Retina 2016 Syllabus

Retina 2016
Winds of Innovations
Program Directors
Jennifer I Lim MD and Carl D Regillo MD
In conjunction with the American Society of Retina Specialists,

the Macula Society, the Retina Society, and Club Jules Gonin
McCormick Place
Chicago, Illinois
Friday Saturday, Oct. 14 15, 2016
Presented by:
The American Academy of Ophthalmology
Supported in part by an unrestricted educational grant
from Genentech.
Retina 2016 Planning Group

Jennifer I Lim MD FARVO
Program Director
Carl D Regillo MD FACS
Program Director
Mark S Humayan MD PhD
Richard F Spaide MD
Former Program Directors
2015 Pravin U Dugel MD
Jennifer I Lim MD
2014 Peter K Kaiser MD
Pravin U Dugel MD
2013 Tarek S Hassan MD
Peter K Kaiser MD
2012 Joan W Miller MD
Tarek S Hassan MD
2011 Allen C Ho MD
Joan W Miller MD
2010 Daniel F Martin MD
Allen C Ho MD
2009 Antonio Capone Jr MD
Daniel F Martin MD
2008 M Gilbert Grand MD
Antonio Capone Jr MD
2007 John T Thompson MD

M Gilbert Grand MD
2006 Emily Y Chew MD
John T Thompson MD
2005 Michael T Trese MD
Emily Y Chew MD
2004 William F Mieler MD
Michael T Trese MD
2003 Kirk H Packo MD
William F Mieler MD
2002 Mark S Blumenkranz MD
Kirk H Packo MD
2001 George A Williams MD
Mark S Blumenkranz MD
2000 Julia A Haller MD
George A Williams MD
1999 Stanley Chang MD
Julia A Haller MD
1998 Harry W Flynn Jr MD
Stanley Chang MD
1997 H MacKenzie Freeman MD
Harry W Flynn Jr MD
1996 H MacKenzie Freeman MD
1995 Thomas M Aaberg Sr MD
Paul Sternberg Jr MD
Subspecialty Day Advisory Committee

Daniel S Durrie MD
Associate Secretary
Julia A Haller MD
Francis S Mah MD
R Michael Siatkowski MD
Kuldev Singh MD MPH
Nicolas J Volpe MD
Jonathan B Rubenstein MD
Secretary for Annual Meeting
Staff
Ann LEstrange, Scientific Meetings
Specialist
Melanie R Rafaty CMP DES, Director,
Scientific Meetings
Lisa Romero, Presenter Coordinator
Debra Rosencrance CMP CAE, Vice
President, Meetings & Exhibits
Patricia Heinicke Jr, Copy Editor
Mark Ong, Designer
Gina Comaduran, Cover Design
2016 American Academy of Ophthalmology. All rights reserved. No portion may be reproduced without express written consent of the American Academy of Ophthalmology.
ii
Planning Group
2016 Subspecialty Day|Retina
2016 Retina Subspecialty Day Planning Group

On behalf of the American Academy of Ophthalmology and the American Society of Retina Specialists, the Macula Society,
the Retina Society, and Club Jules Gonin, it is our pleasure to welcome you to Chicago and Retina 2016: Winds of Innovations.
Jennifer Irene Lim MD FARVO
AbbVie: C
Alcon Laboratories Inc.: C
Genentech: C,L,S
Icon Bioscience: C,S
Lumenis Inc.: C
Pfizer Inc.: S
Regeneron Pharmaceuticals Inc.: C,L,S
Santen Inc.: C
Abbott: C | Acucela: C,S

Aerpio: C
Alcon Laboratories Inc.: C,S
Allergan: C,S | Bausch+Lomb: C
Bayer Healthcare Pharmaceuticals: C
Genentech: C,S | GlaxoSmithKline: S
NotalVision Ltd.: C,S
Novartis Pharmaceuticals Corp.: C,S
Regeneron Pharmaceuticals Inc.: C,S
ThromboGenics Inc.: S
Mark S Humayun MD PhD
Richard F Spaide MD
1Co. Inc.: C,O,P

Alcon Laboratories Inc.: C,L
Aquesys: C | Clearside: C,O
Eyemedix: C,O,P,S
InnFocus: C,O | Iridex: P
oProbe: C,O,P | Reflow: C,O,P
Regenerative Patch Technologies (RPT):
C,O,P
Replenish: C,O,P
Second Sight: C,O,P
Bausch+Lomb: C
Topcon Medical Systems Inc.: P,C
Program Director
Program Director
PlanningSection
Group
2016 Subspecialty Day

Advisory Committee
Daniel S Durrie MD, Chair
(Refractive Surgery)
Abbott Medical Optics: L,S
AcuFocus Inc.: C,L,O,S
Alcon Laboratories Inc.: S
Allergan: S | Alphaeon: C,L,O
Avedro: L,O,S
Hoopes Durrie Rivera Research
Center: C
Strathspey Crown LLC: C,L,O
Wavetec: O
Julia A Haller MD (Retina)

Celgene: O | Janssen: C
KalVista: C | Merck & Co. Inc.: C
Francis S Mah MD (Cornea)

Abbott Medical Optics Inc.: S,L,C
Aerie: C
Alcon Laboratories Inc.: L,S,C
Allergan: S,L,C
Bausch+Lomb: C,L
CoDa: C | ForeSight: C
NovaBay: C | Ocular Science: O,C
Ocular Therapeutix: C,S
PolyActiva: C | Shire: C
Slack Publishing: C
Sun Pharma: C
Sydnexis: C | TearLab: C
R Michael Siatkowski MD
(Pediatric Ophthalmology)
National Eye Institute: S
Kuldev Singh MD MPH

(Glaucoma)
Abbott Medical Optics Inc.: C
Aerie: C
Allergan: C
Carl Zeiss Meditec: C
ForSight Vision 5: C
InnFocus: C | Ivantis: C
Mynosys: C
National Space Biomedical Research
Institute: C
Santen Inc.: C | Shire: C
Thieme Medical Publishers: C
Transcend: C
U.S. Food and Drug
Administration: C
Nicholas J Volpe MD
(Neuro-Ophthalmology)
Opticent Inc.: O
AAO Staff
Ann LEstrange
None
Melanie Rafaty
None
Lisa Romero
None
Debra Rosencrance
None
Beth Wilson
None
iii
Retina 2016 Contents
Retina Subspecialty Day Planning Group ii

CMEvii
The Charles L Schepens MD Lecture ix
Faculty Listing x
Program Schedule xxxi
Section I:
Masters of Surgery 1
Section II:
Vitreoretinal Surgery, Part I 7
The Charles L Schepens MD Lecture 28
Section III:
The Business of Retina 33
Section IV:
Therapies for Macular and Retinal Vascular Diseases 40
Section V:
Retinal Degenerations 51
Section VI:
Uveitis Panel, Part I 61
Advocating for Patients 62
Section VII:
My Coolest Surgical Video 64
Section VIII:
Pediatric Retina 65
Section IX:
Late Breaking Developments, Part I 69
Section X:
First-time Results of Clinical Trials, Part I 74
Section XI:
Neovascular AMD 80
Section XII:
Imaging 93
Section XIII:
Late Breaking Developments, Part II 100
Section XIV:
Debates 104
Section XV:
Oncology 110
Section XVI:
Diabetes 115
Section XVII:
First-time Results of Clinical Trials, Part II 129
Section XVIII:
Uveitis, Part II 136
Section XIX:
Non-neovascular AMD 141
Section XX:
Vitreoretinal Surgery, Part II 147
Section XXI:
Retinal Vein Occlusion 156
Contents
vi
Contents
Section XXII:
Video Surgical Complications: What Would You Do? 161

Faculty Financial Disclosure 167
Presenter Index 177
Retina Exhibits 179
CME Credit
vii
CME Credit
Academys CME Mission Statement

The purpose of the American Academy of Ophthalmologys
Continuing Medical Education (CME) program is to present
ophthalmologists with the highest quality lifelong learning
opportunities that promote improvement and change in physician practices, performance, or competence, thus enabling such
physicians to maintain or improve the competence and professional performance needed to provide the best possible eye care
for their patients.
2016 Retina Subspecialty Day Meeting Learning

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

Present the established and innovative approaches to management of retinal vascular and surgical retinal conditions
Explain the current management of macular edema secondary to retinal occlusive disease and diabetic retinopathy as well as the newly proven therapies for proliferative
diabetic retinopathies
Explain the pathobiology and management of atrophic
and exudative AMD and other causes of ocular neovascularization
Identify imaging tests most helpful in the diagnosis and
management of retinal conditions and discuss emerging
developments in retinal imaging
Describe new vitreoretinal surgical techniques and
instrumentation
Identify new developments in hereditary retinal degenerations, pediatric retinal diseases, and ocular oncology
Describe newly discovered ocular manifestations of systemic medications and diseases
Discuss effective treatments to manage complications
from medical and surgical interventions
Summarize current and new clinical trial data for retinal
diseases such as AMD, diabetic retinopathy, hereditary
retinal conditions, and retinal vein occlusion
2016 Retina Subspecialty Day Meeting Target

Audience
The intended target audience for this program is vitreoretinal
specialists, members in fellowship training, and general ophthalmologists who are engaged in the diagnosis and treatment
of vitreoretinal diseases.
2016 Retina Subspecialty Day CME Credit

The American Academy of Ophthalmology is accredited by
the Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for physicians.
The American Academy of Ophthalmology designates this
live activity for a maximum of 14 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate
with the extent of their participation in the activity.
Portion of the meeting not eligible for credit include attending Break with the Experts.
Self-Assessment Credit
This activity meets the Self-Assessment CME requirements
defined by the American Board of Ophthalmology (ABO).
Please be advised that the ABO is not an accrediting body for
purposes of any CME program. The ABO does not sponsor this
or any outside activity, and the ABO does not endorse any particular CME activity. Complete information regarding the ABO
Self-Assessment CME Maintenance of Certification requirements is available at http://abop.org/maintain-certification/
part-2-lifelong-learning-self-assessment/sacme/.
NOTE: Credit designated as self-assessment is AMA PRA
Category 1 Credit and is also preapproved by the ABO for the
Maintenance of Certification (MOC) Part II CME requirements.
Teaching at a Live Activity

Teaching instruction courses or delivering a scientific paper or
poster is not an AMA PRA Category 1 Credit activity and
should not be included when calculating your total AMA PRA
Category 1 Credits. Presenters may claim AMA PRA Category 1 Credits through the American Medical Association.
To obtain an application form please contact the AMA at
www.ama-assn.org.
Scientific Integrity and Disclosure of Financial

Interest
The American Academy of Ophthalmology is committed to
ensuring that all CME information is based on the application
of research findings and the implementation of evidence-based
medicine. It seeks to promote balance, objectivity, and absence
of commercial bias in its content. All persons in a position to
control the content of this activity must disclose any and all
financial interests. The Academy has mechanisms in place to
resolve all conflicts of interest prior to an educational activity
being delivered to the learners.
The Academy requires all presenters to disclose on their first
slide whether they have any financial interests from the past 12
months. Presenters are required to verbally disclose any financial interests that specifically pertain to their presentation.
Control of Content
The Academy considers presenting authors, not co-authors, to
be in control of the educational content. It is Academy policy
and traditional scientific publishing and professional courtesy
to acknowledge all people contributing to the research, regardless of CME control of the live presentation of that content. This
acknowledgement is made in a similar way in other Academy
CME activities. Though they are acknowledged, co-authors do
not have control of the CME content and their disclosures are
not published or resolved.
viii
CME Credit
Attendance Verification for CME Reporting

Before processing your requests for CME credit, the Academy
must verify your attendance at Subspecialty Day and/or AAO
2016. In order to be verified for CME or auditing purposes, you
must either:

Register in advance, receive materials in the mail, and

turn in the Subspecialty Day Syllabi exchange voucher(s)
onsite;
Register in advance and pick up your badge onsite if materials did not arrive before you traveled to the meeting;
Register onsite; or
Scan the barcode on your badge as you enter an AAO
2016 course or session room.
CME Credit Reporting

South Level 2.5 and Academy Resource Center, Booth 508
Attendees whose attendance has been verified (see above) at
AAO 2016 can claim their CME credit online during the meeting. Registrants will receive an email during the meeting with
the link and instructions on how to claim credit.
Onsite, you may report credits earned during Subspecialty
Day and/or AAO 2016 at the CME Credit Reporting booth.
Academy Members: The CME credit reporting receipt is not
a CME transcript. CME transcripts that include AAO 2016
credits entered onsite will be available to Academy members on
the Academys website beginning Nov. 10, 2016.
After AAO 2016, credits can be claimed at www.aao.org/

cme.
The Academy transcript cannot list individual course attendance. It will list only the overall credits spent in educational
activities at Subspecialty Day and/or AAO 2016.
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 AAO 2016 and Subspecialty Day for those who need it
for reimbursement or hospital privileges, or for nonmembers
who need it to report CME credit:

CME credit reporting/proof-of-attendance letters

Onsite registration receipt
Instruction course and session verification
Visit www.aao.org/cme for detailed CME reporting information.
The Charles L Schepens MD Lecture
ix

Management Options for Vitreomacular Traction:
Use an Individualized Approach
Friday, Oct. 14, 2016
9:49 AM 10:09 AM
Harry W Flynn Jr MD
Harry W Flynn Jr MD is the J Donald M Gass MD Distinguished Chair in Ophthalmology at the University of Miami
School of Medicine. He is professor of Ophthalmology at the
Bascom Palmer Eye Institute and specializes in medical and
surgical treatment of diseases of the retina and vitreous. He
received a bachelor of science degree at Wake Forest University
in 1967 and his doctor of medicine degree at the University of
Virginia School of Medicine in 1971. After an internship at the
Pacific Medical Center in San Francisco, Dr. Flynn had two
years of active duty in the U.S. Army at the Brook Army Medical Center in San Antonio (1976-1978).
Dr. Flynn has been author or coauthor of more than 500
publications, as well as 88 book chapters. He has edited or
coedited 4 books, including Diabetes and Ocular Diseases:
Past, Current, and Future Therapies and Vitreoretinal Disease:
The Essentials.
Dr. Flynn has held numerous administrative positions,
including president of the Vitreous Society (1992-1993), president of the Miami Ophthalmological Society (1999), and president of the Retina Society (2002-2003). Dr. Flynn has served as
senior editor for Section 12 (Retina) of the Basic and Clinical
Science Course for the American Academy of Ophthalmology.
He has also served as codirector of the Retina Subspecialty Day
for the Academy. He serves on the editorial boards of numerous

journals, including the American Journal of Ophthalmology,
Retina, Ophthalmic Surgery, Lasers and Imaging Retina, and
Evidence-Based Ophthalmology. He has served on the Data
and Safety Monitoring Committees for the Diabetic Retinopathy Clinical Research Network, the SCORE (Standard Care vs.
COrticosteroid for REtinal Vein Occlusion) Study, Regeneron
VIEW 1 and VIEW 2 Studies (VEGF Trap-Eye), and the Neurotech MacTel (Macular Teleangiectasia) Study.
Dr. Flynn received the Academys Life Achievement Honor
Award in 2008, and in 2011 he received the Shaler Richardson
MD Service to Medicine Award from the Florida Society of
Ophthalmology. He received the Hermann Wacker Award from
the Club Jules Gonin in 2012. Dr. Flynn was voted Professor of
the Year by the Bascom Palmer Eye Institute Residents in 2012.
In 2014, he received the Honorary Alumnus recognition from
the Alpha Omega Alpha chapter of the University of Virginia
School of Medicine. He has delivered 28 named lectures, including the J Donald M Gass Lecture at the Retina Society meeting
in 2012.
Dr. Flynn has been married to his wife, Dr. Donna Flynn, for
42 years. They have two children, Mollie and Patrick, and two
grandchildren, Parker and Lily.
Faculty Listing
Faculty
Gary W Abrams MD
Lloyd P Aiello MD PhD
Jayakrishna Ambati MD
Detroit, MI
Professor of Ophthalmology
Kresge Eye Institute
Wayne State University
Boston, MA
Harvard Medical School
Director, Beetham Eye Institute
Head, Section of Eye Research
Joslin Diabetes Center
Charlottesville, VA
Professor and Vice Chair for Research
Ophthalmology
Director, Center for Advanced Vision
Science
University of Virginia
Thomas A Albini MD
Rajendra S Apte MD PhD
Miami, FL
Associate Professor of Clinical
Ophthalmology
Bascom Palmer Eye Institute
Saint Louis, MO
Paul A Cibis Distinguished Professor of
Ophthalmology
Director of Education
Professor of Developmental Biology
Washington University in Saint Louis
School of Medicine
Anita Agarwal MD
Nashville, TN
Vanderbilt Eye Institute
Vanderbilt University School of
Medicine
No photo
available
Hamid Ahmadieh MD
Tehran, Iran
David Almeida MD PhD MBA

Minneapolis, MN
Surgery and Diseases of the Retina,
Vitreous & Macula
VitreoRetinal Surgery, PA
Cofounder
Citrus Therapeutics
Faculty Listing
J Fernando Arevalo MD FACS
Carl C Awh MD
Caroline R Baumal MD

Baltimore, MD
Edmund F. and Virginia Ball Professor
of Ophthalmology
Wilmer Eye Institute & Johns Hopkins
University School of Medicine
Chairman, Department of
Ophthalmology
Johns Hopkins Bayview Medical Center
Nashville, TN
President
Tennessee Retina, PC
Boston, MA
Associate Professor
Tufts University School of Medicine
Vitreoretinal Surgeon
New England Eye Center
xi
Alay S Banker MD
Jorge G Arroyo MD
Ahmedabad, India
Director
Vitreo-retinal surgeon and Uveitis
Specialist
Bankers Retina Clinic and Laser
Centre, Ahmedabad, India
Brookline, MA
Associate Professor of Ophthalmology
Director of Retina Service
Beth Israel Deaconess Medical Center
Francine Behar-Cohen MD
Paris, France
Ophthalmology
Lausanne University, Jules Gonin Eye
Hospital
Director
Inserm UMR1138, Team 17
Andrs I Bastien MD
Robert L Avery MD
Santa Barbara, CA
Founder, California Retina Consultants
Codirector, California Retina Research
Foundation
San Miguel, Argentina

Vitreoretinal Specialist
Universidad de Buenos Aires
Vitreoretinal Consultant
Hospital Italiano de Buenos Aires
Audina M Berrocal MD
Miami, FL
Professor of Clinical Ophthalmology
Bascom Palmer Eye Institute, University
of Miami
Staff Physician
Miami Childrens Hospital AND
Jackson Memorial Hospital
xii
Faculty Listing
Maria H Berrocal MD
Susan B Bressler MD
San Juan, PR
Faculty Department of Ophthalmology
University of Puerto Rico
Director, Berrocal & Associates
Palo Alto, CA
HJ Smead Professor and Chairman
Stanford University School of Medicine
Director of Ophthalmic Innovation
Program, Byers Eye Institute at
Stanford
Baltimore, MD
The Julia G Levy PhD Professor of
Ophthalmology
Wilmer Eye Institute
Johns Hopkins University School of
Medicine
David S Boyer MD
David M Brown MD
Los Angeles, CA
Clinical Professor of Ophthalmology
University of Southern California/ Keck
School of Medicine
Partner, Retina Vitreous Associates
Medical Group
Houston, TX
Baylor College of Medicine
Director of Clinical Research
Blanton Eye Institute
Houston Methodist Hospital
Retina Consultants of Houston
Susanne Binder MD
Vienna, Austria
Department of Ophthalmology
Rudolf Foundation Clinic
The Ludwig Boltzmann Institute for
Retinology and Biomicroscopic Laser
Surgery
No photo
available
Barbara Ann Blodi MD
Neil M Bressler MD
Madison, WI
University of Wisconsin
Medical Director
Fundus Photograph Reading Center
University of Wisconsin
Baltimore, MD
Chief, Retina Division and The James P.
Gills Professor of Ophthalmology
Wilmer Eye Institute - Johns Hopkins
Editor-in-Chief
JAMA Ophthalmology
David J Browning MD PhD

Charlotte, NC
Retina Service
Charlotte Eye, Ear, Nose, and Throat
Associates
Faculty Listing
xiii
Alexander J Brucker MD
R V Paul Chan MD
Philadelphia, PA
Scheie Eye Institute
University of Pennsylvania
Royal Oak, MI
Copresident/ Partner/ Owner
Associated Retinal Consultants
William Beaumont Hospital/ Oakland
Chicago, IL
Professor of Ophthalmology and Visual
Sciences
Illinois Eye and Ear Infirmary
University of Illinois at Chicago
Brandon G Busbee MD
Nashville, TN
Retina Specialist
Physician Partner
Tennessee Retina
Usha Chakravarthy MBBS PhD

Belfast, Northern Ireland
Professor of Ophthalmology and Vision
Science
Queens University of Belfast
Consultant Ophthalmology
The Belfast Health and Social Care
Trust, NHS
Peter A Campochiaro MD
Baltimore, MD
Eccles Professor of Ophthalmology and
Neuroscience
John Hopkins University School of
Medicine
Stanley Chang MD
New York, NY
KK Tse and KT Ying Professor of
Ophthalmology
Columbia University
Steven T Charles MD
Clement K Chan MD
Palm Desert, CA
President and Medical Director
Southern California Desert Retina
Consultants
Associate Clinical Professor, Loma
Linda University
Loma Linda, California
Germantown, TN
University of Tennessee, Memphis
xiv
Faculty Listing
No photo
available
No photo
available
Felix Y Chau MD
Steven M Christiansen MD
Scott W Cousins MD
Chicago, IL
Assistant Professor of Ophthalmology
Iowa City, IA
Durham, NC
Vice Chair for Research, and Professor
of Ophthalmology and Immunology
Duke University
Mina Chung MD
Emily Y Chew MD
Bethesda, MD
Deputy Director of Division of
Epidemiology and Clinical
Applications
National Eye Institute/ National
Institutes of Health
Rochester, NY
Flaum Eye Institute
University of Rochester
Karl G Csaky MD
Dallas, TX
Senior Scientist
Retina Foundation of the Southwest
Partner, Texas Retina Associates
Carl C Claes MD
David R Chow MD
North York, ON, Canada
University of Toronto
Codirector, Toronto Retina Institute
Schilde, Belgium
Head of Vitreoretinal Surgery
Saint Augustinus Hospital (Wilrijk/
Antwerp)
Director, Ophthalmology Medical
Center
Vlaamse Kaai 29 Antwerp/ Belgium
Emmett T Cunningham Jr MD
PhD MPH
Hillsborough, CA
Director, The Uveitis Service
California Pacific Medical Center
Adjunct Clinical Professor of
Ophthalmology
Faculty Listing
xv
Donald J DAmico MD
Kimberly A Drenser MD PhD
Jacque L Duncan MD
New York, NY
Professor and Chairman
Weill Cornell Medical College
Ophthalmologist-in-Chief
New York-Presbyterian
Royal Oak, MI
Professor, William Beaumont Oakland
San Francisco, CA
Professor, Clinical Ophthalmology
University of California, San Francisco
James Philip Dunn Jr MD

Janet Louise Davis MD
Miami, FL
Leach Distinguished Professor of
Ophthalmology
University of Miami Miller School of
Medicine
Director, Uveitis Service
Member, Retina Service
Pravin U Dugel MD
Phoenix, AZ
Managing Partner
Retinal Consultants of Arizona
Roski Eye Institute
Keck School of Medicine
University of Southern California, Los
Angeles
Philadelphia, PA
Director, Uveitis Unit/ Retina Division
The Wills Eye Hospital
Sidney Kimmel Medical College
Thomas Jefferson University
Claus Eckardt MD
Diana V Do MD
Omaha, NE
Joseph Hompes Professor of
Ophthalmology
Vice Chair for Education
Director of Carl Camras Center for
Innovative Research
Truhlsen Eye Institute
University of Nebraska Medical Center
Jay S Duker MD
Boston, MA
Director, New England Eye Center
Tufts Medical Center
Frankfurt, Germany
Klinikum Frankfurt Hchst
xvi
Faculty Listing
Justis P Ehlers MD
Andrew W Eller MD
Harry W Flynn Jr MD
Shaker Heights, OH
The Norman C and Donna L Harbert
Endowed Chair for Ophthalmic
Research
Cole Eye Institute
Cleveland Clinic
Pittsburgh, PA
Retina Service
UPMC Eye Center
University of Pittsburgh School of
Medicine
Miami, FL
The J Donald M Gass Distinguished
Chair in Ophthalmology
Medicine
Ehab N El Rayes MD PhD
Amani Fawzi MD
Cairo, Egypt
Retina Department
Institute of Ophthalmology
Vitreoretinal Consultant
The Retina Clinic
Chicago, IL
Associate Professor Ophthalmology
Feinberg School of Medicine
Northwestern University
William R Freeman MD
La Jolla, CA
Director, Jacobs Retina Center
Shiley Eye Center
University of California, San Diego
Sharon Fekrat MD
Dean Eliott MD
Boston, MA
Associate Director of Retina Service
Massachusetts Eye & Ear Infirmary
Durham, NC
Departments of Ophthalmology and
Surgery
Duke University School of Medicine
Associate Chief of Staff for Surgery
Durham Veterans Affairs Medical
Center
K Bailey Freund MD
New York, NY
New York University
Partner, Vitreous Retina Macula
Consultants of New York
Faculty Listing
xvii
Thomas W Gardner MD MS
Debra A Goldstein MD
M Gilbert Grand MD
Ann Arbor, MI
Professor, Ophthalmology & Visual
Sciences
University of Michigan Medical School
Chicago, IL
Northwestern Memorial Feinberg
School of Medicine
Saint Louis, MO
Retina Surgeon
Retina Consultants
The Retina Institute
Washington University School of
Medicine
Sunir J Garg MD FACS
Justin Gottlieb MD
Philadelphia, PA
The Retina Service of Wills Eye
Hospital
Partner, MidAtlantic Retina
Madison, WI
Professor
University of Wisconsin, Madison
Dilraj Singh Grewal MD

Durham, NC
Fellow
Duke Eye Center
Evangelos S Gragoudas MD
Mark C Gillies MD PhD
Sydney, NSW, Australia
Save Sight Institute
University of Sydney
Boston, MA
Director of Retina Service
Massachusetts Eye and Ear Infirmary
Omesh P Gupta MD
Philadelphia, PA
Attending Surgeon
Retina Service, Wills Eye Hospital
Partner, Mid-Atlantic Retina
xviii
Faculty Listing
Julia A Haller MD
J William Harbour MD
Jeffrey S Heier MD
Philadelphia, PA
Ophthalmologist-in-Chief
William Tasman MD Endowed Chair of
Ophthalmology
Wills Eye Hospital
Professor and Chair of Ophthalmology
Sidney Kimmel Medical College of
Miami, FL
Professor and Vice Chairman
Dr. Mark J Daily Endowed Chair
Associate Director for Basic Research
Sylvester Comprehensive Cancer Center
Boston, MA
Copresident
Director, Vitreoretinal Service
Ophthalmic Consultants of Boston
Allen C Ho MD
Lawrence S Halperin MD
Boca Raton, FL
Clinical Affiliate Professor of Surgery
Charles E Schmidt College of Medicine
Florida Atlantic University
Voluntary Assistant Professor of
Ophthalmology
University of Miami School of Medicine
Mary Elizabeth Hartnett MD

FACS
Salt Lake City, UT
University of Utah
Director of Pediatric Retina
Moran Eye Center
Philadelphia, PA
Director of Retina Research
Mid Atlantic Retina and Wills Eye
Hospital
Nancy M Holekamp MD
Tarek S Hassan MD
Dennis P Han MD
Milwaukee, WI
Jack A and Elaine D Klieger Professor
of Ophthalmology
Medical College of Wisconsin
Vitreoretinal Section Chief
The Froedert & Medical College of
Wisconsin Eye Institute
Royal Oak, MI
Oakland University William Beaumont
School of Medicine
Partner and Director of Vitreoretinal
Training Program
Chesterfield, MO
Director, Retina Service
Pepose Vision Institute
Washington University School of
Medicine
Faculty Listing
xix
No photo
available
Jason Hsu MD
Michael S Ip MD
Lee M Jampol MD
Philadelphia, PA
Assistant Professor of Clinical
Ophthalmology
Retina Service of Wills Eye Hospital
Managing Partner
Mid Atlantic Retina
Pasadena, CA
Chicago, IL
Feinberg Professor of Ophthalmology
Northwestern University
Chair, DRCRnet
No photo
available
Douglas A Jabs MD MBA

Los Angeles, CA
University of Southern California
New York, NY
Professor of Ophthalmology and
Medicine
Icahn School of Medicine at Mount
Sinai
Adjunct Professor of Epidemiology
The Johns Hopkins University
Bloomberg School of Public Health
Mark W Johnson MD
Ann Arbor, MI
Professor of Ophthalmology and Visual
Sciences
University of Michigan
W K Kellogg Eye Center
No photo
available
Deeba Husain MD
Lexington, MA
Raymond Iezzi MD
Rochester, MN
Mayo Clinic
Glenn J Jaffe MD
Durham, NC
Director, Duke Reading Center
Duke University
J Michael Jumper MD
San Francisco, CA
Codirector, Vitreoretinal Fellowship
Partner, West Coast Retina
xx
Faculty Listing
Peter K Kaiser MD
Ivana K Kim MD
John W Kitchens MD
Cleveland, OH
Cleveland Clinic Lerner College of
Medicine
Boston, MA
Retina Service
Massachusetts Eye and Ear
Lexington, KY
Physician, Retina Associates of
Kentucky
Voluntary Faculty
University of Kentucky
Judy E Kim MD
Adrian H Koh MD
Milwaukee, WI
Medical College of Wisconsin
Singapore, Singapore
Managing Partner & Senior Consultant
Eye & Retina Surgeons, Singapore
Executive Director
ESASO Asia
Richard S Kaiser MD
Cherry Hill, NJ
Associate Surgeon
Retina Service of Wills Eye Institute
No photo
available
Amir H Kashani MD PhD
Rosa Y Kim MD
Houston, TX
Pasadena, CA
Ophthalmology
Roski Eye Institute
Gregg T Kokame MD
Aiea, HI
Clinical Professor
John A Burns School of Medicine
University of Hawaii
Medical Director
Hawaii Macula and Retina Institute
Retina Consultants of Hawaii
Szilard Kiss MD
New York, NY
Director of Clinical Research
Weill Cornell Medical College
Faculty Listing
xxi
Derek Y Kunimoto MD JD
Linda A Lam MD
Theodore Leng MD
Paradise Valley, AZ
Co-Managing Partner
Retinal Consultants of AZ
Director, Scottsdale Eye Surgery Center
Los Angeles, CA
Vice Chair
Clinical Satellite Affairs
Roski Eye Institute
Palo Alto, CA
Clinical Assistant Professor of
Ophthalmology
Byers Eye Institute at Stanford
Baruch D Kuppermann MD PhD

Irvine, CA
Professor and Chief
Retina Service
Gavin Herbert Eye Institute
University of California, Irvine
Jennifer Irene Lim MD

Thomas C Lee MD
Los Angeles, CA
Director, Vision Center
Childrens Hospital Los Angeles
Chicago, IL
Marion H Schenk Chair and Professor
of Ophthalmology
Director of the Retina Service
No photo
available
No photo
available
Brenda Laigaie JD
Berwyn, PA
Partner
Wade, Goldstein, Landau & Abruzzo,
PC
Ann-Marie Lobo MD
Yannek I Leiderman MD PhD
Chicago, IL
Chicago, IL
University of Illinois at Chicago, Illinois
Eye and Ear Infirmary
xxii
Faculty Listing
No photo
available
Anat Loewenstein MD
Robert E MacLaren MBChB
Mauricio Maia MD
Tel Aviv, Israel

Director, Department of
Ophthalmology
Tel Aviv Medical Center
Vice Dean
Sackler Faculty of Medicine
Tel Aviv University
Oxford, England
Consultant Vitreoretinal Surgeon
University of Oxford and Oxford Eye
Hospital UK
Honorary Consultant
Moorfields Eye Hospital, London
Assis, Brazil
James C Major MD PhD

Houston, TX
Alice T Lyon MD
Chicago, IL
Director, Vitreoretinal Service
Leonard and Bernice Lavin Endowed
Ophthalmology Research Professor
Northwestern University Feinberg
School of Medicine
Albert M Maguire MD
Bryn Mawr, PA
University of Pennsylvania
Clinical Associate
Childrens Hospital of Philadelphia
Daniel F Martin MD
Cleveland, OH
Chairman, Cole Eye Institute
Cleveland Clinic
Tamer H Mahmoud MD
Mathew W MacCumber MD PhD
Chicago, IL
Rush University Medical Center
Retina Specialist
Illinois Retina Associates, SC
Durham, NC
Program Director, Vitreoretinal
Fellowship
Duke University Eye Center
Colin A McCannel MD
Los Angeles, CA
Jules Stein Eye Institute
Chief of Retina, Division of
Ophthalmology, Department of
Surgery
Harbor-UCLA Medical Center
Faculty Listing
xxiii
Tara A McCannel MD
William F Mieler MD
Darius M Moshfeghi MD
Los Angeles, CA
University of California, Los Angeles
Director of Ophthalmic Oncology
Stein Eye and Doheny Eye Institutes
Winnetka, IL
Interim Head
Professor and Vice Chairman of
Ophthalmology
Department of Ophthalmology &
Visual Sciences
Palo Alto, CA
Director of Ophthalmic Telemedicine,
Director of Pediatric Vitreoretinal
Surgery
Byers Eye Institute, Stanford University
School of Medicine
No photo
available
H Richard McDonald MD
San Francisco, CA
Director, Vitreoretinal Fellowship
Program
Yuki Morizane MD
Timothy G Murray MD MBA
Okayama, Japan
South Miami, FL
Founding Director
Ocular Oncology and Retina (MOOR)
Professor Emeritus of Ophthalmology
and Radiation Oncology
Andrew A Moshfeghi MD MBA

Pauline T Merrill MD
Chicago, IL
Rush University
Partner, Illinois Retina Associates
Los Angeles, CA
Associate Professor and Director
Clinical Trials Unit
Quan Dong Nguyen MD

Omaha, NE
McGaw Endowed Chair in
Ophthalmology and Professor of
Ophthalmology
Truhlsen Eye Institute, University of
Nebraska Medical Center
xxiv
Faculty Listing
Timothy W Olsen MD
Andrew J Packer MD
David W Parke II MD
Atlanta, GA
Chairman Emeritus
Emory University
Hartford, CT
Clinical Professor
University of Connecticut School of
Medicine
San Francisco, CA
CEO, American Academy of
Ophthalmology
Murat Oncel MD
Kirk H Packo MD
Istanbul, Turkey
Istanbul Bilim University Medical
School
Chicago, IL
Sengul C Ozdek MD
Ankara, Turkey
MD, Professor of Ophthalmology
Ophthalmology Department
Gazi University School of Medicine
Fabio Patelli MD
Garbagnate Milanese, Italy
Director, Vitreoretina Service
San Paolo Hospital
University of Milan
Grazia Pertile MD
Susanna S Park MD PhD
Sacramento, CA
Professor
University of California, Davis
Negrar, VR, Italy

Director, Department of
Ophthalmology
Sacro Cuore Hospital
Faculty Listing
xxv
Dante Pieramici MD
William L Rich III MD FACS
Santa Barbara, CA
Partner, California Retina Consultants
Director, California Retina Research
Foundation
Bryn Mawr, PA
Wills Eye Hospital
Falls Church, VA
Medical Director for Health Policy
American Academy of Ophthalmology
Clinical Instructor
Georgetown University
No photo
available
Carmen A Puliafito MD MBA

Los Angeles, CA
Dean, John and Mary Hooval Deans
Chair in Medicine
Professor of Ophthalmology and Health
Management
USC Roski Eye Institute
Elias Reichel MD
Boston, MA
Vice Chairman
New England Eye Center
Stanislao Rizzo MD
Lucca, Italy
Chairman, Ophthalmology
Careggi University Hospital, Florence
No photo
available
Kourous Rezaei MD
Jose S Pulido MD MS
Rochester, MN
Molecular Medicine
The Mayo Clinic
Harvey, IL
Damien C Rodger MD PhD

Los Angeles, CA
Ophthalmology
USC Roski Eye Institute
Research Assistant Professor of
Biomedical Engineering
Viterbi School of Engineering
xxvi
Faculty Listing
No photo
available
Richard B Rosen MD
Reginald J Sanders MD
Ursula M Schmidt-Erfurth MD
New York, NY
Vice Chairman
Surgeon Director
Director of Retina
Director of Research
New York Eye and Ear Infirmary of
Mount Sinai
Mount Sinai School of Medicine
Chevy Chase, MD
Clinical Associate Professor of
Ophthalmology
Georgetown University School of
Medicine
Partner, Retina Group of Washington
Vienna, Austria
Professor and Chair
Medical University of Vienna
Hendrik P Scholl MD
David Sarraf MD
Philip J Rosenfeld MD PhD
Miami, FL
Medicine
Los Angeles, CA
Stein Eye Institute
Baltimore, MD
Wilmer Eye Institute
Johns Hopkins University
Chairman and Professor of
Ophthalmology
University of Basel, Switzerland
Andrew P Schachat MD
Taiji Sakamoto MD PhD

Kagoshima, Japan
Professor and Chair of Ophthalmology
Kagoshima University
Cleveland, OH
Vice Chairman for Clinical Affairs
Cole Eye Institute
Cleveland Clinic
Lerner College of Medicine
Steven D Schwartz MD
Los Angeles, CA
Ahmanson Professor of Ophthalmology
Chief, Retina Division
Stein Eye Institute
David Geffen School of Medicine
Faculty Listing
xxvii
Ingrid U Scott MD MPH
Carol L Shields MD
Rishi P Singh MD
Hershey, PA
Jack and Nancy Turner Professor of
Ophthalmology and Public Health
Sciences
Penn State College of Medicine
Philadelphia, PA
Co-Director, Ocular Oncology Service
Wills Eye Hospital
Thomas Jefferson University Hospital
Cleveland, OH
Staff Physician
Cole Eye Institute, Cleveland Clinic
Foundation
Cleveland Clinic Lerner College of
Medicine
J Sebag MD FACS FRCOphth

FARVO
Jerry A Shields MD
Huntington Beach, CA
Founding Director
VMR Institute for Vitreous Macula
Retina
Philadelphia, PA
Director, Oncology Service
Wills Eye Hospital
Gaurav K Shah MD
Arun D Singh MD
Town and Country, MO

Clinical Professor of Ophthalmology &
Visual Sciences
The Retina Institute
Cleveland, OH
Director, Ophthalmic Oncology
Cole Eye Institute
Cleveland Clinic
Jason S Slakter MD
New York, NY
NYU School of Medicine
Partner, Vitreous Retina Macula
Kent W Small MD
Los Angeles, CA
President, Molecular Insight Research
Foundation
Research Scientist
Regenerative Medicine Institute
Cedars-Sinai Medical Center
xxviii
Faculty Listing
Elliott H Sohn MD
Kartnik Srinivasan MD
Paulo E Stanga MD
Iowa City, IA
Associate Professor
Director of Retina Fellowships
University of Iowa
Tirunelveli, India
Nether Alderley, Cheshire, England

Retinal Regeneration
University of Manchester
Consultant Ophthalmologist and
Manchester Royal Eye Hospital and
MVR Lab at WTCRF/NIHR
No photo
available
Sunil K Srivastava MD
Gisele Soubrane MD PhD
Paris, France
Paris Descartes University
MD, PhD, FEBO, FARVO
Hotel Dieu de Paris
Cleveland, OH
Staff Physician
Cole Eye Institute
Cleveland Clinic Foundation
Giovanni Staurenghi MD
Milan, Italy
Department of Biomedical and Clinical
Science
Luigi Sacco University of Milan
Peter W Stalmans MD PhD
Richard F Spaide MD
New York, NY
Ophthalmologist
Vitreous, Retina and Macula
Leuven, Belgium
UZ Leuven
No photo
available
Jennifer K Sun MD
Boston, MA
Chief, Center for Clinical Eye Research
and Trials
Beetham Eye Institute, Joslin Diabetes
Center
Faculty Listing
Homayoun Tabandeh MD MS
FRCP FRCOphth
Los Angeles, CA
Retina-Vitreous Associates Medical
Group
xxix
Cynthia A Toth MD
Demetrios Vavvas MD
Durham, NC
Joseph AC Wadsworth Professor of
Ophthalmology
Duke University Medical Center
Professor of Biomedical Engineering
Pratt School of Engineering
Duke University
Boston, MA
Monte J Wallace Ophthalmology Chair
in Retina
Hiroko Terasaki MD
Nagoya, Japan
Chairman and Professor
Nagoya University Graduate School of
Medicine
John T Thompson MD
Baltimore, MD
Partner, Retina Specialists
Assistant Professor
The Wilmer Institute
The Johns Hopkins University
Michael T Trese MD
Royal Oak, MI
Clinical Professor Ophthalmology
Eye Research Institute
Oakland University
Chief Pediatric & Adult Vitreoretinal
Surgery
Beaumont Eye Institute
William Beaumont Hospital
Sue J Vicchrilli COT OCS

San Francisco, CA
Director, Coding and Reimbursement
American Academy of Ophthalmology
American Academy of Ophthalmic
Executives
No photo
available
Nadia Khalida Waheed MD
James F Vander MD
Plymouth Meeting, PA
Attending Surgeon
Retina Service
Wills Eye Hospital
Cambridge, MA
Associate Professor in Ophthalmology
Tufts University Medical School
Director, Boston Image Reading Center
xxx
Faculty Listing
John A Wells III MD
Lihteh Wu MD
Young Hee Yoon MD
West Columbia, SC
Partner, Palmetto Retina Center, LLC
Ophthalmology
Palmetto Health
University of South Carolina School of
Medicine
San Jose, Costa Rica

Associate Surgeon
Asociados de Macula Vitreo y Retina de
Costa Rica
Associate Professor
University of Costa Rica
Seoul, Republic of Korea

Asan Medical Center
University of Ulsan College of Medicine
No photo
available
Lucy H Young MD PhD FACS

Royal Oak, MI
Professor and Chair
Oakland University William Beaumont
School of Medicine
Charles C Wykoff MD PhD

Houston, TX
Director of Research
Retina Consultants of Houston
Deputy Chair for Ophthalmology
Blanton Eye Institute
Houston Methodist Hospital
Boston, MA
Marco A Zarbin MD PhD FACS
Tien Yin Wong MBBS
Lawrence A Yannuzzi MD
Singapore, Singapore
Professor and Medical Director
Singapore National Eye Center
Chair of Ophthalmology
Vice Dean of Clinical Sciences
Duke-NUS Medical School/ National
University of Singapore
New York, NY
President and Founder
The Macula Foundation Inc.
Manhattan Eye, Ear and Throat
Hospital/ North Shore Hospital
College of Physicians and Surgeons
Columbia University Medical School
Chatham, NJ
Professor and Chair
Institute of Ophthalmology and Visual
Science
Rutgers-New Jersey Medical School
Program Schedule
xxxi
Retina 2016: Winds of Innovations
In conjunction with the American Society of Retina Specialists,

the Macula Society, the Retina Society, and Club Jules Gonin
Friday, Oct. 14
7:00 AM
CONTINENTAL BREAKFAST
8:00 AM
Opening Remarks

Jennifer Irene Lim MD*

Carl D Regillo MD FACS*
Section I: Masters of Surgery

Moderator: Claus Eckardt MD*
8:05 AM
Suprachoroidal Hemorrhage Management: When, How?
John W Kitchens MD*
8:10 AM
Retinectomy Pearls
Steven T Charles MD*
8:15 AM
Endoscopic Surgery
Jorge G Arroyo MD
8:20 AM
Use of Perfluorocarbon Liquids
Stanley Chang MD*
8:27 AM
Optimal Use of Silicone Oil
Grazia Pertile MD
8:33 AM
27-Gauge Vitrectomy for Retinal Detachment
Maria H Berrocal MD*
Section II: Vitreoretinal Surgery, Part I

Moderators: Steven D Schwartz MD* and Carl C Claes MD*
8:38 AM
Giant Retinal Tear: Vitrectomy Alone Is SufficientPro
Donald J DAmico MD*
8:41 AM
Giant Retinal Tear: Vitrectomy Alone Is SufficientCon
Gary W Abrams MD*
8:44 AM
Audience Vote
8:45 AM
Best Rx for VMT: Ocriplasmin
Peter W Stalmans MD PhD*
8:48 AM
Best Rx for VMT: Air or Gas
Robert L Avery MD*
10
8:51 AM
Best Rx for VMT: PPVx
Caroline R Baumal MD*
11
8:54 AM
Audience Vote
8:55 AM
Office-Based Surgery: Ready for Prime Time? Pro
Tarek S Hassan MD*
12
8:58 AM
Office-Based Surgery: Ready for Prime Time? Con
Nancy M Holekamp MD*
15
9:01 AM
Audience Vote
9:02 AM
Innovative PPVx System: Ultrasonic Vitrectomy
Paulo E Stanga MD*
16
9:07 AM
Update on Heavy Oil Use
Murat Oncel MD
17
9:12 AM
Pharmacotherapy for PVR Update
Richard S Kaiser MD*
19
9:17 AM
New Instrumentation
David R Chow MD*
20
9:23 AM
Intraoperative 3-D OCT
Cynthia A Toth MD*
21
9:28 AM
Myopic Schisis and High Myopia Surgery: When to Intervene
Hiroko Terasaki MD*
24
9:33 AM
Inverted Flap Technique
Stanislao Rizzo MD
26
9:38 AM
Intravitreal Drugs in Vitrectomized Eyes
Damien C Rodger MD PhD*
27
* Indicates that the presenter has financial interest.

No asterisk indicates that the presenter has no financial interest.
xxxii
Program Schedule

9:44 AM
Introduction of the 2016 Charles L Schepens MD Lecture
David W Parke II MD*
9:49 AM

Harry W Flynn Jr MD
28
10:09 AM
REFRESHMENT BREAK and RETINA EXHIBITS
Section III: The Business of Retina

Moderators: James F Vander MD and Lawrence S Halperin MD*
10:50 AM
MACRA and the Future of Physician Payment
33
10:56 AM
Big Data and the Business of Retina
George A Williams MD*
34
11:01 AM
Ambulatory Surgery Centers
Derek Y Kunimoto MD JD*
35
11:06 AM
Modifiers: How and When?
36
11:12 AM
Mergers and Acquisitions: Why, When, and How?
Brenda Laigaie JD
37
11:17 AM
The Lean Office
Dennis P Han MD*
38
Section IV: Therapies for Macular and Retinal Vascular Diseases

Moderator: Susanna S Park MD PhD*
11:22 AM
Placental Growth Factor in MacTel1
40
11:28 AM
Central Serous Choroidopathy Treatment Update
41
11:34 AM
MEK Inhibitors and Complications
Jose S Pulido MD MS
44
11:39 AM
Management of Retinal Diseases in Pregnant Patients
Mark W Johnson MD*
46
11:45 AM
Hemorrhagic Occlusive Retinal Vasculitis
Dean Eliott MD*
48
11:51 AM
Reliability of Compounded Drugs

Usha Chakravarthy MBBS

PhD*
50
Section V: Retinal Degenerations

Moderator: Raymond Iezzi MD*
11:56 AM
Visual Prostheses: Argus II, Subretinal, Bionic Eye
Allen C Ho MD*
51
12:01 PM
Sensory Substitution for Low Vision
Mark S Humayun MD PhD*
54
12:07 PM
North Carolina Macular Dystrophy
Kent W Small MD
55
12:13 PM
Gene Therapy for Leber Amaurosis Type 2Clinical Results
Albert M Maguire MD*
56
12:19 PM
Stargardt: Diagnosis, Course, and Future Directions
Hendrik P Scholl MD*
57
12:24 PM
Current and Future Management of Retinal Degenerations
Hendrik P Scholl MD*
58
12:30 PM
Innovative Gene Therapy: Where We Are and Where We Are Headed
Robert E MacLaren MBChB*
59
12:36 PM
LUNCH and RETINA EXHIBITS
Section VI: Uveitis Panel, Part I

1:55 PM
White Dot Syndrome Cases
Moderator: Sunil K Srivastava MD*
Panelists: Anita Agarwal MD, Thomas A Albini MD, Amani Fawzi MD,
K Bailey Freund MD*, David Sarraf MD*, Lawrence A Yannuzzi MD
2:15 PM
Advocating for Patients

61
John A Wells III MD*
62
Program Schedule
xxxiii
Section VII: My Coolest Surgical Video

Moderator: Carl C Awh MD*

Virtual Moderator: Steven D Schwartz MD*
Panelists: Brandon G Busbee MD*, Sunir J Garg MD FACS*, Justin Gottlieb MD,
Taiji Sakamoto MD PhD*, Lihteh Wu MD*
2:20 PM
Endocryotherapy for the Treatment of a Retinal Hemangioblastoma
2:22 PM
Panel Discussion
2:25 PM
Autologous Neurosensory Retinal Transplant for Closure of

Refractory Large Myopic Macular Hole
2:27 PM
Panel Discussion
2:30 PM
Use Ofnitinol Basket in Dislocated Lens
2:32 PM
Panel Discussion
2:35 PM
NonPenetrating Subretinal Injection
2:37 PM
Panel Discussion
2:40 PM
Retinal Embolectomy

2:42 PM
Panel Discussion
2:45 PM
Vote for Winner
Colin McCannel MD*
64
64
Karthik Srinivasan MS
64
Yuki Morizane MD
64
David Almeida MD PhD

MBA*
64
Section VIII: Pediatric Retina

Moderator: Antonio Capone Jr MD*
2:47 PM
Update on ROP Clinical Trials Results?
R V Paul Chan MD*
65
2:53 PM
Management of Familial Exudative Vitreoretinopathy
Michael T Trese MD*
67
2:58 PM
Pediatric Retina Panel: What the Retina Specialist Should Know
Panel Moderator: Antonio Capone Jr MD*
Panelists: Audina M Berrocal MD*, Felix Y Chau MD*, Kimberly A Drenser MD*,
Mary Elizabeth Hartnett MD FACS*, Thomas C Lee MD
REFRESHMENT BREAK With the Experts and RETINA EXHIBITS

Moderators: M Gilbert Grand MD and Andrew J Packer MD
3:18 PM
AMD, Dry

Emily Y Chew MD
Demetrios Vavvas MD
AMD, Wet

Susan B Bressler MD*

Philip J Rosenfeld MD PhD*
Business of Retina
George A Williams MD*
Diabetic Retinopathy


Lee M Jampol MD*
Lloyd P Aiello MD PhD*
Jennifer K Sun MD*
Vitreolysis

Julia A Haller MD
Peter W Stalmans MD PhD*
Gene Therapy
Albert M Maguire MD*
Intraocular Tumors

Ivana K Kim MD*

Timothy G Murray MD MBA*

68
xxxiv
Program Schedule
Macular Holes

Andrew A Moshfeghi MD MBA*

John T Thompson MD*
New Instrumentation

Carl C Awh MD*

David R Chow MD*
Ocular Imaging

Jay S Duker MD*

Giovanni Staurenghi MD*
Richard B Rosen MD*
Pediatric Retinal Disease

Kimberly A Drenser MD PhD*

Michael T Trese MD*
Retinal Detachment

Steven T Charles MD*

Sunir J Garg MD FACS*
Grazia Pertile MD
Vascular Occlusions

Michael S Ip MD*
Ingrid U Scott MD MPH*
Section IX: Late Breaking Developments, Part I

Moderator: Lucy H Young MD PhD FACS
4:03 PM
Conbercept for Retinal Vein Occlusion: Results of the FALCON Study
Peter K Kaiser MD*
69
4:08 PM
Key Learnings from a Phase 2 Study of Encapsulated Cell Therapy

for the Treatment of Neovascular AMD
Szilard Kiss MD
70
4:12 PM
TREX: Monthly vs. Treat and Extend for Neovascular AMD
Charles C Wykoff MD PhD*
71
4:17 PM
Fundus Abnormalities and Risk Factors in Infants with Microcephaly

Associated with Presumed Zika Virus Congenital Infection in Brazil:
Results of the Zika Virus Study Group
Mauricio Maia MD
73
Section X: First-time Results of Clinical Trials, Part I

Moderator: Andrew P Schachat MD
Panelists: J Fernando Arevalo MD*, David S Boyer MD*, Neil M Bressler MD*
4:22 PM
Results of a Phase 2 Study Using an Anti-Amyloid Beta Monoclonal

Antibody for the Treatment of Geographic Atrophy Secondary to
Age-Related Macular Degeneration
74
4:27 PM
Phase 2b/3 Clinical Trial of Emixustat Hydrochloride
Pravin U Dugel MD
75
4:32 PM
Intravitreal Brimonidine Drug Delivery System (Brimonidine DDS) in

Patients with Geographic Atrophy: A Phase 2 Study
76
4:37 PM
PAN-90806A Novel Topical Treatment for Neovascular AMD
Scott W Cousins MD
77
4:42 PM
Phase 1 Anti VEGF and Ang-2 Inhibition Studies
Karl G Csaky MD*
78
4:47 PM
Ranibizumab and vPDT Combination Therapy Versus Ranibizumab

Monotherapy for Macular PCV: 12-month Results from the
EVEREST II Study
Adrian H Koh MD
79
4:52 PM
Panel Discussion
Section XI: Neovascular AMD

Moderator: Gisele Soubrane MD PhD
5:02 PM
Innovative Treatment Targets
Peter K Kaiser MD*
80
5:08 PM
Long-term Outcomes of Anti-VEGF Therapy for AMD
Mark C Gillies MD PhD*
81
5:13 PM
Optimizing Wet AMD Treatment Outcomes
83

Program Schedule
xxxv
5:18 PM
Latest Findings from the CATT Trials
Daniel F Martin MD
85
5:23 PM
Polypoidal Variants and Outcomes
Gregg T Kokame MD
86
5:28 PM
Prognostic Parameters in Anti-VEGF Therapy for Neovascular AMD

Ursula M Schmidt-Erfurth
MD*
88
5:33 PM
Closing Remarks


5:35 PM
ADJOURN
Saturday, Oct. 15
7:00 AM
CONTINENTAL BREAKFAST
8:00 AM
Opening Remarks


Section XII: Imaging

Moderator: Carmen A Puliafito MD MBA*
8:05 AM
Advances in Spectral Domain OCT Imaging
Nadia Khalida Waheed MD*
93
8:13 AM
Adaptive Optics Update
Jacque L Duncan MD*
94
8:19 AM
Predicting and Quantifying Geographic Atrophy Growth
Theodore Leng MD*
96
8:26 AM
OCT Angiography
Richard F Spaide MD*
97
8:34 AM
Hyperspectral Imaging
Amir H Kashani MD PhD*
99
Section XIII: Late Breaking Developments, Part II

Moderator: Mark S Blumenkranz MD
8:39 AM
Non-invasive Wearable Enhancement for Advanced Peripheral

Visual Field Loss
100
8:43 AM
Treatment of Vitreomacular Traction with Pneumatic Vitreolysis
Clement K Chan MD
101
8:48 AM
Efficacy and Safety of Ocriplasmin Within Subgroups Defined by

SD-OCT Characteristics From The OASIS Study
102
8:53 AM
A New Biosimilar Ranibizumab
Alay S Banker MD
103
Section XIV: Debates

Moderator: Reginald J Sanders MD
8:59 AM
Laser vs. Anti-VEGF for Proliferative Diabetic Retinopathy: Pro
David J Browning MD PhD* 104
9:02 AM
Laser vs. Anti-VEGF for Proliferative Diabetic Retinopathy: Con
Judy E Kim MD*
105
9:05 AM
Audience Vote
9:06 AM
Anticoagulation Requires Modification Prior to Surgery: Pro
Timothy W Olsen MD
106
9:09 AM
Anticoagulation Requires Modification Prior to Surgery: Con
Darius M Moshfeghi MD*
107
9:12 AM
Audience Vote
9:13 AM
Compounded Drugs Are Reliable: Pro
Dante Pieramici MD*
108
9:16 AM
Compounded Drugs Are Reliable: Con
Julia A Haller MD
109
9:19 AM
Audience Vote

xxxvi
Program Schedule
Section XV: Oncology

Moderators: Evangelos S Gragoudas MD* and Ivana K Kim MD*
9:20 AM
Management of Radiation Retinopathy in 2016
Tara A McCannel MD*
110
9:26 AM
Genetics of Ocular Tumors
J William Harbour MD*
111
9:32 AM
Current Management of Ocular Tumors
Arun D Singh MD
112
9:38 AM
Photodynamic Therapy as an Effective Therapy for Malignant

Choroidal Tumors
Jerry A Shields MD
113
9:44 AM
Innovative New Pharmacologic Treatment for Melanoma:

Immunotherapy and Small Molecule Inhibitors
Carol L Shields MD*
114
9:52 AM
REFRESHMENT BREAK and AAO 2016 EXHIBITS
Section XVI: Diabetes

Moderator: Andrew P Schachat MD*
10:37 AM
Protocol S: Anti-VEGF for Proliferative Diabetic Retinopathy
Lee M Jampol MD*
115
10:44 AM
Protocol T: Two-Year Results
116
10:50 AM
Impact of Anti-VEGF on Retinal Perfusion
Jeffrey S Heier MD*
119
10:56 AM
OCT Biomarkers for Treatment Response to Diabetic Macular Edema
Jennifer K Sun MD*
120
11:02 AM
Safety of Anti-VEGF Drugs

Marco A Zarbin MD PhD

FACS*
121
11:07 AM
Subthreshold Laser: What Is the Level of Proof?
Anat Loewenstein MD*
123
11:13 AM
Neurodegenerative Changes in Diabetic Retinopathy
Thomas W Gardner MD MS* 125
11:19 AM
Future Targets for Diabetic Macular Edema Therapy
Peter A Campochiaro MD*
127
Section XVII: First-time Results Clinical Trials, Part II

Moderators: Tien Yin Wong MBBS* and William F Mieler MD
Panelists: Barbara Ann Blodi MD*, Susan B Bressler MD*, William R Freeman MD*,
Elias Reichel MD*, Rishi P Singh MD*
11:27 AM
A Multicenter, Double Masked Phase 2 Clinical Trial Evaluating

Abicipar Pegol for Diabetic Macular Edema
Tarek S Hassan MD
129
11:32 AM
Intravitreal Injection of a Rho-Kinase Inhibitor (Fasudil) Combined with

Bevacizumab versus Bevacizumab Monotherapy for Diabetic Macular
Edema; a Randomized Clinical Trial
Hamid Ahmadieh MD
130
11:37 AM
Efficacy and Safety Trial of Intravitreal Injections Combined With

PRP for the Treatment of CSME Secondary to Diabetes Mellitus (DAVE)
Rosa Y Kim MD
131
11:42 AM
Improvement in Diabetic Retinopathy Progression Status in At-risk

Patients Treated with 0.2 g/day Fluocinolone Acetonide Over 36 Months
Usha Chakravarthy MBBS

PhD
134
11:46 AM
Sarilumab, an Anti-Interleukin-6 Receptor Antibody, for Posterior

Segment Noninfectious Uveitis (NIU): Results of SATURN
Quan Dong Nguyen MD
135
11:51 AM
Panel Discussion

Program Schedule
xxxvii
Section XVIII: Uveitis, Part II

Moderator: Emmett T Cunningham Jr MD PhD MPH
12:06 PM
Pharmacologic Treatments for New Biologics
Debra A Goldstein MD*
136
12:12 PM
Diagnostic and Therapeutic Procedures
Janet Louise Davis MD*
137
12:18 PM
Innovative Suprachoroidal Microneedle
Diana V Do MD*
139
12:24 PM
Uveitis Case Panel
Panel Moderator: Alexander J Brucker MD*
Panelists: James Philip Dunn Jr MD*, Glenn J Jaffe MD*, Ann-Marie Lobo MD*,
Pauline T Merrill MD*
12:40 PM
140
LUNCH and AAO 2016 EXHIBITS
Section XIX: Non-neovascular AMD

Moderators: Jason S Slakter MD* and Deeba Husain MD*
2:00 PM
Complement for Geographic Atrophy: Overview
Philip J Rosenfeld MD PhD*
141
2:05 PM
Nucleoside Reverse Transcriptase Inhibitors Are Promising for AMD
Jayakrishna Ambati MD*
142
2:10 PM
AREDS Update
Emily Y Chew MD
143
2:15 PM
AMD in AIDS
Douglas A Jabs MD MBA*
145
2:20 PM
Emerging Areas of Therapy for Geographic Atrophy
Demetrios Vavvas MD
146
Section XX: Vitreoretinal Surgery, Part II

Moderator: Young Hee Yoon MD*
2:26 PM
Vitrectomy for Vitreous Opacities

J Sebag MD FACS FRCOphth 147

FARVO*
2:31 PM
Vitrectomy for Diabetic Macular Edema
Rajendra S Apte MD PhD*
148
2:36 PM
Whats New in Macular Hole Surgery
John T Thompson MD*
149
2:41 PM
Gore-Tex Sutured IOL
Omesh P Gupta MD
151
2:46 PM
Suprachoroidal Surgery
Ehab N El Rayes MD PhD*
153
2:52 PM
Dislocated IOLs Panel
Panel Moderator: Tamer H Mahmoud MD*
Panelists: Susanne Binder MD, Jason Hsu MD*, Linda A Lam MD,
Yannek I Leiderman MD PhD*, Mathew W MacCumber MD PhD
155
Section XXI: Retinal Vein Occlusion

Moderator: Justis P Ehlers MD*
3:07 PM
What Workup Is Indicated for Retinal Vein Occlusion?
Michael S Ip MD*
156
3:13 PM
Sonothrombolysis
Andrew W Eller MD*
157
3:18 PM
Suprachoroidal Triamcinolone Acetonide Concomitant with

IVT Aflibercept: Phase 2 Retinal Vein Occlusion (RVO) Study
David M Brown MD*
158
3:23 PM
Retinal Vein Occlusion Case Panel
Panel Moderator: H Richard McDonald MD
Panelists: Sharon Fekrat MD*, Szilard Kiss MD*, Baruch D Kuppermann MD PhD*,
Alice T Lyon MD*, Ingrid U Scott MD MPH*

159
xxxviii Program Schedule

3:43 PM
Silicone Oil Droplets Following Intravitreal Injections:

ASRS Adverse Event Reporting
3:48 PM
REFRESHMENT BREAK and AAO 2016 EXHIBITS
Judy E Kim MD
160
Section XXII: Video Surgical ComplicationsWhat Would You Do?

