retina 2011 syllabus

Subspecialty Day

2011OrlandoOctober 21 – 22

RETINA

Retina 2011: The Magical World of Retina

©2011 Ameri can Academy of Oph thal mology. All rights reserved. No por tion may be repro duced with out express writ ten con sent of the Ameri can Academy of Oph thal mology.

Retina 2011 Planning GroupAllen C Ho MDProgram Director

Joan W Miller MDProgram Director

Tarek S Hassan MDPeter K Kaiser MD

Former Program Directors2010 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 MD2005 Michael T Trese MD Emily Y Chew MD2004 William F Mieler MD Michael T Trese MD

2003 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 MD

Robert 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

CoordinatorDebra Rosencrance CMP CAE, Vice

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

Retina 2011The Magical World of RetinaProgram DirectorsAllen C Ho MD and Joan W Miller MD

In conjunction with the American Society of Retina Specialists, the Macula Society, the Retina Society, and Club Jules Gonin

Orange County Convention CenterOrlando, FloridaFriday – Saturday, October 21 – 22, 2011

Presented by:The American Academy of Ophthalmology

Support for the Retina Subspecialty Day Syllabus provided in part by

Dear Colleague:

On behalf of the American Academy of Ophthalmology and the American Society of Retina Specialists, the Macula Society, the Retina Society, and Club Jules Gonin, it is our pleasure to welcome you to Orlando and to Retina 2011: The Magical World of Retina.

The standard components of Retina Subspecialty Day are the lectures and panel discussions presented by leading experts from around the world. We have created opportunities for lively and spirited discussions of controversial issues, including the best way to repair a retinal detachment in the mini-panel discussion “Freaky Friday: Retinal Detachment Techniques”; anti-VEGF for ROP in “Snow White and the Six Dwarfs”; therapeutic options for retinal vein occlusion in “Never a Dull Moment”; and local chemotherapy for retinoblastoma in “Beauty and the Beasts: Retinoblastoma Roundtable.” We continue the tradition of holding discussion panels on the topics of AMD management, diabetic retinopathy, and advanced surgical techniques. We include “best of” approaches to create a core program that addresses what’s new in clinical practice, as well as practical issues that retinologists face daily—from the status of new treatments for diabetic retinopathy to what health care reform means for Retina. Two sessions are reserved for presentation of late-breaking developments. The Schepens Lecture—delivered this year by Stanley Chang MD on “Is Double Peeling Necessary in Surgery for Macular Pucker?”—is certain to be a highlight. Finally, after its popular debut last year, we include the Break With the Experts program on Friday from 2:37 to 3:30. This format allows participants to move freely from topic to topic at their leisure and to interact with our faculty.

Our goal is that attendees will find Retina 2011: The Magical World of Retina to be an informative and entertaining combination of new and useful information for 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 Subspecialty Day Meetings and request that you assist us by completing the evaluation form. We carefully review all comments to better understand your needs. Please indicate the strengths and shortcomings of this program and suggest new ways to meet the needs of our international audience.

Again, we welcome you to Retina 2011: The Magical World of Retina; we hope you find it educational and enjoyable.

Sincerely,

Allen C Ho MD Joan W Miller MD Program Director Program Director

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2011 Subspecialty Day | Retina iii

Retina 2011 Contents

Program Directors’ Welcome Letter ii

CME iv

The Charles L Schepens MD Lecture v

Faculty Listing vi

Program Schedule xxiv

Section I: Vitreoretinal Surgery 1

The Charles L Schepens MD Lecture 15

Section II: Neovascular AMD 16

Surgery by Surgeons Update 33

Section III: Late Breaking Developments 34

Section IV: Pediatric Retina Panel 35

Section V: Inherited Retinal Diseases and Miscellaneous 36

Section VI: Retinal Vein Occlusion 47

Section VII: Business of Retina 55

Section VIII: Non-neovascular AMD 64

Section IX: Imaging 90

Section X: Oncology 101

Section XI: Uveitis 103

Section XII: Late Breaking Developments 112

Section XIII: Diabetes 113

Section XIV: Vitreoretinal Surgery 2 135

Faculty Financial Disclosure 151

Presenter Index 159

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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.

2011 Retina Subspecialty Day Meeting Learning Objectives

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

• Explainthecurrentmanagementofmacularedemasecondary to retinal occlusive disease and diabetic retinopathy

• Explainthepathobiologyandmanagementofatrophicand exudative AMD and other causes of CNV

• Identifyemergingdevelopmentsinretinalimaging• Describenewvitreoretinalsurgicaltechniquesand

instrumentation• Identifynewdevelopmentsinhereditaryretinaldegenera-

tions, pediatric retinal diseases, ocular oncology and uveitis

2011 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.

2011 Retina Subspecialty Day CME Credit

The American Academy of Ophthalmology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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

Scientific Integrity and Disclosure of Relevant 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 relevant financial interest. 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 Annual 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

Level 2, Lobby B; Academy Resource Center, Hall A4, Booth 1359 Attendees whose attendance has been verified (see above) at the 2011 Annual 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 Annual Meeting at the CME Credit Reporting booth.

Academy Members: The CME credit reporting receipt is not a CME transcript. CME transcripts that include 2011 Annual Meeting credits entered onsite will be available to Academy members on the Academy’s website beginning Nov. 16, 2011.

NOTE: CME credits must be reported by Jan. 18, 2012. After the 2011 Annual Meeting, credits can be claimed at www.aao.org.

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 Annual 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 2011 Annual Meeting and Subspecialty Day for those who need it for reimbursement or hospital privileges, or for non-members who need it to report CME credit:

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

Visit the Academy’s website for detailed CME reporting information.

http://www.aao.org

2011 Subspecialty Day | Retina v

The Charles L Schepens MD LectureFriday October 21, 2011

9:19 AM - 9:34 AM

Stanley Chang MD

Stanley Chang MD is the Edward S Harkness Professor and Chairman of the Department of Ophthalmology at Columbia University Medical Center. He is also the K K Tse and Ku Teh Ying Professor of Ophthalmology.

Dr. Chang received a baccalaureate degree from the Massachusetts Institute of Tech-nology and a master’s degree from the University of Pennsylvania, and completed his medical education at the College of Physicians & Surgeons of Columbia University. After ophthalmology residency at Massachusetts Eye and Ear Infirmary, he was a vitreoretinal fellow at the Bascom Palmer Eye Institute in Miami. After fellowship, Dr. Chang joined the faculty of Department of Ophthalmology at Cornell University Medical School, where he became professor of ophthalmology. Appointed the Edward S Harkness Professor and Chairman of the Department of Ophthalmology in 1995, he also serves as director of the Edward S Harkness Eye Institute.

Dr. Chang has developed and pioneered several revolutionary surgical approaches to treat complicated forms of retinal detachment, improving outcomes for patients worldwide. He was the first to use perfluoropropane gas in the management of retinal detachments caused by scar tissue proliferation (PVR) on the retina. This gas is the most frequently used gas in vitreoretinal surgery. He developed perfluorocarbon liquids, a “heavy liquid” used in flattening retinal detachment, and the related surgical techniques for vitreoretinal surgery. In collaboration with Avi Grinblat, he developed a panoramic viewing system and led in the worldwide adaptation by retina surgeons to this technique.

In leading a world-class ophthalmology department and vision research institute, Dr. Chang continues to improve the clinical outcomes for patients through research and innovation. He is the recipient of several honors, including the Hermann Wacker Prize from the Club Jules Gonin, the Helmerich Prize from the American Society of Retinal Specialists, the Lifetime Achievement Award and the Secretariat Award from the Ameri-can Academy of Ophthalmology, the Jackson Lecture and the Alcon Research Institute Award. Consistently named as one of America’s best doctors, Dr. Chang was selected as National Physician of the Year by the Castle Connolly Guides in 2008.

The Charles L Schepens MD Lecture is sponsored by the Retina Research Foundation and Schepens International Society.

vi 2011 Subspecialty Day | Retina

Faculty

Gary W Abrams MDDetroit, MIProfessor and ChairDepartment of OphthalmologyWayne State UniversityDirector, Kresge Eye Institute

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

Nur Acar MDIstanbul, TurkeyAssociate Professor of OphthalmologyBeyoglu Eye Research and Training

Hospital

Lloyd P Aiello MD PhDBoston, MAProfessor of OphthalmologyHarvard Medical SchoolDirector, Beetham Eye InstituteHead Section of Eye ResearchJoslin Diabetes Center

J Fernando Arevalo MD FACSCaracas, DF, VenezuelaProfessor of OphthalmologyWilmer Eye Institute and Johns Hopkins

University School of MedicineChief of Retina DivisionThe King Khaled Eye Specialist Hospital,

Riyadh, Kingdom of Saudi Arabia

Albert J Augustin MDKarlsruhe, GermanyProfessor of OphthalmologyDepartment of Ophthalmology,

Klinikum Karlsruhe Professor and ChairmanRetina Research InstituteBaden-Baden, Germany

Robert L Avery MDSanta Barbara, CACodirectorCalifornia Retina Research FoundationFounderCalifornia Retina Consultants

Marcos P Avila MDGoiania, GO, BrazilFull Professor of OphthalmologyUniversidade Federal de GoiasHead of the Ophthalmology DepartmentUniversidade Federal de Goiás

Carl C Awh MDNashville, TNPresidentTennessee Retina, PC

2011 Subspecialty Day | Retina Faculty Listing vii

Francesco M Bandello MD FEBOMilano, ItalyFull Professor and ChairmanDepartment of OphthalmologyUniversity Vita-SaluteScientific Institute San Raffaele, Milan

Alay S Banker MDAhmedabad, IndiaDirectorBanker’s Retina Clinic and Laser Centre Vitreoretinal Surgeon and Uveitis

SpecialistBanker’s Retina Clinic and Laser Centre

Rubens Belfort Jr MD PhDSao Paulo, SP, BrazilHead ProfessorVision Institute, Federal University of

Sao PauloMember, Academia Ophthalmologica

Internationalis

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

Maria H Berrocal MDSan Juan, PRAssistant ProfessorUniversity of Puerto Rico

Robert B Bhisitkul MDSan Francisco, CAProfessor of Clinical OphthalmologyUniversity of California, San Francisco

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

Retinology and Biomicroscopic Laser Surgery

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

Francesco Boscia MDBari, ItalyAssociate Professor of OphthalmologyUniversity of Bari

viii Faculty Listing 2011 Subspecialty Day | Retina

David S Boyer MDLos Angeles, CAClinical ProfessorUniversity of Southern CaliforniaPartner, Retina Vitreous Associates

Medical Group

Neil M Bressler MDBaltimore, MDThe James P Gills Professor of

OphthalmologyJohns Hopkins University School of

MedicineChief, Retina DivisionWilmer Eye Institute

Susan B Bressler MDBaltimore, MDThe Julia G Levy PhD Professor of

OphthalmologyWilmer Eye InstituteJohns Hopkins University School of

Medicine

David M Brown MD FACSHouston, TXAssistant Clinical Professor of

OpthalmologyWeill Cornell College of Medicine,

The Methodist HospitalDirector of Clinical ResearchRetina Consultants of Houston

Gary C Brown MDWyndmoor, PAProfessor of Ophthalmology and

Director, Retina ServiceWills Eye Hospital, Jefferson Medical

CollegeChief Medical OfficerCenter for Value-Based Medicine

Alexander J Brucker MDPhiladelphia, PAProfessor of OphthalmologyScheie Eye InstituteUniversity of Pennsylvania

Peter A Campochiaro MDBaltimore, MDDepartment of OphthalmologyJohn Hopkins Hospital

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

University School of MedicineCodirector, Fellowship in Vitreoretinal

Diseases and SurgeryAssociated Retinal Consultants

Jose A Cardillo MDAraraquara, SP, BrazilProfessor of OphthalmologyFederal University of Sao Paulo -

UNIFESP/EPM

2011 Subspecialty Day | Retina Faculty Listing ix

R V Paul Chan MDNew York, NYSt Giles Assistant Professor of Pediatric

RetinaWeill Cornell Medical College

Stanley Chang MDNew York, NYEdward Harkness Professor and Chair of

OphthalmologyColumbia UniversityKK Tse and Ku Teh Ying ProfessorColumbia University

Steven T Charles MDMemphis, TNAdjunct Professor of OphthalmologyColumbia College of Physicians &

SurgeonsClinical Professor of OphthalmologyUniversity of Tennesee, Memphis

Emily Y Chew MDBethesda, MDDeputy Director, Division of

Epidemiology and Clinical Applications

National Eye Institute/National Institutes of Health

N H Victor Chong MBCHBOxford, 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, NYAssociate Professor of OphthalmologyFlaum Eye InstituteUniversity of Rochester

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

Antwerp)

W Lloyd Clark MDWest Columbia, SCManaging MemberPalmetto Retina Center, LLC

x Faculty Listing 2011 Subspecialty Day | Retina

Emmett T Cunningham Jr MD PhD MPHHillsborough, CADirector, The Uveitis ServiceCalifornia Pacific Medical CenterAdjunct Clinical Professor of

OphthalmologyStanford University School of Medicine

Donald J D’Amico MDNew York, NYProfessor and Chairman, Department of

OphthalmologyWeill Cornell Medical CollegeOphthalmologist-in-ChiefNew York-Presbyterian Hospital

Janet Louise Davis MDMiami, FLProfessor of OphthalmologyUniversity of Miami Miller School of MedicineDirector, Uveitis ServiceBascom Palmer Eye Institute

Eugene De Juan Jr MDMenlo Park, CAJean Kelly Stock Distinguished Professor

of OphthalmologyUniversity of California, San FranciscoVice ChairmanForSight Labs

Diana V Do MDBaltimore, MDAssistant Professor of OphthalmologyThe Wilmer Eye InstituteThe Johns Hopkins University School of

Medicine

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

Pravin U Dugel MDPhoenix, AZManaging PartnerRetinal Consultants of Arizona Clinical Associate Professor of

OphthalmologyDoheny Eye InstituteKeck School of MedicineUniversity of Southern California, Los

Angeles

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

OphthalmologyTufts University School of Medicine

Claus Eckardt MDFrankfurt, GermanyProfessor of OphthalmologyStaedtische Kliniken Frankfurt-Hoechst

2011 Subspecialty Day | Retina Faculty Listing xi

Justis P Ehlers MDShaker Heights, OHStaff PhysicianCole Eye InstituteCleveland Clinic

Ehab N El Rayes MDCairo, EgyptProfessor of Ophthalmology, Retina

ServiceInstitute of Ophthalmology, Cairo

Dean Eliott MDLos Angeles, CAProfessorDoheny Retina InstituteKeck School of MedicineUniversity of Southern California

Frederick L Ferris MDWaxhaw, NCDirector, Division of Epidemiology and

Clinical ResearchNational Eye Institute / National

Institutes of Health

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

Mitchell S Fineman MDCherry Hill, NJAssociate Professor of OphthalmologyThomas Jefferson University,

Philadelphia, PAAssociate SurgeonWills Eye Institute, Philadelphia, PA

Yale L Fisher MDNew York, NYClinical Professor of OphthalmologyPrebyterian New York Hospital-Cornell

Weil Medical CollegeVoluntary Clinical ProfessorBascom Palmer Eye Institue

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

No photo available

K Bailey Freund MDNew York, NY

xii Faculty Listing 2011 Subspecialty Day | Retina

No photo available

Thomas R Friberg MDPittsburgh, PAProfessor of OphthalmologyUniversity of PittsburghDirector of Retina ServiceUPMC Eye Center

Anne E Fung MDSan Francisco, CAMedical 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

Sunir J Garg MD FACSPhiladelphia, PAMidAtlantic RetinaThe Retina Service of Wills Eye InstituteAssociate Professor of OphthalmologyThomas Jefferson University

Alain Gaudric MDParis, FranceProfessor of OphthalmologyHôpital LariboisièreUniversité Paris 7 – Diderot

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

M Gilbert Grand MDSt Louis, MORetina SurgeonRetina ConsultantsProfessor of Clinical OphthalmologyWashington University School of

Medicine

Julia A Haller MDPhiladelphia, PAOphthalmologist-in-ChiefWills Eye InstituteProfessor and Chair of OphthalmologyJefferson Medical CollegeThomas Jefferson University

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

OphthalmologyMedical College of WisconsinVitreoretinal Section HeadThe Froedtert & The Medical College of

Wisconsin Eye Institute

2011 Subspecialty Day | Retina Faculty Listing xiii

J William Harbour MDSaint Louis, MOPaul A Cibis Distinguished Professor of

OphthalmologyWashington University in Saint LouisDirector, Ocular Oncology ServiceBarnes Retina Institute

Christos Haritoglou MDMunich, GermanyProfessor of OphthalmologyLudwig-Maximilians-University Munich

Tarek S Hassan MDRoyal Oak, MIPartner and Director, Vitreoretinal

ProgramAssociated Retinal ConsultantsAssistant Professor of Biomedical

SciencesOakland University

Jeffrey S Heier MDBoston, MAVitreoretinal SpecialistOphthalmic Consultants of BostonAssistant Professor in OphthalmologyTufts University School of Medicine

Allen C Ho MDPhiladelphia, PAAttending SurgeonMid Atlantic Retina and Wills Eye

InstituteProfessor of OphthalmologyThomas Jefferson University

Joe G Hollyfield PhDCleveland, OHLlura and Gordon Gund Professor of

Ophthalmology ResearchCleveland Clinic Lerner College of

MedicineFull StaffCole Eye InstituteCleveland Clinic

Frank G Holz MDBonn, GermanyProfessor of OphthalmologyUniversity of Bonn

Suber S Huang MD MBACleveland, OHDirector, Center Retina and Macular

DiseaseUniversity Hospitals Eye InstituteSearle Professor and Vice ChairDepartment of Ophthalmology and

Visual SciencesCase Western Reserve University School

of Medicine

G Baker Hubbard MDAtlanta, GAAssociate Professor of OphthalmologyEmory University School of Medicine

xiv Faculty Listing 2011 Subspecialty Day | Retina

Mark S Humayun MD PhDLos Angeles, CAProfessor of Ophthalmology,

Biomedical Engineering, and Cell & Neurobiology

Doheny Eye Institute Keck School of Medicine University of Southern California

Tomohiro Iida MDFukushima, JapanProfessor and Chairman of

OphthalmologyFukushima Medical University School of

Medicine

Michael S Ip MDMadison, WIAssociate Professor of OphthalmologyUniversity of Wisconsin, Madison

Mary Lou Jackson MDBoston, MADirector of Vision Rehabilitation CenterMassachusetts Eye and Ear InfirmaryDepartment of OphthalmologyHarvard Medical SchoolChair, Vision Rehabilitation CommitteeAmerican Academy of Ophthalmology

Glenn J Jaffe MDDurham, NCProfessor of OphthalmologyDuke University

Mark W Johnson MDAnn Arbor, MIProfessor of Ophthalmology and Visual

SciencesUniversity of MichiganDirector, Retina ServiceW K Kellogg Eye Service

Peter K Kaiser MDCleveland, OHProfessor of OphthalmologyCleveland Clinic Lerner College of

MedicineDirector, Digital OCT Reading CenterCole Eye Institute

Richard S Kaiser MDCherry Hill, NJAssociate SurgeonRetina Service of Wills Eye InstituteAssociate Clinical ProfessorThomas Jefferson University

John H Kempen MDPhiladelphia, PAAssociate Professor of Ophthalmology

and EpidemiologyUniversity of PennsylvaniaDirector, Ocular Inflammation Service

and Ophthalmic EpidemiologyScheie Eye Institute

2011 Subspecialty Day | Retina Faculty Listing xv

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

Frank H Koch MDFrankfurt, GermanyProfessor of OphthalmologyUniversity Eye Clinic Frankfurt/Main

Adrian H Koh MDSingapore, SingaporeDirector and Senior ConsultantEye & Retina SurgeonsExecutive DirectorEuropean School of Advanced Studies in

Ophthalmology Asia

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

Jennifer Irene Lim MDChicago, ILProfessor of Ophthalmology, Director,

Retina Service, and Marion H Schenk Esq Chair in Ophthalmology

llinois Eye and Ear InfirmaryUniversity of Illinois at Chicago

Livia R Lumbroso-Le Rouic MDParis, FrancePraticien spécialisteInstitut Curie

Albert M Maguire MDBryn Mawr, PAAssociate Professor of OphthalmologyUniversity of PennsylvaniaClinical AssociateChildren’s Hospital of Philadelphia

Andre Maia MDSao Paulo, SP, BrazilProfessor of OphthalmologyPaulista School of Medicine Federal University of Sao Paulo

(UNIFESP)Chief, Division of Retina and VitreousHospital Medicina dos Olhos

Daniel F Martin MDCleveland, OHChairman, Cole Eye InstituteCleveland Clinic

xvi Faculty Listing 2011 Subspecialty Day | Retina

H Richard McDonald MDSan Francisco, CAClinical Professor of Ophthalmology and

Codirector, Vitreoretinal Fellowship Program

California Pacific Medical Center

William F Mieler MDChicago, ILProfessor and Vice ChairmanDepartment of Ophthalmology and

Visual SciencesUniversity of Illinois at Chicago

Joan W Miller MDBoston, MAHenry Willard Williams Professor of

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

No photo available

Paul Mitchell MD PhDKirribilli, NSW, Australia

Virgilio Morales-Canton MDMexico City, DF, MexicoChief of the Retina DepartmentAsociación para Evitar la Ceguera en

Mexico

No photo available

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

Timothy G Murray MDMiami, FLProfessor of Ophthalmology and

Radiation OncologyBascom Palmer Eye Insitute, University

of Miami Miller School of Medicine

Quan Dong Nguyen MDBaltimore, MDAssociate Professor of OphthalmologyWilmer Eye InstituteDiseases of the Retina and Vitreous, and

UveitisJohn Hopkins University School of

Medicine

Joan M O’Brien MDPhiladelphia, PAChair and Professor of OphthalmologyScheie Eye InstituteUniversity of Pennsylvania

2011 Subspecialty Day | Retina Faculty Listing xvii

Masahito Ohji MDOtsu, Shiga, JapanProfessor and Chairman, Department of

OphthalmologyShiga University of Medical Science

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

Timothy W Olsen MDAtlanta, GAF Phinizy Calhoun Sr Professor and

Chairman of OphthalmologyEmory University

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

Medicine

Andrew J Packer MDHartford, CTClinical ProfessorUniversity of Connecticut, School of

Medicine

Kirk H Packo MDIndian Head Park, ILProfessor and ChairmanDepartment of Ophthalmology Rush University Medical CenterPartnerIllinois Retina Associates

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

Dante Pieramici MDSanta Barbara, CAVice PresidentAmerican Society of Ocular TraumaPresidentCalifornia Retina Research Foundation

John S Pollack MDJoliet, ILAssistant Professor of OphthalmologyRush University Medical CenterPartnerIllinois Retina Associates

xviii Faculty Listing 2011 Subspecialty Day | Retina

Jonathan L Prenner MDPrinceton, NJAssistant Clinical ProfessorRobert Wood Johnson Medical SchoolUniversity of Medicine and Dentistry,

New Jersey

Carmen A Puliafito MD MBALos Angeles, CADean, John and Mary Hooval Dean’s

Chair in MedicineKeck SchoolUniversity of Southern CaliforniaProfessor of Ophthalmology and Health

ManagementDoheny Eye InstituteUniversity of Southern California

Franco M Recchia MDNashville, TNAssociate Professor of Ophthalmology

and Visual SciencesVanderbilt UniversityChief, Retina DivisionVanderbilt Eye Institute

Carl D Regillo MD FACSBryn Mawr, PAProfessor of OphthalmologyThomas Jefferson UniversityDirector, Clinical Retina Research UnitWills Eye Hospital

No photo available

Elias Reichel MDBoston, MAProfessor of OphthalmologyTufts University School of MedicineVice ChairmanNew England Eye Center

Kourous Rezaei MDHarvey, ILAssociate Professor of OphthalmologyRush University Medical CenterPartnerIllinois Retina Associates

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

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

Philip J Rosenfeld MD PhDMiami, FLProfessor of OphthalmologyBascom Palmer Eye Institute Miller School of Medicine University of Miami

2011 Subspecialty Day | Retina Faculty Listing xix

No photo available

Alan J Ruby MDNovi, MIAssociated Retinal Consultants, Royal

Oak, MI

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

Reginald J Sanders MDChevy Chase, MDClinical Associate Professor of

OphthalmologyGeorgetown University School of

MedicinePartnerRetina Group of Washington

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

Ursula M Schmidt-Erfurth MDVienna, AustriaProfessor and ChairMedical University of ViennaDepartment of Ophthalmology and

Optometry

Steven D Schwartz MDLos Angeles, CAAhmanson Professor of Ophthalmology

and Chief, Retina DivisionJules Stein Eye InstituteAssociate Professor of OphthalmologyDavid Geffen School of Medicine at the

University of California, Los Angeles

Johanna M Seddon MDBoston, MAProfessor of OphthalmologyTufts University School of MedicineDirector, Ophthalmic Epidemiology and

Genetics ServiceNew England Eye Center, Tufts Medical

Center

No photo available

Sherif M Sheta MDCairo, Egypt

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

xx Faculty Listing 2011 Subspecialty Day | Retina

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

Michael A Singer MDSan Antonio, TXOphthalmologist, Managing Partner,

and Director of Clinical TrialsMedical Center Ophthalmology

AssociatesAssistant Clinical ProfessorUniversity of Texas Health Science

Center

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

of Medicine

Rishi P Singh MDCleveland, OHStaff PhysicianCole Eye InstituteCleveland Clinic Foundation

Jason S Slakter MDNew York, NYClinical Professor of OphthalmologyNew York University School of

MedicinePartner, Vitreous Retina Macula

Consultants of New York

Lucia Sobrin MDBoston, MAAssistant Professor of OphthalmologyHarvard Medical SchoolAttending PhysicianRetina and Uveitis ServicesMassachusetts Eye and Ear Infirmary

Gisele Soubrane MD PhDCreteil, FranceProfessor of OphthalmologyDepartment of Ophthalmology

University Paris XII MD, PhD, FEBO, FARVOUniversity of Paris XII

Richard F Spaide MDNew York, NYOphthalmologyVitreous, Retina and Macula

Consultants of New York

Sunil K Srivastava MDCleveland, OHAssistant Professor of OphthalmologyEmory University Eye Center

2011 Subspecialty Day | Retina Faculty Listing xxi

Giovanni Staurenghi MDMilan, ItalyProfessor of OphthalmologyDepartment of Clinical Science “Luigi Sacco” University of Milan

Paul Sternberg MDNashville, TNProfessor and ChairmanVanderbilt Eye InstituteVanderbilt University School of

MedicineAssociate Dean for Clinical AffairsVanderbilt University School of

Medicine

William S Tasman MD FACSWyndmour, PAProfessor and Emeritus ChairmanJefferson Medical College of Thomas

Jefferson UniversityRetina Specialists

John T Thompson MDBaltimore, MDPartnerRetina SpecialistsAssistant ProfessorThe Wilmer Institute of The Johns

Hopkins University

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

Michael T Trese MDRoyal Oak, MIPresidentAssociated Retinal Consultants, PCChief Pediatric and Adult Vitreoretinal

SurgeryBeaumont Eye Institute William Beaumont Hospital

Stephen H Tsang MD PhDLos Angeles, CAAssistant Professor of OphthalmologyColumbia College of Physicians &

SurgeonsAssistant Professor of Pathology and

Cell BiologyColumbia University

Russell N Van Gelder MD PhDSeattle, WABoyd K Bucey Memorial Chair,

Professor, and Chairman of Ophthalmology

University of Washington School of Medicine

DirectorUW Medicine Eye Institute

Demetrios Vavvas MDBoston, MAAssistant Professor of OphthalmologyHarvard Medical SchoolJ W Miller Scholar in RetinaMassachusetts Eye & Ear Infirmary

xxii Faculty Listing 2011 Subspecialty Day | Retina

C P Wilkinson MDBaltimore, MDChairman, Department of

OphthalmologyGreater Baltimore Medical CenterProfessor, Department of

OphthalmologyJohns Hopkins University

David F Williams MDMinneapolis, MNPartnerVitreoRetinal Surgery, PAAssistant Clinical Professor of

OphthalmologyUniversity of Minnesota

George A Williams MDRoyal Oak, MIProfessor and ChairDepartment of OphthalmologyOakland University William Beaumont

School of Medicine

Sebastian Wolf MD PhDBern, SwitzerlandProfessor of OphthalmologyUniversity of Bern

Lihteh Wu MDSan Jose, Costa RicaAssociate SurgeonInstituto de Cirugia Ocular

Lawrence A Yannuzzi MDNew York, NYVice Chairman, Department of

Ophthalmology, and Director of Retinal Services

Manhattan Eye, Ear and Throat Hospital

Professor of Clinical Ophthalmology College of Physicians and SurgeonsColumbia University

No photo available

Lucy H Young MD PhD FACSBoston, MAAssociate Professor of OphthalmologyMassachusetts Eye and Ear InfirmaryHarvard Medical School

David N Zacks MD PhDAnn Arbor, MIAssociate Professor of Ophthalmology

and Visual SciencesKellogg Eye Center University of Michigan

Marco A Zarbin MD PhD FACSChatham, NJProfessor and ChairInstitute of Ophthalmology and Visual

ScienceNew Jersey Medical School

2011 Subspecialty Day | Retina Faculty Listing xxiii

Kang Zhang MD PhDLa Jolla, CAProfessor of OphthalmologyUniversity of California, San DiegoDirector, UCSD Institute for Genomic

Medicine

xxiv 2011 Subspecialty Day | Retina

Retina 2011: The Magical World of Retina

FRIDAY, OCTOBER 21, 2011

6:30 AM REGISTRATION/MATERIAL PICKUP/CONTINENTAL BREAKFAST

8:00 AM Opening Remarks Allen C Ho MD* Joan W Miller MD*

Section I: Vitreoretinal Surgery

Moderator: C P Wilkinson MD*

8:05 AM The Vitreomacular Interface and Ocriplasmin 2011 Julia A Haller MD* 1

8:12 AM New Techniques in Widefield Surgical Viewing Masahito Ohji MD* 3

8:19 AM Intraoperative Integration of OCT Justis P Ehlers MD 5

8:26 AM Update on 27-gauge Vitrectomy: Current Indications and Surgical Outcomes Yusuke Oshima MD* 7

8:33 AM Vitreoretinal Surgical Instrumentation Update David R Chow MD* 10

8:40 AM Vitrectomy With IOL Fixation Jonathan L Prenner MD* 11

8:47 AM Staining Internal Limiting Membrane and Epiretinal Membranes Christos Haritoglou MD* 13

8:54 AM Freaky Friday: Retinal Detachment Techniques Mini-Panel Debate

Moderator: H Richard McDonald MD* Panelists: Gary W Abrams MD*, Susanne Binder MD, Donald J D’Amico MD*, Yale L Fisher MD, Thomas R Friberg MD*, Dennis P Han MD*

The Charles L Schepens MD Lecture

9:14 AM Introduction of the 2011 Schepens Lecturer David W Parke II MD*

9:19 AM Is Double Peeling Necessary in Surgery for Macular Pucker? Stanley Chang MD* 15

9:34 AM REFRESHMENT BREAK and RETINA EXHIBITS

Section II: Neovascular AMD

Moderators: Robert B Bhisitkul MD*, Lawrence J Singerman MD*

10:20 AM Interpreting Non-inferiority Trials: The Good, the Bad, and the Ugly Frederick L Ferris MD* 16

10:27 AM Results of the Comparison of AMD Treatment Trials Daniel F Martin MD 19

10:34 AM Clinical and Anatomical Response to Anti-VEGF Therapy in the Comparison of AMD Treatment Trial (CATT) Glenn J Jaffe MD* 20

10:41 AM VEGF Trap-Eye for AMD: VIEW1/VIEW2 Studies Jeffrey S Heier MD* 21

10:48 AM Antiseptics vs. Antibiotics for Intravitreal Injections Harry W Flynn Jr MD* 24

10:55 AM Diagnosis and Management of Polypoidal Choroidal Vasculopathy Adrian H Koh MD* 26

11:02 AM Internal Radiation for AMD: The CABERNET Study Pravin U Dugel MD* 28

11:09 AM To Infinity and Beyond: Future Therapeutics for AMD Jason S Slakter MD* 30

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

2011 Subspecialty Day | Retina Program Schedule xxv


11:16 AM The Incredibles: Neovascular AMD Panel

Moderator: Lawrence A Yannuzzi MD Panelists: Albert J Augustin MD*, Susan B Bressler MD*, David M Brown MD FACS*, K Bailey Freund MD*, Anne E Fung MD*, Annabelle A Okada MD*, Ursula M Schmidt-Erfurth MD*

11:36 AM Surgery by Surgeons George A Williams MD* 33

11:41 AM LUNCH and RETINA EXHIBITS

Section III: Late Breaking Developments

1:00 PM−1:35 PM Moderators: M Gilbert Grand MD, Suber S Huang MD MBA*

Section IV: Pediatric Retina Panel

Snow White and the Six Dwarfs: Anti-VEGF for ROP

Moderators: Kimberly A Drenser MD PhD*, William S Tasman MD FACS1:35 PM Panelists: Alay S Banker MD, Audina M Berrocal MD, R V Paul Chan MD, G Baker Hubbard MD, Franco M Recchia MD*, Michael T Trese MD*

Section V: Inherited Retinal Diseases and Miscellaneous

Moderators: Eugene De Juan Jr MD*, Kang Zhang MD PhD*

1:55 PM The Genetics of Retinitis Pigmentosa Stephen H Tsang MD PhD 36

2:02 PM Attacking Leber Congenital Amaurosis Albert M Maguire MD 39

2:09 PM New Ocular Drug Delivery Devices Robert L Avery MD* 42

2:16 PM Bioelectronics in Ophthalmology Mark S Humayun MD PhD* 44

2:23 PM Low Vision Therapy for Advanced AMD Mary Lou Jackson MD* 45

Break With the Experts

Exhibit Hall C 2:37 PM−3:30 PM

Topic V01: AMD Emily Y Chew MD K Bailey Freund MD* Peter K Kaiser MD* Daniel F Martin MD Philip J Rosenfeld MD PhD*

Topic V02: Diabetic Retinopathy J Fernando Arevalo MD FACS Maria H Berrocal MD* Victor Chong MD* Diana V Do MD* Quan Dong Nguyen MD*

Topic V03: Electronic Medical Records Rishi P Singh MD* David F Williams MD*

Topic V04: Endophthalmitis Harry W Flynn Jr MD* Franco M Recchia MD

Topic V05: Intraocular Tumors Evangelos S Gragoudas MD Jerry A Shields MD

xxvi Program Schedule 2011 Subspecialty Day | Retina


Topic V06: Macular Surgery Steven T Charles MD* Christos Haritoglou MD* Stanislao Rizzo MD* Demetrios Vavvas MD*

Topic V07: Ocular Imaging Frank G Holz MD* Srinivas R Sadda MD* Giovanni Staurenghi MD*

Topic V08: Pediatric Retinal Disease Antonio Capone Jr MD* Timothy G Murray MD

Topic V09: Retinal Coding and Reimbursement Mitchell S Fineman MD* Reginald J Sanders MD

Topic V10: Retinal Detachment Susanne Binder MD Carl C Claes MD* Dean Eliott MD* Dennis P Han MD*

Topic V11: Vascular Occlusions Peter A Campochiaro MD* Julia A Haller MD* Michael S Ip MD*

Topic V12: Uveitis Sunir J Garg MD FACS* John H Kempen MD*

Section VI: Retinal Vein Occlusion

Moderators: Gary C Brown MD*, Dante Pieramici MD*

3:30 PM Hemiretinal Vein Occlusion Characteristics in the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) Study Michael S Ip MD* 47

3:37 PM Longer-term Follow-up on Ranibizumab for Retinal Vein Occlusion: HORIZON Carl C Awh MD 48

3:44 PM VEGF Trap-Eye for Retinal Vein Occlusion: COPERNICUS and GALILEO W Lloyd Clark MD 51

3:51 PM Combination Therapy (Ozurdex and Anti-VEGF Agents) for Retinal Vein Occlusion Michael A Singer MD* 54

3:58 PM Never a Dull Moment: Retinal Vein Occlusion Panel

Moderator: Carmen A Puliafito MD MBA* Panelists: Marcos P Avila MD, Francesco M Bandello MD FEBO*, Marta Figueroa MD*, Sunir J Garg MD FACS*, Steven D Schwartz MD*, Sebastian Wolf MD PhD*

Section VII: Business of Retina

Moderators: John S Pollack MD*, Reginald J Sanders MD

4:18 PM Physician Compensation: What Are You Worth? Antonio Capone Jr MD* 55

4:25 PM The Future of U.S. Physician Services William L Rich MD 56

4:32 PM Retina Electronic Health Record Rishi P Singh MD* 57

4:39 PM The Influence of Pricing and Payer Policy on Choice of Anti-VEGF Agents Mitchell S Fineman MD* 59

4:46 PM The Boy Who Cried Wolf: Management of High-Priced Pharmaceuticals Alan J Ruby MD* 61

4:53 PM Closing Remarks Allen C Ho MD* Joan W Miller MD*

2011 Subspecialty Day | Retina Program Schedule xxvii


SATURDAY, OCTOBER 22, 2011

6:30 AM CONTINENTAL BREAKFAST

8:00 AM Opening Remarks Allen C Ho MD* Joan W Miller MD*

Section VIII: Non-neovascular AMD

Moderators: Paul Mitchell MD PhD*, Johanna M Seddon MD*

8:05 AM New Ideas on the Pathogenesis of AMD Joe G Hollyfield PhD 64

8:12 AM Gene Testing and AMD: Are We Ready to Start? Ivana K Kim MD* 65

8:19 AM Emerging Role of Biomarkers for AMD Paul Sternberg MD 67

8:26 AM Dry AMD Treatments: How Will We Define Success? Philip J Rosenfeld MD PhD* 69

8:33 AM Progression of Geographic Atrophy in the Age-Related Eye Disease Study (AREDS) Emily Y Chew MD 72

8:40 AM Neuroprotection in Retinal Disease Demetrios Vavvas MD* 74

8:47 AM Drug Delivery Implants for Geographic Atrophy Baruch D Kuppermann MD PhD* 75

8:54 AM Complement System and Strategies for Modulation Peter K Kaiser MD* 78

9:01 AM A Complement-Based Gene Therapy for AMD Elias Reichel MD* 81

9:08 AM Visual Cycle Modulation Frank G Holz MD* 82

9:15 AM The Promise of Stem Cells for AMD and Retinal Degenerations Marco A Zarbin MD PhD FACS* 84

9:22 AM REFRESHMENT BREAK and ANNUAL MEETING EXHIBITS

Section IX: Imaging

Moderators: Alain Gaudric MD*, Giovanni Staurenghi MD*

10:10 AM Widefield Autofluorescence: A New Tool for Studying Macular Disease Srinivas R Sadda MD* 90

10:17 AM Imaging of Central Serous Chorioretinopathy Tomohiro Iida MD 91

10:24 AM Deep OCT Choroidal Imaging Richard F Spaide MD* 94

10:31 AM Clinical Applications of Adaptive Optics Technology Mina Chung MD 96

10:38 AM To Infinity and Beyond: OCT, the Next Frontier Jay S Duker MD* 98

Section X: Oncology

Moderators: Evangelos S Gragoudas MD, Andrew P Schachat MD

10:45 AM New Insights in the Molecular Genetics of Uveal Melanoma J William Harbour MD* 101

10:52 AM The Expanding Clinical Spectrum of Retinal Vasoproliferative Tumors Jerry A Shields MD 102

10:59 AM Beauties and the Beasts: Retinoblastoma Roundtable

Moderator: Timothy G Murray MD Panelists: David H Abramson MD FACS, Brenda L Gallie MD*, Livia R Lumbroso-Le Rouic MD, Shizuo Mukai MD, Joan M O’Brien MD, Carol L Shields MD

xxviii Program Schedule 2011 Subspecialty Day | Retina


Section XI: Uveitis

Moderators: Emmett T Cunningham Jr MD PhD MPH, Russell N Van Gelder MD PhD*

11:19 AM Multicenter Uveitis Steroid Treatment (MUST) Trial John H Kempen MD* 103

11:26 AM Mistakes Made in Caring for Uveitis Patients Sunil K Srivastava MD 104

11:33 AM Cancer-Associated Retinopathy Lucia Sobrin MD 106

11:40 AM Newly Identified Causes of Uveitis (Drug Induced, Viral) Janet Louise Davis MD* 108

11:47 AM A Bug’s Life: Update on Infectious Retinitis Lucy H Young MD PhD FACS 110

11:54 AM LUNCH and ANNUAL MEETING EXHIBITS

Section XII: Late Breaking Developments

1:15 PM−1:50 PM Moderators: Stanislao Rizzo MD*, David F Williams MD*

Section XIII: Diabetes

Moderators: Alexander J Brucker MD, Gisele Soubrane MD PhD*

1:50 PM Pathophysiology of Diabetic Retinopathy Lloyd P Aiello MD PhD* 113

1:57 PM Clinical Application of DRCR.net Anti-VEGF Treatment and Follow-up of Diabetic Macular Edema Neil M Bressler MD* 114

2:04 PM Primary Bevacizumab Plus Grid Laser vs. Primary Bevacizumab vs. Grid Laser for Diabetic Macular Edema J Fernando Arevalo MD FACS 115

2:11 PM Ranibizumab for Diabetic Macular Edema: 24-Month Results of RIDE and RISE, Two Phase 3 Randomized Trials David S Boyer MD* 119

2:18 PM Read 3: 0.5- vs. 2.0-mg Ranibizumab for Diabetic Macular Edema Quan Dong Nguyen MD* 123

2:25 PM Iluvien for Diabetic Macular Edema Peter A Campochiaro MD* 125

2:32 PM Micropulse Laser for Diabetic Macular Edema N H Victor Chong MBCHB* 127

2:39 PM Vitrectomy for Diabetic Macular Edema: Current Concepts Tarek S Hassan MD* 129

2:46 PM “Hakuna Matata”: Diabetes Panel

Moderator: Carl D Regillo MD FACS* Panelists: Rubens Belfort Jr MD PhD*, Jose A Cardillo MD, Diana V Do MD*, Mark W Johnson MD*, Frank H Koch MD*, Jennifer Irene Lim MD*, Timothy W Olsen MD*, David N Zacks MD PhD*

3:06 PM REFRESHMENT BREAK and ANNUAL MEETING EXHIBITS

Section XIV: Vitreoretinal Surgery 2

Moderators: Claus Eckardt MD*, Steven T Charles MD*

3:50 PM Trauma During Revolution Sherif M Sheta MD 135

3:57 PM Expanding Indications for Treatment of Lamellar, Myopic Macular Holes and Myopic Foveoschisis John T Thompson MD* 136

4:04 PM Chorioretinal Biopsy: Techniques and Results Dean Eliott MD* 139

4:11 PM Pharmacologic Prevention of Proliferative Vitreoretinopathy: Isotretinoin Study Richard S Kaiser MD* 140

4:18 PM Endophthalmitis Update 2011 William F Mieler MD* 144

2011 Subspecialty Day | Retina Program Schedule xxix


4:25 PM New Developments in LCD Display for Visual Acuity and Reading Metrics Mark S Blumenkranz MD* 149

4:32 PM It’s Kind of Fun to Do the Impossible: Vitreoretinal Panel

Moderators: Kourous Rezaei MD*, Kirk H Packo MD* Panelists: Nur Acar MD, Maria H Berrocal MD*, Francesco Boscia MD*, Carl C Claes MD*, Ehab N El Rayes MD, Andre Maia MD, Virgilio Morales-Canton MD*, Cynthia A Toth MD*, Lihteh Wu MD

4:52 PM Closing Remarks Allen C Ho MD* Joan W Miller MD*

4:55 PM ADJOURN

2011 Subspecialty Day | Retina Section I: Vitreoretinal Surgery 1

The Vitreomacular Interface and Ocriplasmin 2011Julia A Haller MD

I. Mechanism of Posterior Vitreous Detachment (PVD)

A. Vitreous remodelling leads to progressive liquefac-tion with age.

1. Collagen aggregates to form lamellae.

2. Liquefaction occurs in pockets.

3. Pockets then coalesce.

B. Concurrent weakening of adhesion at vitreoretinal interface

C. Liquefied vitreous bursts through hole in the vitre-ous cortex. Residual vitreous gel collapses forward.

II. Anomalous PVD and Vitreomacular Adhesion (VMA)

A. Anomalous PVD = Pathologic PVD

B. Liquefaction without sufficient dehiscence at the vitreoretinal interface

C. No clean separation of the posterior vitreous cortex

D. Tractional force exerted on retina

III. Anomalous VMA can induce vitreomacular traction (VMT).

Incomplete separation of vitreous due to PVD results in VMA. VMA creates a retinal tangential force, causing distortion of the vascular and retinal architecture.

IV. Symptomatic Vitreomacular Adhesion (sVMA)

A. VMA manifests as many retinal disorders. Specifi-cally, an attached vitreous has been associated not only with vitreomacular traction syndrome (VMTS) and macular hole (MH) but also with worse prog-nosis in proliferative diabetic retinopathy, diabetic macular edema, and macular edema secondary to other causes such as retinal vein occlusion. In several of these conditions, there are anecdotal reports, case series, and/or randomized clinical trials that show that if the focal vitreomacular adhesion resolves (whether spontaneously or via vitrectomy), the underlying anatomic defect resolves and functional recovery can be achieved.

B. Most recently, several groups have independently shown an association between attached vitreous and worse prognosis for AMD. Specifically, patients with exudative AMD have a much higher likeli-hood of having focal vitreomacular adhesion than patients with nonexudative AMD.

V. Ocriplasmin: Truncated Form of Human Plasmin

A. A pharmacologic treatment for VMA

B. Potent proteolytic activity against major compo-nents of vitreoretinal interface

C. In contrast to hyaluronidase (Vitrase) and dispase, ocriplasmin induces both liquefaction and vitreous detachment.

Figure 1. Ocriplasmin, a truncated form of human plasmin.

VI. MIVI-TRUST Study Design (2 Studies)

A. Subjects with VMA (defined as vitreous adhesion to the macula within a 6-mm central retinal OCT field surrounded by elevation of the posterior hya-loid) that was symptomatic and deemed eligible for surgical intervention were randomized 2:1 or 3:1 to intravitreal injection of ocriplasmin or placebo vehicle. 652 eyes were enrolled, 464 treated with ocriplasmin and 166 treated with placebo. Primary endpoint of pharmacological resolution of VMA (determined by Duke OCT reading center) was judged at 28 days. Secondary endpoints included pharmacological closure of MH without surgery (reading center determined), induction of total PVD (judged by investigators on ultrasound), visual acu-ity change, visual function/quality of life change, and complications. Followed out to 6 months.

B. Efficacy conclusions

1. 27% of patients had pharmacological resolution of VMA (P < .001).

2. 40.6% of patients had pharmacological closure of MH (P = .004).

3. 13.4% of patients had induction of total PVD (P < .001).

4. 23.7% of patients gained ≥ 2 lines (P < .001) without vitrectomy.

5. 9.7% of patients gained ≥ 3 lines (P < .001) with-out vitrectomy.

C. No significant safety concerns were identified.

2 Section I: Vitreoretinal Surgery 2011 Subspecialty Day | Retina

Selected Readings

1. Benz MS, Packo KH, Gonzalez V, et al. A placebo-controlled trial of microplasmin intravitreous injection to facilitate posterior vitre-ous detachment before vitrectomy. Ophthalmology 2010; 117:791-797.

2. Johnson MW. Posterior vitreous detachment: evolution and compli-cations of its early stages. Am J Ophthalmol. 2010; 149:371-382.

3. Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion: a potential risk factor for exuda-tive age-related macular degeneration? Am J Ophthalmol. 2007; 144:741-746.

4. Hikichi T, Fujio N, Akiba J, Azuma Y, Takahashi M, Yoshida A. Association between the short-term natural history of diabetic macular edema and the vitreomacular relationship in type II diabe-tes mellitus. Ophthalmology 1997; 104:473-478.

5. de Smet MD, Gandorfer A, Stalmans P, et al. Microplasmin intravitreal administration in patients with vitreomacular traction scheduled for vitrectomy: the MIVI I trial. Ophthalmology 2009; 116:1349-1355.

6. Stalmans P, Delaey C, de Smet MD, van Dijkman E, Pakola S. Intravitreal injection of microplasmin for treatment of vitreomacu-lar adhesion: results of a prospective, randomized, sham-controlled phase II trial (the MIVI-IIT trial). Retina 2010; 30:1122-1127.

Figure 2. A representative case from a patient with sVMA and a MH, injected with ocriplasmin.


New Techniques in Widefield Surgical ViewingMasahito Ohji MD

I. Background

Wide-angle viewing systems have been used widely dur-ing vitrectomy because surgeons can see a wide fundus area and can correctly evaluate the pathogenesis during surgery. There are two types of wide-angle viewing systems, the contact lens system and the non-contact lens systems, each of which has advantages and disad-vantages. Non-contact wide-angle viewing systems are popular, but a disadvantage is corneal surface drying, which results in a blurred fundus view. Surgical assis-tants must periodically irrigate with water to prevent corneal drying. However, water droplets may come into contact with the lens surface, which also reduces the quality of the surgical field view.

We discuss the usefulness of combining a wide-angle viewing system and a contact lens to provide a wider fundus view without the help of a surgical assistant.

II. Wide-Angle Viewing System

A. Contact lens

B. Non-contact systems

1. Binocular indirect ophthalmomicroscope (BIOM)

2. Optical Fiber Free Intravitreal Surgery System (OFFISS)

3. Resight

4. Peyman-Wessels-Landers lens

5. EIBOS

III. Advantages and Disadvantages

A. Contact lens

1. Advantages

a. Wider viewing area

b. No need for corneal irrigation

2. Disadvantages

a. Requires assistant to hold the lens

b. Reverse movement of fundus view at XY movement of microscope

B. Non-contact system

1. Advantages

a. Easy to learn (can rotate eyeball, XY of microscope)

b. No need for assistant

2. Disadvantages

a. Requires corneal irrigation

b. Another foot-switch for focus (BIOM)

c. Slightly smaller viewing area

IV. Area and Quality of Fundus View in Non-Contact System Simulated With a Ray-Tracing Method Using the LeGrand Eye Model

A. Distance between cornea and lens:

A smaller distance between the cornea and lens pro-vides wider fundus view.

B. Lens diameter:

A larger lens diameter provides a wider fundus view.

C. A non-contact wide-angle viewing system alone vs. a combination of non-contact wide-angle viewing system and a contact lens:

A combination of a non-contact wide-angle viewing system and a contact lens provides a wider fundus view than the non-contact wide-angle viewing sys-tem alone.

D. Combination of a non-contact wide-angle viewing system with various contact lenses:

The combination of a non-contact wide-angle view-ing system with a biconcave contact lens provides the widest fundus view, followed by the combina-tion of a non-contact wide-angle viewing system and a plano contact lens, and then the combination of a non-contact wide-angle viewing system and a magnifying (meniscus) contact lens.

E. Thickness of contact lenses:

A thinner contact lens combined with a non-contact wide-angle viewing system provides a wider area of fundus view than a thicker contact lens.

F. Quality of fundus view provided by the combina-tion of a non-contact wide-angle viewing system and various contact lenses:

The combination of a non-contact wide-angle view-ing system and a plano contact lens provides the best quality fundus view, followed by the combina-tion of a non-contact wide-angle viewing system and a magnifying contact lens. The combination of a non-contact wide-angle viewing system and a biconcave lens does not provide a fundus view that is adequate for surgery.

V. Advantages of the Combination of a Non-Contact Wide-Angle Viewing System and a Contact Lens

A. Wider fundus view with this combination

B. No need for an assistant to irrigate the corneal sur-face


C. No blurred fundus view resulting from corneal sur-face drying

D. Better quality of fundus view because of the smooth surface of the contact lenses

E. Easy to switch from a wide-angle view to a magni-fied macular image

VI. Surgical Techniques

A. Phacoemulsification and IOL implantation

B. Secure 3 trocar cannula

C. A lens ring held with a silicone ring bridging 2 can-nulas

D. A magnifying contact lens placed on the cornea

E. A non-contact wide-angle viewing system used to remove the vitreous

F. Removal of the non-contact wide-angle viewing system for fine procedures at the macula through a magnifying contact lens only

VII. Conclusion

The combination of the magnifying contact lens and wide-angle viewing system is useful and may make vit-rectomy safer and more efficient.

References

1. LeGrand Y. Form and Space Vision. Bloomington, IN: Indiana Uni-versity Press, 1967.

2. Spitznas M. A binocular indirect ophthalmomicroscope (BIOM) for non-contact wide-angle vitreous surgery. Graefes Arch Clin Exp Ophthalmol. 1987; 225(1):13-15.

3. Tano Y, Kashiwagi T, Manabe R. Contact lenses for vitrectomy made of a high refractive index material. Ganka Shujutsu (J Jpn Soc Ophthalmic Surg). 1988; 1:161-165.

4. Ohji M, Futamura H, Sanger D, et al. Magnifying prismatic lenses for vitrectomy. Jpn J Ophthalmol. 2001; 45(2):199-201.

5. Horiguchi M, Kojima Y, Shima Y. Removal of lens material dropped into the vitreous cavity during cataract surgery using an optical fiber-free intravitreal surgery system. J Cataract Refract Surg. 2003; 29(7):1256-1259.

6. Landers MB, Peyman GA, Wessels IF, Whalen P, Morales V. A new, non-contact wide field viewing system for vitreous surgery. Am J Ophthalmol. 2003; 136(6):1191-1192.

7. Nakata K, Ohji M, Ikuno Y, et al. Wide-angle viewing lens for vit-rectomy. Am J Ophthalmol. 2004; 137(4):760-762.

8. American Society of Retina Specialists Annual Preferences and Trends Survey, 2009. www.asrs.org; access for members only.

9. Kakinoki M, Hirakata A, Landers MBIII, Ohji M. The new ring holder for Peyman-Wessels-Landers 132D upright vitrectomy lens. Retina 2010; 30(8):1316-1317.

10. Kusaka S, Futamura H. New sutureless contact lens ring system for vitrectomy using cannula system. Retina 2010; 30(8):1318-1319.

http://www.asrs.org


I. Background

A. Dramatic impact of OCT in our clinical understand-ing of vitreoretinal diseases

B. High-resolution anatomic information is a natural complement to the operating room theater.

C. New technology such as spectral domain OCT (SD-OCT) and swept source OCT allow for rapid acqui-sition of images required for intraoperative imaging.

II. Premise for Intraoperative OCT Use

A. Provides unique opportunity to understand patho-physiology of surgical vitreoretinal diseases

B. Allows for understanding the acute impact of surgi-cal maneuvers on the ultrastructure of the eye

C. Provides live feedback to the surgeon

D. Possibly provides guidance for surgical maneuvers and interventions

III. Current Intraoperative OCT Systems

A. Modified table-top systems:

Heidelberg

B. Handheld SD-OCT probes

1. Bioptigen

2. Optovue

C. Microscope-mounted probes:

Bioptigen

D. Microscope integrated systems

1. Duke University integrated prototype

2. Carl Zeiss Meditec prototype

3. OptoMedical prototype

IV. Clinical Findings

A. Macular hole

1. Hole architecture dynamics

2. Internal limiting membrane (ILM) peeling

3. Subretinal fluid cuff

4. Outer retinal hyporeflectivity

B. Epiretinal membrane (ERM)

1. ERM/ILM peeling

2. Residual membrane

3. Outer retinal hyporeflectivity

C. Vitreomacular traction

1. Posterior hyaloidal anatomy

2. Architectural changes following hyaloidal eleva-tion

D. Optic pit–related maculopathy

1. Rapid anatomic changes associated with fluid aspiration

2. Suggested connection of schisis with vitreous cavity

E. Rhegmatogenous retinal detachment:

Persistent subclinical subretinal fluid

F. Diabetic tractional detachment:

Identifying tissue planes, residual membranes, and complete membrane peeling

V. Transitioning to Real-Time Intraoperative OCT

A. Limitations of nonintegrated systems

1. Halting surgical procedure

2. Time required for imaging

3. Inability to image actual surgical maneuvers

B. Software processing and enhancements

1. Visualizing intraoperative motion

2. Targeting of OCT scan based on instrumentation location

C. Instrumentation modifications

1. OCT characteristics of current surgical instru-mentation

a. Metallic instruments

b. Silicone instruments

2. OCT-compatible instrument prototypes

VI. Future Needs

A. Integrated heads-up display system

B. Continued refinement of instrumentation

C. Improved acquisition time and scan targeting

D. Real-time presentation of surgeon critical data

Selected Readings

1. Ehlers J, Tao Y, Farsiu S, Maldonado R, Izatt J, Toth C. Integration of a spectral domain optical coherence tomography system into a surgical microscope for intraoperative imaging. Invest Ophthalmol Vis Sci. Epub before print 31 Jan 2011.

2. Ray R, Baranaro D, Fortun J, et al. Intraoperative microscope mounted spectral domain optical coherence tomography for evalua-tion of retinal anatomy during macular surgery. Ophthalmology. In press.

Intraoperative Integration of OCTJustis P Ehlers MD, Sunil K Srivastava MD, and Cynthia A Toth MD


3. Ehlers J, Kernstine K, Farsiu S, Sarin N, Maldonado R, Toth C. Analysis of pars plana vitrectomy for optic pit-related maculopathy with intraoperative optical coherence tomography: a possible con-nection with the vitreous cavity. Arch Ophthalmol. In press.

4. Tao Y, Ehlers J, Toth C, Izatt J. Intraoperative spectral domain optical coherence tomography for vitreoretinal surgery. Opt Lett. 2010; 35:3315-3317.

5. Dayani PN, Maldonado R, Farsiu S, Toth CA. Intraoperative use of handheld spectral domain optical coherence tomography imaging in macular surgery. Retina 2009; 29:1457-1468.

6. Hahn P, Migacz J, Tao YK, Ehlers JP, Izatt JA, Toth CA. Real time cross-sectional intra-surgical imaging of retinal structures using a microscope-mounted OCT system. Program and abstracts of the Association for Research in Vision and Ophthalmology (ARVO) 2011; Abstract #1248.

7. Binder S, Falkner-Radler CI, Hauger C, Phd HM, Glittenberg C. Feasibility of intrasurgical spectral-domain optical coherence tomography. Retina. Epub ahead of print 26 Jan 2011.

8. Scott AW, Farsiu S, Enyedi LB, Wallace DK, Toth CA. Imaging the infant retina with a hand-held spectral-domain optical coherence tomography device. Am J Ophthalmol. 2009; 147:364-373 e2.

9. 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.

10. Wykoff CC, Berrocal AM, Schefler AC, Uhlhorn SR, Ruggeri M, Hess D. Intraoperative OCT of a full-thickness macular hole before and after internal limiting membrane peeling. Ophthalmic Surg Lasers Imaging. 2010; 41(1):7-11.

11. Knecht PB, Kaufmann C, Menke MN, Watson SL, Bosch MM. Use of intraoperative Fourier-domain anterior segment optical coher-ence tomography during Descemet stripping endothelial kerato-plasty. Am J Ophthalmol. 2010; 150(3):360-365.e2.


I. Introduction of Microincision Vitrectomy Surgery (MIVS)

As the transconjunctival MIVS have evolved and become more popular, specific benefits and drawbacks of MIVS have been proved.

A. Advantages of transconjunctival approach

1. Conjunctiva preservation

2. Wound self-sealing, sutureless

3. Patient comfort

4. Less corneal topographic change

5. Potentially rapid visual recovery

6. Reduced operating time

B. Current size of choice

1. 25-gauge1,2

2. 23-gauge3

3. Hybrid

C. Possible disadvantages with the first-generation lineup

1. Fragility of the small-gauge instruments

2. Reduced cutting and flow efficiency

3. Insufficient illumination brightness

4. Complex techniques need for self-sealing wound construction

D. Theoretical concerns and complications

1. Wound leakage

2. Hypotony

3. Choroidal detachment

4. Endophthalmitis

a. High-incidence (> 0.1%) in the early days4,5

b. Much lower-incidence (0~0.08%) reported in the latest studies6-10

II. Changes in Recent MIVS Trends

Increasing use of 25-gauge system rather than 23-gauge system in Japan11

A. 2007: 25-gauge (20%) vs. 23-gauge (18%) vs. 20-gauge (62%)

B. 2009: 20% vs. 40% vs. 40%

C. 2011: 45% vs. 40% vs. 15%

III. Factors in the Increasing Use of 25-gauge Instrumenta-tion

A. Improvement of the instrument rigidity (eg, 25-gauge Plus series from Alcon Laboratories)

B. Much preferable use of wide-angle viewing (WAV) systems (BIOM, Resight, ClariVit lens)

C. Powerful illumination light source with wide-angle illuminating fibers (eg, xenon, mercury vapor light source)

D. New generation vitrectomy machines

1. Ultrahigh speed cutting

2. Duty-cycle control

E. Surgical adjuncts combined with vitrectomy

1. Chromo-vitrectomy (eg, indocyanine green, try-pan blue, brilliant blue G)

2. Pharmaco-therapy-assisted vitrectomy (eg, beva-cizumab, triamcinolone)

3. Chemical vitrectomy: enzymatic vitreolysis (eg, microplasmin)

IV. Rationale of Developing 27-gauge System

A. Dissatisfaction with current 23- and 25-gauge sys-tems

1. The larger the wound, the more the likelihood that wound-sealing related complications (eg, hypotony, choroidal detachment, endophthalmi-tis) will, theoretically, occur.12

2. Complex techniques need self-sealing wound construction.

3. Suture placement to at least one of the scleroto-mies is sometimes needed despite completing angled insertion of the cannulas13,14 (PAT survey 2009, 2010).

B. With recent evolution in instrumentation and vitrectomy machines, it is inevitable that technol-ogy would be pushed further to allow use of even smaller systems because we have known “much smaller would be much better.”

C. We have known that 27-gauge would be the maxi-mum size for self-sealing of the sclera wound with simple insertion technique, because we have used the 27-gauge needle in postoperative management such as fluid-air or fluid-fluid exchanges in vitrecto-mized eyes without encountering any wound-sealing related complications.

D. When it is actually possible to perform transcon-junctival MIVS with 23-, 25- and 27-gauge instru-mentation, is there any rationale to still choose a larger one?

