AAOSub Retina 2012 Syllabus

Retina 2012 The Winds of Change
Program Directors
Joan W Miller MD and Tarek S Hassan MD
In conjunction with the American Society of Retina Specialists, the Macula Society, the Retina Society, and Club Jules Gonin
McCormick Place Chicago, Illinois Friday Saturday, November 9 10, 2012 Presented by The American Academy of Ophthalmology
Sponsored by an unrestricted educational grant by Genentech and Regeneron
Retina 2012 Planning Group Joan W Miller MD Program Director Tarek S Hassan MD Program Director Pravin U Dugel MD Peter K Kaiser MD Former Program Directors 2011 Allen C Ho MD Joan W Miller MD 2010 Daniel F Martin MD Allen C Ho MD 2009 Antonio Capone Jr MD Daniel F Martin MD 2008 M Gilbert Grand MD Antonio Capone Jr MD 2007 John T Thompson MD M Gilbert Grand MD 2006 Emily Y Chew MD John T Thompson MD
2005 2004 2003 2002 2001 2000 1999 1998 1997 1996 1995
Michael T Trese MD Emily Y Chew MD William F Mieler MD Michael T Trese MD Kirk H Packo MD William F Mieler MD Mark S Blumenkranz MD Kirk H Packo MD George A Williams MD Mark S Blumenkranz MD Julia A Haller MD George A Williams MD Stanley Chang MD Julia A Haller MD Harry W Flynn Jr MD Stanley Chang MD H MacKenzie Freeman MD Harry W Flynn Jr MD H MacKenzie Freeman MD Thomas M Aaberg Sr MD Paul Sternberg Jr MD
Subspecialty Day Advisory Committee William F Mieler MD Associate Secretary Donald L Budenz MD MPH Daniel S Durrie MD Robert S Feder MD Leah Levi MBBS R Michael Siatkowski MD Jonathan B Rubenstein MD Secretary for Annual Meeting Staff Melanie R Rafaty CMP, Director, Scientific Meetings Ann LEstrange, Scientific Meetings Specialist Brandi Garrigus, Presenter Coordinator Debra Rosencrance CMP CAE, Vice President, Meetings & Exhibits Patricia Heinicke Jr, Editor Mark Ong, Designer Gina Comaduran, Cover Design
2012 American Academy of Ophthalmology. All rights reserved. No portion may be reproduced without express written consent of the American Academy of Ophthalmology.
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2012 Subspecialty Day
Retina
Dear Colleague: On behalf of the American Academy of Ophthalmology and the American Society of Retina Specialists, the Macula Society, the Retina Society, and Club Jules Gonin, it is our pleasure to welcome you to Chicago and to Retina 2012: The Winds of Change. The standard components of Retina Subspecialty Day are the lectures and panel discussions presented by leading experts from around the world. We have created opportunities for lively and spirited discussions of controversial issues, including a rapid-fire presentation of My Coolest Surgical Video by innovative surgical leaders, with commentary by an expert panel and followed by an audience vote, debate teams presenting arguments on contested topics in the management of diabetic retinopathy with audience pre- and post-debate voting, and expert panels on surgical complications. We continue the tradition of holding discussion panels on the topics of AMD management, retinal vein occlusion, pediatric retinal surgery, and tumor management. We include best of approaches to create a core program that addresses whats new in clinical practice, as well as practical issues that retina specialists face dailyfrom the status of new treatments for diabetic retinopathy to what health care reform means for the field of retina. Two sessions are reserved for presentation of late-breaking developments. The Schepens Lecturedelivered this year by Alan Bird MD on Potential Therapeutic Approaches to AMDis certain to be a highlight. Finally, we include the popular Break With the Experts program on Friday from 3:12 to 3:54, which allows participants to move freely from topic to topic at their leisure and to interact with our faculty on a much more personal level. Our goal is that attendees will find Retina 2012: The Winds of Change to be an informative, interactive, and entertaining experience as we present new and useful information to benefit their professional lives. We thank the dedicated Academy Subspecialty Day staff and the Program Committee for their tireless work. Above all, we thank the outstanding faculty for their enthusiastic efforts in preparing their presentations and course materials to provide the most up-todate and comprehensive review on the diagnosis and management of vitreoretinal diseases. We strive for continual improvement of the Subspecialty Day Meetings and request that you assist us by completing the evaluation. We carefully review all comments to better understand your needs so please take a few moments to indicate the strengths and shortcomings of this program and suggest new ways to meet the needs of our international audience. Again, we welcome you to Retina 2012: The Winds of Change. We hope you find it intellectually stimulating, educational and enjoyable. Sincerely,
Joan W Miller MD Program Director
Tarek S Hassan MD Program Director
Retina
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Retina 2012 Contents
Program Directors Welcome Letter ii CME iv The Charles L Schepens MD Lecture v Faculty Listing vi Program Schedule xxiii Section I: Vitreoretinal Surgery, Part I 1 Cool Surgical Video Panel 13 The Charles L Schepens MD Lecture 14 Section II: Section III: Section IV: Section V: Section VI: Section VII: Section VIII: Section IX: Section X: Section XI: Section XII: Section XIII: Non-neovascular AMD 15 Late Breaking Developments, Part I 34 Pediatric Retina 35 Inherited Retinal Diseases 43 Retinal Vein Occlusion 51 Business of Retina 52 Neovascular AMD 63 Imaging 86 Oncology 105 Late Breaking Developments, Part II 118 Diabetes 119 Vitreoretinal Surgery, Part II 129 Faculty Financial Disclosure 131 Presenter Index 139
Electronic version of Syllabi available at www.aao.org/2012syllabi
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Retina
CME Credit
Academys CME Mission Statement

The purpose of the American Academy of Ophthalmologys Continuing Medical Education (CME) program is to present ophthalmologists with the highest quality lifelong learning opportunities that promote improvement and change in physician practices, performance or competence, thus enabling such physicians to maintain or improve the competence and professional performance needed to provide the best possible eye care for their patients.
Attendance Verification for CME Reporting

Before processing your requests for CME credit, the Academy must verify your attendance at Subspecialty Day and/or the Joint Meeting. In order to be verified for CME or auditing purposes, you must either: Register in advance, receive materials in the mail and turn in the Final Program and/or Subspecialty Day Syllabus exchange voucher(s) onsite; Register in advance and pick up your badge onsite if materials did not arrive before you traveled to the meeting; Register onsite; or Use your ExpoCard at the meeting.
2012 Retina Subspecialty Day Meeting Learning Objectives

Upon completion of this activity, participants should be able to: Explain the current management of macular edema secondary to retinal occlusive disease and diabetic retinopathy Explain the pathobiology and management of atrophic and exudative AMD and other causes of CNV Identify emerging developments in retinal imaging Describe new vitreoretinal surgical techniques and instrumentation Identify new developments in hereditary retinal degenerations, pediatric retinal diseases, and ocular oncology
CME Credit Reporting

Grand Concourse Level 2.5; Academy Resource Center, Hall A - Booth 508 Attendees whose attendance has been verified (see above) at the 2012 Joint Meeting can claim their CME credit online during the meeting. Registrants will receive an e-mail during the meeting with the link and instructions on how to claim credit. Onsite, you may report credits earned during Subspecialty Day and/or the Joint Meeting at the CME Credit Reporting booth. Academy Members: The CME credit reporting receipt is not a CME transcript. CME transcripts that include 2012 Joint Meeting credits entered onsite will be available to Academy members on the Academys website beginning Dec. 3, 2012. NOTE: CME credits must be reported by Jan. 16, 2013. After the 2012 Joint Meeting, credits can be claimed at www.aao.org/cme. The Academy transcript cannot list individual course attendance. It will list only the overall credits spent in educational activities at Subspecialty Day and/or the Joint Meeting. Nonmembers: The Academy will provide nonmembers with verification of credits earned and reported for a single Academysponsored CME activity, but it does not provide CME credit transcripts. To obtain a printed record of your credits, you must report your CME credits onsite at the CME Credit Reporting booths.
2012 Retina Subspecialty Day Meeting Target Audience

The intended target audience for this program is vitreoretinal specialists, members in fellowship training and general ophthalmologists who are engaged in the diagnosis and treatment of vitreoretinal diseases.
2012 Retina Subspecialty Day CME Credit

The American Academy of Ophthalmology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Academy of Ophthalmology designates this live activity for a maximum of 14 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Proof of Attendance
The following types of attendance verification will be available during the Joint Meeting and Subspecialty Day for those who need it for reimbursement or hospital privileges, or for nonmembers who need it to report CME credit: CME credit reporting/proof-of-attendance letters Onsite Registration Form Instruction Course Verification Visit the Academys website for detailed CME reporting information.
Scientific Integrity and Disclosure of Financial Interest

The American Academy of Ophthalmology is committed to ensuring that all continuing medical education (CME) information is based on the application of research findings and the implementation of evidence-based medicine. It seeks to promote balance, objectivity and absence of commercial bias in its content. All persons in a position to control the content of this activity must disclose any and all financial interests. The Academy has mechanisms in place to resolve all conflicts of interest prior to an educational activity being delivered to the learners.
2012 Subspecialty Day | Retina
The Charles L Schepens MD Lecture

Potential Therapeutic Approaches to AMD Friday, November 9, 2012 9:31 AM 9:46 AM
Alan C Bird MD
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Retina
Faculty
Thomas M Aaberg Jr MD
Ada, MI Founder and President Retina Specialists of Michigan Assistant Clinical Professor of Ophthalmology Michigan State University
Lloyd P Aiello MD PhD

Boston, MA Professor of Ophthalmology Harvard Medical School Head, Section of Eye Research, and Director, Beetham Eye Institute Joslin Diabetes Center
Jorge G Arroyo MD
Brookline, MA Associate Professor of Ophthalmology Harvard Medical School Director of Retina Service Beth Israel Deaconess Medical Center
Gary W Abrams MD
Detroit, MI Professor of Ophthalmology Kresge Eye Institute Wayne State University
Arthur W Allen Jr MD
San Francisco, CA Vice Chairman Department of Ophthalmology California Pacific Medical Center President Pacific Eye Associates
Marcos P Avila MD
Goiania, Brazil Full Professor of Ophthalmology and Head of the Ophthalmology Department Universidade Federal de Gois
David H Abramson MD FACS

New York, NY Chief, Ophthalmic Oncology Service Memorial Sloan-Kettering Cancer Center Professor of Ophthalmology Weill Cornell University
Carl C Awh MD J Fernando Arevalo MD FACS

Riyadh, Saudi Arabia Professor of Ophthalmology Wilmer Eye Institute and Johns Hopkins University School of Medicine Chief of Vitreoretina Division The King Khaled Eye Specialist Hospital Riyadh, Kingdom of Saudi Arabia Nashville, TN President Tennessee Retina, PC
Retina
Faculty Listing
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No photo available
James W Bainbridge MA PhD FRCOphth

London, United Kingdom Professor of Retinal Studies University College Consultant Ophthalmologist Moorfields Eye Hospital
Francine Behar-Cohen MD
Paris, France
Susanne Binder MD
Vienna, Austria Professor of Ophthalmology Department of Ophthalmology Rudolf Foundation Clinic Professor of Ophthalmology The Ludwig Boltzmann Institute for Retinology and Biomicroscopic Laser Surgery
Audina M Berrocal MD
Miami, FL Associate Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami Staff Physician Miami Childrens Hospital
Sophie J Bakri MD
Rochester, MN Professor of Ophthalmology Mayo Clinic
Alan C Bird MD
London, England Emeritus Professor of Ophthalmology University College, London
No photo available
Maria H Berrocal MD Francesco M Bandello MD FEBO

Milano, Italy Full Professor and Chairman Department of Ophthalmology University Vita Salute Scientific Institute, San Raffaele, Milan MD, FEBO University Vita Salute San Juan, PR Assistant Professor University of Puerto Rico
Barbara Ann Blodi MD

Madison, WI Professor of Ophthalmology University of Wisconsin Codirector Fundus Photograph Reading Center University of Wisconsin
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Faculty Listing
Retina
Mark S Blumenkranz MD
Palo Alto, CA Professor and Chairman Stanford University School of Medicine
Neil M Bressler MD
Baltimore, MD The James P Gills Professor of Ophthalmology Johns Hopkins University School of Medicine Chief, Retina Division Wilmer Eye Institute
Brandon G Busbee MD
Nashville, TN Retina Specialist Tennessee Retina
David S Boyer MD
Los Angeles, CA Clinical Professor of Ophthalmology University of Southern California Keck School of Medicine Partner, Retina Vitreous Associates Medical Group
Antonio Capone Jr MD
Royal Oak, MI Professor of Ophthalmology William Beaumont Hospital-Oakland University School of Medicine Codirector, Fellowship in Vitreoretinal Diseases and Surgery Associated Retinal Consultants
David M Brown MD
Houston, TX Associate Clinical Professor of Opthalmology Weill Cornell College of Medicine, The Methodist Hospital Director of Clinical Research Retina Consultants of Houston
No photo available
Periklis Brazitikos MD
Thessaloniki, Greece Associate Professor of Ophthalmology Aristotle University of Thessaloniki
Usha Chakravarthy MBBS PhD

Belfast, Northern Ireland Professor of Ophthalmology and Vision Science Queens University of Belfast
Alexander J Brucker MD
Philadelphia, PA Professor of Ophthalmology Scheie Eye Institute University of Pennsylvania
Retina
Faculty Listing
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Wiley Andrew Chambers MD

McLean, VA Clinical Professor of Ophthalmology The George Washington University
Tom S Chang MD
Arcadia, CA Partner Retina Institute of California
N H Victor Chong MD
Oxford, United Kingdom Head of Department Oxford Eye Hospital Clinical Senior Lecturer in Ophthalmology University of Oxford
R V Paul Chan MD
New York, NY St Giles Associate Professor of Pediatric Retina Weill Cornell Medical College
Steven T Charles MD
Memphis, TN Adjunct Professor of Ophthalmology Columbia College of Physicians and Surgeons Clinical Professor of Ophthalmology University of Tennessee, Memphis
David R Chow MD
North York, ON, Canada Assistant Professor of Ophthalmology University of Toronto Codirector Toronto Retina Institute
Stanley Chang MD
New York, NY KK Tse and Ku Teh Ying Professor of Ophthalmology Columbia University
Emily Y Chew MD
Bethesda, MD Deputy Director of Division of Epidemiology and Clinical Applicatons National Eye Institute, National Institutes of Health
Mina Chung MD
Rochester, NY Associate Professor of Ophthalmology Flaum Eye Institute University of Rochester
Faculty Listing
Retina
Carl C Claes MD
Schilde, Belgium Head of Vitreoretinal Surgery Saint Augustinus Hospital (Wilrijk/ Antwerp)
Donald J DAmico MD
New York, NY Professor and Chairman Department of Ophthalmology Weill Cornell Medical College Ophthalmologist-in-Chief New York-Presbyterian Hospital
Jay S Duker MD
Boston, MA Director, New England Eye Center Tufts Medical Center Professor and Chair Department of Ophthalmology
No photo available
No photo available
Karl G Csaky MD PhD

Dallas, TX Vitreoretinal Specialist Texas Retina Associates
Kimberly A Drenser MD PhD

Royal Oak, MI Vitreoretinal Surgeon Associated Retinal Consultants Associate Professor Eye Research Institute Oakland University
Alexander M Eaton MD
Fort Myers, FL
Christine Curcio PhD

Birmingham, AL Professor of Ophthalmology University of Alabama at Birmingham
Claus Eckardt MD
Frankfurt, Germany Professor of Ophthalmology Klinikum Frankfurt Hchst
Pravin U Dugel MD
Phoenix, AZ Managing Partner Retinal Consultants of Arizona Clinical Associate Professor of Ophthalmology Doheny Eye Institute Keck School of Medicine University of Southern California
Retina
Faculty Listing
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Ehab N El Rayes MD PhD

Cairo, Egypt Professor of Ophthalmlogy, Retina Service Institute of Ophthalmology Vitreoretinal Consultant International Eye Hospital
Sharon Fekrat MD
Durham, NC Associate Professor of Ophthalmology Albert Eye Research Institute Duke University Eye Center Chief, Ophthalmology Durham Veterans Affairs Medical Center
Marta Figueroa MD
Madrid, Spain Director of Vitreoretinal Department Vissum Madrid Professor of Ophthalmology University of Alcal de Henares
Dean Eliott MD
Boston, MA Associate Director, Retina Service Massachusetts Eye and Ear Infirmary Harvard Medical School
Frederick L Ferris MD
Waxhaw, NC Director, Division of Epidemiology and Clinical Applications National Eye Institute, National Institutes of Health
Paul T Finger MD
New York, NY Director The New York Eye Cancer Center Clinical Professor of Ophthalmology New York University School of Medicine
Daniel D Esmaili MD
Boston, MA Instructor in Ophthalmology Massachusetts Eye and Ear Infirmary
Philip J Ferrone MD
Great Neck, NY Partner Long Island Vitreoretinal Consultants Assistant Professor of Ophthalmology Columbia University
Harry W Flynn Jr MD
Miami, FL Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami
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Faculty Listing
Retina
No photo available
William R Freeman MD
La Jolla, CA Professor of Ophthalmology University of California, San Diego Director Jacobs Retina Center Shiley Eye Center University of California, San Diego
Anne E Fung MD
San Francisco, CA Medical Retina Consultant Pacific Eye Associates Director, Barkan Research Society California Pacific Medical Center
Andre V Gomes MD
So Paulo, Brazil
No photo available
No photo available
Christine R Gonzales MD
Ashland, OR
Brenda L Gallie MD K Bailey Freund MD

New York, NY Clinical Associate Professor of Ophthalmology New York University Partner Vitreous Retina Macula Consultants of New York Toronto, ON, Canada Professor of Ophthalmology University of Toronto Head, Retinoblastoma Program Hospital for Sick Children
Evangelos S Gragoudas MD
Boston, MA Professor of Ophthalmology Harvard Medical School Director, Retina Service Massachusetts Eye and Ear Infirmary
Alain Gaudric MD
Paris, France Professor of Ophthalmology Hopital Lariboisiere, AP-HP Universit Paris-Diderot
Thomas R Friberg MD
Pittsburgh, PA Professor of Bioengineering and Ophthalmology University of Pittsburgh Director of Retina Service UPMC Eye Center
M Gilbert Grand MD
St Louis, MO Retina Surgeon Retina Consultants, The Retina Institute Professor of Clinical Ophthalmology Washington University School of Medicine
Retina
Faculty Listing
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Julia A Haller MD
Philadelphia, PA Ophthalmologist-in-Chief Wills Eye Hospital Professor and Chair of Ophthalmology Jefferson Medical College Thomas Jefferson University
Jeffrey S Heier MD
Boston, MA Director, Vitreoretina Service Ophthalmic Consultants of Boston Assistant Professor in Ophthalmology Tufts University School of Medicine
Suber S Huang MD MBA

Cleveland, OH Director, Center Retina and Macular Disease University Hospitals Eye Institute Searle Professor and Vice Chair Department of Ophthalmology and Visual Sciences Case Western Reserve University School of Medicine
Dennis P Han MD
Milwaukee, WI Jack A and Elaine D Klieger Professor of Ophthalmology Medical College of Wisconsin Head, Vitreoretinal Section Froedert & The Medical College Eye Institute
Allen C Ho MD
Philadelphia, PA Director of Retina Research Mid Atlantic Retina and Wills Eye Institute Professor of Ophthalmology Thomas Jefferson University
Mark S Humayun MD PhD

Los Angeles, CA Professor of Ophthalmology, Biomedical Engineering and Cell & Neurobiology Doheny Eye Institute Keck School of Medicine University of Southern California
Frank G Holz MD Tarek S Hassan MD

Royal Oak, MI Professor of Ophthalmology Oakland University, William Beaumont School of Medicine Director of Vitreoretinal Program Partner, Associated Retinal Consultants Bonn, Germany Professor of Ophthalmology University of Bonn, Germany
Michael S Ip MD
Madison, WI Associate Professor of Ophthalmology University of Wisconsin-Madison
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Faculty Listing
Retina
No photo available
Timothy L Jackson MBChB

London, England Consultant Ophthalmic Surgeon Kings College Hospital HEFCE Senior Clinical Lecturer Kings College London
Mark W Johnson MD
Ann Arbor, MI Professor of Ophthalmology and Visual Sciences University of Michigan Director, Retina Service W K Kellogg Eye Center
Peter K Kaiser MD
Cleveland, OH Professor of Ophthalmology Cleveland Clinic Lerner College of Medicine Director, Digital OCT Reading Center Cole Eye Institute
No photo available
Glenn J Jaffe MD
Durham, NC Professor of Ophthalmology Duke University
J Michael Jumper MD
San Francisco, CA West Coast Retina Medical Group, Inc.
Ivana K Kim MD
Boston, MA Associate Professor of Ophthalmology Harvard Medical School Retina Service Massachusetts Eye and Ear Infirmary
No photo available
Martine J Jager MD
Oegstgeest, Netherlands Senior Medical Specialist Leiden University Medical Center, Leiden
Kazuaki Kadonosono MD
Yokohama, Japan Professor of Ophthalmology Yokohama City University
Judy E Kim MD
Milwaukee, WI Professor of Ophthalmology Medical College of Wisconsin
Retina
Faculty Listing
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No photo available
John W Kitchens MD
Lexington, KY
Jennifer Irene Lim MD

Chicago, IL Professor of Ophthalmology, Director, Retina Service, and Marion H Schenk Esq Chair in Ophthalmology Illinois Eye and Ear Infirmary University of Illinois at Chicago
Maureen G Maguire PhD

Philadelphia, PA Professor of Ophthalmology University of Pennsylvania
Baruch D Kuppermann MD PhD

Irvine, CA Professor and Chief, Retina Service Gavin Herbert Eye Institute University of California, Irvine
Daniel F Martin MD
Cleveland, OH Chairman, Cole Eye Institute Cleveland Clinic
Anat Loewenstein MD
Tel Aviv, Israel Director of Ophthalmology Tel Aviv Medical Center Professor of Ophthalmology Vice Dean, Sackler Faculty of Medicine, Tel Aviv University
No photo available
Timothy Y Lai MD FRCOphth FRCS

Tsimshatsui, Kowloon, Hong Kong Honorary Clinical Associate Professor The Chinese University of Hong Kong Director, 2010 Retina and Macula Centre
Carlos Mateo MD
Barcelona, Spain Associate Professor of Ophthalmology Instituto de Microciruga Ocular of Barcelona
Ian M MacDonald MD
Edmonton, AB, Canada Professor of Ophthalmology University of Alberta
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Faculty Listing
Retina
No photo available
William F Mieler MD
Chicago, IL Professor and Vice Chairman Department of Ophthalmology and Visual Sciences University of Illinois at Chicago
Shizuo Mukai MD
Boston, MA Assistant Professor in Ophthtalmology Harvard Medical School Surgeon in Ophthalmology Massachusetts Eye and Ear Infirmary
Timothy W Olsen MD
Atlanta, GA F Phinizy Calhoun Sr Professor and Chairman of Ophthalmology Emory University
Joan W Miller MD
Boston, MA Henry Willard Williams Professor of Ophthalmology Harvard Medical School Chief and Chair of Ophthalmology Massachusetts Eye and Ear Infirmary Harvard Medical School
Timothy G Murray MD MBA

Miami, FL Professor of Ophthalmology and Radiation Oncology Bascom Palmer Eye Insitute University of Miami Miller School of Medicine
Jeffrey L Olson MD
Englewood, CO Associate Professor of Ophthalmology University of Colorado, Rocky Mountain Lions Eye Institute
Yusuke Oshima MD Annabelle A Okada MD

Tokyo, Japan Professor of Ophthalmology Kyorin University School of Medicine Suita, Osaka, Japan Associate Professor of Ophthalmology Osaka University Graduate School of Medicine
Darius M Moshfeghi MD
Palo Alto, CA Associate Professor of Ophthalmology Stanford University School of Medicine Director of Telemedicine and Director of Pediatric Vitreoretinal Surgery Byers Eye Institute Stanford University School of Medicine
Retina
Faculty Listing
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Andrew J Packer MD
Hartford, CT Clinical Professor University of Connecticut School of Medicine
Fabio Patelli MD
Garbagnate Milanese, Italy Ophthalmologist, Vitreoretinal Surgeon Milano Retina Center Director, Vitreoretinal Service Igea Clinic, Milan
Eric A Pierce MD PhD

Boston, MA Director, Ocular Genomics Institute Massacusetts Eye and Ear Infirmary
No photo available
Kirk H Packo MD
Indian Head Park, IL Professor and Chairman Department of Ophthalmology Rush University Medical Center Partner, Illinois Retina Associates
Subhransu Ray MD PhD Grazia Pertile MD

Negrar, Verona, Italy Director, Department of Ophthalmology Sacro Cuore Hospital, Negrar (VR) Italy Moraga, CA
Franco M Recchia MD
Nashville, TN Associate, Tennessee Retina, P.C.
David W Parke II MD
San Francisco, CA Executive Vice President and CEO American Academy of Ophthalmology
Dante Pieramici MD
Santa Barbara, CA Assistant Clinical Professor Doheny Eye Institute President, California Retina Research Foundation
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Faculty Listing
Retina
Carl D Regillo MD FACS

Bryn Mawr, PA Professor of Ophthalmology Thomas Jefferson University Director, Retina Service Wills Eye Institute
Stanislao Rizzo MD
Pisa, Italy Director U.O. Chirurgia Oftalmica Azienda Ospedaliero Universitaria Pisana
Philip J Rosenfeld MD PhD

Miami, FL Professor of Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine
Michael A Romansky JD Kourous Rezaei MD

Harvey, IL Associate Professor of Ophthalmology Rush University Medical Center Partner, Illinois Retina Associates Chevy Chase, MD Washington Counsel and Vice President for Corporate Development Outpatient Ophthalmic Surgery Society
Alan J Ruby MD
Novi, MI Associated Retinal Consultants, Royal Oak, MI Professor of Ophthalmology Oakland University William Beaumont School of Medicine
No photo available
Richard B Rosen MD William L Rich MD

Falls Church, VA Medical Director for Health Policy American Academy of Ophthalmology Clinical Instructor Department of Ophthalmology Georgetown University New York, NY Vice Chairman and Surgeon Director, Director of Retina and Director of Research New York Eye and Ear Infirmary Professor of Ophthalmology New York Medical College
Srinivas R Sadda MD
Los Angeles, CA Associate Professor of Ophthalmology University of Southern California Director, Doheny Image Reading Center Doheny Eye Institute
Retina
Faculty Listing
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No photo available
Andrew P Schachat MD
Cleveland, OH Vice Chairman for Clinical Affairs Cole Eye Institute, Cleveland Clinic Professor of Ophthalmology Lerner College of Medicine
Hendrik PN Scholl MD
Baltimore, MD The Dr. Frieda Derdeyn Bambas Professor of Ophthalmology Wilmer Eye Institute John Hopkins University School of Medicine
Gaurav K Shah MD
St Louis, MO Clinical Professor of Ophthalmology and Visual Sciences The Retina Institute
No photo available
Amy C Schefler MD
Houston, TX Clinical Assistant Professor Weill Medical College of Cornell University Associate Partner Retinal Consultants of Houston
Carol L Shields MD Steven D Schwartz MD

Los Angeles, CA Ahmanson Professor of Ophthalmology and Chief, Retina Division Jules Stein Eye Institute, University of California, Los Angeles (UCLA) Professor of Ophthalmology David Geffen School of Medicine at UCLA Philadelphia, PA Codirector, Oncology Service Wills Eye Institute Professor of Ophthalmology Thomas Jefferson University Hospital
Jerry A Shields MD Ursula M Schmidt-Erfurth MD

Vienna, Austria Professor of Ophthalmology Medical University of Vienna Chair Department of Ophthalmology and Optometry Philadelphia, PA Director, Oncology Service Wills Eye Institute Professor of Ophthalmology Thomas Jefferson University
Jonathan E Sears MD
Cleveland, OH Associate Professor of Ophthalmology Cole Eye Institute, Cleveland Clinic Associate Professor of Cell Biology Cell Biology, Cleveland Clinic
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Faculty Listing
Retina
Michael A Singer MD
San Antonio, TX Ophthalmologist, Managing Partner and Director of Clinical Trials Medical Center Ophthalmology Associates Assistant Clinical Professor University of Texas Health Science Center, San Antonio
Rishi P Singh MD
Cleveland, OH Staff Physician Cole Eye Institute Cleveland Clinic Foundation
Gisele Soubrane MD PhD

Paris, France Professor of Ophthalmology Department of Ophthalmology University Paris Descartes, France MD, PhD, FEBO, FARVO Hotel Dieu de Paris
Jason S Slakter MD
New York, NY Clinical Professor of Ophthalmology New York University School of Medicine Partner, Vitreous Retina Macula Consultants of New York
Richard F Spaide MD
New York, NY Ophthalmology Vitreous, Retina and Macula Consultants of New York
Lawrence J Singerman MD
Cleveland, OH Founder, Retina Associates of Cleveland Clinical Professor of Ophthalmology Case Western Reserve University School of Medicine
No photo available
Rachel Smith MD PhD

Atlanta, GA
Sunil K Srivastava MD
Cleveland, OH Staff Physician Cole Eye Institute Cleveland Clinic Foundation
Arun D Singh MD
Cleveland, OH Director, Ophthalmic Oncology Cole Eye Institute Professor of Ophthalmology Cleveland Clinic
Retina
Faculty Listing
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No photo available
Giovanni Staurenghi MD
Milan, Italy Professor of Ophthalmology Department of Clinical Science Luigi Sacco
Trexler M Topping MD
Boston, MA Associate Clinical Professor of Ophthalmology Tufts University School of Medicine Instructor in Ophthalmology Harvard Medical School
Jan C Van Meurs MD

Rotterdam, Netherlands Vitreoretinal Surgeon The Rotterdam Eye Hospital Professor Erasmus University
Paul Sternberg MD
Nashville, TN Professor and Chairman, Vanderbilt Eye Institute Vanderbilt University School of Medicine Associate Dean for Clinical Affairs Vanderbilt University School of Medicine
Cynthia A Toth MD
Durham, NC Professor of Ophthalmology Duke University Medical Center Professor of Biomedical Engineering Pratt School of Engineering Duke University
Luk H Vandenberghe PhD

Boston, MA Lecturer in Ophthalmology Massachusetts Eye and Ear Infirmary Harvard Medical School
Alexander C Walsh MD John T Thompson MD

Baltimore, MD Partner, Retina Specialists Assistant Professor The Wilmer Institute of The Johns Hopkins University
Michael T Trese MD
Royal Oak, MI President, Associated Retinal Consultants, PC Chief, Pediatric and Adult Vitreoretinal Surgery Beaumont Eye Institute Wm Beaumont Hospital
Los Angeles, CA Assistant Professor of Ophthalmology Keck School of Medicine University of Southern California
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Faculty Listing
Retina
David F Williams MD
Minneapolis, MN Partner, VitreoRetinal Surgery, P.A. Assistant Clinical Professor of Ophthalmology University of Minnesota
Lihteh Wu MD
San Jose, Costa Rica Associate Surgeon Instituto de Cirugia Ocular Associate Professor University of Costa Rica
Young Hee Yoon MD

Seoul, Republic of Korea Professor of Ophthalmology Asan Medical Center, University of Ulsan, College of Medicine
George A Williams MD
Royal Oak, MI Professor and Chair, Department of Ophthalmology Oakland University William Beaumont School of Medicine
Lawrence A Yannuzzi MD
New York, NY Vice Chairman, Department of Ophthalmology, and Director of Retinal Services Manhattan Eye, Ear and Throat Hospital/North Shore Hospital Professor of Clinical Ophthalmology College of Physicians and Surgeons Columbia University
David N Zacks MD PhD

Ann Arbor, MI Associate Professor of Ophthalmology and Visual Sciences University of Michigan, Kellogg Eye Center
Retina
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Retina 2012: The Winds of Change
FRIDAY, NOVEMBER 9, 2012

7:00 AM 8:00 AM REGISTRATION/MATERIAL PICKUP/CONTINENTAL BREAKFAST Opening Remarks Joan W Miller MD* Tarek S Hassan MD*
Section I:
8:05 AM 8:15 AM 8:22 AM 8:29 AM 8:36 AM 8:43 AM 8:50 AM
Vitreoretinal Surgery, Part I

Moderators: Tarek S Hassan MD*, Young Hee Yoon MD* Vitreoretinal Instrument Update Role of Retinectomy in Vitreoretinal Surgery Current Role of Endoscopy in Vitreoretinal Surgery Treatment of Suprachoroidal Hemorrhages Recurrent Retinal Detachment: Does Initial Treatment Matter? Chromovitrectomy 2012 Vitrectomy for Lamellar Macular Hole David R Chow MD* Dean Eliott MD* Jorge G Arroyo MD John W Kitchens MD* Gaurav K Shah MD* Lihteh Wu MD* Periklis Brazitikos MD* 1 2 4 6 7 9 11
Cool Surgical Video Panel

Moderator: Tarek S Hassan MD* Panelists: Maria H Berrocal MD*, Mark S Humayun MD PhD*, Fabio Patelli MD, Steven D Schwartz MD* 8:57 AM 8:59 AM 9:01 AM 9:03 AM 9:05 AM 9:07 AM 9:09 AM 9:11 AM 9:13 AM 9:15 AM 9:17 AM 9:19 AM 9:21 AM 9:23 AM 9:25 AM My Coolest Surgical Video Discussion My Coolest Surgical Video Discussion My Coolest Surgical Video Discussion My Coolest Surgical Video Discussion My Coolest Surgical Video Discussion My Coolest Surgical Video Discussion My Coolest Surgical Video Discussion Audience Vote Carl C Claes MD* 13 J Fernando Arevalo MD FACS 13 Claus Eckardt MD* 13 Ehab N El Rayes MD PhD 13 Kazuaki Kadonosono MD 13 Yusuke Oshima MD* 13 Carlos Mateo MD 13
* Indicates that the presenter has financial interest. No asterisk indicates that the presenter has no financial interest.
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Program Schedule
Retina
The Charles L Schepens MD Lecture

9:26 AM 9:31 AM 9:46 AM Introduction of the 2012 Schepens Lecturer Potential Therapeutic Approaches to AMD REFRESHMENT BREAK and RETINA EXHIBITS David W Parke II MD* Alan C Bird MD 14
Section II:
10:30 AM 10:40 AM 10:47 AM 10:54 AM 10:55 AM 11:02 AM 11:09 AM 11:16 AM 11:23 AM 11:28 AM
Non-neovascular AMD
Moderators: Sophie J Bakri MD*, Francesco M Bandello MD FEBO* Pathogenesis of AMD Genetic TestingPro Genetic TestingCon Audience Vote Rapid-fire Phase 2 Trials, Part I Rapid-fire Phase 2 Trials, Part II Neuroprotection for AMD Cell-Based Therapies for AMD Advocating for Patients LUNCH and RETINA EXHIBITS David M Brown MD* Philip J Rosenfeld MD PhD* David N Zacks MD PhD* Allen C Ho MD* George A Williams MD* 21 21 28 29 32 Christine Curcio PhD* Mark S Blumenkranz MD* Frederick L Ferris MD* 15 17 20
Section III:
1:00 PM
Late Breaking Developments, Part I

Moderators: Alexander J Brucker MD*, Paul Sternberg MD A Multi-state Outbreak of Fungal Endophthalmitis Associated With Contaminated Ophthalmologic Products From a Single Compounding Pharmacy Rachel Smith MD MPH 34
1:07 PM 1:14 PM 1:21 PM 1:28 PM 1:35 PM
Responder Analysis of the INTREPID Study of Stereotactic Radiotherapy Timothy L Jackson MBChB* for Wet Age-Related Macular Degeneration First-in-Human Results of a Refillable Drug Delivery Implant Providing Release of Ranibizumab in Patients with Wet AMD The Use of Anterior Segment OCT to Help Predict Steroid Responders After Intravitreal Injections New Insight in the Physiopathology of CSCR: Therapeutic Application Baseline Anatomic Features Predictive of Pharmacologic VMA Resolution in the Phase III Ocriplasmin Clinical Trial Program Anat Loewenstein MD* Michael A Singer MD* Francine Behar-Cohen MD Subhransu Ray MD PhD*
34 34 34 34 34
Section IV:
1:42 PM 1:49 PM 1:56 PM 2:03 PM 2:10 PM
Pediatric Retina
Moderators: Shizuo Mukai MD, Amy C Schefler MD Update on the Study of Telemedicine for ROP Ophthalmic Insurer Perspectives on the Use of Telemedicine for Screening and Diagnosis of ROP and Bevacizumab for ROP Update on the Multicenter Study of Anti-VEGF Treatment for ROP (BLOCK-ROP)* Microplasmin for Pediatric Vitrectomy Study Familial Exudative Vitreoretinopathy: Diagnosis, Management With Wide-Angle Angiography, and Long-term Surgical Results Darius M Moshfeghi MD* Arthur W Allen Jr MD Michael T Trese MD Kimberly A Drenser MD PhD* Franco M Recchia MD* 35 36 38 39 40
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Program Schedule
xxv
2:17 PM
Surgical Video Panel Moderator: Antonio Capone Jr MD* Panelists: Audina M Berrocal MD*, R V Paul Chan MD, Philip J Ferrone MD*, Jonathan E Sears MD
Section V:
2:37 PM 2:44 PM 2:51 PM 2:58 PM 3:05 PM
Inherited Retinal Diseases

Moderators: Marcos P Avila MD, Michael A Singer MD* Update on Gene Therapy Trials in Progress Upcoming Trials in Retinal Degeneration Phase 1b Data for 091001, a Synthetic Retinoid for the Treatment of Leber Congenital Amaurosis and Retinitis Pigmentosa Genetic Testing for Patients With Retinal Degeneration Optogenetics: A New Approach to Retinitis Pigmentosa James W Bainbridge MA PhD FRCOphth* Ian M MacDonald MD* Hendrik PN Scholl MD* Eric A Pierce MD PhD Luk H Vandenberghe PhD* 43 44 46 47 49
Break With the Experts

Moderators: M Gilbert Grand MD, Andrew J Packer MD 3:12 PM 3:54 PM Exhibit Hall E Topic V01: AMD Susanne Binder MD David S Boyer MD* David M Brown MD* Emily Y Chew MD Philip J Rosenfeld MD PhD* Jason S Slakter MD* David R Chow MD* Carl C Awh MD* Carl G Csaky MD PhD* Mark W Johnson MD* Jennifer Irene Lim MD* Alan J Ruby MD* George A Williams MD* Harry W Flynn Jr MD* Carl C Claes MD* Ivana K Kim MD* Timothy G Murray MD MBA* Periklis Brazitikos MD* Carlos Mateo MD Yusuke Oshima MD* Cynthia A Toth MD* Srinivas R Sadda MD* Richard F Spaide MD* Sunil K Srivastava MD Alexander C Walsh MD* Kimberly A Drenser MD PhD* Philip J Ferrone MD* James W Bainbridge MA PhD* FRCOphth
Topic V02: New Instrumentation Topic V03: Diabetic Retinopathy
Topic V04: Business of Retina Topic V05: Endophthalmitis Topic V06: Trauma Topic V07: Intraocular Tumors Topic V08: Macular Surgery
Topic V09: Ocular Imaging
Topic V10: Pediatric Retinal Disease Topic V11: Gene Therapy
xxvi
Program Schedule Topic V12: Enzymatic Vitrectomy Topic V13: Retinal Detachment
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Michael T Trese MD* Gary W Abrams MD* J Fernando Arevalo MD FACS Claus Eckardt MD* Dean Eliott MD* Michael S Ip MD* Sharon Fekrat MD Carl D Regillo MD FACS*
Topic V14: Vascular Occlusions
Section VI:
3:54 PM
Retinal Vein Occlusion

Moderator: Donald J DAmico MD* Retinal Vein Occlusion Panel Panelists: Barbara Ann Blodi MD, Sharon Fekrat MD, Michael S Ip MD*, Carl D Regillo MD FACS*, Rishi P Singh MD* 51
Section VII:
4:14 PM 4:21 PM 4:28 PM 4:35 PM 4:42 PM 4:49 PM 4:56 PM 5:03 PM 5:04 PM
Business of Retina
Moderators: William R Freeman MD*, Anne E Fung MD* The Future of Health Care: Survival of the Fittest Accountable Care Organizations: In or Out? ASC for Retina: Is It Time? ASC for Retina: Balancing Quality With Profit The Office of the Inspector General and Bevacizumab vs. Ranibizumab: No Good Deed Goes Unpunished Managing a Large Modern Practice: Practice Informatics and IT Post-marketing Surveillance Closing Remarks ADJOURN David W Parke II MD* William L Rich MD Michael A Romansky JD Alan J Ruby MD* George A Williams MD* Trexler M Topping MD* Wiley Andrew Chambers MD Joan W Miller MD* Tarek S Hassan MD* 52 54 56 57 58 59 60
SATURDAY, NOVEMBER 10, 2012

7:00 AM 8:00 AM CONTINENTAL BREAKFAST Opening Remarks Joan W Miller MD* Tarek S Hassan*
Section VIII:
8:05 AM 8:12 AM 8:19 AM 8:26 AM
Neovascular AMD
Moderators: Andrew P Schachat MD, Gisele Soubrane MD PhD* Non-inferiority Trials and Subgroups: How to Interpret What You Are About to Hear CATT: Year 2 IVAN: Year 1 MANTA: Year 1 Maureen G Maguire PhD* Daniel F Martin MD Usha Chakravarthy MBBS PhD* Susanne Binder MD 63 65 66 68
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Program Schedule Jeffrey S Heier MD* Brandon G Busbee MD* Peter K Kaiser MD* Emily Y Chew MD Timothy L Jackson MBChB* Timothy Y Lai MD FRCOphth FRCS* Pravin U Dugel MD* David S Boyer MD* Jason S Slakter MD*
xxvii
69 70 73 74 76 77 80 81 82
8:33 AM 8:40 AM 8:47 AM 8:54 AM 9:01 AM 9:08 AM 9:15 AM 9:22 AM 9:29 AM 9:36 AM
VIEW: Year 2 HARBOR: Year 2 How Do I Incorporate What I Just Heard Into My Practice? Aspirin and AMD: What Do I Tell My Patients? Radiation for CNV: Cabernet /MERITAGE/ INTREPID Polypoidal Vasculopathy: Anti-VEGF, Photodynamic Therapy, and Steroids Anti-Platelet Derived Growth Factor: Where Do We Stand? Long-term Delivery Strategies for Neovascular AMD Whats Next in the Neovascular AMD Pipeline? Panel: Management of Neovascular AMD in 2012
Moderator: Lawrence A Yannuzzi MD Panelists: Glenn J Jaffe MD*, J Michael Jumper MD, Annabelle A Okada MD*, Lawrence J Singerman MD*, Giovanni Staurenghi MD* 9:56 AM REFRESHMENT BREAK and JOINT MEETING EXHIBITS
Section IX:
10:40 AM 10:47 AM 10:54 AM 11:01 AM 11:08 AM 11:15 AM 11:22 AM
Imaging
Moderators: Daniel D Esmaili MD, Timothy W Olsen MD* Imaging the Choroid: What You Need to Know Before Deep C Diving When Should I Be Using Fundus Autofluorescence? Whats Next in Imaging? Intraoperative OCT: Is It Actually Useful? Adaptive Optics: Ready for Prime Time? Simple Estimation of Fluid Volumes in Neovascular AMD Panel: How Do You Prefer to Image Disease X? Moderator: Jay S Duker MD* Panelists: Mina Chung MD*, Thomas R Friberg MD*, Alain Gaudric MD*, Richard B Rosen MD*, Ursula M Schmidt-Erfurth MD* Richard F Spaide MD* Frank G Holz MD* Srinivas R Sadda MD* Sunil K Srivastava MD Judy E Kim MD* Alexander C Walsh MD* 86 89 94 97 99 102
Section X:
11:42 AM 11:49 AM 11:56 AM 12:03 PM 12:10 PM
Oncology
Moderators: K Bailey Freund MD*, Martine J Jager MD* Germline BAP1 Mutations in Ocular Melanoma and Other Malignancies Ivana K Kim MD* Practical Approaches to Needle Biopsy and Genetic Diagnosis for Ocular Melanoma New Imaging Techniques for Ocular Tumors Follow-up After Intra-arterial Chemotherapy for Retinoblastoma Panel: Tumor Management: Radiation, Retinopathy, and Masquerade Moderator: Evangelos S Gragoudas MD* Panelists: David H Abramson MD FACS, Paul T Finger MD*, Brenda L Gallie MD, Jerry A Shields MD, Arun D Singh MD Thomas M Aaberg Jr MD* Carol L Shields MD 105 106 116
Timothy G Murray MD MBA* 115
12:30 PM
LUNCH and JOINT MEETING EXHIBITS
xxviii
Program Schedule
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Section XI:
1:55 PM 2:02 PM 2:09 PM 2:23 PM 2:16 PM 2:28 PM
Late Breaking Developments, Part II

Moderators: Tom S Chang MD, Suber S Huang MD MBA* Phase I Study of CNTF for Mactel Long-term Effects of Intravitreal Ranibizumab on Diabetic Retinopathy Severity and Progression A Phase 1 Study Targeting Tissue Factor With a Single Dose of Intravitreal HI-Con1 for Exudative Macular Degeneration A Novel Intravitreal Injection Device New Surgical Technique and New Instrumentation for Safe, Atraumatic Removal of Intraocular Foreign Bodies ARGUS II Emily Y Chew MD Michael S Ip MD* Christine R Gonzales MD* Alexander M Eaton MD* Jeffrey L Olson MD* Mark S Humayun MD PhD* 118 118 118 118 118 118
Section XII:
Diabetes
Moderators: Dennis P Han MD*, Peter K Kaiser MD* I Use the DRCR.net Guidelines in My Clinical Practice (Yes/No)
2:35 PM 2:37 PM 2:40 PM 2:43 PM 2:44 PM 2:45 PM 2:46 PM 2:47 PM 2:51 PM 2:55 PM 2:56 PM 2:57 PM 3:01 PM 3:05 PM 3:06 PM 3:08 PM 3:11 PM 3:14 PM 3:15 PM
Coin Toss and Audience Vote Pro Con Rebuttal, Pro Rebuttal, Con Audience Vote Subthreshold Laser Is an Important Treatment for Macular Edema (Yes/No) Audience Vote Pro Con Audience Vote I Still Use Scissors in Diabetic Vitrectomy (Yes/No) Audience Vote Pro Con Audience Vote Anti-VEGF Is the Ideal Treatment for Diabetic Macular Edema (Yes/No) Coin Toss and Audience Vote Pro Con Rebuttal, Pro Rebuttal, Con Julia A Haller MD* Baruch D Kuppermann MD PhD* Karl G Csaky MD PhD* Dante Pieramici MD* 124 124 128 128 Steven T Charles MD* Carl C Awh MD* 123 123 N H Victor Chong MD* Lloyd P Aiello MD PhD* 122 122 Neil M Bressler MD* Harry W Flynn Jr MD* Mark W Johnson MD* Jennifer Irene Lim MD* 119 119 121 121
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Program Schedule
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3:16 PM 3:17 PM
Audience Vote REFRESHMENT BREAK and JOINT MEETING EXHIBITS
Section XIII:
4:00 PM
Vitreoretinal Surgery, Part II

Moderators: Kirk H Packo MD*, Kourous Rezaei MD* Surgical Complications Video, Part I Moderator: Kirk H Packo MD* Panelists: Gary W Abrams MD*, Marta Figueroa MD*, William F Mieler MD*, Stanislao Rizzo MD, John T Thompson MD* 129
4:40 PM
Surgical Complications Video, Part II Moderator: Kourous Rezaei MD* Panelists: Stanley Chang MD*, Andre V Gomes MD*, Grazia Pertile MD, Jan C Van Meurs MD*, David F Williams MD*
129
5:20 PM 5:22 PM
Closing Remarks ADJOURN
Joan W Miller MD* Tarek S Hassan MD*
Retina
Section I: Vitreoretinal Surgery, Part I
Vitreoretinal Instrument Update

David R Chow MD
NoteS
Retina
Role of Retinectomy in Vitreoretinal Surgery

Dean Eliott MD
I. Retinectomy: Excision of Retina A. Removal of anterior flap of retinal tear in primary retinal detachment B. Removal of retinal incarceration in traumatic or surgical wound C. Removal of fibrotic, contracted retina in proliferative retinopathy (PVR) or proliferative diabetic retinopathy (PDR) II. Retinotomy: Creating a Hole in the Retina (retinal incision only, no excision) A. Drainage retinotomy: 1. To remove subretinal fluid 2. Drainage site is located posteriorly when perfluorocarbon liquid is not used to reattach the retina. 3. Drainage site is located anteriorly when perfluorocarbon use results in anteriorly loculated subretinal fluid. B. Access retinotomy: To remove choroidal neovascular membrane (CNVM), subretinal hemorrhage, subretinal membranes, retained subretinal perfluorocarbon liquid, subretinal foreign body, or to inject subretinal tissue plasminogen activator III. Retinectomy Surgical Technique: General Principles A. Lensectomy in phakic eyes B. Consider scleral buckle to support vitreous base (except in cases with 360-degree retinectomy) C. Retinectomy is performed after attempted complete epiretinal membrane removal; if retinectomy is done before complete epiretinal membrane removal, further epiretinal membrane removal may be difficult. D. Orientation: Circumferential, posterior to vitreous base E. Location 1. Avoid retinectomy edge near 6 oclock position. 2. Most common retinectomy location is inferiorly with edges at 3 oclock and 9 oclock. F. Size 1. Retinectomy should extend into normal retina surrounding areas of traction. 2. Most common retinectomy size is 6 clock hours or 180 degrees. 3. If greater than 270 degrees, extend the retinectomy to 360 degrees. G. Hemostasis: Diathermy is used to delineate intended edge and to prevent intraoperative bleeding.
H. Instruments: Vitrectomy probe or scissors are used to cut retina. I. Adjuvants: May consider perfluorocarbon liquid to stabilize posterior retina. J. Complete excision of anterior retina to prevent postoperative proliferation with resultant traction on the retinectomy edge or ciliary body K. Retinopexy: 360-degree endolaser with confluent endolaser to the retinectomy edge L. Extended tamponade: C3F8 gas or silicone oil 1. Silicone Oil Study showed equal efficacy in eyes with retinectomy. 2. Recent studies favor silicone oil over gas. 3. Redetachment occurs in 4%-25% after oil removal. IV. Incidence of Retinectomy A. PVR 1. Early studies: Retinectomy performed in 2%-8% 2. Silicone Oil Study (1993): Retinectomy performed in 29% overall a. Group 1 (no previous vitrectomy): Retinectomy performed in 20% b. Group 2 (previous vitrectomy): Retinectomy performed in 42% 3. Recent studies: Retinectomy performed more commonly, in up to 64% B. PDR 1. Primary vitrectomy: Retinectomy performed in 5% 2. Reoperation vitrectomy: Retinectomy performed in 25% V. Complications of Retinectomy A. Hemorrhage 1. Usually due to incomplete diathermy 2. Postoperative fibrous proliferation may occur in areas of blood. B. Hypotony 1. Reported in 2%-43% after 180-360 degree retinectomy and in 17%-20% after 360-degree retinectomy 2. Retinectomy exposes retinal pigment epithelium (RPE) and allows posterior outflow and absorption of intraocular fluid by the choroid.
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3. Recurrent fibrous proliferation with resultant ciliary body traction may also lead to hypotony. C. Visual field defect D. Recurrent fibrous proliferation 1. Surgery for macular pucker reported in 22%43%. 2. Severe fibrous proliferation may lead to recurrent retinal detachment and/or hypotony. E. Persistent traction occurs when size of retinectomy is inadequate. F. RPE/choroidal damage may occur when excising retina in area of shallow detachment. G. Retained subretinal perfluorocarbon more likely to occur in cases with large retinectomy; consider saline rinse or small-gauge vitrectomy with valved cannulas for prevention. H. Neovascularization 1. CNVM may rarely occur at edge of retinectomy. 2. Anterior retinal and/or iris neovascularization may occur when anterior retina is incompletely excised. VI. Retinectomy in PDR A. Small posterior focal retinectomy: To relieve persistent traction on pre-existing or iatrogenic breaks B. Large peripheral retinectomy: To remove massive fibrous proliferation caused by severe ischemia
7. Lewis H, Aaberg TM, Abrams GW. Causes of failure after initial vitreoretinal surgery for severe proliferative vitreoretinopathy. Am J Ophthalmol. 1991; 111:8-14. 8. Lewis H, Aaberg TM. Causes of failure after repeat vitreoretinal surgery for recurrent proliferative vitreoretinopathy. Am J Ophthalmol. 1991; 111:15-19. 9. Blumenkranz MS, Azen SP, Aaberg TM, et al.; Silicone Study Group. Relaxing retinotomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy (Silicone Study Report #5). Am J Ophthalmol. 1993; 116:557-564. 10. Bourke RD, Cooling RJ. Vascular consequences of retinectomy. Arch Ophthalmol. 1996; 114:155-160. 11. Abrams GW, Garcia-Valenzuela E, Nanda SK. Retinotomies and Retinectomies. In: Ryan SJ, ed. Retina 3rd ed. CV Mosby; 2000:2311-2343. 12. Joussen AM, Walter P, Jonescu-Cuypers CP, et al. Retinectomy for treatment of intractable glaucoma: long term results. Br J Ophthalmol. 2003; 87:1094-1103. 13. Tseng JJ, Barile GR, Schiff WM, Akar Y, Vidne-Hay O, Chang S. Influence of relaxing retinotomy on surgical outcomes in proliferative vitreoretinopathy. Am J Ophthalmol. 2005; 140:628-636. 14. Quiram PA, Gonzales CR, Hu W, et al. Outcomes of vitrectomy with inferior retinectomy in patients with recurrent rhegmatogenous retinal detachments and proliferative vitreoretinopathy. Ophthalmology 2006; 113:2041-2047. 15. Grigoropoulos VG, Benson S, Bunce C, Charteris DG. Functional outcome and prognostic factors in 304 eyes managed by retinectomy. Graefes Arch Clin Exp Ophthalmol. 2007; 245:641-649. 16. Gupta B, Mokete B, Laidlaw DAH, Williamson TH. Severe folding of the inferior retina after relaxing retinectomy for proliferative vitreoretinopathy. Eye 2008; 22:1517-1519. 17. de Silva DJ, Kwan A, Bunce C, Bainbridge J. Predicting visual outcome following retinectomy for retinal detachment. Br J Ophthalmol. 2008; 92:954-958. 18. Tsui I, Schubert HD. Retinotomy and silicone oil for detachments complicated by anterior inferior proliferative vitreoretinopathy. Br J Ophthalmol. 2009; 93:1228-1233. 19. Tan HS, Mura M, Oberstein SYL, de Smet MD. Primary retinectomy in proliferative vitreoretinopathy. Am J Ophthalmol. 2010; 149:447-452. 20. Kolomeyer AM, Grigorian RA, Mostafavi D, Bhagat N, Zarbin MA. 360 degree retinectomy for the treatment of complex retinal detachment. Retina 2011; 31:266-274.
Selected Readings
1. Machemer R. Retinotomy. Am J Ophthalmol. 1981; 768-774. 2. Machemer R, McCuen BW, de Juan E. Relaxing retinotomies and retinectomies. Am J Ophthalmol. 1986; 102:7-12. 3. Han DP, Lewis MT, Kuhn EM, et al. Relaxing retinotomies and retinectomies: surgical results and predictors of visual outcomes. Arch Ophthalmol. 1990; 109:694-697. 4. Iverson DA, Ward TG, Blumenkranz MS. Indications and results of relaxing retinotomy. Ophthalmology 1990; 1298-1304. 5. Morse LS, McCuen BW, Machemer R. Relaxing retinotomies: analysis of anatomic and visual results. Ophthalmology 1990 ;97:642648. 6. Federman JL, Eagle RC. Extensive peripheral retinectomy combined with posterior 360 retinotomy for retinal reattachment in advanced proliferative vitreoretinopathy cases. Ophthalmology 1990; 97:1305-1320.
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Current Role of endoscopy in Vitreoretinal Surgery

Jorge G Arroyo MD
endoscope, Illuminator, and Laser

E2 EndoOptiks Laser and Endoscopy System This system is a combined diode laser and endoscopy unit with laser output, pulse width, light, and aiming beam intensity controllable on the touch pad or with a foot pedal. It uses a 810-nm diode laser, 175 watt or 300 watt xenon light source, high-resolution camera, and footswitch controller. It is the only autoclavable endoscope available on the market. The traditional endoscope probes come in a 19.5-gauge probe that originally had 10,000 pixels with a 125-degree field of view. The high-resolution probes now have 17,000 pixels with 140-degree field of view, which are a significant improvement. A 23-gauge endoscope probe is also now available. With only 6000 pixels, the view is modest at best. A 300-watt xenon light source is needed to adequately illuminate structures. The laser probe works adequately for endolaser but is quite limited for other tasks. The gradient index (GRIN) lens system provides higher resolution but narrower field of view, is significantly less convenient, and has a greater cost. The camera is attached directly to the hand probe, cannot be autoclaved, and must be covered with sterile drape during surgery.
in some cases of trauma associated with corneal opacification and endophthalmitis.
endoscopic Membrane Peeling

The endoscope can certainly assist in the peeling of both epiretinal and internal limiting membranes. Injecting indocyanine green or other dyes can be safely accomplished with the endoscope. The high level of magnification that can be obtained helps in identifying the edge of a membrane prior to peeling. However, the relatively small field of view at these higher levels of magnification and the lack of stereopsis does make membrane peeling significantly more challenging compared to traditional coaxial microscopy.
Anterior Segment endoscopic Cyclophotocoagulation

The combined endoscope and laser probe has most commonly been used to perform anterior segment endoscopic cyclophotocoagulation (ECP) in patients with glaucoma. This procedure is typically performed after cataract surgery or in patients who are pseudophakic. However, it has been performed in phakic patients as well. After injecting a significant amount of a viscoelastic between the iris and intraocular lens, the endoscopic laser probe is inserted through a cataract wound and used to treat the anterior ciliary processes for approximately 8 clock hours. This will be shown in a video during the talk. If 12 clock hours of treatment are needed, a secondary limbal wound needs to be created.
endoscopy-Assisted Vitrectomy
Endoscopy through a 19.5-gauge or 23-gauge sclerotomy provides additional benefits compared to the coaxial microscope view. An endoscope provides the ability to see the posterior segment structures independent of corneal or lens clarity. Therefore, endoscopy is especially useful in cases with significant corneal scarring, anterior segment scars, hemorrhage, or lenticular opacities. Another advantage of endoscopy-assisted vitrectomy is that given the location of your sclerotomies, your perspective can be changed very easily and quickly. The various endoscopes have differing amounts of degree of field of view, extending between 90 and 140 degrees of view. It is important to note that the wider field of view makes use of an endoscope during vitrectomy much more feasible and safe. Finally, the endoscope also provides high magnification, depending on how close you are to the object in view. This feature is quite helpful in identifying small retinal breaks or small intraocular foreign bodies, as well as other parts of surgery.
Pars Plana eCP

The pars plana approach for ECP allows for a much more extensive treatment of the ciliary processes. Once the vitrectomy is completed, the endoscopic laser probe is inserted through the sclerotomy and used to visualize the pars plana and the ciliary processes. The laser power setting is typically set at 0.35 watts, and the duration is set at continuous. Depending on the proximity of the laser probe to the ciliary processes, a moderately white blanching of the ciliary processes can be obtained. We treat the entire ciliary processes as far anteriorly and as far posteriorly as possible. In patients with a significant amount of pigmentation or in cases where the power is too high or in cases where probe is too close to the ciliary processes, a vapor bubble can be unintentionally created due to the conversion of aqueous into steam. In these cases, increasing the distance between the laser probe and the ciliary processes or decreasing the laser power helps prevent this from occurring. Typically, we treat 12 clock hours of the ciliary processes, and this requires a second port, typically 6 hours away from the first port to be created. Additionally, the endoscopy laser probe can be used to apply excellent peripheral almost confluent panretinal photocoagulation treatment from the equator to the ora serrata 360 degrees around. We do find that the 810-nanometer diode laser does
endoscopy-Assisted Vitrectomy
Endoscopy-assisted vitrectomy may be particularly helpful in cases with ischemic retinopathies such as proliferative diabetic retinopathy or central retinal vein occlusions, uncontrolled glaucoma, or neovascular glaucoma. There are a number of papers looking at endoscopy-assisted vitrectomy in cases of pseudophakic retinal detachment and retained lens material or intraocular foreign bodies. We have found the endoscope to be vital in the treatment of patients who have permanent keratoprostheses and
Retina
produce a very intense laser burn. If needed, an argon laser can be attached to the endoscopic laser probe fiber and used to apply argon green laser spots.
Future
Given the fact that the 23-gauge endoscope provides a suboptimal view, we expect continued improvements in the resolution of this system, especially given the fact that the ease of use of a 23-gauge probe would be extremely helpful and advantageous to the surgeon. The high magnification and variable perspective of the endoscope may also make it amenable to retinal vascular cannulation and subretinal injection of cells or other agents in the future.
Conclusions
Overall, the endoscopic laser probe provides excellent visualization and field of view, especially in cases with corneal, anterior segment, or lenticular opacities. The laser probe and endoscope also allow excellent peripheral panretinal photocoagulation treatment to be performed in patients with peripheral ischemic retinopathies. We have found that 12 clock hours of ECP treatment primarily in patients with neovascular glaucoma effectively lowers the IOP without resulting in hypotony. The intense laser burns created by the diode 810-nanometer laser can be mitigated by connecting an argon green laser source to the laser fiber in this system. Finally, the endoscopic laser probe is only marginally adequate for membrane peeling.
Selected Readings
1. Chen J, Cohn RA, Lin SC, Cortes AE, Alvarado JA. Endoscopic photocoagulation of the ciliary body for treatment of refractory glaucomas. Am J Ophthalmol. 1997; 124(6):787-796. 2. Al Sabti K, Raizada S, Al AbdulJalil T. Cataract surgery assisted by anterior endoscopy. Br J Ophthalmol. 2009; 93:531-534. 3. Sabti KA, Raizada A, Kandari JA, Wani V, Gayed I, Kumar N. Applications of endoscopy in vitreoretinal surgery. Retina 2008; 28(1):159-166.
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treatment of Suprachoroidal Hemorrhages

John W Kitchens MD
NoteS
Retina
Recurrent Retinal Detachment: Does Initial treatment Matter?

