Commissioning Editor: Russell Gabbedy

Development Editor: Ben Davie

Editorial Assistant: Kirsten Lowson
Project Manager: Srikumar Narayanan
Design: Charles Gray
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Marketing Managers (UK/USA): Richard Jones / Radha Mawrie
Ocular Disease: Mechanisms
and Management

Leonard A. Levin, md, phd Daniel M. Albert, md, ms

Canada Research Chair of Ophthalmology and Visual Sciences RRF Emmett A. Humble Distinguished Director of
University of Montreal the UW Eye Research Institute
Montreal, Quebec, Canada F.A. Davis Professor, Department of Ophthalmology
Professor of Ophthalmology and Visual Sciences and Visual Sciences
University of Wisconsin School of Medicine and Public Health
Madison, WI, USA University of Wisconsin-Madison
University of Wisconsin
Madison, WI, USA
SAUNDERS an imprint of Elsevier Inc

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The chapter entitled 44. Optic Atrophy is in the public domain.

First published 2010

The right of Leonard A. Levin and Daniel M. Albert to be identified as authors of this work has been asserted by them in accordance with the
Copyright, Designs and Patents Act 1988.

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List of Contributors

Anthony P Adamis MD Sally S Atherton PhD Audrey M Bernstein PhD

Adjunct Professor Regents Professor and Chair Assistant Professor of Ophthalmology
Division of Ophthalmology and Department of Cellular Biology Department of Ophthalmology
Visual Sciences and Anatomy Mount Sinai School of Medicine
University of Illinois College of Medicine Medical College of Georgia New York, NY, USA
Bronxville, NY, USA Augusta, GA, USA
Pooja Bhat MD
Grazyna Adamus PhD Tin Aung MBBS MMed(Ophth) Fellow
Professor of Ophthalmology and FRCS(Ed) FRCOphth Massachusetts Eye Research &
Graduate Neuroscience Senior Consultant and Head Surgery Institute
Ocular Immunology Laboratory Glaucoma Service Cambridge, MA, USA
Casey Eye Institute Singapore National Eye Centre,
Department of Ophthalmology Deputy Director, Singapore Eye Douglas Borchman PhD
Oregon Health and Science University Research Institute, Professor
Portland, OR, USA Associate Professor Department of Ophthalmology and
National University of Singapore Visual Sciences
Daniel M Albert MD MS Singapore Kentucky Lions Eye Center
Emmett A Humble Distinguished Director University of Louisville
Eye Research Institute, Rebecca S Bahn MD Louisville, KY, USA
Professor and Chair Emeritus, Professor of Medicine
F A Davis Professor, Division of Endocrinology Stephen Brocchini
Lorenz E Zimmerman Professor Mayo Clinic Professor of Chemical Pharmaceutics
Ophthalmology & Visual Sciences Rochester, MN, USA Department of Pharmaceutics
School of Medicine and Public Health The School of Pharmacy
Clinical Sciences Center David Sander Bardenstein MD University of London
University of Wisconsin Professor London, UK
Madison, WI, USA Departments of Ophthamology and Visual
Sciences, and Pathology Claude Burgoyne MD
Ann-Christin Albertsmeyer Can Med Case Western Reserve University School Research Director
Research Assistant (Predoctoral) of Medicine Optic Nerve Head Research Laboratory
Department of Ophthalmology Cleveland, OH, USA Devers Eye Institute
Schepens Eye Research Institute Portland, OR, USA
Boston, MA, USA Neal P Barney MD
Associate Professor of Ophthalmology Michelle Trager Cabrera MD
Nishani Amerasinghe BSc MBBS MRCOphth Department of Ophthalmology and Clinical Associate
Specialist Registrar Visual Sciences Department of Opthalmology
Southampton Eye Unit University of Wisconsin School of Medicine Duke University
Southampton University Hospitals Madison, WI, USA Durham, NC, USA
NHS Trust
Southampton, UK David C Beebe PhD FARVO Richard J Cenedella
The Janet and Bernard Becker Professor of Professor
Michael G Anderson PhD Ophthalmology and Visual Sciences, Department of Biochemistry
Assistant Professor of Molecular Physiology Professor of Cell Biology and Physiology A T Still University of Health Sciences,
and Biophysics Department of Ophthalmology and Kirksville College of Osteopathic Medicine
Department of Molecular Physiology Visual Sciences Kirksville, MO, USA
and Biophysics Washington University
University of Iowa St Louis, MO, USA Jin-Hong Chang PhD
Iowa City, IA, USA Assistant Professor of Ophthalmology
Adrienne Berman MD Department of Opthalmology and
Clinical Assistant Professor Visual Sciences
Department of Ophthalmology and University of Illinois at Chicago
Visual Sciences Chicago, IL, USA
University of Illinois Eye and Ear Infirmary
Chicago, IL, USA
 List of Contributors