Update on 27-gauge Vitrectomy: Current Indications and Surgical OutcomesYusuke Oshima MD


V. Current Lineup of 27-gauge Systems and Instruments

A. 27-gauge disposable vitrectomy kit (Dutch Ophthal-mic Research Center)

1. 27-gauge high-speed vitrectome (2500 cpm)

2. 27-gauge total view light pipe

3. 27-gauge Eckardt type forceps

4. 27-gauge 1-step entry trocar-cannula set

5. 27-gauge infusion line

B. Illumination

1. 27-gauge standard chandelier fiber (Syner get-ics)15

2. 27/29-gauge 1-step entry chandelier fiber (Syner-getics)16

3. 27-gauge twin-light chandelier (Dutch Ophthal-mic Research Center)17

4. 27/29-gauge 1-step entry short shaft light pipe (Synergetics)

5. 29/30-gauge dual chandelier fiber illumination system (Synergetics)18

C. Microforceps

1. Eckardt; long/short (Dutch Ophthalmic Research Center)

2. Asymmetric, endo-gripping (ASICO)

3. Asymmetric (Synergetics)19

D. Membrane pick (Dutch Ophthalmic Research Cen-ter & ASICO)

E. Diathermy (Dutch Ophthalmic Research Center)

F. Endo-laser probe

1. Curved-laser probe (Dutch Ophthalmic Research Center)

2. Straight/curved laser probe (Synergetics)

G. Back-flush needle (MedOne: prototype)

H. Lancet-tipped, short shaft vitrectome for vitreous biopsy20

VI. Indications Update

A. Macular diseases

1. Macular hole (MH)

2. Epiretinal membrane proliferation (ERM), including nonvitrectomizing ERM removal19

3. Macular edema

4. Macular traction syndrome (MTS)

5. Subhyaloid and/or sub-internal limiting mem-brane hemorrhage

6. Subretinal hemorrhage

B. Nonclearing vitreous hemorrhage (VH)

C. Floaters / vitreous opacity / vitreous biopsy

D. Complex diabetic retinopathy complications (newly updated indication)

1. Traction retinal detachment (TRD)

2. Neovascular glaucoma

E. Primary retinal detachment (newly updated indica-tion)

F. Management of cataract surgery complications without dislocated lens fragments

VII. Surgical Outcomes of the Pilot Study21

A. Retrospective study including 31 eyes (31 patients: m/f, 17/14)

B. Mean age: 62.9 ± 8.3 years (range: 40–84 years)

C. Follow-up: 6.9 ± 3.5 months (range: 3-20 months)

D. Indications: ERM (10), MH (7), VH (5), Biopsy (4), TRD (3), MTS (1), macular edema (1)

E. Mean operating time: 34.3 ± 18.8 minutes (range: 10-88 minutes)

F. Instrument conversion: 0%

G. Suture placement to at least 1 sclerotomy: 0%

H. Gas filled eyes: 11 (35%)

I. Anatomic success: 100%

J. IOP

1. Preoperative, 14.6 ± 3.0 mmHg (range: 10-19 mmHg)

2. Postoperative day 1, 14.7 ± 5.1 mmHg (range: 9-31 mmHg)

3. 1 week after surgery, 14.7 ± 5.1 mmHg (range: 9-31 mmHg)

4. Final visit, 13.8 ± 2.4 mmHg (range: 9-19 mmHg)

K. Visual outcomes: Overall favorable

At the last follow-up visit, the mean VA significantly improved to 0.62 (range: 0.1–1.2; P < .001). Twenty eyes (65%) achieved visual recovery exceeding 0.3 logarithm of minimal angle of resolution unit.

VIII. Surgical Results of 27-gauge Vitrectomy for Treating Diabetic TRD

A. Retrospective study including 42 eyes (40 patients: m/f, 17/23)

B. Mean age: 58.9 ± 7.3 years (range: 38-81 years)

C. Follow-up: 11.3 ± 4.5 months (range: 6-19 months)

D. Surgical systems: All surgeries were conducted by 27-gauge vitrectomy with chandelier illumination and WAV system.

E. Instrument conversion: 0%

F. Suture placement to at least 1 sclerotomy: 3/126 (2.4%)

G. Anatomic success: primary 93%, final 100%


H. Results in detail will be presented in the congress (unpublished data)

IX. Surgical Video Demonstration

X. Conclusions and Perspectives21,22

The transconjunctival sutureless 27-gauge system is fea-sible and may reduce concerns about wound-sealing-related complications sometimes observed with 23- and 25-gauge systems. The size of 27-gauge can simplify the technique for creating self-sealing wounds. Cur-rently, macular surgery and diabetic vitrectomy may be the niche areas in which this technology will be most helpful. However, the current cutting efficiency and rigidity of the 27-gauge system have not yet reached levels enabling surgeons to use this this system for every case. This will take a longer time, particularly for vitrectomy in primary retinal detachment cases. How-ever, these drawbacks will be resolved in the very near future with the next-generation vitrectomy machines. It is important to remember that this is first-generation equipment, just becoming commercially available. As with the development of 25-gauge systems during the past several years, continuous renovation with the feed-back of surgeon experience with the 27-gauge system will extend the widespread use of this system to the full spectrum of vitreoretinal diseases in the future.

References

1. Fujii GY, De Juan E Jr, Humayun MS, et al. A new 25-gauge instru-ment system for transconjunctival sutureless vitrectomy surgery. Ophthalmology 2002; 109:1807-1812.

2. Lakhanpal RR, Humayun MS, de Juan E Jr, et al. Outcomes of 140 consecutive cases of 25-gauge transconjunctival surgery for poste-rior disease. Ophthalmology 2005; 112:817-824.

3. Eckardt C. Transconjunctival sutureless 23-gauge vitrectomy. Retina 2005; 25:208-211.

4. Kunimoto DY, Kaiser RS; Wills Eye Retina Service. Incidence of endophthalmitis after 20- and 25-gauge vitrectomy. Ophthalmol-ogy 2007; 114:2133-2137.

5. Scott IU, Flynn HW Jr, Dev S, et al. Endophthalmitis after 25-gauge and 20-gauge pars plana vitrectomy: incidence and outcomes. Retina 2008; 28:138-142.

6. Shimada H, Nakashizuka H, Hattori T, Mori R, Mizutani Y, Yuzawa M. Incidence of endophthalmitis after 20- and 25-gauge vitrectomy causes and prevention. Ophthalmology 2008; 115:2215-2220.

7. Hu AY, Bourges JL, Shah SP, et al. Endophthalmitis after pars plana vitrectomy: a 20- and 25-gauge comparison. Ophthalmology 2009; 116:1360-1365.

8. Oshima Y, Kadonosono K, Yamaji H, et al; Japan Microinci-sion Vitrectomy Surgery Study Group. Multicenter survey with a systematic overview of acute-onset endophthalmitis after trans-conjunctival microincision vitrectomy surgery. Am J Ophthalmol. 2010; 150:716-725.

9. Scott IU, Flynn HW Jr, Acar N, et al. Incidence of endophthalmitis after 20-gauge vs 23-gauge vs 25-gauge pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol. 2011; 249:377-380.

10. Wu L, Berrocal MH, Arévalo JF, et al. Endophthalmitis after pars plana vitrectomy: results of the Pan American Collaborative Retina Study Group. Retina. Epub ahead of print 9 Mar 2011.

11. Oshima Y, Ohji M. Microincision vitrectomy surgery in Japan. Retina Today 2008: 3:34-38.

12. Bamonte G, Mura M, Stevie Tan H. Hypotony after 25-gauge vit-rectomy. Am J Ophthalmol. 2011; 151:156-160.

13. Bourla DH, Bor E, Axer-Siegel R, Mimouni K, Weinberger D. Out-comes and complications of rhegmatogenous retinal detachment repair with selective sutureless 25-gauge pars plana vitrectomy. Am J Ophthalmol. 2010; 149:630-634.

14. Oshima Y, Ohji M, Tano Y. Surgical outcomes of 25-gauge trans-conjunctival vitrectomy combined with cataract surgery for vitreo-retinal diseases. Ann Acad Med Singapore. 2006; 35:175-180.

15. Oshima Y, Awh CC, Tano Y. Self-retaining 27-gauge transconjunc-tival chandelier endoillumination for panoramic viewing during vitreous surgery. Am J Ophthalmol. 2007; 143:166-167.

16. Oshima Y, Chow DR, Awh CC, et al. Novel mercury vapor illumi-nator combined with a 27/29-gauge chandelier light fiber for vitre-ous surgery. Retina 2008; 28:171-173.

17. Eckardt C, Eckert T, Eckardt U. 27-gauge Twinlight chandelier illu-mination system for bimanual transconjunctival vitrectomy. Retina 2008; 28:518-519.

18. Sakaguchi H, Oshima Y, Nishida K, Awh C. A 29/30-gauge dual chandelier illumination system for panoramic viewing during microincision vitrectomy surgery. Retina 2011; 31:1231-1233.

19. Sakaguchi H, Oshima Y, Tano Y. 27-gauge transconjunctival non-vitrectomizing vitreous surgery for epiretinal membrane removal. Retina 2007; 27:1131-1132.

20. Oshima Y, Wakabayashi T, Ohguro N, Nishida K. A 27-gauge sharp-tip short-shaft pneumatic vitreous cutter for transconjuncti-val sutureless vitreous biopsy. Retina 2011; 31:419-421.

21. Oshima Y, Wakabayashi T, Sato T, Ohji M, Tano Y. A 27-gauge instrument system for transconjunctival sutureless microincision vitrectomy surgery. Ophthalmology 2010; 117:93-102.

22. Riemann CD. Initial impression with 27-gauge vitrectomy. Retina Today. 2011; 6:85-87.


Vitreoretinal Surgical Instrumentation UpdateDavid R Chow MD

N O T e S


I. Background

Eyes that require a secondary IOL but have insufficient capsular support present a unique surgical challenge. A host of surgical approaches to these eyes exist. Each approach has potential and distinct disadvantages.1-10

A. Anterior chamber IOL: Corneal decompensation

B. Sutured iris fixation of a posterior chamber IOL (PCIOL): Cystoid macular edema, iris chafing, lens decentration and/or dislocation, suture rupture, lens dislocation

C. Sutured scleral fixation of a PCIOL: Vitreous hem-orrhage, suture erosion, suture knot exposure, lens decentration and/or dislocation

D. Scleral fixation of a PCIOL with glue: Cost, techni-cal challenges

II. Sutureless Sulcus Fixation

A new approach to this surgical challenge has been recently described for the anterior segment surgeon.11,12 This technique can be modified for the vitreoretinal surgeon to allow for simple, efficient, and stable sec-ondary IOL placement without the need for sutures.

III. The Technique

Sutureless sulcus fixation (SSF) of a PCIOL using per-manent incarceration of IOL haptics using intrascleral tunnels

A. SSF advantages

1. Stabilizes the IOL in the posterior segment with-out more technically demanding suturing tech-niques

2. Torsion and decentration is minimized by accu-rate placement of the haptics in scleral tunnels.

3. Haptic incarceration in the sclera secures the axial position of the IOL and decreases the inci-dence of tilt.

B. Technical steps to perform SSF

1. Conjunctival peritomy for 9 temporal clock hours

2. Diathermy (minimal) placed at 6 and 12 o’clock. Episcleral vessels may be important for scleral health and wound healing.

3. Trocars for a three-port 23-gauge or 25-gauge vitrectomy are placed. Vitrectomy and intra-ocular maneuvers performed as required per the particular case.

4. Ciliary sulcus-based sclerotomies are created.

a. 20-gauge MVR blade is used to create a scle-rotomy 2 mm from the limbus exactly at 6 o’clock.

The large gauge sclerotomy is critical to allow for efficient haptic externalization and intra-ocular manipulation.

b. A second, 20-gauge sclerotomy is created 2 mm from the limbus exactly 180 degrees away at 12 o’clock.

5. Scleral tunnels are created.

a. A 23-gauge trocar blade is used to create a straight scleral tunnel exactly parallel to the surgical limbus at a depth approximately 50% of the scleral thickness.

b. The blade is always passed from the temporal side heading nasally to allow for adequate hand position and flattening of the 23-gauge blade.

c. Tunnels should be 2-3 mm long and must connect into the lateral aspect of the 20-gauge ciliary sulcus-based sclerotomy.

d. The hub of the 23-gauge blade should be passed out of the distal side of the tunnel to ensure that whole length of the tunnel is widely dilated.

6. Placement of a PCIOL in aphakic patients

a. A 25-gauge disposable forceps is bent in the middle of the shaft at a 40-degree angle to maximize the angle best suited for haptic externalization.

b. A clear corneal incision is made at 12 o’clock, followed by placement of viscoelastic into the anterior chamber.

c. The infusion is turned down to 10, and a foldable 3-piece IOL is passed through the clear cornea, with attention paid to directing the inferior haptic under the inferior iris.

d. The 25-gauge forceps is then placed through the inferior 20-gauge sclerotomy and used to externalize the leading haptic.

The tip of the haptic does not need to be grasped (technically difficult at times), as the size of the 20-gauge sclerotomy allows for the haptic to bend without breaking during hap-tic externalization, even when grasped in the middle of the haptic.

e. The externalized inferior haptic is then drawn inferiorly so that the IOL is brought into the posterior chamber.

Vitrectomy With IOL FixationJonathan Prenner MD


f. The bent 25-gauge forceps is then used through the superior 20-gauge sclerotomy to externalize the superior haptic, which can be grasped as posterior as the haptic optic junc-tion initially.

Bimanual manipulation can be used to sim-plify externalization of the trailing haptic.

g. The haptics are externally manipulated to achieve optic centration.

h. The 23-gauge scleral tunnels are redilated with the 25-gauge forceps.

i. The 25-gauge forceps is used to guide the inferior then superior haptic into the respec-tive tunnel.

Haptics are either pushed or pulled into the tunnel.

j. Final position of the optic is achieved via hap-tic manipulation.

k. Sclerotomy wounds are checked for leakage and sutured as per surgeon tolerance.

l. Conjunctiva is closed.

7. Repositioning of a PCIOL

a. The malpositioned IOL is prepared for SSF by freeing up the haptics from capsular material:

i. Posteriorly dislocated lenses that are in the bag complex can be freed with the vitrec-tor or forceps.

ii. Subluxed IOLs can be left in the sulcus position. Capsulectomy should be large enough to allow for manipulation without engaging capsular material and or anterior vitreous.

b. A 25-gauge disposable forceps is bent at a 40-degree angle to maximize the angle best suited for haptic externalization.

c. The 25-gauge forceps is then placed through the inferior 20-gauge sclerotomy and used to externalize the leading haptic.

The tip of the haptic does not need to be grasped (technically difficult at times), as the size of the 20-gauge sclerotomy allows for the haptic to bend without breaking during hap-tic externalization, even when grasped in the middle of the haptic.

d. The externalized inferior haptic is then drawn inferiorly so that the IOL is brought into the posterior chamber.

e. The bent 25-gauge forceps is then used through the superior 20-gauge sclerotomy to externalize the superior haptic, which can be grasped as posterior as the haptic optic junc-tion initially.

Bimanual manipulation can be used to sim-plify externalization of the trailing haptic.

f. The haptics are externally manipulated to achieve optic centration.

g. The 23-gauge scleral tunnels are redilated with the 25-gauge forceps.

h. The 25-gauge forceps is used to guide the inferior then superior haptic into the respec-tive tunnel.

Haptics are either pushed or pulled into the tunnel.

i. Final position of the optic is achieved via hap-tic manipulation.

j. Sclerotomy wounds are checked for leakage and sutured as per surgeon tolerance.

k. Conjunctiva is closed.

References

1. Bloom SM, Wyszynski RE, Brucker AJ. Scleral fixation suture for dislocated posterior chamber intraocular lens. Ophthalmic Surg. 1990; 21:851-854.

2. Chan CK. An improved technique for management of dislocated posterior chamber implants. Ophthalmology 1992; 99:51-57.

3. Chang S, Coll GE. Surgical techniques for repositioning a dislocated intraocular lens, repair of iridodialysis, and secondary intraocular lens implantation using innovative 25-gauge forceps. Am J Oph-thalmol. 1995; 119:165-174.

4. Kokame GT, Yamamoto I, Mandel H. Scleral fixation of dislocated posterior chamber intraocular lenses: temporary haptic externaliza-tion through a clear corneal incision. J Cataract Refract Surg. 2004; 30:1049-1056.

5. Maguire AM, Blumenkranz MS, Ward TG, Winkelman JZ. Scleral loop fixation for posteriorly dislocated intraocular lenses: opera-tive technique and long-term results. Arch Ophthalmol. 1991; 109:1754-1758.

6. Smiddy WE, Ibanez GV, Alfonso E, Flynn HW Jr. Surgical manage-ment of dislocated intraocular lenses. J Cataract Refract Surg. 1995; 21:64-69.

7. Thach AB, Dugel PU, Sipperley JO, et al. Outcome of sulcus fixa-tion of dislocated posterior chamber intraocular lenses using tempo-rary externalization of the haptics. Ophthalmology 2000; 107:480-484; discussion by WF Mieler, 2000; 107:485.

8. Por YM, Lavin MJ. Techniques of intraocular lens suspension in the absence of capsular/zonular support. Surv Ophthalmol. 2005; 50:429-462.

9. Wagoner MD, Cox TA, Ariyasu RG, et al. Intraocular lens implan-tation in the absence of capsular support: a report by the American Academy of Ophthalmology (Ophthalmic Technology Assessment). Ophthalmology 2003; 110:840-859.

10. Agarwal A, Kumar DA, Jacob S, et al. Fibrin glue-assisted sutureless posterior chamber intraocular lens implantation in eyes with defi-cient posterior capsules. J Cataract Refract Surg. 2008; 34:1433-1438.

11. Gabor SG, Pavlidis MM. Sutureless intrascleral posterior chamber intraocular lens fixation. J Cataract Refract Surg. 2007; 33:1851-1854.

12. Gabor BS, Prasad S, Georgalas I, et al. Intermediate results of sutureless intrascleral posterior chamber intraocular lens fixation. J Cataract Refract Surg. 2010; 36:254-259.


Introduction

The application of vital dyes to visualize transparent target struc-tures such as the internal limiting membrane (ILM), epimacular membranes, or vitreous has become very popular among vit-reoretinal surgeons. Several dyes are in clinical use and can be applied to selectively visualize the target structure (see Table 1). The dyes are injected into either the fluid-filled or the air-filled globe, and different concentrations are used.

Selective Vital Dyes

Epimacular membranes can be stained using the anionic disazo dye trypan blue,1,2 which is commercially available in a concen-tration of 0.15% for that purpose. The contrast at the level of the ILM using trypan blue is quite poor. Two other dye classes are currently predominantly used for ILM peeling: the cyanine dye indocyanine green (ICG) and the triarylmethane dye bril-liant blue G (BBG). Using these dyes variable staining techniques, including double or even triple staining, can be performed.

Due to tissue-dye interactions and alterations of its collagen structure,3 the stained ILM can be peeled off more easily and (postulating that the dye used provides a high biocompatibil-ity) with less damage to underlying retinal structures such as the nerve fibres and Müller cell endfeet. Both dyes selectively stain the ILM,4,5 although the staining effect seen after ICG use appears more pronounced compared to BBG.6 In contrast to the good biocompatibility of BBG,7,8 ICG has revealed toxic effects in some studies, which underline the narrow safety margin of this dye.9-12 In addition, ICG does not appear to be an ideal candidate for ILM staining, as its maximum absorption is in the near infrared (NIR) and not within the spectral sensitivity of the human eye (see Figure 1),13 meaning that the majority of light absorption of ICG is useless or of low value during vitreoretinal surgery because it is in the invisible NIR and in the bathochromic region of the visible spectrum. As a consequence, relatively high dye concentrations are required to achieve a sufficient contrast on the vitreoretinal interface. In addition, the absorption spec-

trum of ICG overlaps with different types of illumination, posing the risk of phototoxicity to the retina.14,15

Figure 1. First line from left: spectral sensitivity of the eye; center line: aggregated ICG; right line: ICG in solution. Note that the maximum absorption of ICG is in the NIR.

Therefore, it seems that an ideal candidate dye would be a dye incorporating the excellent contrast provided by ICG and the high biocompatibility of brilliant blue (ie, strongly absorbing at visible wavelengths, conveniently tissue binding, nontoxic, and physiologically degradable at a practical time scale). This may be reached by altering the molecular structure of ICG and thereby changing the absorption qualities and the affinity of the dye mol-ecule (see Figure 2).

Staining Internal Limiting Membrane and epiretinal MembranesChristos Haritoglou MD

Table 1.

Dye

epimacular Membrane

ILM

Vitreous

Applicationa

Comments

Indocyanine green (0.5%) --- Selective +++ --- Usually fluid-filled globe Question of toxicity, off-label

Brilliant blue (0.025%) Selective ++ --- Fluid filled-globe (if heavy BBG is used)

Approved in Europe

Trypan blue (0.15%) +++ (+) (+) Fluid- or air-filled globe Approved in Europe

Triamcinolone --- Nonselective (+) +++ Fluid filled-globe No dye, pharmacological properties

Fluoresceine --- --- + Intravitreal, intravenous, or peroral application

a Surgical techniques may vary depending on individual preference.


Figure 2.

This new molecule provides improved absorption and fluo-rescent qualities, equal staining properties, but a better safety profile16 compared to ICG, as it is adapted to the spectral sen-sitivity of the human eye and to the standard illumination used during surgery. In addition, the contrast is thereby enhanced as it implies both the blue absorption color and an even stronger purple fluorescence color. At present, several other dyes have been subjects of experimental in vivo and ex vivo experiments, including, among others, methyl violet, crystal violet, eosin Y, Sudan black B, methylene blue, toluidine blue, light green, indigo carmine, fast green, congo red, Evans blue, brilliant blue, and bromophenol blue.17-20

References

1. Feron EJ, Veckeneer M, Parys-Van Ginderdeuren R, Van Lommel A, Melles GRJ, Stalmans P. Trypan blue staining of epiretinal mem-branes in proliferative vitreoretinopathy. Arch Ophthalmol. 2002; 120:141-144.

2. Veckeneer M, van Overdam K, Monzer J, et al. Ocular toxicity study of trypan blue injected into the vitreous cavity of rabbit eyes. Graefes Arch Clin Exp Ophthalmol. 2001; 239:698-704.

3. Wollensak G, Spoerl E, Wirbelauer C, Pham DT. Influence of indocyanine green staining on the biochemical strength of porcine internal limiting membrane. Ophthalmologica 2004; 218:278-282.

4. Enaida H, Hisatomi T, Hata Y, et al. Brilliant blue G selectively stains the internal limiting membrane/brilliant blue G-assisted mem-brane peeling. Retina 2006; 26: 631-636.

5. Schumann RG, Gandorfer A, Eibl KH, Henrich PB, Kampik A, Haritoglou C. Sequential epiretinal membrane removal with inter-nal limiting membrane peeling in brilliant blue G-assisted macular surgery. Br J Ophthalmol. Epub ahead of print 2010 July 31.

6. Henrich PB, Priglinger SG, Haritoglou C, et al. Quantification of contrast recognizability during brilliant blue G (BBG) and indocya-nine green (ICG) assisted chromovitrectomy. Invest Ophthalmol Vis Sci. Epub ahead of print 2011 Mar 2.

7. Enaida H, Hisatomi T, Goto Y, et al. Preclinical investigation of internal limiting membrane staining and peeling using intravitreal brilliant blue G. Retina 2006; 26:623-630.

8. Lüke M, Januschowski K, Beutel J, et al. Electrophysiological effects of brilliant blue G in the model of the isolated perfused vertebrate retina. Graefes Arch Clin Exp Ophthalmol. 2008; 246(6):817-822.

9. Tsuiki E, Fujikawa A, Miyamura N, Yamada K, Mishima K, Kitaoka T. Visual field defects after macular hole surgery with indo-cyanine green-assisted internal limiting membrane peeling. Am J Ophthalmol. 2007; 143(4):704-705.

10. Haritoglou C, Gandorfer A, Gass CA, Schaumberger M, Ulbig MW, Kampik A. Indocyanine green-assisted peeling of the internal limiting membrane in macular hole surgery affects visual out-come: a clinicopathologic correlation. Am J Ophthalmol. 2002; 134(6):836-841.

11. Rodrigues EB, Meyer CH. Meta-analysis of chromovitrectomy with indocyanine green in macular hole surgery. Ophthalmologica 2008; 222(2):123-129.

12. Yam HF, Kwok AKH, Chan KP, et al. Effect of indocyanine green and illumination on gene expression in human retinal pigment epi-thelial cells. Invest Ophthalmol Vis Sci. 2003; 44:370-377.

13. Langhals H, Haritoglou C. Chemical and spectroscopic aspects of the application of dyes in vitreoretinal surgery. Ophthalmologe 2009; 106(1):16-20.

14. Yip HK, Lai TY, So KF, Kwok AK. Retinal ganglion cells toxicity caused by photosensitising effects of intravitreal indocyanine green with illumination in rat eyes. Br J Ophthalmol. 2006; 90:99-102.

15. Sato T, Ito M, Ishida M, Karasawa Y. Phototoxicity of indocyanine green under continuous fluorescent lamp illumination and its pre-vention by blocking red light on cultured Müller cells. Invest Oph-thalmol Vis Sci. 2010; 51(8):4337-4345.

16. Langhals H, Varja A Laubichler P, Kernt M, Eibl K, Haritoglou C. Cyanine dyes as optical contrast agents for ophthalmological sur-gery. J Med Chem. Epub ahead of print 2011 April 27.

17. Jackson TL, Griffin L, Vote B, Hillenkamp J, Marshall J. An experi-mental method for testing novel retinal vital stains. Exp Eye Res. 2005; 81(4):446-454.

18. Rodrigues EB, Penha FM, de Paula Fiod Costa E, et al. Ability of new vital dyes to stain intraocular membranes and tissues in ocular surgery. Am J Ophthalmol. 2010; 149(2):265-277.

19. Haritoglou C, Strauss R, Priglinger SG, Kreutzer T, Kampik A. Delineation of the vitreous and posterior hyaloid using bromophe-nol blue. Retina 2008; 28:333-340.

20. Haritoglou C, Priglinger SG, Eibl K, et al. Experimental evaluation of aniline and methyl blue for intraocular surgery. Retina 2009; 29:166-173.

2011 Subspecialty Day | Retina The Schepens Lecture 15

Introduction

The surgical management of vitreoretinal interface disorders such as macular hole, macular pucker, vitreomacular traction syndrome, and macular edema has been facilitated by better visu-alization using dyes or other highlighting agents.1 After a core vitrectomy, materials such as triamcinolone (TA), indocyanine green (ICG), trypan blue (TB), or brilliant blue (BBG) are applied to allow better visualization of epiretinal membranes and adher-ent vitreous followed by a separate removal of the internal limit-ing membrane (ILM) of the retina. In cases of macular hole, the removal of ILM appears to reduce the incidence of late reopening of the macular hole. Surgeons who argue against the need for peeling ILM argue that visual outcomes may be better when ILM is not peeled. With macular pucker surgery, specimens of surgi-cally removed epiretinal membranes often demonstrate portions of ILM that accompany the pucker. Yet there is increasing use of stains such as ICG or BBG to identify and peel ILM after peeling of the epiretinal membrane. It has been argued that the recur-rence rate of macular pucker is reduced by “double peeling.” The visual outcomes of such double peeling technique have not been compared to cases done when only the epiretinal membrane has been peeled. We designed a study to compare visual outcomes of eyes with macular pucker using the double peeling technique with a series where only triamcinolone was used to visualize the epiretinal membrane.

Methods

A consecutive series of 40 eyes undergoing vitrectomy for pri-mary macular pucker using TA suspension were retrospectively compared to a similar consecutive series of 40 eyes in which TA was first applied followed by the use of BBG to stain and remove residual ILM. In all cases small-incision vitrectomy was used (23-gauge), with air tamponade. Eyes in which the visual outcome would be compromised by other ocular disorders such as mac-ula-off retinal detachment, advanced glaucoma, or proliferative diabetic retinopathy were excluded. Spectral domain OCT (SD-OCT) was done preoperatively (Cirrus-Zeiss), approximately 1 month postoperatively, and at regular intervals thereafter. The OCTs done at 1 month postoperatively were compared to the preoperative OCT to visualize any residual epiretinal membrane or ILM within the central 3 mm of the scan or in the outer zone of the macula. Retinal thickness and visual acuity at 3 months postoperatively were compared in the two groups of eyes. Cur-rently the study is still in progress, but results will be available by the time of this lecture.

Discussion

The necessity for peeling ILM for macular pucker remains some-what controversial. It has been demonstrated that following peel-ing of ILM in macular pucker, the multifocal ERG amplitudes decreased in areas surrounding the macula despite the improve-ment of visual acuity.2 The specimens removed from 4 eyes demonstrated foot plates of Müller cells on the retinal side of the ILM. Other histological studies of the ILM specimens removed from macular hole show that Müller cell fragments are present with the ILM in up to 63% of eyes.3 The rate or recurrence of epiretinal membranes postoperatively has been reported as 21% in eyes that did not undergo additional surgery.4 In previous studies the visual outcomes comparing eyes with ILM to those with no peeling are similar.5,6 What is the impact of ILM peeling on the retina, and are we able to identify the any effects on visual acuity that might be affected by ILM peeling? Future long-term prospective studies may be needed to answer these issues to help determine the need for and the extent of ILM peeling that is nec-essary.

References

1. Rodrigues EB, Costa EF, Penha FM, et al. The use of vital dyes in ocular surgery. Surv Ophthalmol. 2009; 54:576-617.

2. Tari S, Vidne-Hay O, Greenstein VC, Barile GR, Hood DC, Chang S. Functional and structural measurements for the assessment of internal limiting membrane peeling in idiopathic macular pucker. Retina 2007; 27:567-572.

3. Konstantinidis L, Uffer S, Bovey EH. Ultrastructural changes of the internal limiting membrane during indocyanine green assisted peel-ing versus conventional surgery for idiopathic macular epiretinal membrane. Retina 2009; 29:380-386.

4. Park DW, Dugel PU, Garda J, et al. Macular pucker with and with-out internal limiting peeling: pilot study. Ophthalmology 2003; 110:62-64.

5. Lee JW, Kim IT. Outcomes of idiopathic macular epiretinal mem-brane removal with and without internal limiting membrane peel-ing: a comparative study. Jpn J Ophthalmol. 2010; 54:129-134.

6. Shimada H, Nakashizuka H, Hattori T, Mori R, Mizutani Y, Yuzawa M. Double staining with brilliant blue G and double peel-ing for epiretinal membranes. Ophthalmology 2009; 116:1370-1376.

Is Double Peeling Necessary in Surgery for Macular Pucker?Stanley Chang MD

16 Section II: Neovascular AMD 2011 Subspecialty Day | Retina

Background

The gold standard for demonstrating that a treatment is effec-tive is to perform a randomized clinical trial of a new treatment vs. a standard therapy or placebo. When a proven therapy exists it usually precludes using a placebo as the comparison group. Consider the case of testing a new antibiotic for pneumonia. Certainly one could not randomize patients with pneumonia to the new antibiotic vs. placebo; the control group would have to be “standard care.” A clinical trial to demonstrate that the new treatment was better than “standard care” (superiority trial) would be easy to design, but the results of such a trial could be difficult to interpret. Suppose the new antibiotic was not superior to the standard antibiotic. This would not mean that it is not an effective treatment. A treatment that was equal to the stan-dard treatment, or perhaps even somewhat less effective, might still be considered very useful because it had a better side effect profile, provided choices when the standard failed, was easier to administer, or was less expensive. However, because of random variation it is virtually impossible to show statistically that two treatments are exactly equal.

To address the need for developing new treatments that are equivalent to standard treatment the “equivalence” or “non-inferiority” clinical designs evolved.1 In this design, one chooses the degree to which the new treatment could be worse than the standard treatment and still thought to be clinically acceptable. This “non-inferiority margin” may be based on the magnitude of the treatment effect of standard care relative to no treatment or on an empirically chosen degree of difference from standard treatment that was considered to be not clinically important. The value of this approach is that it provides a statistical method to demonstrate that the new treatment is equivalent or at least not inferior to the standard treatment. An obvious example of a suc-cessful non-inferiority trial is the recently reported Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study.2

Results from CATT demonstrate both how useful this study approach can be and demonstrate some of the difficulties inher-ent in this design. The CATT research group chose a non-inferi-ority margin of a mean difference between treatment groups of 5 letters. They had 6 different treatment differences to compare, so they used confidence intervals around each mean difference of 99.2%.

The Good

Two of the major comparisons of the CATT study demon-strate the value of the non-inferiority study design. This first is the comparison of Avastin with Lucentis, when either is used monthly or p.r.n. As seen in Figure 1, the confidence interval for the difference in mean visual acuity in letters does not overlap the -5 letter non-inferiority margin for either monthly treatment or p.r.n. treatment. Therefore Avastin is identified as non-inferior to Lucentis, and because the confidence interval also does not overlap the +5 letter non-inferiority margin it could also be con-

sidered equivalent, based on the non-inferiority margins chosen in advance by the investigators.

Figure 1.

Figure 2.

The Bad

CATT also demonstrates one of the less desirable outcomes of using the non-inferiority study design. When evaluating whether p.r.n. treatment was equivalent to monthly treatment, the study results were mixed. Lucentis monthly vs. Lucentis p.r.n. resulted in a confidence interval of the mean difference that did not cross the non-inferiority margin, and therefore Lucentis p.r.n. could be considered non-inferior to Lucentis monthly. However, when comparing Avastin p.r.n. with Avastin monthly, the lower bound of the confidence interval of the mean difference did cross the -5 letter inferiority margin. Because the confidence interval also crossed zero difference, we are left in the unfortunate situation

Interpreting Non-inferiority Studies: The Good, the Bad, and the UglyFrederick L Ferris III MD

2011 Subspecialty Day | Retina Section II: Neovascular AMD 17

of being uncertain whether Avastin p.r.n. is worse than Avastin monthly. Based on the confidence interval of the difference, the study results are consistent with Avastin p.r.n. being 5.7 letters worse than Avastin monthly but also consistent with Avastin p.r.n. being 1.6 letters better than Avastin monthly. This means that the study was essentially uninformative as to which dosing regimen was preferable. However, by the study definition one cannot determine that the p.r.n. regimen was non-inferior to the monthly regimen for Avastin.

It is important to note that although Lucentis p.r.n. vs. Lucen-tis monthly met the non-inferiority criterion but Avastin p.r.n. vs. Avastin monthly did not meet the non-inferiority criterion, this does not mean that Lucentis is better than Avastin. The fact that the arbitrary non-inferiority margin was crossed by the Avastin comparison but not the Lucentis comparison does not mean that Lucentis p.r.n. is better than Avastin p.r.n. In this case, the differ-ence is mostly driven by the fact that the confidence interval for the Avastin comparison is broader than the Lucentis comparison. The lower bound of the Avastin comparison is lower than the Lucentis comparison (and happens to go beyond the non-infe-riority limit), while the upper bound of the Avastin comparison is actually higher than the Lucentis comparison, with the mean differences only about a half-letter apart. In total, these analyses leave us uncertain as to whether p.r.n. treatment is non-inferior to monthly treatment.

Figure 3.

The Ugly

The above examples demonstrate how dependent the results of a non-inferiority study are on the width of the confidence interval as well as the actual mean difference between treatment groups. We know that the width of the confidence interval is directly related to the sample size. Clinical trials or observational stud-ies with very large sample sizes can demonstrate statistically significant differences that might be considered meaningless. Although not a primary outcome of the CATT study, the facto-rial study design allows one to compare the two drugs by pooling the treatment techniques (monthly and p.r.n.) and to compare the two treatment techniques by pooling the drugs. Because the treatment effects of the two drugs were so similar and because there is no statistically significant interaction between treatment and treatment technique, such a pooling seems appropriate. In essence this virtually doubles the sample size for the monthly vs.

p.r.n. comparison and results in a narrower confidence interval. In addition, in this analysis one can adjust for known confound-ers, which also can result in further narrowing of the confidence interval.

Figure 4 shows the mean difference between monthly and p.r.n. treatment for all patients in such an adjusted analysis using all the study data (data provided by Maureen Maguire, personal communication). As seen in the figure, there is approximately a 2-letter mean difference between monthly and p.r.n. treat-ment techniques. The 95% confidence interval, which is now considerably narrowed compared to the previous analyses both because as a secondary analysis it is not adjusted for multiple comparisons and because of the pooled data set, lies between the non-inferiority margin and zero. This demonstrates the possibil-ity of reaching the uncomfortable conclusion that can occur in a non-inferiority study. In this case the lower limit of the 95% con-fidence interval did not cross the -5 letter non-inferiority margin, so we can conclude that the treatment was “non-inferior.” How-ever, the upper bound of the confidence interval also did not include zero difference, so we can conclude that p.r.n. treatment was “inferior” to monthly treatment. Being both “non-inferior” and “inferior” seems logically problematic.

Figure 4.

Summary

Because of ethical considerations, non-inferiority trials can be the only reasonable approach to demonstrate the efficacy of a new treatment. When things go well, this study design can be very useful. However, as with superiority trials, one can have results that can be uninformative. There are also situations, particularly when the confidence interval of the difference is smaller than expected, in which one can get into the uncomfortable situation of demonstrating that a treatment is both “non-inferior” and “inferior.” However, to some, this ugly duckling might also be viewed as a lovely swan. If the non-inferiority limit truly repre-sents the margin indicating a clinically meaningful result, there is a reasonable explanation for this apparently illogical conclusion. That is, the result may indicate that the treatment difference is statistically significant (Treatment B is statistically inferior to Treatment A), but that this difference, although statistically sig-nificant, is not clinically meaningful, so Treatment B is non-infe-rior clinically to Treatment A notwithstanding that fact that is it inferior statistically. This of course depends on the interpretation


of what difference is clinically meaningful, and there is often rea-sonable disagreement in the community in this regard.

This underlines the challenge of non-inferiority studies, because there is a certain amount of arbitrariness in defining what is the non-inferiority limit and what sample size is chosen to undertake the study (larger sample sizes decrease the confi-dence intervals, making it more likely to meet the non-inferiority limit). In essence, non-inferiority studies and superiority studies are the same. Groups of patients are randomly assigned to dif-ferent treatments, and one investigates whether there are statisti-cally significant differences between the treatment groups on a predefined and meaningful outcome. Statistical testing allows us to have some estimate of Type I and Type II error. However, from a clinical perspective, the confidence intervals around the difference can be as important as the statistical tests to clinicians as they add the study results to the totality of their clinical infor-mation and decide what treatments to utilize.

References

1. Blackwelder WC. Proving the null hypothesis in clinical trials. Con-trol Clin Trials. 1985; 3:345-353.

2. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011; 364:1897-1908.


Results of the Comparison of AMD Treatment TrialsDaniel F Martin MD

N O T e S


Clinical and Anatomical Response to Anti-VeGF Therapy in the Comparison of AMD Treatment Trial (CATT)Glenn J Jaffe MD

N O T e S


I. Introduction

A. Age-related macular degeneration (AMD) is a lead-ing cause of vision loss and blindness in industrial-ized countries.1

B. Prior to 2000, the only treatment for neovascular AMD was laser ablation to the CNV.2

C. A significant advancement occurred with the find-ing that vascular endothelial growth factor (VEGF), known to promote both vascular growth and per-meability, might be driving the abnormal CNV and retinal edema seen in AMD.3

D. In 2006, two Phase 3 studies (MARINA4 and ANCHOR5) showed that monthly intravitreal injections of 0.3-mg or 0.5-mg ranibizumab not only prevented vision loss in the large majority of patients, but also led to significant visual gain in approximately one-third of patients.

E. To date, the gold standard for wet AMD, based on these studies, is monthly injections with ranibi-zumab.

F. However, because of the social, economic, and quality-of-life burden on the AMD patient popula-tion and their caregivers posed by monthly visits and injections, there remains an unmet need for effective treatment options that allow for decreased frequency of monitoring and/or injections.

G. VEGF Trap-Eye is a soluble decoy receptor fusion protein created using Trap technology.6,7

1. Fusion protein is comprised of key domains from human VEGF receptors 1 and 2 and human IgG Fc.

2. Blocks all VEGF-A isoforms and placental growth factor (PIGF)

3. High affinity: Binds to VEGF-A and PIGF more tightly than native receptors7,8

4. Contains all human amino acid sequences

5. Penetrates all layers of the retina (MW ~ 110,000; unpublished)

6. VEGF Trap-Eye is specially purified and formu-lated for intravitreal injection.

H. The Phase 2 CLEAR-IT 2 trials9,10 demonstrated that VEGF Trap-Eye was efficacious in the treat-ment of wet AMD, with the possibility for less fre-quent intravitreal injections.

II. Methods

A. The largest prospective, controlled Phase 3 program comprised of 2 identical trials of patients with neo-vascular AMD

B. Key inclusion criteria

1. Men and women ≥ 50 years of age

2. Primary active subfoveal and juxtafoveal CNV lesions (juxtafoveal required subfoveal involve-ment with fluid) secondary to AMD

3. ETDRS BCVA of 20/40 to 20/320 in the study eye

4. CNV area ≥ 50% of total lesion

C. Key exclusion criteria

1. Prior ocular (study eye) or systemic treatment or surgery for wet AMD

2. Prior or concomitant therapy with another inves-tigational or anti-VEGF agents

3. Scar, fibrosis, or atrophy involving the center of the fovea

4. Presence of other causes of CNV in the study eye

D. Randomization

1. VIEW 1: 1217 patients in North America

2. VIEW 2: 1240 patients in Europe, Asia, South America, and Australia

3. Patients were randomized in 1:1:1:1 ratio to VEGF Trap-Eye 0.5 mg every month (0.5q4), 2 mg every month (2q4), 2 mg every 2 months following 3 initial monthly doses (2q8), or to 0.5 mg ranibizumab every month (Rq4) (see Fig-ure 1).

Figure 1. VIEW 1 and VIEW 2 study design.

E. Primary endpoint tested using a noninferiority para-digm set with a 10% margin

F. Outcomes

VeGF Trap-eye for AMD: VIeW 1/VIeW 2 StudiesJeffrey S Heier MD


1. Data from the 1-year results were combined into a comprehensive integrated dataset to further analyze the relative efficacy and safety of VEGF Trap-Eye.

2. Primary endpoint: Proportion of patients who maintained visual acuity (lost < 15 letters) at 1 year.

3. Key secondary endpoints: Mean change from baseline in BCVA at Week 52 and proportion of patients who gain ≥ 15 ETDRS letters at Week 52

III. Results

A. Exposure

1. Number of active injections (out of the maxi-mum possible)

a. VIEW 1: 12.1 (13), 12.1 (13), 12.5 (13), and 7.5 (8) for the ranibizumab and 0.5q4, 2q4, and 2q8 VEGF Trap-Eye groups, respectively

b. VIEW 2: 12.7 (13), 12.6 (13), 12.6 (13), and 7.7 (8) for the ranibizumab and 0.5q4, 2q4, and 2q8 VEGF Trap-Eye groups, respectively

B. Efficacy

1. Primary endpoint (proportions of patients main-taining vision at Week 52): All VEGF Trap-Eye groups, including VEGF Trap-Eye dosed 2 mg every 2 months, were noninferior compared with ranibizumab dosed monthly (see Figure 2).

Figure 2. VIEW 1 and 2 integrated: Primary endpoint, maintenance of vision at 1 year.

2. Key secondary endpoint, mean improvement in ETDRS letter score at Week 52: In VIEW 1, the VEGF Trap-Eye 2q4 group was statistically superior to ranibizumab; all other arms were similar to each other. In VIEW 2, all treatment arms were similar to each other (see Figure 3).

Figure 3. VIEW 1, VIEW 2, and integrated: Mean change in visual acuity compared to baseline.

3. Key secondary endpoint, proportions of patients gaining ≥ 15 ETDRS letters from baseline: 32.4%, 33.4%, 29.8%, and 31.0% for the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively, and these results were similar across all treatment groups.

C. Safety (integrated dataset)

1. Incidences of ocular treatment-emergent adverse events (TEAEs) were similar across treatment arms. The most frequent were conjunctival hem-orrhage, eye pain, macular degeneration, retinal hemorrhage, and reduced visual acuity.

2. Proportion of patients with at least 1 serious adverse event (SAE) in the study eye were similar among all treatment groups: 3.2%, 2.1%, 1.8%, and 2.0% for the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively.

3. Proportion of patients with any Antiplatelet Trialists’ Collaboration (APTC) arterial throm-boembolic event were similar among treatment arms: 1.5%, 1.0%, 2.0%, and 2.3% for the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively.

4. No differences were seen in hypertension and serious systemic AEs among treatment groups.

IV. Conclusions

A. All VEGF Trap-Eye groups in both studies, includ-ing 2 mg dosed every 2 months, were noninferior to ranibizumab in the proportion of patients maintain-ing visual acuity, and provided visual acuity gains similar to that seen with monthly ranibizumab.

B. The regimen of 2 mg dosed every 2 months allows for decreased intravitreal injections and may also decrease the need for monthly monitoring.

C. VEGF Trap-Eye was generally well tolerated and had a generally favorable safety profile.


References

1. Congdon NG, Friedman DS, Lietman T. Important causes of visual impairment in the world today. JAMA 2003; 290(15):2057-2060.

2. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degenera-tion: results of a randomized clinical trial. Arch Ophthalmol. 1991; 109:1220-1231.

3. Yancopoulos GD. Clinical application of therapies targeting VEGF. Cell 2010; 143(1):13-16.

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

5. 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.

6. Economides AN, Carpenter LR, Rudge JS, et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med. 2003; 9(1):47-52.

7. Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc Natl Acad Sci U S A. 2002; 99(17):11393-11398.

8. Rudge J, Holash J, Hylton D, et al. Inaugural article: VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci. 2007; 104:18363-18370.

9. Heier JS, Boyer D, Nguyen QD, et al. 1-year results of CLEAR-IT 2, a Phase 2 study of vascular endothelial growth factor Trap-Eye dosed as-needed after 12-week fixed dosing. Ophthalmology. In press.

10. Brown DM, Heier JS, Ciulla T, et al. Primary endpoint results of a phase 2 study of vascular endothelial growth factor Trap-Eye in wet age-related macular degeneration. Ophthalmology. In press.


Background

Intravitreal injections are one of the most common medical procedures in the United States. Associated endophthalmitis is a potentially devastating complication occurring after approxi-mately 1 out of 1000–5000 injections.1,2

Certain methods are common practice, and guidelines have been published in attempts to minimize the risk of endophthal-mitis.3 Two major points of interest are the use of antisepsis and antibiotics.

Antisepsis

Povidone-iodine (PI) provides broad spectrum microbicidal activity when used for perioperative ophthalmic antisepsis.

Activity and availability • Thepovidonecomponentishydrophilicandactsasacar-

rier to transfer bactericidal iodine to the prokaryotic cell membrane, causing rapid cytotoxicity. The PI kill-time is short, ranging from 15 to 120 seconds for concentrations of 0.1% to 10%,4 and PI has been shown to be bacte-ricidal over a wide range of concentrations (0.005% to 10%).

• PIbeforecataractsurgerysignificantlydecreasestherateof postoperative endophthalmitis.5

• Therearenoreportedcasesofresistancetoitsbactericidaleffects.

• PIisinexpensive,withtheaveragecostofa30milliliterbottle of 5% ophthalmic preparation solution being $12.00 (www.redbook.com).

Toxicity and allergy• AdversereactionstoPIareusuallyrelatedtoitsirritant

effect or an allergic contact dermatitis.7 • Anaphylaxistoiodinedoesnotexist,andtherehavebeen

no reported cases of anaphylaxis to PI related to ophthal-mic use.

• ManycliniciansapplyadditionalPItotheconjunctivaimmediately preceding insertion of the needle through the pars plana. If a small amount of PI is inadvertently introduced into the vitreous cavity during the injection, it is unlikely to cause a problem; animal models have shown ocular tolerance following intravitreal injection of signifi-cant volumes of PI.8

Alternatives

Chlorhexidine is more effective than PI at reducing surgical-site infections in some instances, such as during central line placement and general surgery preparation.9 However, chlorhexidine can be toxic to the corneal endothelium and is potentially ototoxic. In most situations, chlorhexidine should not used to prepare the eyelids and ocular surface before intraocular surgery.

Antibiotics

Prophylactic topical antibiotics are frequently used in patients undergoing intravitreal injections.

Pre–intravitreal injection topical antibiotics • Topicalantibioticsbeforethedayofinjectiondonot

reduce the rate of postinjection endophthalmitis and do not reduce conjunctival bacterial counts more than imme-diate preinjection PI application.10,11

• Topicalantibioticshavesignificantlylongerkill-timesthan PI, so when antibiotics are given immediately prior to an intravitreal injection there is insufficient time for an adequate biological effect.12

• Intheeventthatendophthalmitisdoesdevelop,preinjec-tion antibiotics may increase the risk of resistance of the causative organism.

• Therefore,preinjectionantibioticseitherbeforethedayofinjection or immediately prior to injection are not gener-ally recommended.

Post–intravitreal injection topical antibiotics

Fluoroquinolones are frequently utilized because of their benign side-effect profile and because of their broad spectrum of antimicrobial activity. The value of this prophylaxis is debatable, and recent data suggest that we should reconsider this practice. Analysis of antibiotic susceptibility patterns among conjunctival isolates from patients undergoing intra-vitreal injections found most organisms sensitive to gentami-cin (≥ 85%) and fewer isolates sensitive to fluoroquinolones, with resistance rates to ciprofloxacin, levofloxacin, and gati-floxacin being 42%, 39%, and 22%, respectively.13

Bacterial resistance associated with the use of topical antibiotics • Ahighrateoffluoroquinoloneresistancehasbeen

reported among bacterial isolates recovered from patients with endophthalmitis, and recent application of topical fluoroquinolones has been associated with fluoroquino-lone resistance.14

• Suchresistanceappearstobeincreasing.15 • Exposureofocularandnasopharyngealfloratotopical

ophthalmic antibiotics led to the emergence of resistant strains in a short time period.16

• Thisproblemmaybeespeciallytrueinthesettingofmonthly intravitreal injections in which the same topical antibiotic is used repeatedly in the same eye.

Cost of antibiotics

The average wholesale cost of commonly prescribed topical antibiotics given for post–intravitreal injection prophylaxis is between $8 and $90 (www.redbook.com), including poly-myxin B / trimethoprim, gentamicin, gatifloxacin, and moxi-floxacin.

Antiseptics vs. Antibiotics for Intravitreal InjectionsHarry W Flynn Jr MD, Charles C Wykoff MD PhD, and Philip J Rosenfeld MD PhD

http://www.redbook.com

http://www.redbook.com


Medico-legal issues • TheOphthalmicMutualInsuranceCompany(OMIC)

provides malpractice insurance for approximately 25% of ophthalmologists in active practice in the United States.

• From2006throughthefirstquarterof2011,OMIChasreceived no claims or lawsuits related to intravitreal injec-tion endophthalmitis prophylaxis or lack thereof.

• ThereforeOMICstates,“Decisionsregardinguseofanti-microbial and antiseptic prophylaxis should be based on best available science and not risk mitigation” (David W Parke II MD, chair, Claims Committee, OMIC, personal communication, 2011).

• Inlightofthesefactors,manypractitionersaretrendingaway from routinely dispensing postinjection antibiotics, and large clinical trials suggest they may not be neces-sary.17

Conclusions

• Antisepsishasprovenefficacyandplaysanimportantrolein ocular preparation for intraocular procedures, whether before cataract surgery or before intravitreal injection.

• PIhastheadvantagesoflow-cost,broad-spectrumactiv-ity, widespread availability, fast bactericidal rate, and absence of resistance.

• Availabledataincreasinglyindicatethattopicalantibioticseither before or after intravitreal injection are not neces-sary, provide a large monetary burden to our health care system, and may be counterproductive by contributing to significant bacterial resistance.

• Thecommunitystandardcontinuestoevolve,butthereappears to be a shift toward focusing on antisepsis and away from the use of peri-intravitreal injection antibiotics.

References

1. McCannel CA. Meta-analysis of endophthalmitis following intra-vitreal injection of anti-VEGF agents: causative organisms and pos-sible prevention strategies. Retina 2011; 31(4):654-661.

2. Moshfeghi AA, Rosenfeld PJ, Schwartz SG, et al. Endophthalmitis after intravitreal anti-vascular endothelial growth factor antago-nists: a six-year experience at a university referral center. Retina 2011; 31(4):662-668.

3. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intra-vitreous injections. Retina 2004; 24(5 suppl):S3-19.

4. Berkelman RL, Holland BW, Anderson RL. Increased bactericidal activity of dilute preparations of povidone-iodine solutions. J Clin Microbiol. 1982; 15(4):635-639.

5. Speaker MG, Menikoff JA. Prophylaxis of endophthalmitis with topical povidone-iodine. Ophthalmology 1991; 98(12):1769-1775.

6. Shimada H, Arai S, Nakashizuka H, et al. Reduction of anterior chamber contamination rate after cataract surgery by intraoperative surface irrigation with 0.25% povidone-iodine. Am J Ophthalmol. 2002; 151(1):11-17 e1.

7. Wykoff CC, Flynn HW Jr, Han DP. Allergy to povidone-iodine and cephalosporins: the clinical dilemma in ophthalmic use. Am J Oph-thalmol. 2011; 151(1):4-6.

8. Whitacre MM, Crockett RS. Tolerance of intravitreal povidone-iodine in rabbit eyes. Curr Eye Res. 1990; 9(8):725-732.

9. Darouiche RO, Wall MJ Jr, Itani KM, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med. 2010; 362(1):18-26.

10. Moss JM, Sanislo SR, Ta CN. A prospective randomized evaluation of topical gatifloxacin on conjunctival flora in patients undergoing intravitreal injections. Ophthalmology 2009; 116(8):1498-1501.

11. Halachmi-Eyal O, Lang Y, Keness Y, Miron D. Preoperative topical moxifloxacin 0.5% and povidone-iodine 5.0% versus povidone-iodine 5.0% alone to reduce bacterial colonization in the conjuncti-val sac. J Cataract Refract Surg. 2009; 35(12):2109-2114.

12. Hyon JY, Eser I, O’Brien TP. Kill rates of preserved and preserva-tive-free topical 8-methoxy fluoroquinolones against various strains of Staphylococcus. J Cataract Refract Surg. 2009; 35(9):1609-1613.

13. Moss JM, Sanislo SR, Ta CN. Antibiotic susceptibility patterns of ocular bacterial flora in patients undergoing intravitreal injections. Ophthalmology 2010; 117(11):2141-2145.

14. Fintelmann RE, Hoskins EN, Lietman TM, et al. Topical fluoroqui-nolone use as a risk factor for in vitro fluoroquinolone resistance in ocular cultures. Arch Ophthalmol. 2011; 129(4):399-402.

15. Miller D, Flynn PM, Scott IU, et al. In vitro fluoroquinolone resis-tance in staphylococcal endophthalmitis isolates. Arch Ophthalmol. 2006; 124(4):479-483.

16. Kim SJ, Harranain TS. Ophthalmic antibiotics and antimicrobial resistance. Ophthalmology. In press.

17. Bhavsar AR, Googe JM Jr, Stockdale CR, et al. Risk of endophthal-mitis after intravitreal drug injection when topical antibiotics are not required: the Diabetic Retinopathy Clinical Research Network laser-ranibizumab-triamcinolone clinical trials. Arch Ophthalmol. 2009; 127(12):1581-1583.


I. Background

A. Polypoidal choroidal vasculopathy (PCV) is a macu-lar disorder characterized by recurrent hemorrhage within the retina and retinal pigment epithelium (RPE).

B. It is characterized by presence of choroidal vascular channels ending in polyp-like dilatations in the peri-papillary and macular area

C. Prevalence of PCV is highest in nonwhites, espe-cially Asians, accounting for 23%-55% of Asian patients with clinical appearance of neovascular AMD and only 8%-13% of white patients.

II. Definition

A. Involves primarily inner choroidal vasculature

B. Two fundamental elements: abnormal choroidal network of vessels (branching vascular network, BVN); and polyp-like nodular structures projecting from the plane of the inner choroid toward the RPE

III. Natural History

A. Remitting relapsing course

B. Chronic recurrent serosanguineous RPE and neuro-sensory detachments

C. PCV has a more favorable visual prognosis than choroidal neovascularization.

IV. Clinical Diagnostic Features

A. Clinically visible orange subretinal nodules

B. Large hemorrhagic pigment epithelial detachments

C. Massive submacular hemorrhage

D. Chronic neurosensory detachment

E. Characteristic findings on indocyanine green angi-ography (ICGA)

V. Fluorescein Angiographic Patterns

A. Occult CNV: 46%

B. Hemorrhagic PED: 35%

C. Minimally classic CNV: 19%

VI. ICGA

A. ICGA is the gold standard of diagnosis of PCV.

B. Nodular hyperfluorescence appears early within 5-6 minutes.

C. Plane of hyperfluorescence is internal to larger cho-roidal vessels when viewed stereoscopically.

D. Late phase (30 minutes) may show hypofluorescent core of polypoidal lesions surrounded by halo of hyperfluorescence from wall staining.

E. Very late phase (45 minutes) shows staining and dif-fuse leakage (choroidal silhouetting).

VII. Treatment Options

A. Extra- and juxtafoveal lesions: focal laser photoco-agulation

B. Subfoveal

1. Verteporfin photodynamic therapy (PDT)

2. Verteporfin PDT – intravitreal triamcinolone acetonide (IVTA)

3. Anti-vascular endothelial growth factor (VEGF)

4. Verteporfin PDT – anti-VEGF combination therapy

VIII. Focal Laser Ablation

A. Induces closure of polyps with resolution of exuda-tion

B. Effective in the short term but lesions tend to recur

IX. Verteporfin Photodynamic Therapy

A. Verteporfin PDT has angio-occlusive properties that cause regression of polyps.

B. Complete occlusion in 80%-100% of patients at 1 year

C. Relatively low number of treatments required (fewer than 3)

D. Potential complications

1. Subretinal hemorrhage

2. Breakthrough vitreous hemorrhage

3. RPE rip or tear

4. RPE atrophy

X. Anti-VEGF Therapy

A. Biological rationale for anti-VEGF therapy

1. Increased levels of VEGF in aqueous humor samples of patients with PCV

2. Histopathology shows strong expression of VEGF and down-regulation of pigment-epithe-lium derived factor (PEDF) in vascular endothe-lium and RPE cells in an eye with PCV.

B. Retrospective case series in cases treated with anti-VEGF monotherapy

1. Mean logMAR vision improved from 0.61 to 0.51 at Month 3, stable through to Month 12.

Diagnosis and Management of Polypoidal Choroidal VasculopathyAdrian Koh MD


2. Significant reduction in exudation and macular thickening

3. Persistent polypoidal lesions on ICGA in all eyes at 3 months

XI. PDT-Ranibizumab Combination Therapy

A. EVEREST study design

1. Third arm of the SUMMIT trials of investigating combination therapy for neovascular AMD and PCV

2. 6-month multicenter double-masked randomized controlled clinical trial in 19 Asian sites

3. Primary endpoint: complete regression of PCV lesions on ICGA

4. Secondary outcomes: mean change in visual acu-ity, number of treatments, macular thickness on OCT, change in polyp area, change in lesion size, ocular and systemic safety

5. 61 patients randomized into 3 treatment groups: PDT alone, ranibizumab alone, PDT with ranibi-zumab

6. Same-day full-fluence standard PDT or sham, and ranibizumab or sham treatment

7. Initial 3 loading doses of ranibizumab or sham

B. Re-treatment criteria at Month 3

1. Partial or incomplete regression of polyps: Re-treat with randomized treatment

2. Complete regression of polyps: Persistent fluores-cein leakage, treat with verteporfin PDT/sham; if > 5 letter loss from best measured vision, re-treat with ranibizumab/sham

C. Results

1. Complete regression of all polyps at Month 3 seen in 78% PDT-ranibizumab group, 71% PDT monotherapy group, and 29% ranibizumab monotherapy group (P < .05 between PDT-containing treatments and ranibizumab mono-therapy).

2. Complete regression of at least 1 polyp at 3 months seen in 83%, 86%, and 43%, respec-tively.

3. Mean change of polyp area was 30% in com-bination therapy group compared to 18% PDT group, 14% ranibizumab group.

4. Vision improved in all 3 treatment groups.

5. Mean change in vision was +10.9 letters (PDT-ranibizumab), +9.2 letters (ranibizumab alone), and +7.5 letters (PDT alone).

6. Central retinal thickness OCT changes greatest in combination therapy group.

7. Safety: No severe ocular or systemic adverse events were reported.

XII. Conclusions

A. Verteporfin PDT is the only treatment associated with complete polyp regression.

B. EVEREST demonstrates that verteporfin PDT with or without ranibizumab was superior to ranibi-zumab alone in achieving complete polyp regression on ICGA, with encouraging functional and morpho-logical results.

C. Further investigation of verteporfin therapy for PCV is warranted (eg, reduced fluence).


Introduction

The CABERNET Trial is a multicenter, masked, randomized, prospective, controlled study of the Epi-Rad90 Ophthalmic Sys-tem for the treatment of subfoveal choroidal neovascularization associated with wet AMD. A total of 493 eyes in 493 subjects (1 eye per subject) were randomized at a 2:1 ratio at 41 sites in the United States, Europe, South America, and Israel.

Study Design

Subject randomization was stratified by study center, by type of lesion (predominantly classic, minimally classic, or occult), and by baseline ETDRS visual acuity (> 53 letters or ≤ 53 letters) using a 2:1 randomization scheme.

Subjects enrolled into Study Arm A received a single surgical procedure with the Epi-Rad90 Ophthalmic System and 2 injec-tions of ranibizumab (0.5 mg). The first injection was adminis-tered immediately following surgery, and the second was admin-istered at the Month 1 visit. Subjects enrolled into Study Arm B received ranibizumab (0.5 mg) administered monthly for the first 3 injections, followed by protocol-mandated quarterly injections for 2 years.

Subjects were re-treated with ranibizumab (0.5 mg) if one of the following was present: a 10 ETDRS letter loss of visual acuity, a > 50 micron central retinal thickness increase on OCT from the lowest documented central retinal thickness, any new macular hemorrhage or new neovascularization as documented by fluorescein angiography.

The CABERNET trial is designed to evaluate the safety and efficacy of the Epi-Rad90 Ophthalmic System in the treatment of subfoveal CNV associated with AMD. The co-primary efficacy outcomes are:

• Lossof15ormorelettersofBCVAscoreat24monthscompared to baseline, or

• Gainof15morelettersofBCVAscoreat124monthscompared to baseline.

The trial will have shown benefit of the Epi-Rad90 Ophthal-mic System if after 24 months of follow-up the data demonstrate either:

• NoninferiorityofEpi-Rad90OphthalmicSystemcom-pared to Lucentis with regard to the proportion of eyes losing 15 or more ETDRS letters, with a noninferiority margin of 10%, or

• SuperiorityofEpi-Rad90OphthalmicSystemoverLucen-tis with regard to the proportion of eyes gaining 15 or more ETDRS letters.

Data will be presented, including 2-year follow-up on the full cohort. The study is designed to follow subjects for 3 years to detect long-term retinal microvascular changes that are possible with radiation treatment of the retina.

Background

Ionizing radiation has the ability to prevent proliferation of vascular tissue by inhibiting neovascularization. After radiation doses as low as 6 Gy, vascular endothelium demonstrates mor-phologic and DNA changes, inhibition of replication, increased cell permeability, and apoptosis. Fibroblast proliferation and subsequent scar formation, a hallmark of end-stage neovascular AMD, are also inhibited. CNV membranes, which contain endo-thelial cells that are proliferating due to the hypoxic environment as well as the localized inflammatory cell populations, are more sensitive to radiation damage than is the normal retinal vascula-ture and nonproliferating capillary endothelial cells.

Investigational Device

The Vidion ANV Therapy System is a 90Strontium/90Yttrium applicator that is designed to deliver a therapeutic dose of radia-tion to the CNV while minimizing exposure to other intraocular structures. Following pars plana vitrectomy, the sealed radiation source is placed temporarily over the fovea in the vitreous cav-ity, via an intraocular cannula, a concept termed “epimacular brachytherapy” (see Figure 1).

In contrast to external beam radiotherapy, a large single frac-tion treatment dose can be delivered to a small volume of the macula with less irradiation of normal ocular structures and sur-rounding tissues.

Figure 1. Dosimetry pattern of the Vidion ANV Therapy System super-imposed upon en face image of the retina.

Results

The CABERNET study began enrollment on June 2007, with 493 subjects enrolled in October 2009. Baseline patient demo-graphics and baseline characteristics are shown in Table 1. Postrandomization data will be presented, including 467 subjects with 2 years of follow-up.

Internal Radiation for AMD: The CABeRNeT Study Pravin U Dugel MD


Table 1. The CABeRNeT Study: Patient Demographics and Baseline Characteristics

Total

Gender

Male, n/N (%) 162/493 (33)

Female, n/N (%) 331/493 (67)

Age (years)

n 493

Mean (SD) 77.6 (8.7)

Range (min, max) 50, 96

Quartiles (25th, median, 75th) 72, 79, 84

Race and ethnicity, n/N (%)

White (not of Hispanic origin) 432/493 (88)

Hispanic origin 41 (8)

Asian or Pacific Islander 18 (4)

American Indian or Alaska Native 1 (<1)

Other 1 (<1)

Denominators are the number of randomized subjects with data for that category.


