooperatief U.A., Amsterdam, the Nether-
lands). Refractive inlay.
becomes miotic, the refraction of the eye experiences a shift toward posi-
tive spherical values.
• Icolens (Neoptics AG, Hünenberg, Switzerland). Refractive inlay.
One of its disadvantages is that when it is used in association with
myopic correction, it is necessary to remove a significant amount of corneal Corneal Reshaping Inlay
tissue. This is why it is mainly done in hyperopes. It also requires an effi- Raindrop
cient excimer laser beam profile that can compensate for the loss of energy Formerly known as the PresbyLens or Vue + lens (ReVision Optics, Lake
that happens while the peripheral cornea is ablated. This is one of the Forest, CA, USA), it’s made of biocompatible hydrogel material and 80%
main difficulties in targeting specifically high negative asphericity values water. It has a thickness of 10 µm at the periphery and 32 µm at the center;
with this technique. A relatively flatter central cornea and more highly the diameter is 2 mm (Fig. 3.10.2).30 The inlay is permeable, allowing the
curved corneal midperiphery were described by Avalos (PARM technique), passage of nutrients and oxygen.9,34–36 It reshapes the anterior central
and a proprietary peripheral presby-LASIK algorithm was described and corneal surface, creating a hyperprolate region, resulting in a multifocal
patented by Tamayo. cornea.36 It has no refractive power.34,35
It should be placed in the nondominant eye at a minimum depth
Laser Blended Vision of 150 µm with a residual stromal bed thickness of 300 µm and has to
be aligned over the center of the light-constricted pupil.35–37 The central
This technique combines a low degree of asphericity and micromonovi- corneal thickness of the eye should be 500 µm or thicker. After the inlay is
sion in the near eye to achieve good near and distance vision.19 A sphericity positioned over the center of the pupil, it has to dry for 30 seconds before
between −0.58 and −0.70 is created to increase the depth of field. the flap is repositioned.37
Reinstein et al.19 reported good visual outcomes with this technique, Barragan et al.30 reported the results of a 1-year follow up using the
achieving binocular visual acuity of 20/20 at distance and J3 at near in Raindrop inlay in emmetropic presbyopes. In their study, 100% of eyes
99% of patients. These hybrid techniques combine the best features of the achieved an uncorrected near visual acuity (UNVA) of 0.2 logMAR or
multifocal cornea and monovision, achieving good visual outcomes. better in the operative eye, and binocularly, 100% of patients achieved an
The rates of spectacle independence with central presby-LASIK vary UNVA of 0.18 logMAR or better. No eye lost two or more lines of corrected
from 72%20 to 93%.16 A loss of corrected distance visual acuity (CDVA) of distance visual acuity (CDVA) or corrected near visual acuity (CNVA).
at least one line has been reported with central16,21–25 and peripheral26–28 Yoo et al.38 measured the corneal and optical aberrations in 22 emme- 143
presby-LASIK. tropic presbyopes with a mean addition power of +1.97 ± 0.30 D. All
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3
Refractive Surgery
Fig. 3.10.2 Raindrop corneal inlay.
patients gained monocular and binocular UNVA. For a 4-mm pupil size,
significant increases occurred in total root mean square (RMS), coma-like
RMS, and spherical-like RMS. Overall, 82% of the patients were satisfied
or very satisfied with their near vision, and 13.6% reported that they needed
glasses for near vision more often after surgery than before surgery. More-
over, 37% of patients reported glare. They concluded that the procedure Fig. 3.10.3 Flexivue Inlay. (Image from Malandrini A, Martone G, Menabuoni L.
can induce higher-order aberrations (HOA) but had moderate effects on Bifocal refractive corneal inlay implantation to improve near vision in emmetropic
presbyopic patients. J Cataract Refract Surg 2015;41:1962–72.)
the entire optical system.
In a study by Alió et al.,33 increases in spherical aberrations, coma, and
total HOA were reported with the implantation of hydrogel inlays.
Whitman et al.39 reported the clinical outcomes with the Raindrop inlay
in patients with emmetropic presbyopia. In total, 340 patients completed
a 1-year follow-up, and on average, they had an improvement in UNVA of
five lines and in uncorrected intermediate visual acuity (UIVA) of 2.5 lines.
However, the uncorrected distance visual acuity (UDVA) decreased by 1.2
lines. Contrast sensitivity loss occurred at the highest spatial frequen-
cies with no loss of binocularly. Eighteen inlays were replaced because of
decentration, and 11 were explanted (five patients were dissatisfied with
their vision, two had inlay misalignment, two had epithelial ingrowth, one
had visual symptoms associated with decreased visual acuity, and 1 had
recurrent central corneal haze that failed to respond to topical treatment).
Refractive Inlays
Presbia Flexivue Microlens
The Presvia Flexivue Microlens, a transparent hydrophilic concave–convex
disc made of a clear copolymer of hydroxyethylmethacrylate and methyl-
methacrylate with an ultraviolet blocker.31,36,40 It has a diameter of 3.2 mm
and a thickness of 15–20 µm, depending on the additional power. The
central 1.8 mm diameter of the disc is plano in power, and the periph-
eral zone has an add power, ranging from +1.25 D–3.00 D in 0.25-D incre- Fig. 3.10.4 Icolens Inlay. (Image taken from Baily C, Kohnen T, O’Keefe M.
ments. At the center, there is an opening of 0.15 mm that facilitates the Preloaded refractive-addition corneal inlay to compensate for presbyopia implanted
transfer of nutrients and oxygen through the cornea (Fig. 3.10.3).31,34–36,40 using a femtosecond laser: one-year visual outcomes and safety. J Cataract Refract
It has a refractive power of 1.4583 and a light transmission of 95% at a Surg 2014;40:1341–8.)
wavelength above 410 nm.36,40
During distance vision, light rays pass through the central zone of the
inlay that does not have refractive power (plano), so they will be sharply Malandrini et al.31 performed a 36-month follow-up study in 26 eyes,
focused on the retina. Light rays that pass through the refractive peripheral and the mean preoperative UNVA and UDVA were 0.76 logMAR and
zone will focus in front of the retina. 0.00 logMAR, respectively, compared with 0.10 logMAR and 0.15 logMAR,
During near vision, rays passing through the central zone of the inlay postoperatively. Overall, 62% of the eyes lost more than 1 line of UDVA,
will focus behind the retina, and those passing through the peripheral and 19% lost more than two lines of UDVA. Also, 8% of the eyes lost
refractive zone of the inlay will be focused on the retina.31,40 The rays more than 1 line of CDVA at 36 months. The mean spherical aberration
passing through the peripheral clear cornea will be blocked by the pupil.40 increased after surgery. Explantation was performed in six eyes because of
It is implanted in the nondominant eye. The corneal pocket is within reduced UDVA, halos, and glare; 6 months after explantation, the CDVA
a depth of 280–300 µm34,36,40 and is centered over the patient’s visual axis in all cases had returned to preoperative levels.
based on the first Purkinje reflex. The corneal inlay power is calculated by
decreasing the preoperative CNVA manifest refraction SE by 0.25 D.31 Icolens (Neoptics AG)
Limnopoulou et al.40 reported in their 1-year follow-up study a UNVA This corneal inlay is made of a copolymer of hydroxyethyl methacrylate
of 20/32 or better in 75% of operated eyes; the UDVA decreased signifi- and methyl methacrylate. It has a bifocal design with a peripheral positive
cantly in the operated eye from 20/20 to 20/50, but binocular UDVA was refractive zone for near vision and a central zone for distance vision.41 It
not significantly altered. HOA increased and contrast sensitivity decreased has a diameter of 3 mm, a peripheral thickness of 15 µm, and a central
in the operated eye. They included 47 emmetropic presbyopes between 45 0.15 mm hole for nutrient flow (Fig. 3.10.4).35,41
144 and 60 years old. No removals of the inlay and no intra- or postoperative Baily et al.41 reported the results of the Icolens 12 months after implan-
complications occurred. tation. The inlay was implanted in the nondominant eye of emmetropic
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3.10

Fig. 3.10.5 KAMRA Inlay in a Light-Colored Eye. (Image taken from Abbouda A,
Javaloy J, Alió JL. Confocal microscopy evaluation of the corneal response following
AcuFocus KAMRA inlay implantation. J Refract Surg 2014;30:172–8.)
TABLE 3.10.2 Inlay Characteristics

Characteristic ACI7000 (First One) ACI7000T ACI7000PDT (Latest)
Thickness 10 µm 5 µm 5 µm Fig. 3.10.6 Iron Deposits in the Periphery on the Inlay (Red Arrows) and in the
Holes 1600 1600 8400 Center of the Inlay (Green Arrow). (Image taken from Dexl AK, Ruckhofer J, Riha
W, et al. Central and peripheral corneal iron deposits after implantation of a small-
Diameter 25 µm 25 µm 5–11 µm
aperture corneal inlay for correction of presbyopia. J Refract Surg 2011;27;876–80.)
patients through a corneal pocket created by femtosecond laser at a depth with a slight compromise in uncorrected monocular distance visual acuity
of 290 µm; 52 patients were included. The UNVA improved from N18/ in the implanted eye without a binocular effect on the UDVA.
N24 preoperatively to N8 postoperatively, with 100% of patients having N16 Seyeddain et al.46 performed a 3-year follow-up with 32 emmetropic
or better, and nine patients having N5 or better. The mean UDVA in the presbyopic patients and reported that although there were significant gains
surgical eye worsened significantly from 0.05±0.12 logMAR preoperatively in UNVA and UIVA, 28.3% of patients lost one line of CDVA.
to 0.22±0.15 logMAR postoperatively. There was a loss of CDVA, with 77% Dexl et al.48 described iron corneal deposits after implantation of the
of the patients losing more than one line (they believe this was secondary AcuFocus corneal inlay (ACI 7000) in 18 eyes (56%), but these deposits did
to a neuro-optical phenomenon related to the implant). Seven inlays were not have any influence on distance, near, uncorrected, or corrected visual
removed because of inadequate centration, three secondary to ambiguous acuity (Fig. 3.10.6).
ocular dominance, and one because the patient had unrealistic expectation, Alió et al.42 reported that after removal of the KAMRA inlay, the topog-
for a total of 11 inlays removed. raphy and aberrometry were not permanently affected, and more than 60%
of the patients had a CNVA, CDVA, UNVA, and UDVA similar to their
Small Aperture Inlays preoperative values. The study involved 10 eyes and had a follow-up of 6
KAMRA months after the inlay removal. The reason for removal in eight eyes was
The KAMRA inlay (AcuFocus Inc., Irvine, CA, USA) is the most widely subjective dissatisfaction with visual symptoms (glare, starburst, blurry
used corneal inlay,35 with nearly 20,000 inlays implanted worldwide.9,36 It vision, and halos). One case was related to an inadvertent thin flap, and
is made of polyvinylidene fluoride. The latest design (ACI 7000PDT) has the other was related to insufficient near vision.
a 3.8-mm diameter with a central 1.6-mm aperture and a thickness of Abbouda et al.49 analyzed the corneal tissue appearance 6 months after
5 µm. It has 8400 microperforations ranging in diameter from 5 to 11 µm KAMRA inlay implantation by confocal microscopy; the study included
to allow nutritional flow through the cornea.9,34–36,42 It also has nanoparti- 12 eyes in which one of three models of the KAMRA inlay had been
cles of carbon, which43,44 has a light transmission of 5%.43 Because it is an implanted. The epithelial layers appeared normal in all patients. A low
opaque inlay, it may be visible in light-colored eyes (Fig. 3.10.5).9 grade of keratocyte activation was found in all patients. Few patients had
The KAMRA inlay improves near vision by increasing the depth of an elevated number of activated keratocytes, and they had a reduction in
focus35,36 through the principle of small aperture optics. It is implanted in UNVA (needed reading glasses), CNVA, and CDVA. The UDVA was not
the nondominant eye in a lamellar pocket that is 200–220 µm. Its implan- affected. Subbasal nerve plexus was detected in 10 patients, and the branch
tation does not cause scotomas in the visual field.34 It allows a normal pattern was found in eight patients. Four patients had the inlay explanted,
visualization of the central and peripheral fundus and a good quality of the main reason being subjective dissatisfaction with visual symptoms and
central and peripheral imaging and optical coherence tomography (OCT) poor vision. All of them had a donut appearance at the slit-lamp examina-
scans.45 However, annular shadows visible on the GDx VCC scans have tion. None of the patients had refractive postoperative changes. They con-
been reported.46 cluded that the corneal tolerance to the inlay is good and that it modifies
The inlay has evolved over the years, with the same artificial aperture of the normal structure of the corneal layer without associated complications.
3.8-mm outer diameter and 1.6-mm inner diameter. Table 3.10.2 describes Keratocyte activation is an important variable for the refractive outcome
the inlay characteristics. after KAMRA inlay implantation; flap thickness depth, low laser energy
Tomita et al.43 evaluated the outcomes of KAMRA inlay implantation cut, and topical corticosteriod treatment are helpful to avoid it.
and simultaneous LASIK in hyperopic, myopic, and emmetropic patients. Lin et al.50 compared the contrast sensitivity before and after implanta-
With a 6-month follow-up, they concluded that the procedure was safe and tion of the KAMRA inlay in 507 patients. They reported that postoperatively
improved distance and near visual acuity. However, postoperative symp- contrast sensitivity was mildly reduced monocularly but not binocularly,
toms like halos, glare, and night-vision disturbances were observed. and that it remained within the normative ranges.
Igras et al.47 reported a 1-year follow-up of combined LASIK and This inlay can be implanted also in patients with previous cataract
KAMRA inlay implantation. Of 132 patients evaluated, 85% were hyperme- surgery who have a monofocal IOL, as reported by Huseynova et al.51 They
tropic, 11% emmetropic, and 4% myopic. By 12 months, 97% of patients implanted the KAMRA inlay in 13 pseudo-phakic patients with a mono-
had J3 or better UNVA. Also, 6.3% of patients lost one line of CDVA in focal IOL. Four patients had LASIK at the time of the inlay implantation.
the implanted eye, and none lost two or more lines compared with their There was no change in mean UDVA after the inlay implantation, and the
preoperative VA. Two inlays were explanted, one due to poor night vision mean UNVA improved by five lines. Three eyes lost two lines, and one eye
and one secondary to persistent hyperopic shift and corneal haze. They lost one line of UDVA. Two eyes lost two lines, and one eye lost one line of 145
concluded that a significant improvement occurred in near visual acuity CDVA (Table 3.10.3, Table 3.10.4, Fig. 3.10.7).
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Presbyopic IOLs Rotationally Asymmetrical IOLs (Varifocal)
3 Correction of presbyopia with premium IOLs has been the best option,
because they provide good distance and near visual outcomes and specta-
These are characterized by an inferior segmental near add.57 The IOL has a
larger section for distance vision and a smaller reading segment, with only
one transition zone. The near add varies from +1.5 D to +3.00 D, depend-
cle independence. However, perfection has not been achieved with these ing on the patient’s visual needs.61
Refractive Surgery
IOLs, which can be divided in two main groups, multifocal IOLs and
accommodative IOLs. Patient Selection Criteria
Adequate patient selection is the most important part in implanting a mul-
Multifocal IOLs tifocal IOL. We must know the patient’s visual expectations and make sure
The perfect multifocal IOL must provide excellent near, intermediate, that we can fulfill them by selection of the correct IOL, because depending
and distance visual acuity; should not produce photic phenomena; and on the IOL design, the patient can have better near or intermediate dis-
should be pupil independent. The design has to be aspherical and able to tance vision. Also, patients’ expectations have to be realistic, and we have
be implanted through a small incision to allow the performance of micro to inform them of the visual side effects that they may experience with the
incision cataract surgery (<2 mm). Sadly, there is no single multifocal IOL multifocal IOLs (glare, halos) and that a process of neuroadaptation exists
that can provide all these factors at the same time. that takes a couple of months.
The aim of these IOLs is to provide patients with spectacle indepen- The correct IOL power calculation is crucial, and emmetropia should be
dence for both near and distance vision through the division of the incom- the target. It has been reported62 that the cause of 20% of cases of multifo-
ing light into two or more foci52–55 independently of capsular mechanics cal IOL explantation is incorrect IOL power.
and ciliary body function.56 Astigmatism correction is mandatory for a good performance of the
Multifocal IOLs can be divided based on their design as rotationally multifocal IOL. Patients with irregular astigmatism are not good candi-
symmetrical IOLs (which can be further divided as: diffractive, refractive, dates for a multifocal IOL63 because its correction is not easy or predictable.
or a combined design) and rotationally asymmetrical IOLs (also called var- Patients with corneal abnormalities like central scars and Fuchs’ dystro-
ifocal IOLs).53–57 phy are not suitable candidates for multifocal IOL implantation.63
Because many of the multifocal IOLs are pupil dependent, an adequate
Rotationally Symmetrical function before and after surgery is needed. Therefore, if a patient has a
Diffractive IOLs. These IOLs have in them surface rings that form a very small pupil diameter that needs surgical manipulation, the surgeon
discontinued optical density, so when the light particles encounter these should be very careful to not damage the iris sphincter. Patients with larger
rings, it is directed toward two focal points (near and distance; light pupils may experience glare and halos after multifocal IOL implantation.63
changes direction and slows down when encountering an edge of discon- Identification of zonular weakness during surgery is very important, as
tinuity [principle of diffraction])53,55,58 or three foci (near, intermediate, and decentration or tilt of the multifocal IOL can have a detrimental effect on
distance) in case of the trifocal IOLs.53 the visual acuity. This can be prevented by the implantation of a capsular
Diffractive IOLs can be categorized as apodized and nonapodized. tension ring.63,64
The term apodization is derived from the Greek words for “cutting off Any macular alteration must be recognized before implantation of a
the feet.”58 The apodized IOLs have a gradual decrease in diffractive step multifocal IOL, especially if the patient has these predisposing factors:
heights from the center to the periphery55,58 to create a smooth transition of
light between the focal points. Under myopic conditions (when the pupil is
on mydriasis), the light is more focused to the distant point.55 CORNEAL APPROACH OF PRESBYOPIA
These are the most commonly implanted multifocal IOLs.59
The steps on the nonapodized IOLs have a uniform height from the
center to the periphery, so the light is equally distributed in both focal
points independently of the pupil size.55 conventional
The extended range of vision IOLs is also diffractive, and they provide monovision
near vision by the correction of achromatic and spherical aberrations.60 crossed
Refractive IOLs. These IOLs have concentric zones of different diop-
tric power to achieve multifocality. They are pupil dependent and may be central
affected by decentration.
corneal
presby-LASIK peripheral
approach
TABLE 3.10.3 Advantages and Disadvantages of Corneal Inlays
hybrid
Minimally invasive Patient must tolerate monovision
Reversible Decrease in distance visual acuity refractive
No need to remove corneal tissue Decrease in contrast sensitivity
No need for a cataract Presence of halos
inlays small aperture
Quick recovery Corneal topography changes in the long
Doesn’t affect visual field testing term
Can be combined with other refractive Induction of higher-order aberrations reshaping inlays
procedures Corneal haze in long term
Normal visualization of central and Inlay centration is crucial
peripheral fundus Dry eye Fig. 3.10.7 Corneal Approach of Presbyopia.
TABLE 3.10.4 Corneal Inlays

Inlay Material Type of Inlay Measurements Mechanism of Action
Raindrop Biocompatible hydrogel 80% water Corneal Thickness of 10 µm at the periphery Reshapes the anterior corneal, creating a hyperprolate region →
reshaping inlay and 32 µm at the center multifocal cornea
Diameter: 2 mm
Flexivue Clear copolymer of hydroxyethylmethacrylate Refractive inlay Thickness: 15–20 µm The central 1.8 mm diameter of the disc is plano in power (for
and methylmethacrylate with an ultraviolet Diameter: 3 mm distance vision), and the peripheral zone has an add power
blocker ranging from +1.25 D–3.0 D in 0.25 D increments (for near vision)
Icolens Copolymer of hydroxyethyl methacrylate and Refractive inlay Thickness: 15 µm Bifocal design
methyl methacrylate Diameter: 3 mm Central zone for distance and peripheral positive refractive zone
for near
146 KAMRA Polyvinylidene fluoride, nanoparticles of

carbon
Small aperture
inlay
Thickness: 5 µm
Diameter: 3.8 mm
Increases the depth of focus through the principle of small
aperture optics
booksmedicos.org
Fig. 3.10.8 AcrySof Restor
SN6AD3. (Image from Alió J, LENTIS MPLUS LS-313 IOL
Pikkel J. Multifocal intraocular 3.10
lenses. The art and the practice.
1st ed. Editorial Springer;

Switzerland 2014.)
11.0 mm 6.0 mm
male gender, former or current smoker, and history of heart disease.65

A macular disease is a relative contraindication for the implantation of a
multifocal IOL65 because these patients have a reduced contrast sensibility
that can be worsened by a multifocal IOL. Thus the macula should be eval-
uated with either a macular function test or OCT.
Retinal diseases like Stargardt and retinitis pigmentosa are absolute
contraindications for multifocal IOL implantation. Other diseases like dia-
betic retinopathy, macular degeneration, and epiretinal membranes have
a decreased contrast sensitivity that may be worsened by the multifocal
IOL.63 Glaucoma is a relative contraindication for the use of multifocal Fig. 3.10.9 Lentis Mplus LS-313 IOL. (Image on the left from Alió J, Pikkel J.
IOLs. If the patient has an early glaucoma or controlled ocular hyperten- Multifocal intraocular lenses. The art and the practice. 1st ed. Editorial Springer;
sion, a multifocal IOL can be implanted, but IOL implantation should be Switzerland 2014. Image on the right from http://www.device.com.au/shop/
avoided in patients with progressive and advanced glaucoma.66 oculentis/.)
There are many multifocal IOLs available on the market; we will discuss
the most popular ones. Diopter range: Mplus: +15.00 D to +25.00 D in 0.5 D steps, Mplus X:
AcrySof Restor SN6AD3 (Alcon Laboratories, Inc.) −10.00 D to +1.00 D in 1.0 D steps, and from +0.00 D to +36.00 D in
Apodized diffractive and refractive technologies 0.5 D steps
Type: One-piece multifocal IOL Incision size: 2.6 mm
Material: hydrophobic acrylic 360° continuous square optic and haptic edge (Fig. 3.10.9)
Filter: UV and blue light Pupil-independent IOL
Pupil dependent: No
Optic diameter: 6 mm The design has an inferior surface-embedded segment with the optical
Overall diameter: 13 mm power required for near vision and seamless transitions between the near
Refractive index: 1.47 and far zones.
Power range: +6.00 to +34.00 D Light in the near vision zone is refracted to the near focus, and the rest is
Near addition at lens plane: +4.00 D refracted to the far focus.59
Incision size: >2.2 mm Light hitting the transition area of the embedded sector is reflected
away from the optical axis to prevent superposition of interference or
The central 3.5 mm of the optic zone has 12 concentric steps of gradually diffraction.57,59
decreasing (1.3–1.2) step heights. Surrounding this apodized region is the The position of the near segment does not have a detrimental effect on the
refractive area that directs light to a distance focal point for large pupil visual performance,69 although the manufacturer recommends an inferior
diameters.67 placement.
In bright light with constricted pupils, the lens sends light energy to Symfony (Abbott Medical Optics, Inc.)
near and distant focal points; in low light with dilated pupils, the apodized Type: diffractive nonapodized achromatic
diffractive lens sends a greater amount of energy to distance vision to min- Material: UV-blocking hydrophobic acrylic
imize visual disturbances (Fig. 3.10.8).68 Optic diameter: 6 mm
Lentis Mplus LS-313 (Oculentis GmbH) Overall diameter: 13 mm
Type: one piece, refractive rotationally asymmetrical multifocal IOL Power range: +5.00 D to +34.00 D in 0.50 D increments
(varifocal) Refractive index: 1.47
Material: HydroSmart acrylate copolymer with hydrophobic surface
Optic diameter: 6.0 mm It has a biconvex wavefront-designed anterior aspherical surface and a pos-
Overall diameter: 11.0 mm terior achromatic diffractive surface (Fig. 3.10.10).
Refractive index: 1.46 This IOL elongates the focus and corrects the corneal chromatic
Addition at IOL plane: +3.00 D and spherical aberration using an achromatic technology also known as 147
Addition at spectacle plane: +2.5 D “extended range of vision.”60,70
booksmedicos.org
Fig. 3.10.10 TECNIS
3 Symfony IOL. (Image

from http://eyewiretoday.
com/news.asp?t=474.)
Refractive Surgery
Fig. 3.10.11 AT LISA Tri 839 mp IOL. (Image from Alió J, Pikkel J. Multifocal
intraocular lenses. The art and the practice. 1st ed. Editorial Springer; Switzerland
2014.)
Fig. 3.10.12 FineVision Micro

F IOL. (Image from Alió J, Pikkel
J. Multifocal intraocular lenses.
The art and the practice. 1st ed.
Editorial Springer; Switzerland
2014.)
The chromatic aberrations have a detrimental effect on vision because

they reduce contrast vision and induce blur.71
The improvement of both aberrations increases the retinal image
quality with a better tolerance of decentration and without sacrificing the
depth of field.72
It provides better near, intermediate, and distance vision than aspheri-
cal monofocal IOLs, and in contrast to multifocal IOLs, it does not induce
aberrations to extend the depth of focus.60
Because it provides an elongated focal area rather than various focal
points, halos are not as common as with the multifocal IOLs. In fact,
one study70 reported that 90% of patients in whom a Symfony IOL was
implanted reported no or mild halos or photic phenomena, and the visual
results were better than those obtained with a rotationally asymmetrical
multifocal IOL or an apodized diffractive IOL. intermediate, and distant foci are adjusted according to the pupil aperture.
AT LISA tri 839 MP (Carl Zeiss Meditec AG) The IOL distributes 43% of light energy to far vision, 28% to near vision,
Type: one-piece trifocal diffractive aspherical IOL and 15% to intermediate vision for a 3-mm pupil, and the remaining light
Material: hydrophilic acrylic 25% with hydrophobic surface energy is lost (Fig. 3.10.12).74
Optic diameter: 6 mm Panoptix (Alcon)
Overall diameter: 11 mm Type: one piece, aspherical
Power range: from plano to +32.00 D in 0.5 D increments Material: hydrophobic, ultraviolet- and blue light–filtering acrylate/
Near addition at the IOL plane: +3.33 D for near vision, +1.66 D for inter- methacrylate copolymer
mediate vision Optic diameter: 6.0 mm
Incision size: 1.8 mm. Overall diameter: 13.0 mm
Asphericity: −0.18 µm.
It has a 4.5-mm diffractive area in the center with 15 diffractive zones and
The central 4.34 mm of the IOL optic is the trifocal zone, and the periph- an outer refractive rim (Fig. 3.10.13).
eral bifocal zone is from 4.34 to 6 mm with diffractive rings covering the Light distribution is 25% to near (40 cm), 25% to intermediate (60 cm),
entire optic diameter (Fig. 3.10.11).73 and 50% to distance vision.
There is a more physiological transition from different distances
Fine Vision Micro F (Physiol) because of an advanced optical technology, so the light from the first focal
Type: one-piece trifocal point is diffracted to the distance focus. This helps to create a fourth focal
Optic: diffractive anterior surface, aspherical posterior surface point at 1.20 m, making this IOL a quadrafocal IOL, although it acts as a
Material: 25% hydrophilic acrylic trifocal IOL.75
Optic diameter: 6.15 mm Based on laboratory simulations, the performances in image quality,
Overall diameter: 10.75 mm photic phenomena, and resolution are equivalent between the Panoptix
Power range: +10.00 D to +35.00 D in 0.5 D increments IOL and the AT LISA tri 839MP and FineVision Micro F trifocal IOL.76
Near addition at spectacle plane: +1.75 D intermediate vision, +3.5 D near
vision Clinical Outcomes and Quality of Life
Incision size: >1.8 mm Carballo-Alvarez et al.74 evaluated visual outcomes 3 months after bilateral
Asphericity: −0.11 µm implantation of the FineVision trifocal IOL. They reported adequate near,
Pupil-dependent IOL intermediate, and far vision, with satisfactory contrast sensitivity and no
significant photic phenomena.
148 The anterior surface of the IOL is convoluted. By the varying of the A comparison between the FineVision trifocal and the Restor IOL
height of the diffractive step, the amounts of light distributed to the near, reported similar refractive outcomes, reading speeds, and patient
booksmedicos.org
PANOPTIX IOL TABLE 3.10.5 Multifocal Intraocular Lens Complications
Complications Following Multifocal IOL Surgery
3.10
IOL decentration
15 rings

IOL tilt
+3.25 D near and Inadequate pupil size
+2.17 D intermediate Residual refractive error
add power Posterior capsule opacification
Photopic phenomena and contrast sensitivity
Dry eye
4.5 mm
Accommodating IOLs
Accommodating IOLs have been designed to mimic physiological accom-
modation and avoid the optical side effects of multifocal IOLs.
IOLs proposed to restore accommodation have initially been designed
to do so by enabling a forward movement of the optic component during
an accommodation effort.80
These IOLs employ one of three basic approaches to restore
accommodation:
Fig. 3.10.13 Panoptix IOL. (Image from Kohnen T. First implantation of a diffractive
quadrafocal (trifocal) intraocular lens. J Cataract Refract Surg 2015;41:2330–2.) 1. Change in axial position
• Single optic
81
 The accommodative effect is dependent on IOL power, so it pro-
vides limited near vision.82
satisfaction, although the intermediate distance in the defocus curve was
■ Crystalens
better in the trifocal IOL group. Spectacle independence was achieved in
■ Tetraflex
80% of the patients with the trifocal IOL and in 50% of the patients with
■ 1CU
the bifocal IOL.77
Similar outcomes were reported by a study comparing the Restor IOL
• Dual optic
 They consist of a mobile front optic and a stationary rear optic
with the AT LISA tri. The latter gave better intermediate visual acuity,
that are interconnected with spring-type haptics.83
whereas near and distance visual acuity were good with both IOLs. The
■ Synchrony
Quality of Vision questionnaire showed similar visual disturbances
2. Change in shape or curvature
between the two groups.78
A comparison of the visual outcomes and intraocular optical quality
• FluidVision
between the Lentis Mplus and the Restor IOL reported that the UNVA
• NuLens
3. Change in refractive index or power
and distance-corrected near visual acuity (DCNVA) were better with the
Lentis Mplus, although this IOL significantly induced HOA. The inter-
• Lumina
mediate VA and the photopic contrast sensitivity were better with the For the newest accommodating IOLs, researchers have found the sulcus
Restor IOL.59 instead of the capsular bag to be the ideal place to provide a real accom-
Patient satisfaction with multifocal and toric multifocal IOLs is very modative outcome. Capsular contraction has shown to be a major problem
good, ranging from 93% to 95%.53 for accommodating IOLs implanted in the capsular bag. An asymmetrical
capsular contraction causes the plate haptics to vault in opposite directions
Complications (Z-syndrome, Fig. 3.10.14),84 inducing astigmatism, even >1 D of lenticu-
The most common visual symptoms of multifocal IOLs are glare and lar astigmatism.85 Although this capsular contraction can be treated by an
halos.52,53,79 These phenomena are secondary to the light division into two Nd:YAG laser capsulectomy, some patients may need an IOL exchange.85,86
or more foci that happens with a multifocal IOL; the light in the out-of- Here we review some of the most popular and recently introduced
focus image reduces the contrast of the in-focus image.52 accommodating IOLs:
Other symptoms include starbursts, shadows, and negative and pos-
itive dysphotopsia.53 A decrease in contrast sensitivity has been reported 1) IOLs With Change in Axial Position, Single Optic
also.52,53 Multifocal aspherical IOLs have been developed to improve these Crystalens HD (Bauch & Lomb)
visual phenomena. A meta-analysis compared the visual outcomes between This IOL was designed by Dr J. Stuart Cumming80 and was the first accom-
aspherical and spherical multifocal IOLs, and aspherical multifocal IOLs modating IOL approved by the FDA.
achieved better image quality than spherical multifocal IOLs and also had Type: biconvex single-optic
less spherical aberrations.52 Material: biocompatible third generation silicone (Biosil)
Although no multifocal IOL design exists without night vision dis- Refractive index: 1.428
turbances, patients may adapt to them in a 6-month period53 through a Two sizes are available depending on the required power: 12.0 mm
process of neuroadaptation,63 which is faster with fully diffractive IOLs (HD520) for 10.00–16.50 D and 11.5 mm (HD500) for 17.00–33.00 D.
because the pupil does not affect the visual outcome.74 The center is biaspheric to increase the depth of focus, so it provides better
Posterior capsule opacification is the most common complication after near and intermediate focus.
cataract surgery. A study73 compared the ND:YAG capsulotomy rates after It has a double mechanism to improve near visual: (1) axial movement
the implantation of the FineVision Micro F and AT LISA tri 839MP trifocal of the optic and (2) variation of the radius of curvature of the anterior
IOLs, and the ND:YAG capsulotomy rate was significantly higher with the surface (Fig. 3.10.15).87
AT LISA tri 839MP IOL, although both IOLs had the same incidence of
posterior cystoid macular edema. Alió87 compared the visual acuity outcomes and ocular optical quality
It is important to note that not every patient is going to adapt to the between the Crystalens HD and a monofocal IOL (Acri.Smart 48S). The
multifocality and visual side effects, and some may want an IOL exchange UNVA was significantly better in the accommodating IOL group, but no
(photopic phenomena and waxy vision can only be treated by IOL exchange). significant difference in CNVA occurred between the two groups. Also
Kamiya et al.62 reported the reasons for multifocal IOL explantation. The there was no difference in the intraocular aberrometric coefficient.
principal reason, accounting for 36% of all cases, was decreased contrast A study comparing the visual outcomes between the Crystalens HD
sensitivity; of these, 34% was for photopic phenomenon, 32% for unknown and the Lentis M-Plus88 showed the latter achieved better DCNVA, and no
origin, including neuroadaptation failure, 20% for incorrect IOL power, significant differences occurred in postoperative UNVA or CNVA between
14% for preoperative excessive expectation, 4% IOL decentration, and 4% the groups. The near add was reduced significantly after surgery in both
for anisometropia. It is important to note that 70% of the eyes from which groups, with a lower near-add power in the Lentis M-Plus group. Regard-
the multifocal IOL was explanted had an UDVA of 20/20 or better, which ing optical quality, a significantly larger amount of IOL tilt existed in the
means that the side effects of multifocal IOLs can be really disturbing for Lentis M-Plus group, but the difference in mean ocular HOA was not sta- 149
the patient (Table 3.10.5). See Table 3.10.6 for a review on Multifocal IOLs. tistically significant. The Crystalens HD had significantly better contrast
booksmedicos.org
3
TABLE 3.10.6 Review of Multifocal IOLs
IOL Name* Manufacturer Near Addition (D) Pupil Independent (Yes/No) Aspheric (Yes/No)
Refractive (concentric rings)
Refractive Surgery
Array (SA40N) Abbott Medical Optics +3.50 No No

M-flex (580F, 630F) Rayner Ltd. +3.00, +4.00 No Yes
M-flex T (588F, 638F) (toric) Rayner Ltd. +3.00, +4.00 No Yes
PA154N Allergan +3.50 No No
PY-60MV Hoya +3.00 No No
TrueVista 68STUV Storz +4.00 No No
ReZoom (NXG1) Abbott Medical Optics +3.50 No No
SFX MV1 Hoya +2.25 No No
UV360M4-07 Ioptex Research, Inc. +4.00 No No
Refractive (sector shaped)
LENTIS Mplus (LS-312 MF15) Oculentis GmbH +1.50 Yes Yes
LENTIS Mplus (LS-312 MF30, LS-313 MF30) Oculentis GmbH +3.00 Yes Yes
LENTIS Mplus (LU-313 MF30) Oculentis GmbH +3.00 Yes Yes
LENTIS Mplus toric (LU-313 MF30T) Oculentis GmbH +3.00 Yes Yes
LENTIS Mplus X (LS-313 MF30) Oculentis GmbH +3.00 Yes Yes
SBL-3 Lenstec +3.00 Yes Yes
Diffractive
Acri.Twin (733D, 737D) Acri.Tech/Carl Zeiss Meditec +4.00 Yes Yes
AcriviaReviol (BB MF 613, BB MFM 611) VSY Biotechnology +3.75 Yes Yes
CeeOn 811E Pharmacia +4.00 Yes No
Diffractiva-aA Dr. Schmidt +3.50 Yes No
OptiVis Aaren Scientific +2.80 No Yes
Tecnis (ZM900, ZM001, ZMA00, ZMB00) Abbott Medical Optics +4.00 Yes Yes
Tecnis ZMT (toric) Abbott Medical Optics +4.00 Yes Yes
Diffractive, trifocal
FineVision Physiol +1.75, +3.50 No Yes
AT Lisa tri 839MP Carl Zeiss Meditec +1.66, +3.33 Yes No
Hybrid refractive diffractive
AT Lisa (801, 802, 809M) former Carl Zeiss Meditec +3.75 Yes Yes
Acri.Lisa (376D, 536D, 366D)
AT Lisa toric (909M) former Carl Zeiss Meditec +3.75 Yes Yes
Acri.Lisa (466TD) (toric)
ReSTOR (SA60D3, SN60D3, MN60D3) Alcon Laboratories +4.00 No Yes
ReSTOR (SN6AD1, SN6AD2, SN6AD3) Alcon Laboratories +3.00, +2.50, +4.00 No Yes
ReSTOR (SND1T2/3/4/5) (toric) Alcon Laboratories +3.00 No Yes
*Intraocular lens names are listed as spelled by the manufacturer and not per journal style.
Fig. 3.10.15 Crystalens

IOL. (Image from Alió
Z-SYNDROME INDUCED BY CAPSULAR CONTRACTION
JL, Plaza-Puche AB,
Montalban R, Javaloy
J. Visual outcomes
with a single-optic
accommodating
intraocular lens and
a low-addition-power
posterior vault hinge rotational asymmetric
multifocal intraocular
lens. J Cataract Refract
Surg 2012;38:978–85.)
anterior capsulotomy lens capsule
anterior vault hinge
Fig. 3.10.14 Z-Syndrome Induced by Capsular Contraction. (Image from Page

TP, Whitman J. A stepwise approach for the management of capsular contraction
150 syndrome in hinge-based accommodative intraocular lenses. Clin Ophthalmol
2016;10:1039–46.)
booksmedicos.org
3.10

Fig. 3.10.16 Tetraflex IOL. (Image from Wolffsohn JS1, Davies LN, Gupta N, et al.
Mechanism of action of the tetraflex accommodative intraocular lens. J Refract Surg
2010;26:858–62.)
sensitivity results under photopic conditions at all spatial frequencies.

They concluded that both IOLs had limitations in providing complete
near-vision outcomes.
With ray-tracing aberrometry, it was shown that the Crystalens accom- Fig. 3.10.17 Synchrony IOL. (Image from Bohórquez V, Alarcon R. Long-term
modative power was lower than 0.4 D.89 reading performance in patients with bilateral dual-optic accommodating
intraocular lenses. J Cataract Refract Surg 2010;36:1880–6.)
Commercially available: Yes
1CU (Human Optics AG)
Type: one-piece biconvex Bohórquez et al.92 evaluated reading ability at 1 and 2 years after the
Material: hydrophilic acrylic implantation of the Synchrony IOL. The reading speed, mean reading
Optic diameter: 5.5 mm acuity, and mean critical print size were significantly better by 2 years post-
Total diameter: 9.8 mm operatively. They concluded that these results were a consequence of true
Mechanism of action: anterior movement of the optic; four haptics for the accommodation, although the reasons for the improved reading skills at 2
transduction of the ciliary muscle contraction years postoperatively were not fully clear.
Saiki et al.90 performed a 4-year follow-up of patients who received the 1CU
Commercially available: No, it has been discontinued
IOL and reported that the amplitude of accommodation was not enough
to provide good near vision. One possibility for the lack of accommoda-
tion is the contraction of the capsule. 3) IOLs With Change in Shape or Curvature
Not commercially available; it has been discontinued FluidVision (Powervision, Inc). This IOL has an overall diameter of
10.0 mm and an optic diameter of 6.0 mm. It is made of acrylic material;
Tetraflex (Lenstec Inc)
the haptics and interior of the optic are filled with silicone oil. During
Type: one-piece IOL
accommodation, the silicon oil is pushed into the optic through fluid chan-
Material: hydroxyethylmethacrylate (HEMA)
nels that connect the haptics to the optic. This inflates the lens, which
Optic diameter: 5.75 mm
increases the dioptric power for near vision.93a When the eye focuses at far,
Overall diameter: 11.5 mm
fluid flows from the optic body back into the haptics, flattening the lens
Refractive index: 1.46
and decreasing the dioptric power.
Incision size: 2.5–3.0 mm
In a pilot study, Roux reported a subjective accommodation of 2.5 D.93b
Mechanism of action: Increase in HOA with accommodative effort91 rather
The lens is implanted through a 4-mm incision; the results of this study
than forward movement within the capsular bag as was the original
have not been published yet.
proposed action (Fig. 3.10.16).
Commercially available: Yes, although the results have been contradictory. Commercially available: No, still in trials.
Nulens (DynaCurve). This IOL consists of polymethyl methacrylate
2) IOLs With Change in Axial Position, Dual Optic
(PMMA) haptics, a PMMA anterior reference plane that provides distance
Synchrony (Visiogen Inc.)
vision correction, a small chamber that contains a solid silicone gel, and a
Type: one-piece dual optic
posterior piston with an aperture in the center (Fig. 3.10.18).
Material: silicone
Power range: +16.00 D to +28.00 D in 0.5 D steps
Mechanism of action: The piston is pressed, making the flexible gel bulge
The anterior IOL component has a high plus power beyond that required and resulting in an increase or decrease in IOL optical power.
to produce emmetropia, and the posterior component has a minus power It is inserted at the sulcus and must be implanted through a limbal inci-
to return the eye to emmetropia. A bridge with a spring function connects sion of 9 mm.
the two components. Once the IOL is in the capsular bag, the tension of It can provide up to 10.00 D of accommodation, improving near visual
the bag compresses the optics. This leads to strain energy in the haptics acuity without compromising DVA.94
that is released when there is an attempt to accommodate (Fig. 3.10.17).82,92 Commercially available: No
A comparison of the visual and ocular performances between the Crys-
talens HD and the Synchrony IOL was made by Alió et al.82 No statistically 4) IOL With Change in Refractive Index or Power
significant differences occurred in UDVA, CDVA, and near or interme- Lumina (Akkolens). This IOL consists of two optical elements, each
diate visual outcomes between the two IOLs. Reading acuity and reading having an elastic U-shaped loop with a spring function, and nonelastic
speed were similar in both groups. Contrast sensitivity was significantly connections to the main body of the lens (Fig. 3.10.19).
better in patients who received the Synchrony IOL. HOA were higher in The optics are aspherical, The anterior one has a power of 5.0 D, and
the Crystalens HD group. Both IOLs had limitations in providing adequate the power of the posterior one depends on the required correction of the 151
near visual outcomes. eye (10–25 D).
booksmedicos.org
3
Refractive Surgery
Fig. 3.10.19 Lumina IOL. (Image from Alió JL, Simonov A, Plaza-Puche AB, et al.
Visual outcomes and accommodative response of the Lumina accommodative
intraocular lens. Am J Ophthalmol 2016;164:37–48.)
Fig. 3.10.18 Nulens IOL in the Human Eye. (Image from Alió JL, Ben-nun
J, Rodríguez-Prats JL, et al. Visual and accommodative outcomes 1 year after
implantation of an accommodating intraocular lens based on a new concept. J
Cataract Refract Surg 2009;35:1671–8.)
Fig. 3.10.20 Types of Presbyopic IOLs.

TYPES OF PRESBYOPIC IOLS
single optic
change in axial
position
dual optic
change in shape
accommodative
or curvature
change in
presbyopic IOLs refractive power
diffractive
rotationally refractive
symmetrical
multifocals
rotationally diffractive-
asymmetrical refractive
It must be implanted at the sulcus, and its size is customized based vision without compromise of distance vision. Primary outcomes are still
on the sulcus to sulcus diameter, as measured by OCT at the 12 o’clock pending.97
meridian.
During accommodation, the IOL is compressed by the contraction Topical Treatment
of the ciliary muscle, and the optics move in opposite directions, increas- This is an emerging topic that is under clinical evaluation; the mechanism
ing the optical power of the lens. When the muscle relaxes, the springs of action is through ciliary body stimulation, miosis, and lens softening.
force the elements back to their original state, decreasing the optical power.
It has been proven through subjective and objective methods that the FOV Tears
Lumina IOL improves near, intermediate, and far vision without affecting A topical treatment is available for the correction of near vision, with sci-
contrast sensitivity and with an accommodative power between 1.5 and entific evidence reporting a gain of two to three lines of UCVA. The oph-
6.0 D.95 thalmic solution contains pilocarpine, phenylephrine, polyethylene glycol,
Comments. The long-term effectiveness of accommodating IOL nepafenac, pheniramine, and naphazoline, and this combination stimu-
implantation for presbyopia treatment still has to be demonstrated (Fig. lates the contraction of the ciliary body and maintains a physiological pupil
3.10.20). diameter. FOV tears are commercially available in some Latin American
countries.98
Other Treatments
Scleral Expansion Bands Liquid Vision
This treatment is based on Schachar’s theory of accommodation, which This is a combination of aceclidine (parasympathomimetic) and tropi-
states that presbyopia is secondary to an increase in the lens diameter, camide. Its mechanism of action is through a pinhole effect. The pilot
which causes a reduction in the space between the lens and the ciliary study reported a gain of more than three lines of near vision. It is being
body such that upon contraction the zonules can no longer exert their tested in a phase IIb trial.99
effect on the lens due to a loss of tension.96
The Refocus Group is conducting a phase III study of a new scleral EV06 (Encore Vision)
implant surgery. Four PMMA segments are inserted in scleral tunnels An increment of the lens elasticity may be achieved by topical treatment
152 at a depth of 400 µm, 4 mm from the limbus to restore accommodation. with lipoic acid choline ester 1.5% (EV06, Encore Vision), which reduces
Preliminary reports indicate good uncorrected near and intermediate the lens protein disulfides.
booksmedicos.org
The lens disulfide bonds that form between the crystalline proteins Gil-Cazorla R, Shah S, Naroo SA. A review of the surgical options for the correction of pres-
byopia. Br J Ophthalmol 2016;100:62–70.
are broken down because of the dihydrolipoic acid (a reduced active agent
of lipoic acid), thus increasing the lens elasticity. A phase I/II study has
Gooi P, Ahmed IK. Review of presbyopic IOLs: multifocal and accommodating IOLs. Int
Ophthalmol Clin 2012;52(2):41–50.
3.10
shown good outcomes.100 Greenstein S, Pineda R 2nd. The quest for spectacle independence: a comparison of multi-
focal intraocular lens implants and pseudophakic monovision for patients with presby-

opia. Semin Ophthalmol 2017;32(1):111–5.
KEY REFERENCES Kamiya K, Hayashi K, Shimizu K, et al. Multifocal intraocular lens explantation: a case series
of 50 eyes. Am J Ophthalmol 2014;158:215–220.e1.
Alió JL, Amparo F, Ortiz D, et al. Corneal multifocality with excimer laser for presbyopia Lindstrom RL, Macrae SM, Pepose JS, et al. Corneal inlays for presbyopia correction. Curr
correction. Curr Opin Ophthalmol 2009;20:264–71. Opin Ophthalmol 2013;24:281–7.
Alió JL, Grzybowski A, El Aswad A, et al. Refractive lens exchange. Surv Ophthalmol Pepose JS, Burke J, Qazi MA. Benefits and barriers of accommodating intraocular lenses.
2014;579–98. Curr Opin Ophthalmol 2017 Jan;28(1):3–8.
Alió JL, Grzybowski A, Romaniuk D. Refractive lens exchange in modern practice: when and Rosen E, Alió JL, Dick HB, et al. Efficacy and safety of multifocal intraocular lenses following
when not to do it? Eye Vis 2014;1:1–13. cataract and refractive lens exchange: Metaanalysis of peer-reviewed publications. J Cart
Alió JL, Simonov A, Plaza-Puche AB, et al. Visual outcomes and accommodative response of Refract Surg 2016;42:310–28.
the Lumina accommodative intraocular lens. Am J Ophthalmol 2016;164:37–48. Seyeddain O, Hohensinn M, Riha W, et al. Small-aperture corneal inlay for the correction of
Braga-Mele R, Chang D, Dewey S, et al. Multifocal intraocular lenses: relative indications presbyopia: 3-year follow-up. J Cataract Refract Surg 2012;38:35–45.
and contraindications for implantation. J Cataract Refract Surg 2014;40:313–22.
Davidson RS, Dhaliwal D, Hamilton DR, et al. Surgical correction of presbyopia. J Cataract
Refract Surg 2016;42:920–30. Access the complete reference list online at ExpertConsult.com
Garcia-Gonzalez M, Teus MA, Hernandez-Verdejo JL. Visual outcomes of LASIK-induced
monovision in myopic patients with presbyopia. Am J Ophthalmol 2010;150:381–6.
153
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REFERENCES 37. Steinert RF, Schwiegerling J, Lang A, et al. Range of refractive independence and mech-
anism of action of a corneal shape – changing hydrogel inlay: results and theory. J Cat-
1. Goertz AD, Stewart WC, Burns WR, et al. Review of the impact of presbyopia on quality
of life in the developing and developed world. Acta Ophthalmol 2014;92:497–500.
aract Refract Surg 2015;41:1568–79.
38. Yoo A, Kim JY, Kim MJ, et al. Hydrogel inlay for presbyopia: objective and subjective
3.10
2. Glasser A. Accommodation: mechanims and measurement. Ophthalmol Clin North visual outcomes. J Refract Surg 2015;31(7):454–60.
39. Whitman J, Dougherty PJ, Parkhurst GD, et al. Treatment of presbyopia in emmetropes

Am 2006;19:1–12.
3. Zhang F, Sugar A, Arbisser L, et al. Crossed versus conventional pseudophakic monovi- using a shape-changing corneal inlay one-year clinical outcomes. Am Acad Ophthalmol
sion: patient satisfaction, visual function, and spectacle independence. J Cataract Refract 2016;123:466–75.
Surg 2015;41:1845–54. 40. Limnopoulou AN, Bouzoukis DI, Kymionis GD, et al. Visual outcomes and safety
4. Kim J, Shin HJ, Kim HC, et al. Comparison of conventional versus crossed monovision of a refractive corneal inlay for presbyopia using femtosecond laser. J Refract Surg
in pseudophakia. Br J Ophthalmol 2015;99:391–5. 2013;29(1):12–18.
5. Schwartz R, Yatziv Y. The effect of cataract surgery on ocular dominance. Clin Ophthal- 41. Baily C, Ophth M, Kohnen T, et al. Preloaded refractive-addition corneal inlay to com-
mol 2015;9:2329–33. pensate for presbyopia implanted using a femtosecond laser: one-year visual outcomes
6. Hayashi K, Ogawa S, Manabe S, et al. Binocular visual function of modified pseudopha- and safety. J Cataract Refract Surg 2014;40:1341–8.
kic monovision. Am J Ophthalmol 2015;159(2):232–40. 42. Alió JL, Abbouda A, Huseynli S, et al. Removability of a small aperture intracorneal
7. Greenstein S, Pineda R 2nd. The quest for spectacle independence: a comparison of inlay for presbyopia correction. J Refract Surg 2013;29(8):550–6.
multifocal intraocular lens implants and pseudophakic monovision for patients with 43. Tomita M, Kanamori T, Iv GOW, et al. Simultaneous corneal inlay implantation and
presbyopia. Semin Ophthalmol 2017;32(1):111–5. laser in situ keratomileusis for presbyopia in patients with hyperopia, myopia, or
8. Ito M, Shimizu K, Niida T, et al. Binocular function in patients with pseudophakic emmetropia: six-month results. J Cart Refract Surg 2012;38:495–506.
monovision. J Cart Refract Surg 2014;40(8):1349–54. 44. Naroo SA, Paramdeep SB. Clinical utility of the KAMRA corneal inlay. Clin Ophthalmol
9. Davidson RS, Dhaliwal D, Hamilton DR, et al. Surgical correction of presbyopia. J Cat- 2016;10:913–19.
aract Refract Surg 2016;42:920–30. 45. Casas-llera P, Ruiz-Moreno JM, Alió JL. Retinal imaging after corneal inlay implanta-
10. Goldberg DB. Laser in situ keratomileusis monovision. J Cataract Refract Surg tion. J Cataract Refract Surg 2011;37:1729–31.
2001;27:1449–55. 46. Seyeddain O, Hohensinn M, Riha W, et al. Small-aperture corneal inlay for the correc-
11. Farid M, Roger F. Patient selection for monovision laser refractive surgery. Curr Opin tion of presbyopia: 3-year follow-up. J Cataract Refract Surg 2012;38:35–45.
Ophthalmol 2009;20:251–4. 47. Igras E, Caoimh RO, Paul O, et al. Long-term results of combined LASIK and monocu-
12. Ito M, Shimizu K, Iida Y, et al. Five-year clinical study of patients with pseudophakic lar small-aperture corneal inlay implantation. J Refract Surg 2016;32(6):379–84.
monovision. J Cataract Refract Surg 2012;38:1440–5. 48. Dexl AK, Ruckhofer J, Riha W, et al. Central and peripheral corneal iron deposits after
13. Garcia-Gonzalez M, Teus MA, Hernandez-Verdejo JL. Visual outcomes of LASIK-induced implantation of a small-aperture corneal inlay for correction of presbyopia. J Refract
monovision in myopic patients with presbyopia. Am J Ophthalmol 2010;150:381–6. Surg 2011;27(12):876–80.
14. Finkelman YM, Ng JQ, Barrett GD. Patient satisfaction and visual function after pseu- 49. Abbouda A, Javaloy J, Alió JL. Confocal microscopy evaluation of the corneal response
dophakic monovision. J Cart Refract Surg 2009;35:998–1002. following AcuFocus KAMRA inlay implantation. J Refract Surg 2014;30(3):172–8.
15a. Wilkins MR, Allan BD, Rubin GS, et al. Randomized trial of multifocal intraocu- 50. Lin L, Vilupuru S, Pepose JS. Contrast sensitivity in patients with emmetropic pres-
lar lenses versus monovision after bilateral cataract surgery. Am Acad Ophthalmol byopia before and after small-aperture inlay implantation. J Refract Surg 2016;32(6):
2013;120:2449–56. 386–93.
15b. Ruiz LA, inventor; Apparatus and method for performing presbyopia corrective 51. Huseynova T, Kanamori T, Waring GO, et al. Outcomes of small aperture corneal inlay
surgery. US patent 5 533 997. July 9, 1996. implantation in patients with pseudophakia. J Refract Surg 2014;30(2):110–15.
16. Ryan A, Keefe MO. Corneal approach to hyperopic presbyopia treatment: six-month 52. Liu J-P, Zhang F, Zhao J-Y, et al. Visual function and higher order aberration after
outcomes of a new multifocal excimer laser in situ keratomileusis procedure. J Cataract implantation of aspheric and spherical multifocal intraocular lenses: a meta-analysis.
Refract Surg 2013;39:1226–33. Int J Ophthalmol 2013;6(5):690–5.
17. Verma S, Mosquera SA. Presbyopic LASIK using hybrid bi-aspheric micro-monovision 53. Rosen E, Alió JL, Dick HB, et al. Efficacy and safety of multifocal intraocular lenses
ablation profile for presbyopic corneal treatments. Am J Ophthalmol 2015;160(3):493–505. following cataract and refractive lens exchange: Metaanalysis of peer-reviewed publica-
18. Baudu P, Penin F, Mosquera SA. Uncorrected binocular performance after biaspheric tions. J Cart Refract Surg 2016;42:310–28.
ablation profile for presbyopic corneal treatment using AMARIS with the PresbyMAX 54. Alió JL, Grzybowski A, Romaniuk D. Refractive lens exchange in modern practice: when
module. Am J Ophthalmol 2013;155:636–47. and when not to do it? Eye Vis 2014;1:1–13.
19. Reinstein DZ, Cantab MA, Carp GI, et al. LASIK for presbyopia correction in emme- 55. Gooi P, Ahmed IK. Review of presbyopic IOLs: multifocal and accommodating IOLs.
tropic. J Refract Surg 2012;28(8):531–9. Int Ophthalmol Clin 2012;52(2):41–50.
20. Alió JL, Chaubard JJ, Caliz A, et al. Correction of presbyopia by technovision central 56. Lane SS, Morris M, Nordan L, et al. Multifocal intraocular lenses. Ophthalmol Clin
multifocal LASIK (presbyLASIK). J Refract Surg 2006;22(5):453–60. North Am 2006;19:89–105.
21. Alió JL, Amparo F, Ortiz D, et al. Corneal multifocality with excimer laser for presby- 57. Alió JL, Plaza-Puche AB, Javaloy J, et al. Comparison of a new refractive multifocal
opia correction. Curr Opin Ophthalmol 2009;20:264–71. intraocular lens with an inferior segmental near add and a diffractive multifocal intraoc-
22. Saib N, Abrieu-Lacaille M, Berguiga M, et al. Central PresbyLASIK for hyperopia and ular lens. Ophthalmology 2012;119(3):555–63.
presbyopia using micro-monovision with the technolas 217P platform and SUPRACOR 58. Davison JA, Simpson MJ. History and development of the apodized diffractive intraocu-
algorithm. J Refract Surg 2015;31(8):540–6. lar lens. J Cataract Refract Surg 2006;32(5):849–58.
23. Uthoff D, Pölzl M, Hepper D, et al. A new method of cornea modulation with excimer 59. Alió J, Plaza-Puche AB, Javaloy J, et al. Comparison of the visual and intraocular optical
laser for simultaneous correction of presbyopia and ametropia. Graefe’s Arch Clin Exp performance of a refractive multifocal IOL with rotationaly asymmetry and an apodized
Ophthalmol 2012;250(11):1649–61. diffractive multifocal IOL. J Refract Surg 2012;28(2):100–5.
24. Jackson WB, Tuan K-MA, Mintsioulis G. Aspheric wavefront-guided LASIK to 60. Pedrotti E, Bruni E, Bonacci E, et al. Comparative analysis of the clinical outcomes
treat hyperopic presbyopia: 12-month results with the visx platform. J Refract Surg with a monofocal and an extended range of vision intraocular lens. J Refract Surg
2011;27(7):519–29. 2016;32(7):436–42.
25. Luger MH, Ewering T, Arba-Mosquera S. One-year experience in presbyopia correc- 61. McNeely RN, Pazo E, Spence A, et al. Comparison of the visual performance and quality
tion with biaspheric multifocal central presbyopia laser in situ keratomileusis. Cornea of vision with combined symmetrical inferonasal near addition versus inferonasal and
2013;32(0):644–52. superotemporal placement of rotationally asymmetric refractive multifocal intraocular
26. Technique P, Pinelli R, Ortiz D, et al. Correction of presbyopia in hyperopia with a lenses. J Cataract Refract Surg 2016;42:1721–9.
center-distance, paracentral-near technique using the technolas 217z platform. J Refract 62. Kamiya K, Hayashi K, Shimizu K, et al. Multifocal intraocular lens explantation: a case
Surg 2008;24:494–500. series of 50 eyes. Am J Ophthalmol 2014;158:215–220.e1.
27. Epstein RL, Gurgos MA. Presbyopia treatment by monocular peripheral presbyLASIK. J 63. Braga-Mele R, Chang D, Dewey S, et al. Multifocal intraocular lenses: relative indica-
Refract Surg 2009;25:516–23. tions and contraindications for implantation. J Cataract Refract Surg 2014;40:313–22.
28. El Danasoury AM, Gamaly TO, Hantera M. Multizone LASIK with peripheral near zone 64. Alió JL, Plaza-puche AB, Piñero DP. Rotationally asymmetric multifocal IOL implanta-
for correction of presbyopia in myopic and hyperopic eyes: 1-year results. J Refract Surg tion with and without capsular tension ring: refractive and visual outcomes and intraoc-
2009;25:296–305. ular optical performance. J Refract Surg 2012;28(4):253–8.
29a. Barraquer JI. Queratomileusis para la correccion de la miopia. Arch Soc Am Oftalmol 65. Klein BR, Brown EN, Casden RS. Preoperative macular spectral-domain optical coher-
Optom 1964;5:27–48. ence tomography in patients considering advanced-technology intraocular lenses for
29b. Yilmaz O, Bayraktar S, Agca A, et al. Intracorneal inlay for the surgical correction of cataract surgery. J Cart Refract Surg 2016;42(4):537–41.
Presbyopia. J Cataract Refract Surg 2008;34(11):1921–7. 66. Teichman JC, Vold SD, Ahmed IIK. Top 5 pearls for implanting premium IOLs in
30. Barragan GE, Gomez S, Chayet A, et al. One-year safety and efficacy results of a hydro- patients with glaucoma. Int Ophthalmol Clin 2012;52(2):65–71.
gel inlay to improve near vision in patients with emmetropic presbyopia. J Refract Surg 67. Alió JL, Grabner G, Plaza-Puche A, et al. Postoperative bilateral reading perfor-
2013;29(3):166–72. mance with 4 intraocular lens models: six-month results. J Cataract Refract Surg
31. Malandrini A, Martone G, Menabuoni L, et al. Bifocal refractive corneal inlay implan- 2011;37(5):842–52.
tation to improve near vision in emmetropic presbyopic patients. J Cart Refract Surg 68. Ortiz D, Alió JL, Bernabéu G, et al. Optical performance of monofocal and multifocal
2015;41:1962–72. intraocular lenses in the human eye. J Cataract Refract Surg 2008;34(5):755–62.
32. Mulet E, Alió JL, Knorz M. Hydrogel intracorneal inlays for the correction of hyperopia. 69. Song IS, Yoon SY, Kim JY, et al. Influence of near-segment positioning in a rotationally
Ophthalmology 2009;116:1455–60. asymmetric multifocal intraocular lens. J Refract Surg 2016;32(4):238–43.
33. Alió JL, Shabayek M, Robert M-M, et al. Intracorneal hydrogel lenses and corneal aber- 70. Cochener B. Clinical outcomes of a new extended range of vision intraocular lens: Inter-
rations. J Refract Surg 2005;21:247–52. national Multicenter Concerto Study. J Cataract Refract Surg 2016;42:1268–75.
34. Lindstrom RL, Macrae SM, Pepose JS, et al. Corneal inlays for presbyopia correction. 71. Perez-Merino P, Dorronsoro C, Llorente L, et al. In vivo chromatic aberration in eyes
Curr Opin Ophthalmol 2013;24:281–7. implanted with intraocular lenses. Invest Ophthalmol Vis Sci 2013;54:2654–61.
35. Konstantopoulos A, Mehta J. Surgical compensation of presbyopia with corneal inlays. 72. Weeber H, Piers P. Theoretical performance of intraocular lenses correcting both spher-
Expert Rev 2015;12(3):341–52. ical and chromatic aberration. J Refract Surg 2012;28:48–52.
36. Arlt E, Krall E, Moussa S, et al. Implantable inlay devices for presbyopia: the evidence to 73. Bilbao-Calabuig R, Llovet-Osuna F, Gonzàlez-López F, et al. Nd:YAG capsulotomy rates
date. Clin Ophthalmol 2015;9:129–37. with two trifocal intraocular lenses. J Refract Surg 2016;32(11):748–52.
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74. Carballo-Alvarez J, Vazquez-Molini JM, Sanz-Fernandez JC, et al. Visual outcomes after 87. Alió JL, Piñero DP, Plaza-puche AB. Visual outcomes and optical performance with a
3 bilateral trifocal diffractive intraocular lens implantation. BMC Ophthalmol 2015;15:1–6.

75. Kohnen T. First implantation of a diffractive quadrafocal (trifocal) intraocular lens. J
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76. Carson D, Xu Z, Alexander E, et al. Optical bench performance of 3 trifocal intraocular
monofocal intraocular lens and a new-generation single-optic accommodating intraocu-
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88. Alió JL, Plaza-Puche AB, Montalban R, et al. Visual outcomes with a single-optic accom-
modating intraocular lens and a low-addition-power rotational asymmetric multifocal
lenses. J Cart Refract Surg 2016;42(9):1361–7. intraocular lens. J Cataract Refract Surg 2012;38:978–85.
Refractive Surgery
77. Jonker SM, Bauer NJ, Makhotkina NY, et al. Comparison of a trifocal intraocular lens 89. Pérez-Merino P, Birkenfeld J, Dorronsoro C, et al. Aberrometry in patients implanted
with a +3.0 bifocal IOL: results of a prospective randomized clinical trial. J Cataract with accommodative intraocular lenses. Am J Ophthalmol 2014;157:1077–89.
Refract Surg 2015;41:1631–40. 90. Saiki M, Negishi K, Dogru M, et al. Biconvex posterior chamber accommodating intra-
78. Gundersen KG, Potvin R. Comparison of visual outcomes and subjective visual quality ocular lens implantation after cataract surgery: long-term outcomes. J Cataract Refract
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79. Alió JL, Grzybowski A, El Aswad A, et al. Refractive lens exchange. Surv Ophthalmol dative intraocular lens. J Refract Surg 2010;26(11):858–62.
2014;59(6):579–98. 92. Bohórquez V, Alarcon R. Long-term reading performance in patients with bilateral
80. Werner L, Olson RJ, Mamalis N. New technology IOL optics. Ophthalmol Clin North dual-optic accommodating intraocular lenses. J Cataract Refract Surg 2010;36(11):1880–6.
Am 2006;19(4):469–83. 93a. Kohl JC, Werner L, Ford JR, et al. Long-term uveal and capsular biocompatibility of a
81. Beiko G. Status of accommodative intraocular lenses. Curr Opin Ophthalmol new accommodating intraocular lens. J Cataract Refract Surg 2014;40:2113–19.
2007;18:74–9. 93b. ÓhEineachain R. Accommodating Intraocular Lens Study. Eurotimes stories. July 2017.
82. Alió JL, Plaza-Puche AB, Montalban R, et al. Near visual outcomes with single-optic and 94. Alió JL, Ben-nun J, Plaza AB. Visual and accommodative outcomes 1 year after implan-
dual-optic accommodating intraocular lenses. J Cart Refract Surg 2012;38:1568–75. tation of an accommodating intraocular lens based on a new concept. J Cataract Refract
83. Menapace R, Findl O, Kriechbaum K. Accommodating intraocular lenses: a crit- Surg 2009;35:1671–8.
ical review of present and future concepts. Graefe’s Arch Clin Exp Ophthalmol 95. Alió JL, Simonov A, Plaza-Puche AB, et  al. Visual outcomes and accommodative response
2007;245:473–89. of the Lumina accommodative intraocular lens. Am J Ophthalmol 2016;164:37–48.
84. Pepose JS, Burke J, Qazi MA. Benefits and barriers of accommodating intraocular 96. Gil-Cazorla R, Shah S, Naroo SA. A review of the surgical options for the correction of
lenses. Curr Opin Ophthalmol 2017;28(1):3–8. presbyopia. Br J Ophthalmol 2016;100:62–70.
85. Page TP, Whitman J. A stepwise approach for the management of capsular contrac- 97. Krader CG. Closing in on presbyopia. Ophthalmol Times Eur 2016;12(6):15–16.
tion syndrome in hinge-based accommodative intraocular lenses. Clin Ophthalmol 98. Renna A, Vejarano LF, la Cruz ED, et al. Pharmacological treatment of presbyopia by
2016;10:1039–46. novel binocularly instilled eye drops: a pilot study. Ophthalmol Ther 2016;5(1):63–73.
86. Kramer GD, Werner L, Neuhann T, et al. Anterior haptic flexing and in-the-bag sublux- 99. Pharmacological solutions for presbyopes under development. Primary Care Optometry
ation of an accommodating intraocular lens due to excessive capsular bag contraction. J News. 2015.
Cart Refract Surg 2015;41(9):2010–13. 100. Krader CG. Regaining lens elasticity. Ophthalmol Times Eur 2016;12(6):18–20.
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Part 4 Cornea and Ocular Surface Diseases
Section 1 Basic Principles
Corneal Anatomy, Physiology, and

Wound Healing 4.1
Ayad A. Farjo, Matthew V. Brumm, H. Kaz Soong, Christopher T. Hood
Definition: The cornea represents the transparent anterior wall of the Embryology, Anatomy, and Physiology
globe. of the Cornea
Epithelium
The corneal epithelium is derived from surface ectoderm at approximately
5–6 weeks of gestation. It is composed of nonkeratinized, nonsecretory,
Key Features stratified squamous epithelium (Fig. 4.1.1), which is four- to six-cell-layers
• The cornea, including the tear film, is the major refractive surface of thick (40–50 µm). The epithelium is covered with a tear film of 7 µm thick-
the eye. ness, which is optically important in masking microirregularities of the
• It provides structural integrity for the anterior part of the eye. anterior epithelial surface. The tear–air interface, together with the under-
• It is a key barrier against infection. lying cornea, provides roughly two thirds of the total refractive power of
the eye. The mucinous portion of tears, which forms the undercoat of the
tear film and is produced by the conjunctival goblet cells, interacts closely
with the corneal epithelial cell glycocalyx to allow hydrophilic spreading of
INTRODUCTION the tear film with each blink of the eyelid. The tear film also helps protect
the corneal surface from microbial invasion and from chemical, toxic, or
A healthy cornea, together with the overlying tear film, is necessary to foreign body damage. Thus, the ocular surface tear film and the corneal
provide a proper anterior refractive surface and to protect the eye against epithelium share an intimate mutual relationship, both anatomically and
infection and structural damage to the deeper components of the eye. The physiologically.
average adult cornea is 11.5–12 mm1 in horizontal diameter and about Corneal epithelial cells undergo orderly involution, apoptosis, and des-
1 mm smaller in vertical diameter. The anterior refractive power is +43.00 quamation. Complete turnover of corneal epithelial cells occurs in about
to +43.50 diopters (D). The shape of the cornea is prolate, being steeper 7–10 days,2 with the deeper cells eventually replacing the desquamating
centrally and flatter peripherally, which creates an aspherical optical superficial cells in an apically directed fashion. The most superficial cells
system. of the corneal epithelium form an average of two to three layers of flat,
Fig. 4.1.1 Cross-sectional view of the

CROSS-SECTIONAL VIEW OF THE CORNEAL EPITHELIAL CELL LAYER corneal epithelial cell layer.
tear film
glycocalyx layer
apical microvilli
superficial
cells
wing cells
basal cells
basement
membrane hemidesmosomes tight junctions
155
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polygonal cells. Extensive apical microvilli and microplicae characterize the active dendritic macrophages derived from bone marrow and capable
4 cell membranes of the superficial cells, which, in turn, are covered by a

fine, closely apposed, charged glycocalyceal layer. The apical membrane
projections increase the surface area of contact and adherence between the
of antigen processing, are present in the peripheral corneal epithelium
near the limbus. Under certain conditions (e.g., corneal graft rejection or
injury), these cells are found among the central corneal epithelial cells.
tear film’s mucinous undercoat and the cell membrane. Laterally, adjacent Human lymphocyte antigens are expressed by these corneal Langerhans’
Cornea and Ocular Surface Diseases
superficial cells are joined by barrier tight-junctional complexes, which cells. Langerhans’ cells have been detected in the epithelial basal cell layer
restrict entry of tears into the intercellular spaces. Thus a healthy epithelial and in Bowman’s membrane in pathological inflammatory conditions,
surface repels dyes, such as fluorescein and rose bengal. such as Thygeson’s superficial punctate keratitis. After treatment with
Beneath the superficial cell layer are the suprabasal or wing cells, so topical corticosteroids, these cells are no longer detectable by laser confo-
named for their cross-sectional alar shapes. This layer is about two to cal microscopy.7
three cells deep and consists of cells that are less flat than the overlying
superficial cells but possess similar tight, lateral, intercellular junctions. Stroma
Beneath the wing cells are the basal cells, the deepest cellular layer of the In week 7 of gestation, after the establishment of the primitive endothe-
corneal epithelium. The basal cell layer is composed of a single-cell layer of lium, a second wave of neural crest cells forms the early corneal stroma.
columnar epithelium approximately 20 µm tall. Besides the stem cells and Akin to the dermis of the skin, the corneal stroma provides important
transient amplifying cells, basal cells are the only corneal epithelial cells structural integrity and comprises roughly 90% of the corneal thickness.
capable of mitosis.3,4 They are the source of both wing and superficial cells The stroma differs from other collagenous structures in its transparency
and possess lateral intercellular junctions characterized by gap junctions and biomechanical properties. These functional properties result from the
and zonulae adherens. The basal cells are attached to the underlying base- precise organization of stromal fibers and extracellular matrix, and the rel-
ment membrane by an extensive basal hemi-desmosomal system. This atively dehydrated state of the corneal stroma.7–11 The fibers are aligned in
attachment is of pivotal importance in preventing the detachment of the a parallel fashion within each lamella, and arranged at angles relative to
multilayer epithelial sheet from the cornea. Abnormalities in this bonding fibers in adjacent lamellae.12,13 This network reduces forward light scatter
system may result clinically in either recurrent corneal erosion syndromes and contributes to the mechanical strength of the cornea. The peripheral
or in persistent, nonhealing epithelial defects. stroma is thicker than the central stroma and the collagen fibrils may
The basement membrane is composed of an extracellular matrix mate- change direction to run circumferentially as they approach the limbus.13,14
rial secreted by the basal cells. Following destruction of the basement Bowman’s membrane is the acellular condensate of the most anterior
membrane, about 6 weeks are required for it to reconstitute and heal. The portion of the stroma.
epithelial bond to the underlying, newly laid basement membrane tends The stromal collagen fibrils, which provide the major tensile strength to
to be unstable and weak during this period. The epithelium also adheres the cornea, are composed mostly of type I collagen, but require a heterod-
relatively poorly to bare stroma or Bowman’s layer. Under ordinary con- imeric complex with type V collagen to obtain their unique and narrow
ditions, type IV collagen and laminin are the major components of the diameter.15–17 They are surrounded by specialized proteoglycans, consist-
basement membrane; however, fibronectin production increases to high ing of keratan sulfate or chondroitin sulfate/dermatan sulfate side chains,
levels during acute epithelial injury. The basement membrane, approxi- which help regulate hydration and structural properties. Keratocytes, the
mately 0.05 µm in thickness, adheres to the underlying Bowman’s mem- major cell type of the stroma, comprise approximately 10% of the stroma
brane through a poorly understood mechanism that involves the anchoring by volume and are involved in maintaining the extracellular matrix envi-
fibrils and plaques.5 ronment.18,19 More keratocytes are situated in the anterior stroma than in
Epithelial stem cells—undifferentiated pluripotent cells that serve as an the posterior stroma.20 Morphological differences between the anterior and
important source of new corneal epithelium—have been localized to the posterior stromal keratocytes, such as fenestrations, have been identified.21
limbal basal epithelium. As the cells migrate to the central cornea, they Corneal “crystallins,” representing 25%–30% of soluble protein in kerato-
differentiate into transient amplifying cells (cells capable of multiple but cytes, appear to be responsible for reducing backscatter of light from the
limited cellular division) and basal cells. The corneal epithelial cell layer keratocytes and maintaining corneal transparency.22
mass appears to be the complex resultant of three phenomena. According Dua et al. have proposed unique biomechanical properties of the most
to the “X, Y, Z hypothesis,” X is the proliferation of basal epithelial cells, posterior 6–15 microns of the stroma (pre-Descemet’s layer [PDL]23,24).
Y is the centripetal mass movement of peripheral epithelial cells, and Z These five to eight lamellae of compact collagen appear distinct on electron
is the cell loss resulting from death and desquamation.6 These three phe- microscopy and may be of relevance as a plane of cleavage in keratoplasty.
nomena probably are not totally independent of each other but, rather, are The electron microscopic details of this membrane were first illustrated in
controlled by a complex interactive feedback mechanism that maintains 1972 by Fine and Yanoff.25
the status quo, vis-à-vis cell density, cell distribution and polarity, and cell Corneal shape and curvature are governed by the intrinsic biome-
layer thickness. These cytodynamics are likely to be responsible for the chanical structure and extrinsic environment (Fig. 4.1.3). Anterior corneal
striking verticillate (vortex or whorl-like) biochemical deposition patterns stromal rigidity in particular appears to be important in maintaining the
seen in Fabry’s disease (Fig. 4.1.2) and drug deposition keratopathies (e.g., corneal curvature.26 Organizational differences in the collagen bundles of
from chloroquine and amiodarone). Langerhans’ cells, immunologically the anterior stroma may contribute to a tighter cohesive strength in this
MAJOR CORNEAL LOADING FORCES IN THE STEADY-STATE
epithelial
barrier
swelling lamellar
pressure tension
intralamellar
cohesive
forces intraocular
endothelial pressure endothelial
pump barrier
156 Fig. 4.1.2 Whorl-like deposition keratopathy in corneal epithelium seen in Fabry’s Fig. 4.1.3 Major corneal loading forces in the steady state. (Illustration courtesy
disease. William J. Dupps, MD, PhD.)
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area and may explain why the anterior curvature resists change to stromal Descemet’s membrane throughout life, beginning in utero at the week
hydration much more compared with the posterior stroma, which tends to
develop folds more easily. Corneal nerves and sensation are derived from
8 stage. The anterior portion of Descemet’s membrane formed in utero
has a distinctive banded appearance when viewed by electron microscopy, 4.1
the nasociliary branch of the first (ophthalmic) division of the trigeminal but Descemet’s membrane produced after birth is unbanded and has an
nerve. In the superficial cornea, the nerves enter the stroma radially in amorphous ultrastructural texture. This membrane is approximately 3 µm
Corneal Anatomy, Physiology, and Wound Healing

thick trunks forming plexiform arrangements, which eventually perforate thick at birth, but thickens to 10 µm with age. Endothelial cell density and
Bowman’s membrane to provide a rich plexus beneath the basal epithe- topography continue to change throughout life. From the second to eighth
lial layer.27 The fibers appear to directly communicate with keratocytes and decades of life, the cell density declines from approximately 3000–4000
epithelial cells28 and may play an important role in corneal homeostasis. cells/mm2 to around 2600 cells/mm2, and the percentage of hexagonal
cells declines from about 75% to around 60%.35 The central endothelial cell
Endothelium density decreases at an average rate of 0.3% per year in normal corneas.36
In early embryogenesis, the posterior cornea is lined with a neural As a result of endothelial activity, the stroma is maintained in a rel-
crest-derived29 monolayer of orderly arranged cuboidal cells.30 By the atively deturgesced state (78% water content).37 One hypothesis is that
78-mm stage, the cells become flattened and tightly abut one another. At this endothelial activity is mediated by a pump–leak process; net fluid
this stage, immediately anterior to the flattened layer is a discontinuous, egress from the corneal stroma follows movement down an osmotic gra-
homogeneous acellular layer, which in time becomes Descemet’s mem- dient from a relatively hypo-osmotic stroma toward a relatively hypertonic
brane.31 By the 120-mm and 165-mm stages of development, the endothe- aqueous humor. This passive bulk fluid movement requires no energy.
lial monolayer is uniform in thickness, spans the entire posterior corneal The energy-requiring processes are the intracellular and membrane-bound
surface, and fuses with the cells of the trabecular meshwork.31 Similarly, ion transport systems, which generate the osmotic gradient. The two most
Descemet’s membrane becomes continuous and uniform, fusing periph- important ion transport systems are the membrane-bound Na+, K+-ATPase
erally with the trabecular beams.31 The fusion site, known as Schwalbe’s sites and the intracellular carbonic anhydrase pathway.38 Activity in both
line, is a gonioscopic landmark that defines the end of Descemet’s mem- these pathways produces a net flux from stroma to aqueous humor. The
brane and the start of the trabecular meshwork. At birth, the endothelium barrier portion of the endothelium is unique in that it is permeable to
is approximately 10 µm thick.32 some degree, permitting the ion flux necessary to establish the osmotic
The intact human endothelium is a monolayer, which appears as a gradient.31,33
honeycomb-like mosaic when viewed “en face” (Fig. 4.1.4). The individual Little in vivo mitotic potential exists within the normal endothelium
cells continue to flatten over time and stabilize at about 4 µm in thickness in but may come into play in pathological situations. Although the exact
adulthood (Fig. 4.1.5).33 The posterior surface of the endothelium is devoid minimum number of cells per millimeter squared required to maintain
of villi, except in certain pathological conditions, in which it may develop corneal deturgescence is not known, corneas with central cell counts below
epithelioid characteristics. Adjacent cells share extensive lateral interdig- 500 cells/mm2 may be at risk for development of corneal edema. Endothe-
itations and possess gap and tight junctions along their lateral borders. lial cell morphology (size and shape) appears to correlate with pump func-
The lateral membranes contain a high density of sodium (Na+), potassium tion. An increase in cell size (polymegathism) and an increase in variation
(K+)–adenosine triphosphatase (ATPase) pump sites.34 The basal surface of cell shape (pleomorphism) correlate to reduced ability of the endothelial
of the endothelium contains numerous hemi-desmosomes that promote cells to deturgesce the cornea.39,40
adhesion to Descemet’s membrane. Endothelial cells contain numerous In vivo assessment of endothelial function relies on measurements of
mitochondria and a prominent Golgi apparatus, and continuously secrete corneal thickness or on clinical morphological studies of the endothelial
monolayer with specular microscopy. Measurement of the corneal thick-
ness (pachymetry) indirectly reflects endothelial function. The average
central corneal thickness is around 0.5 mm and gradually increases toward
the periphery to around 0.7 mm. Normally, as a diurnal variation, corneas
tend to be slightly thicker just after the person awakes in the morning.
This increase in thickness is the consequence of diminished evaporation
of water from underneath the closed eyelids, and the result of reduced noc-
turnal metabolic activity of the endothelium. Such overnight corneal swell-
ing is more exaggerated in persons with unhealthy endothelium, causing
blurred vision in the morning, but it gradually resolves later during the
day.
Endothelial Responses to Stress

Fig. 4.1.4 Specular Photomicrograph of Normal Endothelium. Note the dark, Mild endothelial stress may result in cell size and shape changes, whereas
well-defined cell borders, the regular hexagonal array, and the uniform cell size. (Bar greater stress may result in cell loss as well as irreversible alterations in
≡ 50 µm.) the endothelial cytoskeleton.41 Sources of stress may include metabolic
disorders (hypoxia or hyperglycemia), toxins (drugs or their preserva-
tives), injury (trauma or surgery), or alterations in pH or osmolarity. For
Bowman's epithelium example, contact lenses cause a hypoxic stress of varying degree to the
membrane endothelium.42 Over time, this may result in alteration of the morphology,
microanatomy, and possibly the function of the endothelium.43,44 Hypergly-
cemia is another common metabolic stress that may produce changes in
the endothelium. When compared with age-matched controls, the corneal
endothelium in patients with type 1 and type 2 diabetes has a lower mean
cell density and greater pleomorphism and polymegathism.45,46
Tissue manipulation, fluid flow in the anterior chamber, and intracam-
eral pharmacological agents introduced during anterior segment surgery
may cause damage to the endothelium.47,48 Ophthalmic viscoelastic mate-
rials (composed of hydroxypropyl methylcellulose, chondroitin sulfate, or
Descemet's sodium hyaluronate) provide significant protection against intraoperative
endothelium membrane
trauma to the endothelium.49,50
Glaucoma has been associated with endothelial cell loss. Compared
with age-matched controls, significantly lower endothelial cell counts were
noted in patients with glaucoma and ocular hypertension in one study.51
Cell counts were inversely proportional to the mean intraocular pressure
Fig. 4.1.5 Light Micrograph of Normal Endothelium (×100). Note the single-cell in the glaucoma and ocular hypertension groups. Mechanisms of cell loss
endothelial layer with a Descemet’s membrane of uniform thickness (epithelial may include direct damage from intraocular pressure, congenital alter- 157
surface at top of figure). (Courtesy Dr David Barsky.) ations of endothelium in glaucoma, and drug toxicity.52
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4
Fig. 4.1.7 Recurrent Erosion in a Diabetic Cornea. Note the abnormally

thick basement membrane (asterisk) and the intralamellar split within (arrow)
Fig. 4.1.6 Light Micrograph That Shows the Leading Edge of Migrating Rat (hematoxylin & eosin).
Corneal Epithelium as It Tapers to a Layer of One-Cell Thickness. As the
epithelial defect is rapidly covered by migrating cells, it is initially coated with a thin,
rarefied cell population prior to onset of mitotic activity (hematoxylin & eosin).
or dystrophies), ocular surface inflammation or atopic disease, medica-
mentosa, dry eyes, neurotrophic and exposure keratopathies, conjunctival
disease (e.g., mucous membrane pemphigoid, radiation keratoconjunctivi-
CORNEAL WOUND HEALING tis, and Stevens–Johnson syndrome), extensive damage to the limbal stem
Epithelial Injury cells, and eyelid abnormalities.
In neurotrophic corneas, it is possible that interruption of corneal
Within minutes after a small corneal epithelial wound, cells at the edge of innervation results in depletion of growth factors and substance P, a neu-
the abrasion begin to cover the defect as rapidly as possible by a combina- rogenic chemical known to regulate corneal physiological functions.59
tion of cell migration and cell spreading. A longer delay of up to 4–5 hours Diabetic corneas may manifest as abnormally thickened and easily delam-
is seen in larger defects. This lag phase is necessary for the preparatory inated basement membranes (Fig. 4.1.7), perhaps akin to basement mem-
cellular changes of an anatomical, physiological, and biochemical nature to brane abnormalities elsewhere, as in the ciliary epithelium and the renal
occur before rapid cell movement. Various cell membrane extensions, such glomeruli.52 A combination of pharmacological interruption of corneal
as lamellipodia, filopodia, and ruffles, develop at the leading edge of the nerve function and damage to the epithelial cells and substrate may cause
wound. Anchoring hemi-desmosomes disappear from the basal cells. This persistent epithelial defects associated with topical anesthetic abuse.60,61
early nonmitotic wound coverage phase is remarkable for its speed; the Evidence also implicates matrix metalloprotease-9 (gelatinase B) as a factor
cells have been measured to migrate at a rate of 60–80 µm/h (Fig. 4.1.6).53 that may impact epithelial healing and/or desquamation.62,63
The migrating sheet of epithelial cells is attached most firmly to the under-
lying substrate at the leading margin. The relatively firmer adhesion at Stromal Injury
the leading margin suggests that the epithelial sheet movement may have
“front-wheel drive,” with the less well-anchored cells behind the leading Similar to skin, stromal wound healing consists of repair, regeneration,
margin being pulled forward, possibly by intracellular contractile mech- and remodeling,15 involving a complex interplay of cytokines, growth
anisms that involve actin.54 Fibronectin, a ubiquitous extracellular matrix factors, and chemokines.64 Importantly, stromal repair differs from der-
protein present in plasma and in fresh wounds, is thought to be one of the matological healing in that it occurs avascularly and ideally maintains
key elements in the mediation of cell-to-substrate adhesion and cell migra- corneal clarity. The reparative cascade begins with activation of stromal
tion. Present on the extracellular side of adhesion plaques, it is thought to keratocytes (Fig. 4.1.8), which enlarge in size within the first 6 hours after
mediate the linkage between the vinculin–talin–integrin complex and the injury and migrate into the injured area within 24 hours, becoming more
substrate during epithelial migration after a wound has occurred. Laminin, fibroblast-like in appearance and behavior.65 Activation of the keratocytes
a less ubiquitous extracellular matrix protein, is thought to serve a similar may be triggered by epithelial factors,65 and regeneration of a fully func-
function. tional epithelial basement membrane appears to have a critical role in the
At 24–30 hours after medium-sized epithelial injuries, mitosis or cell maintenance of corneal stromal transparency after mild injuries and recov-
proliferation begins and restores the rarefied epithelial cell population. ery of transparency when opacity is generated after severe injuries.67 The
After large epithelial injuries, significant increases in cellular division reparative cascade that follows typically results in corneal opacity in the
occur as late as 96 hours.55 Only the basal cells, transient amplifying cells, affected area. The keratocytes within the area of injury undergo apopto-
and the limbal stem cells partake in this reconstitutive mitosis.3,4 The sis, peaking 4 hours after the initial insult.66 Apoptosis appears to modu-
corneal epithelial stem cells, which reside at the limbus in the Pallisades late the wound healing response by influencing the activation of adjacent
of Vogt, cannot be regenerated after injury.56,57 Limbal stem cell deficiency keratocytes.
is an increasingly recognized cause of nonhealing epithelial defects. The Within 1–2 weeks, myofibroblasts with contractile properties enter
extracellular matrix, in addition to other environmental signals, such as the area under the epithelium and become involved in the remodeling
cytokines and growth factors, likely plays a central role in regulating epi- of the stroma, with increased expression of matrix metalloproteases.15,68
thelial stem cell commitment, corneal differentiation, and participation in These cells may be responsible for the “haze” seen after corneal injury
corneal wound healing.58 In laboratory and clinical trials, agents known to or surgery.70 The remodeling process sometimes can continue over a pro-
influence epithelial migration, mitosis, apoptosis, adhesion, and differenti- longed period of several years and may eventually restore corneal clarity in
ation have been studied as possible therapeutic agents to enhance corneal the affected area. Certain corneal surgeries, such as laser in situ keratomil-
epithelial healing, including growth factors, fibronectin, and retinoids. eusis, may cause a progressive loss of keratocytes over time through an as
Primarily mitogenic agents and growth factors also stimulate production yet unclear mechanism.69
of extracellular matrix components to enhance cell-to-substrate adhesion.
Bowman’s layer does not regenerate following injury. Endothelial Injury
Various pathological conditions may delay or prevent the normal
corneal epithelial healing process. These include the following: damage Nonperforating puncture injuries of the anterior cornea that do not
158 to the cellular substrate (caused by herpetic or other infectious disease, directly involve the endothelium (e.g., those that occur when the cornea
diabetes mellitus, chemical burns, or basement membrane injuries and/ is struck by small, high-velocity particles) may cause concentric lesions of
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may even be torn or ruptured, as in forceps delivery injuries and in corneal
hydrops in keratoconus. When injured, Descemet’s membrane curls in
toward the stroma and surrounding endothelial cells slide in to cover the 4.1
defect and produce new Descemet’s membrane.72 Although normal endo-
thelium does not appear to replicate in vivo, recent evidence suggests that

endothelial cells retain a degree of latent proliferative potential even into
adulthood.71 Recently, rho-kinase inhibitors have demonstrated potential in
treating endothelial damage, with evidence of accelerated endothelial cell
spread in rabbit models and clearing of corneal edema in small human
trials.73
KEY REFERENCES
Bonanno JA. Molecular mechanisms underlying the corneal endothelial pump. Exp Eye Res
2012;95:2–7.
Fini ME, Stramer BM. How the cornea heals: cornea-specific repair mechanisms affecting
surgical outcomes. Cornea 2005;24:S2–11.
Kawamoto K, Chikama T, Takahashi N, et al. In vivo observation of Langerhans cells
by laser confocal microscopy in Thygeson’s superficical punctate keratitis. Mol Vis
2009;15:1456–62.
Maurice DM. The structure and transparency of the corneal stroma. J Physiol 1957;136:263–86.
Netto MV, Mohan RR, Ambrosio R Jr, et al. Wound healing in the cornea: a review of refrac-
tive surgery complications and new prospects for therapy. Cornea 2005;24:509–22.
Oliveira-Soto L, Efron N. Morphology of corneal nerves using confocal microscopy. Cornea
Fig. 4.1.8 Transmission electron micrograph of the corneal stroma. Activated 2001;20:374–84.
keratocytes with dilated endoplasmic reticulum (inset: black arrow) and prominent Pflugfelder SC, Farley W, Luo L, et al. Matrix metalloproteinase-9 knockout confers resis-
tance to corneal epithelial barrier disruption in experimental dry eye. Am J Pathol
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2005;166:61–71.
border of the micrograph. A normal keratocyte (asterisk), noticeably smaller than Qazi Y, Wong G, Monson B, et al. Corneal transparency: genesis, maintenance and dysfuc-
the activated cells, is visible above the scale bar. (Bar ≡ 5.0 µm.) (Reproduced with tion. Brain Res Bull 2010;81:198–210.
permission from Ohno K, Mitooka K, Nelson LR, et al. Keratocyte activation and Rao SK, Ranjan Sen P, Fogla R, et al. Corneal endothelial cell density and morphology in
apoptosis in transplanted human corneas in a xenograft model. Invest Ophthalmol normal Indian eyes. Cornea 2000;19:820–3.
Vis Sci 2002;43:1025–31.) Soong HK. Vinculin in focal cell-to-substrate attachments of spreading corneal epithelial
cells. Arch Ophthalmol 1987;105:1129–32.
Stiemke MM, Edelhauser HF, Geroski DH. The developing corneal endothelium: cor-
relation of morphology, hydration and Na/K ATPase pump site density. Curr Eye Res
1991;10:145–56.
the endothelium arising from rapid focal distortion of the cell layer. Buck- Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthal-
ling of the endothelial layer also can result from excessive corneal bending mol Vis Sci 1983;24:1442–3.
in large-incision surgeries and/or from lens fragments striking the endo- Van den Bruel A, Gailly J, Devriese S, et al. The protective effect of ophthalmic viscoelastic
devices on endothelial cell loss during cataract surgery: a meta-analysis using mixed
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lesions, clinically seen as serpentine, grayish lines on the endothelium. Yee RW, Matsuda M, Schultz RO, et al. Changes in the normal corneal endothelial cellular
The damaged cells are rapidly replaced by enlargement of the surrounding pattern as a function of age. Curr Eye Res 1985;4:671–7.
cells and their centripetal migration into the injured region. Clinically, by
slit-lamp biomicroscopy, these endothelial lesions disappear 1–3 days after Access the complete reference list online at ExpertConsult.com
injury. With more severe trauma, the underlying Descemet’s membrane
159
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17. Birk DE. Type V collagen: heterotypic type I/V collagen interactions in the regulation of 55. Arey LB, Cavode WM. The method of repair in epithelial wounds of the cornea. Anat Rec
fibril assembly. Micron 2001;32:223–37. 1943;86:75–82.
18. Hahnel C, Somodi S, Weiss DG, et al. The keratocyte network of human cornea: a 56. Castro-Muñozledo F. Review: corneal epithelial stem cells, their niche and wound
three-dimensional study using confocal laser scanning fluorescence microscopy. Cornea healing. Mol Vis 2013;19:1600–13.
2000;19(2):185–93. 57. Joe AW, Yeung SN. Concise review: identifying limbal stem cells: classical concepts and
19. Hassell JR, Birk DE. The molecular basis of corneal transparency. Exp Eye Res new challenges. Stem Cells Transl Med 2014;3(3):318–22.
2010;91:326–35. 58. Castro-Muñozledo F. Review: corneal epithelial stem cells, their niche and wound
20. Zheng T, Le Q, Hong J, et al. Comparison of human corneal cell density by age and healing. Mol Vis 2013;19:1600–13.
corneal location: an in vivo confocal microscopy study. BMC Ophthalmol 2016;16:109. 59. Kingsley RE, Marfurt CF. Topical substance P and corneal epithelial wound closure in
21. Ojeda JL, Ventosa JA, Piedra S. The three-dimensional microanatomy of the rabbit and the rabbit. Invest Ophthalmol Vis Sci 1997;38:388–95.
human cornea. A chemical and mechanical microdissection – SEM approach. J Anat 60. Yagci A, Bozkurt B, Egrilmez S, et al. Topical anesthetic abuse keratopathy: a commonly
2001;199:567–76. overlooked health care problem. Cornea 2011;30:571–5.
22. Ren S, Liu T, Jia C, et al. Physiological expression of lens α-, β-, and γ-crystallins in 61. Dass B, Soong HK, Lee B. Effects of proparacaine on actin cytoskeleton of corneal epithe-
murine and human corneas. Mol Vis 2010;16:2745–52. lium. J Ocul Pharmacol 1988;4:187–94.
23. Dua HS, Said DG. Clinical evidence of the pre-Descemets layer (Dua’s layer) in corneal 62. Sivak JM, West-Mays JA, Yee A, et al. Transcription factors Pax6 and AP-2alpha interact
pathology. Eye (Lond) 2016;30(8):1144–5. to coordinate corneal epithelial repair by controlling expression of matrix metalloprotein-
24. Dua HS, Faraj LA, Said DG, et al. Human corneal anatomy redefined: a novel pre-De- ase gelatinase B. Mol Cell Biol 2004;24:245–57.
scemet’s layer (Dua’s layer). Ophthalmology 2013;120(9):1778–85. 63. Pflugfelder SC, Farley W, Luo L, et al. Matrix metalloproteinase-9 knockout confers
25. Fine BS, Yanoff M. Ocular histology. A text and atlas. New York: Harper & Row Publish- resistance to corneal epithelial barrier disruption in experimental dry eye. Am J Pathol
ers; 1972. p. 154–5. 2005;166:61–71.
26. Muller LJ, Pels E, Vrensen GFJM. The specific architecture of the anterior stroma 64. Netto MV, Mohan RR, Ambrosio R Jr, et al. Wound healing in the cornea: a review of
accounts for maintenance of corneal curvature. Br J Ophthalmol 2001;85:437–43. refractive surgery complications and new prospects for therapy. Cornea 2005;24:509–22.
27. Oliveira-Soto L, Efron N. Morphology of corneal nerves using confocal microscopy. 65. Stramer BM, Zieske JD, Jung JC, et al. Molecular mechanisms controlling the fibrotic
Cornea 2001;20:374–84. repair phenotype in cornea: implications for surgical outcomes. Invest Ophthalmol Vis
28. Muller LJ, Pels L, Vrensen GF. Ultrastructural organization of human corneal nerves. Sci 2003;44:4237–46.
Invest Ophthalmol Vis Sci 1996;37:476–88. 66. Wilson SE, He YG, Weng J, et al. Epithelial injury induces keratocyte apoptosis: hypoth-
29. Beebe DC, Coats JM. The lens organizes the anterior segment: specification of neural esized role for the interleukin-1 system in the modulation of corneal tissue organization
crest cell differentiation in the avian eye. Dev Biol 2000;220:424–31. and wound healing. Exp Eye Res 1996;62:325–7.
30. Sevel D, Isaacs R. A reevaluation of corneal development. Trans Am Ophthalmol Soc 67. Torricelli AA, Singh V, Santhiago MR, et al. The corneal epithelial basement membrane:
1988;136:178–207. structure, function, and disease. Invest Ophthalmol Vis Sci 2013;54(9):6390–400.
31. Watsky MA, McDermott ML, Edelhauser HF. In vitro corneal endothelial permeabil- 68. Mohan RR, Hutcheon AE, Choi R, et al. Apoptosis, necrosis, proliferation, and myofibro-
ity in rabbit and human: the effects of age, cataract surgery and diabetes. Exp Eye Res blast generation in the stroma following LASIK and PRK. Exp Eye Res 2003;76:71–87.
1989;49:751–67. 69. Erie JC, McLaren JW, Hodge DO, et al. Long-term corneal keratoctye deficits after pho-
32. Nuijts RMMA. Ocular toxicity of intraoperatively used drugs and solutions. New Amster- torefractive keratectomy and laser in situ keratomileusis. Trans Am Ophthalmol Soc
dam: Kugler Publications; 1995. 2005;103:56–66, discussion 67–8.
33. Joyce NC. Proliferative capacity of corneal endothelial cells. Exp Eye Res 2012;95:16–23. 70. Torricelli AA, Santhanam A, Wu J, et al. The corneal fibrosis response to epithelial-stro-
34. Stiemke MM, Edelhauser HF, Geroski DH. The developing corneal endothelium: cor- mal injury. Exp Eye Res 2016;142:110–18.
relation of morphology, hydration and Na/K ATPase pump site density. Curr Eye Res 71. Konomi K, Zhu C, Harris D, et al. Comparison of the proliferative capacity of human
1991;10:145–56. corneal endothelial cells from the central and peripheral areas. Invest Ophthalmol Vis
35. Yee RW, Matsuda M, Schultz RO, et al. Changes in the normal corneal endothelial cellu- Sci 2005;46:4086–91.
lar pattern as a function of age. Curr Eye Res 1985;4:671–7. 72. Choi SO, Jeon HS, Hyon JY, et al. Recovery of Corneal Endothelial Cells from Periphery
36. Rao SK, Ranjan Sen P, Fogla R, et al. Corneal endothelial cell density and morphology in after Injury. PLoS ONE 2015;10(9):e0138076.
normal Indian eyes. Cornea 2000;19:820–3. 73. Okumura N, Inoue R, Okazaki Y, et al. Effect of the Rho Kinase Inhibitor Y-27632 on
37. Bonanno JA. Molecular mechanisms underlying the corneal endothelial pump. Exp Eye corneal endothelial wound healing. Invest Ophthalmol Vis Sci 2016;57:1284–92.
Res 2012;95:2–7.
38. Riley M. Transport of ions and metabolites across the corneal endothelium. In: McDevitt
D, editor. Cell biology of the eye. New York: Academic Press; 1982. p. 53–95.
159.e1
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Section 1 Basic Principles
Anterior Segment Imaging Modalities

Anam Akhlaq, Paula Kataguiri, Ricardo Nosé, Nicolas J. Pondelis, Pedram Hamrah 4.2
coherence tomography (AS-OCT), for example, can be used to visualize
Definition: Anterior segment (AS) imaging allows topographic, anatomical structures anterior to the iris, and the structures behind the
anatomical, and cellular visualization of ocular tissues. iris are best seen with ultrasound biomicroscopy (UBM). In vivo confocal
microscopy (IVCM) provides layer-by-layer images of the entire cornea at
a cellular level, whereas specular microscopy can best assess the corneal
endothelium. Corneal topography and wavefront imaging can visualize
topography-related abnormalities. Finally, meibography demonstrates
Key Features meibomian gland (MG) abnormalities that are difficult to discern with
• Anterior segment optical coherence tomography is essential in pre- slit-lamp biomicroscopy. The detailed principles, functions, and clinical
and postoperative evaluation for lamellar corneal transplantations, applications of AS imaging modalities are discussed below.
refractive surgery, and ectasia-related disorders. It may be utilized for
the diagnosis and management of ocular surface neoplasia.
• Ultrasound biomicroscopy is a valuable tool for the assessment of ANTERIOR SEGMENT OPTICAL
anterior segment tumors and corneal opacities.
• Specular microscopy is useful in evaluation of the corneal COHERENCE TOMOGRAPHY
endothelium, in Fuchs’ endothelial corneal dystrophy and for AS-OCT is a noninvasive, noncontact imaging device that allows
preoperative planning of anterior segment surgery. cross-sectional, anatomical imaging of the eye,1 with the use of an interfer-
• In vivo confocal microscopy has a high sensitivity and specificity for ence pattern of reflected light,2–4 and relies on images reconstructed from
detection of Acanthamoeba and fungal keratitis. It can be utilized cross-sectional scans (A-scans). Since the advent of original time domain
in the evaluation of corneal nerve and inflammatory changes in the (TD) OCT, the technology has rapidly evolved with the development of the
cornea for dry eye disease, neuropathic corneal pain, neurotrophic higher resolution Fourier domain (FD-OCT) (5-µm FD-OCT versus 18-µm
keratopathy, and related conditions. It also has utility in visualization TD-OCT resolution), and faster speed of A-scans (26,000 scans/sec FD-OCT
of Demodex mites in the eyelids. versus 2,000 scans/sec TD-OCT), resulting in fewer motion artifacts and
• Topography and wavefront imaging are critical in the evaluation the capability to obtain three-dimensional images of ocular tissues. The
and management of refractive surgery, cataract surgery, corneal more recent spectral domain (SD, 5 µm) and swept-source (SS, up to
transplantations, astigmatism, and corneal ectasia. 2.6 µm) OCTs provide even higher-resolution images (SD, 5 µm and SS,
• Meibography can be used to assess structural abnormalities of up to 2.6 µm) and higher speed of A-scans (about 50,000 scans/sec SD-OCT
meibomian glands in dry eye disease and related disorders. versus 100,000 scans/sec SS-OCT).3 Although TD AS-OCT has deeper pen-
etration due to longer wavelength, the SD-OCT and SS-OCT have better
signal-to-noise ratio and allow for more structural detail.5 A comparison
summary of the types of AS-OCT devices is provided in Table 4.2.1.
INTRODUCTION Application of the “en face” technique provides a layer-by-layer horizon-
tal sectioning of the tissue. These sections allow for identification of micro-
Advances in anterior segment (AS) imaging over the past decade have rev- structural information throughout the scanned area that is not available
olutionized clinical care by allowing topographical, anatomical, and cellu- with standard AS-OCT scans. Moreover, AS-OCT angiography (OCTA),
lar visualization of tissues. The choice of imaging modalities used depends which has recently been described, allows for visualization and quantifica-
on the tissue to be visualized and the suspected pathology. AS optical tion of vessel density in the cornea, iris, and sclera (Fig. 4.2.1).6
TABLE 4.2.1 Anterior Segment Optical Coherence Tomography (OCT) Operating Systems
Fourier-Domain OCT FD-OCT)

Types Time-Domain OCT (TD-OCT) Spectral-Domain OCT (SD-OCT) Swept-Source OCT (SS-OCT)
Subtypes/ Heidelberg Slit- Plex Elite
Examples Visante Lamp OCT RTVue iVue Avanti XR Cirrus Spectralis Envisu_C Class 3D-OCT Casia Triton 9000
Manufacturer Carl Zeiss Heidelberg Optovue Optovue Optovue Carl Zeiss Heidelberg Bioptigen, Topcon Tomey, Topcon Carl Zeiss
Meditec, Engineering, Inc., Inc., Inc., Meditec, Engineering Bioptigen Medical Nagoya, Medical Meditec,
Dublin, Heidelberg, Fremont, Fremont, Fremont, Dublin, Inc., Research Systems, Japan Systems, Dublin,
CA Germany CA CA CA CA Triangle Park, Oakland, Oakland, CA
NC NJ NJ
Light source Beam Broadband light sources (Spectrometer) Swept-source laser
Wavelength (nm) 1310 1310 840 840 840 840 820 1310 850 1310 1050 1060
Depth (mm) 6 7 2–2.3 2–2.3 3 2 1.9 1.6–2.4 3–6 6 12 3
Resolution 18 × 60 25 × 20-100 5 × 15 5 × 15 3-5 × 15-25 5 × 15 3.9 × 14 2.4-7.5 6 × 20 10 × 30 2.6 × 20 5.5 × 20
(µm) (axial ×
transverse)
Imaging speed 2,000 200 26,000 26,000 70,000 27,000- 40,000 32,000 50,000 30,000 100,000 100,000
(A-scans/sec) 68,000
160 Image size (mm) 6 × 16 15 × 7 13 × 9 13 × 9 12 × 9 - - 20 × 2.5 12 × 9 16 × 16 16 × 16 12 × 12
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4.2

A B
Fig. 4.2.1 (A) Optical coherence tomography angiography (OCTA) image showing vessels in the cornea (arrow). (B) En face OCT image showing corneal neovascularization
(arrow).
Tear Film Height
Tear Film Depth
A B
Tear meniscus Area
C Fig. 4.2.2 Anterior segment optical coherence tomography

(AS-OCT) showing tear film height, depth, and area.
Clinical Applications risk-assessment, and diagnosis of patients with ectasia-related disorders

by assessment of area and range of thinning (see Fig. 4.2.3B).1,8 Postop-
Tear Film Evaluation erative AS-OCT can further be used to monitor complications, such as
Tear meniscus height, depth, area, radius of curvature, and volume can be interface fluid or haze, and flap dislocation.1 Patients with prior refractive
measured using AS-OCT (Fig. 4.2.2).1 Thus, AS-OCT is a valuable nonin- correction, who require cataract surgery may benefit from additional data
vasive tool for the evaluation of the tear film abnormalities. obtained using AS-OCT for the latest biometry formulas to improve sur-
gical outcomes.1
Refractive Surgery and Ectasia-Related Disorders
AS-OCT scans of the healthy corneas show corneal layers as seen in Fig.
4.2.3, A, and allow for the evaluation of flap thickness and stromal bed Penetrating and Endothelial
after refractive surgery.1 Thus AS-OCT measurements of preoperative Keratoplasty–Related Procedures
corneal thickness and postoperative residual stroma thickness may help AS-OCT can provide valuable information both intraoperatively and
in risk stratification of patients by an ectasia scoring system.1,7 Simi- postoperatively for penetrating corneal grafts and endothelial kerato- 161
larly, corneal thinning can be measured by using AS-OCT for screening, plasty detachment. Endothelial grafts can be visualized on AS-OCT for
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4 EPITHELIUM
BOWMAN'S LAYER
STROMA
DESCEMET'S
MEMBRANE
B A
B
D
Fig. 4.2.4 Anterior segment optical coherence tomography (AS-OCT) showing
Fig. 4.2.3 An anterior segment optical coherence tomography (AS-OCT) image (A) conjunctival tumor extending to the corneal epithelium; the lesion is seen as
of (A) normal cornea; (B) keratoconus, seen as central corneal thinning, identified hyperreflective epithelium; (B) conjunctival nevus; lesion shows cystic spaces on
with markings; (C) endothelial corneal graft, shown with yellow arrow; and AS-OCT.
(D) corneal keratoprosthesis; arrows show posterior side of the front plate of
the keratoprosthesis.
anatomic relationship to surrounding structures can be assessed further by
using AS-OCT (Fig. 4.2.4).8,11 AS-OCT can complement UBM in imaging
orientation, position and interface fluid intraoperatively, and for detach- and is superior to UBM for imaging ocular surface tumors.11,12 For example,
ment postoperatively using warning signs, such as interface fluid and poor squamous cell neoplasia presents as a localized area of hyperreflective
margins.9,10 Intraoperative AS-OCT can assess dissection depth in deep thickened epithelium with an abrupt transition between the normal and
anterior lamellar keratoplasty (DALK) and identify graft orientation and thickened area; a lymphoma manifests as a hyporeflective, homogeneous
the need for repositioning for Descemet’s membrane endothelial kera- subepithelial mass; a melanoma presents as a hyperreflective subepithelial
toplasty (DMEK) and Descemet’s membrane stripping automated endo- mass; and nevi present with cysts in a subepithelial mass.11,12
thelial keratoplasty (DSAEK).10 Postoperative graft adherence/detachment
status in DMAEK and DSAEK also may be seen (Fig. 4.2.3C).1,9 Moreover, Cataract Surgery and Intraocular Lens Implantation
keratoprosthesis (KPro) offers a useful alterative for patients with severe Pre- and postoperative AS-OCT imaging helps assess the anterior chamber
corneal pathology, (Fig. 4.2.3D), identifying corneal thinning and melting (AC) in evaluation of phakic intraocular lenses.1 Preoperative AS-OCT
under the front plate.9 can determine the AC angle, width, and lens rise, whereas postopera-
tive AS-OCT can evaluate surgical wounds and assess for complications,
Ocular Surface Tumors including angle-closure glaucoma and corneal decompensation.1 Further,
162 Although conjunctival and corneal tumors can be observed clinically by as detailed above, AS-OCT may aid in biometry in patients who have pre-
using slit-lamp biomicroscopy, their exact location, depth, extent, and viously undergone LASIK surgery.
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TABLE 4.2.2 Types of Commercially Available Specular Microscopes
Contact Specular Microscopes Noncontact Specular Microscopes
4.2
CL-1000xz (HAI Labs Inc., Lexington, MA) CL-1000nc (HAI Labs Inc., Lexington, MA)

CELLCHEK Series (Konan Medical USA, Inc.,
Irvine, CA)
CellCheck D (eyebank) (Konan Medical
USA, Inc., Irvine, CA)
CEM-530 (Nidek Fremont, CA)
EM-3000 (Tomey, Inc., Phoenix, AZ)
SP-1P (TopCon Medical, Inc., Tokyo, Japan)
Keratitis
Keratitis may be diagnosed clinically, but the areas of necrosis and infil-
tration may be better assessed by using AS-OCT, particularly in opaque
corneas. Because AS-OCT allows for quantitative measurement of corneal
thickness, it serves as an additional aide in detection and treatment of
keratitis and corneal ulcers.1 Localization of stromal necrosis and radial
hyperreflective stromal bands in Acanthamoeba keratitis can further be
translated for rapid diagnosis and reduction of perforation rates as a result
of earlier intervention.1,13
A
Miscellaneous Uses
AS-OCT has several other applications, such as grading of cells in anterior
uveitis and visualization of intracorneal implants.1 Further, it is useful in
screening corneas from eye banks for corneal abnormalities, such as prior
LASIK surgery.
Limitations
AS-OCT has limited ability to visualize structures posterior to iris as a
result of pigmentation, whereas UBM is more useful clinically.
SPECULAR MICROSCOPY
Specular microscopy allows for imaging and analysis of the corneal endo-
thelium. It works on the basic principle of light reflection using a mirror:
the angle of incidence is equal to that of reflection. As light passes through
a media with higher index of refraction, most of it is reflected; this reflected
light is captured by a detection lens. The endothelial cells can be imaged
because their refractive index is greater than that of the aqueous humor.
The light source can be a stationary or moving slit or spot; wider slit allows
greater field, but reduced contrast and resolution.14 Specular microscopy
can be contact or noncontact and automated or manual, or both.15 The
types of specular microscopes are shown in Table 4.2.2. B
Specular microscopy provides pachymetric measurements and endo-
thelial cell analysis (density and morphology), including endothelial cell
Fig. 4.2.5 Specular microscopy image of (A) normal endothelium quantified using
density, mean cell area, coefficient of variation (standard deviation divided fixed-frame method; (B) endothelium with Fuchs’ endothelial corneal dystrophy;
by mean area of cells), and percentage of hexagonality or pleomorphism note the presence of guttae (arrow) and dysmorphic cells.
(percentage of cells with variation from normal hexagonal shape). Coeffi-
cient of variation and pleomorphism are the more sensitive indicators of syndrome.18,19 In FECD, the mosaic endothelium presents dark areas
endothelial dysfunction and stress, as even at low endothelial density (<500 (guttae) (see Fig. 4.2.5B).20 Bilateral involvement, with donut-shaped ves-
cells/mm2) the endothelial function may remain uncompromised.15 icles and clearly defined black rings anterior to the cells may be seen in
The fixed-frame method allows for cell quantification within a fixed area PPMD; whereas in ICE syndrome, many pentagonal cells are seen with
(Fig. 4.2.5A), and the variable-frame method allows the observer to make intracellular dark areas.19 In advanced ICE disease, a “reversal appearance”
an accurate boundary around the edges of the cells.15,16 In contrast, the occurs with black areas and white margins.
center method requires the centers of contiguous cells to be marked man-
ually, hence peripheral cells are not counted as they do not have adjoining Intraocular Surgery Evaluation
cells. Moreover, the center-flex method requires delineating the boundary Permanent corneal edema occurs at low epithelial cell density (300–700
of an area, followed by marking of cell centers. cells/mm2) or presence of other morphological abnormalities (coefficient
of variation >40% or <50% hexagonal cells). Loss of cells with ocular
Clinical Applications surgery is estimated to be between 0 and 30%; preoperative assessment of
the patients’ endothelium to assess cell density may reduce postoperative
The normal corneal endothelium comprises hexagonal and similar size complications.
cells (see Fig. 4.2.5A).17 The cell density decreases with aging (0.5% per
year). Examples of cell abnormalities include guttae (excrescences of the Donor Cornea Evaluation
Descemet’s membrane).16 Contact lens wear can cause transient or chronic Specular microscopy is particularly important in assessment of donor
changes to the endothelial cell morphology.16 corneas to assess for sufficient endothelial cell density and donor quality.21
Corneal Dystrophies Limitations

Specular microscopy is a valuable tool to diagnose different endothelial One of the limitations of specular microscopy is that it is difficult to image
disorders, such as Fuchs’ endothelial corneal dystrophy (FECD), poste- endothelial cells through edematous or opaque corneas. In these cases, 163
rior polymorphous dystrophy (PPMD), or iridocorneal endothelial (ICE) confocal microscopy provides superior image quality.
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4
TABLE 4.2.3 Commercially Available Meibography Devices
Topcon slit-lamp microscope (Topcon Cooperation, Tokyo, Japan)
EyeTop Topographer (Costruzione Strumenti Oftalmici, Florence, Italy)
Epithelium
Stroma Sirius Scheimpflug Camera and Cobra Fundus Camera (bon Optic Vertriebs GmbH,
Descemet’s Lübeck, Germany)
Membrane
Oculus Keratograph 5M (Oculus, Wetzlar, Germany)
Iris
Lipiview II (TearScience, Morrisville, North Carolina, USA)
LipiScan™ with Dynamic Meibomian Imaging™ (TearScience, Morrisville, North Carolina,
USA)
Ciliary Body
TABLE 4.2.4 Grading Systems to Assess
Meibomian Gland Dysfunction
Characteristics Grade 0 Grade 1 Grade 2 Grade 3 Grade 4
Gland dropout None 33% 34%–66% >66% -
Partial glands None <25% of 25%–75% of >75% of -
Fig. 4.2.6 Ultrasound biomicroscopy image of a patient with anterior synechiae (red
image image image
arrow).
Loss of total meibomian None <1/3 1/3–2/3 >2/3 -
gland area
Area of loss 0% 25% 25%–50% 51%–75% 75%
ULTRASOUND BIOMICROSCOPY Ocular Trauma

Because ocular trauma can present with opaque corneas or hyphema,
UBM uses high frequency (20–100 MHz) ultrasound waves and is useful UBM is an especially useful modality to evaluate damage to the internal
for the evaluation of deeper structures in the eye and in opaque corneas.14 structures of the eye. It can evaluate nonmetallic foreign bodies less than
Echoes from tissues at different depths are recorded at different time inter- 1 mm that may be missed even by computed tomography (CT). Iriododi-
vals and can be used to construct the image. In general, higher frequency alysis can be caused with blunt trauma and is viewed as a detached iris by
waves have lesser penetration, and lower frequency waves have lower pen- using UBM. A cyclodialysis cleft may be missed with gonioscopy, but a
etration. Most UBMs in use today have scan rate of 35–50 MHz, giving an cleft that separates the ciliary body and scleral spur are evident on UBM;
axial resolution of 42 µm, and a depth of 4–5 mm.11,22 reattachment of ciliary body after cyclodialysis has been observed by using
UBM. Because the intraocular lens vault can be seen, traumatic cataract,
Clinical Applications lens displacement, subluxation, rupture of lens capsule, and zonular
damage may be seen.
Using UBM, surface epithelium, Bowman’s layer, and Descemet’s mem-
brane can be identified as reflective structures, while the endothelium Limitations
cannot be identified. As a result of penetration of sound through the pig-
mented epithelium, UBM can visualize the structures posterior to the iris, UBM needs contact with the globe, hence patients have better tolerance to
which is not possible with an AS-OCT. Hence, posterior chamber struc- its application with topical anesthesia. It has a limited depth of penetration
tures, including lens zonules, ciliary body, and anterior choroid, can be behind the anterior vitreous and has a limited field of view. Further, it
visualized (Fig. 4.2.6).22 has a relatively poor interobserver reproducibility in the assessment of AC
angle, iris dimensions, and ciliary sulcus diameter.
Ocular Masses
Although no imaging technique can replace histopathological examination,
UBM has shown utility in the diagnosis of anterior segment tumors. Solid
MEIBOGRAPHY
tumors can be identified and the extent of involvement seen.11 UBM has Meibography comprises various in vivo techniques that can study the
shown superiority over AS-OCT in image quality and assessment of tumor structure of meibomian glands (MGs) and their abnormalities.25,26 Tra-
margins and posterior surface of both pigmented and nonpigmented ditionally, using white light and an infrared camera, meibography has
tumors. For evaluation of anterior surface tumor, conjunctival nevi, and evolved over time to employ infrared or near-infrared spectrum of light
anatomical relationships, AS-OCT may be superior. However, posterior (wavelength 650–700 nm) and a camera with filter for infrared light or
shadowing with AS-OCT is not seen with UBM.11 Dermoid tumors of the infrared-sensitive film for photography or videography. Infrared light may
limbus appear as hyperreflective masses, whereas pigmented conjunctival not be visible to the naked eye but provides high-resolution images.25,26
nevi present with cysts.11 For solid tumors and conjunctival melanomas, Meibography may be employed using transillumination (contact), direct
UBM can assess the margins and depth.11,22 illumination (noncontact), interferometry, or by AS-OCT. In contact mei-
bography, transilluminated MGs are seen after a fiberoptic light probe
Glaucoma touches the palpebral surface of an everted eyelid. In noncontact meibog-
The corneoscleral junction can be seen as a line of reflectivity change raphy, the infrared light probe does not touch the lid, and a camera is used
between the sclera (highly reflective) and cornea; the corneal spur is to visualize glands. This technique is more tolerable for patients because
1 mm posterior to corneoscleral junction. Hence, it can be used to assess of its noncontact nature and now has been employed in various slit-lamps
the anterior chamber (AC) (angle, depth, and angle opening distance and other imaging devices.25–27 The technique of using an AS-OCT device
[AOD]), iris (thickness, distance from ciliary process, contact lens, or to view MGs is termed OCT meibography.25 Ocular surface interferometers
zonules), ciliary sulcus (diameter and distance of process from trabecu- use white light, which produces a color interference pattern when it strikes
lar meshwork), and other angles (trabecular–iris angle, iris–lens angle, the lipid–aqueous interface. This interference is quantified to assess MG
and iridocorneal angle).23,24 The scleral spur may be identified manu- structure and lipid layer thickness (LLT), as well as blink dynamics as mea-
ally for improved accuracy. In glaucoma evaluation, UBM has shown sures of MG function.28 A list of some commercially available meibogra-
promise in evaluation of mechanisms underlying glaucoma, such as phy devices is given in Table 4.2.3.
acute angle closure caused by pupillary block (bowed iris causing angle
blockade), plateau iris (AC shallower than in controls, but deeper than in Clinical Applications
patients with pupillary block), ciliary effusion syndrome, lens dislocation/
subluxation, and ciliary body masses (cyst or tumor). Postoperatively, UBM Normal MGs appear as hyperilluminated acini clusters that are surrounded
is highly useful especially if clinical examination cannot differentiate by hyperilluminated ducts, adjacent to orifices and hypoilluminated areas
between pupillary block and malignant glaucoma. As UBM can assess ana- between the MGs. The noncontact technique shows a similar image, but
164 tomical relationships, it can also be used to evaluate anatomical changes the contrast is inverted.29 There are several classification systems in liter-
with diseases. ature to assess MGs (Table 4.2.4).25 These include systems based on the
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4.2

B
A D
Fig. 4.2.7 (A) Meibography with anterior segment optical coherence tomography (AS-OCT) showing dysfunctional meibomian glands (MGs) (red arrow); glands are
shortened, wider and do not reach the lid margin; (B–D) Lipiscan images in dynamic illumination mode, adaptive transillumination mode, and dual mode, respectively;
images show loss of glands (red arrows) and shortened glands that do not reach the lid margins (yellow arrows).
number of glands, percentage of partial glands, and percentage area of

TABLE 4.2.5 Comparison of the Types
gland dropout (Fig. 4.2.7).27,30
of In Vivo Confocal Microscopes
Meibomian Gland Dysfunction HRT III with Rostock Cornea
The most commonly studied disease that causes an alteration of MG mor- Types Module (Heidelberg Engineering) Confoscan 4 (Nidek, Inc.)
phology is meibomian gland dysfunction (MGD). Viewing the MGs can Light source 670 nm laser beam Variable slit
help differentiate the aqueous-deficient subtype of dry eye disease (DED) Objective magnification × 63 × 40
from the evaporative type related to MGD. MGD can be seen on meibogra- Numerical aperture 0.95 0.75
phy as a decrease in acinar density and wall homogeneity and an increase
Axial (z-axis) resolution 1 µm 26 µm
in acinar and duct diameter.25 MG dropout of the lower lid is a highly effec-
tive parameter to measure MGD as it correlates with the acinar histological Image size 400 µm × 400 µm 460 µm × 345 µm
findings.31,32 Stability Applanation device provides Noncontact objective
stability lens; less stable while
changing focal planes
Limitations Ease of use Needs manual adjustment to User-friendly (automatic
change focal plane after 80 µm, alignment and
In contact meibography, patient tolerability is lower compared with non- or requires add-on joystick scanning)
contact meibography; topical anesthesia may need to be employed in
contact meibography.
a decrease in density of superficial and basal epithelial cells and kerato-
IN VIVO CONFOCAL MICROSCOPY cytes. Inflammation associated with DED may present with activated ker-
atocytes (identified by increased nuclear reflectivity) and with an increase
IVCM allows for real-time, layer-by-layer, and near-histological resolution in density and activation of dendritic cells (Fig. 4.2.8A).36,37 A decrease in
cellular imaging in four dimensions.33 The principle of IVCM is confocal- length, number, and density of nerve fibers in subbasal nerve plexus and
ity: By utilizing a white or laser light and pinhole, light is focused at a point, an increase in width, tortuosity, reflectivity, and beading can be seen in
and reflected scattered light is deflected through a second confocal aper- patients with DED and neuropathic corneal pain (NCP) (Fig. 4.2.8B–F).33,36
ture.34,35 Because of different indices of refraction of the various structures, Abnormal nerve regeneration with presence of microneuromas may be
different types of light scatter differently. Size, orientation, and surface of seen in patients with NCP.33
structures may influence light scatter; rough surfaces scatter beam broadly,
and vice versa.35 Through slicing of a tissue in various focal planes, various Infectious Keratitis and Demodex
layers can be visualized, a concept known as “optical slicing.”34 The types IVCM is a useful noninvasive tool to support the identification of various
of IVCMs in use are discussed in Table 4.2.5. Cellular details of the cornea infectious agents. Acanthamoeba cysts and trophozoites can be visualized
magnified up to 800-fold, including epithelial cells, keratocytes, endothelial directly as bright reflective areas (Fig. 4.2.9A).38 Filaments of Fusarium
cells, corneal nerves, and immune and inflammatory cells, including den- solani, Aspergillus, and Candida and bacterial keratitis caused by microspo-
dritic cells, can be viewed by laser IVCM.33,34 ridia and Borrelia, as well as mites, such as Demodex, can also be distin-
guished (see Fig. 4.2.9B,C).38,39 Moreover, a decrease in subbasal nerve
Clinical Applications density can be observed in patients with herpetic diseases.33
Dry Eye Disease and Neuropathic Corneal Pain Corneal Deposits and Corneal Dystrophies
Changes from normal architecture can be seen in several corneal disorders Corneal deposits, such as in amiodarone-induced keratopathy, present 165
using IVCM. With DED, epithelial and stromal changes may be viewed as with bright intracellular inclusions on IVCM, whereas long, atypical and
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A B C
D E F
Fig. 4.2.8 In vivo confocal microscopy (IVCM) showing changes in the subepithelial layer (A); arrow represents dendritic cells associated with inflammation in the basal
epithelium. Image of subbasal plexus showing (B) loss of nerves (arrow) in dry eye disease; (C) tortuosity (arrow); (D) nerve beading (arrow); (E) nerve hyperreflectivity (arrow)
in a patient with DED; (F) microneuromas (arrow) in a patient with neuropathic corneal pain.
centripetal epithelial cells are seen in wave-like epitheliopathy. Different point. Slit-scanning tomography utilizes a slit beam to visualize both the
types of corneal dystrophies, although diagnosed clinically, can be assessed anterior and posterior corneal surfaces to assess corneal shape and thick-
by IVCM, and examples are given below.40,41 Epithelial basement mem- ness. Corneal power and curvature of the posterior cornea are not accu-
brane dystrophy presents with hyperreflective linear tissue and cysts in rate with this technique; in addition, the power for the anterior cornea
the epithelium, distorted basal epithelial cells, and abnormal subbasal is less sensitive than that by Placido disc. Scheimpflug tomography is
nerve plexus.40 Patients with Meesman’s dystrophy have dark areas of the another technique that has a high depth of focus. Both anterior and poste-
basal epithelium with bright spots and a distorted subbasal nerve plexus.40 rior cornea, AC, and lens can be visualized. Like slit-scanning techniques,
Among stromal dystrophies, lattice dystrophy is visualized as linear, curvature differences are difficult to detect. Types of commercially avail-
branching, and ill-defined hyperreflective filaments, whereas bright round, able hybrid (combination) devices are given in Table 4.2.6. The resulting
irregular or trapezoid deposits are seen with granular dystrophy.42 Among data are displayed as a corneal curvature maps, consisting of colors cor-
stromal dystrophies, needle-shaped hyperreflective intrastromal crystal- responding to corneal power and curvature. Steep contours are displayed
line material are seen in Schnyder’s crystalline corneal dystrophy (see Fig. as warm colors (e.g., red), whereas flat contours correspond to cool colors
4.2.9D).43 Among endothelial dystrophies, FECD presents with guttae, thick (e.g., green, blue). Other maps generated include refractive maps (calculate
Descemet’s membrane, and hyperreflective pleomorphic endothelium.40 true corneal power), elevation maps (show elevation/depression at both
anterior and posterior cornea in comparison to a computer-generated best-
fit line; anterior surface is scaled to 10 µm and posterior to 20 µm), and
Limitations pachymetry maps (reveal corneal thickness). When interpreting maps, it
IVCM has a limited field of view; several nonlapping images or image is important to be cognizant of the scale used. A standard way to present
reconstruction are needed. the power of the corneal surface is with the axial power map solution by
using a scale whose fixed range (+30.00 to +65.50 D) is broad enough
TOPOGRAPHY AND TOMOGRAPHY to encompass most variations in corneal curvature and whose standard
contour interval (+1.50 D) will highlight only topographic features of clini-
Corneal topography is a method of visualizing the corneal surface, and cal significance.45 Corneal topography powers displayed are best viewed as
tomography involves measuring the entire corneal shape. The standard estimates and should not be routinely used in planning cataract surgery
corneal topographer consists of three components: a Placido disc made for intraocular lens calculations.46 Peripheral corneal power estimates are
up of multiple circles that can be projected onto the corneal surface, a less precise than central measurements.
video camera capable of capturing the reflected image of these rings, and
a computer with software to digitize the resultant captured images.44 The Clinical Applications
digitized image is broken down to individual points around each circle.
The distance of every point is measured from the center of the Placido Refractive Surgery
166 disc image (Fig. 4.2.10). Point-source color topographer can use color LED Corneal topography is used primarily as a screening tool to evaluate pro-
targets and give accurate readings with reconstruction of every single spective refractive surgical candidates and as a diagnostic aid in evaluating
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A B
Fig. 4.2.9 In vivo confocal microscopy (IVCM) images showing (A) Acanthamoeba cysts; shown with arrow, visualized as a result of a darker double wall outside the cyst;
(B) Demodex, visualized in follicles, shown with arrow; (C) fungal filaments in the stroma, shown with arrows; (D) Schnyder’s dystrophy; needle-shaped hyperreflective
intrastromal crystalline material is seen.
A B
167
Fig. 4.2.10 A classic Placido disc mapped (A) in an individual with normal topography; (B) in a cornea with pellucid marginal degeneration, shows ring widening inferiorly.
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Fig. 4.2.11 Topography maps (by Galilei) of a patient with keratoconus; inferior thinning of the anterior curvature (red area) in axial map correlates with lower pachymetry
and anterior and posterior elevation.
TABLE 4.2.6 A Comparison of the Types of Topography Devices

Device Orbscan Pentacam Galilei Visante Omni
Manufacturer Bausch & Lomb, Rochester, NY Oculus, Inc., Wetzlar, Germany Ziemer Opthalmic Systems AG, Port, Carl Zeiss Meditec AG, Dublin, CA
Switzerland
System Placido disc and slit scanning Scheimpflug camera (50 images Dual (vertical and horizontal) AS-OCT device (Visante) that attaches
hybrid with 180° rotation in 2 seconds) Scheimpflug camera Placido hybrid to a Placido disc device (Atlas)
Source of illumination White light 475 nm Blue, UV free, LED 470 nm Blue, UV free, LED 1310 nm superluminiscent LED
Type of system Noncontact Noncontact Noncontact Noncontact
Image size (mm) – 5.6 × 4.5 7.4 × 7.4 10 × 3
Number of images/scan 40 25–100 15–60 512
Number of points/scan 9000–23,000 >25,000 >122,000 2048
Time of scan (sec) 1.5 2 1-2
patients with poor vision following refractive surgery. Irregular corneas topography; for example, irregular ablation profiles, and decentered laser
with steepening are poor candidates for refractive surgery as they are at ablations can be assessed with these devices (Fig. 4.2.12).44,48
high risk for postoperative ectasia.44,47 In eyes with a history of refractive
surgery, intraocular lens calculations using regular algorithms are inac- Astigmatism
curate; topography data can help understand the new anterior–posterior Another area where videokeratography plays an important role is the eval-
corneal surface ratio. uation of patients with significant astigmatism.49 In the past, only the ante-
rior cornea was measured to evaluate astigmatism, but more recently, the
Ectasia-Related Disorders contribution of posterior cornea has been highlighted. Topographic images
Keratoconus and contact lens use are the most common causes of irregular can be helpful in assessing impact of conjunctival lesions, including pte-
corneas in the screening population. Steep (i.e., red) areas isolated in the rygia and Salzmann’s nodular degeneration, as well as planning interven-
inferior cornea suggest keratoconus. Many topographers come equipped tions, such as astigmatic keratotomy, limbal relaxing incisions, or removal
168 with programs to alert the clinician when a diagnosis of keratoconus is of tight sutures after keratoplasty.50 Three-dimensional images can be used
likely (Fig. 4.2.11). Postoperative patients with poor vision should undergo to assess corneal and lens densitometry, a measure of light backscatter.
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WAVEFRONT ANALYSIS or curved sheets of light. Wavefront aberration is calculated as the differ-
Wavefront analysis examines the interaction of light with the optical

ence between the actual wavefront and an ideal wavefront.
Hartmann–Shack devices employ microlenslet arrays to characterize 4.2
system of an eye, giving a snapshot of the entire optical system.51 With a the surface of wavefronts: if the wavefront is flat, it will form a perfect
perfect optical system, a point source of light emanating from the back of lattice of points corresponding to the axis of each lenslet; if the wavefront

the eye creates a locus of points, with the same optical path length and in is aberrated, it will result in a displaced spot on the grid (Fig. 4.2.13). The
the same temporal phase, that exit the pupillary plane in the form of a flat displacement in location, from the ideal, represents a measure of the shape
sheet called an unaberrated wavefront. With imperfections in the cornea or of the wavefront. The complex shapes can be analyzed by deconstruction
lens, optical aberrations are created, causing the wavefront to exit as bent using Zernike’s and Fourier’s polynomial equations and basic shapes
(Fig. 4.2.14).51
Wavefront maps are displayed as two-dimensional maps: green indi-
cates minimal distortion, blue characterizes myopic wavefronts, and red
represents hyperopic wavefront errors (Fig. 4.2.15A). The root mean square
value quantifies the wavefront error and compares it to normal: values
approaching 1 µm for individual aberrations are considered abnormal.
Clinical Applications
Refractive Surgery
Wavefront technology has utility in refractive errors, especially in laser abla-
tion for spherocylindrical errors. Traditional lasers can induce spherical
aberrations; custom laser treatment that incorporates a wavefront-designed
algorithm helps limit this and improves night vison (as aberrations are
more pronounced with wider pupil) (see Fig. 4.2.15B).52
Limitations
Wavefront may be affected by pupil size, vitreous or lens opacities, and the
quality of the tear film. Hence, it may not be accurate in some conditions,
such as DED. Additionally, the resolution of a wavefront is much lower
than that of topography.
SUMMARY
The above-mentioned modalities have clinical utility in various diseases.
The choice of modality depends on the clinical experience of the physician
and the area to be visualized.
Financial Support: NIH R01-EY022695 (PH), NIH R21-EY025393 (PH),
Fig. 4.2.12 Decentered laser ablation pattern. Blue area represents laser-induced Tufts Medical Center Institutional Support (PH). The funding organiza-
corneal flattening and the pupil is outlined with a black circle. Patients with tions had no role in the design or conduct of this research.
decentered ablations may have poor vision and night vision problems such as glare Conflict of Interest: Dr. Hamrah is consultant for Heidelberg Engineer-
or ghosting of images. ing, Allergan, Eyegate Pharmaceuticals, and Dompe Pharmaceuticals.
Fig. 4.2.13 Schematic of Hartmann–Shack device used

HARTMANN—SHACK to capture wavefront data. (Courtesy AMO VISX.)
outgoing wave
CCD CCD lenslet

image camera array
169
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Fig. 4.2.14 The fundamental Zernike’s
4 shapes. Complex wavefront maps can be

deconstructed to determine the individual
contribution of these shapes. Spherical
aberration is a fourth-order term and
is represented by the central figure in

row 4. Coma is a third-order term and is
represented by the two central figures in
row 3.
A B
Fig. 4.2.15 (A) Normal wavefront map. The left side of the map shows total aberrations including nearsightedness and astigmatism. The right side represents higher-order
optical aberrations only. (B) Wavefront map of a patient with post-LASIK night vision problems. The patient complaints are most likely caused by spherical aberration.
170
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KEY REFERENCES Pult H, Nichols JJ. A review of meibography. Optom Vis Sci 2012;89:E760–9.
Ramos JL, Li Y, Huang D. Clinical and research applications of anterior segment optical
Cavanagh HD, El-Agha MS, Petroll WM, et al. Specular microscopy, confocal microscopy,
and ultrasound biomicroscopy: diagnostic tools of the past quarter century. Cornea
coherence tomography – a review. Clin Exp Ophthalmol 2009;37:81–9.
Rao SK, Padmanabhan P. Understanding corneal topography. Curr Opin Ophthalmol
4.2
2000;19:712–22. 2000;11:248–59.
Sayegh RR, Pineda R 2nd. Practical applications of anterior segment optical coherence

Cruzat A, Qazi Y, Hamrah P. In vivo confocal microscopy of corneal nerves in health and
disease. Ocul Surf 2017;15:15–47. tomography imaging following corneal surgery. Semin Ophthalmol 2012;27:125–32.
Ehlers JP. Intraoperative optical coherence tomography: past, present, and future. Eye (Lond) Shukla AN, Cruzat A, Hamrah P. Confocal microscopy of corneal dystrophies. Semin Oph-
2016;30:193–201. thalmol 2012;27:107–16.
Janssens K, Mertens M, Lauwers N, et al. To study and determine the role of anterior Smolek MK, Klyce SD, Hovis JK. The Universal Standard Scale: proposed improvements to
segment optical coherence tomography and ultrasound biomicroscopy in corneal and the American National Standards Institute (ANSI) scale for corneal topography. Oph-
conjunctival tumors. J Ophthalmol 2016;2016:1048760. thalmology 2002;109:361–9.
Kaufman SC, Musch DC, Belin MW, et al. Confocal microscopy: a report by the American Wise RJ, Sobel RK, Allen RC. Meibography: a review of techniques and technologies. Saudi
Academy of Ophthalmology. Ophthalmology 2004;111:396–406. J Ophthalmol 2012;26:349–56.
Keane PA, Ruiz-Garcia H, Sadda SR. Clinical applications of long-wavelength (1,000-nm)
optical coherence tomography. Ophthalmic Surg Lasers Imaging 2011;42(Suppl.):S67–74.
Lim SH. Clinical applications of anterior segment optical coherence tomography. J Ophthal- Access the complete reference list online at ExpertConsult.com
mol 2015;2015:605729.
Pavlin CJ, Foster FS. Ultrasound biomicroscopy. High-frequency ultrasound imaging of the
eye at microscopic resolution. Radiol Clin North Am 1998;36:1047–58.
171
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REFERENCES 27. Arita R. Validity of noninvasive meibography systems: noncontact meibography equipped
with a slit-lamp and a mobile pen-shaped meibograph. Cornea 2013;32(Suppl. 1):S65–70.
1. Lim SH. Clinical applications of anterior segment optical coherence tomography. J Oph-
thalmol 2015;2015:605729.
28. Zhao Y, Tan CL, Tong L. Intra-observer and inter-observer repeatability of ocular surface
interferometer in measuring lipid layer thickness. BMC Ophthalmol 2015;15:53.
4.2
2. Maslin JS, Barkana Y, Dorairaj SK. Anterior segment imaging in glaucoma: an updated 29. Wise RJ, Sobel RK, Allen RC. Meibography: a review of techniques and technologies.
Saudi J Ophthalmol 2012;26:349–56.

review. Indian J Ophthalmol 2015;63:630–40.
3. Kaufman SC, Musch DC, Belin MW, et al. Confocal microscopy: a report by the Ameri- 30. Yoo YS, Na KS, Byun YS, et al. Examination of gland dropout detected on infrared mei-
can Academy of Ophthalmology. Ophthalmology 2004;111:396–406. bography by using optical coherence tomography meibography. Ocul Surf 2017;15:130–8.
4. Rio-Cristobal A, Martin R. Corneal assessment technologies: current status. Surv Oph- e1.
thalmol 2014;59:599–614. 31. Fasanella V, Agnifili L, Mastropasqua R, et al. In vivo laser scanning confocal microscopy
5. Keane PA, Ruiz-Garcia H, Sadda SR. Clinical applications of long-wavelength (1,000-nm) of human meibomian glands in aging and ocular surface diseases. Biomed Res Int
optical coherence tomography. Ophthalmic Surg Lasers Imaging 2011;42(Suppl.):S67–74. 2016;2016:7432131.
6. Li Y, Lu CD, Jia Y, et al. Anterior segment angiography with 1050 nm swept-source 32. Finis D, Pischel N, Schrader S, et al. Evaluation of lipid layer thickness measure-
optical coherence tomography. Invest Ophthalmol Vis Sci 2015;56:4512. ment of the tear film as a diagnostic tool for Meibomian gland dysfunction. Cornea
7. Randleman JB, Trattler WB, Stulting RD. Validation of the Ectasia Risk Score System for 2013;32:1549–53.
preoperative laser in situ keratomileusis screening. Am J Ophthalmol 2008;145:813–18. 33. Cruzat A, Qazi Y, Hamrah P. In vivo confocal microscopy of corneal nerves in health and
8. Ramos JL, Li Y, Huang D. Clinical and research applications of anterior segment optical disease. Ocul Surf 2017;15:15–47.
coherence tomography – a review. Clin Exp Ophthalmol 2009;37:81–9. 34. Lemp MA, Dilly PN, Boyde A. Tandem-scanning (confocal) microscopy of the full-thick-
9. Sayegh RR, Pineda R 2nd. Practical applications of anterior segment optical coherence ness cornea. Cornea 1985;4:205–9.
tomography imaging following corneal surgery. Semin Ophthalmol 2012;27:125–32. 35. Guthoff RF, Baudouin C, Stave J. Atlas of confocal laser scanning in-vivo microscopy in
10. Ehlers JP. Intraoperative optical coherence tomography: past, present, and future. Eye opthalmology – principles and applications in diagnostic and therapeutic ophtalmology;
(Lond) 2016;30:193–201. 2006.
11. Janssens K, Mertens M, Lauwers N, et al. To study and determine the role of anterior 36. Kheirkhah A, Rahimi Darabad R, Cruzat A, et al. Corneal epithelial immune dendritic
segment optical coherence tomography and ultrasound biomicroscopy in corneal and cell alterations in subtypes of dry eye disease: a pilot in vivo confocal microscopic study.
conjunctival tumors. J Ophthalmol 2016;2016:1048760. Invest Ophthalmol Vis Sci 2015;56:7179–85.
12. Nanji AA, Sayyad FE, Galor A, et al. High-resolution optical coherence tomography as 37. Villani E, Mantelli F, Nucci P. In-vivo confocal microscopy of the ocular surface: ocular
an adjunctive tool in the diagnosis of corneal and conjunctival pathology. Ocul Surf allergy and dry eye. Curr Opin Allergy Clin Immunol 2013;13:569–76.
2015;13:226–35. 38. Vaddavalli PK, Garg P, Sharma S, et al. Role of confocal microscopy in the diagnosis of
13. Yamazaki N, Kobayashi A, Yokogawa H, et al. In vivo imaging of radial keratoneuritis in fungal and acanthamoeba keratitis. Ophthalmology 2011;118:29–35.
patients with Acanthamoeba keratitis by anterior-segment optical coherence tomography. 39. Labbe A, Khammari C, Dupas B, et al. Contribution of in vivo confocal microscopy to the
Ophthalmology 2014;121:2153–8. diagnosis and management of infectious keratitis. Ocul Surf 2009;7:41–52.
14. Cavanagh HD, El-Agha MS, Petroll WM, et al. Specular microscopy, confocal microscopy, 40. Shukla AN, Cruzat A, Hamrah P. Confocal microscopy of corneal dystrophies. Semin
and ultrasound biomicroscopy: diagnostic tools of the past quarter century. Cornea Ophthalmol 2012;27:107–16.
2000;19:712–22. 41. Weiss JS, Moller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies–edition
15. Doughty MJ. Evaluation of possible error sources in corneal endothelial morphometry 2. Cornea 2015;34:117–59.
with a semiautomated noncontact specular microscope. Cornea 2013;32:1196–203. 42. Takahashi N, Sasaki K, Nakaizumi H, et al. Specular microscopic findings of lattice
16. McCarey BE, Edelhauser HF, Lynn MJ. Review of corneal endothelial specular corneal dystrophy. Int Ophthalmol 1987;10:47–53.
microscopy for FDA clinical trials of refractive procedures, surgical devices, and new 43. Kobayashi A, Sugiyama K, Huang AJ. In vivo confocal microscopy in patients with
intraocular drugs and solutions. Cornea 2008;27:1–16. central cloudy dystrophy of Francois. Arch Ophthalmol 2004;122:1676–9.
17. Tsubota K, Yamada M, Naoi S. Specular microscopic observation of normal human 44. Rao SK, Padmanabhan P. Understanding corneal topography. Curr Opin Ophthalmol
corneal epithelium. Ophthalmology 1992;99:89–94. 2000;11:248–59.
18. Brooks AM, Grant G, Gillies WE. Differentiation of posterior polymorphous dystro- 45. Smolek MK, Klyce SD, Hovis JK. The Universal Standard Scale: proposed improvements
phy from other posterior corneal opacities by specular microscopy. Ophthalmology to the American National Standards Institute (ANSI) scale for corneal topography. Oph-
1989;96:1639–45. thalmology 2002;109:361–9.
19. Liu YK, Wang IJ, Hu FR, et al. Clinical and specular microscopic manifestations of irido- 46. Koch DD, Wakil JS, Samuelson SW, et al. Comparison of the accuracy and reproduc-
corneal endothelial syndrome. Jpn J Ophthalmol 2001;45:281–7. ibility of the keratometer and the EyeSys Corneal Analysis System Model I. J Cataract
20. Chiou AG, Kaufman SC, Beuerman RW, et al. Confocal microscopy in cornea guttata Refract Surg 1992;18:342–7.
and Fuchs’ endothelial dystrophy. Br J Ophthalmol 1999;83:185–9. 47. Wilson SE, Klyce SD. Screening for corneal topographic abnormalities before refractive
21. Wiffen SJ, Nelson LR, Ali AF, et al. Morphologic assessment of corneal endothelium surgery. Ophthalmology 1994;101:147–52.
by specular microscopy in evaluation of donor corneas for transplantation. Cornea 48. Cavanaugh TB, Durrie DS, Riedel SM, et al. Centration of excimer laser photorefractive
1995;14:554–61. keratectomy relative to the pupil. J Cataract Refract Surg 1993;19(Suppl.):144–8.
22. Pavlin CJ, Foster FS. Ultrasound biomicroscopy. High-frequency ultrasound imaging of 49. Harris DJ Jr, Waring GO 3rd, Burk LL. Keratography as a guide to selective suture
the eye at microscopic resolution. Radiol Clin North Am 1998;36:1047–58. removal for the reduction of astigmatism after penetrating keratoplasty. Ophthalmology
23. Pavlin CJ, Buys YM, Pathmanathan T. Imaging zonular abnormalities using ultrasound 1989;96:1597–607.
biomicroscopy. Arch Ophthalmol 1998;116:854–7. 50. Cairns G, McGhee CN. Orbscan computerized topography: attributes, applications, and
24. Salcan I, Aykan U, Yildirim O, et al. Quantitative ultrasound biomicroscopy study of limitations. J Cataract Refract Surg 2005;31:205–20.
biometry of the lens and anterior chamber. Eur J Ophthalmol 2012;22:349–55. 51. Chalita MR, Finkenthal J, Xu M, et al. LADARWave wavefront measurement in normal
25. Pult H, Nichols JJ. A review of meibography. Optom Vis Sci 2012;89:E760–9. eyes. J Refract Surg 2004;20:132–8.
26. Qazi Y, Hamrah P. Objective metrics of ocular surface disease in contact lens wearers: 52. McCormick GJ, Porter J, Cox IG, et al. Higher-order aberrations in eyes with irregular
meibography. Curr Ophthalmol Rep 2015;3:122–31. corneas after laser refractive surgery. Ophthalmology 2005;112:1699–709.
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Section 2 Congenital Abnormalities
Congenital Corneal Anomalies

Paula Kataguiri, Kenneth R. Kenyon, Hormuz P. Wadia, Roshni A. Vasaiwala 4.3
Definition: Developmental abnormalities of the cornea present at Epidemiology, Pathogenesis, and Ocular Manifestations
Most cases are sporadic, although autosomal recessive and autosomal dom-
birth.
inant pedigrees have been reported.12 In microcornea, because the remain-
der of the eye is normal in size, lens development may cause angle-closure
glaucoma. Microphthalmos in association with dermal aplasia and sclero-
cornea is termed MIDAS (microphthalmia, dermal aplasia, and sclerocor-
Key Features nea) syndrome (caused by deletion in Xp22).13,14 An autosomal dominant
• Inherited or sporadic but not acquired. variant of microcornea plus other anterior segment anomalies has been
• Generally involve dysgeneses of anterior segment mesenchyme. described.15 Microcornea also occurs in conjunction with numerous
• Frequent association with iris, angle, and lens anomalies. other anomalies, including the “micro-” syndrome of microcornea, con-
genital cataract, mental retardation, retinal dystrophy, optic atrophy, hypo-
genitalism, and microcephaly.5,16,17 It is also associated with fetal alcohol
INTRODUCTION syndrome.18
Developmental corneal anomalies are evident at birth, consequent to Treatment

genetic, teratogenic, or idiopathic causes. During gestational week 5, as Treatment involves spectacle correction for high hyperopia resulting from
the lens vesicle separates from the surface ectoderm, the neural crest mes- flat anterior corneal curvature. Other associations, such as cataract and
enchyme migrates between the surface ectoderm and the optic cup.1 The glaucoma, are managed independently.
first wave of mesenchyme becomes the corneal endothelium and trabec-
ular meshwork, the second becomes corneal keratocytes, and the third Megalocornea
becomes the anterior iris stroma. Aberrations in this process result in
the anomalies of corneal size, shape, and clarity, most commonly poste- Epidemiology, Pathogenesis, and Ocular Manifestations
rior polymorphous dystrophy, Peters’ anomaly, congenital glaucoma, and Megaloconea with bilateral anterior segment enlargement is defined as
sclerocornea. Although pediatric keratoplasty is a challenging and complex horizontal corneal diameter of greater than 12 mm at birth or greater than
procedure, recent series with a 40-month mean follow-up reported up to 13 mm after age 2 years (Fig. 4.3.2). Most commonly associated with muta-
78% graft success.2 However, medical therapy remains the predominant tions in the CHRDL (Xq23) gene, which encodes ventropin,19–21 defective
management (52.7%) of such eyes.3 growth of the optic cup is hypothesized to leave larger space for the devel-
opment of the cornea. Congenital megalocornea with childhood secondary
glaucoma from spherophakia and/or ectopia lentis is a distinct condition
SIZE AND SHAPE ANOMALIES caused by recessive LTBP2 (14q24) mutations that must to be distinguished
Microcornea from buphthalmos—enlargement of the entire globe secondary to primary
congenital/infantile glaucoma.22
The normal horizontal corneal diameter is 9.5–10 mm at birth increas- A number of variants have been described, and of those, the autosomal
ing to 10–12.5 mm by adulthood. An adult cornea that is less than 10 mm dominant form without other ocular abnormalities is the least common.
horizontally is considered microcornea4 and may occur in conjunction X-linked recessive megalocornea is more frequent and is associated with
with microphthalmos, often associated with colobomas of the iris, retina, iris transillumination, pigment dispersion, lens subluxation, arcus, and
choroid, and even optic nerve (Fig. 4.3.1).5–11 In contrast, nanophthalmos central crocodile shagreen.23,24 Endothelial cell density is normal, and this
is a small functional eye that retains normal internal organization and confirms that the enlargement does not arise from corneal stretching,
proportion. and corneal clarity and thickness usually are normal.25 The genetic locus
for X-linked megalocornea resides in the Xq21–q22.6 region. Megalocor-
nea has been associated with congenital miosis,26 ectopia lentis, ectopia
pupillae, mental retardation, congenital Marfan’s syndrome, albinism,
and Neuhauser’s syndrome.20,27 Further distinction, however, is required
from megalophthalmos, a probably autosomal recessive condition, com-
Fig. 4.3.1 prising an enlarged cornea in an overall enlarged eye without glaucoma,
Colobomatous
also resulting in increased axial length (often >30 mm), juvenile cataract,
Microphthalmos.
and high myopia.28
The cornea
is reduced in
diameter but clear Treatment
and the inferior Treatment is not necessary apart for spectacle correction for myopic
iris coloboma is refractive error and for somewhat challenging cataract surgery in a much
typical. enlarged anterior segment.29
Corneal Absence
Developmental absence of the cornea does not occur in isolation, rather as a
concomitant of severe dysgenesis of the anterior segment or the entire eye.
Anophthalmos—total or subtotal absence of the entire eye—is consequent
to, for example, extreme developmental disorders.30–32 Cryptophthalmos
172 involves partial or complete failure of eyelid formation, corneal dermoids,
and either a hypoplastic anterior segment or a rudimentary cyst-like globe
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Fig. 4.3.3
Mesenchymal
Dysgenesis of 4.3
the Anterior
Segment. (A)

Typical Peters’
anomaly type
I with central
corneal opacity.
(B) Congenital
anterior
staphyloma
includes features
of Peters’ anomaly
plus extreme
corneal ectasia
and thinning.
B
TABLE 4.3.1 Relationship of Embryonic Neural Crest Migratory
Fig. 4.3.2 Megalocornea. (A) The cornea is clear but enlarged to 14 mm diameter “Waves” to Various Anomalies
bilaterally. (B) Gross examination of postmortem specimen discloses normal
cornea of large diameter and heavily pigmented trabecular meshwork probably
Mesenchymal Wave Abnormality
consequent to iris pigment dispersion. (B, Courtesy Dr. M. Yanoff.)
Anomaly 1st 2nd 3rd
Posterior embryotoxon x
Axenfeld–Rieger syndrome x x
with absence of anterior segment. Cryptophthalmos associated with sys- Peters’ anomaly x x
temic anomalies, such as syndactyly and genitourinary defects, is known as Posterior keratoconus x
Fraser’s syndrome, an autosomal recessive trait.33 Pseudo-cryptophthalmos Sclerocornea x
occurs when the lids fail to separate, but the underlying globe is intact.
Congenital Anterior Staphyloma

Keratoglobus (see Chapter 4.18) is not congenital, but a more extreme Posterior Embryotoxon
corneal ectasia may be present at birth as part of congenital anterior
staphyloma, often also in concert with severe variants of Peters’ anomaly Posterior embryotoxon is highly prevalent, occurring in perhaps 24% of a
(Fig. 4.3.3). This anomaly is usually unilateral and frequently also presents random population.34 It comprises thickening and anterior displacement
with iris developmental defects. Anterior staphyloma may occur conse- of Schwalbe’s line, most readily apparent in the temporal cornea (Fig.
quent to inflammatory or infectious corneal thinning in utero. 4.3.4). The term toxon, derived from the Greek word for “bow,” in reference
to the crescent of Schwalbe’s line, when present alone has no functional
ANOMALIES OF CORNEAL CLARITY significance.
Depending on the affected wave(s) of neural crest mesenchyme migration,

various corneal, angle and/or iris structures are compromised (Table 4.3.1).
Corneal Keloids
Keloids are white, glistening, protuberant lesions that involve all or part
Anterior Embryotoxon of the cornea. Although usually resulting from trauma or ocular inflam-
mation, they may be evident at birth. Histopathologically comprising an
Anterior embryotoxon represents a congenitally apparent widening of the irregular array of collagen, fibroblasts, and capillaries within the corneal
superior limbal transition from sclera to cornea. The term also describes stroma, they sometimes progress and may be associated with oculodigi-
arcus juvenilis, an appearance similar to arcus senilis but present at birth. tal disorders, such as Lowe’s syndrome.35 In otherwise healthy eyes, ker-
Although often sporadic, autosomal dominant and autosomal recessive atoplasty is appropriate.36,37 For lesions where growth causes discomfort, 173
pedigrees have been described. corneal dissection with a conjunctival flap may halt progression.
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Fig. 4.3.4
4 Posterior
Embryotoxon.
Anteriorly
displaced
Schwalbe’s line is
evident nasally,
superiorly and
temporally.
Dermoids
Dermoids are choristomas, defined as benign growths of tissue not nor-
mally present at a given location, and in the cornea they typically develop
at the inferotemporal limbus where fusion of optic cup fissure occurs. At
times they may involve larger areas of the cornea, the entire limbus, the
entire cornea, or the interior of the eye. They usually are round, domed,
pink to white to yellow in color and may have hair or, in the lipodermoid
variant, globules of lipid. Depending on size, they constitute a minor cos-
metic concern but may induce astigmatism or even consequent amblyo-
pia, in which case surgical excision is indicated as also for larger lesions
of anatomical and cosmetic concern. Limbal dermoids may be associated
with other malformations, commonly Goldenhar’s syndrome, comprising B
lid colobomas, hemi-facial microsomia, preauricular skin tags, and other
ear anomalies (Fig. 4.3.5). Other mandibular and other facial anomalies Fig. 4.3.5 Goldenhar’s Syndrome. Limbal dermoid (A) associated with preauricular
may be concomitant and may be part of trisomy 8 mosaicism.38 skin tags, and ear anomalies (B).
Histopathology confirms the presence of skin-like collagen with skin
adnexal appendages, which include hair follicles, sweat and sebaceous
glands, and fat. When indicated, surgical treatment usually consists of
simple superficial lamellar dissection, although the depth of the lesion, on
rare occasions, requires focal lamellar keratoplasty.39 Although infrequent,
dermoids may involve the full thickness of the eye wall; ultrasound biomi-
croscopy40 is useful to avoid surgical surprises. Rare spontaneous partial
regression has been reported.41
Axenfeld’s Anomaly and Rieger’s Syndrome

Axenfeld’s anomaly comprises bilateral posterior embryotoxon often asso-
ciated with iris strands adherent to Schwalbe’s line (Fig. 4.3.6). Rieger’s
syndrome includes Axenfeld’s anomaly plus iris atrophy, corectopia, and
polycoria. Dental anomalies and a flattened midface and nasal bridge are
common with the Axenfeld–Rieger syndrome (Fig. 4.3.7). Thus in describ-
ing this spectrum, the term anomaly refers to the localized anatomical
changes, whereas the term syndrome describes more widespread ocular
and systemic findings. Glaucoma occurs in about half the patients with
Axenfeld–Rieger syndrome.42 Seemingly, Axenfeld’s anomaly and Rieger’s
syndrome arise from retention of neural crest remnants and primordial Fig. 4.3.6 Axenfeld’s Anomaly. Histological section shows an iris process attached
endothelium on the iris and chamber angle.43 Defects in the PITX2 and to the anteriorly displaced Schwalbe’s ring (posterior embryotoxon). (Courtesy Dr.
FOXC1 gene on chromosome 4q25 and in the FKHL7 gene on 6p25, as R. Y. Foos.)
well as other defects, have been found in different patients with Axenfeld–
Rieger syndrome.44,45 Differential diagnosis includes iridocorneal endo-
thelial syndrome (which is acquired and usually unilateral), posterior corneal stromal opacity and iris strands arising from the collarette and
polymorphous dystrophy with iridocorneal adhesions, and iridogoniodys- attaching to the periphery of the opacity. Initially, a central endothelium
genesis syndrome.46,47 and Descemet’s membrane defect results in marked corneal edema (see
Fig. 4.3.3); with time, however, the endothelium can regenerate centrally,
Peters’ Anomaly and the edema may regress.48–50 So-called posterior keratoconus and the
internal ulcer of von Hippel may be considered as Peters’ anomaly without
Ocular Manifestations iris adhesions. A type II variant has been characterized with lens adher-
Peters’ anomaly comprises another mesenchymal dysgenesis condition, ence to the posterior cornea and/or cataract. Type I usually is unilateral,
with most cases being sporadic but also exhibiting recessive and occasional whereas type II is frequently bilateral. Other associated ocular anomalies
174 dominant inheritance. In 80% of cases, the condition is bilateral. The (Fig. 4.3.8) most frequently include glaucoma in greater than 50% cases
manifestations are variable, with the classic type I consisting of a central but also include microcornea, cornea plana, sclerocornea, chorioretinal
booksmedicos.org
Fig. 4.3.7
Axenfeld–Rieger
Syndrome. 4.3
Polycoria with
glaucoma LM

bilaterally in
a patient with
dental and facial
anomalies.
Fig. 4.3.9 Peters’ Anomaly. Histopathological section demonstrates lens material

(LM) attached to the posterior cornea. Centrally, the endothelium, Descemet’s
membrane, and Bowman’s layer are not present. Large space (arrow) is fixation
shrinkage artifact. (Courtesy Dr. M. Yanoff.)
Fig. 4.3.8
Mesenchymal Questioning whether keratoplasty for funicular Peters’ anomaly is effec-
Dysgenesis of tive, a recent study of 14 such cases61 disclosed 11 patients (78.6%) had clear
the Anterior grafts at 30 months’ follow-up, with 10 gaining seemingly useful vision.
Segment. This
For eyes with localized central opacity and clear midperiphery, optical iri-
infant combines
features of Peters’ dectomy can afford a far more simplified and visually effective course. Of
anomaly type II increasing importance to surgical decision making is the use of spectral
plus peripheral domain–optical coherence tomography (SD-OCT) to facilitate anterior
sclerocornea and segment microstructural resolution in these complex and variable situa-
bilateral glaucoma. tions.62 For children at high risk for keratoplasty failure, the Boston kera-
toprosthesis has become an alternative51 because despite the challenges of
long-term management, useful vision may result.63,64
Sclerocornea
Sclerocornea defines a nonprogressive, noninflammatory scleral-like
clouding of the cornea, which may be peripheral or diffuse (see Fig. 4.3.8).
Resulting from defective second wave mesenchyme migration, it can cause
corneal flattening or cornea plana because of limbal involvement. Sclero-
cornea additionally may be associated with other entities in the spectrum
of anterior segment developmental defects (see Table 4.3.1), such as Peters’
anomaly (see Fig. 4.3.9). Glaucoma is common, as are other systemic and
ocular anomalies, as previously discussed. Inheritance may be autosomal
coloboma, iris coloboma, angle and iris dysgenesis, persistent hyperplas- dominant, recessive, or X-linked, although most cases are sporadic and
tic primary vitreous, microphthalmos, optic nerve hypoplasia, and foveal usually bilateral. Once glaucoma has been controlled, penetrating kera-
hypoplasia.51 toplasty or perhaps the Boston keratoprosthesis is appropriate, although
outcomes usually are poor because of glaucoma and/or optic nerve
Systemic Associations anomalies.
Systemic associations include short stature, facial dysmorphism, devel-
opmental delay, and delayed skeletal maturation, constituting the auto-
somal recessive Krause–Kivlin syndrome. Peters’-plus syndrome consists Congenital Hereditary Endothelial Dystrophy and
of ocular Peters’ anomaly as well as syndactyly, genitourinary anomalies, Congenital Stromal Corneal Dystrophy
brachycephaly, central nervous system anomalies, cardiac disease, or
deafness.52–54 Peters’ anomaly may be part of fetal alcohol syndrome.55 These two inherited corneal dystrophies are manifest at birth and, as such,
Mutations at the PAX 6 locus on chromosome 11p13 in few patients with comprise congenital corneal anomalies.
Peters’ anomaly56,57 are of interest because this gene appears to be import- Congenital hereditary endothelial dystrophy appears as diffuse bilateral
ant in embryogenesis regulation and also is abnormal in aniridia and corneal edema in the absence of elevated intraocular pressure. Although
autosomal dominant keratitis.58 Mutations in the CYP1B1 gene might be initially held to have both autosomal dominant and recessive forms, recent
causative in Peters’ anomaly59 because this and other gene defects (e.g., evidence localizes the genetic defect to 20p13, responsible for sodium
Axenfeld–Rieger syndrome, 4q25) have been implicated in ocular develop- borate transport, and the recent International Committee for Classifi-
ment as well as glaucoma.60 cation of Corneal Diseases report65 recognizes only autosomal recessive
inheritance. The often-profound corneal edema results from a primary
Pathology dysgenesis of the corneal endothelium with concomitant Descemet’s layer
The pathology of Peters’ anomaly shows absence of central Descemet’s changes and is appropriately considered a mesenchymal dysgenesis dis-
membrane and endothelium (Fig. 4.3.9), which may undergo repair over order. Rarely is intraocular pressure elevated. The results of keratoplasty
time. Other features include residual fibrosis in the opacified stroma and generally are favorable.
central absence of Bowman’s layer. Congenital stromal corneal dystrophy is a rare autosomal dominant
condition resultant from a genetic defect at 12q21.33 producing abnormal-
Treatment and Outcome ity of decorin.65 Clinically diffuse corneal clouding results from myriad
Primary therapy includes treatment of glaucoma, if present. Penetrating flake-like, whitish stromal opacities. Visual loss is variable, and when 175
keratoplasty is clearly appropriate when corneal opacification is bilateral. uncommonly indicated, keratoplasty may be successful.
booksmedicos.org
KEY REFERENCES Mader TH, Stulting D. Technique for the removal of limbal dermoids. Cornea 1998;17:66–7.
4 Alward WL. Axenfeld–Rieger syndrome in the age of molecular genetics. Am J Ophthalmol

2000;130:107–15.
Churchill AJ, Booth AP, Anwar R, et al. PAX 6 is normal in most cases of Peters’ anomaly.
Mayer UM. Peters’ anomaly and combination with other malformations. Ophthalmic Pediatr
Genet 1992;13:131–5.
Meire FM. Megalocornea, clinical and genetic aspects. Doc Ophthalmol 1994;87:1–1121.
Mejia LF, Acosta C, Santamaria JP. Clinical, surgical, and histopathologic characteristics of
corneal keloid. Cornea 2001;20:421–4.
Eye 1998;12:299–303.
Cook CS. Experimental models of anterior segment dysgenesis. Ophthalmic Pediatr Genet Michaeli A, Markovich A, Rootman DS. Corneal transplants for the treatment of congenital
1989;10:33–46. corneal opacities. J Pediatr Ophthalmol Strabismus 2005;42:34–44.
Dana MR, Schaumberg DA, Moyes AL, et al. Corneal transplantation in children with Peters’ Miller MT, Epstein RJ, Sugar J, et al. Anterior segment anomalies associated with the fetal
anomaly and mesenchymal dysgenesis. Multicenter Pediatric Keratoplasty Study. Oph- alcohol syndrome. J Pediatr Ophthalmol Strabismus 1984;21:8–18.
thalmology 1997;104:1580–6. Rezende RA, Uchoa UB, Uchoa R, et al. Congenital corneal opacities in a cornea referral
Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX 6 locus are found in het- practice. Cornea 2004;23:565–70.
erogeneous anterior segment malformations including Peters’ anomaly. Nat Genet Shields MB, Buckley E, Klintworth GK, et al. Axenfeld–Rieger syndrome: a spectrum of
1994;6:168–73. developmental disorders. Surv Ophthalmol 1985;29:387–409.
Harissi-Dagher M, Colby K. Anterior segment dysgenesis: Peters anomaly and sclerocornea.
Int Ophthalmol Clin 2008;48:35–42.
Heon E, Barsoum-Homsy M, Cevrette L, et al. Peters’ anomaly, the spectrum of associated Access the complete reference list online at ExpertConsult.com
ocular malformations. Ophthalmic Pediatr Genet 1992;13:137–43.
176
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1. Cook CS. Experimental models of anterior segment dysgenesis. Ophthalmic Paediatr
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33. Tessier A, Sarreau M, Pelluard F, et al. Fraser syndrome: features suggestive of prenatal
diagnosis in a review of 38 cases. Prenat Diagn 2016;36(13):1270–5.
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2. Michaeli A, Markovich A, Rootman DS. Corneal transplants for the treatment of con- 34. Ozeki H, Shirai S, Majima A, et al. Clinical evaluation of posterior embryotoxon in one
institution. Jpn J Ophthalmol 1997;41:422–5.

genital corneal opacities. J Pediatr Ophthalmol Strabismus 2005;42(1):34–44.
3. Rezende RA, Uchoa UBC, Uchoa R, et al. Congenital corneal opacities in a cornea refer- 35. Cibis GW, Tripathi RC, Tripathi BJ, et al. Corneal keloid in Lowe’s syndrome. Arch Oph-
ral practice. Cornea 2004;23(6):565–70. thalmol 1982;100(11):1795–9.
4. Kenyon KR, Starck T, Cockerham G, et al. Corneal dysgeneses, dystrophies, and degen- 36. Mejía LF, Acosta C, Santamaría JP. Clinical, surgical, and histopathologic characteristics
erations. In: Albert & Jakobiec’s principles & practice of ophthalmology. Elsevier; 2008. p. of corneal keloid. Cornea 2001;20(4):421–4.
497–551. doi:10.1016/B978-1-4160-0016-7.50046-1. 37. Vanathi M, Panda A, Kai S, et al. Corneal keloid. Ocul Surf 2008;6(4):186–97.
5. Warburg M, Sjö O, Fledelius HC. Autosomal recesssive microcephaly, microcornea, con- 38. Nischal KK. Genetics of congenital corneal opacification – impact on diagnosis and treat-
genital cataract, mental retardation, optic atrophy, and hypogenitalism: micro syndrome. ment. Cornea 2015;34(Suppl. 10):S24–34.
Am J Dis Child 1993;147(12):1309. 39. Mader TH, Stulting D. Technique for the removal of limbal dermoids. Cornea
6. Kabzińska D, Mierzewska H, Senderek J, et al. Warburg micro syndrome type 1 associ- 1998;17(1):66–7.
ated with peripheral neuropathy and cardiomyopathy. Folia Neuropathol 2016;3:273–81. 40. Lanzl IM, Augsburger JJ, Hertle RW, et al. The role of ultrasound biomicroscopy in sur-
7. Asahina M, Endoh Y, Matsubayashi T, et al. Novel RAB3GAP1 compound hetero- gical planning for limbal dermoids. Cornea 1998;17(6):604–6.
zygous mutations in Japanese siblings with Warburg micro syndrome. Brain Dev 41. Rončević MB, Dorešić JP, Md LD. Large congenital corneal dermoid with spontaneous
2016;38(3):337–40. partial regression: the first report. Cornea 2011;30(2):219–21.
8. Patil-Chhablani P, Kekunnaya R, Nischal KK. Complex cases in pediatric cataract. Dev 42. Mandal AK, Pehere N. Early-onset glaucoma in Axenfeld and Rieger anomaly: long-term
Ophthalmol 2016;57:85–106. surgical results and visual outcome. Eye (Lond) 2016;30(7):936–42.
9. Ho DK, Levin AV, Anninger WV, et al. Anterior chamber pathology in Alagille syndrome. 43. Shields MB, Buckley E, Klintworth GK, et al. Axenfeld-Rieger syndrome. A spectrum of
Ocul Oncol Pathol 2016;2(4):270–5. developmental disorders. Surv Ophthalmol 1985;29(6):387–409.
10. Pedurupillay CRJ, Barøy T, Holmgren A, et al. Kaufman oculocerebrofacial syndrome 44. Alward WLM. Axenfeld-Rieger syndrome in the age of molecular genetics. Am J Oph-
in sisters with novel compound heterozygous mutation in UBE3B. Am J Med Genet thalmol 2000;130(1):107–15.
2015;167(3):657–63. 45. Micheal S, Siddiqui SN, Zafar SN, et al. A novel homozygous mutation in FOXC1 causes
11. Pasyanthi B, Mendonca T, Sachdeva V, et al. Ophthalmologic manifestations of Haller- Axenfeld Rieger syndrome with congenital glaucoma. PLoS ONE 2016;11(7):e160016–19.
mann-Streiff-Francois syndrome: report of four cases. Eye (Lond) 2016;30(9):1268–71. 46. Walter MA, Mirzayas F, Mears AJ, et al. Autosomal-dominant iridogoniodysgenesis and
12. Vingolo EM, Steindl K, Forte R, et al. Autosomal dominant simple microphthalmos. J Axenfeld-Rieger syndrome are genetically distinct. Ophthalmol 1996;103(11):1907–15.
Med Genet 1994;31(9):721–5. 47. Rao A, Padhy D, Sarangi S, et al. Unclassified Axenfeld-Rieger syndrome: a case series
13. Zvulunov H, Kachko D, Manor L, et al. Reticulolinear aplasia cutis congenita of the face and review of literature. Semin Ophthalmol 2018;33(3):300–7.
and neck: a distinctive cutaneous manifestation in several syndromes linked to Xp22. Br 48. Ni W, Wang W, Hong J, et al. A novel histopathologic finding in the Descemet’s mem-
J Dermatol 1998;138(6):1046–52. brane of a patient with Peters Anomaly: a case-report and literature review. BMC Oph-
14. Cape CJ. Phenotypic variation in ophthalmic manifestations of MIDAS syndrome thalmol 2015;15:139.
(microphthalmia, dermal aplasia, and sclerocornea). Arch Ophthalmol 2004;122(7):1070. 49. Townsend WM, Font RL, Zimmerman LE. Congenital corneal leukomas. 2. Histopatho-
15. Salmon JF, Wallis CE, Murray ADN. Variable expressivity of autosomal dominant micro- logic findings in 19 eyes with central defect in Descemet’s membrane. Am J Ophthalmol
cornea with cataract. Arch Ophthalmol 1988;106(4):505–10. 1974;77(2):192–206.
16. Graham JM, Hennekam R, Dobyns WB, et al. MICRO syndrome: an entity distinct from 50. Kenyon KR. Mesenchymal dysgenesis in Peter’s anomaly, sclerocornea and congenital
COFS syndrome. Am J Med Genet 2004;128A(3):235–45. endothelial dystrophy. Exp Eye Res 1975;21(2):125–42.
17. Khan K, Al-Maskari A, McKibbin M, et al. Genetic heterogeneity for recessively inher- 51. Harissi-Dagher M, Colby K. Anterior segment dysgenesis: Peters anomaly and sclerocor-
ited congenital cataract microcornea with corneal opacity. Invest Ophthalmol Vis Sci nea. Int Ophthalmol Clin 2008;48(2):35–42.
2011;52(7):4294–6. 52. Heon E, Barsoum-Homsy M, Cevrette L, et al. Peters’ anomaly. The spectrum of associ-
18. Strömland K. Visual impairment and ocular abnormalities in children with fetal alcohol ated ocular and systemic malformations. Ophthalmic Paediatr Genet 1992;13(2):137–43.
syndrome. Addict Biol 2004;9(2):153–7. 53. Mayer UM. Peters’ anomaly and combination with other malformations (series of 16
19. Webb TR, Matarin M, Gardner JC, et al. X-linked megalocornea caused by mutations in patients). Ophthalmic Paediatr Genet 1992;13(2):131–5.
CHRDL1 identifies an essential role for ventroptin in anterior segment development. Am 54. Maillette de Buy Wenniger-Prick LJJM, Hennekam RCM. The Peters’ plus syndrome: a
J Hum Genet 2012;90(2):247–59. review. Ann Genet 2002;45(2):97–103.
20. Davidson AE, Cheong S-S, Hysi PG, et al. Association of CHRDL1 mutations and vari- 55. Miller MT, Epstein RJ, Sugar J, et al. Anterior segment anomalies associated with the
ants with X-linked megalocornea, Neuhäuser syndrome and central corneal thickness. fetal alcohol syndrome. J Pediatr Ophthalmol Strabismus 1984;21(1):8–18.
Anderson MG, ed. PLoS ONE 2014;9(8):e104163–12. 56. Hanson IM, Fletcher JM, Jordan T, et al. Mutations at the PAX6 locus are found in
21. Fecarotta C, Huang W. Pediatric genetic disease of the cornea. J Pediatr Genet heterogeneous anterior segment malformations including Peters’ anomaly. Nat Genet
2015;03(04):195–207. 1994;6(2):168–73.
22. Khan AO, Aldahmesh MA, Alkuraya FS. Congenital megalocornea with zonular weak- 57. Churchill AJ, Booth AP, Anwar R, et al. PAX 6 is normal in most cases of Peters’
ness and childhood lens-related secondary glaucoma – a distinct phenotype caused by anomaly. Eye (Lond) 1998;12(Pt 2):299–303.
recessive LTBP2 mutations. Mol Vis 2011;17:2570–9. 58. Mirzayans F, Pearce WG, MacDonald IM. Mutation of the PAX6 gene in patients with
23. Meire FM. Megalocornea. Clinical and genetic aspects. Ophthalmic Lit 1995;3(48):181. autosomal dominant keratitis. Am J Hum Genet 1995;57(3):539–48.
24. Pletz C, Hentsch R. Hereditary anterior megalophthalmus – a genealogical study of 12 59. Vincent A, Billingsley G, Priston M, et al. Further support of the role of CYP1B1 in
patients in 4 generations. Klin Monbl Augenheilkd 2000;217(5):284–8. patients with Peters anomaly. Mol Vis 2006;12:506–10.
25. Skuta GL, Sugar J, Ericson ES. Corneal endothelial cell measurements in megalocornea. 60. Doward W, Perveen R, Lloyd IC, et al. A mutation in the RIEG1 gene associated with
Arch Ophthalmol 1983;101(1):51–3. Peters’ anomaly. J Med Genet 1999;36(2):152–5.
26. Meire FM, Delleman JW. Autosomal dominant congenital miosis with megalocornea. 61. Basdekidou C, Dureau P, Edelson C, et al. Should unilateral congenital corneal opacities
Ophthalmic Paediatr Genet 1992;13(2):123–9. in Peters’ anomaly be grafted? Eur J Ophthalmol 2011;21(6):695–9.
27. Antiñolo G, Rufo M, Borrego S, et al. Megalocornea-mental retardation syndrome: an 62. Hong J, Yang Y, Cursiefen C, et al. Optimising keratoplasty for Peters’ anomaly in infants
additional case. Am J Med Genet 1994;52(2):196–7. using spectral-domain optical coherence tomography. Br J Ophthalmol 2017;101(6):820–7.
28. Meire FM. Megalocornea. Doc Ophthalmol 1994;87(1):1–121. 63. Dana R, Schaumberg DA, Moyes AL, et al. Corneal transplantation in children with
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2009;35(12):2042–6. 64. Nischal KK. Congenital corneal opacities – a surgical approach to nomenclature and clas-
30. Plaisancié J, Brémond-Gignac D, Demeer B, et al. Incomplete penetrance of biallelic sification. Eye (Lond) 2007;21(10):1326–37.
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31. Deml B, Reis LM, Lemyre E, et al. Novel mutations in PAX6, OTX2 and NDP in anoph- edition 2. Cornea 2015;34(2):117–59.
thalmia, microphthalmia and coloboma. Eur J Hum Genet 2015;24(4):535–41.
176.e1
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Section 3 External Diseases
Blepharitis
Jihad Isteitiya, Neha Gadaria-Rathod, Karen B. Fernandez, Penny A. Asbell 4.4
Definitions: Blepharitis is a general term describing inflammation of PATHOGENESIS
the eyelids, whereas marginal blepharitis is inflammation of the eyelid The pathophysiology of blepharitis involves a complex interaction of
margin, which can be subdivided into anterior and posterior blepharitis. various factors, including abnormal lid-margin secretions, lid-margin
Anterior blepharitis involves inflammation of the lid margin anterior organisms, and a dysfunctional precorneal tear film. Several classifica-
to the gray line and concentrated around the eyelashes and hair tion systems exist for blepharitis.2,8–10 It can be anatomically subdivided
follicles. It may be accompanied by squamous debris, scurfs, and into anterior blepharitis (Fig. 4.4.1) and posterior blepharitis. Alternatively,
collarettes around the lashes. Posterior blepharitis involves inflammation blepharitis can be classified according to the presenting clinical features
posterior to the gray line, which may have various causes, including into staphylococcal, seborrheic, mixed staphylococcal and seborrheic, and
meibomian gland dysfunction (MGD) and conjunctivitis. MGD (Fig. 4.4.2).
MGD is defined as a chronic, diffuse abnormality of the MGs, The lid inflammation characteristic of blepharitis is most often caused
commonly characterized by terminal duct obstruction and/or by a combination of anterior and posterior factors of varying degrees. In
qualitative/quantitative changes in glandular secretion. It may result in most types of blepharitis, some MG involvement occurs.11 MGs are tubu-
alteration of the tear film, symptoms of eye irritation, clinically apparent loacinar, holocrine glands that produce and secrete meibum, an oily sub-
inflammation, and ocular surface disease.1 stance that produces the lipid layer of the preocular tear film.12 Embedded
in the tarsal plates, normally 30–40 MGs occur in the upper lid and 20–30
glands in the lower lid. Each MG consists of a main duct surrounded by
grape-like acinar clusters. These ducts open into the lid margin just ante-
rior to the mucocutaneous junction, delivering meibum to the tear film.
Key Features
• Chronic burning, irritation, foreign body sensation, epiphora.
• Inflammatory changes of the eyelid including thickening, erythema,
hyperkeratinization, vascularization, telangiectasia, or notching.
• Presence of scurf, collarettes, and sleeves along lashes.
• Minimal meibomian gland secretion with pressure or abnormal
meibum, which is turbid, foamy, or granular in appearance.
Associated Features
• Tylosis (thickening and distortion of the lid margin).
• Poliosis (loss of lash pigmentation).
• Punctal misdirection and/or scarring.
• Conjunctival hyperemia.
• Perilimbal superficial corneal neovascularization.
• Catarrhal infiltrates.
• Acne rosacea.
Fig. 4.4.1 Anterior blepharitis.
INTRODUCTION
Blepharitis, first described by Elschnig in 1908,2 poses a significant chal-
lenge for the clinician because of its chronic nature and availability of
diverse treatment options but minimal scientific evidence for their efficacy.
Nonetheless, given the prevalence of blepharitis, its association with dry
eye disease (DED), and its effect on quality of life, better understanding
and management of this condition is essential for reducing ocular discom-
fort and improving the patient’s quality of life.1
EPIDEMIOLOGY
MGD is one of the most common disorders encountered by eyecare pro-
viders. MGD is now considered the leading cause of evaporative dry eye.1
The prevalence of MGD varies considerably in published studies, from
3.5% to almost 70%.1,3–7
This striking difference is partly attributed to inconsistent diagnostic
criteria among countries and to varying age distribution between study
groups.1,7 The prevalence of MGD is affected by age, with older patients at 177
increased risk of developing MGD. Fig. 4.4.2 Meibomian gland dysfunction.
booksmedicos.org
MGD is defined as a chronic, diffuse abnormality of MGs, commonly rosacea, dilated and telangiectatic vessels at the lid margin and interpalpe-
4 characterized by terminal duct obstruction and/or qualitative/quantitative

changes in the glandular secretion.9 Alterations in the composition of the
meibomian secretions occur in patients with chronic blepharitis.12–14 Alter-
bral hyperemia may be seen.
ation in nonpolar lipids raises the melting point of the meibum, leading
DIAGNOSIS AND ANCILLARY TESTING
to thickening of the meibum and stagnation. Decreased amounts of polar Blepharitis is mainly a clinical diagnosis. However, ancillary testing may
lipids result in uneven spreading of tears,15 likely leading to instability of be considered in those who have chronic disease or are unresponsive to
the tear film and hyperosmolarity, increased bacterial growth, evaporative therapy, to monitor treatment effect, and for research purposes.
dry eye, and ocular surface inflammation, including keratinization, scar- Culture samples taken from the eyelid margins may grow the typical
ring, and retraction of the gland orifices, thus further exacerbating MGD. bacteria associated with blepharitis, as well as viruses, such as herpes
Several factors can aggravate MGD, such as increasing age, contact lens simplex, herpes zoster, and molluscum contagiosum. Microscopic exam-
wear, and hormonal imbalance.10,11,14 ination of the epilated lashes may show Demodex eggs, and adult mites.18
Several bacteria, fungi (Pitysporum), and parasites (Demodex) also have MG secretion can be analyzed by its quality and expressibility. This can
been implicated. The most common organisms isolated from patients be done by digital pressure or with the use of a device that applies a stan-
with chronic blepharitis include Staphylococcus epidermidis, Propionibacte- dard pressure that is equivalent to the pressure exerted on the lids during
rium acnes, corynebacteria, and Staphylococcus aureus.16 S. epidermidis and a normal blink.23 This device targets a standard area of one third of the
S. aureus produce lipolytic enzymes, such as triglyceride lipase, cholesterol total number of glands (8–10 glands). Expressibility is graded according to
esterase, and wax esterase, which hydrolyze wax and sterol esters with the the number of glands that express fluid; decreased expressibility indicates
release of highly irritating free fatty acids, resulting in the disruption of disease. Although it sounds simple, marked variability exists among indi-
the tear film integrity.12 In seborrheic blepharitis, the increased amount of viduals, and hence a definite cutoff between normal and abnormal cannot
low viscosity meibum favors the growth of bacteria and leads to inflam- be defined. Moreover, the location of the glands along the lid margin influ-
mation of the lids.14 Acne rosacea is a relatively common chronic skin ences their expressibility. It was found that nasal glands tend to express
disease characterized by persistent erythema, telangiectasis, papules, pus- most actively, followed by central glands, and then temporal glands.24 The
tules, and sebaceous gland hypertrophy, predominantly affecting the fore- quality of glandular secretion can be evaluated in terms of appearance.
head, cheeks, and nose. Although the pathogenesis is still unclear, studies It can be classified as clear, cloudy opaque, viscous, or toothpaste-like by
suggest that it is primarily caused by an altered innate immune response using various grading schemes.21,25
in those with a genetic predisposition. Certain reactive oxygen species and More recently, interferometry has been developed to measure the lipid
infectious agents, such as Demodex folliculorum and Helicobacter pylori also layer of tears. The patient’s eye is illuminated with light directed at the
have been implicated.17 corneal surface; light passes through the tear film and is reflected into
a camera, forming an interference pattern called an interferogram. The
OCULAR MANIFESTATIONS interferometer measures the lipid layer thickness of a defined area of tear
film and captures the blink profile during a designated time interval. A
Typical symptoms of blepharitis include redness, itching, burning, crust- positive correlation between tear film lipid layer thickness and expressible
ing along the lid margin, loss of lashes, stickiness of lashes, and tearing. MGs suggests that a low lipid layer thickness indicates a high probability
Furthermore, as MGD has been suggested to be the leading cause of DED,1 of MGD.26
presenting symptoms, such as dryness, ocular irritation, and fluctuating Changes in MG morphology and gland dropout can be assessed using
vision, may indicate the need for the clinician to examine the lid margin. meiboscopy. This is done with transillumination through the skin and
These symptoms are chronic, usually waxing and waning, and may be observing the glandular silhouette through the everted mucosal side.
exacerbated by some environmental factors, such as wind, smoke, dust, Photodocumentation of the same is called meibography.18 The disadvantage
cosmetic products, and so on. Symptoms usually are bilateral but may be of the transillumination method is that it may be tedious and time con-
asymmetrical. The presence of predominantly unilateral symptomatology suming. Noncontact meibography applies the same principle but is easier
should alert the clinician to consider other diagnoses, such as sebaceous and more rapid than transillumination. It uses an infrared transmitting
cell carcinoma, which may masquerade as chronic unilateral blepharitis. filter attached to a slit lamp and video camera.27 Photographs are taken,
External examination using slit-lamp biomicroscopy is essential in and MG morphology and dropout are then analyzed. Recent advancements
establishing diagnosis and determining the type of blepharitis. Staphy- to the technology now include mobile, handheld, pen-shaped systems with
lococcal anterior blepharitis is more common in the younger population an infrared light-emitting diode fixed to the camera, which enables cap-
and has a female preponderance. Findings include vascularization and turing of videos and images that are comparable in quality with previous
erythema of the lid margin, telangiectasia, eyelid edema, loss or misdirec- meibography systems. It is convenient and applicable for examination of
tion of lashes, collarettes around the base of the lashes, and crusting or MGs in patients of all ages.28
hyperkeratosis. Chronic findings of ulceration, punctal misdirection, and Keratography permits visual assessment of the topography of the
scar formation may be seen. There can be signs of corneal involvement in corneal surface, allowing for an analysis of tear film stability by comparing
severe cases, presenting with phlyctenulosis, corneal neovascularization, the irregularities in recorded images. In addition to evaluating TBUT, kera-
thinning, or marginal ulceration. Seborrheic blepharitis is more common tography can examine MGs, tear meniscus height, and lipid layer.29
in the older age group. It presents with scurfs, which is a term used to refer In vivo laser scanning confocal microscopy is a contact technique can
to the scales, oily debris, and greasy material that collects along the lash be used to examine the microstructure of MG acinar units and measure
shaft as a result of hypersecretion from MGs.18 In blepharitis associated their size.30
with Demodex sp. infestation, the most commonly seen finding is coating
of the lash with cylindrical dandruff-like material (sleeves).19 TREATMENT
Clinical signs of MGD may include rounding, thickening, and irreg-
ularity of the eyelid margin; changes in the lid vascularity and presence The goal of all the treatments of MGD is to improve the flow of meibo-
of telangiectasia; pouting, plugging, and narrowing of the gland orifices; mian gland secretions, thus achieving normal tear film stability.31
reduction in volume and number of glands secreting liquid; and changes Treatment strategies aiming at improving the quality of the meibum
in gland secretion quality, clarity, and viscosity with greater pressure include a combination of lid hygiene, management of MGD, reduc-
required to express secretions.19,20 “Non-obvious MGD” is a common ing bacterial colonization of the lids, suppression of inflammation, and
form of obstructive MGD that shows no obvious signs of inflammation, restoring tear quality.32 It is crucial to educate patients about the chronic,
hypersecretion, or purulent secretion of the glands but may become more recurrent nature of the disease and the need for long-term intervention.
apparent with pressure on the lid as the meibum orifices are examined.21 Despite the availability of diverse treatment options, very few treatments
In chronic MGD, there may be cicatricial changes along the lid margin, have been extensively evaluated for safety and efficacy in randomized con-
and the mucocutaneous junction may migrate anterior to the MG line.22 trolled trials, and most are typically not approved by the U.S. Food and
Subtle signs, such as the frothy quality of the tear meniscus, and decreased Drug Administration (FDA) for use in blepharitis specifically. Treatment
Schirmer’s scores and tear breakup time (TBUT), may be found. Other recommendations are largely dependent on clinical experience and pub-
ocular conditions, such as recurrent chalazia, trichiasis, and keratocon- lished case reports.
junctivitis sicca, may be seen. External examination of the face and skin Lid hygiene, the mainstay of treatment for blepharitis, consists of
178 may reveal associated dermatological problems, such as seborrheic der- warm compresses, lid massage, lid scrubs, and avoidance of excessive eye
matitis, atopy, herpes zoster ophthalmicus, and acne rosacea. In ocular makeup. Treatment with warm compresses involves the placement of a
booksmedicos.org
warm washcloth on closed lids daily for 5–10 minutes. The goals of heat As change in tear composition and tear film stability may be a key
therapy are to soften and loosen encrustations, liquefy the solidified and
stagnant secretions, and to dilate ducts. This is followed by lid massage.
contributor to lid margin inflammation, supplementation of the tear film
may improve both MGD and DED. Treatment options include tears, gels, 4.4
The eyelid is held taut at the outer corner with one hand while the index ointments, environmental control, and moisture goggles. A newer class
finger of the other hand sweeps from the inner corner of the lid toward of tear substitutes involving the use of lipid-containing eyedrops, lipo-
Blepharitis
the ear while applying pressure. This is repeated several times to express somal sprays, emulsion-type eyedrops, and ointments that may be more
the MG contents, which have melted during the warm compresses step. effective than saline-based artificial tears in DED associated with MGD.41,42
Cleansing with lid scrubs is usually done once or twice daily initially. Dietary supplementation with omega-3 fatty acids has been shown to be
Commercially available scrubs or a cotton-tipped applicator soaked with a effective in improving signs and symptoms of DED and MGD by reduc-
weak solution of baby shampoo can be used to rub along the lid margin to ing ocular surface inflammation and improving the lipid composition of
remove deposits and the abnormal oily secretions from the lids. Patients meibum.11
should be instructed to avoid excessive scrubbing and massage because Several additional methods of treatment exist that have been found
these actions can lead to ocular irritation. to be helpful when used in conjunction with the core interventions
Besides self-care, therapeutic MG expression as an in-office procedure mentioned above. Antiseborrheic shampoos, such as those containing
performed by the clinician can help relieve MGD by using probes and/ selenium sulfide or tar, may be helpful when seborrheic dermatitis is sig-
or mechanical pressure to open and express meibum. Intraductal MG nificant. Weekly lid scrubs with 50% tea tree oil and daily lid scrubs with
probing is a relatively nontraumatic method that utilizes small stainless tea tree shampoo are effective in eradicating Demodex infestation of the
steel probes to open the MG orifices, and this may mechanically open and lids but can be irritating to the ocular surface.43 As MGD may be related to
dilate the natural orifices and ducts of the MGs. androgen deficiency or receptor dysfunction, topical androgens are being
Participants currently are being recruited for a randomized, double-blind evaluated as a possible therapeutic option for patients with MGD.44
trial investigating the efficacy of intraductal MG probing compared with A growing interest exists in the role of blepharitis, especially MGD,
a sham procedure in patients with refractory MGD.33 However, therapeu- in understanding and treating ocular surface disease, especially DED.
tic expression may be painful to the patient.34 The BlephEx device, a less However, to date, there is still limited understanding of what findings are
invasive method of microexfoliation of the lid margins, utilizes a rapidly clinically pathological and associated with signs and symptoms of ocular
rotating microsponge to remove lid debris and microbial biofilm from disease and what treatments would most benefit patients. Current research
the lid margins.35 Recently, a new thermopulsation device has been devel- is addressing environmental, dietary, pharmacological, and surgical inter-
oped, and it allows heat to be applied to the palpebral surfaces of the lids ventions to better understand blepharitis and to optimize the treatment of
directly over the MGs while simultaneously applying graded pulsatile pres- this chronic ocular condition.
sure to the outer eyelid surfaces, thereby gently expressing MGs during
heating. The automated treatment device has two main components: a lid
warmer and an eye cup. The lid warmer resembles a large oval scleral lens KEY REFERENCES
designed to rest on the bulbar conjunctiva and vault the cornea. The eye Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland
cup contains an inflatable air bladder that massages the eyelids to express dysfunction: report of the subcommittee on management and treatment of meibomian
MGs in the upper and lower eyelids simultaneously.36 gland dysfunction. Invest Ophthalmol Vis Sci 2011;52:2050–64.
Topical antibiotics are added when underlying bacterial infection is sus- Graham JE, Moore JE, Jiru X, et al. Ocular pathogen or commensal: a PCR-based study
of surface bacterial flora in normal and dry eyes. Invest Ophthalmol Vis Sci 2007;48:
pected. Bacitracin and erythromycin ophthalmic ointments are effective 5616–23.
agents for anterior blepharitis. Generally, ointments are applied directly Ibrahim OMA, Matsumoto Y, Dogru M, et al. The efficacy, sensitivity, and specificity of in
to the lid margins to avoid toxicity to the ocular surface. Fluoroquino- vivo laser confocal microscopy in the diagnosis of meibomian gland dysfunction. Oph-
lone eyedrops have minimal ocular toxicity and have a wide coverage of thalmology 2010;117:665–72.
Ishida R, Matsumoto Y, Onguchi T, et al. Tear film with “Orgahexa EyeMasks” in patients
organisms. Topical fusidic acid has shown efficacy in patients with ocular with meibomian gland dysfunction. Optom Vis Sci 2008;85:684–91.
rosacea blepharitis. Although not yet approved by the FDA, topical metro- Joseph MA, Kaufman HE, Insler M. Topical tacrolimus ointment for treatment of refractory
nidazole gel 0.75%–1% also may be effective when used on the lid margin anterior segment inflammatory disorders. Cornea 2005;24:417–20.
for treatment of ocular rosacea.32 Systemic antibiotics, such as cloxacil- Knop E, Knop N, Millar T, et al. The international workshop on meibomian gland dysfunc-
tion: report of the subcommittee on anatomy, physiology, and pathophysiology of the
lin, may be added for treatment of persistent or recurrent staphylococcal meibomian gland. Invest Ophthalmol Vis Sci 2011;52:1938–78.
blepharitis. Oral tetracyclines are commonly used in the management of Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry eye
rosacea and MGD. They are mainly used for their anti-inflammatory and symptoms and gland location. Cornea 2008;27:1142–7.
lipid-regulating properties, rather than for their antimicrobial effects. They Lane SS, Dubiner HB, Epstein RJ, et al. A new system, the LipiFlow, for the treatment of
meibomian gland dysfunction. Cornea 2012;31:396–404.
decrease the production of bacterial lipases, thus reducing the concentra- Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian
tion of free fatty acids and their deleterious effects on lipid composition.37 gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc 2008;106:336–56.
They exert anti-inflammatory effects resulting from inhibition of matrix Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive meibo-
metalloproteinases, cytokines, lymphocyte and neutrophil activation, and mian gland dysfunction. Cornea 2010;29:1145–52.
Meadows JF, Ramamoorthy P, Nichols JJ, et al. Development of the 4-3-2-1 meibum express-
chemotaxis. They also have antiangiogenic and antiapoptotic properties.38 ibility scale. Eye Contact Lens 2012;38:86–92.
They usually are used in doses ranging from 250 mg once to four times Nelson JD, Shimazaki J, Benitez-del-Castillo JM, et al. The international workshop on meibo-
a day (tetracycline and oxytetracycline) to 50–100 mg once or twice a day mian gland dysfunction: report of the definition and classification subcommittee. Invest
(doxycycline and minocycline). Low doses of doxycycline 20 mg may be Ophthalmol Vis Sci 2011;52:1930–7.
Nien CJ, Massei S, Lin G, et al. Effects of age and dysfunction on human meibomian glands.
used when long-term therapy is required. A 40 mg/day slow-release dose Arch Ophthalmol 2011;129:462–9.
of doxycycline is approved for treatment of rosacea and is used by some Pult H, Riede-Pult BH. Non-contact meibography in diagnosis and treatment of non-obvious
clinicians. Tetracycline use is limited by its common side effects, which meibomian gland dysfunction. J Optom 2012;5:2–5.
include sun sensitivity and gastrointestinal upset and known contraindica- Rubin M, Rao SN. Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepha-
tions for use in pregnant women and children. Oral macrolide antibiotics, ritis. J Ocul Pharmacol Ther 2006;22:47–53.
Scaffidi RC, Korb DR. Comparison of the efficacy of two lipid emulsion eyedrops in increas-
such as erythromycin and azithromycin, are safer and also have immuno- ing tear film lipid layer thickness. Eye Contact Lens 2007;33:38–44.
modulatory and anti-inflammatory effects similar to those of tetracyclines. Schaumberg DA, Nichols JJ, Papas EB, et al. The international workshop on meibomian
Recently, the use of a topical azithromycin (1%) was suggested as an effec- gland dysfunction: report of the subcommittee on the epidemiology of, and associated
tive treatment of posterior blepharitis, with a significant improvement in risk factors for, MGD. Invest Ophthalmol Vis Sci 2011;52:1994–2005.
Siak JJ, Tong L, Wong WL, et al. Prevalence and risk factors of meibomian gland dysfunc-
MG secretion quality, eyelid redness, tear quality, and overall symptomatic tion: the Singapore Malay eye study. Cornea 2012;31:1223–8.
relief, but results from studies regarding efficacy are mixed.39 Stanek S. Meibomian gland status comparison between active duty personnel and U.S. vet-
In cases with more severe lid margin inflammation, a short-term course erans. Mil Med 2000;165:591–3.
of topical corticosteroids or antibiotic–corticosteroid combinations may be Tomlison A, Bron AJ, Korb DR, et al. The international workshop on meibomian gland
dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci
utilized. Long-term use of corticosteroids is limited by serious side effects, 2011;52:2006–49.
such as cataracts, glaucoma, and infection. Topical immunomodulators, Veldman P, Colby K. Current evidence for topical azithromycin 1% ophthalmic solution in
such as cyclosporine A 0.05%, a calcineurin inhibitor, have been shown to the treatment of blepharitis and blepharitis-associated ocular dryness. Int Ophthalmol
be beneficial in the treatment of MGD in conjunction with rosacea and/ Clin 2011;51:43–52.
or DED, with a significant improvement in lid margin inflammation and
signs of DED.40 Nearly all suggested treatments have not received FDA Access the complete reference list online at ExpertConsult.com 179
approval for use in lid disease.
booksmedicos.org
REFERENCES 24. Blackie CA, Korb DR. The diurnal secretory characteristics of individual meibomian
glands. Cornea 2010;29:34–8.
1. Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian gland
dysfunction: executive summary. Invest Ophthalmol Vis Sci 2011;52:1922–9.
25. Meadows JF, Ramamoorthy P, Nichols JJ, et al. Development of the 4-3-2-1 meibum
expressibility scale. Eye Contact Lens 2012;38:86–92.
4.4
2. Mathers WD, Shields WJ, Sachdev MS, et al. Meibomian gland dysfunction in chronic 26. Finis D, Pischel N, Schrader S, et al. Evaluation of lipid layer thickness measure-
ment of the tear film as a diagnostic tool for meibomian gland dysfunction. Cornea
Blepharitis
blepharitis. Cornea 1991;10:277–85.
3. Lin PY, Tsai SY, Cheng CY, et al. Prevalence of dry eye among an elderly Chinese popu- 2013;32:1549–53.
lation in Taiwan: the Shihpai Eye Study. Ophthalmology 2003;110:1096–101. 27. Pult H, Riede-Pult BH. Non-contact meibography: keep it simple but effective. Cont Lens
4. Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eye among the elderly. Am J Anterior Eye 2012;35:77–80.
Ophthalmol 1997;124:723–8. 28. Arita R, Itoh K, Maeda S, et al. A newly developed noninvasive and mobile pen-shaped
5. Jie Y, Xu L, Wu YY, et al. Prevalence of dry eye among adult Chinese in the Beijing Eye meibography system. Cornea 2013;32:242–7.
Study. Eye (Lond) 2009;23:688–93. 29. Best N, Drury L, Wolffsohn JS. Clinical evaluation of the Oculus Keratograph. Cont Lens
6. Uchino M, Dogru M, Yagi Y, et al. The features of dry eye disease in a Japanese elderly Anterior Eye 2012;35:171–4.
population. Optom Vis Sci 2006;83:797–802. 30. Randon M, Liang H, El Hamdaoui M, et al. In vivo confocal microscopy as a novel
7. Viso E, Rodriguez-Ares MT, Abelenda D, et al. Prevalence of asymptomatic and symp- and reliable tool for the diagnosis of Demodex eyelid infestation. Br J Ophthalmol
tomatic meibomian gland dysfunction in the general population of Spain. Invest Oph- 2015;99:336–41.
thalmol Vis Sci 2012;53:2601–6. 31. Qiao J, Yan X. Emerging treatment options for meibomian gland dysfunction. Clin Oph-
8. McCulley JP, Dougherty JM, Deneau DG. Classification of chronic blepharitis. Ophthal- thalmol 2013;7:1797–803.
mology 1982;89:1173–80. 32. Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian
9. Nelson JD, Shimazaki J, Benitez-del-Castillo JM, et al. The international workshop on gland dysfunction: report of the subcommittee on management and treatment of meibo-
meibomian gland dysfunction: report of the definition and classification subcommittee. mian gland dysfunction. Invest Ophthalmol Vis Sci 2011;52:2050–64.
Invest Ophthalmol Vis Sci 2011;52:1930–7. 33. Infirmary MEaE. Intraductal Meibomian Gland Probing Trial (MGP). 2014–2016.
10. Jackson WB. Blepharitis: current strategies for diagnosis and management. Can J Oph- 34. Maskin SL. Intraductal meibomian gland probing relieves symptoms of obstructive mei-
thalmol 2008;43:170–9. bomian gland dysfunction. Cornea 2010;29:1145–52.
11. Macsai MS. The role of omega-3 dietary supplementation in blepharitis and meibomian 35. Gunnarsdottir S, Kristmundsson A, Freeman MA, et al. Demodex folliculorum – a
gland dysfunction (an AOS thesis). Trans Am Ophthalmol Soc 2008;106:336–56. hidden cause of blepharitis. Laeknabladid 2016;102:231–5.
12. Bron AJ, Tiffany JM. The contribution of meibomian disease to dry eye. Ocul Surf 36. Lane SS, DuBiner HB, Epstein RJ, et al. A new system, the LipiFlow, for the treatment of
2004;2:149–65. meibomian gland dysfunction. Cornea 2012;31:396–404.
13. McCulley JP, Shine WE. Meibomian secretions in chronic blepharitis. Adv Exp Med Biol 37. Dougherty JM, McCulley JP, Silvany RE, et al. The role of tetracycline in chronic bleph-
1998;438:319–26. aritis. Inhibition of lipase production in staphylococci. Invest Ophthalmol Vis Sci
14. Knop E, Knop N, Millar T, et al. The international workshop on meibomian gland dys- 1991;32:2970–5.
function: report of the subcommittee on anatomy, physiology, and pathophysiology of the 38. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress
meibomian gland. Invest Ophthalmol Vis Sci 2011;52:1938–78. MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal epithe-
15. Bron AJ, Tiffany JM, Gouveia SM, et al. Functional aspects of the tear film lipid layer. Exp lium in experimental dry eye. Exp Eye Res 2006;83:526–35.
Eye Res 2004;78:347–60. 39. Veldman P, Colby K. Current evidence for topical azithromycin 1% ophthalmic solution
16. Yamasaki K, Gallo RL. The molecular pathology of rosacea. J Dermatol Sci 2009;55:77–81. in the treatment of blepharitis and blepharitis-associated ocular dryness. Int Ophthalmol
17. Oltz M, Check J. Rosacea and its ocular manifestations. Optometry 2011;82:92–103. Clin 2011;51:43–52.
18. Tomlinson A, Bron AJ, Korb DR, et al. The international workshop on meibomian 40. Rubin M, Rao SN. Efficacy of topical cyclosporin 0.05% in the treatment of posterior
gland dysfunction: report of the diagnosis subcommittee. Invest Ophthalmol Vis Sci blepharitis. J Ocul Pharmacol Ther 2006;22:47–53.
2011;52:2006–49. 41. Scaffidi RC, Korb DR. Comparison of the efficacy of two lipid emulsion eyedrops in
19. Liu J, Sheha H, Tseng SC. Pathogenic role of Demodex mites in blepharitis. Curr Opin increasing tear film lipid layer thickness. Eye Contact Lens 2007;33:38–44.
Allergy Clin Immunol 2010;10:505–10. 42. Goto E, Dogru M, Fukagawa K, et al. Successful tear lipid layer treatment for refractory
20. Foulks GN, Bron AJ. Meibomian gland dysfunction: a clinical scheme for description, dry eye in office workers by low-dose lipid application on the full-length eyelid margin.
diagnosis, classification, and grading. Ocul Surf 2003;1:107–26. Am J Ophthalmol 2006;142:264–70.
21. Blackie CA, Korb DR, Knop E, et al. Nonobvious obstructive meibomian gland dysfunc- 43. Gao YY, Di Pascuale MA, Elizondo A, et al. Clinical treatment of ocular demodecosis by
tion. Cornea 2010;29:1333–45. lid scrub with tea tree oil. Cornea 2007;26:136–43.
22. Yamaguchi M, Kutsuna M, Uno T, et al. Marx line: fluorescein staining line on the inner 44. Sullivan BD, Evans JE, Krenzer KL, et al. Impact of antiandrogen treatment on the fatty
lid as indicator of meibomian gland function. Am J Ophthalmol 2006;141:669–75. acid profile of neutral lipids in human meibomian gland secretions. J Clin Endocrinol
23. Korb DR, Blackie CA. Meibomian gland diagnostic expressibility: correlation with dry eye Metab 2000;85:4866–73.
symptoms and gland location. Cornea 2008;27:1142–7.
179.e1
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Section 3 External Diseases
Herpes Zoster Ophthalmicus

Majid Moshirfar, Gene Kim, Brian D. Walker, Orry C. Birdsong 4.5
Definition: Infection of varicella (chickenpox) in the ophthalmic Ophthalmic Herpes Zoster
division of the trigeminal dermatome most frequently affecting the The frequency of herpes zoster ophthalmicus (HZO) is second only to tho-
nasociliary branch. racic dermatomal occurrence, with up to 250 000 cases occurring yearly in
the United States.4,17 Of these, 50%–70% suffer visual morbidity with sever-
ity increasing in the 5th–8th decades of life.4,17 The virus most commonly
establishes latency in the trigeminal sensory ganglion and reactivates in
Key Features 10%–25% of the population.17 The ophthalmic division of the trigeminal
• Herpes zoster ophthalmicus can affect any of the ocular or adnexal nerve is affected 20 times more frequently than the maxillary or mandib-
tissues. ular divisions.18 Ocular involvement occurs in more than 70% of patients
• Treatment with antivirals promotes healing of rashes and prevents with zoster of the first (ophthalmic) division of the trigeminal nerve. Naso-
ocular complications. ciliary branch involvement with skin lesions located on the inner corner of
the eye, tip of the nose (Hutchinson’s sign), and root or side of the nose
is predictive (50%–85%) of ocular involvement and is strongly prognostic
for ocular inflammation and corneal sensory denervation.13,19 The eye may
Associated Features be seriously affected in up to 50% of cases in the absence of Hutchinson’s
• Postherpetic neuralgia. sign.20
HZO usually begins with a prodrome of influenza-like illness, which is
characterized by fatigue, malaise, nausea, and mild fever; this is accompa-
EPIDEMIOLOGY AND PATHOGENESIS nied by progressive pain and skin hyperesthesia, which is characterized by
a burning painful area along a specific dermatome, followed by a diffuse
Herpes zoster (zoster, shingles) is a neurocutaneous disease caused erythematous or maculopapular rash that appears 3–5 days later. These
by human herpes virus 3 (HHV-3), the same virus that causes varicella eruptions can progress to form clusters of papules and clear vesicles and
(chickenpox). It is a member of the herpes virus family (Herpesviridae) evolve through stages of pustulation, vesiculation, and crusting. Patients
and exclusively infects human or simian cells. Varicella zoster virus with deeper involvement of the dermis may develop permanent scars with
(VZV) is the smallest of the alphaherpes viruses and has very stable linear loss of normal pigmentation. Rarely, herpes zoster may manifest with oph-
double-stranded DNA. It has an icosohedral capsid and lipid envelope, thalmic symptoms in the absence of cutaneous eruptions.8,21
which contains glycoproteins for cell entry.1
Herpes zoster has the highest incidence of any neurological disease,
with an annual occurrence of approximately 1 million cases in the United
CLINICAL MANIFESTATIONS
States.2. The lifetime risk is about 30%, and 50% of those living until 85 HZO may affect all ocular and adnexal tissues and manifest with a diverse
years of age will be affected.2–5 The reported incidence varies from 3.2 to array of signs and symptoms. Ocular or extraocular involvement may
4.2 per 1000 individuals per year. Increased risk of developing zoster is occur at the time of the cutaneous eruptions or years later.
associated with older age (incidence of 10 per 1000 individuals over 80 The skin of the forehead and upper eyelid is commonly affected and
years) and immunosuppression.6 strictly obeys the midline with involvement of the ophthalmic division of
In temperate climates, primary infection with this virus usually occurs the trigeminal nerve (Fig. 4.5.1). Zoster involves the deep dermis, in con-
before age 10 years, manifesting clinically as chickenpox (varicella). The trast to herpes simplex, which is limited to the epidermis. Deep involve-
virus then establishes a latent state in the sensory ganglia. In circum- ment may cause numerous lid complications, such as scarring, entropion,
stances of diminished virus-specific and cell-mediated immunity, the and ectropion. Conjunctival findings include hyperemia, petechial hemor-
virus may reactivate and spread to the corresponding dermatome along rhages, papillary or follicular reaction, or, rarely, pseudo-membrane. Epis-
a spinal or cranial nerve to generate the characteristic unilateral vesicular cleritis and scleritis are common and tend to progress toward the limbus,
exanthem. The accompanying inflammation of the sensory nerve and skin causing vasculitis and sterile corneal infiltrates.22
damage are purportedly responsible for the acute pain.7,8 Corneal pathology tends to result from three pathophysiological mechan-
Physical trauma and surgery have been correlated with the develop- ics: (1) active viral infection; (2) immune-mediated inflammation; and (3)
ment of zoster.9–12 Other reported triggers include tuberculosis, syphilis, chronic neurotrophic keratopathy. Active viral infections tend to affect the
radiation therapy, and corticosteroids.13 epithelium, leading to punctate epithelial keratitis and pseudo-dendrites
The epidemiology of zoster ultimately is dependent on the transmis- (Fig. 4.5.2). Pseudo-dendrites are typically smaller than typical dendrites,
sion and spread of VZV in a population. The spread of primary varicella and lack terminal end-bulb formations. Immune-mediated stromal kera-
(chickenpox) infection is of primary importance, but latent and reactivated titis can take multiple forms. Nummular keratitis is the earliest finding
infections play an important role in maintaining VZV infections within a of corneal stromal involvement and presents during the second week of
population. Latently infected older adults and immunosuppressed patients the disease in 25%–30% of patients.22 It is characterized by multiple, fine,
are important reservoirs of the virus, as these groups are more likely to granular, coin-shaped infiltrates in the anterior stroma and may cause per-
experience reactivation. When zoster does occur, the virus can be trans- manent scarring. Chronic interstitial keratitis may lead to deep corneal
mitted to a seronegative individual during the vesicular phase of the rash neovascularization and lipid keratopathy. Disciform keratitis is a deep
and cause a primary varicella infection. A zoster exposure with a seroposi- stromal infiltrate that develops 3–4 months after the acute phase, charac-
tive, latently infected individual may result in a subclinical reinfection and terized by a central disc-shaped area of diffuse corneal edema that results
boost humoral and cellular VZV immunity but is unlikely to cause acute from endotheliitis and anterior chamber inflammation. Perilimbal vasculi-
varicella or herpes zoster.14 Herpes zoster may develop in immunocompe- tis from immune-complex deposition can lead to sterile, peripheral, ante-
tent patients who harbor the latent virus and who are re-exposed to it by rior cornea stromal infiltrates.
180 contact with someone who has active varicella or zoster infection (primary, Active zoster infections travel through branches of the ophthalmic divi-
spontaneous, or infectious zoster).13,15,16 sion of the cranial nerve.6 Each reactivation damages the corneal nerves
booksmedicos.org
inflammation leads to pupillary seclusion, chronic angle-closure glaucoma,
and, possibly, corticosteroid-response glaucoma.
Posterior segment manifestations of HZO include retinal perivascu- 4.5
litis, ischemic optic neuropathy, and forms of necrotizing retinopathy.
These complications are uncommon but vision threatening. Two forms of

retinitis are worth noting: acute retinal necrosis (ARN), which tends to
occur mainly in immunocompetent patients, and progressive outer retinal
necrosis (PORN), which occurs mainly in immunocompromised patients.
ARN tends to present with severe ocular inflammation, whereas PORN
appears less inflamed but has a much faster and vision-threatening clini-
cal course.22 PORN is characterized by multifocal, deep retinal lesions that
rapidly progress to confluence with minimal or no intraocular inflamma-
tion, an absence of vascular inflammation, and perivenular clearing of
retinal opacification.20
External ocular motor palsies frequently occur in acute HZO. Infections
may affect the third, fourth, and sixth cranial nerves. These complications
are thought to be from vasculitis within the orbital apex and frequently
resolve within a year.
Postherpetic Neuralgia
Pain that continues following rash healing has been termed postherpetic
neuralgia (PHN). Pain in HZO has three phases: (1) acute pain—first 30
days during and after rash onset; (2) subacute herpetic neuralgia—between
30 and 120 days; and (3) PHN when greater than 120 days.23,24
PHN can occur in any patient with HZO; however, it usually is not seen
in patients less than 50 years of age, and its frequency increases until age
Fig. 4.5.1 Herpes zoster ophthalmicus involving the V1 distribution. 70 years. It afflicts about one half of all patients with herpes zoster who
are older than 70 years and appears to be more severe in older patients.13
The pain may occasionally be so extreme and persistent that some patients
consider suicide.13 Risk factors for PHN include greater acute pain sever-
ity,24,25 greater rash severity,26,27 and presence of a painful prodrome pre-
ceding the rash.28 Additional risk factors for PHN include older age and
female gender.23
HERPES ZOSTER OPHTHALMICUS IN ACQUIRED

IMMUNE DEFICIENCY SYNDROME
HZO is an important early clinical marker for acquired immunodefi-
ciency syndrome (AIDS), especially in high-risk younger patients.29–31
Immunocompromised patients have a higher incidence, greater severity,
and more prolonged course of ocular involvement, as well as PHN, com-
pared with immunocompetent patients with HZO.32 All nonpregnant,
young patients with HZO should be tested for human immunodeficiency
virus (HIV). PORN is reported with increasing frequency in patients
with AIDS. Following cytomegalovirus retinopathy, PORN is the second
most frequent opportunistic retinal infection in patients with AIDS in
North America.33
DIAGNOSIS
The diagnosis of herpes zoster disease generally is based on clinical find-
ings, although in recent decades, the clinical manifestations and spread of
VZV have shifted. This change may confound clinical impressions (e.g.,
HSV lesions may appear to be zosteriform and be difficult to differentiate
from zoster). Differential diagnosis includes eczema herpeticum, eczema
vaccinatum, impetigo contagiosum, enterovirus-associated exanthema,
contact dermatitis, drug eruptions, and insect bites.
Fig. 4.5.2 Peripheral corneal epithelial pseudo-dendrites in a patient with a history Cytological examination of cutaneous vesicular scrapings reveals multi-
of herpes zoster ophthalmicus. (Courtesy Hu AY, et al. Late varicella-zoster virus ple eosinophilic intranuclear inclusions (Lipschutz’s bodies) and multinu-
dendriform keratitis in patients with histories of herpes zoster ophthalmicus. Am J cleated giant cells (Tzanck’s preparation). Specimens (cutaneous vesicular
Ophthalmol 2010;149:214–20 e3.) scraping or conjunctival swab) must be transported to the laboratory as
quickly as possible under low temperature conditions (4 °C).33 Immune
electron microscopy techniques using specific peroxidase-labeled mono-
causing progressive neurotrophic keratopathy. Late-stage HZO gives the clonal antibodies against specific virus antigens can directly detect VZV.34
picture of chronic epitheliopathy with filamentary keratitis and anterior VZV-DNA can be obtained via anterior chamber paracentesis or vitreous
stromal scars from a compromised ocular surface. The risk of secondary tap and analyzed using real-time polymerase chain reaction.35 Fluorescent
bacterial infection may be high in this setting.20 antibody techniques, cytospin direct immunofluorescence staining, and
HZO can cause nongranulomatous or granulomatous iridocyclitis rapid direct immunofluorescence assays (SimulFluor direct fluorescent
(anterior uveitis) with keratic precipitates. It often has a chronic course, antibody) are additional methods for detecting VZV.36
necessitating topical corticosteroids for control. Specific signs include Serological tests to detect herpes zoster antibodies are of limited use
elevated intraocular pressure from trabeculitis and sectoral, vasoocclu- because cross-reactivation between VZV and HSV can occur. Following
sive iris atrophy. Glaucoma from HZO is often multifactorial. An early zoster infection, a booster of IgG is detected for 2 weeks and then falls to 181
cause is from trabeculitis that resolves with corticosteroids, but chronic lower levels and could persist at that level for years.37
booksmedicos.org
MANAGEMENT weeks of treatment is often required for pain relief.53 PHN may be severe,
4 HZO is treated with oral antivirals: acyclovir, famciclovir, or valacyclovir.

Acyclovir (800 mg, five times daily for 7–10 days), reduces viral shedding
intractable, and permanent, with some patients requiring psychiatric and
pain clinic care, and occasionally trigeminal rhizotomy or stellate ganglion
block may occur.54
and the chance of systemic dissemination, and reduces the incidence and Findings of a meta-analysis reveal that famciclovir and valacyclovir
severity of ocular complications, particularly if used within 72 hours of significantly reduce the duration but not the incidence of PHN. Studies
onset of symptoms.38,39 Acyclovir also can shorten the duration of pain if have shown corticosteroids to have no beneficial effect in the treatment
taken within the first 3 days of onset of symptoms.40,41 Intravenous acyclo- of PHN.55,56 Amitriptyline for 90 days reduced the incidence of pain at 6
vir is recommended in immunocompromised patients.38,42 months. Finally, a single trial of percutaneous electrical nerve stimula-
Famciclovir (500 mg, three times daily for 7 days) is a prodrug of penci- tion (PENS) in 50 patients reported decrease in pain incidence at 3 and 6
clovir and has a much higher bioavailability (77%) compared with acyclovir months compared with famciclovir.57
(18%). It has been shown to be well tolerated and safe with similar efficacy
to acyclovir.43 PREVENTION
Valacyclovir (1000 mg three times daily for 7 days) is the L-valine ester
of acyclovir and has higher bioavailability (80%) compared with acyclovir The varicella vaccine is available in two formulations which are both given
(18%). It has similar activity to acyclovir in the prevention of the sequelae subcutaneously: Varivax (Merck) and Zostavax (Merck). The former pre-
of herpes zoster and has been shown to be as effective in preventing vents primary varicella infections in infants, and the latter prevents reac-
ocular complications of HZO. Comparative analysis also has shown that tivation of zoster in adults. Both utilize live attenuated virus. Differences
tolerability of the two drugs was similar.44 Valacyclovir has been shown to in administration are that Zostavax is only administrated once and has 14
significantly accelerate the resolution of pain compared with acyclovir.45 times the concentration of Varivax, which is given twice.58
Comparisons between valacyclovir and famciclovir treatment in HZO have Studies have shown that Zostavax reduces the incidence of zoster by
not shown significant difference in resolution of pain or rash.46 50%, PHN by 60%, and HZO by 49% and that it reduces the severity of
Of note, acute renal failure rarely has been reported with these medi- illness in those with reactivation of the virus.59,60 The efficacy of all three
cations, especially intravenous administration.47,48 As a result, kidney func- vaccine measures has been shown to decrease as time after vaccination
tion should be monitored closely and renal dosing guidelines followed increases.61 The most common adverse effect is pain and erythema at the
when appropriate. Dosing for children should be executed with reference injection site with equivalent rates of adverse events of 1.4% for the vaccine
to appropriate dosing guidelines. Acyclovir and valacyclovir are thought to and placebo group.62 The vaccinated group, however, did have a higher
be safe for use during pregnancy.49 rate of serious adverse events. Case reports in the literature describe
exacerbation of chronic HZO, exacerbation of uveitis, new-onset retini-
Management of Ocular Manifestation tis in immunocompromised patients, and dermatological and dissemi-
nated disease after Zostavax administration in patients with a history of
Palliative therapy, including Burow’s solution, cool compresses, mechani- HZO.58,63–71 Despite these reports and possible risks, a history of HZO is
cal cleansing of the involved skin, and topical antibiotic ointment without currently not a contraindication to the vaccination.
corticosteroid, are helpful in treating skin lesions. The Centers for Disease Control and Prevention and the Advisory Com-
Oral acyclovir has been shown to be effective for the punctate, mittee on Immunization Practices recommend that the zoster vaccine be
pseudo-dendritic, and delayed corneal mucous plaque forms of herpes administrated to adults age 60 years and above for the prevention of herpes
zoster epithelial keratitis.40,41 Debridement may be helpful. zoster, including those who have already had a case of zoster.
Neurotrophic keratitis or epithelial defects associated with herpes
zoster keratitis may be treated with nonpreserved artificial tears, eye oint- KEY REFERENCES
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and post herpetic neuralgia, vol. 11. 2nd ed. Pain research and clinical management.
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Canada and the United Kingdom. Epidemiol Infect 2001;127:305–14.
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tolysis.22 Topical cycloplegics prevent ciliary spasm associated with herpes vir and acyclovir for the treatment of herpes zoster ophthalmicus. Ophthalmology
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nia, another subtype of neuralgia.52 Capsaicin cream (0.025%) is effective Access the complete reference list online at ExpertConsult.com
when applied to the involved skin three to four times daily, although 2
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33. Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis 68. Bhalla P, Forrest GN, Gershon M, et al. Disseminated, persistent, and fatal infection due
syndrome: a variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthal- to the vaccine strain of varicella-zoster virus in an adult following stem cell transplanta-
mology 1994;101:1488. tion. Clin Infect Dis 2015;60:1068–74.
34. Wolff MH, Schunemann S, Rahaus M, et al. Diagnosis of varicella-zoster virus associ- 69. Gershon AA, Gershon MD. Pathogenesis and current approaches to control of varicel-
ated diseases with special emphasis on infections in the immunocompromised host. In: la-zoster virus infections. Clin Microbiol Rev 2013;26:728–43.
Wolff MH, Schunemann S, Schimdt A, editors. Varicella-zoster virus. Molecular biology, 70. Levin MJ, DeBiasi RL, Bostik V, et al. Herpes zoster with skin lesions and meningitis
pathogenesis and clinical aspects. Contributions to microbiology, 3. Basle: Karger; 1999. caused by 2 different genotypes of the Oka varicella-zoster virus vaccine. J Infect Dis
p. 150–7. 2008;198:1444–7.
35. Kaneko H, Iida T, Aoki K, et al. Sensitive and rapid detection of herpes simplex virus and 71. Lai YC, Yew YW. Severe autoimmune adverse events post herpes zoster vaccine:
varicella-zoster virus by loop-mediated isothermal amplification (LAMP). J Clin Microbiol a case-control study of adverse events in a national database. J Drugs Dermatol
2005;43:3290–6. 2015;14:681–4.
182.e1
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Section 4 Conjunctival Diseases
Conjunctivitis: Infectious and

Noninfectious 4.6
Jonathan B. Rubenstein, Tatyana Spektor
self-limiting, lasting 7–10 days, antibiotic therapy usually speeds the reso-
Definition: Conjunctivitis is infectious or non-infectious inflammation lution and lessens the severity of the disease. A broad-spectrum antibiotic
of the mucous membrane lining eye wall and inner lids. with good Gram-positive coverage, such as a third- or fourth-generation
fluoroquinolone, 10% sodium sulfacetamide, or trimethoprim-polymyxin,
may be used for 7–10 days.
Key Features
• Infectious causes may be bacterial, fungal parasitis, or viral. Hyperacute Bacterial Conjunctivitis
• Infectious conjunctivitis can be classified by duration of symptoms. The most common cause of hyperacute bacterial conjunctivitis is N. gonor-
• The diagnosis is usually made clinically. If the diagnosis is not readily rhoeae.1 This oculogenital disease is seen primarily in neonates and sexu-
apparent, laboratory studies may be helpful in determining etiology. ally active young adults. Transmission is by contact with infected urine or
• May be noninfectious causes of conjunctivitis. genital secretions. Symptoms develop within 24 hours, and signs include
profuse, thick, yellow-green purulent discharge, painful hyperemia, che-
mosis of the conjunctiva, and tender preauricular nodes. Untreated cases
may lead to peripheral corneal ulceration and eventual perforation with
INFECTIOUS CONJUNCTIVITIS possible endophthalmitis. A similar, but milder form of conjunctival and
Bacterial Infections corneal disease is caused by primary or secondary infection with Neisse-
ria meningitides. Primary meningococcal conjunctivitis is extremely rare in
Bacterial conjunctivitis is characterized by a rapid onset of unilateral con- adults and can be invasive (followed by systemic meningococcal disease) or
junctival hyperemia, lid edema, and mucopurulent discharge. The second noninvasive (isolated conjunctival infection).5 If invasive disease is present,
eye typically becomes involved 1–2 days later. close contacts should receive prophylaxis with a single dose of ciprofloxa-
The pathogenesis of bacterial conjunctivitis usually involves a disrup- cin 500 mg or rifampin 600 mg twice daily for 2 days.6
tion of the host defense mechanisms, for example, abnormalities of the Treatment is directed at the specific pathogen. Conjunctival scraping
ocular surface secondary to eyelid abnormalities, tear film abnormalities, for Gram staining and culture on blood and chocolate agar are strongly
or systemic immunosuppression.1,2 Bacterial conjunctivitis can be classi- recommended. Gram-negative diplococci are suggestive of Gonococcus.
fied into three clinical types: acute, hyperacute, and chronic (see Table 4.6.1 An effective regimen for gonococcal conjunctivitis is a single dose of 1 g
for a list of common pathogens).1 of intramuscular ceftriaxone. If a corneal ulcer is present, hospitalization
Conjunctival membranes and pseudo-membranes may occur in bac- with 1 g intravenous ceftriaxone for 3 days is recommended. Topical med-
terial conjunctivitis in association with Neisseria gonorrhoeae, β-hemolytic ications may include bacitracin, ciprofloxacin, or erythromycin ointment
streptococci, and Corynebacterium diphtheria. Pseudo-membranes, which every 1–2 hours. Frequent irrigation, every 30–60 minutes, with normal
include inflammatory cells and an exudate containing mucus and pro- saline or balanced salt solution, also is recommended. Adults are often
teins, are loosely adherent to the underlying conjunctival epithelium and treated empirically for concurrent chlamydial infection with azithromycin
can be peeled away with no bleeding or damage to the epithelium. True 1 g once or doxycycline 100 mg twice a day for 7 days.7 In meningococ-
membranes occur with more intense inflammation. The conjunctival epi- cal conjunctivitis, systemic treatment includes intravenous penicillin, or
thelium becomes necrotic, and firmer adhesions are formed between the for penicillin-resistant infections, intravenous cefotaxime or ceftriaxone.5
necrotic cells and the overlying coagulum. When the membrane is peeled, Patients need to be seen daily to rule out corneal involvement.
the epithelium tears to leave a raw, bleeding surface.
Acute Bacterial Conjunctivitis

Acute bacterial conjunctivitis usually begins unilaterally with hyperemia,
irritation, tearing, mucopurulent discharge, and mattering of the lids (Fig.
4.6.1). Punctate epithelial keratitis also may occur. The most common
pathogens include Staphylococcus aureus, Streptococcus pneumoniae, and
Haemophilus influenzae.1 Other common ocular manifestations include
blepharitis, keratitis, marginal ulcers, and phlyctenulosis.3 The pathogens
H. influenzae, S. pneumoniae, and Moraxella catarrhalis occur more com-
monly in young children and may occur in institutional epidemics.4 H.
influenzae is often associated with systemic infection, including upper
respiratory infections, and acute otitis media.
The treatment of acute bacterial conjunctivitis consists of topical
antibiotic drops or ointments. Although these infections normally are
TABLE 4.6.1 Pathogens That Cause Bacterial Conjunctivitis

Acute Hyperacute Chronic
Staphylococcus aureus Neisseria gonorrhoeae Staphylococcus aureus
Streptococcus pneumoniae Neisseria meningitidis Moraxella lacunata
Haemophilus influenzae Enteric bacteria
Fig. 4.6.1 Acute Bacterial Conjunctivitis. This patient was culture-positive for 183
Pneumococcus.
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4
Fig. 4.6.2 Staphylococcal Marginal Keratitis. Note the inferior marginal corneal
ulcers and the blepharoconjunctivitis. Fig. 4.6.3 Acute Bilateral Viral Conjunctivitis. This 22-year-old man has
pharyngoconjunctival fever, and the conjunctivitis was preceded by a viral upper
respiratory tract infection.
Chronic Bacterial Conjunctivitis

Chronic bacterial conjunctivitis, lasting longer than 3 weeks, may result
from a number of organisms and is often associated with blepharitis. The
most common organisms are S. aureus and Moraxella lacunata; other caus-
ative organisms include the enteric bacteria Proteus mirabilis, Escherichia
coli, Klebsiella pneumoniae, Serratia marcescens, and Branhamella catarrhalis
from the upper respiratory tract.1 The most common causative agent is S.
aureus, which colonizes the eyelid margin and then causes direct infection
of the conjunctiva or conjunctival inflammation through its elaboration of
exotoxins.8 Chronic angular blepharoconjunctivitis of the inner and outer
canthal angles most commonly results from M. lacunata. A chronic follic-
ular conjunctivitis may accompany both types.
The clinical signs of chronic staphylococcal conjunctivitis include
diffuse conjunctival hyperemia with papillae or follicles, minimal muco-
purulent discharge, and conjunctival thickening. Erythema of the eyelid,
telangiectasis, lash loss, collarettes, recurrent hordeolae, and ulcerations at
the base of the cilia can be seen. The cornea may demonstrate marginal
corneal ulcers (Fig. 4.6.2).
Treatment combines proper antimicrobial therapy and good lid hygiene,
which includes warm compresses and eyelid scrubs. Azithromycin drops
and erythromycin or bacitracin ointments are effective adjunctive topical Fig. 4.6.4 Epidemic Keratoconjunctivitis. Early pseudo-membrane formation may
antibiotics. When severe inflammation exists, antibiotic and corticosteroid be seen in the inferior fornix.
combination drops or ointments can be rubbed into the lid margins after
the lid scrubs. Oral therapy with tetracycline 250 mg four times a day, dox-
ycycline 100 mg one to two times a day, or minocycline 50 mg one to two 4.6.3). The conjunctivitis is predominantly follicular with a scant watery
times a day may be needed for more severe infections. discharge, hyperemia, and mild chemosis. The cornea may be involved
with a fine punctate epitheliopathy. Preauricular lymph nodes are enlarged
Adenoviral Conjunctivitis in about 90% of cases. The disease resolves spontaneously within 2 weeks,
so treatment is usually supportive with cold compresses, artificial tears,
Viral conjunctivitis is extremely common. The diagnosis usually can be and judicious use of vasoconstrictor eyedrops.
made clinically.8 Many different viruses cause conjunctivitis, and each pro-
duces a slightly different disease. Epidemic Keratoconjunctivitis
Adenoviruses produce the most common viral conjunctivitides with Epidemic keratoconjunctivitis (EKC) is produced by adenovirus serotypes
varying degrees of severity. The spectrum consists of follicular conjuncti- 8, 19, and 37. It is a more severe type of conjunctivitis and typically lasts
vitis, pharyngoconjunctival fever, and epidemic keratoconjunctivitis. These for 7–21 days. EKC produces a mixed papillary and follicular response of
infections are spread via respiratory droplets or direct contact from fingers the conjunctival stroma with a watery discharge, hyperemia, chemosis,
to the lids and conjunctival surface. The incubation period is usually 5–12 and ipsilateral preauricular lymphadenopathy (Fig. 4.6.4).8,11 Subconjunc-
days and the clinical illness is present for 5–15 days.9 tival hemorrhages, conjunctival membrane formation, and lid edema are
common (see Fig. 4.6.4; Fig. 4.6.5).10 Histologically, these conjunctival
Follicular Conjunctivitis membranes consist of fibrin and leukocytes with occasional fibroblast
Follicular conjunctivitis is the mildest form and is associated with adeno- infiltration. Both true membranes and pseudo-membranes may occur,
virus serotypes 1 through 11 and 19.10 It has an acute onset and is initially and conjunctival scarring and symblepharon formation may follow their
unilateral with possible involvement of the second eye within 1 week. It is resolution.
manifested by a watery discharge and conjunctival hyperemia and usually Corneal involvement is variable. Most patients have a diffuse, fine,
is accompanied by follicular and papillary conjunctival changes with pre- superficial keratitis within the first week of the disease. Focal, elevated,
auricular lymphadenopathy on the affected side. Most cases resolve spon- punctate epithelial lesions that stain with fluorescein develop by days 6–13
taneously, without sequelae, within days to weeks. (Fig. 4.6.6), producing a foreign body sensation. By day 14, subepithelial
opacities develop under the focal epithelial lesions in 20%–50% of cases
Pharyngoconjunctival Fever (Fig. 4.6.7). These opacities often are visually disabling and may persist
Pharyngoconjunctival fever is the most common ocular adenoviral infec- for months to years, but eventually they resolve with no scarring or vas-
184 tion11 and is produced by adenovirus serotypes 3, 4, and 7. It is charac- cularization.12 The diagnosis of EKC is made clinically, but a rapid immu-
terized by a combination of pharyngitis, fever, and conjunctivitis (Fig. nodetection assay (RPS Adeno Detector; Rapid Pathogen Screening; South
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Williamsport, PA) is now available and is capable of detecting all 53 adeno-
viral serotypes with a reported sensitivity of 89% and specificity of 94%.13
Treatment aims at alleviation of symptoms and minimization of trans- 4.6
mission of this highly contagious disease. Patients may be infectious for
up to 14 days after onset,10,14,15 and outbreaks are especially common in
Conjunctivitis: Infectious and Noninfectious

ophthalmology offices and clinics. Transmission usually occurs from eye
to fingers to eye; tonometers, contact lenses, and eyedrops are other routes
of transmission. Preventive measures include frequent hand washing, rel-
ative isolation of infected individuals in an office setting, and disinfection
of ophthalmic instruments.16,17 During the stage of acute conjunctivitis,
treatment usually is supportive and includes cold compresses and decon-
gestant eyedrops. When patients have decreased visual acuity or disabling
photophobia from subepithelial opacities, topical corticosteroid therapy
may be beneficial. High-dose topical corticosteroids, such as 1% prednis-
olone acetate three to four times a day, or difluprednate twice a day, can
help eliminate subepithelial infitrates.18 However, some believe that use
of topical corticosteroids prolongs viral shedding and worsen symptoms
if the infectious virus is herpes simplex. Cidofovir, an antiviral agent, has
been investigated in the treatment of EKC.19,20 Although the application
Fig. 4.6.5 Pseudo-Membrane in Epidemic Keratoconjunctivitis. An early pseudo- of cidofovir drops may prevent the formation of corneal opacities, use
membrane is forming in the inferior fornix. has been limited by local toxicity and commercial unavailability. Others
have advocated the use of topical gancyclovir. Currently, the utility of a
povidone-iodine 0.4%/dexamethasone 0.1% combination ophthalmic sus-
pension is being investigated.21
Acute Hemorrhagic Conjunctivitis

Acute hemorrhagic conjunctivitis, also known as Apollo disease, was first
described in Ghana in 1969.22 Two picornaviruses, enterovirus 70 and cox-
sackievirus A24, are the usual causative agents.23,24 Less commonly, it is
caused by adenovirus type 11. A rapid onset of severe, painful follicular
conjunctivitis occurs, with chemosis, tearing, lid edema, and tiny subcon-
junctival hemorrhages. The hemorrhages are petechial at first and then
coalesce, appearing posttraumatic. The cornea may demonstrate a fine
punctate keratopathy and, rarely, subepithelial opacities. The conjunctivi-
tis resolves within 4–6 days, but the hemorrhages clear more slowly. The
disease occurs in epidemics, especially in developing countries, with more
than 50% of the local population affected in some cases. Very rarely, cases
caused by enterovirus type 70 can result in a polio-like paralysis, which
remains permanent in up to one third of affected individuals.
Herpes Simplex Conjunctivitis

Primary herpes simplex conjunctivitis usually occurs in children under 5
Fig. 4.6.6 Epidemic Keratoconjunctivitis Subepithelial Infiltrates. These years of age. Most cases are undocumented because of their nonspecific
infiltrates develop 2 weeks after the onset of the disease and persist for months to nature. Typical signs include ocular irritation, watery discharge, mixed
years. papillary and follicular conjunctivitis, hemorrhagic conjunctivitis, and pre-
auricular lymphadenopathy.25 Most cases are unilateral but may become
bilateral. Epidermal vesicular eruptions of the eyelids and lid margins may
accompany the conjunctivitis (Fig. 4.6.8), and the cornea may be involved.
Corneal involvement may include a coarse, punctate epithelial keratitis,
TIME COURSE OF THE CLINICAL FEATURES marginal infiltrates, or a dendritic ulcer. Although herpetic blepharocon-
OF EPIDEMIC KERATOCONJUNCTIVITIS junctivitis is associated mainly with the primary disease, it may occur as a
manifestation of recurrent disease with or without typical herpetic kerati-
tis.25 Most ocular herpetic infections result from herpes simplex virus type
1. Infections that result from the type 2 serotype may be seen in newborns
incubation or adults who have a history of oral–genital contact.26
period conjunctivitis The conjunctivitis usually resolves spontaneously in 7–14 days without
(8 days) treatment,25 although some physicians administer topical antiviral drops
superficial punctate to patients with corneal involvement or to patients with lid vesicles, with
keratitis the goal of preventing corneal involvement. Care should be taken to avoid
the cavalier use of corticosteroids in the treatment of patients who have
focal an acute follicular conjunctivitis because some of these patients may have
keratitis herpetic disease and corticosteroids may enhance the severity of herpetic
epithelial keratitis.
subepithelial infiltrates
(may last for months to years)
Other Causes of Viral Conjunctivitis
period of infectivity
c. 14 days Other causes of viral conjunctivitis include the rubella, rubeola,
varicella-zoster, Epstein–Barr virus infection, Newcastle disease, and Zika
virus infections.23 Rubella virus produces a nondescript, catarrhal follicu-
1 0 1 2 3 4 5 6 lar conjunctivitis associated with the systemic disease. Rubeola produces
exposure onset of time (weeks) a catarrhal, papillary conjunctivitis with tearing, pain, and photophobia.
disease Pale, discrete, avascular spots, which resemble Koplik’s spots seen in the
mouth, may appear on the conjunctiva. Varicella-zoster virus produces 185
Fig. 4.6.7 Time course of the clinical features of epidemic keratoconjunctivitis. pustules and phlyctenule-like lesions on the conjunctiva, and a follicular
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Fig. 4.6.8 Primary
4 Herpes Simplex
Blepharoconjunctivitis.
Note the bilateral vesicular
eruptions in this child
who has a primary herpes

simplex infection.
Fig. 4.6.9 Giemsa Staining of a Conjunctival Scraping. The epithelial cells show
basophilic cytoplasmic inclusions typical of a chlamydial infection.
keratitis. Eventually, multiple reinfections lead to scarring and cicatrization

of the cornea, conjunctiva, and eyelids.
The trachoma complications that cause blindness occur as a result of
corneal ulceration, severe conjunctival scarring, and eyelid deformities
with their concomitant effects on the ocular surface.32 Arlt’s line (a hor-
izontal line that results from conjunctival scarring at the junction of the
anterior one third and posterior two thirds of the conjunctiva) is a charac-
teristic finding on the superior pretarsal conjunctiva. Herbert’s pits are a
unique sequelae of trachoma33; these sharply delineated depressions occur
BOX 4.6.1 Causes of Chronic Follicular Conjunctivitis after necrosis and cicatrization of limbal follicles, and the resultant clear
space is filled with epithelium. A diffuse haze of the superior cornea may
• Chlamydiasis result after regression of the superior pannus. Eyelid deformities, such as
• Trachoma trichiasis, distichiasis, entropion, and ectropion, all may occur. Corneal
• Adult inclusion conjunctivitis complications, including scarring, vascularization, ulceration, and perfora-
• Molluscum contagiosum tion, lead to decreased visual acuity and possible blindness.
• Drug-induced or toxic conjunctivitis Treatment of trachoma usually consists of a 3- to 4-week course of oral
• Bacterial conjunctivitis tetracycline (tetracycline 1 g/day or doxycycline 100 mg/day) or oral eryth-
• Axenfeld’s chronic follicular conjunctivitis romycin. The clinical response may be slow and take 9–18 weeks to be
• Merrill–Thygeson-type follicular conjunctivitis seen. More recently, a single 20 mg/kg dose of oral azithromycin has been
• Parinaud’s oculoglandular syndrome shown in several randomized controlled trials to be as effective as 6 weeks
• Folliculosis of childhood of topical tetracycline.31,34,35 Topical azithromycin 1.5% twice daily for 2–3
days has also been found to be as effective as the single oral dose with a
low recurrence rate.36 Widespread repeated use of systemic antibiotics in
endemic areas has been tried in an attempt to eradicate the disease with
conjunctivitis may occur with recurrent skin disease. Follicular conjunc- slow resolution of active trachoma.37
tivitis associated with the Epstein–Barr virus occurs in association with
infectious mononucleosis.27 Newcastle disease viral conjunctivitis occurs Adult Inclusion Conjunctivitis
in poultry workers and veterinarians in whom direct conjunctival inocula- Adult inclusion conjunctivitis results from C. trachomatis serotypes D to K.
tion of the virus has occurred while handling infected birds.28 The disease It presents as a unilateral red eye with mucopurulent discharge, marked
is self-limiting, lasts 7–10 days, and leaves no ocular sequelae. Zika virus hyperemia, papillary hypertrophy, and a predominant follicular conjunc-
is a mosquito-borne infection that has led to many outbreaks in Africa tivitis. A tender, enlarged preauricular lymph node is common. Women
and Asia, and most recently, in 2015, it has reached the Americas. The often have a concomitant vaginal discharge secondary to a chronic cervici-
virus may present with fever, rash, arthralgia, and conjunctivitis in approx- tis, and men may have symptomatic or asymptomatic urethritis. The con-
imately 20% of cases. Symptoms are generally self-limiting, although fetal junctivitis is often chronic, lasting many months. Keratitis may develop 1
transmission may lead to brain defects.29 week after onset. Corneal involvement includes a superficial punctate kera-
titis, small marginal or central infiltrates, EKC-like subepithelial infiltrates,
Chronic Follicular Conjunctivitis limbal swelling, and a superior limbal pannus. The untreated disease has
a chronic course, and keratitis or iritis can occur in the later stages of the
Chronic follicular conjunctivitis lasts more than 16 days (Box 4.6.1).8 Chla- disease.
mydia trachomatis, an obligate intracellular bacterium, is the most common Diagnosis is based on the clinical appearance plus laboratory test
cause; it causes three clinical syndromes—trachoma, adult inclusion con- results. Basophilic intracytoplasmic epithelial inclusions are seen with
junctivitis, and neonatal conjunctivitis. Giemsa staining of conjunctival scrapings (Fig. 4.6.9). Immunofluorescent
staining of the conjunctival scrapings is also useful. Serum immunoglob-
Trachoma ulin G titers to Chlamydia may be obtained.
Trachoma, which results from C. trachomatis serotypes A to C, is endemic The modes of transmission include orogenital activities and hand-to-
in many parts of the world, including Africa, the Middle East, Latin eye spread of infective genital secretions. The incubation period is 4–12
America, Central Asia, and South-East Asia.30 Current reports indicate that days. One in 300 patients who have genital chlamydial disease develops
active trachoma affects approximately 150 million people worldwide, with adult inclusion conjunctivitis.38 It is important to treat all sexual partners
about 10 million people developing secondary trichiasis and approximately simultaneously to prevent reinfection and also to rule out other venereal
6 million blinded from sequelae of the disease. After an incubation period diseases, such as gonorrhea and syphilis. Treatment consists of systemic
of 5–10 days, trachoma manifests as a mild, mucopurulent conjunctivi- antibiotics, as topical antibiotics are relatively ineffective in the treatment
tis that is typically self-limiting and heals without permanent sequelae.31 of the eye disease. A single 1-g dose of azithromycin or doxycycline 100 mg
Repeated infections, however, result in chronic inflammation, including twice a day for 7 days is the recommended treatment. Tetracyclines should
186 follicular conjunctivitis and papillary hypertrophy of the upper palpebral be avoided in children younger than 7 years of age and in pregnant or
conjunctiva, a superior superficial corneal pannus, and fine epithelial lactating women.
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TABLE 4.6.2 Causes of Neonatal Conjunctivitis
Causes Time of Onset (Postpartum)
4.6
Chemical (povidone-iodine) 1–36 hours

Chlamydia 5–14 days
Neisseria gonorrhoeae 24–48 hours
Bacteria (Staphylococcus, Streptococcus, Haemophilus, 2–5 days
Moraxella, Escherichia coli, Pseudomonas)
Virus (herpes simplex virus types 1 and 2) 3–15 days
The cause of the conjunctivitis is established by the clinical picture, time course, and
laboratory confirmation.
TABLE 4.6.3 Guidelines for Treatment of Neonatal Conjunctivitis

Infection Treatment
Chlamydia Oral erythromycin 50 mg/kg/day in four divided
doses for 14 days
Bacteria Fig. 4.6.10 A 10-day-old infant who has unilateral conjunctivitis. The mother had an
Gram-positive Erythromycin 0.5% ointment four times a day untreated chlamydial infection of the birth canal.
Gram-negative, gonococcal Intravenous or intramuscular ceftriaxone
25–50 mg/kg single dose
Gram-negative, others Gentamicin or tobramycin ointments occur, a second course of the same therapy may be given. The mother and
Viral Trifluorothymidine drops every 2 hours for 7 days her sexual partners should be treated with oral azithromycin 1 g in a single
dose or oral amoxicillin 500 mg three times daily for 7 days.46
Neonatal Conjunctivitis (Ophthalmia Neonatorum) Neisserial Infections

Neonatal conjunctivitis caused by N. gonorrhoeae, a Gram-negative diplo-
Conjunctivitis of the newborn is defined as any conjunctivitis that occurs coccus that can penetrate an intact epithelium, has decreased significantly
within the first month of life (Table 4.6.2).39 It may be a bacterial, viral, since the advent of prophylactic agents. The clinical picture of gonococcal
or chlamydial infection or a toxic response to topically applied chemicals. conjunctivitis consists of the development of a hyperacute conjunctivitis
Because the infectious agent may produce a severe localized infection of 24–48 hours after birth characterized by marked eyelid edema, profound
the eye plus a potentially serious systemic infection, precise identification chemosis, and excessive purulent discharge. The discharge often is so
of the cause is essential. copious that it reaccumulates immediately after the eye has been wiped
Not all infants exposed to infectious agents in the birth canal develop clean. Conjunctival membrane formation may occur. Because the organ-
conjunctivitis; the duration of the exposure is an important factor in the ism may penetrate an intact epithelium, corneal ulceration with possible
development of disease. Prevention with good prenatal care and treat- perforation can occur if the conjunctivitis is not treated adequately.47
ment of chlamydial, gonococcal, or herpetic infections during pregnancy Diagnosis is made by identification of Gram-negative intracellular dip-
significantly lower the incidence of neonatal conjunctivitis. Proper eye lococci on conjunctival smears. The organism is best cultured on choco-
cleaning using sterile cotton followed by the instillation of erythromycin late agar or Thayer–Martin agar incubated at 37 °C in 10% carbon dioxide,
or tetracycline antibiotic ointments immediately after birth helps prevent and sensitivities should be obtained. Prompt diagnosis by examination of
neonatal ocular infection. Previous studies suggested that instillation of immediate Gram staining is essential to timely and effective therapy.
2.5% povidone-iodine as prophylaxis has superior bactericidal effects and Local treatment consists of aqueous penicillin G drops 10 000–20 000
also is active against viruses, most notably herpes simplex.40 However, units. Drops are given every hour with a loading dose of one drop every 5
recent studies suggest topical tetracycline and erythromycin ointment minutes for 30 minutes. Systemic therapy also should be instituted with
may be more effective in prevention of ophthalmia neonatorum given that intravenous or intramuscular ceftriaxone 25–50 mg/kg in a single dose
5%–10% of patients treated with povidone-iodine developed a chemical (see Table 4.6.3). For disseminated disease, consultation with an infectious
conjunctivitis.41,42 disease specialist is recommended. The mother and her sexual partners
should be treated with intramuscular ceftriaxone 250 mg in a single dose.
Chlamydial Infections
The most frequent cause of neonatal conjunctivitis in the United States Other Bacterial Infections
is C. trachomatis. Infants whose mothers have untreated chlamydial infec- Many different organisms can cause bacterial neonatal conjunctivitis. Bac-
tions have a 30% –40% chance of developing conjunctivitis and a 10%–20% teria are probably transmitted through the air to the infant shortly after
chance of developing pneumonia.43 Symptoms typically develop 5–14 days birth and may be associated with nasolacrimal duct obstruction. These
after delivery and may be unilateral or bilateral. Initially, infants have a infections are usually caused by Gram-positive bacteria (S. aureus, S. epi-
watery discharge that may progressively turn mucopurulent. Signs include dermidis, S. pneumoniae, and S. viridans). Gram-negative organisms that
lid edema, a papillary conjunctival response, and pseudo-membrane have been implicated include Haemophilus species, E. coli, Proteus species,
formation (Fig. 4.6.10). Usually, the infection is mild and self-limiting; K. pneumoniae, Enterobacter species, and Serratia marcescens.48 Rarely, pseu-
severe cases, however, may occur and result in conjunctival scarring and domonas sp. causes corneal ulceration and perforation.49
a peripheral corneal pannus with corneal scarring. If either erythromycin Typically, these infections arise 2–5 days after birth. Signs include lid
or tetracycline ointment is applied within 1 hour of delivery, the chance of edema, chemosis, and conjunctival injection with discharge. The work-up
developing chlamydial conjunctivitis is markedly decreased.44 includes conjunctival scrapings for Gram staining and cultures, the results
Laboratory data are very helpful in the diagnosis. Enzyme-linked immu- of which direct the choice of therapy. For Gram-positive organisms, eryth-
nosorbent assay is nearly 90% sensitive and over 95% specific and provides romycin 0.5% ointment four times a day is administered. Gentamicin,
results within several hours. A direct immunofluorescent monoclonal tobramycin, or fluoroquinolone drops or ointment four times a day can be
antibody stain of conjunctival smears is the most useful serological test used for Gram-negative organisms (see Table 4.6.3).
because it has over 95% sensitivity and 77%–90% specificity for Chlamydia,
depending on the prevalence of the disease. It may show infections missed Viral Infections
by other assays and can be read immediately. Polymerase chain reaction Viral conjunctivitis of the newborn is rare but can be associated with signif-
(PCR) and ligase chain reaction also are available and are approximately icant morbidity and mortality. Both herpes simplex virus type 1 and herpes
90% sensitive and 100% specific.45 simplex type 2 can be associated with conjunctivitis, but type 2 infection
Topical therapy alone is not sufficient to treat chlamydial conjunctivitis. is more common.50 Type 1 may be transmitted by a kiss from an adult
The recommended treatment is oral erythromycin syrup 50 mg/kg/day in who has an active “cold sore,” and type 2 is more commonly transmitted 187
four divided doses for 14 days (Table 4.6.3). If complete response does not through the birth canal. Onset is usually within the first 2 weeks of life
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and may be associated with vesicular skin lesions of the lid or lid margin
4 (see Fig. 4.6.8). The conjunctivitis may be followed by herpetic keratitis or

keratouveitis. Vitritis, retinitis, retinal detachment, optic neuritis, and cata-
ract all have been reported in association with neonatal ocular herpes. The
diagnosis may be confirmed by the presence of eosinophilic intranuclear
inclusions on smears, positive viral culture results, or positive results from

monoclonal antibody immunoassays.
Treatment consists of trifluoridine 1% drops every 2 hours for 7 days,
acyclovir ointment five times a day, or ganciclovir drops five times a day
(see Table 4.6.3). Herpes simplex type 2 may be more resistant to treat-
ment. In cases of systemic disease associated with pneumonitis, septi-
cemia, and meningitis, systemic acyclovir or valcyclovir should be used.
Good prenatal care and frequent culture and treatment of mothers who
have known herpes genital infections decrease the incidence of herpetic
neonatal conjunctivitis.
Fungal and Parasitic Conjunctivitis

Focal eyelid or conjunctival granulomas can be caused by rare infections, Fig. 4.6.11 Parinaud’s Oculoglandular Syndrome. Granulomatous palpebral
including blastomycosis, sporotrichosis, rhinosporidiosis, cryptococcosis, conjunctivitis.
leishmaniasis, and ophthalmomyiasis.
Microsporidial Keratoconjunctivitis
Microsporidae are obligate, intracellular, spore-forming protozoan par-
asites that can cause disseminated disease or localized keratoconjuncti-
vitis.51 It is more commonly seen in immunocompromised patients but
has been reported in immunocompetent patients with contact lens use,
trauma, prior refractive surgery, or exposure to contaminated water or
soil.52 Clinical symptoms include pain, redness, and, occasionally, visual
blurring. Superficial, multifocal, coarse, punctate epithelial keratitis, and
a diffuse papillary conjunctivitis are typical.53 Diagnosis is made with
ocular surface scraping and the visualization of acid-fast spores in con-
junctival epithelial cells upon staining with modified trichrome, potassium Fig. 4.6.12 Parinaud’s Oculoglandular Syndrome. Prominent preauricular
hydroxide plus calcofluor white, or Gram stain.52,53 Confocal microscopy lymphadenopathy.
demonstrates spores that are hyperreflective dots. Electron microscopy is
the gold standard for diagnosis. Treatment includes topical fumagillin and
oral albendazole or itraconazole.52 Topical fluoroquinolones are effective as
monotherapy.54
Loiasis
Loa loa is a filarial nematode that is transmitted from human to human by
the bite of an infected female deer fly (genus Chrysops) that is indigenous
to West and Central Africa. The adult worm can migrate subcutaneously
from the bite area to the eye. Skin manifestations and conjunctivitis can
be present. Extraction of the filarial worm is curative. Treatment consists
of diethylcarbamazine 2 mg/kg three times daily for 3 weeks.55 Ivermectin
150 mg/kg can be used, but significant side effects include subconjuncti-
val and retinal hemorrhages and retinal “cottonwool” spots.56 Concurrent
corticosteroids and/or antihistamines can be used to decrease the side
effects of treatment.
Parinaud’s Oculoglandular Syndrome

Fig. 4.6.13 Molluscum Contagiosum Lesion on the Lower Eyelid. This patient had
Parinaud’s oculoglandular syndrome is an uncommon granulomatous an accompanying chronic follicular conjunctivitis secondary to the toxic effect of
conjunctivitis seen in approximately 5%–10% of patients with systemic viral proteins from this lesion.
infection caused by Bartonella henselae (cat scratch disease).57 B. henselae
are small, fastidious Gram-negative rods that affect approximately 22 000
patients in the United States per year.58 Ocular symptoms include unilateral because of its superior intraocular and central nervous system penetration.
redness, epiphora, foreign body sensation, and mild lid swelling. Serous In more severe infections, these medications can be given intravenously,
discharge may be present; if an abscess forms and ruptures, purulent dis- and rifampin can be used as an adjuvant.59
charge may be noted. Granulomatous nodules develop on the palpebral
and bulbar conjunctiva approximately 3 days after inoculation (Fig. 4.6.11).
Necrosis and ulceration of the overlying epithelium is common.59 Firm
NONINFECTIOUS CONJUNCTIVITIS
and tender regional lymphadenopathy of the preauricular, submandibular, Toxic Follicular Conjunctivitis
and, occasionally, cervical nodes are a hallmark of the disease (Fig. 4.6.12).
Optic neuroretinitis and multifocal chorioretinitis may develop. Diagno- Toxic follicular conjunctivitis follows chronic exposure of the conjunctiva
sis can be made by indirect immunofluorescence antibody testing or by to a variety of foreign substances, including molluscum contagiosum of
enzyme immunoassay. Serological testing includes cultures and PCR. the lid margin, infection of the lashes by Phthirus pubis, use of eye cos-
The course of the disease in immunocompetent patients is usually metics, and prolonged use of eye medications. Molluscum contagiosum
self-limiting, and the disease resolves without antibiotic therapy. Therapy infections are caused by a poxvirus and are common in patients with HIV
is recommended for immunocompromised patients. Currently recom- infection. The infection is characterized by elevated, round, pearly white,
188 mended therapies include oral erythromycin, doxycycline, or azithromycin. waxy, noninflammatory lesions with umbilicated centers (Fig. 4.6.13).
In adults, doxycycline 100 mg twice daily is thought to be more effective When these lesions occur on or near the eyelid margin, the viral proteins
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BOX 4.6.2 Ocular Medications That Cause Toxic
Follicular Conjunctivitis 4.6
• Neomycin
• Idoxuridine

• Gentamicin
• Trifluorothymidine
• Dipivefrin
• Pilocarpine
• Apraclonidine
• Eserine
• Atropine
• Epinephrine (adrenaline)
• Preservatives (thimerosal, benzalkonium chloride)
spill onto the conjunctiva to cause a chronic follicular conjunctivitis.60 The

virus itself does not grow in the conjunctiva; rather, the conjunctivitis is
a toxic reaction to its proteins. Removal of the lesion or curettage until it
bleeds internally eliminates this condition. A
Most commonly, toxic follicular conjunctivitis occurs in association
with eye medications, such as neomycin, gentamicin, idoxuridine, and
other topical antivirals, as well as many glaucoma medications, including
brimonidine, pilocarpine, and other miotics (Box 4.6.2). These drugs incite
type IV delayed hypersensitivity reaction with periocular erythema and
follicular conjunctivitis. In contact lens wearers, any proteolytic enzymes/
chemicals used for contact lens cleaning or preservative-containing soaking
solutions can cause toxic conjunctivitis. A marked follicular response also
can accompany the use of eye cosmetics, such as mascara and eyeliner.
A common finding is dark granules from the cosmetic incorporated in
the follicles. If symptomatic, patients usually respond well to discontinua-
tion of the cosmetic and substitution of smaller amounts of hypoallergenic
preparations.
Erythema Multiforme Major (Stevens–Johnson