Aimee Chappelow MD Annegret Hella Dahlmann-Noor Joseph L Demer MD PhD

Cole Eye Institute Dr med PhD FRCOphth FRCS(Ed) DipMedEd The Leonard Apt Professor of
The Cleveland Clinic Foundation Senior Clinical Research Associate Ophthalmology,
Cleveland, OH, USA Ocular Biology and Therapeutics Professor of Neurology
UCL Institute of Ophthalmology Jules Stein Eye Institute
Anuj Chauhan PhD London, UK David Geffen School of Medicine
Associate Professor and Director of University of California, Los Angeles
the Graduate Programs Reza Dana MD MPH MSc Los Angeles, CA, USA
Department of Chemical Engineering Professor and Director of Cornea Service
University of Florida Massachusetts Eye & Ear Infirmary Suzanne M Dintzis MD PhD
Gainesville, FL, USA Harvard Medical School Assistant Professor
Boston, MA, USA Department of Pathology
Abbot F Clark PhD University of Washington School of
Professor of Cell Biology and Anatomy Helen Danesh-Meyer MBChB FRANZCO Medicine
and Director Sir William & Lady Stevenson Associate Seattle, WA, USA
North Texas Eye Research Institute Professor of Ophthalmology
University of North Texas Health Department of Ophthalmology J Crawford Downs PhD
Science Center University of Auckland Associate Scientist and Research Director
Fort Worth, TX, USA Auckland, New Zealand Ocular Biomechanics Laboratory
Devers Eye Institute
Ellen B Cook PhD Julie T Daniels BSc(Hons) PhD Portland, OR, USA
Associate Scientist Reader in Stem Cell Biology and
Department of Medicine Transplantation Henry Edelhauser PhD
University of Wisconsin School of Medicine UCL Institute of Ophthalmology Ferst Professor and Director of
and Public Health London, UK Ophthalmology Research
Madison, WI, USA Department of Ophthalmology
Darlene A Dartt PhD Emory University Eye Center
Zélia M Corrêa MD PhD Senior Scientist, Harold F. Johnson Atlanta, GA, USA
Assistant Professor of Ophthalmology Research Scholar
Department of Ophthalmology Schepens Eye Research Institute, David Ellenberg MD
University of Cincinnati College Associate Professor Research Fellow
of Medicine Harvard Medical School Department of Ophthalmology and
Cincinnati, OH, USA Schepens Eye Research Institute Visual Sciences
Boston, MA, USA University of Illinois at Chicago
Scott Cousins MD Chicago, IL, USA
The Robert Machemer Professor of Mohammad H Dastjerdi MD
Ophthalmology and Immunology, Postdoctoral Fellow Victor Elner MD PhD
Vice Chair for Research Schepens Eye Research Institute The Ravitz Foundation Professor of
Department of Ophthalmology Boston, MA, USA Ophthlamology and Visual Sciences
Duke University School of Medicine Professor, Department of Pathology
Durham, NC, USA Nigel W Daw PhD Kellogg Eye Center
Professor Emeritus of Ophthalmology and University of Michigan
Gerald Cox MD PhD FACMG Visual Science Ann Arbor, MI, USA
Staff Physician in Genetics, Children’s Departments of Ophthalmology and
Hospital Boston Visual Science Steven K Fisher PhD
Instructor of Pediatrics, Harvard University of Yale Professor, Molecular Cellular and
Medical School New Haven, CT, USA Developmental Biology
Vice President of Clinical Research Neuroscience Research Institute
Genzyme Corporation Daniel G Dawson MD University of California, Santa Barbara
Cambridge, MA, USA Visiting Assistant Professor of Santa Barbara, CA, USA
Ophthalmology
Scott Adam Croes MS PhD Emory University Eye Center Robert Folberg MD
Professor of Human Anatomy Atlanta, GA, USA Dean, Oakland University William
and Physiology Beaumont School of Medicine,
Department of Biology Alejandra de Alba Campomanes Professor of Biomedical Sciences, Pathology,
Shasta College MD MPH and Ophthalmology
Redding, CA, USA Director of Pediatric Ophthalmology Oakland University William Beaumont
San Francisco General Hospital School of Medicine
Karl G Csaky MD PhD San Francisco, CA, USA Rochester, MI, USA
Associate Professor
Department of Ophthalmology
Duke University
Durham, NC, USA