Introduction

The treatment of choroidal neovascularization (CNV) secondary to AMD began with the advent of thermal laser photocoagula-tion in the early 1980s. Almost 20 years later, photodynamic therapy (PDT) with verteporfin was approved by the FDA 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 PDT in conjunction with intraocular injection of triam-cinolone 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 ben-efits to date.

The advent of anti-angiogenic drugs, particularly anti-vascular endothelial growth factor (VEGF) agents, began with the approval of pegaptanib sodium in December of 2004. Pegaptanib, a selective blocker of VEGF-165, has demonstrated the ability to slow the rate of vision loss, but it did not show significant improvement in vision in a majority of patients. The introduction of ranibizumab changed the paradigm for CNV treatment. Randomized, controlled clinical trials showed that monthly ranibizumab treatment resulted in stabilization of vision in more than 90% of patients, as well as improvement in vision of a significant nature in about one-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 1-year outcomes of therapy with these 2 agents were similar in the study groups receiving monthly treatments.

emerging Therapies

The main driver of the neovascular process in AMD is VEGF. The process by which VEGF is generated and acts upon vascular endothelial cells to stimulate blood vessel growth is a compli-cated cascade of events. Each of these steps offers the possibility of therapeutic intervention. Activation of this cascade may occur through hypoxia, exposure to certain growth factors, or other inciting stimuli. Multiple molecular interactions then occur, which result in the production of VEGF. One of these key steps in the cascade leading to generation of VEGF involves a molecule known as mTOR, the mammalian target of rapamycin. This is a protein kinase that regulates cell proliferation, motility, survival, and protein synthesis. It leads to the activation of hypoxia induc-ible factors (HIF1-alpha, in particular), which results in the acti-vation 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, and plans for further clinical development of this compound are under discus-sion. 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 pre-vent rejection of organ transplants, and research into its oph-thalmic application is under way. A nonsteroidal small molecule that inhibits both TORC1 and TORC2 complexes of mTOR, Palomid 529, inhibits the PI3-K/Akt/mTOR transduction path-way. Palomid 529 is in Phase 1 clinical trials for patients with advanced neovascular AMD.

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. Preclinical evaluation of another small interfer-ing RNA drug that is specifically targeted toward HIF1α is also under way, with plans for bringing it to clinical stage evaluation.

Once VEGF is generated, the target 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, and bevacizumab), an additional drug known as VEGF Trap-Eye is currently under-going clinical study for inhibition of VEGF. The VEGF Trap-Eye is a fusion protein that combines features of two different VEGF receptor sites, thus allowing a higher binding affinity than the anti-VEGF drugs currently in clinical use. This molecule has demonstrated effectiveness in improving visual acuity and reduc-ing CNV size and OCT thickness in 2 large Phase 3 clinical trials in a direct head-to-head comparison with ranibizumab.

Another molecule, KH902, is a recombinant human VEGF receptor-Fc fusion protein has been studied in a Phase 1 trial of patients with CNV secondary to neovascular AMD. Injections of KH902 ranging from 0.05 mg to 3.0 mg were found to be safe and tolerable, with measurable reduction in exudation noted. A Phase 1b study designed to assess the efficacy and safety of mul-tiple 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.

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

To Infinity and Beyond: Future Therapeutics for exudative AMDJason S Slakter MD


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 are currently being 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 is currently undergoing Phase 1 trials involving single and multiple injections for patients with CNV. One advantage of this molecule is that it may not only inhibit VEGF but may also inhibit the effects of other growth factors and cytokines leading to angiogenesis, inflammation, and fibrosis. Another integrin antagonist is volociximab, a high-affinity monoclonal antibody that binds to α5β1 integrin and blocks the binding of α5β1 integrin to fibronectin, thereby inhibiting a pivotal interaction required for angiogenesis. Volociximab administration has resulted in strong inhibition of rabbit and primate retinal neovas-cularization and laser-induced choroidal neovascularization in cynomolgus monkeys. A Phase 1 study of volociximab in combi-nation with ranibizumab in patients with wet AMD is ongoing.

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, or 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. Addi-tional trials are under way. Another tyrosine kinase inhibitor, AL39324, which is administered intravitreally, is being studied in a Phase 2 clinical trial, comparing combined use with ranibi-zumab to ranibizumab alone for exudative 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 occlusion of vascular lumen and cessation of blood flow in the effected ves-sels. It is currently undergoing Phase 2 testing with intravenous administration in patients with the polypoidal variant of AMD seen commonly in Asia. 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 and 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), a humanized and optimized monoclo-nal antibody specifically targeted against S1P, can bind S1P at physiologically relevant concentrations. A Phase 1 multicenter, dose-escalation study of LT1009 administered as a single intra-vitreal injection in patients with exudative AMD is under way.

There have been a number of endogenous physiological inhibitors of angiogenesis that have been identified, one of which is pigment epithelium derived factor (PEDF). Normally produced in the eye, PEDF is known to regulate or control normal blood vessel growth, protect photoreceptors, and inhibit 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 intra-vitreal or periocular 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.

Platelet-derived growth factor (PDGF) is responsible for the recruitment, growth, and survival of pericytes and serves to regulate vascular maturation. E1030 is a pegylated aptamer that binds and inhibits PDGF, and has been shown to inhibit or strip pericytes in preclinical models. In a Phase 1 clinical study in com-bination with ranibizumab, E1030 was well tolerated and dem-onstrated significant regression of neovascular lesions indicating potential bioactivity. Phase 1 studies are under way.

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 overactivation of inflammation at the level of the retinal pigment epithelium and choroid, leading the development of all stages of AMD.

Several drugs are currently under development in an attempt to control the complement pathway and potentially modulate the development of AMD, not only in its more advanced stages but perhaps even as early as the development of drusen themselves. An aptamer directed against complement factor C5 is currently undergoing Phase 1 testing in an ascending multiple-dose study, delivered intravitreally in combination with ranibizumab in patients with exudative AMD. Another agent, POT-4, which is a small molecule derivative of Compstatin, is directed against complement factor C3. This drug has completed Phase 1 testing in patients with exudative AMD with an excellent safety profile. The Phase 1 study demonstrated that some patients exhibited a reduction in exudation following a single drug injection. A Phase 2 study is under way.

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.


Finally, the use the radiation as an adjunct to the treatment of CNV secondary to AMD is currently being explored by two dif-ferent means. One involves the use of epimacular brachytherapy in combination with ranibizumab. Several clinical trials compar-ing the combination approach to ranibizumab monotherapy are under way. The other approach is the office-based radiosurgical system, where patients are exposed to X-radiation through an external beam that is stereotactically focused on the macula. Phase 2 studies are under way.

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.

3. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355:1419-1431.

4. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macu-lar degeneration. N Engl J Med. 2006; 355:1432-1444.

5. Dejneki NS, Kuroki AM, Fosnot J, et al. Systemic rapamycin inhib-its retinal and choroidal neovascularization in mice. Mol Vis. 2004; 10:964-972.

6. 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.

7. 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.

8. 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.

9. 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.

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

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. Tong JP, Yao YF. Contribution of VEGF and PEDF to choroidal angiogenesis: a need for balanced expressions. Clin Biochem. 2006; 39(3):267-276.

17. 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.

18. 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.

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

20. 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.

21. Edwards AO, Ritter R III, Abel KJ, et al. Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308:421-424.

22. Zarbin MA, Rosenfeld, PJ. Pathway-based therapies for age-related macular degeneration: an integrated survey of emerging treatment alternatives. Retina 2010; 30:1350-1367.

2011 Subspecialty Day | Retina Surgery by Surgeons Update 33

2011 Surgery by Surgeons UpdateGeorge A Williams MD

With this year’s passage of legislation in Kentucky that allows optometrists to perform laser surgery, the American Academy of Ophthalmology’s partnership with ophthalmic subspecialty and state societies on the Surgery by Surgeons campaign becomes even more important in protecting quality patient eye care across the country.

In 2009-2010, the Eye M.D.s serving on the Academy’s Secre-tariat for State Affairs collaborated with the leadership of many state ophthalmology societies on legislative battles in which optometry continued to push for expanded scope of practice. Leadership of subspecialty societies provided essential support in some of these battles. Success was reached in Idaho, Maine, Mississippi, Nebraska, South Carolina, Texas, Washington and West Virginia, where surgery provisions were removed and/or bills were defeated.

In 2011, the stakes were raised with the disappointing out-come in Kentucky. The Kentucky legislation also includes the creation of an independent optometric board; no other board or state agency has the authority to question what constitutes the practice of optometry. The Secretariat for State Affairs continues to work diligently with state society leaders in South Carolina, Nebraska, Tennessee and Texas to ensure that a Kentucky outcome is not repeated elsewhere. For example, following the passage of legislation in Kentucky, fundraising material by orga-nized optometry in Tennessee made it clear that they would like to replicate optometry’s outcome in Kentucky and have begun discussions with state legislators.

The Surgical Scope Fund (SSF) is a critical tool of the Surgery by Surgeons campaign to protect patient quality of care. 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. The American Society of Retina Specialists (ASRS), the Retina Society and the Macula Society each contributed to the SSF in 2010, and the Academy counts on their contributions in 2011.

The results in Kentucky should be viewed as a failure neither of the SSF nor of the Academy’s Secretariat for State Affairs, which geared up immediately to strategize with Kentucky Academy physician leadership. In a period of 15 days, with no advanced warning, optometry was able to introduce and pass a bill in the Kentucky state legislature and secure its passage into law. A SSF disbursement actually assisted with critical media efforts and powerful public messaging favoring ophthalmology and quality patient eye care for the citizens of Kentucky. This should be a lesson to each Eye M.D. in the country about the importance of contributions to your state eyePAC and to the SSF.

Leaders of the ASRS, the Macula Society and the Retina Society are part of the American Academy of Ophthalmology’s Ophthalmology Advocacy Leadership Group (OALG), which

has met for the past four years in the Washington DC area to provide critical input and to discuss and collaborate on the American Academy’s advocacy agenda. The three retina societ-ies remain crucial partners to the Academy in its ongoing federal and state advocacy initiatives. As 2011 Congressional Advocacy Day (CAD) partners, the three retina societies ensured a strong presence of retina specialists to support ophthalmology’s priori-ties as over 350 Eye M.D.s had scheduled CAD visits to members of Congress in conjunction with the Academy’s 2011 Mid-Year Forum in Washington DC. ASRS has plans to further engage more retina specialists in advocacy efforts.

At the state level, the Academy’s Surgery by Surgeons cam-paign has demonstrated a proven track record. Kentucky was an outlier; the Academy’s SSF has helped 31 state ophthalmology societies reject optometric surgery language.

Help us help you protect our patients and quality eye care. The Academy’s SSF remains a critical tool in the Surgery by Sur-geons campaign. The SSF Committee works hard on your behalf to ensure the ongoing strength and viability of the SSF.

Thomas Graul MD (Nebraska): Chair

Arezio Amirikia MD (Michigan)

Kenneth P Cheng MD (Pennsylvania)

Bryan S Lee MD PhD (Maryland): Consultant

Richard G Shugarman MD (Florida)

Stephanie J Marioneaux MD (Virginia)

Bryan S Sires MD PhD (Washington)

Andrew Tharp MD (Indiana)

Ex-officio members:

Cynthia A Bradford MD

Daniel J Briceland MD

The SSF is our collective fund to ensure that optometry does not legislate the right to perform surgery. Do not forget about Congress, where ophthalmology’s influence is through OPH-THPAC. Just as a strong state presence is needed, so do we need to remain strong in the federal arena. While OPHTHPAC is the third largest medical PAC, a mere 15% of the Academy’s mem-bership contribute.

The Kentucky legislation is not in the best interests of patient safety and quality patient care. Ophthalmology needs the active support of every member—and this includes contributions to the SSF, state eye PACs and OPHTHPAC.

Please respond to your SSF Committee and OPHTHPAC Committee colleagues when they call on you and your subspe-cialty society to contribute. There are some decisions that require thought, but donating $500 to the SSF and OPHTHPAC is the easy answer for you and your patients. Do it today. Do it now.

34 Section III: Late Breaking Developments 2011 Subspecialty Day | Retina

Late Breaking Developments

N O T e S

2011 Subspecialty Day | Retina Section IV: Pediatric Retina Panel 35

Pediatric Retina Panel

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36 Section V: Inherited Retinal Diseases and Miscellaneous 2011 Subspecialty Day | Retina

The Genetics of Retinitis PigmentosaKnowing How the Varieties of RP Are Transmitted Can Be Half the Battle of Treatment

Stephen H Tsang MD PhD, Kyle Wolpert BA

This article is reprinted with permission from Retinal Physician, Nov. 2010, www.retinalphysician.com/archive.aspx ?searchOptions=rbIssue&tm=11/1/2010.

Retinitis pigmentosa (RP) is a heterogeneous group of diseases characterized by progressive rod-cone dysfunction. Patients initially present with nyctalopia from rod photoreceptor loss, progress to tunnel vision, and ultimately experience central vision loss. RP is also the most common form of inherited retinal degeneration, affecting one in 3000 people.1,2

Genetics Basics

As a genetically heterogeneous set of disorders, the specific mutation involved in any given case of RP dictates the inheri-tance pattern and strongly influences the prognosis. As such, a careful family history is essential both for diagnosis and genetic counseling. When possible, the family members of a new RP patient should be examined in order to better define the inheri-tance pattern. Often, family members may be younger than the age at which the disease develops, which can make this process difficult.

Electroretinogram (ERG) testing, which provides a global assessment of rod and cone function, can measure electrophysi-ological disturbances long before photoreceptor loss occurs, or changes can be seen on fundus examination.1,3 Thus, ERG test-ing can help determine whether younger family members will present with the disease later in life, which is useful both for the construction of a pedigree and also for counseling purposes; for example, ERG screening may help a young patient identify plau-sible career paths.

Described inheritance patterns of RP include autosomal dominant (15% to 35% of cases), autosomal recessive (60%), X-linked recessive (5% to 18%), and mitochondrial. If no other family members are affected, the disease is likely the result of an autosomal recessive (AR) mutation. If the disease presents only in men and is transmitted maternally, then it is likely an X-linked recessive (XLR) mutation. Unlike the recessive modes of inheri-tance, autosomal dominant (AD) transmission is marked by disease occurrence in every generation and father-to-son trans-mission.

The rarest form of inheritance is X-linked dominance. These patients are almost always women, as such traits are generally lethal in men. It is possible that a sporadic case could represent a new autosomal dominant mutation, but this is rare. However, the possibility underscores the need for genetic testing to ensure an accurate diagnosis. Mitochondrial mutations are passed maternally and often present systemic problems. Identifying the inheritance pattern involved can help to determine the prognosis, both for the patient and the rest of his or her family.

Autosomal Dominant

Between 15% and 35% of all cases of RP follow an autosomal dominant inheritance pattern.4,5 As stated previously, AD inheri-tance is marked by occurrence in each generation and father-to-son transmission of the disease. Compared to AR forms, the AD forms of the disease tend to be more mild, progress more slowly, and present later in life. Patients present with reduced visual acu-ity and loss of color vision in late adulthood and progress to legal blindness. In the first 2 decades of life, patients with autosomal dominant RP may be funduscopically indistinguishable from healthy patients. Mutations in rhodopsin, the visual pigment, are responsible for 30% of AD forms of RP. In patients with RP, autofluorescence imaging often shows a characteristic ring of hyperautofluorescence before abnormalities appear on fundus examination (see Figure 1); as such, autofluorescence imaging can help to provide presymptomatic clinical evaluation of the patient and predict the course of the disease.6-8

Figure 1. Autofluorescence images of (A) normal 22-year-old woman, and (B) 29-year-old man with autosomal dominant RP. Note the char-acteristic ring of dense hyperautofluorescence surrounding the macula (circles). The patient showed minor abnormality of RPE activity, which suggests a mild type of retinitis pigmentosa.

Genetic counseling for patients with AD RP is relatively straightforward. Assuming that only one of the patient’s parents is affected, each of the patient’s children will have a 50% chance of inheriting the mutant allele and thus the disease. Furthermore, an affected patient’s siblings each have a 50% chance of being affected. Siblings and children that do not have the allele (as determined by ERG testing) will not pass the disease on to their own children.

Autosomal Recessive

Autosomal recessive forms of retinal degeneration tend to be more severe, progress more rapidly, and present earlier than the AD forms (see Figure 2). As stated previously, the AR inheritance pattern is characterized by sporadic appearance and occurrence in both men and women.

www.retinalphysician.com/archive.aspx?searchOptions=rbIssue&tm=11/1/2010

http://www.retinalphysician.com/archive.aspx?searchOptions=rbIssue&tm=11/1/2010

2011 Subspecialty Day | Retina Section V: Inherited Retinal Diseases and Miscellaneous 37

Genetic counseling for patients with AR retinitis pigmen-tosa is more complicated than for the AD forms. If a patient is affected with an AR form of RP, then both of their parents must have been heterozygous carriers. This means that each of their siblings has a 25% chance of developing the disease and a 50% chance that they are asymptomatic carriers; thus, if a sibling does not have the disease, then there is still a 66% chance that they are carriers. The patient’s children will not develop the disease, but each will be a heterozygous carrier, so it may reappear in later generations.

Figure 2. Autofluorescence image of a 36-year-old woman with autoso-mal recessive RP. Note the ring of hyperautofluorescence surrounding the macula (circles), attenuated arterioles (arrowheads), and pigmented hypoautofluorescent areas of atrophic RPE in the periphery.

X-Linked Recessive

The X-linked recessive form of retinal degeneration is often the most severe (see Figure 3A). It has an early onset, with teenage men showing rod degeneration followed by cone degeneration. Female heterozygous carriers can show patchy areas of rod degeneration due to X-chromosome inactivation, and they pres-ent with a metallic, tapeto-like sheen apparent both in autofluo-rescent and color photographs (see Figures 3B, 3C, and 3D).9 The ERG in such carriers is typically affected by age 60.

Genetic counseling for those affected is nuanced due to the nature of the sex chromosomes. Sisters of affected men have a 50% chance of being heterozygous carriers, but they will not develop the disease. Brothers of affected men have a 50% chance of developing the disease, but if they do not, then they will not be heterozygous carriers. Sons of affected men will not be affected. Daughters will be heterozygous carriers, and as such, their own children will have a 50% chance of receiving the mutant allele.

Figure 3. Autofluorescence image of 30-year-old man with X-linked recessive RP (A). Note the widespread zonal areas of hypoautofluo-rescent atrophic RPE. (B) Autofluorescence image of the right eye of a heterozygous carrier of an X-linked recessive allele demonstrating char-acteristic tapeto-like metallic sheen. Autofluorescence image of the same heterozygous patient’s left eye showing more advanced tapeto-like sheen, as well as hypoautofluorescent patches of atrophic RPE and peripheral mottled zonal degeneration. Autofluorescence image of a healthy patient given to help illustrate the changes seen in heterozygous carriers. The calibration bar in the center of the top of the image allows quantification of the image brightness.

Genetic Testing

It is essential that patients with RP submit to genetic testing, both for purposes of prognosis and for the improved understanding of the genetics of RP. There are 15 genes known to be associated with autosomal dominant RP, 17 genes associated with autoso-mal recessive RP, and 2 genes associated with X-linked RP.

There is currently a 30% chance that blood submitted for genetic testing will be matched with a known mutation within 1 year of submission. Knowing the inheritance pattern before submitting blood for genetic testing is important because there are different gene chips used when testing for RP genes: one with dominant mutations and one with recessive mutations.10 This helps to streamline the process by avoiding the need for extrane-ous testing, making it more cost efficient.

Genetic tests can cost the patient hundreds of dollars, so reducing the price by narrowing the scope of the test is impor-tant. Genetic testing of all patients is important because the geno-type-phenotype correlation can vary such that different members of a family express the disease differently or, alternatively, that different mutations manifest similar fundus alterations.8

Genetic testing for mitochondrial mutations is much more complicated than standard testing. In genetic testing of normal DNA, a blood sample is taken and submitted for testing, but mitochondrial testing requires a biopsy of the retina itself.


Gene Therapy

For many years, cures for RP have been largely unavailable. However, recent developments point to the promise that, in some cases, gene therapy could arrest the progression of RP and perhaps even restore lost vision. Gene therapy can be difficult in most organ systems because the body’s immune response causes a rejection of the introduced material. However, the eye is a rather immunoprivileged site, and as such, gene delivery using adeno-associated virus has been shown to be effective.

Several studies published in 2008 demonstrated the efficacy of gene therapy to help patients with an early-onset autosomal recessive form of retinal dystrophy, known as Leber’s congenital amaurosis.11 -13 Gene therapy success can be measured nonin-vasively through the use of techniques such as ERG testing and autofluorescence imaging.

One major impediment to the development of gene therapies is that they are gene specific. This is why it is crucial that the database of known mutations be expanded. The inheritance pattern of a given mutation is also important for determining the relative likelihood of the development of successful gene therapies. Recessive genes are relatively easy to treat with “gene-replacement” therapy because the eye simply lacks a functional copy of the gene; if a functional copy is introduced, then results can be seen. Dominant genes are more complicated because they require “gene correction” in order to essentially override the del-eterious effects of the mutant allele.

Cell replacement therapy using induced pluripotent stem cells is another treatment currently in development that may be an effective treatment for both AD and AR forms of RP.14 Mito-chondrial gene therapy is not currently a realistic possibility. However, stem-cell therapy has worked as a temporary treat-ment for the bone marrow in Pearson syndrome, so similar stem-cell therapy may someday be available for the retinal atrophy resulting from mitochondrial disorders.

Summary

More treatments for RP are foreseeable in the coming decade, but genetic testing of RP patients is essential in order both to understand better the genetic associations of the disease and to direct efforts at developing treatments. However, even before implementing genetic testing, it is important to obtain, as much as possible, a complete family history in order to identify the inheritance pattern of the disease. The inheritance pattern has serious implications for the prognosis of the patient and is critical for genetic counseling for the patient and his or her family.

References

1. Humphries P, Kenna P, Farrar J. On the molecular genetics of reti-nitis pigmentosa. Science 1992; 256:804-808.

2. McKusick VA. Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Vol CD-ROM. 12th ed. Bal-timore, MD: The Johns Hopkins University Press, 1998.

3. Berson EL, Gouras P, Hoff M. Temporal aspects of the electroret-inogram. Arch Ophthalmol. 1969; 81:207-214.

4. Bunker CH, Berson EL, Bromley WC, Hayes RP, Roderick TH. Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol. 1984; 97:357-365.

5. Ayuso C, Garcia-Sandoval B, Najera C, Valverde D, Carballo M, Antinolo G. Retinitis pigmentosa in Spain. The Spanish Multicen-tric and Multidisciplinary Group for Research into Retinitis Pig-mentosa. Clin Genet. 1995; 48:120-122.

6. Lima LH, Cella W, Greenstein VC, et al. Structural assessment of hyperautofluorescent ring in patients with retinitis pigmentosa. Retina 2009; 29:1025-1031.

7. Tsang SH, Vaclavik V, Bird AC, Robson AG, Holder GE. Novel phenotypic and genotypic findings in X-linked retinoschisis. Arch Ophthalmol. 2007; 125:259-267.

8. Tsui I, Chou CL, Palmer N, Lin CS, Tsang SH. Phenotype-genotype correlations in autosomal dominant retinitis pigmentosa caused by RHO, D190N. Curr Eye Res. 2008; 33:1014-1022.

9. Zeiss CJ, Ray K, Acland GM, Aguirre GD. Mapping of X-linked progressive retinal atrophy (XLPRA), the canine homolog of retini-tis pigmentosa 3 (RP3). Hum Mol Genet. 2000; 9:531-537.

10. Tsang SH, Tsui I, Chou CL, et al. A novel mutation and pheno-types in phosphodiesterase 6 deficiency. Am J Ophthalmol. 2008; 146:780-788.

11. 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.

12. 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.

13. 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.

14. Gouras P, Kong J, Tsang SH. Retinal degeneration and RPE trans-plantation in Rpe65(-/-) mice. Invest Ophthalmol Vis Sci. 2002; 43:3307-3311.


I. Definitions

A. Gene therapy

Introduction of exogenous DNA (transgene) into host tissue with the production of a therapeutic molecule; expression of exogenous DNA by host transcription-translational system results in the production of therapeutic RNA, DNA, peptides, or proteins.

B. Vector

A biologic (usually a modified virus) that inserts exogenous DNA into target tissue

C. Expression

Production of the therapeutic molecule by host cells

D. Stability

Duration of expression

E. Efficiency

Percentage of host cells demonstrating expression

F. Transduction

Expression of the exogenous DNA in the targeted cell

II. Background

The field of in vivo gene therapy has largely emerged within the last 15 years. Hundreds of clinical trials have been conducted for a variety of diseases involving diverse organ systems. Demonstration of efficacy/cure of severe combined immunodeficiency (“bubble-boy disease”) using ex vivo gene replacement has provided proof-of-principle for gene therapy. There have been several clinical gene therapy trials for retinal diseases.

Advances in molecular biology/genetics have been the main factors responsible for tremendous progress over the last decade. These have resulted in (1) delineation of the molecular bases of various diseases and (2) develop-ment of gene transfer technology through advances in virology (“vectorology”).

III. Principles of Gene Therapy

A. A major misconception about gene therapy is that its application is limited to genetic disease. Gene therapy is simply a delivery system for drugs (bio-active substances). Any disease that would benefit by the local production of a genetically engineered protein, peptide, RNA, or RNA fragment would be a potential candidate for gene therapy.

B. Proof-of-principle has been established in animal models for a variety of genetic and nongenetic reti-nal diseases. For example:

1. Acquired: retinal neovascularization, choroidal neovascularization

a. Anti-VEGF strategies using RNAi, antisense RNA

b. Production of PEDF

2. Genetic: retinitis pigmentosa, Leber amaurosis, retinal/macular dystrophies

a. For recessive diseases, replacement with “wild-type” gene or gene correction resulting in production normal enzyme, eg, RPE-65, Peripherin/RDS(Prph2)

b. For dominant disease, neutralization of toxic “dominant” substance (eg ribozyme therapy for rhodopsin mutants causing dominant RP)

IV. Technique of Retinal Gene Therapy

A. As with any other drug, the gene therapy agent (ie, vector) has to somehow be applied in order to work. Systemic (eg, intravenous) administration of vec-tors increases toxicity by enhanced exposure to the immune system; furthermore, it will not result in any appreciable uptake in the retina. Vectors need to come in direct contact with their target cells as they do not cross tissue planes. They are engineered not to replicate and therefore do not spread beyond the field of administration. In addition, since retinal neurons do not replicate, the vector do not become diluted over time.

B. Administration procedures and the cells types that are transduced:

1. Subretinal injection: retinal pigment epithelium, photoreceptors, Müller cells

2. Intravitreal injection: ganglion cells, optic nerve, Müller cells, ciliary body, anterior chamber structures

3. Ex vivo gene therapy can be used to create encapsulated implants; site of “drug” delivery depends on site of surgical implantation.

C. Different vectors have different “tropisms” for any given cell; it is not enough simply to come in contact with the cell; receptor interactions determine if a cell will be transduced. Different viral vector (eg, chi-meras) can be combined or otherwise engineered to change their tropism for certain cell types. Vectors are chosen based on several factors, including:

1. Stability of expression:

Adeno-associated virus (AAV)—very stable, possibly lifelong expression; recombinant adeno-virus (rAd)—less stable, but often “intense” expression; lentivirus—stable, intense expression

Attacking Leber Congenital AmaurosisGene Therapy Update

Albert M Maguire MD


2. Tropism/efficiency:

At present, rAd and lentivirus have a limited number of cell types that are efficiently trans-duced; AAV has numerous serotypes (clades) with different tropisms for numerous cell types.

3. Cargo capacity:

The size of the DNA/trangene that can be “spliced” into a given viral vector is limited and vector dependent: rAd and lentivirus can accom-modate large genes such as the Stargardt ABCR; AAV has a smaller capacity and may require “split vector” technology to carry bigger pieces of DNA.

V. Other Considerations

A. What then, are the problems in developing gene therapy for human applications? Especially for systemic diseases, the host immune response to the gene therapy vector or, in some cases, to the trans-gene product itself, both reduces the stability of expression and causes pathogenic effects. Vectors are, after all, viruses and the body has evolved to eliminate this antigenic material. This problem of immune response can be manipulated on the host side by iatrogenic immunosuppression (eg, cortico-steroids) or on the vector side by choice of virus or recombinant engineering.

1. Pathogenicity:

Vectors are genetically engineered to reduce antigenicity and to prevent replication. However, after vector administration, local and serum anti-bodies to the vector (and sometimes the trans-gene product) are produced. The host immune response can be severe, resulting in local tissue damage or significant systemic reactions.

2. Stability:

One consequence of host immune response is the elimination of vector and the resultant disappear-ance of the therapeutic product. This is a signifi-cant limitation in systemic treatment of chronic disease.

B. The retina has several unique characteristics that make it a favorable target for gene therapy.

1. Size/volume:

The amount of tissue requiring transduction for successful therapy is drastically less than for vis-ceral organs (milligrams vs. kilograms of tissue); the amount of vector is hundreds of times less than that used in systemic therapy, thus trans-lating into a commensurately smaller antigenic load.

2. Surface/volume ratio:

Due to the epithelial architecture of the retina, it is possible to have the vector come in contact with entire populations of cells: eg, RPE, photo-receptors.

3. Immune privilege/deviation:

The retina is not just anatomically sequestered from the systemic immune system; there exist several mechanisms that promote tolerance to foreign antigens such as:

a. Suppression of delayed type hypersensitivity (DTH)

b. Anterior chamber–associated immune devia-tion (ACAID)

c. Posterior chamber inhibition of development of cytotoxic T cells and of complement-fixing antibodies

4. Immunosuppressive factors, including trans-forming growth factor-β, Fas ligand, melanocyte-stimulating hormone, vasoactive intestinal pep-tide, and calcitonin gene-related peptide

VI. Current Applications

There are several ongoing human clinical trials evaluat-ing the safety of AAV vector-mediated gene transfer of wild-type RPE65 in patients with LCA2. Preliminary data demonstrate compelling evidence for short-term safety and efficacy. This disease is ideal for demonstrat-ing gene therapy efficacy due to the presence of viable cells that can recover function acutely (versus measur-ing a delayed/long-term response in preventing degen-eration). Clinical trials using gene therapy for other retinal disease/degeneration have been initiated.

Most recently, readministration of vector to the contra-lateral eye has been performed in patients with LCA2 with evidence for efficacy and no safety concerns. This is significant in terms of the immunologic tolerance of repeated exposure to a viral vector when administered in the subretinal space.

A. Nonspecific promoters using AAV 2 vector

1. CHOP-UPenn TIGEM-SUN trial: 12 pediatric and young adult patients. Published data show all subjects with either subjective (visual acu-ity) and/or objective (pupillometry) evidence for improved visual/retinal function.

2. UPenn/UFl trial: 9 adult and pediatric subjects. Results demonstrate 3/3 adult patients with improved dark adaptometry and shift in fixation in one individual.

3. UFl-UMass-Oregon trial: Phase 1/2 trial has ini-tiated enrollment.

B. RPE-specific promoter using AAV 2 vector

UK/ Targeted Genetics trial: Adult and older chil-dren. Published data show longer-term safety data and 1/3 subjects with subjective evidence (eg, micro-perimetry) for efficacy.

C. Currently, the CHOP-UPenn has completed enroll-ment for the Phase 1 trial (12 subjects including 5 children) and a Phase 3 study is planned. For a com-pleted list of active trials refer to www.clinicaltrials .gov.

www.clinicaltrials.gov

http://www.clinicaltrials.gov


D. Additional gene therapy trials for Stargardt disease, Usher syndrome, juvenile retinoschisis, and exuda-tive macular degeneration are being planned by various groups including biotech companies.

Selected Readings

1. Maguire A, Bennett J. Gene therapy for retinal disease. In: Jaffe GJ, Ashton P, Pearson PA. eds. Intraocular Drug Delivery. Taylor & Francis Group; 2006: 157-173.

2. Maguire A, Simonelli F , Pierce EA, et al. Safety and efficacy of gene transfer for Leber’s congenital amaurosis. N Engl J Med. 2008; 358:2240.

3. Bainbridge JWB, 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.

4. Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy for RPE65 isomerase deficiency activates the retinoid cycle of vision but with slow rod kinetics. Proc Natl Acad Sci USA. 2008; 105(39):15112-15117.


I. Background

A. Traditionally most ophthalmic medicines have been delivered topically.

B. We are entering an era of retinal pharmacotherapy.

1. Exponential increase in intravitreal injection rates

2. Available medicines for:

a. Macular degeneration

b. Retinal vein occlusion

c. Diabetic macular edema

d. Uveitis

e. Infection

II. Challenges to Delivery

A. Barriers to penetration

1. Cornea

2. Conjunctiva

3. Sclera

4. Blood-ocular barrier

a. Tight junctions of endothelial cells

b. Tight junctions of retinal pigment epithelium (RPE) and ciliary epithelium

B. Larger size of biologics

C. Stability of biologics

III. Topical Delivery

A. Drug-eluting punctal plugs

1. Latanoprost

2. Olopatadine (Patanlol)

B. Iontophoresis

IV. Sub-Tenon or Subconjunctival Injections

Sirolimus (rapamycin): Altering formulation to suspen-sion improves duration of action.

V. Suprachoriodal Space Cannulation

VI. Intravitreal Devices

A. Approved

1. Vitrasert (1996)

a. Ganciclovir

b. Cytomegalovirus retinitis

c. 6-month duration

2. Retisert (2005)

a. Fluocinolone

b. Uveitis

c. 3-year duration

3. Ozudex (2009)

a. Dexamethasone

b. Retinal vein occlusion, uveitis

c. 3-6 month duration

B. In development

1. Iluvien (Medidur)

a. Fluocinolone

b. 2-3 year duration


2. I-vation

a. Trimcinolone

b. 18-36 month duration


3. Brimonidine biodegradable implant

4. Latanoprost biodegradable implant

5. Nanoparticles and liposomes

a. Pegaptanib (Macugen)

b. Verisome biodegradable platform

c. Voclosporin LUX 214

d. Ranibizumab (Lucentis)

6. Laser-activated reservoirs

VII. Encapsulated Cell Technology: Neurotech

A. Ciliary neurotrophic factor (CNTF) made by RPE cells

B. 3+ year duration

C. Retinitis pigmentosa and geographic atrophy trials

VIII. Ocular Pump: Replenish

A. Implantable, refillable

B. Programmable to deliver nanoliter doses

Selected Readings

1. Yasukawa T, Tabata Y, Kimura H, Ogura Y. Recent advances in intraocular drug delivery systems. Recent Pat Drug Deliv Formul. 2011; 5(1):1-10.

New Ocular Drug Delivery DevicesRobert L Avery MD


2. Choonara YE, Pillay V, Danckwerts MP, Carmichael TR, du Toit LC. A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases. J Pharm Sci. 2010; 99(5):2219-2239.

3. Edelhauser HF, Rowe-Rendleman CL, Robinson MR, et al. Oph-thalmic drug delivery systems for the treatment of retinal diseases: basic research to clinical applications. Invest Ophthalmol Vis Sci. 2010; 51(11):5403-5420.

4. Anderson OA, Bainbridge JW, Shima DT. Delivery of anti-angio-genic molecular therapies for retinal disease. Drug Discov Today. 2010; 15(7-8):272-282.

5. Hsu J. Drug delivery methods for posterior segment disease. Curr Opin Ophthalmol. 2007; 18(3):235-239.

6. Kuno N, Fujii S. Biodegradable intraocular therapies for retinal dis-orders: progress to date. Drugs Aging. 2010; 27(2):117-134.

7. Kuppermann BD, Loewenstein A. Drug delivery to the posterior segment of the eye. Dev Ophthalmol. 2010; 47:59-72.

8. Lee SS, Robinson MR. Novel drug delivery systems for retinal dis-eases: a review. Ophthalmic Res. 2009; 41(3):124-135.

9. Alexis F, Pridgen EM, Langer R, Farokhzad OC. Nanoparticle tech-nologies for cancer therapy. Handb Exp Pharmacol. 2010; 197:55-86.


I. Definition and Impact of Bioelectronics for Medical Applications

II. Common Features Across Most Implantable Bioelec-tronics

A. Power and data

B. Hermetic packaging

C. Interface polymers

D. Heat dissipation

E. Implant half-life

III. Visual Prostheses

A. Nonretinal prosthesis

1. Visual cortical

2. Optic nerve

3. Sensory substitution devices

B. Retinal prostheses

1. Subretinal prosthesis

2. Epiretinal prosthesis: SSMP Argus II clinical trial results

3. Future of retinal prostheses

IV. Mini Drug Pump

A. Drug delivery approaches and their limitations

B. Fabrication of MEMS mini drug pump

C. Pump performance

D. Pump biocompatibility

E. Future plans

Bioelectronics in OphthalmologyMark Humayun MD PhD


Introduction

Despite advances in treatments for AMD, a large number of adults live with loss of central vision that impacts activities such as reading, driving, and recognizing faces. Advances in imaging both scotomas and fixation have augmented our knowledge of how patients compensate for their vision loss and how rehabilita-tion can assist them. Comprehensive rehabilitation goes beyond simply supplying devices that magnify.

Background

The Eye Disease Prevalence Research Group estimated in 2004 that late AMD affected more than 1.75 million individuals in the United States. Increasing longevity means that individuals may live 30 or 40 years with chronic vision loss from AMD. Vision rehabilitation aims to assist such individuals with devices and practical strategies.

evaluation of Remaining Visual Function

The loss of central vision in patients with AMD can be charac-terized by a clinical triad: visual acuity, contrast sensitivity, and documentation of both central scotomas and habitual fixation. This is outlined below in 2 contrasting cases.

Case 1Patient A has acuity 20/800 O.D., 20/80 O.S. The left eye has severe loss of contrast sensitivity. Macular perimetry with supra-threshold testing, in the better-seeing left eye, demonstrates a small central area of seeing retina (in the central circle) sur-rounded by dense scotoma (open circles). The patient is habitu-ally fixating in the small area of central field (F1- Fovea) but also uses eccentric fixation (F2).

Figure 1.

Assessment of Patient A: This patient is able to read smaller print with low levels of magnification; however, she finds it very difficult to read larger print due to the limited area of central vision. With education and training, she was made aware of how she switches between fixing with the fovea and fixing with the eccentric area of fixation (preferred retinal loci, or PRL). She was trained to use magnification when fixing with the PRL. She was advised about using audio output on her iPhone, assisted to use computer accessibility, and educated about fall prevention.

Case 2Patient B has acuity 20/500 O.D., 20/150 O.S. Despite asymmet-ric visual acuity, his contrast sensitivity is symmetric (log 1.05 O.D. and O.S.) and only moderately reduced. His better-seeing left eye has a central scotoma. He is fixing with unstable eccen-tric fixation using a PRL located between the disc and fovea.

Figure 2.

Assessment of Patient B: This patient complained that he misreads the end of words. With education about his scotoma he appreciated how the central field defect was obscuring the field right of fixation, hence the ends of words. He was trained to use appropriate magnification, text-to-speech software, and strate-gies to self-administer medications accurately.

Model of Multidisciplinary Low Vision Rehabilitation

The circle diagram in Figure 3 illustrates how the ophthalmolo-gist, at the 6 o’clock position, is in a unique position to advise patients about options for rehabilitation and facilitate the con-tinuum of care represented by the circle.2

Low Vision Therapy for Advanced AMDMary Lou Jackson MD


Figure 2.

elements of Comprehensive Vision Rehabilitation

Five elements that are assessed and addressed in Comprehensive Vision Rehabilitation are outlined in the American Academy of Ophthalmology Preferred Practice Pattern Vision Rehabilitation for Adults guide.3 Each is described briefly below.

Reading Reading is the most common goal that patients express when presenting for rehabilitation. Reading requires intact central visual field. For those with normal vision it is estimated that an area of 4 by 6 degrees is required to read fluently. Patients may have central scotomas that involve the fovea or they may have scotomas that are located only in a paracentral region. Tradi-tional perimetry requires central fixation and is inaccurate when patients have disease that impacts ability to fixate with the fovea. Macular perimeters include real-time tracking of retinal location and, hence, accurate perimetry. Various configurations of scoto-mas impact reading in a variety of ways. Left paracentral scoto-mas, for example, cause one to have difficulty with page naviga-tion, as the beginning of the next line is obscured. As described above, a right-sided scotoma obscures the ends of words, and a foveal-sparing scotoma makes it difficult to read large print or use moderate magnification as there is a very limited area of central field. A prospective, observational case series of 25 patients with recent loss of vision in the second eye due to macu-lar disease demonstrated that all patients enrolled in that trial had developed a consistent PRL by 6 months, most (16) were not aware of using such eccentric fixation, and 11 were using multi-ple PRLs by one year.4 Ongoing research is evaluating the benefit of training eccentric viewing. Electronic devices, which combine a video camera and a monitor, offer not only variable magnifica-tion but also enhanced contrast and binocular viewing.

Independent activities of daily livingWithout rehabilitation, patients with central vision loss become dependent on others to read their mail, manage their finances, organize medications, and prepare meals. Medicare and most insurance companies fund both a low vision evaluation by an ophthalmologist or optometrist and training by an occupational therapist to train patients to use devices and alternate strategies.

Patient safetyCentral vision loss increases the risk of falling, making errors when taking medications, or sustaining burns or cuts. These risks can be addressed in rehabilitation.

ParticipationTransportation alternatives, when patients cannot drive, and other barriers to participating in one’s community are addressed in rehabilitation.

Psychosocial well-beingAll patients with vision loss must make adjustments. Vision loss increases risk of depression. Also, up to one-third of patients with AMD who present for Vision Rehabilitation experience Charles Bonnet syndrome, recurrent visual hallucinations with insight, and may be anxious about why they experience such a peculiar symptom.5

Summary

Overall, the treating ophthalmologist is in a unique position to encourage patients with AMD to access vision rehabilitation. Such a recommendation can benefit the patient, and it may also allow the retinal specialist to gain practice efficiencies as topics that patients may wish to discuss with their ophthalmologist can be discussed and addressed in practical ways by the vision reha-bilitation clinician.

References

1. Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Oph-thalmol. 2004; 122(4):477-485.

2. Jackson ML. Addressing core competencies in ophthalmology resi-dent education: what the vision rehabilitation setting offers. J Aca-demic Ophthalmol. 2010; 3(1):15-21.

3. American Academy of Ophthalmology. Preferred Practice Pattern: Vision Rehabilitation for Adults. AAO: San Francisco, 2007.

4. Crossland M, Culham L, Stamatina A, Rubin G. Preferred retinal locus development in patients with macular disease. Ophthalmol-ogy 2005; 112(9):1579-1585.

5. Jackson ML, Bassett K, Nirmalan P, Sayre E. Contrast sensitivity and visual hallucinations in patients referred to a low vision reha-bilitation clinic. Br J Ophthalmol. 2007; 91(3):272-276.

2011 Subspecialty Day | Retina Section VI: Retinal Vein Occlusion 47

Hemiretinal Vein Occlusion Characteristics in the Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) StudyMichael S Ip MD

Purpose

The SCORE Study consists of 2 multicenter randomized trials investigating the safety and efficacy of standard of care vs. intra-vitreal triamcinolone to treat branch (BRVO) and central retinal vein occlusion (CRVO). In the SCORE study, participants with hemiretinal vein occlusion (HRVO) were considered a subset of BRVO. We present the Fundus Photograph Reading Center (FPRC) baseline evaluation of HRVO from color fundus photo-graphs (FP), fluorescein angiograms (FA), and optical coherence tomograms (OCT) compared with all BRVO and CRVO base-line features.

Methods

The SCORE reading center definition of HRVO is an RVO involving either the superior or inferior hemisphere where the retinal hemorrhages are nearly equal in the 2 altitudinal quad-rants (nasal and temporal aspects) of the involved hemisphere. HRVO characteristics at baseline are evaluated using 3 imag-ing modalities: FP for the area of retinal thickening and area of hemorrhage within a 16 disc area ETDRS grid, FA for the area of leakage within the grid, and OCT scans for center point thickness.

Results

Baseline FPRC evaluation of 48 HRVO participants represent a subset of the 682 participants (271 CRVO, 411 BRVO) evalu-ated from November 2004 to February 2008. The number of inferior and superior HRVO is nearly equal (25 superior; 23 inferior).

For participants with HRVO, the mean area of retinal thick-ening is 9.9 disc areas (DA) (CRVO 12.3 DA/BRVO 7.5 DA) and mean area of retinal hemorrhage is 4.4 DA (CRVO 3.7 DA/BRVO 2.9 DA) within the grid. On FA, the mean area of fluores-cein leakage within the grid is 8.3 DA (CRVO 10.9 DA/BRVO 7.0 DA). OCT shows a mean center point thickness of 580 µm for HRVO (CRVO 658 µm/BRVO 524 µm)

Conclusion

In the SCORE Study, comparison of baseline characteristics between HRVO and BRVO and CRVO revealed that the mean areas of retinal thickening, fluorescein leakage, and center point thickness on OCT fell in between those measurements for BRVO and CRVO participants. However, the mean area of retinal hem-orrhage was greater for HRVO participants than for both BRVO and CRVO participants.

48 Section VI: Retinal Vein Occlusion 2011 Subspecialty Day | Retina

I. Retinal Vein Occlusion

A. Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic reti-nopathy. Macular edema (ME) is a major cause of vision loss in patients with RVO.

B. Worldwide prevalence estimates indicate that approximately 16.4 million adults are affected by RVO: 13.9 million by branch RVO (BRVO) and 2.5 million by central RVO (CRVO).1

C. In BRVO patients, visual acuity (VA) may improve over time without intervention, although improve-ment beyond 20/40 is uncommon.2 Patients with CRVO typically have a poor baseline visual acuity VA, which may deteriorate over time if untreated.3

II. Ranibizumab Treatment in RVO: BRAVO and CRUISE Studies

A. Elevated intraocular vascular endothelial growth factor (VEGF) levels have been reported in patients with BRVO and CRVO,4-7 and excess VEGF pro-duction may be a major contributor to ME develop-ment.8-10

B. Ranibizumab (Lucentis; Genentech, South San Fran-cisco, CA) is a high-affinity anti-VEGF Fab, which binds to and neutralizes all isoforms of VEGF-A and their biologically active degradation products.11

C. BRAVO and CRUISE were Phase 3, multicenter, randomized studies that assessed efficacy and safety of ranibizumab in patients with BRVO (BRAVO)9 and CRVO (CRUISE).8

1. In both studies, patients received 6 consecutive monthly sham or ranibizumab (0.3 mg or 0.5 mg) injections (treatment period), followed by a 6-month observation period, during which patients received re-treatment as needed accord-ing to protocol-specified criteria: BCVA ≤ 20/40 or central subfield thickness (CST) ≥ 250 µm.8,9

2. Patients randomized to sham could receive 0.5-mg ranibizumab during the observation period, while patients randomized to ranibizumab remained on their assigned dose.8,9

3. In BRAVO and CRUISE, monthly ranibizumab provided rapid and sustained clinically and sta-tistically significant benefits in BCVA and central foveal thickness (CFT)8,9 that were maintained during the observation period.12

4. Monthly ranibizumab was associated with low rates of ocular and nonocular adverse events (AEs).8,9

III. HORIZON RVO Study

A. HORIZON RVO was a 24-month, open-label, sin-gle-arm, multicenter, extension study that assessed long-term safety and efficacy of ranibizumab in patients with ME secondary to RVO who had com-pleted BRAVO or CRUISE.

1. Patients were evaluated quarterly (mandatory) or more frequently if physician deemed necessary.

2. Eligible patients received intraocular injections of ranibizumab 0.5 mg at ≥ 30-day intervals based on protocol-specified re-treatment criteria: mean CST ≥ 250 μm on OCT or the presence of ME deemed by the investigator to be affecting the patient’s VA.

3. Patients from BRAVO were eligible for rescue laser treatment if VA was 20/40 or worse and vision loss was due to perfused ME.

4. Enrolled patients were followed for up to 24 months or until 30 days after FDA approval of ranibizumab for RVO.

5. Ocular and nonocular (eg, potentially related to systemic VEGF inhibition, myocardial infarction, and cerebrovascular accident) AEs were assessed.

6. Efficacy outcomes included mean changes from HORIZON RVO baseline in BCVA and CFT at Month 12, and the proportion of patients who gained ≥ 15 ETDRS letters between HORIZON RVO baseline and Month 12.

7. The number of ranibizumab injections and res-cue laser treatments (for BRVO patients) were assessed.

B. Results

1. 608 patients were enrolled in HORIZON RVO; 304 patients each from BRAVO and CRUISE. Of these, 205 patients (67%) from BRAVO and 181 patients (60%) from CRUISE completed Month 12 of HORIZON RVO; 88% of patients prematurely discontinued due to study termina-tion 30 days following FDA approval of ranibi-zumab for RVO.

2. Across treatment groups, BRAVO patients received a mean of 2.5 injections and CRUISE patients received a mean of 3.8 injections of 0.5-mg ranibizumab through Month 12 of HORI-ZON RVO. Approximately 29% of patients received no ranibizumab injections during HORIZON RVO.

Longer-term Follow-up on Ranibizumab for Retinal Vein Occlusion: HORIZON RVOCarl Awh MD


3. Fewer than 13% of BRVO patients received rescue laser therapy during HORIZON RVO; of these, most (29 out of 33) received only 1 laser treatment.

C. Safety was consistent with previous Phase 3 ranibi-zumab trials.

1. The rate of ocular serious AEs (SAEs) in the study eye was between 2% and 9% across treat-ment groups. Twelve BRVO patients and 18 CRVO patients experienced at least 1 ocular SAE in HORIZON RVO.

2. In BRVO and CRVO patients, incidence of SAEs potentially related to systemic VEGF inhibition in the study eye was between 1% and 6% during HORIZON RVO. Twelve BRVO patients and 11 CRVO patients experienced at least 1 SAE potentially related to systemic VEGF inhibition.

D. Efficacy outcomes

1. From BRAVO baseline, BRVO patients receiving sham/0.5-mg, 0.3/0.5-mg, and 0.5-mg ranibi-zumab had mean changes in BCVA of +15.6,

+14.9, and +17.5 letters, respectively, at Month 12 of HORIZON RVO (see Figure 1A). BCVA remained stable in BRVO patients over the first 12 months of HORIZON RVO, with mean changes within ±2 letters from HORIZON RVO baseline (see Figure 1B).

2. From CRUISE baseline, CRVO patients in the sham/0.5-mg, 0.3/0.5-mg, and 0.5-mg ranibi-zumab groups had mean changes in BCVA of +7.6, +8.2, and +12.0 letters, respectively, at Month 12 of HORIZON RVO (see Figure 2A). Over the first 12 months of HORIZON RVO, BCVA decreased in CRVO patients, with mean reductions of 4 to 5 letters from HORIZON RVO baseline (see Figure 2B).

3. Mean increases in CFT between HORIZON RVO baseline and Month 12 were minimal for BRVO patients in the sham/0.5-mg, 0.3/0.5-mg, and 0.5-mg ranibizumab groups (3.7 µm, 6.3 µm, 35.3 µm, respectively), and greater in CRVO patients (79.7 µm, 88.3 µm, 68.4 µm, respectively).

Figure 1. Mean change in VA up to Month 12 of HORIZON RVO in BRAVO patients from (A) BRAVO baseline and (B) HORIZON RVO baseline. Vertical bars are ± 1 SEM. *Includes patients with data available at that time point and BRAVO baseline. † Includes patients with data available at HORIZON RVO baseline and Month 12. Abbreviations: RVO indicates reti-nal vein occlusion; SEM, standard error of the mean; VA, visual activity.

Figure 2. Mean change in VA up to Month 12 of HORIZON RVO in CRUISE patients from (A) CRUISE baseline and (B) HORIZON RVO baseline. Vertical bars are ± 1 SEM. * Includes patients with data available at that time point and CRUISE baseline. † Includes patients with data available at HORIZON RVO baseline and Month 12. Abbreviations: RVO indicates reti-nal vein occlusion; SEM, standard error of the mean; VA, visual acuity.


IV. Conclusions

Long-term treatment with 0.5-mg ranibizumab dur-ing HORIZON RVO was well tolerated, with no new safety events. Ocular SAE rates ranged from 2.2% to 9.3%, while rates of SAEs potentially related to systemic VEGF inhibition were consistent with prior ranibizumab trials. Study-defined re-treatment cri-teria maintained improvements achieved at the end of BRAVO for both VA and CFT in BRVO patients but did not seem sufficient to maintain VA and CFT improvements achieved by the end of CRUISE in CRVO patients.

References

1. Rogers S, McIntosh RL, Cheung N, et al; International Disease Consortium. The prevalence of retinal vein occlusion: pooled data from population studies in the United States, Europe, Asia, and Australia. Ophthalmology 2010; 117(2):313-319 e1.

2. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Oph-thalmology 2010; 117(6):1094-1101 e5.

3. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Oph-thalmology 2010; 117(6):1113-1123 e15.

4. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994; 331(22):1480-1487.

5. Noma H, Funatsu H, Yamasaki M, et al. Pathogenesis of macular edema with BRVO and intraocular levels of VEGF and interleu-kin-6. Am J Ophthalmol 2005; 140(2):256-261.

6. Yoshimura T, Sonoda KH, Sugahara M, et al. Comprehensive anal-ysis of inflammatory immune mediators in vitreoretinal diseases. PLoS One 2009; 4(12):e8158.

7. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macu-lar edema due to retinal vein occlusions: implication of VEGF as critical stimulator. Mol Ther. 2008; 16(4):791-799.

8. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occusion: six month primary end point results of a Phase III study. Ophthalmology 2010; 117(6):1124-1133 e1.

9. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macu-lar edema following branch retinal vein occlusion: six-month pri-mary end point results of a Phase III study. Ophthalmology 2010; 117(6):1102-1112 e1.

10. Ozaki H, Hayashi H, Vinores SA, et al. Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res. 1997; 64(4):505-517.

11. Ferrara N, Damico L, Shams, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006; 26(8):859-870.

12. Ho A, et al. Ranibizumab in patients with macular edema follow-ing retinal vein occlusion: 12-month outcomes of BRAVO and CRUISE. Program and abstracts of the Association for Research in Vision and Ophthalmology (ARVO); Fort Lauderdale, FL; 2010.


I. Introduction

A. Central retinal vein occlusion (CRVO)

1. CRVO is an important cause of vision loss in older adults, affecting approximately 2.5 million persons worldwide.1,2

2. CRVO is characterized by dilated tortuous reti-nal veins, retinal hemorrhage, cotton-wool spots, and optic disc swelling. The primary cause of vision loss is macular edema, stemming from an obstructive thrombus in the retinal vein.

3. The occlusion results in decreased retinal perfu-sion and retinal hypoxia, with development of intraretinal hemorrhage, fluid exudation, and possibly, neovascular complications.

4. In the absence of a proven and effective therapy for visual decline associated with CRVO, the standard-care treatment had been observation and panretinal photocoagulation.3,4

5. Recently, large and controlled studies showed that central retinal thickness and visual acuity may be improved with intravitreal corticoste-roids or anti-VEGF agents.5,6

B. VEGF Trap-Eye

1. Vascular endothelial growth factor (VEGF), a hypoxia-inducible angiogenic and vascular permeability factor, is strongly implicated in the edema and neovascularization associated with CRVO.7

2. VEGF Trap-Eye is specifically designed to block VEGF-A and placental growth factor (PlGF).

a. A fusion protein comprised of key domains from human VEGF receptors 1 and 2 and human IgG Fc

b. Blocks all VEGF-A isoforms and PlGF

c. High affinity: Binds to VEGF-A and PlGF more tightly than native receptors

d. Contains all human amino acid sequences

e. Penetrates all layers of the retina (MW ~ 110,000)

f. VEGF Trap-Eye is specially purified and for-mulated for intravitreal injection.

II. Methods

A. Two Phase 3 studies conducted in patients with CRVO (see Figure 1)

Figure 1. COPERNICUS and GALILEO: CRVO Phase 3 study design.

B. COPERNICUS was conducted in North America, and GALILEO was conducted in Europe and the Asia-Pacific region.

C. Key inclusion criteria

1. Macular edema secondary to CRVO with central retinal thickness ≥ 250 µm

2. ETDRS BCVA of 20/40 to 20/320 (73 to 24 let-ters) in the study eye

D. Key exclusion criteria

1. Previous use of intraocular or periocular cortico-steroids in the study eye

2. Previous treatment with anti-angiogenic drugs in the study eye

3. Prior panretinal laser photocoagulation or macu-lar laser photocoagulation in the study eye

4. CRVO disease duration > 9 months

E. Treatment groups and randomization

1. Patients were randomized 3:2 to 2-mg VEGF Trap-Eye or sham injections every 4 weeks.

2. Week 24 to Week 52, patients received either 2-mg VEGF Trap-Eye as needed (p.r.n.) or sham injections based on re-treatment criteria.

F. Outcomes

1. Primary endpoint: The proportion of patients who gained ≥ 15 ETDRS letters from baseline at Week 24

2. Key secondary endpoint: The change in BCVA from baseline to Week 24

VEGF Trap-Eye for Retinal Vein Occlusion: COPERNICUS and GALILEOW Lloyd Clark MD


3. Week 24 (primary analysis) results are described below.

III. Results

A. Efficacy

1. Patients randomized: 189 patients in COPERNI-CUS and 177 patients in GALILEO

2. Primary endpoint: Statistically significant differ-ences between patients receiving VEGF Trap-Eye treatment compared with sham were seen at Week 24 (see Table 1) in both studies.

3. Key secondary endpoint: Statistically significant differences between VEGF Trap-Eye treatment and sham were seen in the mean change in letters of vision (see Table 2) in both studies.

B. Safety

1. In both studies, 2-mg VEGF Trap-Eye treatment was generally well tolerated (see Table 3).

2. COPERNICUS: The most frequently reported treatment-emergent adverse events (TEAEs) were conjunctival hemorrhage, visual acuity reduced, and eye pain.

3. GALILEO: The most frequently reported TEAEs were eye pain, conjunctival hemorrhage, and elevated IOP.

IV. Conclusions

A. Results from the COPERNICUS and GALILEO studies were consistent.

B. In patients with macular edema secondary to CRVO, dosing monthly with 2-mg VEGF Trap-Eye resulted in a statistically significant improvement in visual acuity compared with sham treatment.

C. VEGF Trap-Eye treatment was generally well toler-ated and had a generally favorable safety profile.

Table 1. Proportion of Patients Who Gained ≥15 ETDRS Letters From Baseline

2-mg VEGF Trap-Eye Sham P-value

COPERNICUS 56.1% 12.3% (P < .0001)

GALILEO 60.2% 22.1% (P < .0001)

Table 2. Mean Change From Baseline for BCVA in ETDRS Letters

2-mg VEGF Trap-Eye Sham P-value

COPERNICUS 17.3 –4.0 (P < .001)

GALILEO 18 3.3 (P < .0001)

Table 3. Ocular Serious Adverse Events in Study Eye in ≥ 2% of Patients in Any Arm

COPERNICUS GALILEO

2-mg VTE Sham 2-mg VTE Sham

n (safety analysis set) 114 74 104 68

No. of patients with at least 1 SAE 4 (3.5%) 10 (13.5%) 3 (2.9%) 6 (8.8%)

Vitreous hemorrhage 0 4 (5.4%) – –

Glaucoma 0 2 (2.7%) 0 2 (2.9%)

Macular edema – – 0 2 (2.9%)

Iris neovascularization 0 2 (2.7%) – –

Retinal hemorrhage 0 2 (2.7%) – –

Abbreviations: VTE indicates VEGF Trap-Eye; SAE, serious adverse event.


References

1. Mitchell P, Smith W, Chey T, Wang JJ, Chang A. Prevalence and associations of retinal vein occlusion in Australia: the Blue Moun-tains Eye Study. Arch Ophthalmol. 1996; 114(10): 1243-1247.

2. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of reti-nal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010; 117(2): 313-3139 e1.

3. Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2007; 114(3): 507-519, 524.

4. Central Vein Occlusion Study Group. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlu-sion. The Central Vein Occlusion Study Group N report. Ophthal-mology 1995; 102(10):1434-1444.

5. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial com-paring 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(9):1101-1114.

6. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2008; 117(6):1124-1133 e1.

7. Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006; 26(8):859-870.


Objective

To evaluate the long-term effects of combination therapy by determining if a sustained-released corticosteroid injection (dexa-methasone intravitreal implant 0.7 mg) with an anti-VEGF agent (bevacizumab) can be synergistic for the treatment of retinal vein occlusion (RVO) in terms of visual acuity and central field thickness on OCT. This clinical trial was launched to determine if these 2 medications combined could minimize the number of injections and increase the duration of effects, as well as to mir-ror a physician in a common office setting. The extension trial was to determine if the increase in vision and decrease in OCT thickness could be replicated and if the duration of effect and safety could be maintained.

Methods

The study is a prospective, nonrandomized, open-label pilot extension to the original 6-month combination study presented last year.1 Patients, diagnosed with either central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO), received anti-VEGF injection followed by dexamethasone 0.7-mg sustained-release implant 2 weeks later. Previously treated and naive patients were included, and exclusion criteria included history of vitrectomy and/or rubeotic or advanced glaucoma. Best corrected visual acuity (Snellen), Cirrus OCT, and IOP mea-surements were obtained at every visit. Patients were re-treated if OCT central field thickness increased by 50 microns from previ-ous measurements or if vision decreased by 6 letters. IOP greater than 22 was treated with topical medication. Patients were con-verted during the extension phase to FDA-approved ranibizumab from bevacizumab if insurance permitted.

Results

Fifty-eight patients received combination therapy. Twenty-eight patients of the original 32 received at least 12 months of follow-up. Thirty-three patients had bevacizumab initially, 9 had ranibi-

zumab initially, and 16 switched during the study. Mean visual acuity improved by 11 letters in Month 1, 15 letters in Month 3, 18 in Month 6, 13 in Month 8, and 13 in Month 12. Thirty-eight percent of patients gained 3 lines or more in visual acuity in Month 1, 35% in Month 3, 40% in Month 6, 46 % in Month 8, and 34% in Month 12. Mean OCT thickness decreased by 140 μm at 2 weeks, 144 μm in Month 1, 96 μm in Month 3, 93 μm in Month 6, 173 μm in Month 9, and 159 μm in Month 12. Reports of OCT thickness less than 300 μm were seen with 54% of patients at 2 weeks, 80% in Month 1, 65% in Month 3, 59% in Month 6, 55% in Month 9, and 74% in Month 12. Re-treatment was needed approximately 17 weeks after the dexa-methasone intravitreal implant injection in the first cycle, and after 16 weeks in the second cycle. Eighteen patients (30%) were treated once. IOP greater than or equal to 23 was seen in 17% of patients (10/58) in the first 6 months, and in 18% (18/45) in the second 6 months.

Conclusion

Combination therapy using an anti-VEGF agent and dexametha-sone 0.7-mg sustained release implant is synergistic, providing sustained increases in visual acuity, as well as reduction in central field thickness over multiple treatment cycles in patients diag-nosed with RVO. In addition, this therapy can provide predict-able intervals for re-treatment. The IOP profile is similar to other dexamethasone implant studies.

Reference

1. Singer MA, Bell DJ, Wood PA, Board T. Combination treatment using anti-VEGF therapy and sustained release dexamethasone 0.7mg for retinal vascular disease. Presented at the 2010 meeting of the American Society of Retinal Specialists; Vancouver, Canada; and in Retina 2010: A Panretinal Perspective (Abstracts of 2010 AAO Subspecialty Day). San Francisco: AAO; 2010, late-breaking presentation.