Moderator: Kourous Rezaei MD*
Panelists: Mina Chung MD*, J Michael Jumper MD*, Andrew A Moshfeghi MD MBA*,
Kirk H Packo MD*, Gaurav K Shah MD*, Elliott H Sohn MD*
4:18 PM
Scleral Buckle
4:23 PM
Panel Discussion
4:28 PM
Macular Fold
4:33 PM
Panel Discussion
4:38 PM
Epiretinal Membrane Peeling
4:43 PM
Panel Discussion
4:48 PM
Staining
4:53 PM
Panel Discussion
4:58 PM
Giant Retinal Tear Detachment

5:03 PM
Panel Discussion
5:08 PM
Closing Remarks

5:10 PM
ADJOURN

Sengul C Ozdek MD*
161
Fabio Patelli MD
162
Jay S Duker MD*
164
Andrs I Bastien MD*
165
Homayoun Tabandeh MD
MS FRCP FRCOphth*
166

Suprachoroidal Hemorrhage Management:

When, How?
John Kitchens MD
Choroidal hemorrhage (or suprachoroidal hemorrhage, SCH)
is a potentially devastating complication of intraocular surgery
and trauma. Although choroidal hemorrhage occurs most
commonly after anterior segment surgery (corneal transplant,
incisional glaucoma surgery, and cataract surgery), retina
specialists are often the end of the road when it comes to
managing this complication. Achieving optimal outcomes for
these patients depends on preoperative management as well
as surgical approach. Preoperatively, management of discomfort with gabapentin and oral corticosteroids is critical. Also
critical is the timing of surgical intervention. Ideally, the SCH
should be maximally liquified in order to allow for complete
drainage. Surgically, a variety of techniques can be employed
to allow for drainage of the SCH. These techniques can range
from traditional drainage of the SCH with a scleral cut-down to
transconjunctival techniques that may provide greater control
and less trauma to the conjunctiva, which can be advantageous
in cases related to glaucoma filtering surgery. Surgical videos of
a variety of these techniques will highlight the critical steps of
each surgical approach.
Retinectomy Pearls
Steve Charles MD
Retinectomy (Charles 1978) is defined as removing all retina,

vitreous, and epiretinal membrane anterior to a circumferential,
so-called relaxing retinotomy (Machemer 1978). Retinectomy
produces less hypotony than relaxing retinotomy, probably
because of debulking of proliferating retinal pigment epithelial
(RPE) and glial cells as well as elimination of substrate (scaffold), extending from the posterior edge of the vitreous base
anteriorly to the ciliary body. A total capsulectomy should be
performed using end-grasping forceps if lensectomy if required
rather than leaving capsule so a sulcus IOL can be implanted
at a later date. Residual lens epithelial cells associated with
remaining capsule are highly reactive, causing inflammation
that leads to ciliary body membranes and resultant hypotony
and concave iris. Debulking of proliferating RPE and glial cells
also reduces recurrent proliferative vitreoretinopathy (PVR). All
silicone oil reoperations should be performed under oil; forceps
membrane peeling, subretinal surgery, and retinectomy work
very well under oil. There is no need to remove oil and use liquid
perfluorocarbons and then replace the oil at the end of the case
in PVR reoperations with oil present. These additional unnecessary steps add time and cost, as well as increasing inflammation. Liquid perfluorocarbons often become subfoveal in PVR
cases. There is no need for buckles in PVR cases. Buckles cause,
on average, a 2.75D myopic shift, damage the conjunctiva and
episclera, making glaucoma surgery less effective, cause strabismus, pain, slight ptosis, and increase operating time and cost.
Many surgeons currently perform retinectomy under BSS or,

even worse, under liquid perfluorocarbons. Retinectomy should
be performed under air as a final step in the reattachment
experiment as a subset of the interface vitrectomy. The steps
in the reattachment experiment are as follows: (1) Remove all
apparent vitreous traction including anterior loop traction.
(2) Perform inside-out forceps membrane peeling for all apparent, peelable epiretinal membranes. (3) Remove or segment
subretinal bands that alter the retinal contour using punchthrough retinotomy without diathermy or a retinotomy. (4)
Initiate drainage of subretinal fluid through existing retinal
breaks or a posterior drainage retinotomy if needed. (5) Start
fluidair exchange when the height of the retinal detachment
stops decreasing. (6) Perform simultaneous drainage of subretinal fluid and fluidair exchange until the retina reattaches
or subretinal air appears or the reattachment process stalls.
(7) Perform vitrectomy under air if residual vitreous traction is
identified. (8) Perform forceps peeling of epiretinal membrane
under air if additional membrane is identified. (9) Use punchthrough retinotomy and end-grasping forceps to remove subretinal bands under air if bands are preventing reattachment. (10)
If the retina remains partially detached, use incremental retinectomy under air, using diathermy or endolaser hemostasis only to
large vessels. If 270-degree retinectomy is needed, extend to 360
degrees because experience has shown the remaining 90 degrees
will typically contract later.
Endoscopic Surgery
Jorge G Arroyo MD
I. Endoscope-Assisted Vitrectomy

A. Independent of media
B. Variable perspective
C. High magnification (small field of view)
D. Particularly helpful in complex intraocular foreign

body cases
A. Independent of media
B. Helps identify and remove small lens fragments

hidden behind iris
A. Ciliary body membrane peeling in cases of hypo

tony
B. Macular membrane (difficult due to lack of stereopsis)
II. Endoscope-Assisted Lensectomy

III. Endoscope-Assisted Membrane Peeling
IV. Endoscopic Diode Laser Photocoagulation

A. Excellent treatment of peripheral retina
B. Spares long posterior vessels and nerves
V. Endoscopic Cyclophotocoagulation

A. Neovascular glaucoma
B. Recalcitrant glaucoma
Use of Perfluorocarbon Liquids

Stanley Chang MD
Perfluorocarbon liquids (PFCLs) are a versatile tool during

vitreoretinal surgery for complex forms of retinal detachment.
This video will cover several intraoperative scenarios where
PFCL can be helpful and potential complications can be minimized when PFCLs are properly used. The following maneuvers
will be demonstrated:
1. Peeling the internal limiting membrane (ILM) for a case
of retinal detachment secondary to macular hole in a
highly myopic eye with PFCL assistance
2. Flattening the retinal detachment with proliferative vitreoretinopathy (PVR) and posterior retinal breaks
3. Using PFCL to protect the retina during retrieval of a
dislocated IOL, phacofragmentation of a dislocated dense
cataract, and removal of intruded Miragel implants
Retinal detachment with macular hole in a highly myopic
eye should be managed first with the use of intravitreal triamcinolone to highlight any layers of adherent cortical vitreous
(vitreoschisis). Following removal of the adherent vitreous, the
retinal detachment is flattened by a fluidair exchange, with
internal drainage of subretinal fluid through the macular hole.
This should be done slowly so that the macular hole does not
enlarge. The ILM must be removed so that the macular hole can
be closed, reducing the potential for recurrent retinal detachment. Under air, brilliant blue dye is injected to stain the ILM.
After removal of the dye, fluid is reintroduced into the vitreous
and ILM peeling is initiated. If the retina is too mobile, the
subretinal fluid is aspirated through the macular hole and PFCL
is injected to immobilize the retina. The edge of ILM can then
be identified, and ILM can be gently peeled under PFCL using
a tangential peeling force. The PFCL is then removed, and a
fluidair exchange can be done for the gas tamponade.
Posterior retinal breaks are often encountered in reoperations of eyes with retinal detachments and PVR. All posterior
epiretinal membranes are peeled from the retina before using
PFCL first. Membranes should be carefully dissected so that
existing breaks are not enlarged and minimal new breaks
develop. The second step will be to reduce any anterior PVR
forces that are causing retinal foreshortening by debulking the
peripheral anterior vitreous. Then a small amount of PFCL is
injected within the funnel of the detachment, to test how well
the retina flattens. If the retinal breaks flatten, PFCL injection
is continued. If the retina anterior to the PFCL bubble remains
elevated, it may be necessary to release the anterior tractional
forces by making a relaxing retinotomy. Once the retinal breaks
are flattened under PFCL, it may be possible to free any curled
edges of the retinal breaks.
PFCLs are occasionally helpful in the management of dislocated IOL or dense nuclear lens fragments. With IOLS the PFCL
is used to elevate the edge of the capsular bag or IOL so that it
can be more safely grasped with forceps and brought anteriorly. If the lens falls back, the macula is protected by the PFCL.
PFCL can be added to stabilize the eye volume if a corneal incision is necessary to remove and IOL. PFCL can also be used to
protect the macula during fragmentation of dense brunescent
cataract fragments. We have also used PFCL during removal of
fragment of a Miragel scleral buckle that has gradually swollen
and intruded into the vitreous over time.
Selected Readings
1. Chang S, Kwun RC. Perfluorocarbon liquids in vitreoretinal surgery. In: Ryan S, ed. Retina, 4th ed. St. Louis: Elsevier (Mosby);
2006: ch 128, pp 2179-2190.
2. Dalma-Weiszhausz J, Franco-Cardenas V, Dalma A. A modified
technique for extracting dislocated lenses with perfluorocarbon
liquids and viscoelastics. Ophthalmic Surg Lasers Imaging 2006;
41:572-574.
Optimal Use of Silicone Oil

Grazia Pertile MD
Indications
Silicone oil should be used when a long-term tamponade is
required but cannot be provided by long-acting gas. In particular, in cases of:

Initially closed retinal break that is expected to reopen,

usually due to proliferative vitreoretinopathy (PVR)
Chorioretinal traumatic lesions, especially when positioned posterior to the equator and therefore at high risk
of PVR
Inferior large retinotomies that are at risk of dehiscence
due to vitreous base contraction or PVR
Diabetic patients with severe proliferative retinopathy or
anterior proliferation at high risk of recurrent vitreous
hemorrhage
Patients who cannot position
Preventable Complications

Unpreventable Complications

Injection Techniques
The aim is to reach an almost complete filling of the vitreous
cavity with silicone oil. In order to remove virtually all the fluid,
two techniques can be used:
1. First perform an air exchange, and then inject silicone oil.
The major disadvantages of the temporary use of air are
the risk of slippage of the retina, in cases of large retinotomies, and weakening of lens-zonules that can facilitate
the passage of oil in the anterior chamber during the postoperative period.
2. Inject perfluorocarbon liquid (PFCL) up to the level of
the sclerotomies, and then inject oil, while aspirating the
meniscus of fluid remaining between oil and PFCL.
In the past, it was demonstrated that silicone oil does not fit
into small recesses, such as those adjacent to indentation caused
by scleral buckling. Take into consideration the removal of
(part) of the buckling material that can interfere with the tamponade.
If possible, maintain a separation between anterior and

posterior segment to prevent silicone oil from coming into
contact with the cornea. For this reason, it is preferable
to perform a phacoemulsification and IOL implantation,
rather than lensectomy alone.
Avoid temporary increase of the IOP during oil injection to prevent migration of silicone oil into the anterior
chamber through an area of zonulolysis.
In aphakic eyes, perform a peripheral iridectomy at the
6 oclock position to enable the aqueous to pass from the
posterior to the anterior chamber, when the silicone oil
occludes the pupil.
Increase of the IOP in absence of overfilling

Migration of silicone oil into the anterior chamber, in
cases of severe hypotony
27-Gauge Vitrectomy for Retinal Detachments

Mara H Berrocal MD
I. Introduction
The introduction of the 27-gauge vitrectomy platform

has provided surgeons with the opportunity to develop
new techniques to surgically repair retinal detachments. The combination of high-speed cutting rates,
enhanced fluidic control, and very small gauge instruments allows for exquisite finesse and precision when
performing maneuvers during vitrectomy. In this video
presentation, different techniques will be shown for
repairing retinal detachments utilizing 27-gauge vitrectomy instruments.
A. Traction retinal detachments (TRD)

1. Segmentation
2. Blunt probe dissection
3. Back-shave
4. Surface peeling with probe
B. Combined traction and rhegmatogenous retinal

detachments

1. 7500-10,000 c/m ideal
2. All the techniques used in TRD
3. Chandelier usually not needed, only in select

cases
4. Viscodissection only if very adherent membranes
C. Rhegmatogenous retinal detachment
1. Shaving of membranes from the surface possible
2. Chandelier for bimanual dissection useful
3. Probe can be used as scissors in periphery dissection.
4. Probe to perform relaxing retinotomies
III. Limitations

A. Not suitable for 5000 cs or heavy silicone oil

removal or injection
B. Can be used in giant retinal tears but the drying of

the edge is lengthier
C. Learning curve in patients with anterior pathology

to avoid bending instruments
II. Surgical Techniques and Pearls

D. Retinal detachments with proliferative vitreoretinopathy
Selected Readings
1. Toygar O, Mi CW, Miller DM, Riemann CD. Outcomes of transconjunctival sutureless 27g vitrectomy with silicone oil infusion.
Graefes Arch Clin Exp Ophthalmol. Epub ahead of print 2016
Apr 19.
2. Toygar O, Berrocal MH, Charles M, Riemann CD. Next-generation dual-bore cannula for injection of vital dyes and heavy liquids
during pars plana vitrectomy. Retina 2016; 36(3):582-587.
3. Khan MA, Shahlaee A, Toussaint B, Hsu J, Sivalingam A, Dugel
PU, Lakhanpal RR, Riemann CD, Berrocal MH, Regillo CD, Ho
AC. Outcomes of 27 gauge microincision vitrectomy surgery for
posterior segment disease. Am J Ophthalmol. 2016; 161:36-43.
1. Primary vitrectomy or combined buckle-vitrectomy
4. Osawa S, Oshima Y. Innovations in 27g vitrectomy for sutureless microincision vitrectomy surgery. Retina Today, July/August
2014; 42-45.
2. High-speed cutting to minimize movement of

detached retina
5. Berrocal MH. A minimalist approach to surgery for diabetic retinal detachment. Retina Today, April 2014; 65-68.
3. Inject perfluorocarbon liquids through cannula

with side port
4. Can perform airfluid exchange with vitrectomy probe
Giant Retinal Tear:

Vitrectomy Alone Is SufficientPro
Donald J DAmico MD
Giant retinal tears, defined as tears (not dialyses) greater than
90 degrees in size, include a spectrum with varying degrees of
complexityincluding extent, irregularity such as radial rips,
associated ocular trauma, and many other confounding factors
such as proliferative vitreoretinopathy, to name but a fewand
it is clearly impossible to generalize the optimum treatment
strategy across this full range of complexity. Restricting ourselves to the management of primary or straightforward
giant retinal tears, we can consider their management by the 6
potential elements of surgery: vitrectomy, retinopexy, positioning the retinal flap, lensectomy, scleral buckling, and tamponade. Vitrectomy and positioning of the retinal flap by perfluorochemical are the essence of the contemporary approach, and
although there are important choices to be made, retinopexy
and a tamponade are also essential; consequently, there is no
controversy at all regarding 4 of the 6 elements of surgery.
The controversy revolves around the necessity of adding a
scleral buckle and/or also performing a lensectomy to secure
the best results in giant retinal tear repair. In the add a scleral
buckle and/or perform lensectomy controversy, surgeons and
published series differ widely. Some surgeons favor avoiding
scleral buckles,1-5 while others favor adding a scleral buckle as
virtually a matter of routine6 or only for certain types of giant
tears.7,8 Still others advocate buckling as a measure to preserve
the crystalline lens while also addressing the vitreous base.9
These differences regarding the necessity of scleral buckles in
the management of giant retinal tears will be resolved by continued exchange of our experiences and outcomes as vitreoretinal surgery continues its remarkable evolution.
References
1. Chang S, Lincoff H, Zimmerman NJ, Fuchs W. Giant retinal
tears: surgical techniques and results using perfluorocarbon liquids. Arch Ophthalmol. 1989; 107:761-766.
2. Krieger AE, Lewis H. Management of giant retinal tears without
scleral buckling: use of radical dissection of the vitreous base and
perfluoro-octane and intraocular tamponade. Ophthalmology
1992; 99:491-497.
3. Batman C, Cecik O. Vitrectomy with silicone oil or long-acting
gas in eyes with giant retinal tears: long-term follow-up of a randomized trial. Retina 1999; 19:188-192.
4. Ambresin A, Wolfensberger TJ, Bovey EH. Management of giant
retinal tears with vitrectomy, internal tamponade, and peripheral
360 degree retinal photocoagulation. Retina 2003; 23:622-628.
5. Jain N, Kozak JA, Niziol LM, Musch DC, Zacks DN. Vitrectomy
alone in the management of giant retinal tears. Ophthalmic Surg
Lasers Imaging Retina. 2014; 45:421-427.
6. Gonzalez MA, Flynn HW Jr, Smiddy WE, Albini TA, Tenzel P.
Surgery for retinal detachment in patients with giant retinal tear:
etiologies, management strategies, and outcomes. Ophthalmic
Surg Lasers Imaging Retina. 2013; 44:232-237.
7. Pitcher JD III, Khan MA, Storey PP, et al. Contemporary management of rhegmatogenous retinal detachment due to giant retinal
tears: a consecutive case series. Ophthalmic Surg Lasers Imaging
Retina. 2015; 46:566-570.
8. Goezinne F, La Heij EC, Berendschot TTJM, et al. Low redetachment rate due to encircling scleral buckle in giant retinal tears
treated with vitrectomy and silicone oil. Retina 2008; 28:485-492.
9. Verstraeten T, Williams GA, Chang S, et al. Lens-sparing vitrectomy with perfluorocarbon liquid for the primary treatment of
giant retinal tears. Ophthalmology 1995; 102:17-20.
Giant Retinal Tear:

Vitrectomy Alone Is SufficientCon
Gary W Abrams MD
There have been no randomized clinical trials comparing repair
of retinal detachments associated with giant retinal tears with
or without use of a scleral buckle. There are several small clinical series in the literature with conflicting results. Some report
successful repair of giant tears with vitrectomy alone, while others report lack of a scleral buckle as a risk factor for redetachment. There are no reported series that indicate that placement
of a scleral buckle is a risk factor for failure of surgery.
The rationale for a scleral buckle is to help relieve traction on the vitreous base at the ends of the giant tear and on
the non-torn retina. While aggressive shaving of the vitreous
base will eliminate traction in some eyes, complete shaving
may be difficult, particularly in phakic eyes. Most will agree
that certain giant retinal tears will benefit from placement of
a scleral buckle: in the presence of any degree of proliferative
vitreoretinopathy (PVR), a scleral buckle should be placed. For
giant tears greater than 270 degrees, there is already adequate
relaxation of the retina, so there is no need for a scleral buckle.
For giant tears less than 270 degrees, with or without PVR, a
low buckle with a 42 band is easily placed, but not tightened,
prior to vitrectomy. The scleral buckle should be localized to
support each end of the giant tear unless it extends posterior to
the equator (if one end of the tear extends posterior to the equator, it is adequate to localize that end at the equator). Slippage of
the giant tear can be avoided by careful drying of the posterior
edge of the giant tear during perfluorocarbon liquid (PFCL)air
exchange or by direct PFCLsilicone oil exchange. An unfolded
giant tear in an eye filled with air or silicone oil does not slip
when tightening the scleral buckle. While some uncomplicated
giant tears may do well without a scleral buckle if the vitreous
base can be adequately shaved, most will benefit from placement of a low encircling scleral buckle.
Selected Readings
1. Al-Khairi AM, Al-Kahtani E, Kangave D, Abu El-Asrar AM.
Prognostic factors associated with outcomes after giant retinal
tear management using perfluorocarbon liquids. Eur J Ophthalmol. 2008; 18:270-277.
2. Goezinne F, La Heij EC, Berendschot TT, Gast ST, Liem AT, Lundqvist IL, Hendrikse F. Low redetachment rate due to encircling
scleral buckle in giant retinal tears treated with vitrectomy and
silicone oil. Retina 2008; 28:485-492.
Best Rx for VMT: Ocriplasmin

Peter Stalmans MD PhD
Review of relevant drug safety information through clinical

development and following approval provides a unique opportunity to continuously assess the safety profile of drugs. Clinical
trial and cumulative postmarketing data on the safety profile
of ocriplasmin, obtained from the fourth periodic benefitsrisk evaluation report (PBRER4),1 suggest the safety profile
of ocriplasmin has been consistent with the Phase 3 clinical
trials.2 Recent publications have also contributed to a better
understanding of the safety profile of ocriplasmin and suggest
that the pharmacologic action of ocriplasmin on the vitreous
and vitreoretinal interface can cause symptoms associated with
changes in tractional forces.3,4 Several postmarketing Phase 4
studies that are currently ongoing or completed have demonstrated that long-term efficacy in real-world settings is far better
than indicated by the Phase 3 trials, because of better patient
selection.5 Moreover, the results from these trials show a consistent safety profile of ocriplasmin, with less severe adverse events
compared to vitrectomy surgery.6
References
1. Ocriplasmin 4th periodic benefit-risk evaluation report. ThromboGenics NV. Dec. 4, 2014.
2. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis
with ocriplasmin for vitreomacular traction and macular holes.
N Engl J Med. 2012; 367(7): 606-615.
3. Kaiser PK, Kampik A, Kuppermann BD, Girach A, Rizzo S, Sergott RC. Safety profile of ocriplasmin for the pharmacologic treatment of symptomatic vitreomacular adhesion/traction. Retina
2015; 35(6): 1111-1127.
4. Hahn P, Chung MM, Flynn HW Jr, et al. Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: a comprehensive analysis of premarketing and postmarketing experiences.
Retina 2015; 35(6):1128-1134.
5. Kuppermann BD. Ocriplasmin for the treatment of symptomatic
vitreomacular adhesion/traction. US Ophthalmic Rev. 2015;
8(1):55-59.
6. Stalmans P. Ocriplasmin is safe and its indications should be
expanded: pro. Paper presented at Retina Subspecialty Day,
Annual Meeting of the American Academy of Ophthalmology;
2015; Las Vegas.
10
Best Rx for VMT: Gas

Robert L Avery MD
I. Procedure

A. Early use for macular hole
B. Use for vitreomacular traction (VMT)
C. Gas choice
II. Advantages

A. Cost-effective
B. Office-based
C. High success rate
D. Lack of dyschromatopsia/ ERG changes
III. Disadvantages

A. Inability to fly
B. Positioning requirements
C. Increased floaters
D. Risk of retinal detachment
Selected Readings
1. Chan CK, Wessels IF, Friedrichsen EJ. Treatment of idiopathic
macular holes by induced posterior vitreous detachment. Ophthalmology 1995; 102(5):757-767.
2. Mori K, Saito S, Gehlbach PL, Yoneya S. Treatment of stage 2
macular hole by intravitreous injection of expansile gas and induction of posterior vitreous detachment. Ophthalmology 2007;
114(1):127-133.
3. Gupta B, McHugh D. Pneumatic retinopexy for the management
of impending macular hole: an optical coherence tomography
study. Int Ophthalmol. 2011; 31(1):23-24.
4. Jorge R, Costa RA, Cardillo JA, Uno F, Bonomo PP, Farah ME.
Optical coherence tomography evaluation of idiopathic macular
hole treatment by gas-assisted posterior vitreous detachment. Am
J Ophthalmol. 2006; 142(5):869-871.
5. Rodrigues IA, Stangos AN, McHugh DA, Jackson TL. Intravitreal injection of expansile perfluoropropane (c(3)f(8)) for the
treatment of vitreomacular traction. Am J Ophthalmol. 2013;
155(2):270-276.e2.
6. Mein C. Pneumatic vitreolysis for treatment of focal vitreomacular traction and early small macular holes. Presented at ASRS;
July 14, 2015; Vienna.
7. Steinle NC. Comparison of three non-surgical treatments for
vitreomacular traction (VMT). Presented at ARVO; May 2, 2016;
Seattle, WA.
11
Best Rx for VMT: PPVx
The Best Treatment for Vitreomacular Traction Is Vitrectomy

Caroline Baumal MD
Current options for vitreomacular traction (VMT) include
observation, ocriplasmin, intravitreal injection of an expansile
gas bubble, or vitrectomy (PPV). Observation should be considered in minimally symptomatic patients, as many of these
eyes remain stable. In symptomatic patients, a brief period of
observation to allow for spontaneous resolution may be considered before evaluating therapeutic options. The rate of release of
focal VMT after ocriplasmin is only 26.5%, with the potential
for side effects immediately after injection including loss of acuity, floaters, photopsia, and dyschromatopsia. Ellipsoid zone
attenuation, electroretinographic abnormalities, and retinal
tears have also been reported. There have been 2 small, retrospective, nonrandomized published series evaluating a total of
16 eyes with isolated VMT treated with intravitreal injection
of expansile gas. This intervention of expansile gas was only
offered to selected patients without prospective randomization.
Vitrectomy has the highest anatomical success rate, as it
relieves both the anterior-posterior and the tangential traction
exerted by abnormal vitreous on the retina. This is consistent
with 3-D OCT demonstrating complex multifaceted vitreoretinal attachments in VMT. Most eyes with VMT also have an
associated epiretinal membrane (ERM), which can be addressed
during PPV. Intraoperative adjuvants such as triamcinolone and
indocyanine green may further highlight the vitreous and internal limiting membrane, respectively, and improve anatomical
results for VMT. Vision improvement after PPV has been variable but probably is in the range of 80%. This may be affected
by chronicity of VMT until PPV is performed, delay in presentation, cataract, and other factors. The extent, size, and chronicity of VMT likely play an important role in explaining why the
less invasive options of intravitreal expansile gas or ocriplasmin
have limited efficacy. Retinal tears have been reported after all
three treatments, likely due to the tenacious nature of vitreous
in eyes that develop VMT.
6. Bottos J, Elizalde J, Rodrigues EB, Farah M, Maia M. Vitreomacular traction syndrome: postoperative functional and anatomic outcomes. Ophthalmic Surg Lasers Imaging Retina. 2015;
46:235-242.
7. Gandorfer A, Benz MS, Haller JA, et al; MIVI-TRUST Study
Group. Association between anatomical resolution and functional
outcomes in the MIVI-TRUST studies using ocriplasmin to treat
symptomatic vitreomacular adhesion/ vitreomacular traction,
including when associated with macular hole. Retina 2015;
35:1151-1157.
8. Sharma P, Juhn A, Houston S, et al. Efficacy of intravitreal ocriplasmin on vitreomacular traction and full-thickness macular
holes. Am J Ophthalmol. 2015; 861-867.
9. Novack RL, Staurenghi G, Girach A, Narendran N, Tolentino M.
Safety of intravitreal ocriplasmin for focal vitreomacular adhesion in patients with exudative age-related macular degeneration.
Ophthalmology 2015; 122:796-802.
10. Varma R, Haller JA, Kaiser PK. Improvement in patient-reported
visual function after ocriplasmin for vitreomacular adhesion:
results of the Microplasmin for Intravitreous InjectionTraction
Release Without Surgical Treatment (MIVI-TRUST) trials. JAMA
Ophthalmol. 2015; 133:997-1004.
11. Amoaku W, Cackett P, Tyagi A, et al. Redesigning services for
the management of vitreomacular traction and macular hole. Eye
2014; 28:S1-S10.
12. Hager A, Seibel I, Riechardt A, Rehak M, Joussen AM. Does ocriplasmin affect the RPE-photoreceptor adhesion in macular holes?
Br J Ophthalmol. 2015; 99:635-638.
13. Rodrigues IA, Stangos AN, McHugh DA, Jackson TL. Intravitreal injection of expansile perfluoropropane (C3F8) for the treatment of vitreomacular traction. Ophthalmology 2013; 155:270276.
Selected Readings
14. Duker, JS, Kaiser PK , Binder S, et al. The International Vitreomacular Traction Study Group classification of vitreomacular
adhesion, traction, and macular hole. Ophthalmology 2013;
120(12):2611-2619.
1. Yu G, Duguay J, Marra KV, et al. Efficacy and safety of treatment

options for vitreomacular traction: a case series and meta-analysis. Retina. Epub ahead of print 2016 Jan 16.
15. Jackson TL, Nicod E, Angelis A, et al. Pars plana vitrectomy for
vitreomacular traction syndrome: a systematic review and metaanalysis of safety and efficacy. Retina 2013; 33:2012-2017.
2. Day S, Martinez JA, Nixon PA, et al. Intravitreal sulfur hexafluoride injection for the treatment of vitreomacular traction syndrome. Retina 2016; 36:733-737.
16. Stalmans P, Duker JS, Kaiser PK, et al. OCT-based interpretation

of the vitreomacular interface and indications for pharmacologic
vitreolysis. Retina 2013; 33(10):2003-2011.
3. Chan C. Management of focal vitreoretinal traction with pneumatic vitreolysis. Presented at American Ophthalmological Society meeting; May 19-22, 2016; Colorado Springs, CO.
17. Witkin AJ, Patron ME, Castro LC, et al. Anatomic and visual
outcomes of vitrectomy for vitreomacular traction syndrome.
Ophthalmic Surg Lasers Imaging Retina. 2010; 41:425-431.
4. Pritchard EWJ, Ilyas SU, Amar SK, Yang YC, Narendran N.

Clinical characteristics and selection of treatment modality for
patients with vitreomacular traction: real-world implementation
of NICE guidance (TA297). Clin Ophthalmol. 2016; 10:79-85.
18. Chang LK, Fine HF, Spaide RF, Koizumi H, Grossniklaus HE.
Ultrastructural correlation of spectral-domain optical coherence
tomographic findings in vitreomacular traction syndrome. Am J
Ophthalmol. 2008; 146,1:121-127.
5. Tzu JH, John VJ, Flynn Jr HW, et al. Clinical course of vitreomacular traction managed initially by observation. Ophthalmic
19. Koizumi H, Spaide RF, Fisher YL, et al. Three-dimensional evaluation of vitreomacular traction and epiretinal membrane using
spectral-domain optical coherence tomography. Am J Ophthalmol. 2008; 145:509-518.
12
Office-Based Surgery: Ready for Prime Time? Pro

Tarek S Hassan MD
I. Key Definitions (Merriam-Webster Dictionary)

IV. Why Some Think We Are Not Ready for Office Vitrectomy, and Why They Are Wrong
A. Ready

1. Prepared mentally or physically for some experience or action
A. Office vitrectomy simply cannot be done.

1. Inability to fully achieve surgical goals: Not

true; has been done in many eyes
2. Prepared for immediate use

B. Naysayer
1. One who denies, refuses, opposes, or is skeptical

or cynical about something
2. A person who says something will not work or

is not possible
a. OVIT: Hilton et al., Retina, Dec. 2002:

results

i. 225 patients; 23-g, 1-port office vitrectomy; multifunction instrument with both
cutting and infusion (Visitrec)
ii. Diagnoses: endophthalmitis, uveitis,

intravitreal lens fragments, ghost cell
glaucoma, rhegmatogenous retinal
detachment
iii. Surgical goals achieved in all cases.
iv. Only 1 eye required a second procedure in

the operating room.
II. Are We Ready?

A. Mentally prepared for office based surgery: Absolutely

1. Done in many fields for at least 2 decades
2. More procedures done in more and more specialties in recent years

B. Mentally prepared for office-based vitrectomy:

Should be Absolutely

1. Some have been ready for more than 20 years.
2. More surgeons realize they are ready because

advancing technology has made it possible, safe,
and potentially preferable in many cases.
b. Intrector (Insight Instruments): results,

examples

i. Updated portable 23-g handheld vitrector

with simultaneous infusion; 1-port vitrectomy
ii. Koch and Koss, Arch Ophthalmol. Dec

2011
C. Those who are not prepared for office vitrectomy

now are stuck with long-held misconceptions, fear
of change, and a poor understanding of current
technology.
III. The Most Important Considerations for Any Surgery
A. Patient safety
B. Patient outcomes
C. Patient ease and comfort
D. Physician ease and comfort

1. Easy scheduling
2. Easy facility access
3. Comfortable surroundings
4. Efficient delivery of care
(a) 4509 eyes; space-clearing AMD procedures, endophthalmitis, vitreous hemorrhage, retinal detachment
(b) Extremely high surgical success; very

low complication rates
c. Retrector (Insight Instruments): examples

i. Updated handheld 23-g handheld vitrector with retractable MVR needle; 2-port
vitrectomy (used with separate infusion
line)
ii. Higher cut rates (1270 cpm)
iii. Very successful; similar indications as

Intrector
d. VersaVit (Synergetics): examples
E. Successful management of adverse operative scenarios
i. Small full-function console; standard

3-port vitrectomy
F. Family ease and comfort
ii. Significantly smaller footprint
G. Reimbursement
iii. Portable
iv. Less expensive machine and packs
v. All vitreoretinal surgical procedures are

possible (except pars plana lensectomy
with phacofragmotome).

(a) Currently used for vitrectomy in many

OR settings
(b) Has been used for office vitrectomy
3. Few surgical indications: Not true; increasing

and evolving indications

a. Currently

i. Portable vitrectomy: Media and spaceclearing procedures (eg, endophthalmitis,

vitreous hemorrhage, AMD, uveitis,
floaters, aqueous misdirection, vitreous
prolapse and/or incarceration, etc.)
ii. Full console vitrectomy: All vitreoretinal procedures except lensectomy with
phacofragmotome (coming?)
2. Insufficient technology: Not true; current and

future systems/devices

13
a. Currently available

i. Intrector: Single-port vitrectomy
ii. Retrector: Two-port vitrectomy
iii. Versa Vit: Standard 3-point vitrectomy
i. Fully functioning office operating room
b. Future technology and new applications of

improving technology
ii. Ability to do all vitreoretinal surgical procedures
i. Full-sized consoles used in the office

setting (eg, Alcon Constellation,
Bausch+Lomb Stellaris PC, DORC Eva,
etc.)
b. Future
4. Those that never really considered office vitrectomy = Naysayers

a. Unaware or disbelieving of many specialties

that do office surgery
(a) Size/space is not a limitation to office

use.
i. With local, regional, and even general

anesthesia
(b) Can be used in a dedicated procedure

room without difficulty
ii. ENT, Urology, OB/GYN, Plastic Surgery,

Ortho, OMFS, GI, etc.
ii. Ultra high speed vitreous cutter
b. Unaware or disbelieving of numerous ophthalmologists who perform office cataract

surgery: topical or peribulbar anesthesia
(b) More than 1 millioncpm
(c) Effectively liquefies vitreous; nearly

tractionless
c. Surgeons that own their ASCs and do not

welcome such a transition
d. General natural resistance to progress and

change
(a) Bausch+Lomb ultrasonic harmonics

vitreous cutter
(d) Potentially effective for atraumatic

small-gauge media clearing procedures
iii. Heads up (3-D) vitrectomy: Cameras
visualize the posterior segment; 3-dimensional image projection
B. Not safe

1. Lack of sterility

a. Currently many office treatment rooms are

likely more sterile than some third-world
hospital operating rooms with open windows, unmasked OR staff, reused disposable instrumentation, etc.
b. Sterility problems solved by technology
(a) Currently microscopes are used to capture surgical images.
(b)
Soon, cameras will replace microscopes.

(c) Digital image enhancement and the

use of large, high-definition monitors
allow for vitrectomy using much lower
levels of intraocular light. Helps solve
issues with the delivery of intraocular
light during 1- or 2-port portable vitrectomies. Reduces overall footprint of
the surgical setup
(d) Currently available and future systems:
Heads up 3-D surgery using an external monitor (NGenuity, Alcon); Wearable headsets; no monitor required:
The Future
iv. Adjunctive enzymatic vitrectomy: autologous plasmin enzyme and/or ocriplasmin
to liquefy vitreous and simplify vitrectomy
i. SurgiCube (SurgiCube International BV):

Any room provided with sterile OR conditions

(a) Modular unit provides a localized,

optimally filtered, ultraclean surgical
environment.
(b) Ultracleanair flow is blown directly

on the operating surface, using laminar downflow technique.
(c) Game changer: Many advantages for

patient and physician
14

ii. Operio mobile sterile air zone unit

(a) Directed, nonturbulent ultraclean air

flow over the surgical site and/or sterile instruments
(b) Small and transportable, with integrated foldable sterile instrument tray
V. What We Need

iii. Usable for both OR area and/or clean

room
a. Small footprint and full-size vitrectomy consoles have essentially full surgical capability
to manage intraoperative emergencies.
b. Need hospital emergency procedures with IV

sedation; anesthesiologist if general anesthesia
C. Unregulated

1. Historically, not subject to the same local, state,

and federal regulations as hospitals or ambulatory surgical centers
2. Much greater oversight and accreditation or

registration are now provided by multiple state
agencies (Boards of Medicine and Departments
of Health, specialty societies, AMA, Joint Commission, etc.).
2. Inability to handle operative or anesthetic emergencies

D. Not reimbursed

1. No facility fees paid by Medicare, Medicaid;

potentially by private payers
2. Surgeon fees reimbursable
3. Further work is being done in this area by CMS

with input of the Academy and other societies.
A. Ability to see the future and understand the evolution of technology: Now at the tip of the iceberg

1. More people are optimizing the safety and delivery specifics of office vitrectomy.
2. Need to understand that most vitreoretinal procedures can be done in the office
3. Must understand the trend of miniaturization of

required operating spaces
B. Willingness to break from old dogma and look to

rapidly advancing technology to solve problems
with existing delivery of surgical care issues
C. Foresight to eliminate negativity and obstructionism towards the inevitable
VI. Office vitrectomy is ready now and will be increasingly done

A. Soon and often
B. Ultimately as the standard of care for most conditions and patients

1. Not for every patient or every condition (medically compromised patients, trauma, etc.)
2. However, most patients will benefit from progress toward office vitrectomy.
C. Disbelievers of office vitrectomy

1. Impossible to argue against office vitrectomy

with any actual facts
2.
Dont fall on the wrong side of history! We are
ready!
15
Office-Based Surgery: Ready for Prime Time? Con

Nancy M Holekamp MD
I. Introduction
b. CMS mostly negative comments
A. Office-based vitrectomy procedures have been

reported in the literature dating back to 1996.
c. Opposed by the Outpatient Ophthalmic Surgery Society
B. So why hasnt office vitrectomy come into the

mainstream over the last 20 years?
d. Surgeons professional fee will not cover the

total cost.
C. Significant obstacles to adoption
e. High volume required to be profitable is

unlikely for vitrectomy surgery with patient
selection.
II. Significant Obstacles to Adoption

A. Patient safety

1. Elderly patients with significant comorbidities
2. Could not use IV sedation (requires Class B certification)
3. The unexpected complication
B. Infection prevention/control requires both stated

and federal regulation/certification
C. Economics

a. Room build-out requirements
b. Costs for equipment
2. Per-case costs
3. Centers for Medicare and Medicaid Services

(CMS) do not pay a facility fee for in-office surgery.

a. Currently in review for cataract surgery
A. Possible but not widely adopted: 1 group with over

20,000 cases
B. Oral sedation as opposed to IV sedation
C. Premium IOLs and refractive procedures can offset

costs.
D. Higher volume can make economics work.
E.
Ocular Surgery News survey from April 2016:
Should cataract surgery be performed in an office
setting?
1. Capital costs

III. Lessons Learned From In-Office Cataract Surgery
1. Yes: 29.4%
2. No: 70.54%
IV. Conclusion
Office-based vitrectomy surgery is not ready for prime
time.
16
Innovative PPVx System: Ultrasonic Vitrectomy

New Prototype of the Hypersonic Vitrector:
Fluidics Analysis and Histopathological Findings
Paulo E Stanga MD
Purpose
The purpose of our research was to evaluate the effect of gauge
size, percentage of ultrasound power (US), and aspiration settings on flow rate performance and on the retinal layers using a
new prototype of hypersonic vitrector (HV).
We compared our results using this new technology with
those obtained with a currently commercially available pneumatic guillotine vitrector (GV).
Setting
The liquification and excision of the vitreous body using lowpower HV is a promising new alternative to pneumatic GV
systems.
Methods
Vitrectomy surgery (pars plana vitrectomy; PPV) was performed using the HV (Bausch+Lomb; St. Louis, MO, USA) and
a currently commercially available pneumatic GV and 23-gauge
(23G) needles with both technologies (Stellaris PC Vitrectomy
System, Bausch+Lomb; St. Louis, MO, USA).
Predetermined aspiration levels (50, 100, 200, 300, 400,
500, and 600 mmHg) for both systems were used.
In studies for fluidics analysis, cut rates for guillotine cutter (0, 500, 1000, 1500, 2000, 3000, 4000, and 5000 cuts per
minute [CPM]) and percentages of US power for the 23G and
25G UHV needles (0%, 10%, 20%, 30%, 40%, and 50%) were
used in BSS and porcine vitreous. Porcine eyes were obtained
within 12-24 hours of slaughter, and the anterior segment was
removed at the pars plana to allow for open-sky vitrectomy surgery of undiluted vitreous. The vials with BSS and the sectioned
eyes were weighed on a high-precision balance (high-speed [2
samples/s] weight scale precise to 0.0001g). Two independent
observers performed 6 measurements of the mass of BSS and
the vitreous before (n = 3) and after (n = 3) vitrectomy surgery. Results were converted to volume removed as a function
of time-flow rate (ml/min), using the arithmetic mean of the
weight calculations.
For the histopathological assessment, cut rates for guillotine

cutter (3000 and 5000 CPM) and percentages of US power
for the UHV needles (10%, 20%, 30%, 40%, and 50%) were
used in 14 consecutive cadaveric porcine eyes obtained within
12-24 hours of slaughter. Six closed PPVs and 8 open-sky PPVs
(after removal of the anterior segment at the pars plana) were
performed. The UHV and GV were held at 3 to 5 mm in front
of the macula. The effects of US and guillotine technology were
also tested in 4 cadaveric porcine crystalline lenses submerged
in BSS and by touching the posterior capsule with both the
UHV and the GV. The crystalline lens and the retinal specimens
were evaluated using microscopy and histochemical methods.
Results
There was no vitreous flow at zero cut rates or US % (off) for
either HV or GV. Needle gauge of HV did not affect flow rate
when used with either BSS or vitreous. However, gauge size
strongly affected flow rate when using the GV (P < .01), in both
BSS and vitreous. Wall thickness of HV needles did not affect
flow rates either in BSS or vitreous.
There were no macroscopic retinal defects associated with
the use of either the HV or the GV at 10%, 20%, 30%, 40%, or
50% US and 3000 and 5000 cut rates. Neither needle gauge nor
wall thickness of the HV affected the molecular structure of the
retina layers.
Conclusions
Flow rate is not affected by gauge of HV needle for similar ports
and vacuums, and this could allow for the use of smaller gauge
and port size, as well as lower infusion pressures than with a
GV.
Furthermore, the retinal structure does not seem to be
affected by gauge of the HV needle for similar ports and vacuums. The use of an HV in the middle of the vitreous cavity
and at 3 to 5 mm from the retina and at the described US % of
power may be safe.
Hypersonic vitrectomy is a promising new alternative to the
currently commercially available guillotine-based technology
for vitrectomy systems.
17
Update on Heavy Oil Use

Murat Oncel MD
Long-acting gases and silicone oil are effective internal tamponade agents; however, because their specific gravity is lower
than that of the vitreous fluid, they may provide adequate support for the superior breaks and detachments complicated by
proliferative retinopathy (PVR). However, its density, which is
lower than that of water, may result in fluid accumulation in the
inferior quadrant, which is not covered by silicone oil, and ineffective tamponade at the retinal breaks. Therefore, an aqueous
environment with inflammatory and cellular proliferation may
promote development of inferior PVR. Indeed, most reproliferations of PVR can be seen in these areas that are not covered by
the silicone oil tamponade in the upright position. In the supine
position, the PVR soup shifts to the premacular areas, thereby
enhancing the risk for formation of premacular epiretinal membranes and cystoid macular edema. Thus, a specific role may
exist for an internal tamponade agent with higher specific gravity, such as heavy silicone oils.
Theoretical benefits of heavy silicone oil in complicated retinal detachments are as follows:
1. Breaks and retinotomy edges in the lower periphery can
efficiently be supported in the upright position.
2. The instantaneous interruption of an open communication between the subretinal space/ retinal pigment epithelial cells and the preretinal space through the patent
break might lower the risks for a PVR development and a
reopening break.
3. Displacement of the proliferative mixture of residual
aqueous, inflammatory, and retinal pigment epithelial
cells away from lower retina and the posterior pole could
result in reduction of postoperative PVR and cystoid
macular edema.
4. The tamponade effect at the posterior pole may lead to a
faster and longer-lasting reattachment of the macula.
5. Redetachments should arise predominantly in the superior periphery where they are easier to treat with gas tamponades.
6. Redetachments should have a higher percentage of macula on situations.
However, initial clinical series of various heavy tamponades
have reported significant complication rates. Some clinical evidence seems to presume that heavy silicone oils are more prone
to intraocular inflammation than standard silicone oil if they
remain in the eye for several months. In most studies, the heavy
silicone oil (HSO) was removed between 3 and 6 months postoperatively.
Recently developed heavy tamponades have demonstrated
better results and fewer complications than the earlier used substances, and are slowly gaining acceptance within the vitreoretinal community, despite notable skepticism.
Indications
Heavy silicone oils are commonly used in complicated types
of rhegmatogenous retinal detachments (RRDs) and redetachments. They are used in patients with PVR and without PVR.
Many series also include patients with previous blunt and penetrating trauma. Patients with RRD not complicated by PVR
are mainly those who have breaks or tears in the lower fundus
periphery. The largest subgroups are patients with giant tears
or large, multiple, and posterior breaks. Another subgroup is
myopic patients with RRD, associated with a macular hole, a
posterior staphyloma, or recurrent macular holes. Uncommon
indications that were included into clinical trials as single cases
only were tractional RD associated with diabetic retinopathy,
retinoschisis, endophthalmitis, hypotony, and retinal necrosis.
Few patients with breaks in the superior periphery in addition
to inferior pathology have been treated with heavy silicone oils.
The patients ability to keep an appropriate posture postoperatively has also been a rational behind the use of heavy tamponades in some patients with RRD.
Heavy Silicone Oils

Oxane HD
Oxane HD (Bausch+Lomb; Toulouse, France) is a mixture
of 5700 mPas PDMS and RMN-3 (perfluorooctyl-5-methylhex-2-ene), a mixed fluorinated and hydrocarbonated olefin.
The surface tension and the interfacial tension of this agent
against water are similar to those of perfluorocarbon liquids
(41mN/m), and its specific gravity is only slightly greater
than that of water (1.02g/cm3). Its high viscosity (3800mPas)
reduces the risk of early emulsification. The rate of inflammatory reactions related to the use of Oxane HD was reported as
from 3% to 37% of treated patients.
Densiron 68
Densiron 68 (Fluoron; Neu Ulm, Germany) is an admixture
of F6H8 (30.5%) and PDMS 5000 mPas (69.5%); thereby, the
viscosity was increased to 1387 mPas. This translated into a
reduced ability for dispersion and emulsification, consequently
irritability to ocular structures.
HeavySil (HSIL)
HeavySil (ALCHIMIA srl; Padua, Italy) is made from the combination of high purity 75% silicone oil 5000cSt (polydimethysiloxane) and 25% perfluoroalkyloxyoctane (C11H11F13o);
it has a density of 1032 and a viscosity of 1500cSt. Its stability
and high affinity for silicone oil are due to the presence of a partially fluorinated ether instead of an alkane.
Densiron Xtra
Densiron Xtra (Fluoron; Neu Ulm, Germany) is the latest
heavy silicone oil on the market. It has improved the properties of Densiron 68 by exchanging the basic silicone. Densiron
Xtra no longer uses a Newtonian 5000-cSt silicone oil but the
Siluron Xtra with its dynamic viscosity. Siluron Xtra incorporates a mixture of 2 silicone oils with different viscosities; 90%
of the Xtra is a 1000-cSt oil, 10% is a high molecular weight
silicone oil with a viscosity of 2.500.000cSt (423000da). The
advantages are (1) it is easier to inject, (2) injection time is dra-
18
matically reduced compared to Densiron 68, and (3) it could be

injected through 25- and even 27-gauge cannulas. Explantation
is easy due to the bubble effect. Xtra has less emulsification risk
compared to Densiron 68, and hence, less inflammation.
We will present our initial results using Densiron Xtra,
which is the latest heavy silicone on the market, on complicated
retinal detachments.
In conclusion, the introduction of HSOs represents an
improvement in vitreoretinal techniques. The real utility of the
use of HSOs depends on the correct selection of the patients for
the treatment.
5. Schwartz SG, Flynn HW Jr, Lee WH, Wang X. Tamponade in

surgery for retinal detachment associated with proliferative vitreoretinopathy. Cochrane Database of Systematic Reviews 2014,
Issue 2. Art. No.: CD006126.
References
8. Cillino S, Cillino G, Ferraro LL, Casuccio A. Treatment of persistently open macular holes with heavy silicone oil (Densiron
68) versus C2F6: a prospective randomized study. Retina 2016;
36(4):688-694.
1. Caramoy A, Schrder S, Fause S, Kirchhof B. In vitro emulsification assessment of new silicone oils. Br J Ophthalmol. 2010;
94(4): 509-512.
6. Oncel M, Acikalin B. Heavy silicone oil vs standard silicone oil

for the management of complicated retinal detachment: a prospective study. Paper presented at American Academy of Ophthalmology; 2006; abstract 301.
7. Caramoy A, Kearns VR, Chan YK, et al. Development of emulsification resistant heavier-than-water tamponades using high
molecular weight silicone oil polymers. J Biomater Appl. 2015;
30(2):212-220.
2. Heimann H, Stappler T, Wong D. Heavy tamponade 1. A review

of indications, use, and complications. Eye 2008; 22:1342-1359.
9. Avitabile T, Bonfiglio V, Buccoliero D, et al. Heavy versus standard silicone oil in the management of retinal detachment with
macular hole in myopic eyes. Retina 2011; 31(3):540-546.
3. Morescalchi F, Costagliola C, Duse S, et al. Heavy silicone oil and

intraocular inflammation. Biomed Res Int. 2014; 2014: 574825.
10. Dooley IJ, Duignan ES, Kilmartin DJ. Long term heavy silicone
oil tamponade. Int Ophthalmol. 2016; 36(1):3-7.
4. Joussen A, Rizzo S, Kirchhof D, et al. Heavy silicone oil versus

standard silicone oil in as vitreous tamponade in inferior PVR
(HSO Study): interim analysis. Acta Ophthalmologica. 2011;
89(6):483-486.
Pharmacotherapy for PVR Update

Richard S Kaiser MD
N OTE S
19
20
New Instrumentation
David R Chow MD
N OTE S
21
Intraoperative 3-D OCT

Cynthia A Toth MD, Oscar M Carrasco-Zevallos MS, Michael Seider MD, and Joseph A Izatt PhD
Perioperative OCT
With the translation of OCT to ophthalmology, some of the
earliest uses were in preoperative surgical planning and postoperative monitoring of macular diseases such as macular holes,
epiretinal membranes, tractional retinal detachment, diabetic
macular disease, myopic schisis, and retinal detachment. For
surgical planning, OCT imaging revealed cross-sectional macular details that were not available from other modalities, such
as photography or ophthalmoscopy. After surgery, OCT was
used to examine for the closure of macular holes and subretinal
or intraretinal fluid and persisting membranes or traction.1-4
Absence of feedback during surgery limited the use of OCT to
ensuring the achievement of surgical endpoints.
Handheld OCT During Surgical Pauses

Technological development, intraoperative applications, and
translational challenges
Intraoperative OCT was first achieved with handheld systems
with later use of attachments to suspend an OCT handpiece
on the side of the microscope or an armature to stabilize and
suspend an OCT scanning head over the eye.5-9 Intraoperative
OCT (iOCT) provides novel information during surgery, such
as the absence of membranes across the macular surface after
peeling or change in the contour of a macular hole, in the location of subretinal fluid, or in an elevated curl of internal limiting
membrane.10-17
Ophthalmic microsurgery has to be halted to move the OCT
scanning optics over the patients eye; thus the information cannot be used in real time during an operation. Additional surgical time is therefore required to pause for imaging.
ence of macular hole or subretinal fluid, and indicate an impact

of such information on surgical decision making.22-25
With visualization of live 2-D B-scans, it is difficult to
maintain a view of an instrument and of surgical tissue during
the range of a surgical motion (eg, as the surgeon peels a membrane); it can be challenging to maintain the area of interest
within the location of the B-scans, and surgical instruments
produce shadows. Image size, pixel resolution, and contrast
within the microscope oculars are limited compared to those on
an external screen, and one cannot view images in full 3-D via a
monocular heads-up display. Integrating instruments and iOCT
technology will be important in overcoming these challenges.26
Live 3-D OCT Imaging of Surgery

An investigational, custom, ultrafast swept source OCT system
(SS-OCT) integrated into a microscope mechanical interface
with custom graphic processing unit software has resulted in
the first system capable of live MI-OCT imaging of 3-D volumes.27 Linking the 3-D iOCT volume capture to projection via
stereoscopic heads-up display (in both microscope oculars) has
been described as 4-D MI-OCT.28,29
Live 2-Dimensional (2-D) OCT Imaging in Surgery

Incorporating optical systems within the viewing path of the
operating microscope enables OCT imaging during surgical
maneuvers. Microscope-integrated (MI-OCT) systems using
spectral domain (SD-OCT) allowed capture of live 2-D OCT
imaging during surgery and subsequent viewing of 3-D volumes, usually on an external screen, at pauses in surgery.18-20
These have rapidly evolved to options for viewing the OCT
images with a monitor adjacent to the microscope and to
include a monocular heads-up display within the surgical eyepiece for intrasurgical viewing of 2-D images by the surgeon.19
MI-OCT has been used for review and analysis at pauses
between surgery and for real-time 2-D viewing of surgical
instrument-tissue interactions in systems with heads-up display.
The heads-up viewing of surgery with live 2-D iOCT is a revolutionary adjunct to the decades-old conventional surgical view
with transpupillary or endoillumination of the retinal surface
with visible light. Studies have shown multiple uses of iOCT
information, such as to assess completeness of peel or the pres-
Figure 1. Conventional microscope view of a surgeon peeling an epiretinal membrane (left) with 2-D OCT cross-sectional view of the forceps
and membrane (center) and 3-D view of the vitreoretinal interface and
the instrument grasping the epiretinal membrane (right).
Under approved research protocols, the 4-D MI-OCT investigational system enables stereoscopic surgeon viewing of near
real-time 3-D iOCT during retinal surgery for macular hole,
epiretinal membrane, and diabetic traction detachments. Furthermore, in research applications in the laboratory, surgical
maneuvers can be performed/ visualized by only 4-D iOCT,
without the use of the conventional microscope view. Studies
22
have shown a benefit of iOCT in resident training and the utility

of iOCT information in vitreoretinal surgery.30,31
Despite the rapid capture and processing, current 4-D
iOCT technology does not yet reach the speed necessary for
video-rate volumetric viewing. While stereoscopic viewing has
been achieved within the microscope oculars, image size, pixel
resolution, and contrast within the microscope oculars remain
limited compared to those on an external screen. Instrument
shadowing, field of view, and surgical viewpoint limit the full
utilization of 4-D iOCT.
The 4-D iOCT is positioned to inform surgical procedures
that are not currently achievable with conventional surgical
imaging. Future development of faster iOCT systems, OCTcompatible instruments, and refinements to control of surgeon
viewpoint will improve iOCT volumetric visualization of the
vitreoretinal interface, retinal surface, and retinal and subretinal structures. This provides a unique opportunity to improve
surgical outcomes.
12. Henry CR, Berrocal AM, Hess DJ, Murray TG. Intraoperative
spectral-domain optical coherence tomography in Coats disease.
Ophthalmic Surg Lasers Imaging. 2012; 80-84.
References
1. Wilkins JR, Puliafito CA, Hee MR, et al. Characterization of
epiretinal membranes using optical coherence tomography. Ophthalmology 1996; 103(12):2142-2151.
17. Ehlers JP, Han J, Petkovsek D, Kaiser PK, Singh RP, Srivastava
SK. Membrane peeling-induced retinal alterations on intraoperative OCT in vitreomacular interface disorders from the PIONEER
Study. Invest Ophthalmol Vis Sci. 2015; 56(12):7324-7330.
2. Mikajiri K, Okada AA, Ohji M, et al. Analysis of vitrectomy for

idiopathic macular hole by optical coherence tomography. Am J
Ophthalmol. 1999; 128(5):655-657.
18. Tao YK, Ehlers JP, Toth CA, Izatt JA. Intraoperative spectral
domain optical coherence tomography for vitreoretinal surgery.
Opt Lett. 2010; 35(20):3315-3317.
3. Gallemore RP, Jumper MJ, McCuen BW, Jaffe GJ, Postel EA,
Toth CA. Diagnosis of vitreoretinal adhesions in macular disease
with optical coherence tomography. Retina 2000; 20(2):115-120.
19. Ehlers JP, Tao YK, Farsiu S, Maldonado R, Izatt JA, Toth CA.
Integration of a spectral domain optical coherence tomography
system into a surgical microscope for intraoperative imaging.
Invest Ophthalmol Vis Sci. 2011; 52(6):3153-3159.
4. Massin P, Allouch C, Haouchine B, et al. Optical coherence

tomography of idiopathic macular epiretinal membranes before
and after surgery. Am J Ophthalmol. 2000; 130(6):732-739.
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(10):1457-1468.
6. Ray R, Baraano DE, Fortun JA, et al. Intraoperative microscopemounted spectral domain optical coherence tomography for
evaluation of retinal anatomy during macular surgery. Ophthalmology 2011; 118(11):2212-2217.
7. Pichi F, Alkabes M, Nucci P, Ciardella AP. Intraoperative SDOCT in macular surgery. Ophthalmic Surg Lasers Imaging. 2012;
43(6):54-60.
8. Riazi-Esfahani M, Khademi M, Mazloumi M, Khodabandeh A,
Riazi-Esfahani H. Macular surgery using intraoperative spectral
domain optical coherence tomography. J Ophthalmic Vis Res.
2015; 10(3):309.
9. Branchini LA, Gurley K, Duker JS, Reichel E. Use of handheld
intraoperative spectral-domain optical coherence tomography in
a variety of vitreoretinal diseases. Ophthalmic Surg Lasers Imaging. 2016; 47(1):49-55.
10. 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(2):364373.
11. 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.
13. Ehlers JP, Dupps WJ, Kaiser PK, et al. The Prospective Intraoperative and Perioperative Ophthalmic Imaging With Optical
Coherence Tomography (PIONEER) study: 2-year results. Am J
Ophthalmol. 2014; 158(5):999-1007.
14. Ehlers JP, Xu D, Kaiser P, Singh R, Srivastava S. Intrasurgical
dynamics of macular hole surgery: an assessment of surgeryinduced ultrastructural alterations with intraoperative optical
coherence tomography. Retina 2014; 34(2):213-221.
15. Ehlers JP, Tam T, Kaiser P, Martin D, Smith G, Srivastava S. Utility of intraoperative optical coherence tomography during vitrectomy surgery for vitreomacular traction syndrome. Retina 2014;
34(7):1341-1346.
16. Ehlers JP, Ohr MP, Kaiser PK, Srivastava SK. Novel microarchitectural dynamics in rhegmatogenous retinal detachments identified with intraoperative optical coherence tomography. Retina
2013; 33:1428-1434.
20. Binder S, Falkner-Radler CI, Hauger C, Matz H, Glittenberg C.