x

C Stephen Foster MD FACS FACR
Founder and President, Ocular Immunology
and Uveitis Foundation,
Clinical Professor of Ophthalmology
Harvard Medical School,
Founder and President
Massachusetts Eye Research and
Surgery Institution
Cambridge, MA, USA
Gary N Foulks MD FACS
The Arthur and Virginia Keeney Professor
of Ophthalmology and Vision Science
Division of Ophthalmology
University of Louisville School of Medicine
Louisville, KY, USA
Frederick T Fraunfelder MD
Professor of Ophthalmology
Casey Eye Institute
Portland, OR, USA
Frederick W Fraunfelder MD
Associate Professor of Ophthalmology
Casey Eye Institute
Portland, OR, USA
Anne Fulton MD
Senior Associate in Ophthalmology
Department of Ophthalmology
Children’s Hospital Boston
Boston, MA, USA
Ronald Gaster MD
Professor of Ophthalmology
Department of Opthalmology
University of California
Irvine, CA, USA
Stylianos Georgoulas MD
Ocular Repair and Regeneration
Biology Unit
UCL Institute of Ophthalmology
London, UK
Michael S Gilmore PhD
The C L Schepens Professor of
Ophthalmology
Harvard Medical School,
Senior Scientist
Schepens Eye Research Institute
Boston, MA, USA
Ilene K Gipson PhD
Senior Scientist and Professor of
Ophthalmology
Department of Ophthalmology
Schepens Eye Research Institute
Boston, MA, USA
Michaël J A Girard PhD
Ocular Biomechanics Laboratory
Devers Eye Institute, Legacy Health System
Portland, OR, USA
Lynn K Gordon MD PhD
Associate Professor Ophthalmology
Jules Stein Eye Institute
UCLA School of Medicine
Los Angeles, CA, USA
Irene Gottlob MD
Professor of Ophthalmology
Department of Cardiovascular Sciences
Ophthalmology Group
University of Leicester
Leicester Royal Infirmary
Leicester, UK
John D Gottsch MD
The Margaret C Mosher Professor of
Ophthalmology
Johns Hopkins School of Medicine
Wilmer Eye Institute
Baltimore, MD, USA
Frank M Graziano MD PhD
Professor of Medicine
Department of Medicine
University of Wisconsin School of Medicine
and Public Health
Madison, WI, USA
Hans E Grossniklaus MD MBA
Professor of Medicine
Emory Eye Center
Emory University School of Medicine
Atlanta, GA, USA
Deborah Grzybowski PhD
Professor of Ophthalmology and
Biomedical Engineering
The Ohio State University
College of Medicine
Columbus, OH, USA
Clyde Guidry PhD
Associate Professor of Ophthalmology
Department of Ophthalmology
University of Alabama School of Medicine
Birmingham, AB, USA
Neeru Gupta MD PhD FRCSC DABO
Professor of Ophthalmology and Vision
Sciences, Laboratory Medicine and
Pathobiology, University of Toronto,
Director
Glaucoma & Nerve Protection Unit
Keenan Research Centre at the Li Ka Shing
Knowledge Institute
St Michael’s Hospital
Toronto, ON, Canada
David H Gutmann MD PhD
The Donald O Schnuck Family Professor
Department of Neurology,
Director, Neurofibromatosis Center
Washington University School of Medicine
St Louis, MO, USA
List of Contributors
Vinay Gutti MD
Private Practice
Cornea, External Disease and
Refractive Surgery
La Mirada Eye and Laser Center
La Mirada, CA, USA
John R Guy MD
Bascom Palmer Eye Institute
Miami, FL, USA
J William Harbour MD
The Paul A Cibis Distinguished Professor
of Ophthalmology
Department of Ophthalmology and
Visual Sciences
Washington University School of Medicine
St Louis, MO, USA
Mary Elizabeth Hartnett MD
Professor of Ophthalmology
Department of Ophthalmology
University of North Carolina
Chapel Hill, NC, USA
Sohan S Hayreh MD MS PhD DSc FRCS(Edin)
FRCS(Eng) FRCOphth(Hon)
Professor Emeritus of Ophthalmology
Department of Ophthalmology & Director
Ocular Vascular Clinic
University of Iowa Hospitals and Clinics
Iowa City, IA, USA
Susan Heimer PhD
Postdoctoral Research Fellow
Schepens Eye Research Institute and
Department of Ophthalmology
Harvard Medical School
Boston, MA, USA
Robert Hess DSc
Professor and Director of Research
Department of Ophthalmology
McGill University
Montreal, QC, Canada
Nancy M Holekamp MD
Partner, Barnes Retina Institute,
Professor of Clinical Ophthalmology
Department of Ophthalmology and
Visual Sciences
Washington University School of Medicine
St Louis, MO, USA
Suber S Huang MD MBA
The Philip F. and Elizabeth G. Searle
Professor of Ophthalmology,
Vice-Chair, Department of Ophthalmology
& Visual Sciences
Case Western Reserve University School
of Medicine,
Director, Center for Retina and
Macular Disease
University Hospitals Eye Institute
Cleveland, OH, USA
xi
 List of Contributors