Combination Therapy (Ozurdex and Anti-VEGF Agents) for Retinal Vein OcclusionCombination Treatment Using Anti-VEGF Therapy and Sustained Release Dexamethasone 0.7 mg for Retinal Vascular Disease — Extension Trial

Michael A Singer MD, Darren Bell MD, Paul Woods BS, Angela Herro MD, Salaman Porbandarwalla MD, Beatrice Guajardo COA, Joseph M Pollard MPH, Jamie L Herrmann BA

2011 Subspecialty Day | Retina Section VII: Business of Retina 55

Physician Compensation: What Are You Worth?Antonio Capone Jr MD

I. Talking About Compensation

II. Common Models

A. Practice settings

B. Compensation and practice culture

1. Salary

2. Equal shares

3. Productivity

4. Hybrid

III. Developing a Compensation Plan

A. Components

1. Financial productivity

2. Clinical productivity

3. Other

a. Administration

b. Academic

c. Research

d. Other

B. Compensating retiring retinologists

IV. Key Considerations

A. Impact on practice culture

B. Building consensus

C. Focus on fairness

D. Review and revise

Selected Readings

1. Physician compensation eight percent of health care costs. Jackson Healthcare website, May 26, 2011. www.jacksonhealthcare.com/ media-room/press-releases/md-salaries-as-percent-of-costs.aspx. Accessed August 15, 2011.

2. Dunham DP. Evolution of compensation in academic medicine. MGMA APA Matrix, Summer 2005.

3. Greenfield WR. In search of an effective physician compensation formula. Fam Pract Manag. 1998; 5(9):50-57.

4. Johnson B, Walker-Keegan DL. Physician Compensation Plans: State-of-the-Art Strategies. Medical Group Management Associa-tion; 2006.

5. Medical Group Management Association’s Physician Compensa-tion and Production Survey, 2010 report based on 2009 data.

6. Recchia FM, Carlson BR, Sternberg P. The future of the academic ophthalmologist. Retinal Physician, January 2009.

http://www.jacksonhealthcare.com/media-room/press-releases/md-salaries-as-percent-of-costs.aspx

http://www.jacksonhealthcare.com/media-room/press-releases/md-salaries-as-percent-of-costs.aspx

56 Section VII: Business of Retina 2011 Subspecialty Day | Retina

Prior to the passage of Medicare and Medicaid in 1963, the elderly and the poor represented the largest group of Americans without significant access to health care. In 1963, only 50% of Medicare beneficiaries had health insurance. With implementa-tion of Medicare and Medicaid, access to ophthalmic services dramatically expanded, and so did the costs. In order to attract physicians to participate, Medicare used familiar commercial intermediaries to administer the plan and physicians were paid “usual, customary and reasonable” fees. In 1989 Congress passed amendments to the Social Security Act to pay physicians on the basis of resource use, Resource Based Relative Value Scale (RBRVS).

However, the volume of services exploded and health care spending accounted for almost 16% of GDP by 2010. From 1996 to 2002, employer-sponsored premiums increased 85%. In 2008, the average premium for a family of 4 was $12,846 (one-third out of pocket). Out-of-pocket costs for a family of 4 aver-aged $16,900 in 2009, rising to $18,000 in 2010 and projected to rise to $36,000 by 2019. Out-of-pocket medical spending was the major factor in the loss of purchasing power of the American middle class. There was also the realization that although the United States had the world’s highest spending on health care, our outcomes and quality lagged behind that of almost all indus-trialized nations. Out of control spending and less than optimal quality stimulated the passage of the Patient Protection and Affordable Care Act (PPACA) of 2010.

The passage of PPACA will lead to fundamental changes in how medical services are delivered. The impact of PPACA will be characterized by:

• Increaseddemandforservices• Paymentreform• Emphasisonquality• ComparativeEffectivenessResearch(CER)• Afocusonpopulationhealth,healthdisparities,and

patient centeredness

Demand for Physician Services

When 32 million Americans obtain health care coverage in 2015 and the Baby Boomers invade Medicare, it will strain ophthalmic resources. Our production of new ophthalmologists will remain stagnant. The profession will practice team-based care utilizing extenders. We will become managers and not merely providers of eye care. Technology and the use of remote imaging for screening of diabetic retinopathy and macular degeneration will be integral to our success in meeting the demands of society.

Payment Reform

Payment reform will lead to a dramatic change in how we are paid. We will be paid on the basis of quality, patient-reported outcomes, patient satisfaction, and the efficiency with which these services are delivered. Unfettered fee for service that rewards the volume of services provided will be phased out. By 2015 those of us who achieve validated quality scores will be

rated on the efficiency of how that care is delivered. Those who reach quality goals in an efficient manner for 2 to 4 quality mea-sures will be rewarded with an increased payment for all of our services the following year. Those who are inefficient will have their payments cut.

High-quality, efficient ophthalmologists will be rewarded with referrals. Those who utilize a disproportionate amount of resources will be shunned.

Quality

Current validated ophthalmic quality measures emphasize pro-cesses of care. New measures will not only note that you appro-priately performed a service, it will also measure your outcomes. How often does a postop cataract extraction patient require readmission within 30 days? What percentages of wet AMD patients have stable vision after 1 year? Other domains of qual-ity include efficiency scores and patient reported outcomes (eg, VF 14). Our outcomes will be publicly reported and will be part of maintenance of board certification. We will have widespread adoption of electronic health records by 2015 and will report data to an ophthalmic registry. The use of the registry is impera-tive to achieve individual professional improvement.

Comparative Effectiveness Research

CER will be operational by 2014. Physicians and patients will have access to evidence-based comparative studies of competing drugs, devices, procedures, or processes of care. The CATT was a seminal study not only for its role in AMD but as a template for future comparative effectiveness studies. The CATT trial entailed a rewrite of the HHS clinical trial policy, which will facilitate the work of the Patient Centered Outcomes Research Institute (PCORI), the CER entity created in PPACA.

Health Care Disparities

Robust research will be funded to elucidate the cause of outcome disparities in some patient populations. These disparities are not just financial but are due to discrepancies in cultural literacy and other factors that remain to be explored. We will be graded on our ability to not only deliver services effectively but to improve the health of the population where we practice.

Patient Centeredness

As noted above, patients are paying a greater percentage of their health care costs out of pocket. As a result they want data to deter-mine the value of the services they attain. They will receive public data on our costs, quality, outcomes, and patient satisfaction.

Ophthalmology and all of medicine will deliver care and be reimbursed for services very differently from how we practiced in the past. Those who practice evidence-based care in an efficient and patient-centered way while attaining good outcomes will be rewarded. If as a profession we keep patients and quality the cen-ter of our professional lives, then we will continue to prosper.

The Future of U.S. Physician ServicesWilliam L Rich III MD


I. Introduction

Like it or not, electronic health record systems (EHR) systems are slated to become commonplace in ophthal-mology over the next few years regardless of practice setting, geographic location, and subspecialty focus. Retina in particular faces significant obstacles to this progression based on the unique features of its practice with regard to clinical workflow and data manage-ment. For example, just in the management of AMD, monthly visits are commonplace, with the acquisition of large amounts of imaging material over the lifetime of the patient. In addition, retina specialists are used to manual entry methods such has hand drawings of vitreoretinal pathology. These obstacles are among the reasons why adoption of EHR systems has been poor. In 2006, the American Academy of Ophthalmology’s survey of its members found a 12% adoption rate, in comparison to 17% for physicians across all other medical specialties. A Health Information Technology for Economic and Clinical Health (HITECH) $27 bil-lion grant might help offset some costs, but there is no textbook or preferred practice pattern to go by on how to begin this process.

At the Cleveland Clinic, we’ve successfully imple-mented EMR in a subset of our practice with a com-plete roll out expected in the first quarter of 2012. This discussion will focus on the pearls of the process such as identifying essential functions to look for in vendors, tips on the implementation process, and methods by which to track development and meaningful use.

II. Pros of Retina EMR Adoption

A. Access

B. Compliance

C. Portability enhances efficiency.

D. Quality outcomes/research

E. Protection when medical audits occur

F. Security/transparency

G. Less space or medical record storage costs

H. Transcriptions to referring physicians, communica-tion with each other

I. Components can be globally modified with the click of a keystroke. For example, an audit showed another practice lacked a particular exam compo-nent. We could implement that within the matter of a day.

J. We easily realized that the gap of lost bills declined significantly with electronic billing.

K. Allows for the determination of practice efficiencies. For example, you can determine times of check-in to check-out of clinic and all the intervals in between. This allows for a reallocation of resources based on reporting.

II. Cons of Retina EMR Adoption

A. Whatever you think you will save by convert-ing from paper charts (storage fees, personnel for records management) you will spend in information technology maintenance, T1 lines, and electronic backup and storage.

B. You will always need a software upgrade. Expect bugs and annoyances.

C. Keystroke entry is virtually universal. There is little to no utilization of touch screen capabilities in cur-rent models.

D. Cannot collect hard data points from imaging sys-tems (eg, SD-OCT central subfield readings cannot be extracted from the reports and placed within the EMR).

III. Why adopt EMR?

A. Ready available data helps your credibility.

B. Patient education tool

C. Coordinated care when on the same network with primary care physicians and endocrinology

D. ePrescribing

E. Patients access their own records.

IV. Why not adopt EMR?

A. Decrease in efficiency and lost revenue on the initial implementation

B. You will never break even with any of the current government incentives.

C. You will need to either adopt or upgrade your exist-ing imaging systems. No available EMR system inte-grates an EHR with an imaging PACS system.

V. EMR Incentive and Penalty Program

A. HITECH incentive program

B. Penalty program

VI. How to Comply With the Current Program

A. Acquire a certified product

B. Use it in a meaningful way (eg, ePrescribing)

C. Report that you are using it (outcomes measures)

Retina Electronic Health RecordRishi P Singh MD


VII. Meaningful Use

A. Complete clinical and practice objectives

B. Report on 6 quality measures among others upcom-ing (see table attached)

C. Provide the ability to exchange electronic informa-tion

VIII. ePrescribing

A qualified eRx system is one that is capable of all of the following:

A. Generate a complete active medication list incor-porating electronic data received from applicable pharmacies and pharmacy benefit managers (PBMs) if available

B. Select medications, print prescriptions, electronically transmit prescriptions, and conduct all alerts

C. Provide information related to lower cost, therapeu-tically appropriate alternatives (if any)

D. Provide information on formulary or tiered formu-lary medications, patient eligibility, and authoriza-tion requirements received electronically from the patient’s drug plan (if available)

IX. Options for Choosing a System

A. Government certification of product

B. Partner up or go it alone

1. Partner with a local hospital system and retool their EMR package for ophthalmology

2. Partner with another practice. Just because you share systems doesn’t mean that you have to share billing.

C. Consider cloud-based vs. server-based services

1. Cloud based to a large part depends on your Internet connection.

2. Server based depends on your internal building wiring; minimal acceptable level of 10 mega-bytes/sec.

D. Determine the level of customization needed: multi-specialty group vs. retina only practice. Some prac-tices choose different systems for different special-ties.

X. Essential Features to Look For

A. Other practices that have successfully used the same system. Do your homework.

B. Direct letter generation for referring physician

C. Dictation integration

D. Drawing tools

E. Integration with devices to receive HL-7 informa-tion

F. Level of support from the EMR vendor: Initial train-ing, ongoing tech support, possible upgrades

XI. The Implementation Process

A. Train everyone else except your physicians for start-ers.

B. Choose physician champion (in addition to a tech, biller/coder/admin champion).

C. Upgrade the imaging system first, if needed.

D. Customize your templates, medication lists, post-operative instructions, patient handouts, queries needed for PQRI reporting.

E. Downbooking vs. rollout month

F. Do not load old paper records

XII. Focusing on the Ergonomics of Your EMR System

A. Largest screen possible and multiple screens

B. Try tablet devices, but reality is that software wasn’t created for those systems and therefore will likely be inefficient for entry. Additionally, they will tax your wireless network environment.

C. Focus on the patient rather than on the computer screen.

D. Employ scribes/techs to work behind you for the documentation.

XIII. The Drawing Dilemma

A. Drawing numbers have declined with the implemen-tation of EMR.

B. Drawbacks

1. Lack of precise tools, image sets

2. Drawing without annotation = double work

XIV. Potential Pitfalls

A. Cost

B. IT support

C. Communication of EMR between coding/billing, pharmacies, imaging products

D. Adoption

E. Reliability

F. Transfer of records


I. Study Setting

A. Retina-only subspecialty practice

B. Time period analyzed: Last quarter of 2010 and first quarter of 2011

C. Analysis limited to anti-VEGF injections for eyes with wet AMD.

D. Ranizumab (Lucentis) was FDA approved for use in the treatment of wet AMD.

E. Bevacizumab (Avastin) was used off-label for the treatment of wet AMD.

F. Ranizumab was the first choice in treatment for patients with wet AMD.

II. Policy Change

One Medicare HMO changed its policy regarding the coverage of Part B drugs beginning January 2011.

A. Prior to January 2011, Part B drugs, including rani-zumab, were covered at 100% of Medicare allow-able.

B. After January 1, 2011, Part B drug policy now cov-ered only 80% of the Medicare allowable.

III. Data

A. Fourth quarter of 2010

1. Traditional Medicare (n = 3825 injections)

a. 2880/3825 (75.3%) received ranizumab

b. 945/3825 (24.7%) received bevacizumab

2. Medicare Advantage Plan A (n = 548 injections)



B. First quarter of 2011

1. Traditional Medicare (n = 3918 injections)



2. Medicare Advantage Plan A (n = 496 injections)



3. Medicare Advantage Plan B (n = 125 injections)



IV. Analysis

A. Payer policy regarding coverage for anti-VEGF therapies has a significant effect on the administra-tion of specific anti-VEGF therapies.

B. The Medicare Avantage Plan policy change from 100% coverage to 80% coverage resulted in a much lower usage of ranizumab, with a shift to a higher usage of bevacizumab in the patients covered by this plan (see Figure 1).

Figure 1

C. Traditional Medicare had no policy change and showed no change in anti-VEGF use between quarters.

Figure 2.

The Influence of Pricing and Payor Policy on Choice of Anti-VEGF AgentsMitchell S Fineman MD, Allen C Ho MD, Lisa D Mack, Bryan Caruth


D. Another Medicare Avantage Plan that did not change policy regarding the coverage for anti-VEGF therapies showed frequency of use for anti-VEGF therapies similar to traditional Medicare.

Figure 3.


I. Overview

A. The use of high-priced injectable drugs is likely to continue to increase as new drugs come to market.

B. Delays in reimbursement and unpaid claims will stress the financial health of retina practices.

C. Changing medical economics may add an additional challenge to the use of high-cost drugs.

II. Challenges Associated With High-Priced Medications: Overview

A. Difficulty in reimbursements with initial introduc-tion of new drugs

B. Cash flow issues

C. Accounts receivable/accounts payable balances

D. Contractual agreements (buy in, buy out)

E. Physician compensation

F. End of year accounting issues

III. Difficulty in Reimbursements

A. Lack of J code for new drugs delays reimbursement on initial use.

B. Billing of drug without unique J code may result in delayed reimbursement.

C. Delay in obtaining unique code by manufacturer

D. Difficulty in dealing with multiple insurance compa-nies without unique code

IV. Cash Flow Issues

A. Decision to purchase drugs through an intermedi-ary: Advantages

1. Potentially longer payment terms

Currently for purchases through intermediary for Lucentis purchases allows up to 100 days for payment. This gives practices an extended win-dow in which to pay for the drug.

2. Easier accounting: Expense is incurred when the check is written to intermediary.

In a cash-basis practice, which most retina prac-tices are, expenses are recorded at the time of payment for the drug (when the check is written). This allows for easier tracking of the expense as it is usually paid after the reimbursement for the drug has been collected. Therefore, on a bal-ance sheet, the income and expense will tend to match, making the accounting more straightfor-ward.

3. Prepayment allowed: You can pay any time within payment window.

Most intermediary companies will give practices a variable time window in which to pay. Even though the practice may have up to 100 days to pay, there is no penalty for prepayment (payment before 100 days). This allows the practice to pay for the drug once the reimbursement is paid if they wish.

B. Purchase through intermediary: Disadvantages

1. Price for drug may be higher due to intermedi-ary.

Currently, Genentech affords a discount on drugs purchased directly from company through Lucentis direct. Discount may result in increased revenue to practice to offset claims that are not fully reimbursed and administrative costs in try-ing to track and manage payments and receipts.

2. Tendency to generate excess “cash on hand” due to payment terms.

The 100-day payment window allows for the generation of excess cash in the practice. The practice will have collected on accounts receivable for up to 90 days before payment is required. This money will be deposited in the practice account and will appear as “excess cash” or profit. Practices have to be careful to track the drug revenue separately from practice revenue generated by patient management.

3. Lack of the kind of benefits associated with credit cards (cash back, etc.).

Most credit card companies have some type of awards program.

C. Credit card purchases directly from manufacturer: Advantages

1. Discount on drug cost: Added source of revenue to practice.

This helps to offset reduced reimbursements for injections and other procedures associated with the high cost of managing these patients and the high administrative costs in tracking drug charges/payments.

2. Benefits of credit card purchases: Awards pro-grams that may include cash back, airline miles, etc.

3. Ordering directly from the manufacturer

The Boy Who Cried Wolf: Management of High-Priced PharmaceuticalsAlan J Ruby MD


D. Credit card purchases directly from manufacturer: Disadvantages

1. Establishing credit card accounts

Most practices choose to set up individual credit cards for drug purchases. Establishing a large enough credit line for the practice itself may be difficult until payment history is established. Individual cards allow each physician to gain the benefits of the credit card purchases. Establishing credit may, however, involve applications, finan-cial records, etc. for each of the cards.

2. Payments of credit card balances

This is extremely complicated and requires that one person in the practice be designated to man-age the balances. Currently, purchases directly from Genentech are posted onto the credit card after 60 days, with an additional 30 day grace period from the card company for payment. To ensure that the cards do not go over their credit limits, payments can be timed to hit credit cards at the time that the drug posting occurs at 60 days. This ensures that no purchase will be denied due to the credit limit being reached.

3. Accounting issues created by credit cards

Unlike purchases paid for by checks, purchases made by credit cards must be recorded as an expense at the time that the order is placed. This means that the practice will immediately have an expense on its accounting that is not offset by income from the drug reimbursement. At the end of the year this can be a benefit to the group. Excess cash in the practice can be carried over to the next year because the posting of the drug as an expense will reduce the profit shown to the corporation by adding an expense without a con-comitant receipt.

4. Management of excess cash created by differ-ences in payment terms

5. Distribution of “excess cash on hand” to physi-cians

V. Contractual Issues Arising as a Result of Use of High-Cost Drugs

A. Buy in/buy out agreements and the impact of drug inventory

1. Stock purchase

Most practices divide the buy-in agreement into at least 2 parts. Incoming partners are asked to “purchase” their share of the hard assets of the corporation as stock either as a pre-tax or a post-tax purchase. Inventory of drugs is considered a hard asset of the corporation and therefore is included in the purchase price. If a practice keeps a large inventory of drug, the incoming partner will be required to purchase his/her share of this inventory. This can add tens of thousands of dol-lars to the value of the stock that the incoming physician needs to purchase.

2. Stock redemption

This inventory issue may unfairly benefit a departing partner in the same way that it hurt a buying-in partner. Since the inventory is consid-ered a hard asset, the departing partner will be entitled to his/her share of value of the inventory on their way out. In the above example, they would be entitled to $25,000.

B. Buy-in/buy-out agreements and the impact of rising accounts payable

1. Payment of share of accounts receivable

In most practices, incoming physicians will be required to pay their share of the outstanding accounts receivables to the practice, adjusted for collection rate. Including the drug in this calcula-tion can dramatically alter the size of the buy-in. Practices that are high utilizers of high-cost drugs can have accounts receivables in the millions for the drug, greatly raising the cost of the buy-in for the incoming partner. To complicate the mat-ter, many practices will take the net of accounts receivable/payable to determine the amount of the buy-in.

2. Effect of a negative balance between AR/AP and creation of debt

Let’s take an example where the practice had an excess of cash at the end of the year because of the length of time allowed to pay for the high-cost drug. The practice disperses this “excess” as compensation to partners in lieu of paying the drug company. Since they took cash that was meant for drug payment as income, there is now a shortfall that has to be made up. This can be accomplished by reducing the compensation to the partners the following year, by taking out a loan to pay back the amount, or by reduc-ing bonuses at the end of the year. However, incoming physicians will be penalized because they will see a reduction in their compensation commensurate with that of the original partners if their compensation is tied to that of the senior partners.

3. Impact of disparity on AR/AP on buy-out

The negative impact on the buy-in is reversed for the buy-out. Many practices calculate the amount of the buy-out using only accounts receivable because in years past, the amount of accounts payable was trivial. That has drasti-cally changed with the utilization of high-priced drugs. If the buy-out contract does not take into account the account payables, it is very likely that the remaining partners will actually be tak-ing a loss when a partner leaves and is paid his or her share of the AR. That is why it is critical to make sure that the contract includes a provision for an offset for this difference against any AR that the departing partner is due.


VI. Impact of High-Priced Drugs on Physician Compensation

A. Costly drugs may result in an increase in physician compensation as a result of the difference between the AWP and the reimbursement price.

1. Difference usually set at 4%

2. The actual difference may be higher if the prac-tice can purchase drug as discounted price. For example, purchases directly from manufacturer may be discounted more than purchases from a distributor.

3. Depending on volume of drug used by the prac-tice, this may increase the total amount of rev-enue available to the practice for distribution as compensation to partners.

4. Ability to collect from patients will greatly influ-ence this number.

B. End-of-year accounting rules may also impact physi-cian compensation (see below).

VII. End-of-Year Accounting Issues

A. Treatment of profit at years’ end as a result of dis-parity between collections and accounts receivable/payable

1. As most retina practices are set up as a corpora-tion to avoid double taxation, all profits at the end of the year must be paid out of the corpora-tion to avoid double taxation.

2. Usually, excess profit will be paid out to partners as “bonus compensation” and the tax paid by the individual.

3. The use of high-priced drugs may create a situ-ation where there is excess cash or profit as a result of the difference in the collections and the time that the payment is due.

a. Payment for drugs typically has a 60-100 day delay between the time that the charge for the drug is incurred and the time that the drug needs to be paid for.

b. This difference can create huge amounts of “excess cash”—money that is actually being accrued to ultimately pay the drug bill.

c. This “cash” may be in the bank at years’ end and need to be dealt with as profit if not dis-tributed.

d. Cash cannot be left in the bank because it will show up as profit to the corporation. Options for dealing with this cash include payment to the drug company for outstanding accounts payable or distribution to the partners as income.

64 Section VIII: Non-neovascular AMD 2011 Subspecialty Day | Retina

Abstract

This presentation will discuss the causal aspects of the underlying pathogenic pathways of AMD. The data indicating that AMD is an inflammatory disorder will be reviewed, along with the notion that participation of the immune system is required to drive AMD pathology. The concept that an inflammatory signal from the outer retina is fundamentally involved in the disease process and is required for targeting the disease to the outer retina in the macula will also be explored. Several potential sources of an AMD inflammatory signal from the outer retina will be dis-cussed, and an animal model for AMD generated with one of the putative inflammatory signals will be presented.

Disclosure

JGH has been a consultant with Genentech, Neotope, Alcon, and Merck. He has conducted research supported by Alcon, Genen-tech, and Merck. He is an inventor of a biomarker and animal model for AMD that is licensed to SKS Ocular and will be dis-cussed in this presentation.

New Ideas on the Pathogenesis of AMDJoe G Hollyfield PhD

2011 Subspecialty Day | Retina Section VIII: Non-neovascular AMD 65

I. AMD is a complex genetic disorder.

A. Multiple genes and haplotypes are associated with AMD.1

B. Known genetic variants account for approximately 50% of the heritability of AMD.2

C. Identification of genetic risk factors has elucidated biologic pathways relevant to disease pathogenesis.

II. Genetic testing is becoming widely available.

A. Macula Risk

B. RetnaGene (Sequenom)

C. deCODE genetics

D. 23 and me

E. ARUP Laboratories

III. Evaluation (ACCE)3

A. Analytic validity

1. Accuracy and reliability of test

2. Genotyping accuracy is quite high with current technology.

3. Sample handling is likely a greater source of error.

B. Clinical validity

1. Ability of test to accurately discriminate between risk groups

2. Area under receiver operating curve (AUC)4

a. Measure of discrimination power

b. Perfect classifier AUC=1

i. For screening individuals with increased risk of disease, recommended AUC > 0.75.

ii. For presymptomatic diagnosis, recom-mended AUC > 0.99.

c. Current models achieve AUC ~0.80 for AMD.4-6

3. Positive predictive value (PPV)

a. What percentage of cases identified by test as “high-risk” will actually develop disease?

b. PPV increases with disease prevalence.

i. PPV ~30% if prevalence of advanced dis-ease is 15%.4,5

ii. Higher PPV if test applied to population with early-stage disease.

C. Clinical utility

1. Treatment response

a. Correlations between genotype and response to anti-VEGF treatment have been inconsis-tent.7-9

b. There is some suggestion of decreased benefit from AREDS supplements in patients with CFH Y402H risk allele.10

2. Preventative strategies

D. Ethical, legal, and social implications

IV. Examples From Other Diseases

A. Breast cancer

1. Genetic counseling and evaluation for testing is recommended by U.S. Preventive Services Task Force only for “women whose family history is associated with increased risk of deleterious mutations in BRCA1 or BRCA2 genes.”11

2. Preventative measures

a. Insufficient evidence to evaluate efficacy of intensive surveillance or chemoprevention in women with mutations

b. Evidence for benefit from prophylactic sur-gery

B. Alzheimer disease (AD)12

1. APOE e4 allele associated with increased risk for AD (2-fold to 10-fold for homozygotes)

2. Numerous recommendations against APOE genotyping to predict AD risk

a. Low sensitivity and specificity

b. Lack of preventative options

c. Difficulty in effectively communicating impli-cations of results

3. Randomized controlled trials conducted to evaluate risks and benefits of APOE genotyping (REVEAL Study)13

a. No short-term psychological risk

b. Misunderstanding of actual risk of AD was common.

c. APOE e4 individuals more likely to report behavioral changes.

i. Use of dietary supplements

ii. Long-term care insurance changes

Gene Testing and AMD: Are We Ready to Start?Ivana K Kim MD


References

1. DeAngelis MM, Silveira AC, Carr EA, Kim IK. Genetics of age-related macular degeneration: current concepts, future directions. Semin Ophthalmol. 2011; 26(3):77-93.

2. Maller J, George S, Purcell S, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influ-ences risk of age-related macular degeneration. Nat Genet. 2006; 38(9):1055-1059.

3. Centers for Disease Control and Prevention. ACCE. www.cdc.gov/genomics/gtesting/ACCE/FBR/index.htm. Accessed June 3, 2011.

4. Jakobsdottir J, Gorin MB, Conley YP, Ferrell RE, Weeks DE. Inter-pretation of genetic association studies: markers with replicated highly significant odds ratios may be poor classifiers. PLoS Genet. 2009; 5(2):e1000337.

5. 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. Hum Genomics. 2011; 5(5): 1-21.

6. Seddon JM, Reynolds R, Maller J, Fagerness JA, Daly MJ, Rosner B. Prediction model for prevalence and incidence of advanced age-related macular degeneration based on genetic, demographic, and environmental variables. Invest Ophthalmol Vis Sci. 2009; 50(5):2044-2053.

7. Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr. Phar-macogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol. 2009; 93(5):610-613.

8. Kloeckener-Gruissem B, Barthelmes D, Labs S, et al. Genetic asso-ciation with response to intravitreal ranibizumab (Lucentis(R)) in neovascular AMD patients. Invest Ophthalmol Vis Sci. Epub ahead of print 4 Feb 2011.

9. McKibbin M, Ali M, Bansal S, et al. CFH, VEGF and HTRA1 pro-moter genotype may influence the response to intravitreal ranibi-zumab therapy for neovascular age-related macular degeneration. Br J Ophthalmol. Epub ahead of print 10 May 2011.

10. Klein M, Francis P, Rosner B, et al. CFH and LOC387715/ARMS2 genotypes and treatment with antioxidants and zinc for age-related macular degeneration. Ophthalmology 2008; 115(6):1019-1025.

11. US Preventive Services Task Force. Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Suscepti-bility: Recommendation Statement. September 2005. www.uspreventiveservicestaskforce.org/uspstf05/brcagen/ brcagenrs.htm. Accessed June 3, 2011.

12. Goldman JS, Hahn SE, Catania JW, et al. Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. Epub ahead of print 16 May 2011.

13. Green RC, Roberts JS, Cupples LA, et al; REVEAL Study Group. Disclosure of APOE genotype for risk of Alzheimer’s disease. N Engl J Med. 2009; 361(3):245-254.

http://www.cdc.gov/genomics/gtesting/ACCE/FBR/index.htm

http://www.uspreventiveservicestaskforce.org/uspstf05/brcagen/brcagenrs.htm

http://www.cdc.gov/genomics/gtesting/ACCE/FBR/index.htm

http://www.uspreventiveservicestaskforce.org/uspstf05/brcagen/brcagenrs.htm


I. Biomarker

A. Characteristic that is objectively measured and eval-uated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention

B. May be a naturally occurring molecule, gene, clini-cal feature, or characteristic

II. Morphologic Predictors of AMD

A. Are there clinical findings that predict whether or not a patient will develop AMD?

1. Drusen size and number

B. Are there clinical findings associated with risk for development of advanced AMD?

1. AREDS severity study (9-step scale)

a. 6-step drusen area scale

b. 5-step pigmentary abnormality study

2. AREDS simplified scale

a. 1 risk factor per eye for large drusen

b. 1 risk factor per eye for any pigment abnor-mality

c. Are there OCT-based biomarker changes?

i. Subretinal drusenoid deposits associated with late AMD

ii. Measuring optical density of subretinal fluid may distinguish AMD from central serous retinopathy.

d. Are there angiographic-based biomarker changes?

i. Angiographic features in one eye predic-tive of risk in fellow eye

III. Genetic Predictors of AMD

A. Are there predictors of disease?

1. Somatic mutations

a. Complement factor H (CFH) LOC387715: Homozygous carriers of at risk alleles have increased risk.

b. ARMS2/HTRA1: Similar findings, but mean-ing of loci uncertain

c. Other implicated genes in the complement cascade

i. C2/BF

ii. C3

iii. CFI

2. Mitochondria DNA polymorphisms

B. Are there predictors of progression of disease?

1. CFH Y402H and LOC 387715 A69S have inde-pendent effect.

2. Seddon et al, 2007

IV. Quantitative Predictors of Disease

A. Inflammatory markers

1. CRP

a. Multiple studies implicate

b. Others not supportive

2. Other inflammatory markers associated with AMD

a. IL-6, Seddon et al, 2005

b. Fas Ligand, Jiang et al, 2008

c. Complement components and fragments: Reynolds, 2009

B. Oxidative stress markers

1. CEP-oxidative protein modification of DHA

a. CEP adducts and antibodies increased in AMD patients

b. Genetic risk + CEP markers → large odds ratios

2. Other oxidative stress markers

a. Plasma homocysteine

b. Plasma thiol redox status

c. 8-OHdG in aqueous

C. Other

Changes in lipid profiles: Decreased HDL, increased LDL in AMD

V. Clinical/Phenotypic Predictors of Treatment Response

A. Lesion size: Larger lesions, poorer prognosis

B. Angiographic characteristics: Differential response to photodynamic therapy (PDT) with occult vs. minimally classic vs. predominantly classic

VI. Genetic Predictors of Treatment Response (Pharmacogenomics)

A. Antioxidants and zinc therapy: CFH and LOC387715/ARMS2

1. Klein et al, 2008

a. Interaction with CFH and antioxidant/zinc

Emerging Role of Biomarkers for AMDPaul Sternberg Jr MD


b. No interactions with LOC387715

2. Lee and Brantley, 2008

B. PDT

1. CFH Y402H TT patients fare worse with PDT (Brantley et al, 2009).

2. Various studies both show and do not show association.

C. Anti-VEGF

1. CFH Y402H CC associated with poorer out-come with bevacizumab (Brantley et al, 2007).

2. CFH CC more likely to need reinjection with ranibizumab (Lee et al, 2009).


The definition of success when treating dry AMD will ultimately be the restoration of lost visual function as well as the preserva-tion of visual function. However, our near future goal should focus on the preservation of visual function. The term “visual function” takes into account a wide range of visual activities, such as visual acuity, as tested using a range of ambient light conditions, contrast sensitivity, dark adaptation, and reading speed, to name just a few. When distilled down to the most fun-damental definition of success, most of us would agree that the preservation of visual acuity scores using standardized testing conditions would be an acceptable definition when treating dry AMD.

The obvious limitation of visual acuity when testing new treatments for dry AMD is the slow progression of vision loss as the disease progresses through the foveal center. By the time central visual acuity has been lost, significant disease progression has already occurred. For diseases where central visual acuity is lost late in the disease process, surrogate endpoints have been employed when testing new treatments. These surrogate end-points serve as harbingers of future central visual acuity loss and can be used in early stage trials when smaller, faster studies are needed to test the viability of a new treatment or in later stage tri-als as a replacement for visual acuity. Surrogate endpoints have been used in diseases such as retinitis pigmentosa and glaucoma, where central visual acuity loss is an end-stage outcome. In reti-nitis pigmentosa, studies have used the reduction in visual field loss and the loss of electrophysiologic responses, and in glau-coma, studies have used the reduction in IOP and visual field loss as surrogate endpoints when testing new treatments. If the pro-gression of these surrogate endpoints can be slowed or stopped, then we assume these results can be extrapolated to preventing future vision loss.

Unanswered questions in dry AMD include which surrogate endpoint best reflects future disease progression, and which surrogate endpoint can be used in early phase clinical trials to rapidly identify effective treatments for dry AMD? Table 1 lists potential surrogate endpoints for Dry AMD treatment trials.

Table 1. Potential Surrogate Clinical Trial Endpoints for Dry AMD Drugs

Reducing the progression of dry AMD to wet AMD

Reducing the need for anti-VEGF therapy in eyes with wet AMD

Reducing the formation or progression of GA

Decreasing the enlargement rate of GA

Decreasing drusen volume in the central macula without progression to CNV or GA

Stabilizing drusen volume in the central macula

Abbreviations: GA indicates geographic atrophy; CNV, choroidal neovascularization.

Progression of Dry AMD to Wet AMD

In previous dry AMD trials, several surrogate endpoints have been used to investigate novel therapies. The Age-Related Eye Disease Study (AREDS) investigated antioxidant vitamins and minerals as a treatment for slowing the progression of dry AMD to wet AMD.1 A similar surrogate endpoint was used to investi-gate a drug known as anecortave acetate (Retaane, Alcon Labs). In this trial, known as the Anecortave Acetate Risk-Reduction Trial (AART), anecortave acetate failed to slow the progression of dry to wet AMD during an interim analysis and the study was terminated (ClinicalTrials.gov identifier: NCT00333216). While the AREDS results were encouraging and the AREDS vitamins are now widely used by patients with dry AMD as a way of slowing the progression of their disease, it is unclear at this time whether this preparation actually slows the progression of dry AMD.2

While preventing the conversion of dry to wet AMD is an attractive surrogate endpoint, its use in early phase clinical trials is hampered by the need for thousands of patients over several years to determine treatment efficacy. Moreover, the widespread successful use of vascular endothelial growth factor (VEGF) inhibitors in treating wet AMD has diminished the threat of vision loss associated with wet AMD and diminished the impor-tance of slowing the conversion of dry to wet AMD, unless the treatment can also slow the progression of the underlying dry AMD.

The importance of slowing the underlying dry AMD became evident when we examined patients with wet AMD who were successfully converted back to dry AMD following treatment with anti-VEGF drugs. In this population, most of the vision loss appeared to result from the progression of the underlying dry AMD.3 Therefore, if a treatment prevents the conversion of dry to wet AMD but the underlying dry AMD can’t be stopped, then the treatment is unlikely to have additional benefit compared with anti-VEGF drugs alone in treating our patients with dry AMD. For example, if patients with dry AMD were injected with anti-VEGF drugs, then the conversion from dry to wet AMD could be prevented, but the underlying dry AMD would still progress.

Decreased Re-treatment With Anti-VEGF Drugs in Eyes With Wet AMD

If a treatment could stop or slow the progression of dry AMD, then it seems reasonable to assume that fewer treated eyes would progress from dry to wet AMD. If this decreased progression from dry to wet AMD in treated eyes is due to a decrease in the up-regulation of VEGF, then a treatment that stops the progres-sion of dry to wet AMD and down-regulates VEGF might also decrease the need for re-treatment with anti-VEGF drugs in eyes with wet AMD. If this is true, then a surrogate endpoint for test-ing a new dry AMD drug might be to show a decreased need for re-treatment with anti-VEGF drugs in wet AMD. While this seems like a reasonable approach (and there are genetic and his-topathologic data suggesting an important role for complement

Dry AMD Treatments: How Will We Define Success?Philip J Rosenfeld MD PhD, Zohar Yehoshua MD MHA, Carlos Alexandre de A Garcia Filho MD


activation in dry AMD4 and data from cell culture and animal studies suggesting a role for complement activation in VEGF up-regulation5,6), this endpoint has never been successfully used in a clinical study.

Geographic Atrophy

The enlargement of geographic atrophy (GA) is an objective clin-ical sign of advancing dry AMD. GA represents the loss of pho-toreceptors and the loss of retinal pigment epithelium (RPE), and the enlargement of GA represents the irreversible loss of visual function in the area where the GA is located.7 Consequently, if a treatment can slow or stop the enlargement of GA, then this treatment should prevent the loss of visual acuity that would result as GA enlarges through the foveal center. This is known as central GA.

One clinical trial endpoint could be the progression to central GA, which was used in AREDS2 and is currently being used in AREDS2. However, this clinical trial endpoint provides no clear advantage over visual acuity in clinical trials. Since the amount of growth that is required for the loss of the foveal center will depend on the closest distance from the edge of the GA to the foveal center at the start of the study, it then becomes important to compare eyes that have borders of GA at similar distances to the foveal center. In practice, this is not routinely done. Most patients with GA are heterogeneous with respect to the distance from the closes border of GA to the foveal center. As a result, it is difficult to conclude anything useful from the appearance of cen-tral GA and the concurrent loss of visual acuity that results.

An example of why it’s difficult to use central GA and visual acuity loss as an endpoint in studies investigating GA was dem-onstrated recently in the study of ciliary neurotrophic factor (CNTF).8 In this study, CNTF appeared to preserve visual acu-ity while having no apparent affect on the progression of GA. Without knowing the exact details of all the eyes with GA and the closest approach of GA to the foveal center at the start of the study in each eye, it is impossible to draw any conclusion about the drug. As a result, the visual acuity outcome could be misleading.

Several strategies have been used to image and follow the progression of GA. Historically, color fundus imaging was the gold standard in visualizing and measuring the enlargement rate of GA. AREDS validated the use of a color fundus photograph–based classification system to establish guidelines for predicting the likelihood of disease progression,9 and Sunness pioneered the use of color fundus imaging in following the enlargement rate of GA.10,11 However, color fundus imaging provides only a 2-dimensional, en face representation of the macula, and estimat-ing the extent of atrophic areas using color imaging can be chal-lenging, even for reading centers, due to interpatient variability of fundus pigmentation, media opacities, and the ambiguous borders of atrophic lesions.12 Fundus autofluorescence (FAF) using a fundus camera or a confocal scanning laser ophthalmo-scope (SLO) has proven useful in following patients with AMD, especially patients at risk for progression to GA or with well-established GA.13 When using FAF to image GA, the clinician assumes that the loss of autofluorescence in the posterior pole of AMD patients correlates with the loss of lipofuscin, which is the most prominent fluorophore in the posterior pole and con-tained within the RPE. Consequently, an area with decreased autofluorescence is an indirect assessment of RPE integrity, while the absence of autofluorescence is thought to represent an area

of absent RPE. However, there are limitations to the use of this FAF strategy, such as the assumption that the absence of auto-fluorescence truly represents loss of RPE and photoreceptors; the increased difficulty of detecting GA and its boundaries in the presence of cataracts; and, when using the SLO-based imaging system, the difficulty in identifying the boundaries of GA in close proximity to the center of the macula due to the retinal xantho-phylls, which absorb the excitation light and block FAF from the underlying RPE. FAF may be particularly useful in predicting rates of progression in eyes with GA based on the appearance of the hyper-autofluorescence patterns seen around the border of GA.14

Spectral domain OCT (SD-OCT) is another imaging strategy capable of identifying GA reproducibly based on the anatomic absence of the RPE. Using the OCT fundus image (OFI), which visualizes GA as a bright area due to the increased penetration of light into the choroid where atrophy of the RPE and choriocapil-laris has occurred, Yehoshua et al reported that measurements of GA were highly reproducible and could be used to measure the progression rates of GA.12 In addition, this imaging approach for GA identifies the area that corresponds to the actual loss of photoreceptors and retinal pigment epithelium as seen on indi-vidual B-scans, which should directly correlate with the loss of visual function. The OFI correlates well with the GA visualized on clinical examination, fundus photography, and autofluores-cence imaging.15 The major advantage of using the enlargement rate of GA as a clinical trial endpoint involves the use of a square root transformation strategy to calculate the growth rate, which results in needing far fewer patients and shorter follow-up time to demonstrate a treatment effect compared with conventional area measurements and other endpoints such as visual acuity and conversion from dry to wet AMD.12

Drusen

The idea of eliminating drusen and influencing the progression of dry AMD was the basis of the laser-to-drusen studies. These trials confirmed the clinical observation that laser photocoagula-tion to the macula caused the disappearance of drusen based on color fundus imaging. However, there was no evidence that this overall loss of drusen resulted in any benefit in terms of prevent-ing visual acuity loss or the development of CNV and geographic atrophy.16 However, these studies relied on the en face appear-ance of drusen when assessing the clinical stage of dry AMD, and these images did not provide information on the geometry of drusen other than their area measurements. Unfortunately, a reli-able and reproducible method for measuring the morphology of drusen was not available at the time of these trials. Instead, these trials relied on large numbers of patients at different stages of dis-ease progression to adequately power their studies and overcome the uncertainty associated with determining drusen size, type, and area as assessed by reading centers.16

Drusen morphology can now be reproducibly measured using SD-OCT imaging, and the possibility of using the progression of drusen volume and area as a clinical trial endpoint is being revisited. Yehoshua et al have studied the natural history of drusen in the absence of any GA.17 By using a RPE deforma-tion map, which is created from a large number of low-density B-scans acquired using a raster scanning pattern, they were able to reproducibly follow the area and volume of drusen, and these maps showed that drusen were far more dynamic in their mor-phology than previously appreciated. Over time, most drusen


increase their volume and area, but about 12% per year decrease their volume significantly, with most of these eyes progressing to GA or CNV. However, 4%-5% of these eyes per year decrease their drusen volume without progressing to advanced AMD and without developing any obvious sign of photoreceptor or RPE loss based on SD-OCT imaging. If a treatment could decrease the drusen load while preserving normal anatomy, then this treat-ment might be able to preserve long-term visual function. Even if a treatment could stabilize drusen volume and area without pro-gression to GA or CNV, then this treatment might be beneficial and the stabilization of the drusen load might serve as a viable clinical trial endpoint.

How might this endpoint be different than the endpoint used in the laser-to-drusen trials, and why should we expect a differ-ent outcome? This SD-OCT endpoint is different because of the way the drusen are being measure, and the population with dru-sen are being followed. This SD-OCT endpoint utilizes a popula-tion of eyes with drusen that are far more homogeneous than the heterogeneous population studied by color fundus imaging in the laser-to-drusen trials. These eyes in the laser-to-drusen trial con-tained a variety of drusen at different stages of progression scat-tered throughout the macula, and focal areas of GA could not be well visualized and excluded. By using SD-OCT imaging to enroll patients, investigators can identify eyes with a volume of drusen (at least 0.03 mm3) underlying the central macula with-out evidence of GA. This requirement results in a more homoge-neous population representing eyes at risk of central vision loss, and these eyes are at an earlier stage of disease progression since no GA would be present. By investigating such a population of drusen patients, researchers will need to study far fewer eyes for less time (only 6 months) compared with the number of patients and length of follow-up in the laser-to-drusen trials.17

Another endpoint would be the stabilization of drusen vol-ume, but this endpoint requires more eyes than an endpoint looking at the reduction of drusen volume. To test these SD-OCT endpoints, studies investigating the effect of new treat-ments on the volume and area of drusen in eyes with dry AMD are currently under way.

Summary

While the preservation of visual function will define the long-term success of any dry AMD treatment, the short-term success will be defined by surrogate endpoints such as a reduction in the enlargement rate of GA, which is the most appealing of all the surrogate endpoints. Modifying the natural history of drusen progression is another attractive surrogate endpoint and could be used as a way to rapidly screen for drugs with potential therapeutic benefit, since it’s unclear at this time whether drusen regression correlates with the long-term prevention of GA and CNV. Both SD-OCT and autofluorescence provide the most use-ful approaches for imaging GA, and SD-OCT is the most useful approach for measuring drusen morphology. Over the next few years, we will learn whether surrogate endpoints truly correlate with the long-term preservation of visual function and whether success can be achieved with any of the emerging treatments for dry AMD.

References

1. A randomized, placebo-controlled, clinical trial of high-dose supple-mentation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001; 119:1417-1436.

2. Lindblad AS, Lloyd PC, Clemons TE, et al. Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. Arch Ophthalmol. 2009; 127:1168-1174.

3. Rosenfeld PJ, Shapiro H, Tuomi L, et al. Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibi-zumab clinical trials. Ophthalmology 2011; 118:523-530.

4. Anderson DH, Radeke MJ, Gallo NB, et al. The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Prog Retin Eye Res. 2010; 29:95-112.

5. Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement com-ponents C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006; 103:2328-2333.

6. Cortright DN, Meade R, Waters SM, et al. C5a, but not C3a, increases VEGF secretion in ARPE-19 human retinal pigment epi-thelial cells. Curr Eye Res. 2009; 34:57-61.

7. Csaky KG, Richman EA, Ferris FL III. Report from the NEI/FDA Ophthalmic Clinical Trial Design and Endpoints Symposium. Invest Ophthalmol Vis Sci. 2008; 49:479-489.

8. 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.

9. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005; 123:1570-1574.

10. Sunness JS, Bressler NM, Tian Y, et al. Measuring geographic atro-phy in advanced age-related macular degeneration. Invest Ophthal-mol Vis Sci. 1999;40:1761-1769.

11. Sunness JS, Gonzalez-Baron J, Applegate CA, et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology 1999; 106:1768-1779.

12. Yehoshua Z, Rosenfeld PJ, Gregori G, et al. Progression of geo-graphic atrophy in age-related macular degeneration imaged with spectral domain optical coherence tomography. Ophthalmology 2011; 118:679-686.

13. 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.

14. Holz FG, Bindewald-Wittich A, Fleckenstein M, et al. Progression of geographic atrophy and impact of fundus autofluorescence pat-terns in age-related macular degeneration. Am J Ophthalmol. 2007; 143:463-472.

15. Lujan BJ, Rosenfeld PJ, Gregori G, et al. Spectral domain optical coherence tomographic imaging of geographic atrophy. Ophthal-mic Surg Lasers Imaging. 2009; 40:96-101.

16. Parodi MB, Virgili G, Evans JR. Laser treatment of drusen to pre-vent progression to advanced age-related macular degeneration (Cochrane Review). In: Cochrane Database of Systemic Reviews, 2009:CD006537.

17. Yehoshua Z, Wang F, Rosenfeld PJ, et al. Natural history of drusen morphology in age-related macular degeneration using spectral domain optical coherence tomography. Ophthalmology. Epub before print 1 July 2011.


Introduction

Geographic atrophy (GA) associated with age-related macular degeneration (AMD) remains a major cause of vision loss with no proven effective therapy. Outcomes of functional change such as BCVA in GA may not be clinically meaningful, as per-sons with extensive involvement of the retina may still maintain “good” central vision. Regulatory agencies have recognized this clinical problem and have accepted structural changes as reason-able outcome measurements in clinical trials. In GA, the growth of the lesion size measured on fundus photography or other imaging such as fundus autofluorescence is considered an accept-able outcome measurement. The growth of lesions associated with GA is measured in the Age-Related Eye Disease Study. This presentation will discuss these analyses. The ocular features that predispose to the development of GA in AMD are also evaluated, as they may give us important clues to pathogenesis.

Method

The Age-Related Eye Disease Study (AREDS) was designed as both a study of clinical course of age-related lens opacity and AMD and as a randomized, controlled trial of high-dose anti-oxidants and zinc to reduce progression of these eye diseases, common in the elderly.1 Participants were followed for a median of 10 years.

In this study of GA progression in AREDS, the baseline and annual fundus photographs from 2 clinical sites were reviewed for the potential ocular factors that are associated with the devel-opment of any GA. AREDS participants who had developed GA at least 4 years following enrollment in the study were included in the analyses.2 Retrospectively, the annual fundus photographs were evaluated prior to the development of GA to identify spe-cific fundus lesions that are most commonly seen prior to the development of GA. A subset of AREDS participants’ annual fundus photos demonstrating GA at baseline was evaluated with planimetry to evaluate the rate of growth of the GA lesions over the course of the study.3 The development of CGA was also examined over time, in relation to the presence of large drusen and retinal pigmentary changes and the severity of AMD (pres-ence or absence of advanced AMD) in the fellow eye.

Results

In the analyses of the progression to GA, 95 eyes of 77 par-ticipants developed GA at least 4 years following enrollment in the study. Average time from baseline to initial appearance of GA was 6.6 years (range: 4-11 years). The fundus photo-graphic assessments demonstrated that large drusen formation was initially detected, followed by hyperpigmentation, drusen regression, and then hypopigmentation. This eventually leads to geographic atrophy. Drusen were found in 100% of eyes later developing GA, drusen > 125 µm in diameter in 96% of eyes, confluent drusen in 94%, hyperpigmentation in 96%, drusen > 250 µm in 83%, and hypopigmentation in 82%. In 25% of the cases, highly refractile deposits were seen in the area of

regression. If the examination includes the entire macula beyond the area of drusen regression, a majority of the cases had some refractile deposits in the macula. Time from lesion appearance to onset of GA varied by lesion type, ranging from large drusen (5.9 years) to hypopigmentation (2.5 years) and refractile depos-its (2.5 years), and generally followed a uniform sequence of appearance.

We also measured the growth rate of the lesions of geographic atrophy using planimetry on fundus photographs of 181 AREDS participants, obtained at baseline, Year 2, and annually there-after.3 The measurements made from these fundus photographs were conducted in 2 different reading centers with excellent agreement. We measured only lesions of at least 0.5 disc areas at baseline, and the median size was approximately 4.3 mm2 with a mean of 5.8 mm2, ranging from 1 mm2 to 45 mm2. These geographic lesions grew 2.03 mm2 (standard error of the mean, 0.24 mm2) at 1 year, 3.78 mm2 (0.24 mm2) at 2 years, 5.93 mm2 (0.34 mm2) at 3 years, and 1.78 mm2 (0.086 mm2) per year overall. An important predictor of subsequent GA growth was baseline size. Median time to developing central GA after any GA diagnosis was 2.5 years (95% CI, 2.0-3.0). Average visual acuity decreased by 3.7 letters at first documentation of central GA, and by 22 letters at year 5.

Discussion

Gass originally concluded almost 4 decades ago that most cases of GA resulted from the fading of the drusen.4 Sarks et al reported clinicopathological studies of AMD and concluded that drusen-related atrophy was the most common form of GA.5 Using AREDS data, we confirmed that eyes with AMD usu-ally develop GA following the regression of pre-existing large, confluent drusen. This process may occur over several years and usually follows a distinctive pathway. Regression of large and often “giant” confluent drusen is associated first with overly-ing hyperpigmentation, followed by hypopigmentation. It is also often accompanied by deposition of refractile deposits in the involved area and terminates in some cases with GA, an end stage of severe AMD.

The growth rate analyses demonstrated excellent agreement among the 2 fundus photograph reading centers. We do not have fundus autofluorescence (FAF), but information of the longitudi-nal changes would be helpful in evaluating the comparison of the FAF with color photography.

A number of other investigators have also measured the growth rate in GA. Holz et al 6 reported a median growth rate of 1.52 mm2 per year following 1.8 median years of follow-up in 129 participants (195 eyes) whose median baseline GA area was 7.04 mm2. Sunness7 et al demonstrated a median growth rate of 2.2 mm2 per year after 2 years in 131 patients (212 eyes) whose median baseline GA area of 7.9 mm2. Although the median size of the GA lesion at baseline was smaller than these 2 series, our yearly median growth rate was similar, at 1.71 mm2 per year with a median follow-up of 6 years.

These AREDS data will contribute to our knowledge of the natural history of GA development associated with AMD and

Progression of Geographic Atrophy in the Age-Related Eye Disease Study (AREDS)Emily Y Chew MD for the Age-Related Eye Disease Study Research Group


provide investigators of future studies of GA with information for the design and planning of treatment trials for this blinding condition.

References

1. The Age-Related Eye Disease Study Research Group. A random-ized, placebo-controlled, clinical trial of high-dose supplementa-tion with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol. 2001; 119:1417-1436.

2. Klein ML, Ferris FL, Armstrong J, Huang TS, Chew EY, Bressler SB, Chandra S; AREDS Research Group. Retinal precursors and the development of geographic atrophy associated with age-related macular degeneration. Ophthalmology 2008; 115(6):1026-1031.

3. Lindblad AS, Lloyd PC, Clemons TC, et al; Age-Related Eye Dis-ease Study Research Group. Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26. Arch Ophthalmol. 2009; 127:1168-1174.

4. Gass JD. Drusen and disciform macular detachment and degenera-tion. Arch Ophthalmol. 1973; 90:206-217.

5. Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988; 2:552-557.

6. Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S; FAM-Study Group. Progression of geographic atrophy and impact on fundus autofluorescence pat-terns in age-related macular degeneration. Am J Ophthalmol. 2007; 143(3):463-472.

7. Sunness JS, Margalit E, Srikumaran D, et al. The long-term natural history of geographic atrophy from age-related macular degenera-tion: enlargement of atrophy and implications for interventional clinical trials. Ophthalmology 2007; 114(2):271-277.


Statistics

• AMDisthemostcommoncauseofseverevisionlossinpeople aged 50 and older in developed countries.

• Itisestimatedthat1.8millionAmericansareaffectedbyadvanced disease; 7.3 million are affected by intermediate disease.

• 2.9millionAmericansareprojectedtosufferfromadvanced disease by the year 2020.

• AstheU.S.populationages,AMDwillbeamorecommoncause of vision loss than diabetic eye disease and glaucoma combined.

• AlthoughcurrenttreatmentsforAMDhaveadramaticimpact, photoreceptor cell loss continues for many patients, leading to vision loss.

Background

• Aclearroutetosuccessforthetreatmentofthesediseases,where photoreceptor degeneration is prominent and asso-ciated with vision loss, would be the development of neu-roprotective agents.

• Unfortunately,noeffectiveneuroprotectivestrategieshavebeen found thus far despite more than a decade of intense effort.

• Themainreasonforthisfailuremaybethataunifactorialapproach has been utilized thus far.

• DiseasessuchasAMDarepolygenicandmultifactorial.For this reason, successful approaches at developing effec-tive neuroprotective therapies need to utilize multiple models and interfere with multiple pathways.

• Thisprincipleofthesynergisticbenefitofamultifacetedapproach has been demonstrated and validated in dis-eases such as cancer and HIV, where the use of a singular therapeutic approach today would be considered a major fallacy.

Approach

The approach we have taken over the past several years is to study multiple models of photoreceptor cell loss and to investi-gate multiple molecular pathways of cell death signaling. Specifi-cally, we have studied photoreceptor cell death mechanisms in:

• Retinaldetachmentasamodelofphotoreceptordegen-eration

• Achemical-based,inducedmodelofdryAMD(PolyICand lipid peroxide)

• GeneticmodelsinmicethatleadtopathologytypicalofAMD (CX3CR1-/-CCL2-/-)

• Geneticdeficiencythatleadstoajuveniletypeofretinaldegeneration (retinitis pigmentosa)

With the use of these critical disease models we have:

• Demonstratedtheinvolvementofredundantsignalingpathways (RIPKinases-Caspases) as effectors in cell death in retinal degenerations, demonstrating why previous uni-modal attempts for neuroprotection have failed

• Identifiedeffectivestrategiestosuccessfullyinterfereinmultiple death pathways and protect photoreceptor cells using combination therapies1,2

We have the first evidence that these redundant death path-ways are operative in multiple animal models of degenerative eye diseases, showing that these pathways lie downstream of many different upstream death signaling effectors.

In addition to the RIPKinase-Caspase dual axis, inflammation and free radicals play a role in photoreceptor cell death and pro-vide targets for effective neuroprotection.3,4

Natural agents with multiple neuroprotective roles such as bile acids (TUDCA)5 may also serve as therapeutic modalities

A holistic view of the fundamental cellular problem and a multipronged approach has a high potential to deliver a real solution for degenerative diseases of the eye.

References

1. Trichonas G, Murakami Y, Thanos A, Morizane Y, Kayama M, Debouck CM, Hisatomi T, Miller JW, DG Vavvas. Receptor inter-acting protein kinases mediate retinal detachment-induced photo-receptor necrosis and compensate for inhibition of apoptosis. Proc Natl Acad Sci U S A. 2010; 107(50):21695-21700.

2. Murakami Y, Miller JW, Vavvas DG. RIP Kinase-mediated necrosis as an alternative mechanism of photoreceptor death. Oncotarget. E-pub ahead of print 10 June 2011; PMID: 21670490.

3. NakazawaT, Hisatomi T, Nakazawa C, et al. Monocyte chemoat-tractant protein 1 mediates retinal detachment-induced photorecep-tor apoptosis. Proc Nat lAcad Sci U S A. 2007; 104(7):2425-2430.

4. Roh M, Murakami Y, Thanos A, Vavvas D, JW Miller. Edara-vone, a ROS scavenger, ameliorates photoreceptor cell death after experimental retinal detachment. Invest Ophthalmol Vis Sci. 2011; 52(6):3825-3831.

5. Mantopoulos D, Murakami Y, Comander J, Roh M, Miller JW, D Vavvas. Tauroursodeoxycholic acid (TUDCA) protects photo-receptors from cell death after experimental retinal detachment. PLoSONE. In press.

6. Boatright JH, Moring AG, McElroy C, et al. Tool from ancient pharmacopoeia prevents vision loss. Mol Vis. 2006; 12:1706-1714.

7. Nakazawa T, Kayama M, Ryu M, Kunikata H, Watanabe R, Yas-uda M, Kinugawa J, Vavvas D, JW Miller. Tumor necrosis factor α mediates photoreceptor death in a rodent model of retinal detach-ment. Invest Ophthalmol Vis Sci . 2011; 52(3):1384-1391.

8. Zacks DN, Zheng QD, Han Y, Bakhru R, JW Miller. FAS-medi-ated apoptosis and its relation to intrinsic pathway activation in an experimental model of retinal detachment. Invest Ophthalmol Vis Sci. 2004; 45(12):4563-4569.

Neuroprotection in Retinal DiseasesDemetrios Vavvas MD


Introduction

Geographic atrophy (GA) is the atrophic form of late AMD. GA is a major cause of both moderate and severe central visual loss and is bilateral in over 50% of people with this condition. GA usually progresses slowly, over years, and often spares the foveal center until late in the course of the disease. GA is typically char-acterized by a progressing course leading to degeneration of reti-nal pigment epithelium (RPE) and photoreceptor cells (Nowak, 2006), and has been interpreted as the natural evolution of AMD if neovascular events do not occur before GA develops (Roth et al, 2004). GA presents as an area of loss of RPE associated with loss of the overlying photoreceptors within the central macula, which causes the affected region of the retina to become dysfunc-tional. There is currently no established treatment to prevent GA or to slow its progression (Nowak, 2006; Sunness et al, 2007).

Apoptosis is a normal process of genetically programmed cell death that destroys cells that are injured or unneeded. Apoptotic cell morphology includes the shrinkage of cellular nucleus and cytoplasm, chromatin condensation, formation of apoptotic bodies, and internucleosomal DNA fragmentation. Debris from apoptotic cells is eliminated through phagocytosis. Apopto-sis is normally an important homeostatic function. However, excessive or uncontrolled apoptosis has been implicated in the pathogenesis or poor outcome of many ocular diseases, includ-ing glaucomatous optic neuropathy, diabetic macular ischemia, chronic macular edema, retinitis pigmentosa, retinal detach-ments, and GA. Apoptosis is also implicated in CNS diseases such as Alzheimer and Parkinson diseases. Cell death signals involved in apoptosis include glutamate excitotoxicity/NMDA receptor activation, increased levels of intracellular Ca++, activa-tion of caspases, mitochondrial cytochrome c leakage, release of inflammatory cytokines (eg, TNFa, interleukins) and nitric oxide and reactive oxygen species (free radicals). Additionally, expres-sion of apoptosis-promoting genes (eg, bax) and underexpression of apoptosis-inhibitory genes (eg, bcl-2, bcl-xL) is observed. Cell survival signals include neurotrophins (growth factors such as CNTF, BDNF, and bFGF), expression of apoptosis-suppressing genes (eg, bcl-2, bcl-xL), endogenous antioxidants (eg, glutathi-one, catalase, super oxide dismutase), and adrenergic alpha2-receptor–mediated pathways.

Stopping retinal neuronal cell death associated with GA is a balancing act. In normal eyes, various factors promote either the survival or death of retinal neurons and photoreceptors. Retinal cell viability depends on a balance between cell survival and death signals. The goal of neuroprotective therapy is to tip the balance in favor of cell survival by blocking cell death signals and enhancing cell survival signals. Given that GA is a slowly pro-gressive disease over a period of years, long-term mediation of the disease with pharmacotherapeutic agents is likely to require a drug delivery strategy. Currently, 3 different drugs in extended-release drug delivery implants are being tested in patients with GA: the Neurotech encapsulated cell technology, which releases ciliary neurotrophic factor (CNTF), the Allergan biodegradable brimonidine drug delivery system, and the Alimera Iluvien fluo-cinolone acetonide drug delivery implant.

The Neurotech Encapsulated Cell Technology CNTF Implant for GA

Encapsulated cell technology (ECT) enables controlled and sus-tained delivery of CNTF to the vitreous and the retina. A CNTF-secreting ECT intraocular implant (designated NT-501) has been developed by Neurotech USA for sustained delivery of CNTF to the retina (Tao et al, 2002). The NT-501 implants are small cap-sules of hollow fiber membrane in which live human RPE cells engineered to secrete CNTF (NTC-201 cells) are encapsulated. The physical characteristics of the membrane allows for the outward diffusion of therapeutics (CNTF in this case) and other cellular metabolites and the inward diffusion of nutrients neces-sary to support cell survival. In addition, the cells in the implants are protected from rejection by the host immune system (Tao et al, 2002).

ECT implants are distinct from other drug delivery implants in that they do not primarily store drug but rather produce the therapeutic drug to be delivered in situ. The implants are capable of secreting protein continuously for more than 2 years, the lon-gest time tested (W Tao, unpublished observation). The resulting vitreous CNTF levels are consistent over time and are effective in photoreceptor preservation (Talcott et al, 2011) and visual acuity stabilization (Zhang et al, 2011). The ECT implant can be engineered to achieve the optimal dose for treatment. Treatment can be terminated if necessary by simply retrieving the implant.

The promise of growth factors as potential therapeutics for photoreceptor degeneration was first demonstrated in 1990 (Faktorovich et al, 1990). Since then, many growth factors, neu-rotrophic factors, and cytokines have been tested in a variety of photoreceptor degeneration models, mainly by intravitreal injec-tion of purified recombinant proteins in short-term experiments (LaVail MM, et al, 1992, 1998). Among them, ciliary neuro-trophic factor (CNTF) has been shown to be effective in almost every model (LaVail MM, et al, 1998). Li and colleagues studied the effect of CNTF on cone degeneration secondary to rod loss in transgenic rats carrying the murine rhodopsin mutation S334ter. Using peanut agglutinin (PNA) and cone opsins specific antibod-ies to identify cone outer segments (COS), they found that cone degeneration begins with loss of COS, followed by cone cell death about 2 months later in those animals. The loss of COS in the S334ter-3 rats initially occurs in numerous small patches throughout the retina. Surprisingly, those PNA-negative patches became smaller or completely resolved after CNTF treatment. The reappearance of PNA staining in the previous PNA-negative areas suggests regeneration of COS. Additional experiments showed that the density of cones with outer segments 10 days after CNTF treatment was greater than the baseline density, confirming that CNTF treatment does indeed promote regenera-tion of COS. Furthermore, their experiments demonstrated that sustained delivery of CNTF by CNTF-secreting implants results in long-term preservation of cones and cone function in the rat model (Li et al, 2010).