Gaurav K Shah MD, Almony Arghavan MD, Kevin Blinder MD, Ahmad Baseer MD
I. Trends in Retinal Detachment Repair II. Current Surgical Methods for Retinal Detachment Repair A. Pneumatic retinopexy B. Scleral buckling procedure C. Primary pars plana vitrectomy D. Combined scleral buckling procedure and pars plana vitrectomy III. Preoperative factors for surgical decision making A. Extent of retinal detachment B. Location of retinal breaks C. Lens status D. Myopia E. Lattice degeneration F. Status of fellow eye IV. Retrospective study A. To identify differences among eyes that failed initial surgical repair of rhegmatogenous retinal detachment (RRD) B. 286 consecutive cases C. Initial surgical repair of RRD 1. Determined by surgeon preference 2. Proliferative vitreoretinopathy excluded 3. Scleral buckle (SB): 63 eyes 4. Pars plana vitrectomy (PPV): 88 eyes 5. Combined SB/PPV: 135 eyes D. Data 1. Age 2. Sex 3. Phakic status 4. Macula status 5. Extent of RRD 6. Location of break 7. Presence of lattice degeneration 8. Presence of high myopia 9. History of RRD in fellow eye E. Results 1. Single operation success rate 2. Recurrent retinal detachment a. Days to first recurrent retinal detachment b. Total number of procedure c. Secondary procedure d. Secondary cataract e. Conclusions 1. Single operation success rate 2. Patients that fail a primary scleral buckle a. Require fewer number of secondary procedures b. Require a lower rate of silicone oil injection c. Have a lower incidence of cataract formation d. Require a lower rate of PPL 3. Scleral buckling surgery still remains an integral part of retinal detachment repair surgery.
Selected Readings
1. Almony A, Nudleman E, Shah GK, et al. Techniques, rationale, and outcomes of internal limiting membrane peeling. Retina 2012; 32:877-891. 2. Schwartz SG, Kuhl DP, McPherson AR, Holz ER, Mieler WF. Twenty-year follow-up for scleral buckling. Arch Ophthalmol. 2002; 120:325-329. 3. Richardson EC, Verma S, Green WT, Woon H, Chignell AH. Primary vitrectomy for rhegmatogenous retinal detachment: an analysis of failure. Eur J Ophthalmol. 2000; 10:160-166. 4. Campo RV, Sipperley JO, Sneed SR, et al. Pars plana vitrectomy without scleral buckle for pseudophakic retinal detachments. Ophthalmology 1999; 106:1811-1816. 5. Brazitikos PD, Androudi S, Christen WG, Stangos NT. Primary pars plana vitrectomy versus scleral buckle surgery for the treatment of pseudophakic retinal detachment: a randomized clinical trial. Retina 2005; 25:957-964. 6. Sharma YR, Karunanithi S, Azad RV, et al. Functional and anatomic outcome of scleral buckling versus primary vitrectomy in pseudophakic retinal detachment. Acta Ophthalmol Scand. 2005; 83:293-297. 7. Weichel ED, Martidis A, Fineman MS, et al. Pars plana vitrectomy versus combined pars plana vitrectomy-scleral buckle for primary repair of pseudophakic retinal detachment. Ophthalmology 2006; 113:2033-2040. 8. Stangos AN, Petropoulos IK, Brozou CG, Kapetanios AD, Whatham A, Pournaras CJ. Pars-plana vitrectomy alone vs vitrectomy with scleral buckling for primary rhegmatogenous pseudophakic retinal detachment. Am J Ophthalmol. 2004; 138:952-958. 9. Heimann H, Bartz-Schmidt KU, Bornfeld N, Weiss C, Hilgers RD, Foerster MH; Scleral Buckling versus Primary Vitrectomy in Rhegmatogenous Retinal Detachment Study Group. Scleral buckling

versus primary vitrectomy in rhegmatogenous retinal detachment: a prospective randomized multicenter clinical study. Ophthalmology 2007; 114:2142-2154.
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10. Goto T, Nakagomi T, Iijima H. A comparison of the anatomic successes of primary vitrectomy for rhegmatogenous retinal detachment with superior and inferior breaks. Acta Ophthalmol. 2012; 13:1755. 11. Mehta S, Blinder KJ, Shah GK, Grand MG. Pars plana vitrectomy versus combined pars plana vitrectomy and scleral buckle for primary repair of rhegmatogenous retinal detachment. Can J Ophthalmol. 2011; 46:237-241. 12. Azad RV, Chanana B, Sharma YR, Vohra R. Primary vitrectomy versus conventional retinal detachment surgery in phakic rhegmatogenous retinal detachment. Acta Ophthalmol Scand. 2007; 85:540-545. 13. Sun Q, Sun T, Xu Y, et al. Primary vitrectomy versus scleral buckling for the treatment of rhegmatogenous retinal detachment: a meta-analysis of randomized controlled clinical trials. Curr Eye Res. 2012; 37:492-499.
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Chromovitrectomy 2012
A Focus on Brilliant Blue G and other Novel Dyes

Lihteh Wu MD, Mauricio Maia MD, Michel E Farah MD, Cristian Carpentier MD, Arturo Alezzandrini MD, Maria H Berrocal MD, J Fernando Arevalo MD; for the Pan American Collaborative Retina Study (PACORES) Group
Introduction
The vitreous is composed mostly (98%) of water, with the remainder consisting of macromolecules such as collagen fibrils and hyaluronan. As we age, the vitreous undergoes several biochemical changes that lead to progressive liquefaction of the vitreous gel. This eventually leads to a posterior vitreous detachment (PVD). An anomalous PVD may occur when there is no clean separation along the vitreoretinal interface. Surgical, histopathological, and imaging advances over the past 2 decades have demonstrated that traction along the vitreoretinal interface induced by an anomalous PVD plays an important role in several diseases. Depending on where in the eye the strongest vitreoretinal adhesion is, an anomalous PVD may evolve into several clinical conditions. For instance, if the strongest adhesions are found in the retinal periphery, a tear or detachment ensues. If strong adhesions are found in the macula, epiretinal membrane (ERM), macular hole (MH), and the vitreomacular traction syndrome (VMTS) may develop.1,2 Release of this traction by removal of the offending tissues has been advocated as a solution. There are 3 tissues of particular interest to the vitreoretinal surgeon, namely the posterior hyaloid, ERM, and the internal limiting membrane (ILM). One of the major difficulties encountered by vitreoretinal surgeons in dealing with these tissues is that these are usually thin, transparent, and difficult to visualize. Staining of these transparent tissues with vital dyes during vitrectomy greatly simplifies the procedure. The term chromovitrectomy has been used to describe the use of vital dyes to stain transparent tissues to facilitate their manipulation during vitreous surgery.3 Over the past decade several substances, including indocyanine green (ICG), trypan blue (TB), and brilliant blue G (BB), have been used during vitrectomy as staining agents. Their staining capabilities have been confirmed, but concerns over retinal toxicity remain.4 gous blood may be injected into the vitreous cavity to coat the vitreous.5 Triamcinolone acetonide (TA) is a well-tolerated corticosteroid that has been used in the pharmacological treatment of several diseases such as uveitis, diabetic macular edema (DME), and retinal vein occlusions. Once injected into the vitreous cavity, the triamcinolone particles adhere to the vitreous gel, making its visualization and identification easy. As an added benefit, its use during vitrectomy may improve outcomes by reducing the breakdown of the bloodretinal barrier and preretinal fibrosis. Currently this is the most widely used technique to visualize the posterior hyaloid.4,5 A comparative study of fluorescein, ICG, TA, and TB concluded that TA highlighted the vitreous best.6 A recent study demonstrated that a 20% solution containing the natural dyes lutein and zeaxanthin precipitates on the vitreous surface, staining it orange.7
epiretinal Membranes
Refinements in instrumentation and surgical techniques over the past 2 decades have made ERM removal a typical indication for macular surgery. Clinically significant ERMs range from dense opaque tissues to fine transparent membranes. Given their transparent nature, fine ERMs pose a challenge even to experienced surgeons. TB binds to degenerated cell elements. It does not stain live cells or tissues with intact cell membranes, since there is no uptake of the dye. Cataract surgeons have long used 0.06% TB to stain the anterior capsule during phacoemulsification. ERMs stain prominently with 0.15% TB. Clinical studies suggest that TB is relatively safe at these doses; however, animal and in vitro studies show that a dose-dependent toxicity may appear above 0.3%. TB remains the dye of choice when peeling ERMs.4,8
Posterior Hyaloid
Traction exerted by the posterior hyaloid has been implicated in the pathogenesis of several conditions such as proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR), penetrating trauma, and MH. Therefore the surgical goal of any vitrectomy should be posterior hyaloid separation and removal of as much vitreous as possible. Despite the development of several surgical techniques, at times the surgeon may not know for sure if the posterior hyaloid has been removed. In patients with conditions that are characterized by breakdown of the bloodretinal barrier such as PVR, uveitis, retinal vein occlusions, and diabetic retinopathy, a preoperative intravenous injection of fluorescein sodium 1 to 2 days prior to the scheduled vitrectomy stains the vitreous a greenish color, facilitating its identification. Blood in the vitreous cavity coats the vitreous by adhering to its collagen fibrils. The normally transparent vitreous becomes opaque, making it easier to visualize and remove. In eyes with no pre-existing vitreous hemorrhage, a small amount of autolo-
Internal Limiting Membrane (ILM)

The ILM is made up of the basement membrane of the Mller cells. In eyes with anomalous PVD, glial cells can migrate onto the surface of the ILM, which serves as a scaffold for cellular proliferation. This cellular proliferation may exert macular traction and contribute to the pathogenesis of ERMs, MH, VMTS, and DME, among other entities.9 In idiopathic macular holes it is generally agreed that ILM peeling is important in achieving closure of large and chronic holes.10 Tangential traction from the ILM has been implicated in the pathogenesis of macular holes. An autopsy study of a patient who had undergone successful macular hole closure showed an area of absent ILM surrounding the sealed macular hole.11 In contrast, a histopathological specimen of an eye with a reopened macular hole revealed an ERM with ILM surrounding the open macular hole.12 In other conditions such as DME and ERM, peeling of the ILM is controversial. Surgical specimens from removed ERMs
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often show fragments of the ILM interspersed among the ERM. ILM peeling may reduce the risk of recurrence following ERM removal. By removing the ILM one can be assured that the ERM is completely removed. In a recent prospective study by the Pan American Collaborative Retina Study Group, it was found that there was little correlation between the surgeons unaided observation and the brilliant blue stained observation of the ILM. Thus if the surgeon believes that ILM peeling is important in epimacular membrane surgery, staining should be strongly encouraged. The first vital dye to be used to stain the ILM was ICG.13 As the ICG binds to the ILM, the biomechanical stiffness of the ILM increases, making peeling of the ILM much easier.14 However, the initial enthusiasm that greeted the use of ICG has been tempered following numerous reports of toxicity.4 A meta-analysis of chromovitrectomy with ICG compared to peeling of the ILM without staining in macular hole surgery showed similar anatomic outcomes in both groups. However, the functional results were much worse in eyes where ICG was used to stain the ILM.15 To avoid toxicity ICG should be used at the lowest possible concentration. The surgery should be swift and illumination used sparingly. BB also has a high affinity for the ILM. In animal and in vitro studies, BB appears to be relatively safe at doses up to 0.25 mg/mL.4 However, contact with the retinal pigment epithelium (RPE) should be avoided since RPE atrophy has been documented following subretinal migration of BB. In general BB appears to be a safer alternative than ICG for ILM peeling. TB does not stain the ILM as well as BB or ICG.8 Different dyes including indigo carmine, fast green, light green, bromophenol blue, and evans blue are under investigation.16
References
1. Sebag J. Anatomy and pathology of the vitreo-retinal interface. Eye (Lond) 1992; 6(pt 6):541-552. 2. Sebag J. Anomalous posterior vitreous detachment: a unifying concept in vitreo-retinal disease. Graefes Arch Clin Exp Ophthalmol. 2004; 242:690-698. 3. Rodrigues EB, Meyer CH, Kroll P. Chromovitrectomy: a new field in vitreoretinal surgery. Graefes Arch Clin Exp Ophthalmol. 2005; 243:291-293. 4. Farah ME, Maia M, Rodrigues EB. Dyes in ocular surgery: principles for use in chromovitrectomy. Am J Ophthalmol. 2009; 148:332-340. 5. Schmidt JC, Chofflet J, Horle S, Mennel S, Meyer CH. Three simple approaches to visualize the transparent vitreous cortex during vitreoretinal surgery. Dev Ophthalmol. 2008; 42:35-42. 6. Guo S, Tutela AC, Wagner R, Caputo AR. A comparison of the effectiveness of four biostains in enhancing visualization of the vitreous. J Pediatric Ophthalmol Strabismus 2006; 43:281-284. 7. Sousa-Martins D, Maia M, Moraes M, et al. Use of lutein and zeaxanthin alone or combined with brilliant blue to identify intraocular structures intraoperatively. Retina Epub ahead of print 26 March 2012. doi 10.1097/IAE.0b013e318239e2b6. 8. Farah ME, Maia M, Furlani B, et al. Current concepts of trypan blue in chromovitrectomy. Dev Ophthalmol. 2008; 42:91-100. 9. Almony A, Nudleman E, Shah GK, et al. Techniques, rationale, and outcomes of internal limiting membrane peeling. Retina 2012; 32:877-891. 10. Mester V, Kuhn F. Internal limiting membrane removal in the management of full-thickness macular holes. Am J Ophthalmol. 2000; 129:769-777. 11. Funata M, Wendel RT, de la Cruz Z, Green WR. Clinicopathologic study of bilateral macular holes treated with pars plana vitrectomy and gas tamponade. Retina 1992; 12:289-298. 12. Fekrat S, Wendel RT, de la Cruz Z, Green WR. Clinicopathologic correlation of an epiretinal membrane associated with a recurrent macular hole. Retina 1995; 15:53-57. 13. Burk SE, Da Mata AP, Snyder ME, Rosa RH Jr, Foster RE. Indocyanine green-assisted peeling of the retinal internal limiting membrane. Ophthalmology 2000; 107:2010-2014. 14. Wollensak G. Biomechanical changes of the internal limiting membrane after indocyanine green staining. Dev Ophthalmol. 2008; 42:82-90. 15. Rodrigues EB, Meyer CH. Meta-analysis of chromovitrectomy with indocyanine green in macular hole surgery. Ophthalmologica 2008; 222:123-129. 16. Rodrigues EB, Penha FM, Farah ME, et al. Preclinical investigation of the retinal biocompatibility of six novel vital dyes for chromovitrectomy. Retina 2009; 29:497-510.
toxicity
The toxic effects of any vital dye depend on the dye concentration, the osmolarity of the dye solution, the dye exposure time, and the illumination time. Recommendations to avoid toxicity include paying close attention to achieving dilutions with physiological osmolarities. The lowest concentration that will achieve staining should be used. The light pipe should remain far from the macula to avoid any light toxicity and photodynamic effect of the dye.4 Macular holes pose a particular problem since the bare RPE of the floor of the hole may come in contact with any dye and produce potential RPE toxicity. Some have suggested covering the hole with blood, viscoelastic, or perfluorocarbon liquid.
Conclusions
Transparent tissues such as the posterior hyaloid, ERM, and the ILM play an important role in several diseases of the posterior pole. Surgical removal of these tissues is a principal surgical objective. Staining of these tissues with a variety of vital dyes facilitates their identification and removal. Several dyes are currently in routine clinical use; however, the ideal staining agent has not yet been found. Any dye that is injected intravitreally has the potential to become toxic.
Retina
11
Vitrectomy for Lamellar Macular Hole

Lamellar macular hole (MH) is a distinct clinical entity, defined as absence of the inner macular tissue in the foveola region (ie, break of the inner retinal layers and intraretinal splitting) not extending to the level of the retinal pigment epithelium (RPE); lamellar MH occurs via interruption of the typical MH formation process or by the unroofing of the central fovea in chronic cystoid macular edema (CME).1-3 Despite the original description from Gass in 1976,1 the lamellar MH entity was not completely understood until recently with the widespread use of OCT; previously misdiagnosed cases of lamellar MHs can now be identified and their characteristics described very accurately.4-6 Tomographic studies of lamellar MHs with respect to their natural evolution7 or surgical outcomes8-10 are limited, retrospective in nature,8 and involve usually a limited number of patients.9,10 The clinical diagnosis of lamellar MHs was done in the preOCT era based only on biomicroscopy and fluorescein angiography. A small number of studies exist on lamellar MH entity, and those dated before the OCT advent are of little value nowadays, since lamellar MH is mainly an OCT-based diagnosis;11,12 in particular, there are studies in the literature from the past decade on macular pseudoholes (MPHs) that can now be reidentified as studies referring to lamellar MHs.12 Furthermore, with the widespread use of tomography, even the Gass theory of Mueller cell proliferation above the fovea, leading to a centripetal tangential traction on the fovea as the principal initiating step in the formation of MHs, has been brought into question.13 In the present study, we report our results of surgical intervention/ observation in a series of patients diagnosed with lamellar MH. It has been reported that most lamellar MH patients have mild complaints of metamorphopsia and limited central visual acuity (VA) loss, which uncommonly progresses to further deterioration of VA.7 In a very recent study by Theodossiadis and associates,7 the authors studied the natural course of lamellar MH in 41 cases and found an increase in the lamellar MH diameter by an average of 13.7% and deterioration in best-corrected VA (BCVA) in 22% of the cases studied, over a period of 37.1 months. Visual deterioration could be possibly relatedas the authors concludeto the enlargement of the lamellar MH diameter. Surgical treatment of lamellar MHs remains controversial, and some authors believe that there is no proof that surgical intervention is helpful,6,10 whereas other studies8-11 found vitrectomy with epiretinal membrane (ERM)internal limiting membrane (ILM) removal to be beneficial with respect to the VA result and foveal OCT appearance. In the report by Witkin and associates,11 4 patients underwent vitrectomy for lamellar MH, with only 1 case being judged anatomically and visually successful. Two of their patients developed full-thickness MHs after vitrectomy. Conversely, Hirakawa and associates9 recently reported 2 patients with improved vision after vitrectomy with ILM peeling and gas tamponade for lamellar MH. Kokame achieved similar results in a case report of a single patient.10 The largest study reported so far, by Garretson and associates,8 found vitrectomy beneficial for 93% of their patient cohort, with a mean gain of 3 Snellen lines of VA.
In our study,14 BCVA improved in 17 out of the 20 cases (85%) operated with a lamellar MH associated with an ERM; 3 cases retained the same BCVA postoperatively. Mean BCVA improvement was 2.6 Snellen lines, which was statistically significant (P = .002, paired t test). None of the cases deteriorated in terms of BCVA. Our hypothesis for the beneficial role of vitrectomy in lamellar MHs is that the ERM-ILM removal releases the tangential traction to the edges of the lamellar MH. Even in cases in which the lamellar MH still persists after surgical intervention, the surgically removed ERM-ILM prevents further lamellar MH stretching and VA deterioration, and so even in these cases there is a beneficial role of the surgical approach. Although there is no evidence that C3F8 use and facedown position are necessary in lamellar MH surgery, we decided to follow the same surgical approach we routinely use in cases of full-thickness MHs. Posterior vitreous detachment was present in all but 1 of our study cases of lamellar MHs with an ERM. Little information exists with respect to this finding in the literature. To our knowledge, in the only study reported,8 the authors presume retrospectively from the patients perioperative report that vitreous was attached in 17 out of the 27 patients (in the remaining 10 cases, there was no perioperative note on the vitreous attachment). In our patient cohort, vitreous was detached in almost all cases (except from cases with lamellar MH secondary to CME), and we believe that this feature represents another diagnostic criterion of the lamellar MHs. With respect to the presence of an ERM, most of the recent OCT studies7-11 report ERMs in the majority of patients with lamellar MHs; our belief is that ERM represents another distinct feature of lamellar MHs. Many of the ERMs associated with a lamellar MH have an unusual thickened appearance of moderate reflectivity on ultrahigh-resolution OCT.11 The high prevalence of ERMs in lamellar MHs suggests that ERM contraction plays a role in lamellar hole formation; removal of the ERM is mandatory to improve the surgical results and to stabilize or improve the VA in these cases.
References
1. GassJD. Lamellar macular hole: a complication of cystoid macular edema after cataract extraction. Arch Ophthalmol. 1976; 94:793800. 2. AllenAW, GassJD. Contraction of a perifoveal epiretinal membrane simulating a macular hole. Am J Ophthalmol. 1976; 82:684691. 3. GassJD. Lamellar macular hole: a complication of cystoid macular edema after cataract extraction. Arch Ophthalmol. 1976; 94:793800. 4. TakahashiH, KishiS. Tomographic features of a lamellar macular hole formation and a lamellar hole that progressed to full-thickness macular hole. Am J Ophthalmol. 2000;130:677-679. 5. HeeMR, PuliafitoCA, WongC, etal.Optical coherence tomography of macular holes. Ophthalmology 1995; 102:748-756.
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6. HaouchineB, MassinP, TadayoniR, etal.Diagnosis of macular pseudoholes and lamellar macular holes by optical coherence tomography. Am J Ophthalmol. 2004; 138:732-739. 7. TheodossiadisPG, GrigoropoulosVG, EmfietzoglouI, etal.Evolution of lamellar macular hole studied by optical coherence tomography. Graefes Arch Clin Exp Ophthalmol. 2009; 247:13-20. 8. GarretsonBR, PollackJS, RubyAJ, etal.Vitrectomy for a symptomatic lamellar macular hole. Ophthalmology 2008; 115:884886. 9. HirakawaM, UemuraA, NakanoT, etal.Pars plana vitrectomy with gas tamponade for lamellar macular holes. Am J Ophthalmol. 2005; 140:1154-1155. 10. KokameGT, TokuharaKG. Surgical management of inner lamellar macular hole. Ophthalmic Surg Lasers Imaging. 2007; 38:61-63. 11. WitkinAJ, KoTH, FujimotoJC, etal.Redefining lamellar holes and the vitreomacular interface: an ultra-high resolution optical coherence tomography study. Ophthalmology 2006; 113:388-397. 12. MassinP, PaquesM, MasriH, etal.Visual outcome of surgery for epiretinal membranes with macular pseudoholes. Ophthalmology 1999; 106:580-585. 13. GassJD. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol. 1995; 119:752759. 14. Androudi S, Stangos A, Brazitikos P. Lamellar macular holes: tomographic features and surgical outcome. Am J Ophthalmol. 2009; 148:420-426.
Retina
Cool Surgical Video Panel
13
My Coolest Surgical Video
the Use of Viscoelasticsin Severe trauma Cases

Carlos Mateo MD

Claus Eckardt MD
I Shrunk the Gauge...

Yusuke Oshima MD
Proliferative Vitreoretinopathy (PVR) after Vitrectomy with Silicone oil for Retinal Detachment Associated with Giant Retinal tear
J Fernando Arevalo MD FACS
the Development of Retinal endovascular Surgery

Kazuaki Kadnosono MD

Carl C Claes MD
Suprachoroidal Buckling, Indications, evaluation and technique

Ehab N El Rayes MD PhD
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the Charles L Schepens MD Lecture
Retina
Potential therapeutic Approaches to AMD

therapeutic targets for early Age-Related Macular Disease
Alan C Bird MD
Changes in age-related macular disease (AMD) may affect choroid, Bruch membrane, the retinal pigment epithelium (RPE), and photoreceptor cells. The nature of the changes and the mechanisms by which they are generated are partly understood and have given rise to novel forms of treatment that are under trial. It is hoped that these will cause slowing or reversal of these changes with consequent reduction or abolishment of the risk of loss of central vision. Early histological studies indicated that photoreceptor loss may occur early in the disease process, and these findings accord with functional studies that reveal up to 3.4 log units of photopic function in eyes with early AMD but normal visual acuity. Both functional and histological data indicate that rod loss is greater than cone loss. It is widely believed that photoreceptor loss may be due to lack of metabolic support consequent upon thickening of Bruch membrane or RPE dysfunction. A recent histological study supports the view that major photoreceptor loss may occur early in disease, implying that the functional loss is due to cell loss, at least in part. In addition, the changes vary from one donor to another. In particular there is an inverse relationship between Bruch membrane thickening and RPE autofluorescence. Finally, photoreceptor loss may occur in the absence of obvious physical changes in other tissues. These findings imply that specific therapeutic approaches may not be suitable for all cases. If these conclusions are correct, better phenotyping will be needed to select cases for therapeutic trials and monitor therapeutic effect.
Retina
Section II: Non-neovascular AMD
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Pathogenesis of AMD
Christine A Curcio PhD
Introduction
The best approach to improve care for our patients is to follow the biology.1
Determining the composition of signature lesions was a means to identifying affected pathways in diseases like Alzheimer disease and atherosclerosis. For AMD, key lesions are drusen and basal linear deposit (BlinD), two forms (lump and layer) of the same lipid-rich material. Major constituents of drusen are now known. The first testable biochemical model for the main pathway has been articulated.2 Non-neovascular AMD is a metabolic and vascular disease affecting the photoreceptor support systemretinal pigment epithelium (RPE) and choroidsecondarily causing photoreceptor degeneration. Bruch membrane (BM), the choroids inner wall, is a subendothelial space, substrate for RPE attachment, and route for outer retinal nutrition and metabolite removal. Drusen and BlinD form on BMs inner surface, outside the bloodretina barrier and within the systemic circulation. AMDs largest risk factor is aging, suggesting that older eyes harbor clues to lesion pathogenesis. Major genetic risk factors include the alternative complement pathway and cholesterol and lipoprotein metabolism, among others.3,4 There is no consistent relationship between AMD and any measure of plasma atherogenic or antiatherogenic lipoproteins. Nor have plasma-lipid lowering statins proven consistently beneficial.
BM Lipoproteins: Main Pathway of Drusen

Nineteenth-century pathologists described drusen as fatty globules.5 Early discovery is a surrogate for abundance. Histochemically detectable esterified and unesterified cholesterol is present in all drusen.6 Lipids are the most abundant druse component, representing 40% of hard druse volume.7 Apolipoprotein immunoreactivity decreases in macular drusen, suggesting that high-risk drusen have proportionally higher lipid content.8 Soft drusen, oily and biomechanically unstable, are present in macula only.9 The backdrop to druse biogenesis is a marked accumulation of oil red O binding neutral lipid within macular BM throughout adulthood in normal eyes, thought to create a hydrophobic barrier.10 This process superficially resembles, but is distinct from, systemic perifibrous lipid accumulation, whereby plasma apoBlipoproteins insudate into and bind to dense connective tissue in normal arterial intima (plus cornea, sclera, and tendons), setting up atherosclerotic plaques in hemodynamically vulnerable locales.11 Lipid-preserving ultrastructure, histochemistry, comprehensive lipid profiling, and gene expression combine with epidemiology to indicate that the RPE constitutively secretes large apoB containing lipoproteins into BM for clearance. These intraocular lipoproteins are 60-80nm diameter spherical particles with neutral lipid cores rich in esterified cholesterol and surfaces containing apoB-100, apoA-I, apoE, and apoC-I. They accumulate in the BM elastic layer starting in early adulthood, filling in toward the RPE. In older persons, a layer of almost pure lipoprotein par-
ticles on BM inner surface (lipid wall) separates the RPE basal lamina from BM and represents the direct precursor to BlinD. RPE expresses genes for apoB and for microsomal triglyceride transfer protein, required for apoB lipidation and secretion, a combination signifying a constitutive lipoprotein secretor. RPE cell lines secrete apoB. Highly differentiated polarized RPE secrete apoE-immunoreactive particles, ultrastructurally identical to lipoprotein-containing structures in native BM, which are capable of binding exogenously applied complement.12 Lipid profiling of BM lipoproteins indicates that the major fatty acid is linoleate, implicating diet as the upstream source of this constituent, rather than photoreceptor outer segments, rich in docosahexaenoate. Functional consequences of the oil spill in BM include impaired transport of large molecules or multimolecular complexes including plasma lipoproteins delivering lipophilic essentials like carotenoids and vitamin E to RPE and photoreceptors via LDL and SRB-I receptors. Complexes of this size and physiological relevance can cross BM at higher rates than in arterial intima and block transport of subsequent particles,13 providing proof-of-principle for a hydrophobic barrier. Other consequences are the formation of highly toxic, proinflammatory/ proangiogenic compounds like linoleate hydroperoxide and 7-ketocholesterol,14,15 known troublemakers from atherosclerotic plaque. Additional abundant protein components of drusen include TIMP-3 and many proteins of the complement cascade, including the terminal component membrane attack complex (C5b9).16,17 Advanced glycation end products likely enhance retention of lipoproteins18 that activate complement. Amyloid -peptide is a volumetrically small druse component of interest because of its significance in Alzheimer disease.19 One large age-related change that does not appear directly related to druse biogenesis is RPE lipofuscin, rich in bis-retinoids. Lipofuscin granules appear in a small proportion (6%) of isolated drusen or shed into basal laminar deposits of eyes with advanced disease. Macular topographies of lipofuscin accumulation and RPE-BM pathology are not correlated.20 In vivo hyperautofluorescence in AMD eyes can be accounted for by vertically superimposed RPE cells.21 Thus lipofuscin is not a significant druse constituent or an obvious predisposing factor.
AMD Lesions in the Subretinal Space

Remarkably, high-resolution imaging and new histopathology suggest a process parallel to that in BM involving cholesterolcontaining deposits in the subretinal space. Subretinal drusenoid debris (SDD) is an organized, extracellular lesion at the RPEs apical aspect first described in 198822 and later correlated with reticular pseudodrusen.23,24 Histologically detectable in 87% of a small AMD series, SDD is abundant in the rod-rich perifovea, in contrast to BlinD, abundant under the cone-rich fovea.25 This first linkage of lesion topography to rods and cones suggests involvement of differential aspects of photoreceptor physiology, such as cholesterol homeostasis of outer segment membranes.
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Implications and Conclusions

Open biological questions include bases for AMDs predilection for macula, domain-specific lipid trafficking pathways within RPE, and lipid trafficking mechanisms between RPE and photoreceptors. New opportunities for therapeutic intervention, summarized as the Oil Spill Strategies,2 include refurbishing BM before implanting new cells, modulating RPE lipoprotein outflow using agents developed for controlling hepatic VLDL and/ or diverting cholesterol to other pathways, and modifying RPE physiology through diet and plasma lipoprotein-delivered agents. In sum, vectorial outflow and retention of lipoproteins required by photoreceptor and RPE physiology plausibly provides chronic inflammatory stimuli for extracellular lesion formation in genetically susceptible persons. Twice the prevalence of Alzheimer disease, AMD at physiologic and molecular levels resembles cardiovascular disease more than a primary neurodegeneration. Cardiovascular disease has declined steadily for 4 decades due to reduction of population risk factors and application of pathway-specific pharmaceuticals. New information about druse biology illuminates a similar way forward for AMD.
11. Kruth HS. The fate of lipoprotein cholesterol entering the arterial wall. Curr Opin Lipidology. 1997; 8:246-252. 12. Johnson LV, Forest DL, Banna CD, et al. Cell culture model that mimics drusen formation and triggers complement activation associated with age-related macular degeneration. Proc Natl Acad Sci USA. 2011; 108(45):18277-18282. 13. Cankova Z, Huang J-D, Kruth H, et al. Passage of low-density lipoproteins through Bruchs membrane and choroid. Exp Eye Res. 2011; 93(6):947-955. 14. Spaide R, Ho-Spaide W, Browne R, et al. Characterization of peroxidized lipids in Bruchs membrane. Retina 1999; 19:141-147. 15. Moreira EF, Larrayoz IM, Lee JW, et al. 7-ketocholesterol is present in lipid deposits in the primate retina: potential implication in the induction of VEGF and CNV formation. Invest Ophthalmol Vis Sci. 2009; 50(2):523-532. 16. Hageman GS, Luthert PJ, Chong NHC, et al. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruchs membrane interface in aging and agerelated macular degeneration. Progr Ret Eye Res. 2001; 20:705732. 17. Crabb JW, Miyagi M, Gu X, et al. Drusen proteome analysis: an approach to the etiology of age-related macular degeneration. Proc Natl Acad Sci U S A. 2002; 99(23):14682-14687. 18. Handa JT, Verzijl N, Matsunaga H, et al. Increase in the advanced glycation end product pentosidine in Bruchs membrane with age. Invest Ophthalmol Vis Sci. 1999; 40:775-779. 19. Johnson LV, Leitner WP, Rivest AJ, et al. The Alzheimers A-peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A. 2002; 99:11830-11835. 20. Jackson GR, Owsley C, Curcio CA. Photoreceptor degeneration and dysfunction in aging and age-related maculopathy. Ageing Res Rev. 2002; 1:381-396. 21. Rudolf M, Vogt SD, Curcio CA, et al. Histological basis of variations in retinal pigment epithelium autofluorescence in eyes with geographic atrophy. Ophthalmology 2012. In revision. 22. Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988; 2:552-577. 23. Zweifel SA, Spaide RF, Curcio CA, et al. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 2010; 117(2):303-312.e.1. 24. Sarks J, Arnold J, Ho IV, et al. Evolution of reticular pseudodrusen. Br J Ophthalmol. 2011; 95(7):979-985. 25. Curcio CA, Messinger JD, Sloan KR, et al. Subretinal drusenoid debris (SDD) predominant in perifovea, basal linear deposit (BlinD) predominant in fovea in atrophic age-related macular degeneration (AMD). Invest Ophthalmol Vis Sci. 2012; 53:e-abstract 1892.
References
1. Miller JW. Treatment of age-related macular degeneration: beyond VEG-F. Jpn J Ophthalmol. 2010; 54:523-528. 2. Curcio CA, Johnson M, Rudolf M, et al. The oil spill in ageing Bruchs membrane. Br J Ophthalmol. 2011; 95:1638-1645. 3. Chen W, Stambolian D, Edwards AO, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A. 2010; 107(16):7401-7406. 4. Neale BM, Fagerness J, Reynolds R, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A. 2010; 107(16):7395-7400. 5. Wedl C. Grundzge der pathologischen Histologie (translated by G. Busk). Vienna: Carl Gerold & Sohn; 1854. 6. Curcio CA, Millican CL, Bailey T, et al. Accumulation of cholesterol with age in human Bruchs membrane. Invest Ophthalmol Vis Sci. 2001; 42:265-274. 7. Wang L, Clark ME, Crossman DK, et al. Abundant lipid and protein components of drusen. PLoS ONE. 2010; 5(4):e10329. 8. Malek G, Li C-M, Guidry C, et al. Apolipoprotein B in cholesterolcontaining drusen and basal deposits in eyes with age-related maculopathy. Am J Pathol. 2003; 162:413-425. 9. Rudolf M, Clark ME, Chimento M, et al. Prevalence and morphology of druse types in the macula and periphery of eyes with agerelated maculopathy. Invest Ophthalmol Vis Sci. 2008; 49(3):12001209. 10. Pauleikhoff D, Harper CA, Marshall J, et al. Aging changes in Bruchs membrane: a histochemical and morphological study. Ophthalmology 1990; 97:171-178.
Retina
17
Genetic testingPro
Introduction
The recognition in 2005 of the importance of complement factor H-polymorphism revolutionized our understanding of the genetics of AMD, particularly the late stages of choroidal neovascularization and geographic atrophy. In addition to unequivocally corroborating previously fragmentary evidence on the importance of complement dysregulation in the pathogenesis of the disease, it also validated genome-wide association studies (GWAS) as valuable clinical tools to help better understand the genetic basis of late-onset diseases such as AMD.1-4 This approach to disease pathogenesis led to subsequent publications confirming the accuracy of the initial observations as well as identifying additional disease-causing genes of major importance such as ARMS2, and protective haplotypes in the same complement loci that were associated with disease causation. 5-6 These represent tantalizing clues that have potentially profound importance in terms of developing effective therapies in the future. However, a number of prospective clinical trials have been initiated to put these mechanisms to the test using various agents that modulate activity in the complement cascade, and as of the time of the writing of this review, none had yet shown convincing positive results. Additionally, several companies have released commercial products that offer patients genetic testing, based upon this methodology, to quantify their genetic risk of the development of late stage AMD. 7-9 This confluence of events raises the important question:
If genetic tests are available to help quantify the potential risk of developing late onset macular degeneration, and there is not a corresponding therapeutic intervention arising from that information, should that test be employed in clinical practice, recognizing the obvious value in clinical research from such testing.
The remainder of this discussion focuses on the answer to that question, taking the initial premise this will represent: the pro argument in this debate forum. In that regard this does not necessarily represent the personal opinion of the author but rather an examination of the positive case, based upon literature review and the clinical experience and the judgment of the author.
Arguments in Favor of Genetic testing

Genetic susceptibility is thought to only account for 60%-70% of the risks for the development of late stage AMD, at least based upon current data. 1-9 The remainder is due to environmental factors, and so tests that quantify that risk should be valuable at least in terms of modifying behavior to control environmental risk factors, such as smoking, sunlight exposure, medication use, or diet. However, there may be simpler and cheaper ways to assess risks than complex SNP analysis and gene sequencing. As an example, Ferris et al published a simplified severity scale for AMD based upon analysis of AREDS data from 4710 patients. In it they used 1 point each for either large drusen or pigment epithelial abnormalities, giving each patient a grade of 0 to 5, depending upon how many points were present, with a maxi-
mum of 2 per eye. This grading scale fairly accurately predicted the development of late stage AMD. For patients with 0 factors, this was 0.5%, with 1 factor estimates a 3% risk; 2 factors, 12%; 3 factors, 25%; and 4 factors, 50% over 5 years of followup. 10 When comparing this to the report of sensitivity and specificity for various genetically based tests, it seems that at least on a cost and simplicity basis, that fundus examination alone may be sufficient to assess late-stage risk in the large majority of patients to stratify late-stage risk for those already in the earlier stages of non-neovascular AMD. On the other hand, it could be argued that once these changes of drusen and pigment epithelial abnormalities are already present, the die has been cast, and patients are on an irreversible path toward late-stage disease regardless of the determination of risks by more complex means, and thus that earlier genetic analysis is necessary. The existing data would seem to suggest that argument is not true. In the AREDS 1 study, the use of antioxidants, multivitamins, and zinc was found to be associated with a significant reduction in the risks of late-stage AMD. Importantly, this protective benefit only seemed to exist for patients with more advanced stages of nonexudative AMD, with no appreciable benefit shown for earlier stage AMD. This would seem to argue, at least for this group, that prophylactic therapy interventions, targeted at a later time point in the natural history of the disease, can easily be identified through ophthalmoscopy alone. 11 It could, however, be reasonably argued, that had this study been conducted for a longer period of time, that the potential benefits would have been manifested. In this instance, in which patients with either minimal drusen or no drusen were treated, a relatively strong argument could be made for identifying those without increased genetic risks so as to avoid treating those patients who presumably would have a low likelihood of developing the disease, and sparing them the cost and small but non-zero risks of complications from treatment. A second line of reasoning promoting the use of genetic testing would be to identify those patients at higher risk of late stage AMD early in their lifetime prior to exhibiting early features such as drusen or pigment such that there could be a meaningful intervention in terms of modification of risk factors, particularly smoking, diet, and light exposure. Again there is statistical evidence that the cessation of smoking reduces the increased risk of late-stage AMD based upon retrospective studies, but the precise magnitude of this effect, particularly amplified over many decades, remains uncertain. A statistical basis for informing a patient that they were likely to develop late-stage AMD based upon genetic profile would be a more compelling argument for lifestyle risk modification than a more generic blanket warning about healthy behaviors. 12 A third argument to perform routine testing would be to inform pharmacologic therapy for patients who have already developed the late stages of the disease, particularly exudative AMD, at present, and potentially geographic atrophy in the future. To date, the literature regarding potential pharmacogenomics effects is scanty and contradictory. The widespread availability and use of genetic testing may allow for important retrospective studies to be done, which through their scope and
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need for long-term follow-up might be difficult to replicate in a prospective randomized controlled trial format. Meta-analysis of large data sets has proved to be useful and should be increasingly important as new forms of therapy for late-stage AMD become available. However, this argument is mostly directed at potential identification of treatment effects for large populations and pathogenesis rather than the specific management of an individual patient. A fourth argument is that for younger individuals so disposed, with a strong family history of exudative AMD, genetic testing can be useful in terms of defining risks. For those that did not carry the risk alleles, there would be considerably improved peace of mind. For those carrying the risk alleles, there would be more than ample opportunity to modify risk factors, or initiate therapy at an earlier time.
ICD-9 codes for AMD: nonspecific AMD 362.50, nonexudative AMD 362.51, exudative AMD 362.52, and drusen 362.57. The costs vary but typically range from $500 to $1,000, depending on coverage, and the tests are therefore not inexpensive.
Conclusion
There are a number of potential advantages to the adoption of genetic testing for patients currently being either evaluated or treated for AMD. These include (1) early identification for treatment with pharmacologic methods including antioxidants, multivitamins, and other dietary supplements, prior to the onset of early stage ophthalmoscopic manifestations of disease such as drusen and pigment epithelial abnormalities. (2) Early stage identifications of patients at risk in order to provide a well-informed basis for modification of potential environmental risk factors, including smoking, diet, and light exposure. (3) Assessment of pharmacogenomic factors to treatment response particularly in early stage diseases, including drusen and pigment epithelial atrophy associated with complement dysregulation as newer forms of targeted therapy become available. (4) The use of such data when employed in a widespread fashion for meta-analysis of retrospective studies evaluating pathogenesis, phenotype-genotypic correlations, and ultimately pharmocogenomic responses. (5) As a tool to lessen anxiety or provide a basis for lifestyle modification in younger relatives of affected individuals.
existing Commercial efforts

At present there are thought to be two principal providers of commercial genetic testing to clinicians and patients for the purpose of assessing late-staged macular degeneration risk, and several others in the wings. These include the Macular Risk Test provided by the Arctic Group of Companies (Bonita Springs, Flor., USA) and Sequenom CMM (Grand Rapids, Mich., USA). Both of these employ similar basic methodology in assessing genes or biomarkers (single nucleotide polymorphism [SNPs]) thought to be associated with increased risk for AMD. Although their general approach is similar, the use of validated genetic markers to make an assessment of the risk for a given individual, the number of markers assayed, and the bioinformatics approach to data analysis differ between the two companies. Sequenom uses a panel of 13 separate SNPs from 4 different chromosomes, primarily focusing on the various alleles of the alternate complement pathway factor-H, chromosome 1, as well as C2 and CFB genes on chromosome 6 LOC387I55/AMS2 on chromosome 10, and C3 on chromosome 19. Univariate and multivariate logistic regression analysis is employed to determine a level of risk based upon the calculated probability of the development of CNV, in turn based upon differences between allele frequency in a pool of 1709 patients and 1473 disease-free controls. These results are well documented in a peer-reviewed publication. 7 The risk profile of Arctic Technologies is based upon 4 separate loci, 2 in the complement cascades CFH and C3, the ARMS2 locus on chromosome 10, and the ND2 locus, thought to be associated with haplo groups J and T, associated with control of mitochondrial function. Additionally based upon epidemiologic data, it uses smoking as an independent variable in conjunction with the 4 other genomic loci to calculate a risk ranging 1 through 5. 8 Two other companies with less well-developed products offerings include 23andMe and deCODEme. However, with an increasing emphasis on demonstrations of cost-effectiveness as necessary criteria for the approval of both diagnostic and therapeutic interventions, the issue remains unsettled with regard to the potential benefits of this modality, recognizing that the risks are minimal, aside from the issue of inappropriate disclosure. Insurance coverage may vary from region to region, and at present, because this is a therapeutic rather than a diagnostic study, with low risks, it has not been cleared or approved by the U.S. FDA or thought to be subject to its regulation. Laboratories providing this testing are required to undergo CLIA certification and testing, to ensure the quality and validity of the test results and the provision of 1 of the 4 the
References
1. Edwards AO, Ritter III R, Abel KJ, et al. Complement Factor H polymorphism and age-related macular degeneration. Science. 2005; 308(2720):421-424. 2. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005; 102(20):7227-7232. 3. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risks of age-related macular degeneration. Science. 2005; 308(2720):419-421. 4. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005; 308(2720):385-389. 5. Jakobsdottir J, Conley YP, Weeks DE, et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Gen. 2005; 77(3):389-407. 6. Rivera A, Fisher SA, Fritsche LG, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Gen. 2005; 14(21):3227-3236. 7. Hageman GS, Gehrs K, Lejnine S, et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration. Human Genomics. 2011; 5(5):420-440. 8. Seddon JM, Reynolds R, Maller J, et al. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009; 50(5):2044-2053. 9. Udar N, Atilano SR, Memarzadeh M, et al. Mitochondrial DNA haplogroups associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009; 50(6):2966-2974.
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10. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005; 123(11): 1570-1574. 11. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8. Arch Ophthalmol. 2001; 119(10):1417-1436. 12. Tuo J, Ross RJ, Reed GF, et al. The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples. Ophthalmology 2008; 115(11):1891-1898.
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Genetic testingCon
What is the purpose of genetic testing for AMD? If the purpose is research, there is little debate as to whether it should be done. The genetic associations with AMD that have been identified are beyond what anyone would have predicted. These associations have great research promise. They may allow us to better understand the etiology of disease, suggest new treatment approaches, and help predict the response of individuals to various therapies. However, it is a separate question as to whether, at this time, routine genetic testing is useful to individual patients in understanding their risk of disease. If there were no other predictors of risk for development of late AMD (neovascular AMD or geographic atrophy), one might argue that there would be value to a patient. However, a simple inexpensive clinical method does exist to provide patients with an estimate of their risk of progression to vision loss. One only has to do a dilated eye exam to assess a patients risk for AMD, and it is really not even an extra exam, since persons in the age range should routinely be screened for signs of all 4 of the leading causes of blindness: AMD, cataract, glaucoma, and diabetic retinopathy. The risk of AMD can be assessed by counting the presence in each eye of large drusen and/or pigmentary changes. Based on the presence of these two easily identified lesions one can estimate a patients risk of developing late AMD and vision loss. For a patient with neither large drusen nor pigmentary changes associated with at least some drusen, the 5-year risk of progressing to advanced AMD is about 0.5%. One risk factor and the 5-year risk increases to 3%. Once one has two or more risk factors, the risk of late AMD has a greater clinical importance. With two risk factors, the 5-year risk is 12%, this doubles to 25% with three risk factors and doubles again to 50% with four risk factors (both large drusen and pigmentary changes in both eyes). This simple clinical approach can provide a patient with a 100-fold difference in risk assessment, from 0.5% in 5 years to 50%.1 This clinical risk estimate can be further refined with answers to a few questions regarding demographic/ environmental risk factors. For example, the estimated 5-year risk for a 75-year-old with a simple score of 4 would be lower than 50% for nonsmokers (38%) and higher for smokers (58%). The risk can be further modified by age and family history of AMD. Based on Age-Related Eye Disease Study (AREDS) data, we published an AMD risk calculator that allows one to assess the effects of these clinical factors on the 1- to 10-year risk of developing advanced AMD (www.ohsucasey.com/amdcalculator; date accessed: 7.5.2012).4 If available, genetic information can be added, but the further modification of risk is of little or no clinical significance in most individuals. This is illustrated by two commonly used methods of assessing the overall accuracy of predictive models: the C statistic and the Brier Score, both of which show virtually no differences in models with and without the inclusion of genetic information. While the model incorporates only variants in the two genes most strongly associated with AMD (CFH and ARMS2), the inclusion of all other known variants did not contribute to the genetic effect. Using the risk calculator, one can estimate the effect of positive vs. negative genetic testing on the estimate of risk. For a nonsmoker whose risk is 38% without taking into account
genetic testing, being genetically homozygous negative for CFH and ARMS2 decreases the risk to 29% vs. 50% for homozygous positive on both. For a smoker the risks would be 35% and 71%, respectively. What are the clinical implications of knowing this doubling of risk? Suppose you were the 75-year-old smoker with 4 risk factors. You would be told that on average you had a 58% 5-year risk of developing late AMD. Being negative or positive genetically, even in the extreme, modifies this risk to 35% vs. 71%. Even though the risk is almost double for the homozygous positive person in both genes, the message for the person seems similar to that without the genetic information. They are at high risk and should discuss with their ophthalmologist the appropriate interventions and follow-up. The added information from the genetic testing is unlikely to change the follow-up recommendations. Similarly, suppose you were a 75-year-old nonsmoker with no risk factors. The 5-year risk estimate with no genetic information is approximately 0%. The homozygous positive and negative 5-year risk is 0% and 1%, respectively. Because about 47 million of the approximately 55 million in the United States at risk for AMD are in this low risk group, it seems that routine testing of this group would provide very little of value. For one risk factor, the same 5-year risk estimates would be 3%, 6%, and 8%, respectively. These differences, while perhaps consistent with a doubling of risk at the genetic extremes, are probably clinically meaningless with regard to patient management. In summary, although genetic testing can modify AMD risk assessment in some individuals, there is minimal effect on overall performance measures of currently available predictive models and there is relatively little clinical value beyond what one can easily obtain with a clinical examination. As more information on the genetics of AMD becomes available, more information about different phenotypes of AMD becomes available, and more effective preventive measures are discovered, we can anticipate a greater role for genetics in the future.
References
1. Ferris FL, Davis MD, Clemons TE, et al; Age-Related Eye Disease Study (AREDS) Research Group. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005; 123(11):1570-1574. 2. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL III; Age Related Eye Disease Study Group. Risk factors for the incidence of advanced age-related macular degeneration in the Age-Related Eye Disease Study (AREDS). AREDS Report No. 19. Ophthalmology 2005; 112:533-539. 3. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308(5720):385-389. 4. Klein M, Francis PJ, Ferris FL, Hamon SC, Clemons T. Risk assessment model for development of advanced age-related macular degeneration. Arch Ophthalmol. 2011; 129(12): 1543-1550.
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Rapid-fire Phase 2 trials, Parts I and 2