Feasibility of intrasurgical spectral-domain optical coherence
tomography. Retina 2011; 31(7):1332-1336.
21. Tao YK, Srivastava SK, Ehlers JP. Microscope-integrated intraoperative OCT with electrically tunable focus and heads-up display
for imaging of ophthalmic surgical maneuvers. Biomed Opt
Express. 2014; 5(6):1877-1885.
22. Hahn P, Migacz J, OConnell R, et al. Preclinical evaluation and
intraoperative human retinal imaging with a high-resolution
microscope-integrated spectral domain optical coherence tomography device. Retina 2013; 33(7):1328-1337.
23. Ehlers JP, Kaiser PK, Srivastava SK. Intraoperative optical coherence tomography utilizing the RESCAN 700: preliminary results
from the DISCOVER study. Br J Ophthalmol. 2014; 98(10):13291332.
24. Ehlers JP, Goshe J, Dupps WJ, et al. Determination of feasibility
and utility of microscope-integrated optical coherence tomography during ophthalmic surgery: the DISCOVER study RESCAN
results. JAMA Ophthalmol. 2015; 133(10):1124-1132.
25. Pfau M, Michels S, Binder S, Becker MD. Clinical experience with
the first commercially available intraoperative optical coherence
tomography system. Ophthalmic Surg Lasers Imaging Retina.
2015; 46(10):1001-1008.
26. Ehlers JP, Srivastava SK, Feiler D, Noonan AI, Rollins AM, Tao
YK. Integrative advances for OCT-guided ophthalmic surgery and
intraoperative OCT: microscope integration, surgical instrumentation, and heads-up display surgeon feedback. PLoS One. 2014;
9(8):e105224.
27. Carrasco-Zevallos OM, Keller B, Viehland C, et al. Real-time 4D
visualization of surgical maneuvers with 100 kHz swept-source

microscope integrated optical coherence tomography (MIOCT) in
model eyes. Invest Ophthalmol Vis Sci. 2014; 55(13):1633.
28. Viehland C, Keller B, Carrasco-Zevallos OM, et al. Enhanced volumetric visualization for real time 4D intraoperative ophthalmic
swept-source OCT. Biomed Opt Express. 2016; 7(5):1815-1829.
29. Shen L, Carrasco-Zevallos OM, Keller B, et al. Novel microscopeintegrated stereoscopic heads-up display for intrasurgical optical
coherence tomography. Biomed Opt Express. 2016; 7(5):17111726.
30. Todorich B, Shieh C, DeSouza PJ, et al. Impact of microscopeintegrated OCT on ophthalmology resident performance of anterior segment surgical maneuvers in model eyes. Invest Ophthalmol Vis Sci. In press.
31. Carrasco-Zevallos OM, Keller, B, et al. Optical coherence tomography for retinal surgery: perioperative analysis to real-time fourdimensional image-guided surgery. Invest Ophthalmol Vis Sci. In
press.
23
24
Myopic Schisis and High Myopia Surgery:

When to Intervene
Hiroko Terasaki MD
Introduction
Macular retinal detachment without macular hole (MH) in a
highly myopic eye was reported over 20 years ago.1 After the
development of OCT, Takano and Kishi2 demonstrated retinoschisis-like structural changes and tractional retinal detachment in highly myopic eyes with posterior staphyloma. These
are believed to represent prodromal stages of retinal detachment with macular hole (MHRD).3
The term myopic traction maculopathy (MTM) has been
proposed to encompass all these pathologic conditions.4 Prodromal stages of MHRD include epiretinal membrane, lamellar hole or pseudohole, vitreomacular traction, retinoschisis
(schisis-like inner retinal fluid), macular tractional retinal
detachment, and full-thickness macular hole without retinal
detachment. Vitrectomy with or without internal limiting
membrane peeling is a common treatment modality for these
prodromal stages in the attempt to prevent the development of
MHRD.5
Representative Conditions From a Surgical Point of

View
1. MTMS2-foveal retinoschisis6: Relatively stable condition including pseudohole configuration (see Figure 1a).
2. MTMS4-entire retinoschisis: Progression to foveal
retinal detachment or full-thickness MH (see Figure 1b).
Forty-three percent of S4 progresses within 3 years or can
spontaneously regress (3.9%).6
Figure 1.
3. Special configuration: MTM with a champagne glass

shape (see Figure 1c).
4. MTM with foveal detachment including impending MH
(see Figure 1d).
Surgical Results
We analyzed 87 eyes with MTM without MH that underwent
vitrectomy at our institution. Surgery included silicone oil (SO)
tamponade in 17 eyes because of impending MH or for other
reasons. Of the remaining 70 eyes, MH developed postoperatively in 3 eyes (4.3%). These 3 eyes all had MTM with foveal
detachment before surgery (representing 7.1% of 42 eyes with
MTM with foveal detachment, and 9.3% of 32 eyes with foveal
detachment not receiving SO tamponade). None of the 17 eyes
that received SO tamponade developed MH postoperatively.
Indications for Vitrectomy

Since no postoperative MH developed in eyes with MTM
without foveal retinal detachment in our data, this stage may
be an indication for surgery if the patient is symptomatic with
decreased vision. On the other hand, if patients can be followed
closely, surgery can be performed once progression to foveal
detachment is confirmed. However, when MTM eyes have a
champagne glass foveal configuration with decreased visual
acuity, surgery should probably be performed before foveal retinal detachment develops, since this condition may evolve into
an impending MH soon after foveal detachment.
25
Surgical Complications
References
1. Development of MH with or without retinal detachment

during or after surgery
2. Paravascular hole formation with or without retinal
detachment during surgery
3. Nerve fiber layer damage with or without increased IOP
1. Phillips CI. Retinal detachment at the posterior pole. Br J Ophthalmol. 1958; 42:749-753.
Conclusions
MTM without foveal detachment with decreased visual acuity
or MTM soon after foveal detachment may be good a indication for surgical intervention. However, adequate discussion
with the patient is necessary, including expected outcomes and
potential complications.
2. Takano M, Kishi S. Foveal retinoschisis and retinal detachment in

severely myopic eyes with posterior staphyloma. Am J Ophthalmol. 1999; 128:472-476.
3. Among many other reports, see Kobayashi H, Kishi S. Vitreous
surgery for highly myopic eyes with foveal detachment and retinoschisis. Ophthalmology 2003; 110:1702-1707.
4. Panozzo G, Mercanti A. Optical coherence tomography findings in myopic traction maculopathy. Arch Ophthalmol. 2004;
122:1455-1460.
5. Summarized in Ohno-Matsui K, Lai TY, Lai CC, Cheung CM.
Updates of pathologic myopia. Prog Retin Eye Res. 2016; 52:156187.
6. Shimada N, Tanaka Y, Tokoro T, Ohno-Matsui K. Natural course
of myopic traction maculopathy and factors associated with progression or resolution. Am J Ophthalmol. 2013; 156: 948-957.
26
Inverted Flap Technique

Stanislao Rizzo MD
Background
Inverted internal limiting membrane (ILM) flap technique, first
reported by Michalewska et al1 in 2010, is considered an effective surgical technique for treating large idiopathic full-thickness macular holes (FTMH) and myopic macular holes (MH).
This innovative technique increased the rate of complete macular hole closure to 98% for large idiopathic MHs (diameter
exceeding 400 m) and to about 100% for high myopic MHs.
In the inverted ILM flap technique, after core vitrectomy
and dye staining, the ILM is not removed completely from the
retina but is left in place, attached to the edges of the macular
hole. This ILM remnant is then inverted upside-down to cover
the macular hole. Finally, fluidair exchange is performed.
Several mechanisms are proposed to explain tissue repair
following inverted ILM flap technique. The inverted ILM, containing Mller cell fragments, may induce glial cell proliferation, resulting in macular hole filling that enhances closure. It
may also work as a scaffold for tissue proliferation, thus providing an environment to instruct correct photoreceptors position,
finally improving postoperative vision. This hypothesis is in
agreement with histopathologic findings suggesting that basement membrane is required for cell proliferation.
Figure 1
Observations
In our experience inverted ILM flap technique appeared to be a
safe and successful procedure for the management of large idiopathic MHs and myopic MHs. We treated 20 patients affected
by idiopathic large MHs (diameter >400m) and 20 patients
affected by myopic large MHs (diameter >400m) with pars
plana vitrectomy and inverted ILM flap technique. Swept
source OCT (SS-OCT), OCT angiography, and adaptive optic
images were used to assess the anatomical outcomes of surgery,
while BCVA, microperimetry, and multifocal electroretinogram
(mfERG) were used to evaluate the functional outcomes during a 6-month follow-up. Macular hole closure was observed
in 97.5% of the patients after 1 surgery. On the OCT images,
the healing process showed the appearance of a hyper-reflective
material filling the macular hole; gradually this material contracted, inducing the hole closure (see Figures 1 and 2). All
patients showed improvement of visual function (both in BCVA
and mfERG responses) during the first 3 months after surgery.
In conclusion, vitrectomy with inverted ILM flap technique
seems to be a safe and effective surgery for idiopathic and
myopic large macular holes, improving both functional and
anatomical outcomes. The postoperative evaluation with new
retinal imaging techniques, such as SS-OCT, OCT angiography,
and adaptive optics, and functional tests such as microperimetry and multifocal ERG may help to elucidate the structural and
functional changes associated with this surgical technique and
to understand the mechanisms of the postoperative improvement of the retinal architecture.
Figure 2
References
1. Michalewska Z, Michalewski J, Adelman RA, Nawrocki J.
Inverted internal limiting membrane flap technique for large
macular holes. Ophthalmology 2010; 117:2018-2025.
2. Michalewska Z, Michalewski J, Dulczewska-Cichecka K, Nawrocki J. Inverted internal limiting membrane flap technique for
surgical repair of myopic macular holes. Retina 2014; 34:664669.
3. Hayashi H, Kuriyama S. Foveal microstructure in macular holes
surgically closed by inverted internal limiting membrane flap technique. Retina 2014; 34(12):2444-2450.
27
Intravitreal Drugs in Vitrectomized Eyes

I. Pharmacokinetics of the Vitreous Cavity
II. Special Considerations in Eyes After Vitrectomy
III. Specific Drugs

A. Anti-VEGF
B. Steroids
1. Triamcinolone acetonide
2. Dexamethasone implant
3. Suprachoroidal triamcinolone acetonide
4. Fluocinolone acetonide intravitreal implant

C. Other agents
IV. Special Treatment Considerations and Conclusions
Selected Readings
1. Ahn J, Kim H, Woo SJ, et al. Pharmacokinetics of intravitreally
injected bevacizumab in vitrectomized eyes. J Ocul Pharmacol
Ther. 2013; 29(7):612-618.
2. Chang-Lin JE, Burke JA, Peng Q, et al. Pharmacokinetics of a
sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes. Invest Ophthalmol Vis Sci.
2011; 52(7):4605-4609.
3. Ahn SJ, Ahn J, Park S, et al. Intraocular pharmacokinetics of
ranibizumab in vitrectomized versus nonvitrectomized eyes.
4. Chin HS, Park TS, Moon YS, Oh JH. Difference in clearance of
intravitreal triamcinolone acetonide between vitrectomized and
nonvitrectomized eyes. Retina 2005; 25(5):556-560.
28
2016 Charles L Schepens MD Lecture

Harry W Flynn Jr MD and Nidhi Relhan MD
I. The International Vitreomacular Traction Study

Group in 2013 provided a clinically applicable classification system that is predictive of therapeutic outcomes and is useful for the execution and analysis of
clinical studies.1

A. Vitreomacular adhesion (VMA) is defined as

perifoveal vitreous separation with remaining
vitreomacular attachment and unperturbed foveal
morphologic features.
B. Vitreomacular traction (VMT) is characterized by

anomalous posterior vitreous detachment (PVD)
accompanied by anatomic distortion of the fovea,
which may include pseudocysts, macular schisis,
cystoid macular edema, and subretinal fluid. VMT
is further subclassified by the diameter of vitreous
attachment to the macular surface as measured by
OCT, with attachment of 1500 m or less defined
as focal and attachment of more than 1500 m as
broad. When associated with other macular disease, VMT is classified as concurrent.
C. Full-thickness macular hole (FTMH) is defined as

a foveal lesion with interruption of all retinal layers
from the internal limiting membrane to the retinal
pigment epithelium. FTMH is primary if caused
by vitreous traction, and secondary if directly
the result of pathologic characteristics other than
VMT. FTMH is subclassified by size of the hole as
determined by OCT and the presence or absence of
VMT. This is in contrast to the older classification
of the macular hole (MH) stages proposed by Dr.
Gass.2,3
II. Management Options for VMT
Management options for VMT include pars plana vitrectomy, pneumatic vitreolysis, enzymatic vitreolysis,
and observation.

A. Pars plana vitrectomy (PPV) for VMT

1. Smiddy (1988):
In the pre-OCT era, reported 16 eyes that
underwent PPV for VMT; postoperative visual
acuity (VA) was either stable or improved.4
2. de Bustros (1994):
Also in the pre-OCT era, PPV for prevention of
MH examined patients with FTMH in 1 eye.
Fellow eyes with stage 1 hole were randomized
to surgery vs. observation. FTMH developed
in 10 of 27 (37%) in the PPV group, 14 of 35
(40%) in the observation group (P = .81). Study
terminated early because of low recruitment.5
3. Sonmez (2008):
Reported 21 of 24 eyes that underwent PPV and
improved by 1 line or more. Visual improvement
was greater in the eyes with focal (or V-shaped)
VMT on OCT.6
4. Witkin (2010):
Studied the visual and OCT results of PPV for
symptomatic VMT. Mean VA improved from
preoperative VA of 20/122 to postoperative VA
of 20/68 (P = .005). Improvement in vision was
less in eyes with lamellar separation of inner and
outer foveal layers than in those with cystoid
macular edema and perifoveal VMT.7
5. Davis (2010):
Retrospective case series of PPV for 36 eyes in
which the diagnosis of VMT was supported
by time-domain OCT (2002-2007). Two-line
improvement was seen in 50%, but FTMH
developed in 2 eyes (5.5%). It was noted that
patients with symptom duration of <6 months
were more likely to obtain VA of 20/40 or better
compared with patients with longer symptom
duration.8
6. Jackson (2013):
Meta-analysis of 21 PPV studies including a
total of 259 eyes. Mean age was 70.5 years, and
mean overall VA improvement was from 20/94
to 20/53. VA improved in 64.3% of patients,
and it improved by at least 2 lines in 32.9%.
The intraoperative or postoperative complications included retinal detachment in 4.56% and
FTMH in 1.44%.9
7. Chang (2014):
Evaluated cost-effectiveness and cost utilities for
treatment options for VMAs and full-thickness
MHs. As a primary procedure, PPV was the
most cost-effective therapy in this study. The
other treatment options had similar costs per
QALYs (quality-adjusted life years) saved and
compared favorably with costs of therapy for
other retinal diseases.10
8. Gonzalez (2015):
PPV in 41 consecutive eyes with preoperative
and postoperative spectral domain OCT (SDOCT). Mean age was 60.5 years (46-77), and
internal limiting membrane peeling was performed in 38 eyes (93%). Visual improvement
of 1 line or more was seen in 56% of the eyes.
3 interventions: 54, intravitreal ocriplasmin;

32, C3F8 gas injection; 27, SF6 injections. VMT
release at final follow-up was 84% with C3F8,
56% with SF6, and 48% with ocriplasmin.
The conclusions stated that C3F8 gas injections
showed superior VMT release rates compared to
the other two methods.15
Traction was released from the fovea in all eyes

as confirmed by SD-OCT. FTMH developed in
4 eyes (9.8%). Complications included 1 intraoperative retinal break but no retinal detachments.11

B. Pneumatic vitreolysis for VMT
Pneumatic vitreolysis involves injecting expansile

gas into the vitreous cavity for treatment of VMT.
It is hypothesized that gas bubble destabilizes the
vitreous integrity by accentuating liquefaction
(synchysis). Cortical vitreous collapses during the
absorption phase of bubble, resulting in PVD (syneresis). Long-acting gas bubble serves as a cushion
for more gentle or innocuous PVD.

5. Yu et al (2016):
Evaluated treatment options for VMT and

reported a retrospective, consecutive case series
and meta-analysis. In this reported case series,
0/10 controls, 3/7 intravitreal ocriplasmin
(IVO, P = .10), 7/8 intravitreal expansile gas
(pneumatic vitreolysis [PV]; P, 0.01), and 10/10
pars plana vitrectomy (P, .01) treated eyes experienced VMT release at Day 28. No patients
developed retinal tears or detachment. One
pneumatic vitreolysis-treated eye (12.5%) developed a macular hole. Meta-analysis of 23/131
prospective or retrospective and consecutive
articles performed also revealed that 63 eyes
were treated with pneumatic vitreolysis, 726
eyes were treated with intravitreal ocriplasmin,
and 253 eyes were characterized as the control
group (saline injection). The weighted rate of
VMT resolution for the control group was
0.09 (95% CI, 0.06-0.13), PV was 0.84 (95%
CI, 0.76-0.92), and intravitreal ocriplasmin
was 0.26 (95% CI, 0.23-0.29). The authors
concluded that pneumatic vitreolysis may be as
effective as or superior to nonsurgical options
for VMT release at Day 28, with a similar risk
profile.16
1. Chan (1995):
Treatment of idiopathic MH by gas-induced
PVD (pre-OCT era). In this pilot study, 11
patients with an impending MH (stages 1-A and
1-B) and 7 patients (8 eyes) with FTMH (stages
2 and 3) received gas injections. A complete PVD
was achieved in 18 of 19 eyes without a prior
PVD within 2 to 9 weeks after gas injection. Ten
of the 11 impending holes (all 7 had stage 1-A
holes; 3 of 4 had stage 1-B holes) resolved after
gas injection. After gas tamponade, 3 of 6 early
full-thickness (stage 2) MHs closed. None of
the stage 3 MHs closed after gas injection. The
mean BCVA of the successful eyes was 20/32.
There were no major complications.12
2. Rodriguez (2013):
Pneumatic vitreolysis for 15 eyes with idiopathic
(7), DME (6), AMD (1), and impending MH (1)
related VMT, after single injection of 0.3 cc of
100% C3F8. The release of VMT was seen in 6
(40%) at 1 month and 9 (60%) at 6 months. PPV
was performed in 4. No adverse events were
seen with mean follow-up of 398.7 days. The
predictors of treatment success included area
of adhesion less than 750 microns, maximum
foveal thickness less than 500 microns, low vitreous face reflectivity, and absence of DME.13
3. Chan and Mein (2016):
Analyzed 35 eyes (34 patients) with symptomatic VMT that underwent pneumatic vitreolysis
(2010-2015). The appropriate CPT code for
pneumatic vitreolysis is 67025. A complete
PVD developed in 31 eyes (88.6%) at a mean
(median) of 3.6 (3.5) weeks after C3F8 gas injection. PVD developed in 20 of 24 eyes (83.0%)
with VMT only. In eyes with a small stage 2
MH, PVD with MH closure was reported in 8
of the 11 eyes (73%).14
C. Enzymatic vitreolysis for VMT

1. Ocriplasmin:
Microplasmin, a 27 kDa recombinant selective

serine protease subunit of human plasmin. This
pharmacological agent is capable of cleaving
collagen, laminin, as well as fibronectin. It was
approved by the FDA in 2012 for the treatment
of symptomatic VMA.

4. Steinle and Avery (2016):

Presented data comparing outcomes of 3 nonsurgical approaches for the management of
symptomatic VMT, including intravitreal injection of SF6 or C3F8 or ocriplasmin. 113 consecutive patients with VMT were treated with 1 or
29
a. Stalmans (2010):
A prospective, randomized, sham-controlled
Phase 2 trial (The MIVI-IIT trial) evaluated
the ability of a single or repeated injection
of microplasmin to release VMT. This study
enrolled 60 patients with VMA (41, no MH;
19, stage 1-B/2 MHs). Within 28 days of
sham and 75, 125, and 175-g microplasmin
administration, nonsurgical resolution of
VMA was observed in 8%, 25%, 44%, and
27% of the patients, respectively. The results
support the use of microplasmin as a nonsurgical treatment for VMA.17
b. Stalmans (2012):
MIVI 006 and 007 studies are two multicenter randomized double-blind Phase 3
trials comparing a single intravitreal injec-
30

tion of ocriplasmin to intravitreal placebo.
Subjects had symptomatic focal VMA,
although MHs greater than 400 microns
were excluded. A total of 652 randomized
patients (464 receiving ocriplasmin; 188
receiving placebo) were included in the study.
Primary endpoint in this study was resolution of VMA by OCT by Day 28. MIVI 006
was in the United States only, and MIVI 007
was in the European Union and the United
States combined. Both studies independently
showed statistical significance in terms of
achieving VMA resolution. The pooled data
showed a release rate of 26.5% compared to
10.1% in the placebo group.18

of VMT/VMA patients. Improvement in

BCVA from baseline at Month 24 (2 lines)
was reported in 50.5% in the ocriplasmin
group vs. 39.1% in the control sham group.22

c. Kim (2013):
Retrospective review of all patients with
symptomatic VMA treated with intravitreal
ocriplasmin over a period of 5 months. In
this study, 8/19 patients (42%) exhibited
resolution of VMA, and macular hole closed
after injection in 6/12 patients (50%). A
higher proportion of VMA resolution was
observed in patients with the following baseline characteristics: age less than 65 years,
focal adhesion less than or equal to 1500 m,
presence of macular hole, phakic status, and
absence of epiretinal membrane.19
d. Fahim and Johnson (2014):
Case report described a patient with VA loss,

visual field constriction, pupillary abnormalities, attenuated retinal arteries, loss of outer
retinal signals on SD-OCT, and severely
reduced electroretinography (ERG) responses
(B-waves were reduced more than A-waves).
It was postulated that enzymatic cleavage of
intraretinal laminin is a biologically plausible
mechanism for acute ocriplasmin retinal
toxic effects.20
e. Tibbetts and Witkin (2014):
Case report demonstrated that disruption
of photoreceptor inner segment/ outer segment (IS/OS) (ellipsoid) layer on SD-OCT
and reduced ERG amplitudes correspond
to an ocriplasmin recipients symptoms of
darkened vision. It was postulated that ocriplasmin may have a diffuse enzymatic effect
on photoreceptors or the retinal pigment
epithelium that is not limited to areas of vitreomacular adhesion.21
f. Tolentino (2014):
The OASIS trial, a Phase 3b, 24-month,
randomized, double-masked and multicenter
study with optional crossover treatment with
single intravitreal injection of ocriplasmin
0.125 mg reported VMA/VMT resolution at
Day 28 in 41.7% in the ocriplasmin group vs.
6.2% of the control sham group (P < .001),
confirming ocriplasmin efficacy for treatment
g. Kaiser (2015):
Safety analyses based on MIVI 006 and
MIVI 007 studies assessing intravitreal ocriplasmin injection reported adverse events
(AEs), serious AEs, and suspected adverse
drug reactions. In a total of 465 eyes injected
with ocriplasmin (125 mg) and 187 eyes
treated with placebo injection in these studies, the overall AE rate was 69.0% in the
placebo group and 76.6% for ocriplasmintreated patients. Most AEs occurring in
the study eye were reported to be mild or
moderate in severity, and transient. All suspected adverse drug reactions were ocular,
nonserious, of mild intensity, and transient.
The authors concluded that intravitreal ocriplasmin injection provides a generally welltolerated pharmacologic treatment option
for patients with symptomatic vitreomacular
adhesion/ vitreomacular traction, including
when associated with full-thickness macular
holes 400 mm in diameter.23
h. Hahn (2015):
The ASRS Therapeutic Surveillance Committee showed that acute decrease in visual
acuity was observed in 7.7% of 999 eyes in
a premarketing clinical trial program and in
1.3% of 4387 eyes in postmarketing survey.
Dyschromatopsia was observed in 1.6%
and 0.5%, respectively; retina tear/ detachment, in 1.9% and 0.4 %; lens subluxation/
phacodonesis, in 0.2% and 0.02%; impaired
pupillary reflex, in 0.5% and 0.3%. The
changes of IS/OS were not assessed in the
original study as no SD-OCT imagining was
employed. It was seen in 0.2% in the postmarketing survey. Retinal vessel findings
were seen in 1 case and 2 cases, respectively.
ERG changes were seen in 10 cases and 2
cases, respectively.24
i. Lim (2016):
The Macula Society Collaborative Retrospective Study of Ocriplasmin for Vitreomacular Traction reviewed 208 eyes with
VMT, including 75 eyes with macular hole,
with at least 1 month follow-up. Macular
hole closure without vitrectomy occurred in
15% by Week 1, in 35% by Week 4, and in
40% by Week 12. Following treatment for
VMT, the VMT resolved in 45% of eyes by 1
week, 43% of eyes by 1 month, 58% of eyes
by 12 weeks, and 74% of eyes at final visit.
Overall, MH closure occurred in 65/75 eyes
(87%) by the last visit. ERGs were performed
in 9 eyes, 8 of which had macular hole. The
ERG was severely diminished in 3 of 9 eyes
were patients with fellow eye MH and patients

with advanced macular diseases such as DME
and wet AMD.30
at 1-2 days post-ocriplasmin compared to

baseline. Two eyes showed no change in the
ERG at 4 weeks but improved on the ERG
by 12 weeks. One eye had persistent ERG
change to 18 months. The ERG was reported
as showing minor to no change in the 6 other
eyes. Seven eyes (5%) with no prior record
of MH developed a macular hole, 3 (1.4%)
developed a retinal tear, 6 (2.9%) had RPE
changes reported, and 4 eyes (1.9%) developed a retinal detachment. At the last follow-up visit, 10 eyes (4.5%) had undergone
cataract surgery and 1 eye (0.5%) underwent
a scleral buckle procedure. There was no
report of any case with endophthalmitis. The
authors conclude that with intravitreal ocriplasmin adverse events were not infrequent
but were mostly not serious.25

The OASIS MP-1 substudy reported the

effects of ocriplasmin, and VMT/symptomatic VMA resolution on visual fixation and
macular sensitivity using microperimetry
were evaluated for 27/220 patients who were
enrolled in the larger OASIS trial. Short-term
results of the OASIS MP-1 substudy suggest
that in the ocriplasmin group, fixation and
sensitivity parameters tended to be better
than in the sham group over time.26
2. Anti-VEGF (2016):
Schwartz et al reported a case of VMT in DME
with progressive release of traction after 4 injections of aflibercept. VA improved from 20/50 to
20/30 after release of VMT.24
3. Luminate (ALG -1001) (2016):
Updated the data set from 6 medical centers

involving 230 eyes of 185 patients. The mean
age was 72.2 years (range: 41-92), mean followup was 29.5 months. Fifty-four eyes presented
with grade 1 VMT and VA of 20/31. The VA on
the last exam was 20/34. Seventy-five eyes presented with grade 2 VMT and VA of 20/38. The
VA on the last exam was 20/41. Fourteen eyes
presented with grade 3 VMT and VA of 20/48.
The VA on the last exam was 20/34.31
Fifty-one of 230 study eyes (22.2%) had spontaneous release of VMT during the mean of 29.5
months of follow-up. The time to spontaneous
release on OCT was mean of 16.3 months and
median 9.7 months. The study eyes that underwent treatment include 8 eyes that had PPV: 6 of
230 (2.6%) for MH, 1 for grade 2 VMT, and 1
for grade 3 VMT. Five of those 8 eyes had better
than 20/40 final VA. One eye received intravitreal injection of ocriplasmin with no release of
VMT and yet maintained a VA of 20/30. The
mean time to development of FTMH was 17.5
months for 6 patients.
A. PPV achieves consistent release of VMT but has a

low risk of postoperative FTMH. After additional
surgery for the FTMH, MH closure and favorable
visual outcomes can be achieved.
B. Pneumatic vitreolysis is a safe, effective, and minimally invasive approach to achieve nonsurgical
release of VMT with a high rate of success. This
approach seems to be the most cost-efficient, with
few reported complications.
C. Enzymatic vitreolysis is an effective nonsurgical

approach but has relatively high cost and frequent
side effects. Clinical trials have shown modest
effectiveness of this nonsurgical approach compared with saline injection.
D. Observation: Using observation alone, the

untreated clinical course is often favorable.
Approximately 35% of patients will have spontaneous resolution of VMT and achieve stable or
1. Punjabi (2007):
Observation is a viable option for patients with
small FTMH and VMT. Spontaneous closure
occurred in stage 2 idiopathic FTMHs with
VMT as documented by OCT.29
2. John (2014):
A noncomparative case series (3 medical centers)
of 106 eyes that were managed by observation
alone. The patients with VMA noted on SDOCT were selected by the individual physician.
The patients that were excluded from the study
3. Tzu (2015):
III. Conclusions
D. Observational management of VMT

The study eyes were graded. The term grade

was specifically chosen as it does not imply
sequential progression, as opposed to the term
stage. Grade 1 was incomplete separation of
cortical vitreous with foveal attachment. Grade
2 was grade 1 with any intraretinal cyst, cleft,
or schisis. Grade 3 is grade 2 with neurosensory
elevation of the retina from the retinal pigment
epithelium (subretinal fluid). High rate of spontaneous separation of VMT with time. Four of
106 eyes (3.6%) developed FTMH and underwent PPV with successful hole closure.
j. Sadda (2016):
Kuppermann et al conducted a prospective, double masked, placebo-controlled Phase 2 clinical

study, performed in 106 patients with symptomatic focal VMA over 20 sites in the United States
and Europe. This study showed 65% of patients
treated with a 3.2-mg dose of Luminate (ALG1001), an integrin antagonist, achieved release
of VMA or VMT by 90 days. This study demonstrated that Luminate was well tolerated in all
dosing groups. No safety issues were identified.28
31
32

improved VA. Rates of progression to FTMH are
low, but symptoms of visual disturbance may persist in untreated patients with VMT.
E. The risk/ benefit/ cost ratio of each option must be

evaluated for the individual patient. Observational
management can be considered for eyes with better
VA or patients with complex ocular and/or systemic diseases.

16. Yu G, Duguay J, Marra KV, et al. Efficacy and safety of treatment
options for vitreomacular traction: a case series and meta-analysis. Retina 2016.
17. Stalmans P, Delaey C, de Smet MD, van Dijkman E, Pakola
S. Intravitreal injection of microplasmin for treatment of vitreomacular adhesion: results of a prospective, randomized,
sham-controlled Phase II trial (the MIVI-IIT trial). Retina 2010;
30(7):1122-1127.
References
18. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis

with ocriplasmin for vitreomacular traction and macular holes. N
Engl J Med. 2012; 367(7):606-615.
1. Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction Study Group classification of vitreomacular
adhesion, traction, and macular hole. Ophthalmology 2013;
120(12):2611-2619.
19. Kim BT, Schwartz SG, Smiddy WE, et al. Initial outcomes following intravitreal ocriplasmin for treatment of symptomatic vitreomacular adhesion. Ophthalmic Surg Lasers Imaging Retina.
2013; 44(4):334-343.
2. Gass JD. Idiopathic senile macular hole: its early stages and
pathogenesis. Arch Ophthalmol. 1988; 106(5):629-639.
20. Fahim AT, Khan NW, Johnson MW. Acute panretinal structural
and functional abnormalities after intravitreous ocriplasmin injection. JAMA Ophthalmol. 2014; 132(4):484-486.
3. Johnson RN, Gass JD. Idiopathic macular holes: observations,

stages of formation, and implications for surgical intervention.
Ophthalmology 1988; 95(7):917-924.
4. Smiddy WE, Michels RG, Glaser BM, deBustros S. Vitrectomy for
macular traction caused by incomplete vitreous separation. Arch
Ophthalmol. 1988; 106(5):624-628.
5. de Bustros S; Vitrectomy for Prevention of Macular Hole Study
Group. Vitrectomy for prevention of macular holes: results of
a randomized multicenter clinical trial. Ophthalmology 1994;
101(6):1055-1059; discussion 1060.
6. Sonmez K, Capone A Jr, Trese MT, Williams GA. Vitreomacular
traction syndrome: impact of anatomical configuration on anatomical and visual outcomes. Retina 2008; 28(9):1207-1214.
7. Witkin AJ, Patron ME, Castro LC, et al. Anatomic and visual
outcomes of vitrectomy for vitreomacular traction syndrome.
Ophthalmic Surg Lasers Imaging. 2010; 41(4):425-431.
8. Davis RP, Smiddy WE, Flynn HW Jr, Puliafito CA. Surgical
management of vitreofoveal traction syndrome: optical coherence
tomographic evaluation and clinical outcomes. Ophthalmic Surg
Lasers Imaging. Mar-Apr 2010;41(2):150-156.
9. Jackson TL, Nicod E, Angelis A, et al. Pars plana vitrectomy for
vitreomacular traction syndrome: a systematic review and metaanalysis of safety and efficacy. Retina 2013; 33(10):2012-2017.
10. Chang JS, Smiddy WE. Cost evaluation of surgical and pharmaceutical options in treatment for vitreomacular adhesions and
macular holes. Ophthalmology 2014; 121(9):1720-1726.
11. Gonzalez MA, Flynn HW Jr, Bokman CM, Feuer W, Smiddy
WE. Outcomes of pars plana vitrectomy for patients with vitreomacular traction. Ophthalmic Surg Lasers Imaging Retina. 2015;
46(7):708-714.
12. Chan CK, Wessels IF, Friedrichsen EJ. Treatment of idiopathic
macular holes by induced posterior vitreous detachment. Ophthalmology 1995; 102(5):757-767.
13. Rodrigues IA, Stangos AN, McHugh DA, Jackson TL. Intravitreal injection of expansile perfluoropropane (c(3)f(8)) for the
treatment of vitreomacular traction. Am J Ophthalmol. 2013;
155(2):270-276 e272.
14. Chan C, Mein C. Pneumatic vitreolysis for treatment of focal
mvitreomacular traction. Macula Society; Feb. 26, 2016; Miami,
Florida.
15. Steinle N, Dhoot D, Pieramici DJ, et al. Comparison of three nonsurgical treatments for vitreomacular traction (VMT). ARVO;
May 2, 2016; Seattle, Washington; Abstract Number: 1806.
21. Tibbetts MD, Reichel E, Witkin AJ. Vision loss after intravitreal
ocriplasmin: correlation of spectral-domain optical coherence
tomography and electroretinography. JAMA Ophthalmol. 2014;
132(4):487-490.
22. Tolentino M. Long-term clinical outcomes with ocriplasmin: the
OASIS study-baseline demographics and ocular characteristics.
23. Kaiser PK, Kampik A, Kuppermann BD, et al. Safety profile of
ocriplasmin for the pharmacologic treatment of symptomatic vitreomacular adhesion/traction. Retina 2015;35(6):1111-27.
24. Hahn P, Chung MM, Flynn HW Jr, et al. Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: a comprehensive analysis of premarketing and postmarketing experiences.
Retina 2015; 35(6):1128-1134.
25. Lim JI , Glassman AR, Aiello LP, et al. Macula Society Collaborative Retrospective Study of Ocriplasmin for Vitreomacular
Traction. ARVO; May 2, 2016; Seattle, Washington; Abstract
Number: 1805.
26. Sadda SR, Kozma-Wiebe P, Meunier E. The OASIS MP-1 substudy: characterization of the effect of ocriplasmin on microperimetry parameters. ARVO; May 2, 2016; Seattle, Washington;
Abstract Number: 1805.
27. Schwartz SG, Flynn HW Jr. Progressive release of vitreomacular traction with aflibercept. Ophthalmic Surg Lasers Imaging
Retina. 2016; 47.
28. Kuppermann BD, Boyer DS, Kaiser PK, et al. Topline results
from prospective, double-masked, placebo controlled phase 2
clinical study evaluating Luminate (ALG-1001) in patients with
symptomatic focal vitreomacular adhesion. ARVO; May 2, 2016;
Seattle, Washington; Abstract Number: 1809.
29. Punjabi OS, Flynn HW Jr, Legarreta JE, Gregori G, Knighton
RW, Puliafito CA. Documentation by spectral domain OCT of
spontaneous closure of idiopathic macular holes. Ophthalmic
Surg Lasers Imaging. 2007; 38(4):330-332.
30. John VJ, Flynn HW Jr, Smiddy WE, et al. Clinical course of
vitreomacular adhesion managed by initial observation. Retina
2014; 34(3):442-446.
31. Tzu JH, John VJ, Flynn HW Jr, et al. Clinical course of vitreomacular traction managed initially by observation. Ophthalmic
Surg Lasers Imaging Retina. 2015; 46(5):571-576.
33
MACRA and the Future of Physician Payment
How Has the ACA Affected Retina Practices? How Will MACRA Affect
Retinal Practice?
When physicians and health policy mavens are asked to name
the federal legislation with the greatest impact on domestic
retinal practice, most would suggest the passage of Medicare
in 1964. Yes, Medicare greatly expanded access for the elderly
and the disabled, increased physician revenues, and stimulated
investment in new technology. However, it produced little disruption in day-to-day practice. In reality the 2015 passage of the
Medicare Payment and CHIP Reauthorization Act (MACRA) is
far more impactful.
The MACRA (aka the SGR fix bill) Notice of Proposed Rule
Making published in the Federal Register in April of 2016, if
implemented as written, will dramatically change practice and
reimbursement for all U.S. physicians. New MACRA policies
include the following:

Repeal of the sustainable growth rate (SGR) methodology

+0.5% updates for 5 years (retinologists will never see a
$1!)
Fundamentally changes the way Medicare determines
and updates payments to physicians
MACRA has two major goals. First, the elimination of

traditional fee for service, with future payments based on the
ability of physicians to provide services under risk contracts.
The proposed revenue targets for patients from risk contracts
(alternative payment models) are 25% in 2019, rising to 75% in
2013. Sheer fantasy. Second, an emphasis on improvements in
the quality of care by measuring physician performance on
quality reporting, use of information technology, clinical practice improvements, and cost.
MACRA provides two pathways to avoid cuts and achieve
bonuses: participation in alternative payment models (APMs)
and MIPS (Merit Based Incentive Payment System). The schedule of payment bonuses and penalties is outlined in the legislation.
Adjustment factor plus or minus:

2019: 4%
2020: 5%
2021: 7%
2022: 9%
Physicians with fewer than 100 Medicare patients and

$10,000 in charges are excluded. That would cover zero retinal
specialists.
The APM pathway transfers financial risk from the U.S.
Treasury and Medicare Trust fund to physicians by incentivizing the development of and physician participation in risk contracts, or alternative payment models (APMs). APMs provide
a yearly 5% bonus on Medicare payments from 2019 to 2024
that then decreases to 0.75%. However, there are no APMs
available for the retina specialty. For ophthalmologists the
MIPS pathway is the only viable option.
MIPS is a complex program that measures your performance
in the following four areas, with weights in 2019 based on 2017
performance.

Quality measures: 50% in 2019

Cost (resource use): 10% in 2019
Clinical practice improvement: 15%
Advancing Care Info. (Meaningful Use): 25%
Weights can change over time. When 75% of eligible professionals achieve Meaningful Use, the weight could be reduced to
15% to emphasize other categories. Resource use will increase
to 30%.
This presentation will delineate the how retinal physicians
integrated with the Academys IRIS Registry are positioned to
navigate and succeed in the incredibly complex changes mandated by MACRA.
34
Big Data and the Business of Retina

The passage of the Medicare Access and CHIP Reauthorization

Act of 2015 (MACRA) represents the most significant change in
health care payment policy since the advent of Medicare. There
is broad congressional and policy consensus that the present
system of fee-for-service payment must transition to a valuebased system measuring quality and cost. Upon implementation
of MACRA, ophthalmologists and retinal specialists in particular will experience unprecedented changes in reimbursement
and the delivery of care. Success in this new model is predicated
on data. Retinal specialists will need real-world, real-time data
to determine their quality and cost of care. At present, a Qualified Clinical Data Registry (QCDR) such as the IRIS Registry
appears to be the most likely mechanism for successful participation.
In 2017, CMS will implement the Quality Payment Program
involving two paths: the Merit-based Incentive Payment System
(MIPS) and the Advanced Alternative Payment Models (APM).
Although at the time of this writing the rules are not yet finalized, it is clear that the vast majority of retina specialists will
take the MIPS path. Participation in a QCDR such as IRIS is
likely to be the best mechanism for MIPS reporting. A QCDR
will facilitate reporting in the four MIPS categories of quality
(replacing PQRS and the quality component of the value modifier), advancing care information (replaces EHR Meaningful
Use), clinical practice improvement activities, and resource use.
As of April 2016, IRIS had data from 7866 ophthalmologists in 1704 practices comprising 88 million office visits from
24.5 million unique patients. It is projected that by January
2017 there will be data from 130 million office visits and that
by January 2018 there will be 40 million unique patients. These
data comprise over 350 measures taken directly from the EHR
of enrolled ophthalmologists, providing an unprecedented
opportunity for analysis of clinical outcomes, practice and billing patterns, and treatment trends.
As just one example, at the end of 2015, IRIS had comprehensive data including disease state, drugs, pre- and post-treatment
vision, comorbidities, and complications on 4,572,677 intravitreal injections from 611,818 patients. This is truly Big Data.
A detailed analysis of this dataset will be presented, with an
emphasis on implications for health policy. Initial findings
demonstrate that 47% of injections were bevacizumab, 25%
were ranibizumab (either dose), and 28% were aflibercept.
Interestingly, these proportions change by disease; bevacizumab
comprises 42% of all injections for AMD and 62% for diabetic
retinopathy. For AMD, over 20% of patients are treated with
two or more drugs, demonstrating the need for patients and ophthalmologists to have access to all available proven therapies.
Data analysis on this scale is a game changer that will facilitate our quest in the challenge to provide high-value retinal care.
35
Ambulatory Surgery Centers
ASC Update: Multiplying Revenue From ASC ownership

Derek Kunimoto MD JD

I. Introduction

A. Three current strategies for multiplying revenue

from an ASC

1. Out of network billing
2. Contractual joint venture (management agreement)
3. Anesthesia services
III. Contractual Joint Ventures

A. Definition of contractual joint venture from OIG

special advisory bulletin 2003: A contractual joint
venture is any common enterprise with mutual economic benefit.
B. Many are designed to avoid or limit federal issues,

so state issues are the most pertinent.
C. OIG advisory opinion 602: Arrangements that

carve out Medicare patients immediately draw the
attention of the OIG and may still implicate the
anti-kickback statute.
D. Management agreement: agreement to split revenue

from OON billing
B. Regulatory Landscape

1. The Department of Health and Human Services

Office of Inspector General (OIG) has issued
special fraud alerts dealing with physician
compensation arrangements with increasing frequency.
2. Deputy chief states that OIG is hiring additional

lawyers to investigate physicians.
3. Example of fraud charges in 2015, which

included doctors
4. There is also increasing interest in physician

compensation arrangements at the state level.
II. Out of Network (OON) Billing

A. What is it?
B. Spectrum of OON
C. Is it uncommon?
D. Medicare patient facility fee vs. OON facility fee
E. Claims process and collection
F. Financial impact
G. Sounds great, but payers have taken an active

stance against OON (eg, litigation by Cigna and
Aetna).
H. Landmines:

1. If any Medicare patient slips through
2. If financial disclosure does not get signed
1. Federal fraud and abuse issues: Compliance is

contingent on no government patients slipping
through the cracks: that requires no human
errors! How reasonable of an assumption is
that?

a. Secondary insurers may not be available up

front, but may come through after the fact.
b. Data entry errors
2. State fraud and abuse issues (eg, AZ law prohibits fee splitting: ASC cannot split fees with
licensed health care providers)
3. State fraud and abuse issue (eg, AZ physician

licensing: broader language prohibits MDs from
dividing a professional fee for referrals.)
4. State fraud and abuse issue (eg, AZ law requires

physicians to inform patients when they have a
direct financial interest.)
IV. Anesthesia Services

A. Profit to ASC with anesthesia package
B. Profit to ASC with anesthesia employees
C. Profit to ASC with anesthesia independent contractors
36
Modifiers: How and When?

I. Modifier 25

A. Impact on new and established patient exams
B. Applicable CPT codes
II. Modifier 57

A. Impact on new and established patient exams
B. Applicable CPT codes

III. Modifier 59
When appropriate to unbundle surgeries and testing
services
IV. Modifiers in Global Period
Clinical examples of modifier 58, 78, and 79
37
Mergers and Acquisitions: Why, When, and How?