A Phase 2 study of CNTF-secreting implants in patients with dry AMD (GA) was completed recently, and the 12-month data was reported (Zhang et al, 2011). Visual acuity stabilization was

Drug Delivery Implant for Geographic AtrophyBaruch D Kuppermann MD PhD


achieved with minimal loss in eyes treated with high-dose CNTF implants, as compared with eyes treated with low-dose implants and sham operation. No visual acuity loss occurred in eyes with 20/63 or better baseline vision when treated with high-dose implants. The same effects continued to 18 months following implant (W Tao, unpublished observation). These findings are consistent with results from the Phase 1 trial and animal models that CNTF protects cone photoreceptors.

Adaptive optics scanning laser ophthalmoscopy is a technol-ogy that enables direct observation of cone cells in the retina of patients. Using this imaging technology, Talcott and colleagues (Talcott et al, 2011) monitored cone density in 3 patients (2 with RP and 1 with Usher syndrome type 2) over 2 years. In each patient, one eye was sham-treated and the other was implanted with a CNTF-secreting implant. During the 2-year interval, they observed a decrease in cone density of 9%-24% in 8 of 9 locations sampled in sham-treated eyes. However, in the CNTF treated eyes the cone density remained stable in all 12 locations studied. The difference between CNTF and sham-treated eyes is remarkable and indicates a protective effect of CNTF on cone cells in human patients (Talcott et al, 2011).

The Allergan Brimonidine Drug Delivery System for GA

Experimental data demonstrate that brimonidine protects retinal ganglion cells, bipolar cells, and photoreceptors from degenera-tion following a variety of insults including retina ischemia, ocu-lar hypertension, retinal phototoxicity, and partial optic nerve crush (Burke and Schwartz, 1996; Lai et al, 2002; WoldeMussie et al, 2001). This retinal neuroprotective property of brimoni-dine is mediated by alpha-2 adrenergic receptors (Wheeler et al, 2003), which are located throughout the mammalian retina (WoldeMussie et al, 2006). The mechanism of action involves pathways that resist apoptosis or programmed cell death and include (1) increasing the expression of the cytokine basic fibro-blast growth factor (bFGF) mRNA, which has been shown to delay apoptosis (Konig et al, 1997); (2) increasing the expression of anti- to pro-apoptotic proteins (BCL2/BAX) that regulate mitochondrial membrane permeability and inhibit apoptosis (Tatton et al, 2003); and (3) suppressing the accumulation of excitotoxic levels of glutamate that cause neuronal cell death (Donello et al, 2001).

The Brimonidine Tartrate Posterior Segment Drug Delivery System (Brimo PS DDS) applicator system is a sustained-release polymeric implant containing brimonidine tartrate within an applicator designed to deliver the implant directly into the vitre-ous humor. This drug delivery system is composed of a biode-gradable polymer matrix containing the active ingredient brimo-nidine tartrate. The Brimo PS DDS is injected into the vitreous humor through a 22-gauge needle with an applicator system. The polymer matrix slowly degrades so that there is no need to remove the implant. The goal of the slow release of brimonidine tartrate from the implant is to result in sustained nontoxic, thera-peutic drug levels in the RPE.

A Phase 2 clinical trial is under way evaluating the Brimo PS DDS in patients with GA. Approximately 120 patients were enrolled in this 2-year study. Eligible patients with bilateral GA and vision between 20/40 and 20/200 were randomly assigned to 3 treatment groups (in a 2:2:1 ratio) to receive Brimo PS DDS Applicator System at 1 of 2 doses (200 μg or 400 μg) or sham treatment. Each patient had an intravitreal injection or sham treatment in the treated eye and a sham treatment in the fellow

eye on Day 1 and a repeat dose of the assigned treatment and fel-low eye sham treatment at Month 6. Patients will be followed for up to 24 months after the initial treatment. Results are pending.

The MAP-GA Trial: Low-Dose Sustained-Release Fluocinolone Acetonide for GA

The MAP-GA trial, supported by Alimera Sciences, was designed to test the hypothesis that low-dose sustained release fluocino-lone acetonide (FA) is capable of slowing the progression of GA in patients with dry AMD. It is a randomized, double-masked, fellow eye comparison study in which all patients receive an implant in 1 eye that releases either 0.2 or 0.5 micrograms of FA per day. Forty patients will be enrolled with dry AMD and bilateral GA, between 0.5 and 11 MPS disc areas. The study’s primary outcome measure is the photographically measured lesion enlargement area as measured via color and autofluores-cence fundus photographs, interpreted by the DARC reading center. Secondary outcome measures will include the square-root of lesion area, standard and low-luminance ETDRS visual acuity, drusen volume, retinal thickness as measured by spectral domain OCT, fluorescein angiograms, and number of treatments for CNV. Patients who received both doses will be combined for the primary analysis. Enrollment is currently under way.

The rationale for MAP-GA comes from in-vivo studies in RCS and S334-ter rats by Glybina et al (2009, 2010), which showed that animals treated with 0.2 micrograms per day of FA had significantly less retinal thinning and less reduction of B-wave amplitude than control animals. Low-dose sustained-release fluocinolone profoundly dampened retinal neuroinflam-mation by 5-fold as seen in retinal wholemounts stained for microglial cells, with the effect primarily visible in the inner and outer retina where activated microglia are found. Alimera, who is developing the Iluvien sustained-release FA implant for diabetic macular edema, agreed to fund the MAP-GA trial, with Ray Iezzi from Mayo Clinic as principal investigator. If the MAP-GA trial shows that FA slows GA, this would support the hypothesis that suppression of retinal neuroinflammation slows the rate of retinal degeneration and may lead to multiple strate-gies for treating dry AMD and photoreceptor degenerative dis-eases such as retinitis pigmentosa.

Conclusion

GA is a slowly progressive retinal degenerative condition for which a variety of neuroprotective pharmacotherapeutic strate-gies are being evaluated. Given the chronicity of the disease, extended-release drug delivery implants are likely to be an important component of this approach. Three distinct drug delivery systems with not only different drugs but different tech-nologies are being actively investigated in clinical trials. The Neu-rotech ECT technology utilizes modified RPE cells to produce the neurotrophin CNTF, which is then released into the vitreous cavity. The implant requires a brief surgery to suture the intra-vitreal implant to the scleral wall, where it remains for 2 years or more before being removed. A Phase 2 trial has been completed, showing some benefit. The Allergan brimonidine posterior seg-ment drug delivery system utilizes a biodegradable polymer sys-tem to release brimonidine into the vitreous cavity. The implant is injected into the eye through the pars plana. The drug releases while the implant polymers biodegrade, with the result that once the drug is fully delivered, the implant itself degrades, leaving no remnants in the eye. The neuroprotective effect of brimonidine


is via mediating alpha 2 receptors in the retina. A Phase 2 trial is fully enrolled. Finally, the Alimera Iluvien FA implant is being evaluated in a small pilot study to determine the role of steroids in the mediation of GA. The Iluvien implant is injected into the vitreous cavity through the pars plana, but the implant does not biodegrade. Enrollment in the pilot study is under way.

References

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2. Donello JE, Padillo EU, Webster ML, Wheeler LA, Gil DW. Alpha(2)-adrenoceptor agonists inhibit vitreal glutamate and aspar-tate accumulation and preserve retinal function after transient isch-emia. J Pharmacol Exp Ther. 2001; 296:216-223.

3. Faktorovich EG, Steinberg RH, Yasumura D, Matthes MT, LaVail MM. Photoreceptor degeneration in inherited retinal dys-trophy delayed by basic fibroblast growth factor. Nature 1990; 347(6288):83-86.

4. Glybina IV, Kennedy A, Ashton P, Abrams GW, Iezzi R. Photore-ceptor neuroprotection of RCS rats via low dose intravitreal sus-tained-delivery fluocinolone acetonide. Ophthalmol Vis Sci. 2009; 50:4847-4857.

5. Glybina IV, Kennedy A, Ashton P, Abrams GW, Iezzi R. Intravitre-ous delivery of the corticosteroid fluocinolone acetonide attenuates retinal degeneration in S334ter-4 rats. Ophthalmol Vis Sci. 2010; 51:4243-4252.

6. Lai RK, Chun T, Hasson D, et al. Alpha-2 adrenoceptor agonist protects retinal function after acute retinal ischemic injury in the rat. Vis Neurosci. 2002; 19:175-185.

7. LaVail MM, Unoki K, Yasumura D, Matthes MT, Yancopoulos GD, Steinberg RH. Multiple growth factors, cytokines, and neuro-trophins rescue photoreceptors from the damaging effects of con-stant light. Proc Natl Acad Sci U S A. 1992; 89(23):11249-11253.

8. LaVail MM, et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest Ophthalmol Vis Sci. 1998; 39(3):592-602.

9. Li Y, Tao W, Luo L, et al. CNTF induces regeneration of cone outer segments in a rat model of retinal degeneration. PLoS One. 2010; 5:e9495.

10. Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep. 2006; 58:353-363.

11. Roth F, Bindewald A, Holz FG. Key pathophysiologic pathways in age-related macular disease. Graefes Arch Clin Exp Ophthalmol. 2004; 242:710-716.

12. Sunness JS, Margalit E, Srikumaran D, Applegate CA, Tian Y, Perry D, et al. The longterm natural history of geographic atrophy from age-related macular degeneration. Ophthalmology 2007;114:271-277.

13. Talcott KE, Ratnam 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.

14. Tao W, et al. Encapsulated cell-based delivery of CNTF reduces photoreceptor degeneration in animal models of retinitis pigmen-tosa. Invest Ophthalmol Vis Sci. 2002; 43(10):3292-3298.

15. Tatton W, Chen D, Chalmers-Redman R, et al. Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer’s disease: anti-apoptosis by alpha-2-adrenergic receptor activation. Surv Ophthalmol. 2003;48(suppl 1):S25-S37.

16. Wheeler L, WoldeMussie E, Lai R. Role of alpha-2 agonists in neu-roprotection. Surv Ophthalmol. 2003; 48(suppl 1):S47-S51.

17. WoldeMussie E, Ruiz G, Wijono M, Wheeler LA. Neuroprotection of retinal ganglion cells by brimonidine in rats with laser-induced chronic ocular hypertension. Invest Ophthalmol Vis Sci. 2001; 42:2849-2855.

18. WoldeMussie E, Wijono M, Ruiz G. Differential distribution of alpha 2 adrenergic receptors in light or dark adapted retinas of rats. Invest Ophthalmol Vis Sci. 2006; 47(suppl):S3749.

19. 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.


I. Introduction

A. AMD is the most common cause of visual loss in elderly patients in the Western world.

B. There are 2 forms of AMD:

1. Dry or nonexudative form

a. Most common form accounting for 80%-90% of cases

b. Rarely leads to severe vision loss and legal blindness

c. Slowly progressive condition characterized by the accumulation of drusen in the retina

d. Transport of nutrients and wastes by the retinal pigment epithelium slows down, with these waste products accumulating under the retina in the form of drusen.

e. As this process continues, overlying photo-receptors may become damaged, leading to geographic atrophy (GA). GA is present in 3.5% of people aged 75 years or more, and its prevalence exceeds 22% in those over 90 years of age

2. Exudative, or wet, form

a. Leads to over 90% of severe vision loss

b. Characterized by the formation of choroidal neovascularization (CNV)

C. Treatment of dry AMD: Currently no known thera-peutic approach

II. Inflammation/Complement and AMD

A. The blood-retina barrier (BRB) protects neural and photoreceptor components from the infiltration of circulating pro-inflammatory cells and immuno-genic substances.

B. Small nucleotide polymorphisms in various immune-related genes have been linked to AMD.

1. Many of these genes are thought to function in signaling pathways used by the immune system to mount a cellular response against invading pathogens.

2. Deficiencies in regulatory complement factors may lead to chronic inflammation and increase the risk from macular degeneration significantly in those containing these defective genes.

C. Complement is part of our innate immune system which mounts an immediate nonspecific response upon initial pathogen invasion of the host.

1. Comprised of over 30 serum and cell surface proteins that subserve important roles in immune recognition and effector function

2. Activation of the complement cascade results in the generation of a number of active byproducts with immunoprotective, immunoregulatory, and proinflammatory properties.

3. Immune complement traditionally mediates the opsonization of pathogens via the classical, alter-native, and lectin pathways, which all converge into a common terminus—a secondary product of C5 cleavage, C5b, assembles with complement factors 6-9 to form the membrane attack comple-ment (MAC), which destroys the cell to which it is bound, the membrane attack complex (MAC). Classical pathway: Activation of the classical pathway is not thought to be majorly involved in AMD.

4. Lectin pathway

Mannose- or N-acetylglucosamine-containing sugar structures that are particularly abundant on bacterial cell surfaces lead to activation of mannan-binding lectin–associated proteases 1 and 2 (MASP1/2).

5. Alternative pathway

a. Differs from the classical pathway in that no specific antibody-antigen interaction is required for complement mediated cell lysis.

b. Excessive complement activation via the alter-native pathway significantly contributes to the pathobiology of AMD.

c. A critical mediator in the alternative pathway, factor C3b, that is able to bind to a diverse array of proteins and polysaccharides present on pathogen membranes.

i. C3b is generated by the cleavage of C3 in a reaction carried out by C3 convertase.

ii. This enzyme is also constructed in the clas-sical and lectin pathways as a complex of C2a and C4b or in the alternative pathway as a complex of the Factor D cleaved com-ponent of Factor B, Bb, and hydrolyzed C3.

d. Different forms of C3 convertase feed into a common pathway that supplies the comple-ment cascade with abundant C3b, as well as C3a and C5a, both potent anaphylatoxins and direct leukocyte chemoattractants.

e. Complement factor H (CFH) is an endog-enous soluble complement inhibitor, capable

Complement System and Strategies for ModulationComplement Inhibition for Dry AMD

Peter K Kaiser MD


of inactivating C3b through Factor I binding, thus preventing complement mediated host cell death.

i. A panel of single nucleotide polymor-phisms (SNPs) within the human CFH gene significantly increases AMD risk.

(a) CFH gene is located on chromosome 1, in the region 1q25-31 that harbors the ARMD1 locus.

(b) CFH immunoreactivity is increased in drusen and at the RPE/choroid inter-face.

(c) Y402H variant increased AMD risk by approximately 2.7-fold in patients of European descent, and up to 43% of cases of AMD. Leads to reduction of heparin binding affinity of the Y402H CFH variant to host cell membranes, thereby suppressing C3b inhibition and allowing for unimpeded alternative complement pathway activation.

ii. SNPs in chromosome 10q26 (genes PLE-KHA1/LOC387715/HTRA1), Factor B (BF) complement component 2 (C2), and complement factor 3 (C3) are also associ-ated with AMD.

(a) One or 2 copies of the LOC387715 A69S allele (serine 69) were 2.4 and 5.7 times more likely to develop AMD.

(b) Nonsynonymous coding change (R102G) in the third exon of C3

(c) Common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast)

(d) SNP in C3 (rs2230199)

(e) H10 (L9H variant of BF and E318D variant of C2) and H7 (variant in intron 10 of C2 and R32Q variant of BF) confer a significantly reduced risk of AMD.

iii. C3a and C5a, known components of AMD drusen, have also been linked to the up-regulation of VEGF-A.

III. Complement Treatment Approaches

A. C3 inhibition

POT-4 is a cyclic 13 amino acid peptide, which interferes with the cleavage of C3, the component all 3 pathways of complement activation converge on.

1. First complement inhibitor studied in patients with AMD

2. POT-4 forms an intravitreal gel deposit that functions as a depot for the drug.

3. Phase 1 data indicate that it is safe and well toler-ated at the doses studied, and a Phase 2 study is now under way.

B. C5 inhibition: Targets the terminal complement component C5, which is critical for membrane attack complex formation and production of the highly proinflammatory molecule C5a.

1. Eculizumab (Soliris, Alexion Pharmaceuticals) h5G1.1-mAb is a humanized monoclonal anti-body (mAb) that was derived from the murine anti-human C5 antibody m5G1.1.

a. FDA approved for the treatment of paroxys-mal nocturnal hemoglobinuria

b. Specifically binds the terminal complement protein C5, thereby inhibiting its cleavage to C5a and C5b during complement activation

c. Blockade of the complement cascade at C5 prevents the release of proinflammatory mediators and the formation of MAC while preserving complement function essential for opsonization of microorganisms and clear-ance of immune complexes.

d. Phase 2 COMPLETE (COMPLement inhibi-tion with Eculizumab for the Treatment of non-Exudative age-related macular degenera-tion) study is ongoing in patients with dry AMD.

e. ARC-1905 (Ophthotech, New York, NY), an injectable pegylated aptamer that inhibits the complement component C5: Phase 1 trials in dry AMD as well as CNV (in combination with an anti-VEGF agent) are currently under way.

2. FCFD5414S (Genentech, South San Francisco, CA) is a recombinant humanized monoclonal antibody fragment directed against factor D, a rate-limiting enzyme in the alternative comple-ment activation pathway.

a. Phase 1 study completed and suggested that intravitreal administration in patients with geographic atrophy was safe and well toler-ated.

b. Phase 2 study is under way.

C. Factor B inhibition: Humanized antibody fragment TA106

D. Factor D inhibition: FCFD4514S is a recombinant humanized monoclonal antibody fragment directed against factor D.

1. Safe during Phase 1 testing on patients with GA

2. Phase 2 trial is currently under way.

E. Replacement of defective CFH in patients afflicted with risk-enhancing mutations is another approach that is being explored. TT30 is a recombinant fusion protein designed to replace defective CFH.


IV. Conclusions

A. Dry AMD represents only a minority of severe vision loss in patients with AMD. Clinically signifi-cant visual problems have occurred as a result of this stage of the disease, which may also serve as a precursor for more advanced exudative disease.

B. Intervention at this early stage may offer the best opportunity for good maintenance of visual acuity in patients with AMD, and active studies are under way to identify products for this condition.


I. Complement Implicated as an Important Factor in AMD

A. Genetic data

B. Histopathologic data

II. Membrane Attack Complex (MAC)

A. MAC is the final endpoint in the complement cas-cade.

B. MAC creates a pore that causes cell lysis and cell death.

C. CD59 is a naturally occurring, typically membrane-bound protein that blocks MAC formation.

D. CD59 protects normal cells from lysis by comple-ment.

III. Direct Evidence for the Role of MAC in AMD

A. MAC deposition has been observed in human eyes with drusen (Anderson DH, 2002) and geographic atrophy (Mullins RF, 2011)

B. Pretreatment with HMR59 reduces CNV formation by 56% relative to control mouse eyes in a laser CNV model (Kumar-Singh R, 2011)

IV. Advantages of Gene Therapy Approach to Drug Delivery

A. Improves drug delivery to the retina

B. Sustained, local, and therapeutic levels

C. Avoids systemic toxicity

D. Can be delivered by a single intravitreal injection

E. A novel treatment for AMD

V. HMR59 is a gene therapy approach targeting MAC deposition.

A. AAV2 based gene therapy

B. Produces soluble CD59 that blocks membrane attack complex (MAC)

C. Delivered via intravitreal injection

VI. Conclusions

A. Blocking MAC formation using gene therapy that locally produces soluble CD59 is a promising approach for treating AMD.

B. May be useful both for treating dry AMD and for the conversion of dry AMD to neovascular AMD

C. Hemera Biosciences, Inc. (Boston, MA) has licensed the technology and is planning clinical trials.

A Complement-Based Gene Therapy for AMDElias Reichel MD


Background

“Dry AMD” creates a substantial disability in older individuals and is an important unmet medical need. Several lines of experi-mental and clinical evidence indicate that toxic by-products of the visual cycle play a pathophysiological role in the develop-ment and progression of both early and late dry AMD. Visual cycle modulators aim at reducing the accumulation of such toxic compounds in the retinal pigment epithelium and thus at slowing progression of the disease.

Rationale

Geographic atrophy (GA) represents the advanced form of dry AMD. GA in the context of AMD represents an unmet clinical need, with increasing incidence and prevalence in the elderly. Atrophic lesions continuously enlarge over time and are associ-ated with a corresponding absolute scotoma. While the foveal retina may be spared for some time, foveal involvement results in severe visual loss.

Areas of GA are characterized by loss of the retinal pigment epithelium (RPE), outer layers of the neurosensory retina, and the corresponding choriocapillaris. The initiating event and anatomical layer in GA development, however, is still unknown. The loss of photoreceptors may be secondary to degenerative processes at the level of the RPE.

Several lines of experimental and clinical evidence indicate that the RPE plays an important role in the pathogenesis of GA associated with AMD. In the postmitotic RPE cells, lipofuscin (LF) accumulates in the lysosomal compartment with age and, in an accelerated fashion, in various complex as well as mono-genetic retinal diseases, including Best disease, Stargardt disease, and AMD. LF is thought to be mainly derived from the chemi-cally modified residues of incompletely digested photoreceptor outer segment discs. Experimental findings suggest that certain molecular compounds of LF, such as N-retinylidene and N-reti-nylethanolamine (A2-E), may interfere with normal cell function via various molecular mechanisms including inhibition of lyso-somal degradation, autophagy, and phagocytosis.

Fluorophores such as A2-E can now be detected in vivo by using fundus autofluorescence (FAF) imaging techniques. With the advent of confocal scanning laser ophthalmoscopy (cSLO), it is possible to document FAF and its spatial distribution and intensity over large retinal areas in the living human eye. It has been shown that areas with increased FAF intensities and there-fore excessive RPE LF load surrounding atrophy, in the so-called junctional zone of atrophy, can be identified. Areas of increased FAF may precede the development of new areas of GA or the enlargement of the existing atrophic patches. In the natural his-tory Fundus Autofluorescence in Age-related Macular Degenera-tion (FAM) Study, it has been shown that eyes with large areas of increased FAF outside atrophy were associated with higher rates of GA progression over time compared to eyes with smaller areas of increased FAF outside atrophy at baseline. In addition, certain abnormal patterns of increased FAF in the border zone confer risk for fast progression. These findings suggest that the area of

increased FAF surrounding the atrophy at baseline is positively correlated with the degree of spread of GA over time.

Modulation of the visual cycle thus represents a rational therapeutic approach for degenerations associated with accu-mulations of A2E. By modulating visual cycling to first protect rod photoreceptors, it is assumed that cone cells can also be preserved.

Fenretinide

Dietary vitamin A (retinol) is a precursor for a toxic metabolite within lipofuscin, A2E. The normal physiological complex facili-tates delivery of retinol to the RPE and other tissues. Fenretinide (ReVision Therapeutics) competes with retinol for binding to ret-inol-binding protein (RBP) and prevents binding of transthyretin (TTR). By reducing the levels of circulating retinol it is assumed that the level of toxic fluorophores in the retinal pigment epithe-lium is subsequently reduced. Over time, this effect is expected to slow growth of GA lesions.

Safety of systemic delivery of fenretinide has been shown in over 8000 patient-years of human exposure for other indications (eg, oncology). It appears to be well tolerated at doses equivalent to those being currently tested in clinical trials in ophthalmology.

Delayed dark adaptation induced by fenretinide has been reported, but this appears to be reversible. Recently, the results of a Phase 2 double-masked, placebo-controlled, dose-ranging trial encompassing 246 subjects has been reported. Two doses, 100 mg and 300 mg vs. placebo were taken orally. All patients had pure GA at the study eye. Outcome measures included change in lesion size, fluorescein angiography, contrast sensitiv-ity, and BCVA.

In that study it was demonstrated that fenretinide caused a dose-dependent, reversible reduction in serum RBP. There was a trend for reduced lesion growth with reductions in serum RBP. However, lesion growth rates in subjects who achieved an RBP reduction of ≥ 60% were not statistically different from placebo. Lesion growth rates in subjects who received fenretinide with a smaller particle size (IDS), regardless of the extent of RBP reduc-tion, however, were reported as significantly lower than placebo. Furthermore, an effect of fenretinide on reducing CNV incidence in GA patients was noted. Effects may be due to multiple mecha-nisms of fenretinide action.

ACU-4429

ACU-4429 (Acucela) is a small, nonretinoid molecule that modu-lates the isomerase, RPE 65, required to convert transretinol to 11-cis-retinal in the RPE. In mouse models of retinal degenera-tion it has been shown that ACU-4429 prevents the accumula-tion of A2E.

In a Phase1 trial it has been demonstrated that ACU-4429 is well tolerated and induces a dose-dependent modulation of the visual cycle. A key marker for determinations of pharmacologic visual cycle modulation is the time course of recovery of rod sensitivity after exposure to a bleaching light. After dark adapta-tion, electroretinographic findings demonstrated a dose-related

Visual Cycle ModulationFrank G Holz MD


slowing of the rate of recovery that reached its maximum on Day 2 and returned to baseline by Day 7. Mean area under the con-centration curve and peak plasma concentration increased pro-portionally with increasing doses. A dose-dependent inhibition of the b-wave of the electroretinograms was noted, and linear phar-macokinetics across doses were demonstrated. Adverse events, including dyschromatopsia and alteration in dark adaptation, were mild and visual in nature, transient, and resolved within a few days.

Efficacy and safety of that agent are being further evaluated in a multicenter, randomized, double-masked, placebo-controlled study.

Conclusions

The aberrant accumulation of lipofuscin and vitamin A-derived toxins, such as N-retinylidene-N-retinylethanolamine (A2E) and related fluorophores, has been implicated in the pathogenesis of GA. Therefore, this pathway represents a target to influence the natural course of advanced dry AMD. Visual cycle modula-tors have been developed to slow the accumulation of such toxic by-products of the visual cycle. Ongoing clinical trials need to be completed before such treatments can be recommended to patients. Further research into molecular mechanisms is needed.

Selected Readings

1. Akula JD, Hansen RM, Tzekov R, et al. Visual cycle modulation in neurovascular retinopathy. Exp Eye Res. 2010; 91:153-161.

2. Eldred GE, Lasky MR. Retinal age pigments generated by self-assembling lysosomotropic detergents. Nature 1993; 361:724-76.

3. Golczak M, Maeda A, Bereta G, et al. Metabolic basis of visual cycle inhibition by retinoid and nonretinoid compounds in the ver-tebrate retina. J Biol Chem. 2008; 283:9543-9554.

4. Hamel CP, Tsilou E, Pfeffer BA, Hooks JJ, Detrick B, Redmond TMl. Molecular cloning and expression of RPE65, a novel retinal pigment epithelium-specific microsomal protein that is post-transcriptionally regulated in vitro. J Biol Chem. 1993; 268:15751-15757.

5. Holz FG, Bellmann C, Staudt S, Schütt F, Völcker HE. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001; 42:1051-1056.

6. Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HPN, Schmitz-Valckenberg S. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007; 143:463-472.

7. Holz FG, Schütt F, Kopitz J, et al. Inhibition of lysosomal degrada-tive functions in RPE cells by a retinoid component of lipofuscin. Invest Ophthalmol Vis Sci. 1999; 40:734-737.

8. Kubota R, Boman NL, David R, Mallikaarjun S, Patil S, Birch D. Safety and effect on rod function of ACU-4429, a novel small-mol-ecule visual cycle modulator. Retina. Epub ahead of print 21 Apr 2011.

9. Liu J, Itagaki Y, Ben-Shabat S, Nakanishi K, Sparrow JR. The bio-synthesis of A2E, a fluorophore of aging retina, involves the forma-tion of the precursor, A2-PE, in the photoreceptor outer segment membrane. J Biol Chem. 2000; 275:29354-29360.

10. Maeda A, Maeda T, Golczak M, et al. Effects of potent inhibitors of the retinoid cycle on visual function and photoreceptor protec-tion from light damage in mice. Mol Pharmacol. 2006; 70:1220-1229.

11. Mata NL, Moghrabi WN, Lee JS, et al. RPE65 is a retinyl ester binding protein that presents insoluble substrate to the isomerase in retinal pigment epithelial cells. J Biol Chem. 2004; 279:635-643.

12. Mata NL, Weng J, Travis GH. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. Proc Natl Acad Sci USA. 2000; 97:7154-7159.

13. Radu RA, Mata NL, Nusinowitz S, Liu X, Sieving PA, Travis GH. Treatment with isotretinoin inhibits lipofuscin accumulation in a mouse model of recessive Stargardt’s macular degeneration. Proc Natl Acad Sci USA. 2003; 100(8):4742-4747.

14. Sieving PA, Chaudhry P, Kondo M, et al. Inhibition of the visual cycle in vivo by 13-cis retinoic acid protects from light damage and provides a mechanism for night blindness in isotretinoin therapy. Proc Natl Acad Sci USA. 2001; 98:1835-1840.

14. Sparrow JR, Parish CA, Hashimoto M, Nakanishi K. A2E, a lipo-fuscin fluorophore, in human retinal pigmented epithelial cells in culture. Invest Ophthalmol Vis Sci. 1990; 40:2988-2995.

16. Sparrow JR, K Nakanishi, CA Parish. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epi-thelial cells. Invest Ophthalmol Vis Sci. 2000; 41:1981-1989.

17. Bui TV, Vogel R, Mata NL. Serum retinol binding protein as a biomarker for fenretinide-mediated slowing of lesion growth in patients with geographic atrophy. Program and abstracts of the Association for Research in Vision and Ophthalmology (ARVO) 2011, abstr. #3538.

18. Xue L, Gollapalli DR, Maiti P, Jahnq WJ, Rando RR. A palmi-toylation switch mechanism in the regulation of the visual cycle. Cell 2004; 117:761-771.


I. Stem Cells: Definitions and Classes1

A. Stem cells are:

1. Unspecialized cells with the capacity for unlim-ited self-renewal

2. Each daughter cell has the capacity to remain a stem cell or to differentiate into more specialized, tissue- or organ-specific cells.

3. Two transcription factors, Nanog and Oct4, are associated with helping to keep the cells in an undifferentiated state with the capacity for self-renewal

B. Human embryonic stem cells (hESCs)

1. In the blastocyst (3-5-day-old, preimplantation-stage embryo), the inner cell mass (ICM) gives rise to the entire body of the organism (eg, brain, heart, lung); hESCs are derived from the ICM of the blastocyst.

2. Pluripotent: Can form all lineages of the body (ectoderm, mesoderm, endoderm). Totipotent stem cells can form all lineages of the organism (including placenta).

3. hESCs can be obtained without destruction of the embryo.2

C. Adult (somatic) stem cells

1. Typically generate the cell types of the tissue in which they reside

2. Multipotent: Can form multiple cell types of one lineage (eg, retinal progenitor cell)

3. Present in many organs and tissues: brain, bone marrow, peripheral blood, blood vessels, skel-etal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. Reside in a specific area of each tissue (called a “stem cell niche”). Some types of stem cells are pericytes. May remain quiescent for long periods until activated by a normal need for more cells to maintain tissues, or by disease or injury.

4. Some examples:

a. Limbal stem cells: Give rise to corneal epithe-lium3, 4

b. Neural stem cells: Give rise to neurons, astro-cytes, and oligodendrocytes.

c. Adult Müller cells might be a source of photo-receptors.5,6

d. Hematopoietic stem cells: Give rise to red blood cells, B & T cells, natural killer cells,

neutrophils, basophils, eosinophils, mono-cytes, and macrophages

e. Mesenchymal stem cells: Give rise to osteo-cytes, chondrocytes, adipocytes, and other connective tissue cells

D. Induced pluripotent stem cells (iPSCs)

1. Adult (somatic) cells can be reprogrammed to an embryonic state using somatic nuclear cell transfer.7 Nuclear transfer may be more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentia-tion for applications in disease modeling or treat-ment.8

2. Takahasi and Yamanka et al,9,10 and Yu et al11 showed that adult (including human) cells also can be genetically reprogrammed to an embryonic stem cell–like state by being forced to express transcription factors: iPSCs cells have been generated from mouse and human somatic cells by introducing Octamer 3/4 (Oct4), sex determining region Y box–containing gene 2 (Sox2), Kruppel-like factor 4 (Klf4), and cellular myelocytomatosis oncogene (c-Myc),10 or Oct4, Sox2, Nanog, and Lin2811 using retroviruses or lentiviruses.

3. Human iPSCs express stem cell markers and can produce cells from all 3 germ layers.

4. Although iPSCs are pluripotent stem cells, iPSCs and ESCs do differ in some important ways. iPSCs have the theoretical advantage of not being rejected by the patient from whom they are derived (vs. ESCs, unless the ESCs were harvested from the patient as an embryo), but abnormal gene expression in some cells differen-tiated from iPSCs (both via a retroviral and epi-somal approach) can induce a T-cell-dependent immune response in a syngeneic recipient.12 This response is likely due to the abnormal expression of antigens (eg, Zg16, Hormad1) not expressed during normal development or differentiation of ESCs, leading to loss of tolerance.12 Expression of these antigens is a reflection of epigenetic dif-ferences (eg, DNA methylation) between iPSCs and ESCs.8,13-17 Continuous passaging of iPSCs may help attenuate these differences,18 but iPSCs clearly seem to be at greater risk for tumor for-mation (eg, due to p53 suppression) than ESCs.

5. The therapeutic potential of iPSCs has been demonstrated in animal models of sickle cell ane-mia19 and Parkinson’s disease.20 However, iPSCs

The Promise of Stem Cells for AMD and Retinal DegenerationsMarco Zarbin MD PhD FACS


that contain multiple viral vector integrations are not suitable for human clinical trials. The use of genome-integrating viruses can cause insertional mutagenesis and unpredictable genetic dysfunc-tion.21, 22 The oncogenic properties of some tran-scription factors (eg, c-Myc) also creates safety concerns. Some progress to improve the safety of iPSCs has occurred:

a. Modified protocols that do not require c-Myc, Sox-2, and/or Klf4 have been described.23-27

b. Mouse iPSCs can be created without viral vec-tors.28-31 For example, repeated transfection of 2 expression plasmids (ie, nonintegrating vector), one containing the complementary DNAs (cDNAs) of Oct3/4, Sox2, and Klf4 and the other containing the c-Myc cDNA, into mouse embryonic fibroblasts creates iPSCs without evidence of plasmid integra-tion.

c. Other vector-free methods, using modified synthetic mRNA,32 recombinant proteins that can penetrate the plasma membrane of somatic cells,33,34 or exposing somatic cells to ESC-conditioned media35 have been used to reprogram cells to pluripotency, which may be safer than using viral vectors to induce reprogramming.32

6. Human iPSCs might be used to study disease pathogenesis, for high-throughput screening to identify small molecule therapy, and as cell-based therapy for regenerative medicine.36,37

II. Embryonic vs. Adult vs. Induced Pluripotent Stem Cells for Cell Replacement vs. Rescue Therapy

A. Embryonic stem cell

1. Pluripotent

2. Can be grown relatively easily

3. More likely to be rejected since ESCs are more likely to be derived from allogeneic donor

4. May or may not harbor disease-causing genes, depending on donor status

B. Adult stem cell

1. Multipotent

2. Relatively hard to harvest

3. Might not be rejected (if derived from recipient)

4. Harbors disease-causing genes of donor

C. Reprogrammed cell: Nuclear transfer, cell fusion, or genetic manipulation to create a pluripotent cell.

1. Pluripotent

2. Can be grown relatively easily

3. Less likely to be rejected than ESC, but might be even if implanted into donor of origin12

4. May retain epigenetic features of the cell type of origin8

5. Unless manipulated, harbors same disease-causing genes as donor. For diseases like AMD, though, the time for redeveloping retinal pig-ment epithelium (RPE) damage might exceed the expected life span of the recipient.

D. To be useful for cell-based replacement therapy, stem cells must:

1. Proliferate extensively to generate sufficient quantities of material to serve as “universal donor”

2. Differentiate into the desired cell type(s)

a. hESC-derived RPE can spontaneously dedif-ferentiate to nonRPE-like cells and spontane-ously redifferentiate into RPE-like cells, indi-cating phenotypic instability.38 The cultures may not retain a stable phenotype after 5-8 passages.

b. ESCs and iPSCs vary in their tendency to dif-ferentiate into cells of a given lineage.8,39

c. What defines a “differentiated” RPE cell? Summarized by Bharti et al40

i. 154 “signature” genes have been defined from studies of native fetal RPE, cultured fetal RPE, and native adult RPE41

ii. microRNA expression is important in induction and maintenance of stable epi-thelial monolayers42

iii. functional activity: phagocytosis of outer segments

iv. apical-basal polarization: distribution of channels, receptors, transporters; basal (VEGF, IP-10, RANTES, MCP-3) vs. api-cal (MCP-1, IL-6, IL-8, PEDF, TGF-beta1 and 2) secretion

v. transepithelial resistance (tight junctions, especially CLAUDIN 19) ~200 Ω/cm2

vi. resting membrane potential (apical: -50-60 mV)

vii. fluid transport (5-10 µl/cm2/h)

viii. regulate volume and composition of sub-retinal space

ix. anatomy: cuboidal, confluent monolayer

x. immunologic properties: T-cell suppres-sion

d. What defines a photoreceptor cell? Gene expression profiling has been used to deter-mine how closely ESC-derived retinal cells resemble normal retina, the developmental stage of the ESC-derived cells (relative to fetal retinal cells), and whether there are significant contaminating nonretinal cells.43 These stud-ies indicate that some minimal contamination


with nonretinal cells (eg, RPE, ciliary epithe-lium) can occur, but that undifferentiated, pluripotent cells decline with time in culture, which may mean that a longer duration dif-ferentiation protocol may minimize the risk of teratoma formation. Some features of photoreceptor differentiation rely on interac-tions with surrounding cells. Interaction of photoreceptors with RPE is critical for foveal development.44 Interaction with Müller cells via zonula adherens (crumbs homolog 1 protein) is important for normal outer retinal organization.45

e. Influence of the microenvironment on cell dif-ferentiation

i. The retinal and subretinal microenviron-ment can influence the differentiation and functionality of transplanted cells, includ-ing expression of developmental markers and markers of proliferation.46-49

ii. Abnormalities in the Bruch membrane may prevent transplanted hESC-derived RPE from surviving and differentiating long-term in AMD eyes.50 Since Bruch membrane is derived from mesoderm, there is no expectation that hESC- or iPSC-derived RPE will manufacture Bruch membrane.

3. Survive in the recipient after transplant: Human iPSC-derived RPE survive ~4 months in RCS rats (xenograft).51,52

a. Abnormalities in RPE in AMD eyes might prevent transplanted ESC-derived photore-ceptor transplants from surviving.53

b. Cone survival depends on rod survival.54-56 Therefore, it might be best to transplant a mixture of rods and cones to achieve improvement in cone-mediated visual func-tion.

4. Integrate into the surrounding tissue after trans-plant:

a. Targeted disruption of glial reactivity and dis-ruption of the outer limiting membrane may improve integration of transplanted cells.57-59 Developmental age of the donor cells may be critical for successful integration with host retina,60 but it is not clear that this is the case.61

b. Synaptic reorganization of the retina occurs in association with photoreceptor degeneration in retinitis pigmentosa.62 This reorganization might limit the extent of functional photore-ceptor integration with the host.

5. Function appropriately for the duration of the recipient’s life.

E. To be useful for cell-based rescue therapy, stem cells must elaborate needed trophic factors and not pro-liferate in an uncontrolled manner.

1. In a preclinical model of glaucoma, intravitreal somatic neural stem cells63 and bone marrow-derived mesenchymal stem cells64 can substan-tially reduce retinal ganglion cell death.

2. In rhodopsin knockout mice, bone marrow-derived mesenchymal stem cells rescue photore-ceptors.65

3. Subretinal bone marrow–derived mesenchymal stem cells rescue photoreceptors in RCS rats.66

4. hESC-derived RPE elaborate neurotrophic sub-stances that have been shown to support photo-receptor survival in preclinical models of retinal degenerative disease.50

F. RPE cell transplants are an attractive starting point for cell-based combination replacement and rescue therapy in the eye because:

1. hESCs and iPSCs can be induced to differentiate into RPE relatively easily, and one can generate large quantities of cells with stable genotype and appropriate phenotype.

a. A 2-step process, typically requiring weeks in culture:

i. convert ESCs or iPSCs into cells with neu-roectodermal properties

ii. differentiate neuroectodermal cells into RPE cells

b. Only a part of the ESC or iPSC culture is transformed into RPE, which may mean that the cultures are heterogeneous.

c. hESC-derived RPE tend to resemble fetal RPE more closely than adult RPE, and iPSC-derived RPE seem to be in a unique differen-tiation state.38,51,67-69

d. Both hESC- and iPSC-derived RPE express differentiation markers: tyrosinase (mela-nin), premelanosomal protein-17 (melanin), Bestrophin-1 (chloride channel), MERTK (phagocytosis), focal adhesion kinase, PEDF/VEGF (growth factors), RPE65/RLBP1 (visual cycle).

2. RPE cells integrate easily with host photorecep-tors.

3. RPE cells elaborate trophic substances that sup-port photoreceptors.50,70,71

4. There is abundant evidence for transplant effi-cacy in preclinical models.

5. Diseases in which RPE cells appear to be targeted primarily include Best disease72,73 and some forms of retinitis pigmentosa74,75 and secondarily include Stargardt macular dystrophy76, 77 and AMD.53,78


6. However, in the case of AMD eyes, survival and proper differentiation on submacular Bruch membrane may be problematic.50

III. Ocular Tissues Derived From Stem Cells

A. Limbal stem cell: corneal epithelium

B. ?Trabecular meshwork progenitor cells: trabecular meshwork cells79

C. From both ESCs and iPSCs:

1. Retinal ganglion cells80-82

2. Retinal pigment epithelial cells38,49,51,52,83-86

3. Photoreceptors47,84-88

IV. Stem Cell Treatment of Retinal Degenerative Disease: Preclinical Models

A. Bone marrow-derived lineage-negative hematopoi-etic stem cells (intravitreal) rescue photoreceptors (primarily cones) in rd1 and rd10 mice.89

B. Bone marrow-derived mesenchymal stem cells res-cue photoreceptors in rhodopsin knockout mice.65

C. Endothelial progenitor cells promote vascular repair and reversal of ischemic injury in ischemic retinopa-thies.90

D. hESCs replace photoreceptors in mnd mice,91 rd1 mice,92 and in Crx-/- mice (a model of Leber congeni-tal amaurosis).93

E. hESC-derived RPE rescue photoreceptors in Royal College of Surgeons (RCS) rats.38,48,67,83,94

F. iPSC-derived RPE rescued photoreceptors in RCS rats.52

G. Human neural progenitor cells rescue photorecep-tors in RCS rats.95

V. Stem Cells: Human Clinical Trials for Retinal Disease

A. Stargardt macular dystrophy: Subretinal transplan-tation of hESC derived RPE (MA09-hRPE) cells in patients with Stargardt macular dystrophy (SMD): ClinicalTrials.gov Identifier NCT01345006.

1. Sponsor: Advanced Cell Technology

2. Design: Phase 1/2, open-label, prospective, multicenter study to determine the safety and tol-erability of subretinal transplantation of hESC-derived RPE cells in patients with SMD. There will be 4 cohorts, each consisting of 3 patients. The enrolled cohorts will be as follows:

a. 3 SMD patients: 50,000 MA09-hRPE cells transplanted

b. 3 SMD patients: 100,000 MA09-hRPE cells transplanted

c. 3 SMD patients: 150,000 MA09-hRPE cells transplanted

d. 3 SMD patients: 200,000 MA09-hRPE cells transplanted

3. Centers:

a. Jules Stein Eye Institute (Los Angeles, Califor-nia), PI: Steven Schwartz MD

b. Casey Eye Institute (Portland, Oregon), PI: Peter Francis MD PhD

B. AMD: Safety and tolerability of sub-retinal trans-plantation of hESC-Derived RPE (MA09-hRPE) cells in patients with advanced dry age related macular degeneration (Dry AMD): ClinicalTrials.gov Identifier NCT01344993.

1. Sponsor: Advanced Cell Technology

2. Design: This study is a Phase 1/2, open-label, nonrandomized, sequential, multicenter safety and tolerability trial to evaluate the effect of subretinal injection of hESC-derived RPE cells in patients with advanced dry AMD and to perform exploratory evaluation of potential efficacy end-points to be used in future studies of RPE cellular therapy. Eligible patients will receive a single uni-ocular subretinal infusion of MA09-hRPE cells in 1 of 4 dose levels

a. 3 patients: 50,000 cells transplanted

b. 3 patients: 100,000 cells transplanted

c. 3 patients: 150,000 cells transplanted

d. 3 patients: 200,000 cells transplanted

3. Center: Jules Stein Eye institute (Los Angeles, California), PI: Steven Schwartz MD

C. Retinitis pigmentosa (RP): ClinicalTrials.gov identi-fier NCT01068561.

1. Sponsor: University of Sao Paulo, Brazil

2. Design: A prospective Phase 1, nonrandomized open-label study of RP patients with best-cor-rected ETDRS visual acuity (BCVA) worse than 20/200. Standardized ophthalmic evaluation per-formed at baseline and at Weeks 1, 4, 12, and 24 (±1) following intravitreal injection of 10 x 106 autologous bone marrow stem cells (ABMDSC)/ 0.1ml, 3-3.5 mm posterior to the limbus with a 27-gauge needle.

3. 3 patients with RP and 2 with cone-rod dystro-phy underwent intravitreal injection of autolo-gous bone marrow-derived mononuclear cells in a Phase 1 study with no adverse effects (and no documented benefit at 10-months follow-up).96

VI. Summary

Why should one develop cell-based therapy in the cur-rent era of pathway-based pharmacological therapy for retinal disease? Transplanted cells can secrete numer-ous molecules that may exert a beneficial effect on the host retina and/or choroid even if they do not cure the underlying disease.54,67,70,71,97 Ideally, with a single transplant operation, many different pathways can be modified, which may reduce the chance of “escape” associated with monotherapy as well as the need for repeated drug administration. In addition, transplanted


cells can replace dead cells (eg, photoreceptors). Due to their pluripotency and unlimited proliferative capac-ity, stem cells seem to be a logical choice for starting material. Although preclinical studies demonstrate the feasibility of using ESCs and iPSCs for treating degen-erative retinal diseases associated with abnormalities in the RPE and/or photoreceptors, some issues may limit the use of stem cells in clinical practice. These issues include immunogenicity of the cells, stability of cell phenotype (both inherent and environment-induced), and the propensity to form tumors in situ. In the case of nonexudative AMD, cell transplants might prevent progression of geographic atrophy (through replace-ment of dysfunctional or dead RPE) and might even bring about some visual improvement in selected cases (through rescue of photoreceptors that are dying but not dead). Cell-based therapy may one day be sight-restoring for patients who are blind due to retinal degeneration of various etiologies. RPE transplantation is an attractive starting point for this sort of therapy since these cells can integrate with the host retina easily.

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78. Anderson DH, Radeke MJ, Gallo NB, et al. Prog Retin Eye Res. 2010; 29(2):95-112.

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90 Section IX: Imaging 2011 Subspecialty Day | Retina

Widefield Autofluorescence: A New Tool for Studying Macular and Retinal DiseaseSrinivas R Sadda MD

Fundus autofluorescence (FAF) imaging has become an impor-tant tool in clinical ophthalmology, in part by providing a func-tional assay of the status of the retinal photoreceptors and retinal pigment epithelium (RPE). Fundus autofluorescence appears to correlate with the lipofuscin content within RPE cells. Accumu-lation of lipofuscin is a common downstream event in normal aging as well as in many disease processes. Excess lipofuscin accumulation, producing hyperfluorescence on FAF imaging, may be a sign of a stressed and dysfunctional RPE cell. Subse-quent loss of autofluorescence may herald the loss of the RPE and associated photoreceptors.

FAF imaging has a number of common applications as a tool for aiding or confirming the diagnosis in a variety of macula and retinal degenerations (eg, Best disease where the vitelliform lesions are intensely hyperfluorescent), as well as in retinal vas-cular disorders such as parafoveal telangiectasis where depletion of luteal pigment can result in abnormal foveal autofluorescence. More recently, FAF imaging was added as a potentially useful tool in screening for evidence of hydroxychloroquine toxicity. FAF imaging is also an important tool in clinical trials of patients with atrophic AMD. Certain patterns of hyperautofluorescence surrounding the areas of atrophy may identify individuals who are more likely to progress and may be better candidates for ther-apeutic intervention. In addition, the high contrast of FAF imag-

ing for delineating the borders of atrophic and intact retina/RPE improves the accuracy and reproducibility of measuring atrophy in these individuals. Geographic atrophy measured as decreased autofluorescence on FAF imaging may prove to be an acceptable marker of efficacy in registration clinical trials.

More recently, FAF imaging capability has been introduced to widefield imaging devices—in particular the Optos 200Tx wide-field instrument. This device allows for imaging of up to a 200 degree field of view with visualization of the peripheral retina. Assessment of a series of over 300 consecutive retinal patients in our institution has revealed that peripheral autofluorescence abnormalities are common in patients with retinal disease, pres-ent in over two-thirds of individuals. Some patterns of peripheral autofluorescence appear to be characteristic of certain disease such as Harada disease, and may eventually prove to be useful in diagnosis. Peripheral FAF abnormalities are also common in eyes with AMD, present in over 60% of individuals, and more com-monly in patients with advanced or neovascular AMD. The sig-nificance of these abnormalities will be studied more extensively in the OPERA substudy of the AREDS2 trial.

In summary, peripheral FAF abnormalities are common in eyes with macular disease. The significance of these findings is worthy of further scrutiny.

2011 Subspecialty Day | Retina Section IX: Imaging 91

Introduction

Central serous chorioretinopathy (CSC) is characterized by an idiopathic serous retinal detachment including the macular area. Although neurosensory detachment in CSC disappears sponta-neously within about 3 months and visual prognosis is usually good, persistent and recurrent retinal detachment sometimes cause visual dysfunction and visual loss. Gass1 proposed cho-riocapillaris hyperpermeability was the cause of CSC, and later studies found multifocal areas of choroidal vascular hyperperme-ability in CSC patients seen during indocyanine green angiog-raphy (ICGA).2-6 However, the pathogenesis of CSC is still not fully understood. In this outline, morphological and pathophysi-ological conditions demonstrated by noninvasive and advanced imaging techniques of CSC are discussed.

OCT

A lot of studies for CSC had reported using OCT, because OCT can noninvasively help us to evaluate the resolution of subretinal fluid and the morphological retinal changes during the clini-cal course. Neurosensory retina was thickened within the area of retinal detachment in acute CSC,7 and foveal thickness was thinner than baseline in chronic CSC.8,9 However, the structure of the detached sensory retina was preserved in CSC compared with rhegmatogenous retinal detachment, which had a thickened outer nuclear layer (ONL) due to cystic changes.10

Newly developed spectral domain OCT (SD-OCT) provides high-resolution and detailed images of detached and/or reat-tached retina. Microstructural changes occur in the photorecep-tor layer of detached retina, and the visualization of external limiting membrane (ELM) and photoreceptor layers is associated with visual function.11 Also, the preservation of ONL thickness and the continuity of photoreceptor inner and outer segment junction (IS/OS) are positively correlated with visual acuity in resolved CSC.12

On OCT images of CSC during the period of absorption, irregularly thickened and elongated photoreceptor outer seg-ments have been observed in the subretinal space.13-17 OCT also visualizes the subretinal yellow deposits (yellowish, dot-like pre-cipitates and yellow material) as highly reflective tissue in CSC. Precipitates are not only on the posterior surface of the detached retina but also in the detached neurosensory retina.17

Figure 1. SD-OCT shows irregularly thickened and elongated photore-ceptor outer segments in the subretinal space.

Enhanced Depth Imaging OCT

Until recently, no method has been able to observe choroidal changes in vivo except for ICGA. A method to improve imaging of the choroid using commercially available OCTs was devel-oped—enhanced depth-imaging OCT (EDI-OCT)18—and by using this technique, the choroid in eyes with CSC was found to be thick.19 We also reported thickened choroid in CSC and the association with choroidal vascular hyperpermeability in ICGA.20 Similarly, choroidal thickness in fellow eyes of patients with CSC was thicker than that in age-matched, normal eyes.

On the other hand, verteporfin photodynamic therapy (PDT) is one of the therapies for resolution of leakage and consequently of subretinal fluid in both acute and chronic CSC. However, the mechanism of action of PDT in CSC has not been completely understood. Choroidal thickness and hyperpermeability seen during ICGA is reduced after half-dose verteporfin PDT.21 It may explain the relatively low rates of recurrence of CSC after PDT; the induced changes within the choroid caused by PDT may nor-malize the choroidal permeability to the extent that abnormally increased hydrostatic pressure is less likely to occur.

Figure 2. EDI-OCT images before and after PDT for CSC. The subfoveal choroidal thickness was 365 μm at baseline (A) and reduced to 300 μm 3 months after PDT (B).

Fundus Autofluorescence

Fundus autofluorescence is thought to be an intrinsic optical property of the tissue. Short-wave autofluorescence (SW-AF) excited by a 488-nm light source mainly originates from lipofus-cin in the retinal pigment epithelium (RPE). A major fluorophore

Imaging of Central Serous ChorioretinopathyTomohiro Iida MD


of lipofuscin is A2E. Recent studies suggested that the precursors of A2E (A2PE) in the sensory retina also showed autofluores-cence and had cytotoxic effects. In eyes with CSC, the hyperau-tofluorescence of precipitates was reported in the area of retinal detachment.13-15,22 We reported the subretinal yellow deposits demonstrated the hyper-SW-AF in half the eyes at initial exami-nation, and in the remaining half during the follow-up.22 These findings indicate that formation of yellow deposits is associated with shedding of the photoreceptor outer segments and metabo-lism by phagocytes. A2E and A2PE are known to induce the photoreceptor and RPE cell damage.

Infrared autofluorescence (IR-AF) excited by a 787-nm light source can originate from melanin in the RPE. Melanin plays an important role in the protection of eyes against phototoxicity. The subretinal yellow deposits with hyper-SW-AF and hyper-IR-AF turned to show the hypo-SW-AF and hypo-IR-AF during long-term follow-up.22,23 We speculate that the deposits contrib-ute to the characteristic changes of autofluorescence through the modification of melanin in the RPE.

Figure 3. SW-AF (A, C) and IR-AF (B, D) images of CSC. Subretinal deposits with hyperfluorescence were observed in both the images of SW- and IR-AF (A and B, arrows). Three years after reattachment, deposits turned to show hypo-SW-AF and hypo-IR-AF (C and D, arrowheads).

Figure 4. Hypothesis of photoreceptor and RPE cell damage in CSC. Adapted from Sekiryu et al.23

Conclusions

Preserved detached sensory retina saves good visual acuity; however, discontinuous ELM or IS/OS on SD-OCT may lead to visual dysfunction. Fundus autofluorescence can detect the sub-retinal and RPE abnormality. Although it is still unclear whether subretinal yellow deposits affect the clinical implications in CSC, the existence of depositions may be associated with photorecep-tor outer segment and RPE cell damage. EDI-OCT is helpful in monitoring the proposed site for pathophysiologic changes in CSC and the choroid.

References

1. Gass JD. Pathogenesis of disciform detachment of the neuroepithe-lium. II. Idiopathic central serous choroidopathy. Am J Ophthal-mol. 1967; 63:587-615.

2. Scheider A, Nasemann JE, Lund OE. Fluorescein and indocyanine green angiographies of central serous choroidopathy by scanning laser ophthalmoscopy. Am J Ophthalmol. 1993; 115:50-56.

3. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Oph-thalmol. 1994; 112:1057-1062.

4. Piccolino FC, Borgia L. Central serous chorioretinopathy and indo-cyanine green angiography. Retina 1994; 14:231-242.

5. Iida T, Kishi S, Hagimura N, et al. Persistent and bilateral choroidal vascular abnormalities in central serous chorioretinopathy. Retina 1999; 19:508-512.

6. Spaide RF, Goldbaum M, Wong DW, Tang KC, Iida T. Serous detachment of the retina. Retina 2003; 23:820-846.

7. Iida T, Hagimura N, Sato T, et al. Evaluation of central serous cho-rioretinopathy with optical coherence tomography. Am J Ophthal-mol. 2000; 129:16-20.

8. Eandi CM, Chung JE, Cardillo-Piccolino F, et al. Optical coherence tomography in unilateral resolved central serous chorioretinopathy. Retina 2005; 25:417-421.

9. Furuta M, Iida T, Kishi S. Foveal thickness can predict visual out-come in patients with persistent central serous chorioretinopathy. Ophthalmologica 2009; 223:28-31.

10. Maruko I, Iida T, Sekiryu T, et al. Morphologic changes in the outer layer of the detached retina in rhegmatogenous retinal detach-ment and central serous chorioretinopathy. Am J Ophthalmol. 2009; 147:489-494.

11. Ojima Y, Hangai M, Sasahara M, et al. Three-dimensional imaging of the foveal photoreceptor layer in central serous chorioretinopa-thy using high-speed optical coherence tomography. Ophthalmol-ogy 2007; 114:2197-2207.

12. Matsumoto H, Sato T, Kishi S. Outer nuclear layer thickness at the fovea determines visual outcomes in resolved central serous chorio-retinopathy. Am J Ophthalmol. 2009; 148:105-110.

13. Piccolino FC, de la Longrais RR, Ravera G, et al. The foveal pho-toreceptor layer and visual acuity loss in central serous chorioreti-nopathy. Am J Ophthalmol. 2005; 139:87-99.

14. Spaide RF, Klancnik JM Jr. Fundus autofluorescence and central serous chorioretinopathy. Ophthalmology 2005; 112:825-833.

15. Spaide R. Autofluorescence from the outer retina and subretinal space: hypothesis and review. Retina 2008; 28:5-35.

16. Matsumoto H, Kishi S, Otani T, et al. Elongation of photoreceptor outer segment in central serous chorioretinopathy. Am J Ophthal-mol. 2008; 145:162-168.


17. Kon Y, Iida T, Maruko I, et al. The optical coherence tomography-ophthalmoscope for examination of central serous chorioretinopa-thy with precipitates. Retina 2008; 28:864-869.

18. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol. 2008; 146:496-500.

19. Imamura Y, Fujiwara F, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in central serous cho-rioretinopathy. Retina 2009; 29:1469-1473.

20. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness in fellow eyes of patients with central serous chorioretinopathy. Retina. Epub ahead of print 9 April 2011.

21. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of central serous chorioretinopathy. Ophthalmol-ogy 2010; 117:1792-1799.

22. Maruko I, Iida T, Ojima A, et al. Subretinal dot-like precipitates and yellow material in central serous chorioretinopathy. Retina. Epub ahead of print 3 Nov 2010.

23. Sekiryu T, Iida T, Maruko I, et al. Infrared fundus autofluorescence and central serous chorioretinopathy. Invest Ophthalmol Vis Sci. 2010; 51:4956-4962.


Introduction

The choroid is an integral structure in the eye that accounts for most of the ocular blood flow and participates in many disease processes but is difficult to adequately image in clinical examina-tion. Commercially available contact B-scan ultrasonography has an axial resolution of about 0.15 mm and a much lower lateral resolution. At times it is difficult to differentiate the choroid from the sclera using clinical B-scan ultrasonography devices. Fluorescein angiography provides limited information about the choroid because of light scattering and absorption by the pig-ment in the retinal pigment epithelium (RPE) and choroid and by blood in the choroid. The excitation and fluorescence of indocya-nine green (ICG) occurs in the near-infrared region, which has improved ability to penetrate pigmented tissue as compared with visible light. ICG is helpful in examining vascular structures in the choroid, but it does not supply much information about non-vascular problems in the choroid and does not supply any cross-sectional information. Optical coherence tomography (OCT) is used to obtain cross-sectional images of the retina, but imaging of the choroid is limited to a certain extent by light scattering and absorption, but more importantly by depth-dependent roll-off in sensitivity and resolution with increased depth imaging for spec-tral domain OCT (SD-OCT) instruments. Increased visualization of the choroid is possible in albinism, and the ability to visualize the depth of the choroid using OCT has been used in a grading system of ocular albinism.1

Methods to Use OCT to Visualize the Choroid

Enhanced depth imaging OCTA method devised to enable conventional SD-OCT to image the choroid was called enhanced depth imaging OCT (EDI-OCT). This method pushed the peak sensitivity of the SD-OCT device close to the choroidal scleral junction and then used the conju-gate of the typical image used in SD-OCT analysis. This method is now simply performed in a variety of SD-OCT instruments—for example, by selecting either the “EDI” button when using the Heidelberg Spectralis or the “Choroidal” imaging selection when using the Topcon 3D OCT 2000. With SD-OCT you pick between imaging the vitreous and vitreoretinal interface well (the typical way of using these devices) or imaging the choroid well (EDI-OCT).

Swept source OCTIn a SD-OCT a light source is used that essentially is capable of providing a range of wavelengths simultaneously. The inter-ferometric signal is passed through a grating to separate the component frequencies, and the signal is detected by a line charge coupled device (CCD). This leads to problems for signals arising out of deeper layers. With swept source devices the light source produces a single wavelength of light at any instance, and the output of light is swept across a range of frequencies. The resultant signal is detected by a photodiode, which is capable of detecting signals much more rapidly than can a CCD. Swept source OCTs (SS-OCT) typically operate at much higher scan

rates than do SD-OCTs. In addition, the detection methodol-ogy suffers less roll-off of sensitivity with increasing depth. The light sources commonly available for swept source imaging have a wavelength of approximately 1 micron, which has a slightly better ability to penetrate tissue than do the wavelengths of light used for conventional SD-OCT. So the vitreous, retina, and cho-roid can be imaged simultaneously.

With the possibility of increased depth imaging, SS-OCT device designers have an incentive to design instruments that have a larger total depth of scanning. A typical SD-OCT can scan a depth of about 2 mm or less. SS-OCT can easily exceed this amount, and with suppression of the conjugate image it has the potential to image a depth more than 5 mm. This does not trans-late into imaging 5 mm through dense tissue, however.

Imaging the choroid

NormalsThe measurement of the thickness of the choroid was found to be highly reproducible.3 In a study of 54 normal, nonmyopic eyes, the choroidal thickness was greatest in the subfoveal location. The thickness of the choroid decreased rapidly in the nasal direc-tion and less so in the temporal direction. The subfoveal choroi-dal thickness was 287 (standard deviation [±] 76) microns, which decreased to 145 ± 57 µm 3 mm nasal to the fovea and 261 ± 77 µm 3 mm temporal to the fovea. The choroidal thickness showed a negative correlation with age for the subfoveal location (r = -0.424; P = .001). Regression analysis showed that subfoveal choroidal thickness decreased 1.56 µm for each year of age.

High myopiaA group of 31 patients (55 eyes) with a mean age of 59.7 ± years and a mean refractive error of –11.9 ± 3.7 D was evaluated with EDI-OCT.4 The mean subfoveal choroidal thickness was 93.2 (±62.5) μm, and was negatively correlated with age (P = .006) and refractive error (P < .001).4 In a follow-up study of 145 eyes, the association of decreasing choroidal thickness with increasing age and myopic refractive error was confirmed. In addition, the visual acuity in highly myopic eyes with no observable pathology otherwise was found to be inversely correlated with choroidal thickness.5

Highly myopic eyes have varying pigmentary changes over time, particularly over areas of the most pronounced choroidal thinning. The choroid becomes thinner nearer to the optic nerve, finally becoming obliterated in regions of what typically is called “peripapillary atrophy.” If the choroid becomes thin to the point of obliteration in the macular region, the area shows depigmen-tation because of the lack of the choroid and overlying RPE. This has been termed “chorioretinal atrophy” even though the cho-roid and RPE are absent and not atrophic.