Syndrome) and Toxic Epidermal Necrolysis
Erythema multiforme, unlike cicatricial pemphigoid, is an acute, gen-
erally self-limiting, nonprogressive inflammatory disorder of the skin
and mucous membranes; it is classified into minor and major forms.
The minor form primarily involves the skin and lasts 2–3 weeks in its
acute phase. Erythema multiforme major, also known as Stevens–Johnson
syndrome, is the more serious variant, characterized by skin lesions and
erosive involvement of mucous membranes that lasts up to 6 weeks.61
Toxic epidermal necrolysis is a severe variant of erythema multiforme
major that is characterized by massive denudation of the epidermis and is
more commonly seen in children and in patients with AIDS.62 Erythema
multiforme major classically occurs in previously healthy young people,
men more than women, in their first 3 decades of life.61 A genetic pre- B
disposition may exist for the development of Stevens–Johnson syndrome
with ocular involvement, in association with human leukocyte antigens Fig. 4.6.14 Acute Phase of Stevens–Johnson Syndrome. This child has the
HLA-Bw44 and HLA-B12.63 The disease can be fatal in 2%–25% of patients, typical target-shaped macular skin lesions. (A) The head, with an associated
with death often secondary to sepsis. About 25% of those who have ery- blepharoconjunctivitis. (B) The leg.
thema multiforme suffer a recurrence over their lifetime.
The exact cause of erythema multiforme is unknown, although the
disease seems to be precipitated by numerous antigens, including bacteria If extensive skin necrosis occurs, the condition is labeled toxic epidermal
(e.g., Mycoplasma pneumoniae), viruses, fungi, and drugs. Herpes simplex necrolysis (Fig. 4.6.15). The extent of mucous membrane involvement
virus and Mycoplasma have a particularly strong association. Coxsackievirus usually parallels the extent of skin involvement. Any mucous membrane
and Histoplasma capsulatum also have been implicated.64 Drugs implicated may be involved, but the mouth and eyes are affected most frequently and
in the development of erythema multiforme include the sulfonamides, most severely. In one study, 100% of patients had stomatitis and 63% had
penicillin, barbiturates, nonsteroidal anti-inflammatory medications, salic- conjunctivitis.66 The diagnosis is confirmed by skin or mucosal biopsy
ylates, mercurial agents, arsenic, allopurinol, phenylbutazone, phenytoin, demonstrating multiple necrotic keratinocytes or full-thickness epidermal
and topical ophthalmic scopolamine (hyoscine), tropicamide, and propara- necrosis with subepidermal blistering.64
caine.65 In addition, the onset of the disease has been related to neoplasms, The acute phase of ocular involvement lasts 2–3 weeks.67 The lids
radiation therapy, collagen vascular diseases, and vaccinations.62 become swollen, ulcerated, and crusted. Patients develop an acute bilat-
Erythema multiforme often begins with a prodromal period for up to eral conjunctivitis, with chemosis, vesicles and bullae, pseudo-membranes
2 weeks with symptoms of malaise, fever, headache, and an upper respi- or membranes, and eventual ulceration. A more purulent conjunctivitis
ratory tract infection. Next, skin lesions develop symmetrically on the may develop as a result of bacterial secondary infection.65 The major ocular
extremities with sparing of the trunk and can reoccur for 2–6 weeks before re- problems occur from the cicatricial stage, after the acute toxic episode sub-
epithelization (Fig. 4.6.14). The primary cutaneous lesion is a round, erythe- sides. Conjunctival scarring and symblepharon may occur despite all sup-
matous macule that develops into a papule and then a vesicle or bulla. portive measures (Fig. 4.6.16). Destruction of the conjunctival goblet cells, 189
Eventually, large bullae can rupture, which results in epidermal necrosis. lacrimal gland, and accessory lacrimal gland tissue results in a severe dry
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considered. Unlike in cicatricial pemphigoid, eyelid or conjunctival surgery
4 does not stimulate further scarring. Conjunctival or buccal mucous mem-

brane grafts may be considered to restore the ocular surface. Transplanta-
tion of cryopreserved amniotic membrane grafts within the first 2 weeks of
the onset of symptoms has been shown in numerous case reports to facili-
tate rapid epithelial healing and prevent many of the debilitating cicatricial
complications.69 Stem cell transplantation through the use of living-related
or cadaveric conjunctival and limbal allografts is often done with subse-
quent penetrating keratoplasty or keratoprosthesis in patients with severe
corneal complications.
Epidermolysis Bullosa
Epidermolysis bullosa comprises a group of skin and mucous membrane
diseases that are characterized by the tendency to form blisters after minor
trauma.70 Symptoms occur shortly after birth or in early childhood and
have a tendency to recur throughout the patient’s life. Men and women
are affected equally, and both hereditary and acquired autoimmune forms
exist.71 The hereditary forms of epidermolysis bullosa may be classified as
Fig. 4.6.15 Severe Skin and Conjunctival Necrosis. The patient has toxic
simple (autosomal dominant), junctional (autosomal recessive), and dys-
epidermal necrolysis.
trophic (autosomal dominant or recessive).
Ocular problems have been described with all three types; they are,
however, associated mostly with the dystrophic form, which is the most
common form of the disease. Patients may have conjunctival blisters and
marked conjunctival scarring, with symblepharon formation and eyelid
ectropion or entropion.72 A granular epithelial clouding of the cornea can
occur, as can ulcers and opacification secondary to conjunctival scarring
similar to that seen in cicatricial pemphigoid or erythema multiforme.
Patients who have the junctional form, a rare type, have more primary
corneal problems, such as recurrent erosions, and little conjunctival
involvement. The acquired, autoimmune form may have both primary
corneal subepithelial vesicles and secondary corneal involvement associ-
ated with conjunctival scarring and symblepharon.
Treatment is based on the severity of disease. A majority of patients can
be treated conservatively with ocular lubricants. Various types of corneal
surgery, including keratoplasty, may be indicated if significant scarring and
visual loss occurs. Tarsorrhaphy and ectropion/entropion surgery may be
considered for patients with more severe disease.73
Graft-versus-Host Disease
Fig. 4.6.16 Stevens–Johnson Syndrome. Residual conjunctival scarring is evident Graft-versus-host disease (GVHD) is a common complication of allogeneic
over the superior tarsal plate. Symblepharon formation and fibrous bands are
bone marrow transplantation and results from donor-grafted cells attack-
present at the canthal angles.
ing host tissue antigens. Involved tissues include skin, gastrointestinal
tract, lungs, liver, and eyes. Acute or chronic (developing after day 100 fol-
eye, just as in cicatricial pemphigoid. Entropion, trichiasis, and lagophthal- lowing transplantation) disease can occur, but ocular manifestations are
mos combined with the dry eye can produce severe corneal problems, such more common with chronic GVHD. Ocular complications are secondary
as ulceration, vascularization, opacification, limbal stem cell deficiency, to two main mechanisms: conjunctival inflammation in acute disease sec-
and eventual perforation.67 Although the acute phase of erythema multi- ondary to T cell–mediated immunity and in chronic disease secondary to
forme may leave extensive conjunctival scarring in its wake, progressive infiltration of the lacrimal gland by T lymphocytes causing destruction
scarring does not occur when the acute disease has subsided, unlike cica- and fibrosis of the lacrimal gland and conjunctiva. Both pathways lead to
tricial pemphigoid. Fortunately, recurrences rarely involve the conjunctiva. keratoconjunctivitis sicca. Signs and symptoms include aqueous tear defi-
The histological changes in erythema multiforme suggest an underly- ciency, conjunctival erosions, corneal epithelial erosions, and cicatricial
ing vasculitis or perivasculitis.61 Mononuclear cells, eosinophils, and poly- lagophthalmos.73 Histologically, the conjunctiva in GVHD is characterized
morphonuclear neutrophils accumulate around the vessels or within the by decreased conjunctival goblet cell density, increased squamous meta-
vessel wall and induce fibrinoid necrosis of the wall. Subepithelial bullae plasia, and infiltration of inflammatory cells.74 Therapy consists mainly
are seen in the acute phase, and pseudo-membranes and true membranes of aggressive lubrication, autologous serum tears, punctal plugs, and
are found. Conjunctival goblet cell densities are reduced. Immunoglobu- decreasing ocular inflammation with topical corticosteroids and/or topical
lins and complement are also deposited at the dermal–epidermal junction. cyclosporine or tacrolimus. Bandage contact lenses and fluid ventilated gas
Treatment often varies with the severity of the condition. Patients who permeable sclera lenses also provide symptomatic relief. Mucolytic agents,
have a more severe initial presentation suffer the worst late ocular com- such as 10% acetylcysteine, can be used to treat severe filamentary kerati-
plications. In the acute phase, local treatment involves lubrication of the tis. Severe ocular disease accompanied by systemic complications warrants
ocular surface. Frequent lysis of developing symblepharon may have no increased systemic immunosuppression. Malta et al. suggested that treat-
effect on the eventual structure. Unfortunately, local medical treatment of ment with topical cyclosporine 1 month prior to bone marrow transplanta-
the acute condition often has little influence on the severity of the even- tion could help delay or prevent lacrimal gland damage and decrease the
tual cicatricial complications. However, systemic corticosteroids (predni- ocular symptoms of early GVHD.75
sone 60–80 mg/day for 3–4 weeks) may help control the acute disease.68
Plasmapheresis, systemic cyclosporine, and intravenous immunoglobulins Xeroderma Pigmentosa
have had variable results and remain controversial.64 Secondary bacterial
conjunctivitis should be suspected and treated, if present; an antibiotic that Xeroderma pigmentosa is an autosomal recessive disease characterized
could, however, stimulate another toxic reaction should be avoided. The by impaired ability to repair damage to DNA caused by ultraviolet radia-
cicatricial stage is treated with frequent nonpreserved artificial tears and/ tion. Ocular manifestations include keratoconjunctivitis sicca, photopho-
or ointments, topical cyclosporine, autologous serum tears, punctual occlu- bia, tearing, blepharospasm, and burning. Conjunctival inflammation,
190 sion, and tarsorrhaphy to control dry eye symptoms and prevent sequelae. telangiectasia, and hyperpigmentation are common findings. Patients
Surgery to correct lid keratinization, entropion, and trichiasis should be often develop pingueculae or pterygia. The patient’s impaired ability to
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repair DNA leads to cutaneous neoplasms, including squamous cell car- KEY REFERENCES
cinoma, basal cell carcinoma, and melanoma, in that order of frequency.
Neoplasms of the ocular surface and eyelids occur in approximately 11% Allansmith MR. The eye and immunology. St Louis: CV Mosby; 1982. p. 75–81.
Buznach N, Dagan R, Greenberg D. Clinical and bacterial characteristics of acute bacterial
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of patients and often are seen at the limbus. Progressive atrophy of the conjunctivitis in children in the antibiotic resistance era. Ped Inf Dis J 2005;24:823–8.
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Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guide-
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Chandler JW. Neonatal conjunctivitis. In: Tasman W, Jaeger EA, editors. Duane’s clinical
ophthalmology, vol. 4. Philadelphia: JB Lippincott; 1995. p. 6.2–6.
Kawasaki Disease David M, Rumelt S, Weintraub Z. Efficacy comparison between povidone iodine 2.5% and tet-
racycline 1% in prevention of ophthalmia neonatorum. Ophthalmology 2011;118:1454–8.
Kawasaki disease is a rare self-limiting vasculitis of childhood that presents Friedlander MH. Immunology of ocular infections. In: Friedlander MH, editor. Allergy and
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Gordon JY. The evolution of antiviral therapy for external ocular viral infections over
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and erythema of the oral mucosa. Iridocyclitis is another common finding. Isenberg SJ, Apt L, Wood M. A controlled trial of povidone-iodine as prophylaxis against
There are no sequelae from the ocular symptoms, but prompt recognition ophthalmia neonatorum. N Engl J Med 1995;332:562–6.
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thalmology, vol. 4. Philadelphia: JB Lippincott; 1990. p. 5.3–7.
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blindness. Some may develop pseudo-membranes over mucosal tissue US Preventive Services Task Force. Ocular prophylaxis for gonococcal ophthalmia neonato-
elsewhere in the body. The disease predominantly is described in children rum. Clinical Summary of US Preventive Services Task Force Reaffirmation Recommen-
but has been reported in both young and old. The etiology is unclear, but dation. AHRQ Publication No. 10-05146-EF-3, 2011. http://www.uspreventiveservicestask
type I plasminogen deficiency is thought to be a predisposing factor for force.org/uspstf10/gonocup/gonocupsum.htm.
the disease. Management is difficult with frequent recurrences following
excision. Topical plasminogen and fibrinolytic therapy has been tried with Access the complete reference list online at ExpertConsult.com
some success.77
191
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book of ophthalmology, vol. 8. External diseases. London: CV Mosby; 1994. p. 2.8–9. 64. Lin A, Patel N, Yoo D, et al. Management of ocular conditions in the burn unit: thermal
24. Yin-Murphy M. Viruses of acute hemorrhagic conjunctivitis. Lancet 1973;1:545–6. and chemical burns and Stevens–Johnson syndrome/toxic epidermal necrolysis. J Burn
25. Uchio E, Takeuchi S, Itoh N, et al. Clinical and epidemiological features of acute follicu- Care Res 2011;32:547–60.
lar conjunctivitis with special reference to that caused by herpes simplex virus type 1. Br 65. Dohlman CH, Doughman DJ. The Stevens–Johnson syndrome. In: Castroviejo R, editor.
J Ophthalmol 2000;84:968–72. Symposium on the cornea. Transactions of the New Orleans Academy of Ophthalmology.
26. Oh JO. Ocular infections of herpes simplex virus type II in adults. In: Darrell RW, editor. St Louis: CV Mosby; 1972. p. 236–52.
Viral diseases of the eye. Philadelphia: Lea & Febiger; 1985. p. 59–62. 66. Yetiv JZ, Bianchine JR, Owen JA. Etiologic factors of the Stevens–Johnson syndrome.
27. Garau J, Kabins S, DeNosaquo S, et al. Spontaneous cytomegalovirus mononucleosis South Med J 1980;73:599–602.
with conjunctivitis. Arch Intern Med 1977;137:1631–2. 67. Arstikaitis MJ. Ocular aftermath of Stevens–Johnson syndrome. Arch Ophthalmol
28. Trott DG, Pilsworth R. Outbreaks of conjunctivitis due to Newcastle disease virus in 1973;90:376–9.
chicken broiler factory workers. Br J Med 1965;3377:1514–7. 68. Tonnesen MG, Soter NA. Erythema multiforme. J Am Acad Dermatol 1979;1:357–64.
29. Slenczka W. Zika virus disease. Microbiol Spectr 2016;4:10–19. 69. Shay E, Kheirkhah A, Liang L, et al. Amniotic membrane transplantation as a new
30. Polack S, Brooker S, Kuper H, et al. Mapping the global distribution of trachoma. Bull therapy for the acute ocular manifestations of Stevens–Johnson syndrome and toxic epi-
WHO 2005;83:913–19. dermal necrolysis. Surv Ophthalmol 2009;54:686–96.
31. Mabey DC, Solomon AW, Foster A. Trachoma. Lancet 2003;362:223–9. 70. Fine JD. Epidermolysis bullosa: clinical aspects, pathology and recent advances in
32. Dawson CR, Jones BR, Tarizzo M. Guide to trachoma control. Geneva: World Health research. Int J Dermatol 1986;25:143–57.
Organization; 1981. p. 56. 71. Boothe WA, Mondino BJ, Donzis PB. Epidermolysis bullosa. In: Gold DH, Weingeist TA,
33. Dawson CR, Juster R, Marx R, et al. Limbal disease in trachoma and other ocular chla- editors. The eye in systemic disease. Philadelphia: JB Lippincott; 1990. p. 634–6.
mydial infections: risk factors for corneal vascularization. Eye 1989;3:204–9. 72. Tong L, Hodgkins PR, Denyer J, et al. The eye in epidermolysis bullosa. Br J Ophthalmol
34. Tabbara KF, Abu-el-Asrar A, al-Omar O, et al. Single-dose azithromycin in the treatment 1999;83:323–6.
of trachoma: a randomized, controlled study. Ophthalmology 1996;103:842–6. 73. Jabs DA, Wingard J, Green WR, et al. The eye in bone marrow transplantation. III. Con-
35. Bailey RL, Arullendran P, Whittle HC, et al. Randomised controlled trial of single-dose junctival graft-vs-host disease. Arch Ophthalmol 1989;107:1343–8.
azithromycin in treatment of trachoma. Lancet 1993;342:453–6. 74. Townley JR, Dana R, Jacobs DS. Keratoconjunctivitis sicca manifestations in ocular graft
36. Cochereau I, Goldschmidt P, Goepogui A, et al. Efficacy and safety of short duration azi- versus host disease: pathogenesis, presentation, prevention, and treatment. Semin Oph-
thromycin eye drops versus azithromycin single oral dose for the treatment of trachoma thalmol 2011;26:251–60.
in children: a randomized, controlled, double-masked clinical trial. Br J Ophthalmol 75. Malta JB, Soong HK, Shtein RM, et al. Treatment of ocular graft-versus-host disease with
2007;91:667–72. topical cyclosporine 0.05%. Cornea 2010;29:1392–6.
37. Keenan JD, Lakew T, Alemayehu W, et al. Slow resolution of clinically active trachoma 76. Zhu FH, Ang JY. The Clinical diagnosis and management of kawasaki disease: a review
following successful mass antibiotic treatments. Arch Ophthalmol 2011;129:512–13. and update. Curr Infect Dis Rep 2016;18:32.
38. Tullo AB, Richmond SJ, Esty PL. The presentation and incidence of paratrachoma in 77. Schuster V, Seregard S. Ligneous conjunctivitis. Surv Ophthalmol 2003;48:369–88.
adults. J Hyg 1981;87:63–9.
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Allergic Conjunctivitis
Jonathan B. Rubenstein, Tatyana Spektor 4.7
Definition: Allergic conjunctivitis is inflammation of the conjunctiva
due to an immediate hypersentivity reaction to environmental allergens.
Key Features
• Itching and redness are common presenting symptoms.
• Treatment includes mast-cell stabilizers, antihistamines, combination
medications, cool compresses, corticosteroids, and allergen
avoidance.
ACUTE ALLERGIC CONJUNCTIVITIS:

SEASONAL/PERENNIAL
Acute allergic conjunctivitis is a type I immediate hypersensitivity reaction
mediated by immunoglobulin E (IgE) and subsequent mast-cell activa-
tion,1 stimulated by direct exposure to environmental allergens. The reac-
tion may be limited to the eye, or it may be part of a generalized allergic Fig. 4.7.1 Chronic Atopic Conjunctivitis. Mild conjunctival injection with
reaction with nasal and respiratory symptoms. Often a family history of numerous giant cobblestone papillae.
atopy is present. Cytological examination of conjunctival scrapings shows
eosinophilic infiltration. Elevated levels of IgE and histamine are found in
the tear film.2 Acute allergic conjunctivitis is divided into seasonal aller-
gic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC).3 The
onset of symptoms for SAC is seasonally related to circulating aeroanti-
gens. PAC is considered a variant of SAC that persists throughout the year,
although seasonal exacerbations often are seen.2 Clinical symptoms and
signs are typically bilateral and consist of itching, burning, and mild to
moderate injection that can progress to various degrees of chemosis with
superior tarsal conjunctiva papillary reaction. A watery or mucoid “stringy”
discharge may be seen.4
CHRONIC ATOPIC KERATOCONJUNCTIVITIS

Chronic atopic keratoconjunctivitis (AKC) is an inflammatory disease that
can lead to disabling symptoms involving both the conjunctiva and the
cornea. It can present between the late teens through the fifth decade and
has a slight male predilection. A large majority of patients have concom-
itant eczema or asthma.1 Between 20% and 40% of patients with atopic
dermatitis also have AKC.5 Clinical symptoms include intense bilateral
itching, tearing, burning, photophobia, blurred vision, and a stringy mucus
discharge. Periorbital eczema, lid edema, conjunctival chemosis, and aller-
gic shiners are common findings. Papillary hypertrophy of the upper tarsal Fig. 4.7.2 Vernal Conjunctivitis. Cobblestone papillae cover the superior tarsal
conjunctiva is the most common sign (Fig. 4.7.1). Cobblestone papillae on conjunctiva.
the superior tarsal conjunctiva also may occur. Gelatinous limbal hyper-
plasia and nodules may be present with or without Horner–Trantas dots incidence between ages 11 and 13 years. Recent studies have found an asso-
(areas of eosinophils and degenerating cellular debris). In severe cases, ciation between low serum vitamin D levels in children with vernal con-
cicatrizing conjunctivitis with subepithelial fibrosis, symblepharon forma- junctivitis.7 The prominent symptom is intense pruritus. Other complaints
tion, and forniceal shortening may develop.2 Histopathologically, a mixture include photophobia, burning, tearing, mild ptosis, and a thick, ropy,
of mast cells, eosinophils, and lymphocytes are found in the conjunctival yellow, mucoid discharge. It is classically thought to be an IgE-mediated
epithelium. type 1 hypersensitivity reaction; however, studies have also noted T helper
2 lymphocyte involvement in a type IV immune reaction.2
VERNAL CONJUNCTIVITIS The three forms of the vernal conjunctivitis are palpebral, limbal, and
mixed.8 The palpebral form is marked by cobblestone papillae on the supe-
Vernal conjunctivitis is a bilateral, recurrent inflammation of the conjunc- rior tarsal conjunctiva (Fig. 4.7.2) with minimal involvement of the lower
tiva that tends to occur in children and young adults with a history of atopy. lid. After initial papillary hypertrophy, the connective tissue of the substan-
Its onset is most common in the spring and summer months, and the tia propria undergoes hyperplasia and proliferation to form giant papillae.
inflammation often goes into remission during the cooler months.6 The The pressure of the cornea flattens the tops of the giant papillae to produce
192 highest incidence is in the warm, temperate Middle East–Mediterranean a cobblestone pattern. Tiny twigs of vessels are found in the centers of the
region and Mexico. Boys are affected twice as often as girls, with a peak papillae, which help differentiate these from the large follicles without the
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4.7
Fig. 4.7.3 Vernal Catarrh. Clinical appearance of the less commonly seen limbal Fig. 4.7.4 Vernal Catarrh. Histological examination of a conjunctival smear shows
reaction. (Courtesy Dr. I. M. Raber.) the presence of many eosinophils. (Courtesy Dr. I. M. Raber.)
TABLE 4.7.1 Medications Used in the Treatment of Allergic Conjunctivitis

Category Examples Comments
Histamine 1 (H1) receptor Levocabastine, emedastine difumarate Use for isolated, acute allergic attacks.
agonists Use alone or in combination with mast-cell stabilizers and nonsteroidal anti-inflammatory drugs (NSAIDs).
Mast-cell stabilizers Cromolyn sodium, lodoxamide, pemirolast, Most useful for chronic allergies.
nedocromil sodium May take 1–2 weeks to be effective.
Pemirolast and nedocromil have antihistamine effects as well.
Nedocromil also reduces eosinophil and neutrophil chemotaxis.
Antihistamines with mast Olopatadine, alcaftadine, bepotastine, These medications combine the immediate effect of selective antihistamines with the long-term effects of
cell–stabilizing activity ketotifen fumarate, azelastine, epinastine, mast-cell stabilization.
bepotastine They have convenient once- or twice-a-day dosing.
Ketotifen and azelastine have anti-inflammatory properties as well.
Topical NSAIDs Ketorolac, nepafenac, bromfenac Can reduce itching, but stings when applied.
Vasoconstrictors Naphazoline/pheniramine, naphazoline/ Available over the counter; instruction must be given to avoid chronic use because of the risk of rebound
antazoline redness; relieves redness, but not other symptoms.
Topical corticosteroids Loteprednol, fluorometholone, rimexolone May be useful in serious cases or until control is achieved with other agents.
Side-effects limit chronic use.
Oral antihistamines Fexofenadine, loratadine, cetirizine, ebastine, Useful when systemic allergic symptoms are present but may cause dry eyes.
mizolastine, desloratadine
Immunomodulators Tacrolimus, cyclosporine Useful in refractory cases or situations where corticosteroid use is not appropriate.
central vessels seen in trachoma. The limbal form is marked by a broad, preservative-free artificial tears (refrigerated), and avoidance of allergens
thickened, gelatinous opacification of the superior limbus that can override can help alleviate symptoms. Unfortunately, avoidance of the offending
the cornea (Fig. 4.7.3). Tiny, twig-like vessels arise in the centers of these antigens is often difficult, thus medications are used for further symptom-
rounded lumps, as opposed to limbal follicles, where the vessels appear atic control (Table 4.7.1).
around the sides of the elevations. Histologically, the tissue is infiltrated Treatment regimens include topical decongestants, antihistamines,
with lymphocytes, plasma cells, macrophages, basophils, many eosin- mast cell–stabilizing agents, and anti-inflammatory agents. Topical decon-
ophils, and an increased number of conjunctival goblet cells (Fig. 4.7.4). gestants, which act as vasoconstrictors, can be used symptomatically with
Horner–Trantas dots, which are white, chalk-like gelatinous nodules com- mild allergic reactions to alleviate erythema and tearing. However, chronic
posed of eosinophils and epithelial debris located at the limbus, are charac- use can lead to rebound hyperemia that limits their efficacy. Histamine (H1
teristic in limbal vernal keratoconjunctivitis (VKC). Patients with VKC also receptor–specific) antagonists (see Table 4.7.1) can be used for intermittent,
have elevated levels of histamine with other cytokines and immunological acute allergic reactions from a limited exposure to the antigen. Mast-cell
molecules in the tear film. stabilizers (see Table 4.7.1) are used as long-term maintenance therapy for
The cornea is involved in about half the cases. Corneal manifestations chronic allergies.9 They act by reducing intracellular, calcium-dependent
include a superficial pannus and a punctate epithelial keratitis. Small, gray secretory events and decreasing synthesis/secretion of leukotrienes,
patches of necrotizing epithelium may involve the upper one third to two chemokines, and other proinflammatory mediators.10 Combination med-
thirds of the cornea—in severe cases, the cornea appears to be dusted with ications that act as both mast-cell stabilizers and H1-specific antagonists
flour.8 The affected area stains with fluorescein. A vernal “shield ulcer” (see Table 4.7.1) have become a mainstay of treatment. 3,10
develops as a horizontal oval, shallow, nonvascularized, indolent ulcer of Preseasonal treatment with a combination medication has been shown
the superior cornea (see Fig. 4.7.4) that leads to severe discomfort. The to suppress clinical symptoms in patients with SAC.11 Noncorticosteroidal
edges are composed of shaggy, gray, dead epithelial cells, and infiltration of anti-inflammatory agents and topical corticosteroids can be used to reduce
the underlying superficial stroma is present. After the ulcer heals, a mild the acute inflammatory response in severe cases until the mast-cell sta-
corneal opacity may persist at the level of Bowman’s layer. bilizers and antihistamines take effect. Corticosteroids are then tapered
off as the therapeutic effects of the maintenance medications take hold.
Topical cyclosporine 0.5%–2% has also been effective in the treatment of
TREATMENT OF ALLERGIC/ATOPIC VKC, atopy, and other forms of severe allergic disease.12 Topical tacroli-
KERATOCONJUNCTIVITIS mus ointment, which is known to inhibit T-lymphocyte activation, has
been used to treat corticosteroid-resistant or unresponsive AKC, VKC,
Treatment of all of the above conditions is based on the severity and and severe cases of GPC.5,13 Evaluation by an allergist is recommended in 193
chronicity of the disease in each patient. For all cases, cold compresses, severe cases.
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4
Fig. 4.7.6 Microbial Allergic Keratoconjunctivitis Associated With

Fig. 4.7.5 Allergic Dermatoconjunctivitis. Contact allergy of the eyelids after Staphylococci. A staphylococcal marginal infiltrate is seen in the superior cornea.
exposure to neomycin eyedrops. The skin shows a typical eczematous dermatitis.
ALLERGIC DERMATOCONJUNCTIVITIS
Contact allergy of the eyelids and conjunctiva represents the most common
form of allergic reaction seen by the ophthalmologist. It represents a
delayed, cell-mediated (type IV) hypersensitivity reaction. In patients
with previous sensitization, the immune reaction can take 48–72 hours to
develop. Common stimuli include eyedrops (neomycin, gentamicin, idox-
uridine, atropine, thimerosal, and penicillin13), cosmetics, clothing, jewelry,
plastics, animal or vegetable products, and industrial chemicals.14 The reac-
tion usually begins with severe itching and a papillary conjunctivitis that
is worse on the inferior palpebral conjunctiva. A mucoid or mucopurulent
discharge is seen. The adjacent skin of the lower lids and lateral canthi
becomes involved in a typical eczematous dermatitis (Fig. 4.7.5). Chronic
exposure can lead to keratinization of the lid with punctal edema and ste-
nosis. The cornea may show punctate epithelial keratitis and erosions.
Conjunctival scrapings show monocytes, polymorphonuclear neutrophil
leukocytes, mucus, and eosinophils. Treatment includes eliminating the Fig. 4.7.7 Giant Papillary Conjunctivitis. Giant papillae cover this patient’s
antigenic stimulus and quieting the eye with antihistamines, mast-cell sta- superior tarsal conjunctiva after chronic exposure to soft contact lenses.
bilizers, and topical corticosteroids.
MICROBIAL ALLERGIC CONJUNCTIVITIS cases of nontuberculous phlyctenular disease or persistent staphylococcal

blepharoconjunctivitis.
Microbial allergic conjunctivitis is a type IV hypersensitivity response to
the toxic protein breakdown products of bacterial disintegration, most
commonly from chronic staphylococcal blepharoconjunctivitis. The forma-
GIANT PAPILLARY CONJUNCTIVITIS
tion of bacterial breakdown products causes an allergic response in the Giant papillary conjunctivitis (GPC) is a syndrome of inflammation of the
conjunctiva and cornea.15 Typically, patients do not have a history of atopy. upper palpebral conjunctiva associated with contact lens wear, ocular pros-
Marginal infiltrates of the cornea can be associated with this condition theses, and protruding ocular sutures.16,17 It is primarily linked to contact
(Fig. 4.7.6).14 lens wear and is seen 10 times more frequently in soft lens wearers than in
Phlyctenular keratoconjunctivitis is another manifestation of micro- rigid lens wearers.17 The average time for the development of symptoms is
bial allergic conjunctivitis. In the past, it was commonly associated with 8 months for soft lens wearers and 8 years for hard lens wearers. Estimates
tuberculosis. Today, it is most frequently seen with chronic staphylococcal of the prevalence vary from 1% to 5% of soft lens users to 1% of rigid lens
blepharoconjunctivitis. Other possible sources include Candida albicans, users.
Coccidioides immitis, Chlamydia, parasites, and lymphogranuloma vene- Patients complain of mild itching after removal of the contact lenses
reum. Phlyctenular disease presents as slightly raised, small, pinkish white and increased mucus on the lenses and in the nasal canthus upon
or yellow nodules surrounded by dilated vessels located on conjunctiva awaking. They also complain of increased lens awareness, blurring of
near the limbus or into peripheral cornea. After a few days, the center of vision after hours of lens wear, excessive lens movement, and eventual
the lesion then ulcerates, sloughs, and clears without scarring. Classically, contact lens intolerance. Signs initially include a generalized thickening
there is no clear zone between the limbus and the lesion. Involvement is and hyperemia of the superior pretarsal conjunctiva. The normally small
usually bilateral and seasonal (occurring more in spring and summer), and papillae become elevated. The conjunctiva becomes more translucent and
the condition occurs most frequently in children and young adults. eventually becomes opaque secondary to cellular infiltration. Macropapil-
Treatment includes identifying the inciting organism and eradicating lae (0.3–1.0 mm) and giant papillae (1.0–2.0 mm) then form (Fig. 4.7.7).
it. Twice-daily lid scrubs (mechanical debridement of the lid margins Trantas dots and gelatinous nodules may develop at the limbus.18 Inspec-
with dilute baby shampoo or commercially prepared lid scrub pads) can tion of the contact lenses almost always reveals whitish protein deposits.
usually achieve symptomatic improvement. Topical antibiotic or antibiotic– The histology of GPC shows irregular thickening of the conjunctival
corticosteroid combination ointments or drops rubbed into the lid margins epithelium over the papillae, with epithelial downgrowth into the stroma.
may reduce the number of bacterial colonies. Corticosteroids are reserved The epithelium and stroma show infiltration of lymphocytes, plasma
for chronic recalcitrant blepharoconjunctivitis and are beneficial early in cells, polymorphonuclear neutrophil leukocytes, eosinophils, basophils,
the treatment of phlyctenular disease. Tuberculosis should be ruled out, and macrophages along with fibroblast proliferation. The number of
194 when appropriate. Systemic antibiotics, such as oral tetracycline 250 mg eosinophils and basophils is considerably lower than that seen in vernal
four times a day or oral doxycycline 100 mg twice a day, can help in conjunctivitis.
booksmedicos.org
The cause of GPC is multifactorial. Patients likely have environmen- KEY REFERENCES
tal antigens that adhere to the mucus and proteins that normally coat the
surface of all contact lenses.19 These antigens, which persist as deposits on Abelson MB, McLaughlin JT, Gomes PJ. Antihistamines in ocular allergy: are they all created
equal? Curr Allergy Asthma Rep 2011;11:205–11.
4.7
the contact lenses, are forced into repeated contact with the superior tarsal Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. J Allergy Clin
conjunctiva with blinking. Mechanical trauma also is an important factor
Immunol 2006;106:1019–32.
in the pathogenesis of GPC and develops in patients who have ocular Elhers WH, Donshik PC. Giant papillary conjunctivitis. Curr Opin Allergy Clin Immunol
prostheses and exposed suture ends. The repeated mechanical trauma 2008;8:445–9.
Garcia DP, Alperte JI, Cristobal JA, et al. Topical tacrolimus ointment for treatment of
induces expression of interleukin-8 with recruitment of dendritic cells intractable atopic keratoconjunctivitis: a case report and review of literature. Cornea
that increases the number of antigen-presenting cells.5 Repeated expo- 2011;30:462–5.
sure to antigens combined with the trauma from contact lens wear may Lambiase A, Leonardi A, Sacchetti M, et al. Topical cyclosporine prevents seasonal recur-
stimulate a type IV basophil hypersensitivity of the conjunctiva. A type I rences of vernal keratoconjunctivitis in a randomized, double-masked, controlled 2-year
study. J Allergy Clin Immunol 2011;128:896–7.
IgE-mediated immediate hypersensitivity reaction occurs as well. Meisler DM, Zaret CR, Stock EL. Trantas’ dots and limbal inflammation associated with soft
Treatment of the condition requires removal of the inciting factor. contact lens wear. Am J Ophthalmol 1980;89:66–9.
Loose sutures should be removed, and ocular prostheses may need to be Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and prospects for
refitted. In contact lens wearers, initial discontinuation of lens wear is nec- future treatment. J Allergy Clin Immunol 2005;115:118–22.
Sanchez MC, Parra BF, Matheu V. Allergic conjunctivitis. J Invest Allergol Clin Immunol
essary until the inflammation subsides, which can take months. Lens wear 2011;21(Suppl. 2):1–19.
may resume once symptoms improve, but decreasing daily wear time and Seamone CD, Jackson WB. Immunology of the external eye. In: Tasman W, Jaeger EA,
good lens hygiene are essential. Patients must be instructed to clean their editors. Duane’s clinical ophthalmology, vol. 4. Philadelphia: JB Lippincott; 1995. p.
contacts thoroughly each night, and an attempt should be made to remove 2.29–32.
Shimura M, Yasuda K, Miyazawa A, et al. Preseasonal treatment with topical olopatadine
preservatives from the lens care system. Disinfection with a hydrogen suppresses the clinical symptoms of seasonal allergic conjunctivitis. Am J Ophthalmol
peroxide system and regular enzymatic treatment help decrease buildup 2011;151:697–702.
on the lenses. Often switching to a different lens polymer allows more Stock EL, Meisler DM. Vernal conjunctivitis. In: Tasman W, Jaeger EA, editors. Duane’s clin-
than 80% of patients to continue contact lens wear.20 Daily disposable soft ical ophthalmology, vol. 4. Philadelphia: JB Lippincott; 1995. p. 9.1–5.
Tuft SJ, Kemeny DM, Dart JK, et al. Clinical features of atopic keratoconjunctivitis. Ophthal-
contact lenses should be encouraged and often are well tolerated. If soft mology 1991;98:150–8.
lenses do not work, a rigid gas-permeable lens can be tried. In the early
stages of GPC a combination drop of antihistamine and mast-cell stabi-
lizer can be effective in the resolution of some symptoms. Maintenance Access the complete reference list online at ExpertConsult.com
therapy with combination drops is typically necessary to prevent recur-
rence. A short course of topical corticosteroids or corticosteroid-sparing
medications, such as cyclosporine or tacrolimus, can lessen the symptoms
in severe cases.
195
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REFERENCES 11. Shimura M, Yasuda K, Miyazawa A, et al. Preseasonal treatment with topical olopatadine
suppresses the clinical symptoms of seasonal allergic conjunctivitis. Am J Ophthalmol
1. Ono SJ, Abelson MB. Allergic conjunctivitis: update on pathophysiology and prospects
for future treatment. J Allergy Clin Immunol 2005;115:118–22.
2011;151:697–702.
12. Lambiase A, Leonardi A, Sacchetti M, et al. Topical cyclosporine prevents seasonal recur-
4.7
2. Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. J Allergy rences of vernal keratoconjuncitivitis in a randomized, double-masked, controlled 2-year
study. J Allergy Clin Immunol 2011;128:896–7.
Clin Immunol 2006;106:1019–32.
3. Stahl JL, Barney NP. Ocular allergic disease. Curr Opin Allergy Clin Immunol 13. Garcia DP, Alperte JI, Cristobal JA, et al. Topical tacrolimus ointment for treatment of
2004;4:455–9. intractable atopic keratoconjunctivitis: a case report and review of literature. Cornea
4. Tuft SJ, Kemeny DM, Dart JK, et al. Clinical features of atopic keratoconjunctivitis. Oph- 2011;30:462–5.
thalmology 1991;98:150–8. 14. Rheinstrom SD. The conjunctiva. In: Chandler JW, Sugar J, Edelhauser HF, editors. Text-
5. Sanchez MC, Parra BF, Matheu V. Allergic conjunctivitis. J Invest Allergol Clin Immunol book of ophthalmology, vol. 8. External diseases. London: Mosby; 1994. p. 2.8–9.
2011;21(Suppl. 2):1–19. 15. Woods AC. The diagnosis and treatment of ocular allergy. Am J Ophthalmol
6. Beigelman MN. Vernal conjunctivitis. Los Angeles: University of Southern California 1949;32:1457–78.
Press; 1950. 16. Srinivasan BD, Jacobiec FA, Iwamoto T, et al. Giant papillary conjunctivitis with ocular
7. Bozkurt B, Artac H, Ozdemir H, et al. Serum vitamin D levels in children with vernal prosthesis. Arch Ophthalmol 1979;97:892–5.
keratoconjunctivitis. Ocul Immunol Inflamm 2016;1–5. 17. Binder PS. The physiologic effects of extended wear soft contact lenses. Ophthalmology
8. Stock EL, Meisler DM. Vernal conjunctivitis. In: Tasman W, Jaeger EA, editors. Duane’s 1980;87:745–9.
clinical ophthalmology, vol. 4. Philadelphia: JB Lippincott; 1995. p. 9.1–5. 18. Meisler DM, Zaret CR, Stock EL. Trantas’ dots and limbal inflammation associated with
9. Foster CS, Duncan J. Randomized clinical trial of topically administered cromolyn soft contact lens wear. Am J Ophthalmol 1980;89:66–9.
sodium for vernal keratoconjunctivitis. Am J Ophthalmol 1980;90:175–81. 19. Fowler SA, Allansmith MR. Evolution of soft contact lens coatings. Arch Ophthalmol
10. Abelson MB, McLaughlin JT, Gomes PJ. Antihistamines in ocular allergy: are they all 1980;98:95–9.
created equal? Curr Allergy Asthma Rep 2011;11:205–11. 20. Elhers WH, Donshik PC. Giant papillary conjunctivitis. Curr Opin Allergy Clin Immunol
2008;8:445–9.
195.e1
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Tumors of the Conjunctiva

James J. Augsburger, Zélia M. Corrêa, Bita Esmaeli 4.8
Definition: Spectrum of malignant and benign neoplasms,
choristomas, and hamartomas arising from or occurring within
the conjunctiva, and nonneoplastic epibulbar tumors frequently
misdiagnosed clinically as a conjunctival malignant neoplasm.
Key Features
• Solid mass or discrete lesion of conjunctiva.
• Wide spectrum of color, texture, and size of tumor and associated
features.
• Substantial differences in age at onset and clinical behavior after
detection.
CONJUNCTIVAL MALIGNANT NEOPLASMS

A conjunctival malignant neoplasm is a tumor (three-dimensional mass) Fig. 4.8.1 Conjunctival and Corneal Intraepithelial Neoplasia (CIN). The corneal
composed of cancer cells involving the conjunctival epithelium, the epithelium is thickened and translucent in the medial and superomedial portions of
stroma, or both. The lesions mentioned in this section are all malignant the cornea.
neoplasms (cancerous tumors) and neoplasias of the conjunctiva. There
are three principal categories of malignant neoplasms and neoplasias of
the conjunctiva: (1) ocular surface squamous neoplasms and neoplasias
(squamous cell carcinoma and its variants), (2) conjunctival melanoma,
and (3) conjunctival lymphoma. Several other uncommon but clinically
important conjunctival neoplasms will also be mentioned.
Ocular Surface Squamous Neoplasia

The term ocular surface squamous neoplasia (OSSN) encompasses a
number of related nonmelanocytic cancers that arise within the epithelium
of the conjunctiva, cornea, or both. These cancers range from conjuncti-
val and corneal intraepithelial neoplasia (CIN) (essentially carcinoma in situ
within the ocular surface epithelium) to nodular squamous cell carcinoma
and variants thereof, including mucoepidermoid carcinoma.
Conjunctival/corneal intraepithelial neoplasia is a localized or diffuse
replacement of normal conjunctival or corneal epithelium by malignant
cells derived from the stratified squamous epithelium.1 CIN becomes
evident clinically when it involves the corneal epithelium and produces a
translucent whitening or graying of the involved portions of that epithelium
(Fig. 4.8.1). The lesion can cause substantial impairment of visual acuity if
Fig. 4.8.2 Leukoplakic Squamous Cell Carcinoma of Conjunctiva. The discrete
it involves the central cornea. When malignant epithelial cells involve only white hyperkeratotic limbal plaque is associated with prominent conjunctival blood
a portion of the thickness of the epithelium pathologically, the condition vessels.
is called conjunctival or corneal squamous epithelial dysplasia. When neo-
plastic epithelial cells replace full-thickness conjunctival epithelium but do
not invade the substantia propria, the condition is referred to as squamous white accumulation of abnormally keratinized conjunctival epithelium
cell carcinoma in situ. Most ocular tumor specialists advise excision of con- overlying the tumor proper. The gelatinous tumor (Fig. 4.8.3) appears as a
junctival lesions suspected of being ocular surface squamous neoplasms, translucent nodule fed and drained by prominent dilated epibulbar blood
and surgical scraping of abnormal appearing corneal epithelium suspected vessels. The papillary tumor (Fig. 4.8.4) appears as a pink to reddish mass
of being corneal intraepithelial neoplasia with submission of the excised that exhibits prominent vascular loops internally on slit-lamp biomicros-
specimens to pathology to confirm or rule out the clinical diagnosis before copy. Many larger tumors exhibit more than one or these clinical patterns
initiating therapies such as topical interferon therapy or topical chemother- (Fig. 4.8.5). Some larger tumors also exhibit ulceration or even intracorneal
apy (see “Management of Conjunctival Tumors Suspected of Being Malig- or intraocular invasion that can be determined by slit-lamp biomicroscopy
nant Neoplasms or Neoplasias” below). or ultrasound biomicroscopy (UBM). Aggressive and neglected tumors can
Squamous cell carcinoma of the conjunctiva is a malignant neoplasm of invade the orbit and extend partially around the eye, a circumstance that
the stratified squamous epithelium of the conjunctiva.2,3 It appears as a may necessitate exenteration of the orbit.
hypervascularized epibulbar tumor that is located most frequently at the Mucoepidermoid carcinoma (Fig. 4.8.6) is a particularly aggressive form
196 limbus medially or temporally. Such tumors occur in three principal clin- of OSSN that has a strong tendency to recur following attempted exci-
ical patterns. The leukoplakic tumor (Fig. 4.8.2) is characterized by hard, sion, invade the eye wall, and invade the orbit.4 It resembles conventional
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Fig. 4.8.3 Papillomatous Squamous Cell Carcinoma of Conjunctiva. The pink Fig. 4.8.6 Mucoepidermoid Carcinoma of Conjunctiva. This tumor resembles a
limbal tumor contains multiple fine intralesional corkscrew blood vessels and is papillary squamous cell carcinoma near the limbus but has a nodular subepithelial
associated with dilated afferent and efferent conjunctival blood vessels. portion extending posteriorly.
squamous cell carcinoma quite closely clinically and on routine hematoxy-

lin and eosin–stained microslides but can be distinguished by the presence
of prominent goblet cells containing mucin (revealed by stains, such as
Alcian blue and mucicarmine) and positive immunoreactivity to immunos-
tain CK7. Because of its aggressively invasive behavior, this ocular surface
squamous neoplasm ultimately prompts exenteration in many cases.
Squamous cell carcinoma of the conjunctiva and its variants are the
most common primary conjunctival malignant neoplasms encountered
in clinical practice.5 The average annual incidence of squamous cell car-
cinoma of the conjunctival across all age groups has been estimated to be
approximately 17–20 new cases per million persons per year. For a pop-
ulation with an average life expectancy of 70 years, this average annual
incidence translates to a cumulative lifetime incidence of approximately 1
case per 700–850 persons. Most tumors of this category are encountered
in persons over age 50 years. Risk factors for occurrence include a history
of repeated, intense, sunlight exposure; male gender; outdoor occupations;
advanced age; cigarette smoking; a history of squamous cell carcinoma of
the skin of the head and neck; blond hair and light complexion; xeroderma
pigmentosum; acquired immunodeficiency syndrome (AIDS); and con-
junctival infection by human papilloma virus (HPV) types 16 and 18.
Fig. 4.8.4 Gelatinous Squamous Cell Carcinoma of Conjunctiva. The translucent Conjunctival Melanoma
limbal mass is associated with dilated afferent and efferent conjunctival blood
vessels. Malignant melanoma of the conjunctiva is a cancerous neoplasm that arises
from melanocytes that are present normally within the basal layers of the
conjunctival epithelium.6,7 This form of cancer ranges from a flat patch of
acquired conjunctival and corneal intraepithelial melanocytic intraepithe-
lial neoplasia (conjunctival–corneal melanoma in situ, malignant primary
acquired melanosis) to nodular epibulbar tumors. Most conjunctival mela-
nomas are dark brown but some appear partially if not entirely amelanotic.
The only reliable way to distinguish an amelanotic conjunctival melanoma
from squamous cell carcinoma or other amelanotic malignant neoplasm is
by pathological analysis of the excised or biopsied tumor.
Primary acquired melanosis (PAM) of the conjunctiva refers to a patch
of intraepithelial melanocytic hyperplasia to neoplasia that develops from
a previously unaffected region of the conjunctiva in an adult individual
(Fig. 4.8.7).6 Such melanotic conjunctival patches may contain only benign
or mildly atypical intraepithelial melanocytes (benign acquired melanosis)
or markedly atypical malignant melanoma cells (malignant PAM or PAM
with severe atypia). Although larger and more heterogeneously melanotic
conjunctival lesions are more likely to contain malignant melanoma cells
compared with smaller and more homogeneously melanotic lesions, no
reliable clinical way exists to distinguish between benign and malignant
PAM. Excision or biopsy of the lesion with pathological analysis of the
intraepithelial melanocytes is necessary for its classification as benign
PAM versus PAM with severe atypia (intraepithelial melanoma). Nodular
conjunctival melanoma frequently develops from patches of malignant
PAM. Underlying PAM should be suspected in cases with nodular con-
Fig. 4.8.5 Invasive Squamous Cell Carcinoma of Conjunctiva Exhibiting junctival melanoma associated with patchy flat melanotic conjunctiva.
Leukoplakic, Papillary and Gelatinous Components Plus Central Ulceration. Nodular conjunctival melanoma appears as a solid epibulbar tumor fed 197
Note blood within the corneal stroma at the pupillary margin of the tumor. and drained by prominent conjunctival blood vessels (Fig. 4.8.8). Such a
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Fig. 4.8.7 Primary Acquired Melanosis of Conjunctiva and Cornea. The lesion is Fig. 4.8.10 Malignant Lymphoma of Conjunctiva. The tumor is a lumpy, pink,
completely flat within the corneal, limbal, and bulbar conjunctival epithelium. ridge-like mass involving inferior bulbar and forniceal conjunctiva.
metastasize tend to involve regional lymph nodes (preauricular, parotid,

and submandibular) on the ipsilateral side of the head and neck initially.8
Because of this, clinical evaluation should include palpation of the head
and neck looking for enlarged lymph nodes. If lymph node metastasis is
suspected clinically, lymph node mapping and excision should be consid-
ered in conjunction with initial treatment of the conjunctival tumor.
Conjunctival Lymphoma
Conjunctival lymphoma is a form of extranodal non-Hodgkin’s lymphoma
that arises within the conjunctival substantia propria.9,10 Tumors of this
type appear as salmon-colored subepithelial masses (Fig. 4.8.10) that can
be unilateral or bilateral and unifocal to multifocal in each affected eye.
Pathological analysis of such tumors characteristically shows a monoclo-
nal collection of atypical lymphoid cells that usually are of B-scan lineage.
Different histopathological patterns are associated with varying likelihoods
of systemic lymphoma ranging from very low (mucosa associated lym-
phoid tumor [MALT] lymphoma) to reasonably high (diffuse large B-cell
lymphoma and mantel cell lymphoma). Because of this, histopatholog-
Fig. 4.8.8 Nodular Melanotic Conjunctival Melanoma at Limbus. Note dilated ical analysis of a biopsy specimen from such a tumor always is appro-
conjunctival blood vessels associated with lesion. priate to assess prognosis and develop a management plan. The most
common current treatment for isolated low-grade conjunctival lymphoma
is low-dose fractionated external beam radiation therapy with shielding of
the cornea and lens.
In addition to these three most common conjunctival malignant neo-
plasms, readers should be familiar with uncommon conjunctival malig-
nant neoplasms described below.
Conjunctival Kaposi’s sarcoma is a malignant neoplasm that arises from
blood vessels and possibly other tissue elements within the conjunctival
stroma.11,12 It occurs predominantly in individuals with AIDS or other
forms of systemic immunosuppression. The tumor characteristically
appears as a dark red, frequently hemorrhagic, conjunctival mass (Fig.
4.8.11) that grows rapidly if untreated. Since introduction of therapeutic
regimens that control many of the systemic features of human immuno-
deficiency virus (HIV) infection, such lesions are much less common than
they were several decades ago.
Sebaceous cell carcinoma (Fig. 4.8.12) is a malignant neoplasm that arises
from the meibomian glands in the tarsal conjunctiva or the Zeis glands
associated with the cilia at the lid margins.13,14 It frequently is misdiag-
nosed as chronic blepharoconjunctivitis and treated as such for weeks to
months before the correct diagnosis is suspected and confirmed patholog-
Fig. 4.8.9 Conjunctival Melanoma Associated With Primary Acquired Melanosis ically. This form of ocular surface cancer has a strong tendency to involve
of Conjunctiva. The nodular conjunctival tumor adjacent limbus is almost the conjunctival epithelium diffusely (pagetoid spread), a feature that
completely amelanotic. makes it extremely difficult to eradicate surgically. Histopathological anal-
ysis of a tumor specimen is the only reliable way to distinguish sebaceous
tumor can arise de novo (i.e., from conjunctiva that appeared normal prior carcinoma from squamous cell carcinoma and its variants.
to the tumor’s development) or from a patch of PAM. As indicated above, Rhabdomyosarcoma is a malignant neoplasm that may arise from pre-
most conjunctival melanomas are melanotic (brown); however, some are viously normal muscle cells. Primary orbital rhabdomyosarcoma is much
hypomelanotic or amelanotic (Fig. 4.8.9). The most common location for more common than primary conjunctival rhabdomyosarcoma.15 Primary
development of a conjunctival melanoma is at or adjacent to the limbus conjunctival rhabdomyosarcoma usually appears as a rapidly enlarging pale
medially or temporally. Such tumors are less likely to metastasize com- pink to tan tumor within the conjunctival substantia propria (Fig. 4.8.13).
198 pared with those that develop in the caruncle or semilunar fold or from The tumor usually develops during the first 2 decades of life. Biopsy of the
the forniceal or palpebral conjunctiva. Conjunctival melanomas that tumor with pathological analysis of the specimen is essential for prompt
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Fig. 4.8.11 Kaposi’s Sarcoma of Conjunctiva. Note the intensely red color of Fig. 4.8.14 Leukemic Tumor of Conjunctiva. The tumor is a well-defined, reddish-
the tumor and presence of associated subconjunctival blood. This patient had pink, ridge-like mass involving the superior fornix.
underlying acquired immunodeficiency syndrome (AIDS).
Fig. 4.8.12 Sebaceous Carcinoma of Conjunctiva. The tumor replaces semilunar Fig. 4.8.15 Conjunctival Nevus. The tumor is partly melanotic but predominantly
fold and caruncle and involves much of the palpebral conjunctiva and lid margin of tan and associated with moderately prominent conjunctival blood vessels.
the lower eyelid.
presenting sign of leukemia in some individuals, and the initial manifesta-

tion of relapse of some previously treated leukemias.
BENIGN CONJUNCTIVAL NEOPLASMS

AND NEOPLASIAS
A benign conjunctival neoplasm is an acquired tumor composed of noncan-
cerous cells and develops within previously normal-appearing conjunctival
epithelium, substantia propria, or both. A conjunctival choristoma is a con-
genital tumor of the conjunctiva composed of noncancerous cells that are
not normally present within that tissue. A conjunctival hamartoma is a con-
genital tumor of the conjunctiva composed of noncancerous cells that are
present normally in that tissue but are present in excessive number and
with atypical or disorganized tissue architecture. Although tumors of the
latter two types are not precisely “neoplasms,” they are lumped together
with benign neoplasms and neoplasias in this section.
Conjunctival Nevus
Fig. 4.8.13 Rhabdomyosarcoma of Conjunctiva and Orbit Presenting as
Epibulbar Tumor. The tumor appears as a pink mass arising from the superior The conjunctival nevus is a benign neoplasm consisting of mildly atypical
fornix. but noncancerous melanocytes that arose from normal conjunctival mela-
nocytes within the basal layers of the conjunctival epithelium.18 This tumor
diagnosis and successful treatment. Treatment usually consists of debulk- is, by far, the most common primary ocular neoplasm encountered in clin-
ing of the tumor followed by several cycles of systemic chemotherapy and ical practice. The typical lesion is not present at birth in most patients but
orbital external beam radiation therapy. develops later in life (most frequently within the first 2 decades of life) from
Leukemic conjunctival tumors of the substantial propria develop in some previously normal appearing conjunctiva, typically at the limbus medially
patients with leukemia.16,17 Tumors of this type (Fig. 4.8.14) appear similar or temporally. The lesion appears as a discrete brown to tan conjuncti- 199
to conjunctival lymphomas. They are extremely uncommon but can be the val tumor in most patients (Fig. 4.8.15) but is completely amelanotic and
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Fig. 4.8.16 Benign Acquired Melanosis of Conjunctiva. The bulbar conjunctival

melanosis is more prominent OS (left eye) than OD (right eye) but was evident
along the limbus OU (both eyes) symmetrically in this dark-skinned individual.
Fig. 4.8.18 Squamous Papilloma of Conjunctiva. The tumor is a pink columnar

tumor arising from the peripheral bulbar conjunctiva.
Fig. 4.8.17 Conjunctival and Intrascleral Hemangioma. This congenital vascular

tumor is composed of bright red superficial blood vessels and darker intrascleral
blood vessels.
translucent in some persons. The lesion is typically not associated with any
prominent dilated tortuous epibulbar feeder and drainer blood vessels. On
slit-lamp biomicroscopy, numerous intraepithelial microcysts commonly
are evident within such a lesion. Limited slow enlargement and darkening Fig. 4.8.19 Lymphangioma of Conjunctiva. The limited bulbar conjunctival tumor
of such lesions is frequently reported by the parents of the affected child. consists of dilated lymphatic channels filled with yellow-tinted clear fluid.
Such lesions appear to have very limited malignant potential.
Benign Acquired Melanosis of Conjunctiva Conjunctival Lymphangioma

A conjunctival lymphangioma (Fig. 4.8.19) is an ill-defined tumor of the
Many patients (particularly those of races with dark pigmentation) develop conjunctival substania propria composed of mature lymphatic channels in
progressive acquired conjunctival melanosis, almost always bilaterally and excessive amounts.22 In most cases, the conjunctival tumor is the anterior
most frequently in the limbal region (Fig. 4.8.16), as they age.19 In some and, therefore, visible portion of a more extensive orbital lymphangioma.
patients, the melanosis also involves the bulbar, forniceal, and even pal- Such tumors are probably congenital in many cases (in which case they
pebral conjunctiva in patchy fashion. This form of acquired conjunctival should be categorized as conjunctival hamartomas) but frequently do not
melanosis is almost always benign histopathologically and rarely gives rise show up until late in childhood to early adult years, typically in associa-
to conjunctival melanoma. tion with an upper respiratory or sinus infection. The lesion may enlarge
abruptly and sometimes fills with blood. Piecemeal excision of the lesion,
Conjunctival Hemangioma supplemented by cryotherapy, frequently is performed to treat prominent
A conjunctival hemangioma is a benign blood vessel tumor of the conjunc- tumors of this type.
tival stroma.20 In many patients, the lesion is present at birth. In such
patients, the lesion should probably be regarded as a hamartoma. Small Conjunctival Choristomas
lesions of this type are usually asymptomatic and can be left alone. In Conjunctival choristomas are benign congenital tumors composed of non-
contrast, complex epibulbar hemangiomas (Fig. 4.8.17) can be objection- malignant cells and tissues that do not occur normally in the conjunctiva.
able cosmetically. Repeated sessions of cryotherapy often are quite effec- The cells and tissues that comprise the tumor are generally arranged hap-
tive in reducing the size and decreasing the brightness of such lesions. hazardly. The tumor frequently contains both mesodermal and ectodermal
In the authors’ experience, attempts to excise such lesions or treat them elements, in which case it is referred to as a dermoid tumor. Because many
with sclerosing solutions usually are unsuccessful and frequently make the of the conjunctival tumors categorized as choristomas are not detected
situation worse. Fortunately, such tumors have limited if any malignant until late childhood to early adulthood, their congenital nature frequently
potential. cannot be verified. Several discrete subtypes of conjunctival choristomas
exist, including those discussed below.
Conjunctival Squamous Papilloma
A benign squamous papilloma of the conjunctiva is a neoplasm composed Limbal Dermoid
of nonmalignant vascularized fronds of subepithelial connective tissue The limbal dermoid is the most frequently encountered type of conjunctival
covered by intact stratified squamous epithelium (Fig. 4.8.18).21 It may be choristoma. This lesion is present at birth and appears as an off-white to
columnar or sessile in shape. Many lesions of this type that have been fleshy tumor overlying the corneoscleral limbus, most commonly infero-
200 evaluated microbiologically have been found to harbor HPV type 6 or 11, temporally (Fig. 4.8.20).23 The typical tumor contains both mesodermal ele-
and others have been linked to other HPV subtypes. ments (most commonly fibroblasts, hair follicles, and fat) and ectodermal
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Fig. 4.8.20 Limbal Dermoid Tumor. The tumor is an off-white, discoid mass Fig. 4.8.22 Dermolipoma of Conjunctiva. This tumor is pale pink with a yellowish
straddling the limbus inferotemporally. tint and soft to palpation.
Fig. 4.8.21 Solid Dermoid Tumor of Conjunctiva. The tumor is heterogeneously Fig. 4.8.23 Conjunctival Osteoma. This epibulbar tumor is hard but nontender. It
pigmented and contains several protruding hair shafts. is off-white in color and therefore difficult to image well.
elements (epithelial cells). Such lesions are a typical feature of Goldenhar’s

syndrome and often are bilateral in individuals with this disorder. Excision NONNEOPLASTIC LESIONS AND DISORDERS
of the lesion by lamellar or penetrating keratoplasty can be performed if SIMULATING MALIGNANT CONJUNCTIVAL
the lesion is objectionable cosmetically, causing induced astigmatism with
potential for amblyopia.
NEOPLASMS AND NEOPLASIAS
A wide variety of completely benign nonneoplastic lesions and disorders
Conjunctival Solid Dermoid can simulate malignant conjunctival neoplasms and neoplasia, including
The conjunctival solid dermoid is a nodular nonlimbal conjunctival tumor congenital anomalies, degenerative lesions, foreign bodies, various types
composed of benign mesodermal and ectodermal cells.24 A tumor of this of inflammatory lesion, secondary acquired pigmentations, and others. In
type is generally heterogeneously pigmented and frequently exhibits prom- the following section, we mention several of the lesions in this category
inent hair shafts protruding from its surface (Fig. 4.8.21). Such tumors most commonly mistaken for the three principal types of malignant con-
are commonly not noted until late childhood or early adolescence, and the junctival neoplasms and neoplasia.
timing of development of these lesions is unknown. Treatment is simple
excision.
Lesions Simulating Ocular Surface Squamous
Conjunctival Dermolipoma Neoplasms and Neoplasias
The conjunctival dermolipoma is a soft tissue tumor composed almost exclu-
sively of fat within the substantia propria of the conjunctiva, almost always Conjunctival Hyperplasia
superotemporally.25 The tumor appears similar to a prolapsed orbital fat Conjunctival hyperplasia is a noncancerous thickening of the stratified squa-
pad that develops in some older adults (Fig. 4.8.22); true conjunctival der- mous epithelium of the conjunctiva due to abnormal proliferation of epi-
molipomas, however, tend to become apparent much earlier in life. thelial cells.27 In most cases, some of the transition from columnar basal
cells to flattened external surface cells is retained. Histopathologically, the
Conjunctival Osteoma lesion is generally described as pseudo-adenomatous hyperplasia (when the
The conjunctival osteoma is a rare benign conjunctival choristoma com- thickened epithelium contains dilated “glandular” spaces) and as squamous
posed predominantly of bone that develops within the substantia propria, cell hyperplasia (when it does not contain such spaces).
most commonly in the superotemporal fornix region (Fig. 4.8.23).26 The
lesion enlarges slowly and asymptomatically and usually is not noted until Conjunctival Keratosis/Hyperkeratosis/Dyskeratosis
the teenage years. It generally is found when the affected individual rubs Conjunctival keratosis is a localized degenerative lesion of the limbal conjunc-
the eye and identifies a hard epibulbar lesion. The lesion is usually excised tiva, in which focally abnormal stratified squamous epithelium produces 201
to reassure the patient and family of its benign character. superficial keratin (which is not elaborated by normal conjunctiva).27,28 A
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Fig. 4.8.24 Actinic Keratosis of Conjunctiva Simulating Ocular Surface Fig. 4.8.26 Atypical Pinguecula Simulating Ocular Surface Squamous
Squamous Neoplasia. This tumor exhibits limited overlying leukoplakia. Neoplasia. This lesion is thickened, exhibits whitish keratinization on its surface and
is associated with dilated surrounding conjunctival blood vessels.
Fig. 4.8.25 Bilateral Hereditary Intraepithelial Dyskeratosis of Conjunctiva Fig. 4.8.27 Pyogenic granuloma of palpebral conjunctiva simulating ocular surface
Simulating Ocular Surface Squamous Neoplasia. This lesion resembles squamous squamous neoplasia.
cell carcinoma of the conjunctiva quite closely. A similar lesion was present on the
fellow eye of this patient.
lesion of this type is indistinguishable clinically from leukoplakic squa- This tumor is a nonneoplastic mass composed of aggregates of imma-
mous cell carcinoma (Fig. 4.8.24). When the amount of keratin produced ture blood vessels and fibroblastic stroma, accompanied by lymphocytes,
by the conjunctiva at the affected site is prominent, it is referred to as plasma cells, and scattered neutrophils. It is believed to be a focally aber-
hyperkeratosis. Conjunctival dyskeratosis refers to nonmalignant aberrant rant form of conjunctival healing following an injury (which may be sur-
maturation of the conjunctival stratified squamous epithelium associated gical incision). The lesion appears a vascularized pink to red conjunctival
with thickening of the epithelium and elaboration of keratin. This lesion is tumor that projects abruptly from the conjunctival surface (Fig. 4.8.27).
most characteristically encountered bilaterally in an autosomal dominantly Such lesions frequently recur after a simple excision, and intensive focal
inherited condition known as bilateral hereditary intraepithelial dyskeratosis anti-inflammatory drug therapy and cryotherapy to the involved conjunc-
(Fig. 4.8.25).29 tiva coupled with excision often are required to eradicate them. Other
inflammatory lesions of the conjunctiva of interest to ophthalmologists
Inflamed Pinguecula/Hypertrophic Pterygium include juvenile xanthogranuloma, foreign body granuloma, microbial
Pinguecula and pterygium are common degenerative conjunctival lesions granuloma (including tuberculoma), and various nonmicrobial inflam-
that usually are easy to distinguish from ocular surface squamous neo- matory granulomas associated with systemic condition (e.g., sarcoidosis,
plasms and neoplasias. However, atypical pingueculae and pterygia that lupus).32-35
become inflamed, abnormally thick, and hypervascularized can be diffi-
cult to distinguish from squamous cell carcinoma and its variants (Fig. Viral Papilloma of Conjunctiva
4.8.26). In addition, conjunctival epithelial dysplasia and invasive neoplasia The viral papilloma of the conjunctiva is a reactive inflammatory lesion
have been identified histopathologically in association with some promi- induced by conjunctival infection by human papilloma virus.36 The lesion
nent pingueculae and pterygia that have been excised. Because of this, all frequently resembles conjunctival squamous papilloma quite closely but
lesions suspected to be an atypical pinguecula or a pterygium that come to is more likely to be multifocal (Fig. 4.8.28) and much more likely to affect
excision should be submitted for histopathological analysis. young children and adolescents. Attempts to excise such lesions frequently
result in exuberant proliferation of new lesions. Cryotherapy to individ-
Inflammatory Granuloma of Conjunctiva ual lesion is sometimes effective in destroying them. However, recurrent
A variety of inflammatory tumors of the conjunctiva composed in large lesions following excision with cryotherapy frequently require supplemen-
part of nonneoplastic chronic and acute inflammatory cells can simulate tal treatment with topical interferon drops or chemotherapeutic drops
202 conjunctival squamous cell carcinoma quite closely. The most common (mitomycin C, 5-fluorouracil). Some success has also been reported when
of these is undoubtedly the pyogenic granuloma of the conjunctiva.30,31 such lesions were treated by oral cimetidine.
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Fig. 4.8.28 Viral papillomas of conjunctiva simulating papillary conjunctival Fig. 4.8.30 Uveal prolapse and incarceration in eye wall laceration simulating
squamous cell carcinoma. conjunctival melanoma.
Fig. 4.8.29 Iridociliary melanoma with anterior transcleral extension simulating Fig. 4.8.31 Nodular Anterior Scleritis Simulating Conjunctival Neoplasm. The
conjunctival melanoma. conjunctiva and sclera are thickened and hyperemic diffusely, and this lesion was
tender to palpation.
Lesions Simulating Conjunctival Melanoma and palpation of the reddened area through the eyelid. UBM can demonstrate
Malignant Primary Acquired Melanosis the localized scleral thickening in such cases. Treatment usually consists of
corticosteroids and, if necessary, other anti-inflammatory drugs.
Posterior Uveal Melanoma With Anterior Transcleral
Extension Ciliary Body Staphyloma
Some uveal melanomas that involve the ciliary body extend transclerally The ciliary body staphyloma is a localized thinning of the sclera, usually in
to the episcleral surface via scleral neural or vascular foramina.37,38 The response to a prior injury or surgery or a prior episode of nodular or nec-
epibulbar tumor in such cases usually is dark brown and frequently asso- rotizing scleritis, that then bulges as a result of intraocular pressure.42 In
ciated with prominently dilated epibulbar blood vessels (Fig. 4.8.29). The most cases, the lesion appears as a smoothly elevated bluish-brown scleral
distinguishing feature that is obvious on slit-lamp biomicroscopy is the mass without involvement of the overlying conjunctiva and without prom-
absence of conjunctival epithelial involvement. Ocular transillumination inently dilated epibulbar blood vessels in that location (Fig. 4.8.32). Ocular
typically reveals a distinct shadow produced by the ciliary body portion of transillumination shows prominent transmission of light through the eye
the tumor. Ocular ultrasonography (possibly UBM) will confirm the pres- wall corresponding to the visible dark lesion. UBM can confirm the thin-
ence of the underlying ciliary body tumor. ning of the eye wall and absence of any underlying ciliary body tumor.
Conjunctival Argyrosis
Occult Eyewall Laceration With Incarceration of Conjunctival argyrosis is an acquired dark gray to black pigmentation of
Uveal Tissue the conjunctiva that develops in response to chronic application of silver
Some individuals who have suffered a conjunctival and eye wall laceration nitrate drops.43 Affected individuals often were given some silver nitrate
will not recognize the extent of their injury and not get evaluated by an eye drops many years ago as treatment for a conjunctival infection and con-
specialist for weeks to years following that injury.39 In some such cases, tinued to take the drops for years after the original problem resolved. The
uveal tissue is incarcerated into the wound (Fig. 4.8.30). This uveal tissue conjunctival pigmentation can simulate primary acquired melanosis of the
can be mistaken for a conjunctival melanoma.40 conjunctiva quite closely (Fig. 4.8.33).
Nodular Anterior Scleritis Lesions Simulating Conjunctival Lymphoma

Nodular anterior scleritis is a severe inflammatory reaction to some incit-
ing event that develops within the anterior sclera.41 The eye is painful and Benign Reactive Lymphoid Hyperplasia of the Conjunctiva
the affected area of the sclera and overlying conjunctiva are extremely Benign reactive lymphoid hyperplasia (BRLH) of the conjunctiva is a 203
reddened and thickened (Fig. 4.8.31). The eye is frequently very tender to nonmalignant infiltrative mass of the conjunctiva composed principally
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Fig. 4.8.32 Ciliary Body Staphyloma Simulating Conjunctival Melanoma. Note Fig. 4.8.35 Sarcoid granulomas of inferior forniceal and palpebral conjunctiva
the absence of prominently dilated conjunctival blood vessels associated with this simulating conjunctival lymphoma.
lesion.
Limited lesions may be left untreated, but extensive lesions of this type
usually are treated by low-dose external beam radiation therapy.
Inflammatory Granulomas of Conjunctiva

Certain inflammatory granulomas of the conjunctiva, including those caused
by microbial organisms (e.g., tuberculoma), nonmicrobial inflammatory
disorders (e.g., sarcoid granuloma), and foreign bodies, can resemble
malignant lymphoma of the conjunctival quite closely (Fig. 4.8.35).33–35
Biopsy or excision of the mass with histopathological and microbiological
analysis of the specimen generally is required for diagnosis and to guide
subsequent patient management.
MANAGEMENT OF CONJUNCTIVAL TUMORS

SUSPECTED OF BEING MALIGNANT
NEOPLASMS OR NEOPLASIAS
Clinically suspected conjunctival malignant neoplasms and neoplasias
usually are managed by surgical excision45,46 (if possible) or biopsy (if the
lesion involves an extensive portion of the conjunctiva) followed by supple-
Fig. 4.8.33 Argyrosis of conjunctiva simulating primary acquired melanosis of mental therapy of the retained conjunctiva by methods such as cryotherapy47
conjunctiva. (liquid nitrogen spray or cryoprobe therapy), topical immunotherapy48,49
(interferon eyedrops [off-label therapy]), topical chemotherapy50–52 (mito-
mycin C or 5-fluorouracil eyedrops [off-label therapy]), or radiation
therapy46,53 (epibulbar strontium-90 applicator therapy, radioactive plaque
brachytherapy, or external beam radiation therapy) if malignant neoplasia
is confirmed pathologically. The goal of treatment is complete eradication
of the cancer cells with preservation of the eye and retention or recovery
of good vision. Surgical excision of suspected conjunctival neoplasms and
neoplasias should include at least a 1-mm margin of clinically uninvolved
conjunctiva around the visible lesion, whenever possible. The ophthalmic
surgeon should give thoughtful consideration to closure of the surgical
defect by mobilizing the retained conjunctiva around the defect and cre-
ating relaxing conjunctival incisions for advancement flaps as needed or
arranging for implantation of a mucous membrane (e.g., amniotic mem-
brane) graft when primary closure is impossible.54,55 In general, lamellar
sclerectomy and keratectomy should be avoided, whenever possible, and
suspected scleral or corneal invasion by the neoplasia should be managed
by supplemental cryotherapy, radiation therapy, or both as indicated subse-
quent to the excisional procedure.
Because conjunctival melanomas tend to metastasize via lymphatics to
lymph nodes in the head and neck, all patients with a newly diagnosed
conjunctival melanoma should be evaluated by palpation of the head and
Fig. 4.8.34 Benign lymphoid hyperplasia of conjunctival simulating conjunctival
neck ipsilateral to the tumor to search for clinically detectable lymph
lymphoma.
nodes.56 Those with suspicious lymph nodes by palpation should be evalu-
ated by computed tomography or magnetic resonance imaging of the head
of benign or mildly atypical lymphocytes.44 The infiltrate is characterized and neck to confirm or rule out the physical examination findings. Patients
pathologically by a polyclonal accumulation of benign appearing lymphoid having an extremely large conjunctival melanoma, especially if it involves
cells, usually in a follicular pattern. The lesion can affect one or both eyes the fornices or palpebral conjunctiva, and those whose tumor exhibits
and usually involves the forniceal conjunctiva predominantly (Fig. 4.8.34). ulceration and numerous mitotic figures histopathologically57,58 should be
204 It resembles malignant lymphoma quite closely, and only histopathological considered for sentinel lymph node mapping and biopsy.59–61 If melanoma
and immunopathological analysis can distinguish between these entities. node metastasis is confirmed by biopsy, complete neck dissection with
booksmedicos.org
wider lymph node excision may be considered,58 and systemic immuno- Esmaeli B, Roberts D, Ross M, et al. Histologic features of conjunctival melanoma predictive
of metastasis and death. Trans Am Ophthalmol Soc 2012;110:64–73.
therapy for that metastatic melanoma is likely to be initiated.62
In contrast, squamous cell carcinomas and variants and other malig-
Kamal S, Kaliki S, Mishra DK, et al. Ocular surface squamous neoplasia in 200 patients:
a case-control study of immunosuppression resulting from human immunodeficiency
4.8
nant conjunctival neoplasms rarely metastasize to regional lymph nodes. virus versus immunocompetency. Ophthalmology 2015;122:1688–94.
Consequently, lymph node mapping and sentinel lymph node biopsy gen- Kao A, Afshar A, Bloomer M, et al. Management of primary acquired melanosis, nevus, and

erally are not indicated for such neoplasms. Some aggressive and locally conjunctival melanoma. Cancer Control 2016;23:117–25.
Kenawy N, Garrick A, Heimann H, et al. Conjunctival squamous cell neoplasia: the Liver-
advanced conjunctival melanomas, variants of squamous cell carcinoma pool Ocular Oncology Center experience. Graefes Arch Clin Exp Ophthalmol 2015;253:
(especially mucoepidermoid carcinoma), and sebaceous carcinomas of the 143–50.
conjunctiva will have invaded the orbit extensively prior to diagnosis, and Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv Ophthalmol
such cases may be treated by orbital exenteration if complete excision is 1983;27:211–32.
Kirkegaard MM, Coupland SE, Prause JU, et al. Malignant lymphoma of the conjunctiva.
not possible.63,64 Surv Ophthalmol 2015;60:444–58.
Suspected lymphomas of the conjunctiva warrant a special comment. Nanji AA, Sayyad FE, Karp CL. Topical chemotherapy for ocular surface squamous neoplasia.
Optimal current analysis of such lesion involves testing of both fixed tissue Curr Opin Ophthalmol 2013;24:336–42.
and fresh tumor specimens (for flow cytometry and gene rearrangement Rankin JK, Jakobiec FA, Zakka FR, et al. An improved approach to diagnosing and treating
conjunctival mucoepidermoid carcinoma. Surv Ophthalmol 2012;57:337–46.
studies).9,10 When such lesions are excised or a biopsy performed, the Seregard S. Conjunctival melanoma. Surv Ophthalmol 1998;42:321–50.
tissue obtained in the procedure should be divided in approximately equal Shields CL, Fasiuddin AF, Mashayekhi A, et al. Conjunctival nevi: clinical features and
parts in the operating room. One of these specimens should be submitted natural course in 410 consecutive patients. Arch Ophthalmol 2004;122:167–75.
in formalin for conventional histopathological and immunohistochemical Shields JA, Saktanasate J, Lally SE, et al. Sebaceous carcinoma of the ocular region. Asia Pac
J Ophthalmol (Phila) 2015;4:221–7.
studies. The other half should be submitted as moistened fresh tumor Sudesh S, Rapuano CJ, Cohen EJ, et al. Surgical management of ocular surface squamous
to the pathology laboratory for flow cytometry and gene rearrangement neoplasms: the experience from a cornea center. Cornea 2000;19:278–83.
testing. The most common treatment for localized low-grade conjunctival Sun EC, Fears TR, Goedert JJ. Epidemiology of squamous cell conjunctival cancer. Cancer
lymphoma is low-dose external beam radiation therapy.65 Epidemiol Biomarkers Prev 1997;6:73–7.
Youef YA, Finger PT. Squamous carcinoma and dysplasia of the conjunctiva and cornea. An
analysis of 101 cases. Ophthalmology 2012;119:233–40.
KEY REFERENCES
Andrew NH, Coupland SE, Pirbhai A, et al. Lymphoid hyperplasia of the orbit and ocular Access the complete reference list online at ExpertConsult.com
adnexa: a clinical pathologic review. Surv Ophthalmol 2016;61:778–90.
205
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REFERENCES 34. Tulvatana W, Sansopha L, Pisarnkorskul P. Primary conjunctival tuberculoma: a case
report. J Med Assoc Thai 2001;84(Suppl. 1):S127–30.
1. Youef YA, Finger PT. Squamous carcinoma and dysplasia of the conjunctiva and cornea.
An analysis of 101 cases. Ophthalmology 2012;119:233–40.
35. Mocan MC, Bozkurt B, Orhan D, et al. Juvenile xanthogranuloma of the corneal limbus.
Report of two cases and review of the literature. Cornea 2008;27:739–42.
4.8
2. Kenawy N, Garrick A, Heimann H, et al. Conjunctival squamous cell neoplasia: the 36. Kaliki S, Arepalli S, Shields CL, et al. Conjunctival papilloma: features and outcomes
based on age at initial examination. JAMA Ophthalmol 2013;131:458–593.

Liverpool Ocular Oncology Center experience. Graefes Arch Clin Exp Ophthalmol
2015;253:143–50. 37. Meyer A, D’Hermies F, Morel X, et al. Differential diagnosis of conjunctival melanoma:
3. Kamal S, Kaliki S, Mishra DK, et al. Ocular surface squamous neoplasia in 200 patients: exteriorized uveal melanoma. J Fr Ophtalmol 1997;20:775–8.
a case-control study of immunosuppression resulting from human immunodeficiency 38. Noble J, Qazi FA, Lakosha HK, et al. Extrascleral extension in association with ciliocho-
virus versus immunocompetency. Ophthalmology 2015;122:1688–94. roidal melanoma: ultrasound biomcroscopy with histopathological correlation. Can J
4. Rankin JK, Jakobiec FA, Zakka FR, et al. An improved approach to diagnosing and treat- Ophthalmol 2005;40:616–18.
ing conjunctival mucoepidermoid carcinoma. Surv Ophthalmol 2012;57:337–46. 39. Zoroquiain P, Ganimi MS, Alghamdi S, et al. Traumatic iridial extrusion mimicking a
5. Sun EC, Fears TR, Goedert JJ. Epidemiology of squamous cell conjunctival cancer. conjunctival melanocytic neoplasm. Ecancermedicalscience 2016;10:620.
Cancer Epidemiol Biomarkers Prev 1997;6:73–7. 40. Marr BP, Shields JA, Shields CL, et al. Uveal prolapse following cataract extraction sim-
6. Seregard S. Conjunctival melanoma. Surv Ophthalmol 1998;42:321–50. ulating melanoma. Ophthalmic Surg Lasers Imaging 2008;39:250–1.
7. Kenawy N, Lake SL, Coupland SE, et al. Conjunctival melanoma and melanocytic 41. Jabs DA, Mudun A, Dunn JP, et al. Episcleritis and scleritis: clinical features and treat-
intra-epithelial neoplasia. Eye (Lond) 2013;27:142–52. ment results. Am J Ophthalmol 2000;130:469–76.
8. Savar A, Esmaeli B, Ho H, et al. Conjunctival melanoma: local-regional control rates, and 42. Pavlin CJ, Easterbrook M, Hurwitz JJ, et al. Ultrasound biomicroscopy in the assessment
impact of high-risk histopathologic features. J Cutan Pathol 2011;38:18–24. of anterior scleral disease. Am J Ophthalmol 1993;116:628–35.
9. Kirkegaard MM, Coupland SE, Prause JU, et al. Malignant lymphoma of the conjunctiva. 43. Tendler I, Pulitzer MP, Roggli V, et al. Ocular argyrosis mimicking conjunctival mela-
Surv Ophthalmol 2015;60:444–58. noma. Cornea 2017;36:747–8.
10. Kirkegaard MM, Rasmussen PK, Coupland SE, et al. Conjunctival lymphoma – an inter- 44. Andrew NH, Coupland SE, Pirbhai A, et al. Lymphoid hyperplasia of the orbit and ocular
national multicenter retrospective study. JAMA Ophthalmol 2016;134:406–14. adnexa: a clinical pathologic review. Surv Ophthalmol 2016;61:778–90.
11. Reiser BJ, Mok A, Kukes G, et al. Non-AIDS-related Kaposi sarcoma involving the tarsal 45. Sudesh S, Rapuano CJ, Cohen EJ, et al. Surgical management of ocular surface squa-
conjunctiva and eyelid margin. mous neoplasms: the experience from a cornea center. Cornea 2000;19:278–83.
12. Shuler JD, Holland GN, Miles SA, et al. Kaposi sarcoma of the conjunctiva and 46. Westekemper H, Meller D, Darawsha R, et al. Operative therapy and irradiation of con-
eyelids associated with the acquired immunodeficiency syndrome. Arch Ophthalmol junctival melanoma. Ophthalmologe 2015;112:899–900.
1989;197:858–62. 47. Li AS, Shih CY, Rosen L, et al. Recurrence of ocular surface squamous neoplasia treated
13. Shields JA, Saktanasate J, Lally SE, et al. Sebaceous carcinoma of the ocular region. Asia with excisional biopsy and cryotherapy. Am J Ophthalmol 2015;160:213–19.
Pac J Ophthalmol (Phila) 2015;4:221–7. 48. Shah SU, Kaliki S, Kim HJ, et al. Topical interferon alfa-2b for management of ocular
14. McConnell LK, Syed NA, Zimmerman MB, et al. An analysis of conjunctival map biop- surface squamous neoplasia in 23 cases. Arch Ophthalmol 2012;130:159–64.
sies in sebaceous carcinoma. Ophthal Plast Reconstr Surg 2017;33:17–21. 49. Garip A, Schaumberger MM, Wolf A, et al. Evaluation of a short-term topical interferon
15. Shields CL, Shields JA, Honavar SG, et al. Clinical spectrum of primary ophthalmic α-2b treatment for histologically proven melanoma with primary acquired melanosis
rhabdomyosarcoma. Ophthalmology 2001;108:2284–92. with atypia. Orbit 2016;35:29–34.
16. Kincaid MC, Green WR. Ocular and orbital involvement in leukemia. Surv Ophthalmol 50. Ballalai PL, Erwenne CM, Martins MC, et al. Long-term results of topical mitomycin C
1983;27:211–32. 0.02% for primary and recurrent conjunctival-corneal intraepithelial neoplasia. Ophthal
17. Rosenberg C, Finger PT, Furlan L, et al. Bilateral epibular granulocytic sarcomas: a case Plast Recontr Surg 2009;25:296–9.
of an 8-year-old girl with acute myeloid leukemia. Grafes Arch Clin Exp Ophthalmol 51. Joag MG, Sise A, Murillo JC, et al. Topical 5-fluorouracil 1% as primary treatment for
2007;245:170–2. ocular surface squamous neoplasia. Ophthalmology 2016;123:1442–8.
18. Shields CL, Fasiuddin AF, Mashayekhi A, et al. Conjunctival nevi: clinical features and 52. Nanji AA, Sayyad FE, Karp CL. Topical chemotherapy for ocular surface squamous neo-
natural course in 410 consecutive patients. Arch Ophthalmol 2004;122:167–75. plasia. Curr Opin Ophthalmol 2013;24:336–42.
19. Kao A, Afshar A, Bloomer M, et al. Management of primary acquired melanosis, nevus, 53. Graue GF, Tena LB, Finger PT. Electron beam radiation for conjunctival squamous carci-
and conjunctival melanoma. Cancer Control 2016;23:117–25. noma. Ophthal Plast Reconstr Surg 2011;27:277–81.
20. Shields JA, Mashayekhi A, Kligman BE, et al. Vascular tumors of the conjunctiva in 140 54. Asoklis RS, Damijonaityte A, Butkiene L, et al. Ocular surface reconstruction using
cases. Ophthalmology 2011;118:1747–53. amniotic membrane following excision of conjunctival and limbal tumors. Eur J Oph-
21. Sjo N, Heegaard S, Prause JU. Conjunctival papilloma. A histopathologically based retro- thalmol 2011;21:552–8.
spective study. Acta Ophthalmol Scand 2000;78:663–6. 55. Lee JH, Kim YH, Kim MS, et al. The effect of surgical wide excision and amniotic mem-
22. Seca M, Borges P, Reimao P, et al. Conjunctival lymphangioma: a case report and brief brane transplantation with adjuvant topical mitomycin C treatment in recurrent conjunc-
review of the literature. Case Rep Ophthalmol Med 2012;336573. tival-corneal intraepithelial neoplasia. Semin Ophthalmol 2014;29:192–5.
23. Xin M, Gong YR, Jiang SH, et al. Preoperative evaluation and outcome of corneal 56. Pfeiffer ML, Savar A, Esmaeli B. Sentinel lymph node biopsy for eyelid and conjunc-
transplantation for limbal dermoids: a ten-year follow-up study. Int J Ophthalmol tival tumors: what have we learned in the past decade? Ophthal Plast Reconstr Surg
2016;9:1756–60. 2013;29:57–62.
24. Mansour AM, Barber JC, Reinecke RD, et al. Ocular choristomas. Surv Ophthalmol 57. Esmaeli B, Roberts D, Ross M, et al. Histologic features of conjunctival melanoma pre-
1989;33:339–58. dictive of metastasis and death. Trans Am Ophthalmol Soc 2012;110:64–73.
25. McNab AA, Wright JE, Caswell AG. Clinical features and surgical management of der- 58. Savar A, Esmaeli B, Ho H, et al. Conjunctival melanoma: local-regional control rates, and
molipomas. Aust NZ J Ophthalmol 1990;18:159–62. impact of high-risk histologic features. J Cutan Pathol 2011;38:18–24.
26. Vachette M, Moulin A, Zografos L, et al. Epibulbar osseous choristoma: a clinicopatho- 59. Ivan D, Kim S, Esmaeli B, et al. Sentinel lymph node biopsy for ocular adnexal mela-
logical cases series and review of the literature. Klin Monbl Augenheilkd 2012;229:420–3. noma: experience in 30 patients. Ophthalmology 2009;116:2217–23.
27. Margo CE, Grossniklaus HE. Pseudoadenomatous hyperplasia of the conjunctiva. Oph- 60. Cohen VM, Tsimpida M, Hungerford JL, et al. Prospective study of sentinel lymph node
thalmology 2001;108:135–8. biopsy for conjunctival melanoma. Br J Ophthalmol 2013;97:1525–9.
28. Mauriello JA, Napolitano J, McLean I. Actinic keratosis and dysplasia of the conjunctiva: 61. Pfeiffer ML, Ozgur OK, Myers JN, et al. Sentinel lymph node biopsy for ocular adnexal
a clinicopathological study of 45 cases. Can J Ophthalmol 1995;30:312–16. melanoma. Acta Ophthalmol 2017;95:e323–8.
29. Bui T, Young JW, Frausto RF, et al. Hereditary benign intraepithelial dyskeratosis: report 62. Ford J, Thuro BA, Thakar S, et al. Immune checkpoint inhibitors for treatment of
of a case and re-examination of the evidence for locus heterogeneity. Ophthalmic Genet metastatic melanoma of the orbit and ocular adnexa. Ophthal Plast Reconstr Surg
2016;37:76–80. 2017;33:e82–5.
30. Ferry AP. Pyogenic granulomas of the eye and ocular adnexa: a study of 100 cases. Trans 63. Shields JA, Shields CL, Gunduz K, et al. Clinical features predictive of orbital exentera-
Am Ophthalmol Soc 1989;87:327–43. tion for conjunctival melanoma. Ophthal Plast Reconstr Surg 2000;16:173–8.
31. Al-Towerki AA. Pyogenic granuloma. Int Ophthalmol 1996;19:287–91. 64. Hwang IP, Jordan DR, Brownstein S, et al. Mucoepidermoid carcinoma of the conjunc-
32. Chung HS, Feder RS, Weston BC, et al. Suture reaction masquerading as a conjunctival tiva. A series of three cases. Ophthalmology 2000;107:801–5.
malignancy. Can J Ophthalmol 2006;41:207–9. 65. Pinnix CC, Dabaja BS, Milgrom SA, et al. Ultra-low-dose radiotherapy for definitive man-
33. Schilgen G, Sundmacher R, Pomjanski N, et al. Bilateral large conjunctival tumours as agement of ocular adnexal B-cell lymphoma. Head Neck 2017;39:1095–100.
primary manifestation of sarcoidosis – successful treatment with steroid-depot-injec-
tions. Klin Monbl Augenheilkd 2006;223:326–9.
205.e1
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Pterygium and Conjunctival

Degenerations 4.9
Roni M. Shtein, Alan Sugar
located nasally much more often than temporally. When a pinguecula

Definition: Secondary deterioration or deposition in the conjunctiva, crosses the limbus onto the cornea, it is called a pterygium. Current infor-
distinct from dystrophies. mation, however, suggests that pinguecula do not progress to pterygium
and that the two are distinctly different disorders. Pingueculae are asso-
ciated with a two- to threefold increased incidence of age-related macular
degeneration, possibly through a common light exposure effect.1
Key Features The causes of pingueculae are not known with certainty. There is,
• Common. however, good evidence of an association with increasing age and ultravi-
• Bilateral usually. olet light exposure. Pingueculae are seen in most eyes by age 70 years and
• Typically does not affect vision. in almost all by age 80 years.2 Chronic sunlight exposure has been found
to be a factor by association with outdoor work and equatorial residence.
In some studies, the strength of this association is less than that for pte-
rygium.3 It is thought that the predominantly nasal location is related to
Associated Features reflection of light from the nose onto the nasal conjunctiva. The effect of
• Increased prevalence with age. ultraviolet light may be mediated by mutations in the p53 gene.4
• Often associated with chronic light exposure. Pingueculae rarely are associated with symptoms other than a minimal
• May occur after past inflammation. cosmetic defect. They may become red with surface keratinization. When
• Not inherited. inflamed, the diagnosis of pingueculitis is made.
Distinguishing pingueculae from other lesions usually is not a problem
because of the typical appearance. Conjunctival intraepithelial neoplasia
INTRODUCTION may be difficult to differentiate from keratinized pinguecula. Gaucher’s
disease type I may be associated with tan pingueculae, but this is not a
Degenerations of the conjunctiva are common conditions that, in most specific finding.5
cases, have relatively little effect on ocular function and vision. They Histopathologically, pingueculae are characterized by elastotic degener-
increase in prevalence with age as a result of past inflammation, long-term ation of the collagen with hyalinization of the conjunctival stroma, collec-
toxic effects of environmental exposure, or aging itself. Conjunctival tion of basophilic elastotic fibers, granular deposits, and noninvolvement
degenerations may be associated with chronic irritation, dryness, or pre- of the cornea.6
vious history of trauma. Progression to involve the cornea may occur, as Pingueculitis responds to a brief course of topical corticosteroids or
in pterygium. nonsteroidal anti-inflammatory agents.7 Chronically inflamed or cosmeti-
cally unsatisfactory pingueculae rarely warrant simple excision.
PINGUECULA
Pingueculae are elevated, horizontally oriented areas of bulbar conjunctival
PTERYGIUM
thickening that are white to yellow in color and adjoin the limbus in the Pterygium is a growth of fibrovascular tissue on the cornea and conjunc-
palpebral fissure area (Fig. 4.9.1). They are less transparent than normal tiva. It occurs in the palpebral fissure, much more often nasally than tem-
conjunctiva, often have a fatty appearance, are usually bilateral, and are porally, although either or both (“double” pterygium) occur (Fig. 4.9.2).
Elevated whitish opacities (“islets of Vogt”) and an iron deposition line
(“Stocker”) may delineate the head of the pterygium on the cornea. Like
pinguecula, it is a degenerative lesion, although it may appear similar to
pseudo-pterygium, which is a conjunctival adhesion to the cornea sec-
ondary to previous trauma or inflammation, such as peripheral corneal
ulceration. A pseudo-pterygium often has an atypical position and is not
adherent at all points, so a probe can be passed beneath it peripherally.
Like pinguecula, pterygium is associated with ultraviolet light expo-
sure.3 It occurs at highest prevalence and most severely in tropical areas
near the equator and to a lesser and milder degree in cooler climates.8
Outdoor work and both blue and ultraviolet light have been implicated in
its causation. The use of hats and sunglasses is protective.8 Theories of
pathogenesis of pterygia include the possibility of damage to limbal stem
cells by ultraviolet light and by activation of matrix metalloproteinases.9
The histopathology of pterygium is similar to that of pinguecula except
that Bowman’s membrane is destroyed within the corneal component and
vascularization is seen.9 Evaluation using spectral domain optical coher-
ence tomography reveals pterygium as an elevated, wedge-shaped mass
of tissue separating the corneal epithelium from Bowman’s membrane,
which appears abnormally wavy and interrupted and often destroyed, with
206 Fig. 4.9.1 Nasal Pinguecula. Elevated conjunctival lesion encroaches on nasal satellite masses of subepithelial pterygium tissue beyond the clinically
limbus. seen margins.10
booksmedicos.org
4.9
Pterygium and Conjunctival Degenerations

Fig. 4.9.3 Senile Scleral Plaque. Calcium deposition appears as a gray scleral
A plaque under the medial rectus muscle insertion.
Fig. 4.9.2 Double Pterygium. (A) Note both nasal and temporal pterygia in a
57-year-old farmer. (B) It is the invasion of the cornea that distinguishes a pterygium
from a pinguecula.
Pterygia warrant treatment when they cause discomfort (not responsive

to conservative therapy), encroach upon the visual axis, induce significant
Fig. 4.9.4 Primary Localized Conjunctival Amyloid. There is irregularity of the
astigmatism, or become cosmetically bothersome. Aggressive or recurrent
conjunctiva superonasally with fixed folds. Resolving subconjunctival hemorrhages
pterygia may cause restrictive strabismus and distortion of the eyelids. A noted superiorly are associated with amyloid deposition in blood vessel walls.
variety of surgical techniques have been developed. The goal of treatment
is prevention of recurrence. The recurrence rates after simple excision are
very high: Of recurrences, 50% reoccur within 4 months of excision and In lesions secondary to systemic disease, other forms of amyloid protein
nearly all within 1 year.11 Beta-radiation applied postoperatively to the pte- may be seen.17 All patients should be evaluated for lymphoproliferative and
rygium base was popular for many years but is associated with late scleral systemic diseases. Amyloid involving the skin of the eyelids has been sug-
necrosis.12 Currently, the most widely used techniques are conjunctival gested to be a sign of systemic involvement.18
autografting and amniotic membrane transplantation.12 Adjuvant use of Conjunctival amyloid may appear as a yellowish, well-demarcated,
mitomycin-C application—either pre-, intra-, or postoperatively—has been irregularly elevated mass. It generally involves the fornices, with the supe-
associated with scleral melt in some situations.13 Fibrin-based glues have rior fornix and tarsal conjunctiva most commonly affected. In vivo confo-
been used to minimize operating time and discomfort associated with cal microscopy of conjunctival amyloid shows hyporeflective material in
sutures, and to reduce the amount of suturing required.14 a lobular pattern in the substantia propria and around the blood vessels
in the conjunctiva without associated inflammation.19 Recurrent subcon-
SENILE SCLERAL PLAQUES junctival hemorrhages may be associated with amyloid deposition in blood
vessel walls. Biopsy is required for definitive diagnosis.17
Senile scleral plaques occur in the sclera of elderly patients and often are Lesions generally are treated symptomatically, although debulking exci-
misinterpreted as a melting process similar to that of corneal degenera- sion can be performed for chronic irritation. Although it may not cause
tions or as conjunctival depositions. These lesions appear as yellow, gray, full regression of deposited amyloid, radiotherapy may be used to prevent
or black vertical bands just anterior to the insertion of the medial and progression.20
lateral rectus muscles (Fig. 4.9.3). They become more common after age
60 years and, like pinguecula and pterygium, may be related to ultravio-
let light exposure.15 Histologically, calcium deposits along with decreased
CONJUNCTIVAL MELANOSIS
cellularity and hyalinization are seen. These lesions do not need therapy. Conjunctival melanosis is a common finding with advancing age. The
appearance is that of a flat, pigmented area on the conjunctiva. Primary
CONJUNCTIVAL AMYLOID acquired melanosis is a risk factor for development of conjunctival mela-
noma and is discussed in detail in Chapter 4.8.
Deposition of amyloid in the conjunctiva has been reported in both primary Secondary melanosis of the conjunctiva is generally benign and tends
and secondary localized forms (Fig. 4.9.4) and secondary to systemic proc- to be more frequently bilateral. Secondary melanosis occurs following
esses.16 Chronic conjunctival inflammation may cause secondary localized trauma, chronic inflammation of the conjunctiva, and in individuals with
amyloidosis, a true degenerative change. In the primary localized forms, darker skin pigmentation.21 Secondary melanosis generally is not associ-
light-chain immunoglobulins deposited by monoclonal B cells and plasma ated with atypia and can be observed. If the lesions are noted to be elevated 207
cells have been demonstrated by immunohistochemistry. or where uncertainty exists, biopsy should be performed.
booksmedicos.org
KEY REFERENCES Mackenzie FB, Hirst LW, Battistutta D, et al. Risk analysis in the development of pterygia.
4 Austin P, Jakobiec FA, Iwamoto T. Elastodysplasia and elastodystrophy as pathologic bases of

ocular pterygium and pinguecula. Ophthalmology 1983;90:96–109.
Bozkurt B, Kiratli H, Soylemezoglu F, et al. In vivo confocal microscopy in a patient with
Ophthalmology 1992;99:1056–61.
Scroggs MW, Klintworth GK. Senile scleral plaques: a histopathologic study using
energy-dispersive X-ray microanalysis. Hum Pathol 1991;22:557–62.
Soliman W, Mohamed TA. Spectral domain anterior segment optical coherence tomography
assessment of pterygium and pinguecula. Acta Ophthalmol 2012;90:461–5.
conjunctival amyloidosis. Clin Exp Ophthalmol 2008;36:173–5.

Folberg R, Jakobiec FA, Bernardino VB, et al. Benign conjunctival melanocytic lesions. Clin- Taylor HR, West S, Munoz B, et al. The long-term effects of visible light on the eye. Arch
icopathologic features. Ophthalmology 1989;96:436–61. Ophthalmol 1992;110:99–104.
Leibovitch I, Selva D, Goldberg RA, et al. Periocular and orbital amyloidosis: clinical charac-
teristics, management, and outcome. Ophthalmology 2006;113:1657–64.
Lucas RM. An epidemiological perspective of ultraviolet exposure – public health concerns. Access the complete reference list online at ExpertConsult.com
Eye Contact Lens 2011;37:168–75.
Ma DH, See LC, Liau SB, et al. Amniotic membrane graft for primary pterygium: compar-
ison with conjunctival autograft and topical mitomycin C treatment. Br J Ophthalmol
2000;84:973–8.
208
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REFERENCES 11. Hirst LW, Sebban A, Chant D. Pterygium recurrence time. Ophthalmology 1994;101:755–8.
12. Ma DH, See LC, Liau SB, et al. Amniotic membrane graft for primary pterygium: com-
1. Pham TQ, Wang JT, Rochtchina E, et al. Pterygium/pinguecula and the five-year inci-
dence of age related maculopathy. Am J Ophthalmol 2005;139:536–7.
parison with conjunctival autograft and topical mitomycin C treatment. Br J Ophthalmol
2000;84:973–8.
4.9
2. Panchapakesan J, Hourihan F, Mitchell P. Prevalence of pterygium and pinguecula: the 13. Lindquist TP, Lee WB. Mitomycin C-associated scleral stromalysis after pterygium
surgery. Cornea 2015;34:398–401.
Pterygium and Conjunctival Degenerations

Blue Mountains Eye Study. Aust N Z J Ophthalmol 1998;26(Suppl. 1):S2–5.
3. Lucas RM. An epidemiological perspective of ultraviolet exposure – public health con- 14. Romano V, Cruciani M, Conti L, et al. Fibrin glue versus sutures for conjunctival auto-
cerns. Eye Contact Lens 2011;37:168–75. grafting in primary pterygium surgery. Cochrane Database Syst Rev 2016;(12):CD011308.
4. Dushku N, Hatcher SL, Albert DM, et al. P53 expression and relation to human pap- 15. Scroggs MW, Klintworth GK. Senile scleral plaques: a histopathologic study using ener-
illomavirus infection in pingueculae, pterygia and limbal tumors. Arch Ophthalmol gy-dispersive X-ray microanalysis. Hum Pathol 1991;22:557–62.
1999;117:1593–9. 16. Knowles DM 2nd, Jakobiec FA, Rosen M, et al. Amyloidosis of the orbit and adnexae.
5. Chu FU, Rodriguez MM, Cogan DG, et al. The pathology of pingueculae in Gaucher’s Surv Ophthalmol 1975;19:367–84.
disease. Ophthalmol Paediatr Genet 1984;4:7–11. 17. Leibovitch I, Selva D, Goldberg RA, et al. Periocular and orbital amyloidosis: clinical
6. Austin P, Jakobiec FA, Iwamoto T. Elastodysplasia and elastodystrophy as pathologic characteristics, management, and outcome. Ophthalmology 2006;113:1657–64.
bases of ocular pterygium and pinguecula. Ophthalmology 1983;90:96–109. 18. Moorman CM, McDonald B. Primary (localised non-familial) conjunctival amyloidosis:
7. Frucht-Pery J, Siganos CS, Solomon A, et al. Topical indomethacin solution versus dexa- three case reports. Eye 1997;11:603–6.
methasone solution for treatment of inflamed pterygium and pinguecula: a prospective 19. Bozkurt B, Kiratli H, Soylemezoglu F, et al. In vivo confocal microscopy in a patient with
randomized clinical study. Am J Ophthalmol 1999;127:148–52. conjunctival amyloidosis. Clin Experiment Ophthalmol 2008;36:173–5.
8. Mackenzie FB, Hirst LW, Battistutta D, et al. Risk analysis in the development of ptery- 20. Tyradellis C, Peponis V, Kulwin DR. Surgical management of recurrent localized eyelid
gia. Ophthalmology 1992;99:1056–61. amyloidosis. Ophthal Plast Reconstr Surg 2006;22:308–9.
9. Chui J, Di Girolamo N, Wakefield D, et al. The pathogenesis of pterygium: Current con- 21. Folberg R, Jakobiec FA, Bernardino VB, et al. Benign conjunctival melanocytic lesions.
cepts and their therapeutic implications. Ocul Surf 2008;6:24–43. Clinicopathologic features. Ophthalmology 1989;96:436–61.
10. Soliman W, Mohamed TA. Spectral domain anterior segment optical coherence tomogra-
phy assessment of pterygium and pinguecula. Acta Ophthalmol 2012;90:461–5.
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Ocular Cicatricial Pemphigoid/Mucous

Membrane Pemphigoid 4.10
Ahmed Al-Ghoul, Steven Kane, Deepinder K. Dhaliwal
Definition: A heterogeneous group of chronic, systemic, inflammatory, TABLE 4.10.1 Clinical Features and Frequency in
subepithelial, blistering diseases. Mucous Membrane Pemphigoid
Site Clinical Features Frequency (%)
Oral mucosa Oral mucosal vesicles/bullae 30–84
Key Features and pharynx Desquamative gingivitis
Pharyngitis and scarring
• Subepithelial bulla formation, rupture, and scarring of mucous
membranes and skin. Conjunctiva Conjunctivitis and progressive scarring 60–80
• Female-to-male ratio of 2 : 1. Nose/sinus Epistaxis 18–50
• Type II immune linear deposition of immunoglobulin A (IgA), IgG, Nasal mucosa/turbinate ulcers
IgM, and/or complement (C3) on the conjunctival epithelial basement Skin Localized, erythematous plaques with recurrent 17–23
vesicles and bullae on the scalp and face that heal
membrane.
with atrophic scars
• Systemic immunosuppressive treatment is critical in suppressing Recurrent vesiculobullous eruptions of the inguina
conjunctival inflammation and disease progression. and/or extremities
Esophagus Dysphagia 7–27
Esophageal strictures
Larynx Intermittent hoarseness or dysphonia 5–30
Associated Features Supraglottic inflammation and scarring
• Be aware of the significant extraocular morbidities that can occur, Anus/vagina Blisters, erosions, and scarring with or without 5–11
such as esophageal stricture formation. fusion of tissues
• Surgical management of ocular cicatricial pemphigoid traditionally Adapted from Chang JH, McCluskey PJ. Ocular cicatricial pemphigoid: manifestations and
carries a poor prognosis. management. Curr Allergy Asthma Rep 2005;5:333–8; Foster CS. Cicatricial pemphigoid.
Trans Am Ophthalmol Soc 1986;84:527–663; Foster CS, Sainz de la Maza M. Ocular cicatricial
pemphigoid review. Curr Opin Allergy Clin Immunol 2004;4:435–9; Mondino BJ, Brown SI.
Ocular cicatricial pemphigoid. Ophthalmology 1981;88:95–100; Thorne JE, Anhalt GJ, Jabs DA.
INTRODUCTION Mucous membrane pemphigoid and pseudopemphigoid. Ophthalmology 2004;111:45–52;
Hardy KM, Perry HO, Pingree GC, et al. Benign mucous membrane pemphigoid. Arch Dermatol
1971;104:467–75; and Elder MJ, Lightman S. The immunological features and pathophysiology
Ocular cicatricial pemphigoid (OCP) is an autoimmune disease character- of ocular cicatricial pemphigoid. Eye 1994;8:196–9.
ized by chronic progressive conjunctival inflammation and scarring. This
condition belongs to a heterogeneous group of chronic, systemic, inflam-
matory, subepithelial, blistering diseases termed mucous membrane including BP180, BP230, α6 β4 integrin, laminin 5, and type VII collagen,
pemphigoid.1 They share the similar manifestations of subepithelial bulla have been identified in patients with mucous membrane pemphigoid. In
formation, rupture, and scarring of mucous membranes and skin.2 particular, α6 β4 integrin has been strongly linked with OCP. This antigen
The incidence of mucous membrane pemphigoid varies between 1 in is an important component of hemi-desmosomes required for epithelial
20 000 to 1 in 46 000 in the ophthalmic literature, with a female-to-male cell attachment to the basement membrane, and its targeting may explain
ratio of approximately 2 : 1.2 The average age of diagnosis is in the seventh the formation of subepithelial bullae seen in OCP.9 Recent studies have
decade of life (age range 30–90 years), and an average diagnostic lag of shown abnormal serum levels of interleukin-4 (IL-4), IL-5, IL-6, tumor
2.8 years has been reported because of the nonspecific nature of early necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-
disease.3,4 No racial or geographical predilection has been reported. Oral β) during the active phase of the disease, suggesting an abnormal immune
involvement in mucous membrane pemphigoid occurs in up to 84% of system regulation. Further support for the autoimmune nature of mucous
cases. The risk of ocular disease in patients seen with only extraocular membrane pemphigoid comes from the observed association with other
manifestations is estimated to be 5% per annum for the first 5 years of autoimmune diseases, such as rheumatoid arthritis, systemic lupus ery-
follow-up with eventual involvement in up to 80% of cases.5,6 Approxi- thematosus, and polyarteritis nodosa.3,10 A genetic predisposition for devel-
mately 50% of patients presenting with OCP will have extraocular lesions.7 oping mucous membrane pemphigoid also has been postulated by linkage
The clinical presentation and frequency of extraocular tissue involvement studies. Specific human leukocyte antigen (HLA) class II alleles, such as
is listed in Table 4.10.1. the DQB1*0301, are significantly associated with severe disease phenotype
and anti–basement membrane zone IgG antibody response in mucous
PATHOGENESIS membrane pemphigoid.1
The histopathology of OCP demonstrates local infiltration by mac-
Although the cause of mucous membrane pemphigoid remains unknown, rophages, neutrophils, T cells, mast cells, and eosinophils into the con-
research continues to unravel more clues as to the pathogenesis of this junctiva.2,11 The presence of these cells in conjunction with antibody/
complex condition. The hallmark of this autoimmune disease is the type complement deposition results in the inflammatory response with subse-
II immune linear deposition of immunoglobulin A (IgA), IgG, IgM, quent bullae formation, rupture, and eventual scarring.
and/or complement (C3) on the conjunctival epithelial basement mem-
brane. Autoantibodies form against different components of the basement
membrane, with certain autoantigens being more specific for particular
CLINICAL FINDINGS
mucosal regions in the body. This likely explains the clinical heterogene- Ocular cicatricial pemphigoid presents with nonspecific symptoms of 209
ity seen in mucous membrane pemphigoid.8 Multiple target autoantigens, irritation, burning, and tearing and can manifest as recurrent papillary
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4
Fig. 4.10.4 Stage IV ocular cicatricial pemphigoid (OCP) showing end-stage findings
Fig. 4.10.1 Stage I ocular cicatricial pemphigoid (OCP) characterized by conjunctival
of keratinization of the ocular surface and ankyloblepharon.
subepithelial scarring.
to inferior fornix foreshortening. Stage III describes symblepharon forma-

tion typically starting with the inferior fornix. As a result of the cicatrizing
process, lid abnormalities become a major confounder in the overall prog-
nosis. Trichiasis, entropion, and lagophthalmos contribute to the exposure
and abrasion of the corneal surface.12 Damage to mucin-producing goblet
cells, meibomian glands, and lacrimal glands leads to keratinization, which
along with ankyloblepharon formation and corneal scarring define the
end-stage, which is stage IV. As such, in addition to staging disease pro-
gression, the extent of conjunctival inflammation should be graded from
inactive (0) to severe (4+).4 By assessing the stage of the disease process
and degree of conjunctival inflammation, appropriate therapy for these
patients can be determined more accurately.
DIAGNOSIS
Early diagnosis is the key to preventing the blinding consequences of OCP.
The diagnosis ideally rests on both clinical suspicion and immunopathol-
ogy of biopsied conjunctiva and/or other involved tissues.14 Biopsy using
immunopathological techniques provides the only definitive evidence of
Fig. 4.10.2 Stage II ocular cicatricial pemphigoid (OCP) characterized by forniceal
foreshortening.
ocular cicatricial pemphigoid, and should encompass an area with both
inflamed and noninflamed tissues. Active oral lesions may be biopsied
to aid in diagnosis.15 Tissue samples should be fresh or fixed in Zeus’ or
Michel’s fixative for no more than 5 days.1 Linear deposition of IgG, IgA,
IgM, and/or complement (C3) at the epithelial basement membrane zone
of inflamed conjunctiva is seen using direct immunofluorescence (DIF)
techniques, with a sensitivity between 20% and 84%.2,16 If the DIF study
findings are negative and the clinical suspicion is high, a more sensitive
test, such as the immunoperoxidase assay, should be employed.1 To date,
indirect immunofluorescent testing to detect circulating autoantibodies in
patients’ sera has a limited role. Newer serological tests that show promise
in the diagnosis of mucous membrane pemphigoid are being developed.3
Serum and saliva IgG and IgA antibodies may be helpful diagnostic
markers and have shown high positive predictive value.17
In making the diagnosis of OCP, other causes must be considered.
Adenovirus and herpes simplex virus infections, chlamydia, diphtheria,
gonorrhea, and beta-hemolytic Streptococcus infection can all cause a mem-
branous conjunctivitis that results in conjunctival scarring. Radiation,
thermal, and chemical burns, as well as mechanical or surgical trauma,
can cause conjunctival shrinkage and symblephara. Systemic practolol
and D-penicillamine and topical epinephrine, echothiophate iodide, and
pilocarpine all have been associated with inducing ocular pemphigoid-like
Fig. 4.10.3 Stage III ocular cicatricial pemphigoid (OCP) characterized by features. Allergic and inflammatory conditions, such as atopic and rosacea
symblepharon formation. keratoconjunctivitis, respectively, as well as systemic conditions such as
Sjögren’s syndrome, sarcoidosis, and progressive systemic sclerosis also
conjunctivitis. In some cases, patients do not experience ocular symptoms can present as cicatrizing conjunctivitis. Other autoimmune diseases, such
even with advanced signs of conjunctival scarring. The ocular involvement as pemphigus vulgaris, erythema multiforme, Stevens–Johnson syndrome,
initially can be unilateral but progresses, usually within 2 years, to bilateral toxic epidermal necrolysis, epidermolysis bullosa acquisita, lichen planus,
involvement with asymmetry in the severity and rate of evolution.4,12 dermatitis herpetiformis, and linear IgA disease, among others, are asso-
The disease progression of OCP has classically been documented into ciated with cicatrizing conjunctivitis to varying degrees. Biopsy results in
one of four stages (Figs. 4.10.1–4.10.4).4 Stage I denotes chronic conjunc- addition to clinical history, presentation, and course can help distinguish
210 tivitis with subepithelial fibrosis and an unstable tear film. This leads to all of these differential diagnoses from the systemic, chronic, progressive,
dryness and exacerbation of the cicatrization process.2,12,13 Stage II refers and bilateral ocular cicatricial pemphigoid.1–3,5
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TREATMENT transplantation, and type I Boston keratoprosthesis implantation for visual
The goal of therapy in OCP is to suppress inflammation, promote healing,

rehabilitation are potential surgical options but are often unsuccessful as
a result of the autoimmune inflammatory nature of the disease.5 A type 4.10
and prevent cicatrization. Local measures include the use of lubricating II Boston keratoprosthesis or osteo-odonto-keratoprosthesis, each with its
drops, punctal occlusion, autologous serum, and contact lenses for the dry own set of complications, can be a limited, but viable, last resort.30
Ocular Cicatricial Pemphigoid/Mucous Membrane Pemphigoid

eye component, and lid hygiene and oral tetracyclines for the blepharitis,
and epilation for trichiasis management.
Systemic immunosuppressive treatment for OCP is critical to prevent
CONCLUSIONS
the otherwise invariable progression to conjunctival and corneal scarring The prognosis of OCP depends on how soon diagnosis and treatment is
and eventual blindness. The use of such agents is particularly challenging initiated. Up to 60% of patients diagnosed with OCP are at an advanced
because patients usually are older, the disease is chronic, other extraocu- stage (stage III or more) at the time of diagnosis. Nevertheless, control of
lar tissues can be involved, and the systemic immunosuppressive agents the ocular inflammation in OCP can be achieved in up to 90% of patients
required to control the disease have many side effects. In addition, the when appropriately treated.31 Because of the generalized mucosal involve-
majority of patients are diagnosed late in the course of the disease, thus ment of this disease, one should be aware of the significant extraocular
requiring aggressive and long-term therapy.18 Therefore, the use of sys- morbidities that can occur. In particular, esophageal stricture formation
temic agents should be co-managed with the patient’s primary care physi- can be fatal secondary to reflux into the trachea.2
cian, rheumatologist, or oncologist. In summary, ocular cicatricial pemphigoid remains a very difficult con-
Clinical studies regarding systemic therapy in OCP remain limited. dition to treat as a result of its progressive autoimmune nature and the
When choosing an immunosuppressive agent, the stage of ocular disease lack of sensitive techniques to detect the disease at earlier stages. As newer
and the degree of inflammation should be considered. Although dapsone diagnostic techniques and therapeutic options evolve, the overall outcome
and sulfasalazine were historically the first-line treatment for mild to mod- for patients will continue to improve.
erate inflammation, other immunosuppressive agents have shown better
efficacy and fewer side effects. Mycophenolate mofetil may be a better
first-line agent of choice for OCP presenting without sight-threatening
KEY REFERENCES
complications.19–21 Methotrexate also may be a good first-line option, Ahmed M, Zhein G, Khawaja F, et al. Ocular cicatricial pemphigoid: pathogenesis, diagnosis
although it may have more side effects (including hepatic and pulmonary and treatment. Prog Retinal Eye Res 2004;23:579–93.
Chang JH, McCluskey PJ. Ocular cicatricial pemphigoid: manifestations and management.
fibrosis) compared with mycophenolate mofetil.22 For vision threaten- Curr Allergy Asthma Rep 2005;5:333–8.
ing, progressive OCP cyclophosphamide, either alone or in conjunction Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroid in ocular
with prednisone, may be the treatment of choice.7,23,24 Use of low-dose cicatricial pemphigoid. Br J Ophthalmol 1995;79:246–64.
intravenous pulses of cyclophosphamide, according to the findings of Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc 1986;84:527–663.
Foster CS, Sainz de la Maza M. Ocular cicatricial pemphigoid review. Curr Opin Allergy Clin
the Euro-Lupus trials, may improve the side-effect profile.25 Given their Immunol 2004;4:435–9.
dangerous long-term side-effect profile, systemic corticosteroids should Hardy KM, Perry HO, Pingree GC, et al. Benign mucous membrane pemphigoid. Arch Der-
only be used as a temporizing measure until other immunomodulatory matol 1971;104:467–75.
medications take effect.5 Options to achieve remission for patients with Kirzhner M, Jakobiec FA. Ocular cicatricial pemphigoid: a review of clinical features, immu-
nopathology, differential diagnosis, and current management. Semin Ophthalmol
contraindications or adverse reactions to conventional treatment or who 2011;26:270–7.
failed conventional therapy include intravenous immunoglobulin and Laforest C, Huilgol SC, Casson R, et al. Autoimmune bullous diseases: ocular manifestations
rituximab.26–29 Biological agents may be considered in patients whose and management. Drugs 2005;65:1767–79.
conditions are resistant to cyclophosphamide. Anti–TNF-α medications Mondino BJ, Brown SI. Ocular cicatricial pemphigoid. Ophthalmology 1981;88:95–100.
Thorne JE, Anhalt GJ, Jabs DA. Mucous membrane pemphigoid and pseudopemphigoid.
including etanercept, infliximab, and pentoxifylline have shown benefit.15,21 Ophthalmology 2004;111:45–52.
Surgical management of OCP traditionally has carried a poor progno-
sis.12 It is important to completely suppress the inflammatory component
of the disease prior to surgical intervention. Repairing trichiasis and entro- Access the complete reference list online at ExpertConsult.com
pion helps reduce ocular surface irritation and decompensation. Corneal
transplantation for scarred and opaque cornea, ocular surface recon-
struction with limbal stem cell transplantation and amniotic membrane
211
booksmedicos.org
REFERENCES 17. Ali S, Kelly C, Challacombe SJ, et al. Salivary IgA and IgG antibodies to bullous pem-
phigoid 180 noncollagenous domain 16a as diagnostic biomarkers in mucous membrane
1. Kirzhner M, Jakobiec FA. Ocular cicatricial pemphigoid: a review of clinical features,
immunopathology, differential diagnosis, and current management. Semin Ophthalmol
pemphigoid. Br J Dermatol 2016;174(5):1022–9.
18. Tan A, Tan DT, Tan XW, et al. Osteo-odonto keratoprosthesis: systematic review of surgi-
4.10
2011;26(4–5):270–7. cal outcomes and complication rates. Ocul Surg 2012;10:15–25.
19. Queisi M, Sein M, Lamba N, et al. Update on ocular cicatricial pemphigoid and emerg-
Ocular Cicatricial Pemphigoid/Mucous Membrane Pemphigoid

2. Mondino BJ, Brown SI. Ocular cicatricial pemphigoid. Ophthalmology 1981;88:95–100.
3. Ahmed M, Zhein G, Khawaja F, et al. Ocular cicatricial pemphigoid: pathogenesis, diag- ing treatments. Surv Ophthalmol 2016;61:314–17.
nosis and treatment. Prog Retinal Eye Res 2004;23:579–93. 20. Daniel E, Thorne JE, Newcomb CW, et al. Mycophenolate mofetil for ocular inflamma-
4. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc 1986;84:527–663. tion. Am J Ophthalmol 2010;149(3):423–432.e1–e2.
5. Chang JH, McCluskey PJ. Ocular cicatricial pemphigoid: manifestations and manage- 21. Sobolewska B, Deuter C, Sierhut M. Current medical treatment of ocular mucous mem-
ment. Curr Allergy Asthma Rep 2005;5:333–8. brane pemphigoid. Ocul Surf 2013;11(4):259–66.
6. Foster CS, Sainz de la Maza M. Ocular cicatricial pemphigoid review. Curr Opin Allergy 22. McCluskey P, Chang JH, Singh R, et al. Methotrexate therapy for ocular cicatricial pem-
Clin Immunol 2004;4:435–9. phigoid. Ophthalmology 2004;111(4):796–801.
7. Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroid in 23. Foster CS, Wilson LA, Ekins MB. Immunosuppressive therapy for progressive ocular
ocular cicatricial pemphigoid. Br J Ophthalmol 1995;79:246–64. cicatricial pemphigoid. Ophthalmology 1982;89(4):340–53.
8. Oyama N, Setterfield JF, Powell AM, et al. Bullous pemphigoid antigen II (BP180) and 24. Fosdick WM, Parsons JL, Hill DF. Long-term cyclophosphamide therapy in rheumatoid
its soluble extracellular domains are major autoantigens in mucous membrane pemphi- arthritis. Arthritis Rheum 1968;11(2):151–61.
goid: the pathogenic relevance to HLA class II alleles and disease severity. Br J Dermatol 25. Houssiau FA, Vasconcelos C, D’Cruz D, et al. The 10-year follow-up data of the Euro-Lu-
2006;154:90–8. pus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.
9. Chan RY, Bhol K, Tesavibul N, et al. The role of antibody to human B4 integrin in con- Ann Rheum Dis 2010;69(1):61–4.
junctival basement membrane separation: Possible in vitro model for ocular cicatricial 26. Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, et al. Rituximab for patients with
pemphigoid. Invest Ophthalmol Visual Sci 1999;40:2283–90. refractory mucous membrane pemphigoid. Arch Dermatol 2011;147:843–9.
10. Letko E, Bhol K, Colon J, et al. Biology of interleukin-5 in ocular cicatricial pemphi- 27. Sami N, Letko E, Androudi S, et al. Intravenous immunoglobulin therapy in patients with
goid. Graefes Arch Clin Exp Ophthalmol 2002;240:565–9. ocular cicatricial pemphigoid: a long-term follow-up. Ophthalmology 2004;111(7):1380–2.
11. Bernauer W, Wright P, Dart JK, et al. The conjunctiva in acute and chronic mucous mem- 28. Foster CS, Chang PY, Ahmed AR. Combination of rituximab and intravenous immuno-
brane pemphigoid: an immunohistochemical analysis. Ophthalmology 1993;100:339–46. globulin for recalcitrant ocular cicatricial pemphoid: a preliminary report. Ophthalmol-
12. Laforest C, Huilgol SC, Casson R, et al. Autoimmune bullous diseases: ocular manifesta- ogy 2010;117(5):861–9.
tions and management. Drugs 2005;65:1767–79. 29. Maley A, Warren M, Haberman I, et al. Rituximab combined with conventional therapy
13. Nelson JD, Wright JC. Conjunctival goblet cell densities in ocular surface disease. Arch versus conventional therapy alone for the treatment of mucous membrane pemphigoid
Ophthalmol 1984;102:1049–51. (MMP). J Am Acad Dermatol 2016;74:835–40.
14. Elder MJ, Lightman S. The immunological features and pathophysiology of ocular cica- 30. Iaccheri B, Roque M, Fiore T, et al. Ocular cicatricial pemphigoid, keratomycosis, and
tricial pemphigoid. Eye 1994;8:196–9. intravenous immunoglobulin therapy. Cornea 2004;23:819–22.
15. External Disease and Cornea. Basic and Clinical Science Course (BCSC). American 31. Miserocchi E, Baltatzis S, Roque MR, et al. The effect of treatment and its related
Academy of Ophthalmology, 2014. p. 344–5. side effects in patients with severe ocular cicatricial pemphigoid. Ophthalmology
16. Mondino BJ. Cicatricial pemphigoid and erythema multiforme. Ophthalmology 2002;109:111–18.
1990;97:939–52.
211.e1
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Section 5 Scleral and Episcleral Diseases
Episcleritis and Scleritis

Sarju S. Patel, Debra A. Goldstein 4.11
Definition of Episcleritis: Inflammation of the connective tissue Diagnosis and Ocular Manifestations
between the sclera and the conjunctiva. Episcleritis can be described as simple, in which all or part of the episclera
is diffusely inflamed, or nodular, in which inflammation is confined to a
localized area with the presence of well-defined, red nodules. Nodular epis-
cleritis often is associated with a more discomfort and a more prolonged
Key Features course compared with simple episcleritis. Bilateral inflammation is seen
• Self-limiting. in 40% of patients.1 Topical phenylephrine blanches overlying conjunctival
• Less painful than scleritis. vessels and inflamed episcleral vessels.
• Blanches with topical neosynephrine.
• Does not cause damage to the globe. Differential Diagnosis
The differential diagnosis includes conjunctivitis, which is more superfi-
cial; phlytenulosis, which is typically mobile; and scleritis, which is deeper
Associated Feature and more painful.
• Systemic association in less than one third of patients.
Systemic Associations
An underlying cause for episcleritis is found in approximately one third of
Definition of Scleritis: A disorder of inflammation and necrosis cases.1,2 In two series of 94 and 85 patients with episcleritis, 68%–73% were
centered on the sclera. found to have no associated disease; 13%–15% had a connective tissue or
vasculitic disease; 7% had rosacea; 1%–7% had atopy; and 1%–6% had an
associated infection (herpes zoster, herpes simplex, cat scratch disease,
Key Features Lyme disease).1,2
• Focal or diffuse redness or violaceous discoloration. Treatment
• Scleral thickening, acutely. Some patients may benefit from treatment for cosmesis or alleviation
• May develop scleral thinning. of discomfort. Many physicians elect to treat with topical corticoster-
• Nodules. oids, demonstrated in a randomized double-masked trial to be superior
• Necrosis. to placebo for the treatment of episcleritis.3 However, the use of topical
• Pain. corticosteroids may be detrimental because of the risk of rebound inflam-
mation when the drugs are tapered.2 Some patients respond well to topical
nonsteroidal anti-inflammatory drugs (NSAIDs). Systemic NSAIDs also
Associated Features may be used for the treatment of severe or recurrent episcleritis, although
• Rheumatoid arthritis, granulomatosis with polyangiitis (Wegener’s significant side effects may be associated with their use (see section on
granulomatosis), other vasculitic/connective tissue diseases. scleritis). Treatment of underlying blepharitis is important.
• Keratitis and iritis.
• Glaucoma. Scleritis
• Exudative retinal detachment.
Epidemiology and Pathogenesis
Scleritis is more associated with different systemic diseases compared with
INTRODUCTION uveitis, so the evaluation and treatment for both conditions differ. In most
cases, scleral inflammation is noninfectious. However, scleral infection
The sclera is a dense, poorly vascularized connective tissue structure com- caused by bacterial, protozoan, or fungal organisms, such as Pseudomonas,
posed of collagen, elastin, proteoglycans, and glycoproteins. It is embryo- Mycobacterium, Acanthomoeba, or Aspergillus, may cause severe scleritis
logically derived from the neural crest and the mesoderm. that is difficult to treat (Fig. 4.11.1). Scleritis typically occurs in the sixth
The sclera may be affected by a number of inflammatory and nonin- decade of life, but may occur in adolescents and in very old adults. Females
flammatory processes. This chapter will describe episcleritis, focusing on are more commonly affected, and bilateral inflammation occurs in nearly
scleritis, a more serious and often vision-threatening condition. 40% of cases.1
INFLAMMATORY DISEASES Ocular Manifestations

Scleritis may be unilateral, bilateral, or alternate from eye to eye. The dura-
Episcleritis tion of inflammation is variable and may last only a few months or persist
for years. The involved area may appear violaceous because the inflamma-
Epidemiology and Pathogenesis tion occurs in deeper tissues (Fig. 4.11.2). The whole eye may be involved,
Episcleritis refers to inflammation of the loose connective tissue between or inflammation may localize to one or more quadrants. The involved area
the sclera and the conjunctiva. Patients often complain of discomfort or usually is tender to palpation, although pain may occur in seemingly unin-
irritation rather than true pain. Slit-lamp microscopic examination usually volved areas. The pain typically is deep and boring in nature and often
localizes any edema to the area that overlies the sclera. The sclera itself is wakes the patient from sleep.
not thickened. Accompanying uveitis is very rare. On slit-lamp microscopy, the overlying conjunctival vessels usually are
Episcleritis is a self-limiting condition, generally running its course in found to be engorged. The episclera may be edematous and inflamed. At
212 a few days, although nodular disease may last for weeks. Recurrence is times, the secondary inflammation in the conjunctiva and episclera makes
common, but structural damage to the eye does not occur. it difficult to appreciate the underlying scleral inflammation. Topical
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4.11

A Fig. 4.11.2 Scleritis With a Violaceous Hue Caused by Deep Inflammation.
Vessels do not blanch with topical phenylephrine.
Region of active scleritis

Uninflamed sclera
Fig. 4.11.3 Diffuse scleritis in a patient with rheumatoid arthritis (A). Note that on
anterior segment optical coherence tomography, there is diffuse scleral thickening
with normal globe contours in the affected area compared with the adjacent
unaffected sclera (B).
C
phenylephrine blanches the overlying conjunctiva and, to a much lesser
Fig. 4.11.1 (A,B) Tuberculous scleritis. Note yellow necrotizing nodules in two extent, the episclera and may permit better delineation of the depth of
patients with mycobacterial scleritis. Both patient spontaneously perforated and inflammation. The red-free (green) light on the slit lamp may be used to
required enucleation, despite four-drug therapy for tuberculosis and concomitant determine the level of inflammation.
immunomodulatory therapy. (C) Necrotizing Acanthomoeba sclerokeratitis in a Anterior scleritis is classified as diffuse (Fig. 4.11.3A) or nodular (Fig.
72-year-old female. Note the diffuse deep injection, the area of profound scleral 4.11.4). It also may be necrotizing or nonnecrotizing. Necrotizing scleritis
thinning superiorly and active necrotizing, nodular scleritis nasally. usually is extremely painful and presents with areas of avascularity in the
sclera. Avascular areas may result in scleral thinning, which can progress
to staphyloma formation and exposure of bare uvea (Fig. 4.11.5). A simple
grading system for scleritis, which has been described in the literature, has 213
helped standardize the assessment of scleritis (Fig. 4.11.6).4
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4
Fig. 4.11.5 Inactive Necrotizing Scleritis in a Patient With Long-Standing

Rheumatoid Arthritis. The patient has had episodes of marked inflammation, but
the disease has been quiescent on long-term immunosuppressive therapy.
A
deposits that have the appearance of spun sugar or cotton candy in the
deep cornea (Fig. 4.11.10). This variant is known as sclerosing keratitis.5
A number of mechanisms may result in elevation of intraocular pres-
sure (IOP). Inflammatory cells may block scleral emissary vessels, which
results in elevated episcleral venous pressure and hence elevated IOP.
Ciliary body effusion may cause angle closure as the lens–iris diaphragm
rotates anteriorly. Accompanying uveitis may be responsible for glaucoma
if the trabecular meshwork is clogged with inflammatory cells and debris.
Corticosteroid use may result in secondary elevation of IOP.
Differential Diagnosis
Conjunctivitis usually can be differentiated from scleritis by the presence
of discharge, superficial inflammation, and the lack of severe aching or
pain. Episcleritis may sometimes be confused with scleritis, although the
two conditions can usually be differentiated based on history and clinical
examination.
Ciliary flush (injection) that accompanies acute iritis may be confused
B with scleritis. However, the ciliary flush usually is restricted to the area
adjacent to the limbus, and iritis appears to be the predominant finding.
Fig. 4.11.4 Large Scleral Nodule of Undetermined Etiology. Note the yellow Solid-appearing subretinal masses that mimic melanomas can occur in
area, which probably represents scleral necrosis (A). A representative anterior patients with scleritis (Fig. 4.11.11).6,7 Computed tomography (CT) may be
segment optical coherence tomography image also illustrates a very thickened and
helpful in making the diagnosis of scleritis in these cases, demonstrating
disorganized sclera with a central zone of activity and possible necrotic activity (B).
a contrast-enhancing mass that is uniformly isodense with sclera. A-scan
ultrasonography usually demonstrates high internal reflectivity in scleritis
(as opposed to low internal reflectivity in melanoma), and a B-scan may
Scleromalacia perforans is a very rare type of painless necrotizing scleri- demonstrate thickened sclera.
tis, which typically occurs in women with a long-standing history of rheu-
matoid arthritis. Diagnosis and Ancillary Testing
Posterior scleritis refers to inflammation behind the equator of the globe The diagnosis of anterior scleritis is clinically based. It is important to
and may be difficult to diagnose if anterior scleritis is not also present. examine the patient with the room lights on. The lid should be lifted and
Symptoms of posterior scleritis may include pain, blurred vision, and the eyes examined from a distance, as scleritis may be missed if the patient
photophobia, although the patient may be fairly asymptomatic. Some is examined only at the slit lamp in a dark room.
patients with posterior scleritis develop proptosis, shallowing of the ante- The diagnosis of posterior scleritis can be difficult. Fluorescein angiog-
rior chamber, exudative retinal detachments, choroidal detachments, disc raphy may be helpful because it may demonstrate characteristic subretinal
swelling, and chorioretinal changes (Figs. 4.11.7A and 4.11.8A). Chorioreti- leakage spots that coalesce as the study progresses (see Fig. 4.11.8B). Only
nal changes may consist of subretinal exudates and hemorrhages, as well Vogt–Koyanagi–Harada syndrome has a similar picture on fluorescein
as a stippled appearance to the retinal pigment epithelium in long-standing angiogram.8
disease. B-scan ultrasonography is extremely useful in the diagnosis of posterior
Scleral inflammation may cause structural damage to the eye, resulting scleritis. The T-sign, representing fluid in Tenon’s capsule, is highly char-
in scleral translucency and thinning (see Fig. 4.11.5). Ocular complications acteristic of posterior scleritis, although it is not always present (see Fig.
were encountered in nearly 45% of cases in one study, including anterior 4.11.7C). Thickening of the posterior sclera usually can be demonstrated
uveitis (26%), decreased vision (16%), peripheral keratitis (13%), and ocular on B-scan.9 CT of the orbits with contrast material may show the so-called
hypertension (14%).1 Decreased vision is associated most with necrotiz- ring sign of enhancement of the sclera, suggestive of posterior scleri-
ing and posterior scleritis, although vision may be decreased as a result tis. Magnetic resonance imaging has not proved to be any more useful
of cystoid macular edema in any type of scleritis. Significant amounts of than CT and may even be less helpful,10 although it avoids the radiation
induced astigmatism necessitate performance of retinoscopy in all patients risks associated with CT. Ultrasound biomicroscopy and anterior segment
with anterior scleritis and reduced vision. optical coherence tomography may help characterize severity and extent of
Scleritis adjacent to the cornea may be associated with a focal or diffuse disease (see Figs. 4.11.3B and 4.11.4B).11
keratitis. Focal keratitis may manifest as a ring infiltrate at the limbus, The workup of a patient with scleritis includes an evaluation for sys-
214 without the peripheral clear zone that is seen with staphylococcal marginal temic vasculitis, connective tissue disease, and infection. Much of this
infiltrates (Fig. 4.11.9). Sclerokeratitis also may present with crystalline information can be gained from a detailed history. Laboratory tests might
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Scleritis Grading 4.11
(Following 10% Phenylephrine application)

+3 (severe): Diffuse +4 (necrotizing): Diffuse
redness of the sclera, the redness of the sclera
details of superficial and with scleral thinning and
deep episcleral vessels uveal show
can’t be observed
+2 (moderate): Purplish pink appearance of the sclera with

significantly tortuous and engorged deep episcleral vessels
+1 (mild): Diffuse pink appearance of the sclera around

mildly dilated deep episcleral vessels
+0.5 (minimal/trace): Localized pink appearance of the

sclera around minimally dilated deep episcleral vessels
+0 (none): Complete blanching after 10% PE
Fig. 4.11.6 Standardized grading system for scleritis. (Reproduced from Sen HN, Sangave AA, Goldstein DA, et al. A standardized grading system for scleritis. Ophthalmology
2011;118:768–71.)
include erythrocyte sedimentation rate, rheumatoid factor, anticitrullinated scleritis. Scleritis has been observed in 18% of patients with inflammatory
protein antibody, antineutrophil cytoplasmic antibodies (C- and P-ANCA), bowel disease and may correspond to gastrointestinal (GI) disease activity,
antiproteinase 3, antimyeloperoxidase antibodies (anti-PR3, anti-MPO), as does accompanying large joint peripheral arthritis.17 Pyoderma gangre-
and antinuclear antibody. Review of systems and a relevant family history nosum and Cogan’s syndrome can be associated with scleritis.18 Sarcoid-
may prompt the clinician to order human leukocyte antigen B27 or inflam- osis can cause granulomatous scleritis.
matory bowel serology. Specific serological test for syphilis (including Infectious conditions, such as tuberculosis, acanthomoebiasis, syphi-
fluorescent treponemal antibody absorption test, microhemagglutination lis, and leprosy, may result in granulomatous, nodular scleritis (see Fig.
test for Treponema pallidum, syphilis immunoglobulin G enzyme immu- 4.11.1A). Herpes zoster and herpes simplex may cause scleritis (Fig. 4.11.13).
noassay) should be obtained for all patients with ocular inflammation. A When herpesviruses cause scleritis, it usually is in the late recovery phase
complete blood count and urinalysis may be considered. Chest radiogra- of the disease rather than during acute infection.14
phy may be performed to look for evidence of tuberculosis, sarcoid, or Necrotizing scleritis can be triggered by ocular surgery (Fig. 4.11.14); it
granulomatosis with polyangiitis (GPA). ANCA, anti-PR3, and anti-MPO has been reported weeks to months after cataract surgery, penetrating kera-
testing often is positive in cases of GPA, microscopic polyarteritis, and toplasty, muscle surgery, glaucoma surgery, and even pterygium surgery.19–21
other related vasculitides.12 Two different patterns of immunofluorescence Evidence exists of underlying connective tissue disease in some of these
staining have been identified. Classic ANCA (C-ANCA) and anti-PR3 are patients, but in others, no causative factor can be found. Infectious causes
more specific for GPA and other closely related vasculitides. The positivity must be sought in all patients with postoperative scleritis.
of this test may depend, in part, on disease activity; in some patients, the
test becomes negative with treatment or a decrease in disease activity.13 Pathology
Scleral biopsy should be done only in exceptional circumstances. The
Systemic Associations surgeon should be prepared either to place a scleral reinforcement graft or
Underlying systemic disease is present in approximately 35%–50% of use some other tissue, such as periosteum, to replace the sclera that has
patients with scleritis.1,14 Rheumatoid arthritis is the most frequently asso- been sampled for biopsy, as severe thinning of the sclera can result in an
ciated condition,15 and scleritis may be the first manifestation, preceding unexpected encounter with intraocular contents.
joint disease.16 Other connective tissue diseases that can present with Histopathological examination may reveal one of four patterns of
scleritis include GPA, polyarteritis nodosa, systemic lupus erythematosus, inflammation, which can correlate with disease etiology22,23: zonal, necro-
and relapsing polychondritis (Fig. 4.11.12). tizing granulomatous; diffuse, nonnecrotizing; necrotizing with microab-
Psoriatic arthritis and ankylosing spondylitis, although usually associ- scesses; and nonzonal, nondiffuse granulomatous. Antigen–antibody
ated with acute iritis, can at times be associated with scleritis.15 Inflam- complexes mediate zonal, necrotizing granulomatous inflammation, 215
matory bowel disease, especially Crohn’s disease, can be associated with which is most often associated with systemic disease.22,23 Lymphocytes
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who have only mild redness, no active secondary uveitis or keratitis, and no
4 visual problems may not require therapy, but must be closely monitored.
Topical nonsteroidal agents may be of some benefit in patients who
have mild episcleritis, but they are of no benefit in true scleritis. Most
topical corticosteroids do not have any marked beneficial anti-inflammatory
effect in cases of true scleritis, although they may be helpful in controlling

secondary uveitis. Difluprednate, a newer topical corticosteroid, has been
shown to have scleral penetration in rabbit models and may be a useful
therapeutic agent in scleritis, but clinical data on its use in human scleritis
are lacking.24
Oral NSAIDs should be considered the first line of treatment in patients
A
with mild and moderately severe scleritis. They have been reported to be
effective in diffuse scleritis and mild nodular scleritis.25 Indomethacin
OCT Image 50 mg three times a day or, in the sustained-release form, 75 mg twice a
day, can be very effective. Other nonsteroidal agents that appear to work
well are piroxicam and naprosyn. Ibuprofen, diclofenac, tolmetin, sulin-
dac, and others also may be of benefit.
All systemic nonsteroidal agents carry the risk of significant side effects.
Long-term therapy may result in allergic reactions, GI problems, and
kidney damage. An increased risk of cardiac events has been reported with
both cyclooxygenase-2 (COX-2)–specific and COX-2–nonspecific NSAIDs.
These medications should be avoided in those patients with significant
cardiac risk factors, especially in patients with prior myocardial infarction,
prior stroke, or recent cardiac arrhythmias.26 Patients who take NSAIDs
Thickness Chart may require other medications to prevent or treat GI side effects. Options
600
include histamine 2 (H2) receptor antagonists (e.g., ranitidine, famotidine,
500 cimetidine), coating agents (e.g., sucralfate), gastric acid secretion inhibi-
400 tors (e.g., the synthetic prostaglandin E1 analogue misoprostol), and proton
300 pump inhibitors (e.g., omeprazole). The NSAIDs that are selective COX-2
200 inhibitors may have fewer GI side effects but appear to be less potent anti-
100 inflammatory agents.
0 A-scan
Systemic corticosteroids often are used as initial therapy for patients
0 10 20 30 40 50 60 70 80 90 100 110 120 with moderate to severe scleritis. The usual starting dose is 1 mg/kg/day
B
of prednisone, but in severe cases, doses up to 1.5 mg/kg/day or even
intravenous pulse corticosteroids may be required. The prednisone is then
slowly tapered to a best-tolerated dose. Many patients require therapy for
6 months to a year or longer. Patients who require more than 3 months
of treatment or 5 mg of chronic daily prednisone should be considered
for corticosteroid-sparing agents. Occasionally, patients who take their
full dose of oral prednisone in the morning experience pain at night. If
the dose is divided and taken twice a day, this night pain may be relieved
without increasing the total dose.
Pulse intravenous methylprednisolone at 0.5–1 g may be required in
some patients with severe scleritis. This high dose may be used once a
day for 3 days or once every other day for three doses and then reduced to
once a week. Oral prednisone is often required to supplement the pulses.27
All systemic corticosteroids may result in adrenal suppression, weight
gain, mood changes, blood pressure elevation, blood sugar elevation, oste-
oporosis, and aseptic necrosis of the femoral head. Any patient who is on
oral prednisone for longer than 1 year, even on an every-other-day sched-
ule, should have a bone density evaluation.
Subconjunctival injection has been proposed as a method of cortico-
steroid delivery in cases of nonnecrotizing anterior scleritis.28 Its use typ-
ically is limited to adjunctive therapy in cases of nonnecrotizing localized
disease, cognizant of the at least theoretical risk of scleral thinning and
perforation.
Immunosuppressive or immunomodulatory therapy may be required
C
in patients with scleritis who are unresponsive to or intolerant of predni-
sone, or who require long-term therapy (see Fig. 4.11.5). In patients with
Fig. 4.11.7 (A) A 72-year-old male with bilateral posterior scleritis. Note the bilateral
severe rheumatoid arthritis and GPA, morbidity and mortality are reduced
proptosis. (B) Optical coherence tomography demonstrating subretinal fluid.
with the use of immunosuppressive agents.29 Many patients with necrotiz-
(C) B-scan demonstrating T-sign, and marked choroidal thickening. The T-sign is
believed to be due to fluid in Tenon’s capsule and is very characteristic of posterior ing scleritis require immunosuppressive therapy to preserve vision. Evi-
scleritis, although it is not always present. dence exists that well-managed immunosuppressives have less long-term
toxicity compared with high- or moderate-dose prednisone.30 All immuno-
modulatory therapy for scleritis is used off label.
and plasma cells appear in diffuse nonnecrotizing inflammation, which Oral or subcutaneous methotrexate (7.5–25 mg weekly) has been
is often idiopathic.22,23 Necrotizing inflammation with microabscesses is reported to be of benefit in reducing or eliminating the need for systemic
observed in infectious scleritis. corticosteroid therapy.31 Azathioprine at a dose of 1.5–2 mg/kg/day also
may reduce or eliminate the need for corticosteroids.25,30 However, both
Treatment these agents can result in hepatic and hematological toxicity. Mycophe-
Medical Treatment nolate mofetil, another antimetabolite drug, may have lower toxicity and
Most patients who have active scleritis require therapy. Some physicians higher efficacy.32
recommend that treatment be continued until all redness is gone from the Cyclosporine, which acts in part by interfering with interleukin-2, has
216 eye. However, if no pain and no evidence of any damage to the eye exist, been used with some success in the treatment of scleritis.30 At doses of
the side effects of the therapy may outweigh the benefits. Some patients 10 mg/kg/day, it is nephrotoxic, so it is almost always used at lower doses,
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4.11

A
Fig. 4.11.9 Ring Corneal Ulcer in a Patient With Rheumatoid Arthritis and
Scleritis. (A) Note the white, creamy infiltrates in the cornea, indicating active
inflammation, and the lack of a lucid interval between the limbus to the ulcer.
(B) Other eye of the same patient. Note the scarring and vascularization from a
previously active ring ulcer.
B
Fig. 4.11.8 Fluorescein Angiography. (A) Fundus photograph demonstrating

exudative retinal detachment and choroidal folds in posterior scleritis. (B) The
same eye shows choroidal folds and areas of subretinal leakage, which increase
in intensity in the late phases of the angiogram. Only Vogt–Koyanagi–Harada
syndrome and posterior scleritis exhibit this subretinal leakage pattern. Many
patients with posterior scleritis do not have this leakage pattern, however.
such as 5 mg/kg/day as an initial dose and 3–5 mg/kg/day as a mainte-

nance dose. However, at these doses, it may be impossible to discontinue
the use of corticosteroids. As such, cyclosporine is used as an adjunctive
therapy, permitting lower doses of systemic corticosteroids, or in com-
bination with other agents such as antimetabolites.33,34 Systemic hyper-
tension, renal failure, hirsutism, and gingival hyperplasia all may occur
with cyclosporine. Tacrolimus (FK-506) has a different structure from that
of cyclosporine but has similar intracellular actions and is supplied in a
topical ointment that has been shown to be effective in a small number of
scleritis cases.35
Fig. 4.11.10 Diffuse Scleritis Active Nasally. Note the active sclerosing keratitis
Biological medications have been shown to be particularly effective
nasally and chronic changes from prior sclerosing keratitis temporally. The temporal
in treating scleritis. Tumor necrosis factor inhibitors, which include scleritis has completely resolved.
infliximab, adalimumab, etanercept, certolizumab, and golimumab, typ-
ically act rapidly in controlling inflammation. The majority of data in
uveitis and scleritis are for infliximab and adalimumab. Although adali- These agents are usually prescribed and monitored in conjunction with a
mumab recently received U.S. Food and Drug Administration approval rheumatologist.
for the treatment of noninfectious intermediate, posterior, and panuve- Alkylating agents, such as chlorambucil and cyclophosphamide, may
itis in adults, its use in scleritis is still off label. In addition, rituximab be of benefit and usually enable oral prednisone to be tapered or discon- 217
has been shown to have excellent efficacy in refractory cases of scleritis.36 tinued.37,38 In some cases, a 3- to 6-month course of chlorambucil, with
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4
Fig. 4.11.11 Subretinal Mass Mimicking an Amelanotic Melanoma in a Patient

With Scleritis. In this patient, the mass disappeared with cyclophosphamide
therapy.
Fig. 4.11.13 Necrotizing Anterior Scleritis Secondary to Herpes Zoster. The
patient underwent extracapsular cataract extraction 2 weeks earlier, which
precipitated ophthalmic zoster.
Fig. 4.11.12 Patient With Relapsing Polychondritis. Note inflammation of the

superior half of the pinna.
Fig. 4.11.14 Necrotizing Scleritis Induced by Trabeculectomy Surgery. Note the

reduction of the white blood cell count to 2400–3500, results in prolonged large conjunctival vessels seen in this 75-year-old woman; these are frequently seen
remission of ocular inflammatory disease.37,38 Alkylating agents may have after severe scleritis.
hematological toxicity, and blood counts must be monitored frequently.
Cyclophosphamide has the added risk of hemorrhagic cystitis, so ade- Many patients who have scleritis develop cataracts. Surgery for cataracts
quate hydration is imperative. Cyclophosphamide works more rapidly in such patients should be undertaken only when the disease has been in
(frequently within a few days to a week) compared with chlorambucil. remission for at least 3 months. The physician should be alert to recognize
Pulse intravenous cyclophosphamide also has been used in severe sight- recrudescence of scleral inflammation after surgery.
or life-threatening disease. Because alkylating agent use may increase the
risk of late malignancy and sterility, detailed informed consent should be Course and Outcome
obtained before starting therapy. These agents may result in premature Most patients with mild or moderate scleritis maintain excellent vision.
gonadal failure in males and females and are also teratogenic, so patients The length of time during which scleritis is active varies from patient to
must be counseled carefully. patient. In a minority of patients, the disease is active for months and then
goes into long-term remission. In other patients, the disease is active for
Surgical Treatment several years. In some patients, the disease seems to move from eye to eye
Surgery for scleritis may be performed when scleral perforation or exten- or to move from one area of sclera to another.
sive thinning exists with significant risk for scleral rupture. However, Necrotizing scleritis portends a worse prognosis compared with non-
most patients who have thin sclera and even staphyloma formation do necrotizing disease. Patients with necrotizing scleritis have a high inci-
not require structural reinforcement. If the decision is made to reinforce dence of visual loss and a 21% 8-year mortality.14,40 Immunosuppressive
the sclera, available agents include fresh or preserved donor sclera, perios- therapy appears to lessen these risks.
teum, or fascia lata. Donor sclera is relatively easy to use, but after several
months, it may start to dissolve, as did the originally diseased tissue.
Autologous periosteum can be harvested from the tibial crest and may be KEY REFERENCES
218 a better agent to use, as it may be less likely to necrose compared with Calthorpe CM, Watson PG, McCarthy ACE. Posterior scleritis: a clinical and histological
donor sclera.39 survey. Eye 1988;2:267–77.
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Foster CS, Sainz de la Maza M. The sclera. New York: Springer-Verlag; 1994. Sainz de la Maza M, Foster CS, Jabbur NS. Scleritis associated with systemic vasculitic
Lin P, Bhullar S, Tessler HH, et al. Immunologic markers as potential predictors of sys- disease. Ophthalmology 1995;102:687–92.
temic autoimmune disease in patients with idiopathic scleritis. Am J Ophthalmol
2008;145:463–71.
Sen HN, Sangave AA, Goldstein DA, et al. A standardized grading system for scleritis. Oph-
thalmology 2011;118:768–71.
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O’Donoghue E, Lightman S, Tuft S, et al. Surgically induced necrotizing scleritis (SINS): Tu EY, Culbertson WW, Pflugfelder SC, et al. Therapy of nonnecrotizing anterior scleritis
precipitating factors and response to treatment. Br J Ophthalmol 1992;76:17–21. with subconjunctival corticosteroid injection. Ophthalmology 1995;102:718–24.

Rao NA, Marak GE, Hidayat AA. Necrotizing scleritis: a clinicopathologic study of 41 cases. Watson PG, Hayreh SS. Scleritis and episcleritis. Br J Ophthalmol 1976;60:163–91.
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Riono W, Hidayat A, Rao N. Scleritis. Ophthalmology 1999;106:1328–33. 1976.
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large cohort of patients of scleritis and episcleritis. Ophthalmology 2012;119:43–50.
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4. Sen HN, Sangave AA, Goldstein DA, et al. A standardized grading system for scleritis. 26. Solomon DH, Glynn RJ, Rothman KJ, et al. Subgroup analyses to determine cardiovas-
Ophthalmology 2011;118:768–71. cular risk associated with nonsteroidal antiinflammatory drugs and coxibs in specific
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19. Sainz de la Maza M, Foster CS. Necrotizing scleritis after ocular surgery: a clinicopatho- short-term high-dose chlorambucil for sight-threatening ocular inflammation. Ophthal-
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20. O’Donoghue E, Lightman S, Tuft S, et al. Surgically induced necrotizing scleritis (SINS): 39. Koenig SB, Sanitato JJ, Kaufman HE. Long-term follow-up study of scleroplasty using
precipitating factors and response to treatment. Br J Ophthalmol 1992;76:17–21. autogenous periosteum. Cornea 1990;9:139–43.
21. Galanopoulos A, Snibson G, O’Day J. Necrotizing anterior scleritis after pterygium 40. Tuft SJ, Watson PG. Progression of scleral disease. Ophthalmology 1991;98:467–71.
surgery. Aust N Z J Ophthalmol 1994;22:167–73.
219.e1
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Section 6 Corneal Diseases
Bacterial Keratitis
Jeremy D. Keenan, Stephen D. McLeod 4.12
dilatation and increased vascular permeability, which results in the pro-
Definition: Corneal disease caused by bacterial organisms. duction of an antimicrobial transudate. The conjunctiva also contains
conjunctiva-associated lymphoid tissue (CALT), which consists of nodules
of small and medium-sized lymphocytes responsible for local antigen
Key Feature processing. Plasma cells, macrophages, and a variety of T cells also are
present, as well as IgG, IgA, and IgM, which are brought in by the con-
• Cellular infiltration of the corneal epithelium or stroma, corneal junctival vasculature.
inflammation, and necrosis.
The natural microbial environment of the ocular surface consists of
both sessile and free-floating bacteria. This population is kept in check by
the antimicrobial features of the tear film, and by the products of resident
Associated Features microbes; these products, called bacteriocins, are high-molecular-weight
• Lid edema. proteins that inhibit the growth of pathogens, such as pneumococci and
• Conjunctival inflammation. Gram-negative bacilli.
• Discharge. In the majority of cases where bacterial keratitis develops, at least one
• Anterior chamber reaction. risk factor that represents a compromise of one or more of these defense
• Hypopyon. mechanisms can be identified. In developed countries, soft contact lens
wear is the most important risk factor. Contact lenses likely cause physio-
logical and traumatic changes to the ocular surface, additionally providing
INTRODUCTION a scaffold for bacterial biofilm formation.5,6 Extended or overnight contact
lens wear and poor lens hygiene substantially increase the risk; unfortu-
Infectious keratitis is one of the leading causes of blindness in the world. nately, daily disposable lenses may not reduce this risk. Corneal trauma,
Because, in most cases, these infections represent preventable or treatable as well as keratorefractive procedures, such as laser in situ keratomileusis
ophthalmic diseases, a thorough understanding of the epidemiology, diag- (LASIK), can disrupt the epithelial barrier and allow invasion of infectious
nosis, and treatment of the various forms of infectious keratitis is essential organisms into the stroma (Fig. 4.12.1).7 Lid abnormalities, such as entro-
for eye-care practitioners and public health officials. pion or ectropion, exposure of the corneal surface, or trichiasis, can cause
breakdown of the protective corneal epithelium. Poor tear production
EPIDEMIOLOGY AND PATHOGENESIS can lead to a reduction of antimicrobial tear components and epithelial
desiccation and damage. Epithelial problems, such as bullous keratopa-
The estimated incidence of ulcerative keratitis in the United States is 28 thy, medication toxicity, and prior herpetic infection, can allow microbial
per 100 000 person years, with a higher incidence among contact lens adherence and invasion. Drugs that may be smoked, such as cocaine and
wearers (130 per 100 000 person years).1 The incidence of infectious kera- methamphetamine, have been associated with microbial keratitis, prob-
titis in the developing world is even higher, with estimated incidence rates ably because of a direct toxic effect, exposure keratopathy, neurotrophic
ranging from 100 to 800 per 100 000 person years.2 Given the potential changes, or mechanical trauma (Fig. 4.12.2). Local or systemic immune
blinding complications of severe bacterial keratitis, these infections are a compromise can lead to impairment of local immune defenses. This is
significant public health issue.3 A host of bacterial organisms can cause most commonly caused by the use of topical corticosteroids, but immuno-
infectious keratitis. The incidence of infection by specific organisms varies suppression, malignancy, malnutrition, or extensive burns also can cause
by region. Practitioners should be aware of the local epidemiological pat- it. Occasionally, keratitis can be established via the corneoscleral limbus by
terns of corneal infection. Whereas staphylococcal species are most com- hematogenous spread.
monly seen in Canada and the eastern and northeastern United States,
Pseudomonas infection is more common in the southern United States.
Streptococcus pneumoniae was once the most common pathogen isolated
CLINICAL FEATURES
from bacterial corneal ulcers, but as contact lens wear and related infec- The clinical signs and symptoms of bacterial keratitis depend greatly on the
tious keratitis have increased, the relative incidence of pseudomonal and virulence of the organism and the duration of infection. Other influential
staphylococcal infection has increased. These two organisms account for factors include the previous status of the cornea and the use of corticoster-
the majority of infections associated with contact lens wear, followed by oids. Patients may describe decreased vision, pain, and photophobia. The
Serratia marcescens. Corneal infections that occur in patients with systemic cardinal corneal sign is a localized or diffuse infiltration of the epithelium
debilitating conditions, such as alcohol abuse, malnutrition, or diabetes or stroma (Fig. 4.12.3). Commonly, epithelial absence over a gray-white
often are associated with Moraxella. In the developing world, streptococcal necrotic stromal infiltrate occurs. Less commonly, a stromal abscess can
corneal infection remains the most common, followed by staphylococcal appear beneath an intact epithelium. Infiltration and edema of the cornea
and pseudomonal keratitis. can appear distant to the primary site of infection. Occasionally, bacterial
The corneal surface is normally well protected by a variety of mecha- keratitis can present with predominantly multifocal epithelial infiltration,
nisms.4 The eyelids and eyelashes form a physical outer barrier to foreign especially in the setting of soft contact lens wear.
material, and the blink reflex sweeps away debris trapped in tears. A second Other ocular structures usually demonstrate associated inflamma-
line of defense is the tear film, which contains a variety of antimicrobial tion. Some degree of lid erythema and edema, conjunctival injection
and anti-inflammatory factors, such as lactoferrin, lysozyme, beta-lysin, and chemosis, tearing, and discharge often occur. A nonspecific con-
tear-specific albumin, and immunoglobulin A (IgA). Finally, the corneal junctival papillary response might be seen. Anterior chamber inflam-
and conjunctival epithelial cells provide a barrier via their tight junctions, mation often is present, ranging from cells and flare in milder cases to
express molecules important for innate immunity (e.g., toll-like receptors), hypopyon in more severe cases. The aqueous might become dense and
and produce a variety of antimicrobial peptides. fibrinoid, and fibrinous endothelial plaques may develop. The hypopyon
220 The conjunctiva provides additional protection from infection. The usually is sterile unless accompanied by a full-thickness corneal
conjunctiva contains mast cells, which, when activated, induce vascular perforation.
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4.12
Bacterial Keratitis
A
Fig. 4.12.3 Bacterial corneal infection with dense central necrotic ulcer and infiltrate.
Fig. 4.12.1 Keratitis. (A) Severe keratitis caused by Pseudomonas following

radial keratotomy. (B) Scarring at the interface of a LASIK flap and bed following
Aspergillus keratitis.
Fig. 4.12.4 Streptococcal bacterial keratitis with infiltration of the central cornea.
Infection tends to occur in compromised corneas, such as those with

bullous keratopathy, herpetic disease, and persistent epithelial defect.
Usually a well-defined, cream-colored or gray-white stromal infiltrate with
an overlying epithelial defect is seen. Sometimes multiple foci of abscesses
can develop that resemble fungal satellite lesions. S. aureus tends to cause
more severe infiltration and necrosis than S. epidermidis. Over time, the
former can extend deep into the stroma, and necrosis of this abscess can
lead to perforation. A hypopyon and endothelial plaque can be seen.
Streptococcus
Streptococci are Gram-positive cocci. On stained smears, most species
tend to appear in chains, but they also can be arranged singly, in pairs, or
in loose clusters. The most common species causing keratitis is Streptococ-
cus pneumoniae (Pneumococcus), which appears as lancet-shaped diplococci
arranged with the flattened ends together. Streptococcal species are distin-
guished by their ability to hemolyze red blood cells. Streptococcus viridans
and S. pneumoniae do so partially (alpha-hemolysis), S. pyogenes completely
(beta hemolysis), and gamma-hemolytic species do not hemolyze red blood
Fig. 4.12.2 Epithelial Defect, Stromal Infiltrate, and Hypopyon Associated
cells at all.
With Crack Cocaine Use. Candida, Streptococcus, and Haemophilus species were Pneumococcal infections can readily spread, producing a deep stromal
recovered from scrapings of the infiltrate. abscess, fibrin deposition, plaque formation, severe anterior chamber reac-
tion, hypopyon, and iris synechiae (Fig. 4.12.4). The advancing necrosis
often produces an undermined leading edge with overhanging tissue.
Gram-Positive Cocci Infection by Streptococcus pyogenes occurs less frequently but has a similar,
severe presentation and course. Group viridans Streptococcus spp. tend
Staphylococcus to cause less aggressive disease and are associated with a more indolent
Staphylococci are Gram-positive cocci, which, on stained smears, tend to course, as is seen in infectious crystalline keratopathy.
appear singly or in pairs, although clusters of organisms can be seen. The Infectious crystalline keratopathy describes a particular pattern of
two most common species that cause keratitis are Staphylococcus aureus corneal infiltration characterized by needle-like opacities that can be found
and Staphylococcus epidermidis, both of which are commonly found on skin, at all levels of the corneal stroma (Fig. 4.12.5). The crystalline opacities
eyelids, and the conjunctiva. Although non-aureus strains are usually less range from fine, feathery, and white to thick, brown, arborizing aggrega-
virulent, antibiotic resistance tends to be more common, and aggressive tions, without apparent cellular infiltrate or ocular inflammation. The entity 221
keratitis occasionally occurs. most frequently occurs in corneal grafts but has also been associated with
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Fig. 4.12.5 Infectious crystalline keratopathy caused by Streptococcus viridans. Fig. 4.12.6 Serrated border and satellite lesions in keratitis caused by Nocardia.
other conditions, such as incisional keratotomy, epikeratophakia, contact keratitis, the infection can be indolent, with a stromal abscess covered by
lens wear, chemical burns, and topical anesthetic abuse. Long-term corti- an intact epithelium.
costeroid therapy is thought to play a role in the pathogenesis. Although
the viridans group of streptococci accounts for most cases, other organ- Filamentous Bacteria
isms associated with infectious crystalline keratopathy include S. pneumo-
niae, Haemophilus aphrophilus, Peptostreptococcus, Pseudomonas aeruginosa, Actinomyces and Nocardia
and a number of other bacteria, as well as Candida and Alternaria fungal Actinomyces and Nocardia are Gram-positive, filamentous bacteria. Acti-
species. nomyces is obligatorily anaerobic and nonacid-fast, whereas Nocardia is
obligatorily aerobic and variably acid-fast. On Gram staining, the filaments
Gram-Positive Bacilli of these organisms are seen as branching and intertwined; some might
display terminal clubs, and the filaments often fragment into bacillary and
Bacillus coccoid forms.
Bacillus cereus is an aerobic, spore-forming, typically Gram-positive rod, Actinomycotic keratitis is usually part of a mixed infection with other
although considerable variability in staining characteristics has been noted. organisms that might have different antibiotic sensitivities. Infection is
They are ubiquitous and are found in water, in soil, and on vegetation. rare and usually follows trauma. Typically, the ulcer bed appears dry and
Corneal infection, therefore, can be seen after penetrating injury, especially necrotic and is surrounded by a yellow demarcating gutter.10 Alternatively,
when soil contamination occurs. Bacillus infection also has been reported ring abscesses have been described. Inflammation can be severe, with
in contact lens–related keratitis. Posttraumatic infection characteristically iritis and a hypopyon.
develops within 24 hours of injury and is associated with chemosis, pro- Infections by Nocardia also tend to follow trauma, especially if soil
found lid edema, and proptosis. A diffuse or a peripheral ring of micro- contamination occurs. The ulcer is characteristically superficial, with a
cystic edema often occurs, followed by a circumferential corneal abscess. wreath-shaped gray-white infiltrate and an undermined necrotic edge (Fig.
This is an extremely virulent organism, and perforation of the cornea can 4.12.6). The base might assume a cracked windshield appearance. Nocardia
develop within hours. keratitis often resembles fungal infection, with a filamentous-appearing
border and satellite lesions.
Corynebacterium
The corynebacteria, which include C. diphtheriae, are Gram-positive,
club-shaped or pleomorphic rods arranged in the so-called Chinese-letter
Gram-Negative Rods
formation, Y’s, or palisades. An infrequent cause of keratitis, the clinical Pseudomonas
picture characteristically begins with diffuse epithelial haze, followed by Pseudomonas aeruginosa is the most common Gram-negative organism iso-
stromal necrosis and melting. lated from corneal ulcers and is a frequent cause of contact lens–associated
keratitis. These aerobic bacilli are found in moist environments and fre-
Listeria quently contaminate inadequately chlorinated swimming pools and hot
Listeria monocytogenes is a Gram-positive, short, rod-shaped facultative tubs, ventilators, nebulizer and vaporizer solutions, and ophthalmic solu-
anaerobe. Infection usually occurs in animal handlers. It can colonize per- tion bottles. The organism readily adheres to damaged epithelium. Stromal
sistent epithelial defects and lead to a necrotizing keratitis. Typically, a ring invasion is rapid.
ulcer and an exuberant anterior chamber reaction with fibrinous exudate Pseudomonas keratitis tends to progress rapidly if inadequately treated.
and a hypopyon occur. Most commonly, the organism produces destructive enzymes, such as pro-
tease, lipase, elastase, and exotoxin, which result in necrotic, soupy ulcer-
Clostridium ation. The organism’s surface glycocalyx protects it against phagocytosis
Clostridia are anaerobic, spore-forming, Gram-positive bacilli. Infre- and complement attack. The ulcer often extends peripherally and deeply
quently, clostridial conjunctivitis can be associated with the development within hours and rapidly can involve the entire cornea (Fig. 4.12.7). Ring
of a marginal keratitis. Direct corneal infection is associated with marked ulcers can develop. The corneal epithelium peripheral to the primary ulcer
edema and a frothy, bullous keratitis caused by trapped intraepithelial, sub- typically develops a diffuse gray, ground-glass appearance. The corneal
epithelial, and intrastromal gas produced by the organism. Gas might also stroma appears to dissolve into a greenish-yellow mucous discharge that
be seen in the anterior chamber.8 fluoresces under ultraviolet (but not under cobalt blue) light. The suppu-
rative ulcer frequently thins to a descemetocele that perforates. The ulcer
Propionibacterium acnes often is associated with a marked anterior chamber reaction and hypopyon
Propionibacterium acnes is an anaerobic, nonspore-forming, Gram-positive formation. Extensive keratitis can extend to the limbus and produce an
rod. It forms part of the normal flora of the eyelid and conjunctiva. Kera- infectious scleritis.
titis can be established in the setting of corneal disease, trauma, surgery, Less virulent strains follow a more indolent course. Multifocal epithelial
222 contact lens wear, or chronic topical corticosteroid use.9 Although kera- infection also can be seen, with multiple intraepithelial gray-white nodules
titis caused by P. acnes can assume the appearance of typical infectious accompanied by a granular-appearing stromal infiltrate and anterior
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with angular blepharoconjunctivitis characterized by a gray, ulcerated infil-
trate separated from the limbus by a clear crescent. Central indolent ulcers
also occur. These most often develop in the lower half of the cornea as 4.12
a gray infiltrate that eventually forms an oval-shaped ulcer. The infection
tends to extend deeply rather than peripherally and does so slowly. The
Bacterial Keratitis
anterior chamber reaction can be vigorous. Uncommonly, perforation can
occur.
Haemophilus
Haemophilus influenzae is a Gram-negative bacillus or coccobacillus that
can cause conjunctivitis that leads to keratitis. Infrequently, keratitis has
been associated with contact lens wear and chronic corneal disease. The
infection usually is superficial but extensive; it can be suppurative and
might be associated with a hypopyon.
Gram-Negative Cocci
Neisseria
Neisseria gonorrhoeae and N. meningitidis are Gram-negative, intracellular
diplococci. In corneal and conjunctival scrapings they are found within
Fig. 4.12.7 Infection of the Cornea Caused by Pseudomonas. There is liquefying epithelial cells. In a newborn with ophthalmia neonatorum, gonorrheal
necrosis, advanced central thinning, and hypopyon formation. conjunctivitis is a significant concern because the organism can invade
through an intact epithelium. Corneal infection often is peripheral and can
progress to perforation and endophthalmitis. In adults, ocular gonorrhea
is accompanied by a copious weeping, hyperpurulent discharge. Kerati-
tis most commonly occurs after prolonged conjunctivitis. The transient,
usually peripheral subepithelial infiltrates that might be seen likely repre-
sent a type III hypersensitivity reaction. Keratitis is characterized by diffuse
edema or a ring ulcer with hypopyon. A significant risk of corneal necrosis
and perforation exists.
Meningococcal conjunctivitis also can be complicated by keratitis,
although this is less common than with gonococcal conjunctivitis. Typi-
cally, the keratitis is multifocal, and a peripheral infiltrate progresses to
ulceration.
Moraxella (Branhamella) catarrhalis

Moraxella catarrhalis is a Gram-negative diplococcus that resembles N. gon-
orrhoeae. However, on smears of the conjunctiva, it is not found within
epithelial cells. It can be a constituent of the normal flora of the conjunc-
tiva and is an opportunistic pathogen. Although it can be associated with
both neonatal and adult conjunctivitis, it is an infrequent cause of keratitis.
Fig. 4.12.8 Intraepithelial infiltration of the cornea by Pseudomonas in a hydrophilic Mycobacteria

contact lens wearer.
Nontuberculous Mycobacteria
Of this group of organisms, the Mycobacterium abscessus/chelonae complex
chamber inflammation (Fig. 4.12.8). Diffuse epithelial disease is most com- and M. fortuitum are most commonly associated with ocular disease,
monly seen in association with hydrophilic contact lens wear. although M. avium-intracellulare and M. gordonae also have been reported
to cause infectious keratitis.11,12 These long rods are acid-fast; that is, they
Serratia retain red basic fuchsin dye with Ziehl–Neelsen staining. Nontuberculous
These Gram-negative rods are found in soil, water, food, and the gastro- mycobacteria can grow in disinfectant and are found free in the environ-
intestinal tract. Keratitis often occurs in association with hydrophilic ment, including soil. Keratitis most commonly follows trauma or surgery
contact lens wear. The infection may begin as a superficial central or and has been associated with penetrating keratoplasty and refractive
paracentral ulcer that invades the deeper layers of the cornea, producing surgery. These corneal ulcers tend to be indolent and have been confused
a deep, ring-shaped keratitis. Exotoxins and protease can produce aggres- with mycotic keratitis. The infiltrated base of this typically nonsuppurative
sive ulceration and perforation. Contact lens–associated disease also can ulcer characteristically assumes a “cracked windshield” appearance, with
present with multiple gray intraepithelial nodules that assume a branching multiple radiating lines. Satellite lesions, immune ring, and endothelial
linear pattern, accompanied by a granular-appearing stromal infiltrate and plaque formation might develop as the infection progresses.
anterior chamber inflammation.
Escherichia, Klebsiella, and Proteus DIAGNOSIS

Infection by this group of Gram-negative rods is associated with contact The presumptive diagnosis of infectious keratitis is based primarily on
lens wear and diseased eyes. The features of corneal infection can be clinical history and physical examination, but confirmation of infectious
similar to those seen in a virulent pseudomonal infection, with aggressive infiltration and definitive identification of the offending organism can be
necrosis, ring ulcer formation, and perforation. Alternatively, the keratitis achieved only by examining stained smears of corneal scrapings and lab-
might be less aggressive with indolent ulceration and a moderate anterior oratory cultures of these scrapings. In practice, specific identification of
chamber reaction. Suppurative keratitis caused by Escherichia coli is typi- the offending organism and antibiotic sensitivity data are necessary only if
cally more indolent but is usually accompanied by severe iridocyclitis and they can guide modification of antibiotic treatment if the initial antibiotic
hypopyon formation. regimen fails. Approximately 95% of suspected bacterial ulcers respond
favorably to a well-chosen initial antibiotic regimen, so treatment modifica-
Moraxella tion rarely is necessary.13,14 Many practitioners, therefore, defer diagnostic
Moraxella species are large, Gram-negative (or Gram-variable) bacilli that stains and cultures for selected cases of suspected bacterial keratitis. Some
are described as having a square “boxcar” shape. They are found in pairs evidence exists that small infiltrates that are not associated with advanced
and chains. Moraxella keratitis occurs most frequently in patients with suppuration or severe intraocular inflammation respond favorably to this 223
alcoholism and debilitated patients. Marginal ulcers occur in association approach.14 Scrapings are mandatory if the infection is advanced or central
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TABLE 4.12.1 Common Culture Media BOX 4.12.1 Differential Diagnosis of Corneal Infiltration
Medium Organism Comment and Ulceration
Blood agar Aerobic bacteria 37 °C for bacteria Infectious Noninfectious
• Bacteria • Chronic epithelial defect
Saprophytic fungi Room temperature for fungi

Chocolate agar Haemophilus, Neisseria, 5%–10% carbon dioxide • Fungi • Autoimmune disease
Moraxella • Parasites • Rheumatoid arthritis
Brain–heart infusion (BHI) Bacteria • Acanthamoeba • Mooren’s ulcer
Fungi • Microsporidiosis • Terrien’s marginal degeneration
• Onchocerciasis • Staphylococcal marginal disease
Sabouraud’s dextrose agar Fungi Room temperature
• Viruses • Phlyctenulosis
Enriched thioglycollate broth Aerobic and anaerobic Good for small inocula but • Herpes simplex virus • Contact lens–related infiltration
bacteria prone to contamination • Varicella-zoster virus • Vernal keratoconjunctivitis (shield ulcer)
Löwenstein–Jensen agar Nontuberculous • Epstein–Barr virus • Smokable drug–induced
mycobacteria • Measles • Anesthetic abuse
Escherichia coli plated Acanthamoeba Transport sample to plate in • Mumps • Xerophthalmia, keratomalacia
nonnutrient agar Page’s saline • Spirochetes
• Syphilis
• Lyme disease
TABLE 4.12.2 Stains for Smears and Corneal Scrapings
Stain Organism Comment DIFFERENTIAL DIAGNOSIS
Gram Bacteria, fungi, Stains walls of fungi
Acanthamoeba, See Box 4.12.1.
microsporidia
Giemsa Bacteria, fungi,
chlamydial inclusions,
All stain blue; does not
demonstrate intranuclear
SYSTEMIC ASSOCIATIONS
Acanthamoeba, inclusions; stains fungal Mechanisms that protect the cornea from infection involve both mechan-
microsporidia cytoplasm ical and immunological strategies. Systemic conditions that affect the
Gomori’s methenamine Fungi Difficult technique mechanical protective function of the lids as a result of lagophthalmos or
silver (GMS) reduced blinking include chronic alcoholism, dementia, parkinsonism,
Ink–potassium hydroxide Fungi Displays fungal walls general anesthesia, and coma. Bullous conditions that affect both skin and
Periodic acid–Schiff (PAS) Fungi eye, such as erythema multiforme and ocular cicatricial pemphigoid, are
Acridine orange Bacteria, fungi, Requires fluorescent microscope associated with an increased risk of infectious keratitis not only because
Acanthamoeba of lagophthalmos but also because of inflammatory cicatricial conjunctival
Calcofluor white Fungi, Acanthamoeba Requires fluorescent microscope changes. Patients with human immunodeficiency virus infection are more
Weber Microsporidia likely to develop infectious keratitis and have a more fulminant presenta-
Ziehl–Neelsen Mycobacteria, Nocardia, tion, presumably as a result of impaired local immune defenses.1,18 Malnu-
Actinomyces trition and conditions caused by vitamin deficiency, such as xerophthalmia
and scurvy, appear to increase the risk of posttraumatic infection.
or if history or examination is at all suggestive of filamentous bacterial,

nontuberculous mycobacterial, gonococcal, mycotic, or protozoal infection.
PATHOLOGY
When scrapings of corneal ulcers are obtained, material should be Histopathologically, bacterial keratitis is characterized by inflammation,
taken from the most active regions. The eye is anesthetized with topical necrosis, and angiogenesis. Bacteria and host each contribute to the inflam-
anesthetic, and a heat-sterilized platinum spatula or blade is used to firmly matory response. Although virulence factors are specific to each organism,
scrape the leading edges of the ulcer. Multiple areas of a large ulcer should bacteria generally produce a variety of toxins and proteases that result in
be sampled. If significant corneal thinning is evident, care must be exer- degradation of connective tissue and host defense factors, and necrosis.19
cised not to precipitate perforation. Some investigators have reported Corneal infection results in recruitment of inflammatory cells, with a pre-
acceptable organism recovery rates with scrapings performed with a dominance of polymorphonuclear leukocytes (PMNs) that arrive initially
calcium alginate swab moistened with soy broth.15 Scrapings should be via the tear film and later via proliferating limbal blood vessels. PMNs not
placed on a slide for staining and directly applied to culture media to max- only phagocytize bacteria and necrotic stroma but also release lysosomal
imize the chance of recovery. enzymes that contribute to stromal necrosis and corneal thinning. If the
Commonly used culture media are described in Table 4.12.1. Multi- bacterial population overwhelms the cornea’s protective mechanisms or if
ple C-streaks should be used on agar plates because it is often difficult the necrosis progresses unchecked, corneal perforation and possibly end-
to identify an organism recovered in culture as the offending pathogen, ophthalmitis will result. However, if the infection is brought under control,
and growth outside of the C-streak might indicate contamination. The the infiltrate will decrease in size and the epithelium will heal over the
most commonly applied stains are Gram and Giemsa stains (Table 4.12.2). ulcer. Scar tissue is produced by activated keratocytes and transformed his-
Gram stain is useful to identify bacteria and yeasts. Giemsa stain is useful tiocytes. Angiogenesis might be stimulated by the inflammation, but these
for cytology and to identify bacteria (all stain blue), fungi, and chlamydial vessels usually regress with time.
inclusions. If filamentous bacterial or nontuberculous mycobacterial infec-
tion is suspected, Ziehl–Neelsen staining should be performed. Molecular
diagnosis of bacterial keratitis is possible with polymerase chain reaction
TREATMENT
assays targeting 16S ribosomal RNA; however, this approach is limited by Infectious keratitis should be considered an ocular emergency. Antibiotic
false positives, presumably from normal ocular surface flora.16 therapy must be initiated promptly.20 Topical administration is the route
Corneal biopsy is indicated when an apparent infection fails to resolve of choice because it provides rapid, high levels of drug in the cornea
in spite of antimicrobial treatment, when the identity of the organism is and anterior chamber (Table 4.12.3). Subconjunctival injection may be
in doubt or when conventional scrapings have failed to demonstrate a rea- helpful in cases with scleral spread or in patients unable to instill fre-
sonably culpable organism.17 Corneal stromal biopsy is sometimes neces- quent eyedrops. Systemic administration results in relatively low antibi-
sary to identify protozoan, mycobacterial, or mycotic organisms. As with otic levels in the cornea and is generally advised only when keratitis is
corneal scrapings, the corneal biopsy specimen should incorporate the complicated by scleritis or a risk of perforation or endophthalmitis exists.21
active edge and base of the ulcer. If the infiltrate is sequestered within the Antibiotic-soaked collagen shields enhance topical delivery in animal
stroma, a lamellar technique is required. Tissue obtained through biopsy models, but the clinical usefulness of this method has not been estab-
should be sectioned, with a portion submitted to the pathologist for micro- lished.22 Severe or central ulcers are typically treated with a loading dose
224 scopic examination, and a portion used for direct inoculation of plates and (e.g., every 5–15 minutes for the first hour) followed by application every
broth for culture and sensitivity studies. 30–60 minutes. If a combination of two antibiotics is prescribed, the drops
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The cephalosporins are a class of beta-lactam antibiotics with efficacy
TABLE 4.12.3 Commonly Used Antibiotics for the
Treatment of Bacterial Keratitis
against Gram-positive organisms and some Gram-negative bacilli, such as
E. coli, Klebsiella, and P. mirabilis. Cefazolin, a first-generation cephalospo- 4.12
Antibiotic Concentration Route Activity rin, is relatively nontoxic to the corneal epithelium, and the agent most
commonly used for treatment of infectious keratitis. A third-generation
Bacterial Keratitis
Aminoglycosides Gram-negatives, staphylococci,
some streptococci (not agent, ceftazidime, has efficacy against P. aeruginosa and is an option for
pneumococcus) resistant cases.
Amikacin 20–50 mg/mL Topical Also active against The penicillins are effective against many Gram-positive organisms,
50 mg/mL Subconjunctival nontuberculous mycobacteria such as streptococcal and staphylococcal species, as well as gonococcal and
Gentamicin 14 mg/mL Topical some anaerobic species. However, many staphylococcal strains produce
40 mg/mL Subconjunctival beta-lactamase, which inactivates penicillin. Moreover, approximately
Tobramycin 14 mg/mL Topical 10% of patients have an allergic reaction to penicillins. The penicillin
40 mg/mL Subconjunctival and penicillin-derived antibiotics can be administered both topically and
Cephalosporins Active against Gram-positive subconjunctivally.
organisms and some Gram- Vancomycin is a useful agent against staphylococcal organisms when
negative bacilli cephalosporins are ineffective or poorly tolerated. Vancomycin is a glyco-
Cefazolin 50–100 mg/mL Topical peptide antibiotic with activity against methicillin-resistant staphylococci
200 mg/mL Subconjunctival and other Gram-positive organisms. However, to minimize the develop-
Fluoroquinolones Active against Gram-negatives, ment of resistance, empirical therapy should be used judiciously.30
fair to good against Empiric therapy may need to be altered depending on the results of
Gram-positives microbiological tests. Keratitis caused by Neisseria gonorrhoeae should be
Besifloxacin 6 mg/mL Topical treated systemically with a single dose of intramuscular ceftriaxone, and
Ciprofloxacin 3 mg/mL Topical the patient should be given systemic azithromycin or doxycycline for possi-
Gatifloxacin 3 mg/mL Topical ble chlamydial co-infection.31 In addition, patients with gonococcal keratitis
Levofloxacin 5–15 mg/mL Topical should have the conjunctival sac irrigated frequently with normal saline,
Moxifloxacin 5 mg/mL Topical followed by topical administration of a fluoroquinolone antibiotic solu-
Ofloxacin 3 mg/mL Topical
tion. Keratitis caused by N. meningitides should prompt empiric therapy
with a third-generation cephalosporin, which can be changed to penicillin
Penicillins
depending on the results of susceptibility testing. Actinomyces infections
Penicillin G 100 000 U/mL Topical Active against nonpenicillinase-
generally have poor in vitro susceptibility to aminoglycosides and fluoro-
1 000 000 U/mL Subconjunctival producing Gram-positive
organisms
quinolones, and usually are treated with topical sulfacetamide or penicil-
lin, as well as with subconjunctival penicillin. Nocardia keratitis is typically
Methicillin 50 mg/mL Topical Active against penicillinase-
200 mg/mL Subconjunctival producing Gram-positive
treated topically with amikacin or a sulfonamide, and oral trimethoprim
organisms and sulfamethoxazole for cases that progress on topical therapy.32 Non-
Piperacillin 7 mg/mL Topical Active against Gram-positives and tuberculous mycobacterial keratitis has been successfully treated with
200 mg/mL Subconjunctival some Gram-negatives, including fluoroquinolone antibiotics, although in general the susceptibilities of ami-
Pseudomonas kacin and clarithromycin are superior to those of the fluoroquinolones.12
Vancomycin 33 mg/mL Topical Active against Gram-positive Prolonged therapy of these recalcitrant mycobacterial infections often is
100 mg/mL Subconjunctival organisms, including methicillin- needed, and in certain cases, lamellar or penetrating keratoplasty might
resistant staphylococci be necessary.
If antibiotic susceptibility testing is available, these data can be used as
a relative guide in choosing antibiotics that might have a higher probabil-
ity of eradicating the offending microbe. Antibiotic sensitivities are most
are given in an alternating fashion. Subsequent reductions are dictated by commonly measured by disc diffusion or serial dilution methods. These
the response of the infection. tests typically report the susceptibility of the bacterial isolate to each tested
Initially, empirical topical therapy should be instituted with a drug based on the minimum inhibitory concentration (MIC), which is the
broad-spectrum antibiotic regimen.23 The most commonly used regimens lowest concentration of antibiotic that inhibits bacterial growth. However,
include fluoroquinolone monotherapy or combination therapy with a ceph- it is important to recognize that most laboratories base the definition of
alosporin and aminoglycoside; these two regimens are thought to have resistance on MIC thresholds that have been established for the expected
similar efficacy in most cases, with approximately 90% of cases responding serum concentration of the antibiotic. With frequent ophthalmic applica-
to therapy (see Table 4.12.3).13,24 tion of a topical antibiotic preparation, relatively high corneal concentra-
Fluoroquinolone antibiotics demonstrate excellent activity against tions of many antibiotics can be established; therefore, organisms cultured
Gram-negative organisms and good to excellent activity against Gram- from a corneal infiltrate may be reported as “resistant” to a particular anti-
positive organisms. Of the commercially available ophthalmic fluoro- biotic but respond to treatment because of the effect of high local concen-
quinolones, the newer agents (levofloxacin, moxifloxacin, gatifloxacin, and tration.33 Nonetheless, higher MICs are associated with larger corneal scars
besifloxacin) offer enhanced Gram-positive coverage compared with the and worse visual acuity, which suggests that tailoring therapy based on
older agents (ofloxacin and ciprofloxacin).25 Ciprofloxacin remains the MIC may be of benefit.34
fluoroquinolone of choice for P. aeruginosa. Although fluoroquinolone If a single antibiotic is chosen initially and is effective in treating the
monotherapy is thought to be effective in most cases, emerging resistance infection, there is seldom a reason to change therapy. If a combination
has been noted for several organisms responsible for infectious kerati- of antibiotics is initially effective, administration of the less effective (by
tis, including P. aeruginosa and S. aureus.26,27 Therefore, fluoroquinolone susceptibility studies) of the two often can be halted after a few days. For-
monotherapy should be applied with great caution and with careful obser- tified preparations can be replaced by commercial preparations, and the
vation for a clinical response. frequency of application can be gradually tapered. Treatment should be
The aminoglycosides most commonly used for the treatment of infec- continued at least until the epithelium has completely healed. Pseudomo-
tious keratitis are gentamicin and tobramycin. Both are prepared at a nas aeruginosa can reappear after apparent resolution if treatment is halted
“fortified” concentration of 9–20 mg/mL. These antibiotics provide excel- early; antibiotic administration should be maintained for at least a week
lent Gram-negative coverage and also are active against staphylococci and after epithelial healing.
some streptococci but not against pneumococci. Tobramycin may be more The initial sign of effective treatment is failure of the infiltrate to
active than gentamicin against P. aeruginosa.28 Amikacin is a semisynthetic worsen; however, it is not uncommon for ulcers to initially worsen before
aminoglycoside that is useful in the treatment of Gram-negative organ- stabilizing, even with an effective initial antibiotic regimen. The early signs
isms resistant to gentamicin and tobramycin, as well as nontuberculous of a resolving infection include stabilization of the area and depth of the
mycobacterial organisms. Because infectious keratitis following refractive infiltrate and reduced activity at the infiltrate’s margins. Signs of continu-
surgery often is caused by mycobacteria, amikacin may be given empiri- ing improvement include progressive healing of the epithelial defect, clear-
cally in this situation.29 Aminoglycosides tend to inhibit epithelial wound ing of the infiltrate, reduced corneal edema adjacent to the infiltrate, and 225
healing and can cause a punctate epitheliopathy. decreasing inflammation and anterior chamber reaction. It is important to
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note that corneal stromal necrosis might progress in spite of effective anti-
4 microbial treatment because of the lytic activity of immigrant leukocytes.

In addition, immunological ring infiltrates can appear many days after the
initiation of effective antimicrobial treatment and might be erroneously
interpreted to indicate worsening of the infection.
If the corneal ulcer fails to improve, corneal scraping should be per-

formed (or repeated) for smear and culture. In the case of indolent
infections, antibiotic treatment might be interrupted for 24–48 hours to
decrease the inhibitory effect of antibiotic treatment and, thus, increase
the probability of recovering the organism. If no organism is recovered in
bacterial culture and the disease worsens, noninfectious and nonbacterial
causes of ulcerative keratitis must be considered (see Box 4.12.1). Appropri-
ate cultures for nontuberculous mycobacteria, fungi, and protozoal organ-
isms should be obtained. If repeat cultures are negative and the ulcer does
not improve, corneal biopsy might be necessary. When obtaining corneal
biopsy, the specimen should be sent for both microbiological and histo-
pathological evaluation.17
Besides antimicrobial therapy, adjunctive treatments have been em-
ployed in an effort to minimize the adverse sequelae of corneal infection,
such as perforation, vascularization, and scarring. Corticosteroids can be
used to suppress the inflammatory response that leads to these adverse se- Fig. 4.12.9 Bacterial infection leading to central necrosis, thinning, and perforation,
quelae. Corticosteroids reduce the host inflammatory response, thereby im- sealed with cyanoacrylate tissue adhesive.
proving patient comfort and theoretically resulting in less stromal scarring.
However, corticosteroids also have been shown to delay re-epithelization OUTCOME
of corneal ulcers, and if antibiotic therapy is inadequate, to promote bac-
terial replication.35 The Steroids for Corneal Ulcers Trial (SCUT) was a The visual outcomes of bacterial keratitis vary greatly. In general, the most
randomized placebo-controlled trial that found that topical corticosteroid important predictor of final visual outcome is the visual acuity at diagno-
therapy started after at least 48 hours of antibiotics did not significantly sis; patients with worse vision at diagnosis will have worse vision after
improve visual acuity at 3 months, although corticosteroids were associ- the ulcer has healed.44 Relatively small infiltrates that do not involve the
ated with improved vision in the most severe ulcers.36 The rate of corneal central cornea might leave stromal scarring that is only faintly discerned
perforation was similar in the two treatment groups. Subgroup analyses on slit-lamp microscopy and has no visual consequence; more extensive
produced similar findings for pseudomonal ulcers, but not for Nocardia ulceration and infiltration can result in significant scarring and irregular
ulcers, which had significantly worse outcomes with corticosteroid treat- astigmatism. Residual scarring is thought to cause vision loss by blocking
ment.37,38 A secondary analysis of SCUT found that corticosteroids signifi- light, causing light scatter, and/or inducing irregular astigmatism. Per-
cantly improved 3-month visual acuity if started within 3 days of initiating sistent anterior stromal scars can sometimes be removed by excimer laser
antibiotic therapy, but had no effect if the delay was 4 days or later.39 This phototherapeutic keratectomy, but deeper scars require lamellar or pene-
suggests that corticosteroids may be safely used for non-Nocardia bacteri- trating keratoplasty. In the absence of significant opacification, irregular
al keratitis to reduce pain and inflammation and that severe ulcers given astigmatism is best treated with a rigid contact lens. Corneal inflammation
prompt corticosteroid therapy may even have a benefit in visual outcomes. can lead to neovascularization; these vessels may regress with time, and
However, corticosteroids should not be used if there is any suspicion of regression might be aided by corticosteroid therapy. Ocular inflammation
fungal or amoebic keratitis, or if doubt exists about the efficacy of the an- also can lead to synechiae formation, elevated intraocular pressure, and
timicrobial regimen. Nonsteroidal anti-inflammatory agents might help cataract.
reduce the adverse sequelae of infectious inflammation, but, again, they
should be used only in the presence of effective antimicrobial treatment.40 KEY REFERENCES
Cycloplegic agents are useful in reducing discomfort caused by ciliary body
spasm and can be used periodically to decrease synechiae formation. Final- Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida
and emerging resistance to fluoroquinolones. Ophthalmology 2000;107:1497–502.
ly, in vitro studies have suggested that stromal necrosis may be prevented Alexandrakis G, Haimovici R, Miller D, et al. Corneal biopsy in the management of progres-
by several potential collagenase inhibitors, including acetylcysteine, citrate, sive microbial keratitis. Am J Ophthalmol 2000;129:571–6.
and doxycycline.41 The clinical utility of these collagenase inhibitors, how- American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice
ever, remains unclear. Pattern Guidelines. Bacterial Keratitis. San Francisco, CA: American Academy of Oph-
thalmology; 2013.
Surgical intervention is warranted when necrosis progresses to perfo- Anshu A, Parthasarathy A, Mehta JS, et al. Outcomes of therapeutic deep lamellar kera-
ration or impending perforation and may be considered for corneal ulcers toplasty and penetrating keratoplasty for advanced infectious keratitis: a comparative
that are unresponsive to medical therapy. For small perforations without study. Ophthalmology 2009;116:615–23.
extensive surrounding necrosis, cyanoacrylate glue can be applied (Fig. Dart JK, Radford CF, Minassian D, et al. Risk factors for microbial keratitis with contem-
porary contact lenses: a case-control study. Ophthalmology 2008;115:1647–54, 54.e1–3.
4.12.9). Small perforations also have been successfully managed with fibrin Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of ulcerative keratitis in Northern Cali-
glue and multilayered amniotic membrane grafts.42 If the perforation is fornia. Arch Ophthalmol 2010;128:1022–8.
large or necrosis is extensive, corneal transplantation might be necessary. Jhanji V, Young AL, Mehta JS, et al. Management of corneal perforation. Surv Ophthalmol
The choice between a small-diameter patch graft and a large-diameter graft 2011;56:522–38.
Lalitha P, Srinivasan M, Manikandan P, et al. Relationship of in vitro susceptibility to moxi-
and between a penetrating procedure and a lamellar procedure depends floxacin and in vivo clinical outcome in bacterial keratitis. Clin Infect Dis 2012;54:1381–7.
on the size, depth, and location of the ulcer. Deep anterior lamellar kerato- McLeod SD, Kolahdouz-Isfahani A, Rostamian K, et al. The role of smears, cultures, and
plasty is an option for corneas that have not yet perforated; this technique antibiotic sensitivity testing in the management of suspected infectious keratitis. Oph-
may reduce the risk of graft failure and appears to have similar rates of thalmology 1996;103:23–8.
Moshirfar M, Welling JD, Feiz V, et al. Infectious and noninfectious keratitis after laser in
disease recurrence compared with penetrating keratoplasty.43 Therapeutic situ keratomileusis – occurrence, management, and visual outcomes. J Cataract Refract
keratoplasty can result in favorable surgical outcomes, although the pro- Surg 2007;33:474–83.
cedure can be complicated by the difficulties involved in operating on a O’Brien TP, Maguire MG, Fink NE, et al. Efficacy of ofloxacin vs cefazolin and tobramycin
perforated globe, concurrent infection, and inflammation that threatens in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study Research
Group. Arch Ophthalmol 1995;113:1257–65.
graft success. Conjunctival flaps can be used to treat infections that fail to Srinivasan M, Mascarenhas J, Rajaraman R, et al. Corticosteroids for bacterial keratitis: the
improve with medical therapy; this strategy might be especially useful in Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol 2012;130:143–50.
peripheral infectious ulceration. The vascularized conjunctival tissue helps
admit blood vessels that aid in healing and scarring. Conjunctival flaps Access the complete reference list online at ExpertConsult.com
should not be placed over a corneal perforation.
226
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REFERENCES 23. McLeod SD, LaBree LD, Tayyanipour R, et al. The importance of initial management in
the treatment of severe infectious corneal ulcers. Ophthalmology 1995;102(12):1943–8.
1. Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of ulcerative keratitis in Northern
California. Arch Ophthalmol 2010;128(8):1022–8.
24. Constantinou M, Daniell M, Snibson GR, et al. Clinical efficacy of moxifloxacin
in the treatment of bacterial keratitis: a randomized clinical trial. Ophthalmology
4.12
2. Upadhyay MP, Karmacharya PC, Koirala S, et al. The Bhaktapur eye study: ocular trauma 2007;114(9):1622–9.
25. McDonald M, Blondeau JM. Emerging antibiotic resistance in ocular infections and the
Bacterial Keratitis
and antibiotic prophylaxis for the prevention of corneal ulceration in Nepal. Br J Ophthal-
mol 2001;85(4):388–92. role of fluoroquinolones. J Cataract Refract Surg 2010;36(9):1588–98.
3. Whitcher JP, Srinivasan M. Corneal ulceration in the developing world – a silent epi- 26. Garg P, Sharma S, Rao GN. Ciprofloxacin-resistant Pseudomonas keratitis. Ophthalmol-
demic. Br J Ophthalmol 1997;81(8):622–3. ogy 1999;106(7):1319–23.
4. Akpek EK, Gottsch JD. Immune defense at the ocular surface. Eye (Lond) 27. Alexandrakis G, Alfonso EC, Miller D. Shifting trends in bacterial keratitis in south Florida
2003;17(8):949–56. and emerging resistance to fluoroquinolones. Ophthalmology 2000;107(8):1497–502.
5. Schein OD, Glynn RJ, Poggio EC, et al. The relative risk of ulcerative keratitis among 28. Rhee MK, Kowalski RP, Romanowski EG, et al. A laboratory evaluation of antibi-
users of daily-wear and extended-wear soft contact lenses. A case-control study. Microbial otic therapy for ciprofloxacin-resistant Pseudomonas aeruginosa. Am J Ophthalmol
Keratitis Study Group. N Engl J Med 1989;321(12):773–8. 2004;138(2):226–30.
6. Dart JK, Radford CF, Minassian D, et al. Risk factors for microbial keratitis with contem- 29. Moshirfar M, Welling JD, Feiz V, et al. Infectious and noninfectious keratitis after laser
porary contact lenses: a case-control study. Ophthalmology 2008;115(10):1647–54, 54.e1–3. in situ keratomileusis – occurrence, management, and visual outcomes. J Cataract
7. McLeod SD, Flowers CW, Lopez PF, et al. Endophthalmitis and orbital cellulitis after Refract Surg 2007;33(3):474–83.
radial keratotomy. Ophthalmology 1995;102(12):1902–7. 30. Fiscella RG. Vancomycin use in ophthalmology. Arch Ophthalmol 1995;113(11):1353–4.
8. Ostler HB, Ostler MW. Diseases of the external eye and adnexa: a text and atlas. Balti- 31. Workowski KA, Berman S, Centers for Disease Control and Prevention (CDC).
more: Williams & Wilkins; 1992. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep
9. Zaidman GW. Propionibacterium acnes keratitis. Am J Ophthalmol 1992;113(5):596–8. 2010;59(RR–12):1–110.
10. McLean JM. Oculomycosis. Trans Am Acad Ophthalmol Otolaryngol 1963;67:149–63. 32. DeCroos FC, Garg P, Reddy AK, et al. Optimizing diagnosis and management of nocar-
11. Moore MB, Newton C, Kaufman HE. Chronic keratitis caused by Mycobacterium gor- dia keratitis, scleritis, and endophthalmitis: 11-year microbial and clinical overview. Oph-
donae. Am J Ophthalmol 1986;102(4):516–21. thalmology 2011;118(6):1193–200.
12. Girgis DO, Karp CL, Miller D. Ocular infections caused by non-tuberculous myco- 33. Ormerod LD, Heseltine PN, Alfonso E, et al. Gentamicin-resistant pseudomonal infec-
bacteria: update on epidemiology and management. Clin Experiment Ophthalmol tion. Rationale for a redefinition of ophthalmic antimicrobial sensitivities. Cornea
2012;40(5):467–75. 1989;8(3):195–9.
13. O’Brien TP, Maguire MG, Fink NE, et al. Efficacy of ofloxacin vs cefazolin and tobra- 34. Lalitha P, Srinivasan M, Manikandan P, et al. Relationship of in vitro susceptibil-
mycin in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study ity to moxifloxacin and in vivo clinical outcome in bacterial keratitis. Clin Infect Dis
Research Group. Arch Ophthalmol 1995;113(10):1257–65. 2012;54(10):1381–7.
14. McLeod SD, Kolahdouz-Isfahani A, Rostamian K, et al. The role of smears, cultures, and 35. Srinivasan M, Lalitha P, Mahalakshmi R, et al. Corticosteroids for bacterial corneal
antibiotic sensitivity testing in the management of suspected infectious keratitis. Oph- ulcers. Br J Ophthalmol 2009;93(2):198–202.
thalmology 1996;103(1):23–8. 36. Srinivasan M, Mascarenhas J, Rajaraman R, et al. Corticosteroids for bacterial keratitis:
15. Benson WH, Lanier JD. Comparison of techniques for culturing corneal ulcers. Ophthal- the Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol 2012;130(2):143–50.
mology 1992;99(5):800–4. 37. Sy A, Srinivasan M, Mascarenhas J, et al. Pseudomonas aeruginosa keratitis: outcomes
16. Kim E, Chidambaram JD, Srinivasan M, et al. Prospective comparison of microbial and response to corticosteroid treatment. Invest Ophthalmol Vis Sci 2012;53(1):267–72.
culture and polymerase chain reaction in the diagnosis of corneal ulcer. Am J Ophthal- 38. Lalitha P, Srinivasan M, Rajaraman R, et al. Nocardia keratitis: clinical course and effect
mol 2008;146(5):714–23, 23.e1. of corticosteroids. Am J Ophthalmol 2012;154(6):934–9.e1.
17. Alexandrakis G, Haimovici R, Miller D, et al. Corneal biopsy in the management of pro- 39. Ray KJ, Srinivasan M, Mascarenhas J, et al. Early addition of topical corticosteroids in the
gressive microbial keratitis. Am J Ophthalmol 2000;129(5):571–6. treatment of bacterial keratitis. JAMA Ophthalmol 2014;132(6):737–41.
18. Nanda M, Pflugfelder SC, Holland S. Fulminant pseudomonal keratitis and scleritis in 40. Gritz DC, Lee TY, Kwitko S, et al. Topical anti-inflammatory agents in an animal model
human immunodeficiency virus-infected patients. Arch Ophthalmol 1991;109(4):503–5. of microbial keratitis. Arch Ophthalmol 1990;108(7):1001–5.
19. Fleiszig SM, Evans DJ. The pathogenesis of bacterial keratitis: studies with Pseudomonas 41. Jhanji V, Young AL, Mehta JS, et al. Management of corneal perforation. Surv Ophthal-
aeruginosa. Clin Exp Optom 2002;85(5):271–8. mol 2011;56(6):522–38.
20. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice 42. Hick S, Demers PE, Brunette I, et al. Amniotic membrane transplantation and fibrin
Pattern Guidelines. Bacterial Keratitis. San Francisco: American Academy of Ophthal- glue in the management of corneal ulcers and perforations: a review of 33 cases. Cornea
mology; 2013. 2005;24(4):369–77.
21. Leibowitz HM, Ryan WJ Jr, Kupferman A. Route of antibiotic administration in bacterial 43. Anshu A, Parthasarathy A, Mehta JS, et al. Outcomes of therapeutic deep lamellar ker-
keratitis. Arch Ophthalmol 1981;99(8):1420–3. atoplasty and penetrating keratoplasty for advanced infectious keratitis: a comparative
22. Willoughby CE, Batterbury M, Kaye SB. Collagen corneal shields. Surv Ophthalmol study. Ophthalmology 2009;116(4):615–23.
2002;47(2):174–82. 44. Srinivasan M, Mascarenhas J, Rajaraman R, et al. Visual recovery in treated bacterial
keratitis. Ophthalmology 2014;121(6):1310–11.
226.e1
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Fungal Keratitis
Definition: Corneal disease caused by fungal organisms. CLINICAL FEATURES
Fungal infection tends to arise in traumatized, diseased, and immuno-
compromised corneas. The keratitis tends to be slowly progressive and
insidious, but rapid infiltrate development does not rule out fungal
Key Feature infection. In some cases, the epithelium might heal over an intrastro-
• Cellular infiltration of the corneal epithelium or stroma, corneal mal infiltrate that produces little inflammation and minimal discom-
inflammation, and necrosis. fort. Conversely, inflammation might be so severe as to result in satellite
lesions and hypopyon formation. The ulcer and infiltrate itself can assume
protean appearances and might be indistinguishable from a bacterial ulcer.
However, certain features suggest a filamentous fungal infection, includ-
Associated Features ing feathery edges or a dry, gray, elevated infiltrate and satellite lesions (Fig.
• Long-term corticosteroid use. 4.13.1).3 Compared with other fungal pathogens, Aspergillus may be more
• Trauma involving vegetative matter. likely to have a ring infiltrate, and dematiaceous fungi may be more likely
• Corneal infiltrate with feathery borders or satellite lesions. to have a pigmented or raised infiltrate.4,5 Although a ring infiltrate and
endothelial plaque are suggested as indicators of fungal keratitis, many
cases do not demonstrate these features, which merely reflect corneal and
INTRODUCTION anterior chamber inflammation.
Fungal infections of the cornea are relatively infrequent in the developed

world but cause a large proportion of keratitis in many parts of the devel-
DIAGNOSIS
oping world. Although these infections can cause devastating damage if A high level of suspicion for nonbacterial keratitis must be maintained at
allowed to progress unchecked, advances in antimicrobial therapy and sur- all times, especially in those areas where the incidence of fungal keratitis
gical technique have improved their prognosis. Recognition and prompt, is relatively high (Fig. 4.13.2). Important historical elements include pre-
aggressive therapy of fungal infections are extremely important. existing corneal disease, chronic corticosteroid use, trauma, contact lens
wear, and recent surgery, including laser-assisted in situ keratomileusis
EPIDEMIOLOGY AND PATHOGENESIS (LASIK).6
Definite diagnosis requires laboratory confirmation. Scrapings for
Fungi are ubiquitous organisms that are recognized more frequently as stains and culture should be obtained as described for bacterial keratitis.
ocular pathogens in agrarian, tropical countries than in the developed If fungal infection is suspected after LASIK, the flap must be elevated
world. For clinical purposes, fungi can be classified on a morphological to obtain samples. Smear diagnosis is primarily made with Giemsa or
basis into filamentous, yeast, and diphasic forms. Filamentous organisms ink-potassium hydroxide stains, though fungal elements are also visible
are multicellular with branched hyphae. Septate filamentous organisms, on Gram stain (Fig. 4.13.3). Gomori’s methenamine silver stain is generally
such as Fusarium and Aspergillus, have hyphae that are divided by cell considered the stain that best demonstrates fungal organisms.
walls. Other filamentous fungi, including Mucor and Rhizopus, are nonsep- Culture media used to demonstrate fungal growth include Sabouraud’s
tate. Septate filamentous fungi can be further divided into nonpigmented agar, potato dextrose agar, and brain–heart infusion broth, although many
hyaline species (e.g., Fusarium, Aspergillus) and pigmented dematiaceous fungi will grow on blood agar kept at room temperature. Most ocular
species (e.g., Alternaria, Curvularia). Yeasts, such as Candida and Crypto-
coccus, are unicellular fungi that reproduce by budding, but in tissue, they
might develop elongated buds (pseudo-hyphae) or real hyphae. Dimorphic
fungi, such as Histoplasma, Coccidioides, and Blastomyces, demonstrate both
a yeast phase that occurs in tissues and a mycelial phase that appears on
culture media and saprophytic surfaces.
The incidence of fungal keratitis in the United States has historically
been quite low, but rates of Fusarium keratitis increased dramatically in
the mid-2000s because of an epidemic related to a contact lens solution.1
Although the rate of Fusarium keratitis decreased after the solution was
withdrawn from the market, microbiology laboratories have continued to
detect elevated numbers of filamentous fungi. Fungal keratitis is more
common in tropical climates. In these areas, septate filamentous fungi,
most notably Fusarium and Aspergillus, are the most common causative
organisms. In contrast, Candida is the predominant cause in more tem-
perate climates.
The risk factors associated with fungal keratitis depend on the setting.2
In the tropics, corneal trauma, which might be trivial, frequently pre-
cedes infection. Concurrent contamination with plant material presents
an increased risk for fungal keratitis. However, in colder climates, where
Candida infections predominate, fungal infections are more commonly
seen in patients with corneal pathology or with an ocular surface that
is locally immunosuppressed by chronic corticosteroid use or systemic 227
disease. Fig. 4.13.1 Feathery stromal infiltrates typical of fungal keratitis.
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4
Fig. 4.13.4 Keratoplasty specimen demonstrating fungal infiltration of the anterior

stroma and inflammatory cells.
TABLE 4.13.1 Antifungals

Fig. 4.13.2 Fusarium fungal keratitis.
Agent Route Dosage/Concentration
Polyenes
Amphotericin B Topical 0.15%
Subconjunctival 0.5–1 mg
Intracameral 7.5–10 µg in 0.1 mL
Natamycin Topical suspension 5%
Imidazoles
Clotrimazole Topical 1%
Econazole Topical 2%
Ketoconazole Topical 5%
Oral 300 mg/day
Miconazole Topical suspension 1%
Topical cream 2%
Subconjunctival 5–10 mg
Triazoles
Fluconazole Topical 0.2%
Oral 200 mg/day
Itraconazole Topical 1%
Oral 100–200 mg twice daily
Voriconazole Topical 1%
Oral 200 mg twice daily
Intracameral 100 µg in 0.1 mL
Intrastromal 50 µg in 0.1 mL
Fig. 4.13.3 Gram stain of scraping from corneal ulcer caused by Fusarium
demonstrating branching fungal hyphae. Posaconazole Oral 200 mg four times daily
Pyrimidines
Flucytosine Topical 2%
fungal isolates demonstrate growth within 2–3 days, although it is prudent Oral 50–150 mg/kg/day divided twice daily
to wait 2 weeks before confirmation of no growth. Fungal susceptibility Echinocandins
criteria are poorly standardized and not performed at most laboratories. Caspofungin Topical 0.5%
Corneal scrapings can be investigated with polymerase chain reaction Micafungin Topical 0.1%
techniques that target a common fungal ribosomal RNA (rRNA), although
the high sensitivity of these methods carries the risk of false positives
because of contamination, either at the site of corneal scraping or in the alcoholism, diabetes, and vitamin A deficiency. Fungal keratitis is not asso-
laboratory. ciated with systemic fungemia.
In vivo confocal microscopy can be used to detect fungal hyphae and
is particularly useful for diagnosis of deep infections that cannot easily be
scraped.7 Fungal filaments appear as highly reflective double-walled struc-
PATHOLOGY
tures measuring between 3 and 8 µm.8 Destructive fungal infection is advanced by organism adherence, inva-
Since some cases of keratitis may develop deep in the stroma with sion, growth, and subsequent damage caused by direct toxicity and host
intact overlying corneal tissue, a deep corneal biopsy might be necessary response. The mycelia of filamentous organisms tend to extend along the
to obtain tissue for laboratory studies (Fig. 4.13.4). corneal lamellae, whereas more virulent organisms can cross lamellae and
even penetrate Descemet’s membrane, leading to intracameral infection.9,10
DIFFERENTIAL DIAGNOSIS The inflammatory host response is similar to that described in bacterial
infection, with both mycotic and host factors leading to an inflammatory
For the differential diagnosis of fungal keratitis, see Box 4.12.1. As a result cell infiltrate, necrosis, and neovascularization.
of indolent progression and failure to respond to antibacterial medica-
tion, fungal keratitis often is misdiagnosed as herpetic or amebic disease.
Fungal infection following LASIK must be differentiated from the sterile
TREATMENT
interface infiltration of post-LASIK diffuse lamellar keratitis and from The efficacy of currently available antifungal agents is limited, and a
infection caused by bacterial species. relatively high medical treatment failure rate exists. The agents most
commonly used for fungal keratitis include the polyenes and azoles
SYSTEMIC ASSOCIATIONS (Table 4.13.1).
Polyene medications, such as amphotericin B, natamycin, and nystatin,
228 Fungal keratitis caused by less virulent organisms, such as Candida, often bind to fungal cell wall ergosterol, thus disrupting the cell. The polyenes
is associated with conditions that lead to immunocompromise, such as are effective against both filamentous and yeast forms. Amphotericin B is
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particularly effective against yeasts and is the agent of choice for kerati- The course of treatment is typically protracted. Antifungal treatment is
tis caused by Candida species, but it is less effective against filamentous
organisms. Natamycin is effective against yeasts and has a broad spectrum
usually maintained over 12 weeks, with strict vigilance as medicines are
tapered. If fungal keratitis fails to respond to medical therapy, surgical 4.13
of activity against filamentous organisms. The polyenes do not penetrate intervention should be considered. Because of the propensity for fungal
well through in an intact corneal epithelium.11 Periodic debridement of elements to invade deeply and, in some cases, penetrate Descemet’s mem-
Fungal Keratitis
the cornea may enhance penetration of topical medications, although it is brane, advanced cases require penetrating keratoplasty to ensure com-
unclear that debridement results in better outcomes.12 plete removal of the invading fungus. In general, penetrating keratoplasty
Azole medications, which include the imidazoles (e.g., miconazole, clo- should be performed sooner rather than later to maximize the probabil-
trimazole, and ketoconazole) and the triazoles (e.g., fluconazole, itracon- ity of a graft margin free of infection and to minimize the risk of end-
azole, posaconazole, and voriconazole) inhibit synthesis of ergosterol in ophthalmitis or infectious scleritis. As generous a clear margin as possible
the cell wall. Azoles generally have good activity against yeasts but have should be included in the excised cornea.18 Less advanced cases might be
more variable activity against filamentous organisms. Voriconazole has amenable to lamellar keratoplasty, but the surgeon must be confident that
good corneal penetration when given topically, and good intraocular con- the entire infection has been encompassed by the lamellar dissection. If
centrations when given orally. Voriconazole can be administered as an there is any question about the depth of infection, the procedure should be
intracameral or intrastromal injection.13 Potential adverse effects of oral converted to a full-thickness penetrating excision.19
voriconazole include visual phenomena and hepatotoxicity; liver function
therefore should be monitored.
Other antifungal agents have a role for treatment of fungal keratitis.
OUTCOME
The pyrimidine flucytosine blocks fungal thymidine synthesis. Flucytosine Patients with deep stromal infection and those treated with corticosteroids
is well absorbed when administered orally, and it also can be applied as appear to respond particularly poorly to medical therapy. Medical failure
a topical solution. Echinocandins, such as caspofungin and micafungin, occurs in approximately 15%–20% of cases.12 Although penetrating kera-
inhibit beta-glucan in cell walls and have shown promise as a topical toplasty can successfully eliminate the organism and restore the integrity
therapy for fungal keratitis. of the eye, a delay in surgery or advanced disease might allow catastrophic
Once the diagnosis has been made, fungal keratitis should be treated extension of infection to the anterior chamber and sclera, especially in
with frequently applied topical antifungal medication. An oral triazole the case of preoperative topical corticosteroid use, perforation, or limbal
should be considered for deep stromal infection. Ulcers are typically treated involvement.20
with a loading dose (e.g., every 5–15 minutes for the first hour) followed by
application every 30–60 minutes. The frequency of applications is reduced
on the basis of clinical response. Intracameral injections of amphotericin
KEY REFERENCES
B or voriconazole can be administered for infections that have penetrated Chen WL, Tsai YY, Lin JM, et al. Unilateral Candida parapsilosis interface keratitis after laser
in situ keratomileusis: case report and review of the literature. Cornea 2009;28:105–7.
Descemet’s membrane. Chidambaram JD, Prajna NV, Larke NL, et al. Prospective study of the diagnostic accuracy of
The Mycotic Ulcer Treatment Trial (MUTT) was a randomized controlled the in vivo laser scanning confocal microscope for severe microbial keratitis. Ophthal-
trial that found that fungal ulcers randomized to natamycin had better mology 2016;123(11):2285–93.
vision at 3 months compared with those randomized to voriconazole—a Keay LJ, Gower EW, Iovieno A, et al. Clinical and microbiological characteristics of
fungal keratitis in the United States, 2001–2007: a multicenter study. Ophthalmology
result driven largely from the efficacy of natamycin among Fusarium 2011;118:920–6.
ulcers.14 A companion trial found no benefit to oral antifungal therapy: Perry HD, Doshi SJ, Donnenfeld ED, et al. Topical cyclosporin A in the management of
in MUTT II, fungal ulcers were treated with topical therapy and random- therapeutic keratoplasty for mycotic keratitis. Cornea 2002;21:161–3.
ized to oral voriconazole or placebo. After 3 months, the rate of perfora- Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a randomized
tion or therapeutic keratoplasty was not significantly different between the trial comparing natamycin vs voriconazole. JAMA Ophthalmol 2013;131(4):422–9.
Prajna NV, Krishnan T, Rajaraman R, et al. Effect of Oral Voriconazole on Fungal Keratitis
voriconazole and placebo groups.15 in the Mycotic Ulcer Treatment Trial II (MUTT II): a randomized clinical trial. JAMA
Because these infections can be tenacious, and host suppression of Ophthalmol 2016;134(12):1365–72.
infection is very important, corticosteroid use is generally not recom- Prakash G, Sharma N, Goel M, et al. Evaluation of intrastromal injection of voriconazole as
mended in the management of fungal keratitis. However, patients who are a therapeutic adjunctive for the management of deep recalcitrant fungal keratitis. Am J
Ophthalmol 2008;146:56–9.
already using corticosteroids at the time of diagnosis should have their Shi W, Wang T, Xie L, et al. Risk factors, clinical features, and outcomes of recurrent fungal
medication gradually tapered off because abrupt cessation of corticosteroid keratitis after corneal transplantation. Ophthalmology 2010;117:890–6.
therapy can result in an intense host inflammatory response leading to per- Thomas PA, Leck AK, Myatt M. Characteristic clinical features as an aid to the diagnosis
foration.16 The propensity for corticosteroids to enhance microbial viability of suppurative keratitis caused by filamentous fungi. Br J Ophthalmol 2005;89:1554–8.
can present a particular dilemma for the treatment of fungal infection in
a corneal graft. In vitro studies have suggested that topical cyclosporine Access the complete reference list online at ExpertConsult.com
A might possess antifungal properties, and this agent has been used as
an alternative for reducing inflammation and the subsequent risk of graft
failure in the setting of fungal graft infection.17
229
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REFERENCES 10. Ishida N, Brown AC, Rao GN, et al. Recurrent Fusarium keratomycosis: a light and elec-
tron microscopic study. Ann Ophthalmol 1984;16(4):354–6, 8–60, 62–6.
1. Gower EW, Keay LJ, Oechsler RA, et al. Trends in fungal keratitis in the United States,
2001 to 2007. Ophthalmology 2010;117(12):2263–7.
11. O’Day DM, Head WS, Robinson RD, et al. Corneal penetration of topical amphotericin B
and natamycin. Curr Eye Res 1986;5(11):877–82.
4.13
2. Keay LJ, Gower EW, Iovieno A, et al. Clinical and microbiological characteristics of 12. Prajna NV, Mascarenhas J, Krishnan T, et al. Comparison of natamycin and voriconazole
for the treatment of fungal keratitis. Arch Ophthalmol 2010;128(6):672–8.
Fungal Keratitis
fungal keratitis in the United States, 2001–2007: a multicenter study. Ophthalmology
2011;118(5):920–6. 13. Prakash G, Sharma N, Goel M, et al. Evaluation of intrastromal injection of voriconazole
3. Thomas PA, Leck AK, Myatt M. Characteristic clinical features as an aid to the diagno- as a therapeutic adjunctive for the management of deep recalcitrant fungal keratitis. Am
sis of suppurative keratitis caused by filamentous fungi. Br J Ophthalmol 2005;89(12): J Ophthalmol 2008;146(1):56–9.
1554–8. 14. Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a random-
4. Oldenburg CE, Prajna VN, Prajna L, et al. Clinical signs in dematiaceous and hyaline ized trial comparing natamycin vs voriconazole. JAMA Ophthalmol 2013;131(4):422–9.
fungal keratitis. Br J Ophthalmol 2011;95(5):750–1. 15. Prajna NV, Krishnan T, Rajaraman R, et al. Effect of Oral Voriconazole on Fungal Kerati-
5. Garg P, Vemuganti GK, Chatarjee S, et al. Pigmented plaque presentation of dematia- tis in the Mycotic Ulcer Treatment Trial II (MUTT II): a randomized clinical trial. JAMA
ceous fungal keratitis: a clinicopathologic correlation. Cornea 2004;23(6):571–6. Ophthalmol 2016;134(12):1365–72.
6. Chen WL, Tsai YY, Lin JM, et al. Unilateral Candida parapsilosis interface kerati- 16. Peponis V, Herz JB, Kaufman HE. The role of corticosteroids in fungal keratitis: a differ-
tis after laser in situ keratomileusis: case report and review of the literature. Cornea ent view. Br J Ophthalmol 2004;88(9):1227.
2009;28(1):105–7. 17. Perry HD, Doshi SJ, Donnenfeld ED, et al. Topical cyclosporin A in the management of
7. Chidambaram JD, Prajna NV, Larke NL, et al. Prospective study of the diagnostic accu- therapeutic keratoplasty for mycotic keratitis. Cornea 2002;21(2):161–3.
racy of the in vivo laser scanning confocal microscope for severe microbial keratitis. Oph- 18. Xie L, Dong X, Shi W. Treatment of fungal keratitis by penetrating keratoplasty. Br J
thalmology 2016;123(11):2285–93. Ophthalmol 2001;85(9):1070–4.
8. Vaddavalli PK, Garg P, Sharma S, et al. Role of confocal microscopy in the diagnosis of 19. Xie L, Shi W, Liu Z, et al. Lamellar keratoplasty for the treatment of fungal keratitis.
fungal and acanthamoeba keratitis. Ophthalmology 2011;118(1):29–35. Cornea 2002;21(1):33–7.
9. Naumann G, Green WR, Zimmerman LE. A histopathologic study of 73 cases. Am J 20. Shi W, Wang T, Xie L, et al. Risk factors, clinical features, and outcomes of recurrent
Ophthalmol 1967;64(4):668–82. fungal keratitis after corneal transplantation. Ophthalmology 2010;117(5):890–6.
229.e1
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Parasitic Keratitis
Definition: Corneal disease caused by protozoal organisms.
Key Feature
• Cellular infiltration of the corneal epithelium or stroma, corneal
inflammation, and necrosis.
Associated Features
• Delay in diagnosis is common.
• Pain may be greater than physical findings.
• Early cases may demonstrate pseudo-dendrites.
• Later cases may show ring infiltrate in the cornea.
INTRODUCTION Fig. 4.14.1 Epithelial ridges seen in Acanthamoeba keratitis. (Courtesy Joel Sugar,
MD.)
Parasitic infections of the cornea are a significant cause of ocular mor-
bidity. Acanthamoeba keratitis is increasingly recognized in the developed
world as a potentially disastrous complication of contact lens wear and
requires early, aggressive treatment. Onchocerca infection is still encoun-
tered in some parts of the developing world.
ACANTHAMOEBA KERATITIS
Acanthamoebae, found ubiquitously in water, soil, and air, are free-living
protozoans that exist in an active trophozoite form and a dormant cyst
form. The trophozoite feeds on microorganisms and reproduces by binary
fission, but if deprived of a food source, it will encyst. Cysts are resistant to
desiccation, temperature extremes, and various chemicals and can remain
dormant for years. Acanthamoebae are typically speciated according to
morphological characteristics, although they can also be classified into one
of 15 genotypes. The vast majority of keratitis is caused by the T4 genotype.1
Keratitis caused by Acanthamoeba is less common than that caused
by bacteria or fungi, although the incidence of Acanthamoeba keratitis Fig. 4.14.2 Perineuritis seen in Acanthamoeba keratitis. (Courtesy Joel Sugar, MD.)
increased in the United States for several years in the mid-2000s because
of an epidemic related to a contact lens solution.2 The biggest risk factor for
Acanthamoeba keratitis in the developed world is contact lens wear, with
approximately 90% of cases occurring in contact lens wearers.3 Most cases
are seen in soft contact lens wearers, although orthokeratology may convey
increased risk. Trauma is the other major risk factor and accounts for the
vast majority of Acanthamoeba keratitis seen in developing countries.4
Other risk factors include exposure to water, especially fresh water sources,
swimming pools or hot tubs, and homemade contact lens solutions.
Clinical Features
Since a delay in treatment has been shown to adversely affect visual
outcome, clinicians must be acutely aware of the sometimes subtle
early signs of Acanthamoeba infection. Early infection is confined to
the epithelium, which demonstrates irregularity and multifocal infiltra-
tion, pseudo-dendrites, or elevated epithelial ridges (Fig. 4.14.1). Stromal
radial perineuritis is thought to be very specific for Acanthamoeba ker-
atitis, although it does not appear in many cases (Fig. 4.14.2). Limbitis
230 is common, and may account for significant pain. Later stages of infec-
tion are characterized by nonspecific stromal infiltration (Fig. 4.14.3) or a Fig. 4.14.3 Ring infiltrate in corneal Acanthamoeba infection.
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Fig. 4.14.5 Light
microscopic view
of a corneal section 4.14
demonstrating
Acanthamoeba cysts.
Parasitic Keratitis
(Courtesy Joel Sugar, MD.)
organism to enter the stroma, where it may enter progressively deeper

Fig. 4.14.4 Double-walled and bright spot cystic structures on confocal microscopy. layers of the stroma. The organism can become encysted in the corneal
stroma and can cause inflammatory sequelae for months after successful
characteristic ring infiltrate (Fig. 4.14.4), and uveitis.5 When present, fluctu- antimicrobial treatment.11
ating, nongranulomatous anterior chamber inflammation may contribute
to the formation of cataract or elevated intraocular pressure. In the most Treatment
severe cases, hypopyon, anterior scleritis, or perforation (sometimes asso-
ciated with optic neuritis) can occur.6 Treatment of Acanthamoeba keratitis is based on eradication of cysts from
It has been reported frequently that patients experience severe pain far the cornea.12 Although trophozoites are susceptible to many antimicro-
out of proportion to clinical findings, but this is an unreliable diagnostic bial agents, the cysts are largely resistant. The most effective medications
sign, and some patients have reduced or absent corneal sensation. are the biguanide antiseptic agents chlorhexidine and polyhexamethylene
biguanide (PHMB), which act by inhibiting membrane function and are
Diagnosis consistently cysticidal (Table 4.14.1).13 Second-line agents include the diami-
dines (hexamidine, pentamidine, and propamidine), which inhibit DNA
Diagnosis is based on characteristic clinical findings and supported by synthesis. Diamidines also generally are cysticidal, though their activity is
microbiological investigations. Cysts are visible with routine stains, such more variable. Azole medications have activity against trophozoites but are
as Giemsa, Gram, and ink-potassium hydroxide, and with stains that generally not cysticidal. There are reports of effective treatment with oral
require fluorescent microscopy, such as Calcofluor white and acridine and topical voriconazole, although the in vitro susceptibility patterns for
orange.7 Scrapings should be plated on nonnutrient agar and overlaid this agent have not been well characterized. Aminoglycosides such as neo-
with Escherichia coli to assess for growth of trophozoites; plates should be mycin and paromomycin were used in the past, but these agents are not
observed for longer than 7 days. If plates are not available, scrapings can cysticidal and cause significant corneal toxicity, so there is little rationale
be transported to the laboratory in Page’s saline. Culture and smear of to support their use.
samples from contact lens cases and cleaning solutions also can reveal There is little consensus on the best way to treat Acanthamoeba ker-
Acanthamoeba. atitis. A clinical trial compared chlorhexidine monotherapy and PHMB
Polymerase chain reaction (PCR) assays targeting Acanthamoeba 18S monotherapy and found no significant differences, with high success rates
ribosomal RNA (rRNA) have been shown to be more sensitive than culture in both groups (78% and 86%, respectively).14 Because cysts can be difficult
or smear but are not currently available at most laboratories.8 to eradicate, many clinicians treat with multiple agents, usually with one
In vivo confocal microscopy can be used to visualize Acanthamoeba of the biguanide agents and one of the diamidines. As with other types of
cysts in the corneal epithelium and stroma. Cysts appear as round, hyper- infectious keratitis, topical therapy initially should be applied frequently
reflective structures measuring 10–25 µµm, often with a “bright spot” (every 30–60 minutes), and then the frequency can be reduced based on
or double-walled morphology (see Fig. 4.14.4).9 The technique has been the clinical response. Topical medications generally are continued for many
shown to have good sensitivity and specificity.10 months. Pain should be addressed with cycloplegics and oral nonsteroidal
Corneal biopsy should be considered for cases with only deep stromal anti-inflammatory drugs.
involvement or when microbiological tests are negative (Fig. 4.14.5). Biop- The role of corticosteroids in the treatment of Acanthamoeba infec-
sies should be stained with hematoxylin and eosin, periodic acid–Schiff, tion has not been established. Corticosteroids promote excystment and
and methenamine silver stains. proliferation of trophozoites and lead to worse visual outcomes when
used before starting anti-amebic treatment.15,16 However, corticosteroids
Differential Diagnosis also reduce pain and inflammation and may reduce the likelihood of
corneal vascularization. A large retrospective study found that initiation
See Box 4.12.1. The pseudo-dendrites of early disease and the ring infiltrate of corticosteroids after a median of 2 weeks of antiamebic therapy was
of more advanced disease are often mistakenly identified as representing not associated with worse outcomes in eyes with Acanthamoeba kerati-
herpetic keratitis. In those cases that are refractory to treatment, herpetic tis and persistent inflammation, providing some reassurance for patients
keratitis and bacterial superinfection should be considered. requiring anti-inflammatory therapy.17 Antiamebic agents should be started
before and continued during corticosteroid therapy.
Pathology The role of therapeutic keratoplasty for active Acanthamoeba keratitis
is controversial. Recurrence of Acanthamoeba infection has been reported
Trophozoites bind to the corneal epithelium and establish infection. This to occur in more than half the grafts, leading to poor postoperative visual 231
is followed by thinning and necrosis of the epithelium, which allow the outcomes.18 Others have found much lower rates of recurrence, and good
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4
TABLE 4.14.1 Antiamebic Medications
Agent Trade Name Manufacturer Dosage Form Concentration for Ocular Use Availability Comment
Cationic Antiseptics
Chlorhexidine Solution 0.02% As 20% concentrate Used as disinfectant

Polyhexamethylene Baquacil Zeneca Solution 0.02% As 20% pool disinfectant Used also as a preservative, contact
biguanide (PHMB) lens solutions
Aromatic Diamidines
Propamidine isethionate Brolene Mays & Baker Solution 0.1% w/v 10 mL Over-the-counter in UK
Hexamidine Désomédine Chauvin Solution 0.1% Available in Europe
Azoles
Clotrimazole Lotrimin Schering Suspension 1% As powder from manufacturer Poor suspension; difficult to make
Fluconazole Diflucan Roerig Solution 0.2% As 2 mg/mL solution Withdraw from vial with filter needle
Ketoconazole Nizoral Janssen Oil solution 5% As 200 mg tablet In mortar, dissolve 2.5 200 mg tablets
in 10 mL of peanut oil
Miconazole Monistat Janssen Solution 1% As 10 mg/mL solution Simple 1 : 1 solution or directly from
vial via filter
Voriconazole Vfend Pfizer Oral 200 mg twice daily As 200 mg tablet Monitor liver function
1% As 200 mg vial
(Adapted from Richard G. Fiscella, RPh, MPH.)
visual outcomes.19 Antiacanthamebic medications should be continued can be used, with potassium hydroxide plus Calcofluor white, Gram,
after keratoplasty. and modified Ziehl–Neelsen most consistently detecting microsporidia.26
Giemsa staining characteristics are more variable. Microsporidia are dif-
Outcome ficult to recover in culture. PCR assays that target the 16S rRNA subunit
have been developed but are not performed by most laboratories.27 The
With timely diagnosis, Acanthamoeba organisms can be eradicated from confocal microscope can reveal intraepithelial microsporidia, but these
the cornea by medical therapy. A minority of patients develop rapidly pro- organisms, which measure 1–5 µm, approach the resolution limits of this
gressive cataract and glaucoma, presumably from prolonged exposure to instrument.28 Electron microscopy performed on body fluids is considered
topical medications or to the host inflammatory response.20 Severe corneal the gold standard for diagnosis of microsporidial infection.
inflammation and necrosis can result in substantial scarring, necessitat-
ing penetrating keratoplasty for visual rehabilitation. Optical keratoplasty Differential Diagnosis
performed well after eradication of Acanthamoeba infection carries a good
prognosis, but results of therapeutic keratoplasty performed during active See Box 4.12.1.
infection are much more variable.18,21
MICROSPORIDIOSIS Microsporidial infection can involve nearly every organ system in severely
Epidemiology and Pathogenesis immunocompromised patients with HIV infection (usually CD4 cell
counts <100/µL). The gastrointestinal system is most commonly involved,
Microsporidia are ubiquitous obligate intracellular parasites closely related representing a major cause of malabsorption and diarrhea in patients
to fungi.22 Although it is a rare disease, diagnosis of microsporidial kera- with acquired immunodeficiency syndrome (AIDS). Ocular infections
titis is increasing. This is especially true in Asia, where the disease may are second in frequency and may result from nasopharyngeal infection
correspond with the monsoon season.23 Several risk factors occur for or from urine-to-finger-to-eye contamination. When ocular microsporid-
microsporidial keratitis. Immune compromise is the most notable risk ial infections are diagnosed, the patient must be fully examined for other
factor, especially in persons with human immunodeficiency virus (HIV) areas of involvement. Other common infections include sinusitis, hepati-
infection. Other states of immunosuppression, including local immuno- tis, peritonitis, cholangitis, myositis, bronchiolitis, pneumonia, encephali-
suppression with topical corticosteroids, make infection more likely. Other tis, cystitis, and nephritis. Rare manifestations include urethritis, prostatic
major risk factors include trauma, which is often associated with exposure abscess, tongue ulcer, and skeletal and cutaneous involvement.
to water or mud, and contact lens wear.24 Although previously considered
to occur primarily in the setting of HIV, infection is increasingly being Treatment
observed in immunocompetent persons.
The optimal treatment regimen for ocular microsporidiosis is not well
Clinical Features defined. Several medications are currently used, including oral agents, such
as albendazole and itraconazole, and topical agents, such as fumagillin,
Two distinct clinical presentations are possible with ocular microsporidial propamidine, chlorhexidine, PHMB, voriconazole, and the fluoroquinolo-
infection: superficial keratoconjunctivitis, which is caused by encephali- nes. Fumagillin is one of the more frequently used medications; a 10 mg/
tozoon species, and deep stromal keratitis, which is caused by nosema, mL suspension can be applied hourly for 24 hours and then tapered based
vittaforma, and trachiplestophora species. The keratoconjunctivitis form on clinical response. Albendazole has been used when ocular microspo-
usually was seen in immunocompromised persons in the past, although ridiosis was refractory to topical therapy.29 A placebo-controlled random-
this entity is now recognized in immunocompetent persons as well.25 ized clinical trial performed with immunocompetent patients found no
Microsporidial keratoconjunctivitis is characterized by minimal conjuncti- benefit of PHMB.30 This trial found that the disease may be self-limiting
vitis, diffuse punctate epitheliopathy, and coarse epithelial opacities, some in immunocompetent patients; the placebo group experienced clinical cure
of which stain with fluorescein. Symptoms include pain, photophobia, an average of 9 days after diagnosis.
blurred vision, and foreign body sensation. Microsporidial stromal keratitis
usually is seen in immunocompetent individuals, where it is often misdi- Outcome
agnosed as herpetic keratitis. Stromal infection is characterized by deep
stromal infiltrates with or without corneal neovascularization and uveitis. Treatment of microsporidial keratoconjunctivitis is usually successful,
especially in immunocompetent patients. Immunocompromised persons
Diagnosis can develop chronic infections when antimicrosporidial treatment is with-
drawn. In such an event, a low maintenance dose of one drop a day might
232 Diagnosis of microsporidial keratitis usually is made by inspection of be sufficient to control the keratoconjunctivitis. Visual acuity improvement
smears obtained from corneal or conjunctival scrapings. Several stains is usually seen after the superficial keratitis resolves.30 Disease involving
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the corneal stroma is difficult to treat, and recrudescence is common. Differential Diagnosis
Some authors advocate full-thickness keratoplasty in these cases because
microsporidia can invade the anterior chamber, and lamellar keratoplasty Similar skin lesions can be seen in association with microfilarial infection 4.14
does not preclude recurrence.31 caused by Mansonella perstans. Skin nodules and uveitis also can be seen
with sarcoidosis.
Parasitic Keratitis
ONCHOCERCIASIS
Epidemiology and Pathogenesis Besides being present in skin lesions, the microfilariae can be identified
Onchocerciasis, also known as “river blindness,” is a major cause of blind- in blood vessels, visceral organs, the central nervous system, urine, and
ness worldwide. Onchocerciasis affects approximately 18 million people, sputum. Superficial lymph nodes draining areas with cutaneous concen-
of whom 270 000 are rendered blind.32 The vast majority of cases occur in trations of the worms can become painlessly enlarged.
the 34 countries in Africa where the disease is still endemic. The causative
organism, Onchocerca volvulus, is a filarial nematode that is transmitted by Pathology
the Simulium black fly, which breeds in the fast-flowing rivers and streams
of Africa, Brazil, Mexico, the Middle East, and parts of Central America. The destructive inflammation caused by Onchocerca infection is stimu-
The fly introduces larvae of O. volvulus into the skin during a blood meal, lated by antigens released by dead and dying organisms. The host immune
forming a skin nodule of adult worms. After developing into adult worms, response results in migration of eosinophils and neutrophils into the
females shed hundreds of thousands of microfilariae that migrate through corneal stroma. Degranulation of these inflammatory cells releases cyto-
skin and have particular affinity for eyes. Dying microfilariae incite an toxic proteins that disrupt the normal functioning of the corneal cells,
inflammatory reaction that results in the cutaneous and ocular clinical resulting in corneal opacity.37
manifestations. An endosymbiont bacteria, Wolbachia, plays an important
role in development of larvae, and also possibly in the long-term survival Treatment
of adult worms.33
Eye disease is related to the inflammatory response generated by the The skin nodule containing the adult worms should be surgically removed.
nematodes, which can be found in the conjunctival epithelium, corneal Oral ivermectin kills microfilariae but not adult worms. A 6-week course
stroma, iris, ciliary body, sclera, extraocular muscles, and optic nerve of doxycycline 100–200 mg/day is used to clear Wolbachia endosymbionts
sheath. The severity of ocular findings depends on the strain of microfilar- and results in long-term sterilization of adult worms.38 Ivermectin has
iae; strains from the savanna regions of West Africa induce a more severe been shown to reverse even advanced sclerosing keratitis and iridocycli-
inflammatory response and sclerosing keratitis, which is typically absent tis, but treatment is not effective for chorioretinal lesions, which progress
in infections caused by the rain forest strain.34,35 despite treatment.39 Iridocyclitis should be treated with corticosteroids and
cycloplegia. From a public health perspective, the mainstay of treatment
is oral ivermectin given as a single dose (150 µg/kg) repeated annually or
Clinical Features biannually. Mass drug administrations are delivered to entire communities
Early infection with the Onchocerca worm is marked by a diffuse papular in endemic areas.
dermatitis, accompanied by intense pruritus.32 Other cutaneous findings
can range from lichenification to asymptomatic depigmentation to sub- Outcome
dermal nodules. Onchocerciasis can involve virtually all ocular tissues. Lid
nodules and edema, chronic conjunctivitis with injection, chemosis, and Although anterior segment inflammation and lesions respond well to treat-
phlyctenule-like conjunctival masses can develop. Corneal involvement ment, severe visual impairment can result from chorioretinitis, which, in
is marked by a fine interpalpebral epithelial punctate keratitis that over- advanced cases, often continues to progress in spite of treatment. Health
lies white subepithelial flake-like opacities and discrete nummular scars, programs are aimed at blindness prevention through mass treatment, pre-
and stromal edema caused by an intrastromal worm. These worms can vention, and vector control. Evidence exists that prolonged repeated mass
be visualized at the slit lamp on retroillumination at all corneal levels ivermectin distributions can disrupt transmission of O. volvulus, suggest-
as S- or C-shaped fine, motile filaments. Sclerosing keratitis represents ing that elimination of disease may eventually be possible.40
more severe, blinding corneal disease. It tends to appear as an anterior
stromal haze centered at the 3 and 9 o’clock positions separated from the
limbus by a clear zone. Both infiltration and neovascularization are pro-
KEY REFERENCES
gressive and can encroach on the visual axis as the entire cornea becomes Bacon AS, Frazer DG, Dart JK, et al. A review of 72 consecutive cases of Acanthamoeba
keratitis, 1984–1992. Eye (Lond) 1993;7:719–25.
involved. Calcific band keratopathy and uveitis can develop, as well Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis and treatment update
as scleritis. 2009. Am J Ophthalmol 2009;148:487–99.e2.
Microfilariae might be observed in the anterior chamber, especially Hall LR, Pearlman E. Pathogenesis of onchocercal keratitis (river blindness). Clin Microbiol
in the inferior angle on gonioscopy, or on the anterior lens capsule. In Rev 1999;12:445–53.
Kitzmann AS, Goins KM, Sutphin JE, et al. Keratoplasty for treatment of Acanthamoeba
some cases, the accompanying uveitis can be severe, leading to corectopia, keratitis. Ophthalmology 2009;116:864–9.
synechiae, occluded pupil, and secondary glaucoma. Chorioretinal lesions Loh RS, Chan CM, Ti SE, et al. Emerging prevalence of microsporidial keratitis in Singapore:
appear as asymmetrical lesions peripheral to the macula or around the epidemiology, clinical features, and management. Ophthalmology 2009;116:2348–53.
optic nerve. Peripapillary chorioretinitis with optic nerve edema can result Mabey D, Whitworth JA, Eckstein M, et al. The effects of multiple doses of ivermectin on
in optic atrophy, another significant cause of visual impairment. ocular onchocerciasis. A six-year follow-up. Ophthalmology 1996;103:1001–8.
Sharma S, Das S, Joseph J, et al. Microsporidial keratitis: need for increased awareness. Surv
Diagnosis Tu EY, Joslin CE, Sugar J, et al. Prognostic factors affecting visual outcome in Acanthamoeba
keratitis. Ophthalmology 2008;115:1998–2003.
Diagnosis is based on observation and identification of the worm. It can be Tu EY, Joslin CE, Sugar J, et al. The relative value of confocal microscopy and superficial
corneal scrapings in the diagnosis of Acanthamoeba keratitis. Cornea 2008;27:764–72.
recovered from skin from an excised nodule or from a bloodless skin snip Udall DN. Recent updates on onchocerciasis: diagnosis and treatment. Clin Infect Dis
from the scapula, iliac crest, or lower calf. The worm count in skin snips 2007;44:53–60.
is correlated with the intensity of infection. Serological tests are available,
although some have difficulty discriminating O. volvulus from other filarial Access the complete reference list online at ExpertConsult.com
infections.36
233
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REFERENCES 22. Sharma S, Das S, Joseph J, et al. Microsporidial keratitis: need for increased awareness.
Surv Ophthalmol 2011;56(1):1–22.
1. Booton GC, Joslin CE, Shoff M, et al. Genotypic identification of Acanthamoeba sp. iso-
lates associated with an outbreak of acanthamoeba keratitis. Cornea 2009;28(6):673–6.
23. Reddy AK, Balne PK, Garg P, et al. Is microsporidial keratitis a seasonal infection in
India? Clin Microbiol Infect 2011;17(7):1114–16.
4.14
2. Joslin CE, Tu EY, Shoff ME, et al. The association of contact lens solution use and Acan- 24. Loh RS, Chan CM, Ti SE, et al. Emerging prevalence of microsporidial kerati-
tis in Singapore: epidemiology, clinical features, and management. Ophthalmology
Parasitic Keratitis
thamoeba keratitis. Am J Ophthalmol 2007;144(2):169–80.
3. Tu EY, Joslin CE, Sugar J, et al. Prognostic factors affecting visual outcome in Acan- 2009;116(12):2348–53.
thamoeba keratitis. Ophthalmology 2008;115(11):1998–2003. 25. Chan CM, Theng JT, Li L, et al. Microsporidial keratoconjunctivitis in healthy individu-
4. Bharathi MJ, Ramakrishnan R, Meenakshi R, et al. Microbial keratitis in South India: als: a case series. Ophthalmology 2003;110(7):1420–5.
influence of risk factors, climate, and geographical variation. Ophthalmic Epidemiol 26. Joseph J, Murthy S, Garg P, et al. Use of different stains for microscopic evalua-
2007;14(2):61–9. tion of corneal scrapings for diagnosis of microsporidial keratitis. J Clin Microbiol
5. Bacon AS, Frazer DG, Dart JK, et al. A review of 72 consecutive cases of Acanthamoeba 2006;44(2):583–5.
keratitis, 1984–1992. Eye (Lond) 1993;7(Pt 6):719–25. 27. Joseph J, Sharma S, Murthy SI, et al. Microsporidial keratitis in India: 16S rRNA gene-
6. Iovieno A, Gore DM, Carnt N, et al. Acanthamoeba sclerokeratitis: epidemiology, clinical based PCR assay for diagnosis and species identification of microsporidia in clinical
features, and treatment outcomes. Ophthalmology 2014;121(12):2340–7. samples. Invest Ophthalmol Vis Sci 2006;47(10):4468–73.
7. Bharathi MJ, Ramakrishnan R, Meenakshi R, et al. Microbiological diagnosis of infective 28. Sagoo MS, Mehta JS, Hau S, et al. Microsporidium stromal keratitis: in vivo confocal
keratitis: comparative evaluation of direct microscopy and culture results. Br J Ophthal- findings. Cornea 2007;26(7):870–3.
mol 2006;90(10):1271–6. 29. Gritz DC, Holsclaw DS, Neger RE, et al. Ocular and sinus microsporidial infection cured
8. Thompson PP, Kowalski RP, Shanks RM, et al. Validation of real-time PCR for labora- with systemic albendazole. Am J Ophthalmol 1997;124(2):241–3.
tory diagnosis of Acanthamoeba keratitis. J Clin Microbiol 2008;46(10):3232–6. 30. Das S, Sahu SK, Sharma S, et al. Clinical trial of 0.02% polyhexamethylene biguanide
9. Tu EY, Joslin CE, Sugar J, et al. The relative value of confocal microscopy and superficial versus placebo in the treatment of microsporidial keratoconjunctivitis. Am J Ophthalmol
corneal scrapings in the diagnosis of Acanthamoeba keratitis. Cornea 2008;27(7):764–72. 2010;150(1):110–15.e2.
10. Chidambaram JD, Prajna NV, Larke NL, et al. Prospective study of the diagnostic accu- 31. Das S, Sharma S, Sahu SK, et al. Intraocular invasion by microsporidial spores in a case
racy of the in vivo laser scanning confocal microscope for severe microbial keratitis. Oph- of stromal keratitis. Arch Ophthalmol 2011;129(4):513–15.
thalmology 2016;123(11):2285–93. 32. Udall DN. Recent updates on onchocerciasis: diagnosis and treatment. Clin Infect Dis
11. Yang YF, Matheson M, Dart JK, et al. Persistence of acanthamoeba antigen following 2007;44(1):53–60.
acanthamoeba keratitis. Br J Ophthalmol 2001;85(3):277–80. 33. Tamarozzi F, Halliday A, Gentil K, et al. Onchocerciasis: the role of Wolbachia bacterial
12. Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis and treatment update endosymbionts in parasite biology, disease pathogenesis, and treatment. Clin Microbiol
2009. Am J Ophthalmol 2009;148(4):487–99.e2. Rev 2011;24(3):459–68.
13. Elder MJ, Kilvington S, Dart JK. A clinicopathologic study of in vitro sensitivity testing 34. Dadzie KY, Remme J, Baker RH, et al. Ocular onchocerciasis and intensity of infection in
and Acanthamoeba keratitis. Invest Ophthalmol Vis Sci 1994;35(3):1059–64. the community. III. West African rainforest foci of the vector Simulium sanctipauli. Trop
14. Lim N, Goh D, Bunce C, et al. Comparison of polyhexamethylene biguanide and chlor- Med Parasitol 1990;41(4):376–82.
hexidine as monotherapy agents in the treatment of Acanthamoeba keratitis. Am J Oph- 35. Dadzie KY, Remme J, Rolland A, et al. Ocular onchocerciasis and intensity of infection
thalmol 2008;145(1):130–5. in the community. II. West African rainforest foci of the vector Simulium yahense. Trop
15. McClellan K, Howard K, Niederkorn JY, et al. Effect of steroids on Acanthamoeba cysts Med Parasitol 1989;40(3):348–54.
and trophozoites. Invest Ophthalmol Vis Sci 2001;42(12):2885–93. 36. Burbelo PD, Leahy HP, Iadarola MJ, et al. A four-antigen mixture for rapid assessment
16. Robaei D, Carnt N, Minassian DC, et al. The impact of topical corticosteroid use before of Onchocerca volvulus infection. PLoS Negl Trop Dis 2009;3(5):e438.
diagnosis on the outcome of Acanthamoeba keratitis. Ophthalmology 2014;121(7):1383–8. 37. Hall LR, Pearlman E. Pathogenesis of onchocercal keratitis (river blindness). Clin Micro-
17. Carnt N, Robaei D, Watson SL, et al. The impact of topical corticosteroids used in con- biol Rev 1999;12(3):445–53.
junction with antiamoebic therapy on the outcome of Acanthamoeba keratitis. Ophthal- 38. Hoerauf A, Specht S, Buttner M, et al. Wolbachia endobacteria depletion by doxycycline
mology 2016;123(5):984–90. as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized place-
18. Kitzmann AS, Goins KM, Sutphin JE, et al. Keratoplasty for treatment of Acanthamoeba bo-controlled study. Med Microbiol Immunol 2008;197(3):335.
keratitis. Ophthalmology 2009;116(5):864–9. 39. Mabey D, Whitworth JA, Eckstein M, et al. The effects of multiple doses of ivermectin on
19. Nguyen TH, Weisenthal RW, Florakis GJ, et al. Penetrating keratoplasty in active Acan- ocular onchocerciasis. A six-year follow-up. Ophthalmology 1996;103(7):1001–8.
thamoeba keratitis. Cornea 2010;29(9):1000–4. 40. Diawara L, Traore MO, Badji A, et al. Feasibility of onchocerciasis elimination with
20. Herz NL, Matoba AY, Wilhelmus KR. Rapidly progressive cataract and iris atrophy during ivermectin treatment in endemic foci in Africa: first evidence from studies in Mali and
treatment of Acanthamoeba keratitis. Ophthalmology 2008;115(5):866–9. Senegal. PLoS Negl Trop Dis 2009;3(7):e497.
21. Robaei D, Carnt N, Minassian DC, et al. Therapeutic and optical keratoplasty in the man-
agement of Acanthamoeba keratitis: risk factors, outcomes, and summary of the litera-
ture. Ophthalmology 2015;122(1):17–24.
233.e1
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Herpes Simplex Keratitis

Sonal S. Tuli, Matthew J. Gray 4.15
or aerosolization. The virus enters epithelial cells on contact, replicates,
Definition: Herpes simplex viral infection of the cornea. enters the sensory nerve endings, and travels in a retrograde fashion to
the trigeminal ganglion, where it remains latent (Fig. 4.15.2). The cornea
also may be a site of HSV latency and replication.9–13 After an initial round
Key Features of replication in the trigeminal ganglion, the virus travels back down the
• Dendritic ulcer: classic feature of epithelial disease. nerve in an antegrade fashion, causing primary infection in about 6% of
• Focal endotheliitis (disciform keratitis): classic feature of stromal patients. It then remains latent until certain triggers cause it to reactivate,
disease. replicate, and travel back down the nerve to cause recurrent infection. It is
not clear if the initial infection occurs by direct contact of ocular tissues
with infected secretions, or if the initial infection occurs in the orolabial
area with the virus then spreading to the neurons supplying the eye in the
Associated Features trigeminal ganglion (back-door spread).12
• Decreased corneal sensation.
• Underlying granulomatous keratic precipitates. PRIMARY HSV INFECTION
Primary HSV ocular infection most commonly manifests as blepharocon-
EPIDEMIOLOGY junctivitis (often with conjunctival ulceration) that heals without scarring
(Fig. 4.15.3). The associated follicular conjunctivitis is often mistaken for
Human herpesviruses (Table 4.15.1) have in common a state called adenoviral conjunctivitis (Fig. 4.15.4); up to a third of unilateral follicular
“latency,” where the virus remains dormant in cells and periodically reacti- conjunctivitis may be culture-positive for HSV.14–16 Other features include
vates. Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) have an affinity lid vesicles and conjunctival dendrites. Keratitis is rare, occurring in only
for the sensory ganglion cells and, therefore, are called neurotrophic viruses. 3%–5% of cases, although severe bilateral disease can occur in atopic or
These viruses are ubiquitous, and in most parts of the world, exposure to immunocompromised patients.5,17–19
HSV-1 is almost universal by late adulthood.1,2 HSV keratitis (HSVK) is
the most common cause of corneal blindness in developed nations.3 In RECURRENT HSV INFECTIONS
the United States, the incidence of new cases of HSVK is estimated at
24 000 per year, and the total number of episodes at 58 000 per year with a Multiple factors are thought to trigger recurrence, including fever, menses,
prevalence over 400 000.4,5 HSV-1 infections more commonly occur in the sunlight, irradiation, and emotional stress. Anecdotal reports have also
orolabial area and HSV-2 in the genital area.6 implicated prostaglandin analogues, immunosuppression, and refractive
surgery. Recurrent disease, estimated to occur in 27% of patients at 1 year
HERPES SIMPLEX VIRUS and over 60% at 20 years, commonly causes keratitis (HSVK), although it
can affect all parts of the eye.5 The risk of a subsequent recurrent infection
HSV, a large double-stranded DNA virus, has an icosahedral capsid sur- increases with the number of recurrences to 83% at 20 years after one or
rounded by a poorly defined tegument enclosed in a host cell membrane- more recurrences.5
derived envelope with viral-derived glycoprotein projections (Fig. 4.15.1). HSVK is broadly classified into epithelial and stromal/endothelial ker-
Newly formed virions, which replicate in the cell nucleus, egress by atitis. This classification not only is anatomical but also is important for
budding from the cell membrane, destroying the cell in the process. understanding the pathophysiology of HSVK and for planning treatment.
Recurrent infections progressively destroy sensory ganglion cells, dimin-
ishing corneal sensation, one of the hallmarks of HSVK.
Serum antibody production to HSV infections is inconsistent and only HSV STRUCTURE
partially protective. The major immune response to HSV is T lymphocyte
mediated.7,8
viral surface
glycoproteins
Life Cycle of HSV
Initial HSV infection is usually asymptomatic and occurs by direct contact envelope and
of mucous membranes with infected secretions rather than by fomites tegument
virion
TABLE 4.15.1 Human Herpesviruses of Medical Importance
Abbreviation Nomenclature Disease Caused icosadeltahedral
HSV-1 Herpes simplex type-1 Oral, ocular, genital herpes, whitlow caspid
HSV-2 Herpes simplex type-2 Genital, oral, ocular herpes, whitlow
VZV Varicella zoster virus Chickenpox, herpes zoster (shingles)
CMV Cytomegalovirus Retinitis, range of systemic diseases
viral DNA
EBV Epstein–Barr virus Infectious mononucleosis
HHV-6 Human herpesvirus-6 Exanthem subitum (roseola)
HHV-7 Human herpesvirus-7 Exanthem subitum (roseola)
234 KSRV Kaposi’s sarcoma–related virus Kaposi’s sarcoma Fig. 4.15.1 Herpes simplex virus (HSV) structure.
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Fig. 4.15.2 Life cycle of herpes simplex virus (HSV).
LIFE CYCLE OF HSV
4.15

initial recurrent
infection infection
? corneal
latency
? ?
retrograde antegrade
active
replication
TG
latency in
ganglion
Fig. 4.15.4 Follicular conjunctivitis.
Fig. 4.15.3 Blepharoconjunctivitis.

corneal hypoesthesia.20 However, the associated inflammation may cause
Epithelial Keratitis significant photophobia. It includes the conditions discussed below.
Caused by actively replicating virus on the corneal surface, this usually Dendritic Ulcer
starts as epithelial vesicles, punctate keratitis, or opaque plaques that This classic herpetic lesion consists of a linear, dichotomously branching
coalesce and break down centrally. Initial episodes present with foreign lesion with terminal bulbs (Fig. 4.15.5). The borders consist of acantholytic, 235
body sensation, but subsequent episodes usually are painless because of infected cells and are slightly raised, grayish, and stain with Rose Bengal
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4
Fig. 4.15.5 Dendrite. Fig. 4.15.7 Disciform keratitis.
while fluorescein leaks between these poorly adherent cells into the stroma
GEOGRAPHICAL VERSUS METAHERPETIC ULCER and stains the periphery—so-called “reverse staining” (see Fig. 4.15.6).
Stromal/Endothelial Keratitis
Usually an immune-mediated response to nonreplicating viral particles,
stromal keratitis can affect all layers of the cornea and may even involve
the trabecular meshwork and iris. It is classified based on the predominant
site and type of involvement.
Endotheliitis
This is the most common form, and it manifests as overlying stromal
edema from endothelial dysfunction. Long-standing stromal edema leads
to permanent scarring and decreased vision.
Localized Endotheliitis
Fig. 4.15.6 Geographical Versus Metaherpetic Ulcer. Geographical ulcer (left): This appears as a disc-shaped area of corneal edema called disciform kera-
large fluorescein-staining epithelial defect with peripheral dichotomous branching
titis (Fig. 4.15.7). Minimal stromal inflammation occurs without epithelial
and terminal bulbs that stain with Rose Bengal metaherpetic ulcer (right): Rose
Bengal staining of unhealthy epithelial cells across ulcer base and fluorescein
involvement, although microcystic edema and bullae may develop later
leakage into stroma and periphery (reverse staining). Note heaped up epithelial cells in some cases. Focal keratic precipitates underlying the edema are highly
at ulcer edge. suggestive but may be difficult to visualize. Sharp demarcation between
involved and uninvolved stroma distinguishes this from other causes of
stromal edema.
stain. The central epithelial defect stains with fluorescein. The underlying
stroma may have minimal inflammation. On resolution, a dendrite-shaped Diffuse and Linear Endotheliitis
scar, called ghost dendrite, may remain in the superficial stroma. These are rare and usually accompanied by trabeculitis and elevated intra-
ocular pressure. Pseudo-guttae and Descemet’s folds may cause confusion
Geographical Ulcer with Fuchs’ dystrophy. Linear keratic precipitates can resemble allograft
Patients who are immunocompromised, on topical corticosteroids, or have rejection.
long-standing, untreated ulcers can develop very large epithelial defects.21
However, dichotomous branching and terminal bulbs are often seen at the Necrotizing Keratitis
periphery and the staining is similar to dendritic keratitis. The significantly greater inflammation is thought to be a reaction to live
viral particles in the corneal stroma (Fig. 4.15.8). It is most commonly seen
Marginal Keratitis in patients with multiple recurrences, especially with HSV-2. Difficult to
These lesions located near the limbus can resemble staphylococcal distinguish from other causes of microbial keratitis without a high index
catarrhal ulcers. An epithelial defect and lack of corneal sensation can aid of suspicion, it may cause corneal melting and perforation. Frequently,
in diagnosis. Significant stromal inflammation can occur because of the it is associated with uveitis and trabeculitis that may lead to recalcitrant
proximity to limbal blood vessels. More resistant to treatment, they fre- glaucoma.
quently become trophic ulcers.22
Immune Stromal Keratitis
Metaherpetic (Trophic) Ulcer This manifests as focal, multifocal, or diffuse stromal opacities or an
This is not associated with live virus and results from inability of the immune ring (Fig. 4.15.9). It often is accompanied by stromal edema and
epithelium to heal (Fig. 4.15.6). It is called a trophic ulcer if it arises de a mild anterior chamber reaction. The epithelium and endothelium are
novo or a metaherpetic ulcer if it follows a dendrite or geographical ulcer, relatively spared. It also is called interstitial keratitis (IK) and can lead to
although the terms are used interchangeably. The causes are multifacto- deep stromal vascularization. HSV is now the most common cause of IK,
rial and include toxicity from antiviral medications, unrecognized trauma, especially unilateral, in the United States.13 Unlike syphilitic IK, HSV neo-
lack of neural-derived growth factors, poor tear surfacing, and underlying, vascularization is usually unilateral, sectoral, at multiple levels within the
low-grade stromal inflammation. Neurotrophic ulcers start as roughened stroma, and leads up to a stromal scar.
epithelium that breaks down to produce an epithelial defect with smooth
margins. The borders are grayish, elevated, and consist of multiple layers Lipid Keratopathy
236 of epithelium. In contrast to geographical ulcers, Rose Bengal stains the Newly formed or inflamed vessels are permeable to lipid because of the
unhealthy epithelial cells attempting to migrate across the base of the ulcer action of vascular endothelial growth factor. Once exuded, the lipid collects
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4.15

Fig. 4.15.10 Keratouveitis.
Fig. 4.15.8 Necrotizing keratitis. Culture

Corneal swabs placed in viral or chlamydia transport media are transported
at 4°C. Cultures following Rose Bengal corneal staining may be falsely neg-
ative as Rose Bengal is virucidal with exposure to light.27 Unfortunately,
intracellular HSV is unaffected, and Rose Bengal cannot be used in vivo.28
DNA Testing
PCR is very rapid and extremely sensitive and specific. Strains also can
be identified for epidemiological purposes. This is rapidly becoming the
testing of choice for viral diseases.
Fluorescent Antibody Testing

A nitrocellulose membrane or corneal swab smeared on a slide may be
used. This gives rapid results, but sensitivity and specificity are lower than
those of culture. Fluorescein staining interferes with this test.29
Tzanck’s Smear
Papanicolaou or Giemsa stains of corneal smears show multinucleated
giant cells and intranuclear eosinophilic inclusion bodies (Cowdry type A).
Although low in sensitivity and specificity, this rapid and cheap test can be
done in most laboratories.
Serum Antibody Testing

Fig. 4.15.9 Interstitial keratitis with lipid keratopathy. Immunoglobulin M (IgM) or rising titers of IgG may be present in chil-
dren but most adults have IgG to HSV, limiting its use in diagnosis.1
within keratocytes and intercellular matrix and is the major cause of vision
loss requiring corneal transplantation in patients with HSV.
HERPETIC EYE DISEASE STUDY
Prior to the Herpetic Eye Disease Study (HEDS), the standard therapy
Keratouveitis for all forms of HSVK was with topical antivirals. The HEDS was under-
Uveitis is usually granulomatous with large “mutton fat” keratic precipi- taken to assess the effect of adding corticosteroids and acyclovir to conven-
tates on the endothelium (Fig. 4.15.10). Although often immune mediated, tional therapy with trifluridine (TFT). It was a prospective, randomized,
sectoral iritis with a plasmoid aqueous is caused by release of live virus double-masked, placebo-controlled, multicenter study divided into six
from the sympathetic nerves.23 It can lead to significant morbidity from trials: three therapeutic, two preventive, and one cohort.
synechiae, iris atrophy, cataracts, and glaucoma. Unilateral uveitis with 1. Herpes Stromal Keratitis, Not on Corticosteroid Trial: Compared with
high intraocular pressure often is caused by HSV. the placebo group, patients receiving prednisolone phosphate drops had
faster resolution and fewer treatment failures. However, delaying corti-
Miscellaneous Syndromes costeroid treatment did not affect the eventual visual outcome.30
Herpes has been implicated in various chronic, unilateral diseases of the 2. Herpes Stromal Keratitis, on Corticosteroid Treatment: There was no
iris and trabecular meshwork. HSV DNA has been isolated by polymerase apparent benefit in adding oral acyclovir to topical corticosteroids and
chain reaction (PCR) from the endothelium of corneas with iridocorneal TFT. However, visual acuity improved over 6 months in more patients
endothelial (ICE) syndrome and from the aqueous humor of patients with on acyclovir.31
Posner–Schlossman syndrome and Fuchs’ heterochromic iridocyclitis.24–26 3. Herpes Simplex Virus Iridocyclitis, Receiving Topical Corticosteroids:
More treatment failures occurred in the placebo group than in the acy-
DIAGNOSIS clovir group, indicating a potential benefit to adding oral acyclovir to
topical corticosteroids and antivirals.32
Diagnostic testing is seldom needed in epithelial HSVK because of its A meta-analysis of these three trials evaluated the risk of subsequent
classic clinical features and is not useful in stromal keratitis as live virus epithelial keratitis in patients with stromal keratouveitis. Although the 237
rarely is present. risk was higher in the corticosteroid-alone group, it was not statistically
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4
TABLE 4.15.2 Current Antivirals
Drug (Trade Name) Route Dose Frequency Adverse Effects
Trifluridine (Viroptic) Topical drops 1.00% Every 2 hours Follicular conjunctivitis, epitheliopathy
Vidarabine (Ara-A)(compounded) Topical ointment 3.00% Five times a day As above

Ganciclovir (Zirgan) Topical gel 0.15% Five times a day Stinging, burning, blurring of vision
Acyclovir (Zovirax) Topical ointment 3.00% Five times a day Headache, nausea, nephrotoxicity, neurotoxicity
Oral – treatment 400 mg Five times a day
Oral –prophylaxis 400 mg Twice a day
Valacyclovir (Valtrex) Oral –treatment 500 mg Three times a day As above, thrombotic thrombocytopenic purpura and
Oral –prophylaxis 500 mg Once a day hemolytic uremic syndrome in immunosuppressed
Famciclovir (Famvir) Oral –treatment 250 mg Three times a day As acyclovir
Oral –prophylaxis 250 mg Once a day
significant. The risk was also higher in patients with a previous history Metaherpetic Keratitis
of epithelial keratitis and in nonwhite patients.33
4. Herpes Simplex Virus Epithelial Keratitis Trial: In the treatment of The basic principle is surface support including elimination of toxic med-
acute HSV epithelial keratitis with TFT, the addition of oral acyclovir ications, punctal occlusion, artificial tear supplements, bandage contact
offered no additional benefit in preventing subsequent stromal keratitis lenses, autologous serum tears, and amniotic membrane grafts.41 The cau-
or iritis.34 tious use of topical corticosteroids may be necessary if there is significant
5. Acyclovir Prevention Trial: Oral acyclovir reduced the risk of any form underlying inflammation.
of recurrent ocular herpes by 41% and stromal keratitis by 50%. The
risk of multiple recurrences decreased from 9% to 4%. However, the Medications
protection did not persist once acyclovir was discontinued.35
6. Ocular HSV Recurrence Factor Study: No association was found Antivirals
between psychological or other forms of stress and HSV recurrences.36 All current antivirals are nucleoside analogs that competitively inhibit viral
Previous episodes of epithelial keratitis were not a predictor for future DNA polymerase (Table 4.15.2). They also may interfere with host DNA
occurrences, whereas previous, especially multiple, episodes of stromal synthesis and cause significant toxicity. Acyclovir and ganciclovir are the
keratitis markedly increased the probability of subsequent stromal most specific for viral polymerase and thymidine kinase and, therefore, are
keratitis.37 the least toxic. Acyclovir resistant HSV-1 has been reported and requires
monitoring for cases of HSVK refractory to this treatment.42–44
This study had some limitations:
1. Many of the trials had inadequate recruitment or high dropout rate. Corticosteroids
2. Oral acyclovir in the prevention trials was only used for 3 weeks. Typically, either 1% prednisolone acetate or 0.1% dexamethasone are used.
3. The corticosteroid regimen was standardized and not tailored to The frequency should be based on the severity of inflammation and taper-
inflammation. ing must be very gradual to prevent rebound inflammation.
4. TFT was used in both the study and placebo groups in all the therapeu-
tic trials. Surgery
Surgery is usually performed when corneal scarring limits vision. However,
TREATMENT surgery also may be necessary as a therapeutic measure in patients with
nonhealing ulcers or impending perforations from necrotizing keratitis.
Treatment of HSV is diametrically different for epithelial and stromal ker-
atitis, reflecting the fact that epithelial disease is caused by live replicating Penetrating Keratoplasty
virus, whereas stromal disease is essentially an immune response to viral When penetrating keratoplasty is considered, it is preferable to wait at
antigen. Prompt and appropriate treatment may minimize the risk of scar- least 6 months after an episode of HSVK before attempting corneal trans-
ring, the major cause of morbidity from HSVK. plantation because the success rate increases in a quiescent eye.45 Unfor-
tunately, the results of corneal transplantation for HSVK are uniformly
Infectious Epithelial Keratitis poor. Reactivation and rejection occur in 44% and 46%, respectively, by 2
years.45 Prophylactic acyclovir started prior to surgery and continued for at
Although epithelial keratitis spontaneously resolves in approximately 50% least 6 months to 2 years decreases the risk of HSVK recurrence and graft
of cases, treatment is advised for ulcers larger than 4 mm, marginal ulcers, failure. 46,47 Lifelong oral prophylactic antivirals may be considered because
and ulcers with underlying stromal inflammation. Topical antivirals, the the HEDS found that the risk of recurrence increases to baseline on stop-
mainstay of treatment, are very effective and have a low incidence of resis- ping antiviral prophylaxis. Lamellar grafts are not recommended because
tance. Both topical trifluridine and ganciclovir have proven to be successful recurrence occurs at the interface.
in the treatment of epithelial keratitis and are commercially available in
the United States. 38,39 Gentle wiping debridement is a very good adjunct Conjunctival Flap
therapy as infected cells are poorly adherent. This results in much faster This may be useful in patients with medical contraindications for surgery
resolution, less inflammation, and consequently less scarring.40 Off-label or chronically inflamed keratitis. Ambulatory vision may be possible
use of oral antivirals also appears to be a safe and effective alternative to through the flap.
topical therapy.
Amniotic Membrane Transplantation
Amniotic membrane transplantation aids the healing of neurotrophic
Stromal Keratouveitis ulcers in HSVK, presumably by decreasing inflammatory cell and matrix
The mainstay of treatment is topical corticosteroids because they decrease metalloproteinase levels in the cornea.48
inflammation and, thus, scarring. Simultaneous antiviral prophylaxis is
recommended because evidence suggests that HSV reactivation while on
corticosteroids results in severe epithelial disease or necrotizing keratitis.
FUTURE DIRECTIONS
Oral antivirals are preferred because they decrease the risk of HSV reac- Heat shock and glycoprotein subunit vaccines have shown some promise
tivation at the ganglion level and do not have the corneal toxicity asso- in clinical trials in decreasing the number and severity of recurrences.49
ciated with topical antivirals. Aggressive topical and systemic antivirals Immunomodulatory factors, such as cytokines may serve as adjuncts to
238 along with corticosteroids are necessary in necrotizing keratitis and focal corticosteroid therapy by skewing the immune response toward milder
serous iritis. disease.50 Newer antivirals such as cidofovir may be more effective and
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cause less toxicity compared with current therapy.51,52 Interferon, although Herpetic Eye Disease Study Group. Psychological stress and other potential triggers for
recurrences of herpes simplex virus eye infections. Arch Ophthalmol 2000;118:1617–25.
ineffective as monotherapy, increases the efficacy of antivirals, and other
agents, such as nerve growth factor and apolipoprotein E mimetic peptide,
van Rooij J, Rijneveld WJ, Remeijer L, et al. Effect of oral acyclovir after penetrating ker-
atoplasty for herpetic keratitis: a placebo-controlled multicenter trial. Ophthalmology
4.15
have shown a benefit in animal models of HSVK.40,51–54 Gene therapy may 2003;110:1916–19.
prove to be useful in the future—ribozymes and small interfering RNAs Wilhelmus KR, Coster DJ, Donovan HC, et al. Prognosis indicators of herpetic keratitis.

have shown promise in cell culture experiments, but their instability in Analysis of a five-year observation period after corneal ulceration. Arch Ophthalmol
1981;99:1578–82.
vivo has been a barrier to clinical use.55 Wilhelmus KR, Dawson CR, Barron BA, et al. Risk factors for herpes simplex virus epithelial
keratitis recurring during treatment of stromal keratitis or iridocyclitis. Herpetic Eye
KEY REFERENCES Disease Study Group. Br J Ophthalmol 1996;80:969–72.
Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled
Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of oral trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology
acyclovir for herpes simplex stromal keratitis. Ophthalmology 1994;101:1871–82. 1994;101:1883–95.
Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel (Virgan; 0.15%) in the treatment Young RC, Hodge DO, Liesegang TH, et al. Incidence, recurrence, and outcomes of herpes
of herpes simplex keratitis. Cornea 1997;16:393–9. simplex virus eye disease in Olmsted County, Minnesota, 1976–2007: the effect of oral
Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for iridocyclitis caused antiviral prophylaxis. Arch Ophthalmol 2010;128:1178–83.
by herpes simplex virus. Arch Ophthalmol 1996;114:1065–72.
Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for the prevention of
stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. The
Epithelial Keratitis Trial. Arch Ophthalmol 1997;115:703–12.
Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus eye disease:
effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol
2000;118:1030–6.
239
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REFERENCES 29. Subhan S, Jose RJ, Duggirala A, et al. Diagnosis of herpes simplex virus-1 keratitis:
comparison of Giemsa stain, immunofluorescence assay and polymerase chain reaction.
1. Cowan FM, French RS, Mayaud P, et al. Seroepidemiological study of herpes simplex
virus types 1 and 2 in Brazil, Estonia, India, Morocco, and Sri Lanka. Sex Transm Infect
Curr Eye Res 2004;29:209–13.
30. Wilhelmus KR, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled
4.15
2003;79:286–90. trial of topical corticosteroids for herpes simplex stromal keratitis. Ophthalmology
1994;101:1883–95.

