aao sub retina_2012_syllabus

©2012 American Academy of Ophthalmology. All rights reserved. No portion may be reproduced without express written consent of the American Academy of Ophthalmology.

Retina 2012The Winds of Change Program DirectorsJoan 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 PlaceChicago, IllinoisFriday – Saturday, November 9 – 10, 2012

Presented byThe American Academy of Ophthalmology

Sponsored by an unrestricted educational grant by Genentech and Regeneron

Retina 2012 Planning GroupJoan W Miller MDProgram Director

Tarek S Hassan MDProgram Director

Pravin U Dugel MD Peter K Kaiser MD

Former Program Directors2011 Allen C Ho MD Joan W Miller MD2010 Daniel F Martin MD Allen C Ho MD2009 Antonio Capone Jr MD Daniel F Martin MD2008 M Gilbert Grand MD Antonio Capone Jr MD2007 John T Thompson MD M Gilbert Grand MD2006 Emily Y Chew MD John T Thompson MD

2005 Michael T Trese MD Emily Y Chew MD2004 William F Mieler MD Michael T Trese MD2003 Kirk H Packo MD William F Mieler MD2002 Mark S Blumenkranz MD Kirk H Packo MD2001 George A Williams MD Mark S Blumenkranz MD2000 Julia A Haller MD George A Williams MD1999 Stanley Chang MD Julia A Haller MD1998 Harry W Flynn Jr MD Stanley Chang MD1997 H MacKenzie Freeman MD Harry W Flynn Jr MD1996 H MacKenzie Freeman MD1995 Thomas M Aaberg Sr MD Paul Sternberg Jr MD

Subspecialty Day Advisory CommitteeWilliam F Mieler MDAssociate Secretary

Donald L Budenz MD MPHDaniel S Durrie MDRobert S Feder MD Leah Levi MBBSR Michael Siatkowski MD

Jonathan B Rubenstein MD Secretary for Annual Meeting

StaffMelanie R Rafaty CMP, Director, Scientific

Meetings Ann L’Estrange, Scientific Meetings SpecialistBrandi Garrigus, Presenter CoordinatorDebra Rosencrance CMP CAE, Vice

President, Meetings & ExhibitsPatricia Heinicke Jr, EditorMark Ong, DesignerGina Comaduran, Cover Design

ii 2012 Subspecialty Day | Retina

Dear Colleague:

On behalf of the American Academy of Ophthalmology and the American Society of Retina Spe-cialists, 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 pre-sented 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 surgi-cal 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 what’s new in clinical practice, as well as practical issues that retina specialists face daily—from 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 Lecture—delivered this year by Alan Bird MD on “Potential Therapeutic Approaches to AMD”—is 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 informa-tion 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-to-date 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 sug-gest 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 Tarek S Hassan MD Program Director Program Director

2012 Subspecialty Day | Retina iii

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: Non-neovascular AMD 15

Section III: Late Breaking Developments, Part I 34

Section IV: Pediatric Retina 35

Section V: Inherited Retinal Diseases 43

Section VI: Retinal Vein Occlusion 51

Section VII: Business of Retina 52

Section VIII: Neovascular AMD 63

Section IX: Imaging 86

Section X: Oncology 105

Section XI: Late Breaking Developments, Part II 118

Section XII: Diabetes 119

Section XIII: Vitreoretinal Surgery, Part II 129

Faculty Financial Disclosure 131

Presenter Index 139

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

http://www.aao.org/2012syllabi

iv 2012 Subspecialty Day | Retina

CME Credit

Academy’s CME Mission Statement

The purpose of the American Academy of Ophthalmology’s Continuing Medical Education (CME) program is to pres-ent ophthalmologists with the highest quality lifelong learning opportunities that promote improvement and change in physi-cian practices, performance or competence, thus enabling such physicians to maintain or improve the competence and profes-sional performance needed to provide the best possible eye care for their patients.

2012 Retina Subspecialty Day Meeting Learning Objectives

Upon completion of this activity, participants should be able to:

• Explainthecurrentmanagementofmacularedemasec-ondary to retinal occlusive disease and diabetic retinopa-thy

• Explainthepathobiologyandmanagementofatrophicand exudative AMD and other causes of CNV

• Identifyemergingdevelopmentsinretinalimaging• Describenewvitreoretinalsurgicaltechniquesandinstru-

mentation • Identifynewdevelopmentsinhereditaryretinaldegenera-

tions, pediatric retinal diseases, and ocular oncology

2012 Retina Subspecialty Day Meeting Target Audience

The intended target audience for this program is vitreoretinal specialists, members in fellowship training and general ophthal-mologists 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 pro-vide continuing medical education for physicians.

The American Academy of Ophthalmology designates this live activity for a maximum of 14 AMA PRA Category 1 Cred-its™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Scientific Integrity and Disclosure of Financial Interest

The American Academy of Ophthalmology is committed to ensuring that all continuing medical education (CME) informa-tion 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 con-tent. All persons in a position to control the content of this activ-ity 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.

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:

• Registerinadvance,receivematerialsinthemailandturnin the Final Program and/or Subspecialty Day Syllabus exchange voucher(s) onsite;

• Registerinadvanceandpickupyourbadgeonsiteifmate-rials did not arrive before you traveled to the meeting;

• Registeronsite;or• UseyourExpoCardatthemeeting.

CME Credit Reporting

Grand Concourse Level 2.5; Academy Resource Center, Hall A - Booth 508Attendees 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 Meet-ing credits entered onsite will be available to Academy members on the Academy’s 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 atten-dance. 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 Academy-sponsored 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.

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 nonmem-bers who need it to report CME credit:

• CMEcreditreporting/proof-of-attendanceletters• OnsiteRegistrationForm• InstructionCourseVerification

Visit the Academy’s website for detailed CME reporting infor-mation.

http://www.aao.org/cme

2012 Subspecialty Day | Retina v

The Charles L Schepens MD LecturePotential Therapeutic Approaches to AMD

Friday, November 9, 20129:31 AM – 9:46 AM

Alan C Bird MD

vi 2012 Subspecialty Day | Retina

Thomas M Aaberg Jr MDAda, MI Founder and PresidentRetina Specialists of MichiganAssistant Clinical Professor of

OphthalmologyMichigan State University

Gary W Abrams MDDetroit, MI Professor of OphthalmologyKresge Eye InstituteWayne State University

David H Abramson MD FACSNew York, NY Chief, Ophthalmic Oncology ServiceMemorial Sloan-Kettering Cancer CenterProfessor of OphthalmologyWeill Cornell University

Lloyd P Aiello MD PhDBoston, MA Professor of OphthalmologyHarvard Medical SchoolHead, Section of Eye Research, andDirector, Beetham Eye InstituteJoslin Diabetes Center

Arthur W Allen Jr MDSan Francisco, CA Vice Chairman Department of OphthalmologyCalifornia Pacific Medical CenterPresidentPacific Eye Associates

J Fernando Arevalo MD FACSRiyadh, Saudi ArabiaProfessor of OphthalmologyWilmer Eye Institute and Johns Hopkins

University School of MedicineChief of Vitreoretina DivisionThe King Khaled Eye Specialist HospitalRiyadh, Kingdom of Saudi Arabia

Jorge G Arroyo MDBrookline, MA Associate Professor of OphthalmologyHarvard Medical SchoolDirector of Retina ServiceBeth Israel Deaconess Medical Center

Marcos P Avila MDGoiania, BrazilFull Professor of Ophthalmology andHead of the Ophthalmology DepartmentUniversidade Federal de Goiás

Carl C Awh MDNashville, TN PresidentTennessee Retina, PC

Faculty

2012 Subspecialty Day | Retina Faculty Listing vii

James W Bainbridge MA PhD FRCOphthLondon, United KingdomProfessor of Retinal StudiesUniversity CollegeConsultant OphthalmologistMoorfields Eye Hospital

Sophie J Bakri MDRochester, MN Professor of OphthalmologyMayo Clinic

Francesco M Bandello MD FEBOMilano, ItalyFull Professor and ChairmanDepartment of OphthalmologyUniversity Vita Salute Scientific Institute, San Raffaele, MilanMD, FEBOUniversity Vita Salute

No photo available

Francine Behar-Cohen MDParis, France

Audina M Berrocal MDMiami, FL Associate Professor of OphthalmologyBascom Palmer Eye InstituteUniversity of MiamiStaff PhysicianMiami Children’s Hospital

Maria H Berrocal MDSan Juan, PR Assistant ProfessorUniversity of Puerto Rico

Susanne Binder MDVienna, AustriaProfessor of OphthalmologyDepartment of OphthalmologyRudolf Foundation ClinicProfessor of OphthalmologyThe Ludwig Boltzmann Institute for

Retinology and Biomicroscopic Laser Surgery

Alan C Bird MDLondon, EnglandEmeritus Professor of OphthalmologyUniversity College, London

No photo available

Barbara Ann Blodi MDMadison, WI Professor of OphthalmologyUniversity of WisconsinCodirectorFundus Photograph Reading CenterUniversity of Wisconsin

viii Faculty Listing 2012 Subspecialty Day | Retina

Mark S Blumenkranz MDPalo Alto, CA Professor and ChairmanStanford University School of Medicine

David S Boyer MDLos Angeles, CA Clinical Professor of OphthalmologyUniversity of Southern CaliforniaKeck School of MedicinePartner, Retina Vitreous Associates

Medical Group

No photo available

Periklis Brazitikos MDThessaloniki, GreeceAssociate Professor of OphthalmologyAristotle University of Thessaloniki

Neil M Bressler MDBaltimore, MD The James P Gills Professor of

OphthalmologyJohns Hopkins University School of

MedicineChief, Retina DivisionWilmer Eye Institute

David M Brown MDHouston, TX Associate Clinical Professor of

OpthalmologyWeill Cornell College of Medicine, The

Methodist HospitalDirector of Clinical ResearchRetina Consultants of Houston

Alexander J Brucker MDPhiladelphia, PA Professor of OphthalmologyScheie Eye InstituteUniversity of Pennsylvania

Brandon G Busbee MDNashville, TN Retina SpecialistTennessee Retina

Antonio Capone Jr MDRoyal Oak, MI Professor of OphthalmologyWilliam Beaumont Hospital-Oakland

University School of MedicineCodirector, Fellowship in Vitreoretinal

Diseases and SurgeryAssociated Retinal Consultants

Usha Chakravarthy MBBS PhDBelfast, Northern IrelandProfessor of Ophthalmology and Vision

ScienceQueen’s University of Belfast

2012 Subspecialty Day | Retina Faculty Listing ix

Wiley Andrew Chambers MDMcLean, VA Clinical Professor of OphthalmologyThe George Washington University

R V Paul Chan MDNew York, NY St Giles Associate Professor of Pediatric

RetinaWeill Cornell Medical College

Stanley Chang MDNew York, NY KK Tse and Ku Teh Ying Professor of

OphthalmologyColumbia University

Tom S Chang MDArcadia, CA PartnerRetina Institute of California

Steven T Charles MDMemphis, TN Adjunct Professor of OphthalmologyColumbia College of Physicians and

SurgeonsClinical Professor of OphthalmologyUniversity of Tennessee, Memphis

Emily Y Chew MDBethesda, MD Deputy Director of Division of

Epidemiology and Clinical Applicatons

National Eye Institute, National Institutes of Health

N H Victor Chong MDOxford, United KingdomHead of DepartmentOxford Eye HospitalClinical Senior Lecturer in

OphthalmologyUniversity of Oxford

David R Chow MDNorth York, ON, CanadaAssistant Professor of OphthalmologyUniversity of TorontoCodirectorToronto Retina Institute

Mina Chung MDRochester, NY Associate Professor of OphthalmologyFlaum Eye InstituteUniversity of Rochester

x Faculty Listing 2012 Subspecialty Day | Retina

Carl C Claes MDSchilde, BelgiumHead of Vitreoretinal SurgerySaint Augustinus Hospital (Wilrijk/

Antwerp)

No photo available

Karl G Csaky MD PhDDallas, TX Vitreoretinal SpecialistTexas Retina Associates

Christine Curcio PhDBirmingham, AL Professor of OphthalmologyUniversity of Alabama at Birmingham

Donald J D’Amico MDNew York, NY Professor and ChairmanDepartment of OphthalmologyWeill Cornell Medical CollegeOphthalmologist-in-ChiefNew York-Presbyterian Hospital

Kimberly A Drenser MD PhDRoyal Oak, MI Vitreoretinal SurgeonAssociated Retinal ConsultantsAssociate ProfessorEye Research InstituteOakland University

Pravin U Dugel MDPhoenix, AZ Managing PartnerRetinal Consultants of ArizonaClinical Associate Professor of

OphthalmologyDoheny Eye InstituteKeck School of MedicineUniversity of Southern California

Jay S Duker MDBoston, MA Director, New England Eye CenterTufts Medical CenterProfessor and Chair Department of

Ophthalmology

No photo available

Alexander M Eaton MDFort Myers, FL

Claus Eckardt MDFrankfurt, GermanyProfessor of OphthalmologyKlinikum Frankfurt Höchst

2012 Subspecialty Day | Retina Faculty Listing xi

Ehab N El Rayes MD PhDCairo, EgyptProfessor of Ophthalmlogy, Retina

ServiceInstitute of OphthalmologyVitreoretinal ConsultantInternational Eye Hospital

Dean Eliott MDBoston, MA Associate Director, Retina ServiceMassachusetts Eye and Ear InfirmaryHarvard Medical School

Daniel D Esmaili MDBoston, MA Instructor in OphthalmologyMassachusetts Eye and Ear Infirmary

Sharon Fekrat MDDurham, NC Associate Professor of OphthalmologyAlbert Eye Research InstituteDuke University Eye CenterChief, OphthalmologyDurham Veterans Affairs Medical Center

Frederick L Ferris MDWaxhaw, NC Director, Division of Epidemiology and

Clinical ApplicationsNational Eye Institute, National

Institutes of Health

Philip J Ferrone MDGreat Neck, NY PartnerLong Island Vitreoretinal ConsultantsAssistant Professor of OphthalmologyColumbia University

Marta Figueroa MDMadrid, SpainDirector of Vitreoretinal DepartmentVissum MadridProfessor of OphthalmologyUniversity of Alcalá de Henares

Paul T Finger MDNew York, NY DirectorThe New York Eye Cancer CenterClinical Professor of OphthalmologyNew York University School of

Medicine

Harry W Flynn Jr MDMiami, FL Professor of OphthalmologyBascom Palmer Eye InstituteUniversity of Miami

xii Faculty Listing 2012 Subspecialty Day | Retina

William R Freeman MDLa Jolla, CA Professor of Ophthalmology University of California, San DiegoDirectorJacobs Retina CenterShiley Eye CenterUniversity of California, San Diego

K Bailey Freund MDNew York, NY Clinical Associate Professor of

OphthalmologyNew York UniversityPartnerVitreous Retina Macula Consultants of

New York

Thomas R Friberg MDPittsburgh, PA Professor of Bioengineering and

OphthalmologyUniversity of PittsburghDirector of Retina ServiceUPMC Eye Center

Anne E Fung MDSan Francisco, CA Medical Retina ConsultantPacific Eye AssociatesDirector, Barkan Research SocietyCalifornia Pacific Medical Center

No photo available

Brenda L Gallie MDToronto, ON, CanadaProfessor of OphthalmologyUniversity of TorontoHead, Retinoblastoma ProgramHospital for Sick Children

Alain Gaudric MDParis, FranceProfessor of OphthalmologyHopital Lariboisiere, AP-HPUniversité Paris-Diderot

No photo available

Andre V Gomes MDSão Paulo, Brazil

No photo available

Christine R Gonzales MDAshland, OR

Evangelos S Gragoudas MDBoston, MA Professor of OphthalmologyHarvard Medical SchoolDirector, Retina ServiceMassachusetts Eye and Ear Infirmary

M Gilbert Grand MDSt Louis, MO Retina SurgeonRetina Consultants, The Retina InstituteProfessor of Clinical OphthalmologyWashington University School of

Medicine

2012 Subspecialty Day | Retina Faculty Listing xiii

Julia A Haller MDPhiladelphia, PA Ophthalmologist-in-ChiefWills Eye HospitalProfessor and Chair of OphthalmologyJefferson Medical CollegeThomas Jefferson University

Dennis P Han MDMilwaukee, WI Jack A and Elaine D Klieger Professor of

OphthalmologyMedical College of WisconsinHead, Vitreoretinal Section Froedert & The Medical College Eye

Institute

Tarek S Hassan MDRoyal Oak, MI Professor of OphthalmologyOakland University, William Beaumont

School of MedicineDirector of Vitreoretinal ProgramPartner, Associated Retinal Consultants

Jeffrey S Heier MDBoston, MA Director, Vitreoretina ServiceOphthalmic Consultants of BostonAssistant Professor in OphthalmologyTufts University School of Medicine

Allen C Ho MDPhiladelphia, PA Director of Retina ResearchMid Atlantic Retina and Wills Eye

InstituteProfessor of OphthalmologyThomas Jefferson University

Frank G Holz MDBonn, GermanyProfessor of OphthalmologyUniversity of Bonn, Germany

Suber S Huang MD MBACleveland, OH Director, Center Retina and Macular

DiseaseUniversity Hospitals Eye InstituteSearle Professor and Vice ChairDepartment of Ophthalmology and

Visual SciencesCase Western Reserve University School

of Medicine

Mark S Humayun MD PhDLos Angeles, CA Professor of Ophthalmology, Biomedical

Engineering and Cell & NeurobiologyDoheny Eye Institute Keck School of MedicineUniversity of Southern California

Michael S Ip MDMadison, WI Associate Professor of OphthalmologyUniversity of Wisconsin-Madison

xiv Faculty Listing 2012 Subspecialty Day | Retina

No photo available

Timothy L Jackson MBChBLondon, EnglandConsultant Ophthalmic SurgeonKing’s College HospitalHEFCE Senior Clinical LecturerKing’s College London

Glenn J Jaffe MDDurham, NC Professor of OphthalmologyDuke University

No photo available

Martine J Jager MDOegstgeest, NetherlandsSenior Medical SpecialistLeiden University Medical Center,

Leiden

Mark W Johnson MDAnn Arbor, MI Professor of Ophthalmology and Visual

SciencesUniversity of MichiganDirector, Retina ServiceW K Kellogg Eye Center

No photo available

J Michael Jumper MDSan Francisco, CAWest Coast Retina Medical Group, Inc.

Kazuaki Kadonosono MDYokohama, JapanProfessor of OphthalmologyYokohama City University

Peter K Kaiser MDCleveland, OH Professor of OphthalmologyCleveland Clinic Lerner College of

MedicineDirector, Digital OCT Reading CenterCole Eye Institute

Ivana K Kim MDBoston, MA Associate Professor of OphthalmologyHarvard Medical SchoolRetina ServiceMassachusetts Eye and Ear Infirmary

Judy E Kim MDMilwaukee, WI Professor of OphthalmologyMedical College of Wisconsin

2012 Subspecialty Day | Retina Faculty Listing xv

No photo available

John W Kitchens MDLexington, KY

Baruch D Kuppermann MD PhDIrvine, CA Professor and Chief, Retina ServiceGavin Herbert Eye InstituteUniversity of California, Irvine

No photo available

Timothy Y Lai MD FRCOphth FRCSTsimshatsui, Kowloon, Hong KongHonorary Clinical Associate ProfessorThe Chinese University of Hong KongDirector, 2010 Retina and Macula

Centre

Jennifer Irene Lim MDChicago, IL Professor of Ophthalmology,Director, Retina Service, andMarion H Schenk Esq Chair in

OphthalmologyIllinois Eye and Ear InfirmaryUniversity of Illinois at Chicago

Anat Loewenstein MDTel Aviv, IsraelDirector of OphthalmologyTel Aviv Medical CenterProfessor of OphthalmologyVice Dean, Sackler Faculty of Medicine,

Tel Aviv University

Ian M MacDonald MDEdmonton, AB, CanadaProfessor of OphthalmologyUniversity of Alberta

Maureen G Maguire PhDPhiladelphia, PA Professor of OphthalmologyUniversity of Pennsylvania

Daniel F Martin MDCleveland, OH Chairman, Cole Eye InstituteCleveland Clinic

Carlos Mateo MDBarcelona, SpainAssociate Professor of OphthalmologyInstituto de Microcirugía Ocular of

Barcelona

xvi Faculty Listing 2012 Subspecialty Day | Retina

William F Mieler MDChicago, IL Professor and Vice ChairmanDepartment of Ophthalmology and

Visual SciencesUniversity of Illinois at Chicago

Joan W Miller MDBoston, MA Henry Willard Williams Professor of

OphthalmologyHarvard Medical SchoolChief and Chair of OphthalmologyMassachusetts Eye and Ear InfirmaryHarvard Medical School

Darius M Moshfeghi MDPalo Alto, CA Associate Professor of OphthalmologyStanford University School of MedicineDirector of Telemedicine andDirector of Pediatric Vitreoretinal

SurgeryByers Eye InstituteStanford University School of Medicine

No photo available

Shizuo Mukai MDBoston, MA Assistant Professor in OphthtalmologyHarvard Medical SchoolSurgeon in OphthalmologyMassachusetts Eye and Ear Infirmary

Timothy G Murray MD MBAMiami, FL Professor of Ophthalmology and

Radiation OncologyBascom Palmer Eye InsituteUniversity of Miami Miller School of

Medicine

Annabelle A Okada MDTokyo, JapanProfessor of OphthalmologyKyorin University School of Medicine

Timothy W Olsen MDAtlanta, GA F Phinizy Calhoun Sr Professor and

Chairman of OphthalmologyEmory University

Jeffrey L Olson MDEnglewood, CO Associate Professor of OphthalmologyUniversity of Colorado, Rocky

Mountain Lions Eye Institute

Yusuke Oshima MDSuita, Osaka, JapanAssociate Professor of OphthalmologyOsaka University Graduate School of

Medicine

2012 Subspecialty Day | Retina Faculty Listing xvii

Andrew J Packer MDHartford, CT Clinical ProfessorUniversity of Connecticut School of