Sudha K Iyengar PhD Peng Tee Khaw PhD FRCP FRCS FRCOphth Leonard A Levin MD PhD
Professor FIBiol FRCPath FMedSci Canada Research Chair of Ophthalmology
Departments of Epidemiology & Biostatistics Professor of Ocular Healing and Glaucoma and Visual Sciences
and Department of Ophthalmology and Consultant Ophthalmic Surgeon, Department of Ophthalmology
Case Western Reserve University Director of Research and Development, University of Montreal,
Cleveland, OH, USA Moorfields Eye Hospital NHS Professor, Department of Ophthalmology
Foundation Trust, and Visual Sciences
Allen T Jackson Director, National Institute for Health University of Wisconsin
Massachusetts Eye Research and Biomedical Research Centre, Madison, WI, USA
Surgery Institute Programme Director, Eyes & Vision, UCL
Harvard Medical School Partners Academic Health Science Centre Geoffrey P Lewis PhD
Cambridge, MA, USA London, UK Research Biologist, Neurobiology
Neuroscience Research Institute
L Alan Johnson MD Alice S Kim MD University of California, Santa Barbara
Private Practice Division of Ophthalmology Santa Barbara, CA, USA
Sierra Eye Associates Maimonides Medical Center
Reno, NV, USA Brooklyn, NY, USA Zhuqing Li MD PhD
Staff Scientist
Peter F Kador PhD Henry Klassen MD PhD Laboratory of Immunology
Professor Assistant Professor National Eye Institute
Departments of Ophthalmology and Department of Ophthalmology National Institutes of Health
Pharmaceutical Sciences University of California, Irvine, Bethesda, MD, USA
University of Nebraska Medical Center School of Medicine
Omaha, NE, USA Orange, CA, USA Amy Lin MD
Assistant Professor of Ophthalmology
Alon Kahana MD PhD Paul Knepper MD PhD Department of Ophthalmology
Full Member, University of Michigan Research Scientist Loyola University
Comprehensive Cancer Center, University of Illinois at Chicago Maywood, IL, USA
Attending Surgeon, C S Mott Department of Opthalmology &
Children’s Hospital, Visual Science Robert A Linsenmeier PhD
Assistant Professor Chicago, IL, USA Professor of Biomedical Engineering,
Department of Ophthalmology and Neurobiology & Physiology, and
Visual Sciences Jane F Koretz PhD Ophthalmology
Kellogg Eye Center Professor of Biophysics Biomedical Engineering Department
University of Michigan Biochemistry and Biophysics Program Northwestern University
Ann Arbor, MI, USA Rensselaer Polytechnic Institute, Evanston, IL, USA
Science Center
Randy Kardon MD PhD Troy, NY, USA Robert Listernick MD
Professor and Director of Professor of Pediatrics, Feinberg School of
Neuro-ophthalmology, Mirunalini Kumaradas MD Opth(SL) Medicine, Northwestern University,
Pomerantz Family Chair in Ophthalmology, FRCS (UK) Attending Physician
Director for Iowa City VA Center for Lecturer Division of General Academic Pediatrics
Prevention and Treatment of Vision Loss Faculty of Medicine Children’s Memorial Hospital
Department of Ophthalmology and University of Colombo Chicago, IL, USA
Visual Sciences Colombo, Sri Lanka
University of Iowa and Department of Martin Lubow MD
Veterans Affairs Jonathan H Lass MD Associate Professor of Ophthalmology
Iowa City, IA, USA The Charles I Thomas Professor and Department of Ophthalmology
Chairman The Ohio State University Eye and
Maria Cristina Kenney MD PhD Department of Ophthalmology and Ear Institute
Professor of Ophthalmology Visual Sciences Columbus, OH, USA
The Gavin Herbert Eye Institute Case Western Reserve University,
Orange, CA, USA Director, University Hospitals Eye Institute Andrew Maniotis PhD
Cleveland, OH, USA Visiting Associate Professor of
Timothy Scott Kern PhD Bioengineering
Professor of Medicine David Lederer MD Division of Science and Engineering
Department of Medicine Fellow University of Illinois at Chicago
Division of Clinical and Molecular Department of Ophthalmology Chicago, IL, USA
Endocrinology Duke University
Center for Diabetes Research Durham, NC, USA Pascale Massin MD PhD
Case Western Reserve University Professor of Ophthalmology
Cleveland, OH, USA Mark Lesk MSc MD FRCS(C) CM DABO Ophthalmology Department
Director of Vision Health Research Lariboisiere Hospital
University of Montreal Paris, France
Montreal, QC, Canada