Brenda N Laigaie JD
I. The Impetus for the Surge to Merge

1. Reduce costs while improving quality of care
2. Improve care coordination
3. Improve patient outcomes
4. Assign responsibility for patient populations
III. Merger Options

A. Directives of Patient Protection and Affordable

Care Act of 2010 (PPACA)
1. Electronic Health Records (EHR) and Practice

Management Systems (PMS)
2. Expensive equipment and drugs
3. Facilities, space, and personnel
4. Compliance
C. Declining reimbursement and changing payment
structures
A. Fully integrated (standard merger/ acquisition)

1. Merger/ acquisition vs. organic growth
2. Financial and clinical integration
3. One tax ID number (TIN)
B. Increased expenses
B. Care center/ division-based affiliation model (mega

groups)

1. Single entity (single TIN) comprised of multiple

care centers or divisions (eg, physician
practices) that provide treatment to patients
2. Parent entity (mega group) employs all physicians and staff.

a. Common payroll and benefits structure
b. Common billing and centralized management
3. Care center/ division maintains a level of autonomy.
1. Pay-for-performance and value

a. Fee-for-service with pay-for-performance
a. Physician compensation
b. Value-based modifier
b. Buy-ins and payouts
c. Meaningful Use
c. Office hours, vacations
d. Physician Quality Reporting System (PQRS)
d. Restrictive covenants
e. Merit-based Incentive Payment System

(MIPS)
e. Decisions to hire/ fire
4. Care center decisions are subject to some degree

of approval by mega group.
5. Care center pays portion of collections to mega

group for overhead corporate expenses.
2. Alternative Payment Models

a. Capitation (PMPM)/ global capitation (percentage of premium): withholds/ risk pools
b. Bundled payments/ episode of care
c. Shared savings and shared risk models (eg,

ACOs)
IV. How to Merge Successfully and Compliantly

A. Some loss of control

1. There must be some commonality; autonomy

within reason.
2. Stark and antitrust concerns
II. The Benefits of Mergers and Acquisitions

A. A seat at the table
B. Maintaining patient base and referral sources
C. Economies of scale and shared expenses
1. Common 401(k) and retirement plans
D. Group purchasing
2. Investment advisor group
E. Clinical trials
C. Addressing staff resistance
F. Access to payer contracts
D. Its still work.
G. Ability for success with risk contracting
H. Attractive to ACOs, CINs, Patient Centered Medical Homes
1. Combining PMS, billing systems, and EHR (or

at least getting them to communicate)
2. Renegotiating all payer contracts
3. Details, details, details
I. Attractive to private equity investors
B. Changes to benefits programs
38
The Lean Office

Dennis P Han MD
Lean is a philosophy that considers wasteful the expenditure

of resources for any goal other than the creation of value. In
1990, Lean production was a phrase used to describe the
Toyota Production System in the influential book The Machine
that Changed the World (Womack, Jones, and Roos, 1990).
Although Lean originated in manufacturing, it can be applied
to any process, whether operational or administrative.
In health care delivery, value can be defined as those steps
that potentially improve patient health, such as physician/
patient face-to-face time, technician time, or image acquisition
time. Time and resources spent that interfere with value delivery
is considered waste. Patients and payers appreciate and pay for
value (things that improve health) and desire nothing else.
Wastes in health care have been categorized into 8 major
forms, derived from Lean production philosophy, and can be
remembered by the helpful mnemonic, Wisdom to change.
Waiting: A worker waits because information, space, or
authority are missing.
Transportation: Equipment (or patient) kept too far from

workspace
Overproduction: Unnecessary effort spent on rapid throughput at one step when the bottleneck is somewhere else
To create an efficient process, it is fundamental that Lean
tools and principles be applied. You must start by observing
your process from start to finish and include all team members,
while doing the following:

Inventory: Too much or too little, in the wrong place; for

example, too many patients in a waiting room that are not
being cared for, or unused and expired medications
Skills: Unutilized human resources
Defects: Doing things over because they werent done right
the first time
Overprocessing: Redundant steps, such as having to write
things twice, excess paperwork, EHR inflexibilities
Motion: Excessive worker movement between tasks
Collect basic data on how long each step takes and how
much waiting occurs between steps.
Look for wastes that interfere with flow.
Identify issues in workload distribution.
Defer problem solving until you have a full grasp of the
situation, while receiving input from frontline workers at
every step in your process.
Identify bottlenecks and the things that create them.
Diagram your current state with a value stream map;
use it to communicate, persuade, and elicit helpful input
from all staff; also use it to strategize your approach for
maximal effect, eliminating wastes where they make the
most impact.
Once you have a grasp of the situation, envision a target state

with synchronized physician flow and patient flow (see Figure
1), and direct your efforts toward this state:

Establish ways to remove changeover activities from the

physicians flow.
Reduce movement by staff and patients by reconfiguring
space, equipment, and supplies.
Figure 1. Achieving synchrony in clinic flowmatching the dual flows of physician and patient.
Standardize tasks to create consistency in quality and

effort expended; make baseline workload as level as possible among workers.
Create parallel processes and reduce in-series processes.
Isolate and diffuse expected variation by proactive scheduling.
Coordinate variation with visual communication (whiteboard), a multifunctional and mobile team, and a team
leader functioning to dynamically coordinate physician
flow with patient flow.
Consolidate your gains with metrics: What gets measured gets managed.
Use the Plan-Do-Check-Adjust (PDCA) approach to
introduce change.
39
Tools Used by the Lean Practitioner

Lean boot camps to teach and illustrate the basic fundamentals of Lean
5S: Sort, straighten, shine, standardize, sustain: a workplace efficiency practice (start with this first for quick
gains and staff engagement)
Value stream mapping: Observe and characterize your
patient care process from start to finish
A3 problem solving: A method or discipline of analyzing a problem, finding its root causes, and implementing
countermeasures
Selected Reading
1. Han DP, Suneja A. Make Your Clinics Flow with Synchrony: A
Practical and Innovative Guide for Physicians, Managers, and
Staff. Milwaukee: ASQ Quality Press; 2016.
40
Placental Growth Factor in MacTel1

N OTE S
41
Central Serous Chorioretinopathy Treatment Update

Photodynamic Therapy
Jennifer I Lim MD

laser (argon, krypton, and micropulse laser),

beta-blockers, carbonic anhydrase inhibitors,
H. pylori treatment, and nutritional supplements (Icaps, lutein)
I. Background

A. Natural history

1. Propensity for spontaneous resolution; 15%50% develop recurrence (5% chronic)
2. Types
a. Acute = usually self-limiting, spontaneously

resolves, usually within 3 months, and VA
usually recovers to 20/30 or better
b. Chronic = recurrent and/or persistent neurosensory or retinal pigment epithelial (RPE)

detachment (PED), which can result in progressive RPE atrophy and visual loss; usually
defined as greater than 6 months
b. PDT or micropulse laser treatment were most

promising for future study.
c. Little difference between anti-VEGF (ranibizumab or bevacizumab) and observation
d. Half-dose PDT of acute central serous chorioretinopathy (CSC) probably results in

small improvement in vision (MD 0.10
logMAR; 95% CI, 0.18 to 0.02), less
recurrence (risk ratio [RR], 0.10; 95% CI,
0.01 to 0.81), and less persistent CSC (RR,
0.12; 95% CI, 0.01 to 1.02) at 12 months
compared to sham.
e. Ongoing steroid blocker, PDT, anti-VEGF

studies without results for analysis in study
B. Management

1. Determine inciting factors and eliminate when

possible
2. Observe for acute = most common initial

approach
3. Treat based upon patients needs and natural

history
II. Photodynamic Therapy

A. Evidence

1. Case series of PDT for chronic CSC showed

60%-80% complete resolution and partial resolution in remainder.
2. Randomized controlled trial of 63 patients with

acute CSC: PDT vs. placebo
4. Treatment options

a. Photodynamic therapy with verteporfin

(PDT)
b. Steroid hormone antagonists (ketoconazole,

mifepristone, finasteride, eplerenone)
c. Rifampin (induces cytochrome P450)
d. Laser/micropulse laser
1. Case series of PDT showed evidence of efficacy.
2. Meta-analysis reviewed 319 patients.4

a. PDT superior to laser for subretinal fluid

(SRF) resolution (P = .005)
b. PDT better than anti-VEGF for SRF (P =

.007) and decreased central macular thickness (CMT) (P = .002)
c. Half-dose PDT vs. placebo: improved BCVA,

decreased CMT, and resolved SRF (P < .001)
d. Half-fluence vs. full-fluence PDT effective (P

< .001)
3. Meta-analysis reviewed 25 studies of 1098 eyes

(1098 patients) followed from 16 weeks to 12
years5 (substantial proportion trials were not
masked, low quality evidence).

a. Anti-VEGF (ranibizumab, bevacizumab),

PDT (full-dose, half-dose, 30% low-fluence),
a. Half-dose PDT
b. Stable or improved VA in all PDT vs. 79%

placebo
B. Prospective randomized controlled study of PDT

vs. high-density subthreshold micropulse (HSML)
= PLACE trial6
C. Comparison of PDT to other treatment

1. Maximum 8 months follow-up after first treatment
2. Primary outcome = complete absence of SRF on

spectral domain OCT (SD-OCT)
3. Secondary outcomes = BCVA, microperimetry,

and National Eye Institute Visual Function
Questionnaire
C. Case-control studies of effectiveness of PDT

1. PDT vs. observation7
a. Eyes with new-onset CSC observed for 6

months: CSC resolved in 41 eyes; PDT done
for 36 eyes.
b. Recurrence rates: 51.2% in spontaneous

group vs. 25% in PDT group
42

2. Prospective, noncomparative, interventional

case series of half-dose PDT8

a. 14 chronic CSC eyes
b. Improvement in macular sensitivity
c. Improvement correlates with recovery of

inner segment/ outer segment line and cone
outer segment tips at 6 and 12 months.
b. VA benefit better with worse initial VA
c. SRF resolved in 80%; early resorption within

6 weeks
d. FA cessation of leakage in 76%
e. Safe: Rare complications = atrophy in 4%;

atherosclerotic vascular disease (ASVD), 2%
2. Standard vs. reduced fluence PDT10
a. 42 eyes
b. Similar outcomes for VA and resolution of

SRF
a. PDT eyes followed mean 14.8 months
b. Improved BCVA at 1, 3, 6, and 12 months (P

< .05 at all time points)
c. Both parameters safe and effective, with

similar BCVA increase and SRF resolution
2. Half-dose vs. observation retrospective study12
a. 192 eyes: 75 half-dose and 117 no treatment
b. 74.1 months follow-up
c. Decreased risk of recurrence: 20% half-dose

PDT vs. 53.8% untreated
3. Half-dose vs.
half-fluence13
a. Mean follow-up = 20.7 months for halffluence and 22.3 months for half-dose
b. Both parameters: improved VA, decreased

central foveal and choroidal thickness
4. Half-dose PDT retrospective interventional case

series14

a. 204 eyes in 204 patients
b. 12 months: 89.2% resolved SRF
c. Improved BCVA at 12 months (P < .0001)
1. Predictive value of choroidal thickness for CSC

recurrence15

a. Retrospective, observational, comparative

case series
b. 57 eyes with chronic CSC (52 patients)

2. Choroidal volume decreases with half-fluence
PDT and extends beyond the treatment site.16
a. FA leakage correlated with SD-OCT, SRF,

RPE thickening, RPE double-layer sign, RPE
detachment, and RPE thickening.
b. ICGA hyperfluorescence correlated with

superficial choroidal hyperreflective spots.
1. Fundus autofluorescence usually does not

improve after spontaneous resolution of CSC.
2. After PDT, fundus autofluorescence may

decrease and then return to baseline.20
H. PDT vs. laser
1. Half-dose and half-time retrospective comparative study11

e. Less effective if intense indocyanine green

angiography (ICGA) hyperpermeability or
lower BCVA before PDT
G. Effect on RPE
E. Alternative PDT treatment parameters (recent

studies)

a. No difference in response to PDT based upon

fluence setting, fluorescein angiography (FA)
leakage type, fluid location (SRF vs. PED) or
corticosteroid exposure
d. No systemic adverse events or ASVD
1. Macula Society series of 265 eyes of 237

patients9

F. Effect on choroidal thickness
D. Retrospective case series

Half-dose PDT vs. subthreshold diode-laser micropulse (SDM)17

1. 62 eyes (62 patients): SDM (n = 20), PDT (n =

24), observation controls (n = 18)
2. Prospective FA, fundus autofluorescence (FAF),

CMT, BCVA, and contrast VA (CVA)
3. Reduced leakage: 60% SDM vs. 66.7% PDT vs.

37.5% controls at 16 weeks
4. CMT decreased by 69.7 m in SDM group;

109.8 m, PDT group; 89 m, controls
5. BCVA improved by +6.7, SDM group; +8.5,

PDT group; +1.5 ETDRS letters, controls
6. CVA was best improved in the PDT group.
7. No secondary RPE alterations could be detected

by FAF after any intervention.
I. Corticosteroid-associated CSC18
1. Equally effective in patients with steroid-associated as without
2. Continuation of corticosteroids at time of PDT

did not seem to adversely affect PDT response.
References
1. Gass JD. Pathogenesis of disciform detachment of the neuroepithelium. Am J Ophthalmol. 1967; 63:1-139.
2. Liew G, Franzco GQ, Gillies M, Fraser-Bell S. Central serous
chorioretinopathy: a review of epidemiology and pathophysiology.
Clin Exp Ophthalmol. 2013; 41:201-214.
43
3. Chan WM, Lai TY, Lai RY, et al. Half-dose verteporfin photodynamic therapy for acute central serous chorioretinopathy:
one-year results of a randomized controlled trial. Ophthalmology
2008; 115:1756-1765.
12. Lai TY, Wong RL, Chan WM. Long-term outcome of half-dose
verteporfin photodynamic therapy for the treatment of central
serous chorioretinopathy (an American Ophthalmological Society
Thesis). Trans Am Ophthalmol Soc. 2015; 113:T81-T827.
4. Ma J, Meng N, Xu X, et al. System review and meta-analysis on

photodynamic therapy in central serous chorioretinopathy. Acta
Ophthalmol. 2014; 92(8):e594-601.
13. Kim YK, Ryoo NK, Woo SJ, Park KH. Comparison of visual and
anatomical outcomes of half-fluence and half-dose photodynamic
therapy in eyes with chronic central serous chorioretinopathy.
Graefes Arch Clin Exp Ophthalmol. 2015; 253(12):2063-2073.
5. Salehi M, Wenick AS, Law HA, et al. Interventions for central

serous chorioretinopathy: a network meta-analysis. Cochrane
Database of Systemic Reviews 2015, Issue 12. Art. No.:
CD011841.
6. Breukink MB, Downes SM, Querques G, et al. Comparing halfdose photodynamic therapy with high-density subthreshold
micropulse laser treatment in patients with chronic central serous
chorioretinopathy (the PLACE trial): study protocol for a randomized controlled trial. Trials 2015; 16:419.
7. Ozkaya A, Alkin Z, Ozveren M, et al. The time of resolution and
the rate of recurrence in acute central serous chorioretinopathy
following spontaneous resolution and low-fluence photodynamic
therapy: a case-control study. Eye (Lond). Epub ahead of print
2016 Apr 22.
8. Fujita K, Shinoda K, Imamura Y, et al. Correlation of integrity of
cone outer segment tips line with retinal sensitivity after half-dose
photodynamic therapy for chronic central serous chorioretinopathy. Am J Ophthalmol. 2012; 154:579-585.
9. Lim JI, Glassman AR, Aiello LP, et al. Collaborative retrospective
Macula Society study of photodynamic therapy for chronic central serous chorioretinopathy. Ophthalmology 2014; 121:10731078.
10. Reibaldi M, Cardascia N, Longo A, et al. Standard fluence versus
low-fluence photodynamic therapy in chronic central serous chorioretinopathy: a non-randomized clinical trial. Am J Ophthalmol. 2010; 149:307-315.
11. Liu HY, Yang CH, Yang CM, et al. Half-dose versus half-time
photodynamic therapy for central serous chorioretinopathy. Am J
Ophthalmol. 2016; 167:57-64.
14. Fujita K, Imamura Y, Shinoda K, et al. One-year outcomes with

half-dose verteporfin photodynamic therapy for chronic central
serous chorioretinopathy. Ophthalmology 2015; 122:555-561.
15. Kim YK, Ryoo NK, Woo SJ, Park KH. Choroidal thickness
changes after photodynamic therapy and recurrence of chronic
central serous chorioretinopathy. Am J Ophthalmol. 2015;
160:72-84.
16. Munk MR, Shah R, Pappas F, et al. Multimodal imaging and choroidal volumetric changes after half-fluence PDT in central serous
chorioretinopathy. Curr Eye Res. 2016; 41(1):97-106.
17. Kretz FT, Beger I, Koch F, et al. Randomized clinical trial to compare micropulse photocoagulation versus half-dose verteporfin
photodynamic therapy in the treatment of central serous chorioretinopathy. Ophthalmic Surg Lasers Imaging Retina. 2015;
46(8):837-843.
18. Breukink MB, Mohabati D, van Dijk EH, et al. Efficacy of photodynamic therapy in steroid-associated chronic central serous
chorioretinopathy: a case-control study. Acta Ophthalmol. Epub
ahead of print 2016 May 6.
19. Ojima A, Iida T, Sekiryu T, et al. Photopigments in central serous
chorioretinopathy. Am J Ophthalmol. 2011; 151(6):940-952.
20. Ozmert E, Batioglu F. Fundus autofluorescence before and after
photodynamic therapy for chronic central serous chorioretinopathy. Ophthalmologica 2009; 223(4):263-268.
44
MEK Inhibitors and Complications

Jose S Pulido MD MS
There is an epidemic that has already started. MEK inhibitors have shown that they are useful for cutaneous melanomas
(REF). Recently they are being evaluated in thyroid cancer and
nonsmall cell lung cancer. MEK inhibitors are a billion dollar
market, and this will soon be more.
Figure 3. Progression-free survival and disease progression or death

according to subgroup: trametinib vs. chemo.
Schoenberger SD, Kim SJ. Bilateral multifocal

central serous-like chorioretinopathy due to MEK
inhibition for metastatic cutaneous melanoma. Case
Rep Ophthalmol Med. 2013; 201:673796.
Figure 1.
54-year-old female started on dabrafenib and trametinib.

Three weeks later she presented with decreased vision
20/60 and 20/50, subretinal fluid (SRF).
Stopped both medicines; SRF resolved.
Resumed both but trametinib at a lower dose
SRF returned; dabrafenib continued but trametinib
stopped.
SRF resolved.
Figure 2.
Ocular eventsmostly grade 1 (seen by eye exam but

asymptomatic) or grade 2 (vision equal to or better than
20/40)occurred in 9% of patients in the trametinib group,
with blurred vision as the most frequent single ocular event
(4%); reversible chorioretinopathy (grade 3, 20/40 to 20/200)
occurred in 1 patient (<1%).
Figure 4.
Urner-Bloch U, et al. Transient MEK inhibitorassociated retinopathy in metastatic melanoma.

Ann Oncol. 2014; 25(7):1437-1441.

32 placed on bimetinib (MEK inhibitor); 20 only MEK

inhibitor and 12 on MEK inhibitor and BRAF inhibitor
Patients examined at baseline, 15 days, then every 28
days.
19 developed retinopathy (61%).
Only 8/19 had symptoms.
Pathophysiology
Autoantibodies against bestrophin were present in 3 of 6
patients. These autoantibodies were also reported earlier in
a patient with choroidal malignant melanoma in the left eye
and vitelliform lesions in the right eye. It has been proposed
that dysfunction of bestrophin results in abnormal fluid and
ion transport by the RPE. It is possible that treatment with
binimetinib triggers (tumor) cells to stimulate the generation or
release of antibodies that could play a role in thepathogenesis of
serous retinopathy. Moreover, an autoantibody attack against
certain RPE epitopes could result in compromised RPE ion
homeostasis, resulting in an abnormal electro-oculogram.
I dont think it is from autoantibodies, since it happens so
fast. We hypothesized that it was a biochemical effect. We have
placed these inhibitors on iPSC-derived RPE cells.
Figure 5.
Figure 6.
Van Dijk EH, et al. Serous retinopathy associated

with mitogen-activated protein kinase kinase
inhibition (binimetinib) for metastatic cutaneous
and uveal melanoma. Ophthalmology 2015;
122(9):1907-1916.

45
30 patients with cutaneous melanoma and 5 with uveal

melanoma treated with binimetinib
26/35 (75%)
On OCT, lesions were detected between a few hours and
26 days (median: 14 days) after the start of binimetinib.
Figure 7.
RNA-seq shows that over 600 proteins are either upregulated or downregulated.
46
Management of Retinal Diseases in Pregnant Patients

Mark W Johnson MD and Julie M Rosenthal MD
I. Pregnancy-Induced Physiologic, Hormonal, and Metabolic Changes That May Affect the Retina
b. Usually associated with complicated pregnancy
c. Often results in severe bilateral vision loss

with only partial recovery
A. Increase in serum cortisol levels
B. Increase in blood pressure, generally during third

trimester
C. Increasing insulin resistance (decreasing glycemic

control) during second and third trimesters
2. Retinal arteriolar occlusions from amniotic

fluid embolism; rare, usually fatal
3. Retinal vein occlusion; most often in third trimester and postpartum period
D. Increase in blood volume; reaches peak in second

trimester
III. Retinal/Choroidal Diseases That May Be Exacerbated

by Pregnancy
E. Hypercoagulability
II. Retinal/Choroidal Diseases That May Be Induced by
Pregnancy
A. Idiopathic central serous chorioretinopathy (ICSC)

1. Pregnancy is a known trigger for active episodes

of ICSC.
2. Likely related to hypercortisolemia
3. High rate of subretinal fibrin formation (up to

90%)
4. Management
A. Hypertensive retinopathy and choroidopathy

1. Pregnancy-induced hypertension syndromes

b. Eclampsia: pre-eclampsia plus seizures
a. If no fibrin in or near fovea and patient near

term, consider observation and expect resolution after delivery.
b. If fovea threatened by fibrin, consider OCTguided laser treatment (avoid fluorescein

angiography and photodynamic therapy
[PDT] if possible).
2. Fundus findings

a. Retinal arteriolar constriction, cotton-wool

spots, retinal hemorrhages, retinal edema,
lipid exudates
b. Subretinal fluid (choroidal ischemia)
c. Ischemic optic neuropathy
a. Pre-eclampsia: hypertension, peripheral

edema, and proteinuria (occurs in 5%-8% of
pregnant women)
3. Course: In most cases, changes are reversible

after delivery and normalization of blood pressure.
B. Diabetic retinopathy

1. Retinopathy progression during pregnancy

a. Retinopathy progression occurs at double the

rate in pregnant women compared with nonpregnant women.
1. HELLP syndrome (hemolysis, elevated liver

enzymes, low platelets)
b. After adjusting for HgA1C, pregnancy itself

is associated with progression.
a. Occurs in up to 15% of women with preeclampsia
c. Diabetes in Early Pregnancy Study
b. Infant mortality in up to 25%
c. Bilateral exudative retinal detachment,

yellow-white subretinal deposits, vitreous
hemorrhage
B. Exudative retinal detachment

i. Two-step ETDRS progression occurred in

55% of patients with moderate nonproliferative diabeticretinopathy (NPDR) at
baseline.
ii. Progression to proliferative diabeticretinopathy (PDR) occurred in 6.3% with

mild NPDR and 29% with moderate
NPDR at baseline.
d. Only effective treatment is prompt delivery.
2. Disseminated intravascular coagulation (DIC)
3. Thrombotic thrombocytopenic purpura (TTP)
d. Risk factors for progression are similar to

those in patients who are not pregnant.
e. Diabetes Control and Complications Trial
C. Retinal vascular occlusive disease

1. Postpartum Purtscher-like retinopathy

a. Typically occurs within 24 hours of delivery
i. Retinopathy in type 1 diabetes mellitus

progresses at a faster rate during pregnancy.
ii. Long-term risk of progression of early

retinopathy is probably not increased by
pregnancy.
iii. Recommend increased surveillance during pregnancy and first year postpartum
i. Eye examination during first trimester

with follow-up visits determined by the
severity of retinopathy (moderate NPDR,
every 3-6 months; severe NPDR or worse,
every 1-3 months)
ii. Gestational diabetes does not require eye
examination during pregnancy.
b. PDR
i. Recommend panretinal photocoagulation

at diagnosis
ii. Avoid anti-VEGF therapy
c. Diabetic macular edema

i. If mild, consider observation, since edema

may resolve after delivery.
ii. If treatment needed, consider focal laser

or intravitreal triamcinolone.
iii. Avoid anti-VEGF therapy if possible.
IV. General Management Considerations

A. Intravitreal medications

1. Triamcinolone does not achieve significant

serum levels when given intravitreally and is
likely safe in pregnancy.
2. Anti-VEGF agents

a. Several small case series show no harmful

effects on fetus when mother received up to 6
intravitreal anti-VEGF injections.
b. Of the three commercially available agents,

ranibizumab is cleared from bloodstream
most quickly and has least effect on plasma
VEGF, but comparative fetal safety data are
not available.
a. AAO Preferred Practice Patterns (http://

www.aao.org/preferred-practice-pattern/
diabetic-retinopathy-ppp-updated-2016)

c. Recommendations
47
tions in pregnant women without reports of

adverse fetal effects.
2. Management recommendations

3. Where possible, use OCT and/or OCT angiography instead of invasive angiography.
C. Verteporfin PDT
1. No data on gestational exposure in humans are

yet available.
2. Where possible, use thermal laser instead of PDT.
D. Vitreoretinal surgery

1. It is prudent to avoid elective surgeries during

pregnancy.
2. If surgery is absolutely necessary, have obstetrical team involved.
3. Local anesthesia is preferred over general anesthesia.

a. Lidocaine is considered safe for use during

pregnancy.
b. Bupivacaine and mepivacaine should be

avoided in pregnancy.
Selected Readings
1. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J
Ophthalmol. 2014; 98(12):1636-1641.
2. Blodi BA, Johnson MW, Gass JDM, Fine SL, Joffe LM.
Purtschers-like retinopathy after childbirth. Ophthalmology
1990; 97:1654-1659.
3. Chew EY, Mill JL, Metzge BE, et al. Metabolic control and progression of retinopathy. The Diabetes in Early Pregnancy Study.
Diabetes Care 1995; 18(5):631-637.
4. The Diabetes Control and Complications Trial Research Group.
Effect of pregnancy on microvascular complications in the
diabetes control and complications trial. Diabetes Care 2000;
23(8):1084-1091.
5. Errera MH, Kohl RP, da Cruz L. Pregnancy-associated retinal diseases and their management. Surv Ophthalmol. 2013;
58(2):127-142.
6. Morrison JL, Hodgson LAB, Lim LL, Al-Qureshi S. Diabetic retinopathy in pregnancy: a review. Clin Experiment Ophthalmol.
Epub ahead of print 2016 April 7. doi: 10.1111/ceo.12760
7. Kitzmiller JL, Block JM, Brown FM, et al. Managing preexisting
diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care 2008; 31(5):1060-1079.
i. Use intravitreal anti-VEGF agents in pregnant women only if absolutely necessary.
8. Klein BE, Moss SE, Klein R. Effect of pregnancy on progression

of diabetic retinopathy. Diabetes Care 1990; 13(1):34-40.
ii. Consider routine pregnancy testing before

starting injections in women of childbearing age.
9. Polizzi S, Mahajan VB. Intravitreal anti-VEGF injections in

pregnancy: case series and review of literature. J Ocul Pharmacol
Ther. 2015; 31(10):605-610.
B. Angiography

1. Fluorescein angiography dye crosses the placenta and is present in breast milk for 72 hours,
but no adverse fetal events reported.
2. Indocyanine green dye does not cross the placenta and is used for non-ophthalmic indica-
10. Schultz KL, Birnbaum AD, Goldstein DA. Ocular disease in pregnancy. Curr Opin Ophthalmol. 2005; 16(5):308-314.
11. Sheth BP, Mieler WF. Ocular complications of pregnancy. Curr
Opin Ophthalmol. 2001; 12(6):455-463.
12. Sunness JS, Haller JA, Fine SL. Central serous chorioretinopathy
and pregnancy. Arch Ophthalmol. 1993; 111(3):360-364.
48
Hemorrhagic Occlusive Retinal Vasculitis

Dean Eliott MD
I. General Features of Hemorrhagic Occlusive Retinal

Vasculitis (HORV)

A. Extremely rare condition
B. Can occur after any intraocular procedure; usually

cataract surgery
C. Delayed presentation of sudden painless severe

visual loss; mean onset of symptoms 1 week after
the procedure (range: 1 day 1 month)
1. Intracameral bolus
2. Anterior chamber irrigating solution
3. Intravitreal injection
A. Severe peripheral nonperfusion
B. Peripheral retinal vasculitis
C. Macular ischemia in advanced cases
D. Intraretinal hemorrhages correspond to areas of

vasculitis and nonperfusion
D. Strong association with intraocular vancomycin

IV. Fluorescein Angiography
V. Differential Diagnosis

A. Acute postoperative endophthalmitis; pain, hypopyon, and severe vitritis are not present in HORV.
B. Viral retinitis
E. Exact cause is currently unproven
1. White areas of retinitis are not present in

HORV.
2. Viral retinitis is not associated with a recent surgical procedure.
II. Timing

A. If HORV occurs after one eye undergoes cataract

surgery, it can also occur in the second eye after the
second eye undergoes surgery, even if the second
surgery is performed years later (if vancomycin is
used).
B. In bilateral sequential cataract surgery separated by
a few weeks, the first eye can be normal until the
second eye undergoes surgery, and then HORV can
occur simultaneously in both eyes very soon after
the second surgery (if vancomycin is used).
1. May be associated with cataract surgery
2. Findings present on postoperative day 1, unlike

HORV, which typically has a normal exam at
this time.
3. Severe venous dilation and tortuosity are not

characteristic of HORV.
III. Clinical Findings on Presentation

C. Central retinal vein occlusion (CRVO) or combined

central retinal artery occlusion/ CRVO
D. Medication toxicity

1. Toxic anterior segment syndrome (TASS): Has

severe corneal edema and findings on postoperative day 1, unlike HORV.
2. Aminoglycoside toxicity: Has macular infarction with minimal or no peripheral vascular

occlusion, while HORV has severe peripheral
vascular occlusion and vasculitis.
3. Cefuroxime toxicity: Intracameral injection of

overdoses has been associated with TASS and
retinal hemorrhages.
A. Visual acuity

1. Usually severely reduced
2. May be normal in mild cases
B. Cornea: Normal or mild corneal edema
C. Anterior chamber

1. Mild to moderate inflammation
2. No hypopyon
D. Vitreous: Mild to moderate inflammation
E. Retina

VI. Clinical Course

A. There are some cases of presumed endophthalmitis

(cases with retinal findings out of proportion to
inflammation and without hypopyon) that in retrospect were probably HORV.
1. Peripheral retinal involvement in all cases

a. Large patches of intraretinal hemorrhages,

often along venules
b. Small dot/blot hemorrhages
c. Sectoral retinal vasculitis

2. Macular involvement in severe cases: macular
whitening
1. These cases were treated with intravitreal vancomycin and had progression of retinal ischemia
documented on fluorescein angiography performed before and after vancomycin treatment.
2. These cases had particularly poor outcomes,

with most eyes progressing to no light perception.
B. Visual outcomes are often poor.

1. The majority of eyes are worse than 20/200.
2. Approximately one-quarter of eyes progress to

no light perception.
3. A few asymptomatic cases are 20/20.
C. Neovascular glaucoma is common, occurring in

approximately 50% of eyes.
D. Eyes that received certain treatments appeared to

have more favorable outcomes.

1. Steroids (topical, periocular, intraocular, and/or

systemic)
2. Early anti-VEGF treatment
3. Early panretinal photocoagulation
VII. Etiology

A. Immunology experts were consulted.
B. They hypothesize that this may represent a rare

Type III hypersensitivity reaction to vancomycin.
C. Presumed similar mechanism to leukocytoclastic

vasculitis and Henoch-Schonlein purpura, which
are Type III hypersensitivity reactions in the skin
that have rarely been associated with vancomycin.
VIII. American Society of Retina Specialists/ American

Society of Cataract and Refractive Surgery Task Force

A. HORV registry developed at www.asrs.org
B. Currently, 36 eyes of 22 patients have been identified with HORV. All cases received intraocular
vancomycin.
49
C. 2014 ASCRS member survey

1. 50% of respondents were using intracameral

antibiotics for endophthalmitis prophylaxis
during cataract surgery. Among those using
prophylactic antibiotics, 52% of American surgeons were using vancomycin.
2. Many high-volume cataract surgeons using

intracameral vancomycin have never knowingly
experienced HORV, and the task force believes
it to be extremely rare.
D. Acknowledgments
Task force members: Chang DF, Charles S, Eliott
D, Hoffman RS, Jumper JM, Mamalis N, Miller
KM, Witkin AJ, Wykoff CC
Selected Readings
1. Nicholson LB, Kim BT, Jardon J, Townsend-Pico W, Santos C,
Moshfeghi AA, Albini TA, Eliott D, Sobrin L. Severe bilateral
ischemic retinal vasculitis following cataract surgery. Ophthalmic
2. Witkin AJ, Shah AR, Engstrom RE, Kron-Gray MM, Baumal
CR, Johnson MW, Witkin DI, Leung J, Albini TA, Moshfeghi
AA, Batlle, IR, Sobrin L, Eliott D. Postoperative hemorrhagic
occlusive retinal vasculitis: expanding the clinical spectrum and
possible association with vancomycin. Ophthalmology 2015;
122:1438-1451.
3. Chang DF, Braga-Mele R, Henderson BA, et al. Antibiotic prophylaxis of postoperative endophthalmitis after cataract surgery:
results of the 2014 ASCRS member survey. J Cataract Refract
Surg. 2015; 41:1300-1305.
4. ASRS-ASCRS Task Force; Chang DF, Charles S, Eliott D, et al.
Clinical Alert: HORV Association with Intraocular Vancomycin.
July 20, 2016. Available at: http://www.ascrs.org/node/26101.
50
The Reliability of Compounded Drugs

Compounding is a traditional part of pharmacy practice. It

refers to the preparation of medicines on prescription by a registered medical practitioner for tailoring the drug or combinations
of drugs, their concentration, to the individual requirements of
a patient. This is of value and importance because drugs that are
commercially manufactured and marketed are not necessarily in
the ideal dose or formulation for administration to all patients,
and thus the product dispensed by the compounding pharmacy
is customized to unique patient requirements.
In the United States, compounding pharmacies are regulated
by the state boards of pharmacy but the level of oversight can
vary markedly, with some states engaging in little or no supervisory activities or instituting few checks to ensure safe and reliable practices.
An outbreak of fungal meningitis following the use of steroids prepared by the New England Compounding Centre put
the role of compounding pharmacies in drug safety and reliability firmly into public view and evoked a degree of scrutiny never
seen previously.
Compounded Drugs in Ophthalmology

In ophthalmology, compounding of drugs for topical and intraocular use is common. In particular, attention has been focused
on the compounding of bevacizumab (Avastin), an anticancer
agent that is highly effective in the management of exudative
maculopathies. The main driver for the use of bevacizumab in
preference to the licensed preparations of ranibizumab (Lucentis) and or aflibercept (Eylea) is the huge price differential. Bevacizumab is marketed in vials at a concentration of 25mg/mL,
and 1 vial can be apportioned into many small doses of 1.25
mg / 50 microliters, which are dispensed in prefilled syringes for
intravitreal administration. Thus the price of a prefilled syringe
may be as low as 1/50th of the cost of the licensed preparations.
Bevacizumab is the most commonly used drug for the exudative
maculopathies of wet AMD, diabetic macular edema, and retinal vein occlusion across a huge swathe of the underdeveloped
world, as well as in many parts of the developed world. However, unscrupulous practices in compounding pharmacies have
led to outbreaks of endophthalmitis, and notable ones in the
United States, Canada, and Australia.
Regulatory Oversight Afforded to Compounding

Pharmacies

Registration with the U.S. Food and Drug Administration (FDA) or other regulatory bodies in countries outside
the United States
International Academy of Compounding Pharmacists
(IACP)
Compounding Quality and Accountability Act
Local or state level regulations on tracking activities of
compounding pharmacies. Regular inspections.
Reporting of adverse events associated with their products
Sterile processing (environmental monitoring, handling
of materials in appropriate laminar flow hood systems,
technicians trained in sterile procedures, with access to
appropriate sterile equipment, including gloves)
Tests for presence of particulates
Tests for sterility and stability
Tests for endotoxins
Specification of use-by dates
In addition there is a responsibility and onus on hospitals

and clinicians to ensure that they obtain compounded drugs
only from reliable sources, and they should show awareness of
regulatory deficiencies.
This presentation will provide a brief overview of preparation to prescription by compounding pharmacies, along with
safety and reliability of products using anti-VEGF therapies as
the model.
51
Visual Prostheses: Argus II, Subretinal, Bionic Eye
Argus II Retinal Prosthesis System Update: Clinical Trial Data and

Worldwide Commercialization
Allen C Ho MD and the Argus II Study Group

I. The Argus II Retinal Prosthesis System (Second Sight

Medical Products; Sylmar, Calif.)

C. Clinical trial design

1. Prospective, nonrandomized, multicenter, single-arm trial; 30 subjects followed for 10 years
2. Key inclusion criteria: Subjects with severe to

profound outer retinal degeneration
3. Within-subject controls were fellow eye safety

and System OFF performance
A. Argus II implanted and external components

1. Implanted components include a hermitically

sealed electronics package, receiving antenna,
and an electrode array.
2. Visual field of approximately 20 degrees with

60 individually programmable electrodes
II. Results

A. Subject demographics

1. Of the 30 subjects, 29 had retinitis pigmentosa,

and 1 had choroideremia.
2. 9 female and 21 male subjects
3. Age range was 28-77 years; mean age: 58 years

10 years
4. Baseline vision: No light perception, 1 subject;

bare light perception, 29 subjects

Figure 1. Implanted components of the Argus II System.
3. External components include a pair of glasses

with a video camera and transmitting antenna
coil connected by a cable to a body-worn video
processing unit.
B. Implant duration and long-term device reliability

and functionality

1. As of May 19, 2016, duration of implant ranged

from 1.2 years (for a subject who was explanted
at that time) to 9 years. Average implant duration: over 7 years with functionality.
2. Total subject-years of implant: 217
3. There were 3 partial or complete explants as of

May 19, 2016.
4. There were 2 additional device failures that

remain implanted.
Figure 2. External components of the Argus II System.
B. Surgical procedure
Standard vitreoretinal surgical techniques are used
to implant the device in a single eye; a retinal tack
is used to affix the array epiretinally.
C. Adverse events

1. As of 5 years post-implant, there were 24 serious

adverse events among 12 subjects. The other 18
subjects had not experienced any serious adverse
events. All events were treated with standard
techniques, and there were no lost eyes in the
study.
2. Improved safety profile in commercial experience compared with clinical trial
52
Table 1. Safety Profile Improving in the Commercial

Setting: SAEs in Year 1Clinical Trial vs. Commerciala
Clinical Trial
All Commercial
N = subjects/patients
30
111
Conjunctival dehiscence
10.0%
1.3%
Conjunctival erosion
10.0%
5.1%
Corneal opacity
3.3%
0.0%
Endophthalmitis, infective
10.0%
0.0%
Epiretinal membrane
3.3%
0.0%
Scleritis
0.0%
1.3%
Hyphema
0.0%
1.3%
Hypotony
6.7%
2.5%
Inflammation, ocular
0.0%
1.3%
Re-tack
6.7%
0.0%
Retinal detachment
6.7%
2.5%
Retinal tear
3.3%
0.0%
Sclerotomy leak
0.0%
1.3%
Uveitis
3.3%
0.0%
Vitreous hemorrhage
0.0%
1.3%
Figure 4. Direction of motion testing.
Kaplan-Meier estimates of cumulative SAE rates (as of July 2015).
D. Performance

1. Visual function was measured with square

localization (testing the ability to find a highcontrast target), direction of motion (testing
the ability to discriminate the direction of a
high-contrast bar), and grating visual acuity
(estimating the visual acuity on a scale of 2.9 to
1.6 logMAR).
Performance was improved with the System ON

compared to System OFF at all time points out
to 5 years post-implant on all 3 visual function
assessments.
Figure 3. Square localization testing.
Figure 5. Grating visual acuity testing.
2. Functional vision was assessed with the orientation and mobility door task (finding a fabric
door on a wall) and the orientation and
mobility line task (following a white line painted
on black rubber tiles). The Functional Lowvision Observer Rated Assessment (FLORA)
was also used to assess functional vision and
quality of life at 1 and 3 years post-implant. The
FLORA was performed in the subjects home by
a low vision therapist.
Performance on the door and line tasks
improved with the System ON compared to
OFF at all time points. The FLORA showed
that a large majority of subjects lives had been
affected positively by the Argus II System.
III. Commercialization

A. CE Mark was obtained in 2011, allowing the commercialization of the Argus II System in the European Economic Area.
B. United States FDA approval under the Humanitarian Device Exemption program was obtained in
2013, with Health Canada approval the following
year.
C. The Argus II System is currently available in 12

countries.

Figure 6. Mobility door task.
53
Over 150 commercial patients have been implanted

worldwide, and including clinical trial subjects,
Argus II has demonstrated acceptable safety in this
blind population and proven reliability with longterm functionality beyond 8 years.
Figure 7. Mobility line task.

Figure 9. Argus II impact.
Selected Readings
1. Humayun MS, Dorn JD, da Cruz L, et al. Interim results from the
international trial of Second Sights visual prosthesis. Ophthalmology 2012; 119(4):779-788.
2. Ho AC, Humayun MS, Dorn JD, et al. Long-term results from an
epiretinal prosthesis to restore sight to the blind. Ophthalmology
2015; 122(8):1547-1554.
Figure 8. Functional Low Vision Observer Rated Assessment (FLORA).
3. da Cruz L, Dorn JD, Humayan MS, et al. Five-year safety and

performance results from the Argus II Retinal Prosthesis System
clinical trial. Ophthalmology. In press.
4. Kitiratschky VB, Stingl K, Wilhelm B, et al. Safety evaluation of
retina implant alpha IMS: a prospective clinical trial. Graefes
Arch Clin Exp Ophthalmol. 2015; 253(3):381-387.
5. Ayton LN, Blamey PJ, Guymer RH, et al. First-in-human trial
of a novel suprachoroidal retinal prosthesis. PLOS ONE. 2014;
9(12):e115239.
54
Sensory Substitution for Low Vision

I. Historical Background
II. Target Patient Population
III. Sensory Substitution Devices
IV. Tactile/Vibrotactile
V. Auditory
VI. Neural Plasticity
VII. Future Directions
55
North Carolina Macular Dystrophy (NCMD / MCDR1)

Kent Wilson Small MD, Adam P DeLuca PhD, Richard Alan Lewis MD MS, Monique J Leys MD,
Benjamin Bakall MD PhD, Virginie Puech MD, Klaus Rohrschneider MD, Rosemary Silva Garcia MD,
Fadi Shaya BS, Nitin Udar PhD, Elise Heon MD, Charles A Garcia MD, Thomas A Rice MD,
Gerald Fishman MD, James C Folk MD, Bernard Puech MD, Edwin Stone MD PhD

I. Clinical Variable Expressivity

A. Many names given a single disease in a single family
B. Ascertainment of families/ genealogy/ IRB

approved (35 families total)
II. Genetic Linkage Mapping of North Carolina Macular

Dystrophy (NCMD)/ MCDR1

A. Genetic physical map of NCMD/ MCDR1
B. NexGen DNA sequencing of defined region
III. Bioinformatics Analysis of Sequencing Data

A. Three mutations causing MCDR1 in a non-coding

region 12KB from gene (PRDM13)
B. One mutation causing MCDR1, duplication of

PRDM13 (Belize family)
C. One mutation causing MCDR3, duplication of

IRX1
IV. Initial Publication of 11 Families, New Data on an

Additional 19 Families with NCMD

A. Mutations found in 12 of the 19 New NCMD

families (see Table 1)
B. All point mutation in non-coding region
C. This confirms our initial findings of the causative

mutations of NCMD which are in a DNASE hypersensitivity regulatory binding site, causing overexpression of PRDM13, a retinal/ macula transcription factor.
Selected Readings
1. Small KW, Deluca AP, Whitmore SS, et al. North Carolina Macular Dystrophy is caused by dysregulation of the retinal transcription factor PRDM13. Ophthalmology 2016; 123(1):9-18.
2. Small KW, Weber JL, Roses A, et al. North Carolina macular
dystrophy is assigned to chromosome 6. Genomics 1992; 13: 681685.
3. Small KW. North Carolina macular dystrophy, revisited. Ophthalmology 1989; 96:1747-1754.
4. Small KW, Puech B, Mullen L, Yelchits S. North Carolina macular dystrophy phenotype in France maps to the MCDR1 locus.
Mol Vis. 1997; 3:1.
5. Small KW, Garcia CA, Gallardo G, et al. North Carolina macular
dystrophy (MCDR1) in Texas. Retina 1998; 18:448-452.
6. Small KW, Udar N, Yelchits S, et al. North Carolina macular
dystrophy (MCDR1) locus: a fine resolution genetic map and haplotype analysis. Mol Vis. 1999; 5:38.
7. Small KW, Killian J, McLean WC. North Carolinas dominant
progressive foveal dystrophy: how progressive is it? Br J Ophthalmol. 1991; 75:401-406.
8. Small KW, Hermsen V, Gurney N, et al. North Carolina macular
dystrophy and central areolar pigment epithelial dystrophy: one
family, one disease. Arch Ophthalmol. 1992; 110:515-518.
9. Small KW. North Carolina macular dystrophy: clinical features,
genealogy, and genetic linkage analysis. Trans Am Ophthalmol
Soc. 1998; 96:925-961.
10. Watanabe S, Sanuki R, Sugita Y, et al. Prdm13 regulates subtype
specification of retinal amacrine interneurons and modulates
visual sensitivity. J Neurosci. 2015; 35(20):8004-8020.
Table 1.
Family #
Family Location
Referring Physician
Origin of Mutation
Chromosomal Position of Mutation
704
W. Virginia
Leys
N Carolina
CHR6: 100040906
705
Texas
Lewis
N Carolina
CHR6: 100040906
715
West Virginia
Leys
N Carolina
CHR6: 100040906
720
Seattle
Schneiderman
N Carolina
CHR6: 100040906
773
Ohio
KWS
N Carolina
CHR6: 100040906
732
Arizona
Bakall
N Carolina
CHR6: 100040906
730
Mexico / NY
Agemi
N Carolina
CHR6: 100040906
714
Belgium
Cremers / Hoynig
French
CHR6:100040987
718
Germany
KWS
French
CHR6:100040987
771
W. Virginia
Leys
French
CHR6:100040987
775
Germany
Rohrschneider
French
CHR6:100040987
731
Riverside, CA
KWS
French
CHR6:100040987
Abbreviation: CHR6 indicates chromosome 6.
56
Gene Therapy for Leber Amaurosis Type 2

Clinical Results
Albert M Maguire MD
Extensive laboratory testing has been done to characterize the
efficacy, toxicity, and stability of various gene therapy techniques. To a large extent, these features are determined by the
specific gene therapy agents (vectors) that are use to treat host
cells with transgene products. Numerous studies have demonstrated that recombinant viral vectors such as adeno-associated
virus (AAV) have desirable pharmacologic characteristics for
clinical applications. Evidence gained in animal models has
shown that, in addition to efficient gene transfer, AAV exhibits
a stable and prolonged expression in some instances for the
lifetime of the treated animal.1 For these reasons, gene therapy
with AAV agents has been considered a most promising candidate for treatment of chronic diseases such as retinitis pigmentosa. However, the efficacy and duration of effect also depend
on host factors such as the biology of the disease treated, the
timing (ie, age at which treatment is applied), environmental
factors, and the likeall of which have important implications
for human clinical applications.
After establishing treatment efficacy, the most important
issue concerning any therapy for a chronic retinal disease is
that of duration of effect. Demonstrating efficacy may be a
straightforward proposition when an acute change in function
occurs (eg, improved vision). However, when efficacy is defined
by arrest or retardation of disease progression, demonstrating a
treatment benefit may be difficult. Measuring duration of treatment effect, especially in slowly progressive conditions such as
dry AMD or retinitis pigmentosa, can be problematic. Natural
history studies of inherited retinal degeneration have shown
that the minimum length of time required to detect a change
in disease activity is on the order of years (typically >3 years
under ideal testing conditions). Adding to this the many other
nonretinal variables influenced by the therapeutic intervention,
such as cataract, nystagmus, and amblyopia, accurate measurement of the treatment effect including duration can be difficult
to establish.
Several groups have shown that gene therapy in patients with
Leber congenital amaurosis type 2 (LCA2) can improve visual
function even to near normal levels in some young individuals.2,3 However, the degree and duration of treatment effect has
shown considerable variability between different studies and, to
a great extent, different subjects within the same trial. Indeed,
the apparent difference in results is not surprising, based simply
on the fact that no two trials examined the same outcome measures! In one investigation, a minority of subjects demonstrated
improved visual function, and when improvement was present,
the effect was essentially extinguished after 1 year.4 In other
investigations, a larger proportion of subjects showed improvement, often to a much greater degree, and treatment effect
appeared to be sustained at least 3 years or more before a diminution was evident.2, 5-7
Comparison of results is difficult because of the numerous

differences between the various trials, including study drug
(plus pharmacological adjuncts), study design, surgical technique, and testing procedures. In addition, while the patients in
all these studies had LCA2 as a result of lack-of-function gene
defects, the disease is surprisingly heterogeneous in its clinical
manifestations, further complicating the analysis of treatment
effect in these exceedingly small study populations. A definitive trial to address the issue of duration of effect will require
a study design incorporating appropriate (eg, interocular) controls, standard dosing and delivery of vector, and highly sensitive and reproducible outcome measures that are available to all
investigators and not customized, laboratory-based constructs.
The ability to measure a change in the rate of disease progression is likewise of critical importance, as a delay in vision loss,
especially after a resetting of the baseline function, is very
much a clinically meaningful improvement compared to no
treatment.
References
1. Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal
gene therapy for Leber congenital amaurosis shows advancing
retinal degeneration despite enduring visual improvement. Proc
Natl Acad Sci USA. 2013; 110(6): E517-525.
2. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects
of RPE65 gene therapy for Lebers congenital amaurosis: a phase
1 dose-escalation trial. Lancet 2009; 374(9701): 1597-1605.
3. Cideciyan AV, Hauswirth W, Aleman TS, et al. Human RPE65
gene therapy for Leber congenital amaurosis: persistence of early
visual improvements and safety at 1 year. Hum Gene Ther. 2009;
20(9):999-1004.
4. Bainbridge JW, Mehat MS, Sundaram V, et al. Long-term effect
of gene therapy on Lebers congenital amaurosis. N Engl J Med.
2015; 372(20): 1887-1897.
5. Bennett J, Ashtari M, Wellman J, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl
Med. 2012; 4(120):120ra15.
6. Bennett J, Wellman J, Marshall K, et al. AAV2 gene therapy contralateral eye administration in childhood onset blindness due to
RPE65 mutations: results of a follow-on Phase 1/2 study. Lancet.
In press.
7. Jacobson SG, Cideciyan AV, Roman AJ, et al. Improvement and
decline in vision with gene therapy in childhood blindness. N Engl
J Med. 2015; 372(20):1920-1926.
57
Stargardt: Diagnosis, Natural History, and

Future Directions
Hendrik P Scholl MD
Stargardt macular dystrophy (STGD1, OMIM 248200) is the
most common form of juvenile degeneration1 and is caused by
mutations in the ABCA4 gene.2 Although no approved treatment is available, several treatment options, including stem
cell therapy3 (ClinicalTrials.gov identifier NCT01469832,
NCT02445612), gene therapy4 (ClinicalTrials.gov identifier
NCT01736592, NCT01367444), and pharmacotherapy5 (ClinicalTrials.gov identifier NCT02402660), are currently in clinical trials. The Natural History of the Progression of Atrophy
Secondary to Stargardt Disease (ProgStar; http://progstar.org/)
Study aims to characterize the natural history using a variety of
structural and functional measures and will provide quantitative measures of disease progression to evaluate the safety and
efficacy of forthcoming treatments.6
References
1. Scholl HPN, Strauss RW, Singh MS, et al. Emerging Therapies for
Inherited Retinal Degenerations. Sci Transl Med. In press.
2. Allikmets R, Singh N, Sun H, et al. A photoreceptor cell-specific
ATP-binding transporter gene (ABCR) is mutated in recessive
Stargardt macular dystrophy. Nat Genet. 1997; 15(3):236-246.
3. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic

stem cell-derived retinal pigment epithelium in patients with agerelated macular degeneration and Stargardts macular dystrophy:
follow-up of two open-label phase 1/2 studies. Lancet 2015;
385(9967):509-516.
4. Binley K, Widdowson P, Loader J, et al. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors:
safety and biodistribution of StarGen for Stargardt disease. Invest
Ophthalmol Vis Sci. 2013; 54:4061-4071.
5. Issa PC, Barnard AR, Herrmann P, Washington I, MacLaren
RE. Rescue of the Stargardt phenotype in Abca4 knockout mice
through inhibition of vitamin A dimerization. Proc Natl Acad Sci
USA. 2015; 112:8415-8420.
6. Strauss RW, Ho A, Muoz B, Cideciyan AV, Sahel JA, Sunness JS,
Birch DG, Bernstein PS, Michaelides M, Traboulsi EI, Zrenner E,
Sadda S, Ervin AM, West S, Scholl HP; Progression of Stargardt
Disease Study Group. The Natural History of the Progression of
Atrophy Secondary to Stargardt Disease (ProgStar) Studies: design
and baseline characteristics: ProgStar report no. 1. Ophthalmology 2016; 123:817-828.
58
Current and Future Management of Retinal

Degenerations
Hendrik P Scholl MD
Inherited retinal degenerations (IRDs) are a genetically and phenotypically heterogeneous group of disorders affecting the function and viability of photoreceptor cells and are among the leading causes of blindness in developed countries. Recent advances
in molecular genetics and cell biology have helped to elucidate
pathophysiological mechanisms underlying IRDs and to identify novel therapeutic approaches including pharmacotherapy,
gene therapy, stem cell therapy, and optogenetics, most of
which have entered the clinical phase of development. Artificial
replacement of photoreceptors by retinal prostheses has even
received market approval. Unprecedented precision of retinal
imaging and visual function testing will facilitate more efficient
clinical trial design. In individual IRD patients, disease stage
will likely determine whether the therapeutic strategy should
comprise photoreceptor rescue to delay or arrest the progression
of visual loss, or if a retinal replacement approach is required to
achieve restoration of vision.
Selected Readings
3. Campochiaro PA, Strauss RW, Lu L, et al. Is there excess oxidative stress and damage in eyes of patients with retinitis pigmentosa? Antiox Redox Signal. 2015; 23(7):643-648.
4. Jacobson SG, Cideciyan AV, Ratnakaram R, et al. Gene therapy
for Leber congenital amaurosis caused by RPE65 mutations:
safety and efficacy in 15 children and adults followed up to 3
years. Arch Ophthalmol. 2012; 130:9-24.
5. MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a Phase
1/2 clinical trial. Lancet 2014; 383:1129-1137.
6. Sahel JA, Roska B. Gene therapy for blindness. Ann Rev Neurosci. 2013; 36:467-488.
7. Zrenner E, Bartz-Schmidt KU, Benav H, et al. Subretinal electronic chips allow blind patients to read letters and combine them
to words. Proc Biol Sci. 2011; 278:1489-1497.
8. Humayun MS, Dorn JD, da Cruz L, et al. Interim results from the
international trial of Second Sights visual prosthesis. Ophthalmology 2012; 119:779-788.
1. Koenekoop RK, Sui R, Sallum J, et al. Oral 9-cis retinoid for

childhood blindness due to Leber congenital amaurosis caused by
RPE65 or LRAT mutations: an open-label Phase 1b trial. Lancet
2014; 384:1513-1520.
9. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem
cell-derived retinal pigment epithelium in patients with age-related
macular degeneration and Stargardts macular dystrophy: followup of two open-label Phase 1/2 studies. Lancet 2013; 385:509516.
2. Scholl HP, Moore AT, Koenekoop RK, et al. Safety and proofof-concept study of oral QLT091001 in retinitis pigmentosa due
to inherited deficiencies of retinal pigment epithelial 65 protein
(RPE65) or lecithin:retinol acyltransferase (LRAT). PLOS ONE
2014; 10:e0143846.
10. Singh S, Charbel Issa P, Butler R, et al. Reversal of end-stage

retinal degeneration and restoration of visual function by photoreceptor transplantation. Proc Natl Acad Sci USA. 2013; 110:11011106.
59
Innovative Gene Therapy:

Where We Are and Where We Are Headed
Background
Gene therapy with adeno associated viral (AAV) vectors shows
great promise as potential treatment for patients with inherited
retinal diseases. The AAV vector has a protein shell in the shape
of an icosahedron that surrounds a single-stranded DNA molecule. There is no envelope or cell membrane around the protein
shell (known as the capsid) and no enzymesjust the 3 proteins
that make up the capsid. Hence most of the immunogenic material that is present in larger viruses, such as adenovirus and
lentivirus, is absent. There is little doubt now that safety with
AAV has been shown in a number of studies, with the main
risks being identified as inflammation and damage to the retina
as a result of surgery. There is a current debate about whether to
deliver the AAV vector by an intravitreal or a subretinal route.
The intravitreal route is much easier to perform surgically but
has the disadvantage of predisposing to inflammation, which
may result in reduced transduction efficiency. The subretinal
route is less likely to be immunogenic and may also provide a
better pharmacokinetic environment for transduction of outer
retinal cells, such as the retinal pigment epithelium and photoreceptors. However, the subretinal approach raises significant
challenges for the surgeon, particularly in patients with endstage retinal degenerations, in which the retina is thin and may
be more prone to damage.
Gene Therapy Dosing

In traditional medicines there is much attention on achieving
the correct dose when submitting a drug to the FDA for regulatory approval. Examples might include serum levels, hepatic or
renal excretion, and minimum effective concentration from in
vitro studies. From this it is usually possible to estimate the dose
that is effective in 50% of the population and the dose that is
toxic in 50% of the population, giving what is known as ED50
and TD50 values, respectively. With gene therapy, however, we
have to rewrite the rule book because we are dealing with a
biological product that needs to initiate a biological process,
and this process is currently highly variable between individual
patients. This is before even considering the variability of the
retinal disease at presentation, in which there may be variable
numbers of cells remaining and variable degrees of disruption of
the outer bloodretinal barrier.
For this reason it is extremely difficult, if not impossible, to
work out the effective dose of AAV for a given individual undergoing retinal gene therapy. The strategy should therefore be to
give the maximum dose that will be tolerated without causing death of cells through gene overexpression and to regulate
the immune response to this dose by administering systemic
steroids during the period immediately after the gene therapy
surgery.
We know from studies in the liver that the human body can
tolerate up to 1014 genome particles; however, this does generate
an immune response that results in antibody-mediated capsid
destruction and hence a reduction in overall transduction efficiency. Hence increasing the dose of AAV may actually be coun-
terproductive if it leads to inflammation. In the eye we know

from the work of Bainbridge and colleagues (2015) that a subretinal injection of 1012 genome particles caused inflammation
in 5 of 8 patients, despite the use of adjunctive steroids around
the time of surgery. It should, however, be remembered that this
number does not represent the total number of viral particles
because the calculation of genome particles includes only the
AAV viral capsids that have the correct gene within. There will
be many additional empty viral particles (capsids) that would
contribute the immune response. It is therefore somewhat frustrating that in virtually all of the gene therapy clinical trials
reported to date, there is no mention of the total viral capsid
dose; the articles report only on the gene-containing particle
dose. It is, however, possible to identify the proportion of empty
capsids using electron microscopy, and improved technologies
of ultracentrifugation can reduce the number of empty capsids
to 10%-20% of the total genome particles.
With regard to identifying the minimum dose for therapeutic efficiency, a pragmatic approach needs to be considered as
it will be impossible to model each individual disease scenario
in every patient. The situation here is again different to that of
traditional drug dosing, which results in predictable plasma levels. We know from observations in female carriers of X-linked
diseases affecting the retina that in most cases degeneration
will not be significant as long as 50% of the cells carry a functional copy of the gene. In a female carrier there is random
inactivation of the X chromosome in individual photoreceptors
and retinal pigment epithelial cells. Hence a female carrier of
an X-linked disease presents a scenario similar to that of the
affected male who has received gene therapy successfully to
50% of his cells. It is therefore likely that retinal degeneration
will be slowed sufficiently with 50% transduction, and there
may not be a great need to go higher than this. For instance, to
go from 75% to 90% transduction of retinal cells may require
a log unit higher dose, which may then create problems with
inflammation and possible overexpression toxicity in some
cells. Hence the gene therapy dose should be the maximum that
is safely tolerated in virtually all patients and that is known to
be therapeutic. In individual patients transduction levels will
vary, but this does not matter as long as we meet the minimum
transduction of, say, 50% of cells in the majority of individuals.
Gene Therapy Surgery

Over most of the 20th century, ophthalmologists around the
world sought ways to reattach the retina as a means of saving sight. Now in the 21st century, as we move into the age of
gene therapy to treat retinal diseases, we are trying to learn
the reverse: how to detach the retina safely for the subretinal
administration of viral vectors. Like all new surgical techniques
in ophthalmology, the technology is still lagging behind the concept and we have to learn our way with the emerging gene therapy clinical trials. There is no doubt that it is possible to detach
the retina safely and that the subretinal fluid will be reabsorbed
quickly with minimal damage to the overlying photoreceptors.
The difficulty, however, is achieving this in 100% of patients,
60
because invariably complications will arise. Use of new technologies such as intraoperative OCT and robotic surgery devices
may help improve safety in subretinal administration.
The success of surgery is inherently linked to the concept of
dose and safety. This is because a significant reflux of viral suspension into the vitreous cavity will reduce the number of viral
particles available to the retinal pigment epithelium or photoreceptors. At the same time, the dispersion of these particles
within the vitreous cavity may also predispose to inflammation
targeting the residual capsids. Hence getting the surgery right
is the first step in considering the dose required to see a treatment effect. There is no doubt therefore that the new era of gene
therapy is with us. Furthermore it is now critically important
that retinal specialists engage with gene therapy scientists to
work out the best ways of delivering the virus that is safe and
effective.
Section VI: Uveitis Panel, Part I
61
Uveitis PanelPart I
Sunil K Srivastava MD, Thomas A Albini MD, Anita Agarwal MD, Amani Fawzi MD, K Bailey Freund MD,
David Sarraf MD, Lawrence A Yannuzzi MD
N OTE S
62
2016 Advocating for Patients

John A Wells III MD
Ophthalmologys goal to protect sight and empower lives

requires active participation with and commitment to advocacy
efforts. Contributions to the following three critical funds by all
ophthalmologists is part of that commitment:
1. OPHTHPAC Fund
2. Surgical Scope Fund (SSF)
3. State Eye PAC
Your ophthalmologist colleagues serving on Academy committeesthe Surgical Scope Fund Committee, the Secretariat
for State Affairs, and the OPHTHPAC Committeeare dedicating significant time to advocating for patients and the profession. The OPHTHPAC Committee is identifying congressional
advocates in each state to maintain close relationships with federal legislators in order to advance ophthalmology and patient
causes. The Secretariat for State Affairs is collaborating closely
with state ophthalmology society leaders to protect Surgery by
Surgeons at the state level. Both groups require robust funds
from both the Surgical Scope Fund and the OPHTHPAC Fund
in order to protect quality patient care.
These committed ophthalmologists serving on your behalf
have a simple message to convey: It takes the entire community of ophthalmologists to be effective.