Medicine

Kirk H Packo MDIndian Head Park, IL Professor and ChairmanDepartment of Ophthalmology Rush University Medical CenterPartner, Illinois Retina Associates

David W Parke II MDSan Francisco, CA Executive Vice President and CEOAmerican Academy of Ophthalmology

Fabio Patelli MDGarbagnate Milanese, ItalyOphthalmologist, Vitreoretinal SurgeonMilano Retina CenterDirector, Vitreoretinal ServiceIgea Clinic, Milan

No photo available

Grazia Pertile MDNegrar, Verona, ItalyDirector, Department of OphthalmologySacro Cuore Hospital, Negrar (VR) Italy

Dante Pieramici MDSanta Barbara, CA Assistant Clinical ProfessorDoheny Eye InstitutePresident, California Retina Research

Foundation

Eric A Pierce MD PhDBoston, MA Director, Ocular Genomics InstituteMassacusetts Eye and Ear Infirmary

Subhransu Ray MD PhD Moraga, CA

Franco M Recchia MDNashville, TN Associate, Tennessee Retina, P.C.

xviii Faculty Listing 2012 Subspecialty Day | Retina

Carl D Regillo MD FACSBryn Mawr, PA Professor of OphthalmologyThomas Jefferson UniversityDirector, Retina ServiceWills Eye Institute

Kourous Rezaei MDHarvey, IL Associate Professor of OphthalmologyRush University Medical CenterPartner, Illinois Retina Associates

William L Rich MDFalls Church, VA Medical Director for Health PolicyAmerican Academy of OphthalmologyClinical InstructorDepartment of OphthalmologyGeorgetown University

Stanislao Rizzo MDPisa, ItalyDirector U.O. Chirurgia OftalmicaAzienda Ospedaliero Universitaria Pisana

Michael A Romansky JDChevy Chase, MD Washington Counsel and Vice President

for Corporate DevelopmentOutpatient Ophthalmic Surgery Society

No photo available

Richard B Rosen MDNew York, NY Vice Chairman and Surgeon Director,

Director of Retina and Director of Research

New York Eye and Ear InfirmaryProfessor of OphthalmologyNew York Medical College

Philip J Rosenfeld MD PhDMiami, FL Professor of OphthalmologyBascom Palmer Eye InstituteUniversity of Miami Miller School of

Medicine

Alan J Ruby MDNovi, MI Associated Retinal Consultants, Royal

Oak, MIProfessor of OphthalmologyOakland University William Beaumont

School of Medicine

Srinivas R Sadda MDLos Angeles, CA Associate Professor of OphthalmologyUniversity of Southern CaliforniaDirector, Doheny Image Reading CenterDoheny Eye Institute

2012 Subspecialty Day | Retina Faculty Listing xix

Andrew P Schachat MDCleveland, OH Vice Chairman for Clinical AffairsCole Eye Institute, Cleveland ClinicProfessor of OphthalmologyLerner College of Medicine

No photo available

Amy C Schefler MDHouston, TX Clinical Assistant ProfessorWeill Medical College of Cornell

UniversityAssociate PartnerRetinal Consultants of Houston

Ursula M Schmidt-Erfurth MDVienna, AustriaProfessor of OphthalmologyMedical University of ViennaChairDepartment of Ophthalmology and

Optometry

No photo available

Hendrik PN Scholl MDBaltimore, MD The Dr. Frieda Derdeyn Bambas

Professor of Ophthalmology Wilmer Eye InstituteJohn Hopkins University School of

Medicine

Steven D Schwartz MDLos Angeles, CA Ahmanson Professor of Ophthalmology

and Chief, Retina DivisionJules Stein Eye Institute, University of

California, Los Angeles (UCLA)Professor of OphthalmologyDavid Geffen School of Medicine at

UCLA

Jonathan E Sears MDCleveland, OH Associate Professor of OphthalmologyCole Eye Institute, Cleveland ClinicAssociate Professor of Cell BiologyCell Biology, Cleveland Clinic

Gaurav K Shah MDSt Louis, MO Clinical Professor of Ophthalmology and

Visual SciencesThe Retina Institute

Carol L Shields MDPhiladelphia, PA Codirector, Oncology ServiceWills Eye InstituteProfessor of OphthalmologyThomas Jefferson University Hospital

Jerry A Shields MDPhiladelphia, PA Director, Oncology ServiceWills Eye InstituteProfessor of OphthalmologyThomas Jefferson University

xx Faculty Listing 2012 Subspecialty Day | Retina

Michael A Singer MDSan Antonio, TX Ophthalmologist, Managing Partner and

Director of Clinical TrialsMedical Center Ophthalmology

AssociatesAssistant Clinical ProfessorUniversity of Texas Health Science

Center, San Antonio

Lawrence J Singerman MDCleveland, OH Founder, Retina Associates of ClevelandClinical Professor of OphthalmologyCase Western Reserve University School

of Medicine

Arun D Singh MDCleveland, OH Director, Ophthalmic OncologyCole Eye InstituteProfessor of OphthalmologyCleveland Clinic

Rishi P Singh MDCleveland, OH Staff PhysicianCole Eye InstituteCleveland Clinic Foundation

Jason S Slakter MDNew York, NY Clinical Professor of OphthalmologyNew York University School of

MedicinePartner, Vitreous Retina Macula

Consultants of New York

No photo available

Rachel Smith MD PhDAtlanta, GA

Gisele Soubrane MD PhDParis, FranceProfessor of OphthalmologyDepartment of Ophthalmology University Paris Descartes, FranceMD, PhD, FEBO, FARVOHotel Dieu de Paris

Richard F Spaide MDNew York, NY OphthalmologyVitreous, Retina and Macula

Consultants of New York

Sunil K Srivastava MDCleveland, OH Staff PhysicianCole Eye InstituteCleveland Clinic Foundation

2012 Subspecialty Day | Retina Faculty Listing xxi

Giovanni Staurenghi MDMilan, ItalyProfessor of OphthalmologyDepartment of Clinical Science “Luigi

Sacco”

Paul Sternberg MDNashville, TN Professor and Chairman, Vanderbilt Eye

InstituteVanderbilt University School of

MedicineAssociate Dean for Clinical AffairsVanderbilt University School of

Medicine

John T Thompson MDBaltimore, MD Partner, Retina SpecialistsAssistant ProfessorThe Wilmer Institute of The Johns

Hopkins University

No photo available

Trexler M Topping MDBoston, MA Associate Clinical Professor of

OphthalmologyTufts University School of MedicineInstructor in OphthalmologyHarvard Medical School

Cynthia A Toth MDDurham, NC Professor of OphthalmologyDuke University Medical CenterProfessor of Biomedical EngineeringPratt School of EngineeringDuke University

Michael T Trese MDRoyal Oak, MI President, Associated Retinal

Consultants, PCChief, Pediatric and Adult Vitreoretinal

SurgeryBeaumont Eye Institute Wm Beaumont Hospital

Jan C Van Meurs MDRotterdam, NetherlandsVitreoretinal SurgeonThe Rotterdam Eye HospitalProfessorErasmus University

Luk H Vandenberghe PhDBoston, MA Lecturer in OphthalmologyMassachusetts Eye and Ear InfirmaryHarvard Medical School

Alexander C Walsh MDLos Angeles, CA Assistant Professor of OphthalmologyKeck School of MedicineUniversity of Southern California

xxii Faculty Listing 2012 Subspecialty Day | Retina

David F Williams MDMinneapolis, MN Partner, VitreoRetinal Surgery, P.A.Assistant Clinical Professor of

OphthalmologyUniversity of Minnesota

George A Williams MDRoyal Oak, MI Professor and Chair, Department of

OphthalmologyOakland University William Beaumont

School of Medicine

Lihteh Wu MDSan Jose, Costa RicaAssociate SurgeonInstituto de Cirugia OcularAssociate ProfessorUniversity of Costa Rica

Lawrence A Yannuzzi MDNew 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 SurgeonsColumbia University

Young Hee Yoon MDSeoul, Republic of KoreaProfessor of OphthalmologyAsan Medical Center, University of

Ulsan, College of Medicine

David N Zacks MD PhDAnn Arbor, MI Associate Professor of Ophthalmology

and Visual SciencesUniversity of Michigan, Kellogg Eye

Center

2012 Subspecialty Day | Retina xxiii

Retina 2012: The Winds of Change

FRIDAY, NOVEMBER 9, 2012

7:00 AM REGISTRATION/MATERIAL PICKUP/CONTINENTAL BREAKFAST

8:00 AM Opening Remarks Joan W Miller MD* Tarek S Hassan MD*

Section I: Vitreoretinal Surgery, Part I

Moderators: Tarek S Hassan MD*, Young Hee Yoon MD*

8:05 AM Vitreoretinal Instrument Update David R Chow MD* 1

8:15 AM Role of Retinectomy in Vitreoretinal Surgery Dean Eliott MD* 2

8:22 AM Current Role of Endoscopy in Vitreoretinal Surgery Jorge G Arroyo MD 4

8:29 AM Treatment of Suprachoroidal Hemorrhages John W Kitchens MD* 6

8:36 AM Recurrent Retinal Detachment: Does Initial Treatment Matter? Gaurav K Shah MD* 7

8:43 AM Chromovitrectomy 2012 Lihteh Wu MD* 9

8:50 AM Vitrectomy for Lamellar Macular Hole Periklis Brazitikos MD* 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 My Coolest Surgical Video Carlos Mateo MD 13

8:59 AM Discussion

9:01 AM My Coolest Surgical Video Yusuke Oshima MD* 13

9:03 AM Discussion

9:05 AM My Coolest Surgical Video Kazuaki Kadonosono MD 13

9:07 AM Discussion

9:09 AM My Coolest Surgical Video Ehab N El Rayes MD PhD 13

9:11 AM Discussion

9:13 AM My Coolest Surgical Video Claus Eckardt MD* 13

9:15 AM Discussion

9:17 AM My Coolest Surgical Video J Fernando Arevalo MD FACS 13

9:19 AM Discussion

9:21 AM My Coolest Surgical Video Carl C Claes MD* 13

9:23 AM Discussion

9:25 AM Audience Vote

* Indicates that the presenter has financial interest.No asterisk indicates that the presenter has no financial interest.

xxiv Program Schedule 2012 Subspecialty Day | Retina

* Indicates that the presenter has financial interest.No asterisk indicates that the presenter has no financial interest.* Indicates that the presenter has financial interest.No asterisk indicates that the presenter has no financial interest.

The Charles L Schepens MD Lecture

9:26 AM Introduction of the 2012 Schepens Lecturer David W Parke II MD*

9:31 AM Potential Therapeutic Approaches to AMD Alan C Bird MD 14

9:46 AM REFRESHMENT BREAK and RETINA EXHIBITS

Section II: Non-neovascular AMD

Moderators: Sophie J Bakri MD*, Francesco M Bandello MD FEBO*

10:30 AM Pathogenesis of AMD Christine Curcio PhD* 15

10:40 AM Genetic Testing−Pro Mark S Blumenkranz MD* 17

10:47 AM Genetic Testing−Con Frederick L Ferris MD* 20

10:54 AM Audience Vote

10:55 AM Rapid-fire Phase 2 Trials, Part I David M Brown MD* 21

11:02 AM Rapid-fire Phase 2 Trials, Part II Philip J Rosenfeld MD PhD* 21

11:09 AM Neuroprotection for AMD David N Zacks MD PhD* 28

11:16 AM Cell-Based Therapies for AMD Allen C Ho MD* 29

11:23 AM Advocating for Patients George A Williams MD* 32

11:28 AM LUNCH and RETINA EXHIBITS

Section III: Late Breaking Developments, Part I

Moderators: Alexander J Brucker MD*, Paul Sternberg MD

1:00 PM A Multi-state Outbreak of Fungal Endophthalmitis Associated With Rachel Smith MD MPH 34 Contaminated Ophthalmologic Products From a Single Compounding Pharmacy

1:07 PM Responder Analysis of the INTREPID Study of Stereotactic Radiotherapy Timothy L Jackson MBChB* 34 for Wet Age-Related Macular Degeneration

1:14 PM First-in-Human Results of a Refillable Drug Delivery Implant Providing Anat Loewenstein MD* 34 Release of Ranibizumab in Patients with Wet AMD

1:21 PM The Use of Anterior Segment OCT to Help Predict Steroid Responders Michael A Singer MD* 34 After Intravitreal Injections

1:28 PM New Insight in the Physiopathology of CSCR: Therapeutic Application Francine Behar-Cohen MD 34

1:35 PM Baseline Anatomic Features Predictive of Pharmacologic VMA Subhransu Ray MD PhD* 34 Resolution in the Phase III Ocriplasmin Clinical Trial Program

Section IV: Pediatric Retina

Moderators: Shizuo Mukai MD, Amy C Schefler MD

1:42 PM Update on the Study of Telemedicine for ROP Darius M Moshfeghi MD* 35

1:49 PM Ophthalmic Insurer Perspectives on the Use of Telemedicine for Screening and Diagnosis of ROP and Bevacizumab for ROP Arthur W Allen Jr MD 36

1:56 PM Update on the Multicenter Study of Anti-VEGF Treatment for ROP (BLOCK-ROP)* Michael T Trese MD 38

2:03 PM Microplasmin for Pediatric Vitrectomy Study Kimberly A Drenser MD PhD* 39

2:10 PM Familial Exudative Vitreoretinopathy: Diagnosis, Management With Wide-Angle Angiography, and Long-term Surgical Results Franco M Recchia MD* 40

2012 Subspecialty Day | Retina 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: Inherited Retinal Diseases

Moderators: Marcos P Avila MD, Michael A Singer MD*

2:37 PM Update on Gene Therapy Trials in Progress James W Bainbridge MA PhD FRCOphth* 43

2:44 PM Upcoming Trials in Retinal Degeneration Ian M MacDonald MD* 44

2:51 PM Phase 1b Data for 091001, a Synthetic Retinoid for the Treatment of Leber Congenital Amaurosis and Retinitis Pigmentosa Hendrik PN Scholl MD* 46

2:58 PM Genetic Testing for Patients With Retinal Degeneration Eric A Pierce MD PhD 47

3:05 PM Optogenetics: A New Approach to Retinitis Pigmentosa Luk H Vandenberghe PhD* 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*

Topic V02: New Instrumentation David R Chow MD*

Topic V03: Diabetic Retinopathy Carl C Awh MD* Carl G Csaky MD PhD* Mark W Johnson MD* Jennifer Irene Lim MD*

Topic V04: Business of Retina Alan J Ruby MD* George A Williams MD*

Topic V05: Endophthalmitis Harry W Flynn Jr MD*

Topic V06: Trauma Carl C Claes MD*

Topic V07: Intraocular Tumors Ivana K Kim MD* Timothy G Murray MD MBA*

Topic V08: Macular Surgery Periklis Brazitikos MD* Carlos Mateo MD Yusuke Oshima MD* Cynthia A Toth MD*

Topic V09: Ocular Imaging Srinivas R Sadda MD* Richard F Spaide MD* Sunil K Srivastava MD Alexander C Walsh MD*

Topic V10: Pediatric Retinal Disease Kimberly A Drenser MD PhD* Philip J Ferrone MD*

Topic V11: Gene Therapy James W Bainbridge MA PhD* FRCOphth

xxvi Program Schedule 2012 Subspecialty Day | Retina


Topic V12: Enzymatic Vitrectomy Michael T Trese MD*

Topic V13: Retinal Detachment Gary W Abrams MD* J Fernando Arevalo MD FACS Claus Eckardt MD* Dean Eliott MD*

Topic V14: Vascular Occlusions Michael S Ip MD* Sharon Fekrat MD Carl D Regillo MD FACS*

Section VI: Retinal Vein Occlusion

Moderator: Donald J D’Amico MD*

3:54 PM 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: Business of Retina

Moderators: William R Freeman MD*, Anne E Fung MD*

4:14 PM The Future of Health Care: Survival of the Fittest David W Parke II MD* 52

4:21 PM Accountable Care Organizations: In or Out? William L Rich MD 54

4:28 PM ASC for Retina: Is It Time? Michael A Romansky JD 56

4:35 PM ASC for Retina: Balancing Quality With Profit Alan J Ruby MD* 57

4:42 PM The Office of the Inspector General and Bevacizumab vs. Ranibizumab: No Good Deed Goes Unpunished George A Williams MD* 58

4:49 PM Managing a Large Modern Practice: Practice Informatics and IT Trexler M Topping MD* 59

4:56 PM Post-marketing Surveillance Wiley Andrew Chambers MD 60

5:03 PM Closing Remarks Joan W Miller MD* Tarek S Hassan MD*

5:04 PM ADJOURN

SATURDAY, NOVEMBER 10, 2012

7:00 AM CONTINENTAL BREAKFAST

8:00 AM Opening Remarks Joan W Miller MD* Tarek S Hassan*

Section VIII: Neovascular AMD

Moderators: Andrew P Schachat MD, Gisele Soubrane MD PhD*

8:05 AM Non-inferiority Trials and Subgroups: How to Interpret What You Are About to Hear Maureen G Maguire PhD* 63

8:12 AM CATT: Year 2 Daniel F Martin MD 65

8:19 AM IVAN: Year 1 Usha Chakravarthy MBBS PhD* 66

8:26 AM MANTA: Year 1 Susanne Binder MD 68

2012 Subspecialty Day | Retina Program Schedule xxvii


8:33 AM VIEW: Year 2 Jeffrey S Heier MD* 69

8:40 AM HARBOR: Year 2 Brandon G Busbee MD* 70

8:47 AM How Do I Incorporate What I Just Heard Into My Practice? Peter K Kaiser MD* 73

8:54 AM Aspirin and AMD: What Do I Tell My Patients? Emily Y Chew MD 74

9:01 AM Radiation for CNV: Cabernet /MERITAGE/ INTREPID Timothy L Jackson MBChB* 76

9:08 AM Polypoidal Vasculopathy: Anti-VEGF, Photodynamic Therapy, Timothy Y Lai MD and Steroids FRCOphth FRCS* 77

9:15 AM Anti-Platelet Derived Growth Factor: Where Do We Stand? Pravin U Dugel MD* 80

9:22 AM Long-term Delivery Strategies for Neovascular AMD David S Boyer MD* 81

9:29 AM What’s Next in the Neovascular AMD Pipeline? Jason S Slakter MD* 82

9:36 AM 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: Imaging

Moderators: Daniel D Esmaili MD, Timothy W Olsen MD*

10:40 AM Imaging the Choroid: What You Need to Know Before Deep “C” Diving Richard F Spaide MD* 86

10:47 AM When Should I Be Using Fundus Autofluorescence? Frank G Holz MD* 89

10:54 AM What’s Next in Imaging? Srinivas R Sadda MD* 94

11:01 AM Intraoperative OCT: Is It Actually Useful? Sunil K Srivastava MD 97

11:08 AM Adaptive Optics: Ready for Prime Time? Judy E Kim MD* 99

11:15 AM Simple Estimation of Fluid Volumes in Neovascular AMD Alexander C Walsh MD* 102

11:22 AM 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*

Section X: Oncology

Moderators: K Bailey Freund MD*, Martine J Jager MD*

11:42 AM Germline BAP1 Mutations in Ocular Melanoma and Other Malignancies Ivana K Kim MD* 105

11:49 AM Practical Approaches to Needle Biopsy and Genetic Diagnosis for Ocular Melanoma Thomas M Aaberg Jr MD* 106

11:56 AM New Imaging Techniques for Ocular Tumors Timothy G Murray MD MBA* 115

12:03 PM Follow-up After Intra-arterial Chemotherapy for Retinoblastoma Carol L Shields MD 116

12:10 PM 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

12:30 PM LUNCH and JOINT MEETING EXHIBITS

xxviii Program Schedule 2012 Subspecialty Day | Retina


Section XI: Late Breaking Developments, Part II

Moderators: Tom S Chang MD, Suber S Huang MD MBA*

1:55 PM Phase I Study of CNTF for Mactel Emily Y Chew MD 118

2:02 PM Long-term Effects of Intravitreal Ranibizumab on Diabetic Retinopathy Michael S Ip MD* 118 Severity and Progression

2:09 PM A Phase 1 Study Targeting Tissue Factor With a Single Dose of Christine R Gonzales MD* 118 Intravitreal HI-Con1 for Exudative Macular Degeneration

2:23 PM A Novel Intravitreal Injection Device Alexander M Eaton MD* 118

2:16 PM New Surgical Technique and New Instrumentation for Safe, Atraumatic Jeffrey L Olson MD* 118 Removal of Intraocular Foreign Bodies

2:28 PM ARGUS II Mark S Humayun MD PhD* 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 Coin Toss and Audience Vote

2:37 PM Pro Neil M Bressler MD* 119

2:40 PM Con Harry W Flynn Jr MD* 119

2:43 PM Rebuttal, Pro Mark W Johnson MD* 121

2:44 PM Rebuttal, Con Jennifer Irene Lim MD* 121

2:45 PM Audience Vote

Subthreshold Laser Is an Important Treatment for Macular Edema (Yes/No)


2:47 PM Pro N H Victor Chong MD* 122

2:51 PM Con Lloyd P Aiello MD PhD* 122


I Still Use Scissors in Diabetic Vitrectomy (Yes/No)


2:57 PM Pro Steven T Charles MD* 123

3:01 PM Con Carl C Awh MD* 123


Anti-VEGF Is the Ideal Treatment for Diabetic Macular Edema (Yes/No)

3:06 PM Coin Toss and Audience Vote

3:08 PM Pro Julia A Haller MD* 124

3:11 PM Con Baruch D Kuppermann MD PhD* 124

3:14 PM Rebuttal, Pro Karl G Csaky MD PhD* 128

3:15 PM Rebuttal, Con Dante Pieramici MD* 128

2012 Subspecialty Day | Retina Program Schedule xxix



3:17 PM REFRESHMENT BREAK and JOINT MEETING EXHIBITS

Section XIII: Vitreoretinal Surgery, Part II

Moderators: Kirk H Packo MD*, Kourous Rezaei MD*

4:00 PM Surgical Complications Video, Part I 129

Moderator: Kirk H Packo MD* Panelists: Gary W Abrams MD*, Marta Figueroa MD*, William F Mieler MD*, Stanislao Rizzo MD, John T Thompson MD*

4:40 PM Surgical Complications Video, Part II 129

Moderator: Kourous Rezaei MD* Panelists: Stanley Chang MD*, Andre V Gomes MD*, Grazia Pertile MD, Jan C Van Meurs MD*, David F Williams MD*

5:20 PM Closing Remarks Joan W Miller MD* Tarek S Hassan MD*

5:22 PM ADJOURN

2012 Subspecialty Day | Retina Section I: Vitreoretinal Surgery, Part I 1

Vitreoretinal Instrument UpdateDavid R Chow MD

N o t e S

2 Section I: Vitreoretinal Surgery, Part I 2012 Subspecialty Day | Retina

Role of Retinectomy in Vitreoretinal SurgeryDean 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 prolifera-tive retinopathy (PVR) or proliferative diabetic reti-nopathy (PDR)

II. Retinotomy: Creating a Hole in the Retina (retinal inci-sion only, no excision)

A. Drainage retinotomy:

1. To remove subretinal fluid

2. Drainage site is located posteriorly when perfluo-rocarbon liquid is not used to reattach the retina.

3. Drainage site is located anteriorly when perfluo-rocarbon use results in anteriorly loculated sub-retinal fluid.

B. Access retinotomy: To remove choroidal neovas-cular membrane (CNVM), subretinal hemorrhage, subretinal membranes, retained subretinal perfluo-rocarbon 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, fur-ther epiretinal membrane removal may be difficult.