Drugs in Phase 2 Clinical trials for Dry AMD
David M Brown MD, Philip J Rosenfeld MD PhD, Zohar Yehoshua MD MHA
The nonexudative or dry form of AMD is characterized by a well-defined constellation of clinical features, including drusen, pigment abnormalities (focal hyper- or hypopigmentation of the retinal pigment epithelium [RPE]), and geographic atrophy (GA) of the macula. The cause of AMD is thought to be multifactorial, resulting from a combination of genetic and environmental risk factors. Several theories developed to explain the pathogenesis of AMD include oxidative damage, lipofuscin accumulation, chronic inflammation with mutations in loci encoding proteins in the complement pathway and others, choroidal ischemia, mitochondrial damage,1 decreased DICER 1 activity in RPE cells of GA patients, increased bone morphogenetic protein-4 (BMP-4) in RPE and extracellular matrix of eyes with drusen and GA.2-4 It is believed that these factors are in part responsible for the pathological alterations in the choroid, RPE, and retina. These processes lead to a cascade of events resulting in the loss of central vision secondary from the loss of photoreceptors, RPE, and the choriocapillaris. While the primary site of injury in the formation of drusen and GA is still unknown, most histopathological studies suggest that injury or senescence of the RPE is the primary event, with photoreceptor cell death and choriocapillaris atrophy developing secondary to RPE loss.5 Primary photoreceptor loss may also play a role in GA onset and progression, as well as direct injury to the choroidal circulation.6 Currently, there is no proven therapy that stops the progression of dry AMD. While smoking cessation and diet supplementation based on AREDS formula vitamin trials combined with a healthy diet are the only recommended interventions for slowing disease progression to choroidal neovascularization, the progression of AMD to GA continues. The ultimate goal of treating dry AMD is to target the underlying cause of the disease and prevent, or at least slow, the loss of vision, which will require the preservation of the choroid, RPE, and photoreceptors. at amino acid position 402 within the CFH protein. Protective alleles associated with the complement pathway have also been reported. Two of the 5 CFH-related genes (CFHR1-5), which lie within the regulators of complement activation (RCA) locus on chromosome 1q32, known as CFHR1 and CFHR3, are considered to be protective against AMD.17 There are several treatment strategies to modulate the complement system that include blocking various effectors molecules, such as C3, C5, factor B, and factor D, as well as re-establishing control and homeostasis of the system, such as augmentation with protective form of complement factor H. Inhibition at C5 may have some advantages over C3 inhibition. C5 inhibition prevents terminal complement activity, but the more proximal complement functions are maintained such as production of C3a and C3b anaphylatoxins, which are required for opsonization and clearance of immune complexes and apoptotic bodies. These complement-mediated activities may be required to prevent bacterial infection and may preserve desired complement-mediated activities. One way to investigate whether complement activation affects the enlargement rate of GA would be to see if lesions with faster enlargement rates are associated with the at-risk alleles within the complement loci. Recent publications have reported that variants at CFH and C3 confer significant risks for GA and AMD, but no associations have been reported between progression rates of GA and these at-risk alleles.18,19 While data may suggest that other factors may be responsible for modulating the rate of disease progression, these data certainly dont preclude the use of complement inhibition as a viable treatment strategy for GA in dry AMD. AL-78898A (Potentia Pharmaceuticals; Louisville, Ky., USA/ Alcon Research; Fort Worth, Texas, USA) AL-78898A (previously known as POT-4) is a cyclic peptide comprised of 13 amino acids derived from compstatin. POT-4 binds reversibly to complement component 3 (C3) and prevents cleavage to active fragments C3a and C3b, as well as the subsequent release of all downstream anaphylatoxins, and prevents the formation of terminal membrane attack complex. As a C3 inhibitor, POT-4 inhibits all 3 major pathways of complement activation. POT-4 has unique slow-release properties owing to the formation of an intravitreal gel at higher doses, which provides sustained release of the drug and should permit less frequent intravitreal injections to achieve prolonged complement inhibition. Compastin has demonstrated effective complement inhibition with negligible toxicity.20 The Phase 1 dose-escalation study with POT-4, known as Assessment of Safety of Intravitreal POT-4 Therapy for Patients with Neovascular AMD (ASaP), was performed on patients with advanced CNV and was completed successfully without any safety concerns at the highest dose of up to 1.05 mg. There was evidence of depot formation in the intravitreal cavity at doses of 0.45 mg and 1.05 mg. At the 1.05-mg dose, these deposits lasted for more than 6 months. A Phase 2 study (NCT01157065) has been completed to further investigate the anti-VEGF properties of AL-78898A identified in the Phase 1 study. AL-78898A was combined with ranibizumab therapy
Drugs to Suppress Inflammation (see table 1)

Complement inhibition Over the past decade, evidence has emerged implicating the role of the complement cascade in AMD. Histopathological studies have identified various complement components in drusen, within the Bruch membrane, and in the anterior choroid.7,8 Moreover, deposits similar in appearance to drusen in AMD have been found in eyes of patients with complement-mediated renal diseases.9 Genetic association studies using different populations have shown that polymorphisms associated with disease have been localized within or close to genes that encode complement proteins.10 In 2005, four groups identified a genetic polymorphism in complement factor H (CFH) that were strongly associated with an increased risk of developing AMD.11-14 In addition, polymorphisms within other complement genes, such as complement component 3 (C3) genes15 and the complement factor B (CFB)/ complement component 2 (C2) locus,16 have been associated with an increased risk of AMD. The most common risk-conferring CFH genetic variant for AMD is the Y402H polymorphism, resulting in a tyrosine-to-histidine substitution
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in eyes with wet AMD to investigate whether AL-78898A prolongs the anti-VEGF effect of ranibizumab. This strategy should help estimate the appropriate dosing interval of POT-4 in future dry AMD trials. Another Phase 2 study was recently initiated to evaluate the safety and efficacy of 12 monthly intravitreal injections of 0.400 mcg of AL-78898A in slowing down the rate of progression of GA (NCT01603043). Eculizumab (SOLIRIS, Alexion Pharmaceuticals; Cheshire, Conn., USA). Eculizumab is a humanized monoclonal antibody derived from a murine antibody directed against human C5. Eculizumab specifically binds C5 and prevents cleavage to C5a and C5b and the downstream activation and formation of the membrane attack complex (MAC). Eculizumab is FDA approved for intravenous treatment of paroxysmal nocturnal hemoglobinuria. At the Bascom Palmer Eye Institute, a Phase 2 study was performed to evaluate the safety and efficacy of intravenous eculizumab for the treatment of patients with dry AMD. This trial is known as the COMPLement Inhibition with Eculizumab for the Treatment of Non-Exudative Age-Related Macular Degeneration (COMPLETE) Study. In this study, 30 patients with GA measuring from 1.25 mm2 to 18 mm2 and 30 patients with drusen with a volume of at least 0.03 mm3 within a 3-mm diameter circle centered on the fovea were randomized 2:1 to receive intravenous (IV) eculizumab or a saline placebo. Half of the patients in the eculizumab group received the low dose of eculizumab (600 mg via IV infusion for 4 weeks followed by 900 mg every 2 weeks until Week 26), while the other half received the high dose (900mg eculizumab via IV infusion for 4 weeks followed by 1200 mg every 2 weeks until Week 26). After 26 weeks, patients were followed without treatment every 3 months for an additional 6 months. A total of 60 patients were enrolled. After 26 weeks of treatment, no differences were detected between the treatment and placebo groups. Eculizumab did not prevent the growth of GA and did not decrease the drusen volume in the 2 separate cohorts. The growth rate of GA didnt show any correlation with the number of at-risk alleles carried by the subject; however, drusen growth showed positive association with number of CFH at-risk alleles. One-year follow-up is currently under way. ARC-1905 (Ophthotech; Princeton, NJ, USA) ARC-1905 is an intravitreally administered anti-C5 pegylated aptamer. The drug blocks the cleavage of C5 into C5a and C5b, thus blocking downstream complement activation. Unlike monoclonal antibodies, aptamers are synthesized single-stranded polyribonucleotides and generally do not elicit an immune response that could limit their efficacy. Aptamers are also small nonprotein molecules that could be formulated in a sustained-release platform. ARC-1905 is currently in Phase 1/2 trials for both dry and wet AMD. A Phase 1/2 dose-escalation study investigating ARC1905 in combination with ranibizumab therapy for the treatment of wet AMD was performed. An ongoing Phase 1/2 study investigating ARC1905 in eyes with dry AMD to prevent the growth of GA was also performed. This study randomized subjects between 2 intravitreal doses (0.3 mg and 1.0 mg) given at baseline and Months 1, 2, 6, and 9. This study has been completed and the results are pending (NCT00950638). LFG316 (Novartis) LFG316 is an intravitreally administrated anti-C5 antibody. A Phase 1 study to assess the safety and tolerability of intravitreal
LFG316 in patients with advanced AMD (GA or CNV) has been completed (NCT01255462). A Phase 2 study (NCT01527500) designed to study the efficacy of 6 successive monthly doses of intravitreal (IVT) LFG316 on the growth of GA is currently under way. FCFD4514S (Genentech/Roche) FCFD4514 is a monoclonal antibody fragment (Fab) directed against factor D. Factor D is the rate-limiting enzyme involved in the activation of the alternative complement pathway. A Phase 1 dose-escalation clinical trial of intravitreal FCFD4514 has been completed and the medication was well tolerated up to a 10-mg dose. A Phase 2 study (NCT01229215) is currently under way for the treatment of GA in dry AMD patients. In this study, patients were randomized between a sham injection and monthly or every other month injections of 10-mg FCFD4514S for 18 months. Another Phase 2 (NCT01602120) study has been initiated, which is an extension to the previous study and will assess the long-term safety and tolerability of repeated intravitreal administration ofFCFD4514Sin patients with GA. Patients are eligible to participate who have completed the 18-month treatment regimen from the previous study. Additional Anti-Inflammatory Drugs Fluocinolone acetonide (Iluvien) (Alimera Sciences; Alpharetta, Ga., USA) Iluvien is a nonbioerodible polyimide tube containing 180 g of the corticosteroid fluocinolone acetonide. It is inserted via a 25-gauge intravitreal injector, which creates a self-sealing wound. A Phase 2 study (NCT00695318) is under way involving 40 patients with bilateral GA, and the primary outcome is the difference in the enlargement rate of GA in treated compared with untreated eyes. The study eye is randomized to a high (0.5 g/day) or a low (0.2 g/day) dose, and the fellow eye serves as a control. The study is currently under way. Sirolimus (Rapamycin, Santen) Sirolimus is a macrolide fungicide that has the ability to inhibit the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth, proliferation, motility, survival, protein synthesis, and transcription. Sirolimus possesses a broad spectrum of therapeutic action, inhibiting inflammation, angiogenesis, fibrosis, and hyperpermeability. It is being used as a potent immunosuppressive and anti-inflammatory agent. Sirolimus is currently in a Phase 1/2 NEI study to determine the safety and efficacy of subconjuctivally administrated sirolimus for the treatment of GA and if it can help preserve vision in these patients (NCT00766649). This study is currently active and not recruiting patients. Patients with bilateral GA may be eligible for this study. One eye of eligible participants is randomized to treatment while the fellow eye will be observed. Participants will receive a 20-microliter (440-microgram) subconjunctival injection of sirolimus in the study eye at baseline and every 2 months thereafter. Another Phase 1/2 NEI study is currently recruiting patients with bilateral GA. The aim of this study is to assess the use of serial intravitreal injection (every 2 months for 2 years) of sirolimus in patients with bilateral GA. The primary outcome is the rate of change in area of GA in the study eye and fellow eye at 2 years compared with baseline. Secondary outcomes will include changes in best-corrected visual acuity (BCVA), changes in drusen area, and the development of
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table 1. Drugs to Suppress Inflammation Drug

Eculizumab (Soliris)
Mechanism of Action
Monoclonal antibody against complement component 5 (Intravenous) Aptamer against complement component 5 (intravitreal) Inhibits complement component 5 (intravitreal) Inhibits complement component 3 (intravitreal) Fab derived from a monoclonal antibody against complement factor D (intravitreal) Glucocorticoidmediated suppression of inflammation (intravitreal) mTOR inhibitor (intravitreal)
Sponsor
Alexion
trial Subjects
Geographic atrophy and drusen
Clinical Study Phase

Phase 2
Clinical trial Identifier

NCT00935883 (ongoing)
ARC1905
Ophthotech
Geographic atrophy and/or drusen
Phase 1/2
NCT00950638 (completed)
LFG316
Novartis
Geographic atrophy
Phase 2
AL 78898A
Alcon
Geographic atrophy
Phase 2
FCFD4514S
Genentech/Roche
Geographic atrophy
Phase 2 Phase 2
NCT01229215 (ongoing) NCT01602120 (not yet recruiting) NCT00695318 (ongoing)
Fluocinolone acetonide (Iluvien)
Alimera Sciences
Geographic atrophy
Phase 2
Sirolimus (Rapamycin)
NEI
Geographic atrophy
Phase 2
NCT00766649 (ongoing) NCT01445548 (ongoing)
Glatiramer acetate (Copaxone)
Induces glatiramer acetatespecific suppressor T-cells and downregulates inflammatory cytokines (subcutaneous)
Kaplan Medical Center
Drusen
Phase 2/3
CNV (NCT01445548). Intravitreal sirolimus will also be investigated in AREDS2 patients with central GA, but this study has not yet been initiated. Glatiramer acetate (Copaxone, Teva Pharmaceuticals; KfarSaba, Israel) Copaxone is an immunomodulatory agent approved for the treatment of multiple sclerosis that induces specific suppressor T-cells and downregulates inflammatory cytokines. It is administered subcutaneously and is being investigated in patients with drusen. A Phase 1 study evaluating the safety and efficacy of weekly treatment over 12 weeks with subcutaneous glatiramer acetate in patients with dry AMD has shown that glatiramer acetate reduces drusen area.21 A Phase 2/3 study has been started to evaluate the efficacy and safety of glatiramer acetate in arresting progression of dry AMD, including progression to wet (NCT00466076).
Drugs to Improve Choroidal Circulation and Protect Against Ischemia

Trimetazidine and Alprostadil Trimetazidine is a drug currently used for the treatment of angina pectoris. Trimetazidine improves myocardial glucose utilization by stopping fatty acid metabolism, and it is considered to have cytoprotective effects in ischemic conditions. Other uses for this drug include the treatment of vertigo, tinnitus, and vision loss due to vascular causes. A multicenter, randomized, placebo-controlled study in Europe investigated the off-label use of trimetazidine (Vastarel MR, 35-mg tablet), and the primary goal of this study was to slow the conversion of dry AMD to wet AMD. The results of this trial have been published, and the treatment failed to prevent CNV. Subgroup analyses suggest that this drug could be tested as preventive therapy for GA, although the overall comparison showed no statistically significant differences in the progression of GA.22 Another drug being investigated for its vasodilatory effect is Alprostadil, also known as prostaglandin E1 (PGE1). The presumed rationale is based on the belief that
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improved circulation would slow the progression of AMD. This multicenter, randomized, placebo-controlled study performed in Europe has been completed but not yet published. MC-1101 (MacuCLEAR, Inc.; Plano, Tex., USA) MC-1101 is a topical agent that has been shown to increase mean choroidal blood flow, and it also possesses anti-inflammatory and antioxidative properties. MC-1101 aims to maintain the integrity of the Bruch membrane by restoring choroidal blood flow, controlling inflammation, and restoring RPE function through its antioxidative effects. The active ingredient of MC-1101 is approved for use as an oral antihypertensive drug, and its safety and tolerability profile is well characterized. A Phase 1, proof-of-concept, open-label, placebo-controlled study was performed in which healthy volunteers and patients with early dry AMD self-administered MC1101 to the front of the eye using the VersiDoser ophthalmic delivery system (Mystic Pharmaceuticals; Austin, Tex., USA) over 3 days. In this study, 31 subjects (11 AMD patients and 20 normal) aged 50 to 89 were treated contralaterally with MC-1101 and placebo and dosed a total of 7 times over 3 days. MC-1101 was found to be safe and well tolerated with no significant safety-related issues reported. Mild and transitory ocular hyperemia was the most common treatment-related adverse event, which occurred in 21 (68%) MC-1101-treated eyes and 1 (3%) vehicle-treated eye; however, this was expected given MC-1101s mechanism of action. Results for choroidal blood flow found increased blood volume and velocity values in MC-1101-treated eyes 2 hours after dosing, which returned to baseline 2 hours later. In the AMD group, modest increases in blood flow were found 30, 60, and 120 minutes post-dosing at Visit 1.23 A Phase 2/3 controlled, doublemasked, single center study is under way (NCT 01601483). A single eye of 60 individuals with mild to moderate dry AMD will be randomly assigned to receive either topical 1%MC-1101or a vehicle control 3 times a day over 2 years. The study design will assess the efficacy, safety, and tolerability ofMC-1101for these patients. This study is not yet open for recruitment.
3 lines of vision compared with 75% of the patients in the shamtreatment group (P = .078).27 A statistically significant increase in macular thickness in the group receiving active treatment was observed, as previously documented in animal studies, indicating expansion of the outer nuclear layer. However, there were no statistically significant differences observed in the progression of GA at 12 months for either the high-dose or low-dose groups compared with the sham group. Brimonidine Tartrate Intravitreal Implant (Allergan; Irvine, Calif., USA) The brimonidine tartrate intravitreal sustained-release implant is a -2 adrenergic receptor agonist that is currently available as an ophthalmic solution (Alphagan P, Allergan; Irvine, Calif., USA) for the lowering of IOP in patients with open-angle glaucoma or ocular hypertension. Brimonidine stimulates the production of neurotrophic factors and has been shown to protect photoreceptors in animal models of retinal degeneration.28 However, the exact mechanism of action is unknown. Brimonidine tartrate has been formulated as an intravitreal implant using the Allergan Novadur posterior segment drug delivery system (PS DDS). The implant delivers the drug to the retinal tissue over a period of up to 3 months. The efficacy and safety of the brimonidine tartrate intravitreal implant for the treatment of dry AMD is currently under investigation in a Phase 2 study that is being carried out in 2 stages. Stage 1 is a 1-month, patient-masked, dose escalation, safety evaluation of the implant, and stage 2 is a randomized, double-blind, dose-response, sham-controlled evaluation of the safety and efficacy of the implant in which the primary efficacy endpoint is the change from baseline in the area of GA at 1 year (NCT00658619). Patients with GA in both eyes received the implant (200 g or 400 g) in one eye and sham treatment in the fellow eye as a control, and the implant was replaced at 6 months. Patients were followed up for 2 years. Results have not yet been released. AL-8309B (Tandospirone) (Alcon Research Ltd.; Ft. Worth, Tex., USA) AL-8309B is a selective serotonin 1A receptor agonist that is under development as a topical ophthalmic solution for use in dry AMD patients with GA. In animal studies, tandospirone protected the retina from light damage, and this protection was dose-dependent. A multicenter, randomized, double masked, placebo-controlled Phase 3 clinical trial (NCT00890097) known as the Geographic Atrophy Treatment Evaluation (GATE) trial was performed to investigate the effects of topical AL-8309B (1.0 and 1.75%) in patients with GA.29 Patients received 1 drop of an ophthalmic solution (1.75%, 1.0%, or vehicle) twice daily into the study eye for 2 years. The primary efficacy endpoint was the rate of progression of GA. The study has been completed, but the results have not yet been released. Antiamyloid therapy This novel therapeutic strategy for the preservation of photoreceptors and the RPE is borrowed from the treatments under development for Alzheimer disease since amyloid is present in both diseases. Amyloid oligomers are toxic to cells, and diseases with amyloid deposition exhibit abundant fibrils of various lengths that are the end product of stepwise protein/peptide misfolding. These fibrils as believed to accumulate as extracellular deposits and drusen have been found to contain fibrillar amyloid, which may damage RPE cells and promote inflammation that contributes to AMD progression.30-32
Drugs to Protect Photoreceptors and RPe (Neuroprotection)

See Table 2 Ciliary Neurotrophic Factor (CNTF/NT-501) Ciliary neurotrophic factor (CNTF) is a cytokine member of the IL-6 family and a potent neuroprotective agent. CNTF has been shown to inhibit photoreceptor apoptosis in an animal model of retinal degeneration24 and was investigated as a treatment for dry AMD. CNTF receptors have been identified on Mueller glial membranes, as well as rod and cone photoreceptors.25 Neurotech (Lincoln, RI, USA) developed a CNTF sustained-release platform that produces CNTF for a year or longer. Human RPE cells engineered to produce large amounts of this neurotrophic agent are encapsulated in a device measuring approximately 5 mm X 1 mm, and the semipermeable polymer outer membrane has pores that permit CNTF to diffuse from the encapsulated device. A Phase 1, open-label study demonstrated that this device could safely be implanted, and the efficacy outcomes showed both subjective and objective visual acuity improvement in eyes of patients with retinitis pigmentosa.26 A Phase 2 trial for the treatment of GA showed an apparent stabilization of visual acuity at 12 months, with 96.3% of the high-dose group losing fewer than
Retina
25
table 2. Drugs to Protect Photoreceptors and RPe (Neuroprotection) Drug

Trimetazidine
Mechanism of Action
Anti-ischemic agent with cytoprotective effects (oral) Vasodilatory effect
Sponsor
Institute de Recherches Internationales Servier UCB, Inc.
trial Subjects
Drusen in study eye, wet AMD in fellow eye Geographic atrophy

Phase 2/3

ISRCTN99532788 (completed)
Alprostadil (Prostaglandin E1; PGE1): intravenous MC-1101
Phase 2
Increase choroidal blood flow (topical) Neuroprotection: rescues photoreceptors from degeneration (intravitreal) Neuroprotection: alpha-2 adrenergic receptor agonist (intravitreal) Neuroprotection: 5-HT1A receptor agonists (selective serotonin1A receptor agonist) (topical) Neuroprotection: binds and eliminates amyloid (intravenous) Neuroprotection: binds and eliminates amyloid (intravenous)
MacuCLEAR
Dry AMD
Phase 2/3
NCT01601483 (not yet recruiting) NCT00447954 (completed)
NT-501: encapsulated ciliary neurotrophic factor (CNTF) Brimonidine tartrate
Neurotech Pharmaceuticals
Geographic atrophy
Phase 2
Allergan
Geographic atrophy
Phase 2
Tandospirone (AL8309B)
Alcon
Geographic atrophy
Phase 2/3
RN6G (PF-04382923)
Pfizer
Geographic atrophy
Phase 2 Phase 1
NCT01577381 (not recruiting yet) NCT01003691 (ongoing) NCT01342926 (ongoing)
GSK933776
GlaxoSmithKline
Geographic atrophy
Phase 2
RN6G (PF-4382923, Pfizer) RN6G is a humanized monoclonal antibody that targets the C-termini of amyloid -40 and amyloid -42. Intravenous treatment with RN6G is intended to prevent the accumulation of amyloid -40 and amyloid -42 and to prevent their cytotoxic effects.31 In a mouse model of AMD, systemic treatment with RN6G decreased the amount of amyloid in the eye and prevented damage to the retina in a mouse model of AMD.33 A Phase 1 clinical trial has been completed successfully, and a Phase 2 trial is under way. The purpose of this study is to determine the efficacy, safety, and tolerability of multiple doses ofRN6Gin AMD subjects with GA. The primary outcome is the mean reduction in the rate of growth of GA at 30 days after the last dose at Day 309 and at end of the study at Day 449. This study is under way (NCT01577381). GSK933776 (GlaxoSmithKline) GSK933776 is a humanized monoclonal antibody directed against amyloid-. It is administered intravenously, and a Phase 2 multicenter randomized, double masked, placebo controlled study in patients with GA is under way (NCT01342926). Patients will be randomized and treated monthly with placebo, 3, or 6 mg/kg GSK933776 and will be followed for 18 months. The
primary endpoint is the rate of change in GA area from baseline and the secondary endpoint is the change in best-corrected visual acuity from baseline.
Visual Cycle Modulators (see table 3)

Aberrant accumulation of lipofuscin within the RPE is a prominent early pathologic feature of dry AMD.34 Visual cycle modulators are intended to reduce the accumulation of toxic fluorophores such as A2E (pyridinium bis-retinoid formed from 2 molecules of vitamin A aldehyde and 1 molecule of ethanolamine), a major component of lipofuscin in the RPE. Lipofuscin is an autofluorescent amalgamation of lipids, proteins, and retinoid derivatives that forms during daily phagocytic uptake of photoreceptor outer segment tips. Fundus autofluorescence imaging reveals areas of intense autofluorescence surrounding the leading edges of the GA, which is thought to identify the excess accumulation of lipofuscin. These areas of increased autofluorescence have been shown to precede enlargement of GA, resulting in the loss of retinal tissue, suggesting a toxicity associated with the lipofuscin.35 A2E, which is formed in a nonenzymatic process through a covalent linkage between all-transretinal molecules with amine-containing lipids, has been impli-
26
Retina
table 3. Visual Cycle Modulators Drug

Fenretinide
Mechanism of Action
Visual cycle inhibitor: retinol analog inhibits binding of retinol to RBP (oral) Visual cycle inhibitor: non-retinoid, inhibits RPE65 preventing trans- to cisisomerization (oral)
Sponsor
Sirion Therapeutics
trial Subjects
Geographic atrophy

Phase 2

ACU-4429
Acucela
Geographic atrophy
Phase 2
cated as a cause of RPE cell death by inflammation, complement activation, CNV induction, and apoptosis. The reduction of all-trans-retinal levels is the goal of several proposed therapeutic approaches. Fenretinide (ReVision Therapeutics) Fenretinide [4-hydroxy (phenyl) retinamide] displaces all transretinol from retinol binding proteins (RBP) in the circulation and causes dose-dependent, reversible reduction in circulating RBP and retinol. The unique requirement of the eye for retinol delivered by RBP renders the eye more susceptible to reductions in serum RBP-retinol compared to other tissues. During treatment with fenretinide, levels of retinol within the eye are dramatically reduced, thus down-regulating photoreceptor metabolism. In 2005, investigators discovered that fenretinide effectively halted the formation of A2E and related fluorophores in an animal model of Stargardt disease.36 Fenretinide was under investigation by Sirion Therapeutics (Tampa, Flor., USA) for the treatment of GA, and a Phase 2b clinical trial to evaluate patients with GA was completed (NCT00429936). Patients received placebo, 100 mg, or 300 mg daily dose for 24 months. After 2 years, it was reported that patients receiving fenretinide had a reduced incidence of developing CNV compared with the placebo, but the drug did not slow the progression of GA. However, not all patients receiving active drug achieved reduced RBP and retinol levels of 50% or greater due to a change in the manufacturing of the drug and its subsequent decreased bioavailability. Fenretinide was well tolerated in this study, but it did cause side effects such as problem with dark adaptation and dry eye symptoms.37 ACU-4429 (Acucela, Inc.; Seattle, Wash., USA) ACU-4429 is an orally administered, small nonretinoid molecule that inhibits conversion of all-trans-retinyl ester to 11-cis-retinol via inhibition of the isomerase known as RPE65. ACU-4429 functions as an enzyme inhibitor rather than by reducing the availability of a precursor, so its effects should be potentially longer-lasting than fenretinide and require less frequent dosing. However, there may be greater risk of side effects, such as nyctalopia. By modulating isomerization, ACU-4429 slows the visual cycle in rod photoreceptors and decreases the accumulation of A2E. A Phase 1 clinical trial (NCT00942240) in 46 healthy volunteers was completed and has shown that the drug was safe and well tolerated as a single dose. The drug also effectively reduced rod phoreceptor electrophysiologic function in a dose-dependent manner.38 The most common adverse events were vision related and included dyschromatopsia, night blindness, blurred vision, and photophobia. All adverse events were mild to moderate,
transient in nature, and resolved within a few days. A larger, multidose, dose-escalation Phase 2 trial is under way in AMD patients with GA (NCT01002950).
Summary
Numerous pharmacotherapies are being investigated for the treatment of dry AMD. These treatments are based on strategies that seem relevant to the pathogenesis of AMD. These approaches have the potential to intervene earlier in the disease process before vision is compromised. It will take years before we know if any of them are successful. Regardless of whether any of these drugs succeed, the clinical trials will provide a wealth of natural history data on the progression of dry AMD and provide us with extensive experience using several different clinical trial endpoints and imaging modalities to track disease progression. As we refine our clinical trial design and investigate novel drugs for the treatment of dry AMD, it is likely that a treatment breakthrough may occur within the next decade.
References
1. Zarbin MA, Rosenfeld PJ. Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 2010; 30(9):1350-1367. 2. Kaneko H, Dridi S, Tarallo V, et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 2011; 471:325-330. 3. Yu AL, Fuchshofer R, Kook D, et al. Subtoxic oxidative stress induces senescence in retinal pigment epithelial cells via TGF-beta release. Invest Ophthalmol Vis Sci. 2009; 50:926-935. 4. Zhu D, Wu J, Spee C, et al. BMP4 mediates oxidative stressinduced retinal pigment epithelial cell senescence and is overexpressed in age-related macular degeneration. J Biol Chem. 2009; 284:9529-9539. 5. Dunaief JL, Dentchev T, Ying GS, Milam AH. The role of apoptosis in age-related macular degeneration. Arch Ophthalmol. 2002; 120:1435-1442. 6. Johnson PT, Brown MN, Pulliam BC, et al. Synaptic pathology, altered gene expression, and degeneration in photoreceptors impacted by drusen. Invest Ophthalmol Vis Sci. 2005; 46:47884795. 7. Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002; 134:411-431.
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27
8. van der Schaft TL, Mooy CM, de Bruijn WC, de Jong PT. Early stages of age-related macular degeneration: an immunofluorescence and electron microscopy study. Br J Ophthalmol. 1993; 77:657661. 9. Mullins RF, Aptsiauri N, Hageman GS. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond). 2001; 15:390-395. 10. Gehrs KM, Jackson JR, Brown EN, et al. Complement, age-related macular degeneration and a vision of the future. Arch Ophthalmol. 2010; 128:349-358. 11. Hageman GS, Anderson DH, Johnson LV, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A. 2005; 102:7227-7232. 12. Edwards AO, Ritter R III, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308:421-424. 13. Haines JL, Hauser MA, Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308:419-421. 14. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308:385389. 15. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007; 357:553-561. 16. Gold B, Merriam JE, Zernant J, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006; 38:458-462. 17. Hageman GS, Hancox LS, Taiber AJ, et al. Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med. 2006; 38:592-604. 18. Klein ML, Ferris FL III, Francis PJ, et al. Progression of geographic atrophy and genotype in age-related macular degeneration. Ophthalmology 2010; 117(8):1554-1559, 1559.e1. 19. Scholl HP, Fleckenstein M, Fritsche LG, et al. CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD. PLoS One. 2009; 4:e7418. 20. Holland MC, Morikis D, Lambris JD. Synthetic small-molecule complement inhibitors. Curr Opin Investig Drugs. 2004; 5:11641173. 21. Landa G, Butovsky O, Shoshani J, et al. Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry agerelated macular degeneration. Curr Eye Res. 2008; 33:1011-1013. 22. Cohen SY, Bourgeois H, Corbe C, et al. Randomized clinical trial France DMLA2: effect of trimetazidine on exudative and nonexudative age-relatedmacular degeneration. Retina 2012; 32:834-843. 23. Ralston PG Jr, Sloan D, Waters-Honcu D, et al. A pilot, open-label study of the safety of MC-1101 in both normal volunteers and patients with early nonexudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2010; 51:E-Abstract 913.
24. Tao W, Wen R, Goddard MB, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002; 43:32923298. 25. Beltran WA, Zhang Q, Kijas JW, et al. Cloning, mapping, and retinal expression of the canine ciliary neurotrophic factor receptor alpha (CNTFRalpha). Invest Ophthalmol Vis Sci. 2003; 44:36423649. 26. Emerich DF, Thanos CG. NT-501: an ophthalmic implant of polymer-encapsulated ciliary neurotrophic factor-producing cells. Curr Opin Mol Ther. 2008; 10:506-515. 27. Zhang K, Hopkins JJ, Heier JS, et al. Ciliary neurotrophic factor delivered by encapsulated cell intraocular implants for treatment of geographic atrophy in age-related macular degeneration. Proc Natl Acad Sci U S A. 2011; 108:6241-6245. 28. Saylor M, McLoon LK, Harrison AR, Lee MS. Experimental and clinical evidence for brimonidine as an optic nerve and retinal neuroprotective agent: an evidence-based review. Arch Ophthalmol. 2009; 127:402-406. 29. Mata NL, Vogel R. Pharmacologic treatment of atrophic agerelated macular degeneration. Curr Opin Ophthalmol. 2010; 21:190-196. 30. Isas JM, Luibl V, Johnson LV, et al. Soluble and mature amyloid fibrils in drusen deposits. Invest Ophthalmol Vis Sci. 2010; 51:1304-1310. 31. Johnson LV, Leitner WP, Rivest AJ, et al. The Alzheimers A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degeneration. Proc Natl Acad Sci U S A. 2002; 99:11830-11835. 32. Wang J, Ohno-Matsui K, Yoshida T, et al. Amyloid-beta up-regulates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: Another mechanism of complement activation in age-related macular degeneration. J Cell Physiol. 2009; 220:119-128. 33. Ding JD, Lin J, Mace BE, et al. Targeting age-related macular degeneration with Alzheimers disease based immunotherapies: anti-amyloid-beta antibody attenuates pathologies in an age-related macular degeneration mouse model. Vision Res. 2008; 48:339-345. 34. Beatty S, Koh H, Phil M, et al. The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2000; 45:115-134. 35. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging: review and perspectives. Retina 2008; 28:385-409. 36. Radu RA, Han Y, Bui TV, et al. Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. Invest Ophthalmol Vis Sci. 2005; 46:4393-4401. 37. Decensi A, Torrisi R, Polizzi A, et al. Effect of the synthetic retinoid fenretinide on dark adaptation and the ocular surface. J Natl Cancer Inst. 1994; 86:105-110. 38. Kubota R, Boman NL, David R, et al. Safety and effect on rod function of ACU-4429, a novel small-molecule visual cycle modulator. Retina 2012; 32:183-188.
28
Retina
Neuroprotection for AMD

I. The Problem A. Photoreceptor cell death is a major component of AMD, both exudative and nonexudative. B. Significant contributor to vision loss in AMD C. Is there a potential to improve visual outcomes by preventing photoreceptor death? II. Studying the Problem A. Animal models: Discussion of the relevant animal models B. Human data: Discussion of findings from patient eyes III. Insights Into the Solution Discussion of the molecular pathways activated in the retina that control photoreceptor survival IV. Therapies A. Current clinical trials B. Future therapies
Retina
29
Cell-Based therapies for AMD

Allen C Ho MD
I. Background A. Despite the advent of biological therapeutics, unmet medical needs persist for retinal diseases and retinal degenerations. 1. Nonresponders in neovascular AMD and diabetic macular edema 2. No effective treatment for geographic atrophy (GA) due to AMD B. Cell-based products have the potential to meet some of these needs. 1. Secretion of supportive trophic factors in the pathological microenvironmentfor example a macula with GA Adult Umbilical Cells CNTO 2476 (Centocor Janssen J&J) preserve retinal structure in the Royal College of Surgeons rat retinal degeneration model1
3. Challenges exist in the development of cell-based products: Ability to scale, predictability of animal models, surrogates for disease, the allograft vs. xeno-graft, potential need for targeted cell delivery and new surgical techniques and instrumentation, measurable endpoints C. Retina has unique advantages as a target for cellbased therapies.2,3 1. The retina is an accessible target tissue with vitreous surgery techniques for delivery of cell-based therapies. 2. Ocular immune privilege may reduce rejection of cell-based therapies delivered to the retina. 3. Diagnostic imaging techniques such as OCT, autofluorescent imaging, fluorescein angiography, adaptive optics, and multifocal electroretinography afford many unique structure-function correlations. 4. Because of these advantages, retinal diseases have moved to the forefront of clinical trials utilizing cell-based therapies. D. Cell-based therapy sources: stem cells and somatic cells 1. Stem cells: Two classic properties a. Self-renewal: Numerous cycles of cell division without differentiation b. Potency: Ability to differentiate into specialized cell types (totipotent, pluripotent, multipotent, unipotent)
Figure 1. Almost complete absence of photoreceptors at postnatal day 90 (P90).
2. Stem cell-based therapy: Sources a. Embryonic stem cells: Cell cultures derived from blastocyte or earlier stage embryo b. Adult (somatic) stem cells: Pluripotent adult stem cells are rare; although they can be found in umbilical cord blood,4 most adult stem cells are lineage restricted multipotent or unipotent.5,6 c. Induced pluripotent stem cells (iPSC): Can be derived directly from adult tissues such as skin fibroblasts and then differentiated into a variety of cell types. Recent work has provided evidence that both human photoreceptors and retinal pigment epithelium (RPE) can be derived from iPSC.6-8
Figure 2. Significant preservation 69 days post-treatment (P90).
2. Tissue regeneration: Replacement of diseased cells and tissue
d. Cell-based therapy (non stem cell): Lack the ability to divide without differentiation and are typically differentiated cells; for example, autologous RPE sheet transplantation, human umbilical tissue-derived cells (CNTO 2476)
30
Section II: Non-neovascular AMD II. Current Cell-Based Therapy Phase 1/2 Clinical Trials for Retinal Disease (adapted from Tibbets et al3, 9-12)
Retina
table 1. Current Cell-Based therapy Selected enrollment Criteria

Age > 18 Genetic testing for Stargardt Treated eye 20/400 Untreated eye 20/320 Geographic atrophy in AMD (38, 41) Regenerative RPE derived from ESCs Subretinal implantation of 50,000 to 200,000 cells Advanced Cell Technology Age > 55 Treated eye 20/400 and >250 microns GA in central fovea Untreated eye 20/400 Retinitis pigmentosa (RP) and conerod dystrophy (40, 42) Trophic Autologous bone marrowderived stem cells 0.1 ml suspension of 10x106 stem cells delivered by intravitreal injection University of So Paulo Age > 18 Diagnosis of RP Vision <20/200 ERG response, visual field, central macular thickness by OCT, BCVA Four of 5 patients with 1-line VA improvement at 10 months but no change in macular thickness, ERG response or retinal perfusion. No adverse events. Publication pending
Retinal Disease(s)
Stargardt macular dystrophy (37, 41)
Mode of Action
Regenerative
type of Stem Cells

RPE-derived from ESCs
Method of transplantation
Subretinal implantation of 50,000 to 200,000 cells
Sponsoring entity
Advanced Cell Technology
Clinical trial endpoints (in addition to safety)

OCT, FA, autofluorescence, fundus photos, multifocal ERG
Published Clinical trial Results

One patient with VA improvement from hand motions to 20/800 (5 ETDRS letters) at 4 months. No adverse events.
OCT, FA, autofluorescence, fundus photos, multifocal ERG
One patient with VA improvement from 21 to 28 ETDRS letters at 4 months. No adverse events.
Geographic atrophy in AMD (39)
Trophic
Umbilical tissue- CNTO 2476 derived cells delivered by microcatheter to subretinal space
Centocor, Inc. d/b/a Janssen Research and Development, LLC, a division of Johnson & Johnson
Age > 50 Vision O.U. 20/200 Area of GA 2.6mm2 involving the fovea.
VA, GA lesion size, OCT, FA
Abbreviations: RPE indicates retinal pigment epithelium; ESC, embryonic stem cell; ERG, electroretinography; VA, visual acuity; GA, geographic atrophy; ETDRS, Early Treatment Diabetic Retinopathy Study.
III. Phase 1/2a, Multicenter, Randomized, Dose Escalation, Fellow-Eye Controlled, Study Evaluating the Safety and Clinical Response of a Single, Subretinal Administration of Human Umbilical Tissue-Derived Cells (CNTO 2476) in Subjects With Visual Acuity Impairment Associated With Geographic Atrophy Secondary to Age-related Macular Degeneration (Janssen / Johnson & Johnson) at Wills Eye Hospital and Retina Institute of California (Drs Chang and Samuel) A. Primary objective To evaluate the safety and tolerability of CNTO2476, administered subretinally using the iTrack Model 275 microcatheter in subjects with visual acuity impairment associated with the GA secondary to AMD.
B. Secondary objectives 1. To select 2 optimal doses for Phase 2a 2. Evaluate the effect of CNTO 2476 on clinical response 3. Evaluate the safety and performance of the surgical instruments and delivery system C. Key ocular inclusion criteria 1. Subfoveal GA O.U. 2. BCVA 20/200 O.U. (Phase 1) D. Key ocular exclusion criteria 1. Neovascular AMD
Retina
Section II: Non-neovascular AMD G. Trial update
31
2. Evidence of other significant eye disease E. Investigational cell product 1. CNTO 2476 is human umbilical tissue-derived cells, an allogeneic cell-based product. 2. Putative mechanism of action: Trophic factor influences 3. Dose escalation 60K, 120K, 300K, 560K cells delivered F. Targeted surgical delivery of CNTO 2476 cells using the iTRACK 275 illuminated microcatheter to the subretinal space of the temporal macula 1. Surgical technique includes sclerotomy, creation of choroidal fistula and subretinal bleb, microcatheter delivery of cells 2. Surgical technique refinement in animal eyes 3. Endoptiks illuminated intraocular endoscope for improved surgical visualization
1. 19 subjects have been enrolled and 18 treated in an extended Phase 1 portion; goal: 30 subjects 2. Safety results 3. Clinical response H. Summary Cell-based therapy and other innovative surgical delivery systems may help in the treatment of retinal diseases and retinal degenerations. Currently, stem cell- and umbilical tissue cell-based therapies are in Phase 1/2 clinical trials for GA due to AMD.
References
1. Lund RD, et al. Cells isolated from umbilical cord tissue rescue photoreceptors and visual functions in a rodent model of retinal disease. Stem Cells 2007; 25:602-611. 2. Bull ND, Martin KR. Concise review: toward stem cell-based therapies for retinal neurodegenerative diseases. Stem Cells 2011; 29(8):1170-1175. 3. Tibbetts MD, Samuel MA, Chang TS, Ho AC. Stem cell therapy for retinal disease. Curr Opin Ophthalmol. 2012; 23(3):226-224. 4. Ratajczak MZ, Machalinski B, Wojakowski W, Ratajczak J, Kucia M. A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues. Leukemia 2007; 21(5):860-867. 5. Barrilleaux B, Phinney DG, Prockop DJ, OConnor KC. Review: ex vivo engineering of living tissues with adult stem cells. Tissue Eng. 2006; 12(11):3007-3019. 6. Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res. 2007; 100(9):1249-1260. 7. Parameswaran S, Balasubramanian S, Babai N, et al. Induced pluripotent stem cells generate both retinal ganglion cells and photoreceptors: therapeutic implications in degenerative changes in glaucoma and age-related macular degeneration. Stem Cells 2010; 28(4):695-703. 8. Meyer JS, Shearer RL, Capowski EE, et al. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc Natl Acad Sci U S A. 2009; 106(39):16698-16703. 9. Safety and tolerability of sub-retinal transplantation of human embryonic stem cell derived retinal pigmented epithelial (hESCRPE) cells in patients with Stargardts macular dystrophy (SMD). 2012 [updated 2012 July; cited 2012 August 8]; Available from: http://clinicaltrials.gov/ct2/show/NCT01469832. 10. Safety and tolerability of sub-retinal transplantation of hESC derived RPE (MA09-hRPE) cells in patients with advanced dry age related macular degeneration (dry AMD). 2012 [updated 2012 May 17; cited 2012 August 8]; Available from: http://clinicaltrials. gov/ct2/show/NCT01344993. 11. Autologous bone marrow-derived stem cells transplantation for retinitis pigmentosa. 2012 [updated 2011 September 19; cited 2012 August 8]; Available from: http://clinicaltrials.gov/ct2/show/ NCT01068561. 12. A study of the safety and efficacy of CNTO2476 in patients with age-related macular degeneration. 2012 [updated 2012 August 2; cited 2012 August 8]; Available from: http://clinicaltrials.gov/ct2/ show/NCT01226628.
Figure 3. Subretinal iTrack 275 microcatheter delivery of cells into the subretinal space.
Figure 4. iTrack Model 275 microcatheter connected to an iLuminTM light source.
32
Advocating for Patients
Retina
2012 Advocating for Patients

Ophthalmologys goal in protecting quality patient eye care remains a key priority for the Academy. As health care delivery evolves, with narrowing practice margins making efficiency of increasing importance, all Eye M.D.s should consider their contributions to the following three funds as (a) part of their costs of doing business and (b) their individual responsibility in advocating for patients: 1. OPHTHPAC Fund 2. Surgical Scope Fund (SSF) 3. State Eye PAC While the Academy fully supports the concept of an integrated eye care delivery team, it also remains firm on defining appropriate roles for the various eye care providers as demonstrated via its Surgery by Surgeons campaign.
2012 Congressional Advocacy Day (CAD) partners, the three retina societies ensured a strong presence of retina specialists to support ophthalmologys priorities as over 350 Eye M.D.s had scheduled CAD visits to members of Congress in conjunction with the Academys 2012 Mid-Year Forum in Washington. The three retina societies remain crucial partners to the Academy in its ongoing federal and state advocacy initiatives.
Surgical Scope Fund (SSF)

At the state level, the Academys Surgery by Surgeons campaign has demonstrated a proven track record. While Kentucky was an outlier, the Academys SSF has helped 33 state/ territorial ophthalmology societies reject optometric surgery language. The Academys Secretariat for State Affairs, in partnership with state ophthalmology societies, battled optometry across the country in 2011 to protect patient access to quality medical surgical care. Several ophthalmic subspecialty societies also provided critical support when called upon. Although there was a setback in Kentucky, ophthalmology derailed O.D. surgery initiatives in 7 states and achieved its first proactive victory in Oklahoma. The SSF is a critical tool of the Surgery by Surgeons campaign to protect patient quality of care and our collective fund to ensure that optometry does not legislate the right to perform surgery. The Academy relies not only on the financial contributions via the SSF by individual Eye M.D.s but also the contributions made by ophthalmic state, subspecialty and specialized interest societies. All three retina societies contributed to the SSF in 2011 and the Academy counts on their contributions in 2012. With last years passage of legislation in Kentucky that allowed optometrists to perform laser surgery, the American Academy of Ophthalmologys partnership with ophthalmic subspecialty and state societies in the Surgery by Surgeons campaign became even more important in protecting quality patient eye care across the country. The Academys Secretariat for State Affairs redoubled its efforts with target states, including Tennessee and others, while adding professional media training to the resources provided to prepare Eye M.D.s in advance of any anticipated legislative or regulatory move.
oPHtHPAC Fund
OPHTHPAC is acrucial part of the Academys strategy to protect and advance ophthalmologys interests in key areas, including physician payments in Medicare as well as protecting ophthalmology from federal scope of practice threats. Established in 1985, today OPHTHPAC is one of the largest and most successful political action committees in the physician community. In 2010, Politico highlighted OPHTHPAC as one of the most successful health PACs in strategic giving in the 2010 election. By making strategic election campaign contributions and independent expenditures, OPHTHPAC helps us elect friends of ophthalmology to federal leadership positions, ultimately resulting in beneficial outcomes for all Eye M.D.s. For example, 20 physicians, including 2 ophthalmologists, were elected to Congress in 2010. Thanks to the OPHTHPAC contributions made in the 2007-2010 timeframe, ophthalmology realized an 8% increase in Medicare payments (other specialties experienced significant decreases). Among the significant impacts of OPHTHPAC: Averted significant cuts to Medicare payments due to the Sustainable Growth Rate (SGR) formula Protected Practice Expense increases for ophthalmology when attacked by other specialties Exempted ultrasound from imaging cuts Protected the in-office ancillary services exception Secured physician exemption from Red Flag (creditor) rules Secured reversal of a CMS decision to cut reimbursement for Avastin Delayed Medicare penalties dates in health reform law Secured appointment of full-time ophthalmology national program director in the Department of Veterans Affairs Leaders of the American Society of Retina Specialists (ASRS), the Macula Society and the Retina Society are part of the American Academy of Ophthalmologys Ophthalmic Advocacy Leadership Group (OALG), which has met for the past five years in the Washington, DC, area to provide critical input and to discuss and collaborate on the Academys advocacy agenda. As
State eye PAC

State ophthalmology societies can not count on the SSF alone equally important is the presence of a strong state Eye PAC, which provides financial support for campaign contributions and legislative education to elect ophthalmology-friendly candidates for the state legislature. The Secretariat for State Affairs strategizes with state ophthalmology societies on target goals for state eye PAC levels.
Action Requested: Advocate for Your Patients!!