2. Liedtke W, Opalka B, Zimmermann CW, et al. Age distribution of latent herpes simplex
virus 1 and varicella-zoster virus genome in human nervous tissue. J Neurol Sci 31. Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of
1993;116:6–11. oral acyclovir for herpes simplex stromal keratitis. Ophthalmology 1994;101:1871–82.
3. NEI. Facts About the Cornea and Corneal Disease. http://www.nei.nih.gov/health/ 32. Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for iridocyclitis
cornealdisease/. caused by herpes simplex virus. Arch Ophthalmol 1996;114:1065–72.
4. Liesegang TJ, Melton III LJ, Daly PJ, et al. Epidemiology of ocular herpes simplex. Inci- 33. Wilhelmus KR, Dawson CR, Barron BA, et al. Risk factors for herpes simplex virus epi-
dence in Rochester, Minn, 1950 through 1982. Arch Ophthalmol 1989;107:1155–9. thelial keratitis recurring during treatment of stromal keratitis or iridocyclitis. Herpetic
5. Young RC, Hodge DO, Liesegang TH, et al. Incidence, recurrence, and outcomes of Eye Disease Study Group. Br J Ophthalmol 1996;80:969–72.
herpes simplex virus eye disease in Olmsted County, Minnesota, 1976–2007: the effect of 34. Herpetic Eye Disease Study Group. A controlled trial of oral acyclovir for the prevention
oral antiviral prophylaxis. Arch Ophthalmol 2010;128:1178–83. of stromal keratitis or iritis in patients with herpes simplex virus epithelial keratitis. The
6. Tran T, Druce JD, Catton MC, et al. Changing epidemiology of genital herpes simplex Epithelial Keratitis Trial. Arch Ophthalmol 1997;115:703–12.
virus infection in Melbourne, Australia, between 1980 and 2003. Sex Transm Infect 35. Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus eye disease:
2004;80:277–9. effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol
7. Stuart PM, Summers B, Morris JE, et al. CD8(+) T cells control corneal disease following 2000;118:1030–6.
ocular infection with herpes simplex virus type 1. J Gen Virol 2004;85:2055–63. 36. Herpetic Eye Disease Study Group. Psychological stress and other potential triggers for
8. Banerjee K, Biswas PS, Rouse BT. Elucidating the protective and pathologic T cell species recurrences of herpes simplex virus eye infections. Arch Ophthalmol 2000;118:1617–25.
in the virus-induced corneal immunoinflammatory condition herpetic stromal keratitis. 37. Kip KE, Cohen F, Cole SR, et al. Recall bias in a prospective cohort study of acute
J Leukoc Biol 2005;77:24–32. time-varying exposures: example from the herpetic eye disease study. J Clin Epidemiol
9. Kaye SB, Lynas C, Patterson A, et al. Evidence for herpes simplex viral latency in the 2001;54:482–7.
human cornea. Br J Ophthalmol 1991;75:195–200. 38. La Lau C, Oosterhuis JA, Versteeg J, et al. Acyclovir and trifluorothymidine in herpetic
10. Abghari SZ, Stulting RD, Petrash JM. Detection of herpes simplex virus type 1 laten- keratitis: a multicenter trial. Br J Ophthalmol 1982;66:506–8.
cy-associated transcripts in corneal cells of inbred mice by in situ hybridization. Cornea 39. Colin J, Hoh HB, Easty DL, et al. Ganciclovir ophthalmic gel in the treatment of herpes
1992;11:433–8. simplex keratitis. Cornea 1977;16:393–9.
11. Cook SD, Hill JM, Lynas C, et al. Latency-associated transcripts in corneas and ganglia of 40. Wilhelmus KR. The treatment of herpes simplex virus epithelial keratitis. Trans Am
HSV-1 infected rabbits. Br J Ophthalmol 1991;75:644–8. Ophthalmol Soc 2000;98:505–32.
12. Labetoulle M, Maillet S, Efstathiou S, et al. HSV1 latency sites after inoculation in the lip: 41. Jeng BH, Dupps WJ Jr. Autologous serum 50% eyedrops in the treatment of persistent
assessment of their localization and connections to the eye. Invest Ophthalmol Vis Sci corneal epithelial defects. Cornea 2009;28:1104–8.
2003;44:217–25. 42. Carter SB, Cohen EJ. Development of herpes simplex virus infectious epithelial keratitis
13. Faraji LA, Said DG, Al-Aqabal M, et al. Clinical evaluation and characterisation of corneal during oral acyclovir therapy and response to topical antivirals. Cornea 2016;35:692–5.
vascularization. Br J Ophthalmol 2016;100:315–22. 43. Duan R, de Vries RD, Osterhaus AD, et al. Acyclovir-resistant HSV-1 isolates from
14. Darougar S, Hunter PA, Viswalingam M, et al. Acute follicular conjunctivitis and kerato- patients with herpetic keratitis. J Infect Dis 2008;198:659–63.
conjunctivitis due to herpes simplex virus in London. Br J Ophthalmol 1978;62:843–9. 44. Piret J. Boidvin G. Antiviral resistance in herpes simplex virus and varicella-zoster virus
15. Jones B. The management of ocular herpes. Trans Ophthalmol Soc UK 1959;79:425–37. infections: diagnosis and management. Curr Opin Infect Dis 2016;29(6):654–62.
16. Jones BR, Andrews BE, Henderson WG, et al. The pattern of conjunctivitis at Moorfields 45. Lomholt JA, Baggesen K, Ehlers N. Recurrence and rejection rates following corneal
during 1956. Trans Opthalmol Soc UK 1957;77:291–302. transplantation for herpes simplex keratitis. Acta Ophthalmol Scand 1995;73:29–32.
17. Souza PM, Holland EJ, Huang AJ. Bilateral herpetic keratoconjunctivitis. Ophthalmology 46. van Rooij J, Rijneveld WJ, Remeijer L, et al. Effect of oral acyclovir after penetrating
2003;110:493–6. keratoplasty for herpetic keratitis: a placebo-controlled multicenter trial. Ophthalmology
18. Margolis TP, Ostler HB. Treatment of ocular disease in eczema herpeticum. Am J Oph- 2003;110:1916–19.
thalmol 1990;110:274–9. 47. Bhatt UK, Abdul Karim MN, Prydal JI, et al. Oral antivirals for preventing recurrent
19. Wilhelmus KR, Falcon MG, Jones BR. Bilateral herpetic keratitis. Br J Ophthalmol herpes simplex keratitis in people with corneal grafts. Cochrane Database Syst Rev
1981;65:385–7. 2016;(11):CD007824.
20. Kodama T, Hayasaka S, Setogawa T. Immunofluorescent staining and corneal sen- 48. Heiligenhaus A, Li HF, Yang Y, et al. Transplantation of amniotic membrane in murine
sitivity in patients suspected of having herpes simplex keratitis. Am J Ophthalmol herpes stromal keratitis modulates matrix metalloproteinases in the cornea. Invest Oph-
1992;113:187–9. thalmol Vis Sci 2005;46:4079–85.
21. Wilhelmus KR, Coster DJ, Donovan HC, et al. Prognosis indicators of herpetic kerati- 49. Stanberry LR. Clinical trials of prophylactic and therapeutic herpes simplex virus vac-
tis. Analysis of a five-year observation period after corneal ulceration. Arch Ophthalmol cines. Herpes 2004;11(Suppl. 3):161A–9A.
1981;99:1578–82. 50. Bauer D, Lu M, Wasmuth S, et al. Immunomodulation by topical particle-mediated
22. Thygeson P. Marginal herpes simplex keratitis simulating marginal catarrhal ulcer. administration of cytokine plasmid DNA suppresses herpetic stromal keratitis without
Invest Ophthalmol 1971;10:1006. impairment of antiviral defense. Graefes Arch Clin Exp Ophthalmol 2006;244:216–25.
23. Sundmacher R, Neumann-Haefelin D. [Herpes simplex virus isolations from the aqueous 51. Romanowski EG, Bartels SP, Gordon YJ. Comparative antiviral efficacies of cidofovir,
humor of patients suffering from focal iritis, endotheliitis, and prolonged disciform kera- trifluridine, and acyclovir in the HSV-1 rabbit keratitis model. Invest Ophthalmol Vis Sci
titis with glaucoma (author’s transl)]. Klin Monatsbl Augenheilkd 1979;175:488–501. 1999;40:378–84.
24. Alvarado JA, Underwood JL, Green WR, et al. Detection of herpes simplex viral DNA in 52. Lambiase A, Coassin M, Costa N, et al. Topical treatment with nerve growth factor in an
the iridocorneal endothelial syndrome. Arch Ophthalmol 1994;112:1601–9. animal model of herpetic keratitis. Graefes Arch Clin Exp Ophthalmol 2008;246:121–7.
25. Yamamoto S, Pavan-Langston D, Tada R, et al. Possible role of herpes simplex virus in 53. Bhattacharjee PS, Neumann DM, Foster TP, et al. Effective treatment of ocular HSK with
the origin of Posner–Schlossman syndrome. Am J Ophthalmol 1995;119:796–8. a human apolipoprotein E mimetic peptide in a mouse eye model. Invest Ophthalmol
26. Barequet IS, Li Q, Wang Y, et al. Herpes simplex virus DNA identification from aqueous Vis Sci 2008;49:4263–8.
fluid in Fuchs heterochromic iridocyclitis. Am J Ophthalmol 2000;129:672–3. 54. Liu J, Lewin AS, Tuli SS, et al. Reduction in severity of a herpes simplex virus type 1
27. Brooks SE, Kaza V, Nakamura T, et al. Photoinactivation of herpes simplex virus by Rose murine infection by treatment with a ribozyme targeting the UL20 gene RNA. J Virol
Bengal and fluorescein. In vitro and in vivo studies. Cornea 1994;13:43–50. 2008;82:7467–74.
28. Stroop WG, Chen TM, Chodosh J, et al. PCR assessment of HSV-1 corneal infection 55. Higaki S, Fukuda M, Shimomura Y. Virological and molecular biological evidence sup-
in animals treated with Rose Bengal and lissamine green B. Invest Ophthalmol Vis Sci porting herpes simplex virus type 1 corneal latency. Jpn J Ophthalmol 2015;59(2):131–4.
2000;41:2096–102.
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Peripheral Ulcerative Keratitis

Sarkis H. Soukiasian 4.16
limbal vessels resulting from the large size of the latter two molecules.
Definition: Destructive inflammation of the peripheral cornea Additionally, the adjacent conjunctival blood vessels and lymphatics not
associated with corneal epithelial sloughing and keratolysis. only provide peripheral corneal access to the afferent and efferent arcs of
the immune system but may be sources of inflammatory effector cells and
cytokines involved in the production of collagenase and proteoglycanase,
Key Features which may contribute to corneal degradation.9,10
• Peripheral corneal ulceration. Although the exact pathophysiological mechanisms of PUK are unclear,
• Unilateral or bilateral. circulating immune complex deposition, autoimmune reactions to corneal
• Progresses circumferentially and posteriorly and may perforate. antigens, and hypersensitivity reactions to exogenous antigens have been
• May be associated with systemic collagen vascular diseases. proposed, with evidence suggesting that both humoral and cell-mediated
• Can be a presenting feature of a previously undiagnosed systemic mechanisms (T cell and B cell) are involved.11–13 Locally produced or cir-
collagen vascular disorder. culating immune complexes lodged in limbal or peripheral corneal blood
• Frequently requires systemic immunosuppressive vessels may activate the classic complement pathway in the presence of C1
immunomodulatory therapy. (the recognition unit of the classic complement pathway). Immune vascu-
• Imperative to exclude a primary or secondary infectious etiology. litis resulting in damage to the vessel wall with leakage and the chemotaxis
of various inflammatory cells, proteins, and proinflammatory cytokines
and the production of metalloproteinases by local resident cells may accel-
erate and propagate the peripheral corneal destructive process.
Associated Features
• Episcleritis. OCULAR MANIFESTATIONS
• Scleritis.
• Iridocyclitis. The presenting symptoms of PUK are not specific. Foreign body sensation,
pain, and photophobia are seen when there is epithelial erosion and ulcer-
ation. Vision may be affected if the peripheral inflammatory process pro-
INTRODUCTION ceeds centrally or from induced astigmatism. Occasionally, an associated
anterior uveitis may contribute to the photophobia with reduction of visual
Peripheral ulcerative keratitis (PUK) is used to describe a group of destruc- acuity. Pain may be severe if associated scleritis occurs.
tive inflammatory diseases involving the peripheral cornea whose final The hallmark clinical features include epithelial loss, demonstrated
common pathway is characterized by sloughing of corneal epithelium and with fluorescein staining, and various amounts of stromal inflammatory
keratolysis (corneal “melting”). The vast majority of cases are mediated by infiltration, and/or thinning caused by keratolysis (corneal melting), which
local and systemic immunological processes, although some cases may be may occur at any clock hour of the peripheral cornea, with or without an
infectious in origin and must be properly evaluated. PUK may be associ- intervening clear zone from the limbus (Fig. 4.16.1). The process may pro-
ated with systemic vasculitides, particularly the collagen vascular diseases, gress circumferentially, centrally, and posteriorly, potentially resulting in
in about half of the noninfectious cases.1 Necrotizing scleritis often is asso- perforation (Fig. 4.16.2). The specific clinical findings at presentation will
ciated in such cases1 and is suggestive of possible active vasculitis, with depend on the severity and rate of progression of the disease, as well as the
PUK being the presenting feature of a systemic inflammatory condition, timing between the onset and clinical evaluation. Corneal melting, once
such as granulomatosis with polyangiitis (GPA) (formerly known as Wege- initiated, may progress very rapidly. The amount of stromal loss may be
ner’s granulomatosis) or polyarteritis nodosa. If not properly treated, PUK underappreciated because of debris and necrotic material deposited at the
can progress to perforation resulting in significant ocular morbidity, and
when associated with a systemic autoimmune condition, may be poten-
tially life-threatening.2
ANATOMY AND PATHOGENESIS

The unique characteristics and anatomy of the peripheral cornea con-
tributes to the predilection of this region to be involved in both local and
systemic immunological reactions.3,4 There are no clear-cut borders that
delineate the peripheral cornea, with an arbitrary central limit beginning
around 3.5–4.5 mm from the visual axis and extending out to the junction
of the ill-defined transition between limbus and the sclera and conjunctiva.
Distinct anatomical differences of the peripheral cornea include the greater
thickness (up to 0.7 mm) with tight collagen bundle packing; a vascular
arcade that originates from the anterior ciliary arteries and extends approx-
imately 0.5 mm into the clear cornea (providing the nutritional supply but
also access to the efferent arm of the immune response); and accompa-
nying lymphatics, which drain to the regional lymph nodes.5 There also
are unique immunological characteristics of the peripheral cornea com-
pared with the central cornea, including the presence of more Langerhans’
cells,6,7 and higher concentrations of immunoglobulin M8 and the first Fig. 4.16.1 Patient With Early Nasal Peripheral Ulceration Measuring About 1 O’
240 component of complement (C1) (important in the activation of the classic Clock Hour. There is inflammatory stromal infiltrate more central to the ulceration
complement pathway), likely caused by limited central diffusion from the with associated episcleral inflammation.
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BOX 4.16.1 Etiologies of PUK
Ocular Noninfectious
4.16
• Idiopathic
• Acne rosacea (ocular)

• Mooren’s ulcer
• Traumatic, postoperative (may be a presenting feature of a systemic
autoimmune disorder)
• Exposure/neuroparalytic keratopathy
Ocular Infectious
• Bacterial (Staphylococcus, Streptococcus, Gonococcus [rare])
• Viral (herpes simplex and herpes zoster)
• Amebic (Acanthamoeba)
• Fungal
Systemic Noninfectious
Collagen Vascular Diseases/Vasculitis
A • Rheumatoid arthritis (common)
• Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides
• Granulomatosis with polyangiitis (previously Wegener’s
granulomatosis) (relatively common)
• Polyarteritis nodosa (less common)
• Microscopic polyangiitis (MPA) (less common)
• Churg–Strauss syndrome (less common)
• Relapsing polychondritis (uncommon)
• Systemic lupus erythematosus (less common)
• Progressive systemic sclerosis/scleroderma (rare)
• Giant cell arteritis (very rare)
Other Systemic Autoimmune
• Cicatricial pemphigoid (especially with trichiasis) (rare)
• Inflammatory bowel disease (very rare)
• Sarcoidosis (very rare)
• Sjögren’s syndrome
• Leukemia/malignancy (very rare)
• Inflammatory bowel disease (usually associated with a nonulcerative
peripheral keratitis)
B
• Giant cell arteritis (rare)
Systemic Infectious
Fig. 4.16.2 Progressive Circumferential Peripheral Corneal Ulceration. • Gonorrhea
(A) A 60-year-old female with idiopathic peripheral ulcerative keratitis. Slit-lamp • Bacillary dysentery
microscopy demonstrates depth of stromal necrolysis. There is inflammatory
infiltrate at both the peripheral and central edges. (B) Fluorescein staining
• Tuberculosis
demonstrates area of ulceration.
• Borreliosis (Lyme disease—very rare)
• Varicella zoster
• Helminthiasis
base of the ulcer but may become more apparent after corneal scrapings
are performed to evaluate for infectious causes. Limbal, conjunctival, and
episcleral injections occur frequently. Concurrent scleritis denotes a higher
likelihood of active vasculitis.1 The finding of PUK with scleritis portends
a worse ocular and systemic outcome than when scleritis occurs alone.14 DIFFERENTIAL DIAGNOSIS
Cataract and glaucoma may occur as a result of the inflammatory process
or the use of corticosteroids. PUK is a clinical diagnosis and identifying the cause is paramount for
the proper management. Infections may cause peripheral corneal inflam-
SYSTEMIC ASSOCIATIONS mation and ulceration and must be rapidly recognized (see Box 4.16.1)
because therapy is markedly different from that for PUK caused by auto-
Nearly 50% of patients with PUK have an associated systemic disease, with immune disease–mediated conditions (Fig. 4.16.3). However, patients with
the large majority of these being the collagen vascular diseases (CVDs) autoimmune disease–associated PUK may become secondarily infected,
(Box 4.16.1). Rheumatoid arthritis (RA) is the most common CVD associ- and thus infectious causes must always be excluded in the initial workup.
ated with PUK, likely due to its high prevalence in the population (affect- Local inflammatory causes include Staphylococcus marginal ulcers, which
ing 2.5%–3% of adults). Granulomatosis with polyangiitis (GPA) (formerly begin with an infiltrate adjacent to the limbus separated by a characteris-
known as Wegener’s granulomatosis) and other antineutrophil cytoplasmic tic clear zone with progression to ulceration and rosacea-associated bleph-
antibody (ANCA)–associated vasculitides, although relatively rare, are an aroconjunctivitis and which may result in a peripheral keratitis with or
important cause of PUK. An associated scleritis may occur in a significant without a clear zone.
portion of patients, the presence of which, especially when necrotizing, Mooren’s ulcer is a specific form of unilateral or bilateral PUK that is
suggests an active vasculitic process.1 In general, patients with rheumatoid characterized by a chronic, usually severely painful, single or multicentric
arthritis (RA)–associated PUK usually have an established systemic diag- corneal ulcer that begins in the periphery adjacent to the sclera with a
nosis with evidence of advanced disease (subcutaneous nodules, vasculitis, characteristic steep, undermined, or overhanging central margin and occa-
cardiac involvement15) or clinical findings supportive of the diagnosis of sionally infiltrated leading central border without associated scleritis16 (see
RA. However, in up to 25% of patients, the PUK may be the initial pre- also Chapter 4.17).
senting feature of potentially lethal undiagnosed systemic vasculitis,1 high- Noninflammatory cause of thinning of the peripheral cornea, as seen
lighting the importance of a thorough systemic evaluation. Additionally, with Terrien’s marginal degeneration, pellucid marginal degeneration, and
in patients with scleritis, the additional presence of PUK portends poor marginal furrow can be distinguished from PUK because of lack of inflam- 241
ocular and systemic prognosis.14 mation and typically an intact epithelium.
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4
A Fig. 4.16.4 Peripheral Ulcerative Keratitis (PUK) Following Conjunctival

Resection for Diagnostic and Therapeutic Purposes. Same Patient as in
Fig. 4.16.2.
BOX 4.16.2 Workup of Peripheral Ulcerative

Keratitis (Noninfectious)
• CBC
• RF
• Anti-CCP
• c-ANCA and p-ANCA
• ESR and CRP, CIC
• Urine analysis
• Radiographs
• Chest
• Sinus
ANCA, antineutrophil cytoplasmic antibody; anti-CCP, anti-cyclic citrullinated protein
antibodies; c-ANCA, antineutrophil cytoplasmic antibodies/cytoplasmic staining pattern;
CBC, complete count; CIC, circulating immune complexes; CRP, C-reactive protein; ESR,
erythrocyte sedimentation rate; MPA, microscopic polyangiitis; GPA, granulomatosis with
polyangiitis; p-ANCA, antineutrophil cytoplasmic antibodies/perinuclear staining pattern;
B RF, rheumatoid factor.
Fig. 4.16.3 Herpes Simplex Virus Peripheral Keratitis (Polymerase Chain

Reaction Positive) (A). Image of the Same Patient With Fluorescein (B).
useful adjunct in milder cases of RA-associated PUK, it is not effective in
GPA, microscopic polyangiitis, Churg–Strauss syndrome, and polyarteritis
nodosa. In these cases, topical corticosteroids may promote progression
DIAGNOSTIC AND ANCILLARY TESTING and even enhance perforation and thus must be used judiciously.17 Topical
cyclosporin A may have some benefit as an adjunct when combined with
A thorough history must be obtained about any previous history of ocular the appropriate systemic therapy.
infections, including ocular and nonocular herpetic disease, contact lens Systemic corticosteroids, in the form of oral prednisone 1 mg/kg/day,
wear, and current and previous medication, trauma, or surgery. Because are very commonly used for the acute management of more severe cases
PUK may be an initial or presenting feature of an underlying systemic col- of PUK. If progression occurs, pulsed methylprednisolone (0.5–1.0 g) for
lagen vascular disease (see Box 4.16.1), a comprehensive review of systems three consecutive days may be effective.18 However, corticosteroids alone
should be obtained, with particular questions related to various systems may be inadequate to control the progressive ocular disease process or
involved in the systemic diseases associated with PUK. A complete oph- impact the systemic morbidity and mortality in patients who have active
thalmic examination to exclude local pathologies is critical. A compre- systemic autoimmune disease. The prolonged use of corticosteroids also
hensive physical examination should be performed by the appropriate will result in significant systemic side effects often necessitating alterna-
specialist when an underlying systemic process is suspected. tive corticosteroid-sparing immunosuppressive agents.
Laboratory tests are listed in Box 4.16.2. Appropriate testing should In severe cases of PUK, where there is progression and threat of per-
exclude infectious etiologies. foration, therapy with systemic corticosteroids at doses up to 100 mg/day
combined with immunosuppressive agents must be used. The presence
of vasculitis is a key factor in deciding if systemic immunosuppressive
TREATMENT therapy will be required (with concurrent associated scleritis highly sug-
Medical Treatment gestive of an active vasculitis process). Other indications for systemic
immunosuppressive therapy are noted in Box 4.16.3.
Prior to therapy, infectious causes need to be excluded by the appropriate Various systemic immunosuppressive agents, such as methotrexate,
culture techniques, with antimicrobial therapy administered if infections azathioprine, mycophenolate mofetil, cyclosporin A, and cyclophospha-
are suspected. Prophylactic topical antibiotics often are used to prevent mide, have demonstrated some clinical efficacy for inflammatory eye
secondary infections. disease, including PUK19,20 (Table 4.16.1). Although the drugs chosen are
In milder, unilateral cases of peripheral ulcerative keratitis (and typ- somewhat nonspecific and the choices are limited by the lack of pro-
ically when not associated with a systemic CVD), topical corticosteroids spective clinical trials, accumulated data suggest that cyclosporin A with
may be considered as initial therapy (at times combined with conjunc- dosages in the range of 2.5 mg/kg/day may be a reasonable initial choice
242 tival resection with the latter being not only therapeutic but of potential for idiopathic PUK, especially if nephrotoxicity is not a concern. It may be
diagnostic value) (Fig. 4.16.4). Although topical corticosteroids may be a switched to or combined with an alternative immunosuppressive agent if
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TNF blockers. Long-term close monitoring is required as disease recur-
TABLE 4.16.1 Immunomodulatory/Immunosuppressive
Therapy in PUK
rence and relapse may occur (especially when associated with systemic vas-
culitis), requiring immediate re-initiation of systemic therapy.25,26 4.16
Drug Disease Indication Dosage A physician with expertise in the appropriate use and proper monitor-
ing of potential complications should administer the immunosuppressive

Azathioprine RA, GPA, and RP 2 mg/kg/day
(second choice) regimen.
Cyclophosphamide GPA and PAN (first 2 mg/kg/day
choice), RA (severe), Surgical Treatment
RP (second choice)
Methotrexate RA (first choice), 10–25 mg/wk PO or SC Surgical treatments may be required in the management of PUK and to
maintenance for GPA maintain the integrity of the globe but are typically adjunctive because
Cyclosporine A Idiopathic (first 2–2.5 mg/kg twice daily when used alone, they will not influence the underlying immunologi-
choice), RA, RP cal process and the potential lethal systemic consequences. Conjunctival
(second choice) resection27,28 may temporarily remove the local cellular mediators and col-
Mycophenolate Alternative to 1 g twice daily, with maximum of 1.5 g lagenases important in progression of the disease process and may be of
mofetil azathioprine twice daily great diagnostic help; for example, identification of significant microangii-
Biological Agents tis would support the use of immunosuppressive therapy (see Fig. 4.16.4).
Anti-TNF However, as a therapeutic adjunct, it is limited to localized unilateral
Infliximab RA, Crohn’s disease For RA 3 mg/kg IV infusion at 0, 2, disease without any associated systemic inflammatory disorder.
6 weeks then every 8 weeks Cyanoacrylate adhesive29 in conjunction with immunosuppressive
For Crohn’s disease, 5 mg/kg 0, 2, and therapy may be used in patients with impending perforation and may
6 weeks; then every 8 weeks delay the need for tectonic corneal surgery. Conjunctival flaps, amniotic
Dosage may be increased interval of membrane grafts,30 and tectonic lamellar and penetrating corneal grafts31
treatment reduced may be required to preserve the integrity of the globe, with a guarded prog-
Adalimumab RA, Crohn’s disease 40 mg SC every 4 weeks nosis,32 and should be used in conjunction with systemic immunosuppres-
Anti-CD22 (B cell) RA, GPA, MPA For GPA 375 mg/m2 once weekly for sive therapy.
Rituximab 4 weeks
For RA two 1000 mg IV infusion
separated by 2 weeks, preceded COURSE AND OUTCOME
by 30 minutes with 100 mg of IV
prednisolone The course, duration, and outcome are variable and dependent on the
Dosage may be increased interval of underlying cause of PUK and on prompt and appropriate management.
treatment reduced Many patients with mild or moderate PUK may maintain good vision if the
RA, rheumatoid arthritis; WG, Wegener’s granulomatosis; GPA, granulomatosis with inflammatory process is rapidly controlled. The prognosis is more guarded
polyangiitis; RP, relapsing polychondritis; PAN, polyarteritis nodosa; PO, per os (oral); PUK, when PUK is associated with a systemic CVD. Significant visual loss and
peripheral ulcerative keratitis; SC, subcutaneous; IV, intravenous. ocular morbidity may develop with corneal perforation. Both ocular prog-
nosis and systemic prognosis are more guarded when concomitant scleri-
tis exists, especially necrotizing scleritis. Even in cases where no systemic
condition can be identified initially, continued surveillance should be
BOX 4.16.3 Indications for Systemic Immunomodulatory maintained. In up to 25% of cases, a systemic disorder is recognized after
Therapy in Peripheral Ulcerative Keratitis (PUK) the presentation of the eye disease. Failure to identify and concurrently
treat an associated systemic inflammatory disease may lead to significant
1. PUK associated with a potentially lethal systemic disease, such as rheu- ocular and systemic morbidity and even mortality. Systemic immunomod-
matoid arthritis, Wegener’s granulomatosis, relapsing polychondritis, ulatory therapy is required when progression occurs with local therapy, an
polyarteritis nodosa association with collagen vascular diseases, or bilateral Mooren’s disease.
2. PUK with associated scleritis
3. Bilateral Mooren’s ulcer
4. Disease progression despite local conjunctival resection and tectonic KEY REFERENCES
procedures (e.g., tissue adhesive) Brown SI, Mondino BJ. Therapy of Mooren’s ulcer. Am J Ophthalmol 1984;98:1–6.
Dana RM, Quin Y, Hamrah P. Twenty-five-year panorama of corneal immunology. Emerging
concepts in the immunopathogenesis of microbial keratitis, peripheral ulcerative kerati-
tis, and corneal transplant rejection. Cornea 2000;19:625–43.
Feder RS, Krachmer JH. Conjunctival resection for the treatment of the rheumatoid corneal
inadequate response or progression occurs. However, if the PUK is found ulceration. Ophthalmology 1984;91:111–15.
to be associated with a specific systemic CVD, then immunosuppressives Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients developing
proven to be effective for the treatment of the systemic disease should necrotizing scleritis or peripheral ulcerative keratitis: effect of systemic immunosup-
pression. Ophthalmology 1984;91:1253–63.
be considered. In cases of GPA-associated PUK (or with more severe or Huerva V, Sanchez MC, Traveset A, et al. Rituximab for peripheral ulcerative keratitis with
rapidly progressive PUK associated with other CVDs), especially when Wegener granulomatosis. Cornea 2010;29:708–10.
accompanying necrotizing scleritis exists, cytotoxic immunosuppressives, Messmer EM, Foster CS. Destructive corneal and scleral disease associated with rheumatoid
such as cyclophosphamide (2 mg/kg orally), together with corticosteroids arthritis. Cornea 1995;14:408–17.
(oral or pulse intravenous) are the first-line therapy, with oral or subcuta- Messmer EM, Foster CS. Vasculitis peripheral ulcerative keratitis. Survey Ophthalmol
1999;43:379–96.
neously injected methotrexate useful for maintenance. Mondino BJ. Inflammatory diseases of the peripheral cornea. Ophthalmology 1988;95:463–72.
The role of biological agents, such as the anti–tissue necrosis factor Pharm M, Chow CC, Baldwi D, et al. Use of infliximab in the treatment of peripheral ulcer-
(TNF) and anti–B cell monoclonal antibodies, in the treatment of PUK ative keratitis in chronic disease. Am J Ophthalmol 2011;152:183–6.
has become more accepted because of more cumulative experience in the Robin JB, Schanzlin DJ, Verity SM, et al. Peripheral corneal disorders. Surv Ophthalmol
1986;31:1–36.
form of case reports, small series, personal experiences of those who treat Sainz de la Maza M, Foster CS, Jabbur NS, et al. Ocular characteristics and disease associ-
severe inflammatory eye disease21–24 and because of their well-established ations in scleritis-associated peripheral keratopathy. Arch Ophthalmol 2002;120:15–19.
efficacy in the treatment of systemic inflammatory diseases, such as RA, Soukiasian SH, Foster CS. Mooren’s ulcer. In: Margo C, Hamed LM, Mames RN, editors.
GPA, spondyloarthropathies, inflammatory bowel disease, and other sys- Diagnostic problems in clinical ophthalmology. Philadelphia: WB Saunders; 1994. p.
220–7, [ch 28].
temic vasculitides. A recent study found systemic rituximab more effective Squirrell DM, Winfield J, Amos RS. Peripheral ulcerative keratitis ‘corneal melt’ and rheu-
in controlling GPA-associated progressive PUK (11 of 11) than cyclophos- matoid arthritis: a case series. Rheumatology 1999;38:1245–8.
phamide (5 of 10).25 However, the high cost of these drugs and the uncer- Tauber J, Sainz de la Maza M, Hoang-Xuan T, et al. An analysis of the therapeutic decision
tain long-term side effects may be limiting more widespread use. Systemic making regarding immunosuppressive chemotherapy for peripheral ulcerative keratitis.
Cornea 1990;9:66–73.
therapy should be continued for a period of at least 6 months to 1 year after
initial control of inflammation has been achieved with proper monitor-
ing for drug-related side effects. Lymphoma and other malignancies, some Access the complete reference list online at ExpertConsult.com 243
fatal, have been reported in children and adolescent patients treated with
booksmedicos.org
REFERENCES 17. Messmer EM, Foster CS. Vasculitis peripheral ulcerative keratitis. Survey Ophthalmol
1999;43:379–96.
1. Tauber J, Sainz de la Maza M, Hoang-Xuan T, et al. An analysis of the therapeutic deci-
sion making regarding immunosuppressive chemotherapy for peripheral ulcerative ker-
18. Meyer PAR, Watson PG, Franks W, et al. Pulsed immunosuppressive therapy in the
treatment of immunologically induced corneal and scleral disease. Eye 1987;1:487–95.
4.16
atitis. Cornea 1990;9:66–73. 19. Squirrell DM, Winfield J, Amos RS. Peripheral ulcerative keratitis ‘corneal melt’ and
rheumatoid arthritis: a case series. Rheumatology 1999;38:1245–8.

2. Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients develop-
ing necrotizing scleritis or peripheral ulcerative keratitis: effect of systemic immunosup- 20. Messmer EM, Foster CS. Vasculitis peripheral ulcerative keratitis. Survey Ophthalmol
pression. Ophthalmology 1984;91:1253–63. 1999;43:379–96.
3. Robin JB, Schanzlin DJ, Verity SM, et al. Peripheral corneal disorders. Surv Ophthalmol 21. Thomas JW, Pflugfelder SC. Therapy of progressive rheumatoid arthritis-associated
1986;31:1–36. corneal ulceration with infliximab. Cornea 2005;24:722–4.
4. Mondino BJ. Inflammatory diseases of the peripheral cornea. Ophthalmology 22. Atchia II, Kidd CE, Bell RW. Rheumaotid arthritis-associated necrotizing scleritis and
1988;95:463–72. peripheral ulcerative keratitis treated successfully with infliximab. J Clin Rheumatol
5. Hogan MJ, Alvarado JA. The limbus. In: History of the human eye: an atlas and textbook. 2006;12:291–3.
2nd ed. Philadelphia: WB Saunders; 1971. p. 112–82. 23. Pharm M, Chow CC, Baldwi D, et al. Use of infliximab in the treatment of peripheral
6. Gillette TE, Chandler JW, Griener JV. Langerhans’ cells of the ocular surface. Ophthal- ulcerative keratitis in chronic disease. Am J Ophthalmol 2011;152:183–6.
mology 1982;89:700–11. 24. Huerva V, Sanchez MC, Traveset A, et al. Rituximab for peripheral ulcerative keratitis
7. Jager MJ. Corneal Langerhans cells and ocular immunology. Regional Immunol with Wegener granulomatosis. Cornea 2010;29:708–10.
1992;4:186–95. 25. Ebrahimiadib B, Modjtahedi BS, Roohipoor R, et al. Successful Treatment Strategies in
8. Allansmith MR, McClellan BH. Immunoglobulins in the human cornea. Am J Ophthal- Granulomatosis with Polyangiitis – Associated Peripheral Ulcerative Keratitis. Cornea
mol 1975;80:123–32. 2016;35:1459–65.
9. Brown SI. Mooren’s ulcer: histology and proteolytic enzymes of the adjacent conjunctiva. 26. Joshi L, Tanna A, McAdoo SP, et al. Long-term outcomes of rituximab therapy in ocular
Br J Ophthalmol 1975;59:670–4. granulomatosis wit polyangiitis: impact on localized and non localized disease. Ophthal-
10. Eiferman RA, Carothers DJ, Yankeelov JA. Peripheral rheumatoid ulceration and evi- mology 2015;122(6):1262–8.
dence for conjunctival collagenase production. Am J Ophthalmol 1979;87:703–9. 27. Feder RS, Krachmer JH. Conjunctival resection for the treatment of the rheumatoid
11. Dana RM, Quin Y, Hamrah P. Twenty-five-year panorama of corneal immunology. corneal ulceration. Ophthalmology 1984;91:111–15.
Emerging concepts in the immunopathogenesis of microbial keratitis, peripheral ulcer- 28. Brown SI, Mondino BJ. Therapy of Mooren’s ulcer. Am J Ophthalmol 1984;98:1–6.
ative keratitis, and corneal transplant rejection. Cornea 2000;19:625–43. 29. Fogle JA, Kenyon KR, Foster CS. Tissue adhesive arrests stromal melting in the human
12. Reynolds I, John SL, Tullo AB, et al. Characterization of two corneal epithelium-derived cornea. Am J Ophthalmol 1980;89:795–802.
antigens associated with vasculitis. Invest Ophthalmol Vis Sci 1998;39:2594–601. 30. Solomon A, Meller D, Prabhasawat P, et al. Amniotic membrane grafts for nontraumatic
13. Gottsch JD, Liu SH. Cloning and expression of human corneal calgranulin C (CO-Ag). corneal perforations, descemetoceles, and deep ulcers. Ophthalmology 2002;209:694–703.
Curr Eye Res 1998;17:870–4. 31. Raizman MB, Sainz de la Maza M, Foster C. Tectonic keratoplasty for peripheral ulcer-
14. Sainz de la Maza M, Foster CS, Jabbur NS, et al. Ocular characteristics and disease asso- ative keratitis. Cornea 1991;10:312–16.
ciations in scleritis-associated peripheral keratopathy. Arch Ophthalmol 2002;120:15–19. 32. Messmer EM, Foster CS. Destructive corneal and scleral disease associated with rheuma-
15. Jayson MIV, Easty DL. Ulceration of the cornea in rheumatoid arthritis. Ann Rheum Dis toid arthritis. Cornea 1995;14:408–17.
1977;36:428–32.
16. Soukiasian SH, Foster CS. Mooren’s ulcer. In: Margo C, Hamed LM, Mames RN, editors.
Diagnostic problems in clinical ophthalmology. Philadelphia: WB Saunders; 1994. p.
220–7, [ch 28].
243.e1
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Noninfectious Keratitis
Roshni A. Vasaiwala, Charles S. Bouchard 4.17
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Definition: Corneal inflammation with no known infectious etiology. TABLE 4.17.1 Noninfectious Keratitis
Dermatological Mucous membrane pemphigoid
Erythema multiforme (Stevens–Johnson syndrome, toxic
Key Feature epidermal necrolysis)
• Diverse group of diseases with corneal inflammation as the common Rosacea
feature. Mechanical Ectropion/entropion
Contact lens–related keratitis
Lid defects
Trichiasis
Associated Feature Lagophthalmos
• Systemic inflammatory disease. Exophthalmos
Dellen
Immunological/Allergic Collagen vascular disease (rheumatoid melting)
INTRODUCTION Mooren’s ulcer
Staphylococcal marginal infiltrate
In this chapter, well-characterized clinical entities that, to date, have no
Phlyctenular keratoconjunctivitis
known infectious cause are presented. A list of noninfectious corneal
inflammatory diseases is given in Table 4.17.1.1 Vernal keratoconjunctivitis
The term noninfectious keratitis describes a wide range of entities with Graft-versus-host disease
some common clinical features and of no known infectious etiology. These Atopic keratoconjunctivitis
include focal or diffuse inflammation, abnormal epithelial healing, and Allograft rejection (penetrating keratoplasty [PKP], Descemet’s
neovascularization.1 These findings result, in part, from the proximity of stripping endothelial keratoplasty [DSEK], Descemet’s
the peripheral cornea and its access to the afferent and efferent pathways membrane endothelial keratoplasty [DMEK])
of the limbal vasculature. Clinical symptoms associated with noninfectious Lacrimal Keratoconjunctivitis sicca (primary, secondary)
keratitis include photophobia, pain, redness, and decreased visual acuity. Neurological Neurotrophic keratitis (fifth cranial nerve, diabetes)
Visual loss may result from an irregular surface, corneal opacity, or altered Neuroparalytic keratitis (seventh cranial nerve)
topography from corneal thinning. Approaches to management include (1) Nutritional Keratomalacia
determination of the specific cause; (2) promotion of epithelial healing; Postinfectious Viral (herpes simplex, herpes zoster)
(3) limitation of ulceration and stromal loss; and (4) support of repair.1 Bacterial
Both local and systemic routes of therapy may be necessary for optimal
Fungal
outcomes.
Postsurgical Delayed epithelial healing (diabetes mellitus)
Diffuse lamellar keratitis (DLK)
THYGESON’S SUPERFICIAL Traumatic Chemical injury (alkali, acid)

Thermal injury
PUNCTATE KERATITIS Radiation
Epidemiology and Pathogenesis Other Thygeson’s superficial punctate keratitis

Acute leukemia
Thygeson’s superficial punctate keratitis (TPSK) is a bilateral, epithelial Pyoderma gangrenosum
keratitis of unknown cause and was first described by Phillips Thygeson Cutaneous porphyria
in 1950.2 It is characterized by an insidious onset of focal corneal epithelial
Terrien’s marginal degeneration
inflammation with a pattern of exacerbations and remissions. The disease
(Adapted from Kenyon KR. Decision-making in the therapy of external eye disease.
can last from 1 month to 24 years, with an average duration of 3.5 years. Noninfected corneal ulcers. Ophthalmology 1982;89:44–51.)
TSPK usually begins in the second and third decades (mean age, 29 years),
with a range of 2.5–70 years. No clear gender predilection exists, although
a female preponderance has been suggested. (HLA)-Dw3 and HLA-DR3 expression, both of which are HLA loci associ-
No established cause for this disease is known, and no clear trigger ated with immune response genes.5
mechanisms or associated systemic illnesses have been identified. The
clinical manifestations of TSPK resemble those of viral keratitis. There are Ocular Manifestations
conflicting reports about a viral cause.3,4
The characteristic exacerbations and remissions of the disease may The lesions of TSPK typically appear in the central cornea as small,
be caused by an altered immune response to an unknown exogenous or round or oval, discrete, granular, white-gray, fine, dot-like intraepithelial
244 endogenous antigen. A genetic predisposition may be present because opacities. The number of lesions ranges from 3–40, and occasionally the
some patients demonstrate an increase in human leukocyte antigen lesions appear stellate (Fig. 4.17.1). Stromal edema and associated cellular
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BOX 4.17.1 Differential Diagnosis of Thygeson’s Superficial
Punctate Keratitis 4.17
• Herpes simplex keratitis
• Other viral keratitis (adenovirus)
• Molluscum contagiosum keratitis
• Exposure keratitis
• Blepharokeratitis
• Neurotrophic keratopathy
• Staphylococcal keratitis
• Traumatic keratopathy
• Dry eye disease
• Acanthamebic keratitis (early)
Fig. 4.17.1 Corneal punctate lesions characteristic of Thygeson’s superficial punctate Pathology
keratopathy. These typically occur in a noninflamed eye. (Courtesy Joel Sugar, MD.)
Corneal scrapings of the lesions demonstrate atypical and degenerated epi-
thelial cells and a mild mononuclear and polymorphonuclear cell infiltrate.
Confocal microscopy has demonstrated the accumulation and aggregation
of Langerhans’ cells in the basal cell layer of the corneal epithelium in
association with decreased density of the subepithelial nerve plexus of
affected eyes, suggesting an immune response.6
Treatment
Topical low-dose corticosteroids decrease the signs and symptoms of TSPK
and probably are most effective during acute exacerbations. The course
of the disease may be prolonged with the chronic use of corticosteroids.
Topical 2% cyclosporine or tacrolimus7 have been effective in the manage-
ment of TSPK, with few side effects.8 Therapeutic bandage contact lenses
may be used to improve visual acuity and improve comfort in more symp-
tomatic patients. The use of antiviral agents has been evaluated, but no
convincing evidence exists that they are effective.9 Photorefractive keratec-
tomy may reduce the recurrences in the central ablated cornea, suggest-
ing that some unknown inflammatory signal may reside in the superficial
corneal stroma.10,11
Fig. 4.17.2 A Patient Who Has Thygeson’s Superficial Punctate Keratopathy.

Slit-lamp appearance of the fine subepithelial haze and relative lack of corneal Course and Outcome
inflammation between lesions are shown. Most patients with TSPK recover completely with no loss of visual acuity,
although up to 44% may be left with faint subepithelial opacities.
infiltration generally are absent (Fig. 4.17.2). Subepithelial opacities occur

in 44% of patients. TSPK is bilateral in 96% of patients. Conjunctival SUPERIOR LIMBIC KERATOCONJUNCTIVITIS
inflammation is absent.
Active lesions are resistant to mechanical removal and appear elevated
OF THEODORE
following fluorescein staining with negative staining. During remissions, Epidemiology and Pathogenesis
the epithelium is flat and without stain over the previous areas of keratitis.
Although most lesions are central, peripheral lesions do occur and may be Superior limbic keratoconjunctivitis (SLK) is a chronic, focal, ocular
associated with delicate, peripheral vascularization in chronic cases. surface disease characterized by episodes of recurrent inflammation of the
Symptoms include tearing, foreign body sensation, photophobia, and superior cornea and limbus, as well as of the superior tarsal and bulbar
burning. Visual acuity may be decreased by the subepithelial opacities but conjunctiva.12 It occurs primarily in adults age 30–55 years and is more
generally returns to normal following resolution of the keratitis. common in women (3 : 1). It typically is bilateral, but unilateral disease may
occur.
Diagnosis Although the pathophysiology is unclear, mechanical trauma from tight
upper lids or loose redundant conjunctiva could lead to the known dis-
Thygeson2 outlined five characteristic features of TSPK: (1) chronic, ruption of normal epithelial development.13 This mechanical hypothesis
bilateral punctate inflammation; (2) long duration, with remissions and is supported by the increased lid apposition in patients with exophthalmic
exacerbations; (3) healing without significant scarring; (4) absent clinical thyroid disease, who are known to have an increased incidence of SLK,14 as
response to topical antibiotics; and (5) striking symptomatic and clinical well as increased lubrication being an effective treatment modality.15
response to topical corticosteroids.
The diagnosis of TSPK generally can be made from the clinical history, Ocular Manifestations
results of slit-lamp examination, and the unusually rapid response to
topical corticosteroids. No specific systemic associations have been The classic sign of SLK is bilateral local hyperemia of the superior bulbar
reported for this disease. conjunctiva (Fig. 4.17.3), which also appears keratinized, thickened, and
redundant. The opposing superior palpebral conjunctiva demonstrates a
Differential Diagnosis delicate papillary reaction with associated hyperemia. Fine fluorescein or
Rose Bengal punctate staining usually is present. Keratoconjunctivitis sicca
One of the most characteristic features of TSPK is its lack of associated occurs in 25%–50% of patients and must be evaluated in all patients with
conjunctival inflammation. All the other disease entities in Box 4.17.1 have SLK.14 A fine filamentary keratitis of the superior cornea and limbus may
either obvious associated features or signs of local or diffuse conjunctival be present (Fig. 4.17.4). A delicate superior corneal pannus suggests more 245
inflammation. long-standing disease.
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4 BOX 4.17.2 Differential Diagnosis of Superior Limbic
Keratoconjunctivitis of Theodore
Keratoconjunctivitis With Filaments
• Ptosis/lid occlusion
• Keratoconjunctivitis sicca
• Neurotrophic keratitis
• Herpes simplex epithelial keratitis
• Recurrent corneal erosion
• Trauma
• Bullous keratopathy
• Medicamentosa
Keratoconjunctivitis Without Filaments
• Keratoconjunctivitis induced by contact lens
• Limbal vernal keratoconjunctivitis
• Phlyctenulosis
• Thygeson’s superficial punctate keratitis
Fig. 4.17.3 Superior Limbic Keratoconjunctivitis. Slit-lamp appearance of focal
superior bulbar conjunctival injection is shown with Rose Bengal staining.
common treatments for SLK. If this type of inflammation goes undiag-
nosed in patients with chronic GVHD, they can develop limbal stem cell
deficiency, scarring, and loss of vision.16
Systemic associations include thyroid disease and collagen vascular
disease. In one study in a referral university setting, 65% of patients who
had SLK were found to also have thyroid dysfunction.14 Of those patients
who had SLK and thyroid disease, 90% had ophthalmopathy, and 49% had
severe thyroid disease necessitating orbital decompression. SLK is a strong
negative prognostic factor for patients who have thyroid disease.14
Pathology
The superior bulbar conjunctiva demonstrates keratinization of the epi-
thelium with intracellular accumulation of glycogen and abnormal chro-
matin. A predominantly polymorphonuclear infiltrate occurs. Acanthosis,
squamous metaplasia, dyskeratosis, balloon degeneration of nuclei, and
decreased goblet cell density, and conjunctival stromal edema occur. Upreg-
ulation of transforming growth factor-β2 and tenascin support an increase
Fig. 4.17.4 Superior Limbic Keratoconjunctivitis. Slit-lamp appearance of superior in mechanical stress.15 Altered expression of cytokeratins also suggests an
filamentary keratitis is shown. abnormality of epithelial differentiation.17 One study found elevated levels
of matrix metalloproteinases (MMP-1 and MMP-3) in surgical specimens
Characteristic symptoms include a gradual onset of burning, tearing, from patients with SLK compared with controls, suggesting a possible role
foreign body sensation, mild photophobia, and sometimes mucus dis- of MMP imbalance in the pathogenesis.18
charge. Patients may notice pain and decrease in vision if the filamentary Changes in the superior palpebral conjunctiva are somewhat different,
component is severe or occurs within the visual axis. with an increase in polymorphonuclear neutrophil leukocytes, lympho-
cytes, and plasma cells. The overlying epithelium contains hypertrophic
Diagnosis goblet cells.
The diagnosis of SLK is made from the history of irritation, photophobia,

and the specific pattern of superior corneal and conjunctival inflammation
Treatment
and staining. Superior filamentary keratitis supports the diagnosis. Because a large proportion (25%–50%) of patients who have SLK also have
DED, care must be taken to treat any concurrent aqueous tear deficiency
Differential Diagnosis with unpreserved teardrops and, if indicated, punctal occlusion.19 Associ-
ated blepharitis also must be managed. Any lid surgery, especially ptosis
The differential diagnosis of SLK is shown in Box 4.17.2. Filamentary ker- repair, should be evaluated carefully because possible exacerbation of SLK
atitis may occur in up to 40% of patients with SLK. The distribution of may be caused by lid tightening and possible secondary exposure.
filaments on the upper cornea and limbus may help differentiate SLK Surgical approaches to treatment involve the destruction or resection
from dry eye disease (DED), in which filaments occur more typically on of the presumed abnormal conjunctival epithelium. Simple resection or
the lower half of the cornea. recession of the conjunctiva with Tenon’s capsule can be very effective.
An inflammatory condition associated with soft contact lens wear may Use of cryotherapy and thermocautery has been reported, with symptom
resemble SLK. Although many signs and symptoms of this contact lens– improvement in 75% of patients treated with the latter.20
related SLK are similar to those of SLK of Theodore, filaments are usually Bandage contact lenses and pressure patching have been used to
absent, vision may be decreased (unusual in SLK), and no female predi- manage severe symptoms of photophobia, ocular discomfort, and associ-
lection or associated thyroid dysfunction exists. More importantly, symp- ated filamentary keratitis. SLK often recurs, however, after lens wear has
toms generally improve with discontinuation of contact lens wear. Contact been discontinued.
lens–induced keratoconjunctivitis may be a more appropriate term for this Topical hypertonic saline solutions may help reduce the excessive
entity, with SLK reserved for the specific condition described by Theodore.12 mucus production and associated filaments. N-acetylcysteine (Mucomyst),
SLK-like inflammation can occur in patients with chronic ocular in 10%–20% solution, may offer relief in severe cases. Topical cromolyn or
graft-versus-host disease (GVHD).16 These patients present with the typical lodoxamide may offer symptomatic relief of itching.
246 signs of SLK, including conjunctival injection and staining of the supe- The chronic use of topical corticosteroids should be discouraged. Topical
rior conjunctiva and cornea. They also tend to show good response to the cyclosporine A and autologous serum have been reported to be effective in
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4.17
Fig. 4.17.5 Acute Mooren’s Ulcer. Peripheral thinning and an overlying epithelial Fig. 4.17.6 Mooren’s Ulcer. Peripheral thinning is present in a relatively quiet eye in
defect are present in an inflamed eye. (Courtesy Joel Sugar, MD.) this patient who had a history of Mooren’s ulcer, now in remission.
some cases.21,22 Topical vitamin A eyedrops may be variably effective during in this form, occurring in about one third of patients. Associated cataract,
inflammatory periods.23 Topical tacrolimus 0.03% ointment has been suc- secondary glaucoma, and uveitis may be seen.
cessful in the treatment of cases refractory to the above treatment modal- Chronic Mooren’s ulcer ultimately results in a central island of hazy
ities.24 Topical rebamipide, a medication initially used to increase gastric stromal tissue with severe peripheral thinning (Fig. 4.17.6). No scleral
mucosa mucin, has been shown to improve SLK in patients with thyroid involvement occurs, although associated conjunctival and episcleral
disease.25 inflammation may be seen. No clear zone exists between the ulcer and
the limbus, which distinguishes Mooren’s ulcer from other forms of PUK.
Course and Outcome Visual loss as a result of severe, irregular corneal astigmatism and scarring
is common.
Many of the proposed therapies have been effective, and the overall prog-
nosis is excellent because the visual axis usually is not affected. Diagnosis
Mooren’s ulcer is, by definition, not associated with any systemic abnor-
MOOREN’S ULCER mality, except for the occasional association with hepatitis C. Collagen vas-
Epidemiology and Pathogenesis cular disease must be excluded. Patients should also be tested for hepatitis
C virus.32 Patients who have other systemic diseases, including leukemia,
Mooren’s ulcer, a rare, chronic, painful, peripheral ulcerative keratitis pyoderma gangrenosum, and syphilis, also may develop PUK.33
(PUK), was first described in detail as a clinical entity by Mooren in 1867.26 Patients complain of severe ocular pain, photophobia, and tearing. The
Two clinical types of primary Mooren’s ulcer have been described.27 The overlying epithelium in other degenerative corneal lesions remains intact.
limited type is typically unilateral, occurs in the fourth decade or later, and
is more responsive to local surgical and medical therapy. The second type, Differential Diagnosis
which is more resistant to systemic immunosuppression, involves a bilat-
eral, painful, relentless, progressive destruction of the cornea, usually in Although there are many other causes of PUK (Box 4.17.3), Mooren’s ulcer
younger individuals (third decade), many of whom are of African descent. is an unusual and severe inflammatory disease without known associated
The pathogenesis of Mooren’s ulcer is unknown but appears to involve systemic disease (except perhaps hepatitis C).
an autoimmune reaction against a specific target molecule in the corneal
stroma, which may occur in genetically susceptible individuals.28 Both Pathology
cellular and humoral mechanisms have been postulated.29 The conjunc-
tival epithelium demonstrates increased levels of several inflammatory Three zones of corneal involvement have been described. The superficial
mediators.30 stroma contains lymphocytes, plasma cells, polymorphonuclear leuko-
Interestingly, there have been several reported cases of Mooren’s cytes, disrupted collagen lamellae, and neovascular elements. The mid-
ulcer in patients with concurrent hepatitis C whose corneal inflamma- stroma demonstrates an increase in the number of fibroblasts, and the
tion responded to systemic interferon-α (IFN-α).31 These cases suggest a deep stroma is infiltrated primarily by macrophages. The epithelial base-
common antigenic source.32 ment membrane is disrupted at the leading edge, and the characteristic
infiltrate contains primarily neutrophils.
Ocular Manifestations Conjunctival resections from patients with Mooren’s ulcer demonstrate
increased levels of inflammatory mediators, including vascular cell adhe-
Mooren’s ulcer is characterized by a progressive, crescentic, peripheral sion molecule-1 (VCAM-1), very late activation-4, intercellular adhesion
corneal ulceration that is slightly central to the corneoscleral limbus. It molecule-1 (ICAM-1), and lymphocyte function–associated antigen-1.27
is associated with a characteristic extensive, undermined, “overhanging”
edge (Fig. 4.17.5). It progresses with an anterior, stromal, yellow-white infil- Treatment
trate at the advancing margin. An overlying epithelial defect then devel-
ops. Progressive stromal melting follows, which affects first the deeper and A stepladder approach to manage this aggressive disease has been pro-
subsequently the anterior stroma. The ulcer progresses circumferentially posed. This includes local, systemic, and surgical therapies.34 Initial treat-
and centrally. A re-epithelized, conjunctivalized, thinned cornea remains. ment should begin with topical corticosteroids, followed by conjunctival
Patients in whom Descemet’s membrane has a minimal overlying stroma resection if the inflammation is not controlled. Topical cyclosporine drops
may be predisposed to perforation either spontaneously or following and tacrolimus ointment have been effective in some cases.35 In addition,
minor trauma. bandage contact lenses, as well as amniotic membrane transplantation,36
In the more aggressive form of Mooren’s ulcer, the inflammation may may reduce discomfort and promote epithelial healing in refractory cases. 247
affect the entire cornea and perilimbal tissue. Perforation is not uncommon Topical administration of IFN-α may be helpful.37
booksmedicos.org
4 BOX 4.17.3 Differential Diagnosis of Mooren’s Ulcer
Collagen Vascular Disease
• Rheumatoid arthritis
• Juvenile rheumatoid arthritis
• Systemic lupus erythematosus

• Wegener’s granulomatosis
• Progressive systemic sclerosis
• Relapsing polychondritis
• Polyarteritis nodosa
• Cogan’s syndrome
Oculodermatological Conditions
• Stevens–Johnson syndrome
• Rosacea
• Psoriasis
• Benign mucous membrane pemphigoid
• Ichthyosis Fig. 4.17.7 Neurotrophic Keratitis. Slit-lamp appearance in a patient who
• Pyoderma gangrenosum developed a paracentral epithelial defect with minimal subepithelial inflammation.
Corneal Degenerations
• Terrien’s marginal degeneration
• Pellucid marginal degeneration
• Involutional marginal degeneration
Other
• Staphylococcal marginal infiltrate
Systemic immunosuppression with cyclophosphamide followed by aza-

thioprine may be initiated if treatment with conjunctival resection fails.
Systemic immunosuppressive treatment of the more aggressive bilateral
disease has included corticosteroids, cyclosporine, methotrexate, and
infliximab.34,38,39 Systemic IFN-α2b has been effective in the treatment of
patients who are positive for hepatitis C virus and have Mooren’s ulcer.31
Systemic workup for vasculitis or collagen vascular disease is mandatory
for patients who are suspected of having Mooren’s ulcer. The primary goal
of therapy is to slow the severe progression of the corneal loss, although
50% of cases may be unresponsive to all medical therapy.34
Small perforations can be managed with cyanoacrylate adhesive but
large perforations require lamellar or full-thickness keratoplasty.
Surgical management for visual rehabilitation is a challenge as pen- Fig. 4.17.8 Neurotrophic Keratitis. Slit-lamp appearance in a patient who has
etrating keratoplasty is usually associated with disease recurrence, graft a partial seventh nerve palsy. He was treated with ciprofloxacin and developed
rejection, and melting. deposits of the antibiotic on the cornea.
Course and Outcome Ocular Manifestations

Most patients who have unilateral disease respond fairly well to topical Mackie47 characterized three stages of neurotrophic keratitis. Stage I
corticosteroids and conjunctival resection. For more severe bilateral cases, includes an often subtle irregular corneal surface, which later develops
the prognosis is poor. into an easily recognized punctate keratitis. Stage II is characterized by
a frank epithelial defect, which typically is associated with mild anterior
stromal edema and inflammation (Fig. 4.17.7). Folds in Descemet’s mem-
NEUROTROPHIC KERATITIS brane often develop. The epithelium at the edges of the defect tends to be
Epidemiology and Pathogenesis characteristically “heaped up” or “rolled” with grayish, swollen epithelium.
The ulcer usually is found in the lower, exposed, paracentral cornea and is
Lesions of the fifth cranial nerve from the trigeminal nucleus to the cornea generally oval in shape (Fig. 4.17.8). Stage III involves stromal melting and
may lead to abnormalities of the normal corneal sensation and trophic occasionally perforation. Characteristic symptoms include red eye, mild
stimulation. The trophic ulceration that results leads to abnormal repair of foreign body sensation, blurred vision, and lid edema.
corneal epithelium secondary to increased apoptosis and reduced prolifera-
tion of epithelial cells and reduced reflex tearing.40 Normally, a bidirectional Diagnosis
interaction occurs between epithelial cells and nerve endings. Adrenergic
stimulation leads to increased cyclic adenosine monophosphate, which A history of surgery, irradiation, stroke, or decreased hearing should be
inhibits mitosis.41 Cholinergic stimulation leads to increased cyclic gua- established, in addition to a previous history of red eye. Decreased corneal
nosine monophosphate, which increases cell turnover.41 Substance P sensation is evident with or without a decrease in conjunctival sensation.
may play a role in normal and abnormal epithelial cell turnover.41–43 Dis- Decreased aqueous tear production may be associated with neurotrophic
ruption of the sensory and sympathetic pathways is thought to lead to keratopathy.48
decreased cell division.41 Cells, therefore, fail to resist the effects of trauma
(microtrauma) and desiccation, which normally lead to reflex tearing.44,45 Differential Diagnosis
Increased inflammatory cytokines, such as interleukin-6 (IL-6), may play a
role in nerve degeneration in herpes simplex infection.46 The differential diagnosis of decreased corneal sensation is given in Box
Varicella zoster keratitis (8% of patients) and herpes simplex keratitis 4.17.4. Herpes simplex and herpes zoster are the most common causes, and
are the most common causes of neurotrophic keratitis. In addition to trau- each has a characteristic initial clinical presentation. Topical drug toxicity,
matic damage to the ophthalmic branch of the fifth cranial nerve following contact lens wear, dry eye, chronic exposure, and limbal stem cell defi-
various surgical procedures, stroke, irradiation to eye or adnexa, aneurysm, ciency may contribute to decreased corneal sensation. Finally, diabetes is a
248 multiple sclerosis, toxic chemical reactions, and brainstem hemorrhages well-described cause of neurotrophic keratitis and may result in epithelial
may lead to trigeminal dysfunction and corneal ulceration. healing problems.
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BOX 4.17.4 Differential Diagnosis of Decreased
Corneal Sensation 4.17
• Lesions to the ophthalmic division of the trigeminal nerve
• Surgery
• Acoustic neuroma
• Trauma
• Infectious disease
•
Herpes simplex
•
Herpes zoster
• Contact lens wear
• Diabetes
• Topical agents
• Anesthetics
• Beta-blockers
• Nonsteroidal anti-inflammatory agents
Fig. 4.17.9 Terrien’s Marginal Degeneration. Advancing lipid deposits and

Systemic Associations superficial vascular pannus are present. (Courtesy Joel Sugar, MD.)
Diabetic peripheral neuropathy may result in decreased corneal sensation.

may have episcleral or scleral inflammation. Patients typically are 20–40
Pathology years of age, although it may present in childhood. It is found more com-
monly in men than in women (3 : 1).62
Histological changes include acanthotic, hyperplastic epithelium with rete The cause is unknown. Two types have been documented. One type
peg formation, stromal scarring, destruction or disruption of Bowman’s occurs primarily in the older population. It usually is asymptomatic and
membrane, and corneal neovascularization. Intracellular edema, irregular- slowly progressive. The other, more inflammatory type characteristically
ity and loss of the epithelial microvilli, and loss of the superficial epithe- occurs in younger patients and may be associated with episcleritis or
lial cell layer of the cornea may be seen.40 Epithelial cell attachments are scleritis.63
abnormal.
Ocular Manifestations
Treatment Terrien’s degeneration usually starts superiorly with mild, punctate, sub-
The goals of treatment are to prevent progression of epithelial damage, epithelial and/or anterior stromal opacities. A clear area exists between the
promote healing, facilitate repair, and prevent recurrence. For mild punc- opacities and the limbus. This opacification is followed by the development
tate keratitis, frequent lubrication with unpreserved artificial tear drops of a peripheral, superficial, fine vascular pannus, which progresses over
and ointment may be effective. Aqueous tear deficiency should be docu- years to include a linear subepithelial opacity at the advancing edge. The
mented. For more severe disease, punctal occlusion may be indicated. thinning slowly begins between the limbus and the line of lipid deposi-
For small epithelial defects, topical ointment with patching may aid in tion. Typically, a steeper sloping of the cornea occurs at the advancing edge
healing. Mild topical corticosteroids may reduce the associated anterior (Fig. 4.17.9), without the overlying edge characteristic of Mooren’s ulcer.
stromal scarring but should be used cautiously. The thinning progresses circumferentially, but the overlying epithelium
For persistent epithelial defects and stromal lysis, patching or soft typically remains intact. Perforation is rare but may occur. Corneal hydrops
contact lens wear may be tried, but patients usually respond best to lateral has been reported, which may present as a clear intracorneal pocket of
or medial tarsorrhaphy (temporary with suture or botulinum-A toxin injec- aqueous rather than stromal clouding.64
tion,48 or permanent). Improved corneal sensation and promotion of epi- Irregular corneal astigmatism from progressive flattening of the verti-
thelial healing may occur following treatment with topical nerve growth cal meridian and high against-the-rule astigmatism is characteristic. Initial
factor.49,50 Collagenase inhibitors play an important role in normal corneal conservative management includes the use of rigid gas-permeable contact
health and repair.51 Collagenase inhibitors may play a supportive role in lenses. Rarely, Terrien’s degeneration may present as a pseudo-pterygium
the management of neurotrophic keratopathy.52 Autologous serum may be with a broad, flat, leading edge that arises in an oblique axis. Underlying
effective.53,54 Scleral contact lenses may offer superior long-term efficacy corneal thinning should be monitored carefully. Intraocular lenses have
compared with soft bandage lenses.55,56 Conjunctival flaps may be neces- been placed successfully through the furrow.
sary in severe cases. Corneal perforation can be managed with cyanoac-
rylate glue and lamellar or penetrating keratoplasty. Amniotic membrane Diagnosis
in its sutureless form or secured with or without fibrin glue has been
used as an effective patch graft in the management of persistent epithe- Terrien’s marginal degeneration is distinguished from other peripheral
lial defects and deep corneal neurotrophic ulcers refractory to conventional corneal thinning disorders by the lack of inflammation, presence of super-
treatment.57–60 Management of any eyelid abnormality must be aggressive. ficial vascularization, advancing linear deposition of lipid, lack of epithe-
lial defect, and slow progressive course. Collagen vascular disease should
Course and Outcome be ruled out. No known systemic disorders occur with Terrien’s marginal
degeneration.
Patients with superficial punctate staining should be maintained on daily
and evening lubrication. Persistent epithelial defects respond best to tar- Differential Diagnosis
sorrhaphy. Patients should be advised that neurotrophic ulcerations tend
to recur and can be difficult to heal. More severe sterile or infectious ulcers The differential diagnosis of Terrien’s marginal degeneration is outlined
may progress to descemetocele or perforation. in Box 4.17.5. Terrien’s generally is easy to distinguish from Mooren’s ulcer
because usually no pain or inflammation occurs. The epithelium is intact,
and no overhanging edge exists. Marginal furrow degeneration is bilateral
TERRIEN’S MARGINAL DEGENERATION and avascular, with only minimal, if any, thinning.
Terrien’s marginal degeneration is a slowly progressive, bilateral, periph-
Pathology
eral corneal thinning disorder associated with corneal neovascularization, Bowman’s membrane is typically absent or has degenerated (Fig. 4.17.10).
opacification, lipid deposition, and thinning.61 High degrees of astigma- Thinning and occasional breaks in Descemet’s membrane may be seen. 249
tism, particularly against-the-rule, may be seen. Up to one third of patients Subepithelial fibrillar collagen degeneration has been demonstrated by
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4
B Fig. 4.17.11 Patient with lax eyelid syndrome (LES)
Fig. 4.17.10 Terrien’s Degeneration. (A) Histological section shows limbus on the lenses. Because Terrien’s degeneration typically lacks an associated epithe-
left (iris not present) and central cornea to the right. (B) Note the marked stromal lial defect, the risk of infectious keratitis and acute corneal thinning is low.
thinning, thickened epithelium, and loss of Bowman’s membrane on the limbal side.
BOX 4.17.5 Differential Diagnosis of Terrien’s LAX EYELID CONDITION, LAX EYELID
Marginal Degeneration SYNDROME, AND FLOPPY EYELID SYNDROME
• Marginal furrow degeneration Epidemiology and Pathogenesis
• Dellen
• Collagen vascular disease The term “floppy eyelid syndrome” (FES) was first used in 1981 to describe
• Pellucid marginal degeneration the association of rubbery, lax upper eyelids with tarsal papillary conjunc-
• Sclerokeratitis tivitis seen in young obese men.67 In 1994, Van den Bosch and Lemji pro-
• Keratoconjunctivitis sicca posed a new classification system to include three related conditions: (1)
• Staphylococcal marginal keratitis lax eyelid condition (LEC), describing patients with laxity of the eyelids
• Infectious corneal ulcer in patients of any age without conjunctivitis, and not necessarily obese
(Figs. 4.17.11 and 4.17.12); (2) lax eyelid syndrome (LES), in patients with
LEC who also had chronic conjunctivitis; and (3) floppy eyelid syndrome
light microscopy, and an unknown stromal material in phagocytic cells has (FES), in patients who had LES and were obese.68,69 Eyelid laxity is actually
been demonstrated by electron microscopy.63 a very common, but overlooked, clinical finding. Ansari reported a high
prevalence (54%) of eyelid laxity in the upper or lower eyelids in a veter-
Treatment an’s administration population associated with significant ocular surface
morbidity.70
Usually no treatment is required, unless perforation or impending perfora- Obstructive sleep apnea (OSA) is highly prevalent, affecting 34% of
tion occurs. Severe astigmatism may be managed with spectacles or rigid men and 17% of women.71 OSA is a significant public health problem that
contact lenses. More severe thinning may require crescentic, full-thickness, has remained undiagnosed in 82% of patients and is responsible for $115
or lamellar keratoplasty.65 Eccentric, full-thickness grafts have been per- billion dollars in healthcare expenditures annually in the United States.72
formed, with an increase in graft rejection. Recently, case reports have Woog first reported the association between OSA and FES in 1990, with
been published in which corneal collagen cross-linking has been used to multiple subsequent studies supporting this association.73–80 Chambe et al.
halt progression and even reverse some of the degenerative changes seen showed that LEC/FES was observed in 15.8% of patients without OSA,
in the condition.66 25.8% of patients with OSA, and 40% of patients with severe OSA defined
as the apnea-hypopnea index (AHI) score > 30.77 In another study that
Course and Outcome included 89 patients with OSA, 16% were found to have FES, and 60.67%
were found to have increased eyelid laxity.79 Additionally, Acar et al. studied
250 Most patients who have Terrien’s degeneration do not progress to corneal 51 patients and monitored the effect of positive airway pressure on clini-
perforation and can be managed successfully with glasses or rigid contact cal symptoms of FES. A significant improvement occurred in FES with
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positive airway pressure.78 A positive correlation between the severity of The pathophysiology of OSA is complex and incompletely under-
FES and the severity of OSA has also been reported (Table 4.17.2).77,78 Robert
also reported that LEC itself is strongly associated with OSA.81
stood.84 A systemic elastin dysfunction may account for the multisystem
changes reportedly associated with OSA. Sériès et al. demonstrated elastin 4.17
The pathology of FES was first reported by Netland et al. in 1994, and changes in soft palate specimens from patients with OSA undergoing
these authors demonstrated a decreased concentration of elastin in the uvulopalatopharyngoplasty (UPPP).85 Ryan et al. demonstrated selective
tarsal plate of patients with FES.82 This observation was later corroborated activation of inflammatory cytokines in an in vitro model of intermittent
by Schlötzer-Schrehardt et al., who demonstrated papillary hyperplasia, hypoxia.86 They further demonstrated that circulating tumor necrosis
keratinization, and subepithelial infiltrate of the tarsal conjunctiva, as well factor alpha (TNF-α) levels were higher in patients with OSA (2.56 pg/
as co-localization of elastin loss with increased presence of matrix metallo- mL; interquartile range [IQR] 2.01–3.42 pg/mL) than in control subjects
proteinase, particularly MMP-7 and MMP-9, in the tarsal conjunctiva and (1.25 pg/mL; IQR 0.94–1.87; P < .001) but normalized with continuous
near the ciliary roots, accounting for the clinical sign of lash ptosis (Figs. positive airway pressure (CPAP) therapy (1.24 pg/mL; IQR 0.78–2.35 pg/
4.17.13 and 4.17.14).83 Ischemia–reperfusion injury has been proposed as the mL; P < .002). Circulating neutrophil levels were higher in patients with
most likely mechanism in LEC. OSA than in control subjects. Taban et al. found elevated plasma leptin
levels in patients with LES. Leptin was proposed to trigger the inflamma-
tory cascade by up-regulating MMP-9, resulting in breakdown of elastin.87
TABLE 4.17.2 Clinical Findings in Patient With Lax Eyelids and
Obstructive Sleep Apnea
Control Mild Moderate Severe MEDIAL CANTHAL TENDON LAXITY
Clinical Finding No OSA OSA OSA OSA Sig (P < .05)
FES 23.1% 41.7% 66.7% 74.6% P < .01 Horizontal resting position
OSDI 12.57 22.90 45.94 56.68 P < .01
+/− 17.64 +/− 16.78 +/− 22.03 +/− 22.5
Schirmer (mm) 10.76 9.83 7.73 6.97 P < .01
+/− 3.58 +/− 2.53 +/− 2.42 +/− 2.15
TBUT (seconds) 10.53 9.46 7.29 6.82 P < .01
+/− 3.64 +/−2.40 +/−2.13 +/−2.20
Corneal Stain 0.26 0.40 0.98 1.14 P < .01
+/− 0.60 +/− 0.71 +/− 0.72 +/− 0.90
FES, floppy eyelid syndrome; OSA, obstructive sleep apnea; OSDI, ocular surface disease index;
TBUT, tear break-up time.
A -1 0 1 2 3 4
Lateral distraction test
0 1 2 3 4 5 6
B
Fig. 4.17.13 Clinical grading system for lax eyelids. (From Olver J, Sathia PJ, Wright
Fig. 4.17.12 Patient with lax eyelid condition (LEC) M. Lower eyelid medial canthal tendon laxity. Ophthalmology 2001;108(12):2321–5.)
Fig. 4.17.14 Clinical grading system for lax eyelids. (From

Liu DT, Di Pascuale MA, Sawai J, Gao Y, Tseng SCG. Tear film
dynamics in floppy eyelid syndrome. Invest Ophthalmol Vis Sci
2005;46(4):1188–94.)
A B
C D 251
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Nadeem identified multiple circulating inflammatory factors associated
4 with OSA, including CRP, TNF-α, ICAM, IL-6, IL-8, VCAM, and selec-
tins.88 Becker reported the elevation of MMP-9 in the tear film of patients
with OSA.89
FES has been associated with a variety of anterior and posterior segment
conditions. Anterior ophthalmic findings include keratoconus, ptosis,
eyelash ptosis, meibomianitis, blepharitis, and ocular surface disor-
ders including superficial punctate keratitis and chronic conjunctivitis.90
Patients with FES may present with a variety of symptoms including eye
irritation, redness, discharge, pain, swelling of the eyelids, and foreign body
sensation.91 In addition, patients with LEC tend to have a more reactive
ocular surface, probably as a result of increased concentration of MMPs,
particularly MMP-7 and MMP-9 in the conjunctival epithelium, and also
in the tear film.89 The presence of an increase in MMPs may predispose
patients with FES to develop more severe manifestations of a wide variety A
of ocular surface diseases, including DED; phlyctenular disease; superior
limbic keratoconjunctivitis; neurotrophic keratitis; and many other nonin-
fectious ocular inflammatory diseases.
Because of the strong association between LEC and OSA, the diag-
nosis of FES becomes a critical risk factor for a wide variety of posterior
segment neurovascular ocular diseases as well.77 These include retinal vas-
cular occlusion,92 nonarteritic anterior ischemic optic neuropathy,93,94 and
glaucoma.95–98 Kremmer reported a halting of progressive field loss follow-
ing CPAP treatment in a patient with low-tension glaucoma.99 OSA and B C
FES should be considered risk factors for those patients, and OSA should
be a considered a potential modifiable factor, in addition to IOP, for the Fig. 4.17.15 Histopathology of eyelid (hematoxylin and eosin stain) (From
development and progression of glaucoma.100 A positive family history in Schlötzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, Cursiefen C, Kruse FE,
these patients with OSA can be elicited as well. Holbach LM. The pathogenesis of floppy eyelid syndrome involvement of matrix
metalloproteinases in elastic fiber degradation. Ophthalmology 2005;112(4):694–704.)
Diagnosis
Several methods exist for diagnosing the presence and severity of lid laxity.
Olver et al. described two methods of grading medial canthal tendon
laxity.101 They described the horizontal resting position method, which
grades the severity of lid laxity based on the resting position of the lower
punctum (Fig. 4.17.15). Normal, or grade 0, was defined as the location of
the lower punctum just medial to a vertical line made perpendicular to
the upper punctum. Grading ranged from −1 to 6 based on the extent of
displacement of the lower punctum at rest. Olver et al. also used the lateral A B
distraction method, which grades the severity of lid laxity on the basis of
displacement of the lower punctum laterally from resting position with
minimal pressure. They used several anatomical landmarks to describe
the degree of lateral displacement including the plica semilunaris, medial
corneal limbus, visual axis, and lateral corneal limbus.
Beis et al. defined hyperelasticity as upper lid eversion resulting in
exposure of the tarsal conjunctival for 3 seconds with the eyes in the infe-
rior gaze position.102 They then separated the severity of FES (LEC) into
stages 1 and stage 2, with stage 1 describing tarsal conjunctival exposure
lasting less than 6 seconds in the inferior gaze positioning and stage 2 C D
describing exposure for greater than 6 seconds.
Liu et al. separated the severity of FES (LEC) into grade 0 to grade 3
(Fig. 4.17.16).103 Grade 0 referred to no visibility of the upper eyelid tarsal
conjunctiva with eversion and, thus, no floppy eyelid. Grade 1 or mild FES
(LEC) described exposure of less than one third of the tarsal conjunctiva.
Grade 2 or moderate FES (LEC) included exposure of one third to one half
of the tarsal conjunctiva. Grade 3 or severe FES was described as more E F
than one half of the tarsal conjunctiva exposed.
Finally, Robert et al. defined the vertical hyperlaxity of the eyelids as the Fig. 4.17.16 Elastin changes in lax eyelids (Von Gieson stain). (From Schlötzer-
maximal distance between the palpebral rim and the center of the pupil in Schrehardt U, Stojkovic M, Hofmann-Rummelt C, Cursiefen C, Kruse FE, Holbach
primary position after manual traction on the eyelid.81 They also noted the LM. The pathogenesis of floppy eyelid syndrome involvement of matrix
presence of spontaneous tarsal eversion. metalloproteinases in elastic fiber degradation. Ophthalmology 2005;112(4):694–704.)
In a general ophthalmology practice, however, most cases of LEC/FES
probably are overlooked. This reflects the national statistics of 80% of
patients with OSA being undiagnosed. Bouchard et al. supported this con- film) has been managed with treatment for DED, with over-the-counter
clusion and reported the diagnosis of LEC in only 4% of the 11 975 patients artificial teardrops. In some cases, tear production is decreased, but many
with OSA in an academic institution who were seen in the eye clinic over have normal tear production and are unresponsive to topical lubricants.
a 5-year period.100 Some patients with LES, as in Acar’s study, are treated for their associ-
ated chronic papillary conjunctivitis, without identifying the eyelid laxity.
Differential Diagnosis Associated findings of blepharoptosis, lash ptosis, and ectropion, as well
as the meibomianitis that often accompanies the LEC, can be managed
252 Because the diagnosis of LEC often is missed, a large population of patients separately.90 Dermatochalasis can mask the LEC as well. Nocturnal lagoph-
with mild to moderate LEC and LES (with elevated MMP in their tear thalmos can also be managed.
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Systemic Associations topical lubricants and gels and ointments at bedtime may be of some
As mentioned previously, OSA is strongly associated with eyelid laxity.

benefit.
Conjunctival changes include chronic papillary conjunctivitis associated 4.17
OSA is defined as greater than five apnea/hypopnea events per hour, and with nocturnal lid eversion and metalloproteinase elevation. Management
severity is graded as mild, moderate, or severe. The respiratory distur- of the ocular surface as well as therapeutic bandage with contact lens wear
bance index (RDI) measures the number of events per hour. The history may be tried.
of snoring and daytime fatigue as well as lax eyelids should prompt sus- Corneal and ocular surface disease associations include (1) keratoconus,
picion of sleep apnea. Not all patients with OSA have daytime sleepiness (2) corneal scarring, (3) corneal neovascularization, (4) filamentary kerati-
and are described as having OSA. Most patients do not remember waking tis, (5) corneal erosion, (6) microbial keratitis, and (7) corneal thinning/
at night during the apneic episode, which makes the diagnosis more melting.90 Association with keratoconus is well known and should be
difficult. Apnea results in peripheral vasoconstriction and then regional suspected in these patients and managed appropriately. Chronic ocular
vasodilation of the cerebral and myocardial circulation. Postapneic hyper- surface disease associated with LES can result in corneal scarring, neovas-
ventilation leads to hypocapnia and peripheral vasodilation. Lack of subse- cularization, and microbial keratitis.
quent vasodilation in the ophthalmic vessels in glaucomatous eyes could Finally, in addition to managing the above eyelid and ocular surface dis-
then lead to a cerebrovascular “steal” from the blood flow to the optic nerve eases, one of the most important recommendations for ophthalmologists
head. Hypercapnia also increases intracranial pressure and causes meta- is to identify the patients at risk for OSA and refer them for a sleep study.
bolic stress and acidosis. As a result of chronic intermittent hypoxia, the Evaluation of all patients with complaints of chronic irritation should
increase in sympathetic tone in OSA associated with intermittent hypoxic include a careful evaluation of the eyelid laxity including distraction test
episodes is thought to result in endothelial damage.84,86,88 OSA affects the of both the upper and lower lids as well as tarsal conjunctival inflamma-
vascular endothelium through oxidative stress, inflammation, atheroscle- tion. Patients with complaints of chronic irritation with a normal Schirm-
rosis and a decreases in nitric oxide.84 The vasoconstrictor, endothelin-1 er’s score and who are unresponsive to frequent topical preservative-free,
has been shown to upregulate in OSA and in NTG. OSA then has a role teardrops should suggest a diagnosis other than aqueous tear deficiency
in vascular regulation. (caused by Demodex, lax eyelids, allergic conjunctivitis). Identification of
OSA has been associated with increasing risk of neurovascular disease lax eyelids should prompt an evaluation of sleep apnea and the many asso-
(diabetes), including pulmonary, cardiovascular (atherosclerosis, heart ciated ocular (and systemic) neurovascular diseases associated with sleep
disease, peripheral neuropathy), and cerebrovascular disease (stroke, apnea (glaucoma, ischemic optic neuropathy, papilledema, retinal vein
cognitive decline, depression, headache, and nonarteritic ischemic optic occlusion). A careful snoring history needs to be obtained from both the
neuropathy).104,105 OSAS also is associated with pulmonary hypertension, patient and partner as a key element for the diagnosis of sleep apnea and
myocardial infarction, cardiac arrhythmia, congestive heart failure, stroke, lax eyelid condition (LEC).106,109 A history of snoring and daytime fatigue
cardiac related mortality, and all may cause mortality.106 as well as lax eyelids should prompt suspicion of sleep apnea.109,110 STOP-
BANG or Berlin Questionnaires validated for diagnosing OSA should also
Pathology be administered (Video 4.17.1). See clip:
4.17.1
The pathology of LEC involves a decreased concentration of elastin colocal-
ized with MMP in the tarsal plate (see Fig. 4.17.12).82,83 KEY REFERENCES
The pathophysiology of FES has been thought to result from a process Chambe J, Laib S, Hubbard J, et al. Floppy eyelid syndrome is associated with obstructive
of ischemia–reperfusion injury from the pressure of the globe onto the sleep apnea: a prospective study on 127 patients. J Sleep Res 2012;21(3):308–15.
eyeball while sleeping. Indeed, the nocturnal eversion of the eyelid with Cher I. Superior limbic keratoconjunctivitis: multifactorial mechanical pathogenesis. Clin
contact of the eyeball and tarsal conjunctiva has been thought to account Exp Ophthalmol 2000;28:181–4.
Culbertson WW, Ostler HB. The floppy eyelid syndrome. Am J Ophthalmology 1981;568–75.
for the chronic conjunctivitis.91 Additional hypothesis includes a systemic Faridi O, Park SC, Liebmann JM, et al. Glaucoma and obstructive sleep apnoea syndrome.
elastin dysfunction.84–89 Clin Experiment Ophthalmol 2012;40:408–19.
Jacobs DS. Update on scleral lenses. Curr Opin Ophthalmol 2008;19:298–301.
Kafkala C, Choi J, Zafirakis P, et al. Mooren ulcer: an immunopathologic study. Cornea
TREATMENT 2006;25:667–73.
Kenyon KR. Decision-making in the therapy of external eye disease. Noninfected corneal
There is a wide variety of eyelid, tear film, conjunctival, corneal, and ulcers. Ophthalmology 1982;89:44–51.
ocular surface changes that are associated with LES. The eyelid changes Kervick GN, Pflugfelder SC, Haimovici R, et al. Paracentral rheumatoid corneal ulceration:
include (1) lax eyelids, (2) blepharoptosis, (3) ectropion, (4) lagophthal- clinical features and cyclosporine therapy. Ophthalmology 1992;99:80–8.
Khokhar S, Natung T, Sony P, et al. Amniotic membrane transplantation in refractory neu-
mos, (5) eyelash ptosis, (4) meibomianitis, and (5) infestation by Demodex rotrophic corneal ulcers: a randomized, controlled clinical trial. Cornea 2005;24:654–60.
brevis.90 Infrared thermography demonstrates increased blood flow to McCallum RM, Allen NB, Cobo LM, et al. Cogan’s syndrome: clinical features and outcomes.
the eyelids and perioral region.103 Management of eyelid laxity depends Arthritis Rheum 1992;35(Suppl. 9):S51.
on the severity of the disease. For mild disease an eye shield at bedtime Nagra PK, Rapuano CJ, Cohen EJ, et al. Thygeson’s superficial punctate keratitis: 10 years’
experience. Ophthalmology 2004;111:34–7.
might be helpful. Most of these patients, however, use a CPAP machine Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by inter-
at night, which precludes the use of a shield. The CPAP device may mittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–7.
result in worsening ocular symptoms. For more severe disease, treatment Smith VA, Hoh HB, Easty DL. Role of ocular matrix metalloproteinases in peripheral ulcer-
approaches include full thickness upper eyelid wedge resection, and lateral ative keratitis. Br J Ophthalmol 1999;83:1376–83.
van den Bosch WA, Lemij HG. The lax eyelid syndrome. Br J Ophthalmol 1994;78:666–70.
tarsal strip.107 Wood TO, Kaufman HE. Mooren’s ulcer. Am J Ophthalmol 1971;71:417–22.
The tear film changes include lipid tear deficiency, decreased BUT, and
MMP-9 elevation with associated punctate keratopathy (see Table 4.17.2).
Most patients also have meibomian gland dysfunction and may benefit Access the complete reference list online at ExpertConsult.com
from oral omega-3 fatty acids.108 Short-term topical corticosteroid use and
253
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REFERENCES 45. Mackie IA. Role of the corneal nerves in destructive disease of the cornea. Trans Oph-
thalmol Soc UK 1978;98:343–7.
1. Kenyon KR. Decision-making in the therapy of external eye disease. Noninfected corneal
ulcers. Ophthalmology 1982;89:44–51.
46. Chucair-Elliott AJ, Jinkins J, Carr MM, et al. IL-6 contributes to corneal nerve degenera-
tion after herpes simplex virus type I infection. Am J Pathol 2016;186:2665–78.
4.17
2. Thygeson P. Superficial punctate keratitis. JAMA 1950;144:1544–9. 47. Mackie IA. Role of the corneal nerves in destructive disease of the cornea. Trans Oph-
thalmol Soc UK 1978;98:343–7.
3. Lemp MA, Chambers RW, Lundy J, et al. Viral isolate in superficial punctate keratitis.
Arch Ophthalmol 1974;91:8–10. 48. Kirkness CM, Adams GG, Dilly PN, et al. Botulinum toxin-A induced protective ptosis
4. Connell PP, O’Reilly J, Coughlan S, et al. The role of common viral pathogens in Thy- in corneal disease. Ophthalmology 1988;95:473–80.
geson’s superficial punctate keratitis. Br J Ophthalmol 2007;91:1038–41. 49. Tan MH, Bryars J, Moore J. Use of nerve growth factor to treat congenital neurotrophic
5. Darrell RW. Thygeson’s superficial punctate keratitis: natural history and association corneal ulceration. Cornea 2006;25:352–5.
with HLA-DR3. Trans Am Ophthalmol Soc 1981;74:486–516. 50. Bonini S, Lambiase A, Rama P, et al. Topical treatment with nerve growth factor for
6. Kawamoto K, Chikama T, Takahashi N, et al. In vivo observation of Langerhans cells neurotrophic keratitis. Ophthalmology 2000;107:1347–51.
by laser confocal microscopy in Thygeson’s superficial punctate keratitis. Mol Vis 51. Corrales RM, Stern ME, De Paiva CS, et al. Desiccating stress stimulates expres-
2009;15:1456–62. sion of matrix metalloproteinase by corneal epithelium. Invest Ophthalmol Vis Sci
7. Zhai J, Gu J, Yuan J, et al. Tacrolimus in the treatment of ocular diseases. Biodrugs 2006;47:393–33302.
2011;25:89–103. 52. Moon SW, Yeom DJ, Chung SH. Neurotrophic corneal ulcer development following
8. Nagra PK, Rapuano CJ, Cohen EJ, et al. Thygeson’s superficial punctate keratitis: 10 cataract surgery with a limbal relaxing incision. Korean J Ophthalmol 2011;25:210–13.
years’ experience. Ophthalmology 2004;111:34–7. 53. Choi JA, Chung SH. Combined application of autologous serum eye drops and sili-
9. Nesburn AB, Lowe GH, Lepoff NJ, et al. Effect of topical trifluridine on Thygeson’s cone hydrogel lenses for the treatment of persistent epithelial defects. Eye Contact Lens
superficial punctate keratitis. Ophthalmology 1984;91:1188–92. 2011;37:370–3.
10. Fite SW, Chodosh J. Photorefractive keratectomy for myopia in the setting of Thygeson’s 54. Jeng BH, Dupps WJ. Autologous serum 50% eyedrops in the treatment of persistent
superficial punctate keratitis. Cornea 2001;20:425–6. corneal epithelial defects. Cornea 2009;28:1104–8.
11. Goldstein MH, Feistmann JA, Bhatti MT. PRK-pTK as a treatment for a patient with 55. Gumus K, Gire A, Pflugfelder SC. The successful use of Boston ocular surface prosthe-
Thygeson’s superficial punctate keratitis. CLAO J 2002;28:172–3. sis in the treatment of persistent corneal epithelial defect after herpes zoster ophthal-
12. Theodore FH. Superior limbic keratoconjunctivitis. Eye, Ear. Nose Throat Monthly micus. Cornea 2010;29:1465–8.
1963;42:25–8. 56. Jacobs DS. Update on scleral lenses. Curr Opin Ophthalmol 2008;19:298–301.
13. Cher I. Superior limbic keratoconjunctivitis: multifactorial mechanical pathogenesis. 57. Kruse FE, Rohrschneidwer K, Volcker HE. Multilayer amniotic membrane transplanta-
Clin Exp Ophthalmol 2000;28:181–4. tion for reconstruction of deep corneal ulcers. Ophthalmology 1999;106:1504–10.
14. Kadramas EF, Bartley GB. Superior limbic keratoconjunctivitis. A prognostic sign for 58. Khokhar S, Natung T, Sony P, et al. Amniotic membrane transplantation in refrac-
severe Graves’ ophthalmopathy. Ophthalmology 1995;102:1472–5. tory neurotrophic corneal ulcers; a randomized, controlled clinical trial. Cornea
15. Matsuda A, Tagawa Y. Matsududa H. TGF-beta2, tenascin, and integrin beta1 expression 2005;24:654–60.
in superior limbic keratoconjunctivitis. Jpn J Ophthalmol 1999;43:251–6. 59. Hick S, Demers PE, Brunette I, et al. Amniotic membrane transplantation and fibrin
16. Sivaraman KR, Jivrajka RV, Soin K, et al. Superior limbic keratoconjunctivitis-like inflam- glue in the management of corneal ulcers and perforations: a review of 33 cases. Cornea
mation in patients with chronic graft-versus-host disease. Ocul Surf 2016;14:393–400. 2005;24:369–77.
17. Matsuda A, Tagawa Y, Matsuda H. Cytokeratin and proliferative cell nuclear antigen 60. Pachiqolla G, Prasher P, DiPascuale MA, et al. Evaluation of the role of ProKera in the
expression in superior limbic keratoconjunctivitis. Curr Eye Res 1996;15:1033–8. management of ocular surface and orbital disorders. Eye Contact Lens 2009;35:172–5.
18. Sun YC, Hsiao CH, Chen WL, et al. Overexpression of matrix metalloproteinase-1 61. Lopez JS, Price FW, Whitcup SM, et al. Immunohistochemistry of Terrien’s and
(MMP-1) and MMP-3 in superior limbic keratoconjunctivitis. Invest Ophthalmol Vis Sci Mooren’s corneal degeneration. Arch Ophthalmol 1991;109:988–92.
2011;52:3701–5. 62. Austin P, Brown SI. Inflammatory Terrien’s marginal corneal disease. Am J Ophthal-
19. Yang HY, Fujishima H, Toda I, et al. Lacrimal punctal occlusion for the treatment of mol 1981;92:189–92.
superior limbic keratoconjunctivitis. Am J Ophthalmol 1997;124:80–7. 63. Iwamoto T, DeVoe AG, Farris RL. Electron microscopy in cases of marginal degenera-
20. Udell IJ, Kenyon KR, Sawa M. Treatment of superior limbic keratoconjunctivitis by ther- tion of the cornea. Invest Ophthalmol Vis Sci 1972;11:241–57.
mocauterization of the superior bulbar conjunctiva. Ophthalmology 1986;93:162–6. 64. Ashenhuurst M, Slomovic A. Corneal hydrops in Terrien’s marginal degeneration: an
21. Perry HD, Doshi-Carnevale S, Donnenfeld ED, et al. Topical cyclosporine A 0.5% as unusual complication. Can J Ophthalmol 1987;22:328–30.
a possible new treatment for superior limbic keratoconjunctivitis. Ophthalmology 65. Hahn TW, Kim JH. Two step annular tectonic lamellar keratoplasty in severe Terrien’s
2003;110:1578–81. marginal degeneration. Ophthalmic Surg 1993;24:831–4.
22. Goto E, Shimmura S, Shimazaki J, et al. Treatment of superior limbic keratoconjuncti- 66. Hafezi F, Gatzioufas Z, Seller TG, et al. Corneal collagen cross-linking for Terrien mar-
vitis by application of autologous serum. Cornea 2001;20:807–10. ginal degeneration. J Refract Surg 2014;30:498–500.
23. Ohashi Y, Watanabe H, Kinoshita S, et al. Vitamin A eyedrops for superior limbic kera- 67. Culbertson WW, Ostler HB. The floppy eyelid syndrome. Am J Ophthalmology
toconjunctivitis. Am J Ophthalmol 1988;105:523–7. 1981;568–75.
24. Kymionis GD, Klados NE, Kontadakis GA, et al. Treatment of superior limbic keratocon- 68. van den Bosch WA, Lemij HG. The lax eyelid syndrome. Br J Ophthalmol 1994;78:666–70.
junctivitis with topical tacrolimus 0.03% ointment. Cornea 2013;32:1499–501. 69. Fowler A, Dutton J. Floppy eyelid syndrome as a subset of lax eyelid conditions: rela-
25. Takahashi Y, Ichinose A, Kakizaki H. Topical rebamipide treatment for superior tionships and clinical relevance (an ASOPRS Thesis). Ophthal Plast Reconstr Surg
limbic keratoconjunctivitis in patients with thyroid eye disease. Am J Ophthalmol 2010;26(3):195–204.
2014;157:807–12. 70. Ansari Z, Singh R, Alabiad C, et al. Prevalence, risk factors and morbidity of eyelid
26. Mooren A. Ophthalmiatrische beobachtungen. Berlin: A Hirschwald; 1867. p. 107–10. laxity in a veteran population. Cornea 2015;34:32–6.
27. Wood TO, Kaufman HE. Mooren’s ulcer. Am J Ophthalmol 1971;71:417–22. 71. Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breath-
28. Gottsch JD, Li Q, Ashraf F, et al. Cytokine-induced calgranulin C expression in kerato- ing in adults. Am J Epidemiol 2013;177(9):1006–14.
cytes. Clin Immunol 1999;91:34–40. 72. The Harvard Medical School Division of Sleep Medicine. The price of fatigue: the sur-
29. Taylor CJ, Smith SI, Morgan CH, et al. HLA and Mooren’s ulceration. Br J Ophthalmol prising economic costs of unmanaged sleep apnea. 2010.
2000;84:72–5. 73. Woog JJ. Obstructive sleep apnea and the floppy eyelid syndrome. Am J Ophthalmol
30. Kafkala C, Choi J, Zafirakis P, et al. Mooren ulcer: an immunopathologic study. Cornea 1990;110(3):314–15.
2006;25:667–73. 74. Mojon DS, Goldblum D, Fleischhauer J, et al. Eyelid, conjunctival, and corneal findings
31. Mozami G, Auran JD, Florakis GJ, et al. Interferon treatment of Mooren’s ulcers associ- in sleep apnea syndrome. Ophthalmology 1999;106(6):1182–5.
ated with hepatitis C. Am J Ophthalmol 1995;119:365–6. 75. Kadyan A, Asghar J, Dowson L. Ocular findings in sleep apnoea patients using contin-
32. Wilson SE, Lee WM, Murakami C, et al. Mooren-type hepatitis C virus associated uous positive airway pressure. Eye 2009;24(5):843–50.
corneal ulceration. Ophthalmology 1994;101:736–45. 76. Karger RA, White WA, Park W, et al. Prevalence of floppy eyelid syndrome in obstruc-
33. Bouchard CS, Meyer M, McDonnell JF. Peripheral ulcerative keratitis in a leukemic tive sleep apnea–hypopnea syndrome. Ophthalmology 2006;113(9):1669–974.
patient with pyoderma gangrenosum. Cornea 1997;16:480–2. 77. Chambe J, Laib S, Hubbard J, et al. Floppy eyelid syndrome is associated with obstruc-
34. Tandon R, Chawla B, Verma K, et al. Outcome of treatment of Mooren ulcer with topical tive sleep apnea: a prospective study on 127 patients. J Sleep Res 2012;21(3):308–15.
cyclosporine A 2%. Cornea 2008;27:859–61. 78. Acar M, Firat H, Acar U, et al. Ocular surface assessment in patients with obstructive
35. Zhao JC, Jin XY. Immunological analysis and treatment of Mooren’s ulcer with cyclo- sleep apnea-hypopnea syndrome. Sleep Breath 2013;17:583–8.
sporin A applied topically. Cornea 1993;12:481–8. 79. Muniesa MJ, Huerva V, Sanchez-de-la-Torre M, et al. The relationship between floppy
36. Ngan ND, Chau HT. Amniotic membrane transplantation for Mooren’s ulcer. Clin eyelid syndrome and obstructive sleep apnea. Br J Ophthalm 2013;97(11):1387–90.
Experiment Ophthalmol 2011;39:386–92. 80. Wang P, Yu D-J, Feng G, et al. Is floppy eyelid syndrome more prevalent in obstructive
37. Foster CS. Systemic immunosuppressive therapy for progressive bilateral Mooren’s sleep apnea syndrome patients? J Ophthalmol 2016;2016:6980281.
ulcer. Ophthalmology 1985;92:1436–9. 81. Robert PY, Adenis JP, Tapie P, et al. Eyelid hyperlaxity and obstructive sleep apnea
38. Erdem U, Kerimoglu H, Gundogan F, et al. Treatment of Mooren’s ulcer with topical (O.S.A.) syndrome. Eur J Ophthalm 1997;7(3):211–15.
administration of interferon alfa 2a. Ophthalmology 2007;114:446–9. 82. Netland PA, Sugrue SP, Albert DM, et al. Histopathologic features of floppy eyelid syn-
39. Fontana L, Parente G, Neri P, et al. Favourable response to infliximab in a case of bilat- drome. Involvement of tarsal elastin. Ophthalmology 1994;101(1):174–81.
eral refractory Mooren’s ulcer. Clin Experiment Ophthalmol 2007;35:871–3. 83. Schlötzer-Schrehardt U, Stojkovic M, Hofmann-Rummelt C, et al. The pathogenesis of
40. Ferrari G, Chauhan SK, Ueno H, et al. A novel mouse model for neurotrophic keratop- floppy eyelid syndrome involvement of matrix metalloproteinases in elastic fiber degra-
athy: trigeminal nerve stereotactic electrolysis through the brain. Invest Ophthalmol Vis dation. Ophthalmology 2005;112(4):694–704.
Sci 2011;52:2532–9. 84. Madani M, Madani F. Epidemiology, pathophysiology, and clinical features of obstruc-
41. Reid TW, Murphy CJ, Iwahashi CK, et al. Stimulation of epithelial cell growth by the tive sleep apnea. Oral Maxillofacial Surg Clin N Am 2009;21:369–75.
neuropeptide substance P. J Cell Biochem 1993;52:476–85. 85. Series F, Chakir J, Boivin D. Influence of weight and sleep apnea on the immunological
42. Araki-Sasaki K, Aizawa S, Hiramoto M, et al. Substance P induced cadherin expression and structural features of the uvula. Am J Resp Crit Care Med 2004;170:1114–19.
and its signal transduction in a cloned human corneal epithelial cell line. J Cell Physiol 86. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by
2000;182:189–95. intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–7.
43. Gilbard JP, Rossi SR. Tear film and ocular surface changes in a rabbit model of neuro- 87. Taban M, Taban M, Perry JD. Plasma leptin levels in patients with floppy eyelid syn-
trophic keratitis. Ophthalmology 1990;97:308–12. drome. Ophthalm Plast Reconstr Surg 2006;22(5):375–7.
44. Heigle TJ, Pflugfelder SC. Aqueous tear production in patients with neurotrophic kera- 88. Nadeem R, Molnar J, Madbouly EM, et al. Serum inflammatory markers in obstructive 253.e1
titis. Cornea 1996;15:135–8. sleep apnea: a meta-analysis. J Clin Sleep Ed 2013;9:1003–12.
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89. Becker M, Kirk C, Narala R, et al Lax Eyelid Syndrome (LES), Obstructive Sleep Apnea 101. Olver J, Sathia PJ, Wright M. Lower eyelid medial canthal tendon laxity. Ophthalmology
4 Syndrome (OSAS), and Ocular Surface Inflammation. ARVO Abstract #3888-A0036,

Seattle WA, 2016.
90. Culbertson W, Tseng S. Corneal disorders in floppy eyelid syndrome. Cornea
1994;13(1):33–42.
2001;108(12):2321–5.
102. Beis PG, Brozou CG, Gourgoulianis KI, et al. The floppy eyelid syndrome: evaluating lid
laxity and its correlation to sleep apnea syndrome and body mass index. ISRN Ophthal-
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91. Ezra DG, Beaconsfield M, Collin R. Floppy eyelid syndrome: stretching the limits. Surv 103. Liu DT, Di Pascuale MA, Sawai J, et al. Tear film dynamics in floppy eyelid syndrome.
Ophthalmol 2010;55(1):35–46. Invest Ophthalmol Vis Sci 2005;46(4):1188–94.

92. Chou KT, Huang CC, Tsai DC, et al. Sleep apnea and risk of retinal vein occlusion: a 104. De Torres-Alba F, Gemma D, Armada-Romero E, et al. Obstructive sleep apnea and
nationwide population-based study of Taiwanese. Am J Ophthalmol 2012;154:200–5. coronary artery disease: from pathophysiology to clinical implications. Pulmonary Med-
93. Bilgin G, Koban Y, Arnold AC. Nonarteritic anterior ischemic optic neuropathy and icine 2013;2013:1–9.
obstructive sleep apnea. J Neuroophthalmol 2013;33:232–4. 105. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for
94. Archer EL, Pepin S. Obstructive sleep apnea and nonarteritic anterior ischemic optic stroke and death. N Engl J Med 2005;353:2034–41.
neuropathy: evidence for an association. J Clin Sleep Med 2013;9:613–18. 106. Redline S. Screening for obstructive sleep apnea: implications for the sleep health of the
95. Walsh JT, Montplaisir J. Familial glaucoma with sleep apnoea: a new syndrome? Thorax population. JAMA 2017;317(4):368–70.
1982;37:845–9. 107. Ezra DG, Beaconsfield M, Sira M, et al. Long-term outcomes of surgical approaches to
96. Faridi O, Park SC, Liebmann JM, et al. Glaucoma and obstructive sleep apnoea syn- the treatment of floppy eyelid syndrome. Ophthalmology 2010;117(4):839–46.
drome. Clin Experiment Ophthalmol 2012;40:408–19. 108. Epitropoulos AT, Donnenfeld ED, Shah ZA, et al. Effect of oral re-esterified omega-3
97. Shi Y, Liu P, Guan J, et al. Association between glaucoma and obstructive sleep apnea nutritional supplementation on dry eyes. Cornea 2016;35(9):1185–91.
syndrome: a meta-analysis and systemic review. PLoS ONE 2015;10(2):e0115625. 109. Jonas DE, Amick HR, Feltner C, et al. Screening for obstructive sleep apnea in adults:
98. Liu S, Lin Y, Liu X. Meta-analysis of association of obstructive sleep apnea with glau- evidence report and systematic review for the US Preventive Services Task Force. JAMA
coma. J Glaucoma 2016;25:1–7. 2017.
99. Kremmer S, Niederdraing N, Ayertey HD, et al. Obstructive sleep apnea syndrome, 110. Redline S, Baker-Goodwin S, Epstein M, et al. Patient partnerships transforming sleep
normal tension glaucoma, and nCPAP therapy – a short note. Sleep 2003;26:161–2. medicine research and clinical care: perspectives from the sleep apnea patient-centered
100. Bouchard C, Maki S, Undevia N, et al. The association of systemic and ocular disease outcomes network. J Clin Sleep Med 2016;12:1053–8.
and the under diagnosis of floppy eyelid syndrome in patients with obstructive sleep
apnea. Invest Ophthalmol Vis Sci 2014;55:E-Abstract 1465.
253.e2
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Keratoconus and Other Ectasias

Joel Sugar, Debora E. Garcia-Zalisnak 4.18
Fig. 4.18.1
Definition: Corneal ectasia is a group of disorders affecting the Characteristic
shape of the cornea and include keratoconus, pellucid marginal conical steeping
corneal degeneration, post–refractive surgery corneal steepening, and of the cornea in
keratoglobus. keratoconus.
Key Features
• Usually bilateral, although often asymmetric.
• Isolated to cornea.
• Noninflammatory.
Associated Features
• Obesity.
• Sleep apnea.
• Down syndrome.
• Atopic disease.
KERATOCONUS
Keratoconus is a disorder characterized by progressive corneal steepening,
most typically inferior to the center of the cornea, with eventual corneal
thinning, induced myopia, and both regular and irregular astigmatism.
Epidemiology and Pathogenesis Bowman’s layer, and deep stromal stress lines that clear when pressure
The pathogenesis of keratoconus is not fully understood, although both is applied to the globe. A ring of iron deposition (Fleischer’s ring) (Fig.
genetic and environmental processes are likely to be involved. Keratoconus 4.18.2) can accumulate in the epithelium at the base of the cone. Steepen-
is probably not a single disorder but, rather, a phenotypic expression of ing of the cornea leads to clinical signs which include protrusion of the
several possible causes. lower eyelid on downgaze (Munson’s sign), focusing of a light beam shone
A hallmark of keratoconus is stromal thinning, which may be related from temporally across the cornea in an arrowhead pattern at the nasal
to alterations in enzyme levels in the cornea, causing stromal degradation. limbus (Rizutti’s sign), and a dark reflex in the area of the cone on obser-
This is supported by multiple studies suggesting increased levels of degra- vation of the cornea with the pupil dilated using a direct ophthalmoscope
dative lysosomal enzymes and decreased levels of inhibitors of proteolytic set on plano (Charleaux’s sign) (Fig. 4.18.3). In addition, a scissoring reflex
enzymes in corneal epithelium.1,2 These findings are consistent with the can be found on retinoscopy. In some patients who have keratoconus,
observation of increased collagenolytic and gelatinolytic activity in kerato- especially if associated with trisomy 21 (Down syndrome), acute corneal
conic cells.3,4 hydrops may occur, in which an abrupt rupture of Descemet’s membrane
Increased apoptosis of stromal keratocytes has been reported in kerato- results in acute overhydration of the cornea and accumulation of lakes of
conus, as suggested by confocal microscopy.5,6 It is postulated that this loss fluid within the corneal stroma. Over time, endothelial cells spread over
of keratocytes results in a decrease in collagen and extracellular matrix pro- the posterior stromal defect to lay down new Descemet’s membrane and
duction, leading to reduced stromal mass. Other investigators have sug- recompensate the cornea (Fig. 4.18.4).
gested that abnormalities in corneal collagen and its cross-linking may be
the cause of keratoconus.7 Diagnosis
Eye rubbing is strongly associated with the development of keratoco-
nus. The mechanism by which eye rubbing contributes to keratoconus is Topography and tomography are useful to confirm the diagnosis of ker-
not completely understood, but it may be related to mechanical epithelial atoconus and, in some cases, even to make the diagnosis of subtle cases
trauma, triggering a wound-healing response that leads to keratocyte apop- without clinical manifestations (see Fig. 4.18.3). Both placido disc and rotat-
tosis. Other factors, such as slippage of collagen fibrils and a decrease in ing Scheimpflug camera systems for assessing corneal curvature are reli-
ground substance viscosity, may play a role.8 The cytokine interleukin-6 able in distinguishing keratoconic eyes from normal eyes, although there
has been suggested as a mediator of eye rubbing and stromal degradation.9 may be differences in posterior elevation measurements between the two
The prevalence of keratoconus in the general population varies in dif- systems.11 The Rabinowitz criteria can be used for the diagnosis of keratoco-
ferent series. A recent study that evaluated 4.4 million patients from a nus, and they include K greater than +47.20 diopters (D), inferior-versus-su-
mandatory health insurance database found the estimated prevalence of perior corneal dioptric asymmetry value greater than +1.40 D, KISA%
keratoconus in the general population to be 1 out of 375 persons.10 greater than 60%, which is suggestive of the disease, whereas more than
100% strongly suggests keratoconus, and a pachymetry/asymmetry index
Ocular Manifestations of less than 105. KISA% index quantifies the topographical features seen in
keratoconus. It includes the K-value, the inferior–superior dioptric asym-
254 Manifestations of keratoconus include steepening of the cornea, especially metry, and the AST index, which quantifies the degree of regular corneal
inferiorly (Fig. 4.18.1), thinning of the corneal apex, scarring at the level of astigmatism.12
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Fig. 4.18.2 Severe Apical Thinning in a
Cornea With Keratoconus. A broader slit-
beam view of the same cornea (B) reveals 4.18
extensive stromal apical scarring and
linear breaks in Bowman’s layer.

A B
Fig. 4.18.3 Charleaux’s sign in keratoconus, delineating the extent of the cone.
Fig. 4.18.4 Massive Hydrops in Keratoconus. Note the large tear in Descemet’s
membrane.
Such analyses have been used to demonstrate that keratoconus is
almost always a bilateral disease, even when not evident in the fellow eye have been found to have lower odds of keratoconus, and no association
as seen under at the slit lamp. has been found between keratoconus and allergic rhinitis, mitral valve
The inheritance pattern of keratoconus is incompletely defined. In the disorder, aortic aneurysm, or depression.14 Other systemic associations
past, it was believed that more than 90% of cases were sporadic. With the include Ehlers–Danlos, Marfan’s, Cruzon’s, and Apert’s syndromes.
advent of videokeratography to assess family members, however, pedigrees Ocular-associated disorders include Leber’s congenital amaurosis, retinitis
have been analyzed. These studies show corneal changes consistent with pigmentosa, and retinopathy of prematurity. Fuchs’ dystrophy and poste-
keratoconus in some asymptomatic family members, which suggests an rior polymorphous dystrophy have been reported as well.
autosomal dominant pattern of inheritance.13
Pathology
Differential Diagnosis Histopathology shows irregular epithelium and breaks in Bowman’s layer
The differential diagnosis of keratoconus includes pellucid marginal with fibrosis filling in the breaks and extending beneath the epithelium
corneal degeneration, post–refractive surgery corneal ectasia, posttrau- (Fig. 4.18.5), and central corneal thinning. With hydrops, breaks at the level
matic corneal ectasia, protrusion of the cornea after corneal thinning from of Descemet’s membrane are seen with inward curling of the membrane,
ulceration, and keratoglobus. which is otherwise normal. Electron microscopy shows decreased thick-
ness of the cornea with fewer lamellae. The collagen fibrils in the lamellae
Systemic Associations are thinned mildly, and the space between fibrils is decreased.15,16
A number of systemic and ocular disorders have been described in asso-

ciation with keratoconus. Conditions found to have increased odds of
Treatment
keratoconus include sleep apnea, asthma, and Down syndrome. Inter- Treatment consists of spectacles for myopic astigmatism and then rigid 255
estingly, patients with diabetes mellitus and collagen vascular disease contact lenses or scleral lenses once spectacle-corrected visual acuity
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4
Fig. 4.18.5 Keratoconus. Breaks in Bowman’s layer, with fibrosis that extends
beneath the epithelium, can be seen. The stroma shows scarring.
Fig. 4.18.6 Pellucid Marginal Corneal Degeneration. The point of greatest

(SCVA) becomes inadequate. When contact lenses fail, surgical treatment protrusion is just above the area of maximal thinning (located inferiorly).
is indicated. In one series, the reasons for penetrating keratoplasty were
contact lens intolerance (83%), frequent contact lens displacement (8.5%),
and unsatisfactory visual acuity despite good fit of contact lenses (8.5%).17
Standard surgical treatment consists of deep anterior lamellar kerato- have postulated that recurrence could be related to incomplete excision of
plasty (DALK) or penetrating keratoplasty (PKP). Keratoconus accounted the cone at the time of surgery, unrecognized keratoconus in the corneal
for 14.8% of all penetrating keratoplasty and 38.3% of all DALK carried donor, or host cellular activity that causes changes in the donor corneal
out in the United States in 2015.18 At the time of keratoplasty, decreas- material.30
ing the donor/recipient size disparity reduces postkeratoplasty myopia.19 In one study on the long-term outcomes of intracorneal ring segments,
Primary advantages of DALK over PKP include increased structural integ- with 17 eyes and 5-year follow-up, Intacs placement reduced mean spher-
rity and reduced risk of graft rejection. Some surgical techniques, such as ical equivalent refractive error from −5.54 ± 5.02 D to −3.02 ± 2.65 D (P ≡
the big-bubble technique, have reduced surgical operating time, though it .01), reduced mean keratometry from 49.59 ± 5.10 D to 48.02 ± 4.99 D (P ≡
remains challenging to perform, especially for inexperienced surgeons.20 .009), and improved uncorrected visual acuity in 77% of patients.31 Compli-
Bowman’s layer graft is another surgical technique in the treatment of ker- cations of Intacs include infection, corneal melt, and ring extrusion. One
atoconus. It was shown to be beneficial in a small series, where reduction study showed significant postoperative problems in 30% of Intacs with
and stabilization of corneal ectasia were achieved in eyes with progressive, thinning and ring exposure.32
advanced keratoconus.21 Results of long-term follow-up of corneal cross-linking are promising.
Intracorneal ring segments, first described for keratoconus in 2000,22 Data from the Siena Eye Cross Study in Italy revealed a mean hyperopic
have been shown in several studies to be successful in reducing myopia shift in spherical equivalent of +2.15 D and a mean reduction in ker-
and astigmatism and improving SCVA.23 The ring segments can be atometry of +2.26 D on 4-year follow-up of 44 patients.33 Complications
inserted into the stroma either via mechanical dissection or femtosecond include temporary stromal edema, temporary or permanent corneal haze,
laser assistance. Currently Intacs (Addition Technology, Sunnyvale, CA) is corneal scarring, sterile infiltrates, infectious keratitis, and diffuse lamellar
the only intrastromal corneal ring segment approved in the United States. keratitis.34–38
Another less invasive technique that was approved by the Food and Both intracorneal ring segments and corneal cross-linking are most
Drug Administration (FDA) in the United States in August 2016 is com- likely to be beneficial in patients with mild to moderate keratoconus
bined riboflavin–ultraviolet A rays (UVA) corneal cross-linking. This proce- without corneal scarring; in these patients, stabilization of keratoconus
dure, first described in 1998,24 consists of photopolymerization of corneal may obviate or delay the need for keratoplasty. More advanced cases typi-
stroma by combining riboflavin (photosensitizing substance) with UVA. cally need keratoplasty for optimal visual outcome.
This process increases corneal rigidity and thus reduces the likelihood of
further ectasia. Cross-linking is indicated in patients with documented pro-
gressive corneal ectasia. Contraindications include corneal thickness less
PELLUCID CORNEAL DEGENERATION
than 400 microns (although use of hypotonic solutions may allow swell- Pellucid marginal corneal degeneration appears to be a variant of keratoco-
ing to greater than this level prior to treatment), prior herpetic infection, nus, with some different clinical features. Corneal thinning and protrusion
concurrent infection, severe corneal scarring, history of poor epithelial are seen in the inferior peripheral cornea; the thinning begins 1–2 mm
wound healing, severe ocular surface disease, and autoimmune disor- inside the inferior limbus in a horizontal oval band approximately 2 mm
ders.25 Various protocols with different treatment and epithelium handling in radial extent and 6–8 mm in horizontal extent (Fig. 4.18.6). The involved
are under ongoing evaluation. Currently, the only FDA-approved protocol area is clear, and usually no iron line occurs central to it. Hydrops may
in the United States is the “epithelium off” protocol, where the cornea is occur. The central cornea is regular, but usually with marked against-the-
treated after epithelial removal, but “transepithelial” corneal cross-linking rule astigmatism. Some patients who have pellucid may have more typical
continues to be studied and refined.26-28 central corneal changes of keratoconus, as may family members, although
the inheritance of pellucid is not clear. Pathology appears to be the same
Course and Outcome as in keratoconus. Treatment, as for keratoconus, consists of spectacles
or contact lenses. When these modalities are insufficient, results are best
The natural course of untreated keratoconus can be unpredictable, found with large, eccentric keratoplasty. Outcomes of keratoplasty in pellu-
although progressive myopia, irregular astigmatism, and corneal scarring cid marginal degeneration are poorer than in keratoconus because of the
are typical. It is widely estimated that 10%–20% of patients with keratoco- more peripheral location of corneal thinning.
nus undergo keratoplasty, although a recent report found as much as a 25%
reduction in the performance of keratoplasty since corneal cross-linking
began to be used.29 Keratoplasty outcomes in terms of graft clarity and
KERATOGLOBUS
improved vision are excellent, although residual astigmatism and myopia Epidemiology and Pathogenesis
remain problematic. Recurrence of keratoconus after keratoplasty may
256 rarely occur, although thinning and ectasia at the inferior host–graft junc- At least two forms of keratoglobus appear to exist: (1) a congenital or juve-
tion is not uncommon 15 or more years after keratoplasty. Some authors nile form and (2) an acquired adult form. The acquired form may be an
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end-stage form of keratoconus—patients have been described with initial of corneal mesenchymal dysgenesis. Treatment usually is not necessary,
keratoconus followed by later keratoglobus—or acquired keratoglobus may
be seen with no known prior keratoconus. The congenital form appears
although occasionally keratoplasty is indicated.
4.18
to be part of at least two different autosomal recessive syndromes. One
is Ehlers–Danlos syndrome type VI. Another clinically similar syndrome, POST–REFRACTIVE SURGERY

but with normal lysyl hydroxylase activity, is brittle corneal syndrome with
associated blue sclera and red hair, which mimics Ehlers–Danlos syn-
CORNEAL ECTASIA
drome type VI.39 Corneal ectasia is an uncommon yet serious complication that can occur
after refractive surgery. Its prevalence has been reported to be 0.04%–0.6%,
Ocular Manifestations although some believe this is an underestimation. Ectasia is thought to
be a consequence of disrupting the biomechanical integrity of the cornea
Keratoglobus is a disorder characterized by the presence of limbus-to-lim- below a certain threshold. The FDA’s current guidelines prohibit leaving
bus corneal thinning with globular corneal protrusion. The thinning is less than 250 µm of untouched tissue, but most refractive surgeons prefer
usually greatest in the corneal periphery or midperiphery. Hydrops may to leave 300 µm or more.44 Risk factors for ectasia include an abnormal
occur, and perforations may result from relatively minor trauma. In preoperative corneal topography, >40% of tissue altered, a low preoperative
Ehlers–Danlos syndrome type VI, patients have diffuse corneal thinning corneal thickness, high myopia, and younger age.44,45
with corneal rupture spontaneously or after minor trauma, and corneal Corneal cross-linking has currently emerged as a proposed treatment
hydrops is common. Blue sclerae are present. These patients may have sys- to not only treat but also, ideally, prevent corneal ectasia that occurs after
temic connective tissue abnormalities as well, with hyperextensible joints, refractive surgery. A recent study from Japan found no case of post-LASIK
bone anomalies, and hearing loss.39 A defect in lysyl hydroxylase activity ectasia in 673 eyes, with follow-up ranging from 3 months up 3.5 years.
is present. Given the prevalence of ectasia, as stated above, this may or may not be
clinically significant, but more studies should be performed for further
Pathology evaluation.46
Pathology of acquired keratoglobus is similar to that of keratoconus,

whereas congenital keratoglobus shows an absence of Bowman’s mem- KEY REFERENCES
brane, stromal disorganization, and thickening of Descemet’s membrane Balasubramanian S, Pye D, Wilcox MD. Effects of eye rubbing on the levels of protease,
with breaks.40 protease activity and cytokines in tears: relevance in keratoconus. Clin Exp Optom
2013;96:214–18.
Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet A
Treatment corneal cross-linking for keratoconus in Italy: the Siena Eye Cross Study. Am J Ophthal-
mol 2010;149:585–93.
Treatment includes protection from trauma. Outcomes of penetrating Eye Bank Association of America. 2009 statistical report. Washington: Eye Bank Association
keratoplasty are typically poor because of severe host peripheral thinning. of America; 2010.
Lamellar epikeratoplasty has been used successfully to reinforce thin Godefrooij D, de Wit G, Uiterwaal C, et al. Age-specific incidence and prevalence of keratoco-
nus: a nationwide registration study. Am J Ophthalmol 2017;175:169–72.
corneas and, in some cases, to improve vision.41 For acquired keratoglobus, Kymionis GD, Siganos CS, Tsiklis NS, et al. Long-term follow-up of INTACS in keratoconus.
large penetrating keratoplasty may be successful. Am J Ophthalmol 2007;143:236–44.
Nowak D, Gajecka M. The genetics of keratoconus. Middle East Afr J Ophthalmol 2011;18:2–6.
O’Brart DP. Corneal collagen crosslinking for corneal ectasias: a review. Eur J Ophthalmol
POSTERIOR KERATOCONUS 2017;27(3):253–69.
Rabinowitz YS. Videokeratographic indices to aid in screening for keratoconus. J Refract
Posterior keratoconus refers to a congenital corneal anomaly in which the Surg 1995;11:371–9.
posterior corneal surface protrudes into the stroma, which usually occurs Shimmura S, Tsubota K. Deep anterior lamellar keratoplasty. Curr Opin Ophthalmol
in a localized area, but may be more diffuse. This disorder usually is spo- 2006;17:349–55.
Van Dijk K, Liarakos V, Parker J, et al. Bowman layer transplantation to reduce and stabilize
radic, unilateral, and nonprogressive. Bilateral and familial cases do occur progressive, advanced keratoconus. Ophthalmology 2015;122:909–17.
but are less frequent. The anterior corneal contour is often affected min- Wallang B, Das S. Keratoglobus. Eye (Lond) 2013;27:1004–12.
imally, although anterior protrusion and even a surrounding iron line Woodward M, Blachley T, Stein J. The association between sociodemographic factors,
have been described. Frequently, scarring occurs in the stroma anterior to common systemic disease, and keratoconus: an analysis of a nationwide health care
claims database. Ophthalmology 2016;123:457–65.
the Descemet’s bulge. On pathological examination, scarring at the level
of Bowman’s membrane is seen and thinning of Descemet’s membrane
with excrescences has been reported variably.42,43 Descemet’s membrane Access the complete reference list online at ExpertConsult.com
changes and congenital nature of this disorder suggest that it is a variant
257
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REFERENCES 24. Spoerl E, Huhle M, Seiler T. Induction of cross-links in corneal tissue. Exp Eye Res
1998;66:97–103.
1. Kenney MC, Chwa M, Atilano SR, et al. Increased levels of catalase and cathepsin V/L2
but decreased TIMP-1 in keratoconus corneas: evidence that oxidative stress plays a role
25. O’Brart DP. Corneal collagen crosslinking for corneal ectasias: a review. Eur J Ophthal-
mol 2017;27(3):253–69.
4.18
in this disorder. Invest Ophthalmol Vis Sci 2005;46:823–32. 26. Rubinfeld R, Talamo J, Stulting D. Quantitative analysis of trans-epithelial corneal
riboflavin loading. Presented at: International Crosslinking Congress. 2016: Zurich,

2. Wojcik K, Blasiak J, Kurowska A, et al. Oxidative stress in the pathogenesis of keratoco-
nus. Klin Oczna 2013;115:311–16. Switzerland.
3. Balasubramina S, Mohan S, Pye D, et al. Proteases, proteolysis and inflammatory mol- 27. Carossi A, Mazzotta C, Paradiso A, et al. Transepithelial corneal collagen crosslink-
ecules in the tears of people with keratoconus. Acta Ophthalmol 2012;90:e303–9. ing for progressive keratoconus: 24 month clinical results. J Cataract Refract Surg
4. Fini ME, Yue B, Sugar J. Collagenolytic/gelatinolytic mettaloproteinases in normal and 2013;39:1157–63.
keratoconus corneas. Curr Eye Res 1992;11:849–62. 28. Stulting R, Woolfson J, Trattler B, et al. Corneal crosslinking without epithelial removal.
5. Ku JYF, Niederer RL, Patel DV, et al. Laser scanning in vivo confocal analysis of kerato- Presented at: International Crosslinking Conference; 2016: Zurich, Switzerland.
cyte density in keratoconus. Ophthalmology 2008;115:845–50. 29. Goderfrooij D, Gans R, Imhof S, et al. Nationwide reduction in the number of corneal
6. Kymionis G, Diakonis F, Kalyvianaki M. One-year follow-up corneal confocal microscopy transplantations for keratoconus following the implementation of cross-linking. Acta
after corneal cross-linking in patients with post laser in situ keratomileusis ectasia and Ophthalmol 2016;94:675–8.
keratoconus. Am J Ophthalmol 2009;147:774–8. 30. Bergmanson J, Goose J, Patel C. Recurrence or re-emergence of keratoconus – what is
7. Goldich Y, Marcovich A, Barkana Y, et al. Safety of corneal collagen cross-linking with the evidence telling us? Literature review and two case reports. Ocul Surf 2014;12:267–72.
UV-A and riboflavin in progressive keratoconus. Cornea 2010;29:409–11. 31. Kymionis GD, Siganos CS, Tsiklis NS, et al. Long-term follow-up of INTACS in keratoco-
8. McMonnies CW. Mechanisms of rubbing-related corneal trauma in keratoconus. Cornea nus. Am J Ophthalmol 2007;143:236–44.
2009;28:607–15. 32. Kanellopoulos AJ, Pe LH, Perry HD, et al. Modified intracorneal ring segment implanta-
9. Balasubramanian SA, Pye DC, Wilcox MD. Effects of eye rubbing on the levels of prote- tions (INTACS) for the management of moderate to advanced keratoconus: efficacy and
ase, protease activity and cytokines in tears: relevance in keratoconus. Clin Exp Optom complications. Cornea 2006;25:29–33.
2013;96:214–18. 33. Caporossi A, Mazzotta C, Baiocchi S, et al. Long-term results of riboflavin ultraviolet A
10. Godefrooij D, de Wit G, Uiterwaal C, et al. Age-specific incidence and prevalence of ker- corneal cross-linking for keratoconus in Italy: the Siena Eye Cross Study. Am J Ophthal-
atoconus: a nationwide registration study. Am J Ophthalmol 2017;175:169–72. mol 2010;149:585–93.
11. Quisling S, Sjoberg S, Zimmerman B, et al. Comparison of Pentacam and OrbscanIIz 34. Mazzotta C, Balestrazzi A, Baiocchi S, et al. Stromal haze after combined riboflavin UVA
on posterior curvature topography measurements in keratoconus eyes. Ophthalmology corneal collagen cross-linking in keratoconus: in vivo confocal microscopic evaluation.
2006;113:1629–32. Clin Experiment Ophthalmol 2007;35:580–2.
12. Rabinowitz YS. Videokeratographic indices to aid in screening for keratoconus. J Refract 35. Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking.
Surg 1995;11:371–9. J Cataract Refract Surg 2009;35:1358–62.
13. Nowak D, Gajecka M. The genetics of keratoconus. Middle East Afr J Ophthalmol 36. Pollhammer M, Cursiefen C. Bacterial keratitis early after corneal crosslinking with ribo-
2011;18:2–6. flavin and ultraviolet-A. J Cataract Refract Surg 2009;35:588–9.
14. Woodward M, Blachley T, Stein J. The association between sociodemographic factors, 37. Rama P, Di Matteo F, Matuska S, et al. Acanthamoeba keratitis with perforation after
common systemic disease, and keratoconus: an analysis of a nationwide health care corneal crosslinking and bandage contact lens use. J Cataract Refract Surg 2009;35:788–91.
claims database. Ophthalmology 2016;123:457–65. 38. Kymionis GD, Portaliou DM, Bouzoukis DI, et al. Herpetic keratitis with iritis after
15. Akhtar S, Alkatan H, Kirat O. Ultrastructural and three-dimensional study of post LASIK corneal crosslinking with riboflavin and ultraviolet A for keratoconus. J Cataract Refract
ectasia cornea. Microsc Res Tech 2014;77:1–8. Surg 2007;33:1982–4.
16. Akhtar S, Bron A, Salvi S. Ultrastructural analysis of collagen fibrils and proteoglycans in 39. Al Hussain H, Zeisberger S, Huber P, et al. Brittle cornea syndrome and its delineation
keratoconus. Acta Ophthalmol 2008;86:764–72. from the kyphoscoliotic type of Ehlers–Danlos syndrome (EDS VI): report on 23 patients
17. Lim N, Vogt U. Characteristics and functional outcomes of 130 patients with keratoconus and review of literature. Am J Med Genet 2004;124A:28–34.
attending a specialist contact lens clinic. Eye (Lond) 2002;16:54–9. 40. Wallang B, Das S. Keratoglobus. Eye (Lond) 2013;27:1004–12.
18. Eye Bank Association of America. 2015 statistical report. Washington: Eye Bank Associa- 41. Javadi MA, Kanavi MR, Ahmadi M, et al. Outcomes of epikeratoplasty for advanced kera-
tion of America; 2016. toglobus. Cornea 2007;26:154–7.
19. Shoja M, Besharati M. A comparison of the effect of donor-recipient trephine size dispar- 42. Abdala-Figuerola A, Navas A, Ramirez-Miranda A, et al. Scheimpflug and optical coher-
ity on refractive error in keratoconus. Saudi Med J 2007;28:1391–2. ence tomography analysis of posterior keratoconus. Cornea 2016;35:1368–71.
20. Shimmura S, Tsubota K. Deep anterior lamellar keratoplasty. Curr Opin Ophthalmol 43. Varma D, Brownstein S, Hodge W, et al. Generalized posterior keratoconus: clinical
2006;17:349–55. pathologic correlations. Can J Ophthalmol 2008;43:480–2.
21. Van Dijk K, Liarakos V, Parker J, et al. Bowman layer transplantation to reduce and sta- 44. Santhiago M, Giacomin N, Smadja D, et al. Ectasia risk factors in refractive surgery. Clin
bilize progressive, advanced keratoconus. Ophthalmology 2015;122:909–17. Ophthalmol 2016;10:712–20.
22. Colin J, Cochener B, Savary G, et al. Correcting keratoconus with intracorneal rings. J 45. Rapuano C. Prevention of Iatrogenic Keratectasia. Klin Monbl Augenheilkd
Cataract Refract Surg 2000;26:1117–22. 2016;233:695–700.
23. Pinero DP, Alio JL, El Kady B, et al. Refractive and aberrometric outcomes of intracor- 46. Tomita M. Combined laser in-situ keratomileusis and accelerated corneal cross-linking:
neal ring segments for keratoconus: mechanical versus femtosecond-assisted proce- an update. Curr Opin Ophthalmol 2016;27:304–10.
dures. Ophthalmol 2009;116:1675–87.
257.e1
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Anterior Corneal Dystrophies

Michael H. Goldstein, Joel Sugar, Bryan Edgington 4.19
Definition: Bilateral disorders, most of which are inherited, in which Ocular Manifestations
an abnormal substance accumulates primarily in the corneal epithelium. The most common clinical manifestations of ABMD are recurrent erosion
syndrome (RES) and blurry or distorted vision. Most patients with RES
describe mild pain on awakening, subsiding within minutes to hours,
but larger erosions can cause severe pain, which may take hours to days
Key Features to resolve. Patients also note blurred vision or occasionally monocular
• Typically bilateral. diplopia or image ghosting. Although ABMD is often thought to be the
• Progressive. most common cause for RES, other conditions (including trauma), can
• Involvement is anterior to corneal stroma. cause RES.7–9 In some cases, both entities are present, and the diagnosis
of ABMD is made by carefully examining the unaffected eye after trauma.
Patients with ABMD and a history of a traumatic abrasion are even more
likely to develop RES. The clinical symptoms of ABMD overlap consid-
Associated Features erably with recurrent erosions secondary to trauma. In both conditions,
• Many are associated with recurrent erosion syndrome. recurrent erosions are felt to be secondary to friability of the superficial
• Not associated with systemic disease, with rare exceptions. epithelium caused by poor adhesion of epithelial cells to each other and to
the underlying basement membrane.10,11
In patients with blurred or distorted vision, which is thought to be
INTRODUCTION related to central ABMD changes, corneal topography can be very helpful
in identifying irregular astigmatism as the source of the visual problem. In
In general, most corneal dystrophies are autosomal dominant, bilateral addition, a trial with a soft bandage contact lens can be a helpful diagnostic
disorders that primarily affect one or more layers of an otherwise normal or therapeutic tool.
cornea, progress slowly after their appearance in the first or second decade, ABMD is characterized by several changes apparent in the anterior
and are not associated with any systemic disease. Historically, corneal dys- cornea on slit-lamp examination. They often are seen best with a dilated
trophies were categorized by the involved corneal layer. The distinctive pupil and retroillumination. Cases may be subtle and can be detected by
clinical appearance of most corneal dystrophies allows accurate diagno- looking for negative staining using cobalt blue filter after the application
sis based on clinical grounds. Transmission electron microscopy is the of fluorescein (Fig. 4.19.1). Corneal findings seen with ABMD include
most accurate method for histopathological diagnosis.1 Genetic studies on intra-epithelial microcysts (dots) (Fig. 4.19.2), map-like grayish patches,
corneal dystrophies, however, also provide insight at a basic molecular level and fingerprint parallel lines (Fig. 4.19.3).12–14 The condition is referred to
and are assisting in refining the classification systems. Several corneal dys- as Cogan’s microcystic dystrophy when only microcysts are present. Confo-
trophies are closely related at the molecular level with different phenotypes cal microscopy is helpful in corneas with a history of erosions that appear
resulting from mutations within the same gene. For example, the BIGH3 to be normal on clinical examination. With confocal microscopy, corneas
gene on chromosome 5q31 is associated with granular corneal dystrophy with recurrent erosions or ABMD showed deposits in basal epithelial cells,
(types I, II, and III), lattice corneal dystrophy (types I, IIIA, IIIA-like, and subbasal microfolds and streaks, damaged subbasal nerves, or altered mor-
IV), and corneal dystrophy of Bowman’s layer (types I and II).2 phology of the anterior stroma.15,16
The anterior corneal dystrophies involve Bowman’s layer and involve
the epithelium as well. Some also may involve the anterior stroma. This
categorization, however, is arbitrary because many of the stromal dystro-
phies also involve Bowman’s layer and the epithelium. The genetic under-
standing of these disorders makes this classification even less appropriate,
and many of these conditions will ultimately be better classified and named
by their specific biochemical defects (Table 4.20.1).3
ANTERIOR BASEMENT MEMBRANE DYSTROPHY

Introduction
Anterior basement membrane dystrophy (ABMD), also termed epithelial
basement membrane dystrophy (EBMD), map-dot-fingerprint corneal dystrophy,
and Cogan’s microcystic dystrophy, is the most common anterior corneal
dystrophy.1

ABMD has been reported to occur in approximately 3%–6% of the general
population but is much more common over age 40 years.4,5 Familial pat-
terns have been described for ABMD,4 but many patients with the disorder
will not have any known family history, which has caused some debate
as to whether ABMD is actually a corneal dystrophy or a degenerative Fig. 4.19.1 Area of epithelial thickening, demonstrating negative staining, in a
258 change.3 Point mutations in the TGFBI/BIGH3 gene have been reported patient with anterior basement membrane dystrophy. (Courtesy Anthony J. Aldave,
in two families showing autosomal dominant inheritance.6 MD.)
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to the underlying stroma.17 The use of 23- or 25-gauge needles instead of
30-gauge needles may decrease the risk of corneal perforation.20 Micro-
puncture should be used with caution for erosions in the visual axis 4.19
because central corneal scarring can lead to decreased vision.
PTK is a safe and effective procedure for recurrent corneal erosions

(trauma and ABMD) refractory to conventional treatment as well as to treat
visually significant ABMD.21–25 In the great majority of patients, visual fluc-
tuation and monocular diplopia or “ghost images” resolved.21–24,26 A hyper-
opic shift can be an adverse side effect in some individual cases.19,24 It is
possible to combine PTK with PRK to manage the hyperopic shift in select
patients.27–29 ABMD has been reported as a risk for increasing complication
rates after laser-assisted in situ keratomileusis (LASIK) including epithelial
defects and epithelial ingrowth, so these patients may be better candidates
for photorefractive keratectomy (PRK).30
DB superficial keratectomy appears to be an effective and safe method
of treating recurrent erosions (both posttraumatic and ABMD). Little
refractive shift occurs with this method.31,32 As an alternative to DB, an
Amoils epithelial scrubber may be used to debride the epithelium and buff
Bowman’s layer.33 The DB procedure is simple, office-based, and inexpen-
sive, so it may be the preferred technique in some settings.34
Fig. 4.19.2 Opaque epithelial cysts in a patient with epithelial basement membrane MEESMANN’S EPITHELIAL DYSTROPHY
dystrophy. (Courtesy Anthony J. Aldave, MD.)
Meesmann’s epithelial dystrophy is a rare, bilateral condition confined to
the corneal epithelium. It is an autosomal dominant disorder that leads to
fragility of the anterior corneal epithelium. It has been linked to mutations
in locus 12q13 (KRT3) and 17q12 (KRT12) that are specifically expressed in
the epithelium.35–38
Symmetrical intraepithelial microcysts appear in the first few years of
life and are visible only at the slit lamp. They are concentrated within the
visual axis and midperiphery. They are seen best with indirect illumination
or retroillumination. Typically, patients are either asymptomatic or report
mild symptoms, including recurrent erosions or minimal loss of visual
acuity. These symptoms usually can be treated with topical lubricants only.
Surgical intervention is rarely needed.
Histological examination shows two characteristic findings in the
corneal epithelium: (1) intracellular “peculiar substance” and (2) intraep-
ithelial microcysts containing cellular debris.39–41 The epithelial cells are
rich in glycogen and many contain the fibrogranular “peculiar substance,”
possibly derived from tonofilaments.31,32 Moreover, a nonspecific thicken-
ing of the epithelial basement membrane occurs without any apparent
modification of Bowman’s layer or superficial stroma.39–41
REIS–BÜCKLER DYSTROPHY
Introduction
Fig. 4.19.3 Prominent epithelial map lines in a patient with epithelial basement
membrane dystrophy. (Courtesy Anthony J. Aldave, MD.) “True” Reis–Bückler dystrophy, also known as corneal dystrophy of Bowman’s
layer type I (CDB I) or granular dystrophy type III, is discussed here.
Pathology Epidemiology and Pathogenesis

The clinical appearance of ABMD corresponds well with the pathology. Reis–Bückler dystrophy has an autosomal dominant inheritance and has
Specimens from affected patients show protrusions of sheets (maps) or been linked to a specific defect in the keratoepithelin gene on chromo-
rows of thickened basement membrane (fingerprints) into the superficial some 5q31. An arginine replaced by a glycine at codon 555 has been found
epithelium as well as mounds of thickened basement membrane beneath in families with this disorder, although other defects have been found in
the epithelium. Microcysts of degenerated cellular material accumulate other families.42,43 No systemic associations are known. The diagnosis is
within the epithelium (dots). A bilaminate subepithelial layer of fibrogran- made on the basis of clinical appearance, although differentiation from
ular material often occurs.1,10,11 honeycomb dystrophy often is difficult.
Treatment Ocular Manifestations

The majority of patients with recurrent corneal erosions will respond Reis–Bückler dystrophy is characterized by recurrent, painful, corneal
to conventional forms of therapy, such as topical lubricants, patching, epithelial erosions that often begin in the first 1–2 years of life. Minimal
debridement, or bandage soft contact lenses.17 Topical hyperosmotic solu- corneal changes are seen at first, but then ring and map-like opacities
tions are well tolerated and appear to be effective in treating recurrent appear at the level of Bowman’s membrane; these become denser and
corneal erosion in some cases.18 Therapy with a combination of medica- more irregular over time (Fig. 4.19.4). By the second or third decade of
tions that inhibit metalloproteinase-9 (topical corticosteroid and oral doxy- life, the painful erosions diminish as corneal sensitivity decreases, but the
cycline) may produce rapid resolution and help prevent further recurrence increasing fibrosis results in visual difficulty.
in cases unresponsive to conventional therapies.19
In some cases, surgical intervention will be required. Anterior stromal
micropuncture, superficial keratectomy, excimer laser ablation (photother-
Pathology
apeutic keratectomy [PTK]), and diamond burr (DB) superficial keratec- Pathology shows eosinophilic and fibrotic material beneath the corneal
tomy have all been used.8 Anterior stromal puncture was the first to be epithelium and within the anterior stroma, with destruction of Bowman’s 259
described, and presumably stimulates more secure epithelial adhesion membrane. The material is somewhat granular in appearance. Electron
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pattern. The disorder is inherited as an autosomal dominant disorder. A
4 defect has been found in the keratoepithelin gene.44

In one family, a defect was found on chromosome 10q24. No known
associated systemic abnormality exists. Histopathology shows wavy, sub-
epithelial fibrosis with disruption of Bowman’s layer and epithelial base-
ment membrane. Electron microscopy reveals that curly collagen filaments

replace Bowman’s layer.45 Treatment is the same as that for Reis–Bückler
dystrophy, namely, superficial keratectomy or excimer ablation. Kerato-
plasty may become necessary after multiple recurrences.
KEY REFERENCES
Boutboul S, Black GC, Moore JE, et al. A subset of patients with epithelial basement mem-
brane corneal dystrophy have mutations in TGFBI/BIGH3. Hum Mutat 2006;27:553–7.
Dastgheib KA, Clinch TE, Manche EE, et al. Sloughing of corneal epithelium and wound
healing complications associated with laser in situ keratomileusis in patients with epi-
thelial basement membrane dystrophy. Am J Ophthalmol 2000;130:297–303.
Fig. 4.19.4 Reis–Bückler Corneal Dystrophy. Note the irregular opacities at the Fine BS, Yanoff M, Pitts E, et al. Meesmann’s epithelial dystrophy of the cornea. Am J Oph-
level of Bowman’s layer. thalmol 1977;83:633–42.
Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratin K3 or K12
genes cause Meesmann’s corneal dystrophy. Nat Genet 1997;16:184–7.
Klintworth GK. Advances in the molecular genetics of corneal dystrophies. Am J Ophthalmol
1999;128:747–54.
microscopy shows rod-shaped bodies that replace Bowman’s layer and lie Laibson PR, Krachmer JH. Familial occurrence of dot (microcystic), map, fingerprint dystro-
between epithelial cells. These pathological findings are the same as those phy of the cornea. Invest Ophthalmol 1975;14:397–9.
Mullahy JE, Afshari MA, Steinert RF, et al. Survey of patients with granular, lattice, Avellino,
seen in superficial granular dystrophy (granular dystrophy type III). and Reis–Bückler’s corneal dystrophies for mutations in the BIGH3 and gelsolin genes.
Arch Ophthalmol 2001;119:16–22.
Treatment Reidy JJ, Paulus MP, Gona S. Recurrent erosions of the cornea: epidemiology and treatment.
Cornea 2000;19:767–71.
Soong HK, Farjo Q, Meyer RF, et al. Diamond burr superficial keratectomy for recurrent
Treatment of Reis−Bückler dystrophy is symptomatic for the recurrent corneal erosions. Br J Ophthalmol 2002;86:296–8.
erosions. Superficial keratectomy, either by mechanical stripping or by Sridhar MS, Rapuano CJ, Cosar CB, et al. Phototherapeutic keratectomy versus diamond
excimer laser ablation, is the appropriate treatment for the visual distur- burr polishing of Bowman’s membrane in the treatment of recurrent corneal erosions
bance. Recurrence may be relatively rapid and keratoplasty may become associated with anterior basement membrane dystrophy. Ophthalmology 2002;109:674–9.
Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of the epithe-
necessary after multiple treatments. lium, Bowman’s layer and stroma. Surv Ophthalmol 1978;23:71–122.
Weiss JS, Moller HU, Aldave AJ, et al. IC3D Classification of corneal dystrophies – edition
THIEL–BEHNKE DYSTROPHY 2. Cornea 2015;34:117–59.
Yee RW, Sullivan LS, Lai HT, et al. Linkage mapping of Thiel–Behnke corneal dystrophy
(CDB2) to chromosome 10q 23-q24. Genomics 1997;46:152–4.
Also known as honeycomb dystrophy, Waardenburg and Jonkers dystrophy, or Zaltentein WN, Holopainen JM, Tervo TM. Phototherapeutic keratectomy for epithelial
corneal dystrophy of Bowman’s membrane II (CDB II), Thiel–Behnke dys- irregular astigmatism: an emphasis on map-dot-fingerprint degeneration. J Refract Surg
trophy often is confused in the literature with Reis–Bückler dystrophy. 2007;23:50–7.
Patients have recurrent erosions, although less severe than those asso-
ciated with Reis–Bückler dystrophy. A reticular array of anterior stromal Access the complete reference list online at ExpertConsult.com
opacities develops and elevates the corneal epithelium in a “saw-tooth”
260
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REFERENCES 24. Orndahl MJ, Fagerholm PP. Phototherapeutic keratectomy for map-dot-fingerprint
corneal dystrophy. Cornea 1998;17:595–9.
1. Waring GO, Rodrigues MM, Laibson PR. Corneal dystrophies. I. Dystrophies of the epi-
thelium, Bowman’s layer and stroma. Surv Ophthalmol 1978;23:71–122.
25. Dinh R, Rapuano CJ, Cohen EJ, et al. Recurrence of corneal dystrophy after excimer laser
phototherapeutic keratectomy. Ophthalmology 1999;106:1490–7.
4.19
2. Klintworth GK. Advances in the molecular genetics of corneal dystrophies. Am J Oph- 26. Orndahl MJ, Fagerholm PP. Phototherapeutic keratectomy for map-dot-fingerprint
corneal dystrophy. Cornea 1998;17:595–9.

thalmol 1999;128:747–54.
3. Weiss JS, Moller HU, Aldave AJ, et al. IC3D Classification of corneal dystrophies – 27. Ho CL, Tan DT, Chan WK. Excimer laser phototherapeutic keratectomy for recurrent
edition 2. Cornea 2015;34:117–59. corneal erosions. Ann Acad Med Singapore 1999;28:787–90.
4. Laibson PR, Krachmer JH. Familial occurrence of dot (microcystic), map, fingerprint 28. Jain S, Austin DJ. Phototherapeutic keratectomy for treatment of recurrent corneal
dystrophy of the cornea. Invest Ophthalmol 1975;14:397–9. erosion. J Cataract Refract Surg 1999;25:1610–14.
5. Hillenaar T, van Cleynenbreugel H, Remeijer L. How normal is the transparent cornea? 29. Zaidman GW, Hong A. Visual and refractive results of combined PTK/PRK in patients
Effects of aging on corneal morphology. Ophthalmology 2012;119:241–8. with corneal surface disease and refractive errors. J Cataract Refract Surg 2006;32:958–61.
6. Boutboul S, Black GC, Moore JE, et al. A subset of patients with epithelial base- 30. Dastgheib KA, Clinch TE, Manche EE, et al. Sloughing of corneal epithelium and wound
ment membrane corneal dystrophy have mutations in TGFBI/BIGH3. Hum Mutat healing complications associated with laser in situ keratomileusis in patients with epithe-
2006;27:553–7. lial basement membrane dystrophy. Am J Ophthalmol 2000;130:297–303.
7. Williams R, Buckley RJ. Pathogenesis and treatment of recurrent erosion. Br J Ophthal- 31. Soong HK, Farjo Q, Meyer RF, et al. Diamond burr superficial keratectomy for recurrent
mol 1985;69:453–7. corneal erosions. Br J Ophthalmol 2002;86:296–8.
8. Reidy JJ, Paulus MP, Gona S. Recurrent erosions of the cornea: epidemiology and treat- 32. Malta JB, Soong HK. Diamond burr superficial keratectomy in the treatment of visual-
ment. Cornea 2000;19:767–71. ly-significant anterior corneal lesions. Arq Bras Oftalmol 2008;71:415–18.
9. Reeves SW, Kang PC, Zlogar DF, et al. Recurrent corneal erosion syndrome: a study of 33. Hodkin MJ, Jackson MN. Amoils epithelial scrubber to treat recurrent corneal erosions.
365 episodes. Ophthalmic Surg Lasers Imaging 2010;1–2. J Cataract Refract Surg 2004;30:1896–901.
10. Ghosh M, McCulloch C. Recurrent corneal erosion, microcystic epithelial dystrophy, map 34. Sridhar MS, Rapuano CJ, Cosar CB, et al. Phototherapeutic keratectomy versus diamond
configurations and fingerprint lines in the cornea. Can J Ophthalmol 1986;21:246–52. burr polishing of Bowman’s membrane in the treatment of recurrent corneal erosions
11. Dark AJ. Cogan’s microcystic dystrophy of the cornea: ultrastructure and photomicros- associated with anterior basement membrane dystrophy. Ophthalmology 2002;109:674–9.
copy. Br J Ophthalmol 1978;62:821–30. 35. Irvine AD, Corden LD, Swensson O, et al. Mutations in cornea-specific keratin K3 or K12
12. Cogan DG, Donaldson DD, Kuwabara T, et al. Microcystic dystrophy of the corneal epi- genes cause Meesmann’s corneal dystrophy. Nat Genet 1997;16:184–7.
thelium. Trans Am Ophthalmol Soc 1964;62:213–25. 36. Nichini O, Manzi V, Munier FL, et al. Meesmann corneal dystrophy (MECD): report of 2
13. Guerry D. Observations on Cogan’s microcystic dystrophy of the corneal epithelium. Am families and a novel mutation in the cornea specific keratin 12 (KRT12) gene. Ophthal-
J Ophthalmol 1966;62:65–73. mic Genet 2005;26:169–73.
14. Levitt JM. Microcystic dystrophy of the corneal epithelium. Am J Ophthalmol 37. Corden LD, Swensson O, Swensson B, et al. A novel keratin 12 mutation in a German
1971;72:381–2. kindred with Meesmann’s corneal dystrophy. Br J Ophthalmol 2000;84:527–30.
15. Rosenberg ME, Tervo TMT, Petroll WM, et al. In vivo confocal microscopy of patients 38. Coleman CM, Hannush S, Covello SP, et al. A novel mutation in the helix termination
with corneal recurrent erosion syndrome or epithelial basement membrane dystrophy. motif of keratin K12 in a US family with Meesmann corneal dystrophy. Am J Ophthalmol
Ophthalmology 2000;107:565–73. 1999;128:687–91.
16. Hernandez-Quintela E, Mayer F, Dighiero P, et al. Confocal microscopy of cystic disor- 39. Tremblay M, Dube I. Meesmann’s corneal dystrophy: ultrastructural features. Can J Oph-
ders of the corneal epithelium. Ophthalmology 1998;105:631–6. thalmol 1982;17:24–8.
17. McLean EN, MacRae SM, Rich LF. Recurrent erosion. Treatment by anterior stromal 40. Chiou AG, Florakis GJ, Copeland RL, et al. Recurrent Meesmann’s corneal epithelial dys-
puncture. Ophthalmology 1986;93:784–8. trophy after penetrating keratoplasty. Cornea 1998;17:566–70.
18. Foulks GN. Treatment of recurrent corneal erosion and corneal edema with topical 41. Fine BS, Yanoff M, Pitts E, et al. Meesmann’s epithelial dystrophy of the cornea. Am J
osmotic colloidal solution. Ophthalmology 1981;88:801–3. Ophthalmol 1977;83:633–42.
19. Dursun D, Kim MC, Solomon A, et al. Treatment of recalcitrant recurrent corneal ero- 42. Mullahy JE, Afshari MA, Steinert RF, et al. Survey of patients with granular, lattice, Avel-
sions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids. Am lino, and Reis–Bückler’s corneal dystrophies for mutations in the BIGH3 and gelsolin
J Ophthalmol 2001;132:8–13. genes. Arch Ophthalmol 2001;119:16–22.
20. Katsev DA, Kincaid MC, Fouraker BD, et al. Recurrent corneal erosion: pathology of 43. Takahashi K, Murakami A, Okisaka S. Keratoepithelin mutation (R555Q) in a case of
corneal puncture. Cornea 1991;10:418–23. Reis–Bückler’s corneal dystrophy. Jpn J Ophthalmol 2001;44:191.
21. Cavanaugh TB, Lind DM, Cutarelli PE, et al. Phototherapeutic keratectomy for recur- 44. Yee RW, Sullivan LS, Lai HT, et al. Linkage mapping of Thiel–Behnke corneal dystrophy
rent erosion syndrome in anterior basement membrane dystrophy. Ophthalmology (CDB2) to chromosome 10q 23-q24. Genomics 1997;46:152–4.
1999;106:971–6. 45. Kuchle M, Green WR, Volcker AG, et al. Reevaluation of corneal dystrophies of Bow-
22. Zaltentein WN, Holopainen JM, Tervo TM. Phototherapeutic keratectomy for epithelial man’s layer and the anterior stroma (Reis–Bückler’s and Thiel–Behnke types): a light
irregular astigmatism: an emphasis on map-dot-fingerprint degeneration. J Refract Surg and electron microscopy study of eight corneas and a review of the literature. Cornea
2007;23:50–7. 1995;14:333–54.
23. Pogorelov P, Langenbucher A, Kruse F, et al. Long-term results of phototherapeu-
tic keratectomy for corneal map-dot-fingerprint dystrophy (Cogan–Guerry). Cornea
2006;25:774–7.
260.e1
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Stromal Corneal Dystrophies

Joel Sugar, Praneetha Thulasi 4.20
keratoepithelin production at locus 5q31. The most common mutation is
Definition: An inherited, bilateral disorder in which an abnormal
at codon 124, where arginine is replaced by cysteine.
substance accumulates in the cornea.
Key Features Rod-like glassy opacities appear in the anterior stroma in the first or second
• Characteristically bilateral. decade and become denser over time, resulting in linear, often branching
• Progressive. opacities (Figs. 4.20.1 and 4.20.2). These opacities are most dense anteri-
• Isolated to the cornea. orly and centrally, with a clear zone in the periphery. The lines are rela-
tively fine, as opposed to the more ropy opacities seen in lattice dystrophy
type III. Although this disorder is bilateral, it can be asymmetrical.
Associated Features
• Usually autosomal dominant. Clinical Presentation
• Not associated with systemic disease, with rare exceptions. Patients often present in their first and second decades with pain and
decreased vision. Recurrent erosions are common and, over time, can lead
INTRODUCTION to anterior stromal haze that can limit vision. Patients often need corneal
transplantation by their fourth decade.
Corneal dystrophy is classically bilateral, progressive, and isolated to the
cornea. The disorder is generally inherited, usually in a dominant fashion,
and often appears clinically to involve only one layer of the cornea. With
the progressive identification of genes involved in these entities, a better
pathophysiological understanding and ultimately better treatment will be
developed. Epithelial and endothelial dystrophies are discussed in their
respective chapters.
The stromal dystrophies are classified as such because they appear to
accumulate material predominantly in the stroma. As was noted in Chapter
4.19 this categorization is, however, arbitrary because many of the stromal
dystrophies also involve Bowman’s layer and the epithelium. The genetic
understanding of these disorders makes this classification even less appro-
priate. Many of these conditions ultimately will be classified and named
by their specific biochemical defects (Table 4.20.1). The classification of
corneal dystrophies has recently been reviewed in 2015 and standardized
by an international committee and published as “The International Classi-
fication of Corneal Dystrophies (IC3D).”1
GELATINOUS DROP-LIKE DYSTROPHY

Gelatinous drop-like dystrophy was previously categorized as stromal but Fig. 4.20.1 Lattice Dystrophy Type I. This patient has very fine, rod-like opacities in
is now considered an epithelial/subepithelial dystrophy, as described in the the anterior stroma.
most recent IC3D classification.
LATTICE DYSTROPHY TYPE I

Genetics
This disorder is autosomal dominant, with mutation in the transform-
ing growth factor-β–induced (TGFBI) gene, resulting in abnormal
TABLE 4.20.1 Corneal Dystrophies Due to

Keratoepithelin Gene Defects
Dystrophy Defect
Reis–Bückler’s Arg555Gly, Arg124Leu, Arg555Gln
Thiel–Behnke Arg124Leu (other families chromosome 10)
Lattice I Arg124Lys
Lattice IIIA Arg124Thr, Pro501Thr
Lattice IV Leu527Arg
Granular I Arg555Trp, Arg124Ser
Granular II (Avellino) Arg124His
Fig. 4.20.2 Lattice Dystrophy Type I. Denser, ropier opacities than those shown in 261
Fig. 4.20.1.
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Fig. 4.20.3 Lattice
4 Dystrophy Type I.
Histopathology using
Congo red stain shows the
amyloid accumulations
throughout the stroma

(arrows).
Fig. 4.20.4 Granular Dystrophy. Note the more crumb-like opacities in this patient
who has sufficient clear cornea to have normal acuity.
Pathology Pathology
Histopathologically, dense deposits are seen in the stroma. These stain The pathology is similar to that of lattice dystrophy type I.
with Congo red, periodic acid–Schiff (PAS), and Masson’s trichrome (Fig.
4.20.3). Dichroism and birefringence are seen with polarized light and flu- Treatment
orescence is seen with thioflavin-T. All of these findings are characteristic
for amyloid, a β-pleated protein structure. The amyloid appears to be dis- Treatment, if necessary, is the same as for lattice dystrophy type I, although
tinct from that seen in lattice dystrophy type II.2 Descemet’s membrane additional consideration must be given to the risk of corneal exposure
and the endothelium are normal. Electron microscopy shows extracellular from facial neuropathy. Animal studies on gene silencing therapy hold
masses of fine, electron-dense randomly aligned fibrils characteristic of promise.9
amyloid protein.3
Other Lattice Dystrophies
Treatment Multiple subtypes of lattice dystrophy have been described based on geno-
Initial treatment consists of soft contact lenses for corneal epithelial ero- typical and phenotypical variations, especially as the genetics of those
sions. Phototherapeutic keratectomy may be a good option to treat anterior with atypical features are further explored. Lattice dystrophy types III, I/
visually significant deposits, although epithelial healing may be delayed, III, and IV and the polymorphic variant have delayed onset at age greater
and recurrences may occur.4 When visual acuity decreases significantly, than 40 years and have thicker, ropy lattice lines.10,11 Type IIIA has identi-
deep anterior lamellar keratoplasty (DALK) is the procedure of choice cal changes but has more recurrent erosions.12 Many of these variants are
because it has a benefit over penetrating keratoplasty (PKP) in minimizing geographically restricted.
the risk of rejection.5 Epithelial cells are thought to be the source of these
deposits, and although PKP has not shown statistically significant results,
presence of transplanted limbal stem cells may have fewer recurrences.6
GRANULAR CORNEAL DYSTROPHY TYPE I
Recently, investigators have been studying the efficacy of fibronectin drops Genetics
after corneal epithelium debridement in improving visual acuity in this
condition.7 This disorder is autosomal dominant, with mutation in the TGFBI gene
at locus 5q31.
SYSTEMIC AMYLOIDOSIS WITH Ocular Manifestation

CORNEAL LATTICE Previously called Groenouw’s dystrophy type I, granular corneal dystrophy is
Genetics characterized by the presence of discrete opacities in the corneal stroma
that do not extend to the limbus, and the intervening stroma is clear. The
Locus 9q34 mutation in gelsolin protein is involved in actin modulation. opacities have irregular crumb-like or flake-like shapes and are whitish
or slightly glassy in appearance (Fig. 4.20.4). The pattern within a given
Ocular Manifestations family appears to be consistent. No systemic associations are known.
Often classified as lattice dystrophy type II, this is part of the systemic dis-
order familial amyloid polyneuropathy type IV (Finnish type), also known
Patient Presentation
as Meretoja’s syndrome. In this disorder, fine lattice lines extend to the Many patients have no symptoms, whereas some patients develop recur-
limbus and are not related to corneal nerves, although the sub-basal nerve rent erosions. In the fifth decade or later, some patients develop visual
density is reduced.8 Patients may have increased risk of glaucoma and also difficulties as the opacities become prominent in the superficial stroma.
can present with facial weakness with lid lag. Anterior stromal opacities tend to be much more visually significant than
Systemic associations include multiple cranial neuropathies and sys- posterior stromal opacities.
temic amyloid deposition.
Pathology
Patient Presentation Histopathological findings show red staining (Fig. 4.20.5) with Masson’s
Patients often present with this condition during routine examinations. trichrome stain without Congo red staining. Electron microscopy shows
Visual disturbance is less compared with that in lattice dystrophy type I, electron-dense, rod-like deposits and microfibrils, which are present
262 and recurrent erosions are less frequent. Patients also can present with lid in keratocytes as well as epithelial cells.13 The material is thought to be
lag and corneal exposure. phospholipid.
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Fig. 4.20.5 Granular
Corneal Dystrophy.
Masson’s trichrome staining 4.20
shows accumulation
of hyaline material in

the corneal stroma and
beneath the epithelium.
Fig. 4.20.6 Macular Corneal Dystrophy. Note the stromal haze between the
denser macular opacities in this 40-year-old woman.
MACULAR CORNEAL DYSTROPHY

Treatment In macular corneal dystrophy, three types have been defined on the basis of
Because the superficial deposits are often the most visually significant, immunoreactivity to specific markers of antigenic keratan sulfates (AgKS).
vision often improves with excimer ablation and does not impair future In type I, there is no AgKS reactivity in the cornea or in the serum. In type
keratoplasty.14,15 Patients who require keratoplasty do well, and DALK is IA, the keratocytes manifest AgKS reactivity, but neither the serum nor
the procedure of choice.16 Granules do recur superficially in the graft, at the extracellular material in the cornea does.25 In type II, all the abnormal
times in a swirling pattern that suggests the epithelium is the source of deposits in the cornea as well as the serum have positive AgKS reactivity.
the deposits.16 There are a few case reports of concurrent limbal stem cell Clinically and histopathologically, types I and II are indistinguishable.26
transplantations with improved long-term outcomes.17
Genetics
GRANULAR CORNEAL DYSTROPHY TYPE 2 This disorder is autosomal recessive, with mutations in the CHST6 gene at
A dystrophy that combines features of both granular and lattice dystro- locus 16q22, leading to abnormal keratan sulfate.27
phies has been described, with the majority of the original patients coming
from the Avellino region of Italy. This is also referred to as Avellino gran- Ocular Manifestations
ular dystrophy.
Faint anterior stromal white opacities are seen early in life, often in the first
Genetics decade. The opacities progress over time and a grainy, ground-glass haze
becomes evident between the opacities and then throughout the stroma
This disorder autosomal dominant, with mutation in the TGFBI gene at from limbus to limbus, down to Descemet’s membrane. Over time, the
locus 5q31. cornea thins,28 and the endothelium may develop guttae, although endo-
thelial decompensation is rare (Fig. 4.20.6).
Ocular Manifestations Although abnormalities in keratan sulfate in the blood and in cartilage
have been reported, no systemic clinical abnormalities have been found in
Patients have granular deposits in the anterior stroma along with lattice-like patients who have macular corneal dystrophy.
lines deeper within the stroma. These lines rarely cross and are whiter
than lattice corneal dystrophy. A gray subepithelial haze may develop cen- Patient Presentation
trally after repeat corneal erosions and can affect visual acuity.
Patients often present with decreased vision and photophobia in their
Patient Presentation second and third decades. They also may have recurrent erosions and
decreased corneal sensitivity.
Similar to granular corneal dystrophy type I, patients often present with
decreased vision over time and may have epithelial erosions. Homozygotes
have worse symptoms compared with heterozygotes.18,19
PATHOLOGY
Pathology shows glycosaminoglycan (GAG) accumulation within and
Pathology outside stromal keratocytes, beneath the corneal epithelium, and within
corneal endothelial cells. This is evident with Alcian blue, colloidal iron
Histopathology shows superficial, discrete, red granular deposits with Mas- (Fig. 4.20.7), and PAS staining. Electron microscopy shows intracytoplas-
son’s trichrome stain, as well as mid-to-deep stromal fusiform deposits mic vacuoles that contain GAGs, and the extracellular matrix contains
with the typical Congo red and other stains characteristic of lattice dystro- fibrillogranular GAGs.29
phy type I.20
Treatment
Treatment Treatment consists of corneal transplantation and has good outcomes. In
Treatment is the same as for granular and lattice dystrophies. These indi- those without apparent endothelial involvement, DALK has shown compa-
viduals, even heterozygotes, are at high risk of aggressive recurrence of rable results to PKP in multiple studies at up to 5 years of follow-up.30–32
deposits predominantly in the interface if they undergo laser in situ ker- Although PKP has a higher risk of rejection, DALK has a higher risk of
atomilieusis (LASIK).21–23 Although surface ablation by itself can lead to endothelial failure. Higher rates of intraoperative perforations and need for
mild exacerbation, it may improve vision and delay corneal transplanta- conversion to PKP have been reported. Phototherapeutic keratectomy can 263
tion, with heterozygotes doing better than homozygotes.24 improve vision for a short period but there is a high risk of recurrence.33
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Fig. 4.20.7
4 Macular Corneal
Dystrophy.
Colloidal
iron shows
accumulation of
glycosaminoglycan
at all levels of the
cornea.
Fig. 4.20.9 Findings Typical of Central Cloudy Dystrophy (Posterior Crocodile

Shagreen). Such patients are almost always asymptomatic.
Patient Presentations
Patients complain of severe photophobia. They often can have decreased
corneal sensation and may retain much better scotopic vision than phot-
opic vision.
Pathology
Histopathology shows oil red O–positive material throughout the stroma,
which is more prominent peripherally, in Bowman’s membrane, and
just anterior to Descemet’s membrane. If a surgeon suspects Schnyder’s
corneal dystrophy, it is advisable to send fresh tissue that has not been
preserved. Electron microscopy shows membrane-bound intracellular and
extracellular vacuoles that contain electron-dense materials throughout the
stroma and cholesterol clefts that may be seen in the anterior stroma.37
The accumulated material appears to be phospholipid with esterified and
unesterified cholesterol.
Treatment
Treatment consists of DALK when the acuity declines sufficiently.38 Photo-
therapeutic keratectomy may be beneficial in some patients.39 Corneal ero-
sions may result in better vision after their resolution because of decreased
Fig. 4.20.8 Schnyder’s Crystalline Dystrophy. This patient has a paracentral ring
number of superficial crystals.40
of crystals. (Courtesy Frederick Brightbill, MD.)
CENTRAL CLOUDY DYSTROPHY

Determining absence of endothelial involvement at the time of surgery
remains a challenge. Recurrence in grafts is infrequent.
Genetics
This disorder is autosomal dominant, with no genetic abnormality.
SCHNYDER’S CORNEAL DYSTROPHY
Genetics Central cloudy dystrophy, also known as central cloudy dystrophy of François,
This disorder is autosomal dominant, with mutation in the UBIA phen- has the same clinical appearance as Vogt’s posterior crocodile shagreen,
yltransferase domain containing 1 (UBIAD1) gene at locus 1p36 and is with the exception being that central cloudy dystrophy appears to be dom-
involved in the synthesis of vitamin K2. inantly inherited, whereas posterior crocodile shagreen appears to be spo-
radic. These disorders have central corneal haze in a mosaic pattern like
Ocular Manifestations that on crocodile skin and involves the posterior stroma (Fig. 4.20.9).
Schnyder’s corneal dystrophy is an autosomal dominant disorder with

variable phenotypical expression. Younger patients present with central
Patient Presentations
corneal opacity with or without central subepithelial corneal crystals (Fig. Patients often are asymptomatic.
4.20.8). With advancing age, arcus lipoides and more diffuse stromal haze
may emerge. In up to 50% of patients, however, even in those from the Pathology
same family, such crystals may not be evident. Weiss called this Schnyder’s
crystalline dystrophy sine crystals.34 Histopathology shows a “saw-tooth” disarray of the corneal stromal lamel-
264 Systemic hypercholesterolemia is frequent both in affected and unaf- lae.41 Electron microscopy shows extracellular vacuoles, some containing
fected family members.35 Genu valgum (knock-knees) is rarely associated.36 fibrillogranular material and electron-dense deposits.42
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Treatment Treatment
No treatment is necessary. No treatment is necessary. 4.20
FLECK DYSTROPHY CONGENITAL STROMAL CORNEAL DYSTROPHY

Fleck dystrophy is also referred to as speckle dystrophy, François–Neeten’s dys- Congenital stromal corneal dystrophy is present at birth and nonprogres-
trophy, or cornea en moucheté. sive, so it better fits the category of congenital anomalies. Nonetheless, it
is referred to as a dystrophy and resembles many of the other dystrophies.
Genetics
This disorder is autosomal dominant, with mutation in the phosphoinosit-
Genetics
idase kinase FYVE finger containing gene at locus 2q34. This disorder is autosomal dominant, with a truncating mutation in the
decorin (DCN) gene at locus 12q21.
Patients have discrete, small, white-to-gray opacities, which may be solid
in appearance or have clear centers, scattered throughout the stroma. The Congenital hereditary stromal dystrophy is a very rare disorder that is
corneal epithelium and endothelium are uninvolved. characterized by the presence of bilateral feathery or flaky, white, diffuse
stromal clouding, most prominent in the central cornea. The corneal epi-
Patient Presentation thelium is normal, and no corneal edema occurs. The opacification is
present at birth and is nonprogressive. Without treatment, visual acuity is
Most patients are asymptomatic, although the occasional patient may be reduced significantly, and nystagmus may ensue.
photophobic.
Pathology The differential diagnosis includes congenital corneal edema (from con-
Histopathology shows distension of some keratocytes with membrane- genital hereditary endothelial dystrophy), congenital glaucoma, and pos-
bound vacuoles containing GAGs (staining with Alcian blue and colloidal terior polymorphous dystrophy. The absence of epithelial edema and the
iron) and complex lipids (staining with oil red O and Sudan black).43 The presence of normal corneal thickness and intraocular pressure, however,
epithelium and the endothelium are normal. Electron microscopy shows exclude these. Corneal haze from metabolic disorders usually is less
membrane-based inclusions with delicate granular material in some evident at birth, increases over time, and is associated with systemic find-
keratocytes.44 ings. In congenital stromal corneal dystrophy, no known systemic abnor-
malities have been found.
Treatment
No treatment is necessary.
Pathology
Histopathology reveals normal epithelium and Bowman’s layer, whereas
the stroma shows separation of lamellae with layers of normal fibrillar
POSTERIOR AMORPHOUS arrangement separated by loosely packed layers of irregular and amor-
phous arrayed collagen, shown to be accumulated decorin material.52
CORNEAL DYSTROPHY The collagen fibrils are about half the normal diameter. The normally
Genetics banded anterior portion of Descemet’s membrane lacks bandings, but
the posterior portion of Descemet’s membrane and the endothelium are
This disorder is autosomal dominant, with deletion of chromosome normal.53
12q21.33-q22 coding for four small leucine-rich proteoglycans45 that are
thought to play roles in collagen fibrillogenesis and matrix assembly. Treatment
Treatment consists of DALK, usually with good outcomes.
Posterior amorphous corneal dystrophy is a rare disorder, dominantly KEY REFERENCES
inherited, and defined by the presence of central and peripheral, deep
corneal, gray, broad sheets of opacification.46 Those with centroperiph- Bredrup C, Stang E, Bruland O, et al. Decorin accumulation contributes to the stromal
opacities found in congenital stromal corneal dystrophy. Invest Ophthalmol Vis Sci
eral changes were flat and hypermetropic, whereas those with less severe 2010;51(11):5578–82.
peripheral form were less hypermetropic and had keratometry readings Dighiero P, Niel F, Ellies P, et al. Histologic phenotype-genotype correlation of corneal dys-
above 41.47 Iridocorneal adhesions have been reported.48 The disorder trophies associated with eight distinct mutations in the TGFBI gene. Ophthalmology
appears to be nonprogressive, which has prompted the recommendation 2001;108(4):818–23.
Kawashima M, Kawakita T, Den S, et al. Comparison of deep lamellar keratoplasty and
that this entity be considered a dysgenesis rather than a dystrophy.49 penetrating keratoplasty for lattice and macular corneal dystrophies. Am J Ophthalmol
2006;142(2):304–9.
Patient Presentation Reddy JC, Murthy SI, Vaddavalli PK, et al. Clinical outcomes and risk factors for graft failure
after deep anterior lamellar keratoplasty and penetrating keratoplasty for macular
corneal dystrophy. Cornea 2015;34(2):171–6.
Patients often present in their first decade, but vision is minimally affected. Szentmáry N, Langenbucher A, Hafner A, et al. Impact of phototherapeutic keratectomy on
the outcome of subsequent penetrating keratoplasty in patients with stromal corneal
Pathology dystrophies. Am J Ophthalmol 2004;137(2):301–7.
Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies – edition 2.
Cornea 2015;34(2):117–59.
Histopathological evaluation has shown irregular disorganization of the Woreta FA, Davis GW, Bower KS. LASIK and surface ablation in corneal dystrophies. Surv
corneal lamellae anterior to Descemet’s membrane, with lipid deposition Ophthalmol 2015;60(2):115–22.
in the cytoplasm of some keratocytes.50 Electron microscopy shows abnor-
mal keratocytes and abnormally oriented collagen fibers, with disorgani-
zation of the posterior stromal lamellae.50 A report described a case where
subepithelial deposits and a thick collagenous layer posterior to Descem-
et’s membrane were found.51
265
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REFERENCES 27. Akama TO, Nishida K, Nakayama J, et al. Macular corneal dystrophy type I and type II
are caused by distinct mutations in a new sulphotransferase gene. Nat Genet 2000;26(2):
1. Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies –
edition 2. Cornea 2015;34(2):117–59.
237–41.
28. Kocluk Y, Yalniz-Akkaya Z, Burcu A, et al. Corneal topography analysis of stromal corneal
4.20
2. de la Chapelle A, Tolvanen R, Boysen G, et al. Gelsolin-derived familial amyloidosis dystrophies. Pak J Med Sci 2015;31(1):116–20.
29. Hori S, Tanishima T. Transmission and scanning electron microscopic studies on endo-

caused by asparagine or tyrosine substitution for aspartic acid at residue 187. Nat Genet
1992;2(2):157–60. thelial cells in macular corneal dystrophy. Jpn J Ophthalmol 1982;26(2):190–8.
3. Dighiero P, Niel F, Ellies P, et al. Histologic phenotype-genotype correlation of corneal 30. Reddy JC, Murthy SI, Vaddavalli PK, et al. Clinical outcomes and risk factors for graft
dystrophies associated with eight distinct mutations in the TGFBI gene. Ophthalmology failure after deep anterior lamellar keratoplasty and penetrating keratoplasty for macular
2001;108(4):818–23. corneal dystrophy. Cornea 2015;34(2):171–6.
4. Das S, Langenbucher A, Seitz B. Excimer laser phototherapeutic keratectomy for granu- 31. Sogutlu Sari E, Kubaloglu A, Unal M, et al. Deep anterior lamellar keratoplasty versus
lar and lattice corneal dystrophy: a comparative study. J Refract Surg 2005;21(6):727–31. penetrating keratoplasty for macular corneal dystrophy: a randomized trial. Am J Oph-
5. Kawashima M, Kawakita T, Den S, et al. Comparison of deep lamellar keratoplasty and thalmol 2013;156(2):267–74.e1.
penetrating keratoplasty for lattice and macular corneal dystrophies. Am J Ophthalmol 32. Cheng J, Qi X, Zhao J, et al. Comparison of penetrating keratoplasty and deep lamellar
2006;142(2):304–9. keratoplasty for macular corneal dystrophy and risk factors of recurrence. Ophthalmol-
6. Spelsberg H, Reinhard T, Henke L, et al. Penetrating limbo-keratoplasty for granular and ogy 2013;120(1):34–9.
lattice corneal dystrophy: survival of donor limbal stem cells and intermediate-term clin- 33. Hafner A, Langenbucher A, Seitz B. Long-term results of phototherapeutic keratec-
ical results. Ophthalmology 2004;111(8):1528–33. tomy with 193-nm excimer laser for macular corneal dystrophy. Am J Ophthalmol
7. Morita Y, Chikama T, Yamada N, et al. New mode of treatment for lattice corneal dystro- 2005;140(3):392–6.
phy type I: corneal epithelial debridement and fibronectin eye drops. Jpn J Ophthalmol 34. Weiss JS. Schnyder crystalline dystrophy sine crystals. Recommendation for a revision of
2012;56(1):26–30. nomenclature. Ophthalmology 1996;103(3):465–73.
8. Rosenberg ME, Tervo TM, Gallar J, et al. Corneal morphology and sensitivity in lattice 35. Kohnen T, Pelton RW, Jones DB. Schnyder corneal dystrophy and juvenile, systemic
dystrophy type II (familial amyloidosis, Finnish type). Invest Ophthalmol Vis Sci hypercholesteremia. Klin Monbl Augenheilkd 1997;211(2):135–7.
2001;42(3):634–41. 36. Weiss JS. Visual morbidity in thirty-four families with Schnyder crystalline corneal
9. Butler JS, Chan A, Costelha S, et al. Preclinical evaluation of RNAi as a treatment for dystrophy (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc
transthyretin-mediated amyloidosis. Amyloid 2016;23(2):109–18. 2007;105:616–48.
10. Fujiki K, Hotta Y, Nakayasu K, et al. A new L527R mutation of the betaIGH3 gene 37. McCarthy M, Innis S, Dubord P, et al. Panstromal Schnyder corneal dystrophy. A clinical
in patients with lattice corneal dystrophy with deep stromal opacities. Hum Genet pathologic report with quantitative analysis of corneal lipid composition. Ophthalmology
1998;103(3):286–9. 1994;101(5):895–901.
11. Hida T, Proia AD, Kigasawa K, et al. Histopathologic and immunochemical features of 38. Mehta JS, Vithana EN, Venkataraman D, et al. Surgical management and genetic anal-
lattice corneal dystrophy type III. Am J Ophthalmol 1987;104(3):249–54. ysis of a Chinese family with the S171P mutation in the UBIAD1 gene, the gene for
12. Stock EL, Feder RS, O’Grady RB, et al. Lattice corneal dystrophy type IIIA. Clinical and Schnyder corneal dystrophy. Br J Ophthalmol 2009;93(7):926–31.
histopathologic correlations. Arch Ophthalmol 1991;109(3):354–8. 39. Paparo LG, Rapuano CJ, Raber IM, et al. Phototherapeutic keratectomy for Schnyder’s
13. Rodrigues MM, Streeten BW, Krachmer JH, et al. Microfibrillar protein and phospho- crystalline corneal dystrophy. Cornea 2000;19(3):343–7.
lipid in granular corneal dystrophy. Arch Ophthalmol 1983;101(5):802–10. 40. Chern KC, Meisler DM. Disappearance of crystals in Schnyder’s crystalline corneal dys-
14. Woreta FA, Davis GW, Bower KS. LASIK and surface ablation in corneal dystrophies. trophy after epithelial erosion. Am J Ophthalmol 1995;120(6):802–3.
Surv Ophthalmol 2015;60(2):115–22. 41. Meyer JC, Quantock AJ, Thonar EJ, et al. Characterization of a central corneal cloudiness
15. Szentmáry N, Langenbucher A, Hafner A, et al. Impact of phototherapeutic keratectomy sharing features of posterior crocodile shagreen and central cloud dystrophy of Francois.
on the outcome of subsequent penetrating keratoplasty in patients with stromal corneal Cornea 1996;15(4):347–54.
dystrophies. Am J Ophthalmol 2004;137(2):301–7. 42. Karp CL, Scott IU, Green WR, et al. Central cloudy corneal dystrophy of Francois. A
16. Lyons CJ, McCartney AC, Kirkness CM, et al. Granular corneal dystrophy. Visual results clinicopathologic study. Arch Ophthalmol 1997;115(8):1058–62.
and pattern of recurrence after lamellar or penetrating keratoplasty. Ophthalmology 43. Nicholson DH, Green WR, Cross HE, et al. A clinical and histopathological study of
1994;101(11):1812–17. Francois-Neetens speckled corneal dystrophy. Am J Ophthalmol 1977;83(4):554–60.
17. Lang SJ, Eberwein P, Reinshagen H, et al. Simultaneous transplantation of limbal stem 44. Purcell JJ Jr, Krachmer JH, Weingeist TA. Fleck corneal dystrophy. Arch Ophthalmol
cells may reduce recurrences of granular dystrophy after corneal transplantation: 2 long- 1977;95(3):440–4.
term case reports. Medicine (Baltimore) 2015;94(20):e789. 45. Aldave AJ, Rosenwasser GO, Yellore VS, et al. Linkage of posterior amorphous corneal
18. Okada M, Yamamoto S, Inoue Y, et al. Severe corneal dystrophy phenotype caused by dystrophy to chromosome 12q21.33 and exclusion of coding region mutations in KERA,
homozygous R124H keratoepithelin mutations. Invest Ophthalmol Vis Sci 1998;39(10): LUM, DCN, and EPYC. Invest Ophthalmol Vis Sci 2010;51(8):4006–12.
1947–53. 46. Carpel EF, Sigelman RJ, Doughman DJ. Posterior amorphous corneal dystrophy. Am J
19. Fujiki K, Hotta Y, Nakayasu K, et al. Homozygotic patient with betaig-h3 gene mutation Ophthalmol 1977;83(5):629–32.
in granular dystrophy. Cornea 1998;17(3):288–92. 47. Moshegov CN, Hoe WK, Wiffen SJ, et al. Posterior amorphous corneal dystrophy. A new
20. Holland EJ, Daya SM, Stone EM, et al. Avellino corneal dystrophy. Clinical manifesta- pedigree with phenotypic variation. Ophthalmology 1996;103(3):474–8.
tions and natural history. Ophthalmology 1992;99(10):1564–8. 48. Dunn SP, Krachmer JH, Ching SS. New findings in posterior amorphous corneal dystro-
21. Wan XH, Lee HC, Stulting RD, et al. Exacerbation of Avellino corneal dystrophy after phy. Arch Ophthalmol 1984;102(2):236–9.
laser in situ keratomileusis. Cornea 2002;21(2):223–6. 49. Grimm BB, Waring GO 3rd, Grimm SB. Posterior amorphous corneal dysgenesis. Am J
22. Awwad ST, Di Pascuale MA, Hogan RN, et al. Avellino corneal dystrophy worsening after Ophthalmol 1995;120(4):448–55.
laser in situ keratomileusis: further clinicopathologic observations and proposed patho- 50. Johnson AT, Folberg R, Vrabec MP, et al. The pathology of posterior amorphous corneal
genesis. Am J Ophthalmol 2008;145(4):656–61. dystrophy. Ophthalmology 1990;97(1):104–9.
23. Banning CS, Kim WC, Randleman JB, et al. Exacerbation of Avellino corneal dystrophy 51. Roth SI, Mittelman D, Stock EL. Posterior amorphous corneal dystrophy. An ultra-
after LASIK in North America. Cornea 2006;25(4):482–4. structural study of a variant with histopathological features of an endothelial dystrophy.
24. Inoue T, Watanabe H, Yamamoto S, et al. Recurrence of corneal dystrophy resulting from Cornea 1992;11(2):165–72.
an R124H Big-h3 mutation after phototherapeutic keratectomy. Cornea 2002;21(6):570–3. 52. Bredrup C, Stang E, Bruland O, et al. Decorin accumulation contributes to the stromal
25. Dang X, Zhu Q, Wang L, et al. Macular corneal dystrophy in a Chinese family related opacities found in congenital stromal corneal dystrophy. Invest Ophthalmol Vis Sci
with novel mutations of CHST6. Mol Vis 2009;15:700–5. 2010;51(11):5578–82.
26. Edward DP, Thonar EJ, Srinivasan M, et al. Macular dystrophy of the cornea. A systemic 53. Witschel H, Fine BS, Grützner P, et al. Congenital hereditary stromal dystrophy of the
disorder of keratan sulfate metabolism. Ophthalmology 1990;97(9):1194–200. cornea. Arch Ophthalmol 1978;96(6):1043–51.
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Diseases of the Corneal Endothelium

Noel Rosado-Adames, Natalie A. Afshari 4.21
triphosphatase (Na+,K+–ATPase) pump activity,14 which leads to a reduc-
Definition: Diseases affecting the innermost layer of the cornea, which tion in ion flux across the endothelium.11 Molecular biological studies of
is in charge of regulating the hydration state of the corneal stroma. corneal buttons from patients with FD suggest that apoptosis may play
an important role in endothelial cell degeneration.15 Recent studies have
demonstrated an oxidant–antioxidant imbalance in FD cells, which, in
turn, leads to oxidative DNA damage and apoptosis.16
Several genetic loci have been identified in patients with FD.3 The first
Key Features genetic locus was mapped to chromosome 13, called Fuchs’ corneal dystro-
• Bilateral presentation. phy locus 1 (FCD1).17 Subsequently, three other loci, FCD2,18 FCD3,19 and
• Corneal clarity affected (variable degree). FCD4,20 were mapped to chromosomes 18, 5, and 9, respectively. Addition-
• Hereditary pattern. ally, other reports have provided evidence for potential linkage to chromo-
somes 1, 7, 15, 17, and X by genome-wide linkage analysis.21
Multiple causal genetic mutations have been linked to FD. Mutations in
the ion cotransporter encoded by the SLC4A11 gene, also associated with
congenital hereditary endothelial dystrophy, have been linked to the devel-
Associated Features opment of FD.22,23 Additionally, mutations in the transcription factor TCF8
• Key clinical features on slit-lamp examination. gene, also associated with posterior polymorphous corneal dystrophy, have
• Severe cases usually require corneal transplantation. been identified in patients with FD.20 A third causal gene for FD, LOXHD1,
was identified on chromosome 18.24 This gene has been associated with
the development of progressive hearing loss in humans.
A strong association has been discovered between FD and trinucleotide
INTRODUCTION repeats (TNRs) in the transcription factor 4 (TCF4) gene in chromosome
18.25–28 This gene encodes the E2-2 transcription factor, which is involved
The effects of external trauma and of ophthalmic and systemic disease on in cellular growth and differentiation.25 Expansion of TNR lead to messen-
human corneal endothelium are best understood by first reviewing the ger RNA (mRNA) missplicing, which leads to RNA toxicity.26 TNR expan-
anatomy and physiology of the adult human endothelium. A comprehen- sion in TCF4 of more than 50 is highly specific for FD.27 Changes to the
sive review of this material can be found in Chapter 4.1. endothelial barrier function, a known event in the development of FD,
was identified as a key biological process influenced by the missplicing
events.28
FUCHS’ DYSTROPHY Mutations in the gene COL8A2 that codes for the α2-chain of type VIII
Introduction collagen have been reported in patients with an early onset endothelial
dystrophy that was previously considered an early form of FD.29 Recent
Fuchs’ endothelial corneal dystrophy (FD) is a bilateral, noninflammatory, studies suggest that the endothelial dystrophy linked to mutations in
progressive loss of endothelial cells that results in corneal edema and COL8A2 represents a disease that is phenotypically distinct from FD.2
reduction of vision. Its key features include the presence of central guttae,
folds in Descemet’s membrane, stromal edema, and microcystic epithelial Ocular Manifestations
edema. Corneal endothelial degeneration is the primary defect that leads to
the development of corneal edema. Associated features include prominent The earliest slit-lamp finding in FD is the presence of focal excrescences
corneal nerves, stromal opacification, recurrent corneal erosions, female of extracellular matrix in Descemet’s membrane, called guttae (cornea
gender predominance, and familial predisposition. guttata). In the earliest stages of this disease, the guttae first emerge in the
central corneal endothelium (Fig. 4.21.1). Guttae are not specific to FD and
Epidemiology and Pathogenesis may be seen in asymptomatic patients and in the setting of both uveitis
and nonspecific superficial keratopathies. Up to 11% of eyes in patients
FD is the most common corneal dystrophy to require keratoplasty, account- older than age 50 years have guttae.30 Pathologically identical lesions in
ing for approximately 3.1% of all penetrating keratoplasties (PKPs) and peripheral Descemet’s membrane are known as Hassall–Henle warts and
47.1% of all endothelial keratoplasties in the United States in 2015.1 The are part of the normal aging process (see Chapter 4.22).
genetic basis of FD is complex and heterogeneous, demonstrating vari- The guttae initially appear on specular reflection as scattered, discrete,
able expressivity and incomplete penetrance.2 FD is likely to be complex isolated dark structures, smaller than an individual endothelial cell.31 An
in etiology, with genetic as well as environmental factors playing a role associated fine pigment dusting may be observed within the central endo-
in its pathogenesis.3 A significant variation occurs in expressivity between thelium. At this stage, referred to as stage 1, the patient’s vision usually
males and females, with a 3–4 : 1 female/male ratio recorded at the time of is normal, and the stroma and epithelium are uninvolved.3,30 Over time,
keratoplasty.4 It is equally common among white and black patients who these individual excrescences increase in number, enlarge, and fuse with
undergo keratoplasty but is relatively rare in Asian patients.5 adjacent guttae to disrupt the normal endothelial monolayer’s specular
Development of guttae and the onset of symptoms are more common in reflection.31 This produces a roughened surface with a specular reflection
middle age.6 Patients with FD are believed to have an increased incidence similar to beaten metal in appearance. Eventually, this process expands
of open-angle glaucoma.7 Short axial length, shallow anterior chamber, from the center of the cornea to involve the corneal periphery. As the dis-
and angle-closure glaucoma also have been seen in conjunction with order progresses, the endothelial monolayer becomes attenuated in thick-
FD.8 FD has been associated with keratoconus.9–11 The progressive loss of ness, with an increase in average cell size (polymegathism), a decrease in
endothelial cell function is primary in nature rather than secondary to any the percentage of hexagonal shaped cells, and an increase in the coefficient
266 alteration in aqueous humor flow rate12 or constituency.13 Endothelial dys- of variation in cell size (pleomorphism). In the last stages of the dystrophy,
function is mainly a result of a reduction in sodium, potassium–adenosine effacement of the endothelium results in overlying stromal edema. At this
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4.21

Fig. 4.21.1 Slit-Lamp View of Fuchs’ Dystrophy (FD). Note the guttae on the Fig. 4.21.2 Specular Photomicrograph of Fuchs’ Dystrophy (FD). Note dark areas
image of the endothelium reflected on the speculum. that represent guttae adjacent to areas of enlarged endothelial cells. (Spacing of
grid 0.1 mm.)
point, the endothelium becomes more difficult to observe using conven-

tional specular microscopy, but it may still be visualized using confocal
microscopy.31
As endothelial function progressively declines, the fluid accumulated
in the stroma during nighttime lid closure is removed at a reduced rate,
which results in significant stromal edema upon awakening.32 This heralds
the onset of stage 2.3,30 Patients note blurred vision, glare, and colored halos
around lights. Initially, the stromal edema is localized in front of Descem-
et’s and behind Bowman’s membrane.33 Eventually, the entire stroma
swells, taking on a ground-glass appearance. With the increase in corneal
thickness, the posterior stroma and Descemet’s membrane are thrown
into folds. Vision at this time is variable.
With progressive endothelial dysfunction, bulk fluid flow across the
cornea results in microcystic and bullous epithelial edema. This develop-
A
ment represents stage 3 of the disease.3,30 With involvement of the epithe-
lial layer, the optical quality of the tear–air interface is severely degraded,
which produces a profound reduction in vision. With the onset of epithelial
edema, basal adhesion complexes become disrupted to produce recurrent
corneal erosions. As a slit-lamp marker of recurrent epithelial sloughing,
duplication of basement layers occurs, which creates fingerprint and map
changes.
If erosions are prominent, a vascular pannus between epithelium and
Bowman’s membrane may be induced and results in an anterior stromal
haze, with further reduction in vision, representing stage 4 of the disease.3
However, the associated secondary fibrotic layer produced within the
pannus often reduces or eliminates the painful recurrent epithelial ero-
sions experienced by the patient. With the increase in stromal edema, gly-
cosaminoglycans elute from the stroma,34 causing disorganization of the
collagen fibrils, which contributes to additional stromal opacification.
Diagnosis and Ancillary Testing

The earliest observable change suggestive of FD is the presence of guttae
on slit-lamp examination (see Fig. 4.21.1). Specular microscopy provides B
endothelial cell counts, as well as a photographic record that can be a
useful educational aid for the patient (Fig. 4.21.2). Subtle stromal edema Fig. 4.21.3 Characteristic Wart-Like Bumps Present Within Descemet’s
can be observed using sclerotic scatter techniques. Corneal pachymetry Membrane. (A) Periodic acid–Schiff stain. (B) Scanning electron microscopy shows
documents increased corneal thickness. As the disease progresses, more this better. (Courtesy Dr. R. C. Eagle, Jr.)
obvious signs may develop, which include folds in Descemet’s membrane,
stromal haze, microcystic and bullous epithelial edema, subepithelial fibro-
sis, and pannus formation. When corneal opacification precludes specular
microscopy, confocal microscopy can be used to image the endothelium Pathology
and obtain reliable endothelial cell counts.31,32
Light microscopy findings include a thickened Descemet’s membrane,
Differential Diagnosis which may be laminated in appearance with buried guttae, guttae on the
surface, or devoid of guttae but thickened (Fig. 4.21.3).4 The endothelial
Differential diagnosis includes posterior polymorphous corneal dystrophy, layer is attenuated. Electron microscopy in FD shows characteristic thick-
congenital hereditary endothelial dystrophy, aphakic or pseudo-phakic ening of Descemet’s membrane caused by the deposition of an addi-
bullous keratopathy, and Hassall–Henle bodies. No associated systemic tional posterior banded layer (PBL), posterior to the posterior nonbanded 267
diseases exist.3,30 layer. The PBL is markedly thickened and contains abnormally deposited
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collagen and the classic posterior excrescences, guttae.3 The production of development of autosomal recessive CHED.50 A related X-linked endothe-
4 this morphologically abnormal Descemet’s membrane serves as a marker

for a dysfunctional endothelium.35
lial dystrophy has been described in males that clinically resembles CHED
very closely.51
CHED is believed to result from abnormal neural crest cell terminal
Treatment induction during the late term to perinatal period. At this time, failure to
complete final differentiation of the endothelial monolayer occurs, which

Early stages of the disease may be managed medically, temporizing results in a dysfunctional endothelium.52 This dysfunctional endothelium
the need for a keratoplasty. Medical management includes the use of is believed to have faulty growth regulation mechanisms that lead to accu-
hypertonic solutions or ointments and decreasing ambient humidity. If mulation of a functionally abnormal and structurally exaggerated form of
intraocular pressure (IOP) is above 20 mm Hg (2.67 kPa), attempts to posterior nonbanded Descemet’s membrane.53
lower it may reduce the force that drives fluid into the stroma. Treatment
measures for painful erosions include hypertonics, bandage contact lenses, Ocular Manifestations
anterior stromal puncture, and conjunctival flaps.
With progressive corneal edema refractory to medical management, The usual presentation is bilateral, symmetrically edematous, cloudy
keratoplasty usually is offered. PKP was traditionally performed for the corneas evident at birth or early in the postnatal period.49 Examination
treatment of advanced cases.36 If the patient shows signs of visually sig- reveals the corneas to have a diffuse gray-blue, ground-glass coloring.49
nificant cataracts, keratoplasty may be combined with cataract extraction.37 Corneal thickness is 2–3 times normal and often greater than 1 mm cen-
In recent years, endothelial keratoplasty, including Descemet’s stripping trally. Both IOP and horizontal corneal diameter are normal. Rarely, CHED
automated endothelial keratoplasty (DSAEK or DSEK) and Descemet’s is associated with glaucoma and should be considered if corneal opacifica-
membrane endothelial keratoplasty (DMEK), has been performed as an tion fails to resolve after normalization of IOP.54
alternative to conventional full-thickness corneal transplantation for the Closer examination reveals the texture of the epithelial surface to be
treatment of endothelial disorders.38–42 In fact, endothelial keratoplasties irregular, with a diffuse pigskin-like roughness.49 Occasionally, discrete
represented 92% of the total keratoplasties performed in 2015 in patients white dots may be seen in the stroma. In areas where stromal opacifica-
with FD.1 The DSAEK procedure involves replacing the diseased endothe- tion is less dense, Descemet’s membrane appears gray, and on specular
lium and deep stroma with a posterior lamellar disc of tissue, including reflection may have a peau d’orange texture.49 The endothelial layer may
donor corneal endothelium, Descemet’s membrane, and posterior corneal or may not be visualized. A fine corneal pannus may be seen, as well as
stroma. DMEK involves replacing the diseased tissue with just the donor low-grade inflammation.
endothelium and Descemet’s membrane. Both DSAEK and DMEK have
been demonstrated to be superior to PKP in terms of earlier visual recov- Diagnosis
ery, postoperative refractive outcomes, wound- and suture-related compli-
cations, and intraoperative and late suprachoroidal hemorrhage risk.40,43 A tentative diagnosis usually is possible when examination under anesthe-
Studies have reported faster visual rehabilitation and better best corrected sia demonstrates typical bilateral stromal opacification, gross corneal thick-
visual acuity with DMEK compared with DSAEK.44 With DMEK, patients ening, normal horizontal diameter, normal IOP, and absence of breaks in
also had a lower rate of endothelial rejection (1%) at 2 years compared with Descemet’s membrane.
DSAEK (9%) and PKP (17 %).45
Course and Outcome Differential diagnosis includes congenital glaucoma without buphthalmos,
Long-term outcomes of patients with FD undergoing PKP have shown that posterior polymorphous corneal dystrophy, macular stromal dystrophy,
graft clarity approached 90%, and approximately 60% of patients achieved mucopolysaccharidosis, intra-uterine infection, and birth trauma from
20/40 (6/12) or better visual acuity 5 years after transplantation.35 Results forceps. Harboyan’s syndrome is an entity defined as CHED accompa-
after DSAEK have shown that average best-corrected visual acuity (BCVA; nied by progressive, sensorineural hearing loss.55,56 This disorder has been
mean 9 months after surgery) ranged from 20/34 to 20/66.40 One year linked to the SLC4A11 gene mutation.56
after DMEK surgery, patients had an average BCVA of 20/24, with 98% of
patients achieving 20/30 or better.46 Reports of graft survival rates at 5 years Pathology
for DMEK and DSAEK were similar to those reported for PKP in patients
with FD (95%, 95%, and 93% respectively).41,47 Light microscopy shows epithelial atrophy with basal cell hydrops, sub-
epithelial calcification or fibrosis, patchy loss of Bowman’s membrane,
and variable vascularization or spheroidal degeneration of the stroma.53
CONGENITAL HEREDITARY Descemet’s membrane is thickened, often with discrete laminations. The
endothelial layer is attenuated.53
ENDOTHELIAL DYSTROPHY
Introduction Treatment
48
First described by Maumenee in 1960, congenital hereditary endothelial If the edema is stationary and mild, use of hypertonics and desiccating
dystrophy (CHED) is but one of the many causes of bilateral corneal cloud- measures may be employed. Usually, however, these patients require
ing in full-term infants and usually requires keratoplasty. Key features of keratoplasty because of the bilateral nature of the corneal edema. Kerato-
this autosomal dominant or recessive condition are a corneal thickness plasty in infants and children is a high-risk procedure and is technically
2–3 times normal, normal IOP, and normal corneal diameter. Associated difficult, and the long-term prognosis for graft clarity is worse than it is
features are corneal pannus, nystagmus, and esotropia. for adults. No definitive clinical guidelines have emerged with regard to
the timing of surgical intervention, as a result of significant heterogene-
Epidemiology and Pathogenesis ity in disease severity, follow-up periods, and patient ages at both diag-
nosis and surgery, among the few published studies.57 Delayed PKP
Prevalence, incidence, and gender distribution for this disorder are (after age 12 years) may offer better graft outcomes and visual progno-
unknown. The onset is usually at birth in a term infant; corneal clouding sis in patients with CHED, even in the presence of nystagmus, accord-
may be maximal at birth or progress over a period of years. Family pedigree ing to a publication.58 DSAEK has been performed in recent years as
studies support that autosomal dominant (CHED1) and recessive (CHED2) a therapeutic alternative for CHED. DSAEK performed in eyes with
forms exist, as well as sporadic occurrences. Autosomal recessive inheri- CHED has allowed rapid restoration of corneal clarity while minimizing
tance is associated with bilateral corneal edema without photophobia but intraoperative and postoperative complications normally associated with
with nystagmus that is present at birth.49 Autosomal dominant inheritance pediatric PKP.59
is associated with the progressive onset of corneal edema 1–2 years post The decision regarding surgery may be difficult because despite sig-
partum with photophobia but without nystagmus.49 Autosomal dominant nificant corneal haze and absence of a red reflex, patients often seem to
and autosomal recessive forms of CHED have been linked to chromosome see much better than expected.60 If patients maintain good fixation with
268 20, mapped to the loci 20p11.2-q11.2 and 20p13, respectively.50 Mutations in normal alignment, surgery may be delayed; loss of fixation or development
the SLC4A11 gene in chromosome 20 have been highly associated with the of nystagmus may lead to earlier intervention.60
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Course and Outcome
In one large study, during a mean follow-up period of over 70 months, 69% 4.21
of eyes retained full graft clarity. Postoperative visual acuity improvement
of 1 or more Snellen lines was seen in 5 of 10 eyes in which the patients

were old enough for accurate assessment of visual acuity; however, just
four of these 10 eyes attained a visual acuity of 20/200 or better.61 First graft
survival rates range from 25% at 3 months in earlier studies to 62%–90%
at 2–3 years in more recent series.57,60,61
Results from a small series of patients older than age 12 months who
underwent DSAEK revealed that BCVA of 20/40 or better was achieved in
8 of the 9 patients, and visual acuity of 20/70 was achieved in the remain-
ing patient. In the infant group, the three patients who had DSAEK were
able to “fix and follow” after the procedure.59
POSTERIOR POLYMORPHOUS
CORNEAL DYSTROPHY
Introduction
First described in 1916 by Koeppe, this rare dystrophy has a clinical spec-
trum that ranges from congenital corneal edema to late-onset corneal Fig. 4.21.4 Slit-lamp appearance of vesicles in posterior polymorphous dystrophy.
edema in middle age. Many cases are subclinical—the majority of patients Note the small vesicular lesions on retroillumination. (Courtesy Dr. Richard Yee.)
have good vision and only subtle slit-lamp and specular micrographic
abnormalities. Posterior polymorphous corneal dystrophy (PPCD) is a
bilateral autosomal dominant disorder characterized by polymorphic pos-
terior corneal surface irregularities with variable degrees of corneal decom-
pensation. Key features consist of the following:
• Vesicular, curvilinear, and placoid irregularities found on slit-lamp
examination
• Rounded dark areas with central cell detail that produce a doughnut-like
pattern on specular microscopy
• Epithelial-like transformation of endothelium on histological
examination
• Reduced vision from the corneal edema.
Associated features are iridocorneal adhesions, peripheral anterior syn-
echiae, glaucoma, and a tendency to recur in graft patients. Some of these
features overlap with iridocorneal endothelial (ICE) syndrome, Peters’
anomaly, and Axenfeld–Rieger syndrome, suggesting that PPCD may be
part of a broader spectrum of disorders united by abnormalities of ter-
minal neural crest cell differentiation.62,63 PPCD associated with posterior
amyloid degeneration of the cornea, keratoconus, and Alport’s syndrome
has been reported.62,64,65
Fig. 4.21.5 Slit-Lamp Appearance of the Band Form of Posterior Polymorphous
Epidemiology and Pathogenesis Dystrophy. Note the vertical serpentine band. (Courtesy Dr. Richard Yee.)
The prevalence of this rare disorder in the general population is unknown.
This autosomal dominant condition presents with variable genetic pene- Ocular Manifestations
trance and expressivity.66,67 PPCD has been linked to three chromosomal
loci: (1) PPCD1 (OMIM 122000) on chromosome 20p11.2-q11.2; (2) PPCD2 The most common finding is isolated vesicles bilaterally, which appear as
(OMIM 609140) on chromosome 1p34.3–p32.3; and (3) PPCD3 (OMIM circular or oval transparent cysts with a gray halo, diameters in the range
609141) on chromosome 10p11.2.67 Specific genes at each locus have been of 0.2–1 mm, at the level of Descemet’s membrane, best viewed by retroil-
identified, but there is some controversy regarding the role of these genes lumination with a widely dilated pupil (Fig. 4.21.4).83,84 The cysts may be
in the pathogenesis of this condition.68–74 Mutations in the homeobox gene few or many, widely separated or clustered close together to create conflu-
VSX1 in PPCD1 were demonstrated in PPCD families,69,70 but other studies ent geographical patches. Less common are band-shaped or “snail track”
did not replicate these results.70,71 Reports have associated the COL8A2 areas, which typically have scalloped edges and are about 1 mm across (Fig.
gene within the PPCD2 locus, coding for the α2-chain of type VIII col- 4.21.5).83 Their length can range from 2–10 mm.84 In both vesicular and
lagen, with PPCD,29,74 as well as contributing to the pathogenesis of an band presentations, the overlying stroma and epithelium are uninvolved,
early-onset endothelial corneal dystrophy. The contribution of this gene and vision is normal. The least common slit-lamp finding is placoid or
has been questioned as additional studies have failed to identify similar diffuse endothelial involvement.83 Patients who have placoid-type PPCD
mutations within analyzed PPCD cohorts.74–76 Studies investigating a can- often present with reduced vision. Specular microscopy of the presenting
didate gene at the PPCD3 locus demonstrated disease-causing mutations lesions shows them to be sharply demarcated from uninvolved endothe-
in the zinc finger E-box binding homeobox 1 gene ZEB1, previously known lium. In this presentation, Descemet’s membrane and the posterior stroma
as TCF8.77–81 The ZEB1 gene has the strongest association to PPCD based are hazy, and usually areas of corneal edema and iridocorneal adhesions
on linkage, association, and familial segregation analyses.81 occur.84
The pathogenesis of PPCD is attributed to focal metaplasia of endothe- On specular microscopy, the vesicles appear as circular dark rings
lial cells into a population of aberrant keratinized epithelial-like cells.62,65 around a lighter, although mottled, center in which cellular detail is
Immunohistochemical analyses of these transformed cells show that they evident.83–87 These vesicles represent steep-sided, shallow depressions
contain antigens and cytokeratins that usually are associated with epithe- in the endothelium83; the steep sides correspond to the peripheral dark
lial cells.82 The transformation of a single-cell layer of endothelium into ring seen on specular reflection, and the depressed center corresponds to
a multilayered epithelium-like tissue is believed to be responsible for the the lighter, mottled central portion (Fig. 4.21.6). Specular microscopy of
loss of stromal deturgescence, the observed specular microscopic patterns, the band-shaped areas shows them to be composed of a chain of over- 269
and the tendency toward synechiae formation. lapping vesicles, which create a shallow trench with scalloped borders
booksmedicos.org
juxtaposition of normal-appearing endothelial cells adjacent to epithelial
4 cell-like areas that show myriad surface microvilli.86,87 Transmission elec-

tron microscopy shows multilayered cells that contain numerous desmo-
somes and intracytoplasmic filaments.86,87 Cell culture studies demonstrate
features similar to cultured epithelial cell lines.87
Treatment
The majority of patients require no treatment; those with corneal opacifi-
cation are offered keratoplasty. Traditionally, penetrating keratoplasty was
performed in this group of patients. Recent reports have shown the imple-
mentation of endothelial keratoplasty with positive results.88,89
Course and Outcome

In the majority of patients, PPCD is believed to be a nonprogressive type
of dystrophy, usually without vision impairment. Those patients who
require keratoplasty appear to be at risk for recurrence of this dystrophy
in the grafted cornea,90–92 as well as for the development of glaucoma.87
It is thought that the genesis of this behavior is the epithelial-like trans-
formation and subsequent migration of host endothelium, which causes
the endothelium to encroach on the donor corneal tissue and host angle
Fig. 4.21.6 Specular Photomicrograph of Vesicles in Posterior Polymorphous
structures.87
Dystrophy. Note the doughnut-like appearance of the vesicles. (Courtesy Dr.
Richard Yee.)
KEY REFERENCES
that represent the edges of individual vesicles that have fused.83 Patients Adamis AP, Filatov V, Tripathi BJ, et al. Fuchs’ endothelial dystrophy of the cornea. Surv
with PPCD may exhibit broad-based iridocorneal adhesions and periph- Ophthalmol 1993;38:149–68.
eral anterior synechiae. These most often are seen in corneas with placoid Aldave AJ, Han J, Frausto RF. Genetics of the corneal endothelial dystrophies: an
areas of involvement.84 Elevation of IOP refractory to medical measures evidence-based review. Clin Genet 2013;84(2):109–19.
Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding the
is common in these patients. All patients who have PPCD have reduced alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy.
endothelial cell counts compared with age-matched controls.83,85 Hum Mol Genet 2001;21:2415–23.
Busin M, Beltz J, Scorcia V. Descemet-stripping automated endothelial keratoplasty for con-
genital hereditary endothelial dystrophy. Arch Ophthalmol 2011;129:1140–6.
Diagnosis Droutsas K, Lazaridis A, Papaconstantinou D, et al. Visual outcomes after Descemet mem-
brane endothelial keratoplasty versus Descemet stripping automated endothelial
The majority of patients are diagnosed with use of the slit lamp that keratoplasty-comparison of specific matched pairs. Cornea 2016;35(6):765–71.
helps visualize vesicular, band-like, or placoid areas on the posterior Elhalis H, Azizi B, Jurkunas UV. Fuchs’ endothelial corneal dystrophy. Ocul Surf 2010;8:
corneal surface. The diagnosis of PPCD in patients with corneal edema of 173–84.
unknown cause is based on light and electron microscopy of the excised Hemadevi B, Veitia RA, Srinivasan M, et al. Identification of mutations in the SLC4A11 gene
in patients with recessive congenital hereditary endothelial dystrophy. Arch Ophthalmol
buttons obtained during keratoplasty. 2008;126:700–8.
Iliff BW, Riazuddin SA, Gottsch JD. The genetics of Fuchs′ corneal dystrophy. Expert Rev
Differential Diagnosis Ophthalmol 2012;7(4):363–75.
Lee WB, Jacobs DS, Musch DC, et al. Descemet’s stripping endothelial keratoplasty: safety
and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology
Differential diagnosis includes tears in Descemet’s membrane, interstitial 2009;1818–30.
keratitis, FD, and ICE syndrome (discussed in detail in Chapter 10.20). As Ozdemir B, Kubaloğlu A, Koytak A, et al. Penetrating keratoplasty in congenital hereditary
in PPCD, endothelial cells in ICE syndrome may show epithelial charac- endothelial dystrophy. Cornea 2012;31:359–65.
teristics, leading to speculation that they represent a spectrum of the same Price MO, Fairchild KM, Price DA, et al. Descemet’s stripping endothelial keratoplasty
five-year graft survival and endothelial cell loss. Ophthalmology 2011;118:725–9.
disease.63 No systemic associations exist except for rare reports of PPCD Riazuddin SA, Parker DS, McGlumphy EJ, et al. Mutations in LOXHD1, a recessive-deafness
associated with Alport’s syndrome. locus, cause dominant late-onset Fuchs corneal dystrophy. Am J Hum Genet
2012;90(3):533–9.
Schaumberg DA, Moyes AL, Gomes JA, et al. Corneal transplantation in young children with
Pathology congenital hereditary endothelial dystrophy. Multicenter Pediatric Keratoplasty Study.
Am J Ophthalmol 1999;127(4):373–8.
Light microscopy shows pits in the posterior corneal surface, which corre- Vithana EN, Morgan PE, Ramprasad V. SLC4A11 mutations in Fuchs endothelial corneal
spond to the vesicles seen on slit-lamp examination. Descemet’s membrane dystrophy. Hum Mol Genet 2008;17:656–66.
in these areas is attenuated, and the endothelium may be multilayered.86,87 Wieben ED, Aleff RA, Tosakulwong N, et al. A common trinucleotide repeat expansion
within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.
In other areas, Descemet’s membrane appears multilayered, of variable PLoS ONE 2012;7(11):e49083.
thickness, and with attenuation or loss of endothelium. Discontinuities
in Descemet’s membrane with anterior migration of cells to form slit-like
structures or clefts in pre-Descemet’s stroma have been described.64 Scan- Access the complete reference list online at ExpertConsult.com
ning electron microscopy of keratoplasty buttons may show a striking
270
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plasty. Exp Eye Res 2012;95:40–7.
1. Eye Banking Statistical Report. Washington: Eye Bank Association of America; 2015.
2. Iliff BW, Riazuddin SA, Gottsch JD. The genetics of Fuchs′ corneal dystrophy. Expert Rev
43. Spaniol K, Borrelli M, Holtmann C, et al. Complications of Descemet’s membrane endo-
thelial keratoplasty. Ophthalmologe 2015;112(12):974–81.
4.21
Ophthalmol 2012;7(4):363–75. 44. Droutsas K, Lazaridis A, Papaconstantinou D, et al. Visual outcomes after Descemet
membrane endothelial keratoplasty versus Descemet stripping automated endothelial

3. Elhalis H, Azizi B, Jurkunas UV. Fuchs’ endothelial corneal dystrophy. Ocul Surf
2010;8:173–84. keratoplasty-comparison of specific matched pairs. Cornea 2016;35(6):765–71.
4. Afshari NA, Pittard AB, Siddiqui A, et al. Clinical study of Fuchs corneal endothelial 45. Anshu A, Price MO, Price FW Jr. Risk of corneal transplant rejection significantly reduced
dystrophy leading to penetrating keratoplasty: a 30-year experience. Arch Ophthalmol with Descemet’s membrane endothelial keratoplasty. Ophthalmology 2012;119(3):536–40.
2006;124(6):777–80. 46. Guerra FP, Anshu A, Price MO, et al. Descemet’s membrane endothelial keratoplasty:
5. Santo RM, Yamaguchi T, Kanai A, et al. Clinical and histopathologic features of corneal prospective study of 1-year visual outcomes, graft survival, and endothelial cell loss. Oph-
dystrophies in Japan. Ophthalmology 1995;102:557–67. thalmology 2011;118(12):2368–73.
6. Wilson SE, Bourne WM. Fuchs’ dystrophy. Cornea 1988;7:2–18. 47. Schlögl A, Tourtas T, Kruse FE, et al. Long-term clinical outcome after Descemet mem-
7. Kolker AE, Hetherington J Jr. Becker–Shaffer’s diagnosis and therapy of the glaucomas. brane endothelial keratoplasty. Am J Ophthalmol 2016;169:218–26.
5th ed. St Louis: CV Mosby; 1983. p. 275. 48. Maumenee AE. Congenital hereditary corneal dystrophy. Am J Ophthalmol 1960;50:
8. Pitts JF, Jay JL. The association of Fuchs’ corneal endothelial dystrophy with axial hyper- 1114–24.
metropia, shallow anterior chamber, and angle closure glaucoma. Br J Ophthalmol 49. Waring IIIGO, Rodrigues MM, Laibson PR. Corneal dystrophies II endothelial dystro-
1990;74:601–4. phies. Surv Ophthalmol 1978;23:147–67.
9. Lipman RM, Rubenstein JB, Torczynski E. Keratoconus and Fuchs’ corneal endothelial 50. Hemadevi B, Veitia RA, Srinivasan M, et al. Identification of mutations in the SLC4A11
dystrophy in a patient and her family. Arch Ophthalmol 1990;108:993–4. gene in patients with recessive congenital hereditary endothelial dystrophy. Arch Oph-
10. Orlin SE, Raber IM, Eagle RC Jr, et al. Keratoconus associated with corneal endothelial thalmol 2008;126:700–8.
dystrophy. Cornea 1990;9:299–304. 51. Schmid E, Lisch W, Philipp W, et al. A new X-linked endothelial corneal dystrophy. Am J
11. Cremona FA, Ghosheh FR, Rapuano CJ, et al. Keratoconus associated with other corneal Ophthalmol 2006;141:478–87.
dystrophies. Cornea 2009;28:127–35. 52. Bahn CF, Falls HF, Varley GA, et al. Classification of corneal endothelial disorders based
12. Wilson SE, Bourne WM, O’Brien PC, et al. Endothelial function and aqueous humor on neural crest origin. Ophthalmology 1984;91:558–63.
flow rate in patients with Fuchs’ dystrophy. Am J Ophthalmol 1988;106:270–8. 53. Kirkness CM, McCartney A, Rice SC, et al. Congenital hereditary corneal oedema of Mau-
13. Wilson SE, Bourne WM, Maguire LJ, et al. Aqueous humor composition in Fuchs’ dys- menee: its clinical features, management, and pathology. Br J Ophthalmol 1987;71:140–4.
trophy. Invest Ophthalmol Vis Sci 1989;30:449–53. 54. Mullaney PB, Risco JM, Teichmann K, et al. Congenital hereditary endothelial dystrophy
14. McCartney MD, Wood TO, McLaughlin BJ. Moderate Fuchs’ endothelial dystrophy associated with glaucoma. Ophthalmology 1995;102:186–92.
ATPase pump site density. Invest Ophthalmol Vis Sci 1989;30:1560–4. 55. Harboyan G, Mamo J, Der Kaloustian V, et al. Congenital corneal dystrophy: progressive
15. Borderie VM, Baudrimont M, Vallee A, et al. Corneal endothelial cell apoptosis in sensorineural deafness in a family. Arch Ophthalmol 1981;85:27–32.
patients with Fuchs’ dystrophy. Invest Ophthalmol Vis Sci 2000;41:2501–5. 56. Desir J, Abramowicz M. Congenital hereditary endothelial dystrophy with progressive
16. Szentmáry N, Szende B, Süveges I. Epithelial cell, keratocyte, and endothelial cell apop- sensorineural deafness (Harboyan syndrome). Orphanet J Rare Dis 2008;3:28.
tosis in Fuchs’ dystrophy and in pseudophakic bullous keratopathy. Eur J Ophthalmol 57. Schaumberg DA, Moyes AL, Gomes JA, et al. Congenital hereditary endothelial dystro-
2005;15:17–22. phy Multicenter Pediatric Keratoplasty Study. Am J Ophthalmol 1999;127:373–8.
17. Sundin OH, Jun AS, Broman KW, et al. Linkage of late-onset Fuchs’ corneal dystrophy to 58. Ozdemir B, Kubaloğlu A, Koytak A, et al. Penetrating keratoplasty in congenital heredi-
a novel locus at 13pTel-13q1213. Invest Ophthalmol Vis Sci 2006;47:140–5. tary endothelial dystrophy. Cornea 2012;31:359–65.
18. Sundin OH, Broman KW, Chang HH, et al. A common locus for late onset Fuchs’ 59. Busin M, Beltz J, Scorcia V. Descemet-stripping automated endothelial keratoplasty for
corneal dystrophy maps to 18q212-q2132. Invest Ophthalmol Vis Sci 2006;47:3919–26. congenital hereditary endothelial dystrophy. Arch Ophthalmol 2011;129:1140–6.
19. Riazuddin SA, Eghrari AO, Al-Saif A, et al. Linkage of a mild late-onset phenotype 60. Sajjadi H, Javadi MA, Hemmati R, et al. Results of penetrating keratoplasty in CHED:
of Fuchs corneal dystrophy to a novel locus at 5q331-q352. Invest Ophthalmol Vis Sci congenital hereditary endothelial dystrophy. Cornea 1995;14:18–25.
2009;50:5667–71. 61. Schaumberg DA, Moyes AL, Gomes JA, et al. Corneal transplantation in young chil-
20. Riazuddin SA, Zaghloul NA, Al-Saif A, et al. Missense mutations in TCF8 cause late-on- dren with congenital hereditary endothelial dystrophy. Multicenter Pediatric Keratoplasty
set Fuchs corneal dystrophy and interact with FCD4 on chromosome 9p. Am J Hum Study. Am J Ophthalmol 1999;127(4):373–8.
Genet 2010;86(1):45–53. 62. Molia LM, Lanier JD, Font RL. Posterior polymorphous dystrophy associated with poste-
21. Afshari NA, Li YJ, Pericak-Vance MA, et al. Genome-wide linkage scan in Fuchs endothe- rior amyloid degeneration of the cornea. Am J Ophthalmol 1999;127:86–8.
lial corneal dystrophy. Invest Ophthalmol Vis Sci 2009;50:1093–7. 63. Anderson NJ, Badawi DY, Grossniklaus HE, et al. Posterior polymorphous membranous
22. Vithana EN, Morgan PE, Ramprasad V. SLC4A11 mutations in Fuchs endothelial corneal dystrophy with overlapping features of iridocorneal endothelial syndrome. Arch Ophthal-
dystrophy. Hum Mol Genet 2008;17:656–66. mol 2001;119:624–5.
23. Riazuddin SA, Vithana EN, Seet LF. Missense mutations in the sodium borate cotrans- 64. Feil SH, Barraquer J, Howell DN, et al. Extrusion of abnormal endothelium into the
porter SLC4A11 cause late-onset Fuchs’ corneal dystrophy. Hum Mutat 2010;31:1261–8. posterior corneal stroma in a patient with posterior polymorphous dystrophy. Cornea
24. Riazuddin SA, Parker DS, McGlumphy EJ, et al. Mutations in LOXHD1, a recessive-deaf- 1997;16:439–46.
ness locus, cause dominant late-onset Fuchs corneal dystrophy. Am J Hum Genet 65. Ross JR, Foulks GN, Sanfilippo FP, et al. Immunohistochemical analysis of the patho-
2012;90(3):533–9. genesis of posterior polymorphous dystrophy. Arch Ophthalmol 1995;113:340–5.
25. Baratz KH, Tosakulwong N, Ryu E, et al. E2-2 protein and Fuchs’s corneal dystrophy. N 66. Cibis GW, Krachmer JA, Phelps CD, et al. The clinical spectrum of posterior polymor-
Engl J Med 2010;363:1016–24. phous dystrophy. Arch Ophthalmol 1977;95:1529–37.
26. Du J, Aleff RA, Soragni E, et al. RNA toxicity and missplicing in the common eye disease 67. Vincent AL, Niederer RL, Richards A, et al. Phenotypic characterization and ZEB1 muta-
Fuchs endothelial corneal dystrophy. J Biol Chem 2015;290(10):5979–90. tional analysis in posterior polymorphous corneal dystrophy in a New Zealand popula-
27. Wieben ED, Aleff RA, Tosakulwong N, et al. A common trinucleotide repeat expansion tion. Mol Vis 2009;15:2544–53.
within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy. 68. Heon E, Greenberg A, Kopp KK, et al. VSX1: a gene for posterior polymorphous dystro-
PLoS ONE 2012;7(11):e49083. phy and keratoconus. Hum Mol Genet 2002;11:1029–36.
28. Wieben ED, Aleff RA, Tang X, et al. Trinucleotide repeat expansion in the transcription 69. Valleix S, Nedelec B, Rigaudiere F, et al. H244R VSX1 is associated with selective cone
factor 4 (TCF4) gene leads to widespread mRNA splicing changes in Fuchs’ endothelial ON bipolar cell dysfunction and macular degeneration in a PPCD family. Invest Ophthal-
corneal dystrophy. Invest Ophthalmol Vis Sci 2017;58(1):343–52. mol Vis Sci 2006;47:48–54.
29. Biswas S, Munier FL, Yardley J, et al. Missense mutations in COL8A2, the gene encoding 70. Aldave AJ, Yellore VS, Principe AH, et al. Candidate gene screening for posterior poly-
the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy. morphous dystrophy. Cornea 2005;24:151–5.
Hum Mol Genet 2001;21:2415–23. 71. Gwilliam R, Liskova P, Filipec M, et al. Posterior polymorphous corneal dystrophy in
30. Wilson SE, Bourne WM. Fuchs’ dystrophy. Cornea 1988;7:2–18. Czech families maps to chromosome 20 and excludes the VSX1 gene. Invest Ophthalmol
31. Laing RA, Leibowitz HM, Oak SS, et al. Endothelial mosaic in Fuchs’ dystrophy. Arch Vis Sci 2005;46:4480–4.
Ophthalmol 1981;99:80–3. 72. Hosseini SM, Herd S, Vincent AL, et al. Genetic analysis of chromosome 20-related
32. Mandell RB, Polse KA, Brand RJ, et al. Corneal hydration control in Fuchs’ dystrophy. posterior polymorphous corneal dystrophy: genetic heterogeneity and exclusion of three
Invest Ophthalmol Vis Sci 1989;30:845–52. candidate genes. Mol Vis 2008;14:71–80.
33. Adamis AP, Filatov V, Tripathi BJ, et al. Fuchs’ endothelial dystrophy of the cornea. Surv 73. Yellore VS, Papp JC, Sobel E, et al. Replication and refinement of linkage of posterior
Ophthalmol 1993;38:149–68. polymorphous corneal dystrophy to the posterior polymorphous corneal dystrophy 1
34. Kangas TA, Edelhauser HF, Twining SS, et al. Loss of stromal glycosaminoglycans locus on chromosome 20. Genet Med 2007;9:228–34.
during corneal edema. Invest Ophthalmol Vis Sci 1990;31:1994–2002. 74. Aldave AJ, Rayner SA, Salem AK, et al. No pathogenic mutations identified in the
35. Levy SG, Moss J, Sawada H, et al. The composition of wide-spaced collagen in normal COL8A1 and COL8A2 genes in familial Fuchs corneal dystrophy. Invest Ophthalmol Vis
and diseased Descemet’s membrane. Curr Eye Res 1996;15:45–52. Sci 2006;47:3787–90.
36. Pineros O, Cohen EJ, Rapuano CJ, et al. Long-term results after penetrating keratoplasty 75. Kobayashi A, Fujiki K, Murakami A, et al. Analysis of COL8A2 gene mutation in Japa-
for Fuchs’ endothelial dystrophy. Arch Ophthalmol 1996;114:15–18. nese patients with Fuchs’ endothelial dystrophy and posterior polymorphous dystrophy.
37. Payant JA, Gordon LW, VanderZwaag R, et al. Cataract formation following corneal trans- Jpn J Ophthalmol 2004;48:195–8.
plantation in eyes with Fuchs’ endothelial dystrophy. Cornea 1990;9:286–9. 76. Yellore VS, Rayner SA, Emmert-Buck L, et al. No pathogenic mutations identified in the
38. Terry MA, Ousley PJ. Deep lamellar endothelial keratoplasty in the first United States COL8A2 gene or four positional candidate genes in patients with posterior polymor-
patients: early clinical results. Cornea 2001;20:239–43. phous corneal dystrophy. Invest Ophthalmol Vis Sci 2005;46:1599–603.
39. Busin M, Arffa RC, Sebastiani A. Endokeratoplasty as an alternative to penetrating kera- 77. Aldave AJ, Yellore VS, Yu F, et al. Posterior polymorphous corneal dystrophy is associated
toplasty for the surgical treatment of diseased endothelium: initial results. Ophthalmol- with TCF8 gene mutations and abdominal hernia. Am J Med Genet A 2007;143A:2549–56.
ogy 2000;107:2077–82. 78. Krafchak CM, Pawar H, Moroi SE, et al. Mutations in TCF8 cause posterior polymor-
40. Lee WB, Jacobs DS, Musch DC, et al. Descemet’s stripping endothelial keratoplasty: phous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells.
safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmol- Am J Hum Genet 2005;77:694–708.
ogy 2009;1818–30. 79. Liskova P, Tuft SJ, Gwilliam R, et al. Novel mutations in the ZEB1 gene identified in
41. Price MO, Fairchild KM, Price DA, et al. Descemet’s stripping endothelial keratoplasty Czech and British patients with posterior polymorphous corneal dystrophy. Hum Mutat
five-year graft survival and endothelial cell loss. Ophthalmology 2011;118:725–9. 2007;28:638. 270.e1
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80. Yellore VS, Rayner SA, Nguyen CK, et al. Analysis of the role of ZEB1 in the pathogen- 87. Krachmer JH. Posterior polymorphous corneal dystrophy: a disease characterized by
4 esis of posterior polymorphous corneal dystrophy. Invest Ophthalmol Vis Sci 2012;53:
273–8.
81. Aldave AJ, Han J, Frausto RF. Genetics of the corneal endothelial dystrophies: an evi-
dence-based review. Clin Genet 2013;84(2):109–19.
epithelial-like endothelial cells which influence management and prognosis. Trans Am
Ophthalmol Soc 1985;83:413–75.
88. Bromley JG, Randleman JB, Stone D, et al. Clinicopathologic findings in iridocor-
neal endothelial syndrome and posterior polymorphous membranous dystrophy after
82. Ross JR, Foulks GN, Sanfilippo FP, et al. Immunohistochemical analysis of the patho- Descemet stripping automated endothelial keratoplasty. Cornea 2012;31:1060–4.
genesis of posterior polymorphous dystrophy. Arch Ophthalmol 1995;113:340–5. 89. Studeny P, Jirsova K, Kuchynka P, et al. Descemet membrane endothelial keratoplasty
83. Laganowski HC, Sherrard ES, Kerr Muir MG. The posterior corneal surface in posterior with a stromal rim in the treatment of posterior polymorphous corneal dystrophy. Ind J
polymorphous dystrophy: a specular microscopical study. Cornea 1991;10:224–32. Ophthalmol 2012;60:59–60.
84. Hirst LW, Waring GO III. Clinical specular microscopy of posterior polymorphous endo- 90. Boruchoff SA, Weiner MJ, Albert DM. Recurrence of posterior polymorphous corneal
thelial dystrophy. Am J Ophthalmol 1983;95:143–55. dystrophy after penetrating keratoplasty. Am J Ophthalmol 1990;109:323–8.
85. Brooks AMV, Gillies WE. Differentiation of posterior polymorphous dystrophy from other 91. Sekundo W, Lee WR, Aitken DA, et al. Multirecurrence of corneal posterior polymor-
posterior corneal opacities by specular microscopy. Ophthalmology 1989;96:1639–45. phous dystrophy. Cornea 1994;13:509–15.
86. Henriquez AS, Kenyon KR, Dohlman KH, et al. Morphologic characteristics of posterior 92. Merjava S, Malinova E, Liskova P, et al. Recurrence of posterior polymorphous corneal
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270.e2
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Maria A. Woodward, Shahzad I. Mian, Alan Sugar 4.22
Definition: Secondary deterioration or deposition in the cornea,
distinct from dystrophies.
Key Features
• Common.
• Bilateral usually.
• Typically does not affect vision.
Associated Features
• Increased prevalence with age.
• Often associated with chronic light exposure.
• May occur after inflammation.
• Not inherited. A
INTRODUCTION
Degenerations of the cornea are common conditions that, in most cases,
have relatively little effect on ocular function and vision. These conditions
occur with increasing age, as a result of past inflammation, and with
long-term toxic effects of environmental exposure. Unlike corneal dystro-
phies, corneal degenerations are not inherited, may be unilateral or bilat-
eral, and often are associated with corneal vascularization. Degenerations
tend to involve the peripheral cornea and may overlap the limbus and
conjunctiva.
The conditions that occur in the corneal periphery are discussed first,
followed by the conditions that occur more centrally. This is an arbitrary
division as many conditions, such as spheroidal degeneration or band ker-
atopathy, can be found in either or both locations. B
CORNEAL ARCUS (ARCUS SENILIS) Fig. 4.22.1 Arcus Senilis. (A) Corneal arcus in an older man. (B) Histological section
shows that the lipid is concentrated in the anterior and posterior stroma as two red
Corneal arcus presents as a gray-to-white, occasionally yellow, band of triangles, apex to apex, with the bases being Bowman’s and Descemet’s membranes,
peripheral corneal opacification. It consists of fine dots, has a clear zone both of which are infiltrated heavily by fat (red staining), as is the sclera.
(clear interval of Vogt) between it and the limbus, and has a diffuse central
border with a sharper peripheral border (Fig. 4.22.1). It begins superiorly
and inferiorly and spreads to involve the entire periphery. Deposits begin IIa dyslipoproteinemia but a decreased risk for type IV.5 In older patients,
in the deep stroma with progression to involve the superficial stroma. arcus does not correlate with mortality.6
Arcus is almost always bilateral but can be asymmetric in unilateral carotid
vascular disease (decreased arcus) or chronic ocular hypotony (increased
arcus).1
LIPID KERATOPATHY
Arcus is the most common corneal degeneration. In men, the fre- Lipid keratopathy may be peripheral, central, or diffuse and is similar in
quency increases with age and occurs in essentially all men older than 80 appearance to arcus. It occurs mainly in a secondary form, but rarely may
years of age. The presentation is delayed by 10 years in women.1 be seen in a primary form. Primary lipid keratopathy has features of a
Arcus deposits consist of extracellular corticosteroid esters of lipopro- corneal dystrophy, is usually bilateral, and the central lipid, often with cho-
teins, mostly of low density. Lipid material leaks from limbal capillaries lesterol crystals, may severely decrease vision.7
with central flow being limited because of a functional barrier to the flow Secondary lipid keratopathy appears as a white or yellow stromal deposit
of large molecules in the cornea.2,3 separated by a narrow, clear zone from corneal stromal neovascularization8
Strong evidence exists for an association with increased plasma choles- (Fig. 4.22.2). It often is denser than arcus and may appear as a circular
terol and low-density lipoprotein cholesterol, particularly when it occurs deposit at the end of long-standing stromal vessels. It can follow corneal
in men younger than 50 years (arcus juvenilis). Men with arcus juveni- edema, as in hydrops.9 Histological evaluation shows that the material con-
lis have a fourfold increased relative risk of mortality from coronary heart sists of intra- and extracellular lipids.10
disease and cardiovascular disease. Arcus in young men, therefore, is a Lipid deposition may occur secondary to systemic lipid processing dis-
useful clinical indication for the need for lipid and cardiovascular eval- orders. Defects in esterification of cholesterol and in lipoprotein scaveng- 271
uation.4 Young patients who have arcus have an increased risk for type ing have been implicated in lecithin cholesterol acetyltransferase (LCAT)
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TERRIEN’S MARGINAL CORNEAL
4 DEGENERATION
This condition is described in Chapter 4.17.
PERIPHERAL CORNEAL GUTTAE

The corneal endothelium undergoes degeneration with age, as manifested
by a decreasing endothelial cell density14 and thickening of the posterior,
nonbanded layer of Descemet’s membrane.15 Degenerating endothelial
cells produce localized nodular thickening of Descemet’s membrane,
known as guttae. The relationship of central guttae to Fuchs’ corneal endo-
thelial dystrophy (FD) is discussed elsewhere (see Chapter 4.21). Peripheral
guttae, known as Hassall–Henle warts, are visible in normal adult corneas
and are thought to be truly degenerative and unrelated to FD. They are not
associated with functional corneal changes.
CALCIFIC BAND KERATOPATHY

Band keratopathy is a common corneal degeneration that can occur at
Fig. 4.22.2 Dense Lipid Keratopathy. Note the central and peripheral lipid any age, presenting in the central or peripheral cornea. It most commonly
deposits that followed zoster keratitis with vascularization. occurs secondary to chronic corneal diseases, particularly uveitis, advanced
glaucoma, keratitis, or trauma; primary idiopathic forms rarely occur.
Band keratopathy can present secondarily with elevated serum calcium or
phosphate in systemic diseases, including sarcoidosis, hyperparathyroid-
ism, vitamin D toxicity, metastatic neoplasm to bone, and chronic renal
failure with secondary hyperparathyroidism. Researchers have described
a toxic form resulting from mercurial preservatives in pilocarpine and an
acute form after intracameral tissue plasminogen activator injection.16 In
children, band keratopathy may be the presenting sign of chronic uveitis
as a result of juvenile idiopathic arthritis. Band keratopathy may occur
after localized corneal damage from intraocular silicone oil and phosphate
forms of corticosteroids.17,18
Histologically, calcium is deposited as the hydroxyapatite salt in the
epithelial basement membrane, basal epithelium, Bowman’s layer,19 and
anterior stroma. The mechanism of calcium deposition in the cornea is
unknown but occurs primarily in the exposed area of the cornea. Deposi-
tion of calcium may result from the precipitate tears leave when they evap-
orate or because the exposed cornea is at a lower pH than other areas.19
The most severely affected areas are the middle and inferior thirds of the
cornea, which are the areas of greatest exposure to the atmosphere.
Corneal calcium deposits as a horizontal band and begins near the
corneal periphery (Fig. 4.22.4). As the deposits move centrally, the band
has clear void circles where Bowman’s layer is traversed by nerve endings.
Fig. 4.22.3 Vogt’s Limbal Girdle. The fimbriated peripheral corneal opacity is The deposits begin as a gray haze and can become densely white with a
visible in the 9 o’clock position (arrow). rough, pebbly surface.
Patients can have symptoms of pain, foreign body sensation, recur-
rent corneal erosions, and decreased vision. The rate of development and
deficiency, Fish-eye disease, and Tangier disease. Disorders of high-density progression of disease is variable.20 If band keratopathy causes persistent
lipoprotein function appear to allow accumulation of cholesterol centrally pain or decreased vision, corneal surgery is indicated. The surgery involves
within the cornea.1 removing the epithelium over the deposits, applying 0.05 mol/L disodium
ethylenediaminetetraacetic acid to chelate the calcium and dissolve it,
VOGT’S WHITE LIMBAL GIRDLE and using a brush or surgical blade to remove remaining calcium.21 The
process can take a few minutes to an hour, depending on the density of the
Vogt11 was the first to describe two types of limbal girdle—white, arc-like calcium. Excimer laser phototherapeutic keratectomy also may be used to
opacities in the cornea central to the limbus in the 3 o’clock and 9 o’clock remove the calcium deposits.22
positions. Type I is a mild, early form of calcific band keratopathy. Type
II lacks a peripheral clear zone and consists of fine, white radial lines,
located nasally more often than temporally (Fig. 4.22.3). The prevalence of
SPHEROIDAL DEGENERATION
this condition increases with age to essentially 100% in those older than Spheroidal degeneration may occur in the cornea or the conjunctiva. Other
80 years of age.12 names for this degeneration include climatic droplet keratopathy, hyaline
Histologically, Vogt’s limbal girdle type II is made up of hyperelastotic degeneration, and local designations, such as Labrador keratopathy.23,24
and hyaline deposits peripheral to Bowman’s layer, similar to those seen in Spheroidal degeneration occurs as a primary corneal form, a secondary
a pingueculum and pterygium. corneal form, and a conjunctival form. The frequency of this degeneration
increases with age and varies with geographical location—occurring most
SENILE CORNEAL FURROW DEGENERATION often in areas that have high sunlight exposure (snow or sand) and high
winds. It is twice as prevalent in men as in women. The prevalence varies
Furrow degeneration is a painless bilateral thinning of peripheral cornea. A from 6% in England to greater than 60% in Labrador. It is thought to be
peripheral corneal furrow can occur between corneal arcus and the limbus a result of ultraviolet light exposure and may be associated with blue-light
in older adults.11 Often the clear area may appear to be furrowed, but it was exposure.25,26 Other risk factors are drying of the cornea and repeated
considered to be falsely thinned by Vogt.11,13 Rarely, true thinning with no corneal trauma. Secondary forms can occur with corneal scars, lattice dys-
inflammation, vascularization, or induced corneal astigmatism can occur trophy, and glaucoma.
in this region. Furrow degeneration does not require any therapy, but the Spheroidal degeneration presents as fine droplets, yellow or golden
272 location and degree of thinning should be evaluated when considering in color, beneath the epithelium (Fig. 4.22.5). The droplets appear oily,
location for cataract incisions. although they are not composed of lipid. In the primary form, droplets
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4.22
Fig. 4.22.6 Hudson–Stähli Line. Thin horizontal brown line in inferior cornea of a
A healthy 57-year-old male. (Courtesy the photography department, WK Kellogg Eye
Center, University of Michigan.)
E
Histologically, deposits appear as extracellular amorphous globules,
which may coalesce in Bowman’s layer and spill over to anterior stroma.
P These globules consist of a protein material with elastotic features, as in
pingueculae. The source of the protein is unknown, but it has been postu-
lated to result from the action of ultraviolet light on proteins from limbal
vessels.23,28
CB The majority of cases of spheroidal degeneration are asymptomatic.
Patients with visual loss may be treated with superficial keratectomy and,
when necessary, lamellar or penetrating keratoplasty.
S
IRON DEPOSITION
B Iron deposition occurs in the corneal epithelium in several clinical situ-
ations. The prototype is the Hudson–Stähli line, which is located at the
Fig. 4.22.4 Band Keratopathy. (A) Calcium deposits in the cornea of a 13-year-
junction of the middle and lower thirds of the cornea (Fig. 4.22.6). It is
old with juvenile rheumatoid arthritis. (B) A fibrous pannus (P) is present between yellow-brown in color, curves downward at its center, and is usually about
the epithelium (E) and a calcified Bowman’s membrane (CB). Some deposit is also 0.5 mm wide and 1–2 mm long. It is seen most clearly in blue light as a
present in the anterior corneal stroma (S). black line. Similar iron deposition occurs in keratoconus at the base of the
cone (Fleischer’s ring), around filtering blebs (Ferry’s line), central to a pte-
rygium (Stocker’s line), around Salzmann’s nodules, within the margin of
corneal grafts, between radial keratotomy scars, and following laser in situ
keratomileusis (LASIK) or intrastromal corneal ring placement.29,30 The
source of the iron is unknown but most likely comes from the tear film. It
is postulated that altered tear flow secondary to distorted corneal shape is a
factor in the formation of these lines and that epithelial migration patterns
affect the shape of the Hudson–Stähli line.
Histologically, the iron is deposited intracellularly in corneal epithelial
cells as a ferritin-like material, possibly hemosiderin.31 Iron lines do not
affect vision or cause any symptoms and thus require no treatment.
Coats’ white ring is an iron deposition that occurs in the anterior
portion of Bowman’s layer. It appears as a tiny ring of white dots, most
often inferiorly, and is asymptomatic.32 It is thought to result from previ-
ous iron deposition by a corneal foreign body.
CROCODILE SHAGREEN
Crocodile shagreen appears as anterior or posterior polygonal opac-
Fig. 4.22.5 Spheroidal Degeneration. Central spheroidal droplets in the cornea of ities in the corneal stroma that occur as a consequence of aging. Croc-
an eye that is blind as a result of glaucoma.
odile shagreen was first described by Vogt.11 The pattern resembles that
of crocodile skin and is thought to be related to the oblique insertion of
begin peripherally and advance centrally between the palpebral fissures. the collagen lamellae that constitute the corneal stroma33,34 (Fig. 4.22.7).
As the condition advances, the droplets become larger, more nodular, and In vivo confocal microscopy demonstrates the mosaic pattern of the colla-
more opaque lifting the central corneal epithelium. Three stages of the gen lamella.35 Crocodile shagreen is a very common, although frequently
primary form have been described: subtle, finding in older patients. The anterior form is more common than
the posterior form, with the opacities in posterior crocodile shagreen
• Grade I—fine shiny droplets are present only peripherally without
presenting more peripherally and, thus, may be indistinguishable from
symptoms.
corneal arcus.
• Grade II—the central cornea is involved and vision ≥20/100 (6/30). Familial forms of posterior crocodile shagreen have been described in
• Grade III—there are large corneal nodules and vision ≥20/200 (6/60). a dominant juvenile form and in a form associated with X-linked megalo-
These forms are always bilateral. Grade III disease may be rapidly pro- cornea. Central cloudy dystrophy of François appears to be similar and is 273
gressive and lead to corneal ulceration with secondary bacterial infection.27 likely not a true dystrophy (see Chapter 4.20).
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4
Fig. 4.22.7 Posterior Crocodile Shagreen. A mottled, gray pattern is visible in the Fig. 4.22.9 Corneal Keloid Recurrence. A central, elevated, fibrous opacity is
central cornea. present centrally. The photo was taken 6 months after superficial keratectomy for
the original lesion.
the central cornea or by altering the corneal shape. They may be associated
with recurrent corneal erosions.39
Histologically, thinned epithelium overlies hyalinized avascular colla-
gen. Bowman’s layer is damaged or focally absent and replaced by material
that is similar to basement membrane.40 Usually, evidence of old keratitis
is seen in the surrounding stroma. In vivo confocal microscopy studies
show irregular epithelium and activated keratocytes in the area of the
nodule.41,42 Many patients who have peripheral nodules are asymptomatic
and require no treatment. If vision is altered or if recurrent erosions are
frequent, the nodules may be removed by peeling from the underlying
stroma or excimer laser phototherapeutic keratectomy.23 Recurrences have
been found after all forms of treatment.43
CORNEAL KELOIDS
Corneal keloids are uncommon and result from progressive growth of
fibrous tissue on the cornea that outgrows the original boundaries. They
typically appear months or years following trauma, surgery, or inflamma-
tory processes. The appearance is consistent with an elevated gray-white
mass involving the entire stroma or isolated nodules (Fig. 4.22.9).
Fig. 4.22.8 Salzmann’s Nodular Degeneration. Severe corneal involvement in an Histologically, poorly arranged collagen fibers, myofibroblasts, and
elderly woman. blood vessels are noted in early stages. In later stages, compaction of colla-
gen and reduction in vascularity and cellularity occurs. Significant keloids
CORNEA FARINATA may be treated with superficial keratectomy, lamellar keratoplasty, or pen-
etrating keratoplasty.44,45
First described by Vogt, cornea farinata occurs in the corneas of older
patients, is without symptoms, and is recognized as an incidental finding.11 CORNEAL AMYLOID DEGENERATION
The corneal opacities in this condition are fine, dust-like dots of white or
gray color in the deep central stroma, just anterior to Descemet’s layer.36 Amyloid is a group of hyaline proteins deposited in tissues in a variety
The Latin word farinata, meaning “like wheat flour,” refers to the appear- of systemic and localized conditions. Familial localized amyloidosis is
ance of the dots. The bilateral deposits are best visualized by slit-lamp seen in the cornea as lattice, Avellino’s, and gelatinous drop-like corneal
retroillumination. The cause of the condition is unknown. The histol- dystrophies.
ogy suggests that the deposits may be composed of lipofuscin in stromal The degenerative forms of amyloid seen in the cornea and conjunc-
keratocytes.37 tiva are secondary, localized, and nonfamilial. These occur as nonspe-
cific corneal deposits that follow corneal trauma, keratitis, or chronic
SALZMANN’S CORNEAL DEGENERATION intraocular inflammation. Usually, they are diagnosed with histopathology
after removal of nonspecific corneal opacities.46
Salzmann’s corneal degeneration may occur at any age but is primarily a A specific form of corneal amyloid degeneration has been described as
condition of older adults. It has been associated with phlyctenular keratitis, polymorphic amyloid degeneration.47 It is characterized by the presence of
interstitial keratitis, vernal keratitis, trachoma, or Thygeson’s superficial deep central corneal stromal glass-like deposits that often indent Descem-
punctate keratitis. It also occurs with no history of prior corneal disease. It et’s layer (Fig. 4.22.10). They are bilateral, generally occur after age 50
typically develops several decades after previous keratitis. It may be unilat- years, and do not affect vision. Histologically, they appear similar to lattice
eral or bilateral and occurs more often in women than in men. dystrophy deposits composed of amyloid. The cause is unknown.
Salzmann’s corneal degeneration appears as white-to-gray or light-blue Another stromal deposition with features of both spheroidal degener-
nodules that elevate the epithelium in the superficial corneal stroma (Fig. ation and amyloid deposition has been called climatic proteoglycan stromal
4.22.8). The nodules may be single or in clusters, often at the edge of old keratopathy.48 This has been described in Saudi Arabian patients with risk
corneal scars. Each nodule is about 0.5–2 mm in diameter, not vascular- factors similar to those of spheroidal degeneration. The patients have bilat-
ized, and separated from other nodules by clear cornea. The onset of the eral, horizontal, oval, central anterior stromal, ground-glass haze that con-
274 lesions is gradual, over many years, during which time they increase in sists of both proteoglycan and amyloid on histopathology. This condition
both size and number.38 They may decrease vision by encroaching upon does not usually affect vision.48
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KEY REFERENCES
Barchiesi BJ, Eckel RH, Ellis PP. The cornea and disorders of lipid metabolism. Surv Oph-
thalmol 1991;36:1–22.
4.22
Carlson KH, Bourne WM, McLaren JV, et al. Variations in human corneal endothelial cell
morphology and permeability to fluorescein with age. Exp Eye Res 1988;47:27–41.
Duran JA, Rodriguez-Ares MT. Idiopathic lipid corneal degeneration. Cornea 1991;10:166–9.
Gass JDM. The iron lines of the superficial cornea. Arch Ophthalmol 1964;71:348–58.
Gray RH, Johnson GJ, Freedman A. Climatic droplet keratopathy. Surv Ophthalmol
1992;36:241–53.
Krachmer JH, Dubord PJ, Rodriguez MM, et al. Corneal posterior crocodile shagreen and
polymorphic amyloid degeneration. Arch Ophthalmol 1983;101:54–9.
Mannis MJ, Krachmer JH, Rodriguez MM, et al. Polymorphic amyloid degeneration of the
cornea. Arch Ophthalmol 1981;99:1217–23.
Najjar DM, Cohen EJ, Rapuano CJ, et al. EDTA chelation for calcific band keratopathy:
results and long-term follow-up. Am J Ophthalmol 2004;147:1056–64.
O’Connor GR. Calcific band keratopathy. Trans Am Ophthalmol Soc 1972;70:58–85.
Vannas A, Hogan MJ, Wood I. Salzmann’s nodular degeneration of the cornea. Am J Oph-
thalmol 1975;79:211–19.
Vogt A. Textbook and atlas of slit lamp microscopy of the living eye. Bonne: Wayenborgh
Editions; 1981.
Waring GO, Malaty A, Grossniklaus H, et al. Climatic proteoglycan stromal keratopathy, a
new corneal degeneration. Am J Ophthalmol 1995;120:330–41.
Fig. 4.22.10 Polymorphic Amyloid Degeneration. Glassy, fine deep corneal Access the complete reference list online at ExpertConsult.com
deposits in the central cornea of an older woman.
275
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REFERENCES 25. Norn M, Franck C. Long-term changes in the outer part of the eye in welders. Acta Oph-
thalmol 1991;69:382–6.
1. Barchiesi BJ, Eckel RH, Ellis PP. The cornea and disorders of lipid metabolism. Surv
26. Taylor HR, West S, Munoz B, et al. The long-term effects of visible light on the eye. Arch
Ophthalmol 1992;110:99–104.
4.22
2. Cogan DG, Kuwabara T. Arcus senilis, its pathology and histochemistry. Arch Ophthal- 27. Ormerod LD, Dahan E, Hagele JE, et al. Serious occurrences in the natural history of
advanced climatic keratopathy. Ophthalmology 1994;101:448–53.
mol 1959;61:553–60.
3. Crispin S. Ocular lipid deposition and hyperlipoproteinaemia. Prog Retin Eye Res 28. Johnson GJ, Overall M. Histology of spheroidal degeneration of the cornea in Labrador.
2002;21:169–224. Br J Ophthalmol 1978;62:53–61.
4. Fernandez A, Sorokin A, Thompson PD. Corneal arcus as coronary artery disease risk 29. Probst LE, Almasswary MA, Bell J. Pseudo-Fleischer ring after hyperopic laser in situ
factor. Atherosclerosis 2007;193:235–40. keratomileusis. J Cataract Refract Surg 1999;25:868–70.
5. Segal P, Insull W, Chambless LE, et al. The association of dyslipoproteinemia with 30. Assil KK, Quantock AJ, Barrett AM, et al. Corneal iron lines associated with the intras-
corneal arcus and xanthelasma The Lipid Research Clinics Program Prevalence Study. tromal corneal ring. Am J Ophthalmol 1993;116:350–6.
Circulation 1986;73:108–18. 31. Gass JDM. The iron lines of the superficial cornea. Arch Ophthalmol 1964;71:348–58.
6. Moss SE, Klein R, Klein BE. Arcus senilis and mortality in a population with diabetes. 32. Nevins RC, Davis WH, Elliott JH. Coats’ white ring of the cornea – unsettled metal fettle.
Am J Ophthalmol 2000;129:676–8. Arch Ophthalmol 1968;80:145–6.
7. Duran JA, Rodriguez-Ares MT. Idiopathic lipid corneal degeneration. Cornea 33. Tripathi RL, Bron AJ. Secondary anterior crocodile shagreen of Vogt. Br J Ophthalmol
1991;10:166–9. 1975;59:59–63.
8. Cogan DG, Kuwabara T. Lipid keratopathy and atheromas. Circulation 1958;18:519–25. 34. Krachmer JH, Dubord PJ, Rodriguez MM, et al. Corneal posterior crocodile shagreen
9. Shapiro LA, Farkas TG. Lipid keratopathy following corneal hydrops. Arch Ophthalmol and polymorphic amyloid degeneration. Arch Ophthalmol 1983;101:54–9.
1977;95:456–8. 35. Woodward M, Randleman JB, Larson PM. In vivo confocal microscopy of polymorphic
10. Croxatto JO, Dodds CM, Dodds R. Bilateral and massive lipoidal infiltrates of the cornea amyloid degeneration and posterior crocodile shagreen. Cornea 2007;26:98–101.
(secondary lipoidal degeneration). Ophthalmology 1985;92:1686–90. 36. Kobayashi A, Ohkubo S, Tagawa S, et al. In vivo confocal microscopy in the patients with
11. Vogt A. Textbook and atlas of slit lamp microscopy of the living eye. Bonne: Wayenborgh cornea farinata. Cornea 2003;22:578–81.
Editions; 1981. 37. Curran RE, Kenyon KR, Green WR. Pre-Descemet’s membrane corneal dystrophy. Am J
12. Sugar HS, Kobernick S. The white limbus girdle of Vogt. Am J Ophthalmol 1960;50:101–17. Ophthalmol 1974;77:711–16.
13. Rumelt S, Rehany U. Computerized corneal topography of furrow corneal degeneration. 38. Maharana PK, Sharma N, Das S, et al. Salzmann’s nodular degeneration. Ocul Surf
J Cataract Refract Surg 1997;23:856–9. 2016;14:20–30.
14. Carlson KH, Bourne WM, McLaren JV, et al. Variations in human corneal endothelial 39. Wood TO. Salzmann’s nodular degeneration. Cornea 1990;9:17–22.
cell morphology and permeability to fluorescein with age. Exp Eye Res 1988;47:27–41. 40. Vannas A, Hogan MJ, Wood I. Salzmann’s nodular degeneration of the cornea. Am J
15. Lorenzetti DW, Uotila MH, Parikh N, et al. Central cornea guttata, incidence in the Ophthalmol 1975;79:211–19.
general population. Am J Ophthalmol 1967;64:1155–8. 41. Meltendorf C, Buhren J, Bug R, et al. Correlation between clinical in vivo confocal micro-
16. Moissiev E, Gal A, Addadi L, et al. Acute calcific band keratopathy: case report and liter- scopic and ex vivo histopathologic findings of Salzmann nodular degeneration. Cornea
ature review. J Cataract Refract Surg 2014;39:292–4. 2006;25:734–8.
17. Azen SP, Scott IU, Flynn HW, et al. Silicone oil in the repair of complex retinal detach- 42. Roszkowska AM, Aragona P, Spinella R, et al. Morphologic and confocal investiga-
ments. A prospective observational multicenter study. Ophthalmology 1998;105:1587–97. tion on Salzmann nodular degeneration of the cornea. Invest Ophthalmol Vis Sci
18. Taravella MJ, Stulting RD, Mader TH, et al. Calcific band keratopathy associated with the 2011;52:5910–19.
use of topical steroid-phosphate preparations. Arch Ophthalmol 1994;112:608–13. 43. Severin M, Kirchof B. Recurrent Salzmann’s corneal degeneration. Graefes Arch Clin
19. O’Connor GR. Calcific band keratopathy. Trans Am Ophthalmol Soc 1972;70:58–85. Exp Ophthalmol 1990;222:101–4.
20. Lemp MA, Ralph RA. Rapid development of band keratopathy in dry eye. Am J Ophthal- 44. Bourcier T, Baudrimont M, Boutboul S, et al. Corneal keloid: clinical, ultrasonographic,
mol 1977;83:657–9. and ultrastructural characteristics. J Cataract Refract Surg 2004;30:921–4.
21. Najjar DM, Cohen EJ, Rapuano CJ, et al. EDTA chelation for calcific band keratopathy: 45. Gupta J, Grantzala SS, Kashyup S, et al. Diagnosis, management, and histological char-
results and long-term follow-up. Am J Ophthalmol 2004;147:1056–64. acteristics of corneal keloid: a case series and literature review. Asia Pac J Ophthalmol
22. Maloney RK, Thompson V, Ghiselli G, et al. A prospective multicenter trial of 2016;5:354–9.
excimer laser phototherapeutic keratectomy for corneal vision loss. Am J Ophthalmol 46. Dutt S, Elner VM, Soong HK, et al. Secondary localized amyloidosis in interstitial kerati-
1996;122:144–60. tis (IK): clinicopathologic findings. Ophthalmology 1992;99:817–23.
23. Gray RH, Johnson GJ, Freedman A. Climatic droplet keratopathy. Surv Ophthalmol 47. Mannis MJ, Krachmer JH, Rodriguez MM, et al. Polymorphic amyloid degeneration of
1992;36:241–53. the cornea. Arch Ophthalmol 1981;99:1217–23.
24. Serra HM, Holpainen JM, Beuerman R, et al. Climatic droplet keratopathy: An old 48. Waring GO, Malaty A, Grossniklaus H, et al. Climatic proteoglycan stromal keratopathy:
disease in new clothes. Acta Ophthalmol 2015;93:496–504. a new corneal degeneration. Am J Ophthalmol 1995;120:330–41.
275.e1
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Dry Eye Disease

Michael H. Goldstein, Naveen K. Rao 4.23
containing chiefly sterol esters and wax monoesters.3,30 Although only
Definition: A multifactorial disease of the ocular surface characterized 0.1-µm thick, the lipid layer serves to stabilize the tear film by increasing
by deficient tear production and/or excessive tear evaporation, leading surface tension and retarding evaporation.
to loss of homeostasis of the tear film. The tear layer maintains a smooth surface for optical clarity, lubricates
to facilitate eyelid blink, and offers protection against ocular infection.11
Average tear flow is about 1.2-µm/minute.31 Blinking serves to periodi-
Key Features cally distribute tears evenly over the ocular surface and encourages both
• Symptoms: ocular and conjunctival irritation. secretion and mechanical drainage of tears through the lacrimal drainage
• Ocular surface disruption. system. Regulation likely involves both neuronal and hormonal pathways.
Direct innervation of the lacrimal gland, MGs, and goblet cells has been
demonstrated, with M3 class cholinergic receptors predominating in the
Associated Features lacrimal gland.32 Although estrogen has little effect on tear secretion, it
may have a supportive role on the ocular surface.33 Androgens appear to
• Possible autoimmune disease (i.e., Sjögren’s syndrome). have a positive effect on the secretion of both aqueous and lipid tears.34,35
• Possible conjunctival or lid abnormalities.
• Blurred or unstable vision.
Pathophysiology
INTRODUCTION Reduced aqueous tear flow and increased evaporation of the aqueous com-
ponent of tears leads to hyperosmolarity. Tear hyperosmolarity damages
Dry eye disease (DED), also known as dry eye syndrome (DES) or ker- the ocular surface epithelium and sets off a cascade of inflammatory path-
atoconjunctivitis sicca (KCS), is characterized by ocular irritation and ways that leads to apoptotic cell death, loss of goblet cells, and deficient
visual disturbance resulting from alterations of the tear film and ocular mucus production, with resultant tear film instability. Tear film instabil-
surface.1–10 The effects of DED can vary from minor inconvenience to rare ity, in turn, leads to increased evaporation. Implicated cytokines include
sight-threatening complications. Although the diagnosis of DED tradition- mitogen-activated protein (MAP) kinases, nuclear factor-κB (NF-κB),
ally has focused on inadequate secretion or aqueous tear deficiency, the tear interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and matrix metal-
film is a complex and delicately balanced unit dependent on the normal loproteinases (MMP-9, in particular).36–38 In the early stages of DED,
function of several distinct components.10–13 Current treatment is heavily inflammation and mechanical irritation stimulates reflex secretion from
weighted toward supplementation, stimulation, preservation of aqueous the lacrimal gland and increased blink rate. Over time, damage to the
tears, or treatment of ocular surface inflammation, which is satisfactory ocular surface leads to reduction in corneal sensation and impaired reflex
for many patients. DED, however, often involves multiple deficiency states, tearing.10 In advanced cases, chronic conjunctival damage can lead to meta-
which, when disregarded, can result in treatment failure and frustration plasia and keratinization.
for both the patient and the physician. Currently, a large unmet need still
exists for better treatment options for patients with DED. Diagnosis and Classification
EPIDEMIOLOGY The 2017 report for the International Dry Eye Workshop (DEWS II) was
a 2-year effort with 12 subcommittees made up of 150 experts from 23
Estimating the prevalence of DED is complicated by the absence of con- countries. The DEWS II report updated the definition of dry eye as follows:
sensus on a single reliable diagnostic test. Several population-based epi- “Dry eye is a multifactorial disease of the ocular surface characterized by a
demiological studies have utilized questionnaires to assess prevalence of loss of homeostasis of the tear film, and accompanied by ocular symptoms,
dry eye symptoms. American and Australian studies have revealed a preva- in which tear film instability and hyperosmolarity, ocular surface inflam-
lence of 5%–16%, whereas Asian studies have revealed a higher prevalence mation and damage, and neurosensory abnormalities play etiological
of approximately 27%–33%.14–25 roles.”39 The new definition emphasizes the multifactorial nature of DED,
where loss of homeostasis of the tear film is the central pathophysiological
concept. It also recognizes the role of neurosensory abnormalities in the
PATHOGENESIS development of DED. This definition continues to incorporate concepts
Normal Physiology introduced in the first DEWS report that DED results in ocular discomfort,
visual disturbance, and tear film instability with potential damage to the
The stratified tear film is composed of mucin, aqueous, and lipid com- ocular surface.10 This definition encompasses all the clinical entities asso-
ponents. The mucin layer consists of high-molecular-weight glycoproteins ciated with systemic disease, as well as idiopathic DED.
closely adherent to an inherently hydrophobic surface epithelium and its A classification system algorithm for dry eye is depicted in Fig. 4.23.1.
glycocalyx. Mucin provides a smooth, hydrophilic surface permitting even The effect of the environment on an individual’s risk of developing dry
distribution of the overlying aqueous layer. Its primary source is conjunc- eye also is considered. Low blink rate,40,41 wide lid aperture,42–44 aging,45–47
tival goblet cells with a small contribution from surface epithelial cells.26,27 low androgen levels,48,49 high estrogen levels,50,51 and systemic drugs affect
Comprising the largest volume of the tear film, the aqueous is secreted by the so-called milieu interieur.10 Low relative humidity, air conditioning, air
the main lacrimal gland, the accessory glands of Krause and Wolfring, and, travel,52 high wind velocity, and other occupational environmental factors,
minimally, a transudate of the conjunctival vessels and cornea. Consisting such as video display terminal use53 affect the so-called milieu exterieur.10
primarily of water, it also contains electrolytes (sodium [Na], potassium
[K], chloride [Cl]) and proteins, including epidermal growth factor, immu- Aqueous Tear-Deficient Dry Eye
noglobulins (IgA, IgG, IgM), lactoferrin, lysozyme, and other cytokines.28,29
276 These components likely play both a protective and a homeostatic role for Sjögren described KCS in 1933.54 Consequently, defective lacrimal tear
the ocular surface. Last, meibomian glands (MGs) secrete a lipid layer, secretion is subdivided into non-Sjögren’s tear deficiency (NSTD) and
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DRY EYE CLASSIFICATION
4.23
Dry Eye Disease

Tear deficient Dry eye – keratoconjunctivitis sicca Evaporative
Sjögren's syndrome Non-Sjögren tear deficiency
Lacrimal disease Lacrimal obstruction Reflex Oil deficient Lid related Contact lens Surface change
Congenital alacrima Trachoma, cicatricial pemphigoid Neuro-paralytic keratitis

Absent glands Blink Aperture Lid surface
acquired primary Erythema multiforme Contact lens Xerophthalmia
Distichiasis abnormalities abnormalities incongruity
lacrimal gland disease Burns seventh nerve palsy
Rheumatoid arthritis Sarcoid

Systemic lupus erythematosus HIV
Posterior blepharitis
Wegener's granulomatosis Graft vs. host
Obstructive meibomian Anterior blepharitis
Systemic sclerosis Xerophthalmia
gland disease
Primary biliary cirrhosis ablation
Other autoimmune diseases Other diseases
primary secondary
Fig. 4.23.1 Dry eye disease classification. (With permission from Lemp MA. The 1998 Castroviejo Lecture. New strategies in the treatment of dry-eye states. Cornea
1999;18:625–32.)
Sjögren’s syndrome tear deficiency (SSTD). NSTD has no association with

TABLE 4.23.1 Medications Associated With Dry Eye Disease
systemic autoimmune disease, which is a cardinal feature of SSTD.
Mechanism of Action Class Medications
Non-Sjögren’s Tear Deficiency Anticholinergic Antimuscarinics Tolterodine tartrate (Detrol)
NSTD can occur from primary lacrimal gland deficiencies, secondary Scopolamine
lacrimal gland deficiencies, obstruction of lacrimal gland ducts, or reflex Antihistamines (sedating Chlorpheniramine (Chlor-Trimeton)
hyposecretion.10 Primary lacrimal gland deficiencies include age-related compounds are Diphenhydramine (Benadryl)
DED, congenital alacrima, and familial dysautonomia (Riley–Day syn- associated with greater Promethazine (Phenergan)
drome). The most common form of NSTD is age-related DED, which is dryness)
Antiparkinsonian Benzotropine (Cogentin)
associated with ductal and interacinar fibrosis and obstruction within the
Trihexyphenidyl (Artane)
lacrimal gland, possibly as a result of low-grade chronic inflammation.55–57 Antidepressants Amitriptyline (Elavil)
Congenital alacrima is a rare cause of DED in youth, resulting from pri- MAO inhibitors Nortriptyline (Pamelor)
marily absent or hypoplastic lacrimal glands. Familial dysautonomia is Imipramines (Tofranil)
an autosomal recessive multisystem disorder, in which generalized pain Doxepin (Sinequan)
insensitivity accompanies absence of both emotional and reflex tearing. Phenelzine
Defective sympathetic and parasympathetic innervation of the lacrimal Antipsychotics Chlorpromazine (Thorazine)
Thioridazine (Mellaril)
gland and defective sensory innervation of the ocular surface occur.10
Fluphenazine (Prolixin)
Secondary lacrimal gland deficiency from infiltration and damage to Antimanics Lithium
the lacrimal gland in benign lymphoepithelial lesion of Godwin (“Miku- Antiarrhythmics Disopyramide (Norpace)
licz’s disease”), lymphoma, sarcoidosis, hemochromatosis, amyloidosis, Mexiletine (Mexitil)
human immunodeficiency virus/acquired immunodeficiency syndrome Antiadrenergic Alpha-agonists Clonidine (Catapres)
(HIV/AIDS), and graft-versus-host disease all can result in DED.58–61 Sur- Methyldopa (Aldomet)
gical or radiation-induced destruction or denervation of lacrimal tissue Beta-blockers Propranolol (Inderal)
can result in secondary lacrimal deficiency.58 Secondary obstruction of the Metoprolol (Lopressor)
lacrimal gland ducts can occur with trachoma,61 ocular cicatricial pemphi- Diuretic ThiaziDED Hydrochlorothiazide
goid, mucous membrane pemphigoid,62–64 erythema multiforme/Stevens– Other Nonsteroidal anti- Ibuprofen (Advil)
Johnson syndrome,65 chemical burns, and thermal burns.66 inflammatory drugs Naproxen (Naprosyn, Aleve)
Reflex hyposecretion of tears can be conceptually divided into reflex Cannabinoids Marijuana
sensory block (damage to the afferent arm) and reflex motor block (damage
to the efferent, or secretomotor arm). Reflex sensory block occurs with any
reduction in ocular surface sensation and leads to decreased reflex-induced keratectomy resulting in decreased corneal sensation and blink rate are
lacrimal secretion and decreased blink rate, which increases tear evapo- recognized as precipitating causes of dry eye.67,76–79 Systemic medications
ration.10,67 Causes of decreased ocular surface sensation leading to dry are a common source for the inhibition of efferent lacrimal gland stim-
eye include topical anesthetic use,68 contact lens wear,69,70 diabetes melli- ulation through anticholinergic activity or decreased secretion through
tus,17,71–74 aging, and neurotrophic keratitis. systemic dehydration (Table 4.23.1).80 Although DED has been reported
As shown by studies utilizing topical anesthesia, interruption of the in association with menopause, estrogen supplementation has not been
afferent stimulus of tear production, or sensory loss (denervation), results shown to have a beneficial effect.50,81 Alterations in other hormones, espe-
in decreased tear secretion and reduced blink rate.68,75 Damage to affer- cially androgens, which also are reduced during menopause, have been
ent sensory fibers occurs after incisional corneal surgery (penetrating or implicated.
anterior lamellar keratoplasty, radial keratotomy, and limbal cataract inci-
sion) and after damage to the first division of the trigeminal ganglion from Sjögren’s Syndrome Tear Deficiency
trauma, tumor, and herpes simplex or zoster, resulting in reduced tear pro- Sjögren’s syndrome is a clinical condition of aqueous tear deficiency com- 277
duction. Laser-assisted in situ keratomileusis (LASIK) and photorefractive bined with dry mouth. The syndrome is classified as primary (patients
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without a defined connective tissue disease) or secondary (patients who Exposure
4 have a confirmed connective tissue disease).82–84 Primary SSTD refers to
aqueous tear deficiency combined with symptoms of dry mouth, pres-
ence of autoantibodies to Ro(SSA) or La(SSB) antigens, decreased salivary
Excessive exposure of the ocular surface leads to increased evaporative loss
of tears; thus, any disorder that results in increased ocular exposure can
secretion, and presence of lymphocytic foci on minor salivary gland biopsy. cause evaporative DED. Psychological, psychiatric, mechanical, neurologi-
Secondary SSTD is associated with rheumatoid arthritis, systemic lupus cal, or traumatic impairment of eyelid function may result in impaired or
erythematosus, polyarteritis nodosa, Wegener’s granulomatosis, systemic reduced blinking, lagophthalmos, or an increased palpebral fissure width,
sclerosis, primary biliary cirrhosis, and mixed connective tissue disease.10,83 resulting in an evaporative dry eye. Evaporative DED can be seen in thyroid
Both subtypes of SSTD feature progressive lymphocytic infiltration of the eye disease secondary to proptosis or lid retraction.
lacrimal and salivary glands and can be associated with severe and painful
ocular and oral discomfort. The pathogenesis of the tear deficit in SSTD Mucin Deficiency
is infiltration of the lacrimal gland by B and CD4 lymphocytes (with some
CD8 lymphocytes) and by plasma cells, with subsequent fibrosis. Local conjunctival damage from cicatrizing disease or surgical trauma
Revised American-European consensus diagnostic and classification results not only in aqueous tear deficiency but also in depopulation of
criteria for Sjögren’s syndrome were published in 2002.83 One point is mucin-producing goblet cells and creation of anatomical abnormalities of
given for at least one positive response or positive result in each of the the conjunctiva leading to improper tear distribution. Although uncom-
following categories: mon in incidence, trachoma, pemphigoid, erythema multiforme/Stevens–
Johnson syndrome, and chemical and thermal burns can result in severe
• Ocular symptoms—daily dry eye symptoms for more than 3 months,
DED characteristically resistant to aqueous tear replacement therapy.
ocular irritation, use of artificial tears more than three times per day.
• Oral symptoms—daily dry mouth symptoms for more than 3 months,
presence of swollen salivary glands, frequent drinking of liquids to aid Extrinsic Causes
in swallowing.
Vitamin A deficiency can result in extensive goblet cell loss and dysfunc-
• Ocular signs—Schirmer’s test I (without anesthetic) ≤5 mm in 5
tion, leading to an unstable tear film and severe DED (xerophthalmia).93–96
minutes, Rose Bengal score ≥4 according to the van Bijsterveld scoring
Preservatives in many eyedrops (especially benzalkonium chloride) can
system.
lead to ocular surface toxicity and a dry-eye state that may be reversible
• Histopathology—biopsy of minor salivary gland showing inflammation
if eyedrops are switched to nonpreserved formulations. Contact lens wear
with lymphocytic foci.
is commonly associated with DED symptoms. Pre-lens tear film thinning
• Oral signs—reduced salivary flow ≤1.5 mL in 5 minutes, parotid sialog-
time and pre-lens lipid layer thickness is reduced in contact lens wearers
raphy showing salivary duct dilation without obstruction, salivary scin-
with DED symptoms, and may lead to higher evaporative loss.97 Ocular
tigraphy showing signs of decreased saliva production.
allergies can cause a variety of corneal and conjunctival irregularities with
• Autoantibodies—presence of anti-Ro(SSA) antibody, presence of
decrease in tear film stability and consequent DED.
anti-La(SSB) antibody.
For a diagnosis of primary Sjögren’s syndrome, either four of the six
categories (including either histopathology or autoantibodies) or three of
OCULAR MANIFESTATIONS
the four objective categories (ocular signs, histopathology, oral signs, and Regardless of the cause, most forms of DED share similar symptoms,
autoantibodies) must be met. For diagnosis of secondary Sjögren’s syn- interpalpebral surface damage, tear instability, and tear hyperosmolarity.
drome, in patients with a defined connective tissue disease, the presence Typical complaints include burning, itching, foreign body sensation, sting-
of one symptom (ocular or oral) plus two of the three objective categories ing, dryness, photophobia, ocular fatigue, and redness. Although symp-
(ocular signs, histopathology, and oral signs) must be met. toms usually are nonspecific, careful attention to details will help refine
the diagnosis.
Evaporative Dry Eye Disease Patients commonly describe a diurnal pattern of aqueous tear defi-
ciency with progression of symptoms over the day and decompensation
Excessive evaporation that occurs in specific periocular disorders can cause in particular environmental conditions, such as low humidity in airline
dry eye disease with or without concurrent aqueous tear deficiency. Evap- cabins, climate control, and the use of video display terminals.53,98 Con-
oration leads to both loss of tear volume and a disproportionate loss of versely, nighttime exposure, floppy eyelid syndrome, and inflammatory
water, resulting in tear hyperosmolarity. Environmental conditions such conditions often present with worst discomfort upon awakening.
as high altitude, dryness, or extreme heat accelerate evaporative tear loss MGD creates an unstable tear film resulting in intermittent visual blur-
even in normal eyes. Causes of evaporative DED can be intrinsic (disease ring and a gritty or sandy sensation. DED in diabetes and other corneal
affecting lid structures or dynamics) or extrinsic.10 neuropathies may exhibit little or no discomfort and create high risk for
keratolysis.
Meibomian Gland Disease and Blepharitis Common signs of DED include conjunctival injection, decreased tear
meniscus, photophobia, increased tear debris, and loss of corneal sheen
Meibomian gland dysfunction (MGD) leads to both decreased secretion found more commonly in the exposed interpalpebral fissure. Paradoxical
and abnormal composition of the tear film lipid layer. The abnormal com- epiphora in DED is usually a result of reflex tearing. Greater risk for exter-
position leads to MG blockage and reduced effectiveness in the tear film. nal infections exists secondary to decreased tear turnover and desiccation
The resulting ocular surface and eyelid inflammation perpetuates a cycle of the surface epithelium. Instability of the surface epithelium and disor-
of inflammation, scarring, hyperkeratosis, stenosis, and further MGD. dered mucin production may lead to painful and recurrent filamentary ker-
Often associated, bacterial colonization by normal lid commensals atitis. Although keratinization may occur uncommonly in chronic DED,
(Staphylococcus aureus, Propionibacterium acnes, and coagulase-negative vitamin A deficiency also should be suspected.
staphylococci) acts directly by altering secreted lipids and indirectly by Patients who have SSTD tend to have more severe symptoms and more
causing inflammation. Esters and lipases produced by these commen- serious findings compared with NSTD patients. Sterile ulceration of the
sals act on secreted lipids in the tear film, producing soaps that manifest cornea in SSTD can be peripheral or paracentral; both thinning and perfo-
as “meibomian foam.”85,86 An association also is seen with dermatologi- ration of these ulcers can occur (Fig. 4.23.2). Acute lacrimal enlargement
cal conditions, such as seborrheic dermatitis, atopic dermatitis, and acne may be seen in SSTD but should be differentiated from benign lymphoe-
rosacea, a disorder resulting in vascular dilation, telangiectasias, and plug- pithelial lesion of Godwin (Mikulicz’s disease), which results from infiltra-
ging of sebaceous glands of both facial and eyelid skin. Secondary MGD tion of the gland without surface findings.99
can occur with use of 13-cis retinoic acid (isotretinoin) for treatment of
acne,87–89 ingestion of polychlorinated biphenyls in contaminated cooking
oil,90–92 and with cicatricial changes in conditions, such as chemical/
DIAGNOSIS AND ANCILLARY TESTING
thermal burns, trachoma, pemphigoid, erythema multiforme/Stevens– Diagnostic Dye Evaluation
Johnson syndrome, acne rosacea, vernal keratoconjunctivitis, and atopic
keratoconjunctivitis.10 In simple MGD, the MG orifices remain anterior to Fluorescein is a large molecule unable to traverse normal corneal epithelial
278 the mucocutaneous junction, whereas in cicatricial MGD, MG orifices are tight junctions. In advanced DED, these junctions are disrupted, allowing
drawn posteriorly onto the lid and tarsal mucosa. characteristic diffuse subepithelial or punctate staining. Rose Bengal stain,
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15 seconds; alkalinity changes its color to bright orange from tear contact.
Asian populations show a lessened wet-length response with diminishing
racial differences with advancing age.108 4.23
Hyperosmolarity is a common endpoint for all DED. Its measurement
can be a sensitive and specific indicator.106 Its use had previously been
Dry Eye Disease

limited to specialized research centers because of the need for expensive
equipment, but commercially available devices may now make this test
more widely used in the clinic. Researchers also have sampled tears or
ocular surface cells looking for inflammatory biomarkers, such as IL-1,
IL-17, MMP-9, interferon-γ(IFN-γ) and human leukocyte antigen–antigen
D–related (HLA-DR). A qualitative commercial test currently is available to
sample ocular surface tears for MMP-9 in the clinic. Other rarely performed
tests for reduced tear function include fluorophotometry for decreased
protein content, lysozyme levels, ocular ferning, impression cytology, and
lactoferrin assays. Noninvasive imaging of the tear film using meniscom-
etry, lipid layer interferometry, high-speed videography, optical coherence
tomography, and confocal microscopy has been advocated as well.109–113
Fig. 4.23.2 Patient (age 73 years) with rheumatoid arthritis and secondary Sjögren’s
Other Tests
disease. Corneal sensation may be qualitatively assessed with a cotton wisp, but
quantification requires an instrument, such as the Cochet–Bonnet aesthe-
siometer. The tear clearance test measures tear turnover with serial tear
collection after instillation of a standardized volume of dye.105,114 Serological
tests, traditionally including antinuclear, anti-Ro, and anti-La antibodies,
should be performed in patients suspected of having autoimmune DED.
A recently launched commercial diagnostic test combines traditional
biomarkers with novel, proprietary biomarkers to create a more accu-
rate diagnostic test for patients suspected of having Sjögren’s syndrome.
A definitive diagnosis of Sjögren’s syndrome requires minor salivary or,
rarely, lacrimal gland biopsy.
Neither clinical presentation nor individual ancillary tests alone are suf-
ficient for an accurate diagnosis of DED. Because of the therapeutic impor-
tance of appropriate categorization of patients, Pflugfelder et al. combined
standard subjective examination with ancillary tests in the evaluation of
patients with SSTD, NSTD, inflammatory MGD, and atrophic MGD.115
Clinically important results were identified and compiled into an algo-
rithm that helps differentiate patients with DED by using available tests
(Fig. 4.23.4).
TREATMENT
Fig. 4.23.3 Dry eye disease with Rose Bengal staining. Significant advances have been made in treating the many facets of DED,
but it remains a disorder of long-term maintenance rather than perma-
nent cure. Current therapy focuses on restoring a normal ocular surface
a derivative of fluorescein, in a 1% solution or impregnated strips, stains through tear supplementation as well as inhibition of aberrant inflam-
devitalized epithelial cells (Fig. 4.23.3).100 Alternatively, lissamine green mation seen in chronic DED. Since the tear film is a highly integrated
stains for cell death or degeneration, as well as cell-to-cell junction disrup- unit, addressing each component is central to the successful treatment
tion, but does not irritate the eye.101 of DED.
Tear Film Stability Aqueous Tear Deficiency

Tear film instability may be a result of either tear deficiency or evapora- As the first line of treatment, artificial tears increase available tears and,
tive DED. In the tear break-up time (TBUT) test, described by Norn and through dilution, reduce tear hyperosmolarity. Commercial artificial tears
revised by Lemp and Holly, fluorescein dye is instilled and the time inter- differ in electrolyte composition, thickening agents (methylcellulose,
val is measured between a complete blink to the first appearance of a dry hydroxypropyl methylcellulose, polyvinyl alcohol), physiological buffering,
spot in the precorneal tear film.102 TBUTs shorter than 10 seconds indicate tonicity, and preservative system. Individual patient preferences involve
tear film instability. such disparate concerns as cost, comfort, visual blurring, and ease of use.
Preserved tears (i.e., benzalkonium chloride) can be toxic in moderate or
Measurement of Tear Production severe DED, are poorly tolerated, and harmful. For patients with signifi-
cant DED, single-dose, nonpreserved tear preparations are the mainstay
The most common means of measuring tear production has been Schirm- of therapy with bottled tear products a reasonable alternative when pre-
er’s test, the details of which were first published in 1903.103 Jones later served with relatively nontoxic compounds. These less toxic preservatives
advocated the use of topical anesthesia combined with a Schirmer’s test include polyquaternium-1, sodium chlorite, and sodium perborate.116 Some
strip for 5 minutes to reduce the stimulating effect of the filter paper artificial tear preparations are formulated to be hypo-osmotic, with the goal
strip—the “basal” tear secretion test.104 Inconsistencies in its application of balancing the hyperosmolarity of the tear film in DED. Artificial tear
limit repeatability in DED, but it still enjoys widespread use.105 With these ointments are effective for longer-lasting control of symptoms, especially
caveats in mind, the following general guidelines are recommended (when during sleep, but visual blurring limits their daytime usefulness. In addi-
topical anesthesia is used): a 5-minute test that results in less than 5 mm tion, some ointments contain lanolin and parabens, which can be poorly
of wetting confirms the clinical diagnosis of DED, and a result of 6–10 mm tolerated by patients with severe DED. Autologous serum tears contain
of wetting suggests DED.106 trophic factors and other proteins useful in ocular surface maintenance.116
Hamano et al. developed the phenol red thread test to obviate the dis- These can be useful as a preservative-free, biological tear substitute, but
advantages of Schirmer’s test by eliminating the need for anesthesia.107 their preparation is labor intensive.
Three millimeters of a fine dye-impregnated 75-mm cotton thread is Punctal occlusion retards tear drainage, thereby increasing tear volume 279
placed under the lateral one fifth of the inferior palpebral lid margin for on the ocular surface and lowering tear osmolarity. Occlusion may be
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Fig. 4.23.4 Diagnostic algorithm for ocular irritation.
4 ALGORITHM FOR OCULAR IRRITATION (With permission from Pflugfelder SC, Tseng SC,
Sanabria O, et al. Evaluation of subjective assessments
and objective diagnostic tests for diagnosing tear-film
disorders known to cause ocular irritation. Cornea
Symptoms of ocular irritation 1998;17:38–56.)
Consider nontear No
Fluorescein tear break-up time 10 sec
film related problems
Yes
Tear film instability
1. Schirmer 1 5 mm in one or both eyes

2. Aqueous tear deficiency pattern on fluorescein clearance test
3. Grid distortion by xeroscope
Yes No
Aqueous tear deficiency

Meibomian gland pathological signs
1. Absence of nasal-lacrimal reflex 1. Orifice metaplasia
2. Presence of serum autoantibodies 2. Acinar atrophy
3. van Bijsterveld Rose Bengal staining score 3 3. Reduced expressible meibum
4. Exposure zone fluorescein staining score 3
Yes
Yes No
Meibomian gland disease
Sjögren Non-Sjögren
syndrome syndrome
achieved irreversibly by cauterization or semi-permanently with the use of also restoration of the ocular surface. DED-induced ocular surface inflam-
nonabsorbable plugs. Occlusion with collagen plugs provides temporary mation disrupts the epithelial and mucin layers, further exacerbating
relief (3 days to 6 months) and may identify those at risk for epiphora tear film breakdown. Suppression of inflammation creates a supportive
prior to permanent occlusion. Epiphora in the setting of one functional environment for reversal of DED-induced cellular changes.120,121 Topical
punctum is uncommon. cyclosporine A has been shown to increase tear production in a subset of
Secretagogues, agents that stimulate lacrimal gland secretion, require patients through inhibition of lacrimal gland inflammation and suppres-
functional glandular tissue. Oral pilocarpine (Salagen) and cevimeline sion of DED-induced ocular surface inflammation.122–124
(Evoxac) are M3 cholinergic agonists approved for use in dry mouth that Lifitegrast 0.05% is the drug most recently (July 11, 2016) approved by
also stimulate tear secretion.32,117,118 Their effect tends to be greater in oral the U.S. Food and Drug Administration to address DED and is the only
dryness rather than ocular dryness. Systemic cholinergic side effects, such therapy approved to treat both the signs and symptoms of DED. Lifitegrast
as sweating reduce patients’ acceptance. Various nutritional supplements is a topical anti-inflammatory drug that blocks the binding of intercellular
are also touted for DED but without clear confirmation of their efficacy. adhesion molecule-1 (ICAM-1) to lymphocyte function associated antigen-1
(LFA-1) on the T-cell surface. Lifitegrast decreases inflammation by inhibit-
Evaporative Dry Eye Disease ing T-cell recruitment and activation.125,126
Judicious use of low-dose topical corticosteroids has been shown to
Primary treatment of MGD involves improving the quality and quantity of reduce inflammation and allow normal reparative mechanisms to restore
native MG secretions. Lid hygiene, in the form of warm compresses and the natural equilibrium of the ocular surface.127,128 Use of topical corticoster-
lid massage, is effective in improving MG secretion. Several techniques, oids in DED currently is limited because of concerns about adverse events
including the Lipiflow System, have been developed to help with expres- with chronic use, such as glaucoma and cataract. Control of these reac-
sion of meibomian glands. Lid scrubs with dilute detergents decrease the tive epithelial changes restores normal cell morphology, cell-to-cell inter-
seborrheic or bacterial load, thereby breaking the proinflammatory cycle of actions, and critical mucin production and clearly has a role in the global
MGD. Systemic tetracyclines have been shown to decrease local inflamma- treatment of all forms of DED.
tion and improve MG function after several weeks. The antibacterial effect Essential fatty acids cannot be synthesized by humans and must be
also contributes to a decrease in meibomian lipid breakdown products in consumed in the diet. The typical Western diet contains a ratio of omega-6
the tear film. Topical erythromycin or azithromycin applied to the eyelid to omega-3 fatty acids of approximately 25 : 1.114 Omega-6 fatty acids are
margins are alternatives for patients who are unable to tolerate tetracycline precursors to arachidonic acid and proinflammatory molecules, including
derivatives. A number of lipid-like tear substitutes have become commer- prostaglandin E2 and leukotriene B4. Omega-3 fatty acids inhibit synthe-
cially available, which have been used with some success.119 sis of these inflammatory mediators and decrease production of IL-1 and
Correction of eyelid abnormalities that increase exposure of the ocular TNF-α.129,130 Supplementing the diet with omega-3 fatty acids has been
surface, such as lower lid ptosis and lagophthalmos, can stabilize a decom- shown to decrease both signs and symptoms of DED.131 Omega-3 fatty
pensated ocular surface. In severe cases, a partial or complete tarsorrhaphy acids include eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA),
or a conjunctival flap may be necessary to prevent decompensation of the and alpha-linolenic acid (ALA). EPA and DHA are believed to be primarily
cornea. The use of humidifiers, moisture chambers, glasses, or goggles responsible for the beneficial health effects of omega-3 fatty acids. Fish oil
increases periocular humidity and decreases surface evaporative pressure. contains high levels of EPA and DHA, and flaxseed oil contains high levels
New high-Dk (oxygen permeability), high-water-content contact lenses of ALA. Although ALA is converted by the body into EPA and DHA, this
and new polymer lenses, accompanied by proper tear supplementation process is not efficient; much higher quantities of flaxseed oil must there-
and hygiene, are effective in treating patients with DED with poor corneal fore be consumed to achieve equivalent EPA and DHA levels from smaller
wetting. In patients with severe DED, scleral contact lenses can promote quantities of fish oil.132,133
lubrication and slow evaporation of tears from the ocular surface. A number of drugs (mostly topical and a few systemic) are currently
being evaluated in clinical trials aimed at providing new treatment
Ocular Surface Inflammation options for patients with DED.134,135 Success with this research should
provide patients with many more treatment options in the future and
280 A common endpoint of all treatments of DED is not only prevention of has the potential to improve quality of life for patients suffering from
ocular surface inflammation and its consequential cellular changes but DED.136
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population-based assessment. Arch Intern Med 1999;159:1359–63.
Barabino S, Chen Y, Chauhan S, et al. Ocular surface immunity: homeostatic mechanisms
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Schein OD, Munoz B, Tielsch JM, et al. Prevalence of dry eye among the elderly. Am J Oph-
thalmol 1997;124:723–8.
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Craig JP, Nichols KK, Akpek EK. TFOS DEWS II Definition and Classification Report. Ocul Solomon A, Dursun D, Liu Z, et al. Pro- and anti-inflammatory forms of interleukin-1 in the
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Fox RI, Michelson P. Approaches to the treatment of Sjögren’s disease. J Rheumatol Suppl physiology of dry eye. Exp Eye Res 2004;78:409–16.
2000;61:15–21. Sullivan DA, Hammitt KM, Schaumberg DA, et al. Report of the TFOS/ARVO Symposium
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Ophthalmology 2017;124:53–60. J Ophthalmol 1997;124:825–35.
Lemp MA. The 1998 Castroviejo lecture: new strategies in the treatment of dry-eye states. Vitali C, Bombardiecri S, Jonnson R, et al. Classification criteria for Sjögren’s syndrome: a
Cornea 1999;18:625–32. revised version of the European criteria proposed by the American-European Consensus
Rolando M, Zierhut M. The ocular surface and tear film and their dysfunction in dry eye Group. Ann Rheum Dis 2002;1:554–8.
disease. Surv Ophthalmol 2001;45(Suppl. 2):S203–10.
Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eye syndrome among US
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Dry Eye Disease

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ture ovarian failure. Arch Ophthalmol 2004;122:151–6. eye after myopic LASIK. Am J Ophthalmol 2006;141:438–45.
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35. Lemp MA. The 1998 Castroviejo lecture: new strategies in the treatment of dry-eye 80. Fraunfelder FT. Drug-induced ocular side effects. 5th ed. Boston: Butterworth–
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36. Li DQ, Chen Z, Song XJ, et al. Stimulation of matrix logiclloproteinases by hyperosmo- 81. Mathers WD, Stovall D, Lane JA, et al. Menopause and tear function: the influence of
larity via a JNK pathway in human corneal epithelial cells. Invest Ophthalmol Vis Sci prolactin and sex hormones on human tear production. Cornea 1998;17:353–8.
2004;45:4302–11. 82. Fox RI, Robinson CA, Curd JG, et al. Sjögren’s syndrome: Proposed criteria for classifi-
37. Luo L, Li DQ, Corrales RM, et al. Hyperosmolar saline is a proinflammatory stress on cation. Arthritis Rheum 1986;29:477–585.
the mouse ocular surface. Eye Contact Lens 2005;31:186–93. 83. Vitali C, Bombardieri S, Jonnson R, et al. Classification criteria for Sjögren’s syndrome:
38. De Paiva CS, Corrales RM, Villarreal AL, et al. Corticosteroid and doxycycline suppress a revised version of the European criteria proposed by the American-European Consen-
MMP-9 and inflammatory cytokine expression, MAP K activation in the corneal epithe- sus Group. Ann Rheum Dis 2002;1:554–8.
lium in experimental dry eye. Exp Eye Res 2006;83:526–35. 84. Foulks GN, Forstot SL, Donshik PC, et al. Clincial guidelines for management of dry
39. Craig JP, Nichols KK, Akpek EK. TFOS DEWS II Definition and Classification Report. eye associated with Sjogren disease. Ocul Surf 2017;13(2):118–32.
Ocul Surf 2017;15:276–83. 85. Shine WE, McCulley JP. The role of cholesterol in chronic blepharitis. Invest Ophthal-
40. Doughty MJ, Naase T. Further analysis of the human spontaneous eye blink rate by a mol Vis Sci 1991;32:2272–80.
cluster analysis-based approach to categorize individuals with ‘normal’ versus ‘frequent’ 86. Shine WE, Silvany R, McCulley JP. Relation of cholesterol-stimulated Staphylococcus 281.e1
eye blink activity. Eye Contact Lens 2006;32:294–9. aureus growth to chronic blepharitis. Invest Ophthalmol Vis Sci 1993;34:2291–6.
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87. Lambert R, Smith RE. Hyperkeratinization in a rabbit model of meibomian gland dys- 114. Macri A, Pflugfelder SC. Correlation of the Schirmer 1 and fluorescein clearance
4 function. Am J Ophthalmol 1988;105:703–5.