D. Orientation: Circumferential, posterior to vitreous base

E. Location

1. Avoid retinectomy edge near 6 o’clock position.

2. Most common retinectomy location is inferiorly with edges at 3 o’clock and 9 o’clock.

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 retinec-tomy 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 post-operative 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 per-formed in 29% overall

a. Group 1 (no previous vitrectomy): Retinec-tomy 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 absorp-tion of intraocular fluid by the choroid.


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 persis-tent traction on pre-existing or iatrogenic breaks

B. Large peripheral retinectomy: To remove massive fibrous proliferation caused by severe ischemia

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: anal-ysis of anatomic and visual results. Ophthalmology 1990 ;97:642-648.

6. Federman JL, Eagle RC. Extensive peripheral retinectomy com-bined with posterior 360 retinotomy for retinal reattachment in advanced proliferative vitreoretinopathy cases. Ophthalmology 1990; 97:1305-1320.

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 Ophthal-mol. 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 Ophthal-mol. 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 prolifera-tive 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 rhegmatog-enous retinal detachments and proliferative vitreoretinopathy. Oph-thalmology 2006; 113:2041-2047.

15. Grigoropoulos VG, Benson S, Bunce C, Charteris DG. Functional outcome and prognostic factors in 304 eyes managed by retinec-tomy. 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 vit-reoretinopathy. Eye 2008; 22:1517-1519.

17. de Silva DJ, Kwan A, Bunce C, Bainbridge J. Predicting visual out-come following retinectomy for retinal detachment. Br J Ophthal-mol. 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 retinec-tomy 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.


Current Role of endoscopy in Vitreoretinal SurgeryJorge G Arroyo MD

endoscope, Illuminator, and Laser

E2 EndoOptiks Laser and Endoscopy SystemThis system is a combined diode laser and endoscopy unit with laser output, pulse width, light, and aiming beam intensity con-trollable 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-reso-lution camera, and footswitch controller. It is the only autoclav-able 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 reso-lution 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.

endoscopy-Assisted Vitrectomy

Endoscopy through a 19.5-gauge or 23-gauge sclerotomy pro-vides additional benefits compared to the coaxial microscope view. An endoscope provides the ability to see the posterior seg-ment 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 fea-ture is quite helpful in identifying small retinal breaks or small intraocular foreign bodies, as well as other parts of surgery.

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 glau-coma, or neovascular glaucoma. There are a number of papers looking at endoscopy-assisted vitrectomy in cases of pseudopha-kic 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

in some cases of trauma associated with corneal opacification and endophthalmitis.

endoscopic Membrane Peeling

The endoscope can certainly assist in the peeling of both epireti-nal 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 magni-fication 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 cyclophoto-coagulation (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.

Pars Plana eCP

The pars plana approach for ECP allows for a much more exten-sive 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 proxim-ity 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 uninten-tionally 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 cili-ary 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 photocoagula-tion treatment from the equator to the ora serrata 360 degrees around. We do find that the 810-nanometer diode laser does


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.

Conclusions

Overall, the endoscopic laser probe provides excellent visualiza-tion 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 treat-ment 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.

Future

Given the fact that the 23-gauge endoscope provides a subopti-mal 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.

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.


treatment of Suprachoroidal HemorrhagesJohn W Kitchens MD

N o t e S


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 detach-ment (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 proce-dures

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. Pri-mary vitrectomy for rhegmatogenous retinal detachment: an analy-sis 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. Oph-thalmology 1999; 106:1811-1816.

5. Brazitikos PD, Androudi S, Christen WG, Stangos NT. Primary pars plana vitrectomy versus scleral buckle surgery for the treat-ment of pseudophakic retinal detachment: a randomized clinical trial. Retina 2005; 25:957-964.

6. Sharma YR, Karunanithi S, Azad RV, et al. Functional and ana-tomic 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, Wha-tham 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 Rheg-matogenous Retinal Detachment Study Group. Scleral buckling


versus primary vitrectomy in rhegmatogenous retinal detachment: a prospective randomized multicenter clinical study. Ophthalmology 2007; 114:2142-2154.

10. Goto T, Nakagomi T, Iijima H. A comparison of the anatomic successes of primary vitrectomy for rhegmatogenous retinal detach-ment 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 pri-mary repair of rhegmatogenous retinal detachment. Can J Ophthal-mol. 2011; 46:237-241.

12. Azad RV, Chanana B, Sharma YR, Vohra R. Primary vitrectomy versus conventional retinal detachment surgery in phakic rheg-matogenous retinal detachment. Acta Ophthalmol Scand. 2007; 85:540-545.

13. Sun Q, Sun T, Xu Y, et al. Primary vitrectomy versus scleral buck-ling for the treatment of rhegmatogenous retinal detachment: a meta-analysis of randomized controlled clinical trials. Curr Eye Res. 2012; 37:492-499.


Chromovitrectomy 2012A 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 vitreoreti-nal adhesion is, an anomalous PVD may evolve into several clini-cal 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 “chromo-vitrectomy” has been used to describe the use of vital dyes to stain transparent tissues to facilitate their manipulation dur-ing vitreous surgery.3 Over the past decade several substances, including indocyanine green (ICG), trypan blue (TB), and bril-liant blue G (BB), have been used during vitrectomy as staining agents. Their staining capabilities have been confirmed, but con-cerns over retinal toxicity remain.4

Posterior Hyaloid

Traction exerted by the posterior hyaloid has been implicated in the pathogenesis of several conditions such as proliferative vit-reoretinopathy (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 sev-eral 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 break-down of the blood–retinal barrier such as PVR, uveitis, retinal vein occlusions, and diabetic retinopathy, a preoperative intra-venous injection of fluorescein sodium 1 to 2 days prior to the scheduled vitrectomy stains the vitreous a greenish color, facili-tating 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-

gous blood may be injected into the vitreous cavity to coat the vitreous.5

Triamcinolone acetonide (TA) is a well-tolerated cortico-steroid 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 cav-ity, 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 blood–retinal 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 con-cluded 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, stain-ing 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 trans-parent 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

Internal Limiting Membrane (ILM)

The ILM is made up of the basement membrane of the Müller 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 trac-tion 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


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 surgeon’s 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 tem-pered 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 ana-tomic 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 con-centration. 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 epi-thelium (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 investiga-tion.16

toxicity

The toxic effects of any vital dye depend on the dye concentra-tion, 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 physi-ological 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 cur-rently 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.

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 con-cept 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: prin-ciples 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 vit-reoretinal 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 vit-reous. 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 intra-ocular 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 man-agement 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. Indo-cyanine green-assisted peeling of the retinal internal limiting mem-brane. Ophthalmology 2000; 107:2010-2014.

14. Wollensak G. Biomechanical changes of the internal limiting mem-brane 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 chromovit-rectomy. Retina 2009; 29:497-510.


Vitrectomy for Lamellar Macular HolePeriklis Brazitikos MD

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 pre-OCT era based only on biomicroscopy and fluorescein angiogra-phy. 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 wide-spread 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 forma-tion 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 dete-rioration 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 aver-age 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 related—as the authors con-clude—to the enlargement of the lamellar MH diameter.

Surgical treatment of lamellar MHs remains controversial, and some authors believe that there is no proof that surgi-cal 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 under-went vitrectomy for lamellar MH, with only 1 case being judged anatomically and visually successful. Two of their patients devel-oped 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 lamel-lar 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 sig-nificant (P = .002, paired t test). None of the cases deteriorated in terms of BCVA.

Our hypothesis for the beneficial role of vitrectomy in lamel-lar 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 knowl-edge, in the only study reported,8 the authors presume retrospec-tively 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 crite-rion 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 manda-tory to improve the surgical results and to stabilize or improve the VA in these cases.

References

1. Gass JD. Lamellar macular hole: a complication of cystoid macular edema after cataract extraction. Arch Ophthalmol. 1976; 94:793-800.

2. Allen AW, Gass JD. Contraction of a perifoveal epiretinal mem-brane simulating a macular hole. Am J Ophthalmol. 1976; 82:684-691.

3. Gass JD. Lamellar macular hole: a complication of cystoid macular edema after cataract extraction. Arch Ophthalmol. 1976; 94:793-800.

4. Takahashi H, Kishi S. 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. Hee MR, Puliafito CA, Wong C, et al. Optical coherence tomogra-phy of macular holes. Ophthalmology 1995; 102:748-756.


6. Haouchine B, Massin P, Tadayoni R, et al. Diagnosis of macular pseudoholes and lamellar macular holes by optical coherence tomography. Am J Ophthalmol. 2004; 138:732-739.

7. Theodossiadis PG, Grigoropoulos VG, Emfietzoglou I, et al. Evolu-tion of lamellar macular hole studied by optical coherence tomogra-phy. Graefes Arch Clin Exp Ophthalmol. 2009; 247:13-20.

8. Garretson BR, Pollack JS, Ruby AJ, et al. Vitrectomy for a symp-tomatic lamellar macular hole. Ophthalmology 2008; 115:884-886.

9. Hirakawa M, Uemura A, Nakano T, et al. Pars plana vitrectomy with gas tamponade for lamellar macular holes. Am J Ophthalmol. 2005; 140:1154-1155.

10. Kokame GT, Tokuhara KG. Surgical management of inner lamellar macular hole. Ophthalmic Surg Lasers Imaging. 2007; 38:61-63.

11. Witkin AJ, Ko TH, Fujimoto JC, et al. Redefining lamellar holes and the vitreomacular interface: an ultra-high resolution optical coherence tomography study. Ophthalmology 2006; 113:388-397.

12. Massin P, Paques M, Masri H, et al. Visual outcome of surgery for epiretinal membranes with macular pseudoholes. Ophthalmology 1999; 106:580-585.

13. Gass JD. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol. 1995; 119:752-759.

14. Androudi S, Stangos A, Brazitikos P. Lamellar macular holes: tomo-graphic features and surgical outcome. Am J Ophthalmol. 2009; 148:420-426.

2012 Subspecialty Day | Retina Cool Surgical Video Panel 13

My Coolest Surgical Video

the Use of Viscoelastics in Severe trauma CasesCarlos Mateo MD

I Shrunk the Gauge . . .Yusuke Oshima MD

the Development of Retinal endovascular SurgeryKazuaki Kadnosono MD

Suprachoroidal Buckling, Indications, evaluation and technique Ehab N El Rayes MD PhD

My Coolest Surgical VideoClaus Eckardt MD

Proliferative Vitreoretinopathy (PVR) after Vitrectomy with Silicone oil for Retinal Detachment Associated with Giant Retinal tearJ Fernando Arevalo MD FACS

My Coolest Surgical VideoCarl C Claes MD

14 the Charles L Schepens MD Lecture 2012 Subspecialty Day | Retina

Potential therapeutic Approaches to AMDtherapeutic targets for early Age-Related Macular Disease

Alan C Bird MD

Changes in age-related macular disease (AMD) may affect cho-roid, 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 phe-notyping will be needed to select cases for therapeutic trials and monitor therapeutic effect.

2012 Subspecialty Day | Retina Section II: Non-neovascular AMD 15

Pathogenesis of AMDChristine 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 system—retinal pigment epi-thelium (RPE) and choroid—secondarily causing photoreceptor degeneration. Bruch membrane (BM), the choroid’s inner wall, is a subendothelial space, substrate for RPE attachment, and route for outer retinal nutrition and metabolite removal. Drusen and BlinD form on BM’s inner surface, outside the blood–retina bar-rier and within the systemic circulation.

AMD’s 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 athero-genic 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 glob-ules.5 Early discovery is a surrogate for abundance. Histochemi-cally 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 bar-rier.10 This process superficially resembles, but is distinct from, systemic perifibrous lipid accumulation, whereby plasma apoB-lipoproteins insudate into and bind to dense connective tissue in normal arterial intima (plus cornea, sclera, and tendons), set-ting up atherosclerotic plaques in hemodynamically vulnerable locales.11

Lipid-preserving ultrastructure, histochemistry, comprehen-sive lipid profiling, and gene expression combine with epidemiol-ogy to indicate that the RPE constitutively secretes large apoB containing lipoproteins into BM for clearance. These intraocular lipoproteins are 60-80 nm diameter spherical particles with neu-tral lipid cores rich in esterified cholesterol and surfaces contain-ing 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 identi-cal 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 constitu-ent, rather than photoreceptor outer segments, rich in docosa-hexaenoate.

Functional consequences of the oil spill in BM include impaired transport of large molecules or multimolecular com-plexes including plasma lipoproteins delivering lipophilic essen-tials like carotenoids and vitamin E to RPE and photoreceptors via LDL and SRB-I receptors. Complexes of this size and physi-ological 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 conse-quences are the formation of highly toxic, proinflammatory / proangiogenic compounds like linoleate hydroperoxide and 7-ketocholesterol,14,15 known troublemakers from atheroscle-rotic plaque.

Additional abundant protein components of drusen include TIMP-3 and many proteins of the complement cascade, includ-ing the terminal component membrane attack complex (C5b-9).16,17 Advanced glycation end products likely enhance retention of lipoproteins18 that activate complement. Amyloid β-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 iso-lated drusen or shed into basal laminar deposits of eyes with advanced disease. Macular topographies of lipofuscin accumula-tion and RPE-BM pathology are not correlated.20 In vivo hyper-autofluorescence 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 cholesterol-containing deposits in the subretinal space. Subretinal drusenoid debris (SDD) is an organized, extracellular lesion at the RPE’s 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.

16 Section II: Non-neovascular AMD 2012 Subspecialty Day | Retina

Implications and Conclusions

Open biological questions include bases for AMD’s predilection for macula, domain-specific lipid trafficking pathways within RPE, and lipid trafficking mechanisms between RPE and pho-toreceptors. New opportunities for therapeutic intervention, summarized as the Oil Spill Strategies,2 include refurbishing BM before implanting new cells, modulating RPE lipoprotein out-flow 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 pro-vides chronic inflammatory stimuli for extracellular lesion for-mation in genetically susceptible persons. Twice the prevalence of Alzheimer disease, AMD at physiologic and molecular levels resembles cardiovascular disease more than a primary neurode-generation. Cardiovascular disease has declined steadily for 4 decades due to reduction of population risk factors and appli-cation of pathway-specific pharmaceuticals. New information about druse biology illuminates a similar way forward for AMD.

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 Bruch’s 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 sus-ceptibility 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. Grundzüge der pathologischen Histologie (translated by G. Busk). Vienna: Carl Gerold & Sohn; 1854.

6. Curcio CA, Millican CL, Bailey T, et al. Accumulation of choles-terol with age in human Bruch’s membrane. Invest Ophthalmol Vis Sci. 2001; 42:265-274.

7. Wang L, Clark ME, Crossman DK, et al. Abundant lipid and pro-tein components of drusen. PLoS ONE. 2010; 5(4):e10329.

8. Malek G, Li C-M, Guidry C, et al. Apolipoprotein B in cholesterol-containing drusen and basal deposits in eyes with age-related macu-lopathy. Am J Pathol. 2003; 162:413-425.

9. Rudolf M, Clark ME, Chimento M, et al. Prevalence and morphol-ogy of druse types in the macula and periphery of eyes with age-related maculopathy. Invest Ophthalmol Vis Sci. 2008; 49(3):1200-1209.

10. Pauleikhoff D, Harper CA, Marshall J, et al. Aging changes in Bruch’s membrane: a histochemical and morphological study. Oph-thalmology 1990; 97:171-178.

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 asso-ciated with age-related macular degeneration. Proc Natl Acad Sci U S A. 2011; 108(45):18277-18282.

13. Cankova Z, Huang J-D, Kruth H, et al. Passage of low-density lipoproteins through Bruch’s membrane and choroid. Exp Eye Res. 2011; 93(6):947-955.

14. Spaide R, Ho-Spaide W, Browne R, et al. Characterization of per-oxidized lipids in Bruch’s membrane. Retina 1999; 19:141-147.

15. Moreira EF, Larrayoz IM, Lee JW, et al. 7-ketocholesterol is pres-ent 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 hypoth-esis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Progr Ret Eye Res. 2001; 20:705-732.

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 Bruch’s membrane with age. Invest Ophthalmol Vis Sci. 1999; 40:775-779.

19. Johnson LV, Leitner WP, Rivest AJ, et al. The Alzheimer’s Aβ-peptide is deposited at sites of complement activation in patho-logic deposits associated with aging and age-related macular degen-eration. 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 varia-tions 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 pseudodru-sen 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.


Genetic testing—ProMark S Blumenkranz MD

Introduction

The recognition in 2005 of the importance of complement factor H-polymorphism revolutionized our understanding of the genet-ics of AMD, particularly the late stages of choroidal neovascu-larization and geographic atrophy. In addition to unequivocally corroborating previously fragmentary evidence on the impor-tance of complement dysregulation in the pathogenesis of the dis-ease, 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 pro-found 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 cor-responding therapeutic intervention arising from that information, should that test be employed in clinical practice, recognizing the obvi-ous 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 neces-sarily 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 follow-up. 10 When comparing this to the report of sensitivity and speci-ficity 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 pres-ent, 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 argu-ment is not true. In the AREDS 1 study, the use of antioxidants, multivitamins, and zinc was found to be associated with a signifi-cant 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 rela-tively strong argument could be made for identifying those with-out 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 test-ing 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 evi-dence 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 pharmacoge-nomics 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


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 increas-ingly 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 indi-vidual patient.

A fourth argument is that for younger individuals so dis-posed, 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.

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 comple-ment 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

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 iden-tifications 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 atro-phy 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 ret-rospective studies evaluating pathogenesis, phenotype-genotypic correlations, and ultimately pharmocogenomic responses. (5) As a tool to lessen anxiety or provide a basis for lifestyle modifica-tion in younger relatives of affected individuals.

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 haplo-type in the complement regulatory gene factor H (HF1/CFH) pre-disposes 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. Sci-ence. 2005; 308(2720):419-421.

4. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H poly-morphism 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 degen-eration, 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 neovas-cular age-related macular degeneration. Human Genomics. 2011; 5(5):420-440.

8. Seddon JM, Reynolds R, Maller J, et al. Prediction model for preva-lence 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.


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 Ophthal-mol. 2001; 119(10):1417-1436.

12. Tuo J, Ross RJ, Reed GF, et al. The HtrA1 promoter polymor-phism, smoking, and age-related macular degeneration in multiple case-control samples. Ophthalmology 2008; 115(11):1891-1898.


Genetic testing—ConFrederick L Ferris MD

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 under-stand 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 under-standing 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 pro-gression to vision loss. One only has to do a dilated eye exam to assess a patient’s 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, cata-ract, 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 patient’s risk of devel-oping 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 pig-mentary 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 non-smokers (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 signifi-cance 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 vari-ants 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 posi-tive 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 appropri-ate interventions and follow-up. The added information from the genetic testing is unlikely to change the follow-up recommenda-tions.

Similarly, suppose you were a 75-year-old nonsmoker with no risk factors. The 5-year risk estimate with no genetic infor-mation 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 antici-pate 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 poly-morphism in age-related macular degeneration. Science 2005; 308(5720):385-389.

4. Klein M, Francis PJ, Ferris FL, Hamon SC, Clemons T. Risk assess-ment model for development of advanced age-related macular degeneration. Arch Ophthalmol. 2011; 129(12): 1543-1550.

http://www.ohsucasey.com/amdcalculator


Rapid-fire Phase 2 trials, Parts I and 2Drugs 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 histopatho-logical 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 photorecep-tor 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 progres-sion of dry AMD. While smoking cessation and diet supplemen-tation based on AREDS formula vitamin trials combined with a healthy diet are the only recommended interventions for slowing disease progression to choroidal neovascularization, the progres-sion 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 preser-vation of the choroid, RPE, and photoreceptors.