PAC contributions are necessary at the state and federal level to help elect officials who will support the interests of our patients. Academy SSF contributions are used to support the infrastruc-
Retina
Advocating for Patients oPHtHPAC Fund

Ophthalmologys interests at the federal level Support for candidates for US Congress Campaign contributions,legislative education
33
Surgical Scope Fund

Scope of practice at the state level Lobbyists, media, public education, administrative needs Contributions: Unlimited Contributions are 100% confidential
State eyePAC
Support for candidates for State House and Senate Campaign contributions, legislative education
Contributions: Limited to $5,000 Contributions above $200 are on the public record
Contribution limits vary based on state regulations Contributions are on the public record
ture necessary in state legislative/ regulatory battles and for public education. Contributions across the board are needed. SSF contributions are completely confidential and may be made with corporate checks or credit cardsunlike PAC contributions, which must be made by individuals and which are subject to reporting requirements. Please respond to your Academy colleagues who are volunteering their time on your behalf to serve on the OPHTHPAC* and SSF** Committees, as well as your state ophthalmology society leaders, when they call on you and your subspecialty society to contribute. Advocate for your patients now!
**Surgical Scope Fund Committee

Thomas A Graul MD (NE) Chair Arezio Amirikia MD (MI) Ronald A Braswell MD (MS) Kenneth P Cheng MD (PA) John P Holds MD (MO) Bryan S Lee MD PhD (MD) Consultant Stephanie J Marioneaux MD (VA) Andrew Tharp MD (IN) Ex-Officio Members: Cynthia A Bradford MD Daniel J Briceland MD
*oPHtHPAC Committee
Donald J Cinotti MD (NJ) Chair Charles C Barr MD (KY) William Z Bridges Jr MD (NC) Dawn C Buckingham MD (TX) Robert A Copeland Jr MD (Washington DC) James E Croley III MD (FL) Anna Luisa Di Lorenzo MD (MI) Andrew P Doan MD PhD (CA) Warren R Fagadau MD (TX) Michael L Gilbert MD (WA) Alan E Kimura MD (CO) Lisa Nijm MD JD (IL) Andrew J Packer MD (CT) Andrew M Prince MD (NY) Kristin E Reidy DO (NM) Ruth E Williams MD (IL) Ex-Officio Members: Cynthia A Bradford MD (OK) Gregory P Kwasny MD (WI) Michael X Repka MD (MD)
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Section III: Late Breaking Developments, Part I
Retina
Late Breaking Developments, Part I
NoteS
Retina
Section IV: Pediatric Retina
35
Update on the Study of telemedicine for RoP

I. Experimental Analysis of Remote Digital Fundus Imaging (RDFI) in Retinopathy of Prematurity (ROP) A. Theory B. Camera system C. Hub-and-spoke, store-and-forward system D. Use of nurses E. Referral-warranted ROP (RW-ROP) F. Standardized imaging G. Binocular indirect ophthalmoscopy vs. RDFI 1. Interpretation 2. Actual features H. American Academy of Ophthalmology Ophthalmic Technology Assessment of RDFI I. Telemedicine Approaches to Evaluating AcutePhase ROP Trial (e-ROP) 1. RDFI vs. BIO comparison 2. Inter- and intraobserver agreement of RW-ROP 3. Safety events 4. Expense II. Real-world RDFI for ROP A. Theory 1. Disease identification 2. Blindness prevention B. Real-world Networks 1. Stanford University Network for Diagnosis of ROP (SUNDROP) 2. Karnataka Internet Assisted Diagnosis of ROP (KIDROP) III. Implementation of a RDFI Screening Program for ROP A. Personnel B. Photographic technique 1. Training/certification 2. Notification 3. Dilation 4. Speculum 5. Photograph set
C. Image Transfer and Storage 1. HIPAA-compliance 2. Secure/redundant server for storage D. RDFI Report 1. Name 2. Medical record number 3. Birth date 4. Exam date 5. Receipt date 6. Review date 7. Birthweight 8. Gestation age at birth 9. Postmenstrual age at exam 10. Weight at exam 11. Number of images received 12. Hospital 13. Interpreting physician 14. Ocular characteristics by eye a. Number of images b. Lens/pupil status c. Vitreous clarity d. Zone e. Pre-plus or plus f. Stage g. Extent (hours) h. Hemorrhage (quadrants) i. Other abnormalities 15. Interval change 16. Impression 17. Recommendations E. RDFI graders F. Discharge G. Follow-up
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Retina
ophthalmic Insurer Perspectives on the Use of telemedicine for Screening and Diagnosis of RoP and Bevacizumab for RoP
ROP claims are infrequent but costly. Just 22 of 3244 claims in OMIC (Ophthalmic Mutual Insurance Company) were related to ROP. However, the percentage of claims with indemnity payments is twice as high for ROP (47%) compared to all other claims, and the mean payments are about 4 times as high, or about $862,043 vs. $154,063. In looking at the 22 claims (for 19 babies), an attempt was made to identify the cause of claim. Causes were divided into four categories: Clinical, Systems, Physician, and Patient/Parents. By far the system errors were the most common. Examples include problems with discharge and follow-up appointments, hospital transfers, and referrals to a treating ophthalmologist. Medical professional liability insurers are constantly grappling with how to underwrite new technologies and treatments. Telemedicine and bevacizumab for ROP are recent examples. The difficulty is in knowing the potential risks and benefits of these methods because they are so new. OMIC has always made it a policy to insure ophthalmologists for what ophthalmologists do. However, underwriting guidelines are needed to limit risk as much as possible while data and experience are gained. There are several potential issues and concerns regarding telemedicine and bevacizumab for ROP. Telemedicine for ROP can be used for actual, real-time examination or for later review by trained and skilled screeners, either on site or at a distant location. The latter is the most likely use for ROP screening.1 Unfortunately, the current laws covering medical malpractice vary from state to state and were enacted when the patient and physician were often in the same town and almost always in the same state. They were not designed to cover the issues of a remote physician rendering an opinion in a different location, let alone another state. Issues of concern include state licensure, credentialing, privileging, confidentiality, physician/patient relationships, informed consent for real-time patient encounters, jurisdiction if a claim is filed, storage and quality of the images, and training of the readers. Licensure issues arise when the images cross state lines. Some states have dealt with this by loosening laws regarding telemedicine, but others have tightened them. Risk managers advise having a license in both the state where the data are collected and in the state where data are interpreted. The physician needs to pay attention to this or risk being sued for practicing without a license. In addition, credentialing and privileging issues need to be resolved. Is it done at the reading center or at the NICU facility? Usually this has been done by proxy with credentialing and privileging done at the originating site. However, this is in conflict with current CMS regulations, which state that it must be done in both locations. When images are transferred over the Internet there is a risk of less than secure networks resulting in confidentiality and HIPPA breaches. There is also the risk of hackers accessing the data, which may contain sensitive information. The issue of what constitutes a physician/patient relationship is also less than clear in the realm of remote doctors giving opinions on treatment. Ideally this should be spelled out in the informed consent and afford some relief for the distant site. The report should indicate the basis of the interpretation, eg, the interpretation is based solely upon the review of one set of photographs, with a history provided of .... California requires patient consent for telemedicine, defined as real-time, interactive, two-way communication. Therefore reviewing photographs of ROP babies would not be defined as telemedicine. But not all states have addressed this. If a suit is filed, jurisdiction could be an issue, with the plaintiff wanting to have the trial in the most favorable area for litigation awards. One of the potential uses of telemedicine is to improve the care of premature infants in remote areas. However, reading centers commonly are located in urban locations where the indemnity awards are higher. Standard of care definitions vary from state to state, and this could also be an incentive to shop for the most lucrative locale. Images will need to be stored securely and attention paid to quality. Corneal and vitreous haze as well as small palpebral fissures are a problem in very premature infants and could make the interpretation of the retinal image difficult. This could lead to intense scrutiny by subsequent experts regarding the findings, as opposed to a retinal drawing done at the NICU. The readers will have to be credentialed and the process documented should it come into question in a case of alleged misdiagnosis. OMIC has established underwriting guidelines that physicians need to satisfy before they can be insured to practice telemedicine. A few examples include such things as who provides backup grading, how many images are taken per eye per screening, and a 24-hour turnaround. Bevacizumab inhibits vascular endothelial growth factor (VEGF), and it has been shown that VEGF levels are elevated in ROP.2 There are several reports of the successful use of off-label bevacizumab for the treatment of ROP.3,4 As with any new treatment the concern for insurers is the unknown risks and possible complications of this invasive treatment. The early reports show promise, especially in eyes with severe disease and hemorrhage.5 There are several concerns as well as hope that it will be an additional tool to improve outcomes compared to the standard laser treatment that has proven so effective. However, there are risks when a new treatment is used instead of one that is considered a standard of care, especially when the true risk/benefit ratio may not be known for many years, as is the case in premature infants. Therefore the informed consent is very important and will also need to outline the offlabel use of the drug as well as the known risks of intravitreal injections. The small eyes of these infants could increase the risks of lens damage, retinal perforation, and hemorrhage. Prepping the eye may also be an issue, which raises the possibility of increased risk of infection. None of these complications, except
Retina
Section IV: Pediatric Retina References
37
lens damage, are seen with standard laser therapy. Plaintiffs will be quick to point out that if the standard of care was followed the complication would not have occurred. The proper dosage and timing are also currently unknown and have yet to be standardized, and little is known about the long-term consequences of systemic absorption of the drug. Using the standard follow-up protocols used for laser treated eyes may not be appropriate for bevacizumab. For instance, complications such as retinal detachment have been seen later in bevacizumab-treated eyes compared to laser-treated eyes. Therefore the follow-up period should be extended for bevacizumabtreated infants; this may not be the treatment of choice if the parents do not seem likely to bring the infant in for exams. If a detachment is undiagnosed the risk of litigation is real. Systemic effects are not well defined, and this is important because VEGF is critical for growth and development of vital organs such as kidneys, lungs, and brain during the third trimester.6 These organs are already under stress, and it is possible that the use of bevacizumab may result in long-term systemic problems that are unknown. This could result in significant liability in future years as the statute of limitations for these infants runs a few years beyond the attainment of majority. In summary, caution should be used when using intravitreal bevacizumab for ROP treatment as opposed to standard laser until the indications, dosage, intervals, and complications are well established. For those high-risk eyes that have a poor prognosis with laser or would have severe field loss if laser was used, a detailed informed consent is critical.
1. Richter GM, Williams SL, Starren J, Flynn JT, Chaing MF. Telemedicine for retinopathy of prematurity diagnosis evaluation and challenges. Surv Ophthalmol. 2009; 54(6):671-685. 2. Nonobe NI, Kachi S, Kondo M, et al. Concentration of vascular endothelial growth factor in aqueous humor of eyes with advanced retinopathy of prematurity before and after intravitreal injection of bevacizumab. Retina 2009; 29(5):579-585. 3. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011; 364:603-615. 4. Wu WC, Yeh PT, Chen SN, Yang CM, Lai CC, Kuo HK. Effects and complications of bevacizumab use in patients with retinopathy of prematurity: a multicenter study in Taiwan. Ophthalmology 2011; 118(1):176-183. 5. Nazari H, Modarres M, Parvaresh MM, Ghasemi Falavarjani K. Intravitreal bevacizumab in combination with laser therapy for the treatment of severe retinopathy of prematurity (ROP) associated with vitreous or retinal hemorrhage. Graefes Arch Clin Exp Ophthalmol. 2010; 248(12):1713-1718. 6. Hrd AL, Hellstrm A. On the use of antiangiogenetic medications for retinopathy of prematurity. Acta Paediatr. 2011; 100(12):15231527.
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Retina
Update on the Multicenter Study of Anti-VeGF treatment for RoP (BLoCK-RoP)

Michael T Trese MD
Retinopathy of prematurity continues to be a leading cause of blindness in children in developed and developing countries around the world. The standard treatment of peripheral laser ablation and early lens-sparing vitrectomy results in a very high anatomical and visual success rate for this very disabling disease. However, in many areas of the world, where lasers are exceptionally expensive and laser treatment expertise is not available, a pharmacologic treatment for ROP using anti-VEGF drugs may be beneficial. At this time the choice of anti-VEGF drug has been basically bevacizumab (Avastin) or ranibizumab (Lucentis). These drugs bridge a period of increased VEGF in the eye and the endogenous induction of TGF-beta, which down-regulates VEGF at the childs due date. Bevacizumab has been used in clinical settings treating ROP, most of which have been anecdotal, nonrandomized clinical trials. The BEAT-ROP Trial, presented last year, represents an attempt at a more organized utilization of bevacizumab for ROP. It did, however, raise some concerns regarding safety issues. In addition to concerns relative to study design, the study did suggest that an evaluation of anti-VEGF drug in posterior ROP would be worthwhile. For that reason, an in-depth trial of anti-VEGF therapy for ROP has been undertaken by a group of both pediatric ophthalmologists and retinal specialists to determine whether anti-VEGF therapy is a reasonable alternative for treatment of severe ROP. This study will be looking at the use of a variety of dosing regimens as well as multiple agents for anti-VEGF treatment, including the consideration of both bevacizumab and ranibizumab, as in many trials to date, concerns regarding adverse events relative to the use of bevacizumab have been considered. The concern is even higher in a premature infant with developing organs. The dosing of anti-VEGF drug for ROP has been empirically one-half to one-third of the adult dose. If, however, the dosing is based on actual VEGF measurements in vascularly active ROP eyes, this adult dosing may be much higher than is actually needed. Although the safety issues in ROP may be very difficult to evaluate in the short or long run due to the multiple morbidities in children who are born prematurely, it would seem reasonable to assume that the smaller the dose of anti-VEGF drug delivered to the vitreous cavity, the less likely the systemic effects. For this reason, a study is being designed to evaluate the use of anti-VEGF therapy, namely, ranibizumab for ROP treatment. In addition, the duration of the drugs presence in the bloodstream appears to be less for ranibizumab than for bevacizumab. This study will include both clinical and photographic evaluations at a centralized reading center, as well as measurements of systemic drug levels following various doses. The hope is to find the lowest dose of drug, with the lowest systemic exposure, that is considered to be clinically effective. It is important to remember that in many areas where good laser treatment is available, it may not be necessary to use a pharmacologic alternative and therefore expose the child to any potential systemic risk. It is also known that the drug bevacizumab persists longer in the bloodstream, putting the child at more systemic risk, than does ranibizumab. In the treatment of ROP, it may be that a smaller, still efficacious drug with a shorter systemic exposure may be more beneficial for pharmacologic treatment. We hope that in the not too distant future we will have information regarding the use of this smaller, perhaps less potentially threatening molecule in the treatment of severe ROP.
References
1. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the Early Treatment for Retinopathy of Prematurity Randomized Trial. Arch Ophthalmol. 2003; 121:1684-1696. 2. Drenser KA, Trese MT, Capone A Jr. Aggressive posterior retinopathy of prematurity. Retina 2010; 30:S37-40. 3. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011; 364(7):603-615. 4. Moshfeghi DM, Berrocal AM. Retinopathy of prematurity in the time of bevacizumab: incorporating the BEAT-ROP results into clinical practice. Ophthalmology 2011; 118:1227-1228.
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39
Microplasmin for Pediatric Vitrectomy Study

Kimberly Drenser MD PhD
Introduction
Plasminogen is an endogenous zymogen that circulates in the blood and other fluids. Its activated form is plasmin enzyme, which is a serine protease that acts to dissolve fibrin blood clots. Additionally, it cleaves fibronectin, thrombospondin, laminin, and von Willebrand factor and activates collagenases. Its action on laminin and fibronectin makes it a useful surgical adjunct in addressing vitreoretinal adhesions. Plasmin enzyme is able to induce liquefaction of the vitreous and weaken hyaloid attachments at the vitreoretinal interface. Children and infants have particularly strong hyaloid adhesions, which often complicates difficult pediatric vitreoretinal surgeries.
objectives
This presentation will focus on the current status of plasmin and ocriplasmin for use in pediatric vitreoretinal surgery. Appropriate case selection will be reviewed, as will surgical techniques. Surgical outcomes, both intraoperative and long-term postoperative, will be discussed in detail.
Selected Readings
1. Goldenberg DT, Trese MT. Pharmacologic vitreodynamics and molecular flux. Dev Ophthalmol. 2009; 44:31-36. 2. Cohn AD, Quiram PA, Drenser KA, Trese MT, Capone A Jr. Surgical outcomes of epiretinal membranes associated with combined hamartoma of the retina and retinal pigment epithelium. Retina 2009; 29(6):825-830. 3. Wu WC, Drenser KA, Lai M, Capone A, Trese MT. Plasmin enzyme-assisted vitrectomy for primary and reoperated eyes with stage 5 retinopathy of prematurity. Retina 2008; 28(3 suppl):S75-80. Erratum in Retina 2009; 29(1):127. 4. Wu WC, Drenser KA, Capone A, Williams GA, Trese MT. Plasmin enzyme-assisted vitreoretinal surgery in congenital X-linked retinoschisis: surgical techniques based on a new classification system. Retina 2007; 27(8):1079-1085. 5. Wu WC, Drenser KA, Trese MT, Williams GA, Capone A. Pediatric traumatic macular hole: results of autologous plasmin enzymeassisted vitrectomy. Am J Ophthalmol. 2007; 144(5):668-672. 6. Gad Elkareem AM, Willekens B, Vanhove M, Noppen B, Stassen JM, de Smet MD. Characterization of a stabilized form of microplasmin for the induction of posterior vitreous detachment. Curr Eye Res. 2010; 35(10):909-915.
Background
Autologous and maternal plasmin has been used for several years as a surgical adjunct in pediatric cases. Many studies have shown its usefulness in difficult surgical cases and have shown improved final outcomes. Long-term follow-up has also demonstrated safety in children who received an intravitreal injection of plasmin enzyme prior to surgery. Both autologous and maternal plasmin is processed from the patients (or mothers) blood, requiring isolation and concentration of plasminogen, activation, and purification. This process has limited the widespread use of plasmin. More recently, a recombinant plasmin molecule (ocriplasmin) has been developed and comes in a ready-use vial. This development allows for increased access of plasmin to surgeons for pediatric vitreoretinal surgeries.
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Retina
Familial exudative Vitreoretinopathy: Diagnosis, Management With Wide-Angle Angiography, and Long-term Surgical Results
Franco M Recchia MD
I. Clinical Features A. Usually bilateral, asymmetric B. Can present at any age (mean: 6 years; range: 1 month to 50 years) C. Findings of retinopathy of prematurity (ROP) in a full-term child 1. Avascular retinal periphery 2. Vascular buds at junction of vascular and avascular retina 3. Vessel dragging 4. Retinal folds 5. Subretinal, intraretinal, or preretinal exudation 6. Retinal detachment (traction, rhegmatogenous, exudative, or combined) 7. Peripheral retinoschisis D. Associated findings 1. High myopia 2. Anisometropic amblyopia 3. Cataract 4. (Rare): persistent fetal vasculature syndrome (PFVS), Turner syndrome, Marfan syndrome, neurodevelopmental disorders II. Classification of Familial Exudative Vitreoretinopathy (FEVR) table 1. Classification of FeVR Stage
1 2 2A 2B 3 3A 3B 4 4A 4B 5
III. Natural History A. FEVR is a lifelong disease requiring long-term follow-up and regular examinations. B. Typically, long periods of disease quiescence are punctuated by episodes of disease reactivation. C. Retinal detachment may occur up to 20 years following apparent stabilization. D. Prognosis is most guarded in children diagnosed before age 3. E. However, even in adolescence and adults, less severe disease at presentation may progress to more severe disease years later. IV. Genetics A. Inheritance can follow autosomal dominant, autosomal recessive, or X-linked patterns. All can have variable penetrance. B. Four causative genes have been identified (NDP, LRP5, FZD4, TSPAN12). 1. Account for up to 50% of cases of FEVR 2. The type of mutation or the number of genes involved may determine the severity of disease. 3. All genes form part of the Wnt signaling pathway, which is essential for normal retinal vascular growth and development. Thus, genetic abnormality of any part of this pathway may lead to disorders of retinal vasculogenesis. 4. Genetic tests for all 4 genes are available (see below). V. Treatment Paradigms A. Regular, vigilant, lifelong follow-up is essential! 1. Stage 1: Observation or peripheral retinal ablation (especially if fellow eye has limited vision) 2. Stage 2: Complete ablation (typically with laser photocoagulation) of all areas of peripheral retinal nonperfusion 3. Stages 3-5: Scleral buckling or vitrectomy or both 4. Intravitreal anti-VEGF therapy a. Helpful in transient arrest of neovascularization until definitive treatment with laser photocoagulation can be performed b. May promote intense fibrovascular contraction and rhegmatogenous retinal detachment
Clinical Features
Avascular retinal periphery Preretinal neovascularization Without exudate With exudate Macula-sparing retinal detachment Without exudate With exudate Macula-involving retinal detachment Without exudate With exudate Total retinal detachment
Adapted from Pendergast SD, Trese MT. Familial exudative vitreoretinopathy: results of surgical management. Ophthalmology 1998; 105(6):1015-1023.
Retina

VI. Surgical Results A. Indications for treatment 1. Peripheral retinal ablation
41
c. Not a permanent treatment (does not address the underlying problem of chronic retinal ischemia) B. Role of angiography 1. Valuable in establishing diagnosis (demonstration of peripheral retinal nonperfusion, budding of peripheral capillaries, preretinal neovascularization) 2. Essential to guiding treatment a. Often the border of vascular and avascular retina is not evident clinically and can only be seen angiographically. b. Even following apparently complete retinal ablation, areas of nonperfusion (skip areas) or preretinal neovascularization can be detected angiographically. 3. Detection of peripheral retinal nonperfusion in previously unsuspected cases a. Some patients with unilateral PFVS b. Relatives of patients with known FEVR C. Genetic testing 1. Usefulness a. Unequivocal confirmation of diagnosis (only helpful if positive) b. Screening of at-risk relatives c. Genetic counseling 2. Practical aspects a. Tests for all 4 FEVR genes are available through various commercial labs or through the eyeGENE network (NIH-sponsored study) i. Laboratories that perform FEVR genetic testing can be found on the GeneTests website: www.ncbi.nlm.nih.gov/sites/ GeneTests/?db=GeneTests ii. eyeGENE: National Ophthalmic Disease Genotyping Network (www.nei.nih.gov/ resources/eyegene.asp) b. Cost of gene sequencing and turnaround time i. Commercial labs: $500-$2000 per gene (billed to patient or to insurance following preauthorization); 4-6 weeks ii. eyeGENE: No charge following enrollment as a study site; 4-6 months
a. Presence of preretinal neovascularization or exudation b. Increase in size of areas of retinal nonperfusion c. Poor vision in fellow eye 2. Incisional surgery (scleral buckling, vitrectomy) a. Retinal detachment b. Vitreous hemorrhage c. Relentless progression of vascular leakage despite retinal ablation B. Anatomic considerations 1. Tightly adherent posterior hyaloid (often impossible to strip completely) 2. Ischemic peripheral retina is prone to atrophic breaks 3. Proliferative vitreoretinopathy (PVR) is common in pediatric eyes with open breaks. C. Treatment considerations 1. Role of vitrectomy a. Addresses all vectors of vitreoretinal traction b. Necessary in cases of advanced PVR, posterior breaks, giant retinal tears c. Can be used alone for predominantly tractional or exudative detachments d. Internal drainage of subretinal fluid should be avoided (to reduce chance of PVR). 2. Role of scleral buckling a. Support of vitreous base, peripheral breaks, and tightly attached vitreous over ischemic peripheral retina b. Can be used alone for predominantly rhegmatogenous detachment 3. Role of intravitreal anti-VEGF medicines a. May help to reduce vascular activity in advance of planned vitrectomy b. Not a monotherapy
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Retina
table 2. Results of Vitreoretinal Surgery for FeVR-Associated Retinal Detachment Study

Glazer, et al (1995) Shubert and Tasman (1997) Pendergast and Trese (1998) Ikeda, et al (1999) Chen, et al (2012)
No. of eyes
6 8 29 28 24
Age Range (yrs)

1.5-9 0.5-44 0.3-17 4-38 9-30
type of RD
TRD TRD ?? 89% RRD; 11% TRD RRD
Macular Attachment (%)

100% 75% 62% 86% 96%
Stable/Improved VA (%)
84% 63% 93% 71% 96%
>1 Surgery (%)

?? 38% 21% 54% 29%
Minimum Follow-up
?? ?? 6 months ?? ??
Abbreviations: TRD indicates traction retinal detachment; RRD, rhegmatogenous retinal detachment; VA, visual acuity.
Selected Readings
1. Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1995; 93:473-521. 2. Chen SN, Hwang JF, Lin CJ. Clinical characteristics and surgical management of familial exudative vitreoretinopathy-associated rhegmatogenous retinal detachment. Retina 2012; 32(2):220-225. 3. Glazer LC, Maguire A, Blumenkranz, et al. Improved surgical treatment of familial exudative vitreoretinopathy in children. Am J Ophthalmol. 1995; 120(4):471-479. 4. Ikeda T, Fujikado T, Tano Y, et al. Vitrectomy for rhegmatogenous or tractional retinal detachment with familial exudative vitreoretinopathy. Ophthalmology 1999; 106(6):1081-1085. 5. Pendergast SD, Trese MT. Familial exudative vitreoretinopathy: results of surgical management. Ophthalmology 1998; 105(6):1015-1023. 6. Ranchod TM, Ho LY, Drenser KA, et al. Clinical presentation of familial exudative vitreoretinopathy. Ophthalmology 2011; 118(10):2070-2075. 7. Shubert A, Tasman W. Familial exudative vitreoretinopathy: surgical intervention and visual acuity outcomes. Graefes Arch Clin Exp Ophthalmol. 1997; 235(8):490-493. 8. Tagami M, Kusuhara S, Honda S, et al. Rapid regression of retinal hemorrhage and neovascularization in a case of familial exudative vitreoretinopathy treated with intravitreal bevacizumab. Graefes Arch Clin Exp Ophthalmol. 2008; 246(12):1787-1789.
Retina
Section V: Inherited Retinal Diseases
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Update on Gene therapy trials in Progress

Inherited retinal diseases are typically associated with gene defects affecting photoreceptor or retinal pigment epithelial cells. These conditions cause significant visual disability, but recent progress in research promises that some will stand to benefit from gene therapy. The relatively rapid progress of gene therapy for retinal disorders, compared with that of other conditions, attests to the suitability of the eye as a target for gene therapy. The eye is small and anatomically compartmentalized. Retinal cells are stable and can be targeted effectively by precise delivery of only modest doses of vector. The presence of the bloodretinal barrier not only reduces the extent of vector dissemination outside the eye but also limits the severity of immune responses to both the vector and the transgene product, avoiding what has proven to be a major barrier to effective gene therapy for other disorders. The eye is readily accessible to phenotypic examination and investigation of the impact of therapeutic intervention in vivo by fundus imaging and electrophysiological techniques. A range of viral and nonviral vectors can facilitate efficient delivery to retinal cells and many vectors mediate expression that is sustained in the long term. Adeno-associated virus (AAV) is the most commonly used vector for retinal gene therapy, despite its relatively small packaging capacity and slow onset of expression, because it efficiently targets both photoreceptor and retinal pigment epithelial (RPE) cells. A range of naturally occurring and artificially modified AAV serotypes now provide a variety of candidate vectors that have contrasting cellular specificities for targeting of retinal cell subtypes. Efficient targeting of photoreceptor cells or RPE normally depends on delivery of vector to the subretinal space, but gene delivery to the outer retina can be achieved following intravitreal delivery by modification of AAV capsid proteins. Lentivirus vectors have a greater packaging capacity than AAV vectors and target retinal pigment epithelial cells, with a high degree of specificity following subretinal injection. Considerable progress has been made in the development of experimental gene replacement therapies for retinal degenerations resulting from gene defects in photoreceptor cells (including rds, RPGRIP, RS-1) and in RPE cells (including MerTK, RPE65, OA1) using AAV and lentivirus-based vectors. The most feasible approach at present involves provision of normal genes to compensate for gene defects resulting in proteins that lack function, conditions that are typically recessively inherited. However, substantial progress has also been made in the development of strategies to suppress the expression of proteins that have toxic effects in conditions that are typically dominantly inherited. Generic gene therapy approaches that are independent of the disease gene are also being developed. Vector-mediated expression of neurotrophic or antiapoptotic factors can prolong slightly the survival of photoreceptor cells in animal studies, though the safety of long-term delivery of these factors is not yet established. Vector-mediated delivery of a light-activated ion channels to neurons of the inner retina can enable these cells to mediate responses to light, even in the presence of advanced degeneration of the outer retina. The extent to which this approach might compensate for the lost sensitivity and resolution of photoreceptor-mediated vision, however, is not yet known. Generic gene
therapy approaches also offer a potentially powerful approach to the treatment of complex acquired disorders such as those involving angiogenesis, inflammation, and degeneration, by the targeted sustained intraocular delivery of therapeutic proteins. The results of 3 independent clinical trials have demonstrated that gene therapy using AAV2 vectors appears to be safe in the short term and can improve aspects of vision in adults and children with a form of early-onset severe retinal dystrophy caused by defects in RPE65 (Bainbridge et al., 2008; Hauswirth et al., 2008; Maguire et al., 2008). Although the degree of efficacy in humans is yet to match that observed in animal models, these positive findings have led to several additional Phase 1/2 clinical trials of AAV gene therapy for the same condition, and for autosomal recessive retinitis pigmentosa caused by the RPE gene defect MerTK. Clinical trials for photoreceptor disease including lentivirus gene therapy for Stargardt disease and Usher syndrome, and AAV gene therapy for choroideremia have also started. In addition, clinical trials of gene delivery for neovascular AMD are now under way. These include AAV-mediated delivery of the VEGF inhibitor sFlt-1 and lentivirus vector-mediated delivery of endostatin and angiostatin. In only 2 decades, retinal gene therapy has reached the point of real impact in clinical trials. During this exciting new phase of translational research into treatments there are a number of important challenges to be met to ensure that the potential of gene therapy is reached. Novel vector systems that can safely deliver genes efficiently to the outer retina from the vitreous compartment may provide an alternative to subretinal injection, and vector systems with greater packaging capacity are required for efficient delivery of large genes to photoreceptor cells. Careful control of expression levels will enhance the balance of risks for many disorders. For clinical application, it will be important to define the optimal window of opportunity for intervention for specific conditions that extends from the point when the balance of risks justifies intervention to the stage when significant degeneration will preclude benefit. In this early phase of clinical application, trials designed to determine rapidly the impact of intervention, whether by detecting improvements in vision function or slowing severe degenerations, will provide invaluable information that can be used to inform further development in a timely way.
References
1. BainbridgeJW, Smith AJ, Barker SS, et al. Effectof gene therapy on visual function in Leberscongenital amaurosis.N Engl JMed.2008;358:2231-2239. 2. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leberscongenitalamaurosis.N Engl J Med.2008;358:2240-2248. 3. Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008; 19:979-990.
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Upcoming trials in Retinal Degeneration
Gene therapy trials in Human Retinal Dystrophies: Choroideremia

Ian M MacDonald MD, Robert MacLaren PD PhD, Miguel Seabra MD, Shelly Benjaminy BSc, Tania Bubela Phd LLB
Background Information on Human Clinical trials in Retinal Dystrophies
The development of ocular gene therapy for human retinal disease has been led and greatly facilitated by the demonstration of safety and efficacy from subretinal gene delivery in human research subjects affected by Leber congenital amaurosis, after comprehensive repetitive testing in animal models. The consideration of gene therapy as an intervention to prevent loss of function depends upon (1) knowing the genetics of a retinal disorder, (2) understanding the underlying pathophysiology of its disease process, (3) being able to manufacture a suitable vector (lentiviral or adeno-associated viral; integrating into the genome, or not, respectively), (4) refining modern vitreoretinal surgical techniques to deliver the vector to the subretinal space (see Figure 1), and (5) recruiting clinical trial participants based on informed consent with risks and benefits communicated commensurate with phase of trial.
Progress on Choroideremia Gene therapy trials

As gene therapies are being developed for a range of rare genetic eye disorders, choroideremia (CHM) has stood out as a potential target. This has been the case despite the lack of studies first demonstrating the response of a chm animal model to ocular gene therapy. Patients and families with choroideremia have enthusiastically undertaken the first step of gaining access to a future ocular gene therapy trial by requesting genotyping to confirm their diagnosis, through clinical testing and research protocols such as the eyeGENE project of the National Eye Institute, NIH, in anticipation of an ocular gene therapy trial. Preliminary preclinical data on choroideremia from models Gene therapy has a high likelihood of success in patients affected by choroideremia. This is a single gene disorder that affects primarily the eye and results from a deficiency of the normal gene product, Rab escort protein-1, resulting from mutations in the CHM gene. Mammalian species have 2 REP genes, whereas lower species have only 1 REP. REP-1 appears to be necessary in the retina to maintain normal intracellular trafficking; REP-2 does not suffice. Replacement of REP-1 can be assured by gene transfer to the retinal pigment epithelium (RPE) and photoreceptors through subretinal delivery, thereby normalizing cellular function and potentially stopping the progressive retinal degeneration. The CHM/REP-1 gene can easily be accommodated within an adeno-associated viral vector similar to that used in the RPE65 gene therapy trial. The enu-induced zebrafish mutant model of choroideremia does not survive past 6 days when the maternal supply of rep is exhausted. The chm knockout mouse model developed by Cremers and colleagues will not produce an affected male, demonstrating the importance of REP1 in the maintenance of pregnancy. Conditional knockouts of the chm gene have been developed in the mouse RPE and the photoreceptors, which have proved helpful to demonstrate not only the independent degen-
Figure 1
eration of the RPE and photoreceptors that occurs in CHM but also the likely need to deliver the gene to both cell layers. The issue of whether the choroidal vasculature needs to be transduced by gene therapy remains unanswered at present and will likely depend on the results of a human trial. Design of ocular gene therapy trial in human CHM subjects The design of an ocular gene therapy trial will need to first establish safety and then determine, if possible, in a small initial phase if there is any indication of effect on moderating the progressive nature of the disease. Studies comparing the function and anatomy of the treated eye with the untreated eye will require a degree of symmetry between either eye at the initiation of treatment to allow serial analysis of any progression. The design of an ocular gene therapy trial has been greatly aided by the availability of clinical tools to measure both functional responses (with the application of microperimetry, autofluorescence imaging, and electrophysiology) and anatomic changes (with OCT). Many of these tools will monitor the area at the edge of the retinal degeneration to measure change. Preliminary information from the Oxford CHM gene therapy trial As reported by MacLaren and colleagues at the 2012 annual meeting of the Association for Research on Vision and Ophthalmology (Ft. Lauderdale, Flor., USA), some choroideremia patients have already undergone ocular gene therapy in the UK to date. More specifically, despite the potential risk associated with delivering the vector underneath the macula after detachment, the macula has reattached without significant adverse event.
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Preliminary Information on Patient Perceptions of CHM Gene therapy

High-profile failures in clinical trials have historically sullied public trust in gene therapy and compromised support from funding and regulatory bodies. The resurgence of hype surrounding the field, apparent from a longitudinal analysis of media reporting, raises concerns about unrealistic patient and clinician expectations from ocular gene therapy clinical trials. In parallel to the CHM gene therapy trial, we explored how CHM patients and the clinicians responsible for their care perceive the expected therapeutic benefits, potential risks, and hopes for the timeline of clinical implementation. Our interviews with 20 potential clinical trial participants and 14 clinicians illustrate that despite a backdrop of media and communications hype, patients are well informed about the goals of gene therapy and express realistic expectations of visual benefit from gene therapy. Some gaps nevertheless exist between patient and clinician perspectives, most importantly with respect to the time line for clinical implementation and broader availability of this novel therapy. Communication strategies will need to be developed to bridge these gaps and to aid in the responsible translation of gene therapy from bench to bedside.
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Phase 1b Data for 091001, A Synthetic Retinoid for the treatment of Leber Congenital Amaurosis and Retinitis Pigmentosa
NoteS
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Genetic testing for Patients With Retinal Degeneration

Eric Pierce MD PhD
Genetics of Inherited Retinal Degenerations
Inherited retinal degenerations (IRDs) are important causes of blindness. As a group, these diseases are characterized by progressive dysfunction and death of the rod and cone photoreceptor cells of the retina, leading to blindness.1 Over 200 different types of IRDs have been identified across all age groups by clinical and genetic studies.2 Several IRD subtypes, such as Leber congenital amaurosis (LCA), cause clinically significant vision loss in infancy or childhood.3 Other IRD subtypes, such as retinitis pigmentosa (RP), are leading causes of blindness or visual impairment in working-age people (21-60 years).4 IRDs occur in nonsyndromic and syndromic forms; approximately 30%-35% of individuals with RP have associated non-ocular disease. The majority of these syndromic forms of RP are cilia-related disorders, including Bardet-Biedl, Senior Loken, and Usher syndromes that involve retinal degeneration along with other disorders consequent to cilia dysfunction, such as deafness and polycystic kidney disease.4,5 for IRDs. We have also applied exome sequencing to facilitate identification of new IRD disease genes. Results of these studies show that these approaches result in improved diagnostic rates, and that broad genetic testing for mutations in all known disease genes leads to diagnoses that would not have been made with traditional, phenotype-focused testing. We developed a selective exon capture system for all 184 IRD disease genes listed in the RetNet database.2 We used this capture set to sequence the IRD disease genes in 100 patients with RP, LCA, or Usher syndrome whose genetic diagnoses were not known. Captured DNA was sequenced using an Illumina MiSeq, with 8-12 samples sequenced per run. Sequence data was analyzed using an analysis pipeline that we built with a combination of open-source software and custom programs.13 Using this approach, we typically generate 200 megabases of sequence data per patient analyzed, with an average sequence coverage ~150X, and % on target with coverage 10X >95%. Of 100 patients sequenced using this approach to date, we have made genetic diagnoses for 41 (41%). Potentially pathogenic variants were identified in 7 additional patients. Fifty-two patients appear to have mutations in genes not currently known to harbor mutations that cause IRDs. Of note, several of the genetic diagnoses made via the RetNet sequencing approach described above would not have been made using traditional targeted sequencing, such as cases of RP due to mutations in genes initially identified as LCA disease genes, including CEP290 and RPGRIP1. We also identified cases of LCA caused by mutations in RP and Usher syndrome genes, including GPR98 and a de novo mutation in the dominant RP gene PRPF3. We believe this is because clinical diagnoses are not always accurate, and mutations in genes can cause disease with variation in the age of disease onset and specific clinical symptoms.
Genetic Diagnostic testing

Notable progress has been made identifying the genes that harbor mutations that cause IRDs, with over 180 disease genes identified to date.2 However, the identified mutations account for only 50%-60% of patients with these disorders.4,6,7 In addition, comprehensive clinical genetic diagnostic testing for IRDs has not been readily available. Rather, genetic diagnostic testing for patients with IRDs has traditionally focused on testing for a limited number of genes related to specific clinical diagnoses, such as LCA or RP. While improving, even at this level complete testing is not uniformly available (see Table 1). Finding the genetic cause of patients IRDs is increasingly important, as recent early successes with gene therapy for LCA due to mutations in the RPE65 gene suggest that we are entering an era of genetic therapies for IRDs.8-11 In addition to providing information regarding potential therapies, genetic diagnoses can provide improved clarity for patients regarding their condition, their prognosis, and family planning issues.
exome Sequencing for Disease Gene Discovery

For patients who do not have mutations in known genes, whole exome sequencing can be applied on a research basis to identify new IRD disease genes. For example, we applied exome sequencing to identify the cause of LCA in a family with 2 affected children who did not have mutations in the 17 known LCA disease genes. These studies identified a homozygous missense mutation (c.25G>A, p.Val9Met) in the NMNAT1 gene as likely diseasecausing in this family. This mutation segregated with disease in their extended family, including in 3 other children with LCA. NMNAT1 resides in the previously identified LCA9 locus and encodes the nuclear isoform of nicotinamide mononucleotide adenylyltransferase, a rate-limiting enzyme in nicotinamide adenine dinucleotide (NAD+) biosynthesis.14,15 Sequencing NMNAT1 in 284 unrelated LCA families identified 14 rare mutations in 13 additional affected individuals. Functional studies of a subset of these mutations showed that they decreased NMNAT1 enzyme activity. These results are the first to link an NMNAT isoform to disease and indicate that NMNAT1 mutations cause LCA.13
Next-Generation Sequencing for Genetic Diagnostic testing

Exon and exome capture coupled with next-generation sequencing techniques have recently proven to be powerful techniques for the identification of disease genes for Mendelian disorders such as IRDs.12 One attraction of the techniques is that thousands of genetic variants can be identified and examined simultaneously in each sample, permitting identification of potential pathogenic variants both in known disease genes and in novel genes not previously linked to disease. These techniques can also be applied to genetic diagnostic testing, using selective exon capture directed at a specific set of disease genes, or via whole exome sequencing. We have tested the use of exon capture and next generation sequencing technologies to improve genetic diagnostic testing
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table 1. Available Genetic Diagnostic testing for IRDs organization

John and Marcia Carver Nonprofit Genetic Testing Laboratory
tests offered
1. AD-RP 4 genes 2. AR-RP 16 genes 3. LCA 14 genes 4. XL-RP 2 genes* 5. Usher syndrome 6 genes 1. AD-RP 21 genes* 2. AR-RP 23 genes* 3. Cone-Rod Dystrophy 21 genes* 4. CSNB 11 genes* 5. LCA 17 genes* 6. Senior Loken Syndrome 4 genes 7. XL-RP 1 gene 8. Usher syndrome 9 genes* 1. AD-RP 5 genes 2. AR-RP 7 genes 3. LCA 6 genes 4. XL-RP 1 gene 5. Usher syndrome 9 genes* 1. Inherited Retinal Degenerations 185 genes* 1. BBS 13 genes 2. LCA 6 genes 3. RP 18 genes 4. Senior Loken syndrome 6 genes 5. Usher syndrome 9 genes*
testing Method
Allele testing and sequencing
Casey Eye Institute Molecular Diagnostics Laboratory
Sequencing
GeneDx
Allele testing and sequencing
Massachusetts Eye and Ear Infirmary Ocular Genomics Institute Prevention Genetics
Sequencing
Sequencing
Abbreviations: AD-RP indicates autosomal dominant RP; AR-RP, autosomal recessive RP; BBS, Bardet-Biedl Syndrome; CSNB, congenital stationary night blindness; LCA, Leber congenital amaurosis; RP, retinitis pigmentosa. * Indicates testing of all known disease genes.
In summary, selective exon or exome capture and nextgeneration sequencing provide an improved approach for clinical genetic diagnostic testing for IRDs. This type of genetic testing is already available in some centers and is predicted to be widely available in the near future. Obtaining a genetic diagnosis for patients with IRDs is part of providing optimal care for them. Indeed, in the future it is likely that these disorders will be described by their genetic cause in addition to their clinical presentation.
7. Stone EM. Genetic testing for inherited eye disease. Arch Ophthalmol. 2007; 125:205-212. 8. Maguire AM, et al. Safety and efficacy of gene transfer for Lebers congenital amaurosis. N Engl J Med. 2008; 358: 2240-2248. 9. Bainbridge JW, et al. Effect of gene therapy on visual function in Lebers congenital amaurosis. N Engl J Med. 2008; 358:22312239. 10. Cideciyan AV, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA. 2008; 105:15112-15117 11. Maguire AM, et al. Age-dependent effects of RPE65 gene therapy for Lebers congenital amaurosis: a phase 1 dose-escalation trial. Lancet 2009; 374:1597-1605. 12. Bamshad MJ, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011; 12:745-755. 13. Falk M, et al. NMNAT1 Mutations Cause Leber Congenital Amaurosis. Nat Genet. Epub ahead of print 29 July 2012. 14. Keen TJ et al. Identification of a locus (LCA9) for Lebers congenital amaurosis on chromosome 1p36. Eur J Hu Genet. 2003; 11:420-423. 15. Lau C, Niere M, Ziegler M. The NMN/NaMN adenylyltransferase (NMNAT) protein family. Front Biosci. 2009; 14:410-431.
References
1. Pierce EA. Pathways to photoreceptor cell death in inherited retinal degenerations. Bioessays 2001; 23:605-618. 2. RetNet website: www.sph.uth.tmc.edu/Retnet/. 3. Weleber RG. Infantile and childhood retinal blindness: a molecular perspective. Ophthalmic Genet. 2002; 23:71-97. 4. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet 2006; 368:1795-1809. 5. Hildebrandt F, Benzing T, Katsanis N. Ciliopathies. New Engl J Med. 2011; 364:1533-1543. 6. Daiger SP, Bowne SJ, Sullivan LS. Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol. 2007; 125:151-158.
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optogenetics: A New Approach to Retinitis Pigmentosa

Abstract
A new and innovative approach to treat inherited forms of blindness such as retinitis pigmentosa brings together the advances made in our understanding of the retinal neuronal circuitry, retinal gene therapy, and optogenetic engineering. The advanced state of these fields may allow for an optogenetic gene therapy for blindness to go to clinical trial fairly soon. The idea is to introduce in the retina biological light sensors distinct from those in the natural phototransduction cascade in rod and cone photoreceptors. Our ability to do this relies on single protein molecules that in a very basic way can achieve what the endogenous multicomponent visual system does. These tools are called optogenetic tools and can hyperpolarize or depolarize a cell upon light exposure. The strategic placement of these tools, using gene therapy, in the OFF or ON pathways of the retina enables us to build artificial photoreceptors, and hopefully bring back some level of light perception or vision back to patients. that was proven to be a safe and efficient gene delivery vehicle in these studies.1-3 Though these gene addition studies have tremendous potential, they also have significant limitations. First, a tailored gene therapy will need to be developed for each of the disease-causing genes or for certain cases even for each of the disease mutations. Given the high cost both in terms of development time and funds, as well as the small target population per RP gene, this limits the number of gene therapies under clinical development. Second, barring more extensive genetic screening, most patients with RP present themselves in ophthalmologists office at a late stage in the disease progression, with a degenerate retina and limited photoreceptors remaining for this type of gene therapy to succeed.
optogenetic Gene therapy for Blinding Disorders

A novel method to bring back light perception and possibly vision to patients with RP uses naturally occurring proteins that upon light activation are able to depolarize a cell, like light-activated cation channel Channelrhodopsin isolated from Chlamydomonas reinhardtii (ChR2),4 or hyperpolarize, like the Natronomonas pharaonis derived chloride pump (NpHR).5 A third molecule of interest is melanopsin, a light sensitive G-protein-coupled receptor expressed in intrinsically photosensitive retinal ganglion cells involved in regulating circadian rhythms. Melanopsin acts in conjunction with a cation channel already present in the retinal ganglion cell to hyperpolarize the cell.6 When these optogenetic proteins are being expressed in retinal cell types, preclinical studies in mouse and rat models of retinal degeneration have shown to bring back photosensitivity and in some cases more sophisticated features of vision. The strategic placement, using gene therapy, of these molecules can enable levels of retinal computation that in animal models of inherited retinal disease to reconstitute higher levels of vision, including spatial and temporal filtering. Several strategies are actively being explored to bring optogenetic gene therapy to the clinic. A first strategy brings the optogenetic sensor to retinal ganglion cells in order to enable light perception. Ideally, ON and OFF ganglion cells need to be targeted with different type of sensors in order to maintain the response polarity. What is currently being explored for clinical translation is the ubiquitous expression of ChR2 in retinal ganglion cells using AAV via an intravitreal route of administration.7 A second strategy aims at bringing optogenetic sensors to bipolar cells, again ideally in a manner that preserves response polarity. This strategy is attractive, as it would incorporate the inhibitory modulation of retinal ganglion cells by amacrine cell activity in retinal function and likely lead to improved rescue of vision.8 However, implementation of this approach is hampered by our current inability to target bipolar cells and to do so in an ON- or OFF-specific manner. In a similar manner AII amacrine cells could be targeted to express ChR2; however, this approach would achieve activation of both ON and OFF cells with a single optogene. Amacrine cell targeting with gene transfer vectors
Introduction
Retinitis pigmentosa (RP) is a hereditary condition that leads to progressive loss of vision due to defectives genes primarily expressed in rod photoreceptors. More than 44 genes and many more mutations have already been identified in RP and the discovery of novel RP-causing genes is an area of active research. Disease progression is characterized by initial night blindness, followed by tunnel vision and in some cases complete loss of vision. The pathology of the disease is illustrated by an early degeneration of rods and a secondary bystander loss of cones. The evolution of the disease and retinal pathology is highly dependent on the affected gene, the mutation, and other contributing factors. Patients often present themselves with complaints at later stages of the disease, as the impact on everyday life in RP initially is relatively small. Often only when cone degeneration and therefore central vision and acuity are affected is diagnosis made and genetic testing considered. At this stage often rod degeneration is highly advanced and rod-regenerative strategies for therapy may not succeed. Therapeutic options for RP are limited to none, though dietary supplements are investigated to slow down disease progression. Several experimental strategies are actively being explored, including gene therapy, stem cell therapy, and retinal chip prosthesis.
Retinal Gene therapy

A highly attractive approach to stem disease progression and possibly provide a curative effect is gene therapy for RP, in which a mutated gene is corrected, silenced, and/or a correct version is added back. In practice this is more complicated, but it was safely and successfully achieved for an early-onset form of RP called Leber congenital amaurosis (LCA) due to RPE65 mutation in 3 clinical studies. The RPE65 gene in all these studies was delivered to the cells with an adeno-associated viral vector (AAV)
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Section V: Inherited Retinal Diseases References
Retina
also remains difficult in practice, precluding this strategy from progressing to the clinic at this stage. Finally, another avenue for optogenetic gene therapy for blindness is the reactivation of remnant cone photoreceptor bodies. It has been shown that cone cell bodies remain viably present in the fovea even after the loss of photosensitivity in a subset of RP patients. NpHR expression in these cells in animal models activates light-evoked activity in the retinal ganglion cells as well as cortex, leading to visually evoked behavior.9
1. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Lebers congenital amaurosis. N Engl J Med. 2008; 358:2240-2248. 2. Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA. 2008; 105:15112-15117. 3. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Lebers congenital amaurosis. N Engl J Med. 2008; 358:2231-2239. 4. Nagel G, Szellas T, Huhn W, et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci USA. 2003; 100:13940-13945. 5. Schobert B, Lanyi JK. Halorhodopsin is a light-driven chloride pump. J Biol Chem. 1982; 257:10306-10313. 6. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. Melanopsincontaining retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 2002; 295:1065-1070. 7. Bi A, Cui J, Ma YP, et al. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron 2006; 50:23-33. 8. Lagali PS, Balya D, Awatramani GB, et al. Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci. 2008; 11:667-675. 9. Busskamp V, Duebel J, Balya D, et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 2010; 329:413-417.
Remaining Hurdles
Several questions remain before these strategies can be translated to first-in-human studies, including the immunological response to the expression of foreign optogenes. This concern favors the approaches with the human melanopsin optogenetic sensor. Other remaining hurdles revolve around the latency, sensitivity, and dynamic range of the molecules and strategies used. Critical for success in this respect is the ability for adaptation under different light conditions. Continuous research efforts are ongoing that improve the properties of the optogenetic toolset; however, it is thought that for the optogenetic therapy for blinding disorders an external head-mounted display device would be needed that is either computer- or user-operated in order to adjust for the limitations of the optogenes and the therapy.
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Section VI: Retinal Vein occlusion
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Retinal Vein occlusion Panel

Donald J DAmico MD, Barbara Ann Blodi MD, Sharon Fekrat MD, Michael S Ip MD, Carl D Regillo MD FACS, Rishi P Singh MD
NoteS
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Section VII: Business of Retina
Retina
the Future of Healthcare: Survival of the Fittest

David W Parke II MD
Regardless of our politics, regardless of whether we like or dont like the administrations Patient Protection and Affordable Care Act (PPACA) or whether we like or dont like the Ryan-Wyden proposal for premium support, American health careand eye carewill change more fundamentally over this decade than in any single previous decade. The structure, process, payment incentives, payment mechanisms, and players are all changing fundamentallysimultaneously. Why is it changing? Consider the following: America spends $2.7 trillion for health care, almost 18% of the gross domestic product. This is first among top 34 developed countries (Organization for Economic Cooperation and Development). America ranks 31 among 34 countries in providing coverage to all its people (OECD) (ahead of only Turkey, Mexico, and Chile). America ranks 25 among 34 countries in preventing death from heart disease (OECD). While it can be legitimately argued that many of the health quality statistics such as infant mortality, life expectancy, and immunization rates have as much to do with social factors as with medical factors, other statistics such as survival from stroke and heart attack suggest that America does not lead the world and in the process it covers a smaller percentage of its citizens and at far higher cost. This is the rationale driving rapid and comprehensive health system change in the United States. Whether we individually believe each of the statistics or not is immaterial. No policy maker or politician in a position of responsibility is advocating that the system in place in 2009 will serve us in 2020. At the same time, the cacophony surrounding what actually is best or likely to result from the change already in process suggests that it is impossible to plan with certainty. However, by understanding more acutely the drivers to change and the levers that policy makers will use, we can better position our practices and our profession.
System Integration
Why do industries vertically and horizontally integrate? Because they can provide a less expensive product and a seamless experience for customers. In the case of health care, integration has the allure of decreasing care duplication and coordinating care for an advantage in cost, quality, and service. We could talk about efficient use of capital and leveraging assets, but its really just about controlling and integrating enough components of the health care delivery system so that you can decrease inefficiency, monitor quality, and dominate your market. Whether or not these systems are called accountable care organizations (ACOs) or not, they will be similar in structure and operational objectives. What does this have to do with retina? Such systems want physician leaders. First, they want great physicians, but second they want physician leaders. And great physicians who are leaders are in particularly short supply. So what is actionable about that observation? Leadership skills and experience can be
acquired, just as can surgical experience. Retina, within ophthalmology, should be a particularly fertile ground for fostering physician leaders. First, most of us still do some cases in a hospital even if its only trauma cases. Second, we interact with primary care physicians in the management of patients with multiorgan systemic diseases. Third, we manage some of the diseases such as AMD and diabetic retinopathy that are on the radar screen of health systems. The American Hospital Association recently convened a special task force composed almost entirely of physicians. They concluded, thankfully, that the most important attributes of a physician were medical knowledge, surgical skills, and patient care expertise. However, of 11 attributes needed for success in health care, the gaps between importance and availability were most acute for (in order) providing cost-conscious, effective medical care, interpersonal and communication skills, coordinating care with other health care providers, and working effectively with the health care team. Therefore, a key to surviving and thriving in system integration is to become indispensable to the systemas a physician and as a leader of other physicians. And while ophthalmology as a profession has historically been relatively independent of systems, this will change. Whether employed by systems or not, retina specialists will derive patients who are part of integrated systems and will need access to operating rooms and diagnostic facilities and colleagues who are part of systems. System integration creates other challenges. How do you take advantage of integration without being controlled by integration? Health care politics will be local. However, information technology (electronic medical records [EMR]) systems are a key element. Health systems will use participation in their EMR has a golden handcuff for affiliated external practices. Some communities physicians will effectively choose teams among integrated systems or ACOs. Fortunately, because they are less likely to be offered employment by a system, ophthalmology and retina may be able to watch how systems develop before choosing sides. If you question whether or not this is occurring, consider that mergers and acquisitions in the health care industry totaled $227BB in 2011an increase of 43% over the prior year.
the Rise of Service and Quality Standards

A hallmark of integrated systemsand a requirement under the PPACAis the development of service and quality standards. As an example, participation in a specific system could require that all physicians agree that any patient with a nonurgent problem is provided an appointment within 15 working days. It could require that every affiliated practice adopt a uniform approach to surveying patient satisfaction and sharing those results with the system. Practices that are open to such standards and have an infrastructure in place to support it will have an advantage. Similarly, systems will increasingly seek evidence of meaningful compliance with best practices and with process and outcomes measures. Ophthalmologists in systems must play an active role in ensuring that the measures are appropriate, clinically meaningful, and appropriately risk-adjusted. The Acad-
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Section VII: Business of Retina Conclusion
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emys Preferred Practice Patterns and Summary Benchmarks can be helpful in this process by providing evidence-based measures. Likewise, the future Academy-sponsored ophthalmology clinical data registry will be a valuable tool for practices to benchmark their quality and to support appropriate valuation of their services.
Changes in Physician Payment

Fee-for-service is not going awayat least not any time soon. Some retina specialists, by virtue of geography, will continue to have patients not in integrated systems, and they will be paid on a discounted fee-for-service system. Some systems will use variants of withholds, global payment, bundled care, and even modified capitation. Withholds may be linked to performance and service. Those practices willing to consider modification of traditional payment systems may be viewed preferentially by systems.
Survival of the fittest has always been an axiom of any business. Fitter ophthalmology practices have always outperformed less fit practices by the relevant metricssustainability, financial performance, community reputation, etc. The difference now is that the business model is more complex and more competitive. And the margins will likely narrow. Top-quality medical and surgical skills are as critical as ever. But business skills, organizational flexibility, and attention to relevant process and outcome metrics will become the increasingly important differentiator between surviving and thriving.
Selected Readings
1. Blumenthal D. Performance improvement in health careseizing the moment. N Engl J Med. 2012; 366:1953-1955. 2. Combes JR, Arespacochaga E. Lifelong Learning Physician Competency Development. American Hospital Associations Physician Leadership Forum. Chicago Ill.; June 2012. 3. Foran JRH, Sheth NP, Ward SR et al. Patient perception of physician reimbursement in elective total hip and knee arthroplasty. J Arthroplasty. 2012; 27:703-709. 4. Iglehart JK. Primary care update: light at the end of the tunnel. N Engl J Med. 2012; 366:2144-2146. 5. IOM (Institute of Medicine). The Healthcare Imperative: Lowering Costs and Improving Outcomes: Workshop Series Summary. Washington, DC: The National Academies Press; 2010.
Patients as Advocates
Patients can be very effective advocates with integrated systemsjust as they can be with payers. Paradoxically, individual patient relationships fostered by good communication, risk mitigation, service, and quality of care can be a practices best weapon in interfacing with integrated systems. Patients value certain services more than payers. A recent article in the orthopedics literature, for example, found that surveyed patients undergoing a total hip replacement felt that the physician should receive an average of $14,358 for the procedure and estimated that Medicare reimbursement to the surgeon would be $8,212. Medicare actually paid $1,375.
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Accountable Care organizations: In or out?