Age-related choroidal atrophyAlthough choroidal thickness appears to decrease with age, there are some patients who seem to have a pronounced loss of choroidal thickness over time. These patients have remarkable

Deep OCT Choroidal ImagingRichard F Spaide MD


choroidal thinning and adopt some of the fundus appearance of what is seen in myopes. There may be pigmentary granularity in the posterior pole and peripapillary atrophy in the absence of myopia. This condition is known as age-related choroidal atro-phy (ARCA).6 Eyes with thinner choroids seem to have a higher risk for glaucoma.

UveitisA number of studies are under way examining the choroid in inflammatory conditions, with some earlier studies already being published. In Vogt-Koyanagi-Harada disease the choroid is very thick in active cases, and this thickening rapidly decreases with corticosteroid treatment.7,8 The monitoring of choroidal thick-ness may prove to be an efficient mechanism to titrate corticoste-roid dosage in this disease.

Central serous chorioretinopathyGass proposed that central serous chorioretinopathy (CSC) was due to hyperpermeability of the choriocapillaris.9 In the mid-1990s, nearly 3 decades after Gass’s proposal, hyperpermeability of the choroid was demonstrated by a then new technique, ICG angiography. If choroidal vascular hyperpermeability created enough hydrostatic pressure to elevate the RPE and retina, then one would suspect the choroid should be thickened as well. The choroid was found to be remarkably thickened in eyes with CSC.10 Interestingly, eyes treated with focal laser showed no alteration in choroidal thickness even though there was fluid reabsorption. On the other hand, eyes treated with photody-namic therapy showed a decrease in choroidal thickness along with the expected reabsorption of subretinal fluid.11

Summary

Choroidal imaging is easily possible in a clinical setting, and early studies have had interesting and potentially useful findings. The studies so far have been simplistic, and more sophisticated evaluations of the 3-D structure and volume of the choroid can be performed. In addition, visualization and analysis of the internal structure of the choroid is possible. Analysis of the varia-tion of these characteristics with disease state will provide an increased understanding of the pathophysiology and treatment of ocular disorders.

References

1. Seo JH, Yu YS, Kim JH, et al. Correlation of visual acuity with foveal hypoplasia grading by optical coherence tomography in albi-nism. Ophthalmology. 2007; 114:1547-1551.

2. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol. 2008; 146:496-500.

3. Ikuno Y, Maruko I, Yasuno Y, et al. Reproducibility of retinal and choroidal thickness measurements in enhanced depth imaging and high-penetration optical coherence tomography. Invest Ophthalmol Vis Sci. Epub before print 20 Apr 2011.

4. Fujiwara T, Imamura Y, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol. 2009; 148:445-450.

5. Fujiwara T, Imamura Y, Lima LH, Nishida Y, Kurosaka D, Spaide RF. Choroidal B-scan ultrasonography B-scan ultrasonography. Submitted.

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

7. Fong AH, Li KK, Wong D. Choroidal evaluation using enhanced depth imaging spectral-domain optical coherence tomography in Vogt-Koyanagi-Harada disease. Retina. 2011; 31:502-509.

8. 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.

9. Gass JD. Pathogenesis of disciform detachment of the neuroepithe-lium. Am J Ophthalmol. 1967; 63:1-139.

10. 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.

11. 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.

12. Fong AH, Li KK, Wong D. Choroidal evaluation using enhanced depth imaging spectral-domain optical coherence tomography in Vogt-Koyanagi-Harada disease. Retina 2011; 31:502-509.


Introduction

Adaptive optics (AO) retinal imaging is a noninvasive tool that provides images of the living retina on a single cell level. Conven-tional ophthalmoscopy is limited by the optical aberrations of the eye, caused mainly by the cornea and lens. AO retinal imag-ing systems include a wavefront sensor to measure these aberra-tions and a deformable mirror that corrects for them, allowing for high-resolution imaging of retinal cells at a transverse resolu-tion of 2 microns.1

Capabilities of AO Retinal Imaging

Cone photoreceptors were the first cell type demonstrated in the living human retina using AO imaging.2,3 Cones have wave-guid-ing properties, giving them a bright reflectance pattern that can be captured using AO. Cones have been the most well studied cell type using AO technology.

Using selective photobleaching combined with AO imaging, the photopigment class of individual cones in the trichromatic cone mosaic can be identified.4 This technique revealed that the ratio of red and green cones varies widely in individuals with normal color vision.4 In cases of color vision deficiency caused by known mutations in photopigment genes, AO has detected changes in the cone mosaic in eyes with normal visual acuity that appeared healthy by standard clinical tests.5

The fluorescence AO scanning laser ophthalmoscope (FAO-SLO) incorporates AO with a confocal scanning laser and uses intracellular lipofuscin autofluorescence to produce single-cell resolution images of the retinal pigment epithelium (RPE) and the overlying cones simultaneously.6 Quantitative image analyses can be performed to obtain metrics of the density and regular-ity of the cone and RPE mosaics in the same retinal location.7 Studies in the monkey retina have shown that the light levels employed are safe and produce no detectable changes in the retina.8,9

Recently, the optical design of FAOSLO technology has been optimized to provide further improvements in resolution, enabling imaging of foveal cones and individual rod cells, which are smaller than cones and RPE.10,11

Clinical Applications

AO imaging can yield quantitative measurements of cell density12 and irregularity13 in patients with photoreceptor degenerations. In a familial study of autosomal dominant cone-rod dystrophy (AD-CRD), affected members with the identical genetic defect demonstrated significant differences in AO images of the photo-receptor mosaics that were not detectable using standard clinical tests. In a study of patients with macular telangiectasia (MacTel), AO imaging localized retinal crystals to the nerve fiber layer.14

AO imaging is uniquely sensitive in establishing the efficacy of therapy for retinal disease. In a Phase 1 study of the CNTF implant in patients with retinitis pigmentosa, AO imaging dem-onstrated preservation of cone photoreceptors in the study eye,

while all other clinical endpoints tested did not achieve signifi-cance.15

The properties of the FAOSLO imaging, including the ability to assess single rods, cones, and RPE cells in patients, and the capability to perform longitudinal evaluations of the identical retinal locations over time, offer an unparalleled opportunity to increase the speed at which the efficacy of potential therapies can be tested, a major advantage for clinical trials.16

References

1. Gray DC, Wolfe R, Gee BP, et al. In vivo imaging of the fine struc-ture of rhodamine labeled macaque retinal ganglion cells. Invest Ophthalmol Vis Sci. 2008; 49(1):467-473.

2. 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.

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

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

5. Carroll J, Neitz M, Hofer H, Neitz J, Williams DR. Functional photoreceptor loss revealed with adaptive optics: an alternate cause of color blindness. Proc Natl Acad Sci U S A. 2004; 101(22):8461-8466.

6. Gray DC, Merigan W, Wolfing JI, et al. In vivo fluorescence imag-ing of primate retinal ganglion cells and retinal pigment epithelial cells. Opt Express. 2006; 14(16):7144-7158.

7. 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.

8. Morgan JI, Hunter JJ, Masella B, et al. Light-induced retinal changes observed with high-resolution autofluorescence imaging of the retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2008; 49(8):3715-3729.

9. Morgan JI, Hunter JJ, Merigan WH, Williams DR. The reduction of retinal autofluorescence caused by light exposure. Invest Oph-thalmol Vis Sci. 2009; 50(12):6015-6022.

10. Gomez-Vieyra A, Dubra A, Malacara-Hernandez D, Williams DR. First-order design of off-axis reflective ophthalmic adaptive optics systems using afocal telescopes. Opt Express. 2009; 17(21):18906-18919.

11. Dubra A, Sulai Y. The reflective afocal broadband adaptive optics scanning ophthalmoscope. Biomed Opt Express. 2011; 2(6):1757-1768.

12. Wolfing JI, Chung M, Carroll J, Roorda A, Williams DR. High-resolution retinal imaging of cone-rod dystrophy. Ophthalmology 2006; 113(6):1019 e1.

13. Baraas RC, Carroll J, Gunther KL, Chung M, Williams DR, Foster DH, Neitz M. Adaptive optics retinal imaging reveals S-cone dys-trophy in tritan color-vision deficiency. J Opt Soc Am A Opt Image Sci Vis. 2007; 24(5):1438-1447.

Clinical Applications of Adaptive Optics TechnologyMina Chung MD


14. Sallo FB, Leung I, Chung M, et al; the MacTel study group. Retinal crystals in type 2 idiopathic macular telangiectasia. Ophthalmol-ogy. Accepted for publication May 16, 2011.

15. Talcott KE, Ratnam 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.

16. Rossi EA, Chung M, Dubra A, Hunter JJ, Merigan WH, Williams DR. Imaging retinal mosaics in the living eye. Eye (Lond). 2011; 25(3):301-308.


Introduction to OCT

Optical coherence tomography (OCT) was first introduced in 1991 by Huang et al as a high-resolution, noninvasive, in vivo ophthalmic imaging technique.1 Akin to ultrasound, OCT uses low coherence interferometry to detect echo time delays of light, as opposed to sound.2,3 The original devices were based on time domain detection technology, in which the reference arm moves mechanically and light echoes from time delays are measured sequentially to acquire OCT scans at 400 A-scans/second. In contrast, spectral domain OCT (SD-OCT), a type of Fourier domain detection, uses a stationary reference arm, a high-speed spectrometer, and charge coupled device (CCD) camera to detect light echoes simultaneously, thus increasing acquisition speed by 20-100 times.4-7 More than a half-dozen SD-OCT machines are commercially available. Typical acquisition speeds for these devices are between 25,000 and 27,000 A-scans/second, with axial resolution from ~3 to 7 µm, achieved by increasing SLD bandwidth.

The Next Frontier: Hardware

Faster Speed

Advantages of faster speedThe increase in imaging speed offered by high-speed or spectral OCT provides 4 main advantages.

1. Increased number of axial scans per OCT image allows for pixel averaging and dramatic reduction in speckle noise, allowing for higher image quality.

2. Shortened imaging times to fractions of a second reduces motion artifacts, thereby allowing visualization of the true retinal topography.

3. Increased area of retinal coverage without skip area is useful for detection of small retinal changes that may be missed using traditional OCT imaging protocols.

4. Creation of topographic maps with precise registration through 3-D OCT data sets reveal intraretinal layers and small-scale intraretinal abnormalities.

What’s next for faster speed? Swept-source laser (SS-OCT)SS-OCT employs a light source in which a narrowband source is rapidly tuned over a broad optical bandwidth. A-scan informa-tion in SS-OCT is obtained by rapidly measuring, then Fourier-transforming the interference spectrum over time with a tunable, narrow-linewidth laser and photodetectors. No spectrometer / line camera is required, greatly increasing imaging speeds from 16,000 up to 300,000 axial scans per second with balanced detection.8 SS-OCT confers better sensitivity and improved depth range of imaging.

Furthermore, tuning speed of the laser light source can be dramatically improved by Fourier domain mode locking (FDML), which enables a 10-fold increase in imaging speed to rates of 370,000 A-scans/second.9 FDML achieves ultrafast tun-ing speeds by using a long laser cavity consisting of an optical

fiber delay line that stores the entire frequency sweep in the laser cavity, thereby overcoming the dynamic limitations present in standard frequency tuned lasers. Increased speed means more data and the ability to perform such things as Doppler OCT (see Figure 1).

Figure 1. SS-OCT, 3-D rendering.

Increased ResolutionOCT B-scan image resolution can be improved not only through the use of better hardware (ie, broader bandwidth light sources), which mean finer speckle, but also through software modifica-tions that allow for frame averaging. Eye tracking to follow even the slightest eye movements allows a large number of B-scans to be acquired in the same precise location, then averaged together. Resolution of deeper structures of the retina, such as the cho-roid, can also be improved by adjusting the SD-OCT device to maximize its sensitivity at the choroid proximal to the zero-delay line.10

Longer Wavelength Light SourcesCurrently, commercial, standard-resolution OCT instruments use broad-bandwidth superluminescent diode (SLD) with bandwidths centered at a wavelength of 830 nm. It is possible to perform OCT imaging past the maximum water absorption peak, around 1050 nm wavelength.13,14 The scattering behavior of light in biological tissues shows a significant decrease with longer wavelengths. OCT imaging at 1050 nm can deliver deeper tissue penetration to image structures beneath the retinal pig-ment epithelium, as well as delineate the choroidal structure. Furthermore, OCT using a 1050-nm light source can be used to detect depth-resolved physiological correlates of neuronal activ-ity within the retina.11

Functional OCT

Polarization sensitive OCT (PS-OCT)PS-OCT (depth-resolved tissue birefringence) provides better tis-sue-specific contrast between the birefringent retinal nerve fiber layer (RNFL) and other retinal layers, enabling direct identifica-tion of retinal layers based on the intrinsic properties of their interaction with light.16 This technique provides information about the architectural and cellular organization of retinal nerve fibers and may allow for detection of changes in structure before there is a change in RNFL thickness.

To Infinity and Beyond: OCT, the Next FrontierJay S Duker MD, Lauren Branchini BA, Caio Regatieri MD


Intraoperative OCTIntraoperative OCT promises to be a useful clinical tool for vitreoretinal surgery. Currently, it is able to reveal the extent of epiretinal membrane removal and to garner information about foveal contour after membrane peeling. There are both proto-typical and commercially available systems that have been dem-onstrated intraoperatively.17-20

The Next Frontier: Software

Doppler OCTDoppler OCT systems allow measurement of retinal blood flow velocity through retinal vessels by the assessment of light reflec-tivity changes in retinal blood vessels over very short time peri-ods.15 The technique measures either the change in heterodyne frequency during a window in time to calculate the Doppler shift due to moving blood, or the phase change between sequential A-scans in order to provide increased sensitivity to small flows.16 Color Doppler OCT (CD-OCT) measurements of blood flow in the human retina in real time at high data acquisition rates, with the color code of the Doppler images able to distinguish between arteries and veins, have been demonstrated. Doppler OCT may prove to be useful in retinal vascular diseases such as diabetic retinopathy, vascular occlusive diseases, and glaucoma.21 With further development, quantitative Doppler OCT measurements of flow and pulsatility should become more accurate and repro-ducible (see Figure 2).

Figure 2.

C Mode (En-Face) ImagingC mode imaging is a software technique that utilizes dense 3-D OCT data sets that are resampled into a fundus view. This view is able to condense information from the 3-D OCT data set, and enables assessment of microstructure and anatomic relationships that would not otherwise be apparent (see Figure 3). 22

Figure 3. En face imaging.

Conclusions

The next frontiers of OCT technology hold the promise for both continuing research advances and improvements in clinical care. Future improvements in OCT technology will increase the sensitivity and specificity of early disease detection and enable improved monitoring of disease progression and therapy, as well as assisting us to better understand retinal biology and function on a micron level.


References

1. Huang D, Swanson EA, Lin CP, et al. Optical coherence tomogra-phy. Science 1991; 254:1178-1181.

2. Hee MR, Izatt, JA, Swanson EA, et al. Optical coherence tomogra-phy of the human retina. Arch Ophthalmol. 1995; 115:325-332.

3. Fercher AF, Hitzenberger CK, Kamp G, Elzaiat SY. Measurements on intraocular distances by backscattering spectral interferometry. Opt Commun. 1995; 117:43-48.

4. Wojtkowski M, Leitgeb R, Kowalczyk, et al. In vivo human reti-nal imaging by Fourier domain optical coherence tomography. J Biomed Opt. 2002; 7:457-463.

5. Leitgeb RA, Drexler W, Unterhuber A, et al. Ultrahigh resolution Fourier domain optical coherence tomography. Opt Express. 2004; 12:2156-2165.

6. Wojtkowski M, Bajraszewski T, Gorczynska I, et al. Ophthalmic imaging by spectral optical coherence tomography. Am J Ophthal-mol. 2004; 138:412-419.

7. 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; 113:2054 e1-14.

8. Srinivasan V, Adler D, Chen Y, Gorczynska I, Huber R, Duker J, et al. Ultrahigh-speed optical coherence tomography for three-dimen-sional and en face imaging of the retina and optic nerve head. Invest Ophthalmol Vis Sci. 2008; 49: 5103-5110.

9. Huber R, Wojtkowski M, Fujimoto JG. Fourier Domain mode locking (FDML): a new laser operating regime and applications for optical coherence tomography. Opt Express. 2006; 14(8):3225-3237.

10. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol. 2008; 146:496-500.

11. Drexler W. Cellular and functional optical coherence tomography of the human retina: the Cogan lecture. Invest Ophthalmol Vis Sci. 2007; 48: 5339-5351.

12. Hampson KM, Paterson C, Dainty C, Mallen EA. Adaptive optics system for investigation of the effect of the aberration dynamics of the human eye on steady-state accommodation control. J Opt Soc Am A Opt Image Sci Vis. 2006; 23:1082-1088.

13. Povazay B, Bizheva K, Hermann B, et al. Enhanced visualization of choroidal vessels using ultrahigh resolution ophthalmic OCT at 1050 nm. Opt Express. 2003; 11(17):1980-1986.

14. Unterhuber A, Povazay B, Hermann B, Sattmann H, Chavez-Pirson A, Drexler W. In vivo retinal optical coherence tomography at 1040 nm: enhanced penetration into the choroid. Opt Express. 2005; 13(9):3252-3258.

15. Wang Y, Lu A, Gil-Flamer J, Tan O, Izatt JA, Huang D. Measure-ment of total blood flow in the normal human retina using Doppler Fourier-domain optical coherence tomography. Br J Ophthalmol. 2009; 93:634-637.

16. Drexler W, Fujimoto JG. State-of-the-art retinal optical coherence tomography. Prog Retin Eye Res. 2008; 27(1):45-88.

17. Binder S, Falkner-Radler CI, Hauger C, et al. Feasibility of intrasur-gical spectral-domain optical coherence tomography. Retina. Epub ahead of print 26 Jan 2011.

18. 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.

19. Ehlers JP, Tao YK, Farsiu S, et al. Integration of a spectral domain optical coherence tomography system into a surgical microscope for intraoperative imaging. Invest Ophthalmol Vis Sci. 2011; 52(6):3153-3159.

20. Tao YK, Ehlers JP, Toth CA, Izatt JA. Intraoperative spectral domain optical coherence tomography for vitreoretinal surgery. Opt Lett. 2010; 35(20):3315-3317.

21. Wang Y, Bower BA, Izatt JA, Tan O, Huang D. Retinal blood flow measurement by circumpapillary Fourier domain Doppler optical coherence tomography. J Biomed Opt. 2008; 13(6):064003.

22. Srinivasan VJ, Adler DC, Chen Y, et al. Ultrahigh-speed optical coherence tomography for three-dimensional and en face imag-ing of the retina and optic nerve head. Invest Ophthalmol Vis Sci. 2008; 49(11):5103-5110.

2011 Subspecialty Day | Retina Section X: Oncology 101

New Insights in the Molecular Genetics of Uveal MelanomaJ William Harbour MD

Introduction

Uveal melanoma is the most common cancer of the eye and the second most common form of melanoma, with an incidence of 1700-2000 cases per year in the United States. Up to 50% of uveal melanoma patients develop metastasis, which is notori-ously resistant to all forms of therapy and leads to death within 5-7 months on average. By the time the primary eye tumor is diagnosed and treated, micrometastasis has already occurred in many patients. This could explain why the steady improvements in diagnosis and treatment of the primary tumor over the past half-century have not led to improved patient survival.

Nevertheless, there is usually a delay of 2-5 years between diagnosis of the primary eye tumor and detection of metastasis. This gap provides a window of opportunity for instituting adju-vant therapy to delay or prevent the progression of micrometas-tases to overt metastatic disease. The two keys to such a strategy are (1) an accurate biomarker to identify high-risk patients and (2) an adjuvant therapy. Our research has addressed both of these issues. We have developed a highly precise prognostic test based on the expression profile of a 15-gene panel. Further, we discovered mutations in a gene that appear to be responsible for metastasis, thus leading to new insights into targeted therapy.

Gene Expression Profiling vs. Alternative Prognostic Techniques

Many prognostic factors have been identified for uveal mela-noma, including increased patient age, larger tumor diameter and thickness, ciliary body involvement, epithelioid cell type, vasculogenic mimicry patterns, and extraocular tumor extension, but the association between these factors and metastasis is not strong enough to predict accurately in individual patients. Chro-mosomal changes such as monosomy 3 are more accurate but suffer from sampling error due to tumor heterogeneity, as well as technical limitations on small biopsy samples.

To provide an alternative approach, we developed a gene expression profiling (GEP) assay based on the expression of 15 carefully selected genes. Tumors exhibiting the class 1 signature were at low risk, and those with the class 2 signature were at high risk of metastasis. In our hands, this assay was found to be sensitive enough to yield accurate results on extremely small nee-dle biopsy samples, was not as subject to tumor heterogeneity as monosomy 3, and was highly predictive of patient outcome. At least 2 groups have shown independently in head-to-head com-parisons that GEP was more accurate than chromosomal and clinicopathologic factors. We then established a consortium of 10 institutions called the Collaborative Ocular Oncology Group and conducted a prospective study to compare GEP to other prognostic factors in a larger number of patients from multiple centers. In the first 514 patients, GEP outperformed monosomy 3 and all combinations of other prognostic factors.

Discovery of Mutations in BAP1

Recently, we used 2 new powerful technologies to discover the gene that may be responsible for the class 2 signature and metas-tasis in uveal melanoma. Exome capture and next-generation DNA sequencing allowed us to query the entire genome for mutations. This work revealed deleterious mutations in the gene BAP1 (BRCA1-associated protein 1) in almost all class 2 but not class 1 tumors, thus identifying BAP1 as a metastasis suppressor gene, in which mutational inactivation represents the rate-lim-iting step in the metastatic process. Finding the BAP1 mutation has allowed us to focus on the BAP1 pathway as a promising target for therapy. Based on the biological function of the BAP1 protein, we have used computer modeling techniques to identify potential therapeutic agents to offset the adverse effects of BAP1 loss. One such class of therapeutic agents may be histone deacet-ylase (HDAC) inhibitors such as the commonly used epileptic medication valproic acid. Experiments suggest that valproic acid may be effective as an adjuvant agent in uveal melanoma. Clini-cal trials are currently being planned to treat class 2 patients with valproic acid starting at the time of diagnosis of their primary tumor.

Selected Readings

1. Harbour JW, Onken MD, Roberson ED, et al. Frequent muta-tion of BAP1 in metastasizing uveal melanomas. Science 2010; 330:1410-1413.

2. 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 biopsy. Arch Pathol Lab Med. 2007; 131:91-96.

3. Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and pre-dicts metastatic death. Cancer Res. 2004; 64:7205-7209.

4. Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multi-gene expression assay for predicting metas-tasis in uveal melanoma. J Mol Diagn. 2010; 12:461-468.

5. Petrausch U, Martus P, Tonnies H, et al. Significance of gene expression analysis in uveal melanoma in comparison to standard risk factors for risk assessment of subsequent metastases. Eye 2007; 22:997-1007.

6. Tschentscher F, Husing J, Holter T, et al. Tumor classification based on gene expression profiling shows that uveal melanomas with and without monosomy 3 represent two distinct entities. Can-cer Res. 2003; 63:2578-2584.

7. van Gils W, Lodder EM, Mensink HW, et al. Gene expression pro-filing in uveal melanoma: two regions on 3p related to prognosis. Invest Ophthalmol Vis Sci. 2008; 49:4254-4262.

8. Worley LA, Onken MD, Person E, et al. Transcriptomic versus chromosomal prognostic markers and clinical outcome in uveal melanoma. Clin Cancer Res. 2007; 13:1466-1471.

102 Section X: Oncology 2011 Subspecialty Day | Retina

I. Historical Aspects

II. Earlier Literature: Case Report

A. 1983: Early report on 12 cases1

B. 1983-1995: Several additional case reports

C. 1995: Further reports

D. 1995: Report of 103 cases2

1. Primary type

2. Secondary type

3. Many subsequent reports

III. Primary Vasoproliferative Tumors

A. Usually idiopathic

B. No ocular/systemic associations

C. Clinical features

1. Middle aged or older patients

2. Usually inferior equator

3. Yellow red mass

4. Retinal feeder vessels

5. Yellow exudation

6. Exudative detachment

IV. Secondary Vasoproliferative Tumors

A. Clinical features similar to primary type

B. Seen in increasing number of clinical entities

1. Intermediate uveitis

2. Toxocariasis

3. Retinitis pigmentosa

4. Coats disease

5. Neurofibromatosis

6. Chronic retinal detachment

7. Scleral buckle

8. ROP

9. Familial exudative vitreoretinopathy

10. Congenital toxoplasmosis

11. Familial aniridia

12. Congenital retinoschisis

13. Marshall-Stickler syndrome

14. Ocular tuberculosis

V. Pathology

VI. Management

A. Observation

B. Plaque radiotherapy

C. VEGF inhibitors

D. Photodynamic therapy

E. Others

VII. Summary and Conclusions

References

1. Shields JA, Decker WL, Sanborn GE, et al. Presumed acquired reti-nal hemangiomas. Ophthalmology 1983; 90(11):1292-1300.

2. Shields CL , Shields JA, Barrett J, et al. Vasoproliferative tumors of ocular fundus: classification and clinical manifestations in 103 patients. Arch Ophthalmol. 1995; 113(5):615-623.

3. Numerous other subsequent reports.

The Expanding Clinical Spectrum of Retinal Vasoproliferative TumorsJerry A Shields MD, David Reichstein MD, Arman Mashayekhi MD, David Reichstein MD

2011 Subspecialty Day | Retina Section XI: Uveitis 103

Multicenter Uveitis Steroid Treatment (MUST) TrialJohn H Kempen MD

Background

Fluocinolone acetonide implant therapy is a promising, long-lasting local therapy for severe noninfectious intermediate-, pos-terior-, and pan-uveitis. Its effectiveness with respect to standard systemic therapy has not been adequately characterized.

Purpose

To compare the effectiveness of fluocinolone acetonide implant therapy with that of systemic therapy (corticosteroids plus immunosuppressive drugs when indicated) for active or recently active intermediate-, posterior-, and pan-uveitis.

Design

1:1 randomized, parallel treatment design, comparative effective-ness trial at 23 clinical centers in 3 countries (www.clinicaltrials .gov identifier NCT00132691).

Methods

Eligible patients had active or recently active (within 60 days) noninfectious intermediate-, posterior-, or pan-uveitis for which systemic corticosteroid therapy was indicated. Patients were randomized to implant or systemic therapy (expected allocation ratio 1:1). Systemic therapy followed the classical approach of oral corticosteroid therapy supplemented when indicated by cor-

ticosteroid-sparing immunosuppressive drugs following expert panel guidelines. Implant therapy entailed quieting of the ante-rior chamber using topical, periocular, or oral corticosteroids fol-lowed by implant placement within 28 days of randomization in the first eye, and 28 days thereafter for second eyes when appli-cable. Patients were followed quarterly with an additional visit at 1 month following baseline. The study design had 98% power to detect a 7.5 letter (1.5 line) difference between groups in the mean best-corrected ETDRS visual acuity change between base-line and 2 years. Secondary outcomes include control of inflam-mation, ocular and systemic complications of therapy, and both vision-specific and general health-related quality of life measured using standard instruments.

Results

Two hundred fifty-five patients were enrolled (481 eyes with uveitis), randomized to systemic or implant therapy. Patients were followed for at least 2 years under the protocol.

Conclusions

Primary results of the trial will be presented for the first time at a meeting regarding the major study outcomes: visual acuity, con-trol of inflammation, morphologic complications of uveitis, side effects of therapy, and quality of life.

http://www.clinicaltrials.govidentifierNCT00132691

http://www.clinicaltrials.govidentifierNCT00132691

104 Section XI: Uveitis 2011 Subspecialty Day | Retina

I. Introduction

A. Uveitis is a severe inflammatory disease affecting the eye.

B. High risk of vision loss

C. Severe vision loss in some series as high as 33%

D. Often referred to retina physicians for posterior seg-ment complications, for management of posterior inflammation, or for nonresponsive disease

E. Management decisions can affect outcomes both negatively and positively.

F. Can make a bad disease even worse

II. Where We Can Do Better

A. Initiation of immunosuppression

B. Care with local therapy

C. Proper workup/diagnostic testing

D. Surgery

E. Communication among colleagues

1. Early initiation of long-term immunosuppression

a. Nguyen et al (2011)

i. Majority of physicians surveyed do not adhere to recommended guidelines to treat uveitis.

ii. Average dose of prednisone in surveyed patients > 40 mg maintained for duration of 21 months.

iii. Immunosuppressives only prescribed in 12% of cases

b. Repeated bouts of inflammation increase risk of severe vision loss.

c. Strong evidence of cumulative damage lead-ing to irreversible vision loss

d. Recommendations include high-dose cortico-steroids for active uveitis. Add steroid sparing agent if inflammation can not be controlled with low dose prednisone (≤ 10 mg) within 3 months.

e. Good evidence of safety of immunosuppres-sive agents in uveitis patients

f. Evidence of outcomes in uveitis patients

g. Long-acting local delivery devices

2. Local therapy

a. Injections can be useful as supplement.

b. Repeated injections should be sign/indication of need for sustained immunosuppression.

c. Risk of severe rebound when injection runs out or reaches subtherapeutic level

d. Caution in using local injection as primary initial therapy

i. Risk of unmasking undiagnosed infections (examples)

ii. Cannot discontinue injection if untoward reaction occurs

iii. Recommend use of oral steroids prior to initiation of local injections

iv. Caution advised when using local injec-tions in patients with known history of infectious uveitis with cystoid macular edema

3. Workup of uveitis patient

a. No magic formula

b. Cannot rely on specific cookbook

c. Be careful in interpreting both positive and negative results. If patient is not responding despite therapy, reconsider diagnosis (exam-ples).

d. Use systemic review to help guide workup.

e. Use tools available to retina surgeons: vitre-ous biopsy, PCR analysis

4. Surgery

a. Surgery can be beneficial from a diagnosis and therapeutic strategy.

b. There are negative outcomes of surgery unique to uveitis patients (hypotony).

c. Be cautious in operating on patients with active disease.

d. Proper use of steroids/immunosuppression in perioperative period

5. Communication

a. Easy for patients to get lost in the shuffle

b. When managing with other providers, ensure clear communication of how patient’s disease is responding to therapy.

c. If disease is not responding, advocate for change in therapy.

d. Communicate with patient on importance of proper follow-up.

Mistakes Made When Caring for Uveitis Patients Reducing Errors, Improving Outcomes

Sunil K Srivastava MD


Selected Readings

1. Nguyen QD, Hatef E, Kayen B, et al. A cross-sectional study of the current treatment patterns in noninfectious uveitis among specialists in the United States. Ophthalmology 2011; 118(1):184-190.

2. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000; 130:492-513.

3. Thorne JE, Jabs DA, Peters GB, et al. Birdshot retinochoroidopa-thy: ocular complications and visual impairment. Am J Ophthal-mol. 2005; 140:45-51.

4. Thorne JE, Wittenberg SE, Jabs DA, et al. Multifocal choroiditis with panuveitis: incidence of ocular complications and loss of visual acuity. Ophthalmology 2006; 113:2310-2316.

5. Kaçmaz RO, Kempen JH, Newcomb C, et al. Cyclosporine for ocu-lar inflammatory diseases. Ophthalmology 2010; 117(3):576-584.

6. Pujari SS, Kempen JH, Newcomb CW, et al. Cyclophosphamide for ocular inflammatory diseases. Ophthalmology 2010; 117(2):356-365.

7. Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrex-ate for ocular inflammatory diseases. Ophthalmology 2009; 116(11):2188-2198.

8. Kaçmaz RO, Kempen JH, Newcomb C, Gangaputra S, et al. Ocular inflammation in Behçet disease: incidence of ocular complications and of loss of visual acuity. Am J Ophthalmol. 2008; 146(6):828-836.

9. Kempen JH, Gangaputra S, Daniel E, et al. Long-term risk of malig-nancy among patients treated with immunosuppressive agents for ocular inflammation: a critical assessment of the evidence. Am J Ophthalmol. 2008; 146(6):802-812.

10. Erol N, Topbas S. Acute syphilitic posterior placoid chorioretinitis after an intravitreal acetonide injection. Acta Ophthalmol Scand. 2006; 84:435.

11. Song JH, Hong YT, Kwon OW. Acute syphilitic posterior chorio-retinitis following intravitreal triamcinolone acetonide injection. Graefes Arch Clin Exp Ophthalmol. 2008; 246: 1755-1758.

12. Nobrega MJ, Rosa EL. Toxoplasmosis retinochoroiditis after pho-todynamic therapy and intravitreal triamcinolone for a supposed choroidal neovascularization: a case report. Arq Bras Oftalmol. 2007; 70:157-160.

13. O’ Connor GR, Frenkel JK. Editorial: Dangers of steroid treatment in toxoplasmosis—periocular injections and systemic therapy. Arch Ophthalmol. 1976; 94:213.

14. Aggermann T, Stolba U, Brunnner S, Binder S. Endophthalmitis with retinal necrosis following intravitreal triamcinolone acetonide injection. Ophthalmologica 2006; 220:131-133.

15. Ufret-Vincenty RL, Singh RP, Lowder CY, Kaiser PK. Cytomegalo-virus retinitis after fluocinolone acetonide (Retisert) implant. Am J Ophthalmol. 2007; 143:334-335.


I. Paraneoplastic Retinopathy

A. General term describing autoimmune retinopathy associated with a neoplasm

B. Further subdivided into cancer-associated retinopa-thy (CAR) and melanoma-associated retinopathy (MAR)

C. Malignancies associated with CAR

1. Most common solid cancers: lung, breast, gyne-cologic, prostate, colon1

2. Hematological malignancies can also be associ-ated with CAR.

II. Clinical Manifestations

A. Acute to subacute visual symptoms can precede the discovery of malignancy by several months.2

B. High level of suspicion for CAR should be consid-ered in any patient with acute or subacute vision loss, vascular attenuation, and visual field altera-tions in the absence of another etiology.

C. Symptoms

1. Decreased vision, particularly under scotopic conditions

2. Glare

3. Photosensitivity

4. Impaired color perception

D. Signs

1. Attenuation of arterial vasculature

2. Variable degrees of optic disc pallor

3. Variable degrees of chorioretinal or retinal pig-ment epithelial atrophy

4. Subtle vitritis in some cases

E. Ancillary testing

1. Visual field testing

a. Ring or arcuate scotomas

b. Constriction: Can be generalized or localized to within the central 20 degrees

2. Fluorescein angiography3-4

a. May demonstrate perivascular leakage or staining at the optic nerve head

b. A normal angiogram is observed in a signifi-cant number of patients.

3. OCT5

a. Thinning of the photoreceptor cell layer

b. Loss of the inner reflective layer

III. Diagnosis

A. Electroretinography (ERG) and antibody testing are critical steps in the evaluation of a patient suspected to have a paraneoplastic retinopathy based on clini-cal examination.

B. ERG

1. Classically, ERG demonstrates severely dimin-ished or extinguished a and b waves.6-7

2. Electronegative ERG, more typical of MAR, has also been described in CAR.8-9

C. Autoantibody testing

1. The testing is not standardized.10-11

2. Over 18 antigens have been implicated in CAR.

a. Recoverin (23 kDa) and α-enolase (46 kDa) are the most commonly detected antigens.

b. Other potentially pathogenic antigens include transducin (40 kDa), carbonic anhydrase II (30 kDa), and interphotoreceptor retinoid binding protein (145 kDa).

D. Survey for underlying malignancy

1. Because CAR can precede the oncologic diagno-sis by several months, it is imperative to initiate a systemic survey for malignancy in conjunction with the patient’s primary care provider.

2. Testing may be repeated at regular intervals if no cancer is found.

IV. Treatment

A. Untreated, CAR can progress to severe vision loss, often to no light perception.

1. Early initiation of therapy is critical for vision preservation.

2. Despite aggressive immunomodulatory therapy, some patients still progress to significant vision loss.

B. The treatment must target the ocular disease, as the removal of cancer alone does not affect the course of CAR.

C. No standardized approach to treatment of paraneo-plastic retinopathy exists.12

1. Steroids are often tried initially with broadly variable outcomes.

a. Prednisone can control intraocular disease in the short term in some cases.13

Cancer-Associated RetinopathyUpdate on Diagnosis and Treatment

Lucia Sobrin MD


b. The benefit of local steroid administration in CAR is difficult to assess, as there are limited reports in the literature.

2. Multiple steroid-sparing immunomodulatory agents have been reported in the treatment of CAR, with no single approach showing consis-tent, long-term efficacy in this disease. Often, multiple agents are used concurrently or sequen-tially in an attempt to halt visual decline.

a. In 1 report of 6 patients with CAR, immu-nomodulatory therapy was associated with stabilization or improvement in visual fields, visual acuity, or ERG in all patients.14

i. Other than systemic prednisone, which was used in all 6, no 2 patients received the same combination therapy.

ii. Systemic treatments included azathioprine in 3, cyclosporine in 3, and mycopheno-late mofetil and methylprednisolone in 1 patient each.

b. Intravenous immunoglobulin was reported to improve or stabilize disease in 3 patients with CAR.15

c. Plasmapheresis, when used with prednisone, showed some benefit in one report.16

d. Recent reports show stabilization and improvement in vision using newer monoclo-nal pan-lymphocytic (CD52, alemtuzumab)17 and B-cell (CD20, rituximab)18 antibodies in patients failing other therapies.

References

1. Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev. 2009; 8:410-414.

2. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol. 1990; 28:162-167.

3. Suzuki T, Obara Y, Sato Y, Saito G, Ichiwata T, Uchiyama T. Cancer-associated retinopathy with presumed vasculitis. Am J Oph-thalmol. 1996; 122:125-127.

4. Masaoka N, Emoto Y, Sasaoka A, Fukushima A, Ueno H, Ohguro H. Fluorescein angiographic findings in a case of cancer-associated retinopathy. Retina 1999; 19:462-464.

5. Mohamed Q, Harper CA. Acute optical coherence tomographic findings in cancer-associated retinopathy. Arch Ophthalmol. 2007; 125:1132-1133.

6. Matsui Y, Mehta MC, Katsumi O, Brodie SE, Hirose T. Electro-physiological findings in paraneoplastic retinopathy. Graefes Arch Clin Exp Ophthalmol. 1992; 230:324-328.

7. Ohguro H, Yokoi Y, Ohguro I, et al. Clinical and immunologic aspects of cancer-associated retinopathy. Am J Ophthalmol. 2004; 137:1117-1119.

8. Goetgebuer G, Kestelyn-Stevens AM, De Laey JJ, Kestelyn P, Leroy BP. Cancer-associated retinopathy (CAR) with electronegative ERG: a case report. Doc Ophthalmol. 2008; 116:49-55.

9. Kim SJ, Toma HS, Thirkill CE, Dunn JP Jr. Cancer-associated reti-nopathy with retinal periphlebitis in a patient with ovarian cancer. Ocul Immunol Inflamm. 2010; 18:107-109.

10. Forooghian F, Macdonald IM, Heckenlively JR, et al. The need for standardization of antiretinal antibody detection and measurement. Am J Ophthalmol. 2008; 146:489-495.

11. Bazhin AV. The need for standardization of antiretinal antibody detection and measurement. Am J Ophthalmol. 2009; 147:374; author reply: 375.

12. Shildkrot Y, Sobrin L, Gragoudas ES. Cancer-associated retinopa-thy: update on pathogenesis and therapy. Semin Ophthamol. In press.

13. Keltner JL, Thirkill CE, Tyler NK, Roth AM. Management and monitoring of cancer-associated retinopathy. Arch Ophthalmol. 1992; 110:48-53.

14. Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. Management of autoimmune retinopathies with immunosup-pression. Arch Ophthalmol. 2009; 127:390-397.

15. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol. 1999; 117:471-477.

16. Murphy MA, Thirkill CE, Hart WM Jr. Paraneoplastic retinopathy: a novel autoantibody reaction associated with small-cell lung carci-noma. J Neuroophthalmol. 1997; 17:77-83.

17. Espandar L, O’Brien S, Thirkill C, Lubecki LA, Esmaeli B. Success-ful treatment of cancer-associated retinopathy with alemtuzumab. J Neurooncol. 2007; 83:295-302.

18. Mahdi N, Faia LJ, Goodwin J, Nussenblatt RB, Nida Sen H. A case of autoimmune retinopathy associated with thyroid carcinoma. Ocul Immunol Inflamm. 2010; 18:322-323.


I. Drug-Induced Bilateral Iridocyclitis

A. Etiology

1. Moxifloxacin13,14

2. Other oral antibiotics

3. Association with upper respiratory infections

B. Characteristics

1. Pigment dispersion

2. Irregular pupil

3. Tonic pupil in some cases

4. Transillumination defects

C. Course

1. Self-remitting

2. Symptoms of photophobia may be permanent

D. Treatment

1. Topical corticosteroids initially

2. Supportive care

II. Virally Mediated Uveitis

A. Rubella-associated Fuchs uveitis syndrome

1. Intraocular antirubella antibodies9

2. Intraocular rubella RNA by polymerase chain reaction (PCR) amplification2,5,6,10

3. Decreasing incidence after vaccination programs established1

B. Cytomegalovirus

1. 14 cases reported by 2007: Markomichelakis 2002, de Schryver 2006, van Boxtel 2007

2. Corroborated by Rothova12

3. Largest series: Chee 2008 – PCR diagnosis

a. 22.8% of 104 hypertensive iritis

b. 24 cases

i. 18 clinically Posner-Schlossman (30 other cases were negative for cytomegalovirus [CMV])

ii. 5 clinically Fuchs (11 others negative for CMV)

iii. 1 clinically herpes iridocyclitis (13 positive for HSV)

c. 50% of patients treated

d. Response to ganciclovir with relapse off meds in 75%

C. Epstein-Barr virus (EBV) in uveitis

1. 55 patients with uveitis tested for EBV (Yama-moto/Mochizuki, Jpn J Ophthalmol. 2008; 52:463)

2. Qualitative multiplex PCR: 17/60 positive

3. Quantitative real-time PCR: 3/17 positive

4. Antibodies to EBV by complement fixation

5. Caution with overinterpretation of raw PCR data; need quantification and confirmation

D. Candidate organisms detected by PCR

1. Rothova, Netherlands, Am J Ophthalmol. 2010

2. 139 aqueous specimens negative for HSV, VZV, CMV, and toxoplasmosis

3. PCR for 18 viruses and 3 bacteria

4. Positives

a. 1 each for EBV, rubella, and HHV-6

b. 4 positive for parechovirus

i. Similar to enterovirus

ii. Severe sepsis, hepatitis, meningitis in neo-nates

III. Identification of Oligonucleotides in Biological Specimens7

A. Not limited to preselected primers

B. Exploits existence of large gene banks

C. Allows identification of the completely unsuspected

D. Research technique, not currently available

IV. Use of PCR for routine diagnosis of anterior uveitis is uncertain.

A. CMV sheds periodically.

B. Even if suspected, CMV iritis is hard to diagnose conclusively.

References

1. Birnbaum AD, Tessler HH, Schultz KL, et al. Epidemiologic rela-tionship between fuchs heterochromic iridocyclitis and the United States rubella vaccination program. Am J Ophthalmol. 2007; 144(3):424-428.

2. de Groot-Mijnes JD, de Visser L, Rothova A, Schuller M, van Loon AM, Weersink AJ. Rubella virus is associated with fuchs hetero-chromic iridocyclitis. Am J Ophthalmol. 2006; 141(1):212-214.

3. de Groot-Mijnes JD, de Visser L, Zuurveen S, et al. Identification of new pathogens in the intraocular fluid of patients with uveitis. Am J Ophthalmol. 2010; 150(5):628-636.

Newly Identified Causes of Uveitis (Drug Induced, Viral)Janet Davis MD


4. de Schryver I, Rozenberg F, Cassoux N, et al. Diagnosis and treat-ment of cytomegalovirus iridocyclitis without retinal necrosis. Br J Ophthalmol. 2006; 90(7):852-855.

5. de Visser L, Braakenburg A, Rothova A, de Boer JH. Rubella virus-associated uveitis: clinical manifestations and visual prognosis. Am J Ophthalmol. 2008; 146(2):292-297.

6. Markomichelakis NN, Canakis C, Zafirakis P, Marakis T, Mallias I, Theodossiadis G. Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy. Ophthalmology 2002; 109(5):879-882.

7. Muthappan V, Lee AY, Lamprecht TL, et al. Biome representa-tional in silicokaryotyping. Genome Res. 2011; 21(4):626-633.

8. Quentin CD, Reiber H. Fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor. Am J Ophthalmol. 2004; 138(1):46-54.

9. Ruokonen PC, Metzner S, Ucer A, Torun N, Hofmann J, Pleyer U. Intraocular antibody synthesis against rubella virus and other microorganisms in Fuchs’ heterochromic cyclitis. Graefes Arch Clin Exp Ophthalmol. 2010; 248(4):565-571.

10. Suzuki J, Goto H, Komase K, et al. Rubella virus as a possible etiological agent of Fuchs heterochromic iridocyclitis. Graefes Arch Clin Exp Ophthalmol. 2010; 248(10):1487-1491.

11. van Boxtel LA, van der Lelij A, van der Meer J, Los LI. Cytomega-lovirus as a cause of anterior uveitis in immunocompetent patients. Ophthalmology 2007; 114(7):1358-1362.

12. Van der Lelij A, Ooijman FM, Kijlstra A, Rothova A. Anterior uve-itis with sectoral iris atrophy in the absence of keratitis: a distinct clinical entity among herpetic eye diseases. Ophthalmology 2000; 107(6):1164-1170.

13. Wefers Bettink-Remeijer M, Brouwers K, van Langenhove L, et al. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye 2009; 23(12):2260-2262.

14. Willermain F, Deflorenne C, Bouffioux C, Janssens X, Koch P, Caspers L. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye 2010; 24(8):1419.


I. Introduction

Time is of essence when managing posterior segment inflammatory disease with presumed infection. Poly-merase chain reaction (PCR) analyses of aqueous and vitreous specimens have been shown to be helpful in the diagnosis of acute and delayed postop endophthalmitis, toxoplasmic chorioretinitis, viral retinitis, syphilitic retinitis, Mycobacterium tuberculosis, etc. Although diagnostic PCR tests are becoming more commercially available, and quick analytic time of “24 hours upon receipt” is advertised, a 2-3 day delay is not uncommon because the specimen is shipped and particular tests are run only on certain days of the week. Thus even with the availability of much improved diagnostic tests, we are often forced to initiate an empiric therapy based on our clinical findings alone. Further, most of us do not manage patients with infectious retinitis routinely, so it is important to know and review from time to time some of the salient features associated with each type of infection. A good history followed by a very thorough and detailed anterior and posterior segment examina-tion is paramount.

II. Establish Duration/Tempo

A. Rapid worsening within days: acute retinal necrosis (ARN) and bacterial endophthalmitis

B. Vague duration of weeks to months: syphilitic reti-nitis, TB

C. Days to weeks: toxoplasmic retinitis, endogenous fungal endophthalmitis

III. Establish Overall Health Status

A. History of chronic debilitated conditions

B. History of recent invasive procedures

C. History of chronic steroid/immunosuppressant drug use

D. Risk factors for HIV

E. IV drug use

IV. Presence and Degree of Inflammation

A. Minimal/no cells: cytomegalovirus (CMV), progres-sive outer retinal necrosis (PORN)

B. Mild cells with long duration: syphilis, TB

C. Moderate vitritis

1. Rapid development within days: ARN, bacterial endophthalmitis

2. Gradual development within weeks: Toxoplas-mic retinitis, fungal endophthalmitis

V. Appearance of Vitritis

A. Purulent with loose WBCs: Toxoplasmic retitinitis, bacterial endophthalmitis, ARN

B. String-like: fungal endophthalmitis

C. “Headlight in the fog”: source of vitritis from a soli-tary lesion suggestive of toxoplasmic retinitis

VI. Number of Retinal Lesions

A. Solitary in 1 quadrant: toxoplasmic retinitis, CMV

B. Multiple satellite lesions involving 360 deg + rapid progression: ARN, PORN

VII. Retinal Layer Involvement

A. Full thickness retina: CMV, ARN, Toxoplasma, syphilis

B. Outer retina: PORN

C. Deep to the retina/ choroidal: endogenous endo-phthalmitis

VIII. Examine contralateral eye to look for old toxoplasmic chorioretinal scars.

IX. Establish if vision is consistent with visible retinal involvement.

A. PORN may be associated advanced macular isch-emia and optic neuropathy.

B. Syphilitis retinitis may present with only subtle reti-nal infiltrates but poor vision from low grade papil-litis and CME.

C. ARN may be associated with disc edema and optic neuropathy.

X. Posterior Uveitis With Vitritis: Differential Diagnosis

A. Toxoplasmic retinitis

B. Acute retinal necrosis: herpes simplex virus /vari-cella zoster virus

C. Endophthalmitis: exogenous/endogenous

D. Tuberculosis

E. Syphilis

F. Sarcoidosis

G. Autoimmune diseases: lupus, Behçet’s disease

H. Intraocular lymphoma

I. Toxocariasis

A Bug’s Life: Update on Infectious RetinitisLucy H Young MD PhD FACS


XI. Summary

In summary, the initial diagnosis of advanced cases of posterior uveitis is based mainly on clinical grounds, taking into consideration the duration and progression rate of the condition, the appearance of the vitreous inflammation, and the extent of involvement. The value of a thorough history can not be overstated. PCR anal-ysis of aqueous and vitreous specimens in the diagnosis of posterior segment infections can certainly be helpful, but we have to be prepared to act before the laboratory results are available.

A list of PCR labs will be provided.

Selected Readings

1. Van Gelder RN. Review: Polymerase chain reaction diagnostics for posterior segment disease. Retina 2003; 23:445-452.

2. Aizman A, Johnson MW, Elner SG. Treatment of acute retinal necrosis syndrome with oral antiviral medications. Ophthalmology 2007; 114:307-312.

3. Kiss S, Young LH. Diagnosis and treatment of acute retinal necro-sis. Available at: www.ophthalmologyrounds.org, 2009.

4. Flynn HW. The clinical challenge of endogenous endophthalmitis. Retina 2001; 21:572-574.

5. Young LH, Bazari H, Durand ML, Branda JA. Case records of the Massachusetts General Hospital (Case33-2010): a woman with blurred vision and renal failure. N Engl J Med. 2010; 363:1749-1758.

6. Kernt M and Kampik A. Endophthalmitis: pathogenesis, clinical presentation, management and perspectives. Clin Ophthalmol. 2010; 4:121-135.

7. Holland GN. Ocular toxoplasmosis: a global reassessment. Part I: epidemiology and course of disease. Am J Ophthalmol. 2003; 136:973-988.

8. Matos K, Muccioli C, Belfort R Jr, et al. Correlation between clini-cal diagnosis and PCR analysis of serum, aqueous, and vitreous samples in patients with inflammatory eye disease. Arq Bras Oftal-mol. 2007; 70:109-114e. Am J Ophthalmol. 2003; 136:973-988.

9. Lasave AF, Diaz-Llopis M, Muccioli C, et al. Intravitreal clindamy-cin and dexamethasone for Zone 1 toxoplasmic retinochoroiditis at twenty-four months. Ophthalmology 2010; 117:1831-1838.

10. Soheilian M, Ramezani A, Azimzadeh A, et al. Randomized trial of intravitreal clindamycin and dexamethasone versus pyrimethamine, sulfadiazine, and prednisolone in treatment of ocular toxoplasmo-sis. Ophthalmology 2010; 118:134-141.

11. Moshfeghi DM, Dodds EM, Couto CA, et al. Diagnostic approaches to severe, atypical toxoplasmosis mimicking acute reti-nal necrosis. Ophthalmology 2004; 111:716-725.

12. Kuruvilla A. Ocular tuberculosis. Lancet 2003; 361:260-261.

13. Kiss S, Damico FM, Young LH. Ocular manifestations and treat-ment of syphilis. Semin Ophthalmol. 2005; 20:161-167.

14. Rajan MS, Pantelidis P, Tong CYW, et al. Diagnosis of Treponema pallidum in vitreous samples using real time polymerase chain reac-tion. Br J Ophthalmol. 2006; 90:647-648.

http://www.ophthalmologyrounds.org

112 Section XII: Late Breaking Developments 2011 Subspecialty Day | Retina

Late Breaking Developments

N O T E S

2011 Subspecialty Day | Retina Section XIII: Diabetes 113

Pathophysiology of Diabetic RetinopathyLloyd P Aiello MD PhD

N O T E S

114 Section XIII: Diabetes 2011 Subspecialty Day | Retina

Adapted from: Diabetic Retinopathy Clinical Research Network. Rationale for the Diabetic Retinopathy Clinical Research Net-work Intravitreal Anti-VEGF Treatment and Follow-up Proto-col for Center-Involved Diabetic Macular Edema. Submitted to Ophthalmology.

A comparative effectiveness randomized clinical trial by the Diabetic Retinopathy Clinical Research Network (DRCR.net) found that intravitreal ranibizumab with prompt or deferred (≥ 24 weeks) focal/grid laser provided superior visual acuity outcomes compared with prompt laser alone, through at least 2 years in eyes with vision loss from center-involved diabetic macular edema (DME). Following the detailed study treatment protocol in this study required feedback and guidance for intra-vitreal injections, focal/grid laser, and follow-up intervals using a DRCR.net web-based real-time data entry system. Guidance from this system indicated whether treatment was required or could be given at investigator discretion and when follow-up should be scheduled.

Duplication of the detailed protocol is unlikely to be practi-cal in clinical practice. However, published benefits and risks of treatment are related to the study treatment protocol, and for those who would like to emulate the treatment protocol used in the clinical trial, this report provides guidelines based on the underlying clinical rationale behind the DRCR.net pro-tocol. Clinical treatment guidelines include repeating treatment monthly as long as there is improvement in edema compared with the previous month, or until the retina is no longer thick-ened. If thickening recurs or worsens after discontinuing treat-ment, then treatment is resumed. Inherent differences between a computer-driven algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. However, the closer the algorithm is to the one used in the study, the more likely the outcomes will be similar to those published.

Clinical Application of DRCR.net Anti-VEGF Treatment and Follow-up of Diabetic Macular EdemaNeil M Bressler MD


For a complete listing of participating members of PACORES see Appendix 1 of reading #4 below (available at http:// aaojournal.org).

Supported in part by the Arevalo-Coutinho Foundation for Research in Ophthalmology, Caracas, Venezuela.

Introduction

The purpose of this retrospective study is to evaluate the ana-tomical and functional outcomes in patients with diffuse diabetic macular edema (DDME) treated with primary intravitreal beva-cizumab (IVB), 1.25 mg or 2.5 mg, plus grid laser photocoagula-tion (GLP) or primary IVB alone or GLP alone at 24 months of follow-up.

Patients and Methods

This is a retrospective, comparative, and multicentric interven-tional study performed at 5 centers from Venezuela, Costa Rica, Argentina, Spain, and Puerto Rico between May 2006 and May 2009. All patients with DDME treated with primary intravitreal bevacizumab (1.25 mg or 2.5 mg) plus GLP or primary IVB alone or GLP alone were included in this study.

We reviewed the clinical records of 318 consecutive patients (418 eyes) with DDME treated with primary IVB alone (1.25 mg or 2.5 mg), GLP, or combined IVB plus GLP. Each pattern of treatment was separated into different groups. One hundred forty-one (141) eyes of 120 patients with DDME were treated with at least 1 intravitreal injection of 1.25 mg or 2.5 mg of bev-acizumab alone (Group A). The dose of 1.25 mg or a dose of 2.5 mg to be used to treat a patient was determined at the discretion of the treating physician. If a patient received one of the doses at baseline, the same dose was delivered throughout the study. One hundred twenty (120) eyes of 94 patients were treated with GLP therapy (Group B), and 157 eyes of 104 patients were treated with IVB plus GLP (Group C).

An increase or decrease in BCVA was considered to have occurred if there was a change of 2 or more ETDRS lines. Main outcome measures included changes in BCVA and central macu-lar thickness (CMT) measured by OCT.

Patients received re-treatment whenever there was a recur-rence of DDME. Recurrence was defined as a decrease of BCVA associated with an increase of intraretinal fluid due to macular edema on OCT (≥ 50 µm in central macular thickness) and/or fluorescein angiography (FA), after complete or partial resolu-tion in previous follow-up visits.

Results

We reviewed the clinical records of 318 consecutive patients (418 eyes) with DDME. All patients had 24 months of follow-up. One hundred forty-one (141) eyes of 120 patients with DDME were treated with primary IVB alone (Group A), 120 eyes of 94 patients with GLP therapy (Group B), and 157 eyes of 104 patients were treated with IVB plus GLP (Group C). Baseline characteristics of patients in each treatment group are presented in Table 1.

All cases with PDR had had prior scatter panretinal photo-coagulation (PRP) at least 6 months before undergoing IVB or GLP. All eyes had DDME diagnosed by biomicroscopic slitlamp examination, FA, and OCT (Stratus OCT, Carl Zeiss, Dublin, CA) at baseline.

The total number of injections was 5.8 ± 3.2 in Group A and 6.2 ± 4.9 in Group C. The number of macular GLP sessions was 2.2 ± 1.4, and the interval between the first and second laser application was 5.2 ± 3.1 months in Group B. In Group C the time of laser application was prompt (within 1 week) in 75 eyes (47.8%), intermediate (1 week ≤ 24 weeks) in 55 eyes (35%), and deferred (> 24 weeks) in 27 eyes (17.2%).

In all 3 groups we observed improvement of BCVA from baseline to 24 months follow-up. In Group A the mean BCVA improved from baseline logarithm of the minimum angle of reso-lution (logMAR) 0.87 ± 0.4 to logMAR = 0.72 ± 0.5 (P < .0001) at 1 month of follow-up. At 3 and 6 months the mean BCVAs were logMAR = 0.70 ± 0.5 (P < .0001). At 12 and 24 months of follow-up, the mean BCVAs were logMAR = 0.65 ± 0.5 (P < .0001). In Group B, the mean BCVA slightly improved from baseline logMAR 0.77 ± 0.34 to logMAR = 0.75 ± 0.32 (P = .1257) and 0.73 ± 0.32 (P = .1162) at 1 and 3 months of follow-up, respectively. At 6, 12, and 24 months of follow-up, the mean BCVAs were logMAR = 0.72 ± 0.4 (P = .0258), logMAR = 0.71 ± 0.4 (range: 0.1 to 3; P = .0107), and logMAR = 0.65 ± 0.4 (P = .0020), respectively. In Group C, the mean BCVA improved from baseline logMAR 0.76 ± 0.44 to 0.70 ± 0.43 (P < .0001) at 1 month of follow-up. BCVA improved significantly (< 0.05) from baseline, and these changes were maintained throughout the 24 months of follow-up. At 3, 6, 12, and 24 months of follow-up the mean BCVAs were logMAR = 0.69 ± 0.39 (P = .0150), logMAR 0.67 ± 0.4 (P = .0002), logMAR 0.65 ± 0.44 (P = .0001), and logMAR 0.60 ± 0.43 (P < .0001), respectively.

Primary Bevacizumab Plus Grid Laser vs. Primary Bevacizumab vs. Grid Laser for Diabetic EdemaThe Results of the Pan-American Collaborative Retina Study Group at 24 Months

J Fernando Arevalo MD FACS, Andres F Lasave MD, Lihteh Wu MD, Manuel Diaz-Llopis MD, Roberto Gallego-Pinazo MD, Arturo A Alezzandrini MD, and Maria H Berrocal MD for the Pan-American Collaborative Retina Study Group (PACORES)

http://aaojournal.org

http://aaojournal.org


Figure 1. Changes in BCVA after intravitreal bevacizumab (IVB) alone (Group A), grid laser photocoagulation (GLP) (Group B), and IVB plus GLP (Group C) in patients with DDME at 24 months of follow-up.

In Group A (IVB therapy), at 1 month after intravitreal injection of bevacizumab, BCVA improved significantly, and these changes were maintained throughout the 24 months of follow-up. In this group, the mean BCVA improved from base-line 20/160, logMAR 0.87 ± 0.4 (range: 0.1 to 1.8) to 20/100, logMAR = 0.72 ± 0.5 (range: 0.1 to 1.8) (P < .0001) at 1 month of follow-up. At 3 and 6 months, the mean BCVAs were 20/100, logMAR = 0.70 ± 0.5 (range: 0.1 to 1.8; P < .0001). At 12 and 24 months of follow-up, the mean BCVAs were 20/100, log-

MAR = 0.65 ± 0.5 (range: 0.1 to 1.8) at both time points (P < .0001). Twenty-four-month BCVA analysis by subgroups dem-onstrated that 62 eyes (44.6%) remained stable, 74 eyes (52.5%) improved 2 or more ETDRS lines of BCVA, and 5 eyes (3.6%) decreased 2 or more ETDRS lines of BCVA.

In Group B (GLP therapy) there was no statistically signifi-cant difference from baseline BCVA until the first 6 months of treatment. In this group, the mean BCVA slightly improved from baseline 20/125, logMAR 0.77 ± 0.34 (range: 0.3 to 1.4) to 20/100, logMAR = 0.75 ± 0.32 (range: 0.2 to 1.5; P = .1257) and 0.73 ± 0.32 (range: 0.2 to 1.8; P = .1162) at 1 and 3 months of follow-up. However, we found that 6 months after GLP, BCVA improved significantly (< 0.05) from baseline, and these changes were maintained throughout the 24 months of follow-up. At 6, 12, and 24 months of follow-up, the mean BCVAs were 20/100, logMAR = 0.72 ± 0.4 (P = .0258), logMAR = 0.71 ± 0.4 (range: 0.1 to 3; P = .0107), and logMAR = 0.65 ± 0.4 (range: 0.2 to 4; P = .0020), respectively. Twenty-four-month BCVA analysis by subgroups demonstrated that 59 eyes (49.2%) remained stable, 36 eyes (30.0%) improved 2 or more ETDRS lines of BCVA, and 25 eyes (20.8%) decreased 2 or more ETDRS lines of BCVA.

In Group C (IVB plus GLP), the mean BCVA improved from baseline 20/125, logMAR 0.76 ± 0.44 (range: 0.1 to 1.8) to 20/100, logMAR = 0.70 ± 0.43 (range: 0.1 to 1.8; P < .0001) at 1 month of follow-up. At 3, 6, 12, and 24 months of follow-up, the mean BCVAs were 20/100 logMAR = 0.69 ± 0.39 (P = .0150), 20/80 logMAR 0.67 ± 0.4 (P = .0002), 20/80 logMAR

Table 1. Baseline Characteristics of Patients With DDME Included in Each Treatment Group*

Group A (IVB Therapy)

Group B (GLP Therapy)

Group C (IVB Plus GLP)

Number of patients 120 94 104

Number of eyes 141 120 157

Sex

Male 63 (52.5%) 46 (48.9%) 43 (41.3%)

Female 57 (47.5%) 48 (51.1%) 61 (58.7%)

Age (years): Mean, SD 59.4 ± 10.8 64.3 ± 9.0 62.2 ± 8.7

Systemic glycemic control: n (%)

Insulin 71 (50.4%) 49 (40.8%) 79 (50.3%)

Oral hypoglycemic 59 (41.8%) 65 (54.2%) 42 (28%)

Combined therapy 0% 0% 34 (21.7%)

None 11 (7.8%) 6 (5%) 0 (0%)

HbA1c 8.9 ± 1.6% 9.7 ± 1.7% 9.1±1.6%

Grade of DR: n (%)

Mild NPDR 17 (12.1%) 10 (10.6%) 10 (6.4%)

Moderate NPDR 27 (19.1%) 27 (28.7%) 49 (31.2%)

Severe NPDR 38 (27%) 27 (28.7%) 44 (28%)

PDR 59 (41.8%) 30 (31.9%) 54 (34.4%)

*Values represent numbers and percentages; n = number of patients; DDME = diffuse diabetic macular edema; IVB = intravitreal bevacizumab; GLP = grid laser photocoagu-lation; DR = diabetic retinopathy; NPDR = no proliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; HbA1c = glycosylated hemoglobin.