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 stud-ies 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 com-mon risk-conferring CFH genetic variant for AMD is the Y402H polymorphism, resulting in a tyrosine-to-histidine substitution

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 consid-ered to be protective against AMD.17

There are several treatment strategies to modulate the com-plement 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 inhibi-tion. 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 progres-sion 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 don’t 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 subse-quent 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 intra-vitreal 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


in eyes with wet AMD to investigate whether AL-78898A pro-longs 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 injec-tions 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 specifi-cally 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 (COM-PLETE) 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 cen-tered 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 (900-mg 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 didn’t 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 mono-clonal antibodies, aptamers are synthesized single-stranded poly-ribonucleotides and generally do not elicit an immune response that could limit their efficacy. Aptamers are also small nonpro-tein 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 com-pleted 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 initi-ated, which is an extension to the previous study and will assess the long-term safety and tolerability of repeated intravitreal administration of FCFD4514S in patients with GA. Patients are eligible to participate who have completed the 18-month treat-ment 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 µg 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 involv-ing 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 μg/day) or a low (0.2 μg/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 pos-sesses a broad spectrum of therapeutic action, inhibiting inflam-mation, 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 deter-mine 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) sub-conjunctival 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. Sec-ondary outcomes will include changes in best-corrected visual acuity (BCVA), changes in drusen area, and the development of


CNV (NCT01445548). Intravitreal sirolimus will also be inves-tigated in AREDS2 patients with central GA, but this study has not yet been initiated.

Glatiramer acetate (Copaxone, Teva Pharmaceuticals; Kfar- Saba, 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 admin-istered 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 arrest-ing progression of dry AMD, including progression to wet (NCT00466076).

Drugs to Improve Choroidal Circulation and Protect Against Ischemia

Trimetazidine and AlprostadilTrimetazidine is a drug currently used for the treatment of angina pectoris. Trimetazidine improves myocardial glucose utilization by stopping fatty acid metabolism, and it is consid-ered 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 treat-ment 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 prostaglan-din E1 (PGE1). The presumed rationale is based on the belief that

table 1. Drugs to Suppress Inflammation

Drug

Mechanism of Action

Sponsor

trial Subjects

Clinical Study Phase

Clinical trial Identifier

Eculizumab (Soliris) Monoclonal anti-body against comple-ment component 5 (Intravenous)

Alexion Geographic atrophy and drusen

Phase 2 NCT00935883 (ongoing)

ARC1905 Aptamer against complement compo-nent 5 (intravitreal)

Ophthotech Geographic atrophy and/or drusen

Phase 1/2 NCT00950638 (completed)

LFG316 Inhibits complement component 5 (intra-vitreal)

Novartis Geographic atrophy Phase 2 NCT01527500 (ongoing)

AL 78898A Inhibits complement component 3 (intra-vitreal)

Alcon Geographic atrophy Phase 2 NCT01603043 (completed)

FCFD4514S Fab derived from a monoclonal antibody against complement factor D (intravitreal)

Genentech/Roche Geographic atrophy Phase 2

Phase 2

NCT01229215 (ongoing)

NCT01602120 (not yet recruiting)

Fluocinolone acetonide (Iluvien)

Glucocorticoid-mediated suppression of inflammation (intravitreal)

Alimera Sciences Geographic atrophy Phase 2 NCT00695318 (ongoing)

Sirolimus (Rapamycin)

mTOR inhibitor (intravitreal)

NEI Geographic atrophy Phase 2 NCT00766649 (ongoing)


Glatiramer acetate (Copaxone)

Induces glatiramer acetate–specific sup-pressor T-cells and downregulates inflam-matory cytokines (subcutaneous)

Kaplan Medical Center

Drusen Phase 2/3 NCT00466076 (ongoing)


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-inflamma-tory and antioxidative properties. MC-1101 aims to maintain the integrity of the Bruch membrane by restoring choroidal blood flow, controlling inflammation, and restoring RPE func-tion 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 Phar-maceuticals; 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; how-ever, this was expected given MC-1101’s mechanism of action. Results for choroidal blood flow found increased blood volume and velocity values in MC-1101-treated eyes 2 hours after dos-ing, 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, double-masked, 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-1101 or a vehicle control 3 times a day over 2 years. The study design will assess the efficacy, safety, and tolerability of MC-1101 for these patients. This study is not yet open for recruitment.

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 treat-ment of GA showed an apparent stabilization of visual acuity at 12 months, with 96.3% of the high-dose group losing fewer than

3 lines of vision compared with 75% of the patients in the sham-treatment 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, indicat-ing 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 α-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 photorecep-tors 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 μg or 400 μg) 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 photo-receptors and the RPE is borrowed from the treatments under development for Alzheimer disease since amyloid ß is present in both diseases. Amyloid ß oligomers are toxic to cells, and dis-eases with amyloid deposition exhibit abundant fibrils of various lengths that are the end product of stepwise protein/peptide mis-folding. 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


RN6G (PF-4382923, Pfizer)RN6G is a humanized monoclonal antibody that targets the C-termini of amyloid ß-40 and amyloid ß-42. Intravenous treatment with RN6G is intended to prevent the accumulation of amyloid ß-40 and amyloid ß-42 and to prevent their cyto-toxic effects.31 In a mouse model of AMD, systemic treatment with RN6G decreased the amount of amyloid β 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 of RN6G in 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-ß. 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 ethanol-amine), 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 surround-ing 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 non-enzymatic process through a covalent linkage between all-trans-retinal molecules with amine-containing lipids, has been impli-

table 2. Drugs to Protect Photoreceptors and RPe (Neuroprotection)

Drug

Mechanism of Action

Sponsor

trial Subjects



Trimetazidine Anti-ischemic agent with cytoprotective effects (oral)

Institute de Recher-ches Internationales Servier

Drusen in study eye, wet AMD in fellow eye

Phase 2/3 ISRCTN99532788 (completed)

Alprostadil (Prosta-glandin E1; PGE1): intravenous

Vasodilatory effect UCB, Inc. Geographic atrophy Phase 2 NCT00619229 (completed)

MC-1101 Increase choroidal blood flow (topical)

MacuCLEAR Dry AMD Phase 2/3 NCT01601483 (not yet recruiting)

NT-501: encap-sulated ciliary neurotrophic factor (CNTF)

Neuroprotection: res-cues photoreceptors from degeneration (intravitreal)

Neurotech Pharma-ceuticals

Geographic atrophy Phase 2 NCT00447954 (completed)

Brimonidine tartrate Neuroprotection: alpha-2 adrenergic receptor agonist (intravitreal)

Allergan Geographic atrophy Phase 2 NCT00658619 (ongoing)

Tandospirone (AL-8309B)

Neuroprotection: 5-HT1A receptor agonists (selective serotonin1A receptor agonist) (topical)

Alcon Geographic atrophy Phase 2/3 NCT00890097 (completed)

RN6G (PF-04382923)

Neuroprotection: binds and eliminates amyloid β (intrave-nous)

Pfizer Geographic atrophy Phase 2

Phase 1

NCT01577381 (not recruiting yet)


GSK933776

Neuroprotection: binds and eliminates amyloid β (intrave-nous)

GlaxoSmithKline Geographic atrophy Phase 2 NCT01342926 (ongoing)


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 trans-retinol 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 deliv-ered 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 nycta-lopia. 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 vol-unteers 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 strate-gies 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 break-through 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 stress-induced retinal pigment epithelial cell senescence and is overex-pressed in age-related macular degeneration. J Biol Chem. 2009; 284:9529-9539.

5. Dunaief JL, Dentchev T, Ying GS, Milam AH. The role of apopto-sis in age-related macular degeneration. Arch Ophthalmol. 2002; 120:1435-1442.

6. Johnson PT, Brown MN, Pulliam BC, et al. Synaptic pathol-ogy, altered gene expression, and degeneration in photoreceptors impacted by drusen. Invest Ophthalmol Vis Sci. 2005; 46:4788-4795.

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.

table 3. Visual Cycle Modulators

Drug

Mechanism of Action

Sponsor

trial Subjects



Fenretinide Visual cycle inhibi-tor: retinol analog inhibits binding of retinol to RBP (oral)

Sirion Therapeutics Geographic atrophy Phase 2 NCT00429936 (completed)

ACU-4429

Visual cycle inhibi-tor: non-retinoid, inhibits RPE65 pre-venting trans- to cis- isomerization (oral)

Acucela Geographic atrophy Phase 2 NCT01002950 (ongoing)


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; 77:657-661.

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 haplo-type in the complement regulatory gene factor H (HF1/CFH) pre-disposes 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. Sci-ence 2005; 308:419-421.

14. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymor-phism in age-related macular degeneration. Science 2005; 308:385-389.

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: charac-terization, 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. Oph-thalmology 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; 5:1164-1173.

21. Landa G, Butovsky O, Shoshani J, et al. Weekly vaccination with Copaxone (glatiramer acetate) as a potential therapy for dry age-related 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 nonexu-dative 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 deliv-ery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 2002; 43:3292-3298.

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; 44:3642-3649.

26. Emerich DF, Thanos CG. NT-501: an ophthalmic implant of poly-mer-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 neu-roprotective agent: an evidence-based review. Arch Ophthalmol. 2009; 127:402-406.

29. Mata NL, Vogel R. Pharmacologic treatment of atrophic age-related macular degeneration. Curr Opin Ophthalmol. 2010; 21:190-196.

30. Isas JM, Luibl V, Johnson LV, et al. Soluble and mature amy-loid fibrils in drusen deposits. Invest Ophthalmol Vis Sci. 2010; 51:1304-1310.

31. Johnson LV, Leitner WP, Rivest AJ, et al. The Alzheimer’s A beta -peptide is deposited at sites of complement activation in pathologic deposits associated with aging and age-related macular degenera-tion. Proc Natl Acad Sci U S A. 2002; 99:11830-11835.

32. Wang J, Ohno-Matsui K, Yoshida T, et al. Amyloid-beta up-regu-lates complement factor B in retinal pigment epithelial cells through cytokines released from recruited macrophages/microglia: Another mechanism of complement activation in age-related macular degen-eration. J Cell Physiol. 2009; 220:119-128.

33. Ding JD, Lin J, Mace BE, et al. Targeting age-related macular degeneration with Alzheimer’s 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 Ophthal-mol. 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 Can-cer Inst. 1994; 86:105-110.

38. Kubota R, Boman NL, David R, et al. Safety and effect on rod func-tion of ACU-4429, a novel small-molecule visual cycle modulator. Retina 2012; 32:183-188.


Neuroprotection for AMDDavid N Zacks MD PhD

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


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 dia-betic 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 microenvironment—for 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

Figure 1. Almost complete absence of photoreceptors at postnatal day 90 (P90).

Figure 2. Significant preservation 69 days post-treatment (P90).

2. Tissue regeneration: Replacement of diseased cells and tissue

3. Challenges exist in the development of cell-based products: Ability to scale, predictability of ani-mal models, surrogates for disease, the allograft vs. xeno-graft, potential need for targeted cell delivery and new surgical techniques and instru-mentation, measurable endpoints

C. Retina has unique advantages as a target for cell-based therapies.2,3

1. The retina is an accessible target tissue with vitre-ous 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 angiogra-phy, adaptive optics, and multifocal electroreti-nography 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 special-ized cell types (totipotent, pluripotent, multi-potent, unipotent)

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 pro-vided evidence that both human photorecep-tors and retinal pigment epithelium (RPE) can be derived from iPSC.6-8

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)


III. Phase 1/2a, Multicenter, Randomized, Dose Escalation, Fellow-Eye Controlled, Study Evaluating the Safety and Clinical Response of a Single, Subretinal Administra-tion 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 CNTO 2476, 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 surgi-cal 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

II. Current Cell-Based Therapy Phase 1 / 2 Clinical Trials for Retinal Disease (adapted from Tibbets et al3, 9-12)

table 1. Current Cell-Based therapy

Retinal Disease(s)

Mode of Action

type of Stem Cells

Method of transplantation

Sponsoring entity

Selected enrollment Criteria

Clinical trial endpoints (in addition to safety)

Published Clinical trial Results

Stargardt mac-ular dystrophy (37, 41)

Regenerative RPE-derived from ESCs

Subretinal implan-tation of 50,000 to 200,000 cells

Advanced Cell Technology

Age > 18

Genetic testing for Stargardt

Treated eye ≤ 20/400 Untreated eye ≤ 20/320

OCT, FA, autofluores-cence, fundus photos, multi-focal ERG

One patient with VA improve-ment from hand motions to 20/800 (5 ETDRS letters) at 4 months. No adverse events.

Geographic atrophy in AMD (38, 41)

Regenerative RPE derived from ESCs

Subretinal implan-tation 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

OCT, FA, autofluores-cence, fundus photos, multi-focal ERG

One patient with VA improvement from 21 to 28 ETDRS letters at 4 months. No adverse events.

Retinitis pigmentosa (RP) and cone-rod dystrophy (40, 42)

Trophic Autologous bone marrow-derived stem cells

0.1 ml suspension of 10x106 stem cells delivered by intravitreal injec-tion

University of São 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 reti-nal perfusion. No adverse events.

Geographic atrophy in AMD (39)

Trophic

Umbilical tissue-derived cells

CNTO 2476 delivered by micro-catheter 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

Publication pending

Abbreviations: RPE indicates retinal pigment epithelium; ESC, embryonic stem cell; ERG, electroretinography; VA, visual acuity; GA, geographic atrophy; ETDRS, Early Treatment Diabetic Retinopathy Study.


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 sub-retinal space of the temporal macula

1. Surgical technique includes sclerotomy, creation of choroidal fistula and subretinal bleb, micro-catheter delivery of cells

2. Surgical technique refinement in animal eyes

3. Endoptiks illuminated intraocular endoscope for improved surgical visualization

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.

G. Trial update

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, O’Connor 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 pho-toreceptors: 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 (hESC-RPE) cells in patients with Stargardt’s 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.

http://clinicaltrials.gov/ct2/show/NCT01469832







32 Advocating for Patients 2012 Subspecialty Day | Retina

2012 Advocating for PatientsGeorge A Williams MD

Ophthalmology’s 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 con-tributions to the following three funds as (a) part of their costs of doing business and (b) their individual responsibility in advocat-ing 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 appro-priate roles for the various eye care providers as demonstrated via its Surgery by Surgeons campaign.

oPHtHPAC® Fund

OPHTHPAC is a crucial part of the Academy’s strategy to pro-tect and advance ophthalmology’s interests in key areas, includ-ing physician payments in Medicare as well as protecting oph-thalmology from federal scope of practice threats. Established in 1985, today OPHTHPAC is one of the largest and most suc-cessful 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 inde-pendent expenditures, OPHTHPAC helps us elect friends of oph-thalmology to federal leadership positions, ultimately resulting in beneficial outcomes for all Eye M.D.s. For example, 20 physi-cians, 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:

• AvertedsignificantcutstoMedicarepaymentsduetotheSustainable Growth Rate (SGR) formula

• ProtectedPracticeExpenseincreasesforophthalmologywhen attacked by other specialties

• Exemptedultrasoundfromimagingcuts• Protectedthein-officeancillaryservicesexception• SecuredphysicianexemptionfromRedFlag(creditor)

rules• SecuredreversalofaCMSdecisiontocutreimbursement

for Avastin• DelayedMedicarepenaltiesdatesinhealthreformlaw• Securedappointmentoffull-timeophthalmologynational

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 Ophthalmology’s 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 Academy’s advocacy agenda. As

2012 Congressional Advocacy Day (CAD) partners, the three retina societies ensured a strong presence of retina specialists to support ophthalmology’s priorities as over 350 Eye M.D.s had scheduled CAD visits to members of Congress in conjunction with the Academy’s 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 Academy’s Surgery by Surgeons campaign has demonstrated a proven track record. While Kentucky was an outlier, the Academy’s SSF has helped 33 state / territorial ophthalmology societies reject optometric surgery language. The Academy’s 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 Ken-tucky, 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 sur-gery. 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 year’s passage of legislation in Kentucky that allowed optometrists to perform laser surgery, the American Academy of Ophthalmology’s partnership with ophthalmic subspecialty and state societies in the Surgery by Surgeons cam-paign became even more important in protecting quality patient eye care across the country. The Academy’s Secretariat for State Affairs redoubled its efforts with “target” states, including Ten-nessee 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.

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 strat-egizes 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-

2012 Subspecialty Day | Retina Advocating for Patients 33

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 cards—unlike PAC contributions, which must be made by individuals and which are subject to reporting requirements.

Please respond to your Academy colleagues who are volun-teering 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 soci-ety to contribute. Advocate for your patients now!

*oPHtHPAC Committee

Donald J Cinotti MD (NJ) – ChairCharles 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)

**Surgical Scope Fund Committee

Thomas A Graul MD (NE) – ChairArezio Amirikia MD (MI)Ronald A Braswell MD (MS)Kenneth P Cheng MD (PA)John P Holds MD (MO)Bryan S Lee MD PhD (MD) – ConsultantStephanie J Marioneaux MD (VA)Andrew Tharp MD (IN)Ex-Officio Members:

Cynthia A Bradford MDDaniel J Briceland MD

Surgical Scope Fund oPHtHPAC® Fund State eyePAC

Scope of practice at the state level Ophthalmology’s interests at the federal level – Support for candidates for US Congress

Support for candidates for State House and Senate

Lobbyists, media, public education, adminis-trative needs

Campaign contributions,legislative education Campaign contributions, legislative education

Contributions: Unlimited Contributions: Limited to $5,000 Contribution limits vary based on state regula-tions

Contributions are 100% confidential Contributions above $200 are on the public record

Contributions are on the public record

34 Section III: Late Breaking Developments, Part I 2012 Subspecialty Day | Retina

Late Breaking Developments, Part I

N o t e S

2012 Subspecialty Day | Retina Section IV: Pediatric Retina 35

Update on the Study of telemedicine for RoPDarius M Moshfeghi MD

I. Experimental Analysis of Remote Digital Fundus Imag-ing (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 Acute-Phase 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

36 Section IV: Pediatric Retina 2012 Subspecialty Day | Retina

ophthalmic Insurer Perspectives on the Use of telemedicine for Screening and Diagnosis of RoP and Bevacizumab for RoPArthur W Allen Jr MD

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 pay-ments 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/Par-ents. 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 grap-pling 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 dif-ferent location, let alone another state. Issues of concern include state licensure, credentialing, privileging, confidentiality, physi-cian/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 telemedi-cine, but others have tightened them. Risk managers advise hav-ing 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 con-flict 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 relation-ship 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 fis-sures 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 physi-cians need to satisfy before they can be insured to practice tele-medicine. A few examples include such things as who provides backup grading, how many images are taken per eye per screen-ing, 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 treat-ment 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 addi-tional 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 off-label 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. Prep-ping the eye may also be an issue, which raises the possibility of increased risk of infection. None of these complications, except


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 stan-dardized, 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. There-fore the follow-up period should be extended for bevacizumab-treated 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 trimes-ter.6 These organs are already under stress, and it is possible that the use of bevacizumab may result in long-term systemic prob-lems 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 prog-nosis with laser or would have severe field loss if laser was used, a detailed informed consent is critical.

References

1. Richter GM, Williams SL, Starren J, Flynn JT, Chaing MF. Tele-medicine 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 intravit-real 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 Oph-thalmol. 2010; 248(12):1713-1718.

6. Hård AL, Hellström A. On the use of antiangiogenetic medications for retinopathy of prematurity. Acta Paediatr. 2011; 100(12):1523-1527.


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 excep-tionally 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 child’s due date. Bevacizumab has been used in clinical settings treating ROP, most of which have been anecdotal, nonrandom-ized clinical trials. The BEAT-ROP Trial, presented last year, represents an attempt at a more organized utilization of bevaci-zumab 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 poste-rior 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 ophthal-mologists 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 regi-mens as well as multiple agents for anti-VEGF treatment, includ-ing 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 dos-ing 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 morbidi-ties in children who are born prematurely, it would seem reason-able to assume that the smaller the dose of anti-VEGF drug deliv-ered 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 drug’s presence in the blood-stream appears to be less for ranibizumab than for bevacizumab. This study will include both clinical and photographic evalua-tions 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 bevaci-zumab 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 pharma-cologic 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 pre-maturity: results of the Early Treatment for Retinopathy of Prema-turity Randomized Trial. Arch Ophthalmol. 2003; 121:1684-1696.

2. Drenser KA, Trese MT, Capone A Jr. Aggressive posterior retinopa-thy of prematurity. Retina 2010; 30:S37-40.

3. Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Coop-erative 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.


Microplasmin for Pediatric Vitrectomy StudyKimberly 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 attach-ments at the vitreoretinal interface. Children and infants have particularly strong hyaloid adhesions, which often complicates difficult pediatric vitreoretinal surgeries.

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 demon-strated safety in children who received an intravitreal injection of plasmin enzyme prior to surgery. Both autologous and maternal plasmin is processed from the patient’s (or mother’s) 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 (ocri-plasmin) has been developed and comes in a ready-use vial. This development allows for increased access of plasmin to surgeons for pediatric vitreoretinal surgeries.

objectives

This presentation will focus on the current status of plasmin and ocriplasmin for use in pediatric vitreoretinal surgery. Appropri-ate case selection will be reviewed, as will surgical techniques. Surgical outcomes, both intraoperative and long-term postopera-tive, 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. Surgi-cal 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 reti-noschisis: 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. Pediat-ric traumatic macular hole: results of autologous plasmin enzyme-assisted 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 micro-plasmin for the induction of posterior vitreous detachment. Curr Eye Res. 2010; 35(10):909-915.


Familial exudative Vitreoretinopathy: Diagnosis, Management With Wide-Angle Angiography, and Long-term Surgical ResultsFranco 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 avas-cular 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 Clinical Features

1 Avascular retinal periphery

2 Preretinal neovascularization

2A Without exudate

2B With exudate

3 Macula-sparing retinal detachment

3A Without exudate

3B With exudate

4 Macula-involving retinal detachment

4A Without exudate

4B With exudate

5 Total retinal detachment

Adapted from Pendergast SD, Trese MT. Familial exudative vitreoretinopathy: results of surgical management. Ophthalmology 1998; 105(6):1015-1023.