88. Lambert RW, Smith RE. Effects of 13-cis-retinoic acid on the hamster meibomian gland.
J Invest Dermatol 1989;92:321–5.
89. Mathers WD, Shields WJ, Sachdev MS, et al. Meibomian gland morphology and tear
tests with the severity of corneal epithelial and eyelid disease. Arch Ophthalmol
2000;118:1632–8.
115. Pflugfelder SC, Tseng SC, Sanabria O, et al. Evaluation of subjective assessments and
objective diagnostic tests for diagnosing tear-film disorders known to cause ocular irri-
osmolarity changes with Acutane therapy. Cornea 1991;10:286–90. tation. Cornea 1998;17:38–56.
90. Ikui H, Sugi K, Uga S. Ocular signs of chronic chlorobiphenyl poisoning (Yusho) 116. Management and therapy of dry eye disease: report of the Management and Therapy
Fukuoka Igaku Zasshi. Fukuoka Acta Medica 1969;60:432. Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007;5:163–78.
91. Ohnishi Y, Ikui S, Kurimoto S, et al. Further ophthalmic studies of patients with chronic 117. Ono M, Takamura E, Shinozaki K, et al. Therapeutic effect of cevimeline on dry eye
chlorobiphenyls poisoning Fukuoka Igaku Zasshi. Fukuoka Acta Medica 1975;66:640. in patients with Sjögren’s syndrome: a randomized, double-blind clinical study. Am J
92. Ohnishi Y, Kohno T. Polychlorinated biphenyls poisoning in monkey eye. Invest Oph- Ophthalmol 2004;138:6–17.
thalmol Vis Sci 1979;18:981–4. 118. Vivino FB, Al-Hashimi I, Khan Z, et al. Pilocarpine tablets for the treatment of dry
93. Tei M, Spurr-Michaud SJ, Tisdale AS, et al. Vitamin A deficiency alters the expres- mouth and dry eye symptoms in patients with Sjögren syndrome: a randomized, pla-
sion of mucin genes by the rat ocular surface epithelium. Invest Ophthalmol Vis Sci cebo-controlled, fixed-dose, multicenter trial P92-01 Study Group. Arch Intern Med
2000;41:82–8. 1999;159:174–81.
94. Hori Y, Spurr-Michaud S, Russo CL, et al. Differential regulation of membrane-asso- 119. Di Pascuale MA, Goto E, Tseng SC. Sequential changes of lipid tear film after the instil-
ciated mucins in the human ocular surface epithelium. Invest Ophthalmol Vis Sci lation of a single drop of a new emulsion eye drop in dry eye patients. Ophthalmology
2004;45:114–22. 2004;111:783–91.
95. Sommer A, Emran N. Tear production in a vitamin A responsive xerophthalmia. Am J 120. Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol 2004;137:337–42.
Ophthalmol 1982;93:84–7. 121. Pflugfelder SC, Wilhelmus KR, Osato MS, et al. The autoimmune nature of aqueous
96. Smith J, Steinemann TL. Vitamin A deficiency and the eye. Int Ophthalmol Clin tear deficiency. Ophthalmology 1986;93:1513–17.
2000;40:83–91. 122. Barber LD, Pflugfelder SC, Tauber J, et al. Phase III safety evaluation of cyclosporine
97. Nichols JJ, Sinnott LT. Tear film, contact lens, and patient-related factors associated with 01% ophthalmic emulsion administered twice daily to dry eye disease patients for up to
contact lens–related dry eye. Invest Ophthalmol Vis Sci 2006;47:1319–28. 3 years. Ophthalmology 2005;112:1790–4.
98. Sommer HJ, Johnen J, Schongen P, et al. Adaptation of the tear film to work in air-con- 123. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of
ditioned rooms (office-eye syndrome). Ger J Ophthalmol 1994;3:406–8. patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol
99. Tsubota K, Fujita H, Tsuzaka K, et al. Mikulicz’s disease and Sjögren’s syndrome. Invest 2000;118:1489–96.
Ophthalmol Vis Sci 2000;41:1666–73. 124. Sall K, Stevenson OD, Mundorf TK, et al. Two multicenter, randomized studies of the
100. Feenstra RP, Tseng SC. Comparison of fluorescein and Rose Bengal staining. Ophthal- efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye
mology 1992;99:605–17. disease CsA Phase 3 Study Group. Ophthalmology 2000;107:631–9.
101. Norn MS. Lissamine green: Vital staining of cornea and conjunctiva. Acta Ophthalmol 125. Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the treatment of dry eye disease:
(Copenh) 1973;51:483–91. results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS 3).
102. Lemp MA, Holly FJ. Recent advances in ocular surface chemistry. Am J Optom Arch Ophthalmology 2017;124:53–60.
Am Acad Optom 1970;47:669–72. 126. Xiidra™ (lifitegrast ophthalmic solution) 5%, Package Insert, US Approval; 2016.
103. Schirmer O. Studien zur Physiologie and Pathologie der Tranenabsonderung and 127. Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for kerato-
Tranenabfuhr. Albrecht Von Graefes Arch Ophthalmol 1903;56:197–291. conjunctivitis sicca in Sjögren syndrome. Ophthalmology 1999;106:811–16.
104. Jones LT. The lacrimal secretory system and its treatment. Am J Ophthalmol 128. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double-masked, place-
1966;62:47–60. bo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension,
105. Afonso AA, Monroy D, Stern ME, et al. Correlation of tear fluorescein clearance and 05%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed
Schirmer test scores with ocular irritation symptoms. Ophthalmology 1999;106:803–10. tear clearance. Am J Ophthalmol 2004;138:444–57.
106. Methodologies to diagnose and monitor dry eye disease: report of the Diagnostic 129. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflamma-
Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf tory mediator production. Am J Clin Nutr 2000;71(1 Suppl.):343S–8S.
2007;5(2):108–52. 130. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n-3
107. Hamano T, Mitsunaga S, Kotani S, et al. Tear volume in relation to contact lens wear polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor
and age. CLAO J 1990;16:57–61. by mononuclear cells. N Engl J Med 1989;320:265–71.
108. Sakamoto R, Bennett ES, Henry VA, et al. The phenol red thread tear test: a cross-cul- 131. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gammalinolenic acid
tural study. Invest Ophthalmol Vis Sci 1993;34:3510–14. therapy in dry eye syndrome with an inflammatory component. Cornea 2003;22:97–101.
109. Yokoi N, Bron AJ, Tiffany JM, et al. Reflective meniscometry: a non-invasive method to 132. Gebauer SK, Psota TL, Harris WS, et al. n-3 fatty acid dietary recommendations
measure tear meniscus curvature. Br J Ophthalmol 1999;83:92–7. and food sources to achieve essentiality and cardiovascular benefits. Am J Clin Nutr
110. Yokoi N, Takehisa Y, Kinoshita S. Correlation of tear lipid layer interference patterns 2006;83(6 Suppl.):1526S–35S.
with the diagnosis and severity of dry eye. Am J Ophthalmol 1996;122:818–24. 133. Erdinest N, Shmueli O, Grossman Y, et al. Anti-inflammatory effects of alpha linolenic
111. Nemeth J, Erdelyi B, Csakany B, et al. High-speed videotopographic measurement of acid on human corneal epithelial cells. Invest Ophthalmol Vis Sci 2012;53:4396–406.
tear film build-up time. Invest Ophthalmol Vis Sci 2002;43:1783–90. 134. Barabino S, Chen Y, Chauhan S, et al. Ocular surface immunity: homeostatic mecha-
112. Wang J, Aquavella J, Palakuru J, et al. Relationships between central tear film thick- nisms and their disruption in dry eye disease. Prog Retin Eye Res 2012;31:271–85.
ness and tear menisci of the upper and lower eyelids. Invest Ophthalmol Vis Sci 135. Okanobo A, Chauhan SK, Dastjerdi MH, et al. Efficacy of topical blockade of interleu-
2006;47:4349–55. kin-1 in experimental dry eye disease. Am J Ophthalmol 2012;154:63–71.
113. Erdelyi B, Kraak R, Zhivov A, et al. In vivo confocal laser scanning microscopy of the 136. Sullivan DA, Hammitt KM, Schaumberg DA, et al. Report of the TFOS/ARVO Sympo-
cornea in dry eye. Graefes Arch Clin Exp Ophthalmol 2007;245:39–44. sium on global treatments for dry eye disease: an unmet need. Ocul Surf 2012;10:108–16.
281.e2
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Section 7 Miscellaneous Conditions
Complications of Contact Lens Wear

Joshua S. Agranat, Deborah S. Jacobs 4.24
Definition: Inflammatory, metabolic, mechanical, or infectious events
that are associated with contact lens use.
Key Features
• Overall safety record of contact lenses is excellent.
• Low-Dk lenses, overnight wear, and poor lens care practices are
modifiable risk factors for the development of contact lens–related
problems.
• Patient education remains an important avenue for prevention of
complications of contact lens wear.
INTRODUCTION
In the United States, an estimated 40.9 million adults wear contact lenses,
and nearly one third of them have experienced a contact lens–related com-
plication requiring a visit to their doctors.1 Although many contact lenses
are managed by optometrists and opticians, some complications threaten
Fig. 4.24.1 This photo with fluorescein and cobalt lighting shows a diffuse
sight and the long-term health of the eye, which makes it important that
superficial keratitis typical of solution toxicity.
ophthalmologists are well informed about this problem.2–4 This chapter will
discuss toxic and allergic reactions, conditions reflecting metabolic chal-
lenge, corneal inflammatory events (CIEs), and microbial keratitis (MK). switched to care systems with different preservatives or to daily disposable
The long-term sequelae of these contact lens–related complications range lenses to avoid solutions altogether.
from mild, self-limiting disease to vision loss even with proper treatment. There have been case reports of severe toxic reactions to contact lens
Problems related to fit, comfort, and tolerance, including lens warpage, use that resemble central toxic keratopathy syndrome—a constellation
tight lens, dry eye, deposits, and mucin balls, are outside the scope of this of corneal thinning and flattening, hyperopic shift, and marked stromal
chapter. “mud crack” central opacity.6,7 Treatment includes removal of the offend-
ing chemicals; use of preservative-free solutions; topical corticosteroid, if
inflammation is severe; and a change to more frequent lens replacement
TOXIC, ALLERGIC AND MECHANICAL REACTIONS and/or alternative lens material and care system.
Solutions
Toxic or allergic conjunctivitis may be caused by some components of the
Giant Papillary Conjunctivitis
lens care system. The agents frequently responsible for toxic or allergic Giant papillary conjunctivitis (GPC), sometimes called contact lens papillary
reactions are preservatives, disinfectants, surfactant and enzyme cleaners, conjunctivitis (CLPC), was first reported in the 1970s and is thought to be a
and concentrated hydrogen peroxide. Allergic reactions are hypersensitiv- result of both mechanical irritation and immunological stimulation.8–11 It is
ity reactions that occur after repeated exposure to the sensitizing antigen. believed that a cell-mediated reaction to the antigens deposited on contact
In the past, thimerosal was a common offender, but sorbate and benzalko- lenses causes trauma to the tarsal conjunctiva, exposing the antigens to
nium chloride are likely causes now.5 the ocular immune system and initiating the reaction.9,12,13 It should be
Patients with a toxic reaction experience immediate ocular discomfort noted that GPC has also been reported in those who do not wear contact
and conjunctival injection with lens insertion. Toxic conjunctivitis can lenses as a result of other causes of mechanical irritation, such as exposed
occur the first time the solution is used or may result from a buildup of sutures, extruded scleral buckles, foreign bodies, cyanoacrylate glue, ocular
the toxic component in the hydrogel material. Typically, patients have used prostheses, and filtering blebs.14 GPC is characterized by itching, burning,
the care system for 1 month or longer before symptoms of conjunctival increased mucus production, foreign-body sensation, and papillae on the
injection and irritation develop. On examination, conjunctival hyperemia, upper tarsus ranging from 0.3–2 mm14 (Figs. 4.24.2, 4.24.3, 4.24.4). It is the
follicles, superficial punctate keratitis, scattered fine infiltrates, and supe- most common complication of contact lens use.15 Patients typically report
rior limbic keratoconjunctivitis may be seen (Fig. 4.24.1). Discontinuation increased deposits on lenses, which may be visible on examination. Papil-
of the solution results in resolution of symptoms, but if the symptoms and lae are a late finding and are not necessary for diagnosis.
signs are severe, a short course of topical corticosteroids may be needed. Factors associated with GPC include duration of wear, hygiene, history
When resuming lens wear, wearers of hydrogel lenses should replace of atopy/environmental allergy, and the fall and spring seasons.15–18 Lens
their lenses, which may have absorbed the offending agent, but wearers cornea fit, bacterial bioburden, history of adverse ocular events, race, and
of rigid gas-permeable (RGP) lenses may use the same lenses if they are gender are not associated with GPC.19,20
thoroughly cleaned and rinsed. Incorrect use of solutions and cleaners can The initial treatment for GPC is removal of the inflammatory stimulus
contribute to toxic reactions, especially with incomplete rinsing of surfac- via cessation of contact lens wear for 2–4 weeks. When resuming use, it
tant cleaners or failure to neutralize peroxide solutions. Environmental may be helpful to decrease wear time, institute more frequent lens replace-
282 chemical exposure, such as cosmetics and hair sprays, may also lead to ment, optimize lens hygiene with goal of reducing deposits, or prescribe
toxic or allergic reactions when they contaminate lenses. Patients can be a new lens material or design. Limited wear of daily disposable lenses is a
booksmedicos.org
4.24

Fig. 4.24.2 Early to moderate giant papillary conjunctivitis, highlighted with Fig. 4.24.5 Conjunctival injection, corneal pannus, and punctate keratitis seen in
fluorescein dye. contact lens–induced superior limbic keratoconjunctivitis.
Superior Limbic Keratoconjunctivitis

Contact lens wear has been associated with injection and fluorescein stain-
ing of the superior bulbar conjunctiva, termed superior limbic keratocon-
junctivitis (SLK). Patients may experience tearing, burning, foreign body
sensation, and lens intolerance. The appearance is similar to idiopathic
SLK described by Theodore in 1963,22 which, interestingly, is sometimes
treated with therapeutic lenses.23 SLK in contact lens wearers has been
associated with preservatives in contact lens solutions, but mechanical irri-
tation from poor-fitting contact lenses may also be a factor.
In contact lens–associated SLK, the superior corneal epithelium is
irregular with a micropannus and punctate staining (Fig. 4.24.5). A pap-
illary reaction is often present on the superior tarsal conjunctiva, but the
papillae tend to be smaller than those seen in GPC. Discontinuation of
lens wear and topical lubrication is generally effective, but resolution may
take weeks or months. Punctal occlusion may aid in resolution of symp-
toms.24 Patients can return to lens wear after being refitted with new lenses
and switching to hydrogen peroxide disinfection, and nonpreserved saline
Fig. 4.24.3 As giant papillary conjunctivitis progresses, the papillae can grow to daily disposable lenses are another option for SLK patients
greater than 1 mm in size, and advanced lid changes may not resolve completely
with treatment.
CONDITIONS REFLECTING
METABOLIC CHALLENGE
Corneal Hypoxia and Edema
Contact lenses create a physical barrier that impairs the cornea’s natural
ability to harvest oxygen from the atmosphere and may lead to corneal
hypoxia. With continued hypoxia, cell death occurs, leading to erosions or
necrosis and desquamation and causing decreased vision, pain, tearing,
and photoallodynia.25 Chronic low-grade hypoxia causes subtle changes
in corneal physiology and structure. Examination findings may include
central epithelial microcysts and edema (“Sattler’s veil”), neovasculariza-
tion (Fig. 4.24.6), stromal thickening and striae, and endothelial blebs26
(Fig. 4.24.7). The corneal edema can fluctuate throughout the day, typically
being worse in the morning. Lens wear should be discontinued until the
edema resolves and then a high-Dk lens should be substituted.25,27
Neovascularization
As previously mentioned, chronic low-grade hypoxia can cause corneal
Fig. 4.24.4 The use of fluorescein dye highlights the large papillae in this patient
neovascularization. Hypoxia results in the accumulation of lactic acid and
with advanced giant papillary conjunctivitis. carbon dioxide, which stimulates vascular ingrowth26,28 and hypoxic dila-
tion of limbal vessels.29 Although typically associated with low-Dk hydrogel
lenses, neovascularization may also be seen with poorly fit RGP lenses
good way of reintroducing lens wear while minimizing antigen presenta- because of chronic irritation, such as in vascularized limbal keratitis (VLK).
tion. Adjunctive therapies for severe cases include topical mast cell stabiliz- VLK lesions appear as an elevated, opaque mass at the limbal–epithelial
ers, used as initial treatment and for suppressive maintenance, and pulse junction with superficial and deep vascularization.30
regimen of topical corticosteroid, with appropriate monitoring. The role Superficial neovascular changes (pannus) are common in patients
of topical immunomodulators, such as tacrolimus, has been reported.21 wearing soft, low-Dk lenses, and may be acceptable if the pannus is stable
GPC is not vision threatening, and with proper management, resolution and it extends less than 1.5 mm onto the cornea. This superficial neovas-
of redness and discharge is typically expected within 1–2 weeks. When cularization is likely caused by angiogenic factors released in response to 283
inflammation is severe or long-standing, the papillae may remain. chronic limbal trauma and hypoxia. Vascular ingrowth into the corneal
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Fig. 4.24.6 Chronic hypoxia associated with contact lens wear can lead to corneal
neovascularization.
Fig. 4.24.8 Corneal neovascularization can, on rare occasion, lead to an intrastromal

hemorrhage, seen at the 2 o’ clock position in this patient.
Fig. 4.24.7 Stromal thickening and faint endothelial striae are seen in a patient with
chronic stromal edema. Fig. 4.24.9 Contact lens–induced keratopathy (CLIK) progresses to diffuse corneal
scarring and vascularization, seen in this view with areas of superior thickening,
fibrosis, and neovascularization.
stroma is more worrisome because these vessels can lead to lipid exuda-
tion, scarring, and intracorneal hemorrhages (Fig. 4.24.8). Stromal neo-
vascular changes or superficial neovascularization that extends more than lens–induced LSCD depends largely on the severity of disease. Initial
2 mm onto the cornea should be considered abnormal and unacceptable. medical treatment includes discontinuation of wear and optimization of
When the patient is refitted with high-Dk lenses, reduction of the abnor- the tear film and ocular surface via a combination of artificial tears, topical
mal vessels and limbal erythema is expected.31–33 corticosteroid, topical cyclosporine, topical vitamin A, punctal occlusion,
and oral doxycycline.39,40 If maximal medical therapy fails, surgical options
Limbal Stem Cell Deficiency include mechanical removal of conjunctivalized corneal epithelium,
amniotic membrane transplantation, and limbal autograft or allogenic
Limbal stem cell deficiency (LSCD) is caused by the loss of function of transplantation.41–44
corneal epithelial cell precursors. Contact lens–associated LSCD was first
referred to as contact lens–induced keratopathy (CLIK), in which the kerato- Abrasions
conjunctivitis progressed to diffuse corneal scarring and vascularization,
sometimes requiring penetrating keratoplasty.34 Bowman’s membrane is Corneal abrasions are epithelial defects caused by trauma to the ocular
damaged and replaced by fibrous scar tissue with deep stromal vascular- surface. Abrasions frequently occur with contact lens use during the
ization35 (Fig. 4.24.9). insertion or removal process and are caused by fingernails or the lens
The clinical picture of contact lens–induced LSCD is typically milder itself. Abrasions allow bacteria access to the corneal stroma, and there-
than other causes of LSCD as evidenced by the finding that 71.4% of fore careful evaluation for MK is warranted when there is an abrasion in
patients with contact lens–induced LSCD are asymptomatic.36 The slit- the context of contact lens wear. In the setting of contact lens use, recom-
lamp exam in contact lens–induced LSCD demonstrates whorl-like epithe- mended treatment of corneal abrasion is a broad-spectrum antibiotic, such
liopathy, conjunctivalization of the cornea, absence of palisades of Vogt, as a fluoroquinolone or aminoglycoside, which offers prophylaxis against
284 and late fluorescein staining.37 As the disease progresses, findings include Pseudomonas. Patching and topical corticosteroids have no proven benefit
pannus, epithelial defects, scarring, and vision loss.38 Treatment of contact and should not be used in contact lens–associated corneal abrasions.45–47
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CORNEAL INFLAMMATORY EVENTS AND A large study of 6245 lens wearers found lens-related CIE in 159 patients
MICROBIAL KERATITIS (2.5%). Risk factors included age ≤25 years or less and greater than 50
years; refractive error greater than +5.00 diopters (D); smoking; and failure 4.24
There is lack of standardization in the literature and discourse surround- to maintain prescribed wear schedule.74 Further, a meta-analysis of pub-
ing corneal opacities with or without an overlying defect.48–50 It is common lished and presented studies (1991–2006) found a twofold higher risk for

for the terms ulcer, infiltrate, sterile infiltrate, presumed microbial keratitis, CIEs in users of SH lenses worn for up to 30 days compared with low-Dk
and so on to be used imprecisely; the authors of this chapter will there- extended-wear lenses worn for 7 days. However, it was not clear if the
fore use a classification system first proposed by Efron et al.51 This system increased risk was related to the lens material or the wear schedule.73
separates the spectrum of clinical findings into two distinct entities: CIEs The Moorfields Eye Hospital (London, UK) compared daily disposable,
and MK. silicone hydrogel, and planned replacement lenses and found a signifi-
CIEs include an epithelial or subepithelial infiltrate, with or without an cantly reduced risk of toxic/hypersensitivity reactions, papillary conjunc-
epithelial defect, which improves in the absence of treatment and typically tivitis, and metabolic disorders for daily disposables but an increased risk
does not cause scarring. Treatment of CIEs may be hastened by antibiotics of sterile keratitis and mechanical disorders. Silicone hydrogels did not
and/or corticosteroids. However, MK is an epithelial defect with stromal cause hypoxic complications but had an increased risk of sterile keratitis,
involvement or tissue loss (also referred to as “crater”), typically leaves a mechanical disorders, and nonulcerative complications compared to con-
scar, has a presumed or confirmed pathogen and requires intensive treat- ventional soft lenses.75 Risk factors for CIEs included overnight wear, more
ment with antimicrobials. It is acceptable to use the term “ulcer” when days of lens wear per week, poor hand hygiene, smoking, and inexperi-
referring to MK but not to CIEs. ence with use. The authors concluded neither daily disposable lenses nor
silicone hydrogels reduced the overall risk of acute nonulcerative events.75
The Role of Lens Care Systems Corneal scrape and cultures can be obtained to evaluate for infectious eti-
ologies and should especially be acquired if the infiltrate increases, vision
For several years, multipurpose solutions (MPSs) have been the most is affected, or if the infiltrate is large (>1 mm).76 However, it is difficult to
popular lens care products.52 They may contain surfactant cleaners, dis- rely only on culture data to guide clinical decision making. Reported cul-
infecting agents, preservatives, and polymers or conditioners to make the tures of “obvious” MK are positive 43%–86% of the time, yet one study of
contact lens more comfortable. The disinfecting component must contain “sterile” peripheral infiltrates found positive cultures in 50% of the subset
antimicrobial agents sufficient to destroy micro-organisms. Despite of patients.77-80 Many clinicians believe that small peripheral infiltrates do
approval by the U.S. Food and Drug Administration (FDA) and the pop- not require cultures, but cultures on organisms have been performed, par-
ularity of MPS solutions, recent outbreaks of MK have focused attention ticularly if an epithelial defect is present.73,76 When organisms are recov-
on lens care. Studies also suggest other problems with MPS care systems ered, they tend to be less virulent than those associated with central ulcers.
because some solutions can, in fact, increase the binding of Pseudomo- The most common isolate is staphylococcus spp., but even in the face of
nas to epithelial cells and decrease the rate of epithelial cell exfoliation.53 positive culture results, many authors believe that peripheral infiltrates are
Polyhexamethylene biguanide (PHMB)–based systems used with FDA inflammatory because microorganisms are not recovered in most studies,
group II lenses (high water, nonionic) resulted in increased corneal stain- and infiltrates often resolve with corticosteroid therapy alone.76,81
ing, and biguanides used with group IV lenses (high water, ionic) also Discontinuation of lens wear is the first step in the treatment of CIEs.
increased staining and decreased biocide efficacy.54,55 Lens wearers with Depending on location and size of the infiltrate and the capacity for mon-
solution-associated corneal staining were significantly more likely to itoring additional treatment options include topical, broad-spectrum anti-
develop corneal infiltrates.56 In general, hydrogen peroxide care systems biotics, topical corticosteroids, or a combination of the two. The clinical
appear to have the best profile for disinfection of lenses and the lowest appearance can change rapidly, and most patients are seen in 24 hours
incidence of CIEs and corneal staining.57 with modification of therapy, as needed. After resolution, assessment of the
In addition, lens handling greatly increases the incidence of lens con- patient’s wear and replacement schedules, as well as their care regimen,
tamination, with more than half the lenses removed aseptically from the should be made. Extended wear should be discouraged. Reduction of
eye showing microbial contamination. Studies have shown that greater bioburden at the lid margins82 and in lens cases, as well as a switch to
than 50% of lens cases are contaminated. All types of care solutions can daily disposable or hydrogen peroxide care system, should be considered.57
become contaminated, including up to 30% of preserved solutions.58 Not
surprisingly, those who wear contact lenses infrequently had a higher con- Microbial Keratitis
tamination rate. Rinsing lenses with saline or MPS appears to be effective
in reducing contamination.59 Use of daily disposable lenses is a way to Although the overall incidence is low, contact lens wear is now considered
avoid contamination and is associated with lower complication rates com- the major risk factor for MK, with about 65% of all new ulcers related to
pared with other modes of daily soft lens wear.60 contact lens use.83,84 MK can be sight threatening because of corneal scar-
ring and is therefore important to differentiate early-stage MK from CIEs
Corneal Inflammatory Events so as to not delay treatment.
The most important risk factor for MK is overnight or extended lens
Contact lens–related CIEs range from small, asymptomatic lesions to large use,2,3,71,85–87 followed by poor lens/lens case disinfection, smoking, lower
opacities that obscure vision. The opaque lesions are caused by polymor- socioeconomic class, and failure to wash hands.3,88–90 It is surprising that
phonuclear and mononuclear leukocyte recruitment to the cornea and are the surge in disposable single-use contact lenses has not decreased the
likely host response to commensal organisms or lens-related bacteria.29,61 rates of MK; however, there has been a decrease in vision loss caused by
Bacteria can form a biofilm on the surface of the lens or the lens case, and MK in daily contact lens wearers.91 Stapleton reported a higher incidence
one study found that more than 70% of the risk for CIEs was related to the rate of MK with silicone hydrogel (SH) contact lenses compared to daily
exposure to the lens biofilm.62 Multiple other causes, including hypoxia, disposable, and higher rates of MK when SH contact lenses were worn
retrolental debris, and staphylococcal immune complexes, have been pro- overnight compared with conventional hydrogels.92 Overall, daily dispos-
posed and investigated.63–66 The epithelium is usually intact but may show able lenses are associated with less severe MK and are less likely to cause
overlying superficial punctate keratitis, and the anterior chamber shows vision-impairing central MK.
only minimal reaction.67–69 Symptoms typically include irritation, pain, Findings associated with MK include positive corneal culture results,
foreign body sensation, photoallodynia, and tearing. continuous pain after discontinuation of wear, photoallodynia, purulent
The true incidence and significance of peripheral infiltrates is an discharge (Fig. 4.24.10), conjunctival injection, epithelial staining, ante-
area of ongoing study and debate. Sankaridurg et al. found that 1.6% of rior chamber reaction67 and corneal edema that surrounds an infiltrate.
asymptomatic patients with no history of contact lens wear had corneal Stromal opacities in MK are usually larger than 1.5 mm and have overly-
infiltrates at the start of a study comparing spectacle wear and daily dis- ing epithelial defect and purulent discharge. Multiple studies have demon-
posable lenses. Asymptomatic infiltrates were seen in spectacle wearers at strated that pathogenic microorgranisms, especially Pseudomonas spp.,
a rate of 11.3 events per 100 years of wear compared with 20.5 events per fungi, Acanthamoeba, and Nocardia, are the main causes and determinants
100 years in wearers of daily disposable lenses. The daily disposable group of outcome in MK.93–101
had 2.5 symptomatic peripheral ulcers events, but no events were noted in Lee et al. found that Gram-positive bacteria are more prevalent in MK,
the spectacle group.70 Several other studies have reported the incidence of whereas Gram-negative bacteria are more virulent.102
sterile peripheral infiltrates in users of extended-wear disposable lenses to When MK ulcers are suspected, scraping, culture, and Gram stain- 285
be equal to or higher than daily wear.71–73 ing must be performed. The solutions and the lens case should be
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Fig. 4.24.11 Patients with Acanthamoeba keratitis often show radial keratoneuritis
Fig. 4.24.10 This Fusarium ulcer occurred in a contact lens wearer using the lens (arrow) with infiltration along the corneal nerves.
solution brand ReNu with MoistureLoc, which was subsequently withdrawn from
the market.
Acanthamoeba Keratitis
sampled as well, if possible. Aggressive therapy with broad-spectrum, Acanthamoeba is a protozoa found in fresh water and soil and the majority
topical fortified antibiotics should be initiated immediately. A combina- of cases of Acanthamoeba keratitis are associated with contact lenses. The
tion broad-spectrum regimen that includes either cefazolin or vancomy- key risk factors for Acanthamoeba infection involve poor hygiene practices,
cin and tobramycin or gentamicin is recommended. In less severe cases, including using tap water or saline to rinse or store lenses, swimming in
aggressive broad-spectrum monotherapy with a fluoroquinolone is often fresh water while wearing contact lenses, and using hydrogen peroxide
effective.103 Delay in treatment of more than 12 hours increase the risk instead of multipurpose solution.111 However, other studies have indicated
of vision loss.101 The Steroids for Corneal Ulcers Trial (SCUT) identified that hydrogen peroxide is a superior lens disinfectant solution.112 Overall,
that adjunctive topical corticosteroids may be associated with improved it has been estimated that over 80% of Acanthamoeba infections could be
outcomes in bacterial MK not caused by Nocardia spp. and that the worst prevented with proper lens disinfectant systems.113–115
ulcers benefit the most from corticosteroid application.104 However, as will Acanthamoeba keratitis should be suspected in all contact lens wearers
be mentioned later, misdiagnosis in the context of corticosteroid use can who experience foreign body sensation; severe pain out of proportion to
be vision threatening because corticosteroids worsen nonbacterial keratitis, clinical examination findings; lid edema; lack of improvement with anti-
such as that caused by herpes simplex virus, fungal keratitis, and Acan- biotics, antivirals, or corticosteroids; and epithelial findings, including
thamoeba keratitis. punctate epithelial erosions, ring-shaped infiltrates, and pseudo-dendritic
Careful follow-up and adjustment of therapy, based on identification lesions116 (Fig. 4.24.11). If a patient presents with an isolated ring-shaped
of the organism, sensitivity testing, and clinical response, are essential. corneal infiltrate and Acanthamoeba is not found, consideration should be
Unfortunately, MK often causes corneal scarring and decreased acuity given to unrelated causes, such as anesthetic abuse or a type 3 response to
because these lesions are often centrally located; up to 25% of patients are endotoxin (e.g., Wessely immune rings).
left with best-corrected visual acuity of less than 20/200.105 Patients may Definitive diagnosis entails corneal scrapings and cultures, although
require corneal transplantation or RGP lens to improve acuity. there is a role for preliminary confocal microscopy.117 The lesion may be
confused with fungal, bacterial, or herpetic keratitis, and this often leads to
Fungal Keratitis delay in diagnosis and treatment. Even if promptly diagnosed, vision loss
may result because there is no optimal treatment for this condition that
Historically, fungal infections are a rare cause of contact lens–induced MK. causes amebic encystation and medication resistance.
However, the incidence of fungal keratitis is increasing, and the increase Treatment is amebicidal therapy with propamidine isethionate 0.1%
has resulted from contact lens–associated filamentary fungal infections.106 and PHMB 0.02%, for months.118–121 Use of topical corticosteroid can
All types of contact lenses, including daily disposables, have been asso- have detrimental effects on visual outcome, but its use can be considered
ciated with fungal keratitis.107 Candida spp. are the most common non- after initiation of modern antimicrobial therapy.122 Penetrating kerato-
filamentous isolates, and Aspergillus and Fusarium lead the filamentous plasty is often required, but infection may recur in the graft, necessitating
causes.108 enucleation.123–125 Considering the virulence of the organism and its resis-
Patients present with decreased vision, injection, and pain that may tance to treatment, it is critical that proper lens hygiene is emphasized to
be severe. Early filamentous infections have a feathery appearance at the prevent Acanthamoeba infection. Daily disposable lenses may be the best
edges and may be less dense than those seen with bacterial MK. There option for patients who exhibit less than optimal adherence to sanitation
may be a frank epithelial defect, and the anterior chamber reaction may measures.
be mild or severe, even forming a hypopyon. MK caused by yeast infec-
tions are typically more localized, with a small epithelial defect overlying
an infiltrate. Fungal MK may be slowly progressive, often delaying correct
UNSUPERVISED LENS WEAR
diagnosis. Unsupervised lens wear occurs when individuals inexperienced with
Culture and Gram staining of corneal scrapings should be performed contact lens use obtain lenses without a prescription and from unlicensed
if fungal keratitis is suspected. Cultures of the solutions, lenses, and lens sellers. No individualized fitting occurs, and no instruction is given on any
cases are also advised. Unlike suspected bacterial infections, which are aspect of lens wear or care. These lenses are typically plano lenses worn to
often treated empirically pending culture results, treatment for fungal change the color of the eye or for some dramatic effect. The sale of these
keratitis does not typically begin until confirmation with positive culture “black market” lenses occurs at unlikely locations, such as convenience
results, scrapings, confocal microscopy, or (occasionally) a corneal biopsy. stores, nail salons, beauty parlors, theatrical supply houses, flea markets,
The Mycotic Ulcer Treatment Trial (MUTT) demonstrated level 1 evi- and even street vendors. These lenses also are available from Internet sup-
dence that topical natamycin is superior to topical voriconazole in the pliers, some of whom advertise that no prescription is needed. The typical
treatment of fungal keratitis, especially in cases of Fusarium keratitis.109 customer is a young person; the risks may be compounded by overnight
Systemic voriconazole in combination with topical treatment is used wear of these lenses and sharing and swapping of lenses. As these lenses
in severe cases. Interestingly, some fungal keratitis associated with soft gained popularity, eye care professionals have started to see more cases
286 contact lens wear can resolve with topical fluoroquinolone treatment; it is with such problems as infectious keratitis, which sometimes result in loss
postulated that fluoroquinolones augment the innate immune response.110 of vision, hospitalization, and the need for penetrating keratoplasty.126–128 In
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2005, plano, or decorative, lenses were classified as medical devices requir- Appropriate lens selection and patient education regarding lens hygiene
ing a prescription as a result of significant effort by professional eye care
organizations and individuals and concern shared by the FDA.129
can reduce complications. Public health initiatives may be required to
reduce unsupervised lens wear. Regular monitoring by an eye care pro- 4.24
Unsupervised lens wear also occurs with prescription lenses, now vider are critical to primary and secondary prevention. In the event of a
readily available from alternative lens sellers. Despite the legal require- contact lens–related complication, prompt referral, early diagnosis, and

ment for a valid contact lens prescription, some wearers are able to obtain proper treatment typically result in good visual outcomes and allow con-
contact lenses for extended periods without regular eye examinations. If tinuation of contact lens wear.
a lens wearer has no acute problem requiring immediate attention, it is
only at the yearly examination that eye care professionals can examine the
patient for subtle signs of lens problems, review wearing and replacement KEY REFERENCES
schedules, and ensure that the patient is using an appropriate lens care
Chalmers RL, McNally JJ, Schein OD, et al. Risk factors for corneal infiltrates with continu-
system. In contact lens care, if there is no immediate consequence to devi- ous wear of contact lenses. Optom Vis Sci 2007;84(7):573–9.
ation from recommended practices, a slow drift away from good lens care Cope JR, Collier SA, Rao MM, et al. Contact lens wearer demographics and risk behaviors
can occur. In 2006, the FDA issued guidelines emphasizing the impor- for contact lens–related eye infections–United States, 2014. MMWR Morb Mortal Wkly
tance of professional advice, valid contact lens prescriptions, and continu- Rep 2015;64(32):865–70.
Dart JKG, Radford CF, Minassian D, et al. Risk factors for microbial keratitis with contempo-
ing professional care. FDA guidelines succinctly state: “Because of these rary contact lenses: a case-control study. Ophthalmology 2008;115:1647–54.
risks, contact lenses, including decorative contact lenses that are noncor- FDA Document 1613. Guidance for industry, FDA staff, eye care professionals, and consum-
rective, are not safe for use except under the supervision of a practitioner ers: decorative, non-corrective contact lenses. November 26, 2006. http://www.fda.gov/
licensed by law to direct the use of such devices.”130 cdrh/comp/guidance/1613.pdf.
Forister JFY, Forister EF, Yeung KK, et al. Prevalence of contact lens–related complications:
UCLA contact lens study. Eye Contact Lens 2009;35:176–80.
FDA AND CDC RECOMMENDATIONS Sankaridurg PR, Sweeney DF, Holden BA, et al. Comparison of adverse events with daily
disposable hydrogels and spectacle wear: results from a 12-month prospective clinical
The recommendations of the FDA and the Centers for Disease Control trial. Ophthalmology 2003;110(12):2327–34.
Schein OD, Glynn RJ, Poggio EC, et al. The relative risk of ulcerative keratitis among users
and Prevention for contact lens safety are summarized below and can be of daily-wear and extended-wear soft contact lenses. A case-control study. Microbial Ker-
found at www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ atitis Study Group. N Engl J Med 1989;321(12):773–8.
HomeHealthandConsumer/ConsumerProducts/ContactLenses/ and www Schein OD, McNally JJ, Katz J. The incidence of microbial keratitis among wearers of a
.cdc.gov/contactlenses/. 30-day silicone hydrogel extended-wear contact lens. Ophthalmol 2005;112:2172–9.
Skotnitksy C, Sankaridurg P, Sweeney DF, et al. Generalized and local contact lens induced
• Follow the recommended wear schedule. Do not substitute sterile saline papillary conjunctivas (CLPC). Clin Exp Optom 2002;85:193–7.
solutions with multipurpose solutions. Stapleton F, Edwards K, Keay L, et al. Risk factors for moderate and severe microbial keratitis
• Rub and rinse your contact lenses as directed by your eye care in daily wear contact lens users. Ophthalmology 2012;119(8):1516–21.
Stapleton F, Keay L, Edwards K. The incidence of contact lens–related microbial keratitis in
professional. Australia. Ophthalmol 2008;115:1655–62.
• Do not “top off” the solutions in your case. Always discard all of the left- Steinemann TL, Pinninti U, Szczotka LB, et al. Ocular complications associated with
over contact lens solution after each use. Never reuse any lens solution. the use of cosmetic contact lenses from unlicensed vendors. Eye Contact Lens
• Clean, rinse, and air-dry your lens case each time lenses are removed. 2003;29(4):196–200.
Suchecki JK, Ehlers WH, Donshik PC. A comparison of contact lens-related complications in
• Do not expose your contact lenses to any water: tap, bottled, distilled, various daily wear modalities. CLAO J 2000;26:204–13.
lake, or ocean water. Szczotka-Flynn L, Diaz M. Risk of corneal inflammatory events with silicone hydro-
• Contact your eye care professional if you experience any symptoms of gel and low dk hydrogel extended contact lens wear: a meta-analysis. Optom Vis Sci
2007;84(4):247–56.
eye irritation or infection. Szczotka-Flynn L, Pearlman E, Ghannoum M. Microbial contamination of contact lenses,
lens care solutions, and their accessories: a literature review. Eye Contact Lens
2010;36:116–29.
CONCLUSIONS
The overall safety profile of contact lenses is excellent, but wearers are at Access the complete reference list online at ExpertConsult.com
increased risk for both non–sight-threatening and blinding complications.
287
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2. Schein OD, Glynn RJ, Poggio EC, et al. The relative risk of ulcerative keratitis among
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bial Keratitis Study Group. N Engl J Med 1989;321(12):773–8. 45. Petroutsos G, Guimaraes R, Giraud JP, et al. Corticosteroids and corneal epithelial
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of daily-wear and extended-wear soft contact lenses. N Engl J Med 1989;321(12):779–83. 46. Lim CH, Turner A, Lim BX. Patching for corneal abrasion. Cochrane Database Syst Rev
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10. Donshik PC. Giant papillary conjunctivitis. Trans Am Ophthalmol Soc 1994;92:687–744. 53. Li SL, Ladage PM, Yamamoto T, et al. Effects of contact lens care solutions on
11. Skotnitsky C, Sankaridurg PR, Sweeney DF, et al. General and local contact lens surface exfoliation and bacterial binding to corneal epithelial cells. Eye Contact Lens
induced papillary conjunctivitis (CLPC). Clin Exp Optom 2002;85(3):193–7. 2003;29(1):27–30.
12. Pritchard N, Fonn D, Weed K. Ocular and subjective responses to frequent replacement 54. Garofalo RJ, Dassanayake N, Carey C, et al. Corneal staining and subjective symptoms
of daily wear soft contact lenses. CLAO J 1996;22(1):53–9. with multipurpose solutions as a function of time. Eye Contact Lens 2005;31(4):166–74.
13. Palmisano PC, Ehlers WH, Donshik PC. Causative factors in unilateral giant papillary 55. Rosenthal RA, Dassanayake NL, Schlitzer RL, et al. Biocide uptake in contact lenses
conjunctivitis. CLAO J 1993;19(2):103–7. and loss of fungicidal activity during storage of contact lenses. Eye Contact Lens
14. Skotnitsky CC, Naduvilath TJ, Sweeney DF, et al. Two presentations of contact lens– 2006;32(6):262–6.
induced papillary conjunctivitis (CLPC) in hydrogel lens wear: local and general. Optom 56. Carnt N, Jalbert I, Stretton S, et al. Solution toxicity in soft contact lens daily wear is
Vis Sci 2006;83(1):27–36. associated with corneal inflammation. Optom Vis Sci 2007;84(4):309–15.
15. Forister JF, Forister EF, Yeung KK, et al. Prevalence of contact lens–related complica- 57. Carnt NA, Evans VE, Naduvilath TJ, et al. Contact lens–related adverse events and
tions: UCLA contact lens study. Eye Contact Lens 2009;35(4):176–80. the silicone hydrogel lenses and daily wear care system used. Arch Ophthalmol
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contact lens wearers: a retrospective study. Trans Am Ophthalmol Soc 1999;97:205–16, 58. Szczotka-Flynn LB, Pearlman E, Ghannoum M. Microbial contamination of contact
discussion 216–20. lenses, lens care solutions, and their accessories: a literature review. Eye Contact Lens
17. Begley CG, Riggle A, Tuel JA. Association of giant papillary conjunctivitis with seasonal 2010;36(2):116–29.
allergies. Optom Vis Sci 1990;67(3):192–5. 59. Yung MS, Boost M, Cho P, et al. Microbial contamination of contact lenses and lens
18. Allansmith MR, Ross RN. Ocular allergy and mast cell stabilizers. Surv Ophthalmol care accessories of soft contact lens wearers (university students) in Hong Kong. Oph-
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lary conjunctivitis associated with silicone hydrogel contact lens wear. Eye Contact Lens tions in various daily wear modalities. CLAO J 2000;26(4):204–13.
2014;40(3):117–22. 61. Mondino BJ, Kowalski R, Ratajczak HV, et al. Rabbit model of phlyctenulosis and
20. Maldonado-Codina C, Morgan PB, Efron N, et al. Comparative clinical performance catarrhal infiltrates. Arch Ophthalmol 1981;99(5):891–5.
of rigid versus soft hyper Dk contact lenses used for continuous wear. Optom Vis Sci 62. Szczotka-Flynn L, Lass JH, Sethi A, et al. Risk factors for corneal infiltrative events
2005;82(6):536–48. during continuous wear of silicone hydrogel contact lenses. Invest Ophthalmol Vis Sci
21. Diao H, She Z, Cao D, et al. Comparison of tacrolimus, fluorometholone, and 2010;51(11):5421–30.
saline in mild-to-moderate contact lens–induced papillary conjunctivitis. Adv Ther 63. Aquavella JV, DePaolis MD. Sterile infiltrates associated with contact lens wear. Int Oph-
2012;29(7):645–53. thalmol Clin 1991;31(2):127–31.
22. Theodore FH. Superior limbic keratoconjunctivitis. Eye Ear Nose Throat Mon 64. Smolin G, Okumoto M, Nozik RA. The microbial flora in extended-wear soft contact–
1963;42:25–8. lens wearers. Am J Ophthalmol 1979;88(3 Pt 2):543–7.
23. Mondino BJ, Zaidman GW, Salamon SW. Use of pressure patching and soft contact 65. Mondino BJ, Groden LR. Conjunctival hyperemia and corneal infiltrates with chemically
lenses in superior limbic keratoconjunctivitis. Arch Ophthalmol 1982;100(12):1932–4. disinfected soft contact lenses. Arch Ophthalmol 1980;98(10):1767–70.
24. Yang HY, Fujishima H, Toda I, et al. Lacrimal punctal occlusion for the treatment of 66. Mertz PH, Bouchard CS, Mathers WD, et al. Corneal infiltrates associated with dispos-
superior limbic keratoconjunctivitis. Am J Ophthalmol 1997;124(1):80–7. able extended wear soft contact lenses: a report of nine cases. CLAO J 1990;16(4):269–72.
25. Lim L, Tan DT, Chan WK. Therapeutic use of Bausch & Lomb PureVision contact 67. Stein RM, Clinch TE, Cohen EJ, et al. Infected vs sterile corneal infiltrates in contact
lenses. CLAO J 2001;27(4):179–85. lens wearers. Am J Ophthalmol 1988;105(6):632–6.
26. O’Neal MR, Polse KA, Sarver MD. Corneal response to rigid and hydrogel lenses during 68. Suchecki JK, Ehlers WH, Donshik PC. Peripheral corneal infiltrates associated with
eye closure. Invest Ophthalmol Vis Sci 1984;25(7):837–42. contact lens wear. CLAO J 1996;22(1):41–6.
27. Liesegang TJ. Physiologic changes of the cornea with contact lens wear. CLAO J 69. Bates AK, Morris RJ, Stapleton F, et al. ‘Sterile’ corneal infiltrates in contact lens
2002;28(1):12–27. wearers. Eye (Lond) 1989;3(Pt 6):803–10.
28. Holden BA, Mertz GW, McNally JJ. Corneal swelling response to contact lenses worn 70. Sankaridurg PR, Sweeney DF, Holden BA, et al. Comparison of adverse events with
under extended wear conditions. Invest Ophthalmol Vis Sci 1983;24(2):218–26. daily disposable hydrogels and spectacle wear: results from a 12-month prospective clin-
29. Holden BA, Sweeney DF, Swarbrick HA, et al. The vascular response to long-term ical trial. Ophthalmology 2003;110(12):2327–34.
extended contact lens wear. Clin Exp Optom 1986;69(3):112–19. 71. Nilsson SE, Montan PG. The annualized incidence of contact lens–induced keratitis in
30. Robert M, Grohe KAL. Vascularized limbal keratitis, vol. 16. New York: Professional Sweden and its relation to lens type and wear schedule: results of a 3-month prospective
Press: International contact lens clinic; 1987. p. 197–209. study. CLAO J 1994;20(4):225–30.
31. Covey M, Sweeney DF, Terry R, et al. Hypoxic effects on the anterior eye of high-Dk soft 72. Nilsson SE. Seven-day extended wear and 30-day continuous wear of high oxygen
contact lens wearers are negligible. Optom Vis Sci 2001;78(2):95–9. transmissibility soft silicone hydrogel contact lenses: a randomized 1-year study of 504
32. Stefansson E, Foulks GN, Hamilton RC. The effect of corneal contact lenses on the patients. CLAO J 2001;27(3):125–36.
oxygen tension in the anterior chamber of the rabbit eye. Invest Ophthalmol Vis Sci 73. Szczotka-Flynn L, Diaz M. Risk of corneal inflammatory events with silicone hydro-
1987;28(10):1716–19. gel and low dk hydrogel extended contact lens wear: a meta-analysis. Optom Vis Sci
33. Stretton S, Jalbert I, Sweeney DF. Corneal hypoxia secondary to contact lenses: the effect 2007;84(4):247–56.
of high-Dk lenses. Ophthalmol Clin North Am 2003;16(3):327–40, v. 74. Chalmers RL, McNally JJ, Schein OD, et al. Risk factors for corneal infiltrates with con-
34. Bloomfield SE, Jakobiec FA, Theodore FH. Contact lens induced keratopathy: a severe tinuous wear of contact lenses. Optom Vis Sci 2007;84(7):573–9.
complication extending the spectrum of keratoconjunctivitis in contact lens wearers. 75. Radford CF, Minassian D, Dart JK, et al. Risk factors for nonulcerative contact lens
Ophthalmology 1984;91(3):290–4. complications in an ophthalmic accident and emergency department: a case-control
35. Puangsricharern V, Tseng SC. Cytologic evidence of corneal diseases with limbal stem study. Ophthalmology 2009;116(3):385–92.
cell deficiency. Ophthalmology 1995;102(10):1476–85. 76. Baum J, Dabezies OH Jr. Pathogenesis and treatment of “sterile” midperipheral corneal
36. Martin R. Corneal conjunctivalisation in long-standing contact lens wearers. Clin Exp infiltrates associated with soft contact lens use. Cornea 2000;19(6):777–81.
Optom 2007;90(1):26–30. 77. Donshik PC, Suchecki JK, Ehlers WH. Peripheral corneal infiltrates associated with
37. Chan CC, Holland EJ. Severe limbal stem cell deficiency from contact lens wear: patient contact lens wear. Trans Am Ophthalmol Soc 1995;93:49–60, discussion 60–4.
clinical features. Am J Ophthalmol 2013;155(3):544–9.e2. 78. Srinivasan M, Gonzales CA, George C, et al. Epidemiology and aetiological diagnosis of
38. Rossen J, Amram A, Milani B, et al. Contact lens–induced limbal stem cell deficiency. corneal ulceration in Madurai, south India. Br J Ophthalmol 1997;81(11):965–71.
Ocul Surf 2016;14(4):419–34. 79. Levey SB, Katz HR, Abrams DA, et al. The role of cultures in the management of ulcer-
39. Kim BY, Riaz KM, Bakhtiari P, et al. Medically reversible limbal stem cell disease: clini- ative keratitis. Cornea 1997;16(4):383–6.
cal features and management strategies. Ophthalmology 2014;121(10):2053–8. 80. Schaefer F, Bruttin O, Zografos L, et al. Bacterial keratitis: a prospective clinical and
40. Jeng BH, Halfpenny CP, Meisler DM, et al. Management of focal limbal stem cell defi- microbiological study. Br J Ophthalmol 2001;85(7):842–7.
ciency associated with soft contact lens wear. Cornea 2011;30(1):18–23. 81. Holden BA, Reddy MK, Sankaridurg PR, et al. Contact lens–induced peripheral ulcers
41. Dua HS, Azuara-Blanco A. Autologous limbal transplantation in patients with unilateral with extended wear of disposable hydrogel lenses: histopathologic observations on the 287.e1
corneal stem cell deficiency. Br J Ophthalmol 2000;84(3):273–8. nature and type of corneal infiltrate. Cornea 1999;18(5):538–43.
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4 silicone hydrogel lens wear. Optom Vis Sci 2014;91(1):3–12.

83. Erie JC, Nevitt MP, Hodge DO, et al. Incidence of ulcerative keratitis in a defined popu-
lation from 1950 through 1988. Arch Ophthalmol 1993;111(12):1665–71.
84. Stern GA. Contact lens–associated bacterial keratitis: past, present, and future. CLAO J
ophthalmic referral hospital: an eight-year retrospective observational study. Am J Oph-
thalmol 2016;168:227–36.
107. Choi DM, Goldstein MH, Salierno A, et al. Fungal keratitis in a daily disposable soft
contact lens wearer. CLAO J 2001;27(2):111–12.
1998;24(1):52–6. 108. Thomas PA. Fungal infections of the cornea. Eye (Lond) 2003;17(8):852–62.
85. Poggio EC, Abelson M. Complications and symptoms in disposable extended wear 109. Prajna NV, Krishnan T, Mascarenhas J, et al. The mycotic ulcer treatment trial: a random-
lenses compared with conventional soft daily wear and soft extended wear lenses. CLAO ized trial comparing natamycin vs voriconazole. JAMA Ophthalmol 2013;131(4):422–9.
J 1993;19(1):31–9. 110. Munir WM, Rosenfeld SI, Udell I, et al. Clinical response of contact lens–associated
86. Nilsson SE, Montan PG. The hospitalized cases of contact lens induced keratitis in fungal keratitis to topical fluoroquinolone therapy. Cornea 2007;26(5):621–4.
Sweden and their relation to lens type and wear schedule: results of a three-year retro- 111. Brown AC, Ross J, Jones DB, et al. Risk factors for Acanthamoeba Keratitis – a
spective study. CLAO J 1994;20(2):97–101. multistate case–control study, 2008–2011. Eye Contact Lens 2017;doi: 10.1097/ICL
87. Dart JK, Stapleton F, Minassian D. Contact lenses and other risk factors in microbial .0000000000000365.
keratitis. Lancet 1991;338(8768):650–3. 112. Shoff ME, Joslin CE, Tu EY, et al. Efficacy of contact lens systems against recent clinical
88. Stapleton F, Carnt N. Contact lens–related microbial keratitis: how have epidemiology and tap water Acanthamoeba isolates. Cornea 2008;27(6):713–19.
and genetics helped us with pathogenesis and prophylaxis. Eye (Lond) 2012;26(2):185–93. 113. Radford CF, Bacon AS, Dart JK, et al. Risk factors for acanthamoeba keratitis in contact
89. Stapleton F, Edwards K, Keay L, et al. Risk factors for moderate and severe microbial lens users: a case-control study. BMJ 1995;310(6994):1567–70.
keratitis in daily wear contact lens users. Ophthalmology 2012;119(8):1516–21. 114. Stehr-Green JK, Bailey TM, Visvesvara GS. The epidemiology of Acanthamoeba keratitis
90. Lim CH, Carnt NA, Farook M, et al. Risk factors for contact lens–related microbial ker- in the United States. Am J Ophthalmol 1989;107(4):331–6.
atitis in Singapore. Eye (Lond) 2016;30(3):447–55. 115. Radford CF, Minassian DC, Dart JK. Acanthamoeba keratitis in England and Wales:
91. Dart JK, Radford CF, Minassian D, et al. Risk factors for microbial keratitis with con- incidence, outcome, and risk factors. Br J Ophthalmol 2002;86(5):536–42.
temporary contact lenses: a case-control study. Ophthalmology 2008;115(10):1647–54, 116. Yeung EY, Huang SC, Tsai RJ. Acanthamoeba keratitis presenting as dendritic keratitis
1654, 1654.e1–3. in a soft contact lens wearer. Chang Gung Med J 2002;25(3):201–6.
92. Stapleton F, Keay L, Edwards K, et al. The incidence of contact lens–related microbial 117. Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis and treatment update
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93. Cohen EJ, Fulton JC, Hoffman CJ, et al. Trends in contact lens–associated corneal 118. Carrijo-Carvalho LC, Sant’ana VP, Foronda AS, et al. Therapeutic agents and biocides
ulcers. Cornea 1996;15(6):566–70. for ocular infections by free-living amoebae of Acanthamoeba genus. Surv Ophthalmol
94. Cohen EJ, Gonzalez C, Leavitt KG, et al. Corneal ulcers associated with contact lenses 2017;62(2):203–18.
including experience with disposable lenses. CLAO J 1991;17(3):173–6. 119. Kwok PW, Kam KW, Jhanji V, et al. Painless Acanthamoeba Keratitis with normal vision.
95. Laibson PR, Cohen EJ, Rajpal RK. Conrad Berens Lecture. Corneal ulcers related to Optom Vis Sci 2017;94(3):432–5.
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96. Liesegang TJ. Contact lens–related microbial keratitis: Part I: epidemiology. Cornea hexidine as monotherapy agents in the treatment of Acanthamoeba keratitis. Am J Oph-
1997;16(2):125–31. thalmol 2008;145(1):130–5.
97. Varaprasathan G, Miller K, Lietman T, et al. Trends in the etiology of infectious corneal 121. Seal DV. Acanthamoeba keratitis update – incidence, molecular epidemiology and new
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98. Fong CF, Tseng CH, Hu FR, et al. Clinical characteristics of microbial keratitis in a 122. Robaei D, Carnt N, Minassian DC, et al. The impact of topical corticosteroid use before
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99. Lam DS, Houang E, Fan DS, et al. Incidence and risk factors for microbial keratitis 123. Iovieno A, Gore DM, Carnt N, et al. Acanthamoeba sclerokeratitis: epidemiology, clini-
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608–18. 124. Mammo Z, Almeida DR, Cunningham MA, et al. Acanthamoeba Endophthalmitis after
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101. Keay L, Edwards K, Naduvilath T, et al. Factors affecting the morbidity of contact lens– treatment. Drug Resist Updat 2004;7(1):41–51.
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4302–8. with the use of cosmetic contact lenses from unlicensed vendors. Eye Contact Lens
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287.e2
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Section 7 Miscellaneous Conditions
Corneal and External Eye

Manifestations of Systemic Disease 4.25
Paula Kataguiri, Kenneth R. Kenyon, Priti Batta, Hormuz P. Wadia, Joel Sugar
Definition: Disorders with corneal, external, and other anterior CONGENITAL DISORDERS
segment manifestations of systemic diseases and syndromes. Congenital disorders are nonmetabolic disorders present at birth that have
generalized systemic features as well as ocular anterior segment abnormal-
ities. These groupings are arbitrary and may change as genetic information
allows for more specific categorizations. Some craniofacial malformation
Key Feature syndromes with associated anterior ocular findings are given in Table
• External and anterior segment ocular anomalies as well as systemic 4.25.1. Given the severity of these disorders, management is multidisci-
abnormalities. plinary and requires a team approach by ophthalmologists, facial plastic
surgeons, neurosurgeons, and others.1–11
Associated Feature CHROMOSOMAL DISORDERS

• Usually genetic defect with multisystem clinical findings. Syndromes consequent to chromosomal disorders are defined by their
abnormal genetic loci (Table 4.25.2). With rapid advances in molecular
genetics, more thorough understanding of relevant regulatory or other
INTRODUCTION gene mechanisms involved will allow for better interpretation of their
widespread, multisystemic (also see Section I: Genetics). A striking finding
As is broadly evident in multiple other ocular and orbital tissues, systemic is that different chromosomal defects may lead to similar phenotypic
disorders commonly exhibit ocular manifestations. Because of the multi- abnormalities.12–16
plicity and complexity of these disorders, this chapter presents these asso-
ciations largely in tabular form. Where known, the causative genetic loci
and resultant metabolic defects are specified. Finally, as many disorders
INHERITED CONNECTIVE TISSUE DISORDERS
are genetically heterogeneous, only the more commonly associated genetic The inherited connective tissue disorders are striking in their musculo-
loci are listed. skeletal manifestations and often serious in their visceral involvements
TABLE 4.25.1 Craniofacial Malformation Syndromes With Corneal Manifestations

Syndrome Protein Defect Gene Locus Ocular Manifestations Systemic Manifestations
Crouzon’s, Apert’s, and Pfeiffer’s Fibroblast growth factor 10q261 Shallow orbits, decreased motility, secondary corneal Craniofacial malformation and syndactyly
receptor-2 exposure (Apert’s)
Meyer–Schwickerath Connexin43 (Cx43) or gap 6q22-q24 Microphthalmos, microcornea, narrow palpebral Syndactyly, dysplastic tooth enamel and
(oculodentodigital dysplasia) junction alpha 1 gene (GJA1) fissures, blue sclera microcephaly
Goldenhar’s (oculoauriculovertebral Limbal dermoids, microphthalmos, anophthalmos, lid Facial asymmetry, vertebral anomalies,
dysplasia) notching, blepharophimosis ear deformities, mandibular hypoplasia
Hallermann–Streiff Connexin43 6q22-24 Microphthalmos, spontaneously resorbing cataracts, Facial malformation, hypoplastic
macular pigment changes, Coats’ disease mandible, short stature, skin atrophy
TABLE 4.25.2 Chromosomal Disorders With Corneal Manifestations

Genetic Findings Ocular Manifestations Systemic Manifestations
13q deletion Hypertelorism, ptosis, epicanthal folds, microphthalmos, Growth retardation, microcephaly, facial malformation, absent thumbs
retinoblastoma
18p deletion Ptosis, epicanthal folds, hypertelorism, corneal opacity, Brachycephaly, growth retardation, mental retardation
keratoconus, microphthalmos, strabismus
18q deletion Hypertelorism, epicanthal folds, nystagmus, corneal opacity, Growth retardation, mental retardation, facial malformation, microcephaly,
microphthalmos, corneal staphyloma, microcornea prostate cancer, hearing loss, endocrine disorders
4p deletion (Wolf–Hirschhorn Hypertelorism, ptosis, microphthalmos, strabismus, cataract Growth retardation, microcephaly, micrognathia, hypotonia seizures, epilepsy
syndrome)
Turner’s syndrome (45×0) Ptosis, epicanthal folds, strabismus, rarely microcornea, blue Female, short stature, webbed neck, hearing loss
sclera, corneal opacity
Trisomy 13 (Patau’s syndrome) Microphthalmos, corneal opacity, Peters’ anomaly, cataract, Microcephaly, cleft lip and palate, low-set ears
retinal dysplasia (Fig. 4.25.1)
Trisomy 18 (Edwards’ syndrome) Corneal opacity, ptosis, hypertelorism, epicanthal folds, Low birth weight; failure to thrive; brain hypoplasia; cardiac, gastrointestinal,
microphthalmos, colobomas, cataract, retinal dysplasia renal, and musculoskeletal anomalies
Trisomy 21 (Down syndrome) Shortened, slanted palpebral fissure, neonatal ectropion, Cardiac defects, mental retardation, short stature, characteristic facies
later trichiasis and entropion, keratoconus, cataract
288 Partial trisomy 22 (cat’s eye syndrome) Microphthalmos, hypertelorism, colobomas Mental retardation, microcephaly, cardiac anomalies, ear anomalies, anal atresia
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4.25
Corneal and External Eye Manifestations of Systemic Disease

R
C
A B C
Fig. 4.25.1 Trisomy 13. (A) Inferior nasal iris coloboma and leukocoria are present. (B) Light microscopy discloses ciliary body coloboma filled with mesenchymal tissue
containing cartilage (C); note the retinal dysplasia (R). (Generally, in trisomy 13, cartilage is present in eyes less than 10 mm in size.) (C) Karyotype shows extra chromosome in
group 13 (arrow). (A, Courtesy Shaffer DB. In: Yanoff M, Fine BS, editors. Ocular pathology, 4th ed. London, UK: Mosby; 1996. C, Courtesy Drs. B. S. Emanuel and W. J. Mellman.)
TABLE 4.25.3 Inherited Connective Tissue Disorders With Corneal Manifestations

Disease Biochemical Defect Gene Locus Ocular Manifestations Systemic Manifestations
Marfan’s syndrome Fibrillin-I gene mutations 15q21.1 Megalocornea, lens subluxation, high myopia, retinal Long extremities, lax joints, aortic/mitral
(FBN1) detachment, microspherophakia dilatation, aortic dissection
Osteogenesis imperfecta Type I procollagen 17q21.31–q22 Blue sclera, keratoconus, megalocornea, optic nerve Bone deformities, recurrent fractures,
COLIA1 7q22.1 compression otosclerosis, dental anomalies
COLIA2
Ehlers–Danlos syndrome type VIA Lysyl hydroxylase lp36.3–p36.2 Blue sclera, keratoconus, keratoglobus, lens subluxation, Skin stretching, scarring joint
myopia, floppy eyelids, ocular fragility to trauma hypermobility, scoliosis, tissue fragility
Ehlers–Danlos syndrome type VIB Normal lysyl hydroxylase Unknown Same as VIA Same as VIA
TABLE 4.25.4 Disorders of Protein and Amino Acid Metabolism

Metabolite Mode of
Disorder Enzyme Deficiency Gene Locus Accumulated Inheritance Ocular Manifestations Systemic Manifestations
Cystinosis Probable defect of 17p13 Cystine Autosomal All forms: conjunctival and corneal cystine Infantile form (90%): renal failure,
lysosomal cysteine CTNS gene recessive crystals deposition, band keratopathy, death
transport protein blepharospasm, photophobia Adolescent form (5%): renal failure,
Infantile and adolescent forms: retinal skeletal deformities
abnormalities, occasional macular changes Adult form or ocular cystinosis
(Fig. 4.25.2) (5%): no renal failure, nonnephro-
pathic ocular form
Tyrosinemia8 type II Tyrosine transaminase 16q22.1–22.3 Tyrosine Autosomal Dendritiform corneal epithelial changes Palmar–plantar hyperkeratosis,
(tyrosinosis, Richner– deficiency recessive (branches or snowflake opacities), red eye, mental retardation, growth
Hanhart syndrome) photophobia retardation, epilepsy
Alkaptonuria Homogentisate-1, 3q21–q23 Homogentisic Autosomal Pigmentation (ochronosis) of sclera near Joint pain and stiffness
2-dioxygenase acid recessive insertion of horizontal rectus muscles, “oil-
droplet” opacities in limbal corneal epithelium
and Bowman’s layer, pigmented pingueculae
Wilson’s disease Defective excretion of 13q14.3–q21.1 Copper Autosomal Kayser–Fleischer ring, “sunflower” cataract (Fig. Liver dysfunction, spasticity,
copper from hepatic (ATP7B recessive 4.25.3) behavior disturbance, nephrotic
lysosomes gene) syndrome
Lattice dystrophy type II Gelsolin gene defect 9q32-34 Amyloid Autosomal Lattice dystrophy, dry eye, light sensitivity, Progressive cranial neuropathy,
(Meretoja’s syndrome) (G654A–Finnish type) or dominant ptosis, glaucoma facial paralysis, cardiac disease
G654T (Danish type)
(Table 4.25.3). More detailed discussions on this topic are featured else- Protein and Amino Acid Metabolic Disorders
where (also see Chapters 4.3, 4.19, and 4.20).17–22
As specified in Table 4.25.4, the accumulated metabolites are sometimes
METABOLIC DISORDERS amenable to treatment. For cystinosis, therapy is accomplished with oral
cysteamine.23–27 In tyrosinemia, dietary therapy (avoiding phenylalanine
Numerous inherited metabolic disorders affect the eye. Frequently autoso- and tyrosine) keeps tyrosine levels controlled.28,29 Vitamin C and nitisi-
mal recessive, these disorders are often consequent to a defect or reduction none may be effective for alkaptonuria.30,31 Chelation therapies to reduce
of a single lysosomal enzyme (hence the broad term lysosomal storage dis- elevated ceruloplasmin levels in Wilson’s disease utilize D-penicillamine
eases [LSDs]) resulting in accumulation of metabolites in multiple affected and trientine.32–36
tissues. For many disorders, the specific genetic defect has been identified,
and for some (notably Fabry’s disease) synthesis of the defective enzyme Mucopolysaccharidoses
has facilitated enzyme replacement therapy. In contrast to most corneal
dystrophies, corneas affected by metabolic disorders demonstrate abnor- The mucopolysaccharidoses (MPSs) comprise the quintessential LSDs
mality in multiple cell types, affect the peripheral cornea as well as the because their hydrolytic enzyme defects result in progressive intralyso- 289
central cornea, and may be progressive. somal (and eventual extracellular) storage of mucopolysaccharides (more
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4 E
A B
Fig. 4.25.2 Cystinosis. (A) Myriad tiny opacities are highly reflective. (B) Light microscopy of unstained corneal section viewed with polarization demonstrates birefringent
cystine crystals (C); E, epithelium. (A, Courtesy Shaffer DB. In: Yanoff M, Fine BS, editors. Ocular pathology, 4th ed. London, UK: Mosby; 1996.)
A B
Fig. 4.25.3 Wilson’s Disease. (A) Annular deposition (Kayser–Fleischer ring) of golden brown–appearing copper in the periphery of Descemet’s membrane partially
obstructs the view of the underlying iris. Disciform “sunflower” cataract is also present. (B) Light microscopy of unstained section shows copper deposition (arrow) in the
inner portion of peripheral Descemet’s membrane. (Modified from Tso MOM, Fine BS, Thorpe HE. Kayser–Fleischer ring and associated cataract in Wilson’s disease. Am J
Ophthalmol 1975;79:479–88.)
properly termed glycosaminoglycans) (Table 4.25.5), often with variably Hence the accumulation of oligosaccharides and gangliosides result in alter-
profound skeletal and mental consequences. Corneal clouding in varying ations common to both mucopolysaccharidoses and sphingolipidoses.67–70
degrees and patterns, as well as retinal pigmentary degenerations, are the
hallmarks of MPS disorders caused by accumulation of heperan, keratan,
and dermatan sulfates.37–52
OTHER OCULOSYSTEMIC DISORDERS
Apart from the above specified disorders, numerous other systemic dis-
Sphingolipidoses eases have ocular manifestations, and they may be grouped accordingly.
Thus corneorenal syndromes are a disparate group of disorders in which
Also considered LSDs, the sphingolipidoses arise from dysfunction of corneal abnormalities combine with renal disease (Table 4.25.9).71–79
catabolic enzymes, with consequent accumulation of sphingolipids (Table Corneohepatic syndromes are less common (Table 4.25.10).80–83 Oculocu-
4.25.6).53–59 Notable among sphingolipidoses are Tay–Sachs and Niemann– taneous disorders are numerous, and here only the more prominent are
Pick diseases, which are not included as they lack major anterior segment specified (Table 4.25.11).84,85
manifestations.
CONCLUSIONS
Dyslipoproteinemias This largely tabular overview of systemic diseases with corneal, external,
The dyslipoproteinemias (Table 4.25.7) comprise a somewhat diverse group and other anterior segment involvements emphasizes broad manifesta-
of disorders resulting from the multiplicity of lipid metabolic processes tions of specific diseases and thus the critical importance of evaluating
and pathways. In the anterior eye, they variably manifest as eyelid xan- and managing the whole patient and not overfocusing on the eye alone.
thelasmas, corneal arcus, and corneal clouding.60–66 As understanding of the basic disease mechanisms increases, new thera-
peutic interventions will be instituted. One such current strategy includes
Mucolipidoses enzyme replacement therapy, as for example, alpha-L-iduronidase infu-
sions have benefited the mobility of children with MPS type I,39 and
The mucolipidoses (Table 4.25.8) are LSDs whose enzyme defects occur at alpha-galactosidase has helped alleviate clinical symptoms in patients with
the intersection of both glycoprotein and glycolipid metabolic pathways. Fabry’s disease.72
290
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Fig. 4.25.5 Fabry’s Disease. Verticillate changes radiate in the superficial cornea of
Fig. 4.25.4 Mucopolysaccharidosis. In Hurler–Scheie syndrome (MPS I-H/S) the a female carrier.
cornea is diffusely clouded. (Courtesy Shaffer DB. In: Yanoff M, Fine BS, editors.
Ocular pathology, 4th ed. London, UK: Mosby; 1996.)
TABLE 4.25.5 Mucopolysaccharidoses (MPS)

Metabolite
Disorder Enzyme Deficiency Accumulated Mode of Inheritance Gene Locus Ocular Manifestations Systemic Manifestations
Mucopolysaccharidosis α-L-Iduronidase Heparan sulfate Autosomal recessive 4p16.3 Corneal clouding, pigmentary Gargoyle facies, mental
I-H (Hurler) (IDUA gene) Dermatan sulfate retinopathy, optic atrophy, retardation, dwarfism, skeletal
Glycosaminoglycans trabecular involvement dysplasia, valvular heart
(GAGs) disease, hepatosplenomegaly
Mucopolysaccharidosis α-L-Iduronidase Heparan sulfate Autosomal recessive 4p16.3 Corneal clouding, pigmentary Coarse facies, claw-like hands,
I-S (Schieie’s, previously Dermatan sulfate retinopathy, optic atrophy, aortic valve disease
MPS V) glaucoma
Mucopolysaccharidosis α-L-Iduronidase Heparan sulfate Autosomal recessive 4pl6.3 Corneal clouding, pigmentary More severe than I-S, less
I-H/S (Hurler–Scheie; Fig. Dermatan sulfate retinopathy, optic atrophy severe than I-H
4.25.4)
MPS II (Hunter’s) Iduronate sulfate Heparan sulfate X-linked recessive Xq28 Rare corneal clouding, Similar to I-H with less bony
sulfatase (iduronate Dermatan sulfate pigmentary retinopathy, deformity
sulfatase) optic atrophy
MPS III (Sanfilippo’s) Variable, depending Heparan sulfate Autosomal recessive 17q25.3 17q21.1 All forms: clinically clear All forms: mild dysmorphism,
on type 12q14 cornea, occasional slit-lamp progressive dementia, hearing
Chr #14 corneal opacities pigmentary loss, behavior issues
retinopathy, optic atrophy
MPS IV (Morquio’s) A: galactose-6-sulfatase Keratan sulfate, Autosomal recessive 16q24.3 Corneal clouding, optic Severe bony deformity,
B: β-galactosidase chondroitin-6 sulfate Autosomal recessive 3p21.33 atrophy aortic valve disease, normal
intelligence
MPS VI (Maroteaux–Lamy) N-acetylgalactosamine- Dermatan sulfate Autosomal recessive 5q11–q13 Corneal clouding, optic Similar to I-H, but normal
4-sulfatase atrophy intellect
MPS VII (Sly’s) β-glucuronidase Dermatan sulfate Autosomal recessive 7q21.1 Corneal clouding Similar to I-H
Heparan sulfate
TABLE 4.25.6 The Sphingolipidoses

Disorder Enzyme Deficiency Gene Locus Metabolite Accumulated Mode of Inheritance Ocular Manifestations Systemic Manifestations
GM2 gangliosidosis II Hexosaminidase B, 5q13 Ganglioside GM2 Autosomal recessive Membrane-bound vacuoles within Psychomotor retardation,
(Sandhoff’s disease) HEX B chain corneal keratocytes, cherry-red hepatosplenomegaly,
macula Mongolian spots (unusual)
Metachromatic Arylsulfatase A 22q13.31-qter Sulfatide Autosomal recessive Corneal clouding Mental retardation, seizures
leukodystrophy isozymes
(Austin’s juvenile form)
Fabry’s disease α-Galactosidase A Xq22 Ceramide trihexoside X-linked recessive Conjunctival and retinal vascular Renal failure, peripheral
tortuosity, anterior subcapsular lens neuropathy, hypo/
opacities, oculomotor abnormalities, hyperhidrosis, hypoacusis
cornea verticillata (Fig. 4.25.5)
Gaucher’s disease Glucocerebrosidase Iq21 Glucocerebrosidase Autosomal recessive Prominent pinguiculae, white Hepatosplenomegaly, bone
corneal epithelial deposits, vitreous pain, anemia
opacities, paramacular gray ring
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TABLE 4.25.7 The Dyslipoproteinemias
Disorder Deficiency Gene Locus Metabolite Accumulated Mode of Inheritance Ocular Manifestations Systemic Manifestations
Lecithin–cholesterol Lecithin–cholesterol 16q22.1 Free cholesterol Autosomal recessive Dense peripheral arcus, Atherosclerosis,
acyltransferase (LCAT) acyltransferase gray dots in central xanthomas, premature

deficiency stroma, no visual coronary artery disease,
changes hepatosplenomegaly,
anemia, renal
insufficiency
Fish eye disease (high- α-Lecithin–cholesterol 16q22.1 Triglycerides, very low Autosomal dominant Progressive corneal None
density lipoprotein acyltransferase density lipoproteins clouding, increased
lecithin–cholesterol (VLDL); low-density corneal thickness
acyltransferase) lipoproteins (LDL)
Tangier’s disease High-density lipoprotein 9q22–q31 Triglycerides; low Autosomal recessive Fine dot corneal clouding, Lymphadenopathy
(analphalipoproteinemia) (ABCA1 gene) levels of high-density severe visual loss, hepatosplenomegaly,
lipoproteins (HDL), incomplete eyelid coronary artery disease
cholesterol and closure, ectropion, no
phospholipids arcus
Hyperlipoproteinemia I Lipoprotein lipase 8p22 Triglycerides, Autosomal recessive Lipemia retinalis, palpebral Xanthomas
(hyperchylomicronemia) chylomicrons eruptive xanthomata
Hyperlipoproteinemia II, LDL receptor (type 19p13 (type IIa); Type IIa: LDL, cholesterol Autosomal dominant Both forms: corneal arcus, Coronary artery disease
hyper-β-lipoproteinemia IIa); defective lipid 1q21-23 (type Type IIb: LDL, conjunctival xanthomata,
IIA, hyper-β- metabolism in type IIb IIb); others VLDL, cholesterol, xanthelasma
lipoproteinemia IIb triglycerides
Hyperlipoproteinemia III (dys- Abnormality in 19q13.2 VLDL remnants, Autosomal Arcus, xanthelasma, Peripheral vascular
β-lipoproteinemia; broad apolipoprotein E cholesterol, recessive with lipemia retinalis disease, diabetes
β-disease) triglycerides pseudo-dominance mellitus
Hyperlipoproteinemia Lipoprotein lipase; 15q11-13; 21q11; Triglycerides, VLDL Autosomal dominant Arcus, xanthelasma, Vascular disease, diabetes
IV (hyperpre-β- apolipoprotein A others lipemia, retinalis mellitus
lipoproteinemia)
Hyperlipoproteinemia V Apolipoprotein A 11q23 VLDL, chylomicrons Uncertain Lipemia retinalis, no arcus Xanthomas,
(hyperprelipoproteinemia hepatosplenomegaly
and hyperchylomicronemia)
TABLE 4.25.8 Mucolipidoses (Ml)

Disorder Enzyme Deficiency Gene Locus Metabolite Accumulated Mode of Inheritance Ocular Manifestations Systemic Manifestations
ML I (dysmorphic Glycoprotein sialidase 6p.21.3 Sialyl-oligosaccharides Autosomal recessive Macular cherry-red spot, tortuous retinal Coarse facies, hearing
sialidosis, Spranger’s (neuraminidase I) and conjunctival vessels, spoke-like lens loss, normal IQ
syndrome) opacities, progressive corneal clouding
ML II (I-cell disease) GluNac-I- 4q21–q23 Increased plasma Autosomal recessive Small orbits, hypoplastic supraorbital MPS I-H facies, mental
phosphotransferase lysosomal hydrolases ridges and prominent eyes, glaucoma, retardation
megalocornea, corneal clouding
ML III (pseudo-Hurler’s GluNac-I- 4q21–q23 Increased plasma Autosomal recessive Corneal clouding Milder growth and
polydystrophy) phosphotransferase lysosomal hydrolases mental retardation
ML IV (Berman’s Possible ganglioside 19p13.3–p13.2 Sialogangliosides Autosomal recessive Corneal clouding retinal degeneration Slowed psychomotor
syndrome) sialidase development
Galactosialidosis β-Galactosidase 20q13.1 Sialyl-oligosaccharides Autosomal recessive Macular cherry-red spot, diffuse mild Seizures, mental
(Goldberg’s syndrome) Neuraminidase corneal clouding, conjunctival retardation, hearing
telangiectases loss, hemangiomas
TABLE 4.25.9 Corneorenal Syndromes

Syndrome Gene Locus Ocular Manifestations Systemic Manifestations
Alport’s Xq22.3 COL4A5 Posterior polymorphous corneal dystrophy, juvenile Renal failure, hearing loss, lamellated glomerular basement
2q36–q37 arcus, pigment dispersion, lenticonus, retinal membrane
COL4A3-COL4A4 pigmentary changes
Cystinosis 17p13 (See Fig. 4.25.2) Infantile form: renal failure, death
Intermediate form: renal failure
Adult form: no renal failure
Fabry’s disease Xq22 (See Fig. 4.25.5) Renal failure, peripheral neuropathy, angiokeratomas
(See Table 4.25.6)
Lowe’s syndrome Xq26.1 Corneal keloids, glaucoma, congenital cataracts Mental retardation, amino acid urea, tubular acidosis,
(oculocerebrorenal) angiokeratomas, muscle hypotonia, subcutaneous nodules,
artropathy
Wegener’s granulomatosis Nongenetic Marginal keratitis, orbital disease, scleritis, episcleritis Granulomatous vasculitis of lungs, kidneys, nasopharynx
WAGR 11p13 Superficial corneal opacity and vascularization, aniridia, Wilms’ tumor, mental retardation, craniofacial anomalies,
glaucoma, foveal hypoplasia, optic nerve hypoplasia growth retardation
Zellweger’s 2p15(PEX 13)lq2212p 13.3 (PEX 5) Axenfeld’s anomaly, corneal clouding, glaucoma, retinal Craniofacial anomalies, hypotonia seizures, retardation,
7q21–q22(PEX1) degeneration hepatic degeneration, cystic kidneys, cardiac defects, early
6q23–q24 death
292 WAGR, Wilms’ tumor, aniridia, genital anomalies, and mental retardation.
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TABLE 4.25.10 Corneohepatic Syndromes
Syndrome Gene Locus Ocular Manifestations Systemic Manifestations
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Wilson’s disease 13q14.3–21.1 Kayser–Fleisher ring (see Fig. 4.25.3) Liver dysfunction; neurological dysfunction with

dysarthria, spasticity, behavior disturbances
Zellweger’s syndrome 7q21–q22 (See Table 4.25.9) (See Table 4.25.9)
Alagille’s syndrome 20p11.2–p12 Posterior embryotoxon, anterior chamber anomalies, eccentric or Cholestatic liver disease, structural heart defects,
ectopic pupils, chorioretinal atrophy, retinal pigment clumping butterfly vertebrae
TABLE 4.25.11 Oculocutaneous Disorders

Syndrome Protein Defect Gene Locus Ocular Manifestations Cutaneous/Systemic Manifestations
Basal cell nevus syndrome PTCH1 protein 9q22.3, 9q31, lp32 Multiple basal cell carcinomas of the eyelid, Multiple basal cell carcinomas, jaw cysts,
hypertelorism bony anomalies
Xeroderma pigmentosum Nucleotide excision repair (NER 9q22, 2q21, 3p25, 19q13, 11p12, Lid neoplasms, conjunctival and corneal Basal cell carcinoma, squamous cell
(seven types, A–G, plus enzymes (types A-G); DNA 16p13, 13q33, 6p21 neoplasia, corneal exposure, drying carcinomas, and malignant melanomas
variant type V) polymerase (type V) develop in sun-exposed areas
Ichthyosis (multiple types) Filaggrin (ichthyosis vulgaris); lq21(vulgaris),12q11–q13, Eyelid and lash scaling (all types), ectropion Scaly skin
others 14q11.2, X922.32, 19p 12–q12 with corneal exposure (lamellar ichthyosis)
Keratitis–ichthyosis– Connexin-26 13q11-12 Keratoconjunctivitis with corneal pannus Ichthyosis, deafness
deafness syndrome formation
Ectrodactyly–ectodermal TP63 (p63 gene) 3q27-28 Dysplasia of meibomian glands, blepharitis, Lobster-claw deformity of hands and feet,
dysplasia–clefting corneal pannus formation, corneal scarring ectodermal dysplasia, cleft lip and palate
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alkaptonuria. Nat Genet 1996;14(1):19–24. mutant isoforms responsible for mucolipidosis type IV. Nat Commun 2014;5:4681.
31. Arnoux J-B, Le Quan Sang K-H, Brassier A, et al. Old treatments for new insights and 70. Wraith JE. Mucopolysaccharidoses and Mucolipidoses, vol. 113. 1st ed. Elsevier B.V.; 2013.
strategies: proposed management in adults and children with alkaptonuria. J Inherit p. 1723–9. doi:10.1016/B978-0-444-59565-2.00042-3.
Metab Dis 2015;38(5):791–6. 71. Mohan S, Gupta P, Sahai K, et al. Phacoemulsification in a rare case of Alport’s syn-
32. Thomas GR, Roberts EA, Walshe JM, et al. Haplotypes and mutations in Wilson disease. drome. Semin Ophthalmol 2014;29(4):196–8.
Am J Hum Genet 1995;56(6):1315–19. 72. Schiffmann R, Martin RA, Reimschisel T, et al. Four-year prospective clinical trial of
33. Hedera P. Update on the clinical management of Wilson’s disease. Appl Clin Genet alpha galactosidase in children with Fabry disease. J Pediatr 2010;156(5):832–837.e1.
2017;10:9–19. 73. Ersoz MG, Ture G. Cilioretinal artery occlusion and anterior ischemic optic neuropathy
34. Haltia M, Levy E, Meretoja J, et al. Gelsolin gene mutation—at codon 187—in familial as the initial presentation in a child female carrier of Fabry disease. Int Ophthalmol
amyloidosis, finnish: DNA-diagnostic assay. Am J Med Genet 1992;42(3):357–9. 2018;38(2):771–3.
35. Mattila JS, Krootila K, Kivelä T, et al. Penetrating keratoplasty for corneal amyloidosis in 74. Arends M, Wanner C, Hughes D, et al. Characterization of classical and nonclassical
familial amyloidosis, Finnish type. Opthalmology 2015;122(3):457–63. Fabry disease: a multicenter study. J Am Soc Nephrol 2017;28(5):1631–41.
36. Weiss JS, Møller HU, Aldave AJ, et al. IC3D classification of corneal dystrophies–edition 75. Bökenkamp A, Ludwig M. The oculocerebrorenal syndrome of Lowe: an update. Pediatr
2. Cornea 2015;34(2):117–59. Nephrol 2016;31(12):2201–12.
37. Scott HS, Ashton LJ, Eyre HJ, et al. Chromosomal localization of the human alpha-L-idu- 76. Ebrahimiadib N, Modjtahedi BS, Roohipoor R, et al. Successful treatment strategies
ronidase gene (IDUA) to 4p16. 3. Am J Dis Child 1990;45(5):802–27. in granulomatosis with polyangiitis-associated peripheral ulcerative keratitis. Cornea
38. Raymond GV, Pasquali M, Polgreen LE, et al. Elevated cerebral spinal fluid biomarkers 2016;35(11):1459–65.
in children with mucopolysaccharidosis I-H. Sci Rep 2016;6:38305. 77. Cocho L, Gonzalez-Gonzalez LA, Molina-Prat N, et al. Scleritis in patients with granulo-
39. Horovitz DD, Acosta AX, Giugliani R, et al. Alternative alpha iduronidase dose regimen matosis with polyangiitis (Wegener). Br J Ophthalmol 2016;100(8):1062–5.
for patients with mucopolysaccharidosis I: a multinational, retrospective, chart review 78. Tarabishy AB, Schulte M, Papaliodis GN, et al. Wegener’s granulomatosis: clinical man-
case series. Orphanet J Rare Dis 2016;11(1):51. ifestations, differential diagnosis, and management of ocular and systemic disease. Surv
40. Javed A, Aslam T, Jones SA, et al. Objective quantification of changes in corneal cloud- Ophthalmol 2010;55(5):429–44.
ing over time in patients with mucopolysaccharidosis. Invest Ophthalmol Vis Sci 79. Netland PA, Scott ML, Boyle JW, et al. Ocular and systemic findings in a survey of
2017;58(2):954–8. aniridia subjects. J AAPOS 2011;15(6):562–6.
41. Ohden KL, Pitz S, Ashworth J, et al. Outcomes of keratoplasty in the mucopolysaccha- 80. Pandey MK, Burrow TA, Rani R, et al. Complement drives glucosylceramide accumula-
ridoses: an international perspective. Br J Ophthalmol 2017;101(7):909–12. tion and tissue inflammation in Gaucher disease. Nature 2017;543(7643):108–12. 293.e1
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81. Mistry PK, Lopez G, Schiffmann R, et al. Gaucher disease: progress and ongoing chal- 84. Kalamkar C, Radke N, Mukherjee A, et al. Xeroderma pigmentosum with bilateral
4 lenges. Mol Genet Metab 2017;120(1–2):8–21.

82. Hol FA, Hamel B, Geurds M, et al. Localization of Alagille syndrome to 20p11. 2-p12 by
linkage analysis of a three-generation family. Hum Genet 1995;95(6):687–90.
83. Chitayat D, Kamath B, Saleh M. Alagille syndrome: clinical perspectives. Appl Clin Genet
ocular surface squamous neoplasia and review of the literature. BMJ Case Rep 2016:
bcr2016215364–3.
85. Black JO. Xeroderma pigmentosum. Head Neck Pathol 2016;10(2):139–44.
2016;9:75–82.
293.e2
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Section 8 Trauma
Acid and Alkali Burns

Naveen K. Rao, Michael H. Goldstein 4.26
damaging the stroma and the endothelium, as well as intraocular struc-
Definition: Chemical exposure to the eye resulting in trauma ranging tures, such as the iris, lens, and ciliary body. Common causes of alkali
from mild irritation to severe damage of the ocular surface and anterior injury include ammonia (NH3), lye (NaOH), lime (CaOH]2), potassium
segment with permanent vision loss. hydroxide (KOH), and magnesium hydroxide (Mg(OH)2).5,7,10,11 Lime,
found in cement and plaster, is the most common cause of alkali injury.
Damage from lime injury is limited, however, because of the precipita-
tion of calcium soaps that limit further penetration. Lye and ammonia are
Key Features associated with the most severe alkali injuries. Ammonia can be detected
• Alkali burns typically are more severe than acid burns. in the anterior chamber with a rise in aqueous humor pH within seconds
• Acute management directed at eliminating the causative agent. of exposure.12,13 Irreversible intraocular damage has been noted to occur at
• Initial evaluation includes assessment of degree of corneal epithelial aqueous pH levels of 11.5 or greater.14
injury, corneal opacity, and limbal ischemia.
ACID INJURIES
Acids cause superficial damage but generally cause less severe ocular injury
Associated Feature than alkalis, as the immediate precipitation of epithelial proteins offers
• Limbal stem cell deficiency, corneal opacification, corneal some protection by acting as a barrier to intraocular penetration.15 Very
perforation, glaucoma, symblepharon, cicatricial entropion, trichiasis, strong or concentrated acids, however, can penetrate the eye just as readily
fibrovascular pannus. as alkaline solutions. Sulfuric (H2SO4), sulfurous (H2SO3), hydrochloric
(HCl), nitric (HNO3), acetic (CH3COOH), formic (CH2O2), and hydroflu-
oric (HF) acids are frequent causes of acid burns.10 The most common
INTRODUCTION cause is sulfuric acid, which is found in industrial cleaners and automobile
batteries. Hydrofluoric acid causes the most serious acid injuries because
Chemical exposure to the eye can result in trauma ranging from mild irri- of its low molecular weight, which allows easier stromal penetration.16 The
tation to severe damage of the ocular surface and anterior segment with injury may be compounded by thermal burns from heat generated by the
permanent vision loss. Chemical burns constitute 7.7%–18% of all ocular acid’s reaction with water on the tear film.11
trauma.1-4 The majority of victims are young men.5–7 Injuries usually are
caused by accidents at work or home but also may be deliberately caused
by assault.5–9 Many victims report not wearing proper eye protection at the
PATHOPHYSIOLOGY
time of the injury.7 In the household setting, numerous chemicals exist in The severity of ocular injury from alkali or acid is related to the type of
the form of solutions in automobile batteries, pool cleaners, detergents, chemical, the concentration of the solution, the surface area of contact,
ammonia, bleach, and drain cleaners. Although most injuries caused by the duration of exposure, and the degree of penetration. The hydroxyl ion
these are mild with minimal sequelae, but in severe cases, management (OH−) of alkaline solutions saponifies fatty acids in cell membranes leading
can be a challenge (Fig. 4.26.1). to cell lysis, with subsequent hydrolysis and denaturation of proteoglycans
and stromal collagen.17,18 The hydrogen ion (H+) of acidic solutions alters
ALKALI INJURIES the pH, whereas the anion causes protein binding and precipitation in the
corneal epithelium and superficial stroma.19 This protein precipitation pro-
Alkali injuries occur more frequently and are more severe than acid inju- duces the typical ground-glass appearance of the epithelium and acts as a
ries.1,5–8 Alkalis penetrate more readily into the eye compared with acids, barrier to further penetration. If penetration of either alkali or acid occurs,
the hydration of glycosaminoglycans leads to loss of stromal clarity. Loss
of proteoglycans from the stroma results in shrinkage of collagen and can
lead to an acute rise in intraocular pressure (IOP) as a result of distortion
of the trabecular meshwork.20 The release of prostaglandins also contrib-
utes to the rise in IOP following alkali and acid injuries.19,21,22 Chemical
penetration into the eye may acutely damage stromal keratocytes, stromal
nerve endings, corneal endothelium, iris, trabecular meshwork, and ciliary
body.17,19
In addition to corneal and intraocular injury, chemical burns result in
damage to the conjunctiva, limbus, and eyelids.23 Damage to palpebral
and bulbar conjunctiva can lead to loss of goblet cells and chronic dry eye
disease.17 Ischemic necrosis of the conjunctiva causes loss of vasculariza-
tion at the limbus and loss of limbal stem cells, as well as infiltration of
leukocytes.17,19,24 Damage to the corneal epithelium with injury solely to
Bowman’s layer and anterior stroma may lead to recurrent corneal ero-
sions. Damage to the limbal stem cells, however, can result in persistent
corneal epithelial defects, conjunctivalization of the cornea, presence of
goblet cells within the corneal epithelium, and superficial and deep neo-
vascularization.19,23 Late sequelae of severe burns include cicatrization of
the conjunctiva with symblepharon formation and entropion.19 Coagula-
294 Fig. 4.26.1 Complete corneal vascularization and opacification in patient with tion of the posterior lid margin may cause posterior displacement of mei-
previous alkali injury. (Courtesy Anthony J. Aldave, MD.) bomian gland orifices with trichiasis.17
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TABLE 4.26.1 Roper-Hall Classification TABLE 4.26.2 Dua Classification
Grade Prognosis Conjunctival Involvement Corneal Involvement Conjunctival
4.26
I Good None Epithelial damage Grade Prognosis Limbal Involvement Involvement Analog Scale

II Good Less than 33% limbal Stromal haze present but iris details I Very good 0 clock hours (none) 0% (none) 0.0%
ischemia visible II Good Less than 3 clock hours <30% 0.1–3/1–29.9%
III Guarded 33%–50% limbal ischemia Total epithelial loss, stromal haze III Good 3–6 clock hours >30%–50% 3.1–6/31–50%
obscures iris details IV Good to guarded 6–9 clock hours >50%–75% 6.1–9/51%–75%
IV Poor Greater than 50% limbal Cornea opaque, iris and pupil obscured V Guarded to poor 9–<12 clock hours >75%–< 100% 9.1–11.9/75.1–99.9%
ischemia
VI Very poor 12 clock hours (total) 100% (total) 12/100%
From Roper-Hall MJ. Thermal and chemical burns. Trans Ophthalmol Soc UK 1965;85:631–53.
From Dua HS, King AJ, Joseph A. A new classification of ocular surface burns. Br J Ophthalmol
2001;85:1379–83.
After a chemical burn, breakdown of the blood–aqueous barrier may

result in a severe fibrinous inflammatory reaction. Damage to the ciliary In 2001, Dua proposed a new classification system (Table 4.26.2)
body epithelium can cause decreased secretion of ascorbate, resulting in accounting for more recent advances in surgical treatment of ocular
impaired keratocyte collagen synthesis and deficient stromal repair because surface burns and the resultant limbal stem cell deficiency.34 This system is
ascorbate is a cofactor in the rate-limiting step in collagen synthesis.25 based on clock hours of limbal involvement and percentage of total bulbar
Within 12–24 hours of injury, conjunctival necrosis and hydrolysis of conjunctival involvement, and unlike the Roper-Hall classification system,
cellular and extracellular proteins produce chemotactic inflammatory is not based on the degree of corneal stromal haze.34,35 The Dua classifica-
mediators that stimulate the infiltration of the peripheral cornea with neu- tion system subdivides grade IV Roper-Hall injuries into three additional
trophils.1,17,26 The neutrophils potentiate surface inflammation and release categories (grades IV, V, and VI) and provides more up-to-date prognostic
a variety of degradative enzymes such as N-acetylglucosaminidase and information for the most severe ocular surface burns.34–37 It also includes
cathepsin-D.24 Damage to the corneal stroma is mediated by the interac- an analog scale, which allows for more nuanced and flexible recording of
tion among keratocytes, epithelial cells, and neutrophils. Stromal repair injury severity.37
is marked by a balance between collagen synthesis and degradation.27 Ker-
atocytes are multipotent cells capable of producing new type I collagen
as well as type I collagenase, a matrix metalloproteinase (MMP).28 MMPs
THERAPY
are enzymes that can degrade matrix macromolecules, such as collagen. Immediate Phase
The three major groups of MMPs include collagenases, gelatinases, and
stromelysins.27 Keratocyte activity may be regulated by cytokines from epi- Because the area and duration of contact determines the extent of subse-
thelial cells, inflammatory cells, and other keratocytes. A close interaction quent injury and prognosis, immediate copious irrigation upon exposure
exists between keratocytes and the overlying epithelial cells; type I collage- is of paramount importance.12 Irrigation should be continued for at least
nase production by keratocytes is both stimulated and inhibited by epithe- 15 minutes with at least 1 L of irrigant, until the pH of the ocular surface
lial cytokines.29,30 reaches neutrality. Currently available solutions include normal saline,
borate-buffered saline, balanced salt solution, phosphate-buffered saline,
CLINICAL COURSE lactated Ringer’s, and amphoteric solutions that aim to chelate acids and
alkalis and create a reverse osmotic gradient to draw chemicals out of
McCulley divided the course of chemical injury into four distinct phases: the cornea.12,38,39 Some authors discourage the use of phosphate-buffered
immediate, acute (0–7 days), early reparative (7–21 days), and late repar- saline, which may lead to precipitation of calcium in the corneal stroma.39
ative (after 21 days).16 Clinical findings immediately following chemical Borate-buffered saline and amphoteric solutions were found to be most
exposure can be used to assess the severity and prognosis of the injury. effective in reducing aqueous humor pH after an alkali burn.38,39 Normal
The Roper-Hall classification system (Table 4.26.1) provides a prognostic saline and tap water were found to be intermediately effective, and phos-
guideline based on corneal appearance and extent of limbal ischemia.7,31,32 phate buffered saline and lactated Ringer’s were found to have the least
In grade I injury, there is corneal epithelial damage, no corneal opacity, effective buffering capacity.39,40 If access to commercial irrigating solu-
no limbal ischemia, and a good prognosis. In grade II injury, the cornea tions is not immediately available, tap water should be used despite the
is hazy but iris details are visible. Ischemia involves less than one third of fact that it is hypo-osmolar and may contribute to corneal edema.12 If
the limbus, and the prognosis is good. In grade III injury, there is total an acid burn is suspected, a base should never be used for irrigation in
epithelial loss, stromal haze obscuring iris details, and ischemia of one an effort to neutralize the acid. A retained reservoir of chemical in the
third to one half of the limbus, and the prognosis is guarded. In grade IV fornices should be suspected if neutrality cannot be achieved, especially
injury, the cornea is opaque with no view of the iris or pupil, the ischemia with exposure to lime, which can be embedded in the fornices and the
is greater than one half of the limbus, and the prognosis is poor. upper tarsal conjunctiva.33 Eversion of the lids and removal of particulate
In the acute phase during the first week, grade I injuries heal, whereas matter should be performed; a cotton-tipped applicator soaked in ethylene-
in grade II injuries, corneal clarity is recovered slowly. Grade III and IV diaminetetraacetic acid 1% may help with the removal of stubborn lime
injuries have little or no re-epithelization, with no collagenolysis or vascu- particles.41 Necrotic corneal and conjunctival tissues should be debrided to
larization. IOP may be elevated as a result of inflammation and mechan- promote re-epithelization because this debris provides a stimulus for con-
ical distortion of the trabecular meshwork or decreased because of ciliary tinued inflammation with recruitment of neutrophils and mucous mem-
body damage.33 During the early reparative phase, re-epithelization is com- brane pemphigoid production.41
pleted in grade II injury, with clearing of opacification. In more severe
cases, delayed or arrested re-epithelization may occur. Keratocyte prolif- Acute and Reparative Phases
eration occurs with production of collagen and collagenase, resulting in
progressive thinning and potential for perforation.33 After irrigation, all efforts should be made to promote epithelial wound
In the late reparative phase, re-epithelization patterns divide injured healing, prevent infection, reduce inflammation, minimize ulceration, and
eyes into two groups. In the first group, epithelization is complete or is control intraocular pressure. Topical antibiotics should be used if there is
nearly complete, with sparing of limbal stem cells. Corneal anesthesia, any corneal or conjunctival epithelial defect. Topical and systemic ocular
goblet cell and mucin abnormalities, and irregular epithelial basement hypotensive medications may be needed. Better outcomes can be expected
membrane regeneration may persist. In the second group, limbal stem cell with prompt re-epithelization, while delayed or absent re-epithelization
damage is present, resulting in corneal re-epithelization by conjunctival may require surgical intervention. Bandage contact lenses or amniotic
epithelium. This group has the worst prognosis with severe ocular surface membrane transplantation may be used to promote epithelial healing.35,36
damage characterized by vascularization and scarring, goblet cell and Intensive topical corticosteroid therapy every 1–2 hours in the first 1–2
mucin deficiency, and recurrent or persistent erosions.33 Ocular surface weeks decreases the inflammatory response that can delay epithelial
abnormalities may be exacerbated by symblepharon formation, cicatricial migration, and thus helps enhance re-epithelization in the early phases
entropion, and trichiasis.19,23 A fibrovascular pannus results if ulceration of injury.7,42 Corticosteroid use in the first 10 days of injury has no adverse 295
does not occur, compromising visual rehabilitation. effect on outcome with little risk of sterile ulceration.43 Prolonged use of
booksmedicos.org
corticosteroids, however, can be deleterious since corticosteroids can blunt room is either not possible or impractical, a sutureless cryopreserved
4 stromal wound repair by decreasing keratocyte migration and collagen

synthesis.44 Beyond 2 weeks at the peak of the early reparative phase, sup-
pression of keratocyte collagen production by continued use of corticoster-
amniotic membrane patch is commercially available preloaded in a sym-
blepharon ring and can be easily inserted in the office or at the bedside.62
Freeze-dried amniotic membrane preparations also are available and can
oids may offset the benefits of inflammatory suppression and lead to be placed on the cornea under a bandage contact lens.
stromal ulceration.44,45 Corticosteroid use should, therefore, be stressed in Penetrating keratoplasty (PKP) and deep anterior lamellar keratoplasty
the first 2 weeks with subsequent taper as dictated by clinical examina- (DALK) for visual rehabilitation after chemical injury can be fraught with
tion. Medroxyprogesterone 1% is a synthetic progestogenic corticosteroid complications. Prognosis is poor in the setting of glaucoma, hypotony,
that has weaker anti-inflammatory activity compared with corticosteroids. limbal stem cell dysfunction, conjunctival cicatrization, entropion, and
Medroxyprogesterone inhibits collagenase, but unlike corticosteroids, it trichiasis.19 If intraocular complications are minimized in the setting of
minimally suppresses stromal wound repair.44 As such, medroxyproges- an optimized ocular surface and limited deep stromal vessels, PKP or
terone can be substituted for corticosteroid after 10–14 days if worsening DALK may be performed with favorable results. A large-diameter PKP
ulceration is of concern. with or without donor limbal tissue may be considered in the acute and
Topical ascorbate 10% drops every 2 hours, topical citrate 10% drops chronic setting.63–65 Corneal transplantation provides tectonic support in
every 2 hours, and systemic ascorbate (2000 mg per day in divided doses) the event of an impending perforation, and the limbal stem cells of the
restore levels depleted from the aqueous following alkali injury.7 Ascorbate donor address ocular surface issues.63,64 Staged surgery with limbal stem
is a cofactor in the rate-limiting step of collagen synthesis and has been cell transplantation followed by PKP at least 6 weeks later has been shown
shown to decrease the incidence of stromal ulceration.46 Citrate is a calcium to significantly decrease the likelihood of corneal graft failure.66 When it is
chelator that decreases intracellular calcium levels of neutrophils and thus not possible to rehabilitate the ocular surface adequately, keratoprosthesis
impairs chemotaxis, phagocytosis, and release of lysosomal enzymes.47 surgery may be considered.
Applied topically, citrate has been shown to reduce corneal ulceration and
perforation.48 Tetracyclines have been shown to offer protection against col-
lagenolytic degradation. Proposed mechanisms for inhibition of mucous KEY REFERENCES
membrane pemphigoid include suppression of neutrophil collagenase and Basu S, Ali H, Sangwan VS. Clinical outcomes of repeat autologous cultivated limbal epithe-
epithelial gelatinase gene expression, inhibition of α1-antitrypsin degrada- lial transplantation for ocular surface burns. Am J Ophthalmol 2012;153:643–50.
tion, and scavenging of reactive oxygen species.27 Autologous serum tears Basu S, Sureka SP, Shanbhag SS, et al. Simple limbal epithelial transplantation: long-term
clinical outcomes in 125 cases of unilateral chronic ocular surface burns. Ophthalmol-
may also be a useful adjunct medical therapy. Topical amniotic membrane ogy 2016;123:1000–10.
suspension drops have been shown to speed epithelial healing in animal Brodovsky SC, McCarty CA, Snibson G, et al. Management of alkali burns. An 11-year retro-
models.49 Topical and subconjunctival bevacizumab as well as subconjunc- spective review. Ophthalmology 2000;107:1829–35.
tival triamcinolone have been reported to decrease corneal neovasculariza- Dua HS, King AJ, Joseph A. A new classification of ocular surface burns. Br J Ophthalmol
2001;85:1379–83.
tion after alkali burns in animals.50,51 Gupta N, Kalaivani M, Tandon R. Comparison of prognostic value of Roper Hall and Dua
classification systems in acute ocular burns. Br J Ophthalmol 2011;95:194–8.
Surgical Therapy Hoffart L, Matonti F, Conrath J, et al. Inhibition of corneal neovascularization after alkali
burn: comparison of different doses of bevacizumab in monotherapy or associated with
dexamethasone. Clin Exp Ophthalmol 2010;38:346–52.
Surgical interventions that may help stabilize the ocular surface after severe Hong J, Qiu T, Wei A, et al. Clinical characteristics and visual outcome of severe ocular
chemical injury include tarsorrhaphy to promote epithelial healing, super- chemical injuries in Shanghai. Ophthalmology 2010;117:2268–72.
ficial keratectomy to remove localized corneal pannus from focal limbal Huang T, Wang Y, Zhang H, et al. Limbal allografting from living-related donors to treat
stem cell deficiency, limbal stem cell transplantation for diffuse limbal partial limbal deficiency secondary to ocular chemical burns. Arch Ophthalmol
2011;129:1267–73.
stem cell deficiency, and amniotic membrane transplantation. Tenoplasty Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. Oph-
and amniotic membrane transplantation are additional strategies to aid epi- thalmology 1989;96:709–22, discussion 722–3.
thelial healing, Tenoplasty attempts to re-establish vascularity to ischemic Kuckelkorn R, Keller G, Redbrake C. Long-term results of large diameter keratoplasties in
areas of the limbus and to promote re-epithelization.52 In this procedure, the treatment of severe chemical and thermal eye burns. Klin Monatsbl Augenheilkd
2001;218:542–52.
all necrotic conjunctival and episcleral tissues are excised, Tenon’s capsule Macdonald ECA, Cauchi PA, Azuara-Blanco A, et al. Surveillance of severe chemical corneal
is bluntly dissected, and the resultant flap with its preserved blood supply injuries in the UK. Br J Ophthalmol 2009;93:1177–80.
is advanced to the limbus. Limbal stem cell transplantation is covered in Morgan SJ. Chemical burns of the eye: causes and management. Br J Ophthalmol
Chapter 4.30. 1987;71:854–7.
Rihawi S, Frentz M, Becker J, et al. The consequences of delayed intervention when treating
The amniotic membrane is the innermost layer of the placenta and chemical eye burns. Graefes Arch Clin Exp Ophthalmol 2007;245:1507–13.
consists of a stromal matrix, a thick basement membrane, and a single Rihawi S, Frentz M, Schrage NF. Emergency treatment of eye burns: which rinsing solution
epithelial layer. Amniotic membrane transplantation (AMT) has been should we choose? Graefes Arch Clin Exp Ophthalmol 2006;244:845–54.
found to reduce proteolytic activity, increase goblet cell density, and down- Sangwan VS, Basu S, Vemuganti GK. Clinical outcomes of xeno-free autologous cultivated
regulate conjunctival and corneal fibroblasts.53–56 These actions are ben- limbal epithelial transplantation: a 10-year study. Br J Ophthalmol 2011;95:643–50.
Sejpal K, Ali MH, Maddileti S, et al. Cultivated limbal epithelial transplantation in children
eficial in restoring the ocular surface, especially in Roper-Hall grades II with ocular surface burns. JAMA Ophthalmol 2013;131:731–6.
and III chemical burns, and may be considered in the acute or reparative Tandon R, Gupta N, Kalaivani M, et al. Amniotic membrane transplantation as an adjunct to
phases.56,57 Success of AMT in the treatment of grade IV injury may be medical therapy in acute ocular burns. Br J Ophthalmol 2011;95:199–204.
limited because of stem cell loss and ischemia; when used in conjunc- Tejwani S, Kolai RS, Sangwan VS, et al. Role of amniotic membrane graft for ocular chemical
and thermal injuries. Cornea 2007;26:21–6.
tion with limbal stem cell transplantation, however, AMT may provide a Tuft SJ, Shortt AJ. Surgical rehabilitation following severe ocular burns. Eye (Lond)
substrate for stem cell proliferation and re-epithelization.53,57–60 The amni- 2009;23:1966–71.
otic membrane has been shown in some studies to promote more rapid Wagoner MD, Kenyon KR. Chemical injuries of the eye. In: Albert DM, Jakobiec FA, editors.
corneal re-epithelization and to reduce ocular surface inflammation, vas- Principles and practice of ophthalmology. Philadelphia: Saunders; 2000. p. 943–59.
cularization, and scarring. Other studies, however, show similar epithelial
healing times and similar long-term outcomes whether or not AMT was Access the complete reference list online at ExpertConsult.com
performed.36,61 If surgical amniotic membrane placement in the operating
296
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REFERENCES 37. Gupta N, Kalaivani M, Tandon R. Comparison of prognostic value of Roper Hall and Dua
classification systems in acute ocular burns. Br J Ophthalmol 2011;95:194–8.
1. Pfister RR. Chemical injuries of the eye. Ophthalmology 1983;90:1246–53.
2. Liggett PE, Pince KJ, Barlow W, et al. Ocular trauma in an urban population. Review of
38. Herr RD, White GL, Bernhisel K, et al. Clinical comparison of ocular irrigation fluids
following chemical injury. Am J Emerg Med 1991;9:228–31.
4.26
1132 cases. Ophthalmology 1990;97:581–4. 39. Rihawi S, Frentz M, Schrage NF. Emergency treatment of eye burns: which rinsing solu-
tion should we choose? Graefes Arch Clin Exp Ophthalmol 2006;244:845–54.

3. Macewen CJ. Eye injuries: a prospective survey of 5671 cases. Br J Ophthalmol
1989;73:888–94. 40. Rihawi S, Frentz M, Reim M, et al. Rinsing with isotonic saline solution for eye burns
4. Zagelbaum BM, Tostanoski JR, Kerner DJ, et al. Urban eye trauma. A one-year prospec- should be avoided. Burns 2008;34:1027–32.
tive study. Ophthalmology 1993;100:851–6. 41. Kuckelkorn R, Schrage N, Keller G, et al. Emergency treatment of chemical and thermal
5. Hong J, Qiu T, Wei A, et al. Clinical characteristics and visual outcome of severe ocular eye burns. Acta Ophthalmol Scand 2002;80:4–10.
chemical injuries in Shanghai. Ophthalmology 2010;117:2268–72. 42. Ho PC, Elliott JH. Kinetics of corneal epithelial regeneration. II. Epidermal growth factor
6. Macdonald ECA, Cauchi PA, Azuara-Blanco A, et al. Surveillance of severe chemical and topical corticosteroids. Invest Ophthalmol 1975;14:630–3.
corneal injuries in the UK. Br J Ophthalmol 2009;93:1177–80. 43. Donshik PC, Berman MB, Dohlman CH, et al. Effect of topical corticosteroids on ulcer-
7. Brodovsky SC, McCarty CA, Snibson G, et al. Management of alkali burns. An 11-year ation in alkali-burned corneas. Arch Ophthalmol 1978;96:2117–20.
retrospective review. Ophthalmology 2000;107:1829–35. 44. Phillips K, Arffa R, Cintron C, et al. Effects of prednisolone and medroxyprogester-
8. Morgan SJ. Chemical burns of the eye: causes and management. Br J Ophthalmol one on corneal wound healing, ulceration, and neovascularization. Arch Ophthalmol
1987;71:854–7. 1983;101:640–3.
9. Kuckelkorn R, Luft I, Kottek AA, et al. Chemical and thermal eye burns in the residential 45. Brown SI, Weller CA, Vidrich AM. Effect of corticosteroids on corneal collagenase of
area of RWTH Aachen. Analysis of accidents in 1 year using a new automated documen- rabbits. Am J Ophthalmol 1970;70:744–7.
tation of findings. Klin Monatsbl Augenheilkd 1993;203:34–42. 46. Pfister RR, Paterson CA. Ascorbic acid in the treatment of alkali burns of the eye. Oph-
10. Pfister RR, Pfister DR. Alkali injuries of the eye. In: Krachmer JH, Mannis MJ, Holland thalmology 1980;87:1050–7.
EJ, editors. Cornea. Philadelphia: Elsevier Mosby; 2005. p. 1285–93. 47. Pfister RR, Haddox JL, Dodson RW, et al. Polymorphonuclear leukocytic inhibition by
11. McCulley JP. Chemical injuries. In: Smolin G, Thoft RA, editors. The cornea. Boston: citrate, other metal chelators, and trifluoperazine. Evidence to support calcium binding
Little, Brown and Co; 1987. p. 527–42. protein involvement. Invest Ophthalmol Vis Sci 1984;25:955–70.
12. Paterson CA, Pfister RR, Levinson RA. Aqueous humor pH changes after experimental 48. Pfister RR, Nicolaro ML, Paterson CA. Sodium citrate reduces the incidence of corneal
alkali burns. Am J Ophthalmol 1975;79:414–19. ulcerations and perforations in extreme alkali-burned eyes – acetylcysteine and ascorbate
13. Rihawi S, Frentz M, Becker J, et al. The consequences of delayed intervention when have no favorable effect. Invest Ophthalmol Vis Sci 1981;21:486–90.
treating chemical eye burns. Graefes Arch Clin Exp Ophthalmol 2007;245:1507–13. 49. Choi JA, Choi JS, Joo CK. Effects of amniotic membrane suspension in the rat alkali
14. Pfister RR, Friend J, Dohlman CH. The anterior segments of rabbits after alkali burns. burn model. Mol Vis 2011;17:404–12.
Metabolic and histologic alterations. Arch Ophthalmol 1971;86:189–93. 50. Yoeruek E, Ziemssen F, Henke-Fahle S, et al. Safety, penetration and efficacy of topically
15. Friedenwald JS, Hughes WF, Herrmann H. Acid injuries of the eye. Arch Ophtalmol Rev applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical
Gen Ophtalmol 1946;35:98–108. burn. Acta Ophthalmol 2008;86:322–8.
16. McCulley JP. Ocular hydrofluoric acid burns: animal model, mechanism of injury and 51. Saud EE, Moraes HV, Marculino LGC, et al. Clinical and histopathological outcomes of
therapy. Trans Am Ophthalmol Soc 1990;88:649–84. subconjunctival triamcinolone injection for the treatment of acute ocular alkali burn in
17. Tuft SJ, Shortt AJ. Surgical rehabilitation following severe ocular burns. Eye (Lond) rabbits. Cornea 2012;31:181–7.
2009;23:1966–71. 52. Teping C, Reim M. Tenonplasty as a new surgical principle in the early treatment of the
18. Grant WM, Kern HL. Action of alkalies on the corneal stroma. Arch Ophthalmol most severe chemical eye burns. Klin Monatsbl Augenheilkd 1989;194:1–5.
1955;54:931–4. 53. Tejwani S, Kolai RS, Sangwan VS, et al. Role of amniotic membrane graft for ocular
19. Wagoner MD. Chemical injuries of the eye: current concepts in pathophysiology and chemical and thermal injuries. Cornea 2007;26:21–6.
therapy. Surv Ophthalmol 1997;41:275–313. 54. Kim JS, Kim JC, Na BK, et al. Amniotic membrane patching promotes healing and
20. Chiang TS, Moorman LR, Thomas RP. Ocular hypertensive response following acid and inhibits proteinase activity on wound healing following acute corneal alkali burn. Exp
alkali burns in rabbits. Invest Ophthalmol 1971;10:270–3. Eye Res 2000;70:329–37.
21. Paterson CA, Pfister RR. Intraocular pressure changes after alkali burns. Arch Ophthal- 55. Prabhasawat P, Tseng SC. Impression cytology study of epithelial phenotype of ocular
mol 1974;91:211–18. surface reconstructed by preserved human amniotic membrane. Arch Ophthalmol
22. Paterson CA, Pfister RR. The ocular hypertensive response following experimental acid 1997;115:1360–7.
burns in the rabbit eye. Invest Ophthalmol Vis Sci 1979;18:67–74. 56. Lee SB, Li DQ, Tan DTH, et al. Suppression of TGF-beta signaling in both normal con-
23. Schirner G, Schrage NF, Salla S, et al. Conjunctival tissue examination in severe eye junctival fibroblasts and pterygial body fibroblasts by amniotic membrane. Curr Eye Res
burns: a study with scanning electron microscopy and energy-dispersive X-ray analysis. 2000;20:325–34.
Graefes Arch Clin Exp Ophthalmol 1995;233:251–6. 57. Meller D, Pires RTF, Mach RJS, et al. Amniotic membrane transplantation for acute
24. Pfister RR, Pfister DR. Alkali injuries of the eye. In: Krachmer JH, Mannis MJ, Holland chemical or thermal burns. Ophthalmology 2000;107:980–9, discussion 990.
EJ, editors. Cornea. Philadelphia: Elsevier Mosby; 2005. p. 1285–94. 58. Holland EJ, Schwartz GS, Nordlund ML. Surgical techniques for ocular surface recon-
25. Levinson RA, Paterson CA, Pfister RR. Ascorbic acid prevents corneal ulceration and struction. In: Krachmer JH, Mannis MJ, Holland EJ, editors. Cornea. Philadelphia: Else-
perforation following experimental alkali burns. Invest Ophthalmol 1976;15:986–93. vier Mosby; 2005. p. 1799–812.
26. Pfister RR, Haddox JL, Sommers CI, et al. Identification and synthesis of chemotactic 59. Mittal V, Jain R, Mittal R, et al. Successful management of severe unilateral chemi-
tripeptides from alkali-degraded whole cornea. A study of N-acetyl-proline-glycine-pro- cal burns in children using simple limbal epithelial transplantation. Br J Ophthalmol
line and N-methyl-proline-glycine-proline. Invest Ophthalmol Vis Sci 1995;36:1306–16. 2016;100:1102–8.
27. Ralph RA. Tetracyclines and the treatment of corneal stromal ulceration: a review. Cornea 60. Satke Y, Higa K, Tsubota K, et al. Long-term outcome of cultivated oral mucosal epithelial
2000;19:274–7. sheet transplantation in treatment of total limbal stem cell deficiency. Ophthalmology
28. Fini ME, Girard MT. Expression of collagenolytic/gelatinolytic metalloproteinases by 2011;118:1524–30.
normal cornea. Invest Ophthalmol Vis Sci 1990;31:1779–88. 61. Barreiro TP, Santos MS, Vieira AC, et al. Comparative study of conjunctival limbal trans-
29. Johnson-Muller B, Gross J. Regulation of corneal collagenase production: epithelial-stro- plantation not associated with the use of amniotic membrane transplantation for treat-
mal cell interactions. Proc Natl Acad Sci USA 1978;75:4417–21. ment of total limbal defiency secondary to chemical injury. Cornea 2014;33:716–20.
30. Johnson-Wint B, Bauer EA. Stimulation of collagenase synthesis by a 20000-dalton epi- 62. Kheirkhah A, Johnson DA, Paranjpe DR, et al. Temporary sutureless amniotic mem-
thelial cytokine. Evidence for pretranslational regulation. J Biol Chem 1985;260:2080–5. brane patch for acute alkali burns. Arch Ophthalmol 2008;126:1059–66.
31. Ballen PH. Treatment of chemical burns of the eye. Eye Ear Nose Throat Mon 63. Kuckelkorn R, Redbrake C, Schrage NF, et al. Keratoplasty with 11–12 mm diameter for
1964;43:57–61. management of severely chemical-burned eyes. Ophthalmologe 1993;90:683–7.
32. Roper-Hall MJ. Thermal and chemical burns. Trans Ophthalmol Soc UK 1965;85:631–53. 64. Kuckelkorn R, Keller G, Redbrake C. Long-term results of large diameter keratoplasties
33. Wagoner MD, Kenyon KR. Chemical injuries of the eye. In: Albert DM, Jakobiec FA, in the treatment of severe chemical and thermal eye burns. Klin Monatsbl Augenheilkd
editors. Principles and practice of ophthalmology. Philadelphia: Saunders; 2000. p. 2001;218:542–52.
943–59. 65. Vajpayee RB, Thomas S, Sharma N, et al. Large-diameter lamellar keratoplasty in
34. Dua HS, King AJ, Joseph A. A new classification of ocular surface burns. Br J Ophthal- severe ocular alkali burns: a technique of stem cell transplantation. Ophthalmology
mol 2001;85:1379–83. 2000;107:1765–8.
35. Joseph A, Dua HS, King AJ. Failure of amniotic membrane transplantation in the treat- 66. Basu S, Mohamed A, Chaurasia S, et al. Clinical outcomes of penetrating keratoplasty
ment of acute ocular burns. Br J Ophthalmol 2001;85:1065–9. after autologous cultivated limbal epithelial transplantation for ocular surface burns. Am
36. Tandon R, Gupta N, Kalaivani M, et al. Amniotic membrane transplantation as an J Ophthalmol 2011;152:917–24.
adjunct to medical therapy in acute ocular burns. Br J Ophthalmol 2011;95:199–204.
296.e1
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Section 9 Surgery
Corneal Surgery
Allister Gibbons, Ibrahim O. Sayed-Ahmed, Carolina L. Mercado, Victoria S. Chang, Carol L. Karp 4.27
an opaque or irregular cornea). Indications for PKP include keratoconus;
Definition: Corneal procedures performed to either restore vision or previous graft failure or rejection; full-thickness or deep corneal scars;
restore globe integrity. Fuchs’ endothelial dystrophy; pseudo-phakic or aphakic bullous keratop-
athy; chemical burn; corneal ulcer; corneal dystrophy and degeneration;
herpetic keratitis; trauma; or any other causes of corneal decompensation.
Key Features Conditions with primarily posterior pathologies, such as Fuchs’ endothe-
lial dystrophy and pseudo-phakic or aphakic bullous keratopathy, now are
• Careful preoperative preparation and planning are critical to success. commonly treated with EKP. The rate of success of PKP is excellent, but
• Understand intraoperative and postoperative complications and the long-term risk of graft rejection increases significantly with active or
management.
recurrent infection, inflammation, corneal neovascularization, previous
graft rejection, and each subsequent penetrating graft.
It is important to perform a careful preoperative evaluation and have
Associated Feature a thorough discussion with patients about the surgery, visual expectation,
• Be alert to the signs and symptoms of graft rejection. possible complications, and the long postoperative course. The recipient
must be prepared for the lifelong care required. In general, important con-
siderations for the preoperative evaluation for PKP are as follows:
KERATOPLASTY • Visual potential must be evaluated.
• Ocular surface must be optimized before a planned PKP. Conditions
Introduction that may affect the ocular surface include rosacea, dry eyes, blepharitis,
trichiasis, exposure keratopathy, ectropion, and entropion.
The successful outcomes enjoyed by patients who undergo modern pen-
etrating keratoplasty (PKP) and lamellar keratoplasty are the result of
• Intraocular pressure (IOP) must be controlled adequately prior to
surgery.
advances in technology and surgical techniques.
• Ocular inflammation must be recognized and treated.
• Previous corneal diseases and vascularization must be considered. A
Historical Review history of herpetic keratitis significantly reduces the chance of graft
success because of several factors, including recurrent disease in the
Corneal grafting techniques were pioneered by ophthalmologists, such
graft, neovascularization, trabeculitis with increased IOP, and persistent
as Reisinger,1 von Hippel,2 and Elschnig.3 Today keratoplasty is the most
inflammation that may induce rejection.
common and successful human transplantation procedure, with over
45 000 corneal transplantations performed in the United States each year.4
The number of PKP decreased to less than 20 000 in the year 2014, and the Donor Selection
number of endothelial keratoplasty (EKP) increased to over 25 000 in that The Eye Bank Association of America has developed a set of criteria for
same year.4 Optical results have improved significantly as a consequence of donor corneas.5,6 Contraindications for the use of donor tissue for PKP
advances in tissue selection and preservation, techniques, trephines, and include the following:
management of postoperative astigmatism.
Lamellar grafts date back to 1886 when von Hippel2 successfully per-
• Death as a result of an unknown cause.
formed the first lamellar grafting in a human. Lamellar techniques
• Central nervous system diseases, such as Creutzfeldt–Jakob disease,
subacute sclerosing panencephalitis, rubella, Reye’s syndrome, rabies,
have revolutionized the treatment of corneal diseases by offering such
meningitis, and infectious encephalitis.
advantages as faster visual recovery, less postoperative astigmatism,
and decreased risk of suture-related complications compared with PKP.
• Systemic infections, such as human immunodeficiency virus (HIV)
infection, hepatitis viruses B and C infection, septicemia, syphilis,
Because “selective keratoplasty” replaces only the diseased tissue, the risk
Ebola, and infective endocarditis, as well as other relevant communi-
of graft rejection is theoretically lower. EKP now has become the standard
cable diseases, such as West Nile virus, vaccinia virus, or Zika virus
of care for endothelial diseases.
infections.
• Leukemia or actively disseminated lymphomas.
Anesthesia • History of melanoma with known metastatic disease.
Corneal transplantation may be performed under cover of regional or
• Eye diseases, such as retinoblastoma, malignant tumors of the anterior
segment, and active ocular inflammation (e.g., uveitis, scleritis, retini-
general anesthesia, depending on patient preference and cooperation.
tis, and choroiditis).
Typically, local anesthesia entails peribulbar or retrobulbar injection of
lidocaine 2%, bupivacaine 0.75%, and hyaluronidase. A lid block may be
• Prior ocular surgery, including refractive procedures. (Eyes with pre-
vious laser photoablation surgery may be used for tectonic grafts and
employed to prevent squeezing.
posterior lamellar procedures, and pseudo-phakic eyes and eyes that
have undergone glaucoma filtration surgery may be used if they meet
Specific Techniques endothelial criteria by specular microscopy.)
Penetrating Keratoplasty • Congenital or acquired anterior segment abnormalities, such as corneal
scars, keratoconus or Fuchs’ endothelial dystrophy, or associated con-
PKP involves full-thickness replacement of corneal tissue with a healthy
ditions, such as Down syndrome (for penetrating or anterior lamellar
donor graft.
keratoplasty).
Preoperative Evaluation and Diagnostic Approach Prior to PKP, the donor’s history and blood must be evaluated for com-
PKP may be used to provide tectonic support (as in corneal thinning or municable diseases, and donor tissues are inspected by the surgeon with 297
perforation) and to improve visual outcomes (as in the replacement of the slit lamp.
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Surgical Techniques the anterior chamber prior to host trephination, it may be placed to protect
4 Adequate decompression of the globe is ensured prior to PKP because

excessive preoperative IOP may increase the risk of expulsive choroidal
hemorrhage. Intravenous mannitol or mechanical ocular decompression
intraocular structures. The recipient button is then excised using forceps
and corneal scissors (Fig. 4.27.3). The edge of the recipient bed is made
perpendicular for optimal graft–host apposition.
can be considered to reduce IOP. Miotics are placed preoperatively to If the patient requires concurrent cataract extraction, intraocular lens
protect the lens during surgery unless lenticular surgery also is planned. (IOL) explantation, iridectomy, anterior vitrectomy, or a secondary IOL,
Scleral supporting (Flieringa) rings may be used principally in aphakic this may be done prior to trephination if visualization allows. Because
eyes or young patients. the diseased cornea precludes adequate visualization in many cases, an
The size of the graft is determined on the basis of the location of the “open sky” technique is utilized after trephination (Fig. 4.27.4). In cases of
pathology and on clinical judgment. The donor tissue usually is 0.25 mm emergent grafting, such as in the setting of an active infectious process,
larger in diameter compared with the recipient tissue. In certain circum- uncontrolled inflammatory disease, or a recent perforation, an iridectomy
stances, a larger (0.5 mm) donor may be considered in an aphakic eye to is performed to avoid pupillary block.
induce myopia, or a same-size donor button, such as in a recipient with
keratoconus, may be chosen to reduce myopia. The visual axis of the recip-
ient cornea is marked with a marking pen. An inked radial keratotomy
marker may be used to mark the peripheral cornea. A donor corneal button
is punched. In the United States, the most commonly used trephine is the
Barron Donor Cornea Punch (Fig. 4.27.1). The donor is cut from endothe-
lium to the epithelium. The donor also may be cut from the epithelium
to the endothelium by using an artificial anterior chamber and then by
using the same technique described for the recipient cornea. This has the
theoretical advantage of both the donor and the recipient being cut in the
same fashion with the same type of blade, which reduces donor–recipient
disparity and potentially reduces astigmatism.
The recipient cornea may be cut using a variety of trephines, such as
the Hessburg–Barron suction trephine (Fig. 4.27.2), Hanna trephine, or
Castroviejo trephine. More recently, the use of the femtosecond laser to
cut the recipient cornea has been described.7 Excision of the host corneal
button may be performed via partial-thickness trephination followed by a
controlled entry into the anterior chamber using a No. 75 blade, or via a
continued trephination that is stopped as soon as aqueous egress shows
the anterior chamber has been entered. If viscoelastic was not placed into
Fig. 4.27.1 The

Corneal Donor Fig. 4.27.2 Hessburg–Barron Vacuum Trephine. A vacuum corneal trephine may
Button Is Cut. be used to trephinate into the host cornea.
A Barron donor
cornea punch may
be used to cut the
donor tissue from
the endothelial
side.
Fig. 4.27.3 Excision of the Corneal Button. The corneal button is removed
completely using corneal scissors.
A B C
Fig. 4.27.4 Replacement of Anterior Chamber Intraocular Lens. (A) Care is taken when the anterior chamber haptics are removed, as they may become encysted in the
peripheral iris and bleeding may occur on removal. (B) An anterior vitrectomy is performed—an iris hook may be used to improve visualization. (C) A 10-0 Prolene suture is
298 passed beneath the iris, through the scleral sulcus and out through the previously prepared scleral flap. After the suture-supported lens is placed in the sulcus, the suture is
tied to itself beneath the scleral flap. Alternatively, the knot may be rotated beneath the sclera. This is performed on both sides. (Courtesy Dr. W. W. Culbertson.)
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4.27
Corneal Surgery
Fig. 4.27.5 The Corneal Button Is Placed. Care is taken in the placement of
cardinal sutures to ensure appropriate distribution.
Fig. 4.27.7 Subepithelial infiltrates secondary to subepithelial graft rejection.

(Courtesy Dr. W. W. Culbertson.)
suppressant, lubrication, or bandage contact lenses. Resuturing of the

wound may be required if the leak is significant.
Flat Anterior Chamber With Increased Intraocular Pressure. Flat ante-
rior chamber with increased IOP may result from pupillary block, anterior
rotation of the lens–iris diaphragm (as found in choroidal hemorrhage),
choroidal effusion, or aqueous misdirection. The cause must be identified
and treated.
Endophthalmitis. Postoperative endophthalmitis, a devastating com-
Fig. 4.27.6 Placement of 10-0 nylon interrupted sutures in a corneal transplant. plication, may result from a variety of factors, including contamination
of donor tissue, prior infection in the host, or postoperative infection
acquired through a wound leak.
Viscoelastic may be placed in the anterior chamber, and the donor Persistent Epithelial Defect. Epithelial defects that persist beyond 1–2
button then is placed over the recipient bed and sutured in place with four weeks occur more commonly in eyes that have ocular surface disorders,
cardinal sutures (Fig. 4.27.5). Care is taken in the placement of the cardinal such as limbal stem cell deficiency, neurotrophic keratopathy, dry eye
sutures, as proper tissue distribution is paramount. The depth of suture disease (DED), blepharitis, exposure keratopathy, and rosacea. Treatment
is 90% of the corneal thickness. The remaining sutures may be a combi- includes frequent lubrication with preservative-free drops and lubricat-
nation of interrupted and running sutures or solely interrupted sutures ing ointment. Possible causes of ocular surface toxicity, such as topical
(Fig. 4.27.6). Interrupted sutures are suited for vascularized or thinned eyedrops, must be eliminated or minimized. If the defect does not heal,
cornea, as subsequent selective removal may be necessary to prevent the ophthalmic blood derivatives, a tarsorrhaphy, or punctal occlusion may be
advancement of vessels or to control astigmatism. Running sutures have necessary.
the advantage of speedy placement intraoperatively and better tension dis- Primary Graft Failure. Primary graft failure (which is different from
tribution but are more difficult to adjust. Prior to the placement of the graft rejection) is recognized when significant edema of the donor tissue
final sutures, the viscoelastic material in the anterior chamber is removed. in a noninflamed eye is present on the first postoperative day and does not
The running sutures may be adjusted intraoperatively by using a kerato- clear by 2–4 weeks. Primary graft failure may be attributed to either poor
scope. When the suturing is complete, all sutures are rotated such that donor endothelial function or iatrogenic damage to the donor tissue during
the knots are buried within the stroma, and the security of the wound is PKP. The graft is observed for several weeks. Graft failure should be differ-
tested for water tightness by using a combination of a surgical sponge and entiated from Descemet’s membrane detachment. A regraft (either repeat
fluorescein. PKP or EKP) is considered if the corneal edema fails to resolve.
Suture-Related Problems. Loose or broken sutures must be removed to
Complications and Postoperative Management prevent associated infection or neovascularization, which can increase the
Intraoperative complications include poor graft centration, bleeding, likelihood of rejection.
damage to ocular structures (e.g., donor endothelium, iris, lens, or lens Graft Rejection. Graft rejection remains the most common cause of
capsule), or expulsive suprachoroidal hemorrhage. During excision of the graft failure. The overall incidence of endothelial graft rejection has been
recipient button, it is imperative to continuously monitor the depth of the reported as 20%.8 Symptoms include decreased vision, redness, photopho-
anterior chamber and the red reflex. A sudden shallowing of the anterior bia, and pain; however, patients may experience as few as one or even
chamber or disappearance of the red reflex may signify an impending none of these symptoms. Patients must be educated carefully about these
expulsive choroidal hemorrhage. Sealing of the globe can be accomplished symptoms and must be instructed to seek medical attention immediately
quickly by a gloved finger over a partially excised host cornea or with place- should they occur.
ment of a donor cornea or temporary keratoprosthesis. The key manage- Graft rejection may be divided anatomically into three categories:
ment strategy is to close and repressurize the globe.
The success of PKP depends significantly on adequate postoperative • Epithelial rejection—may be recognized by observation of an epithelial
care and management. The surgeon must be able to recognize and manage line. This is seen early before the host epithelium replaces the donor
a variety of possible complications, such as wound leak, infection, glau- epithelium.
coma, and graft rejection or failure. The common postoperative complica- • Subepithelial rejection—multiple subepithelial infiltrates limited to the
tions and their management are discussed in the following subsections. corneal graft may be observed (Fig. 4.27.7).
Wound Leak. A shallow anterior chamber in a soft globe the day after • Endothelial rejection (the most severe type of rejection)—characterized 299
PKP may indicate a wound leak, which may need patching, aqueous by keratic precipitates, iritis, and corneal edema. A Khodadoust line
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4
Fig. 4.27.8 Graft Rejection. Note the inflammatory precipitates and Khodadoust
line secondary to endothelial rejection. (Courtesy Dr. A. Galor.)
may be seen, which represents the advancing front of the host’s inflam-
matory cells against a receding front of donor endothelium (Fig. 4.27.8).
The treatment of graft rejection consists primarily of corticosteroids,

B
usually in topical form. The frequency of the corticosteroid drops is
increased to hourly or even more often in the case of endothelial graft
rejection until the process is reversed. Subconjunctival or Subtenon’s injec- Fig. 4.27.9 Recurrence of Granular Dystrophy in a Graft. (A) Slit-lamp
photograph of a granular dystrophy recurrence in a penetrating keratoplasty graft.
tion of corticosteroids may be used. Systemic corticosteroids (oral or intra-
(B) Anterior segment optical coherence tomography (AS-OCT) image of recurrence
venous) also may be utilized in severe cases. For patients with a history of showing location on Bowman’s layer. (Courtesy Dr. C. Karp.)
multiple rejection episodes either in the current cornea or previous grafts,
systemic immunomodulatory therapy may be considered.
Treatment for Astigmatism. Adequate control of postoperative astigma- Preoperative Evaluation and Diagnostic Approach
tism is vital to achieving the best-corrected visual acuity possible. Typically A tectonic graft is performed to reinforce areas of perforated or thinned
starting at 8–12 weeks after PKP, the patient is followed using serial corneal cornea. Optical lamellar grafts are used to replace diseased anterior cornea
topography. Subsequently, interrupted sutures are removed selectively, to improve visual function and require that the posterior stroma of the
and running sutures are adjusted, as necessary to reduce astigmatism.9 recipient is healthy.
Early suture removal may have a more significant effect on astigmatism, The rationale for a lamellar keratoplasty and the various surgical options
although care is required with regard to wound stability. must be thoroughly discussed with patients. Different modalities can be
Corneal Ulcers. Patients who have undergone PKP are more suscep- used to assess the depth of a scar, the adequacy of the planned remnant
tible to infectious keratitis. Such factors as loose sutures and persistent stromal bed, and the severity of endothelial disease, including topography,
epithelial defects may contribute to the development of corneal ulcers. anterior segment optical coherence tomography (AS-OCT), and specular
Recurrence of Diseases. Various corneal dystrophies and infections may microscopy.
recur in grafts. Among the three most common stromal corneal dystro-
phies [macular, granular (Fig. 4.27.9), and lattice], lattice corneal dystrophy Donor Selection
has the highest recurrence. In the setting of keratic precipitates on a graft Donor Preparation. Criteria for donor tissue selection and screen-
in a patient who has a history of herpes simplex virus infection, it is some- ing are the same as those listed for PKP except that tissue with local eye
times difficult to distinguish recurrence of a disease from graft rejection. disease affecting the corneal endothelium or previous ocular surgery that
It is important, however, to make such a distinction as the treatment for does not compromise the corneal stroma (e.g., a history of endothelial dys-
a recurrence of herpes simplex virus (antiviral agent ± corticosteroid) is trophy or iritis) are acceptable.5
different from treatment for rejection (corticosteroid alone). The observa- In ALK, a fresh or frozen whole donor eye or a corneoscleral donor and
tion of keratic precipitates and corneal edema confined only to the donor artificial anterior chamber may be used to fashion the anterior lamellar
button may suggest graft rejection. Anterior chamber paracentesis and donor tissue. When done manually, an incision is made just inside the
polymerase chain reaction analysis can aid in the diagnosis. limbus of the donor cornea to reach the depth of the desired dissection. A
Martinez dissector or a cyclodialysis spatula is used to extend the dissection
Anterior Lamellar Keratoplasty plane within the corneal stroma and harvest the donor tissue (Fig. 4.27.10).
A concept that has gained popularity in the treatment of corneal disease The tissue harvested may be circular, annular, or any other shape, depend-
is the selective removal of only the diseased tissue. Lamellar keratoplasty ing on the needs of the patient (Fig. 4.27.11). Both the cornea and the sclera
is a procedure in which a partial-thickness graft of donor tissue is used may be used. Usually, the donor tissue is slightly oversized (0.25–0.5 mm)
to provide tectonic stability or optical improvement.10 A partial-thickness in width and thickness compared with the recipient bed.15,16 Donor tissue
section of donor stroma or sclera may be used. Two types of lamellar ker- suitable for PKP should be available in case of a large perforation that may
atoplasty exist: anterior lamellar keratoplasty (ALK) and posterior lamellar occur in the lamellar dissection of the host tissue. Newer microkeratomes
keratoplasty (also referred to as endothelial keratoplasty) (see Chapter 4.29). allow for more efficient host and donor dissection. In particular, the femto-
In ALK, the transplanted tissue does not include corneal endothe- second laser has been helpful in performing lamellar keratoplasty.11
lium, thus avoiding endothelial rejection and allowing donor tissue to be
obtained from older eyes. Indications for ALK mainly include anterior Surgical Techniques
corneal pathology in which the posterior cornea is unaffected, such as Anterior Lamellar Dissection of the Host Tissue. A measurement of the
keratoconus, anterior corneal scars, and corneal dystrophies limited to the affected area is done, and this can be facilitated by OCT preoperatively. A
stroma. Femtosecond lasers can aid in this procedure.11,12 A subtype of ALK trephine is used gently to mark the extent of graft needed. The surgeon
is deep anterior lamellar keratoplasty (DALK), in which the objective is to may opt for a manual dissection of the host stroma or air-assisted dissec-
eliminate all of the host stromal tissue; this can be achieved through the tion using the “big bubble” technique, as described by Anwar.17 Irrespective
300 use of manual dissection,13 viscoelastic, or an air bubble,14 to dissect the of the technique chosen, the goal is to create a smooth, uniplanar recipient
host’s stromal–Descemet’s membrane interface. bed. Elimination of most or all of the host stroma will lead to better final
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SEPARATION OF CADAVERIC CORNEA PARTIAL-THICKNESS TREPHINATION
4.27
scar or
Corneal Surgery
diseased
tissue
lateral trephine
dissection
partial thickness
incision to
desired depth
scar or
diseased trephine
dissector tissue
Fig. 4.27.10 Separation of the Cadaveric Cornea. A dissector, such as the Martinez Fig. 4.27.12 Partial-Thickness Trephination. This is performed on the host in the
dissector or a cyclodialysis spatula, is used to gently separate the cornea along the desired location and to the desired depth. Care must be taken not to perforate the
lamellar cleavage plane through the entire cornea. cornea.
HORSESHOE OR ANNULAR LAMELLAR GRAFT DISSECTION OF DISEASED AREA
bed of
cornea
previously clear
dissected area of
trephine
cornea trephination
crescentic donor
material
cut limbus
forceps
crescentic donor trephine holding tissue
material
64 Beaver area of
blade trephination
Fig. 4.27.11 Donor Tissue Is Harvested. A trephine is placed on the cadaveric Fig. 4.27.13 Dissection of the Diseased Area. The diseased area in the host cornea
globe in the size and shape desired. A horseshoe or annular lamellar graft is being is dissected gently to create a uniplanar, disease-free bed.
harvested here. A combination of corneal and scleral tissue may be harvested to
give a different tissue shape.
stromal depth. The donor tissue margins should not ride anteriorly to the
rim of the recipient bed. At times, an anterior chamber paracentesis may
visual outcomes by eliminating stroma-to-stroma interface. If Descemet’s become necessary before lamellar sutures are placed. ALK may be per-
membrane is violated, the procedure is then converted to a PKP, although formed centrally or in the periphery for corneoscleral melts (Figs. 4.27.15
conversion may be avoided in the setting of small perforations. and 4.27.16).
If a manual dissection is chosen, a partial-thickness trephination is In DALK, a deep anterior lamellar disc is trephined to about 80% total
performed until the desired depth of dissection is reached (Fig. 4.27.12). depth, or the femtosecond laser can be used for this part of the procedure.12
Alternatively, a microkeratome or femtosecond laser may be used for the A paracentesis can be done at this point to inject a small air bubble in the
host.11 A blade is then used to extend the dissection plane along the entire eye to improve visualization of the big bubble because it will push it to the
host corneal tissue until the dissection of the host tissue is completed (Fig. periphery of the anterior chamber; a mild decrease in anterior chamber
4.27.13). In manual ALK, the edge of the host bed should be undermined pressure will also decrease resistance to the big bubble. Some surgeons
to create a horizontal groove using a Paufique knife.16 The donor lamella advocate debulking of the anterior half of the stroma before proceeding
is placed on the recipient bed and secured with interrupted 10-0 nylon with air dissection, whereas others proceed directly with a 27-gauge needle 301
sutures (Fig. 4.27.14). The depth of the suture is about 90% of the corneal or cannula (previously having created a track with a dissector) to the center
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of the cornea (Fig. 4.27.17). Using a 5-cc syringe, air is applied firmly to In femtosecond-assisted lamellar keratoplasty (FALK), the donor and
4 create a bubble. Two types of bubbles have been described. A type 1 bubble
occurs when the stroma is dissected at the level of pre-Descemet’s layer;
this yields a smaller bubble with greater structural integrity (higher burst-
recipient are cut with the femtosecond laser, and the donor lenticule can be
placed without sutures on the recipient bed (Fig. 4.27.18). Only a bandage
contact lens is used in cases when the residual stromal bed is thicker than
ing pressure). A type 2 bubble occurs when the cleavage happens between 250 microns.11
Descemet’s and pre-Descemet’s layers, producing a larger bubble with a

thinner wall and a lower bursting pressure. Complications and Postoperative Management
Viscoelastic material may then be injected into the space created by the In general, anterior lamellar grafts can be very successful (see Figs. 4.27.15
air bubble to facilitate further separation of the layers. The deep stromal and 4.27.16). Complications of ALK are less frequent or less severe in nature
layers are excised, usually in quadrants (see Fig. 4.27.17). The intraoperative compared with those of PKP. Complications of lamellar graft include per-
OCT can aid in determining dissection depth.18 All viscoelastic material is foration of the recipient cornea, interface scarring and vascularization,
removed to avoid a dual anterior chamber. A donor button, the same size persistent epithelial defect, inflammatory necrosis of the graft and graft
as the trephination, is then placed after the removal of Descemet’s mem- melting, infection, astigmatism, and allograft rejection. Careful irrigation
brane and the endothelium and secured using 10-0 nylon sutures. and cleaning of the host bed may reduce the incidence of complications.
ALK has a significantly reduced incidence of allograft rejection because no
transplantation of foreign endothelium is involved.
Perforation of Descemet’s Membrane. This is a relatively common event
LAMELLAR TISSUE SUTURE TO HOST BED early in the surgical learning curve. In small perforations, the case can
proceed as planned, but the surgeon should leave a gas bubble (air or SF6
20%) in the eye to ensure that Descemet’s membrane remains attached to
the stroma. In larger perforations, a combination of gas and a pass-through
suture may be necessary to anchor Descemet’s membrane and avoid its
suture retraction. In larger breaks, conversion to PKP may be required.
lamellar graft Pseudo-Anterior Chamber. A double anterior chamber may occur when
an unrecognized Descemet’s tear occurs, such as during suturing of the
donor graft. Moreover, viscoelastic material has been implicated in certain
cases. The dual chamber may resolve spontaneously, but most surgeons
inject air or SF6 20% in the early postoperative period to enhance recovery
times and potential endothelial cell loss.
Triple Procedure (Combined Procedure)

A triple procedure or combined procedure refers to keratoplasty, combined
with cataract extraction and IOL implantation.

donor lamellar The triple procedure is indicated for patients with a visually significant
suture
tissue cataract who also require corneal transplantation for visual rehabilitation.
Triple procedures are increasingly being performed with the use of the
undermined
DSAEK or DMEK technique for patients with endothelial disease. If visu-
edge
alization permits, cataract extraction may be performed in a closed system
by using standard phacoemulsification techniques. The leading indication
for a triple procedure is Fuchs’ endothelial dystrophy and cataract, which
accounts for up to 77% of eyes that require a triple procedure.19–21
Fig. 4.27.14 The Lamellar Tissue Is Sutured to the Host Bed. Suture placement Compared with PKP, a combined procedure requires the additional
is facilitated if the edge of the host bed is undermined. Traditionally, the graft is calculation of the power of the IOL. Different formulas, such as the Holl-
sutured with 10-0 nylon. aday or the Sanders–Retzlaff–Kraff formula (Eq. 4.27.1),22 in which A is the
Fig. 4.27.15 Lamellar Keratoplasty for Granular

Dystrophy. (A) Preoperative appearance of a patient who
had granular dystrophy limited to the anterior cornea.
(B) Postoperative appearance following manual lamellar
keratoplasty. (Courtesy Dr W. W. Culbertson.)
A B
Fig. 4.27.16 Lamellar Keratoplasty for Peripheral

Corneal Melt and Perforation. (A) Preoperative
appearance of a patient who had a peripheral corneal melt
and perforation (see arrows). (B) Postoperative appearance
after the placement of a horseshoe corneoscleral lamellar
graft. (Courtesy Dr. W. W. Culbertson.)
302 A B
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Fig. 4.27.17 Deep
Anterior Lamellar
Keratoplasty (DALK). 4.27
(A) After 80% trephination
the 30-gauge needle is
Corneal Surgery
advanced until it reaches
the center of the cornea.
(B) Air is released firmly
and steadily forming a
big bubble, in this case
a type 1 bubble was
A B C formed. (C) A “brave
slash” is performed to
access the bubble.
(D) Dissection of
the anterior lamella
is performed until
Descemet’s membrane
is exposed. (E) The
endothelium is removed
from the donor cornea,
then the donor cap is
sutured to the host.
(F) Final result. (Courtesy
Dr. F. A. Valenzuela.)
D E F
constant for an IOL, AL is the axial length, and K is the keratometric mea-
surement. The determination of K varies from surgeon to surgeon. The
authors typically advocate one of two alternative approaches, using either
the average of the surgeon’s past postoperative keratometric readings asso-
ciated with the surgical technique or the K readings from the contralateral
eye. In the instances in which an over- or undersized graft is required,
+1.00–+2.00 diopters (D) is subtracted from the IOL power for a 0.5-mm
oversized graft or +1.00–+2.00 D is added to the IOL power for 0.5-mm
undersizing.16 Postoperative refractive targets must be adjusted in DSAEK
or DMEK triple procedures, as there may be a hyperopic shift associated
with these procedures.23
IOL power = A − 2.5AL − 0.9K [Equation 4.27.1]
Surgical Techniques
Open Sky Cataract Extraction. The detailed surgical technique for PKP
A is described above. Prior to the trephination of the recipient cornea, trypan
blue may be considered for visual augmentation of the capsulotomy. After
the recipient button has been excised, a capsulorrhexis, sufficiently large
to allow subsequent expression of the lens nucleus, is performed. Caution
is maintained during the capsulorrhexis because there is a tendency for
the capsulectomy to extend peripherally, especially with increased posterior
pressure.
After hydrodissection and mobilization of the lens nucleus, the lens
is gently expressed. The remaining cortical material is removed carefully
using an automated irrigation–aspiration instrument or a manual I/A, as
the anterior and posterior capsules tend to collapse toward each other. The
capsular bag is then inflated with viscoelastic material, and the appropriate
posterior chamber IOL is inserted. The authors of this chapter prefer a
rigid or a three-piece IOL in this scenario for increased stability because
of anterior chamber fluctuations. If a posterior capsular tear and anterior
prolapse of vitreous occur, a limited anterior vitrectomy is performed, and
the IOL is inserted either into the ciliary sulcus and sutured to the iris or
sclera or an open-loop anterior chamber IOL may be used. The remainder
of the procedure for PKP is the same as described previously.
B
Artificial Cornea (Keratoprosthesis)
Keratoprosthesis implantation is performed in patients in whom corneal
Fig. 4.27.18 Femtosecond-Assisted Lamellar Keratoplasty (FALK). (A) Residual
transplantation is considered high risk, with a very high likelihood of graft
granular dystrophy and central corneal scar seen in a patient after corneal
transplantation. When the dystrophy recurred, phototherapeutic keratectomy (PTK)
failure, such as those with a history of multiple graft failures or deep neo-
had been performed on the PTK, which eliminated some of the granular deposits vascularization of the cornea.
but caused some corneal haze. (B) After FALK—FALK was performed to remove
the corneal haze and residual anterior granular deposits. FALK (arrowheads) was Boston K-Pro
centered over the visual axis, not over the corneal graft (arrows). (Courtesy Dr. C. L. The Boston Keratoprosthesis (K-Pro) (formerly known as the Dohlman–
Karp.) Doane Kpro) has been under development since the 1960s. It received
Food and Drug Administration (FDA) approval for commercialization in 303
1992. It is the most commonly used keratoprosthesis in the world.23 The
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keratoprosthesis is made of clear polymethyl methacrylate (PMMA) plastic
4 and has two pieces that take the shape of a collar button. The device is
inserted into a corneal graft, which is then transplanted into the recipient’s
cloudy cornea. There are two types of the Boston K-Pro: (1) type I, available
MODIFIED OSTEO-ODONTO KERATOPROSTHESIS
in phakic and pseudo-phakic versions, is used in patients with an adequate

ocular surface, and (2) type II, which is placed through the lids in patients oral mucosa
with severe ocular surface disease. with opening
AlphaCor
The AlphaCor implant, approved by the FDA in 2003, is made of a flexible
hydrogel material similar to a soft contact lens. It contains a central clear
zone that provides refractive power and a peripheral skirt or rim made of a
special material that encourages the eye to heal over the device. The device
is available in two powers: one for aphakic and one for phakic patients. The
two-stage surgery involves the initial implantation of the AlphaCor device
into the cornea of the recipient and the creation of a protective conjunctival
flap over the prosthesis. The subsequent removal of the flap allows light to
pass through the central clear zone to restore vision.24
A retroprosthetic membrane can occur following implantation of any
artificial cornea and can be removed by using a YAG (neodymium-doped
yttrium aluminum garnet) laser, unless highly vascular. Migration of the
AlphaCor under the lamellar flap can occur.
Modified Osteo-Odonto-Keratoprosthesis
The osteo-odonto-keratoprosthesis (OOKP) was first described in Italy
and documented in 1963 by Benedetto Strampelli and later modified by
Giancarlo Falcinelli et al. for the treatment of bilateral corneal blindness
in patients with end-stage ocular surface disorders. Falcinelli’s group has Fig. 4.27.19 Modified Osteo-Odonto Keratoprosthesis (MOOKP). Schematic
completed more than 220 cases, with an anatomical success rate of 94% drawing of the placement of the osteo-odonto-keratoprosthesis between the
and a mean follow-up of 9.4 years.25 The first modified OOKP (MOOKP) grafted buccal mucosa and the scarred and vascularized ocular surface. (Courtesy
was performed in the United States in 2009. Sawatari S, Perez VL, Parel JM, et al. Oral and maxillofacial surgeons’ role in the first
successful modified osteo-odonto-keratoprosthesis performed in the United States.
The newer MOOKP consists of a cylindrical PMMA lens embedded
J Oral Maxillofac Surg 2011:69:1750–56, by kind permission.)
within the patient’s own tissue (heterotopic autograft of the patient’s tooth
root and alveolar bone). The complete implantation is a three-stage pro-
cedure. Initially, the lens, iris, and vitreous are removed from the eye. A Anesthesia
portion of the tooth (preferably canine), bone, and periodontal complex is
concurrently resected, typically with the assistance of an oral maxillofa- Superficial corneal procedures usually are performed under cover of
cial surgeon, and shaped into a thin rectangular lamina. Some surgeons topical anesthesia.
advocate the procurement of the bone lamina from the tibia. The PMMA
lens is mounted into the center of the lamina, and the complex is placed Specific Techniques
into a subcutaneous pocket. After 1–2 months, a patch of buccal mucosa
is obtained and sutured over the scarred and vascularized ocular surface. Superficial Keratectomy
Alternatively, the first two stages may be performed simultaneously. After Preoperative Evaluation and Diagnostic Approach
a minimum period of 3 months, the lamina is retrieved from the sub- Superficial keratectomy may be conducted either mechanically or with the
cutaneous pocket. After trephinating appropriately into both the cornea excimer laser and consists of removal of pathological epithelial or subepi-
and oral mucosa for the cylindrical lens, the prosthesis is then secured to thelial tissues. An AS-OCT may be helpful in delineating the depth of the
the surface of the eye between the layers of the scarred cornea and buccal corneal pathology. Indications include the following:17
mucosa using absorbable suture (Fig. 4.27.19).25
Like any other type of keratoprosthesis, patients after MOOKP require
• Anterior corneal dystrophies.
lifelong follow-up. Early in the postoperative period, a need exists for
• Band keratopathy—often performed in conjunction with EDTA
chelation.
topical broad spectrum antibiotics. Once the mucosa is healed, there is
no need for chronic topical antibiotic treatment. Multiple complications
• Superficial pannus or scar.
can occur after MOOKP, including glaucoma, which is the most common
• Corneal dermoid, pterygium, or Salzmann’s nodules.
cause for loss of vision after MOOKP. For this reason, patients need IOP
• Excision of retained foreign bodies.
estimation (by finger palpation of the globe) and optic nerve head evalua- Superficial keratectomy also is used to obtain corneal tissue for microbi-
tion at every visit. ological or histological examination in the setting of infection or neoplasia.
Outcome Surgical Techniques

After the epithelium has been removed, the abnormal tissue is removed
Corneal grafting techniques, such as PKP, ALK, and triple procedures, manually with a blade, a diamond burr, or the excimer laser. The corneal
have become reliable and popular surgical techniques. Careful attention bed is left as smooth as possible. Bandage contact lenses or antibiotic oint-
to preoperative evaluation, surgical techniques, and postoperative management with a patch may be administered.
ment will improve surgical outcome and patients’ satisfaction.
Complications and Postoperative Management
Bandage soft lenses, antibiotic drops, or aggressive lubrication should be
SUPERFICIAL CORNEAL PROCEDURES continued until the corneal epithelium has healed. Oral analgesics are
Historical Review sometimes necessary to manage postoperative discomfort. Complications
after superficial keratectomy include persistent epithelial defect, infection,
Superficial corneal procedures include corneal glue application (see Chapter and corneal scarring.
4.31), superficial keratectomy for anterior corneal degenerations and dys-
trophies, treatment of band keratopathy using ethylenediaminetetraacetic Corneal Biopsy
acid (EDTA; see Chapter 4.22), and corneal biopsy. With regard to superfi- Preoperative Evaluation and Diagnostic Approach
cial keratectomy for corneal dystrophies and other anterior pathologies, the Corneal biopsy is indicated in patients who have unresponsive and per-
304 advent of excimer laser phototherapeutic keratectomy (PTK) has become sistently culture-negative corneal ulcers.26 Infections that arise from atyp-
an effective alternative. ical mycobacteria, fungus, Acanthamoeba, and Streptococcus viridans with
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Outcome
Eyes that undergo superficial corneal procedures, such as superficial kera- 4.27
tectomy and corneal biopsy, generally heal well. The success of these tech-
niques depends on the rate of re-epithelization and the underlying ocular
Corneal Surgery
surface pathology.
PHOTOTHERAPEUTIC KERATECTOMY
The use of high-energy radiation of wavelength 193 nm is used to treat
corneal pathology and smooth corneal surface irregularities. Laser energy
emitted by the argon–fluoride (ArF) excimer laser for these purposes is
referred to as PTK. The concept was first suggested by Trokel in 1983
and was approved by the FDA in 1995. PTK allows for the precise abla-
tion of selected tissues in width and depth, leading to a regularization of
the stromal bed. This can be used to treat anterior corneal pathology and
thereby defer or eliminate the need for lamellar or penetrating kerato-
plasty.28 Optimal results occur with pathology in the superficial 10%–20%
of the cornea.29-33

Preoperative evaluation includes uncorrected visual acuity, best-corrected
visual acuity by manifest refraction, hard contact lens refraction, pupil size
Fig. 4.27.20 Partial Trephination of the Cornea. A 3-mm dermatological trephine measurements in ambient and near-dark lighting, slit-lamp biomicroscopy,
is used to trephinate the cornea partially—both infected and noninfected cornea
dilated fundus examination, corneal topography, and wavefront analysis.
are straddled.
The type of pathology and the proximity of the pathology to the pupillary
center are documented, and the depth of pathology (as well as total corneal
thickness) should be determined by AS-OCT. To plan the most effective
procedure, determination of the pathology’s ablation characteristics is nec-
essary. The most common indications for PTK include recurrent erosion
syndrome, anterior corneal dystrophies, superficial corneal scars, and
Salzmann’s nodules 29–32
Contraindications to PTK include severe keratoconjunctivitis sicca,
uncontrolled uveitis, severe blepharitis, exposure keratopathy, and sys-
temic immunosuppression. Moreover, PTK should be avoided in patients
who have neurotrophic corneas (including previous herpes simplex or
zoster keratitis or trigeminal nerve injury), collagen vascular disease, and
diabetes because of potential problems with wound healing. Because of
potential for microorganism spread during treatment, PTK should not be
used for deep corneal scars or in active microbial keratitis, including infec-
tious crystalline keratopathy.34,35
Surgical Techniques
Corneal Dystrophies, Scars, and Elevated Opacities
The goals of treatment of anterior stromal dystrophies are to ablate the
confluent opacities in the visual axis and to remove the least amount of
tissue possible to achieve the optimal visual outcome. Typically, the bulk
of the lesions found in epithelial–stromal transforming growth factor-β–
induced dystrophies are located anteriorly (Fig. 4.27.22).36 The middle and
deep stroma often have fewer lesions with intervening clear stroma. Sub-
Fig. 4.27.21 A blade is used to gently dissect the corneal tissue and removed with sequently, deeper lesions are not ablated.37,38
forceps. Masking fluids are used to help fill in depressions and expose eleva-
tions of an irregular corneal surface by absorbing laser energy and thus
shielding depressions. The most important principle is to use just enough
associated crystalline keratopathy are examples of infectious disorders that masking fluid to cover the “valleys.” Carboxymethylcellulose 0.5% is of
may require corneal biopsy for definitive causative organism identification. medium viscosity and efficiently covers the valleys and exposes the ele-
vated areas. Methylcellulose 1%–2% is a high-viscosity fluid that may cover
Surgical Techniques peaks, whereas hydroxypropylmethylcellulose 0.1% with dextran is of low
After topical anesthetic, a sterile, hand-held trephine (2–3 mm dermato- viscosity and may leave valleys as well as peaks partly exposed.37 It often
logical punch) is used at the slit lamp to achieve a partial-thickness treph- is best to use more than one agent, depending on the particular corneal
ination containing the pathological specimen. The size of the trephine surface. Corneal dystrophies may recur after PTK. PTK may be repeated
depends on that of the lesion and the number of studies planned for the for recurrences even with previous grafts (Fig. 4.27.23). The success rate
sample. The trephine is positioned to straddle the junction of diseased for recurrent granular corneal dystrophy type 1 or lattice dystrophy is
and normal corneal tissue (Fig. 4.27.20). After the partial-thickness treph- extremely high and comparable with the high success rate for primary
ination, the edge of the lesion, most easily in the area of healthy corneal Reis–Bückler dystrophy, in which the deposits occur at Bowman’s layer.28
tissue, is lifted using 0.12 forceps and dissected off the cornea using a Macular corneal dystrophy and granular corneal dystrophy type 2 (formerly
blade (Fig. 4.27.21). The femtosecond laser also has been used to perform Avellino’s dystrophy) have deeper lesions. Neither is usually amenable
corneal biopsies.27 The tissue is divided and sent for microbiological and to PTK.
histopathological evaluation. Elevated corneal opacities are often amenable to manual keratectomy
with the use of a blade, which is efficacious when a suitable plane is found
Complications and Postoperative Management to leave a smooth surface on the cornea. When a plane cannot be found, it
Complications can include perforation and postoperative secondary is possible to “debulk” the elevation and smooth the remaining area using 305
infection. the excimer laser. Alternatively, the epithelium may be removed from the
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4
Fig. 4.27.22 Granular Dystrophy. (A) Preoperative anterior appearance of the

opacities in a patient who has granular dystrophy. (B) The same eye 3 months
after phototherapeutic keratectomy. (With permission from Salz JJ, McDonnell PJ,
McDonald MB, editors. Corneal laser surgery. St Louis, MO: Mosby; 1995.)
area over the elevated lesion, and then photoablation performed to the
underlying pathology, the surrounding epithelium is left in place to serve
as a masking agent. 29,31,32
Postoperative Care
In the immediate postoperative period, a bandage soft contact lens is B
applied, and the patient is instructed to use broad-spectrum topical anti-
biotics. Topical corticosteroid, such as prednisolone acetate 1% or fluoro- Fig. 4.27.23 Recurrent Granular Dystrophy in a Penetrating Keratoplasty.
metholone 0.1%, four times a day, is used and tapered to once daily within (A) Preoperative appearance of the opacities in a patient with recurrent granular
1 month. Topical nonsteroidal anti-inflammatory drops may help control dystrophy in a penetrating keratoplasty. (B) Phototherapeutic keratectomy was
pain, which may be severe, so oral analgesics are frequently used.28,31,37 performed and immediately postoperatively there was a dramatic reduction in the
Patients are examined every 24–72 hours until re-epithelization is com- anterior stromal granules. (Bandage contact lens in place.) The patient ultimately
plete, which generally occurs within 1 week.38 developed haze and required a femtosecond-assisted lamellar keratoplasty.
(Courtesy Dr. C. L. Karp.)
Complications
Hyperopia Irregular Astigmatism and Decentration
The most common side effect of PTK is induced hyperopia, which results Irregular astigmatism is an undesirable potential outcome that may be min-
from flattening of the central cornea. To avoid this problem, 1 diopter of imized by using masking agents to help achieve a smooth corneal contour
hyperopic correction is added for every 14–20 µm of PTK tissue ablation, postoperatively. Decentration may also lead to irregular astigmatism.
performed at the time of treatment.39
Pain
Myopia/Myopic Astigmatism Pain may be severe after excimer laser photoablation. Judicious use of
Myopia and myopic astigmatism may be induced when the periphery or topical corticosteroids, nonsteroidal anti-inflammatory agents, chilled bal-
306 paracentral cornea undergoes a deeper ablation compared with the central anced salt solution, and oral pain medication has helped in pain control
cornea, and this may occur in the treatment of paracentral opacities. after excimer laser treatment.40
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Delayed Epithelization astigmatism.42 Medical treatment of the rejection episodes have been
Epithelial healing is usually complete within the first week. Delayed epi-
thelial healing puts the patient at risk for infection and haze. Persistent
reported as successful.
4.27
epithelial defects or recurrent erosions may be more common in patients Outcome
who have preoperative DED, herpes simplex virus infection, or diabetes.
Corneal Surgery
Bandage contact lenses and lubrication are helpful in the promotion of The 193 nm ArF excimer laser is an excellent tool in the treatment of ante-
epithelial healing.28 Punctal plugs often are useful in patients who have rior corneal pathology and surface irregularities. The expense and risks
signs or symptoms of DED. The use of blood derivatives or a temporary associated with penetrating keratoplasty, including the risks of intraocular
tarsorrhaphy may be considered in recalcitrant cases. surgery and anesthesia, may be avoided. Treatment must be individual-
ized on the basis of the type of pathology and its ablation characteristics
Bacterial Keratitis and depth.
Bacterial keratitis is a feared postoperative complication because of the
presence of an epithelial defect and the placement of a contact lens on what
may be an already compromised cornea. Most surgeons performing PTK
KEY REFERENCES
believe the ability of bandage contact lenses to decrease pain and help epi- Anwar M, Teichmann KD. Deep lamellar keratoplasty: surgical techniques for anterior
lamellar keratoplasty with and without baring of Descemet’s membrane. Cornea
thelial wound healing outweighs the risk of bacterial keratitis. Prophylactic 2002;21:374–83.
antibiotic drops are used postoperatively. Stromal infiltrates are managed Ayres BD, Rapuano CJ. Excimer laser phototherapeutic keratectomy. Ocul Surf 2006;4:196–206.
similarly as in patients who have had photorefractive keratectomy. Non- Binder PS. Refractive errors encountered with the triple procedure. In: Cornea, refractive
steroidal anti-inflammatory agents, contact lenses, and infectious keratitis surgery, and contact lens. Transactions of the New Orleans Academy of Ophthalmology.
New York: Raven Press; 1987. p. 111–20.
may lead to infiltrates.32,41 Boruchoff SA, Thoft RA. Keratoplasty: lamellar and penetrating. In: Smolin G, Thoft RA,
editors. The cornea. Boston: Little, Brown; 1994. p. 645–65.
Viral Keratitis Eye Bank Association of America. Medical Standards. June 2015 update www.restoresight.org.
Herpes simplex virus may be reactivated after PTK. Treatment of patients Accessed February 2017.
who have a history of herpes is controversial. In cases that are treated, Glasser DB. Medical standards for eye banking. In: Krachmer JH, Mannis MJ, Holland EJ,
editors. Cornea. St Louis: Mosby; 2011. p. 335–44.
a prophylactic regimen of preoperative and postoperative oral antiviral Jain S, Azar DT. New lamellar keratoplasty techniques: posterior keratoplasty and deep lamel-
therapy is given. lar keratoplasty. Curr Opin Ophthalmol 2001;12:262–8.
McGhee CNJ, Farjo AA, Serdarevic ON, editors. Corneal surgery, theory technique and
Recurrence and Haze tissue. St Louis: Mosby; 2009. p. 383–96.
Nijm LM, Mannis MJ, Holland EJ. The evolution of contemporary keratoplasty. In: Krachmer
Corneal dystrophies treated with PTK may recur. Retreatment may be per- JH, Mannis MJ, Holland EJ, editors. Cornea. St Louis: Mosby; 2011. p. 1321–5.
formed, although the possibilities of increased hyperopia and anisometro- Rapuano CJ. Phototherapeutic keratectomy: who are the best candidates and how do you
pia must be considered. Furthermore, haze often results after PTK and treat them? Curr Opin Ophthalmol 2010;21:280–2.
may be confluent and visually significant. Haze results from the presence Rudnisky CJ, Belin MW, Guo R, et al. Boston Type 1 Keratoprosthesis Study Group. Visual
Acuity Outcomes of the Boston Keratoprosthesis Type 1: Multicenter Study Results. Am
of activated keratocytes and their products (newly formed collagen and pro- J Ophthalmol 2016;162:89–98.
teoglycans in an irregular network).30,42,43 Haze often decreases over time, Tan DT, Dart JK, Holland EJ, et al. Corneal transplantation. Lancet 2012;379:1749–61.
and a period of 12 months is allowed to elapse before the haze is treated. Thompson MJ, Cavanaugh TB. Combined keratoplasty and lens removal: the triple proce-
The intraoperative use of mitomycin C has reduced the likelihood of haze dure. In: Brightbill FS, McDonnell PJ, McGhee CNJ, et al., editors. Corneal surgery,
theory technique and tissue. St Louis: Mosby; 2009. p. 383–96.
and scarring and improved visual outcomes.44 Yoo SH, Hurmeric V. Femtosecond laser-assisted keratoplasty. Am J Ophthalmol
2011;151:189–91.
Graft Rejection
Corneal graft rejection in PTK-treated patients has been reported, as in
Hersh et al.45 for recurrent lattice dystrophy and others for postoperative
307
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23. Zerbe BL, Belin MW, Ciolino JB. Boston Type 1 Keratoprosthesis Study Group.
REFERENCES Results from the multicenter Boston Type 1 Keratoprosthesis Study. Ophthalmology
1. Reisinger F. De Keratoplastic, ein Versuch zur Erweiterring dev Augenhelkunde. Baier-

2006;113:1779, 1–7.
24. Jirásková N, Rozsival P, Burova M, et al. AlphaCor artificial cornea: clinical outcome. Eye
4.27
sche Ann Abhandl 1824;1:207. (Lond) 2011;25:1138–46.
2. Von Hippel A. On transplantation of the cornea. Berichte Ophthalmol Gesellschaft Her- 25. Hille K, Grabner G, Liu C, et al. Standards for modified osteoodontokeratoprosthesis
Corneal Surgery
delberg 1886;18:54. (OOKP) surgery according to Strampelli and Falcinelli: The Rome–Vienna protocol.
3. Elschnig A. On keratoplasty. Prag Med Wochenschr 1914;39:30. Cornea 2005;24:895–908.
4. Eye Bank Association of America. Statistical report 2015. Available at www.restoresight. 26. Madhura G. Joag, Sayed-Ahmed Ibrahim O., Karp CL. The corneal ulcer. In: Mannis MJ,
org. Accessed February 2017. Holland EJ, editors. Cornea. 4th ed. St Louis: Mosby; 2017. p. 241–5.
5. Glasser DB. Medical standards for eye banking. In: Krachmer JH, Mannis MJ, Holland 27. Kim JH, Yum JH, Lee D, et al. Femtosecond corneal biopsy: novel technique of corneal
EJ, editors. Cornea. St Louis: Mosby; 2011. p. 335–44. biopsy by using a femtosecond laser in infectious ulcers. Cornea 2008;27:363–5.
6. Eye Bank Association of America. Medical Standards June 2016 update. Available at www. 28. Stark WJ, Chamon W, Kamp MT, et al. Clinical follow-up of 193 nm ArF excimer laser
restoresight.org. Accessed February 2017. photokeratectomy. Ophthalmology 1992;99:805–11.
7. Daniel MC, Bohringer D, Maier P, et al. Comparison of long-term outcomes of femtosec- 29. Stasi K, Chuck RS. Update on phototherapeutic keratectomy. Curr Opin Ophthalmol
ond laser-assisted keratoplasty with conventional keratoplasty. Cornea 2016;35:293–8. 2009;20:272–5.
8. Bidaut-Garnier M, Monnet E, Prongue A, et al. Evolution of corneal graft survival over a 30. Marshall J, Trokel S, Rothery S, et al. Photoablative reprofiling of the cornea using an
30-year period and comparison of surgical techniques: a cohort study. Am J Ophthalmol excimer laser: photorefractive keratectomy. Lasers Ophthalmol 1986;1:23–44.
2016;163:59–69. 31. Ayres BD, Rapuano CJ. Excimer laser phototherapeutic keratectomy. Ocul Surf
9. Vinciguerra P, Epstein D, Albe E, et al. Corneal topography-guided penetrating ker- 2006;4:196–206.
atoplasty and suture adjustment: new approach for astigmatism control. Cornea 32. Rapuano CJ. Phototherapeutic keratectomy: who are the best candidates and how do you
2007;26(6):675–82. treat them? Curr Opin Ophthalmol 2010;21:280–2.
10. Nijm LM, Mannis MJ, Holland EJ. The evolution of contemporary keratoplasty. In: 33. Fagerholm P. Phototherapeutic keratectomy: 12 years of experience. Acta Ophthalmol
Krachmer JH, Mannis MJ, Holland EJ, editors. Cornea. 4th ed. St Louis: Mosby; 2011. p. Scand 2003;81:19–32.
1249–55. 34. Gottsch JD, Gilbert ML, Goodman DF, et al. Excimer laser ablative treatment of micro-
11. Yoo SH, Hurmeric V. Femtosecond laser-assisted keratoplasty. Am J Ophthalmol bial keratitis. Ophthalmology 1991;98:146–9.
2011;151:189–91. 35. Eiferman RA, Forgey DR, Cook YD. Excimer laser ablation of infectious crystalline kera-
12. Lu Y, Chen X, Yang L, et al. Femtosecond laser-assisted deep anterior lamellar keratoplasty topathy. Arch Ophthalmol 1992;110:18.
with big-bubble technique for keratoconus. Indian J Ophthalmol 2016;64(9):639–42. 36. Salz JJ, McDonnell PJ, McDonald MB, editors. Corneal laser surgery. St Louis: Mosby;
13. Melles GR, Remeijer L, Geerardes AJ, et al. A quick surgical technique for deep, anterior 1995.
lamellar keratoplasty using visco-dissection. Cornea 2000;19:427–32. 37. Thompson V, Durrie DS, Cavanaugh TB. Philosophy and technique for excimer laser
14. Balestrazzi A, Malandrini A, Traversi C, et al. Air-guided manual deep anterior lamel- phototherapeutic keratectomy. Review. Refract Corneal Surg 1993;9(Suppl. 2):81–5.
lar keratoplasty: long-term results and confocal microscopic findings. Eur J Ophthalmol 38. Azar DT, Jain S, Woods R, et al. Phototherapeutic keratectomy: the VISX experience.
2007;17:897–903. In: Salz JJ, McDonnell PJ, McDonald MB, editors. Corneal laser surgery. St Louis:
15. Steele ADM, Kirkness CM. Manual of systematic corneal surgery. New York: Churchill Mosby; 1995. p. 213–26.
Livingstone; 1992. p. 57. 39. Amano S, Kashiwabuchi K, Sakisaka T, et al. Efficacy of hyperopic photorefractive ker-
16. Hersh PS. Ophthalmic surgical procedures. Boston: Little, Brown; 1988. p. 213. atectomy simultaneously performed with phototherapeutic keratectomy for decreasing
17. Anwar M, Teichmann KD. Deep lamellar keratoplasty: surgical techniques for ante- hyperopic shift. Cornea 2016;35:1069–72.
rior lamellar keratoplasty with and without baring of Descemet’s membrane. Cornea 40. Garcia R, de Andrade DC, Teixeira MJ, et al. Mechanisms of corneal pain and impli-
2002;21:374–83. cations for postoperative pain after laser correction of refractive errors. Clin J Pain
18. De Benito-Llopis L, Mehta JS, Angunawela RI, et al. Intraoperative anterior segment 2016;32:450–8.
optical coherence tomography: a novel assessment tool during deep anterior lamellar 41. Rathi VM, Vyas SP, Sangwan VS. Phototherapeutic keratectomy. Indian J Ophthalmol
keratoplasty. Am J Ophthalmol 2014;157(2):334–41. 2012;60:5–14.
19. Thompson MJ, Cavanaugh TB. Combined keratoplasty and lens removal: the triple pro- 42. Epstein RJ, Robin JB. Corneal graft rejection episode after excimer laser phototherapeutic
cedure. In: Brightbill FS, McDonnell PJ, McGhee CNJ, et al., editors. Corneal surgery, keratectomy. Arch Ophthalmol 1994;112:157.
theory technique and tissue. St Louis: Mosby; 2009. p. 383–96. 43. Fantes FE, Hanna KD, Waring GO, et al. Wound healing after excimer laser keratomileu
20. Binder PS. Refractive errors encountered with the triple procedure. In: Cornea, refractive sis (photorefractive keratectomy) in monkeys. Arch Ophthalmol 1990;108:665–75.
surgery, and contact lens. Transactions of the New Orleans Academy of Ophthalmology. 44. Jain S, McCally RL, Connolly PJ, et al. Mitomycin C reduces corneal light scattering after
New York: Raven Press; 1987. p. 111–20. excimer keratectomy. Cornea 2001;20:45–9.
21. Oie Y, Nishida K. Triple procedure: cataract extraction, intraocular lens implantation, and 45. Hersh PS, Jordan AJ, Mayers M. Corneal graft rejection episode after excimer laser pho-
corneal graft. Curr Opin Ophthalmol 2017;28(1):63–6. totherapeutic keratectomy. Arch Ophthalmol 1993;111:735–6.
22. Retzlaff J. Posterior chamber implant power calculation: regressive formula. J Am Intra-
ocular Implant Soc 1980;6:268–73.
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Section 9 Surgery
Conjunctival Surgery
Victoria S. Chang, Carolina L. Mercado, Ibrahim O. Sayed-Ahmed, Allister Gibbons, Carol L. Karp 4.28
Definition: Conjunctival procedures may be used to cover an unstable
or painful corneal surface or to remove pterygia or other abnormal
growths.
Key Features
• Careful preoperative planning is critical for success.
• It is important to have a clear understanding of intraoperative and
postoperative complications and management.
Associated Feature
• Recurrences of pterygium may be more aggressive than initial
pterygium.
HISTORICAL REVIEW
Conjunctival procedures include a bridge conjunctival flap (Gundersen Fig. 4.28.1 360° Peritomy. Westcott scissors are used. The dissection is carried out
flap),1,2 pterygium surgery, conjunctival excision for conjunctivochalasis, toward the corneal limbus with care not to buttonhole the conjunctiva. (Courtesy
limbal stem cell transplantation (see Chapter 4.30), and tumor removal. Dr. R. K. Forster.)
In a conjunctival flap procedure, a hinged flap of conjunctiva is created
to cover an unstable or painful corneal surface. Conjunctival flaps, partial
or total, have remained an effective procedure over the past 100 years for
the treatment of challenging ocular surface disorders in patients with poor Relative contraindications for conjunctival flap include active infectious
visual prognosis. keratitis and corneal perforation in eyes with good visual potential.
Pterygium surgery dates back to 1855, when Desmarres3 first per-
formed a transposition of the pterygium head. In 1872, Arlt recognized the Surgical Techniques
importance of covering the epibulbar defect after pterygium excision and The availability of mobile conjunctiva is evaluated. Typically, the superior
described the first conjunctival graft.4 bulbar conjunctiva offers increased tissue availability. The corneal epithe-
lium is mechanically debrided using a No. 64 blade or a cellulose sponge.
ANESTHESIA Application of lidocaine 4% or absolute alcohol may assist in loosening the
corneal epithelium. A 360° limbal peritomy is then performed (Fig. 4.28.1).
Conjunctival surgeries typically are performed under cover of local, ret- The globe is rotated inferiorly from the donor site using a traction
robulbar, infiltrative, or (rarely) general anesthesia. To prevent squeezing suture placed at the limbus to increase superior exposure. A semicircular
during surgery, a lid block is sometimes employed. General anesthesia is incision, parallel to the corneal limbus, is made as posteriorly as possible.
reserved for pediatric patients and uncooperative adults. The dissection of a thin conjunctival flap is carried anteriorly until the
corneal limbus is reached. Adequate dissection and undermining of this
flap laterally is important for the subsequent anterior mobilization of the
flap over the cornea and to prevent traction. The conjunctival flap is freed
SPECIFIC TECHNIQUES completely from its underlying Tenon’s capsule.
Conjunctival Flap The well-mobilized conjunctival flap then is stretched to cover the
desired area (Fig. 4.28.2). The superior and inferior aspects of the flap are
Preoperative Evaluation and Diagnostic Approach secured on the sclera using interrupted or running 10-0 nylon sutures. The
Common indications for conjunctival flap include the following: edges of the conjunctiva may be reapposed with 7-0 or 8-0 Vicryl suture in
a running fashion (Fig. 4.28.3). Alternatively, fibrin glue has been shown to
• Nonhealing sterile corneal ulcerations secondary to chemical or thermal be a viable option for Gundersen flap surgery, with the possible advantage
injuries, herpetic infections, exposure keratopathies, and other neuro- of reduced surgical and recovery time.5
trophic diseases that are unresponsive to medical treatment. A partial conjunctival flap is used in certain circumstances, such as for
• Painful bullous keratopathy or other chronically inflamed ocular surface focal nonhealing corneal ulcers that do not require coverage of the entire
disorders in eyes with low visual potential, in which penetrating or cornea. The procedure includes scraping of the corneal epithelium, mobi-
selective keratoplasty is not indicated; and in which simpler manage- lization of the conjunctiva in the appropriate quadrant, and suturing of the
ment techniques, such as soft contact lenses or anterior stromal punc- conjunctival flap over the localized corneal defect (see Fig. 4.28.3).
ture, have failed. A total Tenon–conjunctival flap (TCF) has been used to increase corneal
• Necrotizing scleritis resulting in severe melt that is unresponsive to sys- thickness in mildly phthisical eyes in preparation for prosthetic scleral
temic anti-inflammatory treatments, requiring tectonic support. shells.6 A modified Gundersen flap with the use of amniotic membrane
308 • Blind eyes in need of surface preparation for prosthetic shells or cos- transplantation has been reported in a small series of patients as a prom-
metic contact lenses. ising technique.7
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4.28
Fig. 4.28.4 Dissection of the Head of the Pterygium From the Cornea. A blade
is used.
Fig. 4.28.2 Mobilization of the conjunctival flap to the desired area of the cornea.
(Courtesy Dr. R. K. Forster.)
Fig. 4.28.5 Removal of the Body of the Pterygium. Westcott scissors are used
with care to avoid damage to the underlying rectus muscle.
Fig. 4.28.3 Conjunctival Flap Over a Sterile Ulcer. The flap is sutured into position
with 10-0 nylon sutures superiorly and 7-0 Vicryl sutures through the inferior limbal
episclera. (Courtesy Dr. R. K. Forster.)
• Severe irritation not relieved by medical therapy.
• Surgery for unacceptable cosmetic appearance.
• Reduced motility secondary to pterygium.
Complications and Postoperative Management • Recurrence, with more aggressive growth than in primary lesions.
The most common perioperative complication is the creation of a con-
junctival buttonhole during dissection. Buttonholes should be closed by Surgical Techniques
using running or interrupted sutures. Postoperative complications include Several techniques have been described including bare sclera technique,
retraction of the conjunctival flap, hemorrhagic and epithelial mucous conjunctival autograft placement, amniotic membrane transplantation,
cysts, flap loss from epithelial ingrowth, ptosis, and progression or recur- antimetabolites, radiation, and, in cases of severe recurrence, mucous
rence of inflammation or infection, such as that caused by herpes simplex membrane grafts.
virus.8,9
After healing, a cosmetic contact lens may be fitted. In some cases, Bare Sclera Technique/Simple Closure
penetrating keratoplasty is indicated for visual rehabilitation. Because a Although technically simple, this technique can be associated with recur-
conjunctival flap may have destroyed corneal limbal stem cells, a limbal rence rates as high as 40%.9 Surgically, the lesion may be outlined using
allograft may be considered prior to penetrating keratoplasty. spot cautery or a sterile marker. To facilitate dissection, the eye may be
rotated laterally using traction sutures (6-0 Vicryl or silk) placed at the
Pterygium Surgery superior and inferior corneal limbus. The dissection may be initiated at
the corneal side of the pterygium. Using forceps, the head of the pteryg-
Pterygium, most commonly seen at the nasal limbus, is a conjunctival ium is lifted and dissected off the cornea in a lamellar fashion using sharp
fibrovascular growth over the sclera and onto the cornea (see Chapter 4.9 dissection with a blade (Fig. 4.28.4). Alternatively, the scleral portion may
for more information). be removed first, followed by blunt dissection or avulsion of the corneal
portion. The scleral part of the pterygium is excised by using scissors (Fig.
Preoperative Evaluation and Diagnostic Approach 4.28.5). Care is taken to identify the underlying rectus muscle, especially
Surgical indications for excision of the pterygium include the following: in surgery for recurrent pterygium. The corneal defect may be polished by
using a diamond burr. Antimitotic agents, such as mitomycin-C (MMC)
• Growth of pterygium such that it has impinged on or is imminently 0.02%, have been used to prevent recurrence in conjunction with this tech-
threatening the visual axis. nique. Care should be taken to avoid excessive contact of MMC with the 309
• Reduced vision as a result of induced astigmatism. sclera. Instead of leaving the sclera bare, the conjunctiva can be closed
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Fig. 4.28.8 Corneoscleral melt after pterygium excision associated with the use of
radiation.
Fig. 4.28.6 Dissection of the Conjunctival Graft. The limbus is marked and the membranes are secured using similar techniques as conjunctival auto-
healthy conjunctiva is harvested. The conjunctiva is dissected gently with care not grafts and are especially amenable to the use of fibrin glue. The amni-
to buttonhole the donor tissue. otic membrane is placed stromal side adjacent to the scleral bed. Benefits
include shortened operative time and untouched conjunctiva for future
use, such as in glaucoma surgery. However, in a prospective study (mean
follow-up, 11 months) comparing AMT to conjunctival autografts, AMT
had higher recurrence rates for primary (10.9% versus 2.6%), recurrent
(37.5% versus 9.1%), and all pterygia (14.8% versus 4.9%) compared with
conjunctival autografts, respectively.10 These results establish the use of
conjunctival autografting as the procedure of choice for pterygium surgery
unless a conjunctival preserving technique is indicated.
Other Techniques. Several, more recent techniques have been described
to have success in preventing pterygium recurrence after excision. Limbal
conjunctival autograft (LCAU), in which a free conjunctival graft is har-
vested to include the superficial limbus, has been demonstrated to have
a low recurrence rate (6.9%) after 10 years of follow-up.12 Minor ipsilateral
simple limbal epithelial transplantation (mini-SLET), which utilizes amni-
otic membrane and the placement of limbal epithelial pieces, has been
described in the treatment of 10 eyes without recurrence after 8 months
of follow-up.13
Recurrent Pterygium Excision. Excision of recurrent pterygia can be
especially tedious even for the experienced surgeon because of extensive
fibrosis of the pterygium to the sclera and cornea, distortion of tissue
planes and normal anatomy, and symblepharon formation. The rectus
muscle should be isolated in cases of scarring of the muscle sheath prior
to dissection, and all symblepharon must be released to alleviate any motil-
Fig. 4.28.7 Conjunctival Autograft in Position Over the Previously Excised ity restriction.
Pterygium. Two 10-0 nylon sutures are placed at the limbus and 8-0 Vicryl sutures
are used along the conjunctiva in an interrupted fashion. Care is taken to maintain Antimetabolites and Radiation
the limbus-to-limbus position of the graft. MMC has been used preoperatively, intraoperatively, and postoperatively in
pterygium surgery and appears to reduce the recurrence rates (particularly
if amniotic membrane is used). Antimetabolites, however, have been asso-
with 7-0 or 8-0 Vicryl suture, although the recurrence rates have not been ciated with serious complications, including corneal or scleral melts. Thus,
shown to be significantly reduced with primary closure.10,11 MMC should be used judiciously in cases with a high likelihood of recur-
rence. In addition, beta radiation using strontium-90 has been employed
Autograft and shown to reduce recurrence; however, it may cause significant compli-
Conjunctival autografting is considered the “gold standard” for pterygium cations such as scleral necrosis, cataract, and persistent epithelial defects
surgery because of its low rate of recurrence (rates reported as low as 5% (Fig. 4.28.8). Beta radiation after pterygium surgery has been supplanted
in primary cases) and excellent cosmesis.9 After pterygium excision, the largely by conjunctival or amniotic membrane transplantation.
size of the defect is measured. Commonly, in a nasal pterygium, the super-
otemporal bulbar conjunctiva is used as the donor site. Tractional sutures Fibrin Glue
may be used to rotate the eye downward. The donor conjunctiva is outlined Fibrin glue is a two-component tissue adhesive that is used in many surgi-
using spot cautery or a sterile marker and a thin Tenon’s free conjuncti- cal procedures. One component consists of a protein fibrinogen solution,
val flap is dissected with forceps and scissors (Fig. 4.28.6). It is important and the other consists of a thrombin solution. When mixed together, a
to avoid buttonholes and to maintain limbus-to-limbus orientation of the fibrin clot is formed. Several studies have shown that the use of fibrin
conjunctival flap when transferring the flap to the recipient bed to ensure glue decreases postoperative pain and foreign body sensation and leads to
proper positioning of limbal stem cells. Alternatively, the conjunctival flap reduced operative time and blood loss during surgery.14,15 It is being used
may be rotated on a pedicle. The graft is then secured using Vicryl or 10-0 with increasing frequency with both conjunctival autografts and amniotic
nylon sutures (Fig. 4.28.7), or fibrin glue. membranes. Additionally, fibrin glue eliminates or reduces the number
of sutures required. In a recent study, comparing Vicryl sutures to two of
Amniotic Membrane the most commonly used fibrin glues worldwide, Tisseel (Baxter Corp.,
310 Amniotic membrane transplantation (AMT) has been implemented as an Deerfield, IL) and Evicel glue (Omrix Biopharmaceuticals Ltd., Ramat-Gan,
alternative to conjunctival autografting despite its higher cost. Amniotic Israel), Tisseel glue was found to be superior with regard to pterygium
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4.28
Fig. 4.28.9 Thermocautery of Inferior Conjunctivochalasis. Excess conjunctiva
is grasped with smooth forceps approximately 5 mm from the limbus and then
cauterized with a handheld cautery.
Fig. 4.28.10 Conjunctival Resection for Symptomatic Inferior
Conjunctivochalasis. Wescott scissors and smooth forceps are used to excise the
marked crescent of excess conjunctival tissue.
recurrence, patient comfort, and surgical time.16 Patients must understand

that this is an off-label use for fibrin glue. Patients also need to give their Surgical Techniques
consent for blood product use because fibrin glue is derived from pooled After topical anesthesia is instilled, smooth forceps are used to grasp the
human blood. However, it has been used for many years in thousands excess inferior conjunctiva approximately 5 mm from the limbus, which
of surgeries with no documented cases of transmission of hepatitis B or is then marked with a marking pen. Using Wescott scissors and smooth
C, human immunodeficiency virus (HIV) infection, or prion-mediated forceps, the marked crescent of conjunctival tissue is then excised (see Fig.
disease. Furthermore, donated plasma undergoes viral polymerase chain 4.28.10). Vicryl sutures are then used for simple closure of the conjunctiva,
reaction screening prior to use. or an amniotic membrane transplant can be sutured or glued over the
defect.
Complications and Postoperative Management
Complications of pterygium surgery include recurrence of the pteryg- Complications
ium, conjunctival granuloma, subconjunctival hemorrhage, corneoscleral Recurrence of conjunctivochalasis after simple cautery or even excision
dellen, epithelial inclusion cysts, graft retraction or necrosis, corneal or should be discussed with the patient prior to the procedure. Other com-
scleral melt with the use of antimetabolites or beta radiation, and conjunc- plications that may arise after conjunctival excision include conjunctival
tival fibrosis. Topical antibiotics and corticosteroids are prescribed after fibrosis, subconjunctival hemorrhage, granuloma formation, and cicatri-
surgery. Topical corticosteroids generally are used for 1–2 months postop- cial entropion.
eratively to minimize resultant inflammation.
KEY REFERENCES
Conjunctivochalasis Management Gundersen T. Conjunctival flaps in the treatment of corneal disease with reference to a new
technique of application. Arch Ophthalmol 1958;60:880.
Conjunctivochalasis is a loosely adherent, redundant conjunctiva more Lim LS, How AC, Ang LP, et al. Gundersen flaps in the management of ocular surface
commonly found overlying the inferior bulbar surface, typically in older disease in an Asian population. Cornea 2009;28:747–51.
individuals or those with a history of chronic inflammation. Although often Marticorena J, Rodriguez-Ares MT, Tourino R, et al. Pterygium surgery: conjunctival auto-
asymptomatic, it may interfere with normal tear flow, lubrication of the graft using a fibrin adhesive. Cornea 2006;25:34–6.
Prabhasawat P, Barton K, Burkett G, et al. Comparison of conjunctival autografts, amni-
ocular surface, and cause local exposure and associated irritation or pain. otic membrane grafts, and primary closure for pterygium excision. Ophthalmology
Additionally, if prominent nasally, the redundant conjunctiva may occlude 1997;104(6):974–85.
the lower punctum, resulting in epiphora. In patients with significant Rosenfeld SI, Alfonso EC, Gollamudi S. Recurrent Herpes simplex infection in a conjuncti-
symptoms uncontrolled with topical medications, such as artificial tears val flap. Am J Ophthalmol 1993;116:242–4.
and topical corticosteroids, conjunctival cautery and surgical excision have Rosenthal JW. Chronology of pterygium therapy. Am J Ophthalmol 1953;36:1601.
Tseng SC, Prabhasawat P, Lee SH. Amniotic membrane transplantation for conjunctival
been proposed as treatment modalities. These options must be approached surface reconstruction. Am J Ophthalmol 1997;124(6):765–74.
judiciously, as the condition is likely to recur. Simple cauterization of the Zheng K, Cai J, Jhanji V, et al. Comparison of pterygium recurrence rates after limbal
conjunctiva is usually performed in the office after topical gel anesthetic conjunctival autograft transplantation and other techniques: meta-analysis. Cornea
is applied using smooth forceps to grasp the excess inferior conjunctiva 2012;31:1422–7.
Zloto O, Greenbaum E, Fabian ID, et al. Evicel versus tisseel versus sutures for attaching
several millimeters from the limbus, which is then cauterized (Fig. 4.28.9). conjunctival autograft in pterygium surgery: a prospective comparative clinical study.
Additional options include conjunctival resection (Fig. 4.28.10) and scleral Ophthalmology 2017;124(1):61–5.
fixation of the conjunctiva. Surgical consideration should be given only
when conservative treatment modalities are insufficient in providing ade- Access the complete reference list online at ExpertConsult.com
quate relief.
311
booksmedicos.org
REFERENCES 10. Prabhasawat P, Barton K, Burkett G, et al. Comparison of conjunctival autografts, amni-
otic membrane grafts, and primary closure for pterygium excision. Ophthalmology
1. Gundersen T. Conjunctival flaps in the treatment of corneal disease with reference to a
new technique of application. AMA Arch Ophthalmol 1958;60(5):880–8.
1997;104(6):974–85.
11. Fernandes M, Sangwan VS, Bansal AK, et al. Outcome of pterygium surgery: analysis
4.28
2. Lim LS, How AC, Ang LP, et al. Gundersen flaps in the management of ocular surface over 14 years. Eye (Lond) 2005;19(11):1182–90.
12. Young AL, Ho M, Jhanji V, et al. Ten-year results of a randomized controlled trial com-
disease in an Asian population. Cornea 2009;28(7):747–51.
3. Desmarres LA. Traité théorique et practique des maladies des yeux, vol. 2. Paris: G paring 0.02% mitomycin C and limbal conjunctival autograft in pterygium surgery. Oph-
Baillière; 1855. thalmology 2013;120(12):2390–5.
4. Rosenthal JW. Chronology of pterygium therapy. Am J Ophthalmol 1953;36(11):1601–16. 13. Hernandez-Bogantes E, Amescua G, Navas A, et al. Minor ipsilateral simple limbal
5. Chung HW, Mehta JS. Fibrin glue for Gundersen flap surgery. Clin Ophthalmol epithelial transplantation (mini-SLET) for pterygium treatment. Br J Ophthalmol
2013;7:479–84. 2015;99(12):1598–600.
6. Galindo-Ferreiro A, Akaishi PS, Al-Aliwi M, et al. Five years’ experience with tenon- 14. Marticorena J, Rodriguez-Ares MT, Tourino R, et al. Pterygium surgery: conjunctival
conjunctival flaps in phthisical eyes. Semin Ophthalmol 2017;32(5):642–6. autograft using a fibrin adhesive. Cornea 2006;25(1):34–6.
7. Guell JL, Morral M, Gris O, et al. Treatment of symptomatic bullous keratopathy with 15. Kaufman HE, Insler MS, Ibrahim-Elzembely HA, et al. Human fibrin tissue adhesive for
poor visual prognosis using a modified Gundersen conjunctival flap and amniotic mem- sutureless lamellar keratoplasty and scleral patch adhesion: a pilot study. Ophthalmology
brane. Ophthalmic Surg Lasers Imaging 2012;43(6):508–12. 2003;110(11):2168–72.
8. Rosenfeld SI, Alfonso EC, Gollamudi S. Recurrent herpes simplex infection in a con- 16. Zloto O, Greenbaum E, Fabian ID, et al. Evicel versus tisseel versus sutures for attach-
junctival flap. Am J Ophthalmol 1993;116(2):242–4. ing conjunctival autograft in pterygium surgery: a prospective comparative clinical study.
9. Zheng K, Cai J, Jhanji V, et al. Comparison of pterygium recurrence rates after limbal Ophthalmology 2017;124(1):61–5.
conjunctival autograft transplantation and other techniques: meta-analysis. Cornea
2012;31(12):1422–7.
311.e1
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Section 9 Surgery
Endothelial Keratoplasty: Targeted

Treatment for Corneal Endothelial 4.29
Dysfunction IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Marianne O. Price, Francis W. Price, Jr.
rather than sutures to secure the donor tissue, in a technique he called

Definition: Endothelial keratoplasty has significant advantages over posterior lamellar keratoplasty (PLK).16 Later renamed deep lamellar endothe-
penetrating keratoplasty as a targeted method to replace endothelial lial keratoplasty (DLEK), this technique required lamellar dissection of the
cells in the treatment of endothelial dysfunction. recipient and donor corneal tissue. Both dissections were originally done
manually by using a series of curved blades of increasing length.
Melles subsequently eliminated the challenging recipient stromal dis-
Key Feature section and excision steps by peeling the Descemet’s membrane (DM) and
dysfunctional endothelium from the recipient cornea before implanting
• Targeted replacement of corneal endothelium through a small the donor tissue.17 This EKP modification became known as Descemet’s
2–5 mm incision.
stripping with endothelial keratoplasty (DSEK).10,13 Use of a microkeratome
was introduced to facilitate the donor lamellar dissection,12,18 and this tech-
nique variation was referred to as either DSEK or Descemet’s stripping
Associated Features automated endothelial keratoplasty (DSAEK). In 2005, eye banks began
• Rapid visual recovery. performing the donor lamellar dissection with a microkeratome and pro-
• Few activity restrictions. viding “precut” tissue to surgeons.19
• No significant increase in astigmatism. Even though DSEK provides 20/40 or better vision more reliably com-
• Minimal disruption of corneal innervation. pared with PKP, fewer patients than expected achieve 20/20 vision, and
• Lower risk of immunological rejection than with penetrating variations in the donor stromal thickness increase the higher order aber-
keratoplasty. rations of the posterior corneal surface.20 Over time, surgeons have grav-
• Rapid sequential surgery. itated toward use of thinner DSEK tissue, which seems to provide better
vision with less risk of rejection than thicker tissue,21 although the rate of
tissue loss is greater with ultra-thin DSEK.
INTRODUCTION Aiming for exact anatomical replacement with the thinnest possible
tissue, Melles developed a technique for peeling DM and healthy endo-
Penetrating keratoplasty (PKP) was long considered the gold standard for thelium from a donor cornea and implanting it into a recipient eye in a
the treatment of endothelial dysfunction. Advances in endothelial kera- method he called DM endothelial keratoplasty (DMEK).22 The extremely
toplasty (EKP) techniques, coupled with the many advantages it offers to thin DMEK graft is more challenging to handle compared with a thicker
patients, have made it the preferred treatment for endothelial dysfunction DSEK graft (Fig. 4.29.2), leading to the development of hybrid techniques
(Fig. 4.29.1). with a narrow rim of donor stromal tissue ringing a central area of bare
After PKP, it generally takes 6 months to several years for the refrac- endothelium without stroma. The hybrid techniques, known as DMEK-S
tion to stabilize1–3; 10%–15% of the patients typically require a hard contact and DMAEK, were not widely adopted because the risk of tissue loss was
lens for best vision4,5; and a final mean refractive cylinder of 4–5 D is greater than with DMEK.23,24
common.3,5 Furthermore, PKP incision severs all corneal nerves, so the A variation of DMEK, called pre-Descemet’s endothelial keratoplasty
inclination to blink and produce tears is reduced postoperatively. This, (PDEK), utilizes a big bubble to separate the donor Descemet’s membrane
together with the prolonged presence of corneal sutures to hold the graft and endothelium from the donor stroma.25 With a type 1 big bubble, a
in place, increases the risk that ocular surface complications will interfere pre-Descemet’s layer remains attached to Descemet’s membrane, thereby
with recovery.6,7 Moreover, because of the PKP wound, the cornea never providing slightly thicker tissue than in standard DMEK. This results in
regains the full strength of a virgin cornea, so an eye that has undergone easier unfolding and the ability to utilize tissue from younger donors
PKP is forever at increased risk of loss from a traumatic injury.8 who have a thinner Descemet’s membrane. The disadvantages of PDEK
In contrast, EKP involves selective removal of dysfunctional recipient are that the graft diameter is limited by the big bubble diameter to about
corneal endothelium and replacement with donor tissue consisting of 7–7.5 mm and the donor tissue must be cut from the underlying stroma
healthy endothelium, with or without posterior stroma.9 EKP is performed with scissors. Time will tell which of these technique variations become
through a small incision and spares the majority of the host cornea, so dominant for standard noncomplicated cases, such as Fuchs’ dystrophy.
corneal strength and surface topography are minimally altered, and the
technique is essentially refractive–neutral.10–13 Furthermore, corneal inner- INDICATIONS
vation is retained, and corneal sutures are not required, so ocular surface
complications are minimal.14 Finally, the small incision allows rapid EKP is an excellent option for any type of endothelial dysfunction (Box
healing and visual recovery, and patients can resume normal activities 4.29.1).9,13,24–26 With appropriate modifications, EKP can be performed in
within weeks of surgery. eyes with peripheral anterior synechiae, glaucoma filtration surgery, and
iris abnormalities, including aniridia.26–28 If anterior stromal scarring from
EVOLUTION OF EKP TECHNIQUES long-standing corneal edema is significant, replacement of the full corneal
thickness with a PKP may provide better visual acuity. However, in many
Originally described by Tillett in 1956,15 EKP has evolved rapidly, particu- cases, patients who have tolerated long-standing corneal edema also have
312 larly since 1998, when Melles reported successful replacement of dysfunc- other visual limitations (e.g., retinal problems). In such cases, EKP is an
tional endothelium through a scleral–limbal approach, using an air bubble attractive alternative because it quickly resolves the corneal edema and
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PRINCIPAL EK TECHNIQUES
4.29
Endothelial Keratoplasty: Targeted Treatment for Corneal Endothelial Dysfunction

DSEK
DMEK
Fig. 4.29.2 Diagram illustrating the differences between Descemet’s stripping

endothelial keratoplasty (DSEK) and Descemet’s membrane endothelial keratoplasty
(DMEK). The host cornea epithelial and endothelial layers are depicted in sky blue,
the host stroma in pale blue, the donor endothelium in dark blue, and the donor
stroma in medium blue.
B
BOX 4.29.1 Endothelial Keratoplasty: Indications and
Contraindications
Indications
• Essentially all forms of endothelial dysfunction
• Fuchs’ endothelial dystrophy
• Pseudo-phakic or aphakic bullous keratopathy
• Previous failed penetrating keratoplasty
• Posterior polymorphous dystrophy
• Congenital hereditary endothelial dystrophy
• Iridocorneal endothelial (ICE) syndrome
• Endothelial failure from trauma, previous surgery, angle closure or
glaucoma drainage devices
Contraindications
• Advanced keratoconus and anterior stromal dystrophies
• Hypotony
• Stromal opacities that would preclude acceptable postoperative vision
C
that there is no back pressure from periorbital swelling because back pres-
sure can cause the anterior chamber to forcefully shallow while the donor
tissue is being inserted and may even push the donor tissue back out of
the eye.
A 2–5 mm clear corneal or scleral tunnel incision is made in the
recipient eye. Temporal placement of the incision has several advantages
compared with superior placement: Donor button insertion is facilitated
because the corneal diameter is longer horizontally; the superior con-
D junctiva is preserved for future glaucoma surgery, if needed; and orbital
anatomy, such as large brows or sunken globes, is not as important.10 If
Fig. 4.29.1 Slit-lamp images of penetrating keratoplasty (A) and Descemet’s the recipient epithelium is hazy or scarred, it can be removed, generally
membrane endothelial keratoplasty (C), with corresponding anterior segment improving the view into the eye.
optical coherence tomography images (B,D). (A,B from Anshu A, Price MO, Tan If the host Descemet’s membrane has any guttae or other abnormalities,
DTH, et al. Endothelial keratoplasty: a revolution in evolution. Surv Ophthalmol then it should be removed before implanting the donor tissue for optimal
2012;57:236–52, Fig. 1.)
visual results. The anterior chamber is filled with air or viscoelastic to facil-
itate visualization of DM during its removal. A blunt Sinskey hook is used
bullae while maintaining much of the structural integrity of the eye. In to score DM in a circular pattern to outline the area of planned membrane
eyes with significant iris defects, aniridia, and/or aphakia, DSEK is prefer- removal.10 The far edge of DM is grasped with a stripping instrument or
able to DMEK, which can more easily escape into the posterior chamber infusion/aspiration tip and carefully is peeled off and removed from the
or be damaged by contact with an intraocular lens (IOL) or artificial iris eye (Fig. 4.29.3).17 Trypan blue can be injected into the anterior chamber
during unfolding. immediately after stripping DM to facilitate visualization of loose pieces
of Descemet’s membrane or stroma.14 After the membrane is removed, it
can be spread on the surface of the cornea to determine whether removal
SURGICAL TECHNIQUE was complete or whether some fragment might remain in the eye. If vis-
Anesthesia and Recipient Preparation coelastic material was used, care should be taken to completely remove it
from the anterior chamber and back surface of the cornea because retained
EKP is readily performed with topical or local anesthesia. With local anes- viscoelastic material on the stromal surface can impede attachment of the 313
thesia (using a retrobulbar or peribulbar block), it is important to ensure donor tissue and impair vision.29
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4
Fig. 4.29.3 Stripping of host Descemet’s membrane using a 90° angled stripper. Fig. 4.29.5 Air injection to lift and press the donor tissue up against the host
cornea.
Fig. 4.29.4 Lamellar dissection of the donor tissue with a microkeratome in Fig. 4.29.6 Massaging the surface of the recipient cornea to center the Descemet’s
Descemet’s stripping endothelial keratoplasty (DSEK). stripping endothelial keratoplasty (DSEK) donor tissue and remove fluid from the
donor/recipient interface, while the anterior chamber is completely filled with air.
Donor Tissue Preparation and Insertion suture across the anterior chamber and out through a stab incision nasally,
Donor tissue preparation involves three steps: dissection; sizing to the and pull the tissue into the eye.30
appropriate diameter with a trephine (usually 8–9 mm); and insertion. A third method is to place the tissue on a glide or insertion cartridge,
Preparing the donor tissue before opening the patient’s eye allows the insert retina/vitreal intraocular forceps through a nasal stab incision, reach
surgeon to ensure that the tissue will be suitable for transplantation. across the eye and grasp the tip of the donor through the 5-mm temporal
incision, and pull the tissue into the eye (Video 4.29.1).31–33 The tissue also See clip:
Descemet’s Stripping With Endothelial Keratoplasty can be inserted with a single-use inserter. Use of a funnel glide or insertor 4.29.1
The lamellar dissection usually is done with a microkeratome either at the helps the donor tissue curl with the endothelium inward for protection as
eye bank or at the time of surgery (Fig. 4.29.4).19 A donor corneal/scleral it is inserted.32,33
shell is mounted on an artificial anterior chamber designed to accompany Once the donor tissue is in the eye and unfolded stromal side up, the
the microkeratome being used. The artificial anterior chamber can be filled anterior chamber is filled with air to press the donor button up against the
with viscoelastic material, balanced salt solution, or tissue storage solution. recipient cornea (Fig. 4.29.5). While the anterior chamber is completely
The donor thickness is measured, and a microkeratome head of appropri- filled with air, a LASIK (laser-assisted in situ keratomileusis) roller can be
ate depth is selected to provide a posterior donor button of approximately used to help center the donor tissue and massage fluid out of the donor/
0.08–0.15 mm thickness, according to the surgeon’s preference. recipient interface (Fig. 4.29.6).14 Several small incisions can be made in
The donor tissue is carefully transferred from the artificial anterior the peripheral recipient cornea down to the graft interface to help drain
chamber and placed endothelial side up on a standard punch trephine any fluid trapped between the donor and recipient tissue.14 Intraoperative
block, where it is punched to an appropriate diameter, taking into consid- optical coherence tomography (OCT) can help identify fluid in the inter-
eration the horizontal white-to-white dimensions of the recipient cornea face. After 8–10 minutes, many surgeons remove most of the air to prevent
and the anterior chamber depth. The donor tissue is covered with tissue pupillary block, and leave the anterior chamber approximately one third
storage solution while the recipient eye is prepared. full. Some surgeons then have the patients lay face up with a partial air
A variety of insertion techniques are available, including forceps, glides, bubble for 30–60 minutes. Other surgeons leave the anterior chamber
and inserters.10,11,30–33 When using forceps, the posterior donor button is completely filled for 1–2 hours. At the completion of surgery, antibiotics,
folded over on itself like a “taco” with approximately 60% anterior and 40% corticosteroids, dilating drops, and nonsteroidal anti-inflammatory drugs
posterior, and the folded tissue is gently grasped at the leading edge with (NSAIDs) are applied to the treated eye.
forceps that only compress at the tip as the tissue is guided into the eye. A
disadvantage of this method is that it can be difficult to unfold the donor Descemet’s Membrane Endothelial Keratoplasty
314 correctly in the eye, especially for surgeons early in the learning curve. The most common donor tissue dissection technique consists of gently
Another method is to fixate the edge of the donor with a suture, thread the peeling off DM and endothelium (Video 4.29.2).34–37 First, the DM periphery See clip:
4.29.2
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OUTCOMES
Visual Acuity
4.29
EKP provides more rapid and predictable visual recovery than PKP, allow-

ing patients to return to work and daily activities sooner. In large PKP
series, the rate of 20/40 or better vision has ranged from 47%–65% in Fuchs’
dystrophy patients and from 20%–40% in patients with pseudo-phakic or
aphakic bullous keratopathy.3–5,39 Unfortunately, PKP can result in signifi-
cant corneal distortion, so 10%–15% of PKP eyes generally require use of a
hard contact lens for best vision, and in some cases, vision can be limited
to counting fingers or worse.
DSEK is performed through a small incision and causes little to no
corneal distortion. A mean corrected distance visual acuity (CDVA) of
20/40 is generally achieved within 3–6 months of DSEK, and over 90% of
patients without ocular comorbidities achieve 20/40 or better vision.9,13 A
small percentage of patients who have undergone DSEK reach less than
20/40 vision because of irregularities resulting from the lamellar dissec-
tion or from folds that form in the donor tissue as it conforms to the back
Fig. 4.29.7 Descemet’s Membrane Endothelial Keratoplasty (DMEK) Donor of the recipient cornea.40 Thinner DSEK tissue provides better vision than
Tissue Preparation. A nontoothed forceps is being used to peel Descemet’s thicker tissue.21
membrane and endothelium from a donor corneal/scleral rim that is submerged With DMEK, the visual recovery is impressive. In patients without
in corneal storage solution in a cornea viewing chamber. The corneal/scleral rim ocular comorbidities, greater than 70% of those who have undergone
was stained with trypan blue to enhance visualization of the scored edge of the DMEK achieve 20/25 or better vision within 3 months.35,41 Overall the
membrane. visual acuity achieved with DMEK is comparable with that in normal eyes,
and DMEK achieves a more normal posterior corneal surface with fewer
higher-order aberrations than DSEK or PKP.41 Visual recovery is so rapid
after DMEK that fellow eyes can be treated within 1–2 weeks of each other,
with or without combined cataract extraction.42
is scored all the way around. The tissue is stained with trypan blue to
enhance visualization. The peripheral edge is lifted all the way around by
Refractive Changes
using a microfinger or hockey stick–shaped instrument. With the tissue In contrast to PKP, EKP causes little to no change in corneal topogra-
submerged in tissue storage solution, an edge of the membrane is grasped phy, resulting in far less change in spherical equivalent or cylinder. PKP
with forceps and peeled about halfway to the center, quadrant by quad- induces +4.00–+5.00 diopters (D) of refractive cylinder on average and may
rant, with replacement of each section on the stromal base (Fig. 4.29.7). exceed +8.00 D.3,5 DSEK and DMEK cause no significant increase in mean
The tissue is partially trephined, cutting through DM but not completely refractive cylinder.9,13,35 DSEK generally induces +0.50–+2.00 D of hyper-
through the stroma. An edge is grasped with nontoothed forceps, and the opia,9,13 whereas DMEK causes a smaller mean hyperopic shift of about
central DM is gently peeled from the underlying stroma and replaced in +0.25–+0.50 D.35
tissue storage solution. Donor DM and endothelium also can be isolated
using air, fluid, or viscoelastic.23–25 However, using a type 1 big bubble to Graft Survival
detach DM limits the graft diameter to about 7–7.5 mm, and the graft must
be cut from the stroma with scissors. It is not unusual for surgeons who are learning to perform EKP to ini-
Immediately before insertion into the recipient eye (Video 4.29.3), the tially have a higher rate of primary graft failure caused by surgical trauma.
See clip: donor tissue is stained again with trypan blue to improve visualization. However, with experience, the primary graft failure rate should drop to the
4.29.3 The donor tissue naturally curls up endothelium-outward and can be low levels seen with PKP.
placed in a glass pipette or inserter, such as an IOL injector, for placement In an initial consecutive DSEK series, the 5-year graft survival rate was
in the recipient eye. The donor DM is gently unfolded in the correct orien- similar to that reported for PKP in the large multicenter Cornea Donor
tation with a combination of balanced salt solution and air injections. Then Study (95% versus 93% for Fuchs’ dystrophy and 76% versus 73% for
air or a long-acting gas (20% sulfur hexafluoride) is injected beneath the pseudo-phakic or aphakic corneal edema).43,44 PKP regrafts generally have
donor tissue to completely fill the anterior chamber and press the graft up a poor 5-year survival rate of 53% or less,6,39 whereas the 4-year survival
against the host cornea. rate for DSEK under failed PKP was 74% in an initial consecutive series.28
Instead of allowing the donor tissue to naturally curl with the endothe- Previous glaucoma surgery is a major risk factor for graft failure.
lium facing outward, opposite sides can be folded over the middle (trifold Five-year DSEK graft survival was 95% in a series of eyes without previous
technique), with the endothelium facing inward.38 The folded tissue is glaucoma surgery versus 48% in eyes with one or more previous trabe-
pulled into an IOL cartridge and injected into the eye or pulled in with culectomy or glaucoma tube shunt surgeries.45
forceps. Both the PDEK donor preparation method and the trifold DMEK
insertion technique facilitate unfolding the donor tissue inside the recipi- Complications
ent eye. Thus both allow use of younger donor tissue, which otherwise can
be more challenging to unfold. Graft Detachment
Lack of complete adherence between the donor tissue and host cornea is
the most frequent early complication with EKP. Reported rates have ranged
COMBINED PROCEDURES from 0%–82%.9,13 Detachment is addressed by reinjecting air into the eye.
Keys to minimizing the risk of graft detachment are meticulous wound
EKP can be combined with other intraocular surgeries, such as construction to preclude postoperative wound leaks, complete removal of
phacoemulsification, IOL implantation, IOL exchange, secondary lens fluid from the donor/host interface, achieving a firm air tamponade, and
implant, pars plana vitrectomy, or anterior vitrectomy.13,14 Combining cautioning the patient not to rub the eye in the early postoperative period.
EKP with surgeries that require a larger incision can complicate wound For partially detached DSEK grafts, observation is sufficient because
closure and maintenance of an air-tight incision, which is important they frequently will seal down spontaneously over time. With DMEK,
for ensuring donor attachment. A modest mean hyperopic shift typi- partial detachments are more common and less likely to seal down
cally is reported after EKP (in the range of 0.25–0.5 D after DMEK and spontaneously.
0.5–1.5 D after DSEK).9,13,35 Therefore, when cataract extraction and IOL
implantation is performed before EKP, whether as a staged or combined Immunological Rejection
procedure, the expected refractive shift should be factored into the IOL Immunological rejection is a leading cause of PKP failure. Allan et al. 315
calculation. found that the incidence of an initial rejection episode within 2 years of
booksmedicos.org
surgery was significantly lower with EKP than with PKP, and this differ- EKP despite a chronic worldwide shortage of donor corneas.55 Studies
4 ence was thought to be related to the frequently shorter duration of topical

corticosteroid use after PKP to facilitate healing of the large incision.46
DMEK has an extremely low rate of initial rejection episodes. The 2-year
suggest that in patients with Fuchs’ dystrophy, it may be possible to stim-
ulate host endothelial regeneration if the peripheral endothelium is rel-
atively healthy despite central endothelial dysfunction. Further work is
probability of a rejection episode was less than 1% with DMEK, compared needed to accomplish this quickly and reliably.56
with 12% for DSEK and 18% for PKP, in a single-center study that uti- In conclusion, current EKP techniques have significantly increased the
lized the same corticosteroid dosing regimen and rejection evaluation cri- benefits and reduced the risks of grafting for patients with endothelial
teria for all three types of grafts and statistical methods that took length of dysfunction. Future developments of EKP are expected to continue this
follow-up into account.47 These findings are consistent with reports from beneficial trend.
other centers that have had less than 1% cumulative rate of rejection with
DMEK through 2 years compared with 3%–14% rates with DSEK.48–50
KEY REFERENCES
Postkeratoplasty Intraocular Pressure Elevation Allan B, Terry MA, Price FW, et al. Corneal transplant rejection rate and severity after endo-
Intraocular pressure (IOP) elevation is fairly common after both EKP thelial keratoplasty. Cornea 2007;26:1039–42.
and PKP and primarily is associated with the prolonged use of topical Anshu A, Price MO, Price FW. Risk of corneal transplant rejection significantly reduced with
corticosteroids to prevent graft rejection.51 Previous history of glaucoma or Descemet’s membrane endothelial keratoplasty. Ophthalmology 2012;119:536–40.
Anshu A, Price MO, Tan DTH, et al. Endothelial keratoplasty: a revolution in evolution. Surv
ocular hypertension is a key risk factor. DMEK has such a low risk of graft Ophthalmol 2012;57:236–52.
rejection that it is safe to reduce the corticosteroid strength after about 1 Dickman MM, Kruit PJ, Remeijer L, et al. A randomized multicenter clinical trial of ultrathin
month, and this dramatically reduces the risk of IOP elevation.52,53 Descemet stripping automated endothelial keratoplasty (DSAEK) versus DSAEK. Oph-
EKP does not distort the corneal surface so it is easier to obtain accurate thalmology 2016;123:2276–84.
Kruse FE, Laaser K, Cursiefen C, et al. A stepwise approach to donor preparation and inser-
IOP measurements after EKP than it is after PKP. The addition of donor tion increases safety and outcome of Descemet membrane endothelial keratoplasty.
stromal tissue in DSEK does not alter IOP as measured with Goldmann Cornea 2011;30:580–7.
applanation tonometry.54 Lee WB, Jacobs DS, Musch DC, et al. Descemet’s stripping endothelial keratoplasty: safety
and outcomes: a report by the American Academy of Ophthalmology. Ophthalmology
Infrequent Complications 2009;116:1818–30.
Melles GR. Posterior lamellar keratoplasty: DLEK to DSEK to DMEK. Cornea 2006;25:
Since EKP is performed with a small incision and the graft is held in place 879–81.
with an air bubble rather than by sutures, it avoids the suture-related com- Melles GR, Eggink FA, Lander F, et al. A surgical technique for posterior lamellar kerato-
plications seen after PKP, such as infiltrates/abscess, astigmatism, and plasty. Cornea 1998;17:618–26.
suture erosions.9,13 Moreover, being a closed-eye procedure, EKP provides Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 50 eyes: a
refractive neutral cornea transplant. J Refract Surg 2005;21:339–45.
greater tectonic stability and avoids the risk of suprachoroidal hemorrhage Price MO, Baig KM, Brubaker JW, et al. Randomized, prospective comparison of pre-cut vs.
that can result in the loss of the eye with an open-sky procedure, such surgeon-dissected grafts for Descemet stripping automated endothelial keratoplasty. Am
as PKP. However, interface irregularities can occur with lamellar proce- J Ophthalmol 2008;146:36–41.
dures, such as EKP. Interface contaminants, such as retained viscoelastic Price MO, Giebel AW, Fairchild KM, et al. Descemet’s membrane endothelial keratoplasty:
prospective multicenter study of visual and refractive outcomes and endothelial survival.
or retained host DM with guttae, can distort vision. Epithelial down-growth Ophthalmology 2009;116:2361–8.
or in-growth is also a rare but potentially serious complication with EKP, Price MO, Fairchild KM, Price DA, et al. Descemet’s stripping endothelial keratoplasty
but it can be avoided with proper technique. five-year graft survival and endothelial cell loss. Ophthalmology 2011;118:725–9.
Price MO, Price FW Jr, Kruse FE, et al. Randomized comparison of topical prednisolone
acetate 1% versus fluorometholone 0.1% in the first year after Descemet membrane
OUTLOOK endothelial keratoplasty. Cornea 2014;33:880–6.
Rudolph M, Laaser K, Bachmann BO, et al. Corneal higher-order aberrations after Descem-
Endothelial keratoplasty techniques continue to evolve. More work is et’s membrane endothelial keratoplasty. Ophthalmology 2012;119:528–35.
needed to further facilitate EKP techniques, minimize endothelial cell loss, Vajaranant TS, Price MO, Price FW, et  al. Vision and intraocular pressure after
Descemet-stripping endothelial keratoplasty in patients with and without pre-existing
and more accurately predict the final refractive outcome following reso- glaucoma. Ophthalmology 2009;116:1644–50.
lution of edema. Randomized prospective studies are needed to compare
different techniques and determine the best methods.
Donor tissue remains scarce in developing nations. Ex vivo generation Access the complete reference list online at ExpertConsult.com
of donor corneal endothelium could allow more patients to benefit from
316
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atoplasty. Cornea 2007;26:1123–6.
1. Riddle HK Jr, Parker DA, Price FW Jr. Management of postkeratoplasty astigmatism.
Curr Opin Ophthalmol 1998;9:15–28.
31. Mehta JS, Por YM, Beuerman RW, et al. Glide insertion technique for donor cornea lent-
icule during Descemet’s stripping automated endothelial keratoplasty. J Cataract Refract
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2. Binder PS, Waring GO. Keratotomy for astigmatism. In: Waring GO, editor. Refractive Surg 2007;33:1846–50.
32. Busin M, Bhatt PR, Scorcia V. A modified technique for descemet membrane stripping

keratotomy for myopia and astigmatism. St Louis: Mosby–Year Book; 1992. p. 1157–86.
3. Claesson M, Armitage WJ, Fagerholm P, et al. Visual outcome in corneal grafts: a automated endothelial keratoplasty to minimize endothelial cell loss. Arch Ophthalmol
preliminary analysis of the Swedish Corneal Transplant Register. Br J Ophthalmol 2008;126:1133–7.
2002;86:174–80. 33. Elbaz U, Yeung SN, Lichtinger A, et al. EndoGlide versus EndoSerter for the insertion of
4. Price FW Jr, Whitson WE, Marks RG. Progression of visual acuity after penetrating ker- donor graft in Descemet stripping automated endothelial keratoplasty. Am J Ophthalmol
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5. Pineros O, Cohen EJ, Rapuano CJ, et al. Long-term results after penetrating keratoplasty 34. Lie JT, Birbal R, Ham L, et al. Donor tissue preparation for Descemet membrane endo-
for Fuchs’ endothelial dystrophy. Arch Ophthalmol 1996;114:15–18. thelial keratoplasty. J Cataract Refract Surg 2008;34:1578–83.
6. Thompson RW, Price MO, Bowers PJ, et al. Long-term graft survival after penetrating 35. Price MO, Giebel AW, Fairchild KM, et al. Descemet’s membrane endothelial kerato-
keratoplasty. Ophthalmology 2003;110:1396–402. plasty: prospective multicenter study of visual and refractive outcomes and endothelial
7. Price MO, Thompson RW Jr, Price FW Jr. Risk factors for various causes of failure in survival. Ophthalmology 2009;116:2361–8.
initial corneal grafts. Arch Ophthalmol 2003;121:1087–92. 36. Kruse FE, Laaser K, Cursiefen C, et al. A stepwise approach to donor preparation and
8. Elder MJ, Stack RR. Globe rupture following penetrating keratoplasty: how often, why, insertion increases safety and outcome of Descemet membrane endothelial keratoplasty.
and what can we do to prevent it? Cornea 2004;23:776–80. Cornea 2011;30:580–7.
9. Anshu A, Price MO, Tan DTH, et al. Endothelial keratoplasty: a revolution in evolution. 37. Tenkman LR, Price FW, Price MO. Descemet membrane endothelial keratoplasty donor
Surv Ophthalmol 2012;57:236–52. preparation: navigating challenges and improving efficiency. Cornea 2014;33:319–25.
10. Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 50 eyes: a 38. Busin M, Leon P, Scorcia V, et al. Contact lens-assisted pull-through technique for deliv-
refractive neutral cornea transplant. J Refract Surg 2005;21:339–45. ery of tri-folded (endothelium in) DMEK grafts minimizes surgical time and cell loss.
11. Melles GR, Lander F, van Dooren BT, et al. Preliminary clinical results of posterior lamel- Ophthalmology 2016;123:476–83.
lar keratoplasty through a sclerocorneal pocket incision. Ophthalmology 2000;107:1850–6, 39. Williams KA, Hornsby NB, Bartlett CM, et al. The Australian Corneal Graft Registry:
discussion 1857. 2004 Report. Adelaide: Snap Printing; 2004. p. 154.
12. Price MO, Price FW Jr. Descemet’s stripping with endothelial keratoplasty comparative 40. Letko E, Price DA, Lindoso EM, et al. Secondary graft failure and repeat endothelial
outcomes with microkeratome-dissected and manually dissected donor tissue. Ophthal- keratoplasty after Descemet’s stripping automated endothelial keratoplasty. Ophthalmol
mology 2006;113(11):1936–42. 2011;118:310–14.
13. Lee WB, Jacobs DS, Musch DC, et al. Descemet’s stripping endothelial keratoplasty: 41. Rudolph M, Laaser K, Bachmann BO, et al. Corneal higher-order aberrations after
safety and outcomes: a report by the American Academy of Ophthalmology. Ophthalmol- Descemet’s membrane endothelial keratoplasty. Ophthalmology 2012;119:528–35.
ogy 2009;116:1818–30. 42. McKee Y, Price MO, Gunderson L, et al. Rapid sequential endothelial keratoplasty with
14. Price FW Jr, Price MO. Descemet’s stripping with endothelial keratoplasty in 200 eyes: and without combined cataract extraction. J Cataract Refract Surg 2013;39:1372–6.
early challenges and techniques to enhance donor adherence. J Cataract Refract Surg 43. Gal RL, Dontchev M, Beck RW, et al. The effect of donor age on corneal transplant
2006;32:411–18. outcome results of the cornea donor study. Ophthalmology 2008;115:620–6.
15. Tillett CW. Posterior lamellar keratoplasty. Am J Ophthalmol 1956;43:530–3. 44. Price MO, Fairchild KM, Price DA, et al. Descemet’s stripping endothelial keratoplasty
16. Melles GR, Eggink FA, Lander F, et al. A surgical technique for posterior lamellar kera- five-year graft survival and endothelial cell loss. Ophthalmology 2011;118:725–9.
toplasty. Cornea 1998;17:618–26. 45. Anshu A, Price MO, Price FW. Descemet stripping endothelial keratoplasty: Long-term
17. Melles GR, Wijdh RH, Nieuwendaal CP. A technique to excise the Descemet membrane graft survival and risk factors for failure in eyes with pre-existing glaucoma. Ophthalmol-
from a recipient cornea (descemetorhexis). Cornea 2004;23:286–8. ogy 2012;119:1982–7.
18. Gorovoy M. Descemet’s stripping automated endothelial keratoplasty (DSAEK). Cornea 46. Allan B, Terry MA, Price FW, et al. Corneal transplant rejection rate and severity after
2006;25:886–9. endothelial keratoplasty. Cornea 2007;26:1039–42.
19. Price MO, Baig KM, Brubaker JW, et al. Randomized, prospective comparison of pre-cut 47. Anshu A, Price MO, Price FW. Risk of corneal transplant rejection significantly reduced
vs. surgeon-dissected grafts for Descemet stripping automated endothelial keratoplasty. with descemet’s membrane endothelial keratoplasty. Ophthalmology 2012;119:536–40.
Am J Ophthalmol 2008;146:36–41. 48. Sepsakos L, Shah K, Lindquist TP, et al. Rate of rejection after Descemet stripping
20. Melles GR. Posterior lamellar keratoplasty: DLEK to DSEK to DMEK. Cornea automated endothelial keratoplasty in Fuchs dystrophy: three-year follow-up. Cornea
2006;25:879–81. 2016;35(12):1537–41.
21. Dickman MM, Kruit PJ, Remeijer L, et al. A randomized multicenter clinical trial of 49. Dapena I, Ham L, Netukova M, et al. Incidence of early allograft rejection after Descemet
ultrathin Descemet stripping automated endothelial keratoplasty (DSAEK) versus membrane endothelial keratoplasty. Cornea 2011;30:1341–5.
DSAEK. Ophthalmology 2016;123:2276–84. 50. Wu EI, Ritterband DC, Yu G, et al. Graft rejection following Descemet stripping auto-
22. Melles GR, Ong TS, Ververs B, et al. Descemet membrane endothelial keratoplasty mated endothelial keratoplasty: features, risk factors, and outcomes. Am J Ophthalmol
(DMEK). Cornea 2006;25:987–90. 2012;153:949–57.
23. McCauley MB, Price FW, Price MO. Descemet membrane automated endothelial kerato- 51. Vajaranant TS, Price MO, Price FW, et al. Vision and intraocular pressure after Descem-
plasty: hybrid technique combining DSAEK stability with DMEK visual results. J Cataract et-stripping endothelial keratoplasty in patients with and without pre-existing glaucoma.
Refract Surg 2009;35:1659–64. Ophthalmology 2009;116:1644–50.
24. Studeny P, Farkas A, Vokrojova M, et al. Descemet membrane endothelial keratoplasty 52. Price MO, Feng MT, Scanameo A, et al. Loteprednol etabonate 0.5% gel vs. prednisolone
with a stromal rim (DMEK-S). Br J Ophthalmol 2010;94:909–14. acetate 1% solution after Descemet membrane endothelial keratoplasty: prospective ran-
25. Agarwal A, Dua HS, Narang P, et al. Pre-Descemet’s endothelial keratoplasty (PDEK). Br domized trial. Cornea 2015;34:853–8.
J Ophthalmol 2014;98:1181–5. 53. Price MO, Price FW Jr, Kruse FE, et al. Randomized comparison of topical predniso-
26. Price MO, Price FW Jr, Trespalacios R. Endothelial keratoplasty technique for aniridic lone acetate 1% versus fluorometholone 0.1% in the first year after Descemet membrane
aphakic eyes. J Cataract Refract Surg 2007;33:376–9. endothelial keratoplasty. Cornea 2014;33:880–6.
27. Price MO, Price FW Jr. Descemet’s stripping endothelial keratoplasty for treatment of 54. Vajaranant TS, Price MO, Price FW, et al. Intraocular pressure measurements following
iridocorneal endothelial syndrome. Cornea 2007;26:493–7. Descemet stripping endothelial keratoplasty. Am J Ophthalmol 2008;145:780–6.
28. Anshu A, Price MO, Price FW. Descemet’s stripping endothelial keratoplasty under 55. Okumura N, Kinoshita S, Koizumi N. Cell-based approach for treatment of corneal endo-
failed penetrating keratoplasty: visual rehabilitation and graft survival rate. Ophthalmol- thelial dysfunction. Cornea 2014;33:S37–41.
ogy 2011;118:2155–60. 56. Borkar DS, Veldman P, Colby KA. Treatment of Fuchs endothelial dystrophy by Descemet
29. Anshu A, Planchard B, Price MO, et al. A cause of reticular interface haze and its man- stripping without endothelial keratoplasty. Cornea 2016;35:1267–73.
agement after Descemet’s stripping endothelial keratoplasty. Cornea 2012;1365–8.
316.e1
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Section 9 Surgery
Surgical Ocular Surface Reconstruction

Neda Nikpoor, Victor L. Perez 4.30
Definition: Limbal stem cell deficiency is a devastating condition
that can occur as the end result of a diverse set of etiologies. There are
multiple surgical options to treat this disorder that may lead to corneal
blindness.
Key Features
• Tissue harvested from the limbal region contains both corneal
epithelium stem cells and immunogenic cells.
• Surgical approach depends on degree of ocular pathology and
whether ocular damage is unilateral or bilateral.
• Autologous tissue transplantation always should be assessed
first, and if allogeneic tissue is used, long-term systemic
immunosuppression is necessary for graft survival.
Associated Features
• Concurrent ocular pathologies need to be addressed as much Fig. 4.30.1 A total stem cell failure as a result of severe alkali burn.
as possible prior to undertaking ocular surface reconstruction to
improve the success of the procedure. the success of the procedure. A moist, well-lubricated environment and
• Restoring normal eyelid anatomy and achieving a wet ocular surface proper lid anatomy are crucial for increasing the survival rate of these
prior to surgery are essential for good outcomes. transplants.
• Amniotic membrane has been shown to have a variety of desirable • Tissue harvested from the corneal–scleral area includes corneal stem
effects on the ocular surface. cells, fibroblasts, and Langerhans’ cells. The limbus is a highly vascular
• Laboratory ex vivo tissue expansion plays an important role in part of the ocular surface allowing the immune cells to have access to
rehabilitating the ocular surface. this area. Therefore, proper immune suppression is an essential aspect
of ocular surface reconstruction when an immune-compatible source of
INTRODUCTION tissue is not available and an allogeneic graft is used.
• Corneal and conjunctival stem cells may be harvested from either the
The maintenance of the ocular surface is the result of a delicate balance patient’s contralateral eye (autografting) or from a cadaveric or living-
between cell death and regeneration by two rapidly renewing tissues, the related donor (allografting). Tissue from any of these sources then
corneal and conjunctival epithelia. This capacity is dependent on a reser- can be directly transplanted or expanded ex vivo in a laboratory. The
voir of stem cells at the limbus, with the ability to provide young epithelial selection of certain stem cell markers, such as p63 expressed in ex vivo
cells to replace the dying or damaged cells. Corneal stem cells are located expanded cells, can significantly improve long-term graft survival.12
mainly in the palisades of Vogt of the limbal cornea rim, with the highest More recently, nonocular stem cells have demonstrated usefulness as
concentration in the superior and inferior limbus.1 a source for tissue.13
Damage to the corneal stem cells can occur as a result of a variety of
insults, including mechanical, hereditary, chronic inflammatory, and chem-
ical.2–4 Stem cell deficiency is characterized by conjunctivalization of the PREOPERATIVE CONSIDERATIONS
cornea associated with persistent epithelial defects, fibrovascular pannus,
and stromal scarring and can lead to a variety of ocular surface diseases, Some of the important aspects of preoperative evaluation are listed in Table
ranging from mild ocular discomfort to corneal blindness. (Fig. 4.30.1). 4.30.1. Preoperative evaluation can guide the surgeon to the most appropri-
ate modality of treatment and is vital to the success of the ocular surface
HISTORICAL PERSPECTIVES rehabilitation. Foremost to this preoperative planning is distinguishing
between primary and secondary ocular surface failures. Primary failure is
The first modern limbal stem cell transplantation was reported by Kenyon the result of the direct causal agent, which can be chemical injury, inflam-
and Tseng in 1989.5 More recently, in 1997, Pellegrini et al. suggested the matory conditions, or infections. In contrast, secondary failure derives
possibility of expanding stem cells ex vivo for later transplantation.6 Since from factors that result in a decompensated ocular surface; these include
then, multiple groups have published reports utilizing different methods elevated intraocular pressure as well as eyelid and tear abnormalities.
of ocular surface reconstruction for a variety of surface pathologies.4,5,7–10 Before attempting surgical reconstruction, both primary and secondary
With the ever-growing number of procedures around the world, the Cornea causes of ocular surface failure must be addressed and corrected. If appro-
Society issued a standardized nomenclature in 2011.11 priate, lid repair, mucous membrane grafting, tarsorrhaphy, and PROSE
(prosthetic replacement of the ocular surface ecosystem) lenses can be
General Concepts utilized. In addition, a systemic evaluation must be performed to ensure
that the patient is a good candidate for systemic immune suppression,
Some of the main principles of ocular surface reconstruction are as follows: if needed.
In general, patients with ocular surface disorders can be divided into
• The environment and the extracellular matrix on the surface of the eye two main groups: (1) those with total stem cell deficiency and (2) those 317
on which corneal stem cells are transplanted have a profound effect on with partial stem cell deficiency. Each group can then be further divided
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4
TABLE 4.30.1 Preoperative Considerations for
Ocular Surface Reconstructive Surgery
Examination Element Clinical Finding or Significance
Establishment of the diagnosis Loss of palisades of Vogt, persistent epithelial

defects, corneal pannus, etc.
Determination of the etiology of Primary (aniridia, ectodermal dysplasia, etc.);
ocular surface disease secondary (chemical injury, OCP, Stevens–Johnson
syndrome, etc.)
Extent and severity of the disease Cornea only or conjunctival involvement
Extent of ocular inflammation Conjunctival inflammation, intraocular
inflammation, etc.
Status of the fellow eye If normal, may be a source of tissue for autografting
Coexistent ocular pathology Glaucoma, adnexal pathology (e.g., trichiasis, etc.)
Ocular surface lubrication Assessment of tear film insufficiency, and dryness
are vital to success and may require additional
surgical considerations
General health of the patient Renal, cardiac, hepatic status if systemic
immunosuppression is required
Fig. 4.30.2 An amniotic membrane application shortly after severe chemical burn.
OCP, ocular cicatricial pemphigoid.
based on unilateral or bilateral disease, which can each be subdivided into

partial versus total limbal stem cell deficiency (LSCD).
OPERATIVE PROCEDURES
Unilateral Disease
The prototypical example is unilateral chemical injury. Many of the treat-
ment modalities discussed above for relative stem cell deficiency may be
applicable to eyes with total stem cell deficiency with some modifications.
For example, application of amniotic membrane may be helpful in terms
of decreasing ocular surface inflammation as an adjunct to more definitive
treatments.
The main advantage in cases of unilateral stem cell deficiency is that
the contralateral, unaffected eye can be a source of immunologically com-
patible conjunctival and corneal cells, which may allow for a safer reconsti-
tution of the ocular surface.
Partial Stem Cell Deficiency Fig. 4.30.3 The same patient as in Fig. 4.30.2, 2 years after the placement of
amniotic membrane tissue.
Surgical treatments are more successful in this group of patients because
there are some reserves of stem cells present. Causes include entities, such
as mild chemical burn, pterygia, and chronic ocular inflammation. Amniotic Membrane Grafting
If the patient is asymptomatic or minimally symptomatic with a clear The most important properties of amniotic membrane harvested from
central visual axis, some partial peripheral conjunctivalization of the cornea the innermost layer of the placenta include the anti-inflammatory effect
can be well tolerated for long periods.7,8 In these cases, simple lubrication through downregulation of fibroblasts and providing a substrate for prolif-
with preservative-free artificial tears, topical anti-inflammatory drops, and eration of the corneal and conjunctival epithelial cells.15,16 These properties
close follow-up may be sufficient. In the case of acute trauma, some partial are only useful when some reserve of stem cells is present because the
LSCD may be transient and can be observed for resolution with medical amniotic membrane itself is not a source of stem cells.
management. Work by Tseng and others has shown that the application of amniotic
For symptomatic patients there are three main surgical procedures that membrane to eyes with partial stem cell deficiency can improve ocular
can be efficacious either individually or in combination. These include surface health and, in some cases, even restore a near-normal corneal
mechanical debridement, application of amniotic membrane, and autolo- epithelium.17–21 Examples include acute and chronic chemical injuries,
gous limbal stem cell transplantation. acute Stevens–Johnson syndrome, and iatrogenic stem cell deficiency.
In these cases, application of the amniotic membrane, with or without
Mechanical Debridement mechanical debridement, can result in decreased ocular inflammation and
If the visual axis or a larger portion of the peripheral cornea is covered allow the remaining corneal stem cells to repopulate the ocular surface.22
by conjunctival tissue, simple mechanical debridement of this tissue may Amniotic membrane is commercially available in several forms, includ-
allow the remaining corneal stem cells to repopulate the central cornea ing a preserved wet amniotic membrane, a dehydrated form, and a contact
with normal or near-normal epithelium. The procedure can be done lens–mounted membrane.23,24 The amniotic membrane is placed on the
with topical anesthesia and consists of debriding abnormal epithelium eye with the epithelial side up to cover the area of interest. The membrane
with a crescent blade or Weck–Cel sponge followed by the application then can be secured to the cornea or episclera with 10-0 nylon sutures or
of a bandage contact lens. The goal of this procedure is to provide the fibrin glue (Figs. 4.30.2 and 4.30.3).
patient with a fairly clear visual axis and not to make the entire corneal
surface normal. Some investigators have reported success with as little as Autologous Limbal Stem Cell Transplantation
two clock hours of normal limbal cells.6,7 In a variant known as sequen- When there is relative or sectoral stem cell deficiency and the condition
tial sector conjunctival epitheliectomy (SSCE),14 conjunctival sheets are is unilateral, the unaffected part of the eye or the contralateral eye can
debrided every 24–48 hours until the patient has completely re-epithelized. serve as a donor for stem cells. Stem cells can be harvested from either the
Regardless of the number or extent of debridement, patients should be contralateral eye or from normal areas of the affected eye and transplanted
placed on postoperative topical antibiotics and artificial tears. This proce- to the area of stem cell deficiency. The first option is preferred. The surgi-
318 dure can be done in combination with an amniotic membrane graft as cal technique used is identical to that for an autologous graft for total stem
described below. cell deficiency and is described below.
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Total Stem Cell Deficiency the injured eye. Neither living-related donors nor cadavers are perfect
In general, if there is isolated LSCD in one eye, the treatment is autolo-

sources for grafts, and thus both advantages and disadvantages must be
weighed. 4.30
gous stem cell transplantation, or simple limbal epithelial transplantation Living-related donor transplants are advantageous in that harvested
(SLET). If LSCD and a conjunctival defect exist, the treatment involves cells are typically more immunologically compatible than from a random

conjunctival autograft. Presence of symblepharon, conjunctival defect, and source, especially if human lymphocyte antigen (HLA) matching is per-
LSCD may require mucous membrane grafting as well, depending on the formed. Reinhard et al. demonstrated that this allows for longer survival
size of the defect and extent of symblepharon. time of the transplanted cells.35 Specifically, they showed that over 5 years
the grafts with only 0–1 HLA mismatches had a 65% success rate com-
Autologous Limbal Stem Cell Transplantation pared with 14% of unmatched tissue. Living-related donor tissue also has
The traditional surgical approach involves careful dissection of the con- the benefit of stem cells that are fresh. One recent modification is the use
junctival tissue from the limbal area of the affected eye.25–28 A rim of ker- of allogeneic SLET, which is surgically identical to SLET described above
atolimbal tissue from the contralateral eye, including a conjunctival rim except that the donor eye is a living-related donor or cadaver rather than
and anterior cornea, can be harvested. Several tissue grafts can be har- the patient’s fellow eye. The disadvantage of all allogeneic limbal stem cell
vested from the fellow eye. The superior and the inferior 4–5 clock hours techniques is that even with HLA matching, postoperative systemic immu-
of limbus offer the highest concentration of corneal stem cells. This tissue nosuppression is required. Furthermore, the amount of tissue that can be
then can be carefully transported to the prepared bed with the mainte- harvested from the donor eye is limited, and there is a risk of inducing an
nance of correct orientation. The tissue can be sewn into place by using ocular surface disorder in the healthy eye of a donor.
nonabsorbable sutures, taking care not to pass the sutures through the For keratolimbal allograft (KLAL), the tissue can be harvested under
harvested stem cell area. However, now that fibrin glue is widely available, peribulbar anesthesia, similar to what has been described above for con-
it can be used to attach this tissue, thus avoiding the inflammatory reac- junctival limbal autograft. A total of 4 clock hours of tissue may be har-
tion associated with sutures.29 A bandage contact lens is then applied to vested, equally divided from the upper and lower limbus. This donor tissue
the eye. then is placed onto the recipient eye after peritomy and superficial ker-
More recently, Sangwan et al. described SLET, a novel technique.30,31 In atectomy have been performed to prepare the limbus. The donor tissue
this procedure a 2 × 2 mm or 1 clock hour section of autologous limbal is secured to the cornea anteriorly and posteriorly to the episclera using
tissue was excised from the uninvolved eye. The harvested graft was then either fibrin glue or 10-0 nylon sutures. Amniotic membrane may be trans-
divided into eight segments. After the host cornea was scraped of any planted at the same time, as needed.
fibrovascular epithelium, and an amniotic membrane secured with fibrin In contrast, using cadaveric donor tissue allows the surgeon to harvest
glue and the segments were placed epithelial side up on the optimized greater quantities of tissue than can be removed from living eyes. This
ocular surface and secured with fibrin glue, a bandage contact lens was theoretically improves the success of the ocular surface reconstruction,
then fitted to protect the tissue. especially in eyes with severe stem cell deficiency. However, cadaveric
Postoperatively, patients are treated with antibiotics, corticosteroids, and tissue must be screened for communicable diseases. The time necessary
preservative-free artificial tears. The bandage contact lens can be removed for these tests along with tissue damage that occurs during standard tissue
when the ocular surface is stable. Long-term systemic immune suppres- processing can result in stem cells of lower quality. The Minnesota Lions
sion is not necessary in these patients. Eye Bank suggested certain criteria for tissue harvested for KLAL. These
Prior to undertaking the harvesting of limbal tissue for stem cell criteria include obtaining tissue from the youngest donor possible (includ-
transplantation, it should be clearly established that the fellow eye is not ing pediatric sources), taking care to avoid damage to limbal stem cells,
affected, and that there is an ample reservoir of stem cells present. A risk including a 3–4 mm skirt of conjunctiva and a large corneoscleral rim, as
of inducing relative stem cell deficiency to the donor eye does exist if too well as obtaining both donor eyes to ensure adequate tissue.36,37
much tissue is harvested. Most clinicians avoid taking more than 4 clock Some investigators advocate the use of more than one donor eye to
hours of tissue from the donor eye. When concern exists about the health allow complete coverage of the limbus.28 Penetrating keratoplasty (PKP) or
of the fellow eye, allografts may be considered (see below). This method anterior lamellar keratoplasty (ALK) can be performed at the same time, or
is highly successful, with graft survival rates reported up to 100% over a at a later setting when the ocular surface is more stable.26,28 In 2010, Choi
47-month period.32,33 et al. reported a modified technique for both graft harvesting and host bed
Basu et al. recently reported long-term follow up of 125 cases and found preparation by using a femtosecond laser, which showed good short-term
that with this approach, patients had notable improvement in the clinical results.38
appearance of their ocular surface as well as an increase in their visual Postoperatively, patients are treated with topical antibiotics, corticoster-
acuity during the 1.5-year follow-up. The clinical factors associated with oids, and systemic immunosuppression. Because of the relative abundance
failure were identified as acid injury, severe symblepharon, and SLET of Langerhans’ cells and HLA-DR antigens in the limbus, a high rate of
combined with keratoplasty, In addition, the chapter authors’ group has immunological reaction can be expected, which may lead to recurrence
observed poorer outcomes in SLET patients who had autoimmune cica- of stem cell failure, necessitating aggressive and long-term immunosup-
trizing conjunctivitis as the cause of their LSCD.34 Another indication for pression. Although experts agree that postoperative long-term immuno-
SLET is LSCD after treatment of ocular surface neoplasia. It should be suppressive therapy is necessary for the success of nonautologous grafts,
noted that in this scenario, it would be prudent to defer ocular surface the exact regimen and timeframe for treatment are highly variable. One
reconstruction of the affected eye until it has been established that there is commonly used method for postoperative immunosuppression is the Cin-
no recurrence of the neoplasia. cinnati protocol. This technique employs 1 year of corticosteroid coverage
along with systemic tacrolimus, sirolimus, and mycophenolate.39 It is not
Bilateral Disease yet clear to what extent and for how long patients require immunosuppres-
sion after living-related and cadaveric allogeneic SLET.
Entities that can result in total stem cell failure in both eyes include severe The reported outcomes of KLAL vary, depending on the underlying
chemical injuries, Stevens–Johnson disease, ocular cicatricial pemphigoid disease entities and the duration of follow-up. A recent study reported
(OCP), and aniridia. Of note, many known bilateral disorders can be highly successful improvement in ocular surface in up to 89% of living-related
asymmetrical. In cases where a patient’s history would suggest a bilateral donors over a 32-month follow-up.17,32,40–42 In contrast, the same study
process in the setting of a clinically unilateral process, the patient should reported only a 33% success rate for cadaveric donor grafts over the same
be treated as having a bilateral LSCD to avoid possible donor site complica- period. However, the long-term follow-up has shown a trend toward pro-
tions. The conditions in this group are the most difficult to address because gressive decline of stem cell population and destabilization of the ocular
the surgical options to rehabilitate the ocular surface are hindered by the surface despite systemic immunosuppression.43,44
lack of an immunologically compatible source of stem cells. This necessi-
tates the use of either living-related donor tissue or cells harvested from Ex Vivo Expanded Limbal Stem Cells and Nonocular Tissue
cadaver eyes and aggressive systemic and topical immunosuppression. The majority of recent advancements in the area of stem cell transplants
have focused on the harvesting and subsequent ex vivo expansion of limbal
Keratolimbal Allograft and Allogeneic SLET cells. Expansion of stem cells by culturing them in vitro theoretically pro-
Keratolimbal tissue can be harvested from either a living-related donor’s vides a large supply of stem cells that can be used for surface reconstruc-
healthy cornea or from the whole globe or from corneal tissue of a cadav- tion. This allows the surgeon to not only selectively remove fibroblast and 319
eric donor. The harvested allograft can then be transplanted directly onto Langerhans’ cells, which may affect the long-term survival of allografted
booksmedicos.org
cells, but also allows for minimal tissue to be excised from a donor source, treated with the use of topical and possibly systemic immune-modulating
4 decreased the potential risks associated with tissue harvesting.