William L Rich MD
The four main stimuli that led to passage of the Accountable Care Act (ACA) in 2010 are 43 million uninsured, runaway costs, perceived poor quality, and poor coordination of care. How will ACA address these issues? In 2014, 33 million uninsured will have access to health care through the expansion of Medicaid and new financial subsidies that will enable patients to purchase insurance through state exchanges. Dr. Donald Berwick, Director of the Centers for Medicare & Medicaid Services (CMS), summarized his strategy to address the latter three stimuli with changes in system design and payment reform through implementation of his triple aim strategy: Improve health Improve quality and patient experience of care Decrease costs This philosophy has driven all CMS rule making. To design and implement these strategies outside the usual bureaucratic maze, ACA created a new CMS entity, the Center for Medicare and Medicaid Innovation (CMMI). The administration recruited a very bright group of physicians, methodologists, and payment experts to design new health care delivery models to further the integration of care, improve outcomes, improve quality, and decrease costs. All these new models involve payment methodologies that move away from traditional fee for service and reimburse professionals on the quality and efficiency of care. Two new payment models have already been implemented: bundled payments and accountable care organizations. In the initial bundled payment initiatives CMS will combine into a single payment all services for an episode of care. For example, for major joint replacement, this would include the costs of imaging, consults, surgical fee, facility charges, anesthesia, surgeons fee, device cost, readmissions, rehabilitation and nursing home care for a 90-day period. This bundled payment will be paid to a hospital or physician entity that will develop its own plan to allocate revenues. Ophthalmology has several chronic diseases that would be very suitable for outpatient chronic care bundles, but these wont be implemented for several years.
The model for ACO design is based on the Medicare Physician Group Practice Demonstration. Ten large medical groups agreed to be measured on quality outcomes and costs over 5 years. Many achieved goals for simple quality process measures. Those who achieved savings would get a bonus. Three received no bonus at all. Only 2 received a bonus in all 5 years. The demo covered 220,000 lives, and Medicare saved $26.6 million over 5 years, or $121/beneficiary! In summarya failure. Not to be deterred by a lack of evidence, Congress, via the ACA, will proceed ahead with ACOs! An ACO must be patient centered, report on quality and cost measures, coordinate care and demonstrate financial savings. CMS estimates that of the 43 million Medicare beneficiaries, 2 million will be enrolled in ACO in 5 years. The requirements to be certified as an ACO include the following: Accountability for the quality, cost and overall care A contract not less than 3 years A formal legal structure Primary care physicians sufficient for a minimum of 5000 patients Primary care MDs have to sign an exclusive contract with one ACO. Report yearly on 33 quality metrics There are 3 ACO models: pioneer, shared savings, and advanced payment. The pioneer ACO model is designed for existing integrated health care systems (eg, Kaiser, Intermountain Health, Geisinger) that are more structured to take on risk. For the first 2 years, it will share savings and losses with CMS. The third year permits global payment, the new term for capitation. By assuming risk, there is the opportunity for higher profits and losses. Unless you are employed in an integrated health system, you may have access to an ACO through participation in the shared savings model. There were over 150 applications in the first round of ACO evaluation, and 27 were approved in April 2012 that will care for 275,000 Medicare beneficiaries. Local hospital systems or physician groups organized as an IPA to control them. The ACO may retain 50%-60% of any savings after 2% savings over benchmark costs are achieved. The benchmark is determined by the weighted average of Part A and B costs of patients over the previous 3 years who would have been seen by ACO docs and is capped at 10%-15% of the spending target. MDs are paid fees for services directly by Medicare, not by the ACO. How bonuses are allocated is up to the ACO. The advanced payment model was designed to allow small groups of physicians or community health centers to participate in rural or underserved areas without a formal physician or hospital organization. It is a type of shared saving model that will receive upfront capital from Medicare for organizational design. The ACO will receive monthly Medicare checks based on enrollment. They will get killed by hospital contracts. Rule making has mandated some features that are not optimal for an entity undertaking ACO development. What are the risks? Patients are retrospectively assigned to the ACO if they
Accountable Care organizations (ACos)

Elliot Fisher MD, from the Dartmouth Institute for Health Policy, and Glenn Hackbarth JD, the chair of the Medicare Payment Advisory Committee, designed a new model for integrating care to improve quality and decrease costs: an accountable care organization. An ACO is defined as an organization, virtual or real, that agrees to take on the responsibility for providing care for a particular population while achieving specified quality objectives and containing costs. Why ACOs? Fifty percent of Medicare beneficiaries have 5 chronic conditions and are responsible for 76% of Medicare Part A and Part B expenditures. In 1 year each of these patients average 37 physician visits from 14 different professionals and fill 50 prescriptions. Any one who has tried to help an elderly, chronically ill parent navigate Medicare understands the problem.
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attain a plurality of their primary care visits from a professional on the ACOs panel. However, patients are free to attain specialty care wherever they choose and may elect not to have their data shared between ACO docs! The costs of that specialty care are allocated to the ACO. Also, new studies raise questions on the accuracy of the ACOs spending benchmark. Large variations have been describeda big risk for the ACO! Ophthalmologists who have high costs, lower patient satisfaction or surgical outcomes when compared to their peers will lead to ACO losses. They are at risk of fewer future referrals from ACO physicians. There are societal risks if ACOs are widely adopted. There is great concern that the consolidation of market share around large group IPAs and hospital system ACOs will drive up costs and exert further downward pressure on physician fees. In Massachusetts, the consolidation of docs around academic hospital systems led to an increase in unit costs and was the main driver of increased expenditures.
What should you consider when contemplating participation with an ACO? Three suggestions: 1. Do not sign an exclusive contract! You will be precluded from participation in future ACOs in your market. 2. Carefully read all contracts from shared savings ACOs! Watch for any requirement to purchase a preferred EHR that might preclude involvement in other evolving ACOs. In summary, ACOs are only one of the new payment models that will reward you for the provision of high quality, efficient care that is coordinated with primary care doctors. Physicians who continue to rely solely on fee for service and elect not to participate in an ACO or bundled payment initiative will face a sharp reduction in fees in all the new payment reform models under congressional consideration.
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ASC For Retina: Is It time?

Michael A Romansky JD
I. Vitreoretinal (VR) Trends for the Ophthalmic ASC A. Market share of VR cases in ASCs, 2008: 30%1 B. Four-year growth in VR case volume in ASCs: 29%1 C. Average annual growth in VR volume in ASCs: 10%1 D. Share of ASCs performing VR: 41%2 E. Share of ASCs planning to add VR: 20%2 F. Note: ASC facility fees for intensive VR services have doubled since 2007, from about $750 to over $1600 today. II. Volume Growth of VR in ASCs III. If Considering VR in an Existing ASC or in a New Center: A. Payment factors: Reimbursement has doubled since 2008, and VR rates will increase as HOPD rates do. B. Technology C. Efficiencies D. Regulatory issues 1. Medicare Conditions for Coverage
2. Medicare Quality Reporting a. Measures b. Penalties c. Future IV. OOSS Answer: ASC Legislative Reform A. Enactment of The Ambulatory Surgical Center Quality and Access Act of 2011 1. Harmonize rates with HOPDs, same annual update factor as hospitals 2. Rational quality reporting program - 3. Value-based purchasing 4. Repeal CMA limit on same day surgery (Yag) - 5. ASC representation on advisory panel B. New legislation next year
References
1. Strategic Health Care, OPPS Data Source, CPT Codes 67036, 67041, 67042, 67108, 67113. 2. OOSS Mark, Annual Benchmarking of 200 ASCs countrywide.
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ASC for Retina: Balancing Quality With Profit

Alan Ruby MD
I. Vitreoretinal Surgery in an ASC A. Advantages 1. Smaller environment provides for less personnel turnover. 2. Greater efficiency and faster turnaround time, more rapid recovery time 3. Increased productivity in office as a result of increased productivity in operating room B. Disadvantages 1. Potential need for careful case selection 2. Potential lack of instrumentation/ peripherals for complicated cases 3. Inability to operate on babies/ high-risk patients 4. High upfront cost to equip retina room 5. Initial training of staff to perform retinal procedures 6. Reimbursement issues relating to relative cost of ASC procedures vs. hospital-based procedures II. Reimbursements Issue for Retinal Procedures in an ASC A. Rising facility fee reimbursements for common posterior segment surgeries increase appeal of ASCs.
1. Increase in fee schedule to more closely approximate hospital-based surgery a. 67036, pars plana vitrectomy: 2007 = $630; 2011 = $1,547 b. 67041, pars plana vitrectomy, preretinal membrane: 2008 = $1,540; 2011 = $1,547 2. Surgeon fees identical to reimbursements paid for hospital-based surgery. B. Nonreimbursed supplies for vitreoretinal surgery 1. Silicone oil, perfluoro-n-octane, C3F8 canister, indocyanine green 2. Cost of equipment for surgery 3. Transitioning to ASC from hospital-based surgery a. Operating in multispecialty ASC b. Physician-owned and -operated ASC: predicting financial success c. Joint hospitalphysician owned ASC d. Future reimbursement issues for ASC
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the office of the Inspector General and Bevacizumab vs. Ranibizumab: No Good Deed Goes Unpunished
The advent of intravitreal anti-VEGF therapy has revolutionized the management of retinal vascular disease and brought immeasurable clinical benefit to hundreds of thousands of patients afflicted with blinding retinal disease. The development of anti-VEGF therapy is the result of a continuing partnership between ophthalmologists, industry, and clinical trial participants. However, the cost of anti-VEGF therapy is large. In 2010, the combined Part B expenditures for ranibizumab and bevacizumab were $2 billion. This has attracted the attention of health care payers, particularly the Centers for Medicare and Medicaid Services (CMS). As such, the Office of the Inspector General (OIG) for the Department of Health and Human Services (HHS) has recently issued a report on Medicare payments for drugs used to treat wet age-related macular degeneration.1 The OIG was created to protect the integrity of HHS programs and the well-being of beneficiaries by detecting and preventing fraud, waste, and abuse; identifying opportunities to improve program economy, efficiency, and effectiveness; and holding accountable those who do not meet program requirements or who violate federal laws. The OIG has more than 1800 professionals including lawyers, accountants, and investigators to conduct audits, evaluations, and investigations. The OIG collaborates with the Department of Justice when necessary.2 The objectives of the OIG study were as follows: 1. To compare the Medicare payment amount for ranibizumab to physicians acquisition costs 2. To determine the average Medicare contractor payment amount for bevacizumab when used to treat wet AMD and compare it to physicians acquisition costs 3. To examine Medicare contractor payment policies for bevacizumab 4. To examine the factors considered by physicians when choosing bevacizumab The study used Medicare claims data to identify 2 stratified random samples: 1 sample of 160 physicians who received Medicare payment for ranibizumab and 1 sample of 160 physicians who received Medicare payment for bevacizumab. The study sent electronic surveys asking physicians to provide the total dollar amount and quantity purchased of both drugs in the first quarter of 2010. The study also asked physicians to describe the factors that they consider when choosing a drug for the treatment of wet AMD. The study compared physician acquisition costs to Medicare payment amounts obtained from CMS and Medicare contractors. Additionally, it analyzed Medicare contractor payment policies and the reasons physicians reported for administering bevacizumab instead of ranibizumab. The study found that in the first quarter of 2010, physician acquisition costs for ranibizumab and bevacizumab were 5 and 53 percent below the Medicare payment amount, respectively. Medicare contractors payment amounts for bevacizumab when used to treat wet AMD differed by as much as 28 percent, although payment policies were similar. Additionally, the majority of physicians who administered bevacizumab to treat wet AMD reported the substantial cost difference compared to ranibizumab as a primary factor in their decision. Based on these findings the OIG recommended that CMS: 1. Establish a national payment code for bevacizumab when used for the treatment of wet AMD 2. Educate providers about the clinical and payment issues related to ranibizumab and bevacizumab As required by law, CMS replied to both recommendations. They non-concur with the first recommendation and concur with the second. In their reason for declining the first recommendation, they cited the 2009 fiasco in which they proposed to create a national Medicare payment rate of $7.185 per 1.25-mg dose, which was calculated by taking the payment amount for the 10-mg dose of bevacizumab and dividing by 8. The OIG study confirmed the inadequacy of the 2009 proposal by finding ophthalmologists paid on average $26, including drug and compounding costs, per 1.25-mg dose of bevacizumab. The OIG noted the average Medicare contractor payment of $55 per dose was 53% higher than the acquisition cost. The implication is that this payment may be too high. For ranibizumab, ophthalmologists paid $1928 (net of discounts) per vial in the first quarter of 2010, which was 5% below the Medicare payment amount of $2023. This finding demonstrates that the average sales price plus 6% methodology for Part B drug payments is working, at least for CMS. The OIG study provides ophthalmologists with an interesting perspective on payment policy at CMS.
References
1. Department of Health and Human Services. Office of Inspector General. Medicare payments for drugs used to treat wet age-related macular degeneration. Daniel R. Levinson, Inspector General. April 2012. OEI-03-10-00360. 2. Office of Inspector General, U.S. Department of Health & Human Services. www.oig.hhs.gov.
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Managing a Large Modern Practice: Practice Informatics and It

Over the last 20 years our multi-subspecialty ophthalmology practice has become increasingly data driven. Initially all costs were put on spreadsheets, but the new world of health-care reform will call for a much more data-rich group of providers who can use this information to plan changes in their practice, choose contracts for bid based on their own costs of service delivery, and change physician behavior to encourage more costeffective and efficient patient-centered practice. Ophthalmic Consultants of Boston is close to an all-electronic office, with Sage Intergy used to collect demographics , schedule all patients and their testing (OCTs), as well as track the patients within the office. Our EMR is the Partners Healthcare MGH system, which also handles e-prescribing. At the completion of a visit the coding is done immediately by the physician or with the assistance of technical staff with Medaptus, which includes billing for visit, testing, injections, and drugs, and then the diagnosis codes are extracted from a menu (or from history) and one ensures the tests and treatments are justified by diagnoses. Then PQRS criteria are all displayed to check if performed based on the diagnosis billing codes. Practice metrics captured include patient type (new or established), referral source (outside MD, ophthalmologist, internal referral, OD, family member, etc.), insurance payer, both primary and secondary (Medicare, individual carrier, group plan). In addition all visit, diagnostics, procedures, tests, and surgeries are included, as well as anti-VEGF drug injected. All of this information is then shunted into a large data warehouse, and from this large database information of practice metrics are sought using search routines, and then that data is transferred to practice dashboards on the office intranet on Microsoft Sharepoint, viewable by physicians and management staff for planning purposes. Of course billing and collections data are displayed looking at current, past, and predicted performance. On a short-term basis the physician can look at the percentage of utilization of the visits slots filled in the scheduling template, and can compare with current and past averages. Key performance indicators appear at the end of the columns to tell the physician if the schedule is filled, overfilled, or has plenty of space. Also one can drill down the information on each visit day by visit type. Cycle time is the time from patients arrival to the time of the patients departure from the office. We time stamp each transaction (arrival, tech in, tech out, OCT in, OCT out, MD in, MD out, office departure). Lengthened cycle times point to problems, such as OCT or photography backlogs, showing that scheduling paradigms need improvement. Peer-to-peer comparisons enable staff and physicians to improve processes to reduce patient waiting time and improve flow, with resultant patient satisfaction improvement. With patient-centered care in the new health care system, we will be graded by patient satisfaction surveys to determine a portion of our payment. Compliance assessment is aided by being able to compare coding levels for new or established patients with peer-to-peer comparison graphs, diagnostic test utilization, number and types of laser and surgical procedures, and comparisons of usage of the available anti-VEGF drugs used for intravitreal injections. With the need for information to enable reasonable projections, bids, and survival in the next decade of rapidly evolving mechanisms of health care reimbursement, it is imperative that we collect data on current performance, use that data to improve it, and then change our behavior to enable us to continue the highest quality of health delivery in a contracting financial environment.
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Postmarketing Surveillance
Wiley A Chambers MD
This presentation reflects the views of the author and should not be construed to represent the FDAs views or policies.
6. Levacetyl methadol (2003) 7. Propoxyphene (2010) B. Drug-induced liver disease 1. Ticrynafen (1980) 2. Benaxoprofen (1982) 3. Bromfenac (non-ophthalmic) (1998) 4. Trovafloxacin (1998, returned to market) 5. Troglitazone (2000) 6. Pemoline (2005) C. Other cardiovascular (CV) 1. Pergolide: valvulopathy (2007) 2. Fenfluramine: valvulopathy (1997) 3. Rofecoxib: acute myocardial infarction (2004) 4. Sibutramine: CV events (2010) 5. Tegaserod: CV events (2007) 6. Azaribine: arterial thrombosis (1976) 7. Encainide: mortality (1991) 8. Phenylpropanolamine: hemorrhagic stroke (2000) D. Other adverse events 1. Natalizumab: progressive multifocal leukoencephalopathy (2005, returned to market) 2. Zomepirac: anaphylaxis (1983) 3. Suprofen (non-ophthalmic) acute renal failure (1987) 4. Etretinate: birth defects (2002) 5. Rapacuronium: bronchospasm (2001) 6. Temofloxacin: hemolysis, renal failure (1992) 7. Nomifensine: hemolytic anemia (1986) 8. Gatifloxacin (non-ophthalmic): hyper- and hypoglycemia (2006) 9. Aprotinin: increased mortality (2007) 10. Alosetran: ischemic colitis (2000, returned to market) 11. Phenformin: lactic acidosis (1978) 12. Flosequinan: increased mortality (1993) 13. Methaqualone: overdose (1984) 14. Cerivastatin: rhabdomyolysis (2001)
I. All drugs have some risk. II. The FDA monitors the life cycle of a drug product. A. Nonclinical studies B. Phase 1 studies, including First in Man C. Phase 2 studies: dose ranging D. Phase 3 studies E. Phase 4 studies: postmarketing studies F. Postmarking surveillance III. Key Points A. Assessment improves as more individuals receive the drug product. B. Risks are usually not completely known even after the drug product is marketed. The alternative would be to delay the wide availability of the drug product for many years, depriving many patients of the potential benefits of the drug product. C. Initial approval is based on adequate and well-controlled studies. Most ophthalmic products have been studied in 300-3000 patients prior to approval. D. Adverse events that may occur at a frequency of 0.1% or less are unlikely to have been detected in the clinical trials. E. Population will expand following approval. Reactions not seen in clinical trials may and often do occur during marketing period. F. Adverse events that alter the benefit/ risk ratio may lead to withdrawal of the drug product and/or a recall of the drug product. IV. Common Reasons Why Drugs Are Withdrawn Ophthalmic products usually do not have sufficient systemic absorption to cause these concerns. The ophthalmic formulations may remain on the market even when the orally administered product is removed from the market. A. Torsade de pointes 1. Mibefradil (1998) 2. Terfenadine (1998) 3. Astemizole (1999) 4. Grepafloxacin (1999) 5. Cisapride (2000)
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15. Valdecoxib: cardiovascular issues/ Stevens-Johnson syndrome (2005) V. The ophthalmic products that have most commonly been the subject of recalls have been unapproved products. A. AMO Balance Salt Solution B. Camolyn Eye Drops C. Soothe Xtra Hydration D. Pharmacy compounded trypan blue E. Pharmacy compounded brilliant blue F. Pharmacy compounded triamcinolone VI. Currently Marketed Ophthalmic Products That Are Not the Subjects of an Approved New Drug Application A. Homatropine ophthalmic solution B. Scopolamine ophthalmic solution C. Atropine ophthalmic solution D. Lissamine green ophthalmic solution and strips E. Rose bengal ophthalmic solution and/or strips F. Fluorescein ophthalmic drops and/or strips G. Tetracaine ophthalmic solution H. Phenylephrine ophthalmic solution VII. Postmarketing Surveillance Systems A. Active Surveillance B. Passive Surveillance VIII. The FDAs Sentinel Initiative: Active Surveillance A. FDA Amendments Act of 2007 B. Establishes a postmarket risk identification and analysis system to link and analyze safety data from multiple sources, with goals including the following: 1. At least 25,000,000 patients by July 1, 2010 2. At least 100,000,000 patients by July 1, 2012 C. Accesses a variety of sources, including federal healthrelated electronic data (such as data from the Medicare program and the health systems of the Department of Veterans Affairs) D. Also uses private sector healthrelated electronic data (such as pharmaceutical purchase data and health insurance claims data) IX. MedWatch Passive Surveillance A. MedWatch relies on healthcare providers and/or patients to report events, preferably in the form of good case reports. B. Good case reports usually include the following elements: 1. Description of the adverse events or disease experience, including time to onset of signs or symptoms
2. Suspected and concomitant product therapy details (ie, dose, lot number, schedule, dates, duration), including over-the-counter medications, dietary supplements, and recently discontinued medications 3. Patient characteristics, including demographic information (eg, age, race, sex), baseline medical condition prior to product therapy, comorbid conditions, use of concomitant medications, relevant family history of disease, and presence of other risk factors 4. Documentation of the diagnosis of the events, including methods used to make the diagnosis 5. Clinical course of the event and patient outcomes (eg, hospitalization or death) 6. Relevant therapeutic measures and laboratory data at baseline, during therapy, and subsequent to therapy, including blood levels, as appropriate 7. Information about response to de-challenge and re-challenge 8. Any other relevant information (eg, other details relating to the event or information on benefits received by the patient, if important to the assessment of the event) C. For reports of medication errors, good case reports also include full descriptions of the following, when such information is available: 1. Products involved, including the trade (proprietary) and established (proper) name, manufacturer, dosage form, strength, concentration, and type and size of container) 2. Sequence of events leading up to the error 3. Work environment in which the error occurred 4. Types of personnel involved with the error, type(s) of error, and contributing factors X. Reporting Requirements A. Manufacturers of drug products are required to collect and analyze all adverse reactions reported to them. Labeling is updated to reflect newly reported reactions. B. Serious and unexpected (not listed in the current labeling) adverse drug experiences are required to be reported as soon as possible, but in no case later than 15 calendar days from initial receipt. C. In addition, there is quarterly reporting of all adverse drug experiences. Analysis of these events and proposed labeling changes are submitted at least quarterly to the FDA during the first three years of marketing and at least annually afterward.
Selected Readings
1. MedWatch: The FDA Safety Information and Adverse Event Reporting Program. US FDA website. Available at www.fda.gov/ Safety/MedWatch/default.htm. Accessed June 13, 2012.
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2. Code of Federal Regulations. 21 CFR 314.80 Postmarketing reporting of adverse drug experiences. 3. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research. Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment. Available at: www.fda.gov/downloads/ regulatoryinformation/guidances/ucm126834.pdf. Accessed June 13, 2012.
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Section VIII: Neovascular AMD
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Noninferiority Trials and Subgroups: How to Interpret What You Are About to Hear
I. Standard Clinical Trials: When Life Was Simple A. Typically, 2 groups: Active Drug vs. Placebo, or Test Procedure vs. Sham Procedure B. Question of interest: Is active drug different than placebo? C. Hypothesis testing: H0: = 0; HA: 0 D. Alpha () = 0.05 for hypothesis testing; reject the null hypothesis and conclude: Active drug is different from placebo; direction of difference from observed data. E. 95% [(1- )%] CI on the difference: Contains values of true difference for which a hypothesis Hv: = v would be rejected; if the confidence interval does not include 0, we conclude: Active drug is different from placebo. II. Todays Trials in Neovascular AMD: Not So Simple A. More than 2 groups: Different drugs, different doses, different dosing frequencies, no placebo B. Factorial designs; factorial data analysis and all pairwise comparisons C. Question of interest: Is Drug X not worse than established Drug Y? (Noninferiority), possibly also Is Drug X about the same as Drug Y or Is Drug X better than Drug Y? D. Noninferiority margin: Defined differently by different study groups, governmental agencies E. Alpha () level used for testing and confidence intervals adjusted for multiple testing; Bonferroni rule, hierarchical specification of sequence of comparisons, Hochberg procedure F. Choice of outcome measure: Proportion with a 3-line increase in visual acuity (VA), mean change from baseline in VA G. Many possible combinations of the above factors; if allowed to pick and choose which approach to use after seeing the data, a very favorable analysis could be crafted; FDA, EMEA, NIH, and top-tier journals require prespecification. III. Factorial Design and Factorial Analysis A. Factorial design: Two factors (drug, dosing schedule) each with 2 levels ([ranibizumab, bevacizumab], [monthly, p.r.n.]); all 4 treatment combinations tested B. Factorial analysis: A patients change in VA = a base level + a drug effect + a dosing effect + random error. Example: The benefit, if any, of ranibizumab
Figure 1. Strict noninferiority trial.
over bevacizumab is the same amount, under both monthly and p.r.n. dosing (IVAN Year 1, CATT Year 2). C. Nonfactorial analysis: A patients change in VA = a base level + an effect specific to the combination of drug and dosing schedule + random error. Example: The effect of ranibizumab relative to bevacizumab when treatment is monthly can be different from the effect when treatment is p.r.n. (CATT Year 1). D. The factorial analysis combines all patients treated with ranibizumab together and all those treated with bevacizumab together when comparing drugs; the nonfactorial analysis makes separate comparisons of ranibizumab and bevacizumab for monthly treated and p.r.n. treated. E. Nonfactorial analysis requires about twice as many patients but guards against drug effects depending on the dosing schedule, such as ranibizumab and bevacizumab being equal for monthly dosing but bevacizumab being better than ranibizumab for p.r.n. dosing. IV. Noninferiority Trial A. Intent to show that a new drug is not worse than another drug B. Need to rule out values of the true difference that are substantially worse than the standard treatment. A noninferiority margin, , is selected. If the new drug is less than worse than the standard drug, it is noninferior. C. Once is selected, the confidence interval for the difference between drugs is examined to see if the noninferiority margin is crossed.
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Section VIII: Neovascular AMD D. Alternative approaches allow declaring superiority if the confidence interval excludes both the noninferiority margin and 0.
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VI. Adjustment for Multiple Comparisons A. With each statistical test, there is a 5% chance of declaring a difference when none truly exists. When multiple tests are performed within one study, the probability of at least 1 error increases well above 5%. Many, but not all, statisticians believe that actions need to be taken to lower the overall probability of at least 1 error. B. In a factorial analysis, typically no correction is made for more than 1 test. C. A simple approach (Bonferroni) is to divide 0.05 by the number of comparisons to be made and use that level for each statistical test and confidence interval rather than 0.05. This approach is conservative and may be too stringent. Alternative procedures for handling multiple testing exist (eg, Hochberg, which depends on the observed P-values, and hierarchical approaches that require that all comparisons be specified in order of testing before the data are observed). D. In noninferiority trials, adjustment for multiple comparisons leads to wider confidence interval, making crossing the noninferiority limit more likely.
Figure 2. Noninferiority trial allowing superiority.
E. Still other approaches allow declaring equivalence if the confidence interval is wholly contained within and + . V. Choice of Noninferiority Margin A. Goals 1. Make sure new drug is better than placebo even though placebo is not included in the trial 2. Any erosion of the treatment effect is small enough that the improvement by the new drug is still clinically significant B. One formula is to use the lower bound of the 95% CI on the difference of the standard drug from placebo, based on previous clinical trials. This works toward ensuring that the new drug is better than placebo. Usually the margin is made even smaller so that a high proportion of the original treatment effect is preserved. C. A less formulaic approach to assessing how much erosion of treatment effect can be tolerated is to review previous information on the size of improvement that has led physicians and patients to adopt a new treatment. D. Example: For CATT, the mean difference between ranibizumab and sham injection was approximately 20 letters at 1 year, based on results from ANCHOR and MARINA. The lower confidence limit on the improvement ranibizumab was about 17 letters. Review of previous trials of thermal laser and PDT judged minimally effective showed mean improvements of 6 or 7 letters. A limit of 5 letters was chosen, which would preserve at least 12/17 or 70% of the treatment effect of ranibizumab monthly.
Selected Readings
1. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc. Ser. B 1995; 57:289-300. 2. Bland JM, Altman DG. Multiple significance tests: the Bonferroni method. BMJ. 1995; 310:170. 3. Goeman JJ, Solari A, Stijnen T. Three-sided hypothesis testing: simultaneous testing of superiority, equivalence and inferiority. Stat Med. 2010; 29:2117-2125. 4. United States Department of Health and Human Services. Food and Drug Administration. Guidance for Industry: Non-Inferiority Clinical Trials. Draft Guidance. March 2010. 5. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine: reporting of subgroup analyses in clinical trials. N Engl J Med. 2007; 357:2189-2194. 6. Weintraub WS. Cutting through the statistical fog: understanding and evaluating non-inferiority trials. Int J Clin Pract. 2010; 64:1359-1366.
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CATT: Year 2
Daniel F Martin MD
NoTeS
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IVAN: Year 1
Introduction
Ranibizumab has been evaluated in multiple trials1-2 whereas bevacizumab, originally developed to treat cancer and available earlier, has gained widespread acceptance for treating neovascular AMD but without marketing authorization.3-6 The Comparison of AMD Treatment Trials (CATT)7 studied monthly or as needed ranibizumab or bevacizumab (4 groups). CATT reported that distance visual acuity after 1 year was equivalent for the two drugs within each treatment regimen. Ranibizumab as needed and monthly were equivalent; the comparison between monthly and as needed bevacizumab was inconclusive. CATT found no evidence of differences by drug in the frequency of serious adverse events previously associated with anti-VEGF drugs. There were slightly more serious systemic adverse events in the bevacizumab groups. We report here the 1-year findings of the alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularization (IVAN) randomized trial, which also compares monthly or as needed ranibizumab or bevacizumab. IVAN is a multicenter, factorial, noninferiority randomized trial undertaken in the United Kingdom.
The primary outcome is BCVA at 2 years (follow-up is ongoing) with a planned interim analysis at 1 year. A target sample size of 600 patients was planned, giving 90% power to detect noninferiority (significance 2.5% one-sided). In total, IVAN has recruited and treated 610 patients. Secondary outcome measures include (1) contrast sensitivity, near visual acuity, and reading index, (2) lesion morphology and metrics from angiograms and OCTs, (3) cumulative resource use and costs, (4) EQ-5D (generic health-related quality of life), (5) serum VEGF levels, and (6) adverse events. All outcomes except for EQ-5D and serum VEGF were measured at baseline and at visits 3, 6, and 12. EQ-5D was measured at baseline and at visits 3 and 12, and serum VEGF was measured at baseline and at visits 1, 11, and 12. Adverse events were recorded at each visit. The primary safety outcome measure was the occurrence of an arteriothrombotic event or heart failure.
Results
One year after randomization, the comparison between bevacizumab and ranibizumab was inconclusive (bevacizumab minus ranibizumab -1.99 letters, 95% confidence interval (CI) -4.04 to 0.06). Discontinuous treatment was equivalent to continuous treatment (discontinuous minus continuous -0.35 letters, -2.40 to 1.70). Contrast sensitivity and reading index did not differ significantly between drugs or treatment regimens. Near visual acuity was 8% worse in the bevacizumab group (GMR = 0.92, 95% CI, 0.84 to 1.00, P = .058), but did not differ with treatment regimen. Foveal total thickness did not differ by drug but was 9% less with continuous treatment (geometric mean ratio [GMR] 0.91, 0.86 to 0.97, P = .005). Fewer participants receiving bevacizumab had arteriothrombotic events or heart failure (odds ratio 0.23, 0.05 to 1.07, P = .03). There was no difference between drugs in the proportion of patients experiencing serious systemic adverse events (odds ratio 1.35, 0.80 to 2.27, P = .25). Serum VEGF was lower with bevacizumab (GMR 0.47, 0.41 to 0.54, P< .0001) and higher with discontinuous treatment (GMR 1.23, 1.07 to 1.42, P = .004). Bevacizumab was less costly for both treatment regimens (P < .0001). The conclusions of the IVAN study for its 1-year preliminary results were that the comparison of visual acuity at 1 year between bevacizumab and ranibizumab was inconclusive and that visual acuities with continuous and discontinuous treatment were equivalent. Other outcomes were consistent with the drugs and treatment regimens, having similar efficacy and safety.
Study Design
IVAN participants were 50 years or more with untreated neovascular AMD in the study eye who read 25 letters on the ETDRS chart. Participants were randomized to ranibizumab or bevacizumab. A further randomization allocated participants to (continuous) or as needed (discontinuous) treatment regimen. All participants had monthly reviews. Diagnosis was confirmed by fluorescein angiography. IVAN differed from previous trials of neovascular AMD in that even in the absence of subfoveal neovascularization, patients could be enrolled as long as any component of the neovascular lesion such as subretinal fluid or serous pigment epithelial detachment was present under the geometric center of the fovea. To avoid including inactive or advanced disease, lesions comprising >50% fibrosis or blood were excluded. Only 1 eye was studied per patient. The participants were from 23 teaching and general hospitals in the NHS. As in CATT, the drug doses were 0.5-mg ranibizumab and 1.25-mg bevacizumab. All of the participants were treated at visits 0, 1, and 2. Participants randomized to the continuous regimen were treated monthly thereafter, while participants randomized to the discontinuous regimen were not retreated after visit 2, unless prespecified clinical and OCT criteria for active disease were met. If retreatment was needed, a further cycle of 3 doses delivered monthly was required. The retreatment criteria were any subretinal fluid, increasing intraretinal fluid, or fresh blood. If there was uncertainty about these criteria, and visual acuity had dropped by 10 letters, retreatment could be initiated. In the absence of fluid on OCT or visual acuity deterioration, fluorescein leakage >25% of the lesion circumference or expansion of choroidal neovascularization was required to initiate retreatment.
Discussion
One year after randomization in the IVAN trial, the visual acuity comparison by drug was inconclusive. The mean difference between the drugs was 2 letters in favor of ranibizumab, a small difference from a clinical perspective. The difference in visual acuity between continuous and discontinuous regimens was negligible, showing that the treatment regimens were equivalent.
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Although the GMR for near visual acuity appeared to favor ranibizumab, it was only 8% better; this difference is small (0.5 logMAR lines) and, as for distance acuity, is unlikely to be clinically meaningful. A meta-analysis of the IVAN and the CATT found no evidence of any difference in mortality between the drugs. However a statistically significant increase in serious adverse events in the bevacizumab arm compared to ranibizumab was found. The IVAN study also showed that serum VEGF decreased more with bevacizumab than ranibizumab. This finding implies that intravitreal drugs can egress into the circulation. The clinical importance of this finding is difficult to judge, given that other outcomes were similar for the two drugs and regimens. It is possible that the consequences of differential suppression of circulating VEGF will only become apparent after longer follow-up. Interestingly, in a separate presentation at the 2012 annual meeting of the Association for Research in Vision and Ophthalmology, the CATT investigators reported a trend toward a reduced rate of CNV in the fellow eyes of treated with bevacizumab vs. ranibizumab. This finding might relate to greater systemic suppression of VEGF in the bevacizumab-treated patients. If so, it is a helpful effect.
2. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1432-1444. 3. Arevalo JF, Fromow-Guerra J, Sanchez JG, et al; Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collaborative Retina Study Group at 12 months follow-up. Retina 2008; 28:1387-1394. 4. Schouten JS, La Heij EC, Webers CA, et al. A systematic review on the effect of bevacizumab in exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2009; 247:1-11. 5. Tufail A, Patel PJ, Egan C, et al; ABC Trial Investigators. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study [report online]. BMJ. 2010; 340:c2459. 6. Rich RM, Rosenfeld PJ, Puliafito CA, et al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular agerelated macular degeneration. Retina 2006; 26:495-511. 7. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011; 364:1897-1908. 8. Chakravarthy U, Harding SP, Harding SP; IVAN Study Investigators. Ranibizumab versus Bevacizumab to treat neovascular agerelated macular degeneration: one year findings. Ophthalmology 2012; 119(7):1399-1411.
References
1. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-1431.
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MANTA: Year 1
Twelve-Month Results Comparing Ranibizumab or Bevacizumab Treatment in Patients With Neovascular AMD: Multicenter Anti-VeGF Trial in Austria The Manta Study
Susanne Binder MD, Ilse Krebs MD, Leo Schmetterer PhD; for the Manta Study Group
Purpose
To report an observer- and subject-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular (NV) AMD.
Treatment
Three initial monthly injections with either 0.5-mg ranibizumab (Lucentis, Novartis) or 1.25-mg bevacizumab (Avastin, Genentech). Retreatment if VA loss a minimum of 5 letters, increase of central retinal thickness of more than 100 m (OCT), fresh intraor subretinal hemorrhage, new classic CNV, persistent intraretinal fluid (OCT+FA). The study was assigned and financed by the Austrian Ophthalmologic Society. It was organized by Susanne Binder MD and coordinated by Ilse Krebs MD at the Rudolf Foundation Hospital/Ludwig Boltzmann Institute for Retinology. Protocol, randomization, and monitoring were performed by Leo Schmetterer PhD at the department of clinical pharmacology. This PanAustrian study was conducted by the 10 largest eye departments or university eye clinics in Austria. Approval of local ethics committees was received in 2007.
Material and Methods

Noninferiority study based on the data of MARINA, ANCHOR, and FOCUS studies. 320 patients with NV AMD included and randomized to either bevacizumab or ranibizumab treatment.
Main Parameter of Interest

Change of best corrected distance visual acuity (BCDVA) after 1 year.
other Parameters
Number of eyes with BCDVA deterioration of 15 resp. 5 letters. Number of eyes with VA improvement of 0, 5, 15 letters, lesion size, retinal thickness, and adverse events.
Results
321 patients were randomized, 4 were excluded (1 had previous anti-VEGF treatment, 3 received the wrong drug), so that a total of 317 eyes were evaluated. Mean age, sex, baseline BCDVA, and central retinal thickness were comparable in both groups. BCDVA after 1 year was equivalent between bevacizumab (highest gain: 6.2 letters after 4 months and 4.9 letters after 12 months) and ranibizumab (highest gain: 5.8 letters after 3 months and 4.1 letters after 12 months). The 2 drugs were also not different when adjusted for age and baseline BCVA. Mean number of treatments was also similar: 5.8 in the ranibizumab group and 6.1 in the bevacizumab group. Adjusted retinal thickness measurements also showed similar reductions over 1 year (decrease of 89.9m for ranibizumab and 86.3m for bevacizumab, P = .81). Lesion size did decrease in both groups equally (P = .55). Serious adverse events were observed in 9.2% in the ranibizumab group and in 11.6% in the bevacizumab group. Also, the number of deaths (2 and 3, respectively), cardiac disorders, and gastrointestinal disorders were comparable. No serious ocular events (endophthalmitis, pseudoendophthalmitis ) occurred in either group.
examinations
Monthly examinations of BCDVA with ETDRS charts at 4 m, OCT, biomicroscopy of the anterior and posterior segment, and eye pressure. Fluorescein angiographic (FA) examinations at study entrance and after 12 months or when needed. Pregnancy test for women before menopause.
Inclusion Criteria
Age 50 years, presence of subfoveal choroidal neovascularization (CNV) related to AMD, active lesion, BCDVA/ ETDRS on the study eye 20/40-20/320.
exclusion Criteria
Nontreatment nave study eye, status post photodynamic therapy (PDT) or anti-VEGF therapy within 3 months on partner eye, subfoveal fibrosis or atrophy on study eye, pregnancy, presence of ophthalmic disease that makes treatment within 1 year necessary, presence of pigment epithelial rupture, general contraindications against anti-VEGF treatment, iodine allergy.
Conclusion
Bevacizumab was equivalent to ranibizumab at all time points for 1 year. Neither the total number nor the number of adverse events in any subgroup was significantly different.
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VIeW: Year 2
Intravitreal Aflibercept Injection vs. Ranibizumab for Neovascular AMD: 96-Week Results From the VIeW 1 and VIeW 2 Studies
Jeffrey S Heier MD for the VIEW 1 and VIEW 2 Investigators
Purpose
To evaluate the efficacy and safety of intravitreal aflibercept injection (IAI; also referred to as VEGF Trap-Eye) vs. ranibizumab up to 96 weeks of the Phase 3 VIEW-1 and VIEW-2 studies. over 2 years and 4.7, 4.1, 4.6, and 4.2 injections over the followup period after Week 52, for Rq4, IAI 2q4, IAI 0.5q4, and IAI 2q8, respectively. The proportion of patients who required frequent injections (6) in the follow-up period was lower in both the 2q4 and 2q8 groups compared with the Rq4 group (14.0% and 15.9% vs. 26.5%, respectively). In the 25% of patients who required the most intense therapy (greatest number of injections), 2q4 and 2q8 required an average of 1.5 and 1.4 fewer injections compared with Rq4 (6.5 and 6.6 vs. 8.0, respectively). The incidence of ocular and systemic adverse events was balanced across treatment groups. The most frequent ocular adverse events (>10% of patients) were conjunctival hemorrhage, eye pain, retinal hemorrhage, and VA reduced.
Methods
Patients in both studies were randomized to ranibizumab 0.5 mg every month (Rq4), IAI 2 mg every month (2q4), 0.5 mg every month (0.5q4), or 2 mg every 2 months (2q8) following 3 initial monthly doses over the first 52 weeks. From Weeks 52 to 96, patients were dosed at least quarterly with more frequent dosing allowed based on predetermined retreatment criteria. Week 96 outcomes included proportion of patients who maintained visual acuity (VA) (loss of <15 ETDRS letters) and mean change from baseline in best-corrected visual acuity (BCVA). Data from integrated analyses are reported here.
Conclusions
Visual improvements achieved at Week 52 were maintained through Week 96 with intravitreal aflibercept and ranibizumab injections. The original 2q8 aflibercept group achieved efficacy results that were similar to ranibizumab, but with an average of 5.3 fewer aflibercept injections over the 96-week period. Intravitreal aflibercept and ranibizumab had generally favorable safety profiles through Week 96.
Results
At Week 96, proportions of patients maintaining VA were 92%, 92%, 91%, and 92%, and BCVA gains were 7.9, 7.6, 6.6, and 7.6 letters, with averages of 16.5, 16.0, 16.2, and 11.2 injections
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HARBoR: Year 2
Brandon G Busbee MD
efficacy and Safety of 0.5-mg vs. 2.0-mg Ranibizumab in Patients With Wet AMD
I. Age-Related Macular Degeneration (AMD) A. AMD is the leading cause of blindness among individuals 50 years of age in the United States and many other parts of the developed world.1,2 B. Choroidal neovascularization (CNV), which is the hallmark of neovascular or wet AMD, is responsible for the majority of cases of severe vision loss caused by AMD.3 C. Increased expression of vascular endothelial growth factor A (VEGF-A) promotes the development of CNV lesions.4 D. Inhibition of VEGF-A has been shown to block intraocular neovascularization in vivo.5 E. Treatment with ranibizumab (Lucentis, Genentech, Inc.; South San Francisco, Calif., USA), a VEGF-A inhibitor, significantly improves visual acuity in patients with wet AMD.6-8 II. HARBOR Study A. HARBOR was a 24-month, Phase 3, randomized, multicenter, double-masked, dose-response study that evaluated the efficacy and safety of intravitreal 0.5-mg and 2.0-mg ranibizumab administered monthly and on an as-needed (p.r.n.) basis after 3 monthly loading doses in treatment-nave patients with subfoveal wet AMD. B. Patients 50 years of age (N = 1098) were randomized in a 1:1:1:1 ratio to 1 of 4 ranibizumab treatment groups: 0.5 mg monthly (n = 276), 0.5 mg p.r.n. (n = 275), 2.0 mg monthly (n = 274), and 2.0 mg p.r.n. (n = 273). C. The primary efficacy endpoint at Month 12 was the mean change from baseline in best-corrected visual acuity (BCVA). 1. Noninferiority (NI) tests with a prespecified NI margin of 4 letters comparing the 0.5 mg p.r.n. with the 0.5 mg monthly group and the 2.0 mg p.r.n. with the 0.5 mg monthly group were performed. 2. A superiority test assessed the differences between the 2.0 mg monthly and 0.5 mg monthly group. D. Key secondary endpoints at Month 12 included the mean number of ranibizumab injections, the mean change from baseline in central foveal thickness (CFT) over time, and the proportion of patients who gained 15 letters BCVA. 1. Similar secondary endpoints were measured at Month 24.
E. Endpoint analyses were performed using the lastobservation-carried-forward method to impute for missing data. F. Ocular and systemic safety events were also evaluated through Month 24. G. Efficacy outcomes 1. Primary endpoint comparisons a. NI comparisons of 0.5 mg and 2.0 mg p.r.n.to 0.5 mg monthly were not met using NI margin of 4 letters (see Figure 1, top). b. Superiority comparison of 2.0 mg monthly to 0.5 mg monthly was not met (see Figure 1, bottom). 2. Mean BCVA improvements were significant and clinically meaningful for all 4 treatment groups. a. At Month 12, mean change from baseline in BCVA for the 4 groups was (letters): +10.1 (0.5 mg monthly); +8.2 (0.5 mg p.r.n.); +9.2 (2.0 mg monthly); and +8.6 (2.0 mg p.r.n.) (see Figure 2, top). b. The proportion of patients who gained 15 letters from baseline at Month 12 was 34.5%, 30.2%, 36.1%, and 33.0%, respectively. 3. Key secondary VA and anatomic endpoint results were similar among the 4 treatment groups. a. Mean change from baseline in CFT at Month 12 was (m): -172.0, -161.2, -163.3, and -172.4, respectively (see Figure 2, bottom). 4. Mean number of injections was 7.7 (0.5 mg p.r.n.) and 6.9 (2.0 mg p.r.n.). H. Safety outcomes 1. Ocular and systemic safety profiles were consistent with previous ranibizumab trials in AMD and were comparable between groups. a. Serious ocular adverse events in the study eye were rare across all treatment groups. b. No ocular serious adverse events of increased IOP or glaucoma were reported. 2. No new safety events were identified. 3. No evident dose response or dose exposure relationship with respect to key non-ocular and ocular adverse events
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Figure 1. Mean change from baseline in BCVA at Month 12 using Hochberg-adjusted confidence intervals* (adjusted difference in mean change in BCVA compared against 0.5 mg monthly). *Prespecified in HARBOR statistical analysis plan. Adjusted for baseline BCVA score (54 letters, 55 letters) and choroidal neovascularization classification; the last-observationcarried-forward method was used to impute for missing data. Abbreviations: BCVA indicates best-corrected visual acuity; NI, noninferiority; PRN, as needed.
Figure 2. Mean change from baseline to Month 12 in BCVA (top) and CFT (bottom). Vertical bars are 1 standard error of the unadjusted mean. The last-observation-carriedforward method was used to impute for missing data. Abbreviations: BCVA indicates bestcorrected visual acuity; CFT, central foveal thickness (measured by spectral domain OCT); PRN, as needed.
III. Conclusions Although the 2.0-mg group did not meet the prespecified superiority comparison and the p.r.n. groups did not meet the prespecified noninferiority comparison, the HARBOR Study 1-year results demonstrated clinically meaningful visual improvement (+8.2 to +10.1 letters) and improved anatomic outcomes across all 4 treatment groups, with the p.r.n. groups requiring
approximately 4 fewer injections (6.9-7.7) than the monthly groups (11.2-11.3). No safety events were observed despite a 4-fold dose escalation in the study. The HARBOR 2-year efficacy and safety outcomes will be reported. These results will further elucidate the durability of ranibizumab on visual and anatomic outcomes in patients with wet AMD.
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References
1. Friedman DS, OColmain BJ, Munoz B, et al. Prevalence of agerelated macular degeneration in the United States. Arch Ophthalmol. 2004; 122:564-572. 2. Wong TY, Chakravarthy U, Klein R, et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology 2008; 115:116-126. 3. Bressler NM. Age-related macular degeneration is the leading cause of blindness. JAMA. 2004; 291:1900-1901. 4. Lopez PF, Sippy BD, Lambert HM, et al. Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1996; 37:855-868. 5. Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol. 2002; 120:338-346. 6. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1432-1444. 7. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthalmology 2009; 116:57-65 e5. 8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-1431.
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How Do I Incorporate What I Just Heard Into My Practice?

A Comparison of the Recent Comparison Studies: What Do the Studies Mean for Me?
Peter K Kaiser MD
CATT 2-Year Analysis
CATT primary outcome at Year 1 demonstrated that bevacizumab and ranibizumab were noninferior in terms of mean change in visual acuity when dosed monthly. Bevacizumab when dosed p.r.n. was not noninferior to the other drugs and dosing regimens. There was a difference in safety between these 2 antiVEGF agents that did not mirror previous anti-VEGF systemic adverse events. The re-randomization of the second year meant that the number of permutations were too many to reassess all the outcomes done at the primary outcome, so the results were pooled. Mean gain in vision acuity was similar for both agents, but significantly greater for the monthly dosing regimens compared to as-needed regimens. Patients switching from monthly to as-needed regimen for the same agents after 1 year had worse visual acuity results compared to patients who remained on a fixed monthly dosing scheme. Similar to the 1-year results, there were significantly more serious adverse events in the bevacizumab group at Year 2. The numbers of serious adverse events were small in both groups, and most were previously not associated with antiVEGF therapy. CATT was not powered to examine for differences in safety.
VIeW 2-Year Analysis

The VIEW studies were the Phase 3 studies of varying doses and dosing regimens of aflibercept compared to monthly ranibizumab. The 1-year primary outcome reported that all doses and dosing regimens were noninferior to monthly ranibizumab in terms of preventing moderate visual loss. In the second year of the study, patients were treated with the same dosing assignment but followed a apped as needed (p.r.n.) dosing regimen where patients were evaluated monthly to determine if treatment was needed and treated at least once every 12 weeks. At 2 years, the mean change in visual acuity from baseline was similar for the aflibercet 2-mg q8 regimen and the monthly ranibizumab regimen, though in all groups small decreases in BCVA were observed. There were no significant differences in the incidence of serious adverse events or ocular adverse events, with the most frequent events overall (>10%) being conjunctival hemorrhage, eye pain, retinal hemorrhage, and reduced visual acuity.
HARBoR 1-Year Primary outcome

The HARBOR (Ranibizumab Administered Monthly or on an As-Needed Basis in Patients with Subfoveal Neovascular AMD) Phase 4 study compared the standard dose of ranibizumab with a high-dose ranibizumab (2 mg) either monthly or as needed in patients with exudative AMD with a primary outcome at 1 year. The p.r.n. arm received 3 monthly injections at baseline before switching to as needed dosing as determined by spectral domain OCT (all the other studies have used time-domain OCT) It was a noninferiority study with the primary outcome set in discussion with the FDA as a mean change in visual acuity within 4 letters. All doses and regimens were not noninferior to monthly standard dose ranibizumab for the primary outcome All doses and regimens were similarly safe with no difference seen in serious adverse events.
IVAN 1-Year Interim Analysis

The primary outcome of IVAN is at 2 years, and it is a noninferiority study comparing bevacizumab and ranibizumab with a mean change of vision with 4 letters. Similar to CATT, IVAN also compared monthly and asneeded regimens for bevacizumab and ranibizumab; however, the p.r.n. dosing was different with patients having a 3-month loading dose at baseline and with any recurrent leakage getting a rebooster of 3 monthly injections. At 1 year, bevacizumab was not noninferior to ranibizumab in terms of mean change in visual acuity in the pooled analysis. Unlike CATT, there were no significant differences between the as-needed (discontinuous) and monthly (continuous) regimens in terms of mean change in visual acuity. Unlike CATT, there were no differences noted in the proportion of participants experiencing a serious systemic adverse event.
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Aspirin and AMD: What Should I Tell My Patients?