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 fol-lowing 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, auto-somal 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 path-way, which is essential for normal retinal vas-cular 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 abla-tion (especially if fellow eye has limited vision)

2. Stage 2: Complete ablation (typically with laser photocoagulation) of all areas of peripheral reti-nal nonperfusion

3. Stages 3-5: Scleral buckling or vitrectomy or both

4. Intravitreal anti-VEGF therapy

a. Helpful in transient arrest of neovasculariza-tion until definitive treatment with laser pho-tocoagulation can be performed

b. May promote intense fibrovascular contrac-tion and rhegmatogenous retinal detachment


c. Not a permanent treatment (does not address the underlying problem of chronic retinal ischemia)

B. Role of angiography

1. Valuable in establishing diagnosis (demonstra-tion of peripheral retinal nonperfusion, budding of peripheral capillaries, preretinal neovascular-ization)

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 enroll-ment as a study site; 4-6 months

VI. Surgical Results

A. Indications for treatment

1. Peripheral retinal ablation

a. Presence of preretinal neovascularization or exudation

b. Increase in size of areas of retinal nonperfu-sion

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 impos-sible 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, poste-rior breaks, giant retinal tears

c. Can be used alone for predominantly trac-tional 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 rheg-matogenous detachment

3. Role of intravitreal anti-VEGF medicines

a. May help to reduce vascular activity in advance of planned vitrectomy

b. Not a monotherapy

http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests

http://www.nei.nih.gov/resources/eyegene.asp

http://www.nei.nih.gov/resources/eyegene.asp

http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests


Selected Readings

1. Benson WE. Familial exudative vitreoretinopathy. Trans Am Oph-thalmol 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 treat-ment of familial exudative vitreoretinopathy in children. Am J Oph-thalmol. 1995; 120(4):471-479.

4. Ikeda T, Fujikado T, Tano Y, et al. Vitrectomy for rhegmatogenous or tractional retinal detachment with familial exudative vitreoreti-nopathy. Ophthalmology 1999; 106(6):1081-1085.

5. Pendergast SD, Trese MT. Familial exudative vitreoretinopa-thy: 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: surgi-cal 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.

table 2. Results of Vitreoretinal Surgery for FeVR-Associated Retinal Detachment

Study

No. of eyes

Age Range (yrs)

type of RD

Macular Attachment (%)

Stable/Improved VA (%)

> 1 Surgery (%)

Minimum Follow-up

Glazer, et al (1995) 6 1.5-9 TRD 100% 84% ?? ??

Shubert and Tasman (1997)

8 0.5-44 TRD 75% 63% 38% ??

Pendergast and Trese (1998)

29 0.3-17 ?? 62% 93% 21% 6 months

Ikeda, et al (1999) 28 4-38 89% RRD; 11% TRD

86% 71% 54% ??

Chen, et al (2012) 24 9-30 RRD 96% 96% 29% ??

Abbreviations: TRD indicates traction retinal detachment; RRD, rhegmatogenous retinal detachment; VA, visual acuity.

2012 Subspecialty Day | Retina Section V: Inherited Retinal Diseases 43

Update on Gene therapy trials in ProgressJames W Bainbridge MA PhD FRCOphth

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 blood–reti-nal 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 examina-tion 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 expres-sion, 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 pho-toreceptor 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 injec-tion.

Considerable progress has been made in the development of experimental gene replacement therapies for retinal degenera-tions 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 com-pensate for gene defects resulting in proteins that lack function, conditions that are typically recessively inherited. However, sub-stantial progress has also been made in the development of strat-egies 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 expres-sion 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 degenera-tion of the outer retina. The extent to which this approach might compensate for the lost sensitivity and resolution of photorecep-tor-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 chil-dren 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 clini-cal 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 neovas-cular AMD are now under way. These include AAV-mediated delivery of the VEGF inhibitor sFlt-1 and lentivirus vector-medi-ated 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. Care-ful 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 bal-ance 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 func-tion or slowing severe degenerations, will provide invaluable information that can be used to inform further development in a timely way.

References

1. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008; 358:2231-2239.

2. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. 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.

44 Section V: Inherited Retinal Diseases 2012 Subspecialty Day | Retina

Upcoming trials in Retinal DegenerationGene 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 dis-ease 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 con-sideration of gene therapy as an intervention to prevent loss of function depends upon (1) knowing the genetics of a retinal dis-order, (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 poten-tial 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 con-firm their diagnosis, through clinical testing and research proto-cols 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 modelsGene 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 photorecep-tors through subretinal delivery, thereby normalizing cellular function and potentially stopping the progressive retinal degen-eration. 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-

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 trans-duced 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 subjectsThe design of an ocular gene therapy trial will need to first estab-lish safety and then determine, if possible, in a small initial phase if there is any indication of effect on moderating the progres-sive 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 treat-ment to allow serial analysis of any progression. The design of an ocular gene therapy trial has been greatly aided by the availabil-ity 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 trialAs reported by MacLaren and colleagues at the 2012 annual meeting of the Association for Research on Vision and Oph-thalmology (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 detach-ment, the macula has reattached without significant adverse event.

Figure 1


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 surround-ing 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 nev-ertheless exist between patient and clinician perspectives, most importantly with respect to the time line for clinical implementa-tion and broader availability of this novel therapy. Communica-tion strategies will need to be developed to bridge these gaps and to aid in the responsible translation of gene therapy from bench to bedside.


Phase 1b Data for 091001, A Synthetic Retinoid for the treatment of Leber Congenital Amaurosis and Retinitis PigmentosaHendrik PN Scholl MD

N o t e S


Genetic testing for Patients With Retinal DegenerationEric 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 pro-gressive dysfunction and death of the rod and cone photorecep-tor 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 reti-nitis 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 disor-ders, 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

Genetic Diagnostic testing

Notable progress has been made identifying the genes that har-bor mutations that cause IRDs, with over 180 disease genes iden-tified 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 lim-ited 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 suc-cesses 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 poten-tial therapies, genetic diagnoses can provide improved clarity for patients regarding their condition, their prognosis, and family planning issues.

Next-Generation Sequencing for Genetic Diagnostic testing

Exon and exome capture coupled with next-generation sequenc-ing 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 thou-sands of genetic variants can be identified and examined simul-taneously 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 cap-ture 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

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 cap-ture 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 ana-lyzed 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 symp-toms.

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 sequenc-ing to identify the cause of LCA in a family with 2 affected chil-dren 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 disease-causing 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 stud-ies 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 muta-tions cause LCA.13


In summary, selective exon or exome capture and next-generation 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 pre-sentation.

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 muta-tions causing retinitis pigmentosa. Arch Ophthalmol. 2007; 125:151-158.

7. Stone EM. Genetic testing for inherited eye disease. Arch Ophthal-mol. 2007; 125:205-212.

8. Maguire AM, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008; 358: 2240-2248.

9. Bainbridge JW, et al. Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med. 2008; 358:2231-2239.

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 Leber’s 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 dis-ease gene discovery. Nat Rev Genet. 2011; 12:745-755.

13. Falk M, et al. NMNAT1 Mutations Cause Leber Congenital Amau-rosis. Nat Genet. Epub ahead of print 29 July 2012.

14. Keen TJ et al. Identification of a locus (LCA9) for Leber’s con-genital 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.

table 1. Available Genetic Diagnostic testing for IRDs

organization tests offered testing Method

John and Marcia Carver Nonprofit Genetic Testing Laboratory

1. AD-RP – 4 genes2. AR-RP – 16 genes3. LCA – 14 genes4. XL-RP – 2 genes*5. Usher syndrome – 6 genes

Allele testing and sequencing

Casey Eye Institute Molecular Diagnostics Laboratory

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 genes7. XL-RP – 1 gene8. Usher syndrome – 9 genes*

Sequencing

GeneDx 1. AD-RP – 5 genes2. AR-RP – 7 genes3. LCA – 6 genes4. XL-RP – 1 gene5. Usher syndrome – 9 genes*

Allele testing and sequencing

Massachusetts Eye and Ear Infirmary Ocular Genomics Institute

1. Inherited Retinal Degenerations – 185 genes*

Sequencing

Prevention Genetics

1. BBS – 13 genes 2. LCA – 6 genes3. RP – 18 genes4. Senior Loken syndrome – 6 genes5. Usher syndrome – 9 genes*

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.

http://www.sph.uth.tmc.edu/Retnet/


optogenetics: A New Approach to Retinitis Pigmentosa Luk H Vandenberghe PhD

Abstract

A new and innovative approach to treat inherited forms of blind-ness 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 photo-receptors. Our ability to do this relies on single protein molecules that in a very basic way can achieve what the endogenous multi-component visual system does. These tools are called optogenetic tools and can hyperpolarize or depolarize a cell upon light expo-sure. 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.

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 dis-covery 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 contrib-uting 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 muta-tion in 3 clinical studies. The RPE65 gene in all these studies was delivered to the cells with an adeno-associated viral vector (AAV)

that was proven to be a safe and efficient gene delivery vehicle in these studies.1-3

Though these gene addition studies have tremendous poten-tial, 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 ophthalmologist’s 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-pro-tein-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 reti-nal cell types, preclinical studies in mouse and rat models of reti-nal 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 opto-genetic 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 clini-cal translation is the ubiquitous expression of ChR2 in retinal ganglion cells using AAV via an intravitreal route of administra-tion.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


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 rem-nant 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

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 dif-ferent 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 disor-ders 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.

References

1. Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s 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 U S A. 2008; 105:15112-15117.

3. Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber’s 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 U S A. 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. Melanopsin-containing 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 degen-eration. 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. Sci-ence 2010; 329:413-417.

2012 Subspecialty Day | Retina Section VI: Retinal Vein occlusion 51

Retinal Vein occlusion PanelDonald J D’Amico MD, Barbara Ann Blodi MD, Sharon Fekrat MD, Michael S Ip MD, Carl D Regillo MD FACS, Rishi P Singh MD

N o t e S

52 Section VII: Business of Retina 2012 Subspecialty Day | Retina

the Future of Healthcare: Survival of the FittestDavid W Parke II MD

Regardless of our politics, regardless of whether we like or don’t like the administration’s Patient Protection and Affordable Care Act (PPACA) or whether we like or don’t like the Ryan-Wyden proposal for premium support, American health care—and eye care—will change more fundamentally over this decade than in any single previous decade. The structure, process, payment incentives, payment mechanisms, and players are all changing fundamentally—simultaneously.

Why is it changing? Consider the following:

• Americaspends$2.7trillionforhealthcare,almost18%of the gross domestic product. This is first among top 34 developed countries (Organization for Economic Coopera-tion and Development).

• Americaranks31among34countriesinprovidingcov-erage to all its people (OECD) (ahead of only Turkey, Mexico, and Chile).

• Americaranks25among34countriesinpreventingdeathfrom 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 understand-ing 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 experi-ence 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 effi-cient use of capital and leveraging assets, but it’s really just about controlling and integrating enough components of the health care delivery system so that you can decrease inefficiency, moni-tor quality, and dominate your market. Whether or not these sys-tems 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 ophthal-mology, should be a particularly fertile ground for fostering phy-sician leaders. First, most of us still do some cases in a hospital—even if it’s 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 spe-cial task force composed almost entirely of physicians. They con-cluded, thankfully, that the most important attributes of a physi-cian 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 integra-tion is to become indispensable to the system—as 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 integra-tion? 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 com-munities’ physicians will effectively “choose teams” among inte-grated 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 2011—an increase of 43% over the prior year.

the Rise of Service and Quality Standards

A hallmark of integrated systems—and a requirement under the PPACA—is 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 mean-ingful 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, clini-cally meaningful, and appropriately risk-adjusted. The Acad-

2012 Subspecialty Day | Retina Section VII: Business of Retina 53

emy’s 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 ser-vices.

Changes in Physician Payment

Fee-for-service is not going away—at 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 vari-ants of withholds, global payment, bundled care, and even modi-fied capitation. Withholds may be linked to performance and service. Those practices willing to consider modification of tradi-tional payment systems may be viewed preferentially by systems.

Patients as Advocates

Patients can be very effective advocates with integrated sys-tems—just as they can be with payers. Paradoxically, individual patient relationships fostered by good communication, risk mitigation, service, and quality of care can be a practice’s best weapon in interfacing with integrated systems. Patients value cer-tain 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 Medi-care reimbursement to the surgeon would be $8,212. Medicare actually paid $1,375.

Conclusion

“Survival of the fittest” has always been an axiom of any business. “Fitter” ophthalmology practices have always out-performed “less fit” practices by the relevant metrics—sustain-ability, 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-qual-ity 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 dif-ferentiator between surviving and thriving.

Selected Readings

1. Blumenthal D. Performance improvement in health care—seizing the moment. N Engl J Med. 2012; 366:1953-1955.

2. Combes JR, Arespacochaga E. Lifelong Learning Physician Com-petency Development. American Hospital Association’s Physician Leadership Forum. Chicago Ill.; June 2012.

3. Foran JRH, Sheth NP, Ward SR et al. Patient perception of physi-cian 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: Lower-ing Costs and Improving Outcomes: Workshop Series Summary. Washington, DC: The National Academies Press; 2010.


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 Ber-wick, Director of the Centers for Medicare & Medicaid Services (CMS), summarized his strategy to address the latter three stim-uli with changes in system design and payment reform through implementation of his “triple aim” strategy:

• Improvehealth• Improvequalityandpatientexperienceofcare• Decreasecosts

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 adminis-tration recruited a very bright group of physicians, methodolo-gists, 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 organiza-tions.

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, anesthe-sia, surgeon’s 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 won’t be implemented for several years.

Accountable Care organizations (ACos)

Elliot Fisher MD, from the Dartmouth Institute for Health Pol-icy, 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 orga-nization. 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 aver-age 37 physician visits from 14 different professionals and fill 50 prescriptions. Any one who has tried to help an elderly, chroni-cally ill parent navigate Medicare understands the problem.

The model for ACO design is based on the Medicare Physi-cian 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 summary—a failure. Not to be deterred by a lack of evidence, Congress, via the ACA, will pro-ceed 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 fol-lowing:

• Accountabilityforthequality,costandoverallcare• Acontractnotlessthan3years• Aformallegalstructure• Primarycarephysicianssufficientforaminimumof5000

patients• PrimarycareMDshavetosignanexclusivecontractwith

one ACO.• Reportyearlyon33qualitymetrics

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 capita-tion. 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 deter-mined 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 hos-pital 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 enroll-ment. They will get killed by hospital contracts.

Rule making has mandated some features that are not opti-mal for an entity undertaking ACO development. What are the risks? Patients are retrospectively assigned to the ACO if they


attain a plurality of their primary care visits from a professional on the ACO’s panel. However, patients are free to attain spe-cialty 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 ACO’s spending benchmark. Large variations have been described—a big risk for the ACO! Ophthalmolo-gists 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 Mas-sachusetts, 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.


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.


ASC for Retina: Balancing Quality With ProfitAlan 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 proce-dures

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 pos-terior segment surgeries increase appeal of ASCs.

1. Increase in fee schedule to more closely approxi-mate 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 sur-gery

a. Operating in multispecialty ASC

b. Physician-owned and -operated ASC: predict-ing financial success

c. Joint hospital–physician owned ASC

d. Future reimbursement issues for ASC


the office of the Inspector General and Bevacizumab vs. Ranibizumab: No Good Deed Goes UnpunishedGeorge A Williams MD

The advent of intravitreal anti-VEGF therapy has revolution-ized 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 partici-pants. However, the cost of anti-VEGF therapy is large. In 2010, the combined Part B expenditures for ranibizumab and bevaci-zumab 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 includ-ing 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 ranibi-zumab 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 Medi-care 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 treat-ment of wet AMD. The study compared physician acquisition costs to Medicare payment amounts obtained from CMS and Medicare contractors. Additionally, it analyzed Medicare con-tractor 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 per-cent, 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 recom-mendation, 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 find-ing 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, ophthalmolo-gists 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.

http://www.oig.hhs.gov


Managing a Large Modern Practice: Practice Informatics and ItTrexler M Topping MD

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 cost-effective 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 diag-nosis 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 estab-lished), referral source (outside MD, ophthalmologist, internal referral, OD, family member, etc.), insurance payer, both pri-mary and secondary (Medicare, individual carrier, group plan). In addition all visit, diagnostics, procedures, tests, and surger-ies 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 Share-point, 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 per-centage 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 patient’s arrival to the time of the patient’s departure from the office. We time stamp each transac-tion (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 wait-ing 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 deter-mine 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 projec-tions, 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 envi-ronment.


Postmarketing SurveillanceWiley A Chambers MD

This presentation reflects the views of the author and should not be con-strued to represent the FDA’s views or policies.

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 availabil-ity 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-con-trolled 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. Reac-tions 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 oph-thalmic 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)

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 leukoen-cephalopathy (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 hypo-glycemia (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)


15. Valdecoxib: cardiovascular issues / Stevens-John-son 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 Applica-tion

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 FDA’s 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 health‐related electronic data (such as data from the Medicare program and the health systems of the Department of Veterans Affairs)

D. Also uses private sector health‐related 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 ele-ments:

1. Description of the adverse events or disease expe-rience, including time to onset of signs or symp-toms

2. Suspected and concomitant product therapy details (ie, dose, lot number, schedule, dates, duration), including over-the-counter medica-tions, dietary supplements, and recently discon-tinued medications

3. Patient characteristics, including demographic information (eg, age, race, sex), baseline medical condition prior to product therapy, comorbid conditions, use of concomitant medications, rel-evant 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 assess-ment 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 (propri-etary) and established (proper) name, manufac-turer, 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.

http://www.fda.gov/Safety/MedWatch/default.htm

http://www.fda.gov/Safety/MedWatch/default.htm


2. Code of Federal Regulations. 21 CFR 314.80 Postmarketing report-ing 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 Pharmacoepi-demiologic Assessment. Available at: www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf. Accessed June 13, 2012.

http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf

http://www.fda.gov/downloads/regulatoryinformation/guidances/ucm126834.pdf

2012 Subspecialty Day | Retina Section VIII: Neovascular AMD 63

Noninferiority Trials and Subgroups: How to Interpret What You Are About to HearMaureen G Maguire PhD

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: Δ = 0; HA: Δ ≠ 0

D. Alpha (α) = 0.05 for hypothesis testing; reject the null hypothesis and conclude: Active drug is dif-ferent from placebo; direction of difference from observed data.

E. 95% [(1- α)%] CI on the difference: Contains val-ues of true difference for which a hypothesis Hv: Δ = v would be rejected; if the confidence interval does not include 0, we conclude: Active drug is different from placebo.

II. Today’s 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 differ-ent study groups, governmental agencies

E. Alpha (α) level used for testing and confidence inter-vals “adjusted” for multiple testing; Bonferroni rule, hierarchical specification of sequence of compari-sons, 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 sched-ule) each with 2 levels ([ranibizumab, bevacizumab], [monthly, p.r.n.]); all 4 treatment combinations tested

B. Factorial analysis: A patient’s change in VA = a base level + a drug effect + a dosing effect + random error. Example: The benefit, if any, of ranibizumab

over bevacizumab is the same amount, under both monthly and p.r.n. dosing (IVAN Year 1, CATT Year 2).

C. Nonfactorial analysis: A patient’s 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 compari-sons 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, δ, is selected. If the new drug is less than δ worse than the standard drug, it is noninferior.

C. Once δ is selected, the confidence interval for the difference between drugs is examined to see if the noninferiority margin is crossed.

Figure 1. Strict noninferiority trial.

64 Section VIII: Neovascular AMD 2012 Subspecialty Day | Retina

D. Alternative approaches allow declaring superiority if the confidence interval excludes both the noninfe-riority margin and 0.

Figure 2. Noninferiority trial allowing superiority.

E. Still other approaches allow declaring equivalence if the confidence interval is wholly contained within – δ and + δ.

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 pla-cebo, 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 improve-ment that has led physicians and patients to adopt a new treatment.

D. Example: For CATT, the mean difference between ranibizumab and sham injection was approxi-mately 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.

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 prob-ability 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 hierarchi-cal 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.

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 Clini-cal 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: understand-ing and evaluating non-inferiority trials. Int J Clin Pract. 2010; 64:1359-1366.


CATT: Year 2 Daniel F Martin MD

N o T e S


IVAN: Year 1Usha Chakravarthy MBBS PhD

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 neovascu-lar AMD but without marketing authorization.3-6 The Compari-son 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 treat-ments to Inhibit VEGF in Age-related choroidal Neovasculariza-tion” (IVAN) randomized trial, which also compares monthly or “as needed” ranibizumab or bevacizumab. IVAN is a multi-center, factorial, noninferiority randomized trial undertaken in the United Kingdom.

Study Design

IVAN participants were 50 years or more with untreated neo-vascular 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 com-prising > 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 regi-men were treated monthly thereafter, while participants random-ized 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 subreti-nal 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.

The primary outcome is BCVA at 2 years (follow-up is ongo-ing) 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 mea-sured 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 mea-sured 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 bevaci-zumab 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 treat-ment 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 bevaci-zumab 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 prelimi-nary 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.

Discussion

One year after randomization in the IVAN trial, the visual acu-ity 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.


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 clini-cally meaningful.

A meta-analysis of the IVAN and the CATT found no evi-dence 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 pos-sible that the consequences of differential suppression of circulat-ing 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 Oph-thalmology, the CATT investigators reported a trend toward a reduced rate of CNV in the fellow eyes of treated with bevaci-zumab vs. ranibizumab.

This finding might relate to greater systemic suppression of VEGF in the bevacizumab-treated patients. If so, it is a helpful effect.

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.

2. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macu-lar 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 bevaci-zumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collabora-tive 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 degen-eration. Graefes Arch Clin Exp Ophthalmol. 2009; 247:1-11.

5. Tufail A, Patel PJ, Egan C, et al; ABC Trial Investigators. Beva-cizumab 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 age-related macular degeneration. Retina 2006; 26:495-511.

7. CATT Research Group. Ranibizumab and bevacizumab for neo-vascular age-related macular degeneration. N Engl J Med. 2011; 364:1897-1908.

8. Chakravarthy U, Harding SP, Harding SP; IVAN Study Investiga-tors. Ranibizumab versus Bevacizumab to treat neovascular age-related macular degeneration: one year findings. Ophthalmology 2012; 119(7):1399-1411.


MANTA: Year 1Twelve-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 bevaci-zumab in patients with neovascular (NV) AMD.

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 let-ters. Number of eyes with VA improvement of ≥ 0, ≥ 5, ≥ 15 let-ters, lesion size, retinal thickness, and adverse events.