We need each member of the ophthalmology community

to contribute to each of these 3 funds.
to establish relationships with state and federal legislators.
to make a commitment to protect quality patient eye care
and the profession.
OPHTHPAC Fund
OPHTHPAC is a crucial part of the Academys strategy to
protect and advance ophthalmologys interests in key areas,
including physician payments from Medicare as well as protecting ophthalmology from federal scope of practice threats.
Established in 1985, OPHTHPAC is one of the oldest, largest,
and most successful political action committees in the physician
community. We are very successful in representing your profession to the U.S. Congress. As one election cycle ends, a new one
starts. OPHTHPAC is always under financial pressure to support our incumbent friends as well as to make new friends with
candidates. These relationships allow us to have a seat at the
table and legislators willing to work on issues important to us
and our patients.
For the past year, the media and the country have focused
on the U.S. presidential primaries. But the races most important
to ophthalmology involve seats in Congress. The entire House
of Representatives and one-third of the Senate is up for election. Several physicians need our helpand we have many new
friends to make.
In order for ophthalmology to remain seated at the table, we
need to be heavily invested in this years election. That takes
investment by each member of the ophthalmology community,
whether with time or money. Currently, only a minority of
ophthalmologists have realized the vital importance of contributing to OPHTHPAC and the other funds. Right now, major
transformations are taking place in health care and we need
participation from the majority of ophthalmologists so that we
have the resources to better our profession and ensure quality
eye care for our patients.
Among the significant impacts made by OPHTHPAC are the
following:

Repealed the flawed Sustainable Growth Rate (SGR)

formula
Blocked the unbundling of Medicare global surgery
payments
Removed a provision in Medicare fraud and abuse legislation that targeted eyelid surgery
Working to reduce the burdens from Medicares existing
quality improvement programs, such as the EHR Meaningful Use program
Working in collaboration with subspecialty societies to
preserve access to compounded and repackaged drugs
such as Avastin
Working to get the Centers for Medicare and Medicaid
Services to revisit drastic Medicare fee cuts to glaucoma
and retinal detachment surgeries
Working to protect your ability to perform in-office ancillary services in your office
Contributions to OPHTHPAC can be made here at AAO

2016 or online at www.aao.org/ophthpac.
Leaders of the three retina societies, the American Society of
Retina Specialists (ASRS), the Macula Society, and the Retina
Society, are part of the American Academy of Ophthalmologys
Ophthalmic Advocacy Leadership Group (OALG) which has
met for the past nine years in January in the Washington, DC,
area to provide critical input and to discuss and collaborate on
the Academys advocacy agenda. The topics discussed in the
2016 OALG agenda included the impact of the Medicare Access
and the CHIP Reauthorization Act (MACRA); the IRIS Registry and quality reporting under Medicare; data transparency
and public reporting, and a roundtable to discuss challenges
for surgical specialties. At Mid-Year Forum 2016, the Academy
and the three retina societies ensured a strong presence of retina
specialists to support ophthalmologys priorities, and a record
number of ophthalmologists visited members of Congress and
their key health staff to discuss ophthalmology priorities as
part of Congressional Advocacy Day. The ASRS, the Macula
Society, and the Retina Society remain crucial partners with the
Academy in its ongoing federal and state advocacy initiatives.
Surgical Scope Fund (SSF)

The Surgical Scope Fund (SSF) provides grants to state ophthalmology societies to support their legislative, regulatory, and
public education efforts to derail optometric surgery proposals
that pose a threat to patient safety, quality of surgical care, and
surgical standards. Since its inception, the Surgery by Surgeons
campaignin partnership with state ophthalmology societies
63
Surgical Scope Fund
OPHTHPAC Fund
State EyePAC
To derail optometric surgical scope of practice initiatives that threaten patient eye safety and quality
of surgical care
Ophthalmologys interests at the federal level /

support for candidates for U.S. Congress
Support for candidates for State

House and Senate
Political grassroots activities, lobbyists, and media;

No funds may be used for candidates or PACs.
Campaign contributions, legislative education
Campaign contributions, legislative

education
Contributions: Unlimited
Contributions: Limited to $5,000
Contribution limits vary based on

state regulations.
Contributions above $200 are on the public record.
Contributions are on the public record

depending upon state statutes.
Individual, practice and organization

Contributions are 100% confidential.
and with support from the SSFhas helped 32 state/ territorial ophthalmology societies reject optometric scope of practice
expansion into surgery.
In 2016, thanks to Surgical Scope Fund support by Academy
members and tireless advocacy by state ophthalmology society
leaders, ophthalmology continues to champion surgical safety
at state capitols across the country. State ophthalmological societies and the Academys Secretariat for State Affairs faced eight
concurrent Surgery by Surgeons battles, in Alaska, California,
Delaware, Illinois, Iowa, Massachusetts, Pennsylvania, and
Puerto Rico.
In each of these legislative battles, the benefits from Surgical
Scope Fund distributions are crystal clear. The fund has allowed
for successful implementation of patient safety advocacy campaigns, which result in defeating attempts by optometry to
expand their scope of practice to include surgery.
The Academy relies not only on the financial contributions
to the Surgical Scope Fund from individual ophthalmologists
and their practices, but also on the contributions made by
ophthalmic state, subspecialty, and specialized interest societies. The ASRS, Macula Society, and Retina Society each contributed to the Surgical Scope Fund in 2015, and the Academy
counts on their contribution in 2016.
Contributions to the SSF can be made here at AAO 2016 or
online at www.aao.org/ssf.
State Eye PAC

It is also important for all ophthalmologists to support their
respective State Eye PACs because PAC contributions to legislators at the state level must come from individual ophthalmologists and cannot come from the Academy, OPHTHPAC, or the
Surgical Scope Fund. The presence of a strong State Eye PAC,
providing financial support for campaign contributions and
legislative education to elect ophthalmology-friendly candidates
to the state legislature, is critical as scope of practice battles and
many regulatory issues are all fought on the state level.
Action Requested: ADVOCATE FOR YOUR PATIENTS

Academy Surgical Scope Fund contributions are used to support the infrastructure necessary in state legislative/ regulatory
battles and for public education. PAC contributions are necessary at the state and federal level to help elect officials who will
support the interests of our patients. Contributions to each of
these three funds are necessary and help us protect sight and
empower lives. Surgical Scope Fund contributions are completely confidential and may be made with corporate checks or
credit cards, unlike PAC contributions, which must be made by

individuals and are subject to reporting requirements.
Please respond to your Academy colleagues and be part of
the community that contributes to OPHTHPAC, the Surgical
Scope Fund, and your State Eye PAC. Please be part of the community advocating for your patients now.
*OPHTHPAC Committee
Donald J Cinotti MD (NJ) Chair
Janet A Betchkal MD (FL)
William S Clifford MD (KS)
Sidney K Gicheru MD (TX)
Michael L Gilbert MD (WA)
Gary S Hirshfield MD (NY)
David W Johnson MD (CO)
Jeff Maltzman MD (AZ)
Lisa Nijm MD JD (IL)
John D Roarty MD (MI)
Diana R Shiba MD (CA)
Woodford S Van Meter MD (KY)
John (Jack) A Wells III MD (SC)
Charles M Zacks MD (ME)
Ex Officio Members
Daniel J Briceland MD (AZ)
David W Parke II MD (CA)
Michael X Repka MD (MD)
William L Rich III MD FACS (VA)
George A Williams MD (MI)
**Surgical Scope Fund Committee

Kenneth P Cheng MD (PA) Chair
Matthew F Appenzeller MD (NC)
Ronald A Braswell MD (MS)
John P Holds MD (MO)
Cecily A Lesko MD FACS (NJ)
C Blake Myers MD (SC)
William (Chip) W Richardson II MD (KY)
David E Vollman MD MBA (MO)
Ex Officio Members
Daniel J Briceland MD (AZ)
Kurt F Heitman MD (SC)
64
Section VII: My Coolest Surgical Video
My Coolest Surgical Video
Endocryotherapy for the Treatment of a Retinal Hemangioblastoma

Colin McCannel MD
Autologous Neurosensory Retinal Transplant for Closure of

Refractory Large Myopic Macular Hole
Use Ofnitinol Basket in Dislocated Lens

Karthik Srinivasan MS
NonPenetrating Subretinal Injection

Yuki Morizane MD
Retinal Embolectomy
65
Update on ROP Clinical Trials Results

RV Paul Chan MD
Over the past decade we have seen a significant evolution in

how we approach our diagnosis and management of retinopathy of prematurity (ROP). We have seen advances in treatment
and imaging, and in our fundamental understanding of ROP.

I. Risk Factors and ROP Predictive

C. Imaging and computer-facilitated image analysis

A. Weight Gain Only Version of Weight, Insulin-like

Growth Factor-1 (IGF-1), Neonatal, Retinopathy
of Prematurity Model (WINROP 2)

1. Gestational age (GA), birth weight (BW), weight

gain (eliminated serum IGF-1 levels from analysis)
2. Outcome variable: Presence or absence of stage 3
1. Utility of ancillary imaging for ROP diagnosis

and management (eg, fluorescein angiography,
computer-generated mosaic photographs)

a. Compared with color fundus photography

alone, fluorescein angiograms may improve
the sensitivity of diagnosis of ROP by
experts, particularly for stage 3 disease.
b. Compared to multiple individual photographs, computer-generated mosaic photographs may improve the accuracy of imagebased diagnosis for clinically significant
ROP.
B. Childrens Hospital of Philadelphia Retinopathy of

Prematurity Model (CHOP-ROP)

1. GA, BW, and daily weight gain rate
2. Outcome variable: Type 1 and type 2 ROP
1. Gender, race or ethnicity, BW, GA, quadrants

of pre-plus, stage of ROP, presence of retinal
hemorrhage, degree of respiratory support, and
weight gain
2. Outcome variable: Referral-warranted ROP
3. Internal or external validation of the model was

not performed.
2. ROPtool5
C. Telemedicine Approaches to Evaluating AcutePhase Retinopathy of Prematurity Model (e-ROP)

a. Assigns a numerical value to the level of vascular abnormality and tortuosity in images
with ROP present in each of 4 quadrants or
sectors
b. ROPtool was found to have good accuracy

for detection of vascular abnormalities suggestive of plus disease when compared with
expert physician graders.
3. i-ROP system6
a. Develop a computer-based image analysis

system to diagnose severe ROP and model
relative disease severity
b. The i-ROP system performs comparably to

or better than ROP experts in the classification of plus disease.
D. The Colorado Retinopathy of Prematurity prediction model (CO-ROP)

1. BW, GA, and postnatal weight gain
2. Outcome variable: Type 1, type 2, and all ROP
E. Imaging and Informatics for ROP Consortium

(i-ROP)
Models1,2
2. A tele-education system can successfully

improve the ability of physicians to recognize
and accurately diagnose ROP.
Develop quantitative models relating the clinical,

imaging, and genetic features of ROP and to examine genotype-phenotype correlations
II. Telemedicine, Tele-Education, Imaging, and Image
Analysis
A. Telemedicine (eg, e-ROP3)
B. Tele-Education: Global Education Network for

ROP (GEN-ROP)4

1. Develop innovative ways to educate and increase

the workforce for ROP
4. Experts have limited agreement in ROP diagnosis because of differences in cut points for
plus disease and pre-plus disease, but are more
consistent in identifying relative disease severity.
III. Treatment

A. Bevacizumab Eliminates the Angiogenic Threat for

Retinopathy of Prematurity (BEAT-ROP)7

1. Refractive outcomes
2. Management of recurrent ROP: Recurrence after

intravitreal anti-VEGF for ROP is not uncommon, and close follow-up is recommended.
66
B. RAINBOW Study: RAnibizumab Compared With

Laser Therapy for the Treatment of INfants BOrn
Prematurely With Retinopathy of Prematurity
(RAINBOW)8

1. Primary outcome measures

a. Absence of active ROP and unfavorable

structural outcome
b. Time frame: 24 weeks after starting investigational treatment
2. Three arms

a. Ranibizumab, 0.2 mg (bilateral)
b. Ranibizumab 0.1 mg (bilateral)

3. Laser (bilateral)
C. IGF-1/IGFBP3 Prevention of Retinopathy of Prematurity9

1. Study results in extremely premature infants

showed no impact on the primary endpoint of
reducing the severity of ROP.
2. Secondary endpoints showed clinically relevant

effects on severe complications related to lung
and brain damage.
D. i-ROP10
1. In one study performed by the i-ROP consortium, experts recommended treatment for
disease less than type 1 ROP in 9.5% of all eyes
that were treated.
2. With the increased accessibility to imaging
modalities and more options for treatment, we
have the opportunity to rethink our management algorithms for ROP. Future ROP care may
require the integration of imaging, image analysis programs, and predictive models incorporating potential risk factors for progression (eg,
genetic markers).
References
1. Hutchinson AK, Melia M, Yang MB, et al. Clinical models and
algorithms for the prediction of retinopathy of prematurity: a
report by the American Academy of Ophthalmology. Ophthalmology 2016; 123(4):804-816.
2. Cao JH, Wagner BD, Cerda A, et al. Colorado Retinopathy of Prematurity Model: a multi-institutional validation study. J AAPOS.
2016; 20(3):220-225.
3. Quinn GE, Ying GS, Daniel E, et al; e-ROP Cooperative Group.
Validity of a telemedicine system for the evaluation of acutephase retinopathy of prematurity. JAMA Ophthalmol. 2014;
132(10):1178-1184.
4. Chan RV, Patel SN, Ryan MC, et al. The Global Education Network for Retinopathy of Prematurity (GEN-ROP): development,
implementation, and evaluation of a novel tele-education system.
Trans Am Ophthalmol Soc. 2015; 113:T2 21-226.
5. Abbey AM, Besirli CG, Musch DC, et al. Evaluation of screening
for retinopathy of prematurity by ROPtool or a lay reader. Ophthalmology 2016; 123:385-390.
6. Kalpathy-Cramer K, Campbell JP, Erdogmus D, et al; on behalf
of the Imaging and Informatics in Retinopathy of Prematurity
Research Consortium. Plus disease in retinopathy of prematurity:
improving diagnosis by ranking disease severity and using quantitative image analysis. Ophthalmology, in press.
7. Mintz-Hittner HA, Geloneck MM, Chuang AZ. Clinical management of recurrent retinopathy of prematurity after intravitreal
bevacizumab monotherapy. Ophthalmology. Epub ahead of print
2016 May 27.
8. RAINBOW Study: https://clinicaltrials.gov/ct2/show/
NCT02375971
9. IGF-1/IGFBP3 Prevention of ROP: https://clinicaltrials.gov/ct2/
show/study/NCT01096784
10. Gupta MP, Chan RP, Anzures R, et al. Practice patterns in retinopathy of prematurity treatment for disease milder than recommended by guidelines. Am J Ophthalmol. 2016; 163:1-10.
67
Management of Familial Exudative Vitreoretinopathy

Michael Trese MD
I. Familial Exudative Vitreoretinopathy (FEVR)

A. Potentially active lifelong retinal vascular disease
B. Born with avascular peripheral retina and can have

varying amounts of exudate and retinal detachment (exudative and tractional)
C. Mechanism of the progression of the disease was

unknown until widefield fluorescein angiography
(FA) showed progressive posterior capillary loss
and subsequent VEGF-driven exudative and tractional retinal detachment, which can lead to blindness.
II. Genetics
The mutations effecting Wnt signaling, Fz4 binding

site, Norrin will be presented for clinical understanding.
III. Treatment

A. Past

1. Laser ablation of avascular retina as determined

by clinical exam
2. Clinical exam alone was not able to predict flare

up or progression.
B. Present
Use of wide field FA allows visualization of areas of
capillary loss prior to frank exudation and allows
effective laser treatment.
C. Future
Use of widefield FA to identify LAPPEL (late

FA posterior and peripheral leakage), a newly
described lesion that predicts capillary loss and
may be treatable with drugs, avoiding the destructive therapy of laser
Drug treatment that increases intercellular retinal

endothelial adhesion molecules claudin-5 and VEcadherin tightens cell junctions and modulates
ICAM-1 implicated in leucocyte endothelial adhesion (LEA) and can reverse leakage and prevent
capillary loss and the need for destructive laser
treatment. Examples of effects in tissue culture and
patients of steroid, NSAID, and Norrin will be presented.
68
Pediatric Retina Panel: What the Retina Specialist

Should Know
Antonio Capone Jr MD, Audina M Berrocal MD, Felix Y Chau MD, Kimberly A Drenser MD PhD,
Mary Elizabeth Hartnett MD FACS, Thomas C Lee MD
N OTE S
69
Conbercept for Retinal Vein Occlusion: Results of the

FALCON Study
Peter K Kaiser MD and Liu Xiaoling MD

I. Purpose
To evaluate the efficacy and safety of 0.5-mg conbercept treatment in patients with macular edema (ME)
secondary to retinal vein occlusion (RVO).
C. BRVO group

1. Mean number of conbercept injections: 7.0
2. BCVA increased + 14.6 8.7 letters from

baseline at Month 3 (P < .0001), and further
improved to +17.8 10.9 letters at Month 9 (P <
.0001).
3. Central retinal thickness (CRT) decreased 295.5

156.0m at Month 3 and 290.0 165.4m at
Month 9 (P < .0001).
II. Methods

A. Prospective, open-label, Phase 2 clinical study
B. Major eligibility criteria

1. Age of 18 years or older
2. Center-involved macular edema due to branch

RVO (BRVO) or central RVO (CRVO) less than
6 months duration
3. BCVA letter score in the study eye 73
4. Central retinal thickness on OCT 320m
D. CRVO group

1. Mean number of conbercept injections: 7.3
2. BCVA increased +11.5 11.4 letters at Month

3 (P < .0001) and further improved to +14.23
11.7 letters at Month 9 (P < .0001).
3. Central retinal thickness (CRT) decreased 383.6

270.8m at Month 3 and 420.47 235.9m
at Month 9 (P < .0001).
C. All patients received 3 monthly injections of 0.5-mg

conbercept, followed by a 6-month p.r.n. regimen
D. Primary outcome = mean changes in BCVA letter

score
E. Secondary outcomes = mean change in central

retinal thickness (CRT) from baseline, and safety
measures
E. In addition, the mean change from baseline in

macular total volume was statistically significant
(P< .001) at Months 3 and 9 in both groups.
F. Only 2 adverse events were reported: increased IOP

and lens opacity, both coded as mild.
III. Results

A. 60 patients (30 BRVO, 30 CRVO) enrolled
B. 57 patients completed the whole study
IV. Conclusions
The results of our study demonstrated statistically
significant visual acuity and anatomical benefits from
repeated intravitreal injections of conbercept at 3
months (primary outcome) in both BRVO and CRVO
groups, and these outcomes further improved during
the p.r.n. dosing phase through 9 months.
70
Key Learnings from a Phase 2 Study of Encapsulated

Cell Therapy for the Treatment of Neovascular AMD
Szilard Kiss MD
N OTE S
71
TREX: Monthly vs. Treat and Extend for

Neovascular AMD
Two-Year Prospective Trial Results
Charles C Wykoff MD PhD, David M Brown MD, William Ou, John F Payne MD,
and Lloyd Clark MD on behalf of the TREX-AMD Study Group
Objective
Main Outcome Measures at 2 Years
To prospectively assess a treat-and-extend management strategy

compared to monthly dosing with intravitreal ranibizumab in
treatment-nave neovascular AMD
Change in BCVA, proportion of patients achieving 3 or more

lines of VA gain and loss, change in central retinal thickness
(CRT), and mean number of injections in each randomized arm
Background
Results
Neovascular AMD is a leading cause of vision loss. The 2015

American Society of Retina Specialists Global Trends Survey
revealed that 66.2% of retina specialists in the United States
utilize primarily a treat-and-extend management strategy, in
which monthly anti-VEGF intravitreal injections are typically
given until signs of exudation have resolved.1 Then the interval
between treatments is lengthened, as long as there are no signs
of recurrent exudation. Treatment is rendered at every visit, and
the time between visits is individualized. When recurrent disease is detected, the treatment interval is reduced. The goal is to
maintain an exudation-free macula and avoid multiple disease
recurrences, as can occur with p.r.n. dosing, while minimizing
treatment burden through fewer clinical visits, diagnostics, and
treatments.2-6
Sixty patients were enrolled between February 2013 and January 2014. Baseline demographics were well balanced between
patients randomized to the monthly and TREX cohorts. At
baseline, mean age was 77 years and mean BCVA was 60.3 and
59.9 ETDRS letters (20/60 Snellen equivalent) in the monthly
and TREX cohorts, respectively. Fifty patients (83%) completed
Month 24 (M24). Mean ETDRS BCVA letter gains at M24
were similar between cohorts: 10.5 and 8.7 for the monthly
and TREX cohorts, respectively (P = .75). At M24, 7 patients in
the monthly cohort (35%) and 11 patients in the TREX cohort
(28%) gained at least 15 letters (P = .90). At M24, no patient in
the monthly cohort lost more than 2 letters, while 4 patients in
the TREX cohort (10%) lost at least 15 letters; 1 patient experienced a retinal pigment epithelial tear at month 1 and lost 24
letters; 2 patients were maximally extended to 12-week intervals with resolution of exudative disease activity but lost 32 and
27 letters from baseline due to progressive macular atrophy; and
1 patient lost 20 letters due to persistent exudative disease activity at every clinical visit with chronic subretinal fluid despite
monthly dosing.
Anatomic improvements achieved were similar between
the cohorts. At M24, there were no meaningful differences in
mean CRT between the groups, with mean CRT decreases of
200m and 170m for the monthly and TREX cohorts,
yielding an absolute mean CRT of 300m and 309m, respectively. Through M24, the mean number of intravitreal injections administered was 24.5 and 18.6 (range: 10-25) for the
monthly and TREX, cohorts respectively (P < .0001). At M24,
14 patients (47%) were at an extension interval of 8 weeks,
and the mean maximum extension was 9.6 weeks among TREX
patients. Of the 26 TREX patients (65%) who achieved a dry
macula and then became wet over the course of 2 years of the
trial, the extension interval at the time of developing a wet
macula was their maximum extension interval in the majority
of eyes (n = 19, 73%).
Methods
TREX-AMD (Treat and Extend Protocol in Patients with Wet
Age-Related Macular Degeneration) is a Phase 3b, multicenter,
randomized clinical trial (FDA IND 116786).7 Inclusion criteria: patients with treatment-nave exudative AMD with ETDRS
BCVA between 20/32 and 20/500 (Snellen equivalent). Subjects were randomized 1:2 to monthly or TREX cohorts. All
subjects received ranibizumab (0.5 mg) administered monthly
(28 7 days) for 3 treatments. Patients in the monthly cohort
(n = 20) continued to receive monthly treatments. For patients
randomized to TREX (n = 40), beginning at the time of the
third monthly treatment, the interval between treatments was
individualized based on disease activity using a strict prospective protocol: eyes were treated at each visit, no more frequently
than every 4 weeks and no less frequently than every 12 weeks.
At each visit, TREX patients were classified as having a dry
or wet macula and treated monthly until a dry macula was
achieved. A dry macula was achieved upon resolution of intraretinal and subretinal fluid on spectral domain OCT, and resolution of subretinal and intraretinal hemorrhage related to exudative AMD. The presence of a pigment epithelial detachment
without intraretinal or subretinal fluid did not qualify a macula
as wet. When a dry macula was achieved, the interval between
visits was lengthened by 2-week increments. If recurrent exudative disease activity was identified, the interval between visits
was reduced by 2-week increments until a dry macula was again
achieved and stability was demonstrated. The previously identified maximum interval between visits was then repeatedly challenged in a rigid, prospective fashion as reported.7
Conclusions
A treat-and-extend approach to neovascular AMD offers the
opportunity to individualize management while minimizing
treatment burden. The treat and extend neovascular AMD
management strategy employed in the TREX-AMD prospective, randomized trial resulted in visual and anatomic gains
comparable to those obtained with monthly dosing.
72
References
1. Spaide R. Ranibizumab according to need: a treatment for
age-related macular degeneration. Am J Ophthalmol. 2007;
143(4):679-680.
5. Arnold JJ, Campain A, Barthelmes D, et al. Two-year outcomes of

treat and extend intravitreal therapy for neovascular age-related
macular degeneration. Ophthalmology 2015; 122(6):1212-1219.
2. Gupta OP, Shienbaum G, Patel AH, et al. A treat and extend

regimen using ranibizumab for neovascular age-related macular
degeneration clinical and economic impact. Ophthalmology
2010; 117(11):2134-2140.
6. Berg K, Pedersen TR, Sandvik L, et al. Comparison of ranibizumab and bevacizumab for neovascular age-related macular
degeneration according to LUCAS treat-and-extend protocol.
Ophthalmology 2015; 122(1):146-152.
3. Toalster N, Russell M, Ng P. A 12-month prospective trial of

inject and extend regimen for ranibizumab treatment of agerelated macular degeneration. Retina 2013; 33(7):1351-1358.
7. Wykoff CC, Croft DE, Brown DM, et al. Prospective trial of treatand-extend versus monthly dosing for neovascular age-related
macular degeneration: TREX-AMD 1-year results. Ophthalmology 2015; 122(12):2514-2522.
4. Abedi F, Wickremasinghe S, Islam AF, et al. Anti-VEGF treatment

in neovascular age-related macular degeneration: a treat-andextend protocol over 2 years. Retina 2014; 34:1531-1538.
73
Fundus Abnormalities and Risk Factors in Infants with

Microcephaly Associated with Presumed Zika Virus
Congenital Infection in Brazil: Results of the Zika Virus
Study Group
Mauricio Maia MD
N OTE S
74
Results of a Phase 2 Study using an Anti-Amyloid

Beta Monoclonal Antibody for the Treatment of
Geographic Atrophy Secondary to Age-Related
Macular Degeneration
N OTE S
Phase 2b/3 Clinical Trial of Emixustat Hydrochloride

Pravin U Dugel MD
N OTE S
75
76
Intravitreal Brimonidine Drug Delivery System

(Brimonidine DDS) in Patients with Geographic
Atrophy: A Phase 2 Study
N OTE S
PAN-90806A Novel Topical Treatment for

Neovascular AMD
Scott W Cousins MD
N OTE S
77
78
Phase 1 Anti-VEGF and Ang2 Inhibition Studies

Karl G Csaky MD
I. Introduction

A. Angiopoietin/Tie2 axis modulates endothelial cell

stabilization.

1. Ang1/Tie2 interaction results in stable endothelial state.
2. Angiogenesis

a. Endothelial cells produce Ang2; leads to

Ang2/Tie2 interaction
b. Vessel destabilization and leakage
B. Increased vitreous levels of Ang2 in neovascular

AMD, diabetic retinopathy, and retinal vein occlusion
C. The ratio of Ang1/Ang2 can affect VEGF induced

permeability.
D. The goal of therapy is to reduce Ang2 and VEGF

together.
II. Therapeutics

A. Nesvacumab/aflibercept (Regeneron) is a coformulation of nesvacumab (a fully humanized anti-Ang2

monoclonal antibody) and aflibercept, providing
both agents in a single intravitreal injection.
B. RG7716 (Roche/Genentech) is a bispecific mAb

with an anti-VEGF and anti-Ang2 Fab portions
connected to a disabled Fc region.
III. Clinical Trials

A. Nesvacumab/ aflibercept tested in an open-label,

dose-escalation Phase 1 study of the safety and tolerability in 20 patients (10 with neovascular AMD
and 10 with clinically significant DME)

1. No toxicity considered dose-limiting toxicity, and no ocular serious adverse events were
reported.
2. Visual and anatomic improvements were seen

with intravitreal nesvacumab/ aflibercept at all
dose levels.
B. RG7716 tested in an open-label, single and multiple

dose-escalation Phase 1 study of the safety and
tolerability in 24 patients with neovascular AMD
undergoing active anti-VEGF therapy

1. No toxicity considered dose-limiting toxicity, and no ocular serious adverse events were
reported.
2. Visual and anatomic improvements were seen in

all single and multiple doses of RG7716.
Ranibizumab and vPDT Combination Therapy

Versus Ranibizumab Monotherapy for Macular PCV:
12-month Results from the EVEREST II Study
Adrian H Koh MD
N OTE S
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Innovative Treatment Targets

Peter K Kaiser MD
N OTE S
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Long-term Outcomes of Anti-VEGF Therapy for AMD

Mark Gillies MD PhD, Anna Campain PhD, Daniel Barthelmes MD PhD, Judy Simpson PhD,
Jennifer Arnold MB BS (Hons), Robyn Guymer MBBS PhD, Ian McAllister MB BS, Rohan Essex MB BS,
Nigel Morlet MB BS, and Alex Hunyor MB BS
Introduction
The short- to medium-term efficacy of vascular endothelial
growth factor (VEGF) inhibitors for treatment of neovascular
AMD has been well established, preventing vision loss and
providing improvements of 1 to 2 lines lasting up to 2 years.1,2
However, despite more than 7 years of access to approved antiVEGF treatments in many countries, there are very few data
on long-term outcomes. In this presentation, I describe the outcomes of 549 eyes continuing treatment for at least 5 years, and
131 eyes for at least 7 years.
Methods
Observational data were obtained from the Fight Retinal Blindness (FRB) database.2 Treatment-nave eyes receiving at least
1 anti-VEGF injection were eligible for analysis. Long-term
outcomes included the mean change in VA over time and the
frequency of injections and visits.
Results
The mean VA of eyes completing 5 years of treatment improved
from 59.4 to 60.1 ETDRS letters, a gain of 0.7 letters from baseline, and 43% of these eyes had VA 70 letters. After 7 years,
mean VA was 2.6 letters lower than baseline for the 131 eyes
still being treated, and 40% had VA 70 letters. Eyes received
a median of 6 injections in the first year, and 5 injections every
year thereafter. The median number of visits was 9 in the first
year, and varied from 7 to 9 visits every year thereafter.
Long-term visual outcomes presented here are better than
those previously reported in the SEVEN UP study (8.6 letters
at 7 years) and the Comparison of AMD Treatment Trial (3.3
letters at 5 years).3,4 This may be due to differences in baseline
VA and treatment intensity and regimen. Eyes with lower baseline VA have more potential to gain vision, while those receiving
more frequent injections tend to be associated with better VA
outcomes.
Conclusions
We found long-term outcomes of anti-VEGF therapy for neovascular AMD were quite good and better than those in previous reports. Future investigations will need to consider factors
such as baseline VA and treatment intensity when reporting and
comparing outcomes. This study also highlights the importance
of Phase 4 studies in establishing the real-world benefits of antiVEGF therapy for patients with neovascular AMD.
Figure 1. Loess regression of mean VA over time (gray line) compared to the baseline VA of the patients followed that far (black line). The number of
eyes still being followed is shown above the x-axis.
82
References
1. Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology 2012; 119:1388-1398.
2. Gillies MC, Walton R, Liong J, et al. Efficient capture of highquality data on outcomes of treatment for macular diseases: the
Fight Retinal Blindness! Project. Retina 2014; 34:188-195.
3. Rofagha S, Bhisitkul RB, Boyer DS, et al. Seven-year outcomes
in ranibizumab-treated patients in ANCHOR, MARINA, and
HORIZON. Ophthalmology 2013; 120:2292-2299.
4. Maguire MG, Martin DF, Ying G-S, et al; CATT Research
Group. Five-year outcomes with anti-vascular endothelial growth
factor treatment of neovascular age-related macular degeneration:
the comparison of age-related macular degeneration treatments
trials. Ophthalmology. Epub before print 2016 Apr 20. doi:
10.1016/j.ophtha.2016.03.045.
83
Optimizing Wet AMD Treatment Outcomes

Wet AMD treatment starts with frequent, regular intravitreal

injections of anti-VEGF agents with the goal of getting the
macula dry as determined mainly by OCT testing and the fundus examination. For most patients, drying the macula will
translate into some degree of visual improvement, the degree
of which may be limited by a number of variables such as preexisting dry degenerative maculopathy and some potential
permanent damage to retinal pigment epithelium (RPE) and
neurosensory retina by the invading choroidal neovascularization (CNV). Much has been learned over the past decade about
optimizing visual outcomes in this era of anti-VEGF therapy.
Getting the best visual results in the most cost-effective manner
requires both ideal exudation control and early CNV detection.
Disease Control
An OCT-determined exudation-free macula is often achieved
with several frequent (monthly) injections during the induction
phase of therapy. All 3 pan-VEGF A blockers currently available in practice (eg, bevacizumab, ranibizumab, aflibercept)
work well to achieve the goal of a dry macula. To date, significant efficacy differences among the 3 agents have not been
shown to be significantly different in comparative clinical trials
for treating wet AMD. Although complete resolution of exudation is ideal, it may not be possible in all cases and residual
exudative signs such as subretinal fluid or sub-RPE fluid may or
may not be well tolerated over time. Whatever vision improvement is achieved, it will typically occur during the induction
phase. Thereafter, it is all about maintaining the vision gains
by keeping the macula as dry as possible and minimizing CNV
growth over time. The ideal maintenance treatment regimen is
not known, and the best style of treatment may be different for
different patients. Overall, the best course of therapy for a given
patient factors in efficacy, safety, and burden.
For the maintenance phase of therapy, one could continue
with a continuous, fixed-interval approach with injections every
1-2 months. This is rarely practiced because it may represent
overtreatment for many patients and overtreatment translates
into excessive treatment burden and increased risks, both ocular
and systemic. From an ocular standpoint, the risks include an
increased cumulative endophthalmitis rate, sustained elevated
IOP, which is directly correlated with the number of injections,
and theoretically, promoting geographic atrophy, although
this is not a proven side effect of anti-VEGF therapy. From a
systemic standpoint, there can be transient VEGF suppression
with an intravitreal injection, and theoretically, this could put
a patient at some increased risk of hemorrhage or thromboembolic events. To date, such events have not been shown to
occur to a statistically significant degree in clinical trials, but it
remains a possible side effect, particularly for patients at high
risk for stroke.
To minimize side effects and maximize safety along with
being cost-effective, therapy needs to be individualized. Individualizing anti-VEGF treatment during the maintenance
phase of therapy is accomplished by using either a pro re nata
(p.r.n.)ie, as neededapproach or a treat-and-extend
(TAE) approach. For p.r.n., after obtaining a dry macula, the

eye is monitored closely and treated only when there are signs of
recurrent exudation. This approach will help to minimize overtreatment, but it requires frequent monitoring and so the burden
of frequent office visits is not reduced. Moreover, it may not
work as well in the long run across the board. Even with very
close monitoring, the best available imaging techniques, and a
zero tolerance for any signs of recurrent exudation, large-scale
comparative clinical trials such as the CATT (Comparison of
AMD Treatment Trial), IVAN, and HARBOR studies indicated
that this approach, on average, didnt control the disease as well
over time and the visual acuity improvement that was achieved
early in the course of treatment didnt hold up as well as continuous treatment.
The TAE strategy represents a more proactive, individualized approach that appears to represent a good balance between
disease control and treatment burden and accounts for what
over 75% of U.S. retina specialists now routinely use in practice
to treat wet AMD. It is both continuous and individualized
therapy. Treatment is rendered at every patient encounter, but it
is the follow-up and treatment interval that is variable, adjusted
for a given patient in order to maintain a dry macula and minimize recurrences.
Prospective, comparative clinical trials that directly compare TAE to the other approaches are limited, but all published
studies to date, both retrospective and prospective, show very
consistent good visual outcomes with less treatment and fewer
office visits. The visual results appear as good as what are seen
in trials with monthly, continuous, fixed-injection regimens,
and the most recently published studies indicate that the acuity
gains on average hold up well out through 3 years or more of
follow-up, something p.r.n. studies have yet to show.
Maintenance treatment regimens are not mutually exclusive,
and a combination of approaches may be what is necessary to
safely and cost-effectively achieve the best results for a given
patient. Regardless of the specific maintenance treatment regimen utilized, the goals and objectives are the same, which is to
use just enough anti-VEGF treatment to keep the macula as dry
as possible and prevent vision loss from the neovascular process.
Early Detection
Major anti-VEGF trials indicate that the best vision gains are
achieved when the CNV at the time of diagnosis on average is
smaller. Furthermore, the best absolute vision outcomes are
obtained when the baseline visual acuity is good. For example,
recent studies now show that when the visual acuity at baseline
is 20/40 or better, the chances of maintaining that level of good
visual acuity with anti-VEGF therapy is over 70% for up to 2
years.
The problem at this time is that only 13%-40% of patients
with wet AMD in practice present with vision of 20/40 or better
in the involved eye. Increasing the yield of CNV detection with
better vision requires improved AMD screening and detection
mechanisms. Public awareness programs, patient education,
and compliance with home monitoring programs together
84
should make a favorable impact. The advent of electronic

devices such as one that uses preferential hyperacuity perimetry
(PHP) testing for patients to use at home has been validated
to detect the neovascular transformation earlier (with less
vision loss and smaller CNV) than conventional methods. In
the HOME (Home Monitoring of the Eye) study with the PHP
device, the percentage of patients with 20/40 or better vision at
the time of CNV diagnosis was 87%. Increased utilization of
these more sensitive detection techniques will help to increase
the proportion of patients presenting for anti-VEGF therapy
with good vision. That, in turn, followed by ideal disease control, will optimize the absolute vision outcomes and maximize
the proportion of patients maintaining good vision.
Selected Readings
1. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus
verteporfin for neovascular age-related macular degeneration. N
Engl J Med. 2006; 355(14):1432-1444.
2. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;
355(14):1419-1431.
3. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept
(VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 2012; 119(12):2537-2548.
4. Martin DF, Maguire, MG, Fine SL, et al; CATT Research Group.
Ranibizumab and bevacizumab for treatment of neovascular agerelated macular degeneration: two-year results. Ophthalmology
2012; 119(7):1388-1398.

5. Berg K, Pedersen TR, Sandvi L, Bragadottir R. Comparison of
ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol.
Ophthalmology 2015; 122(1):146-152.
6. Rayess N, Houston SK 3rd, Gupta OP, Ho AC, Regillo CD. Three
year treatment outcomes for neovascular AMD using a treat and
extend regimen. Am J Ophthalmol. 2015; 159:3-8.
7. Ying GS, Huang J, Maguire MG, et al; Comparison of Agerelated Macular Degeneration Treatments Trials Research Group.
Collaborators (891) baseline predictors for one-year visual outcomes with ranibizumab or bevacizumab for neovascular age
related macular degeneration. Ophthalmology 2012; 120(1):122129.
8. Regillo CD, Busbee BG, Ho AC, et al. Baseline predictors of
12-month treatment response to ranibizumab in patients with
wet age-related macular degeneration. Ophthalmology 2015;
160(5):1014-1023.
9. Rahimy E, Rayess N, Ho AC, Regillo CD. Treatment outcomes
for neovascular age-related macular degeneration patients with
initial vision better than 20/40 using a treat-and-extend regimen.
Retina 2016; 36:875-880.
10. Chew EY, Clemons TE, Bressler SB, et al; AREDS2-HOME Study
Research Group. Randomized trial of a home monitoring system
for early detection of choroidal neovascularization home monitoring of the Eye (HOME) study. Ophthalmology 2014; 121:535544.
Latest Findings From the CATT Trials

Daniel F Martin MD
N OTE S
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Polypoidal Variants and Outcomes
Polypoidal Choroidal Vasculopathy: A Subtype of Subretinal

Neovascularization With a Worldwide Presence and Therapeutic Implications
Gregg T Kokame MD

I. Polypoidal Choroidal Vasculopathy (PCV)

A. Increasingly recognized worldwide
B. Unique presenting findings in different ethnic

populations
C. Therapeutic implications due to relative anti-VEGF

resistance
II. Clinical Features
A. Clinical findings

1. More subretinal fluid
2. Less intraretinal edema
3. More retinal pigment epithelial (RPE) detachment
4. Significant risk of subretinal hemorrhage
5. Uncommon visible orange polyps
B. OCT findings: A type I subretinal neovascular

membrane (SRNVM) beneath the RPE and above
the Bruch membrane

1. Polyps: Sharply elevated, inverted U-shaped elevations of the RPE with heterogeneous internal
reflectivity
2. Branching vascular network (BVN): Double line

sign with shallow elevation of RPE above the
Bruch membrane
III. Diagnosis

A. Indocyanine green angiography (ICG): Gold standard of diagnosis of PCV
1. Technique
2. When to consider
C. Focal laser extrafoveal polyps
D. Surgery: Significant subretinal hemorrhage and

occasional subretinal surgery for peripapillary subretinal neovascularization with significant leakage
or bleeding
V. Concluding Statement
PCV is a variant of type I subretinal neovascularization1,2 that presents with findings similar to those of
exudative AMD and occurs worldwide.1-4 There is a
higher incidence of anti-VEGF resistance5 and strong
evidence for response anatomically and visually to
PDT6; so the diagnosis is critical to future treatment,
and diagnosis of SRNVM may be more helpful when
done in treatment-nave state. Diagnostic findings
of PCV do change after treatment with anti-VEGF
therapy, as polyps may resolve but branching vascular
networks usually persist. PDT with or without antiangiogenic therapy and steroid is an important treatment
option to consider, markedly decreasing the treatment
burden and allowing vision improvement in difficult
cases. ICG remains the gold standard of diagnosis,7
but other diagnostic modalities can give significant
and useful evidence of PCV (OCT, en face OCT,8 and
OCT angiography).
References
1. Polyps (hyperfluorescent focal subretinal vascular dilation, often with a hypofluorescent halo)
with or without a BVN
1. Kokame GT. Polypoidal choroidal vasculopathy: a type I polypoidal subretinal neovasculopathy. Open Ophthalmol J. 2013; 7:8284.
2. Polyps may resolve after anti-VEGF therapy but

BVN persists.
2. Kokame GT. Prospective evaluation of subretinal location in

polypoidal choroidal vasculopathy (PCV) and response of exudative and hemorrhagic PCV to high dose anti-angiogenic therapy
American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2014; 112:74-93.
B. Photodynamic therapy (PDT) with or without combination therapy (antiangiogenic Rx and steroid)
B. Future diagnostic modalities

1. En face OCT
2. OCT angiography
IV. Therapy
Higher prevalence of anti-VEGF resistance in PCV

A. Antiangiogenic therapy

1. Bevacizumab (Avastin)
2. Ranibizumab (Lucentis)
3. Aflibercept (Eylea)
3. Yannuzzi LA, Ciardella A, Spaide RF, et al. The expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy.
Arch Ophthalmol. 1997; 115(4):478-485.
4. Pereira FB, Veloso CE, Nehemy MB, Kokame GT. Characterization of neovascular age-related macular degeneration in Brazilian
patients. Ophthalmologica 2015; 234(4):233-242.
5. Cho M, Barbazetto IA, Freund KB. Refractory neovascular agerelated macular degeneration secondary to polypoidal choroidal
vasculopathy. Am J Ophthalmol. 2009; 148(1):70-78.

6. Koh AH, Expert PCV panel, Chen LJ, et al. Polypoidal choroidal
vasculopathy: evidence-based guidelines for clinical diagnosis and
treatment. Retina 2013; 33(4):686-716.
7. Kokame GT. Polypoidal choroidal vasculopathy: an important
diagnosis to make with therapeutic implications. Retina 2012;
(32)8:1446-1448.
8. Kokame GT, Hirai K, Yanagihara R. Polypoidal choroidal vasculopathy imaged by indocyanine green angiography and en face
optical coherence tomography. JAMA Ophthalmol. 2015; 133.
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Prognostic Parameters in Anti-VEGF Therapy for

Neovascular AMD
Ursula Schmidt-Erfurth MD
The management of neovascular AMD remains one of the largest dilemmas in modern medicine for patients, doctors, health
care providers, and budgets. Obviously, there is a clear need to
address AMD more efficiently (ie, at an earlier stage) and/or to
apply existing and future treatment options optimally, targeting
the right patient at the right time.
Digital diagnostic tools such as spectral domain OCT (SDOCT) allow fully automated image processing providing the
basis of prognostic evaluation in neovascular AMD. Algorithmic methods are used for computational analysis of OCTs,
including speckle noise removal, motion artifact correction,
detection of the foveal position, segmentation of retinal layers,
and quantification of intraretinal fluid (IRF) and subretinal
fluid (SRF) as well as pigment epithelial detachment (PED) and
drusen. A comprehensive set of automated registration methods
enables longitudinal and interpatient alignment of OCT scans.
Using the described processing pipeline, a successful prediction
of future therapeutic outcomes in patients under clinical therapy
is available and is currently being used at the Vienna Reading
Center (VRC).1
This contribution summarizes recent discoveries in prognostic imaging biomarkers in the management of AMD and provides a perspective on future developments and trends.
Prognostic Imaging Biomarkers in the Management

of Neovascular AMD
Intraretinal fluid (IRF)
Intraretinal cystoid fluid (IRC) has a significant negative impact
on retinal function in neovascular AMD. At initial presentation, IRF reduces BCVA by a mean of 1 ETDRS line. IRF persisting following the loading dose is frequently irreversible and
reduces BCVA by an additional line.4
During anti-VEGF therapy, IRC correlates with an inferior
BCVA outcome at Month 12 of a mean of 3.9 letters. The
number of visits over time showing IRC during a p.r.n. regimen
is correlated with progressive vision loss. During long-term
VEGF inhibition, IRF becomes more and more persistent and
less reactive to therapy. Transient IRC has to be differentiated
from persistent cystoid degeneration, which is not of exudative
origin and will progress over time to form larger cystoid spaces
usually overlying areas of subretinal fibrosis. The fact that IRC
prevalence increases over years may reflect not undertreatment
but progressive neurosensory atrophy. A higher treatment frequency may rather have a detrimental effect if enhancing geographic atrophy.
Early Markers of Progression Toward Neovascular

AMD
Drusen volume is considered a critical pathognomonic marker
of AMD progression and steadily increases over time following
a cubic function (see Figure 1).2 Focal regression of drusen volume is associated with conversion to advanced AMD (neovascular/ atrophic). Drusen regression within 12 months could be
predicted by computational machine learning with an accuracy
of ~60%. Furthermore, areas of external limiting membrane
alteration, ellipsoid zone alteration, and drusen, as well as the
presence of subretinal drusenoid deposits, were significantly
associated with the development of a CNV lesion.3 The onset of
a focal detachment of the retinal pigment epithelium (RPE) may
indicate the incidence of CNV and requires follow-up by diagnostic means such as OCT angiography (OCT-A).
Figure 1. Development of drusen volume over time in eyes with intermediate AMD. Drusen growth (following a cubic function) precedes
abrupt drusen regression, leading to development of advanced AMD. 2
Figure 2. Imaging biomarkers in neovascular AMD. Intraretinal cystoid fluid (orange

etachment (dark red ) are shown.
d
), subretinal fluid (blue
), and pigment-epithelial
Refining analyses of morphological parameters demonstrate

that initial vision correlates significantly with the volume and
horizontal extension of IRF. When 19,456 scans underwent
complete quantification of IRF, the best correlation with BCVA
at baseline was achieved using a coverage-based, foveal areaweighted IRF parameter (R 2=0.59; P<.001). The same baseline parameter also predicted BCVA at 12 months (R 2=0.21;
P=.003). BCVA gain over time correlated with IRC decrease
(R 2=0.40; P<.001).5
Figure 3. Correlation between visual function and the extent of intraretinal cystoid fluid at baseline. Increased coverage by cystoid fluid in
the foveal area is associated with pronounced vision loss.5
When assessing dynamic changes in IRF, an early increase in

IRF after the loading phase in discontinuous anti-VEGF treatment is associated with progressive visual decline and may be
associated with the need for more intensive treatment.6
Under continuous VEGF inhibition, fluid resolution rates
vary, dependent on the compartment location and to a lesser
extent on the therapeutic substance used: IRC resolves in 57%
of aflibercept patients, and 52% of ranibizumab patients; subretinal fluid resolved in 75% of aflibercept and 66% of ranibizumab patients; and pigment-epithelial detachment resolved in
40% of aflibercept and 28% of ranibizumab patients. During
p.r.n. dosing greater proportions of patients showed recurrent
fluid in all treatment dosages and regimens.7
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Subretinal fluid (SRF)

In contrast to IRC, subretinal fluid (SRF) appears to correlate
with superior visual function. This phenomenon is consistently
seen at initial presentation as well as under anti-VEGF therapy.7
SRF also appears to protect the RPE from progressive geographic atrophy.8 It is noteworthy that IRC and SRF present
in an exclusive pattern: Areas harboring IRC are usually free
of SRF and vice versa, suggesting a different pathway in the
pathomechanisms of neovascular AMD. When 88,201 OCT
B-scans of 806 treatment-nave eyes were analyzed automatically, of IRC-affected A-scans, 14% presented with SRF and
35% with PED; of SRF-affected A-scans, 8% presented with
IRC and 6% with PED; and of PED-affected A-scans, 35% presented with IRC and 11% with SRF.9
SRF is also a biomarker for reduced anti-VEGF treatment
requirements. Eyes presenting with SRF and a posterior vitreous detachment (PVD) at baseline showed similar BCVA
gains regardless of treatment frequency (mean difference in
BCVA gains at Month 12 of+2.6 letters, in favor of infrequent
treatment in the EXCITE study). SRF was present in 71%
of patients, and PVD was present in 64% of patients. These
patients may require less frequent treatments than patients
without SRF, without PVD, or without either, who may require
more frequent injections for maintenance of vision.10
Pigment-epithelial detachment (PED)
While PED in treatment-nave neovascular AMD does not
exhibit a substantial effect on visual function, p.r.n. treatment
enhances the decompensation of PED with consecutive IRF
formation, with a marked negative effect on retinal function.11
While computational analyses show a spatial anticorrelation
of SRF with IRC and PED, a co-localization of IRC with PED
is seen at initial presentation.9 Serous PED may disappear as
a component of fluid-pooling under anti-VEGF therapy; however, fibrovascular PED persists even under continuous VEGF-
inhibition due to the continuous activity of the underlying neovascular proliferation.7
Figure 4. Pigment-epithelial detachment as a risk factor for vision loss

during a p.r.n. regimen. In the VIEW study, a subpopulation of eyes
showing PED at baseline developed new-onset cystoid intraretinal
fluid during p.r.n. therapy (dots) and demonstrated progressive visual
decline.
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Subretinal hyper-reflective material (SHRM) and fibrosis

The amount of SHRM correlates tightly with reduced functional outcomes. The major role is played by subretinal fibrosis
as an irreversible end stage of neovascular AMD. Conventional
imaging is unable to differentiate fibrosis from the entire SHRM
complex. Using advanced OCT imaging such as polarizationsensitive OCT (PS-OCT), subretinal fibrosis can be identified
as an intrinsically birefringent structure and can be segmented
quantitatively based solely on tissue-specific contrast. This
allows for an optimized disease management and evaluation of
novel therapeutic strategies. En face imaging provides a precise
mapping of the fibrotic component of the scar tissue. Concomitant RPE loss and co-localized cystoid fluid overlying subretinal
fibrosis confirms its irreversibly poor prognosis in neovascular
AMD.12
Baseline BCVA
Visual function at the time of treatment initiation has an
overwhelming effect on BCVA outcomes. The ceiling effect of
a limited gain in better baseline BCVA can be calculated. In
general, 0.65 letters mean gain at Month 12 can be deducted
for each letter of pre-existing BCVA score. Eyes starting with
lower BCVA will present higher visual gains; however, they may
not reach the visual acuity levels of those starting with higher
BCVA scores.4
Figure 5. Selectively imaging subretinal fibrosis using polarization-sensitive OCT. Fibrotic areas appear as birefringent tissue columns. PS-OCT also
demonstrates loss of melanin-containing RPE cells within the area of fibrosis.
Figure 6. Development of visual acuity over time stratified by baseline visual acuity levels. Despite highest vision gains in patients with poorer starting vision, the best final outcomes were obtained by patients with the best starting visual acuity levels. (Tufail A, et al. Ophthalmology 2014.)
91
Figure 7. Thickness maps of IRC, SRF, and PED over time in a patient with neovascular AMD. Note that IRC and SRF react rapidly to anti-VEGF
therapy, but also recur frequently. In contrast, PED always remains present to a certain extent as a fibrovascular lesion.
Prediction of Future Functional Outcomes and

Treatment Requirements Using Machine Learning
Predictability of exudative recurrences and treatment intervals
Each morphological compartment has an individual signature
of recurrence over time.13 However, while IRC and SRF resolve
significantly already after the first injection, PED persists in
the majority of eyes at a rate of 70% and mostly presents as
fibrovascular PED. Individual intervals of recurrence as well as
the number of required treatments in a p.r.n. regimen can be
predicted by computational image analysis based on the lesion
response during the loading dose with an accuracy of 65%75%.14
Predictability of functional outcomes under anti-VEGF
therapy
Visual acuity outcomes of anti-VEGF therapy are dependent
on the individual retinal morphologic condition (determining BCVA at baseline) and the initial response pattern. Using
machine learning analysis of automatically characterized SDOCT data during the joint loading phase (baseline to Month 3)
in a population of 563 eyes, visual acuity outcomes at Month 12
could be predicted with an accuracy of R 2 = 0.70, P < .001.
Figure 8. Prediction of visual acuity outcomes at Month 12 from the

initial loading phase response in a study population of 563 neovascular
AMD eyes. Prediction of future outcomes was feasible with an accuracy of 70%.
92
Conclusion
Advanced diagnostic imaging visualizes morphological features
in neovascular AMD in great detail and enables qualitative
as well as quantitative analyses. Computer-based automated
algorithms allow reliable large-scale screening and structurefunction correlation to identify clinically and prognostically
relevant evaluation. This approach allows us to significantly
improve the clinical management of an increasing population
affected by neovascular AMD. Validated automated algorithms
have the potential to improve the speed and consistency of clinical decision making and save time in clinical routine. Real-time
reading in reading center settings is already performed and
helps to standardize performance in clinical trials. Scientifically, novel targets for innovative therapeutic strategies can be
identified, and insight into the pathophysiology of AMD disease
is greatly enhanced. Moreover, current and future disease management efforts require efficient risk prediction allowing cohort
enrichment and streamlining of trials. Finally, the ideal therapeutic intervention will target the earliest manifestations and
the clinically most relevant features of AMD progression before
the development of irreversible visual loss, which will require
precise and reliable prognostic tools for AMD management.
References
1. Vienna Reading Center website: http://www.readingcenter.at/
2. Schlanitz FG, Baumann B, Kundi M, et al. Drusen volume development over time and its relevance to the course of age-related
macular degeneration. Br J Ophthalmol. Epub ahead of print
2016 Apr 4. doi: 10.1136/bjophthalmol-2016-308422.
3. Roberts P, et al. Predictors of CNV development in fellow eyes of
patients with unilateral neovascular age-related macular degeneration in SD-OCT. Submitted, 2016.
4. Schmidt-Erfurth U, Waldstein SM. A paradigm shift in imaging
biomarkers in neovascular age-related macular degeneration. Prog
Retin Eye Res. 2015; 50:1-24.
5. Waldstein SM, et al. Correlation of three-dimensionally quantified intra- and subretinal fluid with visual acuity in neovascular
age-related macular degeneration. JAMA Ophthalmol. 2016;
134(2):182-190.