xii

Katie Matatall BS
Department of Ophthalmology &
Visual Sciences
Washington University School of Medicine
St Louis, MO, USA
Russell L McCally PhD
Associate Professor of Ophthalmology,
The Wilmer Eye Institute, Johns Hopkins
Medical Institutions
Principal Professional Staff
Applied Physics Laboratory
Johns Hopkins University
Laurel, MD, USA
Stephen D McLeod MD
Professor of Ophthalmology
Department of Ophthalmology
University of California San Francisco
San Francisco, CA, USA
Muhammad Memon MD
Visiting Academic
Department of Neuroscience
Imperial College London
London, UK
Joan W Miller MD
The Henry Willard Williams Professor of
Ophthalmology and Chair, Harvard
Medical School,
Chief, Department of Ophthalmology
Massachusetts Eye and Ear Infirmary
Boston, MA, USA
Austin K Mircheff PhD
Professor of Physiology & Biophysics and
Professor of Ophthalmology
Department of Physiology & Biophysics
Keck School of Medicine
University of Southern California
Los Angeles, CA, USA
Jay Neitz PhD
The Bishop Professor
Department of Ophthalmology
University of Washington
Seattle, WA, USA
Maureen Neitz PhD
The Ray H Hill Professor
Department of Ophthalmology
University of Washington
Seattle, WA, USA
Christine C Nelson MD FACS
Professor of Ophthalmology and Surgery
Kellog Eye Center
University of Michigan
Ann Arbor, MI, USA
Robert Nickells BSc PhD
Professor of Ophthalmology and
Visual Sciences
Department of Ophthalmology and
Visual Sciences
University of Wisconsin
Madison, WI, USA
Robert B Nussenblatt MD MPH
Department of Pathology and
Cancer Center
University of Illinois
Chicago, IL, USA
Joan M O’Brien MD
Professor of Ophthalmology and Pediatrics
Comprehensive Cancer Center
University of California San Francisco
San Francisco, CA, USA
Daniel T Organisciak PhD
Professor of Biochemistry and
Molecular Biology,
Director, Petticrew Research Laboratory
Department of Biochemistry and
Molecular Biology
Boonshoft School of Medicine
Wright State University
Dayton, OH, USA
Michel Paques MD PhD
Professor of Ophthalmology
Clinical Investigation Center
XV-XX Hospital and University of Paris VI
Paris, France
Heather R Pelzel BSc
Research Assistant
Department of Ophthalmology and
Visual Sciences
University of Wisconsin
Madison, WI, USA
Shamira Perera MBBS BSc FRCOphth
Research Fellow, Singapore Eye
Research Institute,
Consultant
Glaucoma Service
Singapore National Eye Centre
Singapore
Eric A Pierce MD PhD
Associate Professor of Ophthalmology
F M Kirby Center for Molecular
Ophthalmology
University of Pennsylvania School of
Medicine
Philadelphia, PA, USA
Jean Pournaras MD
Research Fellow
Service d’ophtalmologie
Hôpital Lariboisière
Paris, France
List of Contributors
Jonathan T Pribila MD, PhD
Pediatric Ophthalmology and Adult
Strabismus Fellow
Department of Ophthalmology
University of Minnesota
Minneapolis, MN, USA
Frank A Proudlock PhD
Lecturer in Ophthalmology
Ophthalmology Group
University of Leicester
Robert Kilpatrick Clinical Sciences Building
Leicester Royal Infirmary
Leicester, UK
Xiaoping Qi MD
Associate Scientist of Ophthalmology
College of Medicine
University of Florida
Gainesville, FL, USA
Narsing A Rao MD
Professor of Ophthalmology and Pathology,
Keck School of Medicine, University of
Southern California,
Director of Experimental Ophthalmic
Pathology and Ocular Inflammations
Doheny Eye Institute
Los Angeles, CA, USA
Robert Ritch MD
Professor of Ophthalmology, New York
Medical College, Valhalla, NY,
The Shelley and Steven Einhorn
Distinguished Chair in Ophthalmology,
Chief, Glaucoma Services
Surgeon Director
New York Eye and Ear Infirmary
New York, NY, USA
Joseph F Rizzo III
Associate Professor of Ophthalmology
Massachusetts Eye and Ear Infirmary
Harvard Medical School
Boston, MA, USA
Michael D Roberts PhD
Post Doctoral Research Fellow
Ocular Biomechanics Laboratory
Devers Eye Institute
Portland, OR, USA
James T Rosenbaum MD
Professor of Ophthalmology, Medicine and
Cell Biology
The Edward E Rosenbaum Professor of
Inflammation Research
Oregon Health & Science University
Portland, OR, USA
Barry Rouse PhD DSc
Distinguished Professor
Department of Pathobiology
University of Tennessee
Knoxville, TN, USA
xiii
 List of Contributors