0.65 ± 0.44 (P = .0001), and 20/80 logMAR 0.60 ± 0.43 (P < .0001), respectively. Twenty-four-month BCVA analysis by sub-groups demonstrated that 78 eyes (49.7%) remained stable, 58 eyes (36.9%) improved 2 or more ETDRS lines of BCVA, and 21 eyes (13.4%) decreased 2 or more ETDRS lines of BCVA. BCVA analysis by subgroups of all eyes included in this study is showed in Table 2.

In Groups A and C, there were statistically significant differ-ences from baseline BCVA at all time points of follow-up (P < .0001). However, the improvement rate was similar among the three groups (ANOVA; P = .41).

OCT results were available for all 418 eyes at 1-, 3-, 6-, 12-, and 24-month follow-ups. We also found a decrease in CMT in all groups from baseline to the 24-month follow-up (see Figure 2). In Group A, there was a decrease from 446.2 ± 155.8 µm to 330.2 ± 115.6 µm (P < . 0001) at the first month after intravit-real therapy of bevacizumab. At 3 and 6 months, the mean CMT measurements were 341.5 ± 114.9 µm (P < .0001) and 356.1 ± 103.9 µm (P < .0001), respectively. At 12 and 24 months, the mean CMTs were 302.8 ± 89.6 µm (P < .0001), and 273.8 ± 79.5 µm (P < .0001), respectively. In Group B, there was a decrease from 379.1 ± 91 µm to 368.9 ± 84.4 µm (P = .1370) at the first month after grid laser therapy. At 3 and 6 months, the mean CMT measurements were 351.7 ± 86.2 µm (P = .0010) and 333.7 ± 103.9 µm (P < .0001), respectively. At 12 and 24 months of follow-up, the mean CMTs were 303.5 ± 89.6 µm (P < .0001), and 271.2 ± 78.6 µm (P < .0001), respectively. In Group C, there was a decrease from 415.5 ± 144.8 µm to 377 ± 118.6 µm (P < .0001) at the first month after combined therapy. At 3 and 6 months, the mean CMT measurements were 314.9 ± 135.9 µm (P < .0001) and 364.4 ± 140.1 µm (P < .0001), respec-tively. At 12 and 24 months of follow-up, the mean CMTs were 345.1 ± 118.5 µm (P < .0001) and 333 ± 138.5 µm (P < .0001), respectively.

In Group A (IVB therapy), there was a decrease from 446.2 ± 155.8 µm (range: 222 to 1082 µm) to 330.2 ± 115.6 µm (range: 198 to 841 µm) (P < 0. 0001) at the first month after IVB. At 3 and 6 months, the mean CMT measurements were 341.5 ± 114.9 µm (range: 174 to 715 µm; P < .0001) and 356.1 ± 103.9 µm (range: 175 to 705 µm; P < .0001), respectively. At 12 and 24 months of follow-up, the mean CMTs were 302.8 ± 89.6 µm (range: 150 to 524 µm; P < .0001) and 273.8 ± 79.5 µm (range: 135 to 583 µm; P < .0001), respectively.

Figure 2. Changes in macular thickness with OCT after IVB alone (Group A), GLP (Group B), and IVB plus GLP (Group C) in patients with DDME at 24 months of follow-up.

In Group B (GLP therapy), there was a decrease from 379.1 ± 91 µm (range: 220 to 763 µm) to 368.9 ± 84.4 µm (range: 230 to 689 µm; P = .1370) at the first month after grid laser therapy. At 3 and 6 months, the mean CMT measurements were 351.7 ± 86.2 µm (range: 216 to 640 µm; P = .0010) and 333.7 ± 103.9 µm (range: 202 to 581 µm; P < .0001), respectively. At 12 and 24 months of follow-up, the mean CMTs were 303.5 ± 89.6 µm (range: 169 to 531 µm; P < .0001), and 271.2 ± 78.6 µm (range: 156 to 579 µm; P < .0001), respectively.

In Group C (IVB plus GLP), there was a decrease from 415.5 ± 144.8 µm (range: 222 to 1076 µm) to 377 ± 118.6 µm (range: 155 to 900 µm; P < .0001) at the first month after combined therapy. At 3 and 6 months, the mean CMT measurements were 314.9 ± 135.9 µm (range: 150 to 1055 µm; P < .0001) and 364.4 ± 140.1 µm (range: 144 to 1465 µm; P < .0001), respectively. At 12 and 24 months of follow-up, the mean CMTs were 345.1 ± 118.5 µm (range: 142 to 1033 µm; P < .0001) and 333 ± 138.5 µm (range: 132 to 608 µm; P < .0001), respectively. The com-parison among the 3 groups showed higher CMT decreases in Group A than in Groups B and C (ANOVA; P < .001).

In Groups A and C, there were no complications related to the intravitreal injection during the 24 months of follow-up. No ocular or systemic adverse events were observed.

Discussion

Our results indicate that primary IVB at doses of 1.25 mg or 2.5 mg with or without GLP seems to provide fast stability and improvement in BCVA at 24 months. Groups A and C had a statistically significant difference from baseline BCVA at all time points of follow-up (P < .0001). On the other hand, in Group

Table 2. Variation of BCVA at 24 Months After IVB, GLP, and IVB Plus GLP Therapy for the Treatment of DDME*

BCVA (logMAR) Results: n (%)

Group A (IVB Therapy)

Group B (GLP Therapy)

Group C (IVB Plus GLP)

Improved 2 or more lines 74 (52.5%) 36 (30%) 58 (36.9%)

Remained stable 62 (44.6%) 59 (49.2%) 78 (49.7%)

Decreased 2 or more lines 5 (3.6%) 25 (20.8%) 21 (13.4%)

*Values represent number and percentages; logMAR = logarithm of the minimal angle of resolution; BCVA = best-corrected visual acuity; n = number of patients; DDME = diffuse diabetic macular edema; IVB = intravitreal bevacizumab; GLP = grid laser photocoagulation.


B there was no statistically significant difference from baseline BCVA until the first 6 months of treatment. We found that 6 months after GLP, BCVA improved significantly (< .05) from baseline, and these changes were maintained throughout the 24 months of follow-up. However, the improvement rate was similar among the 3 groups (ANOVA; P = .41). In addition, we observed that CMT improved in all treatment groups at 24 months of follow-up, although primary IVB alone produced greater decreases in CMT than treatments in Groups B and C. The comparison among the 3 groups showed higher CMT decreases in Group A than in Groups B and C (ANOVA; P < .001). In addition, the number of eyes that experienced a signifi-cant improvement of visual acuity (2 ETDRS lines or more) was higher (52.5%) in Group A (IVB therapy).

In summary, our study provides evidence to support the use of primary intravitreal bevacizumab with or without GLP as treatment of DDME. These results indicate that primary IVB had a statistically significant difference from baseline BCVA at all time points during 24 months of follow-up, and we observed that primary IVB alone produced greater decreases in CMT than single GLP therapy or IVB plus GLP in patients with DDME. In addition, the number of eyes that experienced a significant improvement of visual acuity was higher in the IVB group.

Selected Readings

1. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide a focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008; 115:1447-1459.

2. Antonetti DA, Barber AJ, Hollinger LA, et al. Vascular endothe-lial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden; 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J Bio Chem. 1999; 274: 23463-23467.

3. Cunningham ET Jr, Adamis AP, Altaweel M, et al; Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology 2005; 112:1747-1757.

4. Arevalo JF, Sanchez JG, Wu L, Maia M, Alezzandrini AA, Brito M, Bonafonte S, Lujan S, Diaz-Llopis M, Restrepo N, Rodríguez FJ, Udaondo-Mirete P; Pan-American Collaborative Retina Study Group. Primary intravitreal bevacizumab for diffuse diabetic macu-lar edema the Pan-American Collaborative Retina Study Group at 24 months. Ophthalmology 2009; 116:1488-1497.

5. 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.

6. Solaiman KA, Diab MM, Abo-Elenin M. Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema. Retina 2010; 30:1638-1645.

7. 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.

8. Han DP, Mieler WF, Burton TC. Submacular fibrosis after photo-coagulation for diabetic macular edema. Am J Ophthalmol. 1992; 113:513-521.

9. Guyer DR, D’Amico DJ, Smith CW. Subretinal fibrosis after laser photocoagulation for diabetic macular edema. Am J Ophthalmol. 1992; 113:652-656.

10. Schachat AP. Better outcomes for patients with diabetic macular edema. Ophthalmology 2011; 118:607-608.

11. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology 2010; 117:2146-2151.

12. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 2010; 33:2399-2405.

13. 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.


I. Diabetic Macular Edema (DME)

A. Diabetic retinopathy is the leading cause of blind-ness in working-aged adults in the United States.1

B. DME is a vision-threatening complication of diabetic retinopathy.2 The prevalence of DME is related to patients’ duration of diabetes.3

C. Vascular endothelial growth factor (VEGF) is a primary vascular permeability factor in DME.4,5 Increased intraocular VEGF has been observed in patients with DME, suggesting that VEGF blockade might be beneficial.6

D. Ranibizumab (Lucentis) is a high-affinity anti-VEGF Fab specifically designed for ophthalmic use. It binds to and neutralizes all isoforms of VEGF-A and their biologically active degradation products, and has a vitreous elimination half-life of approximately 9 days.

II. Ranibizumab Treatment in DME

A. The Early Treatment Diabetic Retinopathy Study (ETDRS) established macular laser as standard of care treatment for DME. Macular laser reduces moderate vision loss over time by 50%. However, relatively few patients with vision loss experience significant improvements in BCVA after laser.7,8

B. In studies controlled for up to 1 year, ranibizumab was shown to be superior to laser treatment and intravitreal steroids in DME patients.8-10

III. RISE and RIDE: Pivotal Phase 3, 24-Month Controlled Studies

A. Study design

1. RISE and RIDE were parallel, Phase 3, mul-ticenter, double-masked, sham-injection-con-trolled studies designed to evaluate the efficacy and safety of ranibizumab in patients with vision loss due to DME.

2. Patients ≥ 18 years with diabetes (type I or II), BCVA 20/40 to 20/230 Snellen equivalent, and central foveal thickness ≥ 275 µm in the study eye were included (1 eye per patient random-ized).

3. Patients were randomized to receive monthly sham injections or intravitreal injections of ranibizumab 0.3 mg or 0.5 mg.

4. All patients were evaluated monthly for macular laser per protocol-specified criteria, beginning at Month 3.

5. The primary outcome was the proportion of patients gaining ≥ 15 letters in BCVA from base-line to 24 months.

6. Increases in patient-reported visual function measured by the overall composite score of the National Eye Institute Visual Function Question-naire 25 (NEI-VFQ 25) were also recorded.

7. Additional details are available at www.Clinical-Trials.gov (NCT00473330 and NCT00473382).

B. Patient disposition and demographics

1. In RISE, 377 patients were randomized to study treatment (sham, 127; ranibizumab 0.3 mg, 125; ranibizumab 0.5 mg, 125). In RIDE, 382 patients were randomized (sham, 130; ranibizumab 0.3 mg, 125; ranibizumab 0.5 mg, 127).

2. Treatment groups in both studies were gener-ally well balanced for baseline demographics and study eye characteristics (see Table 1); more patients in the ranibizumab 0.3 mg group in RISE had BCVA < 20/200 (13.6% vs. 7.2%-8.7% in other groups).

3. The 2-year treatment period was completed by 83.3% of patients in RISE and 84.6% in RIDE.

4. In both studies, the median number of injections in the ranibizumab 0.3 mg and 0.5 mg groups was 24.

5. Substantially more sham-treated patients received macular laser under protocol-specified criteria (70%-74% in sham group vs. 19.7%-39.2% in ranibizumab group).

C. Efficacy outcomes

1. In RISE, at 24 months, 18.1% of sham patients gained ≥ 15 letters, compared with 44.8% of patients receiving ranibizumab 0.3 mg (adjusted difference 24.3%; 95% CI, 13.8-34.8; P < .0001) and 39.2% receiving ranibizumab 0.5 mg (adjusted difference 20.9%, 95% CI, 10.7-31.1; P = .0002) (differences adjusted for baseline BCVA ≤ 55 vs. > 55 letters; baseline HbA1c ≤ 8% vs. > 8%; and prior therapy for DME, yes vs. no). See Figure 1.

2. In RIDE, 12.3% of sham patients gained ≥ 15 letters, compared with 33.6% of patients receiv-ing ranibizumab 0.3 mg (adjusted difference 20.8%; 95% CI, 11.4-30.2; P < .0001) and 45.7% receiving ranibizumab 0.5 mg (adjusted difference 33.3%, 95% CI, 23.8-42.8; P < .0001) (Figure 1).

Ranibizumab for Diabetic Macular Edema: 24-Month Results of RIDE and RISE, Two Phase 3 Randomized TrialsRanibizumab (Anti-VEGF) Improves Vision in Diabetic Macular Edema

David S Boyer MD

http://www.Clinical-Trials.gov

http://www.Clinical-Trials.gov


Table 1. Patient Demographics and Baseline Characteristics

RISE RIDE

Sham

(n = 127)

Ranibizumab Sham

(n = 130)

Ranibizumab

0.3 mg (n = 125)

0.5 mg (n = 125)

0.3 mg (n = 125)

0.5 mg (n = 127)

Age (years), mean (SD) 61.8 (9.8) 61.7 (8.9) 62.8 (10.0) 63.5 (10.8) 62.7 (11.1) 61.8 (10.1)

Male, n (%) 74 (58.3) 73 (58.4) 65 (52.0) 66 (50.8) 73 (58.4) 80 (63.0)

BCVA (letters), mean (SD) 57.2 (11.1) 54.7 (12.6) 56.9 (11.6) 57.3 (11.2) 57.5 (11.6) 56.9 (11.8)

Approximate Snellen equivalent, mean

20/80 +2 20/80 20/80 +2 20/80 +2 20/80 +2 20/80 +2

Previous treatment for CSME, n (%) 94 (74.0) 94 (75.2) 102 (81.6) 92 (70.8) 86 (68.8) 88 (69.3)

Abbreviations: SD indicates standard deviation; BCVA, best corrected visual acuity; CSME, clinically significant macular edema.

Figure 1. Primary endpoint (LOCF): percentage of patients who gained ≥15 ETDRS letters from baseline at 24 months in RISE (A) and RIDE (B). Secondary endpoint: percentage of patients who lost <15 ETDRS let-ters from baseline at 24 months in RISE (C) and RIDE (D). Outcomes on

bars are unadjusted. P values were based on tests for treatment difference stratified by baseline BCVA (≤55 vs. >55 letters), baseline HbA1c (≤8% vs. >8%), and prior DME therapy (yes vs. no).


3. More patients in the ranibizumab group lost < 15 letters compared with the sham group (dif-ference statistically significant in RISE and in patients who received ranibizumab 0.3 mg in RIDE) (Figure 1).

4. Treatment with ranibizumab was associated with rapid and statistically significant vision improve-ments compared with sham as early as 7 days following the first injection (see Figure 2) and at each subsequent time point.

5. Ranibizumab-treated patients experienced rapid reductions in macular edema as measured by OCT; differences between the ranibizumab dose groups and sham groups were statistically signifi-cant at Month 1 (first post-treatment measure-ment) and at each subsequent time point (Figure 2).

6. In both studies, ranibizumab-treated patients reported greater increases in the overall com-posite score of the NEI-VFQ 25 compared with sham; at 24 months these differences were statis-tically significant for RISE (P < .05).

D. Safety outcomes

1. Rates of cataract, intraocular inflammation, and glaucoma adverse events (AEs) were simi-lar among the ranibizumab and sham groups. Increased IOP following injection was more common in the ranibizumab groups as expected, since sham patients did not receive actual intra-vitreal injections. Three tractional retinal detach-ments occurred in sham-treated patients.

2. The most common ocular serious AE (SAE) was vitreous hemorrhage, which occurred in 4 sham-treated eyes (3.3%) and 2 ranibizumab-treated study eyes (0.8%) in RISE and 3 sham-treated study eyes (2.4%) in RIDE.

3. SAEs from the ranibizumab injection procedure included endophthalmitis (1 case in RISE and 3 in RIDE), 3 cases of traumatic cataract, and 1 rhegmatogenous retinal detachment in 10,584 injections.

4. Systemic SAEs potentially related to VEGF inhi-bition occurred in 9.4%-10.6% of sham and 5.6%-11.9% of ranibizumab-treated patients in both studies.

Figure 2. Changes in visual acuity (A) and central foveal thickness (B) from baseline through 24 months (LOCF).


5. SAEs categorized by the Antiplatelet Trialists’ Collaboration (APTC) definitions occurred in 4.9%-5.5% of sham and 2.4%-8.8% of ranibi-zumab-treated patients. Deaths were slightly more common in ranibizumab-treated patients. Cerebrovascular accidents were slightly more common in patients treated with 0.5 mg ranibi-zumab.

IV. Conclusions

Treatment with ranibizumab rapidly and sustainably improved vision in patients with DME. Additional benefits were noted for other measurements of visual acuity (such as preventing moderate vision loss), and substantial improvements were seen in retinal anatomy. Ranibizumab use in DME patients was associated with low risks of ocular and systemic AEs, and no new sig-nificant risks were identified.

References

1. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: U.S. Department of Health and Human Services, Cen-ters for Disease Control and Prevention, 2011; v. 2011.

2. Johnson MW. Etiology and treatment of macular edema. Am J Ophthalmol 2009; 147(1):11-21 e1.

3. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wiscon-sin epidemiologic study of diabetic retinopathy. Ophthalmology 1984; 91(12):1464-1474.

4. Cunha-Vaz J, Faria de Abreu JR, Campos AJ. Early breakdown of the blood-retinal barrier in diabetes. Br J Ophthalmol 1975; 59(11):649-656.

5. Qaum T, Xu Q, Joussen AM, et al. VEGF-initiated blood-retinal barrier breakdown in early diabetes. Invest Ophthalmol Vis Sci. 2001; 42(10):2408-2413.

6. Funatsu H, Yamashita H, Noma H, Mimura T, Yamashita T, Hori S. Increased levels of vascular endothelial growth factor and inter-leukin-6 in the aqueous humor of diabetics with macular edema. Am J Ophthalmol. 2002; 133(1):70-77.

7. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol. 1985;103(12):1796-1806.

8. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011; 118(4):615-625.

9. DRCRnet; Elman MJ, Aiello KP, Beck RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcino-lone plus prompt laser for diabetic macular edema. Ophthalmology 2010; 117(6):1064-1077 e35.

10. Nguyen QD, Shah SM, Skwaja AA, et al; READ-2 Study Group. Two-year outcomes of the READ-2 study. Ophthalmology 2010; 117(11):2146-2151.


Sponsored by the Juvenile Diabetes Research Foundation

Description of the Study

In the READ 3 Study, patients with diabetic macular edema (DME) who meet eligibility criteria and consent to the study are randomized 1:1 to receiving 1 of 2 doses of intravitreal ranibi-zumab (RBZ) (0.5 mg or 2.0 mg) in the designated study eye. The study treatment regimens are similar for both randomized groups; the only difference is the dose of RBZ. The study dura-tion is 24 months, with the primary endpoints being assessed at Month 6 and secondary endpoints assessed at Months 3, 9, 12, 18, and 24.

All patients are followed monthly and receive intravitreal injections of RBZ (0.5 or 2 mg) in the study eye (designated by the investigator) at baseline and Month 1, 2, 3, 4, and 5 (6 man-datory treatments). After the primary endpoints are assessed at Month 6, the patients will be examined monthly. If the study eye meets re-treatment criteria (presence of any fluid on spectral domain OCT or central subfield thickness ≥ 250 μm on Stratus OCT), the study eye will receive treatment with intravitreal RBZ. OCT measurements will be conducted using both the time-domain Stratus OCT and the Spectralis spectral-domain OCT (SD-OCT).

Rationale for Study Design

The READ-1 and READ-2 studies have demonstrated safety of intravitreal RBZ (0.5 mg) in eyes and patients with DME. The READ-1 and READ-2 studies also suggested that eyes with DME, perhaps due to greater presence of angiogenic stimuli such as VEGF (compared to neovascular AMD, for example), requires more angiogenic inhibition, either in frequency or doses of VEGF-antagonists. Patients often have demonstrated recurrence of DME when evaluated at 2-month intervals.

As higher doses of ranibizumab have not yet been tested for improved efficacy in DME, it is possible that greater efficacy could be achieved. It is important to determine if higher doses of a VEGF antagonist such as RBZ can improve bioactivity as mea-sured by changes in visual acuity and/or retinal thickness, or can reduce frequency of treatments in eyes with DME. Nonclinical and early clinical data indicate that higher doses of ranibizumab up to and including 2.0 mg are safe and tolerated by patients. In an early clinical dose-escalation study with the lyophilized formulation, 15 patients tolerated dose escalation up to 2.0 mg ranibizumab and demonstrated no ocular serious adverse events. The maximum tolerated dose of the currently employed liquid formulation is not known. Thus, it is proposed that studies be conducted with a higher dose of RBZ (2 mg) compared to the currently available dose (0.5 mg).

In the READ 3 Study, until the primary endpoint is assessed at Month 6, patients in both groups will receive monthly injec-

tions of RBZ (0.5 mg or 2.0 mg). The 6 intravitreal injections that are given monthly from baseline to Month 5 (inclusive, total of 6 injections) will also allow safety evaluation of monthly injections of higher dose of RBZ, along with assessment of bio-activities. The data obtained from Month 6 to Month 24 will allow assessment of frequency of treatments across the 2 tested dosages.

The READ-3 Study will provide invaluable information about the safety and additional potentials of RBZ in DME when administered at higher dosage.

Participating Members in the READ-3 Study

The READ-3 Study is conducted by the investigators across 13 chosen clinical sites in the United States. The study is sponsored by the Juvenile Diabetes Research Foundation, with the study drug, ranibizumab, provided by Genentech, Inc. The READ-3 Study is governed by a Steering Committee and overseen by a Data Safety and Monitoring Committee.

The Retinal Imaging Research and Reading Center at the Wilmer Eye Institute serves as the Reading Center for the READ-3 Study. The Wilmer Eye Institute at the Johns Hopkins University serves as the Coordinating Center for the READ-3 Study.

The participating clinical centers in the READ-3 Study are as follows:

Site Principal Investigator

Black Hills Eye Institute (Rapid City, SD)

Prema Abraham MD

East Bay Retina Institute (Oakland, CA)

Eugene Lit MD PhD

Eye Care Specialists (Kingston, PA)

Erik Kruger MD

Illinois Retina Associates (Chicago, IL)

John Pollack MD

Retina Group of Florida (Fort Lauderdale, FL)

Larry Halperin MD PhD

Retina Institute of Hawaii (Honolulu, HI)

Michael Bennett MD

Retina Macula Institute (Torrance, CA)

Ron Gallemore MD

Retina Vitreous Associates (Beverly Hills, CA)

David Boyer MD

Southeast Retina Center (Augusta, GA)

Dennis Marcus MD

READ 3: 0.5- vs. 2.0-mg Ranibizumab for Diabetic Macular EdemaRanibizumab for Edema of the mAcula in Diabetes: Protocol 3 With High Dose

Quan Dong Nguyen MD for the READ 3 Study Research Group


Texas Retina Associates (Arlington, TX)

David Callanan MD

Shiley Eye Center Kang Zhang MD PhD

University of California (San Diego, CA)

University of Kansas (Prairie Village, KS)

Andrew Symons MD PhD

Wilmer Eye Institute Johns Hopkins University (Baltimore, CA)

Diana V Do MD

The READ-3 Steering Committee

David Boyer MD (Beverly Hills, CA)

David Callanan MD (Arlington, TX)

Peter Campochiaro MD (Baltimore, MD)

Quan Dong Nguyen MD MSc (Baltimore, MD): Chair

The READ-3 Data Safety and Monitoring Committee

Brian Conway MD (Charlottesville, VA)

David Wilson MD (Portland, OR)

The READ-3 Coordinating Center

Afsheen Khwaja MD

Yasir J Sepah MBBS

The Retinal Imaging Research and Reading Center at Wilmer

Millena Bittencourt MD

Roomasa Channa MD

Raafay Sophie MBBS

Updates of the READ-3 Study

The READ-3 Study began recruitment in April 2010 and finished patient enrollment in October 2010. 152 patients were random-ized. Preliminary results of the READ-3 Study will be presented at the Retina Subspecialty Day at the 2011 Annual Meeting of the American Academy of Ophthalmology in Orlando, Florida.


Diabetic macular edema (DME), a prevalent cause of vision loss, is difficult to manage because of its chronic nature, and therefore therapeutic agents that provide sustained benefit are needed. Fluocinolone acetonide (FAc) intravitreal inserts are nonbioerod-ible cylindrical tubes (3.5x0.37-mm) of polymer loaded with either 0.5 µg/day or 0.2 µg/day of FAc that are inserted into the vitreous cavity through a 25-gauge needle in an outpatient set-ting. These inserts provide consistent and sustained delivery of a submicrogram dose of FAc to the eye for up to 3 years.

The Flucinolone Acetonide for Diabetic Macular Edema (FAME) Study demonstrated substantial visual benefit at the primary endpoint, 2 years after initiation of treatment with FAc inserts.1 Twenty-eight percent of DME patients treated with either 0.5-µg/day or 0.2-µg/day FAc inserts had an improvement in BCVA of ≥ 15 letters in Early Treatment Diabetic Retinopathy Study (ETDRS) letter score compared with 16% in the sham group (P = .018), who received current standard of care treat-ments. In both the FAME A and FAME B trials, the primary endpoint was achieved, and a statistically significant effect vs. the sham group was maintained through Month 33.

Subgroup Analysis

A prespecified subgroup analysis based on the duration of DME from diagnosis to trial randomization was conducted using median duration of DME at study entry (3 years). The primary measure of efficacy (percent improving by 15 letters or greater at 24 months) was examined in both subgroups: DME of 3 years or longer and DME less than 3 years in duration, both assessed at baseline. In FAME A and FAME B, a greater propor-tion of patients with duration of DME of ≥ 3 years at baseline experienced a ≥ 15-letter improvement with both doses vs. sham controls at Month 24. The effect was even more robust than that seen in the full population. In FAME A, the percent-age of patients achieving a ≥ 15-letter improvement was 11.9% in the sham group, 31.8% in the 0.2-µg/day group (P = .004), and 25.0% in the 0.5-µg/day group (P = .041). In FAME B, a ≥ 15-letter improvement was seen in 15.1% of the sham patients, in 37.4% of those in the 0.2-µg/day group (P = .006), and in 32.3% of patients in the 0.5 µg/day group (P = .033).

In this subgroup of patients with chronic DME, the treatment difference remained statistically significant out to Month 36 for the 0.2-µg/day FAc dose in both trials. In FAME A, 13.6% of sham patients and 31.8% of 0.2-µg/day patients achieved a ≥ 15-letter improvement (P = .01). For FAME B, the percentages were 13.2% and 36.4% for sham and 0.2 µg/day, respectively (P = .004).

In those patients with DME of shorter duration at baseline, no significant difference was seen for the treated vs. control patients.

Pharmacokinetics

In a separate pharmacokinetic study,2 aqueous levels of FAc were measured at several time points after insertion of 0.5-µg/day or 0.2-µg/day FAc inserts. One year after insertion of 0.2-µg/day inserts, mean aqueous FAc was 2 ng/mL and remained at that level throughout the entire 3-year measurement period. Mean aqueous FAc was also 2 ng/ml 1 year after insertion of 0.5-µg/day inserts and remained at that level for 2.5 years. The only dif-ference between the 2 inserts regarding pharmacokinetics was seen in the first 3 months, when mean FAc levels were greater for the 0.5-µg/day group. In contrast, mean aqueous FAc levels were 7 ng/ml 1 year after implantation of a Retisert implant. The significance of this difference related to IOP side effects will be discussed.

Adverse Events

The most common study eye, drug-related, serious adverse event was cataract surgery. Of those patients who were phakic at baseline, cataract surgery was done in 80.0% (0.2 µg/day) and 87.8% (0.5 µg/day) of patients in the FAc insert groups, compared with 27.3% of the sham group. The only other seri-ous ocular adverse events seen more frequently in the FAc insert groups than the sham group were related to increased IOP. By Month 36, laser trabeculoplasty was done in 2.5% of the 0.5-µg/day group, 1.3% of the 0.2-µg/day group, and 0% of the sham group. Incisional glaucoma surgery was done in 8.1% of the 0.5-µg/day group, 4.8% of the 0.2-µg/day group, and 0.5% of the sham group. Topical IOP-lowering medications were admin-istered to 38.4% of the 0.2-µg/day group and 47.3% of the 0.5-µg/day group.

Conclusions

At 36 months in the full population, patients treated with 0.2-µg/day FAc inserts (Iluvien) had substantial benefit in visual acuity compared with patients receiving sham injection, and the relative benefit was even greater in patients who had DME ≥ 3 years at baseline. There was little increase in the need for IOP-lowering medications between 2 and 3 years in the 0.2-µg/day insert group. Mean aqueous levels peaked at 4 ng/ml and gradually decreased to 2 ng/ml, where they remained for 3 years in the 0.2-µg/day group. Mean aqueous FAc levels were roughly 3-fold higher during the first year after implantation of Retisert implants compared with those for 0.2-µg/day FAc inserts. The constant low levels achieved with 0.2-µg/day FAc inserts is criti-cal for maximizing the efficacy/toxicity ratio achievable with intraocular steroids for DME. Patients with chronic DME, who generally respond poorly to currently available treatments, responded particularly well to low-dose FAc inserts, and thus the inserts could help in an important area of unmet medical need.

Iluvien for Diabetic Macular EdemaThree-Year Outcomes for the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) Trial

Peter A Campochiaro MD for the FAME Study Group


References

1. Campochiaro PA, Brown DM, Pearson A, et al; for the FAME Study Group. Long term benefit of sustained delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmol-ogy 2011; 118:626-635.

2. Campochiaro PA, Hafiz G, Shah SM, et al; for the FAME Study Group. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology 2010; 117:1393-1399.e1393.


Introduction

Subthreshold micropulsed diode laser photocoagulation is a subject of interest to retinal specialists worldwide. A micropulse 810-nm diode laser is used, according to a minimal intensity pro-tocol (MIP) that does not produce any intraretinal damage that is detectable on clinical examination during, or after, treatment.1,2

Background

Over the last 50 years, retinal photocoagulation has become more refined, effective, and safe. It has become the first line of treatment for numerous chorioretinal disorders, and its effective-ness has been validated by many clinical studies. The precise mechanism of action of laser therapy remains unknown. It is, however, widely believed that in conventional continuous-wave retinal photocoagulation, most of the energy is absorbed by the retinal pigment epithelium (RPE). Laser might produce its therapeutic effects by destroying the oxygen-consuming photo-receptor cells and the RPE, thereby reducing the hypoxic state of the retina. This concept is increasingly being challenged as therapeutic agents such as steroids and anti–vascular endothelial growth factor (VEGF) can reduce edema without destroying photoreceptors.

The heat from conventional laser therapy is conducted to surrounding structures such as the neurosensory retina and the choroid. This can result in collateral thermal damage. The “gray-ish” endpoint of a conventional retinal laser burn signifies that the thermal wave has reached the overlying neurosensory retina with a temperature high enough to damage the natural transpar-ency of the retina. This blanching is typically associated with a rise in temperature of 20-30 degrees C above baseline body temperature.3

It has, however, been suggested that full thickness retinal damage may not be needed to obtain beneficial effects from laser.4 The benefits might be due to the up-and-down regula-tion of angiogenic growth factors (eg, VEGF)5,6 mediated by the biological reaction of RPE cells that have been only sublethally injured. The RPE plays a significant role in the repair of the outer and inner blood-retinal barrier, regardless of the type or location of the laser application. Photothermal elevation that does not produce intraretinal damage visible during, or sometime after, the laser treatment may be termed a “subthreshold” laser treat-ment. Emerging evidence suggests that subthreshold laser treat-ment may be as effective as conventional laser treatment, but with less iatrogenic damage to the tissues surrounding the area of the burn in the RPE.

How Micropulse Laser Works

In micropulse mode, laser energy is delivered with a train of repetitive short pulses (typically 100-300 microseconds each) within an “envelope” whose width is typically in the range of 0.1-0.5 seconds.7,3 Micropulse power as low as 5%-15% of the visible threshold power has been shown to be sufficient to show consistent RPE-confined damage with sparing of the neurosen-

sory retina with light and electron microscopy.8 Subthreshold MIP protocols are designed to produce only sublethal thermal elevations with effects that are invisible during treatment and remain so thereafter. The inner retinal temperature must remain below the threshold of irreversible damage. Any increase in tem-perature at the RPE is axially confined by making the laser expo-sure duration shorter than the thermal relaxation time. Instead of delivering the requisite energy with a single high-peak power pulse, a series of repetitive low-energy pulses are used. Lower energy per pulse reduces peak power, decreases the increase in temperature per pulse, and ultimately results in improved con-finement.3 Minimizing chorioretinal laser damage may permit confluent therapy and re-treatment of the same areas, which may be particularly useful for the treatment of macular edema. Re-treatment is thought to be feasible because MLT does not pro-duce chorioretinal scars that could expand or increase the risk of choroidal neovascularization.

Limitations of MLT

The most significant limitation of MLT is the difficulty of titrat-ing the treatment without the feedback of an ophthalmoscopi-cally visible endpoint. In most published series, a continuous wave power conversion is used, but the conversion ratio is a guestimate. The treatment protocol is not yet well established in terms of the exact laser irradiance that should be delivered to the retina. With the recent development of the yellow micropulse laser, the clinical end points might be much easier to titrate for individual patients, as visible micropulse laser can be achieved in most patients. Adjusting the power to 50%-70% of the visible end point would allow more precise power titration.

Retinal Applications in Diabetic Macular Edema

Since the ETDRS clinical trial showed that laser photocoagula-tion reduced the risk of moderate visual loss by 50% in eyes with clinically significant macular edema, laser treatment has become the standard treatment for DME. Focal treatment is given for localized areas of leakage, and a grid pattern is normally applied for areas of diffuse macular edema. Subthreshold MLT has been shown to be as effective as conventional argon laser for DME.9,10 Changes in macular sensitivity, as measured by microperimetry, may be evident as early as 1 month after MLT, before significant OCT changes in retinal thickness are identified.11 The potential for confluent therapy may be particularly valuable for the re-treatment of persistent or new macular edema.10

In the anti-VEGF era, the role of laser requires further exami-nation. Using a laser that causes retinal scarring might no longer be an acceptable clinical option. However, committing patients to multiple injections with non–foveal involving DME or foveal-involving DME without visual loss would also be difficult to justify. Subthreshold MLT might play a significant role in these groups of patients.

Micropulse Laser for Diabetic Macular EdemaN H Victor Chong MBCHB


References

1. Akduman L, Olk RJ. Subthreshold (invisible) modified grid diode laser photocoagulation in diffuse diabetic macular edema (DDME). Ophthalmic Surg Lasers. 1999; 30(9):706-714.

2. Sivaprasad S, Elagouz M, McHugh D, Shona O, Dorin G. Micro-pulsed diode laser therapy: evolution and clinical applications [review]. Surv Ophthalmol. 2010; 55(6):516-530.

3. Dorin G. Subthreshold and micropulse diode laser photocoagula-tion. Semin Ophthalmol. 2003; 18(3):147-153.

4. Lanzetta P, Dorin G, Piracchio A, et al. Theoretical bases of non-ophthalmoscopically visible endpoint photocoagulation. Semin Ophthalmol. 2001; 16(1):8-11.

5. Glaser BM, Campochiaro PA, Davis JL, et al. Retinal pigment epi-thelial cells release inhibitors of neovascularization. Ophthalmology 1987; 94:780-784.

6. Ogata N, Tombran-Tink J, Jo N, et al. Upregulation of pigment epithelium-derived factor after laser photocoagulation. Am J Oph-thalmol. 2001; 132(3):427-429.

7. Mainster MA. Decreasing retinal photocoagulation damage: prin-ciples and techniques. Semin Ophthalmol. 1999; 14(4):200-209.

8. Kim SY, Sanislo SR, Dalal R, et al. The selective effect of micropulse diode laser upon the retina [ARVO Abstract]. Invest Ophthalmol Vis Sci. 1996; 37(3):S779. Abstract nr. 3584.

9. Figueira C, Khan J, Nunes S, et al. Prospective randomized con-trolled trial comparing subthreshold micropulse diode laser photo-coagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol. 2009; 93(10):1341-1344.

10. Lavinsky D, Cardillo JA, Melo LA Jr, Dare A, Farah ME, Belfort R Jr. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Invest Ophthalmol Vis Sci. Epub ahead of print 23 Feb 2011.

11. Vujosevic S, Bottega E, Casciano M, et al. Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina 2010; 30(6):908-916.


I. The State of Vitrectomy for Diabetic Macular Edema (DME): Some Answers, More Questions

A. Is vitrectomy successful in the treatment of DME?

1. Yes: According to most series1-18

a. Two decades of published series suggest ben-efit in reducing or resolving DME in almost all series.

b. Improved vision in the majority of series

c. Approach to refractory DME has changed over time.

d. In the era prior to widespread intravitreal ste-roid or anti-VEGF therapy (1992-2005)

i. Used in eyes with visibly taut, opacified, glistening posterior hyaloid; VA improve-ment ≥ 2 lines: 49%-92% of eyes; DME – complete resolution: 45%-82% of eyes 1-6

ii. Used in eyes without visibly taut, opaci-fied, glistening posterior hyaloids; VA improvement > 2 lines: 38%-71% of eyes; DME – complete resolution: 43%-100% of eyes7-13

e. In the era of OCTs and intravitreal injections

i. Less attention paid to clinical appearance of posterior hyaloidal traction

ii. More reports of the positive benefit of vit-rectomy in reducing edema and improving vision

iii. More reports of vitrectomy leading to decreased DME but not an improvement in vision

iv. Several authors report the long-term ben-efits of vitrectomy for DME.

2. No: Few series show no benefit to either macular thickness or vision.19

B. In which eyes does vitrectomy work?

1. Eyes with obvious anteroposterior traction by OCT > eyes with obvious tangential posterior hyaloidal traction by OCT > eyes with clinically visible opacified posterior hyaloid without obvi-ous OCT evidence of traction > eyes with refrac-tory DME and suspected posterior hyaloidal traction (no visible hyaloidal opacification) that have minimal or no microaneurysmal leakage and no PVD > eyes with chronic refractory DME with a presumed clinical PVD

2. Just because the posterior hyaloid is attached to an edematous diabetic macula, is it actually exerting traction?

C. Why would vitrectomy work in the treatment of DME?

1. Relieves anteroposterior vitreomacular traction

a. Creates a PVD

b. Eyes with PDR (possibly NPDR) have a prominent premacular cortical vitreous pocket with fibroblasts, astrocytes, and macrophages embedded in, or largely on, the native vitreous collagen20

c. Role of vitreoschisis in DR, currently underes-timated

i. Histologic evidence of vitreoschisis in 81% of 179 eyes with PDR and traction retinal detachment21

ii. Histologic evidence of neovasculariza-tion into posterior vitreous cortex in eyes with early PDR, possible vitreoschisis and macular traction22

2. Relieves tangential traction

a. Can be seen on OCT, particularly spectral domain

b. Histologic studies

i. Electron microscopy: Potentially contrac-tile vitreous and RPE cells in multilayered sheets in removed posterior hyaloid23

ii. Electron microscopy: Single-layered or multilayered cellular membranes situated on a layer of vitreous collagen in removed epimacular tissue24

3. What is the role of peeling the internal limiting membrane (ILM)?

a. Studies6, 25-32

i. VA and anatomic results improve with ILM peeling.

ii. VA not changed but anatomic results improve with ILM peeling.14

iii. Both VA and anatomic results not changed with ILM peeling.16,19

iv. All studies are uncontrolled and unstan-dardized.

Vitrectomy for Diabetic Macular Edema: Current Concepts and QuestionsTarek S Hassan MD


b. Theoretically beneficial to peel ILM:

i. Mechanical relief: Ensures removal of pos-terior hyaloid regardless of whether there is intrinsic ILM pathology

ii. Removal of intrinsically pathologic ILM: Diabetic ILM has increased amounts of fibronectin,33 laminin,33,34 and type I, III, IV, V collagen.34

iii. Removal of intrinsically pathologic ILM: Extensive collagen fibers found on vitreous side of peeled ILM from DME eyes.35

iv. Removal of intrinsically pathologic ILM: ILM in DME eyes is thicker than ILM in other types of pathology such as macular hole: Matsunaga36: Mean DME ILM thickness = 4.8 µm vs. mean macular hole ILM thickness = 1.8 µm; ILM thickening from accumulated extracellular matrices (including HSPG) induces functional dis-turbances in the charged barrier between vitreous and retina, altering fluid shifts between the vitreous and retina

v. Removal of intrinsically pathologic ILM: ILM in DME eyes significantly thickened vs. normal and the thickness is directly correlated with Hgb A1C levels, duration of DM, and age.37

vi. Removal of intrinsically pathologic ILM: Traction is induced directly by the ILM itself.38 Histopathology with immunos-taining revealed a segment of ILM with an inner monolayer of cytokeratin-positive (RPE) and/or glial fibrillary acidic protein-positive cells with smooth muscle actin immunoreactivity. Tangential tractional forces from contractile cells propagate across the fovea via the ILM.

4. Remove vasopermeable factors from the vitreous cavity

a. VEGF, ICAM-1, IL-6 expressed by endothe-lial cells; all have vasopermeable characteris-tics

b. Eyes with diffuse DME have higher vitreous levels of VEGF, sICAM-1, IL-6 than control eyes; levels correlate with severity of DR, degree of fluorescence of DME, and central foveal thickness.39,40

c. Eyes with PDR and DME: IL-6, IL-8, IL-10, IL-13, IP-10, MCP-1, MIP-1β, PDGF, and VEGF in the vitreous fluid were significantly higher than in controls (IL-10 and IL-13 directly correlated with VEGF levels).41

d. Vitreous VEGF clearance increased signifi-cantly after vitrectomy.42

5. Increased microcirculation after vitrectomy

a. Revascularization noted by FA in some cases.

b. Kadonosono et al8: Improved perifoveal cap-illary blood flow demonstrated with video FA using SLO following vitrectomy and posterior hyaloid removal.

c. Park et al43: Preoperative macular blood flow higher in DME eyes than controls. This disparity was normalized after vitrectomy. Theory: Reducing abnormally high macular blood flow (measured by retinal flowmeter) with vitrectomy results in resolution of macu-lar edema.

6. Improve oxygenation of the vitreous cavity and likely retina

a. Holekamp44: Vitrectomy leads to elevated oxygenation of the vitreous cavity.

b. Pre-vit mid-vitreous oxygen tension = 7.1 mmHg; post-vit mid-vitreous oxygen tension = 75.6 mmHg

c. Long-lasting effect of increased posterior seg-ment oxygenation

D. In which eyes should we expect good outcomes?

1. Prognostic features that predict postoperative success

a. Better postoperative outcomes correlated with short duration of DME, little or no macular ischemia, mild preoperative laser, obviously taut posterior hyaloid, good preoperative VA, no preoperative foveal hard exudates.

b. OCT predictors of potential success include less preoperative retinal thickness, less or no macular detachment, posterior hyaloidal trac-tion.

2. Some eyes with good postoperative anatomic outcomes (resolved DME) may have stabilization or loss of VA rather than improvement.

a. Clinical findings: RPE atrophy, macular isch-emia, etc.

b. Postoperative focal macular ERGs: Tera-saki45—25 eyes; vit, ph separation

i. OCT-measured foveal thickness signifi-cantly reduced at 3, 6, and 12 months; VA not significantly improved at 3 and 6 months, only at 12 months postop.

ii. Focal macular ERG did not improve from preop until 12 months postop: Increased mean b-wave amplitude

c. From the DRCR.net prospective data-collec-tion trial46,47

i. VA improvement positively correlated with worse baseline VA, removal of epiret-inal membranes.


ii. Reduction in central subfield thickness on OCT positively correlated with worse baseline VA, greater preoperative retinal thickness, removal of ILM, and OCT evi-dence of preoperative vitreoretinal abnor-malities.

d. Preoperative multifocal ERG predicting post-operative outcomes

e. Kim et al48: 35 eyes

i. Delayed P1 implicit time at the central 7 hexagons (0-5 degrees of eccentricity) cor-related with poorer VA outcomes.

ii. A trend was noted between macular isch-emia and delayed implicit time.

f. Postoperative correlation of photoreceptor integrity with outcomes of vitrectomy

i. Sakamoto et al49: 37 eyes; final VA much better in eyes with complete IS/OS than those with incomplete IS/OS.

ii. Yanyali et al50: 11 eyes; integrity of ELM and IS/OS lines strongly correlated with better postoperative VA recovery.

E. What is the role of enzyme-assisted vitrectomy: plas-min and microplasmin?

1. Nonspecific proteases that degrade glycoproteins like fibronectin, laminin; dose-dependent phar-macologic separation of posterior vitreous from ILM51

2. PVD spontaneously occurs or is easy to create with suction after intravitreal injection of plas-min.

a. Williams52: Easier to create intraoperative PVD, better VA outcomes in diabetic eyes after plasmin

b. Azzolini53: Controlled comparison – patho-logic ILM specimens much cleaner with flat-ter surfaces after plasmin-assisted vitrectomy for DME than those after vitrectomy for DME without plasmin assistance.

i. No difference in anatomic or VA outcomes at 4 months.

ii. At 1 year, VA outcomes better in plasmin assisted cases.

3. Intravitreal plasmin injection without associated vitrectomy reduces refractory DME.

a. Diaz-Llopis et al54; 16 eyes with bilateral DME, refractory to laser; 1 eye of each patient received plasmin, the other did not (control).

i. Plasmin treated eyes had significantly reduced CSDME compared to controls.

ii. Plasmin treated eyes had significantly bet-ter post-treatment VA improvements than controls.

4. Microplasmin: Potential approval following large trials in United States and world will lead to randomized controlled clinical trials and off-label usage vs. DME.

F. What do the results of the DRCR.net vitrectomy for DME trial mean?

1. Results46: 87 eyes…basically a prospective data-reporting study

a. Retinal thickening was significantly reduced in most eyes.

b. VA improvement seen ³ 10 letters in 38%; VA reduction by ³ 10 letters in 22%

c. Low operative complication rate

2. The results have limited applicability: Strong criticisms of the trial

a. Though prospective, this trial was little more than a consistent, broadly applied question-naire or survey.

b. Essentially nothing other than the reporting forms and data to be collected were standard-ized. There was no standardization of nearly every important feature that could impact surgical outcomes: indications for surgery, timing of surgery, duration of macular edema, amount and types of prior therapy, and the specifics of surgical technique (performance and completeness of ILM peeling, PRP laser, intravitreal steroid injection, etc.)

4. Cannot make any substantive conclusions based on any actual evidence

5. Only value is to stimulate a prospective, random-ized, multicenter trial with standardization and control of numerous clinical parameters

G. Why are there conflicting results as to the effect of vitrectomy for DME?

1. Mostly retrospective, nonrandomized, largely uncontrolled trials comparing varying techniques of multiple different surgeons

2. Refractory DME is a very complex condition: Effective comparative studies would need to con-trol for many variables – simply not done to this point

H. How do we approach DME today?

1. Refractory DME is a complex condition, the treatment of which requires complex and coordi-nated approaches and thought.

a. Intravitreal injections of steroids and/or anti-VEGF agents are very beneficial, but they are now potentially used as a panacea – to the detriment of some eyes if continued without clinical success.

b. The key step in managing these eyes is the determination of the presence of macular traction, whether visible or invisible.


c. Most retina specialists have a management paradigm that they follow; it should include vitrectomy.

i. After vitrectomy, anti-VEGF injections can be used.

ii. Short-term benefit possible but drugs cleared quickly55

iii. VEGF is cleared quickly as well following vitrectomy but it is still consistently pro-duced.42

2. Long-acting sustained release devices may offer the next level of pharmacologic therapy, with or without additional vitrectomy.

a. Dexamethasone implant led to statistically and clinically significant improvements in both VA and vascular leakage from CSDME in difficult-to-treat vitrectomized eyes with an acceptable safety profile.56

b. Other compounds in other devices coming in the future for post-vitrectomy use.

II. Summary: Vitrectomy for DME

A. A long-term efficacious treatment for some eyes

B. Questions abound as surgeons improve their under-standing of pathophysiologic mechanisms and refine interventions.

C. Vitrectomy should still have a significant place in the treatment algorithm for chronic refractory CSDME.

1. Need to define its use, particularly versus, and more likely, in combination with intravitreal injection therapy and laser

2. Future pieces of the therapeutic puzzle: New inhibitors of vasopermeability and anti-“other cytokines”

D. Ongoing/upcoming clinical trials must adequately control variables and techniques to attempt to arrive at a true determination of the role of vitrectomy in the treatment of this condition.

1. DRCR.net: not significantly helpful

2. Smaller multicenter series have not been signifi-cantly helpful.

E. DME is a complex condition that can now be faced with more therapeutic choices and a greater under-standing of the disease pathobiology.

F. Every eye is different: Vitrectomy should be consid-ered at a deeper level than “Do I see a membrane?”

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38. Gentile RC, Milman T, Eliott D, Romero JM, McCormick SA. Taut internal limiting membrane causing diffuse diabetic macular edema after vitrectomy: clinicopathological correlation. Ophthalmologica 2011; 226(2):64-70.

39. Funatsu H, Yamashita H, Sakata K, et al. Vitreous levels of vascu-lar endothelial growth factor and intercellular adhesion molecule 1 are related to diabetic macular edema. Ophthalmology 2005; 112:806-816.

40. Funatsu H, Yamashita H, Ikeda T, Mimura T, Eguchi S, Hori S. Vitreous levels of interleukin-6 and vascular endothelial growth factor are related to diabetic macular edema. Ophthalmology 2003; 110:1690-1696.

41. Suzuki Y, Nakazawa M, Suzuki K, Yamazaki H, Miyagawa Y. Expression profiles of cytokines and chemokines in vitreous fluid in diabetic retinopathy and central retinal vein occlusion. Jpn J Oph-thalmol. 2011; 55(3):256-263.

42. Lee SS, Ghosn C, Yu Z, et al. Vitreous VEGF clearance is increased after vitrectomy. Invest Ophthalmol Vis Sci. 2010; 51(4):2135-2138.

43. Park JH, Woo SJ, Ha YJ, Yu HG. Effect of vitrectomy on macular microcirculation in patients with diffuse diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2009; 247(8):1009-1017.

44. Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases oxygen exposure to the lens: a possible mechanism for nuclear cata-ract formation. Am J Ophthalmol. 2005; 139:302-310.

45. Terasaki H, Kojima T, Niwa H, et al. Changes in focal macular electroretinograms and foveal thickness after vitrectomy for dia-betic macular edema. Invest Ophthalmol Vis Sci. 2003; 44:4465-4472.

46. Diabetic Retinopathy Clinical Research Network Writing Commit-tee; Haller JA, Qin H, Apte RS, et al. Vitrectomy outcomes in eyes with diabetic macular edema and vitreomacular traction. Ophthal-mology 2010; 117(6):1087-1093.

47. Flaxel CJ, Edwards AR, Aiello LP, et al. Factors associated with visual acuity outcomes after vitrectomy for diabetic macular edema: diabetic retinopathy clinical research network. Retina 2010; 30(9):1488-1495.

48. Kim YM, Lee SY, Koh HJ. Prediction of postoperative visual out-come after pars plana vitrectomy based on preoperative multifocal electroretinography in eyes with diabetic macular edema. Graefes Arch Clin Exp Ophthalmol. 2010; 248(10):1387-1393.

49. Sakamoto A, Nishijima K, Kita M, Oh H, Tsujikawa A, Yoshimura N. Association between foveal photoreceptor status and visual acuity after resolution of diabetic macular edema by pars plana vit-rectomy. Graefes Arch Clin Exp Ophthalmol. 2009; 247(10):1325-1330.

50. Yanyali A, Bozkurt KT, Macin A, Horozoglu F, Nohutcu AF. Quantitative assessment of photoreceptor layer in eyes with resolved edema after pars plana vitrectomy with internal limiting membrane removal for diabetic macular edema. Ophthalmologica 2011; 226(2):57-63.

51. Verstraeten TC, Chapman C, Hartzer M, Winkler BS, Trese MT, Williams GA. Pharmacologic induction of posterior vitreous detachment in the rabbit. Arch Ophthalmol. 1993; 11:849-854.


52. Williams JG, Trese MT, Williams GA, Hartzer MK. Autologous plasmin enzyme in the surgical management of diabetic retinopathy. Ophthalmology 2001; 108:1902-1905.

53. Azzolini C, D’Angelo A, Maestranzi G, et al. Intrasurgical plas-min enzyme in diabetic macular edema. Am J Ophthalmol. 2004; 138:560-566.

54. Diaz-Llopis M, Udaondo P, Arevalo F, et al. Intravitreal plasmin without associated vitrectomy as a treatment for refractory diabetic macular edema. J Ocul Pharmacol Ther. 2009; 25(4):379-384.

55. Yanyali A, Aytug B, Horozoglu F, Nohutcu AF. Bevacizumab (Avastin) for diabetic macular edema in previously vitrectomized eyes. Am J Ophthalmol. 2007; 144(1):124-126.

56. Boyer DS, Faber D, Gupta S, et al; for the Ozurdex CHAMPLAIN Study Group. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina. E-pub before print 9 Apr 2011.

2011 Subspecialty Day | Retina Section XIV: Vitreoretinal Surgery 2 135

Trauma During RevolutionSherif M Sheta MD

N O T E S

136 Section XIV: Vitreoretinal Surgery 2 2011 Subspecialty Day | Retina

I. Lamellar Macular Holes

Figure 1. Lamellar macular hole with perifoveal thickening associated with epiretinal membrane.

A. OCT essential for diagnosis: Need closely spaced scans to distinguish from foveal cysts

1. Usually associated with epiretinal membrane

2. Less frequently may occur as complication of vitreomacular traction or cystoid macular edema from a variety of etiologies

3. Thickening of perifoveal retina with thinning of central fovea (often with clefts)

B. Natural history

1. Most eyes with lamellar macular holes have rela-tively good visual acuities (20/40 or better) and minimal visual symptoms.

2. Visual acuity is stable in 78% and deteriorated in 22% in a series by Theodossiadis and col-leagues.1

3. Some progress to full-thickness macular holes when associated with vitreomacular traction but less frequently when associated with epiretinal membranes.

C. Surgical treatment

1. Vitrectomy is indicated only for patients with substantial symptoms or recent reduced visual acuity (generally 20/50 or worse).

2. Vitrectomy with removal of epiretinal membrane (if present on OCT): Internal limiting membrane (ILM) removal and air bubble are desirable.

3. Prone positioning for 1-3 days, as some eyes with lamellar macular holes will develop full-thickness macular holes after removal of epiretinal mem-brane/ILM without gas tamponade.

D. Surgical results

1. Initial case reports (Spaide 2000, Hirakawa 2005, Kokame 2007) found improved visual acuity following vitrectomy.

2. Larger series were promising.

a. Massin and colleagues2 studied 50 eyes with macular pseudohole, which included some eyes with lamellar macular holes. Median visual acuity: 20/63 preop, 20/40 postop, with visual acuity improvement of ≥ 2 lines in 62%.

b. Garretson and colleagues3 evaluated results of vitrectomy for lamellar macular holes in 27 eyes. Visual acuity improved in 24 of 27 eyes (89%), with mean improvement of 3.2 Snel-len lines.

c. Engler and colleagues4 reported the results in 10 eyes with vitrectomy for lamellar macular hole. Visual acuity improved a mean of 3 Snellen lines.

d. Andoudi and colleagues5 reported vitrectomy results in 20 eyes. Visual acuity improved in 17 of 20 eyes, with a mean gain of 2.6 Snellen lines.

e. Witkin and colleagues6 evaluated a large series of eyes with vitrectomy for epiretinal membranes and found 16 eyes with lamellar macular holes. Visual acuity improved mod-estly from 20/158 to 20/118 (P = .408), and 2 eyes progressed to full-thickness macular holes. They recommended against vitrectomy for lamellar macular holes.

f. Michalewska and colleagues7 studied 26 eyes with vitrectomy for lamellar macular holes. Visual acuity improved from 20/100 to 20/40.

g. Casperis and colleagues8 reported 45 eyes with vitrectomy for lamellar macular holes associated with epiretinal membranes. Visual acuity improved from 20/40 to 20/25, with a mean improvement of 2.7 lines.

II. Myopic Macular Holes

Macular holes in eyes with myopia of -6 D or greater

Figure 2. Macular hole in eye with high myopia. There is persisting pos-terior hyaloid traction at the nasal edge of the macular hole.

Expanding Indications for Treatment of Lamellar, Myopic Macula Holes and Myopic FoveoschisisJohn T Thompson MD


A. Morphology

1. Some have typical morphology of idiopathic macular holes.

2. Myopic macular holes may be surrounded by rhegmatogenous retinal detachments ranging from limited retinal detachment around the macular hole to total retinal detachment.

3. Eyes with myopic macular degeneration or pos-terior staphylomas may have macular holes that are very difficult to diagnose; spectral domain OCT is essential.

4. Myopic macular holes tend to occur in younger patients than typical idiopathic macular holes: forties and fifties.

B. Natural history: Few of these close spontaneously, and they are more difficult to close than macular holes in nonmyopic eyes.

C. Surgical treatment: Vitrectomy, ILM removal and gas bubble.

1. ILM removal is more difficult because of retinal pigment epithelium (RPE) atrophy in macula and thin retina.

2. ILM staining with indocyanine green (ICG) or brilliant blue G is desirable to assist ILM removal. But avoid use of ICG in eyes with asso-ciated retinal detachment since ICG will diffuse more easily into the subretinal space, causing toxicity.

3. A long-acting gas bubble with 2 weeks prone positioning is important since these holes do not close as easily.

4. Try to avoid using silicone oil as visual results are worse in eyes where silicone oil was used, pos-sibly due to RPE toxicity from oil.

5. Macular buckling can be used to reattach some eyes with myopic macular hole and retinal detachment, but try vitrectomy and gas first.

D. Surgical results

1. Sulkes and colleagues9 treated 13 eyes with high myopia and macular holes. Mean visual acuity improved from 20/152 to 20/89 in this early series.

2. Patel and colleagues10 reported 20 eyes with myopic macular holes without ILM peeling and closed the macular hole in 60% of eyes follow-ing 1 surgery and 85% with 1 or more surgeries. Visual acuity improved > 3 lines in 40% of eyes.

3. Kadonosono and colleagues11 had the first report of vitrectomy for myopic macular hole in 11 eyes with retinal detachment using ILM peeling with ICG. Retinal reattachment was achieved in 91% of eyes.

4. Garcia-Arumi and colleagues12 reported macular hole closure in 87.5% of eyes in their series with ILM peeling.

5. Kwok and colleagues13 found similar results for macular hole surgery in myopic eyes com-pared to nonmyopic eyes when ICG was used to remove the ILM. Macular hole closure was obtained in 90% of eyes, with improvement from 20/160+2 to 20/80+1.

6. Uemoto and colleagues14 obtained higher success with long-acting gas tamponade using C3F8 com-pared to SF6.

7. Uemoto and colleagues15 evaluated eyes with myopic macular holes and retinal detachment. They successfully reattached the retina in 92.3% of 13 eyes with ILM peeling, compared to 50% of 12 eyes without ILM peeling.

8. Asymptomatic macular holes were found in 6.3% of 383 eyes with high myopia using OCT in a study by Coppe and colleagues,16 emphasiz-ing the importance of OCT to detect macular holes in highly myopic eyes.

9. Prognostic factors associated with success of macular hole closure following vitrectomy for myopic macular holes included shorter axial length, ILM peeling, and shorter duration of the macular hole in a study by Lam and colleagues.17

10. Triamcinolone has also been used successfully to peel ILM in a series of eyes with macular hole and retinal detachment by Fang and colleagues.18 They were able to reattach the retina in 88% after 1 surgery.

III. Myopic Foveoschisis

Figure 3. Myopic foveoschisis in eye with high myopia. The schisis between the inner and outer retina is associated with reduced visual acu-ity and was only detected by spectral domain OCT.

A. Morphology

1. Most commonly referred to as “myopic foveos-chisis” now, but has been called “macular reti-noschisis” in the past.


2. Spectral domain OCT is essential for diagnosis.

3. Must distinguish myopic foveoschisis from mac-ular hole with retinal detachment using closely spaced slices since outer retina is often atrophic.

4. Most eyes have either vitreous traction on mac-ula or epiretinal membrane causing traction.

B. Natural history

1. May progress to full-thickness macular hole in 2/8 eyes followed 2 or more years in a series by Shimada and colleagues.19 Retinal detachment without macular hole developed in 2 eyes, and 4 eyes remained stable.

2. Gaucher and colleagues reported worsening visual acuity and schisis in 20 of 29 eyes with a mean follow-up of 31 months.20

C. Surgical treatment

1. Can be considered when there is foveal detach-ment; eyes with perimacular schisis but without foveal involvement are less likely to benefit from surgery.

2. Vitrectomy with ILM peeling and gas tamponade is the preferred method for treatment.

D. Surgical results

1. Ikuno and colleagues21 reported vitrectomy with ILM peeling in 6 eyes, and the foveal detachment resolved in 5 eyes and improved in the remaining eye. Visual acuity improved 2 or more lines in 6/6 eyes.

2. Another series of vitrectomy and gas tamponade without ILM peeling by Kwok and colleagues22 found resolution of the foveal detachment in 77.8% of 9 eyes.

3. The largest surgical series reported to date by Kumagai and colleagues23 evaluated 39 eyes and achieved improved visual acuity in 70% of eyes with foveal detachment (but in only 40% of eyes without foveal detachment).

References

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

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

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

4. Engler C, Schaal KB, Hoh AE, Dithmar S. Surgical treatment of lamellar macular hole. Ophthalmologe 2008; 105:836-839.

5. Androudi S, Stangos A, Brazitikos PD. Lamellar macular holes: tomographic features and surgical outcome. Am J Ophthalmol. 2009; 148:420-426.

6. Witkin AJ, Castro LC, Reichel E, et al. Anatomic and visual out-comes of vitrectomy for lamellar macular holes. Ophthalmic Surg Laser Imaging. Epub ahead of print 5 May 2010.

7. Michalewska Z, Michaleewski J, Odrobina D, et al. Surgical treat-ment of lamellar macular holes. Graefes Arch Clin Exp Ophthal-mol. 2010; 248:1395-1400.

8. Casperis H, Bovey EH. Surgical treatment of lamellar macular hole associated with epimacular membrane. Retina. Epub ahead of print 27 Apr 2011.

9. Sulkes DJ, Smiddy WE, Flynn HW, Feuer W. Outcomes of macular hole surgery in severely myopic eyes: a case-control study. Am J Ophthalmol. 2000; 130:335-339.

10. Patel SC, Loo RH, Thompson JT, Sjaarda RN. Macular hole sur-gery in high myopia. Ophthalmolology 2001; 108:377-380.

11. Kadonosono K, Yazama F, Itoh N, et al. Treatment of retinal detachment resulting from myopic macular hole with internal limit-ing membrane removal. Am J Ophthalmol. 2001; 131:203-207.

12. Garcia-Arumi J, Martinez V, Puig J, Corcostegui B. The role of vitreoretinal surgery in the management of myopic macular hole without retinal detachment. Retina 2001; 21:332-338.

13. Kwok AK, Lai TY. Internal limiting membrane removal in macular hole surgery for severely myopic eyes: a case-control study. Br J Ophthalmol. 2003; 87:885-889.

14. Uemoto R, Saito, Sato S, et al. Better success of retinal reattachment with long-standing gas tamponade in highly myopic eyes. Graefes Arch Clin Exp Ophthalmol. 2003; 241:792-796.

15. Uemoto R, Yamamoto S, Tsukahara I, Takeuchi S. Efficacy of internal limiting membrane removal for retinal detachment result-ing from myopic macular hole. Retina 2004; 24:560-566.