6. Waldstein SM, et al. Association of fluid recurrence with visual
maintenance following the loading phase in anti-VEGF therapy
for neovascular AMD. Presented at ARVO 2016.
7. Waldstein SM, Simader C, Staurenghi G, et al. Morphology and
visual acuity in aflibercept and ranibizumab therapy for neovascular age-related macular degeneration in the VIEW trials.
Ophthalmology. Epub ahead of print 2016 May 4. doi: 10.1016/j.
ophtha.2016.03.037.
8. Sadda SR, et al. Development of atrophy in neovascular AMD
treated with anti-VEGF therapy: results of the HARBOR Study.
Paper presented at Retina Subspecialty Day, Annual Meeting of
the American Academy of Ophthalmology; 2014.
9. Klimscha S, et al. Spatial correspondence between intraretinal
fluid, subretinal fluid and pigment epithelial detachment in neovascular age-related macular degeneration. Submitted, 2016.
10. Waldstein SM, et al. Predictive value of retinal morphologic features for visual acuity outcomes of different ranibizumab treatment regimens for neovascular age-related macular degeneration.
Ophthalmology 2016; 123(1):60-69.
11. Schmidt-Erfurth U, et al. Pigment epithelial detachment followed
by retinal cystoid degeneration leads to vision loss in treatment of
neovascular age-related macular degeneration. Ophthalmology
2015; 122(4):822-832.
12. Roberts P, et al. Automated identification and quantification of
subretinal fibrosis in neovascular age-related macular degeneration using polarization-sensitive OCT. Invest Ophthalmol Vis Sci.
2016; 57(4):1699-1705.
13. Vogl W-D, et al. Spatio-temporal signatures to predict retinal disease recurrence. Inf Process Med Imaging. 2015; 24:152-163.
14. Bogunovic H, et al. Prediction of low and high anti-VEGF treatment requirements during the PRN phase from early OCT images
in neovascular age-related macular degeneration. Presented at
ARVO 2016.
Advances in Spectral Domain OCT Imaging

Nadia K Waheed MD
In the past 2 decades, OCT has profoundly impacted our

understanding of retinal disease and revolutionized the clinical
practice of retina. The introduction of spectral domain OCT,
with its faster scanning speeds, allowed for the 3-dimensional
reconstruction of images and provided higher resolution and
more reproducible images. More recently, the development of
better software and segmentation techniques allows for better
quantification of retinal pathology and its response to pharmacotherapy. Moreover, advanced en face visualization techniques
complement traditional cross-sectional OCT and, in many
cases, allow for a better understanding of the extent of disease.
Now a third generation of OCT instruments allows for the
visualization of retinal vasculature without the use of exogen
ous dyes. Hardware enhancements, such as the development
of higher speed and longer wavelength swept source instrumentation, allow for wider fields of view and deeper imaging, enabling us to better visualize the choroid. As these new
technologies arrive in the clinic and get integrated into clinical
trials, they promise to provide us new insights into the pathogenesis and treatment response in retinal disease.
93
94
Adaptive Optics Update

Jacque L Duncan MD, Austin Roorda PhD, and Jia Qin PhD
I. Adaptive Optics (AO): A New Noninvasive Retinal

Imaging Modality

A. Aberrations in light exiting the eye prevent imaging

individual photoreceptors with single-cell resolution.
B. AO is a technique to precisely measure and compensate for aberrations.1

1. A Shack-Hartmann wavefront sensor measures

aberrations emerging from the pupil illuminated
with a near-infrared scanning laser ophthalmoscope (SLO).
2. Aberrations are communicated to a deformable

mirror that bends its shape to compensate for
and correct aberrations, so that light exits the
face of the mirror in parallel planes.
3. Waveguiding photoreceptors with intact inner

and outer segments are visible as small white
spots.
Figure 1. AO-SLO image of cones in a 74-year-old with AMD in a

region associated with drusen on spectral domain OCT obtained at the
same location shown in the box in Figure 2. Small white spots indicate
light waveguided by individual cones visible and quantifiable.
C. AO-SLO images provide en face images of individual cones to correlate with images from other
modalities.

1. Precise alignment with fundus photos using retinal vascular landmarks
2. Correlate with cross-sectional images of retinal

structure using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence
Figure 2. Composite image in eye with AMD and geographic atrophy

where AO-SLO montage is precisely aligned with images from fundus
autofluorescence and SD-OCT using retinal vascular landmarks. This
permits 3-dimensional assessment of retinal structure and identification of regions of interest to follow longitudinally. White vertical line
indicates location of SD-OCT scan, which is translated temporally
from the fovea for visualization of the AO-SLO montage. A region of
interest where individual cones are unambiguous over diffuse drusen
is indicated with a white box superior to the fovea; the magnified AOSLO image is shown in figure 1.
D. AO-SLO enables observation of cone photoreceptors longitudinally over time.
95
4. Case presentation: 21-year-old woman with

acute macular neuroretinopathy
1. Identify regions of interest where cones are seen

unambiguously
a. Initially visual acuity is reduced to 20/80 and

cones are not visible within foveal area.
2. Monitor cone spacing, cone packing, and cone

density at regions of interest to provide objective, sensitive outcome measure for clinical trials
3. Cone spacing measures of average nearest neighbor distance between cones in a mosaic can be
used as a sensitive, reliable, repeatable outcome
measure in eyes with inherited retinal degeneration.2
b. Five years later, visual acuity recovered to

20/25 with improved visual function in
regions where cones are still not visible but
external limiting membrane is slightly hyperreflective.
c. AO-SLO measures of visual function provide

evidence of residual cones that cannot be
seen with other imaging modalities, which
may be amenable to recovery or treatments.
E. New AO-SLO systems use nonconfocal scattered

light to visualize cone inner segments and retinal
pigment epithelial cells.

1. Nonconfocal split-detector images reveal photoreceptor inner segments,3 improving reliability

of cone identification.
2. Dark field AO-SLO images reveal retinal pigment epithelial cells by dramatically attenuating
backscattered light from photoreceptors.4
3. Multiple offset detection demonstrates cone

inner segments at the margins of geographic
atrophy in AMD5 and can be used to visualize
inner retinal neurons such as retinal ganglion
cells and amacrine cells.6
F. AO-SLO microperimetry
1. Use AO-SLO to correct aberrations and deliver

small visual stimuli precisely to individual cones
or small groups of cones.7
2. Combine with high-speed fundus tracking to

test cone function of individual cones or regions
where cones are not visible.
3. Use AO-SLO microperimetry to assess function

in localized areas where cones are not visible
using confocal images.
G. In summary, AO-SLO is a novel, high-resolution

tool for retinal imaging that provides unique
insight into cone structure and function in patients
with retinal disease.
References
1. Roorda A, Duncan JL. Adaptive optics ophthalmoscopy. Ann Rev
Vis Sci. 2015; 1:19-50.
2. Zayit-Soudry S, Sippl-Swezey N, Porco TC, et al. Repeatability
of cone spacing measures in eyes with inherited retinal degenerations. Invest Ophthalmol Vis Sci. 2015; 56: 6179-6189.
3. Scoles D, Sulai YN, Langlo CS, Fishman GA, Curcio CA, Carroll
J, Dubra A. In vivo imaging of human cone photoreceptor inner
segments. Invest Ophthalmol Vis Sci. 2014; 55:4244-4251.
4. Scoles D, Sulai YN, Dubra A. In vivo dark-field imaging of the retinal pigment epithelium cell mosaic. Biomedical Optics Express.
2013; 4:1710-1723.
5. Rossi EA, Saito K, Granger CE, et al. Adaptive optics imaging of
putative cone inner segments within geographic atrophy lesions.
ARVO Annual Meeting; 2015; Denver, Colorado; E-Abstract
4931.
6. Rossi EA, Sharma R, Granger CE, et al. Individual inner retinal
neurons imaged in the living eye of monkey and human. ARVO
Annual Meeting; 2016; Seattle, Washington; E-Abstract 2805.
7. Tuten WS, Tiruveedhula P, Roorda A. Adaptive optics scanning
laser ophthalmoscope-based microperimetry. Optom Vis Sci.
2012; 89:563-574.
96
Predicting and Quantifying

Geographic Atrophy Growth
Theodore Leng MD

I. Background and Purpose

A. Half of eyes with advanced AMD have geographic

atrophy (GA).
B. Goal: To develop a predictive model to estimate

future areas of GA growth based on quantitative
spectral domain OCT (SD-OCT) characteristics of
GA; fully automated and reproducible
V. Ranking of Predictive Features
VI. Progression Model Evaluation
VIII. Results
II. Methods

A. Dataset of 118 SD-OCT scans from 38 eyes (29

patients) over 5 years
B. 61% female; mean age: 78 years
C. Baseline mean GA area: 2.67 mm 2
D. Mean growth rate: 0.86 mm2/year
III. Machine Learning Algorithm
Random forest classifier / 100 decision trees
IV. Quantitative Features

A. GA segmentation results
B. Drusen segmentation results
C. Maps
D. Axial thickness and reflectivity
VII. Metrics: Dice Index
A. Dice indices
B. Sensitivity/specificity
C. Correlation coefficients
IX. Precision-Recall/ROC Curve
X. Correlation Curves
XI. Conclusion
Areas of photoreceptor loss, inner segment/ outer segment loss, and the height of reticular pseudodrusen
were the most predictive factors for areas of future GA
growth.
XII. Acknowledgments
97
OCT Angiography
Richard F Spaide MD
Optical coherence tomography (OCT) uses interferometric

analysis of interference of short coherence length light to provide
depth-resolved imaging of tissue, such as the retina. The data
related to the structure of the tissue are frequently visualized
as 2-dimensional cross-sectional images, called B-scans, even
though there may be a 3-dimensional matrix of data available. If
multiple images are taken of the same area over time, changes in
reflectance properties of the tissue can be measured. Stationary
tissue shows little variation, while moving elements, blood flow
for instance, shows more prominent changes. Some parameter
of reflectance, such as amplitude or phase of the reflected light,
can be measured and recorded. The change in this parameter
provides information about potential flow. The numeric representation of each small volume of tissue is called a voxel (from
the combination of volume and pixel). The amount of
change of these values from one picture to the next can be represented in a matrix of values. The variation over time for each
voxel forms the basis of a flow imaging technique called OCT
angiography. One picture may be quite similar to another picture and therefore they are, in a sense, correlated. A related idea
is the decorrelation, which is an abstract notion in a mathematical sense. In OCT angiography the word decorrelation is used
to mean change in an image or section of an image over time.
Since OCT images tissue in its depth, we obtain a 3-D block
of information corresponding to flow in a 3-D block of tissue.
We can select various voxels, based on some parameter, such
as depth or tissue plane. To actually view the blood flow, the
brightest voxel in each column of voxels is selected and that
value is placed on a 2-D plane. The 2-D plane is essentially a
projection coming from the volume of voxels. So it is called a
maximal intensity projection image. This forms the basis of en
face imaging. Since the retina, and its corresponding blood supply, is arraigned in layers, en face imaging is a simple yet powerful way to look at various depths within the retina to evaluate
blood flow.
Motion and the artifacts it induces

OCT angiography creates images by evaluating change over
time; it does not image blood or blood vessels. We know that
a moving object will create images that vary over time. The
assumption with OCT angiography is that change over time
means motion, and motion means blood flow. The eye, head,
or body of a patient can move during image acquisition to
cause motion artifacts. These have a variety of manifestations,
some of which can be remedied by software or by eye tracking.
Motion can cause decreased signal strength, discontinuities in
vessels, areas of absent information, and linear defects in the
image.
Projection artifacts
As light passes through tissue it may be altered by moving
blood. Since blood flows over time, the light is altered; when
reflected by deeper layers the reflection of this changing light
will cause the appearance of layers of vessels at anatomically
incorrect levels, such as from the retinal pigment epithelium.
This is called a projection artifact. Currently projection artifacts are extremely common and can be a vexing problem.
Every manufacturer is working on methods to suppress projection artifacts.
Segmentation artifacts
To create an en face image, the volume of flow information has
to be segmented according to the anatomy of the retina. This
can accurately be performed in healthy tissue, but deviation
from normality is associated with increased errors of segmentation. This results in abnormally large or small thicknesses being
sampled and may falsely influence assessment of vascular density. Another type of segmentation defect results in a meandering slab of tissue being sampled. A layer of vessels may be produced, but the layer has no true anatomic correlate in the eye.
Segmentation artifacts are problems that may not be adequately
solved in the near future.
Main Sources of Poor Image Quality

Low signal strength
Any medical image information contains information derived
from the object or tissue being investigated and also contains
spurious alterations in the information content, derived from
a variety of sources. The ratio between the signal, which is
the information component directly related to the tissue being
imaged, and the nonsignal component, often called noise, is a
mathematical relationship from which information content can
be inferred. For example, cataracts or media opacities decrease
the OCT signal but dont directly influence the noise of the
imaging instrument. The signal-to-noise ratio is decreased. The
sum of the two is decreased, and this sum often is scaled to fit
the gray scale of the display device. In the process the image
will appear noisier, since the signal is a smaller proportion of
the whole. Thus while low signal is a defect and not an artifact,
it is accompanied by greater snow in an image, which is an
artifact.
Typical Uses for OCT Angiography

OCT angiography is usually quite helpful in retinal vascular
diseases. It is a modality that can image the inner and deep
plexus of flow and therefore provides anatomic information
that is not easily seen by fluorescein angiography, which images
only the inner plexus. Although OCT angiography does not
image leakage, anatomic changes such as edema, particularly
with cystoid spaces, are readily visible in the structural OCT.
Thus in a diabetic with microaneurysms and areas of nonperfusion in the macula who also shows thickening of the involved
macula with cystoid spaces, it doesnt take much imagination to
know that leakage is also occurring. In a similar fashion, venoocclusive disease is quite good to study with OCT angiography.
Treated CNV is typically easy to detect, and the morphology
of the lesions seen with OCT angiography was quite different
than what was originally expected, particularly considering that
anti-VEGF agents were supposed to cause vascular regression.
98
Imaging CNV secondary to AMD-related macular degeneration in new cases can be quite difficult. Type 2 CNV is readily
seen, and with careful observation Type 3 neovascularization
can be detected. It possible to detect Type 1 CNV with OCT
angiography in fresh cases, but it can be diabolically difficult to
measure lesion sizes because the neovascularization can be quite
difficult to see. In this case, OCT angiography is not a plug-in
replacement for fluorescein angiography. In clinical practice
just knowing CNV is present is often good enough, but for a
reading center lesion measurements can be very time consuming. That said, we really dont know if the lesion boundaries in
fluorescein angiography in Type 1 CNV are really the edges of
the neovascularization or not.
Methods of Display
En face imaging is a powerful technique, but one fraught
with potential for error. Radiologists have been dealing with
3-dimensional datasets for decades and have come up with
many potential solutions. Additional means of displaying the
information include a multiplanar approach, which uses 3
orthogonal planes to look at data. Volume rendering provides
the ability to look at the whole data set, without segmentation
and in 3-D. It is possible to visualize structural information in
the context of the OCT angiographic data.
Parting Words
We have been using fluorescein angiography in retina for more
than 50 years. Retinal specialists can interpret fluorescein
angiograms quickly according to a dogma that has been built
up over decades. The structure of the dogma seems logical,
and given that we have used it for half a century it is logical to
assume there is truth in our methods. OCT angiography is not
a plug-in replacement for fluorescein, and there is a lot that we
have to learn. I dont think it will take 50 years, but it will take
serious effort.
99
Hyperspectral Imaging
and Spectroscopy

Introduction
Results
Hyperspectral imaging (HSI) refers to the combination of

spectroscopy methods that are commonly used to study the
chemical composition of samples with the biological imaging
methods used to study the structural features of a tissue. Most
simply, HSI can be considered quantitative color photography, where the exact amount of various colors in the image can
be quantitated at the nanometer level and attributed to a specific
feature with submillimeter level resolution. For example, HSI
imaging has been used to study the changes in hemoglobin oxygen saturation from retinal vessels and to study the fluorescence
spectra of lipofuscin within retinal pigment epithelium (RPE).
HSI imaging methods capitalize on the specific interactions of
retinal tissue with light of unique wavelengths to provide novel
information about a disease process or anatomic feature.
Hyperspectral imaging using HCTIS and comparable instruments allows accurate measurement of clinically relevant features such as intravascular retinal oxygen content and retinal/
RPE pigment composition. These hyperspectral features are
based on the molecular features of target tissues such as hemoglobin oxygen saturation and RPE pigment composition. Specifically, HSI methods show that retinal vascular oxygen content
is an indicator of disease severity in both diabetic retinopathy
and retinal venous occlusion. In addition, HSI methods suggest
that normal as well as abnormal retinal features have unique
spectral signatures.
Methods
HSI methods are generally noninvasive and have been applied
in basic vision research and clinical ophthalmology settings.
Basic science applications include the use of liquid or solid
state tunable filters with confocal microscopes to study RPE
fluorescence in histological sections. Clinical studies have used
custom-made fundus cameras in a research capacity to study
spectral features of disease models in animals and humans.
Herein, I describe the work from our group using the hyperspectral computed tomographic imaging spectrometer (HCTIS)
and the work of others using custom-made hyperspectral imaging devices to study retinal disease in humans and animal models. Specifically, I discuss the use of HSI methods that provide
new insights into major causes of vision loss, including retinal
vascular diseases (diabetic retinopathy and retinal venous occlusion) and AMD.
Conclusions
While all HSI methods are currently in research and development stages, it is clear that HSI reveals details of retinal structure and function with a precision that is otherwise not possible
with current imaging modalities. Future advances in this imaging modality will provide unique insights into the structure
and functional relationship of retinal tissue at the cellular and
molecular level. The noninvasive potential of HSI methods will
contribute to our understanding of both retinal function and
physiology in healthy subjects as well as in retinal disease.
100
Non-Invasive Wearable Enhancement for Advanced

Peripheral Visual Field Loss
N OTE S
Treatment of Vitreomacular Traction with

Pneumatic Vitreolysis
Clement K Chan MD
N OTE S
101
102
Efficacy and Safety of Ocriplasmin Within

Subgroups Defined by SD-OCT Characteristics
From The OASIS Study
N OTE S
A New Biosimilar Ranibizumab

Alay S Banker MD
N OTE S
103
104
Laser vs. Anti-VEGF for Proliferative Diabetic

Retinopathy: Pro
Why Is There a Debate?
The topic is of interest as a result of the publication of the results
of Protocol S from the Diabetic Retinopathy Clinical Research
Network.1 In this study, 394 eyes (305 patients) with proliferative diabetic retinopathy (PDR) were randomized to receive
either laser panretinal photocoagulation (PRP) or a structured
regimen of intravitreal ranibizumab (IVR) injections. The
patients were followed for 2 years.
The results of the IVR group were noninferior to those of
the PRP group. At 2 years, the visual acuity results favored the
IVR group by 2.2 ETDRS letters. Area under the curve analysis
results favored the IVR group over the 2 years by an average of
4.2 letters relative to the PRP group.
Other results favored the IVR group:
1. Visual field sensitivity loss was worse in the PRP group
(mean decibel difference, 372; 95% CI, 213 to 531; P <
.001).
2. Vitrectomy was more frequent in the PRP group (15% vs.
4%; difference, 9%; 95% CI, 4% to 15%; P < .001).
3. Diabetic macular edema (DME) developed more frequently in the PRP group (28% vs. 9%; difference, 19%;
95% CI, 10% to 28%; P < .001).
There were no differences between the two groups in rates of
systemic adverse events, neovascular glaucoma, vitreous hemorrhage, and selected diabetic retinopathy events.
One eye (0.5%) in the IVR group developed endophthalmitis.
Looking at Efficacy and Safety, IVR Seems to Be the

Winner. What Else Is There to Discuss?
In a world where there are enough ophthalmologists to serve the
affected population, the affected patients have adequate financial resources to pay for health care, and compliance and logistical issues are not a problem, IVR seems better than PRP.
We dont live in that world. Consider some relevant epidemiologic and economic facts.
There are an estimated 285 million people with diabetes in
the world, 17 million of whom have PDR. Seventy percent of the
affected people live in countries with low (<$1036) or middle
(<$12,615) per capita gross national income. Per capita total
health care expenditures in the two largest countries, China (1.4
billion people) and India (1.3 billion people) are $420/year and
$75/year, respectively.
We can estimate the cost of IVR vs. PRP over 2 years from
the data of Protocol S, which published the average number of
visits, doses of IVR, number of focal lasers, and number of PRP
lasers over 2 years. For the purposes of the calculation, let us
assume a cost of $71 for an office visit (CPT 99213), $2000 for
ranibizumab, $125 for intravitreal injection (CPT 67208), $524
for focal laser (CPT 67210), and $1011 for PRP laser (CPT
67228).2,3 This calculation applies to the case with no concomitant diabetic macular edema.
As Table 1 shows, economic considerations favor PRP over
IVR. Even if one substitutes bevacizumab, and its lower costs, for
ranibizumab, the economic case favors PRP. IVR for PDR is not
economically feasible for most of the worlds patients with PDR.
Apart from the economic obstacles, many patients with PDR
are unable or unwilling to participate in the burdensome regimen imposed by serial anti-VEGF injections and monitoring.
In such cases, PRP offers a time-tested, effective treatment for
PDR with a smaller visit burden.
Fortunately, in 2016, the retina specialist has both PRP and
anti-VEGF for managing PDR. For the well-insured patient who
has the resources to comply with the many office visits requisite
to an anti-VEGF regimen, this treatment may be preferable.
However, if one were forced to choose one or the other to manage the worlds PDR case load under real-life constraints, the
obvious choice is PRP.
References
1. Writing Committee for the Diabetic Retinopathy Clinical
Research Network. Panretinal photocoagulation vs intravitreous
ranibizumab for proliferative diabetic retinopathy, a randomized
clinical trial. JAMA 2015; 314:2137-2146.
2. Corcoran Consulting Group. Reimbursement for posterior segment laser photocoagulation. www.corcoranccg.com/digital_files/
FAQs/FAQ_Laser%20Photocoagulation%Topcon_073115.pdf.
Accessed May 29, 2016.
3. Vicchrilli SJ, Edgar JS. E&M or Eye Code: which to choose?
American Academy of Ophthalmology website. Jan. 1, 2015.
www.aao.org/young-ophthalmologists/yo-info/article/e-m-eye
-code-which-to-choose. Accessed May 29, 2016.
Table 1.
Regimen
IVR
PRP
Number
Cost ($)
Number
Cost ($)
Visits in 2 years
22
1562
16
1136
Doses ranibizumab
10
20,000
2.2
4400
Number of intravitreal injections
10
1250
2.2
275
# Focals
0.08
41.92
0.1
52.40
# PRPs
0.06
60.66
1.48
1496.28
Total Cost
$22,914.58
$7359.68
105
Laser vs. Anti-VEGF for Proliferative Diabetic

Retinopathy: Con Laser
Judy E Kim MD
In the last several decades since the Diabetic Retinopathy Study
demonstrated the effectiveness of panretinal photocoagulation (PRP) in preventing severe vision loss,1 it has been the only
treatment for proliferative diabetic retinopathy (PDR). Now,
however, we have another treatment option for PDR.
Protocol S1 from the Diabetic Retinopathy Clinical Research
Network (DRCR.net) was a multicenter randomized clinical
trial comparing PRP to repeated intravitreal injections with
ranibizumab, an anti-vascular endothelial growth factor (antiVEGF) agent, in eyes with PDR. Principal eligibility criteria
included PDR without prior PRP and BCVA letter score 24
(Snellen equivalent 20/320). Participants with 1 study eye
were randomly assigned to repeated ranibizumab injections
(Lucentis, Genentech; South San Francisco, CA) or prompt PRP,
while participants with 2 study eyes received ranibizumab in
one eye and PRP in the other. In either treatment group, all eyes
with center-involved diabetic macular edema (CI-DME) and
visual impairment (visual acuity 78 letters [Snellen equivalent
20/32]) received ranibizumab at baseline followed by asneeded administration to treat DME.
All participants had assessment visits at 16, 32, 52, 68, 84,
and 104 weeks. In addition, participants assigned to ranibizumab also had visits every 4 weeks in the first year to determine the need to retreat neovascularization. Visits could be
extended up to 16 weeks in the second year if injections were
continually deferred. All participants with baseline CI-DME or
those that developed CI-DME during follow-up may have had
additional study visits to assess and treat DME. The protocol
allowed PRP in the ranibizumab group after prespecified failure
criteria had been met. In the PRP group, supplemental PRP was
permitted if the size or amount of neovascularization increased.
The 2-year primary outcome results showed that the eyes
assigned to ranibizumab had visual acuity (VA) that was no
worse than (noninferior to) eyes managed with PRP. Furthermore, throughout the 2-year follow-up, VA (area under the
curve) was superior with ranibizumab compared with PRP.
Ranibizumab-treated eyes also had less visual field loss and

lower rates of vision-impairing CI-DME development. Only
12% of eyes with vitreous hemorrhage (VH) in the ranibizumab
group (6 of 52) compared with 41% of VH eyes in the PRP
group (30 of 69) underwent vitrectomy by the end of 2 years.
It suggests that VH may have been associated with more protracted vision impairment in the PRP group or that investigators
were more comfortable deferring vitrectomy for eyes receiving
anti-VEGF treatment.
Although PRP is often considered a one-and-done treatment, 45% of the eyes assigned to PRP required supplemental
PRP administration to manage active PDR after completion
of initial PRP, on average 7 months after the initial PRP. This
underscores the need to regularly monitor these eyes for worsening as they remain at continued risk of vision loss. Over half
of the PRP eyes also received ranibizumab if there was also
CI-DME at baseline or DME developed during the course of
follow-up. This combined treatment of PRP and ranibizumab
likely lowered the rate of PDR-related complications in the PRP
group. No new safety concerns, systemic or ocular, were associated with ranibizumab.
Therefore, anti-VEGF therapy to manage PDR represents
a novel treatment alternative to PRP, with potential benefits
in patients who may be compliant with follow-up for series of
intravitreal injections.
References
1. Diabetic Retinopathy Study Research Group. Photocoagulation

treatment of proliferative diabetic retinopathy: clinical application
of Diabetic Retinopathy Study (DRS) findings, DRS report number 8. Ophthalmology 1981; 88(7):583-600.
ranibizumab for proliferative diabetic retinopathy: a randomized
clinical trial. JAMA 2015; 314(20):2137-2146.
106
Anticoagulation Requires Modification

Prior to Surgery: Pro
Timothy W Olsen MD
N OTE S
Anticoagulation Requires Modification

Prior to Surgery: Con
N OTE S
107
108
Compounded Drugs Are Reliable: Pro

Dante J Pieramici MD
The compounding of medicines dates back thousands of years.

Compounding fills a number of niches that allows individualized dosing, addition or subtraction of various ingredients,
and repackaging when medically necessary. In the management of retinal diseases compounding of drugs, especially
the anti-VEGF bevacizumab, has become an essential part of
providing this therapy for hundreds of thousands of patients
worldwide. The role of the compounding pharmacy in the
case of bevacizumab is simply repackaging for off-label use of
an FDA-approved medication. This provides dosing for many
patients at an enormous cost saving for payers and patients.
In this instance, there is no direct alteration or dilution of the
medication. There are numerous state, federal, and trade related
regulations overseeing the effective and safe compounding process of thousands of drugs, accounting for billions of dollars in
yearly sales in the United States.
However, there have been sporadic instances of drug contamination, including the infamous 2012 case of the New
England Compounding Center, where contaminated methylprednisolone acetate injections for the treatment of back and
joint disease led to an outbreak of fungal meningitis and death.
In addition, a few instances of contamination of preparations
for intraocular use of bevacizumab, brilliant blue green, and
intravitreal triamcinolone led to visually significant infectious
endophthalmitis.
In response mostly to the New England Compounding
Center incident, Congress enacted the Compounding Quality
Act in 2013. This tightened regulations on compounded drugs
and allowed for more FDA oversight. Regardless of these recent
regulatory changes, in the case of bevacizumab therapy, there is
a nearly 10-year track record of safety and efficacy (representing millions of doses) for this treatment in a variety of retinal
diseases.
109
Compounded Drugs Are Reliable: Con

Julia A Haller MD
Selected Readings
1. How gaps in regulation of compounding pharmacy set the stage
for a multistate fungal meningitis outbreak. Teshome BF, Reveles
KR, Lee GC, Ryan L, Frei CR. J Am Pharm Assoc (2003). 2014;
54(4):441-445.
5. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results.
Goldberg RA, Flynn HW Jr, Miller D, Gonzalez S, Isom RF.
Ophthalmology 2013; 120(7):1448-1453.
2. Fungal endophthalmitis associated with compounded products.

Mikosz CA, Smith RM, Kim M, et al; Fungal Endophthalmitis
Outbreak Response Team. Emerg Infect Dis. 2014; 20(2):248-256.
6. Association of compounded bevacizumab with postinjection

endophthalmitis. VanderBeek BL, Bonaffini SG, Ma L. JAMA
Ophthalmol. 2015; 133(10):1159-1164.
3. Histopathology of Streptococcus mitis/oralis endophthalmitis after intravitreal injection with bevacizumab: a report of 7
patients. Matthews JL, Dubovy SR, Goldberg RA, Flynn HW Jr.
Ophthalmology 2014; 121(3):702-708.
7. Clinical and pathologic features of Bipolaris endophthalmitis

after intravitreal triamcinolone. Minckler D, Small KW, Walsh
TJ. JAMA Ophthalmol. 2014; 132(5):630-632.
4. An outbreak of fungal endophthalmitis after intravitreal injection

of compounded combined bevacizumab and triamcinolone. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. JAMA Ophthalmol. 2013; 131(7):864-869.
110
Management of Radiation Retinopathy in 2016

Tara A McCannel MD
Although radiotherapy is an excellent treatment for local tumor

control of choroidal melanoma, current management strategies of subsequent radiation retinopathy remain disappointing.
There are few successful treatments or cures for patients who
develop the most common forms of radiation retinopathy.
Radiation retinopathy initially begins with involvement
of the macula in the form of incompetent capillaries resulting
in macular edema. This most common type of retinopathy
responds best to anti-VEGF therapy in its initial phases. In cases
where bevacizumab fails to produce a response, the patient can
be switched to aflibercept. When retinal atrophy develops, a
beneficial clinical effect of anti-VEGF therapy becomes less evident. Chronic anti-VEGF treatment in the face of declining or
poor vision is questionable.
If radiation retinopathy progresses, retinal vascular nonperfusion (ie, ischemia), proliferative retinopathy, and vitreous
hemorrhage may develop. Younger patient age has been associated with a higher risk of proliferative retinopathy. Proliferation
and extensive nonperfusion may be treated, usually definitively,
with laser panretinal photocoagulation. Vitreous hemorrhage
due to proliferative radiation retinopathy may be treated with
vitrectomy and endolaser.
Nonperfusion of the retina demonstrated by fluorescein
angiography, with or without proliferation, may progress to
neovascular glaucoma. Prompt, definitive treatment of the
underlying ischemia with panretinal laser photocoagulation
and management of the IOP are important. Anti-VEGF therapy
may be employed initially before definitive therapy is instituted.
If a patient presents with vitreous hemorrhage and elevated
IOP, gonioscopy is critical to determine if the glaucoma is
ghost-cell induced or from neovascularization of the angle.
Anti-VEGF is especially helpful in this latter situation for initial
management of IOP. However, we recommend that patients
with neovascular glaucoma and vitreous hemorrhage be treated
definitively with vitrectomy or vitrectomy with tube shunt if the
glaucoma does not respond to topical therapy. Patients who also
have exudative retinal detachment, diffuse ischemia (usually in
the detached retina), and neovascular glaucoma must be treated
with vitrectomy for retinal detachment repair and endolaser
with silicone oil, in order to save the eye. Enucleation is recommended for eyes that are blind and painful, usually from
uncontrolled IOP.
However, the most prudent strategy in the management

of radiation is to reduce or avoid the occurrence of radiation
retinopathy. This can be achieved by attenuating the radiation
with silicone oil, resulting in less damage to the retina and optic
nerve. Silicone oil 1000 cs has been demonstrated to attenuate
iodine-125 radiation during plaque brachytherapy by 50%60%.1 In a consecutive series of patients that were matched to
control patients who had not received silicone oil during brachytherapy, there was a reduction in radiation retinopathy.2 In the
treatment of exclusively large melanomas, requiring a greater
dose of radiation, using silicone oil for radiation attenuation
resulted in a significant visual benefit at 1 year, with fewer eyes
with poor visual outcomes (light perception or no light perception).3
References
1. Oliver SC, Leu MY, DeMarco JJ, Chow PE, Lee SP, McCannel
TA. Attenuation of iodine 125 radiation with vitreous substitutes
in the treatment of uveal melanoma. Arch Ophthalmol. 2010;
128(7):888-893.
2. McCannel TA, McCannel CA. Iodine 125 brachytherapy with
vitrectomy and silicone oil in the treatment of uveal melanoma:
1-to-1 matched case-control series. Int J Radiat Oncol Biol Phys.
2014; 89(2):347-352.
3. McCannel TA, Kamrava M, Demanes J, Lamb J, Bartlett JD,
Almanzor R, Chun M, McCannel CA. 23 mm iodine-125 plaque
for uveal melanoma: benefit of vitrectomy and silicone oil on
visual acuity. Under review.
Genetics of Ocular Tumors

N OTE S
111
112
Current Management of Ocular Tumors

Arun D Singh MD
I. Introduction
II. Retinal Pigment Epithelial Tumors
B. Malignant

1. Lymphoma
2. Metastasis
A. Congenital hypertrophy of the RPE (CHRPE)
B. CHRPE variants
C. Combined hamartoma of the retina and RPE
A. Inflammation
D. RPE adneoma/ adenocarcinoma
B. Hemorrhage
C. Foreign body
D. Trauma
III. Retinal Tumors
VI. Simulating Conditions
A. Retinoblastoma
B. Retinocytoma
C. Astrocytoma
A. Color photography
D. Hemangioma
B. Fluorescein angiography
VII. Diagnostic Techniques
1. Capillary
C. Indocyanine green angiography
2. Cavernous
D. Ultrasonography
3. AV malformation
E. OCT
4. Vasoproliferative tumor
F. Radiologic techniques
G. Biopsy
IV. Retinal Lymphoma
V. Uveal Tumors

A. Benign

1. Nevus
2. Melanocytoma
3. Bilateral diffuse uveal melanocytic proliferation
4. Hemangioma
5. Neural tumors (eg, Schwannoma)
6. Leiomyoma
VIII. Conclusions
113
Photodynamic Therapy as an Effective Therapy for

Malignant Choroidal Tumors
Jerry A Shields MD
Historically, chemotherapy and/or radiotherapy have been the
most common forms of treatment for choroidal metastasis,
depending on the systemic status of the patient.1-6 The use of
argon laser photocoagulation for treatment of choroidal meta
stasis was described in 1994,7 but it generally failed to provide
complete tumor control. More recently, photodynamic therapy
(PDT) for choroidal metastasis has been more successful in
achieving tumor control with preservation of vision.8,9
Photodynamic therapy involves administration of a photosensitizing agent, verteporfin (Visudyne, QLT; Vancouver, BC,
Canada), that is activated by a short 689-nm wavelength laser.
Verteporfin is infused intravenously and reaches the vasculature of the tumor, at which time laser is applied and activates
the agent, causing formation of oxygen free radicals that lead
to endothelial damage and thrombosis. PDT can also mediate
tumor destruction through direct cytotoxic effects. Choroidal
metastasis is suitable for PDT as this tumor generally is nonpigmented and highly vascular.
Analysis of 32 Eyes With Choroidal Metastasis

Treated With PDT
Purpose
To determine tumor control and visual outcome after PDT for
choroidal metastasis
Design
Retrospective case series
Participants
There were 35 choroidal metastases in 32 eyes of 31 patients
treated with standard fluence PDT.
Methods
Review of medical records
Main Outcome Measures
Post-PDT tumor control and final visual acuity
Results
There were 31 patients in this series; the primary malignancy
was breast carcinoma (n = 11, 35%), lung carcinoma (n = 9,
30%), renal cell carcinoma (n = 3, 10%), and unknown primary site (n = 4, 13%). Mean age at presentation was 61 years
(median: 63; range: 33-77 years). The most common sites of
coexistent non-ocular metastasis were lung (5/31, 16%), bone
(4/31, 13%), and disseminated (11/31, 36%). There were 9
patients (9/31, 29%) without other systemic metastases. Ocular
symptoms included decreased visual acuity (18/31, 58%), floaters (3/31, 10%), and visual field defect (2/31, 6%); 7 (23%) were
asymptomatic. The metastasis had a mean basal diameter of 5.3
mm (median: 5; range: 2-10 mm) and a mean thickness of 2.4
mm (median: 2.4; range 1-4 mm). Out of 31 patients, 7 were
deceased from progressive systemic malignancy before ophthalmic follow-up following PDT. Of the remaining 24 patients
(26 tumors in 25 eyes), followed for a mean of 12 months

(median: 7 months), complete tumor regression was achieved
in 22 (22/26, 85%). Tumor control was achieved with 1 PDT
session in 18 tumors (18/26, 70%) and 2 sessions in 4 tumors
(4/26, 15%), and failure to regress following PDT was found in
4 (4/26, 15%), requiring plaque radiotherapy to achieve control.
Analyses revealed that tumor control (vs. failure) was related
to closer location to the foveola (median: 1.5 vs. 4.0 mm, P =
.04) and adenocarcinoma cell type (19/22, 86% vs. 0/4, 0%,
P = .002). Visual acuity improved or remained stable in 20
eyes (20/25, 80%) and decreased in 5 (5/25, 20%), related to
subfoveal tumor scar (n = 2), persistent subretinal fluid (n = 1),
reactive exudation after PDT (n = 1), and brain metastasis (n =
1). Two patients with tumors that failed to regress developed
decreased vision from radiation maculopathy following plaque
radiotherapy. At the last follow-up, 18 patients (58%) were alive
and 13 (42%) were deceased from systemic metastasis.
Conclusions
Our 8-year experience reveals that PDT is a rapid and effective treatment for small, postequatorial choroidal metastasis,
achieving tumor control in 85% and providing visual stabilization or improvement in 80% of cases.
References
1. Shields CL, Shields JA, Gross NE, et al. Survey of 520 eyes with
uveal metastases. Ophthalmology 1997; 104(8):1265-1276.
2. Stephens RF, Shields JA. Diagnosis and management of cancer
metastatic to the uvea: a study of 70 cases. Ophthalmology 1979;
86(7):1336-1349.
3. Char DH. Treatment of choroidal metastases. Arch Ophthalmol.
1991; 109(3):333.
4. Shields CL, Shields JA, De Potter P, et al. Plaque radiotherapy for
the management of uveal metastasis. Arch Ophthalmol. 1997;
115(2):203-209.
5. Shields CL. Plaque radiotherapy for the management of uveal
metastasis. Curr Opin Ophthalmol. 1998; 9(3):31-37.
6. Jardel P, Sauerwein W, Olivier T, et al. Management of choroidal
metastases. Cancer Treat Rev. 2014; 40(10):1119-1128.
7. Shields JA. The expanding role of laser photocoagulation for
intraocular tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina 1994; 14(4):310-322.
8. Kaliki S, Shields CL, Al-dahmash SA, et al. Photodynamic
therapy for choroidal metastasis in 8 cases. Ophthalmology 2012;
119(6):1218-1222.
9. Khoo CT, Samara WA, Mashayekhi A, et al. Photodynamic therapy as primary treatment for choroidal metastasis: tumor control
and visual outcomes in 32 eyes. Submitted.
114
Innovative New Pharmacologic Treatment for Melanoma:

Immunotherapy and Small Molecule Inhibitors
New Pharmacologic Therapies for Uveal Melanoma
Carol L Shields MD

I. Local Therapy

A. Light-activated AU-011 from Aura Biosciences Inc.
1. Immune checkpoint inhibitors
1. New class of therapy
a. CTLA-4 inhibitors: ipilimumab (Yervoy)
2. Selectively targeted to tumor cells
3. Approved by USFDA
b. PD-1 inhibitors: pembrolizumab (Keytruda),

nivolumab (Opdivo)
4. Technology involves:
a. Virus-like nanoparticles modeled on the
human papilloma virus that selectively attach
to solid tumor without binding normal tissue
b. Nanoparticle coupled with chromophore
c. Laser light applied and chromophore uptakes

heat leading to precise cellular destruction of
the tumor.
5. Animal models successfully completed
6. Human trials (Phase 1-2) are under way for

small to medium choroidal melanoma in the
United States.
II. Systemic Therapy

C. Immunotherapy
A. Targeted drugs

1. Molecular pathway melanoma
2. Use available agents that target a step in melanoma growth

a. G protein blockade
b. Mitogen-activated protein kinase (MAP

kinase) inhibitor
c. MEK inhibitor
d. Others
B. Block tumor vascularization: Systemic anti-VEGF

(Sutent)
2. Vaccines
3. T cell activation

a. Tumor infiltrating lymphocytes (TIL)
b. Immune modulated T cells against cancer

(ImmTACs) IMCgp100 from Immunocore

i. USFDA approved
ii. ImmTAC molecule is an engineered T cell

receptor that recognizes specific HLA
antigens on melanoma and attracts T cells
to attack the tumor.
Selected Readings
1. Spagnolo F, Picasso V, Spano L, et al. Update on metastatic uveal
melanoma: progress and challenges. BioDrugs. Epub ahead of
print 2016 Mar 21.
2. Venza M, Visalli M, Catalano T, et al. Epidrugs in the immunotherapy of cutaneous and uveal melanoma. Anticancer Agents
Med Chem. Epub ahead of print 2016 Apr 25.
3. Shoushtari AN, Carvajal RD. Treatment of uveal melanoma. Cancer Treat Res. 2016; 167:281-293.
4. Schuler-Thurner B, Bartz-Schmidt KU, Bornfeld N, et al. Immunotherapy of uveal melanoma: vaccination against cancer. Multicenter adjuvant phase 3 vaccination study using dendritic cells
laden with tumor RNA for large newly diagnosed uveal melanoma. Ophthalmologe 2015; 112:1017-1021.
5. Buder K, Gesierich A, Gelbrich G, Goebeler M. Systemic treatment of metastatic uveal melanoma: review of literature and
future perspectives. Cancer Med. 2013; 2:674-686.
Protocol S: Anti-VEGF for Proliferative

Diabetic Retinopathy
Lee M Jampol MD
Panretinal photocoagulation (PRP) has been the standard of
care for proliferative diabetic retinopathy (PDR) for 40 years.
Protocol S involved 305 adults (394 study eyes) with PDR who
were randomly assigned to PRP or intravitreous ranibizumab
(0.5mg). The primary outcome was mean visual acuity change
at 2 years. It was a noninferiority study with a 5-letter margin.
Main Outcomes From the Trial

1. Ranibizumab was noninferior.
2. Visual acuity over 2 years was better with ranibizumab
(area under curve).
3. Visual field loss was worse in the PRP group.
4. Vitrectomy was more common in the PRP group.
5. Diabetic macular edema developed more frequently in the
PRP group.
6. Regression of neovascularization was similar.
7. Few ranibizumab eyes required PRP.
8. About half the PRP eyes required ranibizumab, usually
for diabetic macular edema management.
The talk will also briefly describe new post hoc analyses
from the study.
Selected Reading
ranibizumab for proliferative diabetic retinopathy: a randomized
clinical trial. JAMA 2015; 314(20):2137-2146.
115
116
Protocol T: Two-Year Results
Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema

John A Wells III MD for the Diabetic Retinopathy Clinical Research Network
Institute of Diabetes and Digestive and Kidney Diseases,
National Institutes of Health, Department of Health and
Human Services EY14231, EY23207, EY18817. Regeneron
Pharmaceutical provided the aflibercept and Genentech provided the ranibizumab for the study.
OCT, and no anti-VEGF therapy in the past 12 months. Primary outcome was the mean change in vision at 1 year. Groups
were balanced at baseline with respect to vision, OCT thickness, prior laser, and prior anti-VEGF therapy. Retention was
excellent, with 90% of eyes completing the 2-year visit.
Introduction
Treatment
Diabetic macular edema (DME) is a frequent cause of vision

loss in persons with diabetes, affecting an estimated 750,000
people in the United States.1 In 2015, we reported that in a
comparative effectiveness study of intravitreous aflibercept 2
mg, bevacizumab 1.25 mg, or ranibizumab 0.3 mg (Protocol
T), all 3 agents improved vision and reduced edema effectively
at 1 year, but differences were found in a preplanned subgroup
analysis of baseline vision.2 In eyes with baseline vision of
20/32-20/40, all 3 agents improved vision similarly (+8 letters),
but in eyes with baseline vision of 20/50 or worse, aflibercept
improved vision more than bevacizumab and ranibizumab (+19,
+12, and +14 letters for aflibercept, bevacizumab, and ranibizumab, respectively). In both groups, bevacizumab reduced
edema less effectively than the other 2 agents. There were no
differences in preplanned safety analyses between the 3 agents.
We report herein the vision, anatomic, and safety outcomes
through 2 years of follow-up.3
Injections were given every 4 weeks according to a prespecified

algorithm that permitted deferral of injections once the eye was
stable after 2 consecutive injections. At or after 6 months, focal/
grid laser was applied for persistent edema not improving from
the prior 2 injections. A median of 5-6 injections were given in
the second year in the 3 groups, about 40% fewer than in Year
1, with 15-16 injections given in each group over the 2 years.
Focal grid laser was applied at least once in 41%, 64%, and
52% of aflibercept, bevacizumab, and ranibizumab eyes over
the 2 years.
Study Design
Randomized clinical trial of 660 adults enrolled at 89 sites.
Baseline vision 20/32 to 20/320, with center involved DME on
Figure 1. Mean change in visual acuity over 2 years: full cohort.
Vision Outcomes
Overall at 2 years, aflibercept improved vision more than bevacizumab, but a difference between ranibizumab and aflibercept
was not identified (see Figure 1). In eyes with baseline vision
20/32-20/40, all 3 agents improved vision similarly. But in eyes
with baseline vision 20/50, the benefit of aflibercept over
ranibizumab was no longer statistically significantly different,
while bevacizumab remained inferior (see Figure 2).
117
Figure 2. Mean change in visual acuity over 2 years: by baseline visual acuity subgroup.
Figure 3. Mean change in OCT central subfield thickness over 2 years: baseline visual acuity 20/50 or worse.
Anatomic Outcomes
Safety Outcomes
Bevacizumab reduced macular edema on OCT at 2 years less

effectively overall. In eyes with better baseline vision, the reduction was almost 50% less than the other 2 agents at 1 and 2
years. In eyes with worse baseline vision, bevacizumab was less
effective at 1 year but at the 2-year endpoint was inferior only to
aflibercept (see Figure 3).
Rates of prespecified ocular adverse events were similar across

the 3 groups. However, rates of prespecified Antiplatelet Trialists Collaboration (APTC) adverse events (heart attack, stroke,
and death from vascular or unknown causes) were higher in the
ranibizumab group4 (see Table 1). Other rates of prespecified
systemic adverse events were similar across the 3 groups.
118
Table 1. Prespecified Antiplatelet Trialists Collaborationa Adverse Events Through 2 Years

% of Patients With
at Least 1 Event
Aflibercept
(n = 224)
Bevacizumab
(n = 218)
Ranibizumab
(n = 218)
Nonfatal MI
3%
1%
3%
Nonfatal stroke
<1%
3%
5%
Vascular death
1%
4%
4%
Any APTC Event
5%
8%
12%
Global P-Value
0.047b
a Antiplatelet Trialists Collaboration. Collaborative overview of randomised trials of antiplatelet therapy: I: Prevention of death, myocardial infarction, and stroke by
prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists Collaboration. BMJ 1994; 308:81-106.
b
Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab, P = .34; aflibercept-ranibizumab, P = .047; bevacizumab-ranibizumab, P = .20.
Global P-value adjusting for gender, age at baseline, Hemoglobin A1c at baseline, diabetes type, diabetes duration at baseline, insulin use, prior coronary artery disease,
prior myocardial infarction, prior stroke, prior transient ischemic attack, prior hypertension, smoking status: P = .089.
Conclusions
References
Vision gains in all 3 treatment groups seen at 1 year were

maintained in Year 2 with fewer injections and lasers. In eyes
with better baseline vision, all 3 agents were similarly effective through 2 years. In worse baseline vision eyes, aflibercept
was superior to bevacizumab, but not ranibizumab at 2 years.
Bevacizumab reduces edema less in better seeing eyes; in worse
seeing eyes, bevacizumab was inferior to aflibercept at 2 years
but not ranibizumab. Rates of APTC events were higher in the
ranibizumab arm, but this is inconsistent with prior studies and
may be a chance finding.
1. Varma R, Bressler NM, Doan QV, et al. Prevalence and risk factors for diabetic macular edema in the United States. JAMA Ophthalmol. 2014; 132(11):1334-1340.
2. Diabetic Retinopathy Clinical Research Network.Aflibercept,
bevacizumab, or ranibizumab for diabetic macular edema.N Engl
J Med. 2015; 372(13):1193-1203.
3. Wells JA, Glassman AR, Ayala AR, et al.Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year
results from a comparative effectiveness randomized clinical
trial.Ophthalmology 2016; 123(6):1351-1359.
4. Antiplatelet Trialists Collaboration. Collaborative overview of
randomised trials of antiplatelet therapy: I. Prevention of death,
myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994; 308:81-106.
119
The Impact of Anti-VEGF Therapy on

Retinal Perfusion
Jeffrey S Heier MD
Introduction
Previous studies have demonstrated the beneficial impact of
anti-VEGF therapy on varying degrees of macular ischemia,
including the ability to stabilize disease severity. Advances in
wide-field angiography have allowed a greater appreciation
and understanding of peripheral perfusion status. The impact
of anti-VEGF therapy on overall perfusion status is not well
characterized. The objective of the ANDROID (Impact of
Intravitreal Aflibercept Injections on Capillary Nonperfusion)
study was to determine the effect of intravitreal aflibercept on
perfusion status in proliferative diabetic retinopathy (PDR) and
central retinal vein occlusion (CRVO).
Figure 1. Reduction in capillary nonperfusion, combined results (PDR

and CRVO).
Methods
The ANDROID study was a single center, open label, prospective study that randomized eyes with PDR or CRVO to either
monthly intravitreal aflibercept injections (IAIs) for 12 months
or to 6 monthly IAIs followed by IAI every 2 months. Patients
in this latter group could be treated monthly if they met predefined retreatment criteria. Wide-field fluorescein angiography
was obtained using the Optos 200Tx at baseline and at Months
3, 6, and 12. The Digital Angiography Reading Center (DARC)
and Boston Imaging Reading Center (BIRC) measured peripheral nonperfusion in a masked fashion. Secondary outcomes
included change in best-corrected ETDRS vision and change
in central subfoveal thickness (CST) as measured on spectral
domain OCT.
Results
Twenty-four patients were enrolled. Fifteen eyes had PDR,
8 had CRVO, and 1 had a hemi RVO. Wide-angle angiography was of sufficient quality to evaluate nonperfusion in 23
patients; 1 patient did not have nonperfusion at baseline and
was excluded from analysis. The average total area of peripheral nonperfusion at baseline (155.5mm2 , n = 22) improved to
92.9mm2 at 3 months (P = .055, n = 20), 60.7mm 2 at 6 months
(P = .004, n = 21), and 44.5mm2 at 12 months (P = .007, n =
18). Improvement in nonperfusion is shown in Figure 1 as a
percentage of baseline nonperfusion. Grading was performed
by two different readers, and the results were highly correlated and reproducible. At 1 year, 15 eyes (83%) had improved
peripheral perfusion, while 3 worsened (17%). Visual acuity
improved from 59.8 ETDRS letters (20/63) to 69 letters (20/40,
P = .0003); see Figure 2. The baseline CST of 395 improved
to 295 (P = .006). Results were consistent among patients
with PDR and CRVO as well as the two different regimens.
There were no APTC events; nor were there any serious adverse
events.
Figure 2. Change in BCVA from baseline (ETDRS letters).
Conclusions
Previous studies have documented prevention of progressive
capillary nonperfusion with regular anti-VEGF therapy. This
small prospective study provides evidence that peripheral
capillary nonperfusion in patients with PDR and CRVO may
improve following treatment with IAI. Further large-scale studies are required to explore this finding.
Selected Readings
1. Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of
therapy with ranibizumab on diabetic retinopathy severity and
baseline risk factors for worsening retinopathy. Ophthalmology
2015; 122(2):367-374.
2. Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS.
Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular
edema. Ophthalmology 2014; 121:1783-1789.
3. Campochiaro PA, Bhisitkul RB, Shapiro H, Rubio RG. Vascular
endothelial growth factor promotes aggressive retinal nonperfusion in patients with retinal vein occlusion. Ophthalmology 2013;
120:795802.
120
OCT Biomarkers for Treatment Response to

Diabetic Macular Edema
Jennifer K Sun MD
N OTE S
121
Safety of Anti-VEGF Drugs

I. Background
D. Terminal elimination half-life of free AFL (5-6

days) and BVZ (20 days) in plasma after intravenous administration is prolonged because these
agents are recycled in the systemic circulation via
the neonatal Fc receptor,5 whereas RBZ (2 hours)
lacks an Fc component.
An increased risk of various serious systemic adverse

events (SAEs) has been observed in oncology patients
treated systemically with bevacizumab (BVZ), including:1

A. Hypertension (1/3): VEGF nitrous oxide

production vasoconstriction
B. Proteinuria (1/4): VEGF disrupts podocyte-glomerular endothelial cell interactions.
C. Impaired wound healing: in 1/8 within 60 days of

last bevacizumab (BVZ) dose
D. Gastrointestinal perforation (1.5%)
E. Hemorrhage: epistaxis (1/4), grade 3-5 (1/10)
F. Thrombosis: transient ischemic attack (TIA), cerebrovascular accident (CVA), myocardial infarction
(MI), subarachnoid hemorrhage (SAH): 4%
1. Thrombosis is more common in persons >65

years old or with history of thromboembolic
event.
2. Proposed mechanism of thrombosis: VEGF

endothelial cell survival exposure of
pro-coagulant phospholipids on luminal plasma
membrane or underlying matrix production of NO and PGIz proliferation of vascular smooth muscle cells.
IV. Evidence for Systemic Toxicity After Intravitreal

Injection
Evidence for systemic toxicity after intravitreal injection of AFL or RBZ: Patients (n = 541) with DME and
the highest exposure to anti-VEGF agentsmonthly
injection of AFL (2 mg) (VIVID/VISTA) or RBZ
(0.5mg) (RIDE/RISE) for 2 yearsdemonstrate a
highly significant increased risk of all-cause mortality compared to randomized controls (n = 537): Fixed
Peto odds ratio: 2.98 (95% CI, 1.44-6.14, P = .003).6
V. Evidence Against Systemic Toxicity After Intravitreal

Injection

A. RBZ: Individual patient-level data meta-analysis

(IPDMA) of 6 randomized, double-masked, sham/
laser controlled Phase 2 and 3 trials in DME (1767
total patients, 1186 RBZ-treated; RIDE, RISE,
RESTORE, RESOLVE, RELATION, REVEAL)
demonstrated no meaningful differences between
0.5-mg or 0.3-mg cohorts and controls for risk of
CVA or TIA, CVA (excluding TIA), MI, vascular
death, all-cause mortality, or APTC events (95%
CIs for all hazard ratios included 1.0) (Zarbin et al,
unpublished).
II. Diabetic Risk
Patients with diabetic macular edema (DME) have

increased risk of macro- and microvascular complications compared with diabetics without DME.2 Health
care claims demonstrate rates of hospitalized CVA and
MI, respectively, 2.0 and 2.5 times higher in DME
patients vs. non-DME diabetic controls.3
Caveats:

1. In contrast to RIDE/RISE, where patients with

CVA or MI within last 3 months were excluded
from the trial, patients could not be enrolled in
the RESTORE, RELATION, or REVEAL trials
if they had any history of CVA or MI, and this
group comprised 866 (49%) of the 1767 patients
in the IPDMA; also, RESTORE, RELATION,
REVEAL all used p.r.n. posology.
2. In contrast to RIDE/RISE, where patients were

treated with monthly injections, in the IPDMA,
p.r.n. posology accounted for 688 of the 1186
study patients (58%).
III. Pharmacology

A. Aflibercept (AFL) is a 115-kDa recombinant fusion

protein comprising the critical VEGF binding
domains of human VEGF receptors 1 and 2 fused
to the Fc region of human IgG1. Like BVZ and
ranibizumab (RBZ), AFL binds multiple isoforms
of VEGF-A. Unlike RBZ and BVZ, AFL also binds
VEGF-B and placental growth factor,4 which may
contribute to vascular permeability and retinal neovascularization.
B. BVZ is a 149-kDa full-length monoclonal antibody

that binds all isoforms of VEGF-A.
C. RBZ is a fully humanized monoclonal antibody

fragment (48 kDa) without an Fc domain, which
ensures reduced systemic exposure, in contrast to
the other Fc-containing anti-VEGF molecules.
B. AFL: The incidence of death in the intravitreal

AFL (IA) 2mg q4wks, 2mg q8wks, and control
groups was 5.2%, 2.6%, and 1.9%, respectively, in
VISTA, and 2.9%, 4.4%, and 0.8%, respectively,
in VIVID.7
122

VI. Limitations of Statistical Analysis of Infrequent Events

due to Study Design

A. Registration trials are powered to assess efficacy

and not low-frequency adverse events. This may
also be true for meta-analyses, depending on the
event rates and magnitude of the treatment effect.
SAEs following intravitreal injection of anti-VEGF
agents are infrequent. Even though the IPDMA of
RBZ trials brings together data from 1767 patients,
it is still underpowered to detect differences for
AEs that occur infrequently. Given a 1% stroke rate
in the sham group, the power to detect a doubling
of the stroke risk (ie, from 1% to 2%) in the RBZ
0.5-mg treatment group is 25% using a 2-sided 5%
significance level.
B. Bias of ascertainment: In some trials (eg, VIVID/
VISTA), SAEs were not attributed to intravitreal
injection if they occurred >30 days after injection,
and in others (eg, RESTORE), exclusion criteria
reduced likelihood of SAE occurring in the study
population.
VII. Biological Plausibility of Toxicity

A. Biologically relevant serum (drug) is present for at

least 1 month after intravitreal injection of AFL or
BVZ.8
B. Substantial/profound reduction of free plasma
VEGF levels for at least 1 month after intravitreal
injection of clinically relevant doses of AFL or BVZ
has been documented.8
VIII. Biological Implausibility of Toxicity

If VEGF systemic levels are lowered in almost everyone receiving intravitreal9-14 or systemic anti-VEGF
therapy, why does only a subset of patients develop
SAEs?
IX. Pathway Redundancy: A Basis for Low SAE Frequency

after Intravitreal Anti-VEGF Therapy
Many factors (eg, endostatin, galectins, EGF, VEGF)

influence angiogenic response to ischemic stress.
Galectin-induced platelet activation can trigger a
VEGF-independent proangiogenic response.15 Patients
may vary in their capacity to activate these alternative
pathways.
X. Suggested Approach to Minimize Risk of SAEs Given

Data Limitations

A. Use lowest effective dose of anti-VEGF agent.
B. Consider p.r.n. or treat-and-extend posology rather

than monthly injections.
C. Consider pharmacokinetics of the particular agent

you are using.
D. In patients with very recent CVA/MI or with highrisk and urgent need for treatment, you might
consider alternative therapy, such as intravitreal
steroids/ laser/ combination.
References
1. Kamba T, McDonald DM. Mechanisms of adverse effects of antiVEGF therapy for cancer. Br J Cancer. 2007; 96:1788-1795.
2. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl
J Med. 2007; 356:830-840.
3. Nguyen-Khoa BA, Goehring EL, Werther W, et al. Hospitalized
cardiovascular events in patients with diabetic macular edema.
BMC Ophthalmol. 2012; 12:11.
4. Papadopoulos N, Martin J, Ruan Q, et al. Binding and neutralization of vascular endothelial growth factor (VEGF) and related
ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012; 15:171-185.
5. Xu L, Lu T, Tuomi L, et al. Pharmacokinetics of ranibizumab in
patients with neovascular age-related macular degeneration: a
population approach. Invest Ophthalmol Vis Sci. 2013; 54:16161624.
6. Avery RL, Gordon GM. Systemic safety of prolonged monthly
anti-vascular endothelial growth factor therapy for diabetic macular edema: a systematic review and meta-analysis. JAMA Ophthalmol. 2015; 1-9.
7. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal
Aflibercept for diabetic macular edema: 100-week results from
the VISTA and VIVID studies. Ophthalmology 2015; 122:20442052.
8. Avery RL CA, Steinle NC, Dhoot DS, et al. Systemic pharmacokinetics and pharmacodynamics of intravitreal aflibercept, bevacizumab, and ranibizumab. In press.
9. Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab
versus bevacizumab to treat neovascular age-related macular
degeneration: one-year findings from the IVAN randomized trial.
Ophthalmology 2012; 119:1399-1411.
10. Carneiro AM, Costa R, Falcao MS, et al. Vascular endothelial
growth factor plasma levels before and after treatment of neovascular age-related macular degeneration with bevacizumab or
ranibizumab. Acta Ophthalmol. 2012; 90:e25-30.
11. Zehetner C, Kirchmair R, Huber S, Kralinger MT, Kieselbach
GF. Plasma levels of vascular endothelial growth factor before
and after intravitreal injection of bevacizumab, ranibizumab and
pegaptanib in patients with age-related macular degeneration,
and in patients with diabetic macular oedema. Br J Ophthalmol.
2013; 97:454-459.
12. Wang X, Sawada T, Sawada O, Saishin Y, Liu P, Ohji M. Serum
and plasma vascular endothelial growth factor concentrations
before and after intravitreal injection of aflibercept or ranibizumab for age-related macular degeneration. Am J Ophthalmol.
2014; 158:738-744 e1.
13. Yoshida I, Shiba T, Taniguchi H, et al. Evaluation of plasma
vascular endothelial growth factor levels after intravitreal injection of ranibizumab and aflibercept for exudative age-related
macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2014;
252:1483-1489.
14. Avery RL, Castellarin AA, Steinle NC, et al. Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD. Br J
Ophthalmol. 2014; 98:1636-1641.
15. Etulain J, Negrotto S, Tribulatti MV, et al. Control of angiogenesis by galectins involves the release of platelet-derived proangiogenic factors. PLOS ONE 2014; 9:e96402.
123
Subthreshold Laser: What Is the Level of Proof?