In this approach, a minimal amount of limbal tissue (1–2 mm) is har-
vested either from an eye with relative stem cell deficiency, or the normal
agents.
contralateral eye of a patient with unilateral total stem cell deficiency. In

Corneal Transplantation
cases where severe and total bilateral stem cell deficiency exists, cells can Patients with stem cell failure often have corneal pathology, which may
be harvested from either a living-related donor or cadaver eyes. Studies necessitate ALK or PKP. Performing keratoplasty in eyes with stem cell
have demonstrated the ability to use conjunctival tissue as well.45 These failure carries a very poor prognosis for graft survival because of chronic
cells then are amplified in culture media on a carrier, which will be utilized inflammation, vascularization of the ocular surface, and poor epithelial
for transport and transplant of the cells onto the diseased eye. The exact healing after surgery.
method of ex vivo expansion varies widely, with success demonstrated Corneal transplantation, however, may be more successful when the
under many conditions, including both explants and cell suspensions with ocular surface has been reconstituted by using some of the approaches
or without 3T3 mouse fibroblasts and serum. However, regardless of the outlined above. The optimal timing for cornea transplantation is not well
method for culturing the cells, obtaining a high percentage of p63-bright known. Some authors indicate that a stepwise approach, starting with
cells (>3% of all clonogenic cells) is of vital importance to the success of stem cell transplantation followed by keratoplasty when the ocular surface
the graft.12 is stable, may improve the graft survival.36,52 The largest study of pene-
The amplified cells then may be mounted on a substrate. Current sub- trating keratoplasty after cultivated limbal epithelial transplantation was
strates include petrolatum gauze, denuded human amniotic membranes, reported by Sangwan et al., who reported a 93% success rate in terms of
fibrin, 3T3 cells, and bandage soft contact lenses. The recipient eye is then graft clarity, with a mean follow-up time of 8.3 months.52 Currently, the
prepared in a similar manner to the method described for keratolimbal literature supports a two-staged procedure for ocular surface rehabilitation.
grafting. The cultured stem cells and their carrier are transferred onto An article by Basu et al. compared an autologous cultivated limbal stem
the recipient bed, anchored to the limbus with 10-0 nylon sutures and to cell transplantation with either a simultaneous penetrating keratoplasty or
the surrounding conjunctiva with 8-0 Vicryl sutures. A bandage contact a second procedure performed 6 weeks later.53 Over a long-term follow-up,
lens often is placed on the eye and kept in place until the ocular surface they noted an 80% graft survival for the staged procedure versus a 25%
stabilizes.6,46–48 survival rate for the simultaneous technique (Figs. 4.30.4 and 4.30.5).
Although postoperative treatment for allogeneic tissue is similar to that
for patients with keratolimbal grafts as described above, autologous tissue
should be used when possible to avoid the need for immunosuppression.
CONCLUSIONS
Schwab et al. found improvement in the ocular surface of 60% of In summary, the management of limbal stem cell deficiency requires
patients with autologous cells, and in all of the patients (total 4) with allo- careful preoperative case selection and control of comorbid factors, such
geneic cells combined with immunosuppression, with a mean follow-up
period of 13 months.46 Shimazaki et al., on the other hand, found only
a 46.2% success rate in achieving a stable and healthy ocular surface in
allografted patients.49 Furthermore, in this report, the authors did not find
a difference in success rate between this technique and cadaveric limbal
transplantation combined with amniotic membrane. Baylis et al. recently
reviewed 28 case reports and series regarding cultured limbal stem cells
published over a 13-year period and compiled outcome data.50 Despite
wide variation in technique, they noted an overall success rate of 77% for
autografts and 73% for allografts (76% overall). They also demonstrated
that failures typically occurred in the first 2 years before stabilizing. In
a 10-year study of 113 eyes reported in 2010, Rama et al.12 showed a 76%
success rate, with most failures occurring in the first year. They noted
that, as mentioned earlier, grafts with more than 3% p63-bright cells
had a 78% chance of success versus only 11% in those grafts with fewer
than 3%.12
SPECIAL CONSIDERATIONS IN OCULAR

SURFACE RECONSTRUCTION
Fig. 4.30.4 A cadaveric keratolimbal allograft with a subsequent penetrating
Other concurrent pathologies need to be addressed fully prior to under- keratoplasty.
taking ocular surface reconstruction to improve the success of the pro-
cedure. These may include the involvement of other subspecialties, such
as oculoplastic surgery to address eyelid abnormalities and glaucoma to
maximize pressure control.
Ocular Surface Optimization

The ocular surface needs to be lubricated using treatments, such as
preservative-free artificial tears, punctal occlusion, or PROSE lenses. A wet
ocular surface is a requirement prior to proceeding with any surface recon-
struction or limbal stem cell surgery. The use of autologous serum tears
may be beneficial pre- and postoperatively. In fact, Gomes et al. established
that preoperative dry eye was the single most important prognostic factor
for graft survival. To this end, this team recently described the success-
ful use of preoperative transplantation of labial mucous membranes and
minor salivary gland transplantation to improve the ocular surface status.51
Depending on the size of the defect and the extent of the symblepharon,
conjunctival autograft (for unilateral LSCD with conjunctival defect) or
mucous membrane grafting (for symblepharon or bilateral disease) may
be necessary. One important point to consider in reconstructing the eyelid
margin and palpebral conjunctiva is that the mucous membrane graft Fig. 4.30.5 The ocular surface of an eye in a patient with a total limbal stem cell
320 should be smooth and not so bulky as to cause trauma to the cornea. Fur- deficiency following a chemical burn after a simultaneous cadaveric keratolimbal
thermore, the ocular inflammation needs to be maximally and aggressively allograft, penetrating keratoplasty, and amniotic membrane tissue placement.
booksmedicos.org
as eyelid anatomy, immune disease, and a wet ocular surface without expo- Choi SK, Kim JH, Lee D, et al. A new surgical technique: a femtosecond laser-assisted kera-
tolimbal allograft procedure. Cornea 2010;29:924–9.
sure. Some techniques, such as minor salivary gland transplantation and
mucous membrane grafts, may be useful in preparing the ocular surface
Croasdale CR, Schwartz GS, Malling JV, et al. Keratolimbal allograft: recommendations for
tissue procurement and preparation by eye banks, and standard surgical technique.
4.30
for limbal stem cell transplants. In unilateral LSCD, the best results to Cornea 1999;18:52–8.
date are with autologous stem cell transplantations, most recently with a Daya SM, Chan CC, Holland EJ, et al. Cornea Society nomenclature for ocular surface reha-

trend toward SLET for most cases. A role still exists for ex vivo expan- bilitative procedures. Cornea 2011;30:1115–19.
Meisler DM, Perez VL, Proudfit J. A device to facilitate limbal stem cell procurement
sion of cells to avoid harm to the healthy donor eye. Bilateral cases can from eye bank donor tissue for keratolimbal allograft procedures. Am J Ophthalmol
be treated with living-related donor or cadaver transplants and topical and 2005;139:212–14.
systemic immunosuppression. Again, ex vivo expansion may play a role Miri A, Al-Deiri B, Dua HS. Long-term outcomes of autolimbal and allolimbal transplants.
here. Finally, in refractory cases or for patients who are not candidates for Ophthalmology 2010;117:1207–13.
Nassiri N, Pandya H, Djalilian AR. Limbal allograft transplantation using fibrin glue. Arch
the above-mentioned techniques, keratoprosthesis is an option. Ophthalmol 2011;129:218–22.
Pellegrini G, Traverso CE, Franzi AT, et al. Long term restoration of damaged corneal sur-
faces with autologous cultivated corneal epithelium. Lancet 1997;349:990–3.
KEY REFERENCES Rama P, Matuska S, Paganoni G, et al. Limbal stem-cell therapy and long-term corneal
regeneration. N Engl J Med 2010;363:147–55.
Alloway RR, Hanoway MJ, Trofe J, et al. A prospective, pilot study of early corticosteroid Sangwan VS, Basu S, MacNeil S, et al. Simple limbal epithelial transplantation (SLET): a
cessation in high-immunologic-risk patients: the Cincinnati Experience. Transplant Proc novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J
2005;37:802–3. Ophthalmol 2012;96:931–4.
Baradaran-Rafii A, Eslani M, Jamali H, et al. Postoperative complications of conjunctival Sant’ Anna AE, Hazarbassanov RM, de Freitas D, et al. Minor salivary glands and labial
limbal autograft surgery. Cornea 2012;31:893–9. mucous membrane graft in the treatment of severe symblepharon and dry eye in
Basu S, Mohamed A, Chaurasia S, et al. Clinical outcomes of penetrating keratoplasty after patients with Stevens–Johnson syndrome. Br J Ophthalmol 2012;96:234–9.
autologous cultivated limbal epithelial transplantation for ocular surface burns. Am J
Ophthalmol 2011;152:917–24.
Baylis O, Figueiredo F, Henein C, et al. 13 years of cultured limbal epithelial cell therapy: a Access the complete reference list online at ExpertConsult.com
review of the outcomes. J Cell Biochem 2011;112:993–1002.
321
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REFERENCES 28. Holland EJ, Djalilian AR, Schwartz GS. Management of aniridic keratopathy with
keratolimbal allograft: a limbal stem cell transplantation technique. Ophthalmology
1. Wiley L, SundarRaj N, Sun TT, et al. Regional heterogeneity in human corneal and
limbal epithelia: an immunohistochemical evaluation. Invest Ophthalmol Vis Sci
2003;110:125–30.
29. Nassiri N, Pandya H, Djalilian AR. Limbal allograft transplantation using fibrin glue.
4.30
1991;32:594–602. Arch Ophthalmol 2011;129:218–22.
30. Sangwan VS, Basu S, MacNeil S, et al. Simple limbal epithelial transplantation (SLET): a

2. Pfister RR. Chemical injuries of the eye. Ophthalmology 1983;90:1246–53.
3. Schwartz GS, Holland EJ. Iatrogenic limbal stem cell deficiency. Cornea 1998;17:31–7. novel surgical technique for the treatment of unilateral limbal stem cell deficiency. Br J
4. Fernandes M, Sangwan VS, Rao SK, et al. Limbal stem cell transplantation. Indian J Ophthalmol 2012;96:931–4.
Ophthalmol 2004;52:5–22. Review. 31. Basu S, Sureka SP, Shanbhag SS, et al. Simple limbal epithelial transplantation: long-
5. Kenyon KR, Tseng SC. Limbal autograft transplantation for ocular surface disorders. term clinical outcomes in 125 cases of unilateral chronic ocular surface burns. Ophthal-
Ophthalmology 1989;96:709–22, discussion 722–3. mology 2016;123(5):1000–10.
6. Pellegrini G, Traverso CE, Franzi AT, et al. Long term restoration of damaged corneal 32. Miri A, Al-Deiri B, Dua HS. Long-term outcomes of autolimbal and allolimbal trans-
surfaces with autologous cultivated corneal epithelium. Lancet 1997;349:990–3. plants. Ophthalmology 2010;117:1207–13.
7. Dua HS, Gomes JAP, Singh A. Corneal epithelial wound healing. Br J Ophthalmol 33. Baradaran-Rafii A, Eslani M, Jamali H, et al. Postoperative complications of conjunctival
1994;78:401–8. limbal autograft surgery. Cornea 2012;31(8):893–9.
8. Coster DL, Aggarwal RK, Williams KA. Surgical management of ocular surface disorders 34. Nikpoor N, Amescua GA, et al. Simple limbal epithelial transplantation using cryopre-
using conjunctival and stem cells allografts. Br J Ophthalmol 1995;79:977–82. served amniotic membrane for unilateral limbal stem cell deficiency: follow-up data.
9. Dua HS, Azuara-Blanco A. Autologous limbal transplantation in patients with unilateral Poster presented at: World Cornea Congress; 2015 Apr 15–17; San Diego.
corneal stem cell deficiency. Br J Ophthalmol 2000;84:273–8. 35. Reinhard T, Spelsberg H, Henke L, et al. Long-term results of allogeneic penetrating
10. Inatomi T, Nakamura T, Koizumi N, et al. Midterm results on ocular surface reconstruc- limbo-keratoplasty in total limbal stem cell deficiency. Ophthalmology 2004;111:775–82.
tion using cultivated autologous oral mucosal epithelial transplantation. Am J Ophthal- 36. Croasdale CR, Schwartz GS, Malling JV, et al. Keratolimbal allograft: recommendations
mol 2006;141:267–75. for tissue procurement and preparation by eye banks, and standard surgical technique.
11. Daya SM, Chan CC, Holland EJ. Cornea Society nomenclature for ocular surface rehabil- Cornea 1999;18:52–8.
itative procedures. Cornea 2011;30:1115–19. 37. Meisler DM, Perez VL, Proudfit J. A device to facilitate limbal stem cell procurement
12. Rama P, Matuska S, Paganoni G, et al. Limbal stem-cell therapy and long-term corneal from eye bank donor tissue for keratolimbal allograft procedures. Am J Ophthalmol
regeneration. N Engl J Med 2010;363:147–55. 2005;139:212–14.
13. Oie Y, Nishida K. Translational research on ocular surface reconstruction using oral 38. Choi SK, Kim JH, Lee D, et al. A new surgical technique: a femtosecond laser-assisted
mucosal epithelial cell sheets. Cornea 2014;33(Suppl. 11):S47–52. keratolimbal allograft procedure. Cornea 2010;29:924–9.
14. Dua HS. Sequential sector conjunctival epitheliectomy (SSCE). In: Holland EJ, Mannis 39. Alloway RR, Hanaway MJ, Trofe J, et al. A prospective, pilot study of early corticosteroid
M, editors. Ocular surface disease: medical and surgical management. New York: cessation in high-immunologic-risk patients: the Cincinnati experience. Transplant Proc
Springer; 2002. p. 168–74. 2005;37:802–3.
15. Shimmura S, Shimazaki J, Ohashi Y, et al. Anti-inflammatory effects of amniotic mem- 40. Tsubota K, Toda I, Saito H, et al. Reconstruction of corneal epithelium by limbal allograft
brane transplantation in ocular surface disorders. Cornea 2001;20:408–13. transplantation for severe ocular surface disorders. Ophthalmology 1995;102:1486–96.
16. Tseng SCG, Li D-Q, Ma X. Down-regulation of TGF-1, 2, 3, and TGG-receptor II expres- 41. Holland EJ, Schwartz GS. The evolution of epithelial transplantation for severe ocular
sion in human corneal fibroblasts by amniotic membrane. Invest Ophthalmol Vis Sci surface disease and a proposed classification system. Cornea 1996;15:549–56.
1998;39:S428. 42. Tsai RJF, Tseng SCG. Human allograft limbal transplantation for corneal surface recon-
17. Tseng SCG, Prabhasawat P, Barton K, et al. Amniotic membrane transplantation struction. Cornea 1994;13:389–400.
with or without limbal allografts for severe ocular surface disorders. Ophthalmology 43. Solomon A, Ellies P, Anderson DF, et al. Long-term outcome of keratolimbal allograft
1995;102:1486–96. with and without penetrating keratoplasty for total limbal stem cell deficiency. Ophthal-
18. Pires RT, Chokshi A, Tseng SC. Amniotic membrane transplantation or conjunctival mology 2002;109:1159–66.
limbal autograft for limbal stem cell deficiency induced by 5-fluorouracil in glaucoma 44. Ilari L, Daya SM. Long-term outcomes of keratolimbal allografts for the treatment of
surgeries. Cornea 2000;19:284–7. severe ocular surface disorders. Ophthalmology 2002;109:1278–84.
19. Gomes JA, dos Santos MS, Cunha MC, et al. Amniotic membrane transplantation for 45. Santos MA, et al. Survival analysis of conjunctival limbal grafts and amniotic mem-
partial and total limbal stem cell deficiency secondary to chemical burn. Ophthalmology brane transplantation in eyes with total limbal stem cell deficiency. Am J Ophthalmol
2003;110:466–73. 2005;140:223–30.
20. Anderson DF, Ellies P, Pires RT, et al. Amniotic membrane transplantation for partial 46. Schwab IR, Reyes M, Isseroff RR. Successful transplantation of bioengineered tissue
limbal stem cell deficiency. Br J Ophthalmol 2001;85:567–75. replacements in patients with ocular surface disease. Cornea 2000;19:421–8.
21. Sangwan VS, Matalia HP, Vemuganti GK, et al. Amniotic membrane transplantation for 47. Grueterich M, Tseng SC. Human limbal progenitor cells expanded on intact amniotic
reconstruction of corneal epithelial surface in cases of partial limbal stem cell deficiency. membrane ex vivo. Arch Ophthalmol 2002;120:783–90.
Indian J Ophthalmol 2004;52:281–5. 48. Meller D, Pires RTF, Tseng SCG. Ex vivo preservation and expansion of human limbal
22. Ucakhan OO, Koklu G, Firat E. Nonpreserved human amniotic membrane transplanta- epithelial stem cells on amniotic membrane cultures. Br J Ophthalmol 2002;80:463–71.
tion in acute and chronic chemical eye injuries. Cornea 2002;21:169–72. 49. Shimazaki J, Aiba M, Goto E, et al. Transplantation of human limbal epithelium culti-
23. Chuck RS, Graff JM, Bryant MR, et al. Biomechanical characterization of human vated on amniotic membrane for the treatment of severe ocular surface disorders. Oph-
amniotic membrane preparations for ocular surface reconstruction. Ophthalmic Res thalmology 2002;109:1285–90.
2004;36:341–8. 50. Baylis O, Figueiredo F, Henein C, et al. 13 years of cultured limbal epithelial cell therapy:
24. Fournier JH, McLachlan DL. Ocular surface reconstruction using amniotic membrane a review of the outcomes. J Cell Biochem 2011;112:993–1002.
allograft for severe surface disorders in chemical burns: case report and review of the 51. Sant’ Anna AE, Hazarbassanov RM, de Freitas D, et al. Minor salivary glands and labial
literature. Int Surg 2005;90:45–7. mucous membrane graft in the treatment of severe symblepharon and dry eye in patients
25. Meallet MA, Espana EM, Grueterich M, et al. Amniotic membrane transplantation with Stevens–Johnson syndrome. Br J Ophthalmol 2012;96:234–9.
with conjunctival limbal autograft for total limbal stem cell deficiency. Ophthalmology 52. Sangwan VS, Matalia HP, Vemuganti GK, et al. Early results of penetrating keratoplasty
2003;110:1585–92. after cultivated limbal epithelium transplantation. Arch Ophthalmol 2005;123:334–40.
26. Holland EJ. Epithelial transplantation for the management of severe ocular surface 53. Basu S, Mohamed A, Chaurasia S, et al. Clinical outcomes of penetrating keratoplasty
disease. Trans Am Ophthalmol Soc 1996;94:677–743. after autologous cultivated limbal epithelial transplantation for ocular surface burns. Am
27. Tsai RJ, Li LM, Chen JK. Reconstruction of damaged corneas by transplantation of autol- J Ophthalmol 2011;152:917–24.
ogous limbal epithelial cells. N Engl J Med 2000;343:86–93.
321.e1
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Section 9 Surgery
Management of Corneal Thinning,

Melting, and Perforation 4.31
Nicoletta Fynn-Thompson, Michael H. Goldstein
of local (ocular) treatment are to (1) provide local supportive therapy to

Definition: Management of full-thickness or partial-thickness loss of decrease corneal melting; and (2) promote re-epithelization of the corneal
corneal tissue. surface. These goals are accomplished using the following modalities:
aggressive lubrication with preservative-free eyedrops and ointments,
punctal occlusion, placement of a bandage contact lens, patching, oral dox-
ycycline (or equivalent), and tarsorrhaphy. Topical collagenase inhibitors
Key Features and corticosteroids are of some value, but may delay healing and cause
• Concurrent, aggressive treatment of the underlying infectious or perforation by initiating stromal melting. The goal of systemic therapy is
inflammatory condition. to suppress the underlying systemic disorder with immunosuppressive or
• Multiple treatment options, depending on the clinical situation. immunomodulatory therapy. If the underlying autoimmune disease is not
• The primary goal is to re-establish the tectonic integrity of the globe. treated, the corneal pathology will not improve.1–3
Inflammatory corneal disorders caused by infectious organisms (viral,
bacterial, or fungal) also cause thinning and melting of the corneal stroma.
Treating the pathogen aggressively with both topical and oral medications
Associated Features is most important to reduce further destruction of stromal tissue. Some
• Typically a true ophthalmic emergency. advocate the use of concomitant corticosteroid drops once the infection is
• Surgical management often warranted. controlled, but this is controversial. If, despite aggressive therapy, stromal
keratolysis progresses with development of descemetocele, impending
perforation, or frank perforation, the goal becomes maintaining the eye’s
INTRODUCTION integrity.
The integrity of the cornea can be compromised by both inflammatory

and noninflammatory conditions, which may lead to stromal thinning, SURGICAL TREATMENT OF
melting, and perforation. Progression may be slow over months to years,
or may be rapid over hours to days. Rapid, proper recognition and man-
CORNEAL PERFORATIONS
agement of these conditions is crucial to restore vision and to re-establish Tissue Adhesives
the integrity of the eye.
Descemetoceles or impending perforations can be stabilized or temporized
by application of tissue adhesive and placement of a bandage contact lens
CORNEAL THINNING FROM with close follow-up. Studies have shown this procedure arrests the process
NONINFLAMMATORY DISORDERS of ulceration in noninfectious eyes. Application of tissue adhesive is much
easier to perform in impending perforations than in frank perforations.4
Noninflammatory corneal thinning disorders cause progressive ectasia Frank corneal perforations, however, can be treated successfully with appli-
caused by thinning of the stroma. The most common of these disorders cation of tissue adhesives. Although perforations measuring 1–2 mm are
include keratoconus, pellucid marginal degeneration, keratoglobus, and most successfully treated, those measuring up to 3 mm have been closed.
posterior keratoconus. Progressive corneal thinning (ectasia) is a rare but Cyanoacrylate tissue adhesive traditionally has been used (Fig. 4.31.1).5 Its
serious complication after laser refractive surgery. These conditions gen-
erally are slowly progressive. The primary goal, therefore, is to maintain
functional vision (see Chapter 4.18 for more information).
CORNEAL THINNING AND MELTING FROM

INFLAMMATORY DISORDERS
Inflammatory corneal disorders can cause thinning with stromal melting.
These conditions are often associated with pain, epithelial defects, corneal
neovascularization, and other inflammatory changes. Progression is fast
and emergent treatment is warranted upon diagnosis.
Noninfectious inflammatory causes include peripheral ulcerative kera-
titis (PUK), Mooren’s ulcer, Terrien’s marginal degeneration, and collagen
vascular disorders. Infectious inflammatory causes include viral herpetic
keratitis, bacterial keratitis, and fungal keratitis.
PUK suggests an autoimmune-mediated process and often is associ-
ated with rheumatoid arthritis. PUK (see Chapter 4.16) is seen with Wege-
ner’s granulomatosis, systemic lupus erythematosus, polyarteritis nodosa,
ulcerative colitis, and relapsing polychondritis.
322 Medical treatment is directed both locally at the cornea and systemi- Fig. 4.31.1 Corneal perforation sealed with cyanoacrylate glue. (Courtesy Michael H.
cally to address the underlying systemic inflammatory process. The goals Goldstein, MD.)
booksmedicos.org
4.31
Management of Corneal Thinning, Melting, and Perforation

A B C
Fig. 4.31.2 Technique for application of cyanoacrylate glue for treatment of larger corneal perforation. (A) Apply ointment to end of Q-tip. (B) Place small circular disc from
cut drape onto Q-tip and adhere with ointment. (C) Place corneal glue onto disc and then place onto eye. (Courtesy Michael H. Goldstein, MD.)
use to seal corneal perforations was first reported in 1968.6 Cyanoacrylate Patients also benefit from oral doxycycline because of its ability to inhibit
adhesive prevents re-epithelization into the zone of damaged stroma and collagenase. Depending on the cause, infected perforations are treated
prevents collagenase production, which leads to stromal melting.7 with frequent fortified antibacterial, antiviral, or antifungal therapy. Ini-
A common technique is described below, although several other excel- tially, patients should be examined daily, and any complaints of decreased
lent techniques exist. A thorough examination of the eye prior to appli- vision, pain, tearing, or photophobia should be attended to immediately.
cation of the glue must be performed, with attention to the extent of If the bandage lens falls out, it must be replaced. If the glue becomes dis-
perforation, possible lenticular damage, and possible uveal prolapse at the lodged, reapplication is often necessary.
perforation site. Placing the patient in the supine position under an oper- Corneal glue remains in place for weeks to months. It is recommended
ating microscope is easier than examining the patient at the slit lamp. A to leave it in place until it loosens and dislodges on its own, leaving behind
topical anesthetic and lid speculum should be placed in the eye. Debride- a more healthy-appearing stromal tissue.
ment of necrotic tissue from the ulcer crater is performed. This removed The reported potential complications for corneal tissue adhesive appli-
material is plated onto culture media to identify a possible infectious cause. cation include cataract formation,15 corneal infiltrates, increased IOP,16
The tissue adhesive adheres best to basement membrane so debridement giant papillary conjunctivitis,17 retinal toxicity,18 keratitis,19 and iridocorneal
of 1–2 mm of normal epithelium surrounding the ulcer allows for proper and iridolenticular adhesions.20
adhesion of the glue. A methylcellulose spear is used to dry the site. The Studies have shown that fibrin glue causes less neovascularization;
tissue adhesive is then placed in microaliquots on the site of perfora- however, a longer time is required for the adhesive plug to form. Appli-
tion with an applicator. The applicator can be a needle from a tuberculin cation of fibrin glue has been shown to be successful with the additional
syringe,8 a 23-gauge Angiocath catheter (with the needle removed),9 or a placement of amniotic membrane grafts for structural support of a perfo-
micropipette.10 Alternatively, a polyethylene disc can be made and attached rated cornea.21–25
to a sterile wooden stick with ophthalmic ointment, and glue placed on
the disc. Both are applied directly to the site of perforation (Fig. 4.31.2). Penetrating Keratoplasty
The disc can then be removed or left in place.11,12 The goal is to create a
controlled method of placement of the smallest amount of glue to seal If the corneal perforation is not amenable to treatment with corneal glue,
the perforation. The glue will solidify via polymerization over the next few then tectonic grafting is indicated (either a full-thickness or lamellar
minutes. A large, heaped mound over the crater is not necessary and can graft).8 The smallest trephination capable of incorporating the site of per-
cause irritation and discomfort for the patient after the procedure. foration is chosen. Trephination of a soft eye is very difficult but is aided
The eye should be checked for evidence of leakage. If secure, then a by the judicious use of viscoelastic materials. Alternatively, the temporary
bandage contact lens is applied, and the patient is checked at the slit lamp application of cyanoacrylate adhesive and sodium hyaluronate to create a
to confirm that the anterior chamber is forming and the glue is in place. normotensive eye has been described.26 A customized hard contact lens
Application of tissue adhesive in frank corneal perforations is more applied with tissue adhesive to the corneal perforation has been reported
challenging, as preparation of the site is more difficult secondary to the to stabilize the eye and allow for trephination.27 In some cases, handheld
constant flow of aqueous from the perforation. Unless contraindicated, an trephination may be needed. Care must be taken to avoid protrusion of
air bubble can be placed into the anterior chamber to temporarily occlude ocular contents or damaging the iris or lens. The donor cornea should be
the perforation by surface tension. Larger air bubbles risk pupillary secured with interrupted 10-0 nylon sutures.
block and increased intraocular pressure (IOP), so caution must be exer- Several case reports and case series have demonstrated the promising
cised.13 In eyes with flat anterior chambers, to avoid incarceration of uveal use of tectonic Descemet’s stripping automated endothelial (DSAEK) in
tissue or the lens, viscoelastic material may be injected into the anterior managing both impending and sterile corneal perforations.28,29
chamber.14 Postoperative care is challenging. A balance between reducing inflam-
Postoperatively, the patient may be placed on an aqueous suppressant, mation and the possibility of graft rejection, without significantly reducing
if medically tolerated. Patients with noninfectious perforations should the host’s immunity, must be reached. Topical corticosteroids four times
receive a prophylactic broad-spectrum antibiotic four times daily. A protec- daily usually are required. Aggressive antibiotic, antiviral, or antifungal
tive shield should be kept in place at all times. Preservative-free artificial treatment is continued as indicated for infectious cases. For noninfectious 323
tears applied frequently will aid in lubrication with a bandage lens in place. cases, a broad-spectrum antibiotic is used four times daily.
booksmedicos.org
mentioned previously, amniotic membrane in conjunction with fibrin glue
4 has been used to successfully close corneal perforations and restore globe
integrity. Conjunctival flaps are useful for thinning due to ulcerations or
descemetocele formation but are contraindicated in corneal perforations.
Conjunctival resection may be a useful adjuvant therapy in appropriate
cases of corneal melting secondary to PUK.
CONCLUSIONS
Corneal thinning, melting, and perforation can be caused by both inflam-
matory and noninflammatory conditions. Identification and treatment of
these conditions is critical in the successful management of these patients.
If impending or actual perforation occurs, immediate action must be taken
to restore the integrity of the eye. This can be done with tissue adhesives,
patch grafts, PKP, or amniotic membrane grafts.
KEY REFERENCES
Boruchoff SA, Donshik PC. Medical and surgical management of corneal thinnings and
Fig. 4.31.3 Corneal perforation secondary to acute hydrops treated with patch graft. perforations. Int Ophthalmol Clin 1975;15:111–23.
Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients developing
(Courtesy Michael H. Goldstein, MD.)
necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosup-
pression. Ophthalmology 1984;91:1253–63.
Hick S, Demers PE, Brunette I, et al. Amniotic membrane transplantation and fibrin glue
Patch Graft in the management of corneal ulcers and perforations: a review of 33 cases. Cornea
2005;24:369–77.
If the perforation is too large for a tissue adhesive, but too small for a Leahey AB, Gottsch JD, Stark WJ. Clinical experience with N-butyl cyanoacrylate (Nexacryl)
full-sized penetrating keratoplasty (PKP) procedure, then a corneal patch tissue adhesive. Ophthalmology 1993;100:173–80.
graft can be helpful (Fig. 4.31.3). These procedures can temporarily stabi- Maguen E, Nesburn AB, Macy JI. Combined use of sodium hyaluronate and tissue adhesive
lize a perforation or descemetocele or may be a permanent treatment. It is in penetrating keratoplasty for corneal perforations. Ophthalmic Surg 1984;15:55–7.
Nobe JR, Moura BT, Robin JB, et al. Results of penetrating keratoplasty for the treatment of
ideal for peripheral pathology. Care should be taken when used for central corneal perforations. Arch Ophthalmol 1990;108:939–41.
pathology because it can interfere with visual outcome. Rodriguez-Ares MT, Tourino R, Lopez-Valladares MJ, et al. Multilayer amniotic membrane
Gamma-irradiated sterile cornea now is available and very helpful in transplantation in the treatment of corneal perforations. Cornea 2004;23:577–83.
emergency situations. This tissue has a long shelf life, increasing the Sharma A, Kaur R, Kumar S, et al. Fibrin glue versus N-butyl-2-cyanoacrylate in corneal
perforations. Ophthalmology 2003;110:291–8.
number of corneas suitable for transplantation. This tissue eliminates Solomon A, Meller D, Prabhasawat P, et al. Amniotic membrane grafts for nontraumatic
the risk of infection because of its preparation. It can be used only when corneal perforations, descemetoceles, and deep ulcers. Ophthalmology 2002;109:694–703.
viable endothelium is not necessary. Preliminary studies show it is useful Vote BJ, Elder MJ. Cyanoacrylate glue for corneal perforations: a description of a surgical
in corneal patch graft surgery.30 technique and review of the literature. Clin Exp Ophthalmol 2000;28:437–42.
Wagoner MD, Kenyon KR, Foster CS. Management strategies in peripheral ulcerative kerati-
tis. Int Ophthalmol Clin 1986;26:147–57.
Miscellaneous Treatments Weiss JL, Williams P, Lindstrom RL, et al. The use of tissue adhesive in corneal perforations.
Multilayered amniotic membrane grafts alone may be successful in treat-
ing nontraumatic corneal perforations. More favorable outcomes are Access the complete reference list online at ExpertConsult.com
limited to perforations measuring less than 1.5 mm in diameter.13,31 As
324
booksmedicos.org
REFERENCES 17. Carlson AN, Wilhelmus KR. Giant papillary conjunctivitis associated with cyanoacrylate
glue. Am J Ophthalmol 1987;104:437–8.
1. Wagoner MD, Kenyon KR, Foster CS. Management strategies in peripheral ulcerative
keratitis. Int Ophthalmol Clin 1986;26:147–57.
18. Hida T, Sheta SM, Proia AD, et al. Retinal toxicity of cyanoacrylate tissue adhesive in the
rabbit. Retina 1988;8:148–53.
4.31
2. Shiuey Y, Foster CS. Peripheral ulcerative keratitis and collagen vascular disease. Int 19. Ferry AP, Barnert AH. Granulomatous keratitis resulting from use of cyanoacrylate adhe-
sive for closure of perforated corneal ulcer. Am J Ophthalmol 1971;72:538–41.
Management of Corneal Thinning, Melting, and Perforation

Ophthalmol Clin 1998;38:21–32.
3. Foster CS, Forstot SL, Wilson LA. Mortality rate in rheumatoid arthritis patients devel- 20. Markowitz GD, Orlin SE, Frayer WC, et al. Corneal endothelial polymerization of his-
oping necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immuno- toacryl adhesive: a report of a new intraocular complication. Ophthalmic Surg 1995;26:
suppression. Ophthalmology 1984;91:1253–63. 256–8.
4. Nobe JR, Moura BT, Robin JB, et al. Results of penetrating keratoplasty for the treatment 21. Siatiri H, Moghimi S, Malihi M, et al. Use of sealant (HFG) in corneal perforations.
of corneal perforations. Arch Ophthalmol 1990;108:939–41. Cornea 2008;27:988–91.
5. Leahey AB, Gottsch JD, Stark WJ. Clinical experience with N-butyl cyanoacrylate (Nex- 22. Sharma A, Kaur R, Kumar S, et al. Fibrin glue versus N-butyl-2-cyanoacrylate in corneal
acryl) tissue adhesive. Ophthalmology 1993;100:173–80. perforations. Ophthalmology 2003;110:291–8.
6. Webster RG Jr, Slansky HH, Refojo MF, et al. The use of adhesive for the closure of 23. Hick S, Demers PE, Brunette I, et al. Amniotic membrane transplantation and fibrin
corneal perforations. Report of two cases. Arch Ophthalmol 1968;80:705–9. glue in the management of corneal ulcers and perforations: a review of 33 cases. Cornea
7. Vote BJ, Elder MJ. Cyanoacrylate glue for corneal perforations: a description of a surgical 2005;24:369–77.
technique and review of the literature. Clin Exp Ophthalmol 2000;28:437–42. 24. Duchesne B, Tahi H, Galand A. Use of human fibrin glue and amniotic membrane
8. Vanathi M, Sharma N, Titiyal JS, et al. Tectonic grafts for corneal thinning and perfora- transplant in corneal perforation. Cornea 2001;20:230–2.
tions. Cornea 2002;21:792–7. 25. Kim HK, Park HS. Fibrin glue-assisted augmented amniotic membrane transplantation
9. Foster CS. Tissue adhesives. Smolin and Toft’s The cornea: scientific foundations and for the treatment of large noninfectious corneal perforations. Cornea 2009;28:170–6.
clinical practice. 4th ed. Philadelphia: Lippincott Williams and Wilkins; 2005. p. 939–43. 26. Maguen E, Nesburn AB, Macy JI. Combined use of sodium hyaluronate and tissue adhe-
10. Wessels IF, McNeill JI. Applicator for cyanoacrylate tissue adhesive. Ophthalmic Surg sive in penetrating keratoplasty for corneal perforations. Ophthalmic Surg 1984;15:55–7.
1989;20:211–14. 27. Kobayashi A, Shirao Y, Segawa Y, et al. Temporary use of a customized glued-on hard
11. Lin DT, Webster RG Jr, Abbott RL. Repair of corneal lacerations and perforations. Int contact lens before penetrating keratoplasty for descemetocele or corneal perforation.
Ophthalmol Clin 1988;28:69–75. Ophthalmic Surg Lasers Imaging 2003;34:226–9.
12. Boruchoff SA, Donshik PC. Medical and surgical management of corneal thinnings and 28. Graue-Hernandez EO, Zuniga-Gonzalez I, Hernandez-Camarena JC, et al. Tectonic
perforations. Int Ophthalmol Clin 1975;15:111–23. DSAEK for the management of impending corneal perforation. Case Rep Ophthalmol
13. Rodriguez-Ares MT, Tourino R, Lopez-Valladares MJ, et al. Multilayer amniotic mem- Med 2012;2012:916528.
brane transplantation in the treatment of corneal perforations. Cornea 2004;23:577–83. 29. Nahum Y, Bahar I, Busin M. Tectonic descemet stripping automated endothelial kera-
14. Hirst LW, DeJuan E Jr. Sodium hyaluronate and tissue adhesive in treating corneal per- toplasty for the management of sterile corneal perforations in decompensated corneas.
forations. Ophthalmology 1982;89:1250–3. Cornea 2016;35(12):1516–9.
15. Hyndiuk RA, Hull DS, Kinyoun JL. Free tissue patch and cyanoacrylate in corneal perfo- 30. Daoud YJ, Smith R, Smith T, et al. The intraoperative impression and postoperative
rations. Ophthalmic Surg 1974;5:50–5. outcomes of gamma-irradiated corneas in corneal and glaucoma patch surgery. Cornea
16. Weiss JL, Williams P, Lindstrom RL, et al. The use of tissue adhesive in corneal perfora- 2011;30:1387–91.
tions. Ophthalmology 1983;90:610–15. 31. Solomon A, Meller D, Prabhasawat P, et al. Amniotic membrane grafts for nontraumatic
corneal perforations, descemetoceles, and deep ulcers. Ophthalmology 2002;109:694–703.
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Part 5 The Lens

Basic Science of the Lens

Michael E. Boulton 5.1
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Definition: A normally transparent intraocular structure whose GROSS ANATOMY OF THE ADULT HUMAN LENS
function is to alter the pathway of light that has entered the eye to focus
the image on the retina. proliferative capacity
increases
anterior
Key Features pregerminative epithelial central pregerminative

zone cells zone cortex zone
• Normally transparent at birth. germinative germinative
• Increasing opacity with age, infection, surgery, trauma, various zone zone
metabolic states.
• Can alter shape and refractive power to allow for accommodation.
equator equator
Associated Features transitional transitional

• Asymmetric oblate spheroid shape. zone zone
• Avascular.
• Located posterior to the iris and anterior to the vitreous body. embryonic nucleus capsule bow
• Spectral filter. fetal nucleus posterior
• Suspended by the zonules. infantile nucleus
adult nucleus
The lens is a transparent structure that has evolved to alters the pathway
of the light entering the eye. In 2002, the World Health Organization esti- Fig. 5.1.1 Gross Anatomy of the Adult Human Lens. Note the different regions are
mated that lens pathology (cataract) was the most common cause of blind- not drawn to scale.
ness worldwide, affecting more than 17 million people across the globe.1
Cataract surgery is the most common surgical procedure performed in the
developed world.2 The metabolic needs of the lens are met by the aqueous and the vit-
The lens is an asymmetric oblate spheroid that is avascular and lacks reous humor, with the majority of glucose and amino acids coming from
nerves and connective tissue.3 It is located posterior to the iris with its the aqueous. The capsule is freely permeable to water, ions, other small
anterior surface in contact with the aqueous and the posterior surface with molecules, and proteins with a molecular weight up to 70 kDa. In addition,
the vitreous. The lens is suspended by the zonular fibers that arise from epithelial cells and fibers possess a number of channels, pumps, and trans-
the ciliary epithelium and insert 1–2 µm into the outer part of the capsule.4 porters that enable transcellular movement.
Histologically the lens consists of three major components: capsule, epi- The lens acts as spectral filter and readily absorbs the energetic ultravi-
thelium, and lens substance (Fig. 5.1.1). olet (UV) component of the electromagnetic spectrum that, if transmitted,
The lens capsule is an acellular envelope that is continuously synthe- has the potential to damage the retina. The overall transmission of visible
sized by the lens epithelium anteriorly and fiber cells posteriorly. It is light decreases with increasing age, a feature that arises largely from
composed of a number of stacked lamellae, which contain major struc- age-related changes and brunescence.8 The refractive index of the lens
tural proteins and fibronectin.5 The lens epithelium is a single layer of increases from 1.386 in the peripheral cortex to 1.41 in the central nucleus.
cuboidal cells approximately 10 µm high and 15 µm wide, located beneath In addition, the curvature of the lens increases in a similar manner. Thus
the anterior capsule that extends to the equatorial lens bow. Their basal each successive layer of fibers has more refractive power and can bend
surface adheres to the capsule, whereas their anterior surface abuts the light rays to a greater extent. When visible light passes through the lens,
newly formed elongating lens fibers. The proliferative capacity of epithelial it is split into all the colors of the spectrum. The different wavelengths of
cells is greatest at the equator, and cells in the germinative zone are divid- these colors result in differences in refraction (chromatic aberration). As a
ing constantly. Here, newly formed cells are forced into the transitional consequence, yellow light (570–595 nm) normally is focused on the retina,
zone where they elongate and differentiate to form the fiber mass of the blue (440–500 nm) anteriorly, and red (620–770 nm) posteriorly.9 The lens
lens.3 The bulk of the lens is composed of the nucleus and cortex, which is designed to minimize spherical aberration (defocus caused by greater
comprise densely packed lens cytoplasm (“fiber cells”) with very little extra- refraction of light striking the peripheral lens compared to the center) in
cellular space. these ways:
The lens grows throughout life but at a slower rate with increasing age.
The rate of increase in lens weight and equatorial diameter is greater than • The refractive index increases from the periphery to the center of the
that of lens thickness.6 Newly formed fibers are internalized as more are lens.
added at the transitional zone of the lens, and thus the newest fibers are • The curvature of both the anterior and the posterior capsule increases
in the outer cortex, and the oldest fibers are found in the center of the toward the poles.
nucleus. Each growth shell, therefore, represents a layer of fibers that are • The curvature of the anterior capsule is greater than that of its posterior 325
younger than those in the shell immediately preceding it.7 counterpart.
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• Modulation of pupillary size prevents light from striking the periphery lens fiber cells. Soemmerring’s ring is often less visually significant, as the
5 of the lens under nonmydriatic conditions.9,10
Accommodation is the process by which the lens changes its optical

trapped and proliferating residual lens epithelial cells are located in the
periphery, behind the iris.16 While currently no definitive prevention exists,
newer surgical techniques and IOLs may help to decrease the incidence of
power by altering its shape and thus its focusing ability. At rest, the ciliary new cases. The current standard treatment involves the use of a neodymi-
The Lens
muscle is relaxed and the zonules pull on the lens keeping the capsule um:yttrium–aluminum–garnet (Nd:YAG) laser to perform a capsulectomy
under tension and the lens flattened. Accommodation occurs when the in the clinical setting.
ciliary muscle contracts, relaxing the zonules, thus increasing the curvature In conclusion, the lens is a deceptively complex structure that allows
of the anterior surface and decreasing the radius of curvature from 10 mm for the transmission and refraction of light. An orderly structure, stable
to 6 mm. The increase in curvature of the anterior surface increases the metabolic state, and intact antioxidant system are mandatory to maintain
refractive power. Accommodation is accompanied by a decrease in pupil clarity. A full understanding of the basic science related to the lens allows
size (miosis) and convergence of the two eyes.11 for appreciation of the numerous pathologies that affect it and thus their
Adenosine triphosphate (ATP) is the principal source of energy of medical and surgical treatment.
the lens, the majority of which comes from the anaerobic metabolism of
glucose. Approximately 90%–95% of the glucose that enters the normal
lens is phosphorylated to glucose-6-phosphate (G6P) in a reaction catalyzed KEY REFERENCES
by hexokinase. G6P is used either in the glycolytic pathway (80% of total Allen D, Vasavada A. Cataract and surgery for cataract. BMJ 2006;333:128–32.
glucose) or in the pentose phosphate pathway. The 5%–10% of glucose that Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol
1992;37:73–116.
is not converted to G6P either enters the sorbitol pathway or is converted Bennett AG, Rabbetts RB. Ocular aberrations. Clinical visual optics. 2nd ed. London: Butter-
into gluconic acid.12 worths; 1989. p. 331–57.
The protein concentration within the lens is the highest in the body. Chylack LT. Aging changes in the crystalline lens and zonules. In: Albert DM, Jakobiec FA,
The majority of ongoing synthesis generates crystallins and major intrin- editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB
Saunders; 1994. p. 702–10.
sic protein 26 (MIP26). The water-soluble crystallins constitute approxi- Cook CA, Koretz JF, Pfahnl A, et al. Aging of the human crystalline lens and anterior
mately 90% of the total protein content of the lens. The three groups of segment. Vision Res 1994;34:2945–54.
crystallins can be divided into the α-crystallin family and the β/γ-crystallin Duke-Elder S. Accommodation. In: Abrams D, editor. The practice of refraction. 10th ed.
superfamily.13 Edinburgh: Churchill Livingstone; 1993. p. 85–9.
The continuous entry of optical radiation into the lens, especially UV Duke-Elder S. The refraction of the eye – physiological optics. In: Abrams D, editor. The
practice of refraction. 10th ed. Edinburgh: Churchill Livingstone; 1993. p. 29–41.
(295–400 nm), makes the lens particularly susceptible to photochemical Foster A, Resnikoff S. The impact of Vision 2020 on global blindness. Eye 2005;19:1133–5.
reactions leading to generation of reactive oxygen species (ROS). Protec- Kador PF. Biochemistry of the lens: intermediary metabolism and sugar cataract formation.
tion against damage induced by ROS is achieved by a complex antioxidant In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Basic
system that relies heavily on superoxide dismutase, ascorbate, catalase, and sciences. Philadelphia: WB Saunders; 1994. p. 146–67.
Kuszak JR. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev Cytol
glutathione peroxidase.14 1995;163:305–50.
Numerous morphological, biochemical, and biophysical changes occur Kuszak JR, Brown HG. Embryology and anatomy of the lens. In: Albert DM, Jakobiec FA,
to the lens with age.15 Most notable are the age-related changes in color editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB
(more yellow), light transmission (decreased), consistency (increased hard- Saunders; 1994. p. 82–96.
Lerman S. Free radical damage and defense mechanisms in the ocular lens. Lens Eye Toxic
ness), loss of accommodative ability (manifested clinically as presbyopia), Res 1992;9:9–24.
and protein aggregation. The resultant lens opacification, referred to as Lerman S. Lens transparency and aging. In: Regnault F, Hockwin O, Courtios Y, editors.
cataract, results in loss of light transmission. Ageing of the lens. Amsterdam: Elsevier/North-Holland Biomedical Press; 1980. p.
While cataract surgery is safe and commonly performed, a major com- 263–79.
Seland JH. The lens capsule and zonulae. Acta Ophthalmol 1992;70:7–12.
plication is development of a secondary cataract (posterior capsular opaci- Snell RS, Lemp MA. The eyeball. Clinical anatomy of the eye. Oxford: Blackwell Scientific;
fication or Soemmerring’s ring). Posterior capsular opacification (PCO) is 1989. p. 119–94.
the most common and can be further divided into fibrosis type and pearl Zigler JS. Lens proteins. In: Albert DM, Jakobiec FA, editors. Principles and practice of oph-
type (Elschnig’s pearls). Vision can be affected by blockage of the visual thalmology. Basic sciences. Philadelphia: WB Saunders; 1994. p. 97–113.
axis (both) or by progressive decentration of the intraocular lens (IOL)
due to remnant lens epithelial cell proliferation and migration, epithelial– Access the complete reference list online at ExpertConsult.com
mesenchymal transition, collagen deposition, and generation of aberrant
326
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REFERENCES 9. Duke-Elder S. The refraction of the eye – physiological optics. In: Abrams D, editor. The
practice of refraction. 10th ed. Edinburgh: Churchill Livingstone; 1993. p. 29–41.
1. Foster A, Resnikoff S. The impact of Vision 2020 on global blindness. Eye 2005;19:
1133–5.
10. Bennett AG, Rabbetts RB. Ocular aberrations. Clinical visual optics. 2nd ed. London:
Butterworths; 1989. p. 331–57.
5.1
2. Allen D, Vasavada A. Cataract and surgery for cataract. BMJ 2006;333:128–32. 11. Duke-Elder S. Accommodation. In: Abrams D, editor. The practice of refraction. 10th ed.
Edinburgh: Churchill Livingstone; 1993. p. 85–9.

3. Kuszak JR, Brown HG. Embryology and anatomy of the lens. In: Albert DM, Jakobiec
FA, editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB 12. Kador PF. Biochemistry of the lens: intermediary metabolism and sugar cataract forma-
Saunders; 1994. p. 82–96. tion. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Basic
4. Snell RS, Lemp MA. The eyeball. Clinical anatomy of the eye. Oxford: Blackwell Scien- sciences. Philadelphia: WB Saunders; 1994. p. 146–67.
tific; 1989. p. 119–94. 13. Zigler JS. Lens proteins. In: Albert DM, Jakobiec FA, editors. Principles and practice of
5. Seland JH. The lens capsule and zonulae. Acta Ophthalmol 1992;70:7–12. ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994. p. 97–113.
6. Cook CA, Koretz JF, Pfahnl A, et al. Aging of the human crystalline lens and anterior 14. Lerman S. Free radical damage and defense mechanisms in the ocular lens. Lens Eye
segment. Vision Res 1994;34:2945–54. Toxic Res 1992;9:9–24.
7. Kuszak JR. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev 15. Chylack LT. Aging changes in the crystalline lens and zonules. In: Albert DM, Jakobiec
Cytol 1995;163:305–50. FA, editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB
8. Lerman S. Lens transparency and aging. In: Regnault F, Hockwin O, Courtios Y, editors. Saunders; 1994. p. 702–10.
Ageing of the lens. Amsterdam: Elsevier/North-Holland Biomedical Press; 1980. p. 16. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol
263–79. 1992;37:73–116.
326.e1
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Part 5 The Lens


Michael E. Boulton 5.1
This structure is continuously synthesized, anteriorly by the lens epithe-
Definition: A normally transparent intraocular structure whose lium and posteriorly by the fiber cells.
function is to alter the pathway of light that has entered the eye to focus
the image on the retina.
Epithelial Cells
The lens epithelium is a single layer of cuboidal cells approximately 10 µm
Key Features high and 15 µm wide beneath the anterior capsule that extends to the
equatorial lens bow. Their basal surface adheres to the capsule, whereas
• The lens comprises three parts: (1) the capsule, (2) the lens their anterior surface abuts the newly formed elongating lens cytoplasm
epithelium, and (3) the lens fibers.
(“fibers”). Lens epithelial cells have a large array of organelles and contain
• α-, β- and γ-crystallins constitute 90% of the total protein content of dense bodies and glycogen particles. Lateral attachment to adjacent cells
the lens.
occurs through both desmosomes and tight junctions.3,8–10
• Lens function is dependent on the metabolism of glucose to produce Lens epithelial cells contain three cytoskeletal elements: microfilaments
energy, protein synthesis, and a complex antioxidant system.
(actin), intermediate filaments (vimentin), and microtubules (tubulin).
• Lens transparency is dependent on the highly organized structure These elements form a network that provides structural support, control of
of the lens, the dense packing of crystallin, and the supply of
cell shape and volume, intracellular compartmentalization and movement
appropriate nutrients.
of organelles, cell movement, distribution of mechanical stress, and medi-
• The lens can change its focusing power through a process called ation of chromosome movement during cell division.
accommodation.
• The lens exhibits age-related changes in structure, light transmission,
metabolic capacity, and enzyme activity.
• Secondary cataract occurs when residual lens cells after cataract GROSS ANATOMY OF THE ADULT HUMAN LENS
extraction cause opacification of the visual axis.
proliferative capacity
increases
anterior
INTRODUCTION
pregerminative epithelial central pregerminative
The lens is a vital refractive element of the human eye. The World Health zone cells zone cortex zone
Organization estimates that lens pathology (cataract) is the most common germinative germinative
cause of blindness worldwide, affecting over 17 million people.1 Not sur- zone zone
prisingly, cataract surgery is the most common procedure performed in
the developed world.2 An understanding of the basic science of the lens
equator equator
provides valuable insight into the various pathologies involving the lens
and their treatment.
transitional transitional
ANATOMY OF THE LENS zone zone
The adult human lens is an asymmetric oblate spheroid that does not
possess nerves, blood vessels, or connective tissue.3 The lens is located embryonic nucleus capsule bow
behind the iris and pupil in the anterior compartment of the eye. The fetal nucleus posterior
anterior surface is in contact with the aqueous; the posterior surface is infantile nucleus
in contact with the vitreous. The anterior pole of the lens and the front adult nucleus
of the cornea are separated by approximately 3.5 mm.4 The lens is held
in place by the zonular fibers (suspensory ligaments), which run between
Fig. 5.1.1 Gross Anatomy of the Adult Human Lens. Note the different regions are
the lens and the ciliary body. These fibers, which originate in the region
not drawn to scale.
of the ciliary epithelium, are fibrillin rich and converge in a circular zone
on the lens. Both an anterior and a posterior sheet meet the capsule
Fig. 5.1.2 Changes
1–2 mm from the equator and are embedded into the outer part of the THICKNESS OF THE LENS CAPSULE in Thickness of
capsule (1–2 µm deep). It also is thought that a series of fibers meets the the Adult Lens
capsule at the equator.5,6 anterior pole Capsule With
Histologically the lens consists of three major components—capsule, 14m Location.
epithelium, and lens substance (Fig. 5.1.1). 21m 21m
Capsule 17m 17m

The lens is ensheathed by an elastic envelope composed of epithelial cells
and fibers that allows the passage of molecules both into and out of the
23m 23m
lens. Capsule thickness varies by location (Fig. 5.1.2) and, except for the
posterior capsule, increases with age.4–6 The capsule is composed of a
number of lamellae stacked on top of each other that are narrowest near 4m
the outside of the capsule and widest near the cell mass.7 Major structural posterior pole e1
proteins and a small amount of fibronectin are found within the lamellae.8
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Epithelial cell density is greatest in the central zone, where cells nor-
5 mally do not proliferate. These cells are the largest epithelial cells found
in the lens. The proliferative capacity of epithelial cells is greatest at the
equator (see Fig. 5.1.1). Cells here are dividing constantly, with newly
LENS WEIGHT AND CELL NUMBERS WITH AGE
formed cells being forced into the transitional zone where they elongate
The Lens
and differentiate to form the fiber mass of the lens.3,11 weight 250
(mg) c. 761,184 epithelial cells
c. 3,045,100 fibers
Lens Substance
200 c. 1,009,312 epithelial cells
The lens substance, the bulk of the lens, is composed of densely packed c. 3,546,100 fibers
lens cells with very little extracellular space. The adult lens substance con-
sists of the nucleus and the cortex, which are often histologically indistinct.
150
Although the size of these two regions is age dependent, a study of lenses
with an average age of 61 years indicated that the nucleus accounted for
approximately 84% of the diameter and thickness of the lens and the cortex
for the remaining 16%.12 The nucleus is subdivided into embryonic, fetal, 100
infantile, and adult nuclei (see Fig. 5.1.1). The embryonic nucleus contains
the original primary lens fiber cells that are formed in the lens vesicle.
birth
The rest of the nuclei are composed of secondary fibers, which are added 50 c. 402,595 epithelial cells
concentrically at the different stages of growth by encircling the previously c. 1,662,010 fibers
formed nucleus. The cortex, which is located peripherally, is composed of
all the secondary fibers formed after sexual maturation.
0
Fibers are formed constantly throughout life by the elongation of lens 0 20 40 60 80
epithelial cells at the equator. Initially, transitional columnar cells are
age (years)
formed, but once long enough, the anterior end moves forward beneath
the anterior epithelial cell layer and the posterior end is pushed back-
ward along the posterior capsule. The ends of this U-shaped fiber run
Fig. 5.1.3 Increase in Lens Weight and Cell Numbers With Age. Note the
toward the poles of both capsular surfaces.3–6 Once fully matured, the fiber
correlation between these two parameters. (Lens weight data from Phelps Brown N,
detaches from the anterior epithelium and the posterior capsule. Each new Bron AJ. Lens growth. In: Phelps Brown N, Bron AJ, Phelps Brown NA, editors. Lens
layer of secondary fibers formed at the periphery of the lens constitutes a disorders. A clinical manual of cataract diagnosis. Oxford: Butterworth-Heinemann;
new growth shell. Lens fibers are bound by the interlocking of the lateral 1996. p. 17–31. Cell number data from Kuszak JR, Brown HG. Embryology and
plasma membranes of adjacent fibers. Both desmosomes and tight junc- anatomy of the lens. In: Albert DM, Jakobiec FA, editors. Principles and practices of
tions are absent from mature lens fibers, although desmosomes are found ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994. p. 82–96.)
between elongating fibers.3,8,9
Sutures with age.16 The radius of curvature of the anterior surface decreases from
Sutures are found at both the anterior and the posterior poles. They are 16 mm at the age of 10 years to 8 mm by the age of 80 years. There is
formed by the overlap of ends of secondary fibers in each growth shell. No very little change in the radius of curvature of the posterior surface, which
sutures are found between the primary fibers in the embryonic nucleus. remains at approximately 8 mm.
Each growth shell of secondary fibers formed before birth has an anterior
suture shaped as an “erect Y” and a posterior suture shaped as an inverted
Y. The formation of sutures enables the shape of the lens to change from
PHYSIOLOGY OF THE LENS
spherical to a flattened biconvex sphere.3,9,13 Permeability, Diffusion, and Transport
After involution of the hyaloid blood supply to the lens, its metabolic needs
Growth are met by the aqueous and vitreous humor. The capsule is freely perme-
The lens continuously grows throughout life but at a reduced rate with able to water, ions, other small molecules, and proteins with a molecular
increased age.7 The number of both epithelial cells and fibers increases weight of up to 70 kDa. Epithelial cells and fibers possess a number of
by approximately 45%–50% during the first two decades of life (Fig. 5.1.3). channels, pumps, and transporters that enable transepithelial movement
After this, the increase in cell numbers is reduced, with the proportional to and from the extracellular milieu.
increase in fibers being very small.3 During an average lifespan, the surface
area of the lens capsule increases from 80 mm2 at birth to 180 mm2 by the Transport of Ions
seventh decade.5,7 Fiber cells contain large concentrations of negatively charged crystallins.
As a result, positively charged cations enter the lens cell to maintain electri-
Mass cal neutrality, and the osmolarity of the intracellular fluid becomes greater
than that of the extracellular fluid. Fluid flow and swelling are minimized
The weight of the lens increases rapidly from 65 mg at birth to 125 mg by the resting potential of the plasma membrane being set at a negative
by the end of the first year. It then increases at approximately 2.8 mg/ voltage through potassium (K+)-selective channels.
year until the end of the first decade, reaching 150 mg. Thereafter, the rate The Na+ ions that leak into the cells are exchanged actively for K+ ions,
slows to reach a weight of 260 mg by the age of 90 (see Fig. 5.1.3).14 The which diffuse through the lens down their concentration gradient and
average male lens weighs more than that of an age-matched female, with a leave through ion channels in both the epithelial cells and surface fibers.
mean difference of 7.9 ± 2.47 mg.15 There is a net movement of Na+ ions from posterior to anterior and of K+
ions from anterior to posterior.17
Although a pH gradient exists, which increases from the central nucleus
Dimensions to the periphery, the intracellular pH of the lens is approximately 7.0. Lens
The equatorial diameter of the human lens increases throughout life, cells need to continually extrude intracellular protons, which accumulate
slowing after the second decade. The diameter grows from approximately due to inward movement of positive ions from the extracellular space and
5 mm at birth to 9–10 mm in a 20-year-old. The thickness of the lens also lactic acid from anaerobic glycolysis. The pH is regulated by mechanisms
increases but at a much slower rate. The distance from the anterior to capable of increasing and decreasing intracellular acid levels. Molecules,
the posterior poles grows from 3.5–4 mm at birth, to 4.75–5 mm (unac- especially proteins, also act as buffers.
commodated).4,14 The thickness of the nucleus decreases with age due to
compaction, whereas cortical thickness increases as more fibers are added Amino Acid and Sugar Transport
e2 at the periphery. Because the increase in cortical thickness is greater than The majority of amino acids and glucose enter the lens from the aqueous
the decrease in size of the nucleus, the polar axis of the lens increases across its anterior surface. In addition, the lens can convert keto acids
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TRANSMITTANCE OF THE LENS PRINCIPAL ABERRATIONS OF THE LENS
5.1
Spherical aberration
transmittance 100

(%)
80
lens transmittance:
total, 4½ years
60 direct, 4½ years
direct, 53 years
direct, 75 years
40
20
0
300 400 500 600 800 1000 1200 1600 2000
wavelength (nm)
Fig. 5.1.4 Changes in Transmission (UV and Visible) of the Normal Aging Chromatic aberration
Human Lens. (From Boettner EA, Wolter JR. Transmission of the ocular media. Invest
Ophthalmol Vis Sci 1962;1:776–83.)
into amino acids. The lens acts as a pump–leak system: Amino acids are
“pumped” into the lens through the anterior capsule and passively “leak”
out through the posterior capsule.
BIOPHYSICS
Light Transmission
The lens acts as a spectral filter absorbing long ultraviolet B (UV-B,
300–315 nm) and most of the UV-A (315–400 nm) wavelengths. While
there is a transmission band centered around 320 nm of about 8% in
children under 10 years, it is reduced to 0.1% by age 22. By age 60, no
UV radiation transmits across the lens. The total transmittance of the
young lens begins increasing rapidly at about 310 nm and reaches 90%
at 450 nm, compared with the older lens, which begins transmitting at Fig. 5.1.5 Principal Aberrations of the Lens.
400 nm but does not reach 90% total transmittance until 540 nm (Fig.
5.1.4). The overall transmission of visible light decreases with increasing
age, a feature that arises largely from age-related changes and brunescence rates of transmission through the lens and some deviation. As a conse-
in the lens (see Fig. 5.1.4).18,19 quence, yellow light (570–595 nm) is normally focused on the retina;
light of shorter wavelengths, for example blue (440–500 nm), falls in front
because of its slower transmission and increased refraction compared with
Transparency yellow light. Light of longer wavelengths, for example red (620–770 nm),
The lens is opaque during the early stages of embryonic development. As falls behind because of the faster transmission and less refraction (Fig.
development continues and the hyaloid vascular supply is lost, the lens 5.1.5). Because the amount of dispersion between the red and the blue
becomes transparent. Transparency is due to the absence of chromophores images is approximately 1.50–2.00 diopters (D), very little reduction occurs
able to absorb visible light and the presence of a uniform structure that in the clarity of the image that is formed. As the lens accommodates,
scatters light minimally (less than 5% in the normal human lens). Light refraction increases as a result of the increasing power of the lens and,
scatter is minimized in fiber cells once the fibers have elongated and their therefore, the amount of chromatic aberration also increases.20,22–24
organelles have degenerated. Although the epithelial cells contain large
organelles that scatter light, the combined refractive index of this layer and Spherical Aberration
the capsule is no different from the refractive index of the aqueous, so
light scatter is very small. The lens of the human eye is designed to minimize spherical aberration
since: (1) refractive index increases from the periphery to the center of the
Refractive Indices lens; (2) curvature of both the anterior and the posterior capsule increases
towards the poles; and (3) curvature of the anterior capsule is greater than
The refractive index increases from 1.386 in the peripheral cortex to 1.41 in that of its posterior counterpart.
the central nucleus of the lens. Because both the curvature and refractive As a result of these structural features, the focal points of the peripheral
index of the lens increase from the periphery toward the center, each suc- and central rays are similar, which ensures that reduction in the quality of
cessive layer of fibers has more refractive power and therefore can bend the image is minimal (see Fig. 5.1.5). The pupil diameter also affects the
light rays to a greater extent.20 The anterior capsular surface of the lens has amount of spherical aberration, because light rays do not pass through the
a greater refractive index than the posterior capsular surface (1.364–1.381 periphery of the lens (unless the pupil is dilated). The optimal size of the
compared with 1.338–1.357). The increase in refractive index from the pupil needed to minimize this imperfection is 2–2.5 mm.20,22–24
surface to the center results from changes in protein concentration; the
higher the concentration, the greater the refractive power. This increase Accommodation
must occur as a result of both packing and hydration properties, because
protein synthesis in the nucleus is minimal.18,21 The lens is able to change its shape and thus the focusing power of the
eye. This process is known as accommodation, and it enables both distant
Chromatic Aberration and close objects to be brought into focus on the retina. At rest, the ciliary
muscle is relaxed and the zonules pull on the lens keeping the capsule
When visible light passes through the lens, it is split into all the colors of under tension and the lens flattened. Light rays from close objects are e3
the spectrum. The different wavelengths of these colors result in different divergent and are focused behind the retina in this configuration. The lens
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Fig. 5.1.6 Change in Form of the Lens
5 on Accommodation in a Person of Age

29 Years. (A) Relaxed. (B) Accommodated.
(Grid squares 0.4 mm.) Note the change
in curvature of the anterior surface. (From
The Lens
Phelps Brown N, Bron AJ. Accommodation

and presbyopia. In: Phelps Brown N,
Bron AJ, Phelps Brown NA, editors.
Lens disorders. A clinical manual of
cataract diagnosis. Oxford: Butterworth-
Heinemann; 1996. p. 48–52.)
A B
accommodates these objects by contraction of the ciliary muscles, relax- reduced form of flavin adenine dinucleotide (FADH2). These donate their
ing the zonules, thus increasing the curvature of the anterior surface and electrons to oxygen, which releases large amounts of free energy that is
decreasing the radius of curvature from 10 mm to 6 mm. The increase subsequently used to generate ATP. This cycle, which is restricted to the
in curvature of the anterior surface increases the refractive power, so epithelial layer, also provides carbon skeleton intermediates for biosynthe-
that the light rays from close objects are refracted toward each other to a sis, such as amino acids and porphyrins.27,29
greater extent and, therefore, converge on the fovea. Because the front of The bulk of the pyruvate produced by the glycolytic pathway is reduced
the lens has moved forward, the depth of the anterior chamber decreases to lactate by lactate dehydrogenase (see Fig. 5.1.7), which is concentrated
from 3.5 mm to 3.2–3.3 mm. Very little change occurs in the curvature of in the cortex. The formation of lactate results in the reoxidation of NADH
the posterior capsule, which remains at approximately 6 mm (Fig. 5.1.6). to NAD+. Glyceraldehyde-3-phosphate dehydrogenase regulates the activ-
Accommodation is accompanied by a decrease in pupil size and conver- ity of lactate dehydrogenase by controlling the rate of conversion of
gence of the two eyes. glyceraldehyde-3-phosphate into 1,3-diphosphoglycerate and, therefore, the
Accommodation can be divided into both physical and physiological availability of NADH.27–29
processes. Physical accommodation, a measure of the change in shape of The 5%–10% of glucose that is not phosphorylated into G6P either
the lens, is measured in terms of the amplitude of accommodation using enters the sorbitol pathway or is converted into gluconic acid (see Fig.
the unit diopter. It represents a measure of the extent to which objects 5.1.7). Glucose is converted into sorbitol by aldose reductase, an enzyme
close to the eye can be brought into focus. Physiological accommodation, localized to the epithelial layer. Sorbitol is converted by polyol dehydroge-
a measure of the force of ciliary muscle contraction per diopter, is mea- nase into fructose, a less optimal substrate for glycolysis. Both sorbitol and
sured with the unit myodiopter. The myodiopter increases during the act fructose have the potential to increase osmotic pressure and may help to
of accommodation.25,26 regulate the volume of the lens.27–29
BIOCHEMISTRY Protein Metabolism

The lens requires energy to drive thermodynamically unfavorable reac- The protein concentration within the lens is the highest in the body.
tions. Adenosine triphosphate (ATP) is the principal source of this energy, The majority of ongoing synthesis creates crystallins and major intrinsic
the majority of which comes from the anaerobic metabolism of glucose. protein 26 (MIP26). It is thought that this occurs in the epithelial cells and
Nicotinamide adenine dinucleotide phosphate (NADPH), which is pro- cortical fibers, which contain the organelles needed.30
duced principally via the pentose phosphate pathway, is used as a reducing Lens proteins remain stable for long periods because the majority of
agent in the biosynthesis of many essential cellular components, such as the degradative enzymes normally are inhibited. This is coordinated by
fatty acids and glutathione. marking those to be degraded with a small 8.5 kDa protein called ubiqui-
tin. This system, which is ATP dependent, is most active in the epithelial
Sugar Metabolism layer. Lens proteins are broken down into peptides by endopeptidases and
then into amino acids by exopeptidases. Neutral endopeptidase is activated
Approximately 90%–95% of the glucose that enters the normal lens is by both calcium and magnesium and is optimal at pH 7.5 (the pH of the
phosphorylated into glucose-6-phosphate (G6P) in a reaction catalyzed by lens is approximately 7.0–7.2). The principal substrate of this enzyme is
hexokinase. Although this enzyme exists as three different isoforms, only α-crystallin. The calpains (I and II) are localized mainly in the epithelial
types I and II have been found in the lens. Type I has a greater affinity for cells and cortex and function to degrade crystallins and cytoskeletal pro-
glucose and is concentrated in the nucleus, where glucose levels are low. teins. They are cysteine endopeptidases, the activities of which are regu-
Type II, which accounts for 70% of the hexokinase, has a lower affinity for lated by calcium. These enzymes are inhibited by calpastatin, a natural
glucose and is found predominantly in the epithelium and cortex, where inhibitor found at higher concentrations than the calpains. The lens also
glucose levels are higher. G6P is used either in the glycolytic pathway (80% contains a serine proteinase and a membrane-bound proteinase.28,29,31 The
of total glucose) or in the pentose phosphate pathway (hexose monophos- main exopeptidase is leucine aminopeptidase, an enzyme optimal at pH
phate shunt; 10% of total glucose) (Fig. 5.1.7). Hexokinase is saturated by 8.5–9.0, which catalyzes the removal of amino acids from the N-terminal
physiological concentrations of glucose found in the lens and limits the of peptides. Aminopeptidase III has an optimal pH of 6.0 and as a
rate of both glycolysis and the pentose phosphate pathway. Glycolysis also result has a greater activity than leucine aminopeptidase in the normal
is regulated by phosphofructokinase and pyruvate kinase.27,28 lens.28,29,31
The lens lacks vascularity and thus exists in a hypoxic environment,
which results in at least 70% of lens ATP being derived from anaerobic Glutathione
glycolysis. Approximately 3% of lens glucose passes into the more efficient
tricarboxylic acid cycle (see Fig. 5.1.7), generating 25% of lens ATP. Glycol- Glutathione is found at high concentrations in the lens (3.5–5.5 mmol/g
e4 ysis and the tricarboxylic acid cycle generate two energy-rich molecules; wet weight), especially in the epithelial layer. Glutathione has many import-
the reduced form of nicotinamide adenine dinucleotide (NADH) and the ant roles in the lens, including28,29,32:
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Fig. 5.1.7 Overview of the Major
MAJOR PATHWAYS OF GLUCOSE METABOLISM IN THE LENS Pathways of Glucose Metabolism in the
Lens. Percentages represent the estimated 5.1
amount of glucose used in the different
pathways.

5% 5%
Sorbitol Glucose Gluconic acid
Aldose reductase
Polyol dehydrogenase Sorbitol

Hexokinase 90%
pathway
10%
Fructose Glucose-6-phosphate 6-phosphogluconate
Pentose phosphate
Phospho- pathway
Glycolysis Ribulose-5-phosphate
fructokinase
80%
Glyceraldehyde-3-phosphate
Glycercaldehyde-
C6
3-phosphate
dehydrogenase
Tricarboxylic
Pyruvate kinase C4 acid cycle C5
Lactate
dehydrogenase 3%
Lactate Pyruvate Acetyl CoA
C4
• Maintaining protein thiols in the reduced state, which helps to main- ROS have the capacity to damage the lens in many ways29,35:
tain lens transparency by preventing the formation of high molecular
weight crystallin aggregates.
• Peroxidizing membrane lipids results in the formation of aldehydes,
which in turn can form cross-links between membrane lipids and
• Protection of thiol groups involved in cation transport and permeability; proteins.
for example, oxidation of the -SH groups of the Na+,K+-ATPase pump,
which results in an increased permeability to these ions.
• Introducing damage into the bases of the DNA (e.g., base modifica-
tions) and reducing DNA repair efficiency.
• Protection against oxidative damage (see later in this chapter). • Polymerizing and crosslinking proteins result in crystallin aggregation
• Removal of xenobiotics; glutathione-S-transferase catalyzes the conju- and inactivation of many essential enzymes, including those with an
gation of glutathione to hydrophobic compounds with an electrophilic
antioxidant role (e.g., catalase and glutathione reductase).
center.
Protection against damage induced by ROS is achieved in a number
Amino Acid Transport of ways. The superoxide anion undergoes dismutation by superoxide dis-
Glutathione has a half-life of 1–2 days and is recycled constantly by the mutase or by interaction with ascorbate (see below), which results in the
γ-glutamyl cycle; its synthesis and degradation occur at approximately formation of H2O2. This, along with the high levels of exogenous H2O2, is
the same rate (Fig. 5.1.8). Glutathione is synthesized from L-glutamate, detoxified by the enzyme catalase or glutathione peroxidase or both (Fig.
L-cysteine, and glycine in a two-step process that uses 11%–12% of lens 5.1.9).36 Catalase is present in epithelial cells at higher levels than in fibers.
ATP.28,29,32 Reduced glutathione also can be taken into the lens from the Glutathione peroxidase, however, is found in significant amounts in both
aqueous. A reduced glutathione transporter that allows the uptake of glu- epithelial cells and fibers. The glutathione system is thought to provide
tathione by the lens epithelium has been characterized.33 The breakdown the most protection against H2O2, but it also protects against the lipid-free
of glutathione releases its amino acids, which are recycled. radical chain reaction by the neutralization of lipid peroxides.29,32,34,35
Ascorbic acid (vitamin C) plays a major role in the antioxidant system,
Antioxidant Mechanisms although this may be species dependent, because the human lens is rich
in ascorbate (1.9 mg/kg wet weight or 1.1 mmol/kg). Ascorbate is present
The term reactive oxygen species (ROS) refers to highly reactive oxygen at high levels in the outer layers of the lens but virtually absent from
radicals that have the potential to damage lipids, proteins, carbohydrates, the nucleus. It reacts rapidly with superoxide anions, peroxide radicals,
and nucleic acids. These include the superoxide anion, the hydroxyl free and hydroxyl radicals to give dehydroascorbate. It also scavenges singlet
radical, hydroperoxyl radicals, lipid peroxyl radicals, singlet oxygen, and oxygen, reduces thiol radicals, and is important in the prevention of lipid
hydrogen peroxide (H2O2). ROS generally arise from cell metabolism or peroxidation. The ascorbic acid and glutathione systems are coupled, as
photochemical reactions. Photochemical damage occurs when light is dehydroascorbate reacts with the reduced form of glutathione to generate
absorbed by a photosensitizer that, upon photoexcitation, forms a tran- ascorbate and GSSG (oxidized glutathione).31,34,37,38
sient excited triplet state that is long lived, allowing for interaction with This system, however, is not 100% efficient, and a low level of cumula-
other molecules producing free radicals or singlet oxygen. The continu- tive damage occurs throughout life.
ous entry of optical radiation into the lens, in particular the absorption
of shorter wavelengths (295–400 nm), makes lens tissue particularly sus-
ceptible to photochemical reactions. The major ultraviolet (UV) absorb-
LENS CRYSTALLINS
ers in the lens are free or bound aromatic amino acids (e.g., tryptophan), Crystallin Structure
numerous pigments (e.g., 3-hydroxykynurenine), and fluorophores. Reac-
tive oxygen species also can enter the lens from the surrounding milieu Up to 60% of the wet weight of the human lens is composed of proteins.
(e.g., H2O2 is present at high levels in the aqueous humor, 30 mmol/L These lens proteins can be subdivided into water-soluble (cytoplasmic pro- e5
in humans).29,34 teins) and water-insoluble (cytoskeletal and plasma membrane) fractions.
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Fig. 5.1.8 The γ-Glutamyl Cycle. (From
5 Enzymes
THE -GLUTAMYL CYCLE Harding JJ, Crabbe MJC. The lens:
development, proteins, metabolism and
cataract. In: Davson H, editor. The eye.
3rd ed. London: Academic Press; 1984. p.
The Lens
1. Membrane-bound Amino acid 207–492.)

-glutamyltransferase
2. -glutamylcyclotransferase
-Glutamyl
3. 5-oxoprolinase 5-Oxoproline ATP
amino acid
4. -glutamylcysteine 2
3
synthetase
5. Glutathione synthetase ADP + Pi
6. Dipeptidase 6
Cysteinylglycine Glutamate
Amino 1 ATP
Glycine Cysteine
acid
4
Glutathione ADP + Pi
5
-Glutamyl
cysteine
extracellular intracellular ADP + Pi ATP
Fig. 5.1.9 Coupling of the Ascorbic Acid

COUPLING OF THE ASCORBIC ACID AND GLUTATHIONE SYSTEMS and Glutathione Systems.
– +
2O2 + 2H Ascorbate GSSG NAD(P)H2
Nonenzymatic Glutathione reductase
H2O2 + O2 Dehydroascorbate GSH NAD(P)
Catalase Glutathione peroxidase
H2O + 1/2O2 2H2O + GSSG
The water-soluble crystallins constitute approximately 90% of the total is maintained, with the result that the α-crystallins are found in both lens
protein content of the lens.39,40 epithelial cells and fibers, whereas the β- and γ-crystallins are found only
The crystallins found in all vertebrate species can be divided into the in the lens fibers. α-Crystallin synthesis is far greater in the lens epithe-
α-crystallin family and the β/γ-crystallin superfamily. The properties of lium than in the fibers. The α-crystallins are found in both dividing and
these crystallins are summarized in Table 5.1.1. The α-crystallins are the nondividing lens cells, whereas the β- and γ-crystallins are found only in
largest. nondividing lens cells. Differentiation of a lens epithelial cell into a fiber,
The β-crystallins are composed of light (βL) (c. 52 kDa) and heavy (βH) therefore, may be one of the factors that triggers a decrease in transla-
(150–210 kDa) fractions. The light fraction can be further subdivided into tion of the α-crystallin gene and stimulates the synthesis of the β- and
two fractions, βL1 and βL2.39–43 γ-crystallins.45
The smallest of the crystallins are the γ-crystallins. Six members of this
family, known as γA–γF, have a molecular weight of 20 kDa. Crystallin Function
The high concentration of crystallins and the gradient of refractive index are
Crystallin Gene Expression During Lens Growth responsible for the refractive properties of the lens. The short-range order
The α-, β-, and γ-crystallins are synthesized in the human lens during of these proteins ensures that the lens remains transparent. α-Crystallins
gestation, and the absolute quantities of these crystallin families increases may be involved in the assembly and disassembly of the lens cytoskeleton.
during development. The first crystallin to be synthesized is α-crystallin, Similarities in structure between the small heat shock proteins (sHSPs)
which is found in all lens cells. The β- and γ-crystallins are first detected and αβ-crystallin suggest that this crystallin family may provide the lens
e6 in the elongated cells that emerge from the posterior capsule to fill the with stress-resistant properties.40,41,46 α-Crystallins have chaperone-like
center of the lens vesicle.44 Throughout life the same pattern of synthesis functions that enable them to prevent the heat-denatured proteins from
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ant
TABLE 5.1.1 Properties of Different Crystallins
α β γ γs
5.1
Subunits αA, αAI, αB, αB1, Basic: βB1, βB2, γA–γF γs

up to nine βB3
minor subunits Acidic: βA1, βA2,
βA3, βA4
Subunit 20 kDa Basic: 26–32 kDa 20 kDa 24 kDa
molecular Acidic:
weight 23–25 kDa
Native molecular 600–900 kDa βH: 150–200 kDa 20 kDa 24 kDa
weight βL: c. 50 kDa
eq
Number of 30–45 βH: 0–8 1 1
subunits βL: 2
Thiol content Low High High High
N-Terminal Masked Masked Glycine or Masked nu
amino acid alanine
Secondary Predominantly β-pleated sheet β-pleated β-pleated
structure β-pleated sheet sheet sheet
Three- Unknown Two domains Two domains Two domains
dimensional with four with four with four
structure “Greek key” “Greek key” “Greek key”
motifs motifs motifs Fig. 5.1.10 Scanning Electron Micrograph of Equatorial Region of Cortical Fiber
Chromosome αA: 21 βB1–βB4: 22 2 3 Plasma Membranes. Note the circular shade with the fracture of fibers in the deep
αB: 11 βA1/βA3: 17 equatorial cortex (eq) (arrows) and folding fibers in the anterior deep cortex (ant)
βA2: 2 (arrowheads). (nu, lens nucleus). (From Vrensen GFJM. Aging of the human eye lens –
a morphological point of view. Comp Biochem Physiol A Physiol 1995;111:519–32.)
becoming insoluble and facilitate the renaturation of proteins that have Furthermore, the changes in structure of the plasma membrane and the
been denatured chemically.47 They also act as chaperones under conditions degradation of cytoskeletal components may contribute to the increase in
of oxidative stress and therefore may help to maintain lens transparency.48 the number of furrowed membranes and microvilli found on the fiber
Although the function of the β-crystallins is unknown, their structural surface.49 From the fourth decade onward, ruptures are found in the equa-
similarities with the osmotic stress proteins suggest that they also may torial region of cortical fiber plasma membranes (Fig. 5.1.10). Reparation of
act as stress proteins in the lens.46 The γ-crystallins (with the exception these ruptures often prevents the formation of opacities. Any opacities that
of γs-crystallin) are found in the regions of low water content and high do develop become surrounded by deviated membranes and are therefore
protein concentration, such as the lens nucleus. The presence of this isolated from the remainder of the lens.
family of crystallins correlates with the hardness of the lens. Concentra- The lens capsule thickens throughout life. It also increases in surface
tions are higher in those lenses that do not change shape during accom- area as a result of the growth of the lens. Ultrastructural changes include
modation, as in fish, than in those that do, as in the human.40 the loss of laminations and an increase in the number of linear densities.
Although the young lens capsule is known to contain collagen type IV and
the aged capsule collagen types I, III, and IV, the presence of types I and
AGE CHANGES III collagen in the young capsule has yet to be confirmed, but their synthe-
Morphology sis may be age related.53
Continued increases in both the mass and dimensions of the lens are
greatest during the first two decades of life. This results from the prolifer-
Physiological Changes
ation of lens epithelial cells and their differentiation into lens fibers. The Changes to the cellular junctions and alterations in cation permeability
oldest epithelial cells are found in the middle of the central zone under occur with age. The major gap junction protein MIP26 loses some of
the anterior pole. Because cells are added to the periphery of this zone its amino acids to form new variants, which include polypeptides with
throughout life, the age of the cells decreases from the pole toward the molecular weights of 15, 20, and 22 kDa.51,52 The membrane potential of
outer units of this region, so that the newest cells always are found near an isolated, perfused human lens may be −50 mV at the age of 20 years,
the pregerminative zone. Because newly formed fibers are internalized as but only −20 mV at the age of 80 years. Potassium (K+) levels remain con-
more are added at the periphery of the lens, the oldest fibers are found in stant at approximately 150 mmol/L, but the sodium (Na+) content of the
the center of the nucleus and the newest fibers in the outer cortex. Each lens increases from 25 mmol/L at the age of 20 years to 40 mmol/L by
growth shell, therefore, represents a layer of fibers that are younger than the age of 70 years. Thus, the Na+:K+ permeability ratio increases approx-
those in the shell immediately preceding it.49 imately sixfold, which results in a proportionately greater increase in the
As the lens ages, epithelial cells become flatter, flatten their nuclei, sodium content of the lens.54 The change in the ratio of these two ions
develop end-organ failure bodies and vacuoles, and exhibit a dramatic correlates with the increase in optical density of the lens.55 The change
increase in the density of their surface projections and cytoskeletal com- in ion permeability with increasing fiber age is thought to occur due to
ponents. The basal surface area of the cell increases; thus the number of a decrease in membrane fluidity as a result of the age-related increase in
cells needed to cover a region of the growing anterior capsule is less than the cholesterol-to-phospholipid ratio. The lens, therefore, becomes more
that needed to cover a region of the same size in a younger lens. This, in dependent on the Na+,K+-ATPase in the epithelial cells. The decrease in
combination with the decrease in proliferative capacity, means that epithe- membrane potential also results from changes in the free Ca2+ levels,
lial cell density decreases as the lens ages.49,50 which increase from 10 mmol/L at the age of 20 years to approximately
Lens fibers show partial degradation or a total loss of a number of 15 mmol/L by the age of 60 years. It is thought that the Ca2+-ATPase may
plasma membrane and cytoskeletal proteins with age. The most significant be inhibited by the decrease in membrane fluidity, which decreases the
degradation is that of MIP26. Early in life spectrin, vimentin, and actin are rate at which Ca2+ is pumped out of the cell. It also is possible that the
present in both the outer cortical fibers and the epithelial layer, but they increase in Na+ and Ca2+ permeability may result from the increased activ-
are degraded as the fibers age and are further internalized. By 80 years of ity of nonspecific cation channels.54
age, expression of these cytoskeletal proteins is restricted to the epithelial
cells. The cholesterol-to-phospholipid ratio of fiber cell plasma membranes Biophysical Changes
increases throughout life, and consequently membrane fluidity decreases
and structural order increases. These changes, which are known to occur The absorption of both UV and visible light by the lens increases with age.
from the second decade, are greatest in the nucleus and are therefore Free and bound aromatic amino acids (tryptophan, tyrosine, and phenylal- e7
partially responsible for the increase in nuclear sclerosis (hardening).51,52 anine), fluorophores, yellow pigments, and some endogenous compounds
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5 MAIN SPECIES IN THE HUMAN LENS
WHICH ABSORB LIGHT TRANSMITTAL BY THE CORNEA
PRESBYOPIC CHANGES IN AMPLITUDE
OF ACCOMMODATION WITH AGE
The Lens
amplitude of 14
relative 1.2
accommodation (D)
absorbance 12
10
0.8
8
6
0.4
4
0.0 0
295 345 395 445 495
10 20 30 40 50 60 70
yellow, aged proteins wavelength (nm)
age (years)
o--glucoside of 3-hydroxykynurenine
protein-bound tryptophan
Fig. 5.1.11 Main Species in the Human Lens That Absorb Light Transmitted Fig. 5.1.12 Presbyopic Changes in the Amplitude of Accommodation With
by the Cornea. (From Dillon J. The photophysics and photobiology of the eye. J Age. The different colored symbols represent the data obtained from different
Photochem Photobiol B 1991;10:23–40.) publications. (From Fisher RF. Presbyopia and the changes with age in human
crystalline lens. J Physiol 1973;223:765–79.)
(such as riboflavin) are responsible for the absorption properties of the

lens.51 Tryptophan is cleaved in the presence of sunlight and air to form • Stiffness of the lens substance increases, which renders the lens less
N-formylkynurenine and a series of other metabolic products, including deformable.
3-hydroxykynurenineglucoside (3-HKG). Because more than 90% of the • Although the cortex increases in thickness throughout life, very little
UV radiation that reaches the lens is UV-A (315–400 nm), and 3-HKG change occurs in the thickness of the nucleus. The effect of the round-
absorbs light between 295 and 445 nm whereas tryptophan only absorbs ing of the nucleus on the change in curvature of the anterior surface
light between 295 and 340 nm, this glucoside has a relative absorbance during accommodation, therefore, is reduced with age.
that is greater than that of tryptophan in the young human lens (95% com- • The radius of curvature of the anterior capsule decreases, which renders
pared with 5%) (Fig. 5.1.11). the lens rounder. Contraction of the ciliary muscle, therefore, does not
As the lens ages, it changes from colorless or pale yellow to darker greatly alter the shape of the lens.
yellow in adulthood, and brown or black in old age.55 The autofluores- • The distance between the anterior surface of the lens and the cornea
cent properties of the lens also change with age. These changes in col- decreases.
oration, which are limited to the nucleus, are thought to result from the • The internal apical region of the ciliary body moves forward and inward
attachment of 3-HKG and its metabolic derivatives to proteins to produce with age. The zonules, therefore, no longer put the lens under as much
yellow-pigmented proteins that also absorb light. As the concentration of tension in the unaccommodated state.
these yellow pigments increases, they compete with 3-HKG and become
the major absorbing species of the lens.56,57 Because these yellow proteins The increases in curvature and thickness of the lens suggest that the
are fluorescent species, the wavelength absorbed increases to approximately refractive power should increase with age, resulting in myopia. This,
500 nm (see Fig. 5.1.11). A blue fluorophore, which absorbs between 330 however, does not happen because these changes are accompanied by
and 390 nm and fluoresces between 440 and 466 nm, increases as the lens small alterations to the gradient of refractive index. This gradient becomes
ages. Oxygen-dependent photolysis of the blue fluorophore contributes to flatter near the center of the lens and steeper near the surface and, there-
the formation of a green fluorophore, which is excited between 441 and fore, the refractive power of the eye is lowered.63
470 nm and emits between 512 and 528 nm.58 The increased capacity of
the lens to absorb visible light, in combination with the increased scat- Biochemical Changes
tering properties of the lens (because of the aggregation of lens proteins
and possibly the release of bound water), results in a decrease in transpar- The overall metabolic activity of the lens decreases with increasing age,
ency.50 The increase in the total number of photons absorbed is accompa- partially due to decreasing enzyme activities in the cortex and nucleus.
nied by an age-related loss in antioxidant levels, increasing the amount of Many of the enzymes involved in the metabolism of glucose decrease with
photo-oxidative stress. age, including glyceraldehyde-3-phosphate dehydrogenase, G6P dehydro-
Nonenzymatic glycation of proteins by the Maillard reaction results in genase, aldolase, enolase, phosphoglycerate kinase, and phosphoglycerate
the formation of advanced glycation end products, which also increase the mutase. Although overall metabolic activity decreases, the lens still main-
yellowing of the lens. This reaction is initiated by the attachment of a sugar tains the capacity to synthesize proteins, fatty acids, and cholesterol at sub-
molecule (e.g., glucose) to an amino acid, normally valine or lysine. In stantial rates. Decreased metabolic activity, therefore, does not serve as a
young lenses, 1.3% of lysine residues of human crystallins are glycated, significant limiting factor for the production of new lens fibers.51,52
but by the age of 50 this increases to 2.7% and to approximately 4.2% in A reduction in the activity or levels or both of many antioxidants occurs
older lenses.51 Yellow fluorescent photoproducts also are formed in the with increasing age. Because this decrease is greatest in the nucleus, fibers
presence of ascorbic acid, which is present at high levels in the lens.59 in this region of the lens are more susceptible to oxidative damage and
lipid peroxidation. As a result, they rely on the overlying cortical fibers
Accommodation Changes and epithelial layer to protect them. The activity of both catalase and
superoxide dismutase decreases with age, as do levels of ascorbate and
The amplitude of accommodation decreases throughout life from glutathione.50 The reduced activity of both glutathione synthetase and
13.00–14.00 D at the age of 10 years to 6.00 D at 40 years and almost 0.00 D γ-glutamylcysteine synthetase, accompanied by a decrease in the uptake of
by the age of 60 years (Fig. 5.1.12). This manifests clinically as presbyopia. L-cysteine (an amino acid needed for glutathione synthesis), decreases the
The change in accommodative power is attributable to a number of factors, rate of synthesis of reduced glutathione (Fig. 5.1.13).64 This is partly due to
including60–62: reduced activity of glutathione reductase, which converts oxidized glutathi-
one into reduced glutathione. Glutathione peroxidase (which is involved in
e8 • Young’s modulus of capsular elasticity decreases from 700 N/cm2 at the breakdown of lipid peroxides and hydrogen peroxide) levels increase
birth to 150 N/cm2 by the age of 80 years. from birth until approximately 15 years of age and then slowly decrease
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EFFECT OF AGE ON THE CAPACITY
TO SYNTHESIZE REDUCED GLUTATHIONE 5.1

GSHg–1 lens 3000
(cpm 10000–1)
2000
1000
0
0 20 40 60 80 100
age (years)
data from one lens
overlapping data from two lenses Fig. 5.1.14 Fibrosis of the Posterior Capsule. This opacification developed in a
5-year-old child 20 days after extraction of a traumatic cataract (perforation with
a knife). No intraocular lens was implanted. (From Rohrbach JM, Knorr M, Weidle
Fig. 5.1.13 Effect of Age on the Capacity to Synthesize Reduced Glutathione. EG, et al. Nachstar: klinik, therapie, morphologic, and prophylaxe. Akt Augenheilkd
(From Rathbun WB, Murray DL. Age-related cysteine uptake as rate-limiting in 1995;20:16–23.)
glutathione synthesis and glutathione half-life in the cultured human lens. Exp Eye
Res 1991;53:205–12.)
It is thought that many of the HMW aggregates act as precursors for
the accumulation of insoluble proteins. Below the age of 50 years, approx-
TABLE 5.1.2 Levels of Degraded Polypeptides in Water-Soluble High- imately 4% of lens proteins are insoluble, but by the age of 80 years, this
Molecular-Weight Proteins of Human Lenses increases to 40%–50%.67 The increase in insolubility is approximately the
same in the cortex and nucleus before age 30 years, but with increasing
HMW Protein-Associated HMW Protein age, insolubility increases to a greater extent in the lens nucleus. Up to
Donor’s HMW Protein/ Degraded Polypeptides/ as Degraded
Age (years) Lens (mg) Lens (mg) Polypeptides (%) 80% of the nuclear proteins of an aged lens may be insoluble, and most
of the nuclear α-crystallin is insoluble by the age of 45 years.51,52 This con-
16–19 0.16 0.009 5.6
tributes to the loss of lens transparency and the development of senile
38–39 0.93 0.17 18.2
cataract.
49–51 2.17 0.255 11.75 Tryptophan residues in the crystallins are photooxidized to produce pho-
55–56 2.2 0.42 19.1 tosensitizers. This results in a decrease in tryptophan fluorescence and an
60–80 2.3 0.62 26.9 increase in nontryptophan fluorescence throughout life. The oxidation of
HMW, High-molecular-weight. sulfhydryl groups results in the formation of disulfides, which may be one
Adapted from Srivastava OP, Srivastava K, Silney C. Levels of crystallin fragments and of the factors responsible for the age-related decrease in solubility of lens
identification of their origin in water soluble high molecular weight (HMW) proteins of human
lenses. Curr Eye Res. 1996;15:511–20. proteins. Because the γ-crystallins have sulfhydryl groups that are more
exposed, they are more susceptible to this oxidation than are the α- and
β-crystallins.52 Increases in the glycation of crystallins in the presence of
throughout adulthood.51,52 This decreased antioxidant activity coupled with glucose or ascorbic acid results in protein cross-linking and the resultant
increased photon absorption with increasing age promotes photo-oxidative formation of HMW proteins. The α- and βH-crystallins rapidly cross-link;
damage in the lens. βL-crystallins are slower, and no γ-crystallin cross-linking occurs. One of
the modifications that occurs most frequently to aging crystallins is deam-
Crystallins idation of asparagine residues, which results in the formation of aspartic
acid residues, thus altering the structure, destabilizing the protein, and
With increasing age an increase in both the complexity and the increasing its susceptibility to proteolytic degradation.
number of crystallin fractions occurs, which includes accumulation of
high-molecular-weight (HMW) aggregates, partial degradation of crystal-
lin polypeptides, increased crystallin insolubility, photooxidation of tryp-
SECONDARY CATARACT
tophan, the production of photosensitizers, loss of sulfhydryl groups, and A major complication of extracapsular cataract extraction (ECCE) is sec-
nonenzymatic glycation. These changes can alter the short-range spatial ondary cataract (also known as after cataract). Posterior capsule opacifica-
order of the crystallins and thus decrease transparency.50–52,56 tion (PCO) is the most clinically significant type of secondary cataract and
Levels of soluble HMW aggregates (greater than 15×103 kDa) increase develops in up to 50% of patients between 2 months and 5 years after the
from approximately 0.16 mg in the lenses of donors between the ages of 16 initial surgery. The frequency of PCO is age related; almost all children
and 19 years to 2.3 mg by the age of 60 years (Table 5.1.2).65 This increase develop PCO after ECCE, but in adults the incidence is much lower. This
occurs as the result of many factors, including reduced proteolytic enzyme is thought to be because of the higher proliferative capacity of lens epithe-
activity. Most of these aggregates are localized to the lens nucleus and are, lial cells in the young compared with the old.68,69
in the majority of the young, principally composed of α-crystallin.50 As the After ECCE, the lens is composed of the remaining capsule and the
lens ages, these aggregates increase in complexity and become composed residual epithelial cells and cortical fibers that were not removed at the
of a mixture of crystallins. The major subunits thought to be involved are time of surgery. The lens epithelial cells still possess the capacity to pro-
αA-, αB-, and γs-crystallins. Many of these polypeptides undergo posttrans- liferate, differentiate, and undergo fibrous metaplasia. Migration of these
lational modifications, such as the formation of an intramolecular disul- cells toward the center of the posterior capsule, together with the synthesis
fide bond within αA-crystallin, glycation of lysine residues, cross-linking, of matrix components, results in light scatter that reduces visual acuity.
deamidation of αA- and γs-crystallins, and loss of the C-terminal end of In a minority of cases, PCO results from the deposition of fibrin and
αA-crystallin. Such modifications to α-crystallin result in a decrease in other cell types onto the posterior capsule either at the time of surgery or
the capacity of this crystallin to act as a chaperone protein.50,66 Below the postoperatively.69
age of 20 years, approximately 6% of the HMW protein is composed of The two morphologically distinct types of PCO are fibrosis and Elschnig’s
degraded polypeptides, but by the age of 60 years this increases to 27% (see pearls, which occur concurrently. In addition, ECCE procedures may result e9
Table 5.1.2).65 in the formation of a Soemmerring’s ring (Figs. 5.1.14–5.1.16).69,70
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extracellular matrix produced in the fibrosis type of PCO is composed of
5 types I and III fibrillar collagen, collagen type IV, and a number of asso-
ciated proteoglycans (dermatan sulfate, heparin sulfate, and chondroitin
sulfate).72
In cases in which the cut edge of the anterior capsule rests on the intra-
The Lens
ocular lens (IOL) optic, residual anterior capsular cells may proliferate and
extend from this cut edge onto the surface of the IOL, which may result in
the formation of a membranous outgrowth within 1 week postoperatively.73
Detailed studies using polymethylmethacrylate IOLs have shown that cells
do not appear to cover the central part of the optic, and migration onto this
optic decreases as the cells in the region of the anterior capsule in contact
with the optic undergo fibrous metaplasia and begin to opacify. The cells
on the IOL completely disappear within 3 months. It is also possible that
cells may migrate around onto the posterior surface of the IOL implant
and therefore contribute to the formation of PCO.
Growth factors present in both the aqueous and the vitreous have been
implicated in the development of fibrosis-type PCO. These include acidic
and basic fibroblast growth factors, insulin-like growth factor-I, epidermal
growth factor, platelet-derived growth factor, hepatocyte growth factor, and
transforming growth factor-β.
Pearl-Type Posterior Capsule Opacification

The pearls formed in this type of PCO are identical in appearance to Wedl
(bladder) cells involved in the formation of posterior subcapsular cataracts
Fig. 5.1.15 Elschnig’s Pearls. This opacification developed within 3 years of
(see Fig. 5.1.16). Because Wedl cells are known to originate from equatorial
an extracapsular cataract extraction with implantation of a posterior chamber
intraocular lens. (From Rohrbach JM, Knorr M, Weidle EG, et al. Nachstar: klinik,
lens epithelial cells, it is believed that residual cells in this region of the
therapie, morphologic, and prophylaxe. Akt Augenheilkd 1995;20:16–23.) capsule are the predominant cells involved in the formation of pearls. Clin-
ically, cases of pearl formation occur somewhat later than those of fibrosis
(up to 5 years postoperatively).69
Pearls were first observed by Hirschberg74 in 1901 and then by Elschnig75
in 1911; they now are referred to as Elschnig’s pearls. After ECCE, the fiber
mass of the lens is no longer present, and as a result, no internal pres-
sure exists. Newly formed lens fibers, therefore, are no longer forced in
the anterior and posterior directions, which results in the formation of a
mass of cells loosely connected and piled on top of each other. Each pearl
represents the aberrant attempt of one epithelial cell to differentiate into a
new lens fiber, possessing characteristics of both epithelial cells and fibers,
and may be embedded in an extracellular matrix. Visual acuity is affected
only if the pearls protrude into the center of the posterior capsule.76–78
Soemmerring’s Ring
Soemmerring first noticed PCO in humans in 1828.79 After ECCE, the cut
edge of the remaining anterior capsular flap may attach itself to the poste-
rior capsule within approximately 4 weeks postoperatively through the pro-
duction of fibrous tissue. Any residual cortical fibers and epithelial cells,
therefore, are trapped within this sealed structure. The equatorial cells
still retain the capacity to proliferate and differentiate into lens fibers. The
increase in the volume of this lenticular material fills the space between
the anterior and the posterior capsule (see Fig. 5.1.16). Proliferating epi-
thelial cells remain attached to the anterior capsule but also are found to
a lesser extent on the posterior capsule, where they form small isolated
Fig. 5.1.16 Soemmerring’s Ring. Taken from behind the lens of a human eye groups. In some cases the epithelial cells escape from the ring and migrate
obtained postmortem. A three-piece, modified J, polypropylene loop posterior onto the anterior surface of the anterior capsule. Because the ring forms at
chamber intraocular lens is present. (From Apple DJ, Solomon KD, Tetz MR, et al. the periphery of the lens, vision is not affected.76,80,81
Posterior capsule opacification. Surv Ophthalmol 1992;37:73–116.)
Fibrosis-Type Posterior Capsule Opacification Prevention and Treatment of Posterior

Residual lens epithelial cells that are still attached to the anterior capsule
Capsule Opacification
after ECCE are thought to be the predominant cells involved in the forma- Currently there is no reliable treatment to prevent PCO. Posterior cap-
tion of fibrous membranes that can appear within 2–6 months of ECCE.69 sulectomy is the treatment of choice when PCO does affect the visual field.
Remnant epithelial cells left on the anterior capsule differentiate A posterior capsulectomy removes the central part of the posterior capsule
into spindle-shaped, fibroblast-like cells (myofibroblasts), which express and thereby instantly improves vision. Removal is achieved using a neo-
α-smooth muscle actin and become highly contractile. These fibroblastic dymium:yttrium–aluminum–garnet (Nd:YAG) laser (Fig. 5.1.17). In some
cells proliferate and migrate onto the posterior capsule to form a cellular patients with posterior segment problems, proliferation of lens epithelial
layer that secretes extracellular matrix components and a basal lamina-like remnants has been observed within months of the capsulectomy. As a
material. Cellular contraction results in the formation of numerous fine result, the size of the capsulectomy decreases, which may in turn reduce
folds and wrinkles in the posterior capsule. At this stage the capsule is visual acuity. It has been postulated that this occurs because of “activation”
only mildly opacified. No significant visual loss occurs until the cells of the cells, the release of growth factors from the vitreous, the direct stim-
migrate into the visual axis.68,71 More advanced stages of PCO result from ulation of proliferation, or a combination of these factors.82 Removal of the
further proliferation and multilayering of cells on the posterior capsule barrier between the posterior chamber and the vitreous cavity increases the
e10 and are associated with additional extracellular matrix production and the risk of complications such as cystoid macular edema, retinal detachment,
appearance of white fibrotic opacities (see Fig. 5.1.14). The majority of the uveitis, and secondary glaucoma.69
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3. Kuszak JR, Brown HG. Embryology and anatomy of the lens. In: Albert DM, Jakobiec
FA, editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB
Saunders; 1994. p. 82–96.
4. Saude T. The internal ocular media. In: Ocular anatomy and physiology. Oxford: Black-
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well Scientific; 1993. p. 36–52.
5. Snell RS, Lemp MA. The eyeball. Clinical anatomy of the eye. Oxford: Blackwell Scien-

tific; 1989. p. 119–94.
6. Forrester J, Dick A, McMenamin P, et al. Anatomy of the eye and orbit. In: Forrester JV,
Dick AD, McMenamin P, et al, editors. The eye: basic sciences in practice. London: WB
Saunders; 1996. p. 1–86.
7. Seland JH. The lens capsule and zonulae. Acta Ophthalmol 1992;70:7–12.
8. Phelps Brown N, Bron AJ. Lens structure. In: Phelps Brown N, Bron AJ, Phelps
Brown NA, editors. Lens disorders: a clinical manual of cataract diagnosis. Oxford:
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9. Kuszak JR. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev
Cytol 1995;163:305–50.
10. Lo W, Harding CV. Tight junctions in the lens epithelia of human and frog: freeze-fracture
and protein tracer studies. Invest Ophthalmol Vis Sci 1983;24:396–402.
11. Olivero DK, Furcht LT. Type IV collagen, laminin, and fibronectin promote the adhesion
and migration of rabbit lens epithelial cells. Invest Ophthalmol Vis Sci 1996;34:2825–34.
12. Taylor VL, Al-Ghoul KJ, Lane CW, et al. Morphology of the normal human lens. Invest
Ophthalmol Vis Sci 1996;37:1396–410.
13. Kuszak JR. The development of lens sutures. Prog Retina Eye Res 1995;14:567–91.
14. Phelps Brown N, Bron AJ. Lens growth. In: Phelps Brown N, Bron AJ, Phelps
Brown NA, editors. Lens disorders. A clinical manual of cataract diagnosis. Oxford:
Butterworth-Heinemann; 1996. p. 17–31.
15. Harding JJ, Rixon KC, Marriott FHC. Men have heavier lenses than women of the same
age. Exp Eye Res 1977;25:651.
Fig. 5.1.17 Posterior Capsule Following a Nd:YAG laser posterior capsulectomy. 16. Cook CA, Koretz JF, Pfahnl A, et al. Aging of the human crystalline lens and anterior
segment. Vision Res 1994;34:2945–54.
(From Rohrbach JM, Knorr M, Weidle EG, et al. Nachstar: klinik, therapie, 17. Patterson JW. Characterization of the equatorial current of the lens. Ophthalmic Res
morphologic, and prophylaxe. Akt Augenheilkd 1995;20:16–23.) 1988;20:139–42.
18. Lerman S. Lens transparency and aging. In: Regnault F, Hockwin O, Courtios Y, editors.
Ageing of the lens. Amsterdam: Elsevier/North-Holland Biomedical Press; 1980. p.
There have been numerous approaches to prevent PCO.83,84 The 263–79.
implantation of a posterior chamber IOL into the capsular bag after ECCE 19. Zigman S. Photochemical mechanisms in cataract formation. In: Duncan G, editor.
is known to reduce the likelihood that a patient will develop PCO, because Mechanisms of cataract formation in the human lens. London: Academic Press; 1981. p.
the IOL acts as a barrier to the migration of cells around and into the 117–49.
20. Duke-Elder S. The refraction of the eye – physiological optics. In: Abrams D, editor. The
center of the posterior capsule. Posterior convex or biconvex optics sit in practice of refraction. 10th ed. Edinburgh: Churchill Livingstone; 1993. p. 29–41.
the capsular bag with their posterior surface firmly against the posterior 21. de Jong WW, Lubsen NH, Kraft HJ. Molecular evolution of the eye lens. Prog Retina Eye
capsule. Barrier-ridge optics have a rim on the posterior surface of the IOL Res 1994;13:391–442.
to try to block migrating cells. Migration also has been shown to be depen- 22. Bennett AG, Rabbetts RB. Ocular aberrations. Clinical visual optics. 2nd ed. London:
Butterworths; 1989. p. 331–57.
dent on the implant biomaterial. For example, trials have shown that the 23. Elkington AR, Frank HJ. Aberrations of optical systems including the eye. Clinical optics.
posterior capsules of patients who were given polyacrylic implants were 2nd ed. Oxford: Blackwell Scientific; 1991. p. 75–82.
significantly clearer 2 years after implantation than the posterior capsules 24. Moore DC. Geometric optics. In: Coster DJ, editor. Physics for ophthalmologists. Edin-
of those given polymethylmethacrylate or silicone implants. Lens epithelial burgh: Churchill Livingstone; 1994. p. 29–34.
25. Duke-Elder S. Accommodation. In: Abrams D, editor. The practice of refraction. 10th ed.
cells also have been shown to regress in eyes implanted with polyacrylic Edinburgh: Churchill Livingstone; 1993. p. 85–9.
IOLs.84 26. Fisher RF. The ciliary body in accommodation. Trans Ophthalmol Soc UK 1986;105:208–19.
27. Kador PF. Biochemistry of the lens: intermediary metabolism and sugar cataract forma-
tion. In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Basic
KEY REFERENCES sciences. Philadelphia: WB Saunders; 1994. p. 146–67.
28. Harding JJ, Crabbe MJC. The lens: development, proteins, metabolism and cataract. In:
Allen D, Vasavada A. Cataract and surgery for cataract. BMJ 2006;333:128–32. Davson H, editor. The eye. 3rd ed. London: Academic Press; 1984. p. 207–492.
Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol 29. Berman ER. Lens. In: Blakemore C, editor. Biochemistry of the eye. New York: Plenum
1992;37:73–116. Press; 1991. p. 201–90.
Bennett AG, Rabbetts RB. Ocular aberrations. Clinical visual optics. 2nd ed. London: Butter- 30. Bassnett S. The fate of the Golgi apparatus and the endoplasmic reticulum during lens
worths; 1989. p. 331–57. fiber cell differentiation. Invest Ophthalmol Vis Sci 1995;36:1793–803.
Chylack LT. Aging changes in the crystalline lens and zonules. In: Albert DM, Jakobiec FA, 31. Harding J. The normal lens. In: Harding J, editor. Cataract: biochemistry, epidemiology
editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB and pharmacology. London: Chapman & Hall; 1991. p. 1–70.
Saunders; 1994. p. 702–10. 32. Reddy VN. Glutathione and its functions in the lens – an overview. Exp Eye Res
Cook CA, Koretz JF, Pfahnl A, et al. Aging of the human crystalline lens and anterior 1990;50:771–8.
segment. Vision Res 1994;34:2945–54. 33. Kannan R, Yi JR, Zlokovic BV, et al. Molecular characterization of a reduced glutathione
Duke-Elder S. Accommodation. In: Abrams D, editor. The practice of refraction. 10th ed. transporter in the lens. Invest Ophthalmol Vis Sci 1995;36:1785–92.
Edinburgh: Churchill Livingstone; 1993. p. 85–9. 34. Augusteyn RC. Protein modification in cataract. In: Duncan G, editor. Mechanisms of
Duke-Elder S. The refraction of the eye – physiological optics. In: Abrams D, editor. The cataract formation in the human lens. London: Academic Press; 1981. p. 72–115.
practice of refraction. 10th ed. Edinburgh: Churchill Livingstone; 1993. p. 29–41. 35. Lerman S. Free radical damage and defense mechanisms in the ocular lens. Lens Eye
Kador PF. Biochemistry of the lens: intermediary metabolism and sugar cataract formation. Toxic Res 1992;9:9–24.
In: Albert DM, Jakobiec FA, editors. Principles and practice of ophthalmology. Basic 36. Costarides AP, Riley MV, Green K. Roles of catalase and the glutathione redox cycle in
sciences. Philadelphia: WB Saunders; 1994. p. 146–67. the regulation of anterior-chamber hydrogen peroxide. Ophthalmic Res 1991;23:284–94.
Kuszak JR. The development of lens sutures. Prog Retina Eye Res 1995;14:567–91. 37. Sasaki H, Giblin FJ, Winkler BS, et al. A protective role for glutathione-dependent
Kuszak JR, Brown HG. Embryology and anatomy of the lens. In: Albert DM, Jakobiec FA, reduction of dehydroascorbic acid in lens epithelium. Invest Ophthalmol Vis Sci
editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB 1995;36:1804–17.
Saunders; 1994. p. 82–96. 38. Varma SD, Richards RD. Ascorbic acid and the eye lens. Ophthalmic Res 1988;20:164–73.
Lerman S. Free radical damage and defense mechanisms in the ocular lens. Lens Eye Toxic 39. Harding J. The normal lens. In: Harding J, editor. Cataract: Biochemistry, epidemiology
Res 1992;9:9–24. and pharmacology. London: Chapman & Hall; 1991. p. 1–70.
Lerman S. Lens transparency and aging. In: Regnault F, Hockwin O, Courtios Y, editors. 40. Zigler JS. Lens proteins. In: Albert DM, Jakobiec FA, editors. Principles and practice of
Ageing of the lens. Amsterdam: Elsevier/North-Holland Biomedical Press; 1980. ophthalmology. Basic sciences. Philadelphia: WB Saunders; 1994. p. 97–113.
p. 263–79. 41. de Jong WW, Lubsen NH, Kraft HJ. Molecular evolution of the eye lens. Prog Retina Eye
Seland JH. The lens capsule and zonulae. Acta Ophthalmol 1992;70:7–12. Res 1994;13:391–442.
Snell RS, Lemp MA. The eyeball. Clinical anatomy of the eye. Oxford: Blackwell Scientific; 42. Harding JJ, Crabbe MJC. The lens: development, proteins, metabolism and cataract. In:
1989. p. 119–94. Davson H, editor. The eye, vol. 1B. 3rd ed. London: Academic Press; 1984. p. 207–492.
Zigler JS. Lens proteins. In: Albert DM, Jakobiec FA, editors. Principles and practice of oph- 43. Berman ER. Lens. In: Blakemore C, editor. Biochemistry of the eye. New York: Plenum
thalmology. Basic sciences. Philadelphia: WB Saunders; 1994. p. 97–113. Press; 1991. p. 201–90.
44. McAvoy JW. Cell division, cell elongation and the co-ordination of crystallin gene expres-
sion during lens morphogenesis in the rat. J Embryol Exp Morphol 1978;45:271–81.
REFERENCES 45. McAvoy JW. Cell division, cell elongation and the distribution of α-, β- and γ-crystallins
in the rat lens. J Embryol Exp Morphol 1978;44:149–65.
1. Foster A, Resnikoff S. The impact of Vision 2020 on global blindness. Eye 2005;19: 46. Wistow G, Richardson J, Jaworski C, et al. Crystallins: the over-expression of functional
1133–5. enzymes and stress proteins in the eye lens. Biotechnol Genet Eng Rev 1994;12:1–38. e11
2. Allen D, Vasavada A. Cataract and surgery for cataract. BMJ 2006;333:128–32. 47. Horwitz J. The function of α-crystallin. Invest Ophthalmol Vis Sci 1993;34:10–22.
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48. Wang K, Spector A. α-Crystallin can act as a chaperone under conditions of oxidative 66. Yang Z, Chamorro M, Smith DL, et al. Identification of the major components of
5 stress. Invest Ophthalmol Vis Sci 1995;36:311–21.

49. Kuszak JR. The ultrastructure of epithelial and fiber cells in the crystalline lens. Int Rev
Cytol 1995;163:305–50.
50. Chylack LT. Aging changes in the crystalline lens and zonules. In: Albert DM, Jakobiec
the high molecular weight crystallins from old human lenses. Curr Eye Res 1994;13:
415–21.
67. Lerman S. Composition and formation of the insoluble protein fraction in the ocular
lens. Can J Ophthalmol 1970;5:152–9.
FA, editors. Principles and practice of ophthalmology. Basic sciences. Philadelphia: WB 68. Green WR, McDonnell PJ. Opacification of the posterior capsule. Trans Ophthalmol Soc
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Saunders; 1994. p. 702–10. UK 1985;104:727–39.

51. Berman ER. Lens. In: Blakemore C, editor. Biochemistry of the eye. New York: Plenum 69. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsule opacification. Surv Ophthalmol
Press; 1991. p. 201–90. 1992;37:73–116.
52. Harding J. The aging lens. In: Harding J, editor. Cataract: biochemistry, epidemiology 70. Rohrbach JM, Knorr M, Weidle EG, et al. Nachstar: klinik, therapie, morphologie und
and pharmacology. London: Chapman & Hall; 1991. p. 71–82. prophylaxe. Akt Augenheilkd 1995;20:16–23.
53. Marshall GE, Konstas AGP, Bechrakis NE, et al. An Immunoelectron microscope study 71. McDonnell PJ, Stark WJ, Green WR. Posterior capsule opacification: a specular micro-
of the aged human lens capsule. Exp Eye Res 1992;54:393–401. scopic study. Ophthalmology 1984;91:853–6.
54. Duncan G, Hightower KR, Gandolfi SA, et al. Human lens membrane cation permeabil- 72. Ishibashi T, Araki H, Sugai S, et al. Detection of proteoglycans in human posterior
ity increases with age. Invest Ophthalmol Vis Sci 1989;30:1855–9. capsule opacification. Ophthalmic Res 1995;27:208–13.
55. Coren S, Girgus JS. Density of human lens pigmentation: in vivo measures over an 73. Pande MV, Spalton DJ, Marshall J. In vivo human lens epithelial cell proliferation on the
extended age range. Vision Res 1972;12:343–6. anterior surface of PMMA intraocular lenses. Br J Ophthalmol 1996;80:469–74.
56. Vrensen GFJM. Aging of the human eye lens – a morphological point of view. Comp 74. Hirschberg J. Einführung in die Augenheilkunde. II. Hälkft I Abt. Leipzig: Themie; 1901.
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57. Dillon J. The photophysics and photobiology of the eye. J Photochem Photobiol B 75. Elschnig A. Klinisch-anatomischer Beitrag zur Kenntnis des Nachstares. Klin Monatsbl
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58. Ellozy AR, Wang RH, Dillon J. Model studies on the photochemical production of lentic- 76. Kappelhof JP, Vrensen GFJM. The pathology of after-cataract. Acta Ophthalmol
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60. Fisher RF. Presbyopia and the changes with age in the human crystalline lens. J Physiol 78. Kappelhof JP, Vrensen GFJM, de Jong PTVM, et al. An ultrastructural study of Elschnig’s
1973;228:765–79. pearls in the pseudophakic eye. Am J Ophthalmol 1986;101:58–69.
61. Koretz JF. Accommodation and presbyopia. In: Albert DM, Jakobiec FA, editors. Princi- 79. Soemmering DW. Beobachtungen von die organischen Veränderungen in Auge nach
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AJ, Phelps Brown NA, editors. Lens disorders: a clinical manual of cataract diagnosis. 81. Jongebloed WL, Dijk F, Kruis J, et al. Soemmering’s ring, an aspect of secondary cata-
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63. Hemenger RP, Garner LF, Ooi CS. Change with age of the refractive index gradient of 82. Jones NP, McLeod D, Boulton ME. Massive proliferation of lens epithelial remnants after
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64. Rathbun WB, Murray DL. Age-related cysteine uptake as rate-limiting in glutathione syn- 83. Nibourg LM, Gelens E, Kuijer R, et al. Prevention of posterior capsular opacification. Exp
thesis and glutathione half-life in the cultured human lens. Exp Eye Res 1991;53:205–12. Eye Res 2015;136:100–15.
65. Srivastava OP, Srivastava K, Silney C. Levels of crystallin fragments and identification of 84. Pande M, Ursell PG, Spalton DJ. Lens epithelial cell regression on the posterior capsule
their origin in water soluble high molecular weight (HMW) proteins of human lenses. with different intraocular lens materials. Br J Ophthalmol 1998;82:1182–8.
Curr Eye Res 1996;15:511–20.
e12
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Part 5 The Lens

Evolution of Intraocular Lens

Implantation 5.2
Liliana Werner, Andrea M. Izak, Suresh K. Pandey, David J. Apple† IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Definition: Report on the evolution of intraocular lens designs.
Key Features
• Description of anterior and posterior chamber intraocular lens
designs, including lenses now obsolete, and their interaction with
intraocular tissues.
• Recent advances in intraocular lens designs/materials leading to
modern, currently available intraocular lenses.
INTRODUCTION
Cataract is the most prevalent ophthalmic disease. Although a pharma-
cological preventive or therapeutic treatment for this potentially blinding
disease is being actively sought, the solution still appears to be many years
away. Therefore, surgical treatment for cataracts, which typically includes
intraocular lens (IOL) implantation, remains the only viable alternative. Fig. 5.2.1 Posterior View of an Eye (Obtained Postmortem) Showing the
The implantation of IOLs is now a highly successful operation, and the Implantation Site of a Ridley Lens. To the time of death, almost 30 years after
safety and efficacy of the procedure are well established.1 implantation, the patient’s visual acuity remained 20/20 (6/6) in both eyes. Note the
good centration and clarity of the all-polymethyl methacrylate optic in the central
LENS DESIGN AND FIXATION visual axis. The lens was implanted by Reese and Hammdi of Philadelphia.
In 1967 Binkhorst2 proposed a detailed classification of the various means

of fixation for each IOL type. In a 1985 update of this classification, Bink- lens designs. The entity now termed uveitis–glaucoma–hyphema (UGH)
horst3 listed four IOL types according to fixation sites: anterior chamber syndrome was described first when ocular tissue damage occurred that was
angle-supported lenses, iris-supported lenses, capsule-supported lenses, clearly the result of poorly manufactured early anterior chamber lenses.5
and posterior chamber angle (ciliary sulcus)–supported lenses. By common
agreement, most surgeons today differentiate lens types as iris-supported Generation III (Iris-Supported Lenses)
lenses, anterior chamber lenses, and posterior chamber lenses.
From the time of Ridley’s first lens implantation to the present day, the Binkhorst was an early advocate of iris-supported IOLs.3,4 His first lens was
evolution of IOLs can be arbitrarily divided into six generations. a four-loop, iris-clip IOL (Fig. 5.2.2A) design. Although Binkhorst initially
believed that IOL contact with the iris would not cause problems, he soon
Generation I (Original Ridley Posterior noted that iris chafing, pupillary abnormalities, and dislocation developed
Chamber Lens) with the early iris-clip lens. Also, in an effort to circumvent dislocation,
Binkhorst made the anterior loops of his four-loop lens longer, but this
Ridley’s first IOL operation was performed November 29, 1949, on a led to increased corneal decompensation from peripheral touch. His initial
49-year-old woman at St Thomas’ Hospital in London.4 His original IOL implantations were done after ICCE, but occasionally he implanted his
was a biconvex polymethyl methacrylate (PMMA) disc designed to be four-loop lens following ECCE. His positive experience with this procedure
implanted after extracapsular cataract extraction (ECCE) (Fig. 5.2.1). prompted him to modify his iris-clip lens design for implantation follow-
ing ECCE. Binkhorst’s change from ICCE to ECCE and the introduction
Generation II (Early Anterior Chamber Lenses) of his two-loop iridocapsular IOL (see Fig. 5.2.2B) in 1965 were important
advances in both IOL design and mode of fixation.6
As a consequence of the relatively high incidence of dislocations with the
Ridley lens, a new implantation site was considered, with fixation of the Generation IV (Intermediate Anterior
lens in the angle recess. The anterior chamber was chosen because less Chamber Lenses)
likelihood existed of dislocation within its narrow confines. In addition,
anterior chamber lenses could be implanted after either an intracapsular As iris-supported IOLs underwent major modifications from the early 1950s
cataract extraction (ICCE) or an ECCE. up to the beginning of the 1980s, several designs of anterior chamber IOLs
Late endothelial atrophy, corneal decompensation, and pseudopha- were introduced. The problems of tissue chafing and difficulties in correct
kic bullous keratopathy were observed with the original Baron anterior sizing associated with rigid IOLs were addressed by the development of
chamber lens and also developed with many subsequent anterior chamber anterior chamber lenses with more flexible loops or haptics. Unlike the
ill-fated, nylon-looped lenses introduced by Dannheim in the early 1950s, 327
†
Deceased the fixation elements of these anterior chamber IOLs were made from
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Fig. 5.2.2 Binkhorst Iris-Clip Lenses. (A) A correctly
5 positioned Binkhorst four-loop, iris-clip lens, well centered

in an eye that had good visual acuity. Moderate pupillary
distortion and sphincter erosion occur. Note the iris-
fixation suture superior to the site of the large iridectomy.
The Lens
(B) Posterior view of an autopsy globe that contains a

two-loop iridocapsular intraocular lens. Note the rod that
helps to secure the lens to the iris through the iridectomy.
An outer Soemmerring’s ring is present, but the visual axis
remains clear. The optic is well centered.
A B
evolution of ECCE surgery: microscopic surgical techniques; phaco; irido-

capsular fixation; and flexible posterior chamber lenses.
Generation VI (Modern Capsular Lenses –

Rigid PMMA, Soft Foldable, and Modern
Anterior Chamber)
By the end of the 1980s, surgical technique and IOL design and manufac-
ture had advanced to a point at which the older techniques gave way to
more modern ones that allowed consistent, secure, and permanent in-the-
bag (capsular) fixation of the pseudophakos. A marriage between IOL
design and improved surgical techniques has evolved into capsular surgery.
The “capsular” IOLs are fabricated from both rigid and soft biomaterials.
The many changes in surgical techniques that occurred after 1980 and
into the 1990s include the introduction of ophthalmic viscosurgical devices
(OVDs), increased awareness of the advantages of in-the-bag fixation, the
introduction of continuous curvilinear capsulorrhexis (CCC), hydrodis-
section, and the increased use of phaco. Improved small-incision surgical
techniques and IOL designs have resulted in a natural evolution toward
foldable lenses. Most foldable lenses today are manufactured from sili-
Fig. 5.2.3 Modern One-Piece, All-Polymethyl Methacrylate, Kelman-Style cone, hydrogel, or acrylic material (Fig. 5.2.5).11,12
Anterior Chamber Lenses of Four-Point and Three-Point Fixation Designs. Note
the excellent polishing and tissue-friendly Choyce-Kelman–style footplates. These
represent modern, state-of-the-art lenses that should be distinguished clearly from RECENT ADVANCES
the earlier, unsatisfactory, closed-loop anterior chamber lenses. Some general principles and tendencies with regard to the development of
new IOLs in the past decade are11,12:
more stable polymers, usually PMMA and polypropylene. The best lenses
were the various rigid7 and flexible, open-loop, one-piece PMMA designs, • Large fixation holes or foramina incorporated in the haptic compo-
such as the three- and four-point fixation Kelman IOLs.8 Modifications of nents of one-piece plate designs commonly produce fibrous adhesions
the latter have been in use since the late 1970s and are the styles most between the anterior and posterior capsules following ingrowth of fibro-
commonly implanted today (Fig. 5.2.3). cellular tissue through the holes, enhancing the fixation and stability of
these designs within the capsular bag.
• For three-piece foldable designs, the preferred haptic materials are
Generation V (Improved Posterior rigid materials with good material memory, such as PMMA, polyimide
(Elastimide), or polyvinylidene fluoride (PVDF), which enhance lens
Chamber Lenses) centration and stability and provide better resistance to postoperative
The return to Ridley’s original concept of IOL implantation in the poste- contraction forces within the capsular bag.
rior chamber occurred after 1975. Pearce9 of England implanted the first • One of the most important features in foldable lenses that decreases
uniplanar posterior chamber lens since Ridley. It was a rigid tripod design the incidence of posterior capsular opacification (PCO) is the square,
with the two inferior feet implanted in the capsular bag and the superior truncated optic edge, which has an enhanced barrier effect against cell
foot implanted in front of the anterior capsule and sutured to the iris. migration/proliferation on the posterior capsule toward the visual axis.
Shearing10 of Las Vegas introduced a major lens design breakthrough in • Manufacturers have invested heavily and with great success in looped
early 1977 with his posterior chamber lens. The design consisted of an single-piece designs (Fig. 5.2.5B), including designs with modifications
optic with two flexible J-shaped loops. Simcoe of Tulsa introduced his at the level of the optic–haptic junctions to obtain a nonsmooth transi-
C-looped posterior chamber lens shortly after Shearing’s J-loop design tion between these components. This was done because some studies
appeared. The flexible open-loop designs (J-loop, modified J-loop, C-loop, demonstrated that smooth optic–haptic junctions may be sites for PCO
or modified C-loop) still account for the largest number of IOL styles avail- initiation.
able today (Fig. 5.2.4). • New injector systems to be used with the new lens designs have been
One obvious major theoretical advantage that a posterior chamber IOL developed. Manufacturers have also invested in the development of
has over an anterior chamber IOL is its position behind the iris, away injector systems where the IOLs come preloaded and in automated
from the delicate structures of the anterior segment. The return to pos- injection systems.
328 terior chamber lenses coincided with the development of improved ECCE • Special features such as multifocality, extended depth of focus, toric cor-
surgery. Shearing identified four major milestones that have marked the rections, pseudoaccommodation, asphericity, postoperative adjustment
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5.2
Evolution of Intraocular Lens Implantation

A
B B
Fig. 5.2.4 View From Behind of an Autopsy Eye. (A) A Sinskey-style, J-loop Fig. 5.2.5 View From Behind an Autopsy Eye. (A) Posterior view (Miyake
posterior chamber intraocular lens implanted within the lens capsular bag. The optic technique) of a well-implanted Advanced Medical Optics three-piece silicone
is well centered, the visual axis is clear, and there is only minimal regeneration of IOL. The lens was implanted following excellent cortical cleanup in a human eye
cortex in scattered areas. Moderate haziness or opacity occurs at the margins of the obtained postmortem. (B) Gross photograph of the first human eye obtained
anterior capsulotomy, which does not encroach on the visual axis. (B) The placement postmortem with a single-piece AcrySof lens (Alcon Laboratories, Fort Worth, TX)
of the loop of this modified C-style intraocular lens in the capsular bag. accessioned in our laboratory. The lens is well centered and the capsular bag is clear.
(Reproduced from Escobar-Gomez M, Apple DJ, Vargas LG, et al. Scanning electron
of the IOL refractive power, image magnification (telescopic lenses), microscopic and histologic evaluation of the AcrySof SA30AL acrylic intraocular lens.
and protection of the retina against blue or violet light (through incor- J Cataract Refract Surg 2003;29:164–9.)
poration of appropriate chromophores to the IOL optic material) are Binkhorst CD. About lens implantation. 2. Lens design and classification of lenses. Implant
widely available.13 1985;3:11–14.
• The renewed interest in phakic IOLs, which can potentially correct any Binkhorst CD. Lens implants (pseudophakoi) classified according to method of fixation. Br
J Ophthalmol 1967;51:772–4.
refractive error, is also progressing rapidly.14 A trend exists for the use Choyce DP. The Mark VI, Mark VII and Mark VIII Choyce anterior chamber implants. Proc
of foldable materials for these phakic lenses, designed to be inserted R Soc Med 1965;58:729–31.
through small incisions and fixated to the iris or in the posterior Drews RC. Intracapsular versus extracapsular cataract extraction. In: Wilensky JT, editor.
chamber. Most of the angle-supported anterior chamber phakic IOLs Intraocular lenses. Transactions of the University of Illinois Symposium on Intraocular
Lenses. New York: Appleton-Century-Crofts; 1977.
have been abandoned from the market due to issues with the corneal Ellingson FT. The uveitis-glaucoma-hyphema syndrome associated with the Mark VIII ante-
endothelium.15 rior chamber lens implant. J Am Intraocul Implant Soc 1978;4:50–3.
• There is a renewed interest in the piggyback IOL procedure not only Güell JL, Morral M, Kook D, et al. Phakic intraocular lenses part 1: historical overview,
for correction of residual refractive errors but also because of the poten- current models, selection criteria, and surgical techniques. J Cataract Refract Surg
2010;36:1976–93.
tial to implant a low-power multifocal lens to provide spectacle freedom Kelman CD. Anterior chamber lens design concepts. In: Rosen ES, Haining WM, Arnott EJ,
to patients who already are pseudophakic, as well as other specialized editors. Intraocular lens implantation. St Louis: CV Mosby; 1984.
lenses such as toric and aspherical IOLs. In these cases, the “supple- McIntyre JS, Werner L, Fuller SR, et al. Assessment of a single-piece hydrophilic acrylic
mentary” lens is fixated in the ciliary sulcus to avoid interlenticular IOL for piggyback sulcus fixation in pseudophakic cadaver eyes. J Cataract Refract Surg
2012;38:155–62.
opacification (ILO) formation, and it is specially designed to minimize Pearce JL. Experience with 194 posterior chamber lenses in 20 months. Trans Ophthalmol
interaction with intraocular structures and provide appropriate clear- Soc UK 1977;97:258–64.
ance with uveal tissues and the in-the-bag IOL.16 Ridley H. Intra-ocular acrylic lenses. Trans Ophthalmol Soc UK 1951;71:617–21.
Shearing SP. Evolution of the posterior chamber intraocular lenses. J Am Intraocul Implant
Soc 1984;10:343–6.
KEY REFERENCES Werner L. Biocompatibility of intraocular lens materials. Curr Opin Ophthalmol 2008;19:41–9.
Werner L, Olson RJ, Mamalis N. New technology IOL optics. Ophthalmol Clin North Am
Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses: a historical and 2006;19:469–83.
histopathological review. Surv Ophthalmol 1984;29:1–54.
Apple DJ, Werner L. Complications of cataract and refractive surgery: a clinicopathological Access the complete reference list online at ExpertConsult.com 329
documentation. Trans Am Ophthalmol Soc 2001;99:95–107, discussion 107–9.
booksmedicos.org
REFERENCES 9. Pearce JL. Experience with 194 posterior chamber lenses in 20 months. Trans Ophthal-
mol Soc UK 1977;97:258–64.
1. Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses: a historical
and histopathological review. Surv Ophthalmol 1984;29:1–54.
10. Shearing SP. Evolution of the posterior chamber intraocular lenses. J Am Intraocul
Implant Soc 1984;10:343–6.
5.2
2. Binkhorst CD. Lens implants (pseudophakoi) classified according to method of fixation. 11. Apple DJ, Werner L. Complications of cataract and refractive surgery: a clinicopathologi-
cal documentation. Trans Am Ophthalmol Soc 2001;99:95–107, discussion 107–9.

Br J Ophthalmol 1967;51:772–4.
3. Binkhorst CD. About lens implantation. 2. Lens design and classification of lenses. 12. Werner L. Biocompatibility of intraocular lens materials. Curr Opin Ophthalmol
Implant 1985;3:11–14. 2008;19:41–9.
4. Ridley H. Intra-ocular acrylic lenses. Trans Ophthalmol Soc UK 1951;71:617–21. 13. Werner L, Olson RJ, Mamalis N. New technology IOL optics. Ophthalmol Clin North Am
5. Ellingson FT. The uveitis-glaucoma-hyphema syndrome associated with the Mark VIII 2006;19:469–83.
anterior chamber lens implant. J Am Intraocul Implant Soc 1978;4:50–3. 14. Güell JL, Morral M, Kook D, et al. Phakic intraocular lenses part 1: historical overview,
6. Drews RC. Intracapsular versus extracapsular cataract extraction. In: Wilensky JT, editor. current models, selection criteria, and surgical techniques. J Cataract Refract Surg
Intraocular lenses. Transactions of the University of Illinois Symposium on Intraocular 2010;36:1976–93.
Lenses. New York: Appleton-Century-Crofts; 1977. 15. Alió JL, Toffaha BT, Peña-Garcia P, et al. Phakic intraocular lens explantation: causes in
7. Choyce DP. The Mark VI, Mark VII and Mark VIII Choyce anterior chamber implants. 240 cases. J Refract Surg 2015;31(1):30–5.
Proc R Soc Med 1965;58:729–31. 16. McIntyre JS, Werner L, Fuller SR, et al. Assessment of a single-piece hydrophilic acrylic
8. Kelman CD. Anterior chamber lens design concepts. In: Rosen ES, Haining WM, Arnott IOL for piggyback sulcus fixation in pseudophakic cadaver eyes. J Cataract Refract Surg
EJ, editors. Intraocular lens implantation. St Louis: CV Mosby; 1984. 2012;38:155–62.
329.e1
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Part 5 The Lens

Evolution of Intraocular Lens

Implantation 5.2
Liliana Werner, Andrea M. Izak, Suresh K. Pandey, David J. Apple†
Definition: Report on the evolution of intraocular lens designs. LENS DESIGN AND FIXATION
In 1967, Binkhorst11 proposed a detailed classification of the various means
of fixation for each IOL type. In a 1985 update of this classification, Bink-
horst12 listed four IOL types according to fixation sites:
Key features • Anterior chamber angle-supported lenses.

• Iris-supported lenses.
• Description of anterior and posterior chamber intraocular lens • Capsule-supported lenses.
designs, including lenses now obsolete, and their interaction with • Posterior chamber angle (ciliary sulcus)-supported lenses.
intraocular tissues.
• Recent advances in intraocular lens designs/materials, leading to By common agreement, most surgeons today differentiate lens types
modern, currently available intraocular lenses. as follows:
• Iris-supported lenses.
• Anterior chamber lenses.
• Posterior chamber lenses.
INTRODUCTION From the time of Ridley’s first lens implantation to the present day,
the evolution of IOLs can be arbitrarily divided into six generations
Cataract is the most prevalent ophthalmic disease. The number of persons (Table 5.2.1).
who became blind as a result of cataract in 1998 was estimated to be about
17 million worldwide; this number was expected to double by early in the Generation I (Original Ridley Posterior
twenty-first century.1,2 Although a pharmacological preventive or therapeu- Chamber Lens)
tic treatment for this blinding disease is being actively sought, the solu-
tion still appears to be many years away. Therefore, surgical treatment for A practical application of the concept of IOLs began with Ridley,3–7 and
cataracts, which increasingly includes intraocular lens (IOL) implantation, credit for the introduction of lens implants clearly belongs to him.
remains the only viable alternative. Ridley’s first IOL operation was performed on a 49-year-old woman at
Treatment of cataracts has been practiced for centuries using various St Thomas’ Hospital in London on November 29, 1949. His original IOL
surgical and nonsurgical procedures. However, avoidance of complications was a biconvex polymethyl methacrylate (PMMA) disc designed to be
and attainment of high-quality postoperative visual rehabilitation were dif- implanted after extracapsular cataract extraction (ECCE) (Fig. 5.2.1).
ficult in the years before the introduction of modern IOLs. Because signif- Ridley’s procedure was initially met with great hostility by several skep-
icant dioptric power resides in the crystalline lens, its removal results in tical and critical ophthalmologists. However, good results were attained in
marked visual disability. enough cases to warrant further implantation of the Ridley IOL, although
Aphakic spectacle correction has been prescribed throughout history, dislocation of the lens ultimately proved troublesome. It is gratifying to note
but spectacles are less than satisfactory because of the visual distortions that Ridley, who died in 2001, lived long enough to experience the acknowl-
inherent in such high-power lenses. edgment, respect, and honor he so fully deserved for this innovation.
It was not until the late 1940s that the optical advantages that an IOL
could provide in visual rehabilitation were understood and acted on by Generation II (Early Anterior Chamber Lenses)
Ridley.3–7
The implantation of IOLs is now a highly successful operation; the As a consequence of the relatively high incidence of dislocations with the
safety and efficacy of this procedure are well established. The number of Ridley lens, a new implantation site was considered—the anterior chamber,
IOL implants in the United States in 1998 was estimated to be 1.6 million. with fixation of the lens in the angle recess. The anterior chamber was
Implantation data from other countries are scant, but the total number chosen because less likelihood existed of dislocation within its narrow
of implantations per year worldwide is increasing rapidly. Studies are still confines. In addition, anterior chamber lenses could be implanted after
needed to determine which surgical technique(s) and which IOL design(s) either an intracapsular cataract extraction (ICCE) or an ECCE. Also, ante-
are safest, most practical, and most economical for high-volume use in the rior chamber placement of the pseudophakos was considered a simpler
less advantaged areas of the world. For general discussions that review the technical procedure than placement of the lens behind the iris.
evolution and provide clinicopathological overviews of IOLs, see Apple and
coworkers7–10 and Binkhorst.11
TABLE 5.2.1 The Evolution of Intraocular Lenses
Posterior chamber IOLs were reintroduced in the mid-1970s and early
1980s, following a long period of disfavor after the Ridley lens was discon- Generation Date Description
tinued. Jaffe and other authors compared posterior chamber lenses with I 1949–1954 Original Ridley posterior chamber lens
iris-supported lenses and were impressed by the superior results achieved II 1952–1962 Early anterior chamber lenses
with the former type of lens using an extracapsular cataract extraction tech-
III 1953–1975 Iris-supported lenses
nique. The use of posterior chamber IOLs is now clearly the treatment of
IV 1963–1990 Intermediate anterior chamber lenses
choice.
V 1975–1990 Improved posterior chamber lenses
†
VI 1990 to present Modern capsular posterior chamber lenses and modern
anterior chamber lenses
e13
Deceased
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Although many surgeons worked on the concept of this type of lens, poorly manufactured anterior chamber lenses.13 It took many modifica-
5 Baron, in France, is generally credited as being the first designer and

implanter of an anterior chamber lens (Fig. 5.2.2A).10 He first performed
this procedure on May 13, 1952.
tions of the haptic-loop configuration and the lens-vaulting characteristics
(see Fig. 5.2.2B) to develop an anterior chamber lens that allowed a rea-
sonable prediction of long-term success. This was achieved largely because
Late endothelial atrophy, corneal decompensation, and pseudophakic of the advances in lens design by Choyce of England and later by Kelman
The Lens
bullous keratopathy were observed with the original Baron lens and devel- of New York.
oped with many subsequent anterior chamber lens designs. The entity
now termed uveitis–glaucoma–hyphema (UGH) syndrome was described Generation III (Iris-Supported Lenses)
first when ocular tissue damage occurred that was clearly the result of
Relatively frequent dislocation of the Ridley lens and an unacceptably high
rate of corneal decompensation associated with the anterior chamber lenses
that were available in the early 1950s caused some surgeons to discontinue
implantation of IOLs entirely.14 However, iris-supported or iris-fixated IOLs
were introduced subsequently in an attempt to overcome these problems.
Binkhorst in the Netherlands was an early advocate of iris-supported
IOLs.11,12 His first lens was a four-loop, iris-clip IOL (Fig. 5.2.3A) design.
Although Binkhorst initially believed that IOL contact with the iris would
not cause problems, he soon noted that iris chafing, pupillary abnormal-
ities, and dislocation developed with the early iris-clip lens. Also, in an
effort to circumvent dislocation, Binkhorst made the anterior loops of his
four-loop lens longer, but this led to increased corneal decompensation
from peripheral touch.
His initial implantations were done after ICCE, but occasionally he
implanted his four-loop lens following ECCE. His positive experience
with this procedure prompted him to modify his iris-clip lens design for
implantation following ECCE. Binkhorst’s change from ICCE to ECCE
and the introduction of his two-loop iridocapsular IOL (see Fig. 5.2.3B) in
1965 were important advances in both IOL design and mode of fixation.15
His and others’ experiences with the two-loop lens style and its modifi-
Fig. 5.2.1 Posterior View of an Eye (Obtained Postmortem) Showing the cations were influential in the development of modern design concepts
Implantation Site of a Ridley Lens. To the time of death, almost 30 years after of IOLs, including capsular bag–fixated, posterior chamber IOLs. Bink-
implantation, the patient’s visual acuity remained 20/20 (6/6) in both eyes. Note horst’s innovative lens designs and his advocacy of ECCE came at a time
the good centration and clarity of the all-polymethyl methacrylate optic in the when the entire future of IOL implantation was in jeopardy; they provided
central visual axis. The lens was implanted by Dr. W. Reese and Dr. T. Hammdi of the major impetus that set the stage for modern posterior chamber lens
Philadelphia. implantations.
Fig. 5.2.2 Sagittal Section of the Anterior Segment

ANTERIOR CHAMBER LENSES of the Eye. (A) The original 1952 Baron anterior chamber
lens with fixation in the angle recess. Because this one-
piece lens was rigid, sizing problems were unavoidable.
Original 1952 Baron lens Modern anterior chamber lens Note the extremely steep anterior curvature of the
lens. Such excessive anterior vaulting invariably caused
corneal endothelial problems. (B) Placement of a
modern anterior chamber lens fixated in the angle
recess. Note the more subtle anterior vaulting of the
loops and lens optic.
A B
Fig. 5.2.3 Binkhorst Iris-Clip Lenses. (A) A correctly

positioned Binkhorst four-loop, iris-clip lens, well centered
in an eye that had good visual acuity. Moderate pupillary
distortion and sphincter erosion occur. Note the iris
fixation suture superior to the site of the large iridectomy.
(B) Posterior view of an autopsy globe that contains a
two-loop iridocapsular intraocular lens. Note the rod that
helps to secure the lens to the iris through the iridectomy.
An outer Soemmerring’s ring is present, but the visual axis
remains clear. The optic is well centered.
e14 A B
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During the early years of iris-fixated IOLs, many clinical and subclinical
problems emerged, such as dislocation, pupillary deformity and erosion,
iris atrophy with transillumination defects, pigment dispersion, uveitis, 5.2
hemorrhage, and opacification of the media. Many of these complications
were the result of chronic rubbing or chafing of the iris by IOL loops or

haptics. Problems were especially severe with metal loop IOLs and occurred
frequently with multiple-looped lenses because uveal contact and chafing
against the mobile iris tissues were unavoidable with these designs.
An increased incidence of corneal edema occurred in association with
iris-supported lens designs. Corneal decompensation and pseudophakic
bullous keratopathy became major indications for penetrating kerato-
plasty. The well-known coexistence of pseudophakic bullous keratopathy
and cystoid macular edema (CME) has been termed corneal-retinal inflam-
matory syndrome by Obstbaum and Galin.16 Binkhorst’s return to ECCE,
with the introduction of his two-loop iridocapsular lens in 1965 (see Fig.
5.2.3B),17 brought about an almost immediate reduction in the incidence of
many of these complications.
Most iris-supported lenses were biplanar, with the optic placed in front
of the pupil. In general, biplanar IOLs required a larger limbal wound
opening for insertion. The change to capsular fixation after ECCE pro-
vided better stability for the pseudophakos. This important modification
was a forerunner to capsular sac (in-the-bag) fixation of modern posterior Fig. 5.2.4 Modern One-Piece, All-Polymethyl Methacrylate, Kelman-Style
chamber IOLs. Anterior Chamber Lenses of Four-Point and Three-Point Fixation Designs. Note
At the time when iris-supported lenses were in widespread use, and the excellent polishing and tissue-friendly Choyce-Kelman–style footplates. These
until the mid-1980s in many cases, manufacturing methods and surgi- represent modern, state-of-the-art lenses that should be distinguished clearly from
cal techniques were less sophisticated. It is now clear that most modern, the earlier, unsatisfactory, closed-loop anterior chamber lenses.
high-quality anterior and posterior chamber IOLs provide better success
than the IOLs that depend on the iris for support. At present, it is the con-
sensus of surgeons that lens explantation and/or exchange is usually the BOX 5.2.1 Anterior Chamber Lenses
best treatment when a patient who has an iris-supported IOL develops late
Disadvantages of Closed-Loop Anterior Chamber Lenses
complications such as inflammation or corneal decompensation that does
not respond rapidly to conservative therapy.
• Lenses may be difficult to size
• Lenses may have inappropriate vault-compression ratios; when a lens
is compressed, it may vault anteriorly or posteriorly—either type of
Generation IV (Intermediate Anterior response can cause deleterious effects
Chamber Lenses) • Small-diameter loops may cause a “cheese-cutter” effect, particularly
if the lens is too large; subsequent erosion and chafing can cause
As iris-supported IOLs underwent major modifications from the early
uveitis, including cystoid macular edema and pseudophakic bullous
1950s up to the beginning of the 1980s, several designs of anterior chamber
keratopathy
IOLs were introduced.
The problems of tissue chafing and difficulties in correct sizing asso-
• Some lenses have a large contact zone over broad areas of the angle
with the potential for secondary glaucoma
ciated with rigid IOLs were addressed by the development of anterior
chamber lenses with more flexible loops or haptics (Box 5.2.1). Unlike the
• The poorly finished, sharp edges of some lens models can cause
chafing, which leads to sequelae such as uveitis or uveitis–glaucoma–
ill-fated, nylon-looped lenses introduced by Dannheim in the early 1950s,
hyphema syndrome
the fixation elements of these anterior chamber IOLs were made from
more stable polymers, usually PMMA and polypropylene. The best lenses
• Synechiae formation around the small-diameter loops may make the
lens difficult to remove when necessary; tearing of ocular tissues,
were the various rigid18 and flexible, open-loop, one-piece PMMA designs,
hemorrhage, and iridocyclodialysis are possible complications of
such as the three- and four-point fixation Kelman IOLs.19 Modifications of
intraocular lens removal if correct procedures are not used
the latter have been in use since the late 1970s and are the styles most com-
monly implanted today (Fig. 5.2.4). These lenses now are well designed, Advantages of Modern, Open-Loop, One-Piece, All-PMMA Flexible
correctly vaulted, and properly sized and can provide excellent long-term Anterior Chamber Lenses
results. As with the early generation of anterior chamber IOLs, new lens • Most modern lenses have an excellent finish with highly polished
designs included both haptic (footplate) fixation lenses and small-diameter, smooth surfaces and rounded edges from tumble polishing; tissue
round-looped IOLs. contact with any component of these intraocular lenses is much less
Although in the 1950s implantations with early anterior chamber IOLs likely to result in chafing damage
were often disappointing, some models of anterior chamber lenses pro- • Sizing is less critical with flexible, open-loop designs
vided good success, particularly when the lens was properly sized. Two • In contrast to a closed-loop anterior chamber intraocular lens, the
important factors that led to a higher success rate with anterior chamber vault (a well-designed, open-loop lens) is maintained even under
IOL use are improved lens designs and manufacturing techniques. high compression—this minimizes intraocular lens touch against the
More appropriate lens flexibility has decreased the need for perfect cornea anteriorly or against the iris posteriorly
sizing. Increased attention has been given to the anterior–posterior vault- • Point fixation is possible, since the haptic may subtend only small
ing characteristics of IOLs, which has reduced the incidence of intermit- areas of the angle outflow structures
tent touch and uveal chafing problems. Design flaws in older lens styles • Most open-loop intraocular lens designs are much easier to remove,
have been identified and these lenses removed from the market in the when necessary, especially those with Choyce-like haptic or footplate
United States. Tumble polishing of IOLs, particularly one-piece, all-PMMA fixation; the well-polished surfaces of these lenses usually do not
lenses, produces excellent surfaces and edges. The elimination of sharp become completely surrounded by goniosynechiae or cocoon
optic or haptic edges is critical in the production of anterior chamber IOLs. membranes and thus can usually be removed if necessary without
This is even more true than for posterior chamber IOLs, because anterior undue difficulty or excessive tissue damage
chamber IOLs are fixated in a confined space directly adjacent to delicate
anterior segment tissues.
The two major disadvantages of an anterior chamber IOL, as compared
with posterior chamber lens styles, are:
• The difficulty often encountered in IOL sizing, particularly with rigid
lens designs.
• The close proximity of the haptics or loops to delicate tissues such as The close proximity of anterior chamber lens components to the
the trabecular meshwork, corneal epithelium, angle recess, and anterior corneal endothelium is an obvious disadvantage because of the potential e15
iris surface. for corneal decompensation and/or pseudophakic bullous keratopathy as a
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result of contact of the cornea with the IOL. In the past, the most common
5 causes of pseudophakic bullous keratopathy were related to anterior

chamber IOLs that were sized incorrectly, vaulted too steeply, or designed
with an inappropriate amount of flexibility.20
Haptics or spatula-like footplates are one of the two types of fixation
The Lens
elements used for anterior chamber IOLs. Haptics or footplates, popular-

ized by Peter Choyce, are often likened to the flattened portion of a spatula
and were used originally with the more rigid IOL styles. They now are
used with both rigid and flexible modern anterior chamber IOLs. When
IOL removal is necessary for any reason, the footplate generally slides out
of the eye much more easily than does a small-diameter loop and does so
with minimal tissue damage.
Small-diameter lens loops are the second type of fixation element
for anterior chamber IOLs. Loops may be of either an open or a closed
design. Round, small-diameter, closed loops may cause a “cheese-cutter”
effect within the eye and difficulty in removal. A 360° fibrouveal encapsu-
lation, or “cocoon,” often forms around such small-diameter, round loops
as the loops become embedded in the tissues of the angle recess. If the
correct explantation procedure is not used, these adhesions may result in
tissue tears, hemorrhage, and iridocyclodialysis. These anterior chamber A
IOLs,21–25 often generically classified together as “closed-loop lenses,” do
not provide the safety and efficacy achieved by other anterior chamber lens
designs, such as finely polished, flexible, one-piece, all-PMMA lenses (see
Fig. 5.2.4). By 1987 the U.S. Food and Drug Administration had placed
IOLs of the closed-loop design on core investigational status. This had the
effect of removing them from the market in the United States, although it
did not prevent the export of such lenses.
The flexible, open-loop designs,24–28 modifications of the original Kelman
anterior chamber IOLs (with Choyce-style footplates), can be well fin-
ished using tumble polishing, which provides a rounded, “tissue-friendly”
surface at points of haptic contact with delicate uveal tissues. One-piece
IOLs, particularly those with a footplate design, are usually much easier to
explant than IOLs with round, small-diameter loops of either closed-loop
or open-loop design.
Iris- or scleral-fixated, sutured posterior chamber IOLs may be used in
cases formerly reserved for anterior chamber IOLs. Results are encourag-
ing.29,30 Uncertainty still exists as to whether a retropupillary lens is supe-
rior to a modern, well-manufactured, Kelman-style anterior chamber IOL
for cases such as intraoperative capsular rupture or vitreous loss or as a
secondary or exchange procedure. The technique is more difficult than
insertion of a single anterior chamber lens, and therefore it should be B
carried out only by an experienced surgeon.
Fig. 5.2.5 View From Behind an Autopsy Eye. (A) A Sinskey-style, J-loop posterior
Generation V (Improved Posterior chamber intraocular lens implanted within the lens capsular bag. The optic is well
centered, the visual axis is clear, and there is only minimal regeneration of cortex in
Chamber Lenses) scattered areas. Moderate haziness or opacity occurs at the margins of the anterior
The return to Ridley’s4–7 original concept of IOL implantation in the pos- capsulotomy, which does not encroach on the visual axis. (B) The placement of the
loop of this modified C-style intraocular lens in the capsular bag.
terior chamber occurred after 1975. Pearce31 of England implanted the first
uniplanar posterior chamber lens since Ridley.32 This lens was a rigid tripod
design with the two inferior feet implanted in the capsular bag and the The return to posterior chamber lenses coincided with the development
superior foot implanted in front of the anterior capsule and sutured to the of improved ECCE surgery. Shearing33 identified four major milestones
iris. Shearing33 of Las Vegas introduced a major lens design breakthrough that have marked the evolution of ECCE surgery:
in early 1977 with his posterior chamber lens. The design consisted of an
optic with two flexible, J-shaped loops. Simcoe of Tulsa publicly introduced
• Microscopic surgical techniques.
his C-looped posterior chamber lens shortly after Shearing’s J-loop design
• Phacoemulsification (phaco).
appeared. Arnott of London was an early advocate of one-piece, all-PMMA
• Iridocapsular fixation.
posterior chamber IOLs. The flexible open-loop designs (J-loop, modified
• Flexible posterior chamber lenses.
J-loop, C-loop, or modified C-loop) still account for the largest number of Without microscopic surgery, modern IOL implantation would be far
IOL styles available today (Fig. 5.2.5). more difficult. Although phaco was promoted originally because it required
One obvious major theoretical advantage that a posterior chamber IOL only a small wound, it became clear that if an IOL were to be inserted,
has over an anterior chamber IOL is its position behind the iris, away from the wound would have to be enlarged after removal of the cataract, and
the delicate structures of the anterior segment. thus nonultrasonic surgical methods were refined. By 1974, implantation
As posterior chamber lens implantation evolved, the type of fixation of IOLs again began to achieve significant acceptability. A natural marriage
achieved in the early years depended largely on chance or on the sur- between phaco and implantation of IOLs occurred.
geon’s individual preference. As Fig. 5.2.6 illustrates, several loop-fixation As noted previously, Binkhorst11,12,17 was one of the pioneers in the
sites are possible with modern, flexible-loop posterior chamber IOLs. In return to the ECCE procedure. Binkhorst recognized that an intact pos-
general, the loops were anchored in one of three ways: terior capsule enhanced stability, and he also recognized the many advan-
tages of IOL implantation within the capsular sac. Evidence continues to
• Both loops were placed in the ciliary region.
accumulate that CME and retinal detachment occur less frequently with
• Both loops were placed within the lens capsular sac.
ECCE than with ICCE.
• One loop (usually the leading or inferior loop) was placed in the cap-
The introduction of flexible posterior chamber lenses designed to be
sular sac and the other loop (usually the trailing or superior loop) in a
implanted following ECCE largely resolved the debate about ECCE versus
variety of locations anterior to the anterior capsular flap.
ICCE clearly in favor of the extracapsular procedure.
e16 These fixation sites have been confirmed histologically by analyses of Securing both loops in the lens capsular sac is the only type of fixation
postmortem globes implanted with posterior chamber IOLs. in which IOL contact with uveal tissues is avoided.34 Placement of a lens
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POSSIBLE PLACEMENT SITES OF POSTERIOR CHAMBER LENS LOOPS
5.2

3 2
1
5
4
6
7
8
Site 1: loop in the ciliary sulcus.
Site 2: loop after erosion into the ciliary body stroma in the region of the major iris Fig. 5.2.7 Surgeon’s View (Cornea and Iris Removed) of a Porcine Eye Showing
arterial circle. the Capsulorrhexis Procedure. Notice the smooth edges of the anterior capsular
Site 3: loop in contact with the iris root. tear, which is the key feature of this procedure.
Site 4: loop attached to a ciliary process.
Site 5: loop in aqueous without tissue contact (can result in "windshield wiper" syndrome
because of inadequate fixation). posterior capsule firmly against the posterior surface of the IOL optic. This
Site 6: loop in the lens capsular sac. is sometimes termed the “no space, no cells” concept.
Site 7: loop ruptured through the lens capsular sac (a rare occurrence). The quality of surgery and the accuracy of loop placement are important
Site 8: loop in the zonular region between the ciliary sulcus and the lens capsular sac. factors that affect the outcome of the cataract operation. Two very helpful
The loop may penetrate the zonules (zonular fixation) or extend as far posteriorly tools are available to surgeons that make precise loop or haptic placement
as the pars plana (pars plana fixation). possible:
• Ophthalmic viscosurgical devices (OVDs).
Fig. 5.2.6 The Possible Placement Sites of Posterior Chamber Lens Loops. • New methods to control the size, shape, and quality of the anterior
capsulotomy.
• The intercapsular (envelope) technique and its successor, circular con-
BOX 5.2.2 Advantages of Placing Both Loops in the Lens tinuous tear capsulorrhexis, greatly increase the ability to achieve accu-
Capsular Sac rate and permanent loop placement.
Intraocular lens is positioned in the proper anatomical site Generation VI (Modern Capsular
Both loops can be placed symmetrically in the capsular sac as easily as in
the ciliary sulcus Lenses—Rigid PMMA, Soft Foldable,
Intraoperative stretching or tearing of zonules by loop manipulations in and Modern Anterior Chamber)
front of the anterior capsular leaflet is avoided
Low incidence of lens decentration and dislocation
By the end of the 1980s, clinical laboratory studies demonstrated clearly
No evidence of spontaneous loop dislocation
that cataract surgical techniques and IOL design and manufacture had
Intraocular lens is positioned a maximal distance behind the cornea
shown remarkable advances.36–40 Surgical technique and IOL design and
Intraocular lens is positioned a maximal distance from the posterior iris
manufacture had advanced to a point at which the older techniques had
pigment epithelium, iris root, and ciliary processes
given way to more modern ones, which allowed consistent, secure, and
Iris chafing (caused by postoperative pigment dispersion into the anterior
permanent in-the-bag (capsular) fixation of the pseudophakos. A marriage
chamber) is reduced
between IOL design and improved surgical techniques has evolved into
No direct contact by, or erosion of, intraocular lens loops or haptics into
capsular surgery. The “capsular” IOLs are fabricated from both rigid and
ciliary body tissues
soft biomaterials.
Chronic uveal tissue chafing is avoided, and the probability of long-term
The many changes in surgical techniques that occurred after 1980 and
blood–aqueous barrier breakdown is reduced
into the 1990s include the introduction of OVDs,40–43 increased awareness
Surface alteration of loop material is less likely
of the advantages of in-the-bag fixation, the introduction of continuous
Intraocular lens implantation is safer for children and young individuals
curvilinear capsulorrhexis (CCC)44–51 (Fig. 5.2.7), hydrodissection52 (Fig.
Posterior capsular opacification may be reduced
5.2.8), and the increased use of phaco. This has allowed not only much
Intraocular lens may be easier to explant, if necessary
safer surgery but also implantation through a smaller incision than was
possible in the early days of extracapsular extraction.
The evolution from can-opener toward capsulorrhexis (see Fig. 5.2.7)
was initiated by Binkhorst, who developed a two-step (envelope) technique
with one or both loops outside the capsular bag is associated with various that eventually evolved into the single-step CCC. Two clear advantages of
potential complications, including decentration and uveal erosion.34,35 The CCC exist over the early can-opener techniques.
consequences of uveal touch have been learned after experiences with the First, the formation of radial tears (Fig. 5.2.9) is reduced,47 which mini-
earlier iris-fixated IOLs. The excellent success rate now achieved with pos- mizes radial tears of the anterior capsule, which in turn reduce the stability
terior chamber IOL implantation is associated with improved IOL designs of the capsular bag and may allow prolapse of haptics out of the capsular
and improved surgical techniques, including the meticulous placement of bag through the anterior capsular tear. Second, and less commonly recog-
loops (Box 5.2.2). nized, capsulorrhexis provides a stable capsular bag that allows copious
Posterior capsule opacification (PCO; Elschnig pearls, secondary or after hydrodissection, which in turn is very helpful in cortical cleanup. With a
cataract) is a significant postoperative complication in IOL implantation. frayed, emptier capsular edge, such as seen with the can-opener technique,
A well-designed posterior chamber lens in the lens capsular sac provides hydrodissection is difficult without forming unwanted radial tears.
a gentle but taut radial stretch on the posterior capsule. Of the present Hydrodissection (see Fig. 5.2.8) was a term coined by Faust52 in 1984.
open-loop flexible IOLs, the one-piece, all-PMMA posterior chamber This technique, and the many variations thereof (e.g., cortical cleavage
designs with posterior convex or biconvex optics appear to be especially hydrodissection, hydrodelineation), makes the surgery much simpler in
effective in providing a symmetrical stretch. Symmetrical stretch may help that mobilization and removal of cells and cortical material are rendered e17
minimize PCO, as it reduces the folds in the capsular sac and holds the much easier. The long-term risk of PCO is, in turn, clearly minimized
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5
The Lens
Fig. 5.2.8 Surgeon’s View (Cornea and Iris Removed) of a Human Eye (Obtained
Postmortem) Showing Experimental Hydrodissection. In this case the cannula is Fig. 5.2.10 A Modern, One-Piece, All-PMMA, Capsular IOL Implanted
placed immediately under the anterior capsule (cortical cleavage hydrodissection). Experimentally in a Human Eye: Posterior View (Miyake Technique) of the Eye
Hydrodissection is one of the most important maneuvers to help reduce the (Obtained Postmortem). Note the excellent centration and a perfect fit within the
incidence of posterior capsular opacification. capsular bag.
Fig. 5.2.9 Surgeon’s View of an Experimentally Performed Can-Opener

Capsulectomy, With Typical Radial Tears to the Equator of the Anterior Fig. 5.2.11 Scanning Electron Micrograph of a Well-Designed, Tumble-Polished,
Capsule. The cornea and iris are removed from a human eye obtained postmortem. Modified C-Loop, One-Piece, All-PMMA Posterior Chamber Iol. The total length
Following clinical can-opener anterior capsulectomy, one to five radial tears of this capsular IOL design is 12.0 mm. Note the excellent, smooth finish of this well-
invariably occur. (Reproduced with permission from Assia EI, Apple DJ, Tsai JC, polished IOL. (Original magnification ×10.)
et al. The elastic properties of the lens capsule in capsulorrhexis. Am J Ophthalmol
1991;111:628–32.)
capsular bag (which measures about 10.5 mm in diameter). The diameter

of the ciliary sulcus is only slightly larger (approximately 11.0 mm)53 and
because of the more thorough removal of cells in cortical material, espe- actually decreases with age.
cially in the region of the equatorial fornix. These rigid PMMA IOL designs have been found to be very satisfactory
Modern phaco, pioneered by Kelman, has now made possible the in pediatric IOL implantation.54,55 As 90% of the growth of the infantile
removal of lens material through small incisions and the implantation of globe occurs during the first 18 months to 2 years (Fig. 5.2.12), it is fair
IOLs through incisions down to 3 mm in length, as opposed to incisions to assume that “adult” 12 mm lenses can be safely implanted with the
of 11 to 12 mm length in the early days of ECCE. Many real advantages of achievement of good results in children of this age and older (Figs. 5.2.12
small-incision cataract surgery exist, including safer healing (with fewer and 5.2.13). The problem in the past with IOL implantation has been that
risks of complications such as inflammation), more rapid healing, and of PCO. With present techniques, this is best prevented using primary pos-
rapid recovery of visual rehabilitation (with less postoperative astigmatism). terior capsulectomy.
Accompanying the developments of surgical techniques that allow Improved small-incision surgical techniques and IOL designs have
secure in-the-bag implantation, IOLs have evolved that work well with resulted in a natural evolution toward foldable lenses.56–67 Most foldable
these techniques—both rigid PMMA designs (Figs. 5.2.10 and 5.2.11) and lenses today are manufactured from silicone, hydrogel, or acrylic material
foldable IOLs.53 Fig. 5.2.10 shows an example of a modern, state-of-the-art, (Figs. 5.2.14–5.2.16).
one-piece, all-PMMA IOL that is designed for in-the-bag implantation. The earliest designs for which clinical usage was widespread were the
These can be inserted through incisions as small as 5.5–6 mm in length plate lenses known as the “Mazzocco taco.” In early years these were man-
and provide an excellent alternative for the surgeon who finds the almost ufactured poorly and often not implanted properly into the capsular bag,
50-year history of PMMA as a lens biomaterial of comfort. Long-term so many complications ensued. In recent years manufacturing quality
results with these IOLs are excellent and, indeed, these lenses provide has become much better, and these lenses are now satisfactory for clin-
slightly better centration than do some of the more modern foldable lenses ical usage (Figs. 5.2.17 and 5.2.18). The best plate lenses are those with
e18 at the present time. The ideal diameter for a one-piece IOL design such as large positioning holes that allow in-the-bag synechia formation, which
that in Fig. 5.2.10 is 12–12.5 mm, which allows it to fit perfectly into the enhances fixation and stability.64
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GROWTH OF GLOBE AND LENS CAPSULAR BAG
5.2

evacuated 11
capsular bag
diameter (mm) 10
6
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
age (years)
16–19 22 23 24
anterior–posterior axial length of globe (mm)
Fig. 5.2.15 Posterior View (Miyake Technique) of a Well-Implanted Alcon Acrysof
Acrylic IOL. The lens is well centered in the capsular bag after thorough cortical
Fig. 5.2.12 Growth of the Globe and Lens Capsular Bag. These results are based
removal.
on a study of 50 eyes obtained postmortem and demonstrate that the growth of
the globe and lens capsular bag occurs relatively rapidly during the first 18 months
to 2 years. (Reproduced with permission from Wilson ME, Apple DJ, Bluestein EC,
et al. Intraocular lenses for pediatric implantation: biomaterials, designs, and sizing. J
Fig. 5.2.16 A Staar Surgical Corporation Three-Piece IOL With Polyimide

Fig. 5.2.13 Posterior View (Miyake Technique) of an Eye of a 2-Year-Old Child Haptics: Posterior View (Miyake Technique) of an Eye (Obtained Postmortem).
(Obtained Postmortem). This was implanted experimentally with a 12 mm, one- The lens is well centered and positioned in a clean capsular bag.
piece, all-PMMA IOL in the capsular bag. Note the excellent fit in the capsular
bag. (Reproduced with permission from Wilson ME, Apple DJ, Bluestein EC, et al.
Intraocular lenses for pediatric implantation: biomaterials, designs, and sizing. J
Fig. 5.2.14 Posterior View (Miyake Technique) of a Well-Implanted Advanced Fig. 5.2.17 Scanning Electron Micrograph That Shows the Marked Improvement
Medical Optics Three-Piece, Silicone IOL. The lens is implanted following excellent in Plate Lens Manufacture by the 1990S. Note the excellent overall design and e19
cortical cleanup in a human eye obtained postmortem. manufacture finish. (Original magnification ×10.)
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Fig. 5.2.19 View
5 of a Patient Who
Has Silicone
IOL and Who
Later Required
The Lens
Vitreoretinal
Surgery With
Silicone Oil. Note
the dense bubbles
that cover the
optic surface,
impairing both
vision and the
surgeon’s view into
the eye.
Fig. 5.2.18 A Well-Implanted Staar-Chiron–Style Silicone Plate IOL, With

Excellent Cortical Removal and Centration. Posterior view (Miyake technique) of
the eye (obtained postmortem).
A B
Fig. 5.2.20 Gross and Light Microscopic Photographs of a Pseudophakic Human Eye Obtained Postmortem, Implanted With a Silicone Plate Lens With Large
Fenestrations. (A) Miyake–Apple posterior photographic technique. The arrow indicates the fibrotic tissue growing through one of the large fenestrations. (B) Fusion
between anterior and posterior capsules promoted by the fibrocellular tissue growing through the fenestration (Masson’s trichrome; original magnification ×100). PC,
Posterior capsule. (Reproduced from Apple DJ, Auffarth GU, Peng Q, et al. Foldable intraocular lenses: evolution, clinicopathologic correlations, complications. Thorofare, NJ:
Slack; 2000.)
The most commonly implanted designs at present are three-piece vitreoretinal surgery using silicone oil.68 Work is underway to address this
lenses that consist of silicone, acrylic, or hydrogel optics. Plate lenses con- complication by modifications of the biomaterial to change factors such as
tinue to provide excellent results. These lenses can be implanted through its surface characteristics.69 Work is in progress also on the attachment of
incisions smaller than 5 mm in length. Visual rehabilitation is now incred- different styles of haptic materials to the optic to achieve better and more
ibly fast with various further modifications, such as clear corneal incisions stable fixation of the haptics in the capsular bag.
and topical anesthesia. Such surgery is virtually analogous to arthroscopy Note that the various ultramodern designs of anterior chamber lenses
of the eye. developed for both aphakic and phakic implantations are considered
Lens design and manufacture have improved to such an extent that to belong to generation VI. These include the various Kelman–Choyce
perhaps the most important factor in achieving a successful result is not designs and modifications by Baikoff and Clemente (see Fig. 5.2.4). These
the IOL itself, but the quality of surgery. These factors are very import- are categorized here to separate them from the many generally inferior
ant now that high standards exist for results following IOL implantation, anterior chamber IOLs that were available in the earlier intermediate
especially in this era, when IOL implantation is considered not only a period between 1963 and 1990 (generation IV). The ultramodern designs
means of optical rehabilitation after cataract removal but also a bona fide are suitable for specific clinical indications and clearly should not be
refractive procedure. The development of bi- and multifocal IOL designs included in the generic concept that all anterior chamber IOLs are bad.
is one example of this evolutionary process. An increased interest in clear
lens extraction for myopia and the use of phakic IOLs also exemplifies
the evolution toward refractive IOLs. It is of utmost importance to achieve
RECENT ADVANCES
symmetrical capsular bag fixation and good cortical cleanup to minimize There are some general principles and tendencies with regard to the devel-
the chance of complications, such as lens decentration and formation of a opment of new IOLs.
Soemmerring’s ring.
The development of foldable lenses is one of fine-tuning. For example, • Large fixation holes or foramina have been incorporated in the haptic
much effort is now being expended to develop ever more tissue-friendly components of one-piece plate designs (Fig. 5.2.20A). Fibrous adhe-
e20 optic biomaterials. Fig. 5.2.19 reveals a complication that may occur occasions often occur between the anterior and posterior capsules following
sionally in patients who have silicone lenses and who require subsequent ingrowth of fibrocellular tissue through the holes (Fig. 5.2.20B). This
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5.2

A B
Fig. 5.2.21 Light Photomicrograph and Schematic Illustration Showing the Barrier Effect of an IOL Optic With a Square Truncated Edge. (A) Photomicrograph of
a case in which the Soemmerring’s ring (red) remains totally confined to the right of the square optic edge, leaving the posterior capsule (lower left) cell free (Masson’s
trichrome; original magnification ×50). (B) Square truncated optic edge seems to provide an abrupt barrier (arrows), leaving the entire optical zone free of cells. AC, Anterior
capsule; PC, posterior capsule. (A, Reproduced from Werner L, Apple DJ, Pandey SK. Postoperative proliferation on anterior and equatorial lens epithelial cells. In: Buratto L,
Werner L, Zanini M, et al., editors. Phacoemulsification: principles and techniques. Thorofare, NJ: Slack; 2002. p. 603–23. B, Reproduced from Peng Q, Visessook N, Apple DJ,
et al. Surgical prevention of posterior capsule opacification. Part III. Intraocular lens optic barrier effect as a second line of defense. J Cataract Refract Surg 2000;26:198–213.)
A B
Fig. 5.2.22 Gross and Light Microscopy Photographs of the First Human Eye Obtained Postmortem With a Single-Piece Acrysof Lens (Alcon Laboratories, Fort
Worth, TX) Accessioned in Our Center. (A) The lens is well centered and the capsular bag is clear. (B) Light photomicrograph of a histological section from the same eye.
The arrow indicates the imprint of the square edge of the lens optic on the capsular bag, causing a barrier effect that prevented retained/regenerative cortical material from
the Soemmerring’s ring to migrate onto the posterior capsule, opacifying the visual axis (Masson’s trichrome; original magnification ×400). (Reproduced from Escobar-Gomez
M, Apple DJ, Vargas LG, et al. Scanning electron microscopic and histologic evaluation of the AcrySof SA30AL acrylic intraocular lens. J Cataract Refract Surg 2003;29:164–9.)
helps enhance the fixation and stability of these designs within the cap- characteristic—demonstrated an enhanced barrier effect against cell
sular bag.70 It is important to note that this fibrous growth requires at migration/proliferation on the posterior capsule toward the visual axis
least 2 weeks and often much more to establish itself and help anchor (Fig. 5.2.21).72,73
the IOL. This design feature has been incorporated into lenses manu- • Manufacturers have invested heavily and with great success in
factured from silicone (including the Staar toric IOL), hydrogel (hydro- single-piece designs, all fabricated from the same material as the optic
philic acrylic IOLs), and Collamer (Staar CC4203VF) materials. component. The Alcon (SA30AL and SA60AT) AcrySof IOL is a hydro-
• For three-piece foldable designs, the preferred haptic materials are the phobic single-piece acrylic design that has provided excellent results
relatively rigid materials with good material memory, such as PMMA, (Fig. 5.2.22). Other looped single-piece designs are now available, with
polyimide (Elastimide), or poly(vinylidene) fluoride (PVDF).71 These modifications at the level of the optic–haptic junctions to obtain a non-
haptics have appropriate memory characteristics that help enhance lens smooth transition between these components. This was done because
centration and stability and provide better resistance to postoperative some studies demonstrated that smooth optic–haptic junctions may be
contraction forces within the capsular bag. sites for PCO initiation.74
• One of the most important features that has been incorporated in new • Manufacturers also are investing in the development of injector systems
foldable lenses in terms of decreasing the incidence of PCO is the to be used with the new lens designs. Other recent advances are rep-
square, truncated optic edge. Various experimental animal studies by resented by the development of injector systems where the IOLs come
Nishi in Japan, analyses of human autopsy globes in our laboratory, preloaded and by automated injection systems.
and several clinical studies with the three-piece AcrySof lens (MA30BA • Perhaps the most energy and funding are being spent on new and e21
and MA60BM)—the first design identified with this geometric complex IOLs that not only restore the refractive power of the eye after
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5
The Lens
A B
Fig. 5.2.23 Special Intraocular Lenses. (A) Gross photograph of a toric lens (AA-4203TF or AA-4203TL Staar Surgical, Inc.) This lens has basically the same design as
single-piece, plate silicone posterior chamber lenses with large fenestrations but with an incorporated cylindrical correction. (B) Schematic drawing representing an
accommodative lens, the Crystalens, manufactured by Bausch & Lomb (Rochester, NY). This is essentially a plate haptic lens with Elastimide haptics. It is stated that
redistribution of the ciliary body mass during effort for accommodation will result in increased vitreous pressure, which will move the optic of this lens anteriorly within
the visual axis, creating a more plus powered lens. (C) Schematic drawing representing the implantable miniaturized telescope (IMT) (VisionCare Ophthalmic Technologies
Inc., Yehud, Israel). This is designed specifically to improve vision of patients suffering from age-related macular degeneration. The IMT is composed of two parts, an optical
cylinder and a carrying device. The optic cylinder is made of pure glass. The carrying device is made of black PMMA. The latter has a general configuration of a posterior
chamber intraocular lens, with two modified C-loops or haptics that hold the device in the capsular bag. Once in place, the anterior part of the optic extends anteriorly for
approximately 1 mm through the pupil. It is designed to be stabilized approximately 2 mm posterior to the corneal endothelium. (A–C, Reproduced from Werner L, Apple DJ,
Schmidbauer JM. Ideal IOL (PMMA and Foldable) for year 2002. In: Buratto L, Werner L, Zanini M, et al., editors. Phacoemulsification: principles and techniques. Thorofare, NJ:
Slack; 2002. p. 435–52.)
cataract surgery but also provide special features, including multifocal- • The renewed interest in phakic IOLs, which we now realize can poten-
ity, extended depth of focus, toric corrections (Fig. 5.2.23A), pseudoac- tially correct any refractive error, is also progressing rapidly.78 It is some-
commodation (Fig. 5.2.23B), asphericity, postoperative adjustment of what ironic that anterior chamber IOLs, previously relegated by many
the IOL refractive power, image magnification (telescopic lenses) (Fig. surgeons to a wastebasket of discarded devices, have been resurrected
5.2.23C), protection of the retina against blue or violet light (through and researched as a possible lens of choice for refractive correction.
incorporation of appropriate chromophores to the IOL optic material), Most of the angle-supported anterior chamber phakic IOLs, however,
or those that can be inserted through sub 2.0 mm incisions.75 have been abandoned from the market due to issues with the corneal
endothelium.79 Lenses designed for iris fixation and placement in the
Itemization of these IOL designs is not yet useful because proof of
posterior chamber are also available, with good results to date. There is
safety and efficacy is still in great flux. With any IOL, the issue of biocom-
a trend for the use of foldable materials for these phakic lenses, which
patibility must be assessed. Not only do surgeons today seem to be seeking
are designed to be inserted through small incisions (Fig. 5.2.24).
IOLs that are easy to insert/inject through small incisions—perhaps the
main factor influencing manufacturers’ IOL development—but also more
• There is a renewed interest in the piggyback IOL procedure, not only
for correction of residual refractive errors but also because of the poten-
attention is being paid to the interaction of each IOL design within the
tial to implant a low-power multifocal lens to provide spectacle freedom
surrounding capsular bag. Issues such as postoperative cell proliferation
to patients who already are pseudophakic, and other specialized lenses
within the capsular bag—including PCO, anterior capsule opacification
such as toric and aspherical IOLs. In these cases, the supplementary
(ACO), and interlenticular opacification (ILO) with piggyback IOLs—are
lens is fixated in the ciliary sulcus to avoid ILO formation. A supple-
used as one indication of lens biocompatibility.76,77 This goes far beyond
mentary IOL for implantation in the sulcus ideally should be manufac-
the normal postoperative inflammatory reaction observed after cataract
tured from a soft, biocompatible material, with a relatively large optic
surgery with IOL implantation. Different studies from our laboratory
and overall diameters, as well as round and smooth optic and haptic
demonstrated that the choice of IOL design and material can largely influ-
edges. Also, the design configuration should provide appropriate clear-
ence the outcome of these complications, but the role of surgical tech-
ance with uveal tissues and the in-the-bag IOL (Fig. 5.2.25).80
niques should not be underestimated. Last but not least, a “perfect” IOL
e22 would not be effective in preventing excess cell proliferation within the Although a large spectrum of lenses is available today, the IOL of choice
capsular bag after bad surgery. still depends on a surgeon’s personal preference based on multiple factors
booksmedicos.org
5.2

A
Fig. 5.2.25 Pseudophakic Human Eye Obtained Postmortem, Experimentally

Implanted With the Sulcoflex (Rayner Intraocular Lenses, East Sussex, UK)
Supplementary IOL. The capsular bag containing a standard posterior chamber
IOL was removed for gross analysis of the positioning of the Sulcoflex haptics from
the posterior or Miyake–Apple view. No disturbances/distortions to the ciliary
processes were observed. This lens was designed by Amon in Austria. It is a single-
piece, hydrophilic acrylic lens with an optic diameter of 6.5 mm and an overall
diameter of 14.0 mm. The optic has round and smooth edges and a convex–concave
B configuration. The large-diameter undulating haptics are soft with round and
smooth edges and a posterior angulation of 10° in relation to the optic.
personalized to each individual, largely influenced by different features

unique to each patient, such as the patient’s history and clinical status, but
also by the occurrence of intraoperative complications.
KEY REFERENCES
Apple DJ, Kincaid MC, Mamalis N, et al. Intraocular lenses: evolution, designs, complica-
tions, and pathology. Baltimore: Williams & Wilkins; 1989.
Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses: a historical and
Apple DJ, Peng Q, Visessook N, et al. Surgical prevention of posterior capsule opacification.
Part I. Progress in eliminating this complication of cataract surgery. J Cataract Refract
Surg 2000;26:180–7.
C Apple DJ, Werner L. Complications of cataract and refractive surgery: a clinicopathological
documentation. Trans Am Ophthalmol Soc 2001;99:95–107, discussion 107–9.
Fig. 5.2.24 Drawing (A) and Clinical (B) and Gross (C) Photographs Showing Güell JL, Morral M, Kook D, et al. Phakic intraocular lenses part 1: historical overview,
current models, selection criteria, and surgical techniques. J Cataract Refract Surg
Different Types of Phakic Lenses. (A) Cachet lens (Alcon Laboratories, Fort Worth, 2010;36(11):1976–93.
TX, USA). It has a 4-haptic, angle-supported configuration, manufactured from Izak AM, Werner L, Apple DJ, et al. Loop memory of different haptic materials used in
the same hydrophobic acrylic material as posterior chamber AcrySof lenses. the manufacture of posterior chamber intraocular lenses. J Cataract Refract Surg
(B) Artisan lens (Ophtec, Groningen, the Netherlands). This is a one-piece, iris- 2002;28:1229–35.
fixated lens manufactured from PMMA. Artisan haptics (fixation arms) attach to the McIntyre JS, Werner L, Fuller SR, et al. Assessment of a single-piece hydrophilic acrylic
midperipheral, virtually immobile iris stroma, thus allowing relatively unrestricted IOL for piggyback sulcus fixation in pseudophakic cadaver eyes. J Cataract Refract Surg
2012;38(1):155–62.
dilation and constriction of the pupil. Lenses with incorporated cylindrical correction
Ness PJ, Werner L, Maddula S, et al. Pathology of 219 human cadaver eyes with 1-piece or
and a foldable version (silicone optic) are also available. (C) Implantable contact lens 3-piece hydrophobic acrylic intraocular lenses: capsular bag opacification and sites of
(ICL) (Staar Surgical). This is a one-piece plate lens manufactured from a proprietary square-edged barrier breach. J Cataract Refract Surg 2011;37:923–30.
hydrophilic collagen polymer known as Collamer. It can be inserted or injected into Nishi O, Nishi K, Wickstrom K. Preventing lens epithelial cell migration using intraocular
the anterior chamber, then the haptics are placed behind the iris with the help of a lenses with sharp rectangular edges. J Cataract Refract Surg 2000;26:1543–9.
spatula. (A, Courtesy Alcon Laboratories. B and C, Reproduced from Werner L, Apple Werner L. Biocompatibility of intraocular lens materials. Curr Opin Ophthalmol 2008;19:41–9.
DJ, Izak AM. Phakic intraocular lenses: current trends and complications. In: Buratto Werner L, Olson RJ, Mamalis N. New technology IOL optics. Ophthalmol Clin North Am
2006;19(4):469–83.
L, Werner L, Zanini M, et al., editors. Phacoemulsification: principles and techniques. Whiteside SB, Apple DJ, Peng Q, et al. Fixation elements on plate intraocular lens: large posi-
Thorofare, NJ: Slack; 2002. p. 759–77.) tioning holes to improve security of capsular fixation. Ophthalmology 1998;105:837–42.
REFERENCES
1. Apple DJ, Ram J, Wang XH, et al. Cataract surgery in the developing world. Saudi J e23
Ophthalmol 1995;9(1):2–15.
booksmedicos.org
2. Isaacs R, Ram J, Apple DJ. Cataract blindness in the developing world: is there a solu- 43. Madsen K, Stenevi U, Apple DJ, et al. Histochemical and receptor binding studies of
5 tion? J Agromed 1996;3(4):7–21.

3. Kador PF. Overview of the current attempts toward the medical treatment of cataract.
4. Ridley H. Intra-ocular acrylic lenses. Trans Ophthalmol Soc UK 1951;71:617–21.
hyaluronic acid and hyaluronic acid binding sites on corneal endothelium. Ophthalmic
Pract 1989;7(3):1–8.
44. Neuhann T. Theorie und operationstechnik des kapsulorhexis. Klin Monatsbl Augen-
heilkd 1987;190:542–5.
5. Ridley H. Artificial intra-ocular lenses after cataract extraction. St Thomas Hosp Rep 45. Gimbel H, Neuhann T. Development, advantages and methods of continuous circular
The Lens
1952;7(2):12–14. capsulorrhexis techniques. J Cataract Refract Surg 1990;16:31–7.

6. Apple DJ, Sims J. Harold Ridley and the invention of the intraocular lens. Surv Ophthal- 46. Assia EI, Apple DJ, Tsai JC, et al. The elastic properties of the lens capsule in capsulor-
mol 1995;40:279–92. rhexis. Am J Ophthalmol 1991;111:628–32.
7. Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses: a historical 47. Assia EI, Apple DJ, Tsai JC, et al. An experimental study comparing various anterior
and histopathological review. Surv Ophthalmol 1984;29:1–54. capsulectomy techniques. Arch Ophthalmol 1991;109:642–7.
8. Apple DJ, Mamalis N, Brady SE, et al. Biocompatibility of implant materials: a review 48. Assia EI, Apple DJ, Tsai JC, et al. Mechanism of radial tear formation and extension after
and scanning electron microscopic study. J Am Intraocul Implant Soc 1984;10:53–66. anterior capsulectomy. Ophthalmology 1991;98:432–7.
9. Apple DJ, Rabb MF. Ocular pathology: clinical applications and self-assessment. 5th ed. 49. Wasserman D, Apple DJ, Castaneda VE, et al. Anterior capsular tears and loop fixation of
St Louis: CV Mosby; 1998. posterior chamber intraocular lenses. Ophthalmology 1991;98:425–31.
10. Apple DJ, Kincaid MC, Mamalis N, et al. Intraocular lenses: evolution, designs, compli- 50. Assia EI, Legler UFC, Castaneda VE, et al. Clinicopathologic study of the effect of radial
cations, and pathology. Baltimore: Williams & Wilkins; 1989. tears and loop fixation on intraocular lens decentration. Ophthalmology 1993;100:153–8.
11. Binkhorst CD. Lens implants (pseudophakoi) classified according to method of fixation. 51. Auffarth GU, Wesendahl TA, Newland TJ, et al. Capsulorrhexis in the rabbit eye as a
Br J Ophthalmol 1967;51:772–4. model for pediatric capsulectomy. J Cataract Refract Surg 1994;20:188–91.
12. Binkhorst CD. About lens implantation. 2. Lens design and classification of lenses. 52. Faust KJ. Hydrodissection of soft nuclei. J Am Intraocul Implant Soc 1984;10(1):75–7.
Implant 1985;3:11–14. 53. Ohmi S, Uenoyama K, Apple DJ. Implantation of IOLs with different diameters. Nippon
13. Ellingson FT. The uveitis-glaucoma-hyphema syndrome associated with the Mark VIII Ganka Gakkai Zasshi 1992;96:1093–8.
anterior chamber lens implant. J Am Intraocul Implant Soc 1978;4:50–3. 54. Wilson ME, Apple DJ, Bluestein EC, et al. Intraocular lenses for pediatric implantation:
14. Drews RC. The Barraquer experience with intraocular lenses: 20 years later. Ophthalmol- biomaterials, designs, and sizing. J Cataract Refract Surg 1994;20:584–91.
ogy 1982;89:386–93. 55. Wilson ME, Wang XH, Bluestein EC, et al. Comparison of mechanized anterior capsulec-
15. Drews RC. Intracapsular versus extracapsular cataract extraction. In: Wilensky JT, editor. tomy and manual continuous capsulorrhexis in pediatric eyes. J Cataract Refract Surg
Intraocular lenses. Transactions of the university of illinois symposium on intraocular 1994;20:602–6.
lenses. New York: Appleton-Century-Crofts; 1977. 56. Auffarth GU, Wilcox M, Sims JCR, et al. Analysis of 100 explanted one-piece and
16. Obstbaum SA, Galin MA. Cystoid macular edema and ocular inflammation: the corneo- three-piece silicone intraocular lenses. Ophthalmology 1995;102:1144–50.
retinal inflammatory syndrome. Trans Ophthalmol Soc UK 1979;99:187–91. 57. Auffarth GU, Wilcox M, Sims JCR, et al. Complications of silicone intraocular lenses. J
17. Binkhorst CD. The iridocapsular (two-loop) lens and the iris-clip (four-loop) lens in pseu- Cataract Refract Surg Special Issue: Best Papers of 1995 ASCRS Meeting. 1995;38–41.
dophakia. Trans Am Acad Ophthalmol Otolaryngol 1973;77:589–617. 58. Auffarth GU, McCabe C, Wilcox M, et al. Centration and fixation of silicone intraocu-
18. Choyce DP. The Mark VI, Mark VII and Mark VIII Choyce anterior chamber implants. lar lenses: an analysis of clinicopathological findings in human autopsy eyes. J Cataract
Proc R Soc Med 1965;58:729–31. Refract Surg 1996;22:1281–5.
19. Kelman CD. Anterior chamber lens design concepts. In: Rosen ES, Haining WM, Arnott 59. Buchen SY, Richards SC, Solomon KD, et al. Evaluation of the biocompatibility and
EJ, editors. Intraocular lens implantation. St Louis: CV Mosby; 1984. fixation of a new silicone intraocular lens in the feline model. J Cataract Refract Surg
20. Duffin RM, Olson RJ. Vaulting characteristics of flexible loop anterior chamber intraocu- 1989;15:545–53.
lar lenses. Arch Ophthalmol 1983;101:1429–33. 60. Menapace R. Evaluation of 35 consecutive SI-30 phacoflex lenses with high-refractive
21. Mamalis N, Apple DJ, Brady SE, et al. Pathological and scanning electron microscopic silicone optic implanted in the capsulorrhexis bag. J Cataract Refract Surg 1995;21:339–47.
evaluation of the 91Z intraocular lens. J Am Intraocul Implant Soc 1984;10:191–9. 61. Menapace R. English title: current state of implantation of flexible intraocular lenses [in
22. Reidy JJ, Apple DJ, Googe JM, et al. An analysis of semiflexible, closed–loop anterior German]. Fortschr Ophthalmol 1991;88:421–8.
chamber intraocular lenses. J Am Intraocul Implant Soc 1985;11:344–52. 62. Menapace R, Radax U, Amon M, et al. No-stitch, small incision cataract surgery with
23. Waring GO III. The 50-year epidemic of pseudophakic corneal edema. Arch Ophthalmol flexible intraocular lens implantation. J Cataract Refract Surg 1994;20:534–42.
1989;107:657–9. 63. Tsai JC, Castaneda VE, Apple DJ, et al. Scanning electron microscopic study of modern
24. Apple DJ, Brems RN, Park RB, et al. Anterior chamber lenses. I. Complications and silicone intraocular lenses. J Cataract Refract Surg 1992;18:232–5.
pathology and a review of designs. J Cataract Refract Surg 1987;13:157–74. 64. Apple DJ, Kent DG, Peng Q, et al. Verbesserung der befestigung von silikonschiffchen-
25. Apple DJ, Hansen SO, Richards SC, et al. Anterior chamber lenses. II. A laboratory linsen durch den gebrauch von positionierungslochern in der linsenhaptik, Proceedings
study. J Cataract Refract Surg 1987;13:175–89. of the 10th Annual Deutsche Gesellschaft fuer Intraokularlinsen Implantation Meeting,
26. Auffarth GU, Wesendahl TA, Apple DJ. Are there acceptable anterior chamber intraocu- Budapest, Hungary, March 1996.
lar lenses for clinical use in the 1990s? An analysis of 4104 explanted anterior chamber 65. Percival SP, Pai V. Heparin-modified lenses for eyes at risk for breakdown of the
intraocular lenses. Ophthalmology 1994;101:1913–22. blood-aqueous barrier during cataract surgery. J Cataract Refract Surg 1993;19:760–5.
27. Auffarth GU, Wesendahl TA, Brown SJ, et al. Update on complications of anterior 66. Apple DJ, Federman JL, Krolicki TJ, et al. Irreversible silicone oil adhesion to silicone
chamber intraocular lenses. J Cataract Refract Surg Special Issue: Best Papers of 1994 intraocular lenses. A clinicopathologic analysis. Ophthalmology 1996;103:1555–62.
ASCRS Meeting. 1994;70–6. 67. Apple DJ, Park SB, Merkley KH, et al. Posterior chamber intraocular lenses in a series of
28. Auffarth GU, Wesendahl TA, Brown SJ, et al. Update on complications of anterior 75 autopsy eyes. I. Loop location. J Cataract Refract Surg 1986;12:358–62.
chamber intraocular lenses. J Cataract Refract Surg 1995;22:1–7. 68. Apple DJ, Tetz M, Hunold W. Lokalisierte Endophthalmitis: Eine bisher nicht beschrie-
29. Apple DJ, Price FW, Gwin T, et al. Sutured retropupillary posterior chamber intraocular bene Komplikation der extrakapsuären Kataraktextraktion. In: Jacobic KW, Schott K,
lenses for exchange or secondary implantation (The Twelfth Annual Binkhorst Lecture, Gloor B, editors. I. Kongress der Deutschen Gesellschaft für Intraokularlinsen Implanta-
1988). Ophthalmology 1989;96:1241–7. tion (DGII), I. New York: Springer-Verlag; 1988.
30. Duffey RJ, Holland EJ, Agapitos PJ, et al. Anatomic study of transsclerally sutured intra- 69. Piest KL, Kincaid MC, Tetz MR, et al. Localized endophthalmitis: a newly described
ocular lens implantation. Am J Ophthalmol 1989;108:300–9. cause of the so-called toxic lens syndrome. J Cataract Refract Surg 1987;13:498–510.
31. Pearce JL. Experience with 194 posterior chamber lenses in 20 months. Trans Ophthal- 70. Whiteside SB, Apple DJ, Peng Q, et al. Fixation elements on plate intraocular lens:
mol Soc UK 1977;97:258–64. large positioning holes to improve security of capsular fixation. Ophthalmology
32. Drews RC. The Pearce tripod posterior chamber intraocular lens: an independent analy- 1998;105:837–42.
sis of Pearce’s results. J Am Intraocul Implant Soc 1980;6:259–62. 71. Izak AM, Werner L, Apple DJ, et al. Loop memory of different haptic materials used
33. Shearing SP. Evolution of the posterior chamber intraocular lenses. J Am Intraocul in the manufacture of posterior chamber intraocular lenses. J Cataract Refract Surg
Implant Soc 1984;10:343–6. 2002;28:1229–35.
34. Apple DJ, Reidy JJ, Googe JM, et al. A comparison of ciliary sulcus and capsular bag 72. Nishi O, Nishi K, Wickstrom K. Preventing lens epithelial cell migration using intraocu-
fixation of posterior chamber intraocular lenses. J Am Intraocul Implant Soc 1985;11: lar lenses with sharp rectangular edges. J Cataract Refract Surg 2000;26:1543–9.
44–63. 73. Apple DJ, Peng Q, Visessook N, et al. Surgical prevention of posterior capsule opacifi-
35. Miyake K, Asakura M, Kobayashi H. Effect of intraocular lens fixation on the cation. Part I. Progress in eliminating this complication of cataract surgery. J Cataract
blood-aqueous barrier. Am J Ophthalmol 1984;98:451–5. Refract Surg 2000;26:180–7.
36. Apple DJ, Lim ES, Morgan RC, et al. Preparation and study of human eyes obtained 74. Ness PJ, Werner L, Maddula S, et al. Pathology of 219 human cadaver eyes with 1-piece
postmortem with the Miyake posterior photographic technique. Ophthalmology or 3-piece hydrophobic acrylic intraocular lenses: capsular bag opacification and sites of
1990;97:810–16. square-edged barrier breach. J Cataract Refract Surg 2011;37:923–30.
37. Assia EI, Castaneda VE, Legler UFC, et al. Studies on cataract surgery and intraocular 75. Werner L, Olson RJ, Mamalis N. New technology IOL optics. Ophthalmol Clin North Am
lenses at the center for intraocular lens research. Ophthalmol Clin N Am 1991;4:251–66. 2006;19(4):469–83.
38. Assia EI, Legler UFC, Apple DJ. The capsular bag after short- and long-term fixation of 76. Apple DJ, Werner L. Complications of cataract and refractive surgery: a clinicopathologi-
intraocular lenses. Ophthalmology 1995;102:1151–7. cal documentation. Trans Am Ophthalmol Soc 2001;99:95–107, discussion 107–9.
39. Apple DJ, Auffarth GU, Wesendahl TA. Pathophysiology of modern capsular surgery. In: 77. Werner L. Biocompatibility of intraocular lens materials. Curr Opin Ophthalmol
Steinert RF, editor. Textbook of modern cataract surgery: technique, complication, and 2008;19:41–9.
management. Philadelphia: WB Saunders; 1995. 78. Güell JL, Morral M, Kook D, et al. Phakic intraocular lenses part 1: historical overview,
40. Assia EI, Apple DJ, Lim ES, et al. Removal of viscoelastic materials after experimental current models, selection criteria, and surgical techniques. J Cataract Refract Surg
cataract surgery in vitro. J Cataract Refract Surg 1992;18:3–6. 2010;36(11):1976–93.
41. Auffarth GU, Wesendahl TA, Solomon KD, et al. Evaluation of different removal tech- 79. Alió JL, Toffaha BT, Peña-Garcia P, et al. Phakic intraocular lens explantation: causes in
niques of a high viscosity viscoelastic (Healon GV). J Cataract Refract Surg Special Issue: 240 cases. J Refract Surg 2015;31(1):30–5.
Best Papers of 1994 ASCRS Meeting. 1994;30–2. 80. McIntyre JS, Werner L, Fuller SR, et al. Assessment of a single-piece hydrophilic acrylic
42. Glasser DB, Katz HR, Boyd JE, et al. Protective effects of viscous solutions in pha- IOL for piggyback sulcus fixation in pseudophakic cadaver eyes. J Cataract Refract Surg
koemulsification and traumatic lens implantation. Arch Ophthalmol 1989;107:1047–51. 2012;38(1):155–62.
e24
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Part 5 The Lens

Epidemiology, Pathophysiology,
Causes, Morphology, and Visual 5.3
Effects of Cataract
Mark Wevill
it can result in a person being removed from work and dependent on a

Definition: The prevalence, distribution, strategies to reduce the caregiver who is also removed from work.4
cataract prevalence and the disordered physiological processes, causes, The cataract prevalence is influenced by the Cataract Surgical Rate (CSR
and different forms of cataract are discussed. or number of cataract surgeries performed per million people per year),
which varies from less than 200 to over 6000 in different regions. The CSR
is determined by the effectiveness of strategies for stimulating demand
from patients because of good outcomes and how well easily accessible
Key Features cataract surgery is delivered.
• Cataracts develop earlier in developing countries, and the cataract So a high cataract prevalence rate in some developing countries is not
surgical rates are lower, resulting in a higher prevalence of cataracts. for want of a clinical solution but partially due to ineffective implementa-
But improved provision of cataract surgery in some developing tion. For example, Sub-Saharan Africa is resource poor with low surgeon
nations has significantly reduced cataract prevalence. productivity (number of procedures done per year). To reduce cataract prev-
• Factors in cataract pathogenesis include lens protein oxidation, alence, the resource base (infrastructure, equipment, ophthalmologists,
mitochondrial function, failure of protective mechanisms, protein and other ophthalmic workers) must improve, as must management of the
modification, and abnormalities of calcium metabolism, cellular resources to build the right processes for maximal cost-effective resource
proliferation, and differentiation. utilization. Future solutions will have to address these challenges.5
• An accumulation of environmental insults (e.g., ultraviolet light,
toxins, drugs, and systemic diseases) results in age-related cataracts. PATHOPHYSIOLOGY OF CATARACTS
Minor risk factors such as ultraviolet B exposure and smoking can be
modified. The lens transmits, filters, and focuses light onto the retina. The high
• Nutritional, pharmacological, and genetic interventions are being refractive index and transparency of the lens is due to the high concentra-
investigated. tion and orientation of intracellular structural proteins: α, β, and γ crys-
• Anomalies of lens growth are usually associated with other ocular or tallins. The anterior subcapsular layer of cuboidal lens epithelial cells are
systemic disorders. nucleated, actively divide, and account for almost all the metabolic activity
of the lens. Cuboidal cells in the equatorial zone of the lens undergo oxi-
dation and other biochemical, physiological, and structural changes. The
cells elongate into lens fiber cells, lose their intracellular organelles and
EPIDEMIOLOGY OF CATARACTS ability to perform metabolic functions, and form mature lens fibers. Lens
fibers migrate toward the nucleus of the lens and are compacted as more
In 2010 the Vision Loss Expert Group funded by the Bill & Melinda Gates fibers are formed around them, resulting in nucleosclerosis and later in
Foundation, Fight for Sight, and others calculated that cataracts caused opacity.6,7
blindness (visual acuity in the better eye of less than 3/60) in 10.6 million The transparency of the lens is dependent on the regular organiza-
people and moderate to severe visual impairment (MSVI, visual acuity of tion of the lens cells and intracellular lens proteins. The precise mecha-
between 6/18 and 3/60) in 34.4 million people. However, wide regional nisms by which lens proteins both prevent aggregation and maintain lens
variations exist in the prevalence of cataracts. In North America, the prev- transparency are largely unknown. Genetic, metabolic, nutritional, and
alence of blindness and MSVI was 0.3% and 0.4%, respectively. In South environmental insults and ocular and systemic diseases disrupt cellular
Asia, the respective prevalence was 2% and 6.8%. Sub-Saharan Africa is organization and intracellular homeostasis, eventually causing light scat-
similar. However, cataract blindness and MSVI have declined since 1990 tering and absorption, which compromise vision. Once damaged, the lens
due to better provision of cataract surgery. Once again the decline in prev- has limited means of repair and regeneration and may lose its transpar-
alence shows wide regional variations, with the greatest decline in East ency by the formation of opaque lens fibers, fibrous metaplasia, epithelial
Asia, Latin America, and Western Europe, where the prevalence fell by opacification, accumulation of pigment, or formation of extracellular mate-
more than half. The region with the least decline was Sub-Saharan Africa.1 rials. Several interlinked mechanisms for cataract formation have been
The world’s population is increasing (predominantly in developing proposed, and no single theory completely explains age-related cataract
countries), and people will live to greater ages. So without accessible, effi- (the commonest form).7 Much is still unknown about cataractogenesis, but
cient cataract surgery, the prevalence will increase. Developing countries many of the important components are becoming clearer.
bear an increasing burden for cataract blindness because cataracts occur
earlier in life, and the incidence is higher. In India, visually significant cat- Genetics
aract occurs 14 years earlier than in the United States, and the age-adjusted
prevalence of cataract is three times that of the United States.2,3 Cataracts Many inherited genetic syndromes and metabolic disorders are associated
are the leading cause of blindness in middle- and low-income countries, with cataracts, and at least 42 genes and loci have been found to under-
accounting for 50% of blindness but cause 5% of blindness in developed lie Mendelian inherited forms of isolated or primary cataract. Increasing
countries.4 evidence exists that several genes underlying rare forms of inherited cata-
Low-cost small-incision cataract surgery with lens implantation is a ract also can influence susceptibility to the much more prevalent forms of
proven clinical strategy. The socioeconomic effect of cataract surgery is age-related cataract. These observations raise the possibility of molecular
330 substantial. It allows people to increase their economic output to 1500% of genetic links between lens development and aging.8 Age-related cataracts
the cost of the surgery in the first postoperative year, but if left untreated, are inherited as a multifactorial or complex trait. Determining the genetics
booksmedicos.org
of age-related cataracts is difficult because only a small proportion of the complex proteins (e.g., crystallins). Extracellular Ca2+ can be bound to the
genes involved have been identified, similar gene mutations result in dif-
ferent cataract phenotypes, and cataract epigenetics is complex.
outer layer of the cell membrane. Reduced binding of Ca2+ by membrane
proteins increases cell membrane permeability and causes a rise in intra- 5.3
Epigenetics are heritable changes in the gene expression without cellular Ca2+ levels, the formation of calcium oxylate crystals, binding of
changes in the DNA sequence. Most genes involved in cataract formation Ca2+ to insoluble lens proteins, increased light scattering, and nuclear cata-
Epidemiology, Pathophysiology, Causes, Morphology, and Visual Effects of Cataract

show decreased expression. DNA methylation and other histone modifica- ract formation. Increased intracellular Ca2+ levels also affect lens epithelial
tions inhibit RNA transcription, effectively silencing gene expression. For cell differentiation, causing posterior subcapsular cataracts. Corticosteroids
example, in age-related cataracts, the gene DNA for the alpha A-crystallin have been shown to mobilize intracellular Ca2+ in other tissues, which can
protein is hypermethylated.9 Therapy targeted at reversing methylation increase Ca2+ levels. In the future, Ca2+-regulating drugs may be developed
and upregulating RNA transcription may prevent or reduce lens opacities. to prevent cataracts.13
Genes that preserve lens clarity function in diverse processes including
protein synthesis (e.g., structural proteins, chaperones, and cell-cycle- Calpains
control proteins) and reducing oxidative stress (e.g., glutathione peroxi-
dases). Decreased expression reduces lens epithelial cell stress tolerance The roles of calpains in the lens are poorly understood, but they may
and protein synthesis. Increased gene expression also can cause lens opac- degrade accumulated damaged lens proteins. A lack of calpains can lead to
ities, for example, by increasing lens epithelial cell ionic transport (e.g., elevated levels of damaged proteins, reduce optical performance, and cause
calcium-ATPase, which controls calcium channels) and extracellular matrix cataract. Also, excessive stimulation of calpain activity by raised Ca2+ levels
protein production.10 Identifying more genetic and epigenetic determinants can increase proteolysis and cause cataracts. Calpain inhibitors, therefore,
of inherited and age-related cataracts may result in nonsurgical treatments could be useful in the nonsurgical treatment of cataract. However, calpain
for cataract or lifestyle interventions (e.g., diet) and may prevent or reverse inhibitors of high molecular weight are unable to cross membranes, so
cataract formation.11,12 have been of no therapeutic use, whereas others are poorly water soluble
or are toxic to lenses.14
Cell Proliferation and Differentiation
Aqueous growth factors including fibroblast growth factor (FGF), epider-
Protein Modification
mal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived Additive modifications of lens proteins (e.g., crystallins) include methyl-
growth factor (PDGF), and transforming growth factor (TGF-β) promote ation, acetylation, carbamylation, glycation in diabetics, and binding of
proliferation, differentiation into lens fibers, and maturation of the lens ascorbate, which may be the cause of lens discoloration. These additions
fibers. These processes will not occur if growth factor or cytokine concen- occur especially in disease and can alter the function or properties of a
trations are incorrect. Then undifferentiated cells migrate to the posterior protein. Diabetes (reducing sugars), renal failure (cyanate generated from
pole, causing posterior subcapsular cataracts.6 urea), aging (photooxidation products), and corticosteroid use (ketoam-
ines) have been linked to cataracts. Additive modifications can make pro-
teins more susceptible to photooxidation by ultraviolet (UV) light.6,15
Metabolic Disturbance and Osmotic Subtractive modifications include cleavage by enzymes (such as cal-
pains) of crystallin that causes precipitation of lens proteins. Cleavage of
Regulation Failure channel proteins can affect intercellular communication. Neutral modifica-
Altered gene expression changes enzyme growth factor, membrane protein, tions such as isomerization can denature proteins, affecting their function.
and other protein levels, which reduces energy production; changes ion Deamidation changes the charge and affects protein–protein interactions.
transport, calcium metabolism, and antioxidant pathways; and breaks Proteins in the center of the lens are as old as the individual and
down protective mechanisms.6 For example, the lens maintains high intra- are very stable, but over time they can undergo conformational changes
cellular potassium and low sodium levels with the opposite extracellular (unfolding) that expose thiol groups, which are usually “hidden” in the
concentrations via the action of the sodium–potassium ATPase pump. folds of the protein (Fig. 5.3.1). The exposed glutathione groups can be
Pump inactivation causes increased intracellular osmolality, which results oxidized to form disulfide bonds (GSSG), causing aggregation of pro-
in water accumulation and light scatter.6 teins. The conformation changes and aggregation result in scattering and
The aqueous humor is a source of nutrients and mineral ions includ- absorption of light.15
ing calcium (Ca2+). Ca2+ is an intracellular signal that regulates many func-
tions including the permeability of the cell membranes. The extracellular Oxidation
Ca2+ concentration is 10 times the intracellular Ca2+ concentration, which
drives Ca2+ into the epithelial cell. Low intracellular Ca2+ levels also are Oxidation is a key feature in the pathogenesis of most cataracts. Low
maintained by intracellular organelle membrane pumps (on the endo- oxygen levels (O2) are important for maintaining a clear lens. Free radicals
plasmic reticulum, Golgi apparatus, and mitochondria) and by binding to and other oxidants, including reactive oxygen species (ROS) and reactive
Fig. 5.3.1 Conformational changes in lens proteins

CONFORMATIONAL CHANGES IN LENS PROTEINS (unfolding) exposes thiol groups (–SH). Oxidization
to disulfides (–S–S–) causes protein aggregation and
scatters light.
unfolding
oxidation
protein
thiol groups (–SH)
disulfide bonds (–S–S–) 331
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nitrogen species (RNS), are derived from both endogenous sources (mito-
5 chondria, peroxisomes, endoplasmic reticulum, phagocytic cells, etc.)

and exogenous sources (pollution, alcohol, tobacco smoke, heavy metals,
transition metals, industrial solvents, pesticides, and certain drugs like
halothane, paracetamol, and radiation). Free radicals can adversely affect
The Lens
nucleic acids, lipids, and proteins, altering the normal redox status and
leading to increased oxidative stress and cataracts.15
A steep oxygen gradient occurs from the outer part of the lens to the
center. Mitochondria in the lens cortex remove most of the oxygen, thus
keeping nuclear O2 levels low. However, in older people, mitochondrial
function diminishes and superoxide production by the mitochondria
increases, resulting in increased nuclear oxygen and superoxide levels. As
the lens ages, a lens barrier develops at approximately the cortex–nuclear
interface, which impedes the flow of molecules such as antioxidants
(including glutathione) into the nucleus. Unstable nuclear molecules such
as peroxide (H2O2), which are generated in the nucleus or which penetrate
the barrier, therefore, cause protein oxidation. Also, a lower concentration
of antioxidants exists. Decomposition of UV filters in the nucleus also pro-
duces unstable reactive molecules that bind to proteins, especially if anti-
oxidant glutathione (GSH) levels are low. Ascorbate becomes reactive with Fig. 5.3.2 Age-Related Cataract. Nuclear sclerosis and cortical lens opacities are
proteins in the absence of GSH. These oxidative changes can be detected present.
even in the earliest cataracts and are progressive. Elevated levels of super-
oxide H2O2 in the aqueous may cause cortical cataracts, since the cortex is
closest to the aqueous. Copper and iron are present in higher concentra- cortical and nuclear cataract is highest in those with high sun exposure
tions in cataract lenses and are involved in redox reactions, which produce at a younger age. Exposure later in life was more weakly associated with
hydroxyl radicals.16 these cataracts. Wearing sunglasses, especially when younger, has some
protective effect.17 Unfortunately, the risk attributable to sunlight exposure
Defensive Mechanisms is small,18 and cortical cataracts are less debilitating than nuclear or pos-
terior subcapsular cataracts. Therefore, reducing sunlight exposure may
Antioxidant enzymes and antioxidants such as ascorbate, glutathione, have a limited benefit in delaying the onset of cataracts. Exposure to high
tocopherols, and carotenoids maintain lens proteins in the reduced state levels of X-rays and whole-body irradiation also causes cataracts.
and are the primary defense mechanisms. In advanced age-related nuclear
cataracts, more than 90% of protein sulfhydryl groups and almost half of Smoking and Alcohol
all methionine residues in the nuclear proteins become oxidized. Second-
ary defenses include proteolytic and repair processes, which degrade and Smoking causes a threefold increase in the risk of developing nuclear cat-
eliminate damaged proteins, UV filters, and other molecules such as gluta- aracts, and cessation of smoking reduces this risk. Smoking also may be
thione reductase and free radical scavenging systems. Failure of these pro- associated with posterior subcapsular cataracts. Smokers are more likely to
tective mechanisms, a shortage of antioxidants, and increased free radicals have a poor diet and high alcohol consumption, which also are risk factors
result in cell membrane and protein damage.6,16 for cataract. Smoking causes a reduction in endogenous antioxidants.
Tobacco smoke contains heavy metals such as cadmium, lead, and copper,
Other Factors which accumulate in the lens and cause toxicity. No association between
passive smoking and cataract has been demonstrated.19,20 Alcohol use has
Crystallins may have a number of functions. For example α-crystallin may little, if any, association with cataract risk, and study reports are mixed.
be a chaperone that binds to other lens proteins to prevent precipitation.
Decreased crystallin levels cause proteins to precipitate, which leads to Body Mass Index
cataract formation. Phase separation of proteins refers to the hydropho-
bic aggregation of lens proteins causing protein rich and poor regions A number of health-related factors—diabetes, hypertension, and body
in the lens fibers, which results in light scatter. The lipid composition of mass index (BMI)—are associated with various forms of lens opacity, and
the cell membranes also changes with age, which may have functional they may be interrelated. A high BMI increases the risk of developing
consequences. posterior subcapsular and cortical cataracts.20 A high BMI also is associ-
ated with diabetes and hypertension, which are associated with cataracts.
Severe protein-calorie malnutrition is a risk factor for cataracts. Therefore,
CATARACT CAUSES, ASSOCIATIONS, a moderate calorie intake may be optimal to reduce the risk of developing
cataracts.
AND PREVENTION
Age Myopia
The cumulative effect of many environmental factors (UV light, After controlling for age, gender, and other cataract risk factors (diabetes,
x-irradiation, toxins, metals, corticosteroids, drugs, and diseases, including smoking, and education), posterior subcapsular cataracts are associated
diabetes) causes age-related cataracts. Gene expression changes result in with myopia, deeper anterior chambers, and longer vitreous chambers.21
altered enzyme, growth factor, and other protein levels. Protein modifi-
cation, oxidation, conformational changes, aggregation, formation of the Trauma
nuclear barrier, increased proteolysis, defective calcium metabolism, and
defense mechanisms occur with increasing age. Compromised ion trans- Blunt trauma that does not result in rupture of the capsule may allow fluid
port leads to osmotic imbalances and intercellular vacuolation. Age-related influx and swelling of the lens fibers. The anterior subcapsular region
abnormal cellular proliferation and differentiation also produce opacities whitens and may develop a characteristic flower-shaped pattern (Fig. 5.3.3)
(Fig. 5.3.2). There is also an increased incidence of diseases such as diabe- or a punctate opacity. A small capsular penetrating injury results in rapid
tes that causes cataracts. fiber hydration and a localized lens opacity, and a larger rupture results
in complete lens opacification. Penetrating injuries can be caused by acci-
Sunlight and Irradiation dental or surgical trauma such as a peripheral iridectomy or during a
vitrectomy.
UV-B light causes oxidative damage, which is cataractogenic. The level of Electric shocks as a result of lightning or an industrial accident cause
free UV filters in the lens decreases with age, and breakdown products of coagulation of proteins, osmotic changes, and fernlike, grayish white ante-
332 the filters act as photosensitizers that promote the production of reactive rior and posterior subcapsular opacities.22 Ionizing radiation, such as from
oxygen species and oxidation of proteins in the aging lens. The risk of X-rays, damages the capsular epithelial cell DNA, affecting protein and
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and hepatosplenomegaly. Dietary restriction of galactose prevents cataract
progression. Galactokinase deficiency is associated with galactosemia and
cataract but without the systemic manifestations.25 5.3
Fabry’s disease is an X-linked lysosomal storage disorder that results in
accumulation of the glycolipid ceramide trihexoside. The patient suffers

from episodic fever, pains, hypertension, renal disease, and a characteristic
rash. In the affected man and the carrier woman, a typical mild, spokelike,
visually insignificant cataract develops.
Lowe’s or oculocerebrorenal syndrome is a severe X-linked disorder that
results in mental retardation, renal tubular acidosis, metabolic acidosis,
and renal rickets. Congenital glaucoma, cataracts, and corneal keloids can
cause blindness. The lens is small and discoid with a total cataract. Female
carriers may show focal dot opacities in the cortex.
Alport’s syndrome is a dominant, recessive, or X-linked trait disease
causing hemorrhagic nephropathy and sensorineural deafness. Congenital
or postnatal cortical cataract, anterior or posterior lenticonus, and micro-
A spherophakia occur.
Dystrophia myotonica is a dominantly inherited disorder and results
in muscle wasting and tonic relaxation of skeletal muscles. Other fea-
tures include premature baldness, gonadal atrophy, cardiac defects, and
mental retardation. Cataract is a key diagnostic criterion and may develop
early, but usually occurs after 20 years of age and progresses slowly, even-
tually becoming opaque. Early cataract consists of polychromatic dots
and flakes in the superficial cortex. As the opacities mature, a character-
istic stellate opacity appears at the posterior pole. Other ocular features
include hypotony, blepharitis, abnormal pupil responses, and pigmentary
retinopathy.
Rothmund–Thomson syndrome is an autosomal recessive disorder
characterized by poikiloderma, hypogonadism, saddle-shaped nose, abnor-
mal hair growth, and cataracts, which develop between the second and
fourth decades of life and progress rapidly.
Werner’s syndrome or adult progeria is an autosomal recessive disor-
der with features that include premature senility, diabetes, hypogonadism,
and arrested growth. Juvenile cataracts are common. The condition usually
B leads to death at about 40 years of age.
Cockayne’s syndrome causes dwarfism but with disproportionately long
Fig. 5.3.3 Traumatic Cataract. (A) Typical flower-shaped pattern with coronary lens limbs with large hands and feet, deafness, and visual loss from retinal
opacities. (B) Seen in retroillumination in anterior subcapsular region. degeneration, optic atrophy, and cataracts.
Dermatological Disorders
The skin and the lens are of ectodermal origin embryologically. Therefore,
enzyme transcription and cell mitosis. An enlarging posterior pole plaque skin disorders may be associated with cataract formation.
develops. Nonionizing radiation, such as infrared, is the cause of cataract Atopic dermatitis and eczema may affect any part of the body, espe-
in glassblowers and furnace workers working without protective lenses. A cially the limb flexures. Localized proliferation of lens epithelium occurs
localized rise in the temperature of the iris pigment epithelium causes a in some atopic adults, usually as a bilateral, rapidly progressive “shield”
characteristic posterior subcapsular cataract, which may be associated with cataract (a dense, anterior subcapsular plaque with radiating cortical opaci-
exfoliation of the anterior capsule. ties, and wrinkling of the anterior capsule). Posterior subcapsular opacities
also may occur.
Systemic Disorders Ichthyosis is an autosomal recessive disorder that features hypertro-
phic nails, atrophic sweat glands, cuneiform cataracts, and nuclear lens
In uncontrolled type 1 diabetes mellitus in young people, hyperglycemia opacities.
causes glucose to diffuse into the lens fiber, where aldose reductase con- Incontinentia pigmenti is an X-linked dominant disorder that affects
verts it to sorbitol. The cell membrane is impermeable to sorbitol, and skin, eyes, teeth, hair, nails, and the skeletal, cardiac, and central nervous
therefore it accumulates. The osmotic effect draws water into the lens systems. Blistering skin lesions occur soon after birth, followed by warty
fibers, which swell and then rupture. The cataract progresses rapidly with outgrowths. Ocular pathology includes cataract, chorioretinal changes, and
the development of white anterior and posterior subcapsular and cortical optic atrophy.
opacities.
In type 2 diabetic adults, an early onset age-related type of cataract Central Nervous System Disorders
occurs and is more prevalent with longer duration of the diabetes. Many
mechanisms are involved and include sorbitol accumulation, protein gly- Neurofibromatosis (types I and II) is an autosomal dominant disorder
cosylation, increased superoxide production in the mitochondria, and causing numerous intracranial and intraspinal tumors and acoustic neu-
phase separation. During hyperglycemia, glucose is reduced to sorbitol, romata. Ocular features include combined hamartoma of the retina and
depleting antioxidant reserves, and less glutathione is maintained in the retinal pigment epithelium, epiretinal membranes, Lisch nodules (a diag-
reduced form, which causes other oxidative damage. Levels of lens Ca2+ nostic sign), and posterior subcapsular or cortical cataracts that develop in
also are elevated, which activates calpains, causing unregulated proteoly- the second or third decade of life.
sis of crystallins. The cataracts are usually cortical or posterior subcapsu- Zellweger syndrome, also known as hepatocerebrorenal syndrome, is
lar or, less frequently, nuclear and progress more rapidly than age-related an autosomal recessive disorder characterized by renal cysts, hepatospleno-
cataract.23,24 megaly, and neurological abnormalities. Ocular features include corneal
Galactosemia is an autosomal recessive disorder in which a lack of one clouding, retinal degeneration, and cataracts.
of the three enzymes involved in the conversion of galactose into glucose Norrie’s disease is an X-linked recessive disorder that causes leukoko-
causes a rise in serum galactose levels. Galactitol accumulates in the lens ria and congenital infantile blindness and is associated with mental retar-
fibers, drawing water into them. Infantile anterior and posterior subcapsu- dation and cochlear deafness. In the eye, vitreoretinal dysplasia, retinal
lar opacities progress to become nuclear. Galactose 1-phosphate uridyltrans- detachment, vitreous hemorrhage, and formation of a white retrolental 333
ferase galactosemia is associated with failure to thrive, mental retardation, mass occur. Eventually, a cataract forms.
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Ocular Disease and Cataracts cases, narrow and slanted palpebral fissures, blepharitis, strabismus, nys-
5 Inflammatory uveitis (e.g., Fuchs’ heterochromic cyclitis and juvenile idio-

pathic arthritis) usually results in posterior subcapsular or posterior cortical
tagmus, light-colored and spotted irides (Brushfield spots), keratoconus,
and myopia. Cataract also is associated with trisomy 13 (Patau’s syndrome),
trisomy 18 (Edwards’ syndrome), Cri du chat syndrome (deletion of short
lens opacities. Infective uveitis (e.g., ocular herpes zoster, toxoplasmosis, arm of chromosome 5), and Turner’s syndrome (X chromosome deletion).
The Lens
syphilis, and tuberculosis) can cause cataracts, but the organism does not A total cataract is a complete opacity present at birth. It may be hered-
penetrate the lens. In maternal rubella infection, after 6 weeks of gestation, itary (autosomal dominant or recessive) or associated with systemic dis-
the virus can penetrate the lens capsule, causing unilateral or bilateral, orders such as galactosemia, rubella, and Lowe’s syndrome. Infantile
dense, nuclear opacities at birth, or they may develop several weeks or cataracts cause amblyopia if unilateral and may cause strabismus and
months later. Corticosteroid treatment can cause cataracts. Retinal pigment nystagmus if bilateral. The incidence is about 0.4% of newborns, but the
degenerations such as retinitis pigmentosa, Usher’s syndrome, and gyrate majority of cases are not associated with poor vision. Amblyopia depends
atrophy are associated with cataracts, which are usually posterior subcapsu- on the size, location, and density of the cataract. The causes of infantile
lar opacities. Retinal detachment and retinal surgery may cause a posterior cataracts are many and include maternal infections (such as rubella), sys-
subcapsular cataract particularly in association with vitrectomy, silicone oil temic diseases, hereditary disorders, and ocular disease.
injection, and tamponade, or an anterior subcapsular form may develop
because of metaplasia of the lens epithelium after vitreoretinal surgery.
High myopia is associated with posterior cortical, subcapsular, and nuclear
PREVENTION OF CATARACTS
cataracts. Ciliary body tumors may be associated with cortical or lamellar The roles and mechanisms of action of dietary antioxidant vitamins and
cataract in the affected quadrant. Anterior segment ischemia may cause a minerals in the biochemistry and metabolism of the lens are not clear.
subcapsular or nuclear cataract, which progresses rapidly. Ascorbate is a water-soluble antioxidant. Vitamin E is a lipid-soluble anti-
oxidant that inhibits lipid peroxidation, stabilizes cell membranes, and
Toxic Causes enhances glutathione recycling. Beta-carotene, the best-known carotenoid,
is a lipid-soluble antioxidant and a vitamin A precursor and is one of 400
Topical, inhaled, and systemically administered corticosteroids can cause naturally occurring carotenoids. There are mixed reports in the literature
posterior subcapsular cataracts. Direct mechanisms included interaction of with some studies showing no benefit and others showing some benefit
corticosteroids with enzymes that affects their function, e.g., corticosteroid with vitamin A, carotenoids, and combinations of vitamins C and E and
modulation of Na+,K+-ATPase may cause sodium–potassium pump inhi- beta-carotene supplements.27,28
bition affecting osmotic regulation. Corticosteroids also induce crystallin Potential anticataract compounds include aldose reductase inhibitors,
conformational changes, causing aggregation and affect intracellular Ca2+ pantethine, and aspirin-like drugs such as ibuprofen. However, none of
homeostasis, causing protein bonding. Indirectly, corticosteroids affect these agents has been shown to prevent cataracts in a trial setting. No con-
DNA/RNA synthesis of proteins and enzymes, causing metabolic changes, vincing evidence exists that N-acetylcarnosine reverses cataract or prevents
and also may affect ciliary body growth hormone levels responsible for progression of cataract. A decreased risk of developing cataracts occurs
lens cellular differentiation, causing posterior subcapsular opacities.26 with estrogen replacement therapy.29–34 New drugs are under investigation,
Chronic use of long-acting anticholinesterases previously used in the including lanosterol, which decreased protein aggregates in vitro, reduced
treatment of chronic open-angle glaucoma may cause anterior subcapsu- cataract severity, and increase transparency in rabbit cataractous lenses in
lar vacuoles and posterior subcapsular and nuclear cataracts. Pilocarpine, vitro and cataract severity in vivo in dogs.35 Anticataract agents would need
a shorter acting agent, causes less marked changes. The mechanism of to be safe for long-term use and sufficiently inexpensive to compete with
action is unknown. Phenothiazines, such as chlorpromazine, may cause increasingly cost-effective cataract surgery.
deposition of fine, yellow-brown granules under the anterior capsule in Understanding the causes of age-related cataract will be helpful in pre-
the pupillary zone and may develop into large stellate opacities but are venting or delaying cataract formation, but our knowledge is incomplete.
not usually visually significant. The development of the opacities may be Minor risk factors such as UV-B exposure and smoking can be modified
related to the cumulative dose of the medication, and photosensitization but are not likely to result in large reductions in visual disability. The most
of the lens may play a role. Allopurinol used in the treatment of gout is important risk factor, aging, cannot be modified. Other strategies such as
associated with cataracts. Psoralen–UV-A therapy for psoriasis and vitiligo nutritional, pharmacological, and specific medical and genetic interven-
has been shown to cause cataracts in very high doses in animal studies but tions may be helpful in the future but are of unproved benefit at present.
is rare in humans; concomitant UV exposure may be a risk factor. Anti- Integrated and innovative approaches to the provision of surgery, resource
mitotic drugs used in the treatment of chronic myeloid leukemia, such as management, training, start-up capital equipment and consumables, and
busulfan, may cause posterior subcapsular cataract. The antimalarial chlo- cost-recovery mechanisms are required.
roquine (but not hydroxychloroquine), which is also used in the treatment
of arthritis, may cause white, flake-like posterior subcapsular lens opaci-
ties. Amiodarone is used to treat cardiac arrhythmias and causes insignif-
icant anterior subcapsular opacities and corneal deposits. The relationship MORPHOLOGY AND VISUAL EFFECTS
between statins and cataracts is still controversial. OF CATARACT
Siderosis, from a ferrous intraocular foreign body, causes iron deposits
in the lens epithelium and iris and results in a brown discoloration of the MORPHOLOGY
iris and a flower-shaped cataract. Wilson’s disease, an autosomal recessive
disorder of copper metabolism, causes a brown ring of copper deposition Nuclear opacities are caused by a gradual increase in the optical density of
in Descemet’s membrane and the lens capsule, resulting in a sunflower the central nucleus, progressing slowly to involve more superficial layers
cataract—an anterior and posterior capsular disc-shaped polychromatic (see Fig. 5.3.1). The nucleus may change color from clear to yellow to dark
opacity in the pupillary zone with petal-like spokes that is not usually visu- brown.
ally significant. Hypocalcemia in hypoparathyroidism is associated with Cortical opacities are spokelike peripheral opacities that reduce the
cataracts. In children, the cataract is lamellar; in adults it produces an ante- visual acuity as they extend toward the visual axis (see Fig. 5.3.2).
rior or posterior punctate subcapsular opacity. Posterior subcapsular opacities begin at the posterior polar region
then spread toward the periphery. Patients have significant glare disability
Congenital and Juvenile Cataracts because of light scattering at the nodal point of the eye.
Complete opacification of the lens eventually occurs, usually with com-
Congenital cataracts are noted at birth, infantile cataracts occur in the first binations of the different forms. The crystalline lens may swell to form
year, and juvenile cataracts develop during the first 12 years of life. Hered- an intumescent cataract. The cortical material may then liquefy and be
itary cataracts may be associated with other systemic syndromes, such as absorbed causing the solid nucleus to “sink” to the bottom of the capsular
dystrophia myotonica. About one-third of all congenital cataracts are hered- bag.
itary and unassociated with any other metabolic or systemic disorders.
Trisomy 21, or Down syndrome, is the most common autosomal
trisomy, with an incidence of 1 per 800 births. Systemic features include
ASSESSMENT AND GRADING OF CATARACTS
334 mental retardation, stunted growth, mongoloid facies, and congenital heart Grading and classifications of cataracts (Box 5.3.1) are useful in research,
defects. Ocular features include visually disabling lens opacities in 15% of to explore causation, and in trials of anticataract drugs. Slit-lamp direct and
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retroillumination of nuclear, cortical, and posterior subcapsular cataracts is
used in the Lens Opacification Classification System II (LOCS-II). LOCS-II
is reproducible and has been validated.36 A number of Scheimpflug camera 5.3
and optical coherence tomography devices have been developed for objec-
tively quantifying lens opacification.

VISUAL EFFECTS OF CATARACTS
The effect of cataract on vision varies according to the degree of the cata-
ract and the cataract morphology.
Visual Acuity
Reduction in visual acuity has been the standard measure of the visual
effect of cataracts. However, visual acuity can remain good despite other
cataract-related effects on vision that compromise the patient’s ability to
function.
Fig. 5.3.4 Cataracta Centralis Pulverulenta. Opacification of fetal nucleus. Contrast Sensitivity, Glare, and
Wavefront Aberrometry
Cataracts cause reduced contrast sensitivity and increased wavefront aber-
rations, reducing visual acuity especially at low ambient light levels.37
BOX 5.3.1 Infantile Cataracts Glare, which occurs as a result of forward scatter of light, may be produced
by opacities that do not lie within the pupil diameter and, therefore, affect
Anterior Polar Cataract visual function.38
Dominantly inherited, well-defined opacities of the anterior capsule may
affect the vision.
Caused by imperfect separation of lens from surface ectoderm, by epi- Other Effects
thelial damage, or by incomplete reabsorption of the vascular tunic of the The natural aging of the human lens produces a progressive hyperopic
lens. shift. Nuclear changes induce a modification of the refractive index of the
May have anterior or posterior conical projections; if it extends into the lens and produce a myopic shift. Cortical opacities may cause localized
cortex in a rod shape, it is called a “fusiform” cataract. changes in the refractive index of the lens, which may result in monocular
Spear Cataract diplopia. Color perception is affected by the yellowing of the lens nucleus.
Dominantly inherited, polymorphic cataract with needle-like clusters of The morphology, density, and location of lens opacities may cause changes
opacities in the axial region, which may not affect vision. in the visual field.
Coralliform Cataract
Dominantly inherited cataract that consists of round and oblong opacities
grouped toward the center of the lens; they resemble coral. ANOMALIES OF LENS GROWTH
Floriform Cataract The lens is ectodermal and the vascular capsule is mesodermal in origin.
A rare, ring-shaped, bluish white, flower-shaped cataract in the axial A number of exogenous or endogenous influences can affect ectodermal
region. or mesodermal development and can have multiple manifestations in
the eye.
Lamellar Cataract
A common, bilateral, and symmetrical round, gray shell of opacity that
surrounds a clear nucleus; usually dominantly inherited cataract, which Aphakia
may have a metabolic or inflammatory cause. Aphakia is the absence of the lens. Primary aphakia is a rare absence of the
Fibers become opacified in response to a specific insult during their lens. Secondary aphakia is more common, and there are lens remnants.
most active metabolic stage and are pushed deeper into the cortex as Both occur in isolation or with other abnormalities of the anterior segment
normal lens fibers are laid down around it. such as microphthalmos, microcornea, and nystagmus.39
Cataracta Centralis Pulverulenta
Dominantly inherited, nonprogressive cataract consisting of fine, white, Microspherophakia
powdery dots within the embryonic or fetal nucleus (Fig. 5.3.4).
Microspherophakia is the presence of a small, spherical crystalline lens
Congenital Punctate Cerulean Cataract with an increased antero–posterior thickness and steeper than normal
Bilateral, nonprogressive, small, bluish dots scattered throughout the lens anterior and posterior lens curvatures. It is bilateral and may be familial,
with little effect on vision. may occur as an isolated defect, or may be associated with other meso-
Congenital Suture (Stellate) Cataract dermal defects, such as the Weill–Marchesani and Marfan’s syndromes.
Dominantly inherited bluish dots or a dense, chalky band around the The condition causes lenticular myopia and may be associated with lens
sutures affecting one or both fetal sutures, especially posteriorly; may dislocation (usually downward) and pupil block.40,41
interfere with vision.
Mittendorf’s Dot Lenticonus and Lentiglobus
A small (about 1 mm diameter), nonprogressive, white condensation Abnormalities of the central lens curvature include lenticonus (conical)
occurs on the posterior pole of the lens capsule; it may be decentered and lentiglobus (spherical) and may be anterior or posterior. They may
slightly inferonasally and may be attached to a free-floating thread in be associated with abnormalities of the lens epithelium, by traction from
the vitreous gel, which represents the anterior part of the hyaloid artery hyaloid remnants, or by localized areas of capsule weakness, which causes
remnant. bulging. They may be inherited as an autosomal recessive trait or associ-
Congenital Disciform Cataract ated with other abnormalities, such as Alport’s syndrome (familial hem-
Central thinning creates a doughnut shape, which may arise from failure orrhagic nephritis) or Lowe’s oculocerebral syndrome (associated with
of development of the embryonic nucleus. posterior lenticonus). They can cause lenticular myopia with irregular 335
astigmatism.39,41
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presents in childhood or young adulthood. The lens may dislocate com-
5 pletely into the anterior chamber or vitreous or become cataractous. It

may be an autosomal dominant or recessive trait or may be associated
with other developmental abnormalities of the eyes such as iris coloboma,
microspherophakia, aniridia, and ectopia pupillae congenita. It may be
The Lens
associated with systemic disorders such as Marfan’s syndrome (Fig. 5.3.5),

Weill–Marchesani syndrome, homocystinuria, sulfite oxidase deficiency,
and hyperlysinemia. The clinical features of a subluxed lens include irido-
donesis (tremulous iris), fluctuating anterior chamber depth and vision,
and phacodonesis (a visibly mobile lens). Vitreous may herniate into the
anterior chamber. Pupil block may occur with iris apposition to the vitre-
ous face or an anterior dislocated lens (into the anterior chamber).
KEY REFERENCES
Biswas S, Harris F, Dennison S, et al. Calpains: enzymes of vision? Med Sci Monit
2005;11:301–10.
Bourne R, Stevens G, White R, et al. Causes of vision loss worldwide, 1990–2010: a system-
atic analysis. Lancet Glob Health 2013;1(6):e339–49.
Brian G, Taylor H. Cataract blindness – challenges for the 21st century. Bull World Health
Organ 2001;79:249–56.
Chylack LT, Leske MC, McCarthy D. Lens Opacities Classification System II (LOCS). Arch
Fig. 5.3.5 Marfan’s Syndrome. A retroillumination slit-lamp photograph of ectopia Ophthalmol 1989;107:991–7.
lentis associated with Marfan’s syndrome. Floud S, Kuper H, Reeves GK, et al. Risk factors for cataracts treated surgically in postmeno-
pausal women. Ophthalmology 2016;123(8):1704–10.
Jobling AI, Augusteyn RC. What causes steroid cataracts? A review of steroid induced poste-
Lens Coloboma rior subcapsular cataracts. Clin Exp Optom 2002;85(2):61–75.
Liu Y, Wilkins M, Kim T, et al. Cataracts. Lancet 2017;390:600–12.
Shiels A, Hejtmancik J. Molecular genetics of cataract. Prog Mol Biol Transl Sci 2015;134:
Lens coloboma is a unilateral, congenital indentation of the lens periphery 203–18.
that occurs as a result of a localized absence of zonules. It may be asso- Truscott RJ. Age-related nuclear cataract – oxidation is the key. Exp Eye Res 2005;80:
ciated with coloboma of the iris, ciliary body, or choroid, or with ectopia 709–25.
lentis, spherophakia, or localized lens opacities. It may occur because per- West AL, Oren GA, Moroi SE. Evidence for the use of nutritional supplements and herbal
medicines in common eye diseases. Am J Ophthalmol 2006;141:157–66.
sistence of mesodermal vascular capsules remnants prevents the develop- Zhao L, Chen XJ, Zhu J. Lanosterol reverses protein aggregation in cataracts. Nature
ment of zonules in that area. 2015;523(7562):607–11.
Zhao LQ, Li LM, Zhu H. The effect of multivitamin/mineral supplements on age-related
cataracts: a systematic review and meta-analysis. The Epidemiological Evidence-Based
Ectopia Lentis Eye Disease Study Research Group EY. Nutrients 2014;6(3):931–49.
Ectopia lentis, or displaced lens, is usually a bilateral condition caused
by extensive zonular malformation. The lens is subluxated in the oppo- Access the complete reference list online at ExpertConsult.com
site direction to the weak zonules (usually superomedially) and usually
336
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REFERENCES 23. Srivastava SK, Ramana KV, Bhatnagar A. Role of aldose reductase and oxidative
damage in diabetes and the consequent potential for therapeutic options. Endocr Rev
1. Bourne R, Stevens G, White R, et al. Causes of vision loss worldwide, 1990–2010: a sys-
tematic analysis. Lancet Glob Health 2013;1(6):e339–49.
2005;26:380–92.
24. Biswas S, Harris F, Singh J, et al. Role of calpains in diabetes mellitus-induced cataracto-
5.3
2. Chaterjee A, Milton RC, Thyle S. Cataract prevalence and aetiology in Punjab. Br J Oph- genesis: a mini review. Mol Cell Biochem 2004;261:151–9.
25. Elman MJ, Miller MT, Matalon R. Galactokinase activity in patients with idiopathic cata-

thalmol 1982;66:35–42.
3. Khan HA, Leibowitz HM, Ganley JP, et al. The Framingham eye study: 1. Am J Epide- racts. Ophthalmology 1986;93:210–15.
miol 1977;1206:17–32. 26. Jobling AI, Augusteyn RC. What causes steroid cataracts? A review of steroid-induced
4. Liu Y, Wilkins M, Kim T, et al. Cataracts. Lancet 2017;390:600–12. posterior subcapsular cataracts. Clin Exp Optom 2002;85(2):61–75.
5. Sommer A, Taylor H, Ravilla T, et al. Challenges of ophthalmic care in the developing 27. West AL, Oren GA, Moroi SE. Evidence for the use of nutritional supplements and
world. JAMA Ophthalmol 2014;132(5):640–4. herbal medicines in common eye diseases. Am J Ophthalmol 2006;141:157–66.
6. Jobling AI, Augusteyn RC. What causes steroid cataracts? A review of steroid-induced 28. Zhao LQ, Li LM, Zhu H. The effect of multivitamin/mineral supplements on age-related
posterior subcapsular cataracts. Clin Exp Optom 2002;85(2):61–75. cataracts: a systematic review and meta-analysis. The Epidemiological Evidence-Based
7. Truscott RJ. Age-related nuclear cataract – oxidation is the key. Exp Eye Res 2005;80:709–25. Eye Disease Study Research Group EY. Nutrients 2014;6(3):931–49.
8. Shiels A, Hejtmancik J. Molecular genetics of cataract. Prog Mol Biol Transl Sci 29. Kojima M, Sun L, Hata I, et al. Efficacy of α-lipoic acid against diabetic cataract in rat.
2015;134:203–18. Jpn J Ophthalmol 2007;51(1):10–13.
9. Li W, Liu J, Galvin L. Epigenetics and common ophthalmic diseases. Yale J Biol Med 30. Kador P, Betts D, Wyman M, et al. Effects of topical administration of an aldose reduc-
2016;89:597–600. tase inhibitor on cataract formation in dogs fed a diet high in galactose. Am J Vet Res
10. Hawse JR, Hejtmancik JF, Horwitz J, et al. Identification and functional clustering of 2006;67(10):1783–7.
global gene expression differences between age-related cataract and clear human lenses 31. Drel V, Pacher P, Ali T, et al. Aldose reductase inhibitor fidarestat counteracts diabe-
and aged human lenses. Exp Eye Res 2004;79:935–40. tes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and
11. Congdon NG. Prevention strategies for age related cataract: present limitations and apoptosis. Int J Mol Med 2008;21(6):667–76.
future possibilities. Br J Ophthalmol 2001;85:516–20. 32. Matsumoto T, Ono Y, Kuromiya A, et al. Long-term treatment with ranirestat (AS-3201), a
12. Shiels A, Bennett TM, Hejtmancik JF. Cat-Map: putting cataract on the map. Mol Vis potent aldose reductase inhibitor, suppresses diabetic neuropathy and cataract formation
2010;16:2007–15. in rats. J Pharmacol Sci 2008;107(3):340–8.
13. Tang D, Borchman D, Yappert M, et al. Influence of age, diabetes, and cataract on 33. Jobling AI, Augusteyn RC. What causes steroid cataracts? A review of steroid-induced
calcium, lipid-calcium, and protein-calcium relationships in human lenses. Invest Oph- posterior subcapsular cataracts. Clin Exp Optom 2002;85(2):61–75.
thalmol Vis Sci 2003;44:2059–66. 34. Dubois VD, Bastawrous A. N-acetylcarnosine (NAC) drops for age-related cataract.
14. Biswas S, Harris F, Dennison S, et al. Calpains: enzymes of vision? Med Sci Monit Cochrane Database Syst Rev 2017;(2):CD009493.
2005;11:301–10. 35. Zhao L, Chen XJ, Zhu J. Lanosterol reverses protein aggregation in cataracts. Nature
15. Phaniendra A, Jestadi D, Periyasamy L. Free radicals: properties, sources, targets, and 2015;523(7562):607–11.
their implication in various diseases. Indian J Clin Biochem 2015;30(1):11–26. 36. Chylack LT, Leske MC, McCarthy D. Lens Opacities Classification System II (LOCS).
16. Truscott RJ. Age-related nuclear cataract – oxidation is the key. Exp Eye Res 2005;80:709–25. Arch Ophthalmol 1989;107:991–7.
17. Neale RE, Purdie JL, Hirst LW, et al. Sun exposure as a risk factor for nuclear cataract. 37. Ginsburg AP. Contrast sensitivity: determining the visual quality and function of cata-
Epidemiology 2003;14:707–12. ract, intraocular lenses and refractive surgery. Curr Opin Ophthalmol 2006;17:19–26.
18. McCarty CA, Nanjan MB, Taylor HR. Attributable risk estimates for cataract to prioritize 38. Lasa MS, Podgor MJ, Datiles MB, et al. Glare sensitivity in early cataracts. Br J Ophthal-
medical and public health action. Invest Ophthalmol Vis Sci 1999;41:3720–5. mol 1993;77:489–91.
19. Kelly SP, Thornton J, Edwards R, et al. Smoking and cataract: review of causal associa- 39. Wong PC, Dickens CJ, Hoskins D Jr. The developmental glaucomas. In: Tasman W,
tion. J Cataract Refract Surg 2005;31:2395–404. Jaeger EA, editors. Duane’s clinical ophthalmology, vol. 3. Philadelphia: Lippincott Wil-
20. Floud S, Kuper H, Reeves GK, et al. Risk factors for cataracts treated surgically in post- liams and Wilkins; [chapter 51].
menopausal women. Ophthalmology 2016;123(8):1704–10. 40. Chan RT, Collin HB. Microspherophakia. Clin Exp Optom 2002;85:294–9.
21. Praveen MR, Vasavada AR, Jani UD, et al. Prevalence of cataract type in relation to axial 41. Gibbs ML, Jacobs M, Wilkie AO, et al. Posterior lenticonus: clinical patterns and genet-
length in subjects with high myopia and emmetropia in an Indian population. Am J ics. J Pediatr Ophthalmol Strabismus 1993;30:171–5.
Ophthalmol 2008;145(1):176–81.
22. Fraunfelder FT, Hanna C. Electric cataracts. 1: sequential changes, unusual and prognos-
tic findings. Arch Ophthalmol 1972;87:179–83.
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Part 5 The Lens

Patient Workup for Cataract Surgery

Frank W. Howes 5.4
of anesthetic to use and the sedation required and potentially both the pre-
Definition: Preoperative preparation prior to planned lens extraction. and postoperative management (Table 5.4.1 and 5.4.2).
Key Features GENERAL OPHTHALMIC HISTORY

Ophthalmic and medical considerations in the preoperative evaluation AND EXAMINATION
of lens surgery include: Both eyes are assessed fully by routine ophthalmological workup, which
• The morphology of lens opacities and the effects and diagnosis includes tonometry, slit-lamp biomicroscope examination, and posterior
thereof. segment observations under mydriasis to estimate the visual outcome and
• The optics of the eye, including refractive correction modalities. risk category of surgery for the patient. Intercurrent ophthalmic disorders
• The biometric measurements in standard and nonstandard eyes. may prejudice the visual outcome. For example, uveitis may be exacer-
• The optimal medical assessment of the patient for surgery. bated,5 herpes zoster may have left an anesthetic cornea,6 atopic disease
• The social and legal considerations in final aspects of the workup are may predispose the eye to infection,7 and Fuchs’ endothelial dystrophy may
discussed. predispose the eye to corneal edema. Diabetes mellitus increases the pros-
pects of postoperative macular edema.1
The presence of open-angle glaucoma warrants further comment. The
INTRODUCTION aforementioned disease processes need pickup and assessment to avoid
deleterious effect on the eye after cataract surgery. The action of success-
Any patient undergoing cataract surgery requires an accurate ophthalmo- ful cataract surgery on glaucoma and ocular hypertension, however, has
logical workup and careful anamnesis. Although most cataract procedures been demonstrated to have a positive effect on intraocular pressure (IOP)
are uneventful with regard to the patient’s medical condition, any problem control.8
or crisis is potentially ruinous, especially if surgery becomes compli- With the advent of the new minimally invasive glaucoma surgery
cated or prolonged. Therefore it is incumbent on the surgical, anesthetic, (MIGS) procedures, the surgeon should now consider using one of these
nursing, and family doctor teams to be fully aware of their patient’s surgi- devices at the end (or beginning) of a cataract procedure to further facilitate
cal and medical status. improved aqueous outflow, lower IOP,9–11 and improve glaucoma control,
potentially reducing or eliminating the use of topical glaucoma drugs,
which themselves can have an adverse influence on the ocular surface and
MEDICAL HISTORY AND CURRENT visual quality both before and after cataract surgery. There are a number of
THERAPEUTIC REGIMEN MIGS devices available; see a commonly used example at Fig. 5.4.1.
Patient counseling on the procedure and explanation of postoperative
A history of cardiac, bronchopulmonary, or cerebrovascular incidents influ- expectation are vital elements of the preoperative workup. A written expla-
ences the timing and management of surgery, especially if it is recent. nation of the background and process of cataract surgery is invaluable.
Diabetes mellitus and systemic hypertension are common in the popu-
lation predisposed to operable cataract formation, and these conditions
may adversely influence both the surgery and the postoperative course of ASSESSMENT OF LENS OPACITIES12,13
events.1 Ram and coworkers2 carried out a study of more than 6000 patients
who underwent cataract surgery and discovered multiple morbidities that INTRODUCTION
arose from a variety of conditions. The major causes included pulmonary
disease, cardiovascular and hypertensive disorders, diabetes mellitus, and The progressive insolubilization of lens protein with age is believed to
significant orodental problems that required intervention. cause refractive index and density fluctuations, which scatter light and
Ram et al.2 also noted significant postoperative problems in 1.27% of impair vision.
their patients, nearly half of whom required hospitalization. Fisher and
Cunningham3 and Hamed et al.4 noted an even higher morbidity in their TABLE 5.4.2 Systemic Disorders and Lens Opacities
cohort of patients who had cataract surgery (Table 5.4.1).
There are many factors that may affect cooperation and difficulty during Systemic Disorder Appearance in the Eye
surgery, varying from ventilation difficulties to substance abuse (including Myotonic dystrophy Blue dot cortical cataract and posterior subcapsular
examination of identified cataract morphological findings), that may influ- cataract
ence both the surgeon’s and the anesthesiologist’s decision about the form Wilson’s disease Green sunflower cataract (copper) anterior or
posterior subcapsular
Atopic dermatitis Blue dot cortical cataract and posterior subcapsular
cataract
TABLE 5.4.1 Morbidity in Cataract Surgery Patients Hypocalcemia Discrete white cortical opacities
Condition Percentage Diabetes mellitus Snowflake opacities located in anterior and posterior
subcapsular cortex
Significant medical history 84
Acute onset diabetes Cortical wedges caused by lens fiber swelling
Diabetes mellitus 16
Down syndrome Snowflake opacities located in anterior and posterior
Systemic hypertension 47
subcapsular cortex
Ischemic heart disease 38
Systemic conditions requiring Posterior subcapsular lens opacities
Hypothyroidism 18
Undiagnosed tumors 3
corticosteroids (any form of
administration)
337
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Posterior Subcapsular Opacities
5 Posterior subcapsular opacities may develop as isolated entities or may be
associated with other lens opacities. The opacity begins at the posterior
polar region and then spreads toward the periphery. Often, granules and
The Lens
vacuoles are detectable in front of the posterior capsule.
Advanced Cataracts
The crystalline lens may swell and increase in volume because of cortical
processes (intumescent cataract). Complete white opacification of the lens
is called a mature or morgagnian cataract.
If the liquefied cortical material is not—or is only partially—reabsorbed,
the solid nucleus may “sink” to the bottom. Reabsorption of the milky
A cortex causes a reduction in the lens volume, resulting in capsular folding
(hypermature cataract).
GRADING OF LENS OPACITIES

Gradations and classifications of cataracts are useful in determining the
potential difficulty of cataract surgery, in cataract research, in studies to
explore causation, and in trials of putative anticataract drugs. Devices
designed to quantify lens opacification have been developed14; these instru-
ments (such as the Kowa Early Cataract Detector and the Scheimpflug
photo slit lamp) appear to be more accurate when used to assess the for-
mation of nuclear cataracts than that of cortical cataracts.
A rapid method for the gradation of cataract in epidemiological studies
has been reported by Mehra and Minassian15; the area of lenticular opacity
is assessed by direct ophthalmoscopy and graded on a scale from 0 to
5. Highly reproducible, validated systems (Lens Opacities Classification
B System III; see next section) for cataract classification have been developed
by Chylack and coworkers16 to define the effects of specific cataract type
Fig. 5.4.1 Glaukos version 1 iStent (G1) (A) and version 2 iStent inject (G2) (B) and extent very accurately; these enable the effects of specific cataract types
Trabecular microbypass system (MIGS). (Image used with permission from Glaukos on specific visual functions to be quantified.
Inc.)
Lens Opacities Classification System III
The impact of a patient’s cataract on the retinal image may be appre- (Fig. 5.4.2)
ciated on funduscopic examination, which can show interference with the For nuclear opalescence (NO) or nuclear color (NC), a slit beam is focused
red reflex and show the blur of fine retinal vessels. on the lens nucleus and the density of the lens is compared with a set of
standard photographs. If the density is less than that corresponding to the
DIAGNOSIS OF LENS OPACITIES first photograph, NO or NC is zero or “no nuclear cataract”; if NO or NC is
1, the density is equal to or less than that for the second photograph, and
Slit-lamp biomicroscopy is the major method used to observe and assess so on. The photographs represent lens nuclei of increasing density, and
cataracts. However, the image seen often fails to correlate with the patient’s the patient’s cataract is graded accordingly.
visual acuity or function. The relationship between alterations in the struc- For cortical cataracts (category “C”), a retroillumination (red reflex) view
tural proteins, the increase in light scatter associated with conventional through the dilated pupil is used to view the lens, focused first at the ante-
biomicroscopy, and the capacity of visual function is not a simple one. For rior capsule and then at the posterior capsule. The photographs are com-
all lens examinations, the pupil is dilated maximally. pared with standard photographs—each succeeding photograph shows the
pupillary area covered by more cortical cataract.
For posterior subcapsular cataract (category “P”), a retroillumination
CLASSIFICATION OF LENS OPACITIES (also red reflex) view of the lens is used, focused at the posterior capsule.
Nuclear Opacities Again, the patient’s cataract is graded according to standard photographs
(see Fig. 5.4.2).
Initially, an increase in optical density of the nucleus occurs (nuclear scle-
rosis). The fetal nucleus is first involved and then the whole adult nucleus.
The increase in density is followed by an opacification, which implies a
EFFECTS OF OPACITIES ON VISION
change in color, namely from an initial clear to yellow to a subsequent Visual Acuity Reduction
brown (brunescent cataract).
In certain instances, crystals appear in the adult nucleus (or in the Measurement of visual acuity can remain high despite age-related
cortex, usually posteriorly) that, on slit-lamp examination, appear to be of lens opacities.17–18 The severity of the visual disability measured using
different colors (polychromatic luster). high-contrast Snellen acuity charts is not sensitive to visual disability char-
acterized by loss of contrast sensitivity.
Cortical Opacities Usually, visual acuity testing is conducted under ideal circumstances
that are not normally met in the real world. Although not a definitive mea-
The changes in transparency involve most of the cortex of the lens. The surement of visual dysfunction, simple Snellen acuity is the most used
changes evolve as follows: index to determine whether cataract surgery should be performed. The
Preferred Practice Pattern of the American Academy of Ophthalmology
• Hydration of the cortex with development of subcapsular vacuoles. recommends Snellen acuity as the best general guide to the appropriate-
• Formation of ray-like spaces filled with liquid (morgagnian globules), ness of surgery but recognizes the need for flexibility with due regard to
which is at first transparent and later becomes opaque. a patient’s particular functional and visual needs, environment, and risks,
• Lamellar separation of the cortex with development of parallel linear which may vary widely.19
opacities. When the cataract is very dense and opaque, visual acuity may be
338 • Formation of cuneiform opacities that originate at the periphery of the reduced to light perception only (cataract is still the major cause of blind-
lens and spread toward the center. ness throughout the world).
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Fig. 5.4.2 Lens Opacities Classification System III
Simulation Chart.
Lens Opacities Classification System 111 (LOCS 111)
5.4

Opalescence
Nuclear
Colour/
N01 NC1 N02 NC2 N03 NC3 N04 NC4 N05 NC5 N06 NC6
Cortical
C1 C2 C3 C4 C5
Subcapsular
Posterior
P1 P2 P3 P4 P5
Contrast Sensitivity Reduction Visual Field Loss

Patients with cataracts commonly complain of loss of the ability to see According to the morphology, the density, and the location of the opacities,
objects outdoors in bright sunlight and of being blinded easily by approach- the field of vision may be affected.
ing headlamps in nighttime driving.20
Typically, loss of contrast sensitivity in patients who have cataracts has
been reported to be greater at higher spatial frequencies. All cataracts INVESTIGATIONS FOR FURTHER
lower contrast sensitivity—the posterior subcapsular opacities have been
reported to be the most destructive. SURGICAL REFINEMENT
Myopic Shift CORNEAL TOPOGRAPHY23

The natural aging of the human lens produces a progressive hyperopic The use of corneal topography24 is facilitatory in the fulfillment of current
shift. Nuclear changes induce a modification of the refractive index of the expectations of outcomes of surgery of within 0.5 diopters (D) of emmetro-
lens and produce a myopic shift that may be of several diopters or greater. pia, with minimal astigmatism.
It is possible to predict that an aging person who had emmetropia previ-
ously but who can now read with no correction (“second sight”) is devel-
oping nuclear cataract. Together with this aging effect goes the loss of the
PREOPERATIVE TOPOGRAPHY
negative asphericity of the lens in youth, balancing the positive asphericity The preoperative assessment of corneal topography has a number of roles
of the natural cornea.21 The shift to more positive asphericity of the lens in cataract surgery. First, as an alternative to keratometry, it can provide a
with progressive nuclear cataract also reduces visual quality. representative measure of the corneal curvature or power necessary to cal-
If the lens structure becomes heterogeneous, with cortical spoke cata- culate intraocular lens (IOL) power. Second, knowledge of the magnitude
ract for example, the change in refractive index may be uneven and may and location of pre-existing astigmatism is important if it is to be reversed
produce some degree of internal irregular astigmatism and disturbance of by appropriate placement and construction of incisions during surgery.
the higher-order aberrations of Zernike (third order). Furthermore, with the advent of toric IOLs, the decision whether to use
this technology is based on the topographic or keratometric measurement
Monocular Diplopia of corneal astigmatism. Variations in the measurement of corneal astig-
matism are often seen from instrument to instrument with the inherent
Monocular diplopia is common in patients who have lens opacities, par- danger of mal-powering or mal-placing the toric IOL, hence the need to
ticularly cortical spoke cataract, and in conjunction with water clefts that perform more than one form of keratometric assessment.
form radial wedge shapes and contain a fluid of lower refractive index than Modern topographic devices are now capable of measuring higher-order
the surrounding lens. In some cases, patients may complain of polyopia. aberrations (Zernike), which can further help with optimizing surgical out-
comes. The second and third order aberrations of Zernike may be reduced
Glare by removal of the cataract and by accurate biometric measurements. The
fourth order aberration, in particular spherical aberration, which changes
Even minor degrees of lens opacity cause glare because of the forward with age,21 can be modified by IOL choice (differing spherical aberration
scatter of light.22 Such patients often see more poorly in daylight condi- values) to provide better acuity or greater depth of focus.25
tions than in the context of night driving. Unlike contrast sensitivity reduc-
tion, some glare may be produced by opacities that do not lie within the
pupil diameter. The differences between measured visual acuity in a dark-
DETERMINATION OF IOL TYPE AND POWER
ened room and acuity in ambient light that produces glare are useful as Prior to cataract surgery, the power of the IOL that is required to give the
subjective criteria for the justification of surgery. desired postoperative refraction is determined. The final refractive result is
dependent on the accuracy of the biometric data and its appropriate use in
Color Shift relevant calculations.
Achieving emmetropia (or the desired refractive outcome) by optimal
The cataractous lens becomes more absorbent at the blue end of the spec- biometric assessment is the most important aspect of the workup for cata-
trum, especially with nuclear opacities. Usually patients are not aware of ract surgery. With the advent of the new extended range of focus IOLs now 339
this color visual defect until after cataract surgery and visual rehabilitation. available on the market, the default position of the standard monofocal
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IOL is being challenged. The surgeon is now potentially in the position A problem arises if potential material risks and dangers are not dis-
5 where he or she should discuss in detail with his patient why he or she
should not have one of these new lenses. The scope of the art of surgery
has widened since the introduction of these lenses.
closed to a patient before surgery and a complication occurs. The patient
may claim that, with prior knowledge of such a risk, he or she would
not have consented to the surgery. A risk is material when a rational
The factors under consideration for the surgeon are therefore: patient considers the risk of undergoing a certain type of treatment to be
The Lens
significant.
• Is the patient ready for surgery (risk–benefit analysis)?
Problems that arise from consent to perform surgical procedures can
• If so, what is the scope of the workup required as calculated against the
be minimized but not completely avoided, because every contingency
patient’s medical and ophthalmological status?
cannot be reviewed completely. Taking the following steps will ensure that
• What are the patient’s optical needs and what technologies are required
a thorough approach has been used.
to fulfill expectations?
Appropriate patient education is required—the procedure is described
• What workup is required to enhance the accuracy of outcome for those
in a manner that allows the patient to appreciate what will be done to
needs?
treat the eye. Although the decision to proceed has to be the patient’s, the
• What is the surgeons’ expectation in terms of his or her capability of
surgeon must not pass all the responsibility on to the patient; instead
providing the match for the patient’s expectation?
the surgeon should communicate the appropriate degree of confidence in
• And finally, have all the above been conveyed in an understandable
the procedure’s outcome.
manner to the patient?
The surgeon has to assume much of the responsibility for treatment
advice, because the patient cannot appreciate the intricacies of every surgi-
PLANNING THE INCISION cal situation. Ultimately, the patient has to have faith in the ability of the
surgeon not only to carry out the procedure but also to make the judgment
The final part of the patient workup for cataract surgery is planning that the benefits far outweigh the risks. An analogous situation might be
the incision. This involves making the decision on the optimal corneal that of a passenger contemplating a journey on a commercial airliner. If
position of the operative incision in relation to the surgical accessibility the passenger inquires of the pilot what the potential risks are, common
(nose, operating table, side, etc.) for efficient execution of the surgery and sense suggests that the answer would be that they are high in number but
whether the operative incision should be the same as the therapeutic inci- low in expectation. A passenger who decides to make the trip has con-
sion for the management of the corneal astigmatism. The effect of the fidence in the airline and the crew to complete a successful journey. So
incision on astigmatism is modifiable by the axis location of the incision, it is with surgery: The patient must have confidence in the ability of the
the length of the incision, and the proximity to the visual axis (scleral, surgeon and the surgical team to carry out a successful procedure without
limbal, or corneal). knowing each and every pitfall that exists.
The incision-making process also is modified by the decision Alternative approaches to the management of an ophthalmic condi-
about whether to use the toric IOL technology. The factors used in this tion are explained to the patient to enable patient participation in the final
decision-making process relate to the degree of astigmatic refractive error, direction of treatment.
IOL availability, outcome target, and keratometric and topographic mea- When uncertainties exist, the patient is advised of the predictability of
surements. Technology improvements have permitted the importation of the planned procedure, its stability, and its safety. Statistical information
keratometric data from the workup room to the operating theater. Man- on outcome is of limited value when given in a general sense. Few sur-
ufacturers have created imaging systems within microscopes that recog- geons are in a position to give specific statistical information about the
nize and track the eyes being operated on and provide overlay information outcome of their own practices or of certain procedures.
though the microscope oculars to demonstrate exactly where corneal inci- The patient must be given adequate time to decide. At the end of the
sions should be placed and on what axis a toric IOL should be positioned. consultation, a patient must have an opportunity to consider the treatment
Capabilities even extend to overlays for particular capsulorrhexis size and that has been advised or to reverse a decision to proceed. It is inappropri-
IOL centration. ate to obtain a patient’s signed consent for a procedure and then proceed
at very short notice (the same day) with that treatment. The delay between
consent and treatment must be sufficient to allow the patient to consider
the matter fully.
GOOD CLINICAL PRACTICE (SOCIAL AND To ensure that a patient is fully informed with regard to consent for a
LEGAL ASPECTS) surgical procedure, the issues listed in Box 5.4.1 should be covered.
The patient should sign a consent form that states that the procedure
The indications for surgery vary from patient to patient, especially with has been explained fully in language that is comprehensible and that there
the current minimally invasive nature of cataract and lens implant surgery has been sufficient opportunity to ask questions and reconsider consent
(compared with such surgery performed only a few years ago). The visual prior to surgery. A written guide helps patients comprehend the nature of
needs of patients vary according to their ages, occupations, and leisure the planned surgery.
interests. A cataract may not be symptomatic. Visual symptoms and Any surgical intervention is essentially a matter of trust and
outcome expectation affect the risk–benefit ratio. confidence—the trust of the patient in the surgeon’s ability and integrity
Although the risks of technically well-performed small incision surgery and the trust of the surgeon in the patient’s ability to comprehend and
are few in a healthy eye, patients require enough information on which follow the process and to comply with prescriptions for managing the con-
to base their decision to proceed. Most patients are inclined to accept the dition before, during, and after surgery.
professional judgment of the ophthalmic surgeon, but it is implicit that an
adult of sound mind has the right to determine whether surgery should
proceed. Therefore, in the context of cataract surgery, how much informa- BOX 5.4.1 Issues to Discuss With a Patient Prior to
tion is it necessary for an ophthalmologist to disclose to a patient? To what Cataract Surgery
extent should an ophthalmologist shield a patient from the anxieties that • The purpose of the surgery
can accompany a full explanation of diagnosis and treatment? • The surgical procedure
An ophthalmologist must strike a balance between providing enough • The anesthetic requirements
information to enable the patient to give informed consent with respect to • Commonly experienced visual conditions after the surgery, even if
treatment and engendering the confidence and trust that encompasses a temporary
joint decision to proceed. The surgeon shoulders the major responsibility • That temporary postsurgical visual conditions may become permanent
for this, which should be accepted as a consequence of medical and spe- under certain conditions
cialist training. • The serious complications that may follow surgery
In the application of professional judgment, the consideration of alter- • Potential pain or ocular discomfort
native management strategies, risks, and benefits allows a patient to make • The refractive requirements after the surgery (the need to wear and
some sort of informed evaluation of the options. Statistical information the provision of spectacles and/or contact lenses)
based on published data may be confusing: Where does the patient fit into • The potential need for additional procedures (planned staged
the statistics? What are the personal outcome statistics for the surgeon procedures)
340 who offers advice? What guarantees are there that a particular surgeon will • Alternative management of the condition
perform the surgery?
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KEY REFERENCES Rocha K, Vabre L, Chateau N, et al. Expanding depth of focus by modifying higher-order
aberrations induced by an adaptive optics visual simulator. J Cataract Refract Surg
American Academy of Ophthalmology. Preferred practice pattern: cataract in the otherwise
healthy adult eye. San Francisco: American Academy of Ophthalmology; 1989.
2009;35(11):1885–92.
Sanders RD, Gills JP, Martin RG. When keratometric measurements do not accurately reflect
5.4
Chylack LT Jr, Wolfe JK, Singer DM, et al. The Lens Opacities Classification System III. Arch corneal topography. J Cataract Refract Surg 1993;19(Suppl.):131–5.