16. Coppe AM, Rpandelli G, Parisi V, et al. Prevalence of asymptom-atic macular holes in highly myopic eyes. Ophthalmology 2005; 112:2103-2109.

17. Lam RF, Lai WW, Cheung BT, et al. Pars plana vitrectomy and per-fluopropane (C3F8) tamponade for retinal detachment due to myo-pic macular hole: a prognostic factor analysis. Am J Ophthalmol. 2006; 142:938-944.

18. Fang X, Zheng X, Weng Y, et al. Anatomical and visual outcome after vitrectomy with triamcinolone acetonide assisted epiretinal membrane removal in highly myopic eyes with retinal detachment due to macular hole. Eye 2009; 23:248-254.

19. Shimada N, Ohno-Matsui K, Baba T, et al. Natural course of macular retinoschisis in highly myopic eyes without macular hole or retinal detachment. Am J Ophthalmol. 2006; 142:497-500.

20. Gaucher D, Haouchine B, Tadayoni R, et al. Long-term follow-up of high myopic foveoschisis: natural course and surgical outcome. Am J Ophthalmol. 2007; 143:455-462.

21. Ikuno Y, Sayanagi K, Ohji M, et al. Vitrectomy and internal limit-ing membrane peeling for myopic foveoschisis. Am J Ophthalmol. 2004; 137:719-724.

22. Kwok AK, Lai TY, Yip WW. Vitrectomy and gas tamponade with-out internal limiting membrane peeling for myopic foveoschisis. Br J Ophthalmol. 2005; 89:1180-1183.

23. Kumagai K, Furukawa M, Ogino N, Larson E. Factors correlated with postoperative visual acuity after vitrectomy and internal limiting membrane peeling for myopic foveoschisis. Retina 2010; 30:874-880.


Chorioretinal Biopsy: Techniques and ResultsDean Eliott MD

N O T E S


I. Introduction

A. Proliferative vitreoretinopathy (PVR) is the number 1 cause of failure of retinal detachment (RD) repair surgery.1,2

B. PVR forms in approximately 5% of all cases and up to 30% of high-risk cases following RD repair.

C. PVR accounts for approximately 75% of recurrent RDs.

D. The risk of PVR formation and recurrent RD is greatest within 2 to 3 months following RD repair.3

E. PVR is due to differentiation of the retinal pigment epithelium (RPE), fibroblasts, glial cells, and other cells.4

F. PVR is a growth of a fibrocellular matrix on the sur-face, under the retina, and along the hyaloid face.4

II. PVR Risk Factors2,5-8

A. Preoperative PVR

B. Large breaks

C. Previous and/or extensive cryotherapy

D. Blood

E. Uveitis and inflammatory factors

F. Primary RD involves multiple quadrants

III. The Natural History of PVR

A. Uniformly dismal, with total RD, hypotony, and eventually phthisis bulbi.

B. The only known treatment for PVR at this time is pars plana vitrectomy with membrane peeling.

If we can identify the molecular mediators of PVR, can we pharmacologically prevent or minimize its formation?

I. Numerous potential molecular mediators have been identified.9-11

A. Platelet-derived growth factor

B. Tumor necrosis factor

C. Transforming growth factor

D. Calcium-independent phospholipase A2

E. Interleukin 8

F. Interleukin 6

G. Vascular endothelial growth factor

H. Matrix metalloproteinase (MMP)-1, MMP-3

I. Tissue inhibitor of MMP-1

II. Several pharmacologic treatment options have been studied.

A. Corticosteroids (eg, triamcinolone acetonide [TA] and dexamethasone)

1. Vitreous inflammation promotes cellular prolif-eration and the release of cytokines from inflam-matory cells.

2. Intravitreal triamcinolone acetonide (IVTA) enhances visualization of residual cortical gel, and TA-assisted visualization results in fewer recurrent detachments.12

3. IVTA at the end of a pars plana vitrectomy/silicone oil for grade C and D PVR is associated with a high reattachment rate.13

4. Preoperative subconjunctival dexamethasone reduces postoperative flare.14

5. Potential role for the dexamethasone DDS (Ozurdex).

B. Antiproliferative chemotherapeutic agents (eg, 5-fluorouracil [5-FU] and daunomycin)

1. Fluorouracil is a pyrimidine analog that irrevers-ibly inhibits thymidylate synthetase, thus inhibit-ing DNA synthesis.

2. In animal models, 5-FU significantly reduces PVR formation and the number of tractional detachments compared with controls.15-17

3. Daunomycin is a DNA-binding chemotherapeu-tic agent.

4. Adjunctive daunomycin results in a significant reduction in the number of reoperations in cases with severe PVR.18

C. Colchicine

1. Inhibits RPE cell proliferation19

2. Promising in animal studies; however, significant side effect profile limits its clinical use.

D. Heparin plus dexamethasone in infusion fluid

1. Decreased recurrent postoperative PVR com-pared to control20

E. 5-FU plus low molecular weight heparin (LMWH)

1. 5-FU and LMWH are effective in different aspects of the PVR process and may act synergis-tically.

2. LMWH reduces postoperative fibrin after vitrec-tomy.21

Pharmacologic Prevention and Treatment of Proliferative Vitreoretinopathy: Isotretinoin StudyRichard S Kaiser MD, Nikolas JS London MD


3. Heparin binds to fibronectin and multiple growth factors, including fibroblast growth fac-tors and platelet-derived growth factors.22

4. Both 5-FU and LMWH may be added to vitrec-tomy infusion fluid.

5. Significantly lower incidence of postoperative PVR compared to placebo23

F. Anti-VEGF agents

1. Potential role

2. VEGF levels are higher in eyes with retinal detachments compared to eyes with macular hole or macular pucker.10

G. N-acetylcysteine

1. Known for potent antioxidant properties

2. Common uses: acetaminophen overdose or mucolytic

3. Reactive oxygen species likely play a role in PVR.

4. Lei et al showed that intravitreal NAC protects against PVR in a rabbit model.24

H. Glucosamine

1. Naturally occurring monosaccharide and a pop-ular dietary supplement, marketed as a treatment for osteoarthritis

2. Inhibits TGF-β1

3. In a mouse model, glucosamine reduced the appearance of PVR.25

I. Genistin

1. An isoflavone found in dietary plants (eg, soy and kudzu)

2. In a mouse model, intravitreal genistin prevents PVR formation.26

J. Geldanamycin

1. A benzoquinone ansamycin antibiotic with anti-fungal activity

2. Binds to heat shock protein-90 (HSP-90)

3. HSP-90 proteins play important roles in the regulation of cell growth, cell survival, apoptosis, angiogenesis, and oncogenesis.

4. Inhibits proliferation of cultured RPE cells27

K. Fasudil

1. A potent and selective rho-kinase inhibitor

2. Rho and rho-associated kinase (ROCK) are key regulators of focal adhesion, stress fiber forma-tion, and thus cell motility.

3. Fasudil blocks collagen-gel contraction in vitre-ous samples from PVR patients.28

L. Isotretinoin

1. Araiz et al and Nakagawa et al: Lower RD rates in experimentally induced PVR in eyes filled with retinoic acid in silicone oil.29,30

2. Dong et al: Intravitreal implantation of all-trans retinoic acid incorporated into a drug delivery system inhibited the development of PVR and was well tolerated in rabbit eyes.31

3. Veloso et al: Retinoic acid in oil significantly reduced the incidence of PVR, and there was no difference between all-trans retinoic acid and 13-cis-retinoic acid.32

4. Giordano et al: A single injection of retinoic acid-loaded microspheres in suspension in BSS reduced the incidence of TRD after 2 months in a rabbit model of PVR.33

III. Isotretinoin

A. Isotretinoin reduces recurrent detachment rates in human subjects.

1. Fekrat and associates conducted a retrospective study of 10 patients receiving oral isotretinoin (40 mg PO b.i.d. x 4 weeks postoperatively), reporting a higher rate of retinal attachment (P = .061) with a mean follow-up of 8.3 months in the treatment group.34

2. Chang and colleagues treated 16 patients with oral isotretinoin vs. controls (10 mg PO b.i.d. x 8 weeks postoperatively), reporting a higher rate of retinal attachment (93.8% vs. 63.2%), a lower rate of macular pucker formation (18.8% vs. 78.9%), and a higher rate of ambulatory vision (56.3% vs. 10.5%) with a minimum of 1 year follow-up.35

3. In addition, we have noticed a dramatic response in several patients currently being treated for PVR with isotretinoin.

B. Low-dose isotretinoin is safe and effective for acne.

1. A recent study of 638 acne patients followed for 4 years showed that 20 mg/day was beneficial with a greatly reduced side effect profile.36

2. The most common side effects were:

a. Mild cheilitis (91%)

b. Mild xerosis (43%)

c. Epistaxis (2.5%)

3. None developed depression or other psychologi-cal side effects.

IV. The DELIVER Study: Determining the Effect of Low-dose Isotretinoin on Proliferative Vitreoretinopathy

A. Purpose: To evaluate the effect of low-dose oral isotretinoin on recurrent RD in cases complicated by or at risk for PVR.

B. Background and protocol

1. The standard dose of isotretinoin for nodu-lar cystic acne is 1.0 mg/kg per day for 4 to 8


months, for a cumulative dose of about 120 mg/kg.

2. In the DELIVER study, we are treating patients with 20 mg/day (roughly 0.25 to 0.35 mg/kg/day) for 3 months.

C. Arm 1: Prospectively treat patients with high-risk for PVR (60 patients)

Asaria et al showed that nearly 30% of “high-risk” patients developed postoperative PVR.

1. Early stage B or C PVR

2. Hemorrhage

3. Uveitis

4. Multiple quadrants of primary RD

5. Large or multiple breaks

D. Arm 2: Prospectively treat patients with recurrent RDs (60 patients)

1. Inclusion criteria

a. Men 18-70 years old or postmenopausal women 50-70 years old

b. Recurrent PVR-associated RD or

c. Primary RD associated with 1 or more high-risk features

2. Exclusion criteria

a. History of depression, anorexia, liver or pan-creatic disease

b. More than 1 prior surgical RD repair

c. Closed funnel RD

d. Chronic RD, defined as longer than 12 weeks

e. Proliferative diabetic retinopathy

E. Study results: Preliminary results pending

References

1. Rachal WF, Burton TC. Changing concepts of failures after retinal detachment surgery. Arch Ophthalmol. 1979; 97(3):480-483.

2. Thompson JT. Proliferative vitreoretinopathy. In: Ryan SJ, Wilkin-son CP, eds. Retina. Philadelphia: Elsevier; 2006.

3. Mietz H, Heimann K. Onset and recurrence of proliferative vitreo-retinopathy in various vitreoretinal disease. Br J Ophthalmol. 1995; 79(10):874-877.

4. Green RW, Sebag J. Vitreoretinal interface. In: Ryan SJ, Wilkinson CP, eds. Retina. Philadelphia: Elsevier; 2006.

5. Asaria RH, Kon CH, Bunce C, et al. How to predict proliferative vitreoretinopathy: a prospective study. Ophthalmology 2001; 108(7):1184-1186.

6. Nagasaki H, Ideta H, Uemura A, et al. Comparative study of clini-cal factors that predispose patients to proliferative vitreoretinopa-thy in aphakia. Retina 1991; 11(2):204-207.

7. Nagasaki H, Shinagawa K. Risk factors for proliferative vitreoreti-nopathy. Curr Opin Ophthalmol. 1995; 6(3):70-75.

8. Yoshino Y, Ideta H, Nagasaki H, et al. Comparative study of clini-cal factors predisposing patients to proliferative vitreoretinopathy. Retina 1989; 9(2):97-100.

9. Lei H, Velez G, Hovland P, et al. Growth factors outside the PDGF family drive experimental PVR. Invest Ophthalmol Vis Sci. 2009; 50(7):3394-3403.

10. Rasier R, Gormus U, Artunay O, et al. Vitreous levels of VEGF, IL-8, and TNF-alpha in retinal detachment. Curr Eye Res. 2010; 35(6):505-509.

11. Symeonidis C, Papakonstantinou E, Androudi S, et al. Interleukin-6 and the matrix metalloproteinase response in the vitreous during proliferative vitreoretinopathy. Cytokine 2011; 54(2):212-217.

12. Acar N, Kapran Z, Altan T, et al. Pars plana vitrectomy with and without triamcinolone acetonide assistance in pseudophakic retinal detachment complicated with proliferative vitreoretinopathy. Jpn J Ophthalmol. 2010; 54(4):331-337.

13. Chen W, Chen H, Hou P, et al. Midterm results of low-dose intra-vitreal triamcinolone as adjunctive treatment for proliferative vit-reoretinopathy. Retina. Epub ahead of print 11 Feb 2011.

14. Bali E, Feron EJ, Peperkamp E, et al. The effect of a preoperative subconjuntival injection of dexamethasone on blood-retinal barrier breakdown following scleral buckling retinal detachment surgery: a prospective randomized placebo-controlled double blind clinical trial. Graefes Arch Clin Exp Ophthalmol. 2010; 248(7):957-962.

15. Stern WH, Lewis GP, Erickson PA, et al. Fluorouracil therapy for proliferative vitreoretinopathy after vitrectomy. Am J Ophthalmol. 1983; 96(1):33-42.

16. Borhani H, Peyman GA, Rahimy MH, et al. Suppression of experi-mental proliferative vitreoretinopathy by sustained intraocular delivery of 5-FU. Int Ophthalmol. 1995; 19(1):43-49.

17. Blumenkranz MS, Ophir A, Claflin AJ, et al. Fluorouracil for the treatment of massive periretinal proliferation. Am J Ophthalmol. 1982; 94(4):458-467.

18. Wiedemann P, Hilgers RD, Bauer P, et al; Daunomycin Study Group. Adjunctive daunorubicin in the treatment of proliferative vitreoretinopathy: results of a multicenter clinical trial. Am J Oph-thalmol. 1998; 126(4):550-559.

19. Lemor M, de Bustros S, Glaser BM. Low-dose colchicine inhibits astrocyte, fibroblast, and retinal pigment epithelial cell migration and proliferation. Arch Ophthalmol. 1986; 104(8):1223-1225.

20. Williams RG, Chang S, Comaratta MR, et al. Does the presence of heparin and dexamethasone in the vitrectomy infusate reduce reproliferation in proliferative vitreoretinopathy? Graefes Arch Clin Exp Ophthalmol. 1996; 234(8):496-503.

21. Iverson DA, Katsura H, Hartzer MK, et al. Inhibition of intraocular fibrin formation following infusion of low-molecular-weight hepa-rin during vitrectomy. Arch Ophthalmol. 1991; 109(3):405-409.

22. Blumenkranz MS, Hartzer MK, Iverson D. An overview of poten-tial applications of heparin in vitreoretinal surgery. Retina 1992; 12(3 suppl):S71-74.

23. Asaria RH, Kon CH, Bunce C, et al. Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy: results from a randomized, double-blind, controlled clinical trial. Ophthalmology 2001; 108(7):1179-1183.

24. Lei H, Velez G, Cui J, et al. N-acetylcysteine suppresses retinal detachment in an experimental model of proliferative vitreoreti-nopathy. Am J Pathol. 2010; 177(1):132-140.

25. Liang CM, Tai MC, Chang YH, et al. Glucosamine inhibits epi-thelial-to-mesenchymal transition and migration of retinal pigment epithelium cells in culture and morphologic changes in a mouse


model of proliferative vitreoretinopathy. Acta Ophthalmol. Epub ahead of print 1 Apr 2011.

26. You J, Jiang D. [Effect of genistin on proliferative vitreoretinopa-thy]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2010; 35(7):749-753.

27. Wu WC, Wu MH, Chang YC, et al. Geldanamycin and its analog induce cytotoxicity in cultured human retinal pigment epithelial cells. Exp Eye Res. 2010; 91(2):211-219.

28. Kita T. [Molecular mechanisms of preretinal membrane contraction in proliferative vitreoretinal diseases and ROCK as a therapeutic target]. Nippon Ganka Gakkai Zasshi. 2010; 114(11):927-934.

29. Araiz JJ, Refojo MF, Arroyo MH, et al. Antiproliferative effect of retinoic acid in intravitreous silicone oil in an animal model of proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1993; 34(3):522-530.

30. Nakagawa M, Refojo MF, Marin JF, et al. Retinoic acid in silicone and silicone-fluorosilicone copolymer oils in a rabbit model of proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 1995; 36(12):2388-2395.

31. Dong X, Chen N, Xie L, et al. Prevention of experimental prolifera-tive vitreoretinopathy with a biodegradable intravitreal drug deliv-ery system of all-trans retinoic acid. Retina 2006; 26(2):210-213.

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34. Fekrat S, de Juan E Jr, Campochiaro PA. The effect of oral 13-cis-retinoic acid on retinal redetachment after surgical repair in eyes with proliferative vitreoretinopathy. Ophthalmology 1995; 102(3):412-418.

35. Chang YC, Hu DN, Wu WC. Effect of oral 13-cis-retinoic acid treatment on postoperative clinical outcome of eyes with prolifera-tive vitreoretinopathy. Am J Ophthalmol. 2008; 146(3):440-446.

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I. Incidence of Infection

A. Following cataract surgery

1. Endophthalmitis occurs in 0.1%-0.5% of cases following cataract surgery.

2. Most cases develop following routine surgery, though the incidence rises slightly when there is disruption of the posterior capsule and/or loss of lens particles into the vitreous.

B. Following vitrectomy surgery

1. Incidence of infection is incredibly low following routine 20-gauge sutured vitrectomy (< 0.05%), though with small gauge (23- or 25-gauge) surgery or sutureless 20-gauge surgery rates up to 1% have been reported. However, the cur-rent rate is much lower (Scott, Graefes Clin Exp Ophthalmol. 2011), in the range of 0.05% (Oshima, Am J Ophthalmol. 2010).

2. Strict attention to scleral wound creation and closure is essential in limiting the risk.

C. Following intravitreal injection

1. Incidence of infection is generally in the range of 0.1%, though reports as low as 0.009% have been reported (Cavalcante, Clin Ophthalmol. 2010).

2. Guidelines and recommendations have been pub-lished in an attempt to limit the risk of infection (Aiello, Retina 2004. See below).

II. Controversies in the Management of Endophthalmitis

A. Vitrectomy vs. vitreous tap

B. Choice of intravitreal antibiotics

C. Choice and role of intravenous antibiotics

D. Role of newer generation oral antibiotics

E. Role of intravitreal corticosteroids

F. Effect of systemic disease on outcomes

III. Endophthalmitis Vitrectomy Study (EVS)

A. Background

1. The EVS significantly aided our understanding and treatment of postoperative infection.

2. Controversies and unanswered questions do remain, however, and it is not possible to extra-polate results into other clinical settings (bleb-related infection, chronic infection, trauma).

B. Results

1. In the setting of postoperative infection, equal visual outcomes for vitrectomy vs. tap when

presenting vision HM or better (intravitreal van-comycin and amikacin, not ceftazidime)

2. No apparent benefit from the use of systemic intravenous antibiotics (cephalosporins, amino-glycosides)

C. Unresolved/changing issues

1. Choice of intravitreal and systemic antibiotics were the best available at the time.

2. Oral administration of fluoroquinolones was not studied in the EVS, though ciprofloxacin has subsequently been shown to penetrate into the vitreous cavity quite well with oral administra-tion.

3. Fourth-generation fluoroquinolones offer even better penetration into the eye (Hariprasad).

4. Intravitreal corticosteroids were not studied in the EVS, though the use of topical, periocular, and systemic corticosteroids was allowed.

D. Are the EVS results still pertinent?

Only about 31% of vitreoretinal specialists employ the recommendations of the EVS, with the main dif-ference being the modification of antibiotics that are employed.

IV. Fluoroquinolones and Bacterial Endophthalmitis

Fourth-generation fluoroquinolones (gatifloxacin, moxifloxacin, besafloxacin)

A. Better encompass the spectrum of organisms that are commonly encountered in the setting of postop-erative, bleb-related, traumatic, and indolent endo-phthalmitis

B. Better penetration into the eye in comparison to older types of antibiotics

C. When administered systemically, vitreous penetra-tion is very good with moxifloxacin (and previously with gatifloxacin as well).

D. When administered topically, there is reasonable penetration into the vitreous cavity with moxifloxa-cin and gatifloxacin, though the drops need to be given frequently (six times/day) (Hariprasad, Arch Ophthalmol. 2005).

E. Moxifloxacin is rarely employed intravitreally, though studies have shown good safety (Gao, Invest Ophthalmol Vis Sci. 2006).

F. Complications include a uveitis-like syndrome with possible iris sphincter paralysis, and the possibility of MRSA resistance (Major and Flynn, Am J Oph-thalmol. 2010).

Endophthalmitis Update 2011William F Mieler MD


V. General Management

A. Outpatient surgery

B. Vitrectomy or vitreous tap with intravitreal antibi-otic injection (vancomycin 1.0 mg and ceftazidime 2.25 mg)

C. Topical over-the-counter fluoroquinolones q.i.d., topical corticosteroids, and oral moxifloxacin 400 mg/day for 5 to 7 days

D. The need for repeat intravitreal antibiotic injection is very rare.

VI. Intravitreal Injections

A. Prophylaxis against infection, with a rate of approx-imately 0.1%

1. Extensive debate and controversy regarding tech-niques for an intravitreal injections

2. No proven benefit regarding pre-procedure topi-cal antibiotics or the use of post-procedure anti-biotics

3. Panel led by Aiello (Retina 2004) reported on recommendations for prophylaxis.

B. Areas of strong agreement

1. Use povidone iodine for ocular surface, eyelids, and eye lashes.

2. Use speculum and avoid contamination of the needle with eye lashes or eyelid margin.

3. Avoid extensive massage of eyelids either pre- or postinjection (to avoid expressing meibomian glands).

4. Avoid injecting patients who have active eyelid or ocular adnexal infection.

5. Dilate eye.

6. Use adequate anesthetic for each patient (topical drops and/or subconjunctival injection).

7. Avoid prophylactic or post-injection paracentesis.

C. Areas with no consensus

1. Most did not recommend a povidone iodine flush, rather preferred drops; and there was no benefit attributed to drying.

2. Most did not use a sterile drape.

3. Most advocated use of gloves.

4. Use of pre- or postinjection antibiotics: Paucity of published scientific data to support reduction in endophthalmitis

5. IOP check following injection: No consensus on IOP level at which physicians are comfortable to discharge patient

6. No consensus about patient competency to self-report signs and symptoms of endophthalmitis or other adverse events; no consensus on the need for clinical follow-up exam vs. telephone inter-change with physician or nurse

VII. Fungal Endophthalmitis

A. Amphotericin

1. Antifungal agent that acts by alteration of mem-brane permeability by combination with sterols and fungal cytoplasmic membranes

2. Significant systemic toxicity (renal) and potential ocular toxicity

3. Limited applicability

B. Voriconazole

1. Oral administration (400 mg daily)

2. Available for treatment of systemic fungal infec-tions with a broad spectrum of activity

C. Rodent model study

1. Injected up to 1000-fold (10x, 100x, 500x, and 1000x) the MIC level of antibiotic in a rat model (500 μg/ml)

2. No evidence of ERG abnormalities (up to 500 μg/ml), though focal areas of retinal necrosis in the outer retina were seen in eyes treated with 50 to 500 μg/ml.

3. Appears to be safe up to 25 μg/ml

D. Clinical study

1. Excellent penetration into the vitreous cavity with a single oral 400-mg tablet of medication

2. Mean inhibitory vitreous and aqueous MIC90 levels were achieved against a wide spectrum of yeasts, molds, and fungi including Aspergillus species, Candida species, and many others

3. Fusarium not adequately covered by oral admin-istration alone.

E. Summary (Voriconazole)

1. Voriconazole has a broad spectrum of coverage, low MIC90 levels for the organisms of concern, good tolerability, and excellent bioavailability with oral administration.

2. Voriconazole represents a significant advance in the management of fungal endophthalmitis.

VIII. Intravitreal Corticosteroids

A. Potential benefits

1. Inhibit macrophage and neutrophil migration and leakage of proteins and fluid into the area of inflammation

2. Reduce capillary permeability and maintain good vascular tone

3. Stabilize lysosomal membrane (inhibit degranu-lation of white blood cells)

4. Block release of inflammatory mediators (hista-mine, bradykinin)

5. Inhibit prostaglandin production by inhibiting phospholipase A2


B. Rationale for use

1. Immediate, highest possible concentration deliv-ered to target site

2. Injection performed at the same time as the intra-vitreal antibiotic injection

3. Minimal concern regarding systemic complica-tions, and no concern regarding compliance

4. No concerns of noncompliance

C. Summary of literature provides mild evidence for benefit from intravitreal and/or systemic routes of administration.

1. Benefit may be strain- and/or organism-depen-dent, or dependent upon the timing of adminis-tration within the course of the infection.

2. Clinical and experimental evidence suggests that corticosteroids must be given early in the disease.

3. Not employed in the EVS

4. Recommendation for use is dependent upon the discretion of the individual physician.

D. Clinical studies

1. Das (Br J Ophthalmol. 1999) performed a ran-domized, prospective study involving 63 patients (postoperative and post-traumatic) and con-cluded that corticosteroids helped in early reduc-tion of inflammation but had no independent influence on visual outcome.

2. Shah (Ophthalmology 2000) in a retrospec-tive, nonrandomized study of 57 postoperative patients noted that patients who received corti-costeroids had a reduced likelihood of obtaining a 3-line improvement in visual acuity.

3. Dev, Mieler, Han, Pulido, Connor (Eur J Oph-thalmol. 2004) reported in a retrospective study of 42 patients that there was no apparent benefit or harm from the use of intravitreal corticoste-roids.

IX. Effect of Systemic Diseases: Clinical Studies

A. Patients who have another systemic disease gener-ally do not handle a second stressful event as well.

B. In the EVS in patients with diabetes, there was a trend toward better visual outcomes with complete vitrectomy at all levels of presenting vision.

X. Prevention of Endophthalmitis in Cataract Surgery

A. General approaches

1. Antibiotics in infusion solutions

2. Intracameral antibiotics

3. Lenses coated with sustained-release antibiotics

4. Subconjunctival sustained-release devices

5. Control of potential nasal contamination

B. Antibiotics in infusion solutions

1. Numerous previous studies assessing the effect of vancomycin and/or gentamicin added to the infu-sion bottle

2. Sample size generally not adequate to determine a true benefit

3. Appears to decrease the risk of aqueous contami-nation, though impact on development of infec-tion not entirely clear

4. Not extensively employed today

C. Intracameral antibiotics

1. ESCRS (2006) published the results of intra-cameral cefuroxime, showing a nearly 5-fold decrease in the rate of postoperative endophthal-mitis.

2. Study generated considerable controversy.

3. The rate of infection was substantially higher than the generally accepted norms.

4. In 2007, between 6% and 23% of the member-ship of the ASCRS were employing the ESCRS recommendations (Chang, J Cat Refract Surg. 2007).

5. In 2009, 55% of the members of the ESCRS were using intracameral cefuroxime (Gore, J Cat Refract Surg. 2009).

6. Concerns remained regarding flaws in the base-line study (no subconjunctival cefuroxime con-trol arm), a lack of a commercial supplier, and potential dilutional errors in the mixing of the antibiotic all led to a lessened rate of use.

7. Garat (J Cat Refract Surg. 2009) reported in a study of 18,579 patients that a 2.5-mg intracam-eral bolus of cefuroxime reduced the incidence of infection from 0.422% to 0.047%, a relative risk reduction of 88%.

8. Diez (Arch Soc Esp Oftalmol. 2009) reported a study of 4281 eyes, where 1.0 mg of cefuroxime was utilized. The rate of infection dropped to 0.11%.

9. Yu-Wai-Man (J Cat Refract Surg. 2008) reported a comparison study of intracameral vs. subconjunctival cefuroxime in a study of 36,743 patients. Intracameral cefuroxime had a lower rate of infection, with an odds ratio of 3.01 (95% CI, 1.37-6.63).

10. Report by Sharifi (Ophthalmology 2009) docu-mented cost-effectiveness ratio for intracameral cefuroxime as $1403 per case of postoperative endophthalmitis that is prevented. Topical gati-floxacin and/or moxifloxacin would have to be > 19 times more effective to be cost-effective.

XI. Summary

A. Risk of infection is approximately 0.1% for cataract surgery, 3%-7% for open-globe injuries, 7%-13% for eyes with retained intraocular foreign bodies, and 0.1% for intravitreal injections.


B. Considerable improvement in the treatment of endophthalmitis, particularly in the realm of new antimicrobial therapy

C. Intravitreal antibiotics continue to play the key role in the successful treatment of endophthalmitis.

D. Role of orally administered antibiotics (fluoroqui-nolones) is likely to continue to expand.

E. Virtually all cases of infection are now treated in the outpatient setting, making the use of adjunctive oral antibiotic therapy even more attractive.

F. Voriconazole offers dramatic improvement in the treatment of the majority of fungal infections.

G. Role of intravitreal corticosteroids remains contro-versial at the present time.

H. Prophylaxis against infection in the setting of intra-vitreal injections remains controversial, though povidone iodine lid scrub is the best measure in lim-iting the development of infection.

I. Instillation of intracameral antibiotics in eyes under-going cataract surgery is quite common, though how much of a risk reduction it leads to is widely debated.

References

1. Mieler WF, Ellis MK, Williams DF, et al. Retained intraocular for-eign bodies and endophthalmitis. Ophthalmology 1990; 97:1532-1538.

2. Keren G, Alhalel A, Barrov E, et al. The intravitreal penetration of orally administered ciprofloxacin in humans. Invest Ophthalmol Vis Sci. 1991; 32:2388-2392.

3. Aguilar HE, Meredith TA, Shaarawy A, et al. Vitreous cavity pen-etration of ceftazidime after intravenous administration. Retina 1995; 15:154-159.

4. Endophthalmitis Vitrectomy Study Group. Results of the Endo-phthalmitis Vitrectomy Study: a randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol. 1995; 113:1479-1496.

5. Han DP, Wisniewski SR, Wilson LA, et al. Spectrum and suscepti-bilities of microbiologic isolates in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1996; 122:1-17.

6. Sabo JA, Abdel-Rahman SM. Voriconazole: a new triazole antifun-gal. Ann Pharmacother. 2000; 34:1032-1043.

7. Garcia-Saenz MC, Arias-Puente A, Fresnadillo-Martinez MJ, et al. Human aqueous humor levels of oral ciprofloxacin, levofloxacin, and moxifloxacin. J Cataract Refract Surg. 2001; 27:1969-1974.

8. Mattoes HM, Banevicius M, Li D, et al. Pharmacodynamic assess-ment of gatifloxacin against Streptococcus pneumoniae. Antimi-crob Agents Chemother. 2001; 45:2092-2097.

9. Mather R, Karanchak LM, Romanowski EG, et al. Fourth genera-tion fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002; 133:463-466.

10. Zhou L, Glickman RD, Chen R, et al. Determination of voricon-azole in aqueous humor by liquid chromatography-electrospray ionization-mass spectrometry. J Chromatogr. 2002; 776:213-220.

11. Hariprasad SM, Mieler WF, Holz ER. Vitreous and aqueous pen-etration of orally administered gatifloxacin in humans. Arch Oph-thalmol. 2003; 121:345-350.

12. Kowalski RP, Dhaliwal DK, Karanchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Opthhalmol. 2003; 136:500-505.

13. Gao H, Pennesi M, Shah K, Qiao X, Hariprasad SM, Mieler WF, Wu SM, Holz ER. Retinal toxicity of a new antifungal agent vori-conazole-electroretinographic and histopathologic study. Trans Am Ophthlamol Soc. 2003; CI:183-190.

14. Hariprasad SM, Mieler WF, Prince RA, Holz ER, Kim JE. Deter-mination of vitreous, aqueous, and plasma concentrations of orally administered voriconazole in humans. Arch Ophthlamol. 2004; 122:42-47.

15. Hariprasad SM, Mieler WF, Shah GK, et al. Human intraocular penetration pharmacokinetics of moxifloxacin 0.5% via topical and collagen shield routes of administration. Trans Am Ophthalmol Soc. 2004; 102:149-157.

16. Hariprasad SM, Blinder KJ, Shah GK, Apte RS, Rosenblatt B, Holekamp NM, Grand MG, Thomas MA, Mieler WF, Chi J, Prince RA. Human aqueous and vitreous penetration pharmacokinetics of topically administered moxifloxacin 0.5% ophthalmic solution. Arch Ophthalmol. 2005; 123:39-44.

17. Breit SM, Hariprasad SM, Mieler WF, Shah GK, Mills MD, Grand MG. Management of endogenous fungal endophthalmitis using voriconazole and caspofungin. Am J Ophthalmol. 2005; 139:135-140.

18. Hariprasad SM, Shah GK, Mieler WF, et al. Vitreous and aqueous penetration of orally administered moxifloxacin in humans. Arch Ophthalmol. 2006; 124:178-182.

19. Gao H, Pennesi ME, Qioa X, Iyer MN, Wu SM, Holz ER, Mieler WF. Intravitreal moxifloxacin: retinal safety study with electroreti-nography and histopathology in animal models. Invest Ophthalmol Vis Sci. 2006; 47:1601-1611.

20. Alexandrou TJ, Hariprasad SM, Benevento J, Rubin MP, Saidel M, Ksiazek S, Thompson K, Boonlayangoor S, Mieler WF. Reduction of preoperative conjunctival bacterial flora with the use of mupi-rocin nasal ointment. Trans Am Ophthalmol Soc. 2006; 104:196-201.

21. Bahrani HM, Fazelat AA, Thomas M, et al. Endophthalmitis in the era of small gauge transconjunctival sutureless vitrectomy-meta analysis and review of the literature. Semin Ophthalmol. 2010; 25:275-282.

22. George JM, Friscella R, Blair M, et al. Aqueous and vitreous pen-etration of linezolid and levofloxacin after oral administration. J Ocul Pharmacol Ther. 2010; 26:579-586.

23. Shah CP, Garg SJ, Vander JF, Brown GC, Kaiser RS, Haller JA. Post-Injection Endophthalmitis (PIE) Study: outcomes and risk fac-tors associated with endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmology. Epub ahead of print, 25 June 2011.

24. Spierer O, Siminovsky Z, Loewenstein A, Barak A. Outcomes of 20-gauge transconjunctival sutureless vitrectomy. Retina. Epub ahead of print 20 May 2011.

25. Raizman MB. Determining the role for antibiotics in the prevention of endophthalmitis after cataract surgery. Arch Ophthalmol. 2011; 129:501-502.

26. Lauschke JL, Singh R, Wei M, et al. Factors influencing the inci-dence of postoperative endophthalmitis. Am J Ophthalmol. 2011; 151:732.


27. Albrecht E, Richards JC, Pollock T, Cook C, Myers L. Adjunctive use of intravitreal dexamethasone in presumed bacterial endo-phthalmitis: a randomized trial. Br J Ophthalmol. Epub ahead of print 2 Febr 2011.

28. Scott IU, Flynn HW Jr, Acar N, et al. Incidence of endophthalmitis after 20-gauge vs 23-gauge vs 25-gauge pars plana vitrectomy. Graefes Arch Clin Exp Ophthalmol. 2011; 249:377-380.

29. Murjaneh S, Waqar S, Hale JE, Kasmiya M, Jacob J, Quinn AG. National survey of the use of intraoperative antibiotics for pro-phylaxis against postoperative endophthalmitis following cataract surgery in the UK. Br J Ophthalmol. 2010; 94:1410-1411.


Scientific advisory group: David Boyer MD, Los Angeles, CA; Patrick Coady MD, San Francisco, CA; Neil Friedman MD, Palo Alto, CA; Bailey Freund MD, New York, NY; Anne Fung MD, San Francisco, CA; Jeffrey Heier MD, Boston, MA; Eitan Joffe BSc, Palo Alto, CA; Philip Rosenfeld MD, Miami, FL; Lawrence Singerman MD, Cleveland, OH; George Williams MD, Royal Oak, MI

Introduction

With the wide utilization of digital media, including tablet com-puters, smart phones, and ebooks, there is a need to quantify the effects of macular disease on reading performance. Fifteen million iPads were sold in 2010, another 8 million in 2011 as of May 1,1 and in excess of 4 million Kindle readers. Nearly twice as many books are sold electronically as in conventional format on Amazon.2 In addition to these larger format reading devices, approximately 75 million people in the United States use smart phones, with Android-operated phones constituting approxi-mately 36% of the market and iPhones another 26%. These devices are commonly used not only to initiate and receive tele-phone calls but to read email, browse the internet, and accom-plish a variety of reading tasks.3

The digital media revolution necessitates examination of the differences, if any, between conventional printed material and a variety of electronic display devices in terms of their effects on reading performance for patients with normal vision as well as those with reduced visual acuity (VA) due to retinal diseases.

Potential Contributions to Retinal Disease Management

There also exists an opportunity to utilize the widespread avail-ability of telecommunication-enabled personal reading devices and smart phones for the measurement of VA in physicians’ offices, as well as self-administered tests by patients away from the office. With the recent demonstration by the CATT trial5 that p.r.n. dosing of either Lucentis or Avastin was not statisti-cally inferior to monthly dosing with either of those agents, it has became critically important to determine the criteria by which p.r.n. dosing is implemented. Currently it consists of the measurement of VA in the office, in addition to anatomic data obtained by color fundus photography, angiography, and OCT examination. With valid reproducible psychophysical data avail-able from patients tested at home much more frequently than the current monthly office visits, it might be possible to optimize the treatment with anti-VEGF agents according to symptoms and visual performance, provided that information could be reliably and securely transmitted to physicians. Home testing by prefer-ential hyperacuity perimetry on a specially designed fixed device has been suggested as one such potential solution.6

Methods

Thirty consecutive patients with macular disease and vision better than 20/400 and 20 normal controls were recruited. Their distance VA was measured in both eyes with ETDRS let-ter charts at 4 meters. Near vision was measured at a distance of 14 inches under standardized illumination conditions using a Rosenbaum chart and iPhone (Apple Computer, Cupertino, CA, www.apple.com) equipped with specially designed software (Digisight Technologies, Palo Alto, CA, www.digisight.net). In addition, the VA on the iPhone was compared for red and blue fonts, and for normal contrast (black fonts on white back-ground) and inverse (white fonts on black background) contrast. Statistical methods were employed to compare various measures of visual function.

Results

ETDRS distance vision correlated well with the Rosenbaum near card, with a Pearson correlation coefficient of 0.83. There was slightly better VA in the near vision: average difference was -0.06 logMAR (P < .001).

The iPhone screen displaying black fonts on a white back-ground had better readability of equally sized letters than printed fonts on the Rosenbaum card. The average difference between the VA with iPhone and VA with the printed card was -0.17 logMAR—just under 2 lines. The result was highly statistically significant (P = 5x10-10). By decreasing the font size on the LCD screen, it was possible to normalize these results and provide equivalent VA to that of the Rosenbaum card. Pearson correla-tion coefficient between the corrected fonts and the Rosenbaum card was 0.85.

We investigated differences in the ability to read comparably sized red and blue letters on a black background as a possible means of better discriminating patients with abnormal macular function. Patients with normal eyes showed no difference in the VA with red vs. blue letters on a black background. In contrast, VA with blue fonts on a black background was slightly worse (0.07 logMAR units) than red fonts on a black background for patients with macular disease at a statistically significant level (P < .02).

VA with black letters on a white background and white let-ters on black background appeared the same. VA did not change significantly when screen contrast was decreased from 1 to 0.25. However, the test of contrast sensitivity with white letters on black background was found more discriminating than with the normal (black on white) contrast.

The Future: Options for Active Disease Management

The availability of telecommunication-enabled reading devices opens the door to the possibility of remote home monitoring

New Developments in LCD Display for Visual Acuity and Reading MetricsAssessment and Optimization of Visual Performance and Anti-VEGF Retinal Treatment Paradigms Employing Quantitative Vision Testing With Smart Phones

Mark Blumenkranz MD, Daniel Palanker PhD

http://www.apple.com

http://www.digisight.net


of VA and other visual functions in patients who are at high risk for loss of vision due to pre-existing conditions such as a disciform lesion in one eye, large drusen, or nonproliferative diabetic retinopathy. They may also aid in monitoring patients with AMD with regard to their response to and need for addi-tional therapy, if already under treatment with anti-VEGF agents. These data can be accurately and reproducibly collected by patients at home using smart phone–like devices, with their results stored and automatically transmitted to a central server using cloud-based computing. This information can then be accessed via a website, either by patients, or their physicians if given prior authorization by the patients, in a HIPPA compliant fashion. The data can be aggregated, analyzed, and reported in a HIPPA compliant cloud-based computer environment. Organized data accessible via a website to the patient and physi-cian with data analysis and automatic notification features also opens the door to a novel and enhanced electronic personal health record for ophthalmology.

References

1. Wikipedia entry on “IPad.” Available at: http://en.wikipedia.org/wiki/ipad. Accessed July 4, 2011.

2. Perenson MJ. Amazon Kindle book sales soar. PC World, Jan. 27, 2011.

3. Albanesius C. Nintendo 3DS update adding eShop, web browser. PC Magazine/Yahoo News, June 3, 2011.

4. Google News. December 9, 2010.

5. CATT Research Group, Martin DF, Maguire MG, Ying GS, et al. Ranibizumab and Bevacizumab for neovascular age related macular degeneration. N Engl J Med. 2011; 364(20):1897-1908.

6. Lowenstein A. The significance of early detection of age related macular degeneration. Retina 2007; 27:873-878.

7. Ferris FL, Sperduto R. Standardized illumination for visual acuity testing in clinical research. Am J Ophthalmol. 1982; 94:97-98.

8. Wang J, Langer S. A brief review of human perception factors in digital displays for picture archiving and communication systems. J Digit Imaging. 1997; 10:158-168.

http://en.wikipedia.org/wiki/ipad

http://en.wikipedia.org/wiki/ipad

2011 Subspecialty Day | Retina 151

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• 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

152 2011 Subspecialty Day | Retina

2011 Retina Planning Group Financial Disclosures

Allen C Ho MDAlcon Laboratories, Inc.: C,L,SCentocor, Inc.: C,SGenentech: C,L,SGlaxoSmithKline: SMerck & Co., Inc.: CNEI/NIH: SNeovista: C,SOphthotech: C,SOraya: CPaloma: CPRN: C,O,SQLT Phototherapeutics, Inc.: C,SRegeneron: C,SSecond Sight: SThrombogenics: C,L

Joan W Miller MDAlcon Laboratories, Inc.: C,OQLT Phototherapeutics, Inc.: P

Tarek S Hassan MDArctic Dx: C,L,OBausch + Lomb Surgical: C,LEyetech, Inc.: CGenentech, Inc.: C,LInsight Instruments: C,LOptimedica: C,OSynergetics, Inc.: L

Peter K Kaiser MDAlcon Laboratories, Inc.: C,LAllergan, Inc.: C,SArcticDx: C,OBausch + Lomb Surgical: CCarl Zeiss Meditec: LCleveland Clinic Foundation: EGenentech: C,SGlaxoSmithKline: C,SHeidelberg Engineering: CNovartis Pharmaceuticals Corp.: C,L,SOphthotech: C,L,OOptovue: LOraya: C,OTopcon Medical Systems: L

AAO Staff

Ann L’EstrangeNone

Melanie RafatyNone

Debra RosencranceNone


Faculty Financial Disclosures

Gary W Abrams MDAlcon Laboratories, Inc.: C

David H Abramson MD FACSNone

Nur Acar MDNone

Lloyd P Aiello MD PhDAbbott Medical Optics: C Allergan, Inc.: L Eli Lilly & Co.: C,L Eyetech, Inc.: C Genentech: C Genzyme: C GlaxoSmithKline: C Lumenis, Inc.: C Merck & Co., Inc.: C Novartis Pharmaceuticals Corp.: C Optos, Inc.: S Pfizer, Inc.: C Thrombogenetics: C

J Fernando Arevalo MD FACSNone

Albert J Augustin MDAlcon Laboratories, Inc.: C,L Allergan, Inc.: C,L Carl Ziess Meditec: L

Robert L Avery MDAlcon Laboratories, Inc.: C,L Allergan, Inc.: C Genentech: C,L,S Iridex: C Novartis Pharmaceuticals Corp.: C,O QLT Phototherapeutics, Inc.: C Replenish: C,O,P

Marcos P Avila MDNone

Carl C Awh MDNone

Francesco M Bandello MD FEBOAlcon Laboratories, Inc.: C Allergan, Inc.: C Bausch + Lomb Surgical: C Bayer Schering Pharma: C Farmila-Thea Pharmaceuticals: C Novartis Pharmaceuticals Corp.: C Pfizer, Inc.: C

Alay S Banker MDNone

Rubens Belfort Jr MD PhDAlcon Laboratories, Inc.: C,L,S Allergan, Inc.: C,L,S

Audina M Berrocal MDNone

Maria H Berrocal MDAlcon Laboratories, Inc.: C,L Alimera: C

Robert B Bhisitkul MDActiveSight Pharmaceuticals, Inc.: C Allergan, Inc.: L Genentech: L,S Santen, Inc.: C Structus Medical O,P

Susanne Binder MDNone

Mark S Blumenkranz MDAvalanche Biotechnology: O,P Digisight: O Ista Pharmaceuticals: C Optimedica: O,P Vantage Surgical: C,O

Francesco Boscia MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Novartis Pharmaceuticals Corp.: C

David S Boyer MDAlcon Laboratories, Inc.: C,L Allergan, Inc.: C,L Eyetech, Inc.: C Genentech: C,L Novartis Pharmaceuticals Corp.: C,L Optos, Inc.: C Pfizer, Inc.: C,L Regeneron: CScienceBased Health: C

Neil M Bressler MDAbbott Medical Optics Inc.: S Alimera Sciences: S Allergan USA: S Bausch + Lomb, Inc.: S Carl Zeiss Meditec, 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 QLT Inc.: S RegeneronPharmaceuticals,Inc.: SSteba Biotech S.A.: S The Emmes Corporation: S

Susan B Bressler MDBausch + Lomb Surgical: S Genentech: S GlaxoSmithKline: C Notal Vision: S Novartis Pharmaceuticals Corp.: S Regeneron: S

David M Brown MD FACSAlcon 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 Pfizer, Inc.: C Regeneron: C,L

Gary C Brown MDAllergan, Inc.: S Center For Value Based Medicine O Genentech: S

Alexander J Brucker MDAlcon Laboratories, Inc. S Escalon Medical Corp O GENENTECH S GlaxoSmithKline S National Eye Institute S Neurovision O Novartis Pharmaceuticals

Corporation S Ophthotech C,O OPKO O Optimedica O

154 Faculty Financial Disclosures 2011 Subspecialty Day | Retina

Peter A Campochiaro MDAlcon Laboratories, Inc.: S Alimera: S Allergan, Inc.: C Amira: C Genentech: C,S Genezyme: S GlaxoSmithKline: C,S Lpath Inc.: C Oxford BioMedica: S

Antonio Capone Jr MDAlcon Laboratories, Inc.: C Alimera Sciences: C Allergan, Inc.: C,S FocusROP,LLC: O,PGlaxoSmithKline: S Ophthotec: S RetinalSolutions,LLC: O,PThrombogenics: S

Jose A Cardillo MDNone

R V Paul Chan MDNone

Stanley Chang MDAlcon Laboratories, Inc.: C,P Alimera Sciences: C

Steven T Charles MDAlcon Laboratories, Inc.: C,P Topcon Medical Systems: C,P

Emily Y Chew MDNone

N H Victor Chong MDAlcon Laboratories, Inc.: S Allergan: C 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: C Synergetics, Inc.: C

Mina Chung MDNone

Carl C Claes MDAlcon Laboratories, Inc.: C,L

W Lloyd Clark MDNone

Emmett T Cunningham Jr MD PhD MPHNone

Donald J D’Amico MDOphthotech, Inc.: C,O Optimedica, Inc.: C,O

Janet Louise Davis MDCentocor, Inc.: C Novartis Pharmaceuticals Corp.: C Santen, Inc.: S

Eugene De Juan Jr MDBausch + Lomb Surgical: P ForSight Labs: E,O Genentech: P Iridex: O,P NexisVision: C,O Second Sight: C,O,P Synergetics, Inc.: P Transcend Medical: C,O Vision 4: C,O

Diana V Do MDBausch + Lomb Surgical: C Genentech: S Heidelberg Engineering: S Regeneron: SSanten, Inc.: C

Kimberly A Drenser MD PhDAllergan: C FocusROP: 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 Hemera Biosciences: O Merck & Co., Inc.: C NeoVista: C Novartis Pharmaceuticals Corp.: C Ophthotech: C OptiVue: S Paloma Pharmaceuticals: C Serono: C Topcon Medical Systems: S

Claus Eckardt MDDORCInternational,bv/Dutch

Ophthalmic, USA: P

Justis P Ehlers MDNone

Ehab N El Rayes MDNone

Dean Eliott MDAlcon Laboratories, Inc.: L Bausch + Lomb Surgical: C Genentech: L Glaukos Corp.: C National Eye Institute: S Second Sight: S

Frederick L Ferris MDBausch + Lomb Surgical: P

Marta Figueroa MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Novartis Pharmaceuticals Corp.: C

Mitchell S Fineman MDPRN: C,E,O

Yale L Fisher MDNone

Harry W Flynn Jr MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Pfizer, Inc.: C Santen, Inc.: C

K Bailey Freund MDAlcon Laboratories, Inc.: C Alimera: C Genentech: C

Thomas R Friberg MDEyetech, Inc.: C Genentech: C Optos, Inc.: C

Anne E Fung MDGenentech: C,L,S Santen, Inc.: C

Brenda L Gallie MDSolutions by Sequence: O

Sunir J Garg MD FACSAlcon Laboratories, Inc.: L,S Allergan, Inc.: C Genentech: S Neovista: S

Alain Gaudric MDAlcon Laboratories, Inc.: S Allergan, Inc.: C,S Carl Zeiss Meditec: L Novartis Pharmaceuticals Corp.: C,S Thrombogenics: C

2011 Subspecialty Day | Retina Faculty Financial Disclosures 155

Evangelos S Gragoudas MDNone

M Gilbert Grand MDNone

Julia A Haller MDAllergan, Inc.: C Genentech: C Optimedica O Thrombogenics: C

Dennis P Han MDAlcon Laboratories, Inc.: C Allergan, Inc.: S Genentech: S

J William Harbour MDCastle Biosciences: P

Christos Haritoglou MDAllergan: L

Tarek S Hassan MDArctic Dx: C,L,O Bausch + Lomb Surgical: C,L Eyetech, Inc.: C Genentech: C,L Insight Instruments: C,L Optimedica: C,O Synergetics, Inc.: L

Jeffrey S Heier MDAcucela: C Alcon Laboratories, Inc.: C,S Alimera: C,S Allergan, Inc.: C,S Apeliotus Vision Science: C Endo Optiks, Inc.: C Forsight Labs: C Fovea: C Genentech: C,S Genzyme: S GlaxoSmithKline: C,S Heidelberg Engineering: C Kanghong Biotech: C Lpath Inc.: C Molecular Partners: S NeoVista, Inc.: C,S Neurotech, Inc.: C,S Novagali: C Novartis Pharmaceuticals Corp.: C,S Ophthotech: S Oraya Therapeutics: C Paloma, Inc.: C,S Regeneron: C,SRevisionTherapeutics: CScheringPloughResearchInstitute: CSequenom: C VisionCare Ophthalmic

Technologies: C

Allen C Ho MDAlcon Laboratories, Inc.: C,L,S Centocor, Inc.: C,S Genentech: C,L,S GlaxoSmithKline: S Merck & Co., Inc.: C NEI/NIH: SNeovista: C,S Ophthotech: C,S Oraya: C Paloma: C PRN: C,O,SQLT Phototherapeutics, Inc.: C,S Regeneron: C,SSecond Sight: S Thrombogenics: C,L

Joe G Hollyfield PhDNone

Frank G Holz MDAcucela: C Bayer Healthcare: C,L Carl Zeiss Meditec: C,S Genentech: C Heidelberg Engineering: C,L,S Novartis Pharmaceuticals Corp.: C,L Ophthotec: C Optos, Inc.: S Pfizer, Inc.: C

Suber S Huang MD MBAAmerican Academy of Family

Physicians: L American Academy of

Ophthalmology: LAmericanRetinaFoundation: LBausch + Lomb Surgical: C DiabeticRetinopathyClinicalNetwork

(DRCR): LDigital Healtcare, Inc.: O i2i Innovative Ideas, Inc.: O NEHEP/NEI/NIH: LNotal Vision: C,O Philip F and Elizabeth G Searle

Chair: E RetinalDiseasesImageAnalysisReading

Center(REDIARC): C,LSecond Sight: C SurModics, Inc.: C University Hospitals Eye Institute: E

G Baker Hubbard MDNone

Mark S Humayun MD PhDBausch + Lomb Surgical: C,L,O,P,S Reichert: L,SReplenish: C,O,P,SSecond Sight: C,L,O,P,S

Tomohiro Iida MDNone

Michael S Ip MDAllergan, Inc.: S Genentech: C NicOx: C QLT Phototherapeutics, Inc.: C Regeneron: CSirion: C

Mary Lou Jackson MDOptelec USA: S

Glenn J Jaffe MDAbbott Laboratories: C Heidelberg Engineering: C Johnson & Johnson Consumer &

Personal Products Worldwide: C Neurotech USA: C Novartis Pharmaceuticals Corp.: C SurModics, Inc.: C

Mark W Johnson MDOphthotech: C Oraya: C Regeneron: SThrombogenics: S

Peter K Kaiser MDAlcon Laboratories, Inc.: C,L Allergan, Inc.: C,S ArcticDx: C,O Bausch + Lomb Surgical: C Carl Zeiss Meditec: L Cleveland Clinic Foundation: E Genentech: C,S GlaxoSmithKline: C,S Heidelberg Engineering: C Novartis Pharmaceuticals Corp.: C,L,S Ophthotech: C,L,O Optovue: L Oraya: C,O Topcon Medical Systems: L

Richard S Kaiser MDAlimera: C Neovista: C,O, Ophthotech: C,O,

John H Kempen MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Eyegate: S National Eye Institute: S ResearchtoPreventBlindness: SUniversity of Pennsylvania: E

Ivana K Kim MDGenentech: S Regeneron: C


Frank H Koch MDInsight Instruments, Inc.: C VRmagic: C

Adrian H Koh MDAllergan: C Carl Ziess Meditec: C,L Novartis Pharmaceuticals Corp.: C,L,S

Baruch D Kuppermann MD PhDAlimera: S 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 Othera Pharmaceuticals, Inc.: S Regeneron: SThromobogenics: S VitreoRetinalTechnologies: C

Jennifer Irene Lim MDGenentech: L,SIcon Bioscience: SQuark: C Regeneron: C,S

Livia R Lumbroso-Le Rouic MDNone

Albert M Maguire MDNone

Andre Maia MDNone

Daniel F Martin MDNone

H Richard McDonald MDOphthotech: C

William F Mieler MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Genentech: C

Joan W Miller MDAlcon Laboratories, Inc.: C,O QLT Phototherapeutics, Inc.: P

Paul Mitchell MD PhDAllergan, Inc.: C,L Bayer Pharmaceuticals: C,L Novartis Pharmaceuticals Corp.: C,L Pfizer, Inc.: L

Virgilio Morales-Canton MDOraya Therapeutics: C,L

Shizuo Mukai MDNone

Timothy G Murray MDNone

Quan Dong Nguyen MDAbbott Pharmaceuticals, Inc.: S Bausch + Lomb Surgical: CGenentech: SHeidelberg Engineering: SLux Biosciences, Inc.: S Pfizer, Inc.: SRegeneronPharmaceuticals,Inc.: SSanten, Inc.: C,S

Joan M O’Brien MDNone

Masahito Ohji MDAlcon Laboratories, Inc.: C,L Novartis Pharmaceuticals Corp.: C,L Pfizer, Inc.: C,L Sanwa Kagaku Kenkyusho: C Shionogi: C

Annabelle A Okada MDGlaxoSmithKline: C Mitsubishi Tanabe Pharma: L,S Novartis Pharma Japan: L Novartis Pharmaceuticals Corp.: C Pfizer Japan: L Senju Pharmaceutical Corp.: L

Timothy W Olsen MDDobbs Foundation: S Emtech Biotechnology Development

Grant: S GeorgiaResearchAlliance: SNIH/NEI: SNIH/NIA: SResearchtoPreventBlindness: S

Yusuke Oshima MDCarl Zeiss Meditec: L DORCInternational,bv/Dutch

Ophthalmic, USA: L Santen, Inc.: L Topcon Medical Systems: C

Andrew J Packer MD Allergan, Inc.: C,

Kirk H Packo MDAlcon Laboratories, Inc.: C,L,S Alimera Sciences: C Genentech: S OD-OS, Inc.: C,S Optos, Inc.: S Slack, Inc.: L,S

David W Parke II MDOMIC-Ophthalmic Mutual Insurance

Company: C

Dante Pieramici MDAlimera: C,L Genentech: C,L,S Thrombogenics: S

John S Pollack MDAbbott Medical Optics: C Alcon Laboratories, Inc.: C Clarus Acuity Group O

Jonathan L Prenner MDAlimera: C Neovista: C,O Ophthotech: C,L,O

Carmen A Puliafito MD MBAHumphrey Zeiss: P

Franco M Recchia MDAlcon Laboratories, Inc.: C Allergan, Inc.: C Genentech: S Thrombogenics: C

Carl D Regillo MD FACSAlcon Laboratories, Inc.: C,S Allergan: C,S Genentech: C,S GlaxoSmithKline: C,S Lpath, Inc.: S Novartis Pharmaceuticals Corp.: C,S QLT Phototherapeutics, Inc.: C,S Second Sight: S

Elias Reichel MDAkorn Inc.: P Allergan, Inc.: C Eyetech, Inc.: C Genentech: C GlaxoSmithKline: C Ocular Instruments, Inc.: P

Kourous Rezaei MDAlcon Laboratories, Inc.: C,L,S Eyetech, Inc.: C Genentech: L,S

William L Rich MDNone

Stanislao Rizzo MDAlcon Laboratories, Inc.: L iScience: L Novartis Pharmaceuticals Corp.: L

2011 Subspecialty Day | Retina Faculty Financial Disclosures 157

Philip J Rosenfeld MD PhDAcucela: C Alexion: S Chengdu Kanghong Biotech: C GlaxoSmithKline: S Oraya: C Zeiss Meditec: L,S

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 Topcon Medical Systems: P

Reginald J Sanders MDNone

Andrew P Schachat MDNone

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

Johanna M Seddon MDTufts Medical Center: P

Sherif M Sheta MDNone

Carol L Shields MDNone

Jerry A Shields MDNone

Michael A Singer MDAlcon Laboratories, Inc.: S Allergan, Inc.: C,L,S Eli Lilly & Co.: S Genentech: C,L,S NeoVista, Inc.: S Regeneron: ST. ThromboGenics: S

Lawrence J Singerman MDAlcon Laboratories, Inc.: S Allergan, Inc.: C Eyetech, Inc.: C Genentech: C,S National Eye Institute: S Ophthotech: C

Rishi P Singh MDAlcon Laboratories, Inc.: C Genentech: C Inspire Pharmaceuticals, Inc.: 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 Lpath Inc.: C,S NeoVista: S Novagali: S Oraya Therapeutics: C,S OxiGene: C,S Pfizer, Inc.: S QLT, Inc.: S RegeneronPharmaceuticals: L,SReVision: C,S

Lucia Sobrin MDNone

Gisele Soubrane MD PhDAllergan, Inc.: C,L Chibret International: C Novartis Pharmaceuticals Corp.: C

Richard F Spaide MDGenentech: S Topcon Medical Systems: P

Sunil K Srivastava MDNone

Giovanni Staurenghi MDAllergan, Inc.: C Bayer: C Canon: C GlaxoSmithKline: C Heidelberg Engineering: C Ocular Instruments, Inc.: P OD-OS: C Optovue: S Pfizer, Inc.: C Zeiss: S

Paul Sternberg MDNone

William S Tasman MD FACSNone

John T Thompson MDGenentech: S National Eye Institute: S Regeneron: S

Cynthia A Toth MDAlcon Laboratories, Inc.: P Bioptigen, Inc.: S Genentech, Inc.: S National Eye Institute: S Physical Sciences Inc.: C,S

Michael T Trese MDClarity: C FocusROP: C,OGenentech: C Nu-Vue Technologies, Inc.: C,O RetinalSolutionsLLC: C,OSynergetics, Inc.: P ThromboGenics Inc.: C,O

Stephen H Tsang MD PhDNone

Russell N Van Gelder MD PhDAlcon Laboratories, Inc.: C,S Novartis Pharmaceuticals Corp.: S Photoswitch Therapeutics: S

Demetrios Vavvas MDNIH core grant. Lions, Yeatts

Family: S

C P Wilkinson MDFDA: C

David F Williams MDGenentech: C

George A Williams MDAlcon Laboratories, Inc.: C,S Allergan, Inc.: C,S Genentech: S Neurotech: C,S Nu-Vue Technologies, Inc.: O,P OMIC-Ophthalmic Mutual Insurance

Company: E OptiMedica: C,O Pfizer, Inc.: C Thrombogenics: C,O

Sebastian Wolf MD PhDAllergan: C Heidelberg Engineering: C,L Novartis Pharmaceuticals Corp.: C,L

Lihteh Wu MDNone


Lawrence A Yannuzzi MDNone

Lucy H Young MD PhD FACSNone

David N Zacks MD PhDONL Therapeutics: O,P

Marco A Zarbin MD PhD FACSAdvanced Cell Technology: S Celgene: C Eli Lilly & Company: C Foundation Fighting Blindness: C,S Genentech: C Iridex: C Lincy Foundation: S National Eye Institute: S Novartis Pharmaceuticals Corp.: C Pfizer, Inc.: C ResearchtoPreventBlindness: SUniversity of Medicine & Dentistry of

NJ: P Wyeth-Ayerst Pharmaceuticals: C

Kang Zhang MD PhDAccucela: C Genentech: C,S NIH: S


Presenter Index

Aiello*, Lloyd P 113Arevalo, J Fernando 115Avery*,RobertL 42Awh, Carl C 48Blumenkranz*, Mark S 149Boyer*, David S 119Bressler*, Neil M 114Campochiaro*, Peter A 125Capone*, Antonio 55Chang*, Stanley 15Chew, Emily Y 72Chong*, N H Victor 127Chow*,DavidR 10Chung, Mina 96Clark, W Lloyd 51Davis*,JanetLouise 108Dugel*, Pravin U 28Duker*, Jay S 98Ehlers, Justis P 5Eliott*, Dean 139Ferris*, Frederick L 16Fineman*, Mitchell S 59Flynn*, Harry W 24Haller*, Julia A 1Harbour*,JWilliam 101Haritoglou*, Christos 13Hassan*, Tarek S 129Heier*, Jeffrey S 21Hollyfield, Joe G 64Holz*, Frank G 82Humayun*, Mark S 44Iida, Tomohiro 91Ip*, Michael S 47Jackson*, Mary Lou 45

Jaffe*,GlennJ 20Kaiser*, Peter K 78Kaiser*,RichardS 140Kempen*,JohnH 103Kim*, Ivana K 65Koh*, Adrian H 26Kuppermann*, Baruch D 75Maguire, Albert M 39Martin, Daniel F 19Mieler*, William F 144Nguyen*, Quan Dong 123Ohji*, Masahito 3Oshima*, Yusuke 7Prenner*, Jonathan L 11Reichel*,Elias 81Rich,WilliamL 56Rosenfeld*,PhilipJ 69Ruby*,AlanJ 61Sadda*,SrinivasR 90Sheta, Sherif M 135Shields,JerryA 102Singer*, Michael A 54Singh*,RishiP 57Slakter*,JasonS 30Sobrin,Lucia 106Spaide*,RichardF 94Srivastava,SunilK 104Sternberg, Paul 67Thompson*, John T 136Tsang, Stephen H 36Vavvas*, Demetrios 74Williams*, George A 33Young,LucyH 110Zarbin*, Marco A 84


retina 2011 syllabus

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