Emily Y Chew MD
Background
The association of aspirin use and AMD has been controversial. In 1988, there was a suggestion that patients with AMD taking aspirin experienced more hemorrhages.1 This was evaluated in the Macular Photocoagulation Study and there was no difference in the development of hemorrhage in patients consuming or not consuming aspirin.2 Other studies have resulted in inconsistent results.3-7 A recent report suggested that taking aspirin might be associated with the development of the advanced form of AMD.8 The authors have suggested that taking aspirin might cause AMD, and this should be re-examined. This has raised doubts on whether persons with risk for heart disease should be taking aspirin. It has been well-proven that aspirin use does decrease the risk of heart disease.
Results
AREDS and AREDS2 4188 AREDS2 participants who had complete data were analyzed. 2046 (48.8%) are taking aspirin at least 5 times per week and they tend to be older, male, with history of diabetes, hypertension, hypercholesterolemia, and cardiovascular disease. We grouped the participants with AREDS Simple Scale Score of 0, 1, and 2 together (n = 661) as the control group. We compared those with AREDS Simple Scale Score of 3 (bilateral large drusen or pigmentary change in one eye; n = 692), 4 (bilateral large drusen and bilateral pigmentary changes; n = 1369), and 5 (advanced AMD in one eye with bilateral large drusen and pigmentary changes; n = 1466) with the control group. 1304 had NV AMD and 162 had CGA. The multivariate model results, adjusting for potential risk factors, demonstrated statistically significant ORs that ranged from 0.71 to 0.84. No increased risk of advanced AMD with aspirin use was demonstrated. We evaluated 2673 AREDS participants with AMD at baseline. The risk factors for taking aspirin in this cohort were similar to those of AREDS2 participants. The multivariate model results also found a decreased risk of advanced AMD with aspirin intake (OR: 0.68 to 0.83). Data From the Randomized Controlled Clinical Trials of Aspirin While observational data from other studies have been inconsistent as to the association of aspirin use with AMD, there are 2 randomized controlled clinical trials of aspirin that evaluated the outcome of the development of AMD. These include the Womens Health Study9 and the Physicians Health Study.10 The importance of these 2 trials is that they offer a randomized comparison of the effects of aspirin, and these results may help to interpret the data, as observational data have confounding effects that are difficult to tease out. It is particularly difficult to separate out the confounding effects as risks of cardiovascular disease are associated advanced AMD and this the very population that has been recommended to take aspirin. In the Womens Health Study, the risk of developing AMD during the course of the study was relative risk 0.82 (95% CI, 0.64-1.06) and in the Physicians Health Study, the relative risk was 0.78 (95% CI, 0.46-1.32). The combined evaluation of these 2 studies resulted in a relative risk 0.82 (95% CI, 0.65-1.03). Although none of these findings were statistically significant, the relative risks are in the protective direction and certainly were not found to be harmful.
Purpose
To assess the association of aspirin use and AMD in the AgeRelated Eye Disease Study (AREDS) and AREDS2, and other randomized controlled clinical trials of aspirin. These studies include the Physicians Health Study and the Womens Health Study, that evaluated the development of AMD in the clinical trials.
Study Populations and Methods

We used the prevalence data of AMD at baseline of the AREDS participants to assess for its association with aspirin use. We also evaluated the baseline data of AREDS2 participants, again evaluating the association of the prevalence of AMD at baseline with aspirin use. Baseline and annual fundus photographs were obtained in both studies for the central grading of advanced AMD at the Fundus Photographic Reading Center at the University of Wisconsin in Madison, using the same standardized protocol. The severity of AMD was classified with the AREDS simple scale, ranging from no large drusen in either eye to advanced AMD in one eye. This scale was expanded in the most severe end to include the participants with advanced disease in one eye and further separated into either neovascular (NV) AMD or central geographic atrophy (CGA) associated with AMD. Aspirin use was assessed with a standardized questionnaire. Aspirin use was categorized as: (1) less than 5 times per week, (2) more than5 times per week with fewer than 2 tablets per day, or (3) more than 5 times per week with 2 or more tablets per day. Univariate analyses were performed adjusting for age and sex. Multivariable regression analyses were conducted adjusting for additional risk factors including smoking, cardiovascular disease, and other medications. Similar analyses were conducted using the prevalence data from the AREDS2 study. We assessed the association of varying severity of AMD with aspirin use with both variables obtained in the similar manner.
Conclusion
The observational AREDS and AREDS2 results demonstrate an inverse relationship between the various stages of AMD and aspirin use. Randomized controlled clinical trials of aspirin found a nonstatistically significant protective effect of aspirin use in the development of AMD reported by the participant and confirmed by the medical records. Future analyses of the incident
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advanced AMD in both AREDS and AREDS2 may provide further insight into this controversial area.
Message for Patients at Present

The totality of evidence from both the observational studies and the randomized controlled clinical trials of aspirin would suggest that there is no major harmful association of aspirin use with AMD. Persons affected with AMD should consider aspirin when medically indicated.
5. Kiernan DF, Hariprasad SM, Rusu IM, Mehta SV, Mieler WF, Jager RD. Epidemiology of the association between anticoagulants and intraocular hemorrhage in patients with neovascular agerelated macular degeneration. Retina 2010; 30:1573-1578. 6. Douglas IJ, Cook C, Chakravarthy U, Hubbard R, Fletcher AE, Smeeth L. A case-control study of drug risk factors for age-related macular degeneration. Ophthalmology 2007; 114;1164-1169. 7. Klein R, Klein BE, Jensen SC, et al. Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol. 2001; 119:1354-1359. 8. de Jong PTVM, Chakravarthy U, Rahu M, et al. Associations between aspirin use and aging macular disorder: the European Eye Study. Ophthalmology 2011; 119(1):112-118. 9. Christen WG, Glynn RJ, Chew EY, Buring JE. Low-dose aspirin and medical record-confirmed age-related macular degeneration in a randomized trial of women. Ophthalmology 2009; 116(12):23862392. 10. Christen WG, Glynn RJ, Ajani UA, Schaumberg DA, Chew EY, Buring JE, Manson JE, Hennekens CH. Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Ophthalmology 2009; 116(12):2386-2392.
References
1. Kingham JD, Chen MC, Levy MH. Macular hemorrhage in the aging eye: the effects of anticoagulants. New Engl J Med. 1988; 318(7):1126-1127. 2. Klein ML. Macular degeneration: Is aspirin a risk for progressive disease? JAMA. 1991; 266(16):2279. 3. Tilanus MA, Vaandrager W, Cuypers MH, Verbeek AM, Hoyng CB. Relationship between anticoagulant medication and massive intraocular hemorrhage in age-related macular degeneration. Graefes Arch Ophthalmol. 2000; 238;482-485. 4. Wilson HL, Schwartz DM, Bhatt HR, McCulloch CE, Duncan J. Statin and aspirn therapy are associated with decreased rates of choroidal neovascularization among patients with age-related macular degeneration. Am J Ophthalmol. 2004; 137:615-624.
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Radiation for CNV: CABeRNeT/ MeRITAGe/ INTRePID

Radiation is known to preferentially damage proliferating cells, and it therefore has the potential to target the proliferating fibroblasts, inflammatory cells, and endothelial cells that cause vision loss in wet AMD. Early studies, conducted in the 1990s, were somewhat equivocal, but interest has been rekindled following the development of two devices designed specifically for the treatment of wet AMD. The first device uses an endoscopic surgical probe containing a strontium-90 source. Following pars plana vitrectomy, the probe is held over the AMD lesions for approximately 4 minutes, to deliver 24 Gray of epimacular brachytherapy (EMB). Initial results in treatment-naive eyes were impressive, with good visual outcomes and a greatly reduced demand for anti-VEGF therapy. Unfortunately these results were not replicated in a large (N = 494), randomized, controlled trial (CABERNET) that failed to show noninferiority of vision loss. For this reason, studies were initiated to recruit previously treated disease, to determine if EMB has a role as a second-line agent. The MERITAGE study recruited 53 patients with chronic, active wet AMD. Vision tended to decline over time, but the rate of decline was less than prior to EMB, and demand for anti-VEGF therapy appeared to decline. Based on these findings, a large (N = 363), investigatorinitiated, randomized, controlled trial of previously treated disease (MERLOT) was commenced, with results expected early in 2013. The second technique, stereotactic radiotherapy (SRT), uses a robotically controlled device that utilizes low-voltage x-rays to generate 3 sequential, collimated beams of radiation that pass through the inferior sclera and overlap at the macula. It does not require patients to undergo vitrectomy. Preliminary results in a small study of both treatment-naive and previously treated disease were positive, with substantial vision gain and low demand for anti-VEGF therapy. More recently, a Phase 2, dose-ranging, double-masked, randomized, controlled trial (INTREPID) of 230 previously treated patients reported that it met its primary endpoint, namely, a significant reduction in demand for antiVEGF therapy. There were no significant safety concerns, and although the trial was not designed to determine whether vision was the same as or different than with anti-VEGF monotherapy, the results were generally encouraging. Both EMB and SRT have advantages and disadvantages relative to the other, but two differences are key. The first relates to vitrectomy. Vitrectomy may increase vitreous oxygen levels (reducing VEGF), relieve any vitreomacular traction, and enhance generation of the oxygen radicals that mediate the therapeutic effect of radiation. Conversely, vitrectomy induces cataract, costs money, carries surgical risk, and reduces the half-life of anti-VEGF agents. The second main difference relates to the dose delivery profile. With EMB, the dose of radiation received at the retina reduces exponentially with increasing distance from the radiation source. This has the advantage of minimizing radiation exposure to neighboring tissue, but it means that the probe has to be very carefully placed, and if this does not occur then the most active lesion components may receive a subtherapeutic dose of radiation. By contrast, SRT delivers roughly the same dose throughout the treatment zone. This may mean more healthy macular tissue is treated than is necessary, but it ensures that the whole lesion receives the full dose, and it is not dependent on correct probe positioning. In summary, there is a strong scientific argument supporting the use of radiation to treat wet AMD, but the clinical data point in different directions. At present it may be too early to conclude if, or how, radiation should be delivered as a treatment for wet AMD.
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Polypoidal Vasculopathy: Anti-VeGF, Photodynamic Therapy, and Steroids

Timothy YY Lai MD FRCOphth FRCS
I. Basics of Polypoidal Choroidal Vasculopathy (PCV) A. Clinical features of PCV 1. Choroidal abnormality characterized by branching choroidal vascular network (BVN) with surrounding aneurysmal dilatation (polyps) leading to recurrent serous leakage and hemorrhage 2. Considered as a variant of neovascular AMD 3. Polyps may be visible as reddish-orange structures beneath retina. 4. Associated with exudative or hemorrhagic pigment epithelial detachments (PED), subretinal hemorrhage, subretinal exudates, and serous retinal detachment 5. Location of polyps can be subfoveal, juxtafoveal, extrafoveal, or peripapillary. B. Epidemiology of PCV 1. Occurs in middle aged to elderly populations 2. Higher prevalence in Asians and blacks (around 30%-50% of Asians presenting as neovascular AMD), lower in whites C. Investigations for PCV 1. Indocyanine green angiography (ICGA) a. Essential in the diagnosis of PCV b. ICGA demonstrates single or multiple vascular aneurismal dilatation/ polyps arising from inner choroidal vessels in early phase with late hypofluorescence. c. Branching vascular networks might be seen occasionally. 2. Fluorescence angiography (FA) a. Can mimic occult CNV 3. OCT a. Polypoidal lesion can be seen as anterior protrusions of RPE with low-moderate reflectivity beneath the RPE line. Polyps may appear as dome-shaped elevations of the highly reflective RPE layers. b. Useful for detection of shallow subretinal fluid and monitor treatment response II. Natural Course of PCV A. 50% of the patients had a favorable course. The polyps may regress spontaneously. B. 50% had repeated bleeding and leakage, resulting in macular degeneration and visual loss. C. Poor outcome without treatment, therefore treatment indicated in symptomatic PCV. III. Photodynamic Therapy (PDT) for PCV A. One of the most widely described treatment modalities in the literature B. PDT laser spot size is determined by the greatest linear dimension of the lesion (polyps with any interconnecting network) based on ICGA. C. Most studies on PDT for PCV reported short- to mid-term (6-12 months) results with stable or improved vision and regression of polyps in 80% to 95% of eyes. D. Limited data on long-term results of PDT for PCV in the literature suggesting high recurrence rate of up to 64% after 2 years E. Need to follow up patients after PDT for the long term due to recurrence of PCV F. Complications of PDT: post-PDT hemorrhage (9% to 31%); massive suprachoroidal hemorrhage; RPE tear; microrips of RPE IV. Anti-VEGF Therapy for PCV A. Increased vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) expressions found in excised PCV specimens and elevated VEGF levels in aqueous humor of PCV patients. Therefore anti-VEGF therapy might be useful in the treatment of PCV. B. Studies found anti-VEGF therapy may reduce subretinal fluid and causes stabilization of vision. However, polypoidal lesions persisted after treatment. C. Patients presenting as neovascular AMD with treatment refractory to anti-VEGF therapy may be suggestive of PCV. ICGA should be performed in these cases to exclude PCV. V. Combined PDT + Anti-VEGF Therapy A. Rationale of combined therapy 1. Upregulation of VEGF level may occur after PDT, and VEGF promotes angiogenesis and may be associated with increased risk of secondary CNV and recurrence of PCV. 2. PDT to cause thrombosis of the polypoidal lesions and anti-VEGF therapy to treat the CNVlike branching vascular network and to reduce the amount of exudation caused by PCV. 3. Anti-VEGF may also be useful to counteract the upregulation of VEGF following PDT.
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Section VIII: Neovascular AMD B. Efficacy of combination therapy 1. More effective than anti-VEGF monotherapy in resulting polypoidal regression on ICGA 2. Combined PDT and bevacizumab had faster visual recovery compared with patients who had PDT monotherapy. 3. EVEREST study: Phase 3, double-masked, multicentered, randomized, controlled trial on ranibizumab vs. PDT vs. combined therapy: combination therapy or verteporfin PDT resulted in significantly higher proportion having complete regression of polyps on ICGA than ranibizumab alone at 6 months (77.8% vs. 71.4% vs. 28.6%, respectively). VI. Intravitreal or Subtenon Triamcinolone Acetonide A. Small series described the use of subtenon triamcinolone injection; resulted in reduction in size of polyp with reduction of serous macular detachment in some PCV cases. B. Comparative study showed no significant difference in visual outcome between PDT vs. PDT + intravitreal triamcinolone acetonide. VII. Overall Management Strategy (see Figure 1) A. ICGA is essential in the diagnosis of PCV and should be performed in cases suspected of having PCV. B. If the symptomatic polyps and branching vascular network are located a safe distance away from the fovea, direct thermal laser photocoagulation can be considered. C. For symptomatic polyps involving the juxtafoveal or subfoveal area, verteporfin PDT with or without anti-VEGF agents should be considered.
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D. Following treatment, patients should receive regular follow-up with FA, ICGA, and OCT in order to determine the need for retreatment. E. In cases with symptomatic exudation alone without evidence of polyps on angiography, anti-VEGF monotherapy might be considered. F. PCV with massive subretinal hemorrhage >4 disc areas and presented within 10 to 14 days of onset, pneumatic displacement of subretinal hemorrhage can be performed for treatment and subsequent angiography. Verteporfin PDT with or without antiVEGF can then be performed in cases with visible polyps after gas displacement.
Selected Readings
1. Chan WM, Lam DS, Lai TY, et al. Photodynamic therapy with verteporfin for symptomatic polypoidal choroidal vasculopathy: one-year results of a prospective case series. Ophthalmology 2004; 111:1576-1584. 2. Chan WM, Liu DT, Lai TY, et al. Extensive submacular haemorrhage in polypoidal choroidal vasculopathy managed by sequential gas displacement and photodynamic therapy: a pilot study of oneyear follow up. Clin Experiment Ophthalmol. 2005; 33:611-618. 3. Cho M, Barbarzetto IA, Freund KB. Refractory neovascular agerelated macular degeneration secondary to polypoidal choroidal vasculopathy. Am J Ophthalmol. 2009; 148:70-78. 4. Gomi F, Tano Y. Polypoidal choroidal vasculopathy and treatments. Curr Opin Ophthalmol. 2008; 19:208-212. 5. Gomi F, Sawa M, Sakaguchi H, et al. Efficacy of intravitreal bevacizumab for polypoidal choroidal vasculopathy. Br J Ophthalmol. 2008; 92:70-73. 6. Gomi F, Sawa M, Wakabayashi T, et al. Efficacy of intravitreal bevacizumab combined with photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2010; 150:48-54.
Figure 1. Management strategy for symptomatic polypoidal choroidal vasculopathy.
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7. Hirami Y, Tsujikawa A, Otani A, et al. Hemorrhagic complications after photodynamic therapy for polypoidal choroidal vasculopathy. Retina 2007; 27:335-341. 8. Koh A, Lee WK, Chen LJ, et al. EVEREST Study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina Epub ahead of print 21 Mar 2012. 9. Kokame GT, Yeung L, Lai JC. Continuous anti-VEGF treatment with ranibizumab for polypoidal choroidal vasculopathy: 6-month results. Br J Ophthalmol. 2010; 94:297-301. 10. Lai TY, Chan WM. An update in laser and pharmaceutical treatment for polypoidal choroidal vasculopathy. Asia-Pac J Ophthalmol. 2012; 1:97-104. 11. Lai TY, Chan WM, Liu DT, et al. Intravitreal bevacizumab (Avastin) with or without photodynamic therapy for the treatment of polypoidal choroidal vasculopathy. Br J Ophthalmol. 2008; 92:661666. 12. Lai TY, Lam CP, Luk FO, et al. Photodynamic therapy with or without triamcinolone acetonide for symptomatic polypoidal choroidal vasculopathy. J Ocul Pharamcol Ther. 2010; 26:91-95. 13. Lai TY, Lee GK, Luk FO, Lam DS. Intravitreal ranibizumab with or without photodynamic therapy for the treatment of symptomatic polypoidal choroidal vasculopathy. Retina 2011; 31:1581-1588. 14. Lee WK, Lee PY, Lee SK. Photodynamic therapy for polypoidal choroidal vasculopathy: vaso-occlusive effect on the branching vascular network and origin of recurrence. Jpn J Ophthalmol. 2008; 52:108-115.
15. Mauget-Faysse M, Quaranta-El Maftouhi M, De La Marnierre E, Leys A. Photodynamic therapy with verteporfin in the treatment of exudative idiopathic polypoidal choroidal vasculopathy. Eur J Ophthalmol. 2006; 16:695-704. 16. Okubo A, Ito M, Kamisasanuki T, Sakamoto T. Visual improvement following trans-Tenons retrobulbar triamcinolone acetonide infusion for polypoidalchoroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol. 2005; 243:837-839. 17. Ruamviboonsuk P, Tadarati M, et al. Photodynamic therapy combined with ranibizumab for polypoidal choroidal vasculopathy: results of a 1-year preliminary study. Br J Ophthalmol. 2010; 94:1045-1051. 18. Spaide RF, Donsoff I, Lam DL, et al. Treatment of polypoidal choroidal vasculopathy with photodynamic therapy. Retina 2002; 22:529-535. 19. Stangos AN, Gandhi JS, Nair-Sahni J, et al. Polypoidal choroidal vasculopathy masquerading as neovascular age-related macular degeneration refractory to ranibizumab. Am J Ophthalmol. 2011; 150:666-673. 20. Tsuchiya D, Yamamoto T, Kawasaki R, Yamashita H. Two-year visual outcomes after photodynamic therapy in age-related macular degeneration patients with or without polypoidal choroidal vasculopathy lesions. Retina 2009; 29:960-965. 21. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidal vasculopathy: natural history. Am J Ophthalmol. 2002; 133:639-648.
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Anti-Platelet Derived Growth Factor: Where Do We Stand?

Pravin U Dugel MD
NoTeS
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Long-term Delivery Strategies for Neovascular AMD

David S Boyer MD
I. The Need for Ocular Drug Delivery A. Chronicity of back of the eye diseases B. Frequency of intraocular injections, particularly biologics II. Requirements A. Drug safety, short and long term B. Drug must be able to reach the target tissue with therapeutic level. C. Easy and safe to place III. Eyedrops A. Rapid elimination, 5-6 minutes B. 1%-3% reach the intraocular tissues C. Most lost in nasolacrimal system D. Compliance IV. Intravitreal Implants A. Nondissolvable 1. Durasert Technology: Drug core surrounded by polymer layers (Retisert, Vitrasert, Iluvien). Difficult to use with proteins. 2. SurModics uses I-vation technology. 3. Neurotech Pharmaceuticals, Encapsulated Technology: Device implanted surgically in the vitreous containing human retinal pigment epithelial cells. Cells can be modified to produce antiVEGF or platelet derived growth factor. B. Dissolvable: Ozurdex V. Subretinal or Subchoroidal Delivery I-Science: Hollow microcatheter cannulation drug delivery in the suprachoroidal space VI. Microelectromechanical System Electrically controlled device with a reservoir, cannula, and electrolysis pump. VII. The Port Delivery System: Background A. Developed by ForSight Vision4 B. Phase I study completed 1. 20 patients with wet AMD, 12 months follow-up 2. The Port Delivery System delivering ranibizumab
C. The Port Delivery System technology 1. A refillable durable implant 2. Provides sustained intravitreal drug release 3. Compatible with large and small molecule drugs 4. Surgically placed through the pars plana a. 15-minute procedure b. No scleral sutures required 5. Refillable in a clinic-based injection procedure a. Proprietary refill system b. Target refill frequency every 4-6 months 6. The Port Delivery System (PDS) in development a. ForSight Vision4 partnership with Genentech for the development of the PDS with ranibizumab b. Development efforts with other molecules are under way.
Selected Readings
1. Olsen TW. Drug delivery to the suprachoroidal space. Retina 2006: Emerging New Concepts (Abstracts of 2006 American Academy of Ophthalmology Subspecialty Day). San Francisco: American Academy of Ophthalmology; 2006. 2. Edelhauser HF, Boatright JH, Nickerson JM, and the third ARVO/ Pfizer Research Institute Working Group. Drug delivery to posterior intraocular tissues: third annual ARVO/Pfizer ophthalmics research institute conference. Invest Ophthalmol Vis Sci. 2008; 49: 4712-4720. 3. Lee SS, Robinson MR. Novel drug delivery systems for retinal disease. Ophthamic Res. 2009; 41124-41135. 4. Saati S, Lo R, Li PY, et al. Surgical methods to place a novel refillable ocular microelectromechanical system (MEMS) drug delivery device. Invest Ophthalmol Vis Sci. 2007;48: E-Abstract 5791. 5. Duvvuri S, Majumadar S, Mitra AK. Drug delivery to the retina: challenges and opportunities. Expert Opin Biol Ther. 2003; 3(1):45-56.
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Whats Next in the Neovascular AMD Pipeline?

Jason S Slakter MD
Introduction
The treatment of CNV secondary to AMD began with the advent of thermal laser photocoagulation in the early 1980s. Almost 20 years later, photodynamic therapy with verteporfin was approved by the USFDA for the treatment of predominantly classic CNV. Clinical studies demonstrated that PDT had the capability to reduce vision loss compared to no treatment, with stabilization of vision achieved after approximately 6 months. Attempts at combination therapy utilizing photodynamic therapy in conjunction with intraocular injection of triamcinolone as well as other agents has demonstrated some evidence for reduced need for intervention and improvement in vision outcomes in some studies. Randomized clinical trial results of combination PDT + anti-VEGF drugs have yielded minimal benefits to date except in cases with polypoidal type CNV. The advent of antiangiogenic drugs, particularly antivascular endothelial growth factor (VEGF) agents, began with the approval of pegaptanib sodium in December of 2004. Pegaptanib, a selective blocker of VEGF-165, has demonstrated the ability to slow the rate of vision loss, but it did not show significant improvement in vision in a majority of patients. The introduction of ranibizumab changed the paradigm for CNV treatment. Randomized controlled clinical trials showed that monthly ranibizumab treatment resulted in stabilization of vision in more than 90% of patients, as well as improvement in vision of a significant nature in about a third of all patients treated. The off-label use of bevacizumab offered another therapeutic approach with an anti-VEGF treatment similar to ranibizumab. More than 50% of physicians in the United States currently use bevacizumab for the treatment of CNV due to AMD. A largescale comparative clinical trial, the CATT trial, demonstrated that the 2-year outcomes of therapy with these 2 agents were similar in the study groups receiving monthly treatments. Just 1 year ago, aflibercept was approved for treatment of exudative AMD as well. Aflibercept is a fusion protein that combines features of 2 different VEGF receptor sites, thus allowing a higher binding affinity than the anti-VEGF drugs previously in clinical use. This molecule has demonstrated effectiveness in improving visual acuity and reducing CNV size and OCT thickness in 2 large Phase 3 clinical trials in a direct head-to-head comparison with ranibizumab and may provide for longer duration of effect.
emerging Therapies
The main driver of the neovascular process in AMD is thought to be VEGF. The process by which VEGF is generated and acts upon vascular endothelial cells to stimulate blood vessel growth is a complicated cascade of events. Each of these steps offers the possibility of therapeutic intervention. Activation of this cascade may occur through hypoxia, exposure to certain growth factors, or other inciting stimuli. Multiple molecular interactions then occur, which result in the production of VEGF. One of these key steps in the cascade leading to generation of VEGF involves a molecule known as mTOR, the mammalian target of rapamycin.
This is a protein kinase that regulates cell proliferation, motility, survival, and protein synthesis. It leads to the activation of hypoxia inducible factors (HIF1-alpha, in particular), which results in the activation of a number of genes, including those that produce VEGF. A number of agents are being developed to target this portion of the cascade, one of which is sirolimus, which targets mTOR1. Sirolimus (rapamycin) has demonstrated preclinical evidence of anti-inflammatory, antiangiogenic and antifibrotic activity. Phase 1 testing has demonstrated evidence of potential affects in AMD through both subconjunctival and intravitreal delivery approaches. Phase 2 trials have been conducted, but at this time there is no plan to move this molecule forward in AMD. Another molecule, everolimus, or RAD001, is a derivative of rapamycin and works similarly to rapamycin as an mTOR inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants, and research into its ophthalmic application has been considered. A nonsteroidal small molecule that inhibits both TORC1 and TORC2 complexes of mTOR, Palomid 529, inhibits the PI3-K/Akt/mTOR transduction pathway. Palomid 529 is in Phase 1 clinical trials for patients with advanced neovascular AMD, with plans for further studies if the data are positive. REDD1 is another molecule in the cascade leading to VEGF production acting through the mTOR/HIF1 pathway. RTP801i-14, now known as PF-4523665, is a small interfering RNA that has been developed to target the REDD1 molecule to suppress VEGF production as well as inhibit angiogenesis. Results from a Phase 1/2 trial showed that PF-4523655, delivered intravitreally, was safe and well tolerated in patients with exudative AMD. Further development of this molecule for AMD is in doubt, but the information learned from studying this drug has led to the consideration of other molecules. Preclinical evaluation of another small interfering RNA drug that is specifically targeted toward HIF1 is under way, with plans for bringing it to clinical stage evaluation. Once VEGF is generated, the task shifts to directly targeting the VEGF molecule or inhibiting its effects on angiogenesis and permeability. In addition to drugs already in use today to directly block/bind VEGF (pegaptanib, ranibizumab, bevacizumab, and aflibercept), another molecule, KH902, is in clinical development for AMD. KH902 is a recombinant human VEGF receptor-Fc fusion protein that has been studied in a phase 1 trial of patients with CNV secondary to neovascular AMD. Injections of KH902 ranging from 0.05 mg to 3.0 mg were found to be safe and tolerable, with measurable reduction in exudation noted. A Phase 1b study designed to assess the efficacy and safety of multiple intravitreal injections of KH902 at variable dosing regimens in patients with CNV due to AMD is ongoing. A new, novel approach to VEGF binding and inhibition involves one of the most potent naturally occurring VEGF bindersVEGF receptor Flt-1. Preclinical trials have shown that adeno-associated virus serotype 2 (AAV2)-mediated intravitreal gene delivery of sFLT01 efficiently inhibits angiogenesis in the mouse oxygen-induced retinopathy model. There was no toxicity upon persistent ocular expression of sFLT01 for up to 12 months
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following intravitreal AAV2-based delivery in the rodent eye, suggesting that AAV2-mediated intravitreal gene delivery may prove to be an option for future therapy. An ongoing dose escalation study using this technology is under way. In addition to attempting to stop the production of VEGF, or block VEGF directly, other molecules are targeting the receptor site for VEGF binding and endothelial cell activation. One molecule is a small interfering RNA directed against the VEGF receptor 1 that has undergone initial Phase 1 testing for AMD. Another potential target at this level of the cascade is a family of transmembrane proteins known as integrins. These have the role in signaling and modulating downstream activities. Several agents have been studied that target the integrins as a means of controlling neovascularization in AMD. One drug, JSM6427, is a potent, highly specific integrin 51-antagonist that has undergone Phase 1 trials involving single and multiple injections for patients with CNV. One advantage of this molecule is that it may not only inhibit VEGF but may also inhibit the effects of other growth factors and cytokines leading to angiogenesis, inflammation, and fibrosis. Another integrin antagonist is volociximab, a high-affinity monoclonal antibody that binds to 51 integrin and blocks the binding of 51 integrin to fibronectin, thereby inhibiting a pivotal interaction required for angiogenesis. Volociximab administration has resulted in strong inhibition of rabbit and primate retinal neovascularization and laser-induced CNV in cynomolgus monkeys. A Phase 1 study of volociximab, in combination with ranibizumab in patients with wet AMD, was completed, but further testing of the drug is under discussion. A new integrin agent, ALG-1001, is a peptide that inhibits cell adhesion in vitro and arrests aberrant blood vessel growth in vivo, both systemically as well as in the eye. In vitro testing has shown that the compound inhibits cell adhesion meditated by 51, v3, v5, and 21 integrins. Integrins 51, v3, and v5 are implicated in the angiogenic process and are known to be expressed in neovascular ocular tissue from patients with wet macular degeneration and diabetic retinopathy. Ophthalmic preclinical safety studies of ALG-1001 in rabbits and mice with both a single injection as well as repeated multiple injections have shown excellent initial safety and efficacy profiles. Additionally, the compound demonstrated a statistically significant reduction in neovascularization in an AMD mouse model. A Phase 1 Human Safety Study focused on diabetic macular edema patients who are end stage and refractory to current treatment options was completed, and a Phase1/2a study for CNV in AMD is under way. Once VEGF binds to its receptors, it initiates a series of events mediated by molecules known as tyrosine kinases that translate the activation of the VEGF receptor into the activities that we recognize as part of the angiogenic process: blood vessel growth and leakage. Kinase inhibitors block this signal from reaching the intended targets within the cell, thereby preventing the cell from responding to the stimulus. A number of molecules, which can be administered topically, orally, as well as into and around the eye, are currently under clinical investigation in an attempt to control this part of the angiogenic process. One such molecule is pazopanib, a kinase inhibitor that targets multiple VEGF family members. Pazopanib blocks VEGF receptors 1, 2, and 3 and also has substantial activity directed against PDGFR, c-Kit, and fibroblast growth factor receptor 1, among others. By blocking all these different receptors it is hoped that the pericytes and endothelial cells that make up the CNV membrane can be destroyed, thus
potentially not only halting new vessel development but also inducing regression of CNV. A Phase 2a study of 70 patients demonstrated a mean 4.3 letter increase in visual acuity after treatment with pazopanib administered topically. Interestingly, patients with the CFH TT genotype (the naturally occurring wild type gene) exhibited the best visual and anatomic response. Additional trials are under way. A study of systemically administered pazopanib also showed similar effects with the response related to their genetic status. Phase 3 trials are planned. Another tyrosine kinase inhibitor, AL39324, which is administered intravitreally, is being studied in a Phase 2 clinical trial, comparing combined use with ranibizumab vs. ranibizumab alone for exudative AMD. In spite of its central role in angiogenesis, VEGF is not alone in stimulating and sustaining neovascularization in AMD. Therefore, other approaches to controlling CNV are being explored outside the VEGF cascade. For example, fosbretabulin (combrestatin A4 phosphate) is a novel antivascular agent that appears to act on abnormal vascular structures through its effects on endothelial cells. The biologically active metabolite CA4 binds to tubulin and inhibits microtubule assembly, leading to occlusion of vascular lumen and cessation of blood flow in the effected vessels. It has undergone Phase 2 testing with intravenous administration in patients with the polypoidal variant of AMD seen commonly in Asia, and further evaluation is being considered. Another tubulin inhibitor, OX-10X, is a highly lipid-soluble, low molecular weight quinazolinone that can achieve therapeutic concentration in the retina and choroid with topical application. OX-10X has shown the ability to inhibit CNV growth in animal models with both topical and intraocular administration. S1P is an extracellular signaling and regulatory molecule implicated as one of the earliest responses to stress, promoting cellular proliferation, migration, and activating survival pathways. Several lines of evidence suggest that S1P and S1Ps complement of receptors play a major regulatory role in the neovascularization, fibrosis, and inflammation related to AMD. Sonepcizumab (LT1009) is a humanized and optimized monoclonal antibody specifically targeted against S1P and can bind S1P at physiologically relevant concentrations. A Phase 1 multicenter, dose-escalation study of LT1009 administered as a single intravitreal injection in patients with exudative demonstrated an effect in some patients with occult CNV who had retinal pigment epithelium (RPE) detachments. Phase 2 testing of the drug is under way. A number of endogenous physiological inhibitors of angiogenesis have been identified, one of which is pigment epithelium derived factor (PEDF). PEDF is normally produced in the eye and is known to regulate or control normal blood vessel growth and protect photoreceptors, as well as inhibiting endothelial cell migration in vitro. It has been found to be significantly decreased in eyes with AMD. Adenoviral-mediated intraocular delivery of PEDF reduces CNV formation. Ad-PEDF is an intravitreally or periocularly injected transgene that uses a viral vector to deliver the PEDF gene, resulting in the local production of PEDF in the treated eye. A Phase 1 dose-escalation study of this agent in eyes with CNV secondary to AMD showed no significant adverse effects. Another focus of treatment for macular degeneration involves an attempt to modulate the complement system. Complement is part of the innate immune system with multiple activation pathways and a complex cascade of molecular interactions, within which exists a series of endogenous proteins that act to inhibit excessive activation and protect host cells. An ever-growing list
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of genetic studies along with histopathologic studies of drusen and experimental CNV have shown that aberrations in the complement pathway may lead to over-activation of inflammation at the level of the RPE and choroid leading the development of all stages of AMD. Several drugs are currently under development in an attempt to control the complement pathway and potentially modulate the development of AMD, not only in its more advanced stages but perhaps even as early as the development of drusen themselves. An aptamer directed against complement factor C5 is currently undergoing Phase 1 testing in an ascending multiple-dose study, delivered intravitreally in combination with ranibizumab in patients with exudative AMD. Another agent, POT-4, which is a small molecule derivative of compstatin, is directed against complement factor C3. This drug has completed Phase 1 testing in patients with exudative AMD with an excellent safety profile. The Phase 1 study demonstrated that some patients exhibited a reduction in exudation following a single drug injection. A Phase 2 study has been completed as well. Another approach to dealing with neovascularization associated with AMD is to eliminate vitreoretinal traction that may contribute to the exudative process. AL-78898A is being evaluated in a study that will evaluate the safety and efficacy of intravitreal injection of this vitreolytic agent in subjects diagnosed with exudative AMD with focal vitreomacular adhesion.
lar age-related macular degeneration: two year results. Ophthalmology 2012; 119(7):1388-1398. 7. Ohr M, Kaiser PK. Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration. Expert Opin Pharmacother. 2012; 13(4):585-591. 8. Dejneki NS, Kuroki AM, Fosnot J, et al. Systemic rapamycin inhibits retinal and choroidal neovascularization in mice. Mol Vis. 2004; 10:964-972. 9. Shoshani T, Faerman A, Mett I, et al. Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol. 2002; 22(7):2283-2293. 10. Nguyen QD, Shah SM, Hafiz G, et al.; CLEAR-AMD 1 Study Group. A phase I trial of an IV-administered vascular endothelial growth factor trap for treatment in patients with choroidal neovascularization due to age-related macular degeneration. Ophthalmology 2006; 113(9):1522.e1-1522.e14. 11. Lai CM, Shen WY, Brankov M, et al. Long-term evaluation of AAV-mediated sFlt-1 gene therapy for ocular neovascularization in mice and monkeys. Mol Ther. 2005; 12(4):659-668. 12. Maclachlan TK, Lukason M, Collins M, et al. Preclinical safety evaluation of AAV2-sFLT01- a gene therapy for age-related macular degeneration. Mol Ther. 2011; 19(2):326-334. 13. Shen J, Samuel R, Silva RL, et al. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Ther. 2006; 13(3):225-234. 14. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nature Rev Cancer. 2008; 8(8):604617. 15. Umeda N, Shu Kachi S, Akiyama H, et al. Suppression and regression of choroidal neovascularization by systemic administration of an 51 integrin antagonist. Mol Pharmacol. 2006; 69(6):18201828. 16. Raz-Prag D, Zeng Y, Sieving PA, Bush RA. Photoreceptor protection by adeno-associated virus-mediated LEDGF expression in the RCS rat model of retinal degeneration: probing the mechanism. Invest Ophthalmol Vis Sci. 2009; 50:3897-3906. 17. Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007; 6:2012-2021. 18. Nambu H, Nambu R, Melia M, Campochiaro PA. Combretastatin A-4 phosphate suppresses development and induces regression of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2003; 44:3650-3655. 19. Maines LW, French KJ, Wolpert EB, Antonetti DA, Smith CD. Pharmacologic manipulation of sphingosine kinase in retinal endothelial cells: implications for angiogenic ocular diseases. Invest Ophthalmol Vis Sci. 2006; 47(11):5022-5031. 20. Tong JP, Yao YF. Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions. Clin Biochem. 2006; 39(3):267-276. 21. Mori K, Gehlbach P, Ando A, et al. Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci. 2002; 43(7):24282434. 22. Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. 2006; 168(6):2036-2053.
Summary
What the future holds for the treatment of CNV in AMD is likely a combination of the agents discussed and others in earlier stages of development. It is probable that we will utilize agents that control various steps in the angiogenic cascade, as well as those that may act outside the VEGF pathways to control neovascular proliferation. In spite of the advances made to control exudative disease, patients are still faced with the damage from the neovascular process, in the form of fibrotic scars and atrophic degeneration of the RPE, which will require additional lines of research to resolve.
Selected Readings
1. Kaiser PK; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with an open-label extensionTAP Report No. 8. Graefes Arch Clin Exp Ophthalmol. 2006; 244:1132-1142. 2. Gragoudas ES, Adamis AP, Cunningham ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004; 351:2805-2816. 3. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-1431. 4. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1432-1444. 5. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011; 364:1897-1908. 6. Martin DF, Maguire MG, Fine SL, et al.; Comparison of Agerelated Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascu-
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23. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308:385389. 24. Haines JL, Hauser MA Schmidt S, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308:419-421. 25. Edwards AO, Ritter R III, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308:421-424. 26. Zarbin MA, Rosenfeld, PJ. Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 2010; 30:1350-1367.
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Imaging the Choroid: What You Need to Know Before Deep C Diving
Choroidal Imaging With oCT
Richard Spaide MD
The choroid is a multifunctional tissue that is vitally important in visual function. The in vivo structure of the choroid in health and disease is incompletely visualized with traditional imaging modalities, including indocyanine green angiography, ultrasonography, and spectral domain (SD) OCT. Use of new OCT modalities, including enhanced depth imaging (EDI) OCT and swept-source OCT, has led to improved visualization of the choroidal anatomy. Many diseases of the retina, and for that matter the optic nerve, are in some way influenced by the choroid and its blood flow. These include myopia, central serous chorioretinopathy, chorioretinal inflammatory diseases, and primary conditions involving the choroid including age-related choroidal atrophy. Application of these imaging techniques has met some clinical utility in the investigation of intraocular tumors. Extension of these techniques to additional structures has provided new insights into conditions involving the sclera, optic nerve, lamina cribrosa, and subarachnoid space around the nerve.
Blood Flow in the Choroid

Hayreh reported special features about choroidal vasculature from his observations of humans and monkeys.7 The choroidal arteries do not anatomose with one another, and each behaves like an end-artery. There are no anastomoses between the PCAs, or the short PCAs, or the choriocapillaris lobules. The arteries and veins supplying a local region of the choroid do not course parallel to each other. The segment of the choroid supplied by an artery does not correspond exactly with the segment drained by a vein. There is always a certain amount of overlap between the adjacent arterial segments via the veins.8 The peripapillary choroid is a very important region of the choroidal vascular bed because of its important role in the blood supply of the anterior part of the optic nerve, including the optic disc.9
Ways to Image the Choroid

Conventional ways to image the choroid included angiography and ultrasonography. Fluorescein is stimulated by blue light with a wavelength between 465 and 490 nm and emits at a green light with the peak of the emission spectral curve ranging between 520 and 530 nm and a curve extending to approximately 600 nm. Both the excitation and emission spectra from fluorescein are blocked in part by melanin pigment, which acts to decrease visualization of the choroid. Fluorescein extravasates rapidly from the choriocapillaris and fluoresces in the extravascular space, and this also prevents delineation of the choroidal anatomy. Indocyanine green (ICG) absorption peak is between 790 and 805 nm, and it fluoresces in a somewhat longer wavelength range, depending on the protein content and pH of the local environment. Longer wavelengths have the attribute of penetrating the pigmentation of the eye better than the wavelengths used with fluorescein angiography. ICG is 98% protein bound, with 80% binding to larger proteins such as globulins and alpha1-lipoproteins.10 Because ICG is highly protein bound, there is less opportunity for the dye to leak from the normal choroidal vessels. During the earlier phases of ICG angiography the choroidal vessels are fairly easy to discern, but the vertical summation of the choroid is seen.
Choroidal Anatomy
Approximately 95% of the blood flow in the eye goes to the uvea, with choroid accounting for more than 70% of the total.1 The choroid has the highest blood flow per unit weight of tissue of any tissue in the body, about 20 to 30 times greater than that of the retina.2 One main function is to supply oxygen and metabolites to the outer retina, retinal pigment epithelium (RPE), and possibly the prelaminar portion of the optic nerve.3 It is the only source of metabolic exchange for the avascular fovea. The photoreceptors inner segments are replete with mitochondria, and as a consequence the photoreceptors have the highest rate of oxygen use per unit weight of tissue in the body.4 The choroid has additional functions, including acting as a heat sink, absorbing stray light, and in birds, aiding in accommodation.5 The blood from the short posterior ciliary arteries (PCAs) enters the eye and travels through successively smaller branches of arterioles within the choroid to arrive at the choriocapillaris. The choroid is traditionally thought to be arranged in layers of vessels from the outer to inner part of the choroid labeled as the Haller layer, the Sattler layer, and the choriocapillaris. The Haller layer contains larger choroidal vessels, while the Sattler layer has medium-sized vessels. There is no distinct border between these layers or even an established definition of what is meant by large or medium. The pressure of the blood is reduced from about 75% of the systemic blood pressure at the short PCAs to that in the choriocapillaris, which has been measured in rabbits to be approximately 5 to 9.5 mmHg greater than the intraocular pressure.6 The choriocapillaris is a planar layer of small vessels with a lumen slightly larger than a typical capillary. The network of vessels in the choriocapillaris is so tightly arranged in the posterior portion of the eye that specific capillary tubes are more difficult to discern. In the peripheral portions of the eye, anatomic arrangements representing lobules are suggested, but there is no specific anatomic lobular structure in the posterior portion of the eye.
optical Coherence Tomography

SD-OCT uses an interferometer with a low coherence light source and measures the interference spectrum using a spectrometer and a high-speed, line charge coupled device (CCD). The swept source OCT uses a frequency-swept light source and detectors, which measure the interference output as a function of time.11,12 There are some problems inherent in SD technology. The deeper tissues produce higher frequency signals, but the way the grating and detector sample this frequency is not linear. The higher frequencies are bunched together to a greater extent than lower frequencies. In addition, the sensitivity of the detection decreases with increasing frequency. This causes SD-OCT to have decreasing sensitivity and resolution with increasing depth.
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These are less problematic with swept source OCT implementations. In addition, swept source imaging has been conventionally done with instruments using a 1-micron light source. This is further in the infrared spectrum than that used for SD-OCT. The increased wavelength affords greater penetration but also causes the image to have lower resolution for any given bandwidth. To improve the depth imaging capabilities of SD-OCT, the technique of EDI-OCT was developed, which shifts the peak of the sensitivity curve of SD-OCT to the inner sclera.13 This results in high-sensitivity choroidal imaging. The EDI methodology has been incorporated in software of a number of different OCT instruments. There arent many swept source OCTs in clinical application, and none are currently FDA approved. On the other hand many OCT devices can perform EDI-OCT, and the image quality is quite good. Therefore most of the publications about OCT imaging of the choroid have used EDI-OCT. The results of each imaging technique are similar and measurements of various thicknesses are in close agreement. Use of EDI-OCT has become increasingly popular with more widespread awareness, such that the number of papers published in the last few months is greater than all of last year. There are a large number of papers already in print. A short concise summary of the totality of these papers is beyond the scope of this simple review, but larger review articles are appearing in print, or are soon to be published.
tions in the sclera, causing a dome-shaped appearance.23 Some highly myopic eyes show peripapillary intrachoroidal cavitation,24 which has recently been shown to be due to posterior bowing of the sclera neighboring a myopic conus.25
References
1. Parver LM, Auker C, Carpenter DO. Choroidal blood flow as a heat dissipating mechanism in the macula. Am J Ophthalmol. 1980; 89:641-646. 2. Alm A, Bill A. Ocular and optic nerve blood flow at normal and increased intraocular pressures in monkeys (Macaca irus): a study with radioactively labelled microspheres including flow determinations in brain and some other tissues. Exp Eye Res. 1973; 15:15-29. 3. Hayreh SS. The blood supply of the optic nerve head and the evaluation of it: myth and reality. Prog Retin Eye Res. 2001; 20:563593. 4. Wangsa-Wirawan ND, Linsenmeier RA. Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol. 2003; 121(4):547557. 5. Wangsa-Wirawan ND, Linsenmeier RA. Retinal oxygen: fundamental and clinical aspects. Arch Ophthalmol. 2003; 121(4):547557. 6. Maepea O. Pressures in the anterior ciliary arteries, choroidal veins and choriocapillaris. Exp Eye Res. 1992; 54:731-736. 7. Hayreh SS. In vivo choroidal circulation and its watershed zones. Eye (Lond). 1990; 4 (pt 2):273-289. 8. Hayreh SS. Segmental nature of the choroidal vasculature. Br J Ophthalmol. 1975; 59:631-648. 9. Hayreh SS. The blood supply of the optic nerve head and the evaluation of it: myth and reality. Prog Retin Eye Res. 2001; 20:563593. 10. Baker KJ. Binding of sulfobromophthalein (BSP) sodium and indocyanine green (ICG) by plasma alpha-1 lipoproteins. Proc Soc Exp Biol Med. 1966; 122:957-963. 11. Chinn SR, Swanson EA, Fujimoto JG. Optical coherence tomography using a frequency-tunable optical source. Opt Lett. 1997; 22:340-342. 12. Choma M, Sarunic M, Yang C, Izatt J. Sensitivity advantage of swept source and Fourier domain optical coherence tomography. Opt Express. 2003; 11:2183-2189. 13. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol. 2008; 146:496-500. 14. Spaide RF, Campeas L, Haas A, et al. Central serous chorioretinopathy in younger and older adults. Ophthalmology 1996; 103:20702079. 15. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 2009; 29:1469-1473. 16. Maruko I, Iida T, Sugano Y, Ojima A, Ogasawara M, Spaide RF. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmology 2010; 117:1792-1799. 17. Maruko I, Iida T, Sugano Y, Oyamada H, Sekiryu T, Fujiwara T, Spaide RF. Subfoveal choroidal thickness after treatment of VogtKoyanagi-Harada disease. Retina 2011; 31:510-517. 18. Spaide RF. Age-related choroidal atrophy. Am J Ophthalmol. 2009; 147:801-810.
overview of Deeper Imaging of the eye With oCT

Many diseases cause some alteration in the choroid. For example, central serous chorioretinopathy is associated with increased choroidal vascular permeability. This is typically visualized as hyperpermeability seen during ICG angiography.14 Patients with central serous chorioretinopathy have very thick choroids.15 Treating the area of hyperpermeability of the choroid results in decreased signs of hyperpermeability, resolution of the subretinal fluid, and concurrently a decrease in the thickness of the choroid.16 Vogt-Koyanagi-Harada disease causes marked increase in choroidal thickness in acute disease, and with corticosteroid treatment the thickness decreases rapidly with resolution off the subretinal fluid.17 Age-related choroidal atrophy is a primary disease affecting the choroid. Patients with this disease have remarkable thinning of the choroid.18 They often have concurrent pseudodrusen.19 Patients with age-related choroidal atrophy have tessellation of the fundus and often have slight optic nerve pallor. They have decreased threshold sensitivity in the macula by microperimetry testing and if they have pseudodrusen, the microperimetry results are especially affected. The choroid is thinner in myopes. The subfoveal choroidal thickness is correlated to refractive error and negatively correlated to age. Curiously, even among myopes with no macular pathology the visual acuity is highly correlated with choroidal thickness.21 EDI-OCT of inflammatory chorioretinal inflammatory lesions has revealed many new findings. For example the actual inflammatory foci in sarcoidosis or in birdshot can be directly visualized, as well as the response to treatment. Intraocular tumors, particularly nonpigmented tumors, are readily visualized. EDI-OCT and swept source OCT have been used to visualize the optic nerve and lamina cribrosa in glaucoma patients. The amazing finding is the high proportion of eyes that have tears in the lamina cribrosa in glaucoma.22 Because myopes have very thin choroids and scleras it is possible to visualize structures behind the choroid. Some myopes have regional thickness varia-
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19. Switzer DW Jr, Mendona LS, Saito M, Zweifel SA, Spaide RF. Segregation of ophthalmoscopic characteristics according to choroidal thickness in patients with early age-related macular degeneration. Retina 2012; 32:1265-1271. 20. Fujiwara T, Imamura Y, Margolis R, Slakter JS, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol. 2009; 148:445-450. 21. Nishida Y, Fujiwara T, Imamura Y, Lima LH, Kurosaka D, Spaide RF. Choroidal thickness and visual acuity in highly myopic eyes. Retina 2012; 32:1229-1236. 22. Kiumehr S, Park SC, Dorairaj S, et al. In vivo evaluation of focal lamina cribrosa defects in glaucoma. Arch Ophthalmol. Epub ahead of print 9 Jan 2012. 23. Imamura Y, Iida T, Maruko I, Zweifel SA, Spaide RF. Enhanced depth imaging optical coherence tomography of the sclera in domeshaped macula. Am J Ophthalmol. 2011; 151:297-302. 24. Spaide RF, Akiba M, Ohno-Matsui K. Evaluation of peripapillary intrachoroidal cavitation with swept source and enhanced depth imaging optical coherence tomography. Retina 2012; 32:10371044. 25. Ohno-Matsui K, Akiba M, Moriyama M, Ishibashi T, Tokoro T, Spaide RF. Imaging retrobulbar subarachnoid space around optic nerve by swept-source optical coherence tomography in eyes with pathologic myopia. Invest Ophthalmol Vis Sci. 2011; 52:96449650.
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When Should I Be Using Fundus Autofluorescence?