Ophthalmol 1993;111:831–6.
Cuaycong MJ, Gay CA, Emery J, et al. Comparison of the accuracy of computerized video-
keratoscopy and keratometry for use in intraocular lens calculations. J Cataract Refract Access the complete reference list online at ExpertConsult.com
Surg 1993;19(Suppl.):178–81.
Guirao A, Redondo M, Artal P. Optical aberrations of the human cornea as a function of age.
J Opt Soc Am A 2000;17(10):1697–702.
341
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REFERENCES 12. Chitkara DK, Colin J. Morphology and visual effects of lens opacities of cataract. In:
Yanoff M, Duker JS, editors. Ophthalmology. 2nd ed. St Louis: Mosby; 2004. p. 280–2.
1. Wagner T, Knaflic D, Rauber M, et al. Influence of cataract surgery on the diabetic eye: a
prospective study. Ger J Ophthalmol 1996;5:79–83.
13. Cardillo Piccolino F, Altieri G. Classification of cataract. In: Angellini C, editor. Cataract.
Roma: M Zingirian; 1985.
5.4
2. Ram J, Pandav SS, Ram B, et al. Systemic disorders in age related cataract patients. Int 14. Harding JJ. Cataract epidemiology. Curr Opin Ophthalmol 1990;1:10–115.
15. Mehra V, Minassian DC. A rapid method of grading cataract in epidemiological studies

3. Fisher SJ, Cunningham RD. The medical profile of cataract patients. Clin Geriatr and eye surveys. Br J Ophthalmol 1988;72:801–3.
1985;1:339–44. 16. Chylack LT Jr, Wolfe JK, Singer DM, et al. The Lens Opacities Classification System
4. Hamed LM, Lingua DN. Thyroid disease presenting after cataract surgery. J Pediatr Oph- III. Arch Ophthalmol 1993;111:831–6.
thalmol Strabismus 1990;27:10–15. 17. Phelps Brown NA. The morphology of cataract and visual performance. Eye (Lond)
5. Jacquerie F, Comhaire-Poutchinian Y, Galand A. Cataract extraction in uveitis. Bull Soc 1993;7:63–7.
Belge Ophtalmol 1995;259:9–17. 18. Lasa MS, Datiles MB, Freidlin V. Potential vision tests in patients with cataracts. Ophthal-
6. Lightman S, Marsh RJ, Powell D. Herpes zoster ophthalmicus; a medical review. Br J mology 1995;102:1007–11.
Ophthalmol 1981;65:539. 19. American Academy of Ophthalmology. Preferred practice pattern: cataract in the other-
7. Hara T, Hoshi N, Hara T. Changes in bacterial strains before and after cataract surgery. wise healthy adult eye. San Francisco: American Academy of Ophthalmology; 1989.
Ophthalmology 1996;103:1876–9. 20. Regan D, Giaschi DE, Fresco BB. Measurement of glare sensitivity in cataract patients
8. Poley BJ, Lindstrom RL, Samuelson TW, et al. Intraocular pressure reduction after using low-contrast letter chart. Ophthalmic Physiol Opt 1993;13:115–23.
phacoemulsification with intraocular lens implantation in glaucomatous and nonglauco- 21. Guirao A, Redondo M, Artal P. Optical aberrations of the human cornea as a function of
matous eyes: evaluation of a causal relationship between the natural lens and open-angle age. J Opt Soc Am A 2000;17(10):1697–702.
glaucoma. J Cataract Refract Surg 2009;35(11):1946–55. 22. Lasa MS, Podgor MJ, Datiles MB, et al. Glare sensitivity in early cataracts. Br J Ophthal-
9. Samuelson TW, Katz LJ, Wells JM, et al. Randomized evaluation of the trabecular mol 1993;77:489–91.
micro-bypass stent with phacoemulsification in patients with glaucoma and cataract. 23. Corbett MC, Rosen ES. Corneal topography in cataract surgery. In: Yanoff M, Duker JS,
Ophthalmology 2011;118:459–67. editors. Ophthalmology. 2nd ed. St Louis: Mosby; 2004. p. 309–14.
10. Neuhann TH. Trabecular micro-bypass stent implantation during small-incision cataract 24. Nordan LT, Lusby FW. Refractive aspects of cataract surgery. Curr Opin Ophthalmol
surgery for open-angle glaucoma or ocular hypertension: Long-term results. J Cataract 1995;6:36–40.
Refract Surg 2015;41:2664–71. 25. Rocha K, Vabre L, Chateau N, et al. Expanding depth of focus by modifying higher-or-
11. Ferguson TJ, Berdahl JP, Schweitzer JA, et al. Clinical evaluation of a trabecular der aberrations induced by an adaptive optics visual simulator. J Cataract Refract Surg
micro-bypass stent with phacoemulsification in patients with open-angle glaucoma and 2009;35(11):1885–92.
cataract. Clin Ophthalmol 2016;10:1767–73.
341.e1
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Part 5 The Lens

Intraocular Lens Power Calculations

Li Wang, Kourtney Houser, Douglas D. Koch 5.5
Definition: Intraocular lens (IOL) power calculation is a process to Optical Biometry
determine the optimal IOL power to achieve the desired refraction Optical biometry has been shown to be significantly more accurate and
following cataract surgery. reproducible and is rapidly becoming the most prevalent methodology for
the measurement of AL. The most commonly used optical biometers are
IOLMaster (Carl Zeiss Meditec, Jena, Germany) and Lenstar (Haag-Streit,
Koeniz, Switzerland).
Key Features
• Accurate IOL power calculation depends on the precision of the • IOLMaster: The IOLMaster 500 was introduced in 2000 as the first
preoperative biometric data and the accuracy of the IOL formulas. optical biometer. Based on partial coherence interferometry technology,
• New biometers using interferometry and swept-source OCT it uses a 780-nm laser diode to measure AL. The device also provides
have improved accuracy and expanded the number of biometric measurements of keratometry, anterior chamber depth (ACD), and
parameters that can be measured. white-to-white (WTW) distance.
• IOL power calculation is less accurate in special eyes, including short The newer version of this device (IOLMaster 700) uses an optical con-
eyes, eyes with ectatic corneas, or eyes that have undergone corneal figuration that allows telecentric and thus distance-independent
refractive surgery or keratoplasty. The American Society of Cataract keratometry measurement. It uses swept-source optical coherence
and Refractive Surgery (ASCRS) postrefractive IOL calculator is a tomography (OCT) to is measure axial length, central corneal thick-
useful tool. ness (CCT), and lens thickness (LT). It displays a full-length OCT
• When selecting the toricity of the toric IOL, several factors must image, showing anatomical details of a longitudinal cuts through
be taken into account. Imaging and guidance systems for toric IOL the entire eye (Fig. 5.5.1).
alignment have been developed. • Lenstar: Based on optical low-coherence reflectometry technology, the
Lenstar uses an 820-nm laser diode to measure AL, ACD, CCT, and LT.
It calculates keratometry from an array of 32 light reflections projected
off the anterior corneal surface.
INTRODUCTION • Argos (Movu Inc, Komaki, Japan) and OA-2000 (Tomey, Nagoya,Japan):
These are two other new swept-source biometers that recently been
Accurate intraocular lens (IOL) power calculation is a crucial element for
introduced.
meeting the ever-increasing expectations of patients undergoing cataract
surgery. Despite advances in technology and IOL calculation formulas, Studies4–6 have shown that the repeatability of the IOLMaster and
much is yet to be done. The accuracy of IOL power calculations depends Lenstar for all biometric parameter measurements is excellent and that
on the precision of the preoperative biometric data, the accuracy of the IOL agreement between these devices is good. The differences in AL, ACD,
formulas, and the IOL quality control by the manufacturer. and LT between these devices were not shown to produce a statistically
In this chapter, we will discuss (1) ocular biometry; (2) IOL power for- significant difference in IOL power calculation.
mulas; (3) IOL power calculations in special eyes, including short eyes,
long eyes, and eyes with previous corneal refractive surgery; (4) toric IOL
selection; (5) intraoperative wavefront aberrometry; and (6) postoperative
IOL adjustment.
OCULAR BIOMETRY
Accurate biometry is of vital importance in achieving a predictable postop-
erative refraction following cataract surgery. Norrby1 analyzed the sources
of error in IOL power calculation by analyzing the precision of the bio-
metric and clinical measurements. He concluded that the three greatest
sources of error were axial length (AL), effective lens position (ELP), and
postoperative refraction, contributing 79% of the total error.
Ultrasound Biometry
AL has traditionally been measured using ultrasound biometry. With the
applanation technique, the ultrasound probe is placed in direct contact
with the cornea, and corneal compression typically causes the AL to be
falsely shortened. Applanation biometry has given way to noncontact
methods. Although the immersion technique has been shown to be more
reproducible than the applanation technique, both require mindfulness of
the properties of ultrasound. In eyes with high to extreme axial myopia,
the presence of a posterior staphyloma should be considered. Erroneously
long AL readings may occur in eyes with staphylomata. An immersion
A/B-scan approach for AL measurement has been described in the setting
of posterior staphyloma.2
342 With A-scan biometry, errors in AL measurement account for 54% of Fig. 5.5.1 Display From the Swept-Source Optical Coherence Tomography
IOL power error when two-variable formulas are used.3 Biometer IOLMaster 700.
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5.5

Fig. 5.5.2 Poorly reflected LED images from the anterior corneal surface using IOLMaster 700 (top); poorly reflected LED images from the anterior corneal surface using
Lenstar with average keratometry and corneal astigmatism of 43.24 D and 2.05 D@174° (middle), and repeated measurements with average keratometry and corneal
astigmatism of 44.36 D and 0.25 D@167° (bottom).
Although measurements with optical biometry are mostly operator of the anterior and posterior corneal curvatures as along with conic
independent, careful alignment during the scan and inspection of the coefficients (Q-values) obtained by modern anterior segment imaging
measurement quality are still necessary for optimal refractive outcomes systems can be used directly by the program.
(Fig. 5.5.2). • Okulix: Okulix9 is a program package that calculates single rays using
The primary limitation of optical biometry is its inability to measure Snell’s law. AL can be entered either manually or by a computer link
through dense cataracts and other media opacities that obscure the to the measuring device. As an alternative to entering corneal radii
macula. It was reported that with use of an earlier generation of IOLMas- by hand, they also can be taken from a two-dimensional corneal topo-
ter, approximately 10% of eyes could not be accurately measured due to graphic map.
such opacities or fixation difficulties.6 The IOLMaster 700 showed better
penetration in dense posterior subcapsular cataracts, measuring AL suc- Artificial Intelligence Formulas
cessfully in 96% of cases.5
• Radial basis function (RBF): The Hill-RBF calculator10 is an advanced,
IOL POWER FORMULAS self-validating method for IOL power selection employing pattern recog-
nition and a sophisticated form of data interpolation. Based on artificial
The first IOL power formula was published by Fyodorov in 1967. Subse- intelligence, this methodology is entirely data driven. Pattern recogni-
quent formulas were developed and traditionally were classified as the tion for selecting an IOL power is achieved through the process of adap-
second, third, fourth, and newer generations of IOL formulas. Due to the tive learning, the ability to learn tasks based solely on data. Unlike static
development of more advanced IOL formulas, a new classification based theoretical formulas, this approach will be an ongoing project and con-
on how they work is more appropriate. tinuously updated as a “big data” exercise. The greater the number of
surgical outcomes that are fit to the RBF model, the greater the overall
Vergence Formulas depth of accuracy.
• Neural network: Clarke11 developed a computational method based on
The majority of IOL formulas are vergence-based formulas. Based on the neural network in which the software is trained to predict IOL powers
number of variables they use to calculate ELP, these formulas can be cate- using large amount of clinical data from one surgeon with one IOL.
gorized into the following groups: Clinical data include preoperative AL, keratometry, ACD, and LT.
• Two-variable formulas: These include the Holladay 1, Hoffer Q, and
SRK/T, and they use AL and keratometry to calculate the distance from Combination Formulas
the principal plane of the cornea to the thin lens equivalent of the IOL
(i.e., ELP). Thus, a short eye or an eye with a flatter cornea will have a
• Super formula: The Ladas super formula12 amalgamates outcomes from
the above-mentioned two-variable and three-variable vergence formulas
shallower anterior chamber. However, Holladay has shown that excep-
and has a small component of artificial intelligence.
tions to these assumptions exist.7
• Three-variable formula: The Haigis formula uses AL, keratometry, and All of these formulas have some element of regression, as they include
ACD.
constants that are derived from prior patient outcomes. Note that two crit-
• Five-variable formula: The Barrett Universal II formula uses AL, ker- ical data points are not measured: posterior corneal curvature (although
atometry, ACD, LT, and WTW.
this is slowly being integrated) and ELP. Better predictive formulas for esti-
• Seven-variable formula: The Holladay 2 formula uses preoperative refrac- mating ELP will likely require more sophisticated measurements, possibly
tion, age, AL, keratometry, ACD, LT, and WTW.
to include lens diameter, lens volume, and certain angle and iris features.
Ray Tracing Formulas IOL CALCULATIONS IN SPECIAL EYES

• PhacoOptics: With PhacoOptics, IOL power is calculated based on exact IOL Power Calculation in Short Eyes
ray tracing (Snell’s law of refraction). It incorporates the latest gener-
ation ACD prediction algorithms based on the complex relationship In short eyes, the importance of accurate ELP prediction is magnified due
between the preoperative ocular dimensions (ACD and LT) and the to the high power of the IOL and the relatively short distance from the IOL 343
postoperative position of the IOL (postoperative ACD).8 Measurements to the retina. Olsen13 showed that 0.25 mm error in postoperative ACD
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corresponds to a 0.1 diopter (D) error in long eyes with 30 mm AL and a Factors Contributing to Challenges in IOL
5 0.5 D error in short eyes with 20 mm AL.
In IOL calculation formulas that do not use ACD in the ELP calcula-
tion, it is assumed that short eyes have a proportionally shallower anterior
Power Calculation
There are two factors that primarily contribute to challenges in IOL power
calculations in eyes with previous LASIK, PRK, or RK: difficulties in
chamber. However, this assumption breaks down in the many short eyes obtaining accurate corneal refractive power and problems in ELP predic-
The Lens
that in fact have normal anterior chamber anatomy with normal ACD. tion. Following LASIK/PRK/RK, the predicted ELP would be misleading if
Several studies in the literature have compared different IOL power for- the postoperative corneal power were used in the ELP calculation. To avoid
mulas and their accuracy in short eyes. Although it is believed that newer the ELP-related IOL prediction error, Aramberri proposed the double-K
IOL power prediction formulas perform best in short eyes, uncertainty still method.21 With the double-K version of the IOL formulas, the prerefrac-
exists in the literature on whether any of the available formulas perform tive surgery corneal power is used to estimate the ELP and the postre-
better than the others.14–16 fractive surgery corneal power is used to calculate the IOL power. This
In general, our approach for short eyes is to use the Holladay 1, Holla- approach had been previously used by Holladay in his Holladay Consultant
day 2, Hill-RBF, Olsen, and Barrett, favoring the Olsen when there is dis- Program. Several studies have shown that the double-K method improves
agreement. We also try to operate on the nondominant eye first so that we the accuracy of IOL power calculation after LASIK/PRK.21–23
can use its refractive outcome to adjust the IOL power for the second eye,
generally changing the calculated IOL power by one-half of the prediction
error in the first eye. Methods to Improve the Accuracy of IOL Power
Calculations in Postrefractive Eyes
IOL Power Calculation in Long Eyes Many approaches have been proposed to improve the accuracy of IOL
power calculation in eyes following LASIK/PRK/RK. These can be catego-
In long eyes, IOL power formulas tend to select IOLs of insufficient power, rized into three groups depending on the use of historical data acquired
leaving patients with postoperative hyperopia. Inaccurate measurement before refractive surgery was performed.
of preoperative AL has been reported to be the main reason for postop-
erative refractive error in axial high myopia.17 The incidence of posterior Methods Relying on Prior Clinical Data
staphyloma increases with increasing AL. Ultrasonic biometric methods Methods in this category use completely historical data. Clinical studies
can produce errors in the presence of a posterior staphyloma by giving have shown that they are less accurate than the formulas in other catego-
falsely long AL. ries described in the following sections.24 The concern with these methods
Theoretically, optical biometry permits more accurate measurements is their sensitivity to errors in the historically obtained data. A 1.00 D error
when a posterior staphyloma is present. However, in a study investigat- in either the keratometric or refractive values translates to nearly a 1.00 D
ing the accuracy of SRK/T formula in eyes with negative or zero-powered postoperative refractive error.
IOLs, MacLaren and colleagues18 reported consistent hyperopic errors
across all three methods of biometry (A-scan, B-scan, and optical). This Methods Using a Combination of the Surgically Induced
indicates that eliminating or minimizing the adverse impact of posterior Refractive Change (ΔMR) and Current Corneal Power Values
staphylomata on IOL calculations does not prevent hyperopic surprises in These methods modify either corneal power measurements at the time the
long eyes. patient presents for cataract surgery or calculated IOL power based on ΔMR.
We proposed a method for optimizing AL in long eyes (Wang–Koch These methods multiply ΔMR by a fraction of between 0.15 and 0.33,
adjustment).19 Our results showed that this method significantly improved depending on the formula. This translates to an error of 0.15–0.33 D for
the accuracy of IOL power calculation in eyes with IOL powers ≤5.00 D each 1.00 D of error in ΔMR, reducing potential errors caused by having
and significantly reduced the percentage of eyes that would be left hyper- inaccurate historical data. Studies have shown that some of these methods
opic. We recommend using the optimized AL in eyes with AL >25.2 mm. have consistently been among the more accurate approaches.24
Based on the formula, the optimized AL is calculated from the measured
optical or ultrasonic AL using the following equation: Methods Requiring No Historical Data
Several methods requiring no historical data have been proposed. Surgeons
Holladay 1 Optimized AL = 0.8289 × Measured AL + 4.2663 use these approaches most often. The formulas fall into two categories:
Haigis Optimized AL = 0.9286 × Measured AL + 1.562

• Formulas that adjust measured corneal power from the anterior corneal
surface based on either regression analysis or assumed posterior
corneal power, such as the Wang–Koch–Maloney, Shammas, Haigis-L,
SRK T Optimized AL = 0.8544 × Measured AL + 3.7222
Potvin-Hill Pentacam, and Barrett True K No History formulas.
Hoffer Q Optimized AL = 0.853 × Measured AL + 3.5794
• Formulas based on corneal power measurements from both ante-
rior and posterior corneal surfaces. Using the RTVue (Optovue Inc,
Fremont, CA), Tang and colleagues25 developed an OCT-based IOL cal-
Then the optimized AL is entered into the IOLMaster or Lenstar
culation formula using the anterior and posterior corneal powers and
and the calculation is performed again. We recommend selecting the
the central corneal thickness.
IOL power that predicts a minus prediction error close to zero (−0.1 to
−0.2 D), since slight myopic results may occur with this approach of Methods requiring no historical data have been shown to perform as
optimizing AL. well as those using a combination of ΔMR and current corneal power
A recent advance has been the development of the Barrett Universal values. Promising results for the OCT-based IOL formula and Barrett True
II formula, which has been refined to improve outcomes in long eyes. In K formula have been reported.26,27 However, the percentage of eyes within
a study of eyes with AL ≥26.0 mm, Abulafia et al.20 reported that for IOL 0.5 D of target refraction was under 70% for all formulas, the highest value
powers <6.00 D, best results occurred with the Holladay 1 with Wang– being 68.3% for the OCT formula. Obviously, more studies are needed to
Koch adjustment, Haigis with Wang–Koch adjustment, and Barrett Uni- improve the accuracy of corneal power measurements and to develop new
versal II formulas. IOL power calculation formulas in these eyes.
Due to the low IOL powers required in long eyes, accuracy of ELP esti-
mation is not as important as in normal and short eyes. By refining the AL Web-Based Post-Refractive IOL Calculator
value used in current formulas, excellent outcomes can be anticipated as To simplify the complicated and time-consuming calculations discussed
shown in these studies.19,20 above, we developed a web-based post-refractive IOL power calculator in
2007 (Fig. 5.5.3) (http://www.ascrs.org/). This calculator can be used for
eyes with previous myopic LASIK/PRK, hyperopic LASIK/PRK, or RK. We
IOL Power Calculation in Eyes With Previous have performed major updates to the online calculator in the past and will
Corneal Refractive Surgery continue to update it. During the past year, the number of visits to this
calculator was over 120,000.
Cataract surgeons are facing challenges in IOL power calculation in eyes
that have undergone excimer laser photorefractive keratectomy (PRK), Radial Keratotomy
344 laser in situ keratomileusis (LASIK), or radial keratotomy (RK). IOL power calculation in RK eyes is even more difficult due to the greater
irregularity of the anterior corneal curvature and the posterior corneal
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5.5

Fig. 5.5.3 Postrefractive IOL Calculator at American Society of Cataract and Refractive Surgery (http://www.ascrs.org/).
curvature changes. Furthermore, it has been reported that 20%–50% of RK improvements in the accuracy of IOL power calculation in RK eyes are
eyes have a gradual hyperopic shift. We recommend using topographically desirable and await robust techniques to measure anterior and posterior
derived average corneal power over the central 2–4 mm zone. Compen- corneal curvature.
sation for potential error in ELP is still required, with use of double-K
version of IOL formulas if the corneal power is used for ELP prediction. IOL Power Calculation in Keratoconic Eyes
We find relatively lower accuracy in post-RK eyes compared with eyes
following LASIK/PRK. In 95 post-RK eyes, we28 evaluated the accuracy IOL calculations are more difficult in eyes with keratoconus, presumably
of newer IOL formulas (OCT and Barrett True K), and the percentage of due to the irregularity of the cornea and the change in ratio of anterior 345
eyes within 0.5 D of target was less than 50% for all formulas. Further to posterior corneal curvatures. Using the Holladay 1, Barrett, and Olsen
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formulas in 21 keratoconic eyes, we found that the mean refractive predic- • Barrett Toric Calculator: This calculator predicts posterior corneal astig-
5 tion errors were +1.25 D, +1.15 D, and +1.36 D, respectively, and the mag-
nitude of the hyperopic prediction error with Holladay 1 formula increased
with increasing corneal power. Improved corneal imaging technology for
matism based on regression analysis in patients implanted with toric
IOLs.
• Holladay Toric Calculator: With this calculator, IOL spherical power and
accurate anterior and posterior corneal power measurements is needed. the predicted ELP in each eye are used to estimate the effective IOL
The Lens
cylinder power at the corneal plane. It has the option to use the Baylor
nomogram to take into account posterior corneal astigmatism.
IOL Power Calculation in Eyes • Toric calculators provided by manufacturers: The Alcon toric calculator
uses the Barrett toric calculator. The Johnson & Johnson toric calculator
Following Keratoplasty is based on outcomes of their clinical studies combined with the Baylor
Eyes following penetrating keratoplasty may have high amounts of irreg- nomogram. The PhysIOL toric calculator integrates the Abulafia–Koch
ular anterior corneal astigmatism and uncertain posterior corneal values. formula to account for posterior corneal astigmatism when standard
With Descemet’s stripping automated endothelial keratoplasty, corneal keratometry are used.
power changes are less pronounced with minimal astigmatic change but
with a hyperopic shift of around 0.70–1.5 D. Descemet membrane endo- When selecting the IOL toricity, several factors must be taken into account:
thelial keratoplasty induces even more modest refractive changes, with
a reported hyperopic refractive shift of 0.24–0.50 D and minimal change
• The cylindrical power of the toric IOL should be chosen based on the
total corneal astigmatism, taking into consideration anterior and poste-
in refractive astigmatism. Although the complexity of IOL calculation
rior corneal astigmatism and surgically induced astigmatism.
has diminished as procedures have advanced, it remains challenging to
perform IOL power calculation in these eyes.
• The impact of ELP and IOL power on the effective cylinder power of
the IOL at the corneal plane should be considered. Effective toricity
of the IOL diminishes with increasing ACD and lower IOL spherical
TORIC IOL CALCULATION power.
It has been estimated that 30% of cataract patients have more than 0.75 D
• It is desirable to leave patients with a slight WTR astigmatism due to
the normal tendency for corneal astigmatism to drift ATR with advanc-
of corneal astigmatism. Toric IOLs provide consistent and stable correction
ing age.33
of astigmatism. Accurate measurement of total corneal astigmatism is a
critical element in correcting astigmatism during cataract surgery. Abulafia et al.34 reported that with the Barrett toric calculator, 75% and
100% of eyes were within ±0.50 D and ±1.00 D of the predicted residual
astigmatism, respectively. In another study, Abulafia et al.32 evaluated and
Impact of Posterior Corneal Astigmatism compared the accuracy of two toric IOL calculators (the original Alcon toric
Newer technologies, such as Scheimpflug devices and OCT systems, calculator and the Holladay toric calculator) with or without the Abulafia–
are now used in the clinical setting for measuring the posterior corneal Koch formula. Results showed that adjustment of these commercial toric
surface. Several studies using different methodologies reported that the IOL calculators by the Abulafia–Koch formula significantly improved the
posterior cornea has astigmatism that ranges from 0.26 to 0.78 D.29,30 prediction of postoperative astigmatic outcome with 76.9%–78.2% of eyes
There were three new findings in our study30: (1) in corneas with ante- within ±0.5 D and 97.4%–98.7% within ±1.00 D.
rior corneal with-the-rule (WTR) astigmatism, as astigmatism increases,
the posterior cornea is increasingly steep vertically; (2) posterior corneal Imaging and Guidance Systems for Toric
astigmatism is relatively constant in corneas with anterior against-the-rule IOL Alignment
(ATR) astigmatism; and (3) much individual variability occurs in posterior
corneal astigmatism, exceeding at extremes over 0.5 D. Accurate toric lens alignment at the desired meridian is crucial to achieve
effective astigmatism correction. When a toric IOL is misaligned, a reduc-
Selection of Toric IOL Toricity tion occurs in the cylinder correction along the desired meridian and
induction of cylinder at a new meridian.
Several approaches are available to guide the selection of IOL toricity: Traditionally, the eye is manually marked preoperatively. With advances
in technology, several imaging and guidance systems for toric IOL align-
• Baylor Toric IOL Nomogram: Using regression analysis,31 we devel-
ment have been developed:
oped the Baylor Nomogram (Table 5.5.1). It provides a clinical method
to compensate for posterior corneal astigmatism as a function of the
meridian and magnitude of anterior corneal astigmatism.
• TrueVision 3D visualization and guidance system (TrueVision 3D Surgical,
Santa Barbara, CA): The Cassini topographer (i-Optics, The Hague,
• Abulafia–Koch Formula: Based on outcomes of patients implanted with Netherlands) is used to obtain an image of the patient’s eye preopera-
toric IOLs, Abulafia–Koch32 proposed an improved regression formula
tively. This source image is then uploaded to the TrueVision system in
to refine the precision of incorporating the posterior corneal astigma-
the operating room for intraoperative registration.
tism into toric IOL planning. This has been incorporated in the new
In a recent study, we evaluated the accuracy of toric IOL alignment in
Hill-RBF calculator that is available on the Lenstar.
femtosecond laser-assisted cataract surgery using the TrueVision system
compared with manual marking combined with femtosecond laser
marks.35 No significant difference existed between these two methods.
TABLE 5.5.1 Baylor Toric IOL Nomograma (Postoperative Target: • Callisto eye system (Carl Zeiss Meditec, Jena, Germany): Preoperatively,
Up to 0.40 D With-the-Rule Astigmatism) an image of the eye is taken along with keratometry measurements
using the IOLMaster. Both the reference images and keratometry data
Effective IOL Cylinder Power at Corneal Plane (D) WTR (D) ATR (D) are transferred to the Callisto eye computer-assisted surgery system.
0b ≤1.69 (PCRI) <0.39 The toric assistant feature, Z ALIGN, uses the reference axis from the
1.00 1.70–2.19 0.40a–0.79 IOLMaster and the projected target axis in the microscope eyepiece to
1.50 2.20–2.69 0.80–1.29
ensure toric IOL alignment.
2.00 2.70–3.19 1.30–1.79
• VERION image guided system (Alcon Laboratories, Ft. Worth, TX): This
system is composed of the Reference Unit and the Digital Marker.
2.50 3.20–3.69 1.80–2.29
The Reference Unit measures both keratometry and pupil size and
3.00 3.70–4.19 2.30–2.79 captures a high-resolution reference image of the eye that is used for
3.50 4.20–4.69 2.80–3.29 intraoperative tracking and registration. The Digital Marker uses the
4.00 4.70–5.19 3.30–3.79 preoperative image and intraoperative registration to guide toric IOL
ATR, Against-the-rule astigmatism; D, diopter; PCRI, peripheral corneal relaxing incision; WTR, alignment.
with-the-rule astigmatism. Elhofi and Helaly36 compared clinical outcomes following toric IOL
a
Values in the table are the vector sum of the anterior corneal and surgically induced
astigmatism.
alignment with digital image guidance using the VERION and manual
b
If an SN6AT2 is available, consider implanting it in WTR astigmatism of 1.40–1.69 D, and in slit-lamp–assisted preoperative marking. The use of the VERION
346 ATR of 0.30–0.49 D (in this latter case, T3 would be implanted in astigmatism ranging from
0.50–0.79 D).
system resulted in less postoperative deviation from the targeted astig-
matic axis.
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Fig. 5.5.4 The Light Adjustable Lens and the Perfect
THE LIGHT ADJUSTABLE LENS AND THE PERFECT LENS Lens. Top: Exposure to targeted ultraviolet light in the
Light Adjustable Lens resulting in a predictable shape 5.5
change and subsequent locking of the treatment.
iris light lock-in Bottom: (A) Side view of the Perfect Lens and (B) top

view of the Perfect Lens. The concentric diffractive
zones are visible.
light
A B
All of these automated systems using anatomic or topographic land- higher-order aberrations. Ideally, such an IOL could be modified multiple
marks to guide toric IOL alignment seek to decrease the inherent error times to adapt to patient’s changing visual needs and to compensate for
associated with preoperative manual marking alone. As our study showed, aging changes of the cornea.
manual marking can achieve accuracy that matches the automated The Light Adjustable Lens (LAL; Calhoun Vision, Pasadena, CA) (Fig.
systems, but the latter clearly have the advantage of greater convenience. 5.5.4) enables residual spherical and cylindrical errors to be corrected or
However, there is still a need for clinical studies assessing the efficacy of adjusted after the postoperative refraction has stabilized.39–41 In 34 myopic
each of these systems. LASIK/PRK eyes, Brierley39 reported that LAL produced refractive predic-
tion errors within 0.25 D in 74% of eyes, 0.50 D in 97% of eyes, and 1.00 D
in 100% of eyes. Villegas and colleagues40 found that the combination of
INTRAOPERATIVE WAVEFRONT ABERROMETRY two light adjustments induced a maximum change in spherical power
Intraoperative wavefront aberrometry is a tool designed to fine-tune cat- of the LAL of between −1.98 D and +2.30 D and in astigmatism of up to
aract surgery results through aphakic refraction. It allows the surgeon to −2.68 D with axis errors below 9°.
confirm or revise the IOL power, confirm or rotate the toric IOL meridian, Another adjustable IOL under development is the Perfect Lens (Perfect
titrate limbal relaxing incisions, and open penetrating relaxing incisions. Lens, LLC, Irvine, CA) (see Fig. 5.5.4). This technology involves using a
Currently, there is only one commercially available device: femtosecond laser to modify the hydrophilicity and thus the refractive
index and refractive characteristics of defined zones within a standard
• Optiwave Refractive Analysis (ORA) system (WaveTec Vision Systems Inc,
IOL. Changing the relative heights and profiles of the concentric refrac-
Aliso Viejo, CA): Using infrared light and Talbot–Moiré interferometry,
tive zones with the femtosecond laser enables modification of IOL spher-
the ORA system measures the aphakic refraction intraoperatively after
ical aberration, asphericity, toricity, and multi-focality with a repeatable,
cataract extraction. The system calculates the optimal IOL power based
in-office procedure. In a study by Sahler et al., Perfect Lens technology
on the aphakic spherical equivalent, the patient’s preoperatively mea-
altered the power of the IOL to within 0.1 D of the targeted change without
sured AL and keratometry, and the estimated ELP using a proprietary
decreasing the optical quality of the lens.42
algorithm.
In 246 myopic LASIK/PRK eyes, Ianchulev and colleagues37
reported that ORA achieved the greatest predictive accuracy compared CONCLUSION
to Haigis-L and Shammas method, with 67% of eyes within 0.5 D and
Optical biometry is the clinical standard for ocular biometry. With advanced
94% within 1.00 D of the predicted outcome. Fram et al.38 compared the
IOL power calculation formulas, the accuracy of IOL power prediction has
accuracy of ORA, OCT-based formula, Haigis-L, and Masket formula
improved dramatically in recent years. However, refractive surprises still
in LASIK/PRK eyes. There was no significant difference among the
occur, especially in eyes with previous corneal refractive or endothelial
methods.
replacement surgery.
The aphakic refractive data obtained with intraoperative aberrometry In these challenging cases, we warn patients of IOL power calculation
devices take into account a variety of factors, such as the posterior corneal inaccuracy and the possible need for additional surgery, with its associated
astigmatism. However, these measurements have two limitations: (1) ELP cost. The most prudent strategy for the surgeon may be to obtain IOL cal-
cannot be measured with these devices and has to be estimated, and (2) culations using several different methods and select the IOL power based
the cornea and perhaps other factors have been modified by the drops and on the consensus of multiple methods. Future advances are needed in all
surgical trauma. Further studies are desirable to evaluate the performance areas, including methods of measuring corneal power, predicting effective
of intraoperative wavefront aberrometry in patients undergoing cataract lens position, and calculating the lens power.
surgery.
KEY REFERENCES
POSTOPERATIVE IOL ADJUSTMENT Abulafia A, Barrett GD, Rotenberg M, et al. Intraocular lens power calculation for eyes with
an axial length greater than 26.0 mm: comparison of formulas and methods. Cataract
The “holy grail” in this field may be an adjustable IOL. Once the post- Refract Surg 2015;41:548–56.
operative refraction has stabilized, the IOL could be modified to elimi- Aramberri J. Intraocular lens power calculation after corneal refractive surgery: double-K 347
nate the residual spherical and astigmatic refractive errors and residual method. J Cataract Refract Surg 2003;29:2063–8.
booksmedicos.org
Cooke DL, Cooke TL. Comparison of 9 intraocular lens power calculation formulas. J Cata- Norrby S. Sources of error in intraocular lens power calculation. J Cataract Refract Surg
5 ract Refract Surg 2016;42(8):1157–64.

Ford J, Werner L, Mamalis N. Adjustable intraocular lens power technology. J Cataract
Refract Surg 2014;40:1205–23.
Fram NR, Masket S, Wang L. Comparison of intraoperative aberrometry, OCT-based IOL
2008;34:368–76.
Olsen T. Sources of error in intraocular lens power calculation. J Cataract Refract Surg
1992;18:125–9.
Wang L, Hill W, Koch DD. Evaluation of intraocular lens power prediction methods using the
formula, Haigis-L, and Masket formulae for IOL power calculation after laser vision American Society of Cataract and Refractive Surgeons Post-Keratorefractive Intraocular
The Lens
correction. Ophthalmology 2015;122(6):1096–101. Lens Power Calculator. J Cataract Refract Surg 2010;36:1466–73.
Goebels S, Pattmöller M, Eppig T, et al. Comparison of 3 biometry devices in cataract Wang L, Shirayama M, Ma XJ, et al. Optimizing intraocular lens power calculations in eyes
patients. J Cataract Refract Surg 2015;41(11):2387–93. with axial lengths above 25.0 mm. J Cataract Refract Surg 2011;37:2018–27.
Gökce SE, Zeiter JH, Weikert MP, et al. Intraocular lens power calculations in short eyes Wang L, Tang M, Huang D, et al. Comparison of newer IOL power calculation methods for
using 7 formulas. J Cataract Refract Surg 2017;43:892–7. post-corneal refractive surgery eyes. Ophthalmology 2015;122:2443–9.
Hill WE. IOL power selection: think different. 11th annual Charles D. Kelman Lecture AAO,
Las Vegas, 2015.
Koch DD, Ali SF, Weikert MP, et al. Contribution of posterior corneal astigmatism to total Access the complete reference list online at ExpertConsult.com
corneal astigmatism. J Cataract Refract Surg 2012;38:2080–7.
Ma JX, Tang M, Wang L, et al. Comparison of newer IOL power calculation methods for
eyes with previous radial keratotomy. Invest Ophthalmol Vis Sci 2016;57(9):OCT162–8.
348
booksmedicos.org
REFERENCES 22. Awwad ST, Kilby A, Bowman RW, et al. The accuracy of the double-K adjustment for
third-generation intraocular lens calculation formulas in previous keratorefractive
1. Norrby S. Sources of error in intraocular lens power calculation. J Cataract Refract Surg
2008;34:368–76.
surgery eyes. Eye Contact Lens 2013;39:220–7.
23. Wang L, Booth MA, Koch DD. Comparison of intraocular lens power calculation methods
5.5
2. Zaldivar R, Shultz MC, Davidorf JM, et al. Intraocular lens power calculations in patients in eyes that have undergone LASIK. Ophthalmology 2004;111:1825–31.
24. Wang L, Hill W, Koch DD. Evaluation of intraocular lens power prediction methods

with extreme myopia. J Cataract Refract Surg 2000;26(5):668–74.
3. Olsen T. Sources of error in intraocular lens power calculation. J Cataract Refract Surg using the American Society of Cataract and Refractive Surgeons Post-Keratorefractive
1992;18:125–9. Intraocular Lens Power Calculator. J Cataract Refract Surg 2010;36:1466–73.
4. Goebels S, Pattmöller M, Eppig T, et al. Comparison of 3 biometry devices in cataract 25. Tang M, Li Y, Huang D. An intraocular lens power calculation formula based on optical
patients. J Cataract Refract Surg 2015;41(11):2387–93. coherence tomography: a pilot study. J Refract Surg 2010;26:430–7.
5. Kunert KS, Peter M, Blum M, et al. Repeatability and agreement in optical biometry of 26. Wang L, Tang M, Huang D, et al. Comparison of newer IOL power calculation methods
a new swept-source optical coherence tomography-based biometer versus partial coher- for post-corneal refractive surgery eyes. Ophthalmology 2015;122:2443–9.
ence interferometry and optical low-coherence reflectometry. J Cataract Refract Surg 27. Abulafia A, Hill WE, Koch DD, et al. Accuracy of the Barrett True-K formula for intraocu-
2016;42(1):76–83. lar lens power prediction after laser in situ keratomileusis or photorefractive keratectomy
6. Lege BA, Haigis W. Laser interference biometry versus ultrasound biometry in certain for myopia. J Cataract Refract Surg 2016;42(3):363–9.
clinical conditions. Graefes Arch Clin Exp Ophthalmol 2004;242(1):8–12. 28. Ma JX, Tang M, Wang L, et al. Comparison of newer IOL power calculation methods for
7. Holladay JT, Gills JP, Leidlein J, et al. Achieving emmetropia in extremely short eyes with eyes with previous radial keratotomy. Invest Ophthalmol Vis Sci 2016;57(9):OCT162–8.
two piggyback posterior chamber intraocular lenses. Ophthalmology 1996;103(7):1118–23. 29. Dubbelman M, Sicam VA, van der Heijde GL. The shape of the anterior and posterior
8. Olsen T, Hoffmann P. C constant: new concept for ray tracing-assisted intraocular lens surface of the aging human cornea. Vision Res 2006;46:993–1001.
power calculation. J Cataract Refract Surg 2014;40(5):764–73. 30. Koch DD, Ali SF, Weikert MP, et al. Contribution of posterior corneal astigmatism to
9. Hoffmann P, Wahl J, Preussner PR. Accuracy of intraocular lens calculation with ray total corneal astigmatism. J Cataract Refract Surg 2012;38:2080–7.
tracing. J Refract Surg 2012;28(9):650–5. 31. Koch DD, Jenkins RB, Weikert MP, et al. Correcting astigmatism with toric intraocular
10. Hill WE. IOL power selection: think different. 11th annual Charles D. Kelman Lecture lenses: effect of posterior corneal astigmatism. J Cataract Refract Surg 2013;39:1803–9.
AAO, Las Vegas, 2015. 32. Abulafia A, Koch DD, Wang L, et al. New regression formula for toric intraocular lens
11. Clarke GP, Burmeister J. Comparison of intraocular lens computations using a neural calculations. J Cataract Refract Surg 2016;42:663–71.
network versus the Holladay formula. J Cataract Refract Surg 1997;23(10):1585–9. 33. Hayashi K, Hirata A, Manabe S, et al. Long-term change in corneal astigmatism after
12. Ladas JG, Siddiqui AA, Devgan U, et al. A 3-D “Super Surface“ combining modern intra- sutureless cataract surgery. Am J Ophthalmol 2011;151:858–65.
ocular lens formulas to generate a “super formula” and maximize accuracy. JAMA Oph- 34. Abulafia A, Barrett GD, Kleinmann G, et al. Prediction of refractive outcomes with toric
thalmol. 2015;133(12):1431–6. intraocular lens implantation. J Cataract Refract Surg 2015;41:936–44.
13. Olsen T. Calculation of intraocular lens power: a review. Acta Ophthalmol Scand 35. Montes de Oca I, Kim EJ, Wang L, et al. Accuracy of toric intraocular lens axis alignment
2007;85(5):472–85. using a 3-dimensional computer-guided visualization system. J Cataract Refract Surg
14. Kane JX, Heerden AV, Atik A, et al. Intraocular lens power formula accuracy: comparison 2016;42(4):550–5.
of 7 formulas. J Cataract Refract Surg 2016;42:1490–500. 36. Elhofi AH, Helaly HA. Comparison between digital and manual marking for toric intra-
15. Cooke DL, Cooke TL. Comparison of 9 intraocular lens power calculation formulas. J ocular lenses: a randomized trial. Medicine (Baltimore) 2015;94(38):e1618.
Cataract Refract Surg 2016;42(8):1157–64. 37. Ianchulev T, Hoffer KJ, Yoo SH, et al. Intraoperative refractive biometry for predicting
16. Gökce SE, Zeiter JH, Weikert MP, et al. Intraocular lens power calculations in short eyes intraocular lens power calculation after prior myopic refractive surgery. Ophthalmology
using 7 formulas. J Cataract Refract Surg 2017;43:892–7. 2014;121:56–60.
17. Kora Y, Koike M, Suzuki Y, et al. Errors in IOL power calculations for axial high myopia. 38. Fram NR, Masket S, Wang L. Comparison of intraoperative aberrometry, OCT-based IOL
Ophthalmic Surg 1991;22:78–81. formula, Haigis-L, and Masket formulae for IOL power calculation after laser vision cor-
18. MacLaren RE, Sagoo MS, Restori M, et al. Biometry accuracy using zero- and nega- rection. Ophthalmology 2015;122(6):1096–101.
tive-powered intraocular lenses. J Cataract Refract Surg 2005;31:280–90. 39. Brierley L. Refractive results after implantation of a light-adjustable intraocular lens in
19. Wang L, Shirayama M, Ma XJ, et al. Optimizing intraocular lens power calculations in postrefractive surgery cataract patients. Ophthalmology 2013;120:1968–72.
eyes with axial lengths above 25.0 mm. J Cataract Refract Surg 2011;37:2018–27. 40. Villegas EA, Alcon E, Rubio E, et al. Refractive accuracy with light-adjustable intraocular
20. Abulafia A, Barrett GD, Rotenberg M, et al. Intraocular lens power calculation for eyes lenses. J Cataract Refract Surg 2014;40(7):1075–84.
with an axial length greater than 26.0 mm: comparison of formulas and methods. Cata- 41. Ford J, Werner L, Mamalis N. Adjustable intraocular lens power technology. J Cataract
ract Refract Surg 2015;41:548–56. Refract Surg 2014;40:1205–23.
21. Aramberri J. Intraocular lens power calculation after corneal refractive surgery: double-K 42. Sahler R, Billie JF, Enright S, et al. Creation of a refractive lens within an existing intra-
method. J Cataract Refract Surg 2003;29:2063–8. ocular lens using a femtosecond laser. J Cataract Refract Surg 2016;42(8):1207–15.
348.e1
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Part 5 The Lens

Indications for Lens Surgery/Indications

for Application of Different Lens 5.6
Surgery Techniques
Frank W. Howes
Definition: Surgery to the crystalline lens of the eye. BOX 5.6.1 Medical Indications for Lens Surgery
I. Lenticular opacification (cataract)
II. Lenticular malposition
A. Subluxation
Key Features B. Dislocation
• Lens surgery is the most common eye operation. III. Lenticular malformation
• Technical indications for lens surgery are divided into two main A. Coloboma
categories: medical and optical. B. Lenticonus
• All lens surgery for whatever indication should be considered C. Lentiglobus
refractive surgery. D. Spherophakia
IV. Lens-induced inflammation
A. Phacotoxic uveitis (phacoanaphylaxis)
B. Phacolytic glaucoma
INTRODUCTION C. Phacomorphic glaucoma
The indications for lens surgery today may be classified into two main V. Lenticular tumor
categories: A. Epithelioma
B. Epitheliocarcinoma
• Medical – surgical or pathological indication, and VI. Facilitatory (surgical access)
• Optical – or refractive lens exchange. A. Vitreous base
Medical indications arise from pathological states of the lens of varying B. Ciliary body
causes, usually related to lens clarity, lens position, or other lens-related C. Ora serrata
conditions, such as inflammation, glaucoma, or the threat of glaucoma.
Surgical or pathological indications have existed for centuries, if not millen-
nia, and are generally indisputable. Refractive indications for lens surgery, separation in terms of insured payments. The degree to which the opacifi-
in contrast, include clear lens ametropic refractive states. The current high cation obstructs light can, additionally, be measured by laser interferome-
standards of lens surgery in terms of safety, accuracy, and customization try.1 Progressive changes in cataract density over time can be documented
have opened a new world of refractive correction for many patients who by slit-lamp estimation using the Lens Opacification Classification System
were previously considered untreatable. Lens surgery has found an indis- (LOCS-III) devised by Chylack and coworkers,2 by Scheimpflug photogra-
putable position in refractive surgery among the various competitors of phy of nuclear cataracts3 and by Neitz-Kawara retroillumination photogra-
laser surgery, phakic IOL (intraocular lens) surgery, and incisional corneal phy of posterior sub-capsular cataracts.4 A useful figure to use for cataract/
surgery. As customization has improved for each age group and each noncataract separation is approximately 20% opacification on Pentacam
refractive error group, so have the various treatment modalities expanded Scheimpflug densitometry (Fig. 5.6.1).5
or contracted with respect to patient safety and accuracy of outcome.
Cataract in the Presence of Other Ocular Disorders
The decision regarding whether and when to remove a cataract in an oth-
MEDICAL INDICATIONS FOR LENS SURGERY erwise healthy eye usually depends on the impact of the cataract on the
Lenticular Opacification (Cataract) visual function of the eye and the impact of that level of visual impair-
ment on the person’s life. The status of the other eye also is important.
The medical indications for lens surgery (Box 5.6.1) are true pathologi- In healthy eyes whose only disorder is cataract, the presumed outcome
cal states, some of which may threaten the integrity of the whole organ after uncomplicated surgery is better vision than before surgery. Indeed,
(the eye). They also interfere with a major ocular function: focused vision. in high-volume cataract units, a success rate of 98% can be expected. Thus
Lenticular malformation and opacification obstruct the pathway of light; when one applies a risk–benefit ratio with such a high degree of success,
reduce the available quantity of light; scatter light off axis; reduce contrast surgery is usually the mutually agreed upon course.
sensitivity; diminish color intensity; reduce resolution acuity; may alter However, such may not be the case when the cataract is associated with
lens texture in such a way as to contribute to a decrease in accommodation other disorders, especially if they are contributing factors to the loss of
amplitude, particularly in the case of presenile nuclear sclerosis; and, in vision of an eye. Therefore, such conditions as amblyopia, corneal opaci-
the case of progressive nuclear sclerosis, often result in a myopic alteration fication, vitreous opacification, maculopathy, retinopathy, glaucoma, and
of a previously stable lifelong refractive state. optic neuropathy may alter or delay the decision to operate, based not so
It is generally agreed that surgical intervention is indicated when there much on the expected risks but rather on the limited benefits. In some
is “functional” visual impairment. cases, lens surgery is indicated to preserve peripheral vision only for func-
The boundary between refractive surgery and cataract surgery remains tional ambulation. In other cases, maintenance of a posterior segment
somewhat blurred, especially in view of the variable nature of what patients view for treatment purposes in progressive posterior segment conditions 349
deem loss of “functional” vision. A boundary, however, is necessary for the is an indication for lens surgery, even when the expectation for visual
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5
The Lens
A B
Fig. 5.6.1 Pentacam Scheimpflug densitometry (A) and slit-lamp imagery of Lens Opacification Classification System III NO3 cataract (B). (Courtesy Dr Lee Lenton, Vision Eye
Institute Australia.)
improvement may be minimal.11 Also, if the other eye is blind, the surgery The indications for surgery depend on the degree to which the specific
may be delayed. malformation interferes with vision or the integrity of the involved eye.
Systemic conditions may play a role in deciding whether and when to Such abnormalities may be associated with amblyopia. Early detection and
remove a cataract. Is the patient’s diabetes under control? Has there been surgical intervention should be incorporated with a plan for amblyopia
a stroke with hemianopia? Is the patient on systemic anticoagulants? Is therapy.
the patient terminally ill or immunologically suppressed? Does the patient
have Alzheimer’s disease or severe co-operation difficulty? Lens-Induced Ocular Inflammation
Thus, the decision to remove a cataract may become a collaborative
endeavor, with participation by the patient, the patient’s family, the patient’s Phacoanaphylactic endophthalmitis (phacotoxic uveitis) occurs in an
primary physician, the surgeon, a governmental agency, and a third-party immunologically mature and competent host and is related to physical or
payer. The decision, therefore, is determined not only by technological chemical disruption of the lens capsule. Surgery may be the appropriate
findings and expectations, but also by a “holistic” evaluation of the impact treatment for this form of ocular inflammation.
of such a decision on that person’s life, as defined by that society. Various
tests are available to assess degrees of disability, such as the Visual Func- Lens-Induced Glaucoma
tion Index (VF-14)6-9 or the Activities of Daily Vision Scale (ADVS).10,11
Inflammatory Glaucoma (Phacolytic Glaucoma)
Phacolytic glaucoma occurs in an eye with a mature lens in which the lens
Lenticular Malposition capsule is intact. Denatured, nonantigenic liquefied lens material leaks out
Subluxation (the displacement of the lens within the posterior chamber) through the intact lens capsule and elicits a macrophagic, inflammatory
and dislocation (displacement of the lens out of the posterior chamber reaction. The macrophages, engorged with lens material, clog the open
into the anterior chamber or vitreous) of the lens are different degrees of angle, leading to a secondary open-angle glaucoma. Removal of the lens
the same phenomenon and result from dysfunction of the zonules. The and intraocular lens placement is usually curative, obviating the need for
zonules may be defective as a result of congenital malformation, total or other forms of medical or surgical pressure management.
partial agenesis, or a hereditary metabolic disorder, such as Marfan’s syn-
drome. Chronic inflammation and pseudoexfoliation have been shown to Pupil Block and Angle Closure (Phacomorphic Glaucoma)
be associated with a weakness in the zonular fibers or their attachments. Similarly, removal of the lens in this instance is also curative. The growth
Ocular trauma is an obvious cause. Subluxation, in the absence of associ- of the lens with age progressively engulfs anterior segment space and may
ated sequelae, may not be visually significant and may not be an indication ultimately lead to acute angle–closure glaucoma through the mechanism
for lensectomy. Similarly, complete dislocation of an intact lens into the of pupillary block. This is more likely in hyperopic eyes due to the short
inferior vitreous may be a quiescent event in the absence of inflammation axial length and already crowded anterior segments. Lens removal and
and may simply produce a state of refractive aphakia, correctable nonsur- replacement with an intraocular lens greatly increases anterior segment
gically with a spectacle or contact lens or surgically with IOL implantation. space and in most instances resolves the glaucoma.
Subluxation to the extent that the equator of the lens is visible in the mid-
sized pupil is usually visually significant, causing glare, fluctuating vision,
and monocular diplopia. This symptom complex would qualify for lens
REFRACTIVE INDICATIONS FOR LENS SURGERY
surgery. Refinements in measurement technology, ocular anesthesia, incision tech-
nology, lensectomy techniques, ophthalmic viscosurgical devices (OVD)
Lenticular Malformation tissue protection, and IOL technology has allowed the accurate and suc-
cessful correction of refractive errors.
These conditions of abnormal lens development are congenital. They may Almost all the operable tissues and spaces of the eye have, over decades,
be genetic, hereditary, or the result of intrauterine infection or trauma. come under investigation as locations for refractive surgical modulation:
These conditions include lens coloboma, lenticonus, lentiglobus, and corneal epithelial surface, corneal stroma, corneal endothelial surface,
spherophakia, as well as varieties of congenital cataract, such as rubella anterior chamber, iris, pupil, posterior chamber, lens, and sclera. The lens,
and Lowe’s syndrome. Partial iris coloboma or total aniridia, whether con- therefore, assumes its role among the others as a popular location for sur-
genital, traumatic, or surgical, may be an indication for lens surgery to gical refractive modulation, sparing the other tissues where appropriate or
improve visual function or for cosmesis. The availability of aniridia IOLs necessary.
350 (Fig. 5.6.2A) and opaque endocapsular rings (see Fig. 5.6.2B,C) offers great Clear lens replacement stands as a viable procedure today for both myopia
improvements for such patients. and hyperopia, with the abilities now to control astigmatism (Fig. 5.6.3A),
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5.6
Indications for Lens Surgery/Indications for Application of Different Lens Surgery Techniques
A B C
Fig. 5.6.2 Iris Defect Prostheses. (A) Aniridia intraocular lens with opaque peripheral “pseudoiris.” (B) Aniridia endocapsular ring. (C) Iris coloboma endocapsular ring
(diaphragm type 96G). (Courtesy Morcher, GMBh, Germany.)
A B C
D E
Fig. 5.6.3 Older and Modern Intraocular Lens Modifications Providing Functions Additional to Pure Spherical Dioptric Correction. (A) Alcon toric IOL with blue
light filter (from Acryosof IOL). (B) Alcon multifocal IOL with apodized rings also with blue light filter (from Acryosof IOL). (C) Bausch and Lomb (B&L) Akreos aspherical IOL.
(Courtesy B&L Australia). (D) Older-style accommodative polymethyl methacrylate polypseudophakic intraocular lens (Courtesy T. Hara). (E) The C&C Vision CrystaLens model 351
AT-45 silicone multipiece intraocular lens. (Courtesy C&C Inc.)
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modulate higher-order aberration (see Fig. 5.6.3C), and reduce presby-
5 opic symptoms (see Fig. 5.6.3B,E). Patient demand for these services has TABLE 5.6.1 History of Cataract Surgery Techniques
increased dramatically in recent times. Year Technique Place Surgeon
Multifocal IOLs (see Fig. 5.6.3B) represent some of the first attempts 800 Couching India Unknown
at the intraocular correction of presbyopia. Other attempts at the devel-
The Lens
1015 Needle aspiration Iraq Unknown

opment of a truly accommodative pseudophakos have included the intra-
1100 Needle aspiration Syria Unknown
capsular injection of liquid silicone12–14 and the intracapsular placement of
high-water-content poly-HEMA lenses,15 a liquid silicone-filled intracapsu- 1500 Couching Europe Unknown
lar balloon,16,17 multiple IOLs (polypseudophakia)18,19 (see Fig. 5.6.3D), and 1745 ECCE inferior incision France Daviel
the flexing haptic accommodative IOLs (see Fig. 5.6.3E). 1753 ICCE by thumb expression England Sharp
1860 ECCE superior incision Germany von Graefe
1880 ICCE by muscle-hook zonulysis India Smith
INDICATIONS FOR DIFFERENT LENS and lens tumble
SURGERY TECHNIQUES 1900 ICCE by capsule forceps Germany Verhoeff

Kalt
Surgery affecting the human lens can be organized historically by its 1940 ICCE capsule suction erysiphake Europe Stoewer
chronology of development (Table 5.6.1) or divided into four major catego- I. Barraquer
ries by technique (Box 5.6.2). The indications for a particular lens surgery 1949 ECCE posterior chamber IOL and England Ridley
technique may be determined by several factors (Box 5.6.3). Different operating microscope
medical conditions or pathological states of the eye and the lens may favor 1951 Anterior chamber IOLs Italy Strampelli
one technique over another. In some countries, the availability of equip- Germany Dannheim
ment and the level of training of the surgeon may be factors that dictate 1957 ICCE by enzyme zonulysis Spain J. Barraquer
technique. Certain countries have governmental agencies, professional 1961 ICCE by capsule cryoadhesion Poland Krawicz
organizations, academic institutions, insurance payers, or surgical facili- 1967 ECCE by phacoemulsification United States Kelman
ties that regulate and control the types of surgical techniques surgeons J. Shock
may perform. For the purpose of this text, however, only specific medical 1975 Iris-pupil supported IOLs Netherlands Binkhorst
or pathological conditions of the eye are discussed as factors determining Worst
the choice of surgical technique. 1984 Foldable IOLs United States Mazzocco
South Africa Epstein
Intracapsular Cataract Extraction ECCE, Extracapsular cataract extraction; ICCE, intracapsular cataract extraction; IOL, intraocular
lens.
The intracapsular cataract extraction (ICCE) method of lens removal
has not been the procedure of choice in industrialized nations since the
BOX 5.6.2 Lens Surgery Techniques

I. Lens repositioning (“couching”) 2. Pupil
A. Extracapsular 3. Posterior chamber
B. Intracapsular a. Iris fixation (sutured or enclavated)
1. Physical (instrumental) zonulysis b. Ciliary sulcus (sutured or unsutured)
2. Pharmacological (enzymatic) zonulysis 4. Lens capsule
II. Lens removal a. Anterior capsule
A. Total (intracapsular) (1) Haptic sulcus/optic bag
1. Capsule forceps (2) Optic posterior chamber/haptic bag
2. Suction erysiphake b. Intracapsular (“in the bag placement”)
3. Cryoextraction c. Posterior capsule (haptic bag/optic Berger’s space)
B. Partial (extracapsular) 5. Pars plana (sutured)
1. Anterior capsulotomy/capsulectomy B. Optic materials
a. Discontinuous 1. Hydrophobic
b. Continuous (capsulorrhexis) a. Polymethyl methacrylate (PMMA)
c. Linear b. Silicone
2. Nucleus removal c. Acrylic
a. Assembled delivery (large incision) 2. Hydrophilic
(1) Expression (“push”) a. Poly hydroxyethyl methacrylate (poly-HEMA)
(2) Extraction (“pull”) b. Acrylic
b. Disassembled extraction c. Collagen-copolymer
(1) Phacosection C. Optic types
(2) Phacoemulsification-aspiration 1. Monofocal
(a) Ultrasound a. Spherical
(i) linear (1) Plus
(ii) torsional (2) Minus
(b) Laser b. Toric
(c) Water jet c. Telescopic
(d) Impeller d. Prismatic
3. Cortex removal 2. Multifocal
a. Irrigation 3. Accommodative
b. Aspiration IV. Lens enhancement: reversal of presbyopia by scleral expansion
III. Lens replacement (intraocular lens implantation) A. Ciliary cerclage
A. Locations B. Radial anterior ciliary sclerotomy
1. Anterior chamber
a. Angle fixation
352 b. Iris fixation
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development of modern extracapsular techniques in the late 1970s, pri- surgery and adherence to the principles of astigmatism avoidance and cor-
marily because of lower rates of postoperative posterior segment compli-
cations such as hemorrhage, vitreous loss, retinal detachment, and cystoid
rection. In the majority of primary situations for ICCE, the wound needs
to be large and hence constructed appropriately for minimization of astig- 5.6
macular edema. Current indications for planned intracapsular cataract matism induction.
surgery are therefore related only to situations where zonular laxity or defi-
ciency exists and where capsular bag instability is predicted. Under these
circumstances, safe and successful extracapsular surgery with intra-ocu- Extracapsular Extraction (Large-Incision Nuclear
lar lens implant, is often unlikely. Conditions likely to be associated with Expression Cataract Surgery)
these conditions are physical trauma to the eye, diseases processes such as
Marfans Syndrome and psuedoexfoliation, and isolated congenital anom- This technique became popular in the 1980s, as surgeons who had been
alies. Significant subluxation or dislocation of the crystalline lens neces- performing large-incision ICCE and anterior chamber implantation
sitates removal of the entire organ, done either by intracapsular cataract desired the benefits derived from an intact posterior capsule and poste-
surgery or by pars plana fragmentation and aspiration. rior chamber implantation. The technique persists today and is performed
Traditionally, ICCE involved removal of the complete intact lens through in large numbers, particularly in developing countries, where the more
a large incision measuring 12–14 mm. In earlier years these eyes were left advanced small-incision techniques of phacoemulsification (phaco) and
aphakic, with aphakic spectacle correction offered where available. Bilat- foldable lens implantation are not yet available for the masses.
eral surgery was invariably necessary to minimize aniseikonic problems, The only indications for nuclear delivery now relate to (1) hard nuclei
although contact lens correction was satisfactory. Many of these eyes have that cannot be safely emulsified by phaco and (2) capsule rupture with vit-
subsequently had secondary IOLs implanted, with the choice of IOL being reous presentation mid procedure. Cataracts with high-risk corneas (e.g.,
angle based, iris fixed (anterior or posterior) (see Fig. 5.6.4A), or sutured Fuchs’ endothelial dystrophy, corneal graft) were previously considered to
to the ciliary sulcus. be best dealt with by nuclear expression via continuous linear capsulotomy
Modern sulcus fixation IOLs now have design features that enable and intercapsular techniques.20,21 With optimal use of OVDs (“soft shell”)22
them to fibrose into the ciliary processes and sulcus (Fig. 5.6.4B), minimiz- and good technique,23 however, small-incision procedures are now the pro-
ing the chances of posterior dislocation common in previous sulcus fixa- cedure of choice.
tion IOLs. In addition, these lenses are foldable, allowing small-incision
Small-Incision Nuclear Expression Cataract

BOX 5.6.3 Lens Removal Techniques: Ocular Indications Surgery (“Mini-nuc” and Other Techniques)
I. Intracapsular extraction The indications for these techniques24,25 relate in the majority to the ben-
A. Zonular absence/dialysis efits of smaller incision surgery. Socioeconomic factors and instrumenta-
B. Lens subluxation tion availability together with surgeon experience also play a significant
C. Lens dislocation part in the choice of this type of surgery.
II. Nuclear delivery
A. Status of cornea Phacoemulsification
1. Low endothelial cell count
2. Guttate dystrophy This technique of nucleus removal has been performed through incisions
B. Status of cataract ranging from 3.2 mm down to less than 1.0 mm. Combined with fold-
1. Brunescent nuclear sclerosis able lens implantation, the major advantage of phaco is the small inci-
2. Cataracta nigra sion. Many phaco techniques have been described (Box 5.6.4), as have
C. Torn posterior capsule during phacoemulsification some nonultrasound techniques26,27 (of which very few can compete with
D. Zonulodialysis ultrasound). Current techniques use phaco through self-sealing, sutureless
III. Phacosection scleral and clear corneal incisions measuring 1.9–3.2 mm. The smaller
A. Same corneal, cataract, and capsular indications as nuclear delivery incisions are astigmatically neutral. These corneal incisions, if made on
B. Astigmatism management the steep axis of astigmatism and made wider or moved centrally from
IV. Phacoemulsification the limbus, can be used to titrate the amount of astigmatic correction.
A. Status of cornea These effects can be doubled by making similar incisions on the opposite
1. Normal endothelial cell count side of the steep axis on the cornea as well (see Table 5.6.2). The pres-
2. No guttate dystrophy ence therefore of corneal cylinder is an indication for phaco and foldable
B. Status of cataract lens implantation just as is the absence of corneal cylinder. The newest
1. Immature nuclear sclerosis of the cataract surgery techniques involves a combination of techniques,
2. Cortical or subcapsular cataract using femtosecond laser-assisted phaco, where the femtosecond laser can
C. Astigmatism management cut precise corneal incisions, an accurately sized and truly circular capsu-
lorrhexis and partial fragmentation of the lens nucleus, permitting less
Fig. 5.6.4 Examples of Newer Intraocular

Lens (IOL) Designs for Use in Eyes
Without Capsular Support. (A) Artisan IOL
3 for iris fixation, either anterior or posterior.
(B) FH1000 (Lenstec) hydrophilic acrylic
foldable IOL for sulcus fixation by suture
with long-term stability by fibrosis through
peripheral haptic fibrosis holes shown. The
radius of the haptics matches a 13 mm wide
2 sulcus (3) and the optic is reinforced to
counteract any torsional forces. Length of
IOL: 13.25 mm (1); optic width: 6.0 mm (2).
1
A B 353
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5
The Lens
Fig. 5.6.5 Capsulotomy and Capsulectomy in Femtosecond Laser Assisted

Cataract Surgery. (Acknowledgments to C. Chan and G. Sutton, Vision Eye Institute,
Chatswood, Sydney, Australia.)
BOX 5.6.4 Phacoemulsification Techniques

I. Location
A. Anterior chamber (Kelman, Brown)
B. Iris plane (Kratz)
C. Posterior chamber (supracapsular) (Maloney)
D. Capsule (endolenticular, in situ)
1. Anterior capsulectomy (Sinskey)
2. Anterior capsulotomy (intercapsular) (Hara)
II. Techniques
B
A. Carousel
B. Chip-and-flip (Fine)
Fig. 5.6.6 Anterior Capsular Fibrosis. (A) Asymmetric and (B) symmetric anterior
C. Phacofracture capsule fibrosis leading to varying degrees of capsular phimosis. (Courtesy John
1. Divide-and-conquer (Gimbel) Shephard, MD, Las Vegas, NV.)
2. Four-quadrant pregrooved (Shepherd)
3. Nonstop chop (Nagahara)
4. Stop-and-chop (Koch) contracture occasionally can be asymmetrical and cause refractive shift (the
5. Double chop (Kammann) Calhoun light adjustable IOL35 can combat these shifts). Usually, however,
the contracture onto the new-generation square-edged IOLs designed for
the capsular bag maintains posterior capsular clarity.33 Occasionally the
lens epithelial cells (LECs) that induce these changes also migrate behind
ultrasonic energy release.28,29 Where necessary, this technique can be com- the IOL, causing posterior capsular pearls and opacity and necessitating
bined with posterior vitrectomy in a safe manner.30 Nd:YAG posterior capsulectomy (Fig. 5.6.7). Attempts have been made to
destroy remaining LECs with various instruments and chemicals36–41 but
Surgery of the Lens Capsule without great success in vivo up to now (Box 5.6.5). Where an IOL requires
sulcus fixation in proximity to the posterior iris and pigment, a round ante-
The femtosecond laser currently provides the state of the art for capsulec- rior edge is necessary to prevent iris chafe, pigment dispersion, and sec-
tomy. This capsular opening is software guided, so it is perfectly circular ondary inflammation and glaucoma (Fig. 5.6.8).
and set to a diameter and position of choice (Fig. 5.6.5). The continuous
curvilinear capsulorrhexis or CCC31 remains the capsulectomy of choice Zonular Surgery
when a femtosecond laser is not available. The size of the capsulectomy is
usually approximately 4.5–5.5 mm, sufficient to cover the IOL optic edge Maintaining adequate zonular strength as well as capsular bag integrity, as
for “in the bag” placement of an IOL. The continuous margin of the rhexis discussed earlier, is vital to the long-term stability of an intraocular lens.
provides strength for manipulation during surgery, keeps the IOL in the Occasionally the zonule is segmentally damaged, causing segmental cap-
bag away from the iris pigment, and holds the IOL optic and haptic in posi- sular bag laxity and potential surgical difficulty and IOL decentration. A
tion for refractive stability and posterior capsular clarity. Where nucleus number of surgeons have devised similar devices to stabilise segmental
expression is required (unusual) and the opening is too small for passage laxity of the capsular bag. These devices called capsular tension rings are
of the nucleus,34 slits in the rhexis margin may be necessary. inserted into the the fornix of the capsular bag to provide sufficient tension
Good view with optimal red reflex is necessary to execute a CCC. When for intra-ocular lens stability and centration. Cionni (Cincinnati, OH)
lens maturity is such that no or poor red reflex is present, capsular stain- designed modifications to the polymethylmethacrylate capsule tension
ing with trypan blue or indocyanine green is most helpful for visualization. rings (CTRs) to allow them to be sutured to the eye wall,42 thus creating a
Discontinuous capsulorrhexis and inadvertent anterior radial tears or pos- synthetic “pseudozonule” attached to an intracapsular skeletal-supporting
terior capsular tears can cause vitreous presentation and unwanted IOL apparatus (Fig. 5.6.9A,B,C).
complications.32–34 Care is required where the zonule is weak. Capsulophi-
mosis can occasionally be seen where the zonule is weak or damaged with Surgery for Presbyopia
significant CCC contracture (Fig. 5.6.6A and B). Nd:YAG laser anterior
capsular widening may be necessary under these circumstances. Capsu- Many attempts have been made at surgical restoration of accommodation.
354 lar contracture can be vigorous and cause the cessation of accommoda- Many have failed or have had poor outcomes. These range from scleral
tive effect in most of the accommodating IOLs currently available. The implants to expand the anterior peripheral sclera in attempts to allow
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Fig. 5.6.7 Posterior Fig. 5.6.8 Many
Capsular Opacification Intraocular Lenses Are
by Lens Epithelial Cell Now Produced With 5.6
Hyperplasia. Squared Posterior
Edges to Minimize Lens
Epithelial Cell Migration
Toward the Visual Axis.
This example shows the
AMO Sensar AR40e, with
rounded anterior edge and
squared posterior edge.
(Courtesy Abbott Medical
Optics Inc.)
A B C
Fig. 5.6.9 Solutions Past and Present for Zonular Deficiency. (A) Complete closed circular, foldable silicone endocapsular ring. (Courtesy T. Hara.) (B) Open polymethyl
methacrylate endocapsular ring. (Courtesy Morcher, GMBh, Germany.) (C) Cionni-modified endocapsular ring for suturing to sclera to create a pseudozonule. (Courtesy
Morcher, GMBh, Germany.)
near nor distance acuity is compromised (as incorporated into both corneal
BOX 5.6.5 Lens Epithelial Cell Surgery inlay and intraocular lens by Acufocus) for those who have difficulty with
the compromises of multifocality or those who have difficulty with the
I. Primary procedures anisometropia of monovision. These technologies have been slow to gain
A. Mechanical momentum as the multifocal technology has shown significant improve-
1. Capsular polishing ment in recent times. Some of the surgical IOL companies have modi-
2. Capsular vacuuming fied their multifocal technologies to soften the distance optical aberrations
3. Capsular vacuuming with ultrasound inherent in this technology at the small expense of a near point pushed
4. Capsular curettage slightly further out. Because of significant improvement in the optics of
5. Capsular cryotherapy these lenses, companies are using new terms for the extended depth of
B. Pharmacological focus these lenses have instead of the term multifocal. Research continues
1. Hypotonic hydrolavage in this field to maintain an extended depth of focus without penalty of
2. Antimetabolites aberration.
3. Antiprostaglandins
C. Immunological
1. Monoclonal antibodies Monovision
D. Prophylactic posterior capsulotomy/capsulectomy (CCC) Monovision is the state of anisometropia geared toward emmetropia in
II. Secondary procedures one eye (usually the dominant eye) and near-weighted ametropia (myopia)
A. Invasive usually in the nondominant eye. Strictly optically speaking, a myopic
1. Capsulotomy/capsulectomy (CCC) outcome of −3.00 diopters (D) would provide a near focal point at 33 cm.
2. Curettage This amount of anisometropia would in many instances produce asthe-
3. Vacuuming nopic symptoms. In practice, patients need only small amounts of residual
B. Noninvasive myopia to be able to read and perform near visual tasks.
1. Nd:YAG laser capsulotomy/capsulectomy The target refraction, which in the nondominant monovision reading
eye provides the best reading acuity with the least distance acuity loss and
with least anisometropic asthenopia, is between −0.75 D and −1.50 D. This
amount of ametropia, particularly when blended with a small amount of
further space for ciliary action, to accommodative IOL designs placed aspherical defocus43 provides the easiest rehabilitation for the monovision
in the capsular bag. These spectacularly well-engineered devices have patient while maintaining a reasonable amount of near and intermediate
regrettably performed poorly in the majority. Substances injected into the visual acuity. In spite of these guidelines, patients should still undergo, at
capsular bag38 to restore youthful accommodation have yet to reach the the very least, a loose lens (trial frame) demonstration of the monovision
commercial market. Monovision and multifocality remain the mainstay of and, at best, a prolonged contact lens simulation of the suggested surgical
the surgery for presbyopia. These techniques continue to provide the most treatment.
satisfactory results with appropriate patient selection. Attempts have been This route maximizes significantly the number of satisfied patients 355
made to use pinhole technology to provide a depth of field where neither after the surgery.
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Astigmatism
5
TABLE 5.6.2 Penetrating Astigmatic Surgery (PAK) Nomogram
As discussed earlier, the surgeon attending to the needs of the lensectomy Cyl to Incision Distance From Opposite Incision Distance From
patient, whether of medical or refractive indication, needs to maintain a Correct Size (mm) Visual Axis (mm) Size (mm) Visual Axis (mm)
holistic approach to the correction of their patient’s problem. The follow-
The Lens
1.00–1.50 3.2 6.0 nil nil

ing items need to be considered to optimize the outcome for the patient: 1.50–2.00 3.2 6.0 3.2 6.0
• The removal of the opacity or error in the optical system (the cataract). 2.00–2.50 3.5 6.0 3.5 6.0
• The accurate correction of the optical state of the eye (biometry tech- 2.50–3.00 3.5 5.5 3.5 5.5
niques and formulas, astigmatism induction avoidance, and pre- 3.00–3.50 3.5 5.0 3.5 5.0
existing astigmatism correction).
• The execution of the surgery in the safest possible way in the prevailing High levels of astigmatic correction by incision as above can cause
circumstances to minimize complications (sterility, incision creation
secondary higher-order aberration induction (quadrafoil). Now with the
and location, wound closure, perioperative antibiotics, surgical tech-
availability of a number of different toric IOLs (up to 6 D and built on
nique, etc.) while assessing and attending to these items, ensuring that
an aspherical base), all providing a stable astigmatic correction, the need
the best combination of techniques provides the optimal solution for
for high-level PAK is no longer present. It should be noted that in the
the patient, and that includes maintaining the ability to readdress non-
selection of a toric IOL, more than one keratometric/topographic method
optimal outcomes.
should be used to ascertain the presence of corneal cylinder for correction.
The management of the astigmatism in lens surgery (or any anterior Unnecessary correction or overcorrection of cylinder should be avoided.
segment surgery) has become an essential and integral part of the execu-
tion of the operation.
A number of techniques have been described to control astigmatism,
KEY REFERENCES
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The most useful technique that covers the most common astigmatic errors ring. J Cataract Refract Surg 2001;207:977–81.
Apple D, Park S, Merkley K, et al. Posterior chamber intraocular lenses in a series of 75
is “on-axis” incision for small-incision surgery (i.e., operative incision place- autopsy eyes. Part I. Loop location. J Cataract Refract Surg 1986;12:358–62.
ment on the periphery of steep axis of the astigmatism). Other schools of Arsinhoff SA. The viscoelastic soft shell technique. In: Kohnen T, Koch D, editors. Essentials
thought suggest that the surgery should be performed with the smallest in ophthalmology. Berlin, Heidelberg: Springer-Verlag; 2005. p. 50–6. [ch 3.10].
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Am J Ophthalmol 1991;111:628–32.
sions in the appropriate meridian, either partial thickness (limbal relaxing Bali SJ, Hodge C, Chen S, et al. Femtosecond laser assisted cataract surgery in phacovitrec-
incision [LRI]–vertical partial-thickness corneal incisions)44,45 or penetrat- tomy. Graefes Arch Clin Exp Ophthalmol 2012;250(10):1549–51.
ing (penetrating astigmatic keratotomy [PAK]–self-sealing, full-thickness, Bali SJ, Hodge C, Lawless M, et al. Early experience with the femtosecond laser for cataract
perforating incisions, obliquely orientated through the cornea). PAK surgery. Ophthalmology 2012;119:891–9.
Blumenthal M, Assia EI. Extracapsular cataract extraction. In: Nordan LT, Maxwell WA,
is the most effective means of controlling astigmatism but does impli- Davison JA, editors. The surgical rehabilitation of vision. New York: Gower; 1992. [ch 10].
cate corneal perforating, the mechanism of the power of the procedure. Datiles MB III, Magno BV, Freidlin V. Study of nuclear cataract progression using the
Keeping the incisions single pass and thus reducing instrument passage National Eye Institute Scheimpflug system. Br J Ophthalmol 1995;79:527–34.
enhances the watertight closure, minimizes wound leak, and potentially Fine IH, Packer M, Hoffman RS. Nucleofractis techniques. In: Kohnen T, Koch D, editors.
Essentials in ophthalmology. Berlin, Heidelberg: Springer-Verlag; 2005. p. 25–32. [ch
minimizes infective risk. The power of correction in PAK can be enhanced 2.5].
further by creation of a second keratotomy on the opposite side of the first Gimbel HV, Neuhann T. Development, advantages, and methods of the continuous circular
incision (180° opposed). The effect is greatest with penetration, reaching capsulorrhexis technique. J Cataract Refract Surg 1990;16:31–7.
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Pac J Ophthalmol (Phila) 2012;1:5Y10.
sions. The PAK nomogram listed in Table 5.6.2 demonstrates the titration McIntyre DJ. Cataract surgery: techniques, complications and management. In: Steinert RF,
of the astigmatic corrective effect by variation of incision width against editor. Phacosection cataract surgery. Philadelphia: WB Saunders; 1995. p. 119–22.
the optical zone radius (OZR–the proximity of the incision to the pupil/
astigmatic centrum).45 In the execution of cylinder correction, the patients’
axes must be marked prior to lying down for anesthesia (local, topical, or
general) to avoid cyclotorsional error.
356
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3. Datiles MB III, Magno BV, Freidlin V. Study of nuclear cataract progression using the RF, editor. Phacosection cataract surgery. Philadelphia: WB Saunders; 1995. p. 119–22.
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1995;113:1508–13. autopsy eyes. Part I. Loop location. J Cataract Refract Surg 1986;12:358–62.
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1994;112:1419–25. 35. Werner L, Mamalis N. Adjustable power intraocular lenses. In: Kohnen T, Koch D,
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in the aging rhesus money. J Refract Corneal Surg 1994;10:550. ocular lenses on post-operative inflammation and posterior capsular opacification. J Cat-
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Boston, April 9, 1991. ocular-lens-bound sustained drug delivery system: an experimental animal study and lit-
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Ophthalmol Jpn 1987;38:1615–18. 40. Power WJ, Neylav D, Collum LMT. Daunomycin as an inhibitor of human lens epithelial
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refilling the lens of animal eyes with a balloon. J Cataract Refract Surg 1989;15:584–8. 41. Goins KM, Optiz JR, Fulcher SFA, et al. Inhibition of proliferating lens epithelium with
18. Hara T, Hara T, Yasuda A, et al. Accommodative intraocular lens with spring action. Part antitransferrin receptor immunotoxin. J Cataract Refract Surg 1994;20:513–15.
1. Design and placement in an excised animal eye. Ophthalmic Surg 1990;21:128–33. 42. Ahmed II, Crandall AS. Ab externo scleral fixation of the Cionni modified capsular
19. Hara T, Hara T, Yasuda A, et al. Accommodative intraocular lens with spring action. Part tension ring. J Cataract Refract Surg 2001;207:977–81.
2. Fixation in the living rabbit. Ophthalmic Surg 1992;23:632–5. 43. Rocha K, Vabre L, Chateau N, et al. Expanding Depth of focus by modifying higher-or-
20. Galand A. A simple method of implantation within the capsular bag. J Am Intraocul der aberrations induced by an adaptive optics visual simulator. J Cataract Refract Surg
Implant Soc 1983;9:330–2. 2009;35(11):1885–92.
21. Hara T, Hara T. Intraocular implantation in an almost completely retained capsular bag 44. Khng C, Fine IH, Packer M, et al. Improved precision with the millimeter caliper for
with a 4.5 to 5.0 millimeter linear dumbbell opening in the human eye. Ophthalmic Surg limbal relaxing incisions. J Cataract Refract Surg 2005;31:1671–2.
1992;23:545–50. 45. Howes F. Penetrating astigmatic keratotomy. Paris, France: Presentation ESCRS; 2004.
22. Arsinhoff SA. The viscoelastic soft shell technique. In: Kohnen T, Koch D, editors. Essen-
tials in ophthalmology. Berlin, Heidelberg: Springer-Verlag; 2005. p. 50–6. [ch 3.10].
356.e1
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Part 5 The Lens

The Pharmacotherapy of Cataract Surgery

Steve A. Arshinoff, Yvonne A.V. Opalinski, Dominik W. Podbielski 5.7
Definition: Medications used in cataract surgery. TABLE 5.7.1 Commonly Used Agents in the Routine Preoperative
Pharmacotherapy of Cataract Surgery
Class and Agent Concentration Dosage
Nonsteroidal anti- Diclofenac 0.10% 1 drop 2–4 times over 1 h
Key Features inflammatory drugs to Ketorolac 0.50% preceding surgery
• Pharmacotherapeutic agents are used in the preoperative, prevent miosis Flurbiprofen 0.03%
intraoperative, and postoperative periods of cataract surgery. Indomethacin 1%
• Preoperative medications are used as mydriatics, prophylactic Nepafenac 0.1%
antibiotics, and anesthetics. Cycloplegics Tropicamide 1% 1 drop 2–4 times over 1 h
• Intraoperative pharmacotherapeutic agents include irrigating Cyclopentolate 1% preceding surgery
solutions and additives to irrigating solutions, as well as ophthalmic Mydriatics Phenylephrine 2.50% 1 drop twice over 0.5 h
viscosurgical devices and intracameral drugs. preoperatively
• Postoperative medications include antibiotics, corticosteroids, and Antibiotic prophylaxis Gramicidin- 0.025 mg/ml 1 drop 2–4 times over 1 h
nonsteroidal anti-inflammatory drugs. neomycin- 2.5 mg/ml preceding surgery
polymyxin B 10.000 IU/ml
Gentamicin 0.30%
Tobramycin 0.30%
Ciprofloxacin 0.30%
INTRODUCTION Ofloxacin 0.30%
Gatifloxacin 0.30%
With the current ongoing rapid evolution of cataract surgical techniques, Moxifloxacin 0.50%
corresponding changes in the pharmacotherapeutic management of cata- Trimethoprim- 1 mg/ml
ract patients are inevitable. In this chapter, current pharmacotherapeutic polymyxin B (10.000 IU/ml)
practices in the pre-, intra-, and postoperative periods are reviewed. Anesthetic: retrobulbar Lidocaine 1–2% 3–9 mL
or parabulbar Mepivacaine 1–2%
(use becoming Bupivacaine 0.25–0.75%
PREOPERATIVE MEDICATIONS increasingly rare)
Table 5.7.1 provides a summary of commonly used preoperative pharmaco- Anesthetic: intracameral Isotonic, 1–2% 0.1–0.6 mL
(use becoming nonpreserved
therapeutic routines for cataract surgery.
increasingly common) lidocaine
Anesthetic: topical Proparacaine 1–2% 1–2 drops prior to
Pupil Dilatation Tetracaine 0.50% surgery, and then
Benoxinate 0.40% every 10 minutes or as
Sympathomimetic mydriatic agents (phenylephrine 2.5%) and parasym- (oxybuprocaine) needed during surgery
patholytic cycloplegics (tropicamide or cyclopentolate 1.0%) usually are Lidocaine 4%
used together before extracapsular nuclear expression, phacoemulsifica- Bupivacaine 0.75%
tion (phaco), or femtosecond laser-assisted cataract surgery (FLACS). Used
excessively, sympathomimetics increase the possibility of a severe systemic
hypertensive response with associated systemic risks in older adults.1 For
TABLE 5.7.2 Various Popular and Commercially Available
this reason, phenylephrine 10% is not recommended routinely. To assist
adequate pupil dilatation, pilocarpine and other cholinergic miotics should Intracameral Mixtures to Achieve Dilation and Anesthesia
be discontinued 12 to 24 hours before surgery (approximately twice the Behndig IC Mixture (Also
expected duration of action of the specific agent). Drug Made by Leiter’s in USA) Mydrane® Xylo-Phe Phenocaine®
Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly Tropicamide – 0.02% – –
used in cataract surgery to prevent pupillary miosis, reduce surgically Phenylephrine 1.5% 0.31% 0.08% 0.1%
induced inflammation, and prevent postoperative cystoid macular edema.2 hydrochloride
NSAIDs inhibit cyclooxygenase, decreasing prostaglandin synthesis from Lidocaine 1.0% 1% 1% 1%
arachidonic acid.2,3 Prostaglandin E2 (PGE2) enhances the constrictor The above are various popular and commercially available intracameral mixtures to achieve
action of the iris sphincter through a mechanism not dependent on cho- dilation and anesthesia by injecting as the first step in cataract surgery. The mixture
linergic receptors.4,5 Topical flurbiprofen 0.03%, the first agent used for manufactured by Leiter’s Pharmacy in the USA is taken from articles by Behndig et al. from
this indication, was demonstrated to be clinically superior to topical indo- Sweden, Mydrane® is manufactured by Thea, in France, and Phenocaine® by Entod UK. Xylo-
Phe has been proposed by one of the authors (SAA) to be formulated in the operating room,
methacin 1%.5 Currently, diclofenac 0.1%, ketorolac 0.5%, and nepafenac with details available from the author.
0.1% have the same indication.6 Although diclofenac and flurbiprofen ade-
quately maintain mydriasis during surgery,7 ketorolac appears to inhibit
miosis more effectively.8 Anti-infective Prophylaxis
Intracameral mydriatic solutions using cyclopentolate 0.1%, phenyl-
ephrine 1.5%, xylocaine 1% or tropicamide 0.5%, phenylephrine 5%, and No worldwide consensus exists on prophylactic topical antibiotics in cata-
diclofenac 0.1%, in preservative-free solutions are safe to the corneal endo- ract surgery, although their use has been an accepted practice for decades.
thelium and effective in producing and maintaining pupillary dilatation A large randomized study of preoperative topical antibiotics for the pre-
and are used in various combinations (Table 5.7.2).9–11 Effective redilata- vention of endophthalmitis has yet to be carried out. The most import-
tion has also occurred with use of these mydriatics intracamerally during ant source of potential infectious organisms is the patient’s own natural 357
surgery on contracted pupils.12 conjunctival and skin flora. Intraoperative cultures indicate that 5% of
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intraocular surgeries result in measurable anterior chamber contamina-
5 tion from indigenous flora, but the vast majority of patients develop no TABLE 5.7.3 Commonly Used Agents in the Routine Preoperative
adverse clinical sequelae.13 Cultures from the conjunctiva and anterior Pharmacotherapy of Cataract Surgery
chamber of patients who subsequently developed endophthalmitis usually Class and Agent Concentration Dosage
yielded the same bacterial strains. Staphylococci (Staphylococcus epidermidis
The Lens
Agents added Antibiotics 0.3–0.5 mL of 1 : 1000

and S. aureus), diphtheroids (Corynebacterium), streptococci (Streptococcus to irrigating nonpreserved
Vancomycin plus 20 µg/mL
viridans), and Gram-negative bacilli (pseudomonas, serratia, and entero- solutions epinephrine 500 mL
bacteriaceae species, anaerobic Propionibacterium acnes, and others) are Gentamicin 8 µg/mL
irrigating solution
the most common infecting agents in decreasing order of occurrence.14–15 Gentamicin 8–80 µg/mL
Medications should adequately cover these bacteria during the operative Sympathomimetics to
and perioperative periods. Before cataract surgery, topical anti-infective prevent miosis
regimens historically included gramicidin–neomycin–polymyxin B sulfate; Nonpreserved
aminoglycosides, such as gentamicin or tobramycin (which provide epinephrine
Gram-negative and pseudomonas coverage); and the fluoroquinolones— Agents used Antibiotics 0.1 mL intracapsularly
ciprofloxacin, norfloxacin, ofloxacin 0.3%7,16,17 or levofloxacin 0.5%. Of at the end of Vancomycin 1 mg/0.1 mL via side port at end of
the procedure procedure
these, levofloxacin provided superior coverage and anterior-chamber Cefuroxime 1 mg/0.1 mL
penetration, before fourth-generation fluoroquinolone (G4FQ) became Cefazolin 1–2.5 mg/0.1 mL
available.18–21 The G4FQs gatifloxacin 0.3% and moxifloxacin 0.5% are cur- Gatifloxacin 100 µg/0.1 mL
rently preferred because they offer better penetration compared with pre- Moxifloxacin 100 µg/0.1 mL
vious generations (moxifloxacin appears to be better than gatifloxacin),22,23 100–500 µg/
broader-spectrum coverage, lower incidence of bacterial resistance, and 0.1–0.2 mL
equal safety.24–26 Antibacterial prophylaxis for cataract surgery has become Parasympathomimetics 0.5 ml injected into
an increasingly prominent issue after the confirmation of increased inci- Acetylcholine 1% anterior chamber via side
dence of postoperative endophthalmitis with clear corneal incisions.27 port to cause miosis
Carbachol 0.01%
Retrospective studies indicate that endophthalmitis rates are lower with
the postoperative use of topical G4FQ compared with historical controls.28
There have been no prospective studies determining ideal dosing for pro-
phylactic use, but some authors have suggested that administration of anti- its popularity seems to be decreasing in favor of intracameral injection.
biotics 3 days preoperatively may yield superior intraocular drug levels at Furthermore, presence of lidocaine gel prior to povidone-iodine instilla-
surgery. A similar consensus of antibiotic use 1 to 3 days preoperatively tion may reduce its antimicrobial efficacy.48 Topical lidocaine 4% as the
occurred in the 2007 ASCRS member survey.27,29–32 There appeared to be sole anesthetic agent in uncomplicated cataract surgery is also being used
no difference in bacterial load with the use of moxifloxacin either 1 or 3 increasingly.49
days preoperatively.33 Several recent cases raised concerns that prophylactic
use of potent antibiotics in healthy patients with cataract may lead to bac-
terial resistance, thereby theoretically increasing the risk of postoperative INTRAOPERATIVE MEDICATIONS
infection with a resistant strain in patients so treated. Ong-Tone34 demon-
strated that the aqueous concentration of antibiotics administered topically Additives to Irrigating Solutions, Intracameral
is maximal when the drops are given within 2 hours of surgery, render- Antibiotics, and Other Intraocular Drugs Used
ing their administration days in advance unnecessary. Therefore, topical
antibiotic administration every 15 minutes for three to four doses before
During the Surgical Procedure
surgery seems optimal, yielding the highest anterior chamber concentra- Table 5.7.3 gives a summary of commonly used intraoperative pharmaco-
tion, which permits insufficient time for resistant strains to take hold.34 On therapeutic routines. In general, the addition of antibiotics, mydriatics,
a population scale, the authoritative Medical Letter has stated that the risk epinephrine (adrenaline), or lidocaine (lignocaine) is not recommended
of causing resistant strains from the use of antibiotics in ophthalmology is by the companies that produce irrigating solutions for cataract surgery
minimal because of the low number of viable bacteria exposed to the agent; because any effect on stabilizers and preservatives in the solutions could
therefore, long-term preoperative administration of topical antibiotics may alter their pH, chemical balance, or osmolarity and influence the potential
select out existing resistant strains but cannot induce new ones.35–37 toxicities of both the irrigating solution and the additive. Caution is advised
Subconjunctival injections of antibiotics has been shown to reach ade- with any alteration to commercial irrigating solutions.
quate aqueous humor concentrations.38 Retrospective studies have found To prevent intraoperative miosis, nonpreserved epinephrine (1 : 1000)
that subconjunctival antibiotics are effective at lowering the incidence of 0.5 mL/500 mL is the most frequently used additive. This concentration
postoperative endophthalmitis.39,40 appears nontoxic to the corneal endothelium and allows normal endothe-
Complete conjunctival sterility is not achievable with the use of pre- lial function.50
operative antibiotics alone.7 The topical nonselective antiseptic agent A new U.S. Food and Drug Administration (FDA)–approved combina-
povidone-iodine 5%, instilled as a single drop 10 to 30 minutes before tion drug, phenylephrine 1.0%–ketorolac 0.3% (Omidria) has been studied
surgery, is one of the most effective measures to decrease this bacterial for the treatment of intraoperative miosis and postoperative ocular pain.51
flora.41 In fact, a recent prospective study found that topical moxifloxacin The study found that this medication was better than placebo in maintain-
0.5% lacked a significant additive effect on the preoperative reduction of ing mydriasis and preventing postoperative pain in the early postoperative
conjunctival bacterial colonization beyond the effect of povidone-iodine period.
5%.42 No consensus currently exists with regard to the use of 5% or 10% Insufficient evidence exists to support the addition of antibiotics into
concentration of povidone-iodine.43 In the event of a known or suspected the irrigating solution, although smaller studies previously demonstrated a
iodine allergy, polyhexidine or chlorhexidine gluconate is a well-tolerated benefit.52 Vancomycin (20 µg/mL (0.02 mg/mL)) combined with gentami-
alternative, and chlorhexidine is used as a standard in Sweden instead of cin (8 µg/mL (0.008 mg/mL)) in the irrigating solution, has been reported
povidone-iodine.44 to eradicate Gram-positive, coagulase-negative micrococci,53 with minimal
Novel approaches for prophylaxis may be on the horizon, including associated complications.54 Gentamicin alone has been used intraoper-
drug delivery nanoparticles and presoaked intraocular lenses (IOLs) with atively in the dosage range of 8 to 80 µg/mL in the irrigating solution,
antibiotic.45 which avoids retinal toxicity and also decreases the intracameral bacterial
load.55 However, a recent large study showed no significant benefit of anti-
ANESTHETICS biotics added to the irrigating solution, whereas intracameral antibiotics
were very effective.56
Anesthetics are covered in detail in Chapter 5.8. Local injection anesthesia, The postoperative capsular bag is a sequestered avascular site that
both retrobulbar and peribulbar, has fallen increasingly out of favor, and harbors a foreign body (the intraocular lens) and may act as the nidus for
the use of intracameral isotonic nonpreserved lidocaine 1%, preceded by most cases of endophthalmitis. Introduced by James Gills in the early 1990s,
topical lidocaine, has become the standard in many centers. Lidocaine gel intracameral vancomycin (1 mg in 0.1 mL balanced salt solution [BSS]) was
358 is claimed to provide increased corneal hydration and anesthesia equal to the first antibiotic agent injected directly into the capsular bag as the final
that of injections and drops46,47 while minimizing patient discomfort, but surgical step. This mode of delivery is considered superior to antibiotics
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added in the irrigating solution because the concentration achieved in the
TABLE 5.7.4 Chemical Composition of Human Aqueous Humor,
anterior chamber is much higher; furthermore, it is done at the end of the
procedure, leaving a high dose in the anterior chamber for the early post- Vitreous Humor, BSS Plus, and BSS 5.7
operative period.52,57 Considerable discussion occurred among clinicians Human Human Vitreous
and researchers about the safety and efficacy of intracameral injections

Ingredient Aqueous Humor Humor BSS Plus BSS
until the large, multicenter, prospective, randomized, controlled European Sodium 162.9 144 160 155.7
Society of Cataract and Refractive Surgeons (ESCRS) study showed intra- Potassium 2.2–3.9 5.5 5 10.1
cameral cefuroxime (1 mg in 0.1 cc, first proposed by Montan et al.) to be Calcium 1.8 1.6 1 3.3
effective in producing an 80% reduction in endophthalmitis rates.58–61 The
Magnesium 1.1 1.3 1 1.5
global use of prophylactic intracameral antibiotics with cataract surgery
Chloride 131.6 177 130 128.9
has been steadily increasing since the ESCRS study. Dilution of cefurox-
ime remains a problem in the United States, but outside North America, Bicarbonate 20.15 15 25 –
prediluted cefuroxime is available from Thea (France) as Aprokam. Phosphate 0.62 0.4 3 –
However, cefuroxime does not cover multiresistant enterococci. A recent Lactate 2.5 7.8 – –
multicenter retrospective analysis of postoperative endophthalmitis in Glucose 2.7–3.7 3.4 5 –
immediate sequential bilateral cataract surgery found intracameral vanco- Ascorbate 1.06 2 – –
mycin (1 mg in 0.1 mL) and moxifloxacin (100–500 µg in 0.1–0.2 mL) to be Glutathione 0.0019 – 0.3 –
at least as effective as cefuroxime.56 Routine use of vancomycin is contro- Citrate – – – 5.8
versial because it is reserved as the last resort for multiresistant bacteria. Acetate – – – 28.6
The recent discovery of 36 cases of vancomycin-associated hemorrhagic
pH 7.38 – 7.4 7.6
occlusive retinal vasculitis has reduced surgeons’ enthusiasm about using
Osmolality (mOsm) 304 – 305 298
prophylactic intracameral vancomycin.62 Intracameral moxifloxacin has
theoretical benefits because of its potent bactericidal activity, availability (Adapted from Edelhauser HF. Intraocular irrigating solutions. In: Lamberts DW, Potter DE,
Potter DE, editors. Clinical ophthalmic pharmacology. Boston, MA: Little, Brown and Company;
as a self-preserved commercial formulation (Vigamox®; Alcon Laborato- 1987. p. 431–44.)
ries, Fort Worth, TX) requiring only very simple dilution, if any, and the
fact that its mechanism of action differs from current antibiotics of choice
for endophthalmitis, theoretically making any possible breakthrough end-
ophthalmitis cases easily treatable.63–67 Its use is steadily increasing glob- device (OVD) on the cornea at the beginning of surgery to achieve pro-
ally. Mounting evidence supports the use of intracameral antibiotics at longed wetting and reduced need for BSS irrigation with two newer topical
the conclusion of surgery because they achieve supra-threshold antibiotic OVDs specifically targeting this use: Visthesia (NaHa 0.3% + lidocaine 2%;
levels for an extended period.60,68,69 Carl Zeiss Meditech) and Cornea Protect (HPMC 2%; Bausch & Lomb).
Rapid miosis can be produced at the end of the surgical procedure by
using intraocular parasympathomimetics acetylcholine chloride 1% or
carbachol 0.01%.70 Current commercial preparations show no evidence of
OPHTHALMIC VISCOSURGICAL DEVICES
endothelial toxicity, and the choice of agent depends on the desired clinical The introduction of Healon in 1980 for ocular surgery ushered in the
features. Acetylcholine 1% has an onset of less than 1 minute with a rel- era of viscosurgery. OVDs consist of solutions of long-chain biopolymers
atively brief 10-minute duration of miosis, whereas carbachol 0.01% takes (hyaluronic acid with or without chondroitin sulfate, or only hydroxy-
2 minutes to act and lasts 2 to 24 hours. Both agents lower postoperative propyl methylcellulose) in low concentration. They are all pseudoplastic
intraocular pressure spikes.71 Topical carbachol 0.2% is effective to induce in their rheological behavior. Their physical properties tend to correlate
24-hour miosis and reduce postoperative IOP spikes but is no longer com- with each other (i.e., the most viscous solution is also the most elastic
mercially available; therefore, pilocarpine 2% may be used, but its effect and the most cohesive) and are a function of the chain length distribution
lasts only 8 hours, so the patient may be given the pilocarpine minim (in of the rheologically important constituent polymer and its concentration.
countries where minims are available; Bausch & Lomb) to reapply one Recently, the advent of DisCoVisc, a viscous dispersive OVD, demonstrated
drop at bedtime (personal observation – SAA). that the tight correlation between viscosity and cohesion in OVDs can
Agents currently under investigation include low-molecular-weight be avoided, resulting in a new two-dimensional classification, based on
heparin, enoxaparin (10 IU/mL added to standard irrigating solution), zero-shear viscosity and cohesive-dispersive properties (measured as the
which produces a decreased inflammatory response immediately after cat- cohesion-dispersion index [CDI]) (Table 5.7.5). OVDs cannot be correctly
aract surgery with minimal side effects (e.g., hemorrhage).72,73 A prelimi- referred to generically, as each one has different rheological properties, and
nary study of ozonated water (4 parts per million [ppm] concentration) in they are not generically interchangeable in that many surgical maneuvers
anterior chamber irrigation confirmed its bactericidal effects, and this may can be achieved more easily with one type of OVD than another. Before the
potentially be another tool against endophthalmitis.74 advent of viscoadaptive OVDs, superviscous-cohesive and viscous-cohesive
OVDs were recognized as best for creating, stabilizing, and maintaining
Irrigating Solutions spaces (to deepen the anterior chamber in the presence of positive vitreous
pressure and to stabilize the anterior chamber facilitating capsulorrhexis
In the early days of phaco, the only irrigating solutions available were and foldable intraocular lens implantation). Alternatively, medium- and
normal saline, Plasma-Lyte, and lactated Ringer’s solution. Their main lower-viscosity-dispersive OVDs are excellent for the selective isolation of
adverse effect was endothelial cell toxicity. Irrigating solutions with areas of the intraocular surgical field and for enabling fluid partition of the
calcium, glutathione, and bicarbonate form more physiologically balanced anterior chamber (to protect marginal corneas from the turbulence of
solutions (Table 5.7.4).75 Several comparative studies found BSS Plus to phaco, or to keep a frayed piece of iris or bulging vitreous away from the
be protective of the corneal endothelium and hence superior to BSS and phacoemulsifying or irrigation-aspiration tip).77 Superviscous-cohesive and
other irrigating solutions. Unlike BSS, BSS Plus is physiologically similar viscous-cohesive OVDs cannot be used to partition fluid-filled spaces. To
to human aqueous and vitreous, especially with regard to calcium concen- achieve the benefits of both types of older OVDs and to avoid having to deal
tration and the addition of glucose, glutathione, and bicarbonate. BSS Plus with their disadvantages, the “soft shell technique,” or preferably variations
maintains endothelial cell function over periods ranging from 15 minutes of the “Tri-Soft shell technique” can be utilized.78–81 Healon5 and MicroVisc
to in excess of a few hours.58 The buffer in BSS Plus is bicarbonate, which Phaco (iVisc Phaco, Hyvisc Phaco, BD MultiVisc) are viscoadaptive OVDs
is an improvement over the sodium acetate and citrate buffers in BSS. that exhibit either highly viscous-cohesive or pseudodispersive properties,
Nevertheless, BSS Plus is currently used much less frequently compared depending on fluid turbulence in the anterior chamber.82 The dispersive
with BSS because of cost and the progressive reduction in the volume of behavior of lower-viscosity OVDs and the pseudodispersive behavior of vis-
irrigating fluid used in surgery as techniques improve over time. coadaptives are very different.82–84 These characteristics allow the use of
Corneal surface irrigation to maintain hydration and surgical clarity has viscoadaptives for chamber partitioning and yield enhanced versatility over
traditionally been performed throughout intraocular procedures with BSS. earlier OVDs during phaco.85–89 The “ultimate soft shell technique” further
The development of an elastoviscous Hylan Surgical Shield 0.45% (HSS), enhances the scope of utility of viscoadaptive OVDs90,91 and enables the
which decreases the surgeon’s dependence on manual corneal irrigation, benefits of the soft shell technique to be attained using a single viscoad-
is an improvement over BSS in maintaining corneal hydration and clarity aptive OVD. The “tri-soft shell technique” amalgamates the methodology 359
intraoperatively.76 Some surgeons use a drop of ophthalmic viscosurgical of all preceding “soft-shell techniques” into a single systematic method,
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5
TABLE 5.7.5 New Classcifications of OVDs, 2005, Modified and Updated to 2016
Í Cohesive - Dispersive Î
V0 (zero-shear viscosity) Cohesive OVDs Dispersive OVDs
The Lens
range (mPa.s) CDI ≥ 30 (% asp/mm Hg) CDI < 30 (% asp/mm Hg)

7–18 × 106 (ten millions)
I. Viscoadaptives
*Healon 5*
iVisc** (MicroVisc***) Phaco, BD MultiVisc#
1–5 × 106 (millions) II. Higher viscosity cohesives II. Higher viscosity dispersives
A. Super viscous cohesives
*Healon GV* A. Super viscous dispersives
iVisc** (MicroVisc***, HyVisc***) Plus none
BD Visc#, AcnHylon Plus##
105–108 (hundred thousands) B. Viscous cohesives
Viscosity Î
*Healon* B. Viscous dispersives
iVisc** (MicroVisc***, HyVisc***) *DisCoVisc†
Eyefill HC### *Amvisc Plus+
Ophthalin Plus##
*Provisc†
Opegan Hi††
Rayner FR Pro+++
*Amvisc*
Ophthalin##
Eyefill SC###
III. Lower viscosity dispersives

104–105 (ten thousands) III. Lower viscosity cohesives
A. Medium viscosity dispersives
†
Modified from: Arshinoff SA, Jafari M. A. Medium viscosity cohesives
*Viscoat†
none
*Vitrax*, Healon D*, Healon Endocoat*
A new classification of ophthalmic Endogel##
viscosurgical devices (OVDs). J Cataract Rayvisc+++
Refract Surg. 2005; 31:2167–71. OpeleadΦ
*Cellugel†
Eyefill HD###
103–104 (thousands) B. Very low viscosity cohesives
none
B. Very low viscosity dispersives
Opegan††
*OccuCoat++
Icell**, Visilon, Ocuvis, Hymecel,
Adatocel, Celoftal, ...HPMCs
* Abbot Medical Optics, ** iMed Pharma, *** Bohus Biotech, # Bectin Dickinson, ## Carl Zeiss Meditech, ### Croma Pharma, † Alcon laboratories, †† Seikagaku Corporation-Santen, †††
Biotechnology General, ++ Bausch & Lomb, +++ Rayner, Φ Shisheido Co., HPMC = hydroxypropylmethylcellulose, * Available in USA
permitting the surgeon to achieve the benefits of all soft-shell techniques

in a single systematic approach. DisCoVisc is a new, viscous, dispersive TABLE 5.7.6 Commonly Used Agents in the Routine Postoperative
OVD with zero-shear viscosity and is similar to Healon but resembles Pharmacotherapy of Cataract Surgery
Viscoat’s dispersive properties, thus permitting the chamber maintenance
Class and Agent Concentration Dosage
properties of Healon and the dispersive endothelial protection of Viscoat
Corticosteroids Dexamethasone 0.10% 1 drop 4 times daily
using a single OVD syringe.83 Ophtheis FR Pro (Free Radical Protection; Prednisolone 1% for 3–4 weeks
Rayner, UK) is another new type of OVD that possesses rheological proper- Betamethasone 0.10% postoperatively
ties similar to those of Healon but contains sorbitol, as a free-radical scav- Nonsteroidal anti- Diclofenac 0.10% 1 drop 4 times daily for 4
enger, with the intention of increasing endothelial protection. The advent inflammatory Ketorolac 0.50% weeks postoperatively
of FLACS may revolutionize our choices and uses of OVDs because the drugs Nepafenac 0.10% 1 drop 3 times daily for 2
need to stabilize and pressurize the anterior chamber for capsulorrhexis weeks postoperatively
disappears. We will have to study the remaining aspects of FLACS to see Antibiotics Gramicidin–neomycin– 0.025 mg/mL 1 drop 4 times daily
what changes to OVDs will optimize surgery. polymyxin B for 3–4 weeks
Gentamicin 2.5 mg/mL postoperatively
Tobramycin 10 000  IU/mL
Intracameral Medications to Replace Ciprofloxacin
Ofloxacin
0.30%
0.30%
Postoperative Drops Gatifloxacin 0.30%
Moxifloxacin 0.30%
In the last few years, a few ophthalmologists have begun injecting an Trimethoprim- 0.30%
antibiotic-corticosteroid combination, Ti-Moxi (triamcinolone–moxifloxa- polymyxin B 0.50%
cin) or Tri-Moxi-Vanc (triamcinolone–moxifloxacin–vancomycin; Imprimis 1 mg/mL
Pharmaceuticals, San Diego, CA) transzonularly as the final step in cata- (10 000  IU/mL)
ract surgery to avoid using postoperative topical eyedrops. Some authors
have adapted this approach, and some have been very critical.92,93
POSTOPERATIVE MEDICATIONS
360
Postoperative drugs are listed in Table 5.7.6.
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Antibiotics layer of Henle.119 Most patients recover spontaneously, with full restoration
Postoperative regimens of topical antibiotics vary but generally consist of

of visual acuity within 6 months; however, it may require 1 to 2 years to
achieve complete spontaneous resolution.2 5.7
one drop to the operated eye four to six times daily for 1 to 2 weeks. Recent Prophylaxis and treatment have been suggested in the form of systemic
studies support the practice of starting topical antibiotics immediately after and topical NSAIDs. Oral NSAIDs, with regimens of indomethacin 25 mg

cataract surgery, rather than waiting until the first postoperative day.94–96 three times daily 1 week before surgery and 3 weeks postoperatively,2 or
The duration of treatment varies from 5 days in uncomplicated surgery to ibuprofen 200 mg preoperatively and postoperatively, have received mixed
weeks if prolonged inflammation occurs. Injections and collagen shields reviews.120 Literature supports the efficacy of topical NSAIDs,121–123 such as
are increasingly falling out of favor. flurbiprofen 0.03%, diclofenac 0.1%, ketorolac 0.5%, bromfenac 0.09%, and
Subconjunctival injections of antibiotics deliver high aqueous humor nepafenac 0.1% used prophylactically and after surgery to reduce inflam-
levels but have a greater associated risk, notably perforation of the eye, mation.124,125 Piroxicam 0.5% solution used postoperatively appears as effec-
macular infarction, and retinal toxicity. Oral or parenteral antibiotics (e.g., tive as diclofenac, with less ocular irritation.126 The prodrug Nepafenac
fluoroquinolones) reach substantial levels in the anterior chamber but, 0.1% has shown significantly greater ocular bioavailability and potency
being associated with increased side effects, are not advantageous over compared with ketorolac 0.4% and bromfenac 0.09%.125 Usually, preopera-
topical routes of administration.97,98 tively and postoperatively, one drop is administered two to four times daily
for up to 3 weeks to prevent CME. Frequently, in the acute postoperative
period, topical corticosteroids used in conjunction with NSAIDs in the
Corticosteroids and Nonsteroidal treatment of CME127 produce a synergistic effect.128 Recent evidence also
Anti-inflammatory Drugs suggests that solitary topical NSAID treatment is superior to lone corti-
costeroid prophylaxis.129–132 In chronic cases, management continues until
The use of topical corticosteroids and NSAIDs after cataract surgery resolution.2 Indefinite NSAID treatment may be required to maintain CME
reduces postoperative noninfectious inflammation. Both are efficacious in regression,133 which increases interest in the utility of a sustained drug
decreasing inflammation,6,99–101 with no difference between them in terms delivery system, such as Ozurdex.134 Once it has been established, CME
of astigmatic decay. The development of an intraocular biodegradable drug is treated with oral acetazolamide, topical corticosteroids with NSAIDs, or
delivery system containing dexamethasone appears to be an effective alter- posterior sub-Tenon’s injection of long-acting corticosteroids (see Chapter
native to topical drops,102 and because a variety of drugs may be bound to 6.35). Single-dose intracameral, intraoperative, and multiple intravitreal
the polymer matrix, it may play a role in the long-term prevention or treat- postoperative injections of triamcinolone also have safely prompted regres-
ment of cystoid macular edema. Topical NSAIDs have a specific advantage sion of chronic CME with minimal changes in intraocular pressure.99,135–137
over corticosteroids if there are contraindications to corticosteroid use in Oral cyclooxygenase-2-inhibitors were found to successfully resolve CME
a particular patient, as in those with corticosteroid-responsive elevations unresponsive to oral or topical NSAIDs in a small number of patients,
of intraocular pressure, recurrent herpes simplex infection,103 or concern with improvement in visual acuity,138 as has high-dose methylprednisolone
about delayed wound healing.104 Ketorolac 0.5% has shown similar effi- (1000 mg for 3 days)139 in the past. Recent case series investigations suggest
cacy as a single agent in antimiotic and anti-inflammatory activity to an anti–vascular endothelial growth factor (VEGF) as an alternative for recalci-
NSAID–prednisolone 1% combination.105 However, an increased risk of trant CME, but large controlled trials are lacking.140–143 Oral carbonic anhy-
corneal or scleral perforation in the presence of an epithelial defect exists drase inhibitors (CAIs) may be effective in treating refractory CME, but
when NSAIDs are used without concomitant administration of topical their use is guarded because of severe adverse effects.144 Antiglaucomatous
corticosteroids, most commonly reported with diclofenac.106,107 prostaglandin analogues may enhance disruption of the blood–aqueous
Pretreatment for 3 days with an NSAID decreases the postoperative barrier, increasing the incidence of CME after cataract surgery, but this
level of inflammation.108,109 Corticosteroids and NSAIDs are used postop- appears to be a response to the drug’s preservative, and not the drug itself.
eratively, although not as a single solution. The addition of an NSAID to The concurrent application of NSAIDs decreases the incidence of CME
an antibiotic-corticosteroid postoperative regimen reportedly has decreased secondary to these medications and does not adversely influence the anti-
the incidence of noninfectious postoperative inflammatory conditions.110 glaucoma drug’s effect on intraocular pressure.145,146
The corticosteroids dexamethasone 0.1%, prednisolone 1%, and beta-
methasone 0.1% are used most commonly. A new corticosteroid, rimex-
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potential downsides? Editorial. Am J Ophthalmol 2016;164:viii–x. blood flow in early postoperative pseudoaphakias with regard to cystoid macular edema
94. Jensen MK, Fiscella RG, Crandal AS, et al. A retrospective study of endophthalmitis formation. Invest Ophthalmol Vis Sci 2007;48:5647–52.
rates comparing quinolone antibiotics. Am J Ophthalmol 2005;139:141–8. 130. Asano S, Miyake K, Ota I, et al. Reducing angiographic cystoid macular edema and
95. Jensen MK, Fiscella RG, Moshirfar M, et al. Third- and fourth-generation fluoroquinolo- blood-aqueous barrier disruption after small-incision phacoemulsification and fold-
nes retrospective comparison of endophthalmitis after cataract surgery performed over able intraocular lens implantation: multicenter prospective randomized comparison of
10 years. J Cataract Refract Surg 2008;34:1460–7. topical diclofenac 0.1% and betamethasone 0.1%. J Cataract Refract Surg 2008;34:57–63.
96. Wallin T, Parker J, Jin Y, et al. Cohort study of 27 cases of endophthalmitis at a single 131. Endo N, Kato S, Haruyama K, et al. Efficacy of bromfenac sodium ophthalmic solution
institution. J Cataract Refract Surg 2005;31:735–41. in preventing cystoid macular oedema after cataract surgery in patients with diabetes.
97. Bron AM, Pechinot AP, Garcher CP, et al. The ocular penetration of oral sparfloxacin in Acta Ophthalmol 2010;88:896–900.
humans. Am J Ophthalmol 1994;117:322–7. 132. Wielders LH, Schouten JS, Aberle MR, et al. Treatment of cystoid macular edema after
98. Mounier M, Ploy MC, Chauvin M. Study of intraocular diffusion of ofloxacin in humans cataract surgery. J Cataract Refract Surg 2017;43:276–84.
and rabbits. Pathol Biol 1992;40:529–33. 133. Weisz JM, Bressler NM, Bressler SB, et al. Ketorolac treatment of pseudophakic cystoid
99. Simone JN, Pendelton RA, Jenkins JE. Comparison of the efficacy and safety of ketoro- macular edema identified more than 24 months after cataract extraction. Ophthalmol-
lac tromethamine 0.5% and prednisolone acetate 1% after cataract surgery. J Cataract ogy 1999;106:1656–9.
Refract Surg 1999;25:699–704. 134. Williams GA, Haller JA, Kuppermann BD, et al. Dexamethasone posterior-segment
100. Hirneiss C, Neubaur AS. Comparison of prednisolone 1%, rimexolone 1% and ketoro- drug delivery system in the treatment of macular edema resulting from uveitis or irvine-
lac tromethamine 0.5% after cataract extraction. Graefes Arch Clin Exp Ophthalmol gass syndrome. Am J Ophthalmol 2009;147:1048–54.
2005;243:768–73. 135. Conway MD, Canakis C. Intravitreal triamcinolone acetonide for refractory chronic
101. Wielders LH, Schouten JS, Aberle MR, et al. Treatment of cystoid macular edema after pseudophakic cystoid macular edema. J Cataract Refract Surg 2003;29:27–33.
cataract surgery. J Cataract Refract Surg 2017;43:276–84. 136. Jonas JB. Kreissig. Intravitreal triamcinolone for pseudo-phakic cystoid macular edema.
102. Chang DF, Garcia IH, Hunkeler JD, et al. Phase II results of an intraocular steroid Am J Ophthalmol 2003;136:384–6.
delivery system for cataract surgery. Ophthalmology 1999;106:1172–7. 137. Ozkiris A, Erkilic K. Complications of intravitreal injection of triamcinolone acetonide.
103. Masket M. Comparison of the effect of topical corticosteroids and nonsteroidals on post- Can J Ophthalmol 2005;40:63–8.
operative corneal astigmatism. J Cataract Refract Surg 1990;16:715–18. 138. Reis A, Birnbaum F. Cyclooxygenase-2-inhibitors: a new therapeutic option in the treat-
104. Barba KR, Samy A, Lai C, et al. Effect of topical anti-inflammatory drugs on corneal and ment of macular edema after cataract surgery. J Cataract Refract Surg 2005;31:1337–40.
limbal wound healing. J Cataract Refract Surg 2000;26:893–7. 139. Abe T, Hayasaka S, Nagaki Y, et al. Pseudophakic cystoid macular edema treated with
105. Snyder RW, Siekert RW, Schwiegerling J, et al. Acular as a single agent for use as an anti- high-dose intravenous methylprednisolone. J Cataract Refract Surg 1999;25:1286–8.
miotic and anti-inflammatory in cataract surgery. J Cataract Refract Surg 2000;26:1225–7. 140. Arevalo JF, Garcia-Amaris RA, Roca JA, et al. Primary intravitreal bevacizumab for the
106. Arshinoff SA, Mills MD, Haber S. The pharmacotherapy of photorefractive keratectomy. management of pseudophakic cystoid macular edema: pilot study of the pan-American
J Cataract Refract Surg 1996;22:1037–44. collaborative retina study group. J Cataract Refract Surg 2007;33:2098–105.
107. Arshinoff SA, Opalinski Y. The pharmacotherapy of photorefractive keratectomy (PRK). 141. Spitzer MS, Ziemssen F, Yoeruek E, et al. Efficacy of intravitreal bevacizumab in
Comp Ophthalmol Update 2003;4:225–33. Editorial follows on p. 235–6. treating postoperative pseudophakic cystoid macular edema. J Cataract Refract Surg
108. Roberts CW. Pretreatment with topical diclofenac sodium to decrease postoperative 2008;34:70–5.
inflammation. Ophthalmology 1996;103:636–9. 142. Arevalo JF, Maia M, Garcia-Amaris RA, et al. Intravitreal bevacizumab for refractory
109. El-Harazi SM, Ruiz RS, Feldman RM, et al. Efficacy of preoperative versus postoperative pseudophakic cystoid macular edema: the pan-American collaborative retina study
ketorolac tromethamine 0.5% in reducing inflammation after cataract surgery. J Cata- group results. Ophthalmology 2009;116:1481–7.
ract Refract Surg 2000;26:1626–30. 143. Barone A, Russo V, Prascina F, et al. Short-term safety and efficacy of intravitreal beva-
110. Arshinoff SA, Strube YNJ, Ning J, et al. Simultaneous bilateral cataract surgery. J Cata- cizumab for pseudophakic cystoid macular edema. Retina 2009;29:33–7.
ract Refract Surg 2003;29:1281–91. 144. Cox SN, Hay E, Bird AC. Treatment of chronic macular edema with acetazolamide. Arch
111. Yaylali V, Ozbay D. Efficacy and safety of rimexolone 1% versus prednisolone acetate Ophthalmol 1988;106:1190–5.
1% in the control of post-operative inflammation following phacoemulsification cataract 145. Miyake K, Ota I, Mackubo K, et al. Latanoprost accelerates disruption of the blood-aque-
surgery. Int Ophthalmol 2004;25:65–8. ous barrier and the incidence of angiographic cystoid macular edema in early postoper-
112. Paganell F, Cardillo JA. A single intraoperative sub-Tenon’s triamcinolone aceton- ative pseudophakias. Arch Ophthalmol 1999;117:34–40.
ide injection for the treatment of post-cataract surgery inflammation. Ophthalmology 146. Miyake K, Ota I, Ibaraki N, et al. Enhanced disruption of the blood-aqueous barrier and
2005;112:1481. the incidence of angiographic cystoid macular edema by topical timolol and its preser-
113. Negi AK, Browing AC. Single perioperative triamcinolone injection versus standard vative in early postoperative pseudophakia. Arch Ophthalmol 2001;119:387–94.
post-operative steroid drops. J Cataract Refract Surg 2006;32:468–74.
114. Gills JP, Gills P. Effect of intracameral triamcinolone to control inflammation following
cataract surgery. J Cataract Refract Surg 2005;31:1670–1.
361.e2
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Part 5 The Lens

Anesthesia for Cataract Surgery

Keith G. Allman 5.8
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
explains the high proportion of patients with coexisting ischemic heart

Definition: Procedures and medications given to allow successful disease.6
completion of lens removal with minimal risk, pain, and anxiety.
Anticoagulants
Patients on oral anticoagulants and antiplatelet therapy, including aspirin
Key Features and clopidogrel, should continue with these throughout surgery.9–12 The
• Consideration of patient characteristics. risks of cardiovascular complications if these agents are stopped outweigh
• Local anesthesia: considerations, sedatives used, local anesthetics the potential risks of hemorrhage. General anesthesia, sub-Tenon’s block,
used. or topical local anesthesia is recommended.
• Local techniques: topical, retrobulbar—advantages, disadvantages;
peribulbar and sub-Tenon’s—comparison. Diabetes Mellitus
• General anesthesia: techniques, advantages, disadvantages, and Local anesthesia causes the least disruption to diabetic management and is
complications. preferred.13 Normally, patients do not need to fast (see below).
LOCAL ANESTHESIA
INTRODUCTION Local anesthesia can be classified into topical, retrobulbar, peribulbar, and
The advent of small, self-sealing cataract incisions has allowed a change in sub-Tenon’s block.
the practice of anesthesia for cataract surgery. Local and topical techniques
are now the norm, with less than 2% of patients requiring general anes- General Considerations
thesia.1 However, anesthesiology input remains important, as even topical
techniques have been shown to require anesthesiologist intervention for The main advantage of local anesthesia is minimal disruption for the
22%–28% of cases.2,3 patient. Sedation may be useful, particularly in the anxious.14 Patients given
A team approach is important because it allows the surgeon to con- local anesthesia without sedation or with “minimal” sedation (as defined
centrate on the operation while the anesthesiologist cares for the patient.4 by the ASA) need not be starved. 15,16 Guidelines for standard fasting times
should be followed for deeper sedation or general anesthesia.16
Minimal monitoring should include electrocardiography (ECG) and
MEDICAL ASPECTS OF ANESTHESIA FOR pulse oximetry. Older adults and those with systemic illnesses should be
anesthetized in an appropriate environment with backup facilities if inpa-
CATARACT SURGERY tient or critical care is required.17 Supplemental oxygen is given to avoid
Cataract Type and Associated Medical Conditions hypoxia and to minimize claustrophobia. Rebreathing can occur under the
drapes even at 6 L/min of oxygen.
Cataracts can be either congenital or acquired and may be an ocular man- Nonmedical personnel often perform an assessment prior to surgery.
ifestation of a systemic disease. Younger patients may have uncommon Accurate listing for local or general anesthesia can be a problem because
medical conditions, whereas those with acquired cataracts are usually older many patients have comorbidities. A questionnaire filled in by patients has
(average age 75 years) and have comorbidities, such as ischemic heart been shown to be a good initial screening tool, with supplemental medical
disease and chronic obstructive airway disease. In an audit of 1000 cases input as required.14
in Auckland, 43% were identified as American Society of Anesthesiologists Many patients have visual experiences under local anesthesia; in one
(ASA) grades 3–4.5 There is also a significant increase in overall mortal- survey 16% found this distressing.18 Counseling preoperatively has been
ity in those with concurrent hypertension (48%), ischemic heart disease shown to be beneficial in reducing this distress.19,20
(38%), and diabetes (16%).6 All operating room personnel must be trained in basic life support, and
Routine preoperative investigations, however, are not usually indicated, at least one member should have advanced training. The Joint Royal Col-
with the exception of testing for clotting in some patients taking oral anti- leges in the United Kingdom recommend that an anesthetist be present
coagulants, for electrolytes in those having dialysis, and for blood sugar in throughout, whether general or local anesthesia is used, and this is essen-
those with a history of diabetes.7,8 An assessment of the patient’s ability to tial if sharp needle technique or sedation is contemplated. For patients
lie flat and still is important. undergoing topical anesthesia or sub-Tenon’s block, an anesthetist does
not need to be present, unless the site is isolated.8,17
Specific Conditions There are few absolute contraindications to local anesthesia, but patient
refusal and the possibility of noncooperation during surgery remain the
Ischemic Heart Disease commonest.
Ischemia can be provoked by stress and anxiety at the prospect of surgery
and anesthesia. If possible, surgery should be avoided for 3 months after
myocardial infarction, angioplasty, or coronary revascularization. Phenyl-
Topical Anesthesia (see Box 5.8.1)
ephrine drops may result in a significant rise in blood pressure and should More than 60% of all cataract operations are performed with the patient
362 be limited to a 2.5% solution. The oxidative damage resulting in cataract under topical anesthesia in the United States and around 33% in the
formation is linked to free radical formation and atherosclerosis, which United Kingdom.21 Oxybuprocaine (benoxinate) 0.4%, an ester anesthetic,
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BOX 5.8.1 Advantages and Disadvantages of ADVANCEMENT OF NEEDLE IN RETROBULBAR BLOCK
Topical Anesthesia 5.8
Advantages
• No risk associated with needle insertion

• Reduced risk of periocular hemorrhage
• Functional vision is maintained; advantageous for uniocular patients
• Reduced postoperative diplopia and ptosis
Disadvantages
• An awake and talkative patient can be distracting for the surgeon
• No akinesia of the eye
• Less effective anesthesia compared with sub-Tenon’s block
• Increased risk of surgical complications; if difficulties or problems
occur, anesthesia may be inadequate
• May be unsuitable for less experienced surgeons
Adverse Effects of Topical Ocular Anesthetics
• Direct corneal effects—alteration of lacrimation and tear film stability
• Epithelial toxicity—healing has been shown to be delayed when an
epithelial defect occurs (lidocaine does not appear to affect healing) Fig. 5.8.1 Advancement of needle in retrobulbar block.
• Endothelial toxicity—this occurs when penetrating trauma is present
and appears to be related to the preservative benzalkonium
• Systemic effects—lethal toxicity (this is only a problem with cocaine) TABLE 5.8.1 Comparison of Peribulbar and Sub-Tenon’s Block
• Allergy and idiosyncratic reactions Peribulbar Block Sub-Tenon’s Block
Secondary Adverse Effects More pronounced akinesia Less akinesia
• Surface keratopathy Lower rates of chemosis and High rates of chemosis and
subconjunctival hemorrhage subconjunctival hemorrhage
Risk of globe perforation, retrobulbar Complications rarely serious
hemorrhage, myotoxicity Improved analgesia
BOX 5.8.2 Advantages and Disadvantages of Small risk of brainstem anesthesia Lower dose and volume of anesthetic
Retrobulbar Block agent are used
Less painful to perform
Advantages
• Reliable akinesia
• Onset of block is quicker than with peribulbar anesthesia relatively obsolete. For sharp needle anesthesia, peribulbar block offers a
• Low volumes of anesthetic result in a lower intraorbital tension and safer, equally effective method.27,28
less chemosis than with peribulbar blocks
• Temporary loss of visual acuity occurs more reliably than for Peribulbar Block (see also Table 5.8.1)
peribulbar block
The principle of this technique is to instill the local anesthetic outside
Disadvantages the posterior muscle cone and thereby avoid accidental injection into the
• Risk of brainstem anesthesia—reason for the development of the optic nerve (which would cause brainstem anesthesia). This utilizes higher
peribulbar block volumes (6–10 mL) of the local anesthetic compared with the traditional
• Risk of myotoxicity and globe perforation retrobulbar block, and the application of a pressure device is often needed.
Technique
is frequently used. Proparacaine (proxymetacaine) 0.5% is less toxic to With the eye in primary gaze, local anesthetic drops are applied to the
the corneal epithelium, does not sting on application, but has a shorter cornea. At the inferotemporal lower orbital margin, a 25-gauge, 25-mm
duration of action (20 minutes). Other agents, including tetracaine (ame- needle is advanced parallel to the plane of the orbital floor either trans-
thocaine) 0.5%–1%, lidocaine 1%–4%, and bupivacaine 0.5%–0.75%, have cutaneously or transconjunctivally. A degree of upward and inward angu-
longer durations of action but increased corneal toxicity and pain on lation may be needed once the needle goes past the equator of the globe.
application. Local anesthetic (4–6 mL) is injected at a depth of about 20 mm from the
Topical anesthesia may be combined with subconjunctival or, more com- inferior orbital rim (in an eye of normal axial length). No resistance to
monly, intracameral anesthesia to improve patient comfort. Preservative- injection should be felt, and prior aspiration should be performed (Fig.
free lidocaine 1% 0.3–0.5 mL appears to be effective and safe.21,22 5.8.2 and Fig. 5.8.3).
As visual perception is not lost, the patient is asked to focus on a light, After 5 minutes, the degree of akinesia is assessed. If a second medio-
the intensity of which is reduced. Subconjunctival injection of antibiotics canthal injection is required, a 25-gauge, 25-mm needle is inserted between
can be painful and can be avoided by intracameral administration. the medial canthus and the caruncle and directed immediately backward.
Use of topical anesthesia has been increasing throughout the United The medial check ligament is often penetrated. At a depth of 15 mm, after
States and Europe despite several studies demonstrating inferior analge- prior aspiration, another 4–6 mL of solution is injected to produce a more
sia compared with both peribulbar and sub-Tenon’s blocks and a possi- complete block, with akinesia of the orbicularis oculi and levator palpebrae
ble increase in surgical complication rate (4.3% posterior capsular tear for superioris. A Honan balloon or pressure-lowering device is often applied
topical compared with 2.1% for sub-Tenon’s anesthesia).4,23–25 for 5–10 minutes.
With correct selection of patients and surgery performed by experi- Peribulbar block has been reported to be more painful than using
enced surgeons, many centers have shown good results, but because there topical anesthesia.29,30 It is important that adequate training be given to
is no akinesia of the eye, it may not be suitable for inexperienced surgeons decrease complications from the use of all of these blocks.
or uncooperative patients.26
Local Anesthetic Agent
The most common agent used is lidocaine 2% plus hyaluronidase 15 IU/
Retrobulbar Block (see Box 5.8.2) mL. If greater duration of anesthesia is required, the lidocaine can be
With this technique, the aim is to block the oculomotor nerves before they mixed in a ratio of 50 : 50 with bupivacaine 0.5%.
enter the four rectus muscles by depositing the local anesthetic directly Other agents used include 2-chloroprocaine 2%–3%, mepivacaine
into the posterior intraconal space (Fig. 5.8.1). Although the resultant aki- 1%–2%, bupivacaine 0.25%–0.75%, prilocaine 3%, and ropivacaine 0.75%.31
nesia is usually profound, serious complications, such as brainstem anes- Levobupivacaine is the L-isomer of bupivacaine with a higher safety index, 363
thesia, globe perforation, and myotoxicity, have rendered the technique especially in terms of cardiac toxicity. Articaine 2%–4% is an amide local
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Fig. 5.8.2 Inferotemporal peribulbar
5 PERIBULBAR/INFEROTEMPORAL PERIBULBAR INJECTION injection. (A) The needle enters the

orbit at the junction of its floor with the
lateral wall, very close to the bony rim.
(B) The needle passes backward in a
The Lens
sagittal plane parallel to the orbit floor.

(C) It passes the globe equator when the
needle–hub junction reaches the plane
of the iris. (D) After test aspiration, up
to 10 mL anesthetic solution is injected.
site of (Adapted from Hamilton RC. Techniques of
injection orbital regional anaesthesia. Br J Anaesth
2001;86:473–6.)
A B
C D
belly. Myocyte cell death is followed by hypertrophic regeneration and

shortening.43,44
These serious complications have led some authorities to recommend
abandoning sharp needle techniques altogether.42 The UK Royal College of
Ophthalmologists has also stated:
“Sharp needle local anaesthetic techniques have a higher risk of ocular
and systemic complications than sub-Tenon’s or topical techniques and
should only be used when the anaesthetist and surgeon consider it abso-
lutely necessary.”45
In 2017 the UK National Institute for Health and Care Excellence (NICE)
concluded that peribulbar anesthesia should no longer be used for routine
cataract surgery where Topical or sub-Tenon’s anesthesia is possible.46
Certainly, sharp needle blocks are responsible for the majority of oph-
thalmic anesthesia–related problems and are the most common cause of
regional anesthesia–related litigation after centroneuraxial blockade in the
United Kingdom (average settlement £24 000).47,48
Sub-Tenon’s Block (see also Table 5.8.1)

Fig. 5.8.3 Transconjunctival peribulbar injection technique.
This was first described by Turnbull in 1884 when he used open dissec-
anesthetic of low toxicity used predominantly in dentistry. Because of its tion of Tenon’s layer followed by instillation of cocaine. Later modifications
rapid onset, short duration of action, low toxicity, and better penetration of were introduced by Stevens, Greenbaum and Allman.49–53
tissues, it has been shown to produce good quality blocks.32–36 Sub-Tenon’s block involves surface anesthesia and surgical access to
Epinephrine 5 µg/mL is sometimes added to improve onset time, sub-Tenon’s space. In the United Kingdom, this now is the most common
quality, and duration of the block. However, it should be avoided in older method used in cataract surgery, comprising 47% of cases.54
patients with atherosclerosis and has been implicated in optic artery
thrombosis secondary to vasoconstriction. A 50% decrease in pressure in Anatomy
the ophthalmic artery has also been noted. This is described in more detail elsewhere in this text. Briefly, Tenon’s
Hyaluronidase is an enzyme derived from the testicles of rams (previ- capsule (after Jacques René Tenon [1724–1816], French anatomist/surgeon)
ously from the testicles of cattle), although a recombinant version is now is a facial sheath, a thin membrane enveloping the eyeball and separat-
available. It hydrolyzes C1–C4 bonds between glucosamine and glucuronic ing it from orbital fat. The inner surface is smooth and shiny, separated
acid in connective tissue, thus enabling the local anesthetic to penetrate from the outer surface of the sclera by a potential space, the episcleral or
tissues more effectively. The required quantity of the local anesthetic, sub-Tenon’s space. Anteriorly, the capsule fuses with conjunctiva 5–10 mm
therefore, is reduced, and the time to onset decreased. Hyaluronidase may from the limbus. Posteriorly, it fuses with the meninges around the optic
also help prevent damage to the extraocular muscles, especially the inferior nerve. It has been suggested that it is a lymph space and is crossed by
rectus muscle, preventing diploplia.37 numerous delicate bands.
Complications Technique
Most serious complications of peribulbar anesthesia are associated with The conjunctiva is anesthetized first with a topical local anesthetic of
the use of sharp needles. choice. The most common approach is via the infranasal quadrant because
this allows for good distribution of the anesthetic while decreasing the risk
• Globe perforation/penetration. Incidence 1.4–1.9 per 10 000.38–40 More of damage to the vortex veins. The eye is cleaned with 5% iodine, and the
common in high myopes (>26 mm axial length) and with inexperience. patient is asked to look upward and outward. Aseptically, the conjunctiva
Usually results in marked visual loss because of permanent retinal and Tenon’s capsule are held 3–5 mm from the limbus using nontoothed
damage. Moorfield’s forceps (Fig. 5.8.4).52 A small incision is made through these
• Retrobulbar hemorrhage. Incidence 0.6–4.2 per 10 000.38–40 More common layers using blunt-tipped, sprung Westcott scissors, exposing the sclera. A
in those taking anticoagulants. May require surgical decompression. cannula is then advanced into the sub-Tenon’s space and around the globe.
364 • Extraocular myotoxicity. Incidence 25–100 per 10 000.41,42 Related to Sub-Tenon’s anesthesia can be broadly divided into anterior and pos-
inadvertent direct injection of the local anesthetic into the muscle terior techniques. In the former, the cannula tip remains anterior to the
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5.8

A
Fig. 5.8.4 Incision for sub-Tenon’s block. Arrows point to conjunctiva, Tenon’s
capsule, and shining sclera under the Tenon’s capsule. (Reprinted with kind
permission from Kumar CM, Williamson S, Manickham B. A review of sub-Tenon’s
block: current practice and recent development. Eur J Anaesthesiol 2005;22:567–7,
Figure 2c, European Academy of Anaesthesiology, published by Cambridge
University Press.)
globe equator. This reduces the risk of inadvertent misplacement but

increases the rate of chemosis and can make akinesia difficult to achieve.
For more profound akinesia, the cannula tip should be placed posterior to
the equator but must be positioned with care, gently following the curve of
See clip: the globe (Video 5.8.1).
5.8.1
Numerous cannulae have been described.55 The plastic Greenbaum
cannula (12-mm 15-gauge) is suitable for anterior blocks, whereas a metal B
Stevens cannula (25-mm 19-gauge) is most suitable for posterior tech-
niques (Fig. 5.8.5). Fig. 5.8.5 Three cannulae used for sub-Tenon’s anesthesia. (A) Greenbaum cannula
An alternative technique that requires no prior conjunctival incision 15-gauge 12-mm. Middle, Triport cannula (Eagle Laboratories) 21-gauge 25-mm.
(B) Steven’s cannula (Visitec) 19-gauge 25-mm.
uses a pencil-point cannula (25-mm 21-gauge Triport cannula; Eagle Labo-
ratories).55 This reduces the amount of conjunctival damage and decreases
reflux of the local anesthetic. The blunt cannula entry site leaves a very
small, self-sealing wound, which then heals rapidly with less conjunctival BOX 5.8.3 Advantages and Disadvantages of
See clip: scarring compared with traditional techniques (Video 5.8.2). General Anesthesia
5.8.2 The sub-Tenon’s (or episcleral) space also can be accessed using a “B”
beveled needle, as described by Jacques Ripart.56 Although a useful and Advantages
reliable technique, this somewhat negates the advantages of using a blunt • Patient comfort
cannula. • Ideal operating conditions—a quiet, immobile patient and soft eye
The local anesthetic in a dose of 3 to 5 mL is injected; the greater the • Allows for rapid alterations in intraocular pressure, if required
volume, the greater is the degree of akinesia. Lidocaine 2% is usually used • No risk of complications associated with local anesthetic blocks
in combination with hyaluronidase. Addition of hyaluronidase reduces the • No residual paralysis of the eye when the patient is awake
median effective volume (EV50) needed from 6.4 to 2.6 mL.57 Articaine • Bilateral surgery can be performed
2%–4% may be even more effective.36 • Better conditions for teaching
A Honan’s balloon can be used to increase dispersal; however, it is not Disadvantages
usually needed. • Slower turnaround times
Complications are mainly minor (chemosis and subconjunctival hem- • More expensive
orrhage), although orbital inflammation, scleral perforation, cardiovascular • Greater risk in frail older adults
collapse, and sight-threatening and life-threatening complications have all • Greater physiological disruption for patient
been reported.58–61
SEDATIVE AGENTS Fentanyl is a potent, short-acting narcotic analgesic with a duration of

Sedation is a useful adjunct to local anesthesia for many patients— action of about 30 minutes. Given in doses of 25–50 µg, it provides analge-
particularly those who are unduly anxious. sia with minimal sedation and is a useful adjunct to midazolam or propo-
Midazolam, a short-acting, water-soluble benzodiazepine with a half-life fol. Side effects include respiratory depression, nausea, and vomiting.
of 2 hours, has both amnesic and anxiolytic properties, lacks venous Remifentanil is a potent, ultra-short-acting alternative but can cause a
sequelae, and allows rapid patient recovery. It is given intravenously in marked fall in heart rate and blood pressure in older adults.
0.5- to 1-mg increments. Adequate time between doses must be allowed in Dexmedetomidine, an α2 agonist, has also been used as a sedative
older adults, or oversedation could result. Overdoses can be reversed with agent with good effect.63
flumazenil, a specific benzodiazepine antagonist, but its half-life is 1 hour,
so resedation can occur.
Propofol, a short-acting phenol, is an intravenous induction agent suit-
GENERAL ANESTHESIA
able for infusion and sedation. It is characterized by the patient’s rapid General anesthesia is useful in those patients unsuitable for local anesthe-
and clear-headed recovery and is associated with a low incidence of nausea sia; it is the method of choice for babies, children, and the uncooperative
and vomiting. It causes respiratory depression and a fall in blood pressure. (see Box 5.8.3).64
Propofol and midazolam have both been used for patient-controlled In the past, it was necessary to intubate, paralyze, and ventilate the 365
sedation.62 patient. However, with the advent of phacoemulsification (“phaco”) and
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small incision surgery, plus the use of propofol with a laryngeal mask POSTOPERATIVE CARE
5 airway, it is now feasible to have the patient breathing spontaneously.
Avoiding intubation allows for the use of a lighter anesthetic, decreases
cardiovascular depression, and improves recovery. In patients 80 years of
Cataract extraction by phaco is relatively pain-free. In the majority of cases,
simple oral analgesics are sufficient. Nonsteroidal anti-inflammatory drugs
age or older, psychomotor testing has shown that total intravenous anes- should be used with caution in older adults. Topical nonsteroidal analge-
The Lens
thesia with propofol and remifentanil results in significantly faster recov- sics can decrease pain and inflammation68 and have been shown to be
ery of cognitive function compared with etomidate–fentanyl–isoflurane.65 equally effective in reducing the inflammatory response compared with
A recent study that compared balanced anesthesia with total intravenous corticosteroids, with fewer side effects. Corticosteroids should be reserved
anesthesia (TIVA) showed similar cardiovascular effects but decreased for cases with more severe inflammation.69 Topical local anesthesia can
nausea and vomiting, faster recovery, better patient satisfaction, and lower also be used as an adjunct, as it reduces systemic anesthetic requirements.
costs with TIVA.,66,67 This may reduce postoperative nausea and vomiting by avoiding the use of
opiates. Propofol also has antiemetic properties.
Technique
Spontaneous Respiration KEY REFERENCES
A laryngeal mask is inserted, and anesthesia is maintained with either a
continuous propofol infusion or a volatile agent of choice. Target-controlled Ali N, Little BC. Causes of cataract surgery malpractice claims in England 1995–2008. Br J
Ophthalmol 2011;95(4):490–2.
infusion regimens are commonly employed. Propofol 4.5 µg/mL bolus for Allman KG, Theron AD, Byles DB. A new technique of incisionless minimally invasive
induction followed by 3.26 µg/mL maintenance target infusion levels can sub-Tenon’s anaesthesia. Anaesthesia 2008;63(7):782–3.
be combined with either an alfentanil (target blood concentration 25 ng/ Cass GD. Choices of local anesthetics for ocular surgery. Ophthalmol Clin North Am
mL) or remifentanil (target blood concentration 1–1.5 ng/mL) infusion, 2006;19(2):203–7.
Guay J, Sales K. Sub-Tenon’s anaesthesia versus topical anaesthesia for cataract surgery.
although propofol plus topical anesthesia is usually sufficient. The use of Cochrane Database Syst Rev 2015;(8):CD006291.
a laryngeal mask enables faster turnaround times and reduces the cough Lee RM, Thompson JR, Eke T. Severe adverse events associated with local anaesthesia in
associated with extubation. It provides a stable, easily controlled anesthetic, cataract surgery: 1 year national survey of practice and complications in the UK. Br J
resulting in rapid recovery and a low incidence of nausea and vomiting. Ophthalmol 2016;100(6):772–6.
Ezra DG, Allan BD. Topical anaesthesia alone versus topical anaesthesia with intracameral
lidocaine for phacoemulsification. Cochrane Database Syst Rev 2007;(3):CD005276.
Ventilation Greenbaum S. Parabulbar anaesthesia. Am J Ophthalmol 1992;114:776.
The traditional method involves endotracheal intubation, although con- Guyton DL. Strabismus complications from local anesthetics. Semin Ophthalmol
trolled ventilation is possible with a laryngeal mask. This combines the 2008;23(5):298–301.
Kumar CM, Eid H, Dodds C. Sub-Tenon’s anaesthesia: complications and their prevention.
benefits of avoiding intubation and causing paralysis in the patient. Suxa- Eye (Lond) 2011;25(6):694–703.
methonium is avoided, if possible, because a transient rise in intraocu- National Institute for Health and Care Excellence (NICE). Cataracts in adults: management.
lar pressure occurs with its use. Short-acting nondepolarizing blockers NICE guideline [NG77]. Published October 2017. http://www.nice.org.uk/guidance/ng77.
are preferred. Maintenance consists of using a volatile agent or a propo- Schulenburg HE, Sri-Chandana C, Lyons G, et al. Hyaluronidase reduces local anaesthetic
volumes for sub-Tenon’s anaesthesia. Br J Anaesth 2007;99(5):717–20.
fol infusion. Although patient throughput may be slower, this technique Stevens JD. A new local anaesthesia technique for cataract extraction by one quadrant
provides stable, well-controlled anesthesia and is the method of choice for sub-Tenon’s infiltration. Br J Ophthalmol 1992;76:670–4.
certain patients in whom spontaneous respiration would be inappropriate The Royal College of Anaesthetists and The Royal College of Ophthalmologists. Local anes-
(e.g., obese individuals). thesia for ophthalmic surgery. London: Royal College of Anaesthetists and The Royal
College of Ophthalmologists; 2012.
The Royal College of Ophthalmologists. Cataract surgery guidelines. London: Royal College
Conclusions of Ophthalmologists; 2010.
Both spontaneous respiration and ventilation methods are suitable for Turnbull CS. The hydochlorate of cocaine, a judicious opinion of its merits. (Editorial) Med
day-case anesthesia. They are both widely used in all other specialties. Both Surg Rep (Boston) 1884;29:628–9.
propofol and the newer volatile agents sevoflurane and desflurane provide
a particularly rapid and clear-headed recovery.
Hypotension needs to be aggressively treated with vasoconstrictors, Access the complete reference list online at ExpertConsult.com
such as ephedrine or metaraminol, to minimize morbidity.
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caine/lidocaine for peribulbar anaesthesia by inferotemporal injection. Br J Anaesth
1. Chandradeva K, Nangalia V, Hugkulstone CE. Role of the anaesthetist during cat-
aract surgery under local anaesthesia in the UK: a national survey. Br J Anaesth
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34. Ozdemir M, Ozdemir G, Zencirci B, et al. Articaine versus lidocaine plus bupivacaine for
5.8
2010;104(5):577–81. peribulbar anaesthesia in cataract surgery. Br J Anaesth 2004;92:231–4.
35. Gouws P, Galloway P, Jacob J, et al. Comparison of articaine and bupivacaine/lidocaine

2. Gemma M, Gioia L, Dedola E, et al. Anesthesiologist intervention during cataract surgery
under topical or peribulbar anesthesia: a propensity model comparison. Eur J Ophthal- for sub-Tenon’s anaesthesia in cataract extraction. Br J Anaesth 2004;92(2):228–30.
mol 2010;20(4):687–93. 36. Raman SV, Barry JS, Murjaneh S, et al. Comparison of 4% articaine and 0.5% levobupiv-
3. Basta B, Gioia L, Gemma M, et al. Systemic adverse events during 2005 phacoemulsi- acaine/2% lidocaine mixture for sub-Tenon’s anaesthesia in phacoemulsification cataract
fications under monitored anesthesia care: a prospective evaluation. Minerva Anestesiol surgery: a randomised controlled trial. Br J Ophthalmol 2008;92(4):496–9.
2011;77(9):877–83. 37. Hameda S, Devys JM, Xuan TH, et al. Role of hyaluronidase in diploplia after peribulbar
4. Palte HD, Gayer S, Kumar C. Role of the anaesthetist during cataract surgery under local anaesthesia for cataract surgery. Ophthalmology 2005;112:879–82.
anaesthesia. Br J Anaesth 2010;105(2):235. 38. Eke T, Thompson JR. The National Survey of Local Anaesthesia for Ocular Surgery. II.
5. Guise P. Aeroplanes rarely crash nowadays, therefore they don’t need pilots: anaesthesia, Safety profiles of local anaesthesia techniques. Eye (Lond) 1999;13(Pt 2):196–204.
anaesthetics and cataract surgery. Clin Exp Ophthalmol 2005;33:451–2. 39. Eke T, Thompson JR. Serious complications of local anaesthesia for cataract surgery: a 1
6. Hu FB, Hankinson SE, Stampfer MJ, et al. Prospective study of cataract extraction and year national survey in the United Kingdom. Br J Ophthalmol 2007;91(4):470–5.
the risk of coronary heart disease in women. Am J Epidemiol 2001;153:875–81. 40. Lee RM, Thompson JR, Eke T. Severe adverse events associated with local anaesthesia
7. Keay L, Lindsley K, Tielsch J, et al. Routine preoperative medical testing for cataract in cataract surgery: 1 year national survey of practice and complications in the UK. Br J
surgery. Cochrane Database Syst Rev 2009;(2):CD007293. Ophthalmol 2016;100(6):772–6.
8. The Royal College of Anaesthetists and The Royal College of Ophthalmologists. Local 41. Gómez-Arnau JI, Yangüela J, González A, et al. Anaesthesia-related diplopia after cata-
anesthesia for ophthalmic surgery. London, UK: Royal College of Anaesthetists and The ract surgery. Br J Anaesth 2003;90(2):189–93.
Royal College of Ophthalmologists; 2012. 42. Guyton DL. Strabismus complications from local anesthetics. Semin Ophthalmol
9. Konstantatos A. Anticoagulation and cataract surgery: a review of the current literature. 2008;23(5):298–301.
Anaesth Intensive Care 2001;29(1):11–18. 43. Scott AB, Alexander DE, Miller JM. Bupivacaine injection of eye muscles to treat strabis-
10. Jonas JB, Pakdaman B, Saunder G. Cataract surgery under systemic anticoagulant mus. Br J Ophthalmol 2007;91(2):146–8.
therapy with coumarin. Eur J Opthalmol 2006;16:30–2. 44. Scott AB, Miller JM, Shieh KR. Treating strabismus by injecting the agonist muscle
11. Ong-Tone L, Paluck EC, Hart-Mitchell RD. Perioperative use of warfarin and aspirin in with bupivacaine and the antagonist with botulinum toxin. Trans Am Ophthalmol Soc
cataract surgery by Canadian Society of Cataract and Refractive Surgery members: survey. 2009;107:104–9.
J Cataract Refract Surg 2005;31:991–6. 45. The Royal College of Ophthalmologists. Cataract surgery guidelines. London: Royal
12. Kong K-L, Khan J. Ophthalmic patients on antithrombotic drugs: a review and guide to College of Ophthalmologists; 2010.
perioperative management. Br J Ophthalmol 2015;99:1025–30. 46. National Institute for Health and Care Excellence (NICE). Cataracts in adults: manage-
13. Kumar CM, Seet E, Eke T, et al. Glycaemic control during cataract surgery under ment. NICE guideline [NG77]. Published October 2017. http://www.nice.org.uk/guidance/
loco-regional anaesthesia: a growing problem and we are none the wiser. Br J Anaesth ng77.
2016;117(6):687–91. 47. Ali N, Little BC. Causes of cataract surgery malpractice claims in England 1995–2008. Br
14. MacPherson R. Structured assessment tool to evaluate patient suitability for cataract J Ophthalmol 2011;95(4):490–2.
surgery under local anaesthesia. Br J Anaesth 2004;93:521–4. 48. Szypula K, Ashpole KJ, Bogod D, et al. Litigation related to regional anaesthesia: an anal-
15. American Society of Anesthesiologists. http://www.asahq.org/For-Members/Stan- ysis of claims against the NHS in England 1995–2007. Anaesthesia 2010;65(5):443–52.
dards-Guidelines-and-Statements.aspxContinuum%20of %20Depth%20of %20Sedation. 49. Turnbull CS. The hydochlorate of cocaine, a judicious opinion of its merits. (Editorial)
ashx. Accessed June 2012. Med Surg Rep (Boston) 1884;29:628–9.
16. The Royal College of Anaesthetists and College of Emergency Medicine Working Party 50. Greenbaum S. Parabulbar anaesthesia. Am J Ophthalmol 1992;114:776.
on Sedation, Anaesthesia and Airway Management in the Emergency Department. Safe 51. Hansen EA, Mein CE, Mazzoli R. Ocular anaesthesia for cataract surgery: a direct
sedation of adults in the emergency department. London: Royal College of Anaesthetists sub-Tenon’s approach. Ophthal Mic Surg 1990;21:696–9.
and College of Emergency Medicine; 2012. 52. Stevens JD. A new local anaesthesia technique for cataract extraction by one quadrant
17. The Royal College of Anaesthetists. Guidance on the provision of ophthalmic anaesthesia sub-Tenon’s infiltration. Br J Ophthalmol 1992;76:670–4.
services, ch 10. London: The Royal College of Anaesthetists; 2004. p. 49–52. 53. Allman KG, Theron AD, Byles DB. A new technique of incisionless minimally invasive
18. Tan CS, Eng KG, Kumar CM. Visual experiences during cataract surgery: what anaesthe- sub-Tenon’s anaesthesia. Anaesthesia 2008;63(7):782–3.
sia providers should know. Eur J Anaesthesiol 2005;22:413–19. 54. Lee RM, Thompson JR, Eke T. Severe adverse events associated with local anaesthesia
19. Voon LW, Au Eong KG, Saw SM, et al. Effect of preoperative counseling on patient fear in cataract surgery: 1year national survey of practice and complications in the UK. Br J
from the visual experience during phacoemulsification under topical anesthesia: Multi- Ophthalmol 2016;100(6):772–6.
center randomized clinical trial. J Cataract Refract Surg 2005;31:1966–9. 55. Kumar CM, Dodds C, McLure H, et al. A comparison of three sub-Tenon’s cannulae. Eye
20. Leo SW, Lee LK, Au Eong KG. Visual experience during phacoemulsification under (Lond) 2004;18(9):873–6.
topical anaesthesia: a nationwide survey of Singapore ophthalmologists. Clin Exp Oph- 56. Ripart J, Prat-Pradal D, Vivien B, et al. Medial canthus episcleral (sub-Tenon) anesthesia
thalmol 2005;33:578–81. imaging. Clin Anat 1998;11(6):390–5.
21. Ezra DG, Allan BD. Topical anaesthesia alone versus topical anaesthesia with intracam- 57. Schulenburg HE, Sri-Chandana C, Lyons G, et al. Hyaluronidase reduces local anaes-
eral lidocaine for phacoemulsification. Cochrane Database Syst Rev 2007;(3):CD005276. thetic volumes for sub-Tenon’s anaesthesia. Br J Anaesth 2007;99(5):717–20.
22. Tan CS, Fam HB, Heng WJ, et al. Analgesic effect of supplemental intracameral lido- 58. Alwitty A, Koshy Z, Browning AC, et al. The effect of sub-Tenon’s anaesthesia on intra-
caine during phacoemulsification under topical anaesthesia: a randomised controlled ocular pressure. Eye 2001;27:1221–6.
trial. Br J Ophthalmol 2011;95(6):837–41. 59. Ruschen H, Bremner F, Carr C. Complications after sub-Tenon’s eye block. Anesth
23. Srinivasan S, Fern AI, Selvaraj S, et al. Randomised double-blind clinical trail com- Analg 2003;96:273–7.
paring topical and sub-Tenon’s anaesthesia in routine cataract surgery. Br J Anaesth 60. Mukherji S, Esakowitz L. Orbital inflammation after sub-Tenon’s anesthesia. J Cataract
2004;93:683–6. Refract Surg 2005;31:2221–3.
24. Ruschen H, Celaschi D, Bunce C, et al. Randomised control trial of sub-Tenon’s block 61. Kumar CM, Eid H, Dodds C. Sub-Tenon’s anaesthesia: complications and their preven-
versus topical anaesthesia for cataract surgery: a comparison of patient satisfaction. Br J tion. Eye (Lond) 2011;25(6):694–703.
Ophthalmol 2005;89:291–3. 62. Pac-Soo CK, Deacock S, Lockwood G, et al. Patient-controlled; sedation for cataract
25. Davison M, Padroni S, Bunce C, et al. Sub-Tenon’s anaesthesia versus topical anaesthesia surgery using peribulbar block. Br J Anaesth 1996;77:370–4.
for cataract surgery. Cochrane Database Syst Rev 2007;(3):CD006291. 63. Abdalla MI, Al Mansouri F, Bener A. Dexmedetomidine during local anesthesia. J
26. Nicholson G, Mantovani C, Hall GM. Topical anaesthesia for cataract surgery. Br J Anesth 2006;20:54–6.
Anaesth 2001;86:900. 64. Kumar CM, Seet E. Cataract surgery in dementia patients—time to reconsider anaes-
27. Hamilton RC. Techniques of orbital regional anesthesia. Br J Anaesth 1995;75:88–92. thetic options. Br J Anaesth 2016;117(4):421–5.
28. Alhassan MB, Kyari F, Ejere HO. Peribulbar versus retrobulbar anaesthesia for cataract 65. Kubitz J, Epple J, Bach A, et al. Psychomotor recovery in very old patients after total
surgery. Cochrane Database Syst Rev 2008;(3):CD004083. intravenous anaesthesia for cataract surgery. Br J Anaesth 2001;86:203–8.
29. Coelho RP, Weissheimer J, Romao E, et al. Pain induced by phacoemulsion without 66. Weilbach C, Scheinichen D, Thissen U, et al. Anaesthesia in cataract surgery for elderly
sedation using topical or peribulbar anesthesia. J Cataract Refract Surg 2005;31:385–8. people. Anasthesiol Instensivmed Notfallmed Schmerzther 2004;39:276–80.
30. Deruddre S, Benhamou D. Medial canthus single-injection peribulbar anesthesia: a pro- 67. Weibach C, Scheinichen D, Raymondos K, et al. Assessment of anesthesia methods in
spective randomized comparison with classic double-injection peribulbar anesthesia. Reg ophthalmologic surgery by patients, surgeons and anesthesiologists. Ophthalmologe
Anesth Pain Med 2005;30:255–9. 2005;102:783–6.
31. Cass GD. Choices of local anesthetics for ocular surgery. Ophthalmol Clin North Am 68. Goguen ER, Roberts CW. Topical NSAIDS to control pain in clear corneal cataract
2006;19(2):203–7. extraction. Insight 2004;29(3):10–11.
32. Allman KG, McFaden JG, Armstrong J, et al. Comparison of articaine and bupivacaine/ 69. Simone J, Whitacre M. Effects of anti-inflammatory drugs following cataract extraction.
lidocaine for single medial canthus peribulbar anaesthesia. Br J Anaesth 2001;87:584–7. Curr Opin Ophthalmol 2001;12:1263–7.
366.e1
booksmedicos.org
Part 5 The Lens

Phacoemulsification
David Allen
5.9
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
bend in the shaft (Kelman tip) is attached to such a handpiece, then the
Definition: A surgical technique to remove the nuclear portion of a
twisting of the shaft is converted into a sweeping side-to-side motion at
cataractous lens using an aspirating and vibrating ultrasonic handpiece.
the end of the tip. Following this, Abbot Medical Optics (AMO, Santa Ana,
CA) introduced a third modality whereby with their new handpiece (Ellips
FX), the phaco needle is made to traverse laterally while it moves forward,
Key Features taking what they call an elliptical path.
• Changing phacoemulsification (“phaco”) “power” or “amplitude” is The frequency at which a handpiece is set to work depends on the
achieved by changing the stroke length of needle vibration, not by design and materials used. Adjustment of the power setting on the
changing the frequency. machine affects the stroke length (the distance traveled by the tip during
• Evidence is accumulating that direct mechanical action is the most one cycle), but not the frequency. Power is expressed as a percentage of
important factor in phaco. the maximum travel the crystal-tip complex can produce. It is clear that
• Power modulation significantly increases the efficiency of if the frequency remains constant but the distance traveled in each stroke
longitudinal phaco as well as improving the thermal safety. It is less increases, the acceleration of the tip and the maximum speed it reaches
important with torsional phaco. must be greater. It is important to recognize that the power settings on
• Modern pump systems are efficient and high vacuums can be the machine console are indicative only. Some systems have a nonlin-
achieved very quickly with modern flow-based (peristaltic) systems. ear relation between commanded power and stroke length. The smallest
• In a flow-based machine, the aspiration flow rate can be adjusted stroke (at minimum power setting) also varies among systems. In one
completely independently of the preset vacuum limit. commercially available system, 20% power produces tip travel of 50 µm,
• In a vacuum-based (Venturi) machine, the aspiration flow rate is whereas this travel is reached only at 60% power in another machine. As a
generated by the pressure difference between the vacuum chamber consequence, any comparisons between the “efficiency” of different phaco
and the eye. In most machines, the two cannot be completely machines based on comparisons of “power used” are spurious.
dissociated, and a high vacuum results in higher flow rates compared The physical mechanisms that break up nuclear material when a phaco
with a lower vacuum. tip is used have been difficult to elucidate, and the relative importance of
• Modern machines feature a variety of strategies to minimize the various factors is still unclear.1,2 For example, a phaco tip operated at a
postocclusion surge. Postocclusion surge potential is directly related frequency of 44 kHz has a maximum speed of 66 ft/second (20 m/second)
to the maximum set vacuum for any given needle/sleeve/tubing when operated at full power, and the acceleration of the tip is >168 300  ft/
complex. second (>51 000 m/second). Under these conditions, the direct impact of
the tip breaks the frictional forces within the nuclear material. This direct
INTRODUCTION effect is reduced, however, by the forward-propagating acoustic waves or
fluid and particle waves generated by the tip, which tend to push away any
As surgical techniques for the removal of cataract along with drug modu- piece of nucleus in contact with the tip. However, some still postulate that
lation of the consequent biological responses have become more refined, the acoustic shock waves themselves tend to weaken or break some of the
the problems of postoperative infection and inflammation are less import- bonds that hold nuclear material together. The role of cavitation in break-
ant concerns of lens surgeons. As a consequence, it has become possi- ing down lens material remains controversial, but some evidence exists
ble to concentrate on the further refinement of the actual process of lens that it is not required for effective phaco.3
removal. Phacoemulsification (“phaco”) offers the surgeon the possibility Various tip designs are available for the surgeon, but there are three
to break the nucleus into smaller pieces and even into a fine emulsion of key design variations, and each of the tip designs usually is available with
material, all of which can be removed through the probe used to achieve a “cutting tip” angle of 30° or 45°. The tip may be straight with a uniform
the breakup. As a result, it is now possible to minimize trauma to the struc- diameter along its length. The Kelman tip has a 22° angle in the shaft
tures of the eye and to have minimal impact on its shape as a consequence 3.5 mm from the tip. This design is thought to enhance the emulsification
of modern cataract surgery. Achieving this, however, requires the use of action of the tip, as well as allowing the surgeon to use it as a manipu-
very powerful tools. Unfortunately, many surgeons fail to understand the lator. Some tips have a flared termination of the tip (i.e., the outer and
principles that underlie the machines they use. As a consequence of this inner diameter at the end of the tip is greater than that 1–2 mm behind).
relative ignorance, surgery is sometimes performed less efficiently and While the larger mouth creates more holding force, the restriction of the
possibly more dangerously than necessary. inner lumen behind the flare helps suppress postocclusion surge. More
recently, a completely new tip design has been introduced. When torsional
HANDPIECES AND TIPS phaco was developed, the already available Kelman design tip was used.
It seemed logical that rotating the shaft along its long axis would result
The phaco handpiece houses an ultrasonic transducer—a device that con- in a sweeping side-to-side action at the tip end. Although this proved to
verts electrical energy into mechanical vibratory energy. Standard hand- be the case, it was later realized that there was not just simple rotation of
pieces couple the crystal to the phaco tip in such a way that the tip moves the shaft with this design. This realisation resulted in a completely new
backward and forward when the crystals deform. In 2006, Alcon Surgical tip shape, specifically designed for torsional phaco (the “balanced” tip)
(Fort Worth, TX) introduced a handpiece (OZil) that can cause the tip to (Fig. 5.9.1). By significantly reducing the unwanted movement in the shaft,
tort or twist when the crystals deform. It is constructed in such a way that more of the energy produced by the ultrasound crystals is translated into
when oscillating at 32 kHz the crystals produce torsion, and when stimu- sweeping movement at the very end of the tip, giving a stroke length of 367
lated at 44 kHz, they produce traditional linear movement. If a tip with a 190 µ at maximum amplitude compared to 130 µ with the Kelman tip.4
booksmedicos.org
5 VACUUM RISE-TIME
The Lens
Fig. 5.9.1 The balanced tip developed specifically for torsional phaco. (Courtesy vacuum 800
Alcon Surgical.) (mm HG)
700
POWER MODULATION 600
Although some form of simple power modulation (pulsed phaco) has been 500
available for a long time, the introduction in 2001 of the Whitestar software 400
for the AMO Sovereign phaco machine marked a paradigm shift in the
way surgeons controlled the application of phaco power. Breakup of phaco 300
into pulses or bursts has two advantages. First, the pauses (off-period) 200
allow the machine fluidics to pull material back into contact with the tip
following repulsion caused by the jack-hammer effect in traditional longi- 100
tudinal phaco. Second, the pauses prevent significant buildup of heat as a 0
result of frictional movement within the incision, making thermal damage 0 0.5 1 1.5 2 2.5 3
to the cornea less likely. Several machines now allow almost infinite vari- time (seconds)
ation of both duty cycle (the ratio of on-time to off-time) and the length of ASP rate 20 mL/minute
the on-period. It has been shown that such power modulation significantly ASP rate 40 mL/minute
improves the “efficiency” of phacoemulsification (i.e., quicker surgery and ASP rate 60 mL/minute
reduced amount of phaco energy used).5 With the introduction of torsional
phaco the reduced repulsion and reduced thermal effect mean that power Fig. 5.9.2 Vacuum rise-time as a function of aspiration rate. Graph showing the
modulation is less important, although many surgeons continue to apply effect of increasing aspiration rate (pump speed) on the time to reach certain
modulations. vacuum levels.
When first introduced, pulses had a fixed duty cycle of 50% (i.e., the
period with power on and with power off were equal), but power was vari- of pressures does not take place instantaneously. In a standard vacuum
able, whereas bursts were of fixed width, usually with fixed power also. system, because the flow rate is generated by the pressure gradient,
First Bausch & Lomb (Bridgewater, NJ) and now most other manufactur- increasing the vacuum results in increased flow, whereas reducing vacuum
ers have enhanced the various possible combinations of modulation, and lowers the flow. These two parameters cannot normally be modulated
this distinction has become blurred and is probably no longer helpful to independently, although with at least one advanced machine, this is now
try to distinguish between them in advanced machines. possible.
PUMPS AND FLUIDICS Anterior Chamber Hydrodynamics

The function of the phaco pump is twofold—to hold the nucleus onto the It is important to understand the correct meaning of various terms used to
tip and to remove debris created by the tip. With modern techniques the describe the fluid dynamics of phaco. “Vacuum (Limit)” is taken to mean
pump also is used increasingly to aspirate directly the softer parts of the preset maximum vacuum level indicated on the console. In neither
the nucleus. There are two pump principles in general use—flow-driven peristaltic nor vacuum-based systems is this vacuum present in the AC,
and vacuum-driven. Some machines now have the ability to switch between although some degree of vacuum must be present along the aspiration line
the two modes during surgery. (including in the phaco handpiece) to generate outflow. Normally, “flow”
is used to mean aspiration flow rate, which is evacuation flow out of the
Flow-Based (Peristaltic) eye. Fluid also flows out of the eye at a variable rate through the incisions,
often called the incision leakage flow. To avoid confusion, if flow into the
Roller pumps that rotate against compressible tubing or membrane gener- eye is being described, it is necessary to use the term “inflow.” In tradi-
ate flow; this “milks” fluid along the lumen and creates a pressure gradient tional phaco systems, the rate of fluid inflow is determined by the height
between pump and anterior chamber (AC). Recent design changes in the difference between the drip chamber of the fluid reservoir (usually a hung
pumps and sophisticated microprocessor controls have resulted in power- bottle) and the eye. Inflow has been passive in traditional phaco machines;
ful and well-controlled pump systems. The rate at which fluid is aspirated it is reduced in varying amounts by the resistance of the tubing and by any
through the unoccluded phaco tip is set at the machine console in milli- compression of the inflow sleeve around the phaco tip. The recently intro-
liters per minute (mL/min). A low value allows events within the AC to duced “Centurion” phaco machine (Alcon) has an active inflow system
happen slowly; a high value speeds up events and generates more “pulling allowing much more precise control of the AC dynamics and intraocular
power.” Fine adjustments of flow, achieved by changing the speed at which pressure. The system monitors the pressure in the inflow line, the vacuum
the pump turns, allow for personal surgical style or different operating pressure being generated in the outflow line and the aspiration flow rate,
conditions. Recent advanced systems sense when the tip is occluded par- in real time, and adjusts the pressure being applied to the bag containing
tially and then make adjustments to the pump to compensate for reduced the inflow fluid in order to generate sufficient inflow to maintain (within
aspiration. limits) the intraocular pressure (IOP) chosen by the surgeon.
The second pump parameter that can be adjusted is the vacuum level In any system (gravity-fed or with active fluidics) it is essential that the
at which, once achieved, the pump stops. When the tip becomes occluded, inflow potential (the maximum possible under free-flow conditions) at least
the pump continues to turn and move fluid into the cassette, increasing equals, and if possible exceeds, the maximum transient outflow (combined
the vacuum level in the tubing between tip and cassette. Once the preset incisional flow and machine-generated flow); otherwise AC collapse occurs
vacuum has been reached, the pump effectively stops (or turns slowly (see “Postocclusion Surge” later). In a gravity-fed system (the traditional
intermittently to compensate for vacuum loss) for as long as that vacuum system), as the fluid bottle or bag is generally fixed during a given step in
level holds. The rate at which the maximum set vacuum level is reached is the procedure, the height of the bottle is set so that it will generate suffi-
directly proportional to the flow rate (Fig. 5.9.2). cient inflow during postocclusion surge to prevent AC collapse. For most
surgeons, this is set at 80–95 cm above eye level, although some surgeons
set the bottle even higher. When the phaco (or I/A) handpiece is in the
Vacuum-Based eye with irrigation active (foot pedal position 1) then the eye is pressured
These systems generate an adjustable level of vacuum in a chamber in to 80–95 cm H2O, which equates to 59–70 mm Hg. In an ex-vivo model it
the machine; usually, a Venturi pump is used. It is the pressure differ- has been shown that during unoccluded aspiration (foot-pedal position 2)
ence between this chamber and the tip that generates flow. Once the tip the IOP drops significantly because of resistance to inflow in a gravity-fed
is occluded, fluid continues to be removed from the tubing until the pres- system. With an aspiration flow rate of 30 cc/min for example, with a fixed
368 sure within it equals that in the vacuum chamber. It is possible, however, bottle height of 95 cm, the IOP drops from 70 mm Hg to 50 mm Hg6,7
to introduce a damping effect into the system so that the equilibration (Fig. 5.9.3). The effect of this is that during normal surgery with a
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Fig. 5.9.3 Actual intraocular pressure (IOP) with
ACTUAL IOP VS. ASPIRATION RATE different aspiration flow rates. Graph showing how IOP
drops with increasing aspiration in a gravity-fed system 5.9
(two different manufacturers’ machines). Monitored
90
forced infusion system can overcome this. (Taken with
Phacoemulsification
∆P = 2.6 mm Hg permission from Boukhny M, Sorensen GP, Gordon R.
80
Novel phacoemulsification system using feedback-based
monitored forced infusion IOP target control. Presented at ASCRS Annual Meeting,
(95 cm H20) 70
Boston, April 25–29, 2014.)
60
actual IOP (mm Hg)
controlled increasing
50 pressure on the irrigation
fluid bag compensates for
40
pressure losses due to flow
30
20 gravity system 1
gravity system 2
10
0
0 15 30 45 60
aspiration rate (cc/min)
gravity-based phaco system with these typical settings, the IOP will fluctu- membrane. New sleeves for coaxial microincision phaco have now been
ate during cataract removal between 70 and 50 mm Hg, depending on the developed that allow coaxial phaco to be performed through 1.8-mm
foot-pedal position and the degree of tip occlusion. Only very briefly during incisions.
postocclusion surge will it drop significantly lower than 50 mm Hg. The Whether using biaxial or coaxial microincision techniques, it is import-
same ex-vivo study showed that the monitored forced infusion system ant that surgeons understand the importance of fluidics and ensure that
produced no significant IOP changes with aspiration flow rates up to the inflow potential through the reduced sleeve, or the separate infusion
60 cc/min. instrument is greater than the maximum outflow during postocclusion
In traditional longitudinal phaco, an active phaco tip (power-applied) surge with their particular combination of machine, needle, and vacuum
produces forces that push material away from it. This is countered by settings.
the vacuum that holds the material to the tip. The torsional mode of the
Infiniti (Alcon) generates a sweeping horizontal movement without repul-
sion, and lower vacuums can be used. When a surgeon uses a technique
POSTOCCLUSION SURGE
that involves sculpting (e.g., “divide and conquer”8 or “stop and chop”9), a With any pump design, in the occluded state, vacuum is generated in
relatively low flow (≤25 mL/min) with no tip occlusion is required (Video the lumen of the tubing. When the occlusion breaks, fluid rushes into
See clip:
5.9.1). The low flow allows sculpting near or even onto the capsule, without the tubing to equilibrate the pressure difference between the AC and the
5.9.1 the risk of drawing the capsule into the port, and a tip slope of 30° or 45° lumen—“postocclusion surge” (Fig. 5.9.4). During the period of occlusion,
allows the surgeon both to see the tip and to minimize occlusion poten- the walls of the tubing tend to collapse in proportion to the increase in
tial. For subsequent nucleus fragment consumption (or initially in chop vacuum, and dissolved gas is pulled out of solution. On release of the occlu-
techniques), a high flow (20–40 mL/min) is required to pull the nucleus sion the tubing re-expands and often rebounds, and the gas bubbles con-
toward the tip, along with high vacuum (200–600 mm Hg) to hold it in tract resulting in postocclusion surge. The difference between the outflow
See clip:
contact for emulsification (Video 5.9.2). Occlusion in these circumstances surge and the compensating inflow from the irrigation bottle determines
5.9.2 is enhanced by rotation of the tip so that the opening is aligned with the the stability of the AC. Tubing with increased stiffness is said to have
edge of nucleus being grasped. reduced compliance. Cassettes in the irrigation/aspiration line also have
Many phaco systems now offer the surgeon the opportunity to adjust compliance, and a tendency exists for modern versions to have as much as
the fluidics performance, particularly vacuum rise-time, once occlusion possible of the fluid pathway in the cassette made of rigid material.
has been achieved. One use is to have relatively low aspiration flow rates Phaco systems use a variety of other strategies to reduce the problems
during the acquisition of nucleus fragments but set the machine to sig- associated with postocclusion surge. The internal diameter of both the
nificantly increase the flow rate (and hence speed of achieving the preset phaco needle (and any restrictions, such as seen in the flared needle) and
vacuum) once the tip is occluded. Another example would be the reduction outflow tubing modulate the outflow surge. Less compliant outflow tubing
in flow rate on occlusion that some surgeons use when dealing with very and cassettes reduce the rebound effect. Fig. 5.9.5 shows the impact of
soft cataracts or epinucleus. reducing tubing and cassette compliance in three generations of phaco
equipment from a single manufacturer over a 10-year period. The effective
Fluidics of Microincisional Phaco inflow diameter (the gap between the outer wall of the tip and the inner
wall of the sleeve in coaxial phaco, or the internal diameter and outflow
Since 2001, many surgeons have adopted the concept of microincisional port diameters of the irrigation instrument in biaxial phaco), along with
phaco. This was first performed in a biaxial mode10; the infusion was the bottle height/irrigation pressure, determines the amount of inflow
dissociated from what became a “bare” aspiration tip by use of a sepa- and how well it compensates for outflow surge. Manufacturers have dif-
rate cannula inserted through a separate incision. Each incision is only ferent approaches to reducing the problems of postocclusion surge. These
1–1.5 mm wide, and there are a number of IOLs that can be inserted include reducing the vacuum after a given (surgeon-selected) time of full
through sub-2-mm incisions. The reduced maximum incision size results occlusion on the assumption that the occlusion is about to break. Others
in smaller changes to corneal curvature induced by the surgery. In coaxial reduce the aspiration flow rate immediately after a sudden drop in vacuum
phaco, the infusion ports in the infusion sleeve around the phaco tip are is detected. When the vacuum at the tip suddenly decreases on occlusion
positioned close to the aspiration port and, therefore, can create turbulent break, a significant time lag occurs before the pressure-change informa-
flow that can disrupt the attractive force generated by aspiration. In theory, tion is propagated along the tubing to the phaco console. At least one man-
with biaxial phaco these forces are now separated and should result in ufacturer is exploring the possibility of having a pressure sensor in the
better followability. handpiece to eliminate this time lag and thus speed up any programmed
Critics of biaxial surgery point to the degraded fluidics that may be pro- response to postocclusion surge.
duced by a nonconforming bare solid cannula passing through a corneal However good the machine, surgeons need to understand the impact
incision; either incisional leakage must be significant, or the incision is that choice of needle size/shape along with sleeve diameter and bottle 369
so tight as to risk significant tearing of corneal stroma and Descemet’s height may have on AC stability.
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Fig. 5.9.4 Intraocular pressure (IOP) during
5 IOP DURING POSTOCCLUSION CYCLE postocclusion surge. IOP initially maintained by bottle
height. Slight rise when tip occluded. When occlusion
breaks, large pressure difference between tubing and
anterior chamber (AC) results in rapid outflow of fluid
The Lens
causing IOP to drop rapidly until infusion restores

“normal” IOP.
lOP
occlusion
breaks
high outflow
reduces lOP infusion
recovers lOP
unobstructed partial full AC unobstructed

flow occlusion occlusion recovery flow
Fig. 5.9.5 Reduction of postocclusion surge resulting

SURGE RESPONSE IMPROVEMENTS WITH TIME from reduced outflow compliance with time.
Postocclusion surge volumes at different vacuum limits
for original Infiniti phaco machine (2003), Infiniti with
“Intrepid” reduced compliance cassette and tubing
0.16 (2006) and Centurion phaco machine (2013) with new
cassette and tubing (Adapted with permission from
0.14 data provided by Alcon.)
0.12
0.1
surge volume (cc)
infiniti
0.08 intrepid infiniti
0.06 centurion
0.04
0.02
0
300 400 500 600
vacuum limit (mm Hg)
KEY REFERENCES Kelman C. Phaco-emulsification and aspiration. A new technique of cataract removal. A pre-
liminary report. Am J Ophthalmol 1967;64:23–35.
Agarwal A, Agarwal A, Agarwal S, et al. Phakonit: phacoemulsification through a 0.9 mm Koch PS, Katzen LE. Stop and chop phacoemulsification. J Cataract Refract Surg 1994;20:
corneal incision. J Cataract Refract Surg 2001;27:1548–52. 566–70.
Allarakia L, Knoll RL, Lindstrom RL. Soft intraocular lenses. J Cataract Refract Surg Kraff MC, Sanders DR, Lieberman HL. Total cataract extraction through a 3 mm incision: a
1987;13:607–20. report of 650 cases. Ophthalmic Surg 1979;10:46–54.
Cohen SW, Kara G, Rizzuti AB, et al. Automated phakotomy and aspiration of soft congenital Nicoli CM, Dimolanta R, Miller KM. Experimental anterior chamber maintenance in
and traumatic cataracts. Ophthalmic Surg 1979;10:38–45. active versus passive phacoemulsification fluidics systems. J Cataract Refract Surg
Davis PL. Mechanism of phacoemulsification. Letter to the editor. J Cataract Refract Surg 2016;42:157–62.
1994;20:672–3. Pacifico RL. Ultrasonic energy in phacoemulsification: mechanical cutting and cavitation. J
Demircan S, Atas M, Göktas E, et al. Comparison of 45-degree Kelman and 45-degree bal- Cataract Refract Surg 1994;20:338–41.
anced phaco tip designs in torsional microcoaxial phacoemulsification. Int J Ophthalmol Shah PA, Yoo S. Innovations in phacoemulsification technology. Curr Opin Ophthalmol
2015;8:1168–72. 2007;18:23–6.
Gimbel HV. Divide and conquer nucleofractis phacoemulsification: development and varia- Zacharias J. Role of cavitation in the phacoemulsification process. J Cataract Refract Surg
tions. J Cataract Refract Surg 1991;17:281–91. 2008;34:846–52.
Gimbel HV, Neuhann T. Development, advantages, and methods of the continuous circular
capsulorrhexis technique. J Cataract Refract Surg 1990;16:31–7.
370 Kelman C. Cataract emulsification and aspiration. Trans Ophthalmol Soc UK 1970;90: Access the complete reference list online at ExpertConsult.com
13–22.
booksmedicos.org
REFERENCES 6. Boukhny M, Sorensen GP, Gordon R. Novel phacoemulsification system using feedback-
based IOP target control. Presented at ASCRS Annual Meeting, Boston, April 25–29,
1. Pacifico RL. Ultrasonic energy in phacoemulsification: mechanical cutting and cavitation.
2014.
7. Nicoli CM, Dimolanta R, Miller KM. Experimental anterior chamber maintenance in
5.9
2. Davis PL. Mechanism of phacoemulsification. Letter to the editor. J Cataract Refract Surg active versus passive phacoemulsification fluidics systems. J Cataract Refract Surg
2016;42:157–62.
Phacoemulsification
1994;20:672–3.
3. Zacharias J. Role of cavitation in the phacoemulsification process. J Cataract Refract Surg 8. Gimbel HV. Divide and conquer nucleofractis phacoemulsification: development and
2008;34:846–52. variations. J Cataract Refract Surg 1991;17:281–91.
4. Allen D. Power modulation with the Alcon Infiniti lens system. Presented at ASCRS 9. Koch PS, Katzen LE. Stop and chop phacoemulsification. J Cataract Refract Surg
Annual Meeting, San Diego, May 1–5, 2004. 1994;20:566–70.
5. Shah PA, Yoo S. Innovations in phacoemulsification technology. Curr Opin Ophthalmol 10. Agarwal A, Agarwal A, Agarwal S, et al. Phakonit: phacoemulsification through a 0.9 mm
2007;18:23–6. corneal incision. J Cataract Refract Surg 2001;27:1548–52.
370.e1
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Part 5 The Lens

Refractive Aspects of Cataract Surgery

Emanuel S. Rosen 5.10
Definition: Modern cataract surgery not only promises prevention VALUE OF CORNEAL TOPOGRAPHY
of induced refractive errors by the surgical process but also the Fig. 5.10.1 illustrates the importance of preoperative corneal topography
opportunity to enhance the eye’s refractive status. in ensuring that the eye to be operated upon is fully understood: “Under-
stand before you treat.”
Corneal topography contributes significantly to our understanding of
the requirements of cataract refractive surgery. It enables adjustments for
Key Features astigmatism, when required, either intraoperatively or after the operation,
• Importance of the corneal shape before operation. while also detecting serious corneal issues before the operation to avoid
• Value of corneal topography. unexplained poor postoperative visual acuity.
• Prevention of induced corneal astigmatism.
• Treatment of astigmatism. INTRAOPERATIVE MANAGEMENT
• Intraoperation.
• By incisions. OF PREOPERATIVE CORNEAL
• By implant choice. ASTIGMATISM TO PREVENT INDUCTION
• Postoperation. OF CORNEAL ASTIGMATISM
• By corneal laser surgery.
• By toric lens implantation. Corneal Incisions
• By piggyback lens implantation.
In a randomized clinical trial and noncomparative interventional case
series, Tejedor and Murube3 investigated the best location for clear corneal
INTRODUCTION incision (CCI) in phacoemulsification (“phaco”), depending on pre-existing
corneal astigmatism.
When Sir Harold Ridley implanted a human eye with a replacement lens In summary, for cataract CCIs:
(intraocular lens [IOL]) in 1949, he initiated a change in the role of cataract
surgery.1 As IOL implantation technology matured over the following years,
• A superior incision is recommended for at least 1.5 D of astigmatism
with a steep meridian at 90°.
cataract surgery became more than just removing a clouding crystalline
lens; it allowed for the replacement IOL to be adjusted to correct intrinsic
• A temporal incision is recommended for astigmatism less than 0.75 D
and steep meridian at 180°.
refractive error, or ametropia. In other words, there are two strategies for
surgical intervention: first removing the impediment of a cataractous lens
• A nasal incision is recommended for at least 0.75 D of astigmatism with
a steep meridian at 180°.
and then simultaneously incorporating an IOL of measured dioptric power
to neutralize existing ametropia. Beltrame et al.4 compared astigmatic and topographic changes induced
Of course, there are many other aspects to the refractive aspects of cat- by different oblique cataract incisions in 168 eyes having phaco, which were
aract surgery. Accurate biometry is vital (refer to that aspect of cataract randomly assigned to one of three groups: (1) 3.5 mm CCI, 60 eyes (Figs.
management in the discussions in this section). Cataract surgery in eyes 5.10.1–5.10.7 for similar examples); (2) 5.5 mm sutured CCI, 54 eyes; and
that have previously undergone corneal refractive surgery require special
formulas to calculate the correct IOL power after keratometric values have
been changed by that surgery. Management of astigmatism is a fundamen-
tal refractive need in cataract surgery and will be considered here. With the
advent of clinical aberrometers and their application in refractive surgery,
cataract replacement is now taking advantage of the deeper understand-
ing of the relationship, in a refractive sense, between the cornea and the
lens. Near, intermediate, and distance vision needs have to be satisfied by
lens replacement, a task fulfilled by emergent multifocal IOL technology,
pseudo-accommodative IOLs, and the future fulfillment of truly accommo-
dating IOLs. The bases for refractive correction, as an aspect of cataract
surgery, are accurate biometry on the one hand and corneal topography
on the other.
The focus of cataract surgery is to correct the immediate aphakia.
Current techniques and implants offer the opportunity to individualize
patients’ postoperative spherical and astigmatic errors and thus achieve
overall patient satisfaction with regard to refraction.
Intraoperative techniques are the first to be applied (1) to ensure that
astigmatism is not induced and (2) to neutralize it intraoperatively, if pos-
sible. Residual astigmatism after cataract surgery can be corrected by using
four different techniques. These are (1) classic limbal relaxing incisions,
which are easy to perform but have limited precision; (2) corneal laser
refractive surgery (photorefractive keratotomy [PRK]); or (3) laser-assisted
in situ keratomileusis (LASIK), additionally allowing for correction of Fig. 5.10.1 Pellucid marginal corneal degeneration. An example where preoperative
spherical components; and (4) more recently, the use of a piggyback toric corneal topography would have revealed the defect that resulted in “unexplained” 371
intraocular lens in the ciliary sulcus.2 poor visual results after surgery.
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5 OPPOSITE CLEAR CORNEAL INCISION SMALL CLEAR CORNEAL INCISION
The Lens
OZ
OZ
Fig. 5.10.2 Opposite clear corneal incision to correct preoperative astigmatism. Fig. 5.10.4 Small clear corneal incision—no central effect. OZ, optical zone.
Diagram to illustrate symmetry of incisions designed to correct each half of the
steep meridian “bow tie.”
LARGE CLEAR CORNEAL INCISION
OZ
Fig. 5.10.3 Clear corneal incision (2.5 mm). Fig. 5.10.5 Large clear corneal incision—more effect. OZ, optical zone.
(3) 5.5 mm scleral tunnel, 54 eyes. Incisions lay on the 120° semi-meridian.
Corneal topography was performed preoperatively and 1 week, 1 month,
and 3 months postoperatively. Simulated keratometric readings were used
to calculate astigmatism amplitude and surgically induced astigmatism
(SIA). Postoperative topographic changes were determined by subtracting
the preoperative numeric map readings from the postoperative numeric
map readings. At 3 months postoperatively, the mean SIA in the right
and left eyes, respectively, was 0.68 ± 1.14 D (SD) and 0.66 ± 0.52 D in
the 3.5 mm CCI group, 1.74 ± 1.4 D and 1.64 ± 1.27 D in the 5.5 mm CCI
group, and 0.46 ± 0.56 D and 0.10 ± 1.08 D in the scleral tunnel group.
Right and left eyes showed similar SIA amplitude but different SIA merid-
ian orientation. SIA was significantly higher in the 5.5 mm CCI group
than in the other two groups 1 and 3 months postoperatively (P < 0.01). All
groups showed significant wound-related flattening and non-orthogonal
steepening at two opposite radial sectors. Topographic changes were sig-
nificantly higher in the 5.5 mm CCI group and significantly lower in the
scleral tunnel group.
Right and left eyes showed similar SIA amplitudes but different SIA
meridian orientations and topographic modifications, probably because
of the different supero-temporal and supero-nasal corneal anatomic struc-
372 tures. The 5.5 mm CCI induced significantly higher postoperative astigma- Fig. 5.10.6 Topography map of 3-mm clear corneal incision. Peripheral flattening of
tism, SIA, and topographic changes. cornea but no central effect.
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5.10

Fig. 5.10.7 Topography map of 2.5-mm clear corneal incision. No peripheral Fig. 5.10.9 Topography map of 3.7-mm clear corneal incision. (See the
flattening of the cornea or central effect. videokeratograph in Fig. 5.10.8.) The map illustrates the central effect of a larger
peripheral clear corneal incision, with resulting nonorthogonal astigmatic
hemi-meridia.
Fig. 5.10.8 Videokeratograph of a 3.7-mm clear corneal incision. Note the localized Fig. 5.10.10 Postoperative topography map following opposite clear corneal
flattening of the cornea close to incision, also affecting the optical zone. incision for 5 D astigmatism. Note the four hemi-meridia but no manifest or
topographic astigmatism.
TO TREAT PREOPERATIVE Opposite Clear Corneal Incisions

CORNEAL ASTIGMATISM Lever and Dahan6 were the first surgeons to demonstrate that in cataract
Astigmatic Incisions surgery, the CCI has a small flattening effect on corneal curvature, which
can be used to reduce pre-existing astigmatism (PEA). Adding an identical,
The cornea does not have axes but has only meridia, and all references to penetrating CCI opposite the first one enhances the flattening effect. The
corneal incisions for the relief of astigmatic error in the cornea should be extent of flattening affecting the optical zone of the cornea is dependent on
made to the “steep meridian.” the width of the clear corneal tunnel incision and the way it is constructed.
Although a general algorithm can be devised, in general, it is incumbent
Limbal Relaxing Incisions upon each surgeon to devise his or her own algorithm, as the location
of the incision, the knife used, and the length of the tunnel are difficult
Kaufmann et al.5 compared limbal relaxing incisions (LRIs) with place- to standardize. Suffice it to say, the wider the incision and the more cen-
ment of the corneal cataract incision on the steepest keratometric merid- trally it is placed, the greater will be its effect. The local flattening of the
ian for the reduction of pre-existing corneal astigmatism at the time of incision only has a central effect if it is wide enough. Figs. 5.10.2–5.10.15
cataract surgery. In a prospective single-center study, patients having 1.5 D illustrate all the incisions, their effects, and the healing process as depicted
or more of keratometric astigmatism were randomly assigned to two sur- by corneal topography. It is recommended that surgeons wishing to
gical techniques: on-steep meridian incisions (SMIs) consisting of a single utilize the technique should study the effects of their own CCIs through
CCI centered on the steepest corneal meridian; or LRIs consisting of two the medium of corneal topography and thereby derive a personal
arcuate incisions straddling the steepest corneal meridian and a tempo- nomogram.
ral CCI. After 6 months, the flattening effect was 0.35 D (range 0–0.96 D) Paired opposite CCIs (OCCIs) are placed on the steepest meridian to
and 1.10 D (range 0.25–1.79 D), respectively (P ≡ 0.004), thus confirming achieve a reduction in the dioptric power of the central cornea. One CCI is
that the amount of astigmatism reduction achieved at the intended merid- used to perform cataract surgery, and the opposite CCI is made to ensure
ian was significantly more favorable with use of the LRI technique and symmetry of the flattening effect and, therefore, to modulate PEA. Lever 373
remained consistent throughout the follow-up period. and Dahan6 used 2.8- to 3.5-mm OCCIs in 33 eyes having PEA greater
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than 2.00 D and undergoing cataract surgery. The mean astigmatism cor- • The bulk of the cornea is preserved in case of need for correction of
5 rection achieved with this technique was 2.06 D. This technique is simple
and effective and yields stable results that rival those of arcuate keratot-
omy. The OCCI technique has a potential application for the correction of
minor astigmatism with arcuate keratotomies.
• OCCIs also may be referred to as opposite penetrating astigmatic kera-
totomies (OPAKs).
astigmatism in general refractive surgery.
The Lens
Qam-mar and Mullaney7 evaluated the effect of OCCIs in correcting

astigmatism on the steep corneal meridian axis in 14 patients with cata- TORIC INTRAOCULAR LENS IMPLANTATION
racts. They achieved a mean correction of astigmatism of 1.23 ± 0.49 D
(range 0.30–2.20 D). The mean surgically corrected astigmatism by vector Toric intraocular lenses can be used as an alternative or adjunct to corneal
analysis was 2.10 ± 0.79 D (range 0.80–3.36 D). As other studies have astigmatic incisions for correcting PEA in patients with cataracts. They are
shown,6–9 paired OCCIs on the steep corneal meridian correct astigma- a particularly attractive option in those cases where LRIs or OCCIs are not
tism in eyes undergoing cataract surgery with the use of routine surgical powerful or predictable enough. Phaco extraction of a cataract through a
instruments. small (astigmatically neutral) incision with toric intraocular lens implants
The features of OCCIs may be summarized as follows: (TIOLs) is an attractive alternative for patients with cataract and significant
corneal astigmatism (> 1.5 D). The elimination or reduction of preopera-
• OCCIs cause negligible effect on spherical equivalence and, therefore,
tive astigmatism provides many patients with the prospect of clear distance
do not influence biometric calculations.
vision without the aid of glasses.9–11
• Paired incisions are used for symmetric effect. TIOLs for the correction of corneal astigmatism in cataractous and
• Asymmetric OCCIs are used for asymmetric (“bow tie”) astigmatism. pseudophakic eyes. Accurate rotational stability and axial alignment are
• OCCIs are to be placed on a steep corneal meridian. critical to the success of TIOL surgery. Factors that may influence the
rotational stability of the TIOL include IOL design (plate haptic), overall
haptic diameter, IOL material, and the eye’s axial length. TIOL alignment
meridian, size, and integrity of the capsulorrhexis, capsular bag dimen-
sions, and postoperative healing/shrinkage. Despite accurate preoperative
biometry and intraoperative alignment, patients may lose the benefits of
astigmatism correction if the TIOL rotates after the operation.12–14 Cataract
surgery with TIOL allows the correction of high degrees of regular corneal
astigmatism. Toric lens cataract surgery also is valuable as a secondary pro-
cedure, for example, after keratoplasty, with resultant higher degrees of
regular residual astigmatism.15
Spontaneous rotation of a TIOL can occur and will require correction
by surgical intervention to restore the IOL to its correct neutralizing align-
ment in astigmatism. An example of this is the case of a 23-year-old female
with myopic astigmatism who underwent TIOL implantation. Preoperative
uncorrected visual acuity (UCVA) was 20/800 and 20/1200, respectively,
with −7.75 −4.25 × 0° and −8.25 −5.25 × 180°. In the left eye, an UCVA of
20/30 was achieved. After 3 months of successful implantation of TIOL in
the left eye, the patient presented with a sudden decrease in visual acuity
in this eye. UCVA was 20/100 with a refraction of +2.50 −4.50 × 165°. The
toric marks showed a 30° rotation from the original position and required
repositioning of the TIOL, resulting in a final UCVA of 20/25, which
remained stable at 6 months’ follow-up. A TIOL can undergo considerable
Fig. 5.10.11 Preoperative, postoperative, and difference topography maps to rotation, and inevitably this will compromise visual acuity. Its relocation,
illustrate opposite clear corneal incision (OCCI) effect. OCCI OD −15.5/+3.0 × 90 Plano therefore, is required, and more often than not, this will prove to be an
post-op (4.5 mm OCCI); effect of each OCCI illustrated by dotted lines. effective procedure to recover visual acuity.16
Fig. 5.10.12 Preoperative, postoperative,

and difference topography maps to
illustrate opposite clear corneal incision
effect. Opposite clear corneal incision
(OCCI) OD −15.5/+3.0 × 90 Plano post-op
(4.5 mm OCCI).
374
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Fig. 5.10.13 OS (left eye) pre-op OS
+10.25/−4.5 × 175 ≡ 6/6 post-op 6/6−,
+1.25/−0.75 × 155 ≡ 6/5. Note flattening of 5.10
preoperative cylinder in difference map
and residual nonorthogonal astigmatic

hemi-meridia but not significantly
reflected in manifest refraction.
patients with astigmatism were implanted with the ICL. A 3.3-mm inci-
sion was created on the steep meridian in 69 male and 29 female patients.
In this small study, 98% of the patients either retained their good vision or
gained a line of vision with the procedure.19
POSTOPERATIVE MANAGEMENT OF RESIDUAL

OR INDUCED CORNEAL ASTIGMATISM
Corneal Laser Ablative Techniques
Corneal laser ablative techniques (e.g., LASIK, PRK, and variants) have the
advantages of correcting spherical as well as astigmatic refractive errors in
the eyes that have undergone cataract refractive surgery and are preferred
where these options are readily available to the cataract surgeon. In a ret-
rospective study reviewing 23 eyes of 19 patients, Kim et al.20 evaluated
the safety and efficacy of LASIK for correcting refractive error following
cataract surgery. This series, in which patients were a few decades older
than the typical excimer laser candidate, illustrated that laser refractive
surgery is a safe, effective, and predictable method for correcting ame-
Fig. 5.10.14 Corneal aberrations post-op illustrating trefoil and coma aberrations. tropia after cataract extraction with IOL implantation. It demonstrated a
(See topography map in Fig. 5.10.13.) viable, less-invasive alternative to intraocular surgery.21,22
Although comparable in clinical efficacy outcomes with LASIK, the

POST–CATARACT SURGERY PIGGYBACK IOLS
TIOL provides a significantly better postoperative improvement in (CVA) Hsuan et al.23 assessed the role of the Staar Surgical implantable contact
and significantly better postoperative UCVA than preoperative CVA. TIOL lens (ICL) in the correction of pseudophakic anisometropia. Six patients
provides an effective alternative to LASIK through the full range of use with pseudophakic anisometropia ranging from 2.0 to 7.9 D (mean 4.4 D)
and particularly applies when corneal laser surgical facilities are not were given ICLs as an alternative to IOL exchange or conventional piggy-
conveniently available or if the astigmatism is severe. In the event that back IOLs. All patients had a reduction in anisometropia to asymptomatic
enhancement is still required for emmetropia, combined procedures are levels. The mean reduction was 3.15 D. No patient experienced adverse
possible. It should be remembered that all elements of refractive surgery effects. The ICL offers an alternative approach to the management of pseu-
in many cases are part of a process embracing more than one modality of dophakic anisometropia, thereby avoiding some of the risks associated
intervention.17 with IOL exchange, corneal refractive surgery, and conventional piggyback
A 6-month European multicenter clinical trial demonstrated that IOLs, as the ICL is a very thin lens that is easily and safely placed in the
implantation of the Artisan toric phakic IOL (TPIOL) safely, predictably, ciliary sulcus in front of the pseudophacos.
and effectively reduced or eliminated high ametropia and astigmatism Piggyback IOLs to correct postoperative residual astigmatism are avail-
with one procedure, providing an effect that was stable at 6 months after able in spherical and toric forms and may be utilized when corneal laser
surgery.18 surgery is deemed inappropriate for technical or availability reasons. The
Similarly, the Visian Toric Implantable Collamer Lens (STAAR Surgical piggyback IOL is lodged in the sulcus, adjacent to the pseudophacos incor-
Co., Monrovia, CA) may yield excellent results in eyes with high ametropia porated in the capsular bag. Some IOLs are specifically designed for this 375
and astigmatism. It was reported from a military ophthalmic clinic that 98 purpose.24,25
booksmedicos.org
Fig. 5.10.15 OD (right eye) pre-op
5 +10.25/−4.5 × 175 ≡ 6/6−2 postoperative

+0.25 ≡ 6/5 uncorrected visual acuity
(UCVA) 6/5. Topography maps illustrating
sequential healing responses of cornea
The Lens
to opposite clear corneal incision effect.

Difference map illustrates flattening of
original astigmatism. Manifest refraction
virtually plano. Final map illustrates typical
four hemi-meridia with spherical optical
zone.
LIGHT-ADJUSTABLE INTRAOCULAR KEY REFERENCES

LENS IMPLANT Chayet A, Sandstedt C, Chang S, et al. Correction of Myopia after cataract surgery with the
light adjustable lens. Ophthalmology 2009;116:1432–5.
Residual refractive errors after cataract and lens implant surgery are treated Dick HB, Alió J, Bianchetti M, et al. Toric phakic intraocular lens: European multicenter
with corneal incisional surgery, excimer laser corneal surgery, or toric IOL study. Ophthalmology 2003;110:150–62.
Hengerer FH, Hutz WW, Dick HB, et al. Combined correction of axial hyperopia and astig-
primary or secondary implantation (piggyback lens implants), but a one-step matism after cataract surgery with the light adjustable intraocular lens. Ophthalmology
planned refractive outcome remains desirable. The light-adjustable intra- 2011;118:1236–41.
ocular lens implant (LAL) offers the prospect of consulting room, postop- Kohnen T, Klaproth OK. Correction of astigmatism during cataract surgery. Klin Monbl
erative, refractive adjustment of the provisional refractive outcome of the Augenheilkd 2009;226:596–604.
Lever J, Dahan E. Opposite clear corneal incisions to correct pre-existing astigmatism in
primary surgery, even though with secondary adjustment steps but without
cataract surgery. J Cataract Refract Surg 2000;26:803–5.
the requirement for further surgical intervention. The LAL incorporates Olaru G, Gavriş M, Horge I, et al. Toric intraocular lens implantation in cataract patients – 6
a photosensitive silicone macromer in a medical-grade silicone polymer months results. Cornea 2007;26(2):133–5.
matrix. The photosensitive IOL component is 100 µm molded onto the Ridley H. The cure of aphakia. In: Rosen ES, Haining WM, Arnott AJ, editors. IOL implan-
posterior surface of the silicone optic of the IOL. This posterior layer has a tation. New York: Mosby; 1979. p. 37–43.
Sanders DR, Sanders ML. Comparison of the toric implantable collamer lens and custom
higher concentration of ultraviolet (UV) light absorber compared with the ablation LASIK for myopic astigmatism. J Refract Surg 2008;24:773–8.
anterior portion of the implant optic. Selective irradiation of the LAL uses a Shah GD, Mamidipudi PR, Vasvada AR, et al. Rotational stability of a toric intra-ocular
specific UV (365 µm) beam to irradiate the IOL and produces a controlled lens. Influence of axial length and alignment in the capsular bag. J Cat Refract Surg
spherical and/or cylindrical power change; this is undertaken a few weeks 2012;38:54–9.
Tejedor J, Murube J. Choosing the location of corneal incision based on pre-existing astigma-
postoperatively, when the eye’s refraction has stabilized after the cataract tism in phacoemulsification. Am J Ophthalmol 2005;139:767–76.
surgery. In the interim period, the patient has to wear UV-filtering glasses
to prevent unwanted UV radiation entering the eye before it is appropri-
ate to apply the selective exposure, after which the refractive power of the
implant is locked in. Postoperative studies with longer-term follow-up are Access the complete reference list online at ExpertConsult.com
impressive.26–28
376
booksmedicos.org
REFERENCES 14. Shah GD, Mamidipudi PR, Vasvada AR, et al. Rotational stability of a toric intra-ocular
lens. Influence of axial length and alignment in the capsular bag. J Cat Refract Surg
1. Ridley H. The cure of aphakia. In: Rosen ES, Haining WM, Arnott AJ, editors. IOL
implantation. New York: Mosby; 1979. p. 37–43.
2012;38:54–9.
15. Horn JD. Status of toric intraocular lenses. Curr Opin Ophthalmol 2007;18:58–61.
5.10
2. Pisella PJ. Postoperative residual astigmatism after cataract surgery: current surgical 16. Navas A, Muñoz-Ocampo M, Graue-Hernández EO, et al. Spontaneous rotation of a toric
implantable collamer lens. Case Rep Ophthalmol 2010;1:99–104.

methods of treatment. J Fr Ophtalmol 2012;35(3):226–8.
3. Tejedor J, Murube J. Choosing the location of corneal incision based on pre-existing 17. Sanders DR, Sanders ML. Comparison of the toric implantable collamer lens and custom
astigmatism in phacoemulsification. Am J Ophthalmol 2005;139:767–76. ablation LASIK for myopic astigmatism. J Refract Surg 2008;24:773–8.
4. Beltrame G, Salvetat ML, Chizzolini M, et al. Corneal topographic changes induced by 18. Dick HB, Alió J, Bianchetti M, et al. Toric phakic intraocular lens: European multicenter
different oblique cataract incisions. J Cataract Refract Surg 2001;27:720–7. study. Ophthalmology 2003;110:150–62.
5. Kaufmann C, Peter J, Ooi K, et al; The Queen Elizabeth Astigmatism Study Group. 19. Scott D, Barnes MD, chief, US Army, Warfighter Refractive Surgery, Fort Bragg commu-
Limbal relaxing incisions versus on-axis incisions to reduce corneal astigmatism at the nication. Hawaiian Ophthalmology Congress Hawaii; 2012.
time of cataract surgery. J Cataract Refract Surg 2005;31:2261. 20. Kim P, Briganti EM, Sutton GL, et al. Laser in situ keratomileusis for refractive error
6. Lever J, Dahan E. Opposite clear corneal incisions to correct pre-existing astigmatism in after cataract surgery. J Cataract Refract Surg 2005;31:979–86.
cataract surgery. J Cataract Refract Surg 2000;26:803–5. 21. Leccisotti A. Bioptics: where do things stand? Curr Opin Ophthalmol 2006;17(4):399–405.
7. Qam-mar A, Mullaney P. Paired opposite clear corneal incisions to correct pre-existing 22. Kuo IC, O’Brien TP, Broman AT, et al. Excimer laser surgery for correction of ametropia
astigmatism in cataract patients. J Cataract Refract Surg 2005;31:1167–70. after cataract surgery. J Cataract Refract Surg 2005;31:2104–10.
8. Tadros A, Habib M, Tejwani D, et al. Opposite clear corneal incisions on the steep 23. Hsuan JD, Caesar RH, Rosen PH, et al. Correction of pseudophakic anisometropia with
meridian in phacoemulsification: early effects on the cornea. J Cataract Refract Surg the Staar Collamer implantable contact lens. J Cataract Refract Surg 2002;28:44–9.
2004;30:414–17. 24. Khan MI, Muhtaseb M. Performance of the Sulcoflex piggyback intraocular lens in pseu-
9. Kohnen T, Klaproth OK. Correction of astigmatism during cataract surgery. Klin Monbl dophakic patients. J Refract Surg 2011;27(9):693–6.
Augenheilkd 2009;226:596–604. 25. Kahraman G, Amon M. New supplementary intraocular lens for refractive enhancement
10. Olaru G, Gavriş M, Horge I, et al. Toric intraocular lens implantation in cataract patients in pseudophakic patients. J Cataract Refract Surg 2010;36:1090–4.
– 6 months results. Cornea 2007;26:133–5. 26. Schwarz DM. Light adjustable lens. Trans Am Ophthalmol Soc 2003;101:417–36.
11. Kersey JP, O’Donnell A, Illingworth CD. Cataract surgery with toric intraocular lenses 27. Chayet A, Sandstedt C, Chang S, et al. Correction of myopia after cataract surgery with
can optimize uncorrected postoperative visual acuity in patients with marked corneal the light adjustable lens. Ophthalmology 2009;116:1432–5.
astigmatism. Cornea 2007;26:133–5. 28. Hengerer FH, Hutz WW, Dick HB, et al. Combined correction of axial hyperopia and
12. Chang DF. Comparative rotational stability of single piece, open loop acrylic and plate astigmatism after cataract surgery with the light adjustable intraocular lens. Ophthalmol-
haptic silicone Toric intra-ocular lenses. J Cat Refract Surg 2008;34:1842–7. ogy 2011;118:1236–41.
13. Ohmi S. Decentration associated with asymmetric capsular shrinkage and intra-ocular
lens size. J Cat Refract Surg 1993;19:640–3.
376.e1
booksmedicos.org
Part 5 The Lens

Small Incision and Femtosecond

Laser-Assisted Cataract Surgery 5.11
Mark Packer IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
operations such (as) cataract removal, including a handheld instrument

Definition: Small incision cataract surgery is the extraction of the lens having an operative tip vibrating at a frequency in the ultrasonic range
through a corneal incision designed to be self-sealing. with an amplitude controllable up to several thousandths of an inch.”1
Even until recently, the fundamental mechanisms by which the system
known as “phaco” operates has remained controversial. Although some
Key Features authors have described the surgical advantages of a unique type of cavita-
• The refinement of incision placement and architecture, as well as tional energy, others have denied any role for cavitational energy in phaco.2
the reduction of final incision size occasioned by the implantation
of a foldable, injectable intraocular lens, permits the reduction of INCISION CONSTRUCTION AND ARCHITECTURE
postoperative astigmatism and enhancement of refractive cataract
surgery. Since 1992, when Fine described the self-sealing temporal clear corneal
• Continuous curvilinear capsulorrhexis facilitates sculpting techniques, incision (CCI), the availability of foldable IOLs has furthered the trend away
such as divide and conquer, trending to today’s preferred horizontal from scleral tunnel incisions to clear corneal incisions.3 Rosen demon-
and vertical chopping methods. strated through topographic analysis that CCIs 3 mm or less in width do
• Hydrodissection to lyse cortical–capsular connections. not induce significant astigmatism.4 This finding led to increasing interest
• Hydrodelineation to permit phaco within the protective layer of the in T-cuts, arcuate cuts, and LRIs for managing pre-existing astigmatism
epinucleus improves the safety and efficiency of phaco. at the time of cataract surgery. Surgeons recognized many other advan-
• Power modulations, such as millisecond level control of ultrasound tages of the temporal CCI, including better preservation of the conjunctiva,
power application, allow for reduction of the energy required for increased stability of refractive results because of decreased effects from
cataract extraction, protection of the cornea from thermal injury, and lid blink and gravity, ease of approach, elimination of the bridle suture and
enhancement of the rapidity of postoperative visual rehabilitation. iatrogenic ptosis, and improved drainage from the surgical field via the
• Femtosecond laser-assisted surgery represents a relatively new lateral canthal angle.
technology that some surgeons have adopted for cataract extraction. Surgeons originally adopted single-plane incisions utilizing a 3-mm
diamond knife. After pressurizing the eye with viscoelastic through para-
centesis, the surgeon placed the blade on the eye so that it completely
applanated the eye, with the point of the blade positioned at the leading
Associated Feature edge of the anterior vascular arcade. The knife was advanced in the plane
• The separation of irrigation from aspiration made possible through of the cornea until the shoulders, 2 mm posterior to the point of the knife,
biaxial microincision phaco represents an advance in control of the touched the external edge of the incision. Then, the point of the blade was
fluidic behavior of the intraocular environment, permitting greater directed posteriorly to initiate the cut through Descemet’s membrane in
versatility in every step of the cataract extraction procedure. a maneuver known as the dimple-down technique. After the tip entered the
anterior chamber, the initial plane of the incision was re-established to cut
INTRODUCTION through Descemet’s membrane in a straight-line configuration.
Williamson was the first to utilize a shallow 300–400 µm grooved CCI.5
The principal technical features of phaco include the following: Langerman later described the single-hinge incision, in which the initial
groove measured 90% of the depth of the cornea anterior to the edge of
• Watertight, self-sealing corneal incisions.
the conjunctiva.6 Surgeons employed adjunctive techniques to combine
• Intact, round, centered capsulorrhexis with a diameter smaller than that
incisional keratorefractive surgery with CCIs. Osher described the con-
of the intended intraocular lens (IOL) optic.
struction of arcuate keratotomy incisions at the time of cataract surgery
• Efficient ultrasound power modulation and fluidics to protect the for correction of pre-existing corneal astigmatism. Kershner used the tem-
capsule, iris, and cornea.
poral incision by starting with a nearly full-thickness T-cut, through which
• Fastidious cortical cleanup, resulting in a clean capsular bag. he then made his corneal tunnel incision.7 Finally, the recommendation
• Atraumatic IOL insertion through an incision of 1.5–2.4 mm. of LRIs by Gills and Nichamin advanced what ultimately became most
“Phaco” refers to the techniques and technology required for the frag- popular means of reducing pre-existing astigmatism.8,9
mentation and extraction of the crystalline lens through a small corneal Following phaco, lens implantation, and removal of residual viscoelas-
incision and the implantation of an intraocular lens (IOL), resulting in tic, stromal hydration may be performed to seal the incisions by gently irri-
rapid visual rehabilitation and reduced need for optical correction. gating balanced salt solution into the stroma at both edges of the incision
Since the time of its introduction in the late 1960s, phaco has evolved with a 26- or 27-gauge cannula. An intraoperative Seidel test may be used
into a highly effective method of cataract extraction. Incremental advances to ensure sealing. Studies of sequential optical coherence tomography of
in surgical technique and the simultaneous redesign and modification postoperative CCIs have demonstrated that the edema from stromal hydra-
of technology have permitted increased safety and efficiency. Among the tion lasts up to 1 week.10
advances that have shaped modern phaco are incision construction, con- CCIs, by nature of their architecture and location, are associated with
tinuous curvilinear capsulorrhexis, cortical cleaving hydrodissection and unique complications. Chemotic ballooning of the conjunctiva may occur
hydrodelineation, and nucleofractis techniques. as a result of irrigating fluid streaming into an inadvertent conjunctival
The United States patent #3 589 363, filed July 25, 1967, lists Anton incision. In this case, the conjunctiva may be snipped to permit decom-
Banko and Charles D. Kelman as inventors of “an instrument for breaking pression. Incisions that are too short can result in an increased tendency 377
apart and removal of unwanted material, especially suitable for surgical for iris prolapse and poor sealability. A single suture may be required to
booksmedicos.org
Fig. 5.11.1 Backward traction on the capsular flap forms
5 the basis of a predictable technique for rescuing the

capsulorrhexis from a radial tearout. As shown here in
the case of an opaque cataract with trypan blue capsule
stain, the tear has extended too far to the periphery (A).
The Lens
Therefore, the flap is unfolded and laid back in the plane

of the capsulorrhexis from where it was torn (B). The flap is
then pulled with reverse tangential force until the capsule
tears back toward the center (C). Construction of the
capsulorrhexis may then continue (D).
A B
C D
secure the wound. In contrast, a long incision may result in striae in the tear should be stopped and the depth of the anterior chamber assessed.
cornea that compromise the surgeon’s view during phaco. Coarse manip- Frequently, the cause of the peripheral course of the tear is shallowing of
ulation of the phaco tip may result in epithelial abrasions or tears in the anterior chamber. Adding more OVD to deepen the anterior chamber
Descemet’s membrane, compromising self-sealability. Of great concern opposes the posterior pressure, making the lens capsule taut, widening the See clip:
is the risk of incisional burns.11 When incisional burns develop in CCIs, pupil, and permitting inspection of the capsule (Video 5.11.1). 5.11.1
rapid contraction of tissue and loss of self-sealability occur. Suture closure One important technique for redirection of the capsulorrhexis has been
of the wound may induce excessive astigmatism. described by Little.22 In this technique, to rescue the capsulorrhexis from
The literature supports the view that suboptimal construction of CCIs a peripheral tearout, the force applied to the capsular flap is reversed but
may lead to poor coaptation, inadequate sealing, and ingress of bacteria, maintained in the plane of the anterior capsule. It is necessary to first
thereby increasing the risk of acute postoperative bacterial endophthalmitis.12 unfold the capsular flap so that it lies flat against the lens cortex, as it did
However, four large published series have found no greater likelihood of prior to being torn. Force can then be applied with the capsule forceps
infection with corneal versus other types of incisions.13–16 Regardless of the by holding the capsular flap as close to the root of the tear as possible
type of incision, the principle to be followed is that appropriate incision and pulling backward in a retrograde direction along the circumferential
construction and watertight closure are obligatory. Besides poor wound path of the completed portion of the capsulorrhexis. Traction should be
closure, other significant factors that have been associated with higher risk applied in the horizontal plane of the capsule and not upward. The initial
of postoperative infection include posterior capsule rupture, vitreous loss, pull should be circumferentially backward and then, while holding the flap
older age, prolonged surgery, immunodeficiency, active blepharitis, lacri- under tension, directed more centrally to initiate the tear. The forward pro-
mal duct obstruction, inferior incision location, and male gender.17 gress of the capsulorrhexis will uniformly and predictably redirect toward
the center of the capsule (Fig. 5.11.1). If the capsule will not tear easily and
CONTINUOUS CURVILINEAR CAPSULORRHEXIS the entire lens is being pulled centrally, this rescue maneuver should be
abandoned to avoid a wrap-around capsular tear or zonular dialysis. Other
Implantation of the IOL in an intact capsular bag facilitates the permanent rescue techniques, such as completing the capsulorrhexis from the oppo-
rehabilitative benefit of cataract surgery. For many years, surgeons con- site direction or making a relieving cut in the flap edge and continuing in
sidered a “can opener” capsulectomy to be satisfactory for both planned the same direction, represent reasonable alternatives.
extracapsular cataract extraction and phaco. However, in 1991, Wasserman The use of trypan blue to stain the anterior capsule in the absence of
et al. performed a postmortem study that showed that the extension of a good red reflex constitutes an important adjunctive technique for capsu-
one or more V-shaped tears toward the equator of the capsule produced lorrhexis construction. The dye may be injected into the chamber through
instability of the IOL and resulted in malpositioning of the IOL.18 Gimbel paracentesis under air. The air and residual dye are then exchanged for
and Neuhann popularized continuous curvilinear capsulorrhexis (CCC) in viscoelastic. Despite the absence of a red reflex, the capsule is easy to see.
the later 1980s.19–21 The technique of CCC has provided important advantages both for cata-
The basic principles of manual CCC include the following: ract surgery and IOL implantation. Because endolenticular or in situ phaco
must be performed in the presence of an intact continuous capsulectomy
• The continuous capsular tear should be performed in a stable anterior
opening, capsulorrhexis has served as a stimulus for modification of phaco
chamber under pressurization by an ophthalmic viscosurgical device
techniques. The edge of a well-constructed rhexis completely overlaps the
(OVD).
edge of the IOL, ensuring positional stability and enhancing refractive
• The tear should be initiated at the center of the capsule so that the predictability.
origin is included within the circle of the tear.
• The continuous tear may proceed either clockwise or counterclockwise
in a controlled and deliberate fashion, the surgeon regrasping with the HYDRODISSECTION AND HYDRODELINEATION
forceps or repositioning the point of the cystotome/bent needle on the
Hydrodissection has traditionally meant injection of fluid into the cortical
inverted flap to control the vector of the tear.
layer of the lens to separate the nucleus from the cortex and the capsule.
378 A tear that begins moving peripherally or radially is a signal that an Following the adoption of capsulorrhexis, hydrodissection became a critical
existing condition requires immediate attention. Further progress of the step to mobilize, disassemble, and remove the nucleus. Fine first described
booksmedicos.org
cortical cleaving hydrodissection, which is designed to cleave the cortex POWER MODULATIONS
from the capsule and leave the cortex attached to the epinucleus.23 Cortical
cleaving hydrodissection often eliminates the need for cortical cleanup as a Fine described the “choo-choo chop and flip” technique in 1998 and sub- 5.11
separate step in cataract surgery. sequently correlated the reduction of ultrasound energy made possible by
In this technique, the anterior capsular flap is initially elevated with a power modulations with superior uncorrected visual acuity on the first post-
Small Incision and Femtosecond Laser-Assisted Cataract Surgery

26-gauge blunt cannula. Firm and gentle continuous irrigation results in operative day.26,27 Effective phaco time (EPT), absolute phaco time (APT),
a fluid wave that cleaves the cortex from the posterior capsule. The lens and cumulative dissipated energy (CDE) have become standard metrics for
bulges forward because fluid is trapped by equatorial cortical–capsular the utilization of ultrasound energy. Although EPT, APT, and CDE cannot
connections. Depressing the central portion of the lens with the side of be compared across different machines made by different manufacturers,
the cannula forces fluid around the equator and lyses the cortical–capsular when using the same machine, they can be compared from one case to the
connections. Adequate hydrodissection is demonstrated by rotation of the next as a sign of surgical efficiency.
nuclear–cortical complex. The demonstration of free rotation of the lens In Fine’s technique, a 30° straight phaco tip is used bevel down. After
within the capsule represents a critical step in phaco. aspirating the epinucleus uncovered by capsulorrhexis, a horizontal
Hydrodelineation describes separation of the epinuclear shell from the chopper is placed in the golden ring by touching the top center of the
endonucleus by irrigation. The epinucleus acts as a protective cushion nucleus with the tip and pushing the tip peripherally so that it slides
within which phaco forces can be confined. Further, the epinucleus keeps beneath the capsulorrhexis. The chopper is used to stabilize the nucleus
the bag on stretch throughout the procedure, making capsule rupture less by lifting and pulling toward the incision slightly, after which the phaco
likely. tip “lollipops” the nucleus in either pulse mode at 2 pulses per second
To perform hydrodelineation, a 26-gauge cannula is placed in the or at the 80-millisecond burst mode. Burst mode utilizes fixed power and
nucleus, off center to either side, and directed at an angle downward and duration with variable interval. In pulse mode, there is variable power with
forward toward the central plane of the nucleus. When the nucleus starts fixed duration and interval. These power modulations reduce total ultra-
to move, the endonucleus has been reached. At this point, the cannula is sound energy and increase hold. Once the tip is buried in the center of the
directed tangentially to the endonucleus, and a to-and-fro movement of nucleus, vacuum is maintained in foot position 2. The nucleus is scored
the cannula is used to create a tunnel within the epinucleus. The cannula by bringing the chopper to the side of the phaco needle. It is chopped in
is backed out of the tunnel approximately halfway, and gentle but steady half by pulling the chopper to the left and slightly down while moving
pressure on the syringe allows fluid to enter the distal tunnel without the phaco needle, still in foot position 2, to the right and slightly up (Fig.
resistance. A circumferential golden or dark ring will appear, outlining the 5.11.2). Then, the nuclear complex is rotated by 90°. The chop instrument
endonucleus. is again brought into the golden ring, the hemi-nucleus is lollipopped,
Occasionally, an arc, rather than a complete ring, will result, surround- scored, and chopped with the resulting wedge now lollipopped on the
ing approximately one quadrant of the endonucleus. In this instance, the phaco tip and evacuated. The nucleus is rotated so that wedges can be
procedure can be repeated in multiple quadrants until a golden or dark scored, chopped, and removed by high vacuum assisted by short bursts or
ring confirms complete circumferential separation of the endonucleus pulses of phaco. The size of the wedges is varied according to the density
from the epinucleus. of the nucleus.
After evacuation of all endonuclear material, the epinuclear rim is
NUCLEOFRACTIS TECHNIQUES trimmed in each of the three quadrants, mobilizing the cortex. As each
quadrant of the epinuclear rim is rotated to the distal position in the
The recognition that the lens nucleus could be divided and removed from capsule and trimmed, the cortex in the adjacent capsular fornix flows over
within the protective layer of the epinucleus while preserving the capsu- the floor of the epinucleus and into the phaco tip. The floor is pushed back
lorrhexis influenced the development of a plethora of phaco techniques. to keep the bag on stretch until three of the four quadrants of the epinu-
clear rim and cortex have been evacuated. The epinuclear rim of the fourth
Divide and Conquer quadrant is then used as a handle to flip the epinucleus. As the remain-
ing portion of the epinuclear floor and rim is evacuated from the eye, the
In the divide-and-conquer technique originally described by Gimbel,24 a entire cortex is often evacuated with it.
deep crater is sculpted into the center of the nucleus, including the pos- If there is remaining cortex after removal of all the nucleus and epi-
terior plate. However, phaco fracture, described by Shepherd, is often nucleus, there are three options. The phaco handpiece can be left high in
referred to as a “divide and conquer” technique.25 In this technique, the the anterior chamber while the second handpiece strokes the cortex-filled
surgeon sculpts a groove parallel to the incision one and a half to two capsular fornices. Frequently, this results in floating the cortical shell as
times the diameter of the phaco tip, with the tip in a bevel-up position, a single piece and aspirating it through the phaco tip (in foot position 2)
using moderate power and low vacuum. Using the phaco handpiece and a because cortical cleaving hydrodissection has cleaved most of the cortical–
second instrument, the surgeon then rotates the nucleus by 90° and sculpts capsular adhesions.
a second groove perpendicular to the first. Sculpting continues until the Alternatively, if one wishes to complete cortical cleanup with the
red reflex is seen at the bottom of the grooves. A bimanual cracking tech- irrigation–aspiration handpiece prior to lens implantation, the residual
nique is used to create a fracture through the nuclear rim in the plane of cortex can almost always be mobilized as a separate and discrete shell and
one of the grooves. The nucleus is then rotated by 90°, and additional frac- removed without turning the aspiration port down to face the posterior
tures are made until four separate quadrants are isolated. A short burst of capsule.
phaco power with increased vacuum then is used to embed the phaco tip The third option is to visco-dissect the residual cortex by injecting a dis-
into one quadrant, which is pulled into the center for emulsification. The persive viscoelastic through the posterior cortex onto the posterior capsule.
second instrument can help elevate the apex of the quadrant to facilitate The viscoelastic material spreads horizontally, elevating the posterior cortex
its mobilization. and draping it over the anterior capsular flap. At the same time, the periph-
eral cortex is forced into the capsular fornix. The posterior capsule is then
Phaco Chop deepened with a cohesive OVD, and the IOL is implanted, leaving ante-
rior residual cortex anterior to the IOL. Removal of residual OVD material
Nagahara first introduced the “phaco chop” technique by using the natural accompanies mobilization and aspiration of the residual cortex.
fault lines in the lens nucleus to create cracks without creating prior Nonlinear delivery of ultrasonic or sonic frequencies, such as torsional
grooves (Presentation at the American Society of Cataract and Refractive and elliptical phaco, has further improved operating efficiency. Chopping
Surgery Film Festival, 1993). The phaco tip is embedded in the center of techniques in combination with power modulations and nonlinear ultra-
the nucleus after the superficial cortex is aspirated. In horizontal chopping, sound power delivery minimize morbidity and enhance the rapidity of
a second instrument, the phaco chopper, is then passed to the equator of visual rehabilitation.
the nucleus, beneath the anterior capsule, and drawn to the phaco tip to
fracture the nucleus. The two instruments are separated to widen the crack.
In vertical chopping, a sharp-tipped instrument is inserted directly into the
BIAXIAL MICROINCISION CATARACT SURGERY
nucleus beside the embedded phaco needle, and the two instruments are Advances in ultrasound engineering during the late 1990s led to the appli-
again separated as in horizontal chopping. The nucleus is rotated, and this cation of millisecond-level control and variable duty cycles in phaco, vastly
procedure is repeated until several small fragments are created, which are reducing the risk of thermal injury from the phaco needle and permitting 379
then emulsified. removal of the irrigation sleeve. Separation of irrigation from aspiration
booksmedicos.org
5 Performing the initial chop
CHOO-CHOO CHOP AND FLIP
Using ultrasound power Flipping the epinuclear shell

The Lens
A B C
Fig. 5.11.2 The surgeon performs the initial chop of the nucleus by deeply embedding the phaco needle in the center of the nucleus using ultrasound power, and then
maintaining a hold on the nucleus with high vacuum in foot pedal position 2 without ultrasound as the horizontal chopper is brought from the golden ring to the side of
the phaco needle to score the nucleus. The surgeon then completes the chop by separating the instruments with a slight upward movement of the phaco tip and a slight
downward movement of the chopper (A). Each quadrant of nuclear material is in turn impaled, chopped, mobilized, and consumed with high vacuum and low amounts of
ultrasound power (B). Finally, the epinuclear shell is flipped with a helpful push from the chopper (C).
during phaco came to be known as biaxial microincision cataract surgery

(B-MICS) (Video 5.11.2).
See clip:
5.11.2 The advantages of B-MICS include better followability because of the
separation of infusion and aspiration, access to 360° of the capsular bag
with either infusion or aspiration by switching instruments from one hand
to the other, the ability to use the flow of irrigation fluid as a tool to move
material within the capsular bag or anterior chamber (particularly from
an open-ended irrigating chopper or manipulator), prevention of iris bil-
lowing and prolapse in cases of intraoperative floppy iris syndrome, and
significantly decreased risk of vitreous prolapse in the case of a posterior
capsular tear, zonular dialysis, or subluxated cataract, thanks to mainte-
nance of a pressurized stream of irrigation.
Perhaps the greatest advantage of the biaxial technique lies in its ability
to remove the subincisional cortex without difficulty. As originally described
by Brauweiler, by switching infusion and aspiration handpieces between
two microincisions, 360° of the capsular fornices are easily reached, and
cortical cleanup can be performed quickly and safely.28
Since dispersive OVDs do not easily extrude through these small inci-
sions, the anterior chamber is more stable during capsulorrhexis construc-
tion, and there is much less likelihood of an errant tear. This added margin Fig. 5.11.3 The capsulorrhexis is nearly complete in this eye with a history of trauma
of safety is particularly noticeable in cases of zonular compromise, such as and 90° of zonular dialysis visible temporally. The wrinkling of the capsule is a
pseudo-exfoliation and traumatic zonular dialysis (Fig. 5.11.3). The added clear sign of the lack of zonular tension. Nevertheless, because of the increased
chamber stability also can make a difference in control of the capsulor- control allowed by the micro-incisions, which prevent extrusion of viscoelastic, the
rhexis in both high myopia and high hyperopia with an extremely deep or capsulorrhexis will be centered, round, and smaller in diameter than the intraocular
a very shallow anterior chamber, respectively (Video 5.11.3). lens (IOL) as intended.
See clip:
5.11.3
B-MICS VERTICAL CHOP TECHNIQUE

After hydrodissection and hydrodelineation, the phaco needle is first To address the second half of the nucleus, it is first rotated with the
embedded proximally with high vacuum and 40% power. In the other irrigating chopper so that it is in the distal capsule. The phaco needle is
hand is a vertical chopper that will be used to split the nucleus. As vacuum embedded in the smaller hemi-nucleus, and this is subdivided with the
builds to occlusion a rapid rise time enables the phaco needle to quickly irrigating chopper, again using high vacuum and low levels of power (Fig.
grasp the endonucleus. At the point occlusion is reached, the aspiration 5.11.6). As the final quadrant is grasped and pulled centrally for aspiration,
flow rate drops to zero. The surgeon then moves into foot position 2 so the sharp blade of the irrigating chopper is turned sideways as a safety
that high vacuum is maintained and the power drops to zero. The blade precaution (Fig. 5.11.7).
of the irrigating vertical chopper is brought down just distal to the phaco When addressing the epinucleus, the vacuum and aspiration flow are
tip. As a full-thickness cleavage plane develops, dividing the nucleus in reduced. Once three quadrants of the epinuclear shell have been rotated
two, the instruments are separated to insure a complete chop (Fig. 5.11.4). and trimmed, the final quadrant is used to flip the epinuclear bowl into
The lens is then rotated with the irrigating chopper so that the first the phaco needle. After aspiration of the epinucleus, the capsule is almost
hemi-nucleus can be chopped. If there is a disparity in size, the larger entirely clean of cortex (Fig. 5.11.8).
half is moved distally. The phaco needle is now embedded to the right B-MICS with a vertical chop technique allows for efficient lens extraction
by using high vacuum and low levels of power. A quadrant size piece is with rapid visual rehabilitation. This procedure demonstrates some of the
chopped off and consumed (Fig. 5.11.5). The remaining quadrant of the tangible benefits of separating inflow from outflow, use of irrigation fluid
380 first hemi-nucleus is then impaled with the phaco tip and aspirated. Total as an instrument to mobilize material, and reduced effective phaco time
EPT to this point is zero, showing minimal usage of ultrasound. (Video 5.11.4). See clip:
5.11.4
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5.11

Fig. 5.11.4 The phaco tip is embedded in the proximal nucleus bevel down; the Fig. 5.11.7 The final segment of nucleus is grasped with high vacuum and brought
nucleus is then held with high vacuum as the irrigating chopper slices vertically centrally.
downward distal to the phaco tip. The chopper and the phaco tip are then
separated as shown, to divide the nucleus.
Fig. 5.11.5 A quadrant-sized piece of nucleus is chopped and brought centrally, Fig. 5.11.8 At the conclusion of epinucleus aspiration, the capsule is almost entirely
where it will be emulsified and aspirated. free of cortex.
FEMTOSECOND LASER-ASSISTED
CATARACT SURGERY
Femtosecond lasers have a unique ability to create discreet photodisrup-
tion of tissue with minimal collateral effects. This enables very precise
cutting in ocular tissues, including the cornea, the lens capsule, and the
crystalline lens.
Femtosecond lasers are indicated for the following surgical steps:
• Anterior capsulectomy.
• Lens fragmentation.
• Corneal arcuate incisions for treatment of astigmatism.
• Clear corneal incisions.
Anterior Capsulectomy
Laser capsulectomy brings precision and reproducibility to the process of
creating a capsular opening. Studies have shown that laser capsulectomies
are significantly closer to the intended diameter than manual CCCs (Table
5.11.1).29,30 However, concerns have arisen with regard to their resistance to
tearing, which may be related to the surgeon’s learning curve.
The size of the capsulectomy may influence the progression of poste-
rior capsular opacification (PCO). Current practice requires that capsulec- 381
Fig. 5.11.6 A wedge of nucleus is chopped from the remaining hemi-nucleus. tomy be in contact with the optic of the IOL around its circumference.
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5
TABLE 5.11.1 Capsulectomy Data by Group TABLE 5.11.3 Analysis of Mean (SD) CDE as a Function
of Nuclear Cataract Grade
Differences are significant (P ≡ 0.03).
For Grade 0 For Grade 1 For Grade 2 For Grade 3 For Grade 4
Capsulectomy/Capsulorrhexis Diameter (mm)
The Lens
Treatment Mean (SD) Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Group Attempted Measured Attempted–Achieved Groups N N N N N
Laser (n ≡ 49) Laser 1.9 (3.2) 0.0 (0.0) 3.0 (4.0) 9.3 (9.4) 24.0 (18.8)
treatments 3 4 29 25 27
Mean 5.23 5.08 0.16
SD 0.06 0.18 0.17 Control 7.8 (−) 4.4 (2.4) 8.2 (6.1) 15.2 (13.0) 41.2 (24.7)
group 1 7 24 15 7
CCC (n ≡ 24)
Mean 5.36 4.95 0.42 % Difference −75.6% −100.0% −63.4% −38.8% −41.7%
(control vs
SD 0.55 0.53 0.54
laser)
CCC, continuous curvilinear capsulorrhexis; SD, standard deviation.
From Tackman RN, Kuri JV, Nichamin LD, Edwards K. Anterior capsulectomy with an ultrashort-
pulse laser. J Cataract Refract Surg 2011;37:819–24.)
TABLE 5.11.4 Numbers of Subjects and Statistical

Significance by Cataract Grade
TABLE 5.11.2 Percentage of Cases Achieving
the Required Refractive Outcome Grade ≤1 Grade 1 Grade 2 Grade 3 Grade 4
Laser Phaco Laser Phaco Laser Phaco Laser Phaco Laser Phaco
6 Months After Surgery
N≡7 N≡8 N≡4 N≡7 N ≡ 29 N ≡ 24 N ≡ 25 N ≡ 15 N ≡ 27 N≡7
Deviation Laser Manual
P ≡ 0.006 P ≡ 0.006 P < 0.001 P ≡ 0.069 P ≡ 0.052
0.00 13.5% 3.4%
≤ 0.50 81.1% 74.6%
≤ 1.25 100.0% 96.6%
From Uy H, Hill WE, Edwards K. Refractive results after laser anterior capsulotomy. Invest
Ophthalmol Vis Sci 2011;52:5695.
TABLE 5.11.5 Changes in Endothelial Cell Density Between Baseline
and 3 Months After Surgery
Grade 1 Grade 2 Grade 3 Grade 4

However, significant variations in the extent of this contact or areas where Laser Phaco Laser Phaco Laser Phaco Laser Phaco
there is no contact may cause the lens to decenter and tilt as the capsule Mean % change 1.5 −7.0 0.1 −1.3 −0.1 −4.3 −2.4 −1.5
contracts postoperatively.
SD 14.4 9.7 14.9 11.1 10.5 8.7 11.9 8.3
Kranitz and Nagy reported improved overlap of the capsulectomy edge
P value 0.10 > P > 0.05 NS 0.10 > P > 0.05 NS
on the optic of the IOL and less horizontal decentration of the IOL in
cases where laser capsulectomy had been used.31,32 It has been proposed SD, standard deviation.
that the consistency of laser capsulectomy may increase the consistency
of effective lens position (ELP) and hence the ability to hit the targeted
postoperative refractive result. Early data presented by Uy and Hill confirm
this effect.33,34 In a study of 44 cases undergoing laser capsulectomy and 62 Corneal Incisions
cases undergoing manual CCC, a significantly higher proportion produced
the intended refractive outcome at 6 months by a factor of 4. Table 5.11.2 In an early study with cadaver eyes, Masket showed the ability of a
shows results supporting the hypothesis that laser capsulectomy has a pos- single-plane laser incision to be self-sealing at significant intraocular pres-
itive effect on the consistency of ELP. sures (IOPs) and indentations at certain wound tunnel lengths.37 Palanker
reported that three-plane laser incisions were self-sealing and watertight
Lens Fragmentation at physiological IOPs.38 It is not clear whether this applies to the incision
immediately after its creation or at the end of the surgical cases, follow-
Fragmentation of the lens prior to cataract surgery is intended to reduce ing the use of the phaco handpiece and IOL insertion. Fig. 5.11.9 shows
or eliminate the need to use ultrasound energy during disassembly of the the planned corneal incision and the optical coherence tomogram of the
nucleus. In the ideal situation, the nucleus would simply be removed by wound obtained the day after surgery.
aspiration. However, it might be anticipated that harder nuclei will require The effectiveness of laser LRIs or astigmatic keratotomy has yet to be
some ultrasound emulsification. established in the literature, although the precision of laser in creating
In the quest for optimal outcomes, different cutting patterns and algo- incisions of the precise length and depth required suggests that the pro-
rithms (shot placement, energy, and pulse repetition frequency) may all cedure should be more reproducible and reliable than manual methods.
influence the efficiency of the fragmentation. Nichamin has shown some Several authors have shown reduction of astigmatism in patients who have
of the patterns that were evaluated during an early phase of the develop- undergone keratoplasty or in patients with a high degree of astigmatism
ment of lens fragmentation.35 It was found that different patterns had dif- with femtosecond laser arcuate keratotomy.39–42 In addition, some authors
ferent degrees of effectiveness, depending on the hardness of the cataract have reported that femtosecond laser corneal relaxing incisions are effec-
being treated. Overall, the pie pattern proved the most effective over the tive in reducing corneal astigmatism during cataract surgery, and their
range of cataract grades from 1–5+. long-term effectiveness should be evaluated.43
Packer and Uy have presented data on the effectiveness of phaco-
fragmentation by comparing the total ultrasound energy required for dis-
assembly of the nucleus after laser lens fragmentation with that required
CONCLUSIONS
during conventional ultrasound phaco surgery. Their results are shown in Since the time of Charles Kelman’s inspiration while in the dentist’s chair
Tables 5.11.3 and 5.11.4.36 (while having his teeth ultrasonically cleaned), progress in phaco technol-
The reduction in the use of ultrasound energy may lead to other bene- ogy and techniques has produced ever-increasing benefits, including more
fits, such as less corneal edema, faster visual recovery, and a reduction in rapid visual rehabilitation and reduced dependence on contact lenses and
the rate of endothelial cell loss. Packer and Uy reported that endothelial glasses. Creative engineering and surgical ingenuity have acted synergis-
cell density changes from baseline are less following laser lens fragmen- tically to improve outcomes. Advances in technique and technology will
382 tation compared with conventional ultrasound phaco. Table 5.11.5 summa- continue to benefit our patients as we develop the exciting new future of
rizes these results. small-incision cataract surgery.
booksmedicos.org
KEY REFERENCES
Cataract in the Adult Eye, Preferred Practice Pattern, American Academy of Ophthalmol-
ogy, 2011. http://one.aao.org/ce/practiceguidelines/ppp_content.aspx?cid=a80a87ce-9042
5.11
-4677-85d7-4b876deed276. Accessed December 6, 2011.

Fine IH. Architecture and construction of a self-sealing incision for cataract surgery. J Cata-
ract Refract Surg 1991;17:672–6.
Fine IH. Cortical cleaving hydrodissection. J Cataract Refract Surg 1992;18:508–12.
Fine IH, Packer M, Hoffman RS. Use of power modulations in phacoemulsification. J Cata-
Friedman NJ, Palanker DV, Schuele G, et al. Femtosecond laser capsulotomy. J Cataract
Refract Surg 2011;37(3):1189–98.
Kershner RM. Clear corneal cataract surgery and the correction of myopia, hyperopia, and
astigmatism. Ophthalmology 1997;104:381–9.
Masket S, Sarayba M, Ignacio T, et al. Femtosecond laser-assisted cataract incisions: architec-
tural stability and reproducibility. J Cataract Refract Surg 2010;36:1048–9.
Nichamin LD, Chang DF, Johnson SH, et al. ASCRS White Paper: What is the association
between clear corneal cataract incisions and postoperative endophthalmitis? J Cataract
Refract Surg 2006;32:1556–9.
Nubile M, Carpineto P, Lanzini M, et al. Femtosecond laser arcuate keratotomy for the cor-
rection of high astigmatism after keratoplasty. Ophthalmology 2009;116:1083–92.
A Packer M, Fishkind WJ, Fine IH, et al. The Physics of phaco: a review. J Cataract Refract
Surg 2005;31(2):424–31.
Palanker DV, Blumenkranz MS, Andersen D, et al. Femtosecond laser-assisted cataract
surgery with integrated optical coherence tomography. Sci Transl Med 2010;58(1):1–9.
Tackman NR, Villar Kuri J, Nichamin LD, et al. Anterior capsulotomy with an ultrashort-pulse
laser. J Cataract Refract Surg 2011;37:819–24.
Wang L, Zhang S, Zhang Z, et al. Femtosecond laser penetrating corneal relaxing incisions
combined with cataract surgery. J Cataract Refract Surg 2016;42(7):995–1002.
Fig. 5.11.9 Planned incision (A) with dotted line showing part to be opened at time
of surgery with a surgical blade and optical coherence tomography (OCT) if incision
the day after surgery (B).
383
booksmedicos.org
REFERENCES 21. Gimbel HV, Neuhann T. Letter to the editor: continuous curvilinear capsulorrhexis. J
Cataract Refract Surg 1991;17:110.
1. Kelman CD. Phacoemulsification and aspiration: a new technique of cataract removal: a
preliminary report. Am J Ophthalmol 1967;64:23.
22. Little BC, Smith JH, Packer M. Little capsulorrhexis tear-out rescue. J Cataract Refract
Surg 2006;32:1420–2.
5.11
2. Packer M, Fishkind WJ, Fine IH, et al. The physics of phaco: a review. J Cataract Refract 23. Fine IH. Cortical cleaving hydrodissection. J Cataract Refract Surg 1992;18:508–12.
24. Gimbel HV. Divide and conquer nucleofractis phacoemulsification. J Cataract Refract

Surg 2005;31(2):424–31.
3. Fine IH. Architecture and construction of a self-sealing incision for cataract surgery. J Surg 1991;17:281.
Cataract Refract Surg 1991;17:672–6. 25. Shepherd JR. In situ fracture. J Cataract Refract Surg 1990;16:436.
4. Rosen ES. Clear corneal incisions: a good option for cataract patients. A Roundtable 26. Fine IH. The choo-choo chop and flip phacoemulsification technique. Operative Tech
Discussion. Ocular Surgery News, February 1, 1998. Cataract Refract Surg 1998;1:61–5.
5. Williamson CH. Cataract keratotomy surgery. In: Fine IH, Fichman RA, Grabow HB, 27. Fine IH, Packer M, Hoffman RS. Use of power modulations in phacoemulsification. J
editors. Clear-corneal cataract surgery and topical anesthesia. Thorofare: Slack, Inc.; Cataract Refract Surg 2001;27:188–97.
1993. p. 87–93. 28. Brauweiler P. Bimanual irrigation/aspiration. J Cataract Refract Surg 1996;22:1013–16.
6. Langerman DW. Architectural design of a self-sealing corneal tunnel, single-hinge inci- 29. Tackman NR, Villar Kuri J, Nichamin LD, et al. Anterior capsulotomy with an ultra-
sion. J Cataract Refract Surg 1994;20:84–8. short-pulse laser. J Cataract Refract Surg 2011;37:819–24.
7. Kershner RM. Clear corneal cataract surgery and the correction of myopia, hyperopia, 30. Friedman NJ, Palanker DV, Schuele G, et al. Femtosecond laser capsulotomy. J Cataract
and astigmatism. Ophthalmology 1997;104:381–9. Refract Surg 2011;37:1189–98.
8. Gills JP, Gayton JL. Reducing pre-existing astigmatism. In: Gills JP, editor. Cataract 31. Kranitz K, Takacs A, Mihaltz K, et al. Femtosecond laser capsulotomy and manual con-
surgery: the state of the art. Thorofare: Slack, Inc.; 1998. p. 53–66. tinuous curvilinear capsulorrhexis parameters and their effects on intraocular lens cen-
9. Nichamin L. Refining astigmatic keratotomy during cataract surgery. Ocular Surgery tration. J Refract Surg 2011;27(8):558–63.
News, April 15, 1993. 32. Nagy ZZ, Kranitz K, Takacs AI, et al. Comparison of intraocular lens decentration param-
10. Fukuda S, Kawana K, Yasuno Y, et al. Wound architecture of clear corneal incision with eters after femtosecond and manual capsulotomies. J Refract Surg 2011;27(8):564–9.
or without stromal hydration observed with 3-dimensional optical coherence tomogra- 33. Uy H, Hill WE, Edwards K. Refractive results after laser anterior capsulotomy. Invest
phy. Am J Ophthalmol 2011;151:413–9.e1. Ophthalmol Vis Sci 2011;52:5695.
11. Fine IH. Special Report to ASCRS Members: Phacoemulsification incision burns. Letter 34. Hill WE, Uy H. Effective lens position following laser anterior capsulotomy. Presentation
to American Society of Cataract and Refractive Surgery members, 1997. to the Annual Meeting of the American Academy of Ophthalmology 2011; Orlando.
12. Nichamin LD, Chang DF, Johnson SH, et al. ASCRS White Paper: What is the associa- 35. Nichamin LD, Uy H. Choice of fragmentation algorithm impacts the reduction in CDE
tion between clear corneal cataract incisions and postoperative endophthalmitis? J Cata- during cataract surgery. Presentation to the Annual Meeting of the American Academy
ract Refract Surg 2006;32:1556–9. of Ophthalmology 2010; October 16–19, McCormick Place, Chicago.
13. Mollan SP, Gao A, Lockwood A, et al. Post-cataract endophthalmitis: incidence and 36. Packer M, Uy H. Endothelial changes after laser phaco-fragmentation. Presentation to
microbial isolates in a United Kingdom region from 1996 through 2004. J Cataract the Annual Meeting of the American Academy of Ophthalmology 2011; October 22–25,
Refract Surg 2007;33:265–8. Orlando Convention Center, Orlando.
14. Eifrig CW, Flynn HW Jr, Scott IU, et al. Acute-onset postoperative endophthalmitis: 37. Masket S, Sarayba M, Ignacio T, et al. Femtosecond laser-assisted cataract incisions:
review of incidence and visual outcomes (1995–2001). Ophthalmic Surg Lasers architectural stability and reproducibility. J Cataract Refract Surg 2010;36:1048–9.
2002;33:373–8. 38. Palanker DV, Blumenkranz MS, Andersen D, et al. Femtosecond laser-assisted cataract
15. Miller JJ, Scott IU, Flynn HW Jr, et al. Acute-onset endophthalmitis after cataract surgery surgery with integrated optical coherence tomography. Sci Transl Med 2010;58:1–9.
(2000–2004): incidence, clinical settings, and visual acuity outcomes after treatment. Am 39. Nubile M, Carpineto P, Lanzini M, et al. Femtosecond laser arcuate keratotomy for the
J Ophthalmol 2005;139:983–7. correction of high astigmatism after keratoplasty. Ophthalmology 2009;116:1083–92.
16. Oshika T, Hatano H, Kuwayama Y, et al. Incidence of endophthalmitis after cataract 40. Kumar NL, Kaiserman I, Shehadeh-Mashor R, et al. IntraLase-enabled astigmatic ker-
surgery in Japan. Acta Ophthalmol Scand 2007;85:848–51. atotomy for post-keratoplasty astigmatism: on-axis vector analysis. Ophthalmology
17. Cataract in the adult eye; preferred practice pattern, American Academy of Ophthalmol- 2010;117:1228–35.
ogy, 2011. http://one.aao.org/ce/practiceguidelines/ppp_content.aspx?cid=a80a87ce-9042- 41. Abbey A, Ide T, Kymionis GD, et al. Femtosecond laser-assisted astigmatic keratotomy in
4677-85d7-4b876deed276. Accessed December 6, 2011. naturally occurring high astigmatism. Br J Ophthalmol 2009;93:1566–9.
18. Wasserman D, Apple D, Castaneda V, et al. Anterior capsular tears and loop fixation of 42. Bahar I, Levinger E, Kaiserman I, et al. IntraLase-enabled astigmatic keratotomy for post-
posterior chamber intraocular lenses. Ophthalmology 1991;98:425. keratoplasty astigmatism. Am J Ophthalmol 2008;146:897–904.e1.
19. Neuhann T. Theorie und operationstechnik der kapsulorhexis. Klin Monatsbl Augen- 43. Wang L, Zhang S, Zhang Z, et al. Femtosecond laser penetrating corneal relaxing inci-
heilkd 1987;190:542. sions combined with cataract surgery. J Cataract Refract Surg 2016;42(7):995–1002.
20. Gimbel HV, Neuhann T. Development, advantages and methods of the continuous circu-
lar capsulorrhexis technique. J Cataract Refract Surg 1990;16:31.
383.e1
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Part 5 The Lens

Manual Cataract Extraction

Frank W. Howes 5.12
cylindrical induction, particularly if a three-plane (Fig. 5.12.1), valve-type
Definition: Removal of crystalline lens by nonautomated or manual incision is utilized. Combinations of both scleral and corneal sections can
techniques. be used to correct pre-existing cylindrical errors.8 These sections can be
rotated appropriately to reduce cylindrical error in any meridian.
When the incision is fashioned, the third plane of the incision (see Fig.
5.12.1) should be completed only when the anterior capsulectomy has been
Key Features performed. This allows the anterior chamber to maintain depth, with or
• Diversity of techniques for optimal cataract patient outcomes. without viscoelastic material, while the anterior capsulectomy is under-
• Intracapsular cataract extraction or large-incision full lens extraction. taken. Once this is done, the internal incision may be completed.
• Extracapsular cataract extraction or large-incision nucleus expression
cataract surgery.
• Small-incision manual nucleus expression lens surgery (“mininuc” Wound Closure
technique). During closure of a wound cut in the three-plane format, the sutures must
not be overtightened; the edges are merely opposed (incisional gape)9 (see
Fig. 5.12.1). The valve effect of the incision seals the wound. In cases in
INTRODUCTION which leakage is excessive, closure can be obtained by intracameral air.
Further opportunity for cylinder modification arises when sutures are
The techniques of manual cataract surgery remain invaluable in the man- removed. This allows controlled dehiscence of the wound. Dehiscence
agement of certain crystalline lens and zonular pathologies inappropriate induces negative cylindrical effect at the meridian of the suture removal. A
for phacoemulsification (“phaco”). rough guide to timing suture removal is as follows:
The decision regarding the choice of procedure is based on a spectrum
of factors related to the socioeconomic environment (equipment availabil-
• After 1 month, if major wound dehiscence is required to correct cylin-
drical error (3–6 diopters).
ity) and the operative experience (surgeon and team) on the one hand and
to the ophthalmological condition of the patient on the other.
• After 2 months, if minor dehiscence is required to correct cylindrical
error (2–3 diopters).
• At 3–6 months, to resume preoperative cylinder.
Historical Issues • After 6 months, to maintain surgically induced cylinder correction, if
appropriate.
Manual cataract surgery techniques (initially intracapsular cataract
extraction [ICCE] followed by extracapsular cataract extraction [ECCE]) have
been the mainstay of cataract surgery for the majority of the last century.
Much of the value of the manual techniques has been the lower costs and THREE-PLANE SCLERAL SECTION
minimal instrumentation with which the surgery can be performed. These
techniques provide excellent rehabilitation of blindness caused by cataract first part of scleral second part of incision corneal edge third part of
at the expense of only recovery time and stability of refraction over the incision showing tunneled 2–3 mm in of sectioned incision into
first year.1 incisional gape clear cornea conjunctiva anterior chamber
ICCE held favor over ECCE in view of the latter’s potential for com-
plications (inflammation, iritis, phacoanaphylaxis, secondary membranes,
glaucoma2) until the 1950s. The development of systems that provided
simultaneous irrigation while aspirating was the key to the return of the
extracapsular systems. These systems allowed for better removal of lenticu-
lar material (ECCE). These principles reached a high level of technological
sophistication (and expense) in the phaco techniques. The attempts at cost
containment led to the development of manual nucleus expression surgery incised and
through smaller incisions, or the so-called mininuc technique.3–6 deflected
conjunctiva
MANUAL (LARGE-INCISION)
CATARACT SURGERY
These techniques require strict attention to wound construction for
optimal optical outcome.
Incision
An incision of 8–12 mm of arc length around the limbus (corneal, limbal,
scleral, or a combination of all) is required to manually express the nucleus
from the capsular bag in ECCE, whereas an incision of 12–14 mm around Fig. 5.12.1 Three-plane scleral section. This incision is formed with the use of a
the limbus is required in ICCE. Variation in the incision position has a sharp microsurgical knife for the initial vertical segment, followed by use of a
profound influence on the postoperative occurrence of cylindrical error.7 curved dissecting blade to form the intralamellar section of the incision. The final
384 The more corneal the section is placed, the stronger is the influence on vertical portion of the incision is best cut with corneal microscissors. Tissue elasticity
the cylindrical error. The more scleral the section is placed, the less is the produces the incisional gape evident.
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5.12

A B
Fig. 5.12.2 Intracapsular delivery of the lens after it has been brought forward through the pupil with the cryoprobe. (A) The pupil constricts spontaneously as soon as the
maximal diameter of the lens is through. In the lower left of the figure, the moist swab is shown as the swab and the lens are sliding. (B) The cornea has a concave surface,
showing that the eye is soft without forward pressure from the vitreous body. The anterior chamber is reformed with a physiological solution. (From Roper-Hall MJ. Stallard’s
eye surgery. 7th ed. London, UK: Wright; 1989.)
is useful when there is either iris damage (e.g., from trauma) or trabecular
INTRACAPSULAR CATARACT EXTRACTION damage (e.g., associated with glaucoma). Adequate vitreous clearance is a
General Comments10 prerequisite in the case of all of these placement sites, particularly with
ciliary sulcus fixation.
Currently, the need for ICCE is restricted to the need for removal of the
entire crystalline lens. This is necessary when the zonulear fibers are no
longer present or when they are of insufficient strength to withstand the
EXTRACAPSULAR CATARACT EXTRACTION
phaco process or to provide adequate stability for an intraocular lens. Extracapsular surgery entails more steps compared with intracapsular
Zonular dissolution, an essential step in the past, is thus unnecessary surgery in that the capsular bag is left in the eye, held in position by
for today’s indications for ICCE. The cryophake (tip freeze adherence zonular fibers. To initiate the process, a hole is made in the crystalline lens
driven by gaseous expansion) remains the most valuable tool for ICCE in a central position in the visual axis (anterior capsulectomy). The remain-
(Fig. 5.12.2). der of the process involves careful removal of the contents.
Specific Techniques Anterior Capsulectomy

Iris Management The techniques of anterior capsulectomy have changed over the past 30
Full pupillary dilation is necessary for the lens to pass through. Posterior years.11
synechiae may need division or a miotic pupil may need stretching, but
invariably the pupil is sufficiently elastic to permit passage of the lens. A “Can Opener” Capsulectomy
small peripheral iridectomy should be cut at some stage in the procedure The simplest type of capsular opening or capsulectomy is the “can opener”
to avoid pupil block. Occasionally, a radial iridotomy (from peripheral iri- type, in which a number of very close, pinpoint perforations are created
dotomy to pupil margin) is necessary for access to the lens surface for in a central, circular tract in the anterior capsule. Centripetal traction is
cryo-application and optimal “ice ball” formation. It is important to have placed on the central piece of capsule to create a tear along the perfora-
a dry lens bed, free of both iris and cornea, for safe removal of the lens tions. The loose piece is then carefully removed. One advantage of this
without collateral damage. (An assistant elevating the cornea with traction technique is the relative accuracy that can be achieved when visibility is
on a suture placed in mid-incision [incision as described above] will free poor (e.g., for a dense cataract with a poor red reflex or a very small pupil
the surgeon’s nondominant hand to dry the lens and move the iris away that requires the perforations to be made under the pupillary margin).
with a microswab and operate the cryoprobe with the dominant hand to
apply the “ice ball” and appropriate swaying traction to remove the lens.) Linear Capsulectomy and Intercapsular Techniques
Linear capsulectomy techniques enable external expression while the
Vitreous Presentation or Prolapse anterior capsule is utilized to protect the corneal endothelium. In this
After careful removal of the lens, the vitreous face is likely to remain intact method, a curvilinear incision is made in the upper third of the anterior
if unnecessary globe pressure is avoided. Should vitreous emerge from lens capsule to create a slit or envelope opening into the lens capsular
the entry wound, proper excision is necessary to avoid any vitreous trac- bag. After nucleus mobilization and expression and cortical material
tion syndrome. Vitrectomy may be necessary, depending on the intraocu- removal, the IOL can be inserted into the remaining capsular bag. The
lar lens of choice. Identification of prolapsed vitreous will be enhanced by capsulectomy is completed by performing a continuous curvilinear cap-
injection of particulate triamcinolone. sulorrhexis across the remaining capsule to complete the circular central
opening.
Intraocular Lenses
Because the capsular bag has been removed, the choice of intraocular Capsulorrhexis
lens (IOL) support is limited to the angle, iris, or ciliary sulcus (fixated by Capsulorrhexis, or continuous curvilinear capsulectomy, is a quick and,
suture). This should be done with ophthalmic viscosurgical device (OVD) once learned, easy technique for anterior capsule removal. It provides the
protection. best security for the IOL within the capsular bag.12 The initial capsulotomy
An angle-supported lens must be fitted carefully to the individual can be made centrally with a cystotome, or bent needle, or by utilizing the
chamber diameter so that it neither distorts nor moves for endothelial tip of a fine capsulorrhexis forceps. Once the capsule has been opened, a
protection. An iris-supported lens, either anteriorly or posteriorly fixed, piece of anterior capsule is grasped and torn in a circular manner, with
provides safe optical rehabilitation when adequate iris is available. Ciliary continuous change of the tearing vectors to achieve the round opening 385
sulcus lens placement requires transscleral support by suture fixation and (capsulectomy) in the anterior capsule.
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Fig. 5.12.3 Anterior
5 Size, Type, and Position of Capsulectomy

The capsulectomy needs to be large enough for the passage of the nucleus.
The size of the nucleus is age dependent but can be modified by hydro-
chamber
maintainer located
at the 6 o’clock
dissection and hydrodelineation using an appropriate cannula.13 If the position, parallel
The Lens
and adjacent to
nucleus is deemed too big for passage through the capsulectomy (e.g.,
the limbus, in
after an unsuccessful hydrodelineation or after too small an initial capsu- clear cornea. The
lorrhexis), relaxing incisions in the capsulorrhexis are necessary to reduce incision is made
the possibility of capsular dislocation and zonular damage during nucleus into the cornea
expression. During hydrodissection, if the anterior capsular opening is with a stiletto
large enough, part of the equatorial rim of the nucleus can be expressed 1.1 mm wide and
into the anterior chamber, then rotated into the anterior chamber and into beveled 1.5–2 mm.
the incision, and thus removed from the eye. OVD material between the
corneal endothelial surface and the nuclear surface is necessary to prevent
endothelial damage.
The size and shape of the capsulorrhexis can be varied by the surgeon.
A large capsulectomy facilitates surgery, but when this exceeds approxi-
mately 6.5 mm in diameter, the capsulorrhexis becomes difficult to control
because of the presence of the insertion of the zonules.14 When the ante-
rior capsular ridge is crossed, the danger of a peripheral radial irretrievable
split15 is possible (particularly if the anterior chamber is not kept deep; POCKET TUNNEL DISSECTION AREA AND BORDERS
a shallow anterior chamber creates tension on the anterior zonular lig-
ament). Peripheral splits are usually blocked by the zonular fibers, but
unwanted posterior capsular tears may be caused by this mechanism.
Nucleus Expression
The scleral lip of the incision should be depressed to allow the leading
pole of the nucleus to present into the incision. Gentle pressure at the
180° opposing limbus then expresses the nucleus. The appropriate pres-
sure may be applied with a broad-based instrument, such as a vectis or
squint hook. 7 mm corneal internal incision
Alternatively, internal expression with the use of an irrigating vectis is
effective, as long as the nucleus has undergone hydrodissection and partial present pocket tunnel dimension
hydroexpression. The space between the nucleus and the posterior capsule
or cortex is opened with the irrigation function of the vectis. Viscoelastic previous tunnel dimension
material also is useful in defining and holding these spaces and in prevent-
ing posterior capsular and endothelial damage. pocket area 5 mm scleral 1 mm backward extension
external incision of scleral incision
Cortical Washout
The remaining cortex is removed using an irrigation–aspiration technique.
The tip of the irrigation–aspiration cannula (Simcoe) should be kept in Fig. 5.12.4 Pocket tunnel dissection area and borders.
view to avoid unwanted capsular engagement. Difficulties can arise if the
globe pressure causes the anterior chamber to become shallow, closing the
fornix of the capsular bag. Partial closure of the wound and irrigation pro- At both ends of the incision, perpendicular backward continuation inci-
duces a deep and safe anterior chamber within which to work. Cleaning of sions that are 1 mm long are cut. This extension helps accommodate the
the posterior capsule and removal of remaining resistant cortical remnants thickness of the nucleus as it passes through the tunnel. The tunnel is
can be achieved by aspiration using a fine cannula with a polished tip. dissected anteriorly for 3–4 mm (1 mm in the sclera, 1 mm in the limbus
tissue, and 2 mm in the clear cornea). Also, the scleral dissection is
Intraocular Lens Insertion enlarged on both sides of the tunnel beyond the 1 mm backward scleral
Insertion of the IOL is performed under direct vision, with the second incision to make a pocket-like dissection (hence the term “pocket tunnel”
haptic inserted either by circular dialing of the IOL or by direct placement rather than simply “tunnel”). The keratome internal incision is placed par-
with the use of fine forceps.16 When the capsular bag is damaged by com- allel to the curvature of the limbus and is 20% longer than the scleral outer
plication, the sites of IOL placement become the same as those noted in incision. The pocket tunnel facilitates nucleus expression.
the ICCE section. In some circumstances where sufficient capsular support
still exists in spite of capsular damage, posterior chamber implantation can Nucleus Manipulation
be considered (ciliary sulcus placement). Hydrodissection is performed in two separate, anatomically distinct parts
of the lens: the first just under the capsule and the second between the
Mininuc Technique3-6,17 hard-core nucleus and the epinucleus.17 Usually, the hydrodissection under
the capsule partially moves the nucleus to the anterior chamber at the
Anterior Chamber Maintainer 12 o’clock position. If the nucleus does not move anteriorly, the hydro-
An anterior chamber maintainer (ACM) (Fig. 5.12.3) is inserted through dissector cannula is lodged perpendicularly around the equator of the
the clear cornea to the anterior chamber between the 4 o’clock and 8 nucleus and then moved behind the nucleus. The positive IOP in the ante-
o’clock positions, parallel to and near the limbus. The height of the infu- rior segment pushes the posterior capsule away, creating a counterforce to
sion bottle determines the intraocular pressure (IOP). The continuous flow the anterior movement of the hydrodissector cannula while the hard-core
is responsible for the anterior chamber maintenance system. small nucleus is being separated from the epinucleus and the cortex. In
this way, the smallest possible hard-core nucleus is isolated, to be delivered
Capsulorrhexis through the intact capsulorrhexis. At this stage, the nucleus is ready for
The IOP is increased to 40 mm Hg (5.3 kPa). This pressure pushes the expression.
lens backward, which facilitates the formation of capsulorrhexis and pre-
vents accidental radial capsule tear to the periphery.15 A 5- to 6-mm capsu- Nucleus Expression
lorrhexis is preferred. A plastic glide (4 mm wide, 0.2 mm thick) is introduced through the
tunnel under the nucleus. Slight pressure is induced on the glide at the
Sclerocorneal Pocket Tunnel inner limbal area, and the pressure is used to guide the nucleus that is
386 The scleral entrance incision to the sclerocorneal pocket tunnel is frown to be engaged in the sclerocorneal pocket tunnel. This pocket is made to
shaped and 5 mm long and is placed 1 mm behind the limbus (Fig. 5.12.4). accommodate the nucleus at this stage. When the nucleus is well lodged
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Fig. 5.12.5 The
BOX 5.12.1 Complications of Cataract Surgery
nucleus is lodged
in the pocket
Optical power aberrations (sphere and cylinder)
5.12
tunnel and
hydroexpressed Capsule rupture without vitreous loss

out of the eye. Capsule rupture with vitreous loss
The glide is Vitreous capture in incisional wound
located behind the Iris prolapse
nucleus. External Iris capture in incisional wound
expression is Nucleus loss into the posterior segment
performed on Intraocular lens loss into the posterior segment
the glide away Inability to primarily implant intraocular lens because of the above
from the external Glaucoma (aphakic, inflammatory, malignant, pupil block)
incision of the
Corneal endothelial damage
pocket tunnel.
Chronic inflammatory disease
Cystoid macular edema
Retinal detachment
Hypotony
Choroidal edema and effusion
Choroidal hemorrhage
Infection
in the pocket and no leakage of balanced salt solution (BSS) is observed,

slight scleral pressure is induced. The further the nucleus is expressed
(Fig. 5.12.5), the more backward is the location of the scleral pressure.
If the external pressure on the sclera is located near the internal inci- the introduction of anterior capsule staining techniques, advanced grades
sion throughout, an area of leakage is created rather than prevented, of cataract surgery have been performed successfully.18 These techniques
and nucleus expression cannot be completed. The IOP during nucleus continue to prove useful in developing countries, where cost constraints
expression is 40–45 mm Hg (5.3–6.0 kPa), helping hydroexpression of the are a factor in the delivery of sight-saving cataract surgery.19 The results
nucleus. compare favorably with modern phaco surgery.20
Cortex Removal and Intraocular Lens Implantation KEY REFERENCES

Cortex removal and IOL implantation are facilitated by the deep anterior
chamber formation induced by the ACM system. Insertion of the IOL is Assia E, Apple D. Mechanism of radial tear formation and extension after anterior capsulec-
tomy. Ophthalmology 1991;98:432–7.
performed under direct vision, in a similar manner to ECCE, as described Assia EI, Leglar V, Merril JC, et al. Clinicopathologic study of the effect of radial tears and
above. With a smaller incision than those in both ECCE and ICCE, the loop fixation on intraocular lens decentration. Ophthalmology 1993;100:153–8.
techniques of foldable lens insertion, as used in phaco surgery, can be Blumenthal M, Moisseiev J. Anterior chamber maintainer for extracapsular cataract
employed. extraction and intraocular lens implantation. J Cataract Refract Surg 1987;13:204–6.
Blumenthal M, Ashkenazi I, Assia E, et al. Small incision manual extra-capsular cataract
extraction using selective hydrodissection. Ophthalmic Surg 1992;23:699–701.
COMPLICATIONS Gimbel H, Neuhann T. Development, advantages, and methods of the continuous circular
capsulorrhexis. J Cataract Refract Surg 1990;16:31–7.
Complications of cataract surgery tend to be similar among all of the tech- Gogate PM, Kulkarni SR, Krishnaiah S, et al. Safety and efficacy of phacoemulsification com-
niques used, although the incidences of the complications of the different pared with manual small incision cataract surgery by a randomised clinical trial: six
week results. Ophthalmology 2005;112:869–74.
techniques vary (Box 5.12.1). In the majority of cases, these complications Oshika T, Tsuboi S. Astigmatic and refractive stabilisation after cataract surgery. Ophthalmic
occur in relation to capsular damage, with consequential anterior segment Surg 1995;26:309–15.
vitreous and iris involvement, occasionally involving the incision as well. Rao SK, Lam DS. A simple technique for nucleus extractionfrom the capsular bag in manual
Poor technique may lead to inflammatory conditions when lens nucleus small incision cataract surgery. Indian J Ophthalmol 2005;53:214–15.
Sakabe I, Lim SJ, Apple DJ. Anatomical evaluation of the anterior capsular zonular
material has not been completely removed or incisions have been closed free zone in the human crystalline lens [in Japanese]. Nippon Ganka Gakkai Zasshi
poorly. Complications tend to be sequential, increasing the importance of 1995;99:1119–22.
producing a good result at the first surgery. Experience in each technique Storr-Paulsen A, Vangsted P, Perriard A. Long term natural and modified course of surgically
minimizes complications. induced astigmatism after extracapsular cataract extraction. Acta Ophthalmol (Copenh)
1994;72:617–21.
Venkatesh R, Das M, Prasanth S, et al. Manual small incision cataract surgery in eyes with
DISCUSSION white cataracts. Indian J Ophthalmol 2005;53:173–6.
The drive toward smaller-incision surgery has continued, and with new Access the complete reference list online at ExpertConsult.com
techniques of smaller-incision nuclear expression surgery combined with
387
booksmedicos.org
REFERENCES 11. Apple D, Legler VF, Assia EI. Comparison of various capsulectomy techniques in cataract
surgery. An experimental study [in German]. Ophthalmologe 1992;89:301–4.
1. Oshika T, Tsuboi S. Astigmatic and refractive stabilisation after cataract surgery. Ophthal-
mic Surg 1995;26:309–15.
12. Gimbel H, Neuhann T. Development, advantages, and methods of the continuous circu-
lar capsulorrhexis. J Cataract Refract Surg 1990;16:31–7.
5.12
2. Stallard HB. Eye surgery. 1st ed. Bristol: Wright; 1946. p. 263. 13. Blumenthal M. Manual ECCE, the present state of the art. Klin Monatsblad Augenheilkd
1994;205:266–70.