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 neovasculariza-tion (CNV) related to AMD, active lesion, BCDVA/ ETDRS on the study eye 20/40-20/320.

exclusion Criteria

Nontreatment naïve 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 neces-sary, presence of pigment epithelial rupture, general contraindi-cations against anti-VEGF treatment, iodine allergy.

Treatment

Three initial monthly injections with either 0.5-mg ranibizumab (Lucentis, Novartis) or 1.25-mg bevacizumab (Avastin, Genen-tech). Retreatment if VA loss a minimum of 5 letters, increase of central retinal thickness of more than 100 µm (OCT), fresh intra- or subretinal hemorrhage, new classic CNV, persistent intrareti-nal fluid (OCT+FA).

The study was assigned and financed by the Austrian Oph-thalmologic 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 Schmet-terer PhD at the department of clinical pharmacology. This Pan-Austrian study was conducted by the 10 largest eye departments or university eye clinics in Austria. Approval of local ethics com-mittees was received in 2007.

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 89.9 µm for ranibizumab and 86.3 µm 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.

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.


VIeW: Year 2Intravitreal 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. ranibi-zumab up to 96 weeks of the Phase 3 VIEW-1 and VIEW-2 studies.

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 inte-grated analyses are reported here.

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

over 2 years and 4.7, 4.1, 4.6, and 4.2 injections over the follow-up period after Week 52, for Rq4, IAI 2q4, IAI 0.5q4, and IAI 2q8, respectively. The proportion of patients who required fre-quent 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 inci-dence 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, reti-nal hemorrhage, and VA reduced.

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. Intravit-real aflibercept and ranibizumab had generally favorable safety profiles through Week 96.


HARBoR: Year 2efficacy and Safety of 0.5-mg vs. 2.0-mg Ranibizumab in Patients With Wet AMD

Brandon G Busbee MD

I. Age-Related Macular Degeneration (AMD)

A. AMD is the leading cause of blindness among indi-viduals ≥ 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 intravit-real 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-naïve patients with subfoveal wet AMD.

B. Patients ≥ 50 years of age (N = 1098) were random-ized in a 1:1:1:1 ratio to 1 of 4 ranibizumab treat-ment 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 per-formed.

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 last-observation-carried-forward method to impute for missing data.

F. Ocular and systemic safety events were also evalu-ated 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 mar-gin 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 (µm): -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 consis-tent 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


III. Conclusions

Although the 2.0-mg group did not meet the prespeci-fied superiority comparison and the p.r.n. groups did not meet the prespecified noninferiority comparison, the HARBOR Study 1-year results demonstrated clini-cally 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 out-comes in patients with wet AMD.

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-carried-forward method was used to impute for missing data. Abbreviations: BCVA indicates best-corrected visual acuity; CFT, central foveal thickness (measured by spectral domain OCT); PRN, as needed.

Figure 1. Mean change from baseline in BCVA at Month 12 using Hochberg-adjusted confi-dence 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 neovascu-larization classification; the last-observation-carried-forward method was used to impute for missing data. Abbreviations: BCVA indicates best-corrected visual acuity; NI, noninferiority; PRN, as needed.


References

1. Friedman DS, O’Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthal-mol. 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 sys-tematic 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 degenera-tion-related choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1996; 37:855-868.

5. Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of exper-imental 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 verte-porfin 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 verte-porfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study. Ophthal-mology 2009; 116:57-65 e5.

8. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neo-vascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-1431.


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

• CATTprimaryoutcomeatYear1demonstratedthatbevacizumab and ranibizumab were noninferior in terms of mean change in visual acuity when dosed monthly.

• Bevacizumabwhendosedp.r.n.wasnotnoninferiortotheother drugs and dosing regimens.

• Therewasadifferenceinsafetybetweenthese2anti-VEGF agents that did not mirror previous anti-VEGF sys-temic adverse events.

• There-randomizationofthesecondyearmeantthatthenumber of permutations were too many to reassess all the outcomes done at the primary outcome, so the results were pooled.

• Meangaininvisionacuitywassimilarforbothagents,butsignificantly greater for the monthly dosing regimens com-pared to as-needed regimens.

• Patientsswitchingfrommonthlytoas-neededregimenforthe same agents after 1 year had worse visual acuity results compared to patients who remained on a fixed monthly dosing scheme.

• Similartothe1-yearresults,thereweresignificantlymoreserious adverse events in the bevacizumab group at Year 2.

• Thenumbersofseriousadverseeventsweresmallinbothgroups, and most were previously not associated with anti-VEGF therapy.

• CATTwasnotpoweredtoexaminefordifferencesinsafety.

IVAN 1-Year Interim Analysis

• TheprimaryoutcomeofIVANisat2years,anditisanoninferiority study comparing bevacizumab and ranibi-zumab with a mean change of vision with 4 letters.

• SimilartoCATT,IVANalsocomparedmonthlyandas-needed regimens for bevacizumab and ranibizumab; how-ever, 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.

• At1year,bevacizumabwasnotnoninferiortoranibi-zumab in terms of mean change in visual acuity in the pooled analysis.

• UnlikeCATT,therewerenosignificantdifferencesbetween the as-needed (“discontinuous”) and monthly (“continuous”) regimens in terms of mean change in visual acuity.

• UnlikeCATT,therewerenodifferencesnotedinthepro-portion of participants experiencing a serious systemic adverse event.

VIeW 2-Year Analysis

• TheVIEWstudieswerethePhase3studiesofvaryingdoses and dosing regimens of aflibercept compared to monthly ranibizumab.

• The1-yearprimaryoutcomereportedthatalldosesanddosing regimens were noninferior to monthly ranibizumab in terms of preventing moderate visual loss.

• Inthesecondyearofthestudy,patientsweretreatedwith the same dosing assignment but followed a apped as needed (p.r.n.) dosing regimen where patients were evalu-ated monthly to determine if treatment was needed and treated at least once every 12 weeks.

• At2years,themeanchangeinvisualacuityfrombaselinewas similar for the aflibercet 2-mg q8 regimen and the monthly ranibizumab regimen, though in all groups small decreases in BCVA were observed.

• Therewerenosignificantdifferencesintheincidenceofserious 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

• TheHARBOR(RanibizumabAdministeredMonthlyoron an As-Needed Basis in Patients with Subfoveal Neovas-cular 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)

• Itwasanoninferioritystudywiththeprimaryoutcomesetin discussion with the FDA as a mean change in visual acu-ity within 4 letters.

• Alldosesandregimenswerenotnoninferiortomonthlystandard dose ranibizumab for the primary outcome

• Alldosesandregimensweresimilarlysafewithnodiffer-ence seen in serious adverse events.


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.

Purpose

To assess the association of aspirin use and AMD in the Age-Related Eye Disease Study (AREDS) and AREDS2, and other randomized controlled clinical trials of aspirin. These studies include the Physicians Health Study and the Women’s 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 Univer-sity of Wisconsin in Madison, using the same standardized pro-tocol. The severity of AMD was classified with the AREDS sim-ple 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 than 5 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.

Results

AREDS and AREDS24188 AREDS2 participants who had complete data were ana-lyzed. 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 com-pared 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 sig-nificant 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 base-line. 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 incon-sistent 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 Women’s Health Study9 and the Physician’s 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 sepa-rate 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 Women’s 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.

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


advanced AMD in both AREDS and AREDS2 may provide fur-ther 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.

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. Grae-fes 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.

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 age-related 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):2386-2392.

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. Oph-thalmology 2009; 116(12):2386-2392.


Radiation for CNV: CABeRNeT / MeRITAGe / INTRePIDTimothy L Jackson MBChB

Radiation is known to preferentially damage proliferating cells, and it therefore has the potential to target the proliferating fibro-blasts, 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 follow-ing the development of two devices designed specifically for the treatment of wet AMD.

The first device uses an endoscopic surgical probe contain-ing 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), investigator-initiated, randomized, controlled trial of previously treated dis-ease (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 dis-ease 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 anti-VEGF 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 rela-tive to the other, but two differences are key. The first relates to vitrectomy. Vitrectomy may increase vitreous oxygen lev-els (reducing VEGF), relieve any vitreomacular traction, and enhance generation of the oxygen radicals that mediate the thera-peutic effect of radiation. Conversely, vitrectomy induces cata-ract, 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 radia-tion 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.


Polypoidal Vasculopathy: Anti-VeGF, Photodynamic Therapy, and SteroidsTimothy YY Lai MD FRCOphth FRCS

I. Basics of Polypoidal Choroidal Vasculopathy (PCV)

A. Clinical features of PCV

1. Choroidal abnormality characterized by branch-ing choroidal vascular network (BVN) with sur-rounding 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 struc-tures beneath retina.

4. Associated with exudative or hemorrhagic pig-ment 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 vascu-lar 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 pro-trusions of RPE with low-moderate reflectiv-ity 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 treat-ment indicated in symptomatic PCV.

III. Photodynamic Therapy (PDT) for PCV

A. One of the most widely described treatment modali-ties in the literature

B. PDT laser spot size is determined by the greatest lin-ear dimension of the lesion (polyps with any inter-connecting 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 sub-retinal fluid and causes stabilization of vision. How-ever, polypoidal lesions persisted after treatment.

C. Patients presenting as neovascular AMD with treat-ment refractory to anti-VEGF therapy may be sug-gestive 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 CNV-like 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.


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, multi-centered, randomized, controlled trial on ranibi-zumab vs. PDT vs. combined therapy: combi-nation 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 triam-cinolone 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 + intravit-real 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.

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 anti-VEGF 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 haemor-rhage in polypoidal choroidal vasculopathy managed by sequential gas displacement and photodynamic therapy: a pilot study of one-year follow up. Clin Experiment Ophthalmol. 2005; 33:611-618.

3. Cho M, Barbarzetto IA, Freund KB. Refractory neovascular age-related macular degeneration secondary to polypoidal choroidal vasculopathy. Am J Ophthalmol. 2009; 148:70-78.

4. Gomi F, Tano Y. Polypoidal choroidal vasculopathy and treat-ments. Curr Opin Ophthalmol. 2008; 19:208-212.

5. Gomi F, Sawa M, Sakaguchi H, et al. Efficacy of intravitreal beva-cizumab 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.


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 treat-ment for polypoidal choroidal vasculopathy. Asia-Pac J Ophthal-mol. 2012; 1:97-104.

11. Lai TY, Chan WM, Liu DT, et al. Intravitreal bevacizumab (Avas-tin) with or without photodynamic therapy for the treatment of pol-ypoidal choroidal vasculopathy. Br J Ophthalmol. 2008; 92:661-666.

12. Lai TY, Lam CP, Luk FO, et al. Photodynamic therapy with or without triamcinolone acetonide for symptomatic polypoidal cho-roidal 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 vas-cular 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 improve-ment following trans-Tenon’s 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 com-bined 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 vascu-lopathy lesions. Retina 2009; 29:960-965.

21. Uyama M, Wada M, Nagai Y, et al. Polypoidal choroidal vascu-lopathy: natural history. Am J Ophthalmol. 2002; 133:639-648.


Anti-Platelet Derived Growth Factor: Where Do We Stand?Pravin U Dugel MD

N o T e S


Long-term Delivery Strategies for Neovascular AMDDavid S Boyer MD

I. The Need for Ocular Drug Delivery

A. Chronicity of back of the eye diseases

B. Frequency of intraocular injections, particularly bio-logics

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). Dif-ficult to use with proteins.

2. SurModics uses I-vation technology.

3. Neurotech Pharmaceuticals, Encapsulated Tech-nology: Device implanted surgically in the vitre-ous containing human retinal pigment epithelial cells. Cells can be modified to produce anti-VEGF 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 develop-ment

a. ForSight Vision4 partnership with Genentech for the development of the PDS with ranibi-zumab

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 Acad-emy of Ophthalmology; 2006.

2. Edelhauser HF, Boatright JH, Nickerson JM, and the third ARVO/Pfizer Research Institute Working Group. Drug delivery to pos-terior 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 dis-ease. Ophthamic Res. 2009; 41124-41135.

4. Saati S, Lo R, Li PY, et al. Surgical methods to place a novel refill-able 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.


What’s 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 ther-apy 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 antivascu-lar endothelial growth factor (VEGF) agents, began with the approval of pegaptanib sodium in December of 2004. Pegap-tanib, a selective blocker of VEGF-165, has demonstrated the ability to slow the rate of vision loss, but it did not show signifi-cant improvement in vision in a majority of patients. The intro-duction of ranibizumab changed the paradigm for CNV treat-ment. 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 sig-nificant 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 large-scale 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 com-bines 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 thick-ness in 2 large Phase 3 clinical trials in a direct head-to-head comparison with ranibizumab and may provide for longer dura-tion 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, motil-ity, 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 neo-vascular AMD, with plans for further studies if the data are posi-tive.

REDD1 is another molecule in the cascade leading to VEGF production acting through the mTOR/HIF1α 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, deliv-ered 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 evalu-ation of another small interfering RNA drug that is specifically targeted toward HIF1α 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 toler-able, 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 bind-ers—VEGF 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


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 esca-lation 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 recep-tor 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 α5β1-antagonist that has undergone Phase 1 trials involving single and multiple injections for patients with CNV. One advan-tage 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 α5β1 integrin and blocks the binding of α5β1 integrin to fibronectin, thereby inhibiting a pivotal interac-tion required for angiogenesis. Volociximab administration has resulted in strong inhibition of rabbit and primate retinal neovas-cularization 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 α5β1, αvβ3, αvβ5, and α2β1 integrins. Integrins α5β1, αvβ3, and αvβ5 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. Oph-thalmic 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 pro-files. 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 cur-rent 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 admin-istered 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 intra-vitreally, is being studied in a Phase 2 clinical trial, comparing combined use with ranibizumab vs. ranibizumab alone for exu-dative AMD.

In spite of its central role in angiogenesis, VEGF is not alone in stimulating and sustaining neovascularization in AMD. There-fore, other approaches to controlling CNV are being explored outside the VEGF cascade. For example, fosbretabulin (combr-estatin 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 occlu-sion of vascular lumen and cessation of blood flow in the effected vessels. It has undergone Phase 2 testing with intravenous admin-istration 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, promot-ing cellular proliferation, migration, and activating survival pathways. Several lines of evidence suggest that S1P and S1P’s complement of receptors play a major regulatory role in the neovascularization, fibrosis, and inflammation related to AMD. Sonepcizumab (LT1009) is a humanized and optimized mono-clonal antibody specifically targeted against S1P and can bind S1P at physiologically relevant concentrations. A Phase 1 multi-center, 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 pig-ment epithelium (RPE) detachments. Phase 2 testing of the drug is under way.

A number of endogenous physiological inhibitors of angio-genesis 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 path-ways 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


of genetic studies along with histopathologic studies of drusen and experimental CNV have shown that aberrations in the com-plement 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 poten-tially 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 excel-lent 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 associ-ated with AMD is to eliminate vitreoretinal traction that may contribute to the exudative process. AL-78898A is being evalu-ated in a study that will evaluate the safety and efficacy of intra-vitreal injection of this vitreolytic agent in subjects diagnosed with exudative AMD with focal vitreomacular adhesion.

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 neovas-cular process, in the form of fibrotic scars and atrophic degenera-tion 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 extension—TAP 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.



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 Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascu-

lar age-related macular degeneration: two year results. Ophthal-mology 2012; 119(7):1388-1398.

7. Ohr M, Kaiser PK. Intravitreal aflibercept injection for neovascular (wet) age-related macular degeneration. Expert Opin Pharmaco-ther. 2012; 13(4):585-591.

8. Dejneki NS, Kuroki AM, Fosnot J, et al. Systemic rapamycin inhib-its 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 neovas-cularization due to age-related macular degeneration. Ophthalmol-ogy 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 macu-lar degeneration. Mol Ther. 2011; 19(2):326-334.

13. Shen J, Samuel R, Silva RL, et al. Suppression of ocular neovas-cularization with siRNA targeting VEGF receptor 1. Gene Ther. 2006; 13(3):225-234.

14. Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogen-esis and lymphangiogenesis. Nature Rev Cancer. 2008; 8(8):604-617.

15. Umeda N, Shu Kachi S, Akiyama H, et al. Suppression and regres-sion of choroidal neovascularization by systemic administration of an α5β1 integrin antagonist. Mol Pharmacol. 2006; 69(6):1820-1828.

16. Raz-Prag D, Zeng Y, Sieving PA, Bush RA. Photoreceptor protec-tion 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-pharma-codynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and anti-angiogenic 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 endo-thelial 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 neovas-cularization in response to increased expression of pigment epithe-lium-derived factor. Invest Ophthalmol Vis Sci. 2002; 43(7):2428-2434.

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 neovasculariza-tion. Am J Pathol. 2006; 168(6):2036-2053.


23. Klein RJ, Zeiss C, Chew EY, et al. Complement factor H polymor-phism in age-related macular degeneration. Science 2005; 308:385-389.

24. Haines JL, Hauser MA Schmidt S, et al. Complement factor H vari-ant 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.

86 Section IX: Imaging 2012 Subspecialty Day | Retina

Imaging the Choroid: What You Need to Know Before Deep “C” DivingChoroidal 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, ultraso-nography, 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 cho-roidal 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 chorio-retinopathy, 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. Exten-sion 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.

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 tis-sue 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, absorb-ing 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 Sat-tler 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 capil-lary. 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 sug-gested, but there is no specific anatomic lobular structure in the posterior portion of the eye.

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 visu-alization 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 penetrat-ing 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 alpha-1-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 choroi-dal vessels are fairly easy to discern, but the vertical summation of the choroid is seen.

optical Coherence Tomography

SD-OCT uses an interferometer with a low coherence light source and measures the interference spectrum using a spec-trometer 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.

2012 Subspecialty Day | Retina Section IX: Imaging 87

These are less problematic with swept source OCT implementa-tions. 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 tech-nique 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 aren’t many swept source OCTs in clinical applica-tion, and none are currently FDA approved. On the other hand many OCT devices can perform EDI-OCT, and the image qual-ity 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 arti-cles are appearing in print, or are soon to be published.

overview of Deeper Imaging of the eye With oCT

Many diseases cause some alteration in the choroid. For exam-ple, 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 cho-roid.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 concur-rent 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 cor-related 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 visual-ized. EDI-OCT and swept source OCT have been used to visual-ize 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-

tions in the sclera, causing a dome-shaped appearance.23 Some highly myopic eyes show peripapillary intrachoroidal cavita-tion,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 determina-tions 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 evalu-ation of it: myth and reality. Prog Retin Eye Res. 2001; 20:563-593.

4. Wangsa-Wirawan ND, Linsenmeier RA. Retinal oxygen: funda-mental and clinical aspects. Arch Ophthalmol. 2003; 121(4):547-557.

5. Wangsa-Wirawan ND, Linsenmeier RA. Retinal oxygen: funda-mental and clinical aspects. Arch Ophthalmol. 2003; 121(4):547-557.

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 evalu-ation of it: myth and reality. Prog Retin Eye Res. 2001; 20:563-593.

10. Baker KJ. Binding of sulfobromophthalein (BSP) sodium and indo-cyanine 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 tomog-raphy 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 chorioretinop-athy in younger and older adults. Ophthalmology 1996; 103:2070-2079.

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 cho-rioretinopathy. 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 Vogt-Koyanagi-Harada disease. Retina 2011; 31:510-517.

18. Spaide RF. Age-related choroidal atrophy. Am J Ophthalmol. 2009; 147:801-810.


19. Switzer DW Jr, Mendonça LS, Saito M, Zweifel SA, Spaide RF. Seg-regation 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 cho-roid 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 dome-shaped 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; 32:1037-1044.

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; 52:9644-9650.


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 subneu-rosensory space.1 It provides additional information not obtain-able 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 heredi-tary 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 mela-nin derived.2

Peak absorption of luteal pigment is at 460 nm. These absorp-tion properties can be readily recorded in vivo by blue light auto-fluorescence imaging.3 Therefore, blue FAF imaging can also be used to determine the topographic distribution of macular pig-ment. 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 rela-tively 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 dis-eases, understanding pathophysiological mechanisms, identifica-tion 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 interven-tional, therapeutic studies, objective assessment of luteal pigment distribution and density, and RPE melanin-distribution.

Age-related Macular Degeneration (AMD)

Early AMDEarly manifestation of AMD include focal hypo- and hyperpig-mentations at the level of the RPE as well as drusen with extra-cellular 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 hyper-pigmentation 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.

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 correspond-ing 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 pat-terns 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 abnor-malities and diseased areas.

Geographic atrophy in AMDRecently, 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 differ-ence 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

Figure 1. GA due to AMD: atrophic areas appear as sharply demar-cated 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 non-atrophic retina. Surrounding atrophy, in the junctional zone of atrophy, levels of marked FAF intensity are observed that are invisible on fundus photography.


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 slow-ing GA enlargement over time. An additional important finding with FAF imaging in GA patients is the visualization of abnor-mal 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 FAM-study 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 sub-sequently 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 pathophysi-ological role of increased RPE LF accumulation in patients with GA due to AMD.

Choroidal neovascularization in AMDFAF imaging may give important clues in choroidal neovascu-larization (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 photorecep-tor 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 hyper-fluorescence on the comparative fluorescein angiograms, imply-ing that RPE viability is preserved at least initially in CNV devel-opment.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 wide-

Figure 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 con-figuration of increased FAF sur-rounding atrophy. Eyes showing areas with increased FAF directly adjacent to the margin of the atrophic patch(es) and elsewhere are called “diffuse” (5 rapid pro-gressors) 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 reflec-tance 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).


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 anti-VEGF-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 estab-lished that autofluorescent material excessively accumulates in the RPE in association with various genetically determined reti-nal diseases. Increased FAF due to excessive LF accumulation in RPE cells may result from abnormally high turnover of photore-ceptor outer segments or impaired RPE lysosomal degradation of normal or altered phagocytosed molecular substrates.