Daniel R Saban PhD Genevieve Aleta Secker PhD BSc Arun N E Sundaram MBBS FRCPC
Postdoctoral Fellow in Ophthalmology Post-Doctoral Fellow Fellow, Division of Neurology and Vision
Division of Ophthalmology SA Pathology Sciences Research Program, University of
Schepens Eye Research Institute Centre for Cancer Biology Toronto,
Boston, MA, USA Department of Haematology Consultant
Adelaide, SA, Australia Neuro-ophthalmology Center
Alfredo A Sadun MD PhD University Health Network
Thornton Professor of Ophthalmology Srilakshmi M Sharma MRCP MRCOphth Toronto, ON, Canada
and Neurosurgery Uveitis Fellow
Department of Ophthalmology Bristol Eye Hospital Janet S Sunness MD
USC Keck School of Medicine University of Bristol NHS Trust Medical Director
Los Angeles, CA, USA Bristol, UK Richard E Hoover Rehabilitation Services
for Low Vision and Blindness
Abbas K Samadi PhD James A Sharpe MD FRCPC Greater Baltimore Medical Center
Assistant Professor of Surgery and Professor of Neurology, Medicine, Baltimore, MD, USA
Biochemistry Ophthalmology and Visual Sciences, and
Department of Biochemistry Otolaryngology, University of Toronto, Nathan T Tagg MD
University of Kansas Medical Center Director Neurologist and Neuro-ophthalmologist
Kansas City, KS, USA Neuro-ophthalmology Center Walter Reed Army Medical Center
University Health Network National Naval Medical Center
Pranita Sarangi BVSc&AH PhD Toronto, ON, Canada Bethesda, MD, USA
Postdoctoral Research Associate
David H Smith Center for Vaccine Biology Heather Sheardown BEng PhD Daniela Toffoli MD
and Immunology Professor Ophthalmology Resident, PGY-5
University of Rochester Medical Center Department of Chemical Engineering and Department of Ophthalmology
Rochester, NY, USA School of Biomedical Engineering Université de Montréal
McMaster University Montréal, QC, Canada
Andrew P Schachat MD Hamilton, ON, Canada
Professor of Ophthalmology, Lerner College Cynthia A Toth MD
of Medicine Alex Shortt MD PhD MRCOphth Professor of Ophthalmology and
Vice Chairman Clinical Lecturer in Ophthalmic Biomedical Engineering
Cole Eye Institute Translational Research Department of Biomedical Engineering
Cleveland Clinic Foundation Biomedical Research Centre for Duke University
Cleveland, OH, USA Ophthalmology Durham, NC, USA
Moorfields Eye Hospital
Joel E Schechter PhD London, UK Elias I Traboulsi MD
Professor of Cell and Neurobiology Professor of Ophthalmology
Keck School of Medicine Ying-Bo Shui MD PhD Cleveland Clinic Lerner College of Medicine
University of Southern California Senior Scientist Case University
Los Angeles, CA, USA Department of Ophthalmology and The Cole Eye Institute
Visual Sciences Cleveland, OH, USA
A Reagan Schiefer MD Washington University in St Louis
Trainee in Endocrinology St Louis, MO, USA James C Tsai MD
Division of Endocrinology The Robert R Young Professor and
Mayo Clinic Ian Sigal PhD Chairman
Rochester, MN, USA Research Associate Department of Ophthalmology and
Devers Eye Institute Visual Science
Ursula Schlötzer-Schrehardt ProfDr Ocular Biomechanics Laboratory Yale University School of Medicine,
Professor Portland, OR, USA Chief of Ophthalmology, Yale-New
Department of Ophthalmology Haven Hospital
University of Erlangen-Nürnberg James L Stahl PhD Yale Eye Center
Erlangen, Germany Associate Scientist New Haven, CT, USA
Department of Medicine
Ingo Schmack MD University of Wisconsin School of Medicine Budd Tucker PhD
Attending Physician and Public Health Investigator
University of Bochum Madison, WI, USA Department of Ophthalmology
Department of Ophthalmology Schepens Eye Research Institute, Harvard
Bochum, Germany Roger F Steinert MD Medical School
Professor and Chair of Ophthalmology, Boston, MA, USA
Leopold Schmetterer PhD Professor of Biomedical Engineering,
Professor Director, Gavin Herbert Eye Institute
Departments of Clinical Pharmacology and University of California Irvine
Biomedical Engineering and Physics Irvine, CA, USA
Medical University of Vienna
Vienna, Austria