3. Blumenthal M. Manual ECCE, the present state of the art. Klin Monatsbl Augenheilkd
1994;205:266–70. 14. Sakabe I, Lim SJ, Apple DJ. Anatomical evaluation of the anterior capsular zonular
4. Blumenthal M, Moisseiev J. Anterior chamber maintainer for extracapsular cataract free zone in the human crystalline lens [in Japanese]. Nippon Ganka Gakkai Zasshi
extraction and intraocular lens implantation. J Cataract Refract Surg 1987;13:204–6. 1995;99:1119–22.
5. Blumenthal M, Cahane M, Ashkenazi I. Direct intraoperative continuous monitoring of 15. Assia E, Apple D. Mechanism of radial tear formation and extension after anterior cap-
intraocular pressure. Ophthalmic Surg 1992;23:132–4. sulectomy. Ophthalmology 1991;98:432–7.
6. Blumenthal M. Manual nucleus expression through a small incision. In: Yanoff M, 16. Assia EI, Leglar V, Merril JC, et al. Clinicopathologic study of the effect of radial tears and
Duker JS, editors. Ophthalmology. 1st ed. London: Mosby; 1999. loop fixation on intraocular lens decentration. Ophthalmology 1993;100:153–8.
7. Storr-Paulsen A, Vangsted P, Perriard A. Long term natural and modified course of 17. Blumenthal M, Ashkenazi I, Assia E, et al. Small incision manual extra-capsular cataract
surgically induced astigmatism after extracapsular cataract extraction. Acta Ophthalmol extraction using selective hydrodissection. Ophthalmic Surg 1992;23:699–701.
(Copenh) 1994;72:617–21. 18. Venkatesh R, Das M, Prasanth S, et al. Manual small incision cataract surgeryin eyes
8. Howes G. Control of astigmatism in cataract surgery. Presentation at 1986 Annual with white cataracts. Indian J Ophthalmol 2005;53:173–6.
Meeting of the Ophthalmological Society of South Africa (P.O. Box 339, Bloemfontein 19. Rao SK, Lam DS. A simple technique for nucleus extraction from the capsular bag in
9300, South Africa). manual small incision cataract surgery. Indian J Ophthalmol 2005;53:214–15.
9. Koch P. Incisional gape. Mastering phacoemulsification. 4th ed. Thorofare: Slack; 1994. 20. Gogate PM, Kulkarni SR, Krishnaiah S, et al. Safety and efficacy of phacoemulsification
p. 23–4. compared with manual small incision cataract surgery by a randomised clinical trial: six
10. Roper-Hall MJ. Intra-capsular cataract extraction. In: Yanoff M, Duker JS, editors. Oph- week results. Ophthalmology 2005;112:869–74.
thalmology. 1st ed. London: Mosby; 1999.
387.e1
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Part 5 The Lens

Combined Procedures
Saurabh Ghosh, David H.W. Steel, Nicholas K. Wride 5.13
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Definition: Cataract surgery simultaneously combined with other Trabeculectomy and Cataract Surgery
ocular surgery. Phacoemulsification (“phaco”) combined with glaucoma surgery proba-
bly produces better IOP control with fewer complications compared with
manual extraction plus glaucoma surgery, although there are no large
well-controlled, randomized studies on this.4,6,7 However, IOP reduction
and subsequent control seem to be less effective with combined surgery
than with trabeculectomy alone—possibly as a result of more prolonged
Key Features breakdown of the blood–aqueous barrier associated with cataract surgery.8
• Combined surgery for glaucoma and cataract is a valid option in When combined surgery is considered, a single-site approach may be
management. less time consuming, but a two-site approach allows the surgeon to use
• Minimally invasive glaucoma surgery (MIGS) frequently is combined the familiar temporal clear corneal approach to the cataract. There is
with cataract surgery. ongoing debate as to whether a single-site or two-site approach gives better
• Descemet’s stripping automated endothelial keratoplasty (DSAEK), control, and several studies have reported no significant difference in the
rather than penetrating keratoplasty, combined with cataract surgery IOP-lowering effect.
is now the treatment of choice for coexisting cataract and corneal
endothelial disease.
• Refractive outcome from combined DSAEK–Descemet’s membrane Nonpenetrating Glaucoma Surgery and Cataract
endothelial keratoplasty (DMEK) and cataract removal is much more Nonpenetrating glaucoma surgery (deep sclerectomy with or without vis-
predictable than with penetrating keratoplasty. cocanaloplasty) can be combined with phaco. Some studies have reported
• Combined phacovitrectomy, rather than sequential surgery, is used that these techniques are as effective as trabeculectomy when combined
increasingly for some conditions, such as macular hole and pucker, with phaco,9–11 but longer-term studies are required to support this claim.
even when pre-existing lens opacities are minimal, especially in those
older than ages 50–60 years.
Minimally Invasive Glaucoma Surgery
MIGS is potentially less traumatic and has a higher safety profile com-
pared with conventional surgery. These techniques should involve an ab
interno conjunctiva-preserving approach and consequently produce a
INTRODUCTION modest reduction in IOP. Often combined with phaco, in which case it is
termed “phacoplus,” the aim of surgery is to reduce the need for topical
Cataract develops mainly as a response to aging but also as a result of medications in patients with mild-to-moderate glaucoma. Most studies
chemical or biological insults to the eye. The conditions that are commonly performed in patients who undergo MIGS in combination with phaco.
associated with cataract and that lend themselves to combined surgical Because of the large number of patients in this group, the potential market
approaches are glaucoma, corneal opacity, effects of penetrating trauma, for these products is large. Few trials of sufficient quality exist at present
and vitreoretinal disorders. to make firm recommendations. Reviews of the literature are cautious at
best.12,13 These treatments do offer alternatives to patients with glaucoma,
and if studies demonstrate clinical effectiveness over the long term, these
COMBINED GLAUCOMA SURGERY techniques may become more universally adopted.
Overview
The prevalence of significant cataract in people ages 65–74 years is greater
Aqueous Shunts
than 20%, and the prevalence of chronic glaucoma is about 4.5% in people Aqueous shunts, such as the Baerveldt or Ahmed valve, are indicated in
over age 70 years.1,2 The 5-year incidence of nucleus cataract in people the treatment of more complex refractory glaucoma cases where surgery is
with open-angle glaucoma and older than 50 years is estimated to be 20%. required. Phaco can be performed effectively at the time of shunt surgery,
Patient adherence to treatment with topical glaucoma medication, the although the decision to combine the two procedures has to be made on a
most common form of glaucoma treatment, is low.3 case-by-case basis because only small retrospective case series reports are
For these reasons, combining cataract surgery and glaucoma surgery available.14
in a single operation appears to be a valid management option. There has
been a rapid expansion in recent years in the number of devices, implants, Outcomes
and techniques that are less invasive and are safer than those used in tradi-
tional glaucoma surgery. In minimally invasive glaucoma surgery (MIGS), Phaco surgery can be incorporated into many glaucoma procedures. IOP
these techniques are increasingly being combined with cataract surgery. reduction following phacotrabeculectomy is greater than that following
An important consideration is that cataract surgery alone results in an cataract surgery alone, although not as great as following trabeculectomy
intraocular pressure (IOP) drop of up to 5 mm Hg in patients with glau- alone.15 Increasingly, the role of MIGS may offer patients with cataract and
388 coma.4 Complications after glaucoma surgery may increase the risk of an early glaucoma the option not to use topical medication following com-
adverse outcome.5 bined surgery, although further study on this is required.
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Fig. 5.13.1 (A) Patient with combined corneal
and lens opacities. This degree of corneal
opacity demands an “open sky” approach to 5.13
cataract removal. (B) Here, an iris expander
device and an “open sky” technique
Combined Procedures
of cataract extraction are used. (C) “Open sky”
cataract extraction performed. (D) Combined
cataract extraction with intraocular lens (IOL)
implantation and penetrating keratoplasty.
A B
C D
LENS SURGERY COMBINED the range of 25%.19 Multiple reports have suggested that combined cataract
surgery and endothelial grafts (DSAEK and DMEK) were not associated
WITH KERATOPLASTY with any increased complication rate or endothelial cell loss.21,22 Therefore,
Historical Review an argument exists for not subjecting such a cornea to multiple surger-
ies. The decision in individual cases depends on the balance of the risks
Anterior or posterior lamellar corneal surgery is now much more common and benefits. One key decision for the clinician is whether it is possible
compared with penetrating keratoplasty (PKP). Eyes that require kerato- to determine if the main barrier to good vision is the cornea or the lens.
plasty often have an associated increased risk of cataract because of the Another is the likelihood of development of frank decompensation if ker-
underlying pathology (Fig. 5.13.1); this includes corneal perforation as a atoplasty is not carried out. A combined approach may be the best choice
result of trauma or infection. Also, age-related corneal degeneration, such in either circumstance.
as Fuchs’ corneal degeneration, often coexists with age-related cataract. Choice of IOL depends on individual circumstances. In the event that
These factors resulted in the development of a variety of techniques for cataract surgery is part of the primary procedure, a standard IOL can be
combined primary cataract surgery and keratoplasty (“triple procedure”), or placed in the capsular bag. If sufficient capsular and/or zonular support
IOL exchange combined with keratoplasty. Combined cataract surgery and exists, then the best option is a capsule or sulcus-placed posterior chamber
lamellar corneal surgery is often referred to as the “new triple procedure.” IOL. If adequate support is not available, then the choice is a posterior
chamber IOL, either transclerally sutured or iris sutured.23,24
Biometry and IOL power calculation is problematic if PKP or lamel-
Surgical Options lar keratoplasty is combined with cataract surgery. The refractive impact
A retrospective analysis of eyes that underwent PKP for Fuchs’ endothe- of DSEK, however, is reasonably consistent, with a hyperopic shift of
lial dystrophy, with an average follow-up period of 6 years,16 showed an 0.75–1.5 D,25 although this is much less with thinner grafts. With the use
incidence of significant cataract in 75% of patients over 60 years of age. In of DMEK, where little or no stroma is transplanted, the surgery causes
those who subsequently required lens surgery, 13% lost transplant clarity even less change in the refractive power.26
postoperatively. Two recent reports following Descemet’s stripping endo-
thelial keratoplasty (DSEK) showed the presence of cataract in 40% at 1 Specific Techniques
year in one study and cataract extraction rate of 31% and 55% at years 1
and 3, respectively, in patients over 50 years of age.17,18 Similarly, studies The techniques of keratoplasty are dealt with elsewhere. A significant
following Descemet’s membrane epithelial keratoplasty (DMEK) showed a recent trend is toward either anterior or posterior lamellar keratoplasty,
76% progression of cataract.19 Following DSEK/DSAEK the endothelial cell and significant benefit is obtained by the cataract surgeon in these
loss rate can be as high as 56% in the first year,20 although with standard- closed-chamber techniques. The ongoing audit of keratoplasty conducted
ized technique, the endothelial cell loss has been reduced to less than 35%. by the Corneal Graft Registry of the National Health Service (NHS) – Blood 389
In patients undergoing DMEK, the endothelial cell count loss at 1 year is in and Tissue, in the United Kingdom, has shown that during 2010, 26%
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of the surgeries performed were deep posterior lamellar keratoplasty, 15% Phacovitrectomy in these situations offers a number of advantages over
5 were deep anterior lamellar keratoplasty (DALK), and 56% were DSEK,
with the number of endothelial keratoplasty procedures increasing.
Phaco surgery can be difficult because of the poor visibility as a result
vitrectomy followed by subsequent cataract surgery in two steps. Only one
operation is needed, avoiding the surgical difficulties and morbidity asso-
ciated with cataract extraction following vitrectomy. These include small
of the corneal disease. Selected cases with stromal opacity (see Fig. 5.13.1A) pupil size, deep anterior chamber with reverse pupil block, and increased
The Lens
may be suitable for a routine phaco procedure after DALK and use of an mobility of the lens–iris diaphragm with an increased risk of posterior
ophthalmic viscosurgical device in the bed to restore anterior chamber capsule tears.
and capsule visibility.27 In cases of endothelial disease where the stromal Combining phaco and vitrectomy also improves postoperative retinal
clarity is reasonable, a combined phaco with DSEK/DMEK is now the pre- visualization, allowing accurate retinal assessment and treatment, and
ferred technique (Video 5.13.1). This offers much quicker visual rehabili- visual recovery is not delayed by subsequent cataract development. Pha-
See clip:
5.13.1 tation and more predictable refractive outcome than combined PKP and covitrectomy allows more complete anterior vitrectomy and access to the
phaco.28 anterior retina and vitreous base without the risks associated with lens
Such an approach is not always possible, and “open sky” removal of touch.34
the lens may be required. The altered anterior-chamber and lens–iris
diaphragm dynamics, abnormal light reflexes present in the “open sky” Disadvantages
situation (see Fig. 5.13.1),29 and difficulty in controlling the anterior and
posterior capsule increases the risk of surgical complications. Capsulor- Macular hole and macular pucker are the most common clinical scenar-
rhexis can be difficult because of decreased anterior pressure caused by the ios where “nonessential,” optional phacovitrectomy is considered because
“open sky.” Careful use of scissors can be of help. The nucleus is expressed of the high frequency of cataract formation after surgery in these cases
manually after thorough hydrodissection. Manual irrigation–aspiration of in the age group affected. However, not all patients are ideal candidates
the cortex is carried out with the use of a cannula, such as the Simcoe for phacovitrectomy. For some patients, vitrectomy, followed by sequential
cannula. cataract surgery, if needed, is a better option. In patients with diabetes,
When specific endothelial keratoplasty techniques are combined with lens opacities following vitrectomy are paradoxically less common than
cataract surgery, certain additional risks, such as pupil abnormalities and in those without diabetes.35 Among patients with diabetes, there seems
lens subluxation or dislocation, arise either because of the effect of the to be a higher incidence of posterior synechiae, posterior capsule opacity,
air tamponade or anterior chamber depth modulation needed in these and inflammatory anterior uveitis following phacovitrectomy, especially if
surgeries. retinopathy is very active; a large amount of intraoperative laser is needed,
or gas tamponade is used.36 Therefore, although phacovitrectomy is fre-
Complications quently carried out successfully in patients with diabetes who have sig-
nificant lens opacities,37 these patients are not always ideal candidates for
Apart from the possible inherent complications of keratoplasty, the com- phacovitrectomy.
bined procedure carries an increased risk of cystoid macular edema. Other The absence of accurate preoperative biometry secondary to vitreoreti-
complications of combined procedures are the variability of refractive nal pathology, with variable axial length measurements and fixation, also
outcome and the delayed visual rehabilitation compared with straightfor- could be regarded as a relative contraindication to nonessential phacovit-
ward cataract surgery. Weighed against this, however, is the additional risk rectomy. Fellow-eye measurements can be used, but incorrect axial length
of graft failure inherent in the alternative of a two-stage procedure. estimations will result in errors in IOL choice and potentially significant
unplanned ametropia. Similarly, scleral buckling and use of silicone oil
Outcomes alter the final refractive outcome in an unpredictable way. Phacovitrectomy
in eyes with elevated maculae, as occurs with epiretinal membrane and
There are currently no definitive studies providing hard evidence of the macular holes, has been reported to be associated with a myopic shift in
benefit of one approach over another, but with the development of stan- the planned refraction. This is most likely to be related to measuring a
dardized techniques of corneal graft surgery, the new triple procedure short axial length preoperatively with the use of ultrasonography, but it also
shows very similar results to the two-stage approach. may be related to gas-induced, anterior chamber depth changes.38 The use
of partial coherence interferometry (PCI) to measure axial length (which
uses the retinal pigment epithelium [RPE] reflection, rather than the inner
COMBINED PHACOVITRECTOMY retinal surface) can overcome some of these errors.39 However, if PCI
Introduction is used in eyes with thickened maculae, the graphical display should be
inspected. If the inner retinal reflectivity is high (e.g., with a dense epireti-
Both age-related cataract and secondary cataract are a common feature in nal membrane), the device can occasionally interpret this reflective peak as
many patients with vitreoretinal disorders. The widespread acceptance of the RPE. In this situation, the graph cursor can sometimes be adjusted to
phaco in the late 1980s and 1990s and the availability of combined phaco the lower RPE peak manually.40 Details on adjustment and other potential
and vitrectomy machines with single cassettes offered the possibility of errors in measurement can be found in manufacturers’ device manuals. If
efficient combined surgery, with secure wound construction and stable axial length is measured by using ultrasonography, aiming approximately
intracapsular IOL fixation. Although pars plana fragmatome lensectomy 0.5 dioptres hypermetropic or correcting for the preoperative macula thick-
is still performed in specific scenarios, combined phaco with IOL implant ening based on optical coherence tomography (OCT) measurements, can
and vitrectomy (phacovitrectomy) is now an established technique to deal reduce the effect.38,41
with concomitant cataract when vitrectomy is performed. Studies have Similarly, with macula involving retinal detachment, care needs to be
shown that combined phacovitrectomy can be carried out with low mor- taken to ensure that the true axial length is measured rather than from
bidity and good results.30 As confidence with the technique has grown, the detached retina. Sometimes, the scan cursor can be manually changed
indications for combined surgery have expanded. to the RPE peak with optical biometry, but if any doubt exists, the true
axial length should be measured by using combined vector-A/B-scan
biometry.42,43
Indications and Advantages Over Sequential
Noncombined Surgery Specific Techniques
When first introduced, phacovitrectomy was reserved for cases where Lens surgery can be carried out successfully via either a clear corneal inci-
cataract precluded an adequate fundal view during vitrectomy surgery. sion (CCI) or scleral tunnel incision. If valved sclerostomy ports are used,
However, phacovitrectomy now is increasingly used when lens opacities they can be inserted prior to phaco to avoid the risk of wound leak during
are mild or even nonexistent, particularly in patients over 50–60 years of later insertion. If nonvalved ports are used, then all but the infusion port
age.31 In these cases, cataract surgery is not necessary to successfully com- may be more optimally placed after phaco to avoid loss of vitreous cavity
plete the vitrectomy but is done to avoid the need for subsequent cataract fluid and exacerbated lens iris diaphragm retropulsion syndrome, espe-
surgery and hasten visual recovery. Vitrectomy surgery, particularly in the cially in already vitrectomized eyes.44 If a corneal incision is used, then
age group of over 50 years, often results in the development of significant the tunnel should be kept relatively short to avoid interference with the
390 lens opacities, especially if long-acting gases are used, as in macular hole posterior segment view. Similarly, temporal incisions are less axial and less
surgery.32,33 likely to interfere with the fundal view than superior ones. A suture can be
booksmedicos.org
used to secure the wound to avoid wound leak during scleral indentation minimal lens opacities before they undergo, for example, macular hole
See clip:
5.13.2
(Video 5.13.2).
Posterior segment intraocular gas pressure can cause significant prob-
surgery, to avoid delaying visual recovery secondary to postoperative
cataract. 5.13
lems in phacovitrectomy. Anterior displacement of the optic of the IOL
by posterior gas pressure can lead to optic capture by the iris. Similarly, KEY REFERENCES
Combined Procedures
displacement of the anterior capsule onto the iris can lead to postopera-
Chaudhry NA, Cohen KA, Flynn HW Jr, et al. Combined pars plana vitrectomy and lens
tive posterior synechiae formation. There are some possible strategies to management in complex vitreoretinal disease. Semin Ophthalmol 2003;18:132–41.
reduce the incidence of these problems. Sustained postoperative dilatation Chaurasia S, Price FW Jr, Gunderson L, et al. Descemet’s membrane endothelial kerato-
should be avoided, but some clinicians use short-acting mydriatics to dis- plasty: clinical results of single versus triple procedures (combined with cataract
courage synechiae formation. Capsulorrhexis size should be large enough surgery). Ophthalmology 2014;121(2):454–8.
Cherfan GM, Michels RG, de Bustros S, et al. Nuclear sclerotic cataract after vitrectomy
to avoid problems with rhexis phimosis but should aim to just overlap for idiopathic epiretinal membranes causing macular pucker. Am J Ophthalmol
the optic edges by 0.5 mm to hold the optic posteriorly. Capsulorrhexis 1991;111:434–8.
can occasionally be difficult in eyes with vitreous hemorrhage and no red Friedman DS, Jampel HD, Lubomski LH, et al. Surgical strategies for coexisting glaucoma
reflex. In these cases, capsule staining and/or use of the endoillumina- and cataract: an evidence-based update. Ophthalmology 2002;109:1902–13.
tor in the anterior chamber can facilitate visualization. Alternatively, some Gedde SJ, Herndon LW, Brandt JD, et al. Postoperative complications in the Tube Versus
Trabeculectomy (TVT) study during five years of follow-up. Am J Ophthalmol
vitrectomy can be carried out first, if possible, to improve the red reflex 2012;153(5):804–14.
before rhexis is undertaken. IOL optic diameter should be large to reduce Jones SM, Fajgenbaum MA, Hollick EJ. Endothelial cell loss and complication rates with
the risk of optic capture. Lenses with broad haptic fixation offer the advan- combined Descemets stripping endothelial keratoplasty and cataract surgery in a UK
tages of avoiding optic capture and superior IOL centration. centre. Eye (Lond) 2015;29(5):675–80.
Kovács I, Ferencz M, Nemes J, et al. Intraocular lens power calculation for combined cata-
IOL insertion can be performed either before or after vitrectomy is ract surgery, vitrectomy and peeling of epiretinal membranes for macular oedema. Acta
completed. Peripheral vitreous base view can be impaired in pseudophakic Ophthalmol Scand 2007;85:88–91.
eyes, and there is an argument for withholding IOL insertion until after Lochhead J, Casson RJ, Salmon JF. Long term effect on intraocular pressure of phacotrabe-
the posterior segment surgery has been completed. IOLs with rounded, culectomy compared to trabeculectomy. Br J Ophthalmol 2003;87:850–2.
Manvikar SR, Allen D, Steel DH. Optical biometry in combined phacovitrectomy. J Cataract
tapering edges and a gradual reduction in optic power offer advantages Refract Surg 2009;35:64–9.
for “trans-IOL” vitrectomy by avoiding the occurrence of “jack-in-the-box” Patel D, Rahman R, Kumarasamy M. Accuracy of intraocular lens power estimation in eyes
prismatic effects when viewing the posterior segment through the edge having phacovitrectomy for macular holes. J Cataract Refract Surg 2007;33:1760–2.
of the IOL. Posterior capsule opacity appears to be more common after Payant JA, Gordon LW, VanderZwaag TO. Cataract formation following corneal transplanta-
tion in eyes with Fuchs’ endothelial dystrophy. Cornea 1990;9:286–9.
phacovitrectomy, and primary capsulectomy with the vitrectomy cutter can Price MO, Giebel AW, Fairchild KM, et al. Descemet’s membrane endothelial keratoplasty:
be performed to avoid another threat to delayed visual recovery.45 Acrylic prospective multicenter study of visual and refractive outcomes and endothelial survival.
folding IOLs have several advantages over silicone IOLs with less IOL con- Ophthalmology 2009;116:2361–8.
densation during fluid–air exchange and also reduced possibility of sili- Price MO, Price DA, Fairchild KM, et al. Rate and risk factors for cataract formation
and extraction after Descemet stripping endothelial keratoplasty. Br J Ophthalmol
cone oil adherence if oil is subsequently used. 2010;94:1468–71.
Zhang ML, Hirunyachote P, Jampel H. Combined surgery versus cataract surgery alone for
Conclusion eyes with cataract and glaucoma. Cochrane Database Syst Rev 2015;(7):CD008671.
Phacovitrectomy is an effective technique to allow combined cataract Access the complete reference list online at ExpertConsult.com
extraction and vitrectomy. Its use is now being extended to patients with
391
booksmedicos.org
REFERENCES 23. Hardten DR, Holland EJ, Doughman DJ, et al. Early postkeratoplasty astigmatism follow-
ing placement of anterior chamber lenses and transclerally sutured posterior chamber
1. Mitchell P, Cumming RG, Attebo K, et al. Prevalence of cataract in Australia: the Blue
Mountains Eye Study. Ophthalmology 1997;104:581–8.
lenses. CLAO J 1992;18:108–11.
24. Michaeli A, Assia EI. Scleral and iris fixation of posterior chamber lenses in the absence
5.13
2. Chandrasekaran S, Cumming RG, Rochtchina E, et al. Associations between elevated of capsular support. Curr Opin Ophthalmol 2005;16:57–60.
25. Oenig SB, Covert DJ, Dupps WJ Jr, et al. Visual acuity, refractive error, and endothelial
Combined Procedures
intraocular pressure and glaucoma, use of glaucoma medications, and 5-year incident
cataract: the Blue Mountains Eye Study. Ophthalmology 2006;113:417–24. cell density six months after Descemet stripping and automated endothelial keratoplasty
3. Okeke CO, Quigley HA, Jampel HD, et al. Adherence with topical glaucoma med- (DSAEK). Cornea 2007;26:670–4.
ication monitored electronically the Travatan Dosing Aid study. Ophthalmology 26. Price MO, Giebel AW, Fairchild KM, et al. Descemet’s membrane endothelial kerato-
2009;116(2):191–9. plasty: prospective multicenter study of visual and refractive outcomes and endothelial
4. Friedman DS, Jampel HD, Lubomski LH, et al. Surgical strategies for coexisting glau- survival. Ophthalmology 2009;116:2361–8.
coma and cataract: an evidence-based update. Ophthalmology 2002;109:1902–13. 27. Ardjomand N, Fellner P, Moray M, et al. Lamellar corneal dissection for visualization of
5. Gedde SJ, Herndon LW, Brandt JD, et al. Postoperative complications in the Tube the anterior chamber before triple procedure. Eye (Lond) 2007;21:1151–4.
Versus Trabeculectomy (TVT) study during five years of follow-up. Am J Ophthalmol 28. Covert DJ, Koenig SB. New triple procedure: Descemet’s stripping and automated endo-
2012;153(5):804–14. thelial keratoplasty combined with phacoemulsification and intraocular lens implanta-
6. Shingleton BJ, Jacobson LM, Kuperwaser MC. Comparison of combined cataract and tion. Ophthalmology 2007;114:1272–7.
glaucoma surgery using planned extracapsular and phacoemulsification techniques. 29. Groden LC. Continuous tear capsulotomy and phacoemulsification cataract extraction
Ophthalmic Surg Lasers 1995;26:414–19. with penetrating keratoplasty. Refract Corneal Surg 1990;6:458–9.
7. Wishart PK, Austin MW. Combined cataract extraction and trabeculectomy: phacoemul- 30. Chaudhry NA, Cohen KA, Flynn HW Jr, et al. Combined pars plana vitrectomy and lens
sification compared with extracapsular technique. Ophthalmic Surg 1993;24:814–21. management in complex vitreoretinal disease. Semin Ophthalmol 2003;18:132–41.
8. Siriwardena D, Kotecha A, Minassian D, et al. Anterior chamber flare after trabeculec- 31. Ling R, Simcock P, McCoombes J, et al. Presbyopic phacovitrectomy. Br J Ophthalmol
tomy and after phacoemulsification. Br J Ophthalmol 2000;84:1056–7. 2003;87:1333–5.
9. Gimbel HV, Anderson Penno EE, Ferensowicz M. Combined cataract surgery, intraocular 32. Cherfan GM, Michels RG, de Bustros S, et al. Nuclear sclerotic cataract after vitrec-
lens implantation and viscocanalostomy. J Cataract Refract Surg 1999;25:1370–5. tomy for idiopathic epiretinal membranes causing macular pucker. Am J Ophthalmol
10. Gianoli F, Schnyder CC, Bovey E, et al. Combined surgery for cataract and glaucoma: 1991;111:434–8.
phacoemulsification and deep sclerectomy compared with phacoemulsification and trab- 33. Thompson JT. The role of patient age and intraocular gas use in cataract progres-
eculectomy. J Cataract Refract Surg 1999;25:340–6. sion after vitrectomy for macular holes and epiretinal membranes. Am J Ophthalmol
11. Carassa RG, Bettin P, Fiori M, et al. Viscocanalostomy versus trabeculectomy in white 2004;137:250–7.
adults affected by open-angle glaucoma: a 2-year randomized, controlled trial. Ophthal- 34. Elhousseini Z, Lee E, Williamson TH. Incidence of lens touch during pars plana vitrec-
mology 2003;110:882–7. tomy and outcomes from subsequent cataract surgery. Retina 2016;36(4):825–9.
12. Zhang ML, Hirunyachote P, Jampel H. Combined surgery versus cataract surgery alone 35. Smiddy WE, Feuer W. Incidence of cataract extraction after diabetic vitrectomy. Retina
for eyes with cataract and glaucoma. Cochrane Database Syst Rev 2015;(7):CD008671. 2004;24:574–81.
13. Richter GM, Coleman AL. Minimally invasive glaucoma surgery: current status and 36. Shinoda K, O’Hira A, Ishida S, et al. Posterior synechia of the iris after combined pars
future prospects. Clin Ophthalmol 2016;10:189–206. plana vitrectomy, phacoemulsification, and intraocular lens implantation. Jpn J Ophthal-
14. Valenzuela F, Browne A, Srur M, et al. Combined phacoemulsification and Ahmed mol 2001;45:276–80.
glaucoma drainage implant surgery for patients with refractory glaucoma and cataract. J 37. Lahey JM, Francis RR, Kearney JJ. Combining phacoemulsification with pars plana vit-
Glaucoma 2016;25(2):162–6. rectomy in patients with proliferative diabetic retinopathy: a series of 223 cases. Ophthal-
15. Lochhead J, Casson RJ, Salmon JF. Long term effect on intraocular pressure of phacotra- mology 2003;110:1335–9.
beculectomy compared to trabeculectomy. Br J Ophthalmol 2003;87:850–2. 38. Patel D, Rahman R, Kumarasamy M. Accuracy of intraocular lens power estimation in
16. Payant JA, Gordon LW, VanderZwaag TO. Cataract formation following corneal trans- eyes having phacovitrectomy for macular holes. J Cataract Refract Surg 2007;33:1760–2.
plantation in eyes with Fuchs’ endothelial dystrophy. Cornea 1990;9:286–9. 39. Manvikar SR, Allen D, Steel DH. Optical biometry in combined phacovitrectomy. J Cata-
17. Tsui JY, Goins KM, Sutphin JE, et al. Phakic descemet stripping automated endothe- ract Refract Surg 2009;35:64–9.
lial keratoplasty: prevalence and prognostic impact of postoperative cataracts. Cornea 40. Steel D. Refractive outcome and possible errors following combined phaco-vitrectomy.
2011;30:291–5. In: Lois N, Wong D, editors. Complications of Vitreo-Retinal Surgery. Philadelphia: Lip-
18. Price MO, Price DA, Fairchild KM, et al. Rate and risk factors for cataract formation pincott Williams & Wilkins; 2013. p. 260–6.
and extraction after Descemet stripping endothelial keratoplasty. Br J Ophthalmol 41. Kovács I, Ferencz M, Nemes J, et al. Intraocular lens power calculation for combined
2010;94:1468–71. cataract surgery, vitrectomy and peeling of epiretinal membranes for macular oedema.
19. Burkhart ZN, Feng MT, Price FW Jr, et al. One-year outcomes in eyes remaining Acta Ophthalmol Scand 2007;85:88–91.
phakic after Descemet membrane endothelial keratoplasty. J Cataract Refract Surg 42. Rahman R, Kolb S, Bong CX, et al. Accuracy of user-adjusted axial length measurements
2014;40(3):430–4. with optical biometry in eyes having combined phacovitrectomy for macular-off rheg-
20. Dooren BT, Saelens IE, Bleyen I, et al. Endothelial cell decay after descemet’s stripping matogenous retinal detachment. J Cataract Refract Surg 2016;42:1009–14.
automated endothelial keratoplasty and top hat penetrating keratoplasty. Invest Ophthal- 43. Abou-Shousha M, Helaly HA, Osman IM. The accuracy of axial length measurements in
mol Vis Sci 2011;52:9226–31. cases of macula-off retinal detachment. Can J Ophthalmol 2016;51:108–12.
21. Jones SM, Fajgenbaum MA, Hollick EJ. Endothelial cell loss and complication rates with 44. Ghosh S, Best K, Steel DH. Lens-iris diaphragm retropulsion syndrome during
combined Descemets stripping endothelial keratoplasty and cataract surgery in a UK phacoemulsification in vitrectomized eyes. J Cataract Refract Surg 2013;39:1852–8.
centre. Eye (Lond) 2015;29(5):675–80. 45. Jun Z, Pavlovic S, Jacobi KW. Results of combined vitreoretinal surgery and phacoemul-
22. Chaurasia S, Price FW Jr, Gunderson L, et al. Descemet’s membrane endothelial kerato- sification with intraocular lens implantation. Clin Exp Ophthalmol 2001;29:307–11.
plasty: clinical results of single versus triple procedures (combined with cataract surgery).
Ophthalmology 2014;121(2):454–8.
391.e1
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Part 5 The Lens

Cataract Surgery in Complex Eyes

Jesse M. Vislisel, Gary S. Schwartz, Stephen S. Lane 5.14
a crossing fashion to create countertraction and assist with initiation of the
Definition: Cataract surgery in eyes with other pathologies. rhexis. After the capsulorrhexis is begun, pseudo-elasticity of the capsule
may be experienced because of the reduction in counterresistance offered
by the zonules to oppose the tearing forces applied by the surgeon.3 In
Key Features cases of marked zonular loss, capsular hooks or retractors may be utilized
• Zonular integrity is evaluated at the slit lamp preoperatively by to stabilize the bag and facilitate completion of the rhexis.4 If these are
assessing for lens decentration, phacodonesis, and iridodonesis. unavailable, nylon iris fixation hooks can be used in a similar manner,
• Uveitis may complicate cataract surgery as a result of poor dilation, although the tips may tend to inadvertently tear the capsule. After starting
posterior synechiae, zonular laxity, and exaggerated postoperative the rhexis, the surgeon gently retracts the capsular edge with hooks in
inflammation. the direction of the area of dehiscence. After the rhexis is completed, the
• Preoperative endothelial cell density less than 1000/mm2, central hooks may be left in place while hydrodissection and phacoemulsification
corneal thickness greater than 640 µm, and corneal epithelial edema (“phaco”) are performed. A large rhexis (at least 5.5 mm in diameter) is
indicate increased risk for postoperative corneal decompensation in made to facilitate removal of nuclear fragments and prevent postopera-
patients with Fuchs’ corneal dystrophy. tive anterior capsular phimosis. Careful and complete hydrodissection is
• Femtosecond laser-assisted cataract surgery may have distinct performed so that the nucleus rotates easily within the capsular bag with
advantages for certain complex eyes because of ease in minimal zonular stress. Bimanual rotation may be utilized to further
capsulorrhexis creation, assistance with nucleofractis, and reduced reduce zonular stress by simultaneously rotating the nucleus using two
postoperative endothelial cell loss. instruments located 180° apart.
A horizontal chop technique is preferable for nuclear disassembly in
situations of zonular laxity because it causes minimal strain on the zonular
Associated Features fibers. If grooving is performed within the capsular bag, the main incision
• A large capsulorrhexis (≥ 5.5 mm in diameter) facilitates removal should be created in a position so that the phaco needle carves toward the
of nuclear fragments and reduces postoperative anterior capsular area of dehiscence to prevent induction of forces that extend the area of
phimosis in the setting of zonular laxity. zonular loss. If the surgeon feels that zonular support is inadequate for
• Areas of weakened zonules may be stabilized intraoperatively and intracapsular manipulation, the nucleus may be prolapsed from the capsu-
postoperatively by using capsular hooks, capsular tension rings, and lar bag, and phaco can be performed within the anterior chamber.
capsular tension segments. Once the nucleus and epinucleus have been removed, cortical cleanup
must be performed delicately. Stripping the cortex in tangential fashion
INTRODUCTION with forces perpendicular to the radial zonular fibers has been shown to
exert reduced force on the zonule.5 With the nucleus removed, the capsu-
Modern cataract surgery can normally be performed with minimal anesthe- lar bag is floppier in nature, and the area of the dehiscence may be drawn
sia, manipulation of ocular tissue, and postoperative morbidity. Although toward the aspiration tip. In such cases, the surgeon may have more
most surgeons perform routine surgery using the same basic techniques control when the irrigation and aspiration ports are separated to perform
for all patients, in some circumstances, the surgical technique must be bimanual irrigation–aspiration. In this way, the irrigation tip can be used
altered because of specific preoperative conditions in complex eyes. to hold back the capsular fornix of the area of dehiscence while the aspira-
tion tip safely removes cortex.
ZONULAR INSTABILITY After complete removal of the cataract, an appropriate IOL must be
selected. Whenever possible, the IOL is placed within the capsular bag.
When cataract surgery and intraocular lens (IOL) placement are Intracapsular IOL placement without a capsular tension segment or ring
planned for a patient with history of ocular trauma, intraocular surgery, may be appropriate for patients who have small areas of zonular dehis-
pseudo-exfoliation syndrome, or systemic conditions associated with cence. In such cases, a three-piece posterior-chamber intraocular lens
zonulopathy (e.g., Marfan’s syndrome), it is important for the surgeon to (PCL) should be placed so that one of the haptics is oriented toward the
evaluate the status of the zonules. Zonular instability increases the risk area of dehiscence, thus extending the bag in that direction (Fig. 5.14.1).
of intraoperative complications and the likelihood of IOL subluxation If the haptics are rotated so that they are 90° away from the dehiscence,
postoperatively.1,2 the optic is more likely to decenter in a direction away from the area of
Zonular integrity may be evaluated at the slit lamp preoperatively by dehiscence.
looking for the presence of lens decentration, phacodonesis, or focal irido- Mild, diffuse, zonular laxity and zonular dehiscence up to 4 clock hours
donesis. This may be facilitated by having the patient quickly shift the may be managed by placing a capsular tension ring within the capsular
direction of gaze or by gently shaking the slit lamp table with a fist. When bag. Areas of dehiscence greater than 4 clock hours may be managed by
necessary, it often is possible to directly visualize the zonular ligament using capsular tension segments to provide additional capsular support.
fibers by using a gonioprism. If a patient has a history of ocular trauma, Capsular tension segments and some tension rings, such as the Cionni
the eye should also be examined for iridodialysis and vitreous in the ante- ring, have eyelets to allow fixation to the scleral wall with a polypropylene
rior chamber, either of which makes zonular dehiscence likely. or Gore-Tex suture.6 These devices are left in place postoperatively and have
During surgery, care must be taken to preserve as many of the remain- been shown to help expand and center the capsular bag, thus preventing
ing supporting zonules as possible. If discrete areas of zonular dehiscence the lens implant from migrating away from areas of zonular dehiscence.
are present, a cohesive ophthalmic viscosurgical device (OVD) may be used If capsular support is felt to be inadequate for intracapsular lens
to force a dispersive OVD into the area of zonular loss and prevent vitre- placement, an alternative technique should be utilized (Table 5.14.1). A
ous prolapse into the anterior chamber. The anterior capsule may initially sulcus-supported PCL can be placed so that the haptics are 90° away from
dimple under the cystotome tip in the presence of zonular laxity, rather the area of dehiscence (Fig. 5.14.2). This orientation prevents the haptics
392 than being immediately punctured. If difficulty is encountered when from slipping posteriorly into the vitreous chamber. If a continuous curvi-
beginning the anterior capsular tear, two 27-gauge needles may be used in linear capsulorrhexis has been performed, it is advantageous to prolapse
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INTRACAPSULAR POSTERIOR-CHAMBER INTRAOCULAR LENS IMPLANT PLACEMENT WITH ZONULAR DEHISCENCE
5.14
Correct placement Incorrect placement

direction of
decentering of
iris posterior chamber
intraocular lens
oval-shaped equator of
capsulorrhexis capsular bag
haptic
posterior posterior
chamber chamber
intraocular intraocular
zonules lens zonules lens
equator of
haptic points
capsular
away from
bag
area of
zonular
dehiscence
area of zonular area of zonular

dehiscence dehiscence capsulorrhexis
Fig. 5.14.1 Intracapsular Posterior-Chamber Intraocular Lens (PCL) Implant Placement With Zonular Dehiscence. With correct placement within the capsular bag, one
haptic is positioned toward the area of dehiscence to extend the capsule peripherally, stabilize the region, and maintain optic centration. Note that the capsulorrhexis is
ovoid in shape because it has been pulled by the haptic in the direction of the dehiscence. With incorrect placement, the haptics are oriented 90° away from the dehiscence.
In this situation, the PCL may decenter away from the area of dehiscence in the direction of the arrow.
TABLE 5.14.1 Options for Intraocular Lens UVEITIS

Placement After Cataract Extraction Cataract extraction with IOL insertion in patients with uveitis is often made
more difficult because of poor dilation, posterior synechiae, zonular laxity,
Procedure Optic Position Haptic Position Haptic Fixation
and higher levels of postoperative inflammation. If possible, a patient
Intracapsular posterior- Capsular bag Capsular bag Capsular bag
chamber intraocular fornices
should not undergo surgery until the uveitis has been quiescent for at least
lens (PCL) implant 3 months. Even so, patients with a significant history of uveitis should
Intracapsular PCL with Posterior chamber Capsular bag Capsular bag
receive oral prednisone 10 mg/kg daily for up to 1 week prior to surgery fol-
reverse optic capture* fornices lowed by a 2- to 3-week taper. In addition, select patients may benefit from
Sulcus-supported PCL Posterior chamber Ciliary sulcus Ciliary sulcus
intravenous methylprednisolone sodium succinate 125–250 mg during
the surgery. Patients with chronic uveitis secondary to herpes simplex or
Sulcus-supported PCL Capsular bag Ciliary sulcus Ciliary sulcus
with optic capture*
varicella-zoster virus infections should be treated with perioperative oral
antivirals at full treatment doses.
Transscleral fixated PCL Posterior chamber Ciliary sulcus Trans-scleral fixation
Small-incision phaco is the procedure of choice for patients who have
Iris-sutured PCL Posterior chamber Ciliary sulcus Iris sutures
a history of uveitis.10 The smaller incision results in less iris manipula-
Anterior chamber lens Anterior chamber Anterior chamber Anterior chamber tion than large-incision nucleus expression and results in less postopera-
angle
tive inflammation and faster healing. In addition, creating the wound in
Aphakia None None None the avascular clear cornea results in less inflammation compared with a
*The “optic capture” and “reverse optic capture” techniques require an appropriately sized and scleral tunnel incision because the limbal and conjunctival blood vessels
intact continuous curvilinear capsulorrhexis.
are spared.
When necessary, posterior synechiolysis may be performed with use of a
cyclodialysis spatula or viscodissection. The pupil may need to be enlarged
the optic posteriorly into the capsular bag while the haptics remain in the if dilation is inadequate. The surgeon has the choice of manually stretch-
sulcus. This technique often results in more stable optic centration in the ing the pupil by using two instruments usually found on the surgical tray
presence of zonular dehiscence. or by using an instrument specifically designed for pupillary dilation (e.g.,
If insufficient capsule is present to support both haptics, a PCL may be the Beehler pupil dilator or the Malyugin ring). Pupillary membranes, if
sutured to the iris or transsclerally fixated by using suture or other means present, may need to be incised and stripped to further assist with dilation.
(Fig. 5.14.3).7,8 Since transscleral and iris fixation procedures are technically Acrylic lens implants are preferred and usually well tolerated by
difficult to perform, some surgeons may opt for placement of an anterior patients with uveitis.11 Silicone lenses are discouraged in this setting
chamber lens instead. Modern anterior chamber lenses have proven to be because they may accumulate inflammatory precipitates postoperatively.
safe,9 although many surgeons still prefer to keep the IOL as close as pos- In addition, it is best to avoid anterior chamber lenses, iris-sutured PCLs,
sible to the physiological location of the natural crystalline lens. and sulcus-supported PCLs, as they have a tendency to cause postopera-
Femtosecond laser-assisted cataract surgery (FLACS) may have consid- tive inflammation as a result of contact with the iris and the ciliary body.
erable advantages in patients with zonular laxity. In this setting, creation Whenever possible, a capsule-supported PCL is used. If capsular support
of the rhexis is performed by using disruptive laser energy, rather than is not present at the time of IOL implantation, a transsclerally fixated PCL
tearing forces, and thus is not dependent on countertraction from healthy may be placed, or the patient may be left aphakic.
zonules. In addition, much of the nucleofractis technique is performed In vitro and in vivo studies have demonstrated an advantage of heparin
atraumatically by the laser and thus further zonular loss from the mechan- surface-modified polymethyl methacrylate (PMMA) lenses compared with 393
ical action of the phaco tip is avoided. regular PMMA lenses when looking at the adhesion of inflammatory
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5 SULCUS PCL WITH ZONULAR DEHISCENCE
capsulorrhexis is
The Lens
posterior to PCL optic
equator of
capsular bag
posterior
chamber
intraocular
lens
haptic actually
lies on top
of the zonular
ligaments
area of
zonular
dehiscence zonules
Fig. 5.14.2 Sulcus Posterior-Chamber Intraocular Lens (PCL) Placement With Zonular Dehiscence. The PCL is properly placed in the ciliary sulcus with the haptics
oriented 90° away from the area of dehiscence. Placement in this orientation will decrease the likelihood that the haptics will prolapse posteriorly through the area of
dehiscence and into the vitreous cavity.
TRANSSCLERALLY SUTURED POSTERIOR CHAMBER INTRAOCULAR LENS IMPLANT WITH NO ZONULAR SUPPORT
buried knot eyelet on

haptic
iris with peripheral
iridectomy
posterior chamber intraocular

lens haptic with eyelet transscleral suture
peripheral
posterior chamber intraocular
iridectomy
lens haptic with eyelet
iris
posterior chamber
intraocular lens
Fig. 5.14.3 Transscleral Sutured Posterior-Chamber Intraocular Lens (PCL) With No Zonular Support. When no capsular or zonular support is present, a PCL may be
secured by using two transscleral polypropylene or Gore-Tex sutures passed through eyelets on the haptics. The knots are rotated into the sclera to decrease the risk of long-
term complications from knot erosion through the conjunctiva.
cells.12 For this reason, heparin surface-modified PMMA lenses probably assessment on any patients with suspected endothelial dysfunction. Pre-
have an advantage over regular PMMA lenses in patients with history operative risk factors for corneal decompensation in the setting of Fuchs’
of uveitis. However, because of the necessity for a larger incision when dystrophy include endothelial cell density less than 1000/mm2, central
using PMMA lenses, it remains unclear whether heparin surface-modified corneal thickness greater than 640 µm, and the presence of corneal epi-
lenses have an advantage over foldable silicone or acrylic IOLs when other- thelial edema.13
wise small-incision phaco may be performed. The surgeon should strive to minimize damage to the corneal endothe-
lial cells during surgery. Rather than making the incision through temporal
COMPROMISED ENDOTHELIUM clear cornea, a more posterior, scleral tunnel approach may reduce endo-
thelial disruption. A dispersive OVD will be more protective to the corneal
Some patients, such as those with Fuchs’ endothelial dystrophy, have a endothelium than a cohesive OVD. The surgeon may wish to periodically
compromised corneal endothelium at the time of cataract surgery. The refill the anterior chamber with OVD throughout the procedure. Phaco
trauma of intraocular surgery causes further endothelial cell loss, poten- energy and time should be kept to a minimum, thus a chopping nucleof-
394 tially resulting in prolonged, and even irreversible, corneal edema. Pachym- ractis technique is preferred. Nuclear fragments should be emulsified as
etry and specular microscopy may be performed as part of the preoperative posteriorly as possible with the tip of the phaco hand piece directed away
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from the cornea. FLACS is advantageous in these cases because it requires Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses. A historical and
less phaco energy and causes less postoperative reduction in endothelial
cell density.14 Despite all these measures taken, however, corneal decom-
Hasanee K, Butler M, Ahmed IIK. Capsular tension rings and related devices. Curr Opin
5.14
pensation may still occur. Patients with corneal edema may benefit from Lane SS, Agapitos PJ, Lindquist TD. Secondary intraocular lens implantation. In: Lindquist
topical hyperosmotic agents or corneal transplantation postoperatively. It is TD, Lindstrom RL, editors. Ophthalmic surgery. St Louis: Mosby; 1993. p. IG1–118.

critical that adequate informed consent (including a discussion of the pos- MacKool RL. Capsule stabilization for phacoemulsification. J Cataract Refract Surg
2000;26:629.
sibility of post–cataract surgery corneal transplantation) is obtained prior Nakano CT, Motta AFP, Hida WT, et al. Hurricane cortical aspiration technique: one-step
to the procedure. A myopic refractive target is advised if it seems likely that continuous circular aspiration maneuver. J Cataract Refract Surg 2014;40(4):514–16.
subsequent endothelial keratoplasty (EK) will be required, to counter the Popovic M, Campos-Möller X, Schlenker MB, et al. Efficacy and safety of femtosecond
usual hyperopic refractive shift that accompanies EK procedures. laser-assisted cataract surgery compared with manual cataract surgery: a meta-analysis
of 14567 eyes. Ophthalmology 2016;123(10):2113–26.
Raizman MB. Cataract surgery in uveitis patients. In: Steinert RF, editor. Cataract surgery:
technique, complications, and management. Philadelphia: WB Saunders; 1995. p. 243–6.
KEY REFERENCES Seitzman GD, Gottsch JD, Stark WJ. Cataract surgery in patients with Fuchs’ corneal dys-
trophy: expanding recommendations for cataract surgery without simultaneous kerato-
Abela-Formanek C, Amon M, Kahraman G, et al. Biocompatibility of hydrophilic acrylic,
plasty. Ophthalmology 2005;112(3):441–6.
hydrophobic acrylic, and silicone intraocular lenses in eyes with uveitis having cataract
Wagoner MD, Cox TA, Ariyasu RG, et al. IOL implantation in the absence of capsular
surgery: long-term follow-up. J Cataract Refract Surg 2011;37(1):104–12.
support: a report by the AAO. Ophthalmology 2003;110:840–59.
Agarwal A, Kumar DA, Jacob S, et al. Fibrin glue-assisted sutureless posterior chamber. J
Cataract Refract Surg 2008;34:1433–8.
Ahmed IIK, Crandall AS. Ab externo scleral fixation of the Cionni modified capsular tension Access the complete reference list online at ExpertConsult.com
ring. J Cataract Refract Surg 2001;27:977–81.
395
booksmedicos.org
REFERENCES 9. Wagoner MD, Cox TA, Ariyasu RG, et al. IOL implantation in the absence of capsular
support: a report by the AAO. Ophthalmology 2003;110:840–59.
1. Smith SG, Lindstrom RL. Report and management of the sunrise syndrome. J Am Intra-
ocul Implant Soc 1984;10:218–20.
10. Raizman MB. Cataract surgery in uveitis patients. In: Steinert RF, editor. Cataract
surgery: technique, complications, and management. Philadelphia: WB Saunders; 1995.
5.14
2. Apple DJ, Mamalis N, Loftfield K, et al. Complications of intraocular lenses. A historical p. 243–6.
11. Abela-Formanek C, Amon M, Kahraman G, et al. Biocompatibility of hydrophilic acrylic,

and histopathological review. Surv Ophthalmol 1984;29:1–54.
3. Ahmed IIK, Crandall AS. Ab externo scleral fixation of the Cionni modified capsular hydrophobic acrylic, and silicone intraocular lenses in eyes with uveitis having cataract
tension ring. J Cataract Refract Surg 2001;27:977–81. surgery: long-term follow-up. J Cataract Refract Surg 2011;37(1):104–12.
4. MacKool RL. Capsule stabilization for phacoemulsification. J Cataract Refract Surg 12. Ygge J, Wenzel M, Philipson B, et al. Cellular reactions on heparin surface-modified
2000;26:629. versus regular PMMA lenses during the first postoperative month. Ophthalmology
5. Nakano CT, Motta AFP, Hida WT, et al. Hurricane cortical aspiration technique: one-step 1990;97:1216–23.
continuous circular aspiration maneuver. J Cataract Refract Surg 2014;40(4):514–16. 13. Seitzman GD, Gottsch JD, Stark WJ. Cataract surgery in patients with Fuchs’ corneal
6. Hasanee K, Butler M, Ahmed IIK. Capsular tension rings and related devices. Curr Opin dystrophy: expanding recommendations for cataract surgery without simultaneous kera-
Ophthalmol 2006;17:31–41. toplasty. Ophthalmology 2005;112(3):441–6.
7. Lane SS, Agapitos PJ, Lindquist TD. Secondary intraocular lens implantation. In: Lind- 14. Popovic M, Campos-Möller X, Schlenker MB, et al. Efficacy and safety of femtosecond
quist TD, Lindstrom RL, editors. Ophthalmic surgery. St Louis: Mosby; 1993. p. IG1–118. laser-assisted cataract surgery compared with manual cataract surgery: a meta-analysis of
8. Agarwal A, Kumar DA, Jacob S, et al. Fibrin glue-assisted sutureless posterior chamber 14567 eyes. Ophthalmology 2016;123(10):2113–26.
intraocular lens implantation in eyes with deficient posterior capsules. J Cataract Refract
Surg 2008;34:1433–8.
395.e1
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Part 5 The Lens

Pediatric Cataract Surgery

Michael O’Keefe, Caitriona Kirwan, Elie Dahan† 5.15
Definition: Cataracts occurring in the pediatric age group, arbitrarily BOX 5.15.1 Laboratory Tests for Bilateral Nonhereditary
defined as birth to adolescence. Pediatric Cataracts
Complete blood count
Random blood sugar
Plasma calcium and phosphorus
Key Features Urine assay for reducing substances after milk feeding
• Two main approaches are used to remove cataracts in children: pars Red blood cell transferase and galactokinase levels
plana and corneolimbal approach. If Lowe’s syndrome is suspected, screening for amino acids in urine
• Intraocular lenses, contact lenses, and spectacles are the most readily Toxoplasmosis titer
available means to correct aphakia in children. Rubella titer
• Advances in contact lens technology results in improved visual Cytomegalovirus titer
outcomes. Herpes simplex titer
• Use of intraoperative triamcinolone and better surgical techniques
reduces inflammation.
• Postoperative glaucoma remains a major problem. in childhood or other ocular abnormalities can be relevant. Both parents
and all siblings should be examined with a slit lamp to determine any lens
abnormalities. When family history is positive, consultation with a genet-
INTRODUCTION icist is recommended. A thorough examination by a pediatrician to assess
the child’s general health and to elicit information about other congenital
Cataracts in childhood not only reduce vision but also interfere with abnormalities may be helpful
normal visual development.1–3 The management of pediatric cataracts is Laboratory tests in children who have bilateral cataracts in nonhered-
far more complex than the management of cataracts in adults. The timing itary cases are listed in Box 5.15.1. Most unilateral pediatric cataracts are
of surgery, the surgical technique, the choice of the aphakia correction, idiopathic and do not warrant exhaustive laboratory tests.
and amblyopia management are of utmost importance in achieving good, The ophthalmological part of the evaluation starts with a complete
long-lasting results in children.4–10 Children’s eyes are not only smaller ocular examination, which includes an assessment of visual acuity, pupil-
than adults’ eyes, but their tissues are much more reactive as well. The lary response, and ocular motility. Biomicroscopy follows and might neces-
inflammatory response to surgical insult seems more pronounced in sitate sedation or even general anesthesia in very young patients. Indirect
children, often because of iatrogenic damage to the iris. During the past fundus examination with dilated pupils is made unless the cataract is com-
2 decades, the refinements that have occurred in adult cataract surgery plete. A- and B-scan ultrasonography is carried out in both eyes to compare
have contributed to the further development of pediatric cataract surgery axial lengths and to discover any posterior segment abnormalities.
(PCS).2,4–8 Certain adaptations and modifications in surgical technique are
required to achieve results similar to those achieved in adults.2–8 Further- ALTERNATIVES TO SURGERY
more, postoperative amblyopia management forms an integral part of
visual rehabilitation in children.1–10 The development of metabolic cataracts, such as those found in galactose-
mia, can be reversed if they are discovered in the early phases. With the
HISTORICAL REVIEW elimination of galactose from the diet, the early changes in the lens, which
resemble an oil droplet in the center of the lens, can be reversed.12 Later
Discission of soft cataracts was first described by Aurelius Cornelius on, lamellar or total cataracts develop and require surgery.
Celsius, a Roman physician who lived 2000 years ago. Discission remained When lens opacities are confined to the center of the anterior capsule
the method of choice until the middle of the twentieth century. The tech- or the anterior cortex, dilatation of the pupils with cyclopentolate 1% twice
nique consisted of lacerating the anterior capsule and exposing the lens daily can improve vision and postpone the need for surgery. Photophobia
material to aqueous humor for resorption and/or secondary washout. and partial loss of accommodation are side effects of this measure.
Repeated discissions often were required to manage the inevitable second-
ary cataracts.2 Many early complications (e.g., plastic iritis, glaucoma, and ANESTHESIA
retinal detachments) were associated with these early techniques.2,11 With
the advent of vitrectomy machines and viscoelastic substances, as well as General anesthesia is presently the only anesthetic option in PCS. It is
the refinements in cataract surgery, these complications have been reduced extremely important to request deep anesthesia throughout the procedure
markedly over the past 2 decades.2 to minimize iatrogenic damage to iris and cornea.5,7,8 Children’s sclera
is particularly elastic; therefore, any tension on the extraocular muscles
results in loss of anterior chamber depth and increased intraocular pres-
PREOPERATIVE EVALUATION AND sure (IOP). A useful marker for anesthesia depth is the position of the eye
DIAGNOSTIC APPROACH during surgery. If the cornea moves upward or downward, the anesthe-
sia is too light and should be deepened. When this guidance is followed,
A careful history assists the clinician in selecting the investigations needed surgery is easier to perform.
for determining the cataract’s etiology.2 Information on problems during
pregnancy (e.g., infections, rashes or febrile illnesses, exposures to drugs,
toxins, or ionizing radiation) should be elicited. Family history of cataracts
GENERAL TECHNIQUES
396 Unlike in adults, pediatric cataracts are soft. Their lens material can be
†
Deceased aspirated through incisions that are 1–1.5 mm long at the limbus or can
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be subjected to lensectomy through the pars plana. When intraocular lens Fig. 5.15.1
Anterior
(IOL) implantation is intended, a larger limbal wound is needed to intro-
duce the IOL. With the use of foldable implants, the incision is not more Capsulectomy 5.15
than 3 mm. A scleral tunnel is better than a clear corneal incision (CCI). Performed
Unlike in adults, the wound should be securely sutured with 10.0 vicyrl With Use of

a Vitrectomy
sutures to prevent wound dehiscence with iris incarceration—a common
Probe in a Case
complication in children.2,4,5,7,8,10 of Congenital
Cataract. Note
SPECIFIC TECHNIQUES the use of the
anterior chamber
Two main approaches exist for the removal of cataracts in children: the maintainer for
pars plana approach and the corneolimbal approach. a deep anterior
Both techniques have advantages and disadvantages. The pars plana chamber and a
approach was developed with the advent of vitrectomy machines in the late well-dilated pupil.
1970s.13,14 It was intended to deal mainly with very young infants in whom
surgery is more difficult. With the continuing refinements in cataract and
implant surgery in adults, the pars plana approach gradually is being aban-
doned in favor of the limbal approach because the latter allows better pres-
ervation of the capsular bag for lens-in-the-bag IOL placement.2,5,7,8
Pars Plana Approach

The pars plana approach is indicated mainly for neonates and infants
under 2 years of age, particularly for those who have bilateral congenital
cataracts, in which case immediate IOL implantation is not intended.2
The technique requires a guillotine-type vitrectomy and balanced salt
solution (BSS) containing epinephrine (adrenaline) 1:500 000. The loca-
tion of the pars plana in infants can be 1.5–3.5 mm from the limbus. In
the last decade, surgeons have largely abandoned the 20-gauge vitrectomy
apparatus in favor of the 23-gauge or the 25-gauge version. A lensectomy–
anterior vitrectomy is completed, sparing a 2- to 3-mm peripheral rim of
anterior and posterior capsules. These capsule remnants are used to create
a shelf to support a posterior chamber IOL that may be implanted later on
in life.15 It is important to avoid vitreous incarceration in the wounds by
turning off the infusion before withdrawing the vitrectomy cutter from the
eye. This precaution reduces the chances of suffering retinal traction and
detachment later in life.16
This technique is rapid and allows for a permanently clear visual axis.
The postoperative course is normally less complicated than that after the
limbal approach because fewer maneuvers occur in the anterior chamber.
Consequently, the iris and the corneal endothelium suffer less iatrogenic
damage. In cases of children with bilateral cataracts, where an anesthetic
risk exists because of unstable medical status, both eyes can be operated
on sequentially at the same surgery, but treating both eyes as separate
operations. This is now a procedure practiced by some pediatric ophthal-
mologists even when there is no anesthesia-related risk. This has the addi-
tional advantage of reducing the risk of relative amblyopia and freeing up
operating room time, thus reducing trauma to the child.17
Corneolimbal Approach
The corneolimbal approach is the most widely used surgical technique. A
long tunnel limbal incision reduces the risk of iris prolapse. Sometimes,
the pupil is meiotic and will not dilate well. This requires intracameral
phenylephrine 2.5% and/or iris hooks. Viscoelastic materials are necessary
to maintain the anterior chamber depth. Some use an anterior chamber
maintainer (ACM) to maintain the chamber, and it can provide a steady
intraoperative IOP and helps keep the pupil dilated throughout the proce-
dure because of positive hydrostatic pressure.
Two limbal incisions are made with a 23-g micro-vitreo-retinal blade
(MVR; Alcon Laboratories Inc., Fort Worth, TX). These allow for use of
a bimanual technique with one cannula infusing fluid to the anterior
chamber and the opposite one aspirating the lens material.
Various techniques have been described to open the anterior capsule.
The younger the child, the more difficult it is to perform a capsulorrhexis.
Infants have a very elastic anterior capsule that easily tears toward the
periphery. A manual capsulorrhexis using a push/pull technique has been
described.18 A more practical alternative is to use a vitrectomy probe to
create a small central opening in the anterior capsule (Fig. 5.15.1). This
hole can be enlarged gradually by biting into the anterior capsule with
the vitrector until the desired 4- to 5-mm opening is achieved. Another
alternative is the Oertli diathermy system, which has the effect of creat-
ing a controlled central 5-mm round capsulectomy19 (Fig. 5.15.2). Gentle
hydrodissection and hydrodelineation free the lens material, which can 397
be aspirated by using the bimanual technique or with the vitrector. The Fig. 5.15.2 Oertli diathermy system for performing capsulectomy.
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Fig. 5.15.3
5 Elective Posterior
Capsulectomy
and Deep
BOX 5.15.2 Guidelines for the Choice of Intraocular Lens
Dioptric Power
Anterior Children Less Than 2 Years Old
• Do biometry, and undercorrect by 20%, or
The Lens
Vitrectomy. This
is performed • Use axial length measurements only
with the use of a • Axial length, IOL dioptic power
vitrectomy probe, • 17 mm, 25 D
after all the lens • 18 mm, 24 D
material has been • 19 mm, 23 D
aspirated within
the capsular bag.
• 20 mm, 21 D
• 21 mm, 19 D
Children Between 2 and 8 Years Old
• Do biometry, and undercorrect by 10%
the management of contact lenses in children can be very difficult and

costly because of frequent loss of lenses, recurrent infections, and poor
follow-up. The Infant Aphakia Treatment Study (IATS)21 was a multicenter
randomized clinical trial comparing cataract surgery with or without IOL
implantation in infants ages 1–6 months with clinical congenital cataracts.
The IATS authors concluded that there was no significant difference in the
median visual acuity between eyes that underwent primary IOL implan-
tation and those left aphakic. However, significantly more adverse events
occurred, and a need existed for additional intraoperative procedures in the
IOL group. Those authors concluded that primary IOLs should be reserved
for those cases where, in the opinion of the surgeon, the use of handling of
a contact lens would result in significant periods of uncorrected aphakia.
management of the posterior capsular bag is determined by the age of the During the last 2 decades, many technical problems have been overcome.
patient and as to whether an implant should be inserted. Most surgeons One such recent advance is the introduction of extended wear silicone
agree that infants under 6 years of age should receive an elective posterior elastomer and custom rigid gas permeable contact lenses that are a great
capsulectomy and anterior vitrectomy.20 Posterior capsulorrhexis is per- advance.22 Some problems, such as cost of replacement and need for fre-
formed manually or with a vitrector. quent replacement because of changes in refractive error and lens loss,
Its diameter should be at least 4 mm (Fig. 5.15.3). The anterior vitrec- have persisted.
tomy should be generous, removing one third of the vitreous to ensure
a permanently clear visual axis. Smaller posterior capsulectomies and Intraocular Lenses
shallow anterior vitrectomies close, especially in neonates. Posterior cap-
sulectomies, either alone or combined with shallow anterior vitrectomy, The IOL option was originally advocated in cases of unilateral pediatric
does not guarantee a permanent clear visual axis because lens epithelial cataracts because it facilitates amblyopia management by providing more
cells regrow and can form new membranes. permanent correction.2,4,5,7,8,10,13 Implanting an IOL in a growing eye is
A modification of the technique includes a translimbal capsulorrhexis not an ideal solution. The aim in the IOL option, unlike in the contact
and lens aspiration, then insertion of the IOL into the capsular bag. The lens alternative, is to correct most, but not all, of the aphakia; the residual
wound is closed, and the anterior chamber is maintained with either visco- refractive error has to be corrected with the use of spectacles, which can be
elastic or ACM. The surgeon then goes through the pars plana to perform adjusted throughout life.
a posterior capsulorrhexis and anterior vitrectomy by using a vitrector. The implantation of anterior chamber angle supported IOLs in chil-
Leaving the posterior capsule intact, especially in neonates and children dren was discontinued in the mid-1980s. Devastating complications, such
under 2 years of age, results in very early posterior capsule opacification. as secondary glaucoma and corneal decompensation, were attributed to
The use of yttrium–aluminum–garnet (YAG), either immediately after these IOLs, especially in younger patients. Posterior chamber intraocular
surgery or later, has had limited success. Because of logistics, it is not pos- lens (PCL) implantation represents, by far, the best method for the correc-
sible unless the surgeon has access to a horizontal laser system. tion of aphakia.
Selection of Intraocular Lenses

CHOICES FOR CORRECTION OF APHAKIA The choice of the dioptric power of IOL for young children is the main
difficulty faced by the ophthalmologist.2 Pediatric IOLs are not yet readily
IN CHILDREN available,23,24 and the rapid growth of the eye during the first 2 years of life
Spectacles, contact lenses, and IOLs are the most readily available means makes an effective choice difficult2,4,7,8,25–27 (Box 5.15.2). Nevertheless, in the
to correct aphakia in children. 1990s, increasingly positive reports were published on the use of PCLs in
children and even in neonates.
Spectacles The material from which the IOL is made must have a long track
record of safety. Polymethyl methacrylate (PMMA) IOLs have been in use
Aphakic spectacles provide satisfactory correction only in cases of bilateral for more than 50 years; PMMA is probably the safest material to be used
aphakia in which anisometropia does not represent a problem.2 Most of in children until similar follow-up data on other biomaterials become avail-
the patients develop good visual acuity with the use of spectacles, provided able. Nevertheless, during the last decade, many surgeons have switched
that the eyes are not excessively microphthalmic.2 The disadvantages of to the use of foldable hydrophobic IOLs in children. The actual size of the
spectacles are cosmetic concerns and the poor optical quality of high-plus capsular bag and the ciliary sulcus in children has been ascertained by
lenses. the work of Bluestein et al.24 PCLs, which were originally oversized, have
been reduced from 13–14 mm to 12–12.5 mm in diameter in most modern
models. In children, it is even more important to implant an IOL of the
Contact Lenses correct size.24 Pediatric IOLs should not exceed 12 mm in overall diameter,
During the 1970s and 1980s, contact lenses were described as the method considering that the average adult ciliary sulcus diameter rarely exceeds
of choice to correct unilateral and bilateral aphakia in childhood.2,9,10 11.5 mm. Ideally, the pediatric IOL should be available in diameters of the
398 Contact lenses provide better optical correction compared with specta- range 10.5–12 mm.24 The choice of IOL size is determined mainly by the
cles, and their dioptric power can be adjusted throughout life. However, site of implantation (i.e., lens-in-the-bag or ciliary sulcus).
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corneal edema occurs. The inflammation is worse if the surgery has been
LENS IMPLANTATION traumatic. A combination of intense topical and systemic corticosteroids is
used for the first few weeks with use of atropine or cyclopenolate to dilate 5.15
The lens-in-the-bag implantation
the pupil. The medications are tapered over about 4–6 weeks. The use of
triamcinolone 4 mg in 0.1 mL has significantly reduced the inflammation

and lessened the need for intense topical and systemic corticosteroids.30
A
COMPLICATIONS
Intraoperative complications are related to the age of the child at surgery,
The bag-in-the-lens implantation anesthesia, and surgical technique. The anterior chamber tends to col-
lapse, the iris can protrude through the wound, and the pupil constricts.
Deep anesthesia, good surgical technique, ACM, iris hooks, and proper
vitrectomy help minimize these problems.
B
Fig. 5.15.4 Schematic drawing of the lens-in-the-bag implantation (A) and the bag-
Early complications include fibrinous uveitis, high IOP, incarceration of
in-the-lens implantation (B).
iris in the wound, and endophthalmitis. Late complications include dis-
location of the IOL, chronic iritis, glaucoma, and retinal detachment. The
rate of glaucoma or suspected glaucoma in the IATS 1 year after surgery
Both the biometry and the age of the child determine the choice of was 12% at 1 year and 30% at 5 years follow-up, with no difference between
the IOL dioptric power. Two main age groups exist with regard to PCS: eyes that were aphakic and those that were pseudophakic.21 Many reasons
patients younger than 2 years and patients between 2 and 8 years of age. have been reported as a cause of glaucoma; delaying surgery until the
In the first group, the axial length and the keratometric (K) readings infant is 6 weeks old is thought to reduce the risk.31,32
change rapidly, whereas in the second group the changes are slower and
more moderate.25–27 To counteract the large myopic shift that occurs, it is Amblyopia Management
advisable to undercorrect in children with IOLs so that they can grow into
emmetropia or mild myopia in adult life.25–27 The child’s parents must understand that surgery is only the start of visual
Those who are under 2 years of age should receive 80% of the power rehabilitation and that rehabilitation must continue throughout childhood.
needed for emmetropia at the time of surgery. Because the K readings also Unilateral cases are the most difficult to manage.2,4,5,7–10 Amblyopia
change rapidly during the first 18 months of life, it is practical to rely on treatment starts soon after surgery, after postoperative inflammation
the axial length only when the IOL dioptric power is chosen for infants subsides and the medium becomes clear. The initial treatment must be
(Box 5.15.2). The postoperative residual refractive error is corrected by aggressive to boost vision in the deprived eye. Occlusion of the sound eye
spectacles, which can be adjusted at will as the child grows. Infants and is carried out for half the waking day for the first year. Therefore, occlusion
toddlers can tolerate up to 6 D of anisometropia, which disappears within should be maintained 80% to 90% of the waking day. Soon after surgery
2–3 years.27 Most of the infants who have unilateral pseudophakia need a for bilateral aphakia, spectacles are prescribed, a bifocal lens of +3 should
patch over the sound eye for half their waking hours for the first year and be prescribed at 2 years. For unilateral aphakia and pseudophakia, patch-
for 80% to 90% of the waking day until age 4 or 5 years. Patches alleviate ing should be continued until the child is 4–5 years of age. The patch wear
the symptoms of anisometropia but at the same time affect the chances of time can be reduced gradually but should not be abandoned until the child
development of good binocularity.26 reaches 8–9 years of age.
For the age range of 2–8 years, the IOL dioptric power should be 90%
of that needed for emmetropia at the time of surgery (see Box 5.15.2). The
induced anisometropia is moderate and lessens with the expected myopic
Options to Correct Myopic Shift
shift that occurs in adolescence.25–27 The growth of aphakic and pseudophakic eyes is unpredictable. This par-
ticularly applies to pseudophakic eyes.33 A myopic shift of 7 D or more
Implantation in Children Under 2 Years of Age is not uncommon. IOL exchange when an implant has been in place
Intraocular implantation is controversial in infants. However, implantation for more than a year is extremely difficult and carries significant risks.
in those beyond 6 months and beyond 1 year of age is widely practiced, However, contact lenses,22 refractive surgery,34 and secondary IOLs to
particularly in unilateral cases. The most popular approach involves cata- correct the myopia are now the preferred options. Both the techniques and
ract aspiration and capsulectomy through the corneal sclera wound. The the outcome of these various options have produced good visual outcomes
implant is inserted through the corneal sclera wound into the capsular with low risk of complications.
bag. Elective posterior capsulectomy and anterior vitrectomy are performed
through the pars plana. The results of the IATS and improved contact lens
technology may see a shift away from IOL in the age group.21
OUTCOME
The visual outcome depends largely on the type of cataract, the laterality of
Implantation in Children Above 2 Years of Age the pathology, the timing of intervention, the quality of surgery, and, above
For children older than 2 years, the IOL should be inserted because the all, the management of amblyopia. It is possible to achieve nearly normal
eye has reached nearly the adult size, although its sclera is much softer. vision even in cases of unilateral congenital cataracts, provided the ambly-
Gimbel28 has described a special IOL implantation technique for this opia management is aggressive.2–10,24 Binocularity usually is poor in these
group of patients. This technique requires extreme dexterity because cases, but some gross stereopsis can be expected.35 Children with aphakia
both anterior and posterior capsulorrexes are performed. The IOL haptics and pseudophakia certainly should be followed up throughout their child-
are placed in the bag fornices, while the optic is protruded through both hood and preferably throughout life.36
capsulorrhexes to be captured beneath the posterior capsule remnants.
Tassignon recently developed a new technique for a special IOL called
bag-in-the-lens.29 The technique consists of creating an anterior and pos- KEY REFERENCES
terior capsulorhexes. The specially designed IOL has, at its periphery, a Ahmadieh H, Javadi MA, Ahmadi M, et al. Primary capsulectomy, anterior vitrectomy, len-
groove that contains both anterior and posterior capsule rims (Fig. 5.15.4). sectomy, and posterior chamber lens implantation in children: limbal versus pars plana.
Although technically demanding, promising early results indicate that this Ben-Ezra D, Paez JH. Congenital cataract and intraocular lenses. Am J Ophthalmol
technique may eliminate the need for elective anterior vitrectomy. 1983;96:311–14.
Cleary CA, Lanigan B, O’Keeffe M. Intracameral triamcinolone acetonide after pediatric cat-
Postoperative Treatment aract surgery. J Cataract Refract Surg 2010;36:1676–81.
Comber RM, Abdulla N, O’Keefe M. Radio frequency diathermy capsulorhexis of the anterior
The eyes of infants and younger children are highly reactive to surgery. and posterior capsules predominantly results. JCRS 1997;23(Suppl):841–4.
These eyes produce excessive fibrin, and as a result, an intense inflamma- Dahan E, Salmenson BD. Pseudophakia in children: precautions, techniques and feasibility. 399
tory response occurs soon after surgery. The pupil remains meiotic, and J Cataract Refract Surg 1990;16:75–82.
booksmedicos.org
Elston JS, Timms C. Clinical evidence for the onset of the sensitive period in infancy. Br J Scott R, Lambert MD. The timing of surgery for congenital cataract minimizing the risk
5 Ophthalmol 1992;76:327–8.
Flitcroft DI, Knight-Nanan D, Bowell R, et al. Intraocular lenses in children: changes in axial
length, corneal curvature, and refraction. Br J Ophthalmol 1999;83:265–9.
Lambert SR, Drake AV. Infantile cataracts. Surv Ophthalmol 1996;40:427–58.
of glaucoma following cataract surgery while optimising the visual outcome. J AAPOS
2016;203:191–2.
Tassignon MJ, De Veuster I, Godts D, et al. Bag-in-the-lens intraocular lens implantation in
the pediatric eye. J Cataract Refract Surg 2007;33(4):611–17.
Lambert SR, Purohit A, Superak HM, et al. Long term risk of glaucoma after congenital The Infant Aphakia Treatment Study Group, Lambert SR, Lynn MJ, et al. Comparison of
The Lens
cataract surgery. AMJ Ophthalmology 2013;156:355–61. contact lens and intraocular lens correction for monocular aphakia during infancy.
McClatchey SK, Dahan E, Maselli E, et al. A comparison of the rate of refractive growth in JAMA Ophthalmology 2014;132(6):678–82.
pediatric aphakia and pseudophakia eyes. Ophthalmology 2000;107:118–22.
Michael Repka MD. Treatment outcomes of monocular infantile cataract at 5 year follow up
work in progress. JAMA Ophthalmology 2014;132(6):683–4.
O’Keefe M, Kirwan C. Paediatric refractive surgery. J Pediatr Ophthalmol Strabismus Access the complete reference list online at ExpertConsult.com
2006;43(6):333–6.
400
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REFERENCES 19. Comber RM, Abdulla N, O’Keefe M. Radio frequency diathermy capsulorhexis of
the anterior and posterior capsules predominantly results. J Cataract Refract Surg
1. Elston JS, Timms C. Clinical evidence for the onset of the sensitive period in infancy. Br
J Ophthalmol 1992;76:327–8.
1997;23(Suppl.):841–4.
20. Vasavada A, Desai J. Primary posterior capsulorhexis with and without anterior vitrec-
5.15
2. Lambert SR, Drake AV. Infantile cataracts. Surv Ophthalmol 1996;40:427–58. tomy in congenital cataracts. J Cataract Refract Surg 1997;23(Suppl. 1):645–51.
21. The Infant Aphakia Treatment Study Group, Lambert SR, Lynn MJ, et al. Comparison of

3. Birch EE, Stager DR, Leffler J, et al. Early treatment of congenital cataract minimizes
unequal competition. Invest Ophthalmol Vis Sci 1998;39:1560–6. contact lens and intraocular lens correction for monocular aphakia during infancy. JAMA
4. Ben-Ezra D, Paez JH. Congenital cataract and intraocular lenses. Am J Ophthalmol Ophthalmology 2014;132(6):678–82.
1983;96:311–14. 22. Michael Repka MD. Treatment outcomes of monocular infantile cataract at 5 year follow
5. Dahan E. Lens implantation in microphthalmic eyes of infants. Eur J Implant Refract up work in progress. JAMA Ophthalmology 2014;132(6):683–4.
Surg 1989;1:1–9. 23. Wilson ME, Apple DJ, Bluestein EC, et al. Intraocular lenses for pediatric implantation:
6. Guo S, Nelson LB, Calhoun J, et al. Simultaneous surgery for bilateral congenital cata- biomaterials, designs and sizing. J Cataract Refract Surg 1994;20:584–91.
racts. J Pediatr Ophthalmol Strabismus 1990;27:23–5. 24. Bluestein EC, Wilson ME, Wang XH, et al. Dimensions of the pediatric crystalline
7. Dahan E, Salmenson BD. Pseudophakia in children: precautions, techniques and feasi- lens: implications for intraocular lenses in children. J Pediatr Ophthalmol Strabismus
bility. J Cataract Refract Surg 1990;16:75–82. 1996;33:18–20.
8. Dahan E, Welsh NH, Salmenson BD. Posterior chamber implants in unilateral con- 25. McClatchey SK, Dahan E, Maselli E, et al. A comparison of the rate of refractive growth
genital and developmental cataracts. Eur J Implant Refract Surg 1990;2:295–302. in pediatric aphakia and pseudophakia eyes. Ophthalmology 2000;107:118–22.
9. Neumman D, Weissman BA, Isenberg SJ, et al. The effectiveness of daily wear contact 26. Gordon RA, Donzis PB. Refractive development of the human eye. Arch Ophthalmol
lenses for the correction of infantile aphakia. Arch Ophthalmol 1993;111:927–30. 1985;103:785–9.
10. BenEzra D, Cohen E, Rose L. Traumatic cataract in children: correction of aphakia by 27. Dahan E. Insertion of intraocular lenses in the capsular bag. Metab Pediatr Syst Ophthal-
contact lens or by intraocular lens. Am J Ophthalmol 1997;123:773–82. mol 1987;10:87–8.
11. Asrani S, Freedman S, Hasselblad V, et al. Does primary intraocular lens implantation 28. Gimbel HV, Debroff BM. Posterior capsulorrhexis with optic capture: maintaining a clear
prevent ‘aphakic’ glaucoma in children? J AAPOS 2000;4:33–9. Review. visual axis after pediatric cataract surgery. J Cataract Refract Surg 1994;20:658–64.
12. Burke JP, O’Keefe M, Bowell R, et al. Ophthalmic findings in classical galactosemia – a 29. Tassignon MJ, De Veuster I, Godts D, et al. Bag-in-the-lens intraocular lens implantation
screened population. J Pediatr Opthalmol Strabismus 1989;26:165–8. in the pediatric eye. J Cataract Refract Surg 2007;33(4):611–17.
13. Ahmadieh H, Javadi MA, Ahmadi M, et al. Primary capsulectomy, anterior vitrectomy, 30. Cleary CA, Lanigan B, O’Keeffe M. Intracameral triamcinolone acetonide after pediatric
lensectomy, and posterior chamber lens implantation in children: limbal versus pars cataract surgery. J Cataract Refract Surg 2010;36:1676–81.
plana. J Cataract Refract Surg 1999;25:768–75. 31. Lambert SR, Purohit A, Superak HM, et al. Long term risk of glaucoma after congenital
14. Koch DD, Kohnen T. Retrospective comparison of techniques to prevent secondary cata- cataract surgery. AMJ Ophthalmology 2013;156:355–61.
ract formation after posterior chamber intraocular lens implantation in infants and chil- 32. El Shakankiri NM, Lotfy Bayoumi NH. The timing of surgery for congenital cataracts:
dren. J Cataract Refract Surg 1997;23:657–63. delayed surgery for best surgical outcomes. J AAPOS 2016;20:192–3.
15. Dahan E, Salmenson BD, Levin J. Ciliary sulcus reconstruction for posterior implanta- 33. Flitcroft DI, Knight-Nanan D, Bowell R, et al. Intraocular lenses in children: changes in
tion in the absence of an intact posterior capsule. Ophthalmic Surg 1989;20:776–80. axial length, corneal curvature, and refraction. Br J Ophthalmol 1999;83:265–9.
16. McLeod D. Congenital cataract surgeries: a retinal surgeon’s viewpoint. Aust NZ J Oph- 34. O’Keefe M, Kirwan C. Paediatric refractive surgery. J Paediatr Ophthalmol Strabismus
thalmol 1986;14:79–84. 2006;43(6):333–6.
17. Scott R, Lambert MD. The timing of surgery for congenital cataract minimizing the risk 35. Tytla ME, Lewis TL, Maurer D, et al. Stereopsis after congenital cataract. Invest Ophthal-
of glaucoma following cataract surgery while optimising the visual outcome. J AAPOS mol Vis Sci 1993;34:1767–72.
2016;203:191–2. 36. Rabin J, Van Sluyters RC, Malach R. Emmetropization: a vision dependent phenomenon.
18. Nischal KK. Two-incision push-pull capsulorhexis for pediatric cataract surgery. J Cata- Invest Ophthalmol Vis Sci 1981;20:561–4.
ract Refract Surg 2002;28(4):59319.
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Part 5 The Lens

Complications of Cataract Surgery

Thomas Kohnen, Li Wang, Neil J. Friedman, Douglas D. Koch 5.16
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
greater radial length and an anterior entry into the anterior chamber to
Definition: All unwanted events during or after conventional cataract create the self-sealing internal corneal valve. Advantages of tunnel inci-
surgery with potential threat to the normal structure and/or function of sions are increased intraoperative safety, decreased postoperative inflam-
the eye. mation and pain, increased postoperative watertightness, and reduced
surgically induced astigmatism.2
Key Features Tunnel Perforation

• Intraoperative complications, depending on incision, perforation, Tearing of the roof of the tunnel predisposes to excessive intraoperative
detachment of structures, burns, anterior capsule, posterior capsule,
leakage, which compromises anterior chamber stability, and to postoper-
zonulae, capsulorrhexis, iris problems, subluxation, sulcus structure,
ative wound leakage. If the tear occurs at either edge of the roof, surgery
hemorrhage.
usually can be completed using the initial incision, proceeding slowly and
• Postoperative complications, depending on wound characteristics, observing the wound carefully as instruments are introduced or manipu-
epithelial characteristics, corneal irregularities and problems,
lated in the eye. It usually is preferable to suture the incision at the conclu-
intraocular hemorrhage, glaucoma, problems with architecture of the
sion of surgery, even if the wound is watertight, to restore a more normal
implanted intraocular lens, problems with the retina, dislocation of
architecture and prevent external wound gape.
the lens.
If, however, the roof is perforated in the center of the flap, and this
is noted before the anterior chamber is entered, creation of a new inci-
sion should be considered. If the cut is extremely small (e.g., < 0.5 mm),
Associated Feature sometimes the same procedure as for lateral roof tears (see above) can be
• Understanding the mechanism of several complications in cataract used. Before IOL insertion, the opposite margin of the wound is enlarged,
surgery and performing the correct steps to minimize further and to prevent further tearing, the incision is made larger than normal for
unwanted negative results. IOL insertion. Suture closure usually is advisable to restore normal wound
architecture.
If the floor of the tunnel is perforated, which can happen during scleral
INTRODUCTION tunnel dissection, surgery usually can be performed through this wound;
care must be taken to avoid trauma to any prolapsing uveal tissue. The
Phacoemulsification (“phaco”), sutureless, self-sealing tunnel incisions, perforation should be closed with sutures or fibrin glue.
and foldable intraocular lenses (IOLs) have changed cataract surgery dra-
matically over the past 2 decades. Postoperative astigmatism and inflam- Descemet’s Detachment
mation are typically minimal; visual recovery and patients’ rehabilitation
are accelerated. The published literature indicates that modern cataract Detachment of Descemet’s membrane can be a major postoperative com-
surgery, although certainly not free of complications, is a remarkably safe plication, resulting in persistent corneal edema and decreased visual acuity.
procedure, regardless of which extraction technique is used.1 To prevent Descemet’s detachment, the surgeon should carefully observe
Using rigid criteria for scientific validity, Powe et al.1 analyzed 90 studies the inner lip at each phase of the procedure. To avoid blunt stripping of
published between 1979 and 1991, addressing visual acuity (n ≡ 17 390 eyes) Descemet’s membrane during enlargement of the wound, a sharp metal or
or complications (n ≡ 68 316 eyes) following standard nuclear expression diamond blade is recommended.
cataract extraction with posterior chamber IOL implantation, phaco with If detachment is caused by viscoelastic injection, the agent must
posterior chamber IOL implantation, or intracapsular cataract extraction be removed by using a blunt cannula. Intraoperatively, repositioning of
with anterior chamber IOL implantation. Strikingly, the percentage of eyes Descemet’s membrane usually can be achieved by injecting balanced salt
with postoperative visual acuity of 20/40 or better was 89.7% for all eyes solution (BSS) or occasionally air or an ophthalmic viscosurgical device
and 95.5% for eyes with no pre-existing ocular comorbidity. The incidence (OVD) through the paracentesis site. With the experience we have gained
of sight-threatening complications was less than 2%. over the last 5 years with Descemet’s membrane endothelial keratoplasty
In this chapter, the key elements in the prevention, recognition, and (DMEK) air or gas injection (20% sulfahexafluoride [SF6]) can perfectly
management of the major intraoperative and postoperative complications reattach a stripped Descemet’s membrane.
of cataract surgery are discussed. If a visually significant Descemet’s detachment is present postoper-
atively, the authors of this chapter prefer to intervene after 2–3 weeks;
however, late spontaneous reattachment 2–3  months (in one case,
INTRAOPERATIVE COMPLICATIONS 10 months) postoperatively has been reported.3,4 To reattach Descemet’s
Cataract Incision membrane, the patient is positioned at the slit lamp after several drops of
anesthetic agent and antibiotics have been administered. A paracentesis
The cataract incision serves as more than just the port of access to the incision is made inferotemporally. A 27- or 30-gauge cannula is attached to
anterior segment; it is a critical step of the operation that affects ocular a syringe with a filter, and the syringe is filled with 0.5–1 cm3 of air or, for
integrity and corneal stability. The traditional limbal or posterior limbal eyes that have an unsuccessful injection of air alone, an expansive gas (e.g.,
incision has been largely replaced by tunnel constructions, which can SF6). Using the cannula, approximately 50% of the aqueous is drained, 401
be located in the sclera, limbus, or cornea and are characterized by their and the chamber is reformed with injection of the gas. Another technique
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new capsulorrhexis should end with the incorporation of the original
5 tear in an outside-in direction; however, the original tear is often too

peripheral to permit this, and a single radial tear is created).
An alternative approach to a “lost” capsulorrhexis is to convert to a

The Lens
“can opener” capsulectomy. It may, indeed, be safer to have multiple tears,

rather than a single one, because forces that extend these tears can be dis-
tributed to multiple sites, which reduces the likelihood of a tear extending
equatorially.
Excessively Small Capsulorrhexis

If the diameter of the capsulorrhexis opening is excessively small, the tear
should be directed more peripherally and continued beyond the original
point of origin before completion of the capsulorrhexis; this procedure
removes an annulus of capsule and enlarges the opening. If the capsulor-
rhexis has been terminated and the opening is too small, a new tear can be
Fig. 5.16.1 Corneal Burn Following Phacoemulsification (Phaco). In this patient started by making an oblique cut with Vannas scissors or a sharp needle. It
with an apparent filtering bleb, phaco was performed through a temporal, clear usually is preferable to enlarge the capsulorrhexis after IOL implantation,
corneal incision (CCI). Posterior capsular rupture was suspected; the surgeon to minimize the risk of radial tears during lens implantation.
injected a highly retentive ophthalmic viscosurgical device beneath and in front
of the nucleus to minimize the risk of posterior dislocation of the nucleus. Phaco Minimizing Complications When Radial Tears Are Present
was instituted with low flow and vacuum settings, and a severe corneal burn was If radial tears are present, several modifications in surgical technique
immediately produced because of obstruction of the phaco tip by the viscoelastic should be considered to minimize the risk of tear extension into the pos-
material. The incision was closed with several interrupted sutures. Many of these terior capsule:
pulled through the injured tissue, and as a result, additional suturing was required
several days later. Postoperatively, the patient has 5 D of surgically induced • Hydrodissection or hydrodelineation is performed gently to minimize
astigmatism that has persisted for more than 5 years. distention of the capsular bag.
• Cracks during emulsification are made gently away from the area(s) with
radial tears. Alternatively, as much of the nucleus as possible is sculpted
for repairing Descemet’s detachments using intracameral gas injection
within the capsular bag, and the rest is removed at the iris plane. The
at the slit lamp microscope has been reported.5 A 25-gauge needle on a
height of the infusion bottle is kept low to prevent overinflation of the
3-mL syringe filled with the gas and another 25-gauge needle are advanced
anterior chamber (which can cause the tear to extend peripherally).
through the corneoscleral limbus at opposite clock hours with the bevel
up and the needles oriented parallel to the iris plane. The plunger on the
• The IOL should be placed with the haptics 90° away from the tear.
One-piece polymethyl methacrylate (PMMA) lenses tend to maintain
syringe is depressed to inject the gas and fill the anterior chamber while
better centration in these situations. Rotation of the IOL should be min-
aqueous humor is allowed to egress from the opposing 25-gauge needle.
imized. The OVD should be removed in small aliquots while gentle
More complicated cases may require direct suturing.6
infusion of BSS is performed through a side-port incision.
• It is important to avoid anterior chamber collapse at any phase of the
Thermal Burns operation when radial tears are present. Anterior bulging of the poste-
rior capsule can place increased stress on a radial tear, which predis-
Part of the energy produced by the phaco tip is dissipated as heat. This
poses its extension into the equator and posterior capsule. To avoid this,
heat is conducted into the eye along the titanium tip and then cooled by
the chamber is deepened each time the phaco or irrigation–aspiration
the ongoing flow of the irrigation–aspiration fluid. If for any reason the
tip is removed from the eye; this is done by injecting fluid, OVD, or
flow is blocked, a corneal burn can occur within 1–3 seconds. The most
perhaps air through the paracentesis incision with a syringe while the
common cause is inadequate flow through the phaco tip because it has
instrument is removed from the incision.
been obstructed by a retentive OVD; this problem arises from use of low
flow and vacuum settings. The critical warning sign is the appearance of
milky fluid that is produced around the tip as emulsification commences. Nucleus Expression Cataract Extraction
To avoid corneal burns, phaco and irrigation–aspiration functions
should always be tested before the eye is entered. Some of the viscoelastic Complications related to nucleus expression are covered in Chapters 5.11
material that overlies the nucleus can be aspirated before the start of emul- and 5.12.
sification to ensure that aspiration is adequate. To prevent constriction of
the irrigating sleeve, an incision size that is appropriate for each particular Complications During Phaco
phaco tip should be selected. If a burn does occur, meticulous suturing of
the wound with multiple radial sutures (Fig. 5.16.1) is required. A bandage Hydrodissection
contact lens may assist with wound closure. Severe postoperative astigma- Hydrodissection was developed to permit easy rotation of the nucleus in
tism can result. The smaller incision size and new-generation phaco tips the capsular bag and to facilitate removal of various layers of the lens by
continue to contribute to a reduction in the incidence of corneal burns. eliminating their adhesion to surrounding tissues. Two major complica-
tions of hydrodissection are inadequate hydrodissection and overinflation
Anterior Capsulectomy of the capsular bag. The former results in a nucleus that does not rotate,
and this predisposes to zonular dehiscence if excessive force is exerted on
Preventing Radial Tears in the Anterior Capsule the nucleus. This can be avoided by making an additional hydrodissec-
For phaco, the preferred method of anterior capsulectomy is capsulorrhexis. tion, particularly in quadrants that have not been hydrodissected before.
It is now recognized that radial tears in the anterior capsule can pose signif- U-shaped cannulas are useful to hydrodissect subincisional regions of the
icant risks because of their tendency to tear into the equatorial region of the lens not accessible with straight or angulated cannulas.
lens7 and extend into the posterior capsule. This causes posterior capsular Overinflation of the capsular bag can predispose to prolapse of the
rupture, loss of lens material, and IOL decentration. The surgeon’s goal, nucleus into the anterior chamber, which might compromise the ease or
therefore, must be to retain an intact capsulorrhexis. A common cause safety of nucleus emulsification. A serious complication of overinflation
of radial tears is irretrievable loss of the capsulorrhexis tear peripherally is posterior capsular rupture, with loss of the nucleus into the vitreous.
beneath the iris. To prevent this, the following steps should be considered: This is more likely to occur in eyes with long axial lengths, (hyper)mature
cataracts, or with fragile posterior capsules, such as those found in patients
• The anterior chamber should be reinflated with an OVD. who have posterior polar cataracts.8
• The vector forces of the tear should be changed to redirect the tear in a
more central direction. Iris Prolapse or Damage
402 • If the tear is lost beneath the iris, the capsulorrhexis should be restarted Iris prolapse is usually caused when the anterior chamber is entered too
from its origin, proceeding in the opposite direction (if possible, this posteriorly, such as near the iris root. If this is noted early in the case
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and interferes with the easy introduction of instruments into the eye, it is
advisable to suture the incision and move to another location.
A second and more ominous cause of iris prolapse is an acute increase 5.16
of intraocular pressure (IOP) accompanied by choroidal effusion or hem-
orrhage. In this instance, the surgeon should attempt to identify the cause

and lower the IOP. Digital massage on the eye, pressing directly on the
incision, may successfully lower the pressure. It is useful to examine the
fundus to ascertain whether a choroidal effusion or hemorrhage exists.
With choroidal effusion, aspiration of vitreous can be helpful, as can the
administration of intravenous mannitol. If a choroidal hemorrhage occurs
or if the increased IOP from an effusion is resistant to treatment, it usually
is best to terminate the surgery. The wound is sutured carefully; intraoc-
ular miotics are administered, and a peripheral iridectomy may be per-
formed to help reposition the iris. For effusions, surgery can be deferred
until later in the day or the next day, when the fluid dynamics of the
eye have returned to a more normal state. If a limited choroidal hemor-
rhage has occurred, it is best to wait 2–3 weeks before attempting further
surgery.
Trauma to the iris from prolapse or emulsification with a phaco tip
can produce an irregularly shaped pupil and iris atrophy and can predis- Fig. 5.16.2 Subluxated Lens. This patient had a subluxated lens caused by ocular
pose to posterior synechiae formation. If iris damage is produced inferiorly trauma. The crystalline lens was removed using a pars plana approach, and a sulcus-
through contact with the phaco tip, loose strands of tissue should be cut to sutured intraocular lens was implanted.
reduce the likelihood of these being aspirated into the phaco tip. Another
option is to use a single iris hook to retract the inferior iris, holding it away hard nucleus should be extracted by using an intracapsular approach. Pars
from the phaco tip for the duration of the procedure. plana vitrectomy is an excellent option for these cases as well; it certainly
is preferred when the lens is subluxated posteriorly.
Floppy Iris Syndrome The location of the IOL placement depends on the status of the cap-
This complication has been observed during phaco in patients receiving sular bag after cataract removal. If zonular disruption is minimal (fewer
α1-antagonist agents, such as tamsulosin (Flomax). The symptoms include than 3 clock hours), the IOL can be implanted into the capsular bag with
billowing and floppiness of the iris, prolapse of the iris to the main and the haptic orientated in the meridian of the zonular defect. If the zonular
side incisions, and progressive constriction to the pupil during surgery.9 disruption is larger, options include the following:
When treating patients who receive α1-antagonist agents, the surgeon
can try to avoid severe intra- and postoperative complications by preoper-
• Ciliary sulcus implantation, possibly with scleral or iris fixation of one
or both haptics.
ative use of atropine, intraoperative epinephrine (adrenaline), lower phaco
vacuum and aspiration settings, the use of supercohesive OVDs, and
• Insertion of one haptic into the capsular bag and suturing of the second
haptic into the sulcus.
various iris hooks and pupil dilators.10
• Endocapsular ring implantation to stabilize the capsular bag or a Cionni
ring to suture the capsular bag/ring complex to the sclera.13–15
Trapped Nucleus • Anterior chamber lens implantation (angle-supported or iris fixated).16
In this situation, the nucleus seems to be trapped within the capsular bag;
it resists rotation, elevation, or both. This usually indicates a nucleus that
• An angle-supported anterior chamber lens, which is acceptable if no
anterior chamber angle pathology, glaucoma, or uveitis is present.14
requires further hydrodissection, which should be repeated in regions
not previously hydrodissected (e.g., laterally and inferiorly with angled or
• Posterior chamber lens implantation (as iris fixated retropupillary
Artisan type).17
straight cannulas, superiorly with U-shaped cannulas; if these cannulas
are not available, additional paracentesis sites can be created in strategic
locations).11 If this fails to achieve adequate mobilization of the nucleus, Ruptured Posterior Capsule
viscodissection can be performed. An OVD is injected in the plane of the
hydrodissection, which usually results in elevation of the nuclear remnant. Posterior capsule rupture is the most common serious intraoperative com-
When re-entering the eye with the phaco tip, irrigation should not be used plication of cataract surgery.18 Proper management, however, can result in
until a second instrument has been inserted through the stab incision and minimal morbidity to the patient. A posterior capsular rent is more likely
placed below the nucleus; when irrigation and aspiration begin and the to occur in eyes with small pupils, hard nuclei, or pseudo-exfoliation syn-
OVD is removed, the second instrument prevents the nuclear piece from drome. Recent reports suggest that the visual prognosis of patients who
falling back into the posterior chamber. have broken posterior capsules is excellent. The key factors are to mini-
If the capsulorrhexis is small and the nuclear circumference is intact, mize ocular trauma, meticulously clean prolapsed vitreous from the ante-
nuclear elevation through the capsulorrhexis may not be possible. Addi- rior segment, if present, and ensure secure fixation of the IOL.
tional sculpting might be required to thin the nucleus centrally or to
remove some of the peripheral nucleus. After the nucleus has been suf- Before Nucleus Removal
ficiently thinned, an instrument, such as a Sinskey hook or spatula, can A capsular break noted before nucleus extraction is a potential disaster.
be teased posteriorly through the remaining nuclear tissue. This enables The first objective is to prevent the nucleus from being dislodged into
elevation of a portion of the nucleus and thereby facilitates access to the the vitreous cavity. An OVD can be injected posterior and anterior to the
remainder. nucleus to prevent its posterior displacement and to cushion the corneal
endothelium. Another alternative is to insert an instrument through a
Subluxated Lens pars plana incision 3 mm posterior to the limbus into the vitreous, which
The surgical approach for subluxated lenses (Fig. 5.16.2) is determined Kelman had described as “posterior assisted levitation” (Charles Kelman,
by lens stability, lens position, and nuclear density.12 In a subluxated lens personal communication). The nucleus is pushed gently anteriorly so that
with adequate zonular support, phaco (or nuclear expression) can be per- it can be captured in front of the iris and safely removed from the eye.
formed. OVD is injected as needed throughout the surgery to tamponade Once the nucleus or its remnants have been repositioned in the anterior
the vitreous in areas of zonular dehiscence. Extensive hydrodissection and chamber, the choice is to convert or to continue the emulsification. The
viscodissection should be carried out. Depending on the density of the latter course can be more hazardous and predisposes to enlarging the rent
nucleus, either phaco in the capsular bag or anterior chamber phaco under and possibly losing the nucleus into the vitreous. In most circumstances,
a retentive viscoelastic is performed. Any form of zonular stress should be the nucleus should be managed by sufficiently enlarging the wound to
minimized, particularly with nuclear rotation. Although not the topic of facilitate easy extraction of the nucleus on a lens loop. However, in the case
this chapter, femtosecond laser-assisted capsulectomies can help in these of a small break or when only a small amount of nucleus is left, it may be
situations because they produce minimal stress to the zonules. possible to cover the posterior capsular opening with a retentive OVD and
If phacodonesis is present but the lens has not fallen posteriorly, a complete the phaco. A Sheets glide can also be used as a “pseudo-posterior 403
soft nucleus sometimes can be removed by phaco-aspiration, whereas a capsule” to facilitate completion of phaco.
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Vitreous loss almost always accompanies posterior capsular rupture
5 that occurs before nucleus removal. Whenever feasible, vitrectomy should

be performed before the nuclear pieces are removed. Clearly, this should
not be done if it makes loss of the nucleus into the vitreous more likely.
The Lens
During Cortical Irrigation–Aspiration

When capsular rupture occurs during aspiration of the cortex (which is, in
fact, the most common cause),7,19 a key factor is the status of the vitreous.
If no vitreous is present in the anterior segment, vitreous loss often can
be averted. An OVD can be injected through the capsular opening to push
the vitreous posteriorly. Cortical removal can be completed using low-flow
irrigation. Options include using a manual system; a dry approach, aspirat-
ing with a cannula in the chamber filled with OVD; a bimanual approach
through two paracentesis openings; and automated irrigation–aspiration
with all settings reduced.20 The cortex should be stripped first in the region
farthest from the rent, and the direction of stripping should be toward the
rent. Because it can be hazardous to remove the cortex in the region of the
rent, the cortex is sometimes better left in the eye, to avoid the possibility
of enlarging the rent and precipitating vitreous loss. One option to prevent
extension of the rent is to convert the tear into a small posterior capsu-
lorrhexis, which eliminates any radially orientated tears that could extend Fig. 5.16.3 Dropped Nucleus. B-scan ultrasonography 1 day after dislocation of a
with further surgical manipulation. lens nucleus into the vitreous cavity in a patient with high myopia.
If vitreous is present in the anterior segment, vitrectomy should be
performed first, with the necessary caution being taken to prevent exten- stabilization with a capsular tension ring has to be considered to avoid
sion of the rent. Depending on the type of capsular tear, the vitrectomy further postoperative complications.25
is performed through either the limbal incision or the pars plana. The Postoperative examinations should include measurement of IOP and
former approach is used when the tear is located near the incision, which endothelial cell count.
permits vitrectomy with minimal risk of enlargement of the tear. A pars
plana approach is preferred when the tear is remote from the incision Ciliary Sulcus
and, therefore, less accessible anteriorly. In either case, irrigation is pro- If the rent exceeds 4–5 mm in length or extensive zonular loss occurs,
vided with an infusion cannula in the paracentesis opening, or a 23-gauge the capsular bag probably is not adequate for IOL support. In such cases,
trocar is inserted through the pars plana. After a thorough anterior vitrec- the ciliary sulcus is opened with an OVD, and the iris is retracted in all
tomy, the remaining cortical material can be removed using one of the quadrants to assess the status of the peripheral capsule and zonules. The
techniques described earlier or using the vitrector in the aspiration mode IOL is inserted with its haptics oriented away from the area of the rent and
without cutting. positioned in areas of intact zonules and capsule.
Another alternative, if the anterior capsulorrhexis is intact, is sulcus
Intraocular Lens Insertion placement of the IOL, with capture of the optic through the capsulorrhexis.
Careful inspection of the anatomy of the capsule and zonules is required Finally, some surgeons advocate iris suture fixation of one or both haptics
to determine the appropriate site for IOL implantation. There are five to prevent IOL decentration. After the IOL optic is captured through the
choices: capsular bag; iris fixated (retropupillary or prepupillary); ciliary pupil, McCannel sutures are used to secure the haptic(s) to the iris, and
sulcus; sutured posterior chamber; and anterior chamber. then the optic is repositioned through the pupil.
Capsular Bag Sutured Posterior Chamber

If the rent is small and relatively central, and if the anterior capsular If loss of more than 4–5 clock hours of capsule or zonules occurs, the
margins are well defined, the posterior chamber IOL can be implanted ciliary sulcus may be inadequate for lens stability. The lens can be fixated
into the capsular bag. If possible, conversion of posterior capsule tears to to the sclera or to the iris using single or dual 10-0 polypropylene or more
posterior continuous curvilinear capsulorrhexis (CCC) is recommended.21 recently Gore-Tex sutures. If one region of solid peripheral capsule and
With the use of an OVD, posterior CCC is initiated by grasping the advanc- zonules exists, one haptic can be inserted into the sulcus in this area, and
ing tear in the posterior capsule with forceps, and then applying CCC prin- the opposite haptic can be sutured to the sclera or the iris.
ciples. This technique is applied to avoid an anticipated extension of the
inadvertent linear or triangular tear during maneuvers, such as a required Anterior Chamber
vitrectomy or lens placement. The surgeon should ensure that the haptics A Kelman-type multiflex anterior chamber IOL design is a good option
are orientated away from the rent (to avoid haptic placement or subsequent for patients who do not have glaucoma, peripheral anterior synechiae, or
migration into the vitreous) and that the lens is inserted gently to avoid chronic uveitis. A peripheral iridectomy should be performed in these
enlargement of the rent. patients to prevent pupillary block. Iris fixated Artisan anterior chamber
type IOLs have even less complications.
Iris Fixated (Retropupillary or Prepupillary)
This type of fixation can be chosen for cases of aphakia, defect posterior Dropped Nucleus
capsule, or tissue weakness. The great advantage of iris-fixated IOLs is that
no capsular bag is necessary for fixation. These lenses, known as Artisan/ Loss of nuclear material into the vitreous cavity (Fig. 5.16.3) is one of the
Verisyse lenses, have claws which fix them on the iris stroma and are often most potentially sight-threatening complications of cataract surgery.26 Clin-
implanted in patients with aphakia because of failed cataract surgery, ical and cadaver eye studies implicate posterior extension of breaks in the
pseudo-exfoliation syndrome (PEX), or connective tissue weakness (Video capsulorrhexis as a common cause of this complication.7,27 Therefore, the
See clip:
5.16.1
5.16.1). surgeon would be wise to use increased caution when phaco is performed
The implantation itself is a difficult technique because of the danger with capsulorrhexis tears.28 Posterior polar cataract, which predisposes to
of potential loss of the IOL in the vitreous. Potential complications, such posterior capsular dehiscence, is another risk factor for dropped nucleus.29
as endothelial cell loss, decentration, loss of enclavation, and iris damage, Loss of the nucleus into the vitreous cavity can be avoided by recogniz-
have to be considered. ing the early signs of posterior capsular rupture. These include unusual
Koss and Kohnen found no significant loss of endothelial cells after deepening of the anterior chamber, decentration of the nucleus, or loss of
implantation of anterior chamber iris-claw lenses in aphakic eyes. efficiency of aspiration, which suggests occlusion of the tip with vitreous.
The distance from lens to endothelium remained constant pre- and If capsular rupture is noted, the steps outlined earlier should be taken to
postoperatively.22 prevent nucleus loss.
Recent studies have shown an increase in visual acuity after retroiridal Some controversy exists with regard to the appropriate management
404 or sclerafixated implantation of an IOL due to aphakia, luxation, or zonula of loss of the nucleus into the vitreous. Most surgeons recommend com-
insufficiency.23,24 When implanting IOLs in eyes with zonular insufficiency, pleting the procedure with careful anterior vitrectomy and removal of
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remaining accessible lens material. In general, IOL implantation is per- an eye from complete loss of intraocular contents. However, the surgeon
missible; one exception might be loss of an extremely hard, dense nucleus
that would require removal through a limbal incision. If a significant
can assist by using a finger tamponade on the wound while hyperosmotic
solution is given intravenously. The wound should be closed and the ante- 5.16
amount of nuclear material has been retained, vitreoretinal surgery needs rior chamber deepened further, if possible, using a balanced salt solution
to be performed 1–2 days postoperatively. Patients whose eyes have small or an OVD.

residual nucleus fragments may be observed and referred if increased IOP In the event of severe ongoing prolapse of tissue through the incision,
or uveitis refractory to medical treatment develops. Some surgeons advo- a posterior sclerotomy should be performed; this must be done quickly.
cate irrigating the vitreous with fluid in an attempt to float the nucleus Time permitting, a conjunctival peritomy is made 3–4 mm posterior to
back into position. An obvious concern is that this additional turbulence the limbus. Using a microsurgical steel knife, a radial incision approxi-
could increase vitreous traction on the retina resulting in retinal tears and mately 2 mm in length is made, scratching through the sclera to the level
retinal detachment. of the suprachoroidal space. Usually, blood begins to ooze from this site.
As this occurs, infusion of fluid and OVD into the anterior chamber is
Anterior Segment Hemorrhage commenced in an attempt to restore normal anterior segment anatomy.
This bleeding site can be left open, or it can be sutured once the rate of
The presence of intraocular blood prevents the surgeon’s visualization hemorrhage has diminished, the incision has been closed, and the normal
during the procedure, stimulates postoperative inflammation, and synechia anterior chamber depth has been restored. The goal in these cases is to
formation, and accelerates capsular opacification. To minimize the risk of preserve the eye; cataract surgery can always be completed at a later date,
bleeding, discontinuation of anticoagulant therapy before surgery can be typically 2 or more weeks later.
considered if it does not pose a significant medical risk to the patient.30 It is recommended that postoperative examinations should be per-
The sites of anterior segment hemorrhage are either the wound or the formed 1 day, 7–10 days, and 4–6 weeks after cataract surgery.
iris. Steps to minimize or eliminate bleeding from the wound include the
following:
POSTOPERATIVE COMPLICATIONS
• Careful cautery of bleeding vessels in the vicinity of the incision.
• Creation of an adequate internal corneal valve to minimize the likeli- Wound Dehiscence
hood of scleral blood entering the anterior chamber.
With small-diameter tunnel incisions, wound dehiscence is relatively
• Performing a clear corneal incision. uncommon. The creation of an internal corneal valve typically prevents
• Avoid iris trauma, which can lead to iris bleeding. the major complications of wound leakage, inadvertent filtering bleb, and
Intraocular bleeding can be stopped by taking the following measures: epithelial downgrowth. The wound healing process varies according to the
site of the posterior entry. Scleral limbal incisions heal by the ingrowth of
• Temporarily elevating the IOP with a balanced salt solution or an OVD.
episcleral vascular tissue. New fibrovascular tissue is deposited with an ori-
• Injecting a dilute solution of preservative-free epinephrine 1 : 5000 (or a
entation parallel to the edges of the incision and perpendicular to existing
weaker solution).
collagen bundles. Over the ensuing few years, collagen remodeling occurs,
• Direct cautery (if the bleeding vessel can be identified) with a so that the new collagen becomes oriented parallel to existing collagen
needle-tipped cautery probe.
bundles, which increases the strength of the healed area.32 Ultimately, the
The most serious complication of cataract surgery is expulsive hemor- strength of the healed area is approximately 70%–80% that of the native
rhage, which is actually a spectrum of conditions ranging from supracho- tissue. For corneal incisions, closure of the external wound takes place by
roidal effusion to mild hemorrhage to severe hemorrhage with expulsion. apposition or, in areas of wound gape, by epithelial ingrowth. A gradual
A sign of any of these conditions is shallowing of the anterior chamber process of remodeling then occurs; this consists of fibrocytic metaplasia
with posterior pressure that resists further deepening of the chamber, of keratocytes with deposition of new collagen, again parallel to the inci-
sometimes accompanied by a change in the red reflex. These conditions sion, followed, over a number of years, by remodeling similar to that seen
typically occur intraoperatively but also may occur postoperatively, usually with scleral incisions. In the absence of vascular tissue, this process occurs
when the IOP is below normal (Fig. 5.16.4). Choroidal effusion also may be much more slowly than in scleral or limbal tissue. Postoperative abnormal-
a precursor to suprachoroidal hemorrhage, which presumably occurs from ities in wound structure are produced by defects in the tunnel architecture
the rupture of a blood vessel that is placed under stretch. Risk factors for or by defective wound healing because of systemic disorders, pre-existing
suprachoroidal hemorrhage include hypertension, glaucoma, nanophthal- tissue abnormalities (e.g., excessively thin or weak tissue), or incarceration
mos, high myopia, and chronic intraocular inflammation.31 of material, such as lens, vitreous, or iris, in the wound, which inhibits the
If sudden shallowing of the anterior chamber occurs and the eye normal healing process.
becomes firm, the retina should be examined, if possible, to ascertain the
cause. If a dark choroidal elevation is noted, a choroidal hemorrhage is Wound Leakage
likely, and the incision should be closed as quickly as possible. The worst
scenario is expulsion of intraocular contents through the wound. With A wound leak that occurs in the immediate postoperative period usually is
tunnel incisions, the wound typically is self-sealing and resists expulsion the result of inadequate suture closure for a specific wound configuration.
of a significant amount of tissue. This self-sealing construction can save This entity is rare with tunnel constructions. Scleral pocket incisions have
a longer tunnel and can readily be demonstrated to be watertight at the
conclusion of surgery. Corneal incisions as small as 3.5 mm in width seal
remarkably well, even though intraoperative pinpoint posterior lip pres-
sure in these eyes often can induce a wound leak. Some surgeons perform
hydration of the corneal stroma to prevent a wound leak that can be elic-
ited with posterior lip pressure; however, this hydration clears within a
few minutes to hours, and it is uncertain whether it has any actual clinical
value.
Wound leaks in scleral incisions typically are covered by conjunctiva
and usually resolve within a few days; occasionally, they lead to the forma-
tion of a filtering bleb. Medical management of scleral or corneal wound
leaks may include the following:
• Decreasing or discontinuing corticosteroid therapy.
• Administration of prophylactic topical antibiotics.
• Pressure patching.
• Use of a collagen shield, bandage lens, or disposable contact lens.
• Administration of aqueous inhibitors.
Fig. 5.16.4 Choroidal Effusion. This patient experienced deep ocular pain 1 day It usually is necessary to suture a wound if the leak persists after
postoperatively. A choroidal hemorrhage was noted on close examination. This 5–7 days, or if there is a flat anterior chamber, iris prolapse, extensive exter- 405
resolved over several months, leaving no permanent sequelae. nal tissue gape, or excessive against-the-wound astigmatism (Fig. 5.16.5).
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The Lens
Fig. 5.16.5 Wound Dehiscence. This patient had 5 D of against-the-wound

astigmatism following nuclear expression. The surgeon resutured the wound Fig. 5.16.6 Postoperative Hyphema. This hyphema was produced by hemorrhage
4 weeks postoperatively, but the astigmatism immediately recurred. Note the thin, from the scleral incision in a patient who had a small postoperative wound leak.
fragile sclera, sometimes characterized as scleral “melting.” The hyphema resolved once the incision closed, which led to cessation of ongoing
bleeding and restoration of normal intraocular pressure.
Inadvertent Filtering Bleb • Prior endothelial disease or cell loss.

• Intraoperative mechanical endothelial trauma.
Formation of a filtering bleb after cataract surgery occurs if the wound • Excessive postoperative inflammation.
leaks under a sealed conjunctival flap. If early filtration is recognized, • Prolonged postoperative elevation of IOP.
progression might be prevented by discontinuation of corticosteroid treat-
ment. If the patient is asymptomatic, the physician can observe the bleb. Preoperatively, patients should be examined carefully for evidence of
Elimination of the bleb can be considered if it causes irritation, tearing, Fuchs’ dystrophy or other conditions that produce a low endothelial cell
or infection. Blebs that tend to be more symptomatic are tall and cystic count. Patients who have marginal corneal endothelial function may com-
and encroach over the corneal surface. Options for late closure include plain of poorer vision in the morning because of corneal edema produced
cryotherapy, chemical cautery, neodymium:yttrium–aluminum–garnet by hypoxia overnight. Although most patients who have Fuchs’ dystrophy
(Nd:YAG) laser,33 or surgical closure. The latter can be a complex proce- have guttae that are readily visible with slit-lamp examination, in rare
dure because of endothelialization of the fistula. The surgical approach instances, patients can have low endothelial cell counts in the absence
requires excision of the conjunctival bleb, scraping or cryotherapy of the of guttae. It often is advisable to obtain an endothelial cell count in the
cells that line the fistula, and closure of the fistula, which sometimes fellow eye. Finally, corneal pachymetry can be helpful to assess such
requires a scleral patch graft. patients because those with a corneal thickness in excess of approxi-
mately 0.63 mm presumably have marginally compensated corneas and
are at great risk of developing permanent postoperative corneal edema.
Epithelial Ingrowth If the corneal thickness is greater than 0.63 mm but no corneal edema is
Epithelial ingrowth or downgrowth is a rare but serious complication of evident, the authors generally perform cataract surgery alone and advise
intraocular surgery. It occurs most commonly after intracapsular cataract patients of the increased risk of developing postoperative corneal decom-
extraction and less often following nucleus expression; it is extremely rare pensation. If frank epithelial and stromal edema is present, a combined
after phaco. Surface epithelium that invades the intraocular structures, cataract extraction with posterior lamellar or (only rarely nowadays) pene-
such as over the cornea, iris, ciliary body, lens capsule, and Bruch’s mem- trating keratoplasty (PKP) may be advisable.
brane,34 can cause corneal decompensation, chronic anterior uveitis, and Several measures can be taken intra- and postoperatively to minimize
intractable secondary angle-closure glaucoma. Conditions for the onset the risk of corneal injury. Some surgeons may consider nuclear expres-
of this entity are highly variable, but it appears to be more common in sion safer than phaco, and others may consider femtosecond laser-assisted
patients who undergo multiple intraocular procedures or have postopera- surgery (FLACS) safer.36 Techniques to remove the nucleus in the posterior
tive wound dehiscence. chamber seem to minimize endothelial cell loss.37 Evidence suggests that
The presence of epithelial downgrowth may be confirmed by irradiation highly retentive OVDs are more protective when surgical removal of the
of the affected iris with an argon laser (epithelial tissue turns white with nucleus is carried out near the endothelium. Postoperatively, inflammation
argon ablation, compared with the dark or brown appearance of normal should be aggressively treated with topical corticosteroids, and IOP should
iris) or diagnosed with specular micrography (noting a sheet of abnormal be maintained below 20 mm Hg. Mechanical factors, such as Descemet’s
tissue that obliterates the normal endothelial mosaic); however, the defin- detachment or retained nuclear fragments in the angle touching the endo-
itive diagnosis is dependent on the histopathological confirmation of epithelium, should be addressed. For symptomatic relief, hypertonic saline
thelial tissue in the eye. Treatment consists of complete destruction of all ointment is sometimes helpful as a temporary measure. Sequential corneal
intraocular epithelial tissue by using cryotherapy, iridocyclectomy, or pars pachymetry is an excellent way to document the resolution of postoperative
plana vitrectomy. Unfortunately, the prognosis for this postoperative com- corneal edema, which may take up to 3 months; it is usually advisable to
plication is poor, except for a well-defined cyst that can be excised en bloc.35 wait at least this long before recommending penetrating keratoplasty.
Postoperative Astigmatism Hyphema

Complications related to postoperative astigmatism are covered in Chap- A postoperative hyphema is caused by bleeding from the wound or iris
ters 5.4 and 5.18. (Fig. 5.16.6). As the hyphema resolves, the IOP should be controlled. Sur-
gical reintervention to remove a blood clot is indicated if severe, medically
Corneal Edema and Bullous Keratopathy resistant pressure elevation exists for several days. The duration of toler-
ated pressure elevation depends on the patient’s age and the status of the
406 Factors that predispose to corneal edema following cataract surgery include optic nerve. Making clear corneal incisions (CCIs) reduces the incidence
the following: of postoperative hyphema.
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Late hyphema or microhyphema most often is caused by chafing of initial type of CBS, with accumulation of the OVD in the capsular bag, as
the IOL against the iris or ciliary body (uveitis–glaucoma–hyphema [UGH]
syndrome).38 This most typically occurs because of loss of fixation of the
discussed earlier. Late postoperative CBS refers to eyes with accumulation
of a milky-white substance in the closed capsular bag.47–49 Reduction of 5.16
sulcus-fixated posterior chamber IOL; micromovements of the lens cause vision with this type of CBS is rare, and Nd:YAG laser capsulectomy can
chafing against a vessel, which produces the postoperative bleeding. Treat- be performed, if necessary.

ment consists of IOL exchange and ensuring that the new lens is well
fixated; this might require suture fixation to the sclera or implantation of Intraocular Lens Miscalculation
an anterior chamber lens. A rare cause of postoperative bleeding is hem-
orrhage from vascularization of the internal margin of the incision (Swans Complications related to IOL miscalculation are covered in Chapter 5.4.
syndrome)39; this can be diagnosed by noting neovascularization of the
wound using gonioscopy; it is treated by argon laser photocoagulation. Intraocular Lens Decentration and Dislocation
Common causes of IOL decentration and dislocation are asymmetrical
Endocapsular Hematoma loop placement, sunset syndrome, loss of zonular support for a lens fixated
Endocapsular hematoma is the postoperative entrapment of blood between in the capsular bag, and pupillary capture of the IOL optic.50
the posterior surface of the IOL and the posterior capsule.40 It is a variant
of hyphema, with the exception that the blood can become entrapped Asymmetrical Haptic Placement
within the capsular bag for months or even permanently. Fortunately, in Pathological studies indicate that asymmetrical loop placement is an
most instances, the amount of blood is minimal and either does not sig- extremely common occurrence, particularly when “can opener” capsulec-
nificantly impair vision or is absorbed over a few weeks or months.41 When tomies are performed. The incidence of this complication has been greatly
the accumulation is extensive and persistent, Nd:YAG laser posterior cap- reduced with the advent of capsulorrhexis, which permits excellent visual-
sulectomy is curative when used to enable immediate blood flow into the ization of the capsular edge and ensures that a lens placed in the capsular
vitreous, where the blood can be resorbed. bag is retained there. An IOL with asymmetrical loop placement becomes
symptomatic if the lens is decentered sufficiently relative to the pupil;
Intraocular Pressure Elevation symptoms include polyopia, glare, induced myopia (from looking through
the peripheral portion of the IOL), and loss of best spectacle-corrected
Elevation of IOP following cataract surgery is a common occurrence. For- visual acuity (BSCVA). Depending on the severity of the symptoms, treat-
tunately, it is usually mild and self-limiting and may or may not require ment includes IOL repositioning or IOL exchange. In some instances,
prolonged antiglaucoma therapy. Causes of acute pressure elevation are topical miotics can be prescribed; however, few patients prefer this mode
retention of viscoelastic substances, obstruction of the trabecular mesh- of management.
work with inflammatory debris, and pupillary or ciliary block. Patients
who have pre-existing glaucoma are at much greater risk of developing Sunset Syndrome
acute, significant pressure elevation. Prevention of this problem includes Sunset syndrome occurs when a sulcus-fixated posterior chamber IOL dis-
careful removal of the OVD at the time of surgery, control of intraocu- locates through a peripheral break in the zonules, typically inferiorly. Sunset
lar bleeding, and the use of intra- and postoperative antiglaucomatous syndrome is usually an acute, nonprogressive event. Treatment options
agents. Intracameral injection of 0.01% carbachol at the conclusion of again depend on the severity of the patient’s symptoms. The authors have
surgery is effective, as is the postoperative administration of pilocarpine found that simple IOL repositioning is often unsuccessful and predisposes
gel; topical beta-blockers; apraclonidine; and topical, intravenous, or oral to recurrence. Therefore, several other options are recommended:
carbonic anhydrase inhibitors. If marked elevation of IOP is present on
the first postoperative day, this can be immediately controlled by “venting”
• Repositioning the lens, combined with iris fixation sutures.
the anterior chamber. After topical anesthetic agents and antibiotics have
• IOL exchange with a larger, more rigid lens.
been administered, a forceps or other fine instrument is used to depress
• Scleral fixation of a posterior chamber lens.
the posterior lip of the paracentesis incision, which allows the egress of a
• Replacement with an anterior chamber lens.
small amount of OVD and aqueous.42 This is repeated as necessary until
the IOP is brought into the low-normal range. The patient can then be Lens-Bag Decentration
treated with topical antiglaucoma therapy and followed carefully to ensure In rare instances, a lens that is placed in the capsular bag can dislocate as a
that pressure is controlled. result of bag decentration caused by zonular rupture or dehiscence. Treat-
Chronic IOP elevation can be caused by corticosteroid use, retained lens ment of this condition, if sufficiently severe, requires IOL exchange with
(particularly nuclear) material, chronic inflammation, peripheral anterior some form of scleral fixation or implantation of an anterior chamber lens.
synechiae formation, endophthalmitis, and ciliary block. The correct diag-
nosis of the underlying cause is required to institute appropriate therapy. Pupillary Capture
Pupillary capture of the IOL optic consists of the posterior migration of
Capsular Block Syndrome some portion of the iris beneath the IOL optic (Fig. 5.16.7). Predisposing
factors are “can opener” capsulectomy and sulcus implantation of the pos-
Capsular block syndrome (CBS) is initially defined as the entrapment of terior chamber IOL, particularly in the absence of angulated haptics. In
an OVD in the capsular bag because of apposition of the anterior rim of rare instances, however, pupillary capture can occur with capsular fixa-
the capsulorrhexis with the anterior face of the IOL.43,44 This may be more tion of the lens after capsulorrhexis, especially when the capsulorrhexis is
common with acrylic IOLs because of their slightly “stickier” surface. Post- large.51,52 Pupillary capture can produce acute and chronic iritis, posterior
operatively, the bag becomes more distended (perhaps through osmotic synechiae formation, visual loss from deposition of inflammatory cells on
imbibition of aqueous), and the IOL is pushed anteriorly to create a myopic the IOL surface, and, if the lens is displaced sufficiently eccentrically and
refractive shift. This can be prevented by meticulous removal of the OVD anteriorly, chronic endothelial trauma with corneal decompensation. Pupil-
from the bag at the conclusion of surgery. To accomplish this, it is helpful lary capture diagnosed within a few days of its occurrence can be treated
to gently depress the IOL optic to displace the OVD trapped behind the pharmacologically or by manually repositioning the optic into the poste-
IOL.45 Treatment requires Nd:YAG laser puncture of the anterior capsule rior chamber. Chronic pupillary capture may be more difficult to manage,
peripheral to the edge of the capsulorrhexis, which permits the OVD to because firm synechiae form between the iris and posterior capsule. In
escape into the anterior chamber. Alternatively, if the pupil is relatively such situations, the IOL should be repositioned if there are visual symp-
small and the anterior capsule is not accessible to laser treatment, a small toms, chronic uveitis, or corneal endothelial trauma. Chronic cellular pre-
posterior capsulectomy can be performed, which permits the OVD to drain cipitates on the IOL surface can often be managed by the administration of
into the vitreous. Another alternatives is bimanual aspiration–irrigation of topical corticosteroids and occasional Nd:YAG laser “dusting” of the ante-
the material from the capsular bag after the IOL has been dislocated with rior IOL surface.53
the irrigation instruments.
A new classification of CBS includes intraoperative CBS, early postoper- Sulcus-Fixated Intraocular Lens Dislocation
ative CBS, and late postoperative CBS.46 Intraoperative CBS occurs during
rapid hydrodissection using a large amount of BSS and has been discussed Another subtle but important form of IOL dislocation is loss of fixation 407
in the section on hydrodissection. Early postoperative CBS represents the of the sulcus-fixated IOL. This can produce recurrent microhyphema or
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The Lens
Fig. 5.16.7 Pupillary Capture of the Intraocular Lens. Predisposing factors in

this patient included a “can opener” capsulectomy, intraoperative iris trauma, and
nonangulated haptics.
Fig. 5.16.8 Intraocular Lens Dislocation. During surgery, a capsular rupture was
noted. A lens was, however, implanted in the posterior chamber. On the morning
hyphema, as well as chronic iritis and even pigmentary glaucoma. The after surgery, the lens was found to be dislocated posteriorly and inferiorly, and
loss of lens fixation often is subtle, but it can be diagnosed at the slit lamp the patient was referred for treatment. At the time of lens exchange, it appeared
by observing the third and fourth Purkinje images. If the patient is asked that insufficient capsular support was present, and a new lens was sutured into the
ciliary sulcus.
to look eccentrically and then refix centrally, these images can be seen to
flutter or wobble excessively (pseudo-phacodonesis), which indicates lack
of adequate IOL fixation. Intraoperatively, this can be verified by touching Finally, if sufficient intact posterior capsule exists, an attempt can be made
the IOL with an instrument; there is obvious IOL instability. to reopen the capsular flaps to permit fixation of the new lens within the
Pigment dispersion syndrome (PDS) can occur after uneventful cataract capsular bag; this, clearly, is the most desirable location.
surgery and implantation of a posterior-chamber single-piece IOL with a
sharp-edge design after sulcus position of these IOLs. Several days after Cystoid Macular Edema
IOL implantation, marked pigment dispersion can be seen on the iris and
in the trabecular meshwork, associated with an elevation in IOP. Thor- Cystoid macular edema (CME) is the most common cause of unexpected
ough examination showed that the implanted IOL is in the ciliary sulcus. visual loss following cataract surgery.56,57 Fluorescein angiographic CME
After surgical repositioning of the IOLs into the capsular bag, the pigment can occur in up to 50% of patients at 4–8 weeks postoperatively, but clinical
dispersion regressed and the IOP returned to normal limits.54 CME occurs in less than 3% of patients. Recent studies have shown that
macular swelling can be clinically insignificant but can be detected, for
Posterior and Anterior Dislocation example, with optical coherence tomography (OCT).58 The typical time of
onset of clinical CME is 3–4 weeks postoperatively. Predisposing factors
In rare instances, a posterior chamber lens can fall posteriorly and either are intraoperative complications (e.g., vitreous loss or severe iris trauma),
become suspended in the anterior vitreous (Fig. 5.16.8) or dislocate com- vitreous traction at the wound, diabetic retinopathy,59 and pre-existing
pletely into the vitreous cavity. In the former instance, IOL exchange is epiretinal membrane. In cases without predisposing factors, CME typi-
advisable, because the lens is within reach and can produce visual symp- cally resolves over several weeks, although most surgeons prefer to treat
toms or chafe on uveal tissue. Management of a complete posterior IOL this topically with nonsteroidal and corticosteroid drops.60 Other modes
dislocation is more controversial. Although this condition is well tolerated of treatment that have been employed include sub-Tenon’s corticosteroid
in some eyes, in others, the lenses can become entrapped in the vitre- injection, and administration of systemic nonsteroidal anti-inflammatory
ous base and cause vitreous traction and retinal tears, or they can produce drugs with corticosteroids. In patients who have epiretinal membranes,
visual symptoms by intermittently moving into the visual axis. CME may take months to resolve. When associated with diabetic retino-
Even more rarely, anterior dislocation of a posterior chamber lens into pathy, CME often is resistant to medical therapy and can persist indefi-
the anterior chamber may occur.55 This can be prevented with a small and nitely; macular laser photocoagulation is sometimes helpful to document
continuous capsulorrhexis and in-the-bag implantation of the lens. angiographically the leaking vessels and microaneurysms. Patients who
have ongoing structural abnormalities, such as vitreous traction or exten-
Intraocular Lens Exchange sive iris chafing, are less likely to experience spontaneous resolution of
CME and may benefit from surgical correction of the precipitating factor.
Several principles of IOL exchange need to be emphasized. It is generally
preferable to exchange lenses that have haptics that are poorly designed, Endophthalmitis
too short, or deformed from lens malposition in the eye. Patients who
have a marginal corneal endothelium status, generally should be sub- Endophthalmitis can occur in an acute or chronic form. It is character-
jected to the least traumatic surgery possible, such as iris repositioning ized by ciliary injection, conjunctival chemosis, hypopyon, decreased visual
with iris fixation sutures rather than IOL exchange, particularly if the latter acuity, and ocular pain. The acute form generally develops within 2–5 days
requires anterior vitrectomy. It is important to distinguish between IOL of surgery and has a fulminant course (Fig. 5.16.9). Common causative
decentration and pupil displacement. In some instances, the patient’s organisms are Gram-positive, coagulase-negative micrococci, Staphylococ-
symptoms result from an eccentrically displaced pupil in the face of a rel- cus aureus, Streptococcus species, and Enterococcus species.61,62
atively well-positioned IOL. Clearly, surgery, if indicated, should address Chronic endophthalmitis is caused by organisms of low pathogenicity,
the underlying problem by reconstructing the pupil. This can be done by such as Propionibacterium acnes or Staphylococcus epidermidis. It typically is
suturing the pupil in the peripheral region and opening the pupil centrally diagnosed several weeks or longer after surgery. Signs include decreased
with several small sphincterotomies. If certain complications are associ- visual acuity, chronic uveitis with or without hypopyon formation, and, in
ated with the site of the dislocated IOL (e.g., recurrent microhyphema with some instances, plaque-like material on the posterior capsule. Histopatho-
408 a posterior chamber IOL or peripheral anterior synechiae with an anterior logically, this material consists of the offending microorganism embedded
chamber IOL), it may be advisable to place the new lens in a new site. in residual lenticular tissue.
booksmedicos.org
5.16

Fig. 5.16.9 Postoperative Endophthalmitis. This patient developed acute
postoperative endophthalmitis after clear cornea cataract surgery and implantation
of a polymethyl methacrylate (PMMA) posterior chamber intraocular lens. During
cataract surgery, a capsular break occurred, and an anterior vitrectomy was
performed. The patient was treated successfully with vitrectomy and injection of
Fig. 5.16.10 Posterior Capsular Opacification. Elschnig’s pearl formation and
intravitreal antibiotics combined with postoperative topical antibiotic therapy. Final
capsular wrinkling causing a severe decrease of visual acuity.
visual acuity was 20/50 (6/15).
Treatment of endophthalmitis consists of culturing aqueous and vit- The incidence of retinal detachment increases fivefold if an intracapsu-
reous aspirates, followed by administration of intravitreal,63 topical, and lar procedure is performed.69 Predisposing factors include Nd:YAG laser
subconjunctival antibiotics, as discussed elsewhere. In the Endophthalmi- capsulectomy, axial length greater than 24.5 mm, myopic refractive error,
tis Vitrectomy Study, no evidence was found of any benefit from the use lattice degeneration, male gender, intraoperative vitreous loss, postopera-
of systemic antibiotics.64 Pars plana vitrectomy helped increase the final tive ocular trauma, posterior vitreous detachment, and history of retinal
visual outcome only in those patients who had an initial visual acuity of detachment in the fellow eye.67,70,71 Steps to prevent retinal detachment
light perception or worse.64 (For further discussion of endophthalmitis, see include the following:
Chapter 7.9.)
• A careful preoperative fundus examination.
• Preservation of the integrity of the posterior capsule at the time of
Posterior Capsular Opacification surgery.
Secondary cataract formation is a major complication of IOL implantation
• Education of patients with regard to the symptoms of retinal tears and
detachment.
after extracapsular cataract extraction (ECCE; or phaco). The incidence
is in the range of 18%–50% in adults followed up for as long as 5 years;
• Regular postoperative dilated fundus examinations.
in infants and juveniles, an opacification rate of 44% was found within
3 months of surgery after in-the-bag IOL implantation with an intact pos-
terior capsule.65 Posterior capsular opacification (PCO) is caused by prolif-
KEY REFERENCES
eration and migration of residual lens epithelial cells. These can produce Chern S, Yung C-W. Posterior lens dislocation during attempted phacoemulsification. Oph-
thalmic Surg 1995;26:114–16.
visual loss through two mechanisms: Gimbel HV, Condon GP, Kohnen T, et al. Late in-the-bag intraocular lens dislocation: inci-
• Formation of swollen, abnormally shaped lens cells called Elschnig’s dence, prevention, and management. J Cataract Refract Surg 2005;31:2193–204.
Gimbel HV, Sun R, Ferensowicz M, et al. Intra-operative management of posterior capsule
pearls, which migrate over the posterior capsule into the visual axis tears in phacoemulsification and intraocular lens implantation. Ophthalmology
(Fig. 5.16.10). 2001;108:2186–9.
• Transformation into fibroblasts, which may contain contractile ele- Hakin KN, Jacobs M, Rosen P, et al. Management of the subluxated crystalline lens. Oph-
ments (myofibroblasts) and cause the posterior capsule to wrinkle (see thalmology 1992;99:542–5.
Kohnen T. Kapsel- und zonularupturen als komplikation der kataraktchirurgie mit
Fig. 5.16.8). phacoemulsifikation. MD dissertation: University of Bonn; 1989.
Standard treatment of PCO consists of opening the capsule with Kohnen T, Dick B, Jacobi KW. Comparison of induced astigmatism after temporal clear
corneal tunnel incisions of different sizes. J Cataract Refract Surg 1995;21:417–24.
Nd:YAG laser. Complications of this treatment include acute and, in rare Kohnen T, von Ehr M, Schütte E, et al. Evaluation of intraocular pressure with Healon and
instances, chronic IOP elevation, pitting of the IOL, and retinal detach- Healon GV in sutureless cataract surgery with foldable lens implantation. J Cataract
ment. Factors that predispose to retinal detachment include an axial length Refract Surg 1996;22:227–37.
greater than 24.5 mm, male gender, and pre-existing retinal pathology.66–68 Koss MJ, Kohnen T. Intraocular architecture of secondary implanted anterior chamber
iris-claw lenses in aphakic eyes evaluated with anterior segment optical coherence
A related and unusual abnormality is the formation of striae in the pos- tomography. Br J Ophthalmol 2009;93:1301–6.
terior capsule in the absence of abnormal proliferation of lens epithelial Masket S. Post-operative complications of capsulorrhexis. J Cataract Refract Surg 1993;19:
cells. In some patients, this produces a Maddox-rod effect; the typical symp- 721–4.
toms are linear streaks that radiate from lights, and their orientation is 90° Mentes J, Erakgun T, Afrashi F, et al. Incidence of cystoid macular edema after uncompli-
cated phacoemulsification. Ophthalmologica 2003;217:408–12.
from the meridian of the striae. The cause is stretching of the capsular Powe NR, Schein OD, Gieser SC, et al. Synthesis of the literature on visual acuity and com-
bag by the IOL, which produces the striae aligned with the axis of the lens plications following cataract extraction with intraocular lens implantation. Arch Oph-
haptics. Typically, this is present on the first postoperative day but may not thalmol 1994;112:239–52.
be mentioned by the patient until later. In many eyes, the striae resolve in Rho DS. Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketoro-
lac. J Cataract Refract Surg 2003;29:2378–84.
the first or second week after surgery as capsular contraction occurs, which Tappin MJ, Larkin DF. Factors leading to lens implant decentration and exchange. Eye
counteracts the stretch forces of the IOL haptics. If the condition persists 2000;14:773–6.
and is sufficiently symptomatic, it can be corrected readily with a laser Werner L, Zaugg B, Neuhann T, et al. In-the-bag capsular tension ring and intraocular lens
posterior capsulectomy. For further discussion of PCO, see Chapter 5.17. subluxation or dislocation: a series of 23 cases. Ophthalmology 2012;119:266–71.
Wolter-Roessler M, Küchle M. Ergebnisse der Aphakiekorrektur durch retroiridal fixierte
Retinal Detachment Kunstlinse. Klin Monatsbl Augenheilkd 2008;225:1041–4.
Retinal detachment is a well-recognized complication of cataract surgery, Access the complete reference list online at ExpertConsult.com 409
occurring in 0.2% to 3.6% of persons after extracapsular cataract surgery.
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effective phacoemulsification time in femtosecond laser-assisted cataract surgery. Am J
1. Powe NR, Schein OD, Gieser SC, et al. Synthesis of the literature on visual acuity and
complications following cataract extraction with intraocular lens implantation. Arch
Ophthalmol 2014;157:426–32.
37. Koch DD, Liu JF, Glasser DB, et al. A comparison of corneal endothelial changes after use
5.16
Ophthalmol 1994;112:239–52. of Healon or Viscoat during phacoemulsification. Am J Ophthalmol 1993;115:188–201.
38. Johnson SH, Kratz RP, Olson PF. Iris transillumination and microhyphema syndrome. J

2. Kohnen T, Dick B, Jacobi KW. Comparison of induced astigmatism after temporal clear
corneal tunnel incisions of different sizes. J Cataract Refract Surg 1995;21:417–24. Am Intraocul Implant Soc 1984;10:425–8.
3. Assia EI, Levkovich-Verbin H, Blumenthal M. Management of Descemet’s membrane 39. Swan KC. Hyphema due to wound vascularization after cataract extraction. Arch Oph-
detachment. J Cataract Refract Surg 1995;21:714–17. thalmol 1973;89:87–90.
4. Iradier MT, Moreno E, Aranguez C, et al. Late spontaneous resolution of a massive 40. Hagan JC III, Menapace R, Radax U. Clinical syndrome of endocapsular hematoma:
detachment of Descemet’s membrane after phacoemulsification. J Cataract Refract Surg presentation of a collected series and review of the literature. J Cataract Refract Surg
2002;28:1071–3. 1996;22:379–84.
5. Kim T, Hasan SA. A new technique for repairing Descemet membrane detachments 41. Hater MA, Yung CW. Spontaneous resolution of an endocapsular hematoma. Am J Oph-
using intracameral gas injection. Arch Ophthalmol 2002;120:181–3. thalmol 1997;123:844–6.
6. Amaral CE, Palay DA. Technique for repair of Descemet membrane detachment. Am J 42. Laube T, Koch HR, Çubuk H, et al. Druckentlastung nach Staroperation (abstract). Klin
Ophthalmol 1999;127:88–90. Monatsbl Augenheilkd 1995;206:59.
7. Kohnen T. Kapsel- und zonularupturen als komplikation der kataraktchirurgie mit 43. Davison JA. Capsular bag distension after endophacoemulsification and posterior
phacoemulsifikation. MD dissertation: University of Bonn; 1989. chamber intraocular lens implantation. J Cataract Refract Surg 1990;16:312–14.
8. Osher RH, Yu BC-Y, Koch DD. Posterior polar cataracts: a predisposition to intra-opera- 44. Masket S. Post-operative complications of capsulorrhexis. J Cataract Refract Surg
tive posterior capsular rupture. J Cataract Refract Surg 1990;16:157–62. 1993;19:721–4.
9. Chang DF, Campbell JR. Intra-operative floppy iris syndrome associated with tamsulosin 45. Kohnen T, von Ehr M, Schütte E, et al. Evaluation of intraocular pressure with Healon
(Flomax). J Cataract Refract Surg 2005;31:664–73. and Healon GV in sutureless cataract surgery with foldable lens implantation. J Cataract
10. Mamalis N. Intra-operative floppy-iris syndrome. J Cataract Refract Surg 2006;32: Refract Surg 1996;22:227–37.
1589–99. 46. Miyake K, Ota I, Ichihashi S, et al. New classification of capsular block syndrome. J Cat-
11. Koch DD, Liu JF. Multilamellar hydrodissection in phacoemulsification and planned aract Refract Surg 1998;24:1230–4.
extracapsular surgery. J Cataract Refract Surg 1990;16:559–62. 47. Eifrig DE. Capsulorrhexis-related lacteocrumenasia. J Cataract Refract Surg 1997;23:450–4.
12. Hakin KN, Jacobs M, Rosen P, et al. Management of the subluxated crystalline lens. 48. Miyake K, Ota I, Miyake S, et al. Liquefied aftercataract: a complication of continuous
Ophthalmology 1992;99:542–5. curvilinear capsulorrhexis and intraocular lens implantation in the lens capsule. Am J
13. Cionni RJ, Osher RH. Endocapsular ring approach to the subluxed cataractous lens. J Ophthalmol 1998;125:429–35.
Cataract Refract Surg 1995;21:245–9. 49. Namba H, Namba R, Sugiura T, et al. Accumulation of milky fluid: a late complication of
14. Gimbel HV, Sun R. Clinical applications of capsular tension rings in cataract surgery. cataract surgery. J Cataract Refract Surg 1999;25:1019–23.
Ophthalmic Surg Lasers 2002;33:44–53. 50. Tappin MJ, Larkin DF. Factors leading to lens implant decentration and exchange. Eye
15. Cionni RJ, Osher RH, Marques DM, et al. Modified capsular tension ring for patients 2000;14:773–6.
with congenital loss of zonular support. J Cataract Refract Surg 2003;29:1668–73. 51. Nagamoto S, Kohzuka T, Nagamoto T. Pupillary block after pupillary capture of an
16. Gimbel HV, Condon GP, Kohnen T, et al. Late in-the-bag intraocular lens dislocation: AcrySof intraocular lens. J Cataract Refract Surg 1998;24:1271–4.
incidence, prevention, and management. J Cataract Refract Surg 2005;31:2193–204. 52. Khokhar S, Sethi HS, Sony P, et al. Pseudophakic pupillary block caused by pupillary
17. Kohnen T, Hengerer FH. Vorderkammerintraokularlinsen bei Aphakie [Anterior capture after phacoemulsification and in-the-bag AcrySof lens implantation. J Cataract
chamber intraocular lenses for aphakia correction]. Ophthalmologe 2014;111:310–14. Refract Surg 2002;28:1291–2.
18. Ng DT, Rowe NA, Francis IC, et al. Intra-operative complications of 1000 phacoemulsifi- 53. Brauweiler P, Ohrloff C. Das Polieren eiweißbeschlagener Intraokularlinsen mit dem
cation procedures: a prospective study. J Cataract Refract Surg 1998;24:1390–5. Nd:YAG-Laser. Fortsch Ophthalmol 1990;87:78–9.
19. Cruz OA, Wallace GW, Gay CA, et al. Visual results and complications of phacoemulsi- 54. Kohnen T, Kook D. Solving IOL related pigment dispersion syndrome (PDS) with reposi-
fication with intraocular lens implantation performed by ophthalmology residents. Oph- tioning of the primary sulcus implanted single-piece IOL into the capsular bag. J Cataract
thalmology 1992;99:448–52. Refract Surg 2009;35:1459–63.
20. Brauweiler P. Bimanual irrigation/aspiration. J Cataract Refract Surg 1996;22:1013–16. 55. Faucher A, Rootman DS. Dislocation of a plate-haptic silicone intraocular lens into the
21. Gimbel HV, Sun R, Ferensowicz M, et al. Intra-operative management of posterior anterior chamber. J Cataract Refract Surg 2001;27:169–71.
capsule tears in phacoemulsification and intraocular lens implantation. Ophthalmology 56. Mentes J, Erakgun T, Afrashi F, et al. Incidence of cystoid macular edema after uncom-
2001;108:2186–9. plicated phacoemulsification. Ophthalmologica 2003;217:408–12.
22. Koss MJ, Kohnen T. Intraocular architecture of secondary implanted anterior chamber 57. Ray S, D’Amico DJ. Pseudophakic cystoid macular edema. Semin Ophthalmol
iris-claw lenses in aphakic eyes evaluated with anterior segment optical coherence 2002;17:167–80.
tomography. Br J Ophthalmol 2009;93:1301–6. 58. Jagow B, Kohnen T. Anterior optic neuropathy associated with adalimumab. Ophthalmo-
23. Wolter-Roessler M, Küchle M. Ergebnisse der Aphakiekorrektur durch retroiridal fixierte logica 2008;222:292–4.
Kunstlinse. Klin Monatsbl Augenheilkd 2008;225:1041–4. 59. Schatz H, Atienza D, McDonald HR, et al. Severer diabetic retinopathy after cataract
24. Mennel S, Sekundo W, Schmidt JC, et al. Retropupilläre Fixation einer Irisklauenlinse surgery. Am J Ophthalmol 1994;117:314–21.
(Artisan™, Verisyse™) bei Aphakie. Ist die Skleranahtfixierte Intraokularlinse noch state 60. Rho DS. Treatment of acute pseudophakic cystoid macular edema: diclofenac versus
of the art? Spektrum der Augenheilkunde 2004;18:279–83. ketorolac. J Cataract Refract Surg 2003;29:2378–84.
25. Werner L, Zaugg B, Neuhann T, et al. In-the-bag capsular tension ring and intraocular 61. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and susceptibilities of microbio-
lens subluxation or dislocation: a series of 23 cases. Ophthalmology 2012;119:266–71. logic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol 1996;122:1–117.
26. Kim JE, Flynn HW Jr, Rubsamen PE, et al. Endophthalmitis in patients with retained 62. Montan P, Lundstrom M, Stenevi U, et al. Endophthalmitis following cataract surgery in
lens fragments after phacoemulsification. Ophthalmology 1996;103:575–8. Sweden. The 1998 national prospective survey. Acta Ophthalmol Scand 2002;80:258–61.
27. Assia EI, Apple DJ, Barden A, et al. An experimental study comparing various anterior 63. Mamalis N, Kearsley L, Brinton E. Post-operative endophthalmitis. Curr Opin Ophthal-
capsulectomy techniques. Arch Ophthalmol 1991;109:642–7. mol 2002;13:14–18.
28. Chern S, Yung C-W. Posterior lens dislocation during attempted phacoemulsification. 64. Group EVS. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of
Ophthalmic Surg 1995;26:114–16. immediate vitrectomy and of intravenous antibiotics for the treatment of post-operative
29. Aasuri MK, Kompella VB, Majji AB. Risk factors for and management of dropped bacterial endophthalmitis. Arch Ophthalmol 1995;113:1479–96.
nucleus during phacoemulsification. J Cataract Refract Surg 2001;27:1428–32. 65. Apple DJ, Solomon KD, Tetz RM, et al. Posterior capsule opacification. Surv Ophthalmol
30. Saitoh AK, Saitoh A, Taniguchi H, et al. Anticoagulation therapy and ocular surgery. 1992;37:73–116.
Ophthalmic Surg Lasers 1998;29:909–15. 66. Koch DD, Liu JF, Fill EP, et al. Axial myopia increases the risk of retina complications
31. Beatty S, Lotery A, Kent D, et al. Acute intra-operative suprachoroidal haemorrhage in after neodymium-YAG laser posterior capsulotomy. Arch Ophthalmol 1989;107:986–90.
ocular surgery. Eye 1998;12:815–20. 67. Tielsch JM, Legro MW, Cassard SD, et al. Risk factors for retinal detachment after cata-
32. Koch DD, Smith SH, Whiteside SB. Limbal and scleral wound healing. In: Beuerman ract surgery. A population-based case-control study. Ophthalmology 1996;103:1537–45.
RW, Crosson CE, Kaufman HE, editors. Healing processes in the cornea. Houston: Gulf 68. Ninn-Pedersen K, Bauer B. Cataract patients in a defined Swedish population, 1986 to
Publishing; 1989. p. 165–82. 1990. V. Post-operative retinal detachments. Arch Ophthalmol 1996;114:382–6.
33. Geyer O. Management of large, leaking, and inadvertent filtering blebs with the neodym- 69. Javitt JC, Vitale S, Canner JK, et al. National outcomes of cataract extraction. I. Retinal
ium:YAG laser. Ophthalmology 1998;105:983–7. detachment after inpatient surgery. Ophthalmology 1991;98:895–902.
34. Küchle M, Green W. Epithelial ingrowth: a study of 207 histopathologically proved cases. 70. Koch DD, Liu JF, Fill EP, et al. Axial myopia increases the risk of retina complications
Ger J Ophthalmol 1996;5:211–23. after neodymium-YAG laser posterior capsulectomy. Arch Ophthalmol 1989;107:986–90.
35. Knauf HP, Rowsey JJ, Margo CE. Cystic epithelial downgrowth following clear-corneal 71. Haddad WM, Monin C, Morel C, et al. Retinal detachment after phacoemulsification: a
cataract extraction. Arch Ophthalmol 1997;115:668–9. study of 114 cases. Am J Ophthalmol 2002;133:630–8.
409.e1
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Part 5 The Lens

Secondary Cataract
Liliana Werner 5.17
The “E” cells also are responsible for formation of a Soemmerring’s
Definition: Secondary cataract, also known as posterior capsule ring, which is a doughnut-shaped lesion composed of retained/regenerated
opacification (PCO), is the most common complication after cataract cortex and cells that may form following any type of disruption of the
surgery, resulting from migration and proliferation of residual lens anterior lens capsule. This lesion was initially described in connection
epithelial cells (LECs) onto the central posterior capsule, leading to with ocular trauma. The basic pathogenic factor of the Soemmerring’s
decrease in visual function, and ultimately in visual acuity. Opacification ring is the anterior capsular break, which may then allow exit of central
within the capsular bag also may present as anterior capsule nuclear and cortical material out of the lens, with subsequent Elschnig’s
opacification (ACO) or interlenticular opacification (ILO). pearl formation. A Soemmerring’s ring forms every time any form of
extracapsular cataract extraction (ECCE) is done, as manual, automated,
or phacoemulsification (“phaco”) procedures. For practical purposes, it is
useful to consider this lesion as the basic precursor of classic PCO, espe-
cially the “pearl” form. The LECs have higher proliferative capacity in the
Key Features young compared with the old; therefore, the incidence of PCO formation
• Caused by migration and proliferation of residual lens epithelial cells. is higher in younger patients.
• Treatment is most commonly neodymium:yttrium–aluminum–garnet The same cell types mentioned above are involved in other processes
(Nd:YAG) laser. of opacification within the capsular bag (Fig. 5.17.1). These include anterior
• May be exacerbated or ameliorated via surgical techniques and capsule opacification (ACO)4,5 and interlenticular opacification (ILO).6,7 The
specific lens design. latter is the opacification of the space between two or more IOLs implanted
in the bag (piggyback implantation).
Treatment and Prevention

INTRODUCTION The treatment of PCO is typically neodymium:yttrium–aluminum–garnet
Secondary cataract or posterior capsule opacification (PCO) is the most (Nd:YAG) laser posterior capsulectomy. This is a simple procedure in most
common postoperative complication of cataract surgery. Its incidence has cases but is not without risks. Complications include IOL damage, IOL
decreased over the past few decades as the understanding of its pathogen- subluxation or dislocation, retinal detachment, and secondary glaucoma.8
esis has evolved. Advances in surgical technique and intraocular lens (IOL) Therefore, prevention of this complication is important, not only because of
design and materials all have contributed to the gradual decline in PCO the risks associated with its treatment but also because of the costs involved
incidence. However, it remains a major cause of decreased visual acuity in the procedure. Extensive research has been performed on the inhibition of
after cataract surgery, occurring at a rate of between 3% and 50% in the LEC proliferation and migration by pharmacological agents through various
first 5 postoperative years.1 delivery systems, or IOL coatings, in vitro and in vivo animal studies.9–11 Use
of pharmacological and nonpharmacological agents for this purpose in an
PATHOGENESIS unsealed system may increase the risk of toxicity to surrounding intraocular
structures, especially corneal endothelial cells. The Perfect Capsule, a sili-
PCO results from migration and proliferation of residual lens epithelial cone device that reseals the capsular bag allowing isolated safe delivery of
cells (LECs) onto the central posterior capsule. When the cells invade the irrigating solutions into its inner compartment, therefore, was developed.12
visual axis as pearls, fibrotic plaques, or wrinkles, the patient experiences Immunotherapy and gene therapy, as well as physical techniques to kill/
a decrease in visual function and, ultimately, in visual acuity.2 The epi- remove LECs, have been investigated.13,14 We evaluated in our laboratory the
thelium of the crystalline lens consists of a sheet of anterior epithelial efficacy of an Nd:YAG laser photolysis system in removing LECs by using
cells (“A” cells) that are in continuity with the cells of the equatorial lens eyes from human cadavers. Light microscopy and immunohistochemistry
bow (“E” cells). The latter cells comprise the germinal cells that undergo revealed that the laser photolysis system removed LECs from the anterior
mitosis as they peel off from the equator. They constantly form new lens lens capsule and capsule fornix. Along with the cells, laminin, fibronectin,
fibers during normal lens growth. Although both the anterior and equa- and cell debris remained in the untreated areas but were removed by the
torial LECs stem from a continuous cell line and remain in continuity, it treatment, which may be useful for PCO prevention.14
is useful to divide these into two functional groups. They differ in terms While basic research on an effective mechanism for PCO eradication
of function, growth patterns, and pathological processes. The anterior or is evolving, the practical surgeon can apply some principles to prevent it.15
“A” cells, when disturbed, tend to remain in place and not migrate. They Studies done in our laboratory, as well as clinical studies done in other
are prone to a transformation into fibrous-like tissue (pseudo-fibrous centers, have helped in the definition of three surgery-related factors that
metaplasia). help in the prevention of PCO:
In contrast, in pathological states, the “E” cells of the equatorial lens
bow tend to migrate posteriorly along the posterior capsule (e.g., in pos-
• Hydrodissection-enhanced cortical cleanup.
terior subcapsular cataracts, and the pearl form of PCO). In general,
• In-the-bag IOL fixation.
instead of undergoing a fibrotic transformation, they tend to form large,
• Performance of a capsulorrhexis slightly smaller than the diameter of
the IOL optic (Fig. 5.17.2).
balloon-like bladder cells (the cells of Wedl). These are the cells that are
clinically visible as “pearls” (Elschnig’s pearls). These equatorial cells are The same studies helped in the definition of three IOL-related factors
the primary source of classic secondary cataract, especially the pearl form for PCO prevention:
of PCO. In a clinical study by Neumayer et al., significant changes in the
morphology of Elschnig’s pearls were observed within an interval of only • Use of a biocompatible IOL to reduce stimulation of cellular proliferation.
24 hours. Appearance and disappearance of pearls, as well as progression • Enhancement of the contact between the IOL optic and the posterior
410 and regression of pearls within such short intervals illustrate the dynamic capsule.
behavior of regeneratory PCO.3 • An IOL with a square, truncated optic edge.
booksmedicos.org
5.17
Secondary Cataract
A B
C D
Fig. 5.17.1 Different Forms of Opacification Within the Capsular Bag. (A) Human eye from cadaver (posterior or Miyake-Apple view) implanted with a rigid lens, showing
asymmetric fixation and decentration. A doughnut-shaped, white lesion can be seen for 360° in the equatorial region of the capsular bag (Soemmerring’s ring), and the
posterior capsule is fibrotic. (B) Human eye from cadaver (posterior view) implanted with a rigid lens. Soemmerring’s ring is also present. A posterior capsulotomy had
been performed for posterior capsule opacification, and proliferation of Elschnig’s pearls can be seen at the edges of the capsulotomy (arrow). (C) Human eye from cadaver
(posterior view) implanted with a foldable, plate silicone lens. The anterior capsule is fibrotic (arrow). Although Soemmerring’s ring formation can be seen, the posterior
capsule is not opacified. (D) Pair of foldable, hydrophobic acrylic lenses explanted because of interlenticular opacification. The lenses are fused together through the material
within the interlenticular space.
Hydrodissection-Enhanced Cortical Cleanup centration. However, endocapsular fixation functions primarily to enhance
Howard Fine introduced this technique and coined the term cortical cleav- the IOL–optic barrier effect, as will be discussed later. In a series of human
ing hydrodissection. The edge of the anterior capsule is slightly tented up cadaver eyes implanted with different IOLs and analyzed in our laboratory,
by the tip of the cannula while the fluid is injected. The technique is used central PCO and Nd:YAG rates were both influenced by IOL fixation, that
by many surgeons to facilitate cortex and equatorial LEC (“E” cell) removal, is, less PCO and Nd:YAG capsulectomies in eyes where the IOLs were in
also enhancing the safety of the operation. Experimental studies used dif- the bag.15
ferent solutions during the hydrodissection step of the phacoprocedure Marie-José Tassignon proposed a variation of the in-the-bag IOL fixation
(e.g., preservative-free lidocaine 1%, antimitotics, etc.).16 Further studies concept for PCO prevention, named “bag-in-the-lens” implantation.16 This
are necessary to establish the safety and utility of these solutions in terms involves the use of a twin-capsulorrhexis IOL design and performance of
of PCO prevention. anterior and posterior capsulorrhexes of the same size. The biconvex lens
Although a careful cortical cleanup and elimination of as many “E” has a circular equatorial groove in the surrounding haptic, for placement
cells as possible is fundamental to reducing the incidence of PCO, the of both capsules after capsulorrhexis. If the capsules are well stretched
role of anterior capsule polishing and elimination of “A” cells remains around the optic of this lens, the LECs will be captured within the remain-
to be demonstrated. Indeed, Sacu et al. have performed a randomized, ing space of the capsular bag, and their proliferation will be limited to
prospective study to evaluate the effect of anterior capsule polishing on this space, so the visual axis will remain clear (Fig. 5.17.3). Experimental
PCO.17 The anterior capsule was extensively polished in one eye and was and clinical studies showed that bag-in-the-lens implantation was highly
left unpolished in the other eye. Digital slit lamp photographs taken 1 year effective in preventing PCO when the anterior and posterior capsules were
postoperatively by using a standardized photographic technique showed properly secured in the IOL groove.
that anterior capsule polishing caused no significant difference in the
outcome of PCO. Some authors actually believe that the postoperative Capsulorrhexis Size
fibrous metaplasia of remaining “A” cells would push the IOL against the There is evidence that PCO is reduced if the capsulorrhexis diameter is
posterior capsule, and that would explain the relatively low PCO rates of slightly smaller than that of the lens optic so that the anterior edge rests on
eyes implanted with silicone lenses having rounded optic edges.18 the optic. This helps provide a tight fit of the capsule around the optic anal-
ogous to “shrinkwrapping,” which has beneficial effects in maximizing the
In-the-Bag IOL Fixation contact between the lens optic and the posterior capsule. In a retrospec-
The hallmark of modern cataract surgery is the achievement of consis- tive clinical study performed at the John A. Moran Eye Center, Univer-
tent and secure in-the-bag or endocapsular IOL fixation. The most obvious sity of Utah, on patients implanted with different IOLs, including lenses 411
advantage of in-the-bag fixation is the accomplishment of good lens with round or square optic edges, the degree of postoperative PCO was
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immunohistochemical studies on the adhesion of proteins to different
5 IOLs that had been implanted in human eyes from cadavers.20,21 Analyses
of histological sections have demonstrated that fibronectin mediates the
adhesion of this hydrophobic acrylic lens to the anterior and posterior cap-
sules. Analyses of explanted lenses have confirmed the presence of greater
The Lens
amounts of fibronectin on the surfaces of the same lens. However, even

though differences among materials exist, in terms of PCO prevention it
appears that the geometry of the lens, with a square posterior optic edge is
the most important factor (see IOL optic geometry below).
The adhesiveness of the material may have a more direct impact on the
development of ACO. This generally occurs much earlier in comparison
to PCO, sometimes within 1 month postoperatively. When the continuous
curvilinear capsulorrhexis (CCC) is smaller than the IOL optic, the ante-
rior surface of the optic’s biomaterial maintains contact with the adjacent
posterior aspect of the anterior capsule. Any remaining anterior LECs (“A”
cells) in contact with the IOL have the potential to undergo fibrous pro-
liferation; thus, ACO is essentially a fibrotic entity. Studies in our labora-
tory using pseudo-phakic eyes obtained from cadavers showed that ACO
is more common with silicone IOLs, especially the plate designs, because
of the larger area of contact between these lenses and the anterior capsule
(see Fig. 5.17.1C).4 However, the same studies showed that the plate design
resists contraction forces within the capsular bag better than three-piece
silicone lenses with flexible haptics (polypropylene).5 These latter showed
the higher rates of capsulorrhexis phimosis and IOL decentration as a
result of excessive capsular bag fibrosis. Therefore, a tendency exists in
IOL manufacture favoring haptic materials with higher rigidity, such as
polymethyl methacrylate (PMMA), polyimide (Elastimide), and poly(vi-
Fig. 5.17.2 Human Eye Obtained From Cadaver (Posterior View) 19 Months After nylidene) fluoride (PVDF). In the same studies, ACO was less significant
Implantation of a Single-Piece Hydrophobic Acrylic Lens. This is an example of with hydrophobic acrylic lenses having an adhesive surface.
application of the three surgery-related factors for prevention of posterior capsule ACO has been considered a clinical problem when anterior capsular
opacification. The lens was symmetrically implanted in the bag, via capsulorrhexis shrinkage associated with constriction of the anterior capsulectomy opening
smaller than the optic diameter of the lenses (ideally, the capsulorrhexis margin (capsulorrhexis contraction syndrome or capsular phimosis) accompanies
should cover the edge of the lens for 360°). No significant Soemmerring’s ring excessive anterior capsule fibrosis. This has been especially observed in
formation is present. conditions associated with zonular weakness (e.g., pseudo-exfoliation and
advanced age, and with chronic intraocular inflammation. Besides phimo-
sis of the CCC opening, excessive zonular traction, and its sequelae, IOL
dislocation and retinal detachment can occur because of excessive capsu-
lar fibrosis. Excessive opacification of the anterior capsule is problematic
in that it hinders visualization of the peripheral fundus during retinal
examination. Otherwise, a certain degree of ACO is sometimes considered
an advantage because it can prevent potential dysphotopsia phenomena
caused by the square edge of some IOL optic designs. Additionally, ante-
rior capsule fibrosis with contraction of the capsular bag will push the
IOL optic against the posterior capsule, helping in the prevention of PCO
according to the “no space, no cells” theory. This mechanism would explain
the relatively low PCO rates with some silicone lenses, in the absence of a
square optic edge profile, as noted above (hydrodissection-enhanced corti-
cal cleanup).18
The adhesiveness of the IOL material may also have an influence on
ILO formation. To date, all cases of ILO that we have analyzed in our labo-
ratory seem to be related to two hydrophobic acrylic IOLs being implanted
in the capsular bag through a small capsulorrhexis, with its margins over-
lapping the optic edge of the anterior IOL for 360°.6 When these lenses are
implanted in the capsular bag through a small capsulorrhexis, the bioad-
hesion of the anterior surface of the front lens to the anterior capsule edge
and of the posterior surface of the back lens to the posterior capsule pre-
vents the migration of the cells from the equatorial bow onto the posterior
capsule. This migration may be directed toward the interlenticular space.
Fig. 5.17.3 Clinical Photograph Taken 6 Months After Cataract Surgery With
“Bag-in-the-Lens” Implantation in a 64-Year-Old Patient. The area corresponding
In this scenario, the two IOLs are sequestered together with aqueous and
to the optic of the lens is completely free of opacities. (Courtesy Dr. Marie-José LECs in a hermetically closed microenvironment. In addition, the adhesive
Tassignon, Belgium.) nature of the material seems to render the opacifying material very diffi-
cult to remove by any surgical means (see Fig. 5.17.1D).
Based on the common features of different cases of ILO, some surgical
correlated with the degree of anterior capsule overlap.19 Considering all methods were proposed for its prevention. The first option would be to
patients, including the patients distributed in different IOL groups, there implant both IOLs in the capsular bag but with a relatively large-diameter
was always a significant negative, linear correlation between the degree of capsulorrhexis. The other possibility is to implant the anterior IOL in the
overlap and PCO. sulcus and the posterior IOL in the bag with a small rhexis. These should
help sequester the retained/proliferated equatorial LECs within the equa-
Biocompatible Intraocular Lens torial fornix. Reassessment of factors leading to ILO formation is import-
Many definitions for the term “biocompatibility” exist. With regard to ant because of the development of dual-optic accommodating IOLs to be
PCO, materials with the ability to inhibit stimulation of cell proliferation implanted in the capsular bag.7 Additionally, piggyback implantation for
are more “biocompatible.” The “sandwich” theory states that a hydro- correction of residual refractive errors appears to be increasing in popu-
phobic acrylic IOL with a bioadhesive surface would allow only a mono- larity, including implantation of a multifocal IOL in patients with pseudo-
412 layer of LECs to attach to the capsule and the lens, preventing further phakia. However, in these cases the second (anterior) IOL is generally
cell proliferation and capsular bag opacification. We performed two fixated in the ciliary sulcus.
booksmedicos.org
5.17
Secondary Cataract
A B
C D
Fig. 5.17.4 Foldable, Hydrophilic Acrylic Lenses With Square Optic and Haptic Edges. The lens in (B) was modified to incorporate an extra ridge all around the
optic (enhanced square edge; arrow). (C,D) are photographs obtained from rabbit eyes (posterior view), experimentally implanted with the lenses in (A,B), respectively.
Soemmerring’s ring formation is observed in both eyes. The arrow in (C) shows the opacification of the posterior capsule, which started at the level of the optic-haptic
junction. (From: Werner L, Mamalis N, Pandey SK, et al. Posterior capsule opacification in rabbit eyes implanted with hydrophilic acrylic intraocular lenses with enhanced
square edge. J Cataract Refract Surg 2004;30:2403–9.)
Contact Between the IOL Optic and the Posterior Capsule ring in place, this space was found to be smaller or nonexistent. Thus,
Different factors can help maximize the contact between the IOL and the LECs would not find a space to migrate and proliferate onto the posterior
posterior capsule, contributing to the so-called “no space, no cells” concept. capsule. Capsular tension rings also produce a circumferential stretch on
Optic/haptic angulation displacing the optic posteriorly and stickiness of the capsular bag, with the radial distention forces equally distributed. For-
the IOL optic material are the most important lens features for obtaining a mation of traction folds in the posterior capsule, which may be used as an
tight fit between lens and capsule. Three-piece lenses manufactured from avenue for cell ingrowth is thus avoided.
the different haptic materials currently available today have in general a Capsular tension rings may also have a role in the prevention of opaci-
posterior optic/haptic angulation ranging 5°–10°. To keep the advantages of fication of the anterior capsule. The presence of a broad, band-shaped,
the two above-mentioned factors, it is important to achieve endocapsular capsular ring would keep the anterior capsule leaf away from the anterior
lens fixation and to create a capsulorrhexis smaller than the diameter of optic surface and the posterior capsule. This would ultimately lead to less
the lens optic. metaplasia of LECs on the inner surface of the anterior capsule with less
Capsular tension rings may have a role in the prevention of PCO. fibrous tissue formation, as well as less opacification and contraction of
Equatorial capsular tension rings have the ability to maintain the contour this structure. IOLs with design features that also help maintaining the
of the capsular bag and to stretch the posterior capsule. Thus, they have anterior capsule away from the anterior surface of the lens have been eval-
primarily been used in cases of zonular rupture or dehiscence, second- uated in our laboratory.7 A capsular tension ring designed to prevent opaci-
ary to trauma, or when inherent zonular weakness is present, such as in fication within the capsular bag was evaluated in two centers, one in Japan
pseudo-exfoliation syndrome. It has been demonstrated by high-resolution (Nishi O) and the other in Austria (Menapace R).22 Both centers reported
laser interferometric studies that a space exists between the IOL and the a significant reduction in PCO and ACO with the rings, in comparison to 413
posterior capsule with different lens designs. With a capsular tension the contralateral eyes implanted with the same lens design.22
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5 Intraocular Lens Optic Geometry
The square, truncated lens optic edge acts as a barrier, preventing migra-
tion of proliferative material from the equatorial region onto the posterior
capsule.15 The barrier effect is absent in lenses having rounded edges, and
The Lens
proliferative material from the equatorial region has greater free access
to the posterior capsule, opacifying the visual axis. The barrier effect of
the square optic edge is functional when the lens optic is fully in the bag,
in contact with the posterior capsule. When one or both haptics are out
of the bag, a potential space that is present allows an avenue for cellular
ingrowth toward the visual axis. Different modern lenses manufactured
from different materials currently on the market present this important
design feature. Some of them have a square edge on the posterior optic
surface, whereas the anterior optic edge has remained round to prevent
dysphotopsia. Findings from experimental studies which demonstrate that
the square edges of different lenses on the market are not equally “sharp,”
even when the same class of materials is considered, are noteworthy.23,24
The optic–haptic junctions of square-edged single-piece lenses may rep-
resent a site for cell ingrowth and PCO formation.25 At the level of those
junctions, the barrier effect of the square edge appears to be less effective.
We obtained better results regarding PCO formation with a hydrophilic
acrylic single-piece lens having an “enhanced” square edge than with the
standard model of the same design.25 The enhanced edge provided the lens
with a peripheral ridge around the lens optic for 360°. In the standard
model, the square edge profile appeared to be absent at the level of the
optic–haptic junctions (Fig. 5.17.426). Therefore, the square optic edge is
probably the most important IOL design feature for PCO prevention. It
appears, however, that it should be present for 360° around the IOL optic Fig. 5.17.5 Gross Photograph (Miyake-Apple View) of the Anterior Segment
in order to provide an effective barrier effect. of a Rabbit Eye Implanted With a New Disk-Shaped IOL, Taken 5 Weeks
Postoperatively. The lens is a single-piece, hydrophilic acrylic, monofocal lens
suspended between two complete haptic rings that are connected by a pillar of the
INTRAOCULAR LENSES MAINTAINING THE haptic material. This design maintains the capsular bag expanded, with the anterior
CAPSULAR BAG OPEN OR EXPANDED capsule separated from the anterior optic surface. Anterior and posterior capsules
are overall clear. Minimal proliferation is limited to the space between the peripheral
We have recently evaluated the outcome of capsular bag opacification with rings.
a new single-piece, disc-shaped hydrophilic acrylic IOL compared with a
commercially available single-piece, hydrophobic acrylic IOL in the rabbit
eye for 5 weeks (Fig. 5.17.5).27,28 The peripheral rings of the disc-shaped
KEY REFERENCES
lens, by expanding the capsular bag and preventing IOL surface contact Apple DJ, Werner L. Complications of cataract and refractive surgery: A clinicopathological
documentation. Trans Am Ophthalmol Soc 2001;99:95–109.
with the anterior capsule, prevented ACO and PCO. We hypothesized that Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsular opacification. Major review. Surv
IOL designs maintaining an open or expanded capsular bag are associated Ophthalmol 1992;37:73–116.
with bag clarity. Mechanical compression of the inner bag surface (and Charles S. Vitreoretinal complications of YAG laser capsulotomy. Ophthalmol Clin North
residual LECs) by a relatively bulky device/IOL has been one of the possi- Am 2001;14:705–10.
Kavoussi SC, Werner L, Fuller SR, et al. Prevention of capsular bag opacification with a
ble mechanisms advanced to explain this finding. Another factor may be
new hydrophilic acrylic disc-shaped intraocular lens. J Cataract Refract Surg 2011;37:
mechanical stretch of the bag at the level of the equatorial region (main- 2194–200.
taining the overall bag contour), by some devices, such as the capsular Kramer GD, Werner L, Mamalis N. Prevention of postoperative capsular bag opacification
bending ring of Nishi and Menapace,22 and Hara’s equator ring.29 Con- using intraocular lenses and endocapsular devices maintaining an open or expanded
stant irrigation of the capsular bag’s inner compartment by the aqueous capsular bag. J Cataract Refract Surg 2016;42(3):469–84.
Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and
humor also may have an influence on the prevention of proliferation of collagen type IV to intraocular lens materials in human autopsy eyes. Part I: histological
residual LECs. Equatorial stretch and aqueous humor irrigation would sections. J Cataract Refract Surg 2000;26:1792–806.
help explain the PCO preventative effect, even in eyes where there was no Mamalis N, Grossniklaus HE, Waring GO 3rd, et al. Ablation of lens epithelial cells with a
contact between the IOL optic and the posterior capsule. Previous reports laser photolysis system: histopathology, ultrastructure, and immunochemistry. J Cata-
indicated that transforming growth factor-β2 in the normal aqueous humor Meacock WR, Spalton DJ, Boyce J, et al. The effect of posterior capsule opacification on
inhibits proliferation of LECs and corneal endothelial cells.30 According to visual function. Invest Ophthalmol Vis Sci 2003;44:4665–9.
Nishi, constant irrigation by the aqueous humor may prevent certain cyto- Neumayer T, Findl O, Buehl W, et al. Daily changes in the morphology of Elschnig pearls.
kines that are involved in stimulating LEC proliferation from reaching a Am J Ophthalmol 2006;141:517–23.
Werner L, Pandey SK, Escobar-Gomez M, et al. Anterior capsule opacification: a histopatho-
threshold concentration level within the bag compartment; one of these logical study comparing different IOL styles. Ophthalmology 2000;107:463–71.
cytokines would be represented by interleukin-1.31 Werner L, Pandey SK, Apple DJ, et al. Anterior capsule opacification: correlation of patholog-
In summary, development of PCO is multifactorial, and its eradication ical findings with clinical sequelae. Ophthalmology 2001;108:1675–81.
depends on the quality of the surgery as well as on the quality of the IOL Werner L, Apple DJ, Pandey SK, et al. Analysis of elements of interlenticular opacification.
implanted. Each factor described here does not act in isolation; it is their Werner L, Müller M, Tetz M. Evaluating and defining the sharpness of intraocular lenses.
interaction that produces the best results. Research on the prevention of Microedge structure of commercially available square-edged hydrophobic lenses. J Cata-
any form of opacification/fibrosis within the capsular bag is increasing in ract Refract Surg 2008;34:310–17.
importance, especially with the advent of specialized IOLs, such as accom- Werner L, Tetz M, Feldmann I, et al. Evaluating and defining the sharpness of intraocular
lenses: microedge structure of commercially available square-edged hydrophilic intraoc-
modative lenses, which are designed to enable a forward movement of the ular lenses. J Cataract Refract Surg 2009;35:556–66.
optic on efforts of accommodation. The functionality of such lenses will Werner L, Tassignon MJ, Zaugg BE, et al. Clinical and histopathologic evaluation of six
likely require the long-term transparency and elasticity of the capsular bag. human eyes implanted with the bag-in-the-lens. Ophthalmology 2010;117:55–62.
Further research to investigate new proposed mechanisms for capsular bag
opacification prevention, such as with IOLs/devices maintaining an open Access the complete reference list online at ExpertConsult.com
capsular bag, is warranted.
414
booksmedicos.org
REFERENCES 17. Sacu S, Menapace R, Findl O, et al. Influence of optic edge design and anterior capsule
polishing on posterior capsule fibrosis. J Cataract Refract Surg 2004;30:658–62.
1. Apple DJ, Solomon KD, Tetz MR, et al. Posterior capsular opacification. Major review.
Surv Ophthalmol 1992;37:73–116.
18. Spalton DJ. In reply to: Nishi O. Effect of a discontinuous capsule bend. J Cataract
Refract Surg 2003;29:1051–2.
5.17
2. Meacock WR, Spalton DJ, Boyce J, et al. The effect of posterior capsule opacification on 19. Smith SR, Daynes T, Hinckley M, et al. The effect of lens edge design versus anterior
capsule overlap on posterior capsule opacification. Am J Ophthalmol 2004;138:521–6.
Secondary Cataract
visual function. Invest Ophthalmol Vis Sci 2003;44:4665–9.
3. Neumayer T, Findl O, Buehl W, et al. Daily changes in the morphology of Elschnig 20. Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and
pearls. Am J Ophthalmol 2006;141:517–23. collagen type IV to intraocular lens materials in human autopsy eyes. Part I: histological
4. Werner L, Pandey SK, Escobar-Gomez M, et al. Anterior capsule opacification: a histo- sections. J Cataract Refract Surg 2000;26:1792–806.
pathological study comparing different IOL styles. Ophthalmology 2000;107:463–71. 21. Linnola RJ, Werner L, Pandey SK, et al. Adhesion of fibronectin, vitronectin, laminin and
5. Werner L, Pandey SK, Apple DJ, et al. Anterior capsule opacification: correlation of collagen type IV to intraocular lens materials in human autopsy eyes. Part II: explanted
pathological findings with clinical sequelae. Ophthalmology 2001;108:1675–81. IOLs. J Cataract Refract Surg 2000;26:1807–18.
6. Werner L, Apple DJ, Pandey SK, et al. Analysis of elements of interlenticular opacifica- 22. Menapace R, Sacu S, Georgopoulos M, et al. Efficacy and safety of capsular bending ring
tion. Am J Ophthalmol 2002;133:320–6. implantation to prevent posterior capsule opacification: three year results of a random-
7. Werner L, Mamalis N, Stevens S, et al. Interlenticular opacification: dual-optic versus ized clinical trial. J Cataract Refract Surg 2008;34:1318–28.
piggyback intraocular lenses. J Cataract Refract Surg 2006;32:656–62. 23. Werner L, Müller M, Tetz M. Evaluating and defining the sharpness of intraocular lenses.
8. Charles S. Vitreoretinal complications of YAG laser capsulotomy. Ophthalmol Clin North Microedge structure of commercially available square-edged hydrophobic lenses. J Cata-
Am 2001;14:705–10. ract Refract Surg 2008;34:310–17.
9. Fernandez V, Fragoso MA, Billote C, et al. Efficacy of various drugs in the prevention of 24. Werner L, Tetz M, Feldmann I, et al. Evaluating and defining the sharpness of intra-
posterior capsule opacification: experimental study of rabbit eyes. J Cataract Refract Surg ocular lenses: microedge structure of commercially available square-edged hydrophilic
2004;30:2598–605. intraocular lenses. J Cataract Refract Surg 2009;35:556–66.
10. Werner L, Legeais JM, Nagel MD, et al. Evaluation of Teflon-coated intraocular lenses in 25. Werner L, Mamalis N, Pandey SK, et al. Posterior capsule opacification in rabbit eyes
an organ culture method. J Biomed Mater Res 1999;46:347–54. implanted with hydrophilic acrylic intraocular lenses with enhanced square edge. J Cata-
11. Okajima Y, Saika S, Sawa M. Effect of surface coating an acrylic intraocular lens with ract Refract Surg 2004;30:2403–9.
poly(2-methacryloyloxyethyl phosphorylcholine) polymer on lens epithelial cell line 26. Werner L, Mamalis N, Pandey SK, et al. Posterior capsule opacification in rabbit eyes
behavior. J Cataract Refract Surg 2006;32:666–71. implanted with hydrophilic acrylic intraocular lenses with enhanced square edge. J Cata-
12. Maloof A, Pandey SK, Neilson G, et al. Selective death of lens epithelial cells using ract Refract Surg 2004;30:2403–9.
demineralized water and Triton X-100 with PerfectCapsule sealed capsule irrigation: a 27. Kramer GD, Werner L, Mamalis N. Prevention of postoperative capsular bag opacifica-
histological study in rabbit eyes. Arch Ophthalmol 2005;123:1378–84. tion using intraocular lenses and endocapsular devices maintaining an open or expanded
13. Meacock WR, Spalton DJ, Hollick EJ, et al. Double-masked prospective ocular safety capsular bag. J Cataract Refract Surg 2016;42(3):469–84.
study of a lens epithelial cell antibody to prevent posterior capsule opacification. J Cata- 28. Kavoussi SC, Werner L, Fuller SR, et al. Prevention of capsular bag opacification
ract Refract Surg 2000;26:716–21. with a new hydrophilic acrylic disk-shaped intraocular lens. J Cataract Refract Surg
14. Mamalis N, Grossniklaus HE, Waring GO 3rd, et al. Ablation of lens epithelial cells with 2011;37:2194–200.
a laser photolysis system: histopathology, ultrastructure, and immunochemistry. J Cata- 29. Hara T, Hara T, Narita M, et al. Long-term study of posterior capsular opacification pre-
ract Refract Surg 2010;36:1003–10. vention with endocapsular equator rings in humans. Arch Ophthalmol 2011;129:855–63.
15. Apple DJ, Werner L. Complications of cataract and refractive surgery: A clinicopatholog- 30. Nagamoto T, Tanaka N, Fujiwara T. Inhibition of posterior capsule opacification by a
ical documentation. Trans Am Ophthalmol Soc 2001;99:95–109. capsular adhesion-preventing ring. Arch Ophthalmol 2009;127:471–4.
16. Werner L, Tassignon MJ, Zaugg BE, et al. Clinical and histopathologic evaluation of six 31. Nishi O, Nishi K, Ohmoto Y. Effect of interleukin 1 receptor antagonist on the blood-aque-
human eyes implanted with the bag-in-the-lens. Ophthalmology 2010;117:55–62. ous barrier after intraocular lens implantation. Br J Ophthalmol 1994;78:917–20.
414.e1
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Part 5 The Lens

Outcomes of Cataract Surgery

Mats Lundström 5.18
depends on the surgical procedure, the age of the patient, ocular comor-
Definition: Outcomes of cataract surgery include both objective and bidities, and surgical complications, among other things. The refractive
subjective measures. The objective outcomes are typically visual and outcome depends on the surgical procedure, the preoperative status and
refractive. examination, and the intended target refraction. The type of intraocular
lens (IOL), pupil size, and surgical procedure are important for contrast
sensitivity, glare, halos, and other visual disturbances. The patient’s satis-
faction with vision after surgery depends on the preoperative information
Key Features given and the patient’s expectations, as well as the visual outcome.
Objective measures of functional vision:
• Uncorrected visual acuity.
• Best-corrected visual acuity. FIVE PARAMETERS THAT DESCRIBE
• Contrast sensitivity.
• Glare disability. VISUAL FUNCTION
• Visual field.
• Color vision. Visual Acuity Testing
Standardized Visual Acuity Testing
Standardized visual acuity tests measure the ability of a patient to recog-
INTRODUCTION nize standardized optotypes (usually Snellen acuity letters) at a specified
visual angle, illumination, and contrast.2 Visual acuity can be recorded in
Outcomes of cataract surgery can be classified according to objective and various notations, in which normal vision would be Snellen units 20/20 or
subjective findings. Objective measures of functional vision include not 6/6, decimal notation 1.0, or logarithm of minimum angle of resolution
only best-corrected visual acuity (BCVA) but also uncorrected distance (LogMAR) 0.0.
visual acuity, contrast sensitivity, glare disability, visual field, and color
vision. The refractive outcome is important because a cataract extraction is Potential Retinal Acuity Testing
also a refractive procedure. Subjective findings are best evaluated through A special type of acuity test used in cataract patients is the assessment of
structured interviews or questionnaires. potential retinal acuity. This test is essential for patients who have pigment
mottling in the macula and reduced vision, particularly in the presence of
EVALUATION OF OUTCOMES a cataract or other optical aberrations of the eye. In the cataract age group,
the incidence of macular degeneration is at least 10% and may exceed 15%,
Functional vision assessment implies the ability to characterize parameters depending on the age of the patient.3,4 It is important that both the surgeon
of vision and translate these into how well a patient is able to perform and the patient have a realistic expectation of the quality of postoperative
activities in daily life with respect to vision. To do this objectively, the vision, which helps both parties to accurately assess the risk–benefit ratio.
parameters that characterize vision must first be determined. In both clin- Removal of a significant cataract always should be considered, even in the
ical practice and research, these parameters can be allocated to five major presence of an abnormal macula or if the predicted acuity is low.
areas:
• Limiting resolution (high-contrast visual acuity). Contrast Sensitivity Testing
• Contrast performance (contrast sensitivity and threshold).
Contrast sensitivity testing is important for the assessment of both sensory
• Performance at various background illuminations (glare disability).
disease and media opacities. With media opacities, such as cataracts,
• Field of view (visual field).
a general depression occurs in contrast sensitivity at all points, with a
• Color performance (color vision).
slightly greater depression at lower contrasts.5-7
It is important to fully evaluate the visual system in a patient who has a
cataract by using these five parameters. In many cases, the patient does not Glare Testing
present to the clinician with the diagnosis of cataract. The patient usually
presents with complaints of decreased vision or visual disabilities. It is the Glare testing is useful in the assessment of media opacities, such as cat-
clinician’s responsibility to evaluate the patient’s history and examine the aracts. The effects are negligible in sensory disorders, except for a few
patient to determine the cause of the reduced vision. After diagnosis of a macular disorders, such as cystoid macular edema (CME), in which intra-
cataract—or any other diagnosis—has been made, some of the five param- ocular light scatter occurs in the superficial layers of the retina.8,9 Even with
eters that describe visual performance may be found to be less important. this disorder, the changes in glare disability are minimal. Glare testing can
To translate the visual performance or functional vision of a patient be very sensitive and specific to media opacities, but more importantly, it
into the ability to perform a specific activity necessitates knowledge of the gives visual acuity values or equivalents that relate to a person’s vision in
visual requirements needed to carry out that activity. The visual require- daylight, as opposed to vision in a testing room with high-contrast letters.
ments needed to perform specific daily life activities are poorly mapped
out. Therefore, the patient’s self-assessed limitation in carrying out daily Visual Fields
life activities that are dependent on vision is an important part of the out-
comes evaluation. It has been suggested that self-assessed visual function The integrity of visual fields is particularly important in patients with
is the most important part of the outcomes evaluation.1 In the evaluation of sensory disorders, such as glaucoma and optic neuropathies, and patients
outcomes of cataract surgery in daily practice, a proper follow-up time after who have suffered strokes that have affected the visual pathways.10,11 Unfor-
surgery is crucial. Just as status 1 day after surgery may reflect whether the tunately, these disorders also are common in the age group that suffers
surgery was traumatic or not, sufficient time must elapse before the final from cataracts and may go undetected until after the cataract surgery. 415
refraction and patient satisfaction can be evaluated. The visual outcome Additionally, visual field defects that result from strokes may change the
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risk–benefit ratio for cataract surgery, particularly if the stroke occurred of patients should have sphero-equivalent refraction within ±1.00 D of the
5 recently. intended target.19 In a recent study on routine cataract surgery, about 90%
of cataract extractions resulted in a final refraction within ±1.0 D of the
intended target refraction (see Table 5.18.1).4 A suggested standard was a
Color Vision biometry error with a correct sign centered on 0 D and with 87% or more
The Lens
Color vision is specifically important in sensory disease, such as retinopa- of the values within ±1 D of error.4
thies and optic neuropathies, which often show characteristic color vision Surgically induced astigmatism (SIA) may be intentional or not inten-
changes that help make the differential diagnosis and monitor the effect tional. Small-incision cataract surgery results in less SIA than did earlier,
of therapy. In patients who have ocular media disorders, such as cataracts, larger-incision surgical techniques.20–22 The magnitude of SIA may be less
the changes in color vision can usually be correlated with the color of the than 0.5 D on average, depending on incision site and incision size.23–25
cataract. For example, a patient who has a brunescent (yellow-brown) cat- The best outcome of cataract surgery with respect to astigmatism is usually
aract has significant deficiencies in the blue end of the visual spectrum to achieve as low a postoperative astigmatism as possible. SIA can be used
(shorter wavelengths).12 When color deficiencies do not correlate, sensory to achieve this result by varying the placement of the incision. SIA, thereby,
disorders should be suspected. Although color vision testing is very sen- can counteract preoperative astigmatism and result in reduced postopera-
sitive in some disorders, such as central serous maculopathy and CME, tive astigmatism.26,27
by “bleaching” or reducing the apparent brightness, other parameters,
such as visual acuity, visual field, and contrast sensitivity, are also affected, Contrast Sensitivity
which makes routine color testing unnecessary.
Following cataract surgery, in the absence of other ocular disease, the con-
trast sensitivity returns to normal.28,29 Binocular contrast sensitivity may
OBJECTIVE FINDINGS OF CATARACT not be normalized until second eye surgery has been performed, given the
occurrence of cataract in both eyes.30
SURGERY OUTCOMES
Best-Corrected Visual Acuity Glare
The term best-corrected visual acuity implies that the patient’s eye has Studies have documented that the correlation of most of the instruments
been optically corrected to achieve the best visual acuity. In most cases, used for glare testing and outdoor vision testing show a dramatic improve-
this value is obtained with best spectacle refraction. In cases of irregular ment after cataract surgery.6,7,31–34
corneal astigmatism, the BCVA may be attained with a rigid contact lens,
not with spectacles. In recent studies with known preoperative pathology Visual Fields
excluded (best case analyses), between 97% and 98% of the patients who
had received cataract surgery achieved BCVA equal to or better than 20/40 The visual field returns to normal after cataract surgery in the absence of
(6/12; 0.5).4,13 A suggested standard was to achieve a final BCVA of 0.5 or ocular comorbidity.
better in 97% of all cataract extractions in eyes with no ocular comorbidity.4
The corresponding number for all routine patients with cataract, including Color Vision
those with ocular comorbidity, was 94% in a recent report (Table 5.18.1).4
After cataract surgery in patients who have blue-color deficiencies caused
by the cataract, the return to normal color vision is perceived as sensa-
Uncorrected Visual Acuity tional by some patients but is not even noticed by others. Color vision
The term uncorrected visual acuity (UCVA) refers to the patient’s vision returns to normal in the absence of other ocular disease.
in standard conditions with no extraocular optical correction. Unlike
BCVA, several additional factors (e.g., pupil size, degree of refractive error,
and amount of regular astigmatism) also influence the measured visual SUBJECTIVE FINDINGS OF CATARACT
acuity.14–16 UCVA is most useful in the evaluation of specialty lenses, such
as multifocal and toric intraocular lenses (IOLs). The goal when using
SURGERY OUTCOMES
these lenses is to reduce or eliminate the patient’s dependence on glasses Patients’ Self-Assessment of the Visual Outcome
and to achieve good uncorrected distance visual acuity (UCDA) and near
visual acuity. To achieve target refraction is crucial when using multifocal A large number of questionnaires for use in cataract surgery care have
IOLs. Unfortunately, multifocal IOLs have a tendency to give more glare been published.35 They usually cover activity limitations in daily life
and halo compared with monofocal IOLs.17 This applies to most types of because of problems with vision and, therefore, are disease-specific ques-
IOLs with more than one focus, and to construct the optimal IOL for both tionnaires for establishing the health-related quality of life for cataract
near and distant vision is an area of active research. UCVA can be used as patients. On average, about 90% of patients undergoing cataract surgery
a quality characteristic of the surgical procedure, especially on the day after achieve improved self-assessed visual function, according to a multicenter
surgery.18 For this purpose, however, it is relevant to use the target refrac- study using a modern questionnaire (see Table 5.18.1).36,37
tion if, for instance, postoperative myopia is planned. Older patients (>85 years) also benefit from cataract surgery.38,39 The
positive impact of cataract surgery on patients’ self-assessed visual func-
Target Refraction Prediction Error tion seems to be long lasting, provided that no other ocular disease
appears in the operated eye.40,41 Self-assessed poor visual function after cat-
Another factor in the determination of UCVA is the ability to achieve aract surgery may result from an ocular comorbidity, a disturbing cataract
the target postoperative refraction. Most surgeons target the majority of in the fellow eye, or anisometropia.42 Several factors are related to better
their patients for postoperative refractions in the range of 0.0 to −0.50 D. subjective visual outcome. These include younger age, low preoperative
With modern biometry equipment, newer IOL formulas, personalization visual acuity, high postoperative visual acuity, second-eye surgery, and no
of lens constants, and improvements in surgical technique, at least 90% ocular comorbidity.43
CATARACT SURGERY OF ONE OR BOTH EYES

TABLE 5.18.1 Outcome Measures Following Cataract Surgery: Patients with bilateral cataract benefit from bilateral cataract extraction.
Achievements in Some Recent Studies (%). Studies have shown that second-eye cataract surgery adds health-related
Measure All Patients Best Cases
quality of life for such patients.44,45 A remaining cataract in the fellow eye
after first-eye surgery may have a poor effect on binocular vision.30,42
BCVA ≥0.5 (6/12) 944 9713
A bilateral cataract extraction can be performed sequentially with a
Absolute mean prediction error ≤1 D 91.54 97.34
varying interval between the two surgeries so that some patients receive
Better patient reported visual function after surgery 91.537 immediate sequential cataract surgery (ISCS), while others have delayed
than before
416 BCVA, best-corrected visual acuity.
sequential cataract surgery (DSCS) with an interval between the surgeries
of weeks or months. However, same-day bilateral cataract surgery requires
booksmedicos.org
a strict set of operating rules, whereby each eye is treated as an entirely Agency for Health Care Policy and Research; 1993. AHCPR pub. No. 93–0542; Clinical
practice guideline No. 4.
new operative procedure to avoid any possibility of cross contamination.
Rapid rehabilitation of the patient is a worthy goal and a more economic
Hahn U, Krummenauer F, Kölbl B, et al. Determination of valid benchmarks for outcome
indicators in cataract surgery. A multicenter, prospective cohort trial. Ophthalmology
5.18
process for all concerned.46 2011;118:2105–12.
Hard AL, Beckman C, Sjostrand J. Glare measurements before and after cataract surgery.

Acta Ophthalmol Scand 1993;71:471–6.
CATARACT SURGERY IN EYES WITH Holladay JT, Prager TC, Ruiz RS, et al. Improving the predictability of intraocular lens calcu-
lations. Arch Ophthalmol 1986;104:539–41.
OCULAR COMORBIDITY Koch DD. Glare and contrast sensitivity testing in cataract patients. J Cataract Refract Surg
1989;15:158–64.
A substantial number of patients undergoing routine cataract surgery have Laidlaw DA, Harrad RA, Hopper CD, et al. Randomised trial of effectiveness of second eye
cataract surgery. Lancet 1998;352:925–9.
coexisting eye diseases. A sight-threatening ocular comorbidity is the most Leivo T, Sarikkola AU, Uusitalo RJ, et al. Simultaneous bilateral cataract surgery: economic
frequent reason for a poor outcome after cataract surgery.21,42,47–51 However, analysis; Helsinki Simultaneous Bilateral Cataract Surgery Study Report 2. J Cataract
this does not mean that cataract extraction is unnecessary when there is an Refract Surg 2011;37:1003–8.
ocular comorbidity. Studies have shown that many patients with age-related Monestam E. Long-term outcomes of cataract surgery: 15-year results of a prospective study.
macular degeneration and cataract benefit from cataract extraction.52,53 Lundström M, Barry P, Henry Y, et al. Evidence-based guidelines for cataract surgery: guide-
lines based on data in the European Registry of Quality Outcomes for Cataract and
SUMMARY Refractive Surgery database. J Cataract Refract Surg 2012;38:1086–93.
Masket S. Reversal of glare disability after cataract surgery. J Cataract Refract Surg
1989;15:165–8.
All clinicians are aware that good history taking, a thorough examination, McAlinden C, Gothwal VK, Khadka J, et al. Head-to-head comparison of 16 cataract surgery
and quantification of the five areas that describe functional vision are all outcome questionnaires. Ophthalmology 2011;118:2374–81.
important in the determination of indications for surgery and outcome of National Research Council Committee on Vision. Recommended standards for the clinical
surgery. Furthermore, it is extremely important to evaluate the indications measurement and specification of visual acuity. Adv Ophthalmol 1980;41:103–48.
Osher RH, Barros MG, Marques DMV, et al. Early uncorrected visual acuity as a measure-
for, and outcomes of, cataract surgery with respect to health-related quality ment of the visual outcomes of contemporary cataract surgery. J Cataract Refract Surg
of life. This is in the best interests of patients, but it should also be done 2004;30:1917–20.
because of the significant costs to health care linked to this procedure. Rönbeck M, Lundström M, Kugelberg M. Study of possible predictors associated with
self-assessed visual function after cataract surgery: a Swedish National Cataract Register
Study. Ophthalmology 2011;118:1732–8.
KEY REFERENCES
Behndig A, Montan P, Stenevi U, et al. One million cataract surgeries. The Swedish National
Cataract Register 1992–2009. J Cataract Refract Surg 2011;37:1539–45.
Cataract Management Guideline Panel. Cataract in adults: management of functional impair- Access the complete reference list online at ExpertConsult.com
ment. Rockville: US Department of Health and Human Services, Public Health Service,
417
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REFERENCES 26. Ben Simon GJ, Desatnik H. Correction of pre-existing astigmatism during cataract
surgery: comparison between the effects of opposite clear corneal incisions and a single
1. Cataract Management Guideline Panel. Cataract in adults: management of functional
impairment. Rockville: US Department of Health and Human Services, Public Health
clear corneal incision. Craefes Arch Clin Exp Ophthalmol 2005;243:321–6.
27. Qammar A, Mullaney P. Paired opposite clear corneal incisions to correct pre-existing
5.18
Service, Agency for Health Care Policy and Research; 1993. (AHCPR pub. No. 93–0542; astigmatism in cataract patients. J Cataract Refract Surg 2005;31:1167–70.
28. Pfoff DS, Werner JS. Effect of cataract surgery on contrast sensitivity and glare in patients

Clinical practice guideline No. 4).
2. National Research Council Committee on Vision. Recommended standards for the clini- with 20/50 or better Snellen acuity. J Cataract Refract Surg 1994;20:620–5.
cal measurement and specification of visual acuity. Adv Ophthalmol 1980;41:103–48. 29. Hard AL, Beckman C, Sjostrand J. Glare measurements before and after cataract surgery.
3. Lundström M, Barry P, Leite H, et al. The 1998 European Cataract Outcome Study. Acta Ophthalmol Scand 1993;71:471–6.
Report from the European Cataract Outcome Study. J Cataract Refract Surg 2001;27: 30. Lundström M, Albrecht S, Nilsson M, et al. Patients benefit from bilateral same-day cat-
1176–84. aract extraction – a randomized clinical study. J Cataract Refract Surg 2006;32:826–30.
4. Lundström M, Barry P, Henry Y, et al. Evidence-based guidelines for cataract surgery: 31. Sunderraj P, Villada JR, Joyce PW, et al. Glare testing in pseudophakes with posterior
guidelines based on data in the European Registry of Quality Outcomes for Cataract and capsule opacification. Eye (Lond) 1992;6:411–13.
Refractive Surgery database. J Cataract Refract Surg 2012;38:1086–93. 32. Masket S. Relationship between post-operative pupil size and disability glare. J Cataract
5. Williamson TH, Strong NP, Sparrow J, et al. Contrast sensitivity and glare in cataract Refract Surg 1992;18:506–7.
using the Pelli-Robson chart. Br J Ophthalmol 1992;76:719–22. 33. Masket S. Reversal of glare disability after cataract surgery. J Cataract Refract Surg
6. Levin ML. Opalescent nuclear cataract. J Cataract Refract Surg 1989;15:576–9. 1989;15:165–8.
7. Koch DD. Glare and contrast sensitivity testing in cataract patients. J Cataract Refract 34. Hirsch RP, Nadler MP, Miller D. Clinical performance of a disability glare tester. Arch
Surg 1989;15:158–64. Ophthalmol 1984;102:1633–6.
8. Barrett BT, Davison PA, Eustace PE. Effects of posterior segment disorders on oscillatory 35. McAlinden C, Gothwal VK, Khadka J, et al. A Head-to-head comparison of 16 cataract
displacement thresholds, and on acuities as measured using the potential acuity meter surgery outcome questionnaires. Ophthalmology 2011;118:2374–81.
and laser interferometer. Ophthalmic Physiol Opt 1994;14:132–8. 36. Lundström M, Pesudovs K. Catquest-9SF patient outcomes questionnaire. Nine item
9. Alio JL, Artola A, Ruiz-Moreno JM, et al. Accuracy of the potential acuity meter in pre- short-form Rasch-scaled revision of the Catquest questionnaire. J Cataract Refract Surg
dicting the visual outcome in cases of cataract associated with macular degeneration. Eur 2009;35:504–13.
J Ophthalmol 1993;3:189–92. 37. Lundström M, Behndig A, Kugelberg M, et al. The outcome of cataract surgery measured
10. Frisen L. High-pass resolution perimetry and age-related loss of visual pathway neurons. with the Catquest-9SF. Acta Ophthalmol 2011;89:718–23.
Acta Ophthalmol 1991;69:511–15. 38. Lundström M, Stenevi U, Thorburn W. Cataract surgery in the very elderly. J Cataract
11. Ball KK, Beard BL, Roenker DL, et al. Age and visual research: expanding the useful field Refract Surg 2000;26:408–14.
of view. J Opt Soc Am A 1988;5:2210–19. 39. Mönestam E, Wachmeister L. Impact of cataract surgery on the visual ability of the very
12. Cooper BA, Ward M, Gowland CA, et al. The use of the Lanthony New Color Test in old. Am J Ophthalmol 2004;137:145–55.
determining the effects of aging on color vision. J Gerontol 1991;46:320–4. 40. Lundström M, Wendel E. Duration of self-assessed benefit of cataract extraction – a long-
13. Hahn U, Krummenauer F, Kölbl B, et al. Determination of valid benchmarks for term study. Br J Ophthalmol 2005;89:1017–20.
outcome indicators in cataract surgery. A multicenter, prospective cohort trial. Ophthal- 41. Monestam E. Long-term outcomes of cataract surgery: 15-year results of a prospective
mology 2011;118:2105–12. study. J Cataract Refract Surg 2016;42:19–26.
14. Holladay JT. A prospective, randomized, double-masked comparison of a zonal-progres- 42. Lundström M, Brege KG, Florén I, et al. Impaired visual function following cataract
sive multifocal IOL. A discussion. Ophthalmology 1992;99:860. surgery. An analysis of poor outcomes as defined by the Catquest questionnaire. J Cata-
15. Steinert RF, Post CT Jr, Brint SF, et al. A prospective, randomized, double-masked com- ract Refract Surg 2000;26:101–8.
parison of a zonal-progressive multifocal intraocular lens and a monofocal intraocular 43. Rönbeck M, Lundström M, Kugelberg M. Study of possible predictors associated with
lens. Ophthalmology 1992;99:853–60. self-assessed visual function after cataract surgery: a Swedish National Cataract Register
16. Lindstrom RL. Food and Drug Administration update. One-year results from 671 patients Study. Ophthalmology 2011;118:1732–8.
with the 3M multifocal intraocular lens. Ophthalmology 1993;100:91–7. 44. Laidlaw DA, Harrad RA, Hopper CD, et al. Randomised trial of effectiveness of second
17. Javitt JC, Steinert RF. Cataract extraction with multifocal intraocular lens implantation: eye cataract surgery. Lancet 1998;352:925–9.
a multinational clinical trial evaluating clinical, functional, and quality of life outcomes. 45. Lundström M, Stenevi U, Thorburn W. Quality of life after first- and second-eye cataract
Ophthalmology 2000;107:2040–8. surgery. Five-year data collected by the Swedish National Cataract Register. J Cataract
18. Osher RH, Barros MG, Marques DMV, et al. Early uncorrected visual acuity as a mea- Refract Surg 2001;27:1553–9.
surement of the visual outcomes of contemporary cataract surgery. J Cataract Refract 46. Leivo T, Sarikkola AU, Uusitalo RJ, et al. Simultaneous bilateral cataract surgery: eco-
Surg 2004;30:1917–20. nomic analysis; Helsinki Simultaneous Bilateral Cataract Surgery Study Report 2. J Cata-
19. Holladay JT, Prager TC, Ruiz RS, et al. Improving the predictability of intraocular lens ract Refract Surg 2011;37:1003–8.
calculations. Arch Ophthalmol 1986;104:539–41. 47. Desai P, Minassian DC, Reidy A. National cataract surgery survey 1997–8: a report of the
20. Naeser K, Knudsen EB, Hansen MK. Bivariate polar value analysis of surgically induced results of the clinical outcomes. Br J Ophthalmol 1999;83:1336–40.
astigmatism. J Cataract Refract Surg 2002;18:72–8. 48. Mangione CM, Orav EJ, Lawrence MG, et al. Prediction of visual function after cataract
21. Lundström M, Stenevi U, Thorburn W. The Swedish National Cataract Register: a 9-year surgery: a prospectively validated model. Arch Ophthalmol 1995;113:1305–11.
review. Acta Ophthalmol Scand 2002;80:248–57. 49. Schein OD, Steinberg EP, Cassard SD, et al. Predictors of outcome in patients who
22. Behndig A, Montan P, Stenevi U, et al. One million cataract surgeries. The Swedish underwent cataract surgery. Ophthalmology 1995;102:817–23.
National Cataract Register 1992–2009. J Cataract Refract Surg 2011;37:1539–45. 50. Lundström M, Stenevi U, Thorburn W. Outcome of cataract surgery considering the
23. Kohnen S, Neuber R, Kohnen T. Effect of temporal and nasal unsutured limbal tunnel pre-operative situation: a study of possible predictors of the functional outcome. Br J
incisions on induced astigmatism after phacoemulsification. J Cataract Refract Surg Ophthalmol 1999;83:1272–6.
2002;28:821–5. 51. Grimfors M, Mollazadegan K, Lundström M, et al. Ocular comorbidity and self-assessed
24. Alio J, Rodriguez-Prats JL, Galal A, et al. Outcomes of microincision cataract surgery visual function after cataract surgery. J Cataract Refract Surg 2014;40:1163–9.
versus coaxial phacoemulsification. Ophthalmology 2005;112:1997–2003. 52. Lundström M, Brege KG, Florén I, et al. Cataract surgery and quality of life in patients
25. Borasio E, Mehta JS, Maurino V. Surgically induced astigmatism after phacoemulsifica- with age-related macular degeneration. Br J Ophthalmol 2002;86:1330–5.
tion in eyes with mild to moderate corneal astigmatism: temporal versus on-axis clear 53. Armbrecht AM, Findlay C, Aspinall PA, et al. Cataract surgery in patients with age-re-
corneal incisions. J Cataract Refract Surg 2006;32:565–72. lated macular degeneration: one-year outcomes. J Cataract Refract Surg 2003;29:686–93.
417.e1
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Part 6 Retina and Vitreous
Section 1 Anatomy
Structure of the Neural Retina

Hermann D. Schubert 6.1
of the retinal pigment epithelium (RPE; Fig. 6.1.3). At the ora serrata,
Definition: The structure of the neural retina reflects its embryological the pigmented epithelium is continued as RPE; its basement membrane
development and its ultimate purpose: the absorption and processing of becomes Bruch’s membrane. The nonpigmented epithelium of the ciliary
photons of visible light. body and pars plana is continued posteriorly as the neural retina; its base-
ment membrane becomes the internal limiting membrane. The union of
the epithelial layers delimits the anterior cul-de-sac of the subretinal space
at the ora serrata.3
Key Feature The apex-to-apex arrangement between the epithelia that clearly exists
• In a surgical specialty, knowledge of anatomy has to keep pace with anterior to the ora is continued posteriorly by Müller cells that face and
that of imaging and procedures.
Fig. 6.1.2 Apex-to-Apex
ARRANGEMENT OF RETINA AND Arrangement of Retina
INTRODUCTION PIGMENT EPITHELIUM and Pigment Epithelium.
Apical attachments
The primary purpose of the corneoscleral and uveal coats of the eye is to connect the iris and ciliary
provide protection to the retina in addition to providing nourishment and apical junctions body epithelia (red dotted
enabling ocular movement. The retina is derived embryologically from the line).
optic vesicle, an outpouching of the embryonic forebrain.1 The bilayered
neuroepithelial structure of the mature retina reflects the apex-to-apex
arrangement of the original optic cup. It also forms the wall of a cavity, the
vitreous cavity, which is filled with glycosaminoglycans and collagen. The
ocular cavity is homologous to a leptomeningeal cistern2 in that both vitre-
ous and choroid are derived from mesenchyme that sandwiches the neu-
roepithelium on its path away from the brain. The ocular neuroepithelial
cyst has two openings. Anteriorly lies the pupil, which is a full-thickness
aperture, and posteriorly lies the optic nerve in which, similar to a colo-
boma, only derivatives of the inner retinal layers are found. Because the
cell apices are oriented inwardly, the two layers of the optic cup and their
derivatives are enveloped externally by basement membrane (Fig. 6.1.1).
The relationship of the epithelial layers to each other is modified from
anterior to posterior. Anterior to the ora serrata, the pigmented and non-
pigmented epithelia of the iris and ciliary body are joined at their apices by
a system of intercellular junctions (Fig. 6.1.2), which is continuous with the
external limiting layer of the neural retina and the apical junctional girdles
Fig. 6.1.1 Apex-to-Apex

ARRANGEMENT OF MÜLLERIAN GLIA AND Arrangement of Müllerian TRANSITION OF RETINA TO NONPIGMENTED EPITHELIUM AT THE ORA SERRATA
RETINAL PIGMENT EPITHELIAL CELLS Glia and Retinal Pigment
Epithelial Cells. Because
the cell apices face each
internal limiting
other, the neuroepithelia ora serrata
membrane
are enveloped externally
by a basement membrane.
Müller cells vitreous
Note that this basement
base attachments
membrane is elaborated
by a single-layer
neuroepithelium, in basement
contrast to the internal membrane
limiting membrane, which
is formed by Müller cells. apex nonpigmented
epithelium
apex
pigmented
base epithelium
external limiting membrane Bruch's (basement) membrane

RPE cells
Fig. 6.1.3 Transition of Neural Retina to Nonpigmented Epithelium at the Ora
Serrata. The external limiting membrane, which consists of the attachment sites
Bruch’s internal limiting Müller cells of photoreceptors and Müller cells, transforms into the apical junctional system of
membrane membrane
the pars plana epithelia. The internal limiting membrane becomes the basement 419
membrane of the nonpigmented epithelium.
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6 STRUCTURES OF THE RETINA THAT BORDER THE OPTIC NERVE HEAD FOVEAL MARGIN, FOVEAL DECLIVITY, FOVEOLA, AND UMBO
foveal diameter 1500 m margin

Retina and Vitreous
vitreous internal limiting

attachments membrane
foveola 350 m
Müller cells
Müller cells in
inner nuclear layer
internal limiting
membrane central tissue external limiting
meniscus of Kuhnt membrane
retinal pigment
epithelium
capillary declivity umbo fovea
external limiting
arcade externa
membrane
retinal pigment Fig. 6.1.5 Foveal Margin, Foveal Declivity, Foveola, and Umbo. The foveal
epithelium diameter (from margin to margin) measures 1500 µm, and the foveola is 350 µm in
diameter. The foveal avascular zone is slightly larger (500 µm) and is delimited by
Bruch's (basement) intermediary border the capillary arcades at the level of the inner nuclear layer. The foveal excavation
membrane tissue of Kuhnt represents the fovea interna, which is lined by the internal limiting membrane.
nerve axons The fovea externa is represented by the junctional system of the external limiting
membrane. Both fibers of Henle and the accompanying glia assume a horizontal
and radial arrangement in the fovea.
Fig. 6.1.4 Structures of the Retina That Border the Optic Nerve Head. The
junctional system of the external limiting membrane connects with the apical
junctional system of the retinal pigment epithelium and is supported by the
intermediary border tissue of Kuhnt. UMBO AND FOVEOLA
intermittently contact the RPE (see Fig. 6.1.1). Here, the contact is main-
tained not by apical junctions (even though an interreceptor matrix exists) fovea interna
but by the pressure of the vitreous and by suction forces of the RPE. Mülle- clear tissue umbo capillary internal limiting
rian glia are the main structural cells of the neural retina and are found membrane
throughout the retina from the ora to the optic nerve head. inner nuclear layer
At the optic nerve head, the internal limiting membrane continues as
the basement membrane of Elschnig, supported by the glial meniscus of nuclear cake Henle's fibers
Kuhnt (Fig. 6.1.4). The (glial) external limiting membrane joins the apices
outer nuclear layer
of the RPE to form the posterior cul-de-sac of the subretinal space at the
optic nerve,3 which is delimited by a glial border tissue, the intermedi- external limiting
ary border tissue of Kuhnt. This border tissue continues posteriorly at the membrane
choroidal level as the border tissue of Elschnig; both tissues separate the fovea externa umbo
outer retina and choroid from the axons of the inner retina. The axons, in 150–200 m
turn, fixate the posterior retina to the scleral lamina cribrosa and its glial
system. The retina, therefore, is fixed to the choroid directly by the apical Fig. 6.1.6 Umbo (Center) and Foveola. The outer nuclear layer is separated from
junctional system at the ora serrata (anterior cul-de-sac of the subretinal the inner nuclear layer by the horizontal–oblique fibers of Henle. Umbo and foveola
space) and indirectly, via the ciliary body and choroid, to its attachments between few nuclei feature clear müllerian fibers (clear tissue), delimited by fibers
at the scleral spur and sclera. At the nerve head, all neuroepithelial and of Henle externally and by the internal limiting membrane internally. The central
choroidal layers are fixed by both the junctional tissues and the exiting 150–200 µm represents the umbo, where cone concentration is maximal.
axons. The corneoscleral coat protects, moves, and holds the retina in the
appropriate position and allows the object of regard to be focused on the laterally by a junctional system, the external limiting membrane. Their
center of the retina. inner fibers (axons) travel radially and peripherally as fibers of Henle in
the outer plexiform layer (Fig. 6.1.6). As a result of their high concentration
CENTER OF THE MACULA: UMBO and crowding, the central cones have their nuclei arranged in multiple
layers in a circular shape, which resembles a cake (gateau nucleaire).5
The fovea represents an excavation in the retinal center and consists of a Cones, including their inner and outer segments, are surrounded and
margin, a declivity, and a bottom (Fig. 6.1.5). The bottom corresponds to enveloped by the processes of müllerian glia, which concentrate on the
the foveola, the center of which is called the umbo. The umbo represents vitreal side (tissu clair),5 just underneath the internal limiting membrane.7
the precise center of the macula, the area of retina that results in the Some glial cell nuclei are found in this inner layer, but most form part of
highest visual acuity. Usually, it is referred to as the center of the fovea or the laterally displaced inner nuclear layer. Foveal development, therefore,
macula. Although both terms are commonly used clinically, neither is a involves the migration, elongation, concentration, and displacement of
precise anatomical designation. both neuronal cells and, most importantly, glial cells, the main structural
The predominant photoreceptor of the foveola and umbo is the cone. element of the retina. Radiating striae found in the foveal internal limiting
The foveal “nuclear cake” results from the centripetal migration of the membrane are related to fibers of Henle but are probably mediated by glia
photoreceptors and the centrifugal lateral displacement of the bipolars and that elaborate and are connected to the internal limiting membrane. The
ganglion cells during foveal maturation, which occurs 3 months before density of the foveal glia has been measured as 16 600–20 000 cells/mm2.6
and 3 months after term.4,5 Although their individual diameters are nar-
rowed because of extreme crowding, central cones maintain their volume
through elongation, up to a length of 70 µm.5 The central packing of cones
FOVEOLA
takes place in an area of 1500 µm diameter.4 The greatest concentration The bouquet of central cones is surrounded by the foveal bottom, or
of cones is found in the umbo, an area of 150–200 µm diameter, referred foveola, which measures 350 µm in diameter and 150 µm in thickness
to as the central bouquet of cones.5 Estimates of central cone density are (see Fig. 6.1.5). This avascular area consists of densely packed cones
113 000 and 230 000 cones/mm2 in baboons and cynomolgus monkeys, that are elongated and connected by the external limiting membrane.
420 respectively. For the central bouquet, the density of cones may be as high As a result of the elongation of the outer segments, the external limiting
as 385 000 cones/mm2.6 The inner cone segments (myoids) are connected membrane is bowed vitreally, a phenomenon that has been termed fovea
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vessels are located at the level of the internal nuclear layer and leave an
avascular zone of 250–600 µm between them. The declivity also is asso-
ciated with an increase in basement membrane thickness, which reaches 6.1
a maximum at the foveal margin. Internal limiting membrane thickness
and strength of vitreal attachment are inversely proportional; that is, adhe-

sions are strongest in the foveola.3 Not surprisingly, the foveal center is
most affected in traumatic macular holes in which glial opercula suggest
anterior–posterior traction as the cause. The margin of the fovea (margo
foveae) is often seen biomicroscopically as a ring-like reflection of the inter-
nal limiting membrane, which measures 1500 µm (disc size) in diameter
and 0.55 mm in thickness (see Fig. 6.1.7).
PARAFOVEA
The parafovea is a belt that measures 0.5 mm in width and surrounds the
foveal margin (see Fig. 6.1.7). At this distance from the center, the retina
features a regular architecture of layers, which includes 4–6 layers of gan-
glion cells and 7–11 layers of bipolar cells.8
PERIFOVEA
The perifovea surrounds the parafovea as a belt that measures 1.5 mm
A wide (see Fig. 6.1.7). The region is characterized by several layers of gan-
glion cells and six layers of bipolar cells.8
REGIONS OF THE MACULA (AREA CENTRALIS) MACULA, OR CENTRAL AREA

The umbo, foveola, fovea, parafovea, and perifovea together constitute the
macula, or central area.9 The central area can be differentiated from the
extra-areal periphery by the ganglion cell layer. In the macula, the ganglion
cell layer is several cells thick; however, in the extra-areal periphery, it is
only one-cell thick. The macular border coincides with the course of the
perifoveal major temporal arcades and has an approximate diameter of 5.5 mm (see
area
Fig. 6.1.7), which comprises the diameter of the fovea (1.5 mm), twice the
parafoveal
width of the parafovea (2 × 0.5 ≡ 1 mm), and twice the width of the perifo-
area
vea (2 × 1.5 ≡ 3 mm).10
fovea
foveola EXTRA-AREAL PERIPHERY
umbo The peripheral retina is divided arbitrarily into belts of near, middle, far,
and extreme periphery.9 The belt of the near periphery is 1.5 mm wide, and
1.5 0.5 0.5 1.5 the belt of the middle periphery, or equator, is 3 mm wide. The far periph-
mm mm 0.35 mm mm mm
1.5 mm ery extends from the equator to the ora serrata. The width of this belt varies,
B depending on ocular size and refractive error. The average circumference
of the eye is 72 mm at the equator and 60 mm at the ora serrata, and the
Fig. 6.1.7 Normal Fundus With Macula Encompassed by Major Vascular Arcades. average width of this belt is 6 mm. Because peripheral retinal pathology is
The macula, or central area, has the following components from center to periphery: usually charted in clock hours, 1 clock hour corresponds to 5–6 mm of far
umbo, foveola, fovea, parafovea, and perifovea. peripheral circumference. Therefore, the far periphery of the retina may be
divided into 12 squares that measure approximately 6 × 6 mm. As a result
externa. Both the umbo and the foveola represent the most visible part of of the insertion of the posterior vitreous base, most peripheral pathology
the outer retina; however, to the level of the external limiting membrane, falls into these squares. The ora serrata and pars plana are referred to as
all cones and their axons are enveloped by the processes of Müller cells, the extreme periphery.9
which form the vitreal inner layer and elaborate and support the internal
limiting membrane. Thus, the apex-to-apex arrangement of the optic cup
is maintained by the processes of müllerian glia that face the apices of
LAYERS OF THE NEURAL RETINA
the pigment epithelial cells in the foveola. The high metabolic demands With the exception of the fovea, ora serrata, and optic disc, the neural
of central cones are met by direct contact with the pigment epithelium, as retina is organized in layers, dictated by the direction of the müllerian glia,
well as through the processes of glia, whose nuclei lie more peripheral in its structural backbone. Essentially, there is the photoreceptor layer plus
the inner nuclear layer and closer to the perifoveal vascular arcades (see the bipolar and ganglion cell layer, representing the outer first neuron and
Fig. 6.1.6). inner second and third neuron of the visual pathway. The müllerian glia
In pathological conditions, loss of the normal foveolar reflex may indi- elaborate the internal limiting membrane as its basement membrane and
cate a glial disturbance (acute nerve cell damage, cloudy swelling) either extend to the external limiting membrane, where it communicates with
primarily or mediated by the vitreous, which is tightly adherent to the thin the apices of the RPE (Fig. 6.1.8).
internal limiting membrane. Loss of the foveal reflex may thus indicate The inner nuclear layer is home to the nuclei of the müllerian glia, the
traction or edema of glial cells and, secondarily, of cones. The inner glial bipolar cells, and the horizontal and amacrine cells. The amacrine cells
layer may separate from the nuclear layer, which results in cyst-like schisis. lie on the inside of the inner nuclear layer, and the horizontal cells lie on
the outside (see Fig. 6.1.8). The inner nuclear layer has plexiform layers
FOVEA on either side, which connect it to the outer photoreceptor layer and the
(inner) ganglion cell layer. From this simple anatomical consideration, it
The fovea consists of the thin bottom, a 22° declivity (the clivus),3 and a follows that rods and cones synapse with bipolar and horizontal cells in
thick margin (see Figs. 6.1.5–6.1.7). The bottom, or foveola, was described the outer plexiform layer. As a result of the increased length of fibers of
earlier. The declivity of 22° denotes the lateral displacement of the bipo- Henle, the junctional system (the middle limiting “membrane”) is found
lars, horizontal and amacrine cells in the inner nuclear layer, which also in the inner third of the outer plexiform layer, which is the only truly plexi-
includes the nuclei of its müllerian glia. The avascular foveola is sur- form portion of this layer. The bipolar cells and amacrine cells of the inner 421
rounded by the vascular arcades, a circular system of capillaries. These nuclear layer synapse with the dendrites of the ganglion cells in the inner
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plexiform layer. In embryogenesis, müllerian glia, along with their inter-
6 NEURONAL CONNECTIONS IN THE RETINA AND PARTICIPATING CELLS nal limiting membrane and orientation, antedate photoreceptor differenti-
ation; this is analogous to the rest of the central nervous system, in which
structural development precedes individual cell differentiation.
internal limiting
Retina and Vitreous
membrane
KEY REFERENCES
ganglion cell Fine BS, Yanoff M. Ocular histology. A text and atlas. New York: Harper & Row; 1979. p.
111–24.
Gaertner I. The vitreous, an intraocular compartment of the leptomeninx. Doc Ophthalmol
1986;62:205–22.
Hendrickson AE, Yuodelis C. The morphological development of the human fovea. Arch
Hogan MJ, Alvarado JA, Wedell JE. Histology of the human eye. Philadelphia: WB Saunders;
1971. p. 491–8.
amacrine cell bipolar inner nuclear Krebs W, Krebs I. Quantitative morphology of the central fovea in the primate retina. Am J
cell layer Anat 1989;184:225–36.
horizontal cell Mann I. The development of the human eye. New York: Grune & Stratton; 1950.
Polyak SL. The retina. Chicago: University of Chicago Press; 1941.
Rochon-Duvigneaud A. Recherches sur la fovea de la retine humaine et particulierement sur
le bouquet des cones centraux. Arch Anat Microsc 1907;9:315–42.
middle limiting Spitznas M. Anatomical features of the human macula. In: l’Esperance FA, editor. Current
membrane diagnosis and management of retinal disorders. St Louis: CV Mosby; 1977.
Yamada E. Some structural features of the fovea central in the human retina. Arch Ophthal-
mol 1969;82:151–9.
external limiting
membrane Access the complete reference list online at ExpertConsult.com
Müller's
fiber (glia)
cone
rod
Fig. 6.1.8 Neuronal Connections in the Retina and Participating Cells. The inner
nuclear layer contains the nuclei of the bipolar cells (second neuron) and müllerian
glia. The amacrine cells are found on the inside and the horizontal cells on the
outside of this layer, next to their respective plexiform connections.
422
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REFERENCES 6. Krebs W, Krebs I. Quantitative morphology of the central fovea in the primate retina. Am
J Anat 1989;184:225–36.
1. Mann I. The development of the human eye. New York: Grune & Stratton; 1950.
2. Gaertner I. The vitreous, an intraocular compartment of the leptomeninx. Doc Ophthal-
7. Yamada E. Some structural features of the fovea central in the human retina. Arch Oph-
thalmol 1969;82:151–9.
6.1
mol 1986;62:205–22. 8. Spitznas M. Anatomical features of the human macula. In: l’Esperance FA, editor.
Current diagnosis and management of retinal disorders. St Louis: CV Mosby; 1977.

3. Fine BS, Yanoff M. Ocular histology. A text and atlas. New York: Harper & Row; 1979. p.
111–24. 9. Polyak SL. The retina. Chicago: University of Chicago Press; 1941.
4. Hendrickson AE, Yuodelis C. The morphological development of the human fovea. Arch 10. Hogan MJ, Alvarado JA, Wedell JE. Histology of the human eye. Philadelphia: WB Saun-
Ophthalmol 1969;82:151–9. ders; 1971. p. 491–8.
5. Rochon-Duvigneaud A. Recherches sur la fovea de la retine humaine et particulierement
sur le bouquet des cones centraux. Arch Anat Microsc 1907;9:315–42.
422.e1
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Section 1 Anatomy
Retinal Pigment Epithelium

Michael F. Marmor 6.2
Definition: A melanin-containing epithelial layer that lies between the
neural retina and choroid.
Key Features
• Absorption of scattered light.
• Control of fluid and nutrients in the subretinal space (blood–retinal
barrier function).
• Visual pigment regeneration and synthesis.
• Synthesis of growth factors to modulate adjacent structures.
• Maintenance of retinal adhesion.
• Phagocytosis and digestion of photoreceptor wastes.
• Electrical homeostasis.
• Regeneration and repair for degenerative disease.
Fig. 6.2.1 Apical Surface of Human Retinal Pigment Epithelium as Seen
Through a Scanning Electron Microscope. Fine microvilli cover the surface and
INTRODUCTION reach up between the photoreceptor outer segments (which have been peeled
away in this view).
The retinal pigment epithelium (RPE) is a vital tissue for the maintenance
of photoreceptor function.1,2 It is also affected by many diseases of the
retina and choroid. Embryologically, the RPE is derived from the same serves as a free radical stabilizer and can bind toxins and retinotoxic drugs,
neural tube tissue that forms the neural retina, but the cells differentiate such as chloroquine and thioridazine, although it is unclear whether this
into a transporting epithelium, the main functions of which are to met- effect is beneficial or harmful.
abolically insulate and support the overlying neural retina. As a cellular The other major RPE pigment is lipofuscin, which accumulates grad-
monolayer, the RPE is now an attractive target for therapeutic modification ually with age, although it is not clear whether it is directly damaging to
and transplantation.3 RPE cells as it is a component of both normal and pathological aging.
STRUCTURE AND METABOLISM Metabolism and Growth Factors

A number of growth factors are elaborated by RPE cells and serve to modu-
Cellular Architecture and Blood–Retinal Barrier late not only the behavior of the RPE but also the behavior of surrounding
The RPE is a monolayer of interlocking hexagonal cells that are joined by tissues.1,4 Knowledge of these interactions is growing rapidly, and it is now
tight junctions (zonulae occludens), which block the free passage of water recognized that the RPE is a critical part of a complex system of cellular
and ions. This junctional barrier is the equivalent of the blood–retinal cross-talk that controls vascular supply, permeability, growth, immunolog-
barrier of the neuroretina. ical responses, repair, and other processes vital to retinal function. Dys-
In the macular region, RPE cells are small (roughly 10–14 µm in diam- function within these systems contributes to disorders, such as age-related
eter), whereas toward the periphery, they become flatter and broader macular degeneration. Factors produced by the RPE include, among others,
(diameter up to 60 µm). The density of photoreceptors also varies across platelet-derived growth factor, which modulates cell growth and healing;
the retina, but the number of photoreceptors that overlie each RPE cell pigment epithelium-derived factor, which acts as a neuroprotectant and
remains roughly constant (about 45 photoreceptors per RPE cell). vascular inhibitor; vascular endothelial growth factor, which can stimulate
In cross-section, the RPE cell is differentiated into apical and basal con- normal or pathological neovascular growth; fibroblast growth factor, which
figurations. On the apical side (facing the photoreceptors), long microvilli can be neurotropic; transforming growth factor, which moderates inflam-
reach up between (and envelop) the outer segments of the photoreceptors mation; ciliary neurotrophic factor, which supports and rescues cells; and
(Fig. 6.2.1). Melanin granules are concentrated in the apical end of the cell. other immune regulating components, such as Toll-like receptors and
The basal membrane has convoluted infolds to increase the surface area complement factors.
for the absorption and secretion of material. The cell structure is stabilized
by a cytoskeleton of microfilaments and microtubules.
MEMBRANE PROPERTIES AND
Pigments FLUID TRANSPORT
The pigment that gives the RPE its name is melanin, found in cytoplasmic
granules called melanosomes. In older age, melanin granules often fuse with
Ion Channels and Transport Systems
lysosomes and break down, so the fundus in older adults typically appears The RPE membrane contains selective ion channels, and active or facil-
less pigmented. The role of melanin in the eye remains somewhat specula- itative transport systems for ions and for metabolites, such as glucose
tive. The pigment serves to absorb stray light and minimize scatter within and amino acids.5 Different channels and transporters are present on the
the eye, which has theoretical optical benefits. Visual acuity is, however, apical and basal membranes. The net effects of the asymmetrical transport
not degraded in the fundi of the very blond. Further, the appearance of systems are a movement of water across the RPE in the apical-to-basal
the fundus can be misleading with respect to the RPE because the great- direction and the generation of voltage across the RPE, as well as control 423
est racial differences are a result of choroidal pigmentation. Melanin also of protein access to the subretinal space.
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6 MECHANISM OF SEROUS DETACHMENTS
Normal RPE
RPE PHAGOCYTOSIS OF PHOTORECEPTOR OUTER SEGMENTS
Retina and Vitreous
vitreous
retina
normal
RPE
choroid
leak
Damaged RPE/choroid complex
vitreous
Fig. 6.2.3 Retinal Pigment Epithelium (RPE) Phagocytosis of Photoreceptor
retina
Outer Segments. The phagosome, containing the ingested material, enters the RPE
cytoplasm, where it merges with lysosomes to facilitate digestion of the outdated
compromised membranes. (Adapted from Steinberg H, Wood I, Hogan MJ. Pigment epithelial
RPE ensheathment and phagocytosis of extrafoveal cones in human retina. Philos Trans
choroid R Soc Lond 1977;277:459–74.)
leak
Fig. 6.2.2 Mechanism of Serous Detachment. When the retinal pigment

epithelium (RPE) is normal, no serous detachment occurs beyond a focal site of Photoreceptor Renewal and Phagocytosis
leakage. When the RPE is compromised by choroidal or RPE disease that impairs
Photoreceptors are continually exposed to radiant energy (light) and
outward fluid transport, a serous detachment forms until absorption across the
exposed RPE balances the inward leak. oxygen (from the choroid), which facilitates the production of free radi-
cals that can damage membranes. Thus a process of cellular renewal is
needed. Every day, upward of 100 discs at the distal end of the photorecep-
tors are phagocytosed by the RPE (Fig. 6.2.3), while new discs are synthe-
sized.9 The rods shed discs most vigorously in the morning at the onset of
The ability of the RPE to transport water actively is very powerful, light, whereas cones shed more vigorously at the onset of darkness, and
but water also moves out if the RPE barrier function is broken because the outer segments are renewed roughly every 2 weeks. Within the RPE,
of intraocular pressure and osmotic suction from the choroid. One clini- the phagocytosed discs merge with lysosomes so that the material can be
cal implication is that a small RPE break will not cause a serous detach- digested. Necessary fatty acids are recycled, whereas waste products are
ment unless there is also a diffuse loss of RPE transport. Central serous egested across the basal RPE membrane. Residual membrane debris, such
chorioretinopathy involves broad dysfunction in the RPE-choroid complex as A2E, may contribute to the formation of lipofuscin and aging damage
(Fig. 6.2.2).6 to the RPE.
Electrical Activity Retinal Adhesion and Interphotoreceptor Matrix

The RPE generates no direct response to light. However, the asymmet- Adhesion of the retina to the RPE is a complex process involving several
rical transport properties of the apical and basal membranes generate a interactive mechanisms. The neural retina is pressed in place by the vitre-
transepithelial voltage (called the standing potential), which can be mod- ous gel, intraocular fluid pressure, and RPE water transport, which drive
ified secondarily by photoreceptor activity or by endogenously supplied or pull water through the semipermeable tissue. There is some physical
substances.7 Furthermore, light activation of photoreceptors also causes resistance to separation of outer segments from enveloping RPE micro-
the release of a messenger substance that induces a basal RPE depolar- villi. The strongest mechanism for bonding the retina to the RPE space
ization 5–10 minutes later. This late basal depolarization is recorded clini- appears to be the interphotoreceptor matrix (IPM), which is an elaborate
cally as the “light response” of the clinical electroocculography (EOG). The chemical structure with distinct domains that surround the rods and cones
light response is mediated through calcium-dependent chloride channels (Fig. 6.2.4A).10 When neural retina is freshly peeled from the RPE, the IPM
controlled, in part, by the bestrophin gene, which is altered in Best vitel- material stretches dramatically before it breaks, which shows that it is
liform dystrophy or autosomal recessive bestrophinopathy. The EOG is firmly attached to both neural retinal and RPE surfaces (see Fig. 6.2.4B).
very subnormal in Best disease, but is not severely altered in most RPE However, the strength of the IPM adhesive system (as well as RPE fluid
disorders.7 transport) is constantly and acutely dependent on metabolism.11 Retinal
adhesive force drops to near zero within minutes after death, and adhesive
strength can be reversibly restored or enhanced by tissue oxygenation.
PHOTORECEPTOR–RETINAL PIGMENT Retinal detachment disrupts fluid transport and the IPM, and even
when the retina is surgically reattached, it can take several weeks for full
EPITHELIUM INTERACTIONS recovery of IPM morphology, RPE/photoreceptor intercalation and normal
Visual Pigment Regeneration adhesive strength.
Absorption of light in the photoreceptors converts 11-cis- vitamin A to the

all-trans form. This initiates transduction of light to a neural signal and
REPAIR, REGENERATION, AND THERAPY
begins a series of regenerative chemical changes to restore the supply of The RPE is capable of local repair (unlike the neural retina), although
11-cis vitamin A. Vitamin A is split off from the opsin molecule and carried injured cells may migrate and take on altered characteristics. After a focal
by a transport protein to the RPE. In the RPE, vitamin A may be stored laser burn, the RPE cells that surround the burn will divide and fill the
in an ester form, but eventually it is isomerized back to the 11-cis form defect to form a new blood–retinal barrier within 1–2 weeks. However,
by a critical enzyme RPE65, and then recombined with opsin.8 Defects in large RPE defects, such as geographical atrophy, do not heal. Because
several genes, including RPE65, LRAT, RLPB (CRALBP), and RDH, which growth factors from the RPE normally serve to limit excessive proliferation
424 control this regenerative cycle in the RPE, cause Leber congenital amauro- of cells and vasculature, RPE injury becomes a part of the cycle of pathol-
sis or retinitis pigmentosa. ogy that stimulates vascular or fibrous growth in many retinal conditions.
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The RPE monolayer, however, can be cultured and transplanted, and
RPE cells can be genetically engineered or physically stimulated to modify
their metabolic activity. Thus, this tissue may also have an important role 6.2
in the therapy of retinal disorders, ranging from dystrophies to aging.
These new options depend directly on the physical and physiological
Retinal Pigment Epithelium

characteristics of the RPE that have been reviewed above. For example,
nondamaging laser therapy (low energy or micropulses) can stimulate a
release of metabolic factors, including heat shock proteins that ameliorate
A injury. This approach is being explored for the treatment of several dis-
eases, including macular edema and central serous chorioretinopathy.12
Cellular damage to the RPE is specifically causative of several hereditary
dystrophies, including retinitis pigmentosa that involves RPE genes, such
as RPE65 and LRAT, and Stargardt disease in which RPE damage leads to
photoreceptor death. Many groups are now investigating the use of stem
cell and RPE transplantation to put normal RPE back into eyes with these
diseases.3 The ability to culture and modify induced pluripotent stem cells
(iPSC) allows for genetic modification to create designer RPE cells prior
to transplantation,13 although techniques for the culturing of cells, insert-
ing cells to reach a large area of retina, and ensuring cell survival and
function over a lifetime are still evolving. Finally, trials are beginning for
genetic modification of the RPE (as well as other retinal cells) within the
eye through transfection with viral and other gene carriers.14
REFERENCES
1. Sparrow JR, Hicks D, Hamel CP. The retinal pigment epithelium in health and disease.
Curr Mol Med 2010;10:802–23.
2. Marmor MF, Wolfensberger TW, editors. The retinal pigment epithelium. Current
aspects of function and disease. New York: Oxford University Press; 1998.
3. Zarbin M. Cell-based therapy for degenerative retinal disease. Trends Mol Med
2016;22:115–30.
4. Kolomeyer AM, Zarbin MA. Trophic factors in the pathogenesis and therapy for retinal
degenerative diseases. Surv Ophthalmol 2014;59:134–65.
5. Lehmann GL, Benedicto I, Philp NJ, et al. Plasma membrane protein polarity and traf-
ficking in RPE cells: past, present and future. Exp Eye Res 2014;126:5–15.
6. Marmor M. On the cause of serous detachments and acute central serous chorio-
retinopathy. Br J Ophthalmol 1997;81:812–13.
7. Marmor MF. Clinical electrophysiology of the retinal pigment epithelium. Doc Ophthal-
mol 1991;76:301–13.
8. Wright CB, Redmond TM, Nickerson JM. A history of the classical visual cycle. Prog Mol
Biol Transl Sci 2015;134:433–48.
9. Kevany BM, Palaczewski K. Phagocytosis of retinal rod and cone photoreceptors. Physi-
ology(Bethesda) 2010;25:8–15.
10. Hageman GS, Marmor MF, Yao X-Y, et al. The interphotoreceptor matrix mediates
primate retinal adhesion. Arch Ophthalmol 1995;113:655–60.
11. Marmor MF, Yao X-Y. The metabolic dependency of retinal adhesion in rabbit and
B primate. Arch Ophthalmol 1995;113:232–8.
12. Lavinsky D, Wang J, Huie P, et al. Non-damaging retinal laser therapy: rationale and
applications to the macula. Invest Ophthalmol Vis Sci 2016;57:2488–500.
Fig. 6.2.4 Cone Sheaths of the Interphotoreceptor Matrix, Shown by 13. Li Y, Chan L, Nguyen HV, et al. Personalized medicine: cell and gene therapy based
Fluorescent Staining With Peanut Agglutinin. Cone tips indent the sheaths from on patient-specific iPSC-derived retinal pigment epithelium cells. Adv Exp Med Biol
above; the retinal pigment epithelium (RPE) is on the bottom. (A) The matrix sheaths 2016;854:549–55.
are short in a normal eye. (B) They stretch dramatically before breaking as the retina 14. Hafler BP. Clinical progress in inherited retinal degenerations: gene therapy clinical
is peeled from the RPE. This shows that matrix material bonds across the subretinal trials and advances in genetic sequencing. Retina 2017;37:1–7.
space. (Reproduced with permission from Hageman GS, Marmor MF, Yao X-Y,
Johnson LV. The interphotoreceptor matrix mediates primate retinal adhesion. Arch
Ophthalmol 1995;113:655–60.)
425
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Section 1 Anatomy
Retinal and Choroidal Circulation

Caio Vinícius Saito Regatieri, Shiyoung Roh, John J. Weiter 6.3
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Like capillary networks elsewhere in the body, the retinal capillaries

Definition: Retinal and choroidal blood vessels are responsible for assume a meshwork configuration to ensure adequate perfusion to all
nutrition of the posterior segment. It is essential to understand the inner retinal cells (see Fig. 6.3.1C).
choroidal and retinal circulatory systems to better recognize and treat A capillary-free zone is present around each of the larger retinal arteries
disease states of the posterior segment. and veins, but it is more prominent around arteries, where it measures up
to 100 µm in diameter. In the fovea and the far retinal periphery, retinal
capillaries are absent. The FAZ is 400–500 µm in diameter in normal eyes.
Key Features The venous drainage of the retina generally follows the arterial supply.
• Retinal vascular anatomy. Retinal veins (mainly venules) are present in the inner retina, where they
• Choroidal vascular anatomy. occasionally interdigitate with their associated arteries. When two vessels
• Inner and outer blood–retinal barriers. cross, the artery usually lies anterior to the vein, and the two vessels share
• Choroidal and retinal blood flow measurements. a common adventitial coat. Many more arteriovenous crossings occur tem-
porally than nasally because the nasal vessels assume a much straighter
INTRODUCTION course. The crossings are important because they represent the most
common site of branch retinal vein obstructions. The retinal veins drain
Because many of the important diseases of the posterior segment are into the central retinal vein, which also acts as the major efferent channel
caused by changes in the vasculature of the retina and choroid, it is import- for the vessels of the optic nerve (see Fig. 6.3.1A).2
ant to understand the circulatory systems involved to better recognize and
treat disease states of the posterior segment. In this chapter, the anatomy Choroidal Vascular Anatomy
and physiology of these circulatory systems are discussed.
The choroid is, by far, the most vascular portion of the eye and, by weight,
one of the most vascular tissues in the body. The choroid is responsible
POSTERIOR SEGMENT VASCULAR ANATOMY for the vascular support of the outer retina (see Fig. 6.3.1B). A structur-
Retinal Vascular Anatomy ally and functionally normal choroidal vasculature is essential for retinal
function: Abnormal choroidal blood volume and/or compromised flow can
The retinal blood vessels provide nourishment for the inner two thirds result in photoreceptor and retinal pigment epithelium (RPE) dysfunction
of the retina. The central retinal artery, which is the first branch of the and death.3 Other likely functions include light absorption, thermoregula-
ophthalmic artery, is an end artery that has no significant anastomoses.1 tion via heat dissipation, and modulation of intraocular pressure (IOP) via
In the area of the lamina cribrosa, its lumen measures about 170 µm in vasomotor control of blood flow. The choroid also plays an important role
diameter. Typically, just before its exit from the optic nerve, the central in the drainage of the aqueous humor from the anterior chamber via the
retinal artery divides into the superior and inferior papillary arteries, uveoscleral pathway.
which, in turn, divide into nasal and temporal quadratic branches (Fig. The blood supply to the choroid is from branches of the anterior and
6.3.1A). The anatomic division of the retinal arteries into superior and infe- posterior ciliary arteries, branches of the ophthalmic artery. The overall
rior halves is usually maintained throughout the retina because normal structure of the choroid is segmental; this segmental distribution of blood
retinal vessels rarely cross the horizontal raphe (see Fig. 6.3.1A). Cilioreti- begins at the level of the posterior ciliary branches and is mirrored in the
nal arteries, derived from the posterior ciliary arteries, are variably present vortex drainage system. As a result of the segmental distribution, the large
and emanate from the temporal rim of the optic nerve head toward the and medium-sized choroidal arteries act as end arteries.
macula (see Fig. 6.3.1A). Histologically, starting from the retinal (inner) side, the choroid is
Arteries and veins remain in the nerve fiber layer. Throughout the divided into five layers:
retina, the capillaries are arranged in laminar meshworks.2 Depending on
the thickness of the retina, the capillary meshwork can vary from three
• Bruch’s membrane.
layers at the posterior pole to one layer in the periphery. The arterial intra-
• Choriocapillaris (layer of capillaries).
retinal branches supply three layers of capillary networks:
• Sattler’s layer (layer of medium diameter blood vessels).
• Haller’s layer (layer of large diameter blood vessels).
• The radial peripapillary capillaries. • Suprachoroidea (transitional zone between choroid and sclera).4
• Superficial capillaries in the ganglion cell and nerve fiber layers.
The choriocapillaris is a highly anastomosed network of capillaries,
• Deep, denser, capillaries in the inner nuclear layer.
forming a thin sheet apposed to Bruch’s membrane. The fibrous basement
Optical coherence tomography angiography (OCTA) reveals the micro- membrane of the capillary endothelial cells forms the outermost layer of
vasculature and the blood flow in the retinal capillaries in a noninvasive Bruch’s membrane in humans. The choriocapillaris is about 10 µm thick
manner. Automated segmentation of the full-thickness retinal OCTA scans at the fovea, where there is the greatest density of capillaries, thinning to
show in vivo the “superficial” and “deep” retinal vascular plexuses, and about 7 µm in the periphery. The capillaries arise from the arterioles in
choriocapillaris. The superficial plexus shows a continuous and linear Sattler’s layer, each of which gives rise to a hexagonal (or lobular) shaped
shape with a homogeneous wall. The vessels are evenly distributed and domain of a single layer of capillaries, giving a patch-like structure to
resemble a spider’s web. The deep network in healthy eyes has a regular the choriocapillaris. The choriocapillaris has large diameter capillaries
426 distribution around the foveal avascular zone (FAZ), with more complex of 20–25 µm, which allow the passage of multiple red blood cells at any
minute interconnections. moment in time. Unlike the retinal capillaries, the choriocapillaris has
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6.3

A B
C D
Fig. 6.3.1 Angiogram From Scanning Laser Ophthalmoscopy. (A) Normal fluorescein angiogram shows the normal filling of retinal arteries and veins; note the cilioretinal
artery (green arrow). (B) Normal indocyanine green angiogram shows the normal filling of choroidal vessels. (C) Magnified area from image A shows the retinal capillaries
(green arrows) close to the foveal avascular zone. (D) Indocyanine green angiogram shows a choroidal neovascularization (green arrow) secondary to age-related macular
degeneration (AMD).
fenestrations of 700–800 nm diameter, which allows more rapid transport formed by the interaction of retinal glia and pericytes with the retinal vas-
of molecules (leakage).4 cular endothelium cells. In addition to the vascular contribution, the retina
Besides the choriocapillaris, the choroid presents two other vascu- also possesses an epithelial barrier, the RPE, which controls the flow of fluid
lar regions: the outer Haller’s layer of large blood vessels and the inner and nutrients from the highly vascularized choroid into the outer retina.
Sattler’s layer of medium and small arteries and arterioles that feed the Together, the vascular and epithelial components of the BRB maintain the
capillary network, and veins. The stroma (extravascular tissue) contains specialized environment of the neural retina. Both the vascular endothe-
collagen and elastic fibers, fibroblasts, nonvascular smooth muscle cells, lium (inner barrier) and the RPE (outer barrier) possess well-developed
and numerous very large melanocytes that are closely apposed to the blood junctional complexes that include adherens and tight junctions.
vessels. As in other types of connective tissue, there are numerous mast The inner BRB controls permeability from the retinal blood vessels and
cells, macrophages, and lymphocytes. consists of a well-developed junctional complex (adherens and tight junc-
tions) in the vascular endothelial cells as well as no fenestration. The tight
BLOOD–RETINAL BARRIER junctions restrict flux of a wide variety of substances, such as lipids and
protein. The retinal capillaries are relatively impermeable, even to particles
The blood–retinal barrier (BRB) controls the exchange of metabolites and as small as sodium ions. The adherens junctions are essential to devel- 427
waste products between the vascular lumen and the neural retina and is opment of the barrier and influence the formation of the tight junction.
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Together, the adherens junctions and tight junctions create the resistance
6 barrier to the neural parenchyma. Although it is at the endothelium of

the retinal capillaries that the barrier resides, the glial cells may play a
role as metabolic intermediaries between the retinal capillaries and retinal
neurons.5 Thus, macromolecules and ions do not passively diffuse into the
Retina and Vitreous
retina from the circulation but are associated with selective active transport
into the retina.
The outer BRB is formed by tight junctions between cells of the RPE.
The RPE resting on the underlying Bruch’s membrane separates the
neural retina from the fenestrated choriocapillaris and plays an important
role in transporting nutrients from the blood to the outer retina. Although
inter-RPE cell tight junctions are important in the control of paracellular
movement of fluids and molecules between the choroid and retina, the
polarized distribution of membrane proteins in the RPE is also important.
The RPE plays an active role in supplying glucose to the photoreceptors
and also retinol that is required for visual pigment synthesis.6 The recep-
tors that exist on the basal and lateral cell membranes of the RPE for nutri-
ments have to be transported to the outer retina.
Although the retina is protected by the inner (retinal vascular endothe-
lium cells) and outer (RPE) BRBs, in vivo, some leakage probably occurs.
Most likely, this protein leakage is actively transported across the RPE into
the choroid and/or removed through Schlemm’s canal. Choroidal proteins
exit the eye through emissary canals (openings in the sclera for vessels Fig. 6.3.2 Color Doppler Image of the Ophthalmic Artery. The Doppler-shifted
spectrum (time–velocity curve) is displayed at the bottom of the image. Red pixels
and nerves) or through the sclera, probably facilitated by the relatively high
represent blood movement toward to the transducer.
tissue pressure of the eye (IOP).6
In many clinically important pathological conditions, including diabetic
retinopathy, retinal vein occlusion, and some inflammatory diseases, there Unlike retinal arteries, retinal veins show no pulsations in blood veloc-
is a breakdown of the inner BRB, leading to leakage of blood components ity except at the point of exit from the globe.10 The venous pressure of the
to the neural retina. In addition, outer BRB breakdown can occur in con- intraocular veins exiting the eye depends on IOP and coincides with the
ditions such as age-related macular degeneration (AMD) (see Fig. 6.3.1D), pulse, which results in a pulsating venous perfusion pressure. The retinal
central serous chorioretinopathy, accelerated hypertension, and toxemia of venous outflow resistance is located mainly at the lamina cribrosa. The
pregnancy. Breakdown of the outer BRB results in serous retinal detach- closed nature of the eye means that the pulsatile choroidal arterial inflow
ment or RPE detachment. results in a pulse-related change in IOP, which causes a venous pulse.
Depending on the relationship between IOP and venous pressure, this
RETINAL AND CHOROIDAL BLOOD FLOW may result in a clinically visible pulse of the veins at their point of exit
from the globe.
There are several techniques to analyze both qualitatively and quantita- The choroid is primarily a vascular structure supplying the outer retina.
tively the retinal and choroidal blood flow, such as the following: The choroid circulation exhibits one of the highest rates of blood flow in
the body. In fact, per tissue gram, the choroid has four times more blood
• Fluorescein angiogram with dye dilution (Video 6.3.1).
flowing through it than does through the cortex of the kidney. Several
See clip:
6.3.1 • Indocyanine green with dye dilution.
studies showed that the choroid receives 65%–85% and the retina 5% or
• Optical coherence tomography angiography.
less of the ocular blood flow.
• Laser Doppler velocimetry.
Using laser Doppler velocimetry, the choroidal blood flow is documented
• Laser Doppler flowmetry.
to be 800 µL/min, 18 times higher than retinal blood flow. With advancing
• Scanning laser flowmetry.
age, the choroidal blood velocity and choroidal thickness decrease signifi-
• Color Doppler ultrasonography (Fig. 6.3.2).
cantly, and this may be related to the pathogenesis of AMD. Interestingly,
These techniques have greatly enhanced the ability to quantify ocular mean blood pressure, smoking, and gender have no influence on choroidal
perfusion defects in many disorders, including glaucoma, AMD, diabetic blood flow parameters.
retinopathy and vascular occlusions, which are major causes of blindness Studies assessing the choroidal circulation indicate a significant reduc-
in the developed world. However, methods for accurate, reproducible tion of choroidal blood flow and volume in patients with glaucoma, AMD,
measurement of retinal and choroidal blood flow are still being perfected and nonproliferative and proliferative diabetic retinopathy.
because of the difficult access to the retinal and choroidal circulation. The major differences of the retinal and choroidal circulatory systems
Quantitative retinal blood flow is studied mainly by the use of laser are shown in Table 6.3.1.
Doppler flowmetry and laser Doppler velocimetry, which are noninvasive
techniques which permit the assessment of relative blood velocity, volume,
and flow within a sampled volume of tissue. Using these techniques, it RETINA AND CHOROIDAL CIRCULATION
has been shown that the total retinal blood flow in healthy subjects is 44.0
± 13.3 µL/min. The blood flow is highest in the temporal inferior quad-
EVALUATED BY OCTA
rant, followed by that in the temporal superior quadrant, the nasal inferior Fluorescein angiography and indocyanine green angiography have been
quadrant, and the nasal superior quadrant. In all quadrants retinal blood the gold standard modalities for the evaluation of retinal and choroidal vas-
velocities are linearly correlated to vessel diameters.7 culature in the last three decades. The advantage of these imaging modal-
Scanning laser ophthalmoscopic fluorescein angiography has also pro- ities lies in their ability to document retinal and choroidal vasculature
vided important information on retinal hemodynamics in normal indi- through the dynamic assessment of contrast transit over time in the intra-
viduals and those with glaucoma. In healthy individuals, arteriovenous vascular and extravascular spaces. However, their disadvantages include
passage times measured by scanning laser ophthalmoscopic angiography the absence of depth resolution, blurring of details by contrast leakage, and
has been reported as averaging 1.58 ± 0.4 seconds and mean dye velocity the inability to selectively evaluate different levels of the retinal and cho-
averaging 6.67 ± 1.59 mm/sec in a large study of 221 individuals. In the roidal microvasculature. In addition, these angiographic methods require
same study, capillary flow velocity averaged 2.89 ± 0.41 mm/sec in healthy the use of intravenous dye, which may cause adverse reactions, such as
subjects.8 In patients with primary open-angle glaucoma, there is an 11% nausea, vomiting, and, rarely, anaphylaxis.11
reduction in the mean dye velocity within the major retinal arteries. It OCTA is a noninvasive imaging technique, which, in contrast to
has also been noted that arteriovenous passage time within retina is 41% dye-based angiography, is faster and depth-resolved, allowing the evalua-
slower in primary open-angle glaucoma.9 Several studies have shown that tion of the vascular plexuses of the retina and choroid.12 The OCTA soft-
patients with glaucoma suffer from inadequate ocular blood flow and that ware offers the option of 2 × 2 mm, 3 × 3 mm, 6 × 6 mm, and 8 × 8 mm
428 a relationship exists between ocular hemodynamics and progression of the OCTA images and automated segmentation of these full-thickness retinal
disease. scans into the “superficial” and “deep” inner retinal vascular plexuses,
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6.3

A B
C D E F
G H I J
K L
Fig. 6.3.3 (A) Color fundus photo (CFP). (B) Composite optical coherence tomography angiography (OCTA) image. (C) Full-thickness 2 × 2 mm OCTA image (represented
in the green square in CFP). (D) Full-thickness 3 × 3 mm OCTA image (represented in the blue square in CFP). (E) Full-thickness 6 × 6 mm OCTA image (represented in the red
square in CFP). (F) Full-thickness 8 × 8 mm OCTA image (represented in the yellow square in CFP). (G) 3 × 3 mm OCTA image of the “superficial” inner retina. (H) 3 × 3 mm
OCTA image of the “deep” inner retina. (I) 3 × 3 mm OCTA image of the outer retina shows absence of vasculature. The white represents noise. (J) 3 × 3 mm OCTA image
of the choriocapillaris is generally homogeneous. There is black shadowing from retinal vessels. (K) Angiographic reference image of the retina (6 retina 6 mm) and flow
representation in red. (L) Cross-sectional OCTA flow image. (Courtesy Claudio Zett, PhD.)
429
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6
Retina and Vitreous
A B
C D E
Fig. 6.3.4 (A) Color fundus photo (CFP). (B) Composite optical coherence tomography angiography (OCTA) image. (C) Red free. (D) 3 × 3 mm OCTA image of the “superficial”
inner retina (represented in the blue square in red free). (E) 6 × 6 mm OCTA image of the “superficial” inner retina (represented in the red square in red free). (Courtesy Claudio
Zett, PhD.)
TABLE 6.3.1 Major Differences Between the Retinal REGULATION OF RETINAL AND CHOROIDAL
and Choroidal Circulatory Systems BLOOD FLOWS
Property Retinal Circulation Choroidal Circulation Regulation of blood flow through the choroid, as in the body in general,
Supply Central retinal artery Ciliary arteries is under the control of the autonomic nervous system. Stimulation of the
Blood flow Normal for tissue Highest in body cervical sympathetic chain decreases choroidal flow, and sympathectomy
Tissue Inner two thirds of retina Outer one third of retina (photoreceptor
increases it.13 The choroid does not show evidence of autoregulation, the
nourishment and retinal pigment epithelium [RPE] lack of which may have serious consequences. Changes in IOP are not
complex) reflected by compensatory changes in choroidal vascular pressure,13 and
Cellular Tight junctions between Fenestrations in choriocapillaris sudden changes in IOP, as occur in the opening of the eye during surgery,
junctions endothelial cells can induce uveal effusion.
Nature of End artery system Functionally end artery system (lobular- Because the autonomic tonus probably protects the eye from transient
vasculature shaped domain) elevations in the systemic blood pressure under normal circumstances, if
Blood flow Autoregulation Controlled by the autonomic nervous the nervous regulation breaks down in the presence of systemic hyperten-
regulation system sion, fluid may be forced through the retinal pigment epithelial barrier
into the retina.14 Such changes could contribute to the pathology of central
serous chorioretinopathy, cystoid macular edema, and hypotony maculop-
outer retina, and choriocapillaris (Fig. 6.3.3). The OCTA segmentation of athy. The ophthalmic artery and its branches are innervated richly with
the superficial inner retina contains a projection of the vasculature in the adrenergic fibers until the lamina cribrosa is reached.
retinal nerve fiber layer and the ganglion cell layer. The deep inner retina From that point on, no nervous system control of the retinal circulation
OCTA segmentation shows a composite of the vascular plexuses at the occurs.15 The retinal circulation must therefore depend on local autoregu-
border of the inner plexiform layer (IPL) and inner nuclear layer (INL) and lation to maintain a constant metabolic environment. The process of auto-
the border of the INL and outer plexiform layer.12 regulation in a vascular bed maintains constant or nearly constant blood
Published studies suggest that OCTA is efficacious in the evaluation flow through a wide range of perfusion pressures. Autoregulation of the
of common ophthalmological diseases, such age-related macular degen- retina is commonly used today in a much broader sense, to encompass
eration (AMD), diabetic retinopathy, occlusions of arteries and veins, and the local homeostatic blood flow mechanisms that provide a constant met-
glaucoma. OCTA can detect changes in choroidal blood vessel flow and can abolic environment in the retina despite various conditions that tend to
elucidate the presence of choroidal neovascularization in a variety of condi- upset this equilibrium. Blood flow in the retina appears to be primarily
tions, especially in AMD.12 It provides a highly detailed view of the retinal controlled by metabolic needs, especially the need for oxygen16; the accu-
vasculature, which allows for accurate delineation of the FAZ in diabetic mulation of metabolic byproducts, such as carbon dioxide; and changes in
eyes and detection of subtle microvascular abnormalities in diabetic and pH. It is necessary to understand the factors that can influence autoregu-
430 vascular occlusive eyes (Fig. 6.3.4). OCTA is now proven to be an effective lation of the retinal circulation because these may have important clinical
noninvasive tool to evaluate the retina and choroid circulation. implications.17
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KEY REFERENCES Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29(2):144–68.
Regatieri CV, Branchini L, Carmody J, et al. Choroidal thickness in patients with dia-
Feke GT, Zuckerman R, Green GJ, et al. Response of human retinal blood flow to light and
dark. Invest Ophthalmol Vis Sci 1983;24(1):136–41.
betic retinopathy analyzed by spectral-domain optical coherence tomography. Retina
2012;32(3):563–8.
6.3
Geitzenauer W, Hitzenberger CK, Schmidt-Erfurth UM. Retinal optical coherence tomogra- Weiter JJ, Zuckerman R. The influence of the photoreceptor-RPE complex on the inner
retina. An explanation for the beneficial effects of photocoagulation. Ophthalmology

phy: past, present and future perspectives. Br J Ophthalmol 2011;95(2):171–7.
Harris A, Chung HS, Ciulla TA, et al. Progress in measurement of ocular blood flow and 1980;87(11):1133–9.
relevance to our understanding of glaucoma and age-related macular degeneration. Prog Wolf S, Arend O, Sponsel WE, et al. Retinal hemodynamics using scanning laser oph-
Retin Eye Res 1999;18(5):669–87. thalmoscopy and hemorheology in chronic open-angle glaucoma. Ophthalmology
Duker J, Weiter JJ. Ocular circulation. In: Tasman W, Jaeger AE, editors. Duane’s founda- 1993;100(10):1561–6.
tions of clinical ophthalmology. New York: JB Lippincott; 1991.
Kaur C, Foulds WS, Ling EA. Blood-retinal barrier in hypoxic ischaemic conditions: basic
concepts, clinical features and management. Prog Retin Eye Res 2008;27(6):622–47. Access the complete reference list online at ExpertConsult.com
Laties AM, Jacobowitz D. A comparative study of the autonomic innervation of the eye in
monkey, cat, and rabbit. Anat Rec 1966;156(4):383–95.
431
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REFERENCES 10. Michelson G, Harazny J. Relationship between ocular pulse pressures and retinal vessel
velocities. Ophthalmology 1997;104(4):664–71.
1. Hayreh SS. The ophthalmic artery: III. Branches. Br J Ophthalmol 1962;46(4):212–47.
2. Duker J, Weiter JJ. Ocular circulation. In: Tasman W, Jaeger AE, editors. Duane’s foun-
11. Novais EA, Roisman L, de Oliveira PR, et al. Optical coherence tomography angiography
of chorioretinal diseases. Ophthalmic Surg Lasers Imaging Retina 2016;47(9):848–61.
6.3
dations of clinical ophthalmology. New York: JB Lippincott; 1991. 12. de Carlo TE, Romano A, Waheed NK, et al. A review of optical coherence tomography
angiography (OCTA). Int J Retina Vitreous 2015;1:5. eCollection 2015.