The extent and pattern of increased FAF may show character-istic 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 vitelli-form 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 entities—eg, orientation along the retinal veins in

pigmented paravenous chorioretinal atrophy (PPCRA) or ring structure in retinitis pigmentosa (RP), macular dystrophies or cone-rod dystrophy (CRD) (see Figure 5)—the similar appear-ance on FAF images and the concordance of functional findings indicate that these lines in heterogeneous diseases share a com-mon 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 4. Stargardt macular dystrophy/fundus flavimaculatus. Fundu-scopically visible focal flecks show a bright, increased FAF signal. Focal areas of decreased FAF seem to correspond to RPE atrophy.

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 parafo-veal 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 funduscopi-cally visible lesion. On both sides of the ring, there is a normal FAF signal. In with bull’s-eye macula dystrophy (G), a ring of increased FAF borders directly the central lesion.


Macular Telangiectasia

As outlined above, normal eyes show masking of the foveal 488-nm 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 abnor-mally 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 autofluores-cence 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 reti-nopathy. Early on, a pericentral ring of increased FAF intensity may occur associated with pericentral reduction in mfERG amplitudes and pericentral interruption of the photorecep-tor 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

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; 80:2-3.

5. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. Fun-dus autofluorescence and progression of age-related macular degen-eration. Surv Ophthalmol. 2009; 54:96-117.

6. Arnold JJ, Sarks SH, Killingsworth MC, Sarks JP. Reticular pseu-dodrusen: 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 tomogra-phy 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 Oph-thalmol. 1995; 79:407-412.

12. Schmitz-Valckenberg S, Brinkmann CK, Alten F, et al. Semiauto-mated image processing method for identification and quantifica-tion 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 atro-phy 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 auto-fluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001; 42:1051-1056.

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 macu-lar telangiectasia type 2 with increased signal in the center due to a loss of luteal pigment.


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 exu-dative 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, Schmitz-Valckenberg 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 charac-teristics 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 func-tional 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 idio-pathic 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 opti-cal 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.


What’s 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 (SD-OCT)

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 achiev-able with expensive femtosecond titanium sapphire lasers.

C. Multiplexed superluminescent diodes (SLDs) have made UHR OCT commercially feasible (eg, Opto-pol 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 aber-rations.

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 exten-sive 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.


B. Increasing the imaging wavelength is another approach to achieve greater depth penetration (see Figure 2).

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 3.

3. High myopes: 93 microns

Figure 4.

XIV. OCT and Wavelength

Two “windows of opportunity” for retinal OCT imag-ing

XV. Long wavelength (1 micron OCT)

Most future swept source OCT devices will likely oper-ate 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 1050 nm.

XVII. Retinitis Pigmentosa (see Figure 5)

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.

C. Separate visible light laser used to activate photore-ceptors

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

3. May provide functional insight into the RPE


4. Various structures in the eye (choroid, sclera, Bruch, lamina cribrosa, etc.) may have character-istic birefringence patterns … may be altered by disease.

5. May enhance visualization of the extent of the choroid

6. Facilitate detection of retinal microexudates

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 6.

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)

Figure 7.

XXVIII. Advanced Automated Analyses

A. Many groups are developing algorithms for seg-menting various retinal layers.

B. Algorithms for segmenting specific pathologic struc-tures 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

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 limita-tions of existing devices.

C. Applications of OCT in our diagnosis and treatment of patients can be expected to continue to expand.


Intraoperative optical Coherence Tomography: Is It Actually Useful?Intraoperative Spectral Domain oCT

Sunil K Srivastava MD

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 reim-aging 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 posi-tion

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 surgi-cal 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, reproduc-ible image acquisition.

C. Advantages include ability to identify membranes, folds, and changes to retinal architecture after surgi-cal manipulation.

D. Increased subretinal fluid after membrane peeling is an example of previously unidentified change detected by use of intraoperative SD-OCT.


E. Is it useful now? Absolutely. It can provide informa-tion 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 oper-ating 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.

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 limit-ing membrane peeling. Ophthalmic Surg Lasers Imaging. 2010; 41(1):7-11.

3. Ray R, Barañano DE, Fortun JA, et al. Intraoperative microscope-mounted spectral domain optical coherence tomography for evalu-ation 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 visu-alization 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. Inte-gration of a spectral domain optical coherence tomography system into a surgical microscope for intraoperative imaging. Invest Oph-thalmol Vis Sci. 2011; 52(6):3153-3159.

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. Ophthalmol-ogy 2006; 113(11):2054 e1-14.

10. Sano M, Shimoda Y, Hashimoto H, Kishi S. Restored photorecep-tor 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 prog-nosis 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 Ophthal-mol. 2009; 247(3):325-330.

14. Chang LK, Fine HF, Spaide RF, et al. Ultrastructural correlation of spectral-domain optical coherence tomographic findings in vitreo-macular traction syndrome. Am J Ophthalmol. 2008; 146(1):121-127.

15. Koizumi H, Spaide RF, Fisher YL, et al. Three-dimensional evalu-ation 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 Ophthal-mol. 2001; 85(2):231-233.


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 under-standing 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 inte-grated into fundus cameras (FAO), OCTs (AO-OCT), and scan-ning 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 move-ments 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 correct-ing the aberrations of the eye, the AO-SLO system can achieve a transverse resolution on the order of 2 μm.7 This high resolution has allowed noninvasive in vivo visualization of the cone photo-receptors 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 com-pared 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 diagnos-tic and functional information.24,25 Using ophthalmic AO sys-tems, 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-reso-lution 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 regard-ing 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 treat-ment effects of novel retinal therapies as well as selection of ideal subjects.36,37

Despite these promising aspects of AO systems for ophthal-mology and being an important research tool, several impedi-ments 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 data—such as fully automated cone counting software. Progress is being made in this regard. In addi-tion, 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 fur-ther 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 qual-ity 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 cur-rently, progress in optics technology and software development will improve the adaptability of AO systems in the clinical set-ting 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 ophthal-mology. Future applications for AO ophthalmoscopy include longitudinal monitoring of disease progression and investigat-ing 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 poten-tial for success of these therapies.37 As further improvements are


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.

References

1. Miller DT, Williams DR, Morris GM, Liang J. Images of cone pho-toreceptors in the living human eye. Vision Res. 1996; 36(8):1067-1079.

2. Liang J, Williams DR, Miller DT. Supernormal vision and high-resolution retinal imaging through adaptive optics. J Opt Soc Am A. 1997; 14(11):2884-2892.

3. Roorda A, Williams DR. The arrangement of the three cone classes in the living human eye. Nature 1999; 397(6719):520-522.

4. Rha J, Jonnal RS, Thorn KE, et al. Adaptive optics flood-illumi-nation camera for high speed retinal imaging. Opt Express. 2006; 14:4552-4569.

5. Zhang Y, Rha JT, Jonnal RS, Miller DT. Adaptive optics parallel spectral domain optical coherence tomography for imaging the liv-ing retina. Optics Express. 2005; 13:4792-4811.

6. Roorda A, Romero-Borja F, Donnelly W III, et al. Adaptive optics scanning laser ophthalmoscopy. Opt Express. 2002; 10:405-412.

7. Zhang Y, Roorda A. Evaluating the lateral resolution of the adap-tive optics scanning laser ophthalmoscope. J Biomed Opt. 2006; 11:14002.

8. Carroll J, Neitz M, Hofer H, Neitz J, Williams DR. Functional pho-toreceptor loss revealed with adaptive optics: an alternative cause of color blindness. Proc Natl Acad Sci USA. 2004; 101(22):8461-8466.

9. Wolfing JI, Chung M, Carroll J, Roorda A, Williams DR. High resolution retinal imaging of cone-rod dystrophy. Ophthalmology 2006; 113(6):1014-1019.

10. Choi SS, Doble N, Hardy JL, et al. In vivo imaging of the photo-receptor mosaic in retina dystrophies and correlations with visual function. Invest Ophthalmol Vis Sci. 2006; 47(5):2080-2092.

11. Dubra A, Sulai Y, Norris JL, et al. Noninvasive imaging of the human rod photoreceptor mosaic using a confocal adaptive optics scanning ophthalmoscope. Biomedical Optics Express. 2011; 2(7):1864-1874.

12. Doble N, Choi SS, Codona JL, et al. In vivo imaging of the human rod photoreceptor mosaic. Opt Lett. 2011; 36(1):31-33.

13. Chui TY, Song H, Burns SA. Adaptive-optics imaging of human cone photoreceptor distribution. J Opt Soc Am (A). 2008; 25:3021-3029.

14. Duncan JL, Zhang Y, Gandhi J, et al. High-resolution imaging with adaptive optics in patients with inherited retinal degeneration. Invest Ophthalmol Vis Sci. 2007; 48:3283-3291.

15. Ooto S, Hangai M, Takayama K, et al. Photoreceptor damage and foveal sensitivity in surgically closed macular holes: an adaptive optics scanning laser ophthalmoscopy study. Am J Ophthalmol. 2012; 154(1):174-186.

16. Chen Y, Ratnam K, Sundquist SM, et al. Cone photoreceptor abnormalities correlate with vision loss in patients with Stargardt disease. Invest Ophthalmol Vis Sci. 2011; 52(6):3281-3292.

17. Mkrtchyan M, Lujan BJ, Merino D, et al. Outer retinal structure in patients with acute zonal occult outer retinopathy. Am J Ophthal-mol. 2012; 153(4):757-768.

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 occlu-sion 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 photorecep-tor imaging in idiopathic macular telangiectasia type 2 using adap-tive optics scanning laser ophthalmoscopy. Invest Ophthalmol Vis Sci. 2011; (8):5541-5550.

21. Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photo-receptor topography. J Comp Neurol. 1990; 292(4):497-523.

22. Curcio CA, Sloan KR. Packing geometry of human cone photore-ceptors: variation with eccentricity and evidence for local anisot-ropy. 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; 44:4580-4592.

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 parafo-veal capillary leukocyte velocity. Ophthalmology 2005; 112:2219-2224.

29. Tam J, Martin JA, Roorda A. Noninvasive visualization and analy-sis 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 abnor-malities associated with inner retinal pathology in nonglaucoma-tous 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


ciliary neurotrophic factor treatment. Invest Ophthalmol Vis Sci. 2011; 52(5):2219-2226

37. Jacobson SG, Aleman TS, Cideciyan AV, et al. Identifying photo-receptors 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.


Simple estimation of Fluid Volumes in Neovascular AMDAlexander 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 sub-jects 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).

Figure 1.

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

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 simpli-fied measurements

2. Correlations between ground truth and auto-mated measurements

3. Mote Carlo permutation correlation analysis

4. Sensitivities/specificities of simplified and auto-mated 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 measure-ments 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).

b. The best correlations of automated measure-ments 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).


3. Monte Carlo correlation analysis

a. The statistical significance of correlations between simplified and ground truth mea-surements exceeded P = .005 with only one-third of the study’s 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 sensitiv-ity and specificity for detection of increases or decreases in fluid volumes than automated measurements from the OCT machines them-selves.

b. Between the automated measurements, FCS was more specific than macular volume but produced numerous false-negative predic-tions. When a 100-µm 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 detec-tion 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 cor-relates 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 quantita-tive 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. Accu-racy 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 age-related macular degeneration. Br J Ophthalmol. 2009; 93:1453-1460.

4. Sadda SR, Joeres S, Wu Z, et al. Error correction and quantitative subanalysis of optical coherence tomography data using computer-assisted 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: 1071-1078.

Figure 2.


Figure 3.

Figure 4.

2012 Subspecialty Day | Retina Section X: oncology 105

Germline BAP1 Mutations in ocular Melanoma and other MalignanciesIvana 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 Col-leagues1

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 cutane-ous melanoma, defined as:

a. One or more first-degree relatives with cuta-neous or ocular melanoma

b. Two or more affected relatives with cutane-ous 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 germ-line 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 muta-tions more likely to be nevoid type.

5. BAP1 mutations carriers also have atypical mela-nocytic 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 muta-tion 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 cuta-neous-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 predis-pose to malignant mesothelioma. Nat Genet. 2011; 43(10):1022-1025.

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):856-859.

106 Section X: oncology 2012 Subspecialty Day | Retina

Practical Approaches to Needle Biopsy and Genetic Diagnosis for ocular MelanomaThomas 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 sur-vival 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 micrometa-static 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 differen-tiate those at greatest risk from those at lowest risk.

B. Molecular diagnostics

1. Improved our understanding of melanoma

2. Improved our characterization of the tumor’s 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 Chromo-some 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 hybridiza-tion

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 plat-form

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 but-tons for tumor localization and subsequent pro-ton 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


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 mark-ing 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, tis-sue 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 pro-vided tube.

(e) Aspirate the entire cell solution pro-vided. 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 tub-ing.

b. Pass the needle through the pars plana.

c. Cross the vitreous cavity.

d. Enter the tumor at the apex.

e. Ten cc’s 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 aspi-rating 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 pro-vide 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 hem-orrhage.

2. Via the operating room microscope using a chan-delier 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 instrumenta-tion 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


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 tumor’s 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 seed-ing 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 con-secutive patients with choroidal melanoma managed with FNAB and I125 brachy-therapy and 1-6 years of follow-up (mean 2.7 years).

(a) No cases of orbital dissemination occurred.

(b) Metastatic rate was 13% (compa-rable 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 differ-ential diagnosis

2. No cytopathologist available

3. Inadequate visualization of the tumor

VI. Survey of Ocular Oncologists

109 ocular oncologists worldwide were asked to par-ticipate 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 transscler-ally?

1. Mean: 70.31%

2. Range: 0%-100%

G. What percent of biopsies are performed transvit-really?

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


Figure 2.

Figure 1.

Figure 3.

Figure 4.


Figure 6.

Figure 5.

Figure 7.

Figure 8.


2. Tumor thickness

a. Tumors less than 1.5-2.0 mm = transvitreal

b. Tumors greater than 1.5-2.0 mm = trans-scleral

Table 1. of those who do not do both transscleral and transvitreal:

Response Percentage Frequency

Only do transcleral 25.7% 9

Only do transvitreal 2.9% 1

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)

Figure 10.

Figure 9.

Figure 11.


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 ben-efit and those tumors less than 2-2.5 mm thick are usually not biopsied

5. If tumor is too small and near macula, I don’t 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

Figure 13.

Figure 12.


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 advan-tage in terms of longevity with intensive moni-toring, most are not compelled to seek genetic information.

F. How do you use the information clinically? (see Fig-ure 15)

G. Write-in responses

1. I generally have the patient see a medical oncolo-gist who specializes in melanoma; they generally increase metastatic surveillance, and have access to clinical trials. I specifically as the ophthalmol-ogist 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 isn’t a good prophylaxis yet either. But gathering the data to analyze, and stratify as soon as avail-able 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 compel-ling 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 develop-ing 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 legiti-mate preliminary evidence (not hype) may induce me to contact them as candidates for enrollment.

Figure 14.

Figure 15.


5. More likely to utilize imaging as part of surveil-lance in class 2 patients vs. those with a class 1 profile.

6. The chromosome 3 work is iffy and the more recent RNA work has not been validated by another center. The results are not yet conclusive enough to change clinical management, in my opinion.

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 Iver-son, MD, Lectureship. Arch Ophthalmol. 2007; 125(8):1017-1024.

7. Maat W, Jordanova ES, van Zelderen-Bhola SL, et al. The hetero-geneous distribution of monosomy 3 in uveal melanomas: implica-tions 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. Trans-scleral fine-needle aspiration biopsy of macular choroidal mela-noma. Am J Ophthalmol. 2008; 145(2):297-302.

9. Schoenfield L, Pettay J, Tubbs RR, Singh AD. Variation of mono-somy 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 percutane-ous breast biopsy: documentation with comprehensive imaging and clinical implications. Breast J. 2011; 17(6):651-656.


New Imaging Techniques for ocular TumorsTimothy G Murray MD MBA

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


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 (Philadel-phia 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 stan-dard 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 tran-sient 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 prun-ing.

b. Vascular events much less with experience and nearly no event in our practice for over 1 year.

c. Minimize events with heparin, short catheter-ization 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 precipita-tion.

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 tech-nique and dosing.

III. Current Strategy

A. Bilateral retinoblastoma:

Chemoreduction is choice therapy to control bilateral retinoblastoma as well as prevent pinealo-blastoma 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.


References

Clinical studies

1. Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemo-therapy. 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 melpha-lan 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 intraarte-rial chemotherapy for retinoblastoma. Retina 2009; 29:1207-1209.

4. Shields CL, Bianciotto CG, Ramasubramanian A, et al. Intra-arte-rial chemotherapy for retinoblastoma: I. Control of tumor, subreti-nal seeds, and vitreous seeds. Arch Ophthalmol. 2011; 129:1399-1406.

5. Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemo-therapy 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 retino-blastoma. Ophthalmology 2012; 119:188-192.

8. Bianciotto CG, Shields CL, Iturralde JC, et al. Fluorescein angio-graphic findings after intra-arterial chemotherapy for retinoblas-toma. 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 retino-blastoma: 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 ophthalmo-scopic findings of superselective intraophthalmic artery chemo-therapy in a nonhuman primate model. Arch Ophthalmol. 2011; 129:1458-1465.

Editorials

13. Shields CL, Shields JA. Intra-arterial chemotherapy for retinoblas-toma: 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, O’Brien JM. Intra-arterial chemotherapy for advanced retinoblastoma: is the time right for a prospective clinical trial? Arch Ophthalmol. 2011; 129:1487-1489.

118 Section XI: Late Breaking Developments, Part II 2012 Subspecialty Day | Retina

Late Breaking Developments, Part II

N o T e S

2012 Subspecialty Day | Retina Section XII: Diabetes 119


ProNeil M Bressler MD

ConHarry 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 clini-cal 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 con-tinue 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 deci-sion to continue treatment is also complex. In DME, contrasted with wet macular degeneration, it may not be necessary to elimi-nate 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 detach-ment 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 ranibi-zumab 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 unrealis-tic 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 patient’s 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

120 Section XII: Diabetes 2012 Subspecialty Day | 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 clini-cal 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 prac-titioners to strictly follow the DRCR Network study protocols.


Rebuttal, ProMark W Johnson MD

Rebuttal, ConJennifer 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 sev-eral multicentered clinical trials evaluating the efficacy of anti-VEGF 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 param-eters that fall outside of the inclusion criteria for these studies. It is our duty to synthesize all of the anti-VEGF information avail-able to make the best treatment decision in our patient’s interest. In our clinical practices, there are patients who cannot afford ranibizumab for DME. Bevacizumab, based on BOLT, is a treat-ment 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, respec-tively. 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.



Subthreshold Laser Is an Important Treatment for Macular edema (Yes/No)

ProN H Victor Chong MD

ConLloyd P Aiello MD PhD


I Still Use Scissors in Diabetic Vitrectomy (Yes/No)

ProCurved 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 segmenta-tion 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. Port-based 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 delami-nation 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 can-not 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 bet-ter 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 verti-cal 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.

ConCarl 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 vitrec-

tomy.Technology, in the form of smaller-gauge high-speed vitreous

cutters and improved illumination systems, marches on.


Anti-VeGF Is the Ideal Treatment for Diabetic Macular edema (Yes/No)

ProJulia A Haller MD

ConBaruch D Kuppermann MD PhD

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 depen-dent 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 let-ters) 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 Net-work (DRCR.net) study and RESTORE, the proportion of patients with ≥ 3-line improve-ment 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,


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 pathogen-esis of DME.9

B. Based on mechanism of action, intravitreal cortico-steroids 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 blood-retinal 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 monitor-ing and injections than anti-VEGF therapies

a. In pseudophakic eyes treated with 4-mg intra-vitreal 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 ranibi-zumab-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 photo-coagulation with retreatment at 4-month inter-vals, IVTA (4 mg) provided a greater improve-ment 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 aceton-ide (FA) implants (0.2 or 0.5 µg/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 improve-ment 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 thick-ness 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 follow-ing 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 vit-rectomized 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 treat-ments, including anti-VEGF therapies.20

In this study with a patient population that included severe cases for which multiple pre-vious 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 intra-vitreal 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 cor-ticosteroids has been associated with known ocular side effects, including elevations in IOP, cataracts, and glaucoma, their occurrence varies in frequency and severity depending on pharma-cokinetic 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 pharmaco-kinetic and pharmacodynamic properties of different formulations of triamcinolone ace-tonide have been noted.22 These differences


may impact drug durability, efficacy, and safety.

c. With FA, the proportions of patients requir-ing 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 favor-able safety profile (see Table 1).23

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

Dexamethasone 0.7 mg Implant23

IOP increase ≥ 10 mmHg

18/202 (8.9%)a 3/324 (0.9%)

IOP ≥ 35 mmHg 7/202 (3.5%)a 0/324 (0.0%)

Cataract extraction (during 1 year)

8/203 (3.9%)b,c 4/302 (1.3%)c

a Prior to treatment crossover; b Includes patients who were randomized to standard care but received triamcinolone acetonide 4-mg injection as alternative treatment; c Includes 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, cor-ticosteroids 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. Ophthalmol-ogy 2012; 119:789-801.



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 dia-betic 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 com-bined 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 ran-domized 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.

8. Martin DF, Maguire MG, Fine SL, et al; Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group. Ranibizumab and bevacizumab for treatment of neovascu-lar age-related macular degeneration: two-year results. Ophthal-mology. 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 ran-domized trial comparing focal/grid photocoagulation and intravit-real 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 ace-tonide 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. Avail-able 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. Avail-able at: http://clinicaltrials.gov/ct2/results?term=NCT00168337. Accessed June 13, 2012

18. Kuppermann BD, Blumenkranz MS, Haller JA, et al; Dexametha-sone DDS Phase II Study Group. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 2007; 125:309-317.

19. Haller JA, Kuppermann BD, Blumenkranz MS, et al; Dexametha-sone 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 dexameth-asone 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 differ-ences 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 intravit-real implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthal-mology 2011; 118:2453-2460.

http://clinicaltrials.gov/ct2/results?term=NCT00168389

http://clinicaltrials.gov/ct2/results?term=NCT00168337


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 ret-inal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009; 127:1115-1128.