Frank G Holz MD
Introduction
Fundus autofluorescence (FAF) imaging allows for topographic mapping of lipofuscin (LF) distribution in the retinal pigment epithelial (RPE) cell monolayer as well as of other fluorophores that may occur with disease in the outer retina and the subneurosensory space.1 It provides additional information not obtainable with other imaging techniques such as fundus photography, fluorescein angiography, or OCT. Excessive accumulation of LF granules in the lysosomal compartment of RPE cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases. Near-infrared fundus autofluorescence (NIA) images can also be obtained in vivo using the indocyanine-green angiography mode. It has been suggested that the NIA-signal is largely melanin derived.2 Peak absorption of luteal pigment is at 460nm. These absorption properties can be readily recorded in vivo by blue light autofluorescence imaging.3 Therefore, blue FAF imaging can also be used to determine the topographic distribution of macular pigment. Compared to other methods, including heterochromatic flicker photometry, the advantage of FAF imaging is its objective acquisition independent of psychophysical cooperation by the examined individual. Recording of FAF images is noninvasive and requires relatively little time. The intensity of naturally occurring fluorescence of the ocular fundus is about 2 orders of magnitude lower than the background of a fluorescein angiogram at the most intense part of the dye transit. Both scanning laser ophthalmoscopy imaging and fundus camera photography have been used in the clinical setting for the acquisition of fundus autofluorescence. Confocal scanning laser ophthalmoscopy (cSLO) optimally addresses the limitations of low intensity of the autofluorescence signal and the interference of the crystalline lens. FAF imaging has been shown to be useful in a wide spectrum of macular and retinal diseases. The scope of applications now includes identification of diseased RPE in macular/retinal diseases, understanding pathophysiological mechanisms, identification of early disease stages, refined phenotyping, identification of predictive markers for disease progression, monitoring disease progression in the context of natural history as well as interventional, therapeutic studies, objective assessment of luteal pigment distribution and density, and RPE melanin-distribution.
Crystalline drusen typically show a corresponding decreased FAF signal. Increased FAF intensities next to drusen funduscopically corresponding to focal hyperpigmentation and pigment figures have been explained by the presence of melano-LF or changes in the metabolic activity of the RPE. Areas of hypopigmentation on fundus photographs tend to be associated with a corresponding decreased FAF signal, suggesting the absence of RPE cells or degenerated RPE cells with reduced content of LF granules.5 So called reticular pseudodrusen have been identified as a risk factor for the development of late-stage AMD. In patients with geographic atrophy (GA) this specific phenotypic pattern, which is best recognizable by infrared reflectance and fundus autofluorescence imaging, can be detected in over 60% of eyes. The exact morphological correlate of this distinct pattern is controversial. Speculations range from abnormalities in the inner choroid 6 to subretinal deposits;7 the latter is based on the spectral domain OCT changes recorded in presence of reticular pseudodrusen.7-9 The spectrum of FAF findings in patients with early AMD was classified by an international expert group.10 Pooling data from several retinal centers, a system with 8 different FAF patterns was developed, including normal, minimal change, focal increased, patchy, linear, lacelike, reticular, and speckled pattern. This classification demonstrates the relatively poor correlation between visible alterations on fundus photography and notable FAF changes. Based on these results, it was speculated that FAF findings in early AMD may indicate more widespread abnormalities and diseased areas. Geographic atrophy in AMD Recently, FAF imaging has proven particularly useful in GA secondary to AMD. Due to the absence of RPE cells and thus intrinsic LF fluorophores, atrophic areas in GA patients exhibit a severely reduced signal (see Figure 1).11 The high-contrast difference between atrophic and non-atrophic retina permits accurate delineation of lesion boundaries and quantification of uni- or multifocal atrophic areas on FAF images using customized image
Age-related Macular Degeneration (AMD)

Early AMD Early manifestation of AMD include focal hypo- and hyperpigmentations at the level of the RPE as well as drusen with extracellular material accumulating in the inner aspects of the Bruch membrane.4 Drusen visible on fundus photography are not necessarily correlated with notable FAF changes, and areas of increased FAF may or may not correspond with areas of hyperpigmentation or soft or hard drusen.5 Overall, larger drusen are associated more frequently with notable FAF abnormalities than smaller ones, with the exception of basal laminar drusen.
Figure 1. GA due to AMD: atrophic areas appear as sharply demarcated areas with depigmentation on fundus photograph (left). At the corresponding fundus autofluorescence image (right), atrophic patches are clearly delineated by decreased intensity and high-contrast to nonatrophic retina. Surrounding atrophy, in the junctional zone of atrophy, levels of marked FAF intensity are observed that are invisible on fundus photography.
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analysis software (see Figure 2).12 This allows for noninvasive monitoring of atrophy progression over time13,14 and, therefore, assessment of therapeutic effects of novel agents aiming at slowing GA enlargement over time. An additional important finding with FAF imaging in GA patients is the visualization of abnormal FAF distribution in the junctional and perilesional zone surrounding atrophic patches (see Figure 3).15,5,16 Distinct FAF patterns correlate with enlargement rates of GA patches over time.5,14 Such high-risk markers shed light on pathophysiologi-
cal mechanisms and are relevant for the design of interventional trials to reduce sample size and study period in an overall slowly progressing disease. Combining SLO microperimetry and FAF imaging in another study, impaired photopic sensitivity has been observed in areas of abnormal FAF in the junctional zone. 5 Outer retinal atrophy in the context of AMD is a dynamic process with gradual enlargement of atrophic areas over time. Initial natural history studies on atrophy progression in GA patients using FAF imaging demonstrated the occurrence of new atrophic patches and the spread of pre-existing atrophy in areas with abnormally high levels of FAF at baseline.15 The FAMstudy identified large variability of atrophy enlargement between patients, which was explained neither by baseline atrophy nor by any other risk factor in association with AMD, including smoking, lens status, or family history.14 These results have subsequently been confirmed in another large-scale natural history study (the GAP study). The findings underscore the importance of abnormal FAF intensities around atrophy and the pathophysiological role of increased RPE LF accumulation in patients with GA due to AMD. Choroidal neovascularization in AMD FAF imaging may give important clues in choroidal neovascularization (CNV) secondary to AMD. It may be helpful to assess the integrity of the RPE, which may influence the development and behavior of new vascular complexes as well as photoreceptor viability and potential therapeutic success. Patients with early CNV secondary to AMD tend to have patches of continuous or normal autofluorescence corresponding with areas of hyperfluorescence on the comparative fluorescein angiograms, implying that RPE viability is preserved at least initially in CNV development.17 By contrast, eyes with long-standing CNV typically exhibit more areas of decreased signal, which could be explained by photoreceptor loss and scar formation with increased melanin deposition. One other important finding in eyes with CNV is that abnormal FAF intensities typically extend beyond the edge of the angiographically defined lesion, indicating a more wideFigure 3. Abnormal FAF patterns in the junctional zone in patients with GA due to AMD. Eyes with no increased FAF intensity at all are graded as NONE (5 slow progressor). The eyes with increased FAF are divided into 2 groups, depending on the configuration of increased FAF surrounding atrophy. Eyes showing areas with increased FAF directly adjacent to the margin of the atrophic patch(es) and elsewhere are called diffuse (5 rapid progressors) and are subdivided into 5 groups. From left to right: (Top row) fine granular, branching, (bottom row) trickling, reticular, and fine granular with punctuated spots. Eyes with increased FAF only at the margin of GA are split into 3 subtypes (FOCAL [5 slow progressor], BANDED [5 rapid progressor], and PATCHY [5 no data, occurs rarely]) according to their typical FAF pattern around atrophy.
Figure 2. GA quantification over time. First row: near-infrared reflectance images at baseline, Month 6, and Month 12; second row: FAF images; third row: results of semiautomated area measurements based on FAF images using the RegionFinder (Heidelberg Engineering; Germany).
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spread involvement than seen in conventional imaging studies. Increased FAF signal has also been described around the edge of lesions. It has been speculated that this observation may reflect the proliferation of RPE cells around the CNV.18 In eyes with CNV, atrophy may commonly occur and expands also over time, as in eyes with pure late dry AMD. It may represent an important cause for visual loss during antiVEGF-therapy.
Macular and Diffuse Retinal Dystrophies

In macular and diffuse retinal dystrophies, various associated abnormalities in FAF have been described.19 In areas of atrophy, the FAF signal is typically markedly decreased due to loss of the RPE and, thereby, a lack of autofluorescent LF. It is well established that autofluorescent material excessively accumulates in the RPE in association with various genetically determined retinal diseases. Increased FAF due to excessive LF accumulation in RPE cells may result from abnormally high turnover of photoreceptor outer segments or impaired RPE lysosomal degradation of normal or altered phagocytosed molecular substrates. The extent and pattern of increased FAF may show characteristic abnormal distributions in retinal dystrophy disease entities. The funduscopically visible pale/yellowish lesions at the level of RPE/Bruch membrane in Best macular dystrophy, adult vitelliform macular dystrophy, and other pattern dystrophies as well as Stargardt macular dystrophy/ fundus flavimaculatus (see Figure 4) are associated with an intense focally increased FAF signal. Discrete, well-defined lines of increased FAF may occur in various forms of retinal dystrophies.20,21 These lines have no prominent correlate on fundus biomicroscopy, although there is evidence that these lines precisely reflect the border of retinal dysfunction.20,21 Despite the variable orientation of this line in different entitieseg, orientation along the retinal veins in
Figure 4. Stargardt macular dystrophy/fundus flavimaculatus. Funduscopically visible focal flecks show a bright, increased FAF signal. Focal areas of decreased FAF seem to correspond to RPE atrophy.
pigmented paravenous chorioretinal atrophy (PPCRA) or ring structure in retinitis pigmentosa (RP), macular dystrophies or cone-rod dystrophy (CRD) (see Figure 5)the similar appearance on FAF images and the concordance of functional findings indicate that these lines in heterogeneous diseases share a common underlying pathophysiological mechanism.21 It has been concluded that the ring of increased FAF in RP demarcates areas of preserved central photopic function and that constriction of the ring may mirror progressive visual field loss by advancing dysfunction that encroaches over areas of central macular.20
Figure 5. Arcs and rings of increased FAF in patients with retinal dystrophies. (A-C) Arc of increased FAF orientating along the retinal veins in PPRCA. (D) Patient with sector RP: arc with semicircle structure in the parafoveal region. In typical RP (E), there is a ring of increased FAF. Within and outside the ring, there is a normal FAF signal. In presence of a macular dystrophy (F), there is a parafoveal ring of increased FAF. Centrally, there is reduced FAF corresponding to the funduscopically visible lesion. On both sides of the ring, there is a normal FAF signal. In with bulls-eye macula dystrophy (G), a ring of increased FAF borders directly the central lesion.
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pericentral macula. While electrophysiological examination has been thought to represent an adequate tool to diagnose early chloroquine maculopathy, FAF imaging can be used as a highly sensitive tool.
References
1. Holz FG, Schmitz-Valckenberg S, Spaide RF, Bird AC. Atlas of Fundus Autofluorescence Imaging. Berlin, Heidelberg, New York: Springer; 2007. 2. Keilhauer CN, Delori FC. Near-infrared autofluorescence imaging of the fundus: visualization of ocular melanin. Invest Ophthalmol Vis Sci. 2006; 47:3556-3564. 3. Wolf S, Wolf-Schnurrbusch U. Macular pigment measurement: theoretical background. In: Holz FG, Schmitz-Valckenberg S, Spaide RF, Bird AC, eds. Atlas of Autofluorescence Imaging. Berlin, Heidelberg, New York: Springer; 2007. 4. Bird A. Age-related macular disease. Br J Ophthalmol. 1996; 80:23. 5. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol. 2009; 54:96-117. 6. Arnold JJ, Sarks SH, Killingsworth MC, Sarks JP. Reticular pseudodrusen: a risk factor in age-related maculopathy. Retina 1995; 15:183-191. 7. Zweifel SA, Spaide RF, Curcio CA, Malek G, Imamura Y. Reticular pseudodrusen are subretinal drusenoid deposits. Ophthalmology 2010; 117:303-312 e301. 8. Schmitz-Valckenberg S, Steinberg JS, Fleckenstein M, Visvalingam S, Brinkmann CK, Holz FG. Combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging of reticular drusen associated with age-related macular degeneration. Ophthalmology 2010; 117:1169-1176. 9. Fleckenstein M, Charbel Issa P, Helb HM, et al. High-resolution spectral domain-OCT imaging in geographic atrophy associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2008;49:4137-4144. 10. Bindewald A, Bird AC, Dandekar SS, et al. Classification of fundus autofluorescence patterns in early age-related macular disease. Invest Ophthalmol Vis Sci. 2005; 46:3309-3314. 11. von Ruckmann A, Fitzke FW, Bird AC. Distribution of fundus autofluorescence with a scanning laser ophthalmoscope. Br J Ophthalmol. 1995; 79:407-412. 12. Schmitz-Valckenberg S, Brinkmann CK, Alten F, et al. Semiautomated image processing method for identification and quantification of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011; 52:7640-7646. 13. Schmitz-Valckenberg S, Bindewald-Wittich A, Dolar-Szczasny J, et al. Correlation between the area of increased autofluorescence surrounding geographic atrophy and disease progression in patients with AMD. Invest Ophthalmol Vis Sci. 2006;47:2648-2654. 14. Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007; 143:463-472. 15. Holz FG, Bellman C, Staudt S, Schutt F, Volcker HE. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001; 42:10511056. 16. Bindewald A, Schmitz-Valckenberg S, Jorzik JJ, et al. Classification of abnormal fundus autofluorescence patterns in the junctional
Figure 6. Normal (left) and abnormal fundus autofluorescence in macular telangiectasia type 2 with increased signal in the center due to a loss of luteal pigment.
Macular Telangiectasia
As outlined above, normal eyes show masking of the foveal 488nm FAF due to the accumulation of luteal pigment. Reduced macular pigment density in macular telangiectasia (MacTel) type 2 affects this masking. Eyes with MacTel type 2 show an abnormally increased signal in the macular area to variable degree with blue light FAF imaging (see Figure 6).22 A loss of luteal pigment may initially occur in the area temporal to the foveal center.22,23 Quantitative analysis confirmed that the loss of luteal pigment was more pronounced in the temporal compared with the nasal parafoveolar area and suggested that zeaxanthin would be more reduced than lutein.23 FAF imaging is helpful in diagnosing MacTel 2, especially because abnormalities in macular pigment distribution may occur before other phenotypic characteristics such as parafoveal telangiectasia or crystalline deposits in the inner retina occur.
Central Serous Chorioretinopathy

FAF findings in central serous chorioretinopathy are in accord with the involvement of the RPE depending on the disease stage.24 Patients with acute leaks imaged within the first month have minimal abnormalities other than a slight increase in autofluorescence of the serous detachment. Over time, the area of the detachment increasingly exhibits levels of irregular increased autofluorescence. In some patients, discrete granules with increased intensity within the detachment are observed that correspond with the pinpoint subretinal precipitates seen on funduscopy. It has been suggested that these dots may represent macrophages, engorged with phagocytosed outer segments. Patients with chronic disease have irregular levels of autofluorescence with markedly decreased intensity over areas of atrophy. A typical finding also includes the visualization of fluid tracks in the inferior retina.
Chloroquine Retinopathy
FAF imaging may show distinct alterations due to toxic retinal effects of long-term chloroquine therapy.25 Various methods have been proposed to detect early stages of chloroquine retinopathy. Early on, a pericentral ring of increased FAF intensity may occur associated with pericentral reduction in mfERG amplitudes and pericentral interruption of the photoreceptor inner/outer segment junction in the spectral domain OCT. More advanced stages are associated with a more mottled appearance with increased and decreased FAF intensity in the
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zone of geographic atrophy in patients with age related macular degeneration. Br J Ophthalmol. 2005; 89:874-878. 17. Vaclavik V, Vujosevic S, Dandekar SS, Bunce C, Peto T, Bird AC. Autofluorescence imaging in age-related macular degeneration complicated by choroidal neovascularization: a prospective study. Ophthalmology 2008; 115:342-346. 18. McBain VA, Townend J, Lois N. Fundus autofluorescence in exudative age-related macular degeneration. Br J Ophthalmol. 2007; 91:491-496. 19. von Ruckmann A, Fitzke F, Schmitz-Valckenberg S, Webster A, Bird A. Macular and retinal dystrophies. In: Holz FG, SchmitzValckenberg S, Spaide RF, Bird AC, eds. Atlas of Autofluorescence Imaging. Berlin, Heidelberg, New York: Springer; 2007. 20. Robson AG, Michaelides M, Saihan Z, et al. Functional characteristics of patients with retinal dystrophy that manifest abnormal parafoveal annuli of high density fundus autofluorescence; a review and update. Doc Ophthalmol. 2008; 116:79-89. 21. Fleckenstein M, Charbel Issa P, Fuchs HA, et al. Discrete arcs of increased fundus autofluorescence in retinal dystrophies and functional correlate on microperimetry. Eye (Lond). 2009; 23:567-575. 22. Helb HM, Charbel Issa P, RL VDV, Berendschot TT, Scholl HP, Holz FG. Abnormal macular pigment distribution in type 2 idiopathic macular telangiectasia. Retina 2008; 28:808-816. 23. Charbel Issa P, van der Veen RL, Stijfs A, Holz FG, Scholl HP, Berendschot TT. Quantification of reduced macular pigment optical density in the central retina in macular telangiectasia type 2. Exp Eye Res. 2009; 89:25-31. 24. Spaide RF, Klancnik JM, Jr. Fundus autofluorescence and central serous chorioretinopathy. Ophthalmology 2005; 112:825-833. 25. Kellner U, Renner AB, Tillack H. Fundus autofluorescence and mfERG for early detection of retinal alterations in patients using chloroquine/hydroxychloroquine. Invest Ophthalmol Vis Sci. 2006; 47:3531-3538.
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Whats Next in Imaging?

Srinivas R Sadda MD
I. New OCT Technologies and Everything Else! II. Everything Else A. Ocular MRI B. Hyperspectral imaging C. Photoacoustic imaging III. New OCT Technologies IV. Limitations of Existing Spectral Domain OCT (SDOCT) A. Retinal layers are well visualized, but not individual cells. B. Speed is adequate, but still limits scanning area or amount of oversampling. C. Functional data is still relatively limited. D. Dynamic vascular (blood flow/leakage) information is lacking. E. Automatic quantitative data is limited. F. Requires trained operator V. Future OCT Technologies A. Improved resolution B. Improved speed C. Improved penetration D. Functional information E. Vascular/molecular imaging F. Increased automation VI. Improving Axial Resolution A. Axial resolution depends on light source bandwidth and wavelength. B. Automatic quantitative data is limited. C. Requires trained operator
VII. Improving Axial Resolution A. Axial resolution depends on light source bandwidth and wavelength. B. Previously broad bandwidths were only achievable with expensive femtosecond titanium sapphire lasers. C. Multiplexed superluminescent diodes (SLDs) have made UHR OCT commercially feasible (eg, Optopol Copernicus HR). VIII. Improving Transverse Resolution A. Transverse resolution is probably more important; limited to 20 microns by optical aberrations of the eye. B. Adaptive optics systems compensate for these aberrations. IX. AO-OCT vs. AO-SLO X. AO-OCT Isotropic 3-D resolution (3.5 microns x 3.5 microns x 3.5 microns) XI. Improved Speed: Swept Source OCT A. Another Fourier domain OCT technology B. 10X faster than existing SD-OCT instruments C. Also better sensitivity with less roll-off D. At these speeds, fixation/motion is no longer an issue. E. Large areas can be scanned quickly and with extensive averaging. Extensive averaging allows fine structures to be seen. XII. Enhanced Depth Imaging A. Optimizing orientation relative to the zero delay (Spaide inversion) and averaging are two methods to improve visualization of deeper structures (see Figure 1).
Figure 1.
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B. Increasing the imaging wavelength is another approach to achieve greater depth penetration (see Figure 2).
Two windows of opportunity for retinal OCT imaging XV. Long wavelength (1 micron OCT) Most future swept source OCT devices will likely operate in the long wavelength (>1 micron) regime. XVI. Choroidal Visibility: 1050 vs. 840 Comparison study at Doheny of 1050 nm vs. 840 nm. Results: Even when the choroid was fully visible at 840 nm, considerable additional detail was visible at 1050nm. XVII. Retinitis Pigmentosa (see Figure 5)
Figure 2.
XIII. Importance of Choroidal Thickness A. Choroidal thickness varies in different diseases. B. FCP thickness 1. Normal eyes: 280-290 microns 2. CSCR patients: 400-500 microns
Figure 5.
XVIII. Choroidal Volume Quantification XIX. Optophysiology A. Dual laser approach B. High-speed long wavelength used to obtain repeated OCT scans from same location over time, without stimulating photoreceptors.
Figure 3.
C. Separate visible light laser used to activate photoreceptors 3. High myopes: 93 microns XX. Emerging OCT Technologies A. Polarization-sensitive OCT 1. Measures birefringence 2. Can accentuate the retinal pigment epithelium (RPE) (depolarizing) and other structures 3. May provide functional insight into the RPE B. Polarization-sensitive OCT 1. Measures birefringence 2. Can accentuate the RPE (depolarizing) and other structures
Figure 4.
3. May provide functional insight into the RPE
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Section IX: Imaging 4. Various structures in the eye (choroid, sclera, Bruch, lamina cribrosa, etc.) may have characteristic birefringence patterns may be altered by disease. 5. May enhance visualization of the extent of the choroid 6. Facilitate detection of retinal microexudates
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XXI. Measurement of both Doppler shift and incidence angle are needed to compute flow in a vessel. XXII. Flow direction relative to OCT beam is measured by 2 parallel cross-sections. XXIII. Double circular scan transects all retinal branch vessels 6 times per second.
Figure 7.
XXVIII. Advanced Automated Analyses A. Many groups are developing algorithms for segmenting various retinal layers. B. Algorithms for segmenting specific pathologic structures are already becoming available in commercial OCT software (eg, drusen, GA analysis). XXIX. Automated Acquisition A. Binocular self-administered OCT 1. Initial prototype constructed (Walsh, Envision Diagnostics) 2. Scan both eyes simultaneously from adnexa to posterior pole with high-speed SS-OCT
Figure 6.
B. OCT biomicroscopy XXX. Summary A. Advances in OCT technology continue to proceed at a rapid pace. B. These advances are addressing many of the limitations of existing devices. C. Applications of OCT in our diagnosis and treatment of patients can be expected to continue to expand.
XXIV. Algorithm for Total Retinal Blood Flow XXV. Case control comparison confirmed that eyes with glaucoma had lower total retinal blood flow. XXVI. Blood flow is strongly correlated with VF but not with neural tissue loss. XXVII. Phase Variance OCT (OCT Angiography)
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Intraoperative optical Coherence Tomography: Is It Actually Useful?

Intraoperative Spectral Domain oCT
I. Spectral Domain OCT (SD-OCT) vs. Time Domain OCT A. Provides faster acquisition times, reducing motion artifact B. Increased resolution C. Allows repetitive scanning, which can increase image quality D. Allows imaging of larger area E. Allows registration, permitting direct comparison of images obtained at different times F. In summary: fast high-resolution images of macular microstructure II. Is It Useful in the OR? III. Arguments for Yes A. Identify nonvisible membranes B. Identify tissue layers C. Identify changes to microstructure after surgical manipulation D. Assist with operative management; identify surgical endpoints IV. Arguments for No A. Already able to identify membranes B. Does it make a difference with outcomes? C. Need for real time for intraoperative SD-OCT to become useful V. Current Systems A. Hand-held probe (Bioptigen, Optovue) 1. Free hand with stabilizing arm a. Successful imaging reported previously b. Requires steady hold of probe over eye c. Movement artifact d. Minor adjustments can reduce accurate reimaging of same area. 2. Microscope mount a. Steadies probe over eye during surgery b. Allows repeat imaging over the same area c. Allows use of operating microscope foot pedal to make small changes in focus or position d. Probe use requires stopping surgery and bringing probe into operative field. e. Large prospective study at Cleveland Clinic, Cole Eye Institute B. Integrated within microscope 1. Carl Zeiss Meditec prototype a. Cirrus HD-OCT system integrated with surgical microscope b. Offers ability to image macular pathology without need to swing in probe c. Not commercially available yet 2. Duke University Prototype a. Integrated via attachment to microscope b. Par-focal with BIOM c. Prospective trial currently ongoing at Duke University 3. Integration obstacles a. Instrumentation b. Software c. Information overload? VI. Our Experience With Probe A. Examples of uses B. Nonvisible membranes C. Identify remnants D. Decipher folds vs. membranes E. Where to start dissections F. Changes to retinal microstructure after surgical manipulation VII. Summary A. Intraoperative SD-OCT is feasible with currently available systems. B. Microscope mounted probe allows fast, reproducible image acquisition. C. Advantages include ability to identify membranes, folds, and changes to retinal architecture after surgical manipulation. D. Increased subretinal fluid after membrane peeling is an example of previously unidentified change detected by use of intraoperative SD-OCT.
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Section IX: Imaging E. Is it useful now? Absolutely. It can provide information to the surgeon to improve outcomes. F. With future integration it will provide live feedback. VIII. Future Directions A. Commercially available SD-OCT unit within operating room microscope, allowing real-time imaging during surgery B. Surgical instruments with built-in OCT probes C. Prospective study of intraoperative changes with postoperative visual and microperimetry outcomes.
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7. Tao YK, Ehlers JP, Toth CA, Izatt JA. Intraoperative spectral domain optical coherence tomography for vitreoretinal surgery. Opt Lett. 2010; 35(20):3315-3317. 8. Ide T, Wang J, Tao A, et al. Intraoperative use of three dimensional spectral domain optical coherence tomography. Ophthalmic Surg Lasers Imaging. 2010; 41(2):250-254. 9. Srinivasan VJ, Wojtkowski M, Witkin AJ, et al. High-definition and 3-dimensional imaging of macular pathologies with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 2006; 113(11):2054 e1-14. 10. Sano M, Shimoda Y, Hashimoto H, Kishi S. Restored photoreceptor outer segment and visual recovery after macular hole closure. Am J Ophthalmol. 2009; 147(2):313-318 e1. 11. Oh J, Smiddy WE, Flynn HW Jr, et al. Photoreceptor inner/outer segment defect imaging by spectral domain OCT and visual prognosis after macular hole surgery. Invest Ophthalmol Vis Sci. 2010; 51(3):1651-1658. 12. Chalam KV, Murthy RK, Gupta SK, et al. Foveal structure defined by spectral domain optical coherence tomography correlates with visual function after macular hole surgery. Eur J Ophthalmol. 2010; 20(3):572-577. 13. Inoue M, Watanabe Y, Arakawa A, et al. Spectral-domain optical coherence tomography images of inner/outer segment junctions and macular hole surgery outcomes. Graefes Arch Clin Exp Ophthalmol. 2009; 247(3):325-330. 14.Chang LK, Fine HF, Spaide RF, et al. Ultrastructural correlation of spectral-domain optical coherence tomographic findings in vitreomacular traction syndrome. Am J Ophthalmol. 2008; 146(1):121127. 15. Koizumi H, Spaide RF, Fisher YL, et al. Three-dimensional evaluation of vitreomacular traction and epiretinal membrane using spectral-domain optical coherence tomography. Am J Ophthalmol. 2008; 145(3):509-517. 16. Haritoglou C, Ehrt O, Gass CA, et al. Paracentral scotomata: a new finding after vitrectomy for idiopathic macular hole. Br J Ophthalmol. 2001; 85(2):231-233.
Selected Readings
1. Dayani PN, Maldonado R, Farsiu S, Toth CA. Intraoperative use of handheld spectral domain optical coherence tomography imaging in macular surgery. Retina 2009; 29(10):1457-1468. 2. Wykoff CC, Berrocal AM, Schefler AC, et al. Intraoperative OCT of a full-thickness macular hole before and after internal limiting membrane peeling. Ophthalmic Surg Lasers Imaging. 2010; 41(1):7-11. 3. Ray R, Baraano DE, Fortun JA, et al. Intraoperative microscopemounted spectral domain optical coherence tomography for evaluation of retinal anatomy during macular surgery. Ophthalmology 2011; 118(11):2212-2217. 4. Lee LB, Srivastava SK. Intraoperative spectral-domain optical coherence tomography during complex retinal detachment repair. Ophthalmic Surg Lasers Imaging. 2011; 42 Online:e71-4. 5. Ehlers JP, Gupta PK, Farsiu S, Maldonado R, Kim T, Toth CA, Mruthyunjaya P. Evaluation of contrast agents for enhanced visualization in optical coherence tomography. Invest Ophthalmol Vis Sci. 2010; 51(12):6614-6619. 6. Ehlers JP, Tao YK, Farsiu S, Maldonado R, Izatt JA, Toth CA. Integration of a spectral domain optical coherence tomography system into a surgical microscope for intraoperative imaging. Invest Ophthalmol Vis Sci. 2011; 52(6):3153-3159.
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Adaptive optics: Ready for Prime Time?

Judy E Kim MD
Progress in retinal imaging is allowing better visualization of the retina today than ever before and is increasing our understanding of the retina in normal and diseased states. One of the best examples of this progress in retinal imaging in recent years is optical coherence tomography (OCT), which has aided us immensely in diagnosis and management of retinal diseases. While OCT is now an integral part of our clinics, continued efforts are being made to improve resolution in OCT and other imaging modalities. Adaptive optics (AO), a technology that can compensate for optical monochromatic aberrations of the eye that cause blur, has been used to provide high-resolution retinal images.1-3 This is made possible by using a wavefront sensor to measure the ocular aberrations and a deformable mirror to compensate for these aberrations.2 Adaptive optics imaging systems have been integrated into fundus cameras (FAO), OCTs (AO-OCT), and scanning laser ophthalmoscopes (AO-SLO) to image the retina.4-6 Each imaging modality has differing benefits and drawbacks. For instance, FAO has the advantage of brief imaging exposure time, which is critical for imaging patients with significant eye movements such as nystagmus, and AO-OCT can provide unrivaled axial resolution, allowing 3-D imaging of various retinal layers. AO-SLO is capable of confocal imaging with minimal speckle artifacts and high transverse resolution, such that, after correcting the aberrations of the eye, the AO-SLO system can achieve a transverse resolution on the order of 2 m.7 This high resolution has allowed noninvasive in vivo visualization of the cone photoreceptors mosaic even at the foveal center, and, more recently, the rod photoreceptor mosaic.1-3,8-12 These AO-equipped imaging systems have broadened our knowledge of photoreceptors in normal eyes and in eyes with retinal conditions.8-20 Cone density, spacing, and geometrical arrangement can be assessed and quantified. These can be compared between healthy eyes and eyes with disease at various states. Studies have shown that in vivo quantitative measures such as cone spacing and cone:rod ratios at various retinal eccentricities obtained by AO imaging compares favorably with previous histological findings.11,14,21,22 Also there appears to be a wide variation in 3 different cone types in subjects with normal color vision.23 Spatial and temporal variability in photoreceptor reflectance is actively being studied in hopes of gaining diagnostic and functional information.24,25 Using ophthalmic AO systems, various retinal diseases have been imaged to date and have shown that AO imaging can reveal cellular damages even when these changes are undetectable by other imaging modalities. We can expect more findings in the future as more instruments are built around the world. In addition to photoreceptors, AO ophthalmoscopy allows improved visualization of retinal pigment epithelial cells, nerve fibers, and retinal blood vessels, and we can observe individual blood cells moving through tiny blood vessels. 26-29 High-resolution imaging capability made possible with AO system allows detection of structural changes early in the course of disease.30 It can be used to provide insight into longitudinal changes, and can be correlated with measures of visual function.9,16 The AO
system can be incorporated into other visual function systems, such as microperimetry, and gives us further information regarding the correlation between structure and function.31 Thus, AO instrumentation holds much promise in our understanding and management of a number of common ocular conditions, such as diabetic retinopathy, AMD, and glaucoma, as well as rare retinal conditions, such as various inherited retinal disorders.9-20, 28-30, 32-35 Early detection of structural changes at the cellular level can also benefit clinical trials by facilitating documentation of treatment effects of novel retinal therapies as well as selection of ideal subjects.36,37 Despite these promising aspects of AO systems for ophthalmology and being an important research tool, several impediments to their widespread use in the clinic currently exist. One of the greatest limitations to incorporating AO systems in the clinic is the time required to obtain, process, and analyze the images. Currently in the laboratory setting, a significant amount of time, energy, and expertise are required to accomplish these tasks. Because the field of view captured in a single image is quite small, large numbers of images must be obtained, processed, and montaged. Montaging can be challenging when reference points such as retinal vessels are not present or the photographer was not systematic in taking overlapping pictures. There is a need for software that can easily register images, rapidly process and automatically analyze the datasuch as fully automated cone counting software. Progress is being made in this regard. In addition, the images obtained can be less than optimal due to media opacity, small pupil size, inability to maintain fixation, or eye motion. Normative databases with regard to gender, race, and age are needed, and the interpretation of AO images needs further studies. Also the size of the current instruments commonly used in the research setting is large and prohibitive in the office setting. However, several compact design AO systems have been developed and are being tested. Although not yet FDA approved for diagnostic use, some commercial prototypes are available and are small enough to be deployable in the clinics. They are capable of rapid image acquisition and reduced processing time. However, further studies are needed to compare the image quality and resolution obtained from these to those obtained in the research grade instruments, as well as to validate the information obtained from them. While AO may not yet be prime time like OCT is currently, progress in optics technology and software development will improve the adaptability of AO systems in the clinical setting in the near future.38 AO imaging systems offer opportunities to correlate structural changes with functional changes at the cellular level in vivo and hold significant promise for ophthalmology. Future applications for AO ophthalmoscopy include longitudinal monitoring of disease progression and investigating early disease mechanisms in retinal diseases.36 It may allow novel therapies to be targeted to retinal locations with the most preserved photoreceptor mosaic or selection of most optimal subjects for clinical trials, thereby directly increasing the potential for success of these therapies.37 As further improvements are
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made to the AO systems to make them more useful in clinical setting, important new data on the cellular phenotype in retinal degenerations will undoubtedly emerge and will improve the care of our patients.
18. Sallo FB, Leung I, Chung M, et al; MacTel Study Group. Retinal crystals in type 2 idiopathic macular telangiectasia. Ophthalmology 2011; 118(12):2461-2467. 19. Sarda V, Nakashima K, Wolff B, Sahel JA, Paques M. Topography of patchy retinal whitening during acute perfused retinal vein occlusion by optical coherence tomography and adaptive optics fundus imaging. Eur J Ophthalmol. 2011; 21(5):653-656. 20. Ooto S, Hangai M, Takayama K, et al. High-resolution photoreceptor imaging in idiopathic macular telangiectasia type 2 using adaptive optics scanning laser ophthalmoscopy. Invest Ophthalmol Vis Sci. 2011; (8):5541-5550. 21. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol. 1990; 292(4):497-523. 22. Curcio CA, Sloan KR. Packing geometry of human cone photoreceptors: variation with eccentricity and evidence for local anisotropy. Vis Neurosci. 1992; 9(2):169-180. 23. Hofer H, Singer B, Williams DR. Different sensations from cones with the same photopigment. J Vis. 2005; 5:444-454. 24. Pallikaris A, Williams DR, Hofer H. The reflectance of single cones in the living human eye. Invest Ophthalmol Vis Sci. 2003; 44:45804592. 25. Cooper RF, Dubis AM, Pavaskar A, et al. Spatial and temporal variation of rod photoreceptor reflectance in the human retina. Biomed Opt Express. 2011; 2(9):2577-2589. 26. Morgan JI, Dubra A, Wolfe R, Merigan WH, Williams DR. In vivo autofluorescence imaging of the human and macaque retinal pigment epithelial cell mosaic. Invest Ophthalmol Vis Sci. 2009; 50(3):1350-1359. 27. Roorda A, Zhang Y, Duncan JL. High-resolution in vivo imaging of the RPE mosaic in eyes with retinal disease. Invest Ophthalmol Vis Sci. 2007; 48:2297-2303. 28. Martin JA, Roorda A. Direct and noninvasive assessment of parafoveal capillary leukocyte velocity. Ophthalmology 2005; 112:22192224. 29. Tam J, Martin JA, Roorda A. Noninvasive visualization and analysis of parafoveal capillaries in humans. Invest Ophthalmol Vis Sci. 2010; 51:1691-1698. 30. Tam J, Dhamdhere KP, Tiruveedhula P, et al. Disruption of the retinal parafoveal capillary network in type 2 diabetes before the onset of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011; 52(12):9257-9266. 31. Tuten WS, Tiruveedhula P, Roorda A. Adaptive optics scanning laser ophthalmoscope-based microperimetry. Optom Vis Sci. 2012; 89(5):563-574. 32. Akagi T, Hangai M, Takayama K, et al. In vivo imaging of lamina cribrosa pores by adaptive optics scanning laser ophthalmoscopy. Invest Ophthalmol Vis Sci. 2012; 53(7):4111-4119. 33. Takayama K, Ooto S, Hangai M, et al. High-resolution imaging of the retinal nerve fiber layer in normal eyes using adaptive optics scanning laser ophthalmoscopy. PLoS One. 2012; 7(3):e33158. 34. Kocaoglu OP, Cense B, Jonnal RS, et al. Imaging retinal nerve fiber bundles using optical coherence tomography with adaptive optics. Vision Res. 2011; 51(16):1835-1844. 35. Werner JS, Keltner JL, Zawadzki RJ, Choi SS. Outer retinal abnormalities associated with inner retinal pathology in nonglaucomatous and glaucomatous optic neuropathies. Eye (Lond). 2011; 25(3):279-289. 36. Talcott KE, Ratmam K, Sundquist SM, et al. Longitudinal study of cone photoreceptors during retinal degeneration and in response to
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ciliary neurotrophic factor treatment. Invest Ophthalmol Vis Sci. 2011; 52(5):2219-2226 37. Jacobson SG, Aleman TS, Cideciyan AV, et al. Identifying photoreceptors in blind eyes caused by RPE65 mutations: prerequisite for human gene therapy success. Proc Natl Acad Sci USA. 2005; 102:6177-6182 38. Huang G, Qi X, Chui TY, Zhong Z, Burns SA. A clinical planning module for adaptive optics SLO imaging. Optom Vis Sci. 2012; 89(5):563-574.
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Simple estimation of Fluid Volumes in Neovascular AMD

Alexander C Walsh MD, Florian M Heussen MD, Yanling Ouyang MD, Srinivas R Sadda MD
I. Purpose To evaluate simple methods of estimating fluid volumes from spectral domain OCT (SD-OCT) in patients with neovascular AMD (NV-AMD). II. Methods A. Retrospective study of patients with NV-AMD imaged with macular cube SD-OCT scans B. Visits were selected for this study if any SD-OCT B-scan demonstrated any feature of interest: cystoid macular edema (CME), subretinal fluid (SRF), or a pigment epithelial detachment (PED). C. Cross-sectional analysis (CSA) was performed on 1 visit from each subject. D. Longitudinal analysis (LA) was performed on subjects who had 4 or more visits selected. E. Ground truth measurements of feature volumes were made by manual outlining features of interest using validated grading software (3D-OCTOR). G. Automated measurements (taken directly from each OCT machine) included: 1. Total macular volume 2. Foveal central subfield thickness H. Measurement comparisons included: 1. Correlations between ground truth and simplified measurements 2. Correlations between ground truth and automated measurements 3. Mote Carlo permutation correlation analysis 4. Sensitivities/specificities of simplified and automated measurements to detect increases or decreases in feature volumes measured with ground truth methods III. Results A. 45 visits for 25 subjects were included in this study. 1. CSA: 26 visits from 26 eyes of 25 subjects were included in the CSA. 2. LA: 25 visits from 5 eyes of 5 subjects were included in the LA. B. Correlations 1. Cross-sectional analysis (CSA) group a. The best correlations of simplified measures with ground truth measures were maximum height for CME (r2 0.96), number of B-scans for SRF (r2 0.88), and number of B-scans for PED (r2 0.70). b. The best correlations of automated measurements with ground truth measures were FCS thickness for CME (r2 0.47, 0.19), macular volume for SRF (r2 0.38, 0.62), and FCS thickness for PED (r2 0.10, 0.17). 2. Longitudinal analysis (LA) group a. The best correlations of simplified measures with ground truth measures were maximum height for CME (r2 0.98), number of B-scans for SRF (r2 0.97), and maximum height for PED (r2 0.43). F. Simplified measurements for each feature included: 1. Number of B-scans involved in feature 2. Number of A-scans involved in feature 3. Maximum height of feature b. The best correlations of automated measurements with ground truth measures were FCS thickness for CME (r2 0.33), FCS thickness for SRF (r2 0.72, 0.81), and macular volume for PED (r2 0.34, 0.72).
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3. Monte Carlo correlation analysis a. The statistical significance of correlations between simplified and ground truth measurements exceeded P = .005 with only onethird of the studys sample size. b. Many automated measurements failed to achieve statistical significance. When they did, loss of just a few cases often resulted in loss of statistical significance. (Figure 3: see page 104) 4. Sensitivity/specificity analysis a. Simplified measurements have higher sensitivity and specificity for detection of increases or decreases in fluid volumes than automated measurements from the OCT machines themselves. b. Between the automated measurements, FCS was more specific than macular volume but produced numerous false-negative predictions. When a 100-m change in FCS (ie, clinical trials standard) was used as the threshold to detect increases or decreases in fluid volumes, the sensitivity of FCS for detection of changes in ground truth fluid volume dropped to 12.5%. (Figure 4: see page 104) IV. Conclusion The number of B-scans of subretinal fluid or cystoid macular edema in a macular cube SD-OCT scan correlates strongly and robustly with detailed manual
grading but takes seconds instead of hours to measure. Simplified estimators also predict increases or decreases in fluid volumes with high sensitivity and specificity. Automated measurements from OCT machines neither correlate well nor predict changes in volume well when compared to detailed manual measurements. Since these simplified measurements closely approximate reading center measurements, they may be useful to both clinical trials of NV-AMD therapies and clinicians in practice who would like to track subretinal fluid and cystoid macular edema volumes.
Selected Readings
1. Joeres S, Tsong JW, Updike PG, et al. Reproducibility of quantitative optical coherence tomography subanalysis in neovascular age related macular degeneration. Invest Ophthalmol Vis Sci. 2007; 48:4300-4307. 2. Keane PA, Mand PS, Liakopoulos S, Walsh AC, Sadda SR. Accuracy of retinal thickness measurements obtained with Cirrus optical coherence tomography. Br J Ophthalmol. 2009; 93:1461-1467. 3. Mylonas G, Ahlers C, Malamos P, et al. Comparison of retinal thickness measurements and segmentation performance of four different spectral and time domain OCT devices in neovascular agerelated macular degeneration. Br J Ophthalmol. 2009; 93:14531460. 4. Sadda SR, Joeres S, Wu Z, et al. Error correction and quantitative subanalysis of optical coherence tomography data using computerassisted grading. Invest Ophthalmol Vis Sci. 2007;48:839-848. 5. Sadda SR, Keane PA, Ouyang Y, Updike JF, Walsh AC. Impact of scanning density on measurements from spectral domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2010;51: 10711078.
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Germline BAP1 Mutations in ocular Melanoma and other Malignancies

Ivana K Kim MD
I. BAP1 A. BRCA1-associated protein 1 B. Deubiquitinating enzyme located in cell nucleus C. Encoded on chromosome 3 (3p21) D. Tumor-suppressor gene whose loss of function plays a key role in metastatic ocular melanoma II. Frequent Somatic Mutations in Metastasizing Ocular Melanoma First Described by Harbour and Colleagues1 A. Somatic mutations in BAP1 found in 84% of melanomas classified as high-risk for metastasis by expression profiling (class 2) B. No correlation between GNAQ and BAP1 mutation status C. One germline mutation found in original series III. Germline Mutations A. Ocular melanoma2 1. Analysis of 100 ocular melanoma cases a. 50 cases with metastatic disease b. 50 cases without metastatic disease c. The 2 groups were matched for risk factors. i. Age ii. Largest tumor diameter iii. Ciliary body involvement 2. 4/50 (8%) with germline BAP1 mutations in patients with metastases 3. 0/50 (0%) with germline BAP1 mutations in patients without metastases B. Hereditary cutaneous melanoma2 1. Analysis of 200 patients with hereditary cutaneous melanoma, defined as: a. One or more first-degree relatives with cutaneous or ocular melanoma b. Two or more affected relatives with cutaneous or ocular melanoma on one side of the family c. Three or more primary melanomas in the absence of a family history 2. 2/7 patients (28.5%) with cutaneous and ocular melanoma in family history found to have germline BAP1 mutations 3. 1/193 patients (0.52%) with only cutaneous and no ocular melanoma in family history found to have germline BAP1 mutations 4. Cutaneous melanoma in cases with BAP1 mutations more likely to be nevoid type. 5. BAP1 mutations carriers also have atypical melanocytic proliferations.3 C. Other malignancies in BAP1-mutant families 1. Mesothelioma4 2. Lung adenocarcinoma2,5 3. Meningioma5 4. Renal cell2,4 5. Cholangiocarcinoma2 6. Breast2,4 7. Ovarian4 IV. Implications A. Ocular melanoma patients with a family history of cutaneous or ocular melanoma may be at higher risk of metastatic disease. B. Detection of germline BAP1 mutations in blood samples from these patients may confirm high risk of metastasis without need for needle biopsy of tumor. C. Clinical testing in development
References
1. Harbour JW, Onken MD, Roberson ED, et al. Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 2010; 330(6009):1410-1413. 2. Njauw C-NJ, Kim I, Piris A, et al. Germline BAP1 inactivation is preferentially associated with metastatic ocular melanoma and cutaneous-ocular melanoma families. PLoS ONE. 2012; 7(4):e35295. doi:10.1371/journal.pone.0035295. 3. Wiesner T, Obenauf AC, Murali R, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011; 43(10):1018-1021. 4. Testa JR, Cheung M, Pei J, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011; 43(10):10221025. 5. Abdel-Rahman MH, Pilarski R, Cebulla CM, et al. Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet. 2011; 48(12):856859.
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Practical Approaches to Needle Biopsy and Genetic Diagnosis for ocular Melanoma
Thomas M Aaberg JR MD
I. Brachytherapy for Uveal Melanoma A. Performed first by R Foster Moore on February 15, 1929 B. Local control of uveal melanoma now approaches 100% success. C. 80 years after first brachytherapy case, patient survival rates remain unchanged. II. Micrometastatic disease occurs early in specific cases. A. How do we identify these cases? 1. Improve our detection methods, or 2. Identify characteristics of tumors at greatest risk of metastasizing early. B. What do we do once identified? 1. More aggressive metastatic disease surveillance, and/or 2. Initiate prophylactic interventions in the hopes of eradicating or at least controlling micrometastatic disease. III. Identifying High-risk Patients A. Clinical finding 1. Tumor size 2. Location 3. Cell type (epithelioid vs. spindle) 4. These characteristics do not sufficiently differentiate those at greatest risk from those at lowest risk. B. Molecular diagnostics 1. Improved our understanding of melanoma 2. Improved our characterization of the tumors DNA/RNA makeup 3. Improving the identification of those patients at high risk for developing metastatic disease 4. Currently, the two most accepted methods a. Measuring chromosomal gains and losses (chromosomal analysis) b. Measuring the expression of specific genes by neoplastic cells (gene expression profiling) C. Chromosome analysis 1. The most common statistically independent prognostic chromosomal expression associated with metastatic disease is monosomy Chromosome 3, and less frequently gain of 8q. 2. Chromosomal analysis can be performed at most hospital laboratories via a number of methods: a. SNP assay across the chromosome to assess for loss of heterozygosity b. Fluorescence in situ hybridization c. Array-based comparative genomic hybridization 3. Technical yield ranges from 50% to 91%. Greater tissue requirements compared to GEP D. Gene expression profiling (GEP) 1. Proprietary PCR testing on a microfluidic platform 2. Castle laboratories. 3. Differentiates patients into 3 catagories: class 1a, class 1b, and class 2 4. Technical yield is 97%; utilizes preamplification and microfluidics IV. Tissue procurement is necessary for cytogenetic and GEP testing. A. Enucleated eyes: An eye cap (a transverse section through the eye to include a portion of the tumor) will provide ample tissue for chromosomal and GEP analysis. B. Nonenucleated eyes 1. Require minimally invasive technics, such as fine needle aspiration biopsy 2. Excellent cytopathologist V. Fine Needle Aspiration Biopsy (FNAB) of Uveal Melanoma A. Techniques include: 1. Transscleral full thickness 2. Transscleral via a scleral flap 3. Transvitreal B. Transscleral biopsy 1. Typically performed at the time of radiation plaque placement or placement of titanium buttons for tumor localization and subsequent proton beam irradiation 2. Equipment a. Basic surgical tray (ie, Westcott scissors, tooth forceps, needle driver, etc.) b. 27- or 25-gauge 5/8th-inch needle c. 10 cc syringe
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d. Length of tubing with appropriate male and female connectors e. Optional: tissue glue, absolute alcohol 3. Technique a. Create conjunctival flap. b. Isolate 2 or more extraocular muscles on bridle sutures to provide stabilization of the globe. c. Trans-illuminate the globe and mark out the trans-illumination defect. d. Connect the needle to the syringe directly or via a length of tubing. e. Make sure the biopsy field is completely dry. f. It is necessary to know the thickness of the tumor and the thickest point of the tumor in order to minimize the risk of perforating the overlying retina. i. Consider marking the needle with a marking pen or small steri-strip to provide a depth gauge. ii. In thin tumors, angling the needle may be wise as this improves the self-sealing nature of the needle pass, and decreases the risk of passing full thickness through the tumor. iii. When angling the needle, the needle is introduced into the eye with the bevel out. Once in the eye beyond the bevel, rotate the needle 180 degrees, exposing the ostomy of the needle to the choroid and away from the sclera. g. A sawing motion under active suction has improved my cell yield. h. Release suction before exiting the eye. i. Pass off the syringe j. Immediately cover the site with a plaque, tissue glue, or absolute alcohol on a cotton tip applicator. k. Process the specimen promptly. i. Follow local laboratory protocol for tissue processing. ii. Utilize cell prep solution provided by Castle. (a) Detach needle and/or tubing from syringe. (b) Draw air into syringe. (c) Reattach needle and/or tubing to syringe. (d) Forcefully express the air into the provided tube.
(e) Aspirate the entire cell solution provided. I wash the needle with the solution gently. (f) Inject the wash into the designated tube. C. Transvitreal biopsy 1. Indirect ophthalmoscopy a. A 25-gauge 1.5-inch needle is connected to a 10 cc syringe via an intervening length of tubing. b. Pass the needle through the pars plana. c. Cross the vitreous cavity. d. Enter the tumor at the apex. e. Ten ccs of suction is applied. If possible, a sawing motion is performed; however, when performing a transvitreal biopsy one must be exceedingly careful to have the ostomy of the needle well within the tumor and avoid aspirating the retina. f. If retina is aspirated, release vacuum and push the needle back into the tumor, attempting to pull the retina out of the needle ostomy. Extract the needle slowly. i. If the retina remains, place the needle back into the tumor and have the assistant provide a very minute amount of reflux. ii. Do not reflux within the vitreous cavity, as you may seed the vitreous. g. Apply a digit or cotton tip applicator to the biopsy entry site to control intraocular hemorrhage. 2. Via the operating room microscope using a chandelier system and infusion. a. Place a chandelier infusion system. i. Visualization ii. IOP control for hemostasis. b. Place a second trocar through which the biopsy needle or other necessary instrumentation will pass. i. Diathermy ii. Soft tip cannula (enables the delivery of thrombin) D. Complications 1. Rhegmatogenous detachments: Surprisingly low incidence a. Fibrin from blood likely closes the break. b. The tumor acts as a tamponade (ie, internal buckle). 2. Subretinal hemorrhage: Often limited and resolves within 4 months
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Section X: oncology 3. Vitreous hemorrhage: Often limited and resolves within 4 months 4. Misdiagnosis caused by sampling errors a. Tumors have heterogeneous distribution of monosomy 3 abnormality b. GEP may be less affected by heterogeneous cell distribution since this is an assay of the tumors microenvironment. 5. Tumor spread or seeding along needle track a. Needle biopsy of breast masses is one of the most widely accepted uses of FNAB. b. Several studies have looked at the risk of seeding tumor cells following breast biopsy. i. Tumor seeding incidence is approximately 1%. ii. However, as the interval between biopsy and surgery lengthens, the incidence of seeding declines, suggesting that displaced tumor cells are not necessarily viable. c. Data for FNAB in ophthalmology are less plentiful. i. Foos (1988) and colleagues reported on 22 FNABs performed on enucleated eyes. (a) Cells in 67% of all transscleral tracks (b) Cells in 53% of transvitreal tracks (c) However, the number of tumor cells was less than that associated with tumor growth in experimental models. ii. Shields (2007) reported on 140 patients who underwent FNAB immediately prior to I125 brachytherapy. No cases of tumor recurrence along the biopsy track occurred. iii. McCannel (2012) reported on 170 consecutive patients with choroidal melanoma managed with FNAB and I125 brachytherapy and 1-6 years of follow-up (mean 2.7 years). (a) No cases of orbital dissemination occurred. (b) Metastatic rate was 13% (comparable to the 13% rate reported by the COMS), suggesting FNAB did not worsen the prognosis for metastatic disease. E. Billing/reimbursement CPT code: 67415 = fine needle aspiration of orbital contents F. Contraindications to FNAB 1. Children in which retinoblastoma is in the differential diagnosis
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2. No cytopathologist available 3. Inadequate visualization of the tumor VI. Survey of Ocular Oncologists 109 ocular oncologists worldwide were asked to participate in the following survey questions. There were 50 respondents (46% response rate). A. Do you perform some type of analysis that requires a FNAB? (see Figure 1) B. How many uveal melanoma patients are not eligible for biopsy due to safety concerns? 1. Mean: 20.92% 2. Median: 10% 3. Range: 0%-100% C. For eligible patients do you perform analysis for: 1. Enucleated eyes only: 13.5% 2. All cases: 86.5% D. For what percent of uveal melanoma cases do you offer cytogenic testing? (see Figure 2) E. For what percent of uveal melanoma cases do you offer molecular testing? (see Figure 3) F. How many biopsies for uveal melanoma do you perform annually? 1. Mean: 27.41 biopsies 2. Median: 15 biopsies 3. Range: 0-250 biopsies VII. Survey: Technique A. Vitrector for biopsy (see Figure 4) B. Size of needle gauge for biopsy (see Figure 5) C. Flexible tubing to stabilize the needle position (see Figure 6) D. Size of syringe (see Figure 7) E. Scleral window or full-thickness sclera (see Figure 8) F. What percent of biopsies are performed transsclerally? 1. Mean: 70.31% 2. Range: 0%-100% G. What percent of biopsies are performed transvitreally? 1. Mean: 29.69% 2. Range: 0%-100%) H. If you perform both transscleral and transvitreal biopsies, what factors contribute to your decision process? 1. Tumor location a. Anterior tumors = transscleral b. Posterior tumors = transvitreal
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Figure 10.
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2. Tumor thickness a. Tumors less than 1.5-2.0 mm = transvitreal b. Tumors greater than 1.5-2.0 mm = transscleral Table 1. of those who do not do both transscleral and transvitreal: Response
Only do transcleral Only do transvitreal
I. After the biopsy is performed do you seal the biopsy site? 1. Yes = 54% 2. No = 46% J. If so, with what? 1. Suture 2. Cryo 3. Glue: Isodent, Dermabond, Cyanoacrylate K. How is the biopsy performed? (see Figure 9) L. How many tumor sites? (see Figure 10) M. Which fixative? (see Figure 12)
Percentage
25.7% 2.9%
Frequency
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Figure 13.
N. Other category 1. Hanks for chromosome and RNA preservative for GEP 2. Diff-Quick VIII. Survey: Clinical Application A. Do you offer all patients biopsy and analysis of the tumor? (see Figure 13) 1. Yes = 77% 2. No = 33% B. If no, what factors determine whether you offer the procedure? 1. If tumor is small and close to the macula, then may not offer because of concern about risk of subretinal hemorrhage into the macula. 2. Currently, no additional treatment protocols that would alter treatment outcomes based upon this information. I do offer to refer them to a center that does perform biopsy if they desire. 3. Not for diagnosis, but for GEP at present. I believe any adjuvant trial in the near future will require GEP, and aim at the higher risk patients, and do it to be prepared for that. The studies on enucleated cases we have done for 15+ years all were done.
4. Foveal melanomas where potential morbidity of biopsy (causing vision loss) may outweigh benefit and those tumors less than 2-2.5 mm thick are usually not biopsied 5. If tumor is too small and near macula, I dont offer the biopsy since I consider the risk of biopsy. 6. A large insurance carrier in my area has asked me not to do the biopsy. 7. Generally do not offer unless patient asks or is having difficulty deciding on treatment course. C. What percentage of patients declines the offer for testing? 1. Mean: 37.54% 2. Range: 0%-100% D. What reasons are given for declining? (see Figure 14) E. Other category 1. Elderly patients generally not interested 2. That the information would be not affect treatment and knowledge of type 1 or type 2 melanoma with regard to prognosis would be academic only at this time. I find patients would rather not know if the tumor is more likely to be metastatic or not, given there is not currently any
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Figure 14.
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Figure 15.
additional intervention that could help them if this were found to be the case. 3. Some decline to know, or have the information documented. 4. Irrational concern that biopsy will spread tumor cells and thereby worsen prognosis 5. No effective treatment 6. Age and health of the patient 7. They are made aware of the potential risks and possible benefits. They typically choose to avoid the risks. 8. Potential risks of hemorrhage, RD, or ESE 9. The knowledge will not prevent metastasis 10. Once they learn that there is no proven advantage in terms of longevity with intensive monitoring, most are not compelled to seek genetic information. F. How do you use the information clinically? (see Figure 15) G. Write-in responses 1. I generally have the patient see a medical oncologist who specializes in melanoma; they generally increase metastatic surveillance, and have access to clinical trials. I specifically as the ophthalmologist do not change my management. 2. I refer high-risk class II patients to an oncologist with experience with metastatic choroidal mela-
noma for their ongoing metastatic surveillance. They use a more frequent surveillance protocol, with more frequent imaging (liver ultrasound). 3. This is difficult at present! There are not great trials, metastatic surveillance is not shown to have survival benefit, and we are building this bridge as we walk on it. To my knowledge there isnt a good prophylaxis yet either. But gathering the data to analyze, and stratify as soon as available is essential. 4. At present, there is (in my opinion) no legitimate clinical trial of any adjuvant therapy for uveal melanoma. At present, there is also no compelling clinical evidence of any regimen or frquency of surveillance testing for uveal melanoma metastasis improves patient survival. In spite of this, I inform patients that they appear (based on evidence provided by the testing of their FNAB aspirates) to have low (GEP class 1A), relatively low (class 1B), or relatively high risk of developing clinically apparent distant metatases in the future. I advise patients in all three groups about the current lack of compelling evidence about survival benefits of any method of treatment for uveal melanoma metastasis and the concurrent lack of evidence that any regimen or frequency of surveillance testing for metastasis changes their prognosis. At the same time, I inform them that an adjuvant therapy clinical trial based on legitimate preliminary evidence (not hype) may induce me to contact them as candidates for enrollment.
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7. Maat W, Jordanova ES, van Zelderen-Bhola SL, et al. The heterogeneous distribution of monosomy 3 in uveal melanomas: implications for prognostication based on fine needle aspiration biopsies. Arch Pathol Lab Med. 2007; 131:91-96. 8. Young TA, Burgess BL, Rao NP, Glasgow BJ, Straatsma BR. Transscleral fine-needle aspiration biopsy of macular choroidal melanoma. Am J Ophthalmol. 2008; 145(2):297-302. 9. Schoenfield L, Pettay J, Tubbs RR, Singh AD. Variation of monosomy 3 status within uveal melanoma. Arch Pathol Lab Med. 2009; 133:1219-1222. 10. Shields CL, Ganguly A, Bianciotto CG, Turaka K, Tavallali A, Shields JA. Prognosis of uveal melanoma in 500 cases using genetic testing of fine-needle aspiration biopsy specimens. Ophthalmology 2011; 118(2):396-401. 11. Loughran CF, Keeling CR. Seeding of tumour cells following breast biopsy: a literature review. Br J Radiol. 2011; 84(1006):869-874. 12. Robertson EG, Baxter G. Tumour seeding following percutaneous needle biopsy: the real story! Clin Radiol. 2011; 66(11):1007-1014. 13. Brenner RJ, Gordon LM. Malignant seeding following percutaneous breast biopsy: documentation with comprehensive imaging and clinical implications. Breast J. 2011; 17(6):651-656.
Selected Readings
1. Moore RF. Choroidal sarcoma treated by the intraocular insertion of radon seeds. Br J Ophthalmol. 1930; 14(4):145-152. 2. Henkes HE, Manschott WA. The danger of diagnostic biopsy in eyes suspected of an intraocular tumour. Ophthalmologica 1963; 145:467-469. 3. Reese AB. Tumors of the Eye. 3 ed. Hagerstown, MD: Harper & Row; 1976. 4. Augsburger JJ, Shields JA. Fine-needle aspiration biopsy of solid intraocular tumors; indications, instrumentation and techniques. Ophthalmic Surg. 1984; 15:34-40. 5. Glasgo BJ, Brown HH, Zargoza AM, Foos RY. Quantitation of tumor seeding from fine needle aspiration of ocular melanomas. Am J Ophthalmol. 1988; 105:538-546. 6. Shields CL, Ganguly A, Materin MA, et al. Chromosome 3 analysis of uveal melanoma using fine-needle aspiration biopsy at the time of plaque radiotherapy in 140 consecutive cases: the Deborah Iverson, MD, Lectureship. Arch Ophthalmol. 2007; 125(8):1017-1024.
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New Imaging Techniques for ocular Tumors

I. Imaging Techniques A. Historical 1. Fundus photography 2. Fluorescein angiography/Indocyanine green 3. Ultrasonography B. Evolving 1. OCT 2. Autofluorescence 3. High-resolution ultrasound C. Novel 1. Intraoperative imaging 2. Wide-field approaches II. Disease Applications A. Choroidal/ciliary body tumors 1. Uveal melanoma 2. Choroidal hemangioma 3. Choroidal metastases 4. Hemangioblastoma/angioma B. Retinal/subretinal/subretinal pigment epithilial tumors 1. Retinoblastoma 2. Lymphoma 3. Leukemia C. Orbit 1. Metastatic tumors 2. Lymphoma 3. Vascular tumors 4. Developmental tumors
III. Technical Considerations A. Clinic vs. operating room B. Positioning restrictions (horizontal vs. upright) C. Invasive vs. noninvasive D. Registration/image quality/reproducibility IV. Clinical Focus A. Diagnostic enhancement B. Tumor documentation C. Evaluation of treatment response D. Telemedicine E. Educational impact 1. Family 2. Surgical team 3. Physicians in training V. Major Advances in Imaging A. Amazing improvements in diagnostic accuracy B. Improvements in recognition of recurrent/residual disease activity C. Critical in delivery of targeted therapies D. Incorporation of intraoperative evaluations and treatment now possible. E. Telemedicine consensus evaluations VI. Future A. Noninvasive evaluation of tumor surface markers (molecular tumor profiling) B. Improved evaluation of early tumor response C. Wide dissemination of global tumor evaluation
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Follow-up After Intra-arterial Chemotherapy for Retinoblastoma