Anat Loewenstein MD
I. Introduction

A. Conventional laser generally does not improve

vision.
B. Conventional laser produces damage that is not

confined to the retinal pigment epithelium (RPE).

1. Thermal denaturation of the photoreceptors

(PR)
2. Visible burn
3. Scotoma in treated area
1. Short laser exposure results in smaller damage.
2. Selective effect on RPE
3. High temperature is confined to the RPE.
4. Photoreceptor temperature increases are

avoided.
1. The conventional continuous laser beam is

chopped into 100-300 microseconds on
and 1700-1900 microseconds off, and typically each laser shot duration is 200-300 milliseconds (train of 100-150 shots, each 2 milliseconds long).
1. Pretreatment central foveal thickness and

MPDL6
2. Fovea-involved DME with good BCVA and

MPDL7
A. 2RT Retinal Rejuvenation Therapy (Ellex; Adelaide, Australia): Pilot trial8
B. Lumenis Novus (Lumenis Ltd.; Yokneam, Israel)

Treatment
1. Subthreshold MPDL vs. conventional argon

laser1
2. Subthreshold MPDL vs. conventional argon

laser (CGL)2
3. Focal/grid laser photocoagulation vs. normaldensity (ND-) or high-density (HD-) MPDL3
4. Focal/grid laser photocoagulation vs. MPDL4
5. MPDL vs. conventional laser5

a. Meta-analysis of randomized clinical trials

(RCTs)
b. Comprehensive literature search for RCTs
c. Six RCTs were selected, representing 398

eyes.
1. TASMC Study: Preservation of the Photoreceptor Layer9
2. Our current prospective trial10
IV. Subthreshold Laser: What Is the Level of Proof?

Conclusion

2. Micropulse has been shown to be as effective as

conventional photocoagulation in treatment of
diabetic macular edema (DME).
A. Subthreshold micropulse diode laser (MPDL) vs.
conventional laser
e. There was no significant difference in terms

of mean change in CRT from baseline
through 12 months.
II. Many Studies Have Evaluated Subthreshold Laser.

III. Other Subthreshold Lasers
D. Three FDA-approved lasers have optional MicroPulse Mode.

d. MPDL resulted in superior improvements in

BCVA through 12 months compared with
conventional laser.
B. Safety and efficacy
C. Motivation for subthreshold retinal therapy
A. A number of small-scale prospective RCTs have

shown efficacy and superiority of MPDL over conventional laser.

1. Improvement in BCVA, macular thickness, and

retinal damage
2. However, large-scale RCTs are still warranted.
B. Subthreshold laser has potential to provide benefit

to patients:

1. With fovea-involved DME and good vision

when they are not candidates for pharmacotherapy
2. Who are unresponsive to pharmacotherapy
References
1. Laursen ML, Moeller F, Sander B, Sjoelie AK. Subthreshold
micropulse diode laser treatment in diabetic macular oedema. Br J
Ophthalmol. 2004; 88(9):1173-1179.
2. Figueira J, Khan J, Nunes S, et al. Prospective randomized controlled trial comparing subthreshold micropulse diode laser
photocoagulation and conventional green laser for clinically
significant diabetic macular oedema. Br J Ophthalmol. 2009;
93:1341-1344.
3. Lavinsky D, Cardillo JA, Melo LAS, et al. Randomized clinical
trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Invest Ophthalmol Vis Sci. 2011; 52:4314-4323.
124
4. 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.
5. Chen G, Tzekov R, Li W, Jiang F, Mao S, Tong Y. Subthreshold
micro pulse diode laser versus conventional laser photocoagulation for diabetic macular edema: a meta-analysis of randomized
controlled trials. Retina. Epub ahead of print 2016 Apr 18.
6. Mansouri A, Sampat KM, Malik KJ, Steiner JN, Glaser BM;
Medscape. Efficacy of subthreshold micropulse laser in the treatment of diabetic macular edema is influenced by pre-treatment
central foveal thickness. Eye (Lond). 2014; 28(12):1418-1424.

7. Luttrull JK, Sinclair SH. Safety of transfoveal subthreshold diode
micropulse laser for fovea-involving diabetic macular edema in
eyes with good visual acuity. Retina 2014; 34(10):2010-2020.
8. Pelosini L, Hamilton R, Mohamed M, Hamilton AM, Marshall
J. Retina rejuvenation therapy for diabetic macular edema: a pilot
study. Retina 2013; 33(3):548-558.
9. Soiberman U, Goldstein M, Pianka P, Loewenstein A, Goldenberg
D. Preservation of the photoreceptor layer following subthreshold
laser treatment for diabetic macular edema as demonstrated by
SD-OCT. Invest Ophthalmol Vis Sci. 2014; 55(5):3054-3059.
10. Loewenstein A, Goldstein M, Barak A, Goldenberg D, Erlik N,
Bressler NM. Sub-threshold laser treatment of macular edema in
patients with diabetes. Invest Ophthalmol Vis Sci. 2012; 53(417).
125
Neurodegenerative Changes in Diabetic Retinopathy

A New Dimension of Diabetic Retinopathy
Thomas W Gardner MD MS and Vinicius Castro MD PhD

Scientific Summary
The neurovascular unit, comprised of blood vessels, neurons,
and glial cells, coordinates retinal function in response to metabolic activity.1 Diabetes impairs neurovascular unit responses to
hyperoxia and flickering light when the retina appears normal.2
Decompensated adaptive responses and maladaptive changes
result in macular edema and neovascularization, stages of retinal failure.3 Collectively, diabetes is a neurovascular degeneration or sensory neuropathy.
Clinical Implications
The recent focus on diabetic macular edema (DME) emphasizes
examinations for macular thickening. However, retinal sensitivity and thickness decrease when vascular changes are absent
or minimal,4,5 and reduced multifocal electroretinography
findings predict subsequent development of macular edema.6
Progressive diabetes impairs normal adaptive processes, leading
to vasodilation, retinal thinning, and reduced retinal visual field
sensitivity and electrical activity.7,8 Regions of capillary nonperfusion are accompanied by marked retinal thinning and reduced
vision,9 and disorganization of retinal inner layers predicts poor
visual acuity outcome after treatment for DME.10 Recognizing
this new dimension provides new understanding of the mechanisms of vision impairment and prospects for earlier treatment
of retinopathy.
Case Example
Figure 1. Fluorescein angiography
of a patient with nonproliferative
diabetic retinopathy and nonperfused areas temporal to the fovea.
Black line corresponds to spectral
domain OCT line scan shown in
Figure 2.
Figure 2. Spectral domain OCT

line scan of the nonperfused area
shows retinal thinning and disruption of the inner retinal layers
(arrows).
126

Figure 3. Matrix frequency doubling perimetry shows decreased
sensitivity temporal to the fovea,
corresponding to the nonperfused
area on fluorescein angiography.
Threshold values in dB (left) and
grayscale graphic of the threshold with corresponding P values
(right) show markedly reduced
sensitivity. From Castro V, Gardner TW. Evaluating changes
in diabetic retinopathy. Retina
Today, March 2016, p. 66.
References
1. Newman EA. Functional hyperemia and mechanisms of neurovascular coupling in the retinal vasculature. J Cereb Blood Flow
Metab. 2013; 33:1685-1695.
2. Lott ME, Slocomb JE, Shivkumar V, Smith B, Quillen D, Gabbay
RA, Gardner TW, Bettermann K. Impaired retinal vasodilator
responses in prediabetes and type 2 diabetes. Acta Ophthalmol.
2013; 91:e462-e469.
3. Gray EJ, Gardner TW. Retinal failure in diabetes: a feature of retinal sensory neuropathy. Curr Diab Rep. 2015; 15(12):107.
4. Di Leo MA, Caputo S, Falsini B, Porciatti V, Greco AV, Ghirlanda
G. Presence and further development of retinal dysfunction after
3-year follow up in IDDM patients without angiographically
documented vasculopathy. Diabetologia 1994; 37:911-916.
5. van Dijk HW, Verbraak FD, Kok PH, et al. Decreased retinal ganglion cell layer thickness in patients with type 1 diabetes. Invest
Ophthalmol Vis Sci. 2010; 51:3660-3665.
6. Harrison WW, Bearse MA Jr, Schneck ME, et al. Prediction, by

retinal location, of the onset of diabetic edema in patients with
nonproliferative diabetic retinopathy. Invest Ophthalmol Vis Sci.
2011; 52:6825-6831.
7. Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl
J Med. 2012; 366:1227-1239.
8. Abcouwer SF, Gardner TW. Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann N
Y Acad Sci. 2014; 1311:174-190.
9. Dodo Y, Murakami T, Uji A, Yoshitake S, Yoshimura N. Disorganized retinal lamellar structures in nonperfused areas of diabetic
retinopathy. Invest Ophthalmol Vis Sci. 2015; 56:2012-2020.
10. Sun JK, Lin MM, Lammer J, et al. Disorganization of the retinal
inner layers as a predictor of visual acuity in eyes with centerinvolved diabetic macular edema. JAMA Ophthalmol. 2014;
132:1309-1316.
127
Future Targets for Diabetic Macular Edema Therapy

I. Validated Targets

A. VEGF

2. Ang2 neutralizing proteins

a. RO6867461 = bispecific antibody that blocks

VEGF and Ang2
BOULEVARD: RO6867461 vs. ranibizumab
1. New VEGF neutralizing proteins

a. Abicipar pegol

i. PEGylated designed ankyrin repeat protein that binds VEGF
ii. May have longer duration of action than

aflibercept
b. Single chain anti-VEGF antibody fragment

i. 26 kD
ii. Can inject a large amount and therefore

inhibitory levels maintained longer in vitreous, but may also have greater systemic
exposure
2. Reservoir: Ranibizumab port delivery system

(RPDS)
3. Microparticles

a. GB-102 = sunitinib formulated in PLGA

microspheres
b. Sunitinib is a tyrosine kinase inhibitor that

blocks VEGFRs, PDGFRs, c-Met, DLK.
c. Injected in clinic through 27-gauge needle

and forms aggregate in the inferior vitreous
base
i. 150 patients with treatment-nave DME,

28-week study
ii. Arm A: 0.3-mg ranibizumab intravitreal

(IVT) every 4 weeks for 24 weeks (7 injections)
iii. Arm B: 1.5-mg RO6867461 IVT every

4 weeks for 20 weeks (6 injections), followed by 1 sham administration at Week
24
iv. Arm C: 6-mg RO6867461 IVT every 4

weeks for 20 weeks (6 injections), followed by 1 sham administration at Week
24
b. REGN910-3 = antibody directed against

Ang2
RUBY: 300 patients with DME (not treatment nave)

4. Gene transfer: AAV8-ranibizumab
i. Randomized 1:2:3

(a) Group 1 (low-dose): REGN910-3 (3

mg:2 mg) every 4 weeks (Q4) (Day 1,
Week 4, and Week 8) for 3 initial doses
(b) Group 2 (high-dose): REGN910-3

(6 mg:2 mg) Q4 (Day 1, Week 4, and
Week 8) for 3 initial doses
(c) Group 3 (intravitreal aflibercept injection [IAI] alone): IAI 2 mg Q4 (Day 1,

Week 4, and Week 8) for 3 initial doses
B. Tie2 activation

1. AKB-9778

a. Small molecule that blocks vascular endothelial-protein tyrosine phosphatase (VE-PTP),

a phosphatase that inactivates Tie2
b. Self-administered by patients by subcutaneous injections
c. AKB-9778 + ranibizumab more effective

than ranibizumab in reduction of diabetic
macular edema (DME)
d. AKB-9778 monotherapy may regress background diabetic retinopathy
ii. At Week 12, patients will be re-randomized (stratified based on change from
baseline to Week 12 in BCVA) into the
following 3 treatment groups and dosed
from Week 16 through Week 32 as follows:

(a) Group 1 (low-dose): REGN910-3 (3

mg:2 mg) Q8 with a sham injection
administered at nontreatment visits
(b) Group 2 (high-dose): REGN910-3 (6

mg:2 mg)
(c) Group 2a: REGN910-3 high-dose (6

mg:2 mg) at Week 16 and Q8 through
Week 32, with sham injections at nontreatment visits
128

(e) Group 3 (IAI alone)
(f) Group 3a: IAI 2 mg at week 16 and

Q8 through Week 32, with sham injections at nontreatment visits
(d) Group 2b: REGN910-3 high-dose

(6 mg:2 mg) at Week 20 and Q12
through Week 32, with sham injections at nontreatment visits
(g) Group 3b: IAI 2 mg at Week 20 and

Q12 through Week 32, with sham
injections at nontreatment visits
(h) Group 3c: REGN910-3 high-dose (6
mg:2 mg) at Week 16 and Q8 through
Week 32, with sham injections at nontreatment visits
C. Corticosteroids

1. Dexamethasone implant
2. Fluocinolone acetonide implant
3. Suprachoroidal injections of triamcinolone acetonide (Zuprata)
II. Nonvalidated Targets

A. RGD peptide / ALG1001
B. Collagen IV-derived mimetic peptide
C. Plasma kallikrein inhibitor
129
A Multicenter, Double Masked Phase 2 Clinical Trial

Evaluating Abicipar Pegol for Diabetic Macular Edema
Tarek S Hassan MD
N OTE S
130
Intravitreal Injection of a Rho-Kinase Inhibitor

(Fasudil) Combined with Bevacizumab versus
Bevacizumab Monotherapy for Diabetic Macular
Edema; a Randomized Clinical Trial
Hamid Ahmadieh MD
N OTE S
131
Efficacy and Safety Trial of Intravitreal Injections

Combined With PRP for the Treatment of CSME
Secondary to Diabetes Mellitus (DAVE)
Rosa Y Kim MD, David M Brown MD, William C Ou BS, and Charles C Wykoff MD PhD
Purpose
To assess prospectively a 0.3-mg ranibizumab with ultrawide
200 field angiography panretinal photocoagulation combination therapy vs. a 0.3-mg ranibizumab monotherapy for diabetic macular edema (DME).
Methods
Patients with Early Treatment Diabetic Retinopathy Study
(ETDRS) BCVA from 20/32 to 20/400 (Snellen equivalent)
were randomized to receive intravitreal 0.3-mg ranibizumab
pro re nata (p.r.n.) only or in combination with ultrawide 200
field angiography panretinal photocoagulation. Both cohorts
were treated monthly for at least 4 doses followed by a p.r.n.
retreatment based on the predefined criteria (presence of DME

on examination or spectral domain OCT). In the combination
cohort, targeted retinal photocoagulation (TRP) was applied
to areas of peripheral retinal capillary nonperfusion at Week 1,
and additional TRP was repeated at Month 6 and 18 as needed.
Main outcome measures were mean ETDRS BCVA change
from baseline and difference in total number of intravitreal
injections between cohorts.
Results
At baseline, mean age was 55 years (range: 31-75), mean BCVA
was 20/63 (Snellen equivalent), and mean central retinal thickness (CRT) was 530m.
Figure 1. Example of targeted retinal photocoagulation administered in combination therapy cohort.
Table 1. Baseline Patient Demographics

Anti-VEGF only
Anti-VEGF + TRP
Total
% O.D. (O.D./O.S.)
35% (7/13)
55% (11/9)
45% (18/22)
Mean age (range)
54 (45-69)
56 (31-75)
55 (31-75)
% male (male/female)
20% (16/4)
75% (15/5)
78% (31/9)
Mean HbA1C (range)
8.8 (5.9-12.9)
8 (5.9-12.8)
8.4 (5.9-12.9)
Mean DM diagnosis year (range)
2002 (1982-2012)
2001 (1980-2012)
2001 (1980 - 2012)
Mean DME diagnosis year (range)
2012 (2008-2014)
2012 (2010-2014)
2012 (2008 - 2014)
Mean ETDRS BCVA (range)
59.1 (23-75)
60.1 (37-76)
59.6 (23-76)
Snellen equivalent
20/63 (20/400-20/32)
20/63 (20/200-20/32)
20/63 (20/400-20/32)
Mean CRT (range)
573 m (262-1034)
488 m (273-946)
530 m (262-1034)
132
Thirty-six eyes (90%) completed Month 24, at which point

mean BCVA improved by 14.6 and 8.7 letters in the Anti-VEGF
only and Anti-VEGF+TRP cohorts, respectively (P = .16). The
mean number of injections administered through Month 24
were 18.3 (range: 8-25) and 19.7 (range: 10-25) in the AntiVEGF only and Anti-VEGF+TRP cohorts respectively (P = .39).
The mean CRT at Month 24 improved by 297 and 165m in
the Anti-VEGF only and Anti-VEGF+TRP cohorts, respectively
(P = .08). The overall proportion of p.r.n. injections given was
similar between the Anti-VEGF only and Anti-VEGF+TRP
cohorts in both Year 1 (86% vs. 92%, P = .10) and Year 2 (73%
vs. 80%, P = .12).
Figure 2. Mean absolute visual acuity through Month 24 of DAVE.
Figure 3. Mean absolute central retinal thickness through Month 24 of DAVE.
Figure 4. Proportions of patients who gained 10+ and 15+ letters.
Table 2. Proportions of p.r.n. Injections Administered

% p.r.n. Year 1
% p.r.n. Year 2a
% p.r.n. Year 3b
Anti-VEGF only
86% (118/138)
73% (137/188)
64% (87/136)
Anti-VEGF + TRP
92% (141/154)
80% (157/197)
73% (121/166)
P = .12
P = .10
Conclusions
In this prospective randomized trial of 40 eyes with centerinvolving DME with extensive retinal capillary nonperfusion
identified by ultrawide-field 200 fluorescein angiography, comparable visual and anatomic outcomes were demonstrated in
both the Anti-VEGF only and Anti-VEGF+TRP arms through
24 months of follow-up. In this study population (DME with
extensive peripheral nonperfusion), there is no evidence that
TRP reduced treatment burden in the management of DME
with ranibizumab. Up-to-date follow-up will be presented on
the entire cohort.
133
134
Improvement in Diabetic Retinopathy Progression

Status in At-risk Patients Treated with 0.2 g/day
Fluocinolone Acetonide Over 36 Months
N OTE S
Sarilumab, an Anti-Interleukin-6 Receptor Antibody,

for Posterior Segment Noninfectious Uveitis (NIU):
Results of SATURN
Quan Dong Nguyen MD
N OTE S
135
136
Pharmacologic Treatments for New Biologics

Debra Goldstein MD
Biologic agents have dramatically changed the treatment of

uveitis. Most of data are on TNF- inhibitors, infliximab and
adalimumab. These agents are more effective in treating inflammation than antimetabolites such as methotrexate and azathioprine. Data from prospective and retrospective studies support
their efficacy. The doses required for uveitis are typically higher
than for systemic disease. For example, while rheumatologic
disease may be controlled on infliximab doses of 3-5 mg/kg
every 8 weeks, uveitis typically requires higher doses and higher
frequency, often 10 mg/kg every 4 weeks. Similarly, while
adalimumab may be administered every 2 weeks for systemic
disease, it is often required every week for the treatment of
uveitis. Important potential side effects include risk of infection
and possible increased risk of malignancy, as well as the risks of
exacerbation of MS with TNF- inhibitors.
Selected Readings
1. Suhler EB, Lowder CY, Goldstein DA, et al. Adalimumab therapy
for refractory uveitis: results of a multicentre, open-label, prospective trial. Br J Ophthalmol. 2013; 97(4):481-486.
2. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for
refractory uveitis: 2-year results of a prospective trial. Arch Ophthalmol. 2009; 127(6):819-822.
3. Takeuchi M, Kezuka T, Sugita S, et al. Evaluation of the long-term
efficacy and safety of infliximab treatment for uveitis in Behets
disease: a multicenter study. Ophthalmology 2014; 121(10):18771884.
137
Diagnostic and Therapeutic Procedures

I. Introduction: The Expanding Role of Surgical

Management of Uveitis
IV. Biological Plausibility of Vitrectomy as Therapy

A. Natural adjunct to medical therapy, which may

replace it in limited cases
II. Diagnostic Vitrectomy

A. Indications for diagnostic vitrectomy

1. Diagnostic vitrectomy if there is a need for cells

or tissue. If fluid suffices, then only a vitreous
tap or an anterior chamber tap is needed.
2. Case selection
3. Examples and evidence for noninfectious uveitis, uveitis, and masquerade syndromes
B. Technique of safe and effective biopsies of vitreous

and tissue

1. Pars plana vitrectomy: partitioning of specimens and allocation to testing
2. Chorioretinal biopsy: identification of site,

instrumentation, retrieval, fixation
1. The special case of pars planitis
2. Combination with cryoretinopexy and laser

photocoagulation for retinal ablation to
decrease the amount of inflamed retina or initiate corrective healing mechanism
3. Removes inflammatory deposits that may perpetuate immunological reactions
4. Potential to repair and prevent structural complications
5. Jeopardizes future use of the vitreous body as a

drug depot
B. Medical evidence for therapeutic vitrectomy: Two

major reviews of medical literature

C. Medical evidence of the utility of diagnostic vitrectomy and retinal biopsy from case series
III. Vitreoretinal Disease Likely to Benefit From
Therapeutic Surgical Intervention
A. Nonresolving vitreous floaters

1. Combined with cataract extraction
2. Recognition of collagenous floaters that are not

amenable to medical therapy
1. Up to 2005

a. First used with pars plana lensectomy
b. Heterogeneous indications, including endophthalmitis
c. Low-level evidence in case series
d. Fair evidence of benefit
2. Contemporary series, 2005 to present

a. Again shows fair evidence of benefit in lowlevel case series formats
b. Number of published patients and eyes

treated is increasing.
B. Retinal detachment

1. Special concerns in repair of uveitic eyes
2. Epiretinal membranes and proliferative vitreoretinopathy
3. Pars plana exudates
4. Adherent retinal plaques
5. Exudative serous vs. proteinaceous rhegmatogenous detachments
C. Macular edema with epiretinal membrane or vitreomacular traction

1. Vitrectomy alone may be sufficient for nontractional membranes and avoid significant macular trauma.
2. Only vitrectomy has been supported as a potential therapeutic strategy for macular edema,
and this is through the mechanism of better
control of the uveitis.
3. Uveitis with a strong vitreoretinal component

such as intermediate uveitis
C. Additional, recent encouraging evidence for the

benefits of peripheral retinal ablation in the treatment of selected types of uveitis

1. Cryoretinopexy
2. Laser photocoagulation
V. Conclusion

A. Diagnostic vitrectomy and chorioretinal biopsy is

of clear benefit in selected cases. More conservative options should be selected in some cases.
B. Therapeutic vitrectomy in uveitic eyes should follow standard vitreoretinal indications for retinal
detachment and epiretinal membranes with special
precautions in inflamed eyes.
138
C. Role of therapeutic vitrectomy as a disease modifier of uveitis is currently best supported in intermediate uveitis, especially the pars plana subtype,
in which patients it is usually combined with
peripheral retinal ablation.
D. All surgical interventions in uveitic patients are

likely to fail or be associated with significant complications if attention is not directed to adequate
medical control of the uveitis.
Innovative Suprachoroidal Microneedle

Diana V Do MD
N OTE S
139
140
Uveitis Case Panel

Alexander J Brucker MD, James Philip Dunn Jr MD, Glenn J Jaffe MD, Ann-Marie Lobo MD,
N OTE S
Complement for Geographic Atrophy: Overview

N OTE S
141
142
Nucleoside Reverse Transcriptase Inhibitors Are

Promising for AMD

I. Uses for FDA-Approved Nucleoside Reverse

Transcriptase Inhibitors (NRTIs)

A. Treatment of human immunodeficiency virus

(HIV): zidovudine (Retrovir; AZT) was first in
class (approved in 1984). Eight NRTIs are commercially available in the United States.
B. Treatment of hepatitis B virus (HBV): lamivudine

(Epivir; 3TC), tenofovir DF (Viread, TDF), and
emtricitabine (Emtriva, FTC) exhibit anti-HBV
activity.
II. Preclinical Efficacy of NRTIs for AMD

A. NRTIs protect against retinal pigment epithelial

(RPE) degeneration in cells and in mice.1

1. Four of 4 drugs tested were effective: lamivudine (Epivir), stavudine (Zerit), abacavir (Ziagen), and zidovudine (Retrovir).
2. NRTIs reduce CNV volume in laser-treated

mice.1,2 Four of 4 drugs tested were effective:
lamivudine, stavudine, abacavir, and zidovudine.
III. AMD in the HIV+ Population
A. Study of 1825 participants with AIDS. AIDSpositive individuals had 4x increased age-adjusted
prevalence of intermediate AMD vs. AIDS-negative
individuals.3 Effect of medication vs. immune deficiency vs. virus?

1. Relative risk with NRTI use (0.80) (P = 0.27)
2. Antiretroviral treated, immune-restored HIV+

individuals do not have normal immune systems.4
3. HIV infects human RPE cells and augments

phagocytosis.5
B. Study of 10,000 HIV+/HBV+ individuals over 14
years health insurance claims database (unpublished/ meeting abstract): 35% reduction in incidence of AMD in NRTI-using patients.
IV. Later-Generation NRTIs Are Safe

A. Current CDC recommendation for initiation of

HIV therapy: lamivudine/ abacavir or emtricitabine/ tenofovir6
B. Long-term (6 years+) lamivudine monotherapy has

excellent safety profile in HBV+ individuals.7
C. Older-generation NRTIs (eg, AZT, d4T) are not

as safe: mechanism involves mtDNA depletion.
Lamivudine has much lower affinity for human
DNA polymerase gamma (the enzyme responsible
for mitochondrial DNA synthesis) relative to other
NRTIs.8
D. Creation of NRTI derivatives that retain antiinflammatory/retinal-protective properties but

eliminate effect on mtDNA1
E. Intraocular delivery should minimize systemic

effects.
References
1. Fowler BJ, Gelfand BD, Kim Y, et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 2014; 346:1000-1003.
2. Mizutani TM, Fowler BJ, Kim Y, et al. Nucleoside reverse transcriptase inhibitors suppress laser-induced choroidal neovascularization in mice. Invest Ophthalmol Vis Sci. 2015; 56:7122-7129.
3. Jabs DA, Van Nata ML, Sezqin E, et al. Prevalence of intermediate-stage age-related macular degeneration in patients with
acquired immunodeficiency syndrome. Am J Ophthalmol. 2014;
159:1115-1122 e1111.
4. Deeks SG. HIV infection, inflammation, immunosenescence, and
aging. Annu Rev Med. 2011; 62:141-155.
5. Canki M, Sparrow JR, Chao W, Potash MJ, Volsky DJ. Human
immunodeficiency virus type 1 can infect human retinal pigment
epithelial cells in culture and alter the ability of the cells to phagocytose rod outer segment membranes. AIDS Res Hum Retroviruses. 2000; 16:453-463.
6. [Guideline] Panel on Antiretroviral Guidelines for Adults and
Adolescents. Guidelines for the use of antiretroviral agents in
HIV-1-infected adults and adolescents. Department of Health
and Human Services. Jan 28, 2016. AIDSinfo. Available at
http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf.
Accessed: 2016 June 28.
7. Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine
treatment in patients with chronic hepatitis B. Gastroenterology
2003; 125(6):1714-1722.
8. Martin JL, Brown CE, Matthews-Davis N, Reardon JE. Effects
of antiviral nucleoside analogs on human DNA polymerases and
mitochondrial DNA synthesis. Antimicrob Agents Chemother.
1994; 38:2743-2749.
143
AREDS Update
The Age-Related Eye Disease Study (AREDS) and AREDS2 Update-Validation

of the AREDS AMD Detailed and Simplified Scales
Emily Y Chew MD
Introduction
Method
The lack of effective treatment of non-neovascular AMD poses

a huge unmet medical need. Data from the longitudinal studies
of AMD provide value information on the potential outcome
measures that may be important to incorporate into future
studies of AMD.
Analyses of progression to varying degrees of AMD from 2

prospective clinical trials of nutritional supplements for AMD.
AREDS (n= 4757) enrolled participants with varying severity
of AMD, from no AMD to late AMD in one eye. AREDS2 (n=
4203) enrolled participants with bilateral large drusen or large
drusen in the study eye and late AMD in the fellow eye.
Background
The Age-Related Eye Disease Study (AREDS)1 and the AgeRelated Eye Disease Study 2 (AREDS2)2 followed nearly 9000
participants for at least 5 years, with some 3000 followed for
10 years. Data on progression to geographic atrophy have been
explored with both fundus photographs (AREDS and AREDS2)
and fundus autofluorescence (AREDS2). The data from AREDS
were analyzed to produce a detailed scale for progression of
AMD consisting of 12 levels, with 9 and above being severity of
late AMD.3,4 The data from AREDS2 were used to validate the
AREDS AMD scale. One of the goals is to develop a surrogate
outcome for AMD, much like the Early Treatment Diabetic
Retinopathy Study (ETDRS) Classification, which is used to
study the progression of diabetic retinopathy. In addition, the
data from AREDS2 can be used to further validate the AREDS
Simplified Scale, which considers the presence or absence of
large drusen and hyper/hypopigmentary changes of the retinal
pigment epithelium (RPE) in either eye. Each lesion (either large
drusen or the RPE hyper/hypopigmentary change) is given a
point, and the maximum is 4 points for both eyes. Presence of
late AMD (neovascular or geographic atrophy) is given 2 points
as well. Those with medium-sized drusen receive one-half point.
The scale ranges from 0 to 4 and is very useful for clinical use
and for research as well.
Figure 1.
Main Outcome Measures

Five-year incidence of late AMD, assessed by annual masked
centralized fundus photograph grading
Results
Five-year rates of late AMD did not differ between AREDS2
and AREDS participants, within nearly all baseline AMD
detailed severity scale levels: levels 1-3: 2.4% vs. 0.5% (difference: 1.9%; 95% CI, 0.2%-4.0%; P < .001); level 4: 6.5% vs.
4.9% (difference: 1.6%; 95% CI, 1.7%- 4.8%; P = .34); level
5: 8.0% vs. 5.6% (difference: 2.4%; 95% CI, 1.2%-5.9%; P
= .22); level 6: 12.8% vs. 13.7% (difference: 0.9%; 95% CI,
4.8%-3.1%; P = .66); level 7: 26.2% vs. 27.8% (difference:
1.5%; 95% CI, 6.6%-3.5%; P = .54); level 8: 46.4 vs. 44.7%
(difference: 1.7%; 95% CI, 7.5%-10.9%; P = .72). Within
simple scale levels, AREDS2 and AREDS 5-year rates did not
differ significantly except for level 1 (9.4% vs. 3.1%, P = .02):
level 2: 12.8% vs. 11.8%, P = .65; level 3: 26.3% vs. 25.9%, P =
.90; level 4: 45.6% vs. 47.3%, P = .57.
Figure 2.
144
Conclusions
The AREDS detailed and simple AMD severity scales were useful measures for assessing risk of developing late AMD in the
AREDS2 population; these data suggest they should be useful
tools for clinical trials of AMD treatments.
References
1. Age-Related Eye Disease Study Research Group. A randomized,
placebo-controlled, clinical trial of high-dose supplementation
with vitamins C and E, beta carotene, and zinc for age-related
macular degeneration and vision loss: AREDS report no. 8. Arch
Ophthalmol. 2001; 119(10):1417-1436.
2. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013; 309(19):2005-2015.
3. Davis MD, Gangnon RE, Lee LY, et al; Age-Related Eye Disease
Study Group. The Age-Related Eye Disease Study severity scale
for age-related macular degeneration: AREDS Report No. 17.
Arch Ophthalmol. 2005; 123(11):1484-1498.
4. Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad
AS, Milton RC, Bressler SB, Klein R; Age-Related Eye Disease
Study (AREDS) Research Group. A simplified severity scale for
age-related macular degeneration: AREDS Report No. 18. Arch
Ophthalmol. 2005; 123(11):1570-1574.
AMD in AIDS
Antiretroviral-treated, immunorestored, HIV-infected persons

have accelerated and accentuated aging vs. age-matched HIVuninfected persons and have immunosenescence. Results from
the Longitudinal Study of the Ocular Complications of AIDS
Cohort suggest a 4-fold increased age-adjusted prevalence of
intermediate-stage AMD in patients with AIDS.
Reference
1. Jabs DA, Van Natta M, Sezgin E, Pak JW, Danis R; Studies of the
Ocular Complications of AIDS Research Group. Prevalence of
intermediate-stage age-related macular degeneration in patients
with the acquired immunodeficiency syndrome. Am J Ophthalmol. 2015; 115-122.
145
146
Emerging Areas of Therapy for Geographic Atrophy

Demetrios Vavvas MD
N OTE S
147
Vitrectomy for Vitreous Opacities

J Sebag MD FACS FRCOphth FARVO
Background
Vitreous opacities disturb vision,1 but there are no objective
criteria with which to determine clinical severity. This study
developed quantitative ultrasound (QUS)2 and contrast sensitivity (CS)3 testing as objective measures for case selection and
evaluated the safety and efficacy of vitrectomy.
Methods
129 eyes in 102 patients (61 men and 41 women; 59 13 years
old) with subjective floaters and objective vitreous opacities
were evaluated and underwent 25-gauge vitrectomy without
surgical posterior vitreous detachment (PVD) induction, leaving retrolental vitreous intact. Follow-up averaged 19.6 months
(range: 3-69; 100 eyes >6 months, 71 eyes >12 months). CS
was measured in 69 floater eyes and 32 age-matched controls
using Freiburg Acuity Contrast Testing (Weber Index [%W],
where a lower %W means better CS).4 The presence or absence
of PVD was established by ultrasound, and QUS was performed
as previously described, 2 then correlated with visual acuity
(VA), CS, and quality of life assessment by National Eye Institute Visual Function Questionnaire (VFQ).
Results
PVD was the cause of floaters in 66%; and myopic vitreopathy,
in 25%. CS was 75% lower in floater eyes (4.2 1.8%W) than
in controls (2.4 0.9%W; P < .01). There was a strong positive correlation between QUS and CS (R = 0.672, P < .00001),
indicating that increased vitreous echodensity is associated with
proportionally decreased CS. QUS was also correlated with
VA (R = 0.46, P < .0002) and patient unhappiness (VFQ; R
= 0.56; P < .0004). The strongest correlation was between
CS and VFQ (R = 0.68, P < .00001), suggesting that poor CS
accounts for patient unhappiness.
Following limited vitrectomy, CS was normal in 68/69 cases

(99%) at 1 week and 1, 3, 6, 12, 18, and 24 months (P < .0009
for each), VA improved by 14% (P = .03), and VFQ improved
by 26.2% (P < .05). There were no cases of endophthalmitis,
macular edema, or IOP problems; there were 2 transient vitreous hemorrhages (1.4% incidence) and 1 retinal detachment 14
months postop (0.7% incidence). Two years postop, cataract
surgery was required in only 16/76 phakic eyes (21% incidence);
mean age = 63 years, none under 53 years old.
Conclusions
Vitreous floaters decrease CS by 75%, accounting for patient
unhappiness.1-3 Limited 25-gauge vitrectomy without PVD
induction that preserves anterior vitreous in phakic eyes is
effective in restoring normal CS in 99% of eyes, improving VA,
and increasing quality of life as assessed by VFQ testing.4 This
approach can enhance case selection for vitrectomy, as well as
provide useful outcome measures of therapy.5
References
1. Sebag J. Floaters and the quality of life [guest editorial]. Am J
Ophthalmol. 2011; 152:3-4.
2. Mamou J, Wa CA, Yee KM, Silverman RH, Ketterling JA, Sadun
AA, Sebag J. Ultrasound-based quantification of vitreous floaters
correlates with contrast sensitivity and quality of life. Invest Ophthalmol Vis Sci. 2015; 56:1611-1617.
3. Huang LC, Yee KMP, Wa CA, Nguyen JN, Sadun AA, Sebag J.
Vitreous floaters and vision: current concepts and management
paradigms. In: Sebag J, ed. Vitreous: In Health and Disease. New
York: Springer; 2014:771-788.
4. Sebag J, Yee, KMP, Huang L, Wa C, Sadun AA. Vitrectomy for
floaters: prospective efficacy analyses and retrospective safety
profile. Retina 2014; 34:1062-1068.
5. Milston R, Madigan M, Sebag J. Vitreous floaters: etiology, diagnostics, and management. Surv Ophthalmol. 2016; 61(2):211-227.
148
Vitrectomy for Diabetic Macular Edema

Pharmacotherapy has revolutionized the treatment of diabetic

macular edema (DME). Despite these advances, a significant
proportion of patients continue to have chronic and persistent
DME. There is increasing evidence that the vitreomacular interface plays a critical role in the pathogenesis and persistence of
DME. Although there is near universal agreement that vitrectomy is beneficial in situations where DME is associated with
overt vitreomacular traction or epiretinal membranes, newer
data point to the beneficial effects of vitrectomy and internal
limiting membrane peeling in the absence of such epimacular
pathology. Past studies examining the role of vitrectomy for
DME have been confounded by design flaws or inadequate
cohorts. We will summarize the existing evidence regarding surgical approaches to treating DME.
149
Whats New in Macular Hole Surgery?

John T Thompson MD
I. Macular Hole Surgery and the Internal Limiting

Membrane (ILM)
III. Choice of Tamponade
There has been a trend toward using shorter acting

gases (air or SF6) rather than C3F8. Another approach
is to use longer-acting gas (C3F8), but to not have the
patient remain prone at all.
A Cochrane meta-analysis of the literature has

strongly suggested that removal of the ILM improves
the rate of macular hole closure.1

A. Cornish and colleagues1 analyzed 4 randomized

trials including stage 2, 3, and 4 macular holes.
ILM peeling was associated with a higher rate of
primary (odds ratio: 9.27) and final (odds ratio:
3.99) macular hole closure (P < .00001).
B. Some stage 2 macular holes can be closed without

ILM peeling, but it is impossible to predict which
will fail, so its best to always peel ILM.
A. Spectral domain OCT of the macular hole through

the gas bubble in the first few days after vitrectomy
has helped us to better understand the rate of closure of macular holes. Most macular holes close
after 24-48 hours of gas tamponade against the
hole.
B. OCT can be used to individualize the duration of

prone positioning, but this requires several office
visits in the first few days. Closure rates of 96.2%
were achieved with a mean prone positioning duration of 42 hours.3
II. Staining ILM to Facilitate Complete Removal:

Options

A. Triamcinolone dusted on macula
Doesnt stain ILM, but allows identification of

where ILM has been removed
IV. Prone Positioning

A. The duration of strict prone positioning has

decreased from the 2 weeks or more of 20-25 years
ago. There are many variations, such as remaining
prone all of the time for from 1 day to as long as
2 weeks, 50% of the time for some duration, no
prone positioning but just avoid looking up, etc.
These different recipes have not been tested in
randomized trials, but Solebo and colleagues3 in a
Cochrane analysis of 3 randomized trials showed
no significant benefit of prone positioning overall
(relative risk ratios of 1.1, 1.58, and 1.03); however,
there was a significant benefit for holes larger than
400 microns (relative risk: 1.2 and 2.27) in two of
the studies.4
B. A New Zealand registry study of 2456 eyes with

macular holes found SF6 noninferior to C3F8 in
the treatment of macular holes 400 microns.5
No conclusion could be made about holes >400
microns.
C. The 2015 Preference and Trends Survey of the

American Society of Retina Specialists asked the
following: How long do you recommend facedown positioning after macular hole repair? In
the United States 11.6% recommended 8-14 days;
47.6%, 5-7 days; 25.9%, 3-4 days; 7.9%, 1-2 days;
and 6.2% felt no prone positioning was needed.6
B. Trypan blue (0.15%)

1. Available as MembraneBlue from DORC
2. Doesnt stain ILM very well, but does stain

epiretinal membranes reasonably well, with an
excellent safety profile
C. Brilliant Blue G (.025%)

1. Available as ILM-Blue from DORC
2. Stains ILM better, but not quite as good as indocyanine green (ICG) in my opinion
3. Excellent safety profile2
4. Available in the United States only from compounding pharmacies
D. Indocyanine green

1. Usually 0.1% concentration
2. Not approved in the United States specifically

for ILM staining
3. Can cause RPE toxicity so must try to avoid

substantial RPE exposure
4. ICG is used by most retinal surgeons in the

United States to stain ILM due to lack of FDAapproved brilliant blue G
E. Combination of trypan blue (0.15%) and brilliant blue G (.025%) as MembraneBlue-Dual from
DORC

1. Again, not available in the United States
2. Stains both ILM and epiretinal membranes
V. Treating Large Myopic or Chronic Macular Holes

Variations on inverted flap ILM technique originally
described by Michalewska use retained ILM around
edge of macular hole to help fill the hole, creating
a scaffold for the glial plug. This technique shows
improved success with successfully closing large macular holes.7,8
150

VI. Nonsurgical Options: Ocriplasmin

A. Intravitreal ocriplasmin in Phase 3 clinical trials

closed 58.3% of macular holes 250 microns and
36.8% >250 and 400 microns, and this was significantly better than intravitreal saline.9
B. A cost-benefit analysis comparing the cost of treating macular holes with ocriplasmin vs. vitrectomy
showed vitrectomy to be more cost-effective (quality adjusted life year = $5444-$7442) compared
to ocriplasmin (quality adjusted life year = $8159$10,244).10
References
1. Cornish KS, Lois N, Scott NW, et al. Vitrectomy with internal
limiting membrane peeling versus no peeling for idiopathic fullthickness macular hole. Ophthalmology 2014; 121(3):649-655.
2. Azuma K, Noda Y, Hirasawa K, Ueta T. Brilliant blue G-assisted
internal limiting membrane peeling for macular hole: a systematic
review of literature and meta-analysis. Retina 2016; 36(5):851858.
3. Yamashita T, Sakamoto T, Yamashita T, et al. Individualized,
spectral domain-optical coherence tomography-guided facedown
posturing after macular hole surgery: minimizing treatment burden and maximizing outcome. Retina 2014; 34(7):1367-1375.

4. Solebo AL, Lange CA, Bunce C, et al. Face-down positioning or
posturing after macular hole surgery. Cochrane Database of Systematic Reviews 2011, Issue 12. Art. No.: CD008228.
5. Essex RW, Kingston ZS, Moreno-Betancur, et al. The effect of
postoperative face-down positioning and of long-versus short-acting gas in macular hole surgery: results of a registry-based study.
Ophthalmology 2016; 123(5):1129-1136.
6. Stone TW. 2015 American Society of Retina Specialists Preference
and Trends Survey, slide 49. www.asrs.org.
7. Michalewska Z, Michalewski J, Dulczewska-Cichecka, K, et al.
Inverted internal limiting membrane flap technique for surgical
repair of myopic macular holes. Retina 2014; 34(4):664-669.
8. Olenik A, Rios J, Mateo C. Inverted internal limiting membrane
flap technique for macular holes in high myopia with axial length
30 mm. Retina. Epub ahead of print 2016 Mar 10.
9. Dugel PU, Regillo C, Elliott D. Characterization of anatomic and
visual function outcomes in patients with full-thickness macular hole in ocriplasmin Phase 3 trials. Am J Ophthalmol. 2015;
160(1):94-99.
10. Chang JS, Smiddy WE. Cost evaluation of surgical and pharmaceutical options in treatment for vitreomacular adhesions and
macular hole. Ophthalmology 2014; 121(9):1720-1726.
151
Gore-Tex Sutured IOLs

Omesh P Gupta MD
eyelet of the CZ70BD lens. For the AO60 lens, the

suture is passed through the first eyelet anterior to
posterior and through the adjacent eyelet posterior
to anterior. This is then repeated on the other side of
the IOL (see Figure 1). For the CZ70BD lens, there
are a variety of methods for minimizing IOL tilt.
I. Introduction

A. Scleral fixation of a posterior chamber IOL may be

performed by the vitreoretinal surgeon for secondary IOL placement,1scleral-sutured posterior chamber, and iris-sutured posterior chamber IOLs, particularly in situations where concurrent pars plana
vitrectomy (PPV) is required, such as retained lens
material, dislocated IOL, or posteriorly subluxed
crystalline lens.
B. The choice of technique is often influenced by the

patients age, anatomical considerations (eg, prior
trauma with iris tissue loss), other ocular comorbidities (eg, glaucoma), and ultimately, surgeon
preference and comfort level.
C. Gore-Tex suture (WL Gore & Associates; Elkton,

MD) traditionally has been used for cardiac and
vascular surgery. It is a nonabsorbable, expanded
polytetrafluoroethylene (ePTFE) monofilament
suture with greater tensile strength and theoretically lower risk of suture breakdown than alternative suture materials, including the commonly used
polypropylene (Prolene, Ethicon Inc.; Somerville,
NJ).
D. Gore-Tex was initially described for IOL suturing

in 1996 by Rosenthal et al, 2 and to date there are
no reported cases of suture erosion or breakdown.
E. Two-point ab externo scleral fixation technique has

been described for combined PPV using a CZ70BD
IOL (Alcon; Fort Worth, TX) and standard vitreoretinal instrumentation.3 A 4-point fixation technique has been described using a Bausch+Lomb
Akreos AO60 (Bausch+Lomb; Bridgewater, NJ)
that results in excellent centration and stabilization.4
Figure 1. Threading of the CV-8 Gore-Tex

suture through the eyelets of the Bausch+Lomb
Akreos AO60 Lens.
II. Surgical Procedure

A. Conjunctival peritomy is performed temporally and

nasally with the standard infusion line away from
these areas. A toric marker can be used mark the
horizontal plane.
B. Four nonbeveled sclerotomies (2 nasal and 2 temporal) are made, centered on the horizontal plane
and parallel to the limbus. For the Akreos AO60
lens, the sclerotomies are 3mm posterior to the
limbus and 4-5 mm apart from each other, and for
the CZ70BD lens, the sclerotomies are 2mm posterior to the limbus and 1.5mm apart.
C. Standard 3-port PPV can be performed using

self-retaining cannulas in the superotemporal and
superonasal sclerotomies.
D. The CV-8 Gore-Tex suture is threaded through adjacent eyelets of the Akreos AO60 lens or the single
E. A clear corneal or scleral tunnel incision is made

to insert the Akreos AO60 lens through a 3.5-mm
wound or the CZ70BD lens though a 7-mm wound.
F. In a hand-to-hand technique, each end of the GoreTex suture is passed into the anterior chamber and
pulled out of each corresponding sclerotomy using
MAXGrip (Alcon Laboratories; Fort Worth, TX)
or similar forceps. The Akreos AO60 IOL can be
folded along its long axis and introduced into the
anterior chamber, while the CZ70BD cannot be
folded. The sutures are tightened and the IOL is
centered. The sutures are tied using a 3-1-1 or slipknot technique. The suture knots are trimmed and
rotated into a sclerotomy. The corneal incisions and
conjunctival peritomies are then closed, taking care
to ensure the Gore-Tex suture is not exposed.
G. For more information, see Roach L. Gore-Tex: an

alternative for fixation sutures. EyeNet Magazine,
www.aao.org/eyenet/article/gore-tex-alternative
-fixation-sutures.
III. One-Year Outcomes

A. Results

1. A total of 132 eyes of 129 patients underwent

combined PPV and scleral fixation of an intraocular lens using Gore-Tex suture, 65 of which
had potential for follow-up of at least 1 year.
2. A total of 40 eyes (23 right eyes, 17 left eyes) of

39 patients (20 males, 19 females) had follow-up
for a minimum of 1 year.
B. Intraoperative and postoperative complications

1. No intraoperative complications were noted.
152

2. Postoperative complications included transient

vitreous hemorrhage in 6 eyes (16%), cystoid
macular edema in 4 eyes (10%), ocular hypertension in 3 eyes (8%), hyphema in 2 eyes (5%),
and corneal edema in 2 eyes (5%). All complications were managed medically with topical
therapy and resolved without additional surgical
intervention. There were no cases of postoperative hypotony, choroidal detachment, endophthalmitis, suture breakage, suture granuloma
formation, IOL dislocation, retinal detachment,
suprachoroidal hemorrhage, uveitis-glaucomahyphema syndrome or persistent postoperative
inflammation in the follow-up period.
C. Imaging
1. Ultrasound biomicroscopy demonstrated no evidence of iris chafe, and the sutures were placed
posterior to the ciliary body.
2. Anterior segment OCT demonstrated minimal

IOL tilt (less than 5), and the lens was confirmed
to be equivalent to an in-the-bag position.
3. Endoscopic vitrectomy demonstrated the IOL

was sitting comfortably away from the iris and
ciliary body. If the Akreos AO60 IOL was laced
as described, the haptics are pulled back away
from the iris.
References
1. Wagoner MD, Cox TA, Ariyasu RG, Jacobs DS, Karp CL. Intraocular lens implantation in the absence of capsular support: a
report by the American Academy of Ophthalmology. Ophthalmology 2003; 110(4):840-859.
2. Rosenthal KJ. A new technique for secondary sutured IOL
implantation utilizing ab externo 6-0 Prolene or CV-8 Goretex
suture on an atraumatic needle without scleral flap creation.
Baylor Welsh Cataract and Refractive Congress; Sept 5-7, 1996;
Houston, Texas.
3. Khan MA, Gerstenblith AT, Dollin ML, Gupta OP, Spirn MJ.
Scleral fixation of posterior chamber intraocular lenses using
Gore-Tex suture with concurrent 23-gauge pars plana vitrectomy. Retina 2014; 34(7):1477-1480.
4. Khan MA, Gupta OP, Smith RG, et al. Scleral-fixation of intraocular lenses using Gore-tex suture: clinical outcomes and safety
profile. Br J Ophthalmol. 2016; 100(5):638-643.
153
Suprachororidal Surgery
Ehab El Rayes MD PhD
The suprachoroidal approach as a route of managing vitreoretinal problems opened a third approach in how we can manage
some of our vitreoretinal problems. The suprachoroidal space
is around 30m between the outer choroidal surface and the
inner sclera. Via this approach we have treated different vitreoretinal diseases in the eye. Accessing this space safely is done
through the scleral cut done to expose the choroid and create a
pocket to enter the space.1
Using Suprachoroidal Space, Current Indications

Creating suprachoroidal buckles (SCB)
Treatment of severe myopic vitreomacular interface problems
(holes and schisis)
We used a suprachoroidal catheter to reach the posterior pole
in the area of staphyloma to close myopic macular holes or
foveoschisis that failed primary vitrectomy procedure. Forty-six
patients with myopic vitreomacular interface disorders were
included: 27 eyes with foveoschisis and 19 eyes with myopic
macular holes, 13 of which had failed primary vitrectomy
before. Twenty-five eyes out of the 27 with foveoschisis (92.5%)
achieved retinal layer restoration. Two eyes showed partial or
quadratic restoration. Sixteen eyes out of the 19 with myopic
macular holes (84.2%) showed closure of the holes with resolution of the detachment. Two holes showed resolution of detachment, flattening of the edges but with uncompleted closure on
OCT. One eye showed failed closure or flattening due to subretinal hyaluronic acid (Perlane) migration.
Four eyes had choroidal hemorrhages subdivided as follows:
1 eye, minimal track hemorrhage, no interference with spontaneous resolution 2 days postop; 3 eyes, macular hemorrhage, 2
of which needed intervention with TPA with resorption, with
no effect on the buckle effect; 1 eye showed spontaneous resolution and displacement of the blood outside the macula, possibly
due to the indentation effect of the buckle.2,3
Managing retinal breaks (peripheral and posterior)
Using a suprachoroidal cannula as well as a catheter, we were
able to create a SCB through the suprachoroidal approach to
treat peripheral retinal breaks as an alternative to scleral buckles. Through a simple sclerotomy you can treat tears 3 clock
hours on either side of the entry site just using the microscope
and chandelier endoillumination. This had fewer problems than
are seen with scleral buckles, such as refractive changes and
muscle imbalance, as well difficult suturing in thin sclera.
Using the Cannula Trial
Retrospective cohort study of 41 eyes of 41 patients undergoing
SCB for the management of rhegmatogenous retinal detachment
(RRD) secondary to single or multiple retinal breaks. Suprachoroidal indentation was achieved through the introduction
of filler material using a 23-gauge olive-tipped, suprachoroidal
cannula. This allowed for the creation of a suprachoroidal dome
and chorioretinal apposition. Healon 5 (Abbott Medical Optics;
Santa Ana, CA) was used as filler material in all eyes. Com-
bined 25-gauge vitrectomy was performed in 5 eyes. Cryopexy

and laserpexy were used in 37 and 4 eyes, respectively.
Results: Mean visual acuity gain was the primary outcome
measure. Final retinal reattachment rate, single-surgery reattachment rate, and complications were secondary outcome
measures. Mean BCVA improved from 20/1100 to 20/42. Single
surgery reattachment rate was 92.7% (38/41 eyes). Final retinal
reattachment was achieved in all 41 eyes (100%). There was
no statistically significant difference in visual acuity gain or
anatomic reattachment in terms of retinal break quadrant or
extent. No major complications were observed. Two localized
suprachoroidal hemorrhages occurred at the entry site for the
cannula. These resolved without further intervention.4
Using the Catheter Trial
Retrospective cohort study of 59 eyes of 59 patients. Subjects
underwent SCB for the management of RRD secondary to
single or multiple retinal breaks. Suprachoroidal indentation
was achieved through the introduction of long-acting viscoelastic material in the suprachoroidal space overlying the break
using an illuminated, 450-m wide, flex-tip, olive-tip catheter.
This allowed for the creation of a suprachoroidal dome and chorioretinal apposition. Forty-seven eyes (80%) underwent SCB
alone, while in 12 eyes (20%) the procedure was combined with
25-gauge PPV. Cryopexy and laserpexy were used in 36 (61%)
and 23 eyes (39%), respectively.
Results: BCVA improved from a mean logMAR 0.84
(20/140) to 0.23 (20/35). Single surgery reattachment rate
was 85% (50/59.) Final retinal reattachment was achieved in
all eyes (100%). No significant differences were observed in
single-surgery anatomic success rates when stratified by procedure type (85% for SCB alone vs. 83% for SB+PPV, P = .3),
lens status (81% phakic vs. 91% pseudophakic, P = .3), macular
involvement (88% for mac-on and 82% for mac-off detachments, P = .5), or location of break (92% vs. 78% for superior
and inferior breaks, respectively, P = .1). There were no major
intra- or postoperative complications.5-7
Drug delivery
Several authors investigated this potential space for delivering
steroids as well as for a drug reservoir.8,9 We used this space to
inject drugs including steroids for refractory edema. We found
this space could act as a reservoir for larger volumes of steroids
as well as acting as a slow-release reservoir. An interesting
point was the smaller incidence of increased IOP compared to
an intravitreal approach. This approach also helps the washout
effect that happens in vitrectomized eyes. There is also a high
choroidal concentration of the drug.10

Treatment of macular edema: diabetic , central retinal

vein occlusion, hard exudates
Treatment of AMD (anti-VEGF + steroid + others )
Targeted chemotherapy delivery
Other potential drug therapies in a slow-release reservoir
including placement of slow-release steroid implants
placed in the suprachoroidal space.
154
Cell and gene therapy

This route of delivery is used to place devices that deliver cells or
genes to the subretinal and subretinal space.
Drainage of the suprachoroidal space
Other than direct scleral cut down to drain hemorrhages, direct
aspiration using a cannula can achieve immediate and almost
complete drainage even in more posterior trapped suprachoroidal blood.
Suprachoroidal space surgical approach is a new operative
route that can tackle different vitreoretinal problems in the eye.
It avoids some of the potential problems of both vitreal and
scleral approaches. Nevertheless there is a learning curve with
the technique; understanding of the anatomy of the space as
well as the nature of the tissues is an important in having safe
surgery and avoiding complications. It does add to our surgical
approaches and options in treating several vitreoretinal problems.
References
1. El Rayes EN. Suprachoroidal buckling. Dev Ophthalmol. 2014;
54:135-146.
2. El Rayes EN. Supra choroidal buckling in managing myopic
vitreoretinal interface disorders: 1-year data. Retina 2014;
34(1):129-135.