xiv
 List of Contributors

Russell N Van Gelder MD PhD Chih-Wei Wu MD Yeni H Yücel MD PhD FRCPC

Boyd K Bucey Memorial Chair, Fellow, Cornea and External Eye Diseases Professor and Director, Ophthalmic
Professor and Chair Department of Ophthalmology and Pathology
Department of Ophthalmology, Visual Sciences Division of Ophthalmology &
Adjunct Professor University of Illinois at Chicago Vision Sciences
Department of Biological Structure Chicago, IL, USA Laboratory Medicine & Pathobiology,
University of Washington School University of Toronto
of Medicine Ai Yamada MD Keenan Research Centre at the Li Ka Shing
Seattle, WA, USA Postdoctoral Research Fellow Knowledge Institute
Schepens Eye Research Institute and St Michael’s Hospital
Hans Eberhard Völcker MD Department of Toronto, ON, Canada
Professor of Medicine Ophthalmology
Department of Ophthalmology Harvard Medical School Beatrice Y J T Yue PhD
University of Heidelberg Boston, MA, USA The Thanis A Field Professor of
Heidelberg, Germany Ophthalmology and Visual Sciences
Steven Yeh MD Department of Ophthalmology and
Christopher S von Bartheld MD Vitreoretinal Fellow Visual Sciences
Professor of Physiology and Cell Biology Casey Eye Institute University of Illinois at Chicago College
Department of Physiology and Cell Biology Oregon Health and Sciences University of Medicine
University of Nevada School of Medicine Casey Eye Institute, OHSU Chicago, IL, USA
Reno, NV, USA Portland, OR, USA
Marco A Zarbin MD PhD FACS
Jianhua Wang MD PhD Thomas Yorio PhD FARVO The Alfonse A Cinotti MD/Lions Eye
Assistant Professor, Bascom Palmer Professor of Pharmacology and Research Professor and Chair
Eye Institute Neuroscience, Institute of Ophthalmology and
Department of Ophthalmology Provost and Executive Vice President for Visual Science
University of Miami, Miller School of Academic Affairs New Jersey Medical School
Medicine University of North Texas Health Newark, NJ, USA
Miami, FL, USA Science Center
Fort Worth, TX, USA Xinyu Zhang PhD
Judith West-Mays PhD Senior Scientist II
Professor of Pathology and Michael J Young PhD BioTherapeutic
Molecular Medicine Director, deGunzburg Research Center for Alcon Research Ltd
Division of Pathology Retinal Transplantation, Fort Worth, TX, USA
McMaster University Associate Scientist, Schepens Eye
Hamilton, ON, Canada Research Institute, Mei Zheng MD
Associate Professor Resident
Corey B Westerfeld MD Department of Ophthalmology Department of Pathology
Vitreoretinal Surgeon Harvard Medical School Medical College of Georgia
Private Practice Boston, MA, USA Augusta, GA, USA
Eye Health Vision Center
Dartmouth, MA, USA Terri L Young MD FAAO FAOS FARVO
Professor of Neuroscience, Duke University,
Steven E Wilson MD National University of Singapore Graduate
Professor of Ophthalmology Medical School,
Staff Cornea and Refractive Surgeon, Professor of Ophthalmology, Pediatrics
Director, Cornea Research and Medicine
Cole Eye Institute Duke University Medical Center
Cleveland Clinic Foundation Durham, NC, USA
Cleveland, OH, USA

Fabricio Witzel de Medeiros MD

Department of Ophthalmology
University of São Paulo
São Paulo, Brazil

xv
Dedication

To our children: Emily, Eric, Eva, Rachel, and Eli (LAL)

Steven and Michael (DMA)