3. Regatieri CV, Branchini L, Carmody J, et al. Choroidal thickness in patients with dia-
betic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 13. Weiter JJ, Schachar RA, Ernest JT. Control of intraocular blood flow. II. Effects of sympa-
2012;32(3):563–8. thetic tone. Invest Ophthalmol 1973;12(5):332–4.
4. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29(2):144–68. 14. Ernest JT. The effect of systolic hypertension on rhesus monkey eyes after ocular sympa-
5. Runkle EA, Antonetti DA. The blood-retinal barrier: structure and functional signifi- thectomy. Am J Ophthalmol 1977;84(3):341–4.
cance. Methods Mol Biol 2011;686:133–48. 15. Laties AM, Jacobowitz D. A comparative study of the autonomic innervation of the eye in
6. Kaur C, Foulds WS, Ling EA. Blood–retinal barrier in hypoxic ischaemic conditions: monkey, cat, and rabbit. Anat Rec 1966;156(4):383–95.
basic concepts, clinical features and management. Prog Retin Eye Res 2008;27(6):622–47. 16. Feke GT, Zuckerman R, Green GJ, et al. Response of human retinal blood flow to light
7. Garhofer G, Werkmeister R, Dragostinoff N, et al. Retinal blood flow in healthy young and dark. Invest Ophthalmol Vis Sci 1983;24(1):136–41.
subjects. Invest Ophthalmol Vis Sci 2012;53(2):698–703. 17. Weiter JJ, Zuckerman R. The influence of the photoreceptor-RPE complex on the inner
8. Harris A, Chung HS, Ciulla TA, et al. Progress in measurement of ocular blood flow and retina. An explanation for the beneficial effects of photocoagulation. Ophthalmology
relevance to our understanding of glaucoma and age-related macular degeneration. Prog 1980;87(11):1133–9.
Retin Eye Res 1999;18(5):669–87.
9. Wolf S, Arend O, Sponsel WE, et al. Retinal hemodynamics using scanning laser oph-
thalmoscopy and hemorheology in chronic open-angle glaucoma. Ophthalmology
1993;100(10):1561–6.
431.e1
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Section 1 Anatomy
Vitreous Anatomy and Pathology

J. Sebag 6.4
Definition: Vitreous is an extended extracellular matrix situated
between the lens and the retina, approximately 4 mL in volume and
16.5 mm in emmetropic axial length.
Key Features
• Optically clear.
• May modulate growth of the eye.
• Maintains media transparency.
• Serves as a reservoir for antioxidants.
• Plays a role in oxygen physiology of the eye.
• Separates from the retina during aging, in most cases resulting in
innocuous posterior vitreous detachment (PVD).
• Anomalous PVD is a unifying concept in various vitreoretinopathies,
including vitreo-maculopathies and rhegmatogenous retinal
detachment.
Associated Features
• PVD is a common cause of vitreous floaters and may degrade contrast Fig. 6.4.1 Vitreous Obtained at Autopsy on a 9-Month-Old Child. The sclera,
sensitivity function, known as Vision Degrading Myodesopsia. choroid, and retina were dissected off the transparent vitreous, which remained
• Some surgeons advocate vitrectomy for symptomatic vitreous attached to the anterior segment. A band of gray tissue could be seen posterior
floaters to normalize contrast sensitivity function. to the ora serrata. This was a neural retina that was firmly adherent to the vitreous
• PVD and vitrectomy increase oxygen levels contributing to base and could not be dissected. The vitreous was almost entirely gel (because of
cataractogenesis. the young age of the donor) and thus was solid and maintained its shape, although
situated on a surgical towel exposed to room air. (Courtesy The New England Eye
• Anomalous PVD is the inciting event in diseases of the vitreous– Bank, Boston, MA.)
macular interface via vitreomacular traction and vitreoschisis and
contributes to proliferative diabetic retinopathy, macular edema in
diabetes and vein occlusions, and possibly exudative age-related
macular degeneration.
INTRODUCTION
Although vitreous is the largest structure within the eye, constituting 80% STRUCTURE OF HUMAN VITREOUS COLLAGEN FIBRIL
of the ocular volume, investigators of vitreous anatomy are hampered by
two fundamental difficulties:
Chondroitin sulphate
• Attempts to characterize vitreous morphology are efforts to visualize a glycosaminoglycan chain
tissue that is invisible “by design” (Fig. 6.4.1). of type IX collagen
• The various techniques that were previously employed to study vitre-
ous structure were flawed by artifacts induced by tissue fixatives, which
caused precipitation of hyaluronan, formerly called hyaluronic acid. N-propeptide of
type V/XI collagen
The development of slit-lamp biomicroscopy by Gullstrand in 1911 was Type V/XI
collagen
expected to enable clinical investigation of vitreous structure without the
introduction of these artifacts. Nonetheless, a widely varied set of descrip-
tions resulted. This phenomenon even persists in more modern investi-
gations. Consider that in the 1970s, Eisner1 described “membranelles” and
Worst2 described “cisterns”; in the 1980s, Sebag and Balazs3,4 identified
“fibers”; and in the 1990s, Japanese investigators5 described “pockets” in Type IX
N-propeptide collagen
the posterior vitreous,5,6 although the largest one is very likely the same of type II collagen
as Worst’s bursa premacularis.2 What has been largely agreed upon is the
molecular composition of vitreous.4,7–11
Type II collagen
MOLECULAR MORPHOLOGY
Supramolecular Organization Fig. 6.4.2 Structure of Human Vitreous Collagen Fibril. Schematic diagram of the
major heterotypic collagen fibrils of vitreous based on current knowledge of the
432 Vitreous is composed of a dilute meshwork of collagen fibrils (Fig. 6.4.2) structure and biophysical attributes of the constituent molecules. (With permission
interspersed with extensive arrays of hyaluronan molecules.7–9 The collagen from Bishop P. The biochemical structure of mammalian vitreous. Eye 1996;10:64.)
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fibrils provide a solid structure that is “inflated” by the hydrophilic hyaluro- laminae of the hyaloid artery wall.4 Posteriorly, Cloquet’s canal opens into
nan.10 Rheological observations also suggest the existence of an important
interaction between hyaluronan and collagen.12 Balazs hypothesized that
a funnel-shaped region anterior to the optic disc, known as the area of
Martegiani. 6.4
the hydroxylysine amino acids of collagen mediate polysaccharide binding Within the adult human vitreous there are parallel nonbranching fibers
to the collagen chain through O-glycosidic linkages.10 These polar amino that course in an anteroposterior direction (Fig. 6.4.4), arising from the vit-

acids are present in clusters along the collagen molecule, consistent with reous base, where they insert anterior and posterior to the ora serrata. The
proteoglycans attachment to collagen in a periodic pattern.13 connections between the peripheral anterior vitreous fibers and the retina
Hyaluronan–collagen interaction in the vitreous body may be mediated underlie the pathophysiology of retinal tears because of the strong adhe-
by a third molecule. In cartilage, “link glycoproteins” have been identified sion in this location.4 The peripheral vitreous fibers are circumferential
that interact with proteoglycans and hyaluronan.14 Supramolecular com- with the vitreous cortex, whereas the central fibers “undulate” parallel to
plexes of these glycoproteins are believed to occupy interfibrillar spaces. Cloquet’s canal. Ultrastructural studies have demonstrated that collagen,
Bishop8 has elegantly described the potential roles of type IX collagen organized in bundles of parallel fibrils, is the only microscopic structure
chondroitin sulfate chains, hyaluronan, and opticin in the short-range corresponding to these fibers.3 It is hypothesized that visible vitreous fibers
spacing of collagen fibrils and how these mechanisms might break down form when hyaluronan molecules no longer separate the microscopic colla-
in aging and disease. gen fibrils, which results in the aggregation of collagen fibrils into bundles
Many investigators believed that hyaluronan-collagen interaction occurs from which hyaluronan molecules are excluded.3,4,17 The areas adjacent to
on a “physicochemical” rather than a “chemical” level.15 Reversible com- these large fibers have a low density of collagen fibrils and a relatively high
plexes of an electrostatic nature between solubilized collagen and various concentration of hyaluronan molecules. Composed primarily of “liquid vit-
glycosaminoglycans could, indeed, form because electrostatic binding reous,” these areas scatter very little incident light and, when prominent,
between the negatively charged hyaluronan and the positively charged col- constitute the “lacunae” seen with aging (Fig. 6.4.5).
lagen likely occurs in vitreous.
VITREOUS ANATOMY
Macroscopic Morphology
In an emmetropic adult human eye, vitreous is approximately 16.5 mm
in axial length with a depression anteriorly just behind the lens (patel-
lar fossa). The hyloideocapsular ligament of Weiger is the annular region
(1–2 mm in width and 8–9 mm in diameter), where vitreous is attached
to the posterior aspect of the lens. Erggelet’s or Berger’s space is at the
center of the hyaloid capsular ligament. The canal of Cloquet arises from
this space and courses posteriorly through the central vitreous (Fig. 6.4.3),
which is the former site of the hyaloid artery in the embryonic vitreous.16
The former lumen of the artery is an area devoid of collagen fibrils and
surrounded by multifenestrated sheaths that were previously the basal
VITREOUS ANATOMY
Egger's line forming canal of

Wieger's ligament (hyaloideo- Hannover Fig. 6.4.4 The Eye of a 57-Year-Old Man After Dissection of the Sclera, Choroid,
capsular ligament) and Retina, With the Vitreous Still Attached to the Anterior Segment. The
pars plicata specimen was illuminated with a slit-lamp beam shone from the side, and the view
here is at a 90° angle to this plane to maximize the Tyndall effect. The anterior
Berger's space pars plana segment is below and the posterior pole is at the top of the photograph. Bundles
(retrolental space of prominent fibers course anteroposteriorly to exit via the premacular dehiscence
of Erggelet) in the vitreous cortex.
ora
serrata
sclera canal of anterior vitreous

Petit vitreous base
cortex
choroid
retina
Cloquet's canal
secondary
area of Martegiani vitreous
Fig. 6.4.5 Human Vitreous in Old Age. The central vitreous has thickened,
Fig. 6.4.3 Vitreous anatomy according to classic anatomical and histological studies. tortuous fibers. The peripheral vitreous has regions devoid of any structure, which
(Reprinted with permission from Schepens CL, Neetens A, editors. The vitreous and contain liquid vitreous. These regions correspond to “lacunae,” as seen clinically 433
vitreo-retinal interface. New York: Springer-Verlag; 1987:20.) using biomicroscopy (arrows).
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6 MI
Retina and Vitreous
CF
Fig. 6.4.6 Fundus View of Posterior Vitreous Detachment. (A) The posterior Fig. 6.4.7 Ultrastructure of Human Hyalocyte. A mononuclear cell is embedded
vitreous in the left eye of this patient is detached, and the prepapillary hole in the within the dense collagen fibril (CF) network of the vitreous cortex. There is a
posterior vitreous cortex is anterior to the optic disc (arrows, slightly below and to lobulated nucleus (N) with a dense marginal chromatin (C). In the cytoplasm, there
the left of the optic disc here). (B) A slit beam illuminates the retina and optic disc (at are mitochondria (M), dense granules (arrows), vacuoles (V), and microvilli (MI).
bottom) in the center. To the right is the detached vitreous. The posterior vitreous (Courtesy Joe Craft and D. M. Albert, MD.)
cortex is the dense, whitish gray, vertically oriented linear structure to the right of
the slit beam. (Courtesy C. L. Trempe, MD.)
diameter, and contain a lobulated nucleus, a well-developed Golgi complex,
smooth and rough endoplasmic reticula, many large lysosomal gran-
Microscopic Morphology ules (periodic acid–Schiff positive), and phagosomes (Fig. 6.4.7). Balazs10
pointed out that hyalocytes are located in the region of highest hyaluronan
The vitreous cortex is the peripheral “shell” of the vitreous body that concentration and suggested that these cells are responsible for hyaluro-
courses forward and inward from the anterior vitreous base (anterior vitre- nan synthesis. Hyalocyte capacity to synthesize collagen was first demon-
ous cortex) and posteriorly from the posterior border of the vitreous base, strated by Newsome et al.23 Similar to chondrocyte metabolism in the joint,
(posterior vitreous cortex). The posterior vitreous cortex is 100–110 mm hyalocytes may synthesize vitreous collagen at some, but not all, times
thick and consists of densely packed collagen fibrils.4,18 Although no direct during life. The phagocytic capacity of hyalocytes is consistent with the
connections exist between the posterior vitreous and the retina, the poste- presence of pinocytic vesicles and phagosomes and the presence of surface
rior vitreous cortex is adherent to the inner limiting membrane (ILM) of receptors that bind immunoglobulin G and complement.18 It is intriguing
the retina, which is, in part, the basal lamina of retinal Müller cells. Adhe- to consider that hyalocytes are among the first cells to be exposed to any
sion between the posterior vitreous cortex and the ILM probably results migratory or mitogenic stimuli during various disease states, particularly
from the action of various extracellular matrix molecules.19 proliferative vitreoretinopathy. These cells may, therefore, be important in
A hole in the prepapillary vitreous cortex can sometimes be visual- the pathophysiology of proliferative disorders at the vitreous–retinal inter-
ized clinically when the posterior vitreous is detached from the retina face, including macular pucker.24
(Fig. 6.4.6). If peripapillary tissue is torn away during PVD and remains The vitreo–retinal interface is not only important as the site of many
attached to the vitreous cortex about the prepapillary hole, it is referred to tractional and proliferative vitreoretinal disorders25 but also impacts ther-
as Weiss’ ring. Vitreous can extrude through the prepapillary hole in the apeutics. Pharmacologic vitreolysis of vitreoretinal adhesion26–28 as well
vitreous cortex but does so to a lesser extent than through the premacu- as drug delivery to the macula29 and transretinal gene therapies via viral
lar vitreous cortex, where, occasionally, vitreomacular adhesion and axial vectors that must traverse this interface are influenced by the underlying
traction can cause vitreomacular traction syndrome.20 Tangential vitreo- anatomy and biochemistry of the vitreous–retinal interface.30 The basal
macular traction21 is implicated in the pathogenesis of macular holes and laminae surrounding the vitreous body are composed of type IV collagen
macular pucker,22 often with vitreoschisis (see below). closely associated with glycoproteins.18,30
Embedded within the posterior vitreous cortex are hyalocytes. These At the pars plana, the basal lamina has a true lamina densa. The basal
mononuclear phaocytes are spread widely apart in a single layer situated lamina posterior to the ora serrata is the ILM of the retina. The layer imme-
20–50 µm from the ILM of the retina. The highest density of hyalocytes is diately adjacent to the Müller cell is a lamina rara, which is 0.03–0.06 mm
434 in the vitreous base, followed next by the posterior pole, with the lowest thick. The lamina densa is thinnest at the fovea (0.01–0.02 mm) and disc
density at the equator. Hyalocytes are oval or spindle shaped, 10–15 µm in (0.07–0.1 mm). It is thicker elsewhere in the posterior pole (0.5–3.2 mm)
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than at the equator or vitreous base.4,18 The anterior surface (vitreous side) this form of PFV. In this regard, it has recently been proposed that insuffi-
of the ILM is normally smooth, whereas the posterior aspect is irregular,
filling the spaces created by the irregular subjacent nerve fiber layer. This
cient levels of vitreous endostatin may be important in the pathogenesis of
PFV,36 consistent with the aforementioned proteomic studies.32 6.4
feature is most marked at the posterior pole, whereas in the periphery both Improper vitreous biosynthesis during embryogenesis underlies a
the anterior and posterior aspects of the ILM are smooth. The significance variety of developmental abnormalities.37 Normal vitreous biosynthesis

of this topographical variation is not known. At the rim of the optic disc requires normal retinal development because at least some of the vitre-
the ILM ceases, although the basal lamina continues as the “inner lim- ous structural components are synthesized by retinal Müller cells.23 A clear
iting membrane of Elschnig.”31 This membrane is 50 microns thick and gel, typical of normal “secondary vitreous,” appears only over developed
is believed to be the basal lamina of the astroglia in the papilla. At the retina. Thus in various developmental anomalies, such as retinopathy of
central-most portion of the optic disc, the membrane thins to 20 microns, prematurity (ROP), familial exudative vitreoretinopathy, and related enti-
follows the irregularities of the underlying cells of the optic nerve head, and ties, vitreous that overlies undeveloped retina in the peripheral fundus is
is composed only of glycosaminoglycans with no collagen.31 This structure a viscous liquid but not a gel.37 The extent of this finding depends, at least
is known as the central meniscus of Kuhnt. The thinness and chemical com- in ROP, on the gestational age at birth because the younger the individ-
position of these membranes may account for, among other phenomena, ual, the more undeveloped is the peripheral retina, especially temporally.
the frequency with which abnormal cell proliferation arises from or near In other truly congenital conditions, there are inborn errors of collagen
the optic disc in proliferative diabetic retinopathy and macular pucker. metabolism that have now been elucidated. In Stickler’s syndrome, defects
The vitreous body is most firmly attached at the vitreous base, disc, and in specific genes have been associated with particular phenotypes, thus
macula and over retinal blood vessels. The posterior aspect (retinal side) of enabling the classification of patients with Stickler’s syndrome into four
the ILM demonstrates irregular thickening farther posteriorly from the ora subgroups.38 Patients in the subgroups with vitreous abnormalities are
serrata.4,18,30 So-called attachment plaques between the Müller cells and the found to have defects in the genes coding for type II procollagen and type
ILM have been described in the basal and equatorial regions of the fundus V/XI procollagen.
but not in the posterior pole, except for the fovea.4,18,30 It has been hypoth- Ongoing synthesis of both collagen and hyaluronan occurs during devel-
esized that these develop in response to vitreous traction on the retina. opment to adulthood,4 and hyaluronan stabilizes the collagen network.10,11
The thick ILM in the posterior pole dampens the effects of this traction,
except at the fovea, where the ILM is thin. The thinness of the ILM and Aging of the Vitreous Body
the purported presence of attachment plaques at the central macula could
explain the predisposition of this region to changes induced by traction. Substantial rheological, biochemical, and structural alterations occur in vit-
An unusual vitreous–retinal interface overlies retinal blood vessels. Physio- reous during aging.39–41 After age 45–50 years, there is a significant decrease
logically, this may provide a shock-absorbing function to dampen arteriolar in the gel volume and an increase in the liquid volume of human vitre-
pulsations. However, pathologically, this arrangement could also account ous. These findings were confirmed qualitatively in postmortem studies
for the proliferative and hemorrhagic events that are associated with vitre- of dissected human vitreous, and liquefaction was observed to begin in
ous traction on retinal blood vessels. the central vitreous.1,4–6 Vitreous liquefaction actually begins much earlier
than detectable by clinical examination or ultrasonography. Postmortem
studies have found evidence of liquid vitreous at age 4 years and have
AGE-RELATED CHANGES observed that by the time the human eye reaches its adult size (ages 16–18
Embryology and Postnatal Development years) approximately 20% of the total vitreous volume consists of liquid
vitreous.40 In these studies of fresh, unfixed postmortem human eyes, it
Early in embryogenesis, the vitreous is filled with blood vessels, called was observed that after age 40 years, there is a steady increase in liquid
the vasa hyaloidea propria. It is not known what stimulates regression of vitreous, simultaneous with a decrease in gel volume. By age 80–90 years,
this hyaloid vascular system, but recent studies have identified signifi- more than half the vitreous body is liquid. The finding that the central
cant changes in the proteome of the human embryo that may underlie vitreous is where fibers are first observed is consistent with the concept
the process of vascular regression.31 Teleologically, this seems necessary that breakdown of the normal hyaluronan-collagen association results in
not only to induce regression of the vascular primary vitreous but also simultaneous vitreous liquefaction and aggregation of collagen fibrils into
to inhibit subsequent cell migration and proliferation and thereby mini- bundles of parallel fibrils, seen as large fibers (see Fig. 6.4.4).1,4–6 In the pos-
mize light scatter and achieve transparency. Identifying the phenomena terior vitreous, such age-related changes often form large pockets of liquid
inherent in this transformation may reveal how to control pathological vitreous, recognized clinically as lacunae, or pockets.4–6
neovascularization in the eye and elsewhere. Recent studies32 have charac- The mechanism of vitreous liquefaction is not well understood. Gel
terized the proteomic profile of embryonic human vitreous during hyaloid vitreous can be liquefied in vivo through the removal of collagen by exog-
vessel regression in an attempt to identify the factors that might create and enous enzymatic destruction of the collagen network.42 It has also been
maintain a clear vitreous. These studies found that there is upregulation shown that the injection of chondroitinase can induce liquefaction and
of certain pathways with concurrent downregulation of others. These find- “disinsertion” of the vitreous.43 Ocriplasmin is another agent that can
ings may, thus, have relevance to developing new therapeutic strategies induce vitreous liquefaction.26–28,44 Because of its ability to also induce
to induce the regression of pathological neovascularization in ocular and dehiscence at the vitreous–retinal interface,45 this agent received approval
systemic diseases, such as metastatic carcinoma. for pharmacological vitreolysis 27,28
Endogenous vitreous liquefaction may be the result of changes in the
Developmental Anomalies minor glycosaminoglycans and chondroitin sulfate profile of vitreous.4,8,10
Another possible mechanism is a change in the conformation of hyaluro-
Persistent fetal vasculature (PFV) syndrome is an uncommon developmen- nan molecules with aggregation or cross-linking of collagen molecules.
tal anomaly in which the hyaloid vasculature of the primary vitreous fails Singlet oxygen can induce conformational changes in the tertiary structure
to involute. This condition was initially described in detail by Reese33 in of hyaluronan molecules. Free radicals generated by metabolic and photo-
his 1955 Jackson Memorial Lecture, where he named it persistent hyper- sensitized reactions could alter hyaluronan and/or collagen structure and
plastic primary vitreous. The subject was revisited by Goldberg34 in his 1997 trigger a dissociation of collagen and hyaluronan molecules, which ulti-
Jackson Memorial Lecture, where he coined the term PFV. mately results in liquefaction.46 This is plausible because the cumulative
There is a spectrum of PFV severity, ranging from pupillary strands effects of a lifetime of daily exposure to light may influence the structure
and a Mittendorf’s dot to a dense retrolenticular membrane and/or retinal and interaction of collagen and hyaluronan molecules by the proposed free
detachment. Anterior PFV consists of retrolenticular fibrovascular tissue radical mechanism(s).
that attaches to the ciliary processes and draws them centrally, inducing Biochemical studies support the rheological observations. Total vitre-
cataract formation, shallowing of the anterior chamber, and angle-closure ous collagen content does not change after age 20–30 years. However, in
glaucoma. Iris vessel engorgement and recurrent intraocular hemorrhage studies of a large series of normal human eyes obtained at autopsy, the col-
can result in phthisis bulbi, although the prognosis with surgery is often lagen concentration in the gel vitreous at age 70–90 years (approximately
fair.35 Posterior PFV consists of a prominent vitreous fibrovascular stalk 0.1 mg/mL) was twofold greater than at age 15–20 years (approximately
that emanates from the optic nerve and courses anteriorly. Preretinal 0.05 mg/mL).4,40 Because the total collagen content does not change, this
membranes at the base of the stalk are common, often with tractional finding most likely reflects the decrease in the volume of gel vitreous that
retinal folds and traction retinal detachment. The prognosis for posterior occurs with aging and consequent increase in the concentration of the col- 435
PFV is poor, suggesting that pharmacotherapy may be the only solution for lagen that remains in the gel. The collagen fibrils in aging vitreous gel
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retina. PVD can be localized, partial, or total (up to the posterior border
6 of the vitreous base). Autopsy studies have revealed that the incidence of
PVD is 63% by the eighth decade,51 but more commonly in myopic eyes,
where PVD occurs, on average, 10 years earlier than in emmetropic and
hyperopic eyes. Cataract extraction in myopic eyes introduces additional
Retina and Vitreous
effects that promote PVD.4

Vitreous liquefaction in conjunction with weakening of vitreoretinal
adhesion both result in PVD. It is likely that the dissolution of the posterior
vitreous cortex–ILM adhesion at the posterior pole allows liquid vitreous to
enter the retrocortical space via the prepapillary hole and perhaps also the
premacular vitreous cortex. With rotational eye movements, liquid vitreous
can dissect a plane between the vitreous cortex and the ILM, resulting in
true PVD. This volume displacement from the central vitreous to the pre-
A
retinal space causes vitreous syneresis (collapse).
Johnson39 has proposed that this process of hydrodissection follows
a 5-stage (0–4) sequence that is influenced by variations in vitreoretinal
adhesion. Stage 0 is complete attachment throughout the fundus. Stage
1 involves detachment of the perifoveal posterior vitreous cortex, probably
because this is the area where the liquefied gel first gains access to the
retrocortical/preretinal space. There is persistent vitreofoveal adhesion at
stage 1. A 500-µm diameter area of strong vitreoretinal adhesion in the
foveola does not detach until stage 2, at which time there is complete
macular separation. In stage 3, there is PVD involving the entire retina
except for the vitreopapillary zone, a site of strong vitreoretinal adhesion
and thus is the last site of vitreoretinal separation. In stage 4, there is
release of the vitreopapillary adhesion and total PVD. It is this last stage
that is most often symptomatic.
In 1935, Moore52 described “light flashes” as a common complaint
that results from PVD. Wise53 noted that light flashes occurred in 50% of
cases at the time of PVD; they were usually vertical and temporally located.
Voerhoeff54 suggested that the light flashes result from the impact of the
detached posterior vitreous cortex on the retina during eye movement.
“Floaters” are a symptom experienced by patients with PVD. These
B result from entopic phenomena caused by condensed vitreous fibers, glial
tissue of epipapillary origin that adheres to the posterior vitreous cortex,
Fig. 6.4.8 Vitreous Structure in Childhood. (A) The posterior and central vitreous the dense collagen matrix of the posterior vitreous cortex,4 or less com-
in a 4-year-old child has a dense vitreous cortex with hyalocytes. A substantial monly intravitreal blood. Vitreous floaters move with vitreous displacement
amount of vitreous extrudes into the retrocortical (preretinal) space through
during eye movement and scatter incident light, which casts a shadow
the premacular vitreous cortex (arrows). However, no fibers are present in the
on the retina that is perceived as a gray, “hair-like” or “fly-like” structure.
vitreous. (B) Central vitreous structure in an 11-year-old child has hyalocytes in a
dense vitreous cortex. No fibers are seen within the vitreous body. Given time, symptomatic floaters often become less noticeable. Treatment
of symptomatic floaters can be performed. YAG laser treatments are per-
formed by some practitioners.55 There is only evidence for improvement
following YAG laser treatments for Weiss’ ring, not other vitreous opaci-
become packed into bundles of parallel fibrils,3,17 likely with cross-links ties. Limited vitrectomy can safely and effectively cure the condition (see
between them. In patients with diabetes, abnormal collagen cross-links below).
have been identified in the vitreous body, a phenomenon that has been
described for other extracellular matrices in patients with diabetes. These Anomalous Posterior Vitreous Detachment
findings are consistent with the existence of a diabetic vitreopathy,47 inde-
pendent of diabetic retinopathy. The structural effect of these biochemical Anomalous posterior vitreous detachment56 occurs when there is exten-
and rheological changes consists of a transition from a clear vitreous in sive vitreous liquefaction without concurrent weakening of vitreoretinal
youth (Fig. 6.4.8), to a fibrous structure in the adult (see Fig. 6.4.4), which adhesion, resulting in traction at the vitreous–retinal interface. There are
results from aggregation of collagen fibrils.3,4 In patients with diabetes, this various causes for an imbalance between the degree of gel liquefaction
occurs earlier in life because of nonenzymatic glycation of vitreous colla- and weakening of vitreoretinal adhesion. As described above, inborn errors
gen.47 In old age, advanced liquefaction (synchisis; see Fig. 6.4.5) ultimately of collagen metabolism, such as those present in Marfan’s syndrome,
leads to collapse (syneresis) of the vitreous and posterior vitreous detach- Ehlers–Danlos syndrome, and Stickler’s syndrome,38 result in extensive
ment (PVD).39 gel liquefaction at an early age when there is still considerable vitreoretinal
The vitreous base posterior to the ora increases in size with advanc- adhesion. The result is a high incidence of large posterior retinal tears
ing age to nearly 3 mm, bringing the posterior border of the vitreous base and detachments. Systemic conditions, such as diabetes induce biochemi-
closer to the equator.48 This widening of the vitreous base was found to be cal57 and structural58 alterations in vitreous, known as diabetic vitreopathy,47
most prominent in the temporal portion of the globe. The posterior migra- which are important in the pathobiology of proliferative diabetic vitreoreti-
tion of the vitreous base probably plays an important role in the pathogen- nopathy and diabetic macular edema. However, the overwhelming majority
esis of peripheral retinal breaks and rhegmatogenous retinal detachment. of cases are likely caused by an as-yet-unidentified genetic predisposition
Within the vitreous base, a “lateral aggregation” of the collagen fibrils is for firm vitreoretinal adhesion, probably related to the extracellular matrix
present in older individuals,49 similar to aging changes within the central between vitreous and the retina. Fig. 6.4.9 delineates the various deleteri-
vitreous.4,17,39,41 Studies50 have confirmed posterior migration of the poste- ous effects of anomalous PVD.
rior border of the vitreous base during aging and also demonstrated intra- When the entire (full-thickness) posterior vitreous cortex separates
retinal synthesis of collagen fibrils that penetrate the ILM of the retina and from the macula but is still attached peripherally, there can be vitreoretinal
“splice” with vitreous collagen fibrils. These aging changes at the vitreous traction causing peripheral retinal tears and detachments. Autopsy studies
base could contribute to increased traction on the peripheral retina pro- have found that PVD is associated with retinal breaks in 14.3% of all cases.
moting retinal tears and detachment. Patients without diabetes who experience nontraumatic vitreous hemor-
rhage have retinal tears in up to 67% of cases59 and retinal detachments in
Posterior Vitreous Detachment up to 39%59 of cases.
Posterior full-thickness vitreomacular adhesion with peripheral vitreo-
436 The most common age-related event in the vitreous body is PVD,39 defined retinal separation can pull on the macula and induce vitreomacular traction
as separation between the posterior vitreous cortex and the ILM of the syndrome. Persistent vitreomacular adhesion may exacerbate age-related
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Fig. 6.4.9 Schematic of Anomalous Posterior
PATHOPHYSIOLOGY OF ANOMALOUS PVD Vitreous Detachment. Vitreous gel liquefaction without
concurrent dehiscence at the vitreous–retinal interface 6.4
causes various anomalies. If separation of vitreous from
Gel Vitreous and Vitreo-Retinal Adhesion retina is full-thickness in the axial plane but incomplete

in the coronal plane, there can be different forms of
partial posterior vitreous detachment (PVD) (right
Anomalous Aging side of diagram). Posterior separation with persistent
Normal Aging
and Disease peripheral attachment can induce retinal breaks and
detachments. Peripheral vitreoretinal separation with
Liquefaction without Liquefaction with persistent full-thickness vitreomacular adhesion (VMA)
Innocuous PVD can induce vitreomacular traction syndrome (VMTS).
Vitreo-Retinal Dehiscence Vitreo-Retinal Dehiscence
VMA is associated with exudative age-related macular
Some cases of macular hole degeneration (Exud AMD) and diabetic macular
edema. Persistent attachment to the optic disc can
may not have VS
Anomalous PVD induce vitreopapillopathies and also contribute to
neovascularization and vitreous hemorrhage in ischemic
No vitreoschisis (VS) splitting
retinopathies as well as play a role in macular hole
pathophysiology. During PVD, if the posterior vitreous
cortex splits (vitreoschisis) anterior to the level of the
Vitreoschisis (VS) splits the Full thickness vitreous cortex hyalocytes, a relatively thick, cellular membrane remains
posterior vitreous cortex → partial but PVD is only partial attached to the macula. If there is also separation from
thickness vitreo-macular adhesion the optic disc, inward (centripetal) contraction induces
macular pucker. If the split is posterior to the hyalocytes,
the remaining premacular membrane is relatively
thin and hypocellular. Persistent vitreopapillary
Split posterior to Split anterior to
Premacular Peripheral Separation, Posterior Separation, adhesion (present in 87.5% of cases) results in outward
hyalocytes hyalocytes thicker
Membrane but Posterior Adhesion but Peripheral Traction (centrifugal) tangential traction (especially nasally),
thin hypocellular hypercellular inducing a macular hole. (From Sebag J. Anomalous
membrane membrane on macula PVD—a unifying concept in vitreo-retinal diseases.
+ Tangential Traction + Axial Traction
Graefes Arch Clin Exp Ophthalmol 2004;242:690–8;
VPA No VPA Sebag J. Vitreous and vitreo-retinal interface. In: A.
centripetal centripetal Schachat, editor. Ryan’s Retina. London: Elsevier; 2018,
(outward) tangential (inward) Ch 23, pp 544–581.)
contraction contraction
Vitreo-Papillary Vitreo-Macular Retinal Tears

Macular Macular
Adhesion Traction (VMT) Retinal
Hole Pucker
(VPA)/Traction Exudative AMD Detachment
macular degeneration (AMD). It is not clear by what mechanism this thickening.81 Following anomalous PVD with vitreoschisis, the PMM can
occurs, but patients with dry AMD have a two- to threefold higher preva- contract inward toward the fovea (centripetal tangential traction) and cause
lence of total PVD, whereas patients with wet AMD have a three- to four- visual impairment and metamorphopsia, sometimes necessitating surgery
fold higher prevalence of vitreomacular adhesion,60–62 but these conditions (see Chapter 6.33).71
were not influenced by genetic or environmental factors. It is hypothesized
that vitreomacular traction could induce low-grade inflammation and/or Macular Holes
that the adherent posterior vitreous cortex could alter macular oxygen- Primary full-thickness macular holes (FTMHs) are caused by anomalous
ation from ciliary body and the egress of proangiogenic cytokines from PVD with centrifugal (outward) tangential traction of the PMM accentu-
the macula. Similarly, traction on the optic disc can induce vitreopapillary ated by vitreo-papillary adhesion (Fig. 6.4.9). Secondary macular holes can
traction syndromes63 or exacerbate neovascularization with vitreous hem- occur from conditions such as blunt trauma, and lightning strike.
orrhage in proliferative diabetic retinopathy. Moreover, persistent vitreo- Lamellar macular holes are partial-thickness retinal defects that most
papillary adhesion may promote macular hole formation as opposed to commonly occur in association with a thickened posterior premacular
macular pucker.64,65 membrane (LHEP) in degenerative LMH, or a PMM with pucker in trac-
Anomalous PVD can be associated with splitting of the posterior vit- tional LMH. The prevalence of VPA is greater in the latter than the former
reous cortex, called vitreoschisis.66 This may be the first event in macular (see Chapter 6.32).82
pucker and some cases of macular hole pathogenesis.67,68 Vitreoschisis
may also be present in in diabetic macular edema.69 Autopsy studies70 have Diabetic Vitreopathy
reported that PVD was associated with vitreous cortex remnants at the
fovea in 26 of 59 (44%) human eyes. Recent studies67,68 employing com- In diabetes, there is an increase in vitreous glucose levels72 associated with
bined optical coherence tomography and scanning laser ophthalmoscopy increased advanced glycation end products.47,57 In poorly controlled diabe-
imaging detected vitreoschisis in about half the patients with macular tes, fluctuations in systemic glucose levels alter the ionic milieu, influenc-
pucker and macular holes. ing vitreous osmolarity and hydration. This could result in swelling and
contraction of the entire vitreous body via effects on the very hydrophylic
Premacular (Epiretinal) Membrane/Macular Pucker hyaluronan molecules, with consequent traction on structures attached to
The term epiretinal membrane (ERM) is a misnomer. The prefix “epi” the posterior vitreous cortex, such as new blood vessels from the optic disc
means adjacent to, so this could refer to subretinal membranes. The pre and/or retina.73 These events could promote the proliferation of neovas-
macular membrane (PMM) that causes macular pucker contains astrocytes cular fronds and perhaps even induce rupture of these new vessels with
and retinal pigment epithelial (RPE) cells80 as well as hyalocytes. Macular vitreous hemorrhage.
pucker begins when vitreoschisis (Fig. 6.4.9) splits the posterior vitreous Molecular effects of diabetes result in morphological changes within
cortex anterior to hyalocytes leaving a cellular membrane attached to the the vitreous body47,58 (Fig. 6.4.10). The roles of these and other pathological
macula. Contraction is stimulated by connective tissue growth factor.24 changes, such as posterior vitreoschisis,66,69 may lead to therapy designed
Recent studies81 have also identified that nearly half of all eyes with to inhibit diabetic vitreopathy. Alternatively, the induction of innocuous
macular pucker have more than one site of retinal contraction associated PVD early in the course of diabetic retinopathy may have long-term salu- 437
with a higher incidence of intraretinal cysts and significantly more macular brious effects in patients at great risk.26–28
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intertwined ribbons of multilaminar membranes (with a 6-nm periodic-
6 ity), which are characteristic of complex lipids, especially phospholipids,

that lie in a homogeneous background matrix.77 In these investigations,
energy-dispersive X-ray analysis showed calcium and phosphorus to be the
main elements in asteroid bodies. Electron diffraction structural analysis
Retina and Vitreous
demonstrated calcium hydroxyapatite and possibly other forms of calcium

phosphate crystals.
Some reports have suggested an association between asteroid hyalosis
and diabetes mellitus,78–81,83 whereas other investigations found no such
association.84 Asteroid hyalosis appears to be associated with certain pig-
A
mentary retinal degenerations,83 although it is not known whether this is
related to the presence of diabetes in these patients. Yu and Blumenthal85
proposed that asteroid hyalosis results from aging collagen, whereas other
studies86 have suggested that asteroid formation is preceded by depolym-
erization of hyaluronan.
The most interesting aspect of asteroid hyalosis is the marked absence
of patient complaints and symptoms. Although it can be difficult, in some
cases, to examine and image the fundus, these patients often experience
no visual disturbances, whereas patients with PVD can be markedly symp-
tomatic.87,88 It is hypothesized that the explanation is related to the smooth
surfaces of asteroid bodies that may not scatter light in as disturbing a
fashion as the irregular surfaces of the collagen matrix in the detached pos-
terior vitreous cortex and/or the collagen fibrils of the vitreous body.3,4,17,39
The condition of “Vision Degrading Myodesopsia” can be safely cured with
limited vitrectomy that normalizes contrast sensitivity function.89
B
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Fig. 6.4.10 Diabetic Vitreopathy. (A) Right eye of a 9-year-old girl who has a 5-year by combined optical coherence tomography/scanning laser ophthalmoscopy. Retina
2008;28:447–52.
history of type 1 diabetes shows extrusion of central vitreous through the posterior Gupta P, Yee KMP, Garcia P, et al. Vitreoschisis in macular diseases. Br J Ophthalmol
vitreous cortex into the retrocortical (preretinal) space. The subcortical vitreous 2011;95(3):376–80.
appears very dense and scatters light intensely. Centrally, there are vitreous fibers Nguyen J, Yee KMP, Sadun AA, et al. Quantifying visual dysfunction and the response to
(arrows) with an anteroposterior orientation and adjacent areas of liquefaction. surgery in macular pucker. Ophthalmology 2016;123:1500–10.
(B) Central vitreous in the left eye of the same patient shows prominent fibers that Robison C, Krebs I, Binder S, et al. Vitreo-macular adhesion in active and end-stage
resemble those seen in adults without diabetes (see Fig. 6.4.5). (Reprinted with age-related macular degeneration. Am J Ophthalmol 2009;148:79–82.
Sebag J. Age-related differences in the human vitreo-retinal interface. Arch Ophthalmol
permission from Sebag J. Abnormalities of human vitreous structure in diabetes.
1991;109:966–71.
Graefes Arch Clin Exp Ophthalmol 1993;231:257–60.) Sebag J. Anomalous PVD – a unifying concept in vitreo-retinal diseases. Graefes Arch Clin
Exp Ophthalmol 2004;242:690–8.
Sebag J. Diabetic vitreopathy. Ophthalmology 1996;103:205–6.
Sebag J. Floaters and the quality of life. (Guest Editorial). Am J Ophthalmol 2011;152:3–4.
Asteroid Hyalosis Sebag J. Pharmacologic vitreolysis – premise and promise of the first decade. (Guest Edito-
rial). Retina 2009;29:871–4.
This generally benign condition is characterized by small, yellow-white, Sebag J. Vitreoschisis. Graefes Arch Clin Exp Ophthalmol 2008;246:329–32.
spherical opacities throughout the vitreous body. An autopsy study74 Sebag J, editor. Vitreous – in health & disease. New York: Springer; 2014.
Sebag J, Yee KMP, Huang L, et al. Vitrectomy for floaters – prospective efficacy analyses and
of 10 801 eyes found an incidence of 1.96%; with a male/female ratio of retrospective safety profile. Retina 2014;34:1062–8.
2 : 1. Asteroid hyalosis is unilateral in greater than 75% of cases. Asteroid Sebag J, Yee KMP, Nguyen JH, et al. Long-term safety and efficacy of limited vitrectomy for
bodies are associated intimately with the vitreous gel and move with vit- Vision Degrading Vitreopathy from vitreous floaters. Ophthalmology Retina 2018 (in
reous displacement during eye movement, suggesting a relationship with press).
Wang MY, Nguyen D, Hindoyan N, et al. Vitreo-papillary adhesion in macular hole and
age-related collagen fibril degeneration.74 However, PVD, either complete macular pucker. Retina 2009;29:644–50.
or partial, occurs less frequently in individuals with asteroid hyalosis than Yee KMP, Feener E, Madigan M, et al. Proteomic analysis of the embryonic and young
in age-matched controls,75 and this finding does not support age-related human vitreous. Invest Ophthalmol Vis Sci 2015;56(12):7036–42.
degeneration as a cause. Histological studies demonstrate a crystalline Yee KMP, Tan S, Lesnick-Oberstein S, et al. Incidence of cataract surgery after vitrectomy for
vitreous opacities. Ophthalmol Retina 2017;1:154–7.
appearance and a pattern of positive staining to fat and acid mucopolysac-
charide stains that is not affected by hyaluronidase pretreatment.76 Electron
diffraction studies have shown the presence of calcium oxalate monohy- Access the complete reference list online at ExpertConsult.com
drate and calcium hydroxyphosphate. Ultrastructural studies have revealed
438
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REFERENCES 46. Ueno N, Sebag J, Hirokawa H, et al. Effects of visible light irradiation on vitreous struc-
ture in the presence of a photosensitizer. Exp Eye Res 1987;44:863–70.
1. Eisner G. Biomicroscopy of the peripheral fundus. New York: Springer-Verlag; 1973.
2. Worst JGF. Cisternal systems of the fully developed vitreous body in the young adult.
47. Sebag J. Diabetic vitreopathy. Ophthalmology 1996;103:205–6.
48. Teng CC, Chi HH. Vitreous changes and the mechanism of retinal detachment. Am J
6.4
Trans Ophthalmol Soc UK 1977;97:550–4. Ophthalmol 1957;44:335.
49. Gartner J. Electron microscopic study on the fibrillar network and fibrocyte-collagen

3. Sebag J, Balazs EA. Morphology and ultrastructure of human vitreous fibers. Invest Oph-
thalmol Vis Sci 1989;30:187–91. interactions in the vitreous cortex at the ora serrata of human eyes with special regard to
4. Sebag J. The Vitreous-structure, function, and pathobiology. New York: Springer-Verlag; the role of disintegrating cells. Exp Eye Res 1986;42:21–33.
1989. 50. Wang J, McLeod D, Henson DB, et al. Age-dependent changes in the basal retinovitreal
5. Kishi S, Shimizu K. Posterior precortical vitreous pocket. Arch Ophthalmol adhesion. Invest Ophthalmol Vis Sci 2003;44:1793.
1990;108:979–82. 51. Foos RY. Posterior vitreous detachment. Trans Am Acad Ophthalmol Otolaryngol
6. Kakehashi A. Age-related changes in the premacular vitreous cortex. Invest Ophthalmol 1974;76:480–96.
Vis Sci 1996;37:2253. 52. Moore RF. Subjective ‘lightening streak’. Br J Ophthalmol 1935;545–50.
7. Scott JE. The chemical morphology of the vitreous. Eye (Lond) 1992;6:553–5. 53. Wise GN. Relationship of idiopathic preretinal macular fibrosis to posterior vitreous
8. Bishop PN. Structural macromolecules and supramolecular organization of the vitreous detachment. Am J Ophthalmol 1975;79:358–61.
gel. Prog Retin Eye Res 2000;19:323–44. 54. Voerhoeff FH. Are Moore’s lightening streaks of serious portent? Am J Ophthalmol
9. Mayne R. The eye. Connective tissue and its heritable disorders. New York: Wiley-Liss; 1956;41:837–41.
2001. p. 131–41. 55. Huang LC, Yee KMP, Wa CA, et al. Vitreous floaters and vision: Current concepts and
10. Balazs EA. The vitreous. In: Davson H, editor. The Eye, vol la. London: Academic Press; management paradigms. In: Sebag J, editor. Vitreous – in health & disease. New York:
1984. p. 533–89. Springer; 2014. p. 771–88.
11. Crafoord S, Ghosh F, Sebag J. Vitreous biochemistry and artificial vitreous. In: Sebag J, 56. Sebag J. Anomalous PVD – a unifying concept in vitreo-retinal diseases. Graefes Arch
editor. Vitreous – in health & disease. New York: Springer; 2014. p. 81–94. Clin Exp Ophthalmol 2004;242:690–8.
12. Tokita M, Fujiya Y, Hikichi K. Dynamic viscoelasticity of bovine vitreous body. Biorheol- 57. Sebag J, Buckingham B, Charles MA, et al. Biochemical abnormalities in vitreous of
ogy 1984;21:751–65. humans with proliferative diabetic retinopathy. Arch Ophthalmol 1992;110:1472–9.
13. Asakura A. Histochemistry of hyaluronic acid of the bovine vitreous body as studied by 58. Sebag J. Abnormalities of human vitreous structure in diabetes. Graefes Arch Clin Exp
electron microscopy. Nippon Ganka Gakkai Zasshi 1985;89:179–91. Ophthalmol 1993;231:257–60.
14. Hardingham TE. The role of link-protein in the structure of cartilage-proteoglycan aggre- 59. Sarrafizadeh R, Hassan TS, Ruby AJ, et al. Incidence of retinal detachment and visual
gates. Biochem J 1979;177:237–47. outcome in eyes presenting with posterior vitreous separation and dense fundus-obscur-
15. Comper WD, Laurent TC. Physiological function of connective tissue polysaccharides. ing vitreous hemorrhage. Ophthalmology 2001;108:2273–8.
Physiol Rev 1978;58:255–315. 60. Krebs I, Brannath W, Glittenberg K, et al. Posterior vitreo-macular adhesion: a poten-
16. Schepens CL, Neetens A, editors. The vitreous and vitreoretinal interface. New York: tial risk factor for exudative age-related macular degeneration. Am J Ophthalmol
Springer-Verlag; 1987. p. 20. 2007;144:741–6.
17. Sebag J. Age-related changes in human vitreous structure. Graefes Arch Clin Exp Oph- 61. Robison C, Krebs I, Binder S, et al. Vitreo-macular adhesion in active and end-stage
thalmol 1987;225:89–93. age-related macular degeneration. Am J Ophthalmol 2009;148:79–82.
18. Sebag J. Surgical anatomy of vitreous and the vitreo-retinal interface. In: Tasman W, 62. Sebag J, Glittenberg C, Krebs I, et al. Vitreous in AMD. Am J Ophthalmol 2010;149:172–3.
Jaeger E, editors. Clinical ophthalmology, vol. 6. Philadelphia: JB Lippincott; 1994. p. 63. Sebag J. Vitreopapillary traction as a cause of elevated optic nerve head. Am J Ophthal-
1–36. mol 1999;128:261.
19. Sebag J. Age-related differences in the human vitreo-retinal interface. Arch Ophthalmol 64. Sebag J, Wang M, Nguyen D, et al. Vitreo-papillary adhesion in macular diseases. Trans
1991;109:966–71. Am Ophthalmol Soc 2009;107:35–46.
20. Sebag J. Anatomy and pathology of the vitreo-retinal interface. Eye (Lond) 1992;6: 65. Wang MY, Nguyen D, Hindoyan N, et al. Vitreo-papillary adhesion in macular hole and
541–52. macular pucker. Retina 2009;29:644–50.
21. Gass JDM. Reappraisal of biomicroscopic classification of stages of development of a 66. Sebag J. Vitreoschisis. Graefes Arch Clin Exp Ophthalmol 2008;246:329–32.
macular hole. Am J Ophthalmol 1995;119:752–9. 67. Sebag J, Gupta P, Rosen RR, et al. macular holes and macular pucker – the role of vit-
22. Sebag J. Vitreous – the resplendent enigma. (Guest Editorial). Br J Ophthalmol reoschisis as imaged by optical coherence tomography-scanning laser ophthalmoscopy.
2009;93:989–91. Trans Am Ophthalmol Soc 2007;105:121–31.
23. Newsome DA, Linsemayer TF, Trelstad RJ. Vitreous body collagen. Evidence for a dual 68. Gupta P, Yee KMP, Garcia P, et al. Vitreoschisis in macular diseases. Br J Ophthalmol
origin from the neural retina and hyalocytes. J Cell Biol 1976;71:59–67. 2011;95(3):376–80.
24. Kita T, Sakamoto T, Ishibashi T. Hyalocytes – essential vitreous cells in vitreo-reti- 69. Sebag J. Vitreoschisis is diabetic macular edema. Invest Ophthalmol Vis Sci
nal health and disease. In: Sebag J, editor. Vitreous – in health & disease. New York: 2011;52(11):8455–6.
Springer; 2014. p. 151–64. 70. Kishi S, Demaria C, Shimizu K. Vitreous cortex remnants at the fovea after spontaneous
25. Sebag J. Pathology & Pathobiology. In: Sebag J, editor. Vitreous – in health & disease. vitreous detachment. Int Ophthalmol Clin 1986;9:253.
New York: Springer; 2014. Part III. p. 223–436. 71. Nguyen J, Yee KMP, Sadun AA, et al. Quantifying visual dysfunction and the response to
26. Sebag J. Molecular biology of pharmacologic vitreolysis. Trans Am Ophthalmol Soc surgery in macular pucker. Ophthalmology 2016;123:1500–10.
2005;103:473–94. 72. Lundquist O, Osterlin S. Glucose concentration in the vitreous of nondiabetic and dia-
27. Sebag J. Pharmacologic vitreolysis – premise and promise of the first decade. (Guest betic human eyes. Graefes Arch Clin Exp Ophthalmol 1995;232:71–4.
Editorial). Retina 2009;29:871–4. 73. Faulborn J, Bowald S. Microproliferations in proliferative diabetic retinopathy and their
28. Sebag J. Pharmacologic vitreolysis. In: Sebag J, editor. Vitreous – in health & disease. relation to the vitreous. Graefes Arch Clin Exp Ophthalmol 1985;223:130–8.
New York: Springer; 2014. p. 799–816. 74. Fawzi AA, Vo B, Kriwanek R, et al. Asteroid hyalosis in an autopsy population – the
29. Sebag J. Vitreous in AMD therapy – the medium is the message (Guest Editorial). Retina UCLA experience. Arch Ophthalmol 2005;123:486–90.
2015;35(9):1715–18. 75. Rodman HI, Johnson FB, Zimmerman LE. New histopathological and histochemical
30. Halfter W, Sebag J, Cunningham ET. Vitreo-retinal interface and inner limiting mem- observations concerning asteroid hyalitis. Arch Ophthalmol 1961;66:552–63.
brane. In: Sebag J, editor. Vitreous – in health & disease. New York: Springer; 2014. p. 76. Wasano T, Hirokuwa H, Tagawa H, et al. Asteroid hyalosis – posterior vitreous detach-
165–92. ment and diabetic retinopathy. Am J Ophthalmol 1987;19:255–8.
31. Heergaard S, Jensen OA, Prause JU. Structure of the vitreal face of the monkey optic 77. Streeten BA. Disorders of the vitreous. In: Garner A, Klintworth GK, editors. Pathobiol-
disc. Graefes Arch Clin Exp Ophthalmol 1988;226:377–83. ogy of ocular disease – a dynamic approach, Part B. New York: Marcel Dekker; 1982. p.
32. Yee KMP, Feener E, Madigan M, et al. Proteomic analysis of the embryonic and young 1381–419.
human vitreous. Invest Ophthalmol Vis Sci 2015;56(12):7036–42. 78. Smith JL. Asteroid hyalites – incidence of diabetes mellitus and hypercholesterolemia.
33. Reese AB. Persistent hyperplastic primary vitreous. Am J Ophthalmol 1955;30:317–31. JAMA 1958;168:891–3.
34. Goldberg MF. Persistent fetal vasculature. Am J Ophthalmol 1997;124:587–625. 79. Bergren RC, Brown GC, Duker JS. Prevalence and association of asteroid hyalosis with
35. Pollard ZF. Persistent hyperplastic primary vitreous – diagnosis, treatment, and results. systemic disease. Am J Ophthalmol 1991;111:289–93.
Trans Am Ophthalmol Soc 1997;95:487–549. 80. Gandorfer A, Schumann RG, Haritoglou C, et al. Pathology of vitreo-maculopathies. In:
36. Duh EJ, Yao YG, Dagli M, et al. Persistence of fetal vasculature in a patient with Kno- Sebag J, editor. Vitreous – in health & disease. New York: Springer; 2014. p. 265–86.
bloch syndrome – potential role for endostatin in fetal remodeling of the eye. Ophthal- 81. Gupta P, Sadun AA, Sebag J. Multifocal retinal contraction in macular pucker analyzed
mology 2004;111:1885–8. by combined optical coherence tomography/scanning laser ophthalmoscopy. Retina
37. Tozer K, Yee KMP, Sebag J. Vitreous and developmental vitreo-retinopathies. In: Hartnett 2008;28:447–52.
ME, editor. Pediatric retina. Philadelphia: Lippincott; 2013. 82. Nguyen JH, Yee KMP, Nguyen-Cuu J, et al. Structural and functional characteristics of
38. Snead M, Richards AJ. Hereditary vitreo-retinopathies. In: Sebag J, editor. Vitreous – in lamellar macular holes. Retina 2018 (in press).
health & disease. New York: Springer; 2014. p. 41–56. 83. Sebag J, Albert DM, Craft JL. The Alström syndrome – ocular histopathology and retinal
39. Tozer K, Johnson MW, Sebag J. Vitreous aging and posterior vitreous detachment. In: ultrastructure. Br J Ophthalmol 1984;68:494–501.
Sebag J, editor. Vitreous – in health & disease. New York: Springer; 2014. p. 131–50. 84. Hatfield RE, Gastineau CF, Rucke CW. Asteroid bodies in the vitreous – relationship to
40. Denlinger JL, Balazs EA. Hyaluronan and other carbohydrates in the vitreus. In: Sebag J, diabetes and hypercholesterolemia. Mayo Clin Proc 1962;37:513–14.
editor. Vitreous – in health & disease. New York: Springer; 2014. p. 13–20. 85. Yu SY, Blumenthal HT. The calcification of elastic tissue. In: Wagner BM, Smith DE,
41. Sebag J. Ageing of the vitreous. Eye (Lond) 1987;1:254–62. editors. The connective tissue. Baltimore: Williams & Wilkins; 1967.
42. Aguayo J, Glaser BM, Mildvan A, et al. Study of vitreous liquefaction by NMR spectros- 86. Lamba PA, Shukla KM. Experimental asteroid hyalopathy. Br J Ophthalmol 1971;55:
copy and imaging. Invest Ophthalmol Vis Sci 1985;26:692–7. 279–83.
43. Hageman G, Russell S. Chondroitinase-mediated disinsertion of the primate vitreous 87. Garcia G, Khoshnevis M, Yee KM, et al. Degradation of contrast sensitivity function fol-
body. Invest Ophthalmol Vis Sci 1994;35:1260. lowing posterior vitreous detachment. Am J Ophthalmol 2016;172:7–12.
44. Sebag J, Ansari RR, Suh KI. Pharmacologic vitreolysis with microplasmin increases vit- 88. Garcia G, Khoshnevis M, Nguyen-Cuu J, et al. The effects of aging vitreous on contrast
reous diffusion coefficients. Graefes Arch Clin Exp Ophthalmol 2007;245(4):576–80. sensitivity function. Graefes Arch Clin Exp Ophthalmol 2018;256:919–25.
45. Tozer K, Fink W, Sadun AA, et al. Prospective three-dimensional analysis of structure 89. Sebag J, Yee KMP, Nguyen JH, et al. Long-term safety and efficacy of limited vitrectomy
and function in vitreomacular adhesion cured by pharmacologic vitreolysis. Retin Cases for Vision Degrading Vitreopathy from vitreous floaters. Ophthalmology Retina 2018 (in
Brief Rep 2013;7:57–61. press). 438.e1
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Section 2 Ancillary Tests
Contact B-Scan Ultrasonography

Yale L. Fisher, Dov B. Sebrow 6.5
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
• B-scan mode (intensity modulation), used predominantly for anatomi-

Definition: Diagnostic technique that is useful in the evaluation of cal information—it shows cross-sectional images of the globe and orbit.
intraocular and orbital contents.
Both types of sonographic display are complementary. This chapter
focuses on B-scan information.
Key Features Developed in the mid-1950s with water-immersion techniques, B-scan
ultrasonography initially required a laboratory setting. In the early 1970s,
• High-frequency sound waves are emitted and received by a handheld contact devices utilizing methylcellulose or a similar sound-coupling agent
transducer probe. were introduced, and this rapidly increased the availability and popular-
• Images are processed and displayed on a video monitor. ity of B-scan ultrasonography. Subsequent improvements in image quality
and scanning rates made interpretation easier for the examiner.1–8
Associated Features DEVICES

• Adequate interpretation for diagnosis of posterior segment disease
depends on three concepts: Commercially available instruments for ocular and orbital contact B-scan
 Real time. ultrasonography usually employ 10-MHz (megahertz; megacycles per
 Gray scale. second) handheld transducer probes. A motor within the handpiece
 Three-dimensional analysis. moves the ultrasonic source in a rapid sector scan to create cross-sectional
B-scan images. These devices have resolution capacities of approximately
0.15 mm axially and 0.3 mm laterally. Most contact B-scan machines are
INTRODUCTION freestanding and relatively mobile; they consist of a detachable transducer
probe, a signal-processing box, and a display screen. Self-contained proc-
Ophthalmic ultrasonography is a useful diagnostic technique for intra- essing probes, which are capable of integrating with independent com-
ocular and orbital evaluation, especially in the setting of opaque media. puter laptops or desktop units, are also available. (Video 6.5.1)
See clip:
It involves pulse-echo technology, in which high frequency sound waves 6.5.1
are emitted from a handheld transducer probe. Returning echoes are pro-
cessed and displayed on video monitors or oscilloscopes.
TECHNIQUE OF EXAMINATION
Two modes of display are common: The handheld ultrasonic probe is placed gently against the eyelid or sclera
by using a sound-coupling agent, such as methylcellulose or, preferably,
• A-scan mode (time-amplitude), used predominantly for interpretation heat-sensitive ophthalmic gel. The ultrasonographer can move the probe
of tissue reflectivity—the returning echoes form a graph-like image systematically to scan the globe and orbit. Avoiding the lens system of the
seen as vertical deflections from a baseline. globe is important to prevent image artifacts (Fig. 6.5.1).
Fig. 6.5.1 Illustration demonstrating placement of

handheld ultrasonic probe and corresponding B-scan
image with optic nerve (arrow) as reference point.
(Additional material for ultrasound education available
at http://www.OphthalmicEdge.org.)
439
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CONCEPTS OF B-SCAN INTERPRETATION
6 Interpretation of a B-scan ultrasonogram depends on three concepts:
• Real time.
Retina and Vitreous
• Gray scale.
• Three-dimensional analysis.
Real Time
Ultrasound B-scan images are visualized at approximately 32 frames/sec,
allowing motion of the globe and vitreous to be detected. Characteristic
real-time movements are useful for identifying tissues. Detached retinal
movement, for example, appears as a slow undulation, whereas vitreous
movements are usually more rapid. Real-time ultrasonic information is
often critical to surgical decisions.
Gray Scale
A variable gray-scale format displays the returning echoes as intensity-
modulated dots. Strong echoes, such as those seen from sclera or detached
retina, are displayed brightly at high instrument gain and remain visible Fig. 6.5.2 Contact B-Scan Image of a Retinal Detachment. This axial section of a
even when the gain is reduced. Weaker echoes, such as those from vitre- total retinal detachment reveals a highly reflective sheet-like membrane (arrows) in
ous hemorrhage, are seen as lighter shades of gray that disappear when the vitreous space, detached from the posterior eye wall and attached only to the
gain is reduced. Because comparison of echo strengths is critical to tissue optic nerve head.
analysis, the examiner must ensure that all the returning echoes are cap-
tured and displayed. Perpendicularity to the object of regard ensures ade- imaging. The appearance of total retinal detachment, which anatomically
quate comparable interpretive signals. is cone shaped, varies, depending on the position of the examining probe.
Axial images are funnel shaped with attachment to the optic nerve head.
Three-Dimensional Analysis Coronal images show a circular cross-section of the cone.
Although recent detachments have a characteristic undulating move-
Developing a mental three-dimensional image or anatomical map from ment slower than that of the vitreous gel, long-standing detachments
multiple two-dimensional B-scan images is the most difficult concept to appear stiff because of proliferation of scar tissue on the retinal surface.
master. The examiner must learn to create a mental topographical map of
the eye or orbit from as many imaging views as required. Three-dimensional Choroidal Detachment
understanding of ultrasound images is especially critical in the preopera-
tive evaluation of complex retinal detachments and intraocular or orbital Detached choroid appears smooth and convex on imaging. An elevated
tumors. dome is usually localized between the pars plana and the posterior equator
of the globe. Serous choroidal detachments are echolucent within the
suprachoroidal space, whereas hemorrhagic choroidal detachments appear
DISPLAY PRESENTATION reflective. Clotted blood is highly reflective, whereas liquefied blood is
AND DOCUMENTATION usually less so and more mobile during ocular movement. When severe,
the detached choroid can meet at the center of the globe producing retina-
Posterior B-scan images displayed on a screen are presented horizontally. to-retina touch, often termed “a kissing choroidal.”
Areas closest to the probe are imaged to the left of the screen, and those A choroidal detachment can be differentiated from a retinal detach-
farthest away are imaged to the right. The top of the screen correlates with ment by its location, shape, thickness, and movement.
a manufacturer’s mark located on the examining probe that represents the
initial transducer sweep for each sector scan. Registration of the screen Tumors
is critical to understanding and interpreting examinations. Movement of
the probe from one position to another changes the registration, making Evaluation of intraocular tumors requires not only topographical localiza-
instant re-evaluation by the examiner an absolute necessity. Contact tion but also interpretation of gray-scale characteristics. Malignant cho-
B-scan ultrasonography is a dynamic examination. Individual “frozen” roidal melanomas, for example, have the most characteristic ultrasonic
cross-sectional images used for documentation should not alone be used appearance. They are mostly dome shaped or mushroom shaped, and on
for interpretation. (Video 6.5.1) gray scale, their anterior borders are strongly reflective, whereas the pro-
See clip:
6.5.1 gressively deeper portions of the tumor are less reflective. This is caused by
Normal Vitreous Cavity cellular homogeneity that provides a false hollowing appearance. Tissues,
such as orbital fat, localized behind these tumors are often shadowed and
The normal vitreous space is almost clear echogenically. Occasional small appear less reflective as a result of absorption of sound by the tumor.
dots or linear echoes can be seen at the highest gain settings (90 deci-
bels [dB]), but they fade rapidly as the gain is reduced. Real-time scanning
during eye movement usually shows some motion of these fine echoes as
DIGITAL CONTACT ULTRASONOGRAPHY
well as the position of the vitreous face. Advances in electronic and digital software have made the greatest changes
in diagnostic ultrasonography. High-capacity computer memory has revo-
Vitreous Hemorrhage lutionized storage, recall, and transmission of real-time movie segments
for documentation and review.
Intravitreal hemorrhage produces easily detectable diffuse dots and
blob-like vitreous echoes that correlate with the amount of blood present.
Reduction of gain to 70 dB results in rapid fading of all but the densest WHAT’S NEW?
areas of reflectivity. Real-time evaluation usually shows a characteristic
rapid motion during command voluntary eye movement. Anterior Segment High-Frequency
Ultrasonography
Retinal Detachment Although most B-scan focuses on the posterior segment of the globe or the
440 Detached retina appears as a highly reflective sheet-like tissue within the anterior orbit, higher-frequency instruments in the range of 30–100 MHz
vitreous space (Fig. 6.5.2). Small detachments often appear dome-like on are available for anterior segment imaging. Penetration of sound at these
booksmedicos.org
frequencies remains limited (approximately 4–5 mm), but resolution is KEY REFERENCES
greatly augmented (at 40 MHz: axial 23 microns; lateral 35 microns).
Recent development of digital imaging and specialized software has Bronson NR. Quantitative ultrasonography. Arch Ophthalmol 1969;81:400–72.
Bronson NR, Fisher YL, Pickering NC, et al. Ophthalmic contact B-scan ultrasonography for
6.5
improved availability of this technology. Furthermore, the examination the clinician. Baltimore: Williams & Wilkins; 1980.
technique has become less time consuming and more patient friendly,

Coleman DJ. Reliability of ocular and orbital diagnosis with B-scan ultrasound. 1. Ocular
with the introduction of modified, sterile, single-use slip on water condoms diagnosis. Am J Ophthalmol 1972;73:501–16.
covering the exposed and moving transducer. Coleman DJ, Lizzi FL, Jack RL. Ultrasonography of the eye and orbit. Philadelphia: Lea &
Febiger; 1977.
With a simple adjustment of software, clear images of the anterior Coleman DJ, Silverman RH, Lizzi FL, et al. Ultrasonography of the eye and orbit. Philadel-
segment are now possible. These images can complement posterior phia: Lippincott Williams & Wilkins; 2006.
segment evaluations, especially in complex scenarios of opaque media and Fisher YL. Contact B-scan ultrasonography: a practical approach. Int Ophthalmol Clin
abnormalities behind the iris, within the ciliary body, or involving the pars 1979;19:103–25.
Fisher YL. Examination techniques for the beginner [Internet]. New York: Ophthalmic Edge
plana. LLC; 2012 [updated 2009 Sept 22]. Available from: http://www.OphthalmicEdge.org.
Axial, radial, and coronal images in real time are accumulated and Fisher YL. High resolution B-scan ultrasound anterior segment [Internet]. New York:
stored as easily as posterior segment images.9 Ophthalmic Edge LLC; 2014 [updated 2016 Oct 13]. Available from: http://www
.OphthalmicEdge.org.
Purnell EW. Intensity modulated (B-scan) ultrasonography. In: Goldberg RE, Sarin LK,
SUMMARY editors. Ultrasonics in ophthalmology: diagnostic and therapeutic applications. Philadel-
phia: WB Saunders; 1967. p. 102–23.
Contact B-scan ultrasonography provides a convenient, noninvasive means
for the dynamic examination of the vitreoretinal relationship and the eval-
uation of intraocular structures in situations where clinical examination is
not possible because of opaque media. Three-dimensional and digital tech-
nology expands teaching capability and brings the clinical availability of
contact ultrasonography to a larger audience. Ultrasound studies should,
however, be used in conjunction with detailed clinical examination and
other investigational modalities.
441
booksmedicos.org
REFERENCES 6. Fisher YL. Contact B-scan ultrasonography: a practical approach. Int Ophthalmol Clin
1979;19:103–25.
1. Purnell EW. Intensity modulated (B-scan) ultrasonography. In: Goldberg RE, Sarin LK,
editors. Ultrasonics in ophthalmology: diagnostic and therapeutic applications. Philadel-
7. Coleman DJ, Silverman RH, Lizzi FL, et al. Ultrasonography of the eye and orbit. Phila-
delphia: Lippincott Williams & Wilkins; 2006.
6.5
phia: WB Saunders; 1967. p. 102–23. 8. Fisher YL. Examination techniques for the beginner [Internet]. New York: Ophthalmic
Edge LLC; 2012 [updated 2009 Sept 22]. Available from: http://www.OphthalmicEdge.org.

2. Coleman DJ. Reliability of ocular and orbital diagnosis with B-scan ultrasound. 1. Ocular
diagnosis. Am J Ophthalmol 1972;73:501–16. 9. Fisher YL. High resolution B-scan ultrasound anterior segment [Internet]. New
3. Coleman DJ, Lizzi FL, Jack RL. Ultrasonography of the eye and orbit. Philadelphia: Lea & York: Ophthalmic Edge LLC; 2014 [updated 2016 Oct 13]. Available from: http://www
Febiger; 1977. .OphthalmicEdge.org.
4. Bronson NR. Quantitative ultrasonography. Arch Ophthalmol 1969;81:400–72.
5. Bronson NR, Fisher YL, Pickering NC, et al. Ophthalmic contact B-scan ultrasonography
for the clinician. Baltimore: Williams & Wilkins; 1980.
441.e1
booksmedicos.org
Camera-Based Ancillary Retinal

Testing: Autofluorescence, 6.6
Fluorescein, and Indocyanine
Green Angiography
Eric Feinstein, Jeffrey L. Olson, Naresh Mandava
Definition of Fluorescein Angiography: Fluorescein angiography Key Features

(FA) is a diagnostic technique that uses intravenous or oral fluorescein • Intrinsic fluorescence emitted by lipofuscin within the RPE after being
dye to allow the sequential visualization of blood flow simultaneously excited with short to medium wavelength visible light.
through retinal, choroidal, and iris tissue.1 Since its introduction, it has • Photographs can be taken with a scanning laser ophthalmoscope
been an invaluable aid in the diagnosis, management, and treatment of (SLO) or standard/wide-field fundus camera.
chorioretinal diseases.1,2 • Interpretation of resultant images helps to detect and track changes
in lipofuscin accumulation, which corresponds to the health and
function of the RPE.
Key Features
• Intravenous or oral dose of fluorescein sodium dye administered. FLUORESCEIN ANGIOGRAPHY
• Sequential fundus photographs obtained by using a camera Introduction
equipped with appropriate exciting and absorbing filters or light
sources taking advantage of the inherent fluorescent properties of Fluorescein angiography (FA) relies on the special fluorescent property
the dye. of sodium fluorescein (SF)—defined as the ability of certain molecules to
• Reflected light captured on either film or as digital images. emit light of longer wavelength when stimulated by light of shorter wave-
• Interpretation of images critically dependent on an understanding of length. After stimulation, electrons return to their base energy level, emit-
ocular anatomy in both health and disease. ting energy in the form of electromagnetic waves producing visible light.3–5
• Indocyanine green dye, administered intravenously, can be an The dye has a narrow spectrum of light absorption, with the maximum
important adjunct to the diagnosis of chorioretinal disease. peak at 490 nm (485–500 nm, blue visible spectrum). Emission (fluores-
cence) occurs in the yellow-green spectrum with a wavelength of 530 nm
(520–535 nm).3
A stimulation source transmits light energy to the patient’s retina using
Definition of Indocyanine Green Angiography: Indocyanine either a flash/filter or laser in the 485–500 nm range. The energy is then
either reflected back by the retina as blue light, or absorbed by the SF
green angiography (ICGA) is a diagnostic technique that exploits
and emitted back as green light. A capturing device (camera) uses a green
indocyanine green (ICG) dye’s infrared fluorescence and biochemical filter (520–535 nm) to selectively save the fluorescent image onto film or
properties to adequately portray the characteristics of the choroidal a digital surface.
circulation, aiding in the diagnosis of diseases affecting the choroid,
such as idiopathic polypoidal choroidal vasculopathy, exudative age-
related macular degeneration (AMD), and inflammatory diseases, among Purpose of the Test
others.3–5 In normal individuals, the SF molecule freely crosses the wall of highly
permeable capillaries (choriocapillaris) but remains within the lumen of
retinal and larger choroidal vessels because a good percentage circulates
through the blood unbound to plasma proteins. This makes FA the ideal
study for evaluating retinal circulation, its vascular architecture, and the
Key Features status of the inner and outer blood–retinal barrier. Information from the
• Intravenous injection of indocyanine green dye. FA can also be used to study the choroidal circulation and retinal pigment
• Serial photographs taken with digital imaging system to capture epithelial (RPE) cells.6,7 Vascular diseases, such as diabetic retinopathy,
emission for dye. central serous chorioretinopathy, venous occlusive disease, and choroi-
• Interpretation of resultant images critically dependent on dal neovascularization secondary to age-related macular degeneration
understanding of retinal and choroidal anatomy in health and (CNV-AMD), can be clearly demonstrated with FA. These images are used
disease. to select the appropriate therapeutic approach, guide treatment, and assess
therapeutic results.8
Properties of Sodium Fluorescein Dye

Definition of Fundus Autofluorescence: Fundus autofluorescence
(FAF) is a noninvasive retinal imaging modality used in clinical practice SF (sodium resorcinolphathalein) is a yellow-red, synthetic salt dye that is
to map out density of lipofuscin within the retinal pigment epithelium most commonly used to evaluate flow patterns of subterranean waters, as
442 (RPE).
a cosmetic and pharmacological color, and as a labeling agent in protein
research.9 It has a molecular weight of 376.7 kilodaltons (kDa).10 Once
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injected to the bloodstream, approximately 80% of the dye becomes bound
TABLE 6.6.1 Incidence of Adverse Reactions to Intravenous
to plasma proteins (particularly albumin), and the rest remains unbound.10
The dye is metabolized by the liver and kidneys and is eliminated in the Fluorescein Angiography 6.6
urine within 24–36 hours of injection. Its most important property for Reaction Incidence
ophthalmological purposes is its fluorescence. It has a narrow spectrum
Camera-Based Ancillary Retinal Testing: Autofluorescence, Fluorescein, and Indocyanine Green Angiography
Mild Nausea, vomiting sneezing 0%–5% (based on 87% of respondents)
of absorption and excitation that makes the FA technique feasible (see
Urticaria 1 : 82
“Introduction”). SF dye is readily available and produced commercially in
Moderate Syncope 1 : 337
aliquots of 2–3 mL of 25% or 5 mL of 10% sterile aqueous solution.
Other 1 : 769
Overall 1 : 63
Procedure Respiratory 1 : 3800
A good quality FA is highly dependent on a high-resolution fundus camera, Cardiac 1 : 5300
a skilled photographer, and a clear view to the retina. Severe Seizures 1 : 13900
The spherical refractive error of the patient is corrected by simultane- Death 1 : 221781
ously focusing the cross-hairs in the eyepieces reticule and the fundus. Overall 1 : 1900
The focusing wheel is used only for fine focus. Most cameras are equipped
From the survey conducted by Yannuzzi LA, Rohler KT, Tindel LJ, et al. Fluorescein
with a joystick to help align the camera to the patient’s eye. Proper align- angiography complication survey. Ophthalmology 1986;93:611–7.
ment gives even illumination of the fundus, whereas misalignment results
in peripheral and central artifacts in the images. This can be ameliorated
with careful lateral movements of the joystick. Variable amounts of magni- Previous efforts to relate the procedure technique, dye concentrations,
fication can usually be selected, depending on the system, and this should and rate of infusion and volume with the incidence of adverse reactions
be tailored to the pathology being examined. have been inconclusive.7 Although in vivo skin tests remains the most
Pharmacological mydriasis is usually required for most commercially reliable diagnostic tool for the diagnosis of immunoglobulin E–mediated
available equipment, but there are a few that do not require it. Before start- allergy to SF (including severe cases of anaphylaxis), it is not particularly
ing the infusion of the dye, a set of baseline red-free images are taken effective in predicting mild adverse reactions (ARs) because they are not
using a green filter. Green light provides excellent contrast and enhances attributable to immunological mechanisms.11 Special attention should be
the visibility of the retinal vasculature and vitreous–retinal interface. It is paid to patients with reported previous mild or moderate ARs during the
particularly useful in assessing retinal hemorrhages, drusen, epiretinal study because the rate of recurrence is high (48%–68%), and the study
membranes, and exudates. should be avoided, if possible.1
The dye is typically injected in the antecubital vein with a 21-gauge but- The American Academy of Ophthalmology Preferred Practice Patterns
terfly needle in a rapid but controlled infusion (≈ 1 mL/sec) to maximize states that each angiographic facility should have in place an emergency
the contrast of the early filling phase of the angiography.7,11 Although there protocol to minimize risk and manage complications.15 Regular stocking
is no evidence of increased side effects when using higher concentrations and updating of medications is needed, as well as regular training of pho-
of the dye, many practitioners prefer to use a smaller volume of a more tographers and supporting staff to recognize signs and symptoms of ana-
concentrated solution. The two preferred doses are 2.5 mL of a 20% solu- phylaxis. An emergency kit should be available on site and should include
tion and 5 mL of a 10% solution. If the patient is a newborn or premature an airway bag, intravenous equipment, automated external defibrillator,
baby, a 10% solution at a dose of 0.1 mL/kg followed by an isotonic saline oral or intramuscular antihistamines, and autoinjectors of epinephrine.
flush is recommended.12 Infusion of the dye can be done from the left or The protocol should be posted in a prominent place and be visible to
right antecubital vein without changing the times or image qualities. If the everybody.15
patient has undergone mastectomy with lymph node dissection, the dye Although package inserts from most brands of SF dye state that its use
should probably not be injected in the ipsilateral arm because of the risk should be avoided during pregnancy, especially during the first trimester,
of altered lymphatic flow.9 data from several series and animal studies have not been able to iden-
Extravasation of the dye should be avoided, as infiltration is painful and tify a higher rate of birth abnormalities or complications (regardless of
may rarely lead to tissue necrosis. A timer is started after injection of the SF concentration: 10% or 25%).12,16,17 It is therefore reasonable to perform
dye, and image acquisition should begin immediately to capture initial FA on pregnant patients when vision is threatened by potentially blinding
choroidal and retinal filling. Photographs are usually taken at 4-second diseases. Nonetheless, most clinicians prefer to wait until after delivery.
intervals, beginning 15 seconds before injection and continuing with a Nursing mothers are discouraged from breastfeeding for at least 24–48
tapered frequency for 10–20 minutes. However, the timing and the interval hours after FA.18
between exposures should be adjusted on the basis of the pathology that Several technological advances have taken place since the introduction
is being studied. For instance, a choroidal neovascular membrane leaks of film angiography:
profusely early in the study; therefore, photographs should be taken with
more frequency at the beginning of the study to capture the details of the • Confocal scanning laser ophthalmoscope (CSLO) as the energy source: The
membrane. main benefit of switching to CSLO instead of a traditional cobalt blue
flashbulb is that the exact laser wavelength can be selected to gener-
Complications ate the peak emission of light of the SF dye.2,9 This means a signifi-
cant increase of the signal-to-noise ratio in each examination. Despite
FA is an invasive test, and despite being deemed generally safe, it is not the fact that the retina receives a higher emission of light energy with
free of adverse reactions, ranging from mild to severe. Mild reactions are this modality, the toxic threshold is not exceeded because the energy is
defined as transient and resolve spontaneously without treatment. Most emitted only for 0.1–0.7 microseconds.19 This enables high-speed acqui-
commonly these are nausea (approximately 3%–15%), vomiting (up to 7%), sition of images and short movies, allowing a dynamic evaluation of the
sneezing, inadvertent arterial injection, and pruritus.1,13 Moderate adverse blood flow through the retinal and choroidal vessels. The wavelength
reactions resolve with medical intervention. These include urticaria, of the laser can be tuned or combined to acquire images with different
angioedema, syncope, thrombophlebitis, pyrexia, local tissue necrosis, dyes simultaneously (SF and indocyanine green). The procedure is more
and nerve palsy.13 Severe reactions require intensive intervention, and the comfortable for the patient because there is no bright flash (Fig. 6.6.1).9,19
patients may have poor recovery. These reactions include laryngeal edema, • The change of film to digital images: The development of high-resolution
bronchospasm, anaphylaxis, hypotension, shock, myocardial infarction, (high-definition [HD]) cameras along with computers with higher
pulmonary edema, hemolytic anemia, cardiac arrest, tonic-clonic seizures, storage capacity has allowed digital equipment to mostly supplant tra-
and death.1,13 The incidence of adverse reactions has been described in the ditional film equipment.3,4,6 Digital images can have a similar or greater
report on a multicenter, collaborative study (Table 6.6.1).13 The overall inci- resolution than that of a traditional film-based one (4096 × 2736 pixels).6
dence of complications is estimated to be 3%–20%. Although not consid- The coupling of CSLO with pinhole cameras effectively blocks scattered
ered a complication, the yellowing of skin, most commonly in fair-skinned light as well as details outside the optical focus. As a result, greater
individuals, may lead to photosensitivity, and patients should be cautioned detail in the capillary network becomes visible. And, finally, a digital
about exposure to ultraviolet rays. Recently, a case of extensive jaundice image enables real-time correction of gain, exposure, and focus, as
following fluorescein was reported.14 Patients should also be advised about well as instant visualization, which means better image quality.4 It also 443
possible darkening of urine for 24–48 hours after the study. makes the examination and manipulation of the images easier, allows
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Fig. 6.6.1 Fluorescein Angiography (FA)
6 and Indocyanine Green Angiography

(ICGA) Images Taken Simultaneously
in the Same Patient. (A) FA image.
(B) ICGA image, in which, in addition to
Retina and Vitreous
the normal fluorescence of the retinal

vessels, the deep choroidal vessels are
visualized. (Courtesy Jans Fromow-Guerra,
MD: Associate Professor. Asociación para
Evitar la Ceguera en México, IAP. México
DF.)
A B
Fig. 6.6.2 Example of Ultra-Wide Field Fluorescein Angiography (FA) Images

(200° Angle View). Mid-phase angiogram in a patient with proliferative diabetic
retinopathy. Note the neovascularization elsewhere (NVE) along the distance
inferotemporal arcades with surrounding areas of nonperfusion and mild leakage Fig. 6.6.3 Peak Phase Angiogram. Approximately 25 seconds after injection,
from the large vessels. Small areas of punctate hyperfluorescence represent multiple maximal fluorescence of the retinal circulation is evident. Note the intricate detail of
microaneurysms in all quadrants. the perifoveal capillary network.
for the rapid transmission of data by electronic means, and eliminates

the need for physical storage space.4 during the early phases of the angiogram, Bruch’s membrane is stained,
• Wide and ultra-wide angle of view: Traditionally, the standard angle of and choroidal vasculature detail is obscured. A cilioretinal artery is seen
view was 30–50° with a 2.5 magnification,3 making the evaluation of simultaneously with the fluorescence of the choroidal circulation in
peripheral retinal pathology difficult. Contact lens systems increased 10%–15% of patients.
the angle of view to up to 160°.2 A new ultra-wide field system that uses One to three seconds after choroidal filling, the retinal circulation begins
a rotating ellipsoidal mirror with two conjugate focus points combined to fluoresce (at 11–18 seconds). The retinal arterial system should fill com-
with a scanning laser ophthalmoscope creates an ellipsoidal surface pletely in about 1 second. The early arteriovenous phase is characterized by
capable of focusing light rays emanating from the peripheral retina, the passage of fluorescein dye through the central retinal arteries, the pre-
(up to 200°) (Fig. 6.6.2).2,20,21 Ultra-wide field angiography has shown capillary arterioles, and the capillaries, and the late arteriovenous phase is
to be useful for identification and management of peripheral pathology characterized by the passage of dye through the veins in a laminar pattern.
in various diseases, including diabetes, sickle cell anemia, posterior/ During the late arteriovenous phase, maximal fluorescence of the arter-
panuveitis, and pediatric retinal disease, among others.21–24 ies occurs, with early laminar filling of the veins. Laminar filling of veins
is caused by the preferential concentration of unbound fluorescein along
the vessel walls. Several factors are responsible for the laminar pattern
Interpretation of Results of venous filling; these include the more rapid flow of plasma along the
Normal Fluorescein Angiogram vessel wall as well as the higher concentration of erythrocytes in the central
vascular lumen.
The dye first enters the eye in the short posterior ciliary arteries 10–15 Maximal fluorescence is achieved in the juxtafoveal or perifoveal capil-
seconds after injection in patients with normal circulation. The dye is lary network after 20–25 seconds. The normal capillary-free zone, or foveal
then visualized in the choroid and optic nerve head. This initial filling is avascular zone, is approximately 300–500 µm in diameter. A dark back-
dependent on the cardiovascular condition and age of the patient as well ground to this capillary-free zone in the macula is created by blockage of
as the speed of injection. The choroidal circulation is seen initially as the choroidal fluorescence by both xanthophyll pigment and a high-density
choroidal flush—a mottled and patchy fluorescence created as dye fills the of RPE cells in the central macula. This phase of angiography has been
444 choriocapillaris. The patchy appearance is created as separate lobules of termed the peak phase because maximal fluorescence of the capillaries and
the choriocapillaris fill sequentially. As dye leaks from the choriocapillaris enhanced resolution of capillary detail occurs (Fig. 6.6.3). The management
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BOX 6.6.1 Causes of Hypofluorescence BOX 6.6.2 Causes of Hyperfluorescence
Blocked Retinal Fluorescence Pseudo-fluorescence Pooling:
6.6
• Media opacity Autofluorescence
Neurosensory detachment
• Vitreous opacification (hemorrhage, asteroids hyalosis, vitritis) • Central serous
• Subhyaloid hemorrhage. Transmitted Fluorescence chorioretinopathy
• Intraretinal pathology (hemorrhage [vein occlusion], edema) • Geographic atrophy • Optic nerve pit
Blocked Choroidal Fluorescence
• “Bull’s eye” maculopathy • Best disease
• All entities that cause blockade retinal fluorescence. • Macular hole Subretinal neovascularization
• Outer retinal pathology (lipid, hemorrhage, xanthophyll) • Atrophic chorioretinal scar Retinal pigment epithelium
• Subretinal pathology (hemorrhage, lipid, melanin, lipofuscin, fibrin, • Drusen detachment
inflammatory material) Abnormal vessels
• Serous
• Subretinal pigment epithelium pathology (hemorrhage) RETINA
• Fibrovascular
Staining
• Choroidal pathology (nevus, melanoma) • Angioma; Wyburn–Mason • Staphyloma
syndrome
Vascular Filling Defects
• Cavernous hemangioma • Disc
Retina
• Vascular tumor • Sclera
• Occlusion or delayed perfusion • Retinoblastoma • Chorioretinal scar
• Central or branch artery occlusion CHOROID
• Capillary nonperfusion (diabetes, vein occlusion, radiation, etc.) • Melanoma
• Atrophy or absence of retinal vessels • Choroidal neovascularization
Choroid • Choroidal hemangioma
• Occlusion of large choroidal vessels or choriocapillaris (sectoral OPTIC NERVE
infarct, malignant hypertension, toxemia, lupus, choroidopathy, renal • Peripapillary vascular loops
disease)
Leakage
• Atrophy or absence of choroidal vessels or choriocapillaris RETINAL VESSELS
(choroideremia, acute multifocal placoid pigment epitheliopathy)
• Venous occlusive disease
Optic Nerve • Frosted angiitis
• Occlusion (ischemic optic neuropathy) • Phlebitis
• Atrophy or absence of tissue (coloboma, optic nerve pit, optic nerve NEOVASCULARIZATION
hypoplasia, optic atrophy) • Diabetes retinopathy
• Radiation retinopathy
• Sickle cell retinopathy
of microvascular diseases of the retinal capillaries, such as diabetic macular
edema, requires excellent peak phase imaging.
The first pass of fluorescein through the retinal and choroidal vascula-
ture is complete after 30 seconds. The recirculation phases, characterized defects are more difficult to visualize because the native RPE prevents
by intermittent mild fluorescence, follow. After approximately 10 minutes, adequate visualization of the choroidal circulation. In general, occlu-
both the retinal and choroidal circulations generally are devoid of fluores- sive diseases that involve isolated, larger choroidal vessels manifest as
cein. Many normal anatomical structures continue to fluoresce during late sectoral, wedge-shaped areas of hypofluorescence. Systemic diseases,
angiography, such as the disc margin and optic nerve head. The staining including malignant hypertension, toxemia of pregnancy, giant cell arte-
of Bruch’s membrane, choroid, and sclera is more visible in patients who ritis, and lupus choroidopathy, produce zones of hypofluorescence sec-
have lightly pigmented RPE. ondary to focal choroidal nonperfusion. Vascular filling defects of the
optic nerve head may be noted by fluorescein angiography. Ischemic
Abnormal Fluorescein Angiography optic neuropathy manifests as sectoral or complete optic disc hypoflu-
The terms hypofluorescence and hyperfluorescence are used in the inter- orescence, whereas other atrophic or hereditary anomalies of the optic
pretation of fluorescein angiograms. Hypofluorescence is a reduction or nerve head have diffuse hypofluorescence.
absence of normal fluorescence (Box 6.6.1), whereas hyperfluorescence is • Hyperfluorescence: Hyperfluorescence is defined as an abnormal pres-
increased or abnormal fluorescence (Box 6.6.2). ence of fluorescence or an increase in normal fluorescence in the FA.
It can be secondary to increased transmission of choroidal fluorescence
• Hypofluorescence: Hypofluorescence can be categorized into blockage caused by a window defect created by an area with a decreased or absent
(masking of fluorescence) or vascular filling defects. Blocked fluorescence RPE that allows a clear view of the underlying choroidal fluorescence
can provide clues as to the level of the blocking material, such as vitreal, (Fig. 6.6.6). The most frequent cause of hyperfluorescence is leakage of
retinal, or subretinal. Only structures or material anterior to the area of dye from the intravascular space into the extravascular space. In this
fluorescence can block fluorescence. Blocked retinal fluorescence may case a localized, diffuse hyperfluorescent spot increases in both size and
be caused by any element that diminishes the visualization of the retina intensity as the study progresses (Fig. 6.6.7). When the dye leaks into
and its circulation (Fig. 6.6.4). Blockage of retinal fluorescence also an anatomical space (cysts, subretinal space, sub-RPE space) it is called
may localize the pathology to the inner retina. The retinal circulation pooling. In this case, the boundaries of the hyperfluorescence are more
is unique in that the large retinal vessels and precapillary first-order defined, and the speed of appearance depends mostly on the cause (Fig.
arterioles lie in the nerve fiber layer, whereas the capillaries and post- 6.6.8). Finally, staining refers to the deposition of dye within involved
capillary venules are located in the inner nuclear layer. Flame-shaped tissue and occurs in both normal (optic nerve and sclera) and patholog-
hemorrhages are superficial and block all retinal vascular fluorescence, ical states (drusen, disciform scars).
whereas deeper dot or blot hemorrhages (or intraretinal lipid) block
capillary fluorescence but do not block larger superficial vessels. Flu-
orescence may also be blocked by melanin (scars, melanoma, nevus),
INDOCYANINE GREEN ANGIOGRAPHY
lipofuscin deposits (Stargardt disease and Best disease), hemorrhage Introduction
(diabetic retinopathy), and serosanguinous fluid beneath the RPE
(CNV-AMD). Vascular filling defects produce hypofluorescence because Currently there are two commercially available types of imaging systems
of the reduced or absent perfusion of tissues. Retinal vascular filling for indocyanine green angiography (ICGA): modified fundus cameras
defects can involve large-, medium-, or small-caliber vessels. Capillary (which utilize continuous illumination from a halogen bulb and periodic
nonperfusion manifests as vascular filling defects and is typically seen xenon lamp flashes), and scanning laser ophthalmoscope (SLO)–based
in common ischemic disease processes, such as diabetic retinopathy systems, which use a focused laser beam to sweep the retina, allowing 445
and venous occlusive disease (Fig. 6.6.5). Choroidal vascular filling continuous image acquisition (20–30 images per second).25
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Retina and Vitreous
Fig. 6.6.4 Blockage. Fluorescein angiography (FA) image from a patient with
idiopathic macular telangiectasia. In this late-phase angiogram, intraretinal pigment
plaques are blocking (arrow) the background choroidal fluorescence. Note the
significant leakage from the telangiectatic vessels worse temporally as well as
staining of the scleral crescent around the optic nerve. (Courtesy Michael Bono, CRA,
COT Rocky Mountains Lions Eye Institute, Denver, CO.) Fig. 6.6.6 Window Defect. Fluorescein angiography (FA) image from a patient with
an advanced case of Stargardt disease. The picture shows increasing fluorescence
caused by atrophy, noted since the early phases of the angiogram. (Courtesy
Valentina Franco-Cardenas, MD: International Retina Fellow, University of California
Los Angeles (UCLA).)
Properties of Indocyanine Green

ICG (benzoindotricarbocyanin) is an amphiphilic tricarbocyanine dye with
a molecular weight of 775 kDa.26 Because of its ability to form aggregates,
the ICG lyophilisate has to be dissolved in water for injection. In the blood-
stream, the dye is rapidly bound to proteins (98%), especially to albumin,
globulins, and lipoproteins, thus remaining longer in large blood vessels
and having a lesser tendency to diffuse into the interstitial space.10 The dye
has been approved by the U.S. Food and Drug Administration for use in
cardiac, hepatic, and ophthalmic studies.9 ICG is solely metabolized by the
liver through a specific carrier-mediated transport system and excreted in
the biliary system. This explains the rapid elimination of the dye from the
circulation after an intravenous injection.26 The dye has a plasma half-life
of 2–4 minutes.
Procedure
Fig. 6.6.5 Vascular Filling Defect. Ultra-wide field fluorescein angiography (FA)
image of an inferior hemiretinal vein occlusion in the late phase. There are areas Pharmacological mydriasis is usually required with most systems. The
of significant nonperfusion with a large area noted temporal macula (arrow). Note infusion technique is similar to FA, as described above.
the blockage from heme, leakage from large and small vessels in the macula and The dosage of ICG can vary from 20–50 mg of dye dissolved in 2–4 mL
periphery. (Courtesy Hoang Nguyen, COT Rocky Mountains Lions Eye Institute, of aqueous solvent. The preferred technique is to slowly inject 25 mg of
Denver, CO.) ICG dye in 5 mL of water. A higher dosage typically results in a larger
degree of hyperfluorescence and thereby changes excitation. If both FA
and ICGA are performed sequentially, an intravenous catheter may be
placed to avoid multiple needlesticks.18
Although the ICG dye gives off 4% of the fluorescence of SF, its Excitation illumination should be at a maximum, with a video gain of
maximal peak of absorption is at 790–805 nm and has a peak emission +6 dB. Approximately 10 images are acquired over the initial 30 seconds,
of 835 nm.18,19 Both exciting and emitted lights are in the near-infrared starting immediately after injection. The video gain and excitation illu-
spectrum, and this allows deeper penetration through the retina, and the mination levels should not be changed during the transit phase unless
emitted light passes more easily through the RPE, blood, lipids depos- image bloom occurs (an increased fluorescence that obscures images). If
its, pigment, and mild opacities (cataracts) to form images.25 Moreover, this happens, the excitation level is reduced. The best images are retained,
because the dye has a significantly greater molecular weight, and a greater and ideally, the transit of ICG through the choroidal vasculature is cap-
proportion of molecules remain bound to proteins in the bloodstream, the tured again every 15 seconds. Late images at 5, 10, 15, 20, and 40 minutes
ICG dye normally remains within the fenestrated walls of the choriocapil- after injection also are obtained. Alteration of the excitation level can be
laris, unlike SF which leaks freely from these vessels. This property makes increased during the late phase of ICGA if signal intensity is reduced.
446 ICGA an ideal technique for portraying the anatomy and hemodynamics During the very late stages, both excitation and video gain can be increased;
of the choroid (Fig. 6.6.9).3 however, a concomitant reduction in detail results.
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6.6
A B
Fig. 6.6.7 Leakage. Fluorescein angiography (FA) image from a patient with
proliferative sickle cell retinopathy. Ultra-wide field angiogram demonstrates
progressive leakage of dye from the three peripheral sea-fan neovascularization
C temporally. Note the peripheral nonperfusion (arrow) as well as the blockage from old
subhyaloid heme (chevron) below the neovascularization (A–C).
Complications The middle phase occurs 3–15 minutes after ICG injection. It is marked
by continuous fading of the choroidal and retinal vessels. The late phase
Mild adverse reactions, such as nausea, vomiting, sneezing, and transient occurs 15–60 minutes after ICG injections. It demonstrates staining of the
itching, occur in 0.15% of cases.5 Moderate adverse reactions, such as urti- extrachoroidal tissue, giving the choroidal vasculature the illusion of hypo-
carial, syncope, fainting, and pyrexia, may also occur. Severe adverse reac- cyanescence, compared with the background tissue. No retinal vessels are
tions, such as hypotension, shock, anaphylaxis, and death, have also been seen during this phase.18
reported and occur in equal incidence following ICG and FA (1 : 1900).5 Abnormal areas on an ICGA are interpreted as in FA. There can be
ICG is currently available in several pharmaceutical preparations. either hypo- or hypercyanescence. Hypocyanescence can be attributed to
Because some of the manufacturing process adds iodine to allow crystal- blockage (by blood, serous fluid, pigment, or exudates); impaired choroidal
lization of the molecule (≈5% of commercial ICG dyes), crossover allergy perfusion, either by blocked blood flows on a given area or by loss of cho-
to iodine can occur in patients with seafood allergies (shellfish).9,26 Current roidal vasculature tissue (acute posterior multifocal placoid pigment epi-
contraindications to ICGA include prior anaphylactic reaction to ICG dye theliopathy). Hypercyanescence can be caused by a lack of overlying tissue
or contrast agents that contain iodine, hepatic insufficiency, uremia, and (RPE dropout, lacquer cracks), leakage from retinal or choroidal blood
pregnancy. Patients undergoing hemodialysis are also at increased risk of vessels (producing subsequent staining of surrounding tissue), or leakage
complications from ICG.9,18 from abnormal blood vessels (CNV, polypoidal vasculopathy). The terms
When local extravasation of the ICG occurs, minimal damage is hot spots and plaques are used to define areas of intense hypercyanescence
observed, in contrast to SF, which may cause severe tissue necrosis. during the middle to late phases of the ICGA. Hot spots are defined as <1
disc diameter (DD) in size. Hot spots have been attributed to one of three
Interpretation of Results etiologies: polypoidal choroidal neovascularization, retinal angiomatous
proliferation, or occult choroidal neovascularization (Fig. 6.6.11). Plaques,
In the early phase of the test, 2 seconds after ICG injection, filling of both which are more common, are larger (>1 DD), more amorphous, and reveal
the choroidal arteries and choriocapillaris, with early filling of the choroi- less obvious leakage. Combined lesions, which have characteristics of both
dal veins, occurs. The retinal blood vessels are still dark along with the cho- hot spots and plaques, can also occur.18,27,28
roidal “watershed zone” around the optic nerve head. Then, 3–5 seconds Wide and ultra-wide angle of view: Wide-field ICGA allows for up to 160°
after ICG injection, the larger choroidal veins begin to fill and fluoresce field of view and ultra-wide angiography reaches 200° field of view.29,30
along with the retinal arteries as the dye flows. Later, at 6 seconds to 3 Peripheral changes are common on ultra-wide field ICGA in many oph-
minutes, the outer-shed zone is now filled, but the choroidal arteries and thalmic conditions, including, but not limited to, central serous chorio- 447
large choroidal veins begin to fade (Fig. 6.6.10).18 retinopathy, AMD, polypoidal choroidopathy, and myopic degeneration.
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Retina and Vitreous
A
B
Fig. 6.6.8 Pooling. Color picture and fluorescein angiography (FA) sequence from a
patient with central serous chorioretinopathy. (A) & (C), Small arrowheads delineate
an area of neurosensory detachment of the macula with pooling of the dye in
the late phase of the study. (B) & (C), Large white arrows indicate areas of retinal
C pigment epithelium leakage of fluorescein. (Courtesy Valentina Franco-Cardenas,
MD: International Retina Fellow, University of California Los Angeles [UCLA].)
Fig. 6.6.9 Fig. 6.6.10 Final

Indocyanine green stage of the early
angiography phase of a normal
(ICGA) image from indocyanine green
a patient with angiography (ICGA)
severe atrophy of (at 90 seconds of
the retinal pigment the study), where
epithelium (RPE), the retinal and
in which the large choroidal
choriocapillaris, as vessels are clearly
well as medium visible. (Courtesy
and large choroidal Jans Fromow-
vessels, can Guerra, MD:
be observed. Associate Professor.
(Courtesy Jans Asociación para
Fromow-Guerra, Evitar la Ceguera
MD: Associate en México, IAP.
Professor. México DF.)
Asociación para
Evitar la Ceguera
en México, IAP.
448 México DF.)
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6.6
A
A
B Fig. 6.6.12 Widefield Optos photo (A) and corresponding fundus autofluorescence
(B) from a patient with paracentral retinitis pigmentosa. Note the “bull’s eye”
maculopathy centrally, hypoautofluorescence in areas of pigment clumping, and
Fig. 6.6.11 Fluorescein angiography (FA) and indocyanine green angiography
mottled hyperautofluorescence seen in a ring around the macula and optic nerve,
(ICGA) images from a patient with idiopathic polypoidal choroidal vasculopathy
corresponding to RPE changes noted on the Optos fundus photo.
and hemorrhagic pigment epithelial detachment. (A) FA with a large hemorrhagic
pigment epithelial detachment in the temporal macula (arrow) showing blockage
and RPE mottling in the periphery. (B) ICGA demonstrates characteristic saccular
dilations of the choroidal vasculature just temporal to the disc (arrow). The vortex
ampullae are also highlighted (chevron).
ACKNOWLEDGMENTS
The authors thank Valentina Franco-Cardenas, MD, from the University
Uveitic (infectious and noninfectious) peripheral changes, including, but of California Los Angeles (UCLA), and Jans Fromow-Guerra, MD, from
not limited to, posterior uveitis, birdshot chorioretinopathy, acute zonal APEC, for their assistance with the images in the chapter.
occult outer retinopathy, systemic lupus erythematous, and sarcoidosis,
were also identified.31,32
KEY REFERENCES
FUNDUS AUTOFLUORESCENCE Bernardes R, Serranho P, Lobo C. Digital ocular fundus imaging: a review. Ophthalmologica
2011;226:161–81.
Fundus autofluorescence (FAF) is a noninvasive imaging modality that Halperin LS, Olk RJ, Soubrane G, et al. Safety of fluorescein angiography during pregnancy.
works by using autofluorescent molecules called fluorophores (found in Indocyanine green angiography. American Academy of Ophthalmology. Ophthalmology
lipofuscin in RPE cells) to provide diagnostic and prognostic information 1998;105:1564–9.
for retinal diseases (Fig. 6.6.12).33 Camera systems include fundus camera, Yannuzzi LA. Indocyanine green angiography: a perspective on use in the clinical setting.
fundus spectrophotometry, CSLO, and ultra-wide field. FAF is now used Am J Ophthalmol 2011;151:745–51.e1.
Yannuzzi LA, Ober MD, Slakter JS, et al. Ophthalmic fundus imaging: today and beyond.
widely for various pathologies, including, but not limited to, evaluating Am J Ophthalmol 2004;137:511–24.
AMD, macular dystrophies, retinitis pigmentosa, white dot syndromes, Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. Oph-
retinal drug toxicities.34 FAF provides accurate clinical correlation, which thalmology 1986;93:611–17.
has been confirmed by microperimetry and visual field testing. Areas of
decreased FAF demonstrates absolute scotomas, whereas increased FAF Access the complete reference list online at ExpertConsult.com 449
shows no visible correlate but may be a sign of future cell loss.34
booksmedicos.org
REFERENCES 18. Dzurinko VL, Gurwood AS, Price JR. Intravenous and indocyanine green angiography.
Optometry 2004;75:743–55.
1. Lira RP, Oliveira CL, Marques MV, et al. Adverse reactions of fluorescein angiography: a
prospective study. Arq Bras Oftalmol 2007;70:615–18.
19. Hassenstein A, Meyer CH. Clinical use and research applications of Heidelberg retinal
angiography and spectral-domain optical coherence tomography – a review. Clin Experi-
6.6
2. Kaines A, Oliver S, Reddy S, et al. Ultrawide angle angiography for the detection and ment Ophthalmol 2009;37:130–43.
20. Spaide RF. Peripheral areas of nonperfusion in treated central retinal vein occlusion as
management of diabetic retinopathy. Int Ophthalmol Clin 2009;49:53–9.
3. Bennett TJ, Barry CJ. Ophthalmic imaging today: an ophthalmic photographer’s view- imaged by wide-field fluorescein angiography. Retina 2011;31:829–37.
point – a review. Clin Experiment Ophthalmol 2009;37:2–13. 21. Wessel MM, Aaker GD, Parlitsis G, et al. Ultra-wide-field angiography improves the
4. Yannuzzi LA, Ober MD, Slakter JS, et al. Ophthalmic fundus imaging: today and beyond. detection and classification of diabetic retinopathy. Retina 2012;32:785–91.
Am J Ophthalmol 2004;137:511–24. 22. Ghasemi Falavarjani K, Scott AW, Wang K, et al. Correlation of multimodal imaging in
5. Yannuzzi LA. Indocyanine green angiography: a perspective on use in the clinical setting. sickle cell retinopathy. Retina 2016;36(Suppl 1):S111–7.
Am J Ophthalmol 2011;151:745–51.e1. 23. Chi Y, Guo CY, Peng Y, et al. [The application of ultra-wide-field angiography in the eval-
6. Bernardes R, Serranho P, Lobo C. Digital ocular fundus imaging: a review. Ophthalmo- uation and management of patients with posterior, and panuveitis]. Zhonghua Yan Ke Za
logica 2011;226:161–81. Zhi 2016;52(12):924–8.
7. Moosbrugger KA, Sheidow TG. Evaluation of the side-effects and image quality during 24. Lyu J, Zhang Q, Wang SY, et al. Ultra-wide-field scanning laser ophthalmoscopy assists
fluorescein angiography comparing 2 mL and 5 mL sodium fluorescein. Can J Ophthal- in the clinical detection and evaluation of asymptomatic early-stage familial exudative
mol 2008;43:571–5. vitreoretinopathy. Graefes Arch Clin Exp Ophthalmol 2017;255(1):39–47.
8. Sulzbacher F, Kiss C, Munk M, et al. Diagnostic evaluation of type 2 (classic) choroidal 25. Indocyanine green angiography. American Academy of Ophthalmology. Ophthalmology
neovascularization: optical coherence tomography, indocyanine green angiography, and 1998;105:1564–9.
fluorescein angiography. Am J Ophthalmol 2011;152:799–806.e1. 26. Desmettre T, Devoisselle JM, Mordon S. Fluorescence properties and metabolic features
9. Gess AJ, Fung AE, Rodriguez JG. Imaging in neovascular age-related macular degenera- of indocyanine green (ICG) as related to angiography. Surv Ophthalmol 2000;45:15–27.
tion. Semin Ophthalmol 2011;26:225–33. 27. Regillo CD, Benson WE, Maguire JI, et al. Indocyanine green angiography and occult
10. Ciardella AP, Prall FR, Borodoker N, et al. Imaging techniques for posterior uveitis. Curr choroidal neovascularization. Ophthalmology 1994;101:280–8.
Opin Ophthalmol 2004;15:519–30. 28. Lim JI, Sternberg P Jr, Capone A Jr, et al. Selective use of indocyanine green angiography
11. Kalogeromitros DC, Makris MP, Aggelides XS, et al. Allergy skin testing in predict- for occult choroidal neovascularization. Am J Ophthalmol 1995;120:75–82.
ing adverse reactions to fluorescein: a prospective clinical study. Acta Ophthalmol 29. Spaide RF, Orlock DA, Herrmann-Delemazure B, et al. Wideangle indocyanine green
2011;89:480–3. angiography. Retina 1998;18:44–9.
12. Lepore D, Molle F, Pagliara MM, et al. Atlas of fluorescein angiographic findings in eyes 30. Manivannan A, Plskova J, Farrow A, et al. Ultra-wide-field fluorescein angiography of the
undergoing laser for retinopathy of prematurity. Ophthalmology 2011;118:168–75. ocular fundus. Am J Ophthalmol 2005;140:525–7.
13. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. 31. Campbell JP, Leder HA, Sepah YJ, et al. Wide-field retinal imaging in the management
Ophthalmology 1986;93:611–17. of noninfectious posterior uveitis. Am J Ophthalmol 2012;154(5):908–11.
14. Kalkan A, Turedi S, Aydin I. Fluorescein-related extensive jaundice. Am J Emerg Med 32. Klufas MA, Yannuzzi NA, Pang CE, et al. Feasibility and clinical utility of ultra-widefield
2015;33(3):478. indocyanine green angiography. Retina 2015;35(3):508–20.
15. Bearelly S, Rao S, Fekrat S. Anaphylaxis following intravenous fluorescein angiography 33. Eagle RC Jr, Lucier AC, Bernardino VB Jr, et al. Retinal pigment epithelial abnormal-
in a vitreoretinal clinic: report of 4 cases. Can J Ophthalmol 2009;44:444–5. ities in fundus flavimaculatus: a light and electron microscopic study. Ophthalmology
16. Halperin LS, Olk RJ, Soubrane G, et al. Safety of fluorescein angiography during preg- 1980;87(12):1189–200.
nancy. Am J Ophthalmol 1990;109:563–6. 34. Yung M, Klufas MA, Sarraf D. Clinical applications of fundus autofluorescence in retinal
17. Olk RJ, Halperin LS, Soubrane G, et al. Fluorescein angiography – is it safe to use in a disease. Int J Retina Vitreous 2016;2:12.
pregnant patient? Eur J Ophthalmol 1991;1:103–6.
449.e1
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Optical Coherence Tomography in

Retinal Imaging 6.7
Arthi Venkat, Miriam Englander, David Xu, Peter K. Kaiser
limitations in the clinical use of TD-OCT are the limited resolution and
Definition: Optical coherence tomography (OCT) is a noninvasive slow acquisition.2
imaging technique based on the principle of optical reflectometry light,
which enables precise anatomical examination of ocular structures.
Spectral-Domain OCT
In spectral-domain (SD) or Fourier-domain OCT, the light composing the
interference spectrum of echo time delays is measured simultaneously by a
Key Features spectrometer and a high-speed, charge-coupled device, which allows infor-
• High-resolution evaluation of tissue pathology at the cellular level, mation of the full-depth scan to be acquired within a single exposure. The
achieving axial resolution of up to 2–3 µm in tissue. interference spectrum is made up of oscillations with frequencies that are
• Direct correspondence to the histological appearance of the retina, proportional to the echo time delay. By calculating the Fourier transform,
cornea, and optic nerve in health and disease. the machine calculates the axial scan measurements without adjusting the
• Critical tool in the diagnosis and monitoring of ocular disease reference mirror. This results in improved sensitivity and image acquisi-
involving the retina, choroid, optic nerve, and anterior segment. tion speed compared with TD-OCT. As a result, SD-OCT is several orders
of magnitude more sensitive than TD-OCT.2 SD-OCT’s higher acquisition
speeds allow for a shift from two-dimensional to three-dimensional images
of ocular anatomy.
Associated Features
• Easy to use, noninvasive, reproducible, safe. Multifunctional OCT
• Obtainable through most media opacities, including vitreous
hemorrhage, cataract, and silicone oil. Functional extensions to OCT add to the clinical potential of this technol-
• Recent advances allow for a dramatic improvement in the ogy. Polarization-sensitive OCT (PS-OCT) provides intrinsic, tissue-specific
cross-sectional image resolution with improved acquisition speed. contrast of birefringent (e.g., retinal nerve fiber layer [RNFL]) and depo-
• Helpful in the interpretation of pathologies in all layers of the retina larizing (e.g., retinal pigment epithelium [RPE]) tissue with the use of
as well as the vitreous–retinal interface. circular or otherwise polarized light. This allows PS-OCT to be useful in
• Also used for the detection and monitoring of optic nerve, glaucoma, glaucoma diagnosis and for the diagnosis of RPE disturbances associated
and anterior chamber pathology. with some diseases, such as age-related macular degeneration (AMD).3,4
Doppler tomography enables depth-resolved imaging of flow by observ-
ing differences in phase between successive depth scans. This technology
INTRODUCTION provides valuable information about blood flow patterns in the retina and
choroid, allowing absolute quantification of flow within retinal vessels.
Optical coherence tomography (OCT) is a noninvasive imaging technique Ultimately, this adjunct of OCT could potentially reduce the need for fluo-
that allows for the examination of ocular structures. This technique uti- rescein angiography.5
lizes light waves to create the image in a manner similar to ultrasonog-
raphy, except that reflected light, rather than sound, is used to create the
image. Low-coherence light is scanned across the tissue and focused with Time-Encoded Frequency-Domain OCT
an internal lens on the ocular structure of interest. A second beam internal (Swept-Source OCT)
to the OCT unit is used as a reference, and a signal is formed by mea-
suring the alteration of the reference beam and comparing this with the Swept-source OCT, a variation on Fourier-domain OCT, sweeps the fre-
reflected beam. The interface between different ocular tissues can be deter- quency of a narrow band continuous wave light source and collects the
mined by changes in reflective properties between the tissues. Detection of time-dependent interference signal. Here, the advantage lies in high signal
these beams is based on time-domain or spectral-domain protocols.1 to noise ratio detection technology, achieving very small instantaneous
The use of light allows for high resolution and evaluation of tissue bandwidths at high frequencies (20–200 kHz). This dramatically increases
pathology at the cellular level, achieving resolution of 2–3 µm. Other acquisition speed and scan depth. Drawbacks include nonlinearities in the
advantages include ease of use, reproducibility, noninvasiveness, safety, wavelength, especially at high scanning frequencies, and high sensitivity to
and repeatability. In addition, OCT can image through most media opaci- movements of the scanning target.2
ties, including vitreous hemorrhage, cataract, and silicone oil.
High-Speed, Ultra-High-Resolution OCT
OCT TECHNOLOGY PLATFORMS Another variation on Fourier-domain OCT, high-speed, ultra-high-res-
Time-Domain OCT olution OCT (hsUHR-OCT) allows for a dramatic improvement in
cross-sectional image resolution and acquisition speed. The axial resolu-
In time-domain (TD)-OCT, an individual A-scan is acquired by varying the tion of hsUHR-OCT is approximately 3.5 µm, compared with the 10 µm
length of the reference arm in an interferometer such that the scanned resolution in standard OCT. Imaging speeds are approximately 75 times
length of the reference arm corresponds to the A-scan length. The image faster than that with standard SD-OCT. The ultra-high resolution enables
is then constructed by using a false color scale that represents the quanti- superior visualization of retinal morphology in a number of retinal
450 fied amount of backscattered light, with brighter colors representing high abnormalities. hsUHR-OCT further improves visualization by acquiring
reflectivity and darker colors representing little or no reflectivity. The main high-transverse-pixel density, high-definition images.6–8
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Fig. 6.7.1 Optical Coherence Tomography (OCT)
Images of a Normal Retina. (A) Conventional OCT.
A
NFL ONL
IS/OS
INL
OPL
200 µm
(B) Spectral-domain (SD) OCT. (C) Average of 12 SD-OCT 6.7
images (SD-OCT with multiple B-scan averaging). Retinal
structures visible include the hyperreflective retinal
Optical Coherence Tomography in Retinal Imaging

nerve fiber layer (NFL), hyporeflective inner nuclear
layer (INL), hyperreflective outer plexiform layer (OPL),
hyporeflective outer nuclear layer (ONL), hyperreflective
lines that correspond to the junction of the inner and
outer photoreceptor segment layers (IS/OS), retinal
pigment epithelium (RPE)/Bruch’s membrane (BM)
Nasal RPE/BM Temporal complex (RPE/BM), external limiting membrane (ELM),
inner plexiform layer (IPL), ganglion cell layer (GCL), and
choroidal vessels (Ch). Red arrows indicate structures
B 200 µm delineated only by single-scan SD-OCT or SD-OCT with
NFL ONL INL IPL
ELM multiple B-scan averaging. (From Sakamoto A, Hangai
IS/OS OPL
M, Yoshimura N. Spectral-domain optical coherence
tomography with multiple B-scan averaging for
enhanced imaging of retinal diseases. Ophthalmology
2008;115(6):1071–1078.)
Nasal RPE/BM Temporal
C 200 µm
GCL
Ch
Nasal Temporal
TABLE 6.7.1 Commercially Available OCT Systems

System (Company) Axial Resolution (µm) A-Scans per Second Advanced Features
Cirrus HD-OCT5000 (Carl 5 68 000 Fixation-independent scan adjustment; multilayer en face C-scan visualization; high-resolution anterior
Zeiss Meditec) segment imaging; drusen and GA mapping; OCT angiography (AngioPlex)
Spectralis HRAOCT 7 (digital 3.5) 42 000 Point-to-point registration with eye tracking; up to six diagnostic methods in one platform with pinpoint
(Heidelberg Engineering) registration between imaging devices; wide-field imaging module for OCT and FA/ICGA; OCT angiography
Avanti RTVue XR (Optovue) 5 70 000 14-mm wide-field macular scans with wide-field analysis; drusen and GA mapping; OCT angiography
(Angiovue); software for quantitative analysis of OCTA images
3D-OCT 2000 (Topcon) Capable of exportation to common multimedia devices; able to import time-domain Stratus OCT images
OCT-HS100 (Canon) 3 70 000 10-mm scan length; 10-layer segmentation analysis; multilingual interface; Doppler retinal blood flow
analysis capable
SDOCT (Bioptigen) 4 20 000 Handheld head for pediatric patients or animal research; portability facilitates use in an operating room;
Doppler retinal blood flow analysis capable
RS-3000 Advance (Nidek) 3 53 000 12-mm scan length option; segmentation analysis of six distinct retinal layers; OCT angiography capable
(Angioscan)
DRI-OCT-Triton (Topcon) 5 100,000 Swept Source device; deeper penetration and 12-mm scan length; OCT angiography capable
FA, Fluorescein angiography; GA, geographic atrophy; ICGA, indocyanine green angiography; OCT, optical coherence tomography; SOCT, spectral OCT; SDOCT, spectral-domain OCT.
Adaptive Optics OCT Similarly, the RPE layer, Bruch’s membrane, and choriocapillaris are rep-
resented by a red signal because of their higher reflectivity. A third red
The resolution of OCT systems in the axial dimension is set by the coher- line represents the junction of the inner and outer segments (called outer
ence properties of the light source. Current light sources can provide axial segment ellipsoid zone). Inner cellular layers have lower reflectivity and are
resolution below 3 µm, which is more than sufficient to resolve the axial represented by yellow, green, and blue colors. The nonreflective vitreous
dimensions of most retinal cells. However, the lateral resolution is sub- cavity has a black signal, but the posterior hyaloid face can occasionally be
stantially degraded from the diffraction limit by optical aberrations present seen as an additional reflective layer anterior to the NFL (Fig. 6.7.1).
in the eye. Consequently, most ophthalmic OCT systems are designed to The choroid is a highly vascular structure with blood flow and thickness
be operated with a lateral resolution in the range of 15–20 µm. Adaptive varying in relation to the intraocular pressure, perfusion pressure, refrac-
optics OCT (AO-OCT) measures aberrations by using a wavefront sensor tive error, disease state, and age. It is possible to image the choroid with
and uses a wavefront corrector to compensate for the measured aberra- conventional OCT imaging (Fig. 6.7.2).
tions. The ability to correct for diffraction from ocular imperfections allows
for very high resolution (2–3 µm), sufficient for resolution of individual
cells6 (Table 6.7.1).
IMAGE OPTIMIZATION
OCT measures the intensity of a backscattered optical signal, which rep-
ANATOMICAL RESULTS resents the optical properties or reflectivity of the target tissue. The tissue
reflectivity varies among different structures, allowing for measurements
OCT images correspond to the histological appearance of the retina. The that can be displayed as false or pseudo-color or gray-scale images. The 451
highly reflective nerve fiber layer (NFL) is represented by a red signal. gray scale runs continuously from high signal (white) to no signal (black),
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Fig. 6.7.2 Comparative Choroidal Imaging With
6 Optical Coherence Tomography (OCT) Sections

Through the Fovea Obtained With Various OCT
Instruments. (Top) Heidelberg Spectralis spectral-
domain (SD)-OCT using enhanced depth imaging
Retina and Vitreous
to obtain more choroidal details, including better

visualization of the hyporeflective line indicating the
edge of the choroid. (Bottom) Cirrus SD-OCT image in
which choroidal details are visible with oversampling.
and images can contain up to 256 shades of gray corresponding to the Macular Holes
optical reflectivity of the various tissue interfaces. The standard color scale OCT has become the gold standard in diagnosing and monitoring macular
uses a modified continuous rainbow spectrum in which darker colors, holes. OCT technology has been instrumental in the classification of
such as blue and black, represent regions of minimal or no optical reflec- macular hole development, following the sequence of events from antero-
tivity and lighter colors, such as red and white, represent a relatively high posterior vitreofoveal traction to full-thickness macular hole (FTMH)14–16
reflectivity, as described in the Anatomical Results section above.9 (Fig. 6.7.6).
Studies have shown that compared with the color images, the gray-scale
images are easier to interpret and are more informative because of their Lamellar Holes
improved ability to visualize subtle retinal structures, such as photorecep- Lamellar holes are believed to be in the spectrum of macular hole disease
tor inner and outer segment junction (IS/OS), and subtle pathologies, such but, at least in some eyes, represent an aborted process. In these eyes,
as thin epiretinal membranes (ERMs).10 OCT imaging shows an irregular, thinned foveal floor with split foveal
Another method to improve image quality is to average multiple OCT edges and near-normal thickness of the perifoveal retina (Fig. 6.7.7). OCT
scans. Frames with the least amount of motion artifacts are chosen. These images show intact photoreceptors posterior to the area of dehiscence, in
frames are then averaged. Each pixel value is calculated as an average contrast to a full macular hole.
intensity from all frames, to create one frame. On average, 50 frames are
used to create one image.11 Pseudo-Hole
A macular pseudo-hole is a clinical diagnosis given to an eye with the
appearance of a full-thickness defect, but an OCT image that proves an
OCT IMAGE INTERPRETATION alternative diagnosis. OCT images can readily distinguish between macular
Preretinal pseudo-hole and an FTMH.17 As with lamellar holes, OCT shows an intact
photoreceptor layer. Foveal pseudocyst has also been described as an early
The use of OCT has facilitated the diagnosis and description of diseases stage in the development of macular holes. In these cases, the posterior
involving the vitreoretinal interface, including vitreomacular traction syn- hyaloid is partially detached over the posterior pole but is still adherent to
drome, ERMs, macular holes, and schisis. the fovea, causing a biconvex appearance.18
Posterior Vitreous Detachment Intraretinal

The vitreous in a healthy eye is optically clear. When the vitreous is com-
pletely attached, the vitreoretinal interfaces can be detected by the marked Macular Edema
change in reflectivity between the vitreous and the internal limiting mem- OCT has been shown to be able to detect subtle irregularities and has
brane (Fig. 6.7.3). become essential for monitoring the pre- and postoperative courses of
macular edema. Moreover, OCT can aid in differentiating the cause of the
Vitreomacular Traction edema by identifying cystic spaces in CME or by visualizing the poste-
Vitreomacular traction (VMT) is a complication of anomalous partial pos- rior hyaloid in cases of VMT. The advantage of OCT for the assessment
terior vitreous detachment (PVD), where the vitreous is separated from the of macular edema is its accuracy and reproducibility. In addition, retinal
retina throughout the peripheral fundus but remains adherent in a broad thickness more accurately correlates with visual acuity compared with the
region encompassing the macula and/or the optic nerve. A subtle variant degree of fluorescein leakage on fluorescein angiography (FA).19
demonstrates a localized perifoveal vitreous detachment with a small, focal
vitreofoveolar adhesion resulting in an anterior–posterior tractional force Irvine–Gass Syndrome: Cystoid Macular Edema After
that may lead to retinal distortion, cystoid macular edema (CME), or even Cataract Surgery
a macular hole. Several OCT studies have documented that surgical or Approximately 20% of the patients who undergo uncomplicated phacoemul-
pharmacological separation of the vitreofoveal adhesion promotes the res- sification or extracapsular extraction develop CME, which can be detected
olution of macular thickening, usually with improvement in visual acuity on FA. Macular edema after cataract surgery begins in the inner nuclear
in patients with vision loss caused by vitreomacular traction12 (Fig. 6.7.4). layer in the perifoveal area. The central cysts tend to expand to the entire
thickness of the retina to the IS/OS junction (Fig. 6.7.8).
Epiretinal Membrane
An ERM is a result of proliferation of abnormal tissue on the surface of the Retinal Exudates
retina. It is semitranslucent and proliferates on the surface of the internal Exudates in the retina are the result of leakage of fluid and lipoproteins as
limiting membrane. ERM has been found to consist of glial cells, RPE a result of increased vascular permeability. Resorption of the fluid results
cells, macrophages, fibrocytes, and collagen fibers.13 in the precipitation of lipids, most commonly in the outer plexiform layer
On OCT, the ERM appears as a highly reflective thick membrane on of the retina but can also be seen in the subretinal space.20 These exudates
the surface of the retina. The strength of the reflection can differentiate it can be seen in any condition that causes chronic vascular leakage, includ-
452 from the posterior hyaloid, which appears as a minimally reflective signal12 ing, but not limited to, diabetes, hypertension, Coats’ disease, choroidal
(Fig. 6.7.5). neovascularization, retinal macroaneurysm, and capillary hemangioma.
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6.7

Fig. 6.7.3 Stratus time-domain (TD)-OCT (A) and prototype, ultra-high-resolution optical coherence tomography (UHR-OCT) (B) scans of a normal subject. I, Macular linear
scans, whose orientations are depicted in the upper image. II, Peripapillary circular scans. III, Optic nerve head (ONH) linear scans. Inf, inferior; INL, internal nuclear layer; IS/
OS, inner segment/outer segment; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium; Sup, superior; Temp, temporal.
(From Wollstein G, Paunescu LA, Ko TH, et al. Ultrahigh-resolution optical coherence tomography in glaucoma. Ophthalmology 2005;112(2):229–37.)
On OCT, these exudative lesions appear as highly reflective areas that

cause a shadowing effect of the underlying retinal layers (Fig. 6.7.9).
Subretinal
Subretinal Fluid
Subretinal fluid causes a separation of the neurosensory retina from the
underlying RPE. On OCT, an optically empty space can be seen between
the detached retina and the RPE. This cavity is filled with serous fluid.
Causes of subretinal fluid include retinal detachment, central serous
chorioretinopathy, and choroidal neovascular membrane.
Pigment Epithelial Detachment

A retinal pigment epithelial detachment (PED) is formed by the separation
of the RPE from Bruch’s membrane because of the presence of sub-RPE
fluid, blood, fibrovascular membrane, or drusenoid material (Fig. 6.7.10).
Fig. 6.7.4 Vitreomacular Traction (VMT). Vitreofoveolar traction resulting in an The various forms of PEDs differ in their underlying pathogenesis, OCT 453
anterior–posterior tractional force leading to cystic macular edema. appearance, and response to therapy.
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6
ERM Temporal ERM Nasal
Retina and Vitreous
A B C
Fig. 6.7.5 (A) Fundus photograph showing an epiretinal membrane (ERM) on the macula. (B) Reconstructed fundus image corresponding to black box on fundus
photograph. (C) Spectral-domain optical coherence tomography image showing the ERM. (From Legarreta JE, Gregori G, Knighton RW, Punjabi OS, Lalwani GA, Puliafito CA.
Three-dimensional spectral-domain optical coherence tomography images of the retina in the presence of epiretinal membranes. Am J Ophthalmol 2008;145(6):1023–30.)
A B
Fig. 6.7.6 (A) Optical coherence tomography (OCT) scan shows a stage 2 hole. (B) OCT shows a stage 3 hole. (From Smiddy WE, Flynn HW, Jr. Pathogenesis of macular holes
and therapeutic implications. Am J Ophthalmol 2004;137(3):525–37.)
1
ERM
Posterior Hyaloid
A * 3
2x
4 200
B µm
ERM OPL INL IPL GCL RNFL
* OPL
ONL *
ONL
200
D C IS/OS ELM RPE µm
Fig. 6.7.7 (A) Fundus photograph depicting lamellar hole and the direction of optical coherence tomography (OCT) scans. (B) Stratus OCT image demonstrates a lamellar
hole. (C) Ultra-high-resolution optical coherence tomographic (UHR-OCT) image, which also shows intraretinal separation occurring between the outer plexiform layer (OPL)
and the outer nuclear layer (ONL). The foveal photoreceptor layers are intact below the area of foveal dehiscence. (D) Magnification (×2) of UHR-OCT image shows strands of
454 tissue spanning between the separated ONL and OPL (yellow asterisks), and the intraretinal split. (From Witkin AJ, Ko TH, Fujimoto JG, et al. Redefining lamellar holes and the
vitreomacular interface: an ultrahigh-resolution optical coherence tomography study. Ophthalmology 2006;113(3):388–97.)
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6.7

Fig. 6.7.8 Pseudo-phakic cystoid macular edema (CME) 4 weeks following
phacoemulsification cataract surgery.
Fig. 6.7.11 Optical coherence tomography (OCT) image of a retinal pigment

epithelium (RPE) tear.
Choroidal Pathology
Cross-sectional imaging of the choroid is challenging because of light
scattering and absorption. One method using SD-OCT is enhanced
depth imaging (EDI). In EDI, the OCT machine is moved closer to the
eye, thereby placing the peak sensitivity curve closer to the region of the
choroid. Averaging approximately 100 images together improves the image
resolution. The image is then reinverted to correlate to the anatomical ori-
entation of the tissue. Averaging images is possible with instruments that
are capable of eye tracking.23
Choroidal Neovascularization
Choroidal neovascularization (CNV) can complicate many ocular condi-
tions, including AMD, uveitis, myopia, presumed ocular histoplasmosis,
Fig. 6.7.9 Highly reflective hard exudates accumulated in the inner portion of the
neurosensory retina. A faint shadow of low reflectivity is behind the hard exudates angioid streaks, and choroidal rupture. CNV is subdivided into different
in the outer retinal layers and retinal pigment epithelium. subtypes: type 1 (below the RPE), type 2 (above RPE below retina), and type
3 (retinal angiomatous proliferation [RAP]). Choroidal blood vessels invade
the sub-RPE (type 1) or subretinal space (type 2) via a break in Bruch’s
membrane or from an anastomosis with the retinal circulation (type 3).
Histologically, these blood vessels lack endothelial tight junctions, which
leads to serous fluid leakage.
Advancements in high-resolution three-dimensional OCT suggest that
retinal neovascularization alone or concomitant CNV can be present in
early RAP. Early lesions present with extensive macular edema and cyst
formation as the lesion progresses, the neovascularization extends beneath
the retina, and subretinal fluid accumulates. In later stages, serous PED
occurs, and CNV becomes evident. At this stage, it is difficult to differenti-
ate between CNV subtypes. Therefore, OCT is useful in the initial stage of
type 3 neovascularization to image the vessels and the cystic spaces within
the retina. However, once a PED occurs, it is very challenging to assess the
sub-RPE changes.24
NOTE: Applications of OCT in the fields of glaucoma, cornea, and
neuro-ophthalmology are discussed in the other chapters in this text.
OCT Artifacts
Time-Domain OCT
Fig. 6.7.10 Optical coherence tomography (OCT) image through drusenoid pigment Artifacts are commonly encountered with the use of TD-OCT, often related
epithelial detachment (PED). to errors in acquisition or interpretation. Acquisition errors are caused by
the speed of obtaining the image and the presence of media opacities or
optical aberrations. Because of the relatively long acquisition time, exces-
RPE Tear sive eye movements or poor fixation will degrade the image.
RPE tear is a potentially visually devastating complication of PED. The
tear is caused by contraction and retraction of the elevated PED, leading Spectral-Domain OCT
to absence of RPE underneath the neurosensory retina. Tears can be seen Compared with TD-OCT, acquisition speed is about 50 times faster with
after treatments, including laser photocoagulation, photodynamic therapy, SD-OCT, minimizing motion artifacts. In spite of this, acquisition arti-
and anti–vascular endothelial growth factor therapy. Characteristic find- facts can still occur as a result of poor centration of the image or pres-
ings on OCT include focal interruption of the RPE signal, hyperreflectiv- ence of media opacities. In addition, the capability of generating a
ity of the retracted and rolled RPE, and increased reflectivity of the bare three-dimensional image of the macula reduces the chances of missing
choroid as a result of increased signal penetration in the absence of over- focal lesions. SD-OCT also facilitates acquisition of significantly larger 455
lying RPE21,22 (Fig. 6.7.11). numbers of scans, allowing for higher resolution.
booksmedicos.org
KEY REFERENCES Smiddy WE, Flynn HW Jr. Pathogenesis of macular holes and therapeutic implications. Am
6 Bakri SJ, Kitzmann AS. Retinal pigment epithelial tear after intravitreal ranibizumab. Am J
Ophthalmol 2007;143(3):505–7.
Coker JG, Duker JS. Macular disease and optical coherence tomography. Curr Opin Ophthal-
J Ophthalmol 2004;137(3):525–37.
Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical
coherence tomography. Am J Ophthalmol 2008;146(4):496–500.
Wollstein G, Paunescu LA, Ko TH, et al. Ultrahigh-resolution optical coherence tomography
in glaucoma. Ophthalmology 2005;112(2):229–37.
Retina and Vitreous
mol 1996;7(3):33–8.
Fujimoto JG, Drexler W, Schuman JS, et al. Optical coherence tomography (OCT) in ophthal- Yannuzzi LA, Freund KB, Takahashi BS. Review of retinal angiomatous proliferation or type
mology: introduction. Opt Express 2009;17(5):3978–9. 3 neovascularization. Retina 2008;28(3):375–84.
Holz FG, Spaide RF. Medical retina. New York: Springer; 2005.
Mirza RG, Johnson MW, Jampol LM. Optical coherence tomography use in evaluation of the
vitreoretinal interface: a review. Surv Ophthalmol 2007;52(4):397–421. Access the complete reference list online at ExpertConsult.com
Shields CL, Furuta M, Thangappan A, et al. Metastasis of uveal melanoma millimeter-by-mil-
limeter in 8033 consecutive eyes. Arch Ophthalmol 2009;127(8):989–98.
456
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REFERENCES 12. Mirza RG, Johnson MW, Jampol LM. Optical coherence tomography use in evaluation of
the vitreoretinal interface: a review. Surv Ophthalmol 2007;52(4):397–421.
1. Fujimoto JG, Drexler W, Schuman JS, et al. Optical coherence tomography (OCT) in
ophthalmology: introduction. Opt Express 2009;17(5):3978–9.
13. Legarreta JE, Gregori G, Knighton RW, et al. Three-dimensional spectral-domain optical
coherence tomography images of the retina in the presence of epiretinal membranes.
6.7
2. Kiernan DF, Mieler WF, Hariprasad SM. Spectral-domain optical coherence tomogra- Am J Ophthalmol 2008;145(6):1023–30.
14. Gaudric A, Haouchine B, Massin P, et al. Macular hole formation: new data provided by

phy: a comparison of modern high-resolution retinal imaging systems. Am J Ophthalmol
2010;149(1):18–31. optical coherence tomography. Arch Ophthalmol 1999;117(6):744–51.
3. Cense B, Chen TC, Park BH, et al. Thickness and birefringence of healthy retinal nerve 15. Hee MR, Puliafito CA, Wong C, et al. Optical coherence tomography of macular holes.
fiber layer tissue measured with polarization-sensitive optical coherence tomography. Ophthalmology 1995;102(5):748–56.
Invest Ophthalmol Vis Sci 2004;45(8):2606–12. 16. Smiddy WE, Flynn HW Jr. Pathogenesis of macular holes and therapeutic implications.
4. Michels S, Pircher M, Geitzenauer W, et al. Value of polarisation-sensitive optical coher- Am J Ophthalmol 2004;137(3):525–37.
ence tomography in diseases affecting the retinal pigment epithelium. Br J Ophthalmol 17. Haouchine B, Massin P, Tadayoni R, et al. Diagnosis of macular pseudoholes and
2008;92(2):204–9. lamellar macular holes by optical coherence tomography. Am J Ophthalmol 2004;138(5):
5. Yazdanfar S, Rollins AM, Izatt JA. Imaging and velocimetry of the human retinal circu- 732–9.
lation with color Doppler optical coherence tomography. Opt Lett 2000;25(19):1448–50. 18. Haouchine B, Massin P, Gaudric A. Foveal pseudocyst as the first step in macular
6. Miller DT, Kocaoglu OP, Wang Q, et al. Adaptive optics and the eye (super resolution hole formation: a prospective study by optical coherence tomography. Ophthalmology
OCT). Eye (Lond) 2011;25(3):321–30. 2001;108(1):15–22.
7. Sakamoto A, Hangai M, Yoshimura N. Spectral-domain optical coherence tomography 19. Coker JG, Duker JS. Macular disease and optical coherence tomography. Curr Opin Oph-
with multiple B-scan averaging for enhanced imaging of retinal diseases. Ophthalmology thalmol 1996;7(3):33–8.
2008;115(6):1071–8, e1077. 20. Otani T, Kishi S. Tomographic findings of foveal hard exudates in diabetic macular
8. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical edema. Am J Ophthalmol 2001;131(1):50–4.
coherence tomography. Am J Ophthalmol 2008;146(4):496–500. 21. Chang LK, Sarraf D. Tears of the retinal pigment epithelium: an old problem in a new
9. Ray R, Stinnett SS, Jaffe GJ. Evaluation of image artifact produced by optical coherence era. Retina 2007;27(5):523–34.
tomography of retinal pathology. Am J Ophthalmol 2005;139(1):18–29. 22. Bakri SJ, Kitzmann AS. Retinal pigment epithelial tear after intravitreal ranibizumab.
10. Brar M, Bartsch DU, Nigam N, et al. Colour versus grey-scale display of images on Am J Ophthalmol 2007;143(3):505–7.
high-resolution spectral OCT. Br J Ophthalmol 2009;93(5):597–602. 23. Holz FG, Spaide RF. Medical retina. New York: Springer; 2005.
11. Han IC, Jaffe GJ. Evaluation of artifacts associated with macular spectral-domain optical 24. Yannuzzi LA, Freund KB, Takahashi BS, et al. Review of retinal angiomatous prolifera-
coherence tomography. Ophthalmology 2010;117(6):1177–89, e1174. tion or type 3 neovascularization. Retina 2008;28(3):375–84.
456.e1
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Optical Coherence
Tomography Angiography 6.8
Kyle M. Green, Cullen J. Barnett, Amir H. Kashani
a unique variation in the intensity and phase of the backscattered OCT

Definition: Optical coherence tomography angiography (OCTA) is an signal compared with the nonmoving retinal tissue within each repeated
imaging modality that uses variation (or decorrelation) in the optical B-scan at the same location. Several methods of analyzing this variance
coherence tomography (OCT) signal to detect motion in biological have been developed and can be divided into those that use the phase vari-
tissues. ance of light, the intensity variance of light, or both phase and intensity
(see Table 6.8.1).
OCTA images provide a map of retinal vessels with blood flow detect-
able on SD-OCTA devices, but do not provide the rate of blood flow at
Key Features any locations (Fig. 6.8.1). In vitro studies and some in vivo studies suggest
• OCTA can noninvasively detect the movement of red blood cells at that current SD-OCTA devices can detect blood flow in the range of
capillary-level resolution. 0.3–3.3 mm/sec.8 This is approximately the range that has been demon-
• OCTA is particularly useful for detecting regions of impaired strated by confocal scanning laser ophthalmoscopy.9 Flow rates above or
perfusion and neovascularization. below this range may artifactually appear as regions of “nonperfusion.”
• OCTA has been used to evaluate many of the pathological macular Also of note, although RBCs are the most mobile component of retinal
changes in retinal vascular diseases, including diabetic retinopathy, tissue, any particulate motion can theoretically generate similar motion
retinal vein occlusion, macular telangiectasia, and neovascular contrast signal. For example, lipid particulates in solution generate OCTA
age-related macular degeneration. signals as a result of Brownian motion.10 Therefore, the possibility of arti-
factual signal should be considered when interpreting OCTA images.
INTRODUCTION
OCTA VERSUS DYE-BASED
Optical coherence tomography (OCT) is a noninvasive imaging method
that has been used extensively in the field of ophthalmology since 2002.
ANGIOGRAPHY METHODS
OCT generates high-resolution cross-sectional images of the retina based With the rapid adoption of OCTA, it becomes necessary to determine the
on the interference of back-scattered coherent light.1 Progress in OCT appropriate roles of OCTA versus those of fluorescein angiography (FA)
technology has facilitated new OCT-based imaging methods, such as and indocyanine green angiography (ICGA). Table 6.8.2 summarizes many
polarization-sensitive OCT,2 spectroscopic OCT,3 phase-sensitive OCT,4–6 of the strengths, limitations, and practical applications of these methods.
and spectral-domain (SD) OCT angiography (OCTA).7 OCTA is a func- It is important to recognize that although OCTA and dye-based angiog-
tional extension of OCT and is being used increasingly to detect micro- raphy methods provide somewhat similar en face images, they measure
vascular changes in many retinal diseases since approval by the U.S. Food different biological phenomena. Specifically, OCTA is based on light scat-
and Drug Administration in 2016. We will briefly review the biological tering from RBCs and particulate debris, so there is no diffusion of dye on
basis of OCTA imaging, highlight the various methods of generating OCTA images. This fundamental difference is illustrated by the absence of
OCTA images, and discuss the strengths and limitations of this novel “leakage” on OCTA images in subjects who have macular edema on FA.
method. Another illustration of this difference is the variable rate of microaneu-
rysm detection on OCTA in comparison with FA.
BIOLOGICAL BASIS OF OCTA Many studies have demonstrated that OCTA does not directly detect
hyporeflective pockets of intraretinal fluid as observed on OCT. Nor does
OCTA is based on the variation in OCT signal caused by moving particles, OCTA demonstrate the hyperfluorescence that is observed in late phase
such as red blood cells (RBCs), in contrast to stationary surrounding neu- FA in subjects with diabetic macular edema or cystoid macular edema.11–14
rosensory tissue. This variability is relatively analogous to the Doppler shift This is attributed to the notion that fluid within most cystoid spaces does
that moving particles impose on reflected light. Although there are several not contain large particles that can backscatter light.10 In contrast, FA is
different methods of performing OCTA imaging (Table 6.8.1), all of these based on the tissue distribution and fluorescence of dye molecules that
methods differentiate moving particles from static retinal tissue by com- leak into cystoid spaces. Although dye leakage highlights cystoid spaces
paring multiple (two or more) OCT B-scans performed at the same loca- as well as abnormal vessels, such as neovascularization (Fig. 6.8.2), it also
tion.8 This is in contrast to standard OCT, which performs a single B-scan tends to obscure potentially relevant details both in pathological cases as
at each location. Because RBCs are constantly moving, they generate well as normal cases. This is because there is still modest dye leakage from
normal vessels which increases the background noise in FA and ICGA.15–17
For example, high background fluorescence can make it appear as though
the macula is completely ischemic by obscuring fine capillaries in prolifer-
TABLE 6.8.1 Summary of Optical Coherence Tomography ative diabetic retinopathy, whereas OCTA can clearly demonstrate the per-
Angiography (OCTA) Methods sistence of capillaries and visual potential.
Some recent studies have highlighted the significant difference in
Phase-Based OCTA Intensity-Based OCTA Phase + Intensity (Complex) OCTA appearance of microaneurysms on OCTA versus FA,12 whereas others
• Doppler OCTA • Speckle variance • Optical microangiography (OMAG) have shown significant similarities.13 In some cases, the excellent depth
• Phase variance • Correlation mapping • Multiple signal classification OMAG resolution of OCTA images has revealed that lesions consistent with the
• Split-spectrum • Imaginary part-based correlation appearance of microaneurysms on FA are actually small tufts of neovas-
amplitude decorrelation
(SSADA)
mapping
• Split spectrum-phase gradient
cularization.14 It has also been demonstrated that, at least in some cases, 457
microaneurysms are not detected as frequently on OCTA as on FA.12 Even
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Retina and Vitreous
A B
Fig. 6.8.1 Demonstration of various field-of-views in optical coherence tomography

angiography (OCTA). (A) 3 × 3 mm, (B) 6 × 6 mm, and (C) 8 × 8 mm field-of-view
pseudo-colored OCTA of a normal subject. Red represents superficial retinal layer.
C Green represents deep retinal layer. Yellow represents regions of overlay. Images are
from an AngioPlex device.
when microaneurysms are detected on OCTA, they are usually of dif- the possibility of adverse reactions ranging from mild reactions to severe
ferent sizes and shapes compared with those on FA. It is likely that the and possibly life-threatening reactions.16,20,21 An important strength of
reason for this and the discrepancy among studies is that some microan- dye-based imaging methods is that current wide-field systems provide an
eurysms are sclerosed or clotted and without blood flow, whereas others almost comprehensive assessment of the central and peripheral retina.
are patent or partially patent.18 Because OCTA only detects the movement In addition, ICGA is generally superior in detection of choroidal neovas-
of RBCs, sclerosed or clotted microaneurysms will not appear at all on cularization (CNV) compared with current OCTA systems because of the
OCTA. In addition, the flow rate of blood within microaneurysms may limited penetration of the OCTA signal through the retinal pigment epi-
be outside the detection speed of SD-OCTA devices.19 Microaneurysms thelium (RPE). Lastly, compared with OCTA, dye-based angiography has
that are partially sclerosed or partially recanalized will also appear much relatively limited resolution. For example, although FA can delineate the
smaller on OCTA than on FA because only the region with RBC flow foveal avascular zone very well in primates, <40% of the capillaries outside
will be visualized on the former, whereas the whole lesion will stain with the foveal center are visualized on FA as compared with histology.22
dye on FA. Mendis et al. showed that FA assessment of capillary density is ≈50% less
Other considerations for the use of dye-based angiography versus than histology-based assessments.15 Specifically, FA cannot resolve the
OCTA are their practical limitations and strengths (see Table 6.8.2). These radial peripapillary plexus or the capillaries in the deep retinal layers.23
458 considerations include how each method is performed and the resolution In contrast, OCTA clearly and reliably resolves these capillaries in human
of the images. The most important drawback of any dye-based method is subjects.23,24
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TABLE 6.8.2 Strengths and Limitations of Optical Coherence Tomography Angiography (OCTA) Versus Dye-Based Imaging Methods
Imaging Method Strengths Limitationsa Optimal Applications
6.8
Fluorescein angiography • Wide-field imaging • Mild and severe adverse reactions • Baseline evaluation of any retinal vascular
Optical Coherence Tomography Angiography

(FA) • Leakage demonstrates compromised vessels and • Time intensive (15–20 minutes) disease
vascular permeability • Labor intensive (requires nurse or trained • Evaluation of peripheral retina
• Retinal neovascularization photographer) • Detection of neovascularization
Indocyanine green • Wide-field imaging • Requires ancillary supplies • Baseline evaluation of any choroidal vascular
angiography (ICGA) • Leakage demonstrates compromised vessels and • Requires invasive dye injection disease
vascular permeability • Limited time to acquire transit images • Evaluation of peripheral retina
• Choroidal neovascularization and sub-RPE lesions • Leakage from normal vessels increases • Detection of choroidal neovascularization
• Noninvasive background noise • Patients with known dye allergy or sensitivity
• Minimal risk • Relatively low resolution compared to
• Fast (3–4 minutes) histology
• Not labor intensive
OCTA • High resolution (analogous to histology) • Limited resolution of sub-RPE pathology such • Follow-up evaluation of any retinal vascular
• Depth resolved images illustrates peripapillary as CNV disease with macular findings
plexus and deep retinal capillaries • Limited resolution of choriocapillaris changes • Detection of mild perfusion defects
• Repeatable on monthly basis or more often, as • Limited field-of-view • Detection of layer specific perfusion changes
needed • Projection artifacts • Patients who are pregnant, are breast-
• Movement artifacts feeding, have severe renal disease, are
• No specific billing code transplant recipients, or have poor IV access
a
Imitations column applies to both ICGA and FA.
CNV, Choroidal neovascularization; IV, intravenous; RPE, retinal pigment epithelium.
Fig. 6.8.2 Illustration of neovascularization of the disc in a subject with proliferative

diabetic retinopathy. (A) Depth-encoded optical coherence tomography angiography
(OCTA) image of optic disc with overlying neovascularization in red. In this case,
the neovascularization appears red because it is within the same plane or above
the plane of the superficial retinal layer. (B) B-scan illustrates the location of the
A neovascularization above the optic disc. Red = superficial retinal layer; green = deep
retinal layer; yellow = overlap. Images are from an AngioPlex device.
One final caveat with regard to OCTA is the potential to misinterpret any current imaging method, the term “nonperfusion” is misleading and
images because of artifacts.25 In many cases, the artifacts on OCTA are likely inaccurate in many cases. For both dye-based imaging studies as well
similar to and derived from artifacts that are observed on standard OCT as OCTA, there can be very slow blood flow rates that are either obscured
images. The most common in OCTA images is called a “projection arti- by background noise or undetectable. Because of the relatively low resolu-
fact,” where vessels in the superficial retinal layers cast shadows or “projection of FA, impaired perfusion is likely very severe by the time it is detect-
tions” on deeper retinal layers, which results in the artifactual appearance able on FA. In contrast, OCTA can reliably resolve individual capillaries
of vessels where none exists. This is most clinically relevant in the inter- with unprecedented depth-resolution in humans.23,24,26,28 OCTA images
pretation of choroidal pathology and CNV. An excellent review of the demonstrate capillary detail approaching the resolution of histology.15,23,24,29
subject is available,26 and several methods of removing these artifacts have This makes OCTA an ideal method for detecting and monitoring regions
been developed.26,27 of impaired perfusion in subjects with retinal vascular disease (Fig. 6.8.3).
In addition, OCTA can be repeated many times to obtain the ideal image
with essentially no risk to subjects, which is not possible with FA. There-
KEY APPLICATIONS OF SD-OCTA fore, OCTA provides a whole new dimension of depth information regard-
ing the severity of impaired perfusion that is not possible with FA. For
Detection of Impaired Perfusion example, studies have suggested that impairment of perfusion in the deep
(or “Nonperfusion”) retinal layers is more severe in certain diseases, such as paracentral acute
maculopathy,30 diabetic retinopathy,31 and retinal venous occlusion.11,32,33
In this chapter, we refer to “nonperfusion” as “impaired perfusion.” In addition, detection of capillary loss in the macula of patients with dia- 459
Because it is very hard to absolutely demonstrate lack of blood flow with betes28,34 and peripapillary capillary plexus of patients with glaucoma35,36
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Retina and Vitreous
Fig. 6.8.3 Illustration of a region of impaired perfusion in a subject with diabetes

with moderate to severe nonproliferative diabetic retinopathy on clinical examination
and 20/30 vision. (A) Late-phase fluorescein angiography (FA) shows several areas
of hemorrhages, a few microaneurysms, and a limited area of impaired perfusion
in the superonasal quadrant of the macula. (B) 3 × 3 optical coherence tomography
angiography (OCTA) image of the area in the white box in previous panel. OCTA
shows much more clearly the extent of impaired perfusion in relation to the fovea. In
addition, there appears to be general decrease in the perfusion in the deep retinal layer
throughout the image more so than in the superficial layer. Red = superficial retinal
C layer; green = deep retinal layer; yellow = overlap. (C) OCTA scan through the fovea from
the OCTA image above. Images are from an AngioPlex device.
is now possible before clinical lesions are evident. The clinical relevance retinal diseases. For example, in diabetic retinopathy, several studies have
of this additional information remains to be determined, but at the least demonstrated that OCTA-based metrics, such as capillary density, correlate
OCTA will allow for detection of impairment in blood flow (ischemia) with the clinical severity of the disease.31,47–49 Similar metrics have been
much earlier than before and help assess the severity of the impairment demonstrated to correlate with clinical severity of disease in subjects with
with far more precision. retinal venous occlusion,50–53 history of uveitis,54 and glaucoma.36,55
Detection of Choroidal Neovascularization CONCLUSIONS

Many studies have demonstrated that OCTA is useful for detecting and In summary, OCTA is rapidly becoming an important tool for the diag-
assessing the severity of CNV in several diseases, including neovascu- nosis and management of retinal vascular diseases. It is clear that OCTA
lar age-related macular degeneration (AMD),37–39 macular telangiecta- is at least as good as invasive dye studies for assessing the macular com-
sia,40 uveitis,41 and central serous retinopathy,42 among others (Fig. 6.8.4). plications of retinal diseases, such as diabetic retinopathy, retinal venous
Because OCTA is completely noninvasive and easy to perform in the clinic, occlusion, and some forms of macular degeneration. It is also clear that
it provides an unprecedented opportunity for real-time evaluation of retinal the excellent depth and lateral resolution of OCTA in general makes it
vascular changes. For example, the real-time regression of CNV during superior to FA, allowing for detection of much milder vascular changes.
antivascular endothelial growth factor therapy has been demonstrated by The main limitation of OCTA in clinical applications is the field of view,
using OCTA.43 Although OCTA can detect the presence and extent of CNV but this is rapidly improving as commercial systems adopt larger scan pat-
above the RPE (type 2), CNV detection for lesions below the RPE may be terns. Therefore dye-based angiography is still necessary for assessment
more challenging because the RPE is highly reflective and can severely of the peripheral retina. Another major limitation of OCTA is the subop-
attenuate the OCTA signal.38,44–46 Nevertheless, OCTA imaging of CNV timal detection of choroidal neovascularization and other pathology found
lesions can be useful because it can be performed with higher frequency beneath the RPE. It is very likely that emerging swept-source systems with
compared with FA or ICGA. The clinical significance of this has yet to be longer wavelengths of coherent light will overcome both of these limita-
determined, but it is promising that OCTA is allowing earlier detection of tions. For the spectrum of retinal vascular disease that has been managed
lesions that could progress and cause vision loss. with invasive dye studies in the past, it is very likely that OCTA will grad-
ually become the dominant modality for both diagnosis and management
Quantification of Vascular Changes of macular complications. For diseases in which dye-based angiography
had no role, such as glaucoma, OCTA provides a novel tool to assess the
One of the most promising applications of OCTA is objective and quantifi- peripapillary capillary plexus. Given the speed with which clinical interest
able assessment of capillary level changes in the retina. The fact that OCTA around OCTA is evolving, it will not be long before all of these limitations
460 has excellent spatial resolution, poses minimal risk, and is very fast makes are overcome. OCTA stands to change the practice of ophthalmology in the
it amenable for real-time assessment of capillary level changes in several next decade as profoundly as it has changed it in the last.
booksmedicos.org
KEY REFERENCES
de Carlo TE, Chin AT, Bonini Filho MA, et al. Detection of microvascular changes in eyes
of patients with diabetes but not clinical diabetic retinopathy using optical coherence
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tomography angiography. Retina 2015;35(11):2364–70.

Ferrara D, Waheed NK, Duker JS. Investigating the choriocapillaris and choroidal vascu-
lature with new optical coherence tomography technologies. Prog Retin Eye Res
2016;52:130–55.
Hwang TS, Jia Y, Gao SS, et al. Optical coherence tomography angiography features of dia-
betic retinopathy. Retina 2015;35(11):2371–6.
Ishibazawa A, Nagaoka T, Takahashi A, et al. Optical coherence tomography angiography in
diabetic retinopathy: a prospective pilot study. Am J Ophthalmol 2015;160(1):1–11.
Kashani AH, Lee SY, Moshfeghi A, et al. Optical coherence tomography angiography of
retinal venous occlusion. Retina 2015;35(11):2323–31.
Kim AY, Chu Z, Shahidzadeh A, et al. Quantifying microvascular density and morphology in
diabetic retinopathy using spectral-domain optical coherence tomography angiography.
Invest Ophthalmol Vis Sci 2016;57(9):OCT362–70.
Kim AY, Rodger DC, Shahidzadeh A, et al. Quantifying retinal microvascular changes in
uveitis using spectral-domain optical coherence tomography angiography (SD-OCTA).
Koulisis N, Kim AY, Chu Z, et al. Quantitative microvascular analysis of retinal venous occlu-
sions by spectral domain optical coherence tomography angiography. association for
research in vision and ophthalmology (ARVO) abstract 5505 – c0109; 2016; Seattle.
Kuehlewein L, Bansal M, Lenis TL, et al. Optical coherence tomography angiography of type
1 neovascularization in age-related macular degeneration. Am J Ophthalmol 2015;160(4):
739–748.e732.
Matsunaga DR, Yi JJ, De Koo LO, et al. Optical coherence tomography angiography of dia-
betic retinopathy in human subjects. Ophthalmic Surg Lasers Imaging Retina 2015;46(8):
796–805.
Spaide RF, Fujimoto JG, Waheed NK. Image artifacts in optical coherence tomography angi-
ography. Retina 2015;35(11):1–18.
Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiog-
A raphy and optical coherence tomography angiography. JAMA Ophthalmol 2015;133(1):45.
Tan PE, Balaratnasingam C, Xu J, et al. Quantitative comparison of retinal capillary images
derived by speckle variance optical coherence tomography with histology. Invest Oph-
thalmol Vis Sci 2015;56(6):3989–96.
Zhang A, Zhang Q, Chen CL, et al. Methods and algorithms for optical coherence
tomography-based angiography: a review and comparison. J Biomed Opt 2015;20(10):
100901.
Zhang A, Zhang Q, Wang RK. Minimizing projection artifacts for accurate presenta-
tion of choroidal neovascularization in OCT micro-angiography. Biomed Opt Express
2015;6(10):4130–43.
Fig. 6.8.4 Illustration of choroidal neovascularization (CNV) in a subject with

neovascular age-related macular degeneration (AMD). (A) OCTA image of
choriocapillaris slab demonstrates large caliber and irregularly organized vessels in
the CNV complex. (B) B-scan illustrates the boundaries of the OCTA slab shown in
the above panel and location of the CNV within the retinal profile. Images are from
an AngioPlex device.
461
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REFERENCES 31. Kim AY, Chu Z, Shahidzadeh A, et al. Quantifying microvascular density and morphol-
ogy in diabetic retinopathy using spectral-domain optical coherence tomography angiog-
1. Drexler W, Fujimoto JG. State-of-the-art retinal optical coherence tomography. Prog Retin
Eye Res 2008;27(1):45–88.
raphy. Invest Ophthalmol Vis Sci 2016;57(9):OCT362–70.
32. Adhi M, Filho MAB, Louzada RN, et al. Retinal capillary network and foveal avascular
6.8
2. Pircher M, Hitzenberger CK, Schmidt-Erfurth U. Polarization sensitive optical coherence zone in eyes with vein occlusion and fellow eyes analyzed with optical coherence tomog-
raphy angiography. Invest Ophthalmol Vis Sci 2016;57(9):OCT486–9.

tomography in the human eye. Prog Retin Eye Res 2011;30(6):431–51.
3. Kim J, Brown W, Maher JR, et al. Functional optical coherence tomography: principles 33. Rispoli M, Savastano MC, Lumbroso B. Capillary network anomalies in branch retinal
and progress. Phys Med Biol 2015;60(10):R211–37. vein occlusion on optical coherence tomography angiography. Retina 2015;35(11):2332–8.
4. Schwartz DM, Fingler J, Kim DY, et al. Phase-variance optical coherence tomography: a 34. Dimitrova G, Chihara E, Takahashi H, et al. Quantitative retinal optical coherence
technique for noninvasive angiography. Ophthalmology 2014;121(1):180–7. tomography angiography in patients with diabetes without diabetic retinopathy. Invest
5. Wang R, Ma Z, SJ K. Tissue Doppler optical coherence elastography for real time strain Ophthalmol Vis Sci 2017;58(1):190–6.
rate and strain mapping of soft tissue. Appl Phys Lett 2006;89(144103). 35. Akil H, Huang AS, Francis BA, et al. Retinal vessel density from optical coherence
6. Wang R, Kirkpatrick S, Hinds M. Phase sensitive optical coherence elastography for tomography angiography to differentiate early glaucoma, pre-perimetric glaucoma and
mapping tissue micro-strains in real time. Appl Phys Lett 2007;90(164105). normal eyes. PLoS ONE 2017;12(2):e0170476.
7. Ferrara D, Waheed NK, Duker JS. Investigating the choriocapillaris and choroidal vas- 36. Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. Relationship between optical
culature with new optical coherence tomography technologies. Prog Retin Eye Res coherence tomography angiography vessel density and severity of visual field loss in
2016;52:130–55. glaucoma. Ophthalmology 2016;123(12):2498–508.
8. Zhang A, Zhang Q, Chen CL, et al. Methods and algorithms for optical coherence tomog- 37. Inoue M, Jung JJ, Balaratnasingam C, et al. A comparison between optical coherence
raphy-based angiography: a review and comparison. J Biomed Opt 2015;20(10):100901. tomography angiography and fluorescein angiography for the imaging of type 1 neovas-
9. Bedggood P, Metha A. Direct visualization and characterization of erythrocyte flow in cularization. Invest Ophthalmol Vis Sci 2016;57(9):OCT314–10.
human retinal capillaries. Biomed Opt Express 2012;3(12):3264–77. 38. Kuehlewein L, Bansal M, Lenis TL, et al. Optical coherence tomography angiography
10. Fingler J, Schwartz D, Yang C, et al. Mobility and transverse flow visualization using of type 1 neovascularization in age-related macular degeneration. Am J Ophthalmol
phase variance contrast with spectral domain optical coherence tomography. Opt Express 2015;160(4):739–748.e732.
2007;15(20):12636–53. 39. Moult E, Choi W, Waheed NK, et al. Ultrahigh-speed swept-source oct angiography in
11. Kashani AH, Lee SY, Moshfeghi A, et al. Optical coherence tomography angiography of exudative AMD. Ophthalmic Surg Lasers Imaging Retina 2014;45(6):496–505.
retinal venous occlusion. Retina 2015;35(11):2323–31. 40. Thorell MR, Zhang Q, Huang Y, et al. Swept-source oct angiography of macular telangi-
12. Matsunaga DR, Yi JJ, De Koo LO, et al. Optical coherence tomography angiography ectasia type 2. Ophthalmic Surg Lasers Imaging Retina 2014;45(5):369–80.
of diabetic retinopathy in human subjects. Ophthalmic Surg Lasers Imaging Retina 41. Levison AL, Baynes KM, Lowder CY, et al. Choroidal neovascularisation on optical coher-
2015;46(8):796–805. ence tomography angiography in punctate inner choroidopathy and multifocal choroid-
13. Ishibazawa A, Nagaoka T, Takahashi A, et al. Optical coherence tomography angiography itis. Br J Ophthalmol 2017;101(5):616–22.
in diabetic retinopathy: a prospective pilot study. Am J Ophthalmol 2015;160(1):1–11. 42. Bonini Filho MA, de Carlo TE, Ferrara D, et al. Association of choroidal neovasculariza-
14. Hwang TS, Jia Y, Gao SS, et al. Optical coherence tomography angiography features of tion and central serous chorioretinopathy with optical coherence tomography angiogra-
diabetic retinopathy. Retina 2015;35(11):2371–6. phy. JAMA Ophthalmol 2015;133(8):899–906.
15. Mendis KR, Balaratnasingam C, Yu P, et al. Correlation of histologic and clinical images 43. Huang D, Jia Y, Rispoli M, et al. Optical coherence tomography angiography of time
to determine the diagnostic value of fluorescein angiography for studying retinal capil- course of choroidal neovascularization in response to anti-angiogenic treatment. Retina
lary detail. Invest Ophthalmol Vis Sci 2010;51(11):5864–9. 2015;35(11):2260–4.
16. Yannuzzi LA. Indocyanine green angiography: a perspective on use in the clinical setting. 44. Coscas G, Lupidi M, Coscas F, et al. Optical coherence tomography angiography during
Am J Ophthalmol 2011;151(5):745–51.e741. follow-up: qualitative and quantitative analysis of mixed type I and II choroidal neo-
17. Ho AC, Yannuzzi LA, Guyer DR, et al. Intraretinal leakage of indocyanine green dye. vascularization after vascular endothelial growth factor trap therapy. Ophthalmic Res
Ophthalmology 1994;101(3):534–41. 2015;54(2):57–63.
18. Stitt AW, Gardiner TA, Archer DB. Histological and ultrastructural investigation of retinal 45. Coscas GJ, Lupidi M, Coscas F, et al. Optical coherence tomography angiography versus
microaneurysm development in diabetic patients. Br J Ophthalmol 1995;79(4):362–7. traditional multimodal imaging in assessing the activity of exudative age-related macular
19. Ploner SB, Moult EM, Choi W, et al. Toward quantitative optical coherence tomography degeneration: a new diagnostic challenge. Retina 2015;35(11):2219–28.
angiography: visualizing blood flow speeds in ocular pathology using variable interscan 46. Costanzo E, Miere A, Querques G, et al. Type 1 choroidal neovascularization lesion
time analysis. Retina 2016;36(Suppl. 1):S118–26. size: indocyanine green angiography versus optical coherence tomography angiography.
20. Kwiterovich KA, Maguire MG, Murphy RP, et al. Frequency of adverse systemic reac- Invest Ophthalmol Vis Sci 2016;57(9):OCT307–13.
tions after fluorescein angiography. Results of a prospective study. Ophthalmology 47. Agemy SA, Scripsema NK, Shah CM, et al. Retinal vascular perfusion density mapping
1991;98(7):1139–42. using optical coherence tomography angiography in normals and diabetic retinopathy
21. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography complication survey. patients. Retina 2015;35(11):2353–63.
Ophthalmology 1986;93(5):611–17. 48. Zahid S, Dolz-Marco R, Freund KB, et al. Fractal dimensional analysis of optical coher-
22. Weinhaus RS, Burke JM, Delori FC, et al. Comparison of fluorescein angiography with ence tomography angiography in eyes with diabetic retinopathy. Invest Ophthalmol Vis
microvascular anatomy of macaque retinas. Exp Eye Res 1995;61(1):1–16. Sci 2016;57(11):4940–8.
23. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluores- 49. Hwang TS, Gao SS, Liu L, et al. Automated quantification of capillary nonperfusion
cein angiography and optical coherence tomography angiography. JAMA Ophthalmol using optical coherence tomography angiography in diabetic retinopathy. JAMA Oph-
2015;133(1):45. thalmol 2016;134(4):367–73.
24. Matsunaga D, Yi J, Puliafito CA, et al. OCT angiography in healthy human subjects. 50. Koulisis N, Kim AY, Chu Z, et al. Quantitative microvascular analysis of retinal venous
Ophthalmic Surgery, Lasers and Imaging Retina 2014;45(6):510–15. occlusions by spectral domain optical coherence tomography angiography. association
25. Spaide RF, Fujimoto JG, Waheed NK. Image artifacts in optical coherence tomography for research in vision and ophthalmology (ARVO) abstract 5505 – c0109; 2016; Seattle.
angiography. Retina 2015;35(11):1–18. 51. Sellam A, Glacet-Bernard A, Coscas F, et al. Qualitative and quantitative follow-up using
26. Hwang TS, Zhang M, Bhavsar K, et al. Visualization of 3 distinct retinal plexuses by optical coherence tomography angiography of retinal vein occlusion treated with anti-
projection-resolved optical coherence tomography angiography in diabetic retinopathy. vegf. Retina 2017;37(6):1176–84.
JAMA Ophthalmol 2016;134(12):1411–19. 52. Ghasemi Falavarjani K, Iafe NA, Hubschman JP, et al. Optical coherence tomography
27. Zhang A, Zhang Q, Wang RK. Minimizing projection artifacts for accurate presenta- angiography analysis of the foveal avascular zone and macular vessel density after anti-
tion of choroidal neovascularization in OCT micro-angiography. Biomed Opt Express vegf therapy in eyes with diabetic macular edema and retinal vein occlusion. Invest Oph-
2015;6(10):4130–43. thalmol Vis Sci 2017;58(1):30–4.
28. de Carlo TE, Chin AT, Bonini Filho MA, et al. Detection of microvascular changes in eyes 53. Samara WA, Shahlaee A, Sridhar J, et al. Quantitative optical coherence tomography
of patients with diabetes but not clinical diabetic retinopathy using optical coherence angiography features and visual function in eyes with branch retinal vein occlusion. Am
tomography angiography. Retina 2015;35(11):2364–70. J Ophthalmol 2016;166:76–83.
29. Tan PE, Balaratnasingam C, Xu J, et al. Quantitative comparison of retinal capillary 54. Kim AY, Rodger DC, Shahidzadeh A, et al. Quantifying retinal microvascular changes in
images derived by speckle variance optical coherence tomography with histology. Invest uveitis using spectral-domain optical coherence tomography angiography (SD-OCTA).
Ophthalmol Vis Sci 2015;56(6):3989–96. Am J Ophthalmol 2016;171:101–12.
30. Nemiroff J, Kuehlewein L, Rahimy E, et al. Assessing deep retinal capillary ischemia 55. Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. Optical coherence tomography
in paracentral acute middle maculopathy by optical coherence tomography angiography. angiography vessel density in healthy, glaucoma suspect, and glaucoma eyes. Invest Oph-
Am J Ophthalmol 2016;162:121–32.e121. thalmol Vis Sci 2016;57(9):OCT451–9.
461.e1
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Retinal Electrophysiology
Elias Reichel, Kendra Klein 6.9
strength in candela-seconds per meter squared [cd/s/m2]) and the adap-
Definition: Objective functional ancillary testing of the retina and/ tation state3 (Fig. 6.9.1). In preparation, the pupils should be maximally
or retinal pigment epithelium (RPE) that records electrical responses dilated, and the pupil size should be noted before and after the responses
based on various stimuli and assists in the diagnosis and management are recorded. Prior to recording scotopic electroretinograms, the patient
of various retinal diseases, especially inherited retinal dystrophies, should have 20 minutes of dark adaptation, and prior to recording scoto-
autoimmune disorders, inflammations, and medication toxicities. pic electroretinograms, the patient should have 10 minutes of light adap-
tation. Following dark adaptation, weaker flashes of light stimuli should
be presented prior to stronger flashes. Likewise, fluorescein angiography
(FA) and fundus photography should be avoided directly prior to testing.
Key Features Contact electrodes (connected to the positive input) are utilized and
• Electroretinography (ERG) records the electrical response evoked include corneal contact lenses, conjunctival conductive fibers, and lower
from the entire retina by a brief flash of light and consists of an eyelid skin electrodes. The cornea is protected with nonirritating conduc-
a-wave, which represents the photoreceptor response, and a b-wave, tive solution, and topical anesthesia is employed, as necessary. Reference
which represents the combined response of the Müller and bipolar electrodes (connected to the negative input) are incorporated either as a
cells. contact lens–speculum assembly or as skin electrodes placed near each
• The multifocal ERG (mfERG) is a record of multiple local ERG orbital rim. A separate electrode is used as the common electrode and is
responses elicited from the central 40° of the retina. attached to the earlobe, mastoid, or forehead. Full-field (Ganzfeld) stim-
• Electrooculography (EOG) records the standing electrical potential ulation is used for uniform retinal illumination with a fixation spot. The
generated by the RPE. maximum flash duration is 5 milliseconds (ms). The flash strength for
• The International Society for Clinical Electrophysiology of Vision ERG testing is described in units of cd/s/m2, with a weak flash stimulus
(ISCEV) provides worldwide standardized clinical protocols for strength of 0.010 photopic cd/s/m2, a standard flash stimulus of 3 cd/s/
electrophysiological testing, including guidelines for ERG, mfERG, and m2, and a strong flash stimulus of 10 photopic cd s m−2. Light adaptation
EOG testing. and background luminance are set at 30 cd/s/m2. Stimulus and response
names are described by the state of light adaptation and the flash strength
in photopic cd/s/m2.3
INTRODUCTION Normal values for full-field ERG vary by laboratory, so normal intralab-
oratory value ranges should be given with every ERG report, and reference
Electrophysiology encompasses several objective examination techniques values should be adjusted for age. Ocular pigmentation, high refractive
that measure the function of the retina by measuring action potentials errors, and time of recording should be noted.3
caused by particular patterns of light stimulation within the retina. Clinical An electrophysiological response may be affected in both amplitude
electroretinography (ERG) is useful to determine the existence of retinal and/or timing (Fig. 6.9.2). The a-wave amplitude is measured from the
degenerative conditions caused by hereditary, toxic, metabolic, retinal vas- prestimulus baseline to the a-wave trough, and the b-wave amplitude is
cular, or inflammatory etiologies, being particularly valuable in determin- measured from the a-wave trough to the b-wave peak. Timing includes the
ing the abnormal nature of what clinically appears to be a normal retina. peak time (also called implicit time, t) and is measured from the time of the
Full-field ERG represents a mass-evoked response of the outer retinal flash to the peak of the wave of interest (see Fig. 6.9.2, arrows). The ampli-
layers, which reflects total retinal function. The multifocal (mf)–ERG tude of a flicker ERG is measured from the trough to the peak of a typical
represents a cone-generated response of localized retinal function in the wave, and the implicit time is measured from the midpoint of the stimu-
central macula, which is useful in establishing the presence of macular lus to the following peak. With regard to measuring oscillatory potentials,
dysfunction. Electro-oculography (EOG) represents the standing electrical most clinical applications are noting the presence and waveform of the
potential of the entire eye, which reflects the pigment epithelium. These peaks in comparison with reference data.3
electrophysiological results should be considered in conjunction with Full-field ERG can establish loss of retinal function in pathological
those of complete medical and ophthalmic evaluations, including a careful states, exhibited as alterations in amplitude and timing of the recorded
history and laboratory testing, when indicated.1,2 retinal responses when compared with normative responses and assists in
diagnosis in clinical scenarios that include unexplained loss of peripheral
FULL-FIELD ERG vision, loss of central vision, and nyctalopia.
When retinal degeneration is suspected, full-field ERG can differentiate
The full-field, or Ganzfeld, ERG measures a mass response generated by between an isolated cone abnormality and a condition that involves both
cells from the entire retina. Photoreceptors generate the initial negative the rods and cones. In addition, full-field ERG can differentiate between
component, or a-wave, whereas Müller cells and bipolar cells are respon- stationary forms of night blindness and progressive degenerations. In
sible for the later, positive, b-wave. Both a-wave and b-wave are best illus- cone-rod dystrophy, photopic (cone) responses are affected more compared
trated in the maximal combined rod-cone response. The ganglion cell layer with scotopic (rod) responses; the reverse is true in rod-cone dystrophy.
does not contribute to the ERG. The full-field ERG is useful for establish- However, as each of these dystrophies progresses, both rods and cones
ing generalized loss of rod or cone function, or both. Patients who have can become affected.4 In retinitis pigmentosa, for example, the earliest
focal macular disorders do not have abnormalities of full-field ERG ampli- sign of retinal damage is a delayed cone implicit time. As the disease pro-
tude, nor do patients who have diseases of the inner retina, optic nerve, or gresses, however, the ERG demonstrates both markedly reduced rod and
cortical conditions.1,2 cone responses to bright flash and a markedly reduced cone response to a
Starting in 1989, the International Society for Clinical Electrophysi- 30-hertz (Hz) flicker. Late in the disease course, responses are often non-
ology of Vision (ISCEV) has put forth standardized basic ERG protocols recordable5 (Fig. 6.9.3).
to allow comparison across laboratories, and these protocols are periodi- Full-field ERG testing can be helpful in diagnosing various systemic
462 cally updated. The most recent ISCEV standard for full-field clinical ERG conditions that result in loss of retinal function, such as autoimmune
includes six protocols, which are named according to the stimulus (flash retinopathy, vitamin A deficiency, and various drug toxicities.6 Full-field
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SIX BASIC ERGS DEFINED BY THE ISCEV STANDARD 6.9
Dark-adapted 0.01 ERG Dark-adapted 3.0 ERG Dark-adapted 10.0 ERG Dark-adapted 3.0
(rod response) (combined rod-cone response) oscillatory potentials
peak time
(t)
b 100 µV
b
a a 20 ms 30 µV
10 ms
t t
A B C D
Light-adapted 3.0 ERG Light-adapted 3.0 flicker

(cone response)
b t
100 µV
20 ms
E a F
Fig. 6.9.1 Normal Full-Field Electroretinography (ERG) Responses. The six basic ERG responses are depicted for a normal individual. After a minimum dark adaptation
time of 20 minutes, the dark-adapted or scotopic responses (top four diagrams, A–D) are obtained. (A) The dark-adapted 0.01 ERG (rod response) is obtained using a
dim white flash stimulus of 0.01 cd/s/m2 with a minimum interval of 2 seconds between flashes. (B) The dark-adapted 3.0 ERG (maximal combined rod-cone response) is
obtained with a white flash stimulus of 3.0 cd/s/m2 with a minimum interval of 10 seconds between flashes. (C) The dark-adapted 10.0 ERG is obtained with a white flash
stimulus of 10.0 cd/s/m2 with a minimal interval of 20 seconds between flashes. (D) The dark-adapted 3.0 oscillatory potentials are obtained with a white flash stimulus
of 3.0 cd/s/m2 using high- and low-pass filters. (E–F) After a minimum light adaptation time of 10 minutes, the light-adapted or photopic responses are obtained with a
background luminance of 30 cd/s/m2. (E) The light-adapted 3.0 ERG (single flash cone response) is obtained with a white flash stimulus of 3.0 cd/s/m2 with a minimum
interval of 0.5 seconds between flashes. (F) The light-adapted 3.0 flicker ERG (30-Hz flicker) is obtained with a white flash stimulus of 3.0 cd/s/m2 with a flash rate of 30
stimuli per second. (From McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R. ISCEV standard for full-field clinical electroretinography [2015 update]. Doc
Ophthalmol 2015;130:1–12. Figure 1.)
FULL-FIELD ELECTRORETINOGRAMS OF AN
AMPLITUDE AND TIMING IN FULL FIELD ELECTRORETINOGRAM INDIVIDUAL WHO HAS RETINITIS PIGMENTOSA
Dark-adapted 0.01 ERG (rod response)
Scotopic 0.01 ERG Scotopic 3.0 ERG
100 V/
division
100 µV 100 µV
0 50 100 150 200 250ms 0 50 100 150 200 250ms

A B
A 10 ms/division
Fig. 6.9.2 Illustration of Amplitude and Timing on Full-Field Electroretinogram.
(A) Dark-adapted 0.01 ERG or rod response illustrates latency (dashed black line) and Light-adapted 3.0 flicker ERG (30 Hz flicker)
implicit time, τ (dashed red line). (B) Dark-adapted 3.0 ERG or maximal combined
rod-cone response illustrates both a-wave (solid black line) and b-wave (solid red line) 50 V/
amplitudes.
division
ERG likewise is useful in evaluating activity in certain uveitic conditions,

such as birdshot chorioretinopathy, multiple evanescent white dot syn-
drome (MEWDS), and acute posterior multiple placoid pigment epitheli-
opathy (APMPPE).7 Additionally, full-field ERG testing has a role in ocular
trauma in establishing a diagnosis of siderosis when an iron-containing on
small metallic intraocular foreign body is suspected, and serial ERGs can
be helpful in monitoring the health of the retina in these cases.6
In a number of retinal conditions, inner retinal dysfunction is a predom- B 10 ms/division
inant feature. In these cases, many of which lack defining fundus features,
ERG can be crucial for accurate diagnosis. Particular inherited conditions, Fig. 6.9.3 Full-Field Electroretinogram in Retinitis Pigmentosa. (A) Dark-adapted
such as congenital stationary night blindness and X-linked retinoschisis, 0.01 ERG or rod response to a single flash of bright white light is diminished
have “electronegative” ERG, in which the waveform to a high-intensity markedly, consistent with the diagnosis of a retinal degeneration. (B) The light- 463
flash under scotopic conditions has a preserved a-wave with a selectively adapted 3.0 flicker ERG (30 Hz flicker) is completely extinguished.
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reduced b-wave. Likewise, several acquired conditions, such as central
6 retinal artery occlusion, ischemic central retinal vein occlusion, diffuse 3-Dimensional Topographic Plot
unilateral subacute neuroretinitis, and melanoma-associated retinopathy
can demonstrate this distinct ERG phenotype along with retinotoxicities
from vigabatrin, methanol, and quinine. In these disorders, the selective
Retina and Vitreous
b-wave reduction highlights the predominance of post-photoreceptor inner

retinal dysfunction.6
Although an ERG phenotype may often be nonspecific, there are a few
instances in which electrophysiological responses are pathognomonic for
a particular disease. One such disease is cone dystrophy with supernor-
mal rod ERG, a recessively inherited disorder with an underlying genetic
defect in KCNV2. The electroretinogram is characterized by reduced
and delayed photopic responses, reduced and delayed dim flash scotopic
responses, and a disproportionate increase in b-wave amplitude with rel-
atively small increases in stimulus intensity. The dark-adapted 11.0 ERG
has a normal a-wave slope with a broadened and squared shape with a late
S
negative a-wave peak. In enhanced S-cone syndrome, a recessively inher- N T
ited disorder associated with a mutation in NR2E3, the scotopic 3.0 ERG, I
although reduced, has a waveform similar to that of the photopic 3.0 ERG,
both of which are dominated by S-cone responses. Further, the S-cone 0 2 4 6 8 10 12 14 nV/deg–2
ERG is markedly increased compared with normal.8 A
Last, in certain clinical scenarios, a normal ERG can provide reassur-
ance to both the patient and the physician.
Trace Array
MULTIFOCAL ERG
Multifocal ERG (mfERG) has supplanted focal ERG testing and records
multiple (61 or 103 hexagons) local ERG responses elicited from the central
40–50° of the retina under light-adapted conditions. These responses are
then displayed individually so that abnormal spatial variations can be local-
ized to their corresponding areas in the macula, perimacula, or remain-
ing posterior pole. Worldwide standardized protocols for mfERG testing
have been set forth by the ISCEV. mfERG typically displays both an array
of individual mfERG traces and a three-dimensional topographic plot9
(Fig. 6.9.4).
Clinically, mfERG is most useful to assess macular function in patients
with unexplained or central loss of vision who may have normal results on
full-field ERG. mfERG can aid in the diagnosis of macular diseases, includ-
ing Stargardt dystrophy, cone dystrophy, and occult macular dystrophy.9,10 500 nV
Multifocal ERG plays an important role in the assessment of drug-
induced retinopathy, particularly chloroquine and hydroxychloroquine
toxicity. The 2011 American Academy of Ophthalmology revised screen- 0 80 ms
ing recommendations for chloroquine and hydroxychloroquine toxicity B
recommended addition of at least one objective test, such as mfERG,
spectral-domain optical coherence tomography, or fundus autofluores- Fig. 6.9.4 Normal Multifocal Electroretinogram. (A) Three-dimensional
cence to be used with 10-2 automated visual fields. Further, recommen- topographic plot. (B) Trace array.
dations specified that mfERG could be used in place of visual fields. Most
commonly, mfERG demonstrates a paracentral ring depression of signals
around the fovea. This can be followed by central amplitude reduction
and widespread depression in advanced retinopathy. In patients taking the
medications mentioned above, mfERG can be a quantitative measure of
retinal function, potentially providing a more sensitive objective test com- KEY REFERENCES
pared with other modalities, allowing earlier recognition of dysfunction.11,12 Arden GB, Constable PA. The electro-oculogram. Prog Retin Eye Res 2006;25(2):207–48.
Arden GB, Fojas MR. Electrophysiological abnormalities in pigmentary degenerations of the
retina. Assessment of value and basis. Arch Ophthalmol 1962;68:369–89.
ELECTRO-OCULOGRAPHY Audo I, Robson AG, Holder GE, et al. The negative ERG: clinical phenotypes and disease
mechanisms of inner retinal dysfunction. Surv Ophthalmol 2008;53(1):16–40.
EOG measures the difference in electrical potential between the front Berson EL, Sandberg MA, Maguire A, et al. Electroretinograms in carriers of blue cone
and the back of the eye, which is mostly a function of the retinal pigment monochromatism. Am J Ophthalmol 1986;102(2):254–61.
epithelium (RPE) and regulated, in part, by the bestrophin gene. EOG Hood DC, Bach M, Brigell M, et al. ISCEV standard for clinical multifocal electroretinogra-
phy (mfERG) (2011 edition). Doc Ophthalmol 2012;124(1):1–13.
is performed by placing electrodes on the skin of the medial and lateral McCulloch DL, Marmor MF, Brigell MG, et al. ISCEV standard for full-field clinical electro-
canthal angles of each eye, in addition to placing a ground electrode on the retinography (2015 update). Doc Ophthalmol 2015;130:1–12.
forehead. The electric potential across the eye is recorded as the patient’s Moschos MM, Gouliopoulos NS, Kalogeropoulous C. Electrophysiological examination in
eyes move back and forth horizontally under both dark (scotopic) and uveitis: a review of the literature. Clin Ophthalmol 2014;8:199–214.
Riggs LA. Electroretinography in cases of night blindness. Am J Ophthalmol 1954;38(1:2):70–8.
light (photopic) conditions. Clinical EOG is represented as an Arden ratio
Sutter EE, Tran D. The field topography of ERG components in man–I. The photopic lumi-
(light/dark ratio), which is the ratio of the highest amplitude in light to the nance response. Vision Res 1992;32(3):433–46.
lowest amplitude in dark. Normal values should exceed 1.5. Clinically, EOG Vincent A, Robson AG, Holder GE. Pathognomonic (diagnostic) ERGs: a review and update.
is most useful in aiding the diagnosis of Best disease and differentiating Retina 2013;33(1):5–12.
this entity from adult-onset vitelliform macular dystrophy and pattern dys-
trophy. Worldwide standardized protocols for EOG testing are have been Access the complete reference list online at ExpertConsult.com
set forth by the ISCEV.13,14
464
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REFERENCES 8. Vincent A, Robson AG, Holder GE. Pathognomonic (diagnostic) ERGs: a review and
update. Retina 2013;33(1):5–12.
1. Holmgren F. Metod att objectivera effecten af ljusintryck pa retina. Upsala Lakareforen
Forh 1865;1:184.
9. Hood DC, Bach M, Brigell M, et al. ISCEV standard for clinical multifocal electroretinog-
raphy (mfERG) (2011 edition). Doc Ophthalmol 2012;124(1):1–13.
6.9
2. Creel DJ. Clinical electrophysiology. In: Kolb H, Fernandez E, Nelson R, editors. Webvi- 10. Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced
by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol 2007;143(5):
sion: the organization of the retina and visual system [internet]. Salt Lake City: University
of Utah Health Sciences Center; 1995–2005 May 1 [Updated 2007 Jul 2]. 801–9.
3. McCulloch DL, Marmor MF, Brigell MG, et al. ISCEV standard for full-field clinical elec- 11. Dettoraki M, Moschos MM. The role of multifocal electroretinopathy in the assess-
troretinography (2015 update). Doc Ophthalmol 2015;130:1–12. ment of drug-induced retinopathy: a review of the literature. Ophthalmic Res 2016;56:
4. Riggs LA. Electroretinography in cases of night blindness. Am J Ophthalmol 169–77.
1954;38(1:2):70–8. 12. Tsang AC, Pirshahid SA, Virgili G, et al. Hydroxychloroquine and chloroquine retino-
5. Iijima H, Yamaguchi S, Hosaka O. Photopic electroretinogram implicit time in retinitis pathy: a systematic review evaluating the multifocal electroretinogram as a screening
pigmentosa. Jpn J Ophthalmol 1993;37(2):130–5. test. Ophthalmology 2015;122:1239–51.
6. Audo I, Robson AG, Holder GE, et al. The negative ERG: clinical phenotypes and disease 13. Marmor MF, Brigell MG, McCulloch DL, et al. ISCEV standard for clinical electro-ocu-
mechanisms of inner retinal dysfunction. Surv Ophthalmol 2008;53(1):16–40. lography (2010 update). Doc Ophthalmol 2011;122(1):1–7.
7. Moschos MM, Gouliopoulos NS, Kalogeropoulous C. Electrophysiological examination 14. Arden GB, Constable PA. The electro-oculogram. Prog Retin Eye Res 2006;25(2):
in uveitis: a review of the literature. Clin Ophthalmol 2014;8:199–214. 207–48.
464.e1
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Section 3 Basic Principles of Retinal Surgery
Light and Laser Injury

Caroline R. Baumal 6.10
to the retina and choroid during laser photocoagulation. Photochemical or
Definition: Structural damage to the retina produced by a light phototoxic effects occur with low-to-moderate irradiances that are below
source. coagulation thresholds and with shorter wavelengths, in particular UV
and visible blue wavelengths. Damage to cellular components occurs at
temperatures too low to cause thermal destruction, which may account
Key Features for a delay of 24–48 hours before the appearance of a lesion. Absorption
of a photon by the outer electrons of a molecule produces an excited
• Mechanism of damage is often photochemical. molecular state, which can drive a chemical reaction. Because the energy
• Thermal enhancement of retinal damage is possible. per photon is inversely proportional to its wavelength, short-wavelength
• Sources include solar eclipse, welding arc, operating microscope, and photons have more energy with which to induce a photochemical reac-
handheld laser pointer.
tion. Long-wavelength visible light also can induce photochemical changes
when tissues are sensitized by an exogenous photosensitizer, as with pho-
todynamic therapy. At intermediate values of irradiance and exposure,
Associated Features more than one of the above mechanisms may be in effect.
• Delayed appearance of the lesion after the injury by hours to days. The ocular media transmit 75%–90% of electromagnetic radiation in
• Variable recovery of vision. the range of 400–1064 nm.4 Several mechanisms exist to reduce retinal
• Severity of damage proportional to duration and intensity of light exposure. The cornea absorbs most UVB (280–315 nm) and UVC
exposure. (<280 nm), as well as some IR radiation, and reflects up to 60% of inci-
dent light that is not perpendicular to its surface.4 The lens absorbs most
UVA (315–400 nm) and visible blue wavelengths. Intrinsic ocular defenses
INTRODUCTION against retinal light damage include xanthophyll absorption of near-UV
and blue light to protect photoreceptors, temperature control by the choroi-
The potentially damaging effects of light on the retina have been recog- dal circulation, intracellular molecular detoxification of free radicals, and
nized since the time of Plato, who described eclipse blindness. Breakdown retinal pigment epithelium (RPE)–mediated photoreceptor renewal.5 Phys-
of the intrinsic ocular protective mechanisms and/or exposure to external iological protective mechanisms include squint and blink reflexes, eyebrow
high-risk conditions can produce light or photic damage to the retina. The ridge, aversion response, and pupillary miosis. Light damage to the retina
development and severity of light-induced damage depends on a number may occur when protective mechanisms are impaired or as a result of
of factors, including ocular anatomical protective mechanisms, area of deliberate gazing at a light source. Young patients may be at increased risk
tissue involved, and the parameters of the light source, such as the wave- because of efficient light transmission through clear ocular media.
length, duration of exposure, and the total energy exposure.
PHOTIC RETINOPATHY
LIGHT INTERACTION WITH THE RETINA Photic retinopathy is a general term for light-induced retinal damage. It is
The eye primarily perceives radiation in the optical spectrum, comprising most often caused by inadvertent exposure. The mechanism is typically
the visible (400–760 nm), ultraviolet (UV; 200–400 nm), and infrared (IR; photochemical, with potential enhancement by elevated tissue temperature
>760 nm) wavelengths. Radiation in this region can be produced by the and increased blood oxygen tension.6 Increased chorioretinal pigmentation
sun, ophthalmic instruments, and lasers. facilitates light absorption in the RPE and may elevate the background
Tissue effects produced by light are classified as mechanical, thermal, retinal temperature and thermally enhance photochemical damage. It has
or photochemical and determined by irradiance (watt per square centime- been hypothesized that retinal defenses against toxic free radicals from
ter [W/cm2]), wavelength, duration of light exposure and the absorption light and oxygen are overwhelmed by supranormal light exposure. Damage
of target tissue.1 Table 6.10.1 outlines tissue effects induced by commer- manifests as a disorder of RPE and photoreceptor outer segments.7 Retinal
cial ophthalmic lasers. Mechanical injury results from high irradiance, phototoxic injury was originally considered permanent; however, visual
short-duration exposure in the nanosecond (10−9) to picosecond (10−12) recovery has been noted in solar retinopathy, laser pointer, welding arc, and
range, and the energy strip electrons from molecules and disintegrates operating microscope phototoxicity. Mild photochemical damage may not
target tissue into plasma. This is the mechanism of photodisruption. At mod- be symptomatic or visible ophthalmoscopically, and case reports represent
erate irradiance and exposure greater than 1 microsecond (µsec), thermal the more severe injuries. The extent of retinal injury and the likelihood of
effects result from a critical temperature rise in tissue. Elevation of retinal visual recovery depend on multiple factors, including the location and area
temperature by 10–20°C produces protein denaturation and enzyme inac- of exposed retina, duration, intensity, spectrum of the light source, and
tivation, which results in photocoagulation, cellular necrosis, and hemosta- host susceptibility factors, including age, nutritional status, ocular pigmen-
sis.2,3 Long visible and infrared (IR) wavelengths produce thermal injury tation, core temperature, clarity of ocular media, and pre-existing retinal
disease. Individuals with emmetropia and hyperopia may be at increased
risk caused by effective light focusing on the retina.5 Systemic photosensi-
tizing agents, such as tetracycline and psoralen, may predispose to photo-
TABLE 6.10.1 Tissue Effects Induced by
chemical damage.
Commercial Ophthalmic Lasers
Laser Modality Mechanism of Damage Solar Retinopathy
Argon laser Photocoagulation
Solar retinopathy, which describes retinal injury induced by direct or indi-
Transpupillary therapy (TTT) Photocoagulation
rect solar viewing, is also referred to as foveomacular retinitis, photoretini-
Photodynamic therapy (PDT) Photochemical injury
Neodymium:yttrium–aluminum–garnet (Nd:YAG) laser Photodisruption
tis, and eclipse retinopathy. The harmful effects of solar viewing have been 465
recognized for centuries. Foveomacular retinitis was initially described
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as bilateral decreased vision and foveal lesions in military persons after rod outer segment changes and scattered RPE degeneration. The good
6 solar viewing.8 Solar retinopathy has been associated with religious sun
gazing, solar eclipse observing, telescopic solar viewing, sunbathing, psy-
chiatric disorders, and psychotropic drug use.9 Solar radiation induces
visual prognosis has been attributed to the resistance of the foveal cones to
photochemical damage.13
Eclipse retinopathy describes similar macular damage after solar eclipse
photochemical retina damage, which may be enhanced by elevated tissue viewing. Evaluation of visual morbidity associated with the full solar
Retina and Vitreous
temperature. Direct solar observation through a 3-mm pupil produces a eclipse on August 11, 1999, demonstrated abnormal macular appearance
4°C temperature rise, which is below thermal damage thresholds.3 Sus- in 84% of symptomatic patients with rare cases of persistent symptoms.14,15
tained solar viewing for more than 90 seconds through a constricted pupil Excessive light exposure in rats has been shown to induce irreversible neu-
exceeds the threshold for photochemical retinal damage.10 Solar observa- ronal apoptosis of retinal cells, which may account for permanent visual
tion through a dilated 7-mm pupil produces a 22°C increase in retinal tem- impairment as well as gliovascular responses, which may be responsible
perature, which is above photocoagulation thresholds.3 for the transient clinical symptoms.16
Symptoms usually develop 1–4 hours after solar exposure and may No specific therapy exists for solar retinopathy. Further episodes of solar
include unilateral or bilateral decreased vision, metamorphopsia, sco- viewing should be discouraged. Eclipse viewing without proper protective
tomata, chromatopsia, photophobia, afterimage, and periorbital ache. eyewear with tested solar filters should be discouraged. Oral corticoster-
Acuity ranges from 20/40–20/200 acutely. A small yellow spot with a gray oids have been used to treat acute lesions, but their beneficial effect
margin measuring up to 200 µm may develop in the parafoveal area cor- has not been demonstrated conclusively because vision often improves
responding to the image of the sun (Fig. 6.10.1A).3,9 A lesion may not be spontaneously.
visible in mild cases. Histopathology of acute solar retinopathy demon-
strates RPE injury with necrosis, detachment, irregular pigmentation, and Welding Arc Exposure
minimal photoreceptor damage.11 Fluorescein angiography (FA) may be
normal or reveal RPE transmission defects (see Fig. 6.10.1B). The yellow Welding arcs emit radiation, and the most common injury is keratitis
lesion is replaced by focal depression with RPE mottling or lamellar hole caused by corneal absorption of UV rays. Retinal injury is rare but can
and vision usually improves to 20/20–20/40 within 6 months, although occur after a welding arc viewing without proper ocular protection.17 The
scotomata or metamorphopsia can persist. Optical coherence tomogra- retinal temperature increase is below photocoagulation thresholds, and
phy (OCT; see Fig. 6.10.1C) demonstrates disrupted reflectivity in the injury is produced by photochemical effects from UV and short blue wave-
outer retina and ellipsoid layer.12 Ultrastructural findings in experimen- length exposure. The symptoms and clinical course are similar to solar
tally induced solar retinopathy have demonstrated parafoveal cone and retinopathy. A yellow edematous foveal lesion develops acutely (Fig. 6.10.2),
A B
466 Fig. 6.10.1 Solar Retinopathy. In the right eye (A) and left eye (B), of the same patient. (C) Fluorescein angiography of solar retinopathy in the left eye. Transmission
hyperfluorescence corresponds to the retinal pigment epithelium defect. (D) Optical coherence tomography of solar retinopathy, left eye.
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6.10

A B
Fig. 6.10.2 Optical Coherence Tomography of Welding Arc Retinopathy That Occurred After Shield Failure. (A) Right eye. (B) Left eye.
A B
Fig. 6.10.3 Acute Retinal Phototoxicity, 2 Weeks After Cataract Surgery. (A) Perifoveal fluorescein mottling in the early-stage angiogram. (B) Modest fluorescein leakage
and retinal pigment mottling in the late phase. Visual acuity is 20/60. (Courtesy Gordon A. Byrnes, MD.)
which is replaced over time by RPE irregularity or lamellar hole. No effec- vitreous surgery.7 The most frequent cause is the operating microscope
tive therapy exists, and vision usually improves with time, with permanent as initially described after uncomplicated extracapsular cataract extraction,
vision effects being rare. with reported incidence ranging from 0% to 7%.21–23 The mechanism of
Phototoxicity has also been described following brief incidental light intraoperative phototoxicity is photochemical, with potential thermal
exposure from camera flashes or welding arcs in four patients who were enhancement. Because operating microscopes generate little UV radiation,
taking photosensitizing drugs (hydrochlorothiazide, furosemide, allopuri- photochemical damage probably is caused by short-wavelength visible blue
nol, and benzodiazepines).18 and green light. The incorporation of UV and IR filters in the intraocular
lens (IOL) and microscope may reduce, but do not completely eliminate,
Lightning Maculopathy the risk of photic and thermal effects, respectively, as demonstrated by
experimentally induced human photic retinal injury in a blind phakic eye
Lightning maculopathy describes acute visual loss and macular changes after 60 minutes of operating microscope exposure with UV and IR filtered
after lightning injury. Vision loss may be severe to light perception light.24
and lesions may include macular edema, macular hole, cyst, or a solar Few patients show symptoms immediately after exposure, and the level
retinopathy–like picture, cataract, retinal detachment, retinal artery occlu- of vision depends on lesion size and location. A foveal lesion can produce
sion, and relative afferent pupillary defect.19 Visual recovery often occurs severe permanent vision loss, whereas an eccentric lesion is compatible
over time, even with severe maculopathy. High-dose intravenous methyl- with good acuity and pericentral scotoma. The lesion shape matches the
prednisolone treatment may play a role in vision recovery, and its use was surgical illuminating source. Immediately after exposure, there is little evi-
associated with reversal of lightning-induced blindness in two cases.20 dence of macular pathology but within 24–48 hours, a yellow lesion, mea-
suring 0.5–2.0 disc diameter at the level of the RPE, with retinal edema
develops. FA acutely reveals dye leakage (Fig. 6.10.3), which may simu-
Retinal Phototoxicity From late choroidal neovascularization (CNV). Over weeks, the yellow lesion is
Ophthalmic Instruments replaced by RPE clumping and atrophy (Fig. 6.10.4A), which correspond
angiographically to blocking and transmission defects, respectively (see
Ophthalmologists use a variety of powerful light sources. Retinal injury Fig. 6.10.4B). Other long-term sequelae include postoperative erythrop-
caused by light exposure from the operating microscope and endoillu- sia, retinal surface wrinkling, and choroidal neovascularization.25,26 Mild
mination has been described. Iatrogenic phototoxicity has been reported light-induced retinal injuries may be overlooked clinically because subtle 467
after cataract extraction, combined anterior segment procedures, and postoperative pigmentary changes may be attributable to other causes.
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6
Retina and Vitreous
A B
Fig. 6.10.4 Chronic Retinal Phototoxicity in the Left Eye. (A) Visual acuity is 20/50 (6/15). A well-defined area of retinal pigment epithelium mottling is present. The patient
also has congenital retinal venous tortuosity. (B) Fluorescein angiography reveals blocking and transmission defects without late fluorescein leakage. (Courtesy Gordon A.
Byrnes, MD.)
Histopathology of acute operating microscope–induced injury has not occur with damage caused by solar viewing.11 The relationship between
revealed RPE and photoreceptor damage.27 In primates, early photic lesions light and AMD has been evaluated with epidemiological studies. In the
have demonstrated photoreceptor damage and disruption of RPE tight Chesapeake Bay watermen study, no association was found between cumu-
junctions, with regeneration of photoreceptor outer segments 3–5 months lative UVA or UVB exposure and mild or advanced AMD.31 An association
after injury.26 This may correspond to recovery of vision after injury noted was noted between blue or visible light exposure during the preceding 20
in some human eyes. Operating microscope phototoxicity has been associ- years and the risk of developing advanced AMD.32 In the Beaver Dam Eye
ated with surgical factors, including microscope brightness, wavelength of Study, no association was found between estimated ambient UVB expo-
light exposure, surgical duration, and technique. Retinal phototoxic lesions sure and AMD.33 The amount of outdoor leisure time in summer was
may occur after short-duration (under 30 minutes) phacoemulsification associated with increased retinal pigmentation in men and late AMD in
and were associated with near emmetropia and diabetic retinopathy.28 both men and women. To date, no study has yet conclusively defined the
The risk of photic damage may increase after IOL insertion, which can relationship between long-term UV light exposure and AMD. Until this is
focus incoming light on the retina. Patient susceptibility factors include clarified, sunglasses to filter UV and blue light may be considered for indi-
increased body temperature and blood oxygenation, chorioretinal pigmen- viduals at risk, such as those with pseudo-phakia and those with aphakia
tation, pre-existing maculopathy, pupillary dilatation, diabetes mellitus, who do not wear UV-protective intraocular lenses and individuals with
retinal vascular disease, deficiencies of either ascorbic acid or vitamin A, decreased ocular pigmentation or at risk of AMD.5
and photosensitizer use. Photic damage secondary to endoillumination
during vitrectomy is uncommon and can be avoided by minimizing length
of surgery and light output, filters, maximizing light pipe distance from
LASER INJURY
the retina and using eccentric endoillumination techniques.29 Laser applications in industrial, military, and laboratory situations account
There is no specific treatment for acute lesions, and spontaneous visual for many cases of accidental retinal injury, resulting from either direct
improvement usually occurs within months, even when lesions involve the laser exposure or its reflections. It usually occurs when the laser is fired
macula. Methods to reduce the risk include reduction of coaxial illumina- inadvertently around an individual without ocular protection. The retinal
tion and operative time, use of IR and UV filters in the microscope and tissue damage depends on the laser parameters and ranges from a small,
IOL, placement of an air bubble in the anterior chamber to defocus inci- subtle lesion to macular hole formation and extensive hemorrhage and
dent light, and use of a corneal cover. disruption of the retina and choroid. Accidental foveal photocoagulation
The irradiance produced by the indirect ophthalmoscope and the can produce immediate loss of vision up to 20/200, with a foveal cyst or
fundus camera is lower than experimentally determined retinal injury yellow discoloration of the RPE (Fig. 6.10.5). Long-term evaluation may
thresholds. Furthermore, the total energy delivered to the eye is less under reveal RPE irregularities, epiretinal membrane, macular hole, and gliosis.
nonoperative conditions than in operative conditions. These instruments Recovery of vision is variable and is related to the extent and location of the
have not been shown to produce acute retinal injury in humans; however, initial injury.34 On the basis of findings from animal models, corticoster-
prolonged exposure to the indirect ophthalmoscope has been shown to oids have been variably used to treat laser-induced retinal injuries.
produce lesions in primates. The cumulative effect of repeated examina- Laser operators and persons in the laser vicinity are at risk from
tion is unknown, and it is recommended that retinal examinations be per- laser light scattered from optical interfaces, such as contact lenses and
formed with the minimal illumination required. mirrors; therefore protective goggles should be worn by these individuals.
Lasers for retinal photocoagulation contain filters to protect the operator.
Decreased color discrimination in a tritan color-confusion axis had been
LIGHT EXPOSURE AND AGE-RELATED noted in ophthalmologists who used argon blue-green laser.35 This may
MACULAR DEGENERATION have been caused by chronic exposure to reflections from the argon blue
aiming beam, so currently lasers use either red or green aiming beam to
An association between long-term solar exposure and age-related macular minimize operator risk.
degeneration (AMD) was considered when AMD was found to be less
common in patients with nuclear cataract.30 Histopathology of acute photic LASER POINTERS
injury reveals damage to the macular RPE and photoreceptors, which is
the same tissue depth and geographical location as changes observed in Laser pointers are portable low-energy devices that emit a narrow, coher-
AMD.23 Solar viewing acutely damages the RPE and produces RPE pig- ent, low-powered laser beam. In the United States, lasers are classified
468 mentary irregularities, which are similar in appearance to those in AMD, by American National Standards Institute and the U.S. Food and Drug
although the diffuse thickening of Bruch’s membrane noted in AMD does Administration (FDA) specifications that a handheld laser for use as
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A B
C D
Fig. 6.10.5 Laser Pointer–Induced Macular Injury in a 6-Year-Old Boy. Vision measured 20/200 acutely in
both eyes (OU), and color photograph revealed yellow streaks radiating from the fovea center (A–B). Optical
coherence tomography (OCT) revealed blurring of the ellipsoid and interdigitation zones and opacification
of Henle’s layer (C–D). Three years after the injury, vision improved to 20/40 with residual focal outer retinal F
defect (E–F).
a pointer must be a class 1, 2 (<1 milliwatt [mW]), 2A, or 3A (1–5 mW) of choroidal effusion after extensive panretinal photocoagulation can be
device. In contrast, class 3B lasers generate 5–500 mW, and class 4 lasers reduced by spreading treatment over multiple sessions. Secondary CNV
generate over 500 mW. and hemorrhage caused by damage to Bruch’s membrane can be mini-
Laser pointers are common and have the potential for misuse that could mized by reducing laser intensity and duration and by avoiding small spot
lead to inadvertent ocular exposure and secondary retinal damage.36–40 It is sizes (50 µm).
difficult to produce ocular injury with a low-energy class 3A laser pointer
unless with inappropriate, prolonged, foveal exposure. Certain individual
factors, such as age, pre-existing maculopathy, and clarity of the ocular KEY REFERENCES
media, play a role in determining susceptibility. The mechanism depends Cruickshanks KJ, Klein R, Klein BEK. Sunlight and age-related macular degeneration. The
on the wavelength but appears to be thermal chorioretinal damage or Beaver Dam Eye Study. Arch Ophthalmol 1993;111:514–18.
Jorge R, Costa RA, Quirino LS, et al. Optical coherence tomography findings in patients with
phototoxicity. Handheld lasers are readily available on the Internet from late solar retinopathy. Am J Ophthalmol 2004;137:1139–43.
dubious sources that may not comply with FDA standards, with power Kleinmann G, Hoffman P, Schechtman E, et al. Microscope-induced retinal phototoxicity in
outputs exceeding class 3A, or may have inaccurate device labeling. Hand- cataract surgery of short duration. Ophthalmology 2002;109:334–8.
held devices that exceed recommended standards can produce permanent Lee G, Baumal CR, Lally D, et al. Retinal injury after inadvertent handheld laser exposure.
Retina 2014;34:2388–96.
retinal injury and visual impairment with resultant photoreceptor damage Mainster MA, Ham WT, DeLori FC. Potential retinal hazards. Instrument and environmen-
as shown by optical coherence tomography (OCT).40–42 tal light sources. Ophthalmology 1983;90:927–32.
Damage manifests as unilateral or bilateral transient visual abnormali- McDonnell HR, Irvine AR. Light-induced maculopathy from the operating microscope in
ties, scotoma, and perimacular RPE disturbances.36 OCT reveals acute pho- extracapsular cataract extraction and intraocular lens implantation. Ophthalmology
toreceptor damage and opacification of Henle’s layer, with some recovery 1983;90:945–51.
McGhee CNJ, Crain JP, Moseley H. Laser pointers can cause permanent retinal injury if
of vision over time (see Fig. 6.10.5).41,42 Systemic corticosteroids have been used inappropriately. Br J Ophthalmol 2000;84:229–30.
shown to improve lesions in primate models of laser injury. Priebe LA, Cain CP, Welch AJ. Temperature rise required for the production of minimal
lesions in the Macaca mulatta retina. Am J Ophthalmol 1975;79:405–43.
Weng CY, Baumal CR, Albini TA, et al. Self-induced laser maculopathy in an adolescent boy
COMPLICATIONS OF THERAPEUTIC RETINAL utilizing a mirror. Ophthalmic Surg Lasers Imaging Retina 2015;46:485–8.
White TJ, Mainster MA, Wilson PW, et al. Chorioretinal temperature increases from solar
LASER PHOTOCOGULATION observation. Bull Math Biophys 1971;33:1–17.
Yannuzzi LA, Fisher YL, Krueger A, et al. Solar retinopathy; a photobiological and geophysi-
With proper laser use, complications are rare, but risks and informed cal analysis. Trans Am Ophthalmol Soc 1987;85:120–58.
consent should be discussed with patients when laser is used clinically.
Inadvertent photocoagulation of the fovea, cornea, iris, or lens can be Access the complete reference list online at ExpertConsult.com 469
minimized with careful technique and appropriate laser settings. The risk
booksmedicos.org
REFERENCES 22. Khwarg SG, Linstone FA, Daniels SA, et al. Incidence, risk factors, and morphology in
operating microscope light retinopathy. Am J Ophthalmol 1987;103:255–63.
1. Mainster MA, Ham WT, DeLori FC. Potential retinal hazards. Instrument and environ-
mental light sources. Ophthalmology 1983;90:927–32.
23. Byrnes GA, Chang B, Loose I, et al. Prospective incidence of photic maculopathy after
cataract surgery. Am J Ophthalmol 1995;119:231–2.
6.10
2. Priebe LA, Cain CP, Welch AJ. Temperature rise required for the production of minimal 24. Robertson DM, McLaren JW. Photic retinopathy from the operating microscope. Arch
Ophthalmol 1989;107:373–5.

lesions in the Macaca mulatta retina. Am J Ophthalmol 1975;79:405–43.
3. White TJ, Mainster MA, Wilson PW, et al. Chorioretinal temperature increases from 25. Leonardy NJ, Dabbs CK, Sternberg P Jr. Subretinal neovascularization after operating
solar observation. Bull Math Biophys 1971;33:1–17. microscope burn. Am J Ophthalmol 1990;109:224–5.
4. Boettner EA, Wolter JR. Transmission of the ocular media. Invest Ophthalmol 26. Tso MOM, Woodford BJ. Effect of photic injury on the retinal tissues. Ophthalmology
1962;1:776–83. 1983;90:952–3.
5. Mainster M. Light and macular degeneration: a biophysical and clinical perspective. Eye 27. Green WR, Robertson DM. Pathologic findings of photic retinopathy in the human eye.
1987;1:304–10. Am J Ophthalmol 1991;112:520–7.
6. Lanum J. The damaging effects of light on the retina. Empirical findings. Theoretical and 28. Kleinmann G, Hoffman P, Schechtman E, et al. Microscope-induced retinal phototoxicity
practical implications. Surv Ophthalmol 1978;22:221–49. in cataract surgery of short duration. Ophthalmology 2002;109:334–8.
7. Michels M, Sternberg P Jr. Operating microscope-induced retinal phototoxicity: patho- 29. Van den Biesen PR, Berenschot T, Verdaasdonk RM, et al. Endoillumination during vit-
physiology, clinical manifestations and prevention. Surv Ophthalmol 1990;34:237–52. rectomy and phototoxicity thresholds. Br J Ophthalmol 2000;84:1372–5.
8. Cordes FC. A type of foveo-macular retinitis observed in the US Navy. Am J Ophthalmol 30. Sperduto RD, Hiller R, Seigel D. Lens opacities and senile maculopathy. Arch Ophthal-
1944;27:803–16. mol 1981;99:1004–8.
9. Yannuzzi LA, Fisher YL, Krueger A, et al. Solar retinopathy; a photobiological and geo- 31. West SK, Rosenthal FS, Bressler NM, et al. Exposure to sunlight and other risk factors
physical analysis. Trans Am Ophthalmol Soc 1987;85:120–58. for age-related macular degeneration. Arch Ophthalmol 1989;107:875–9.
10. Sliney DH, Wolbarsht ML. Safety with lasers and other optical sources. A comprehensive 32. Taylor HR, West S, Munoz B, et al. The long-term effects of visible light on the eye. Arch
handbook. New York: Plenum; 1980. Ophthalmol 1992;110:99–104.
11. Tso MOM, LaPiana FG. The human fovea after sungazing. Trans Am Acad Ophthalmol 33. Cruickshanks KJ, Klein R, Klein BEK. Sunlight and age-related macular degeneration.
Otolaryngol 1975;79:788–95. The Beaver Dam Eye Study. Arch Ophthalmol 1993;111:514–18.
12. Jorge R, Costa RA, Quirino LS, et al. Optical coherence tomography findings in patients 34. Thach AB, Lopez PF, Snady-McCoy LC, et al. Accidental Nd:YAG laser injuries to the
with late solar retinopathy. Am J Ophthalmol 2004;137:1139–43. macula. Am J Ophthalmol 1995;119:767–73.
13. Hope-Ross MW, Mahon GJ, Gardiner TA, et al. Ultrastructural findings in solar retino- 35. Berninger TA, Canning CR, Gunduz K, et al. Using argon laser blue light reduces oph-
pathy. Eye 1993;7:29–33. thalmologists’ color contrast sensitivity. Arch Ophthalmol 1989;107:1453–8.
14. Michaelides M, Rajendram R, Marshall J, et al. Eclipse retinopathy. Eye 2001;15:148–51. 36. Lee G, Baumal CR, Lally D, et al. Retinal injury after inadvertent handheld laser expo-
15. Wong SC, Eke T, Ziakas NG. Eclipse burns: a prospective study of solar retinopathy fol- sure. Retina 2014;34:2388–96.
lowing the 1999 solar eclipse. Lancet 2001;357:199–200. 37. Weng CY, Baumal CR, Albini TA, et al. Self-induced laser maculopathy in an adolescent
16. Thanos S, Heiduschka P, Romann I. Exposure to a solar eclipse causes neuronal death boy utilizing a mirror. Ophthalmic Surg Lasers Imaging Retina 2015;46:485–8.
in the retina. Graefes Arch Clin Exp Ophthalmol 2001;239:794–800. 38. McGhee CNJ, Crain JP, Moseley H. Laser pointers can cause permanent retinal injury if
17. Naidoff MA, Sliney DH. Retinal injury from a welding arc. Am J Ophthalmol used inappropriately. Br J Ophthalmol 2000;84:229–30.
1974;77:663–8. 39. Mainster MA, Timberlake GT, Warren KA, et al. Pointers on laser pointers. Ophthalmol-
18. Mauget-Faysse M, Quaranta M, Francoz N, et al. Incidental retinal phototoxicity asso- ogy 1997;104:1213–14.
ciated with ingestion of photosensitizing drugs. Graefes Arch Clin Exp Ophthalmol 40. Robertson DM, Lim TH, Salomao DR, et al. Laser pointers and the human eye: a clinico-
2001;239:501–8. pathologic study. Arch Ophthalmol 2000;118:1686–91.
19. Lee MS, Gunton KB, Fischer DH, et al. Ocular manifestations of a remote lightning 41. Bhavsar K, Wilson D, Margolis R, et al. Multimodal imaging in handheld laser–induced
strike. Retina 2002;22:808–10. maculopathy. Am J Ophthalmol 2015;159:227–31.
20. Norman ME, Younge BR. Association of high-dose intravenous methylprednisolone with 42. Hossein M, Bonyadi J, Soheilian R, et al. SD-OCT features of laser pointer maculopa-
reversal of blindness from lightning in two patients. Ophthalmology 1999;106:743–5. thy before and after systemic corticosteroid therapy. Ophthalmic Surg Lasers Imaging
21. McDonnell HR, Irvine AR. Light-induced maculopathy from the operating microscope 2011;42 Online:e135–8.
in extracapsular cataract extraction and intraocular lens implantation. Ophthalmology
1983;90:945–51.
469.e1
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Scleral Buckling Surgery

Bozho Todorich, Lisa J. Faia, George A. Williams 6.11
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
intraretinal edema or epiretinal proliferation. In patients with opaque

Definition: Closure of retinal breaks by scleral indentation. media, the retinal status may not be visualized. Diagnostic ultrasonogra-
phy is critical in establishing retinal detachment.
Key Features DIFFERENTIAL DIAGNOSIS

• Identification, localization, and treatment of retinal breaks. Not all retinal detachments are rhegmatogenous. Other causes include
• Scleral imbrication. tractional retinal detachments (as in advanced diabetic retinopathy), exuda-
tive retinal detachments (as in uveitic conditions, tumors, or uveal effusion
syndrome), and combined detachments.
Associated Features
• Anatomical success rate high—generally 80%–90%. ALTERNATIVES TO SCLERAL BUCKLING
• External drainage of subretinal fluid sometimes performed.
• Can be combined with vitrectomy surgery. Rhegmatogenous retinal detachments can be repaired by other surgical
techniques. Pneumatic retinopexy involves injection of an expansible gas
bubble into the vitreous and postoperative positioning so that the gas
INTRODUCTION bubble closes the retinal break.3 The break is treated with either cryopexy
or laser photocoagulation. Pneumatic retinopexy is generally reserved for
Although primary vitrectomy is being increasingly utilized, an essential detachments in the superior hemiretina with a single break or several
surgical procedure for the repair of certain rhegmatogenous retinal detach- closely spaced breaks with clinical posterior vitreous detachment and no
ments is scleral buckling. The goal of scleral buckling is to close retinal inferior retinal pathology.
breaks by indenting the eye wall, thus preventing the passage of liquefied Vitrectomy techniques, described in Chapter 6.12, also can be used to
vitreous into the subretinal space. This flexible approach incorporates the repair rhegmatogenous retinal detachments. The indications for scleral
benefits and advantages of different techniques and materials, maximiz- buckling versus pneumatic retinopexy or vitrectomy remain controversial.
ing the rate of anatomical and visual success while minimizing potential
complications. ANESTHESIA
HISTORICAL REVIEW Scleral buckling can be performed with the patient placed under local
or general anesthesia. The anesthetic technique that is used is a matter
Recognition of vitreoretinal traction and retinal breaks in the pathogen- of surgeon and patient preference. The advantages of local anesthesia
esis of retinal detachment by Gonin in 1919 ushered in the era of repair, include shorter operating time, quicker postoperative recovery, and pos-
in which drainage of subretinal fluid and treatment of retinal breaks sibly decreased morbidity and mortality. However, retrobulbar placement
were employed. Custodis, 30 years later, introduced the concept of scleral of local anesthetic is not without risk. Perforation of the globe, particularly
buckling. The introduction of the binocular indirect ophthalmoscope and in patients with myopia, and damage to the optic nerve may result in per-
scleral depression by Schepens in 1951 revolutionized the localization of manent visual loss. Respiratory arrest and grand mal seizures also have
peripheral retinal pathology. Advancements were made when Schepens been reported with inadvertent intrathecal administration of retrobulbar
combined scleral dissection, diathermy, and intrascleral implantation of anesthetic. These complications can be minimized with a subconjunctival
silicone buckles for scleral buckling. Lincoff et al. refined Custodis’ proce- or a peribulbar technique.4,5
dure by using silicone sponge explants and cryotherapy.1,2
GENERAL TECHNIQUES
PREOPERATIVE EVALUATION AND A peritomy (conjunctival opening) is performed either at the limbus or
DIAGNOSTIC APPROACH several millimeters posterior to it. Because of considerable conjunctival
manipulation, radial relaxation incisions are recommended to prevent
The diagnosis of rhegmatogenous retinal detachment is suggested by tearing. In patients who have filtering blebs or recent limbal wounds, the
symptoms of floaters, photopsia, peripheral vision loss, and decreased peritomy can be extended posteriorly to avoid those areas. If only one or
central vision in cases of macular involvement. In patients with clear two quadrants are to be buckled, conjunctiva and Tenon’s capsule can be See clip:
media, the diagnosis is confirmed by indirect ophthalmoscopy with scleral reflected in the required quadrants only (Video 6.11.1). 6.11.1
depression. Slit-lamp biomicroscopy with a three-mirror contact lens may After the peritomy, the space between Tenon’s capsule and sclera is
also be helpful in identification of retinal pathology and localization of entered, the muscle insertion is engaged with a muscle hook, and the con-
retinal breaks. The location and type of retinal breaks, as well as the size nections to Tenon’s capsule are identified and separated from the muscle.
and duration of retinal detachment, are factors that help determine the A traction suture is placed around each of the four rectus muscles. After
timing and type of scleral buckling procedure performed. all recti have been isolated, the surface of the sclera is inspected for evi-
470 Optical coherence tomography (OCT) is useful in documenting subret- dence of thinning (most common superotemporally), staphyloma, and
inal fluid, especially in the macula, and the extent of any accompanying anomalous vortex veins. Traction on the extraocular muscle insertions may
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LOCATION OF PREFERRED DRAINAGE SITES
6.11

retinal tear
X
X
X X
Fig. 6.11.1 Felt-tip pen purple mark on sclera denoting posterior margin of small
flap tear.
X preferred drainage sites
produce a bardycardic oculocardiac reflex, so it is important to carefully
monitor patient’s heart rate during this step. Fig. 6.11.2 Location of preferred drainage sites.
No aspect of scleral buckling is more critical than accurate placement
of the buckle, requiring precise localization of retinal breaks on the scleral
surface. For small flap tears or holes, a single mark on the posterior edge
of the break is sufficient. Larger flap tears and nonradial tears require The anteroposterior position of the encircling element depends on
localization of both the anterior and posterior extents of the break (Fig. the location of the pathology to be supported. When retinal breaks in the
See clip:
6.11.1) (Video 6.11.2). detached retina are associated with traction, the buckle should be posi-
6.11.2 tioned such that the posterior edge of the break lies on the posterior crest
Treatment of Retinal Breaks of the buckle. The buckling effect should extend for 30° on either side
of the tear and extend anteriorly to the ora serrata. When the encircling
The rationale for the treatment of retinal breaks is to create an adhesion element supports pathology in the attached retina, such as a retinal break,
between the retinal pigment epithelium (RPE) and the retina. This is it should be positioned to support the most posterior aspect of the pathol-
accomplished by inducing a thermal injury by using one of three energy ogy. If no specific pathology is to be supported, the encircling element
sources: diathermy, cryotherapy, or laser. The morphological and cellular should support the posterior margin of the vitreous base.
response of the retina and RPE to each of these energy sources is essen- The height of the encircling element (imbrication) can be obtained in
tially similar. After 2 weeks, all three modalities show comparable effects two ways. For thin encircling elements, such as solid silicone bands, the
on the retinal adhesive force.6 explant can be shortened in relation to the circumference of the globe. The
second method is via suture placement. This technique is used with wider
Explant Scleral Buckling Techniques and thicker explants and does not require the element to be shortened
in relation to the ocular circumference. The farther apart the bites of the
Explant techniques allow the placement of buckling elements to support mattress suture are placed, the greater the height when the sutures are See clip:
retinal pathology.7 Explants are made of either solid silicone rubber or sili- tightened7 (Video 6.11.1). 6.11.1
cone sponges and come in a variety of sizes and shapes. They are secured
to the sclera with partial-thickness scleral sutures (Video 6.11.2). For most Drainage of Subretinal Fluid
See clip:
6.11.2 detachments, the selected element is not as important as the accurate
localization and placement of it. Proper placement requires an effective Indications for drainage of subretinal fluid during scleral buckling remain
suturing technique, involving the use of a spatula needle with a 5-0 nonab- controversial. Some authors believe that most cases can be managed
sorbable suture, such as polyester, nylon, or polypropylene. The suture is without drainage, whereas others believe that drainage is a crucial aspect
placed either snug with the band (buckle height achieved by circumferen- of the procedure.7,8 The rationale for drainage is twofold:
tial tightening of the band) or 1 mm or more on each side (buckle height
achieved by suture imbrication. To ensure that the most posterior edge
• To diminish intraocular volume, allowing elevation of the buckle
without elevating intraocular pressure (IOP).
of the break is supported, the posterior suture is placed a minimum of
2–3 mm posterior to the scleral localization mark.
• To allow the retina to settle on the elevated buckle by removing fluid
from the subretinal space.
Element placement can be either segmental or encircling. Segmental
buckles usually are reserved for detachments with single or closely spaced Effective drainage places the retinal breaks in juxtaposition to the
retinal breaks, <1 clock hour in extent. Although segmental buckles close choroid overlying the buckle, thus facilitating closure.
isolated tears effectively, they are less useful in preventing new breaks The selection of an external drainage site is affected by several factors
because they provide no support elsewhere. Encircling procedures are par- (Fig. 6.11.2). Although the location of subretinal fluid is a primary concern,
ticularly indicated in patients with the following conditions: it is not necessary to drain where the amount of fluid is greatest but,
rather, where there is adequate fluid to safely enter the subretinal space.
• Multiple breaks in different quadrants. Whenever possible, it is preferable to drain just above or below the hori-
• Aphakia. zontal meridian, either temporally or nasally (see Fig. 6.11.2), avoiding the
• Pseudo-phakia. major choroidal vessels and vortex veins.
• Myopia. Drainage in the posterior third of the bed of the buckle is preferred. This
• Diffuse vitreoretinal pathology, such as extensive lattice degeneration or provides adequate support of the drainage site in the event of a complica-
vitreoretinal degeneration. tion, such as retinal incarceration or choroidal hemorrhage, and immedi- 471
• Proliferative vitreoretinopathy (PVR). ate closure when the buckle is tightened. If, because of the configuration
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of the detachment or the position of the buckle, it is not possible to drain
6 in the bed of the buckle, closure of the site with a suture should be consid-
ered. Drainage outside the bed of the buckle allows the buckle to be pulled
up as drainage proceeds. Entry through the choroid and into the subretinal
space is performed with a needle (27–30 gauge), with the presence of fluid
Retina and Vitreous
signifying entry into the subretinal space. As the fluid drains, it is import-
ant to maintain a relatively normal and constant IOP to prevent retinal
incarceration and choroidal hemorrhage (Video 6.11.3).
See clip:
6.11.3
After successful drainage and closure of the site, the buckle is posi-
tioned with the appropriate preplaced scleral sutures. Any suture that over-
lies a retinal break is tightened first. The encircling band, if present, is
then adjusted with a silicone sleeve. As the sutures are tightened, they
are secured with temporary ties, as this allows easy adjustment of buckle
height and position, and the optic nerve is inspected for perfusion. Once
the buckle is positioned and the band adjusted, the fundus is inspected
again to determine the status of the breaks and perfusion of the optic
nerve.
Nondrainage procedures can be used to reattach the retina, with
success rates comparable with those of drainage procedures. The primary
advantage of a nondrainage procedure is that it avoids the potential com-
plications associated with drainage. In eyes with relatively shallow detach-
ments, the eye may soften enough after scleral depression and cryopexy Figure 6.11.3 Cross-sectional hematoxylin and eosin–stained section of an eye with
to allow placement of the buckle without IOP problems. Waiting several history of scleral buckling procedure. Fibrous capsule outlining the prior location of
minutes between tightening of the scleral sutures also may soften the eye. buckling element is observed (black arrows).
However, nondrainage techniques often require the IOP to be lowered by
additional medical or surgical means. An injection of a small volume of
air or gas (0.2–0.4 cc of 100% SF6 or C3F8) is often used as an adjunct in
drainage or nondrainage buckles, to promote closure of the retinal break.
Chandelier-Assisted Scleral Buckling

Chandelier-assisted scleral buckling is a relatively novel technique in
which traditional scleral buckle placement and maneuvers (e.g., marking
of retinal breaks, cryopexy, and external drainage) are performed under
wide-angle visualization through the operating microscope. The visualiza-
tion is enabled by endoillumination provided by a small-gauge fiberoptic
chandelier placed near the beginning of the case. The advantage of this
procedure is that it allows for identification of all retinal breaks even in the
far periphery, which is very helpful to less experienced surgeons. It is also
a great tool for teaching as it allows simultaneous viewing by the surgeon
and vitreoretinal fellow. The chief disadvantage of the chandelier during
primary scleral buckle is that it requires entry into the vitreous cavity and
carries a small risk of vitreous incarceration at the sclerotomy site.
Closure
After final adjustments, the sutures are tied and the knots rotated poste-
riorly. Tenon’s capsule and the globe can then be irrigated with an antibi-
otic solution. Retrobulbar irrigation with 0.75% bupivacaine significantly Figure 6.11.4 Intraoperative image of an eye undergoing scleral buckle
decreases postoperative pain after general or local anesthesia. removal demonstrates the fibrous capsule being cut and reflected by the blade
Tenon’s capsule is then identified in all quadrants. A layered closure, longitudinally along the axis of the buckling element (yellow arrow).
initially closing Tenon’s capsule to the muscle insertions, ensures that the
explant and the nonabsorbable sutures are covered by Tenon’s capsule and
removes the tension on the conjunctival closure, minimizing the possibil- despite attempts to avoid large fluctuations in IOP during drainage, and is
ity of buckle erosion. During conjunctival closure, the relaxation incisions identified by the characteristic dimpled appearance of the retina over the
are typically closed with 6-0 plain gut suture or 7-0 vicryl. The conjunctiva site. Minimal degrees of incarceration rarely result in retinal breaks, but
is secured at the limbus with one or more sutures. large amounts of incarceration require support with a buckle.
Long-term, a fibrous capsule forms overlying the scleral buckle, which Choroidal or subretinal hemorrhage is perhaps the most feared com-
maintains the scleral buckle position and indentation effect (Figs. 6.11.3 plication of subretinal fluid drainage. This usually occurs at the time of
and 6.11.4). choroidal perforation and is marked by the appearance of blood at the site.
If this occurs, the drainage site should be closed as quickly as possible with
either the buckle or a suture and the IOP elevated above the systolic perfu-
COMPLICATIONS sion pressure. If the drainage site is temporal, the eye should be positioned
Intraoperative Complications to place the located site as inferiorly as possible to prevent gravitation of
the blood to the fovea.
Scleral Perforation
Scleral perforation during suture placement is a potentially devastating
complication. Perforation usually is noticed at the time of suture place- Glaucoma
ment and is heralded by the presentation of blood, pigment, or subretinal A variety of secondary glaucomas may develop after scleral buckling.
fluid through the suture tract. Angle closure after scleral buckling may take place with or without pupil-
lary block. One presumed mechanism of closure is shallow detachment of
Drainage Complications the ciliary body, which results in anterior displacement of the ciliary body
472 The most common drainage complications are retinal incarceration and and occlusion of the angle. Anterior segment ischemia also may cause
choroidal or subretinal hemorrhage.8 Retinal incarceration may occur glaucoma.
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Infection and Extrusion
Scleral buckling materials constitute foreign bodies and therefore carry
the risk of infection and extrusion. The incidence of explant infection and 6.11
extrusion is about 1%. Effective management of infected scleral buckling
material usually requires removal. Topical and systemic antibiotics occa-

sionally result in symptomatic improvement, but they are rarely curative.
Removal of the scleral buckling material carries a redetachment risk of
4%–33%.
Choroidal Effusion
Accumulation of serous or serosanguinous fluid in the suprachoroidal
space is relatively common after scleral buckling, referred to as a choroi-
dal (or ciliary body) effusion. Choroidal effusion is related to the size and A
extent of the scleral buckle.9
Cystoid Macular Edema and Residual Subretinal Fluid

Using cryotherapy and explant techniques, the incidence of angiographic
cystoid macular edema (CME) 4–6 weeks after surgery in phakic eyes is
25%–28%, and typically resolves spontaneously.10 Additional therapies,
such as corticosteroids, may be needed for resolution.11
Macular Pucker
Macular pucker is a major cause of decreased vision after scleral buck-
ling, with the incidence in the range of 3%–17%.12 Risk factors identified
include preoperative PVR of grade B or greater, age, total retinal detach-
ment, and vitreous loss during drainage.10 B
Diplopia Fig. 6.11.5 (A) Optical coherence tomography of acute retinal detachment of 3 days’
The incidence of postoperative diplopia is low. In a series of 750 patients duration. Note the retinal edema. (B) Optical coherence tomography of same eye 6
who underwent scleral buckling for retinal reattachment, 3.3% complained weeks after scleral buckling. Note the persistent subfoveal fluid despite resolution of
of diplopia postoperatively.13 The incidence of diplopia is greater after reop- retinal edema and retinal attachment.
erations involving buckle revision and with larger buckles.
Changes in Refractive Error

The extent of change in refractive error after scleral buckling depends only 40%–60% of patients have a final visual acuity of 20/50 or better.18–20
on the surgical technique employed. Segmental buckles have little effect Preoperatively, OCT documents the status of the macula and the presence
on refractive error. However, large radial elements, such as full-thickness of retinal edema (Fig. 6.11.5). Postoperatively, OCT may demonstrate the
sponges that extend anteriorly beyond the ora serrata, may induce an presence of CME or residual subretinal fluid.21
irregular astigmatism. Encircling procedures induce the greatest change
in refractive error, greater for phakic than for aphakic eyes, because of the
anterior displacement of the lens, resulting in an increased myopic shift.14
KEY REFERENCES
Burton RL, Cairns JD, Campbell WG, et al. Needle drainage of subretinal fluid: a random-
ized clinical trial. Retina 1993;13:13–16.
OUTCOME Girard P, Karpouzas I. Visual recovery after scleral buckling surgery. Ophthalmologica
1995;209:323–8.
The anatomical results following scleral buckling are impressive, with an Girard P, Mimoun G, Karpouzas I, et al. Clinical risk factors for proliferative vitreoretinopa-
overall reattachment rate of around 90%. Unfortunately, the visual results thy after retinal detachment surgery. Retina 1994;14:417–24.
Hassan TS, Sarrafizadeh R, Ruby A, et al. The effect of duration of macular detachment on
after scleral buckling do not parallel the anatomical results. Multiple results after the scleral buckle repair of primary macula-off retinal detachments. Oph-
factors correlate with visual and anatomical prognosis. Detachments with thalmology 2002;109:146–52.
the macula attached (macula-on detachments) at the time of surgery have Lobes LA, Burton TC. The incidence of macular pucker after retinal detachment surgery. Am
a significantly better prognosis compared with detachments in which the J Ophthalmol 1978;85:72–7.
macula is involved. Some series demonstrate successful anatomical reat- Meredith TA, Reeser FH, Topping TM, et al. Cystoid macular edema after retinal detachment
surgery. Ophthalmology 1980;87:1090–5.
tachment in 99% of cases of macula-on retinal detachments.15,16 However, Smiddy WE, Loupe DN, Michels RG, et al. Extraocular muscle imbalance after scleral buck-
decreased visual acuity can occur, usually caused by postoperative macular ling surgery. Ophthalmology 1989;96:1485–90.
changes, such as CME or macular pucker. Approximately 10% of patients Smiddy WE, Loupe DN, Michels RG, et al. Refractive changes after scleral buckling surgery.
who have macula-on detachments suffer a visual loss of two Snellen lines Arch Ophthalmol 1989;107:1469–71.
Williams GA, Aaberg TM Sr. Techniques of scleral buckling. In: Ryan SJ, editor. Retina, vol.
or greater with respect to their preoperative vision. 4. Philadelphia: Elsevier Mosby; 2006. p. 1035–70.
Detachment of the macula results in a variable degree of permanent Wolfensberger TJ, Gonvers M. Optical coherence tomography in the evaluation of incom-
photoreceptor damage that correlates with the duration of the detach- plete visual acuity recovery after macula-off retinal detachment. Graefes Arch Clin Exp
ment.17 Macula-off detachments are usually larger and of greater duration Ophthalmol 2002;24:85–9.
compared with macula-on detachments; therefore, it is not surprising that
macula-off retinal detachments have a lower rate of success. Although the Access the complete reference list online at ExpertConsult.com
overall anatomical success rate for macula-off detachments is at least 90%,
473
booksmedicos.org
REFERENCES 12. Lobes LA, Burton TC. The incidence of macular pucker after retinal detachment surgery.
1. Wilkinson CP, Rice TA. History of retinal detachment surgery. In: Michels RG, editor.
Retinal detachment. 2nd ed. St Louis: Mosby; 1997. p. 251–334.
13. Smiddy WE, Loupe DN, Michels RG, et al. Extraocular muscle imbalance after scleral
buckling surgery. Ophthalmology 1989;96:1485–90.
6.11
2. Schepens CL. Retinal detachment and allied disease. Philadelphia: WB Saunders; 1983. 14. Smiddy WE, Loupe DN, Michels RG, et al. Refractive changes after scleral buckling
surgery. Arch Ophthalmol 1989;107:1469–71.

3. Hilton GF, Grizzard WS. Pneumatic retinopexy. A two-step outpatient operation without
conjunctival incision. Ophthalmology 1986;93:626–41. 15. Tani P, Robertson DM, Langworthy A. Rhegmatogenous retinal detachment without
4. Mein CE, Woodcock MG. Local anesthesia for vitreoretinal surgery. Retina 1990;10: macular involvement treated with scleral buckling. Am J Ophthalmol 1980;90:503–8.
47–9. 16. Wilkinson CP. Visual results following scleral buckling for retinal detachments sparing
5. Orgel IK, Williams GA. Peribulbar anesthesia for scleral buckling surgery. Vitreoretinal the macula. Retina 1981;1:113–16.
Surg Technol 1992;1:4–5. 17. Woo SJ, Lee KM, Chung H, et al. Photoreceptor disruption related to persistent submac-
6. Kita M, Negi A, Kawano S, et al. Photothermal cryogenic and diathermic effects on ular fluid after successful scleral buckle surgery. Korean J Ophthalmol 2011;25(6):380–6.
retinal adhesive force in vivo. Retina 1991;11:441–4. 18. Girard P, Mimoun G, Karpouzas I, et al. Clinical risk factors for proliferative vitreoreti-
7. Williams GA, Aaberg TM Sr. Techniques of scleral buckling. In: Ryan SJ, editor. Retina, nopathy after retinal detachment surgery. Retina 1994;14:417–24.
vol. 4. Philadelphia: Elsevier Mosby; 2006. p. 1035–70. 19. Girard P, Karpouzas I. Visual recovery after scleral buckling surgery. Ophthalmologica
8. Burton RL, Cairns JD, Campbell WG, et al. Needle drainage of subretinal fluid: a ran- 1995;209:323–8.
domized clinical trial. Retina 1993;13:13–16. 20. Hassan TS, Sarrafizadeh R, Ruby A, et al. The effect of duration of macular detachment
9. Packer AJ, Maggiano JM, Aaberg TM, et al. Serous choroidal detachment after retinal on results after the scleral buckle repair of primary macula-off retinal detachments. Oph-
detachment surgery. Arch Ophthalmol 1983;101:1221–4. thalmology 2002;109:146–52.
10. Meredith TA, Reeser FH, Topping TM, et al. Cystoid macular edema after retinal detach- 21. Wolfensberger TJ, Gonvers M. Optical coherence tomography in the evaluation of incom-
ment surgery. Ophthalmology 1980;87:1090–5. plete visual acuity recovery after macula-off retinal detachment. Graefes Arch Clin Exp
11. Wu JS, Lin CJ, Hwang JF, et al. Influence of systemic steroids on subretinal fluid after Ophthalmol 2002;24:85–9.
scleral buckle surgery for macula-off retinal detachment. Retina 2011;31(1):99–104.
473.e1
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Vitrectomy
Michael Engelbert, Stanley Chang 6.12
IN THIS CHAPTER
Additional content
available online at
ExpertConsult.com
Slit-lamp examination is used to evaluate the anterior segment struc-

Definition: Vitrectomy is an intraocular surgery during which the tures, whereas indirect biomicroscopy allows for assessment of vitreoreti-
vitreous is removed to allow for adjunctive procedures to repair retinal nal anatomy. When a gas bubble tamponade is planned, the depth of the
and/or macular pathology or to remove foreign, abnormal, or dislocated anterior chamber is assessed because a large bubble may result in shal-
tissue or material from the posterior segment or to place therapeutic lowing and angle-closure glaucoma. The cornea, size of the dilated pupil,
medications, devices, or tamponades into the eye. and clarity of the lens are noted to ensure that, intraoperatively, the retina
can be visualized adequately. In pseudo-phakic eyes, the type of intraocu-
lar lens (IOL) and its composition are studied. Because of its hydrophobic
properties, a silicone IOL may develop condensation on its surface during
fluid–air exchange, and the placement of silicone oil intravitreally may
Key Features result in adhesion of oil droplets to the implant surface, which reduces the
Three ports in pars plana to accommodate: clarity of the optical zone. Gonioscopic evaluation is carried out in patients
• Infusion to replace intraocular volume and maintain IOP and to with diabetes and those who have inflammatory conditions.
infuse vitreous tamponade. The status of the vitreous is best studied using indirect biomicroscopy—
• Endoillumination cutter, forceps, scissors, endodiathermy, endolaser. either a noncontact +78.00 diopters (D) or +90.00 D lens or a contact lens
• Visualization with contact or noncontact viewing system. may be used. The absence or presence of separation of the posterior
hyaloid surface is determined first, as this finding is critical to the surgical
approach in macular conditions. These findings are supplemented by those
INTRODUCTION of careful indirect ophthalmoscopy, which provides information about
the severity of epiretinal membrane (ERM) proliferation, the location of
Since its genesis, remarkable advances in vitreous surgery have established retinal breaks, and anatomical changes in the vitreous base and peripheral
this microsurgical procedure as the second-most common intraocular retinal structures. Optical coherence tomography (OCT) as an adjunctive
operation after cataract extraction. Progress in two major areas has fueled diagnostic tool has revolutionized the assessment of the vitreous–retinal
the extraordinarily rapid growth in vitreous surgical techniques: interface as well as the retina, retinal pigment epithelium (RPE), and sub-
retinal space at a close to ultrastructural level in a noninvasive fashion.
• Understanding of the pathoanatomical changes that affect the retina
This has greatly facilitated the distinction between “true” macular holes,
and vitreous.
pseudo- and lamellar holes, as well as cystic macular edema. Sensitivity,
• Introduction of new technology and instrumentation. specificity, and reproducibility exceed that of a contact lens examination. It
In the early years, vitrectomy was used to restore ambulatory vision in is also increasingly being used to help prognosticate surgical outcomes for
eyes that were otherwise destined to become blind. Both removal of opac- macular hole and macula-off detachment surgery.
ified vitreous and removal of fibrovascular tissue in diabetic retinopathy In cases of media opacity, ultrasonographic evaluation provides an
often resulted in restoration of functional vision. Eyes that had complicated accurate map of the vitreoretinal relationships. In particular, the mobil-
retinal detachments, such as those associated with proliferative vitreoret- ity of retinal detachment, delineation of tractional regions, and localiza-
inopathy or that resulted from severe penetrating injury, were regarded tion of vitreous or subretinal hemorrhage may be depicted. The location
as inoperable previously. As advances in technology continued and the and dimensions of prior scleral buckling elements may be determined. In
safety of the vitrectomy procedure was established, the focus shifted to trauma situations, ancillary tests using computed tomography or orbital
newer applications (e.g., macular surgery). The goals of this surgery are radiographic analysis may be necessary to aid in the localization of foreign
to improve and restore central visual acuity in such conditions as macular bodies and damage to periocular structures.
pucker, macular hole, and retinal detachment.
INDICATIONS AND ALTERNATIVES TO SURGERY
HISTORICAL REVIEW The surgical indications for vitrectomy are given in Box 6.12.1. These
In 1970, Machemer and Parel introduced the first instrument to cut and include a wide range of conditions, some of which involve the vitreous
remove vitreous, and the first vitrectomy procedure was in a patient with or retina focally, whereas others represent more diffuse processes. Other
See clip: diabetes who had a long-standing vitreous hemorrhage (Video 6.12.1). chapters in this book describe the alternative medical approaches for many
6.12.1 of the listed conditions.
PREOPERATIVE EVALUATION AND ANESTHESIA

DIAGNOSTIC APPROACH The majority of vitrectomies are carried out under local anesthesia (retro-
The preoperative evaluation of patients who are to undergo vitrectomy bulbar block, peribulbar block, or subconjunctival irrigation) with moni-
includes a careful examination of the eye and assessment of the patient’s tored anesthesia care. In instances of extreme patient apprehension or an
medical status and risk of anesthesia-related complications. The surgeon inability to cooperate, general anesthesia is required. When using general
474 reviews the planned procedure with the patient to explain expected out- anesthesia and intraoperative gas administration, it is important to dis-
comes and potential benefits and risks. continue inhalation of nitrous oxide at least 20 minutes prior to the final
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BOX 6.12.1 Indications for Vitrectomy
Diabetic Retinopathy
6.12
• Nonclearing or repeated vitreous hemorrhage
• Traction retinal detachment
Vitrectomy
• Combined traction and rhegmatogenous retinal detachment
• Progressive fibrovascular proliferation
• Macular distortion by fibrovascular proliferation
• Macular edema that results from a taut posterior hyaloid
Retinal Detachment
• Retinal detachment with proliferative vitreoretinopathy
• Giant retinal tears
• Retinal detachment with posterior retinal breaks
• Some primary retinal detachments
Complications of Anterior Segment Surgery
• Dislocated lens fragments
• Dislocated intraocular lens
• Aphakic or pseudo-phakic cystoid macular edema
• Endophthalmitis
• Choroidal hemorrhage Fig. 6.12.1 Typical small gauge vitrectomy cutters of 23-, 25-, and 27-gauge cutters
• Epithelial downgrowth showing the relative sizes of the cutting tips.
• Anesthetic needle perforation
Trauma
• Hyphema evacuation
• Traumatic cataract or dislocated lens Fig. 6.12.2 Small-
• Posterior penetration injuries with vitreous hemorrhage and/or retinal Gauge Instruments
Also Include Forceps
detachment
and Scissors. Tips
• Reactive intraocular foreign body of the forceps have
• Subretinal membranes or hemorrhage been designed to
• Traumatic macular holes provide more delicate
Macular Surgery grasping of tissue
• Macular pucker (top), whereas scissors
can be straight or
• Macular hole curved to conform to
• Massive subretinal hemorrhage the shape of the eye
• Vitreomacular traction syndrome (bottom).
• Myopic traction maculopathy
• Retinal detachment secondary to optic pit, and other optic nerve
anomalies
• Transplantation of retinal photoreceptors or retinal pigment
epithelium
Pediatric Retinal Disorders
• Retinopathy of prematurity
• Persistent hyperplastic primary vitreous
• Familial exudative vitreoretinopathy
• Giant retinal tears/dialysis
• Juvenile retinoschisis injection of gas. Otherwise, elevated intraocular pressure or an inadequate
• Juvenile rheumatoid arthritis gas fill may result.
• Retinal detachment secondary to choroidal coloboma
• Retinal detachment in “morning glory” syndrome or optic nerve GENERAL TECHNIQUES
colobomas
• Gene therapy for treatment of retinal degenerations Microincision vitrectomy uses instruments of 23-gauge,1 25-gauge,2 or
Tumors
27-gauge3 caliber (Fig. 6.12.1) and has replaced standard 20-gauge vitrec-
• Choroidal melanoma tomy for most cases in the hands of most surgeons. Microincision vit-
• Complications of retinal angiomatosis rectomy employs self-retaining microcannula ports, which are inserted
• Combined hamartoma of the retina and retinal pigment epithelium transconjunctivally by using trocar needles. During insertion, the needles
• Intraocular lymphoma are directed at such an angle that a beveled self-sealing incision results.
• Diagnostic vitrectomy, fine needle aspiration The cannulas are placed 3.5–4.0 mm posterior to the corneal limbus,
depending on the phakic status of the eye. Usually the inferior cannula
Uveitis is connected to an infusion line to replace the vitreous removed with
• Viral retinitis—cytomegalovirus infection, acute retinal necrosis balanced saline. A vitreous cutter probe, and a fiberoptic light probe are
• Intraocular infections—bacterial, viral, fungal, parasitic inserted through the superior sclerotomy openings. “Valved” cannulas,
• Ophthalmomyiasis which have a thin membrane covering the entrance of the cannula, are
• Inflammatory conditions—sarcoidosis, Behçet’s syndrome, uveal increasingly utilized so that fluid egress from the eye is limited during the
effusion procedure and turbulent flow and pressure oscillation in the eye are min-
• Pars planitis imized. Additional light fibers of 2-gauge or 27-gauge (“chandelier” light-
• Whipple’s disease ing) can be inserted through the pars plana to supplement the light from
• Familial amyloidosis the fiberoptic probe or allow two instruments to be placed into the eye
• Hypotony for bimanual dissection. An assortment of additional instruments, such as
forceps, scissors, and laser probes, is also available for membrane manip-
ulation (Fig. 6.12.2). Even the most complex vitrectomies can be done with
smaller gauges, with 20-gauge instruments still required to remove dense 475
lens fragments or foreign bodies. Most of the small-gauge incisions are
booksmedicos.org
6
Retina and Vitreous
Fig. 6.12.4 A vitreous cutter with a beveled tip can allow the port to be closer
to the retinal surface. This is particularly useful in cases of proliferative diabetic
retinopathy.
Fig. 6.12.3 Wide-angle indirect contact lenses afford a view of much of the retina,
Epiretinal Membrane Dissection
here during air–fluid exchange. Inferiorly, a buckle anterior to the equator is visible. Two types of epiretinal proliferation are encountered:
• Fibrovascularproliferation, which contains neovascularization, most
commonly seen in proliferative diabetic retinopathy (PDR).
self-sealing, but occasionally, a single transconjunctival suture is necessary
• Nonvascular membranes, found in PVR and macular pucker.
to close a leaky opening. In cases of PDR, the surgical goals are to separate the posterior hyaloid
A high-resolution surgical microscope is used to view the fundus during from the retinal surface peripherally and to remove the epiretinal prolif-
surgery. A plano-concave contact lens is used most commonly, but addi- erative tissue or release its tractional effects centrally and/or peripherally.
tional surgical viewing lenses (e.g., prism lenses, lenses of higher refrac- Surgical techniques employed to remove the proliferative tissue are:
tive index) have been developed to improve intraoperative visualization. Of
increasing acceptance is the use of contact or noncontact wide-field or pan-
• Segmentation.
oramic viewing systems based on the principles of binocular indirect oph-
• Delamination.
thalmoscopic visualization (Fig. 6.12.3). Such systems offer an expanded
• En bloc dissection.
visualization area and increased depth of focus but require that an image The dissections are achieved by using microsurgical instruments. The
inverter be mounted on the microscope. Recently, systems using binoc- smaller-gauge cutters are able to access small openings in the tissue planes
ular video cameras placed onto the body of a surgical microscope have and can be quite effective in removing layers of fibrovascular proliferation.
been developed for vitrectomy. The surgeon views a large surgical monitor Scissors that cut perpendicularly across fibrovascular tissue or scissors that
with three-dimensional glasses and is able to perform the delicate surgical have curved blades to cut between the retinal attachments of the prolifer-
maneuvers required. Advantages for such an approach are that lower illu- ative tissue are available. The use of lit, multifunction instruments allows
mination is required, and ergonomically, the surgeon’s neck and back are for bimanual delamination of tissue, which can be carried out more safely
less prone to stress. and with less bleeding. Attainment of the surgical objectives results in a
stabilization of the retinopathy and vision.
Nonvascular ERMs are found in PVR and, in a less severe form,
SPECIFIC TECHNIQUES macular pucker. Such membranes may adhere strongly to the surface of
Lensectomy the retina and are best removed by using end-gripping membrane forceps;
a bimanual approach with the use of an illuminated membrane pick and
Lensectomy is indicated when cataract prevents visualization of the fundus forceps reduces the possibility of the formation of iatrogenic retinal tears.
or when the lens is subluxated. Furthermore, the lens is removed if vitreo- It is recognized now that mechanical effects of the posterior hyaloid at
retinal traction located at or anterior to the vitreous base must be dissected, the vitreous–retinal interface may result in macular hole formation and
which is most frequently seen in proliferative vitreoretinopathy (PVR) and central visual loss. The actual structural changes within this layer of cor-
trauma. Ultrasonic fragmentation of the lens is usually approached from tical vitreous that cause retinal pathology are unclear. A critical step in
the pars plana with the lens equator entered by the fragmentation probe. the surgical management is separation of the posterior hyaloid from the
If no IOL is to be placed, the capsule is excised completely by using the retina. After a central vitrectomy has been performed, the adherent layer
vitreous cutter or removed en bloc with forceps. of cortical vitreous at the vitreous–retinal interface is engaged and elevated
It has become increasingly common to combine standard phacoemul- by using the vitreous cutter. The posterior hyaloid is most adherent at the
sification, using an acrylic foldable IOL, with vitrectomy.4 This combined optic disc and at the macular region. After separation of the hyaloid, noted
approach speeds the recovery time for stabilization of visual acuity. by observation of Weiss’ ring, the vitreous layer can be excised out to the
periphery.
Vitreous Cutters
The vitreous cutting technology used is the guillotine cutter. This instru-
Intraoperative Tissue Staining
ment, which comes in 20, 23, 25, and 27 gauges, consists of a round Because many preretinal tissues, such as the cortical vitreous, ERM, and
needle-like shaft small opening near the tip. Tissue is aspirated into the internal limiting membrane, are transparent by nature, several chemicals
port and cut by an inner hollow sleeve that moves back and forth along the can aid in their visualization during vitrectomy. Intravitreal indocyanine
long axis of the probe. Currently, cutting speeds of up to 10 000 cuts/min green (ICG) dye was first employed to stain the internal limiting mem-
are attainable. Higher cutting speeds result in less traction on the tissue, brane in order to facilitate peeling and complete removal. ICG is widely
and theoretically, fewer iatrogenic tears would occur when the probe is employed, especially for macular hole surgery. However, photosensitiv-
working near the surface of the retina. Higher cutting rates have also been ity and the creation of deeper cleavage planes when peeling the internal
introduced by modifying the inner cutting sleeve to have two openings so limiting membrane have been observed. This has prompted the use of
that with each stroke, the tissue is cut twice with one cycle. Enhancements, alternative stains, such as trypan blue for staining of ERM; brilliant blue
such as placing the port closer to the end of the probe or beveling the end for staining of the internal limiting membrane (Fig. 6.12.5); and triam-
476 of the probe, also allow the port to be placed closely to the tissue that is cinolone, which appears to be particularly useful in highlighting cortical
being cut (Fig. 6.12.4). vitreous (Fig. 6.12.6).
booksmedicos.org
Other applications of perfluorocarbon liquids are to float dislocated lens
fragments or dislocated IOLs anteriorly, to provide intraocular hemostasis
by localization of bleeding, and to express liquefied subretinal blood from 6.12
under the retina.
Vitrectomy
Endophotocoagulation
Laser photocoagulation is applied around retinal breaks and circumferen-
tial retinotomies; in general, 2–3 rows of treatment are adequate. In more
advanced cases of retinal detachment, such as PVR, laser spots may be
placed contiguously in two or three rows on the anterior slope of the scleral
buckle. In PDR, scatter photocoagulation is applied to areas of peripheral
ischemia, thus reducing the risk of neovascular glaucoma.
Gas and Silicone Oil Tamponade

The final step in vitreous surgery is to decide whether it is necessary to fill
the vitreous space by using a tamponade agent. An automated air-infusion
pump is used to perform the fluid–air exchange. A flute needle is used
actively or passively to aspirate the intraocular fluid as air is infused
through the infusion line.
In cases where no retinal detachment exists, a bubble tamponade may
be unnecessary; but in some cases, air is used to smooth out retinal folds
or to allow visualization through a hemorrhagic medium postoperatively.
In macular hole surgery, a longer-lasting gas bubble is useful as its buoyant
Fig. 6.12.5 Staining of internal limiting and epiretinal membranes, in this case force may help to close the hole. When retinal detachment is present, the
with brilliant blue, can be particularly helpful in cases where poor and irregular subretinal fluid must be evacuated to achieve a complete fill with gas and
pigmentation of the fundus make visualization challenging, in this case in a high ensure that the retina flattens without posterior folds. Perfluorocarbon
myopic eye with tractional foveoschisis. liquid may be injected to flatten the retina up to the level of peripheral
retinal breaks—the posterior subretinal fluid is expressed anteriorly. Inter-
nal drainage of the remaining subretinal fluid is accomplished by place-
ment of the aspirating needle through the retinal break as air enters the
eye. The descending air bubble flattens the anterior retinal detachment
and forces the anterior subretinal fluid through the retinal break. When
the subretinal fluid has been aspirated completely or nearly completely, the
perfluorocarbon liquid may be removed.
The type of gas used is dependent on the individual clinical situation.6
In eyes with simple retinal detachment, the role of the gas bubble is to
allow adequate time for the chorioretinal adhesion from laser treatment
to form. Usually, air or sulfur hexafluoride, which persists for 10–14 days,
may be used. For more complex retinal detachments, such as PVR, trauma,
and giant retinal tears, a longer-lasting gas bubble is usually required. Per-
fluorohexane or perfluoropropane gases are chosen frequently in these
situations.
Silicone oil tamponade may also be used as a long-term tamponade
agent. This clear viscous liquid, which is immiscible with water, replaces
the vitreous. Its surface tension and mild buoyant force mechanically hold
the retina against the choroid. The advantage of silicone oil is that the
patient has vision through the oil bubble and that extensive prone-head
positioning (required with gas bubbles) is unnecessary. However, silicone
oil may require surgical removal months after the retina has been reat-
tached. The results of a multicenter, randomized clinical trial, in which the
use of perfluoropropane gas was compared with the use of silicone oil for
the treatment of severe PVR, found no statistically significant difference in
the final retinal reattachment rate between the two modalities.7
Fig. 6.12.6 Cortical vitreous stains particularly well with triamcinolone, and this can
aid in its complete and safe removal, as in this case of myopic foveoschisis.
COMPLICATIONS
Many of the potential complications of vitreous surgery may be real-
Perfluorocarbon Liquids ized during the later postoperative period. The rate of complications has
decreased gradually as improvements in technology have been introduced.
Perfluorocarbon liquids are useful as an intraoperative mechanical tool. However, experience, surgical skill, and training are also significant factors
The various perfluorocarbon liquids currently used in vitreous surgery that can reduce the rate of complications. The more widely described
have different physical and optical properties. Perfluoro-n-octane, because intraoperative and postoperative complications encountered with vitreous
of the better visibility it allows, low viscosity, and high vapor pressure, is surgery are given in Box 6.12.2.
the most commonly used of these. Giant retinal tears with large, inverted
posterior flaps can be repositioned easily into their normal anatomical
position, which allows for the successful management of this condition
OUTCOMES
without the use of special equipment to rotate the patient intraoperatively.5 The introduction of new surgical techniques and instrumentation and
In PVR, as perfluorocarbon liquid flattens the posterior retina, retinal improved knowledge of the pathophysiology of abnormal vitreoretinal
folds are opened and allow for traction and visualization of additional structural changes have resulted in a steady improvement in the anatom-
membranes. A posterior retinotomy for internal drainage of subretinal ical and visual results of vitreous surgery. Some of the results reported
fluid is no longer necessary. The retina is stabilized as membrane dissec- for the most common indications of vitrectomy are given in Table 6.12.1
tion proceeds, and large retinotomies, when necessary, can be carried out and represent significant advances in the surgical treatment of retinal 477
more safely. disorders.
booksmedicos.org
KEY REFERENCES
6
TABLE 6.12.1 Surgical Outcomes in Vitreous Surgery
Abrams GW, Azen SP, McCuen BW II, et al. Vitrectomy with silicone oil or long-acting gas
Vitreoretinal Disorder Outcome in eyes with severe proliferative vitreoretinopathy: results of additional and long-term
Diabetic vitreous hemorrhage 89% improvement with clear vitreous 8
follow-up. Silicone Study Report 11. Arch Ophthalmol 1997;115:335–44.
Retina and Vitreous
Borne MJ, Tasman W, Regillo C, et al. Outcomes of vitrectomy for retained lens fragments.
Diabetic traction retinal detachment 66%–95% retinal reattachment rate9
Proliferative vitreoretinopathy 94% final retinal reattachment rate10 Chang S. Intraocular gases. In: Ryan S, Glaser BM, editors. Retina. 2nd ed. St Louis: Mosby;
Giant retinal tears 96% final retinal reattachment rate5 1994.
Chang S, Lincoff H, Zimmerman NJ, et al. Giant retinal tears: surgical techniques and
Macular pucker 80%–90% visual improvement by two or more results using perfluorocarbon liquids. Arch Ophthalmol 1989;107:761–6.
Snellen lines11 Coll GE, Chang S, Sun J, et al. Perfluorocarbon liquid in the management of retinal detach-
Idiopathic macular hole 85% visual improvement by two or more lines12 ment with proliferative vitreoretinopathy. Ophthalmology 1994;102:630–8.
Dislocated lens fragments 68% final visual acuity 20/40 (6/12) or better13 Eckardt C. Transconjuctival sutureless 23 gauge vitrectomy. Retina 2005;25:208–11.
Fujii GY, De Juan E Jr, Humayun MS, et al. A new 25-gauge instrument system for transcon-
Retinal detachment 70%–90% primary reattachment rate14 junctival sutureless vitrectomy surgery. Ophthalmology 2002;109(10):1807–12, discussion
1813.
Gardner T, Blankenship GW. Proliferative diabetic retinopathy: principles and techniques
of surgical treatment. In: Ryan S, Glaser BM, editors. Retina. 2nd ed. St Louis: Mosby;
BOX 6.12.2 Potential Complications of Vitreous Surgery 1994.
Koenig SB, Mieler WF, Han DP, et al. Combined phacoemulsification, pars plana vitrectomy,
Intraoperatively and posterior chamber intraocular lens insertion. Arch Ophthalmol 1992;110:1101–4.
• Corneal epithelial defect McDonald HR, Johnson RN, Ai E, et al. Macular epiretinal membranes. In: Ryan S, Glaser
• Posterior retinal breaks BM, editors. Retina. 4th ed. St Louis: Mosby; 2006.
Melberg NS, Thomas MA, Dickinson JD, et al. Surgical removal of subfoveal choroidal neo-
• Peripheral retinal breaks vascularization: ingrowth site as a predictor of visual outcome. Retina 1996;16:190–5.
• Choroidal hemorrhage (rare) Oshima Y, Wakabayashi T, Sato T, et al. A 27-gauge instrument system for transconjunctival
sutureless microincision vitrectomy surgery. Ophthalmology 2010;117:93–102.e2.
Postoperatively Sjaarda RN, Thompson JT. Macular hole. In: Ryan S, Glaser BM, editors. Retina. 4th ed. St
• Retinal breaks Louis: Mosby; 2006.
• Rhegmatogenous retinal detachment Thompson JT, de Bustros S, Michels RG, et al. Results and prognostic factors in vitrectomy
• Elevated intraocular pressure (multiple potential causes) for diabetic vitreous hemorrhage. Arch Ophthalmol 1987;105:191–5.
• Neovascular glaucoma
• Angle-closure glaucoma Access the complete reference list online at ExpertConsult.com
• Inflammatory debris
• Corticosteroid response
• Overfilling with gas
• Anterior hyaloidal fibrovascular proliferation
• Fibrin deposition in the anterior chamber (not rare, especially in
individuals with diabetes)
• Progressive nuclear sclerosis (almost universal in phakic eyes)
• Corneal decompensation
• Hypotony
• Endophthalmitis (incidence 1 in 2500)
478
booksmedicos.org
REFERENCES 8. Thompson JT, de Bustros S, Michels RG, et al. Results and prognostic factors in vitrec-
tomy for diabetic vitreous hemorrhage. Arch Ophthalmol 1987;105:191–5.
1. Eckardt C. Transconjuctival sutureless 23 gauge vitrectomy. Retina 2005;25:208–11.
2. Fujii GY, De Juan E Jr, Humayun MS, et al. A new 25-gauge instrument system for
9. Gardner T, Blankenship GW. Proliferative diabetic retinopathy: principles and techniques
of surgical treatment. In: Ryan S, Glaser BM, editors. Retina. 2nd ed. St Louis: Mosby;
6.12
transconjunctival sutureless vitrectomy surgery. Ophthalmology 2002;109(10):1807–12, 1994.
10. Coll GE, Chang S, Sun J, et al. Perfluorocarbon liquid in the management of retinal
Vitrectomy
discussion 1813.
3. Oshima Y, Wakabayashi T, Sato T, et al. A 27-gauge instrument system for transconjunc- detachment with proliferative vitreoretinopathy. Ophthalmology 1994;102:630–8.
tival sutureless microincision vitrectomy surgery. Ophthalmology 2010;117:93–102.e2. 11. McDonald HR, Johnson RN, Ai E, et al. Macular epiretinal membranes. In: Ryan S,
4. Koenig SB, Mieler WF, Han DP, et al. Combined phacoemulsification, pars plana vitrec- Glaser BM, editors. Retina. 4th ed. St Louis: Mosby; 2006.
tomy, and posterior chamber intraocular lens insertion. Arch Ophthalmol 1992;110:1101–4. 12. Sjaarda RN, Thompson JT. Macular hole. In: Ryan S, Glaser BM, editors. Retina. 4th ed.
5. Chang S, Lincoff H, Zimmerman NJ, et al. Giant retinal tears: surgical techniques and St Louis: Mosby; 2006.
results using perfluorocarbon liquids. Arch Ophthalmol 1989;107:761–6. 13. Borne MJ, Tasman W, Regillo C, et al. Outcomes of vitrectomy for retained lens frag-
6. Chang S. Intraocular gases. In: Ryan S, Glaser BM, editors. Retina. 2nd ed. St Louis: ments. Ophthalmology 1996;103:971–6.
Mosby; 1994. 14. Steel D. Retinal Detachment. BMJ Clin Evid. 2014;2014:pii: 0710.
7. Abrams GW, Azen SP, McCuen BW II, et al. Vitrectomy with silicone oil or long-acting
gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term
follow-up. Silicone Study Report 11. Arch Ophthalmol 1997;115:335–44.
478.e1
booksmedicos.org
Intravitreal Injections and

Medication Implants 6.13
Ryan W. Shultz, Maya H. Maloney, Sophie J. Bakri
Definition: Intravitreal injections and implants, most often BOX 6.13.1 Intravitreal Injection Technique
administered as an office procedure, are a safe, effective, and common Recommendations
method of delivering medication locally to the eye.
Preinjection
• External ocular examination, visual acuity, and intraocular pressure
check
Key Features • Informed consent form
• Topical anesthesia is usually sufficient. • Anesthesia (topical or subconjunctival)
• Sterile technique is used. • Topical povidone–iodine (5% for the ocular surface, 10% for the lids
• Small-gauge needles (30-gauge or smaller) can be used for and lashes)
intravitreal injections. Injection
• Effective method to deliver antivascular endothelial growth factor • Surgical pause confirming the correct patient, laterality, and
medications, corticosteroids, antibacterial and antiviral agents, air, medication
and gas. • Surgical gloves (sterile or nonsterile)
• Placement of sterile lid speculum or manual lid retraction
• Caliper to measure 3.5–4.0 mm posterior to limbus in preferred
Associated Features quadrant
Complications include:

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Ophthalmology

Edinburgh London New York Oxford Philadelphia St Louis Sydney 2019

First edition 1999

Chapter 6.5: “Contact B-Scan Ultrasonography” by Yale L. Fisher, Dov B. Sebrow

Chapter 7.2: “Mechanisms of Uveitis” by Igal Gery, Chi-Chao Chan

Chapter 11.8: “Torsional Strabismus” by Scott K. McClatchey, Linda R. Dagi

Content Strategist: Russell Gabbedy

Last digit is the print number: 9 8 7 6 5 4 3 2 1

Part 2: Optics and Refraction

Part 3: Refractive Surgery

Part 4: Cornea and Ocular Surface Diseases

Part 5: The Lens

Part 6: Retina and Vitreous

Part 7: Uveitis and Other Intraocular Inflammations

Part 8: Intraocular Tumors

Part 10: Glaucoma

Part 11: Pediatric and Adult Strabismus

Part 12: Orbit and Oculoplastics

Chapter 5.9 Phacoemulsification Part 10: Glaucoma

Preface to First Edition

Fundamentals of Human Genetics

DNA double helix

Fundamentals of Human Genetics

Anaphase Metaphase Anaphase II

large egg and

normal 9 der (9) myelogenous leukemia) is

Fundamentals of Human Genetics

Pedigrees with a mitochondrial trait

normal female fraternal twins

affected. Incontinentia pigmenti is probably inherited as an X-linked dom-

Fundamentals of Human Genetics

3’ AC T AC T AC T A A A AC T C T GG T T G ACC T G AC ACCCC T C T CCC T C T C T T T GG T A T GG T ACC T GG A AG 5’

insertions donor template

T A A A AC T C TGG T TGACC TGAC AGC TGT CC T CCCC T C T CCC T C T C T T TGG

A T T T TGAGACC A AC TGGA T TG T CGAC AGGA A T T TGC AGG T A TGGGGAGAGGGA

T A A A AC T C TGG T TGACC T A AC AGC TGT CC T T A A ACG T CC A T ACCCC T C T CCC T

Fundamentals of Human Genetics

Molecular Genetics of Selected

trichrome and have been termed “hyalin.” In lattice dystrophy, branching

Schematic gene structure

ATG 5a TAA 368

1 2 3 4 5 6 7 8 9 10 11 12 13 72 179 259 501

Proposed protein structure

Molecular Genetics of Selected Ocular Disorders

Fig. 1.2.4 Human Rhodopsin Mutations. The red

G90D P23H K296E A292E

1 biological activity or because they interfere with the normal expression of

SORSBY’S MACULAR DYSTROPHY ALBINISM

Mutations in mitochondrial DNA are an important cause of human

Molecular Genetics of Selected Ocular Disorders

retina tumor CONGENITAL FIBROSIS SYNDROMES AND

retina AUTOSOMAL DOMINANT OPTIC ATROPHY

Fig. 1.2.6 Metabolism of Tyrosine to Produce

tyrosine tyrosine hydroxylase dihydroxyphenylalanine dopamine

Molecular Genetics of Selected Ocular Disorders

Genetic Testing and Genetic Counseling

1 sufficient specificity and sensitivity that testing will be clinically useful.

Genetic Testing and Genetic Counseling

Ocular Defects Associated With Genetic Diseases

Fig. 2.5.9 The 60 D, 78 D, and 90 D lenses produce