Anti-VeGF Is the Ideal Treatment for Diabetic Macular edema (Yes/No)

Rebuttal, ProKarl G Csaky MD

Rebuttal, ConDante Pieramici MD

2012 Subspecialty Day | Retina Section XIII: Vitreoretinal Surgery, Part II 129

Surgical Complications Video, Part I

N o T e S

Surgical Complications Video, Part II

N o T e S

2012 Subspecialty Day | Retina 131

Financial Disclosure

The Academy’s Board of Trustees has determined that a finan-cial relationship should not restrict expert scientific, clinical, or nonclinical presentation or publication, provided that appropri-ate 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, indepen-dence, objectivity, and scientific rigor in all individual or jointly sponsored CME activities.

All contributors to Academy educational activities must dis-close any and all financial relationships (defined below) to the Academy annually. The ACCME requires the Academy to dis-close the following to participants prior to the activity:

• anyknownfinancialrelationshipsameetingpresenter,author, contributor, or reviewer has reported with any manufacturers of commercial products or providers of commercial services within the past 12 months

• anymeetingpresenter,author,contributor,orreviewer(hereafter referred to as “the Contributor”) who report they have no known financial relationships to disclose

For purposes of this disclosure, a known financial relation-ship is defined as any financial gain or expectancy of financial gain brought to the Contributor or the Contributor’s family, business partners, or employer by:

• directorindirectcommission;• ownershipofstockintheproducingcompany;• stockoptionsand/orwarrantsintheproducingcompany,

even if they have not been exercised or they are not cur-rentlyexercisable;

• financialsupportorfundingfromthirdparties,includingresearch support from government agencies (e.g., NIH), devicemanufacturers,and/orpharmaceuticalcompanies;or

• involvementinanyfor-profitcorporationwheretheCon-tributor or the Contributor’s family is a director or recipi-ent of a grant from said entity, including consultant fees, honoraria, and funded travel.

The term “family” as used above shall mean a spouse, domes-tic partner, parent, child or spouse of a child, or a brother, sister, or spouse of a brother or sister, of the Contributor.

Category Code Description

Consultant/Advisor C Consultantfee,paidadvisoryboards or fees for attending a meeting (for the past one year)

Employee E Employed by a commercial entity

Lecture fees L Lecture fees (honoraria), travel fees or reimbursements when speaking at the invitation of a commercial entity (for the past one year)

Equityowner O Equityownership/stockoptionsof publicly or privately traded firms (excluding mutual funds) with manufacturers of com-mercial ophthalmic products or commercial ophthalmic services

Patents/Royalty P Patentsand/orroyaltiesthatmight be viewed as creating a potential conflict of interest

Grant support S 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

132 2012 Subspecialty Day | Retina

2012 Retina Planning Group Financial Disclosures

Pravin U Dugel MDAbbott Medical Optics: CAlcon Laboratories, Inc.: CAllergan, Inc.: CArticDx: C,OGenentech: CMacusight: C,ONeovista: C,ONovartis Pharmaceuticals Corp.: LOra: CThromboGenics: C

Tarek S Hassan MDArctic Dx: C,L,OBausch + Lomb Surgical: C,LEyetech, Inc.: CGenentech, Inc.: C,LInsight Instruments: C,LOptimedica: C,ORegeneronQLT:CSynergetics Inc.: L

Peter K Kaiser MDAlcon Laboratories, Inc.: CArcticDx: C Bayer: CGenentech: C,SNovartis Pharmaceuticals Corp.: C,SRegeneron:C,SSKS Ocular LLC: C,O

Joan W Miller MDAlcon Laboratories, Inc.: CNovartis Pharmaceuticals Corp.: OQLTPhototherapeutics,Inc.:P

AAO Staff

Brandi GarrigusNone

Ann L’EstrangeNone

Melanie RafatyNone

Debra RosencranceNone

Beth WilsonNone


Faculty Financial Disclosures

Thomas M Aaberg Jr MDAllergan: L Synergetics, Inc.: C

Gary W Abrams MDAlcon Laboratories, Inc.: C

David H Abramson MD FACSNone

Lloyd P Aiello MD PhDAbbott 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

Arthur W Allen Jr MDNone

J Fernando Arevalo MD FACSNone

Jorge G Arroyo MDNone

Marcos P Avila MDNone

Carl C Awh MDArctic 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

James W Bainbridge MA PhD FRCOphthGene Signal: C Oxford Biomedica: C

Sophie J Bakri MDAllergan, Inc.: C Genentech: C

Francesco M Bandello MD FEBOAlcon 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

Francine Behar-Cohen MDAllergan: SEssilr: CEyevensys SAS : O,C Fournier: S, CNovartis Pharmaceuticals Corporation: SPfizer, Inc.: CSolid Drug Dev: S Solvay: CSteba Biotech: STeva Pharmaceutical Industries, Ltd.: C

Audina M Berrocal MDNone

Maria H Berrocal MDAlcon Laboratories, Inc.: C,L

Susanne Binder MDNone

Alan C Bird MDNone

Barbara Ann Blodi MDNone

Mark S Blumenkranz MDAvalanche Biotechnology: O,P Digisight: O Ista Pharmaceuticals: C Optimedica: O,P Vantage Surgical: C,O

David S Boyer MDAlcon 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:CPfizer, Inc.: C

Periklis Brazitikos MDAlcon Laboratories, Inc.: L Novartis Pharmaceuticals Corp.: C

Neil M Bressler MDAbbott 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 RegeneronPharmaceuticals,Inc.:SSteba Biotech S.A.: S The EMMES Corporation: S Thrombogenics: S

David M Brown MDAlcon 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,LSteba Biotech: CThrombogenics: C

134 Faculty Financial Disclosures 2012 Subspecialty Day | Retina

Alexander J Brucker MDEscalon Medical Corp: O Genentech: S GlaxoSmithKline: S National Eye Institute: S Neurovision: O Ophthotech: C,O Optimedica: O

Brandon G Busbee MDAkorn, Inc.: P Alimera: C Elan: C Genentech: C,L Regeneron:LSynergetics, Inc.: C Thrombogenics: C

Antonio Capone Jr MDAlcon Laboratories, Inc.: C Alimera Sciences: C Allergan, Inc.: C,S FocusROP,LLC:O,PGenentech: C,S GlaxoSmithKline: S Ophthotec: S RetinalSolutions,LLC:O,PThrombogenics: S

Usha Chakravarthy MBBS PhDAllergan, Inc.: C Bausch + Lomb Surgical: C,L Neovista, Inc.: C Novartis Pharmaceuticals Corp.: C,L Oraya Therapeutics: C,L Pfizer, Inc.: C,L

Wiley Andrew Chambers MDNone

R V Paul Chan MDNone

Stanley Chang MDAlcon Laboratories, Inc.: C Alimera Sciences: C

Tom S Chang MDNone

Steven T Charles MDAlcon Laboratories, Inc.: C, PTopcon Medical Systems: C, P

Emily Y Chew MDNone

N H Victor Chong MDAlcon Laboratories, Inc.: S Allergan: C,L,S Bayer: C,L Iridex: C Novartis Pharmaceuticals Corp.: C,L,S Pfizer, Inc.: C,L,S

David R Chow MDArctic Dx: C Bausch + Lomb Surgical: L Katalyst: C Novartis Pharmaceuticals Corp.: L Synergetics, Inc.: C

Mina Chung MDLowyMedicalResearchInstitute:SNational Eye Institute: S RochesterCTSI:SThome Foundation: S

Carl C Claes MDAlcon Laboratories, Inc.: C,L

Karl G Csaky MDAcucela: 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 QLTPhototherapeutics,Inc.:C

Christine Curcio PhDBausch + Lomb: L Genentech: L Global Sight Network: E National Eye Institute: S

Donald J D’Amico MDLux Biosciences, Inc.: C Ophthotech, Inc.: C,O Optimedica, Inc.: C,O

Kimberly A Drenser MD PhDFocusROP:ORetinalSolutions:OSynergetics, Inc.: C

Pravin U Dugel MDAbbott 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

Jay S Duker MDAlcon Laboratories, Inc.: C Carl Zeiss Meditec: S EMD/Serono:CEyeNetra: C,O Genentech: C Hemera Biosciences: O Neovista: C Novartis Pharmaceuticals Corp.: C Ophthotech: O OptoVue: S Paloma Pharmaceuticals: C QLTPhototherapeutics,Inc.:CThrombogenics: CTopcon Medical Systems: S

Alexander Eaton MDAlcon 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:SRevitalid,Inc.:OThromboGenics, Inc.: C

Claus Eckardt MDDORCInternational,bv/Dutch

Ophthalmic, USA: P

Ehab N El Rayes MD PHDNone

Dean Eliott MDAlimera: C Arctic: C Bausch + Lomb Surgical: C Genentech: C Glaukos Corp.: C Ophthotech: C Thrombogenics: C

Daniel D Esmaili MDNone

Sharon Fekrat MDNone

Frederick L Ferris MDBausch + Lomb: P

Philip J Ferrone MDAlcon Laboratories, Inc.: S Allergan: C,L,S Arctic DX: C,O Bausch + Lomb: C Genentech: C,L,S Regeneron:C,L,S

2012 Subspecialty Day | Retina Faculty Financial Disclosures 135

Marta Figueroa MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Novartis Pharmaceuticals Corp.: C

Paul T Finger MDThe Eye Cancer Foundation, Inc.: L,S

Harry W Flynn Jr. MDAlimera: C Allergan, Inc.: C Pfizer, Inc.: C Santen, Inc.: C

William R Freeman MDAllergan: C OD-OSRetinaCareUnlimited:C

K Bailey Freund MDGenentech: C,S QLTPhototherapeutics,Inc.:CRegeneron:C

Thomas R Friberg MDEyetech, Inc.: C Genentech: C Optos, Inc.: C Pfizer, Inc.: S

Anne E Fung MDAlcon Laboratories, Inc.: C Genentech: C,L,S Ista Pharmacuticals: C Santen, Inc.: C Sequenom: C Thrombogenics: C

Brenda L Gallie MDSolutions by Sequence: O

Alain Gaudric MDAlcon Laboratories, Inc.: S Allergan, Inc.: S Bayer: S Novartis Pharmaceuticals Corp.: S

Andre V Gomes MDDORCInternationalbv/PatchOpthalmic

USA: C Novartis Pharmaceuticals Corp.: CVolk: C

Christine R Gonzales MDAlimera: C Allergan: L Iconic Therapeutics: S Lpath Inc.: S OPHTEC: S Pfizer, Inc.: S Regeneron:S

Evangelos S Gragoudas MDQLTPhototherapeutics,Inc.:P

M Gilbert Grand MDNone

Julia A Haller MDAdvanced Cell Technology: C Allergan, Inc.: C Genentech: C Optimedica: O Regeneron:CThrombogenics: C

Dennis P Han MDAllergan, Inc.: S Genentech: S Ophthotech: S Regeneron:S

Tarek S Hassan MDArtic 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:CSynergetics Inc.: L

Jeffrey S Heier MDAcucela: 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 QLTOphthalmics:CQLTTherapeutics:CQLT,Inc.:CQuarkPharmaceuticals:CRegeneron:C,SSequenom: C

Allen C Ho MDAlcon Laboratories, Inc.: C,L,S Genentech: C,L,S Janssen: C,L,S Merck & Co., Inc.: C NEI/NIH:SOphthotech: C,S PRN:C,O,SRegeneron:C,L,SSecond Sight: S Thrombogenics: C,L

Frank G Holz MDAcucela: 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

Suber S Huang MD MBAAlcon Laboratories, Inc.: L Bausch + Lomb Surgical: C i2i Innovative Ideas, Inc.: O Notal Vision: C RetinalDiseasesImageAnalysisReading

Center(REDIARC):C,LSequenom: C

Mark S Humayun MD PhDAlcon Laboratories, Inc.: C,L Bausch + Lomb Surgical: C,L,O,P,S Replenish:C,O,P,SSecond Sight: C,L,O,P,S

Michael S Ip MDAllergan, Inc.: S Eye Technology, Ltd.: C Genentech: C NicOx: C Notal Vision: C QLTPhototherapeutics,Inc.:CRegeneron:CSirion: C

Timothy L Jackson MBChBBausch + Lomb: C DORCInternational,bv/Dutch

Ophthalmic, USA: L NeoVista: C,L,S Novartis Pharmaceuticals Corp.: S Oraya: S Thrombogenics: C,L

Glenn J Jaffe MDAbbott Laboratories: C Heidelberg Engineering: C Neurotech USA: C SurModics, Inc.: C


Martine J Jager MDAeon Astron: S

Mark W Johnson MDGlaxoSmithKline: C Ophthotech: C Oraya: C Regeneron:S

J Michael Jumper MDCovalent Medical LLC: ODORCInternational,bvDutch

Ophthalmic, USE: L

Kazuaki Kadonosono MDNone

Peter K Kaiser MDAlcon Laboratories, Inc.: C ArcticDx: C Bayer: C Genentech: C,S Novartis Pharmaceuticals Corp.: C,S Regeneron:C,SSKS Ocular LLC: C,O

Ivana K Kim MDGenentech: C,S Regeneron:C

Judy E Kim MDAlimera Sciences: C Allergan, Inc.: C,S Genentech: C,S

John W Kitchens MDGenentech: C,L MyWhiteCoat.com: O Optos, Inc.: C,L Regeneron:C,LSynergetics, Inc.: C,L

Robert K Koenekoop MD PhDQLTPhototherapeutics,Inc.:C,S

Baruch D Kuppermann MD PhDAlimera: 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:SThrombogenics: C,S

Timothy Y Lai MD FRCOphth FRCSAllergan: C,L Bayer Healthcare: C,L,S Heidelberg Engineering: L Novartis Pharmaceuticals Corp.: C,L,S Oxigene, Inc.: S Pfizer, Inc.: S

Jennifer Irene Lim MDIcon Bioscience: S, Quark:CRegeneron:C,SSanten, Inc.: C

Anat Loewenstein MDAllergan, Inc.: C,L Forsightlabs: C Lumenis, Inc.: C,L Notal Vision, Ltd.: C, Novartis Pharmaceuticals Corporation:

C,L Orabio: C

Ian M MacDonald MDNovartis Pharmaceuticals Corp.: L

Maureen G Maguire PhDInspire Pharmaceuticals, Inc.: S Merck & Co., Inc.: C

Daniel F Martin MDNone

Carlos Mateo MDNone

William F Mieler MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Genentech: C

Joan W Miller MDAlcon Laboratories, Inc.: C Novartis Pharmaceuticals Corp.: O QLTPhototherapeutics,Inc.:P

Darius M Moshfeghi MDConvene, 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

Shizuo Mukai MDNone

Timothy G Murray MD MBAAlcon Laboratories, Inc.: C Thrombogenics, Inc.: C

Annabelle A Okada MDMitsubishi Tanabe Pharma: L,S Novartis Pharma Japan: L Novartis Pharmaceuticals Corp.: C Pfizer Japan: L XOMA, Corp.: C

Timothy W Olsen MDDobbs Foundation: S Emtech Biotechnology Development

Grant: S GeorgiaResearchAlliance:SJohnson & Johnson: S NIH/NEI:SNIH/NIA:SResearchtoPreventBlindness:S

Jeffrey L Olson MDShape Memory Alloy Chip: P

Yusuke Oshima MDAlcon Laboratories, Inc.: C,L Carl Zeiss Meditec: L DORCInternational,bv/Dutch

Ophthalmic, USA: L Santen, Inc.: L Synergetics, Inc.: C,L Topcon Medical Systems: C

Andrew J Packer MDNone

Kirk H Packo MDAlcon 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

David W Parke II MDOMIC-Ophthalmic Mutual Insurance

Company: C

Fabio Patelli MDNone

Grazia Pertile MDNone

Dante Pieramici MDAlimera: C Allergan: S Genentech: C,S Regeneron:SThrombogenics: C

2012 Subspecialty Day | Retina Faculty Financial Disclosures 137

Eric A Pierce MD PhDNone

Subhransu Ray MD PhDGenentech: C,Santen, Inc.: C

Franco M Recchia MDAlcon Laboratories, Inc.: C Genentech: L Thrombogenics: C

Carl D Regillo MD FACSAlcon Laboratories, Inc.: C,S Allergan: C,S Genentech: C,S GlaxoSmithKline: C,S Novartis Pharmaceuticals Corp.: C,S QLTPhototherapeutics,Inc.:C,SSecond Sight: S

Kourous Rezaei MDAlcon Laboratories, Inc.: C,L,S Alimera Sciences: C BMC: C Genentech: L,S

William L Rich MDNone

Stanislao Rizzo MDNone

Michael A Romansky JDNone

Richard B Rosen MDAllergan: 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

Philip J Rosenfeld MD PhDAcucela: 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

Alan J Ruby MDGenentech: L

Srinivas R Sadda MDAllergan, Inc.: C Carl Zeiss Meditec: L,S Genentech: CHeidelberg Engineering: C Optos, Inc.: S Optovue, Inc.: S Regeneron:CTopcon Medical Systems: P

Andrew P Schachat MDNone

Amy C Schefler MDNone

Hendrik PN Scholl MDAMD Therapy Fund: C American Health Assistance Foundation:

S Food and Drug Administration (FDA): C Foundation Fighting Blindness: S QLTPhototherapeutics,Inc:CSanofi Fovea: C Usher III Initiative: C

Ursula M Schmidt-Erfurth MDAlcon Laboratories, Inc.: C,L BayerHealthcare: C,L Novartis Pharmaceuticals Corp.: C,L

Steven D Schwartz MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Bausch + Lomb Surgical: C,L Genentech, Inc.: C,L OptiMedica: C,L,O Optos, Inc.: C,L

Jonathan E Sears MDNone

Gaurav K Shah MDAbbott Medical Optics: C Alcon Laboratories, Inc.: C,L Allergan, Inc.: C DORCInternational,bv/Dutch

Ophthalmic, USA: C iScience: C Neovista: C

Carol L Shields MDNone

Jerry A Shields MDNone

Michael A Singer MDAlcon Laboratories, Inc.: S Allergan, Inc.: C,L,S Eli Lilly & Company: S Genentech: C,L,S

Lawrence J Singerman MDAlcon 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

Arun D Singh MDNone

Rishi P Singh MDAlcon Laboratories, Inc.: C Bausch + Lomb: C Genentech: C

Jason S Slakter MDAcucela: C,S Alcon Laboratories, Inc.: S Alimera: S Allergan, Inc.: S Bayer HealthCare: S Centocor, Inc.: S Corcept: S Fovea/SanofiAventis:SGenentech: 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.:SRegeneronPharmaceuticals:L,SReVision:C,SSanofi-Aventis: S SKS Ocular, LLC: O

Rachel Smith MD PhDNone

Gisele Soubrane MD PhDAllergan, Inc.: C,L Chibret International: C Novartis Pharmaceuticals Corp.: C


Richard F Spaide MDGenentech: S Thombogenics: C Topcon Medical Systems: P

Sunil K Srivastava MDAllergan, Inc.: SBausch + Lomb Surgical: C,SNovartis Pharmaceuticals Corp.: S

Giovanni Staurenghi MDAlcon 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 QLTPhototherapeutics,Inc.:CZeiss: S

Paul Sternberg MDNone

John T Thompson MDGenentech: S National Eye Institute: S Regeneron:S

Trexler M Topping MDBoston Eye Surgery & Laser Center: O National Eye Institute: S OMIC-Ophthalmic Mutual Insurance

Company: E

Cynthia A Toth MDAlcon Laboratories, Inc.: P Bioptigen, Inc.: S Genentech, Inc.: S National Eye Institute: S Physical Sciences Incorporated: C,S

Michael T Trese MDFocusROP:C,OGenentech: C Nu-Vue Technologies, Inc.: C,O RetinalSolutionsLLC:C,OSynergetics, Inc.: P ThromboGenics Inc.: C,O

Jan C Van Meurs MDDORCInternational,bv/Dutch

Ophthalmic, USA: P

Luk H Vandenberghe PhDGenSight Biologics: O GlaxoSmithKline: P National Eye Institute: L ReGenXBiosciences:P

Alexander C Walsh MDEnvision Diagnostics: E,O,P

David F Williams MDGenentech: C

George A Williams MDAlcon 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

Lihteh Wu MDHeidelberg Engineering: L

Lawrence A Yannuzzi MDNone

Young Hee Yoon MDAlcon Laboratories, Inc.: C Allergan: L,S Bayer: L

David N Zacks MD PhDMassachusetts Eye and Ear Infirmary: P ONL Therapeutics, LLC: O University of Michigan: P


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 43Behar-Cohen, Francine 34Binder, 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*,DavidR 1Claes*, Carl C 13 Csaky*, Karl G 128 Curcio*, Christine 15 Drenser*, Kimberly A 39 Dugel*, Pravin U 80Eaton*, Alexander M 118Eckardt*, Claus 13 ElRayes,EhabN 13 Eliott*, Dean 2 Ferris*, Frederick L 20 Flynn Jr*, Harry W 119Gonzales*,ChristineR 118Haller*, Julia A 124 Heier*, Jeffrey S 69 Ho*, Allen C 29 Holz*, Frank G 89Humayun*, Mark S 118Ip*, Michael 118Jackson*, 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 121Loewenstein*, Anat 34MacDonald*, Ian M 44 Maguire*, Maureen G 63 Martin, Daniel F 65 Mateo, Carlos 13 Moshfeghi*, Darius M 35 Murray*, Timothy G 115Olson*, Jeffrey L 118Oshima*, Yusuke 13 Parke II*, David W 52 Pieramici*, Dante 128 Pierce, Eric A 47Ray*,Subhransu 34Recchia*,FrancoM 40 Rich,WilliamL 54 Romansky,MichaelA 56 Rosenfeld*,PhilipJ 21 Ruby*,AlanJ 57 Sadda*,SrinivasR 94 Scholl*, Hendrik PN 46 Shah*, Gaurav K 7 Shields, Carol L 116Singer*, Michael A 34Slakter*, Jason S 82 Smith,Rachel 118 Spaide*,RichardF 86Srivastava*, 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


aao sub retina_2012_syllabus

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