Foreword
Translational research offers both the opportunity and the
challenge for medical research in the decades ahead, as phy-
sicians and clinician-scientists work to understand disease
by utilizing the vast storehouse of detailed biological infor-
mation that has been uncovered about the eye and visual
system. Ultimately, the practice of medicine, and delivery of
care to ameliorate disease, advances best and most effectively
upon understanding the causative pathophysiology, as is
addressed in this book.
I am delighted to see the advances represented in the
chapters of this book. While no one volume can encompass
the entirety of the clinical medicine of ophthalmology, the
editors have assembled a broad and expert group of clini-
cian-scientists who have written thoughtfully and cogently
on many topics of modern ophthalmic disease research.
These chapters are multidisciplinary and provide a good
source of current knowledge. Clearly much work lies ahead
of us to fully understand the causes, biological mechanisms
and treatments of ocular and vision diseases. This book,
Ocular Disease: Mechanisms and Management, provides a sub-
stantial starting point to launch insightful studies that will
move our field even closer to rational therapeutics.
One of the drivers of this new understanding of disease
comes from the vigorous work of the vision research com-
munity over the past two decades, which has led to identify-
ing more than 500 genes that cause Mendelian ocular
diseases. These genes encompass a wide assortment of condi-
tions that clinicians diagnose and treat, and no tissues are
spared. We have identified genes that cause retinal and
macular degenerations, glaucoma, uveitis, cataract and
corneal dystrophies, optic neuropathies, and amblyopia,
strabismus and ocular motility disorders.
Disease gene discovery recently advanced into the previ-
ously intractable realm of the more common and wide-
spread conditions that have genetically complex etiology. In
2005 several groups independently identified the first gene
that conveys substantial risk for developing age-related
macular degeneration, the complement factor H gene.
Shortly thereafter several additional AMD risk genes were
identified in the immune pathways, including complement
modulatory factors, using the new and powerful techniques
of haplotype mapping and genome-wide association studies.
This new basic knowledge forced our attention toward the
immune cascade as harboring mechanisms that culminate
in vision loss from macular degeneration in as many as one
in seven of the elderly.
As disease gene identification rocketed ahead, attention
turned to genomics and studies of the expression, cellular
localization and biological function of the aberrant gene
products. It is these considerations that the present book
addresses, for ultimately a true understanding of disease
mechanisms, in many cases, lies buried within the genomic
biology of these diseases.
Studying any one of these genes requires major effort to
piece together an understanding of the relationship between
gene and disease. Consider, for example, the TIGR/MYOC
gene that encodes the protein myocillin that is expressed in
the trabecular meshwork. Mutations in this gene result in
early onset or even congenital dysregulation of intraocular
pressure and leads to severe glaucoma in humans. Yet labo-
ratory-created mice carrying the myocilin gene knockout
show only a minimal phenotype. Two lessons are immedi-
ately apparent: first, we have a long path ahead to translate
genetic discoveries into identifiable mechanisms of disease
and pathophysiology that will support rationally designed
therapeutic interventions. Second, although our field of eye
disease research is amazingly rich in mouse models that
generally mimic the human condition with good fidelity
across a variety of ocular conditions, the fullest understand-
ing of human disease mechanisms ultimately will require
that we turn our attention directly to careful and detailed
analysis of disease in human patients, as is considered in this
textbook.
The future for treating diseases of the eye and visual
system will require novel insight into disease biology. But
already we can see major areas of opportunity to employ a
new range of therapeutic interventions, from gene therapy
to stem cells for regenerative medicine. This new book is the
medical companion to the basic textbook Adler’s Physiology
of the Eye. This companion volume by Levin and Albert
tackles the translation of basic knowledge into the realm of
medical understanding and practice and thereby highlights
that the best of basic and clinical knowledge increasingly
have an interdependent existence and future.
Paul A. Sieving MD, PhD
Director, National Eye Institute, NIH
Bethesda, MD
September 2009
Preface
The eye is a microcosm for the world of disease. Its synonym,
“the globe,” has profound implications because, in addition
to the geometric meaning, within its tablespoon of contents
there is a world of physiology and pathophysiology. Autoim-
mune diseases, neoplasms, infections, neurodegenerations,
infarcts: these all occur within the eye and the eye’s transit
stations within the central nervous system. Almost all of the
same pathophysiological principles that apply to the eye
apply equally to the body.
This book is a guide to the world of ocular disease. Each
chapter is written by scientists who carry out exciting research
in the corresponding field. Like tour guides who are native
to a region or country, these experienced authors can help
the reader travel through a scientific landscape, pointing out
new features of familiar territory and blazing trails through
areas of wilderness. We believe this familiarity with the
mechanics of the disease lend each chapter an immediacy
and relevance that will inform the reader for and serve as a
map or GPS for his or her subsequent visits. The chapters
themselves are deliberately succinct, a Baedeker somewhere
between a gazetteer and a comprehensive travelogue, but
with all the critical details that make understanding of a
specific pathological mechanism possible.
This book arose from a long-running a series named
“Mechanisms of Ophthalmic Disease” in the Archives of
Ophthalmology. Similar goals to those enunciated above were
followed in soliciting chapters from internationally recog-
nized experts in specific areas of ophthalmic pathophysiol-
ogy, targeted to readers of the Archives who had curiosity
about current advances in diagnosing and treating eye
disease. The concept – focused reviews by working scientists
describing up-to-date research in a clinically relevant area
– has been carried through to “Ocular Disease: Mechanisms
and Management.” The world of disease is covered from
pole to pole, and the book is organized by “continent”, i.e.
area of disease. A short publication cycle has been used so
that the information contained within is as current today as
is possible with contemporary publishing technology. Criti-
cal references are at the end of each chapter, and more
extensive references are available online.
We hope that this book will be as instructive for the
readership as it has been for its editors and the authors in
its planning and writing. Its successful production would not
have been possible without the contributions of Laura Cruz,
who did the administrative organizing for the authors, and
the helpful involvement of the publisher, particularly Russell
Gabbedy and Ben Davie.
LAL
DMA