3. El Rayes EN, Elborgy E. Suprachoroidal buckling: technique and
indications. J Ophthalmic Vis Res. 2013; 8(4):393-399.
4. El Rayes EN, Mikhail M, El Cheweiky H, Elsawah K,Maia A.
Suprachoroidal buckling for the management of rhegmatogenous
retinal detachment (RRD) secondary to peripheral retinal breaks.
Retina. In press.
5. Mikhail M, El Rayes EN, Kojima K, Ajlan R, Rezende R. Catheter-guided suprachoroidal buckling of rhegmatogenous retinal
detachments secondary to peripheral retinal breaks. Graefes Arch
Clin Exp Ophthalmol. Submitted.
6. El Rayes N, Oshima Y. Suprachoroidal buckling for retinal
detachment. Retina 2013; 33:4.
7. Oshima Y, El Rayes N, Matsumura N, Sakaguchi H. Suprachoroidal buckling technique. Retina Today, May/June 2013.
8. Olsen TW, Ferg X, Wabner K, et al. Cannulation of the supra choroidal space: a novel drug delivery methodology to the posterior
segment. Am J Ophthalmol. 2006; 142:777-787.
9. Rizzo S, Ebert FG, Bartolo ED, et al. Suprachoroidal drug infusion for the treatment of severe subfoveal hard exudate. Retina
2012; 32:766-784.
10. El Rayes E. Suprachoroidal steroid delivery: enforcing our management for refractory macular edema. Retina Today, July/August
2013.
Dislocated IOLs Panel

Tamer H Mahmoud MD, Susanne Binder MD, Jason Hsu MD, Linda A Lam MD,
Yannek I Leiderman MD PhD, Mathew W MacCumber MD PhD
N OTE S
155
156
What Workup Is Indicated for Retinal Vein Occlusion?

Michael Ip MD
I. Epidemiology of Retinal Vein Occlusion

A. Retinal vein occlusion includes central (CRVO),

hemiretinal (HRVO), and branch (BRVO).
B. The 5-year incidence was between 2 to 6 cases per

1000 persons in the Beaver Dam Eye Study.
C. We will discuss other studies such as the Blue

Mountains Eye Study (BMES), the Atherosclerosis
Risk in Communities Study (ARIC), the Beijing
Eye Study, and the Eye Disease Case Control Study,
among others.
II. Risk Factors

A. The multiple risk factors will be discussed.
B. These risk factors include (common): HTN, DM,

glaucoma, cardiovascular disease
C. These risk factors include (less common): serum

homocysteine, antiphospholipid antibody, etc.
III. Modification of Risk Factors
IV. Need for Annual General Health Assessment
V. Need for and Advisability of Targeted Medical

Workup

A. Review of literature presented regarding need for

targeted medical workup
B. Pros discussed
C. Cons discussed
D. Recommendations
Sonothrombolysis
Andrew W Eller MD
I. Introduction

A. Retinal vein occlusion demographics
B. Existing therapies
II. Unmet Medical Need
Occlusion persists to varying degrees.
III. Sonolysis Approach
Principle of cavitation
IV. Preclinical Results
Efficacy and safety in photothrombosis model
V. Clinical Results
Results in subjects with retinal vein occlusion
VI. Conclusions
157
158
Suprachoroidal Triamcinolone Acetonide

Concomitant with IVT Aflibercept:
Phase 2 Retinal Vein Occlusion (RVO) Study
David M Brown MD
N OTE S
Retinal Vein Occlusion Case Panel

H Richard McDonald MD, Sharon Fekrat MD, Szilard Kiss MD, Baruch D Kuppermann MD PhD,
Alice T Lyon MD, Ingrid U Scott MD MPH
N OTE S
159
160
Silicone Oil Droplets Following Intravitreal Injections:

ASRS Adverse Event Reporting
Judy E Kim MD
N OTE S
Scleral Buckle
Sengul C Ozdek MD
This presentation is about transmuscular migration of an encircling band through rectus muscles and straddling of the cornea.
This rare condition has never been reported to be associated
with glaucoma. We describe a unique case with transmuscular
migration of encircling buckle as a probable cause of glaucoma.
A 17-year-old female presented with transmuscular migration
of buckle and high IOP. Limbal/ corneal migration of the silicone band was thought to be the main reason for the IOP rise;
therefore, scleral band removal was performed. One month
after removal, the patient was free of glaucoma medications and
IOP was within normal limits. The retina remained attached
during all postoperative visits. Transmuscular migration of the
encircling band through rectus muscles and straddling of the
cornea may act as a trigger for glaucoma.
161
162
Macular Fold
Fabio Patelli MD
Introduction
Macular fold is a rare and severe complication after surgery for
retinal detachment. When it happens, visual acuity (VA) can
be compromised if the fold is in the fovea and surgery to unfold
the retina is necessary. Vitrectomy in these eyes is very complex
with uncertain anatomical and functional results. Spontaneous
resolution of the fold is described but can take months, with
poor visual outcome.
Case Report
A 65-year-old man underwent vitrectomy for a superior macula
on/off retinal detachment (see Figure 1). At the end of the surgery, gas injection (SF6 20%) was performed. In the postoperative period the patient did not maintain the correct prone position. At the 1-week follow-up the retina was attached, VA was
count fingers (CF), but a macular fold was present (see Figure
2). Ten days after the first surgery a second vitrectomy to unfold
the retina was performed.
Figure 1. Fundus picture of superior bullous retina detachment with

macula on/off.
Figure 2. (a) Fundus picture of macular fold after surgery. (b) OCT image of macular fold involving the fovea.
163
Figure 3. (a, b) Fundus picture and OCT image of macular fold 3 days after surgery for unfolding the macula. (c, d)
Fundus picture and OCT image of macular fold 10 days after surgery for unfolding the macula. (e, f) Fundus picture
and OCT image of macular fold 3 months after surgery for unfolding the macula.
Despite the surgery the macular fold remained, though

smaller than before, and VA remained CF. During the followup a spontaneous and slow resolution of the macula fold was
observed at OCT (see Figure 3), but the VA remained CF.
Macular fold remains a rare but possible complication of retinal detachment. The role of vitrectomy to unfold the retina is
unclear. The surgical technique consists of retina redetachment
at the posterior pole using a 41-gauge needle and subretinal
BSS, retina massage using a backflush, and fluidair exchange
with prone position postop.
Surgery should be done as soon as possible, but even if the
surgery is well done a macular fold could persist. A spontaneous resolution is described with poor visual outcomes if the fold
involves the fovea.
Selected Readings
1. Ruiz-Moreno JM, Montero JA. Sliding macular fold following
retinal detachment surgery. Graefes Arch Clin Exp Ophthalmol.
2011; 249(2):301-303.
2. Ahn SJ, Woo SJ, Ahn J, Park KH. Spontaneous resolution of macular fold following retinal reattachment: morphologic features on
SD-OCT. Ophthalmic Surg Lasers Imaging. 2011; 42.
3. El-Amir AN, Every S, Patel CK. Repair of macular fold following retinal reattachment surgery. Clin Experiment Ophthalmol.
2007; 35(9):791-792.
4. Witkin AJ, Hsu J. Surgical repair of macular fold after vitrectomy
for bullous rhegmatogenous retinal detachment. Retina 2012;
32(8):1666-1669.
164
Epiretinal Membrane Peeling

Jay S Duker MD
N OTE S
165
Staining
Andrs Bastien MD
The internal limiting membrane (ILM) is a basement membrane

for the Mller cells of the retina. Cellular proliferation on the
ILM can cause distortion of the membrane and can lead to the
formation of epiretinal membranes (ERM) and macular holes
(MH). The removal of the ILM can help to cure both pathologies (ERM/MH),1-5 but the transparent nature of ILM makes it
very difficult to peel.
We can improve the poor visibility using several stains, like
indocyanine green (ICG) and trypan blue (TB),6-9 but several
papers have noted the potential retinal toxicity of both adjuvants.10-12 The brilliant blue G (BBG), known as acid blue 90
and Coomassie brilliant blue G250, has been used to stain proteins in biological testing. Enaida et al were the first to publish
BBGs advantages, like high staining ability, high safety, high
affinity to ILM, and low affinity to ERM.13-16
We present a case of a 64-year-old man with decreased
visual acuity and metamorphopsias. He had an idiopathic
ERM, and the BCVA was 20/60. Vitrectomy was done through
a standard 3-port pars plana approach using the Accurus system (Alcon/ Grieshaber; Fort Worth, Texas), then 0.20 mL of
0.25 mg/mL BBG was injected through a soft-tip silicon cannula onto the posterior pole and the ERM was peeled using a
ILM forceps. Then we decided to reinject BBG in order to stain
the ILM; a subretinal collection of BBG was detected in extratemporal fovea localization, and the surgeon decided to leave
it there and finish the surgery. Subretinal BBG was present for
2 days, and after 10 days no signs of BBG were observed. The
visual acuity was 20/40 with improvement in metamorphopsia
and OCT after 6 months postoperatively; some RPE defects
were found, especially in the zone where the BBG subretinal
deposit was.
The Pan American Collaborative Retina Study Group
(PACORES Group) put together 14 cases with accidental subretinal BBG from different surgeons. In all cases the initial
postoperative visual acuity was poor but improved with time.
The principal cause of damage was the jet stream with possible
traumatic damage to RPE.17
Several problems can occur with subretinal injection of
ICG, like retinal degeneration, retinal pigment epithelial (RPE)
atrophy after 2 weeks, and apoptotic cell death in the inner and
outer nuclear layers, especially the photoreceptors. Trypan blue
causes less retinal degeneration; BBG has no detectable toxic
effects after 2 months.15 In order to avoid this complication we
can inject the dye decreasing the IOP; inject over the light pipe;
with dual bore cannula or to make a mixture with BBG and
sodium hyaluronate.18
References
1. Park DW, Dugel PU, Garda J, et al. Macular pucker removal with
and without internal limiting membrane peeling: pilot study.
Ophthalmology 2003; 110:62-64.
2. Bovey EH, Uffer S, Achache F. Surgery for epimacular membrane:
impact of retinal internal limiting membrane removal on functional outcome. Retina 2004; 24:728-735.
3. Kwok A, Lai TY, Yuen KS. Epiretinal membrane surgery with or

without internal limiting membrane peeling. Clin Experiment
Ophthalmol. 2005; 33:379-385.
4. Oh HN, Lee JE, Kim HW, Yun IH. Clinical outcomes of double
staining and additional ILM peeling during ERM surgery. Korean
J Ophthalmol. 2013; 27:256-260.
5. Sandali O, Sanharawi M, Basli E, et al. Epiretinal membrane
recurrence: incidence, characteristics, evolution and preventive
and risk factors. Retina 2013; 33:2032-2038.
6. Burk SE, Da Mata AP, Snyder ME, Rosa RH Jr, Foster RE. Indocyanine green-assisted peering of the retinal internal limiting
membrane. Ophthalmology 2000; 107(11):2010-2014.
7. Kadonosana K, Itoh N, Uchio E, Nakamura S, Ohno S. Staining
of internal limiting membrane in macular hole surgery. Arch Ophthalmol. 2000; 118(8):1116-1118.
8. Feron EJ, Veckeneer M, Parys-Van Ginderdauren R, Van Lommel A, Meller GR, Stalmans P. Trypan blue staining of epiretinal
membranes in proliferative vitreoretinopathy. Arch Ophthalmol.
2002; 120(2):141-144.
9. Perrier M, Sebag M. Trypan blue-assisted peeling of the internal
limiting membrane during macular hole surgery. Am J Ophthalmol. 2003; 135(6):903-905.
10. Kawaji T, Hirata A, Inomata Y, Koga T, Tanihara H. Morphological damage in rabbit retina caused by subretinal injection of
indocyanine green. Graefes Arch Clin Exp Ophthalmol. 2004;
242(2):158-164.
11. Rezai KA, Farrokh-Siar L, Ernest JT, van Seventer GA. Indocyanine green induces apoptosis in human retinal pigment epithelial
cells. Am J Ophthalmol. 2004; 137(5):931-933.
12. Rezai KA, Farrokh-Siar L, Gasyna EM, Ernest JT. Trypan blue
induces apoptosis in human retinal pigment epithelial cells. Am J
Ophthalmol. 2004; 138(3):492-495.
13. Enaida H, Hisatomi T, Goto Y, et al. Preclinical investigation of
internal limiting membrane peeling and staining using intravitreal
brilliant blue G. Retina 2006; 26(6):623-630.
14. Hisatomi T, Enaida H, Matsumoto H, et al. Staining ability and
biocompatibility of brilliant blue G: preclinical study of brilliant
blue G as an adjunct for capsular staining. Arch Ophthalmol.
2006; 124(4):514-519.
15. Ueno A, Hisatomi T, Enaida H, et al. Biocompatibility of brilliant blue G in a rat model of subretinal injection. Retina 2006;
27(4):499-504.
16. Enaida H, Hisatomi T, Hata Y, et al. Brilliant blue G selectively
stains the internal limiting membrane/brilliant blue G-assisted
membrane peeling. Retina 2006; 26(6):631-636.
17. Maia M, et al. Subretinal brilliant blue G migration during internal limiting membrane peeling. Br J Ophthalmol. 2009; 93:1687.
18. Uemoto R, Nakasato-Sonn H, Meguro A, Ito N, Yazama F,
Mizuki N. Staining internal limiting membrane with a mixture of
BBG and sodium hyaluronate. Br J Ophthalmol. 2013; 97(6):690693.
166
Giant Retinal Tear Detachment

Homayoun Tabandeh MD MS FRCP FRCOphth
A 62-year-old pseudophakic myopic male presented with a

2-week history of blurred vision, loss of nasal visual field, and
severe floaters in the left eye. On examination the BCVA was
20/70. Dilated funduscopy showed extensive vitreous pigment
clumps and haze. Retinal detachment was present involving
the supratemporal and inferotemporal quadrants. A giant retinal tear (GRT) extended from approximately 1.0 to 5 oclock
meridians.
The patient underwent 23-gauge pars plana vitrectomy, perfluorocarbon liquid (PFCL), and endolaser photocoagulation.
Airfluid exchange was performed; care was taken to remove
the peripheral meniscus of fluid around the PFCL bubble before
proceeding to remove PFCL. Once PFCL was removed, slippage
and circumferential folding of temporal retina was noted. Subretinal fluid was trapped under the area of slippage/ fold.
In the setting of GRT-associated retinal detachment, slippage of the retina occurs following airPFCL exchange. Retinal
slippage may result in long-term retinal folds and may compromise the effectiveness of retinopexy. Removal of the peripheral
meniscus of fluid around the PFCL bubble with frequent drying
of the edge of the GRT helps reduce the chances of slippage.
However, despite these maneuvers, fluid may track to the subretinal space, predisposing to slippage. Trapped peripheral subretinal fluid in the quadrant adjacent to the GRT may also contribute to slippage. Direct silicone oilPFCL exchange reduces
the chances of slippage.
Once slippage occurs, attempts at drying the edge of the

GRT does not usually succeed since the fluid is trapped posterior to the rim of attached retina. Postoperative positioning may
unfold the retina in some cases. Removal of subretinal fluid
through a drainage retinotomy reduces the amount of fluid;
however, it does not address retinal folding and slippage. Intraoperative management of retinal slippage requires removal of
the subretinal fluid with simultaneous unfolding of the retina.
Reinjection of PFCL unfolds the retina and displaces the subretinal fluid. Slippage may occur again, once the PFCL is removed.
The current presentation illustrates a technique whereby a
soft tip cannula is placed within the subretinal space, partially
engaging the retina. The retina is gently pulled peripherally,
unfolding the retina, while simultaneously aspirating the subretinal fluid. Once the fluid is removed, the slippage does not
recur.
Financial Disclosure
167
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resolved.
Portion of the meeting not eligible for credit include attending Break with the Experts.
Gary W Abrams MD
Carl C Awh MD
Retrosense Therapeutics Inc.: C,P,S
Alimera Sciences Inc.: C

Allergan: L,C
Bausch+Lomb: C
Genentech: L,C
Liberty Biosecurity: O
Merck & Co. Inc.: C
Metro Midwest Biotech: O
Ophthotech: O,C
Regeneron Pharmaceuticals Inc.: L,C
Research to Prevent Blindness: S
Washington University: P

ArcticDx Inc.: C,O
Bausch+Lomb: C,P
Genentech: C
GlaxoSmithKline: S
Katalyst: C,O
Ohr Pharmaceuticals: S
Ophthotec: S
Regeneron Pharmaceuticals Inc.: S
Roche Diagnostics: S
Tyrogenex: S
Volk Optical: C
Alay S Banker MD
None
EyEngineering Inc.: C
Springer SBM LLC: P
Jorge G Arroyo MD
Novartis Pharmaceuticals
Corporation: C
Santen, Inc.: C
Allergan: C,L
Atrus Therapeutics: O
Genentech: C,L
None
Andres I Bastien MD
Robert L Avery MD
Allergan: L
Bayer Healthcare Pharmaceuticals: L
Novartis Pharmaceuticals Corp.: C
Anita Agarwal MD
None
Hamid Ahmadieh MD
None
Lloyd P Aiello MD PhD

Genentech: C
Kalvista: C
Roche Diagnostics: C
Sanofi Fovea: C
Thomas A Albini MD
Allergan: C,L
Inflammasome Therapeutics: O
iVeena Delivery: O
iVeena Holdings: O
iVeena Pharma: O
Olix Pharmaceuticals Inc.: C

Alimera Sciences Inc.: C,O
Allergan: C
Bausch+Lomb: C
Genentech: C,S
Notal Vision Inc.: C
Novartis Pharmaceuticals Corp.:
C,L,O
Regeneron Pharmaceuticals Inc.: C,O
Replenish: C,O,P
Disclosures current as of 9/23/2016

Check the Mobile Meeting Guide / Online Program for the most up-to-date financial disclosures.
Caroline R Baumal MD
Allergan: C
Francine Behar-Cohen, MD
None
Audina M Berrocal MD
DORC International, bv/Dutch
Ophthalmic, USA: L
Visunex: C
169
Maria H Berrocal MD
David M Brown MD
Alcon Laboratories Inc.: L,C

Alimera Sciences Inc.: L
Allergan: L
Regeneron Pharmaceuticals Inc.: O

Alimera Sciences Inc.: C,S
Allergan: C,S
Avalanche: C
Genentech: C,S
Heidelberg Engineering: C
Optos Inc.: C
Quantel Medical: C
Santen Inc.: C,S

Allergan: C,S
Aura Biosciences: S
FocusROP: O
Genentech: S
Iconic Therapeutics: S
Ohr Pharmaceuticals: S
Otsuka Pharmaceutical Co.: S
Retinal Solutions: O,P
Spark Therapeutics: C
Aerpio: S
Diabetic Retinopathy Clinical
Research: S
Genentech: S
Novartis Pharmaceuticals Corp.: S
Pfizer Inc.: S
Regeneron Pharmaceuticals: S

Allergan: C
Novartis Pharmaceuticals Corp.: L,C
Roche: S
Susanne Binder MD
None
Barbara Ann Blodi MD

None
Adverum Biotechnologies: O,P
Combangio: O,P
Digisight Technologies: O,P,C
Lagunita Biosciences: O,C
Oculeve Corp.: O
Optimedica Corp.: P,O
David S Boyer MD
Aerpio: C
Allegro: C
Allergan: C,L
Bausch+Lomb: C
Genentech: C
Glaukos Corp.: C
Hoffman La Roche, Ltd.: C
Lpath Inc.: C
Neurotech: C
Ohr Pharmaceuticals: C
Optovue: C
Regeneron Pharmaceuticals Inc.: C
Santen Inc.: C
Taiwan Liposomal Company: C
Alexander J Brucker MD
Alcon: S
DRCR.net: S
Genentech: S
GSK: S
Mercke: S
Ophthotech: O,S
Regeneron Pharmaceuticals Inc.: O,S
Brandon G Busbee MD
Aerpio Therapeutics: C
Akorn Inc.: P
Genentech: C
Valeant: C,P
Neil M Bressler MD
Bayer Healthcare Pharmaceuticals: S

Genentech: S
Lumenis, Inc.: S
Novartis Pharmaceuticals Corporation: S
Regeneron Pharmaceuticals, Inc.: S
AbbVie: S
Aerpio: C,S
Allegro: C,O
Allergan: S
Applied Genetic Technologies: C
AsclipiX: C
Genentech: C,S
Genzyme: S
GlaxoSmithKline: S
Graybug: O,P
Intrexon: C
Oxford BioMedica: S
Regeneron: C,S
RegenX Bio: C,S
Roche: C,S
Rxi: C
Susan B Bressler MD
Boehringer Ingelheim GmbH: S
Notal Vision Inc.: S

Clement K Chan MD
Acucela: S
Allergan: C,S
GENENTECH: C,S
National Eye Institute: C,S
Ophthotec: S
Regeneron Pharmaceuticals, Inc: S
Theratechnologies Inc: S
R V Paul Chan MD
Allergan: C
Bausch+Lomb: C
Visunex Medical Systems: C
Stanley Chang MD
Steven T Charles MD
Alcon Laboratories Inc.: C,P
Felix Y Chau MD
National Eye Institute: S,P
Emily Y Chew MD
None
David R Chow MD
Allergan: C,L
Bausch+Lomb: L
Ophthalmic, USA: L
Katalyst: C
Optovue: L
Synergetics Inc.: P
170
Jay S Duker MD
Dean Eliott MD
None
Allergan: C
Aura Biosciences: C
CoDa Therapeutics: C
Eleven Biotherapeutics: C
Hemera Biosciences: O
Lumenis Inc.: C
Ocudyne: C
Omeros: C
Ophthotech: C
Optovue: C
Santen Inc.: C
ThromboGenics Inc.: C
Topcon Medical Systems Inc.: C

Allergan: C
Ophthalmic, USA: C
Neurotech: S
Ocata Therapeutics: S
Ophthotech: C
Santen Inc.: C
Jacque L Duncan MD
Sharon Fekrat MD
AGTC: C
Avalanche Biotechnologies Inc.: C
California Institute for Regenerative
Medicine: C,S
Foundation Fighting Blindness: C,S
Ionis Pharmaceuticals Inc.: C
Neurotech USA Inc.: S
Ocugen Inc.: C
Okuvision: C
QLT Phototherapeutics Inc.: C
Shire Human Genetic Therapies Inc.: C
Alcon Laboratories Inc.: P

Prana: C
Regeneron Pharmaceuticals Inc.: L

Ophthotech Inc.: O
James Philip Dunn Jr MD
K Bailey Freund MD
Abbvie: C,L
Claus Eckardt MD
AbbVie: C
Sanofi Fovea: S

Ophthalmic, USA: P
Diana V Do MD
Justis P Ehlers MD

DigiSight: C
Genentech: C
Optos Inc.: C
Optovue: C
Allergan: C,S
Clearside: C
Genentech: C,S
Santen Inc.: C,S
Thomas W Gardner MD MS
Allergan: C
FocusROP: O
Retinal Solutions: O

Bioptigen: C,P
Genentech: S
Leica: C
Ohio Department of Development: S
Santen Inc.: C
Synergetics Inc.: P
Thrombogenics: C,S
Pravin U Dugel MD
Ehab N El Rayes MD PhD
Mark C Gillies MD PhD
Dose Medical: C
Graybug Vision: C
Optos: C
Shire Human Genetic Therapies: C

Ophthalmic, USA: C
Medone Surgical: P
Allergan: C,L,S
Bayer Healthcare Pharmaceuticals:
C,L,S
Novartis Pharmaceuticals Corp.: C,L,S
Opthea: C
Mina Chung MD
GlaxoSmithKline: C
Lowry Med Res: S
Santen Inc.: C
VirtualScopics: C
Carl C Claes MD
Scott W Cousins MD
None
Karl G Csaky MD
Allergan: C
Genentech: C,L
GlaxoSmithKline: C
Ophthotech: O,C
Santen Inc.: C,S
Emmett T Cunningham Jr MD
PhD MPH
None
Donald J DAmico MD
Kimberly A Drenser MD PhD

Andrew W Eller MD
None
Amani Fawzi MD
None
Harry W Flynn Jr MD
None
Allergan: C
Genentech: C
Neurovision: C,O
Spinnaker Biosciences: L
Kalvista: C
Novo Nordisk: C,S
Sunir J Garg MD FACS

Aldeyra: S
Allergan Inc.: C,S
Centocor Inc.: S
Deciphera: C
EyeGate Pharmaceuticals Inc.: S
Genentech: L
171
Debra A Goldstein MD
Tarek S Hassan MD
AbbVie: C
Allergan: C
Bausch+Lomb: C
Clearside: C
pSivida: C
Santen Inc.: C

Allergan: C
ArcticDx Inc.: C,O
Genentech: C
Insight Instruments: C,P
Ocugenix: C
1Co. Inc.: C,O,P

Aquesys: C
Clearside: C,O
Eyemedix: C,O,P,S
InnFocus: C,O
Iridex: P
oProbe: C,O,P
Reflow: C,O,P
Regenerative Patch Technologies (RPT):
C,O,P
Replenish: C,O,P
Second Sight Medical Products Inc.:
C,O,P
Justin Gottlieb MD
None
Evangelos S Gragoudas MD
Aura Biosciences: C
Iconic Therapeutics: C
Ocata Therapeutics: C
Valeant Pharmaceuticals: P
M Gilbert Grand MD
None

None
Omesh P Gupta MD
None
Julia A Haller MD
Celgene: O
Janssen: C
KalVista: C
Merck & C: C
ThromboGenics: S
Lawrence S Halperin MD
Dennis P Han MD
Acucela Inc.: S
Alkeus Pharmaceuticals Inc.: S
FlowOne, LLC: C
Neurotech USA Inc.: S
Tyrogenex Inc.: C
Castle Biosciences Inc.: P,C
Mary Elizabeth Hartnett MD

FACS
Jeffrey S Heier MD
Acucela: S
Aerpio Therapeutics: C
Allegro Ophthalmics: C
Allergan: C
Apellis: S
Astellas: S
Chengdu Kanghong Biotech: C
Corcept: S
EyeGate Pharmaceuticals Inc.: S,C
Genentech: S,C
Genzyme: S
Johnson & Johnson: S,C
Kala Pharmaceuticals: S,C
Neurotech: S
Ocudyne: S
Ocular Therapeutix: O
Ophthotech: S
Quark Pharmaceuticals: C
Regeneron Pharmaceuticals Inc.: S,C
RetroSense: C
SciFluor: C
Stealth Biotherapeutics: S,C
Tyrogenex: S
Valeant Pharmaceuticals: C
Voyager Therapeutics: C
Allen C Ho MD
Second Sight Medical Products Inc.: C,S
Nancy M Holekamp MD
Allergan: C,L,S
Genentech: C,L,S
Katalyst: C,P
Neurotech: S
Regeneron: L,C
Jason Hsu MD
Genentech: S
Ophthotech Inc.: S,C
Optovue: C
Santen Inc.: S
UCB: C
Deeba Husain MD
None
Raymond Iezzi MD
Michael S Ip MD
Boehringer Ingelheim: C
Omeros: C
Quark: C

None
Glenn J Jaffe MD
Abbott: C
Neurotech: C
Lee M Jampol MD
Janssen Pharmaceuticals: C
Mark W Johnson MD
Hoffman La Roche, Ltd.: S
Tyrogenex: C
J Michael Jumper MD
Allergan: S
Covalent Medical: O
Ophthalmic, USA: C,L
Genentech: S
Ophthotech: S
172
Peter K Kaiser MD
John W Kitchens MD
Linda A Lam MD
Aerpio: C
Alcon Laboratories, Inc.: C,L
Allegro: C
Bayer Healthcare Pharmaceuticals: C,L
Biogen Inc: C
Digisight: C
Kanghong: C
Novartis Pharmaceuticals Corporation:
C,L
Ohr: C,O
Omeros: C
ONL Therapeutics: C
Ophthotech: C,L,O
Regeneron Pharmaceuticals Inc.: C,L
Santen: C
SciFluor Lide Sciences: C
Shire: C
Thrombogenics: C

Allergan: C
Bausch+Lomb: C
Genentech: S
Optos Inc.: C
None
Adrian H Koh MD
Richard S Kaiser MD
Alcon Laboratories, Inc.: C

Allergan: C,L
Bayer Healthcare Pharmaceuticals: L,C
Carl Zeiss Meditec: C,L
Heidelberg Engineering: C,L
Novartis Pharmaceuticals Corporation:
C,L
Santen, Inc.: C
Topcon Medical Systems Inc.: C,L
Neurotech: C
Pan Optica: C
Gregg T Kokame MD
Thomas C Lee MD
None
Yannek I Leiderman MD PhD

Ophthalmic, USA: C
Genentech: C,L
Johnson & Johnson: C
Regeneron Pharmaceuticals Inc.: C,L
Theodore Leng MD
Allergan: S
Genentech: C,S
Jennifer Irene Lim MD
Astellas Pharmaceuticals Inc.: C

Carl Zeiss Meditec: C,L,S
Regenerative Patch Technologies Inc.: S
Reichert Technologies Inc.: S
Bausch+Lomb: C,L
Genentech: S
Heidelberg Engineering: L
Humphrey Zeiss: C
AbbVie: C
Genentech: C,L,S
Icon Bioscience: C,S
Lumenis Inc.: C
Pfizer Inc.: C
Santen Inc.: C
Ivana K Kim MD
Derek Y Kunimoto MD JD
Ann-Marie Lobo MD

Allergan: C
Biophytis: C
Genentech: S
Iconic Therapeutics: C
Bausch+Lomb: C
Ophthalmic, USA: C
Scottsdale Eye Surgery Center: O
Judy E Kim MD
Aerpio: C
Allegro: C,S
Ampio: C
Apellis: S
Dose: C
Genentech: C,S
Glaukos Corp.: C
GlaxoSmithKline: S
Neurotech: C
Ophthotech: C,S
Abbott: C
Allergan: C
Bausch+Lomb: C
Clearside: S
Santen Inc.: C
Visunex: C
Bausch+Lomb: C
Notal Vision, Inc.: S
Corporation: L
Optos, Inc.: S
Rosa Y Kim MD
None
Szilard Kiss MD
Allergan: C,S
Genentech: C,S
Neurotech: C
Optos Inc.: C
Baruch D Kuppermann MD PhD
Brenda Laigaie JD
None

Anat Loewenstein MD
Allergan Inc.: C,L
Bayer: C,L
ForSight Lab: C
Notal Vision, Ltd.: C
Novartis Pharmaceuticals Corp.: C,L
Alice T Lyon MD
Genentech: S
National Eye Institute: C
Mathew W MacCumber MD PhD
Andrew A Moshfeghi MD MBA
Kirk H Packo MD

Allergan: S
Covalent Medical: O
Genentech: C,S
Neurotech, USA: S
Optos Inc.: S
Regeneron: C,S
StemCells Inc.: S
Thrombogenics: C,S

Allergan: C
Genentech: C
OptiStent: O
Optos Inc.: C
Versl: C,O
Visunex: C,O
Abbott Medical Optics Inc.: S

Alcon Laboratories Inc.: C,L,S
Alimera Sciences Inc.: C,L,S
Allergan: S
Covalent Medical: O
Genentech: S
Mobius: S
Optoview: S
US Retina: O
Vision Care Inc.: S

Ophthalmic, USA: C
Alcon Laboratories, Inc.: C,L

Clarity Medical Systems, Inc.: L
Genentech, Inc.: C
Grand Legend Technology, LTD: C,O
Iconic Therapeutics, Inc.: C
InSitu Therapeutics, Inc.: C,O,P
Oraya Therapeutics, Inc.: C,O
Promisight, Inc.: O
Synergetics, Inc.: C
Versl, Inc: O,C
Visunex Medical Systems, Co. Ltd.: C,O
Mauricio Maia MD
Timothy G Murray MD MBA
Fabio Patelli MD
None
None
Quan Dong Nguyen MD
Grazia Pertile MD
Genentech: L
AbbVie: S
Allergan: C
Bausch Lomb: C
GENENTECH: S, C
Oligasis: C
Psivida: S
Regeneron Pharmaceuticals Inc.: C, S
Santen, Inc.: C
XOMA: S
None
Impact Genetics: C
Corporation: C
Timothy W Olsen MD
None
H Richard McDonald MD
Murat Oncel MD
None
None
Sengul C Ozdek MD
AbbVie: C,S
Santen Inc.: C,S
Allergan: C
Novartis Pharmaceuticals Corp.: L,C

NightstarX LTD: C,E,O,P
University of Oxford: E,P
Albert M Maguire MD
Spark Therapeutics: S
Tamer H Mahmoud MD
Daniel F Martin MD
None
Colin A McCannel MD
Ophthalmic, USA: C,L
GENENTECH: S
Tara A McCannel MD
William F Mieler MD
None
Yuki Morizane
Genentech: S
Imacular Regeneration: O
Andrew J Packer MD
None
None

173
Susanna S Park MD PhD

Allergan: S
Genentech: S
David W Parke II MD
OMIC-Ophthalmic Mutual Insurance
Company: C
Dante Pieramici MD
Allergan: S,L
Genentech: C,L,S
Johnson & Johnson: S
Santen Inc.: C,S
Carmen A Puliafito MD MBA

Jose S Pulido MD MS
None

Abbott: C
Acucela: S
Aerpio: C
Allergan: C,S
Bausch+Lomb: C
Genentech: C,S
GlaxoSmithKline: S
Notal Vision Inc.: C,S
174
Elias Reichel MD
Ursula M Schmidt-Erfurth MD
Akorn Inc.: P
Boston Image Reading Center: O
Eleven Biotherapeutics: C,O
EyeGate: C
Hemera Biosciences: O
Iconic: C
Kala: C
Lutronic: C
Ocular Instruments Inc.: P
Ophthotech: O
Panoptica: C,O

Boehringer Ingelheim Pharmaceuticals
Inc.: C
Genentech: C
None
Acucela: S,C
Apellis: O,C,S
Archillion Pharmaceuticals: C
Astellas Institute for Regenerative
Medicine (AIRM): C,S
Boehringer-Ingelheim: C
Carl Zeiss Meditec: C,S,L
Cell Cure Neurosciences: C
Chengdu Kanghong Biotech: C
CoDa Therapeutics: C
Digisight: O
Genentech: C,S
GlaxoSmithKline: S
Healios KK: C
Hemera Biosciences: C
MacRegen: C
NGM Biopharmaceuticals: C
Ocudyne: C,O
Tyrogenex: C,S
Stanislao Rizzo MD
Taiji Sakamoto MD PhD
None
Alcon Laboratories Inc.: L

Bausch+Lomb: C
Bayer Healthcare Pharmaceuticals: L,C
Novartis Pharmaceuticals Corp.: L
Santen Inc.: L
Senju: C
Kourous Rezaei MD
Bryn Mawr Communication: C
Covalent: O
Ophthotech: E,O

Allergan: C
Allomind: C
Mini Pumps LLC: P
NeuroRecovery Technologies: P
Second Sight Medical Products Inc.: P
Richard B Rosen MD
Allergan: S
Clarity: C
Genentech: S
Nano Retina: C
Ocata: C
Optovue: C
Reginald J Sanders MD
None
David Sarraf MD
Allergan: S
Genentech: C,S
Optovue: S,C,L
Regeneron: S
Andrew P Schachat MD
American Academy of
Ophthalmology: C
AnGes: C
Cleveland Clinic Foundation: E
Easton Capital: O
Elsevier: P
State of Ohio: E

Hendrik P Scholl MD
Genentech: C
Sanofi Fovea: C
Steven D Schwartz MD
Allergan: C,S
Avalanche: O
Bausch+Lomb: S,L
Genentech: C,S
OptiMedica: S
Optos Inc.: C,S
Ingrid U Scott MD MPH

Thrombogenics: C
J Sebag MD FACS FRCOphth

FARVO
None
Gaurav K Shah MD
Allergan: C,S
QLT Phototherapeutics Inc.: L
Carol L Shields MD
Aura Bioscience: C
Jerry A Shields MD
None
Arun D Singh MD
None
Rishi P Singh MD
Alcon Laboratories, Inc.: C,S
Biogen Inc: C
GENENTECH: C,S
Optos, Inc.: C
Regeneron Pharmaceuticals, Inc.: C,S
Shire: CAura Bioscience: C
Jason S Slakter MD
Paulo E Stanga MD
John T Thompson MD
Ampio: S
aTyr: S
Aura: S
Bayer HealthCare: L,S
Genentech: S,C
GlaxoSmithKline: S
Johnson & Johnson: C,S
Lpath Inc.: C,S
Ocucure: S
Ohr Pharma: E,O,S
Oraya Therapeutics: C,S
Regeneron Pharmaceuticals: C,S
Sanofi-Aventis: S
Santen Inc.: S
SKS Ocular, LLC: O
Tyrogenix: C,S
Allergan: C,L
Bausch+Lomb: C,L,S
Optos Inc.: C,L,S
Second Sight Medical Products Inc.:
C,L,S
Second Sight: L
ThromboGenics Ltd: C,L
Topcon Medical Systems Inc.: C,L,P,S
Genentech: S
Regeneron Pharmaceuticals: S
Kent W Small MD
None
Elliott H Sohn MD
GlaxoSmithKline: S
Oxford Biomedica: S
Regeneron: S
Gisele Soubrane MD PhD

None
Richard F Spaide MD
Bausch+Lomb: C
Topcon Medical Systems Inc.: C,P
Karthik Srinivasan
None
Sunil K Srivastava MD
Allergan: S
Bausch+Lomb Surgical: C,S
Bioptigen: P
Carl Zeiss Inc.: C
Optos Inc.: C
Sanofi Fovea: C
Santen Inc.: C,L
Synergetics Inc.: P
Peter W Stalmans MD PhD

Bausch+Lomb: C
Carl Zeiss Inc.: C
Ophthalmic, USA: C
Nano-Retina: C
Vitreq: C
Giovanni Staurenghi MD
Allergan: C
Centervue: L,S,C
Genentech: C
Heidelberg Engineering: C,L,S
Optos Inc.: C,S
Optovue: L,S
Roche: C
Zeiss: C,S
Cynthia A Toth MD
Alcon Laboratories Inc.: P
Hemosonics: P
Research to Prevent Blindness: S
The Hartwell Foundation: S
The James Andrew Family Charitable
Foundation: S
The Triangle Community Foundation: S
Michael T Trese MD
Digisight: O
Focus ROP: C,O
Retinal Solutions LLC: C,O
James F Vander MD
None
Demetrios Vavvas MD
None
Jennifer K Sun MD
Boston Micromachines: S
Genentech: S
Corporation: C
Optovue: S
Vindico Medical Education: L
None
Homayoun Tabandeh MD MS
FRCP FRCOphth
Alimera Sciences Inc.: O
Allergan: S
Ophtec: S
Hiroko Terasaki MD
Alcon Laboratories Inc.: L,S
Bayer Healthcare Pharmaceuticals: L
Carl Zeiss Meditec Co., Ltd: L
Hoya Corp.: S
Kowa: L,S
Nidek Inc.: P,L,S
Novartis Pharmaceuticals Corp.: L,S
Otsuka Pharmaceutical Co., Ltd.: L,S
Pfizer Inc.: L,S
Rohto Pharmaceutical Co., Ltd.: L
Santen Inc.: L,S
Senju: L,S
Wakamoto: L,S

175
Nadia Khalida Waheed MD

Carl Zeiss Meditec: S
Genentech: C
Nidek Inc.: L
Optovue: L
John A Wells III MD

Aerpio: S
Allergan: S
Emmes: S
Genentech: S
Iconic Pharmaceuticals: C,S
Jaeb Center for Health Research: C,S
KalVista: S
LPath Inc.: S
Neurotech: S
Ophthotech Corp.: S
Optos Inc.: S
Panoptica: C,S
Regeneron : S
176
Charles C Wykoff MD PhD
Young Hee Yoon MD

Allergan Inc.: C,S
Covalent Medical: O
ForSight: C,O
Johnson & Johnson: C
OMIC-Ophthalmic Mutual Insurance
Company: E
OptiMedica: C,O
Retrosense: C,O
ThromboGenics: C,O
Vitamin Health: C

Allergan: C,L,S
Bayer: C,L,S
Allergan Singapore Pte Ltd: C,L

Allergan Inc.: C,L
Bayer Healthcare Company Ltd.: C,L,S
Bayer Healthcare Pharmaceuticals Inc.:
C,L,S
Novartis Pharma AG: C,L,S

Allegro Ophthalmics: S
Allergan: C,L,S
Apellis Pharmaceutical: S
Bayer Healthcare Pharmaceuticals: C,S
Clearside: C,S
Ophthalmic, USA: C
DRCR.network: S
Genentech: C,S
Iconic Therapeutics: S
ONL Therapeutics: C
Ophthotech Corp: S
Regeneron: C,L,S
ThromboGenics Inc.: C,S
Lihteh Wu MD
Lawrence A Yannuzzi MD
Bayer Health: C,L

Heidelberg Engineering: L
Quantel Medical: C,L
None
Tien Yin Wong MBBS

Lucy H Young MD PhD FACS

None

Calhoun Vision Inc.: C
EyEngineering: C
Genentech: C
Helios, KK: C
Makindus: C
Ophthotech Inc.: C
Rutgers University: P
Presenter Index
Presenter Index
Abrams*, Gary W 8
Agarwal, Anita 61
Ahmadeh, Hamid 130
Albini, Thomas A 61
Almeida*, David 64
Ambati*, Jayakrishna 142
Apte*, Rajendra S 148
Arroyo, Jorge G 3
Avery*, Robert L 10
Banker, Alay S 103
Bastien*, Andrs I 165
Baumal*, Caroline R 11
Behar-Cohen, Francine 40
Berrocal, Audina M 68
Berrocal*, Maria H 6
Binder, Susanne 155
Brown*, David 158
Browning*, David J 104
Brucker*, Alexander J 140
Campochiaro*, Peter A 127
Capone*, Antonio 68
Chakravarthy*, Usha 50, 134
Chan, Clement K 101
Chan*, R V Paul 65
Chang*, Stanley 4
Charles*, Steven T 2
Chau*, Felix Y 68
Chew, Emily Y 143
Chow*, David R 20
Christiansen, Steven M 100
Cousins, Scott W 77
Csaky*, Karl G 78
DAmico*, Donald J 7
Davis*, Janet Louise 137
Do*, Diana 139
Dresner*, Kimberly A 68
Dugel*, Pravin U 75
Duker*, Jay S 164
Duncan*, Jacque L 94
Dunn*, James Philip 140
El Rayes*, Ehab N 153
Eliott*, Dean 48
Eller, Andrew W 157
Fawzi, Amani 61
Fekrat*, Sharon 159
Flynn Jr, Harry W 28
Freeman, William R 76
Freund*, K Bailey 61
Gardner*, Thomas W 125

Gillies*, Mark C 81
Goldstein*, Debra A 136
Grewal, Dilraj Singh 64
Gupta, Omesh P 151
Haller*, Julia A 109
Han*, Dennis P 38
Harbour*, J William 111
Hartneh*, Mary Elizabeth 68
Hassan*, Tarek S 12, 129
Heier*, Jeffrey S 119
Ho*, Allen C 51
Holekamp*, Nancy M 15
Humayun*, Mark S 54
Hsu*, Jason 155
Ip*, Michael S 156
Jabs*, Douglas A 145
Jaffe*, Glenn J 140
Jampol*, Lee M 115
Johnson*, Mark W 46
Kaiser*, Peter K 69, 80
Kaiser*, Richard S 19
Kashani*, Amir H 99
Kim*, Judy E 105, 160
Kim, Rosa Y 131
Kiss, Szilard 70, 159
Kitchens*, John W 1
Koh, Adrian 79
Kokame*, Gregg T 86
Kunimoto*, Derek Y 35
Kuppermann*, Baruch D 159
Laigaie, Brenda 37
Lam, Linda A 155
Lee, Thomas C 68
Leiderman*, Yannek I 155
Leng*, Theodore 96
Lim*, Jenifer Irene 41
Lobo*, Ann-Marie 140
Loewenstein*, Anat 123
Lyon*, Alice T 159
MacCumber, Mathew W 155
MacLaren*, Robert E 59
Maguire*, Albert 56
Mahmoud*, Tamer H 155
Maia, Mauricio 73
Major, James C 102
Martin, Daniel F 85
McCannel, Colin 64

McCannel*, Tara A 110

McDonald, H Richard 159
Merrill*, Pauline T 140
Morizane, Yuki 64
Moshfeghi*, Darius M 107
Nguyen*, Quan Dong 135
Olsen*, Timothy W 106
Oncel, Murat 17
Ozdek*, Sengul C 161
Patelli, Fabio 162
Pertile, Grazia 5
Pieramici*, Dante 108
Pulido, Jose S 44
Regillo*, Carl D 83
Rich, William L 33
Rizzo, Stanislao 26
Rodger*, Damien C 27
Rosenfeld, Philip J 74, 141
Sarraf*, David 61
Schmidt-Erfurth*, Ursula M 88
Scholl*, Hendrik P 57, 58
Scott*, Ingrid U 159
Sebag, Jerry 147
Shields*, Carol L 114
Shields, Jerry A 113
Singh, Arun D 112
Small, Kent W 55
Spaide*, Richard F 97
Srinivasin, Karthi K 64
Srivastava*, Sunil K 61
Stalmans*, Peter W 9
Stanga*, Paulo E 16
Sun*, Jennifer K 120
Tabandeh*, Homayoun 166
Terasaki*, Hiroko 24
Thompson*, John T 149
Toth*, Cynthia A 21
Trese*, Michael T 67
Vavvas, Demetrios 146
Vicchrilli, Sue J 36
Waheed*, Nadia Khalida 93
Wells*, John A 62, 116
Williams*, George A 34
Wykoff*, Charles C 71
Yannuzzi, Lawrence A 61
Zarbin*, Marco A 121
177
61 60
62 59
63 58
64 57
65 56
66 55
67 54
68 53
69 52
70 51
71 50
72 49
73 48
74 47
75 46
90
89
88
87
86
85
84
83
82
81
80
79
78
77
76
Food Prep Area
43 18
44 17
45 16
41 20
42 19
38 23
39 22
40 21
36 25
37 24
33 28
34 27
35 26
31 30
32 29
13
14
15
11
12
8
9
10
6
7
3
4
5
1
2
CATERING
CATERING
Food Prep Area
Food Prep Area
Food Prep Area
Food Prep Area
SESSION ROOM
Food Prep Area
RETINA BREAK WITH THE EXPERTS
Food Prep Area
Food Prep Area
ESCALATORS CLOSED
ENTRANCE
STARBUCKS
INTERNATIONAL
CENTER
OPHTHALMOLOGY
JOB CENTER
YO
LOUNGE
VOLUNTEER
LOUNGE
SPEAKER
READY
ROOM
SO
LOUNGE
North, Level 3, Hall B

Friday, October 14
Exhibits
Food Prep Area
CATERING
(Breakfast only)
Syllabus
Exchange
Surgical
Scope
RETINA POSTER BOARDS
The Academy, McCormick Place and their contractors can make no warranties as to the accuracy of the floor plans. The floor plan is not final and is subject to change.
DOWN TO
HALL C
Food Prep Area
EXHIBIT FLOOR PLAN
Subspecialty Day
AAO 2016
McCormick Place
North, Level 3, Hall B
October 14-15, 2016
Retina Subspecialty Day
To/From Grand Concourse
Retina Exhibits
Retina Exhibits
Alcon
McKesson Specialty Health
13
Alimera Sciences
Allergan
MedOne Surgical, Inc.
87
NeurOptics
American Society of Retina Specialists

Avella Specialty Pharmacy
Bausch+Lomb
OCuSOFT, Inc.
Bryn Mawr Communications

Castle Biosciences, Inc.
OD-OS
62
DGH Technology, Inc.
12
Elsevier
25
44
Pine Pharmaceuticals
35
41
ProVision Diagnostics
DORC International, bv/Dutch Ophthalmic, USA

Ellex
47
Phoenix Clinical, Inc.

PODIS
21
56
81
Optovue, Inc.
36
89
Quantel Medical
64
40
Regeneron Pharmaceuticals, Inc.
5
24
Retinal Physician
39
20
FCI Ophthalmics
11
Retina Specialist
Focus ROP, LLC
23
Retina World Congress
GENENTECH
ifa Systems AG
SLACK Incorporated
49, 71
Sonomed Escalon
75
Innova Systems, Inc.
63
38
33
ThromboGenics, Inc., Medical Affairs
54
Intelligent Retinal Imaging Systems
10
Topcon Medical Systems

USRetina
68
30
Keeler Instruments, Inc.
VisionCare Ophthalmic Technologies
LIGHTMED USA, Inc.
79
Visunex Medical Systems
LKC Technologies, Inc.
74
Vitreq B.V.
Lumenis Vision
MacuLogix, Inc.
Wolters Kluwer
34
Mallinckrodt Pharmaceuticals
83
Volk Optical, Inc.
26
73
Zeiss
16
80
48
Vindico Medical Education
45
51
59
Spark Therapeutics
66
Insight Instruments, Inc.
Katena
60
Second Sight Medical Products, Inc.
42
Heidelberg Engineering
IRIDEX
86
27
Optos, Inc.
46
Ceatus Media Group
Diopsys, Inc.
65
Oculus Surgical, Inc.
31
32
CuraScript SD
29
Ocular Instruments, Inc.
18
Besse Medical
77
61
Notal Vision
85
Beaver - Visitec International
Doctorsoft
Nextech
76
4
28
37
43
179

Retina 2016 Syllabus

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Retina 2016 Syllabus

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Retina 2016

In conjunction with the American Society of Retina Specialists,

Retina 2016 Planning Group

2007 John T Thompson MD

Subspecialty Day Advisory Committee

2016 Subspecialty Day|Retina

2016 Retina Subspecialty Day Planning Group

Jennifer Irene Lim MD FARVO

Carl D Regillo MD FACS

Abbott: C | Acucela: C,S

Mark S Humayun MD PhD

1Co. Inc.: C,O,P

2016 Subspecialty Day|Retina

2016 Subspecialty Day

Julia A Haller MD (Retina)

Francis S Mah MD (Cornea)

Kuldev Singh MD MPH

2016 Subspecialty Day|Retina

Retina 2016 Contents

Retina Subspecialty Day Planning Group ii

Vitreoretinal Surgery, Part I 7

The Charles L Schepens MD Lecture 28

The Business of Retina 33

Therapies for Macular and Retinal Vascular Diseases 40

Uveitis Panel, Part I 61

Advocating for Patients 62

My Coolest Surgical Video 64

Late Breaking Developments, Part I 69

First-time Results of Clinical Trials, Part I 74

Late Breaking Developments, Part II 100

First-time Results of Clinical Trials, Part II 129

Uveitis, Part II 136

Non-neovascular AMD 141

Vitreoretinal Surgery, Part II 147

Retinal Vein Occlusion 156

2016 Subspecialty Day|Retina

Video Surgical Complications: What Would You Do? 161

2016 Subspecialty Day|Retina

Academys CME Mission Statement

2016 Retina Subspecialty Day Meeting Learning

2016 Retina Subspecialty Day Meeting Target

2016 Retina Subspecialty Day CME Credit

Teaching at a Live Activity

Scientific Integrity and Disclosure of Financial

Attendance Verification for CME Reporting

Register in advance, receive materials in the mail, and

CME Credit Reporting

2016 Subspecialty Day|Retina

After AAO 2016, credits can be claimed at www.aao.org/

CME credit reporting/proof-of-attendance letters

Visit www.aao.org/cme for detailed CME reporting information.

The Charles L Schepens MD Lecture

2016 Subspecialty Day|Retina

The Charles L Schepens MD Lecture

for the Academy. He serves on the editorial boards of numerous

2016 Subspecialty Day|Retina

Lloyd P Aiello MD PhD

Rajendra S Apte MD PhD

David Almeida MD PhD MBA

2016 Subspecialty Day|Retina

J Fernando Arevalo MD FACS

J Fernando Arevalo MD FACS

San Miguel, Argentina

2016 Subspecialty Day|Retina

The Charles L Schepens MD Lecture

John W Kitchens MD*

Steven T Charles MD*

Jorge G Arroyo MD