Carol L Shields MD, Carlos Bianciotto MD, Enzo Fulco MD, Swathi Kaliki MD, Ann Leahey MD, Pascal Jabbour MD, Jerry A Shields MD
I. Methods of Chemotherapy Delivery A. Intravenous 1. Termed chemoreduction 2. Agents: vincristine, etoposide, carboplatin for 6 cycles 3. Complications a. Eye complications: None b. Systemic complications: Minimal (Philadelphia experience, 700 children) i. renal toxicity: <1% ii. ototoxicity: <1% iii. leukemia: 0% iv. second cancers: 0% at 11 years B. Subtenons: Used in conjunction with intravenous chemotherapy C. Intravitreal: For recurrent vitreous seeds after standard therapy D. Intra-arterial chemotherapy 1. Termed IAC 2. Catheterization of the ophthalmic artery 3. Agents: melphalan, carboplatin, topotecan for 3 cycles 4. Complications a. Eye complications include: i. choroidal atrophy: 10% ii. retinal artery obstruction: 5% iii. ophthalmic artery obstruction: 2% iv. minor side effects of eyelid edema, ptosis, dysmotility b. Systemic complications include minor transient cytopenia. Risk for leukemia. II. What have we learned with intra-arterial chemotherapy over the past 5 years? A. Tumor control 1. Tumor control for primary treatment a. Group A: Not used b. Group B: Not used c. Group C: 100% control d. Group D: Nearly 100% control e. Group E: 33% control 2. Tumor control for secondary treatment is 50% to 80%. 3. Tumor control can be excellent with only 1 or 2 cycles for some Group C or D eyes. 4. Retinal detachment will settle flat in about 75% of cases. 5. Vitreous seeds control in 67% of cases. 6. Subretinal seeds control in 82% of cases. B. Complications 1. Minor complications include eyelid ptosis, cilia loss dysmotility, skin erythema. 2. Major complications include vascular events. a. Fluorescein can show retinal vascular pruning. b. Vascular events much less with experience and nearly no event in our practice for over 1 year. c. Minimize events with heparin, short catheterization time, stratify melphalan dose per age, peek catheter into ophthalmic artery ostium without entering fully. 3. Monkey studies have shown endothelial toxicity from melphalan and carboplatin. 4. Human enucleation following treatment has shown refractile material in arteries consistent with foreign body or chemotherapy precipitation. 5. Several editorials written on this topic due to risk for complications. 6. Complications are currently uncommon in our practice as we have gained experience with technique and dosing. III. Current Strategy A. Bilateral retinoblastoma: Chemoreduction is choice therapy to control bilateral retinoblastoma as well as prevent pinealoblastoma and minimize second cancers in germline mutation children. B. Unilateral retinoblastoma: If Group C or D, then intra-arterial chemotherapy is used. If Group E, intra-arterial chemotherapy vs. enucleation is considered.
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References
Clinical studies 1. Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010; 21:203-212. 2. Abramson DH, Dunkel IJ, Brodie SE, et al. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology 2008; 115:1398-1404. 3. Shields CL, Ramasubramanian A, Rosenwasser R, Shields JA. Superselective catheterization of the ophthalmic artery for intraarterial chemotherapy for retinoblastoma. Retina 2009; 29:1207-1209. 4. Shields CL, Bianciotto CG, Ramasubramanian A, et al. Intra-arterial chemotherapy for retinoblastoma: I. Control of tumor, subretinal seeds, and vitreous seeds. Arch Ophthalmol. 2011; 129:13991406. 5. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: II. Treatment complications. Arch Ophthalmol. 2011; 129:1407-1415. 6. Shields CL, Kaliki S, Shah S, Jabbour P, Bianciotto CG, Shields JA. Effect of intra-arterial chemotherapy on retinoblastoma-induced retinal detachment. Retina 2012; 32:799-804. 7. Shields CL, Kaliki S, Shah SU, et al. Minimal exposure (1 or 2 cycles) of intra-arterial chemotherapy in the management of retinoblastoma. Ophthalmology 2012; 119:188-192. 8. Bianciotto CG, Shields CL, Iturralde JC, et al. Fluorescein angiographic findings after intra-arterial chemotherapy for retinoblastoma. Ophthalmology 2012; 119:843-849. 9. Shields CL, Kaliki S, Rojanaporn D, Al-Dahmash S, Bianciotto C, Shields JA. Intravenous and intra-arterial chemotherapy for retinoblastoma: what have we learned. Curr Opin Ophthalmol. 2012; 23: 202-209. Pathology studies 10. Eagle RC Jr, Shields CL, Bianciotto CG, et al. Histopathologic observations after intra-arterial chemotherapy for retinoblastoma. Arch Ophthalmol. 2011; 129:1416-1421. 11. Wilson MW, Qaddoumi I, Billups C, et al. A clinicopathological correlation of 67 eyes primarily enucleated for advanced intraocular retinoblastoma. Br J Ophthalmol. 2011; 95:553-558. Animal study 12. Wilson MW, Jackson JS, Phillips BX, et al. Real-time ophthalmoscopic findings of superselective intraophthalmic artery chemotherapy in a nonhuman primate model. Arch Ophthalmol. 2011; 129:1458-1465. Editorials 13. Shields CL, Shields JA. Intra-arterial chemotherapy for retinoblastoma: the beginning of a long journey [editorial]. Clin Experiment Ophthalmol. 2010; 38:638-643. 14. Abramson D. Chemosurgery for retinoblastoma: what we know after 5 years. Arch Ophthalmol. 2011; 129:1492-1493. 15. Wilson MW, Haik BG, Dyer MA. Superselective intraophthalmic artery chemotherapy: what we do not know. Arch Ophthalmol. 2011; 129:1490-1491. 16. Levin MH, Gombos DS, OBrien JM. Intra-arterial chemotherapy for advanced retinoblastoma: is the time right for a prospective clinical trial? Arch Ophthalmol. 2011; 129:1487-1489.
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Section XI: Late Breaking Developments, Part II
Retina
Late Breaking Developments, Part II
NoTeS
Retina
Section XII: Diabetes
119
I Use the DRCR.net Guidelines in My Clinical Practice (Yes/No)

Pro
Neil M Bressler MD
Con
Harry W Flynn Jr MD
The results from the DRCR network are based on well-designed multicenter collaborative clinical trials following strict protocols for eligibility, randomization, treatment and follow-up. In clinical practice, many of our patients do not meet the entry criteria for the individual DRCR protocols and as such, we must tailor our treatments to the individual patient. Granted, most of us believe that anti-VEGF therapy is the modality of choice in patients with diabetic macular edema (DME) and moderate to advanced visual loss. Beyond the DRCR reports, controversies exist and require physician judgment. First, many factors go into the decision to initiate and continue treatment with anti-VEGF therapy. The DRCR network in Protocol I did not study patients with better than 20/32 (about 20/40 Snellen acuity). Therefore, we do not have DRCR guidelines for treatment of these patients. Similarly, the study used central retinal thickness measurements of DME using time domain OCT in Protocol I. Nowadays, most of us are using spectral domain OCT, which provides better macular details but also gives a greater baseline central retinal thickness. The decision to continue treatment is also complex. In DME, contrasted with wet macular degeneration, it may not be necessary to eliminate all cystic change by continued injections over an extended time. Many patients appear to stabilize even though a few tiny cysts are not completely resolved. Reduced severity of NPDR and PDR after anti-VEGF injection is an added benefit shown by the DRCR, but the risks include progressive traction retinal detachment in eyes with pre-existing fibrovascular proliferative disease. Second, the anti-VEGF agent of choice and the dosage are is still up for debate. In Protocol I, intravitreal ranibizumab in a dose of 0.5 mg for 4 or more consecutive months during the first year was the basis for the favorable outcomes. The FDA has recently approved 0.3-mg ranibizumab based on the RISE and RIDE studies. Similarly, favorable outcomes have been published in the BOLT study using 1.25-mg bevacizumab, which appears to provide similar rates of visual acuity improvement and similar rates of uncommon adverse events. On a practical basis, I prefer to use intravitreal 1.25-mg bevacizumab in treating DME in my own practice. Third, the costs of treatments are highly variable. If ranibizumab injections are used as in Protocol I, the cost could be as high as $30,000 to $45,000 for the drug alone. In comparison, bevacizumab on a similar schedule would cost less than $1,000. Our waiting rooms are currently overwhelmed with injection patients, and this DRCR style of treatment for DME is unrealistic given our existing workforce in Ophthalmology. Although we may treat monthly during the first 3 to 6 months of management, we can revert back to less frequent injections after an initially favorable response. Fourth, we have to consider the patients assessment of the DRCR-style treatment requirements using study guidelines. Going beyond the safety and efficacy, how do patients feel about multiple monthly injections compared to one or two grid laser
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Retina
treatments? Is the 5-letter gain (compared to laser) worth the added time and hassle to patients and their families? In summary, the DRCR network has provided excellent clinical trials data to assist us in managing our patients. Ultimately, the community will decide the true standard of care for DME. The American Academy of Ophthalmology has not yet adopted the DRCR network guidelines into the 2011-2012 Preferred Practice Pattern, and therefore we cannot expect individual practitioners to strictly follow the DRCR Network study protocols.
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I Use the DRCR.net Guidelines in My Clinical Practice (Yes/No)

Rebuttal, Pro
Mark W Johnson MD
Rebuttal, Con
Jennifer I Lim MD
The results of the DRCR should not be the sole guide to therapy for diabetic macular edema (DME). In 2012, we now have several multicentered clinical trials evaluating the efficacy of antiVEGF therapy for DME. Such anti-VEGF therapy has utilized predominantly ranibizumab, although there are Phase 2 studies that have evaluated bevacizumab. These studies have utilized several treatment regimens, ranging from monthly treatment in the RIDE/ RISE studies to the initial monthly and then p.r.n. regimens of the DRCR studies. I use the totality of all the clinical trials data to guide my practice in the management of DME. In our clinical practices, there are patients who have parameters that fall outside of the inclusion criteria for these studies. It is our duty to synthesize all of the anti-VEGF information available to make the best treatment decision in our patients interest. In our clinical practices, there are patients who cannot afford ranibizumab for DME. Bevacizumab, based on BOLT, is a treatment option for these patients. There are also patients for whom anti-VEGF may be contraindicated, and there are other studies on steroids that can guide our therapy. In summary, there are several other Phase 3 clinical trials such as RESTORE and RIDE/ RISE that are available to offer us guidance in our choice of therapy and treatment regimen. There are also Phase 2 studies such as DAVINCI and BOLT that lend evidence to efficacy of bevacizumab and aflibercept, respectively. The DRCR is not the only study on anti-VEGF therapy for DME, although it was the first Phase 3 anti-VEGF study and also an excellent one. In addition, studies such as FAME and FAMOUS show evidence that steroids have an effect on DME. One should not base treatment only on the DRCR but use the variety of information available to formulate a treatment plan for DME.
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Subthreshold Laser Is an Important Treatment for Macular edema (Yes/No)

Pro
N H Victor Chong MD
Con
Retina
123
I Still Use Scissors in Diabetic Vitrectomy (Yes/No)

Pro
Curved Scissors Delamination for Diabetic Traction Retinal Detachment Surgery Steve Charles MD
Design and manufacturing advances in recent years have enabled safe use of the vitreous cutter for the removal and segmentation of epiretinal membranes (ERM) in diabetic traction retinal detachment (TRD) cases. Higher cutting rates (ie, at least 5000 cuts/minute) as well as smaller diameters produce port-based flow limiting, which reduces pulsatile vitreoretinal traction. Portbased flow limiting limits surge and iatrogenic retinal breaks after sudden elastic deformation of dense epiretinal membrane through the port. New manufacturing methods allow the port to be closer to the tip, improving access to epiretinal membranes in TRD cases. There are two types of cutter delamination. Foldback delamination is performed by placing the cutter on the anterior surface of the ERM just behind the leading edge. Trans-orifice pressure causes flexible, typically thinner, ERM to fold back into the port. This method is safer than conformal cutter delamination but cannot be used unless the ERM is flexible. Conformal cutter delamination is utilized for rigid, thicker ERM that cannot fold back into the port. Conformal means that the angle of attack is constantly altered by rotating the cutter along the long axis to cause rotation of the port away from the retina while maintaining apposition of the cutter port to ERM. Curved scissors such as the Alcon DSP 25G scissors are better for both segmentation and delamination because the retinal surface is concave; the curve reduces the chances of impaling the tips in retina. There is no longer any rationale for either vertical or horizontal scissors. In addition, blade thickness is far less than blade width, one curved scissors blade can be introduced under the ERM in the potential space between ERM and retina in order to perform access segmentation without lifting the ERM and tearing the retina. Simply rotating the scissors after access segmentation so that both blades are under the ERM to begin delamination eliminates tool exchange and reduces the number of tools needed.
Con
Carl C Awh MD
In Tennessee, there are two approaches to dissecting diabetic membranes. My esteemed opponent from Memphis routinely uses scissors. In Nashville, I do not. I will argue my position, while respecting his. Hunters once used flint arrowheads. Writers once used quill and ink. And, retina surgeons once used scissors for diabetic vitrectomy. Technology, in the form of smaller-gauge high-speed vitreous cutters and improved illumination systems, marches on.
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Anti-VeGF Is the Ideal Treatment for Diabetic Macular edema (Yes/No)

Pro
Julia A Haller MD
Con
I. The Case Against Anti-VEGF Therapies as the Ideal Treatment for Diabetic Macular Edema (DME) A. The efficacy of anti-VEGF therapies is highly dependent on the treatment protocol and frequency of repeat injections. 1. In RISE and RIDE, monthly administration of 0.5-mg ranibizumab (Lucentis, Genentech Inc.; South San Francisco, Calif., USA) resulted in 39.2% of patients in RISE and 45.7% of patients in RIDE experiencing 3 or more lines (15 letters) gain in BCVA at 24 months.1 Unlike the rapid increase and stabilization of visual acuity seen in patients with AMD in ANCHOR and MARINA, visual improvement after the first 3 doses in RISE and RIDE, while dramatic, was approximately two-thirds of the maximal improvement observed overall and there was gradual, continued improvement for the remainder of the 24-month study duration.1-3 2. Less frequent dosing results in less-than-maximal improvements in visual acuity and/or anatomic outcomes. a. In studies in which retreatment was based on visual acuity and/or OCT, such as the Diabetic Retinopathy Clinical Research Network (DRCR.net) study and RESTORE, the proportion of patients with 3-line improvement from baseline was reduced compared to RISE/RIDE (DRCR.net: at Year 2 only 28%30% of patients had 3-line improvement with a median of 2-3 ranibizumab injections; RESTORE: 22.6%-22.9% of patients 3-line improvement and mean of 7 ranibizumab injections over 12 months).4,5 b. In a randomized study of bevacizumab or laser therapy in patients with DME (BOLT) that employed OCT-guided retreatment after 3 initial injections (every 6 weeks), the proportion of patients gaining 3 lines BCVA from baseline was only 11.9% after 12 months and 32% at 24 months with a median of 13 bevacizumab injections.6,7 B. Optimal treatment of DME with anti-VEGF therapy appears to require monthly injections or frequent monitoring for an indefinite treatment duration similar to other indications.4,5,8 Based on the differences seen with responses to monthly compared to less-frequent dosing regimens,
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p.r.n. dosing of anti-VEGF therapies might not be an option for the treatment of DME. II. The Case for Corticosteroids as an Alternative Ideal Therapy for DME A. Inflammation plays a critical role in the pathogenesis of DME.9 B. Based on mechanism of action, intravitreal corticosteroids target multiple pathways in inflammation rather than just VEGF. 1. Corticosteroids inhibit phospholipase A2, which in turn leads to the inhibition of thromboxane, leukotriene, and prostaglandin synthesis and therefore prevents vasodilation and capillary hyperpermeability.9 2. Corticosteroids also decrease VEGF synthesis by destabilizing VEGF mRNA so overall VEGF levels are reduced.9 3. Because increased vascular permeability occurs as a response to multiple cytokines (such as IGF-1, bFGF, interleukin-6, and tumor necrosis factor in addition to VEGF), corticosteroids may provide more effective stabilization of the bloodretinal barrier, leading to a reduction of edema.10 C. Although not currently approved for the treatment of DME, off-label intravitreal corticosteroid use in the clinical trial setting (including Phase 2 studies) has suggested efficacy and safety. 1. Clinical trials that have examined the efficacy of corticosteroids in the treatment of DME have favorable visual acuity and anatomic outcomes, and more importantly, have longer duration of action therefore requiring less frequent monitoring and injections than anti-VEGF therapies a. In pseudophakic eyes treated with 4-mg intravitreal triamcinolone (IVTA; Trivaris, Allergan Inc.; Irvine, Calif., USA) plus prompt laser in the DRCR.net ranibizumab study mentioned above, visual acuity was comparable to eyes treated with ranibizumab with fewer injections at Year 1 and 2.4 At Year 2, 11% of IVTA patients had 15 letter increase in visual acuity and with a median of 1 treatment (compared to 11%-12% of ranibizumab-treated patients with 15 letter increase in visual acuity and median of 2-3 injections).4 b. In a separate DRCR.net study that compared the efficacy and safety of IVTA to focal/grid photocoagulation with retreatment at 4-month intervals, IVTA (4 mg) provided a greater improvement in visual acuity than laser (increases of 4 letters and 0 letters, respectively) at 4 months, although this benefit was lost at Year 1 and later.11,12 c. Comparison of intravitreal fluocinolone acetonide (FA) implants (0.2 or 0.5 g/day; Iluvien, Alimera Sciences; Alpharetta, Ga., USA) to sham injections resulted in a significantly greater pro-
portion of patients with 3 line improvement at 24 months (28%), with up to 25% of patients requiring 1 or more additional injections during Year 2.13 In pseudophakic patients, 7-letter mean improvement was noted by 6 months and remained through 24 months.13 d. An initial study of a single injection of 0.4-mg or 0.8-mg free dexamethasone produced transient improvements in BCVA and central foveal thickness with few adverse events.14 2. Dexamethasone intravitreal implant (Ozurdex, Allergan Inc.; Irvine, Calif., USA; approved for macular edema due to retinal vein occlusion [RVO]15) currently is being investigated for DME in 3-year, Phase 3 studies.16,17 a. In Phase 2 studies, the proportion of patients with persistent macular edema (including patients with diabetic retinopathy) with 15-letter improvement in BCVA following a single implant was significantly higher with dexamethasone implants (18%) than with observation at 180 days; central retinal thickness and fluorescein leakage were also reduced.18,19 b. In a prospective, open-label, multicenter, 6-month study of a single implant in vitrectomized patients, statistically significant improvements in BCVA were seen by 1 week after implants were administered; 11% of patients gained 15 letters from baseline by Week 13 and reduced vascular leakage despite previous failure of multiple treatments, including anti-VEGF therapies.20 In this study with a patient population that included severe cases for which multiple previous therapies had produced no response, 30.4% experienced 10-letter improvement from baseline at Week 13.20 c. In a retrospective open-label study in eyes with persistent DME, dexamethasone intravitreal implant improved BCVA and CRT within the first few days after the injection; these improvements lasted up to 4 months.21 3. Although the use of off-label intravitreal corticosteroids has been associated with known ocular side effects, including elevations in IOP, cataracts, and glaucoma, their occurrence varies in frequency and severity depending on pharmacokinetic properties and formulations.9,22 a. In the DRCR.net studies, elevated IOP and cataract surgery were more frequent with IVTA than with other treatments.4,5,11,12 b. Differences in particle size and the pharmacokinetic and pharmacodynamic properties of different formulations of triamcinolone acetonide have been noted.22 These differences
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Section XII: Diabetes may impact drug durability, efficacy, and safety. c. With FA, the proportions of patients requiring surgery for cataract extraction (phakic eyes) was higher than with sham injections.13 d. Administration of dexamethasone as a single or repeated intravitreal implants has a favorable safety profile (see Table 1).23
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8. Martin DF, Maguire MG, Fine SL, et al; Comparison of AgeRelated Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012; 119(7):1388-1398. 9. Stewart MW. Corticosteroid use for diabetic macular edema: old fad or new trend? Curr Diab Rep. 2012; 12(4):364-375. 10. Gardner TW, Antonetti DA, Barber AJ, LaNoue KF, Levison SW. Diabetic retinopathy: more than meets the eye. Surv Ophthalmol. 2002; 47 suppl 2:S253-262. 11. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008; 115:1447-1449. 12. Diabetic Retinopathy Clinical Research Network (DRCR.net); Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009; 127:245-251. 13. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology 2011; 118:626-635.e2. 14. Chan CK, Mohamed S, Lee VY, Lai TY, Shanmugam MP, Lam DS. Intravitreal dexamethasone for diabetic macular edema: a pilot study. Ophthalmic Surg Lasers Imaging. 2010; 41:26-30. 15. OZURDEX [prescribing information], Allergan, Inc. Irvine, CA. 16. A study of the safety and efficacy of a new treatment for diabetic macular edema. Clinicaltrials.gov identifier: NCT00168389. Available at: http://clinicaltrials.gov/ct2/results?term=NCT00168389. Accessed June 13, 2012 17. A study of the safety and efficacy of a new treatment for diabetic macular edema. Clinicaltrials.gov identifier: NCT00168337. Available at: http://clinicaltrials.gov/ct2/results?term=NCT00168337. Accessed June 13, 2012 18. Kuppermann BD, Blumenkranz MS, Haller JA, et al; Dexamethasone DDS Phase II Study Group. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007; 125:309317. 19. Haller JA, Kuppermann BD, Blumenkranz MS, et al; Dexamethasone DDS Phase II Study Group. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010; 128:289-296. 20. Boyer DS, Faber D, Gupta S, et al; Ozurdex CHAMPLAIN Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011; 31:915-923. 21. Zuchiatti I, Lattaznzio R, Querques G, et al. Intravitreal dexamethasone implant in patients with persistent diabetic macular edema. Ophthalmologica 2012; doi: 10.1159/000336225. 22. Zacharias LC, Lin T, Migon R, Ghosn C, Orilla W, Feldmann B, Ruiz G, Li Y, Burke J, Kuppermann BD. Assessment of the differences in pharmacokinetics and pharmacodynamics between four distinct formulations of triamcinolone acetonide. Retina. Epub ahead of print 17 Sept 2012. 23. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011; 118:2453-2460.
Table 1. elevated IoP and Cataracts at Month 12 in Patients With Branch Retinal Vein occlusion or Central Retinal Vein occlusion Triamcinolone Acetonide 4 mg24,25
IOP increase 10 mmHg IOP 35 mmHg Cataract extraction (during 1 year)
aPrior
Dexamethasone 0.7 mg Implant23

3/324 (0.9%) 0/324 (0.0%) 4/302 (1.3%)c
18/202 (8.9%)a 7/202 (3.5%)a 8/203 (3.9%)b,c
to treatment crossover; bIncludes patients who were randomized to standard care but received triamcinolone acetonide 4-mg injection as alternative treatment; cIncludes patients with phakic lens at baseline.
III. In conclusion, because of the different mechanism of action, longer duration of action, requirement for less frequent monitoring, and long-lasting visual acuity and anatomic outcomes with a favorable safety profile, corticosteroids may be a viable treatment option for DME
References
1. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012; 119:789-801. 2. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-1431. 3. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1432-1444. 4. Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117:1064-1077. 5. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE Study Group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011; 118:615-625. 6. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 2010; 117:1078-1086. 7. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. Epub ahead of print. 9 Apr 2012. doi:10.1001/archophthalmol.2012.393.
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24. Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009; 127:1101-1114. 25. Scott IU, Ip MS, VanVeldhuisen PC, Oden NL, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009; 127:1115-1128.
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Anti-VeGF Is the Ideal Treatment for Diabetic Macular edema (Yes/No)

Rebuttal, Pro
Karl G Csaky MD
Rebuttal, Con
Dante Pieramici MD
Retina
Section XIII: Vitreoretinal Surgery, Part II
129
Surgical Complications Video, Part I
NoTeS
Surgical Complications Video, Part II
NoTeS
Retina
131
Financial Disclosure
The Academys Board of Trustees has determined that a financial relationship should not restrict expert scientific, clinical, or nonclinical presentation or publication, provided that appropriate disclosure of such relationship is made. As an Accreditation Council for Continuing Medical Education (ACCME) accredited provider of CME, the Academy seeks to ensure balance, independence, objectivity, and scientific rigor in all individual or jointly sponsored CME activities. All contributors to Academy educational activities must disclose any and all financial relationships (defined below) to the Academy annually. The ACCME requires the Academy to disclose the following to participants prior to the activity: any known financial relationships a meeting presenter, author, contributor, or reviewer has reported with any manufacturers of commercial products or providers of commercial services within the past 12 months any meeting presenter, author, contributor, or reviewer (hereafter referred to as the Contributor) who report they have no known financial relationships to disclose For purposes of this disclosure, a known financial relationship is defined as any financial gain or expectancy of financial gain brought to the Contributor or the Contributors family, business partners, or employer by: direct or indirect commission; ownership of stock in the producing company; stock options and/or warrants in the producing company, even if they have not been exercised or they are not currently exercisable; financial support or funding from third parties, including research support from government agencies (e.g., NIH), device manufacturers, and/or pharmaceutical companies; or involvement in any for-profit corporation where the Contributor or the Contributors family is a director or recipient of a grant from said entity, including consultant fees, honoraria, and funded travel. The term family as used above shall mean a spouse, domestic partner, parent, child or spouse of a child, or a brother, sister, or spouse of a brother or sister, of the Contributor.
Category Consultant / Advisor
Code C
Description Consultant fee, paid advisory boards or fees for attending a meeting (for the past one year) Employed by a commercial entity Lecture fees (honoraria), travel fees or reimbursements when speaking at the invitation of a commercial entity (for the past one year) Equity ownership/stock options of publicly or privately traded firms (excluding mutual funds) with manufacturers of commercial ophthalmic products or commercial ophthalmic services Patents and/or royalties that might be viewed as creating a potential conflict of interest Grant support for the past one year (all sources) and all sources used for this project if this form is an update for a specific talk or manuscript with no time limitation
Employee Lecture fees
E L
Equity owner
Patents / Royalty
Grant support
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2012 Retina Planning Group Financial Disclosures
Pravin U Dugel MD
Abbott Medical Optics: C Alcon Laboratories, Inc.: C Allergan, Inc.: C ArticDx: C,O Genentech: C Macusight: C,O Neovista: C,O Novartis Pharmaceuticals Corp.: L Ora: C ThromboGenics: C
AAO Staff Brandi Garrigus

None
Ann LEstrange
None
Melanie Rafaty
None
Tarek S Hassan MD
Arctic Dx: C,L,O Bausch + Lomb Surgical: C,L Eyetech, Inc.: C Genentech, Inc.: C,L Insight Instruments: C,L Optimedica: C,O Regeneron QLT: C Synergetics Inc.: L
Debra Rosencrance
None
Beth Wilson
None
Peter K Kaiser MD
Alcon Laboratories, Inc.: C ArcticDx: C Bayer: C Genentech: C,S Novartis Pharmaceuticals Corp.: C,S Regeneron: C,S SKS Ocular LLC: C,O
Joan W Miller MD
Alcon Laboratories, Inc.: C Novartis Pharmaceuticals Corp.: O QLT Phototherapeutics, Inc.: P
2012 Subspecialty Day | Retina
133
Faculty Financial Disclosures
Thomas M Aaberg Jr MD
Allergan: L Synergetics, Inc.: C
Francesco M Bandello MD FEBO

Alcon Laboratories, Inc.: C Alimera Sciences, Inc.: C Allergan, Inc.: C Bausch + Lomb Surgical: C Bayer Schering Pharma: C Farmila-Thea Pharmaceuticals: C Genentech: C Novartis Pharmaceuticals Corp.: C Pfizer, Inc.: C Sanofi Aventis: C Thrombogenics: C
David S Boyer MD
Alcon Laboratories, Inc.: C,L Allegro: C Allergan, Inc.: C,L Bayer: C Eyetech, Inc.: C Genentech: C,L Glaukos Corp.: C GSK: C iCo Therapeutics: C Neurotech: C Novartis Pharmaceuticals Corp.: C Optos, Inc.: C ORA: C Pfizer, Inc.: C
Gary W Abrams MD
Alcon Laboratories, Inc.: C
David H Abramson MD FACS

None

Abbott Medical Optics: C Allergan, Inc.: L Eli Lilly & Company: C,L Genentech: C Genzyme: C Kalvista: C,O Novartis Pharmaceuticals Corp.: C Optos, Inc.: S Pfizer, Inc.: C Thrombogenics: C
Francine Behar-Cohen MD
Allergan: S Essilr: C Eyevensys SAS : O,C Fournier: S, C Novartis Pharmaceuticals Corporation: S Pfizer, Inc.: C Solid Drug Dev: S Solvay: C Steba Biotech: S Teva Pharmaceutical Industries, Ltd.: C
Alcon Laboratories, Inc.: L Novartis Pharmaceuticals Corp.: C
Neil M Bressler MD
Abbott Medical Optics Inc.: S Alimera Sciences: S Allergan USA: S Bausch & Lomb Incorporated: S Bristol-Meyers Squibb Company: S Carl Zeiss Meditec, Inc.: S Diagnos, Inc.: S ForSight Labs, LLC: S Genentech, Inc.: S Genzyme Corp.: S Lumenis, Inc.: S Notal Vision: S Novartis Pharma AG: S Pfizer, Inc.: S Regeneron Pharmaceuticals, Inc.: S Steba Biotech S.A.: S The EMMES Corporation: S Thrombogenics: S
None
J Fernando Arevalo MD FACS

None
Audina M Berrocal MD
None
Jorge G Arroyo MD
None
Maria H Berrocal MD
Alcon Laboratories, Inc.: C,L
Marcos P Avila MD
None
Susanne Binder MD
None
Carl C Awh MD
Arctic DX: C,O Bausch + Lomb Surgical: C,L Genentech: C,L,S Katalyst: C Neovista: C,O Notal Vision, Ltd.: C Pfizer, Inc.: C Synergetics, Inc.: C,O,P Volk Optical: C
Alan C Bird MD
None
Barbara Ann Blodi MD

None
Avalanche Biotechnology: O,P Digisight: O Ista Pharmaceuticals: C Optimedica: O,P Vantage Surgical: C,O
David M Brown MD
Alcon Laboratories, Inc.: C Alimera: C Allergan, Inc.: C Bayer Pharmaceuticals: C Carl Zeiss Meditec: C Genentech: C,S Heidelberg Engineering: C,L Molecular Partners: C Novartis Pharmaceuticals Corp.: C,S Paloma: C Pfizer, Inc.: C Regeneron: C,L Steba Biotech: C Thrombogenics: C

Gene Signal: C Oxford Biomedica: C
Sophie J Bakri MD
Allergan, Inc.: C Genentech: C
134
Retina
Alexander J Brucker MD
Escalon Medical Corp: O Genentech: S GlaxoSmithKline: S National Eye Institute: S Neurovision: O Ophthotech: C,O Optimedica: O
N H Victor Chong MD
Alcon Laboratories, Inc.: S Allergan: C,L,S Bayer: C,L Iridex: C Novartis Pharmaceuticals Corp.: C,L,S Pfizer, Inc.: C,L,S
Jay S Duker MD
Alcon Laboratories, Inc.: C Carl Zeiss Meditec: S EMD/Serono: C EyeNetra: C,O Genentech: C Hemera Biosciences: O Neovista: C Novartis Pharmaceuticals Corp.: C Ophthotech: O OptoVue: S Paloma Pharmaceuticals: C QLT Phototherapeutics, Inc.: C Thrombogenics: C Topcon Medical Systems: S
Brandon G Busbee MD
Akorn, Inc.: P Alimera: C Elan: C Genentech: C,L Regeneron: L Synergetics, Inc.: C Thrombogenics: C
David R Chow MD
Arctic Dx: C Bausch + Lomb Surgical: L Katalyst: C Novartis Pharmaceuticals Corp.: L Synergetics, Inc.: C
Mina Chung MD
Lowy Medical Research Institute: S National Eye Institute: S Rochester CTSI: S Thome Foundation: S
Alexander Eaton MD
Alcon Laboratories, Inc.: C Allergan, Inc.: S EyeO2Scan, LLC : O Genentech: S I Tech JV Development Company, LLC: O,P IC Labs, LLC: O Macusight: S Neuron Systems: O Regeneron: S Revitalid, Inc.: O ThromboGenics, Inc.: C
Antonio Capone Jr MD
Alcon Laboratories, Inc.: C Alimera Sciences: C Allergan, Inc.: C,S FocusROP, LLC: O,P Genentech: C,S GlaxoSmithKline: S Ophthotec: S Retinal Solutions, LLC: O,P Thrombogenics: S
Carl C Claes MD
Alcon Laboratories, Inc.: C,L
Karl G Csaky MD
Acucela: C Allergan, Inc.: C,S Genentech: C,L,S Heidelberg Engineering: C Iridex: S Merck & Co., Inc.: C Novartis Pharmaceuticals Corp.: C Ophthotech: C,O QLT Phototherapeutics, Inc.: C

Allergan, Inc.: C Bausch + Lomb Surgical: C,L Neovista, Inc.: C Novartis Pharmaceuticals Corp.: C,L Oraya Therapeutics: C,L Pfizer, Inc.: C,L
Claus Eckardt MD
DORC International, bv/Dutch Ophthalmic, USA: P
Christine Curcio PhD

Bausch + Lomb: L Genentech: L Global Sight Network: E National Eye Institute: S
Ehab N El Rayes MD PHD

None
Wiley Andrew Chambers MD

None
Dean Eliott MD
Alimera: C Arctic: C Bausch + Lomb Surgical: C Genentech: C Glaukos Corp.: C Ophthotech: C Thrombogenics: C
R V Paul Chan MD
None
Donald J DAmico MD
Lux Biosciences, Inc.: C Ophthotech, Inc.: C,O Optimedica, Inc.: C,O
Stanley Chang MD
Alcon Laboratories, Inc.: C Alimera Sciences: C
Tom S Chang MD
None
Kimberly A Drenser MD PhD

FocusROP: O Retinal Solutions: O Synergetics, Inc.: C
Daniel D Esmaili MD
None
Steven T Charles MD
Alcon Laboratories, Inc.: C, P Topcon Medical Systems: C, P
Sharon Fekrat MD
None
Pravin U Dugel MD
Abbott Medical Optics: C Alcon Laboratories, Inc.: C Allergan, Inc.: C ArticDx: C,O Genentech: C Macusight: C,O Neovista: C,O Novartis Pharmaceuticals Corp.: L Ora: C Thrombogenics: C
Bausch + Lomb: P
Emily Y Chew MD
None
Philip J Ferrone MD
Alcon Laboratories, Inc.: S Allergan: C,L,S Arctic DX: C,O Bausch + Lomb: C Genentech: C,L,S Regeneron: C,L,S
Retina
135
Marta Figueroa MD
Alcon Laboratories, Inc.: C Allergan, Inc.: C Novartis Pharmaceuticals Corp.: C
Evangelos S Gragoudas MD
QLT Phototherapeutics, Inc.: P
Allen C Ho MD
Alcon Laboratories, Inc.: C,L,S Genentech: C,L,S Janssen: C,L,S Merck & Co., Inc.: C NEI / NIH: S Ophthotech: C,S PRN: C,O,S Regeneron: C,L,S Second Sight: S Thrombogenics: C,L
M Gilbert Grand MD
None
Paul T Finger MD
The Eye Cancer Foundation, Inc.: L,S
Julia A Haller MD
Advanced Cell Technology: C Allergan, Inc.: C Genentech: C Optimedica: O Regeneron: C Thrombogenics: C
Harry W Flynn Jr. MD

Alimera: C Allergan, Inc.: C Pfizer, Inc.: C Santen, Inc.: C
Frank G Holz MD
Acucela: C Bayer Healthcare: C,L Carl Zeiss Meditec: C,S Genentech: C,S Heidelberg Engineering: C,L,S Novartis Pharmaceuticals Corp.: C,L Ophthotec: C Optos, Inc.: S Pfizer, Inc.: C
William R Freeman MD
Allergan: C OD-OS Retina Care Unlimited: C
Dennis P Han MD
Allergan, Inc.: S Genentech: S Ophthotech: S Regeneron: S
K Bailey Freund MD
Genentech: C,S QLT Phototherapeutics, Inc.: C Regeneron: C
Tarek S Hassan MD
Artic DX: C,L,O Bausch + Lomb Surgical: C,L Eyetech, Inc.: C Genentech, Inc.: C,L Insight Instruments: C,L Optimedica: C,O Regeneron, QLT: C Synergetics Inc.: L
Thomas R Friberg MD
Eyetech, Inc.: C Genentech: C Optos, Inc.: C Pfizer, Inc.: S
Suber S Huang MD MBA

Alcon Laboratories, Inc.: L Bausch + Lomb Surgical: C i2i Innovative Ideas, Inc.: O Notal Vision: C Retinal Diseases Image Analysis Reading Center (REDIARC): C,L Sequenom: C
Anne E Fung MD
Alcon Laboratories, Inc.: C Genentech: C,L,S Ista Pharmacuticals: C Santen, Inc.: C Sequenom: C Thrombogenics: C
Jeffrey S Heier MD
Acucela: C Alcon Laboratories, Inc.: S Alimera: S Allergan, Inc.: C,S Bausch + Lomb: C Bayer Healthcare: C Endo Optiks, Inc.: C Forsight Labs: C Fovea: C,S Genentech: C,S Genzyme: C,S GlaxoSmithKline: C,S Heidelberg Engineering: C Ista Pharmacuticals: C Kato Pharmaceuticals: C Lpath Inc.: C NeoVista, Inc.: C,S Neurotech, Inc.: S Notal Vision: C,S Novartis Pharmaceuticals Corporation: S Ophthotech: S Oraya Therapeutics: C Paloma, Inc.: C,S QLT Ophthalmics: C QLT Therapeutics: C QLT, Inc.: C Quark Pharmaceuticals: C Regeneron: C,S Sequenom: C
Mark S Humayun MD PhD

Alcon Laboratories, Inc.: C,L Bausch + Lomb Surgical: C,L,O,P,S Replenish: C,O,P,S Second Sight: C,L,O,P,S
Brenda L Gallie MD
Solutions by Sequence: O
Michael S Ip MD
Allergan, Inc.: S Eye Technology, Ltd.: C Genentech: C NicOx: C Notal Vision: C QLT Phototherapeutics, Inc.: C Regeneron: C Sirion: C
Alain Gaudric MD
Alcon Laboratories, Inc.: S Allergan, Inc.: S Bayer: S Novartis Pharmaceuticals Corp.: S
Andre V Gomes MD
DORC International bv/Patch Opthalmic USA: C Novartis Pharmaceuticals Corp.: C Volk: C

Bausch + Lomb: C DORC International, bv/Dutch Ophthalmic, USA: L NeoVista: C,L,S Novartis Pharmaceuticals Corp.: S Oraya: S Thrombogenics: C,L
Christine R Gonzales MD
Alimera: C Allergan: L Iconic Therapeutics: S Lpath Inc.: S OPHTEC: S Pfizer, Inc.: S Regeneron: S
Glenn J Jaffe MD
Abbott Laboratories: C Heidelberg Engineering: C Neurotech USA: C SurModics, Inc.: C
136
Retina
Martine J Jager MD
Aeon Astron: S
Timothy Y Lai MD FRCOphth FRCS

Allergan: C,L Bayer Healthcare: C,L,S Heidelberg Engineering: L Novartis Pharmaceuticals Corp.: C,L,S Oxigene, Inc.: S Pfizer, Inc.: S

Alcon Laboratories, Inc.: C Thrombogenics, Inc.: C
Mark W Johnson MD
GlaxoSmithKline: C Ophthotech: C Oraya: C Regeneron: S
Annabelle A Okada MD
Mitsubishi Tanabe Pharma: L,S Novartis Pharma Japan: L Novartis Pharmaceuticals Corp.: C Pfizer Japan: L XOMA, Corp.: C
J Michael Jumper MD
Covalent Medical LLC: O DORC International, bv Dutch Ophthalmic, USE: L
Jennifer Irene Lim MD

Icon Bioscience: S, Quark: C Regeneron: C,S Santen, Inc.: C
Timothy W Olsen MD
Dobbs Foundation: S Emtech Biotechnology Development Grant: S Georgia Research Alliance: S Johnson & Johnson: S NIH/NEI: S NIH/NIA: S Research to Prevent Blindness: S
Kazuaki Kadonosono MD
None
Anat Loewenstein MD
Allergan, Inc.: C,L Forsightlabs: C Lumenis, Inc.: C,L Notal Vision, Ltd.: C, Novartis Pharmaceuticals Corporation: C,L Orabio: C
Peter K Kaiser MD
Alcon Laboratories, Inc.: C ArcticDx: C Bayer: C Genentech: C,S Novartis Pharmaceuticals Corp.: C,S Regeneron: C,S SKS Ocular LLC: C,O
Jeffrey L Olson MD
Shape Memory Alloy Chip: P
Ian M MacDonald MD
Novartis Pharmaceuticals Corp.: L
Yusuke Oshima MD
Alcon Laboratories, Inc.: C,L Carl Zeiss Meditec: L DORC International, bv/Dutch Ophthalmic, USA: L Santen, Inc.: L Synergetics, Inc.: C,L Topcon Medical Systems: C
Ivana K Kim MD
Genentech: C,S Regeneron: C

Inspire Pharmaceuticals, Inc.: S Merck & Co., Inc.: C
Judy E Kim MD
Alimera Sciences: C Allergan, Inc.: C,S Genentech: C,S
Daniel F Martin MD
None
John W Kitchens MD
Genentech: C,L MyWhiteCoat.com: O Optos, Inc.: C,L Regeneron: C,L Synergetics, Inc.: C,L
Carlos Mateo MD
None
Andrew J Packer MD
None
William F Mieler MD
Alcon Laboratories, Inc.: C Allergan, Inc.: C Genentech: C
Kirk H Packo MD
Alcon Laboratories, Inc.: C,L,S Alimera Sciences: C,S Allergan: S Genentech: S Lumenis, Inc.: S OD-OS, Inc.: C,S Optos, Inc.: S Thrombogenics: L,S Vision Care Inc.: C,S
Robert K Koenekoop MD PhD

QLT Phototherapeutics, Inc.: C,S
Joan W Miller MD
Alcon Laboratories, Inc.: C Novartis Pharmaceuticals Corp.: O QLT Phototherapeutics, Inc.: P

Alimera: C,S Allegro Ophthalmics LLC: C Allergan, Inc.: C,L,S Fovea: C Genentech: C,S Glaukos Corp.: C GlaxoSmithKline: C,S NeoVista: C Neurotech: C Novagali: C Novartis Pharmaceuticals Corp.: C,L Ophthotech: C,L Regeneron: S Thrombogenics: C,S
Convene, LLC: O,P Genentech, Inc.: C Grand Legend Technology, LTD: C,O InSitu Therapeutics, Inc.: C,O,P MyWhiteCoat: C,O OcuBell: C,O Oraya Therapeutics, Inc.: C,O Synergetics, Inc.: C Thrombogenics: C VersaVision: O,P
David W Parke II MD
OMIC-Ophthalmic Mutual Insurance Company: C
Fabio Patelli MD
None
Grazia Pertile MD
None
Dante Pieramici MD
Alimera: C Allergan: S Genentech: C,S Regeneron: S Thrombogenics: C
Shizuo Mukai MD
None
Retina
137
Eric A Pierce MD PhD

None
Alan J Ruby MD
Genentech: L
Michael A Singer MD
Alcon Laboratories, Inc.: S Allergan, Inc.: C,L,S Eli Lilly & Company: S Genentech: C,L,S
Subhransu Ray MD PhD

Genentech: C, Santen, Inc.: C
Srinivas R Sadda MD
Allergan, Inc.: C Carl Zeiss Meditec: L,S Genentech: C Heidelberg Engineering: C Optos, Inc.: S Optovue, Inc.: S Regeneron: C Topcon Medical Systems: P
Franco M Recchia MD
Alcon Laboratories, Inc.: C Genentech: L Thrombogenics: C
Lawrence J Singerman MD
Alcon Laboratories, Inc.: S Allergan, Inc.: S Eyetech, Inc.: C Genentech: S GlaxoSmithKline: S Lux Biosciencse: S MacTel: S National Eye Institute: S Notal Vision: S Novartis Pharmaceuticals Corp.: S Ophthotech: C Opko: O
Carl D Regillo MD FACS

Alcon Laboratories, Inc.: C,S Allergan: C,S Genentech: C,S GlaxoSmithKline: C,S Novartis Pharmaceuticals Corp.: C,S QLT Phototherapeutics, Inc.: C,S Second Sight: S
Andrew P Schachat MD
None
Amy C Schefler MD
None
AMD Therapy Fund: C American Health Assistance Foundation: S Food and Drug Administration (FDA): C Foundation Fighting Blindness: S QLT Phototherapeutics, Inc: C Sanofi Fovea: C Usher III Initiative: C
Kourous Rezaei MD
Alcon Laboratories, Inc.: C,L,S Alimera Sciences: C BMC: C Genentech: L,S
Arun D Singh MD
None
Rishi P Singh MD
Alcon Laboratories, Inc.: C Bausch + Lomb: C Genentech: C
William L Rich MD
None
Stanislao Rizzo MD
None
Ursula M Schmidt-Erfurth MD
Alcon Laboratories, Inc.: C,L BayerHealthcare: C,L Novartis Pharmaceuticals Corp.: C,L
Jason S Slakter MD
Acucela: C,S Alcon Laboratories, Inc.: S Alimera: S Allergan, Inc.: S Bayer HealthCare: S Centocor, Inc.: S Corcept: S Fovea/SanofiAventis: S Genentech: S GlaxoSmithKline: S KangHong Biotech: S Lpath, Inc.: C,S NeoVista: S Novagali: S Oraya Therapeutics: C,S OxiGene: C,S Pfizer, Inc.: S QLT, Inc.: S Regeneron Pharmaceuticals: L,S ReVision: C,S Sanofi-Aventis: S SKS Ocular, LLC: O
Michael A Romansky JD
None
Steven D Schwartz MD
Alcon Laboratories, Inc.: C Allergan, Inc.: C Bausch + Lomb Surgical: C,L Genentech, Inc.: C,L OptiMedica: C,L,O Optos, Inc.: C,L
Richard B Rosen MD
Allergan: S Clarity: C Genentech: S Johnson & Johnson Consumer & Personal Products Worldwide: C OD-OS: L Ophthalmic Technologies, Inc.: C Optos, Inc.: C Topcon Medical Systems: L
Jonathan E Sears MD
None
Gaurav K Shah MD
Abbott Medical Optics: C Alcon Laboratories, Inc.: C,L Allergan, Inc.: C DORC International, bv/Dutch Ophthalmic, USA: C iScience: C Neovista: C
Philip J Rosenfeld MD PhD

Acucela: C Advanced Cell Technology: S Alexion: S Boehringer Ingelheim: C Canon, Inc.: C Carl Zeiss Meditec: L,S Chengdu Kanghong Biotech: C Digisight: O GlaxoSmithKline: S Oraya: C Sucampo: C Thrombogenics: C
Rachel Smith MD PhD

None
Carol L Shields MD
None
Gisele Soubrane MD PhD

Allergan, Inc.: C,L Chibret International: C Novartis Pharmaceuticals Corp.: C
Jerry A Shields MD
None
138
Retina
Richard F Spaide MD
Genentech: S Thombogenics: C Topcon Medical Systems: P
Boston Eye Surgery & Laser Center: O National Eye Institute: S OMIC-Ophthalmic Mutual Insurance Company: E
David F Williams MD
Genentech: C
Alcon Laboratories, Inc.: C,S Allergan, Inc.: C,S ForSight: C,O Neurotech: C,S Nu-Vue Technologies, Inc.: O,P OMIC-Ophthalmic Mutual Insurance Company: E OptiMedica: C,O Thrombogenics: C
Allergan, Inc.: S Bausch + Lomb Surgical: C,S Novartis Pharmaceuticals Corp.: S
Cynthia A Toth MD
Alcon Laboratories, Inc.: P Bioptigen, Inc.: S Genentech, Inc.: S National Eye Institute: S Physical Sciences Incorporated: C,S
Giovanni Staurenghi MD
Alcon Laboratories, Inc.: C Allergan, Inc.: C Bayer: C Canon: C GlaxoSmithKline: C Heidelberg Engineering: C Ocular Instruments, Inc.: P OD-OS: C Optos, Inc.: C Optovue: S Pfizer, Inc.: C QLT Phototherapeutics, Inc.: C Zeiss: S
Michael T Trese MD
Focus ROP: C,O Genentech: C Nu-Vue Technologies, Inc.: C,O Retinal Solutions LLC: C,O Synergetics, Inc.: P ThromboGenics Inc.: C,O
Lihteh Wu MD
Heidelberg Engineering: L
Lawrence A Yannuzzi MD
None
Jan C Van Meurs MD

DORC International, bv/Dutch Ophthalmic, USA: P
Young Hee Yoon MD

Alcon Laboratories, Inc.: C Allergan: L,S Bayer: L
Paul Sternberg MD
None

GenSight Biologics: O GlaxoSmithKline: P National Eye Institute: L ReGenX Biosciences: P

Massachusetts Eye and Ear Infirmary: P ONL Therapeutics, LLC: O University of Michigan: P
John T Thompson MD
Genentech: S National Eye Institute: S Regeneron: S
Alexander C Walsh MD
Envision Diagnostics: E,O,P
Retina
139
Presenter Index
Aaberg Jr*, Thomas M 106 Aiello*, Lloyd P 122 Allen Jr, Arthur W 36 Arevalo, J Fernando 13 Arroyo, Jorge G 4 Awh*, Carl C 123 Bainbridge*, James W 43 Behar-Cohen, Francine 34 Binder, Susanne 68 Bird, Alan C 14 Blumenkranz*, Mark S 17 Boyer*, David S 81 Brazitikos*, Periklis 11 Bressler*, Neil M 119 Brown*, David M 21 Busbee*, Brandon G 70 Chakravarthy*, Usha 66 Chambers, Wiley Andrew 60 Charles*, Steven T 123 Chew, Emily Y 34, 74 Chong*, N H Victor 122 Chow*, David R 1 Claes*, Carl C 13 Csaky*, Karl G 128 Curcio*, Christine 15 Drenser*, Kimberly A 39 Dugel*, Pravin U 80 Eaton*, Alexander M 118 Eckardt*, Claus 13 El Rayes, Ehab N 13 Eliott*, Dean 2 Ferris*, Frederick L 20 Flynn Jr*, Harry W 119 Gonzales*, Christine R 118 Haller*, Julia A 124 Heier*, Jeffrey S 69 Ho*, Allen C 29 Holz*, Frank G 89 Humayun*, Mark S 118 Ip*, Michael 118 Jackson*, Timothy L 34, 76 Johnson*, Mark W 121
Kadonosono, Kazuaki 13 Kaiser*, Peter K 73 Kim*, Judy E 99 Kim*, Ivana K 105 Kitchens*, John W 6 Kuppermann*, Baruch D 124 Lai*, Timothy Y 77 Lim*, Jennifer Irene 121 Loewenstein*, Anat 34 MacDonald*, Ian M 44 Maguire*, Maureen G 63 Martin, Daniel F 65 Mateo, Carlos 13 Moshfeghi*, Darius M 35 Murray*, Timothy G 115 Olson*, Jeffrey L 118 Oshima*, Yusuke 13 Parke II*, David W 52 Pieramici*, Dante 128 Pierce, Eric A 47 Ray*, Subhransu 34 Recchia*, Franco M 40 Rich, William L 54 Romansky, Michael A 56 Rosenfeld*, Philip J 21 Ruby*, Alan J 57 Sadda*, Srinivas R 94 Scholl*, Hendrik PN 46 Shah*, Gaurav K 7 Shields, Carol L 116 Singer*, Michael A 34 Slakter*, Jason S 82 Smith, Rachel 118 Spaide*, Richard F 86 Srivastava*, Sunil K 97 Topping*, Trexler M 59 Trese*, Michael T 38 Vandenberghe*, Luk H 49 Walsh*, Alexander C 102 Williams*, George A 32, 58 Wu*, Lihteh 9 Zacks*, David N 28

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Retina 2012 The Winds of Change

Sponsored by an unrestricted educational grant by Genentech and Regeneron

2012 Subspecialty Day

Joan W Miller MD Program Director

Tarek S Hassan MD Program Director

2012 Subspecialty Day

Retina 2012 Contents

Electronic version of Syllabi available at www.aao.org/2012syllabi

2012 Subspecialty Day

Academys CME Mission Statement

Attendance Verification for CME Reporting

2012 Retina Subspecialty Day Meeting Learning Objectives

CME Credit Reporting

2012 Retina Subspecialty Day Meeting Target Audience

2012 Retina Subspecialty Day CME Credit

Scientific Integrity and Disclosure of Financial Interest

2012 Subspecialty Day | Retina

The Charles L Schepens MD Lecture

2012 Subspecialty Day

Lloyd P Aiello MD PhD

David H Abramson MD FACS

Carl C Awh MD J Fernando Arevalo MD FACS

2012 Subspecialty Day

James W Bainbridge MA PhD FRCOphth

Maria H Berrocal MD Francesco M Bandello MD FEBO

Barbara Ann Blodi MD

2012 Subspecialty Day

Usha Chakravarthy MBBS PhD

2012 Subspecialty Day

Wiley Andrew Chambers MD

2012 Subspecialty Day

Karl G Csaky MD PhD

Kimberly A Drenser MD PhD

Christine Curcio PhD

2012 Subspecialty Day

Ehab N El Rayes MD PhD

2012 Subspecialty Day

Brenda L Gallie MD K Bailey Freund MD

2012 Subspecialty Day

Suber S Huang MD MBA

Mark S Humayun MD PhD

Frank G Holz MD Tarek S Hassan MD

2012 Subspecialty Day

Timothy L Jackson MBChB

2012 Subspecialty Day

Jennifer Irene Lim MD

Maureen G Maguire PhD

Baruch D Kuppermann MD PhD

Timothy Y Lai MD FRCOphth FRCS

2012 Subspecialty Day

Timothy G Murray MD MBA

Yusuke Oshima MD Annabelle A Okada MD

2012 Subspecialty Day

Eric A Pierce MD PhD

Subhransu Ray MD PhD Grazia Pertile MD

2012 Subspecialty Day

Carl D Regillo MD FACS

Philip J Rosenfeld MD PhD

Michael A Romansky JD Kourous Rezaei MD

Richard B Rosen MD William L Rich MD

2012 Subspecialty Day

Carol L Shields MD Steven D Schwartz MD

Jerry A Shields MD Ursula M Schmidt-Erfurth MD